Enantioselective syntheses of (R)-pipecolic acid, (2R,3R)-3-hydroxypipecolic acid, β-(+)-conhydrine and (−)-swainsonine using an aziridine derived common chiral synthon

Abstract

Concise total syntheses of (R)-pipecolic acid, (R)-ethyl-6-oxopipecolate, (2R,3R)-3-hydroxypipecolic acid and formal syntheses of β-(+)-conhydrine, (−)-lentiginosine, (−)-swainsonine and 1,2-di-epi-swainsonine have been accomplished starting from a common chiral synthon. The present strategy employs regioselective aziridine ring opening, Wittig olefination and RCM as the key chemical transformations.

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Introduction

(S)-Pipecolic acid 1, is a cyclic non-proteinogenic amino acid¹ and its natural and non natural derivatives have found widespread applications in therapeutic chemistry (Fig. 1). Pipecolic acid acts as an integral framework of many pharmaceutically important molecules such as immunosuppressors rapamycin,² FK506, immunomycin,³ the antitumor antibiotic sandramycin,⁴ local anaesthetics like bupivacaine and ropivacaine.⁵ Similarly, (R)-pipecolic acid ent-1 is a key constituent of the histone deacetylase (HDAC) inhibitors recognized as potential anticancer drugs.⁶ (R)-Piperidin-2-ylmethanol 2, a reduced analogue of ent-1 has been used as a precursor in the synthesis of (−)-lentiginosine 6, a naturally occurring alkaloid having amylo-glucosidase enzyme inhibition properties.⁷ 3-Hydroxypipecolic acids are important scaffolds with piperidine skeleton and found in many biologically significant molecules.⁸ Trans-(−)-(2R,3R)-3-hydroxypipecolic acid 3 is a cyclic β-hydroxy-α-amino acid that has been used as a precursor in the synthesis of (−)-swainsonine 4,⁹ a potent anti-cancer drug and specific inhibitor of α-D-mannosidase.¹⁰ The stereochemistry of enantiomer of 3 is found in (+)-febrifugine 10, a potent antimalarial agent,¹¹ and its reduced analogues were found as important structure motifs of (+)-prosopinine 8 and (+)-prosophylline 9 which exhibit analgesic, anaesthetic and antibiotic activities.¹² cis Stereoisomer of 3-hydroxypipecolic acid is main constituent of (+)-isofebrifugine 11 which also shows antimalarial activity and of tetrazomine 12 which shows antitumor antibiotic activities.¹³ Oxopipecolate 7 has been utilized in medicinal chemistry and to prepare an important class of antitumor agents and is useful for the synthesis of pipecolic acid derivatives (Fig. 1).¹⁴ Pipecolic acid and its 3-hydroxy derivatives have also been incorporated in peptides which can induce a β-turn with resultant therapeutic significance¹⁵ and are also useful as organocatalysts.¹⁶ In general, pipecolic acid and its diverse functionalities are useful chiral building blocks for the synthesis of a variety of pharmaceutically important molecules.

Fig. 1 Pipecolic acid and its derivatives.

Owing to their importance, enantiomerically pure syntheses of pipecolic acid and its derivatives has gained wide attention and have been extensively reviewed.^17–19 As part of our continued interest toward development of efficient and practical synthetic routes to piperidine alkaloids,²⁰ we report alternate practical and efficient syntheses of (R)-pipecolic acid ent-1, (R)-ethyl6-oxopipeclate 7, (2R,3R)-3-hydroxypipecolic acid 3 and formal synthesis of (−)-swainsonine 4, (+)-1,2-di-epi-swainsonine 5 and (−)-lentiginosine 6 from trans aziridine-2-carboxylate 13 as the common synthetic precursor derived from commercially available and cheap starting material viz. D-mannitol diacetonide. We have earlier described syntheses of (R) and (S) pipecolic acids and 3-hydroxypipecolic acid from cis aziridine.²⁰

Results and discussion

Enantiomerically pure aziridines have been considered to be prominent precursors in the synthesis of natural and unnatural amino compounds due to their inherent ability to undergo regio and chemoselective nucleophilic ring opening reactions.²¹ Inspite of that, aziridines are relatively less explored compared to their three membered analog oxiranes due to less reactivity and selectivity towards ring opening reactions. However these drawbacks can be overcome by proper manipulations of functional groups attached to aziridine ring.

Thus, as shown in the retrosynthetic plan (Scheme 1), it was envisioned that all of the six piperidine alkaloids could be derived from aziridine carboxylic acid 13 as the common precursor. For the synthesis of (R)-pipecolic acid (ent-1) as well as 3-hydroxypipecolic acid 3, it was surmised that vinyl aziridine ester 14 would serve as ideal substrate. The vinyl aziridine ester 14 could be readily derived from aziridine ester 13 by chain propagation from the acetonide side. Ester 14 by proper choice of reaction conditions could be converted to (R)-ethyl6-oxo-pipecolate 7, which serves as an important intermediate for pipecolic acid derivatives.¹⁴ Compound 7 in turn can be further converted to the intermediate 15, a precursor for the synthesis of (−)-lentiginosine²² and (R)-pipecolic acid ent-1. Aziridine ester 14 on regio and stereoselective ring opening under acidic condition by hydroxyl group could be converted to amino-alcohol 16 which could be further transformed to trans 3-hydroxypipecolic acid 3. Similarly, aziridine ester 13 on propagation from ester side would furnish α,β-unsaturated ester aziridine 17 which on regio and stereoselective ring opening by hydroxy group followed by cyclization, N-allylation and RCM would give intermediate 18, enantiomer of which is well explored towards the synthesis of (+)-swainsonine ent-4 and (−)-8,8a-di-epi-swainsonine ent-5.²³

Scheme 1 Retrosynthetic analysis for target compounds.

The synthetic endeavor for (R)-pipecolic acid ent-1 and derivatives started with readily available and cheap starting material D-mannitol diacetonide 19 (Scheme 2). Accordingly, D-mannitol diacetonide 19 on diol cleavage using NaIO₄ yielded acetonide protected (R)-glyceraldehyde 20 which on Wittig olefination using bromophosphorane²⁴ in dichloromethane afforded bromoester 21. The Gabriel–Cromwell reaction of 2-acrylic carboxylate derivative 21 with benzyl amine in toluene as solvent furnished trans aziridine-2-carboxylate 13 as the major isomer via conjugate addition, proton transfer and S_N2 ring closure in 68% yield.²⁵ The trans aziridine 13 was readily obtained by column chromatography. Acetonide trans aziridine 13 was deprotected using TMSOTf/CH₂Cl₂ at 0 °C,²⁶ to furnish diol 22 in excellent yield (90%). Diol 22 was then subjected to sodium metaperiodate mediated oxidative cleavage to yield crude aldehyde which was subjected to Horner–Wadsworth–Emmons olefination to afford α,β-unsaturated aziridine-ester 14 in 70% yield over two steps. This α,β-unsaturated aziridine carboxylate 14 (Scheme 2) when subjected to palladium mediated transfer hydrogenation conditions,^25b,27 underwent one- pot efficient regioselective aziridine ring cleavage with concomitant olefin reduction, N-debenzylation and cyclisation of resultant amine as the key step to give access to (R)-ethyl6-oxopipecolate 7 in 85% yield. Pipecolate 7 was further converted to (R)-N-Boc-2-piperidinemethanol 15 over two steps using LAH induced lactam/ester reduction followed by protection of resulting crude amino-alcohol as N-Boc derivative in 97% ee by HPLC analysis. (R)-N-Boc-2-piperidinemethanol 15 can be utilized as a precursor towards synthesis of (−)-lentiginosine 6.²² Finally, compound 15 was converted to (R)-pipecolic acid ent-1 by Boc deprotection using TFA followed by oxidation using KMnO₄ in aqueous 3 N H₂SO₄. The synthesis of (R)-pipecolic acid has been achieved in 27% overall yield while (R)-ethyl6-oxo-pipecolate 7 was achieved in 54% overall yield from trans aziridine-2-carboxylate 13 respectively.

