Stereoselective nucleophilic addition of PhSCF2 SiMe3 to chiral cyclic nitrones: asymmetric synthesis of gem-difluoromethylenated polyhydroxypyrrolizidines and -indolizidines.

DOI: 10.1002/asia.201403023

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Asymmetric Synthesis

Stereoselective Nucleophilic Addition of PhSCF2SiMe3 to Chiral Cyclic Nitrones: Asymmetric Synthesis of gemDifluoromethylenated Polyhydroxypyrrolizidines and -indolizidines Korkit Korvorapun, Darunee Soorukram, Chutima Kuhakarn, Patoomratana Tuchinda, Vichai Reutrakul, and Manat Pohmakotr*[a] chiral polyoxygenated cyclic nitrones to provide the corresponding adducts, which were further manipulated to afford gem-difluoromethylenated polyhydroxypyrrolizidines and -indolizidines.

Abstract: Fluoride-catalyzed nucleophilic addition of a difluoro(phenylsulfanyl)methyl group (“PhSCF2”) generated from PhSCF2SiMe3 to nitrones was accomplished in satisfactory yields. High diastereoselectivities were observed with

Introduction

-indolizidines could be achieved starting from chiral cyclic nitrones. Recently, it has been demonstrated that nitrones can undergo fluoride-catalyzed nucleophilic trifluoromethylation using CF3SiMe3.[7] The present work focuses on the stereoselective fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 (1) to chiral cyclic nitrones A yielding fluorinated cyclic amines B after reductive cleavage of the N¢O bond. N-Alkenylation of B gives C which upon reductive desulfanylation/radical cyclization affords chiral gem-difluoromethylenated polyhydroxy-1azabicyclic compounds D (Scheme 1). Notably, polyhydroxypyrrolizidines and -indolizidines are important classes of biologically active natural compounds.[8]

Fluorine-containing compounds are of importance in pharmaceuticals, agrochemicals, and materials due to the unique properties of fluorine atoms that possibly enhance the physical and metabolic stability, lipophilicity, and binding selectivity.[1] The numerous applications of organofluorines have spurred the development of efficient synthetic strategies towards incorporation of fluoroalkyl groups into organic molecules.[2] Of particular interest is the development of novel reagents and methodologies for the introduction of a gem-difluoromethylene moiety into small organic molecules.[3] The syntheses of biologically important gem-difluoromethylenated analogs of natural products have been extensively investigated.[4] In continuation of our research on the utility of PhSCF2SiMe3 (1)[5] as a gem-difluoromethylene radical anion equivalent (CCF2¢), we recently reported an asymmetric synthesis of gem-difluoromethylenated dihydroxypyrrolizidines and -indolizidines.[6] The synthesis involved fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 (1) to chiral N-alkenyl polyoxygenated succinimides followed by sequential intramolecular radical cyclization as the key steps. As part of our on-going research interest in this area, we envisaged that an efficient asymmetric synthesis of gem-difluoromethylenated polyhydroxypyrrolizidines and

Results and Discussion At first, the fluoride-catalyzed nucleophilic difluoro(phenylsulfanyl)methylation reaction of PhSCF2SiMe3 (1) and nitrone 2 a was investigated under a variety of reaction conditions in order to find optimal reaction conditions (Table 1). Thus, treatment of 1 (2 equiv) with nitrone 2 a employing 10 mol % of tetrabutylammonium fluoride (TBAF) in THF at ¢10 8C for 30 min afforded the expected adducts 3 a and 4 a after aqueous workup in 57 and 21 % yields, respectively, together with 5 a (3 %) and 6 a (5 % yield) (Table 1, entry 1). The competing elimination of the Me3SiOH group from 3 a led to the formation of compound 5 a which could then undergo the second difluoro(phenylsulfanyl)methylation leading to 6 a. Comparable results with slightly lower yield of 3 a were obtained when tetrabutylammonium difluorotriphenylsilicate (TBAT) was employed in place of TBAF (Table 1, entry 2). To our delight, the reaction proceeded smoothly affording 3 a in 68 % yield with minimized competing by-products when the reaction was performed employing TBAF (5 mol %) in THF at ¢10 8C for 1 h (Table 1, entry 3). Further reduction of the amount of TBAF employed (from

[a] K. Korvorapun, Dr. D. Soorukram, Dr. C. Kuhakarn, Prof. Dr. P. Tuchinda, Prof. Dr. V. Reutrakul, Prof. Dr. M. Pohmakotr Center of Excellence for Innovation in Chemistry (PERCH-CIC) and Department of Chemistry Faculty of Science Mahidol University Rama VI Road, Bangkok 10400 (Thailand) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/asia.201403023. Chem. Asian J. 2015, 10, 948 – 968

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Ó 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Scheme 1. Proposed synthetic scheme for the preparation of gem-difluoromethylenated polyhydroxypyrrolizidines and -indolizidines and some biologically active pyrrolizidines and indolizidines.

Table 2. Preparation of compounds 3,[a] 7, and 8.

Table 1. Optimization for the fluoride-catalyzed nucleophilic difluoro(phenylsulfanyl)methylation reaction of 1 to nitrone 2 a.

Entry

Catalyst

1 2 3 4

TBAF (10 mol %) TBAT (10 mol %) TBAF (5 mol %) TBAF (1 mol %)

5

CsF (10 mol %)

Conditions ¢10 8C/30 min ¢10 8C/30 min ¢10 8C/1 h ¢10 8C/1 h and rt for 4 h ¢10 8C/30 min

Yield [%][a] 3a 4a

5a

6a

57 45 68 90

21 20 6 –

3 3 – –

5 10 1 –

7[b]

–

–

–

2

Ar

Yield [%][b] 3

7

8

1 2 3 4[c] 5[c]

2a 2b 2c 2d 2e

C6H5 4-CH3C6H4 4-CH3OC6H4 4-ClC6H4 4-NO2C6H4

3 a (90) 3 b (94) 3 c (87) 3 d (65) 3 e (60)

7 a (91) 7 b (81) 7 c (84) 7 d (58) –[d]

8 a (96) 8 b (95) 8 c (92) –[d] –[d]

nylsulfanyl group (-SPh), and subsequent radical cyclization should provide the entry to chiral gem-difluoromethylenated polyhydroxy-1-azabicyclic derivatives of type D (Scheme 1). Indeed, reaction of 1 with chiral nitrones 9 a[9] and 9 b[10] followed by reductive removal[11] of the -OH group yielded 10 a and 10 b, each as a single isomer (19F NMR analysis) in 60 % and 73 % yields (2 steps), respectively (Scheme 2). The relative

5 mol % to 1 mol %) while increasing the reaction time and reaction temperature (¢10 8C for 1 h and room temperature for 4 h) significantly improved the yield of 3 a (90 % yield) without formation of any by-products (Table 1, entry 4). Finally, cesium fluoride was found to be a poor catalyst: 3 a was obtained in low yield (7 % yield), and nitrone 2 a was recovered (85 % yield) (Table 1, entry 5). With the optimized conditions in hand (Table 1, entry 4), the reactions of 1 with aryl-substituted nitrones 2 b–e possessing electronically different substituents were carried out affording the expected adducts 3 b–e in moderate to high yields (60– 94 % yields, Table 2). Among those, the reactions of nitrones 2 d and 2 e bearing electron-deficient substituents required a longer reaction time (¢10 8C for 1 h and room temperature for 16 h) and gave moderate yields of the corresponding adducts 3 d and 3 e, respectively (Table 2, entries 4–5). Next, a-difluoromethylated amines 8 were readily obtained by sequential reductive cleavage of the -OSiMe3 and -SPh groups (Table 2). Thus, treatment of 3 a–d with Zn in acetic acid at 80 8C for 8 h gave the corresponding compounds 7 a–d in moderate to good yields (58–91 % yields) (Table 2, entries 1–4). Reductive removal of the phenylsulfanyl group (-SPh) of compounds 7 a– c [Bu3SnH, AIBN (cat.) in refluxing toluene] readily proceeded www.chemasianj.org

Entry

[a] Reaction conditions: 1 (2 equiv), 2 (1 equiv), TBAF (1 mol %), THF, ¢10 8C (1 h) and rt (4 h). [b] Isolated yields. [c] The reaction was carried out at ¢10 8C (1 h) and rt (16 h). [d] The reaction was not performed.

[a] Isolated yield. [b] 2 a was recovered in 85 % yield.

Chem. Asian J. 2015, 10, 948 – 968

to provide the corresponding products 8 a–c in good yields (Table 2, entries 1–3). At this stage we have successfully demonstrated that PhSCF2SiMe3 (1) could undergo fluoride-catalyzed difluoro(phenylsulfanyl)methylation reaction with nitrones 2 leading to a-difluoromethylated amines 8. On this basis, we envisaged that the reaction of 1 with chiral cyclic nitrones A followed by reductive removal of the -OSiMe3 group, reductive cleavage of the phe-

Scheme 2. Preparation of 10 by fluoride-catalyzed reaction of 1 with chiral nitrones 9 followed by reductive cleavage of the -OH group.

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Full Paper which were determined by 1H NMR spectroscopic analysis after reduction. Treatment of compounds 14 a–d with LiAlH4 in the presence of Me3SiCl in CH2Cl2 at 0 8C for 1.5 h afforded the respective products 13 a (73 % yield), 13 b (50 % yield, E:Z = 78:22), 13 c (46 % yield, E:Z = 92:8), and 13 d (46 % yield, E:Z = 88:12).

stereochemistries of 10 a and 10 b were confirmed by NOE experiments (see the Supporting Information). The observed stereochemical outcomes of 10 a and 10 b could be rationalized in a way that the nucleophile “¢CF2SPh” derived from 1 preferably approached the nitrones 9 a and 9 b from the opposite face to the C3-OBn group in order to avoid steric repulsion (Scheme 2).[12]

Synthesis of gem-difluoromethylenated pyrrolizidines 15 Synthesis of N-allyl, N-propargyl, and N-homoallyl pyrrolidines 11, 12, and 13

When the N-alkylated products 11 and 12 were treated with Bu3SnH (1.75 equiv)/AIBN (20 mol %) in refluxing toluene (0.1 m of 11 or 12), the corresponding gem-difluoromethylenated 1azabicyclic compounds 15 were obtained in good yields (73– 88 % yields) with modest diastereomeric ratios (cis- and transisomers in case of 15 a–b and 15 d–e, and E- and Z-isomers in case of 15 c and 15 f) (Table 3, entries 1–6). It is worth noting that, in almost all cases, the radical cyclization preferentially took place via a 5-exo-trig radical cyclization. A 6-endo-trig radical cyclization was observed in case of the gem-difluoroalkyl radical intermediate derived from 11 a, leading to 15 a’ in low yield (2 % yield) (Table 3, entry 1). Partial separation of the isomeric mixtures of compounds 15 a–e was also conducted (see the Experimental Section). On the basis of the spectroscopic data of 15 a, the major isomer was confirmed to be the trans configuration in which the two substituents on the carbon atoms next to the gem-difluoromethylene were located on the opposite side (NOE experiments, see the Supporting Information). The relative stereochemistries of the major (trans-) and the minor (cis-) isomers of 15 b, 15 d, and 15 e were assigned on the basis of those of 15 a. The stereochemistries of the major (E-isomer) and the minor (Z-isomer) of 15 c were also established (NOE experiments, see the Supporting Information). On the same basis of those of 15 c, the stereochemistries of 15 f can be assigned.

After having chiral cyclic amines 10 a and 10 b in hand, the installation of the unsaturated moiety (allyl or propargyl group) onto the nitrogen atom was performed (using appropriate alkylating agents, anhydr. K2CO3, acetone, reflux, 16 h), affording the N-alkylated products 11 a–c and 12 a–c, respectively, in good yields (77–91 % yields) (Scheme 3).[13] Unexpectedly, under similar reaction conditions, N-alkylation of homoallyl bromide was not successful. The reaction of 10 a and 4-bromo1-butene gave product 13 a in 7 % yield, and the starting pyrrolidine 10 a was recovered in 91 % yield. After several attempts, the suitable conditions were to react 10 a with 4bromo-1-butene in the presence of NaHCO3 in aqueous sodium dodecyl sulfate (SDS) at 80 8C for 24 h, yielding the desired product 13 a in 54 % yield and recovery of 10 a in 33 % yield (Scheme 3). Efforts to extend a variety of alkenyl sidechains of 13 a by a cross-olefin metathesis approach were not successful, possibly due to catalyst poisoning by the lone-pair electrons of the amine nitrogen. Indeed, an alternative synthetic approach to access compounds 13 bearing different alkenyl side-chains was to start from amide 14 a, which was readily prepared in 92 % yield by treatment of 10 a with 3-butenoic acid employing N,N’-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP, cat.) in CH2Cl2 at 0 8C to room temperature for 16 h, followed by cross-olefin metathesis and amide reduction. The cross-olefin metathesis of 14 a with styrene derivatives employing Grubbs II catalyst in refluxing CH2Cl2 afforded the corresponding amides 14 b–d in 49–56 % yields, each as a mixture of E and Z isomers, the ratios of

Synthesis of gem-difluoromethylenated indolizidines 16 By employing the standard desulfanylation/radical cyclization conditions as for 11 a (Bu3SnH/AIBN in refluxing toluene), 13 a

Scheme 3. Preparation of N-allyl, N-propargyl, and N-homoallyl pyrrolidines 11, 12, and 13. Chem. Asian J. 2015, 10, 948 – 968

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Full Paper Table 3. Preparation of gem-difluoromethylenated pyrrolizidines 15 and -indolizidines 16.

Entry Substrate Product (% yield;[a] isomeric ratio)

Entry Substrate Product (% yield;[a] isomeric ratio)

1

6

11 a 15 a (88 %; 89:11)[b,c]

2

12 c 15 f (75 %; 85:15)[b,d]

15 a’ (2 %)

11 b

7

13 a 16 a 16 a’ (78 %; cis:trans:16 a’ = 59:31:10)[e]

15 b (75 %; 82:18)[b,c] 3

8[f]

11 c

13 b (78:22)[g]

15 c (73 %; 83:17)[b,c] 4

16 b (69 %; 59:41)[b,c] 9[f]

12 a

13 c (92:8)[g]

15 d (87 %; 70:30)[b,c] 5

16 c (74 %; 60:40)[b,c] 10[f]

12 b

13 d (88:12)[g]

15 e (87 %; 64:36)[b,c]

16 d (70 %; 60:40)[b,c]

[a] Isolated yield. [b] Determined by 19F NMR analysis of the isolated products as mixtures of two isomers. [c] The diastereomers were partially separated by column chromatography on silica gel (see the Experimental Section). [d] The diastereomers could not be separated by chromatography (silica gel). [e] The minor trans-isomer of 16 a and 16 a’ were partially obtained in 12 and 2 % yield, respectively, after column chromatography on silica gel. [f] The cis- and trans-isomers were partially separated by column chromatography on silica gel. [g] The isomeric ratio (E:Z) was determined by 1H NMR analysis.

stereochemistries can be assigned (NOE experiments, see the Supporting Information). The stereochemical outcomes of compounds 15 can be rationalized as shown in Scheme 4. The gem-difluoroalkyl radical intermediates derived from 11 a,b and 12 a,b are proposed to preferably undergo radical cyclization via a 5-exo-trig mode[14] through the transition states E and F. The half-chair transition state E is energetically more stable, resulting in the formation of thermodynamically more stable trans-isomers of 15 a,b,d,e (see Scheme 4). The transition states to explain the observed stereochemical outcomes of compounds 16 are shown in Scheme 4. The initially formed gem-difluoroalkyl radical intermediates derived from 13 underwent a 6-exo-trig radical cyclization through the transition states G and H. The transition state G is more favorable due to minimized steric repulsion be-

underwent the reaction to provide a mixture of the expected cis- and trans-indolizidines 16 a and 1-azabicyclo[5.3.0]decane derivative 16 a’ in 78 % combined yield in a ratio of 59:31:10 (19F NMR analysis) (Table 3, entry 7). The minor isomer of 16 a and 16 a’ can be partially separated (see the Experimental Section). The relative stereochemistry of the minor isomer of 16 a was confirmed to have the trans configuration in which the two substituents on the carbon atoms next to the gem-difluoromethylene were located on the opposite side (NOSEY experiments, see the Supporting Information). Under similar conditions as for 13 a, 13 b–d yielded the corresponding chiral gem-difluoromethylenated indolizidines 16 b–d in 69–74 % yield, each as a mixture of cis- and trans-isomers (Table 3, entries 8–10). The cis- and trans-isomers of 16 b–d can be partially separated (see the Experimental Section) and their relative Chem. Asian J. 2015, 10, 948 – 968

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Scheme 5. Proposed transition states for the radical cyclization of compounds 11 c and 12 c to the corresponding gem-difluoromethylenated pyrrolizidines 15 c and 15 f.

method involves sequential stereoselective fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 to readily available chiral nitrones followed by reductive cleavage of the hydroxy group, N-alkenylation of the resulting pyrrolidines, intramolecular radical cyclization, and hydrogenolysis of the benzyl protecting group. The developed method provides a general access to chiral gem-difluoromethylenated polyhydroxypyrrolizidine and -indolizidine derivatives and may be applied for the synthesis of analogues of some pyrrolizidine and indolizidine natural products.

Scheme 4. Proposed transition states for the radical cyclization of 11 a,b and 12 a,b to pyrrolizidines 15 a,b,d,e and of 13 a–d to indolizidines 16 a–d.

tween the alkenyl moiety and the quasi-axial hydrogen, thus leading to cis-16 as the major isomers. The less favorable transition state H will give rise to trans-16 as the minor isomers. It is worth noting that the least energetically favorable 7-endotrig radical cyclization also possibly took place in case of compound 13 a. In case of 11 c and 12 c, the radical intermediates underwent radical cyclization via a 5-exo-dig mode through the transition state I leading to a vinylic radical K, which undergoes rapid equilibration to the thermodynamically more stable vinylic radical J in order to avoid the electronic repulsion between the nitrogen lone-pair electrons and the developing radical orbital. Subsequent hydrogen atom abstraction of the vinylic radical J from Bu3SnH leads to the formation of the Eisomers of 15 c and 15 f as the major isomers (Scheme 5).

Experimental Section General Methods 1

H and 13C NMR spectra were recorded on either a Bruker DPX-300 (300 MHz for 1H and 75 MHz for 13C), a Bruker Ascend400 (400 MHz for 1H and 100 MHz for 13C), or a Bruker Avance500 (500 MHz for 1 H and 125 MHz for 13C) spectrometer in CDCl3, CD3OD, or D2O. Chemical shifts (d) are reported relative to NMR solvent peak, and coupling constants (J) are reported in Hertz (Hz). 19F NMR spectra were recorded on either a Bruker Ascend400 (376 MHz) or a Bruker Avance500 (470 MHz) spectrometer in CDCl3, CD3OD, or D2O, and chemical shifts (d) are reported relative to trichlorofluoromethane (d = 0). IR spectra were recorded on a PerkinElmer Spectrum GX FTIR spectrometer. Mass spectra were recorded on a Thermo Finnigan Polaris Q mass spectrometer. High-resolution mass spectra were recorded on either a HR-TOF-MS Micromass model VQ-TOF2 or a Micromass Q-TOF 2 hybrid quadrupole time-of-flight (Q-TOF) mass spectrometer with a Z-spray ES source (Micromass, Manchester, UK). The specific optical rotation values were recorded on a Jasco P-1020 polarimeter. Melting points were recorded with a Bìchi 510 melting point apparatus and are uncorrected. Tetrahydrofuran (THF) was freshly distilled from sodium-benzophenone ketyl. Dichloromethane (CH2Cl2) and toluene were distilled over calcium hydride under an argon atmosphere and stored over activated molecular sieves (4 æ). Acetone was distilled over anhydrous potassium carbonate (anhydr. K2CO3) and stored over activated molecular sieves (4 æ). Methanol was distilled over magnesium powder under an argon atmosphere. All glassware and syringes

Synthesis of chiral gem-difluoromethylenated polyhydroxypyrrolizidines 17 and -indolizidines 18 Having trans-15 and cis-16 in hand, their conversions to the corresponding polyhydroxy derivatives trans-17 and cis-18 were conveniently performed through catalytic hydrogenation (H2/PdCl2 in methanol at room temperature). The results are summarized in Table 4.

Conclusions In summary, we have demonstrated the synthetic utility of PhSCF2SiMe3 as a gem-difluoromethylene building block for the asymmetric synthesis of gem-difluoromethylenated polyhydroxypyrrolizidine and -indolizidine derivatives. The present Chem. Asian J. 2015, 10, 948 – 968

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Full Paper of compound 1 (2.0 mmol) in dry THF (1 mL) was then added. A solution of TBAF (0.1 m in THF, 0.2 mL, 0.02 mmol, 1 mol %) was slowly added to the reaction mixture at ¢10 8C. The resulting reaction mixture was allowed to stir at ¢10 8C for 1 h, followed by stirring at room temperature (4 or 16 h). The progress of the reaction was monitored by thin-layer chromatography (TLC). After the complete consumption of 2, the reaction mixture was quenched at room temperature with H2O (3 mL) and extracted with CH2Cl2 (3 Õ 10 mL). The combined organic phases were washed with brine (10 mL) and dried over anhydrous Na2SO4. Filtration followed by evaporation gave a crude product, which was purified by column chromatography (SiO2).

Table 4. Synthesis of chiral gem-difluoromethylenated polyhydroxypyrrolizidines 17 and -indolizidines 18.

Entry

Starting material

Product (% yield)

trans-15 a

trans-17 a (85 %,[a] 92 %[b])

trans-15 b

trans-17 b (87 %)[b]

trans-15 d

trans-17 c (92 %)[a]

trans-15 e

trans-17 d (82 %)[b]

cis-16 a[d]

cis-18 a (50 %)[c]

cis-16 b

cis-18 b (46 %)[c]

cis-16 c

cis-18 c (70 %)[b]

cis-16 d

cis-18 d (80 %)[c]

1

N-[2,2-Difluoro-1-phenyl-2-(phenylthio)ethyl]-N-phenyl-O-(trimethylsilyl)hydroxylamine (3 a): According to the General Procedure A, the reaction of nitrone 2 a (197.5 mg, 1.0 mmol) and 1 (464.9 mg, 2.0 mmol) in THF (3 mL) with 1 mol % TBAF gave 3 a (384.9 mg, 90 % yield) as a light yellow oil after column chromatography [SiO2 (Art 7736), CH2Cl2/hexanes 1:9]. 1H NMR (500 MHz, CDCl3): d = 7.73–7.69 (m, 2 H; ArH), 7.50–7.41 (m, 3 H; ArH), 7.39– 7.34 (m, 1 H; ArH), 7.31–7.21 (m, 6 H; ArH), 7.10–7.05 (m, 3 H; ArH), 4.70 (dd, J = 15.0, 10.5 Hz, 1 H; CH), 0.22 ppm [s, 9 H; Si(CH3)3]; 13 C NMR (125 MHz, CDCl3): d = 152.6 (C), 136.3 (2 Õ CH), 131.9 (2 Õ CH), 130.3 (C), 129.6 (CH), 129.3 (dd, J = 288.9, 281.4 Hz; CF2), 128.9 (2 Õ CH, C), 128.5 (CH), 128.2 (2 Õ CH), 127.3 (2 Õ CH), 124.2 (CH), 120.7 (2 Õ CH), 79.2 (dd, J = 24.5, 21.3 Hz; CH), 0.0 ppm (3 Õ CH3); 19 F NMR (470 MHz, CDCl3): d = ¢75.6 (dAB, J = 204.5 Hz, 1F; CFF), ¢76.9 ppm (dAB, J = 204.5 Hz, 1F; CFF); IR (neat): n˜ max = 1596 (m), 1486 (s), 1454 (m), 1441 (m), 1251 (s), 1063 (s), 749 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 429 (57) [M + ], 270 (100), 180 (29), 77 (9); HRMS (ESI-TOF) m/z calcd for C23H25F2NOSSi + Na + : 452.1292 +Na] + ; found: 452.1298. [M+

2

3

4

5

The reaction of nitrone 2 a (1.0 mmol) and 1 (2.0 mmol) in THF (3 mL) with 10 mol % TBAF or TBAT at ¢10 8C for 30 min, as indicated in Table 1 (entries 1 and 2), gave 3 a (57 or 45 % yield, respectively) along with by-products 4 a, 5 a, and 6 a.

6

N-[2,2-Difluoro-1-phenyl-2-(phenylthio)ethyl]-N-phenylhydroxylamine (4 a): a white solid; m.p. 162–163 8C (EtOAc/hexanes); 1 H NMR (500 MHz, CDCl3): d = 7.71 (d, J = 7.1 Hz, 2 H; ArH), 7.52– 7.38 (m, 5 H; ArH), 7.35–7.20 (m, 5 H; ArH), 7.07 (d, J = 7.7 Hz, 2 H; ArH), 6.97 (t, J = 7.2 Hz, 1 H; ArH), 5.60 (s, 1 H; OH), 5.01 ppm (dd, J = 15.8, 9.3 Hz, 1 H; CH); 13C NMR (125 MHz, CDCl3): d = 150.1 (C), 136.4 (2 Õ CH), 130.9 (2 Õ CH), 130.8 (C), 129.8 (CH), 129.8 (dd, J = 285.4, 279.4 Hz; CF2), 129.0 (2 Õ CH), 128.7 (2 Õ CH), 128.7 (CH), 127.9 (2 Õ CH), 126.7 (C), 122.7 (CH), 117.1 (2 Õ CH), 75.1 ppm (dd, J = 27.5, 21.6 Hz; CH); 19F NMR (470 MHz, CDCl3): d = ¢73.5 (dd, J = 208.1, 8.5 Hz, 1F; CFF), ¢76.0 ppm (dd, J = 208.1, 15.8 Hz, 1F; CFF); IR (KBr): n˜ max = 3518 (s), 1597 (m), 1488 (s), 1453 (m), 1442 (m), 1346 (m), 1204 (m), 1062 (s), 753 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 357 (15) [M + ], 356 (34) [M + ¢H], 340 (44) [M + ¢OH], 230 (92), 198 (100), 180 (88), 171 (72), 127 (32), 77 (41); HRMS (ESI-TOF) m/z +Na] + ; found: 380.0867. calcd for C20H17F2NOS + Na + : 380.0897 [M+

7

8

[a] Isolated yield after ion-exchange chromatography on Amberlyst A-26 (OH¢ form). [b] Isolated yield after column chromatography on silica gel. [c] Yield after recrystallization. [d] Containing 7 % of 16 a’.

were oven-dried and kept in a desiccator before use. Column chromatography was performed by using Merck silica gel 60 Art 7734 (0.063–0.200 mm) and Art 7736 (< 0.040 mm). Other common solvents, such as dichloromethane, hexanes, ethyl acetate, methanol, and acetone, were distilled before use.

