DOI: 10.1002/chem.201303586

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& Synthetic Methods

Enantioselective Aziridination of Cyclic Enals Facilitated by the Fluorine-Iminium Ion Gauche Effect Istvn Gbor Molnr,[a] Eva-Maria Tanzer,[a] Constantin Daniliuc,[a] and Ryan Gilmour*[a, b] Dedicated to Professor Dr. Duilio Arigoni on the occasion of his 85th birthday

sCF*; Fd…N + ). Consequently, one of the shielding groups on the fluorine-bearing carbon atom is positioned above the p-system, forming the basis of an enantioinduction strategy. Treatment of this intermediate with a “nitrene” source furnished a series of novel, optically active aziridines (e.r. up to 99.5:0.5). Further derivatisation of the product aziridines gives facile access to various amino acid derivatives, including b-fluoroamino acids. Crystallographic analyses of both the aziridines and their derivatives are disclosed.

Abstract: The enantioselective, organocatalytic aziridination of small, medium and macro-cyclic enals is reported using (S)-2-(fluorodiphenyl methyl)-pyrrolidine. Central to the reaction design is the reversible formation of a b-fluoroiminium ion intermediate, which is pre-organised on account of the fluorine-iminium ion gauche effect. This conformational effect positions the fluorine substituent synclinal-endo to the electropositive nitrogen centre thus benefiting from favourable stereoelectronic and electrostatic interactions (sCH !

Introduction

rials can be easily processed to structurally diverse amino acid surrogates. In the context of this study, we sought to provide a general route to small, medium and macro-cyclic amino acid derivatives. Methodology for the preparation of these important materials is surprisingly sparse despite their importance in the life sciences.[6] Herein we present an organocatalytic aziridination of small, medium and macro-cyclic enals mediated by the low molecular weight organocatalyst (S)-2-(fluorodiphenylmethyl)-pyrrolidine; (S)-1.[7, 8] Central to the reaction design was application of the fluorine-iminium ion gauche effect; a reversible conformational phenomenon that is triggered upon union of the substrate aldehyde (2) with the catalyst. The topology of the subsequent b-fluoroiminium motif (3) would be influenced by stabilising hyperconjugative (sCH !sCF*) and electrostatic interactions (N + …Fd).[7a, 9] Consequently, one of the phenyl groups (CFPh2) would be positioned over the p-system, thus directing the facial approach of the nucleophile. Having set the configuration of this first stereocentre, the enamine intermediate can then undergo an intramolecular ring closure to furnish the desired aziridine (Scheme 1). The successful application of this methodology to cyclic enals ranging from five to fifteen-membered ring systems is presented, together with a catalyst molecular editing study, and aziridine derivatisation studies.[10]

Aziridine aldehydes have emerged as valuable reagents in organic synthesis due to their amphoteric nature and structural resemblance to naturally occurring amino acids.[1] Their orthogonally reactive functional groups have been exploited in a number of arenas ranging from the construction of heterocycles, through to peptide ligation and macrocyclisation processes. The versatility of this class of reagents in stereocontrolled synthesis is beautifully exemplified by the work by Yudin and co-workers.[2] Unsurprisingly, enantioselective routes to this class of materials are highly sought after. Organocatalytic strategies using secondary amines are amongst the most direct allowing for the conversion of commercially available a,b-unsaturated aldehydes to the desired products.[3, 4] A sequence of iminium activation, addition of a “nitrene” source to the bcarbon with concomitant enamine trapping and hydrolysis furnishes the aziridine aldehyde. Application of a chiral secondary amine can render this process enantioselective,[5] thus providing facile access to protected aziridine aldehydes: these mate-

[a] I. G. Molnr, Dr. E.-M. Tanzer, Dr. C. Daniliuc,+ Prof. Dr. R. Gilmour Organisch-Chemisches Institut and Graduate School of Chemistry Westflische Wilhelms-Universitt Mnster Corrensstrasse 40, 48149 Mnster (Germany) Homepage: www.uni-muenster.de/Chemie.oc/gilmour E-mail: [email protected]

Results and Discussion

[b] Prof. Dr. R. Gilmour Excellence Cluster EXC 1003, Cells in Motion Mnster (Germany)

As a starting point for this investigation, we elected to study the organocatalytic aziridination of 2-benzylacrylaldehyde (5! 7) mediated by (S)-1 (Table 1). This simple substrate was chosen on account of the UV active chromophore, which would facilitate HPLC analysis. BocNHOTs[11] was employed as