Scheme 2 Synthesis of (R)-pipecolic acid ent-1.

After achieving the site selective functional group transformation at the acetonide group of aziridine-2-carboxylate 13, attention was focussed on regioselective ring opening of aziridine ring in compound 14 by water as the nucleophile. Accordingly, when compound 14 was treated with TFA (2 equiv.) in CH₃CN–H₂O (9 : 1), it underwent regio and stereoselective nucleophilic ring opening reaction using water as nucleophile to afford γ-hydroxy-δ-amino-α,β-conjugated ester 16 as the only isomer in 76% yield (Scheme 3). Selective protection of hydroxyl group of amino-alcohol 16 was achieved using TBSCl, imidazole and cat. DMAP in refluxing dichloromethane to furnish TBS ether 23 in 85% yield. The crucial step viz. reductive cyclization of 23 was carried out under hydrogenation conditions using hydrogen gas and palladium hydroxide over carbon in ethanol to provide amide 24 in 85% yield (Scheme 3). In next step, amido ester 24 was subjected to selective reduction of amide functionality using borane dimethyl sulfide complex in anhydrous THF to furnish the amino ester 25 in 78% yield. Finally, the global deprotection involving ester hydrolysis as well as TBS group deprotection of 25 was carried out in a single step using 6 N HCl to provide (2R,3R)-3-hydroxypipecolic acid 3 in 91% yield. The spectral data and optical rotation values of 3 thus obtained were in good agreement with the reported one.²⁸

Scheme 3 Synthesis of (2R,3R)-3-hydroxy pipecolic acid 3.

In order to ascertain the chiral purity, the lactam 24 was subjected to reduction using lithium aluminum hydride in anhydrous THF followed by N-Boc protection to provide N-Boc derivative 26. The chiral HPLC analysis of the 26 revealed that the chiral purity was ∼97% ee (Scheme 4). Thus, the total synthesis of trans (2R,3R)-3-hydroxypipecolic acid 3 was accomplished in 24.6% overall yield in 8 steps from trans aziridine 13.

Scheme 4 Synthesis of diol 26.

Our endeavor towards formal synthesis of (−)-swainsonine 4 and (+)-1,2-di-epi-swainsonine 5 started with aziridine-2-carboxylate 13, whose acetonide moiety was kept intact as a masked aldehyde while ester group was propagated to give trans-aziridine-α,β-unsaturated ester 17. Thus, trans-aziridne-2-carboxylate 13 on reaction with DIBAL-H (1.2 eq.) yielded aldehyde which was used as such for the next step, Horner–Wadsworth–Emmons reaction on the resultant aldehyde furnished α,β-unsaturated trans aziridine ester 17 in 75% yield over two steps. Following the aziridine ring opening reaction under acidic conditions, compound 17 gave amino alcohol 27 (Scheme 5). Hydroxyl functionality of this amino-alcohol 27 was protected as its TBS ether 28 in 90% yield. Compound 28 on palladium mediated hydrogenation/hydrogenolysis afforded lactam 29 in 92% yield. Allylation of lactam 29 was carried out using allyl bromide and NaH in DMF as the solvent to give N-allylated lactam 30 in 85% yields. Lactam 30 was exposed to 80% aqueous acetic acid at 80 °C to furnish diol 31 by selective deprotection of terminal acetonide functionality in presence of secondary –OTBS group in 75% yield.²⁹ After failing to convert 1,2-diol functionality of the compound 31 into corresponding alkene in one step using PPh₃/I₂/imidazole,³⁰ it was cleaved using NaIO₄ in acetone–water to furnish the crude aldehyde which, without purification, was subjected to 2-carbon Wittig homologation in dichloromethane to yield α,β-unsaturated ester 32 in 75% yield over two steps. Finally, performing the ring closing metathesis reaction on compound 32 using Grubbs' 2^nd generation catalyst³¹ in refluxing anhydrous dichloromethane gave access to key intermediate viz. bicyclic lactam 18 having requisite indolizidine skeleton of swainsonine. Enantiomer of 18 and its conversion to ent-4 and ent-5 is well documented in the literature. The spectral data of 18 were in good agreement with the reported one except for the sign of optical rotation (Scheme 5).

Scheme 5 Synthesis of (−)-swainsonine 4 and (+)-1,2-di-epi-swainsonine 5.

Additionally, aziridine ester 17 when subjected to transfer hydrogenation conditions yielded lactam 33 in excellent yield. Lactam 33 is key intermediate towards the syntheses of β-(+)-conhydrine and its analogues (Scheme 6).³²

Scheme 6 Synthesis of key intermediate 33.

Conclusions

In conclusion, an efficient enantioselective total synthesis (R)-pipecolic acid ent-1, (R)-ethyl-6-oxopipecolate 7 and trans (2R,3R)-3-hydroxypipecolic acid 3. A concise formal synthesis of (−)-swainsonine 4, (+)-1,2-di-epi-swainsonine 5 and (−)-lentiginosine 6 have also been achieved from trans-aziridine-2-carboxylate 13 as the common chiral synthon. The notable features of these syntheses are regio and stereoselective Wittig olefination, ring closing metathesis, reductive cyclisation and regio and stereoselective aziridine ring opening as key chemical transformations.

Syntheses are operationally simple and practical in terms of overall yield. The trans aziridine ester synthon was found to be a versatile highly efficient for the synthesis of various piperidine skeletons.

Experimental

General information

All reagents and solvents were used as received from the manufacturer. HRMS (ESI) were recorded on ORBITRAP mass analyzer (Thermo Scientific, Q Exactive). Mass spectra were measured with ESI ionization in MSQ LCMS mass spectrometer. IR spectra were recorded on a Perkin-Elmer Infrared Spectrophotometer Model 68B or on a Perkin-Elmer 1615 FT Infrared spectrophotometer. Melting points of solids were measured in Buchi melting point apparatus and are uncorrected. Optical rotation values were recorded on P-2000 polarimeter at 589 nm. ¹H (200 and 400 MHz) and ¹³C (50 and 100 MHz) NMR spectra were recorded on Bruker and Bruker Advance 400 spectrometers, using a 1 : 1 mixture of CDCl₃ and CCl₄ as solvent. The chemical shifts (δ ppm) and coupling constants (Hz) are reported in the standard fashion with reference to chloroform, δ 7.27 (for ¹H) or the central line (77.0 ppm) of CDCl₃ (for ¹³C). In the ¹³C NMR spectra, the nature of the carbons (C, CH, CH₂, or CH₃) was determined by recording the DEPT-135 spectra. The following abbreviations were used to explain the multiplicities: br = broad, s = singlet, d = doublet, t = triplet, q = quartet. The reaction progress was monitored by the TLC analysis using thin layer plates precoated with silica gel 60 F₂₅₄ (Merck) and visualized by fluorescence quenching or iodine or by charring after treatment with ethanolic solution of ninhydrin or anisaldehyde. Merck's flash silica gel (230–400 mesh) was used for column chromatography.

