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Synthesis of 2-aryl-3-(2-cyanoethyl)aziridines and their chemical and enzymatic hydrolysis towards γ-lactams and γ-lactones† Karen Mollet,a Lena Decuyper,a Saskia Vander Meeren,a Nicola Piens,a Karel De Winter,b Tom Desmetb and Matthias D’hooghe*a Trans- and cis-2-aryl-3-(2-cyanoethyl)aziridines, prepared via alkylation of the corresponding 2-aryl-3-(tosyl-

Received 16th December 2014, Accepted 2nd January 2015 DOI: 10.1039/c4ob02615b www.rsc.org/obc

oxymethyl)aziridines with the sodium salt of trimethylsilylacetonitrile, were transformed into variable mixtures of 4-[aryl(alkylamino)methyl]butyrolactones and 5-[aryl(hydroxy)methyl]pyrrolidin-2-ones via KOH-mediated hydrolysis of the cyano group, followed by ring expansion. In addition, next to this chemical approach, enzymatic hydrolysis of the former aziridinyl nitriles by means of a nitrilase was performed as well, interestingly providing a selective route towards the above-mentioned functionalized γ-lactams.

Introduction Amino nitriles represent an interesting class of biologically relevant compounds, as several amino nitrile-containing leads are currently on the market or in clinical development. For example, the γ-amino nitrile cyamemazine 1 is an antipsychotic agent widely used to minimize withdrawal symptoms after drug addiction, the δ-amino nitrile levocabastine 2 is used in the treatment of allergic conjunctivitis, and several α-amino nitriles, such as the therapeutically active and selective dipeptidyl peptidase-IV inhibitors vildagliptin 3 and saxagliptin 4, possess antidiabetic activity (Fig. 1).1 In addition, from a chemical point of view, amino nitriles are versatile intermediates for the synthesis of multiple building blocks, and both the amino and the cyano group can be further transformed into a variety of useful functional units. In that respect, amino nitriles have been proven to be suitable starting materials for the synthesis of the corresponding amino acids and their derivatives, both via chemical and enzymatic hydrolysis.2 In the framework of our synthetic interest in 2-(ω-cyanoalkyl)aziridines,3 we have recently demonstrated the applicability of 3-unsubstituted 2-(2-cyanoethyl)aziridines for the construction of novel 3-(aziridin-2-yl)propionamides and potassium 3-(aziridin-2-yl)propanoates by enzymatic and chemical

a SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium. E-mail: [email protected] b Department of Biochemical and Microbial Technology, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4ob02615b

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hydrolysis, respectively.3g Furthermore, 3-(aziridin-2-yl)propionamides have been proven to be good precursors for the synthesis of δ-lactams, and 3-(aziridin-2-yl)propanoates have been rearranged selectively into γ-lactones upon acidification. In both cases, the ring opening occurred at the more substituted aziridine carbon atom, leading to the formation of δ-lactams and γ-lactones as the sole reaction products. As the enhanced electrophilicity of a benzylic aziridine carbon atom could have a pronounced effect on the regiocontrol of (intramolecular) ring-opening reactions, the enzymatic and chemical hydrolysis and the subsequent ring expansion of 2-aryl-3-(2-cyanoethyl)aziridines is explored in the present paper. The chemical industry shows a lot of interest in γ-lactams as they are used as intermediates for the synthesis of agrochemicals, textile auxiliaries, solvents, polymers, stabilizers, dyes and nylon precursors.4 Furthermore, from a biological point of view, functionalized γ-lactams are an important class of compounds as they possess interesting properties such as psychotropic, antihypertensive, antifungal and antidepressant activities.4,5 In addition, γ-lactones are a widespread entity in natural products, and many of them display important biological activities such as germination stimulation, anticancer and anti-HIV activity, whereas other representatives are often used as food additives (flavorants) or constitute valuable building blocks in organic synthesis.6

Results and discussion Within azaheterocyclic chemistry, β-lactams comprise an extraordinary class of strained compounds with diverse synthetic and biological applications.7 In previous work, we have

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Fig. 1

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Amino nitrile-containing bioactive compounds

demonstrated the versatility of functionalized β-lactams for the preparation of a variety of nitrogen-containing acyclic and heterocyclic compounds.8 In particular, substituted 3-chloroβ-lactams have been proven to be suitable precursors for the stereoselective synthesis of azetidines, aziridines and β-aminoalcohols.9 In light of this synthetic relevance, in the present work trans-β-lactams 6a–d were prepared in 61–74% yield by treatment of N-(arylmethylidene)alkylamines 5a–d, synthesized through condensation of the corresponding benzaldehydes with the appropriate primary amines in CH2Cl2 or THF in the presence of MgSO4 as drying agent, with chloroacetyl chloride and 2,6-lutidine in toluene according to a literature protocol.9a,c As the use of imines bearing an N-tert-butyl group in combination with a substituent in the ortho-position of the aromatic ring is known to afford the corresponding cis-4-aryl-3chloroazetidin-2-ones as the major stereoisomers after condensation with chloroketene,9c cis-3-chloro-β-lactam 6e was prepared under the same reaction conditions in order to investigate the possible influence of the relative stereochemistry on further transformations. Subsequently, the latter

4-aryl-3-chloro-β-lactams 6a–e were converted stereospecifically into the corresponding 2-aryl-3-(hydroxymethyl)aziridines 7a–e by a reductive ring contraction in THF using LiAlH4 (1.0 M in THF) at room temperature or under reflux for 2–4 hours, furnishing aziridines 7a–e in 48–77% yield (Scheme 1, Table 1).9c It should be mentioned that whereas trans-aziridines 7a–d were obtained as mixtures of two invertomers (20–34/66–80) due to hindered N-inversion, cis-aziridine 7e appeared as a single invertomer, leading to the conclusion that N-inversion in the latter case is completely blocked due to steric interactions (Table 1).9c Furthermore, attempts to purify trans-3hydroxymethyl-2-(4-methylphenyl)-1-propylaziridine 7d by crystallization or column chromatography failed. In the next stage, 2-aryl-3-(hydroxymethyl)aziridines 7a–c,e were employed as substrates for the preparation of the corresponding new 2-aryl-3-(2-cyanoethyl)aziridines 9a–c,e. Thus, aziridines 7a–c,e were tosylated using tosyl chloride in CH2Cl2 in the presence of Et3N and a catalytic amount of 4-(dimethylamino)pyridine (DMAP), affording the corresponding 2-aryl-3(tosyloxymethyl)aziridines 8a–c,e after stirring for 2–48 hours

