De Novo Asymmetric Syntheses of d-, l- and 8-epi-Swainsonine

Abstract

A highly enantioselective and stereocontrolled approach to d-, l- and 8-epi-d-swainsonine has been developed from achiral furan and γ-butyrolactone. A one-pot hydrogenolysis of both azide and benzyl ether followed by an intramolecular reductive amination has been employed as key step to establish the indolizidine ring system. The absolute stereochemistry was installed by the Noyori reduction and the relative stereochemistry by the use of several highly diastereoselective palladium catalyzed glycosylation, Luche reduction, dihydroxylation and palladium catalyzed azide allylation reactions. This practical approach provide multigram quantities of indolizidine natural product d-swainsonine in 13 steps and 25% overall yield.

1. Introduction

Over the past decade, polyhydroxylated indolizidine alkaloids have received considerable attention because of their interesting structures and their diverse biological activities (e.g., antiviral, antitumor, and immunomodulating activity).¹ The most well-known member d-swainsonine (1) (Figure 1), a trihydroxyindolizidine alkaloid, was isolated from the fungus Rhizoctonia leguminicola² and Metarhizium anisopliae,³ as well as found in the legume Swainsona canescens⁴ and the spotted locoweed Astragalus lentiginosus.⁵ This natural product has shown to be a potent inhibitor of both lysosomal α-mannosidase⁶ and mannosidase II⁷ and has been applied to clinical testing as anticancer drug⁸ to inhibit tumor growth and metastasis.

Figure 1.

Swainsonine and Analogues

Fleet has shown that the enantiomer of d-swainsonine (1), l-swainsonine (2) selectively inhibited narginase (l-rhamnosidase, K_i = 0.45 μM), whereas the d-swainsonine showed no inhibitory activity toward this enzyme.⁹ Due to the biological importance, of both d- and l-swainsonine, as well as several epimers and analogues have become attractive targets for syntheses. Thus, over 35 syntheses of both d- and l-swainsonine have been reported since the first syntheses by Richardson and Fleet.¹⁰ Most of these syntheses reported to date utilize carbohydrate starting materials to introduce asymmetry; whereas, only eight syntheses used achiral starting materials.10a-d,h Herein we report the full account of a short and efficient de novo syntheses of d- and l-swainsonine (1 and 2) from achiral commercially available starting material.¹¹ In addition to describing our optimised route (multigram scale) to d- and l-swainsonine we disclose for first time the use of this approach for the syntheses of 8-epi-swainsonine (3) and 8-hydroxyindolizidine (4).

Our strategy for the synthesis of d-swainsonine is outlined in Scheme 1, which involves a key one-pot reductive cyclization of azido-sugar 6 into 1. Thus, we envisioned that d-swainsonine could be obtained by hydrogenolytic deprotection and reductive amination of bicyclic amine intermediate 5, which can be derived from azide-sugar 6 by reductive N-alkylation. The manno-stereochemistry of azide 6 could be readily installed by diastereoselective dihydroxylation of 7. The allylic azide 7 in turn could be prepared from palladium catalyzed azide allylation, Luche reduction and stereoselective palladium catalyzed protection of pyranone 8α. A Noyori reduction and Achmatowicz oxidation should convert the furfuryl alcohol 9 into pyranone 8α. Eventually, the furfuryl alcohol could be derived from commercially available furan and γ-butyrolactone 11. In addition to providing either swainsonine enantiomer (1 and 2), we envisioned with route being able to provide the diastereomeric and deoxy-analogues 3 and 4.

Scheme 1.

Retrosynthetic Analysis of (-)-d-Swainsonine (1)

2. Results and Discussion

2.1. Approach to pyranones

The syntheses of d- and l-swainsonine as well as 8-epi-swainsonine began with commercially available achiral γ-butyrolactone 11 and furan (Scheme 2).¹² Treatment of γ-butyrolactone 11 with 2-lithiofuran 10 in THF solution afforded furfuryl ketone 12 in 74% yield. Protection of primary alcohol 12 gave TBS-ether 13 (TBSCl/imid. in DMF) in excellent yield (98%). The furfuryl alcohol 9 was obtained from furfuryl ketone 12 by employing a phase transfer variant of the asymmetric Noyori reduction in high enantiomeric excess (> 96% ee) and excellent yield (95%) using an aqueous solution of HCOONa/cetyltrimethylammonium bromide (CTAB).¹³ Alternatively, the Noyori reduction could be accomplished using a THF solution of HCOOH/Et₃N (1:1) in 89% yield, however, this required a 10 fold amount of Noyori catalyst and afforded a slightly lower yield of product. Exposure of furfuryl alcohol 9 to the Achmatowicz conditions¹⁴ (NBS in THF/H₂O) provided the oxidative rearrangement product hemiacetal 14 (84%), which was converted ((Boc)₂O at −78 °C) to a mixture of Boc-protected pyranones 8α and 8β in a good yield (85%) and diastereoselectivity (8:1; α:β).¹⁵ The diastereoselectivity of the Boc-acylation to form pyranones 8α and 8β was decreased (8α/8β in 1:1 ratio) when the reaction was performed at elevated temperature (0 °C to rt).

Scheme 2.

Enantioselective Synthesis of Pyranones

2.2. Synthesis of d-Swainsonine 1 via Protected Swainsonine

With the successful synthesis of pyranone 8α, we next installed manno-stereochemistry and C-1 benzyl ether (Scheme 3). Exposure of the pyranone 8α and benzyl alcohol to our palladium glycosylation conditions¹⁶ (2.5% Pd(0)/5% PPh₃) afforded OBn-protected pyranone 15 as a single diastereomer and in an excellent yield (88%). Diastereoselective reduction of the C-4 ketone in 15 under the Luche condition¹⁷ (NaBH₄/CeCl₃, −78 °C) gave an equatorial allylic alcohol 16 in excellent yield (94%). Dihydroxylation of allylic alcohol 16 using the Upjohn conditions¹⁸ (OsO₄/NMO) afforded triol 17 by in excellent yield (91%). The C-2/C-3 cis-diol 25 was selectively protected as acetonide 18 by treatment with 2,2-dimethoxypropane and catalytic amount of p-TsOH (96%).

Scheme 3.

Diastereoselective Synthesis of Azide 21

In order to convert the C-4 equatorial hydroxyl group into an equatorial azide, an oxidation/reduction/inversion sequence was employed. Swern oxidation of alcohol 18, provided the C-4 ketone 19, which was reduced with NaBH₄ to provide the C-4 axial alcohol 20 in excellent yield for the two steps (93%). Finally, treatment of alcohol 20 with triflic anhydride gave a triflate, which without further purification underwent an S_N2 azide displacement (NaN₃/DMF) to provide azide 21 in 72% yield from 20.

