Asymmetric Synthesis of (−)-Swainsonine,(+)-1, 2-Di-epi-swainsonine

Sujata Bardhan, Daniel C. Schmitt, and John A. Porco, Jr. ..... Quiroz , David Corona , Adrián Covarruvias , José Gustavo Avila-Zárraga , Moisés Romer...
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Asymmetric Synthesis of (-)-Swainsonine, (+)-1,2-Di-epi-swainsonine, and (+)-1,2,8-Tri-epi-swainsonine Karl B. Lindsay and Stephen G. Pyne* Department of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia [email protected] Received May 28, 2002

The asymmetric synthesis of (-)-swainsonine via a nonchiral pool route that involves the Sharpless epoxidation to induce chirality is reported. The key steps involve vinyl epoxide aminolysis, ringclosing metathesis, and intramolecular N-alkylation to prepare the indolizidine ring and a highly diastereoselective cis-dihydroxylation using AD-mix-R. This synthetic strategy also allowed for the diastereoselective synthesis of (+)-1,2-di-epi-swainsonine and (+)-1,2,8-tri-epi-swainsonine. Introduction Naturally occurring (-)-swainsonine 1 is a potent inhibitor of R-D-mannosidase and mannosidase II. Its anticancer and other useful biological activities are most likely associated with its ability to inhibit the processing of glycoproteins.1 These interesting properties have resulted in many studies devoted to its total synthesis and the synthesis of analogues.1,2 Interestingly, the (+)enantiomer of swainsonine3-5 is a selective and potent inhibitor of naringinase (L-rhamnosidase), with a Ki ) 0.45 µM, whereas the natural enantiomer has no inhibitory activity on this enzyme.3 Fleet has indicated the potential of (+)-swainsonine and its analogues as therapeutic agents for the treatment of tuberculosis. Thus, a synthetic strategy that could deliver either (-)- or (+)swainsonine and its analogues would be highly useful for further structure-activity studies. We report here an asymmetric synthesis of (-)-swainsonine 1 via a nonchiral pool route that involves the Sharpless asymmetric epoxidation to induce chirality. This route also allows the synthesis of (+)-1,2-di-epi- and (+)-1,2,8-tri-epi-swainsonine and thus could be readily adapted to the synthesis of (+)-swainsonine and its (-)diastereomers by using the enantiomeric tartarate ester in the asymmetric epoxidation step. Our retrosynthetic analysis of (-)-swainsonine 1 is (1) For a recent review, see: Nemr, A. E. Tetrahedron 2000, 56, 8579-8629. (2) For a recent synthesis of (-)-swainsionine that was published after this paper was submitted, see: Buschmann, N.; Ru¨ckert, A.; Blechert, S. J. Org. Chem. 2002, 67, 4325-4329. For the synthesis of analogues, see: Pearson, W. H.; Guo, L.; Jewell, T. M. Tetrahedron Lett. 2002, 43, 2175-2178. Pearson, W. H.; Guo, L. Tetrahedron Lett. 2001, 42, 8267-8271. Pearson, W. H.; Hembre, E. J. Tetrahedron Lett. 2001, 42, 8273-8276. (3) Davis, B.; Bell, A. A.; Nash, R. J.; Watson, A. A.; Griffiths, R. C.; Jones, M. G.; Smith, C.; Fleet, G. W. J. Tetrahedron Lett. 1996, 37, 8565-8569. (4) Shivlock, J. P.; Wheatley, J. R.; Nash, R. J.; Watson, A. A.; Griffiths, R. C.; Butters, T. D.; Mu¨ller, M.; Watkin, D. J.; Winkler, D. A.; Fleet, G. W. J. J. Chem. Soc., Perkin Trans. 1. 1999, 37, 27352745. (5) Oishi, T.; Iwakuma, T.; Hirama, M.; Itoˆ, S. Synlett 1995, 404406.

SCHEME 1

shown in Scheme 1. The key steps involve cis-dihydroxylation of the alkene 2, which can be prepared by a ringclosing metathesis reaction6-9 of the diene 3. In fact, the alkene 2 has been prepared via a different synthetic route (6) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (7) For the application of the ring-closing metathesis reaction to the synthesis of aza-sugars, see: (a) Huwe, C. M.; Blechert, S. Tetrahedron Lett. 1995, 36, 1621-1624. (b) Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547-550. (c) Huwe, C. M.; Blechert, S. Synthesis 1997, 61-67. (d) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998, 120, 7359-7360. (e) Lindstrom, U. M.; Somfai, P. Tetrahedron Lett. 1998, 39, 7173-7176. (f) Ovaa, H.; Stragies, R.; van der Marcel, G. A.; van Boom, J. H.; Blechert, S. Chem. Commun. 2000, 1501-1502. (g) Subramanian, T.; Lin, C.-C.; Lin, C.-C. Tetrahedron Lett. 2001, 42, 4079-4082. (h) Klitze, C. F.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 5605-5608. (i) Chandra, K. L.; Chandrasekhar, M.; Singh, V. K. J. Org. Chem. 2002, 67, 4630-4633. (8) For the application of the ring-closing metathesis reaction to the synthesis of 2,5-dihydropyrroles from dienes, see: (a) Huwe, C. M.; Velder, J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 23762378. (b) Furstner, A.; Fursterner, A.; Picquet, M.; Bruneau, C.; Dixneuf, P. H. Chem Commun. 1998, 1315-1316. (c) Cerezo, S.; Cortes, J.; Moreno-Manas, M.; Pleixats, R.; Roglans, A. Tetrahedron 1998, 54, 14869-14884. (d) Furstner, A.; Ackermann, L. Chem. Commun. 1999, 95-96. (e) Bujard, M.; Briot, A.; Gouverneur, V.; Mioskowski, C. Tetrahedron Lett. 1999, 40, 8795-8788. (f) Furstner, A.; Liebl, M.; Hill, A. F.; Wilton-Ely, J. D. E. T. Chem. Commun. 1999, 601-602. (g) Ackermann, L.; Furstner, A.; Weskamp, T.; Kohl, F. J.; Hermann, W. A. Tetrhedron Lett. 1999, 40, 4787-4790. (h) Ahmed, M.; Barrett, A. G. M.; Braddock, D. C.; Cramp, S. M.; Procopiou, P. A. Tetrahedron Lett. 1999, 40, 8657-8662. (i) Evans, P. A.; Robinson, J. E. Org. Lett. 1999, 1, 1929-1931. (j) Hunt, J. C. A.; Laurent, P.; Moody, C. J. Chem. Commun. 2000, 1771-1772. (9) Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2002, 731-734. 10.1021/jo025977w CCC: $22.00 © 2002 American Chemical Society

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Published on Web 09/28/2002

Asymmetric Synthesis of (-)-Swainsonine SCHEME 2a

a Reagents: (a) D-(-)-DIPT, Ti(OPri) , TBHP, CH Cl , 4A MS, 4 2 2 -20 °C; (b) (i) DMSO, (COCl)2, CH2Cl2, -60 °C, (ii) Et3N; (c) MePPh3Br, KHMDS, toluene; (d) allylamine, p-TsOH‚H2O (0.1 equiv); (e) (Boc)2O, Et3N, CH2Cl2; (f) Cl2(Cy3P)2RudCHPh, CH2Cl2, reflux; (g) NaH, BnBr, Bu4NI, THF, rt; (h) TFA/anisole, 0 °C; (i) Ph3P, CBr4, Et3N, 0 °C.