[+] X-ray crystallographer. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303586. Chem. Eur. J. 2014, 20, 794 – 800

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Full Paper tries 4–6). Control reactions in the absence of a base or an organocatalyst were performed for completeness and led to little or no product formation (entries 7 and 8). In many cases, solvent variation was also found to impact the reaction outcome as indicated in entries 9 through 15. Whilst chlorinated solvents delivered the desired aziridine aldehyde in good yield and enantioselectivity (entries 9 and 10, e.r. 86.0:14.0 and 86.5:13.5, respectively), it was at the expense of reaction time (24 h, versus 8 h, cf. entry 1). Reactions in acetonitirile also proved to be sluggish and were accompanied by partial erosion of the enantioselectivity (entry 11, e.r. 69.0:31.0). Diethyl ether did prove to be a good reaction medium, but again reaction times were significantly longer than in toluene (entry 12, e.r. 84.5:15.5). Finally, reactions in n-pentane, nhexane and n-heptane (entries 13–15) gave the highest enantioselectivities of the investigation (up to e.r. 92.0:8.0). Having completed an initial base and solvent screen, attention was focussed on the effects of concentration and temperature. To that end, a series of reactions were performed in nheptane using NaOAc as base (1.5 equiv.), and 20 mol % catalyst (S)-1 (Table 2). Although solubility problems were observed

Scheme 1. The fluorine-iminium ion gauche effect for molecular pre-organisation.

Table 1. Enantioselective, organocatalytic aziridination of 2-benzylacrylaldehyde (5). Base additive and solvent screening.[a]

1 2 3 4 5 6 7 8[f] 9 10 11 12 13 14 15

Base

Solvent

t [h]

Yield [%][b]

e.r.[c]

NaOAc Na2CO3 KOtBu DIPEA 2,6-lutidine DBU 0 NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc NaOAc

toluene toluene toluene toluene toluene toluene toluene toluene CHCl3 CH2Cl2 CH3CN Et2O n-pentane[g] n-hexane[g] n-heptane[g]

8 38 42 40 39 23 6d 24 24 24 48 25 32 32 32

94 44 4[d] 56[d] 36[d] 29[e] 10 0 96 95 40[d] 95 81 84 85

87.0:13.0 81.5:18.5 60.5:39.5 56.0:44.0 83.0:17.0 54.0:46.0 84.0:16.0 – 86.0:14.0 86.5:13.5 69.0:31.0 84.5:15.5 92.0:8.0 91.5:8.5 92.0:8.0

Table 2. Enantioselective, organocatalytic aziridination of 2-benzylacrylaldehyde (5). Concentration and temperature screening.[a]

1 2 3 4 5 6

[a] Reactions performed with 100 mmol aldehyde, 120 mmol BocNHOTs, 150 mmol base and 20 mmol (S)-1 in the specified solvent (0.25 mol·L1) at room temperature for the specified time. Stereochemistry of the product was assigned by chemical correlation (see reference [3f]). (S)-1 was prepared from l-proline (98 % ee by HPLC) according to reference [7b]. [b] Yield of the isolated product. [c] e.r. determined by HPLC on an Agilent 1100 series (DAD, Agilent technologies 1200 series) using Reprosil Chiral-AM (5 mm, 250  4.6 mm) and n-hexane:iPrOH 99:1 as eluent. Retention time: 6.93 min (minor enantiomer), 8.49 min (major enantiomer). [d] Reaction terminated before complete conversion. [e] Decomposition of BocNHOTs observed. [f] Reaction carried out without using organocatalyst. [g] Additional amount of solvent (0.2 cm3) was added after 1 h, due to the formation of a thick suspension (c = 0.167 mol·L1).

