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Asymmetric synthesis of 2,5-disubstituted 3hydroxypyrrolidines based on stereodivergent intramolecular iridium-catalyzed allylic aminations Yoshihiro Natori,a Shunsuke Kikuchi,a Takahiro Kondo,a Yukako Saito,a Yuichi Yoshimura,a and Hiroki Takahata*a Intramolecular iridium-catalyzed allylic aminations of homochiral (E)-6-N-nosylaminohept-2en-1-yl methyl carbonates were investigated. The relative position of the 2,5-substituents of the resulting pyrrolidines was found to be controlled by using both enantiomers (4 and 5) of the appropriate chiral ligand, demonstrating a simple and highly stereodivergent synthetic protocol. Selected trans- and cis-2,5-disubstituted 3-hydroxypyrrolidines (2a and 18a) were converted to (+)-bulgecinine (6) and (+)-preussin (7), respectively.

Introduction   Substituted pyrrolidines are very important scaffolds in a variety of biologically active substances and occur in various natural products such as cocaine, hyacinthacine A1, stemonine and kaitocephalin as well as pharmacologically active compounds, such as trandolapril (an angiotensin converting enzyme inhibitor) (Fig. 1).1 The broad range of biological activity of highly functionalized pyrrolidines underlines the importance of having a diversity of versatile and efficient stereoselective methods for their preparation readily available.2 Two main strategies for the stereoselective preparation of highly substituted pyrrolidines have evolved: either asymmetric 1,3-dipolar cycloaddition or a sequential approache in which linear molecules containing the stereocenters are first constructed, followed by diastereoselective cyclization.

 

We recently reported on the stereoselective synthesis of trans2,5-disubstituted 3-hydroxypyrrolidine derivatives via an intramolecular iridium (Ir)-catalyzed allylic amination with allylic carbonates as the starting compounds in preparing 1alkyl-2-deoxy-L-iminofuranoses (3a-c) which were used in a structure-activity relationship (SAR) study of imino sugars (Scheme 1).3

 

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High levels of diastereoselectvity at the C-2 and C-5 positions in cyclizations by the addition of amine N-H functionalities to unsaturated carbon-carbon bonds are currently possible.4 However, there is a drawback to this approach in that the selectivity of the cyclization process is predetermined by the configuration of the substrate and usually only one of a pair of diastereomers are produced. As a continuation of our interest in the development of this type of intramolecular Ir-catalyzed allylic amination, we found that the 2,5-trans/cis diastereoselectivity in cyclizations leading to pyrrolidine formation can be controlled by using both enantiomers (4 and 5) of the appropriate chiral ligand as shown in Scheme 2.

Journal  Name   allyic cyclization reactions using external chiral ligands, as reported by Helmchen.5a,b On the other hand, to the best of our View Article Online knowledge, a similar approach to produce both 2,5-trans/cis DOI: 10.1039/C3OB42229A diastereomers in cyclizations of pyrrolidine has been scarcely investigated.5c We planned to examine the Ir-catalyzed cyclization reaction of allylic carbonate using the (S,S,S)- or (R,R,R)-ligand (4 or 5). Additionally, it was of interest to examine the effect of the geometry of the double-bond (E/Z) on this cylization. Therefore, we required both E and Z isomers of the cyclization precursor. The cyclization precursor 1a (E:Z = 40:1) is available from the (S)-Garner aldehyde (8) following a previously reported procedure, which provides mainly the E isomer (Scheme 4).3

 

 

Accordingly, we report on the use of this strategy for the stereodivergent synthesis of 2,5-disubstituted-3hydroxypyrrolidine alkaloids such as (+)-bulgecinine (6) and (+)-preussin (7) (Scheme 3).

The Z isomer 1b of the cyclization precursor was prepared by a Z-selective Horner-Wadsworth-Emmons reaction using Ando’s reagent6 as a key step, starting with the known alkene 97 (Scheme 5). Ozonolysis of alkene 9 afforded the aldehyde 10 (93%), which was subjected to Ando olefination followed by reduction to give the (Z)-allylic alcohol 11 in 46% yield (2 steps). A series of transformations (1. methyl carbonation of the hydroxy group; 2. hydrolysis of the N-Boc oxzolidine ring; 3. protection of both the hydroxyl and amino groups) from 11 gave the cyclization precursor 1b (Z only) in good yield.

 

Results  and  discussion   Diastereoselective cyclization reactions of allylic carboxylate catalyzed by [Ir(cod)Cl]2 and a chiral phosphoroamidate ligand (4 or 5) A configurational change to obtain both trans/cis diastereomers of 2,6-disubstituted piperidines was achieved for Ir-catalyzed

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With both cyclization precursors 1a (E:Z = 40:1) and 1b (Z only) in hand, the key diastereoselective cyclization using 4 or 5 as a ligand was examined (Table 1).8 In a previous study,3 the cyclization of 1a (E:Z = 40:1) was catalyzed by [Ir(cod)Cl]2 (8 mol%), giving the (S,S,S)-Ligand 4 (16 mol%) and the TBD (32 mol%). The cyclization reaction proceeded smoothly to provide the desired (5R)-vinyl pyrrolidine derivative 2 in 78% yield with a high diastereoselectivity (2a:2b = 12:1) (entry 1). On the other hand, the cyclization of 1a using the (R,R,R)-ligand 5 to confirm the ligand effect for C5 stereochemistry of the cyclization product expectedly resulted in the reversal of the major diastereomer with moderate diastereoselectivity (2a:2b = 1:6) (entry 2). Next, when the substrate 1b (Z isomer only) was reacted under the same conditions, the selectivity of the amination of 1b (Z isomer only) catalyzed by (S,S,S)- and (R,R,R)-ligand (4 and 5), was low. In contrast, the diastereoselectivity was interestingly reversed (entries 3 and 4). The geometry of the allylic carbonate part was very important in terms of diastereoselectivity, although the reason for this remains unclear. It has been reported that the intermolecular Ircatalyzed allylic amination of the (Z)-isomer preferentially yielded the linear amination product with a high Z-selectivity instead of the branched substituted product.9 However, no endo cyclization occurred in the absence of a seven membered product. Because these results were very interesting, additional study is needed. When we used P(OPh)3 as the achiral ligand, no diastereoselectivity was observed, resulting in no substrate control (entries 5 and 6). Table 1. Allylic amination reaction of allylic carbonate 1

Entry

Substrate

Ligand

2a : 2b a

1

1a (E:Z = 40:1)

(S,S,S)

12 : 1

78 c

2

1a (E:Z = 40:1)

(R,R,R)

1:6

74

3

1b (Z = only)

(S,S,S)

1 : 2.4

95

4

1b (Z = only)

(R,R,R)

3.5 : 1

99

5

1a (E:Z = 40:1)

P(OPh)3

1:1

58

6

1b (Z = only)

P(OPh)3

1:1

50

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Yield (%) b

Combined yield of two diastereomers. b Determined by 1H-NMR analysis of the crude mixture. c The reaction afforded the similar result on gram scale (>2 g of 1). (cod = cyclooctadiene, TBD = 1,5,7-Triazabicyclo[4.4.0]dec-5-ene) View Article Online DOI: 10.1039/C3OB42229A

Thus it the 2,5-trans/cis diastereoselectivity of the cyclization can be easily controlled by external control, using both enantiomers (4 and 5) of the appropriate chiral ligand to produce both 2,5-trans/cis-substituted pyrrolidine derivatives, which are expected to function as useful synthons in preparing pyrrolidine alkaloids. The synthesis of (+)-bulgecinine·HCl having 2,5-trans substituted groups First, we examined the synthesis of an enantiomer of (–)bulgecinine (6) which is a common aglycon substituent of bulgecins A, B, and C isolated from Pseudomonas acidophila or Pseudomonas mesoacidophila10, starting from the 2,5-trans substituted pyrrolidine derivative 2a as the synthon. Because of its unique antibacterial activities11, the unusual amino acid core of bulgecinine (6) has attracted considerable attention as targets of total synthesis and biological studies. In fact, a number of syntheses of natural (–)-bulgecinine (6) have been reported in the literature.12 However, a few research groups reported on the synthesis of the enantiomer (+)-bulgecinine (6).12d,13 Accordingly, we planned its preparation along with our continuous interest in the biological activities of both enantiomers.14 Our stereoselective synthesis of (+)-bulgecinine (6)·HCl started with the ozonolysis of a diastereomixture of 2 (2a:2b = 12:1) to furnish the desired aldehyde 14 in 84% yield (Scheme 6). The aldehyde was oxidized under mild conditions followed by the esterification of the resulting carboxylic acid with CH2N2 to provide two separable methyl esters (the desired ester 15a (67%) and the mono-TBS protected ester 15b (28%)). At this stage, the position of the hydroxyl group in 15b was unknown. It’s position was determined to be at C-4, because acetylation of the hydroxyl group gave the secondary acetoxy product (see supporting information). The mono-TBS protected ester 15b was protected by a TBS group to afford 15a in good yield. The deprotection of the Ns group under standard conditions was carried out to give the amine 16 in high yield. Finally, deprotection of TBS groups using 6 N HCl was carried out to provide (+)-bulgecinine (6)·HCl. Optical rotation data of our synthesized (+)-bulgecinine (6)·HCl was in agreement with the [α]D value of (–)-bulgecinine (ent-6)·HCl reported by Datta’s research group12f (our synthesized (+)-bulgecinine (6)·HCl ; [α]D25 = –11.6 (c 0.65, 1 N HCl), previous reported (– )-bulgecinine (ent-6)·HCl ; [α]D25 = +11.71 (c 0.65, 1 N HCl)).