and has been converted to (-)-swainsonine via a cisdihydroxylation (DH) reaction, albeit with modest diasteroselection.10 Diene 3 can readily be obtained from aminolysis9,11 of the (3R,4R)-vinyl epoxide 4, followed by ring closure of the piperidine ring via an intramolecular N-alkylation reaction.12 In practice, however, the hydroxyl group of 2 was protected as its benzyl ether in our final execution of the synthesis of 1. Synthesis of (-)-Swainsonine. Commercially available 4-pentyn-1-ol was converted to the known transallylic alcohol 513 in three high-yielding steps (Scheme 2). Catalytic asymmetric epoxidation14 of 5 using (-)diisopropyl tartarate as the chiral ligand gave the (2R,3R)-epoxy alcohol 6 ([R]29D +21, c 2.2, CHCl3) in 92% (10) de Vicente, J.; Arrayas, R. G.; Canada, J.; Carretero, J. C. Synlett 2000, 53-56. (11) (a) Lindstrom, U. M.; Franckowiak, R.; Pinault, N.; Somfai, P. Tetrahedron Lett. 1997, 38, 2027-2030. (b) Lindstrom, U. M.; Somfai, P. Synthesis 1998, 109-117. (12) (a) Mulzer, J.; Dehmlow, H. J. Org. Chem. 1992, 57, 31943202. (b) Casiraghi, G.; Ulgheri, F.; Spanu, P.; Rassu, G.; Pinna, L.; Gasparri, F. G.; Belicchi, F. M.; Pelosi, G. J. Chem. Soc., Perkin Trans. 1 1993, 2991-2997. (c) Naruse, M.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 1994, 59, 1538-1364. (13) (a) Hayashi, N.; Fujiwara, K.; Murai, A. Tetrahedron 1997, 53, 12425-12468, except that REDAL was used instead of LAH in the reduction of the propargyl alcohol intermediate according to: (b) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K. J. Am. Chem. Soc. 1989, 111, 5330-5334. (14) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.

ee from 1H NMR analysis of its Mosher ester [1H NMR δ 4.51 (dd) (major diast) δ 4.56 (dd) (minor diast)]. Swern15 or TPAP16 oxidation of the primary alcohol 6 gave the corresponding aldehyde that was converted to the vinyl epoxide 7 by a Wittig olefination reaction.17 Using the Swern oxidation, compound 7 was obtained in slightly higher overall yield. Aminolysis of 7 was achieved by heating a solution of 7 in allylamine (10 equiv) with p-TsOH‚H2O (0.1 equiv) as catalyst in a sealed tube for 3 days at 105 °C.9,11 The product anti-amino alcohol 8 was obtained as a single diastereoisomer in 88% yield with clean inversion of stereochemistry at the allylic carbon. The relative stereochemistry of 8 was confirmed by conversion to its oxazolidinone derivative A (eq 1).

The 9 Hz vicinal coupling constant, J4,5, in the 1H NMR spectrum of A was consistent with 4,5-cis relative stereochemistry.9,11 Protection of the amino group of 8 as its N-Boc derivative 9 followed by a ring-closing metathesis reaction at high dilution in refluxing dichloromethane solution gave the 2,5-dihyrdopyrrole derivative 10 in excellent overall yield (94%). The secondary hydroxyl function in 10 was then protected as its benzyl ether 11.18 Treatment of 11 with trifluoroacetic acid in the presence of anisole19 (10 equiv) as a carbocation scavenger gave, after base treatment, the amino alcohol 12 in 75% yield. Cyclization of 12 by activation of the primary hydroxyl and then intramolecular N-alkylation (Ph3P, CBr4, Et3N)12 gave the indolizidine derivative 13 in 74% yield. The relatively low yield in this reaction appears to be due to the co-formation of the pyrrole derivative of 13 as a minor (5-10%) product. Catalytic cis-dihydroxylation of 13 with osmium tetraoxide/N-methylmorpholine N-oxide,20 followed by acetylation with an excess of acetic anhydride/pyridine, gave a 2:1 mixture of diacetates 14 and 15 that were readily separated by column chromatography in yields of 37% and 19%, respectively (Scheme 3). A similar poor diastereofacial selectivity has been reported in the cisdihydroxylation of the alcohol 2 and its TIPS and TBS ethers.5,10,20 However, we have found that the cis-dihydroxylation of 13 using commercially available AD-mix-R in the presence of methanesulfonamide21 followed by acetylation gave 14 in a very highly diastereoselective fashion (14/15 ) 98:2 from 1H NMR analysis of the crude (15) Mancuso, A. J.; Huang, S.; Swern, D. J. Org. Chem. 1978, 43, 2480-2482. (16) Griffith, W. P.; Ley, S. P. Aldrichim. Acta 1990, 23, 13-19. (17) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C. K.; Duyyan, M. E.; Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321-5330. (18) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron Lett. 1976, 3535-3536. (19) Medeiros, E. F. D.; Herbert, J. M.; Taylor, R. J. K.J. Chem. Soc., Perkin Trans. 1 1991, 2725-2730. (20) Mukai, C.; Sugimoto, Y.-i.; Miyazawa, K.; Yamaguchi, S.; Hanaoka, M. J. Org. Chem. 1998, 63, 6281-6287. (21) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Harting, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768-2771. Cliff, M. D.; Pyne, S. G. J. Org. Chem. 1997, 62, 1023-1032.

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Lindsay and Pyne SCHEME 3a

a

Reagents: (a) AD mix-R, MeSO2NH2, ButOH/H2O, 0 °C, 6 d; (b) Ac2O, pyridine, rt, 16 h; (c) 2,2-dimethoxypropane, p-TsOH, 3 h, rt; (d) PdCl2, H2, MeOH, rt, 1 h; (g) 2 M HCl, THF, rt, 20 h; basic ion-exchange.

FIGURE 1. Dihydroxylation of 13.

reaction mixture) and as a single diastereomer in an overall purified yield of 44%. When AD-mix-β was employed the diastereoselectivity was slightly lower (14/ 15 ) 95:5) but the isolated yield of 14 was slightly higher (49%). The high diastereoselectivity in the cis-dihydroxylation reaction of 13 with AD-mix-R or -β is consistent with addition of the bulky osmium reagent to the R-face of the molecule since attack from the β-face would be sterically hindered by the pseudoaxial protons H8a and H3β (Figure 1).10,20 Conversion of 14 to (-)-swainsonine (1), via catalytic hydrogenolysis, followed by base-catalyzed methanolysis (K2CO3/MeOH), gave a sample of (-)-swainsonine 1 that was difficult to purify. Therefore, the crude diol from dihydroxylation of 13 with AD-mix-R was converted to the known acetonide derivative 16. The 1H and 13C NMR spectra of this compound were identical to that reported in the literature,22 while the specific rotation of this compound ([R]26D -54 (c 0.6, CHCl3), lit.12c [R]26D -58.9 (c 0.27, CHCl3) [lit.22a [R]23D -67 (c 0.30, CHCl3))] also compared favorably, considering the 92% ee of the starting epoxide 6. Compound 16 was then converted to (-)-swainsonine 1 using literature procedures12c,22 in 94% overall yield. (-)-Swainsonine 1 prepared by this method had 1H and 13C NMR spectra and TLC mobility identical (22) (a) Zhao, H.; Hans, S.; Chemg, X.; Mootoo, D. R. J. Org. Chem. 2001, 66, 1761-1767. (b) Zhou, W.-S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.F. Tetrahedron Lett. 1995, 36, 1291-1294.