(Z)-N-[2,2-Difluoro-1-phenyl-2-(phenylthio)ethylidene]aniline (5 a): a light yellow oil; 1H NMR (500 MHz, CDCl3): d = 7.74 (d, J = 7.1 Hz, 2 H; ArH), 7.51–7.46 (m, 1 H; ArH), 7.46–7.40 (m, 2 H; ArH), 7.36–7.31 (m, 1 H; ArH), 7.31–7.26 (m, 2 H; ArH), 7.26–7.21 (m, 2 H; ArH), 7.18 (t, J = 7.8 Hz, 2 H; ArH), 7.03 (t, J = 7.4 Hz, 1 H; ArH), 6.71 ppm (d, J = 7.4 Hz, 2 H; ArH); 13C NMR (125 MHz, CDCl3): d = 162.2 (t, J = 28.9 Hz; C), 147.4 (C), 136.7 (2 Õ CH), 131.0 (C), 129.9 (CH), 129.7 (CH), 129.0 (2 Õ CH), 128.9 (2 Õ CH), 128.6 (2 Õ CH), 128.2 (2 Õ CH), 126.8 (C), 126.5 (t, J = 279.1 Hz; CF2), 124.9 (CH), 120.7 ppm (2 Õ CH); 19F NMR (470 MHz, CDCl3): d = ¢73.5 ppm (s, 2F; CF2); IR (neat): n˜ max = 1661 (m), 1592 (w), 1575 (w), 1483 (w), 1474 (m), 1440 (m), 1217 (m), 1128 (m), 1058 (s), 771 (s), 750 (s),

General Procedure A for the Fluoride-Catalyzed Nucleophilic Addition of PhSCF2SiMe3 (1) to Nitrones 2 An oven-dried round-bottomed flask (10 mL) was charged with nitrone 2 (1.0 mmol) and dry THF (2 mL) under an argon atmosphere. The resulting mixture was cooled to ¢10 8C, and a solution Chem. Asian J. 2015, 10, 948 – 968

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Full Paper 699 (s), 691 cm¢1 (s); MS (70 eV): m/z (%): 339 (21) [M + ], 180 (7), 77 (14); HRMS (ESI-TOF) m/z calcd for C20H15F2NS + Na + : 362.0791 +Na] + ; found: 362.0763. [M+

1.0 mmol) and 1 (465.9 mg, 2.0 mmol) in THF (3 mL) with 1 mol % TBAF gave 3 d (302.8 mg, 65 % yield) as a white solid after column chromatography [SiO2 (Art 7736), CH2Cl2/hexanes 1:9]. m.p. 79– 80 8C (CH2Cl2/hexanes); 1H NMR (500 MHz, CDCl3): d = 7.69–7.64 (m, 2 H; ArH), 7.49–7.40 (m, 3 H; ArH), 7.26–7.20 (m, 4 H; ArH), 7.16 (d, J = 7.0 Hz, 2 H; ArH), 7.09–7.04 (m, 1 H; ArH), 7.04–7.00 (m, 2 H; ArH), 4.62 (dd, J = 15.1, 10.2 Hz, 1 H; CH), 0.18 ppm [s, 9 H; Si(CH3)3]; 13 C NMR (125 MHz, CDCl3): d = 152.4 (C), 136.3 (2 Õ CH), 134.7 (C), 133.1 (2 Õ CH), 129.7 (CH), 129.1 (dd, J = 289.0, 281.0 Hz; CF2), 129.0 (2 Õ CH), 128.6 (C), 128.3 (2 Õ CH), 127.6 (2 Õ CH), 127.0 (C), 124.4 (CH), 120.6 (2 Õ CH), 78.5 (dd, J = 24.9, 21.6 Hz; CH), 0.0 ppm (3 Õ CH3); 19F NMR (470 MHz, CDCl3): d = ¢76.1 (dAB, J = 206.1 Hz, 1F; CFF), ¢77.5 ppm (dAB, J = 206.1 Hz, 1F; CFF); IR (neat): n˜ max = 1595 (s), 1487 (s), 1453 (m), 1441 (m), 1251 (s), 1064 (s), 809 (s), 750 (s), 725 (m), 698 cm¢1 (s); MS (70 eV): m/z (%): 465 (25) [M + +2], 463 (48) [M + ], 306 (40), 304 (100), 216 (8), 214 (12), 180 (6); HRMS (ESI+H] + ; found: TOF) m/z calcd for C23H24ClF2NOSSi + H + : 464.1083 [M+ 464.1096.

N-[1,1,3,3-Tetrafluoro-2-phenyl-1,3-bis(phenylthio)propan-2-yl]aniline (6 a): a white solid; m.p. 106–107 8C (toluene/hexanes); 1 H NMR (500 MHz, CDCl3): d = 7.68 (d, J = 7.7 Hz, 2 H; ArH), 7.49– 7.43 (m, 4 H; ArH), 7.36–7.22 (m, 9 H; ArH), 7.07–7.00 (m, 2 H; ArH), 6.74 (t, J = 7.3 Hz, 1 H; ArH), 6.54 (d, J = 7.9 Hz, 2 H; ArH), 4.84 ppm (s, 1 H; NH); 13C NMR (125 MHz, CDCl3): d = 143.0 (C), 137.1 (4 Õ CH), 130.8 (t, J = 295.7 Hz; 2 Õ CF2), 130.7 (2 Õ CH), 130.3 (C), 130.0 (2 Õ CH), 129.1 (CH), 128.9 (4 Õ CH), 128.6 (2 Õ CH), 127.6 (2 Õ CH), 126.1 (2 Õ C), 119.5 (CH), 117.1 (2 Õ CH), 75.1 ppm (t, J = 22.8 Hz; C); 19 F NMR (470 MHz, CDCl3): d = (¢64.5)–(¢67.8) (m, 2F; CFF), ¢71.0 ppm (d, J = 211.0 Hz, 2F; CFF); IR (KBr): n˜ max = 3384 (s), 1599 (s), 1519 (m), 1499 (s), 1475 (m), 1441 (m), 1312 (m), 1253 (s), 1081 (s), 1045 (s), 751 (s), 691 cm¢1 (s); MS (70 eV): m/z (%): 499 (9) [M + ], 340 (82), 242 (17), 211 (100), 183 (17), 77 (12); HRMS (ESI-TOF) m/z +Na] + ; found: 522.0937. calcd for C27H21F4NS2 + Na + : 522.0949 [M+

N-[2,2-Difluoro-1-(4-nitrophenyl)-2-(phenylthio)ethyl]-N-phenylO-(trimethylsilyl)hydroxylamine (3 e): According to the General Procedure A, the reaction of nitrone 2 e (242.8 mg, 1.0 mmol) and 1 (464.7 mg, 2.0 mmol) in THF (3 mL) with 1 mol % TBAF gave 3 e (284.4 mg, 60 % yield) as a yellow viscous oil after column chromatography [SiO2 (Art 7736), CH2Cl2/hexanes 3:7]. 1H NMR (500 MHz, CDCl3): d = 8.09–8.04 (m, 2 H; ArH), 7.63 (d, J = 7.2 Hz, 2 H; ArH), 7.48–7.43 (m, 1 H; ArH), 7.43–7.37 (m, 2 H; ArH), 7.35 (d, J = 8.7 Hz, 2 H; ArH), 7.23–7.16 (m, 2 H; ArH), 7.07–7.02 (m, 1 H; ArH), 6.98–6.94 (m, 2 H; ArH), 4.70 (dd, J = 15.2, 9.5 Hz, 1 H; CH), 0.17 ppm [s, 9 H; Si(CH3)3]; 13C NMR (125 MHz, CDCl3): d = 152.0 (C), 148.0 (C), 137.4 (C), 136.3 (2 Õ CH), 132.6 (2 Õ CH), 129.9 (CH), 129.1 (2 Õ CH), 128.8 (dd, J = 288.9, 280.3 Hz; CF2), 128.5 (2 Õ CH), 126.5 (C), 124.8 (CH), 122.3 (2 Õ CH), 120.3 (2 Õ CH), 78.3 (dd, J = 25.6, 21.7 Hz; CH), 0.0 ppm (3 Õ CH3); 19F NMR (470 MHz, CDCl3): d = ¢76.0 (dAB, J = 208.0 Hz, 1F; CFF), ¢77.7 ppm (dAB, J = 208.0 Hz, 1F; CFF); IR (neat): n˜ max = 1595 (m), 1525 (s), 1486 (s), 1453 (m), 1441 (m), 1348 (s), 1252 (s), 1063 (s), 846 (s), 810 (s), 749 (s), 702 cm¢1 (s); MS (70 eV): m/z (%): 474 (26) [M + ], 315 (100); HRMS (ESI-TOF) m/z calcd for +Na] + ; found: 497.1161. C23H24F2N2O3SSi + Na + : 497.1143 [M+

N-[2,2-Difluoro-2-(phenylthio)-1-(p-tolyl)ethyl]-N-phenyl-O-(trimethylsilyl)hydroxylamine (3 b): According to the General Procedure A, the reaction of nitrone 2 b (211.4 mg, 1.0 mmol) and 1 (466.1 mg, 2.0 mmol) in THF (3 mL) with 1 mol % TBAF gave 3 b (417.6 mg, 94 % yield) as a white solid after column chromatography [SiO2 (Art 7736), CH2Cl2/hexanes 1:9]. m.p. 54–55 8C (CH2Cl2/ hexanes); 1H NMR (500 MHz, CDCl3): d = 7.71–7.67 (m, 2 H; ArH), 7.48–7.40 (m, 3 H; ArH), 7.26–7.21 (m, 2 H; ArH), 7.15 (d, J = 8.1 Hz, 2 H; ArH), 7.10–7.04 (m, 5 H; ArH), 4.66 (dd, J = 14.6, 11.1 Hz, 1 H; CH), 2.37 (s, 3 H; CH3), 0.20 ppm [s, 9 H; Si(CH3)3]; 13C NMR (125 MHz, CDCl3): d = 152.7 (C), 138.3 (C), 136.3 (2 Õ CH), 131.7 (2 Õ CH), 129.5 (CH), 129.4 (dd, J = 288.6, 281.8 Hz; CF2), 128.9 (2 Õ CH), 128.2 (2 Õ CH), 128.1 (2 Õ CH), 127.4 (C), 127.2 (C), 124.1 (CH), 120.7 (2 Õ CH), 78.9 (dd, J = 23.9, 21.6 Hz; CH), 21.2 (CH3), 0.0 ppm (3 Õ CH3); 19F NMR (470 MHz, CDCl3): d = ¢76.0 (dAB, J = 204.2 Hz, 1F; CFF), ¢76.9 ppm (dAB, J = 204.2 Hz, 1F; CFF); IR (neat): n˜ max = 1596 (m), 1515 (m), 1487 (s), 1475 (m), 1441 (m), 1251 (s), 1063 (s), 790 (m), 757 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 443 (100) [M + ], 284 (68), 194 (22); HRMS (ESI-TOF) m/z calcd for C24H27F2NOSSi + Na + : +Na] + ; found: 466.1448. 466.1448 [M+ N-[2,2-Difluoro-1-(4-methoxyphenyl)-2-(phenylthio)ethyl]-Nphenyl-O-(trimethylsilyl)hydroxylamine (3 c): According to the General Procedure A, the reaction of nitrone 2 c (227.4 mg, 1.0 mmol) and 1 (464.5 mg, 2.0 mmol) in THF (3 mL) with 1 mol % TBAF gave 3 c (400.3 mg, 87 % yield) as a white solid after column chromatography [SiO2 (Art 7736), CH2Cl2/hexanes 1:9]. m.p. 73– 74 8C (CH2Cl2/hexanes); 1H NMR (500 MHz, CDCl3): d = 7.71–7.66 (m, 2 H; ArH), 7.48–7.39 (m, 3 H; ArH), 7.25–7.20 (m, 2 H; ArH), 7.18 (d, J = 8.7 Hz, 2 H; ArH), 7.08–7.03 (m, 3 H; ArH), 6.83–6.78 (m, 2 H; ArH), 4.63 (dd, J = 14.3, 11.4 Hz, 1 H; CH), 3.81 (s, 3 H; OCH3), 0.19 ppm [s, 9 H; Si(CH3)3]; 13C NMR (125 MHz, CDCl3): d = 159.7 (C), 152.7 (C), 136.2 (2 Õ CH), 133.0 (2 Õ CH), 129.5 (CH), 129.4 (dd, J = 288.2, 281.8 Hz; CF2), 128.9 (2 Õ CH), 128.2 (2 Õ CH), 127.4 (C), 124.1 (CH), 122.3 (C), 120.7 (2 Õ CH), 112.7 (2 Õ CH), 78.6 (dd, J = 23.6, 21.9 Hz; CH), 55.0 (CH3), 0.0 ppm (3 Õ CH3); 19F NMR (470 MHz, CDCl3): d = ¢76.1 (dAB, J = 203.5 Hz, 1F; CFF), ¢77.0 ppm (dAB, J = 203.5 Hz, 1F; CFF); IR (neat): n˜ max = 1611 (s), 1596 (s), 1585 (m), 1514 (s), 1488 (s), 1453 (m), 1441 (m), 1251 (s), 1116 (m), 1063 (s), 797 (s), 757 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 459 (48) [M + ], 458 (100), 370 (34), 369 (11), 300 (83), 279 (34), 259 (44), 210 (29), 171 (58); HRMS (ESI-TOF) m/z calcd for C24H27F2NO2SSi + Na + : 482.1398 +Na] + ; found: 482.1406. [M+

General Procedure B for the Reductive Cleavage of N¢O bond of Anilines 3 A mixture of aniline 3 (1.0 mmol) and Zn powder (10.0 mmol) in glacial acetic acid (3 mL) was heated under an argon atmosphere at 80 8C for 16 h. Subsequently, the reaction was cooled to room temperature and filtered through a celite pad, and the solids were washed with CH2Cl2 (3 Õ 15 mL). The filtrate was concentrated in vacuo to give a crude product, which was purified by column chromatography (SiO2). N-[2,2-Difluoro-1-phenyl-2-(phenylthio)ethyl]aniline (7 a): According to the General Procedure B, the reaction of 3 a (2.15 g, 5.0 mmol) with Zn (3.33 g, 50.9 mmol) in AcOH (15 mL) gave 7 a (1.55 g, 91 % yield) as a white solid after column chromatography [SiO2 (Art 7736), CH2Cl2/hexanes 1:4]. m.p. 81–82 8C (CH2Cl2/hexanes); 1H NMR (500 MHz, CDCl3): d = 7.64–7.60 (m, 2 H; ArH), 7.50 (d, J = 6.9 Hz, 2 H; ArH), 7.46–7.42 (m, 1 H; ArH), 7.42–7.33 (m, 5 H; ArH), 7.20–7.14 (m, 2 H; ArH), 6.80–6.75 (m, 1 H; ArH), 6.66–6.61 (m, 2 H; ArH), 4.93 (dd, J = 14.6, 6.9 Hz, 1 H; CH), 4.63 ppm (br s, 1 H; NH); 13C NMR (125 MHz, CDCl3): d = 145.7 (C), 136.4 (2 Õ CH), 135.2 (C), 129.9 (CH), 129.3 (t, J = 282.9 Hz; CF2), 129.2 (2 Õ CH), 129.0 (2 Õ CH), 128.7 (CH), 128.5 (2 Õ CH), 128.4 (2 Õ CH), 126.2 (C), 118.7 (CH), 113.9 (2 Õ CH), 63.7 ppm (t, J = 25.0 Hz; CH); 19F NMR (470 MHz, CDCl3): d = ¢77.1 (dd, J = 208.6, 6.3 Hz, 1F; CFF), ¢82.1 ppm (dd,

N-[1-(4-Chlorophenyl)-2,2-difluoro-2-(phenylthio)ethyl]-Nphenyl-O-(trimethylsilyl)hydroxylamine (3 d): According to the General Procedure A, the reaction of nitrone 2 d (231.7 mg, Chem. Asian J. 2015, 10, 948 – 968

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Full Paper General Procedure C for the Reductive Desulfanylation of Anilines 7

J = 208.6, 14.6 Hz, 1F; CFF); IR (KBr): n˜ max = 3429 (s), 1600 (s), 1515 (s), 1498 (s), 1475 (s), 1440 (s), 1302 (s), 1250 (s), 747 (s), 690 cm¢1 (s); MS (70 eV): m/z (%): 342 (31) [M + +H], 341 (24) [M + ], 182 (100), 104 (14), 77 (19); HRMS (ESI-TOF) m/z calcd for C20H17F2NS + H + : +H] + ; found: 342.1151. 342.1128 [M+

A solution of 7 (1.0 mmol) in dry toluene (2 mL) and a solution of AIBN (0.1 mmol) in dry toluene (8 mL) were degassed for 10 min. Bu3SnH (1.75 mmol) was added to the solution of AIBN. The obtained solution was then added dropwise to the solution of 7 at reflux. The reaction was heated at reflux for 16 h. After the completion of the reaction (monitored by TLC), the tin by-products were removed by column chromatography [SiO2 (Art 7734), hexanes (300 mL) then 0–50 % CH2Cl2 in hexanes] to give product 8.

N-[2,2-Difluoro-2-(phenylthio)-1-(p-tolyl)ethyl]aniline (7 b): According to the General Procedure B, the reaction of 3 b (887.5 mg, 2.0 mmol) with Zn (1.31 g, 20.0 mmol) in AcOH (6 mL) gave 7 b (575.6 mg, 81 % yield) as a colorless oil after column chromatography [SiO2 (Art 7736), CH2Cl2/hexanes 1:4]. 1H NMR (500 MHz, CDCl3): d = 7.52–7.48 (m, 2 H; ArH), 7.34–7.28 (m, 1 H; ArH), 7.28– 7.23 (m, 4 H; ArH), 7.08 (d, J = 7.9 Hz, 2 H; ArH), 7.06–7.01 (m, 2 H; ArH), 6.67–6.62 (m, 1 H; ArH), 6.53–6.49 (m, 2 H; ArH), 4.77 (dd, J = 14.3, 7.2 Hz, 1 H; CH), 4.44 (br s, 1 H; NH), 2.24 ppm (s, 3 H; CH3); 13 C NMR (125 MHz, CDCl3): d = 145.8 (C), 138.5 (C), 136.4 (2 Õ CH), 132.2 (C), 129.8 (CH), 129.4 (t, J = 283.0 Hz; CF2), 129.3 (2 Õ CH), 129.2 (2 Õ CH), 129.0 (2 Õ CH), 128.3 (2 Õ CH), 126.2 (C), 118.6 (CH), 113.9 (2 Õ CH), 63.5 (t, J = 24.9 Hz; CH), 21.2 ppm (CH3); 19F NMR (470 MHz, CDCl3): d = ¢77.4 (dd, J = 207.7, 7.1 Hz, 1F; CFF), ¢81.8 ppm (dd, J = 207.7, 14.1 Hz, 1F; CFF); IR (neat): n˜ max = 3412 (m), 1603 (s), 1506 (s), 1475 (m), 1440 (s), 1303 (s), 1252 (s), 783 (m), 748 (s), 691 cm¢1 (s); MS (70 eV): m/z (%): 356 (71) [M + +H], 355 (45) [M + ], 196 (100); HRMS (ESI-TOF) m/z calcd for C21H19F2NS + H + : 356.1285 [M+ +H] + ; found: 356.1279.

N-(2,2-Difluoro-1-phenylethyl)aniline (8 a): According to the General Procedure C, reductive desulfanylation of 7 a (341.8 mg, 1.0 mmol) using Bu3SnH (0.47 mL, 1.77 mmol) and AIBN (16.4 mg, 0.10 mmol) gave 8 a (223.5 mg, 96 % yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3): d = 7.36–7.22 (m, 5 H; ArH), 7.08–7.01 (m, 2 H; ArH), 6.68–6.62 (m, 1 H; ArH), 6.54–6.49 (m, 2 H; ArH), 5.90 (ddd, J = 55.8, 55.8, 2.9 Hz, 1 H; CF2H), 4.62 (ddd, J = 13.3, 13.3, 2.9 Hz, 1 H; CH), 4.31 ppm (br s, 1 H; NH); 13C NMR (125 MHz, CDCl3): d = 146.0 (C), 135.4 (d, J = 2.6 Hz; C), 129.3 (2 Õ CH), 128.9 (2 Õ CH), 128.5 (CH), 127.7 (2 Õ CH), 118.7 (CH), 115.8 (t, J = 245.7 Hz; CF2H), 113.9 (2 Õ CH), 60.2 ppm (t, J = 21.6 Hz; CH); 19F NMR (470 MHz, CDCl3): d = ¢124.9 (dABdd, J = 278.5, 55.8, 13.3 Hz, 1F; CFF), ¢127.0 ppm (dABdd, J = 278.5, 55.6, 13.0 Hz, 1F; CFF); IR (neat): n˜ max = 3415 (m), 1604 (s), 1509 (s), 1455 (m), 1436 (m), 1379 (m), 1317 (m), 1297 (m), 751 (s), 693 cm¢1 (s); MS (70 eV): m/z (%): 234 (84) [M + +H], 233 (100) [M + ], 182 (75); HRMS (ESI-TOF) m/z calcd +H] + ; found: 234.1083. for C14H13F2N + H + : 234.1094 [M+

N-[2,2-Difluoro-1-(4-methoxyphenyl)-2-(phenylthio)ethyl]aniline (7 c): According to the General Procedure B, the reaction of 3 c (920.3 mg, 2.0 mmol) with Zn (1.31 g, 20.0 mmol) in AcOH (6 mL) gave 7 c (623.4 mg, 84 % yield) as a pale yellow oil after column chromatography [SiO2 (Art 7736), CH2Cl2/hexanes 1:4]. 1H NMR (500 MHz, CDCl3): d = 7.65–7.60 (m, 2 H; ArH), 7.46–7.35 (m, 5 H; ArH), 7.19–7.14 (m, 2 H; ArH), 6.94–6.90 (m, 2 H; ArH), 6.79–6.75 (m, 1 H; ArH), 6.65–6.61 (m, 2 H; ArH), 4.88 (dd, J = 14.1, 7.3 Hz, 1 H; CH), 4.57 (br s, 1 H; NH), 3.81 ppm (s, 3 H; OCH3); 13C NMR (125 MHz, CDCl3): d = 159.8 (C), 145.8 (C), 136.3 (2 Õ CH), 129.8 (CH), 129.5 (2 Õ CH), 129.4 (t, J = 283.9 Hz; CF2), 129.2 (2 Õ CH), 129.0 (2 Õ CH), 127.1 (C), 126.2 (C), 118.6 (CH), 114.0 (2 Õ CH), 113.9 (2 Õ CH), 63.2 (t, J = 24.8 Hz; CH), 55.2 ppm (CH3); 19F NMR (470 MHz, CDCl3): d = ¢77.5 (dd, J = 207.4, 7.1 Hz, 1F; CFF), ¢81.9 ppm (dd, J = 207.4, 13.9 Hz, 1F; CFF); IR (neat): n˜ max = 3407 (m), 1603 (s), 1588 (m), 1505 (s), 1475 (s), 1441 (s), 1305 (s), 1276 (s), 1250 (s), 794 (m), 749 (s), 691 cm¢1 (s); MS (70 eV): m/z (%): 372 (50) [M + +H], 212 (100); HRMS (ESI-TOF) m/z calcd for C21H19F2NOS + Na + : 394.1053 +Na] + ; found: 394.1037. [M+

N-[2,2-Difluoro-1-(p-tolyl)ethyl]aniline (8 b): According to the General Procedure C, reductive desulfanylation of 7 b (355.3 mg, 1.0 mmol) using Bu3SnH (0.47 mL, 1.77 mmol) and AIBN (16.7 mg, 0.10 mmol) gave 8 b (236.0 mg, 95 % yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3): d = 7.22 (d, J = 8.0 Hz, 2 H; ArH), 7.10 (d, J = 8.0 Hz, 2 H; ArH), 7.07–7.01 (m, 2 H; ArH), 6.65 (t, J = 7.3 Hz, 1 H; ArH), 6.55–6.50 (m, 2 H; ArH), 5.89 (ddd, J = 55.9, 55.9, 3.0 Hz, 1 H; CF2H), 4.59 (ddd, J = 13.3, 13.3, 3.0 Hz, 1 H; CH), 4.28 (br s, 1 H; NH), 2.26 ppm (s, 3 H; CH3); 13C NMR (125 MHz, CDCl3): d = 146.1 (C), 138.4 (C), 132.3 (C), 129.6 (2 Õ CH), 129.2 (2 Õ CH), 127.6 (2 Õ CH), 118.6 (CH), 115.8 (t, J = 245.5 Hz; CF2H), 113.9 (2 Õ CH), 60.0 (t, J = 21.6 Hz; CH), 21.1 ppm (CH3); 19F NMR (470 MHz, CDCl3): d = ¢125.0 (dABdd, J = 278.1, 55.9, 13.4 Hz, 1F; CFF), ¢127.0 ppm (dABdd, J = 278.1, 55.5, 13.2 Hz, 1F; CFF); IR (neat): n˜ max = 3414 (m), 1604 (s), 1509 (s), 1437 (m), 1380 (m), 1317 (m), 1251 (m), 751 (s), 692 cm¢1 (s); MS (70 eV): m/z (%): 248 (22) [M + +H], 247 (24) [M + ], 196 (100), 104 (32), 77 (12); HRMS (ESI-TOF) m/z calcd for C15H15F2N + H + : +H] + ; found: 248.1242. 248.1251 [M+

N-[1-(4-Chlorophenyl)-2,2-difluoro-2-(phenylthio)ethyl]aniline (7 d): According to the General Procedure B, the reaction of 3 d (928.6 mg, 2.0 mmol) with Zn (1.31 g, 20.0 mmol) in AcOH (6 mL) gave 7 d (437.1 mg, 58 % yield) as a white solid after column chromatography [SiO2 (Art 7734), CH2Cl2/hexanes 1:4]. m.p. 72–73 8C (CH2Cl2/hexanes); 1H NMR (500 MHz, CDCl3): d = 7.74 (d, J = 7.7 Hz, 2 H; ArH), 7.55–7.49 (m, 3 H; ArH), 7.49–7.42 (m, 4 H; ArH), 7.28 (t, J = 7.9 Hz, 2 H; ArH), 6.90 (t, J = 7.3 Hz, 1 H; ArH), 6.71 (d, J = 7.7 Hz, 2 H; ArH), 5.04–4.97 (m, 1 H; CH), 4.74 ppm (d, J = 6.2 Hz, 1 H; NH); 13 C NMR (125 MHz, CDCl3): d = 145.3 (C), 136.3 (2 Õ CH), 134.5 (C), 133.7 (C), 130.0 (CH), 129.7 (2 Õ CH), 129.2 (2 Õ CH), 129.1 (2 Õ CH), 129.0 (t, J = 282.9 Hz; CF2), 128.7 (2 Õ CH), 125.8 (C), 118.9 (CH), 113.8 (2 Õ CH), 63.1 ppm (t, J = 25.2 Hz; CH); 19F NMR (470 MHz, CDCl3): d = ¢76.6 (dd, J = 209.9, 3.8 Hz, 1F; CFF), ¢82.4 ppm (dd, J = 209.9, 14.6 Hz, 1F; CFF); IR (neat): n˜ max = 3412 (m), 1603 (s), 1505 (s), 1491 (s), 1475 (m), 1440 (m), 1303 (s), 1252 (m), 784 (s), 749 (s), 690 cm¢1 (s); MS (70 eV): m/z (%): 376 (14) [M + +H], 375 (10) [M + ], 218 (35), 216 (100), 104 (23), 77 (19); HRMS (ESI-TOF) m/z calcd for +H] + ; found: 376.0745. C20H16ClF2NS + H + : 376.0738 [M+ Chem. Asian J. 2015, 10, 948 – 968

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N-[2,2-Difluoro-1-(4-methoxyphenyl)ethyl]aniline (8 c): According to the General Procedure C, reductive desulfanylation of 7 c (371.9 mg, 1.0 mmol) using Bu3SnH (0.47 mL, 1.77 mmol) and AIBN (16.7 mg, 0.10 mmol) gave 8 c (243.3 mg, 92 % yield) as a pale yellow oil. 1H NMR (500 MHz, CDCl3): d = 7.27–7.21 (m, 2 H; ArH), 7.08–7.02 (m, 2 H; ArH), 6.84–6.79 (m, 2 H; ArH), 6.68–6.63 (m, 1 H; ArH), 6.54–6.49 (m, 2 H; ArH), 5.87 (ddd, J = 56.0, 56.0, 3.0 Hz, 1 H; CF2H), 4.57 (ddd, J = 13.2, 13.2, 3.0 Hz, 1 H; CH), 4.26 (br s, 1 H; NH), 3.70 ppm (s, 3 H; OCH3); 13C NMR (125 MHz, CDCl3): d = 159.7 (C), 146.1 (C), 129.2 (2 Õ CH), 128.8 (2 Õ CH), 127.3 (C), 118.7 (CH), 115.8 (t, J = 245.5 Hz; CF2H), 114.3 (2 Õ CH), 114.0 (2 Õ CH), 59.7 (t, J = 21.7 Hz; CH), 55.2 ppm (CH3); 19F NMR (470 MHz, CDCl3): d = ¢125.3 (dABdd, J = 278.2, 55.9, 13.6 Hz, 1F; CFF), ¢126.8 ppm (dABdd, J = 278.2, 55.9, 12.7 Hz, 1F; CFF); IR (neat): n˜ max = 3406 (m), 1605 (s), 1513 (s), 1464 (m), 1439 (m), 1250 (s), 1123 (s), 830 (m), 752 (s), 693 cm¢1 (s); MS (70 eV): m/z (%): 264 (36) [M + +H], 263 (38) [M + ],

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Full Paper 212 (100), 171 (18), 121 (10), 104 (17), 77 (9); HRMS (ESI-TOF) m/z +Na] + ; found: 286.1000. calcd for C15H15F2NO + Na + : 286.1019 [M+