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T [8C]

t [h]

Yield [%][b]

e.r.[c]

0.25[d] 0.10 0.05 0.01 0.10 0.10

rt rt rt rt 0 40

32 27 27 39 5d 7

85 93 89 93 69[e] 89

92.0:8.0 92.5:7.5 92.5:7.5 91.0:9.0 91.5:8.5 90.5:9.5

[a] Reactions performed with 100 mmol aldehyde, 120 mmol BocNHOTs, 150 mmol NaOAc and 20 mmol (S)-1 in n-heptane at the above indicated temperature for the specified time. Stereochemistry of the product was assigned by chemical correlation (see reference [3f]). (S)-1 was prepared from l-proline (98 % ee by HPLC) according to reference [7b]. [b] Yield of the isolated product. [c] e.r. determined by HPLC on an Agilent 1100 series (DAD, Agilent technologies 1200 series) using Reprosil Chiral-AM (5 mm, 250  4.6 mm) and n-hexane:iPrOH 99:1 as eluent. Retention time: 6.93 min (minor enantiomer), 8.49 min (major enantiomer). [d] Additional amount of solvent (0.2 cm3) was added after 1 h, due to the formation of a thick suspension (c = 0.167 mol·L1). [e] Reaction terminated before complete conversion.

the “nitrene” source throughout this study (BOC = tert-butyloxycarbonyl; Ts = Tosyl). In the initial screen of commonly used bases (1.5 equiv., entries 1–6) NaOAc was quickly identified as the optimal choice when reactions were performed in toluene at room temperature (94 %, e.r. 87.0:13.0, 8 h, Table 1, entry 1). Often, considerable reductions in both yield and selectivity were observed with other common inorganic, or organic bases (entries 2–6). Interestingly, the use of Na2CO3 or KOtBu led to significantly longer reactions times (38 and 42 h, respectively). This was also the case with DIPEA, 2,6-lutidine and DBU (enChem. Eur. J. 2014, 20, 794 – 800

Concentration [mol·L1]

in more concentrated reactions (entry 1), no concentration dependence on the enantioselectivity was observed (entries 1–4). Similarly, temperature variation was also tolerated (entries 5 and 6). Finally, to demonstrate the importance of the aforementioned fluorine gauche effect in the reaction design, a molecular editing study was performed on catalyst (S)-1 (Table 3). The optimised conditions outlined in Tables 1 and 2 were employed. Initially, the effect of modifying the diphenylfluoromethyl 795

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Full Paper product 7 with excellent levels of enantioselectivity (e.r. 94.5:5.5), but significantly longer reaction times as a consequence of steric hindrance. With an optimised series of reaction conditions in hand, and having performed a molecular editing study of the catalyst, a series of small, medium and macrocyclic enals (5, 6, 7, 8, 10, 12 and 15-membered rings, 15–21) were prepared according to established literature procedures (Tables 4 and 5).[7d, 12] Initially, cyclopentene carbaldehyde 15 was subjected to the reaction conditions (Table 4, 20 mol % catalyst, 1.5 equiv. NaOAc, n-heptane, rt, 0.1 mol·L1). Gratifyingly, full conversion was reached after 4 h to furnish the desired aziridine aldehyde in 78 % yield, and with excellent levels of both diastereo- and enantiocontrol (d.r. > 20:1, e.r. 98.5:1.5, Table 4, entry 1). Cyclohexene carbaldehyde 16 also underwent facile aziridination

Table 3. Enantioselective, organocatalytic aziridination of 2-benzylacrylaldehyde (5). Catalyst screening.[a]

t [h]

Yield [%][b]

e.r.[c]

1

86

52[d]

39.5:60.5[g]

2

86

7[d]

41.5:58.5[g]

3

44

79

73.0:27.0

4

27

93

92.5:7.5

Organocatalyst

Table 4. Enantioselective, organocatalytic aziridination of small and medium cyclic enals (15!18) using catalyst (S)-1.[a] 5

66

64[d]

89.5:10.5

6

42

78[e]

87.5:12.5

7

13

93

89.0:11.0

8

45

84[f]

94.5:5.5

Substrate

1

[a] Reactions performed with 100 mmol aldehyde, 120 mmol BocNHOTs, 150 mmol NaOAc and 20 mmol catalyst in n-heptane (0.1 mol·L1) at rt for the specified time. (S)-1 was prepared from l-proline (98 % ee by HPLC) according to reference [7b] and 11–13 prepared according to reference [7d]. Stereochemistry of the product was assigned by chemical correlation (see reference [3f]) [b] Yield of the isolated product. [c] e.r. determined by HPLC on an Agilent 1100 series (DAD, Agilent technologies 1200 series) using Reprosil Chiral-AM (5 mm, 250  4.6 mm) and n-hexane:iPrOH 99:1 as eluent. Retention time: 6.93 min (minor enantiomer), 8.49 min (major enantiomer). [d] Reaction terminated before complete conversion. [e] Reaction carried out on 42 mmol scale. [f] Reaction carried out on 56 mmol scale. [g] Opposite enantiomer is favoured.