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We embarked on the preparation of the cyclization precursor 17 starting with the known alcohol 2018 derived from Lphenylalanine (19) (Scheme 8). An olefin cross metathesis (Grubbs II catalyst) of 20 and (Z)-but-2-ene-1,4-diyl dimethyl dicarbonate (21) (5 eq.) afforded the allylic carbonate 22 as a mixture of E and Z isomers in good yield. At this stage, the ratio of E and Z isomers remained undetermined because of a difficulties associated with the 1H-NMR analysis. After deprotection of the Boc group using trifluoroacetic acid, sequential protection of the hydroxyl with a TBS group and the amine with an Ns group afforded the cyclization precursor 17 in high yield. The ratio of E and Z isomers of 17 was then determined from its 1H-NMR spectrum (E:Z = 13:1).

The synthesis of (+)-preussin (7) having 2,5-cis substituted groups Next, we commenced the synthesis of (+)-preussin (7) containing a 2,5-cis substituted pyrrolidine derivative. (+)Preussin (7) was isolated from a liquid fermentation broth of Aspergillus ochraceus in 1988.15 It shows broad spectrum antifungal activity and has also shown growth-inhibitory and cytotoxic effects on human cancer cells.15a,16 Numerous reports on the synthesis of (+)-preussin (7) as an attractive target have been appeared in the literature.17 Encouraged by the result of the cyclization reaction in Table 1 (entry 2), it was expected that the efficient asymmetric synthesis of a 2,3,5-trisubstituted pyrrolidine such as (+)-preussin (7) with cis-2,5-disutstituted pyrrolidine would be possible. We chose 17 as a precursor of the intramolecular allylic amination using (R,R,R)-ligand 5 to provide the 2,5-cis cyclization product 18a as a major isomer (Scheme 7).  

With the cyclization precursor 17 in hand, the diastereoselective cyclization of the allylic carbonate was examined under similar conditions using the (R,R,R)-ligand 5 (Scheme 9). Predictably, the desired product 18a (2,5-cis) was obtained in good yield with high diastereoselectivity (18a :

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87%, 18b : 8%).19 Next, we converted the obtained pyrrolidine derivative 18a into (+)-preussin (7) via several steps. An olefin cross metathesis between the pyrrolidine derivative 18a and 1nonene provided the alkene 25, the Ns group of which was then removed under standard conditions by treatment with thiophenol in the presence of K2CO3 to give the amine 26. The reductive methylation of 26 afforded the amine 27 in moderate yield. Finally, the amine 27 was treated with TBAF to provide (+)-preussin (7) in good yield. The spectral data for the synthesized (+)-preussin (7) were full agreement with reported values for naturally occurring (+)-preussin (7).15

ARTICLE   reaction promises to be very useful for the synthesis of such compounds. View Article Online

DOI: 10.1039/C3OB42229A

Experimental   General methods Infrared (IR) spectra were recorded on a Perkin–Elmer 1600 series FT-IR spectrometer. Mass spectra (MS) were recorded on a JEOL JMN-DX 303/JMA-DA 5000 spectrometer. Microanalyses were performed on a Perkin–Elmer CHN 2400 Elemental Analyzer. Optical rotations were measured with a JASCO DIP-360 or JASCO P-1020 digital polarimeter. 1HNMR spectra were recorded on a JEOL JNM-AL 400 (400 MHz) spectrometer, using tetramethylsilane as an internal standard. The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. 13CNMR spectra were recorded on a JEOL JNM-AL 400 (400 MHz) spectrometer. Chemical shifts are reported relative to the internal standard (CDCl3; δ 77.00). Column chromatography was carried out on Merck Silica Gel 60 (230–400 mesh) or KANTO Silica Gel 60N (40–50 µm) for flash chromatography. All non-aqueous reactions were carried out under argon atmosphere. Additionally, methyl carboxylate 1a3), alkene 97) and allylic alcohol 2018) were known product, and they were prepared according to reported procedure. (S)-tert-Butyl 4-[(R)-1-{(tert-butyldimethylsilyl)oxy}-3oxopropyl]-2,2-dimethyloxazolidine-3-carboxylate (10)

 

  Conclusion   In summary, the intramolecular iridium-catalyzed allylic cyclization of (E)-allyic methyl carbonates by an exchange in both enantiomers of the (S,S,S)-ligand 4 or the (R,R,R)-ligand 5 afforded the 2,5-trans/cis pyrrolidine derivatives, accompanied with the interconversion of diastereoselectivities. The stereodivergent ring construction was applied to the syntheses of the 2,5-trans/cis pyrrolidine alkaloids (+)-bulgecinine (6)·HCl and (+)-preussin (7). Because a wide variety of natural products and medicinally relevant compounds with 2,5trans/cis substituted pyrrolidine structures exists, this amination

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Ozone was bubbled through a stirred solution of the alkene 9 (1.91 g, 4.96 mmol) in CH2Cl2 (50 mL) at –78 °C. The solution was stirred at –78 °C for 1 h, at which time the solution became blue, and then oxygen was bubbled through the solution until it became colorless. Triphenylphosphine (1.95 g, 7.44 mmol) was then added to the stirred solution at –78 °C and then it was allowed to warm to room temperature over 18 h under argon atmosphere. The solvents were removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/EtOAc = 50:1 → 5:1) to give aldehyde 10 (937 mg, 93%) as a white solid. m.p. 47-49 °C; [α]D28 –23.5 (c 0.86, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 0.06 (s, 3H), 0.10 (s, 3H), 0.87 (s, 9H), 1.47 (s, 15H), 2.53-2.63 (m, 2H), 3.87-3.91 (m, 1H), 4.02 (m, 2H), 4.35 (m,1H), 9.83 (m,1H); 13C-NMR (100 MHz, CDCl3) δ –4.9, –4.3, 14.1, 18.0, 24.7, 25.6, 25.7, 27.3, 28.3, 31.6, 48.4, 61.4, 64.3, 67.9, 80.6, 94.1, 153.3, 201.1; IR (KBr) cm–1: 3007, 2976, 2933, 2896, 2859, 1714, 1475, 1393, 1365, 1300, 1257, 1210, 1178, 1101, 1084, 1060; EI-MS (m/z): 388 (M++1). HRMS Calcd for C19H38NO5Si: 388.2519, Found: 388.2511. Anal. Calcd for C19H37NO5Si: C, 58.88; H, 9.62; N, 3.61. Found: C, 59.23; H, 10.02; N, 3.62. (S)-tert-Butyl 4-[(R,Z)-1-{(tert-butyldimethylsilyl)oxy}-5hydroxypent-3-en-1-yl]-2,2-dimethyloxazolidine-3carboxylate (11)

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NaH (60% dispersion in mineral oil, 273 mg, 6.83 mmol) was added to a solution of ethyl diphenylphocphonoacetate (1.8 mL, 6.83 mmol) in THF (23 mL) at 0 °C. After stirring at 0 °C for 30 min, the suspension was cooled to –78 °C. A solution of aldehyde 10 (883 mg, 2.28 mmol) in THF (23 mL) was added to the suspension via cannula at –78 °C. After stirring at –78 °C for 30 min, the reaction mixture was warmed to 0 °C. The reation was quenched with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (30 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (nhexane/EtOAc = 50:1) to afford a mixture of desired α,βunsaturated ester and inseparable byproduct (887 mg) The obtained mixture of α,β-unsaturated ester and inseparable byproduct (887 mg) was dissolved in CH2Cl2 (19 mL). DIBALH (1.5 M solution in toluene, 3.2 mL, 4.79 mmol) was added dropwise to the solution at –78 °C. After stirring at –78 °C for 1 h, the reaction was quenched with water (10 mL). 10% Aqueous solution of potassium sodium tartrate (20 mL) was added to the mixture and the resulting mixture was then stirred vigorously at room temperature for 5 h. The separated aqueous layer was extracted with CH2Cl2 (3 × 20 mL), and the combined extracts were dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (nhexane/EtOAc = 10:1) to afford alcohol 11 (436 mg, 46 %, 2 steps) as a colorless oil. [α]D25 –42.8 (c 1.29, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.48 (s, 15H), 2.13-2.40 (m, 3H), 3.84-3.90 (m, 2H), 4.03 (m, 1H), 4.11-4.19 (m, 3H), 5.68-5.74 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ –4.6, –4.3, 14.1, 18.0, 22.6, 25.2, 25.9, 27.0, 28.5, 31.6, 32.7, 58.4, 60.3, 63.1, 69.8, 80.5, 127.6, 130.7; IR (neat) cm–1: 3434, 2931, 2858, 1694, 1682, 1473, 1463, 1393, 1254, 1208, 1174, 1097, 1075; EI-MS (m/z): 416 (M++1). HRMS Calcd for C21H42NO5Si: 416.2832, Found: 416.2850. (S)-tert-Butyl 2,2-dimethyl-4-{(R,Z)-11,11,12,12tetramethyl-3-oxo-2,4,10-trioxa-11-silatridec-6-en-9yl}oxazolidine-3-carboxylate (12) Methyl chloroformate (0.24 mL, 3.1 mmol) was added to a solution of allylic alcohol 11 (261 mg, 0.627 mmol), DMAP (18.4 mg, 0.151 mmol) and pyridine (0.51 mL, 6.27 mmol) in CH2Cl2 (6.3 mL) at room temperature. After stirring at room temperature for 13 h, the reaction was quenched with water (5 mL). The whole mixture was extracted with CH2Cl2 (20 mL). The extract was washed with water (3 × 10 mL) and brine (10 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (n-hexane/EtOAc = 20:1) to afford methyl carbonate 12 (290 mg, 98%) as a colorless oil.