Experimental

(S)-Ethyl 2-bromo-3-(2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (21)³³. Freshly prepared (R)-glyceraldehyde acetonide 20 (5.24 g, 0.020 mol) from di-O-isopropylidene D-mannitol 19 was taken in CH₂Cl₂ (75 mL). To this was added a solution of ethyl 2-bromo-2-(triphenylphosphoranylidene) acetate³⁴ (18.8 g, 0.044 mol) in CH₂Cl₂ (150 mL) and stirred for 2 h at room temperature. Organic layer was separated and aqueous layer was extracted with CH₂Cl₂. Combined organic layer was dried over anhydrous Na₂SO₄, filtered and solvent was evaporated under reduced pressure. Residue was purified by column chromatography using pet. ether–ethyl acetate (95 : 5) to give bromoester 21 (E/Z = 7 : 93). R_f: 0.5 (pet. ether–ethyl acetate, 9 : 1); yield: 10.5 g, 84% over two steps; IR (CHCl₃, cm⁻¹): ν_max 2980, 1720, 1620; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.36 (t, J = 8.0 Hz, 3H), 1.41 (s, 3H), 1.46 (s, 3H), 3.70 (dd, J = 6.6 & 8.3 Hz, 1H), 4.27 (q, J = 8.0 Hz, 3H), 4.95 (dd, J = 6.7 & 13.3 Hz, 1H), 7.36 (d, J = 6.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃ + CCl₄): δ 14.1, 25.5, 26.4, 62.6, 68.0, 75.5, 110.2, 116.7, 144.0, 161.4. MS (ESI): m/z: 279 (M + H)⁺.

(2R,3R)-Ethyl 1-benzyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)aziridine-2-carboxylate (13). 8.37 g (0.030 mol) of bromoacrylate 21 was dissolved in dry toluene (100 mL) and the solution was stirred. To this stirred solution was added 3.21 g (0.030 mol) of benzylamine and 3.03 g (0.030 mol) of triethylamine at −5 °C. The reaction mixture was stirred for 24 h at room temperature. Solvent was filtered on simple filter paper, residue was again washed with toluene (20 mL) and concentrated under reduced pressure to yield yellow oil of trans aziridine 13 as major isomer and cis aziridine 33 as minor isomer in ratio of 9 : 1 which were separated using flash chromatography (pet. ether–ethyl acetate, 9 : 1). Yield: 75%; for 13-yield: 68%; for 33-yield: 7%.

(2R,3R)-Ethyl 1-benzyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)aziridine-2-carboxylate (13). R_f: 0.5 (pet. ether–ethyl acetate, 8 : 2); IR (CHCl₃, cm⁻¹): ν_max 2984, 1728, 1599, 1107. [α]²⁵_D +52.41 (c 1, CHCl₃), {lit.¹ [α]²⁵_D +52.8 (c 1, CHCl₃)}.¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.19 (t, J = 8 Hz, 3H), 1.34 (s, 3H), 1.42 (s, 3H), 2.48 (t, J = 2.4 Hz, 1H), 2.63 (d, J = 2.4 Hz, 1H), 3.63–3.68 (m, 1H), 3.86–3.97 (m, 3H), 4.07–4.17 (m, 3H), 7.27–7.32 (m, 5H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ 14.0, 25.5, 26.6, 37.2, 47.4, 54.8, 60.1, 66.4, 75.9, 109.5, 126.9, 128.1, 138.8, 168.5; MS (ESI): m/z: 306.71 [M + H]⁺; HRMS: calculated for C₁₇H₂₄NO₄-306.1700, found-306.1694.

(2S,3R)-Ethyl 1-benzyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)aziridine-2-carboxylate (33). R_f: 0.4 (pet. ether–ethyl acetate, 8 : 2); IR (CHCl₃, cm⁻¹): ν_max 2986, 1728, 1600, 1107; [α]²⁵_D −9.7 (c 1, CHCl₃), {lit.¹ [α]²⁵_D −9.9 (c 1, CHCl₃)}; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.18 (t, 3H), 1.27 (s, 3H), 1.37 (s, 3H), 2.08 (t, J = 6.7 Hz, 1H), 2.23 (d, J = 6.7 Hz, 1H), 3.42 (d, J = 13.0 Hz, 1H), 3.66 (dd, J = 6.0 & 8.0 Hz, 1H), 3.89–3.97 (m, 2H), 4.11–4.22 (m, 3H), 7.27–7.35 (m, 5H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ 14.1, 25.3, 26.8, 40.4, 47.8, 61.0, 63.2, 66.9, 75.2, 109.6, 127.2, 127.9, 128.2, 137.2, 168.9; MS (ESI): m/z: 306.18 [M + H]⁺; HRMS: calculated for C₁₇H₂₄NO₄-306.1700, found-306.1698.

(2R,3R)-Ethyl-1-benzyl-3-((S)-1,2-dihydroxyethyl)aziridine-2-carboxylate (22). To a stirred, ice-cold solution of the aziridine acetonide 13 (0.163 g, 0.53 mmol) in anhydrous CH₂Cl₂ (2 mL) under an inert atmosphere, was added TMSOTf (0.24 mL, 1.3 mmol) in a dropwise manner. The resulting reaction mixture was stirred at the same temperature for 1 h, followed by quenching the reaction by addition of a saturated aqueous NaHCO₃ solution. After stirring the mixture for 5 min, the organic layer was separated and the aqueous layer was saturated with solid NaCl and extracted with CH₂Cl₂ (3 × 10 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. Concentration of the solvent under reduced pressure and column chromatographic purification (pet. ether–ethyl acetate, 7 : 3) of the residue provided the pure acetonide-cleaved product 22 as a thick liquid (0.127 g). R_f: 0.4 (pet. ether–ethyl acetate, 1 : 1); yield: 90%; [α]²⁵_D +20.22 (c 2.1, CHCl₃), {lit.³⁵ [α]²⁵_D +19.6 (c 0.56, CHCl₃)}; IR (CHCl₃, cm⁻¹): ν_max 3588, 3369, 2927, 1727, 1603, 1454, 1371, 1193; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.23 (t, J = 7.2 Hz, 3H), 2.52 (t, J = 2.9 Hz, 1H), 2.75 (d, J = 2.9 Hz, 1H), 3.26–3.32 (m, 1H), 3.44–3.50 (m, 1H), 3.61 (br s, 1H), 3.96 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 7.27–7.31 (m, 5H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ 14.1, 37.4, 46.4, 54.4, 61.3, 65.2, 69.1, 127.5, 128.5, 128.6, 138.4, 168.5; MS (ESI): m/z: 266.13 (M + H) ⁺, 288.10 (M + Na)⁺; HRMS: calculated for C₁₄H₂₀O₄N-266.1387, found-266.1385.

