Synthesis of pyrrolidine iminosugars, (−)-lentiginosine, (−)-swainsonine and their 8a-epimers from D-glycals

Abstract

Synthesis of pyrrolidine iminosugars has been described from D-glycals via dihydroxylation, oxidative cleavage and double nucleophilic displacement as the key steps. The pyrrolidines obtained have been utilized for the synthesis of important bicyclic iminosugars, viz. (−)-lentiginosine and (−)-swainsonine and their 8a-epimers, which are known to be glycosidase inhibitors.

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Introduction

Several polyhydroxylated pyrrolidines found in nature have shown splendid biological properties.^1a Naturally occurring pyrrolidine iminosugars such as 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) 1 (Fig. 1), 3,4-dihydroxy-2,5-bis(hydroxymethyl)pyrrolidine (DMDP) 2, 2,5-dideoxy-2,5-imino-L-glucitol (DGDP) 3, and radicamines A 4 and B 5, have displayed good and yet a broad range of glycosidase inhibition activity,^1b–f while codonopsine 6 and codonopsinine 7 are known for their hypotensive pharmacological activity with no side effects on the mammalian nervous systems.^1g There is an ever-growing interest in the synthesis of such molecules owing to their immense potential from therapeutic as well as synthetic points of view. A number of methods are reported in the literature for the synthesis of pyrrolidine iminosugars from both carbohydrate^2a–c and non-carbohydrate^2d–f starting materials. From our group also, we have recently reported the synthesis and glycosidase inhibition studies of novel synthetic pyrrolidines.³

Fig. 1 Naturally occurring pyrrolidine iminosugars.

The synthetic strategies leading to polyhydroxylated pyrrolidines have often been extended to the synthesis of pyrrolizidines, indolizidines, etc.⁴ Among the many known classes of bicyclic glycosidase inhibitors, indolizidines such as lentiginosine 8, swainsonine 9, castanospermine 10, steviamine 11 (Fig. 2), as well as their unnatural analogues,⁵ have received considerable attention in recent years from both synthetic and biological communities. (−)-Lentiginosine 8 is a potent and specific inhibitor of amyloglucosidase,^6a albeit weaker than its enantiomer, while its 8a-epimer 12 is a weak β-glucosidase inhibitor.^6b (−)-Swainsonine is an important inhibitor of Golgi α-mannosidase,^6c and has gained more significance due to its potential anti-cancer activity.^6d Swainsonine analogue 13 is known to be an inhibitor of α-D-mannosidase,^6e very much like its parent compound. We have been interested in the synthesis of this class of compounds.⁷

Fig. 2 Examples of important indolizidine iminosugars.

In this paper, we report a new concise route towards pyrrolidine iminosugars from the easily available D-glycals, and demonstrate the utility of the pyrrolidines hence obtained, for the synthesis of polyhydroxylated indolizidine iminosugars 8, 9, 12 and 13 shown in Fig. 2.

Results and discussion

We have recently reported the synthesis of dihydroxymethyl dihydroxypyrrolidines from C-2 formyl glycals using dihydroxylation, oxidative cleavage and double nucleophilic displacement as the key steps, and further synthesized steviamine analogues, which showed good inhibitory activity.^7d Following a somewhat similar strategy, we planned the synthesis of the pyrrolidine skeletons from D-glycals, using dihydroxylation, oxidative cleavage and double nucleophilic displacement as the key steps. The retrosynthetic strategy is illustrated in Scheme 1.

Scheme 1 Retrosynthetic strategy for pyrrolidines.

Our synthesis commenced from 3,4,6-tri-O-acetyl-D-glycals 14 and 15 which were converted to their corresponding 6-O-trityl-3,4-dibenzyl-D-glycals 16a and 16b, following a literature procedure.⁸ Glucal 16a was subjected to dihydroxylation reaction using a catalytic amount of OsO₄ along with N-methylmorpholine N-oxide (NMO) as the reoxidant (Scheme 2) to obtain a 2.2 : 1 mixture of diols 17a which were not separated at this stage. Subsequent oxidative cleavage of the diol was carried out using NaIO₄ in an EtOH–H₂O (5 : 1) solvent system, resulting in the dicarbonyl compound 18a which was characterized by proton peaks at δ 7.88 and 9.65 in the ¹H NMR spectrum, corresponding to the formate and aldehyde protons respectively. Compound 18a on reduction using NaBH₄ in MeOH at 0 °C furnished the diol 19a. Mesylation of 19a was carried out using mesyl chloride and triethylamine as a base in CH₂Cl₂ at 0 °C. The resulting compound 20a was not very stable in nature and hence it was quickly purified and treated with benzylamine at 70 °C (Scheme 3) for a double nucleophilic displacement reaction to obtain pyrrolidine 21a. Attempts at cyclisation using other N-protected amines such as tosylamine, benzyl carbamate or tert-butylcarbamate were not successful possibly due to the poorer nucleophilicity of the amines. The trityl protection on the primary alcohol was removed successfully using trifluoroacetic acid (TFA) to yield 22a. The benzyl groups were deprotected using Pd(OH)₂/C and 1 N HCl in methanol, which required around 36 h, to give 1,4-dideoxy-1,4-imino-L-xylitol 23a^9a in 67% yield. In a similar manner, tri-O-acetyl-D-galactal 15b was converted to 1,4-dideoxy-1,4-imino-L-ribitol 23b^9b using the same series of steps. The spectral data of compounds 23a and 23b were found to be in agreement with literature reports.⁹

Scheme 2 Synthesis of dimesylate derivatives 20a and 20b.

Scheme 3 Cyclisation and deprotection reactions.

In order to diversify this strategy and to obtain other pyrrolidine iminosugars, we contemplated inversion of stereochemistry at the C-4 position of pyrrolidines 23a and 23b. At first, we made an unsuccessful attempt to displace the formate group in 18a with iodide using sodium iodide in refluxing acetone. Attempts using Mitsunobu conditions¹⁰ on diol 19a also failed in spite of using excess of reagents and longer reaction times. Next, we tried to replace mesylate groups in 20a with iodides by refluxing with NaI or tetrabutylammonium iodide in acetone or acetonitrile. In both the cases, only the primary mesylate was displaced by iodide, while the secondary mesylate did not get affected at all. However, following a report by Jung and Sun,¹¹ prolonged heating of the dimesylate 20a with KOAc in DMF at 140 °C, along with addition of KOAc in portions, gave us the desired product 24a albeit in 55% yield. Further optimisation studies were carried out and portionwise addition of CsOAc (5 equiv.) over 6 hours with heating at 120 °C in DMF gratifyingly afforded the doubly substituted compound 24a in 72% yield. Compound 24a was characterized by the presence of two acetate peaks at δ 1.97 and 2.07 in the ¹H NMR spectrum, and a strong carbonyl peak at 1742 cm⁻¹ in the IR spectrum. The same reaction was performed on D-galactal-derived dimesylate compound 20b to obtain the corresponding diacetate 24b in 68% yield (Scheme 4).

Scheme 4 Synthesis of pyrrolidines 1 and 29.

Further, the acetate protecting groups in 24a were removed using NaOMe and the diol 25a was again converted to mesylate 26a. Subsequently, nucleophilic displacement with benzylamine, acidic deprotection and hydrogenolysis of benzyl groups in the same manner led to pyrrolidine 1.^9a Similarly, pyrrolidine 29^9c was prepared from 20b, as shown in Scheme 4.

For the construction of the bicyclic molecules, the pyrrolidines 22 and 28 bearing the free primary hydroxyl group seemed to be suitable precursors since they could be easily obtained on gram-scale from glycals using this strategy. These pyrrolidines could be utilized for the synthesis of analogues of lentiginosine and swainsonine via simple manipulations as outlined in the retrosynthetic analysis (Scheme 5).

Scheme 5 Retrosynthetic plan for indolizidines.

Thus, we proceeded with pyrrolidine 22a for the synthesis of lentiginosine analogues, since the stereochemistry of C-2 and C-3 was similar to (−)-lentiginosine 8. For this purpose, we attempted to oxidise hydroxyl using modified Cornforth oxidation conditions,¹² wherein the reaction was found to be slow and unclean on TLC, possibly because of the basic amine moiety present in the molecule. Hence we replaced the benzyl group protection on the amine with the tert-butylcarbamate (Scheme 6) using Pd(OH)₂/C and 1 atm H₂, followed by treatment with Boc₂O in the presence of sodium carbonate as a base to furnish 30a. Next, the primary alcohol was oxidized using Cornforth conditions to obtain aldehyde in a facile manner within 15 minutes. The crude aldehyde was directly subjected to Wittig olefination using methyltriphenylphosphonium bromide and potassium tert-butoxide in THF to furnish alkene 31a. Subsequently, the carbamate group was deprotected using trifluoroacetic acid in dichloromethane following which the crude amine was treated with butenyl bromide in the presence of sodium hydride. The diene 32a was subsequently subjected to ring closing metathesis using 6 mol% of the Grubbs' second generation catalyst in the presence of para-toluenesulfonic acid (PTSA)¹³ to give the cyclised product 33a in 81% yield. One-pot double bond reduction and benzyl group deprotection was achieved under hydrogenation conditions to afford 8a-epi-(−)-lentiginosine 12 in 70% yield. In the same manner, pyrrolidine 28a was converted to (−)-lentiginosine 8 using the same sequence of reactions, as delineated in Scheme 6. The spectral data of the obtained indolizidine compounds were found to be in complete agreement with the literature reports.^6a,b

Scheme 6 Synthesis of lentiginosine 8 and its 8a-epimer 12.

The synthesis of swainsonine analogues emanated from analogous pyrrolidines 22b and 28b, that were obtained from D-galactal. The protecting group on amine 22b was changed from benzyl to Boc using the same method as earlier (Scheme 7). The primary alcohol in the so-obtained pyrrolidine 34a was oxidized and the resulting aldehyde was treated with vinyl magnesium bromide at 0 °C to give a single isomer 35a. Similarly, alcohol 35b was obtained from pyrrolidine 28b.

Scheme 7 Grignard reaction on alcohols 34a and 34b.

Protection of the alcohol moiety in 35a proved to be rather difficult contrary to our expectations. Acetylation of 35a took place quite easily, using acetic anhydride and triethylamine (Scheme 8). Deprotection of the carbamate group on the nitrogen of 36 was done using trifluoroacetic acid, and the corresponding crude free amine obtained was treated with allyl bromide and potassium carbonate for N-allylation. Instead of the desired N-allylated product 37b, we obtained the N-acetyl product 37a. Its formation can be rationalized as a consequence of the facile migration of the acetate group from secondary hydroxyl to amine due to a favourable 5-membered transition state B under basic conditions (Fig. 3). Benzylation of the hydroxyl group of 35a was then attempted using benzyl bromide and sodium hydride, however it led to the migration of the tert-butylcarbonyl group to free hydroxy group, giving 38a instead of 38b. This problem was overcome by carrying out protection under acidic conditions, albeit in low yield. Thus, we protected the hydroxyl group of 35a as its benzyl ether by using benzyl trichloroacetimidate using a catalytic amount of triflic acid,¹⁴ and we obtained only 27% of the required compound 39a (Scheme 9). Under these conditions, the Boc group was partially deprotected to yield 39b, so we proceeded with the crude mixture for Boc deprotection using trifluoroacetic acid. The amine hence obtained was treated with allyl bromide in the presence of K₂CO₃ in acetonitrile at 50 °C to obtain 40a. Finally ring closing metathesis of diene 40a was performed using the procedure used earlier (vide supra) to furnish 41a, and hydrogenation conditions were employed for the reduction of double bond and deprotection of benzyl groups to obtain the fully deprotected compound 13. Using the same series of reactions, pyrrolidine 25b was converted to swainsonine analogue 9. The spectral data of swainsonine analogues 13 and 9 were found to be identical to literature data.^6e,f

Scheme 8 Attempts for the protection of alcohol 35a.