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Journal  Name   [α]D24 –43.4 (c 0.92, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 0.05 (s, 3H), 0.07 (s, 3H), 0.90 (s, 9H), 1.48 (s, 15H), 2.25 (dd, View Article Online J = 6.8, 12.2 Hz, 2H), 3.78 (s, 3H), 3.87-3.91 (m, 2H), 4.09DOI: 10.1039/C3OB42229A 4.11 (m, 1H), 4.35 (brs, 1H), 4.61-4.71 (m, 2H), 5.62-5.75 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ –4.5, –4.3, 18.0, 25.3, 25.9, 26.2, 26.6, 28.4, 33.7, 54.7, 60.9, 62.6, 63.4, 63.6, 69.2, 80.1, 94.0, 124.6, 131.2, 155.7; IR (neat) cm–1 : 2957, 2932, 2858, 1755, 1694, 1463, 1445, 1367, 1265, 1208, 1176, 1096, 1075; EI-MS (m/z) : 474 (M++1). HRMS Calcd for C23H44NO7Si : 474.2887, Found : 474.2891. (5R,6S,Z)-6-Amino-5,7-bis{(tertbutyldimethylsilyl)oxy}hept-2-en-1-yl methyl carbonate (13) To a solution of 12 (42.0 mg, 0.0887 mmol) in CH2Cl2 (1.0 mL) was added TFA (1.0 mL) at 0 °C. After the mixture was stirred at 0 °C for 1 h, the solvents were removed under reduced pressure. Traces of TFA were removed from a mixture by azeotropic distillations with toluene (2 × 5 mL) under reduced pressure at room temperature. The residue was dissolved in CH2Cl2 (1.0 mL). Imidazole (90.5 mg, 1.33 mmol) and TBSCl (53.5 mg, 0.355 mmol) were added to this solution at 0 °C. The reaction was stirred at room temperature for 15 h, and then quenched with water (5 mL). The whole mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (n-hexane/EtOAc = 10:1) to afford amime 13 (37.1 mg, 93%, 2 steps) as a colorless oil. [α]D25 –19.9 (c 1.10, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 0.06 (s, 12H), 0.89 (s, 9H), 0.90 (s, 9H), 2.23-2.27 (m, 1H), 2.46-2.53 (m, 1H), 2.83 (m, 1H), 3.45 (dd, J = 7.2, 9.7 Hz, 1H), 3.66-3.76 (m, 2H), 3.78 (s, 3H), 4.69 (d, J = 7.2 Hz, 2H), 5.635.69 (m, 1H), 5.74-5.83 (m, 1H); 13C-NMR (100 MHz, CDCl3) δ –5.4, –5.3, –4.7, –4.3, 18.0, 18.2, 25.7, 25.8, 25.9, 30.8, 54.7, 56.6, 63.8, 64.9, 73.0, 124.5, 131.9, 155.7; IR (neat) cm–1: 3372, 2956, 2930, 2887, 2858, 1749, 1589, 1472, 1463, 1444, 1409, 1389, 1361, 1267, 1085, 1006; EI-MS (m/z): 447 (M+). HRMS Calcd for C21H45NO5Si2: 447.2836, Found: 447.2821. (5R,6S,Z)-5,7-Bis{(tert-butyldimethylsilyl)oxy}-6-(2nitrophenylsulfonamido)hept-2-en-1-yl methyl carbonate (1b) To a solution of amine 13 (250 mg, 0.559 mmol), Et3N (0.14 mL, 1.01 mmol) and DMAP (16.4 mg, 0.134 mmol) in CH2Cl2 (45 mL) was added 2-nitrobenzenesulfonyl chloride (149 mg, 0.670 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. After evaporation, the residue was diluted with EtOAc (30 mL). The whole mixture was washed successively with brine (15 mL), 5% KHSO4 (15 mL) and brine (15 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (n-hexane/EtOAc = 20:1→15:1) to afford 1b (323 mg, 91%) as a white solid.

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m.p. 56-59 °C; [α]D23 +41.4 (c 1.10, CHCl3); 1H-NMR (400 MHz, CDCl3) δ –0.16 (s, 3H), –0.08 (s, 3H), 0.05 (s, 3H), 0.06 (s, 3H), 0.78 (s, 9H), 0.85 (s, 9H), 2.40 (dd, J = 6.3, 6.3 Hz, 2H), 3.48-3.58 (m, 2H), 3.71 (dd, J = 5.3, 10.1 Hz, 1H), 3.78 (s, 3H), 4.02-4.06 (m, 1H), 4.62-4.65 (m, 2H), 5.66-5.76 (m, 3H), 7.697.75 (m, 2H), 7.86-7.88 (m, 1H), 8.09-8.12 (m, 1H); 13C-NMR (100 MHz, CDCl3) δ –5.9, –5.6, –4.6, –4.3, 18.0, 18.1, 25.7, 25.8, 31.8, 54.8, 59.9, 61.1, 63.7, 71.7, 125.2, 125.4, 130.4, 130.6, 132.9, 133.2, 135.1, 155.7; IR (KBr) cm–1 : 3338, 3090, 3050, 2958, 2934, 2888, 2858, 1752, 1665, 1593, 1548, 1472, 1463, 1442, 1415, 1368, 1347, 1307, 1208, 1175, 1125, 1102, 1080, 1004; FAB-MS (m/z) : 633 (M++1); HRMS Calcd for C27H49N2O9Si2 : 633.2697, Found : 633.2701. Anal. Calcd for C27H48N2O9SSi: C, 51.24; H, 7.64; N, 4.43. Found: C, 51.34; H, 7.85; N,4.37. (2S,3R,5R)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tertbutyldimethylsilyl)oxy}methyl]-1-{(2-nitrophenyl)sulfonyl}5-vinylpyrrolidine (2a) (2S,3R,5S)-3-{(tert-Butyldimethylsilyl)oxy}-2-[{(tertbutyldimethylsilyl)oxy}methyl]-1-{(2-nitrophenyl)sulfonyl}5-vinylpyrrolidine (2b) (Table 1 entry 1) To a solution of [Ir(cod)Cl]2 (8.5 mg, 0.0130 mmol, 8 mol%) and (S,S,S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4a’]dinaphthalen-4-yl)bis(1-phenylethyl)amine ((S,S,S)-Ligand) 4 (13.6 mg, 0.025 mmol, 16 mol%) in THF (0.45 mL) was added dry 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (7.0 mg, 0.050 mmol, 32 mol%). After the mixture was stirred at room temperature for 1 h, a solution of allylic carbonate 1a (E:Z = 40:1, 100 mg, 0.158 mmol) in THF (1.0 mL) was added to the reaction mixture via cannula. After stirring at 40 °C for 12 h, the mixture was concentrated and the residue purified by silica gel column chromatography (n-hexane/EtOAc = 30:1) to give the cyclic compound 2 (2a:2b = 12:1) (68.7 mg, 78%, combined yield of 2a and 2b) as a white solid. These compound data were collected using partially separated 2a (pure) or 2b (pure). 2a ; m.p. 90-92 oC; [α]D24 +137.2 (c 0.96, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.09 (s, 3H), 0.10 (s, 3H), 0.86 (s, 9H), 0.90 (s, 9H), 1.69 (d, J = 13.5 Hz, 1H), 2.51-2.58 (m, 1H), 3.48 (dd, J = 8.3, 10.1 Hz, 1H), 3.96 (dd, J = 3.4, 10.6 Hz, 1H), 4.07 (dd, J = 2.9, 8.2 Hz, 1H), 4.45 (m, 2H), 4.79 (d, J = 8.6 Hz, 1H), 5.06 (d, J = 15.9 Hz, 1H), 5.72-5.81 (m, 1H), 7.53-7.63 (m, 3H), 8.14 (d, J = 6.8 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ –5.5, –5.4, –5.0, –4.9, 17.9, 18.2, 25.7, 25.9, 39.6, 64.1, 64.3, 71.9, 74.8, 117.4, 123.7, 130.6, 131.0,132.8, 135.8, 138.3, 148.9; IR (KBr) cm-1 : 3097, 3030, 2932, 2886, 2888, 1584, 1548, 1472, 1352; FAB-MS (m/z) : 557 (M++1); HRMS Calcd for C25H45N2O6SSi2 : 557.2539, Found : 557.2529. 2b ; m.p. 94-96 °C; [α]D24 +27.2 (c 0.76, CHCl3); 1H-NMR (400 MHz, CDCl3) δ –0.08 (s, 3H), –0.05 (s, 3H), 0.09 (s, 3H), 0.10 (s, 3H), 0.69 (s, 9H), 0.91 (s, 9H), 1.88-2.02 (m, 2H), 3.43 (dd, J = 9.7, 11.6 Hz, 1H), 3.86-3.90 (dd, J = 3.9, 11.6 Hz, 2H), 4.30 (d, J = 3.4 Hz, 1H), 4.36-4.42 (dd, J = 7.3, 17.4 Hz, 1H),