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SCHEME 4a

a Reagents: (a) OsO , NMO, acetone/water; (b) NaH, BnBr, 4 Bu4I, THF; (c) TFA/anisole, CH2Cl2, rt; (d) Ph3P, CBr4, Et3N, CH2Cl2, 0 °C; (e) Pd/C, H2, EtOH, rt, 3 d; (f) Ac2O, pyridine, rt, 16 h.

to an authentic sample of (-)-swainsonine23 and had a specific rotation, [R]26D -71 (c 0.56, MeOH) [lit.12c [R]26D -82.6 (c 1.03, MeOH); lit.22a [R]23D -86 (c 0.30, MeOH); lit.24a [R]23D -74 (c 0.98, MeOH); lit.24b [R]26D -85.5 (c 0.42, MeOH); lit.24c [R]23D -87.2 (c 2.1, MeOH)] that was consistent with the enantiomeric purity of its precursors. Synthesis of (+)-1,2-Di-epi-swainsonine (21). The 2,3-dihyropyrrole 10 could also be converted to (+)-1,2di-epi-swainsonine 21 (Scheme 4) by reversing the order of the dihydroxylation and cyclization reactions. Thus, cis-dihydroxylation of 10 followed by perbenzylation of the resulting triol 17 gave the tri-O-benzyl ether 18 in 81% overall yield (Scheme 4). In this case, the dihydroxylation reaction appeared 100% diastereoselective, since none of the 1,2-diepimeric diastereomer of 17 or 18 could be detected or isolated. The stereochemistry of the DH reaction was completely controlled by the C2 substituent of the 2,3-dihydropyrrole 10. Acid-catalyzed di-deprotection of 18 with trifluoroacetic acid gave the amino alcohol 19, which was cyclized to the indolizidine 20 in 86% overall yield. Catalytic hydrogenolysis of 20 over palladium on carbon gave (+)-1,2-di-epi-swainsonine 21 that had spectral data identical to that reported in the literature.25 This compound was further chartacterized as its triacetate 22, which also had spectral data identical to that reported in the literature, and its specific rotation, [R]23D +57 (c 1.95, CHCl3), closely matched the literature value25 ([R]23D +61.1 (c 2.11, CHCl3)). Synthesis of (+)-1,2,8-Tri-epi-swainsonine (32). For the synthesis of (+)-1,2,8-tri-epi-swainsonine (32), the known E-allylic alcohol 2313b was converted to its corresponding (S,R)-vinyl epoxide 2426 (Scheme 5) using (23) Kindly provided by Dr. Reg Smith, from Phytex Australia, Sydney. (24) (a) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 72177221. (b) Hunt, J. A.; Roush, W. R. J. Org. Chem. 1997, 62, 11121124. (c) Schneider, M. J.; Ungemach, F. S.; Broquist, H. P.; Harris, T. M. Tetrahedron 1983, 39, 29-32. (25) Razavi, H.; Polt, R. J. Org. Chem. 2000, 65, 5693-5706. (26) For the synthesis of racemic 24, see ref 13b.

Asymmetric Synthesis of (-)-Swainsonine SCHEME 5a

In conclusion, a synthetic strategy has been developed that allows the synthesis of (-)-swainsonine, (+)-1,2-diepi-swainsonine, and (+)-1,2,8-tri-epi-swainsonine in a diastereoselective fashion. These syntheses could be readily adapted to the synthesis of (+)-swainsonine and its (-)-diastereomers by using the enantiomeric vinyl epoxides.

Experimental Section

a Reagents: (a) D-(-)-DIPT, Ti(OPri) , TBHP, CH Cl , -20 °C; 4 2 2 (b) (i) DMSO, (COCl)2, CH2Cl2, -60 °C, (ii) Et3N; (c) MePPh3Br, KHMDS, toluene; (d) allylamine, p-TsOH‚H2O (0.1 equiv); (e) (Boc)2O, Et3N, CH2Cl2; (f) Cl2(Cy3P)2RudCHPh, CH2Cl2, reflux; (g) K2OsO4‚H2O, NMO, acetone, water; (h) NaH, BnBr, Bu4NI, THF, rt, 20 h; (i) TFA/CH2Cl2, rt, 2.5 h; (i) Ph3P, CBr4, Et3N 0 °C; (k) PdCl2, H2, rt, 1 h.

analogous chemistry described for the synthesis of the (R,R)-vinyl epoxide 7 in Scheme 2. Vinyl epoxide 24 was converted to the 2,5-dihydropyrrole 27 in high overall yield (78%) by a similar aminolysis reaction with allylamine, followed by N-protection and a RCM reaction. A diastereoselective DH of 27 followed by perbenzylation gave the tri-O-benzyl ether 29 in 78% overall yield and as a single diastereomer. Treatment of 29 with trifluoroacetic acid gave the amino alcohol 30 in 85% yield that was cyclized to its corrersponding indolizidine 31 in 80% yield. Finally, hydrogenolysis of the benzyl protecting groups in 31 using palladium(II) chloride under a hydrogen atmosphere22 gave (+)-1,2,8-tri-epi-swainsonine (32) in 93% yield. This compound had spectral data identical to that reported in the literature,27a and its specific rotation, [R]25D +41 (c 0.84, MeOH), closely matched the literature value27b ([R]D +45.6 (c 0.40, MeOH)). (27) For the synthesis and NMR data of the enantiomer of 32, see: (a) Kim, Y. G.; Cha, J. K. Tetrahedron Lett. 1989, 30, 5721-5724. (b) For an alternative synthesis of 32, see: (b) Keck, G. E.; Romer, D. R. J. Org. Chem. 1993, 58, 6083-6089.