Fig. 3 Rationale for formation of 37a.

Scheme 9 Synthesis of (−)-swainsonine 9 and its 8a-epimer 13.

Conclusion

We have developed a concise method for the synthesis of 1-deoxypyrrolidine azasugars from D-glycals. Also, inversion of stereochemistry has been performed successfully, to obtain other isomers in a practical manner. The pyrrolidines could be easily prepared on gram-scale and their utility has been demonstrated by efficient conversion to indolizidine azasugars via simple manipulations. Hence, this strategy has helped to conveniently achieve the synthesis of (−)-lentiginosine, (−)-swainsonine and their 8a-epimers.

Experimental section

General experimental methods

All experiments were performed in a oven dried apparatus and under nitrogen atmosphere in dry solvents unless indicated otherwise. Commercial grade solvents were distilled or dried by known methods and dry solvents were stored over 4 Å molecular sieves. IR spectra were recorded on a Bruker Vector 22 FT-IR as a thin film or using KBr pellets and are expressed in cm⁻¹. NMR data were recorded on a 400 or 500 MHz JEOL JNM-LA spectrometer using CDCl₃ as a solvent. Chemical shifts are reported in ppm downfield to tetramethylsilane. Coupling constants are reported and expressed in Hz; splitting patterns are designated as br (broad), s (singlet), d (doublet), dd (doublet of doublets), t (triplet), dt (doublet triplets) or m (multiplet). Optical rotations were measured using a polarimeter (Autopol II) at 28 °C. TLC plates were prepared using thin layers of Acme silica gel on microscope slides and visualization of spots was effected by exposure to iodine or spraying with 10% H₂SO₄ and charring. Column chromatography was performed over silica gel (100–200 mesh) using hexane and ethyl acetate as eluent. High resolution mass spectra were recorded by Q-TOF using the electrospray ionization (ESI) method.

(4R,5R,6R)-4,5-Bis(benzyloxy)-6-(trityloxymethyl)tetrahydro-2H-pyran-2,3-diol (17a). The olefin 16a (3.00 g, 5.28 mmol) was dissolved in acetone–H₂O–^tBuOH (4 : 1 : 1, 30 mL) and to this solution at room temperature was added NMO (680 mg, 5.81 mmol) followed by OsO₄ (0.05 mmol) and the mixture was stirred overnight. Then saturated sodium metabisulphite solution (20 mL) was added and stirred for 1 h. The reaction mixture was filtered through a Celite® pad and the filtrate was extracted with EtOAc (3 × 30 mL). Combined organic extracts were washed with brine (1 × 60 mL), dried over Na₂SO₄ and evaporated in vacuo. A small portion of the crude was purified through a short silica gel column to obtain diol 17a as a colourless oil: R_f = 0.4 (hexane–EtOAc = 2 : 1); IR (neat) ν_max: 3400, 2926, 1492, 1449, 1358, 1050, 737, 699 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, 2.2 : 1 mixture of diols): δ 7.49–7.47 (m, 6H, both isomers), 7.38–7.20 (m, 17H, both isomers), 6.91–6.88 (m, 2H, both isomers), 5.34 (br s, 1H, major isomer), 4.88–4.82 (m, 2H, both isomers), 4.70–4.68 (m, 1H, both isomers), 4.58 (br s, 1H, minor isomer), 4.36–4.30 (m, 1H, both isomers), 4.04 (br s, 1H, major isomer), 3.79–3.78 (m, 2H major isomer, 3H minor isomer), 3.66 (br s, 1H, minor isomer), 3.60–3.51 (m, 2H, both isomers), 3.25 (br s, 2H major isomer, 1H minor isomer), 2.56 (br s, 1H, minor isomer), 2.33 (br s, 1H, major isomer); ¹³C NMR (125 MHz, CDCl₃): δ 143.9, 143.8, 138.5, 137.9, 137.7, 128.9, 128.6, 128.5, 128.3, 128.1, 127.9, 127.8, 127.7, 127.1, 96.9, 92.4, 86.6, 86.4, 84.4, 82.4, 77.7, 75.8, 75.6, 75.4, 75.3, 75.0, 74.8, 72.8, 71.0, 62.5, 62.3; HRMS calcd for C₃₉H₃₈NaO₆ [M + Na]⁺ 625.2566, found: 625.2567.

(2R,3R,4S)-3,4-Bis(benzyloxy)-5-oxo-1-(trityloxy)pentan-2-yl formate (18a). To a well stirred solution of diol 17a (2.92 g, 4.86 mmol) in EtOH–H₂O (5 : 1, 30 mL), was added in portions NaIO₄ (3.12 g, 14.58 mmol) and NaHCO₃ (5 mL) over 2 h, followed by vigorous stirring for another 2 h. The solids were filtered out and the filtrate was extracted with dichloromethane (3 × 20 mL). The organic layer was washed with brine (1 × 45 mL), concentrated under vacuum and the residue was purified through a short silica gel column and compound 18a (2.45 g, 75% over 2 steps) was obtained as a colourless oil: R_f = 0.5 (hexane–EtOAc = 3 : 1); [α]²⁸_D = −31.7 (c 0.85, CH₂Cl₂); IR (neat) ν_max: 3440, 2925, 1728, 1492, 1449, 1167, 1091, 699 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 9.65 (s, 1H), 7.88 (s, 1H), 7.40–7.38 (m, 6H), 7.31–7.21 (m, 17H), 6.99–6.98 (m, 2H), 5.32–5.29 (m, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 11.5 Hz, 1H), 4.38–4.29 (m, 3H), 3.91–3.90 (m, 1H), 3.59 (dd, J = 2.5, 11.0 Hz, 1H), 3.38 (dd, J = 4.5, 10.5 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 203.6, 159.8, 143.5, 136.8, 136.4, 128.9, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.2, 127.0, 86.9, 82.2, 74.3, 73.5, 71.4, 61.5; HRMS calcd for C₃₉H₃₆NaO₆ [M + Na]⁺ 623.2410, found: 623.2416.

(2R,3R,4R)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diol (19a). The aldehyde 18a (2.45 g, 4.08 mmol) was dissolved in dry CH₃OH (25 mL) and cooled to 0 °C. To this solution, NaBH₄ (465 mg, 12.25 mmol) was added in 3 portions over 5 min and then stirred for 1 h with gradual warming to room temperature. The reaction mixture was quenched with aq. NH₄Cl (10 mL) and extracted with CH₂Cl₂ (3 × 20 mL). Organic extracts were washed with brine (1 × 40 mL) and dried over Na₂SO₄. Concentration in vacuo gave a residue which was purified by column chromatography to get 1.98 g (84%) of 19a as a colourless oil: R_f = 0.3 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −4.0 (c 1.50, CH₂Cl₂); IR (neat) ν_max: 3431, 3086, 3060, 2929, 2878, 1492, 1449, 1071, 699 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.44–7.42 (m, 6H), 7.31–7.23 (m, 17H), 7.14 (br s, 2H), 4.60 (d, J = 11.7 Hz, 1H), 4.50–4.44 (m, 3H), 4.05 (q, J = 5.5 Hz, 1H), 3.79–3.75 (m, 2H), 3.71 (dd, J = 4.5, 12.0 Hz, 1H), 3.64 (dd, J = 4.5, 9.0 Hz, 1H), 3.39–3.32 (m, 2H), 3.12 (br s, 1H), 2.30 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 143.8, 137.8, 137.6, 128.8, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.2, 86.8, 79.2, 78.3, 73.3, 72.6, 70.6, 64.6, 61.5; HRMS calcd for C₃₈H₃₈NaO₅ [M + Na]⁺ 597.2617, found: 597.2618.

(2R,3S,4R)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diyl dimethanesulfonate (20a). The diol 19a (1.20 g, 2.08 mmol) was dissolved in dry CH₂Cl₂ (12 mL) under N₂ at 0 °C and then Et₃N (1.46 mL, 10.45 mmol), DMAP (2.4 mg, 0.02 mmol) and MsCl (0.40 mL, 5.20 mmol) were added to the reaction mixture. It was stirred for 30 min and then aq. NaHCO₃ (6 mL) was added and again stirred for 10 min. The reaction mixture was extracted with CH₂Cl₂ (3 × 5 mL) and extracts were dried over Na₂SO₄. Evaporation of solvent gave a residue which was purified by column chromatography to yield 1.41 g (93%) of 20a as a colourless viscous liquid: R_f = 0.4 (hexane–EtOAc = 3 : 1); [α]²⁸_D = +1.64 (c 3.65, CH₂Cl₂); IR (neat) ν_max: 3031, 1492, 1450, 1357, 1176 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.41–7.38 (m, 5H), 7.31–7.20 (m, 18H), 7.16–7.14 (m, 2H), 5.03–5.00 (m, 1H), 4.55–4.53 (m, 3H), 4.45 (d, J = 11.1 Hz, 1H), 4.24 (dd, J = 4.6, 11.2 Hz, 1H), 4.16–4.09 (m, 1H), 3.84–3.80 (m, 2H), 3.55–3.50 (m, 2H), 3.01 (s, 3H), 2.86 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 143.2, 137.3, 137.0, 129.0, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 127.6, 127.4, 127.2, 87.6, 81.4, 76.6, 74.0, 73.6, 68.2, 62.8, 38.7, 37.3; HRMS calcd for C₄₀H₄₂NaO₉S₂ [M + Na]⁺ 753.2168, found: 753.2169.

(2S,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(trityloxymethyl)pyrrolidine (21a). The dimesylate compound 20a (1.10 g, 1.53 mmol), was heated in neat benzylamine (10 mL) at 70 °C for 2 h. After the complete consumption of starting material (TLC monitoring), excess amine was neutralised with 1 N HCl (20 mL) and compound 21a was extracted from the aqueous layer using EtOAc (3 × 12 mL). Organic extracts were washed with brine (1 × 20 mL) and dried over Na₂SO₄. The solvent was removed and residue was purified by column chromatography to afford compound 21a (770 mg, 78%) as a yellow oil: R_f = 0.8 (hexane–EtOAc = 4 : 1); [α]²⁸_D = +22.70 (c 2.60, CH₂Cl₂); IR (neat) ν_max: 3402, 3029, 2924, 1492, 1450, 1072 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.45–7.44 (m, 6H), 7.35–7.17 (m, 24H), 4.54 (d, J = 11.9 Hz, 1H), 4.46 (d, J = 12.2 Hz, 1H), 4.42–4.39 (m, 2H), 4.09 (d, J = 4.5 Hz, 1H), 3.99–3.97 (m, 2H), 3.41–3.37 (m, 3H), 3.25 (dd, J = 6.4, 10.0 Hz, 1H), 3.14 (dd, J = 5.5, 11.0 Hz, 1H), 2.35 (dd, J = 4.6, 10.4 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 144.2, 139.0, 138.4, 138.2, 128.9, 128.8, 128.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6, 127.5, 126.9, 126.8, 87.1, 83.6, 82.3, 72.2, 71.4, 65.9, 62.5, 59.3, 57.5; HRMS calcd for C₄₅H₄₄NO₃ [M + H]⁺ 646.3321, found: 646.3326.