1.00 mmol) with 1 (464.2 mg, 2.00 mmol) using 1 mol % of TBAF followed by quenching the reaction with 1 m TBAF solution in THF (2 mL) and reductive cleavage of N¢O bond by using Zn powder (332.1 mg, 5.08 mmol), In metal (23.2 mg, 0.20 mmol), and a saturated aqueous NH4Cl solution (20 mL) in MeOH (15 mL) at reflux gave 10 b (409.6 mg, 73 % yield, over 2 steps) as a white solid after column chromatography [SiO2 (Art 7734), 10–20 % EtOAc in hexanes]. m.p. 59–60 8C (CH2Cl2/hexanes); ½a¤22 D = ¢11.9 (c = 1.03 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.67–7.63 (m, 2 H; ArH), 7.45– 7.25 (m, 18 H; ArH), 4.62 (d, J = 11.4 Hz, 1 H; OCHH), 4.59 (d, J = 11.8 Hz, 1 H; OCHH), 4.55–4.50 (m, 2 H; OCH2), 4.50 (d, J = 11.4 Hz, 1 H; OCHH), 4.46 (d, J = 11.8 Hz, 1 H; OCHH), 4.39 (dd, J = 4.5, 4.2 Hz, 1 H; OCH), 4.02 (dd, J = 7.4, 4.5 Hz, 1 H; OCH), 3.66 (ddd, J = 17.1, 7.5, 4.2 Hz, 1 H; CH), 3.64 (dd, J = 9.7, 3.6 Hz, 1 H; CHH), 3.51 (dd, J = 9.7, 4.8 Hz, 1 H; CHH), 3.46–3.40 (m, 1 H; CH), 2.61 ppm (br s, 1 H; NH); 13C NMR (125 MHz, CDCl3): d = 138.1 (C), 137.9 (C), 137.7 (C), 136.4 (2 Õ CH), 130.6 (t, J = 281.6 Hz; CF2), 129.7 (CH), 129.0 (2 Õ CH), 128.4 (2 Õ CH), 128.3 (4 Õ CH), 127.9 (2 Õ CH), 127.8 (4 Õ CH), 127.7 (2 Õ CH), 127.6 (CH), 126.4 (C), 85.5 (CH), 85.3 (CH), 73.2 (CH2), 72.3 (CH2), 72.2 (CH2), 68.8 (CH2), 67.2 (dd, J = 26.8, 24.0 Hz; CH), 61.4 ppm (CH); 19F NMR (470 MHz, CDCl3): d = ¢76.8 (dd, J = 207.7, 7.1 Hz, 1F; CFF), ¢82.5 ppm (dd, J = 207.7, 16.9 Hz, 1F; CFF); IR (KBr): n˜ max = 3335 (m), 1497 (m), 1453 (m), 1128 (s), 1068 (s), 751 (s), 699 cm¢1 (s); MS (70 eV): m/z (%): 561 (9) [M + ], 439 (19), 402 (9), 181 (29), 160 (31), 91 (100), 65 (22); HRMS (ESI-TOF) m/z calcd for +Na] + ; found: 584.2045. C33H33F2NO3S + Na + : 584.2047 [M+

General Procedure D for the Fluoride-Catalyzed Nucleophilic Addition of PhSCF2SiMe3 (1) to Cyclic Nitrones 9 An oven-dried round-bottom flask (10 mL) was charged with cyclic nitrone 9 (1.0 mmol) and dry THF (2 mL) under an argon atmosphere. The resulting mixture was cooled to ¢10 8C, and a solution of 1 (2.0 mmol) in dry THF (1 mL) was then added. A solution of TBAF (0.1 m in THF, 0.2 mL, 0.02 mmol, 1 mol %) was slowly added to the reaction mixture at ¢10 8C. The resulting reaction mixture was allowed to stir and warm to room temperature (30 min). The reaction was monitored by TLC. After the complete consumption of 9, the reaction mixture was quenched at room temperature with 2 % aqueous HCl solution (1 mL), neutralized with saturated aqueous NaHCO3 solution (3 mL), and extracted with CH2Cl2 (3 Õ 20 mL). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. Filtration followed by evaporation gave a crude product, which was used in the next step without purification. A mixture of the obtained crude product, Zn powder (5 mmol), a catalytic amount of In metal (0.2 mmol), and a saturated aqueous NH4Cl solution (20 mL) in MeOH (15 mL) was heated at reflux for 24 h. After cooling down to room temperature, the reaction mixture was filtered through a celite pad, and the solids were washed with EtOAc (3 Õ 20 mL). The filtrate was concentrated in vacuo. The residue was dissolved with H2O (20 mL) and EtOAc (15 mL), and the two phases were then separated. The aqueous phase was extracted with EtOAc (3 Õ 15 mL). The combined organic phases were washed with saturated aqueous NaHCO3 solution (15 mL) and brine (20 mL), and dried over anhydrous Na2SO4. Filtration followed by evaporation gave a crude product, which was purified by column chromatography (SiO2).

General Procedure E for N-Alkenylation of Pyrrolidines 10 a and 10 b An oven-dried round-bottom flask (25 mL) equipped with a condenser was charged with pyrrolidine 10 (1 mmol), anhydr. K2CO3 (2.5 mmol), dry acetone (10 mL), and alkenylating agent under an argon atmosphere. The reaction mixture was heated at reflux for 16 h, cooled down to room temperature, and filtered to remove salts. The filtrate was concentrated in vacuo to give a crude product, which was purified by column chromatography (SiO2).

(2 R,3S,4S)-3,4-Bis(benzyloxy)-2-[difluoro(phenylthio)methyl]pyrrolidine (10 a): According to the General Procedure D, the reaction of cyclic nitrone 9 a (315.6 mg, 1.06 mmol) with 1 (493.8 mg, 2.13 mmol) using 1 mol % of TBAF followed by reductive cleavage of N¢O bond by using Zn powder (327.5 mg, 5.01 mmol), In metal (23.3 mg, 0.20 mmol), and a saturated aqueous NH4Cl solution (20 mL) in MeOH (15 mL) at reflux gave 10 a (279.1 mg, 60 % yield over 2 steps) as a light yellow oil after column chromatography [SiO2 (Art 7734), 10–30 % EtOAc in hexanes]. ½a¤21 D = + 12.2 (c = 1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.66–7.62 (m, 2 H; ArH), 7.45–7.41 (m, 1 H; ArH), 7.40–7.27 (m, 12 H; ArH), 4.61 (dAB, J = 11.5 Hz, 1 H; OCHH), 4.56 (dAB, J = 11.5 Hz, 1 H; OCHH), 4.53 (s, 2 H; OCH2), 4.29 (dd, J = 4.0, 2.9 Hz, 1 H; OCH), 4.05 (ddd, J = 5.3, 4.8, 2.9 Hz, 1 H; OCH), 3.61 (ddd, J = 15.1, 8.7, 4.0 Hz, 1 H; CH), 3.19 [(dd)ABX, J = 11.6, 5.3 Hz, 1 H; CHH], 3.16 [(dd)ABX, J = 11.6, 4.8 Hz, 1 H; CHH], 1.88 ppm (br s, 1 H; NH); 13C NMR (125 MHz, CDCl3): d = 137.9 (C), 137.7 (C), 136.5 (2 Õ CH), 130.0 (t, J = 280.5 Hz; CF2), 129.8 (CH), 129.0 (2 Õ CH), 128.5 (2 Õ CH), 128.4 (2 Õ CH), 127.9 (2 Õ CH), 127.8 (CH), 127.7 (3 Õ CH), 126.3 (C), 84.6 (CH), 84.1 (CH), 72.3 (CH2), 71.4 (CH2), 69.4 (dd, J = 25.8, 24.3 Hz; CH), 50.9 ppm (CH2); 19F NMR (376 MHz, CDCl3): d = ¢77.7 (d, J = 211.9 Hz, 1F; CFF), ¢82.2 ppm (d, J = 211.9 Hz, 1F; CFF); IR (neat): n˜ max = 3355 (w), 1497 (m), 1475 (m), 1456 (m), 1441 (m), 1365 (m), 1206 (m), 1099 (s), 1028 (m), 749 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 442 (12) [M + +H], 441 (1) [M + ], 358 (5), 282 (84), 181 (39), 146 (35), 91 (100), 65 (19); HRMS (ESI+H] + ; found: TOF) m/z calcd for C25H25F2NO2S + H + : 442.1652 [M+ 442.1650. (2S,3S,4S,5 R)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-5-[difluoro(phenylthio)methyl]pyrrolidine (10 b): According to the General Procedure D, the reaction of cyclic nitrone 9 b (418.5 mg, Chem. Asian J. 2015, 10, 948 – 968

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(2 R,3S,4S)-1-Allyl-3,4-bis(benzyloxy)-2-[difluoro(phenylthio)methyl]pyrrolidine (11 a): According to the General Procedure E, the reaction of 10 a (1.16 g, 2.63 mmol) with allyl bromide (0.56 mL, 6.62 mmol) gave 11 a (1.15 g, 91 % yield) as a colorless oil after column chromatography [SiO2 (Art 7736), CH2Cl2/hexanes 3:7]. 1 ½a¤23 D = + 27.5 (c = 1.00 in CHCl3); H NMR (400 MHz, CDCl3): d = 7.64–7.59 (m, 2 H; ArH), 7.44–7.26 (m, 13 H; ArH), 5.93 (dddd, J = 17.2, 10.1, 7.9, 5.2 Hz, 1 H; CH=CHH), 5.21 (d, J = 17.2 Hz, 1 H; CH= CHH), 5.17 (d, J = 10.1 Hz, 1 H; CH=CHH), 4.60–4.51 (obsc, 3 H; OCHH, OCH2), 4.50 (d, J = 11.5 Hz, 1 H; OCHH), 4.32 (d, J = 2.6 Hz, 1 H; OCH), 3.98–3.93 (m, 1 H; OCH), 3.67 (dd, J = 13.9, 5.2 Hz, 1 H; CHH), 3.33–3.22 (obsc, 2 H; CH, CHH), 3.15 (dd, J = 13.9, 7.9 Hz, 1 H; CHH), 2.81 ppm (dd, J = 11.0, 5.4 Hz, 1 H; CHH); 13C NMR (100 MHz, CDCl3): d = 138.0 (C), 137.6 (C), 136.4 (2 Õ CH), 134.1 (CH), 131.8 (t, J = 280.5 Hz; CF2), 129.4 (CH), 128.8 (2 Õ CH), 128.4 (4 Õ CH), 127.9 (4 Õ CH), 127.8 (CH), 127.7 (CH), 127.0 (C), 118.2 (CH2), 85.6 (d, J = 3.0 Hz; CH), 80.9 (CH), 73.7 (dd, J = 25.0, 24.0 Hz; CH), 72.0 (CH2), 71.1 (CH2), 57.6 (CH2), 56.8 ppm (CH2); 19F NMR (376 MHz, CDCl3): d = ¢70.3 (d, J = 210.6 Hz, 1F; CFF), ¢76.4 ppm (d, J = 210.6 Hz, 1F; CFF); IR (neat): n˜ max = 1497 (m), 1475 (m), 1455 (m), 1441 (m), 1364 (m), 1332 (m), 1098 (s), 1028 (m), 749 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 482 (9) [M + +H], 352 (2), 322 (100), 230 (6), 219 (9), 202 (11), 186 (21), 181 (19), 124 (9), 91 (86), 77 (8), 65 (13); HRMS (ESI+H] + ; found: TOF) m/z calcd for C28H29F2NO2S + H + : 482.1965 [M+ 482.1970.

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Full Paper (2 R,3S,4S)-3,4-Bis(benzyloxy)-1-cinnamyl-2-[difluoro(phenylthio)methyl]pyrrolidine (11 b): According to the General Procedure E, the reaction of 10 a (441.8 mg, 1.00 mmol) with 3-bromo-1-phenyl1-propene (0.18 mL, 1.22 mmol) gave 11 b (502.6 mg, 90 % yield) as a light yellow oil after column chromatography [SiO2 (Art 7734), 0– 1 10 % EtOAc in hexanes]. ½a¤24 D = + 34.1 (c = 1.01 in CHCl3); H NMR (500 MHz, CDCl3): d = 7.66–7.61 (m, 2 H; ArH), 7.44–7.20 (m, 18 H; ArH), 6.54 (d, J = 15.9 Hz, 1 H; CH=CHAr), 6.34 (ddd, J = 15.9, 8.1, 5.4 Hz, 1 H; CH=CHAr), 4.60–4.51 (obsc, 3 H; OCHH, OCH2), 4.50 (d, J = 11.5 Hz, 1 H; OCHH), 4.34 (d, J = 3.0 Hz, 1 H; OCH), 3.98–3.95 (m, 1 H; OCH), 3.86–3.80 (m, 1 H; CHH), 3.38–3.26 (obsc, 3 H; CH, CHH, CHH), 2.86 ppm (dd, J = 11.0, 5.4 Hz, 1 H; CHH); 13C NMR (125 MHz, CDCl3): d = 138.0 (C), 137.7 (C), 136.9 (C), 136.4 (2 Õ CH), 133.2 (CH), 131.7 (t, J = 281.1 Hz; CF2), 129.4 (CH), 128.8 (2 Õ CH), 128.5 (2 Õ CH), 128.4 (4 Õ CH), 127.9 (4 Õ CH), 127.8 (CH), 127.7 (CH), 127.5 (CH), 127.1 (C), 126.5 (2 Õ CH), 125.8 (CH), 85.7 (d, J = 2.5 Hz; CH), 81.1 (CH), 73.9 (t, J = 24.4 Hz; CH), 72.0 (CH2), 71.2 (CH2), 57.2 (CH2), 57.1 ppm (CH2); 19F NMR (470 MHz, CDCl3): d = ¢70.4 (dd, J = 210.7, 9.4 Hz, 1F; CFF), ¢76.4 ppm (dd, J = 210.7, 4.2 Hz, 1F; CFF); IR (neat): n˜ max = 1496 (m), 1475 (m), 1455 (m), 1441 (m), 1365 (m), 1099 (s), 1028 (m), 748 (s), 695 cm¢1 (s); MS (70 eV): m/z (%): 557 (0.3) [M + ], 451 (5), 398 (74), 117 (100), 115 (31), 91 (25), 77 (3), 65 (6); HRMS (ESI-TOF) m/z calcd for C34H33F2NO2S + H + : 558.2278 +H] + ; found: 558.2278. [M+

3.54 (dd, J = 10.8, 8.5 Hz, 1 H; CHH), 3.38 ppm (dd, J = 14.5, 8.3 Hz, 1 H; CHH); 13C NMR (125 MHz, CDCl3): d = 138.3 (C), 138.1 (C), 137.9 (C), 136.4 (2 Õ CH), 135.7 (CH), 132.6 (t, J = 281.9 Hz; CF2), 129.3 (CH), 128.8 (2 Õ CH), 128.3 (4 Õ CH), 128.2 (2 Õ CH), 127.9 (2 Õ CH), 127.8 (2 Õ CH), 127.6 (5 Õ CH), 127.0 (C), 117.0 (CH2), 86.0 (d, J = 2.5 Hz; CH), 83.8 (CH), 73.2 (CH2), 72.4 (t, J = 24.4 Hz; CH), 71.9 (CH2), 71.3 (CH2), 66.8 (CH2), 64.5 (CH), 51.0 ppm (CH2); 19F NMR (470 MHz, CDCl3): d = ¢67.6 (dd, J = 211.5, 11.8 Hz, 1F; CFF), ¢75.4 ppm (d, J = 211.5 Hz, 1F; CFF); IR (neat): n˜ max = 1496 (m), 1456 (s), 1362 (m), 1099 (s), 749 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 602 (0.3) [M + +H], 480 (100), 442 (25), 388 (12), 181 (23), 91 (75), 65 (20); HRMS (ESI-TOF) m/z calcd for C36H37F2NO3S + Na + : +Na] + ; found: 624.2376. 624.2360 [M+ (2S,3S,4S,5 R)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-1-cinnamyl-5-[difluoro(phenylthio)methyl]pyrrolidine (12 b): According to the General Procedure E, the reaction of 10 b (224.7 mg, 0.40 mmol) with 3-bromo-1-phenyl-1-propene (0.15 mL, 1.01 mmol) gave 12 b (208.9 mg, 77 % yield) as a colorless oil after column chromatography [SiO2 (Art 7734), 10–40 % CH2Cl2 in hex1 anes]. ½a¤21 D = + 10.9 (c = 1.03 in CHCl3); H NMR (500 MHz, CDCl3): d = 7.51 (d, J = 7.0 Hz, 2 H; ArH), 7.30–7.08 (m, 23 H; ArH), 6.37 (d, J = 16.0 Hz, 1 H; CH=CHAr), 6.22 (ddd, J = 16.0, 8.1, 4.7 Hz, 1 H; CH= CHAr), 4.49 (dAB, J = 12.5 Hz, 1 H; OCHH), 4.45 (dAB, J = 12.5 Hz, 1 H; OCHH), 4.43 (dAB, J = 11.5 Hz, 1 H; OCHH), 4.40–4.32 (obsc, 3 H; OCHH, OCH2), 4.27–4.24 (m, 1 H; OCH), 4.01–3.97 (m, 1 H; OCH), 3.72 (ddd, J = 12.4, 4.7, 1.5 Hz, 1 H; CHH), 3.61 (dt, J = 12.1, 3.4 Hz, 1 H; CH), 3.58–3.52 (obsc, 2 H; CHH, CHH), 3.49 (dd, J = 10.6, 8.0 Hz, 1 H; CH), 3.45 ppm (dd, J = 14.6, 8.0 Hz, 1 H; CHH); 13C NMR (125 MHz, CDCl3): d = 138.2 (C), 138.0 (C), 137.8 (C), 137.0 (C), 136.4 (2 Õ CH), 132.5 (t, J = 281.9 Hz; CF2), 131.9 (CH), 129.3 (CH), 128.7 (2 Õ CH), 128.4 (2 Õ CH), 128.3 (4 Õ CH), 128.2 (2 Õ CH), 127.9 (2 Õ CH), 127.8 (2 Õ CH), 127.6 (3 Õ CH), 127.5 (2 Õ CH), 127.4 (CH), 127.3 (CH), 126.9 (C), 126.3 (2 Õ CH), 85.9 (d, J = 2.4 Hz; CH), 83.9 (CH), 73.2 (CH2), 72.4 (t, J = 24.6 Hz; CH), 71.9 (CH2), 71.4 (CH2), 66.9 (CH2), 64.7 (CH), 50.5 ppm (CH2); 19F NMR (470 MHz, CDCl3): d = ¢66.0 (dd, J = 211.6, 11.0 Hz, 1F; CFF), ¢73.8 ppm (d, J = 211.6 Hz, 1F; CFF); IR (neat): n˜ max = 1496 (m), 1475 (m), 1454 (m), 1441 (m), 1364 (m), 1099 (s), 1028 (m), 747 (s), 696 cm¢1 (s); MS (70 eV): m/z (%): 677 (0.4) [M + ], 585 (3), 567 (4), 555 (44), 518 (17), 412 (3), 181 (5), 117 (100), 115 (87), 91 (41), 65 (15); HRMS (ESI-TOF) m/z calcd for +Na] + ; found: 700.2671. C42H41F2NO3S + Na + : 700.2673 [M+

(2 R,3S,4S)-3,4-Bis(benzyloxy)-2-[difluoro(phenylthio)methyl]-1[3-(trimethylsilyl)prop-2-yn-1-yl]pyrrolidine (11 c): According to the General Procedure E, the reaction of 10 a (441.9 mg, 1.00 mmol) with 3-bromo-1-(trimethylsilyl)-1-propyne (0.34 mL, 2.08 mmol) gave 11 c (501.9 mg, 91 % yield) as a colorless oil after column chromatography [SiO2 (Art 7734), 0–20 % EtOAc in hex1 anes]. ½a¤23 D = + 70.3 (c = 1.01 in CHCl3); H NMR (500 MHz, CDCl3): d = 7.65–7.61 (m, 2 H; ArH), 7.45–7.27 (m, 13 H; ArH), 4.62 (d, J = 11.7 Hz, 1 H; OCHH), 4.61 (dAB, J = 12.2 Hz, 1 H; OCHH), 4.57 (dAB, J = 12.2 Hz, 1 H; OCHH), 4.53 (d, J = 11.7 Hz, 1 H; OCHH), 4.36–4.33 (m, 1 H; OCH), 3.98 (d, J = 4.7 Hz, 1 H; OCH), 3.83 (d, J = 18.1 Hz, 1 H; CHH), 3.62 (d, J = 18.1 Hz, 1 H; CHH), 3.56 (dt, J = 12.0, 4.2 Hz, 1 H; CH), 3.20 (dABd, J = 10.5, 4.7 Hz, 1 H; CHH), 3.15 (dAB, J = 10.5 Hz, 1 H; CHH), 0.15 ppm [s, 9 H; Si(CH3)3]; 13C NMR (125 MHz, CDCl3): d = 137.9 (C), 137.8 (C), 136.4 (2 Õ CH), 131.3 (t, J = 280.0 Hz; CF2), 129.5 (CH), 128.8 (2 Õ CH), 128.4 (2 Õ CH), 128.3 (2 Õ CH), 127.9 (2 Õ CH), 127.7 (4 Õ CH), 126.7 (C), 99.8 (C), 91.2 (C), 85.2 (d, J = 3.8 Hz; CH), 80.7 (CH), 71.7 (CH2), 71.4 (dd, J = 26.3, 23.8 Hz; CH), 71.1 (CH2), 56.5 (CH2), 42.9 (CH2), 0.0 ppm (3 Õ CH3); 19F NMR (470 MHz, CDCl3): d = ¢71.6 (dd, J = 211.5, 14.1 Hz, 1F; CFF), ¢76.2 ppm (d, J = 211.5 Hz, 1F; CFF); IR (neat): n˜ max = 2166 (m), 1497 (m), 1475 (m), 1455 (m), 1441 (m), 1363 (m), 1326 (m), 1251 (s), 1099 (s), 1028 (s), 985 (s), 845 (s), 749 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 552 (1) [M + +H], 482 (6), 392 (100), 300 (8), 286 (6), 256 (6), 181 (19), 91 (77), 77 (12), 65 (26); HRMS (ESI-TOF) m/z calcd for +Na] + ; found: 574.2027. C31H35F2NO2SSi + Na + : 574.2024 [M+

(2S,3S,4S,5R)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-5-[difluoro(phenylthio)methyl]-1-[3-(trimethylsilyl)prop-2-yn-1-yl]pyrrolidine (12 c): According to the General Procedure E, the reaction of 10b (280.9 mg, 0.50 mmol) with 3-bromo-1-(trimethylsilyl)-1-propyne (0.21 mL, 1.29 mmol) gave 12 c (278.6 mg, 83 % yield) as a colorless oil after column chromatography [SiO2 (Art 7734), 0–10 % 1 H NMR EtOAc in hexanes]. ½a¤23 D = + 50.5 (c = 1.02 in CHCl3); (500 MHz, CDCl3): d = 7.63–7.59 (m, 2 H; ArH), 7.43–7.24 (m, 18 H; ArH), 4.62–4.52 (obsc, 4 H; 2 Õ OCHH, OCH2), 4.47 (d, J = 12.3 Hz, 1 H; OCHH), 4.45 (d, J = 11.8 Hz, 1 H; OCHH), 4.34 (br s, 1 H; OCH), 4.02 (br s, 1 H; OCH), 3.90 (dd, J = 9.5, 5.4 Hz, 1 H; CHH), 3.86 (dt, J = 11.3, 3.9 Hz, 1 H; CH), 3.81 (dAB, J = 18.2 Hz, 1 H; CHH), 3.78 (dAB, J = 18.2 Hz, 1 H; CHH), 3.74–3.69 (m, 1 H; CH), 3.59 (dd, J = 9.5, 7.8 Hz, 1 H; CHH), 0.12 ppm [s, 9 H; Si(CH3)3]; 13C NMR (125 MHz, CDCl3): d = 138.2 (C), 138.1 (C), 137.9 (C), 136.5 (2 Õ CH), 131.7 (t, J = 281.3 Hz; CF2), 129.4 (CH), 128.8 (2 Õ CH), 128.3 (4 Õ CH), 128.2 (2 Õ CH), 128.0 (2 Õ CH), 127.7 (2 Õ CH), 127.6 (4 Õ CH), 127.5 (CH), 126.7 (C), 102.8 (C), 90.4 (C), 85.6 (d, J = 3.8 Hz; CH), 83.3 (CH), 73.3 (CH2), 71.8 (CH2), 71.4 (CH2), 70.7 (dd, J = 25.6, 25.6 Hz; CH), 67.5 (CH), 67.4 (CH2), 39.3 (CH2), ¢0.1 ppm (3 Õ CH3); 19F NMR (470 MHz, CDCl3): d = ¢70.2 (dd, J = 212.7, 7.1 Hz, 1F; CFF), ¢76.3 ppm (d, J = 212.7 Hz, 1F; CFF); IR (neat): n˜ max = 2168 (m), 1497 (m), 1475 (m),

(2S,3S,4S,5 R)-1-Allyl-3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5[difluoro(phenylthio)methyl]pyrrolidine (12 a): According to the General Procedure E, the reaction of 10 b (280.9 mg, 0.50 mmol) with allyl bromide (0.30 mL, 3.55 mmol) at reflux for 2 days gave 12 a (256.0 mg, 85 % yield) as a pale yellow oil after column chromatography [SiO2 (Art 7734), 20–40 % CH2Cl2 in hexanes]. ½a¤22 D = + 17.5 (c = 1.01 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.61–7.57 (m, 2 H; ArH), 7.42–7.24 (m, 18 H; ArH), 5.92 (dddd, J = 17.1, 10.2, 8.3, 4.5 Hz, 1 H; CH=CHH), 5.18 (d, J = 17.1 Hz, 1 H; CH=CHH), 5.11 (d, J = 10.2 Hz, 1 H; CH=CHH), 4.59 (dAB, J = 12.3 Hz, 1 H; OCHH), 4.54 (dAB, J = 12.3 Hz, 1 H; OCHH), 4.52 (dAB, J = 11.6 Hz, 1 H; OCHH), 4.48 (s, 2 H; OCH2), 4.44 (dAB, J = 11.6 Hz, 1 H; OCHH), 4.31 (br s, 1 H; OCH), 4.06 (br s, 1 H; OCH), 3.69–3.59 (obsc, 4 H; 2 Õ CHH, 2 Õ CH), Chem. Asian J. 2015, 10, 948 – 968

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Full Paper 1454 (m), 1365 (m), 1250 (s), 1098 (s), 750 (s), 737 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 672 (1) [M + ], 550 (93), 512 (28), 362 (22), 181 (27), 91 (100), 65 (30); HRMS (ESI-TOF) m/z calcd for +H] + ; found: 672.2774. C39H43F2NO3SSi + H + : 672.2779 [M+

General Procedure F for Cross-Olefin Metathesis of Pyrrolidines 14 a An oven-dried round-bottom flask (25 mL) was charged with 14 a (1 mmol) under an argon atmosphere and then dry CH2Cl2 (3 mL) was added. Subsequently, styrenes (4 mmol) and a solution of Grubbs catalyst, 2nd generation (0.1 mmol) in dry CH2Cl2 (2 mL) were added. The reaction was heated to reflux for 16 h. After that, CH2Cl2 was removed in vacuo to give a crude product, which was purified by column chromatography (SiO2).