Scheme 1

Table 1

Synthesis of 4-aryl-3-chloroazetidin-2-ones 6a–e and 2-aryl-3-(hydroxymethyl)aziridines 7a–e

Entry

R1

R2

Compound (yield)

cis/trans (6)c

Compound (yield)

Major/minor invertomerg

1 2 3 4 5

Bn Bn iPr nPr tBu

H 4-Cl H 4-Me 2-OMe

6a (74%)b 6b (67%)a 6c (74%)b 6d (61%)b 6e (51%)a

3/97 5/95 7/93 2/98 71/29

7a (66%)b 7b (48%)d 7c (66%)e 7d (77%) f 7e (51%)d

74/26 66/34 80/20 80/20 —

a

After crystallisation from EtOH. b After column chromatography (SiO2). c Based on GC analysis of the reaction mixture. d After crystallisation from EtOAc–hexane (30/1). e After crystallisation from EtOAc–hexane (3/2). f Crude yield (purity >85% based on NMR). g Based on 1H NMR analysis of the reaction mixture.

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Scheme 2

at room temperature (Scheme 2). The latter aziridines 8a–c,e were subsequently transformed into the premised 3-(2cyanoethyl)aziridines 9a–c,e with retention of the relative stereochemistry via alkylation with the sodium salt of trimethylsilylacetonitrile under microwave irradiation in THF at 80 °C for 2–3 hours, followed by trimethylsilyl group removal from the initially formed silylated aziridine intermediates upon treatment with a saturated solution of K2CO3 in methanol for 15 minutes at room temperature (Scheme 2, Table 2). In accordance with their 2-unsubstituted counterparts, the nitrile carbon in aziridines 9a–c,e resonated at 119.0–119.9 ppm (13C NMR, CDCl3).3b Also, in 1H NMR, the methylene group next to the nitrile functionality appeared at characteristic chemical shifts of 2.01–2.55 ppm (CDCl3).3b In analogy with 2-aryl-3-(hydroxymethyl)aziridines 7a–d,9c transaziridines 9a–c also appeared as mixtures of two invertomers due to hindered N-inversion, whereas cis-aziridine 9e was obtained as a single invertomer due to the 2,3-cis-configuration (Table 2). It should be mentioned that both diastereomeric antipodes of the new class of 2-aryl-3-(2-cyanoethyl)aziridines, i.e., trans-

Table 2

Synthesis of 2-aryl-3-(2-cyanoethyl)aziridines 9a–c,e

Entry

R1

R2

Compound (yield)

Major/minor invertomerc

1 2 3 4

Bn Bn iPr tBu

H 4-Cl H 2-OMe

9a (48%)a 9b (52%)a 9c (36%)a 9e (47%)b

75/25 83/17 70/30 —

a

After column chromatography (SiO2). b After reversed phase column chromatography (C18). c Based on 1H NMR analysis of the reaction mixture.

and cis-aziridines 9a–c and 9e, can thus be prepared selectively through choice of the appropriate imine for the Staudinger synthesis of the starting β-lactams. Although the chemistry of 3-unsubstituted 2-(cyanomethyl)aziridines and 2-(2-cyanoethyl)aziridines has been exploited quite extensively in previous studies,3 very little is known about the synthetic applicability of the class of 2-aryl-3-(2-cyanoethyl)aziridines 9, pointing to the unexplored nature of this topic. Indeed, aziridines 9 hold interesting potential for further elaboration due to the presence of a strained threemembered ring system and a synthetically useful nitrile functionality at a remote position. In that respect, in previous work, the chemical hydrolysis of 2-(2-cyanoethyl)aziridines using KOH in EtOH/H2O has been studied to furnish the corresponding potassium 3-(aziridin-2-yl)propanoates, which, upon acidification with acetic acid, smoothly rearranged into 4-(aminomethyl)butyrolactones via an 5-exo-tet cyclization of the initially formed zwitterionic intermediates.3g As the enhanced electrophilicity of the benzylic aziridine carbon atom in 2-aryl-3-(2-cyanoethyl)aziridines 9 could have a pronounced influence on the regioselectivity of the latter intramolecular ring-expansion reaction, in the next phase, the aptitude of 2-aryl-3-(2-cyanoethyl)aziridines 9a–c as substrates for the KOH-mediated hydrolysis was investigated by three different procedures. Thus, trans-2-aryl-3-(2-cyanoethyl)aziridines 9a–c were treated with KOH in a two-phase system of ethanol and water under reflux for 16 hours (Scheme 3, Method A) or under microwave irradiation at 100 °C for 10–20 minutes (Scheme 3, Method B and C), resulting in the formation of 4-[aryl(alkylamino)methyl]butyrolactones 10a–c and 5-[aryl(hydroxy)methyl]pyrrolidin-2-ones 11a–c in varying ratios after neutralization of the alkaline medium (Table 3). Despite complete conversion of the starting

Scheme 3

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Table 3 KOH-mediated hydrolysis of trans-2-aryl-3-(2-cyanoethyl)aziridines 9a–c

Entry

R1

R2

Method

Resulta

Compound (yield)

1 2 3 4 5 6

Bn Bn Bn Bn iPr iPr

H H 4-Cl 4-Cl H H

A C C B A B

10a/11a = 80/20 10a/11a = 36/64 10b/11b = 71/29 10b/11b = 59/41 10c/11c = 68/32 10c/11c = 25/75