Alternatively, the acetonide 21 could also be prepared by a short and efficient route that involved a palladium-catalyzed azide installation (Scheme 4),¹⁹ this would eliminate the need for the double inversion at C-4 (18 to 20 to 21). To perform the palladium coupling reaction, a C-4 carbonate leaving group was required. Thus, allylic alcohol 16 was treated with methyl chloroformate and catalytic amount of DMAP to produce allylic carbonate 22 in excellent yield (96%). The allylic azide 7 was formed by a regio- and stereoselective Pd-catalyzed allylation of methyl carbonate 22 with TMSN₃ in the presence of (allylPdCl)₂ and bis(diphenylphosphino)butane in excellent yield (91%). Once again diastereoselective dihydroxylation of allylic azide 7 generated diol 23 (92%), which was protected (2,2- dimethoxypropane/p-TsOH_(cat)) to give acetonide 21 in good yield (97%) and two fewer steps.

Scheme 4.

Synthesis of Azide 21 via Palladium-Catalyzed Azide Allylation and Dihydroxylation

To complete the synthesis of d-swainsonine, a one-pot reductive cyclization was employed to furnish indolizidine ring (Scheme 5). TBS-ether 21 was deprotected to yield primary alcohol 24 by treatment with TBAF. Once again mesylation of 24 (MsCl/Et₃N) produced mesylate 25 in excellent yield (97%, two steps). The azidosugar 25 was converted into a protected swainsonine 31 via a cascade of transformations (global hydrogenolysis, N-alkylation and reductive amination). Mechanistically, this is believed to begin with an azide reduction to produce aminosugar 26, which undergoes an intramolecular N-alkylation to generate amine 27. Hydrogenolytic removal of Bn-protecting group at the anomeric position should result in hemiacetal 28, which exist in equilibrium with hydroxy aldehyde 29. A reductive amination of 29, via bicyclic iminium ion intermediate 30, provided the protected swainsonine 31. This one-pot reaction was performed with hydrogen (1 atm.) in a THF/ethanol solution and required 7 days for complete conversion (85%). Finally, acidic hydrolysis of the acetonide 31 followed by ion-exchange chromatography (Basic HO⁻ form) gave d-swainsonine (1) in excellent yield (95%).

Scheme 5.

Synthesis of d-Swainsonine (1) via a One-pot Reductive Cyclization

2.3. Alternative Synthesis of Swainsonine

Using the same strategy, we found d-swainsonine (1) could also be efficiently synthesized without acetonide protection in four steps from allylic azide 7 (Scheme 6). Deprotection of TBS-ether 7 with a TBAF solution (99%) afforded the primary alcohol 32, which was after mesylation (MsCl/Et₃N) gave mesylate 33 in near quantitative yield (99%). Upjohn dihydroxylation of allylic azide 33 exclusively gave diol 6 (OsO₄/NMO, 93%). Finally, the natural product d-swainsonine 1 was obtained by an analogous azide reduction/N-alkylation/reductive amination sequence under hydrogenation condition (100 psi H₂, Pd(OH)₂/C).

Scheme 6.

Synthesis of d-Swainsonine (1) and 8-Hydroxyindolizidine (4)

In addition, the known indolizidine analogue 8-hydroxyindolizidine (4)²⁰ was also prepared by the same one-pot hydrogenation of allylic azide 33 (68%). It is worth noting this sans-acetonide approach provided 8-hydroxyindolizidine (4) as well as either enantiomer of swainsonine (1 and 2) while using only two protecting groups (Bn and TBS). The route to swainsonine can provide multigram quantities of both enantiomers (3 g of the d-isomer was prepared). The physical and spectral data of our synthetic both d- and l-swainsonine by either way is completely identical to those of the natural materials (¹H NMR, ¹³C NMR, optical rotation and melting point).²¹

2.4. Synthesis of 8-epi-d-Swainsonine

Encouraged by these results, we next investigated the use of this approach for the synthesis of 8-epi-d-swainsonine (Scheme 7). We envisioned this approach starting with the l-pyranone ent-8β . This enantiomeric β-anomer of 8α was readily prepared in three steps from furfuryl ketone 13 by switching to the use of the (S,S)-Noyori catalyst and performing the Boc-acylation at higher temperature (0°C to rt) to ensure more β-pyranone ent-8β was produced (cf, Scheme 2).

Scheme 7.

Synthesis of Allylic Alcohol 36

Palladium catalyzed glycosylation of pyranone ent-8β with benzyl alcohol diastereoselectively afforded the C-1 BnO-pyranone 34 in 88% yield (Scheme 7). Unfortunately, the Luche reduction (NaBH₄/CeCl₃) of pyranone 34 provided a 1:1.3 mixture of allylic alcohols 35 and 36 in 86% yield. Improved diastereoselectivity was obtained (35/36 in a 1:2.5 ratio) when DIBAL-H was used as the reducing agent (89%). The easily separated minor diastereomer, equatorial allylic alcohol 35, could be easily converted into axial allylic alcohol 36 via a 2-step Mitsunobu/ester hydrolysis sequence. Thus, exposure of allylic alcohol 35 to typical Mitsunobu reaction conditions (BzOH, DIAD and PPh₃) yielded benzoate ester 37 with inverted stereochemistry at C-4. Methanolysis of ester 37 (K₂CO₃/MeOH) provided allylic alcohol 35 in good yield (82%, two steps).

With a practical route to allylic alcohol 36 (the C-5 diastereomer of 16) in hand, we explored the analogous application of this approach for the synthesis of 8-epi-d-swainsonine (3) (Scheme 8). Treatment of allylic alcohol 36 with methyl chloroformate formed carbonate 38 (Pyr/DMAP) in 94% yield. The carbonate 38 was coupled with TMSN₃ to give allylic azide ((allylPdCl)₂/dppb) in excellent yield (92%). Stereoselective dihydroxylation of allylic azide 38 under Upjohn conditions (OsO₄/NMO) afforded diol 40 as a single talo-diastereomer. Diol 40 was protected as acetonide 41 in excellent yield (95% two steps). Deprotection of TBS-ether 41 provided primary alcohol 42 (TBAF, 99% yield), which was followed by mesylation to afford mesylate 43 in 98% yield. A one-pot global hydrogenation/hydrogenolysis of azide 43 produced protected 8-epi-d-swainsonine (3) in excellent yield (83%). Eventually, 8-epi-d-swainsonine (3) was obtained by treatment with HCl in 94% yield. The spectral and physical data of 8-epi-d-swainsonine (3) by our approach match those of references reported (¹H NMR, ¹³C NMR, optical rotation and melting point).²²

Scheme 8.

Synthesis of 8-epi-d-Swainsonine (3)

3. Conclusions

In conclusion, a de novo asymmetric approach to d-swainsonine (1), l-swainsonine (2), 8-epi-d-swainsonine (3) as well as 8-hydroxylindolizidine (4) has been developed. Both d- and l-swainsonine were achieved in 13 steps and 25% overall yield from achiral furan 10. These practical syntheses are comparable to the previous carbohydrate-based routes.¹⁰ Key to the successful approach is the use of the Noyori reduction, palladium-catalyzed glycosylation, diastereoselective dihydroxylation, palladium-catalyzed azide allylation and one-pot reductive cyclization. The 8-epi-d-swainsonine (4) was also synthesized in 10 steps in 34% overall yield from Boc-pyranone ent-8β (15 steps from furan 10 in 8% overall yield). Further application of this approach to the synthesis of various analogues is ongoing.

