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Article

Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters

by
Fabio Benedetti
*,
Federico Berti
,
Lidia Fanfoni
,
Michele Garbo
,
Giorgia Regini
and
Fulvia Felluga
*
Department of Chemical and Pharmaceutical Sciences, University of Trieste, via Giorgieri 1. 34127 Trieste, Italy
*
Authors to whom correspondence should be addressed.
Molecules 2016, 21(6), 805; https://doi.org/10.3390/molecules21060805
Submission received: 24 May 2016 / Revised: 14 June 2016 / Accepted: 14 June 2016 / Published: 21 June 2016
(This article belongs to the Special Issue Synthesis of Bioactive Compounds from the Chiral Pool)
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Abstract

:
The four-step conversion of a series of N-Boc-protected l-amino acid methyl esters into enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the reductive elimination of related α-acetoxysulfones. The overall transformation takes place under mild conditions, with good yields, and without loss of stereochemical integrity, being in this respect superior to the conventional Julia reaction of α-amino aldehydes.

Graphical Abstract

1. Introduction

Allylic amines (allylamines) are compounds of significant synthetic and biological interest [1,2,3]. The allylamine fragment is present in natural products [4,5,6] and other biologically-active compounds [7,8,9], including drugs for the treatment of mycosis (terbinafine, naftifine) [10], depression (zimelidine) [11], motion sickness (cinnarizine) [12], migraine and epilepsy (flunarizine) [13] (Figure 1).
On the other hand, the characteristic bifunctional unit can undergo a wide range of chemical transformations, thus making allylamines versatile building blocks in organic synthesis [1]. Chiral allylamines, in particular, are valuable intermediates for the synthesis of a variety of chiral, enantiomerically-pure bioactive compounds [14,15,16,17].
Considerable effort has been devoted to the asymmetric synthesis of α-chiral allylamines, resulting in the development of several approaches, among which the transition metal-catalyzed asymmetric allylic amination has been extensively documented [18,19,20]. Other methods include the asymmetric vinylation of imines [21], the Overman rearrangement of allylic imidates [22], the asymmetric hydrogenation of dienamines [23], the transition metal-catalyzed asymmetric allylic C-H amination [24] and the nitroso-ene reaction [25].
In spite of recent advances in asymmetric synthesis, the olefination of α-amino aldehydes from the chiral pool is still an attractive alternative, as the starting materials can be obtained from the corresponding α-amino acids by several routes [26,27,28]. The synthesis of chiral allylamines by the Wittig [29,30,31], Julia [32,33,34] and Peterson [35] olefination of α-amino aldehydes has been reported, but these approaches are often limited by the chemical and configurational instability of α-amino aldehydes [27].
In the classical Julia reaction [36,37] (Scheme 1), a lithiated aryl alkyl sulfone is added to an aldehyde to give the corresponding α-hydroxysulfone A (pathway a). This, in turn, is converted into the target alkene by in situ acetylation and treatment of the resulting α-acetoxysulfone with sodium or magnesium amalgam [38] or SmI2 [39]. The same α-hydroxysulfone A, however, can be obtained in two steps by the acylation of the lithiated phenylalkylsulfone with an ester, followed by the reduction of the corresponding α-ketosulfone (Scheme 1, pathway b). Chiral allylamines may thus be obtained starting from readily-available α-amino esters that are chemically and configurationally more stable than α-amino aldehydes [40]; furthermore, the additional step of pathway b is not a limitation, as the latter compounds are generally prepared from the corresponding esters in at least one step [26].
This variant of the Julia reaction has been used in the synthesis of E-alkene dipeptide isosteres [41,42], but its wider scope and general applicability is still unexplored. In this paper, we demonstrate that the α-aminoester Julia olefination is a convenient method for the synthesis of terminal and disubstituted allylamines (Scheme 2).

2. Results and Discussion

The synthesis starts with the reaction between N-Boc amino esters 1 and lithiated phenylmethylsulfone 2a, giving the corresponding ketosulfones 3. The experimental conditions for this key step were initially optimized, with respect to yields and ee, using N-Boc alanine methyl ester 1a as the substrate (Table 1) [43].
Addition of 1a to one equivalent of lithiated phenylmethylsulfone 2a, even in the presence of two equivalents of n-BuLi as originally suggested by Lygo [42,44], resulted in a partial conversion into the ketosulfone 3a (Table 1, Entries 1 and 2). The low yields are likely due to the presence of ionizable protons, both in the starting amino ester (NHBoc) and in the ketosulfone product (methylene) that can exchange with lithiated 2a. The yield improved when an excess of BuLi and 2a was employed (Entries 3 and 4); under these conditions, however, the enantiomeric purity of the ketosulfone 3a was modest. The use of TMEDA in association with butyllithium [45] (Entry 6) and of other base systems (Entries 7, 8) was not successful. The best results were eventually obtained with two equivalents of sulfone and four equivalents of butyl lithium [46,47], with the resulting yellow suspension added to the amino ester 1a, at −78 °C under argon. In this case, complete conversion into the ketosulfone 3a was achieved, which was isolated in excellent yield and enantiomeric purity (Entry 9). It has been suggested that, under similar conditions, the dilithiated sulfone 8 is formed and is the reactive nucleophile [46,47]. It seems more likely, however, that the monolithiated species 9 is formed following H/Li exchange with the protected aminoester (Scheme 3) and is the actual nucleophile. A second equivalent of 8 is then required for a further H/Li exchange giving the dilithiated product 12, in agreement with the observed stoichiometry.
The optimized reaction conditions were then applied to the N-Boc-amino esters 1b–f (Table 2), giving the corresponding ketosulfones 3 in good to excellent yields and ee, with the only exception of the protected tyrosine methyl ester 1f; repeated attempts under several reaction conditions invariably led to a significant loss in enantiomeric purity for this compound. With L-proline methyl ester 1g (Entry 7), where no ionizable protons are present, the best optical purity, albeit at the expenses of a lower yield, was obtained by using two equivalents of PhSO2Me and BuLi with respect to the aminoester, whereas racemization was observed by employing the usual conditions. This further confirms that the reactive nucleophile in the reaction with the amino esters is the monolithiated species PhSO2CH2Li, as suggested above (Scheme 3).
Finally, the same conditions were applied to the reaction of amino esters 1e and 1g with phenylethylsulfone 2b (Table 2, Entries 8 and 9), giving the corresponding ketosulfones 3h and 3i, as mixtures of diastereoisomers, in excellent yield.
The ketosulfones 3a–g thus obtained were reduced with NaBH4 (Scheme 2), giving quantitatively the α-hydroxysulfones 4a–g as mixtures of syn (S,S) and anti (S,R) diastereoisomers in ratios from approximately 10:1 for branched Compounds 4b–d (Val, Leu, Ile) to 3:1 for compounds having linear side chains 4a,e,f (Ala, Phe, Tyr) to 1.5:1 for 4g (Pro), in agreement with previous findings [48]. No attempts were made to optimize the stereoselectivity, as the newly-formed stereogenic center is lost in the final step of the synthesis. Not surprisingly, complex mixtures containing all four possible diastereoisomers were obtained in the reduction of ketosulfones 3h and 3i.
Conversion of hydroxysulfones 4 into the allylamines 6 follows the standard protocol of the Julia reaction. Thus, the alcohols 4 were acetylated with acetic anhydride and DMAP, and the corresponding acetoxysulfones 5 were converted to the target aminoalkenes 6 in the final reductive elimination, promoted by sodium amalgam [36] or in situ generated magnesium amalgam [38] (Scheme 2, Table 3). The two methods were shown to proceed with comparable yields and ee, except for 5f: in this case, sodium amalgam caused the deprotection of the phenol group, leading directly to the allylamine 6f′, while the O-protected product 6f was smoothly obtained with magnesium amalgam.
The Julia reaction is known to favor the formation of the E isomer, when leading to disubstituted alkenes [36,37]. Accordingly, when substituted acetates 5h,i were subjected to reductive elimination with Na(Hg), the corresponding allylamines 6h,i were obtained as 4:1 mixtures of E and Z isomers, as determined by NMR. A complete list of the allylamines synthesized in this work with overall yields and enantiomeric excess is reported in Table 3.