10a (35%)b 11a (44%)b 10b (13%)b 11b (35%)b 10c (20%)c 11c (45%)d

Based on 1H NMR analysis of the reaction mixture. b After preparative TLC. c After preparative HPLC. d Crude yield (purity >95% based on NMR). a

aziridines 9a–c, isolated yields of compounds 10a–c and 11a–c are quite low due to a difficult separation. The relative stereochemistry of (4S*,1′R*)-butyrolactones 10a–c and (5R*,1′S*)γ-lactams 11a–c, which is a direct result of the stereochemistry of the starting aziridines 9a–c, could be deduced from the 1H NMR spectra, as the coupling constants of respectively 3.3–4.0 Hz between the protons at C4 and C1′ and 2.3 Hz between the protons at C5 and C1′ correspond well with those reported in the literature for analogous systems.10,11 Furthermore, the relative stereochemistry of (4S*,1′R*)-γ-lactone 10a was confirmed by 1D NOESY experiments, indicating NOE correlations of 2.2% between the aforementioned protons. The spectral data of (5R*,1′S*)-γ-lactam 11a are fully consistent with previously reported data, also mentioning X-ray crystallographic data for this derivative.11b In order to expand the scope, cis-aziridine 9e was also used as substrate for the latter KOH-assisted hydrolysis. Although more drastic reaction conditions were required compared to the ring expansion of trans-2-aryl-3-(2-cyanoethyl)aziridines 9a– c (8 equiv. KOH, 100 °C, 23 h (MW) instead of 5 equiv. KOH, 100 °C, 10–20 minutes (MW)), (4R*, 1′R*)-γ-lactone 10e was obtained selectively in 65% yield after neutralization, and no traces of the corresponding γ-lactam were present in the reaction mixture (Scheme 4). Also in this case, a coupling constant of 6.3 Hz between the protons at C4 and C1′ corresponds well with coupling constants of analogous systems in the literature, confirming the relative stereochemistry of compound 10e.10 From a mechanistic point of view, the formation of γ-lactones 10 can be rationalized considering the initial base-catalyzed hydrolysis of the cyano group in 2-aryl-3-(2-cyanoethyl)aziridines 9 towards the corresponding potassium 3-(aziridin2-yl)propanoates, which rearrange into the observed γ-lactones 10 upon neutralization of the alkaline medium. Indeed, acidification transforms the intermediate potassium salts into the corresponding amino acids, which exist as zwitterionic struc-

Scheme 4

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Scheme 5

tures 12 at neutral pH. Considering the presence of an electrophilic aziridinium moiety and a nucleophilic carboxylate at a remote position, a subsequent intramolecular ring expansion by a 5-exo-tet cyclization of the latter zwitterionic intermediates 12 towards γ-lactones 10 is facilitated (Scheme 5). Although 2-aryl-3-(2-cyanoethyl)aziridines 9 contain an electrophilic aziridine carbon atom in α-position of the aromatic ring (benzylic position), no δ-lactone formation was observed, probably due to a disfavored 6-endo-tet ring closure according to the Baldwin rules as compared to a favored 5-exo-tet cyclization. In this way, the presence of a benzylic position in the starting aziridines 9 does not have a controlling influence on the regioselectivity of the latter intramolecular ring-expansion reaction as compared to their monosubstituted counterparts. Regarding the formation of the observed γ-lactams 11, different reaction pathways can be considered. Firstly, hydroxide-induced regioselective ring opening of the starting aziridines 9 through an SN2 reaction at the benzylic aziridine carbon atom can account for the formation of intermediate γ-amino nitriles 13, which are subsequently susceptible to 5-exo-dig ring closure towards 2-iminopyrrolidines 14 by attack of the amino group across the cyanide moiety. Finally, hydrolysis furnishes γ-lactams 11 (Scheme 6, route A). In order to investigate this mechanistic rationale, 1-benzyl-2-(4-chlorophenyl)-3-(hydroxymethyl)aziridine 7b was converted into the corresponding methyl ether through a Williamson ether synthesis upon treatment with sodium hydride, followed by addition of methyl iodide in THF under reflux for five hours.9c Subsequently, the latter 1-benzyl-2-(4-chlorophenyl)-3-(methoxymethyl)aziridine was treated with KOH under the abovedescribed reaction conditions (5 equiv. KOH, EtOH/H2O (3/1), reflux, 16 h or 5 equiv. KOH, EtOH/H2O (5/1), 100 °C, 10–20 min (MW)), resulting in complete recovery of the starting material. In this way, it is clear that 2-aryl-3-(2-cyanoethyl) aziridines 9a–c,e are reluctant to KOH-assisted ring opening in EtOH–H2O, as could be expected considering the overall low reactivity of nonactivated 1-alkylaziridines.12 A second possible pathway involves the spontaneous intramolecular addition of the lone pair of the aziridine nitrogen atom in aziridines 9 across the cyano group, leading to the formation of intermediate bicyclic aziridinium salts 15, which are subsequently regiospecifically ring opened by hydroxide at the benzylic carbon atom to yield γ-lactams 11 after hydrolysis (Scheme 6, route B). In order to investigate the feasibility of this second

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Scheme 6

route, aziridine 9b was heated under reflux in different solvents (acetonitrile, DMF, iPrOH, EtOH) for 16 h in the presence of water. However, the starting product was recovered completely in all cases, pointing to the relative stability of 2-aryl-3-(2cyanoethyl)aziridines 9 under the given conditions. Finally, in a third route, the synthesis of γ-lactams 11 can occur via 5-exotrig closure of the aziridine nitrogen atom across the imido/ amido and/or carboxyl group in aziridinyl imides 16/aziridinyl amides 17 and/or aziridinyl carboxylic acids 18, initially formed by base-induced hydrolysis of aziridinyl nitriles 9 and subsequent neutralization (Scheme 6, route C and D). Indeed, following the KOH-induced hydrolysis of aziridinyl nitriles 9 by means of LC-MS chromatography, the appearance and subsequent conversion of the mass corresponding to imides 16/ amides 17 could be observed. Furthermore, in order to investigate the reactivity of the nitrile functionality under the abovedescribed conditions, octanenitrile was treated with 5 equiv. KOH, EtOH/H2O (3/1), Δ, 16 h and 5 equiv. KOH, EtOH–H2O (5/1), 100 °C, 10–20 min (MW), resulting in the formation of a mixture of octanamide and octanoic acid in varying ratios. In order to make a distinction between route C and D, intermediates 17 should be prepared and isolated via a different pathway, followed by treatment under the above-described conditions using KOH. Unfortunately, multiple attempts to selec-