General Methods. All reactions were carried out under an atmosphere of nitrogen. Where necessary, reagents and solvents were purified according to literature methods.28,29 NMR spectra were obtained as a CDCl3 solution unless otherwise stated and were referenced to the relevant solvent peak. 13C NMR assignments (s, d, t and q) were made from DEPT experiments. Silica gel chromatography was performed using Merck GF 254 flash silica gel packed by the slurry method. Small-scale separations (2.0 g) were performed using a 50 mm diameter column, each with the stated solvent system. Melting points are uncorrected. Specific rotations were measured using a 10 or a 50 mm cell, the values quoted were an average of 5-10 measurements. They are reported by the following convention: optical rotation [10-1‚deg‚cm3‚g-1] (concentration, solvent). In all cases, HRMS (exact masses) were obtained in lieu of elemental analyses, and 1H and 13C NMR spectroscopy were used as criteria for purity. These spectra are available as Supporting Information. 6-[(4-Methoxyphenyl)methoxy]-2R,3R-epoxyhexan-1ol (6). Powdered 4 Å molecular sieves (3.20 g) were placed in a 250 mL flask with a magnetic stirrer. The flask was heated with a 1400 W heat gun for 10 min and then sealed and flushed with nitrogen. It was then charged with dry dichloromethane (150 mL) and cooled to -15 °C (ice/salt bath). D-(-)-Diisopropyl tartrate (1.020 g, 4.37 mmol), Ti(iPrO)4 (1.241 g, 4.34 mmol), and tert-butyl hydroperoxide (11.7 mL, 58.40 mmol, 5 M solution in decane) were then added sequentially via syringe. The mixture was stirred at -15 °C for 40 min, and then 6-[(4methoxyphenyl)methoxy]-(E)-2-hexen-1-ol13 (6.91 g, 29.24 mmol) dissolved in dry dichloromethane (13 mL) was added via cannula over 10 min. The mixture was stirred at -15 °C for 2.5 h, poured onto water (200 mL), shaken, and then filtered through a pad of Celite. The filtrate was taken and extracted with ethyl acetate (3 × 100 mL), and the combined organic portions were dried (MgSO4), filtered, and evaporated in vacuo to give an oil. The pure product was obtained by column chromatography (increasing polarity from 40% to 100% ethyl acetate in petroleum spirit as eluant), which gave the title compound (3.82 g, 15.14 mmol, 51.8%) and recovered starting material (1.50 g, 6.35 mmol, 21.7%) as clear oils. 6: [R]29D +21 (c 2.2, CHCl3); MS (ES+) m/z 253.1 (6) (M + 1), (CI+) m/z 251 (M - 1); HRMS (CI+) found 251.125634, calcd for C14H19O4 251.128334 (M - 1); 1H NMR (300 MHz) δ 1.00-1.80 (5H, m), 2.89 (1H, td, J ) 8.4, 4.8 Hz), 2.92-3.00 (1H, m), 3.47 (2H, t, J ) 6.3 Hz), 3.54 (1H, dd, J ) 12.6, 4.8 Hz), 3.77 (3H, s), 3.81 (1H, dd, J ) 12.6, 3.0 Hz), 4.41 (2H, s), 6.86 (2H, dt, J ) 8.7, 2.7 Hz), 7.24 (2H, dt, J ) 8.7, 2.7 Hz); 13C NMR (75 MHz) 25.9 (t), 28.2 (t), 55.1 (q), 55.7 (d), 58.5 (d), 61.6 (t), 69.1 (t), 72.4 (t), 113.6 (d), 129.6 (d), 130.2 (s), 159.0 (s). Preparation of Mosher Ester of Alcohol 6. Alcohol 6 (75 mg, 0.297 mmol) was dissolved in dry dichloromethane (1.25 mL), and then triethylamine (250 µL, 1.80 mmol), 4-(dimethylamino)pyridine (36 mg, 0.294 mmol), and finally MTPACl (60 µL, 81 mg, 0.321 mmol) were added. The mixture was stirred (28) Purification of Laboratory Chemicals, 2nd ed.; Perrin, D. D., Amarego, W. L. F., Perrin, D. R., Eds.; Pergamon Press Ltd.: Oxford, England, 1981. (29) Practical Textbook of Organic Chemistry, 5th ed.; Furnis B. S., Hannaford A. J., Smith P. W. G., Tatchell A. R., Eds.; Longmann Scientific and Technical: London, 1989.

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Lindsay and Pyne at rt for 15 min and then applied directly to a silica gel column. Elution with 40% ethyl acetate in petroleum spirit afforded the title compound (135 mg, 0.288 mmol, 97.0%) as a clear oil: MS (CI +) m/z 467 (42) (M - 1); HRMS (CI+) found 467.164546, calcd for C24H26F3O6 467.168149 (M - 1); 1H NMR (300 MHz): major isomer δ 1.50-1.80 (4H, m), 2.82-2.88 (1H, m), 2.98 (1H, ddd, J ) 5.7, 3.3, 2.1 Hz), 3.40-3.50 (2H, m), 3.57 (3H, d, J ) 0.9 Hz), 3.79 (3H, s), 4.19 (1H, dd, J ) 12.0, 6.0 Hz), 4.42 (2H, s), 4.51 (1H, dd, J ) 12.0, 3.3 Hz), 6.88 (2H, dt, J ) 8.4, 2.4 Hz), 7.25 (2H, dt, J ) 8.4, 2.4 Hz), 7.36-7.44 (3H, m), 7.50-7.58 (2H, m, H18), minor isomer inter alia 4.17 (1H, dd, J ) 12.0, 6.0 Hz), 4.56 (1H, d, J ) 12.0, 3.3 Hz); 13C NMR (75 MHz): δ 25.9 (t), 28.3 (t), 54.5 (d), 55.1 (q), 55.4 (q), 56.2 (d), 66.0 (t), 69.0 (t), 72.4 (t), 113.7 (d), 127.2 (d), 128.4 (d), 129.2 (d), 129.6 (d), 130.3 (s), 131.9 (s), 159.1 (s), 166.2 (s) [two carbons not seen due to fluorine coupling]. 6-[(4-Methoxyphenyl)methoxy]-2S,3R-epoxyhexan-1al. Oxalyl chloride (3.60 mL, 39.07 mmol) was dissolved in dichloromethane (54 mL) and the solution cooled to -50 to -60 °C (chloroform/dry ice) under N2. Dimethyl sulfoxide (6.01 mL, 85.25 mmol) was added slowly over 5 min, and then a solution of the alcohol 6 (4.48 g, 17.76 mmol) in dichloromethane (30 mL) was added via cannula. The mixture was stirred at -50 °C for 1 h, and then triethylamine (12.6 mL, 89.12 mmol) was added over 5 min and a solid formed. The reaction was warmed to rt, poured into water (200 mL), and extracted with dichloromethane (100 mL). The organic portion was washed with saturated sodium chloride solution (200 mL), dried (MgSO4), filtered, and concentrated to 80 mL. It was then washed with 1 M HCl (100 mL), 5% sodium carbonate solution (100 mL), and water (100 mL) before it was dried (MgSO4), filtered, and evaporated in vacuo to give the crude, unstable title compound (4.40 g, 95% pure, 4.18 g, aldehyde, 16.7 mmol, 94.0%) as a pungent yellow oil, that was not purified any further: 1H NMR (300 MHz) δ 1.60-1.90 (4H, m), 3.13 (1H, dd, J ) 6.3, 1.8 Hz), 3.25 (1H, m), 3.40-3.55 (2H, m), 3.80 (3H, s), 4.43 (2H, s), 6.88 (2H, d, J ) 8.7 Hz), 7.24 (2H, d, J ) 8.7 Hz), 8.99 (1H, d, J ) 6.3 Hz); 13C NMR (75 MHz) δ 26.0 (t), 28.3 (t), 55.3 (d), 59.2 (d), 68.9 (t), 72.6 (t), 113.7 (d), 129.2 (d), 130.2 (s), 159.0 (s), 198.1 (d). 7-[(4-Methoxyphenyl)methoxy]-3R,4R-epoxy-1-heptene (7). Methyltriphenylphosphonium bromide (11.29 g, 31.61 mmol) and dry toluene (98 mL) were placed in a dry 250 mL flask, and the stirred suspension was cooled to 0 °C. KHMDS (53.2 mL, 26.6 mmol, 0.5 M solution in toluene) was added, and the solution was stirred for 5 min under nitrogen. 6-[(4Methoxyphenyl)methoxy]-2S,3R-epoxyhexan-1-al (4.40 g, 95% pure, 4.16 g aldehyde, 16.62 mmol) in toluene (20 mL) was added via cannula, and then the mixture stirred at 0 °C for 1 h and at rt for 2 h. The reaction was quenched with water (250 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic portions were dried (MgSO4), filtered, and evaporated to give a semisolid. The pure product was obtained by column chromatography (increasing polarity from 5% to 25% ethyl acetate in petroleum spirit as eluant), which gave the title compound (2.76 g, 11.11 mmol, 66.8%) as a clear oil: [R]27D +15 (c 2.0, CHCl3); MS (CI+) m/z 247 (49) (M - 1); HRMS (CI+) found 247.137438, calcd for C15H19O3 247.133420 (M - 1); 1H NMR (300 MHz) δ 1.55-1.90 (4H, m), 2.70-2.90 (1H, m), 3.09 (1H, dd, J ) 7.2, 2.1 Hz), 3.40-3.60 (2H, m), 3.80 (3H, s), 4.43 (2H, s), 5.25 (1H, ddd, J ) 9.6, 1.2, 0.6 Hz), 5.43 (1H, ddd, J ) 17.1, 1.2, 0.6 Hz), 5.56 (1H, ddd, J ) 17.1, 9.6, 7.2 Hz), 6.88 (2H, dt, J ) 9.0, 3.0 Hz), 7.25 (2H, dt, J ) 9.0, 3.0 Hz); 13C NMR (75 MHz) δ 26.0 (t), 28.7 (t), 55.2 (q), 58.7 (d), 60.1 (d), 69.3 (t), 72.5 (t), 113.7 (d), 119.0 (t), 129.2 (d), 130.5 (s), 135.7 (s), 159.1 (s). 7-[(4-Methoxyphenyl)methoxy]-4R-hydroxy-3S-allylaminohept-1-ene (8). The vinyl epoxide 7 (415 mg, 1.671 mmol) was dissolved in allylamine (1.91 g, 33.42 mmol), and then p-toluenesulfonic acid monohydrate (50 mg, 0.237 mmol) was added. The mixture was heated in a sealed tube at 105 °C for 3 d and then cooled. All volatiles were removed in vacuo