((2S,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)pyrrolidin-2-yl)methanol (22a). The trityl ether 21a (750 mg, 1.16 mmol) was dissolved in dry CH₂Cl₂ (8 mL) and cooled to 0 °C and then TFA (0.44 mL, 5.80 mmol) was added dropwise via a syringe. After 30 min, solvent was evaporated and the residue was dissolved in EtOAc (5 mL) and aq. NaHCO₃ (5 mL) was added. The compound was extracted using EtOAc (3 × 5 mL) and extracts were dried over Na₂SO₄. The residue resulting after concentration was purified by column chromatography and 355 mg (76%) of alcohol 22a was obtained as a pale yellow oil: R_f = 0.4 (hexane–EtOAc = 3 : 1); [α]²⁸_D = +36.4 (c 1.40, CH₂Cl₂); IR (neat) ν_max: 3400, 3029, 2923, 2855, 1670, 1495, 1453, 1362, 1072 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.34–7.25 (m, 15H), 4.68 (d, J = 12.0 Hz, 1H), 4.54–4.45 (m, 3H), 4.16–4.08 (m, 3H), 3.88 (d, J = 10.7 Hz, 1H), 3.76 (dd, J = 3.3, 12.0 Hz, 1H), 3.58 (d, J = 12.8 Hz, 1H), 3.35 (dd, J = 6.1, 8.9 Hz, 1H), 3.13 (br s, 1H), 2.50 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 137.7, 137.6, 129.5, 128.6, 128.0, 127.8, 127.7, 83.5, 81.7, 72.2, 72.0, 66.7, 59.5, 55.5; HRMS calcd for C₂₆H₃₀NO₃ [M + H]⁺ 404.2226, found: 404.2226.

(2R,3S,4S)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diyl diacetate (24a). The dimesylate compound 20a (410 mg, 0.57 mmol) and 18-crown-6 (15 mg, 0.057 mmol) were dissolved in dry DMF (5 mL) and heated to 120 °C. To this, CsOAc (655 mg, 3.42 mmol) was added in portions over 6 h and heating continued for another 2 h. Once the reaction was complete (TLC monitoring), the reaction was cooled to room temperature and the contents were poured into ice-cold water (10 mL). The target compound was extracted with EtOAc (3 × 8 mL) and extracts were washed again with ice-cold water (1 × 15 mL), brine (1 × 15 mL) and then dried over Na₂SO₄. Solvent was evaporated and the residue was purified by column chromatography to yield 243 mg (72%) of diacetate 24a as a colourless oil: R_f = 0.7 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −1.54 (c 0.65, CH₂Cl₂); IR (neat) ν_max: 3030, 2926, 1742, 1491, 1449, 1370, 1230 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.40–7.39 (m, 6H), 7.29–7.19 (m, 17H), 7.15–7.14 (m, 2H), 5.31 (q, J = 4.9 Hz, 1H), 4.65 (d, J = 11.3 Hz, 1H), 4.59 (d, J = 11.3 Hz, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.24–4.19 (m, 2H), 4.13 (dd, J = 5.2, 11.6 Hz, 1H), 4.04 (t, J = 5.2 Hz, 1H), 3.62 (q, J = 5.2 Hz, 1H), 3.36 (dd, J = 4.6, 10.4 Hz, 1H), 3.19 (dd, J = 4.9, 10.0 Hz, 1H), 2.07 (s, 3H), 1.97 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 170.7, 170.3, 143.6, 138.0, 137.8, 128.6, 128.4, 128.3, 127.9, 127.8, 127.2, 127.0, 86.7, 76.7, 74.8, 73.1, 72.9, 62.8, 62.0, 21.2, 20.9; HRMS calcd for C₄₂H₄₂NaO₇ [M + Na]⁺ 681.2828, found: 681.2829.

(2R,3R,4S)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diol (25a). The diacetate compound 24a (230 mg, 0.35 mmol) was dissolved in dry MeOH (5 mL). The solution was cooled to 0 °C and a catalytic amount of sodium was added to it. The reaction mixture was stirred with gradual warming to room temperature over 30 min, following which water (5 mL) was added. Extraction was done with EtOAc (3 × 5 mL), and the extracts were dried over Na₂SO₄. The solvent was evaporated in vacuo and the residue purified using column chromatography to obtain diol 25a (160 mg, 80%) as a colourless oil: R_f = 0.5 (hexane–EtOAc = 3 : 1); [α]²⁸_D = −5.0 (c 0.40, CH₂Cl₂); IR (neat) ν_max: 3424, 3031, 2926, 1491, 1449, 1214, 1072 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.43–7.42 (m, 6H), 7.31–7.22 (m, 17H), 7.08–7.06 (m, 2H), 4.60 (s, 2H), 4.51 (d, J = 11.0 Hz, 1H), 4.33 (d, J = 11.3 Hz, 1H), 4.08 (m, 1H), 3.84 (dd, J = 1.2, 5.8 Hz, 1H), 3.79–3.74 (m, 2H), 3.64–3.61 (m, 1H), 3.35 (dd, J = 6.1, 8.8 Hz, 1H), 3.09 (dd, J = 6.1, 8.8 Hz, 1H), 2.69–2.64 (br s, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 143.8, 138.1, 137.7, 128.7, 128.6, 128.4, 128.3, 127.9, 127.2, 86.8, 78.7, 74.3, 72.4, 68.9, 64.4, 60.6; HRMS calcd for C₃₈H₃₈NaO₅ [M + Na]⁺ 597.2617, found: 597.2619.

(2R,3S,4S)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diyl dimethanesulfonate (26a). Dimesylation of diol 25a (150 mg, 0.26 mmol) was performed in the same manner as is described for 19a, to afford 156 mg (82%) of compound 25a as a thick viscous liquid: R_f = 0.5 (hexane–EtOAc = 3 : 1); [α]²⁸_D = +7.9 (c 1.20, CH₂Cl₂); IR (neat) ν_max: 3031, 1742, 1492, 1450, 1371, 1232 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.40–7.38 (m, 6H), 7.30–7.25 (m, 17H), 7.12–7.10 (m, 2H), 4.92–4.89 (m, 1H), 4.62 (s, 2H), 4.45 (d, J = 11.3 Hz, 1H), 4.27 (dd, J = 5.5, 11.0 Hz, 1H), 4.22 (dd, J = 4.9, 11.0 Hz, 1H), 4.17 (d, J = 11.3 Hz, 1H), 3.97–3.95 (m, 1H), 3.69 (dd, J = 5.5, 10.4 Hz, 1H), 3.55 (dd, J = 3.0, 11.3 Hz, 1H), 3.24 (dd, J = 5.5, 11.3 Hz, 1H), 2.97 (s, 3H), 2.84 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 137.4, 137.0, 136.9, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 81.5, 76.0, 74.0, 73.4, 72.4, 68.7, 67.6, 38.6, 37.7; HRMS calcd for C₄₀H₄₂NaO₉S₂ [M + Na]⁺ 753.2168, found: 753.2167.

(2S,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(trityloxymethyl)pyrrolidine (27a). The double nucleophilic displacement as mentioned for dimesylate 20a was carried out on 165 mg (0.23 mmol) of compound 26a to obtain 124 mg (78%) of product 27a as a pale yellow oil: R_f = 0.8 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −10.6 (c 2.45, CH₂Cl₂); IR (neat) ν_max: 3060, 3029, 1493, 1449, 1090, 1075 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.45–7.43 (m, 6H), 7.30–7.19 (m, 24H), 4.50 (s, 2H), 4.39 (d, J = 12.5 Hz, 1H), 4.34 (d, J = 12.5 Hz, 1H), 4.09 (d, J = 13.1 Hz, 1H), 3.94–3.89 (m, 2H), 3.38 (d, J = 13.1 Hz, 1H), 3.29–3.28 (m, 2H), 3.02 (d, J = 10.6 Hz, 1H), 2.87 (q, J = 5.2 Hz, 1H), 2.54 (dd, J = 5.2, 10.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 144.2, 139.0, 138.3, 128.9, 128.8, 128.7, 128.4, 128.2, 127.8, 127.7, 127.6, 126.9, 86.8, 86.0, 81.6, 71.5, 70.8, 69.1, 64.6, 59.3, 57.2; HRMS calcd for C₄₅H₄₄NO₃ [M + H]⁺ 646.3321, found: 646.3328.

((2R,3R,4R)-1-Benzyl-3,4-bis(benzyloxy)pyrrolidin-2-yl)methanol (28a). The trityl ether moiety of compound 27a (120 mg, 0.18 mmol) was deprotected using the same method as was adopted for trityl ether 21a, to afford 61 mg of compound 28a (84%) as a pale yellow oil: R_f = 0.4 (hexane–EtOAc = 3 : 1); [α]²⁸_D = −8.29 (c 2.05, CH₂Cl₂); IR (neat) ν_max: 3205, 3031, 1670, 1454, 1202, 1133 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.44–7.21 (m, 15H), 4.59–4.53 (m, 3H), 4.49–4.43 (m, 2H), 4.29 (d, J = 12.8 Hz, 1H), 4.13 (dd, J = 4.2, 7.9 Hz, 1H), 4.10–4.08 (m, 1H), 3.90 (dd, J = 8.2, 10.4 Hz, 1H), 3.83 (td, J = 3.0, 7.9 Hz, 1H), 3.71 (dd, J = 3.0, 10.1 Hz, 1H), 3.63 (br s, 1H), 3.59–3.51 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 137.5, 137.3, 131.2, 129.0, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 78.3, 73.6, 72.6, 68.1, 61.8, 59.0; HRMS calcd for C₂₆H₃₀NO₃ [M + H]⁺ 404.2226, found: 404.2223.

(2S,3R,4R)-tert-Butyl-3,4-bis(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (30a). The amine 22a (1.05 g, 2.60 mmol) was dissolved in dry CH₃OH (10 mL) and Pd(OH)₂/C (20% w/w, 50 mg) was added to it. The solution was degassed and then stirred under 1 atm H₂ (balloon) for 1 h. The catalyst was filtered through a Celite® pad and the filtrate concentrated in vacuo. The crude amine so obtained was subjected to the next step without purification.