(2R,3S)-Ethyl 1-benzyl-3-((E)-3-ethoxy-3-oxoprop-1-en-1-yl)aziridine-2-carboxylate (14). Diol 22 (0.21 g, 0.79 mmol) was dissolved in acetone–water (3 mL, 2 : 1) at 0 °C, treated with sodium metaperiodate (0.203 g, 0.95 mmol) and stirred at 15 °C for 15 min. The reaction was quenched using ethylene glycol (0.01 mL), extracted with CH₂Cl₂ (3 × 15 mL), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford crude aldehyde which was used as such for next reaction. To a stirred solution of NaH (0.038 g, 1.58 mmol, prewashed with n-hexane) dissolved in THF (2 mL), was added triethyl phosphonoacetate (0.31 mL, 1.58 mmol) slowly at 0 °C and stirred for 10 minutes. The aldehyde from above reaction dissolved in dry THF (3 mL) was added and stirring continued for another 2 h at same temperature until completion of reaction. The reaction was quenched with saturated aqueous NH₄Cl (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were then washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Purification on flash column chromatography (pet. ether–ethyl acetate, 9 : 1) furnished compound 14 (0.168 g) as thick colorless oil. R_f: 0.5 (pet. ether–ethyl acetate, 4 : 1); yield: 0.168 g, 70%; [α]²⁵_D −36 (c 1, CHCl₃); IR (CHCl₃, cm⁻¹): ν_max 2926, 2850, 1720, 1651, 1456, 1368, 1265, 1180, 1030; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.22–1.32 (m, 6H), 2.55–2.73 (m, 1H), 2.46–3.17 (m, 1H), 3.84–4.20 (m, 8H), 6.05–6.25 (m, 1H), 6.60–6.89 (m, 1H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ 14.0, 14.1, 42.9, 45.9, 54.4, 60.2, 61.1, 123.3, 127.6, 127.9, 128.2, 138.4, 145.3, 165.4, 167.8; doubling of peaks in ¹H and ¹³C is attributed to invertomerism; MS (ESI): m/z: 303.28 (M)⁺, 326.21 (M + Na)⁺; HRMS: calculated for C₁₇H₂₁NO₄Na-326.1363, found-326.1358.

(R)-Ethyl 6-oxopiperidine-2-carboxylate (7). To a stirred solution of compound 14 (0.15 g, 0.49 mmol) in ethanol (5 mL) was added ammonium formate (0.27 g, 4.9 mmol) and 10% Pd/C (0.05 g) and refluxed for 1 h under nitrogen atmosphere. Reaction mass was filtered through Celite, dried and column purified (pet. ether–ethyl acetate, 10 : 90) to yield 0.071 g of amide-ester 7 as colourless liquid. R_f: 0.3 (ethyl acetate); yield: 85%; [α]²⁵_D +13.4 (c 1.4, CHCl₃) {lit.³⁶ for ent-7, [α]²⁵_D −13.7 (c 0.3, CHCl₃)}; IR (CHCl₃, cm⁻¹): ν_max 2958, 1739, 1666, 1468, 1198; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.30 (t, J = 7.3 Hz, 3H), 1.78–1.98 (m, 3H), 2.20–2.22 (m, 1H), 2.36–2.47 (m, 2H), 4.1 (dd, J = 5.5 & 7.0 Hz, 1H), 4.24 (qd, J = 1.2 & 7.3 Hz, 2H), 6.65 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ 14.1, 19.2, 25.2, 30.7, 54.7, 61.9, 170.7, 171.9; MS (ESI): m/z: 194.08 (M + Na)⁺; HRMS: calculated for C₈H₁₄O₃N-172.0968, found-172.0966.

(R)-tert-Butyl 2-(hydroxymethyl)piperidine-1-carboxylate (15). To a stirred suspension of LAH (0.22 g, 5.85 mmol) in dry THF (5 mL) was added amide 7 (0.2 g, 1.17 mmol) dissolved in dry THF (5 mL) slowly at 0 °C via syringe under inert atmosphere (N₂ gas). After stirring for 24 h at room temperature, the reaction mixture was cooled to 0 °C, quenched carefully with minimum amount of water followed by 15% NaOH (0.25 mL). Again water (1 mL) was added and stirred for 0.5 h at room temperature. Anhydrous Na₂SO₄ was added and stirring continued for another 0.5 h. Filtration through Celite and concentration under vacuum gave crude amine which was used as such for next reaction. To a solution of amine in THF–water (5 mL, 1 : 1) was added solid NaHCO₃ (0.2 g, 2.34 mmol) and (Boc)₂O (0.536 mL, 2.34 mmol) and then the mixture was vigorously stirred at room temperature for 6 h. The reaction mixture was extracted with ethyl acetate (3 × 10 mL), washed with brine, dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo and purified by column chromatography (pet. ether–ethyl acetate, 8 : 2) to afford 15 as a white solid. R_f: 0.5 (pet. ether–ethyl acetate, 8 : 2); yield: 0.176 g, 70% over two steps; MP: 81–84 °C, lit.³⁷ 81–84 °C; [α]²⁵_D +38.5 (c 1, CHCl₃) {For ent-15 lit.⁵ [α]²⁵_D −40.5 (c 1, CHCl₃)}; IR (CHCl₃, cm⁻¹): ν_max 3443, 2940, 2890, 1655, 1280; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.46 (s, 9H), 1.60–1.65 (m, 6H), 2.11 (br s, 1H), 2.87 (t, J = 13.0 Hz, 1H), 3.59 (dd, J = 5.9 & 11.0 Hz, 1H), 3.79 (dd, J = 9.0 & 11.0 Hz, 1H), 3.93 (br d, J = 13.5 Hz, 1H), 4.25–4.29 (m, 1H); ¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ 19.3, 24.8, 25.1, 28.3, 39.7, 52.0, 60.6, 79.4, 155.8; MS (ESI): m/z: 238 (M + Na)⁺; HRMS: calculated for C₁₁H₂₂O₃N-216.1954, found-216.1600; HPLC detail for racemic hydroxy compound (15): HPLC Kromacil 5-Amycoat column (250 × 4.6 mm). Isopropanol–n-hexane = 4 : 96; flow rate 0.5 mL min⁻¹, λ = 210 nm retention time (min): rt1 = 22.18; rt2 = 24.05 (1 : 1). Enantiomerically pure hydroxy compound (15) HPLC Kromacil 5-Amycoat column (250 × 4.6 mm) isopropanol–n-hexane = 4 : 96; flow rate 0.5 mL min⁻¹, ë = 210 nm retention time (min): rt1 = 22.07 (major); rt2 = 24.02 (>97% ee).

(R)-Piperidine-2-carboxylic acid (ent-1). To a solution of alcohol 15 (0.1 g, 0.465 mmol) in CH₂Cl₂ (5 mL) at 0 °C, was slowly added TFA (0.1 mL, 1.3 mmol) and the reaction mixture was stirred at same temperature for 0.5 h, concentrated and resulting salt was used as such for next step. To a solution of salt from above step in 3 N H₂SO₄ (4.5 mL) at 10 °C, was slowly added KMnO₄ (0.12 g, 0.744 mmol) and the reaction mixture was stirred at room temperature for 3 h, filtered through a pad of Celite and concentrated. (R)-Pipecolic acid ent-1 was isolated after elution on Dowex 50W-X4 ion-exchange column (NH₄OH, 1 N). Yield: 0.044 g, 73%; R_f: 0.4 (CH₂Cl₂–MeOH–NH₄OH, 9 : 1 : 1%); MP: 271–273 °C; lit.³⁸ 271–274 °C; [α]²⁵_D +24.9 (c 1.15, H₂O) {lit.⁵ [α]²⁵_D +25.8 (c 1, H₂O)}; ¹H NMR (400 MHz, D₂O): δ 1.46–1.64 (m, 3H), 1.73–1.80 (m, 2H), 2.14–2.18 (m, 1H), 2.87–2.94 (m, 1H), 3.31–3.54 (m, 1H), 3.78 (dd, J = 8.0 Hz & 10.0 Hz, 1H); ¹³C NMR (100 MHz, D₂O): δ 21.5, 21.6, 26.0, 44.0, 57.2, 172.2; MS (ESI): m/z: 152.28 (M + Na)⁺.