Preparation of 1-{(2 R,3S,4S)-3,4-bis(benzyloxy)-2-[difluoro(phenylthio)methyl]pyrrolidin-1-yl}but-3-en-1-one (14 a): An ovendried round-bottom flask (25 mL) was charged with pyrrolidine 10 a (1.686 g, 3.82 mmol), 4-DMAP (175.0 mg, 1.43 mmol), and dry CH2Cl2 (3.8 mL) under an argon atmosphere. To the reaction solution were added a solution of N,N’-dicyclohexylcarbodiimide (1.5761 g, 7.64 mmol) in dry CH2Cl2 (7.6 mL) and 3-butenoic acid (0.65 mL, 7.65 mmol) at 0 8C. The reaction was stirred and allowed to warm to room temperature overnight (16 h). The reaction mixture was diluted with EtOAc (10 mL) and filtered through a celite pad, and the solids were washed with EtOAc (3 Õ 15 mL). The filtrate was concentrated in vacuo to give a crude product, which was purified by column chromatography [SiO2 (Art 7734), 20–40 % Et2O in hexanes] to provide 14 a (1.7871 g, 92 % yield) as a colorless 1 viscous oil. ½a¤22 D = + 40.2 (c = 1.03 in CHCl3); H NMR [500 MHz, CDCl3, integrated equally for E-(14 aA) and Z-(14 aB) rotamers of 14 a]: d = 7.63 (d, J = 7.3 Hz, 2 H; ArH of 14 aA), 7.60 (d, J = 7.7 Hz, 2 H; ArH of 14 aB), 7.48–7.25 (m, 26 H; ArH of 14 aA and 14 aB), 5.98–5.82 (m, 2 H; CH=CHH of 14 aA and 14 aB), 5.20 (d, J = 10.6 Hz, 1 H; CH=CHH of 14 aA), 5.17 (d, J = 17.6 Hz, 1 H; CH=CHH of 14 aA), 5.10 (d, J = 9.9 Hz, 1 H; CH=CHH of 14 aB), 4.99 (d, J = 17.4 Hz, 1 H; CH=CHH of 14 aB), 4.94 (dd, J = 17.2, 8.7 Hz, 1 H; CH of 14 aA), 4.70–4.62 (obsc, 3 H; 2 Õ OCHH of 14 aA, OCHH of 14 aB), 4.60–4.40 (obsc, 8 H; OCHH of 14 aB, 2 Õ OCHH of 14 aA and 14 aB, OCH of 14 aA and 14 aB, CHH of 14 aB), 4.31 (br d, J = 19.8 Hz, 1 H; CH of 14 aB), 4.11 (td, J = 8.2, 3.4 Hz, 1 H; OCH of 14 aA), 4.05 (td, J = 8.4, 3.9 Hz, 1 H; OCH of 14 aB), 4.03–3.96 (m, 1 H; CHH of 14 aA), 3.44 (dd, J = 10.9, 8.2 Hz, 1 H; CHH of 14 aA), 3.19 (dd, J = 12.0, 8.4 Hz, 1 H; CHH of 14 aB), 3.14 (d, J = 6.4 Hz, 2 H; CH2 of 14 aA), 3.04 [(dd)ABX, J = 16.2, 5.7 Hz, 1 H; CHH of 14 aB], 2.97 ppm [(dd)ABX, J = 16.2, 7.1 Hz, 1 H; CHH of 14 aB]; 13C NMR [125 MHz, CDCl3, determined as a rotameric mixture (65:35) of E-(14 aA) and Z-(14 aB) rotamers of 14 a]: d = 170.8 (C of 14 aB), 170.0 (C of 14 aA), 137.4 (2 Õ C of 14 aB), 137.2 (2 Õ C of 14 aA), 136.7 (2 Õ CH of 14 aB), 136.4 (2 Õ CH of 14 aA), 131.1 (CH of 14 aB), 130.5 (CH of 14 aA), 130.4 (CH of 14 aB), 129.8 (CH of 14 aA), 129.4 (dd, J = 284.6, 282.8 Hz; CF2 of 14 aA), 129.3 (CH of 14 aA), 128.9 (4 Õ CH of 14 aB), 128.5 (4 Õ CH of 14 aA), 128.5 (4 Õ CH of 14 aB), 128.1 (3 Õ CH of 14 aA), 128.0 (4 Õ CH of 14 aB), 127.9 (4 Õ CH of 14 aA), 126.1 (C of 14 aA), 125.1 (C of 14 aB), 118.3 (CH2 of 14 aA), 118.1 (CH2 of 14 aB), 85.8 (CH of 14 aB), 83.5 (CH of 14 aA), 83.1 (CH of 14 aA), 81.6 (CH of 14 aB), 72.3 (2 Õ CH2 of 14 aA), 72.1 (2 Õ CH2 of 14 aB), 67.4 (t, J = 23.4 Hz; CH of 14 aB), 65.1 (dd, J = 28.6, 22.5 Hz; CH of 14 aA), 51.5 (CH2 of 14 aA), 49.6 (CH2 of 14 aB), 39.6 (CH2 of 14 aA), 38.1 ppm (CH2 of 14 aB); due to low intensity, CF2 of Z-rotamers (14 aB) could not be detected by 13C NMR; 19F NMR [470 MHz, CDCl3, determined as a rotameric mixture (65:35) of E-(14 aA) and Z-(14 aB) rotamers of 14 a]: d = ¢75.4 (d, J = 211.7 Hz, 1F; CFF of 14 aB), ¢75.6 (dd, J = 209.5, 7.1 Hz, 1F; CFF of 14 aA), ¢78.6 (dd, J = 209.5, 16.5 Hz, 1F; CFF of 14 aA), ¢82.7 ppm (dd, J = 211.7, 17.4 Hz, 1F; CFF of 14 aB); IR (neat): n˜ max = 1663 (s), 1636 (m), 1497 (m), 1475 (m), 1454 (m), 1441 (m), 1404 (s), 1364 (m), 1205 (m), 1165 (m), 1102 (s), 1059 (s), 1029 (m), 750 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 509 (0.1) [M + ], 350 (17), 349 (17), 242 (14), 181 (26), 91 (100), 77 (5), 65 (16); HRMS (ESI-TOF) m/z calcd for C29H29F2NO3S + Na + : 532.1734 [M+ +Na] + ; found: 532.1738. Chem. Asian J. 2015, 10, 948 – 968

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(E)-1-{(2 R,3S,4S)-3,4-Bis(benzyloxy)-2-[difluoro(phenylthio)methyl]pyrrolidin-1-yl}-4-phenylbut-3-en-1-one (14 b): According to the General Procedure F, a solution of 14 a (509.6 mg, 1.00 mmol) and styrene (0.46 mL, 4.01 mmol) in dry CH2Cl2 (3 mL) was treated with a solution of Grubbs catalyst, 2nd generation (85.3 mg, 0.10 mmol) in dry CH2Cl2 (2 mL) to give 14 b (329.4 mg, 56 % yield, undetermined E- and Z-isomers) as a colorless viscous oil after column chromatography [SiO2 (Art 7734), CH2Cl2/EtOAc/hexanes 1 2:1:7]. ½a¤24 D = + 50.3 (c = 1.02 in CHCl3); H NMR [500 MHz, CDCl3, integrated equally for E-(14 bA) and Z-(14 bB) rotamers of 14 b]: d = 7.58–7.53 (m, 4 H; ArH of 14 bA and 14 bB), 7.43–7.12 (m, 36 H; ArH of 14 bA and 14 bB), 6.43 (d, J = 16.1 Hz, 1 H; CH=CHAr of 14 bA), 6.28–6.12 (obsc, 3 H; CH=CHAr of 14 bA, CH=CHAr and CH= CHAr of 14 bB), 4.91 (dd, J = 16.6, 8.3 Hz, 1 H; CH of 14 bA), 4.65– 4.35 (obsc, 11 H; 2 Õ OCH2 of 14 bA and 14 bB, OCH of 14 bA and 14 bB, CHH of 14 bB), 4.32 (br d, J = 20.2 Hz, 1 H; CH of 14 bB), 4.06 (td, J = 8.0, 3.4 Hz, 1 H; OCH of 14 bA), 4.03–3.95 (obsc, 2 H; CHH of 14 bA, OCH of 14 bB), 3.40 (dd, J = 10.7, 8.0 Hz, 1 H; CHH of 14 bA), 3.24 (d, J = 6.4 Hz, 2 H; CH2 of 14 bA), 3.15 (dd, J = 11.4, 9.1 Hz, 1 H; CHH of 14 bB), 3.12 [(dd)ABX, J = 16.2, 5.3 Hz, 1 H; CHH of 14 bB], 3.06 ppm [(dd)ABX, J = 16.2, 7.1 Hz, 1 H; CHH of 14 bB]; 13C NMR [125 MHz, CDCl3, determined as a rotameric mixture (63:37) of E(14 bA) and Z-(14 bB) rotamers of 14 b]: d = 170.8 (C of 14 bB), 170.1 (C of 14 bA), 137.3 (2 Õ C of 14 bA), 137.2 (C of 14 bA), 136.9 (C of 14 bB), 136.8 (2 Õ C of 14 bB), 136.7 (2 Õ CH of 14 bB), 136.5 (2 Õ CH of 14 bA), 133.2 (CH of 14 bA), 133.0 (CH of 14 bB), 130.4 (CH of 14 bB), 129.8 (CH of 14 bA), 129.4 (dd, J = 286.3, 281.3 Hz; CF2 of 14 bA), 129.3 (CH of 14 bA), 128.9 (4 Õ CH of 14 bB), 128.5 (6 Õ CH of 14 bB), 128.4 (6 Õ CH of 14 bA), 128.0 (3 Õ CH of 14 bA), 127.9 (4 Õ CH of 14 bB), 127.8 (4 Õ CH of 14 bA), 127.5 (CH of 14 bA), 127.4 (CH of 14 bB), 126.3 (2 Õ CH of 14 bA, 2 Õ CH of 14 bB), 126.0 (C of 14 bA), 125.1 (C of 14 bB), 122.6 (CH of 14 bB), 122.0 (CH of 14 bA), 85.8 (CH of 14 bB), 83.5 (CH of 14 bA), 83.1 (CH of 14 bA), 81.6 (CH of 14 bB), 72.3 (2 Õ CH2 of 14 bA), 72.1 (2 Õ CH2 of 14 bB), 67.4 (t, J = 23.1 Hz; CH of 14 bB), 65.2 (dd, J = 30.0, 22.5 Hz; CH of 14 bA), 51.5 (CH2 of 14 bA), 49.7 (CH2 of 14 bB), 38.3 (CH2 of 14 bA), 37.5 ppm (CH2 of 14 bB); due to low intensity, CF2 of Z-rotamers (14 bB) could not be detected by 13C NMR; 19F NMR [470 MHz, CDCl3, determined as a rotameric mixture (63:37) of E-(14 bA) and Z-(14 bB) rotamers of 14 b]: d = ¢75.3 (d, J = 212.2 Hz, 1F; CFF of 14 bB), ¢75.5 (dd, J = 209.7, 7.1 Hz, 1F; CFF of 14 bA), ¢78.5 (dd, J = 209.7, 16.5 Hz, 1F; CFF of 14 bA), ¢83.0 ppm (dd, J = 212.2, 17.9 Hz, 1F; CFF of 14 bB); IR (neat): n˜ max = 1667 (s), 1497 (m), 1475 (m), 1454 (m), 1441 (m), 1413 (s), 1364 (m), 1206 (m), 1164 (m), 1103 (s), 1059 (s), 1029 (m), 750 (s), 694 cm¢1 (s); MS (70 eV): m/z (%): 586 (0.3) [M + +H], 454 (3), 253 (19), 228 (14), 180 (33), 144 (19), 115 (25), 91 (100), 77 (12), 65 (13); HRMS (ESI-TOF) m/z calcd for +Na] + ; found: 608.2049. C35H33F2NO3S + Na + : 608.2047 [M+ (E)-1-{(2 R,3S,4S)-3,4-Bis(benzyloxy)-2-[difluoro(phenylthio)methyl]pyrrolidin-1-yl}-4-(p-tolyl)but-3-en-1-one (14 c): According to the General Procedure F, a solution of 14 a (509.9 mg, 1.00 mmol) and 4-methylstyrene (0.53 mL, 4.02 mmol) in dry CH2Cl2 (3 mL) was treated with a solution of Grubbs catalyst, 2nd generation (84.9 mg,

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Full Paper CH of 14 dA), 4.65–4.35 (obsc, 11 H; 2 Õ OCH2 of 14 dA and 14 dB, OCH of 14 dA and 14 dB, CHH of 14 dB), 4.30 (br d, J = 20.2 Hz, 1 H; CH of 14 dB), 4.06 (td, J = 7.8, 3.3 Hz, 1 H; OCH of 14 dA), 4.03–3.94 (obsc, 2 H; OCH of 14 dB, CHH of 14 dA), 3.41 (dd, J = 10.9, 7.8 Hz, 1 H; CHH of 14 dA), 3.22 (d, J = 6.4 Hz, 2 H; CH2 of 14 dA), 3.15 (dd, J = 12.2, 8.5 Hz, 1 H; CHH of 14 dB), 3.10 [(dd)ABX, J = 16.3, 5.8 Hz, 1 H; CHH of 14 dB], 3.04 ppm [(dd)ABX, J = 16.3, 7.4 Hz, 1 H; CHH of 14 dB]; 13C NMR [125 MHz, CDCl3, determined as a rotameric mixture (61:39) of E-(14 dA) and Z-(14 dB) rotamers of 14 d]: d = 170.7 (C of 14 dB), 170.1 (C of 14 dA), 162.3 (d, J = 246.3 Hz; C of 14 dA), 162.2 (d, J = 244.9 Hz; C of 14 dB), 137.3 (2 Õ C of 14 dA), 137.1 (2 Õ C of 14 dB), 136.7 (2 Õ CH of 14 dB), 136.5 (2 Õ CH of 14 dA), 133.0 (C of 14 dA, C of 14 dB), 132.0 (CH of 14 dA), 131.8 (CH of 14 dB), 130.4 (CH of 14 dB), 129.8 (CH of 14 dA), 129.4 (t, J = 283.1 Hz; CF2 of 14 dA), 129.3 (CH of 14 dA), 129.0 (4 Õ CH of 14 dB), 128.7 (dd, J = 287.5, 283.8; CF2 of 14 dB), 128.5 (6 Õ CH of 14 dB), 128.4 (4 Õ CH of 14 dA), 128.1 (2 Õ CH of 14 dB), 128.0 (3 Õ CH of 14 dA), 127.9 (4 Õ CH of 14 dA), 127.8 (d, J = 7.8 Hz; 2 Õ CH of 14 dA), 127.7 (d, J = 7.8 Hz; 2 Õ CH of 14 dB), 126.0 (C of 14 dA), 125.1 (C of 14 dB), 122.4 (CH of 14 dB), 121.8 (CH of 14 dA), 115.4 (d, J = 21.3 Hz; 2 Õ CH of 14 dA), 115.3 (d, J = 21.3 Hz; 2 Õ CH of 14 dB), 85.8 (CH of 14 dB), 83.4 (CH of 14 dA), 83.1 (CH of 14 dA), 81.5 (CH of 14 dB), 72.3 (2 Õ CH2 of 14 dA), 72.2 (CH2 of 14 dB), 72.1 (CH2 of 14 dB), 67.5 (t, J = 23.1 Hz; CH of 14 dB), 65.2 (dd, J = 29.4, 23.1 Hz; CH of 14 dA), 51.6 (CH2 of 14 dA), 49.7 (CH2 of 14 dB), 38.6 (CH2 of 14 dA), 37.4 ppm (CH2 of 14 dB); 19F NMR [470 MHz, CDCl3, determined as a rotameric mixture (61:39) of E-(14 dA) and Z-(14 dB) rotamers of 14 d]: d = ¢75.3 (d, J = 211.6 Hz, 1F; CFF of 14 dB), ¢75.5 (dd, J = 209.6, 7.1 Hz, 1F; CFF of 14 dA), ¢78.5 (dd, J = 209.6, 16.5 Hz, 1F; CFF of 14 dA), ¢82.9 (dd, J = 211.6, 20.0 Hz, 1F; CFF of 14 dB), ¢114.5 (s, 1F; ArF of 14 dA), ¢114.8 ppm (s, 1F; ArF of 14 dB); IR (neat): n˜ max = 1667 (s), 1662 (s), 1509 (s), 1498 (m), 1475 (m), 1455 (m), 1441 (m), 1409 (s), 1363 (m), 1228 (s), 1158 (m), 1103 (s), 1059 (m), 1029 (m), 750 (s), 699 cm¢1 (s); MS (70 eV): m/z (%): 603 (0.2) [M + ], 181 (29), 162 (13), 135 (12), 133 (11), 115 (13), 109 (11), 91 (100), 77 (2), 65 (15); HRMS (ESI-TOF) m/z calcd for C35H32F3NO3S + +Na] + ; found: 626.1955. Na + : 626.1953 [M+

0.10 mmol) in dry CH2Cl2 (2 mL) to give 14 c (296.0 mg, 49 % yield, undetermined E- and Z-isomers) as a colorless viscous oil after column chromatography [SiO2 (Art 7734), EtOAc/hexanes 1:4]. 1 ½a¤25 D = + 56.6 (c = 1.02 in CHCl3); H NMR [500 MHz, CDCl3, integrated equally for E-(14 cA) and Z-(14 cB) rotamers of 14 c]: d = 7.55 (d, J = 7.3 Hz, 2 H; ArH of 14 cA), 7.53 (d, J = 6.3 Hz, 2 H; ArH of 14 cB), 7.42–7.15 (m, 28 H; ArH of 14 cA and 14 cB), 7.12 (d, J = 7.8 Hz, 2 H; ArH of 14 cB), 7.03 (d, J = 7.8 Hz, 2 H; ArH of 14 cA), 7.00 (d, J = 7.8 Hz, 2 H; ArH of 14 cB), 6.38 (d, J = 16.0 Hz, 1 H; CH=CHAr of 14 cA), 6.22–6.14 (obsc, 2 H; CH=CHAr of 14 cA, CH=CHAr of 14 cB), 6.09 (dt, J = 15.9, 6.5 Hz, 1 H; CH=CHAr of 14 cB), 4.90 (dd, J = 17.0, 8.3 Hz, 1 H; CH of 14 cA), 4.64–4.34 (obsc, 11 H; 2 Õ OCH2 of 14 cA and 14 cB, OCH of 14 cA and 14 cB, CHH of 14 cB), 4.32 (br d, J = 20.1 Hz; 1 H, CH of 14 cB), 4.07–4.01 (m, 1 H; OCH of 14 cA), 4.01– 3.94 (obsc, 2 H; OCH of 14 cB, CHH of 14 cA), 3.39 (dd, J = 10.6, 8.1 Hz, 1 H; CHH of 14 cA), 3.21 (d, J = 6.5 Hz, 2 H; CH2 of 14 cA), 3.14 (dd, J = 12.0, 8.5 Hz, 1 H; CHH of 14 cB), 3.09 [(dd)ABX, J = 16.1, 5.6 Hz, 1 H; CHH of 14 cB], 3.04 [(dd)ABX, J = 16.1, 7.2 Hz, 1 H; CHH of 14 cB], 2.25 (s, 3 H; CH3 of 14 cA), 2.24 ppm (s, 3 H; CH3 of 14 cB); 13 C NMR [125 MHz, CDCl3, determined as a rotameric mixture (64:36) of E-(14 cA) and Z-(14 cB) rotamers of 14 c]: d = 170.9 (C of 14 cB), 170.2 (C of 14 cA), 137.3 (2 Õ C of 14 cA), 137.2 (2 Õ C of 14 cB), 136.7 (2 Õ CH of 14 cB), 136.5 (2 Õ CH of 14 cA), 134.1 (C of 14 cB), 134.0 (C of 14 cA), 133.1 (CH of 14 cA), 132.9 (CH of 14 cB), 130.4 (CH of 14 cB), 129.8 (CH of 14 cA), 129.4 (dd, J = 287.0, 282.3 Hz; CF2 of 14 cA), 129.3 (CH of 14 cA), 129.2 (2 Õ CH of 14 cA), 129.1 (2 Õ CH of 14 cB), 128.9 (4 Õ CH of 14 cB), 128.8 (t, J = 279.2 Hz; CF2 of 14 cB), 128.5 (4 Õ CH of 14 cB), 128.4 (4 Õ CH of 14 cA), 128.0 (3 Õ CH of 14 cA), 127.9 (4 Õ CH of 14 cB), 127.8 (4 Õ CH of 14 cA), 126.3 (C of 14 cA), 126.2 (2 Õ CH of 14 cA, 2 Õ CH of 14 cB), 126.1 (C of 14 cA), 125.9 (C of 14 cB), 125.2 (C of 14 cB), 121.5 (CH of 14 cB), 120.9 (CH of 14 cA) 85.8 (CH of 14 cB), 83.5 (CH of 14 cA), 83.1 (CH of 14 cA), 81.6 (CH of 14 cB), 72.3 (2 Õ CH2 of 14 cA), 72.1 (2 Õ CH2 of 14 cB), 67.4 (t, J = 22.5 Hz; CH of 14 cB), 65.1 (dd, J = 28.8, 22.5 Hz; CH of 14 cA), 51.5 (CH2 of 14 cA), 49.7 (CH2 of 14 cB), 38.9 (CH2 of 14 cA), 37.5 (CH2 of 14 cB), 21.1 ppm (CH3 of 14 cA, CH3 of 14 cB); 19F NMR [470 MHz, CDCl3, determined as a rotameric mixture (64:36) of E-(14 cA) and Z-(14 cB) rotamers of 14 c]: d = ¢75.3 (d, J = 212.0 Hz, 1F; CFF of 14 cB), ¢75.5 (dd, J = 209.6, 7.1 Hz, 1F; CFF of 14 cA), ¢78.6 (dd, J = 209.6, 16.5 Hz, 1F; CFF of 14 cA), ¢83.0 ppm (dd, J = 212.0, 20.2 Hz, 1F; CFF of 14 cB); IR (neat): n˜ max = 1667 (s), 1662 (s), 1513 (m), 1497 (m), 1475 (m), 1455 (m), 1441 (m), 1410 (s), 1363 (m), 1206 (m), 1164 (m), 1103 (s), 1059 (m), 1029 (m), 750 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 600 (0.2) [M + +H], 181 (26), 158 (35), 129 (15), 115 (12), 105 (9), 91 (100), 77 (4), 65 (17); HRMS (ESI-TOF) m/z calcd for C36H35F2NO3S + Na + : +Na] + ; found: 622.2202. 622.2203 [M+

General Procedure G for Amide Reduction of Pyrrolidines 14 to 13 An oven-dried round-bottom flask (10 mL) was charged with 14 (1 mmol) and dry CH2Cl2 (3 mL) under an argon atmosphere. The reaction mixture was cooled to 0 8C and Me3SiCl (1.2 mmol) was added. After stirring for 10 min at 0 8C, a solution of LiAlH4 (1.5 mmol, 2.0 m in THF) was added. The reaction was stirred at 0 8C for 1.5 h. The reaction was monitored by TLC. After the completion of the reaction, it then was quenched by slow addition of 2.0 m aqueous NaOH solution (6 mL) at 0 8C, and stirring was continued for 16 h. The reaction mixture was extracted with CH2Cl2 (3 Õ 20 mL), and the combined organic phases were washed with brine (20 mL) and dried over anhydrous Na2SO4. Filtration followed by evaporation gave a crude product, which was purified by column chromatography (SiO2).

(E)-1-{(2 R,3S,4S)-3,4-Bis(benzyloxy)-2-[difluoro(phenylthio)methyl]pyrrolidin-1-yl}-4-(4-fluorophenyl)but-3-en-1-one (14 d): According to the General Procedure F, a solution of 16 a (509.6 mg, 1.00 mmol) and 4-fluorostyrene (0.48 mL, 4.01 mmol) in dry CH2Cl2 (3 mL) was treated with a solution of Grubbs catalyst, 2nd generation (85.0 mg, 0.10 mmol) in dry CH2Cl2 (2 mL) to give 14 d (301.8 mg, 50 % yield, undetermined E- and Z-isomers) as a colorless viscous oil after column chromatography [SiO2 (Art 7734), CH2Cl2/Et2O/hexanes 3:1:6]. ½a¤26 D = + 54.5 (c = 1.03 in CHCl3); 1 H NMR [500 MHz, CDCl3, integrated equally for E-(14 dA) and Z(14 dB) rotamers of 14 d]: d = 7.57–7.52 (m, 4 H; ArH of 14 dA and 14 dB), 7.42–7.15 (m, 30 H; ArH of 14 dA and 14 dB), 6.92 (dd, J = 8.6, 8.6 Hz, 2 H; ArH of 16 dA), 6.87 (dd, J = 8.7, 8.7 Hz, 2 H; ArH of 14 dB), 6.38 (d, J = 16.0 Hz, 1 H; CH=CHAr of 14 dA), 6.21–6.13 (obsc, 2 H; CH=CHAr of 14 dA, CH=CHAr of 14 dB), 6.06 (dt, J = 16.1, 6.6 Hz, 1 H; CH=CHAr of 14 dB), 4.90 (dd, J = 16.6, 9.1 Hz, 1 H; Chem. Asian J. 2015, 10, 948 – 968

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(2 R,3S,4S)-3,4-Bis(benzyloxy)-1-(but-3-en-1-yl)-2-[difluoro(phenylthio)methyl]pyrrolidine (13 a): According to the General Procedure G, reduction of 14 a (288.5 mg, 0.57 mmol) by using Me3SiCl (90 mL, 0.70 mmol), dry CH2Cl2 (1.7 mL), and LiAlH4 (0.45 mL, 0.90 mmol, 2.0 m in THF) at 0 8C for 1.5 h gave 13 a (206.0 mg, 73 % yield) as a colorless oil after column chromatography [SiO2 (Art 7734), CH2Cl2/hexanes 1:1]. ½a¤23 D = + 36.4 (c = 1.00 in CHCl3); 1 H NMR (500 MHz, CDCl3): d = 7.63–7.59 (m, 2 H; ArH), 7.43–7.27 (m, 13 H; ArH), 5.85 (ddt, J = 17.1, 10.3, 6.7 Hz, 1 H; CH=CHH), 5.11–5.05

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Full Paper (m, 1 H; CH=CHH), 5.03–4.99 (m, 1 H; CH=CHH), 4.58 (dAB, J = 12.3 Hz, 1 H; OCHH), 4.57 (dAB, J = 11.5 Hz, 1 H; OCHH), 4.55 (dAB, J = 12.3 Hz, 1 H; OCHH), 4.51 (dAB, J = 11.5 Hz, 1 H; OCHH), 4.30 (d, J = 3.0 Hz, 1 H; OCH), 4.00–3.96 (m, 1 H; OCH), 3.33 (br d, J = 10.6 Hz, 1 H; CHH), 3.25 (dt, J = 11.9, 4.3 Hz, 1 H; CH), 3.08 (ddd, J = 12.3, 9.8, 6.6 Hz, 1 H; CHH), 2.77 (dd, J = 10.6, 5.4 Hz, 1 H; CHH), 2.56 (ddd, J = 12.3, 9.2, 5.4 Hz, 1 H; CHH), 2.36–2.22 ppm (m, 2 H; CH2); 13C NMR (125 MHz, CDCl3): d = 138.1 (C), 137.7 (C), 136.4 (2 Õ CH), 136.3 (CH), 131.9 (t, J = 281.3 Hz; CF2), 129.3 (CH), 128.8 (2 Õ CH), 128.4 (2 Õ CH), 128.3 (2 Õ CH), 127.9 (4 Õ CH), 127.8 (CH), 127.7 (CH), 127.2 (C), 115.7 (CH2), 85.5 (d, J = 2.5 Hz; CH), 81.2 (CH), 75.1 (dd, J = 25.0, 25.0 Hz; CH), 72.0 (CH2), 71.1 (CH2), 57.1 (CH2), 54.9 (CH2), 32.1 ppm (CH2); 19 F NMR (470 MHz, CDCl3): d = ¢69.9 (dd, J = 210.3, 12.0 Hz, 1F; CFF), ¢76.2 ppm (dd, J = 210.3, 4.0 Hz, 1F; CFF); IR (neat): n˜ max = 1497 (m), 1474 (m), 1455 (m), 1441 (m), 1362 (m), 1098 (s), 1028 (m), 749 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 496 (2) [M + +H], 495 (1) [M + ], 454 (85), 336 (39), 200 (9), 181 (9), 91 (100), 77 (6), 65 (19); HRMS (ESI-TOF) m/z calcd for C29H31F2NO2S + H + : 496.2122 +H] + ; found: 496.2122. [M+