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to give an oil. The pure product was obtained by column chromatography (increasing polarity from 5% to 10% methanol in dichloromethane as eluant), which gave the title compound (450 mg, 1.473 mmol, 88.2%) as a clear oil: [R]28D +10 (c 1.9, CHCl3); MS (CI+) m/z 306 (71) (M + 1); HRMS (CI+) found 306.206574, calcd for C18H27NO3 306.206919 (M + 1); 1H NMR (300 MHz) δ 1.35-1.86 (5H, m), 2.30 (1H, v.br.s), 3.07 (1H, dd, J ) 8.4, 3.3 Hz), 3.14 (1H, ddd, J ) 14.1, 6.0, 1.2 Hz), 3.28 (1H, ddd, J ) 14.1, 6.0, 1.2 Hz), 3.47 (2H, t, J ) 6.0 Hz), 3.63 (1H, dt, J ) 9.3, 3.3 Hz), 3.80 (3H, s), 4.43 (2H, s), 5.05-5.30 (4H, m), 5.71 (1H, ddd, J ) 17.4, 10.5, 8.7 Hz), 5.88 (1H, ddt, J ) 17.1, 10.2, 6.0 Hz), 6.87 (2H, dt, J ) 8.4, 3.0 Hz), 7.25 (2H, dt, J ) 8.4, 3.0 Hz); 13C NMR (75 MHz): δ 26.4 (t), 30.1 (t), 49.5 (t), 55.2 (q), 65.1 (d), 70.0 (t), 72.1 (d), 72.5 (t), 113.7 (d), 116.0 (t), 118.3 (t), 129.3 (d), 130.3 (s), 136.0 (d), 136.6 (d), 159.1 (s). 5R-(3′-[(4-Methoxyphenyl)methoxy]propyl-4S-ethenyl3-(2-propenyl)-2-oxazolidinone (A in eq 1). The amino alcohol 8 (88 mg, 0.288 mmol) was dissolved in dichloromethane (2 mL), and then triethylamine (88 mg, 0.870 mmol) was added. The mixture was cooled to 0 °C, and then triphosgene (44 mg, 0.284 mmol) dissolved in dichloromethane (1 mL) was added via syringe. The mixture was stirred at 0 °C for 2 h, quenched with water (50 mL), and extracted with dichloromethane (3 × 25 mL). The combined extracts were dried (MgSO4), filtered, and evaporated in vacuo to give an oil. The pure product was obtained by column chromatography (increasing polarity from 20% to 40% ethyl acetate in petroleum spirit as eluant), which gave the title compound (72 mg, 0.217 mmol, 75.4%) as a clear oil: [R]23D -29 (c 3.5, CHCl3); MS (CI+) m/z 332 (23) (M + 1); HRMS (CI+) found 332.188349, calcd for C19H26NO4, 332.186184 (M + 1); 1H NMR (300 MHz): δ 1.58-1.88 (4H, m), 3.36-3.46 (3H, m), 3.79 (3H, s), 4.08-4.22 (2H, m), 4.41 (2H, s), 4.44-4.56 (1H, m), 5.12-5.22 (2H, m), 5.28 (1H, ddd, J ) 17.1, 1.5, 0.6 Hz), 5.39 (1H, dd, J ) 10.2, 1.5 Hz), 5.59-5.80 (2H, m), 6.87 (2H, dt, J ) 8.4, 2.5 Hz), 7.24 (2H, dt, J ) 8.4, 2.5 Hz); 13C NMR (75 MHz) δ 25.7 (t), 27.2 (t), 44.3 (t), 55.1 (q), 61.3 (d), 68.9, (t), 72.3 (t), 77.1 (d), 113.6 (d), 118.1(t), 121.8 (t), 129.0 (d), 130.3 (s), 131.3(d), 131.9 (d), 157.3(s), 159.0 (s); 1H NMR (300 MHz, benzene-d6) δ 1.30-1.80 (4H, m), 3.16-3.35 (3H, m), 3.38 (3H, s), 3.56 (1H, t, J ) 9.0 Hz), 4.06 (1H, ddd, J ) 9.0, 7.8, 4.2 Hz), 4.18 (1H, ddt, J ) 15.3, 4.5, 1.5 Hz), 4.33 (2H, s), 4.80 (1H, ddd, J ) 17.1, 1.5, 0.6 Hz), 4.90 (1H, dd, J ) 10.2, 1.5 Hz), 4.95-4.99 (1H, m), 4.99-5.04 (1H, m), 5.19 (1H, ddd, J ) 17.1, 10.2, 9.0 Hz), 5.58 (1H, dddd, J ) 17.1, 9.6, 7.5, 4.5 Hz), 6.85 (2H, dt, J ) 8.7, 2.7 Hz), 7.25 (2H, dt, J ) 8.7, 2.7 Hz); 13C NMR (75 MHz, benzene-d6) δ 26.5 (t), 27.6 (t) 44.6 (t), 54.8 (q), 61.4 (d), 69.3 (t), 72.7 (t), 76.9 (d), 114.0 (d), 117.5 (t), 120.9 (t), 129.4 (d), 131.1 (s), 132.3 (d), 133.1 (d), 157.1 (s), 159.7 (s). N-tert-Butyloxycarbonyl-7-[(4-methoxyphenyl)methoxy]-4R-hydroxy-3S-allylaminohept-1-ene (9). The amino alcohol 8 (1.07 g, 3.503 mmol) was dissolved in dry tetrahydrofuran (35 mL), then triethylamine (587 mg, 6.12 mmol) and di-tert-butyl dicarbonate (1.274 mg, 6.12 mmol) were added. The mixture was stirred at rt for 24 h, and then all volatiles were removed in vacuo to give an oil. The pure product was obtained by column chromatography (increasing polarity from 15% to 40% ethyl acetate in petroleum spirit as eluant), which gave the title compound (1.392 g, 3.433 mmol, 98.0%) as a clear oil: [R]25D -12 (c 1.95, CHCl3); MS (ES+) m/z 406.5 (62) (M + 1); HRMS (CI+) found 406.257853, calcd for C23H36NO5 406.259349 (M + 1); 1H NMR (300 MHz) δ 1.45 (9H, s), 1.551.85 (4H, m), 2.01 (1H, br s) 3.47 (2H, td, J ) 6.0, 2.1 Hz), 3.79 (3H, s), 3.70-3.92 (4H, m), 4.43 (2H, s), 5.05-5.30 (4H, m), 5.79 (1H, ddd, J ) 16.5, 11.4, 6.3 Hz), 6.09 (1H, ddd, J ) 17.4, 10.2, 7.2 Hz), 6.89 (2H, dt, J ) 8.7, 2.4 Hz), 7.25 (2H, dt, J ) 8.7, 2.4 Hz); 13C NMR (75 MHz) δ 26.1 (t), 28.3 (q), 31.5 (br t), 50.5 (br t), 55.1 (q), 65.3 (br d), 69.5 (t), 72.5 (t), 73.1 (br d), 80.2 (s), 113.6 (d), 116.4 (t), 118.4 (t), 129.2 (d), 130.3 (s), 132.3 (br d), 134.9 (d), 159.0 (s), 171.0 (br s). 2S-(1′R-Hydroxy-4′-[(4-methoxyphenyl)methoxy]butyl)-