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ARTICLE   5.08 (d, J = 10.1 Hz, 1H), 5.18 (d, J = 17.4 Hz, 1H), 5.83-5.92 (m, 1H), 7.51-7.54 (m, 1H), 7.61-7.68 (m, 2H), 7.99-8.01 (m, View Article Online 1H); 13C-NMR (100 MHz, CDCl3) δ –5.5,DOI: –5.4, –5.0, 17.9, 18.3, 10.1039/C3OB42229A 25.6, 25.9, 41.1, 62.6, 64.4, 71.2, 72.4, 115.7, 123.8, 130.9, 131.0, 132.8, 133.3, 139.2, 149.0; IR (KBr) cm–1 : 3095, 2956, 2932, 2859, 2886, 1548, 1473, 1440; FAB-MS (m/z) : 557 (M++1); HRMS Calcd for C25H45N2O6SSi2 : 557.2539, Found : 557.2538. Diastereomeric ratio (2a:2b) was determined by 1H-NMR analysis of the crude reaction mixutre. The ratio was caclulated from two peaks (2a ; 5.72-5.81 ppm (m, 1H), 2b ; 5.83-5.92 (m, 1H)). (Table 1 entry 2) To a solution of [Ir(cod)Cl]2 (7.6 mg, 0.0114 mmol, 8 mol%) and (S,S,S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4a’]dinaphthalen-4-yl)bis(1-phenylethyl)amine ((R,R,R)-Ligand) 5 (12.3 mg, 0.0227 mmol, 16 mol%) in THF (0.5 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (6.3 mg, 0.0454 mmol, 32 mol%). After the mixture was stirred at room temperature for 1 h, a solution of allylic carbonate 1a (E:Z = 40:1, 90.0 mg, 0.142 mmol) in THF (1.1 mL) was added to the reaction mixture via cannula. After stirring at 40 °C for 12 h, the mixture was concentrated and the residue purified by silica gel column chromatography (n-hexane/EtOAc = 30:1) to give the cyclic compound 2 (2a:2b = 1:6) (58.5 mg, 74%, combined yield of 2a and 2b) as a white solid. (Table 1 entry 3) To a solution of [Ir(cod)Cl]2 (8.9 mg, 0.0133 mmol, 8 mol%) and (S,S,S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4a’]dinaphthalen-4-yl)bis(1-phenylethyl)amine ((S,S,S)-Ligand) 4 (14.4 mg, 0.0266 mmol, 16 mol%) in THF (0.5 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (7.4 mg, 0.0533 mmol, 32 mol%). After the mixture was stirred at room temperature for 1 h, a solution of allylic carbonate 1a (Z only, 105.4 mg, 0.167 mmol) in THF (1.1 mL) was added to the reaction mixture via cannula. After stirring at 40 °C for 12 h, the mixture was concentrated and the residue purified by silica gel column chromatography (n-hexane/EtOAc = 30:1) to give the cyclic compound 2 (2a:2b = 1:2.4) (88.6 mg, 95%, combined yield of 2a and 2b) as a white solid. (Table 1 entry 4) To a solution of [Ir(cod)Cl]2 (8.9 mg, 0.0133 mmol, 8 mol%) and (R,R,R)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4a’]dinaphthalen-4-yl)bis(1-phenylethyl)amine ((R,R,R)-Ligand) 5 (14.4 mg, 0.0266 mmol, 16 mol%) in THF (0.5 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (7.4 mg, 0.0533 mmol, 32 mol%). After the mixture was stirred at room temperature for 1 h, a solution of allylic carbonate 1a (Z only, 105.4 mg, 0.167 mmol) in THF (1.1 mL) was added to the reaction mixture via cannula. After stirring at 40 °C for 12 h, the mixture was concentrated and the residue purified by silica gel column chromatography (n-hexane/EtOAc = 30:1) to give

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Organic & Biomolecular Chemistry Accepted Manuscript

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(Table 1, entry 5) To a solution of [Ir(cod)Cl]2 (9.4 mg, 0.0134 mmol, 8 mol%) and triphenyl phosphite (7.3 µL, 0.0278 mmol, 16 mol%) in THF (0.5 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (7.8 mg, 0.056 mmol, 32 mol%). After the mixture was stirred at room temperature for 1 h, a solution of allylic carbonate 1a (E:Z = 9:1, 111 mg, 0.175 mmol) in THF (1.1 mL) was added to the reaction mixture via cannula. After stirring at 40 °C for 12 h, the mixture was concentrated and the residue purified by silica gel column chromatography (n-hexane/EtOAc = 30:1→ 15:1) to give the cyclic compound 2 (2a:2b = 1:1) (56.5 mg, 58%, combined yield of 2a and 2b) as a white solid and starting material 1a (41.1 mg, 37%) as a pale yellow oil. (Table 1, entry 6) To a solution of [Ir(cod)Cl]2 (6.9 mg, 0.0102 mmol, 8 mol%) and triphenyl phosphite (5.4 µL, 0.0205 mmol, 16 mol%) in THF (0.4 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (7.0 mg, 0.050 mmol, 32 mol%). After the mixture was stirred at room temperature for 1 h, a solution of allylic carbonate 1b (Z only, 81.0 mg, 0.128 mmol) in THF (0.8 mL) was added to the reaction mixture via cannula. After stirring at 40 °C for 12 h, the mixture was concentrated and the residue purified by silica gel column chromatography (n-hexane/EtOAc = 30:1→15:1) to give the cyclic compound 2 (2a:2b = 1:1) (35.6 mg, 50%, combined yield of 2a and 2b) and starting material 1b (26.7 mg, 33%) as white solids. (2R,4R,5S)-4-{(tert-Butyldimethylsilyl)oxy}-5-[{(tertbutyldimethylsilyl)oxy}methyl]-1-{(2nitrophenyl)sulfonyl}pyrrolidine-2-carbaldehyde (14) Ozone was bubbled through a stirred solution of the 2 (2a:2b = 12:1, 877 mg, 1.57 mmol) in CH2Cl2 (62 mL) at –78 °C. The solution was stirred at –78 °C for 1 h, at which time the solution became blue, and then oxygen was bubbled through the solution until it became colorless. Dimethyl sulfide (0.58 mL, 7.84 mmol) was added to the stirred solution at –78 °C and then it was allowed to warm to room temperature over 10 h under argon atmosphere. The solvents were removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/EtOAc = 10:1 → 3:1) to give aldehyde 14 (736 mg, 84%) as a white solid. m.p. 132-134 oC; [α]D19 +129.8 (c 1.08, CHCl3); 1H-NMR (400 MHz, CDCl3) δ –0.05 (s, 3H), –0.01 (s, 3H), 0.04 (s, 3H), 0.08 (s, 3H), 0.83 (s, 9H), 0.83 (s, 9H), 2.04 (d, J = 13.5 Hz, 1H), 2.49-2.56 (ddd, J = 2.9, 9.2, 13.5 Hz, 1H), 3.38 (dd, J = 7.3, 10.6 Hz, 1H), 3.62 (dd, J = 3.4, 10.6 Hz, 1H), 4.09 (dd, J = 3.4, 7.3 Hz, 1H), 4.39 (dd, J = 2.4, 9.2 Hz, 2H), 7.66 (m, 3H), 8.11 (m, 1H), 9.63 (d, J = 2.4 H, 1Hz); 13C-NMR (100 MHz, CDCl3) δ –5.7, –5.6, –5.0, –4.9, 17.8, 18.1, 25.6, 25.8, 39.1, 62.3, 68.0, 71.1,73.7, 124.4, 130.4, 132.0, 133.9, 135.0, 148.1, 202.0; IR (KBr) cm–1 : 3703, 2958, 2932, 2859, 2888, 1736, 1543, 1473;

8  |  J.  Name.,  2012,  00,  1-­‐3  

FAB-MS (m/z) : 559 (M++1). HRMS C24H43N2O7SSi2 : 559.2329, Found : 559.2312.

Calcd

for

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DOI: 10.1039/C3OB42229A

(2R,4R,5S)-Methyl 4-{(tert-butyldimethylsilyl)oxy}-5-[{(tertbutyldimethylsilyl)oxy}methyl]-1-{(2nitrophenyl)sulfonyl}pyrrolidine-2-carboxylate (15a) (2R,4R,5S)-Methyl 5-[{(tert-butyldimethylsilyl)oxy}methyl]4-hydroxy-1-{(2-nitrophenyl)sulfonyl}pyrrolidine-2carboxylate (15b) A solution of NaClO2 (0.73 M aqueous solution, 1.1 mL) was added to a solution of aldehyde 14 (49.9 mg, 0.0893 mmol), 2methyl-2-butene (0.42 mL, 3.96 mmol) and NaH2PO4·2H2O (97.5 mg, 0.625 mmol) in t-BuOH (3 mL) at 0 °C. After stirring at room temperature for 1 h, the reaction mixture was quenched with water (5 mL). The whole mixture was extracted with EtOAc (3 × 15 mL) and the combined organic layers were dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in Et2O (2 mL) and the solution was coolded to 0 °C. CH2N2 in Et2O (excess) was added to the solution at 0 °C. After stirring at room temperature for 14 h, the solvents was removed under reduced pressure, and the residue was purified by silica gel column chromatography (nhexane/EtOAc = 30:1) to give ester 15a (35.3 mg, 67%) and ester 15b (11.7 mg, 28%) as colorless oils. 15a; [α]D16 +64.8 (c 1.04, CHCl3); 1H-NMR (400 MHz, CDCl3) δ –0.06 (s, 3H), –0.02 (s, 3H), 0.03 (s, 3H), 0.05 (s, 3H), 0.82 (s, 9H), 0.84 (s, 9H), 2.14 (d, J = 13.0 Hz, 1H), 2.46-2.53 (ddd, J = 4.4, 9.7, 13.5 Hz, 1H), 3.45 (dd, J = 7.3, 10.6 Hz, 1H), 3.58 (s, 3H), 3.74 (dd, J = 3.4, 10.6 Hz, 1H), 3.94 (dd, J = 2.4, 6.8 Hz, 1H), 4.41 (d, J = 3.4, 1H), 4.69 (d, J = 8.7, 1H), 7.63-7.67 (m, 3H), 8.36 (m, 1H); 13C-NMR (100 MHz, CDCl3) δ –5.6, –5.0, – 4.9, 17.8, 18.2, 25.5, 25.8, 38.0, 52.1, 62.4, 70.1, 74.8, 124.2, 131.0, 131.5, 133.0, 135.7, 148.2, 171.6; IR (neat) cm–1 ; 3099, 2953, 2931, 2886, 2858, 1765, 1544, 1472; FAB-MS (m/z): 589 (M++1). HRMS Calcd for C25H45N2O8SSi2: 589.2435, Found: 589.2452. 15b; [α]D26 +151.1 (c 1.07, CHCl3); 1H-NMR (400 MHz, CDCl3) δ –0.06 (s, 3H), –0.01 (s, 3H), 0.83 (s, 9H), 1.99-2.06 (m, 1H), 2.67-2.75 (m, 1H), 3.64 (s, 3H), 3.69-3.71 (m, 2H), 4.28-4.30 (m, 2H), 4.61 (d, J = 8.7 Hz, 1H), 7.65-7.73 (m, 3H), 8.09-8.12 (m, 1H); 13C-NMR (100 MHz, CDCl3) δ –5.7, –5.6, 18.1, 27.8, 37.8, 53.0, 61.4, 62.9, 72.0, 75.3, 76.7, 124.4, 130.7, 131.6, 133.7, 134.2, 175.1; IR (neat) cm–1 : 3465, 3098, 2955, 2857, 1732, 1591, 1547, 1471, 1440, 1359, 1256, 1218, 1163, 1115; FAB-MS (m/z) : 475 (M++1). HRMS Calcd for C19H31N2O8SSi : 475.157, Found : 475.1562. Acetylation of mono-TBS protected ester 15b (2R,4R,5S)-methyl 4-acetoxy-5-[{(tertbutyldimethylsilyl)oxy}methyl]-1-{(2nitrophenyl)sulfonyl}pyrrolidine-2-carboxylate (28)

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the cyclic compound 2 (2a:2b = 3.5:1) (92.1 mg, 99%, combined yield of 2a and 2b) as a white solid.