4. Experimental Section²³

4.1. General

¹H and ¹³C spectra were recorded on 270 and 600 spectrometers. Chemical shifts were reported relative to internal tetramethylsilane (δ 0.00 ppm) or CDCl₃ (δ 7.26 ppm) or CD₃OD (δ 4.89 ppm) for ¹H and CDCl₃ (δ 77.1 ppm) or CD₃OD (δ 49.15 ppm) for ¹³C. Optical rotations were measured with a digital polarimeter in the solvent specified. Infrared (IR) spectra were obtained on a FT-IR spectrometer. Flash column chromatography was performed on ICN reagent 60 (60-200 mesh) silica gel. Analytical thin-layer chromatography was performed with precoated glass-backed plates (K6F 60Å, F254) and visualized by quenching of fluorescence and by charring after treatment with p-anisaldehyde or phosphomolybdic acid or potassium permanganate stain. R_f values were obtained by elution in the stated solvent ratios (v/v). Ether, THF, methylene chloride and triethylamine were dried by passing through activated alumina (8 × 14 mesh) column with nitrogen gas pressure. Commercial reagents were used without purification unless otherwise noted. Air and/or moisture-sensitive reactions were carried out under an atmosphere of argon/nitrogen using oven/flamed-dried glassware and standard syringe/septa techniques.

4.1.1. (2S,3S,4S,5S,6R)-2-(benzyloxy)-tetrahydro-6-(3-tert-butyldimethylsilyloxyprop-yl)-2H-pyran-3,4,5-triol (17)

To a t-butanol/acetone (0.53 mL, 1:1, 1 M) solution of allylic alcohol 16 (200 mg, 0.53 mmol) at 0 °C was added a solution of (50% w/v) of N-methyl morpholine N-oxide/water (0.25 mL). Crystalline OsO₄ (1.4 mg, 1 mol %) was added and the reaction was stirred for 24 h. The reaction mixture was concentrated with a small silica gel under reduced pressure, purified using silica gel flash chromatography eluting with 100% EtOAc to give triol 17 (199 mg, 0.48 mmol, 91%); R_f = 0.29 (70% EtOAc/hexane); ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+48$ (c = 3.11, MeOH); IR (thin film, cm^-1) 3397, 2928, 2857, 1455, 1389, 1253, 1061, 833; ¹H NMR (600 MHz, CD₃OD)δ 7.36-7.43 (m, 5H), 4.91 (s, 1H), 4.78 (d, J = 11.4 Hz, 1H), 4.57 (d, J = 11.4 Hz, 1H), 3.97 (m, 1H), 3.83 (dd, J = 9.0, 3.0 Hz, 1H), 3.77 (m, 2H), 3.64 (dd, J = 9.0, 9.0 Hz, 1H), 3.59 (m, 1H), 2.00-2.11 (m, 1H), 1.90-1.97 (m, 1H), 1.66-1.73 (m, 1H), 1.58-1.64 (m, 1H), 1.01 (s, 9H), 0.16 (s, 6H); ¹³C NMR (150 MHz, CD₃OD) δ 138.9, 129.5, 129.0, 128.8, 100.5, 73.6, 72.7, 72.4, 72.1, 64.5, 30.3, 29.0, 26.6, 19.2, -4.9; CIHRMS: [C₂₁H₃₆O₆SiNa⁺]: 435.2176, found: 435.2179.

4.1.2. (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-tetrahydro-6-(3-tert-butyldimethylsilyloxypropyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-7-ol (18)

Para-toluenesulfonic acid monohydrate (19.4 mg, 5 mol%) was added to a stirred solution of diol 17 (840 mg, 2.08 mmol) and 2,2-dimethoxypropane (5.87 mL) in acetone (31.2 mL) for 0.5 h at 0 °C. The reaction mixture was quenched with sodium bicarbonate solution (5 mL), removed acetone in vacuo, extracted with Et₂O (3 × 25 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography eluting with 15% EtOAc/hexane to give 904 mg (2.0 mmol, 96%) of colorless oil acetonide 18: R_f (20% EtOAc/hexane) = 0.40; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+36$ (c = 1.52, CH₂Cl₂); IR (thin film, cm^-1) 3467, 2930, 2857, 1382, 1248, 1087, 835; ¹H NMR (600 MHz, CDCl₃)δ 7.34 (m, 5H), 5.06 (s, 1H), 4.74 (d, J = 11.4 Hz, 1H), 4.51 (d, J = 11.4 Hz, 1H), 4.18 (d, J = 6.0 Hz, 1H), 4.11 (dd, J = 6.0, 7.2 Hz, 1H), 3.67 (m, 2H), 3.56 (ddd, J = 9.0, 9.0, 3.0 Hz, 1H), 3.48 (m, 1H), 2.15 (d, J = 3.0, 1H), 1.83-1.95 (m, 2H), 1.52-1.65 (m, 2H), 1.51 (s, 3H), 1.31 (s, 3H), 0.90 (s, 9H), 0.06 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 137.0, 128.6, 128.3, 128.1, 109.5, 96.2, 78.6, 75.9, 73.2, 69.8, 69.1, 63.3, 28.8, 28.1, 27.9, 26.3, 26.1, 18.5, -5.2; CIHRMS: Calculated for [C₂₄H₄₀O₆SiNa⁺]: 475.2491, found: 475.2492.

4.1.3. (3aS,4S,6R,7aR)-4-(benzyloxy)-dihydro-6-(3-tert-butyldimethylsilyloxypropyl)-2,2-dimethyl-6H-[1,3]dioxolo[4,5-c]pyran-7(7aH)-one (19)

To a solution of (COCl)₂ (0.15 mL, 1.76 mmol) in CH₂Cl₂ (3.5 mL) was added DMSO (0.51 mL, 3.52 mmol) at −78 °C, and the mixture was stirred for 10 min. A solution of alcohol 18 (400 mg, 0.88 mmol) in 1.76 mL CH₂Cl₂ was added to the resulting mixture, stirring for 0.5 h at −78 °C. Then triethylamine (0.50 mL, 3.52 mmol) was added at −78 °C and the reaction mixture was warmed to 0 °C for 1 h. 50 mL water was added to quench the mixture, and the aqueous mixture was extracted (3 × 80 mL) with Et₂O, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography eluting with 15% EtOAc/hexane to give ketone 19 (392 mg, 0.87 mmol, 99%) as a colorless oil: R_f (20% EtOAc/hexane) = 0.61; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+74$ (c = 2.0, CH₂Cl₂); IR (thin film, cm^-1) 2954, 2929, 2857, 1741, 1472, 1253, 1077, 1023, 834; ¹H NMR (600 MHz, CDCl₃.)δ 7.35 (m, 5H), 5.03 (d, J = 1.2 Hz, 1H), 4.76 (d, J = 11.4 Hz, 1H), 4.57 (d, J = 11.4 Hz, 1H), 4.47 (dd, J = 6.6, 1.2 Hz, 1H), 4.46 (d, J = 6.6, 1H), 4.18 (dd, J = 4.8, 8.4 Hz, 1H), 3.65 (m, 2H), 1.90-1.96 (m, 1H), 1.72-1.84 (m, 2H), 1.58-1.65 (m, 1H), 1.48 (s, 3H), 1.35 (s, 3H) 0.90 (s, 9H), 0.05 (s, 6H); ¹³C NMR (67.5 MHz, CDCl₃) δ 196.5, 143.3, 137.1, 128.6, 128.2 (two carbon), 127.9, 92.1, 74.0, 70.6, 62.9, 28.5, 26.0, 18.4, -5.2; CIHRMS: Calculated for [C₂₄H₃₈O₆Si+H⁺]: 451.2514, found: 451.2516.