Thus, the crude amine was dissolved in ethyl acetate (8 mL) and to this solution Boc₂O (0.63 mL, 2.73 mmol) and Na₂CO₃ (828 mg, 7.81 mmol) were added, and the reaction mixture stirred for 2 h. On complete consumption of amine (TLC monitoring), water (10 mL) was added to it. The desired compound was extracted with EtOAc (3 × 8 mL), and the extracts dried over Na₂SO₄. The solvent was evaporated using a rotary evaporator, and the residue purified by column chromatography to obtain 810 mg (75% over 2 steps) of compound 30a as a white solid: mp = 67–69 °C R_f = 0.5 (hexane–EtOAc = 4 : 1); [α]²⁸_D = +28.2 (c 1.10, CH₂Cl₂); IR (neat) ν_max: 3410, 2930, 1692, 1495, 1454, 1408, 1365, 1106 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, 2 : 1 mixture of rotamers): δ 7.37–7.25 (m, 10H, both rotamers), 4.72 (d, J = 11.6 Hz, 1H, minor rotamer), 4.61–4.49 (m, 4H, major rotamer, 3H, minor rotamer), 4.32 (d, J = 6.1 Hz, 1H, major rotamer), 4.21–4.16 (m, 2H, minor rotamer), 4.06–3.98 (m, 3H, major rotamer, 2H, minor rotamer), 3.88–3.76 (m, 2H, both rotamers), 3.62–3.59 (m, 1H, both rotamers), 3.49–3.42 (m, 1H, both rotamers), 1.45 (s, 9H, both rotamers); ¹³C NMR (125 MHz, CDCl₃, 2 : 1 mixture of rotamers): δ 156.3, 154.4, 137.7, 137.4, 128.6, 128.2, 128.0, 127.9, 127.7, 83.4, 82.2, 80.5, 80.3, 79.6, 78.9, 72.9, 72.7, 71.9, 71.7, 63.1, 61.9, 61.4, 59.0, 50.4, 48.9, 28.5; HRMS calcd for C₂₄H₃₂NO₅ [M + H]⁺ 414.2280, found: 414.2281.

(2S,3R,4R)-tert-Butyl-3,4-bis(benzyloxy)-2-vinylpyrrolidine-1-carboxylate (31a). To a well stirred suspension of CrO₃ (296 mg, 2.96 mmol) in CH₂Cl₂ (5 mL) at 0 °C were added Ac₂O (0.56 mL, 5.92 mmol), and pyridine (0.94 mL, 11.84 mmol) and stirred for 15 min. To the resulting brown suspension the alcohol 30a (765 mg, 1.85 mmol) dissolved in CH₂Cl₂ (3 mL), was added at 0 °C. The reaction mixture was stirred vigorously for 1 h with gradual warming to room temperature, following which it was filtered quickly through a short silica gel column and eluted with EtOAc (60 mL). The filtrate was concentrated using a rotavapor and the crude aldehyde was used for the next step without any further purification.

Methyltriphenylphosphonium bromide (1.39 g, 3.88 mmol) was dissolved in dry THF (4 mL) and KO^tBu (845 mg, 5.55 mmol) was added and stirred at room temperature for 1 hour. The colour of the solution became bright yellow, indicating the formation of ylide. The crude aldehyde was dissolved in dry THF (2 mL) and added dropwise to this ylide solution under N₂, at 0 °C. The reaction mixture was stirred for 3 h at room temperature. The contents were then poured into ice-cold water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic portions were washed with brine (1 × 20 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue hence obtained was purified by column chromatography to give olefin 31a (525 mg, 69% over 2 steps) as a colourless oil: R_f = 0.7 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −47.5 (c 0.80, CH₂Cl₂); IR (neat) ν_max: 3379, 2976, 1696, 1476, 1454, 1393, 1174, 1097 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, 6 : 1 mixture of rotamers): δ 7.35–7.25 (m, 10H, both rotamers), 5.82 (br s, 1H, both rotamers), 5.23–5.12 (m, 2H, both rotamers), 4.64–4.21 (m, 5H, both rotamers), 4.07–4.02 (m, 2H, both rotamers), 3.89 (br s, 1H, minor isomer), 3.65 (dd, J = 6.4, 11.6 Hz, 1H, major rotamer), 3.51 (d, J = 11.6 Hz, 1H, minor rotamer), 3.43–3.32 (m, 1H, major rotamer), 1.42 (s, 9H, both rotamers); ¹³C NMR (125 MHz, CDCl₃, 2 : 1 mixture of rotamers): δ 154.7, 138.0, 137.7, 134.4, 133.7, 128.5, 127.8, 127.7, 127.5, 116.8, 116.6, 83.4, 82.9, 79.8, 79.6, 79.0, 72.4, 72.1, 71.4, 60.6, 59.8, 48.8, 48.1, 28.4; HRMS calcd for C₂₅H₃₁NNaO₄ [M + Na]⁺ 432.2151, found: 432.2156.

(2S,3R,4R)-3,4-Bis(benzyloxy)-1-(but-3-enyl)-2-vinylpyrrolidine (32a). The protected amine 31a (500 mg, 1.22 mmol) was dissolved in dry CH₂Cl₂ (6 mL) and cooled to 0 °C. To this solution was added trifluoroacetic acid (0.47 mL, 6.11 mmol) and stirred for 6 h at room temperature. The solvent was removed in vacuo and the residue dissolved in EtOAc (5 mL). The acid was quenched by the gradual addition of aq. NaHCO₃ (5 mL) and the compound was then extracted from the aqueous layer using EtOAc (3 × 5 mL). The combined organic extracts were washed with brine (1 × 10 mL) and dried over Na₂SO₄. Concentration led to the crude amine which was used for the next step without purification.

The crude amine was dissolved in dry THF (4 mL) and cooled to 0 °C. Sodium hydride (146 mg, 60% in oil, 3.66 mmol) was added carefully to the solution, followed by the addition of butenyl bromide (0.19 mL, 1.83 mmol). When the reaction was complete (TLC monitoring), the contents were carefully poured into ice-water (5 mL). Extraction was done with EtOAc (3 × 5 mL) and the extracts were washed with brine (1 × 10 mL) and dried over Na₂SO₄. The solvent was evaporated and the residue purified by column chromatography to afford diene 32a (322 mg, 73% over 2 steps) as a colourless oil: R_f = 0.7 (hexane–EtOAc = 4 : 1); [α]²⁸_D = + 23.33 (c 1.50, CH₂Cl₂); IR (neat) ν_max: 2922, 1697, 1640, 1454, 1363, 1206, 1096 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.34–7.25 (m, 10H), 5.97–5.90 (m, 1H), 5.81–5.73 (m, 1H), 5.27 (dd, J = 1.8, 3.7 Hz, 1H), 5.25 (dd, J = 1.8, 10.4 Hz, 1H), 5.02 (ddd, J = 1.5, 3.0, 17.1 Hz, 1H), 4.96 (dt, J = 0.9, 10.1 Hz, 1H), 4.57–4.50 (m, 2H), 4.42 (s, 2H), 4.06 (dt, J = 2.4, 6.7 Hz, 1H), 3.89 (dd, J = 2.4, 5.8 Hz, 1H), 3.51 (dd, J = 6.7, 9.8 Hz, 1H), 3.07 (dd, J = 5.5, 9.1 Hz, 1H), 2.77–2.71 (m, 1H), 2.25–2.12 (m, 4H); ¹³C NMR (125 MHz, CDCl₃): δ 138.3, 138.1, 136.7, 135.7, 128.5, 128.3, 127.9, 127.8, 127.7, 127.6, 119.1, 115.5, 85.2, 82.5, 71.9, 71.6, 71.0, 57.5, 53.3, 32.3; HRMS calcd for C₂₄H₃₀NO₂[M + H]⁺ 364.2277, found: 364.2276.

(1R,2R,8aS)-1,2-Bis(benzyloxy)-1,2,3,5,6,8a-hexahydroindolizine (33a). The diene (320 mg, 0.89 mmol) was dissolved in dry toluene (8 mL), and to this solution was added PTSA (344 mg, 1.79 mmol), and the Grubbs' second generation catalyst (38 mg, 0.045 mmol). The mixture was heated to reflux for 8 h, following which it was treated with aq. NaHCO₃ solution (5 mL). Extraction was done with EtOAc (3 × 5 mL). Organic extracts were washed with brine (1 × 10 mL), dried and concentrated. The residue was purified by column chromatography to afford 33a as a colourless oil (240 mg, 81%): R_f = 0.5 (hexane–EtOAc = 4 : 1); [α]²⁸_D = + 13.3 (c 1.10, CH₂Cl₂); IR (neat) ν_max: 2922, 1697, 1640, 1454, 1363, 1206, 1096 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.34–7.25 (m, 10H), 5.97–5.90 (m, 1H), 5.81–5.73 (m, 1H), 4.71–4.63 (m, 2H), 4.57–4.50 (m, 2H), 4.06 (dt, J = 2.4, 6.7 Hz, 1H), 3.89 (dd, J = 2.4, 5.8 Hz, 1H), 3.51 (dd, J = 6.7, 9.4 Hz, 1H), 3.34 (m, 1H), 3.25 (m, 1H), 3.07 (dd, J = 5.8, 9.4 Hz, 1H), 2.77–2.71 (m, 1H), 2.25–2.12 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 138.3, 138.1, 136.7, 135.7, 128.5, 128.3, 127.9, 127.8, 127.7, 127.6, 119.1, 115.5, 85.2, 82.5, 71.9, 71.6, 71.0, 57.5, 53.3; HRMS calcd for C₂₂H₂₅NNaO₂[M + Na]⁺ 358.1783, found: 358.1786.

(2R,3R,4R)-tert-Butyl-3,4-bis(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (30b). The procedure used for converting 22a to 30a was followed to obtain 30b (215 mg, 70% over 2 steps) from 28a (300 mg, 0.74 mmol) as a colourless oil: R_f = 0.4 (hexane–EtOAc = 3 : 1); [α]²⁸_D = −16.5 (c 2.85, CH₂Cl₂); IR (neat) ν_max: 3419, 2928, 1691, 1454, 1400, 1366, 1170, 1098 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.36–7.24 (m, 10H), 4.62–4.45 (m, 4H), 4.04–3.97 (m, 2H), 3.84–3.75 (m, 3H), 3.67–3.64 (m, 1H), 3.49–3.47 (m, 1H), 1.46 (s, 9H); ¹³C NMR (125 MHz, CDCl₃): δ 156.8, 137.4, 128.6, 128.0, 127.8, 82.9, 80.6, 80.3, 71.7, 71.6, 65.3, 65.2, 51.3, 28.5; HRMS calcd for C₂₄H₃₁NNaO₅[M + Na]⁺ 436.2100, found: 436.2100.

(2R,3R,4R)-tert-Butyl-3,4-bis(benzyloxy)-2-vinylpyrrolidine-1-carboxylate (31b). The same procedure used for obtaining 31a from 30a was followed to obtain 31b (145 mg, 70% over 2 steps) from 30b (210 mg, 0.51 mmol) as a colourless oil: R_f = 0.7 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −2.85 (c 1.40, CH₂Cl₂); IR (neat) ν_max: 2976, 2928, 1695, 1496, 1454, 1393, 1365, 1171, 1098 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.36–7.25 (m, 10H), 5.85 (br s, 1H), 5.29–5.09 (m, 2H), 4.61–4.41 (m, 4H), 4.21 (br s, 1H), 4.06–4.01 (m, 1H), 3.89 (br s, 1H), 3.78–3.63 (m, 1H), 3.52–3.50 (m, 1H), 1.42 (s, 9H); ¹³C NMR (125 MHz, CDCl₃): δ 154.7, 137.7, 137.1, 128.5, 127.9, 127.7, 115.7, 86.7, 85.4, 81.2, 80.1, 79.8, 79.7, 71.8, 71.7, 71.6, 71.4, 65.3, 51.0, 49.9, 29.7, 28.5; HRMS calcd for C₂₅H₃₁NNaO₄ [M + Na]⁺ 432.2151, found: 432.2152.