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Journal  Name   Ac2O (8.6 mg 0.0843 mmol) was added to a mixture of 15b (20.0 mg, 0.0421 mmol), pyridine (10.0 mg, 0.126 mmol) and DMAP (0.47 mg, 0.00421 mmol) in CH2Cl2 (0.8 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h, and the reaction was quenched with water (1 mL). The whole mixture was extracted with EtOAc (2 × 10 mL). The organic extracts were washed with brine (5 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (n-hexane/EtOAc = 5:1) to afford 28 as a colorless oil (16.8 mg, 77%) [α]D25 +95.0 (c 2.05, CHCl3); 1H-NMR (400 MHz, CDCl3) δ – 0.14 (s, 3H), –0.03 (s, 3H), 0.78 (s, 9H), 2.02 (s, 3H), 2.23 (d, J = 14.0 Hz, 1H), 2.69 (ddd, J = 5.3, 8.7, 14.0 Hz, 1H), 3.65 (s, 3H), 3.78-3.86 (m, 2H), 4.20 (brs, 1H), 4.76 (d, J = 8.7 Hz), 5.16 (d, J = 5.3 Hz), 7.67-7.71 (m, 3H), 8.19-8.21 (m, 1H); 13CNMR (100 MHz, CDCl3) δ –5.8, –5.7, 18.0, 20.9, 25.7, 35.7, 52.3, 61.9, 62.5, 68.6, 124.5, 130.9, 131.7, 133.4, 135.6, 170.4, 171.7; IR (neat) cm–1 : 2954, 2930, 2858, 1759, 1739, 1547; EIMS (m/z) : 517 (M++1). HRMS Calcd for C21H33N2O9SSi : 517.1676, Found : 517.1686. After this acetylation reaction (15b → 28), chemical shift value of C4-H most changed (C4-H of the compound 15b : 4.28-4.30 ppm (m, CH(CH)(CH2)OH), C4-H of the compound 28: 5.16 ppm (d, J = 5.3 Hz, CH(CH)(CH2)OAc)). Additionally, HMBC analysis of 28 revealed the relation between C4-H and carbonyl carbon of the acetoxy group. (2R,4R,5S)-Methyl-4-(tert-butyldimethylsilyloxy)-5-(tertbutyldimethylsilyloxy methyl)pyrrolidine-2-carboxylate (16) PhSH (90 µL, 0.85 mmol) was added to a mixture of 15a (166 mg, 0.28 mmol) and K2CO3 (195 mg, 1.41 mmol) in CH3CN (6.4 mL) at room temperature. The reaction mixture was stirred at 40 °C for 2 h. After filtration, the filtrate was concentrated in vacuo. The residue was diluted with CH2Cl2 (50 mL), and the whole mixture was separated. The organic layer was washed with 10% Na2S2O3 (15 mL) and brine (15 mL), and dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography (n-hexane/EtOAc = 20:1) to give amine 16 (107 mg, 94%) as a pale yellow oil. [α]D20 –7.9 (c 1.01, CHCl3); 1H-NMR (400 MHz, CDCl3) δ 0.03 (s, 6H), 0.05 (s, 6H), 0.85 (s, 9H), 0.89 (s, 9H), 2.04 (m, 1H), 2.04-2.09 (m, 1H), 2.22-2.29 (ddd, J = 4.8, 8.7, 13.5 Hz, 1H), 3.16-3.20 (m, 1H), 3.36-3.40 (dd, J = 7.7, 10.6 Hz, 1H), 3.543.58 (dd, J = 4.8, 10.1 Hz, 1H), 3.72 (s, 3H), 3.80-3.83 (dd, J = 3.4, 8.7 Hz, 1H), 4.14-4.17 (m, 1H); 13C-NMR (100 MHz,CDCl3) δ –5.5, –5.4, –4.8, –4.8, 25.6, 25.9, 37.9, 52.1, 58.5, 64.6, 67.5, 73.0, 132.0, 175.6; IR (neat) cm–1 : 3684, 3664, 2955, 2931, 2896, 1743, 1543, 1472; FAB-MS (m/z) : 404 (M++1). HRMS Calcd for C19H42NO4Si2 : 404.2652, Found : 404.2649. (+)-Bulgecinine (6) · hydrochloride

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ARTICLE  

The solution of amine 16 (40 mg, 0.099 mmol) in 6 N HCl (3.0 View Article Online mL) was stirred at 100 °C for 12 h. After cooling to room DOI: 10.1039/C3OB42229A temperature, the reaction mixture was washed with CH2Cl2 (5 mL). The aqueous layer was evaporated in vacuo, (+)bulgecinine (6) · hydrochloride (16.2 mg, 83%) was obtained as brown amorphous solid. [α]D18 –11.9 (c 1.62, 1 N HCl) ((–)-bulgecinine (ent-6)·HCl ; [α]D25 = +11.71 (c 0.65, 1 N HCl)12f)); 1H-NMR (400 MHz, D2O) δ 2.18 (ddd, J = 4.9, 9.3, 14.1 Hz, 1H), 2.52 (ddd, J = 5.4, 8.8, 14.1 Hz, 1H), 3.62-3.81 (m, 3H), 4.31 (dd, J = 4.4, 8.8 Hz, 1H), 4.41 (dd, J = 4.9, 8.8 Hz, 1H); 13C-NMR (100 MHz, D2O) δ 36.8, 58.7, 59.1, 68.2, 71.2, 172.7; IR (KBr) cm–1 : 3367, 1733, 1627, 1361, 1249; FAB-MS (m/z) :162 (M++1). HRMS Calcd for C6H12NO4 : 162.0766, Found : 162.0767. (5S,6S)-6-{(tert-Butoxycarbonyl)amino}-5-hydroxy-7phenylhept-2-en-1-yl methyl carbonate (22) A solution of alcohol 20 (1.52 g, 5.22 mmol) and (Z)-but-2-ene1,4-diyl dimethyl dicarbonate (21) (5.33 g, 26.1 mmol) in CH2Cl2 (104 mL) was degassed with argon for 30 min. Grubbs catalyst 2nd generation (222 mg, 0.261 mmol, 1 mol%) was added to the solution. The reaction was stirred at room temperature for 12 h. After concentration in vacuo, the residue was purified by flash chromatography (n-hexane/Et2O = 3:1→ 2:1) to give a methyl carbonate 22 (1.76 g, 89%) as a brown oil. [α]D27 –16.5 (c 0.68, CHCl3); 1H-NMR (400 MHz, CDCl3) E isomer δ 1.34 (brs, 1H), 1.41 (s, 9H), 2.21-2.31 (m, 1H), 2.842.95 (m, 2H), 3.61 (brs, 1H), 3.73-3.75 (m, 1H), 3.77 (s, 3H), 4.56 (d, J = 5.9 Hz, 2H), 5.63-5.70 (m, 1H), 5.73-5.80 (m, 1H), 7.19-7.31 (m, 5H); Z isomer δ 1.34 (brs, 1H), 1.41 (s, 9H), 2.21-2.31 (m, 1H), 2.84-2.95 (m, 2H), 3.61 (brs, 1H), 3.73-3.75 (m, 1H), 3.77 (s, 3H), 4.87 (d, J = 9.3 Hz, 2H), 5.63-5.70 (m, 1H), 5.73-5.80 (m, 1H), 7.19-7.31 (m, 5H); 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ 28.3, 29.7, 37.7, 38.6, 54.7, 55.4, 68.1, 70.3, 79.4, 126.4, 127.0, 128.5, 129.3, 132.3, 138.3, 155.6, 156.0; IR (neat) cm–1 : 3428, 3030, 2115, 1748, 1668, 1505, 1455, 1393, 1367, 1268, 1170; EI-MS (m/z) : 379 (M+); HRMS Calcd for C20H29NO6 : 379.1995, Found : 379.1991. (5S,6S)-6-Amino-5-(tert-butyldimethylsilyloxy)-7phenylhept-2-en-1-yl methyl carbonate (24) To a solution of 22 (221 mg, 0.583 mmol) in CH2Cl2 (2.7 mL) was added TFA (2.7 mL) at 0 °C. After the mixture was stirred at room temperature for 1 h, the solvents were removed under reduced pressure. Traces of TFA were removed from a mixture by azeotropic distillations with toluene (2 × 10 mL) under reduced pressure at room temperature. The residue was dissolved in CH2Cl2 (2.7 mL). Imidazole (298 mg, 4.37 mmol) and TBSCl (176 mg, 1.17 mmol) were added to this solution at 0 °C. After being stirred at room temperature for 14 h, the reaction was quenched with water (10 mL). The whole mixture was extracted with CH2Cl2 (3 × 20