(4R,5R,E)-Diethyl 5-(benzylamino)-4-hydroxyhex-2-enedioate (16). To a stirred solution of ester 14 (1.18 g, 3.89 mmol) in CH₃CN–water (9 : 1, 20 mL) was added TFA (0.45 mL, 7.79 mmol) drop wise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred until complete disappearance of starting material (∼5–6 h). Reaction was quenched by excess NaHCO₃, water (10 mL) was added and organic mass was extracted with ethyl acetate (3 × 15 mL). Combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure followed by column chromatographic purification using ethyl acetate–pet ether (15 : 85) to yield 0.95 g of amino-alcohol 16 as thick liquid. R_f: 0.5 (pet ether–ethyl acetate, 7 : 3); yield: 76% over two steps; [α]²⁵_D +20 (c 0.5, CHCl₃); IR (CHCl₃, cm⁻¹): ν_max 3554, 3359, 2980, 1720, 1620; ¹H NMR (200 MHz, CDCl₃ + CCl₄): 1.26–1.34 (m, 6H), 3.53 (d, J = 5 Hz, 1H), 3.68 (d, J = 13 Hz, 1H), 3.94 (d, J = 13 Hz, 1H), 4.13–4.28 (m, 4H), 4.52–4.56 (m, 1H), 6.08 (dd, J = 2 & 15.5 Hz, 1H), 6.75 (dd, J = 4.0 & 15.5 Hz, 1H), 7.27–7.30 (m, 5H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): 14.2, 52.6, 60.3, 61.3, 64.1, 70.1, 122.7, 127.5, 128.2, 128.4, 138.9, 145.2, 165.7, 171.6; MS (ESI): m/z: 344.18 (M + Na)⁺; HRMS: calculated for C₁₇H₂₄O₅N-322.1649, found-322.1640.

(4R,5R,E)-Diethyl 5-(benzylamino)-4-((tert-butyldimethylsilyl)oxy)hex-2-enedioate (23). To a stirred solution of hydroxyl amino ester 16 (0.7 g, 2.18 mmol), imidazole (0.3 g, 4.36 mmol) and DMAP (0.027 g, 0.22 mmol) in CH₂Cl₂ (20 mL) was added TBSCl (0.6 g, 4.36 mmol) dissolved in CH₂Cl₂ (5 mL) slowly at 0 °C after which reaction was heated to reflux for 6 h until completion of reaction. Reaction mass was concentrated under reduced pressure followed by column chromatography using ethyl acetate–pet ether (5 : 95) to yield 0.8 g of hydroxy amino TBS ether 23 as thick colorless liquid. R_f: 0.5 (pet. ether–ethyl acetate, 8 : 2); yield: 85% over two steps. [α]²⁵_D −7.69 (c 1, CHCl₃); IR (CHCl₃, cm⁻¹): ν_max 2980, 1720, 1620; ¹H NMR (500 MHz, CDCl₃ + CCl₄): 0.01 (s, 3H), 0.03 (s, 3H), 0.87 (s, 9H), 1.24–1.31 (m, 6H), 2.17 (br s, 1H), 3.28 (d, J = 5.5 Hz, 1H), 3.65 (d, J = 13 Hz, 1H), 3.84 (d, J = 13.0 Hz, 1H), 4.12–4.20 (m, 5H), 4.47–4.48 (m, 1H), 5.95 (dd, J = 1.5 & 15.5 Hz, 1H), 6.95 (dd, J = 5.2 & 15.5 Hz, 1H), 7.21–7.28 (m, 5H); ¹³C NMR (125 MHz, CDCl₃ + CCl₄): −4.6, −4.4, 14.3, 18.1, 25.7, 52.2, 60.3, 60.7, 65.7, 73.7, 121.7, 127.1, 128.2, 128.3, 139.4, 147.5, 166.0, 172.0; MS (ESI): m/z: 436.68 (M + H)⁺; HRMS: calculated for C₂₃H₃₈ON₅Si-436.2514, found-436.2505.

(2R,3R)-Methyl 3-((tert-butyldimethylsilyl)oxy)-6-oxopiperidine-2-carboxylate (24). The amino ester 23 (0.8 g, 2.2 mmol) was dissolved in ethanol (10 mL) and to that was added catalytic amount of palladium hydroxide over carbon (10%, 20 mg). The resulting reaction mixture was stirred under hydrogen atmosphere using balloon for 2 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using silica gel (pet ether–ethyl acetate, 7 : 3) to provide amide 24 (0.52 g) as a colorless thick oil. R_f: 0.4 (pet. ether–ethyl acetate, 8 : 2); yield: 85%; [α]²⁵_D −26 (c 1.5, CHCl₃); IR (CHCl₃, cm⁻¹): ν_max 3399, 2955, 2857, 1732, 1643, 1215; ¹H NMR (200 MHz, CDCl₃): δ 0.12 (s, 6H), 0.90 (s, 9H), 1.30 (t, J = 7.2 Hz, 3H), 1.68 (br s, 1H), 1.79–1.88 (m, 2H), 2.26–2.40 (m, 1H), 2.54–2.72 (m, 1H), 3.99–4.02 (m, 1H), 4.23 (q, J = 7.2 Hz, 2H), 4.35–4.39 (m, 1H), 5.96 (br s, 1H); ¹³C-NMR (50 MHz, CDCl₃): δ −5.1, −4.9, 14.1, 17.9, 25.6, 26.4, 26.5, 61.8, 62.3, 65.4, 170.1, 171.4. MS (ESI): m/z: 302.2 (M + H)⁺; HRMS: calculated for C₁₄H₂₈O₄NSi-302.1782, found-302.1777.

(2R,3R)-Ethyl 3-((tert-butyldimethylsilyl)oxy)piperidine-2-carboxylate (25). To the amide 24 (0.2 g, 0.7 mmol) in anhydrous THF (5 mL) was added BH₃·DMS (0.2 mL, 2 mmol) dropwise at 0 °C. The resulting reaction mixture was further stirred at 5 °C for 20 h. Methanol (excess) was added to the reaction mixture, stirred for 4 h and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted using dichloromethane (3 × 10 mL). The collected organics were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the crude product which was purified using flash chromatography over silica gel (70 : 30, EtOAc–pet ether) to furnish amine 25 (0.147 g, 78%) as a colorless dense liquid. R_f: 0.5 (pet. ether–ethyl acetate, 2 : 8); yield: 78%; [α]²⁵_D −27 (c 1.0, CHCl₃); IR (CHCl₃, cm⁻¹): ν_max 3436, 3020, 2931, 2400, 1731, 1215 cm⁻¹; ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 0.00 (s, 3H), 0.06 (s, 3H), 0.86 (s, 9H), 1.36 (t, J = 7.3 Hz, 3H), 1.41–1.51 (m, 2H), 1.58–1.68 (m, 2H), 1.84–1.87 (m, 1H), 2.01–2.05 (m, 1H), 2.53–2.64 (m, 1H), 3.11 (dd, J = 1.1 & 10.1 Hz, 1H), 3.32 (d, J = 13.5 Hz, 1H), 3.78 (dt, J = 5.4 & 10.5 Hz, 1H), 3.98 (m, 1H), 4.10–4.18 (m, 1H), 4.31–4.39 (m, 1H); ¹³C-NMR (100 MHz, CDCl₃ + CCl₄): δ −5.3, −4.2, 13.9, 17.8, 23.1, 25.5, 32.2, 52.2, 61.8, 70.2, 70.5, 170.8; MS (ESI): m/z: 288.23 (M + H)⁺, 310.14 (M + Na)⁺; HRMS: calculated for C₁₄H₃₀O₃NSi-288.1989, found-288.1979.