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tively synthesize and isolate intermediates 17 failed. However, as γ-amino acids 18 are supposed to exist as zwitterionic intermediates 12 at neutral pH, the ring enlargement is most likely to occur via intermediate imides 16/amides 17. In addition, the corresponding 3-unsubstituted 2-(2-carbamoylethyl)aziridines have previously been proven to convert spontaneously into ring-expanded piperidinones upon prolonged storage in chloroform according to a similar reaction mechanism, pointing to the relative instability of 2-(2-carbamoylethyl)aziridines and further supporting route C as the most plausible mechanism for this transformation.3g In addition to the above-described chemical approach, the enzymatic hydrolysis of aziridinyl nitriles 9b,c was investigated in the next phase. In general, the chemo-, regio- and stereoselective biocatalytic hydrolysis of nitriles represents a valuable alternative for the chemical approach because it occurs at ambient temperature, in aqueous medium and at neutral pH.13 The enzyme-catalyzed hydrolysis of nitriles is known to proceed via two different pathways to afford either amides or acids depending on the type of enzyme used. Nitrilases catalyze the conversion of organic nitriles to the corresponding carboxylic acids and NH3, whereas nitrile hydratases (NHases) catalyze the conversion of nitriles to amides, which are subsequently transformed into acids and NH3 by amidases. In the next part of this study, the enzymatic hydrolysis of trans-2-aryl3-(2-cyanoethyl)aziridines 9b,c was investigated using nitrilases as the hydrolyzing tools. Thus, aziridinyl nitriles 9b,c were dissolved in MeOH and added to a K3PO4–dithiothreitol– ethylenediaminetetraacetic acid-buffered nitrilase solution, after which the reaction mixture was incubated at 30 °C and 200 rpm for 48–123 hours, leading to complete conversion towards γ-lactones 10b,c and γ-lactams 11b,c in a ratio of 0–5/ 95–100 (based on LC-MS analysis of the reaction mixture) (Scheme 7). From a mechanistic point of view, the cysteine residue in the active site of the nitrilase forms a covalent bond with the nitrile moiety in the starting aziridines 9b,c yielding thioimidates 20b,c, which are further hydrolyzed to the corresponding amino acids 12b,c via intermediate thioesters 21b,c. Finally, intramolecular ring opening results in the formation of γ-lactones 10b,c as the minor constituents (Scheme 7, route a). Apparently, intramolecular attack of the nucleophilic aziridine nitrogen atom in thioimidates 20b,c is preferred, forming bicyclic aziridinium intermediates 15b,c which are subsequently regiospecifically ring opened at the benzylic aziridine carbon atom to form intermediates 14b,c. Hydrolysis then furnishes γ-lactams 11b,c as the major constituents (Scheme 7, route b). Alternatively, analogous intramolecular cyclization of thioesters 21b,c gives raise to the formation of intermediate aziridinium salts 19b,c, which are hydrolyzed towards γ-lactams 11b,c (Scheme 7, route c). It should be stressed that this biocatalytic approach clearly leads to a considerably higher selectivity in favour of γ-lactams 11b,c as compared to the chemical approach, and thus provides an elegant and convenient synthetic route towards functionalized γ-lactams as valuable target compounds.

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Scheme 7

In conclusion, chemical and enzymatic hydrolysis have been used in a complementary way for the synthesis of novel butyrolactones and pyrrolidin-2-ones starting from 2-aryl-3-(2cyanoethyl)aziridines. As compared with their monosubstituted analogues, the enhanced electrophilicity of the benzylic carbon atom in the latter aziridines does not influence the regioselectivity of the observed ring-expansion reaction towards γ-lactones. On the other hand, a high selectivity towards γ-lactams was achieved in the biocatalytic route.

Experimental part General methods Commercially available solvents and reagents were purchased from common chemical suppliers and used without further purification. Melting points were measured using a Buchi B-540 apparatus or a Kofler bench, type WME Heizbank of Wagner & Munz. IR spectra were obtained from samples in neat form with an ATR (Attenuated Total Reflectance) accessory with a Perkin-Elmer Spectrum BX FT-IR spectrometer. 1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSE+ 300) or at 400 MHz (BRUKER AVANCE III-400) in deuterated solvents with tetramethylsilane as internal standard. 13C NMR spectra were recorded at 75 MHz (JEOL ECLIPSE+ 300) or at 100.6 MHz (BRUKER AVANCE III-400). Electron spray (ES) mass spectra were obtained with an Agilent 1100 Series MS (ES, 4000 V) mass spectrometer. High resolution electron spray

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(ES-TOF) mass spectra were obtained with an Agilent Technologies 6210 Series Time-of-Flight. Synthesis of 1-alkyl-4-aryl-3-chloroazetidin-2-ones 6a–e 4-Aryl-3-chloroazetidin-2-ones 6a–e were prepared according to a literature procedure.9c trans-3-Chloro-4-(4-methylphenyl)-1-propylazetidin-2-one 6d Yellow oil, yield 61%; Rf 0.13 (hexane–EtOAc 19/1); IR (ATR): νmax/cm−1 1765 (CO), 2964, 1396, 1361, 1344, 1089, 824, 794, 748; 1H NMR (400 MHz, CDCl3): δ 0.91 (3H, t, J = 7.4 Hz), 1.48–1.57 (2H, m), 2.38 (3H, s), 2.80–2.87 (1H, m), 3.44 (1H, d × t, J = 14.0, 7.7 Hz), 4.47 and 4.51 (2 × 1H, 2 × d, J = 1.6 Hz), 7.19–7.25 (4H, m); 13C NMR (100.6 MHz, ref = CDCl3): δ 11.4, 20.8, 21.2, 42.7, 63.1, 65.9, 126.5, 129.9, 132.1, 139.5, 164.0; MS (70 eV): m/z (%) 238/40 (M+ + H, 100); HRMS (ESI) calcd for C13H17ClNO+: 238.0999 [M + H]+; found: 238.0998. Synthesis of 2-aryl-3-(hydroxymethyl)aziridines 7a–e General procedure: as a representative example, the synthesis of trans-3-hydroxymethyl-2-(4-methylphenyl)-1-propylaziridine 7d is described. To an ice-cooled solution of trans-3-chloro-4(4-methylphenyl)-1-propylazetidin-2-one 6d (0.48 g, 2 mmol, 1 equiv.) in THF (10 mL) was added a solution of LiAlH4 (2.4 mL, 2.4 mmol, 1.2 equiv., 1.0 M in THF) via a syringe. Subsequently, the resulting mixture was stirred under reflux for 4 hours, after which water (2 mL) was added at 0 °C in order to neutralize the excess of LiAlH4. Afterwards, the mixture was