2 3 4 5 6

7 8

group was probed (8 cf. 1). As indicated in Table 3, entry 1, this led to a catastrophic erosion of enantioselectivity (e.r. 39.5:60.5 vs. 92.5:7.5). The analogous, trifluoromethylated catalyst 9 (entry 2), was also screened as an electronic extreme of the parent scaffold. This structural modification had a similar, detrimental effect (e.r. 41.5:58.5). Simple deletion of the fluorine atom from the parent structure (10 cf. 1, entry 3) also had a negative impact on the reaction outcome, causing longer reaction times and reduced yields. Most significant to this study is the reduction in enantioselectivity compared to (S)-1 (e.r. 73.0:27.0 versus 92.5:7.5, entries 3 and 4, respectively). This observation further illustrates the importance of the fluorine substituent in this small molecule catalyst. Modification of the aryl shielding units (11– 13, entries 5–7) did not lead to an enhancement of the enantioselectivity. Finally, the trityl catalyst 14 delivered the desired Chem. Eur. J. 2014, 20, 794 – 800

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Conditions

0.1 mmol scale 4h 0.1 mmol scale 29 h 1.00 mmol scale 39 h 5.00 mmol scale 3d 0.1 mmol scale 8d 1.00 mmol scale 13 d 0.1 mmol scale 6d 1.00 mmol scale 8d

Yield [%][b] (conversion)

d.r.[c]

e.r.

78 (> 99)

> 20:1

98.5:1.5[d]

84 (> 99)

> 20:1

97.5:2.5[d]

81 (> 99)

> 20:1

96.0:4.0[d]

83 (97)

> 20:1

95.5:4.5[d]

93 (> 98)

> 20:1

98.5:1.5[e]

91 (95)

> 20:1

98.5:1.5[e]

85 (97)

> 20:1

99.0:1.0[e]

85 (96)

> 20:1

99.5:0.5[e]

[a] Method A: 1.0 equiv. aldehyde, 1.2 equiv. BocNHOTs, 1.5 equiv. NaOAc and 0.2 equiv. (S)-1 in n-heptane (0.1 mol·L1) at rt for the specified time. (S)-1 was prepared from l-proline (98 % ee by HPLC) according to reference [7b]. Full details for the preparation of the starting materials are provided in the supporting information. [b] Yield of the isolated product. Numbers in parentheses refer to conversion by 1H NMR spectroscopy. [c] d.r. determined by 1H NMR analysis of the crude product. [d] e.r. determined by GC analysis on an Agilent 7890A system using a Supelco b-DEX 120 column. Five-membered ring (from 15): 110 8C isotherm, retention time: 80.56 min (minor enantiomer), 85.37 min (major enantiomer). Sixmembered ring (from 16): 120 8C isotherm, retention time: 73.84 min (minor enantiomer), 75.13 min (major enantiomer). [e] e.r. determined by HPLC analysis after reduction and benzoyl protection on an Agilent 1100 series (DAD, Agilent technologies 1200 series) using Reprosil Chiral-AM (5 mm, 250  4.6 mm) and n-hexane:iPrOH 99:1 as eluent. Retention times: seven-membered ring (from 17): 25.76 min (major enantiomer), 31.15 min (minor enantiomer); eight-membered ring (from 18): 24.39 min (major enantiomer), 29.45 min (minor enantiomer).

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Full Paper tion of the largest substrate in this study (21, entries 3 and 4), also proved fruitful under optimised conditions furnishing the expected products (~ 58 %) with excellent diastereo- and enantioselectivity (> 95:5), as determined by Mosher ester analysis of the corresponding alcohol (see the Supporting Information). To provide rigorous proof of structure by X-ray crystallographic analysis, the eight-membered aziridine aldehyde was reduced (NaBH4) and converted to the corresponding crystalline ester 22 (Figure 1).[13]

Table 5. Enantioselective, organocatalytic aziridination of medium and macrocyclic enals (19, 20, 21) using catalyst (S)-1.[a]

Substrate

Conditions

Yield [%][b] (conversion)

d.r.[c]

e.r.[d]

1

Method B 0.1 mmol scale 50 h

39 (71)

4:1

> 95:5

2

Method B 0.1 mmol scale 51 h

62 (> 99)

10:1

> 95:5

58 (96)

> 20:1

> 95:5

59 (96)