4.1.4. (3aS,4S,6R,7S,7aS)-4-(benzyloxy)-tetrahydro-6-(3-tert-butyldimethylsilyloxypropyl)-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-7-ol (20)

A CH₂Cl₂ (1 mL) solution of ketone 19 (370 mg, 0.82 mmol) and MeOH (1 mL, 1 M) was cooled to 0 °C. NaBH₄ (37 mg, 0.98 mmol) was added and the reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was diluted with ether (20 mL) and quenched with 15 mL of saturated NaHCO₃, extracted (3 × 30 mL) with Et₂O, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography eluting with 15% EtOAc/hexane to give colorless oil 323 mg (0.71 mmol, 87%) of alcohol 20: R_f (20% EtOAc/hexane) = 0.41; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+16$ (c = 1.6, CH₂Cl₂); IR (thin film, cm^-1) 3568, 2928, 2857, 1381, 1251, 1070, 833; ¹H NMR (600 MHz, CDCl₃) δ 7.35 (m, 5H), 5.15 (s, 1H), 4.76 (d, J = 11.4 Hz, 1H), 4.55 (d, J = 11.4 Hz, 1H), 4.22 (dd, J = 4.8, 6.0 Hz, 1H), 4.11 (d, J = 6.0 Hz, 1H), 3.76 (dd, J = 4.8, 9.0 Hz, 1H), 3.63-3.70 (m, 2H), 3.61 (d, J = 6.0, 6.0 Hz, 1H), 3.48 (m, 1H), 2.21 (d, J = 6.0, 1H), 1.84-1.90 (m, 1H), 1.73-1.80 (m, 1H), 1.65-1.71 (m, 1H),1.59-1.64 (m, 1H), 1.58 (s, 3H), 1.38 (s, 3H), 0.90 (s, 9H), 0.05 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 137.1, 128.6, 128.3, 128.1, 109.3, 96.7, 73.6, 72.9, 69.4, 68.5, 66.1, 63.1, 29.4, 27.6, 26.1, 25.9, 25.4, 18.4, -5.2; CIHRMS: Calculated for [C₂₄H₄₀O₆SiNa⁺]: 475.2491, found: 475.2490.

4.1.5. (3aR, 9R, 9aR, 9bS)-octahydro-2,2-dimethyl-[1,3]dioxolo[4, 5-a]indolizin-9-ol (31)

To a solution of acetonide 25 (7.79 g, 17.6 mmol) in dry EtOH/THF (76 mL, v/v = 1:1) was added Pd(OH)₂/C (1.9 g) and the mixture was stirred under H₂ at an 100 psi pressure for 3 days at room temperature. The catalyst was filtered off through a short pad of celite, concentrated under reduced pressure. The resulting crude was purified using silica gel flash chromatography eluting with 30% MeOH/EtOAc to give protected swainsonine 31 (3.2 g, 15.0 mmol, 85%); a colorless needles, R_f = 0.44 (10% MeOH/EtOAc); ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=-72$ (c = 1.0, CH₂Cl₂); mp 102-104; IR (neat, cm^-1) 3194, 2942, 2793, 1466, 1371, 1260, 1209, 1113, 1068; ¹H NMR (600 MHz, CDCl₃) δ 4.67 (dd, J = 6.2, 4.8, 1H), δ 4.24 (dd, J = 6.0, 4.2, 1H), 3.79 (ddd, J = 10.9, 8.9, 4.4, 1H), 3.11 (d, J = 10.8, 1H), 2.96 (dt, J = 10.8, 3.0 Hz, 1H), 2.52 (br s, 1H), 2.09 (dd, J = 10.8, 4.8 Hz, 1H), 2.00-2.03 (m, 1H), 1.82 (ddd, J =10.8, 10.8, 3.6 Hz, 1H), 1.61-1.65 (m, 1H), 1.59 (dd, J = 9.0, 4.8 Hz, 1H), 1.48 (s, 3H) , 1.31 (s, 3H), 1.25(m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 111.3, 79.2, 78.2, 73.8, 67.3, 60.0, 51.6, 33.0, 26.0, 24.9, 24.1.

4.1.6. (2S, 6S)-6-(benzyloxy)-2-(3-tert-butyldimethylsilyloxypropyl)-2H-pyran-3(6H)-one (34)

To a solution of Boc-protected pyranone 8α (5.86 g, 15.8 mmol) and benzyl alcohol (3.28 g, 30.4 mmol) in dry CH₂Cl₂ (8 mL), was added Pd₂(DBA)₃•CHCl₃ (97.7 mg, 0.9 mol% Pd) and PPh₃ (101.5 mg, 3.6 mol%) at 0 °C under argon atmosphere. After stirring for 2 h at 0 °C to room temperature, the reaction mixture was quenched with 200 mL of saturated NaHCO₃, extracted (3 × 200 mL) with Et₂O, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography eluting with 6% EtOAc/hexane to give benzyl ether 34 (5.02 g, 13.30 mmol, 88%) as a colorless oil: R_f (10% EtOAc/hexane) = 0.75; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+10$ (c = 1.4, CH₂Cl₂); IR (thin film, cm^-1) 2954, 2929, 2856, 1695, 1471, 1254, 1092, 1024, 832; ¹H NMR (600 MHz, CDCl₃) δ 7.36 (m, 5H), 6.89 (dd, J = 10.2, 1.8 Hz, 1H), 6.10 (dd, J = 10.2, 1.2 Hz, 1H), 5.37 (d, J = 1.2 Hz, 1H), 4.95 (d, J = 11.4 Hz, 1H), 4.71 (d, J = 11.4 Hz, 1H), 4.09 (dd, J = 7.8, 3.6 Hz, 1H), 3.66 (m, 2H), 2.03-2.09 (m, 1H), 1.85-1.91 (m, 1H), 1.75-1.82 (m, 1H), 1.67-1.74 (m, 1H), 0.91 (s, 9H), 0.06 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 200.0, 146.5, 137.0, 128.6, 128.15 (two carbon), 128.1, 94.6, 78.9, 70.3, 62.9, 28.5, 28.0, 26.0, 18.4, -5.2; CIHRMS: Calculated for [C₂₁H₃₂O₄SiNa⁺]: 399.1962, found: 399.1970.