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filtered through a path of Celite®, and the filtrate was dried over MgSO4. Removal of the drying agent through filtration and evaporation of the solvent afforded trans-3-hydroxymethyl2-(4-methylphenyl)-1-propylaziridine 7d in 77% yield without the need for further purification ( purity >85% based on NMR). Spectral data of 2-aryl-3-(hydroxymethyl)aziridines 7a–c,e were in accordance with those reported in the literature.9c trans-3-Hydroxymethyl-2-(4-methylphenyl)-1-propylaziridine 7d Spectral data based on 1H NMR and 13C NMR analysis of the crude reaction mixture. Major/minor = 80/20; yellow oil, yield 77%; IR (ATR): νmax/ cm−1 3340 (OH), 2958, 2926, 2871, 1516, 1458, 1378, 1049, 806, 747; MS (70 eV): m/z (%) 206 (M+ + H, 100); HRMS (ESI) calcd for C13H20NO+: 206.1539 [M + H]+; found: 206.1540. Major invertomer. 1H NMR (400 MHz, CDCl3): δ 0.80 (3H, t, J = 7.4 Hz), 1.40–1.53 (2H, m), 1.93 and 2.23 (2 × 1H, 2 × (d × d × d), J = 11.9, 8.5, 8.3, 6.6, 6.3 Hz), 2.27–2.32 (1H, m), 2.35 (3H, s), 3.14 (1H, d, J = 3.6 Hz), 3.59 and 3.93 (2 × 1H, 2 × (d × d), J = 11.6, 5.4, 3.5 Hz), 7.07–7.19 (4H, m); 13C NMR (100.6 MHz, ref = CDCl3): δ 11.8, 21.1, 23.0, 43.3, 44.2, 53.5, 62.5, 126.0, 128.7, 130.0, 137.5. Minor invertomer. 1H NMR (400 MHz, CDCl3): δ 0.94 (3H, t, J = 7.4 Hz), 1.59–1.70 (2H, m), 2.27–2.32 (5H, m), 2.42 and 2.94 (2 × 1H, 2 × (d × d × d), J = 11.8, 7.2, 7.0 Hz), 3.84–3.90 (1H, m), 4.04 (1H, d × d, J = 12.1, 3.7 Hz), 7.07–7.19 (4H, m); 13C NMR (100.6 MHz, ref = CDCl3): δ 12.0, 21.0, 23.5, 45.5, 47.7, 54.1, 58.9, 128.9, 130.2, 136.4, 137.0. Synthesis of 2-aryl-3-(2-cyanoethyl)aziridines 9a–c,e General procedure: as a representative example, the synthesis of trans-3-(2-cyanoethyl)-1-isopropyl-2-phenylaziridine 9c is described. To an ice-cooled solution of trans-3-hydroxymethyl1-isopropyl-2-phenylaziridine 7c (0.19 g, 1 mmol, 1 equiv.) in dry CH2Cl2 (10 mL) was added 4-(dimethylamino)pyridine (12.22 mg, 0.1 mmol, 0.1 equiv.), Et3N (0.11 g, 1.1 mmol, 1.1 equiv.) and tosylchloride (0.20 g, 1.05 mmol, 1.05 equiv.), after which the mixture was stirred for 6 hours at room temperature. Afterwards, the reaction mixture was washed with brine (2 × 5 mL) and a saturated NaHCO3 solution (2 × 5 mL). The aqueous phase was extracted with CH2Cl2 (3 × 5 mL), after which the organic fraction was dried (MgSO4), followed by removal of the drying agent and evaporation of the solvent in vacuo. In the next step, trans-1-isopropyl-2-phenyl-3-(tosyloxymethyl)aziridine 8c (0.35 g, 1 mmol, 1 equiv.) was dissolved in dry THF (5 mL), and trimethylsilylacetonitrile (0.14 g, 1.2 mmol, 1.2 equiv.) and sodium hydride (28.80 mg, 1.2 mmol, 1.2 equiv.) were added. The mixture was placed in a 10 mL sealed glass vessel, provided with an appropriate stirring bar and subjected to microwave conditions (80 °C, 3 hours). The reaction mixture was poured into a saturated solution of potassium carbonate in methanol (10 mL) and the resulting mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured into water (30 mL) and was extracted with Et2O (3 × 20 mL). Drying (MgSO4), filtration of the drying agent and evaporation of the solvent in vacuo