Asymmetric Synthesis of (-)-Swainsonine N-tert-butyloxycarbonyl-2,5-dihydropyrrole (10). The diene 9 (500 mg, 1.233 mmol) was dissolved in dry dichloromethane (300 mL), and then benzylidene-bis-tricyclohexylphosphine)dichlororuthenium (65 mg, 0.080 mmol) was added. The mixture was heated to reflux under nitrogen for 20 h, then cooled, before all solvent was removed in vacuo to give a brown oil. The pure product was obtained by column chromatography (increasing polarity from 20% to 50% ethyl acetate in petroleum spirit as eluant), which gave the title compound (443 mg, 1.174 mmol, 95.2%) as a clear oil: [R]24D -85 (c 1.75, CHCl3); MS (ES+) m/z 378.4 (100) (M + 1); HRMS (CI+) found 378.225327, calcd for C21H32NO5 378.228048 (M + 1); 1H NMR (300 MHz) δ 1.18-1.50 (2H, m), 1.48 (9H, s), 1.54-1.74 (2H, m), 3.40-3.56 (2H, m), 3.68-3.80 (1H, m), 3.79 (3H, s), 3.82-4.32 (2H, m), 4.42 (2H, s), 4.58 (1H, d, J ) 8.4 Hz), 4.78 (1H, br. s), 5.60-5.98 (2H, m), 6.85 (2H, d, J ) 8.7 Hz), 7.25 (2H, d, J ) 8.7 Hz); 13C NMR (75 MHz) major rotamer δ 26.2 (t), 28.1 (t), 28.3 (q), 54.6 (t), 55.1 (q), 69.9 (t), 70.5 (d), 72.2 (t), 73.3 (d), 80.3 (s), 113.6 (d), 126.5 (d), 127.1 (d), 129.1 (d), 130.6 (s), 156.1 (s), 158.9 (s), minor rotamer inter alia δ 26.5 (t), 30.0 (t), 54.2 (t), 69.3 (d), 72.4 (d), 125.4 (d), 127.9 (d). 2S-[1′R-Phenylmethoxy-4′-[(4-methoxyphenyl)methoxy]butyl]-N-tert-butyloxycarbonyl-2,5-dihydropyrrole (11). The alcohol 10 (770 mg, 2.040 mmol) was dissolved in dry tetrahydrofuran (16 mL), and then sodium hydride (196 mg, 4.08 mmol, 50% dispersion in paraffin oil), benzyl bromide (0.72 mL, 6.13 mmol), and tetrabutylammonium iodide (76 mg, 0.204 mmol) were added in quick succession. The mixture was stirred at rt under nitrogen for 2 d, quenched with water (50 mL), and extracted with dichloromethane (3 × 40 mL). The combined organic portions were dried (MgSO4), filtered, and evaporated in vacuo to give an oil. The pure products was obtained by column chromatography (increasing polarity from 20% to 60% ethyl acetate in petroleum spirit as eluant), which gave the title compound (708 mg, 1.514 mmol, 74.2%) as a clear oil (a small amount of the corresponding oxazolidone formed from cyclization of the secondary hydroxyl onto the Boc group in 11 was also isolated): [R]24D -96 (c 1.6, CHCl3); MS (CI+) m/z 468 (21) (M + 1); HRMS (CI+) found 466.258533, calcd for C28H38NO5, 466.259349 (M + 1); 1H NMR (300 MHz) δ 1.45 (4.5H, s), 1.49 (4.5H, s), 1.40-1.86 (4H, m), 3.34-3.49 (2H, m), 3.80 (3H, s), 3.82-4.62 (8H, m), 5.74-5.97 (2H, m), 6.87 (2H, d, J ) 8.1 Hz), 7.20-7.36 (7H, m); 13C NMR (75 MHz) many of the signals were paired due to carbamate rotamers δ 26.4/26.5 (t), 28.5 (q), 29.5 (t), 53.6/53.8 (t), 55.1 (q), 68.2/68.4 (d), 69.7/69.8 (t), 72.2/72.4 (t), 73.4/73.9 (t), 78.0/79.0 (d), 79.2/ 79.5 (s), 113.5/113.5 (d), 125.5/125.7 (d), 126.8/127.0 (d), 127.2/ 127.3 (d), 127.5/127.7 (d), 128.0/128.1 (d), 128.9/129.0 (d), 130.2/ 130.4 (s), 138.4/138.7 (s), 153.7/153.9 (s), 158.7/158.8 (s). 2S-(1′R-Phenylmethoxy-4′-hydroxybutyl)-2,5-dihydropyrrole (12). The 2,5-dihydropyrrole 11 (665 mg, 1.422 mmol) was dissolved in dichloromethane (10 mL), and then anisole (1.59 mL, 14.22 mmol) and trifluoroacetic acetic (8 mL, 103.8 mmol) were added. The mixture was stirred at rt for 90 min, and then all volatiles were removed in vacuo at ∼30 °C. The residue was dissolved in chloroform (50 mL) and poured into saturated sodium carbonate solution (40 mL). After extensive shaking, the organic portion was separated, and then the aqueous portion was extracted with chloroform (2 × 50 mL). The combined organic portions were dried (MgSO4), filtered, and evaporated in vacuo to give an amber oil. The pure product was obtained by column chromatography (increasing polarity from 25% to 50% methanol in dichloromethane as eluant), which gave the title compound (310 mg, 1.253 mmol, 88.1%) as a clear oil: [R]24D -83 (c 4.0, CHCl3); MS (CI+) m/z 248 (100) (M + 1); HRMS (CI+) found 248.165414, calcd for C15H22NO2 248.165054 (M + 1); 1H NMR (300 MHz) δ 1.50-1.80 (4H, m), 3.28-3.40 (1H, m), 3.44-3.78 (6H, m), 4.10-4.20 (1H, m), 4.28 (2H, s), 5.80-5.90 (2H, m), 7.20-7.38 (5H, m); 13C NMR