(2R,3R,4R)-3,4-Bis(benzyloxy)-1-(but-3-enyl)-2-vinylpyrrolidine (32b). The procedure used for converting 31a to 32a was used to obtain 32b (90 mg) from 31b (140 mg, 0.34 mmol) in 73% yield as a colourless oil: R_f = 0.4 (hexane–EtOAc = 9 : 1); [α]²⁸_D = +11.0 (c 1.00, CH₂Cl₂); IR (neat) ν_max: 2922, 1695, 1638, 1496, 1454, 1363, 1206, 1096 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.35–7.24 (m, 10H), 5.86–5.70 (m, 2H), 5.12–5.00 (m, 4H), 4.64–4.51 (m, 4H), 3.76 (dd, J = 4.6, 6.8 Hz, 1H), 3.70–3.61 (m, 3H), 3.57 (dd, J = 2.9, 4.6 Hz, 1H), 2.99 (br s, 1H), 2.69 (br s, 1H), 2.34–2.17 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 135.6, 135.4, 132.7, 132.8, 128.0, 127.6, 127.5, 84.5, 79.8, 76.4, 67.8, 63.9, 60.7, 32.7; HRMS calcd for C₂₄H₃₀NO₂[M + H]⁺ 364.2277, found: 364.2272.

(1R,2R,8aR)-1,2-Bis(benzyloxy)-1,2,3,5,6,8a-hexahydroindolizine (33b). The diene 32b was subjected to ring closing metathesis using the same procedure as described for diene 32a (80 mg, 0.22 mmol) to obtain 33b (58 mg, 79%) as a colorless oil: R_f = 0.7 (hexane–EtOAc = 4 : 1); [α]²⁸_D = + 11.0 (c 1.00, CH₂Cl₂); IR (neat) ν_max: 2922, 1695, 1638, 1496, 1454, 1363, 1206, 1096 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.34–7.25 (m, 10H), 5.91–5.88 (m, 1H), 5.82–5.78 (m, 1H), 4.71–4.68 (m, 2H), 4.63–4.52 (m, 2H), 4.35 (dd, J = 2.4, 6.5 Hz, 1H), 4.26 (dd, J = 3.1, 8.2 Hz, 1H), 3.92 (br s, 1H), 3.50 (dd, J = 6.7, 9.8 Hz, 1H), 3.39 (d, J = 11.2 Hz, 1H), 3.14 (d, J = 11.2 Hz, 1H), 2.97 (m, 1H), 2.50 (dd, J = 5.5, 8.2 Hz, 1H), 2.25 (J = 5.5, 8.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 138.3, 138.2, 136.5, 135.8, 128.5, 128.3, 127.9, 127.8, 127.7, 127.6, 121.2, 119.6, 82.3, 81.3, 71.9, 71.6, 71.0, 57.6, 53.5; HRMS calcd for C₂₂H₂₅NNaO₂[M + Na]⁺ 358.1783, found: 358.1782.

(4R,5S,6R)-4,5-Bis(benzyloxy)-6-(trityloxymethyl)tetrahydro-2H-pyran-2,3-diol (17b). The olefin 16b (3.00 g, 5.28 mmol) was subjected to dihydroxylation using the same procedure as 16a, and the diol 17b was obtained as a colourless oil: R_f = 0.4 (hexane–EtOAc = 2 : 1); IR (neat) ν_max: 3402, 3060, 3030, 2925, 1491, 1448, 1077 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, 1.4 : 1 mixture of diols): δ 7.40–7.36 (m, 6H, both isomers), 7.33–7.19 (m, 17H, both isomers), 7.13–7.08 (m, 2H, both isomers), 5.28 (d, J = 3.7 Hz, 1H, major isomer), 4.73–4.63 (m, 2H major isomer, 4H minor isomer), 4.48–4.40 (m, 1H major isomer, 2H minor isomer), 4.13 (t, J = 6.7 Hz, 1H, major isomer), 4.09 (dd, J = 3.6, 10.2 Hz, 1H, minor isomer), 4.04 (br s, 1H, major isomer), 3.97 (d, J = 2.7 Hz, 1H, major isomer), 3.78 (dd, J = 7.9, 9.5 Hz, 1H, minor isomer), 3.75 (dd, J = 2.7, 10.0 Hz, 1H, major isomer), 3.49–3.47 (m, 2H, minor isomer), 3.42–3.38 (m, 2H, major isomer), 3.29 (t, J = 10.2 Hz, 1H, minor isomer) 3.24–3.21 (m, 1H, major isomer), 2.97 (br s, 1H, major isomer), 2.55 (br s, 1H minor isomer), 2.33 (br s, 1H, major isomer); 1.88 (br s, 1H, minor isomer) ¹³C NMR (125 MHz, CDCl₃): δ 143.8, 138.5, 138.4, 128.7, 128.6, 128.2, 128.1, 127.9, 127.8, 127.5, 127.2, 97.3, 92.8, 87.3, 87.2, 82.1, 79.0, 74.6, 74.1, 73.1, 72.9, 72.4, 70.2, 68.9, 62.5, 62.2; HRMS calcd for C₃₉H₃₈NaO₆ [M + Na]⁺ 625.2566, found: 625.2563.

(2R,3S,4S)-3,4-Bis(benzyloxy)-5-oxo-1-(trityloxy)pentan-2-yl formate (18b). Following the procedure for oxidative cleavage of diol 17a, crude diol 17b was converted to 18b (2.20 g, 70% over 2 steps) as a colourless oil: R_f = 0.5 (hexane–EtOAc = 3 : 1); [α]²⁸_D = −7.8 (c 0.90, CH₂Cl₂); IR (neat) ν_max: 3060, 3031, 2928, 1728, 1491, 1449, 1170, 1070 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 9.55 (s, 1H), 8.00 (s, 1H), 7.39–7.37 (m, 6H), 7.31–7.22 (m, 17H), 7.14–7.12 (m, 2H), 5.40 (dd, J = 5.1, 10.0 Hz, 1H), 4.60–4.55 (m, 2H), 4.40–4.46 (m, 2H), 4.15 (t, J = 4.9 Hz, 1H), 3.85 (dd, J = 5.1, 2.0 Hz, 1H), 3.38 (dd, J = 5.1, 10.3 Hz, 1H), 3.32 (dd, J = 5.1, 10.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 201.6, 160.3, 143.4, 137.1, 136.7, 129.0, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.8, 127.3, 87.2, 82.2, 77.7, 74.4, 72.9, 72.1, 61.7; HRMS calcd for C₃₉H₃₆NaO₆ [M + Na]⁺ 623.2410, found: 623.2416.

(2R,3S,4R)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diol (19b). In the same way as 18a was reduced using NaBH₄, the aldehyde 18b (2.45 g, 4.08 mmol) was reduced to furnish 1.92 g (82%) of 19b as a colourless oil: R_f = 0.3 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −5.40 (c 2.05, CH₂Cl₂); IR (neat) ν_max: 3437, 3060, 3030, 2936, 2876, 1491, 1449, 1074 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.51–7.43 (m, 6H), 7.36–7.23 (m, 17H), 7.12–7.10 (m, 2H), 4.68–4.61 (m, 3H), 4.37 (d, J = 10.6 Hz, 1H), 4.01 (t, J = 5.8 Hz, 1H), 3.90 (dd, J = 1.4, 6.4 Hz, 1H), 3.85 (dd, J = 3.9, 11.9 Hz, 1H), 3.72 (dd, J = 3.3, 11.9 Hz, 1H), 3.67–3.65 (m, 1H), 3.37 (dd, J = 6.1, 9.2 Hz, 1H) 3.12 (dd, J = 7.0, 9.2 Hz, 1H); 2.43 (br s, 1H), 2.30 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 143.8, 138.0, 137.7, 128.7, 128.6, 128.4, 128.3, 128.0, 127.9, 127.2, 86.9, 79.5, 77.2, 74.6, 72.5, 70.0, 64.7, 60.8; HRMS calcd for C₃₈H₃₈NaO₅ [M + Na]⁺ 597.2617, found: 597.2615.

(2R,3R,4R)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diyl dimethanesulfonate (20b). The diol 19b (1.20 g, 2.08 mmol) was converted to its mesylate in the same manner as diol 19a, to yield 1.42 g (95%) of 20b as a colourless viscous liquid: R_f = 0.4 (hexane–EtOAc = 3 : 1); [α]²⁸_D = +16.4 (c 0.65, CH₂Cl₂); IR (neat) ν_max: 3031, 1492, 1450, 1357, 1176 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.45–7.14 (m, 25H), 5.10–5.07 (m, 1H), 3.65–3.58 (m, 3H), 4.54 (dd, J = 2.8, 11.4 Hz, 1H), 4.44 (d, J = 10.9 Hz, 1H), 4.31 (dd, J = 3.7, 11.4 Hz, 1H), 3.92 (dd, J = 3.7, 8.3 Hz, 1H), 3.79–3.77 (m, 1H), 3.46 (dd, J = 4.0, 10.6 Hz, 1H), 3.38 (dd, J = 2.8, 6.6 Hz, 1H), 2.98 (s, 3H), 2.88 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 143.1, 137.3, 136.9, 129.5, 129.1, 128.6, 128.4, 128.1, 127.4, 87.7, 80.6, 76.6, 75.0, 72.5, 67.4, 63.4, 39.0, 37.6; HRMS calcd for C₄₀H₄₂NaO₉S₂ [M + Na]⁺ 753.2168, found: 753.2165.

(2S,3S,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(trityloxymethyl)pyrrolidine (21b). The same method for double nucleophilic displacement for 20a was applied to compound 20b (1.10 g, 1.53 mmol) to afford compound 21a (750 mg, 76%) as a yellow oil: R_f = 0.8 (hexane–EtOAc = 4 : 1); [α]²⁸_D = +15.0 (c 0.40, CH₂Cl₂); IR (neat) ν_max: 2923, 1492, 1450, 1355, 1173 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.45–7.41 (m, 6H), 7.31–7.20 (m, 24H), 4.61 (s, 2H), 4.49–4.43 (m, 2H), 3.98 (d, J = 13.2 Hz, 1H), 3.86–3.80 (m, 2H), 3.52 (d, J = 13.2 Hz, 1H), 3.09–3.05 (m, 4H), 2.65 (t, J = 8.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 143.1, 137.3, 136.9, 128.6, 128.5, 128.4, 128.2, 128.1, 127.4, 87.7, 80.6, 82.3, 76.6, 75.0, 72.5, 67.4, 63.4; HRMS calcd for C₄₅H₄₄NO₃ [M + H]⁺ 646.3321, found: 646.3323.