> 20:1

> 95:5

3 4

Method A 0.1 mmol scale 7d Method A 0.9 mmol scale 10 d

[a] Method A: 1.0 equiv. aldehyde, 1.2 equiv. BocNHOTs, 1.5 equiv. NaOAc and 0.2 equiv. (S)-1 in n-heptane (0.1 mol·L1) at rt for the specified time. Method B: 2.5 equiv. aldehyde, 1.0 equiv. BocNHOTs, 1.5 equiv. NaOAc and 0.2 equiv. (S)-1 in n-heptane (0.1 mol·L1) at rt for the specified time. The reaction was monitored by 1H NMR. (S)-1 was prepared from l-proline (98 % ee by HPLC) according to reference [7b]. Full details for the preparation of the starting materials are provided in the supporting information. [b] Yield of the (major) isolated product. Numbers in parentheses refer to conversion by 1H NMR spectroscopy. [c] d.r. determined by 1 H NMR analysis of the crude product. [d] e.r. determined by 19F NMR spectroscopy after reduction and Mosher ester formation of the major diastereoisomer. Chemical shifts (282 MHz, CDCl3): ten-membered ring (from 19) dF = 71.72 (major diastereomer), 71.65 (minor diastereomer); twelve-membered ring (from 20) dF = 71.56 ppm (major diastereomer), 71.49 ppm (minor diastereomer); fifteen-membered ring (from 21) dF = 71.53 ppm (major diastereomer), 71.47 ppm (minor diastereomer).

Figure 1. X-ray crystallographic analysis of the benzoate derivative 22. Two molecules in the asymmetric unit. Only one is shown for clarity. Thermal ellipsoids set at the 30 % probability level.[13]

To demonstrate the versatility of these materials in the preparation of unnatural amino acid derivatives, the aziridine aldehyde 23 was first oxidised to the methyl ester 24 (99 %, Scheme 2).[14] This intermediate could then be processed to the fully protected b-hydroxy (25) or b-fluoro amino acid (26). Treatment of 24 with an ethereal boron trifluoride solution in a H2O/THF mixture furnished 25 in 64 % yield (d.r. 10:1).[15] Similarly, by exposing 23 to HF·pyridine complex,[16] the b-fluoroamino acid derivative 26 was generated (40 %, d.r. 8:1). Gratifyingly, fluoride 26 was crystalline and could be analysed by Xray diffraction (Scheme 2, lower).[17] Reduction of compound 23 to the primary alcohol 27 provided a second route to protected amino acid derivatives, this time as spirocompounds (Scheme 3, upper). Treatment of 27 with TASF [tris(dimethylamino)sulfonium difluorotrimethylsilicate], a source of nucleophilic fluoride, resulted in ring opening of the aziridine with concomitant cyclisation[18] to yield 28 (90 %, two steps from the starting aldehyde). X-ray crystallographic analysis[19] confirmed the expected gauche conformation of the b-fluoroamine motif (fNCCF 61.58; Scheme 3, lower).[20] Pleasingly, this methodology was successfully applied to the larger seven-and fifteen-membered systems to furnish 29 and 30 in 57 and 59 % yield (two steps from the aldehydes), respectively. Finally, Boc deprotection of 23 using tetrabutylammonium fluoride (TBAF) in THF[21] generated the free aziridine aldehyde 31. Consistent with earlier reports from the Yudin lab,[22] this material readily dimerised to furnish 32, further demonstrating

under these conditions irrespective of the reaction scale (Table 4, entries 2–4, e.r. up to 97.5:2.5). Whilst longer reaction times were observed as a consequence of scale up, little erosion of enantioselectivity was observed (Table 4, entries 3 and 4). Cycloheptene carbaldehyde 17 was smoothly converted to the product aziridine aldehyde on both the 100 mmol and 1.0 mmol scales (entries 5 and 6 respectively, e.r. 98.5:1.5). Similarly, it was possible to process cyclooctene carbaldehyde 18 to the respective aziridine aldehyde in good yield (85 %, d.r. > 20:1) and with excellent enantioselectivity (e.r. 99.0:1.0 and 99.5:0.5 for the 100 mmol and 1.0 mmol scale reactions, respectively, entries 7 and 8). The aziridination of cyclodecene carbaldehyde 19 (Table 5, entry 1) proved to be more challenging. Whilst it was possible to prepare the desired aziridine aldehyde with excellent levels of enantioselectivity (e.r. > 95:5), the reaction required 50 h and the yield was modest (39 %, 71 % conversion by 1H NMR spectroscopy, d.r. 4:1). Cyclododecene carbaldehyde 20 also required extended reaction times, but the product could be isolated with synthetically useful yields (62 %) and selectivities (d.r. 10:1, e.r. > 95:5, entry 2). AziridinaChem. Eur. J. 2014, 20, 794 – 800