3. Experimental Section

Glassware was thoroughly oven-dried for reactions using anhydrous conditions. THF was distilled over sodium benzophenone ketyl, under argon; CH2Cl2 and EtOH were distilled over CaH2 under argon. Yields refer to chromatographically and spectroscopically (1H-NMR) homogeneous materials. Reactions were monitored by TLC carried out on silica gel plates using UV light as the visualizing agent and KMnO4 as the developing agent. Silica gel 60 (230−400 mesh) was used for flash column chromatography. NMR spectra were recorded on a Varian 500 MHz spectrometer in CDCl3, unless otherwise stated, at 500 MHz (1H) and 125.68 MHz (13C); chemical shifts are in ppm (δ) with chloroform as the reference (δ = 7.26 for 1H-NMR and 77.16 for 13C-NMR). Coupling constants J are given in hertz. 1H and 13C-NMR resonances were assigned using a combination of DEPT, COSY and HSQC spectra. Infrared spectra were recorded as thin film or Nujol mull on NaCl plates on a Nicolet Avatar FT-IR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA). Melting points are uncorrected. Electrospray (ESI) mass spectra were obtained on a Bruker Daltonics Esquire 4000 spectrometer (Bruker Corporation, Billerica, MA, USA). HRMS analyses were carried out in the ESI mode on a TOF-MS instrument (Bruker Corporation). Enantiomeric excesses were determined by Chiral High Resolution GC analyses on γ- or β-cyclodextrin capillary columns and, for compounds 3f and 6f only, by chiral high pressure liquid chromatography on a Cellulose2 column, with a UV detector operating at λ = 280 nm, eluting with nHex/iPrOH 9:1. Optical rotations were measured at 25 °C with a Jasco P-2000 polarimeter (Jasco Inc, Easton, MD, USA). Commercial reagents and solvents were purchased from Sigma-Aldrich (Milan, Italy); PhSO2Me and PhSO2Et were prepared by reaction of sodium phenylsulfinate with the appropriate iodoalkane according to the literature [49].

3.1. General Procedure for the Synthesis of α-Ketosulfones 3

1.6 M n-BuLi in hexane (2.5 mL, 4 mmol for 3a–f,h; 1.25 mL, 2 mmol for 3g,i) was slowly added at −5 °C, under Ar, to a solution of sulfone 2 (2.0 mmol) in 1.5 mL dry THF, and the mixture was stirred at −5 °C for 30 min (4 h for reactions with sulfone 2b). The resulting yellow suspension was transferred via a syringe to a three-necked flask, containing a 2.5 M solution of the N-Boc amino ester 1 (1 mmol) in dry THF (1M for 3h,i), at −78 °C, under an Ar atmosphere, with stirring. The mixture was stirred overnight while the temperature was allowed to reach 25 °C, and partitioned between 5% aqueous citric acid (water for 3f) and ethyl acetate. The organic phase was extracted with saturated NaHCO3 and brine, dried over Na2SO4 and evaporated to give a solid that was purified by flash chromatography (eluent AcOEt/petroleum ether from 0%–15%).