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afforded the crude product, which was isolated in pure form in 36% yield by means of column chromatography on silica gel (hexane–EtOAc 1/1). trans-1-Benzyl-3-(2-cyanoethyl)-2-phenylaziridine 9a Brown oil, yield 48%; Rf 0.25 (hexane–EtOAc 1/1); IR (ATR): νmax/cm−1 2246 (CN), 2851, 1495, 1452, 1028, 733, 697; MS (70 eV): m/z (%) 263 (M+ + H, 100); HRMS (ESI) calcd for C18H19N2+: 263.1543 [M + H]+; found: 263.1551. Major invertomer. 1H NMR (300 MHz, CDCl3): δ 1.61–1.69 (1H, m), 2.03–2.32 (4H, m), 2.93 (1H, d, J = 12.9 Hz), 3.20 (1H, s(broad)), 3.48 (1H, d, J = 12.9 Hz), 7.18–7.35 (10H, m); 13C NMR (75 MHz, ref = CDCl3): δ 15.2, 29.2, 41.3, 47.6, 56.4, 119.6, 127.1, 127.3, 128.4, 128.6, 128.7, 130.3, 130.3, 139.4. Minor invertomer. 1H NMR (300 MHz, CDCl3): δ 2.03–2.24 (3H, m), 2.41–2.43 (2H, m), 2.52 (1H, s(broad)), 3.90 (2H, s), 7.18–7.35 (10H, m); 13C NMR (75 MHz, ref = CDCl3): δ 16.5, 23.0, 46.3, 47.3, 56.0, 119.1, 126.2, 127.6, 128.2, 128.4, 128.6, 133.5, 139.6. trans-1-Benzyl-2-(4-chlorophenyl)-3-(2-cyanoethyl)aziridine 9b Brown oil, yield 52%; Rf 0.47 (hexane–EtOAc 1/1); IR (ATR): νmax/cm−1 2246 (CN), 1493, 1089, 734, 697; MS (70 eV): m/z (%) 297/9 (M+ + H, 100); HRMS (ESI) calcd for C18H18ClN2+: 297.1153 [M + H]+; found: 297.1160. Major invertomer. 1H NMR (300 MHz, CDCl3): δ 1.61–1.70 (1H, m), 2.01–2.26 (4H, m), 2.94 (1H, d, J = 13.2 Hz), 3.16 (1H, s(broad)), 3.45 (1H, d, J = 13.2 Hz), 7.18–7.36 (9H, m); 13C NMR (75 MHz, ref = CDCl3): δ 15.1, 29.0, 41.6, 46.8, 56.4, 119.5, 127.4, 127.6, 128.6, 131.5, 132.1, 134.2, 139.1. Minor invertomer. 1H NMR (300 MHz, CDCl3): δ 2.01–2.17 (3H, m), 2.40–2.55 (2H, m), 2.51 (1H, s(broad)), 3.89 (2H, s), 7.18–7.36 (9H, m); 13C NMR (75 MHz, ref = CDCl3): δ 16.4, 22.9, 46.6, 55.9, 119.0, 127.2, 127.6, 128.6, 132.1, 134.2, 139.1. trans-3-(2-Cyanoethyl)-1-isopropyl-2-phenylaziridine 9c Yellow oil, yield 36%; Rf 0.17 (hexane–EtOAc 1/1); IR (ATR): νmax/cm−1 2246 (CN), 2966, 2931, 1455, 1365, 1338, 1155, 1012, 730, 699; MS (70 eV): m/z (%) 215 (M+ + H, 100); HRMS (ESI) calcd for C14H19N2+: 215.1543 [M + H]+; found: 215.1544. Major invertomer. 1H NMR (400 MHz, CDCl3): δ 0.75 and 1.13 (2 × 3H, 2 × d, J = 6.2 Hz), 1.64–1.73 (1H, m), 1.95 (1H, septet, J = 6.2 Hz), 2.05–2.13 (1H, m), 2.27–2.31 (1H, m), 2.55 (2H, t, J = 6.9 Hz), 3.09 (1H, d, J = 3.1 Hz), 7.21–7.36 (5H, m); 13 C NMR (100.6 MHz, ref = CDCl3): δ 15.3, 21.7, 22.7, 29.4, 39.5, 47.5, 49.9, 119.5, 127.9, 128.1, 130.2, 133.2. Minor invertomer. 1H NMR (400 MHz, CDCl3): δ 1.17 and 1.19 (2 × 3H, 2 × d, J = 6.5 Hz), 1.64–1.73 (1H, m), 1.95 (1H, septet, J = 6.5 Hz), 2.05–2.13 (2H, m), 2.38–2.45 (1H, m), 2.55 (2H, t, J = 6.9 Hz), 7.21–7.36 (5H, m); 13C NMR (100.6 MHz, ref = CDCl3): δ 16.5, 22.9, 23.0, 29.7, 45.9, 46.3, 52.7, 119.1, 126.2, 126.9, 128.3, 133.2. cis-1-tert-Butyl-3-(2-cyanoethyl)-2-(2-methoxyphenyl)aziridine 9e Yellow oil, yield 47%; Rf 0.08 (MeOH–H2O 1/1); IR (ATR): νmax/ cm−1 2245 (CN), 2965, 2933, 1492, 1462, 1244, 1212, 1108,