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Full Paper

Scheme 2. Top: Derivatisation of aziridine aldehyde 23 into the fully protected b-hydroxy- and b-fluoro-amino acids 25 and 26, respectively. Bottom: Xray crystal structure of b-fluoro-amino acid 26. Two molecules in the asymmetric unit. Only one is shown for clarity. Thermal ellipsoids set at the 30 % probability level.[17]

Scheme 3. Top: Derivatisation of aziridine aldehyde 23 into the spirocyclic derivative 28. [a] Yield over two steps from the starting aldehydes. Bottom: X-ray crystal structure of 28 showing a gauche effect (fNCCF 61.58). Thermal ellipsoids set at 30 % probability level.[19]

the diversity and complexity of this fascinating class of molecules (Scheme 4).

Conclusions The enantioselective aziridination of small, medium and macro-cyclic enals has been reported using the low molecular weight organocatalyst (S)-1 (e.r. up to 99.5:0.5). A focussed molecular editing study revealed that the catalytic efficiency of (S)-1 is a consequence of the fluorine substituent. Deletion (H!F) leads to a notable reduction in enantioselectivity (1 and 10, e.r. 92.5:7.5 cf. 73.0:27.0), thus supporting the notion that a fluorine gauche effect is significant in pre-organising the transient intermediate prior to nucleophilic attack. The versatility of the aziridine aldehydes generated in this study is demonstrated by their facile conversion to various protected amino acid derivatives. It is envisaged that this general route to optically active, cyclic aziridine aldehydes and their derivatives will facilitate their application in chemical biology. Scheme 4. Dimerisation of the unprotected aziridine aldehyde 31. Section of the crude 1H NMR spectrum of 32 (400 MHz, CDCl3) showing diagnostic signals consistent with dimer formation.

Experimental Section General methods

system. All chemicals were reagent grade and used as supplied unless otherwise stated. Solvents for extractions and chromatography were technical grade and distilled prior to use. Reactions performed below 0 8C were carried out using a Julabo FT902 type cryostat. The phosphate buffer used (1 m, pH 7) was prepared from

All reactions using air or moisture sensitive compounds were carried out in flame-dried and evacuated glassware under an atmosphere of argon. Solvents for these reactions were dried according to standard procedures or were taken from the solvent drying Chem. Eur. J. 2014, 20, 794 – 800

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Full Paper KH2PO4 (136 g), solid NaOH (23.3 g) and both were dissolved in H2O (1000 cm3). Extracts were dried over technical grade Na2SO4 or MgSO4. Analytical thin layer chromatography (TLC) was performed on pre-coated Merck silica gel 60 F254 plates (0.25 mm). Visualisation was achieved using ultraviolet light (l = 254 nm) or by dipping in cerium ammonium molybdate (CAM) stain [(NH4)6Mo7O24·4 H2O (50 g), Ce(SO4)2 (10 g) and H2SO4 (100 cm3) in water (900 cm3)] or potassium permanganate stain [KMnO4 (10 g), K2CO3 (65 g) and aqueous NaOH solution (1N, 15 cm3) in water (1000 cm3)] followed by heating. Flash column chromatography was carried out on Fluka silica gel 60 (230–400 mesh). Concentration in vacuo was performed at ~ 20 mbar and 40 8C, drying at ~ 102 mbar and rt unless otherwise stated (caution: some intermediates and products are volatile). 1H NMR, 19F NMR and 13C NMR spectra were recorded by the NMR service at the Institute of Organic Chemistry (WWU Mnster) on a Bruker AV 300 MHz, a Bruker AV 400 MHz, Agilent VVMRS 500 MHz or an Agilent DD2 600 MHz spectrometer at ambient temperature. Chemical shifts d are reported in ppm relative to the residual solvent. Coupling constants J are reported in Hz. The multiplicities are reported as: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, qu = quintet, m = multiplet. Melting points were measured on a Bchi B540 melting point apparatus and are uncorrected. IR spectra were measured on a PerkinElmer Spectrum 100 FTIR spectrometer and reported in cm1. The intensities of the bands are reported as: w = weak, m = medium, s = strong. Optical rotations were obtained using a JASCO P-2000 polarimeter. HPLC spectra were recorded on an Agilent 1100 series (DAD, Agilent technologies 1200 series) using Reprosil Chiral-AM (5 mm, 250  4.6 mm) and n-hexane/i-propanol as the eluent. GC spectra were recorded on an Agilent 7890A system using a Supelco b-DEX 120 column. High-resolution mass spectra (HR ESI MS) were performed by the MS service at the Institute of Organic Chemistry (WWU Mnster) on a Bruker Daltonics MicroTof.