3.2. Spectroscopic and Analytical Data for α-Ketosulfones 3

(3S)-3-(tert-Butoxycarbonylamino)-1-(phenylsulfonyl)-2-butanone (3a) [42]: 89% from 1a and 2a; white solid, mp 115–117 °C, [ α ] D 25 −36 (c 0.8, CHCl3); IR: 3387, 1736, 1700, 1288, 1148 cm−1; 1H-NMR: δ 1.35 (d, J = 7.0 Hz, 3H), 1.44 (s, 9H), 4.24 (d, J = 14.0 Hz, 1H), 4.33 (m, 1H), 4.44 (d, J = 14.0 Hz, 1H), 5.15 (br, 1H), 7.58 (m, 2H), 7.69 (m, 1H), 7.90 (m, 2H) ppm. 13C-NMR: δ 16.1, 28.1, 55.9, 63.2, 80.2, 128.4, 129.3, 134.3, 139.0, 155.3, 198.4 ppm; ESI-MS: m/z 350 [M + Na]+.
(3S)-3-(tert-Butoxycarbonylamino)-4-methyl-1-(phenylsulfonyl)-2-pentanone (3b) [44]: 85% From 1b and 2a; white solid, mp 85–88 °C, [ α ] D 25 −34 (c 1, CHCl3); IR: 3372, 1709, 1506, 1323, 1160 cm−1; 1H-NMR: δ 0.80 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H), 1.44 (s, 9H), 2.29 (m, 1H), 4.20 (d, J = 14.5, 1H), 4.25 (dd, J = 4.6, 8.7 Hz, 1H), 4.43 (d, J = 14.5 Hz, 1H), 5.10 (d, J = 8.7 Hz, 1H), 7.57 (m, 2H), 7.67 (m, 1H), 7.93 (m, 2H) ppm; 13C-NMR: δ 17.0, 19.9, 28.4, 28.9, 64.0, 65.2, 80.5, 128.6, 129.4, 134.4, 139.1, 156.0, 197.8 ppm; ESI-MS: m/z 378 [M + Na]+, 394 [M + K]+.
(3S)-3-(tert-Butoxycarbonylamino)-5-methyl-1-(phenylsulfonyl)-2-hexanone (3c): 89% From 1c and 2a; white solid, mp 76–78 °C; [ α ] D 25 −43 (c 1.6, CHCl3); IR: 3369, 1708, 1511, 1323, 1159 cm−1; 1H-NMR: δ 0.93 (d, J = 6.1 Hz, 3H), 0.94 (d, J = 6.1 Hz, 3H), 1.37–1.44 (s and, 10H), 1.67 (m, 2H), 4.21 (d, J = 13.9 Hz, 1H), 4.28 (m, 1H), 4.49 (d, J = 13.9 Hz, 1H), 5.06 (d, J = 7.1 Hz, 1H), 7.58 (t, 2H), 7.67 (t, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 2H) ppm; 13C-NMR: δ 21.4, 23.1, 24.8, 28.2, 39.1, 58.9, 63.3, 80.5, 128.4, 129.2, 134.2, 138.9, 155.5, 198.6 ppm; ESI-MS: m/z 392 [M + Na]+, 408 [M + K]+. Anal. Calcd. for C18H27NO5S: C, 58.51; H, 7.37; N, 3.79. Found C, 58.50; H, 7.43; N, 3.86.
(3S,4S)-3-(tert-Butoxycarbonylamino)-4-methyl-1-(phenylsulfonyl)-2-hexanone (3d): 86% from 1d and 2a; white solid, mp 83–85 °C;   [ α ] D 25 –0.2 (c 0.9, CHCl3); IR: 3368, 1708, 1504, 1323, 1156 cm−1; 1H-NMR: δ 0.87 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 1.05 (m, 1H), 1.27 (m, 1H), 1.42 (s, 9H), 1.99 (m, 1H), 4.20 (d, 1H), 4.27 (dd, J = 5.0, 8.7 Hz, 1H), 4.43 (d, J = 14.5 Hz, 1H), 5.08 (d, J = 8.7 Hz, 1H), 7.56 (m, 2H), 7.67 (m, 1H), 7.92 (m, 2H) ppm. 13C-NMR: δ 11.6, 16.1, 24.3, 28.4, 35.7, 64.1, 65.0, 80.5, 128.6, 129.4, 134.3, 139.1, 155.9, 197.9 ppm. ESI-MS: m/z 392 [M + Na]+, 408 [M + K]+. Anal. Calcd. for C18H27NO5S: C, 58.51; H, 7.37; N, 3.79. Found C, 58.42; H, 7.40; N, 3.91.
(3S)-3-(tert-Butoxycarbonylamino)-4-phenyl-1-(phenylsulfonyl)-2-butanone (3e) [44]: 94% from 1e and 2a; white solid, mp 137–139 °C; [ α ] D 25 –22 (c 1, CHCl3); IR: 3386, 1732, 1691, 1295, 1147 cm−1; 1H-NMR: δ 1.38 (s, 9H), 2.91 (dd, J = 8.5, 14.0 Hz, 1H), 3.16 (dd, J = 5.5, 14.0 Hz, 1H), 4.22 (d, J = 14.0 Hz, 1H), 4.35 (d, J = 14.0 Hz, 1H), 4.47 (m, 1H), 5.12 (d, J = 6.0 Hz, 1H), 7.15 (m, 2H), 7.23–7.31 (m, 3H), 7.56 (m, 2H), 7.67 (m, 1H), 7.86 (m, 2H) ppm; 13C-NMR: δ 28.2, 36.3, 61.4, 63.7, 80.6, 127.1, 128.4, 128.8, 129.3, 134.3, 136.2, 138.8, 155.4, 197.4 ppm; ESI-MS: m/z 426 [M + Na]+, 442 [M + K]+.
(3S)-3-(tert-Butoxycarbonylamino)-4-[4-(tert-butyldimethylsilyloxy)phenyl]-1-(phenylsulfonyl)-2-butanone (3f): 78% from 1f and 2a; ee 81%; white solid, mp 111–113 °C; [ α ] D 25 −21(c 1, CHCl3); IR: 3369, 1709, 1609, 1584, 1511 cm−1; 1H-NMR: δ 0.19 (s, 6H), 0.98 (s, 9H), 1.39 (s, 9H), 2.86 (dd, J = 8.6, 14.6 Hz, 1H), 3.18 (dd, J = 5.7, 14.6 Hz, 1H), 4.17 (d, J = 13.9 Hz, 1H), 4.32 (d, J = 13.9 Hz, 1H), 4.42 (m, 1H), 5.04 (d, J = 6.4 Hz, 1H), 6.77 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 7.8 Hz, 2H), 7.68 (t, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 2H) ppm; 13C NMR: δ −4.4, 18.2, 25.6, 28.2, 35.7, 61.5, 63.9, 80.6, 120.4, 128.4, 128.5, 129.2, 130.9, 134.2, 138.8, 154.8, 197.6 ppm; ESI-MS: m/z 556.2 [M + Na]+, 572 [M + K]+. Anal. Calcd. for C27H39NO6SSi: C, 60.76; H, 7.37; N, 2.62. Found C, 60.81; H, 7.38; N, 2.55.
1-((2S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinyl)-2-(phenylsulfonyl)-1-ethanone (3g): 60% from 1g and 2a; yellow oil; [ α ] D 25 −43.1 (c 1.6, CHCl3); IR: 1698, 1693, 1323, 1157 cm−1; 1H-NMR (mixture of rotamers): δ 1.36 and 1.43 (2s, 9H), 1.85–1.96 (m, 2H), 2.00–2.24 (m, 2H), 3.46 and 3.55 (m, 2H), 4.18–4.42 (m, 3H), 7.58 (m, 2H), 7.67 (m, 1H), 7.94 (m, 2H) ppm; 13C-NMR (Mixture of rotamers): δ 23.9, 24.8, 28.4 and 28.5, 47.0 and 47.2, 62.8 and 64.1, 65.7 and 66.3, 80.6 and 81.1, 128.6, 129.3 and 129.4, 134.2 and 134.4, 139.3, 153.7 and 155.0, 198.1 and 198.6 ppm; HRMS (ESI) m/z Calcd. for C17H23NNaO5S [M + Na]+ 376.1195, found 376.1192.
(2S,4S) and (2S,4R)-2-(tert-Butoxycarbonylamino)-1-phenyl-4-(phenylsulfonyl)-3-pentanone (3h): A 3:2 mixture of two diastereoisomers (a and b) was obtained from 1e and 2b in 77% yield; white solid; IR: 3390, 1737, 1700, 1286, 1150 cm−1; 1H-NMR: δ 1.28 and 1.37 (2d, 3H), 1.39 (s, 5.4H), 1.44 (s, 3.6H), 2.85 (dd, J = 9.6, 14.0 Hz, 0.67H), 3.02 (dd, J = 7.8, 13.8 Hz, 0.33H), 3.22 (dd, J = 5.0, 13.8 Hz, 0.33H), 3.33 (dd, J = 5.0, 14.0 Hz, 0.67H), 4.40–4.55 (m, 1H), 4.65–4.75 (m, 1H), 4.97 (d, 0.67H), 5.40 (d, 0.33H), 7.17–7.35 (m, 5H), 7.52–7.77 (m, 5H) ppm; 13C-NMR: δ 12.1 (b), 12.5 (a), 28.0 (a), 28.1 (b), 35.0 (a), 37.7 (b), 61.5 (a), 61.6 (b), 65.9 (b), 66.5 (a), 80.2 (b), 80.7 (a), 126.8 (a), 127.1 (b), 128.3 (b), 128.7, 129.1, 129.2, 129.3, 129.5, 129.6, 129.7, 134.3, 134.5, 135.9, 136.0, 136.3, 137.3, 155.4, 155.7, 200.8, 202.2 ppm; ESI-MS: m/z 440 [M + Na]+, 456 [M + K]+. Anal. Calcd. for C22H27NO5S: C, 63.29; H, 6.52; N, 3.35. Found C, 63.23; H, 6.38; N, 3.38.
(2S) and (2R) 1-((2S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinyl)-2-(phenylsulfonyl)-1-propanone (3i): A 55:45 mixture of two diastereoisomers (a and b) was obtained from 1g and 2b in 80% yield. Yellow oil; IR: 1700, 1689, 1322, 1157 cm−1; 1H-NMR (d6-DMSO, 80 °C): δ 1.30 (d, J = 7.4, 1.65H), 1.34 (d, J = 7.4 Hz, 1.35H), 1.35 (s, 4.95H), 1.41 (s, 4.05H), 1.59–2.25 (m, 4H), 3.28–3.45 (m, 2H), 4.55 (dd, J = 3.0, 8.0 Hz, 0.55H), 4.67 (br, 0.45H), 4.73 (m, 0.45H), 4.85 (br, 0.55H), 7.67 (m, 2H), 7.78 (m, 1H), 7.88 (m, 2H) ppm; 13C-NMR (d6-DMSO, 80 °C): δ 12.1 (b), 12.3 (a), 22.7 (a and b), 27.6 (a or b), 27.7 (a or b), 46.1 (b), 46.3 (a), 64.3, 64.7, 65.7, 78.8 (a), 79.0 (b), 128.5, 128.6 and 128.8, 133.7 (b), 133.8 (a), 137.0, 153.0, 201.6 ppm; HRMS (ESI) m/z Calcd. for C18H25NNaO5S [M + Na]+ 390.1351, found 390.1342.

3.3. General Procedure for the Synthesis of Allylamines 6 from Ketosulfones 3

NaBH4 (0.04 g, 1 mmol) was added portion-wise, at 0 °C, to a solution of ketone 3 (1 mmol) in methanol (5 mL). When the reaction was complete (TLC), the solvent was removed in vacuo; aqueous workup and extraction with ethyl acetate gave the β-hydroxysulfones 4 as mixtures of diastereoisomers, whose ratio was determined by NMR. To the crude mixtures of diastereoisomeric alcohols, in the minimum amount of dry dichloromethane, were added, in the order, 2-dimethylaminopyridine (0.01 mmol), triethylamine (10 mmol) and acetic anhydride (5 mmol), at 0 °C with stirring. The reaction mixture was stirred at room temperature until the formation of the product was complete (TLC: AcOEt/petroleum ether 2:8), extracted with 10% aqueous citric acid, saturated NaHCO3 and brine, dried over Na2SO4 and evaporated. If necessary, co-evaporation with toluene was performed to completely remove the excess anhydride. The crude acetates 5 were obtained in quantitative yield and were used in the final step without further purification. Where possible, analytical data are given for the main diastereoisomer obtained in pure form by crystallization (vide infra). Allylamines 6 were finally obtained from β-acetoxysulfones 5 following two methods. Method A: in a Schlenk reactor filled with Ar, Mg powder (2.5 mmol) and HgCl2 (0.1 mmol) were added, in the order, to a 0.2 M solution of sulfone 5 (1mmol, mixture of diastereoisomers) in 3:1 EtOH/THF. The reaction mixture was stirred at room temperature monitoring the progress by TLC (petroleum ether/diethyl ether 8:2); 10% aqueous citric acid was added, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by column chromatography using 9:1 petroleum ether/Et2O as the eluent. Method B: in a round-bottomed flask, 5% Na/Hg amalgam (3 mmol of Na) was added, at −15 °C, under an Ar atmosphere, to a stirred 0.5 M solution of sulfone 5 (1 mmol) in anhydrous, degassed ethanol. The reaction mixture was stirred at room temperature monitoring the progress by TLC (petroleum ether/diethyl ether 8:2); water was added, and the workup as above gave the crude allylamines 6.