(75 MHz) δ 27.5 (t), 28.6 (t), 53.5 (t), 62.8 (t), 67.7 (d), 71.8 (t), 81.6 (d), 127.3 (d), 128.9 (d), 129.0 (d), 127.5 (d), 128.0 (d), 138.2 (s). (8R,8aS)-8-Phenylmethoxy-2,3-dehydroindolizine (13). The amino alcohol 12 (139 mg, 0.562 mmol) was dissolved in dichloromethane (16 mL) and then the solution cooled to 0 °C. Carbon tetrabromide (380 mg, 1.12 mmol) and triphenylphosphine (287 mg, 1.12 mmol) were added, and then the mixture was stirred at 0 °C under nitrogen for 10 min before the addition of triethylamine (2.78 mL, 20.06 mmol). The mixture was stirred at 0 °C for 1.5 h and then left to stand at 4 °C for 5 d before it was poured into water (50 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic portions were dried (MgSO4), filtered, and evaportated in vacuo to give a dark brown semisolid. The pure product was obtained by column chromatography (increasing polarity from 1% to 5% methanol in dichloromethane as eluant), which gave the title compound (95 mg, 0.414 mmol, 73.7%) as a clear oil: [R]24D -115 (c 3.85, CHCl3); MS (CI+) m/z 230 (25) (M + 1); HRMS (CI+) found 230.156073, calcd for C15H20NO 230.154489 (M + 1); 1H NMR (300 MHz) δ 1.14-1.32 (1H, m), 1.52-1.74 (2H, m), 2.20 (1H, ddd, J ) 11.7, 7.1, 3.9 Hz), 2.43 (1H, dt, J ) 11.4, 3.3 Hz), 2.88-3.04 (2H, m), 3.18-3.32 (2H, m), 3.62 (1H, br.d, J ) 13.2 Hz), 4.59 (2H, AB system, J ) 12.3 Hz), 5.89 (1H, ddd, J ) 6.0, 3.9, 2.1 Hz), 6.14 (1H, br. d, J ) 6.3 Hz), 7.20-7.36 (5H, m); 13C NMR (75 MHz) δ 24.2 (t), 30.4 (t), 48.8 (t), 57.6 (t), 70.9 (t), 72.0 (d), 78.3 (d), 127.3 (d), 128.6 (d), 131.2 (d), 127.4 (d), 128.1 (d), 138.6 (s). (1S,2R,8R,8aR)-8-(Phenylmethoxy)-1,2-diacetoxyindolizine (14) and (1R,2S, 8R,8aR)-8-(Phenylmethoxy)-1,2-diacetoxyindolizidine (15). The indolizine 13 (77 mg, 0.336 mmol) was dissolved in acetone (1.9 mL), and then water (1.3 mL), N-methylmorpholine N-oxide (84 mg, 0.716 mmol), and K2OsO4‚2H2O (9 mg, 0.025 mmol) were added. The mixture was stirred at rt for 2 d, and then all volatiles were removed in vacuo to give a crude mixture of diols. This was treated with pyridine (1 mL) and acetic anhydride (1 mL) and the mixture stirred at rt for 1 d. The reaction was quenched with cold saturated sodium bicarbonate solution (40 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic portions were dried (MgSO4), filtered, and evaporated in vacuo to give an oil. The pure products were obtained by column chromatography (increasing polarity from 40% to 100% ethyl acetate in petroleum spirit as eluant), which gave the title compounds 14 (43 mg, 0.124 mmol, 36.8%) and 15 (20 mg, 0.576 mmol, 17.1%) as clear oils. 14: [R]25D -108 (c 2.15, CHCl3); MS (CI+) m/z 348 (69) (M + 1); HRMS (CI+) found 348.180737, calcd for C19H26NO5 348.181098 (M + 1); 1H NMR (300 MHz) δ 1.10-1.28 (1H, m), 1.50-1.80 (2H, m), 1.90 (1H, td, J ) 11.4, 3.0 Hz), 2.01 (6H, s), 2.07 (1H, dd, J ) 9.3, 4.2 Hz), 2.30 (1H, ddd, J ) 11.4, 7.2, 3.3 Hz), 2.57 (1H, dd, J ) 11.4, 7.8 Hz), 2.97-3.10 (2H, m), 3.63 (1H, ddd, J ) 11.1, 9.3, 4.8 Hz), 4.50 (2H, AB system, J ) 11.7 Hz), 5.29 (1H, ddd, J ) 8.4, 6.6, 2.1 Hz), 5.56 (1H, dd, J ) 6.3, 4.2 Hz), 7.20-7.35 (5H, m); 13C NMR (75 MHz) δ 20.6 (q), 20.8 (q), 23.3 (t), 29.5 (t), 52.1 (t), 59.6 (t), 69.8 (d), 70.0 (d), 70.5 (t), 71.1 (d), 72.9 (d), 127.5 (d), 127.7 (d), 128.2 (d), 138.0 (s), 169.8 (s), 169.8 (s). 15: [R]24D +6 (c 1.0, CHCl3); MS (CI+) m/z 348 (69) (M + 1); HRMS (CI+) found 348.180842, calcd for C19H26NO5 348.181098 (M + 1); 1H NMR (300 MHz) δ 1.16-1.32 (1H, m), 1.54 (1H, qt, J ) 13.0, 4.2 Hz), 1.74 (1H, br. d, J ) 12.6 Hz), 1.91 (3H, s), 2.02 (s), 2.08 (1H, td, J ) 11.7, 2.4 Hz), 2.202.36 (3H, m), 2.91 (1H, br. d, J ) 10.8 Hz), 3.33 (1H, ddd, J ) 10.5, 9.0, 4.2 Hz), 3.52 (1H, dd, J ) 9.6, 6.9 Hz), 4.50 (2H, AB system, J ) 10.8 Hz), 5.10-5.25 (2H, m), 7.21-7.35 (5H, m); 13 C NMR (75 MHz): δ 20.7 (q), 20.8 (q), 23.8 (t), 30.0 (t), 51.6 (t), 58.3 (t), 68.3 (d), 68.4 (d), 70.8 (t), 73.7 (d), 79.0 (d), 127.4 (d), 127.7 (d), 128.2 (d), 138.3 (s), 169.6 (s), 169.8 (s). (3aR,9R,9aR,9bS)-Octahydro-2,3-dimethyl-9-(phenylmethoxy)-1,3-dioxolo[4,5-a]indolizine (16). AD-mix-R (697 mg) and (DHQ)2PHAL (17 mg, 0.022 mmol) were dissolved in water (2.7 mL) and tert-butyl alcohol (1.8 mL), and then the