4.1.7. (2S, 3S, 6S)-6-(benzyloxy)-3,6-dihydro-2-(3-tert-butyldimethylsilyloxypropyl)-2H-pyran-3-ol (36)

To a solution of pyranone 34 (6.7 g, 17.7 mmol) in 130 mL THF was added dropwise 1.0 M DIBAL-H in hexane (17.8 mL, 17.8 mmol) at −78 °C under nitrogen atmosphere. The reaction mixture was kept stirring for 3 h at −78 °C, then treated with 1.0 M Na/K tartaric solution (50 mL) and allowed to warm to room temperature. The resulting mixture was extracted with diethyl ether (3 × 200 mL) and the combined organic phases were dried (Na₂SO₄) and concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography eluting with 20 % EtOAc/hexane to afford colorless oil 6.0 g (15.8 mmol, 89%) of allylic alcohol 35 and 36 in 1:2.5. 36: R_f (20% EtOAc/hexane) = 0.61; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+52$ (c = 1.0, CH₂Cl₂); IR (thin film, cm^-1) 3417, 2952, 2928, 2856, 1471, 1254, 1094, 1056, 834; ¹H NMR (600 MHz, CDCl₃) δ 7.27-7.38 (m, 5H), 6.10 (dd, J = 9.6, 4.8 Hz, 1H), 5.86 (d, J = 9.6, 1H), 5.09 (d, J = 1.2 Hz, 1H), 4.92 (d, J = 11.4 Hz, 1H), 4.67 (d, J = 11.4 Hz, 1H), 3.70 (m, 1H), 3.69 (m, 2H), 3.54 (ddd, J = 7.2, 4.8, 2.4 Hz, 1H), 1.97 (d, J = 2.4 Hz, 1H), 1.78-1.84 (m, 1H), 1.69-1.77 (m, 2H), 1.62-1.67 (m, 1H), 0.91 (s, 9H), 0.07 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 137.6, 131.4, 130.9, 128.4, 128.1, 127.8, 97.2, 75.6, 70.0, 63.9, 63.2, 28.7, 27.3, 26.0, 18.4, -5.2; CIHRMS: Calculated for [C₂₁H₃₄O₄SiNa⁺]: 401.2118, found: 401.2132. 35: R_f (20% EtOAc/hexane) = 0.58; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+53$ (c = 1.0, CH₂Cl₂); IR (thin film, cm^-1) 3426, 2932, 2928, 2856, 1471, 1254, 1093, 1056, 834; ¹H NMR (600 MHz, CDCl₃) δ 7.26-7.37 (m, 5H), 5.95 (ddd, J = 9.6, 3.0, 1.8 Hz, 1H), 5.81 (ddd, J = 9.6, 3.6, 1.2 Hz, 1H), 5.16 (dd, J =3.6 1.8 Hz, 1H), 4.87 (d, J = 11.4 Hz, 1H), 4.64 (d, J = 11.4 Hz, 1H), 3.99 (ddd, J = 7.8, 7.2, 2.4 Hz, 1H), 3.68 (m, 2H), 3.47 (ddd, J = 7.8, 7.2, 3.6 Hz, 1H), 2.29 (d, J = 7.2 Hz, 1H), 1.77-1.92 (m, 2H), 1.61-1.71 (m, 2H), 0.92 (s, 9H), 0.08 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 137.7, 132.8, 128.8, 128.4, 128.0, 127.7, 96.0, 78.2, 69.5, 67.2, 63.2, 28.9, 28.8, 26.0, 18.4, -5.2; CIHRMS: Calculated for [C₂₁H₃₄O₄SiNa⁺]: 401.2118, found: 401.2132.

4.1.8. (2S,3S,6S)-6-(benzyloxy)-3,6-dihydro-2-(3-tert-butyldimethylsilyloxypropyl)-2H-pyran-3-yl benzoate (37)

Allylic alcohol 35 (1.1 g, 3.38 mmol) was dissolved in THF (5 mL). The solution was cooled to 0 °C and triphenylphosphine (1.77 g, 6.75 mmol), benzoic acid (0.82 g, 6.75 mmol), and diisopropyl azodicarboxylate (1.33 mL, 6.75 mmol) were added to the solution. The solution was stirred overnight, quenched with saturated aqueous sodium bicarbonate (50 mL), and extracted with ether (3 × 50 mL). The organic fractions were combined, dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography eluting with 5% EtOAc/hexane to afford colorless oil 1.38 g (2.85 mmol, 84%) of allylic ester 37: R_f (20% EtOAc/hexane) = 0.64; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+122$ (c = 1.0, CH₂Cl₂); IR (thin film, cm^-1) 2953, 2927, 2857, 1790, 1717, 1452, 1268, 1108, 1061, 835; ¹H NMR (600 MHz, CDCl₃) δ 8.09-8.10 (m, 2H), 7.52-7.57 (m, 2H), 7.28-7.45 (m, 6H), 6.19 (ddd, J = 10.2, 4.8, 1.8 Hz, 1H), 6.05 (d, J = 10.2 Hz, 1H), 5.28 (ddd, J = 7.2, 4.8, 2.4 Hz, 1H), 5.20 (d, J = 1.2 Hz, 1H), 4.94 (d, J = 11.4 Hz, 1H), 4.74 (d, J = 11.6 Hz, 1H), 3.78 (ddd, J = 7.8, 4.8, 3.0 Hz, 1H), 3.60-3.68 (m, 2H), 1.84-1.90 (m, 1H), 1.75-1.82 (m, 1H), 1.67-1.73 (m, 1H), 1.58-1.65 (m, 1H), 0.08 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 166.3, 137.8, 134.6, 130.6, 129.9, 128.9, 128.5, 128.4, 128.1, 127.8, 127.1, 96.7, 74.0, 69.6, 66.0, 63.1, 28.9, 27.5, 26.0, 18.4, -5.3; CIHRMS: Calculated for [C₂₈H₃₈O₅SiNa⁺]: 505.2381, found: 505.2386.

4.1.9. (2S,3S,6S)-6-(benzyloxy)-3,6-dihydro-2-(3-tert-butyldimethylsilyloxypropyl)-2H-pyran-3-yl-methyl carbonate (38)

To a solution of allylic alcohol 36 (4.0 g, 10.6 mmol) and pyridine (2.62 g, 31.6 mmol) in dry CH₂Cl₂ (53 mL) at 0 °C, was added DMAP (260 mg), and added dropwise methyl chloroformate (6.24 g, 63.6 mmol). After stirring 1 h at 0 °C, a saturated Cu₂SO₄ solution (500 mL) was added and then the mixture was extracted with CH₂Cl₂ (3 × 300 mL), dried (Na₂SO₄), concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography eluting with 5% EtOAc/hexane to give 4.34 g (9.96 mmol, 94%) of colorless oil carbonate 38: R_f (20% EtOAc/hexane) = 0.62; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+110$ (c = 1.4, CH₂Cl₂); IR (thin film, cm^-1) 2955, 2929, 2886, 2857, 1745, 1442, 1264, 1098, 1059, 833; ¹H NMR (600 MHz, CDCl₃) δ 7.35 (m, 5H), 6.12 (ddd, J = 10.2, 4.8, 1.2 Hz, 1H), 6.03 (d, J = 10.2 Hz, 1H), 5.13 (d, J =1.2 Hz, 1H), 4.88 (d, J = 11.4 Hz, 1H), 4.87 (dd, J = 4.8, 1.8 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 3.78 (s, 3H), 3.62-3.73 (m, 3H), 1.73-1.84 (m, 2H), 1.64-1.70 (m, 1H), 1.57-1.63 (m, 1H), 0.90 (s, 9H), 0.06 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 155.8, 137.7, 133.7, 128.4, 128.1, 127.8, 126.5, 96.5, 73.6, 69.4, 69.2, 63.1, 55.0, 28.9, 27.1, 26.0, 18.4, -5.2; CIHRMS: Calculated for [C₂₃H₃₆O₆SiNa⁺]: 459.2173, found: 459.2179.