J = 210.2 Hz, 1F; CFF); IR (neat): n˜ max = 1496 (m), 1475 (m), 1454 (m), 1441 (m), 1362 (m), 1208 (m), 1099 (s), 1028 (s), 747 (s), 694 cm¢1 (s); MS (70 eV): m/z (%): 571 (0.1) [M + ], 454 (100), 414 (10), 214 (5), 91 (64), 65 (7); HRMS (ESI-TOF) m/z calcd for C35H35F2NO2S + Na + : +Na] + ; found: 594.2256. 594.2254 [M+ (2 R,3S,4S)-3,4-Bis(benzyloxy)-2-[difluoro(phenylthio)methyl]-1[(E)-4-(p-tolyl)but-3-en-1-yl]pyrrolidine (13 c): According to the General Procedure G, reduction of 14 c (252.7 mg, 0.42 mmol) by using Me3SiCl (70 mL, 0.55 mmol), dry CH2Cl2 (1.3 mL), and LiAlH4 (0.32 mL, 0.64 mmol, 2.0 m in THF) at 0 8C for 1.5 h gave 13 c (112.6 mg, 46 % yield, d.r. 92:8 as determined by 1H NMR analysis) as a light yellow viscous oil after column chromatography [SiO2 (Art 7734), CH2Cl2/hexanes 1:1]. ½a¤26 D = + 27.7 (c = 1.00 in CHCl3); due to low intensity, only some peaks of the Z-isomer could be detected by 1H NMR; 1H NMR [500 MHz, CDCl3, determined as a diastereomeric mixture (92:8) of E- and Z-isomers of 13 c]: d = 7.54 (d, J = 7.8 Hz, 2 H; ArH), 7.36–7.16 (m, 15 H; ArH), 7.02 (d, J = 7.8 Hz, 2 H; ArH), 6.35 (d, J = 15.9 Hz, 1 H; CH=CHAr), 6.15 (dt, J = 15.9, 7.0 Hz, 1 H; CH=CHAr), 4.54–4.43 (m, 4 H; 2 Õ OCH2), 4.25 (br s, 1 H; OCH), 4.25–4.23 (m, 1 H; OCH of Z-isomer), 3.95–3.92 (m, 1 H; OCH), 3.93– 3.90 (m, 1 H; OCH of Z-isomer), 3.31 (d, J = 10.7 Hz, 1 H; CHH), 3.22 (dt, J = 11.8, 4.2 Hz, 1 H; CH), 3.08 (ddd, J = 12.3, 9.4, 6.8 Hz, 1 H; CHH), 2.74 (dd, J = 10.7, 5.4 Hz, 1 H; CHH), 2.58 (ddd, J = 12.3, 8.8, 5.3 Hz, 1 H; CHH), 2.44–2.30 (m, 2 H; CH2), 2.25 ppm (s, 3 H; CH3); 13 C NMR [125 MHz, CDCl3, determined as a diastereomeric mixture (92:8) of E- and Z-isomers of 13 c]: d = 138.1 (C), 137.7 (C), 136.6 (C), 136.4 (2 Õ CH), 135.0 (C), 132.0 (t, J = 280.6 Hz; CF2), 130.9 (CH), 129.3 (CH), 129.2 (2 Õ CH), 128.8 (2 Õ CH), 128.4 (4 Õ CH), 127.9 (2 Õ CH), 127.8 (3 Õ CH, C), 127.7 (CH), 127.2 (CH), 125.9 (2 Õ CH), 85.6 (d, J = 2.5 Hz; CH), 81.3 (CH), 75.1 (dd, J = 25.0, 23.8 Hz; CH), 72.0 (CH2), 71.1 (CH2), 57.2 (CH2), 55.2 (CH2), 31.4 (CH2), 21.1 ppm (CH3); 19 F NMR [470 MHz, CDCl3, determined as a diastereomeric mixture (92:8) of E- and Z-isomers of 13 c]: d = ¢69.6 (dd, J = 210.4, 11.5 Hz, 1F; CFF), ¢76.1 ppm (d, J = 210.4 Hz, 1F; CFF); IR (neat): n˜ max = 1513 (m), 1497 (m), 1475 (m), 1455 (m), 1441 (m), 1362 (m), 1271 (m), 1208 (m), 1099 (s), 1028 (m), 749 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 585 (0.3) [M + ], 454 (100), 426 (3), 318 (9), 214 (8), 188 (10), 181 (9), 91 (90), 77 (4), 65 (10); HRMS (ESI-TOF) m/z calcd for +H] + ; found: 586.2597. C36H37F2NO2S + H + : 586.2591 [M+

Alternative procedure to synthesize 13 a (N-alkenylation): A mixture of 10 a (220.7 mg, 0.50 mmol), NaHCO3 (105.2 mg, 1.25 mmol), and sodium dodecyl sulfate (SDS) (6.7 mg) in H2O (3 mL) was heated at 80 8C for 5 min prior to the addition of 4-bromo-1-butene (127 mL, 1.25 mmol). The reaction was heated at the same temperature for 4 h. Additional portions of NaHCO3 (105.2 mg, 1.25 mmol) and 4bromo-1-butene (127 mL, 1.25 mmol) were added at 2 and 4 h. The reaction mixture was stirred at 80 8C for 20 h. Subsequently, it was cooled to room temperature and extracted with EtOAc (3 Õ 15 mL). The combined organic phases were dried over anhydrous Na2SO4. Filtration followed by evaporation gave a crude product, which was purified by column chromatography [SiO2 (Art 7734), 0–20 % EtOAc in hexanes] to give 13 a (134.1 mg, 54 % yield) and recovered 10 a (73.3 mg, 33 % yield). (2 R,3S,4S)-3,4-Bis(benzyloxy)-2-[difluoro(phenylthio)methyl]-1[(E)-4-phenylbut-3-en-1-yl]pyrrolidine (13 b): According to the General Procedure G, reduction of 14 b (117.4 mg, 0.20 mmol) by using Me3SiCl (30 mL, 0.70 mmol), dry CH2Cl2 (0.6 mL), and LiAlH4 (0.15 mL, 0.30 mmol, 2.0 m in THF) at 0 8C for 1.5 h gave 13 b (57.0 mg, 50 % yield, d.r. 78:22 as determined by 1H NMR analysis) as a colorless oil after column chromatography [SiO2 (Art 7734), CH2Cl2/hexanes 1:1]. ½a¤25 D = + 25.9 (c = 1.03 in CHCl3); due to low intensity, only some peaks of the Z-isomer could be detected by 1H and 19F NMR; 1H NMR [500 MHz, CDCl3, determined as a diastereomeric mixture (78:22) of E- and Z-isomers of 13 b]: d = 7.60 (d, J = 7.3 Hz, 2 H; ArH), 7.43–7.23 (m, 17 H; ArH), 7.21–7.15 (m, 1 H; ArH), 6.45 (d, J = 15.9 Hz, 1 H; CH=CHAr), 6.28 (dt, J = 15.9, 6.9 Hz, 1 H; CH=CHAr), 4.61–4.50 (m, 4 H; 2 Õ OCH2), 4.32 (br s, 1 H; OCH), 4.32– 4.29 (m, 1 H; OCH of Z- isomer), 4.02–3.98 (m, 1 H; OCH), 3.98–3.95 (m, 1 H; OCH of Z-isomer), 3.38 (d, J = 10.7 Hz, 1 H; CHH), 3.30 (dt, J = 11.8, 3.9 Hz, 1 H; CH), 3.16 (ddd, J = 12.3, 9.2, 7.1 Hz, 1 H; CHH), 3.08–3.01 (m, 1 H; CHH of Z-isomer), 2.81 (dd, J = 10.7, 5.4 Hz, 1 H; CHH), 2.65 (ddd, J = 12.3, 8.8, 5.4 Hz, 1 H; CHH), 2.52–2.38 ppm (m, 2 H; CH2); 13C NMR [125 MHz, CDCl3, determined as a diastereomeric mixture (78:22) of E- and Z-isomers of 13 b]: d = 138.1 (C), 137.7 (C), 137.6 (C), 136.4 (2 Õ CH), 131.9 (t, J = 280.6 Hz; CF2), 131.0 (CH), 129.4 (CH), 128.8 (2 Õ CH), 128.5 (2 Õ CH), 128.4 (5 Õ CH), 128.3 (CH), 128.2 (C), 127.9 (2 Õ CH), 127.8 (2 Õ CH), 127.7 (CH), 126.9 (CH), 126.0 (2 Õ CH), 85.5 (d, J = 3.8 Hz; CH), 81.2 (CH), 75.1 (dd, J = 25.0, 23.8 Hz; CH), 72.0 (CH2), 71.1 (CH2), 57.2 (CH2), 55.1 (CH2), 31.4 ppm (CH2); 19F NMR [470 MHz, CDCl3, determined as a diastereomeric mixture (78:22) of E- and Z-isomers of 13 b]: d = ¢69.4 (d, J = 209.4 Hz, 1F; CFF of Z-isomer), ¢69.6 (dd, J = 210.2, 11.5 Hz, 1F; CFF), ¢76.0 (d, J = 209.4 Hz, 1F; CFF of Z-isomer), ¢76.1 ppm (d, Chem. Asian J. 2015, 10, 948 – 968

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(2 R,3S,4S)-3,4-Bis(benzyloxy)-2-[difluoro(phenylthio)methyl]-1[(E)-4-(4-fluorophenyl)but-3-en-1-yl]pyrrolidine (13 d): According to the General Procedure G, reduction of 14 d (271.1 mg, 0.45 mmol) by using Me3SiCl (70 mL, 0.55 mmol), dry CH2Cl2 (1.35 mL), and LiAlH4 (0.35 mL, 0.70 mmol, 2.0 m in THF) at 0 8C for 1.5 h gave 13 d (122.1 mg, 46 % yield, d.r. 88:12 as determined by 1 H NMR analysis) as a colorless viscous oil after column chromatography [SiO2 (Art 7734), CH2Cl2/hexanes 1:1]. ½a¤26 D = + 26.7 (c = 1.00 in CHCl3); due to low intensity, only some peaks of the Z-isomer could be detected by 1H NMR; 1H NMR [500 MHz, CDCl3, determined as a diastereomeric mixture (88:12) of E- and Z-isomers of 13 d]: d = 7.63 (d, J = 7.5 Hz, 2 H; ArH), 7.46–7.30 (m, 15 H; ArH), 6.99 (dd, J = 8.7, 8.7 Hz, 2 H; ArH), 6.44 (d, J = 15.9 Hz, 1 H; CH= CHAr), 6.23 (dt, J = 15.9, 6.9 Hz, 1 H; CH=CHAr), 4.64–4.52 (m, 4 H; 2 Õ OCH2), 4.35 (br s, 1 H; OCH), 4.35–4.32 (m, 1 H; OCH of Zisomer), 4.05–4.01 (m, 1 H; OCH), 4.03–4.00 (m, 1 H; OCH of Zisomer), 3.41 (d, J = 10.6 Hz, 1 H; CHH), 3.32 (dt, J = 11.8, 4.1 Hz, 1 H; CH), 3.18 (ddd, J = 12.3, 9.0, 7.3 Hz, 1 H; CHH), 2.83 (dd, J = 10.6, 5.3 Hz, 1 H; CHH), 2.67 (ddd, J = 12.3, 8.5, 5.3 Hz, 1 H; CHH), 2.53– 2.39 ppm (m, 2 H; CH2); 13C NMR [125 MHz, CDCl3, determined as a diastereomeric mixture (88:12) of E- and Z-isomers of 13 d]: d = 162.0 (d, J = 245.0 Hz; C), 138.1 (C), 137.7 (C), 136.4 (2 Õ CH), 133.9 (d, J = 3.8 Hz; C), 132.0 (t, J = 280.6 Hz; CF2), 129.8 (CH), 129.4 (CH), 128.8 (2 Õ CH), 128.4 (4 Õ CH), 128.1 (d, J = 1.3 Hz; CH), 127.9 (2 Õ

960


Full Paper CH), 127.8 (3 Õ CH), 127.7 (CH), 127.4 (d, J = 8.8 Hz; 2 Õ CH), 127.2 (C), 115.3 (d, J = 21.3 Hz; 2 Õ CH), 85.5 (d, J = 3.8 Hz; CH), 81.3 (CH), 75.1 (dd, J = 25.0, 23.8 Hz; CH), 72.1 (CH2), 71.1 (CH2), 57.2 (CH2), 55.1 (CH2), 31.4 ppm (CH2); 19F NMR [470 MHz, CDCl3, determined as a diastereomeric mixture (88:12) of E- and Z-isomers of 13 d]: d = ¢69.5 (dd, J = 209.9, 11.5 Hz, 1F; CFF), ¢76.1 (d, J = 209.9 Hz, 1F; CFF), ¢115.6 ppm (tt, J = 9.0, 4.5 Hz, 1F; ArF); IR (neat): n˜ max = 1508 (s), 1475 (m), 1455 (m), 1441 (m), 1362 (m), 1269 (m), 1227 (s), 1098 (s), 1028 (m), 750 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 589 (0.3) [M + ], 454 (86), 318 (9), 214 (8), 188 (9), 181 (8), 123 (7), 109 (10), 91 (100), 77 (4), 65 (11); HRMS (ESI-TOF) m/z calcd for C35H34F3NO2S + H + : 590.2341 [M+ +H] + ; found: 590.2344.

and minor (cis-15 a) isomers]: d = 7.30–7.17 (m, 20 H; ArH of trans15 a and cis-15 a), 4.58 (d, J = 11.7 Hz, 1 H; OCHH of cis-15 a), 4.57 (d, J = 11.8 Hz, 1 H; OCHH of cis-15 a), 4.56 (d, J = 11.7 Hz, 1 H; OCHH of trans-15 a), 4.55 (dAB, J = 11.9 Hz, 1 H; OCHH of trans-15 a), 4.49–4.41 (obsc, 4 H; 2 Õ OCHH of trans-15 a and cis-15 a), 4.22 (dd, J = 5.8, 5.7 Hz, 1 H; OCH of cis-15 a), 4.20–4.15 (m, 1 H; OCH of cis15 a), 4.15–4.09 (obsc, 2 H; 2 Õ OCH of trans-15 a), 3.54 (dt, J = 23.3, 5.8 Hz, 1 H; CH of cis-15 a), 3.49 (td, J = 12.6, 4,7 Hz, 1 H; CH of trans-15 a), 3.27–3.16 (obsc, 3 H; CHH of trans-15 a, CH2 of cis-15 a), 2.81 [(dd)ABXd, J = 11.1, 7.4, 1.0 Hz, 1 H; CHH of trans-15 a], 2.78 [(dd)ABX, J = 11.1, 7.0 Hz, 1 H; CHH of trans-15 a], 2.64–2.56 (m, 1 H; CHH of trans-15 a), 2.53–2.38 (obsc, 3 H; CH of trans-15 a and cis15 a, CHH of cis-15 a), 2.33 (ddd, J = 11.9, 9.2, 1.5 Hz, 1 H; CHH of cis-15 a), 1.03–0.98 ppm (m, 6 H; CH3 of trans-15 a and cis-15 a); 13 C NMR [125 MHz, CDCl3, determined as a diastereomeric mixture (80:20) of major (trans-15 a) and minor (cis-15 a) isomers]: d = 138.1 (C of cis-15 a), 138.0 (C of trans-15 a), 137.9 (C of trans-15 a and cis15 a), 129.8 (t, J = 253.8 Hz; CF2 of trans-15 a), 128.4 (2 Õ CH of trans-15 a), 128.3 (2 Õ CH of trans-15 a), 127.8 (2 Õ CH of cis-15 a), 127.7 (4 Õ CH of trans-15 a), 127.6 (2 Õ CH of trans-15 a and cis-15 a), 126.2 (t, J = 253.8 Hz; CF2 of cis-15 a), 84.7 (CH of cis-15 a), 84.2 (CH of trans-15 a), 82.3 (dd, J = 5.0, 3.8 Hz; CH of trans-15 a), 80.3 (d, J = 8.8 Hz; CH of cis-15 a), 72.5 (dd, J = 28.5, 22.4 Hz; CH of cis-15 a), 72.3 (dd, J = 29.4, 22.1 Hz; CH of trans-15 a), 72.2 (2 Õ CH2 of cis15 a), 72.1 (2 Õ CH2 of trans-15 a), 59.3 (d, J = 8.8 Hz; CH2 of cis-15 a), 58.2 (dd, J = 5.0, 2.5 Hz; CH2 of trans-15 a), 57.7 (CH2 of trans-15 a), 57.5 (CH2 of cis-15 a), 41.4 (dd, J = 23.8, 22.5 Hz; CH of cis-15 a), 38.9 (dd, J = 22.5, 22.5 Hz; CH of trans-15 a), 11.0 (dd, J = 6.3, 2.5 Hz; CH3 of trans-15 a), 8.4 ppm (d, J = 6.3 Hz; CH3 of cis-15 a); due to overlapping, some carbons of cis-15 a could not be detected by 13C NMR; 19F NMR [470 MHz, CDCl3, determined as a diastereomeric mixture (80:20) of major (trans-15 a) and minor (cis-15 a) isomers]: d = ¢107.4 (dt, J = 229.4, 12.3 Hz, 1F; CFF of trans-15 a), ¢112.2 (dt, J = 229.4, 12.6 Hz, 1F; CFF of trans-15 a), ¢114.1 (d, J = 221.8 Hz, 1F; CFF of cis-15 a), ¢118.8 ppm (dt, J = 221.8, 23.4 Hz, 1F; CFF of cis-15 a); IR (neat): n˜ max = 1497 (m), 1456 (s), 1368 (m), 1207 (m), 1116 (s), 1029 (m), 987 (m), 736 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 374 (6) [M + +H], 373 (2) [M + ], 266 (5), 160 (18), 134 (7), 120 (11), 91 (100), 77 (6), 65 (25); HRMS (ESI-TOF) m/z calcd for C22H25F2NO2 + H + : 374.1932 [M+ +H] + ; found: 374.1935.

General Procedure H for the Intramolecular Radical Cyclization of Pyrrolidines 11, 12, and 13 A solution of 11, 12, or 13 (1.0 mmol) in dry toluene (8 mL) and a solution of AIBN (0.4 mmol) in dry toluene (2 mL) were degassed for 10 min. To the solution of 11, 12, or 13 was added Bu3SnH (1.75 mmol) at reflux followed by the dropwise addition of the solution of AIBN (1 mL). After reflux for 2 h, an additional portion of the solution of AIBN (1 mL) was added dropwise at reflux. After reflux for 16 h, the reaction mixture was cooled to room temperature, quenched with saturated aqueous KF solution (10 mL) and extracted with Et2O (3 Õ 20 mL). The combined organic phases were dried over anhydrous Na2SO4. Filtration followed by evaporation gave a crude product, which was purified by column chromatography (SiO2). (2S,6S,7S,7aR)and (2R,6S,7S,7aR)-6,7-Bis(benzyloxy)-1,1-difluoro-2-methylhexahydro-1H-pyrrolizines (trans-15 a and cis15 a) and (1S,2S,8aR)-1,2-bis(benzyloxy)-8,8-difluorooctahydroindolizine (15 a’): According to the General Procedure H, radical cyclization of 11a (289.1 mg, 0.60 mmol) using Bu3SnH (0.28 mL, 1.06 mmol) and AIBN (1.2 mL, 0.12 mmol, 0.1 m solution in toluene) gave a mixture of trans- and cis-15 a (197.6 mg, 88 % yield, d.r. 89:11 as determined by 19F NMR analysis) and 15 a’ (4.8 mg, 2 % yield) after column chromatography [SiO2 (Art 7734), 0–50 % EtOAc in hexanes]. A mixture of trans- and cis-15 a was partially separated by column chromatography [SiO2 (Art 7734), 10–40 % EtOAc in hexanes] to give a trans-15 a (125.9 mg, 56 % yield).

Compound 15 a’: a light yellow oil; ½a¤24 D = + 7.6 (c = 1.00 in CHCl3); H NMR (500 MHz, CDCl3): d = 7.38–7.25 (m, 10 H; ArH), 4.62 (d, J = 11.5 Hz, 1 H; OCHH), 4.56 (d, J = 12.2 Hz, 1 H; OCHH), 4.49 (d, J = 11.5 Hz, 1 H; OCHH), 4.46 (d, J = 12.2 Hz, 1 H; OCHH), 4.24 (dd, J = 6.7, 1.7 Hz, 1 H; OCH), 3.95–3.90 (m, 1 H; OCH), 3.18 (d, J = 10.2 Hz, 1 H; CHH), 3.04–2.97 (m, 1 H; CHH), 2.56 (ddd, J = 10.2, 5.9, 1.7 Hz, 1 H; CHH), 2.36 (dd, J = 21.7, 6.7 Hz, 1 H; CH), 2.28–2.18 (m, 1 H; CHH), 2.11 (dd, J = 11.7, 11.7 Hz, 1 H; CHH), 1.99–1.86 (m, 1 H; CHH), 1.76–1.55 ppm (m, 2 H; CH2); 13C NMR (125 MHz, CDCl3): d = 138.0 (2 Õ C), 128.4 (4 Õ CH), 128.0 (2 Õ CH), 127.9 (2 Õ CH), 127.7 (2 Õ CH), 119.9 (dd, J = 246.3, 240.0 Hz; CF2), 83.5 (CH), 82.0 (CH), 72.3 (d, J = 2.3 Hz; CH2), 71.7 (dd, J = 28.8, 22.5 Hz; CH), 71.2 (CH2), 58.0 (CH2), 50.8 (CH2), 32.8 (dd, J = 25.0, 21.3 Hz; CH2), 22.1 ppm (d, J = 9.6 Hz; CH2); 19F NMR (470 MHz, CDCl3): d = ¢100.8 (d, J = 235.3 Hz, 1F; CFF), ¢114.9 ppm (dddd, J = 235.3, 33.5, 22.9, 10.0 Hz, 1F; CFF); IR (neat): n˜ max = 2793 (m), 1497 (m), 1455 (m), 1360 (m), 1328 (m), 1289 (m), 1107 (s), 737 (m), 698 cm¢1 (s); MS (70 eV): m/z (%): 374 (6) [M + +H], 267 (7), 237 (3), 190 (9), 176 (7), 161 (98), 140 (19), 120 (43), 91 (100), 77 (5), 65 (17); HRMS (ESI-TOF) m/z calcd for +H] + ; found: 374.1938. C22H25F2NO2 + H + : 374.1932 [M+

Trans-15 a (less polar): a colorless oil; ½a¤23 D = + 60.3 (c = 1.05 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.30–7.18 (m, 10 H; ArH), 4.56 (dAB, J = 11.8 Hz, 1 H; OCHH), 4.55 (d, J = 11.7 Hz, 1 H; OCHH), 4.47 (dAB, J = 11.8 Hz, 1 H; OCHH), 4.44 (d, J = 11.7 Hz, 1 H; OCHH), 4.15– 4.08 (obsc, 2 H; 2 Õ OCH), 3.49 (td, J = 12.5, 4,7 Hz, 1 H; CH), 3.26– 3.20 (m, 1 H; CHH), 2.81 [(dd)ABXd, J = 11.2, 7.5, 1.1 Hz, 1 H; CHH], 2.78 [(dd)ABX, J = 11.2, 7.1 Hz, 1 H; CHH], 2.63–2.56 (m, 1 H; CHH), 2.51–2.38 (m, 1 H; CH), 1.00 ppm (dd, J = 7.0, 1.1 Hz, 3 H; CH3); 13 C NMR (125 MHz, CDCl3): d = 138.0 (C), 137.9 (C), 129.8 (t, J = 253.9 Hz; CF2), 128.4 (2 Õ CH), 128.3 (2 Õ CH), 127.8 (2 Õ CH), 127.7 (2 Õ CH), 127.6 (2 Õ CH), 84.3 (CH), 82.3 (dd, J = 4.9, 3.1 Hz; CH), 72.4 (dd, J = 29.3, 22.3 Hz; CH), 72.3 (CH2), 72.2 (CH2), 58.2 (dd, J = 5.4, 1.8 Hz; CH2), 57.7 (CH2), 38.9 (t, J = 23.1 Hz; CH), 11.0 ppm (dd, J = 6.1, 2.4 Hz; CH3); 19F NMR (376 MHz, CDCl3): d = ¢107.4 (dd, J = 227.2, 21.1 Hz, 1F; CFF), ¢112.4 ppm (dd, J = 227.2, 20.1 Hz, 1F; CFF); IR (neat): n˜ max = 1497 (m), 1455 (m), 1367 (m), 1206 (m), 1097 (s), 1042 (m), 1028 (m), 737 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 374 (47) [M + +H], 373 (4) [M + ], 282 (9), 267 (14), 190 (4), 176 (6), 161 (37), 160 (24), 134 (10), 120 (6), 91 (100), 65 (11); HRMS (ESI+H] + ; found: TOF) m/z calcd for C22H25F2NO2 + H + : 374.1932 [M+ 374.1924. A mixture of trans- and cis-15 a (more polar): a colorless oil; 1 H NMR [500 MHz, CDCl3, integrated equally for major (trans-15 a) Chem. Asian J. 2015, 10, 948 – 968

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(2S,6S,7S,7aR)- and (2R,6S,7S,7aR)-2-Benzyl-6,7-bis(benzyloxy)1,1-difluorohexahydro-1H-pyrrolizines (trans-15 b and cis-15 b): According to the General Procedure H, radical cyclization of 11 b

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Full Paper (335.1 mg, 0.60 mmol) using Bu3SnH (0.28 mL, 1.06 mmol) and AIBN (1.2 mL, 0.12 mmol, 0.1 m solution in toluene) gave a mixture of trans- and cis-15 b (202.4 mg, 75 % yield, d.r. 82:18 as determined by 19F NMR analysis) after column chromatography [SiO2 (Art 7734), 0–50 % EtOAc in hexanes]. A mixture of trans- and cis15 b was partially separated by column chromatography [SiO2 (Art 7736), CHCl3/MeOH/hexanes 2:0.2:7.8] to give a trans-15 b (42.6 mg, 16 % yield).

trans-15 b), 32.0 (d, J = 5.6 Hz; CH2 of trans-15 b), 31.2 ppm (d, J = 5.5 Hz; CH2 of cis-15 b); due to overlapping, some carbons of cis15 a could not be detected by 13C NMR; 19F NMR [470 MHz, CDCl3, determined as a diastereomeric mixture (82:18) of major (trans15 b) and minor (cis-15 b) isomers]: d = ¢107.3 (dABt, J = 231.5, 9.5 Hz, 1F; CFF of trans-15 b), ¢109.1 (dABt, J = 231.5, 14.2 Hz, 1F; CFF of trans-15 b), ¢111.7 (d, J = 223.5 Hz, 1F; CFF of cis-15 b), ¢116.4 ppm (dt, J = 223.5, 23.0 Hz, 1F; CFF of cis-15 b); IR (neat): n˜ max = 1497 (m), 1456 (s), 1367 (m), 1207 (m), 1155 (s), 1100 (s), 1029 (m), 737 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 449 (0.4) [M + ], 252 (14), 236 (29), 91 (100), 65 (28); HRMS (ESI-TOF) m/z calcd for +H] + ; found: 450.2254. C28H29F2NO2 + H + : 450.2245 [M+

Trans-15 b (more polar): a colorless oil; ½a¤24 D = + 35.6 (c = 1.01 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.38–7.18 (m, 13 H; ArH), 7.14–7.11 (m, 2 H; ArH), 4.65 (dAB, J = 11.7 Hz, 1 H; OCHH), 4.57 (d, J = 11.6 Hz, 1 H; OCHH), 4.56 (dAB, J = 11.7 Hz, 1 H; OCHH), 4.47 (d, J = 11.6 Hz, 1 H; OCHH), 4.20 (dd, J = 4.6, 4.6 Hz, 1 H; OCH), 4.18– 4.13 (m, 1 H; OCH), 3.63 (ddd, J = 14.9, 8.9, 4.6 Hz, 1 H; CH), 3.29 (dd, J = 10.5, 5.5 Hz, 1 H; CHH), 3.06–2.94 (obsc, 2 H; 2 Õ CHH), 2.82– 2.69 (obsc, 2 H; CH, CHH), 2.68 (dd, J = 10.5, 6.5 Hz, 1 H; CHH), 2.58 ppm (dd, J = 13.8, 10.0 Hz, 1 H; CHH); 13C NMR (125 MHz, CDCl3): d = 139.0 (C), 137.9 (C), 137.8 (C), 129.6 (dd, J = 255.0, 252.5 Hz; CF2), 128.7 (2 Õ CH), 128.6 (2 Õ CH), 128.5 (2 Õ CH), 128.4 (2 Õ CH), 127.8 (4 Õ CH), 127.7 (2 Õ CH), 126.4 (CH), 84.2 (CH), 82.8 (CH), 73.5 (dd, J = 28.8, 22.5 Hz; CH), 72.2 (CH2), 72.1 (CH2), 58.0 (CH2), 56.2 (d, J = 5.0 Hz; CH2), 45.6 (t, J = 22.5 Hz; CH), 32.0 ppm (d, J = 6.3 Hz; CH2); 19F NMR (470 MHz, CDCl3): d = ¢107.2 (dAB, J = 231.9 Hz, 1F; CFF), ¢109.1 ppm (dAB, J = 231.9 Hz, 1F; CFF); IR (CHCl3): n˜ max = 1497 (m), 1456 (s), 1366 (m), 1271 (m), 1155 (m), 1099 (s), 1029 cm¢1 (s); MS (70 eV): m/z (%): 449 (0.1) [M + ], 430 (1), 358 (3), 343 (5), 342 (4), 252 (15), 237 (19), 236 (23), 208 (7), 196 (9), 91 (100), 65 (17); HRMS (ESI-TOF) m/z calcd for C28H29F2NO2 + H + : +H] + ; found: 450.2247. 450.2245 [M+