J. Org. Chem, Vol. 67, No. 22, 2002 7779

Lindsay and Pyne mixture was cooled to 0 °C. Methanesulfonamide (93 mg, 0.978 mmol) and then indolizine 13 (91 mg, 0.397 mmol) dissolved in tert-butyl alcohol (1.7 mL) were added, and the mixture was stirred at 4 °C for 7 d. Sodium sulfite (1.2 g) was added and the mixture stirred at rt for 2 h. All volatiles were removed in vacuo, and then the residue was suspended in methanol (10 mL) and filtered. The solids were washed with methanol (2 × 10 mL) and the combined filtrates evaporated in vacuo to give the crude diol. This was dissolved in dry dichloromethane (2 mL), and then 2,2-dimethoxypropane (0.25 mL, 2.03 mmol) and p-toluenesulfonic acid (105 mg, 0.610 mmol) were added and the mixture stirred at rt for 3 h. The reaction was quenched with saturated sodium bicarbonate solution (30 mL) and extracted with chloroform (3 × 25 mL). The combined organics were dried (MgSO4), filtered, and evaporated in vacuo to give an oil. The pure product was obtained by column chromatography (increasing polarity from 30% to 60% diethyl ether in dichloromethane as eluant), which gave the title compound (60 mg, 0.198 mmol, 49.8%) as a clear oil that had spectral data identical to that reported in the literature:12c,22 [R]25D -54 (c 0.6, CHCl3) [lit.12c [R]26D -59 (c 0.27, CHCl3), lit.22a [R]23D -67 (c 0.3, CHCl3)]; MS (CI+) m/z 304 (100) (M + 1); HRMS (ES+) found 304.1901, calcd for C18H26NO3 304.1913 (M + 1); 1H NMR (300 MHz): δ 1.10-1.26 (1H, m), 1.34 (3H, s), 1.50 (3H, s), 1.56 (1H, dt, J ) 12.0, 4.1 Hz), 1.60-1.65 (1H, m), 1.82 (1H, td, J ) 10.5, 3.0 Hz), 2.08 (1H, dd, J ) 11.1, 4.8 Hz), 2.08-2.22 (1H, m), 2.96 (1H, br. d, J ) 10.5 Hz), 3.11 (1H, d, J ) 10.5 Hz), 3.63 (1H, ddd, J ) 10.8, 8.7, 4.5 Hz), 4.57 (1H, dd, J ) 6.3, 4.5 Hz), 4.67 (2H, s), 4.72 (1H, dd, J ) 5.7, 4.2 Hz), 7.20-7.40 (5H, m); 13C NMR (75 MHz): δ 24.0 (t), 25.0 (q), 26.1 (q), 30.7 (t), 51.7 (t), 60.2 (t), 71.4 (t), 72.4 (d), 74.2 (d), 77.9 (d), 79.4 (d), 110.7 (s), 127.2 (d), 127.6 (d), 128.0 (d), 139.1 (s). (3aR,9R,9aR,9bS)-Octahydro-2,3-dimethyl-1,3-dioxolo[4,5-a]indolizin-9-ol. The acetonide 16 (60 mg, 0.198 mmol) was dissolved in methanol (2 mL), palladium(II) chloride (30 mg, 0.169 mmol) was added, and the mixture was stirred under an atmosphere of hydrogen for 30 min. After being flushed with nitrogen, the mixture was filtered, and the solids were washed with methanol (2 × 5 mL). The filtrates were evaporated to dryness to give a white solid. The pure product was obtained by column chromatography (chloroform/methanol/ 25% NH3(aq) 100:9:1 as eluant), which gave the title compound (42 mg, 0.197 mmol, 100%) as a white solid that had spectral data identical to that reported in the literature:12,22 mp 8082 °C (lit.22 100-104 °C); [R]26D -49 (c 0.42, CHCl3) [lit.12c,22 [R]26D -67 (c 0.46, CHCl3)]; MS (CI+) m/z 214 (100) (M + 1);

7780 J. Org. Chem., Vol. 67, No. 22, 2002

HRMS (CI+) found 214.1440, calcd for C11H20NO3 214.1443 (M + 1); 1H NMR (300 MHz) δ 1.16-1.60 (1H, m), 1.34 (3H, s), 1.51 (3H), 1.59-1.72 (3H, m), 1.86 (1H, ddd, J ) 10.5, 6.0, 4.2 Hz), 2.05 (1H, ddd, J ) 11.7, 7.5, 3.3 Hz), 2.13 (1H, dd, J ) 11.1, 4.2 Hz), 2.61 (1H, br. s), 2.99 (1H, dt, J ) 10.5, 3.0 Hz), 3.15 (1H, d, J ) 10.5 Hz), 3.83 (1H, ddd, J ) 11.1, 9.0, 4.8 Hz), 4.61 (1H, dd, J ) 6.0, 4.5 Hz), 4.71 (1H, dd, J ) 6.3, 4.8 Hz); 13C NMR (75 MHz) δ 24.8 (q), 25.9 (q), 24.0 (t), 33.0 (t), 51.6 (t), 59.9 (t), 67.1 (d), 73.6 (d), 78.1 (d), 79.1 (d), 111.1 (s). (1R,2S,8S,8aS)-Octahydro-1,2,8-indolizinetriol [(-)Swainsonine ] (1). (3aR,9R,9aR,9bS)-Octahydro-2,3-dimethyl-1,3-dioxolo[4,5-a]indolizin-9-ol (43 mg, 0.202 mmol) was dissolved in tetrahydrofuran (2 mL), and then 2 M HCl(aq) (3 mL) was added. The mixture was stirred at rt for 20 h, and then all volatiles were removed in vacuo to give an amber gum. This was dissolved in water (2 mL), applied to Dowex-1 basic ion-exchange resin (OH form), and eluted with water. Evaporation of the eluant afforded (-)-swainsonine (33 mg, 0.191 mmol, 94.3%) as a white solid. This compound had identical TLC mobility (CH2Cl2/MeOH/25% ammonia 50:50:2) and NMR spectra to an authentic sample:23 [R]26D -71 (c 0.56, MeOH) [lit.12c [R]26D -83 (c 1.03, MeOH)]; MS (CI+) m/z 174 (100) (M + 1); HRMS (ES+) found 174.1186, calcd for C8H16NO3 174.1130 (M + 1); 1H NMR (300 MHz, D2O) δ 1.13 (1H, qd, J ) 12.6, 4.8 Hz), 1.41 (1H, qt, J ) 13.5, 4.2 Hz), 1.62 (1H, br. d, J ) 13.6 Hz), 1.82 (1H, dd, J ) 7.8, 3.9 Hz), 1.85-2.00 (2H, m), 2.46 (1H, dd, J ) 11.1, 7.8 Hz), 2.75-2.85 (2H, m), 3.69 (1H, ddd, J ) 11.1, 9.6, 4.8 Hz), 4.15 (1H, dd, J ) 6.0, 3.9 Hz), 4.24 (1H, ddd, J ) 8.1, 6.0, 2.4 Hz); 13C NMR (75 MHz, D2O ref CH3CN): 22.2 (t), 31.5 (t), 50.6 (t), 59.7 (t), 65.2 (d), 67.9 (d), 68.5 (d), 71.8 (d).

Acknowledgment. We thank the Australian Research Council for financial support and the University of Wollongong for a Ph.D. scholarship to K.L. We thank Dr. Reg Smith from Phytex, Australia, for an authentic sample of (-)-swainsonine. Supporting Information Available: Full experimental details for the synthesis of (+)-1,2-di-epi-swainsonine and (+)1,2,8-tri-epi-swainsonine and copies of the 1H or 13C NMR spectra of all new compounds described in this paper. This material is available free of charge via the Internet at http://pubs.acs.org. JO025977W