4.1.10. (2S,3S,6S)-3-azido-6-(benzyloxy)-3,6-dihydro-2-(3-tert-butyldimethylsilyloxyprop-yl)-2H-pyran (39)

To a mixture of carbonate 38 (2.2 g, 5.45 mmol), allylpalladium chloride dimer (43.5 mg, 0.11 mmol) and 1,4-bis(diphenylphosphino)butane (189 mg, 0.44 mmol) in dry THF (1.2 mL) was added TMSN₃ (684 mg, 5.95 mmol) under argon atmosphere. The solution was stirred at room temperature for 0.5 h. Then the reaction mixture was passed Celite pad, concentrated under reduced pressure, and then purified using silica gel flash chromatography eluting with 4% EtOAc/hexane to give 2.0 g (4.96 mmol, 91%) allylic azide 39 as colorless oil: R_f (20% EtOAc/hexane) = 0.64; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+197$ (c = 1.9, CH₂Cl₂); IR (thin film, cm^-1) 2953, 2929, 2857, 2099, 1472, 1253, 1098, 835; ¹H NMR (600 MHz, CDCl₃) δ 7.36 (m, 5H), 6.10 (d, J = 10.2 Hz, 1H), 5.92 (ddd, J = 10.2, 4.8, 1.2 Hz, 1H), 5.17 (d, J = 1.2 Hz, 1H), 4.90 (d, J = 11.4 Hz, 1H), 4.68 (d, J = 11.4 Hz, 1H), 3.72 (ddd, J = 7.2, 4.8, 1.8 Hz, 1H), 3.68 (m, 2H), 3.63 (dd, J = 4.8, 3.0, 1.8 Hz, 1H), 1.81-1.89 (m, 1H), 1.69-1.75 (m, 2H), 1.59-1.64 (m, 1H), 0.91 (s, 9H), 0.07 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 137.8, 133.3, 128.4, 128.1, 127.8, 126.1, 96.8, 75.5, 69.3, 63.1, 55.3, 28.7, 28.6, 26.0, 18.4, -5.2; CIHRMS: Calculated for [C₂₁H₃₃N₃O₆SiNa⁺]: 426.2183, found: 426.2189.

4.1.11. (2S,3S,4S,5S,6S)-5-azido-2-(benzyloxy)-tetrahydro-6-(3-tert-butyldimethylsilyl-oxypropyl)-2H-pyran-3, 4-diol (40)

To a t-butanol/acetone (13.4 mL, 1:1, 1 M) solution of allylic azide 39 (2.7 g, 6.7 mmol) at 0 °C was added a solution of (50% w/v) of N-methyl morpholine N-oxide/water (4 mL). Crystalline OsO₄ (17 mg, 1 mol %) was added and the reaction was stirred for 24 h. The reaction mixture was quenched with 20 mL saturated Na₂S₂O₃ solution, extracted with ether (3 × 200), dried (Na₂SO₄), concentrated under reduced pressure, and then purified using silica gel flash chromatography eluting with 30% EtOAc/hexane to give diol 40 (2.81 g, 6.43 mmol, 96%); colorless oil, R_f = 0.47 (40% EtOAc/hexane); ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+41$ (c = 1.0, CH₂Cl₂); IR (thin film, cm^-1) 3426, 2953, 2929, 2858, 2102, 1471, 1077, 835; ¹H NMR (600 MHz, CDCl₃) δ 7.34 (m, 5H), 4.93 (d, J = 11.4 Hz, 1H), 4.63 (d, J = 7.8 Hz, 1H), 4.56 (d, J = 11.4 Hz, 1H), 4.23 (dd, J = 4.2, 2.4, 1.2 Hz, 1H), 3.95 (ddd, J = 7.8, 4.2, 1.2 Hz, 1H), 3.62-3.72 (m, 3H), 3.56 (dd, J = 3.0, 1.2 Hz, 1H), 2.73 (d, J = 1.2, 1H), 2.53 (d, J = 2.4 Hz, 1H), 1.80-1.87 (m, 1H), 1.71-1.77 (m, 1H), 1.57-1.68 (m, 2H), 0.91 (s, 9H), 0.07 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 137.1, 128.6, 128.3, 128.2, 99.6, 72.5, 70.8, 70.1, 68.9, 63.6, 62.9, 29.3, 27.7, 26.1, 18.4, -5.2; CIHRMS: Calculated for [C₂₁H₃₅N₃O₅SiNa⁺]: 460.2238, found: 460.2243.

4.1.12. (3-((3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)propoxy)(tert-butyl)dimethylsilane (41)

Para-toluenesulfonic acid monohydrate (61.5 mg, 5 mol%) was added to a stirred solution of diol 40 (2.9 g, 6.6 mmol) and 2,2-dimethoxypropane (18.6 mL) in acetone (99 mL) for 0.5 h at 0 °C. The reaction mixture was quenched with sodium bicarbonate solution (100 mL), removed acetone in vacuo, extracted with Et₂O (3 × 200 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography eluting with 5% EtOAc/hexane to give 3.12 g (6.53 mmol, 99%) of colorless oil acetonide 41: R_f (20% EtOAc/hexane) = 0.67; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+96$ (c = 1.0, CH₂Cl₂); IR (thin film, cm^-1) 2952, 2930, 2857, 2102, 1249, 1049, 835; ¹H NMR (600 MHz, CDCl₃) δ 7.27-7.37 (m, 5H), 4.91 (d, J = 11.4 Hz, 1H), 4.66 (d, J = 11.4 Hz, 1H), 4.42 (dd, J = 5.4, 1.8 Hz, 1H), 4.41 (d, J = 7.8 Hz, 1H), 4.05 (dd, J = 7.2, 5.4 Hz, 1H), 3.72 (ddd, J = 8.4, 4.8, 1.8 Hz, 1H), 3.67 (m, 2H), 3.55 (dd, J = 1.8, 1.8 Hz, 1H), 1.84-1.90 (m, 1H), 1.65-1.78 (m, 2H), 1.57-1.64 (m, 1H), 1.37 (s, 3H), 1.31 (s, 3H), 0.91 (s, 9H), 0.06 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 137.2, 128.4, 128.0, 127.8, 109.6, 101.0, 75.8, 74.4, 73.0, 70.1, 62.9, 60.2, 28.7, 29.1, 27.8, 26.3, 26.0, 18.3, -5.2; CIHRMS: Calculated for [C₂₄H₃₉N₃O₅SiNa⁺]: 500.2551, found: 500.2556.