3.4. Spectroscopic and Analytical Data for Alcohols 4, Acetates 5 and Allylamines 6

(3S)-3-(tert-Butoxycarbonylamino)-1-butene (6a) [50]: 68% via alcohol 4a and acetate 5a (Method A). 4a: 3:1 mixture of syn (s) and anti (a) diastereoisomers. Pale yellow oil; IR: 3370, 1693, 1304, 1146 cm−1; 1H-NMR: δ 1.13 (d, J = 8.5 Hz, 2.25H), 1.21 (d, J = 8.5 Hz, 0.75H), 1.40 (s, 9H), 3.21 (m, 1.5H), 3.26 (m, 0.5H), 3.64 (br, 2H), 4.10 (br, 1H), 4.73 (br, 1H), 7.59 (m, 2H), 7.69 (m, 1H), 7.92 (m, 2H) ppm; 13C-NMR: δ 15.4 (s), 18.1 (a), 28.3, 50.1, 59.8 (s), 60.5 (s), 68.5 (s), 68.9 (s), 79.9, 127.3 (s), 127.9 (s), 129.3 (a), 129.4 (s), 133.7 (a), 134.1 (s), 139.1, 155.5 ppm; ESI-MS: m/z 296 [M + Na]+, 368 [M + K]+. 5a: 3:1 mixture of syn (s) and anti (a) diastereoisomers. White solid, mp 110–111 °C; IR: 3358, 1742, 1712, 1521 cm−1; 1H-NMR: δ 1.06 (d, J = 7.0 Hz, 0.75H), 1.09 (d, J = 7.0 Hz, 2.25H), 1.40 (s, 6.75H), 1.42 (s, 2.25H), 1.82 (s, 2.25H), 1.95 (s, 0.75H), 3.37 (m, 2H), 3.86 (br, 1H), 4.43 (br, 0.75H), 4.52 (br, 0.25H) 5.21 (br, 0.75H), 5.34 (br, 0.25H), 7.57 (m, 2H), 7.66 (m, 1H), 7.91 (m, 2H) ppm; 13C-NMR: δ 16.3 (s), 18.1 (a), 20.6, 28.3, 48.3 (s) 49.4 (a), 56.7 (s), 57.8 (a), 69.5 (a), 70.2 (s), 80.0, 128.3, 129.3, 133.9, 139.2, 155.1, 169.8 ppm; ESI-MS: m/z 394 [M + Na]+. 6a: oil, ee 95% (by GLC); [ α ] D 25 –6.0 (c 0.45, CHCl3); 1H-NMR: δ 1.20 (d, J = 8.5 Hz, 3H), 1.44 (s, 9H), 4.22 (br, 1H), 4.45 (br, 1H), 5.10 (m, 2H), 5.81 (m, 1H) ppm; 13C NMR: δ 20.7, 28.4, 48.1, 79.3, 113.6, 140.1, 155.1 ppm; ESI-MS: m/z 194 [M + Na]+.
(3S)-3-(tert-Butoxycarbonylamino)-4-methyl-1-pentene (6b) [51]: 60% via alcohol 4b and acetate 5b (method A). 4b: 10:1 mixture of syn (s) and anti (a) diastereoisomers. Yellow oil; IR: 3368, 1691, 1304, 1146 cm−1; 1H-NMR (syn diastereoisomer): δ 0.87 (d, J = 7.0 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 1.40 (s, 9H), 2.18 (m, 1H), 3.23 (m, 1H), 3.32 (m, 1H), 3.48 (m, 1H), 3.56 (d, J = 2.9 Hz, 1H) 4.12 (m, 1H), 4.41 (d, J = 9.7 Hz, 1H), 7.59 (m, 2H), 7.68 (m, 1H), 7.92 (m, 2H) ppm. 13C-NMR ((2S,3S) diastereoisomer): δ 15.7, 20.0, 27.1, 28.3, 58.5, 60.4, 67.4, 80.1, 128.1, 129.7, 134.4, 139.6, 156.7 ppm; ESI-MS: m/z 380 [M + Na]+, 396 [M + K]+. 5b (syn isomer): white solid, mp: 98–100 °C; [ α ] D 25 −5 (c 0.6, CHCl3); IR: 3365, 1744, 1712, 1523 cm-1; 1H-NMR: δ 0.86 (d, J = 8.5 Hz, 3H), 0.90 (d, J = 8.5 Hz, 3H), 1.41 (s, 9H), 1.62 (m, 1H), 1.75 (s, 3H), 3.33 (d, J = 18.3 Hz, 1H), 3.44 (dd, J = 12.5, 18.3 Hz, 1H), 3.63 (m, 1H), 4.35 (d, J = 13.0 Hz, 1H), 5.29 (m, 1H), 7.57 (m, 2H), 7.66 (m, 1H), 7.90 (m, 2H) ppm; 13C-NMR: δ 17.1, 19.6, 20.6, 28.3, 56.6, 57.3, 68.1, 79.9, 127.4, 128.3, 129.1, 133.9, 139.1, 155.6, 169.7 ppm; ESI-MS: m/z 422 [M + Na]+, 438 [M + K]+. 6b: oil, ee > 99.5% (by GLC); [ α ] D 25 + 28 (c 0.85, CHCl3), lit. [33] + 25 (CHCl3); 1H-NMR: δ 0.88 (d, J = 7 Hz, 3H), 0.90 (d, J = 7 Hz, 3H), 1.44 (s, 9H), 1.77 (m, 1H), 3.98 (br, 1H), 4.50 (br, 1H), 5.12 (m, 2H), 5.73 (m, 1H) ppm. 13C-NMR: δ 18.2, 18.8, 28.6, 32.4, 58.1, 79.3, 115.2, 137.5, 155.7 ppm; ESI-MS: m/z 222 [M + Na]+, 237 [M + K]+.
(3S)-3-(tert-Butoxycarbonylamino)-5-methyl-1-hexene (6c) [52]: 67% via alcohol 4c and acetate 5c (method A). 4c: 7:1 mixture of syn (s) and anti (a) diastereoisomers. Orange oil; IR: 3368, 1694, 1305, 1146 cm−1; 1H-NMR: δ 0.85 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H), 1.31 (m, 2H), 1.39 (s, 9H), 1.60 (m, 1H), 3.25 (m, 1.76H), 3.27 (m, 0.24H), 3.49 (br, 0.12H), 3.56 (br, 0.88H), 3.74, (br, 0.12H), 3.78 (br, 0.88H), 4.10 (m, 1H), 4.55 (br d, J = 7.3 Hz, 0.88H), 4.72 (br d, J = 9.0 Hz, 0.12H), 7.57 (t, 2H), 7.66 (t, 1H), 7.92 (d, 2H) ppm. 13C-NMR: δ 21.5 (s), 22.0 (a), 23.0 (a), 23.6 (s) 24.6 (s), 24.7 (a), 28.2 (s), 28.3 (a), 38.9 (s), 41.3 (a), 52.6 (a), 52.9 (s), 59.8 (s), 60.3 (a), 67.8 (s), 69.4 (a), 79.6 (s), 79.8 (a), 127.9 (s), 128.0 (a), 129.4 (s), 129.5 (a), 134.0 (a), 134.1 (s), 134.2 (a), 139.2 (a), 139.3 (s), 156.1 ppm. ESI-MS: m/z 394 [M + Na]+, 410 [M + K]+. 