(2R,3R)-3-Hydroxypiperidine-2-carboxylic acid (3). A mixture of amine 25 (100 mg, 0.35 mmol) and 6 N HCl (10 mL) was kept at 120 °C for 3 h. The solvent was removed under reduced pressure and the residue was dissolved in H₂O (50 mL). The mixture was loaded on an ion-exchange column (DOWEX 50W X8) and eluted with H₂O and then with aq. NH₃ solution. The eluate of aq. NH₃ was concentrated to dryness under reduced pressure to give 3 (46 mg, 91%) as a crystalline solid. R_f: 0.3 (CH₂Cl₂–MeOH–NH₄OH, 9 : 1 : 1%); yield: 91%; MP: 238–243 °C (dec.), lit.³⁹ 230–238 °C; [α]²⁵_D −13.8 (c 1.0, aq. HCl 10%), {lit.⁷ [α]²⁵_D −14 (c 0.5, aq. HC1 10%)}; IR (CHCl₃, cm⁻¹): ν_max 3287, 2920, 1625, 1405 cm⁻¹; ¹H NMR (400 MHz, D₂O): δ 1.64–1.80 (m, 2H), 2.02–2.08 (m, 2H), 2.22 (s, 1H), 3.07–3.12 (m, 1H), 3.40–3.36 (m, 1H), 3.83 (d, J = 7.8 Hz, 1H), 4.17–4.13 (m, 1H); ¹³C-NMR (100 MHz, D₂O): δ 18.5, 28.7, 42.5, 60.8, 65.5, 170.0; MS (ESI): m/z: 146 (M + H)⁺.

(2S,3R)-tert-Butyl 3-hydroxy-2-(hydroxymethyl)piperidine-1-carboxylate (26). To stirred suspension of LAH (0.152 g, 4 mmol) in anhydrous THF (3 mL) was added the lactam 24 (240 mg, 0.8 mmol) dissolved in anhydrous THF (3 mL) and the reaction mixture was stirred for 8 h at room temperature. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3 × 25 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue thus obtained was purified by flash chromatography (pet ether–ethyl acetate 10 : 90) to afford diol 26 (138 mg) as a white crystalline solid. R_f: 0.5 (pet. ether–ethyl acetate, 2 : 8); yield: 75%; MP: 126–128 °C, lit.⁸ 124–126 °C; [α]²⁵_D +27 (c 1.0, MeOH), {lit.⁴⁰ [α]²⁵_D +29.8 (c 0.99, MeOH)}; IR (CHCl₃, cm⁻¹): ν_max 3448, 3025, 2945, 1674, 1215, 1120, 838 cm⁻¹; ¹H NMR (200 MHz, CDCl₃ + CCl₄ + DMSO-d₆): δ 1.15–1.29 (m, 1H), 1.39 (s, 9H), 1.61–1.82 (m, 3H), 2.69–2.82 (m, 1H), 3.45–3.61 (m, 2H), 3.89–3.92 (m, 2H), 4.08–4.16 (m, 1H); ¹³C (125 MHz, CDCl₃ + CCl₄ + DMSO-d₆): δ 18.8, 26.3, 28.0, 39.6, 59.1, 59.8, 63.8, 79.1, 155.9; MS (ESI): m/z: 232 (M + H)⁺, 254 (M + Na)⁺; HRMS: calculated for C₁₁H₂₁NNaO₄-254.1368, found-254.1369. HPLC detail for racemic dihydroxy compound (26) HPLC chiracel OJ-H column (250 × 4.6 mm). Isopropanol–pet ether = 5 : 95 flow rate 0.5 mL min⁻¹, λ = 210 nm retention time (min): rt1 = 13.39; rt2 = 14.98 (1 : 1). Enantiomerically pure dihydroxy compound (26) HPLC chiracel OJ-H column (250 × 4.6 mm) isopropanol–pet ether = 5 : 95 flow rate 0.5 mL min⁻¹, λ = 210 nm retention time (min): rt1 = 13.18 (major); rt2 = 15.05 (>97% ee).

(E)-Ethyl 3-((2S,3R)-1-benzyl-3-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)aziridin-2-yl)acrylate (17). To a stirred solution of trans-aziridine-2-carboxylate 13 (1 g, 3.27 mmol) in dry CH₂Cl₂ (30 mL) was added DIBAL-H (3.6 mL, 3.6 mmol, 1 M solution in toluene) at −78 °C slowly over period of 15 min and stirred for another 15 min. TLC showed complete conversion of ester to aldehyde. Reaction was quenched by addition of MeOH (0.3 mL) and allowed to warm to 0 °C. Saturated aqueous NH₄Cl (10 mL) was added and stirred for 0.25 h after which organic layer was separated and aqueous layer was washed with CH₂Cl₂ (3 × 20 mL). Combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo and used as such for next reaction. To a stirred solution NaH (0.09 g, 3.6 mmol, prewashed with dry n-hexane) dissolved in THF (10 mL) was added triethyl phosphonoacetate (0.71 mL, 3.6 mmol) slowly at 0 °C and stirred for 10 minutes. The aldehyde from above reaction dissolved in 5 mL of dry THF was added and stirring continued for another 2 h at same temperature until completion of reaction. The reaction was quenched with saturated aqueous NH₄Cl (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were then washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Purification on flash column chromatography (pet. ether–ethyl acetate, 1 : 9) furnished compound 17 (0.75 g) as thick colorless oil. R_f: 0.5 (pet ether–ethyl acetate, 8 : 2); yield: 75%, over two steps; IR (CHCl₃, cm⁻¹): ν_max 2984, 2932, 1716, 1644, 1370, 1265; [α]²⁵_D −34 (c 1, CHCl₃); ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.30 (t, J = 7.0 Hz, 3H), 1.33 (s, 3H), 1.40 (s, 3H), 2.12 (dd, J = 2.6 & 4.9 Hz, 1H), 2.72 (dd, J = 2.4 & 9.9 Hz, 1H), 3.61 (dd, J = 5.5 & 7.9 Hz, 1H), 3.72–3.85 (m, 2H), 3.91–4.09 (m, 2H), 4.20 (q, J = 7.0 Hz, 2H), 6.13 (d, J = 15.2 Hz, 1H), 6.89 (dd, J = 9.9 & 15.2 Hz, 1H), 7.26–7.35 (m, 5H); ¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ 14.2, 25.5, 26.7, 40.1, 49.6, 57.0, 60.3, 66.24, 76.1, 109.5, 125.1, 127.1, 127.9, 128.2, 138.6, 142.9, 165.3; MS (ESI): m/z: 354.15 [M + Na]⁺; HRMS: calculated for C₁₉H₂₆O₄N-332.1862, found-332.1858.