4.1.13. 3-((3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)propan-1-ol (42)

To a solution of TBS-ether 41 (540 mg, 1.13 mmol) in dry THF (1.1 mL), TBAF (1.3 mL, 1.3 mmol) was added at room temperature under the argon atmosphere. After 12 h, the reaction mixture was quenched with sodium bicarbonate solution (500 mL), extracted with Et₂O (3 × 100 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The crude product was purified using silica gel flash chromatography eluting with 40% EtOAc/hexane to give alcohol 42 (401 mg, 1.11 mmol, 98%); as colorless oil, R_f = 0.45 (40% EtOAc/hexane); ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+127$ (c = 0.8, CH₂Cl₂); IR (thin film, cm^-1) 3434, 2988, 2941, 2875, 2102, 1383, 1221, 1046, 854; ¹H NMR (600 MHz, CDCl₃) δ 7.26-7.38 (m, 5H), 4.90 (d, J = 11.4 Hz, 1H), 4.66 (d, J = 11.4 Hz, 1H), 4.42 (dd, J = 5.4, 1.8 Hz, 1H), 4.41 (d, J = 7.8 Hz, 1H), 4.06 (dd, J = 7.8, 5.4 Hz, 1H), 3.73 (ddd, J = 8.4, 4.8, 1.8 Hz, 1H), 3.67 (m, 2H), 3.55 (dd, J = 1.8, 1.8 Hz, 1H), 1.88-1.95 (m, 1H), 1.73-1.81 (m, 1H), 1.65-1.71 (m, 2H), 1.37 (s, 3H), 1.32 (s, 3H); 13C NMR (150 MHz, CDCl₃) δ 137.2, 128.4, 128.2, 127.8, 109.7, 101.1, 75.7, 74.3, 73.1, 70.2, 62.5, 60.3, 29.1, 27.8, 26.3; CIHRMS: Calculated for [C₁₈H₂₅N₃O₅Na⁺]: 386.1686, found: 386.1680.

4.1.14. 3-((3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-tetrahydro-2,2-dimethyl-3aH-[1,3]dioxolo[4,5-c]pyran-6-yl)propyl methanesulfonate (43)

To a stirred solution of alcohol 42 (1.8 g, 4.95 mmol) and Et₃N (1.5 g, 14.9 mmol) in dry CH₂Cl₂ (4.95 mL) was added dropwise CH₃SO₂Cl (1.7 g, 1.49 mmol) at 0 °C. The reaction mixture was allowed to keep stirring for 0.5 h, and then water 30 mL was added, extracted with Et₂O (3 × 200 mL), dried (Na₂SO₄), and concentrated under reduced pressure. The resulting crude product was purified using silica gel flash chromatography eluting with 45% EtOAc/hexane to give mesylate 43 (2.14 g, 4.85 mmol, 98%); colorless solid, mp: 85-87 °C; R_f = 0.61 (50% EtOAc/hexane); ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+110$ (c = 1.2, CH₂Cl₂); IR (thin film, cm^-1) 2988, 2940, 2870, 2104, 1354, 1173, 1051, 832; 1H NMR (600 MHz, CDCl₃) δ 7.26-7.37 (m, 5H), 4.90 (d, J = 11.4 Hz, 1H), 4.67 (d, J = 11.4 Hz, 1H), 4.43 (d, J = 7.8 Hz, 1H), 4.42 (dd, J = 5.4, 1.8 Hz, 1H), 4.30 (m, 1H), 4.25 (m, 1H), 4.06 (dd, J = 7.8, 5.4 Hz, 1H), 3.73 (ddd, J = 8.4, 4.8, 1.8 Hz, 1H), 3.53 (dd, J = 1.8, 1.8 Hz, 1H), 3.01 (s, 3H), 1.92-2.01 (m, 2H), 1.81-1.89 (m, 1H), 1.67-1.72 (m, 1H), 1.37 (s, 3H), 1.33 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 137.1, 128.4, 128.0, 127.8, 109.8, 101.2, 75.6, 74.3, 72.5, 70.4, 69.5, 60.1, 37.5, 27.7, 27.4, 26.3, 26.0; CIHRMS: Calculated for [C₁₉H₂₇N₃O₇SNa⁺]: 464.1462, found: 464.1467.

4.1.15. (3aR,9S,9aR,9bS)-octahydro-2,2-dimethyl-[1,3]dioxolo[4,5-a]indolizin-9-ol (44)

To a solution of acetonide 43 (410 mg, 0.928 mmol) in dry EtOH/THF (4 mL, v/v = 1:1) was added Pd(OH)₂/C (100 mg) and the mixture was stirred under an atmosphere of H₂ at room temperature. After reacting for 1 day, the mixture was concentrated, simply passed a short pad of silica gel to remove palladium toxicity byproduct and concentrated again. The resulting residue was dissolved in EtOH/THF (4 mL, v/v = 1:1) and Pd(OH)₂/C (200 mg) was added. The suspended mixture was stirred for another 6 days under an atmosphere of H₂ at room temperature. Then the catalyst was filtered off through a short pad of Celite, concentrated under reduced pressure. The resulting crude product was purified using silica gel flash chromatography eluting with 30% MeOH/EtOAc to give protected (-)-8-epi-d-swainsonine 44 (164 mg, 0.769 mmol, 83%); a colorless needles, R_f = 0.77 (50% MeOH/EtOAc); ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=-33$ (c = 1.08, CH₂Cl₂); mp: 57.4-59.3 °C; IR (neat, cm^-1); 3513, 2982, 2937, 2786, 1464, 1373, 1262, 1209, 1135, 1018; ¹H NMR (600 MHz, CDCl₃) δ 4.67 (dd, J = 6.0, 4.2 Hz, 1H), 4.56 (dd, J = 6.0, 4.2 Hz, 1H), 3.79 (ddd, J = 10.9, 8.9, 4.4 Hz, 1H), 3.11 (d, J = 10.8 Hz, 1H), 2.96 (dt, J = 10.8, 3.0 Hz, 1H), 2.52 (br s, 1H), 2.09 (dd, J = 10.8, 4.8 Hz, 1H), 2.00-2.03 (m, 1H), 1.82 (ddd, J = 10.8, 10.8, 3.6 Hz, 1H), 1.61-1.65 (m, 1H), 1.59 (dd, J = 9.0, 4.8 Hz, 1H), 1.51 (s, 3H), 1.36-1.40 (m, 1H), 1.28 (s, 3H), 1.21-1.32 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 111.5, 82.0, 78.1, 68.7, 65.8, 60.1, 53.3, 31.4, 25.8, 24.2, 19.7; CIHRMS: Calculated for [C₁₁H₁₉NO₃H⁺]: 214.1443, found: 214.1438.

