Asymmetric synthesis of (-)-swainsonine, (+)-1,2-di-epi-swainsonine, and (+)-1,2,8-tri-epi-swainsonine

Article abstract of DOI:10.1021/jo025977w

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, ring-closing metathesis, and intramolecular N-alkylation to prepare the indolizidine ring and a highly diastereoselective cis-dihydroxylation using AD-mix-α. This synthetic strategy also allowed for the diastereoselective synthesis of (+)-1,2-di-epi-swainsonine and (+)-1,2,8-tri-epi-swainsonine.

Full text of DOI:10.1021/jo025977w

Asym m etr ic Syn th esis of (-)-Sw a in son in e,
(+)-1,2-Di-epi-sw a in son in e, a n d (+)-1,2,8-Tr i-epi-sw a in son in e
Karl B. Lindsay and Stephen G. Pyne*
Department of Chemistry, University of Wollongong, Wollongong, New South Wales 2522, Australia
stephen_pyne@uow.edu.au
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, ring-
closing 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.
SCHEME 1
In tr od u ction
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 re-
sulted 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 inhibi-
tory activity on this enzyme.3 Fleet has indicated the
potential of (+)-swainsonine and its analogues as thera-
peutic 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.
shown in Scheme 1. The key steps involve cis-dihydroxy-
lation of the alkene 2, which can be prepared by a ring-
closing metathesis reaction6-9 of the diene 3. In fact, the
alkene 2 has been prepared via a different synthetic route
We report here an asymmetric synthesis of (-)-swain-
sonine 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.
(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. Tetra-
hedron Lett. 2001, 42, 4079-4082. (h) Klitze, C. F.; Pilli, R. A.
Tetrahedron Lett. 2001, 42, 5605-5608. (i) Chandra, K. L.; Chan-
drasekhar, 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, 2376-
2378. (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.
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.; J ewell, 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.; J ones, 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, 2735-
2745.
(5) Oishi, T.; Iwakuma, T.; Hirama, M.; Itoˆ, S. Synlett 1995, 404-
406.
(9) Lindsay, K. B.; Tang, M.; Pyne, S. G. Synlett 2002, 731-734.
10.1021/jo025977w CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/28/2002
7774
J . Org. Chem. 2002, 67, 7774-7780

Asymmetric Synthesis of (-)-Swainsonine
1
ee from H NMR analysis of its Mosher ester [1H NMR δ
SCHEME 2a
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).
1
The 9 Hz vicinal coupling constant, J 4,5, in the H NMR
spectrum of A was consistent with 4,5-cis relative ster-
eochemistry.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.
a
Reagents: (a) D-(-)-DIPT, Ti(OPri)4, TBHP, CH2Cl2, 4A MS,
-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 cis-
dihydroxylation (DH) reaction, albeit with modest dias-
teroselection.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 hy-
droxyl group of 2 was protected as its benzyl ether in our
final execution of the synthesis of 1.
Syn th esis of (-)-Sw a in son in e. Commercially avail-
able 4-pentyn-1-ol was converted to the known trans-
allylic 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%
Catalytic cis-dihydroxylation of 13 with osmium tet-
raoxide/N-methylmorpholine N-oxide,20 followed by acety-
lation 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 dias-
tereofacial selectivity has been reported in the cis-
dihydroxylation of the alcohol 2 and its TIPS and TBS
ethers.5,10,20 However, we have found that the cis-dihy-
droxylation of 13 using commercially available AD-mix-R
in the presence of methanesulfonamide21 followed by
acetylation gave 14 in a very highly diastereoselective
1
fashion (14/15 ) 98:2 from H NMR analysis of the crude
(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, 3194-
3202. (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.
(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 .; J eong, 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.
J . Org. Chem, Vol. 67, No. 22, 2002 7775

Lindsay and Pyne
SCHEME 3a
SCHEME 4a
a
Reagents: (a) OsO4, NMO, acetone/water; (b) NaH, BnBr,
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.
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.
to an authentic sample of (-)-swainsonine23 and had a
specific rotation, [R]26 -71 (c 0.56, MeOH) [lit.12c [R]26
D
D
-82.6 (c 1.03, MeOH); lit.22a [R]23 -86 (c 0.30, MeOH);
D
lit.24a [R]23D -74 (c 0.98, MeOH); lit.24b [R]26D -85.5 (c 0.42,
MeOH); lit.24c [R]23 -87.2 (c 2.1, MeOH)] that was
D
consistent with the enantiomeric purity of its precursors.
Syn th esis of (+)-1,2-Di-epi-sw a in son in e (21). The
2,3-dihyropyrrole 10 could also be converted to (+)-1,2-
di-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 dihydroxy-
lation 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-deprotec-
tion 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 pal-
ladium 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
F IGURE 1. Dihydroxylation of 13.
reaction mixture) and as a single diastereomer in an
overall purified yield of 44%. When AD-mix-â 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-dihydroxy-
lation reaction of 13 with AD-mix-R or -â is consistent
with addition of the bulky osmium reagent to the R-face
of the molecule since attack from the â-face would be
sterically hindered by the pseudoaxial protons H8a and
H3â (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 H and 13C NMR
1
value25 ([R]23 +61.1 (c 2.11, CHCl3)).
spectra of this compound were identical to that reported
in the literature,22 while the specific rotation of this
compound ([R]26 -54 (c 0.6, CHCl3), lit.12c [R]26 -58.9
D
Syn th esis of (+)-1,2,8-Tr i-epi-sw a in son in e (32).
For the synthesis of (+)-1,2,8-tri-epi-swainsonine (32), the
known E-allylic alcohol 2313b was converted to its corre-
sponding (S,R)-vinyl epoxide 2426 (Scheme 5) using
D
D
(c 0.27, CHCl3) [lit.22a [R]23 -67 (c 0.30, CHCl3))] also
D
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
(23) Kindly provided by Dr. Reg Smith, from Phytex Australia,
Sydney.
1
had H and 13C NMR spectra and TLC mobility identical
(24) (a) Pearson, W. H.; Hembre, E. J . J . Org. Chem. 1996, 61, 7217-
7221. (b) Hunt, J . A.; Roush, W. R. J . Org. Chem. 1997, 62, 1112-
1124. (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.
(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.
7776 J . Org. Chem., Vol. 67, No. 22, 2002