((2S,3S,4R)-1-Benzyl-3,4-bis(benzyloxy)pyrrolidin-2-yl)methanol (22b). The trityl ether 21b (740 mg, 1.14 mmol) was subjected to deprotection following the same procedure as used for 21a, and 375 mg (82%) of alcohol 22b was obtained as a pale yellow oil: R_f = 0.4 (hexane–EtOAc = 3 : 1); [α]²⁸_D = −25.7 (c 0.35, CH₂Cl₂); IR (neat) ν_max: 3332, 3032, 2925, 1672, 1496, 1455, 1202, 1133 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.41–7.25 (m, 15H), 4.69–4.63 (m, 2H), 4.59–4.55 (m, 2H), 4.44 (d, J = 12.6 Hz, 1H), 4.33 (d, J = 12.6 Hz, 1H), 4.19–4.14 (m, 2H), 3.66 (dd, J = 5.1, 13.1 Hz, 1H), 3.62–3.60 (m, 1H), 3.54-3.49 (m, 1H), 3.25 (dd, J = 3.7, 12.6 Hz, 1H), 2.50 (br s,1H); ¹³C NMR (125 MHz, CDCl₃): δ 136.9, 131.0, 130.3, 129.4, 128.8, 128.5, 128.1, 128.0, 78.4, 75.6, 73.3, 73.0, 71.2, 62.7, 58.7, 55.1; HRMS calcd for C₂₆H₃₀NO₃ [M + H]⁺ 404.2226, found: 404.2222.

(2R,3R,4S)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diyl diacetate (24b). The dimesylate 20b (410 mg, 0.57 mmol) was subjected to treatment with CsOAc in the same manner as 20a, to yield 254 mg (68%) of diacetate 24b as a colourless oil: R_f = 0.5 (hexane–EtOAc = 4 : 1); [α]²⁸_D = +36.4 (c 1.40, CH₂Cl₂); IR (neat) ν_max: 3030, 1742, 1491, 1449, 1370, 1230 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.42–7.36 (m, 4H), 7.30–7.20 (m, 19H), 7.13–7.09 (m, 2H), 5.45–5.42 (m, 1H), 4.64–4.52 (m, 3H), 4.46 (d, J = 11.7 Hz, 1H), 4.40 (dd, J = 3.4, 12.0 Hz, 1H), 4.16–4.10 (m, 1H), 3.94 (t, J = 5.4 Hz, 1H), 3.72 (dd, J = 4.8, 8.6 Hz, 1H), 3.39 (dd, J = 6.0, 10.3 Hz, 1H), 3.32 (dd, J = 2.8, 10.3 Hz, 1H), 2.11 (s, 3H), 1.99 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 170.0, 143.8, 137.8, 128.7, 128.4, 128.3, 128.2, 128.0, 127.8, 127.1, 86.6, 76.8, 76.5, 75.4, 73.6, 72.3, 72.2, 72.1, 63.0, 62.6, 21.2, 21.0; HRMS calcd for C₄₂H₄₂NaO₇ [M + Na]⁺ 681.2828, found: 681.2829.

(2R,3S,4S)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diol (25b). The diacetate 24b (230 mg, 0.35 mmol) was subjected to hydrolysis in the same way as 24a, to obtain diol 25b (150 mg, 75%) as a colourless oil: R_f = 0.5 (hexane–EtOAc = 3 : 1); [α]²⁸_D = −2.06 (c 1.45, CH₂Cl₂); IR (neat) ν_max: 3430, 3060, 3030, 2878, 1491, 1449, 1214, 1070 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.44–7.41 (m, 6H), 7.33–7.22 (m, 17H), 7.12–7.11 (m, 2H), 4.64 (d, J = 11.1 Hz, 1H), 4.58 (d, J = 11.4 Hz, 1H), 4.51 (d, J = 11.4 Hz, 1H), 4.47 (d, J = 11.1 Hz, 1H), 4.01 (td, J = 3.4, 6.3 Hz, 1H), 3.82 (dd, J = 4.3, 11.7 Hz, 1H), 3.79–3.75 (m, 2H), 3.71 (dd, J = 4.3, 8.5 Hz, 1H), 3.39 (dd, J = 3.4, 9.7 Hz, 1H), 3.29 (dd, J = 6.6, 9.7 Hz, 1H), 2.73 (br s, 1H), 2.40 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 143.8, 138.0, 137.9, 128.7, 128.5, 128.4, 128.1, 127.9, 127.8, 127.2, 86.9, 79.5, 79.3, 73.9, 72.0, 71.2, 64.7, 61.1; HRMS calcd for C₃₈H₃₈NaO₅ [M + Na]⁺ 597.2617, found: 597.2617.

(2R,3R,4S)-2,3-Bis(benzyloxy)-5-(trityloxy)pentane-1,4-diyl dimethanesulfonate (26b). Dimesylation of diol 25b (150 mg, 0.26 mmol) was performed in the same way as described for 19a to afford 160 mg (87%) of compound 26b as a thick viscous liquid: R_f = 0.5 (hexane–EtOAc = 3 : 1); [α]²⁸_D = −8.08 (c 2.65, CH₂Cl₂); IR (neat) ν_max: 3400, 3061, 2934, 2874, 1597, 1492, 1449, 1357, 1175, 1095, 917 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.41–7.39 (m, 4H), 7.34–7.22 (m, 19H), 7.17–7.15 (m, 2H), 5.03 (br s, 1H), 4.66 (d, J = 11.0 Hz, 1H), 4.61 (d, J = 11.0 Hz, 1H), 4.47–4.40 (m, 3H), 4.20 (dd, J = 2.7, 6.1 Hz, 1H), 3.87–3.81 (m, 2H), 3.73–3.71 (m, 2H), 2.91 (s, 3H), 2.78 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 143.1, 137.4, 137.3, 128.8–127.4 (m, aromatic C), 87.4, 81.5, 81.4, 77.9, 77.8, 74.7, 74.5, 73.5, 69.7, 63.6, 38.7, 38.4; HRMS calcd for C₄₀H₄₂NaO₉S₂ [M + Na]⁺ 753.2168, found: 753.2166.

(2S,3S,4R)-1-Benzyl-3,4-bis(benzyloxy)-2-(trityloxymethyl)pyrrolidine (27b). The double nucleophilic displacement as mentioned for dimesylate 20a was done on 165 mg (0.23 mmol) of compound 26a to obtain 120 mg (81%) of product 27b as a pale yellow oil: R_f = 0.8 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −18.2 (c 0.55, CH₂Cl₂); IR (neat) ν_max: 2923, 2854, 1664, 1492, 1448, 1344, 1152, 1064 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.45–7.44 (m, 6H), 7.30–7.17 (m, 24H), 4.65 (d, J = 12.0 Hz, 1H), 4.53 (d, J = 12.0 Hz, 1H), 4.49–4.43 (m, 1H), 4.10 (t, J = 5.0 Hz, 1H), 3.99 (d, J = 13.7 Hz, 1H), 3.92 (dd, J = 6.3, 10.6 Hz, 1H), 3.52–3.47 (m, 3H), 3.10 (dd, J = 6.0, 11.7 Hz, 1H), 3.02 (dd, J = 5.7, 10.6 Hz, 1H), 2.58 (dd, J = 6.6, 10.6 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 144.4, 139.4, 138.8, 128.9, 128.7, 128.3, 128.2, 127.8, 127.4, 127.3, 126.9, 126.8, 87.0, 78.7, 77.6, 72.9, 71.6, 65.3, 63.5, 59.9, 54.9; HRMS calcd for C₄₅H₄₄NO₃ [M + H]⁺ 646.3321, found: 646.3324.

((2R,3S,4R)-1-Benzyl-3,4-bis(benzyloxy)pyrrolidin-2-yl)methanol (28b). The trityl ether of compound 27b (120 mg, 0.18 mmol) was deprotected using the same method as for trityl ether 21a, to afford 60 mg of compound 28b (83%) as a pale yellow oil: R_f = 0.4 (hexane–EtOAc = 3 : 1); [α]²⁸_D = +24.29 (c 0.70, CH₂Cl₂); IR (neat) ν_max: 3424, 3292, 2865, 1601, 1494, 1453, 1117, 1045, 1027 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.35–7.20 (m, 15H), 4.55 (d, J = 12.0 Hz, 1H), 4.51–4.42 (m, 3H), 4.14–4.09 (m, 2H), 4.01 (d, J = 6.1 Hz, 1H), 3.97–3.93 (m, 1H), 3.76 (br s, 2H), 3.45 (dd, J = 3.4, 7.1 Hz, 1H), 3.37 (dd, J = 3.7, 9.7 Hz, 1H), 3.27–3.24 (m, 1H), 3.21 (dd, J = 7.4, 9.7 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 140.1, 138.3, 138.1, 137.6, 128.5, 128.4, 128.3, 128.2, 127.8, 127.7, 127.6, 127.4, 126.9, 78.9, 77.8, 73.4, 71.8, 71.3, 67.8, 61.6, 58.4, 52.7; HRMS calcd for C₂₆H₃₀NO₃ [M + H]⁺ 404.2226, found: 404.2224.

(2S,3R,4R)-tert-Butyl-3,4-bis(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (34a). The amine 22b (1.05 g, 2.60 mmol) was dissolved in dry CH₃OH (10 mL) and Pd(OH)₂/C (20% w/w, 50 mg) was added to it. The solution was degassed and then stirred under 1 atm H₂ (balloon) for 1 h. The catalyst was filtered through a Celite® pad and the filtrate was concentrated in vacuo. The crude amine obtained was subjected to the next step without purification. The crude amine was dissolved in ethyl acetate (8 mL) and to this solution, Boc₂O (0.63 mL, 2.73 mmol) and Na₂CO₃ (828 mg, 7.81 mmol) were added and the reaction mixture was stirred for 2 h. On complete consumption of amine (TLC monitoring), water (10 mL) was added. The compound was extracted with EtOAc (3 × 8 mL), and the extracts dried over Na₂SO₄. The solvent was evaporated using rotary evaporator, and the residue purified by column chromatography to obtain 772 mg (74% over 2 steps) of compound 34a as a white solid: mp = 67–69 °C; R_f = 0.5 (hexane–EtOAc = 4 : 1); [α]²⁸_D = +5.12 (c 2.15, CH₂Cl₂); IR (neat) ν_max: 3447, 2928, 2867, 1694, 1496, 1454, 1394, 1365, 1106 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, 1.7 : 1 mixture of rotamers): δ 7.32–7.22 (m, 10H, both rotamers), 4.46–4.41 (m, 3H, both rotamers), 4.21 (br s, 1H, major rotamer), 4.11–3.97 (m, 2H, both rotamers), 3.90–3.86 (m, 2H major rotamer, 3H minor rotamer), 3.75 (br s, 1H, major rotamer), 3.50–3.45 (m, 2H, both rotamers), 3.02 (br s, 1H, minor rotamer), 1.47–1.40 (m, 9H, both rotamers); ¹³C NMR (125 MHz, CDCl₃): δ 155.8, 138.0, 137.7, 137.0, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9, 127.6, 80.6, 80.3, 78.2, 78.0, 77.8, 77.5, 73.4, 71.9, 71.7, 68.6, 68.4, 64.4, 63.0, 61.8, 61.4, 28.4; HRMS calcd for C₂₄H₃₂NO₅ [M + H]⁺ 414.2280, found: 414.2281.