4.1.16. (1S, 2R, 8R, 8aR)-octahydroindolizine-1, 2, 8-triol (Swainsonine 1):²⁴

To a solution of diol 6 (4.0 g, 9.96 mmol) in dry EtOH (40 mL) was added Pd(OH)₂/C (1.5 g) and the mixture was stirred under H₂ at an 100 psi pressure for 3 days at room temperature. The catalyst was filtered off through a short pad of celite, concentrated under reduced pressure. The resulting crude product was applied to ion-exchange chromatography (Dowex 1C 8, 200 mesh, OH^- form) eluting with water. Removal of water in vacuo to give colorless needles d-swainsonine 1 (1.48 g, 8.5 mmol, 86%): mp: 143-144 °C; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=80$ (c =1.1, MeOH); [lit. ${[\mathrm{\alpha }]}_{\mathrm{D}}^{23}=74.0$ (c = 0.98, MeOH);²⁴ ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=82.6$ (c = 1.03, MeOH); ^21b ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=73.8$ (c = 0.21, EtOH); ^21c ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=75.7$ (c = 2.33, MeOH)].^21d R_f = (25% MeOH/CHCl3, w 1% NH₄OH) = 0.38; IR (thin film, cm^-1) 3287, 2953, 2722, 1639, 1405, 1338, 1141, 1076; ¹H NMR (600 MHz, CD₃OD) 4.26 (ddd, J = 8.0, 6.0, 2.4, 1H), 4.24 (m, 1H), 3.83 (ddd, J =4.5, 9.3, 10.8 Hz, 1H), 2.95-2.97 (m, 2H), 2.45 (dd, J = 7.2, 10.2 Hz, 1H), 2.08 (m, 1H), 1.92 (ddd, J = 11.6, 11.4, 2.8 Hz, 1H), 1.75 (dd, J = 3.6, 9.6 Hz, 1H), 1.71-1.74 (m, 1H), 1.70 (m, 1H), 1.64 (qt, J =13.2, 4.2 Hz, 1H), 1.25 (qd, J =12.6, 4.8 Hz, 1H); 13C NMR (150 MHz, CD₃OD) δ 75.4, 70.9, 70.0, 67.2, 63.3, 53.3, 34.3, 24.7.

To a solution of protected swainsonine (ent)-31 (100 mg, 0.47 mmol) in THF was added 6 N HCl (0.47 mL) at room temperature over night. The resulting mixture was concentrated under reduced pressure and then eluted with water through an ion exchange column (Dowex 1X8 200 OH, 1 g). Removal of water in vacuo gives colorless needles swainsonine 2 (77.2 mg, 0.45 mmol, 95%). l-swainsonine 2: 1H, ¹³C NMR and IR are same as d-swainsonine 1, mp: 142-143 °C; ${[\mathrm{\alpha }]}_{\mathrm{D}}^{21}=+75$ (c = 0.92, MeOH); [lit. ${[\mathrm{\alpha }]}_{\mathrm{D}}^{21}=+84.3$ (c = 1.02, H₂O); ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=+83.3$ (c = 0.5, MeOH)].

4.1.17. (8R, 8aS)-octahydroindolizin-8-ol (4)

To a solution of mesylate 33 (42 mg, 0.1148 mmol) in dry EtOH/THF (0.5 mL, v/v = 1:1) was added Pd(OH)₂/C (10 mg) and the mixture was stirred under an atmosphere of H₂ at room temperature. After reacting for 1 day, the mixture was concentrated, simply passed a short celite pad to remove byproduct and concentrated again. The resulting residue was dissolved in EtOH/THF (0.5 mL, v/v = 1:1) and Pd(OH)₂/C (10 mg) was added. The suspended mixture was stirred under H₂ at a100 psi pressure for another 2 days at room temperature. Then the catalyst was filtered off through a short pad of celite, concentrated under reduced pressure. The resulting crude product was applied to ion-exchange chromatography (Dowex 1× 8, 200 mesh, OH^- form) eluting with water. Removal of water in vacuo to give 8-hydroxyindolizidine 4 (11 mg, 0.078 mmol, 68%); R_f = 0.25 (MeOH); ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=-7.9$ (c = 0.4, CH3OH); IR (thin film, cm^-1) 3365, 2936, 2805, 1639, 1328, 1069; ¹H NMR (600 MHz, CD₃OD) δ 3.32 (ddd, J = 10.2, 9.0, 4.8 Hz, 1H), 3.06 (ddd, J = 9.0, 9.0, 3.0 Hz, 1H), 2.99 (m, 1H), 2.21 (q, J = 9.0 Hz, 1H), 2.11 (dddd, J = 12.0, 10.2, 6.6, 3.6 Hz, 1H), 1.96-2.01 (m, 2H), 1.70-1.83 (m, 4H), 1.59-1.67 (m, 1H), 1.48-1.57 (m, 1H), 1.22 (dddd, J = 15.0, 12.6, 10.2, 4.2 Hz, 1H),; ¹³C NMR (150 MHz, CD₃OD) δ 73.4, 71.6, 55.1, 52.9, 34.5, 29.2, 25.1, 21.4; CIHRMS: Calculated for [C₈H₁₅NOH⁺]: 142.1232, found: 142.1228.

4.1.18. (1S, 2R, 8S, 8aR)-octahydroindolizine-1, 2, 8-triol ((-)-8-epi-d-swainsonine) (3):²²

To a solution of protected (-)-8-epi-d-swainsonine 44 (120 mg, 0.56 mmol) in THF (1.2 mL) was added 6 N HCl (0.59 mL) at room temperature over night. The resulting mixture was concentrated under reduced pressure and then eluted with water through an ion exchange column (Dowex 1X8 200 OH^-, 1 g). Removal of water in vacuo gave white powder (-)-8-epi-d-swainsonine 3 (92 mg, 0.53 mmol, 94%): R_f= (50 % MeOH/EtOAc) = 0.31; mp: 89-91 °C [lit. mp: 92-93 °C];^22a ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=25$ (c = 0.75, MeOH); [lit. ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=20$ (c = 0.3, MeOH);^22b ${[\mathrm{\alpha }]}_{\mathrm{D}}^{25}=24.8$ (c = 0.67, MeOH)];^22c IR (thin film, cm^-1) 3360, 2937, 2789, 1645, 1329, 1138, 1013; ¹H NMR (600 MHz, CD₃OD) δ 4.32 (m, 2H), 4.20 (ddd, J = 7.2, 6.6, 1.8 Hz, 1H), 3.11 (m, 1H), 2.99 (dd, J = 10.2, 1.8 Hz, 1H), 2.34 (dd, J = 10.2, 7.2 Hz, 1H), 1.98-2.10 (m, 3H), 1.85-1.88 (m, 1H), 1.44-1.53 (m, 2H); ¹³C NMR (150 MHz, CD₃OD) δ 74.3, 70.0, 69.5, 67.6, 63.1, 54.4, 32.2, 20.8; ^22c,d CIHRMS: Calculated for [C₈H₁₅NO₃H⁺]: 174.1130, found: 174.1125.

Supplementary Material

01

Complete experimental procedures and spectral data for all new compounds can be found in the Supporting Information. This material is available free of charge via the Internet.