a mixture of n-pentane:EtOAc 4:1 was used). The resulting solution was concentrated in vacuo and the crude product was then purified by flash-column chromatography on silica gel (n-pentane:EtOAc). 5.0 mmol scale: To a solution of the freshly purified (flash column chromatography, n-pentane:EtOAc) aldehyde (5.0 mmol) in n-heptane (40 cm3) at ambient temperature were added (S)-2-(fluorodiphenylmethyl)-pyrrolidine (S)-1 (1.0 mmol) in n-heptane (10 cm3), tert-butyl p-tolyloxycarbamate (6.0 mmol) and sodium acetate (7.5 mmol), consecutively. The resulting suspension was then stirred at ambient temperature for the specified time. The progress of the reaction was monitored by TLC analysis. Upon consumption of the starting material, the, thick white suspension was filtered through a short plug of silica gel and eluted with a mixture of npentane:EtOAc 7:1 (~ 250 cm3). The resulting solution was concentrated in vacuo and the crude product was then purified by flashcolumn chromatography on silica gel (n-pentane:EtOAc). General procedure for organocatalytic, enantioselective aziridination of substrates 19 and 20 (Method B): To a solution of freshly purified aldehyde (250 mmol) in n-heptane (0.5 cm3) at ambient temperature were added (S)-2-(fluorodiphenylmethyl)-pyrrolidine (S)-1 (20 mmol) in n-heptane (0.5 cm3), tert-butyl p-tolyloxycarbamate (100 mmol) and sodium acetate (150 mmol), consecutively. The resulting white suspension was then stirred at ambient temperature for the specified time. The progress of the reaction was monitored by 1H NMR analysis. Upon consumption of the starting material, the thick, white suspension was filtered through a short plug of silica gel and eluted with a mixture of n-pentane:EtOAc 7:1 (~ 20 cm3). The solution was concentrated in vacuo and the resulting crude product was then purified by flash-column chromatography on silica gel (n-pentane : EtOAc). Full experimental procedures are provided in the Supporting Information.

General procedure for the enantioselective, organocatalytic aziridination of a,b-unsaturated enals

Acknowledgements

General procedure for the optimisation reactions (Tables 1–3): To a solution of 2-benzylacrylaldehyde (100 mmol) in the specified solvent (0.5 cm3) at ambient temperature were added (S)-2-(fluorodiphenylmethyl)-pyrrolidine (S)-1 (20 mmol) in the specified solvent (0.5 cm3), tert-butyl p-tolyloxycarbamate (120 mmol) and the specified base (150 mmol). The resulting suspension was then stirred at the specified temperature for the specified time. The progress of the reaction was monitored by TLC. Upon consumption of the starting material, the thick, white suspension was directly loaded on a silica gel column and eluted with a mixture of n-pentane:EtOAc/10:1 to obtain the crude product (In cases in which the concentrations were c = 0.05 mol·L1 and 0.01 mol·L1, the reaction mixtures were first filtered and then concentrated in vacuo).

We gratefully acknowledge generous financial support from the WWU Mnster Graduate School of Chemistry (IGM), and the Deutsche Forschungsgemeinschaft, DFG EXC 1003 “Cells in Motion - Cluster of Excellence, Mnster”, Germany. Keywords: aziridination · catalysis · enantioselectivity fluorine · gauche effect · pre-organisation