(2S,3S,4R)-tert-Butyl-3,4-bis(benzyloxy)-2-((R)-1-hydroxyallyl)pyrrolidine-1-carboxylate (35a). To a well stirred suspension of CrO₃ (296 mg, 2.96 mmol) in CH₂Cl₂ (5 mL) at 0 °C were added Ac₂O (0.56 mL, 5.92 mmol), and pyridine (0.94 mL, 11.84 mmol) and stirred for 15 min. To the resulting brown suspension, the alcohol 34a (765 mg, 1.85 mmol) dissolved in CH₂Cl₂ (3 mL) was added at 0 °C. The reaction mixture was stirred vigorously for 1 h with gradual warming to room temperature, following which it was filtered quickly through a short silica gel column and eluted with EtOAc (60 mL). The filtrate was concentrated using a rotavapor and the crude aldehyde was used for the next step without any further purification. R_f = 0.6 (hexane–EtOAc = 4 : 1). The aldehyde was dissolved in dry THF (4 mL) and cooled to 0 °C. Vinylmagnesium bromide (5.55 mL, 5.55 mmol, 1.0 M solution in THF) was added to this solution and stirred at room temperature for 2 h. The contents were then poured into saturated NH₄Cl solution (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic portions were washed with brine (1 × 20 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue hence obtained was purified by column chromatography to give olefin 35a (515 mg, 69% over 2 steps) as a colourless oil: R_f = 0.3 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −47.5 (c 0.80, CH₂Cl₂); IR (neat) ν_max: 3379, 2976, 1696, 1476, 1454, 1393, 1174, 1097 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, 3 : 1 mixture of rotamers): δ 7.36–7.28 (m, 10H, both rotamers), 5.99–5.92 (m, 1H, both rotamers), 5.38–5.14 (m, 2H, both rotamers), 4.80–4.73 (m, 1H, both rotamers), 4.64–4.41 (m, 5H, both rotamers), 4.35–4.26 (m, 1H, both rotamers), 4.15–4.00 (m, 2H, major rotamer, 1H minor rotamer), 3.82–3.81 (m, 1H, minor isomer), 3.63–3.48 (m, 2H, both rotamers), 1.47 (s, 9H, minor rotamer), 1.44 (s, 9H, major rotamer); ¹³C NMR (125 MHz, CDCl₃, 3 : 1 mixture of rotamers): δ 156.3, 154.4, 137.7, 137.4, 128.6, 128.2, 128.0, 127.9, 127.7, 83.4, 82.4, 80.5, 80.3, 79.6, 78.9, 72.9, 72.7, 71.9, 71.7, 63.1, 61.9, 61.4, 59.0, 50.4, 48.9, 28.5; HRMS calcd for C₂₆H₃₄NO₅ [M + H]⁺ 440.2437, found: 440.2436.

(2S,3S,4R)-1-Allyl-3,4-bis(benzyloxy)-2-((R)-1-(benzyloxy)allyl)pyrrolidine (40a). To a stirred solution of alcohol 35a (500 mg, 1.14 mmol) in dry cyclohexane–CH₂Cl₂ (2 : 1, 8 mL), was added benzyl trichloroacetimidate (2.28 mL, 1 M solution in hexane), followed by triflic acid (50 μL), and stirred at room temperature for 2 h. The reaction mixture was quenched using aq. NaHCO₃ (5 mL) and extraction was done using EtOAc (3 × 5 mL). Organic extracts were dried and concentrated and the crude residue was dissolved in dry CH₂Cl₂ (5 mL). After cooling to 0 °C, CF₃CO₂H (0.45 mL, 5.70 mmol) was added and the reaction mixture stirred at room temperature for 6 h. The solvent was removed by evaporation and crude residue was dissolved in dry THF (5 mL) and cooled to 0 °C. To the solution was added butenyl bromide (0.3 mL, 2.28 mmol) followed by NaH (135 mg, 3.42 mmol, 60% in oil), and stirred with gradual warming to room temperature over 4 h. The solution was poured carefully over ice-water and extraction was done using EtOAc (3 × 5 mL). Organic extracts were dried and concentrated and the crude residue was subjected to column chromatography to furnish 40a (300 mg, 56% over 3 steps) as a pale yellow oil: R_f = 0.6 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −4.8 (c 1.40, CH₂Cl₂); IR (neat) ν_max: 2922, 1695, 1638, 1496, 1454, 1363, 1206, 1096 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.37–7.24 (m, 15H), 5.98–5.83 (m, 2H), 5.30–5.22 (m, 1H), 5.14–5.05 (m, 1H), 4.56–4.38 (m, 6H), 4.16 (t, J = 7.2 Hz, 1H), 3.97–3.95 (m, 1H), 3.89 (dd, J = 2.0, 5.1 Hz, 1H), 3.79 (dd, J = 5.1, 13.7 Hz, 1H), 3.44 (dd, J = 5.4, 11.2 Hz, 1H), 3.15 (dd, J = 7.4, 13.7 Hz, 1H), 3.02 (dd, J = 5.1, 6.8 Hz, 1H), 2.57 (dd, J = 2.9, 11.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 135.8, 135.6, 132.3, 131.7, 129.0, 128.7, 127.6, 127.5, 119.8, 116.5, 76.4, 73.5, 68.5, 65.4, 43.3; HRMS calcd for C₂₆H₃₄NO₅ [M + H]⁺ 470.2695, found: 470.2696.

(1S,2R,8R,8aS)-1,2,8-Tris(benzyloxy)-1,2,3,5,8,8a-hexahydroindolizine (41a). The diene 40a (290 mg, 0.62 mmol) was subjected to ring closing metathesis using the same procedure as described for diene 32a to obtain 41a (220 mg, 80%) as a colorless oil: R_f = 0.4 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −4.8 (c 1.40, CH₂Cl₂); IR (neat) ν_max: 2922, 1695, 1638, 1496, 1454, 1363, 1206, 1096 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.32–7.22 (m, 15H), 5.91–5.88 (m, 1H), 5.82–5.78 (m, 1H), 4.49–4.34 (m, 7H), 4.18–4.13 (m, 1H), 4.01–3.99 (m, 2H), 3.91–3.87 (m, 1H), 3.84 (dd, J = 4.0, 8.6 Hz, 1H), 3.39 (dd, J = 2.8, 10.3 Hz, 1H), 3.32–3.30 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 138.8, 138.7, 136.4, 136.2, 128.6, 128.4, 128.3, 128.1, 128.0, 127.8, 127.6, 127.4, 127.3, 126.6, 108.7, 85.6, 83.5, 74.8, 73.4, 69.3, 58.1, 51.9; HRMS calcd for C₂₉H₃₁NNaO₃ [M + Na]⁺ 464.2202, found: 464.2201.

(2R,3S,4R)-tert-Butyl-3,4-bis(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (34b). The benzylamine 28b (450 mg, 1.12 mmol) was converted to Boc amine 34b (365 mg, 79%, colorless oil) following the procedure used to obtain 34a. R_f = 0.6 (hexane–EtOAc = 7 : 3); [α]²⁸_D = +5.1 (c 2.15, CH₂Cl₂); IR (neat) ν_max: 3447, 2928, 2867, 1694, 1496, 1454, 1394, 1365, 1106 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, 1.7 : 1 mixture of rotamers): δ 7.32–7.22 (m, 10H, both rotamers), 4.55–4.53 (m, 3H, both rotamers), 4.46–4.41 (m, 3H, both rotamers), 4.21 (br s, 1H, major rotamer), 4.11–3.97 (m, 1H, both rotamers), 3.90–3.86 (m, 1H major rotamer, 2H minor rotamer), 3.75 (br s, 1H, major rotamer), 3.50–3.45 (m, 2H, both rotamers), 3.02 (br s, 1H, minor rotamer), 1.47–1.40 (m, 9H, both rotamers); ¹³C NMR (125 MHz, CDCl₃): δ 155.8, 138.0, 137.7, 137.0, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9, 127.6, 80.6, 80.3, 78.2, 78.0, 77.8, 77.5, 73.4, 71.9, 71.7, 68.6, 68.4, 64.4, 63.0, 61.8, 61.4, 28.4; HRMS calcd for C₂₄H₃₂NO₅ [M + H]⁺ 414.2280, found: 414.2283.

(2R,3S,4R)-tert-Butyl-3,4-bis(benzyloxy)-2-((R)-1-hydroxyallyl)pyrrolidine-1-carboxylate 35b. Compound 34b (350 mg, 0.85 mmol) was subjected to oxidation and vinyl Grignard reactions, using the same procedure as described for 34a, to furnish 35b (260 mg, 70%) as a pale yellow oil: R_f = 0.7 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −1.3 (c 0.75, CH₂Cl₂); IR (neat) ν_max: 3331, 2976, 2929, 1692, 1453, 1391, 1105 cm⁻¹; ¹H NMR (500 MHz, CDCl₃, 3.5 : 1 mixture of rotamers): δ 7.36–7.18 (m, 10H, both rotamers), 6.14–6.07 (m, 1H, major rotamer), 5.70 (br s, 1H, minor rotamer), 5.32–5.05 (m, 1H, both rotamers), 4.75–4.40 (7H, both rotamers), 4.31 (t, J = 8.5 Hz, 1H, major rotamer), 4.15–4.11 (m, 1H, both rotamers), 4.06 (d, J = 4.0 Hz, 1H, minor rotamer), 4.02 (d, J = 4.0 Hz, 1H, major rotamer), 3.95 (dd, J = 2.7, 6.7 Hz, 1H, minor rotamer), 3.79 (br s, 1H, minor rotamer), 3.65–3.47 (m, 2H, major rotamer), 3.34–3.30 (m, 1H, minor rotamer), 1.41 (br s, 9H, major rotamer), 1.38 (s, 9H, minor rotamer); ¹³C NMR (125 MHz, CDCl₃): δ 154.5, 138.3, 138.0, 136.0, 135.3, 128.5–127.5 (m, aromatic), 118.5, 117.9, 80.0, 79.9, 78.7, 78.0, 77.7, 73.2, 72.2, 71.7, 71.5, 69.5, 68.7, 62.6, 61.9, 61.7, 61.5, 53.5, 28.5, 28.4; HRMS calcd for C₂₆H₃₄NO₅ [M + H]⁺ 440.2437, found: 440.2431.

(2R,3S,4R)-1-Allyl-3,4-bis(benzyloxy)-2-((R)-1-(benzyloxy)allyl)pyrrolidine (40b). Following the procedure used to convert 35a to 40a, compound 40b was obtained from 35b (250 mg, 0.57 mmol) in 61% yield (3 steps, 160 mg) as a pale yellow oil: R_f = 0.5 (hexane–EtOAc = 9 : 1); [α]²⁸_D = −6.7 (c 0.50, CH₂Cl₂); IR (neat) ν_max: 2925, 1698, 1640, 1495, 1453, 1361, 1208, 1095 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.35–7.21 (m, 15H), 6.10–5.96 (m, 2H), 5.45 (d, J = 6.8 Hz, 1H), 5.38–5.26 (m, 2H), 5.19 (d, J = 8.7 Hz, 1H), 4.90–4.52 (m, 6H), 4.31 (br s, 1H), 4.10 (dd, J = 2.5, 6.8 Hz, 1H), 3.83–3.81 (m, 1H), 3.75–3.69 (m, 2H), 3.33 (dd, J = 3.1, 5.5 Hz, 1H), 3.09–2.88 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 139.6, 137.3, 136.2, 133.1, 133.0, 130.5, 130.0, 129.3, 129.2, 127.9, 127.8, 116.8, 116.0, 84.5, 75.4, 70.9, 65.4, 46.1; HRMS calcd for C₃₁H₃₆NO₃ [M + H]⁺ 470.2695, found: 470.2691.