5c: 7:1 mixture of syn (s) and anti (a) diastereoisomers. White solid; IR: 3372, 1745, 1707, 1519 cm-1; 1H-NMR: δ 0.86 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 1.13–1.25 (m, 2H), 1.41 (s, 7.9H) 1.43 (s, 1.1H), 1.60 (m, 1H), 1.78 (s, 2.6H), 1.96 (s, 0.4H), 3.35 (m, 1H) 3.44 (m, 1H), 3.76 (m, 0.13H), 3.89 (br, 0.87H), 4.33 (d, J = 10.0 Hz, 0.9H), 4.45 (d, J = 10.0 Hz, 0.1H), 5.18 (m, 0.9H), 5.37 (dbt, J = 9.4, 2.5 Hz, 0.1H), 7.58 (t, 2H), 7.67 (t, 1H), 7.91 (dd, J = 8.0, 1.5 Hz, 2H) ppm. 13C-NMR: δ 20.6, 21.6 (s), 21.8 (a), 23.1 (a), 23.2 (s), 24.6 (a), 24.7 (s), 28.2 (s), 28.3 (a), 39.5 (s), 41.1 (a), 50.6 (s), 52.0 (a), 56.3 (s), 57.8 (a), 69.1 (a), 70.1 (s), 79.8 (a), 79.9 (s) 128.26 (s), 128.33 (a), 129.27 (s) 129.33 (a), 133.8, 139.3, 155.4, 169.7 ppm. ESI-MS: m/z 436 [M + Na]+, 452 [M + K]+. 6c: oil, ee > 99.5% (by GLC); [ α ] D 25 +3.5 (c 1.0, CHCl3); 1H-NMR: δ 0.89 (d, J = 6.7 Hz, 3H) 0.90 (d, J = 6.7 Hz, 3H), 1.31 (m, 2H), 1.42 (s, 9H), 1.65 (sept, 1H), 4.12 (br, 1H), 4.62 (br, 1H), 5.03 (d, J = 9.9 Hz, 1H), 5.12 (d, J = 15.8 Hz, 1H), 5.71 (ddd, J = 6.9, 9.9, 15.8 Hz, 1H) ppm; 13C NMR: δ 22.0, 22.7, 24.4, 28.1, 44.7, 51.0, 79.2, 113.9, 139.4, 155.1 ppm. ESI-MS: m/z 236 [M + Na]+.
(3S,4S)-3-(tert-Butoxycarbonylamino)-4-methyl-1-hexene (6d) [53]: 69% via alcohol 4d and acetate 5d (method A). 4d: 94:6 mixture of syn (s) and anti (a) diastereoisomers. Pale yellow oil; IR: 3370, 1693, 1304, 1146 cm−1; 1H-NMR: δ 0.85 (t, 0.18H), 0.90 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 7.0 Hz, 0.82H), 0.99 (m, 1H), 1.39 (s, 9H), 1.54 (m, 1H), 1.85 (m, 1H), 3.27 (m, 2H), 3.50 (m, 1H), 3.58 (br, 1H), 4.18 (m, 1H), 4.40 (d, J = 9.5 Hz, 0.94H), 4.84 (d, J = 10.0 Hz, 0.06H), 7.58 (m, 2H), 7.68 (m, 1H), 7.92 (m, 2H) ppm. 13C-NMR: δ 11.1 (a), 11.8 (s), 15.6 (a), 16.3 (s), 23.1 (s), 25.7 (a), 28.4, 31.0 (a) 34.2 (s), 58.8 (a), 59.0 (s), 60.4 (s), 60.7 (a), 65.2 (s), 67.2 (s), 80.1, 127.5 (a), 128.0 (s), 129.4 (a), 129.6 (s), 133.8 (a), 134.2 (s), 139.6, 156.6 ppm; ESI-MS: m/z 394 [M + Na]+, 410 [M + K]+. 5d: 94:6 Mixture of syn (s) and anti (a) diastereoisomers. White solid, mp 108–110 °C; [ α ] D 25 −3.8 (c 1.5, CHCl3); IR: 3367, 1746, 1708, 1518 cm−1; 1H-NMR: δ 0.84 (t, J = 7.2 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H), 1.00 (m, 1H) 1.30 (m, 1H), 1.41 (s, 8.5H), 1.43 (s, 0.5H), 1.50 (m, 1H), 1.73 (s, 2.8H), 1.98 (s, 0.2H), 3.29 (d, J = 15Hz, 1H), 3.43 (dd, J = 9.5, 15.0 Hz, 1H), 3.68 (m, 1H), 4.31 (d, 1H, J = 10.0 Hz, 0.94H), 4.55 (d, J = 10.5 Hz, 0.06H), 5.34 (dt, J = 6.3, 1.2 Hz, 0.94H), 5.55 (dt, J = 9.3, 2.2 Hz, 0.06H), 7.57 (m, 2H), 7.66 (m, 1H), 7.90 (m, 2H) ppm. 13C NMR (syn diastereoisomer): δ 10.8, 15.5, 20.6, 24.2, 27.9, 35.1, 56.3, 56.4, 67.9, 80.0, 128.1, 129.1, 133.6, 139.0, 155.5, 169.7 ppm; ESI-MS: m/z 436 [M + Na]+, 452 [M + K]+. 6d: oil, ee > 99.5% (by GLC). [ α ] D 25 + 32 (c 1.0, CHCl3). 1H NMR: δ 0.85 (d, J = 6.5 Hz, 3H,), 0.89 (t, J = 7.5 Hz, 3H), 1.10 (m, 1H), 1.43 (s, 9H), 1.40–1.53 (m, 2H), 4.05 (br, 1H), 4.54 (br, 1H), 5.12 (m, 2H), 5.70 (m, 1H) ppm; 13C-NMR: δ 11.7, 15.0, 25.3, 28.4, 38.6, 56.9, 78.9, 115.2, 136.8, 155.5 ppm; ESI-MS: m/z 236 [M + Na]+, 252 [M + K]+.
(3S)-3-(tert-Butoxycarbonylamino)-4-phenyl-1-butene (6e) [54]: 70% via alcohol 4e and acetate 5e (method B). 4e: 3:1 mixture of syn (s) and anti (a) diastereoisomers. White solid, mp 130–131 °C; IR: 3370, 1692, 1304, 1146 cm−1; 1H-NMR: δ 1.30 (s, 6.75H), 1.35 (s, 2.25H), 2.78–3.01 (m, 2H), 3.16–3.33 (m, 2H), 3.62–3.92 (multiplets, 2H), 4.07 (br, 0.25H), 4.14 (br, 0.75H), 4.55 (br, 0.75H), 4.93 (d, J = 9.5 Hz, 0.25H), 7.16–7.29 (m, 5H), 7.51 (m, 0.5H), 7.57 (m, 1.5H), 7.64 (m, 0.25H), 7.68 (m, 0.75H), 7.82 (m, 0.5H), 7.89 (m, 1.5H) ppm. 13C NMR: δ 28.1 (s), 28.2 (a), 35.8 (s), 38.3 (a), (55.1 (s), 55.8 (a), detected in HSQC only) 59.8 (s), 60.3 (a), 65.7 (a), 68.1 (s), 79.8 (s) 80.0 (a), 126.5 (s), 126.7 (s), 127.8 (a) 127.9 (s), 128.4 (a), 128.5 (s), 129.2 (s), 129.3 (a), 129.4 (a), 129.5 (s), 134.1 (a), 134.2 (s), 136.9, 139.1, 155.7 ppm; ESI-MS: m/z 428 [M + Na]+. 5e (syn isomer): White solid, mp 122–124 °C; [ α ] D 25 −7 (c 1, CHCl3); IR: 3336, 1732, 1705 cm−1; 1H-NMR: δ 1.28 (s, 9H), 1.84 (s, 3H), 2.61 (m, 1H), 2.84 (dd, J = 5.5, 14.0 Hz, 1H), 3.41 (m, 2H), 4.08 (br, 1H), 4.40 (m, 1H), 5.30 (m, 1H), 7.12–7.29 (m, 5H), 7.52–7.57 (m, 2H), 7.66 (m, 1H), 7.81–7.89 (m, 2H) ppm. 13C NMR: δ 20.6, 28.1, 36.8, 53.5, 56.7, 69.7, 80.0, 126.8, 128.2, 128.6, 129.0, 129.3, 133.8, 136.5, 139.3, 155.3, 169.8 ppm; ESI-MS: m/z 470 [M + Na]+, 486 [M + K]+. 6e: white solid, mp 72–74 °C; ee > 99.5%. [ α ] D 25 + 15 (c 0.85, CHCl3); 1H-NMR: α 1.44 (s, 9H), 2.83 (d, J = 6.3 Hz, 2H), 4.47 (br, 2H), 5.08 (m, 2H), 5.80 (m, 1H), 7.17–7.29 (m, 5H) ppm; 13C NMR: δ 28.3, 41.3, 53.3, 79.1, 114.5, 126.2, 128.1, 129.7, 137.1, 137.9, 155.3 ppm; ESI-MS: m/z 270 [M + Na]+.