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mL). The combined organic layers were dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (n-hexane/Et2O = 6:1→1:1) to afford 24 (174 mg, 76 %, 2 steps) as a colorless oil. [α]D23 +2.9 (c 1.30, CHCl3); 1H-NMR (400 MHz, CDCl3) E isomer δ 0.03 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.50 (brs, 2H), 2.21-2.28 (m, 1H), 2.34-2.46 (m, 2H), 2.78-2.82 (m, 1H), 2.862.91 (m, 1H), 3.60 (dt, J = 3.8, 5.8 Hz, 1H), 3.71 (s, 3H), 4.53 (d, J = 6.3 Hz, 2H), 5.58-5.65 (m, 1H), 5.74 (ddd, J = 6.8, 7.3, 15.4 Hz, 1H), 7.11-7.16 (m, 3H), 7.21-7.25 (m, 2H); Z isomer δ 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.50 (br, s, 2H), 2.212.28 (m, 1H), 2.34-2.46 (m, 2H), 2.78-2.82 (m, 1H), 2.86-2.91 (m, 1H), 3.60 (dt, J = 3.8, 5.8 Hz, 1H), 3.69 (s, 3H), 4.66 (m, 2H), 5.58-5.65 (m, 1H), 5.74 (ddd, J = 6.8, 7.3, 15.4 Hz, 1H), 7.11-7.16 (m, 3H), 7.21-7.25 (m, 2H); 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ –4.7, –4.6, –4.2, –4.1, 18.0, 25.7, 25.8, 36.7, 40.4, 40.6, 54.3, 54.6, 55.9, 67.8, 68.2, 74.7, 124.7, 125.8, 126.1, 128.4, 129.1, 131.6, 132.9, 139.6, 155.5, 155.6; IR (neat) cm–1 : 3383, 3028, 2955, 2930, 2857, 1748, 1603, 1495, 1443, 1382, 1361, 1268, 1067; EI-MS (m/z) : 393 (M+); HRMS Calcd for C21H35NO4Si : 393.2335, Found : 393.2341. Anal. Calcd for C21H35NO4Si: C, 64.08; H, 8.96; N, 3.56. Found: C, 63.88; H, 9.16; N, 3.46. (5S,6S)-5-(tert-Butyldimethylsilyloxy)-6-(2nitrophenylsulfonamido)-7-phenylhept-2-en-1-yl carbonate (17)

methyl

To a solution of amine 24 (1.71 g, 4.34 mmol), Et3N (1.1 mL, 7.82 mmol) and DMAP (127 mg, 1.04 mmol) in CH2Cl2 (43 mL) was added 2-nitrobenzenesulfonyl chloride (1.16 g, 5.21 mmol) at 0 °C. The mixture was stirred at room temperature for 12 h. After evaporation, the residue was diluted with EtOAc (100 mL). The whole mixture was washed successively with brine (15 mL), 5% KHSO4 (15 mL) and brine (15 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (n-hexane/Et2O = 6:1→3:1) to afford 17 (2.44 g, 97%) as a pale yellow oil. [α]D26 +52.6 (c 1.21, CHCl3); 1H-NMR (400 MHz, CDCl3) E isomer δ 0.09 (s, 3H), 0.14 (s, 3H), 0.96 (s, 9H), 2.14 (ddd, J = 6.3, 6.8, 13.6 Hz, 1H), 2.32 (ddd, J = 6.8, 7.2, 14.1 Hz, 1H), 2.60 (dd, J = 9.2, 14.1 Hz, 1H), 2.87 (dd, J = 6.3, 14.0 Hz, 1H), 3.73-3.82 (m, 5H), 4.54 (d, J = 5.8 Hz, 2H), 5.47-5.54 (m, 1H), 5.60-5.65 (m, 1H), 5.73, (d, J = 8.2 Hz, 1H), 6.95-6.99 (m, 5H), 7.51-7.59 (m, 2H), 7.71-7.74 (m, 2H); Z isomer δ 0.12 (s, 3H), 0.17 (s, 3H), 0.96 (s, 9H), 2.14 (ddd, J = 6.3, 6.8, 13.6 Hz, 1H), 2.32 (ddd, J = 6.8, 7.2, 14.1 Hz, 1H), 2.60 (dd, J = 9.2, 14.1 Hz, 1H), 2.87 (dd, J = 6.3, 14.0 Hz, 1H), 3.73-3.82 (m, 5H), 4.63 (d, J = 4.8 Hz, 2H), 5.47-5.54 (m, 1H), 5.60-5.65 (m, 1H), 5.78 (d, J = 8.2 Hz, 1H), 6.95-6.99 (m, 5H), 7.51-7.59 (m, 2H), 7.717.74 (m, 2H); 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ –4.7, –4.6, –4.2, 17.9, 25.7, 25.8, 31.2, 36.1, 37.1, 37.9, 54.7, 59.6, 60.3, 63.5, 68.0, 72.8, 73.1, 125.3, 125.4, 126.4, 126.5, 126.8, 128.1, 128.2, 128.8, 128.9, 129.6, 129.7,

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130.8, 131.6, 132.7, 132.8, 132.9, 134.9, 137.3; IR (neat) cm–1 : 3583, 3375, 3028, 2955, 2930, 2887, 2858, 1748, 1673, 1595, View Article Online 1539, 1496, 1471, 1443, 1409, 1361, 1269, 1167, 1074; DOI: 1218, 10.1039/C3OB42229A + FAB-MS (m/z) : 579 (M +1). HRMS Calcd for C27H39N2O8SSi : 579.2196, Found : 579.2182. E/Z isomer ratio was determined by 1H-NMR analysis (E isomer ; 4.54 (d, J = 5.8 Hz, 2H), Z isomer ; 4.63 (d, J = 4.8 Hz, 2H)). (2S,3S,5S)-2-Benzyl-3-(tert-butyldimethylsilyloxy)-1-(2nitrophenylsulfonyl)-5-vinylpyrrolidine (18a) (2S,3S,5R)-2-Benzyl-3-(tert-butyldimethylsilyloxy)-1-(2nitrophenylsulfonyl)-5-vinylpyrrolidine (18b) To a solution of [Ir(cod)Cl]2 (16.2 mg, 0.0241 mmol, 8 mol%) and (R,R,R)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4a’]dinaphthalen-4-yl)bis(1-phenylethyl)amine ((R,R,R)-Ligand) 5 (26.0 mg, 0.0481 mmol, 16 mol%) in THF (0.84 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (13.4 mg, 0.0963 mmol, 32 mol%). After the mixture was stirred for 1 h at room temperature, a solution of allylic carbonate 17 (E:Z = 13:1, 174 mg, 0.301 mmol) in THF (2.0 mL) was added to the reaction mixture via cannula. After stirring for 4 h at 40 °C, the mixture was cooled to room temperature. The reaction was quenched with sat. NH4Cl (5 mL), and the whole mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the crude product, which was purified by silica gel column chromatography (n-hexane/Et2O = 20:1→8:1) to afford 18a (132 mg, 87 %) as a white solid and 18b (12.0 mg, 8%) as a white solid. 18a; m.p. 77-80 °C; [α]D28 +71.5 (c 1.03, CHCl3); 1H-NMR (400 MHz, CDCl3) δ –0.01 (s, 3H), 0.02 (s, 3H), 0.88 (s, 9H), 1.72-1.80 (m, 1H), 2.13-2.20 (m, 1H), 2.87 (dd, J = 6.3, 14.5 Hz, 1H), 3.08 (dd, J = 6.3, 14.0 Hz, 1H), 4.13-4.30 (m, 3H), 5.04 (d, J = 10.6 Hz, 1H), 5.06 (d, J = 17.4 Hz, 1H), 5.73 (ddd, J = 7.2, 10.1, 17.4 Hz, 1H), 7.14-7.18 (m, 1H), 7.22-7.30 (m, 4H), 7.53-7.59 (m, 2H), 7.63-7.67 (m, 1H), 7.79 (d, J = 8.2 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ –5.2, –4.9, 18.1, 25.8, 35.8, 38.7, 59.9, 65.0, 71.3, 115.8, 123.8, 126.2, 128.0, 130.3, 131.1, 131.9, 133.6, 138.3, 139.3, 148.4; IR (KBr) cm–1 : 3091, 3028, 2952, 2894, 2860, 1547, 1495, 1465, 1370, 1346, 1258, 1169, 1124, 1067; FAB-MS (m/z) : 503 (M++1). HRMS Calcd for C25H35N2O5SSi : 503.2036, Found : 503.2041. Anal. Calcd for C25H34N2O5SSi: C, 59.73; H, 6.82; N, 5.57. Found: C, 59.60; H, 6.98; N, 5.52. 18b; m.p. 119-121 °C; [α]D27 +23.9 (c 0.85, CHCl3); 1H-NMR (400 MHz, CDCl3) δ –0.01 (s, 3H), 0.03 (s, 3H), 0.88 (s, 9H), 1.61-1.66 (m, 1H), 1.90-1.98 (m, 1H), 3.08 (dd, J = 2.9, 14.0 Hz, 1H), 3.17 (dd, J = 7.2, 14.0 Hz, 1H), 4.11-4.18 (m, 1H), 4.36 (dt, J = 2.4, 6.8 Hz, 1H), 4.45 (dt, J = 6.8, 10.1 Hz, 1H), 4.69 (d, J = 10.1 Hz, 1H), 5.01 (d, J = 16.9 Hz, 1H), 5.23 (ddd, J = 9.7, 9.7, 16.9 Hz, 1H), 7.17-7.22 (m, 1H), 7.25-7.29 (m, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.55-7.65 (m, 3H), 8.00 (d, J = 8.2 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ –5.1, –5.0, 18.2, 25.9, 36.4, 39.1, 60.4, 65.9, 70.8, 117.6, 123.8, 126.1, 126.6,