(6S,7S,7aR,E)- and (6S,7S,7aR,Z)-6,7-Bis(benzyloxy)-1,1-difluoro-2[(trimethylsilyl)methylene]hexahydro-1H-pyrrolizines (E-15 c and Z-15 c): According to the General Procedure H, radical cyclization of 11 c (220.8 mg, 0.40 mmol) using Bu3SnH (0.19 mL, 0.72 mmol) and AIBN (0.8 mL, 0.08 mmol, 0.1 m solution in toluene) gave an E15 c (89.7 mg, 51 % yield), a mixture of E- and Z-15 c (27.4 mg, 15 % yield, d.r. 63:37 as determined by 19F NMR analysis), and a Z-15 c (12.4 mg, 7 % yield) after column chromatography [SiO2 (Art 7734), 0–30 % EtOAc in hexanes]. E-15 c (less polar): a colorless oil; ½a¤23 D = + 14.5 (c = 1.11 in CHCl3); H NMR (500 MHz, CDCl3): d = 7.43–7.29 (m, 10 H; ArH), 6.27–6.22 (m, 1 H; C=CH), 4.67 (d, J = 11.7 Hz, 1 H; OCHH), 4.64 (dAB, J = 11.8 Hz, 1 H; OCHH), 4.57 (d, J = 11.7 Hz, 1 H; OCHH), 4.56 (dAB, J = 11.8 Hz, 1 H; OCHH), 4.35 (dd, J = 4.7, 4.2 Hz, 1 H; OCH), 4.33–4.27 (m, 1 H; OCH), 3.84 (d, J = 16.0 Hz, 1 H; CHH), 3.58 (ddd, J = 17.5, 8.8, 4.2 Hz, 1 H; CH), 3.48 (d, J = 16.0 Hz, 1 H; CHH), 3.37–3.30 (m, 1 H; CHH), 2.71 (ddd, J = 9.4, 8.1, 3.2 Hz, 1 H; CHH), 0.18 ppm [s, 9 H; Si(CH3)3]; 13C NMR (125 MHz, CDCl3): d = 149.5 (t, J = 22.6 Hz; C), 138.0 (C), 137.7 (C), 128.4 (4 Õ CH), 127.9 (3 Õ CH), 127.7 (4 Õ CH), 121.9 (t, J = 251.2 Hz; CF2), 84.7 (CH), 82.3 (d, J = 5.5 Hz; CH), 72.3 (dd, J = 27.5, 21.3 Hz; CH), 72.2 (2 Õ CH2), 57.4 (CH2), 54.3 (CH2), ¢1.0 ppm (3 Õ CH3); 19F NMR (470 MHz, CDCl3): d = ¢96.0 (dd, J = 244.4, 16.9 Hz, 1F; CFF), ¢104.1 ppm (d, J = 244.4 Hz, 1F; CFF); IR (neat): n˜ max = 1497 (w), 1456 (m), 1366 (m), 1250 (s), 1207 (m), 1156 (m), 1100 (s), 1029 (m), 859 (s), 736 (s), 697 cm¢1 (s); MS (70 eV): m/ z (%): 443 (0.5) [M + ], 423 (3), 352 (13), 317 (8), 230 (10), 211 (9), 170 (7), 91 (100), 77 (12), 65 (24); HRMS (ESI-TOF) m/z calcd for +H] + ; found: 444.2162. C25H31F2NO2Si + H + : 444.2170 [M+

1

A mixture of trans- and cis-15 b (less polar): a colorless oil; 1H NMR [500 MHz, CDCl3, integrated equally for major (trans-15 b) and minor (cis-15 b) isomers]: d = 7.38–7.10 (m, 30 H; ArH of trans-15 b and cis-15 b), 4.66 (d, J = 11.6 Hz, 1 H; OCHH of cis-15 b), 4.65 (dAB, J = 11.7 Hz, 1 H; OCHH of trans-15 b), 4.64 (d, J = 11.5 Hz, 1 H; OCHH of cis-15 b), 4.57 (d, J = 11.6 Hz, 1 H; OCHH of trans-15 b), 4.56 (dAB, J = 11.7 Hz, 1 H; OCHH of trans-15 b), 4.55–4.50 (obsc, 2 H; 2 Õ OCHH of cis-15 b), 4.47 (d, J = 11.6 Hz, 1 H; OCHH of trans-15 b), 4.33 (dd, J = 5.5, 5.5 Hz, 1 H; OCH of cis-15 b), 4.27–4.21 (m, 1 H; OCH of cis15 b), 4.20 (dd, J = 4.7, 4.6 Hz, 1 H; OCH of trans-15 b), 4.18–4.13 (m, 1 H; OCH of trans-15 b), 3.69–3.62 (m, 1 H; CH of cis-15 b), 3.62 (ddd, J = 14.6, 9.1, 4.7 Hz, 1 H; CH of trans-15 b), 3.27 (dd, J = 10.6, 5.5 Hz, 1 H; CHH of trans-15 b), 3.27–3.23 (m, 1 H; CHH of cis-15 b), 3.16 (dd, J = 8.3, 8.2 Hz, 1 H; CH of cis-15 b), 3.06 (dd, J = 13.8, 5.1 Hz, 1 H; CHH of cis-15 b), 3.04–2.92 (obsc, 2 H; 2 Õ CHH of trans15 b), 2.85–2.72 (obsc, 3 H; CH and CHH of trans-15 b, CHH of cis15 b), 2.72–2.63 (obsc, 2 H; CHH of trans-15 b and cis-15 b), 2.63– 2.50 ppm (obsc, 3 H; CHH of trans-15 b, 2 Õ CHH of cis-15 b); 13 C NMR [125 MHz, CDCl3, determined as a diastereomeric mixture (82:18) of major (trans-15 b) and minor (cis-15 b) isomers]: d = 139.0 (C of trans-15 b and cis-15 b), 138.8 (C of cis-15 b), 138.1 (C of cis-15 b), 137.9 (C of trans-15 b), 137.8 (C of trans-15 b), 129.7 (dd, J = 256.4, 252.4 Hz; CF2 of trans-15 b), 128.7 (2 Õ CH of trans-15 b), 128.6 (2 Õ CH of cis-15 b), 128.5 (2 Õ CH of trans-15 b), 128.4 (2 Õ CH of trans-15 b), 128.3 (2 Õ CH of trans-15 b), 127.8 (2 Õ CH of trans15 b and cis-15 b), 127.7 (2 Õ CH of trans-15 b), 127.6 (2 Õ CH of trans-15 b), 126.4 (CH of cis-15 b), 126.3 (CH of trans-15 b), 126.1 (t, J = 254.9 Hz; CF2 of cis-15 b), 84.7 (CH of cis-15 b), 84.2 (CH of trans15 b), 82.8 (t, J = 4.2 Hz; CH of trans-15 b), 80.5 (d, J = 8.4 Hz; CH of cis-15 b), 73.5 (dd, J = 28.9, 22.6 Hz; CH of trans-15 b), 73.0 (dd, J = 28.3, 21.9 Hz; CH of cis-15 b), 72.2 (2 Õ CH2 of cis-15 b), 72.1 (2 Õ CH2 of trans-15 b), 58.0 (CH2 of trans-15 b), 57.9 (d, J = 8.0 Hz; CH2 of cis-15 b), 57.5 (CH2 of cis-15 b), 56.2 (d, J = 6.0 Hz; CH2 of trans15 b), 48.3 (t, J = 22.0 Hz; CH of cis-15 b), 45.6 (t, J = 22.1 Hz; CH of Chem. Asian J. 2015, 10, 948 – 968

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Z-15 c (more polar): a colorless oil; ½a¤21 D = + 48.0 (c = 1.17 in CHCl3); H NMR (500 MHz, CDCl3): d = 7.42–7.29 (m, 10 H; ArH), 5.97–5.93 (m, 1 H; C=CH), 4.66 (d, J = 11.7 Hz, 1 H; OCHH), 4.62 (dAB, J = 11.8 Hz, 1 H; OCHH), 4.56 (d, J = 11.7 Hz, 1 H; OCHH), 4.55 (dAB, J = 11.8 Hz, 1 H; OCHH), 4.37 (dd, J = 4.5, 4.0 Hz, 1 H; OCH), 4.32–4.26 (m, 1 H; OCH), 3.81 (dd, J = 16.1, 1.8 Hz, 1 H; CHH), 3.63 (ddd, J = 17.2, 9.8, 4.0 Hz, 1 H; CH), 3.48 (d, J = 16.1 Hz, 1 H; CHH), 3.33–3.27 (m, 1 H; CHH), 2.71 (ddd, J = 9.4, 8.2, 3.4 Hz, 1 H; CHH), 0.21 ppm [s, 9 H; Si(CH3)3]; 13C NMR (125 MHz, CDCl3): d = 149.2 (t, J = 22.5 Hz; C), 138.1 (C), 137.8 (C), 131.7 (d, J = 1.3 Hz; CH), 128.4 (4 Õ CH), 127.9 (2 Õ CH), 127.8 (3 Õ CH), 127.7 (CH), 123.4 (t, J = 251.9 Hz; CF2), 84.8 (CH), 82.6 (d, J = 5.0 Hz; CH), 74.1 (dd, J = 28.4, 21.8 Hz; CH), 72.2 (2 Õ CH2), 58.0 (t, J = 3.8 Hz; CH2), 57.2 (CH2), ¢0.2 ppm (3 Õ CH3); 19F NMR (470 MHz, CDCl3): d = ¢93.5 (dd, J = 250.3, 16.5 Hz, 1F; CFF), ¢99.8 ppm (dd, J = 250.3, 9.4 Hz, 1F; CFF); IR (neat): n˜ max = 1497 (m), 1456 (m), 1366 (m), 1250 (s), 1189 (m), 1099 (s), 1029 (m), 847 (s), 735 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 443 (0.4) [M + ], 422 (2), 352 (10), 316 (12), 230 (12), 211 (8), 188 (9), 170 (8), 91 (100), 77 (14), 65 (30); HRMS (ESI-TOF) m/z calcd for +H] + ; found: 444.2172. C25H31F2NO2Si + H + : 444.2170 [M+ 1

(2S,5S,6S,7S,7aR)- and (2R,5S,6S,7S,7aR)-6,7-Bis(benzyloxy)-5[(benzyloxy)methyl]-1,1-difluoro-2-methylhexahydro-1H-pyrrolizines (trans-15 d and cis-15 d): According to the General Proce-

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Full Paper dure H, radical cyclization of 12 a (237.4 mg, 0.39 mmol) using Bu3SnH (0.19 mL, 0.72 mmol) and AIBN (0.8 mL, 0.08 mmol, 0.1 m solution in toluene) gave trans-15 d (107.0 mg, 56 % yield), a mixture of trans- and cis-15 d (38.3 mg, 20 % yield, d.r. 24:76 as determined by 19F NMR analysis), and cis-15 d (20.3 mg, 11 % yield) after column chromatography [SiO2 (Art 7734), 0–20 % EtOAc in hexanes].

(d, J = 12.2 Hz, 1 H; OCHH), 4.17 (dd, J = 6.1, 5.4 Hz, 1 H; OCH), 3.96 (dd, J = 7.7, 6.1 Hz, 1 H; OCH), 3.66–3.57 (m, 1 H; CH), 3.44 (dd, J = 9.7, 3.8 Hz, 1 H; CHH), 3.35 (dd, J = 9.7, 6.0 Hz, 1 H; CHH), 2.95 (dd, J = 13.2, 4.1 Hz, 1 H; CHH), 2.94 (dd, J = 12.4, 8.4 Hz, 1 H; CHH), 2.90–2.85 (m, 1 H; CH), 2.84 (dd, J = 12.4, 7.1 Hz, 1 H; CHH), 2.66– 2.54 (m, 1 H; CH), 2.53 ppm (dd, J = 13.2, 10.2 Hz, 1 H; CHH); 13 C NMR (125 MHz, CDCl3): d = 139.0 (C), 138.2 (C), 138.1 (C), 137.8 (C), 129.7 (t, J = 253.8 Hz; CF2), 128.7 (2 Õ CH), 128.5 (2 Õ CH), 128.4 (2 Õ CH), 128.3 (4 Õ CH), 127.8 (4 Õ CH), 127.7 (CH), 127.6 (CH), 127.5 (2 Õ CH), 127.4 (CH), 126.4 (CH), 84.7 (CH), 82.6 (CH), 73.3 (CH2), 72.6 (CH2), 72.3 (dd, J = 22.5, 7.5 Hz; CH), 72.2 (CH2), 71.4 (CH2), 67.9 (CH), 55.4 (d, J = 5.0 Hz; CH2), 45.7 (t, J = 21.9 Hz; CH), 32.0 ppm (d, J = 5.0 Hz; CH2); 19F NMR (470 MHz, CDCl3): d = ¢107.1 (d, J = 231.0 Hz, 1F; CFF), ¢110.0 ppm (dt, J = 231.0, 12.9 Hz, 1F; CFF); IR (CHCl3): n˜ max = 1497 (m), 1455 (s), 1366 (m), 1101 (s), 1028 cm¢1 (s); MS (70 eV): m/z (%): 569 (3) [M + ], 447 (73), 356 (12), 342 (18), 328 (30), 266 (30), 250 (34), 210 (16), 196 (19), 181 (19), 159 (12), 91 (100), 65 (25); HRMS (ESI-TOF) m/z calcd for C36H37F2NO3 + H + : +H] + ; found: 570.2819. 570.2820 [M+

Trans-15 d (less polar): a colorless oil; ½a¤24 D = + 45.2 (c = 1.02 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.46–7.20 (m, 15 H; ArH), 4.74 (d, J = 11.5 Hz, 1 H; OCHH), 4.68 (d, J = 11.7 Hz, 1 H; OCHH), 4.60– 4.53 (obsc, 3 H; OCHH, OCH2), 4.52 (d, J = 11.7 Hz, 1 H; OCHH), 4.29 (dd, J = 6.7, 6.0 Hz, 1 H; OCH), 4.06 (dd, J = 7.4, 6.7 Hz, 1 H; OCH), 3.69 (br s, 1 H; CH), 3.63 (dd, J = 9.7, 3.4 Hz, 1 H; CHH), 3.52 (br s, 1 H; CHH), 3.13–2.91 (obsc, 3 H; CH2, CH), 2.58–2.45 (m, 1 H; CH), 1.14 ppm (d, J = 7.0 Hz, 3 H; CH3); 13C NMR (125 MHz, CDCl3): d = 138.2 (C), 138.1 (C), 137.8 (C), 129.7 (t, J = 245.5 Hz; CF2), 128.4 (2 Õ CH), 128.3 (4 Õ CH), 127.9 (2 Õ CH), 127.8 (2 Õ CH), 127.7 (2 Õ CH), 127.6 (2 Õ CH), 127.5 (CH), 84.6 (CH), 82.1 (CH), 73.4 (CH2), 72.8 (CH2), 72.3 (CH2), 71.6 (CH2), 71.3 (dd, J = 30.0, 22.5 Hz; CH), 67.9 (CH), 57.6 (d, J = 3.8 Hz; CH2), 38.9 (dd, J = 23.1, 23.1 Hz; CH), 11.1 ppm (dd, J = 5.6, 3.1 Hz; CH3); 19F NMR (470 MHz, CDCl3): d = ¢107.9 (d, J = 228.4 Hz, 1F; CFF), ¢113.3 ppm (dt, J = 228.4, 12.2 Hz, 1F; CFF); IR (neat): n˜ max = 1497 (m), 1455 (s), 1367 (s), 1304 (m), 1204 (s), 1115 (s), 1097 (s), 1063 (s), 1028 (s), 736 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 494 (1) [M + +H], 372 (26), 266 (10), 252 (25), 190 (11), 181 (14), 174 (17), 134 (19), 91 (100), 65 (29); HRMS +H] + ; found: (ESI-TOF) m/z calcd for C30H33F2NO3 + H + : 494.2507 [M+ 494.2515.

Cis-15 e (more polar): a colorless oil; ½a¤23 D = ¢42.2 (c = 0.90 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.31–7.27 (m, 4 H; ArH), 7.27– 7.13 (m, 14 H; ArH), 7.13–7.09 (m, 2 H; ArH), 4.67 (d, J = 11.5 Hz, 1 H; OCHH), 4.57 (d, J = 11.6 Hz, 1 H; OCHH), 4.46 (d, J = 11.5 Hz, 1 H; OCHH), 4.44 (dAB, J = 12.1 Hz, 1 H; OCHH), 4.39 (d, J = 11.6 Hz, 1 H; OCHH), 4.37 (dAB, J = 12.1 Hz, 1 H; OCHH), 4.29 (dd, J = 7.2, 6.7 Hz, 1 H; OCH), 4.03 (dd, J = 8.2, 7.2 Hz, 1 H; OCH), 3.63 (br d, J = 23.9 Hz, 1 H; CH), 3.46 (dd, J = 10.3, 3.1 Hz, 1 H; CHH), 3.33 (dd, J = 8.7, 5.9 Hz, 1 H; CHH), 3.27 (dd, J = 8.7, 8.3 Hz, 1 H; CHH), 3.01 (dd, J = 13.8, 5.2 Hz 1 H; CHH), 2.88–2.71 (obsc, 2 H; 2 Õ CH), 2.61 (dd, J = 13.8, 9.6 Hz, 1 H; CHH), 2.46 ppm (dd, J = 10.3, 10.3 Hz, 1 H; CHH); 13 C NMR (125 MHz, CDCl3): d = 138.8 (C), 138.3 (C), 138.2 (C), 137.8 (C), 128.6 (2 Õ CH), 128.5 (2 Õ CH), 128.4 (2 Õ CH), 128.3 (2 Õ CH), 128.2 (2 Õ CH), 127.9 (2 Õ CH), 127.8 (2 Õ CH), 127.7 (CH), 127.6 (CH), 127.5 (2 Õ CH), 127.4 (CH), 126.4 (CH), 125.8 (t, J = 255.0 Hz; CF2), 85.0 (CH), 80.5 (d, J = 7.5 Hz; CH), 73.3 (CH2), 72.8 (CH2), 72.3 (CH2), 71.7 (dd, J = 28.8, 22.5 Hz; CH), 70.9 (CH2), 68.8 (CH), 58.0 (d, J = 7.5 Hz; CH2), 48.1 (t, J = 21.3 Hz; CH), 31.2 ppm (d, J = 5.0 Hz; CH2); 19 F NMR (470 MHz, CDCl3): d = ¢114.5 (d, J = 221.8 Hz, 1F; CFF), ¢118.0 ppm (d, J = 221.8 Hz, 1F; CFF); IR (neat): n˜ max = 1497 (m), 1455 (s), 1371 (m), 1214 (m), 1114 (s), 1068 (s), 1028 (m), 736 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 570 (0.5) [M + +H], 448 (48), 447 (61), 356 (11), 342 (12), 328 (31), 266 (44), 250 (19), 210 (18), 181 (12), 91 (100), 65 (19); HRMS (ESI-TOF) m/z calcd for C36H37F2NO3 + +H] + ; found: 570.2829. H + : 570.2820 [M+

Cis-15 d (more polar): a colorless oil; ½a¤24 D = + 13.6 (c = 0.61 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.40–7.23 (m, 13 H; ArH), 7.23–7.15 (m, 2 H; ArH), 4.74 (d, J = 11.5 Hz, 1 H; OCHH), 4.65 (d, J = 11.6 Hz, 1 H; OCHH), 4.55 (dAB, J = 12.1 Hz, 1 H; OCHH), 4.53 (d, J = 11.5 Hz, 1 H; OCHH), 4.50 (dAB, J = 12.1 Hz, 1 H; OCHH), 4.46 (d, J = 11.6 Hz, 1 H; OCHH), 4.34 (dd, J = 7.4, 6.7 Hz, 1 H; OCH), 4.11 (dd, J = 8.0, 7.4 Hz, 1 H; OCH), 3.70 (br d, J = 23.5 Hz, 1 H; CH), 3.57 (dd, J = 9.8, 3.0 Hz, 1 H; CHH), 3.51–3.39 (obsc, 2 H; CHH, CHH), 2.95–2.86 (m, 1 H; CH), 2.71–2.54 (m, 1 H; CH), 2.42 (dd, J = 11.1, 10.4 Hz, 1 H; CHH), 1.10 ppm (d, J = 6.7 Hz, 3 H; CH3); 13C NMR (125 MHz, CDCl3): d = 138.2 (C), 138.1 (C), 137.6 (C), 128.4 (2 Õ CH), 128.3 (5 Õ CH), 128.0 (2 Õ CH), 127.8 (3 Õ CH), 127.7 (2 Õ CH), 127.6 (CH), 125.8 (t, J = 256.3 Hz; CF2), 84.8 (CH), 80.2 (CH), 73.4 (CH2), 72.9 (CH2), 72.4 (CH2), 71.3 (dd, J = 25.6, 25.6 Hz; CH), 70.6 (br s; CH2), 68.9 (CH), 59.4 (d, J = 7.5 Hz; CH2), 41.1 (t, J = 22.5 Hz; CH), 8.3 ppm (CH3); 19 F NMR (470 MHz, CDCl3): d = ¢116.6 (d, J = 219.0 Hz, 1F; CFF), ¢120.2 ppm (br d, J = 219.0 Hz, 1F; CFF); IR (neat): n˜ max = 1497 (m), 1455 (s), 1369 (s), 1232 (s), 1152 (s), 1118 (s), 1067 (s), 1028 (s), 737 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 493 (0.4) [M + ], 372 (47), 266 (11), 252 (24), 181 (16), 134 (23), 91 (100), 77 (9), 65 (33); HRMS +H] + ; found: (ESI-TOF) m/z calcd for C30H33F2NO3 + H + : 494.2507 [M+ 494.2520.

A mixture of (5S,6S,7S,7aR,E)- and (5S,6S,7S,7aR,Z)-6,7-Bis(benzyloxy)-5-[(benzyloxy)methyl]-1,1-difluoro-2-[(trimethylsilyl)methylene]hexahydro-1H-pyrrolizines (E-15 f and Z-15 f): According to the General Procedure H, radical cyclization of 12 c (265.5 mg, 0.40 mmol) using Bu3SnH (0.19 mL, 0.72 mmol) and AIBN (0.8 mL, 0.08 mmol, 0.1 m solution in toluene) gave a mixture of E- and Z15 f (169.1 mg, 75 % yield, d.r. 85:15 as determined by 19F NMR analysis) as a yellow oil after column chromatography [SiO2 (Art 7734), 0–20 % EtOAc in hexanes]. 1H NMR [500 MHz, CDCl3, integrated equally for major (E-15 f) and minor (Z-15 f) isomers]: d = 7.45–7.25 (m, 30 H; ArH of E-15 f and Z-15 f), 6.23–6.19 (m, 1 H; C= CH of E-15 f), 5.96–6.93 (m, 1 H; C=CH of Z-15 f), 4.72 (d, J = 11.7 Hz, 1 H; OCHH of E-15 f), 4.70 (d, J = 11.6 Hz, 1 H; OCHH of Z15 f), 4.69 (d, J = 11.7 Hz, 1 H; OCHH of E-15 f), 4.68 (d, J = 11.7 Hz, 1 H; OCHH of Z-15 f), 4.61–4.48 (obsc, 8 H; 2 Õ OCHH of E-15 f and Z-15f, OCH2 of E-15 f and Z-15 f), 4.42 (dd, J = 5.6, 4.1 Hz, 1 H; OCH of Z-15 f), 4.40 (dd, J = 5.8, 4.3 Hz, 1 H; OCH of E-15 f), 4.11–4.04 (obsc, 2 H; OCH of E-15 f and Z-15 f), 3.90 (d, J = 16.2 Hz, 1 H; CHH of E-15 f), 3.90–3.85 (m, 1 H; CHH of Z-15 f), 3.79–3.61 (obsc, 6 H;

(2S,5S,6S,7S,7aR)- and (2R,5S,6S,7S,7aR)-2-Benzyl-6,7-bis(benzyloxy)-5-[(benzyloxy)methyl]-1,1-difluorohexahydro-1H-pyrrolizines (trans-15 e and cis-15 e): According to the General Procedure H, radical cyclization of 12 b (208.9 mg, 0.31 mmol) using Bu3SnH (0.14 mL, 0.53 mmol) and AIBN (0.6 mL, 0.06 mmol, 0.1 m solution in toluene) gave a trans-15 e (42.6 mg, 24 % yield), a mixture of trans- and cis-15 e (94.0 mg, 53 % yield, d.r. 60:40 as determined by 19 F NMR analysis), and a cis-15 e (18.0 mg, 10 % yield) after column chromatography [SiO2 (Art 7734), 0–20 % Et2O in hexanes]. Trans-15 e (less polar): a colorless oil; ½a¤24 D = + 24.6 (c = 1.04 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.29–7.06 (m, 20 H; ArH), 4.60 (d, J = 11.5 Hz, 1 H; OCHH), 4.57 (d, J = 11.6 Hz, 1 H; OCHH), 4.46– 4.42 (obsc, 2 H; OCHH, OCHH), 4.42 (d, J = 11.6 Hz, 1 H; OCHH), 4.38 Chem. Asian J. 2015, 10, 948 – 968

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Full Paper (CHCl3): n˜ max = 2807 (m), 1497 (w), 1456 (m), 1375 (m), 1250 (s), 1154 (m), 1125 (m), 1097 (m), 1047 (m), 699 cm¢1 (m); MS (70 eV): m/z (%): 388 (0.5) [M + +H], 281 (5), 204 (6), 175 (32), 174 (31), 148 (8), 134 (22), 91 (100), 77 (16), 65 (31); HRMS (ESI-TOF) m/z calcd +H] + ; found: 388.2080. for C23H27F2NO2 + H + : 388.2088 [M+

CHH of E-15 f and Z-15 f, CHH of E-15 f and Z-15 f, CH of E-15 f and Z-15 f), 3.55 (dd, J = 9.6, 6.5 Hz, 1 H; CHH of E-15 f), 3.54–3.50 (m, 1 H; CHH of Z-15 f), 3.08–3.01 (obsc, 2 H; CH of E-15 f and Z15 f), 0.22 [s, 9 H; Si(CH3)3 of Z-15 f], 0.16 ppm [s, 9 H; Si(CH3)3 of E15 f]; 13C NMR [125 MHz, CDCl3, determined as a diastereomeric mixture (85:15) of major (E-15 f) and minor (Z-15 f) isomers]: d = 149.5 (t, J = 21.9 Hz; C of E-15 f), 149.2 (t, J = 21.8 Hz; C of Z-15 f), 138.2 (2 Õ C of E-15 f and Z-15 f), 138.1 (2 Õ C of E-15 f and Z-15 f), 137.7 (C of Z-15 f), 137.6 (C of E-15 f), 131.2 (CH of Z-15 f), 128.4 (2 Õ CH of E-15 f), 128.3 (2 Õ CH of Z-15 f), 128.2 (4 Õ CH of E-15 f), 128.1 (CH of Z-15 f), 128.0 (2 Õ CH of E-15 f), 127.9 (2 Õ CH of Z-15 f), 127.8 (3 Õ CH of E-15 f), 127.7 (2 Õ CH of Z-15 f), 127.6 (3 Õ CH of E15 f), 127.5 (CH of E-15 f), 127.4 (CH of E-15 f), 123.2 (t, J = 251.9 Hz; CF2 of Z-15 f), 121.7 (t, J = 251.3 Hz; CF2 of E-15 f), 85.3 (CH of Z-15 f), 85.1 (CH of E-15 f), 81.6 (d, J = 6.3 Hz; CH of Z-15 f), 81.3 (d, J = 5.0 Hz; CH of E-15 f), 73.3 (CH2 of E-15 f and Z-15 f), 73.2 (dd, J = 28.8, 22.5 Hz; CH of Z-15 f), 72.6 (CH2 of E-15f), 72.5 (CH2 of Z-15 f), 72.2 (CH2 of E-15 f and Z-15 f), 71.8 (CH2 of E-15 f), 71.3 (dd, J = 27.5, 22.5 Hz; CH of E-15 f), 71.2 (CH2 of Z-15 f), 67.0 (CH of Z-15 f), 66.9 (CH of E-15 f), 57.6 (CH2 of Z-15 f), 53.8 (CH2 of E-15 f), ¢0.2 (3 Õ CH3 of Z-15 f), ¢1.0 ppm (3 Õ CH3 of E-15 f); 19 F NMR [470 MHz, CDCl3, determined as a diastereomeric mixture (85:15) of major (E-15 f) and minor (Z-15 f) isomers]: d = ¢94.2 (dd, J = 248.0, 18.6 Hz, 1F; CFF of Z-15 f), ¢96.1 (dd, J = 241.6, 19.7 Hz, 1F; CFF of E-15 f), ¢103.7 (d, J = 248.0 Hz, 1F; CFF of Z-15 f), ¢108.9 ppm (d, J = 241.6 Hz, 1F; CFF of E-15 f); IR (neat): n˜ max = 1497 (m), 1455 (m), 1367 (m), 1301 (m), 1250 (m), 1208 (m), 1103 (s), 1028 (m), 860 (s), 841 (s), 736 (s), 697 cm¢1 (s); MS (70 eV): m/z (%): 564 (2) [M + +H], 563 (1) [M + ], 442 (46), 350 (7), 336 (15), 322 (20), 294 (5), 260 (12), 244 (14), 243 (16), 204 (11), 181 (12), 166 (7), 91 (100), 77 (12), 65 (23); HRMS (ESI-TOF) m/z calcd for +Na] + ; found: 586.2562. C33H39F2NO3Si + Na + : 586.2565 [M+