(3S)-3-(tert-Butoxycarbonylamino)-4-[4-(tert-butyldimethylsilyloxy)phenyl]-1-butene (6f): 76% via alcohol 4f and acetate 5f (method A). 4f: 5:1 mixture of syn (s) and anti (a) diastereoisomers. White solid, mp 107–109 °C; IR: 3369, 1693, 1610, 1511, 1256, 1145 cm−1; 1H-NMR: δ 0.17 (s, 7.5H) and 0.18 (s, 1.5H), 0.97 (s, 5H) and 0.98 (s, 1H), 1.32 (s, 7.5 H) and 1.35 (s, 1.5H), 2.67–2.95 (m, 2H), 3.14–3.35 (m, 2H), 3.56–3.92 (m, 2H), 4.05 (br, 0.17H) and 4.11 (br, 0.83H), 4.51 (br, 0.83H) and 4.89 (d, J = 8.6, 0.17H), 6.71 (d, 0.36H) and 6.75 (d, 1.64H), 7.01 (overlapping d, 2H), 7.61 (m, 2H), 7.67 (m, 1H), 7.83 (d, 0.36H) and 7.90 (d, 1.64H), ppm.13C-NMR: δ −4.45, 18.2, 25.7, 28.2, 35.0 (s), 37.5 (a), 55.3 (s), 55.9 (a), 59.9 (s), 60.4 (a) 65.7 (a), 68.1 (s), 79.7, 120.0 (a), 120.1 (s), 127.8 (a), 127.9 (s), 129.4, 130.1, 130.4, 134.1, 139.1, 154.4 (s), 155.7 (a) ppm. ESI-MS: m/z 558.2 [M + Na]+, 574.2 [M + K]+. 5f (syn isomer): White solid, mp 159–161 °C; [ α ] D 25 −6.7 (c 1.5, CHCl3), IR: 3369, 1747, 1705, 1609, 1512 cm−1; 1H-NMR: δ 0.16 (s, 6H), 0.96 (s, 9H), 1.30 (s, 9H) 1.80 (s, 3H), 2.45 (m, 1H), 2.84 (m, 1H), 3.43 (m, 2H), 4.04 (br, 1H), 4.48 (br, 1H), 5.29–5.34 (m, 1H) 6.73 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 7.56 (t, 2H), 7.65 (m, 1H), 7.88 (d, J = 7.5 Hz, 2H) ppm; 13C-NMR: δ −4.5, 18.2, 20.6, 25.6, 28.1, 35.9, 53.5, 56.6, 69.7, 79.9, 120.1, 128.2, 129.0, 129.3, 129.9, 133.8, 139.3, 154.4, 155.3, 169.8 ppm; ESI-MS: m/z 600 [M + Na]+, 616.2 [M + K]+. 6f: white solid, mp 51–53 °C; ee = 80% (by HPLC); [ α ] D 25   + 1.2 (c 1, CHCl3); IR 2957, 2930, 2858, 1702, 1610, 1510 cm−1; 1H-NMR: δ 0.19 (s, 6H), 0.98 (s, 9H), 1.41 (s, 9H), 2.76 (m, 2H), 4.36 (br, 1H), 4.47 (br, 1H), 5.06 (dt, J = 10.3, 1.2 Hz, 1H), 5.09 (dt, J = 17.4, 1.2 Hz, 1H), 5.78 (ddd, J = 10.3, 17.4, 5.5 Hz, 1H), 6.76 (d, 2H), 7.02 (d, 2H) ppm; 13C-NMR: δ −4.8, 18.0, 25.7, 28.4, 40.4, 79.0, 114.5, 119.9, 130.0, 130.1, 130.4, 138.2, 154.2 ppm. ESI-MS: m/z 400 [M + Na]+. Anal. Calcd for C21H35NO3Si: C, 66.80; H, 9.34; N, 3.71. Found: C, 66.88; H, 9.26; N, 3.73.
(3S)-3-(tert-Butoxycarbonylamino)-4-[4-(hydroxy)phenyl]-1-butene (6f′): 81% from 5f by method B. White solid, mp 82–84 °C; [ α ] D 26 +21.5 (c 1.5, CHCl3); IR = 3339, 1683, 1615, 1516 cm−1; 1H-NMR: δ 1.41 (s, 9H), 2.75 (m, 2H), 4.35 (br, 1H), 4.50 (br, 1H), 5.07 (dd, J = 10.3, 1.2 Hz, 1H), 5.10 (dd, J = 17.4, 1.2 Hz, 1H), 5.60 (br, 1H), 5.78 (ddd, J = 17.4, 10.3, 5.5 Hz, 1H), 6.75, (d, 2H), 7.01 (d, 2H) ppm; 13C-NMR: δ 28.4, 40.6, 53.7, 79.7, 114.7, 115.3, 129.0, 130.6, 138.1, 154.6, 155.5 ppm; ESI-MS: m/z 286.1 [M + Na]+, 302 [M + K]+. Anal. Calcd for C15H21NO3: C, 68.42; H, 8.04; N, 5.32; O, 18.23; Found: C, 68.41; H, 8.10; N, 5.24.
(2S)-1-(tert-Butoxycarbonyl)-2-vinylpyrrolidine (6g) [35]: 84% via alcohol 4g and acetate 5g (method B). 4g: 3:2 mixture of syn (s) and anti (a) diastereoisomers. Pale yellow oil; IR: 3493, 1687, 1305, 1148 cm−1; 1H-NMR (d6-DMSO, 80 °C): δ 1.38 (s, 5.4H), 1.39 (s, 3.6H), 1.66–1.92 (m, 2H), 3.08–3.40 (m, 2H), 3.66 (m, 0.6H), 3.80 (m, 0.4H), 4.25 (br, 1H), 4.84 (d, J = 6.0 Hz, 0.4H), 4.91 (d, J = 6.5 Hz, 0.6H), 7.63 (m, 2H), 7.70 (m, 1H), 7.89 (m, 2H) ppm; 13C-NMR (d6-DMSO, 80 °C): δ 22.9 (a), 24.7 (s), 26.2 (s), 27.6 (a), 27.8 (s), 30.0 (a), 46.2 (s), 46.7 (a), 58.8 (a), 59.8 (s), 60.4 (a), 60.8 (s), 65.6 (s), 66.8 (a), 78.1 (s), 78.3 (a), 126.3 (a), 127.1 (s), 128.6 (s), 128.8 (a), 132.8 (a), 132.9 (s), 140.26 (a), 140.27 (s), 153.5 (s), 153.8 (a) ppm; ESI-MS: m/z 378 [M + Na]+, 394 [M + K]+. 5g (syn isomer): white solid, mp 140–143 °C; [ α ] D 25 –33.1 (c 1.25, CHCl3) IR: 1747, 1692, 1520 cm−1; 1H-NMR (d6-DMSO, 80 °C): δ 1.38 (s, 9H), 1.67–1.87 (m, 4H), 1.76 (s, 3H), 3.04 (m, 1H), 3.31 (m, 1H), 3.60, 3.65 (part AB of an ABX system, J = 4.1, 7.9, 15.0 Hz, 2H), 3.84 (br, 1H), 5.52 (m, 0.5H), 5.73 (m, 1H), 7.65 (m, 2H), 7.74 (m, 1H), 7.87 (m, 2H) ppm; 13C-NMR (d6-DMSO, 80 °C): δ 19.5, 22.4, 24.7, 27.2, 45.7, 55.6, 58.8, 66.9, 78.0, 127.2, 128.2, 133.0, 139.1, 153.2, 168.1 ppm; ESI-MS: m/z 378 [M + Na]+, 394 [M + K]+. 6g: oil, ee > 99.5% (by GLC); [ α ] D 25 −15 (c 0.75, CHCl3), lit. [18] −15.7 (c 0.55, CHCl3]; 1H-NMR (rotamers): δ 1.43 (s, 9H), 1.69 (m, 1H), 1.77–1.79 (m, 2H), 2.02 (m, 1H), 3.38 (m, 2H), 4.27 (br, 1H), 5.04 (m, 2H), 5.73 (m, 1H) ppm; 13C-NMR (rotamers): δ 22.6 and 23.2, 28.3, 31.4 and 31.8, 46.0 and 46.4, 59.0, 79.0, 113.6, 138.8 and 139.0, 154.8 ppm; ESI-MS: m/z 220 [M + Na ]+.