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General procedure for the organocatalytic, enantioselective aziridination of substrates 15, 16, 17, 18 and 21 (Method A): 0.1 mmol scale: To a solution of the freshly purified (flash column chromatography, n-pentane:EtOAc) aldehyde (100 mmol) in n-heptane (0.5 cm3) at ambient temperature were added (S)-2-(fluorodiphenylmethyl)-pyrrolidine (S)-1 (20 mmol) in n-heptane (0.5 cm3), tert-butyl p-tolyloxycarbamate (120 mmol) and sodium acetate (150 mmol). The resulting suspension was then stirred at ambient temperature for the specified time. The progress of the reaction was monitored by TLC analysis. Upon consumption of the starting material, the thick, white suspension was filtered through a short plug of silica gel and eluted with a mixture of n-pentane:EtOAc 7:1 (approximately 20 cm3, in the case of the five-membered ring Chem. Eur. J. 2014, 20, 794 – 800

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fined as riding atoms. Flack parameter: 0.2(2). CCDC 959950 contains the supplementary crystallographic data. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. a) C. McDonald, H. Holcomb, K. Kennedy, E. Kirkpatrick, T. Leathers, P. Vanemon, J. Org. Chem. 1989, 54, 1213 – 1215; b) Reactions using NBS gave lower yields. For an example see Y. Xuan, H.-S. Lin, M. Yan, Org. Biomol. Chem. 2013, 11, 1815 – 1817. B. A. Bhanu Prasad, G. Sekar, V. K. Singh, Tetrahedron Lett. 2000, 41, 4677 – 4679. G. M. Alvernhe, C. E. Ennakoua, S. M. Lacombe, A. J. Laurent, J. Org. Chem. 1981, 46, 4938 – 4948. For a recent example of aziridine ring opening using chloride see reference [4 i]. Crystallographic data for 26. Formula C13H22FNO4, M = 275.32, colourless crystal, 0.30  0.04  0.02 mm, a = 9.8471(5), b = 16.2955(1), c = 10.6219(2) , b = 115.599(3)8, V = 1537.12(16) 3, 1calc = 1.190 gcm3, m = 0.799 mm1, empirical absorption correction (0.795  T  0.984), Z = 4, monoclinic, space group P21 (No. 4), l = 1.54178 , T = 223(2) K, w and f scans, 12072 reflections collected ( h,  k,  l), [(sinq)/l] = 0.60 1, 4916 independent (Rint = 0.048) and 4425 observed reflections [I > 2s(I)], 359 refined parameters, R = 0.050, wR2 = 0.139, max. (min.) residual electron density 0.14 (0.16) e 3, the hydrogens at N1A and N1B atoms were refined freely; others were calculated and refined as riding atoms. Flack parameter: 0.2(2). CCDC 959951 contains the supplementary crystallographic data. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. G. Righi, S. Ciambrone, A. Pompili, F. Caruso, Tetrahedron Lett. 2007, 48, 7713 – 7716. Crystallographic data for 28. Formula C8H12FNO2, M = 173.19, colourless crystal, 0.20  0.05  0.02 mm, a = 6.6555(1), b = 6.8897(1), c= 18.1630(1) , V = 832.85(2) 3, 1calc = 1.381 gcm3, m = 0.963 mm1, empirical absorption correction (0.830  T  0.981), Z = 4, orthorhombic, space group P212121 (No. 19), l = 1.54178 , T = 223(2) K, w and f scans, 6336 reflections collected ( h,  k,  l), [(sinq)/l] = 0.60 1, 1393 independent (Rint = 0.049) and 1207 observed reflections [I > 2s(I)], 113 refined parameters, R = 0.048, wR2 = 0.138, max. (min.) residual electron density 0.28 (0.26) e 3, the hydrogen at N1 atom was refined freely; others were calculated and refined as riding atoms. Flack parameter: 0.1(3). CCDC 959952 contains the supplementary crystallographic data. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. a) For evidence of a fluorine-amine gauche effect see; C. R. S. Briggs, M. J. Allen, D. O’Hagan, D. J. Tozer, A. M. Z. Slawin, A. E. Goeta, J. A. K. Howard, Org. Biomol. Chem. 2004, 2, 732 – 740; b) For evidence of a fluorine-imine gauche effect see C. Sparr, E. Salamanova, W. B. Schweizer, H. M. Senn, R. Gilmour, Chem. Eur. J. 2011, 17, 8850 – 8857. S. Routier, L. Saug , N. Ayerbe, G. Coudert, J.-Y. M rour, Tetrahedron Lett. 2002, 43, 589 – 591. R. Hili, A. K. Yudin, Angew. Chem. 2008, 120, 4256 – 4259; Angew. Chem. Int. Ed. 2008, 47, 4188 – 4191.

Received: September 10, 2013 Published online on December 11, 2013

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