(4R,5R,E)-Ethyl 5-(benzylamino)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxypent-2-enoate (27). To a stirred solution of ester 17 (1.4 g, 4.2 mmol) in CH₃CN–water (9 : 1, 25 mL) was added TFA (0.64 mL, 8.4 mmol) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred until complete disappearance of starting material (∼5–6 h). Reaction was quenched by addition of excess NaHCO₃, water (10 mL) was added and organic mass was extracted with ethyl acetate (3 × 20 mL). Combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure followed by column chromatographic purification using ethyl acetate–pet. ether (15 : 85) to yield 1.11 g of amino-alcohol 27 as thick liquid. R_f: 0.5 (pet. ether–ethyl acetate, 7 : 3); yield: 80%; IR (CHCl₃, cm⁻¹): ν_max 3453, 2985, 1717, 1656, 1455, 1370, 1263, 1175; [α]²⁵_D −50 (c 1.8, CHCl₃); ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 1.29 (t, J = 7.0 Hz, 3H), 1.32 (s, 3H), 1.39 (s, 3H), 2.74 (dd, J = 3.6 & 5.4 Hz, 1H), 3.77–4.03 (m, 4H), 4.1–4.26 (m, 3H), 4.55 (dd, J = 3.6 & 5.4 Hz, 1H), 6.2 (dd, J = 2 & 15.6 Hz, 1H), 6.9 (dd, J = 3.7 & 15.6 Hz, 1H), 7.26–7.34 (m, 5H); ¹³C NMR (50 MHz, CDCl₃): δ 14.1, 25.1, 26.3, 51.0, 60.3, 61.3, 67.3, 69.0, 74.9, 109.0, 121.3, 127.1, 128.1, 128.4, 139.5, 147.0, 166.1; MS (ESI): m/z: 372.14 [M + Na]⁺. HRMS: calculated for C₁₉H₂₈O₅N-350.1967, found 350.1962.

(4R,5S,E)-Ethyl 5-(benzylamino)-4-((tert-butyldimethylsilyl)oxy)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)pent-2-enoate (28). To a stirred solution of hydroxyl amino ester 27 (1 g, 2.86 mmol), imidazole (0.4 g, 6 mmol) and DMAP (0.0.24 g, 0.2 mmol) in CH₂Cl₂ (20 mL) was added TBSCl (1.27 g, 8.44 mmol) dissolved in CH₂Cl₂ (5 mL) slowly at °C after which reaction was heated to reflux for 6 h until completion of reaction. Reaction mass was concentrated under reduced pressure followed by column chromatography using ethyl acetate–pet ether (5 : 95) to yield 1.18 g of –OTBS protected amino-alcohol 28 as thick colourless liquid. R_f: 0.5 (pet. ether–ethyl acetate, 8 : 2); yield: 90%; IR (CHCl₃, cm⁻¹): ν_max 2984, 2931, 1721, 1657, 1472, 1369, 1260, 1160, 1059. [α]²⁵_D +11.11 (c 2.7, CHCl₃); ¹HNMR (200 MHz, CDCl₃ + CCl₄): δ 0.04 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.31 (t, 3H), 1.35 (s, 3H), 1.40 (s, 3H), 2.72 (br s, 1H), 3.70 (t, J = 7.7 Hz, 1H), 3.84–4.04 (m, 1H), 4.22 (q, 2H), 4.29–4.46 (m, 2H), 6.08 (dd, J = 1.4 & 15.6 Hz, 1H), 7.1 (dd, J = 5.2 & 15.6 Hz, 1H), 7.25–7.36 (m, 5H); ¹³C NMR (50 MHz, CDCl₃): δ −4.9, −4.5, 14.1, 18.1, 25.2, 25.8, 26.8, 53.1, 60.3, 63.7, 66.9, 73.3, 75.5, 108.8, 121.4, 126.9, 128.2, 149.0, 166.2; MS (ESI): m/z: 486.27 [M + Na]⁺; HRMS: calculated for C₂₅H₄₂O₅NSi-464.2832, found-464.2827.

(5R,6S)-5-((tert-Butyldimethylsilyl)oxy)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)piperidin-2-one (29). A suspension of 28 (0.9 g, 1.94 mmol) and 10% Pd(OH)₂/C (60 mg) in MeOH (20 mL) was stirred under a H₂ atmosphere at room temperature for 2.5 h, filtered through Celite and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (EtOAc–pet. ether = 1 : 3) to afford amide 29 (0.59 g) as a colorless thick liquid. R_f: 0.5 (pet. ether–ethyl acetate, 1 : 1); yield: 92%; IR (CHCl₃, cm⁻¹): ν_max 3408, 2927, 1670, 1457, 1380, 1216; [α]²⁵_D −22.9 (c 1.15, CHCl₃). ¹HNMR (400 MHz, CDCl₃ + CCl₄): δ 0.1 (s, 3H), 0.11 (s, 3H), 0.91 (s, 9H), 1.34 (s, 3H), 1.41 (s, 3H), 1.78–1.87 (m, 1H), 1.94–2.01 (m, 1H), 2.29–2.38 (m, 1H), 2.47–2.85 (m, 1H), 3.20 (t, J = 7 Hz, 1H), 3.72–3.77 (m, 1H), 3.84 (dd, J = 5 & 8 Hz, 1H), 4.00–4.1 (m, 2H), 6.02 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ −4.5, −4.1, 17.9, 25.2, 25.8, 26.6, 28.5, 29.1, 61.7, 67.2, 68.1, 76.3, 109.3, 170.6; MS (ESI): m/z: 352.18 [M + Na]⁺; HRMS: calculated for C₁₆H₃₂O₄NSi-330.2101, found-330.2095.

(5R,6S)-1-Allyl-5-((tert-butyldimethylsilyl)oxy)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)piperidin-2-one (30). To the NaH (0.044 g, 1.8 mmol, prewashed with dry n-hexane) in DMF (2 mL) was added amide 29 (0.4 g, 1.21 mmol) in DMF (2 mL) dropwise at 0 °C and stirred for 1 h at room temperature. Allyl bromide (0.154 mL, 1.8 mmol) was added dropwise at 0 °C. The resulting reaction mixture stirred for 3–4 h at room temperature. Reaction mixture was then quenched using water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organics washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude product was column purified on flash chromatography (pet. ether–ethyl acetate, 7 : 3) to afford the allylated product 30 as colorless liquid. R_f: 0.5 (pet. ether–ethyl acetate, 2 : 1); yield: 0.357 g, 85%; IR (CHCl₃, cm⁻¹): ν_max 2986, 1630, 1420, 1107. [α]²⁵_D −83.4 (c 1, CHCl₃); ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ 0.07 (s, 3H), 0.08 (s, 3H), 0.88 (s, 9H), 1.35 (s, 3H), 1.43 (s, 3H), 1.88–1.92 (m, 4H), 2.33–2.44 (m, 1H)), 2.53–2.67 (m, 1H), 3.33–3.37 (m, 1H), 3.54–3.75 (m, 3H), 4.03–4.05 (m, 2H), 4.9 (m, 1H), 5.11–5.24 (m, 2H), 5.61–5.81 (m, 1H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ −4.9, 17.8, 25.4, 25.5, 25.6, 26.3, 26.5, 48.4, 64.4, 65.4, 66.7, 78.5, 109.6, 117.1, 133.4, 168.8; MS (ESI): m/z: 356.41 [M + H]⁺.