(4S)-4-(tert-Butoxycarbonylamino)-5-phenyl-1-butene (6h): 8:2 mixture of E and Z isomers, 60% via alcohol 4h and acetate 5h (method B). 4h: mixture of 4 diastereoisomers in approximately 1:1:3:3 ratio. White solid; IR: 3372, 1704, 1297, 1142 cm−1; 1H-NMR: δ [1.03, 1.06, 1.20 (d, 3H)], [1.23, 1.29, 1.31, 1.36 (s, 9H)], 2.75–3.15 (multiplets, 2H, CH2), 3.20–3.30 (m, 1H, CH(CH3)), [3.70, 3.85, 3.98 (multiplets, 1H, CH(NH))], [3.80, 4.06, 4.15 (multiplets, 1H, CH(OH))], [4.38, 4.50 (br, 1H, OH)], [4.85, 4.99, 5.05 (d, 1H, NH)], 7.20–7.30 (m, 5H), 7.53–7.73 (m, 3H), 7.80–7.91 (m, 2H). 13C-NMR: δ [7.1, 11.0, 11.4, 11.7 (CH3CH)], [28.0, 28.17, 28.22, 28.25 (tBu)], [34.2, 36.8, 38.9, 39.8 (CH2)], [52.4, 52.7, 53.0, 54.8 (CHNH)], [60.6, 63.1, 63.4, 63.6 (CHSO2Ph)], [69.1, 69.4, 70.0, 72.3 (CHOH)], [79.4, 79.7, 79.8 (tBu)], [126.4–137.7 (CAr)], [155.1, 155.4 (CO)]; ESI-MS: m/z 442 [M + Na]+, 458 [M + K]+. 5h: White solid, mixture of four diastereoisomers. IR: 3369, 1747, 1704, 1513 cm−1. 1H-NMR: δ [1.12, 1.16, 1.24, 1.28 (s, 9H, tBu), [1.17, 1.44 (d, 3H, CH3)], [1.99, 2.02, 2.28, 2.35 (s, 3H, COCH3)], 2.45–2.90 (m, 2H, CH2), 3.38 (m, 1H, CHSO2Ph), 3.90–4.10 (m, 1H, CHNH), [4.64, 4.67, 4.77, 4.82 (m, 1H, NH)], 5.25–5.40 (m, 1H, CHOAc), 7.07–7.90 (m, 5H), 7.45–7.60 (m, 3H), 7.76–7.83 (m, 2H) ppm; 13C-NMR: δ [10.8, 12.0, 13.0, 14.2, 20.9, 21.2, 22.1, 22.8, 27.9, 28.0, 28.3, 28.4 (CH3)], [36.4, 37.6, 39.8, 40.7 (CH2)], [52.3, 52.7, 53.1, 54.6 (CHNH)], [60.2, 60.7, 61.1, 61.3 (CHSO2Ph)], [70.5, 71.7, 71.9, 73.9 (CHOAc)], [79.8, 80.1, 80.5, (tBu)], 126.4–138.2 (CAr), [155.0, 155.4, 155.5 (CO)], [170.0, 170.1, 170.3 (CO)] ppm; ESI-MS: m/z 484 [M + Na]+, 500 [M + K]+. 6h: Pale yellow oil, IR: 3340, 1692, 1390, 1365, 1255 cm−1; 1H-NMR: α 1.40 (s, 7.2H), 1.42 (s, 1.8H), 1.47 (d, J = 7.5 Hz, 0.6H), 1.65 (d, J = 7.4 Hz, 2.4H), 2.65–2.95 (m, 2H), 4.23–4.66 (br, 2H), 5.21 (m, 0.2 H), 5.30 (m, 0.8H), 5.52 (m, 1H), 7.10–7.34 (m, 5H) ppm; 13C-NMR: δ 13.1 (Z), 17.7 (E), 28.36 (Z), 28.37 (E), 42.0, 53.2, 79.3, 126.2, 126.3, 128.17 (E) 128.20 (Z), 129.6 (E), 129.7 (Z), 130.9, 137.7 (E), 137.8 (Z), 155.0 (Z), 155.1 (E) ppm; HRMS (ESI) m/z Calcd, for C16H23NNaO2 [M + Na]+ 284.1626, found 284.1628.
1-[(2S)-1-(tert-Butoxycarbonyl)-2-pyrrolidinyl]-1-propene (6i). 85:15 mixture of E and Z isomers, 65% via alcohol 4i and acetate 5i (method B). 4i: mixture of diastereoisomers. Yellow oil; IR: 3420, 1687, 1302, 1148 cm−1; 1H-NMR (major diastereoisomer) δ: 1.37 (d, 3H), 1.44 (s, 9H), 1.70–1.90 (m, 3H), 2.18 (m, 1H), 3.30 (m, 1H), 3.37 (m, 1H), 3.50 (m, 1H), 3.73 (m, 1H), 4.40 (m, 1H), 5.18 (m, 1H), 7.53 (m, 2H), 7.64 (m, 1H), 7.93 (m, 2H) ppm; 13C-NMR (major diastereoisomer) δ: 13.2, 24.3, 27.8, 29.9, 48.1, 60.1, 63.8, 77.4, 80.3, 129.0, 130.1, 134.1, 157.5 ppm; ESI-MS: m/z 392 [M + Na]+, 408 [M + K]+. 5i: yellow oil, mixture of diastereoisomers. IR: 3496, 1744, 1691 cm−1; 1H-NMR (major diastereoisomer): δ 1.40 (br, 12H, CH3), 1.76 (s, 3H, CH3CO), 1.80–2.05 (m, 4H, CH2), 3.07–3.67 (m, 3H, CH2N and CHSO2Ph), 4.2–4.4 (m, 1H, CHN), 5.12 (m, 1H, CHOAc), 7.53 (m, 2H), 7.64 (m, 1H), 7.93 (m, 2H); 13C-NMR (major diastereoisomer): δ 11.9 (CH3), 21.1 (CH3CO), 23.7 (CH2), 28.4 (tBu), 29.4 (CH2), 46.9 (CH2N), 56.9 (CHN), 61.8 (CHSO2Ph), 73.4 (CHOAc), 79.5 (tBu), 128.8, 129.0, 133.5, 139.0, 155.4, 170.2 ppm; ESI-MS: m/z 434 [M + Na]+, 450 [M + K]+. 6i: pale yellow oil, IR: 1695, 1394, 1365, 1252 cm−1; 1H-NMR (d6-DMSO, 80 °C): δ 1.39 (s, 7.65H), 1.40 (s, 1.35H), 1.51 (m, 0.15 H), 1.60–1.65 (m, 0.85H), 1.64 (d, 3H), 1.75 (m, 2H), 1.94 (m, 0.85H), 2.04 (m, 0.15H), 3.20–3.34 (m, 2H), 4.14 (m, 0.85H), 4.48 (m, 0.15H), 5.30–5.50 (m, 2H); 13C-NMR (d6-DMSO, 80 °C): δ 12.2 (Z), 16.6 (E), 22.3 (Z), 22.8 (E), 27.8 (E,Z), 31.3 (E), 32.0 (Z), 45.5 (E), 45.6 (Z), 53.3 (Z), 57.5 (E), 77.5 (E), 77.6 (Z), 122.3 (Z), 123.6 (E), 131.9 (E), 132.5 (Z), 153.2 (E,Z). HRMS (ESI) m/z Calcd. for C12H21NNaO2 [M + Na]+ 234.1470, found 234.1477.