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1046, 1028, 754; 1H NMR (400 MHz, CDCl3): δ 1.08 (9H, s), 1.24–1.33 and 1.40–1.49 (2 × 1H, 2 × m), 2.13 (1H, ∼q, J = 6.5 Hz), 2.26 (2H, t, J = 7.2 Hz), 2.98 (1H, d, J = 6.5 Hz), 3.85 (3H, s), 6.83 (1H, d × d, J = 7.7, 0.8 Hz), 6.91 (1H, t × d, J = 7.7, 0.8 Hz), 7.21 (1H, t × d, J = 7.7, 1.6 Hz), 7.42 (1H, d × d, J = 7.7, 1.6 Hz); 13C NMR (100.6 MHz, ref = CDCl3): δ 15.3, 24.8, 26.9, 35.3, 36.7, 52.9, 55.2, 109.6, 119.9, 120.2, 126.0, 127.8, 129.5, 158.1; MS (70 eV): m/z (%) 259 (M+ + H, 100); HRMS (ESI) calcd for C16H23N2O+: 259.1805 [M + H]+; found: 259.1803. Synthesis of γ-lactones 10a–c,e and γ-lactams 11a–c Method A. General procedure: as a representative example, the synthesis of (4S*,1′R*)-4-[(isopropylamino)phenylmethyl]butyrolactone 10c is described. To a solution of trans-3-(2cyanoethyl)-1-isopropyl-2-phenylaziridine 9c (0.21 g, 1 mmol, 1 equiv.) in a mixture of ethanol–water (3/1) (20 mL) was added potassium hydroxide (0.28 g, 5 mmol, 5 equiv.), and the resulting mixture was heated under reflux for 16 hours. The reaction mixture was neutralized with 1 M HCl and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with H2O (2 × 10 mL) and brine (10 mL). Drying (MgSO4), filtration of the drying agent and evaporation of the solvent afforded a mixture of (4S*,1′R*)-4-[(isopropylamino)phenylmethyl]butyrolactone 10c and (5R*,1′S*)-1-isopropyl-5[hydroxyl( phenyl)methyl]pyrrolidin-2-one 11c in a ratio of 68/32. (4S*,1′R*)-4-[(Isopropylamino)phenylmethyl]butyrolactone 10c was separated and purified from the mixture by preparative HPLC in 20% yield. Method B/C. General procedure: As a representative example, the synthesis of (4S*,1′R*)-4-[(isopropylamino)phenylmethyl]butyrolactone 10c and (5R*,1′S*)-1-isopropyl-5[hydroxyl( phenyl)methyl]pyrrolidin-2-one 11c is described. To a solution of trans-3-(2-cyanoethyl)-1-isopropyl-2-phenylaziridine 9c (0.21 g, 1 mmol, 1 equiv.) in a mixture of ethanol– water (5/1) (4 mL) was added potassium hydroxide (0.28 g, 5 mmol, 5 equiv.). The mixture was placed in a 10 mL sealed glass vessel, provided with an appropriate stirring bar and subjected to microwave conditions (100 °C, 10–20 min). The reaction mixture was neutralized with 1 M HCl and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with H2O (2 × 10 mL) and brine (10 mL). Drying (MgSO4), filtration of the drying agent and evaporation of the solvent afforded a mixture of (4S*,1′R*)-4-[(isopropylamino) phenylmethyl]butyrolactone 10c and (5R*,1′S*)-1-isopropyl5-[hydroxyl( phenyl)methyl]pyrrolidin-2-one 11c in a ratio of 25/75. Method D. General procedure: as a representative example, the synthesis of (4S*,1′R*)-4-[(isopropylamino)phenylmethyl]butyrolactone 10c and (5R*,1′S*)-1-isopropyl-5-[hydroxyl( phenyl)methyl]pyrrolidin-2-one 11c is described. Nitrilase14 (50 mg) was added to 48 mL of a K3PO4–dithiothreitol–ethylenediaminetetraacetic acid buffer (50 mM/20 mM/1 mM, pH = 7.5). A solution of trans-3-(2-cyanoethyl)-1-isopropyl-2-phenylaziridine 9c (0.21 g, 1 mmol, 1 equiv.) in MeOH (2.50 mL) was then added, and the mixture was agitated in a thermomixer

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(30 °C, 200 rpm) for 48 hours, leading to complete conversion towards (4S*,1′R*)-4-[(isopropylamino)phenylmethyl]butyrolactone 10c and (5R*,1′S*)-1-isopropyl-5-[hydroxyl( phenyl)methyl]-pyrrolidin-2-one 11c in a ratio of 5/95. (4S*,1′R*)-4-(Benzylaminophenylmethyl)butyrolactone 10a Yellow oil, yield 35%; Rf 0.72 (EtOAc); IR (ATR): νmax/cm−1 3323 (NH), 1771 (CO), 2923, 1453, 1181, 698; 1H NMR (300 MHz, CDCl3): δ 1.90 (1H, s(broad)), 1.99–2.44 (4H, m), 3.53 and 3.74 (2 × 1H, 2 × d, J = 13.2 Hz), 3.97 (1H, d, J = 3.3 Hz), 4.71–4.77 (1H, m), 7.28–7.49 (10H, m); 13C NMR (75 MHz, ref = CDCl3): δ 23.0, 28.5, 51.1, 63.8, 83.4, 127.2, 128.2, 128.3, 128.5, 128.9, 137.7, 139.9, 177.2; MS (70 eV): m/z (%) 282 (M+ + H, 100); HRMS (ESI) calcd for C18H20NO2+: 282.1489 [M + H]+; found: 282.1499. (4S*,1′R*)-4-[Benzylamino(4-chlorophenyl)methyl]butyrolactone 10b Yellow oil, yield 13%; Rf 0.40 (hexane–EtOAc 1/1); IR (ATR): νmax/cm−1 3325 (NH), 1775 (CO), 2851, 2246, 1493, 1090, 698; 1 H NMR (300 MHz, CDCl3): δ 2.04–2.58 (4H, m), 3.50 and 3.71 (2 × 1H, 2 × d, J = 13.5 Hz), 3.94 (1H, d, J = 4.0 Hz), 4.67 (1H, d × d × d, J = 7.1, 7.1, 4.0 Hz), 7.18–7.38 (9H, m); 13C NMR (75 MHz, ref = CDCl3): δ 23.1, 28.5, 51.1, 63.2, 83.1, 127.3, 128.3, 128.6, 129.1, 129.7, 131.5, 136.4, 139.7, 176.9; MS (70 eV): m/z (%) 316/8 (M+ + H, 100); HRMS (ESI) calcd for C18H19ClNO2+: 316.1099 [M + H]+; found: 316.1101. (4S*,1′R*)-4-[(Isopropylamino)phenylmethyl]butyrolactone 10c Yellow oil, yield 20%; Rf 0.17 (hexane–EtOAc 1/1); IR (ATR): νmax/cm−1 3412 (NH), 1781 (CO), 2990, 1458, 1425, 1200, 1183, 1135, 1066, 799, 720, 708; 1H NMR (400 MHz, CDCl3): δ 1.29 and 1.39 (2 × 3H, 2 × d, J = 6.3 Hz), 1.62–1.70 (1H, m), 1.75–1.83 (1H, m), 2.27–2.36 (1H, m), 2.40–2.48 (1H, m), 3.10 (1H, septet, J = 6.3 Hz), 4.43 (1H, s(broad)), 5.40–5.44 (1H, m), 7.47–7.48 and 7.52–7.55 (3H and 2H, 2 × m); 13C NMR (100.6 MHz, ref = CDCl3): δ 17.4, 20.0, 23.8, 27.2, 49.3, 62.6, 78.4, 128.2, 129.61, 129.65, 130.3, 176.7; MS (70 eV): m/z (%) 234 (M+ + H, 100); HRMS (ESI) calcd for C14H20NO2+: 234.1489 [M + H]+; found: 234.1489. (4R*,1′R*)-4-[(tert-Butylamino)(2-methoxyphenyl)methyl]butyrolactone 10e Spectral data based on 1H NMR and 13C NMR analysis of the crude reaction mixture of (4R*,1′R*)-4-[(tert-butylamino)(2-methoxyphenyl)methyl]butyrolactone 10e. Yellow oil, yield 65%; Rf 0.16 (EtOAc); IR (ATR): νmax/cm−1 3352 (NH), 1774 (CO), 2962, 1490, 1363, 1242, 1182, 1026, 756; 1 H NMR (400 MHz, CDCl3): δ 0.96 (9H, s), 1.91–2.00 (2H, m), 2.03–2.12 (1H, m), 2.42 and 2.59 (2 × 1H, 2 × (d × d × d), J = 17.7, 9.8, 9.8, 8.0, 5.5 Hz), 3.86 (3H, s), 4.35 (1H, d, J = 6.3 Hz), 4.47 (1H, d × d × d, J = 6.6, 6.6, 6.3 Hz), 6.86 (1H, d × d, J = 7.7, 0.8 Hz), 6.95 (1H, t × d, J = 7.7, 0.8 Hz), 7.20–7.25 (1H, m), 7.43 (1H, d × d, J = 7.7, 1.1 Hz); 13C NMR (100.6 MHz, ref = CDCl3): δ 24.8, 29.0, 30.0, 51.1, 53.3, 55.4, 84.4, 110.4, 120.8, 128.2,