A mixture of 16 a’ and cis-16 a (less polar): a colorless oil; 1H NMR [400 MHz, CDCl3, integrated equally for major (cis-16 a) and minor (16 a’)]: d = 7.30–7.17 (m, 20 H; ArH of cis-16 a and 16 a’), 4.57–4.46 (obsc, 4 H; 2 Õ OCHH of cis-16 a and 16 a’), 4.44–4.32 (obsc, 4 H; 2 Õ OCHH of cis-16 a and 16 a’), 4.29 (br s, 1 H; OCH of 16 a’), 4.18 (d, J = 6.66 Hz, 1 H; OCH of cis-16 a), 3.87 (d, J = 5.9 Hz, 1 H; OCH of cis16 a), 3.76 (d, J = 4.0 Hz, 1 H; OCH of 16 a’), 3.13 (d, J = 10.6 Hz, 1 H; CHH of 16 a’), 3.09 (d, J = 10.1 Hz, 1 H; CHH of cis-16 a), 3.09–3.03 (m, 1 H; CHH of 16 a’), 2.95–2.82 (obsc, 2 H; CHH of cis-16 a, CH of 16 a’), 2.75–2.67 (m, 1 H; CHH of 16 a’), 2.48 (dd, J = 10.1, 5.9 Hz, 1 H; CHH of cis-16 a), 2.38–2.28 (m, 1 H; CHH of 16 a’), 2.27 (dd, J = 21.9, 6.6 Hz, 1 H; CH of cis-16 a), 2.23–2.12 (m, 2 H; CH2 of 16 a’), 2.08 (ddd, J = 11.0, 11.0, 3.6 Hz, 1 H; CHH of cis-16 a), 1.85–1.40 (obsc, 7 H; CH of cis-16 a, CH2 of cis-16 a, 2 Õ CH2 of 16 a’), 1.03 ppm (d, J = 6.5 Hz, 3 H; CH3 of cis-16 a); 13C NMR [100 MHz, CDCl3, determined as a mixture (10:90) of 16 a’ and cis-16 a]: d = 138.0 (2 Õ C of cis-16 a), 128.4 (4 Õ CH of 16 a’), 128.3 (4 Õ CH of cis-16 a), 128.0 (2 Õ CH of cis-16 a and 16 a’), 127.8 (2 Õ CH of cis-16 a), 127.7 (2 Õ CH of cis-16 a, 2 Õ CH of 16 a’), 120.4 (dd, J = 249.9, 241.5 Hz; CF2 of cis16 a), 83.5 (CH of cis-16 a), 82.8 (CH of 16 a’), 82.3 (CH of cis-16 a), 80.1 (CH of 16 a’), 72.3 (d, J = 1.7 Hz; CH2 of cis-16 a), 72.0 (dd, J = 28.6, 24.7 Hz; CH of cis-16 a), 71.4 (CH2 of 16 a’), 71.2 (CH2 of cis16 a), 70.8 (CH2 of 16 a’), 60.7 (CH2 of 16 a’), 57.8 (CH2 of cis-16 a), 57.3 (CH2 of 16 a’), 50.9 (CH2 of cis-16 a), 37.7 (t, J = 22.2 Hz; CH of cis-16 a), 30.5 (d, J = 4.8 Hz; CH2 of cis-16 a), 20.7 (dd, J = 8.4, 3.2 Hz; CH2 of 16 a’), 11.8 ppm (dd, J = 4.3, 2.4 Hz; CH3 of cis-16 a); due to low intensity, only some peaks of 16 a’ could be detected by 13 C NMR; 19F NMR [376 MHz, CDCl3, determined as a mixture (10:90) of 16 a’ and cis-16 a]: d = ¢91.9 (dt, J = 241.2, 25.9 Hz, 1F; CFF of 16 a’), ¢99.0 (d, J = 241.2 Hz, 1F; CFF of 16 a’), ¢110.2 (d, J = 235.8 Hz, 1F; CFF of cis-16 a), ¢129.1 ppm (dt, J = 235.8, 29.0 Hz, 1F; CFF of cis-16 a); IR (CHCl3): n˜ max = 2801 (m), 1497 (m), 1465 (m), 1456 (s), 1372 (m), 1328 (m), 1246 (m), 1177 (m), 1101 (s), 1028 (m), 699 cm¢1 (s); MS (70 eV): m/z (%): 388 (1) [M + +H], 387 (0.6) [M + ], 296 (3), 281 (6), 251 (2), 204 (4), 190 (4), 175 (42), 148 (7), 134 (21), 118 (5), 91 (100), 77 (15), 65 (29); HRMS (ESI-TOF) m/z calcd for C23H27F2NO2 + H + : 388.2088 [M+ +H] + ; found: 388.2089.

(1S,2S,7R,8aR)and (1S,2S,7S,8aR)-1,2-Bis(benzyloxy)-8,8-difluoro-7-methyloctahydroindolizines (cis-16 a and trans-16 a) and (1S,2S,9aR)-1,2-bis(benzyloxy)-9,9-difluorooctahydro-1H-pyrrolo[1,2-a]azepine (16 a’): According to the General Procedure H, radical cyclization of 13a (247.8 mg, 0.50 mmol) using Bu3SnH (0.23 mL, 0.87 mmol) and AIBN (1.0 mL, 0.1 mmol, 0.1 m solution in toluene) gave a mixture of cis-16 a, trans-16 a, and 16 a’ (152.0 mg, 78 % yield, d.r. 59:31:10) and recovered 13a (39.6 mg, 16 % yield) after column chromatography [SiO2 (Art 7734), 0–30 % EtOAc in hexanes]. Separation by column chromatography [SiO2 (Art 7734), CH2Cl2/EtOAc/hexanes 3:1:6] gave pure 16 a’ (3.9 mg, 2 % yield) and pure trans-16 a (23.8 mg, 12 % yield), each as a colorless oil, together with a mixture of 16 a’ and cis-16 a (43.0 mg, 22 % yield, d.r. 7:93 as determined by 19F NMR analysis), a mixture of 16 a’, cis16 a, and trans-16 a (22.5 mg, 12 % yield, d.r. 2:91:7 as determined by 19F NMR analysis), and a mixture of cis-16 a and trans-16 a (55.1 mg, 28 % yield, d.r. 47:53 as determined by 19F NMR analysis).

(1S,2S,7 R,8 aR)- and (1S,2S,7S,8 aR)-7-Benzyl-1,2-bis(benzyloxy)8,8-difluorooctahydroindolizines (cis-16 b and trans-16 b): According to the General Procedure H, radical cyclization of 13 b (158.0 mg, 0.28 mmol, d.r. 78:22) using Bu3SnH (0.13 mL, 0.49 mmol) and AIBN (0.56 mL, 56 mmol, 0.1 m solution in toluene) gave cis-16 b (48.0 mg, 37 % yield), a mixture of cis- and trans-16 b (10.3 mg, 8 % yield, d.r. 43:57 as determined by 19F NMR analysis), and trans-16 b (30.7 mg, 24 % yield) after column chromatography [SiO2 (Art 7734), 0–20 % EtOAc in hexanes].

Trans-16 a (more polar): a colorless oil; ½a¤22 D = + 25.8 (c = 0.33 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.30–7.18 (m, 10 H; ArH), 4.54 (d, J = 11.5 Hz, 1 H; OCHH), 4.49 (d, J = 12.3 Hz, 1 H; OCHH), 4.42 (d, J = 11.5 Hz, 1 H; OCHH), 4.38 (d, J = 12.3 Hz, 1 H; OCHH), 4.17 (d, J = 6.7 Hz, 1 H; OCH), 3.88 (d, J = 5.7 Hz, 1 H; OCH), 3.09 (d, J = 10.4 Hz, 1 H; CHH), 2.73 (br d, J = 11.6 Hz, 1 H; CHH), 2.60–2.46 (obsc, 2 H; CHH, CH), 2.39–2.22 (obsc, 2 H; CHH, CH), 2.16–2.05 (m, 1 H; CHH), 1.43 (d, J = 13.2 Hz, 1 H; CHH), 1.03 ppm (d, J = 7.4 Hz, 3 H; CH3); 13 C NMR (125 MHz, CDCl3): d = 138.0 (2 Õ C), 128.3 (4 Õ CH), 128.0 (2 Õ CH), 127.9 (2 Õ CH), 127.7 (2 Õ CH), 121.7 (t, J = 245.5 Hz; CF2), 83.5 (CH), 82.3 (CH), 72.3 (CH2), 71.3 (CH2), 66.7 (t, J = 25.9 Hz; CH), 57.8 (CH2), 45.8 (CH2), 34.9 (t, J = 22.2 Hz; CH), 28.7 (CH2), 13.3 ppm (t, J = 6.0 Hz; CH3); 19F NMR (470 MHz, CDCl3): d = ¢109.2 (dAB, J = 239.2 Hz, 1F; CFF), ¢109.5 ppm (dAB, J = 239.2 Hz, 1F; CFF); IR Chem. Asian J. 2015, 10, 948 – 968

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Cis-16 b (less polar): a colorless oil; ½a¤26 D = + 25.8 (c = 1.02 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.31–7.20 (m, 12 H; ArH), 7.15 (t, J = 7.4 Hz, 1 H; ArH), 7.11 (d, J = 7.2 Hz, 2 H; ArH), 4.57 (d, J = 11.4 Hz, 1 H; OCHH), 4.51 (d, J = 12.3 Hz, 1 H; OCHH), 4.44 (d, J = 11.4 Hz, 1 H; OCHH), 4.40 (d, J = 12.3 Hz, 1 H; OCHH), 4.22 (d, J = 6.2 Hz, 1 H; OCH), 3.88 (d, J = 5.9 Hz, 1 H; OCH), 3.22 (dd, J = 13.6, 3.1 Hz, 1 H; CHH), 3.09 (d, J = 10.1 Hz, 1 H; CHH), 2.91–2.85 (m, 1 H; CHH), 2.47 (dd, J = 10.1, 5.9 Hz, 1 H; CHH), 2.40 (dd, J = 13.6, 10.8 Hz, 1 H; CHH), 2.31 (dd, J = 21.8, 6.2 Hz, 1 H; CH), 1.96 (dd, J = 11.5, 11.5 Hz, 1 H; CHH), 1.94–1.80 (m, 1 H; CH), 1.64–1.48 ppm (m, 2 H; CH2); 13C NMR (125 MHz, CDCl3): d = 139.4 (C), 138.0 (2 Õ C), 129.2 (2 Õ CH), 128.4 (2 Õ CH), 128.3 (4 Õ CH), 128.0 (2 Õ CH), 127.9

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Full Paper (dt, J = 236.4, 23.7 Hz, 1F; CFF); IR (neat): n˜ max = 2793 (m), 1516 (m), 1497 (m), 1454 (s), 1373 (m), 1328 (m), 1212 (s), 1150 (s), 1095 (s), 737 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 478 (0.3) [M + +H], 476 (1) [M + ¢H], 370 (10), 265 (63), 264 (88), 236 (22), 224 (71), 187 (30), 135 (23), 105 (25), 91 (100), 77 (6), 65 (14); HRMS (ESI-TOF) m/z calcd for C30H33F2NO2 + Na + : 500.2377 [M+ +Na] + ; found: 500.2378.

(2 Õ CH), 127.7 (2 Õ CH), 126.2 (CH), 120.4 (dd, J = 250.0, 242.5 Hz; CF2), 83.5 (CH), 82.3 (CH), 72.3 (d, J = 1.3 Hz; CH2), 72.1 (dd, J = 28.8, 21.3 Hz; CH), 71.3 (CH2), 57.8 (CH2), 50.8 (CH2), 45.0 (dd, J = 21.9, 20.6 Hz; CH), 33.0 (CH2), 27.6 ppm (d, J = 6.3 Hz; CH2); 19F NMR (470 MHz, CDCl3): d = ¢109.7 (d, J = 236.2 Hz, 1F; CFF), ¢126.5 ppm (dt, J = 236.2, 23.4 Hz, 1F; CFF); IR (neat): n˜ max = 2794 (m), 1496 (m), 1455 (s), 1373 (m), 1328 (m), 1213 (m), 1149 (s), 1102 (s), 1029 (m), 738 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 463 (1) [M + ], 372 (4), 356 (9), 333 (4), 312 (4), 283 (10), 251 (74), 250 (91), 242 (13), 222 (19), 210 (62), 190 (7), 173 (22), 170 (11), 135 (20), 91 (100), 77 (5), 65 (17); HRMS (ESI-TOF) m/z calcd for C29H31F2NO2 + H + : 464.2401 [M+ +H] + ; found: 464.2402.

Trans-16 c (more polar): a colorless oil; ½a¤28 D = + 33.8 (c = 1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.30–7.18 (m, 10 H; ArH), 7.04 (dAB, J = 7.9 Hz, 2 H; ArH), 6.98 (dAB, J = 7.9 Hz, 2 H; ArH), 4.56 (d, J = 11.5 Hz, 1 H; OCHH), 4.50 (d, J = 12.2 Hz, 1 H; OCHH), 4.44 (d, J = 11.5 Hz, 1 H; OCHH), 4.39 (d, J = 12.2 Hz, 1 H; OCHH), 4.20 (dd, J = 6.6, 1.8 Hz, 1 H; OCH), 3.92–3.88 (m, 1 H; OCH), 3.10 (d, J = 9.7 Hz, 1 H; CHH), 2.91 (dd, J = 13.6, 2.2 Hz, 1 H; CHH), 2.76–2.69 (m, 1 H; CHH), 2.65–2.57 (m, 1 H; CH), 2.57 (dd, J = 9.7, 6.2 Hz, 1 H; CHH), 2.49 (dd, J = 13.6, 12.2 Hz, 1 H; CHH), 2.44–2.32 (obsc, 2 H; CH, CHH), 2.25 (s, 3 H; CH3), 1.89–1.80 (m, 1 H; CHH), 1.47–1.40 ppm (m, 1 H; CHH); 13C NMR (125 MHz, CDCl3): d = 138.0 (C), 137.9 (C), 136.0 (C), 135.9 (C), 129.2 (2 Õ CH), 129.0 (2 Õ CH), 128.4 (4 Õ CH), 128.0 (2 Õ CH), 127.9 (2 Õ CH), 127.7 (2 Õ CH), 121.4 (t, J = 246.3 Hz; CF2), 83.6 (CH), 82.3 (CH), 72.4 (CH2), 71.3 (CH2), 67.5 (dd, J = 28.8, 23.8 Hz; CH), 57.8 (CH2), 45.8 (CH2), 42.4 (dd, J = 22.5, 21.3 Hz; CH), 32.0 (dd, J = 6.9, 4.4 Hz; CH2), 24.2 (d, J = 6.3 Hz; CH2), 21.0 ppm (CH3); 19 F NMR (470 MHz, CDCl3): d = ¢108.0 (dABdd, J = 239.3, 20.9, 12.5 Hz, 1F; CFF), ¢109.0 ppm (dAB, J = 239.3 Hz, 1F; CFF); IR (neat): n˜ max = 2796 (m), 1516 (m), 1497 (m), 1455 (m), 1367 (m), 1327 (m), 1146 (s), 1113 (s), 737 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 478 (2) [M + +H], 370 (5), 326 (7), 265 (55), 264 (66), 236 (23), 224 (61), 187 (21), 135 (21), 105 (21), 91 (100), 77 (6), 65 (18); HRMS (ESI-TOF) m/ +H] + ; found: 478.2559. z calcd for C30H33F2NO2 + H + : 478.2558 [M+

Trans-16 b (more polar): a colorless oil; ½a¤26 D = + 37.5 (c = 1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.38–7.26 (m, 12 H; ArH), 7.22 (t, J = 7.3 Hz, 1 H; ArH), 7.17 (d, J = 7.4 Hz, 2 H; ArH), 4.64 (d, J = 11.5 Hz, 1 H; OCHH), 4.57 (d, J = 12.2 Hz, 1 H; OCHH), 4.52 (d, J = 11.5 Hz, 1 H; OCHH), 4.46 (d, J = 12.2 Hz, 1 H; OCHH), 4.28 (d, J = 6.6 Hz, 1 H; OCH), 3.97 (d, J = 6.2 Hz, 1 H; OCH), 3.18 (d, J = 10.0 Hz, 1 H; CHH), 3.02 (dd, J = 13.3, 2.6 Hz, 1 H; CHH), 2.84–2.78 (m, 1 H; CHH), 2.72–2.64 (m, 1 H; CH), 2.65 (dd, J = 10.0, 6.2 Hz, 1 H; CHH), 2.60 (dd, J = 13.3, 12.4 Hz, 1 H; CHH), 2.53–2.43 (obsc, 2 H; CHH, CH), 1.98–1.88 (m, 1 H; CHH), 1.54–1.48 ppm (m, 1 H; CHH); 13 C NMR (125 MHz, CDCl3): d = 139.1 (C), 138.0 (C), 137.9 (C), 129.1 (2 Õ CH), 128.6 (2 Õ CH), 128.4 (4 Õ CH), 128.0 (2 Õ CH), 127.9 (2 Õ CH), 127.7 (2 Õ CH), 126.4 (CH), 121.3 (t, J = 246.3 Hz; CF2), 83.6 (d, J = 1.3 Hz; CH), 82.3 (CH), 72.4 (CH2), 71.3 (CH2), 67.5 (dd, J = 28.8, 23.8 Hz; CH), 57.8 (CH2), 45.9 (CH2), 42.4 (dd, J = 22.5, 20.0 Hz; CH), 32.4 (dd, J = 6.9, 5.0 Hz; CH2), 24.2 ppm (d, J = 6.3 Hz; CH2); 19F NMR (470 MHz, CDCl3): d = ¢108.1 (dABdd, J = 239.5, 20.4, 12.5 Hz, 1F; CFF), ¢109.0 ppm (dAB, J = 239.5 Hz, 1F; CFF); IR (neat): n˜ max = 2796 (m), 1497 (m), 1455 (s), 1368 (m), 1328 (m), 1146 (s), 1104 (s), 1052 (s), 738 (s), 699 cm¢1 (s); MS (70 eV): m/z (%): 464 (0.2) [M + +H], 463 (0.1) [M + ], 370 (3), 356 (3), 312 (2), 280 (4), 251 (38), 250 (50), 222 (13), 210 (45), 190 (7), 173 (16), 135 (17), 91 (100), 65 (14); +H] + ; HRMS (ESI-TOF) m/z calcd for C29H31F2NO2 + H + : 464.2401 [M+ found: 464.2402.

(1S,2S,7R,8aR)and (1S,2S,7S,8aR)-1,2-Bis(benzyloxy)-8,8-difluoro-7-(4-fluorobenzyl)octahydroindolizines (cis-16 d and trans16 d): According to the General Procedure H, radical cyclization of 13 d (109.4 mg, 0.19 mmol, d.r. 88:12) using Bu3SnH (90 mL, 0.34 mmol) and AIBN (0.38 mL, 38 mmol, 0.1 m solution in toluene) gave cis-16 d (32.6 mg, 36 % yield), a mixture of cis-16 d and trans16 d (12.2 mg, 13 % yield, d.r. 45:55 as determined by 19F NMR analysis), and trans-16 d (19.3 mg, 21 % yield) after column chromatography [SiO2 (Art 7734), 0–20 % EtOAc in hexanes].

(1S,2S,7R,8aR)and (1S,2S,7S,8aR)-1,2-Bis(benzyloxy)-8,8-difluoro-7-(4-methylbenzyl)octahydroindolizines (cis-16 c and trans-16 c): According to the General Procedure H, radical cyclization of 13 c (101.8 mg, 0.17 mmol, d.r. 92:8) using Bu3SnH (85 mL, 0.32 mmol) and AIBN (0.36 mL, 36 mmol, 0.1 m solution in toluene) gave cis-16 c (32.5 mg, 40 % yield), a mixture of cis- and trans-16 c (9.8 mg, 12 % yield, d.r. 37:63 as determined by 19F NMR analysis), and trans-16 c (17.7 mg, 22 % yield) after column chromatography [SiO2 (Art 7734), 0–20 % EtOAc in hexanes].

Cis-16 d (less polar): a colorless oil; ½a¤28 D = + 23.4 (c = 1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.29–7.18 (m, 10 H; ArH), 7.05 (dd, J = 8.6, 5.4 Hz, 2 H; ArH), 6.90 (dd, J = 8.7, 8.6 Hz, 2 H; ArH), 4.54 (d, J = 11.5 Hz, 1 H; OCHH), 4.49 (d, J = 12.2 Hz, 1 H; OCHH), 4.42 (d, J = 11.5 Hz, 1 H; OCHH), 4.39 (d, J = 12.2 Hz, 1 H; OCHH), 4.20 (dd, J = 6.6, 1.3 Hz, 1 H; OCH), 3.87 (d, J = 6.0 Hz, 1 H; OCH), 3.16 (dd, J = 13.8, 3.3 Hz, 1 H; CHH), 3.08 (d, J = 10.1 Hz, 1 H; CHH), 2.90–2.85 (m, 1 H; CHH), 2.46 (dd, J = 10.1, 6.0 Hz, 1 H; CHH), 2.37 (dd, J = 13.8, 10.6 Hz, 1 H; CHH), 2.29 (dd, J = 21.9, 6.6 Hz, 1 H; CH), 1.95 (ddd, J = 11.6, 11.6, 2.2 Hz, 1 H; CHH), 1.88–1.74 (m, 1 H; CH), 1.55 (qd, J = 12.6, 4.3 Hz, 1 H; CHH), 1.50–1.43 ppm (m, 1 H; CHH); 13C NMR (125 MHz, CDCl3): d = 161.5 (d, J = 242.5 Hz; C), 138.0 (C), 137.9 (C), 135.0 (d, J = 9.4 Hz; C), 130.5 (d, J = 7.5 Hz; 2 Õ CH), 128.4 (4 Õ CH), 128.0 (2 Õ CH), 127.8 (2 Õ CH), 127.7 (2 Õ CH), 120.3 (dd, J = 250.6, 241.9 Hz; CF2), 115.2 (d, J = 21.3 Hz; 2 Õ CH), 83.5 (CH), 82.3 (CH), 72.3 (CH2), 72.1 (dd, J = 28.8, 22.5 Hz; CH), 71.3 (CH2), 57.8 (CH2), 50.7 (CH2), 45.0 (dd, J = 21.3, 21.3 Hz; CH), 32.2 (CH2), 27.6 ppm (d, J = 7.5 Hz; CH2); 19F NMR (470 MHz, CDCl3): d = ¢109.6 (d, J = 236.6 Hz, 1F; CFF), ¢117.0 (tt, J = 8.9, 4.6 Hz, 1F; ArF), ¢126.4 ppm (dt, J = 236.6, 20.8 Hz, 1F; CFF); IR (neat): n˜ max = 2795 (m), 1510 (s), 1497 (m), 1454 (m), 1373 (m), 1329 (m), 1222 (s), 1157 (s), 1110 (s), 738 (s), 698 cm¢1 (s); MS (70 eV): m/z (%): 481 (0.2) [M + ], 373 (8), 268 (100), 267 (82), 240 (29), 228 (49), 208 (17), 191 (15), 160 (14), 134 (26), 120 (18), 109 (38), 91 (100), 65 (19); HRMS (ESI-TOF) m/z +Na] + ; found: 504.2129. calcd for C29H30F3NO2 + Na + : 504.2126 [M+

Cis-16 c (less polar): a colorless oil; ½a¤28 D = + 25.1 (c = 1.00 in CHCl3); 1 H NMR (500 MHz, CDCl3): d = 7.29–7.18 (m, 10 H; ArH), 7.03 (dAB, J = 8.0 Hz, 2 H; ArH), 6.99 (dAB, J = 8.0 Hz, 2 H; ArH), 4.55 (d, J = 11.4 Hz, 1 H; OCHH), 4.49 (d, J = 12.3 Hz, 1 H; OCHH), 4.42 (d, J = 11.4 Hz, 1 H; OCHH), 4.39 (d, J = 12.3 Hz, 1 H; OCHH), 4.20 (d, J = 6.5 Hz, 1 H; OCH), 3.87 (d, J = 6.0 Hz, 1 H; OCH), 3.17 (dd, J = 13.6, 2.9 Hz, 1 H; CHH), 3.07 (d, J = 10.1 Hz, 1 H; CHH), 2.89–2.83 (m, 1 H; CHH), 2.45 (dd, J = 10.1, 6.0 Hz, 1 H; CHH), 2.35 (dd, J = 13.6, 10.8 Hz, 1 H; CHH), 2.29 (dd, J = 22.3, 6.5 Hz, 1 H; CH), 2.24 (s, 3 H; CH3), 1.93 (ddd, J = 11.3, 11.3, 2.7 Hz, 1 H; CHH), 1.90–1.75 (m, 1 H; CH), 1.56 (qd, J = 12.8, 4.2 Hz, 1 H; CHH), 1.53–1.46 ppm (m, 1 H; CHH); 13C NMR (125 MHz, CDCl3): d = 138.0 (C), 136.3 (C), 135.7 (C), 129.1 (2 Õ CH), 129.0 (2 Õ CH), 128.3 (4 Õ CH), 128.0 (2 Õ CH, C), 127.8 (2 Õ CH), 127.7 (2 Õ CH), 120.4 (dd, J = 250.6, 241.9 Hz; CF2), 83.5 (CH), 82.4 (CH), 72.3 (d, J = 1.3 Hz; CH2), 72.1 (dd, J = 28.8, 22.5 Hz; CH), 71.2 (CH2), 57.8 (CH2), 50.8 (CH2), 45.1 (dd, J = 21.3, 21.3 Hz; CH), 32.5 (CH2), 27.6 (d, J = 7.5 Hz; CH2), 21.0 ppm (CH3); 19F NMR (470 MHz, CDCl3): d = ¢109.7 (d, J = 236.4 Hz, 1F; CFF), ¢126.5 ppm Chem. Asian J. 2015, 10, 948 – 968

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Full Paper Trans-16 d (more polar): a colorless oil; ½a¤27 D = + 28.4 (c = 1.00 in CHCl3); 1H NMR (500 MHz, CDCl3): d = 7.31–7.19 (m, 10 H; ArH), 7.05 (dd, J = 8.5, 5.4 Hz, 2 H; ArH), 6.92 (dd, J = 8.6, 8.5 Hz, 2 H; ArH), 4.56 (d, J = 11.5 Hz, 1 H; OCHH), 4.50 (d, J = 12.2 Hz, 1 H; OCHH), 4.44 (d, J = 11.5 Hz, 1 H; OCHH), 4.39 (d, J = 12.2 Hz, 1 H; OCHH), 4.20 (dd, J = 6.6, 1.6 Hz, 1 H; OCH), 3.91 (d, J = 5.9 Hz, 1 H; OCH), 3.11 (d, J = 10.1 Hz, 1 H; CHH), 2.92 (dd, J = 13.7, 2.8 Hz, 1 H; CHH), 2.78–2.72 (m, 1 H; CHH), 2.66–2.56 (obsc, 2 H; CHH, CH), 2.51 (dd, J = 13.7, 12.0 Hz, 1 H; CHH), 2.45–2.30 (obsc, 2 H; CHH, CH), 1.90–1.81 (m, 1 H; CHH), 1.45–1.38 ppm (m, 1 H; CHH); 13C NMR (125 MHz, CDCl3): d = 161.6 (d, J = 243.8 Hz; C), 137.9 (C), 137.8 (C), 134.7 (d, J = 3.8 Hz; C), 130.4 (d, J = 7.5 Hz; 2 Õ CH), 128.4 (4 Õ CH), 128.0 (2 Õ CH), 127.9 (2 Õ CH), 127.7 (2 Õ CH), 121.2 (t, J = 246.9 Hz; CF2), 115.4 (d, J = 20.0 Hz; 2 Õ CH), 83.5 (CH), 82.2 (CH), 72.4 (CH2), 71.3 (CH2), 67.5 (dd, J = 27.5, 23.8 Hz; CH), 57.8 (CH2), 45.9 (CH2), 42.4 (dd, J = 22.5, 20.0 Hz; CH), 31.7 (dd, J = 6.3, 6.3 Hz; CH2), 24.2 ppm (d, J = 5.0 Hz; CH2); 19F NMR (470 MHz, CDCl3): d = ¢108.0 (dAB, J = 240.6 Hz, 1F; CFF), ¢108.9 (dAB, J = 240.6 Hz, 1F; CFF), ¢116.6 ppm (s, 1F; ArF); IR (neat): n˜ max = 2798 (m), 1510 (s), 1497 (m), 1455 (m), 1368 (m), 1328 (m), 1222 (s), 1146 (s), 1107 (s), 738 (s), 698 cm¢1 (s); MS (70 eV): m/ z (%): 481 (0.4) [M + ], 268 (51), 240 (18), 228 (48), 191 (11), 160 (10), 135 (22), 121 (14), 109 (32), 91 (100), 65 (18); HRMS (ESI-TOF) m/z calcd for C29H30F3NO2 + H + : 482.2307 [M+ +H] + ; found: 482.2304.