(1S,2R,8R,8aR)-1,2,8-Tris(benzyloxy)-1,2,3,5,8,8a-hexahydroindolizine (41b). The diene 40b (150 mg, 0.32 mmol) was subjected to ring closing metathesis using the same procedure as described for diene 32a to obtain 41b (105 mg, 77%) as a colorless oil: R_f = 0.7 (hexane–EtOAc = 4 : 1); [α]²⁸_D = −11.5 (c 0.90, CH₂Cl₂); IR (neat) ν_max: 2925, 1698, 1640, 1495, 1453, 1361, 1208, 1095 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 7.32–7.22 (m, 15H), 5.91–5.84 (m, 2H), 4.27–4.09 (m, 4H), 3.92–3.70 (m, 6H), 3.12 (dt, J = 2.1, 5.2 Hz, 1H), 3.06 (dd, J = 8.7, 14.3 Hz, 1H), 2.84–2.78 (m, 1H), 2.28–2.24 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 138.2, 138.0, 136.5, 135.8, 128.5, 128.3, 127.9, 127.8, 127.7, 127.6, 115.5, 114.0, 84.2, 82.6, 71.9, 71.3, 57.5, 53.3; HRMS calcd for C₂₉H₃₂NO₃[M + H]⁺ 442.2382, found: 442.2387.

General procedure for hydrogenation conditions to obtain compounds 23a, 23b, 1, 29, 8, 12, 9 and 13. The protected compound (50 mg) was dissolved in CH₃OH (1 mL) and 1 N HCl (1 mL) was added. Then Pd(OH)₂/C (10 mg, 20% w/w) was added and the mixture stirred under 1 atm H₂ (balloon) for 2–3 days. The catalyst was filtered out using Celite® and the filtrate stirred with Dowex (OH⁻) resin (20–30 mg) and then concentrated. The residue was purified by repeated washing with 50% EtOAc–hexane.

(2S,3R,4R)-2-(Hydroxymethyl)pyrrolidine-3,4-diol (23a). Colourless viscous liquid. Yield = 11 mg, 67%; R_f = 0.4 (EtOAc–MeOH = 19 : 1); [α]²⁸_D = −3.3 (c 0.80, H₂O); IR (neat) ν_max: 3353, 3060, 1420, 1232, 1101, 1029 cm⁻¹; ¹H NMR (500 MHz, D₂O): δ 4.10–4.12 (m, 1H), 4.06 (dd, J = Hz, 1H), 3.78 (dd, J = Hz, 1H), 3.63 (dd, J = Hz, 1H), 3.51–3.48 (m, 1H), 3.35 (dd, J = Hz, 1H), 2.53 (br s, 1H); ¹³C NMR (125 MHz, D₂O): δ 76.5, 76.3, 63.1, 58.8, 51.0; HRMS calcd for C₅H₁₂NO₃ [M + H]⁺ 134.0817, found: 134.0815.

(2S,3S,4R)-2-(Hydroxymethyl)pyrrolidine-3,4-diol (23b). Pale yellow viscous liquid. Yield = 10 mg, 64%; R_f = 0.3 (EtOAc–MeOH = 19 : 1); [α]²⁸_D = −50.8 (c 0.45, H₂O); IR (neat) ν_max: 3351, 3064, 1229, 1101, 1027 cm⁻¹; ¹H NMR (500 MHz, D₂O): δ 4.05 (m, 1H), 3.82 (dd, J = 4.9, 7.3 Hz, 1H), 3.67 (dd, J = 4.2, 12.0 Hz, 1H), 3.54–3.53 (m, 1H), 3.08 (dd, J = 4.9, 12.0 Hz, 1H), 3.00 (m, 1H), 2.72 (dd, J = 3.9, 12.0 Hz, 1H); ¹³C NMR (125 MHz, D₂O): δ 72.8, 71.2, 62.5, 61.6, 50.2; HRMS calcd for C₅H₁₂NO₃ [M + H]⁺ 134.0817, found: 134.0814.

(2R,3R,4R)-2-(Hydroxymethyl)pyrrolidine-3,4-diol (1). Colourless viscous liquid. Yield = 10 mg, 64%; R_f = 0.4 (EtOAc–MeOH = 19 : 1); [α]²⁸_D = +6.9 (c 0.50, H₂O); IR (neat) ν_max: 3349, 3062, 1237, 1100, 1028 cm⁻¹; ¹H NMR (500 MHz, D₂O): δ 4.08–4.05 (m, 1H), 3.80–3.76 (m, 1H), 3.63 (dd, J = 5.1, 12.0 Hz, 1H), 3.08–3.06 (m, 1H), 2.94 (dd, J = 5.7, 11.3 Hz, 1H), 2.79–2.76 (m, 2H); ¹³C NMR (125 MHz, D₂O): δ 76.5, 75.2, 63.8, 59.8, 48.7; HRMS calcd for C₅H₁₂NO₃ [M + H]⁺ 134.0817, found: 134.0817.

(2R,3S,4R)-2-(Hydroxymethyl)pyrrolidine-3,4-diol (29). Colourless viscous liquid. Yield = 11 mg, 67%; R_f = 0.3 (EtOAc–MeOH = 19 : 1); [α]²⁸_D = +15.5 (c 0.20, H₂O); IR (neat) ν_max: 3352, 3060, 1233, 1098, 1025 cm⁻¹; ¹H NMR (500 MHz, D₂O): δ 4.45–4.39 (m, 1H), 4.30 (dd, J = 3.5, 4.9 Hz, 1H), 3.92 (dd, J = 5.4, 11.6 Hz, 1H), 3.80 (dd, J = 7.9, 11.6 Hz, 1H), 3.68–3.66 (m, 1H), 3.49–3.45 (m, 1H), 3.16 (dd, J = 6.9, 11.6 Hz, 1H); ¹³C NMR (125 MHz, D₂O): δ 70.1, 69.8, 62.8, 57.5, 46.9; HRMS calcd for C₅H₁₂NO₃ [M + H]⁺ 134.0817, found: 134.0815.

(1R,2R,8aS)-Octahydroindolizine-1,2-diol (12). White solid. Yield = 17 mg, 72%; mp = 128–130 °C; R_f = 0.5 (EtOAc–MeOH = 9 : 1); [α]²⁸_D = +3.9 (c 0.25, MeOH); IR (neat) ν_max: 3356, 2962, 1237, 1100,cm⁻¹; ¹H NMR (500 MHz, D₂O): δ 4.35–4.32 (m, 1H), 4.20 (d, J = 3.8 Hz, 1H), 4.05 (dd, J = 5.9, 11.7 Hz, 1H), 3.69 (d, J = 11.7, 1H), 3.38–3.35 (d, J = 11.7 Hz, 1H), 3.08–3.02 (m, 1H), 2.91 (dd, J = 12.8, 3.1 Hz, 1H), 2.10–1.98 (m, 3H), 1.80–1.56 (m, 3H); ¹³C NMR (125 MHz, D₂O): δ 81.1, 77.9, 67.1, 62.5, 53.2, 25.4, 24.7, 22.7; HRMS calcd for C₈H₁₆NO₂ [M + H]⁺ 158.1181, found: 158.1179.

(1R,2R,8aR)-Octahydroindolizine-1,2-diol (8). White solid. Yield = 15 mg, 66%; mp = 98–102 °C; R_f = 0.5 (EtOAc–MeOH = 9 : 1); [α]²⁸_D = −2.5 (c 0.45, MeOH); IR (neat) ν_max: 3348, 3005, 1241, 1109, 1025 cm⁻¹; ¹H NMR (500 MHz, D₂O): δ 4.10 (m, 1H), 3.65 (m, 1H), 3.05 (m, 1H), 2.89 (dd, J = 2.4, 11.6 Hz, 1H), 2.67 (dd, J = 6.8, 11.6 Hz, 1H), 2.29–2.25 (m, 1H), 2.09–2.07 (m, 1H), 1.96–1.75 (m, 3H), 1.52–1.22 (m, 3H); ¹³C NMR (125 MHz, D₂O): δ 85.0, 77.9, 71.1, 62.5, 55.2, 29.4, 26.7, 25.7; HRMS calcd for C₈H₁₆NO₂ [M + H]⁺ 158.1181, found: 158.1181.

(1S,2R,8R,8aS)-Octahydroindolizine-1,2,8-triol (13). White solid. Yield = 13 mg, 64%; mp = 102–107 °C; R_f = 0.4 (EtOAc–MeOH = 9 : 1); [α]²⁸_D = −57.5 (c 0.70, MeOH); IR (neat) ν_max: 3360, 3008, 1237, 1102, 1025 cm⁻¹; ¹H NMR (500 MHz, D₂O): δ 4.33–4.29 (m, 1H), 4.15–4.12 (m, 1H), 3.87 (dd, J = 6.0, 10.3 Hz, 1H), 3.39 (dd, J = 6.0, 11.1 Hz, 1H), 2.99–2.96 (m, 1H), 2.15–2.12 (m, 1H), 2.10–2.05 (m, 2H), 1.92–1.87 (m, 1H), 1.69–1.65 (m, 1H), 1.58–1.52 (m, 2H); ¹³C NMR (125 MHz, D₂O): δ 71.0, 69.9, 67.1, 63.5, 60.2, 52.2, 19.6; HRMS calcd for C₈H₁₆NO₃ [M + H]⁺ 174.1130, found: 174.1129.

(1S,2R,8R,8aR)-Octahydroindolizine-1,2,8-triol (9). White solid. Yield = 12 mg, 62%; mp = 139–141 °C; R_f = 0.4 (EtOAc–MeOH = 9 : 1); [α]²⁸_D = −82.5 (c 0.45, MeOH); IR (neat) ν_max: 3348, 3005, 1241, 1109, 1025 cm⁻¹; ¹H NMR (500 MHz, D₂O): δ 4.32–4.29 (m, 1H), 4.28 (dd, J = 4.1, 8.0 Hz, 1H), 3.85–3.82 (m, 1H), 2.95–2.86 (m, 2H), 2.57 (dd, J = 7.5, 11.0 Hz, 1H), 2.10–2.02 (m, 1H), 1.98–1.90 (m, 2H), 1.72 (br s, 1H), 1.52 (m, 1H), 1.27–1.24 (m, 1H); ¹³C NMR (125 MHz, D₂O): δ 73.1, 69.5, 69.0, 66.2, 60.3, 51.4, 32.4, 22.7; HRMS calcd for C₈H₁₆NO₃ [M + H]⁺ 174.1130, found: 174.1132.

Acknowledgements

We thank the Department of Science and Technology, New Delhi, for a J. C. Bose National Fellowship (JCB/SR/S2/JCB-26/2010) and the Council of Scientific and Industrial Research, New Delhi, for financial support [Grant no. 02(0214)/13/EMR-II] to Y. D. V.; A. A. A. thanks the Council of Scientific Industrial Research, New Delhi, for a Senior Research Fellowship.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra for all new compounds. See DOI: 10.1039/c3ra47555g

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