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128.6, 130.8, 156.2, 177.7; MS (70 eV): m/z (%) 278 (M+ + H, 100); HRMS (ESI) calcd for C16H24NO3+: 278.1751 [M + H]+; found: 278.1747.

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(5R*,1′S*)-1-Benzyl-5-[hydroxy( phenyl)methyl]pyrrolidin-2-one 11a

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Spectral data of (5R*,1′S*)-1-benzyl-5-( phenylhydroxymethyl)pyrrolidin-2-one 11a were in accordance with those reported in the literature.11b (5R*,1′S*)-1-Benzyl-5-[(4-chlorophenyl)hydroxymethyl]pyrrolidin-2-one 11b Colourless oil, yield 35%; Rf 0.25 (hexane–EtOAc 1/1); IR (ATR): νmax/cm−1 3331 (OH), 1661 (CO), 2926, 1418, 1086, 705; 1H NMR (300 MHz, CDCl3): δ 1.52–1.67 and 1.92–1.99 (2 × 1H, 2 × m), 2.26–2.37 and 2.45–2.57 (2 × 1H, 2 × m), 3.20 (1H, d, J = 3.3 Hz), 3.61 (1H, d, J = 7.7 Hz), 4.25 (1H, d, J = 14.6 Hz), 4.99–5.06 (1H, m), 5.04 (1H, d, J = 14.6 Hz), 7.14–7.38 (9H, m); 13C NMR (75 MHz, ref = CDCl3): δ 17.5, 30.6, 45.0, 63.1, 70.5, 127.2, 128.0, 128.2, 128.6, 129.1, 133.3, 136.6, 138.6, 176.7; MS (70 eV): m/z (%) 316/8 (M+ + H, 100); HRMS (ESI) calcd for C18H19ClNO2+: 316.1099 [M + H]+; found: 316.1099.

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(5R*,1′S*)-1-Isopropyl-5-[hydroxy(phenyl)methyl]pyrrolidin-2one 11c Orange oil, yield 45%; Rf 0.10 (hexane–EtOAc 4/6); IR (ATR): νmax/cm−1 3332 (OH), 1660 (CO), 2972, 1451, 1418, 1368, 1291, 1228, 707; 1H NMR (400 MHz, CDCl3): δ 1.40 and 1.42 (2 × 3H, 2 × d, J = 7.0 Hz), 1.57–1.67 (2H, m), 1.95–2.03 (1H, m), 2.20 (1H, d × d × d, J = 16.9, 10.5, 3.3 Hz), 2.56 (1H, d × t, J = 16.9, 9.5 Hz), 3.90 (1H, d × d × d, J = 9.1, 2.4, 2.3 Hz), 4.25 (1H, septet, J = 7.0 Hz), 5.14 (1H, d, J = 2.3 Hz), 7.28–7.39 (5H, m); 13 C NMR (100.6 MHz, ref = CDCl3): δ 18.1, 19.7, 21.6, 31.4, 44.9, 63.1, 73.7, 125.5, 127.7, 128.5, 140.2, 176.5; MS (70 eV): m/z (%) 234 (M+ + H, 100); HRMS (ESI) calcd for C14H20NO2+: 234.1489 [M + H]+; found: 234.1492.

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Acknowledgements The authors are indebted to Ghent University – Belgium (BOF) for financial support.

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Organic & Biomolecular Chemistry

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12 S. Stanković, M. D’hooghe, S. Catak, H. Eum, M. Waroquier, V. Van Speybroeck, N. De Kimpe and H.-J. Ha, Chem. Soc. Rev., 2012, 41, 643. 13 (a) A. Banerjee, R. Sharma and U. C. Banerjee, Appl. Microbiol. Biotechnol., 2002, 60, 33; (b) B. G. Davis and V. Borer, Nat. Prod. Rep., 2001, 18, 618; (c) L. Martinkova and V. Kren, Biocatal. Biotransform., 2002, 20, 73; (d) C. O’Reilly and P. D. Turner, J. Appl. Microbiol., 2003, 95, 1161; (e) R. DiCosimo, Nitrilases and Nitrile Hydratases. Biocatalysis in the Pharmaceutical and Biotechnology Industries, CRC Press, Boca Raton, FL, 2007, p. 1; (f) M. Kobayashi, T. Nagasawa and H. Yamada, Trends Biotechnol., 1992, 10, 402; (g) N. M. Shaw, K. T. Robins and A. Kiener, Adv. Synth. Catal., 2003, 345, 425; (h) S. M. Thomas, R. DiCosimo and A. Nagarajan, Trends Biotechnol., 2002, 20, 238. 14 A nitrilase screening kit was kindly donated by Codexis, from which nitrilase NIT-P1-121 was found to give the best results and was used for the biocatalytic conversion.

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