((5R,6S)-1-Allyl-5-((tert-butyldimethylsilyl)oxy)-6-((S)-1,2-dihydroxyethyl)piperidin-2-one (31). Protected lactam 30 (0.2 g, 0.56 mmol) was treated with 80% aqueous acetic acid (2 mL), and the resulting mixture was allowed to react at 80 °C. The reaction was monitored by TLC and was judged to be complete after 3 h. The solution was then diluted with H₂O (8 mL) and extracted with EtOAc (3 × 10 mL). The extracts were treated with saturated NaHCO₃ solution, and the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated to give a crude residue that was purified by flash chromatography (pet. ether–ethyl acetate, 1 : 9). Pure terminal diol 31 (0.14 g) was obtained as a thick gummy liquid. R_f: 0.4 (ethyl acetate); yield: 75%; IR (CHCl₃, cm⁻¹): ν_max 3554, 3340, 2986, 1627, 1423, 1107; [α]²⁵_D −34.9 (c 1, CHCl₃); ¹HNMR (200 MHz, CDCl₃ + CCl₄): δ 0.06 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.99–2.11 (m, 2H), 2.14–2.33 (m, 1H), 2.53–2.63 (m, 1H), 3.35–3.37 (m, 1H), 3.54–3.69 (m, 4H), 3.94 (s, 1H), 4.71–4.77 (m, 2H), 5.26–5.58 (m, 2H), 5.72–5.88 (m, 1H); ¹³C NMR (100 MHz, CDCl₃ + CCl₄): −4.8, −4.7, 18.0, 25.3, 25.8, 26.9, 50.3, 64.1, 64.7, 66.1, 73.6, 117.5, 132.8, 171.0; MS (ESI): m/z: 352.23 [M + Na]⁺.

(E)-Ethyl 3-((2S,3R)-1-allyl-3-((tert-butyldimethylsilyl)oxy)-6-oxopiperidin-2-yl)acrylate (32). Diol 31 (0.2 g, 0.607 mmol) was dissolved in acetone–water (3 mL, 2 : 1) at 0 °C, treated with sodium metaperiodate (0.2 g, 0.9 mmol) and stirred at 15 °C for 15 min. The reaction was quenched using ethylene glycol (0.01 mL), extracted with CH₂Cl₂ (3 × 10 mL), washed with brine, dried over anhydrous Na₂SO₄ and filtered. The combined organics were concentrated under reduced pressure to afford crude aldehyde which was used as such for next reaction.

To a solution of aldehyde from above reaction in CH₂Cl₂ (15 mL) was added (carboethoxymethylene) triphenylphosphorane (0.4 g, 1.2 mmol) and the reaction mixture was stirred for 6 h. Solvent was evaporated and the reaction mixture was adsorbed on silica. Purification by column chromatography (pet. ether–ethyl acetate, 8 : 2) gave 32 as a thick liquid (0.167 g). R_f: 0.5 (pet. ether–ethyl acetate, 1 : 1); yield: 75%; IR (CHCl₃, cm⁻¹): ν_max 2986, 1723, 1656, 1630, 1107; [α]²⁵_D −45 (c 1, CHCl₃) ¹HNMR (200 MHz, CDCl₃ + CCl₄): δ 0.06 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.30 (t, J = 7 Hz, 3H), 1.73–1.75 (m, 1H), 1.86–1.93 (m, 1H)), 2.35 (m, 1H), 2.59–2.68 (m, 1H), 2.99 (dd, J = 7 & 16 Hz, 1H), 3.99 (m, 1H), 4.19 (q, J = 7 Hz, 2H), 5.84 (dt, J = 2 & 16 Hz, 1H), 5.11–5.18 (m, 1H), 5.62–5.72 (m, 1H), 5.88 (dd, J = 1 & 16 Hz, 1H), 6.73 (dd, J = 6 & 16 Hz, 1H); ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ −4.8, 14.2, 24.8, 25.6, 26.7, 47.3, 60.7, 64.3, 67.0, 117.3, 123.9, 132.3, 144.5, 165.4, 169.1; MS (ESI) m/z: 390.12 [M + Na]⁺; HRMS: calculated for C₁₉H₃₄O₄NSi-368.2252, found-368.2247.

(8R,8aS)-8-((tert-Butyldimethylsilyl)oxy)-6,7,8,8a-tetrahydroindolizin-5(3H)-one (18). The olefinic compound 32 (0.075 g, 0.2 mmol) and Grubbs' 2^nd generation catalyst (5 mg, 2 mol%) in anhydrous CH₂Cl₂ (50 mL) was refluxed for 5 h. The reaction mixture was filtered through Celite and concentrated in vacuo to provide crude 18. The crude product was purified using column chromatography (pet. ether–ethyl acetate, 1 : 1) to provide the ring closed product 18 (0.044 g, 80%) as a colorless sticky liquid. R_f: 0.3 (pet. ether–ethyl acetate, 1 : 1); yield: 80%; IR (CHCl₃, cm⁻¹): ν_max 1640, 1620; [α]²⁵_D + 53 (c 1, CHCl₃); lit.⁴¹ {for ent-[α]²⁵_D −53.73 (c 1.10, CHCl₃)}; ¹HNMR (400 MHz, CDCl₃ + CCl₄): δ 0.08 (s, 6H), 0.90 (s, 9H), 1.79–1.81 (m, 1H), 2.02–2.03 (m, 1H), 2.39–2.46 (m, 1H), 2.60–2.62 (m, 1H), 3.53–3.55 (m, 1H), 4.02–4.06 (m, 1H), 4.15–4.16 (m, 1H), 4.45–4.50 (m, 1H), 5.92–5.94 (m, 2H); ¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ −4.6, −4.1, 18.0, 25.7, 29.7, 30.2, 53.3, 69.1, 71.1, 126.8, 128.5, 168.2. MS (ESI): m/z: 268.02 [M + H]⁺. HRMS: calculated for C₁₄H₂₆NO₂Si-268.1733; found-268.1741.

(R)-6-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)piperidin-2-one (33). To a stirred solution of aziridine ester 17 (0.66 g, 1.99 mmol) in methanol (10 mL) was added ammonium formate (1.24 g, 19.9 mmol) and 10% Pd/C (100 mg), and the mixture was refluxed for 3 h. The reaction mixture was filtered through Celite, concentrated and purified by column chromatography (pet ether–ethyl acetate, 2 : 8) to afford 33 as a thick yellowish liquid. R_f: 0.4 (ethyl acetate); yield: 0.37 g, 95%; [α]²⁵_D −17.5 (c 1.1, CHCl₃); {lit.⁴² [α]²⁵_D −14.4, (c 0.5, CHCl₃)}; IR (CHCl₃, cm⁻¹): ν_max 3402, 2985, 2936, 1664, 1457, 1371, 1072; ¹H NMR (400 MHz, CDCl₃ + CCl₄): δ 1.20–1.28 (m, 1H), 1.33 (s, 3H), 1.40 (s, 3H), 1.63–1.83 (m, 2H), 1.85–2.01 (m, 1H), 2.17–2.49 (m, 2H), 3.31 (td, J = 5.4 & 8.7 Hz, 1H), 3.66 (dd, J = 5.4 & 8.2 Hz, 1H), 3.86–3.88 (m, 1H), 4.03 (dd, J = 6.0 & 8.2 Hz, 1H), 6.21 (br s, 1H); ¹³C NMR (100 MHz, CDCl₃ + CCl₄): δ 19.7, 24.8, 25.3, 26.8, 31.3, 56.2, 66.2, 79.1, 109.79, 171.2; MS (ESI): m/z: 200.11 (M + H)⁺, 222.10 (M + Na)⁺; HRMS: calculated for C₇H₁₈NO₃-200.1281, found-200.1277.

Acknowledgements

LBK, KPP, PNC and SAK thank CSIR, New Delhi, India for fellowship. We also thank Dr U. R. Kalkote, Dr H. B. Borate, Dr N. B. Dumare and Mr D. B. Kalbhor for helpful discussions. Authors thank CSIR, New Delhi for financial support as XII year plan programme under title ORIGIN (CSC-0108) and ACT (CSC-0301).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra06429e

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