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(2S,3S,5S)-2-Benzyl-3-(tert-butyldimethylsilyloxy)-1-(2nitrophenylsulfonyl)-5-(non-1-enyl)pyrrolidine (25) A solution of 18a (264 mg, 0.525 mmol) and 1-nonene (0.91 mL, 5.25 mmol) in CH2Cl2 (5.3 mL) was degassed with argon for 10 min. The solution was heated to 40 °C and 3 portions of Grubbs catalyst 2nd generation (each 22.3 mg, 0.0262 mmol, 5 mol%) were added after (0 h, 4 h, 10 h). The reaction was stirred an additional 14 h for a total of reaction time of 24 h then cooled to room temperature and concentrated. The residue was purified by flash chromatography (n-hexane/Et2O = 15:1) to give a compound 25 (252 mg, 80%) as a colorless oil. [α]D17 +34.2 (c 1.36, CHCl3); 1H-NMR (400 MHz, CDCl3) E isomer δ 0.03 (s, 3H), 0.07 (s, 3H), 0.91-0.97 (m, 12H), 1.301.37 (m, 10H), 1.76 (dt, J = 8.7, 12.6 Hz, 1H), 1.99-2.06 (m, 2H), 2.16-2.23 (m, 1H), 2.94 (dd, J = 6.3, 14.5 Hz, 1H), 3.13 (dd, J = 6.3, 14.5 Hz, 1H), 4.10-4.29 (m, 2H), 4.34 (dd, J = 6.3, 12.6 Hz, 1H), 5.40 (dd, J = 7.7, 15.5 Hz, 1H), 5.49-5.56 (m, 1H), 7.19-7.35 (m, 5H), 7.57-7.61 (m, 2H), 7.66-7.70 (m, 1H), 7.83 (d, J = 7.2 Hz, 1H); Z isomer δ 0.05 (s, 3H), 0.08 (s, 3H), 0.91-0.97 (m, 12H), 1.30-1.37 (m, 10H), 1.76 (dt, J = 8.7, 12.6 Hz, 1H), 1.99-2.06 (m, 2H), 2.16-2.23 (m, 1H), 2.74-2.77 (m, 1H), 2.85 (dd, J = 6.8, 14.1 Hz, 1H), 3.78-3.85 (m, 2H), 4.56 (dd, J = 7.8, 15.6 Hz, 1H), 5.40 (dd, J = 7.7, 15.5 Hz, 1H), 5.49-5.56 (m, 1H), 7.19-7.35 (m, 5H), 7.57-7.61 (m, 2H), 7.667.70 (m, 1H), 7.83 (d, J = 7.2 Hz, 1H); 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ –5.2, –4.8, 14.1, 18.1, 22.5, 22.6, 25.8, 28.8, 28.9, 29.1, 31.7, 31.8, 32.0, 35.8, 39.2, 59.8, 64.9, 71.4, 123.7, 126.1, 128.0, 128.1, 130.2, 130.8, 131.0, 131.8, 132.3, 132.8, 133.4, 138.5, 148.4; IR (neat) cm–1 : 3030, 2928, 2856, 1548, 1497, 1471, 1373, 1254, 1167, 1128, 1063; FAB-MS (m/z) : 601 (M++1). HRMS Calcd for C32H49N2O5SSi : 601.3131, Found : 601.3112. E/Z isomer ratio was determined by 1H-NMR analysis (E isomer ; 4.34 (dd, J = 6.3, 12.6 Hz, 1H), Z isomer ; 4.56 (dd, J = 7.8, 15.6 Hz, 1H)). (2S,3S,5S)-2-Benzyl-3-(tert-butyldimethylsilyloxy)-5-(non-1enyl)pyrrolidine (26)

ARTICLE   silica gel column chromatography (n-hexane/Et2O = 10:1→1:2) to give amine 26 (705 mg, 91%) as a pale yellow oil. View Article Online [α]D21 –16.5 (c 1.55, CHCl3); 1H-NMR DOI: (40010.1039/C3OB42229A MHz, CDCl3) E isomer δ 0.02 (s, 3H), 0.06 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H), 0.93 (s, 9H), 1.25-1.33 (m, 10H), 1.52-1.58 (m, 1H), 1.92-2.01 (m, 2H), 2.15 (ddd, J = 5.8, 8.2, 13.8 Hz, 1H), 2.77-2.90 (m, 2H), 3.05 (m, 1H), 3.43 (dt, J = 6.8, 7.5 Hz, 1H), 4.14-4.17 (m, 1H), 5.45-5.56 (m, 2H), 7.16-7.29 (m, 5H); Z isomer δ 0.01 (s, 3H), 0.05 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H), 0.93 (s, 9H), 1.251.33 (m, 10H), 1.45-1.47 (m, 1H), 1.92-2.01 (m, 2H), 2.27-2.31 (m, 1H), 2.77-2.90 (m, 2H), 3.05 (m, 1H), 3.81 (dt, J = 7.2, 8.2 Hz, 1H), 4.12-4.13 (m, 1H), 5.34-5.45 (m, 2H), 7.16-7.29 (m, 5H); 13C-NMR (100 MHz, CDCl3) (mixture of E/Z isomers) δ – 5.0, –4.2, 14.1, 18.2, 22.5, 22.6, 25.9, 26.0, 28.8, 29.1, 31.7, 31.8, 32.2, 36.1, 43.0, 59.6, 65.9, 66.0, 73.7, 125.9, 128.3, 128.9, 131.7, 132.9, 140.4; IR (neat) cm–1 : 3424, 3029, 2956, 2929, 2856, 2121, 1638, 1496, 1468, 1362, 1254, 1081; EI-MS (m/z) : 415 (M+). HRMS Calcd for C26H45NOSi : 415.3270, Found : 415.3255. (2S,3S,5R)-2-Benzyl-3-(tert-butyldimethylsilyloxy)-1methyl-5-nonylpyrrolidine (27) HCHO (37% in H2O, 146 µL, 1.80 mmol) was added to a solution of amine 26 (50.3 mg, 0.121 mmol) in MeOH (7.3 mL) at room temperature. After stirring at room temperature for 10 min, PtO2 (27.6 mg, 0.121 mmol) was added to the reaction mixture. The resulting mixture was stirred under hydrogen at atmospheric pressure for 20 h. The mixture was then filtered through a filter paper, and the filter paper was washed with MeOH. The filtrates were concentrated in vacuo, and the residue was purified by silica gel column chromatography (nhexane/Et2OAc = 30:1) to afford amine 27 (26.3 mg, 50%, 2 steps) as a colorless oil. [α]D27 +24.2 (c 1.45, CHCl3); 1H-NMR (400 MHz, CDCl3) δ – 0.10 (s, 3H), –0.03 (s, 3H), 0.87-0,90 (m, 12H), 1.27-1.45 (m, 16H), 1.71 (m, 1H), 2.04-2.06 (m, 1H), 2.21-2.26 (m, 4H), 2.47 (m,1H), 2.75-2.79 (m, 1H), 3.03 (ddd, J = 7.2, 7.3, 7.8 Hz, 1H), 4.14-4.17 (m, 1H), 7.14-7.20 (m, 1H), 7.24-7.28 (m, 4H); 13CNMR (100 MHz, CDCl3) δ –5.0, –4.3, 14.1, 18.2, 22.7, 26.0, 26.7, 29.3, 29.5, 29.6, 29.7, 29.9, 31.2, 40.3, 66.0, 71.1, 73.4, 125.6, 128.1, 129.1; IR (neat) cm–1 : 3028, 2927, 2855, 2782, 1604, 1497, 1463, 1361, 1255, 1140; FAB-MS (m/z) : 432 (M++1). HRMS Calcd for C27H50NOSi : 432.3662, Found : 432.3662. (+)-Preussin (7)

PhSH (574 µL, 5.63 mmol) was added to a mixture of 25 (1.12 g, 1.86 mmol) and K2CO3 (1.29 g, 9.31 mmol) in CH3CN (42 mL) at room temperature. The reaction mixture was stirred at 40 °C for 12 h. After filtration, the filtrate was concentrated in vacuo. The residue was diluted with CH2Cl2 (100 mL), and the whole mixture was washed with 10% Na2S2O3 (30 mL). The water layer was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration and evaporation, the residue was purified by

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TBAF (1.0 M in THF, 76 µL, 0.076 mmol) was added to a solution of amine 27 (19.2 mg, 0.0445 mmol) in THF (2 mL) at 0 °C. After stirring at room temperature for 22 h, the solvents were removed under reduced pressure. The residue was purified by flash chromatography (n-hexane/EtOAc = 4:1) to give a (+)preussin (7) (11.7 mg, 83%) as a colorless oil. [α]D15 +17.1 (c 0.50, CHCl3). (natural (+)-preussin (7); [α]D25 = +22.0 (c 1.0, CHCl3)15a)) 1H-NMR (400 MHz, CDCl3) δ 0.86 (t,

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Org. Chem., 1998, 63, 8411-8416; (c) K. Ando, J. Org. Chem., 1997,

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This work supported in part by a Grant-in-Aid for Young Scientists (B) (No. 23790138) (Y.N.) from JSPS and by a grant of Strategic Research Foundation Grant-aided Project for Private Universities from Ministry of Education, Culture, Sport, Science, and Technology, Japan (MEXT), 2010-2014.

Notes  and  references  

View Article Online

62, 1934-1939.

DOI: 10.1039/C3OB42229A

7

S. N. Murthy, Y. V. D. Nageswar, Synthesis, 2011, 755-758.

8

A chiral (S,S,S)-ligand 4 was purchased from Sigma-Aldrich Co. A chiral (R,R,R)-ligand 5 was prepared according reported procedure. K. Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem. Int. Ed., 2004, 43, 2426-2428.

9

Acknowledgements  

(a) K. Ando, J. Org. Chem., 1999, 64, 6815-6821; (b) K. Ando, J.