0.17 mmol) in dry MeOH (1.7 mL) gave trans-17 b (19.3 mg, 87 % yield) as a white solid after column chromatography [SiO2 (Art 7734), MeOH/CH2Cl2 1:9]. m.p. 182–183 8C (acetone/hexanes); 1 ½a¤22 D = + 19.3 (c = 0.25 in MeOH); H NMR (400 MHz, CD3OD): d = 7.34–7.28 (m, 2 H; ArH), 7.27–7.20 (m, 3 H; ArH), 4.46–4.42 (m, 1 H; OCH), 4.26 (dd, J = 2.0, 2.0 Hz, 1 H; OCH), 4.23 (dt, J = 17.1, 2.2 Hz, 1 H; CH), 3.93 (dd, J = 13.0, 4.4 Hz, 1 H; CHH), 3.67–3.52 (obsc, 3 H; CH, CH2), 3.39 (d, J = 13.0 Hz, 1 H; CHH), 3.06 (dd, J = 14.1, 4.7 Hz, 1 H; CHH), 2.81–2.74 ppm (m, 1 H; CHH); 13C NMR (100 MHz, CD3OD): d = 138.6 (C), 129.9 (2 Õ CH), 129.8 (2 Õ CH), 128.0 (CH), 127.3 (dd, J = 257.0, 246.0 Hz; CF2), 79.0 (dd, J = 33.0, 28.0 Hz; CH), 78.3 (d, J = 5.0 Hz; CH), 77.2 (CH), 62.9 (CH2), 58.1 (d, J = 7.0 Hz; CH2), 45.3 (t, J = 22.0 Hz; CH), 31.1 ppm (d, J = 6.0 Hz; CH2); 19F NMR (376 MHz, CD3OD): d = ¢104.2 (dt, J = 239.3, 18.3 Hz, 1F; CFF), ¢109.7 ppm (d, J = 239.3 Hz, 1F; CFF); IR (KBr): n˜ max = 3293 (s), 1497 (m), 1459 (m), 1437 (m), 1355 (m), 1317 (m), 1278 (m), 1258 (m), 1218 (m), 1149 (m), 1108 (s), 1047 (m), 1033 (m), 750 (m), 703 cm¢1 (m); MS (70 eV): m/z (%): 270 (33) [M + +H], 269 (16) [M + ], 209 (39), 208 (31), 168 (33), 144 (25), 115 (21), 91 (34), 82 (100), 77 (8), 65 (24); HRMS (ESI-TOF) m/z calcd for C14H17F2NO2 + H + : 270.1306 +H] + ; found: 270.1304. [M+ (1S,2S,3S,6S,7 aR)-7,7-Difluoro-3-(hydroxymethyl)-6-methylhexahydro-1 H-pyrrolizine-1,2-diol (trans-17 c): According to the General Procedure I, debenzylation of trans-15 d (84.2 mg, 0.17 mmol) using PdCl2 (61.2 mg, 0.35 mmol) in dry MeOH (3.4 mL) gave trans17 c (35.0 mg, 92 % yield) as a white solid after ion-exchange chromatography [Amberlyst A-26 (OH¢) resin, H2O]. m.p. 104–105 8C 1 H NMR (acetone/hexanes); ½a¤22 D = + 28.3 (c = 0.87 in MeOH); (500 MHz, D2O): d = 4.03 (dd, J = 8.6, 7.8 Hz, 1 H; OCH), 3.70 (dd, J = 9.1, 8.6 Hz, 1 H; OCH), 3.66 (dd, J = 11.7, 3.2 Hz, 1 H; CHH), 3.49 (dd, J = 11.7, 6.1 Hz, 1 H; CHH), 3.20 (ddd, J = 15.9, 7.8, 5.7 Hz, 1 H; CH), 2.91 (dd, J = 11.9, 7.5 Hz, 1 H; CHH), 2.74–2.64 (obsc, 2 H; CH, CHH), 2.61–2.45 (m, 1 H; CH), 0.94 ppm (d, J = 6.7 Hz, 3 H; CH3); 13C NMR (125 MHz, D2O): d = 130.3 (dd, J = 253.8, 248.8 Hz; CF2), 76.3 (CH), 74.8 (t, J = 3.8 Hz; CH), 69.6 (dd, J = 29.4, 24.4 Hz; CH), 68.8 (CH), 62.0 (CH2), 56.6 (d, J = 7.5 Hz; CH2), 37.0 (t, J = 22.5 Hz; CH), 8.4 ppm (d, J = 6.3 Hz; CH3); 19F NMR (470 MHz, D2O): d = ¢111.9 (dt, J = 231.7, 16.9 Hz, 1F; CFF), ¢118.6 ppm (d, J = 231.7 Hz, 1F; CFF); IR (KBr): n˜ max = 3398 (br), 1460 (m), 1384 (m), 1326 (m), 1201 (s), 1144 (s), 1078 (s), 1045 (s), 986 cm¢1 (s); MS (70 eV): m/z (%): 223 (0.8) [M + ], 192 (100), 164 (17), 146 (18), 126 (15), 120 (73), 111 (16); HRMS (ESI-TOF) m/z calcd for C9H15F2NO3 + H + : 224.1098 +H] + ; found: 224.1099. [M+

General Procedure I for Debenzylation of Pyrrolizidines 15 and Indolizidines 16 To a solution of trans-15 or cis-16 (0.1 mmol) in dry MeOH (2 mL) was added PdCl2 (0.2 mmol). The mixture was stirred at room temperature under an atmosphere of H2 (balloon) for 24 h. After the complete consumption of the starting material, as revealed by TLC, the reaction mixture was filtered through a celite pad and the solids were washed with MeOH (3 Õ 10 mL). The filtrate was concentrated in vacuo to give a crude product, which was purified by column chromatography (SiO2), ion-exchange chromatography [Amberlyst A-26 (OH¢ form) resin], or recrystallization. (1S,2S,6S,7 aR)-7,7-Difluoro-6-methylhexahydro-1 H-pyrrolizine1,2-diol (trans-17 a): According to the General Procedure I, debenzylation of trans-15 a (46.4 mg, 0.12 mmol) using PdCl2 (44.5 mg, 0.25 mmol) in dry MeOH (2.5 mL) gave trans-17 a (19.7 mg, 85 % yield) as a white solid after ion-exchange chromatography [Amberlyst A-26 (OH¢) resin, H2O]. Compound trans-17 a was also obtained in 92 % yield (58.6 mg from trans-15 a 125.0 mg, 0.33 mmol) after column chromatography [SiO2 (Art 7734), MeOH/CH2Cl2 1:9]. m.p. 129–130 8C (acetone/hexanes); ½a¤24 D = + 63.0 (c = 1.00 in MeOH); 1H NMR (400 MHz, D2O): d = 4.10–4.00 (obsc, 2 H; 2 Õ OCH), 3.32–3.14 (obsc, 3 H; CH, 2 Õ OH), 3.08–2.98 (m, 1 H; CHH), 2.84 (dd, J = 11.1, 7.4 Hz, 1 H; CHH), 2.70 (dd, J = 11.1, 8.9 Hz, 1 H; CHH), 2.65– 2.47 (obsc, 2 H; CH, CHH), 0.97 ppm (d, J = 6.7 Hz, 3 H; CH3); 13 C NMR (100 MHz, D2O): d = 130.2 (dd, J = 253.9, 249.9 Hz; CF2), 75.8 (CH), 75.5 (t, J = 4.3 Hz; CH), 70.8 (dd, J = 29.7, 23.8 Hz; CH), 57.2 (CH2), 56.9 (d, J = 6.4 Hz; CH2), 37.5 (t, J = 22.6 Hz; CH), 8.9 ppm (d, J = 5.8 Hz; CH3); 19F NMR (376 MHz, D2O): d = ¢111.4 (dt, J = 231.8, 15.3 Hz, 1F; CFF), ¢114.8 ppm (d, J = 231.8 Hz, 1F; CFF); IR (KBr): n˜ max = 3363 (br), 1485 (m), 1460 (m), 1444 (m), 1385 (m), 1348 (m), 1247 (m), 1202 (s), 1170 (s), 1128 (s), 1023 (s), 975 cm¢1 (s); MS (70 eV): m/z (%): 193 (23) [M + ], 178 (67), 161 (25), 149 (31), 133 (100), 121 (19), 105 (23), 95 (23), 81 (31), 69 (30), 55 (42); HRMS (ESI-TOF) m/z calcd for C8H13F2NO2 + H + : 194.0993 +H] + ; found: 194.0989. [M+ (1S,2S,6S,7 aR)-6-Benzyl-7,7-difluorohexahydro-1 H-pyrrolizine1,2-diol (trans-17 b): According to the General Procedure I, debenzylation of trans-15 b (37.1 mg, 82.5 mmol) using PdCl2 (29.5 mg, Chem. Asian J. 2015, 10, 948 – 968

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(1S,2S,3S,6S,7 aR)-6-Benzyl-7,7-difluoro-3-(hydroxymethyl)hexahydro-1 H-pyrrolizine-1,2-diol (trans-17 d): According to the General Procedure I, debenzylation of trans-15 e (43.0 mg, 75.4 mmol) using PdCl2 (27.1 mg, 0.15 mmol) in dry MeOH (1.5 mL) gave trans17 d (18.5 mg, 82 % yield) as a colorless oil after column chromatography [SiO2 (Art 7734), MeOH/CH2Cl2 1:9]. ½a¤24 D = + 25.6 (c = 1.00 in CHCl3); 1H NMR (500 MHz, CD3OD): d = 7.29–7.25 (m, 2 H; ArH), 7.24–7.16 (m, 3 H; ArH), 4.71 (br s, 3 H; OH), 4.02 (dd, J = 8.1, 7.5 Hz, 1 H; OCH), 3.72 (dd, J = 8.5, 8.1 Hz, 1 H; OCH), 3.64 (dd, J = 11.4, 3.0 Hz, 1 H; CHH), 3.47 (dd, J = 11.4, 5.6 Hz, 1 H; CHH), 3.35 (ddd, J = 17.3, 7.5, 5.1 Hz, 1 H; CH), 2.98 (dd, J = 13.6, 4.7 Hz, 1 H; CHH), 2.92 [(dd)ABX, J = 11.9, 10.1 Hz, 1 H; CHH], 2.85 [(dd)ABXd, J = 11.9, 6.9, 1.5 Hz, 1 H; CHH], 2.77–2.65 (m, 1 H; CH), 2.65–2.58 ppm (obsc, 2 H; CH, CHH); 13C NMR (125 MHz, CD3OD): d = 140.4 (C), 131.4 (dd, J = 256.3, 249.0 Hz; CF2), 129.8 (2 Õ CH), 129.6 (2 Õ CH), 127.4 (CH), 78.2 (CH), 77.1 (t, J = 4.1 Hz; CH), 73.0 (dd, J = 28.9, 23.3 Hz; CH), 71.4 (CH), 63.4 (CH2), 56.3 (d, J = 7.3 Hz; CH2), 46.1 (t, J = 21.8 Hz; CH), 32.2 ppm (d, J = 5.6 Hz; CH2); 19F NMR (470 MHz, CD3OD): d = ¢110.2 (dt, J = 234.3, 17.2 Hz, 1F; CFF), ¢117.8 ppm (d, J = 234.3 Hz, 1F; CFF); IR (CHCl3): n˜ max = 3367 (br), 1497 (m), 1455

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Full Paper CH2), 28.9 (d, J = 8.8 Hz; CH2), 21.0 ppm (CH3); 19F NMR (470 MHz, CD3OD): d = ¢113.2 (d, J = 238.1 Hz, 1F; CFF), ¢129.2 ppm (dt, J = 238.1, 24.0 Hz, 1F; CFF); IR (CHCl3): n˜ max = 3393 (br), 2809 (m), 1516 (m), 1451 (m), 1373 (m), 1326 (m), 1302 (m), 1142 (s), 1108 (s), 1072 cm¢1 (s); MS (70 eV): m/z (%): 298 (100) [M + +H]; HRMS (ESITOF) m/z calcd for C16H21F2NO2 + H + : 298.1619 [M+ +H] + ; found: 298.1620. (1S,2S,7 R,8 aR)-8,8-Difluoro-7-(4-fluorobenzyl)octahydroindolizine-1,2-diol (cis-18 d): According to the General Procedure I, debenzylation of cis-16 d (32.5 mg, 67.4 mmol) using PdCl2 (24.5 mg, 0.14 mmol) in dry MeOH (1.4 mL) gave cis-18 d (16.2 mg, 80 % yield) as a white solid after recrystallization (acetone/Et2O). m.p. 1 167–168 8C (acetone/Et2O); ½a¤25 D = ¢6.2 (c = 1.00 in MeOH); H NMR (500 MHz, CD3OD): d = 7.25 (dd, J = 8.6, 5.4 Hz, 2 H; ArH), 7.04 (dd, J = 8.7, 8.6 Hz, 2 H; ArH), 4.37 (dd, J = 7.6, 1.7 Hz, 1 H; OCH), 4.30– 4.25 (m, 1 H; OCH), 3.65 (dd, J = 25.8, 7.6 Hz, 1 H; CH), 3.55–3.48 (obsc, 2 H; 2 Õ CHH), 3.44 (d, J = 11.6 Hz, 1 H; CHH), 3.23 (d, J = 10.2 Hz, 1 H; CHH), 3.17–3.09 (m, 1 H; CHH), 2.54–2.42 (obsc, 2 H; CH, CHH), 1.88 (br d, J = 13.8 Hz, 1 H; CHH), 1.84–1.73 ppm (m, 1 H; CHH); 13C NMR (125 MHz, CD3OD): d = 163.2 (d, J = 241.3 Hz; C), 135.1 (d, J = 3.8 Hz; C), 131.9 (d, J = 8.8 Hz; 2 Õ CH), 120.6 (dd, J = 248.8, 246.3 Hz; CF2), 116.3 (d, J = 21.3 Hz; 2 Õ CH), 76.5 (CH), 76.4 (CH), 72.1 (dd, J = 33.8, 26.3 Hz; CH), 61.1 (br s; CH2), 51.5 (br s; CH2), 44.4 (t, J = 21.3 Hz; CH), 32.4 (CH2), 26.5 ppm (br s; CH2); 19 F NMR (470 MHz, CD3OD): d = ¢114.2 (d, J = 242.8 Hz, 1F; CFF), ¢118.5 (tt, J = 8.5, 4.4 Hz, 1F; ArF), ¢127.7 ppm (d, J = 242.8 Hz, 1F; CFF); IR (KBr): n˜ max = 3434 (br), 3209 (br), 2681 (m), 1509 (s), 1453 (m), 1431 (m), 1384 (m), 1340 (m), 1318 (m), 1251 (m), 1215 (s), 1162 (m), 1123 (s), 834 cm¢1 (s); MS (70 eV): m/z (%): 302 (100) [M + +H], 301 (85) [M + ], 284 (16), 240 (81), 205 (16), 188 (16), 123 (11), 110 (26); HRMS (ESI-TOF) m/z calcd for C15H18F3NO2 + H + : 302.1368 [M+ +H] + ; found: 302.1364.

(m), 1376 (m), 1322 (m), 1289 (m), 1166 (m), 1119 (s), 1075 (s), 1049 (s), 701 cm¢1 (s); MS (70 eV): m/z (%): 300 (5) [M + +H], 299 (5) [M + ], 268 (100); HRMS (ESI-TOF) m/z calcd for C15H19F2NO3 + Na + : 322.1231 [M+ +Na] + ; found: 322.1231. (1S,2S,7 R,8 aR)-8,8-Difluoro-7-methyloctahydroindolizine-1,2-diol (cis-18 a): According to the General Procedure I, debenzylation of cis-16 a (containing 7 % of 16 a’) (43.0 mg, 0.11 mmol) using PdCl2 (39.8 mg, 0.22 mmol) in dry MeOH (2.3 mL) gave cis-18 a (11.6 mg, 51 % yield) as a white solid after recrystallization (MeOH/MeCN). m.p. 226–227 8C (MeOH/MeCN); ½a¤22 D = ¢51.8 (c = 1.10 in MeOH); 1 H NMR (500 MHz, D2O): d = 4.33 (dd, J = 8.3, 3.1 Hz, 1 H; OCH), 4.31–4.27 (m, 1 H; OCH), 3.48–3.37 (obsc, 3 H; CH, 2 Õ CHH), 3.34 (d, J = 12.2 Hz, 1 H; CHH), 2.99 (ddd, J = 12.7, 12.7, 3.0 Hz, 1 H; CHH), 2.26–2.11 (m, 1 H; CH), 2.02–1.94 (m, 1 H; CHH), 1.63 (dtd, J = 14.8, 13.1, 4.4 Hz, 1 H; CHH), 1.02 ppm (d, J = 6.7 Hz, 3 H; CH3); 13C NMR (125 MHz, D2O): d = 119.7 (t, J = 246.3 Hz; CF2), 74.7 (CH), 74.4 (CH), 69.5 (dd, J = 33.1, 25.6 Hz; CH), 58.9 (CH2), 50.5 (CH2), 36.0 (t, J = 21.3 Hz; CH), 27.7 (d, J = 7.5 Hz; CH2), 10.3 ppm (dd, J = 3.8, 2.5 Hz; CH3); 19F NMR (470 MHz, D2O): d = ¢113.6 (d, J = 251.9 Hz, 1F; CFF), (¢127.0)–(¢130.5) ppm (m, 1F; CFF); IR (KBr): n˜ max = 3398 (s), 3277 (s), 2696 (m), 1463 (m), 1374 (w), 1338 (m), 1235 (m), 1130 (s), 1105 (m), 1012 cm¢1 (m); MS (70 eV): m/z (%): 208 (100) [M + +H], 207 (23) [M + ], 206 (27) [M + ¢H], 189 (15), 172 (8), 147 (27), 132 (23), 118 (25); HRMS (ESI-TOF) m/z calcd for C9H15F2NO2 + H + : 208.1149 [M+ +H] + ; found: 208.1141. (1S,2S,7 R,8 aR)-7-Benzyl-8,8-difluorooctahydroindolizine-1,2-diol (cis-18 b): According to the General Procedure I, debenzylation of cis-16 b (43.1 mg, 92.9 mmol) using PdCl2 (33.1 mg, 0.19 mmol) in dry MeOH (1.9 mL) gave cis-18 b (12.0 mg, 46 % yield) as a white semi-solid after recrystallization (acetone/hexanes). ½a¤28 D = ¢10.7 (c = 1.00 in CHCl3); 1H NMR (500 MHz, CD3OD): d = 7.33–7.28 (m, 2 H; ArH), 7.25–7.20 (m, 3 H; ArH), 4.38 (dd, J = 7.3, 1.7 Hz, 1 H; OCH), 4.29–4.26 (m, 1 H; OCH), 3.66 (dd, J = 25.7, 7.3 Hz, 1 H; CH), 3.54–3.47 (obsc, 2 H; 2 Õ CHH), 3.44 (d, J = 11.7 Hz, 1 H; CHH), 3.26 (d, J = 10.3 Hz, 1 H; CHH), 3.11 (dd, J = 11.6, 11.6 Hz, 1 H; CHH), 2.55– 2.43 (obsc, 2 H; CHH, CH), 1.87 (d, J = 14.9 Hz, 1 H; CHH), 1.84– 1.73 ppm (m, 1 H; CHH); 13C NMR (125 MHz, CD3OD): d = 139.2 (C), 130.2 (2 Õ CH), 129.8 (2 Õ CH), 127.8 (CH), 120.6 (t, J = 246.9 Hz; CF2), 76.4 (CH), 76.3 (CH), 72.1 (dd, J = 34.4, 25.6 Hz; CH), 61.5–60.8 (m; CH2), 51.8–51.4 (m; CH2), 44.5 (t, J = 21.3 Hz; CH), 33.1 (CH2), 26.8– 26.3 ppm (m; CH2); 19F NMR (470 MHz, CD3OD): d = ¢114.4 (d, J = 253.1 Hz, 1F; CFF), ¢127.8 ppm (d, J = 253.1 Hz, 1F; CFF); IR (neat): n˜ max = 3364 (br), 1496 (m), 1455 (m), 1378 (m), 1239 (m), 1219 (m), 1127 (s), 1105 (s), 1014 (m), 751 (m), 704 cm¢1 (s); MS (70 eV): m/z (%): 284 (11) [M + +H], 283 (100) [M + ], 222 (13); HRMS (ESI-TOF) m/ +H] + ; found: 284.1463. z calcd for C15H19F2NO2 + H + : 284.1462 [M+

Acknowledgements Financial support from the Center of Excellence for Innovation in Chemistry (PERCH-CIC), the Office of Higher Education Commission and Mahidol University under the National Research Universities Initiative and the Thailand Research Fund (BRG5380019) is gratefully acknowledged. Keywords: cyclization · fluorine · indolizidine · pyrrolizidine · radical reactions [1] For reviews, see: a) J.-P. B¦gu¦, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine, Wiley, New York, 2008; b) K. Mìller, C. Faeh, F. Diederich, Science 2007, 317, 1881 – 1886; c) K. Uneyama, Organofluorine Chemistry, Blackwell Publishing, Oxford, 2006; d) V. A. Soloshonok, Fluorine-Containing Synthons, American Chemical Society: Distributed by Oxford University Press, Washington, DC, 2005; e) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH, Weinheim, 2004; f) Selective Fluorination in Organic and Bioorganic Chemistry, Vol. 110, American Chemical Society, Washington, DC, 1991. [2] For reviews, see: a) V. A. Brunet, D. O’Hagan, Angew. Chem. Int. Ed. 2008, 47, 1179 – 1182; Angew. Chem. 2008, 120, 1198 – 1201; b) G. K. Surya Prakash, J. Hu, Acc. Chem. Res. 2007, 40, 921 – 930; c) M. Shimizu, T. Hiyama, Angew. Chem. Int. Ed. 2005, 44, 214 – 231; Angew. Chem. 2005, 117, 218 – 234; d) J.-A. Ma, D. Cahard, Chem. Rev. 2004, 104, 6119 – 6146; e) T. Hiyama, Organofluorine Compounds: Chemistry and Applications, Springer, New York, 2000. [3] For selected recent references, see: a) D. O’Hagan, J. Fluorine Chem. 2010, 131, 1071 – 1081; b) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Wiley-Blackwell, Oxford, 2009; c) D. O’Hagan, Chem.

(1S,2S,7 R,8 aR)-8,8-Difluoro-7-(4-methylbenzyl)octahydroindolizine-1,2-diol (cis-18 c): According to the General Procedure I, debenzylation of cis-16 c (31.7 mg, 66.3 mmol) using PdCl2 (24.1 mg, 0.14 mmol) in dry MeOH (1.4 mL) gave cis-18 c (13.9 mg, 70 % yield) as a white semi-solid after column chromatography [SiO2 (Art 7734), 5–10 % MeOH in CH2Cl2]. ½a¤25 D = ¢6.8 (c = 1.00 in CHCl3); 1 H NMR (500 MHz, CD3OD): d = 7.08 (dAB, J = 8.0 Hz, 2 H; ArH), 7.05 (dAB, J = 8.0 Hz, 2 H; ArH), 4.58 (br s, 2 H; OH), 4.19 (dd, J = 7.2, 2.4 Hz, 1 H; OCH), 3.99–3.95 (m, 1 H; OCH), 3.15 (dd, J = 13.6, 3.3 Hz, 1 H; CHH), 2.91–2.82 (obsc, 2 H; 2 Õ CHH), 2.59 (dd, J = 10.1, 6.4 Hz, 1 H; CHH), 2.37 (dd, J = 13.6, 10.7 Hz, 1 H; CHH), 2.28 (s, 3 H; CH3), 2.22 (dd, J = 21.9, 7.2 Hz, 1 H; CH), 2.00 (ddd, J = 11.5, 11.5, 3.4 Hz, 1 H; CHH), 1.99–1.88 (m, 1 H; CH), 1.57–1.43 ppm (m, 2 H; CH2); 13 C NMR (125 MHz, CD3OD): d = 137.5 (C), 136.8 (C), 130.1 (2 Õ CH), 130.0 (2 Õ CH), 122.1 (dd, J = 248.8, 242.5 Hz; CF2), 78.9 (d, J = 2.5 Hz; CH), 78.7 (CH), 74.3 (dd, J = 28.8, 22.5 Hz; CH), 61.6 (CH2), 51.9 (CH2), 46.2 (dd, J = 22.5, 18.8 Hz; CH), 33.4 (dd, J = 3.8, 2.5 Hz; Chem. Asian J. 2015, 10, 948 – 968

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Chem. Asian J. 2015, 10, 948 – 968

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Received: September 1, 2014 Published online on November 21, 2014

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1,4-Addition Sequence to 2,4-Dienals for the Synthesis of Chiral Chromans.

Carbamoyl anion addition to nitrones.

Nucleophilic Chiral Phosphines: Powerful and Versatile Catalysts for Asymmetric Annulations.

Stereoselective Pd-catalyzed etherification and asymmetric synthesis of furanomycin and its analogues from a chiral aziridine.

Stereoselective synthesis of perillaldehyde-based chiral β-amino acid derivatives through conjugate addition of lithium amides.

Stereoselective synthesis of isoquinuclidines through an aza-[4 + 2] cycloaddition of chiral cyclic 2-amidodienes.

Stereogenic phosphorus-induced diastereoselective formation of chiral carbon during nucleophilic addition of chiral H-P species to aldehydes or ketones.

Mechanistic insights on the stereoselective nucleophilic 1,2-addition to sulfinyl imines.

Stereoselective nucleophilic fluoromethylation of aryl ketones: dynamic kinetic resolution of chiral α-fluoro carbanions.

Total synthesis of (±)-gephyrotoxin by amide-selective reductive nucleophilic addition.

Stereoselective synthesis of fluoroalkenoates and fluorinated isoxazolidinones: N-substituents governing the dual reactivity of nitrones.

Highly enantioselective synthesis of chiral cyclic allylic amines via Rh-catalyzed asymmetric hydrogenation.

Efficient Synthesis of Chiral Trisubstituted 1,2-Allenyl Ketones by Catalytic Asymmetric Conjugate Addition of Malonic Esters to Enynes.

Stereoselective synthesis of indolines via organocatalytic thioester enolate addition reactions.

Asymmetric synthesis using chiral-encoded metal.

Chiral primary amine catalyzed asymmetric Michael addition of malononitrile to α-substituted vinyl ketone.

Asymmetric syntheses using tert-leucine. 1. An asymmetric synthesis of beta-substituted aldehydes via 1,4-addition of Grignard reagents to chiral alpha, beta-unsaturated aldimines.

One-pot synthesis of GABA amides via the nucleophilic addition of amines to 3,3-disubstituted cyclopropenes.

Synthesis of a cyclic isostere of α-methyl homoserine by a stereoselective acylation-alkylation sequence of a chiral γ-lactam.

Chiral phosphoric acid catalyzed asymmetric addition of naphthols to para-quinone methides.

Double Asymmetric Induction During the Addition of (RP)-Menthyl Phenyl Phosphine Oxide to Chiral Aldimines.

Regioselectivity switch in chiral amine-catalysed asymmetric addition of aldehydes to reactive enals.

Chiral phosphines in nucleophilic organocatalysis.

Stereoselective addition of organocopper reagents to acetylenic esters and amides. Synthesis of juvenile hormone analogs.