4. Conclusions

We have developed a general procedure for the synthesis of α-chiral allylamines from readily available α-amino esters, by a simple modification of the Julia olefination reaction. While retaining all of the advantages of the original Julia reaction, this approach avoids using amino aldehydes as precursors in favor of the more readily-available and chemically and configurationally more stable amino esters. Epimerization at the chiral center, which is a frequent problem in the standard Julia and Wittig olefination of N-protected α-amino aldehydes, is thus prevented, and the desired allylamines are obtained in excellent yield and enantiomeric excess. The approach described here for the synthesis of allylamines is quite general and should provide a useful alternative to the classical Julia reaction whenever the starting aldehyde is unstable or, otherwise, not readily accessible. Moreover, its scope might be further expanded by replacing the phenyl alkyl sulfones of this work with benzotriazolylalkyl sulfones or other heteroarylalkyl sulfones, as in the Julia–Kocienski reaction [55,56], where the intermediate hydroxysulfones directly collapse to alkenes, thus avoiding the final reduction step.

Supplementary Materials

Supplementary materials are available online at https://www.mdpi.com/1420-3049/21/6/805/s1.

Acknowledgments

This work was supported by MIUR (Ministero dell’Università e Ricerca) (Project PRIN 20109Z2XRJ_11). Lidia Fanfoni is grateful to the University of Trieste for a postdoctoral grant, and Giorgia Regini acknowledges INPS (Istituto Nazionale per la Previdenza Sociale) for a PhD fellowship.

Author Contributions

Fabio Benedetti, Fulvia Felluga and Federico Berti conceived and designed the experiments. Lidia Fanfoni, Michele Garbo and Giorgia Regini performed the experiments and analyzed the data. Fabio Benedetti and Fulvia Felluga wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

The following abbreviations are used in this manuscript:
Boc
t-Butoxycarbonyl
n-BuLi
n-Butyllithium
COSY
Correlation Spectroscopy
DEPT
Distortionless Enhancement by Polarization Transfer
ee
Enantiomeric Excess
ESI
Electrospray Ionization
HRGC
High Resolution Gas Chromatography
HPLC
High Performance Liquid Chromatography
HRMS
High Resolution Mass Spectrometry
HSQC
Heteronuclear Single Quantum Coherence Spectroscopy
IR
Infrared
KHMDS
Potassium Hexamethyldisilazanide
MS
Mass Spectrometry
NMR
Nuclear Magnetic Resonance
TBDMS
t-Butyldimethylsilyl
THF
Tetrahydrofuran
TLC
Thin Layer Chromatography
TMEDA
Teramethylethylenediamine

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  • Sample Availability: Samples of the compounds 3a–i, 6a–f are available from the authors.
Molecules 21 00805 g001 550
Figure 1. Bioactive compounds based on the allylamine structure.
Figure 1. Bioactive compounds based on the allylamine structure.
Molecules 21 00805 g001
Molecules 21 00805 sch001 550
Scheme 1. Julia olefination.
Scheme 1. Julia olefination.
Molecules 21 00805 sch001
Molecules 21 00805 sch002 550
Scheme 2. Julia olefination of chiral α-amino esters.
Scheme 2. Julia olefination of chiral α-amino esters.
Molecules 21 00805 sch002
Molecules 21 00805 sch003 550
Scheme 3. Reactions of mono- and bis-lithiated sulfones.
Scheme 3. Reactions of mono- and bis-lithiated sulfones.
Molecules 21 00805 sch003
Table
Table 1. Optimized synthesis of ketosulfone 3a.
Table 1. Optimized synthesis of ketosulfone 3a.
Molecules 21 00805 i001
Entry2a (equiv.)Base (equiv.)T (°C)Yield a %ee a,b %
11n-BuLi (2)−7855<70
21n-BuLi (2)−3066<70
31n-BuLi (3)−7886<70
42n-BuLi (4)−788965
52n-BuLi (4)−3042<70
62n-BuLi/TMEDA (4)−78--
72KHMDS−78--
82NaH−78--
92n-BuLi (4)−7889 c95 c
a By addition of 1a to lithiated 2a; b ee determined after conversion to the allylamine 6a; c By the reverse addition of a suspension of lithiated 2a to 1a.
Table
Table 2. Reactions between amino esters 1 and lithiated sulfones 2 a.
Table 2. Reactions between amino esters 1 and lithiated sulfones 2 a.
Molecules 21 00805 i002
EntryAminoesterSulfoneR2ProductYield%
1Ala (1a)2aH3a89
2Val (1b)2aH3b84
3Leu (1c)2aH3c89
4Ile (1d)2aH3d86
5Phe (1e)2aH3e94
6Tyr (1f) b2aH3f80
7Pro (1g)2aH3g60 c
8Phe (1e)2bMe3h77 d
9Pro (1g)2bMe3i80 c,e
a Reactions were carried out with 2 equivalents of bis-lithiated sulfone (PhSO2CLi2R); b Protected as O-TBDMS (see Scheme 2); c With 2 equivalents of mono-lithiated PhSO2CHRLi; d 3:2 mixture of diastereoisomers; e 55:45 mixture of diastereoisomers.
Table
Table 3. Synthesis of allylamines 6.
Table 3. Synthesis of allylamines 6.
AllylamineMethod aYield b %ee c % AllylamineMethod aYield b %ee c %
6a Molecules 21 00805 i003A (1h)68 (60)956f Molecules 21 00805 i004A d (2h)65 (52)80 e
6b Molecules 21 00805 i005A (2h)60 (50)>996f′ Molecules 21 00805 i006B d (4h)71 (57)ND
6c Molecules 21 00805 i007A (2h)67 (62)>996g Molecules 21 00805 i008B (2h)84 (50)>99
6d Molecules 21 00805 i009A (3h)69 (59)>996h Molecules 21 00805 i010B (4h)71 f (55)ND
6e Molecules 21 00805 i011A (2h)68 (64)>996i Molecules 21 00805 i012B (12h)65 g (52)ND
B (4h)71 (67)>99
a Method A: Mg powder (2.5 eq), HgCl2 (0.1 equiv.), EtOH/THF (3:1), 25 °C; Method B: 5% Na/Hg (3 equiv.), EtOH, −15 °C; b Overall yields from amino esters 1 in brackets; c By chiral HRGC; d From O-TBDMS protected sulfone 5f; e By chiral HPLC; f 80:20 mixture of E and Z isomers; g 85:15 mixture of E and Z isomers.

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Benedetti, F.; Berti, F.; Fanfoni, L.; Garbo, M.; Regini, G.; Felluga, F. Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters. Molecules 2016, 21, 805. https://doi.org/10.3390/molecules21060805

AMA Style

Benedetti F, Berti F, Fanfoni L, Garbo M, Regini G, Felluga F. Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters. Molecules. 2016; 21(6):805. https://doi.org/10.3390/molecules21060805

Chicago/Turabian Style

Benedetti, Fabio, Federico Berti, Lidia Fanfoni, Michele Garbo, Giorgia Regini, and Fulvia Felluga. 2016. "Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters" Molecules 21, no. 6: 805. https://doi.org/10.3390/molecules21060805

APA Style

Benedetti, F., Berti, F., Fanfoni, L., Garbo, M., Regini, G., & Felluga, F. (2016). Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters. Molecules, 21(6), 805. https://doi.org/10.3390/molecules21060805

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