R. Takeuchi, M. Kashio, J. Am. Chem. Soc., 1998, 120, 8647-8655.

10 (a) S. Shinagawa, M. Maki, K. Kintaka, A. Imada, M. Asai, J. Antibiot., 1985, 38, 17-23; (b) A. Imada, K. Kintaka, M. Nakao, S. Shinagawa, J. Antibiot., 1982, 35, 1400-1403. 11 S. Shinagawa, F. Kashara, Y. Wada, S. Harada, M. Asai, Tetrahedron, 1984, 40, 3465-3470. 12 (a) B. Das, D. N. Kumar, Synlett, 2011, 1285-1287; (b) K. Show, P. K. Upadhyay, P. Kumar, Tetrahedron: Asymmetry, 2011, 22, 12341238; (c) S. Chandrasekhar, G. Chandrashekar, K. Vijeendera, G. D. Sarma, Tetrahedron: Asymmetry, 2006, 17, 2864-2869; (d) B. M.

Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University,

Trost, D. B. Horne, M. J. Woltering, Chem. Eur. J., 2006, 12, 6607-

Sendai 981-8558, Japan † Footnotes should appear here. These might include comments

6620; (e) S. P. Chavan, C. Praveen, P. Sharma, U. R. Kalkote, Tetrahedron Lett., 2005, 46, 439-441; (f) J. K. Khalaf, A. Datta, J.

relevant to but not central to the matter under discussion, limited

Org. Chem., 2004, 69, 387-390; (g) K. A. Holt, J. P. Swift, M. E. B.

experimental and spectral data, and crystallographic data.

Smith, S. J. C. Taylor, R. McCague, Tetrahedron Lett., 2002, 43,

Electronic Supplementary Information (ESI) available: [details of any

1545-1548; (h) A. Krasinski, J. Jurczak, Tetrahedron Lett., 2001, 42,

a

supplementary information available should be included here]. See DOI: 10.1039/b000000x/

2019-2021; and references cited there in. 13 (a) A. Madau, G. Porzi, S. Sandri, Tetrahedron : Asymmetry, 1996, 7, 825-830; (b) Y. Yuasa, J. Ando, S. Shibuya, J. Chem. Soc., Perkin

1 2

3 4

(a) J. R. Lewis, Nat. Prod. Rep. 2001, 18, 95-128; (b) D. O’Hagan,

Trans. 1, 1996, 793-802; (c) Y. Yuasa, J. Ando, S. Shibuya, J. Chem.

Nat. Prod. Rep., 2000, 17, 435-446.

Soc., Chem. Commun., 1994, 1383-1384; d) C. Schmeck, L. S.

(a) C. Mothes, C. Caumes, A. Guez, H. Boullet, T. Gendrineau, S.

14 (a) A. Kato, E. Hayashi, S. Miyauchi, I. Adachi, T. Imahori, Y.

Molecules, 2013, 18, 2307-2327; (b) I. Dragutan, V. Dragutan, C.

Natori, Y. Yoshimura, R. J. Nash, H. Shimaoka, I. Nakagome, J.

Mitan, H. C. Vosloo, L. Delaude, A. Demonceau, Beilstein J. Org.

Koseki, S. Hirono, H. Takahata, J. Med. Chem., 2012, 55, 10347-

Chem., 2011, 7, 699-716; (c) B. L. Stocker, E. M. Dangerfield, A. L.

10362; (b) Y. Natori, T. Imahori, K. Murakami, Y. Yoshimura, S.

Win-Mason, G. W. Haslett, M. S. M. Timmer, Eur. J. Org. Chem.,

Nakagawa, A. Kato, I. Adachi, H. Takahata, Bioorg. Med. Chem.

2010, 1615-1637; (d) J. P. Wolfe, Eur. J. Org. Chem. 2007, 571-582;

Lett., 2011, 21, 738-741; (c) Y. Saito, S. Takahashi, N. Azerb, A. T.

(e) P.-Q. Huang, Synlett, 2006, 1133-1149; (f) F.-X. Felpin, J.

Eldefrawi, M. E. Eldefrawi, H. Takahata, Heterocycles, 2009, 79,

Lebreton, Eur. J. Org. Chem., 2003, 3693-3712; (g) H. Yoda, Curr.

1043-1060; d) Y. Yoshimura, C. Ohara, T. Imahori, Y. Saito, A. Kato,

Org. Chem., 2002, 6, 223-243. (h) M. Pichon, B. Figadère,

S. Miyauchi, I. Adachi, H. Takahata, Bioorg. Med. Chem., 2008, 16,

Tetrahedron: Asymmetry, 1996, 7, 927-964. and references cited

8273-8286; (e) Y. Saito, N. Okamoto, H. Takahata, Beils. J. Org.

there in.

Chem., 2007, 3, 37; (f) A. Kato, N, Kato, E. Kano, I. Adachi, K.

Y. Natori, S. Kikuchi, Y. Yoshimura, A. Kato, I. Adachi, H.

Ikeda, L. Yu, T. Okamoto, Y. Banba, H. Ouchi, H. Takahata, N.

Takahata, Heterocycles, 2012, 86, 1401-1417.

Asano, J. Med. Chem., 2005, 48, 2036-2044; (g) H. Takahata, Y.

(a) A. Minatti, K. Muñiz, Chem. Soc. Rev., 2007, 36, 1142-1152; (b)

Banba, H. Ouchi, H. Nemoto, A. Kato, I. Adachi, J. Org. Chem.,

D. M. D’Souza, T. J. J. Müller, Chem. Soc. Rev., 2007, 36, 1095-

2003, 68, 3603-3607; (h) H. Takahata, M. Shimizu, Amino Acids,

1108; (c) N. Toyooka and H. Nemoto, in New Methods for the

2003, 24, 267-272; (i) H. Takahata, Y. Banba, H. Ouchi, H. Nemoto,

Asymmetric Synthesis of Nitrogen Heterocycles, ed. J. L. Vicario, D. Badia and L. Carrillo, 2005, p. 149-163. (d) H. Takahata, H. Bandoh, 5

Hegedus, J. Am. Chem. Soc., 1994, 116, 9927-9934.

Darses, N. Delsuc, R. Moumné, B. Oswald, O. Lequin, P. Karoyan,

A. Kato, I. Adachi, J. Org. Chem., 2003, 68, 3603-3607. 15 (a) J. H. Johnson, D. W. Phillipson, A. D. Kahle, J. Antibiot., 1989,

T. Momose, J. Org. Chem., 1992, 57, 4401-4404.

42, 1184-1185; (b) R. E. Schwartz, J. Liesch, O. Hensens, L. Zitano,

(a) C. Gnamm, K. Brödner, C. M. Krauter, G. Helmchen, Chem. Eur.

S. Honeycutt, G. Garrity, R. A. Fromtling, J. Onishi, R. Monaghan, J.

J., 2009, 15, 10514-10532; (b) C. Gnamm, C. M. Krauter, K. Brödner, G. Helmchen, Chem. Eur. J., 2009, 15, 2050-2054. (c) M. Gärtner, S. Mader, K. Seehafer, G. Helmchen, J. Am. Chem. Soc., 2011, 133, 2072-2075. However, no detail of a formation of pyrrolidine was described in supporting information.

Antibiot., 1988, 41, 1774-1779. 16 T. V. Achenbach, E. P. Slater, H. Brummerhop, T. Bach, R. Müller, Antimicrob. Agents Chemother., 2000, 44, 2794-2801. 17 (a) R. Britton, B. Kang, Nat. Prod. Rep., 2013, 30, 227-236; (b) R. Chowdhury, S. K. Ghosh, Synthesis, 2011, 1936-1945; (c) K.-J. Xiao, Y. Wang, K.-Y. Ye, P.-Q. Huang, Chem. Eur. J., 2010, 16, 12792-

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Organic & Biomolecular Chemistry Accepted Manuscript

J = 7.2 Hz, 3H), 1.26 (m, 16H), 1.43 (dd, J = 6.3, 13.5 Hz, 1H), 1.69-1.72 (m, 1H), 2.13-2.25 (m, 2H), 2.27 (m, 1H), 2.35 (s, 3H), 2.83-2.93 (m, 1H), 3.82 (m, 1H), 7.18-7.22 (m, 1H), 7.287.31 (m, 4H); 13C-NMR (100 MHz, CDCl3) δ 14.1, 22.7, 26.3, 29.3, 29.6, 29.9, 31.9, 33.6, 34.8, 38.6, 39.3, 65.9, 70.4, 73.6, 126.1, 128.4, 129.3, 139.3; IR (neat) cm–1 : 3338, 2925, 2854, 2344, 1730, 1604, 1496, 1456; FAB-MS (m/z) : 318 (M++1). HRMS Calcd for C21H36NO : 318.2797, Found : 318.2794.

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12796; (d) J. A. Draper, R. Britton, Org. Lett., 2010, 12, 4034-4037; (e) F. D. Davis, J. Zhang, H. Qiu, Y. Wu, Org. Lett., 2008, 10, 14331436; (f) N. Gogoi, J. Boruwa, N. C. Barua, Eur. J. Org. Chem., 2006,

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DOI: 10.1039/C3OB42229A

1722-1725; (g) M. B. Bertrand, J. P. Wolfe, Org. Lett., 2006, 8, 2353-2356; (h) S. Canova, V. Bellosta, J. Cossy, Synlett, 2004, 18111813; (i) F. A. Davis, J. Deng, Tetrahedron, 2004, 60, 5111-5115; (j) M. Okue, H. Watanabe, K. Kasahara, M. Yoshida, S. Horinouchi, T. Kitahara, Biosci. Biotechnol. Biochem., 2002, 66, 1093-1096. and

Organic & Biomolecular Chemistry Accepted Manuscript

references cited there in. 18 G. Veerasa, Synth. Commun., 2000, 30, 1479-1487. 19 On gram scale (>2 g of 17), the diastereoselectivity was slightly

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decreased in a 75% (18a) : 14% (18b) ratio.

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Asymmetric synthesis of 2,5-disubstituted 3-hydroxypyrrolidines based on stereodivergent intramolecular iridium-catalyzed allylic aminations.

Intramolecular iridium-catalyzed allylic aminations of homochiral (E)-6-N-nosylaminohept-2-en-1-yl methyl carbonates were investigated. The relative p...
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