Asymmetric Synthesis of (-)-Swainsonine
SCHEME 5a
In conclusion, a synthetic strategy has been developed
that allows the synthesis of (-)-swainsonine, (+)-1,2-di-
epi-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.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were carried out under an
atmosphere of nitrogen. Where necessary, reagents and sol-
vents 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 either
a 10 or a 20 mm diameter column, and large-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-Meth oxyp h en yl)m eth oxy]-2R,3R-ep oxyh exa n -1-
ol (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-[(4-
methoxyphenyl)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).
a
Reagents: (a) D-(-)-DIPT, Ti(OPri)4, TBHP, CH2Cl2, -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) 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 ally-
lamine, 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 trifluo-
roacetic 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 hy-
drogen 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
P r ep a r a tion of Mosh er Ester of Alcoh ol 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-(dimethy-
lamino)pyridine (36 mg, 0.294 mmol), and finally MTPACl (60
µL, 81 mg, 0.321 mmol) were added. The mixture was stirred
specific rotation, [R]25 +41 (c 0.84, MeOH), closely
D
matched the literature value27b ([R]D +45.6 (c 0.40,
MeOH)).
(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.
(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.
J . Org. Chem, Vol. 67, No. 22, 2002 7777

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].
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]28 +10 (c 1.9,
D
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).
6-[(4-Met h oxyp h en yl)m et h oxy]-2S,3R-ep oxyh exa n -1-
a l. 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 dichlo-
romethane (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).
5R-(3′-[(4-Meth oxyp h en yl)m eth oxy]p r op yl-4S-eth en yl-
3-(2-p r op en yl)-2-oxa zolid in on e (A in eq 1). The amino
alcohol 8 (88 mg, 0.288 mmol) was dissolved in dichlo-
romethane (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 petro-
leum spirit as eluant), which gave the title compound (72 mg,
0.217 mmol, 75.4%) as a clear oil: [R]23 -29 (c 3.5, CHCl3);
D
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),
1
131.9 (d), 157.3(s), 159.0 (s); H 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).
7-[(4-Meth oxyph en yl)m eth oxy]-3R,4R-epoxy-1-h epten e
(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-[(4-
Methoxyphenyl)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:
N-ter t-Bu t yloxyca r bon yl-7-[(4-m et h oxyp h en yl)m et h -
oxy]-4R-h yd r oxy-3S-a llyla m in oh ep t-1-en e (9). The amino
alcohol 8 (1.07 g, 3.503 mmol) was dissolved in dry tetrahy-
drofuran (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
[R]27 +15 (c 2.0, CHCl3); MS (CI+) m/z 247 (49) (M - 1);
D
HRMS (CI+) found 247.137438, calcd for C15H19O3 247.133420
1
(M - 1); H 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).
oil: [R]25 -12 (c 1.95, CHCl3); MS (ES+) m/z 406.5 (62) (M +
D
1); HRMS (CI+) found 406.257853, calcd for
C23H36NO5
406.259349 (M + 1); 1H NMR (300 MHz) δ 1.45 (9H, s), 1.55-
1.85 (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).
7-[(4-Met h oxyp h en yl)m et h oxy]-4R-h yd r oxy-3S-a lly-
la m in oh ep t-1-en e (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
2S-(1′R-Hydr oxy-4′-[(4-m eth oxyph en yl)m eth oxy]bu tyl)-
7778 J . Org. Chem., Vol. 67, No. 22, 2002

Asymmetric Synthesis of (-)-Swainsonine
N-ter t-bu tyloxyca r bon yl-2,5-d ih yd r op yr r ole (10). The di-
ene 9 (500 mg, 1.233 mmol) was dissolved in dry dichlo-
romethane (300 mL), and then benzylidene-bis-tricyclo-
hexylphosphine)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
(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,8a S)-8-P h en ylm eth oxy-2,3-d eh yd r oin d olizin e (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 triphenylphos-
phine (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 (443 mg, 1.174 mmol, 95.2%) as a clear oil: [R]24
D
-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
+ 1); H 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).
compound (95 mg, 0.414 mmol, 73.7%) as a clear oil: [R]24
D
-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).
2S-[1′R-P h en ylm eth oxy-4′-[(4-m eth oxyph en yl)m eth oxy]-
bu tyl]-N-ter t-bu tyloxyca r bon yl-2,5-d ih yd r op yr r ole (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
(1S,2R,8R,8aR)-8-(P h en ylm eth oxy)-1,2-diacetoxyin doliz-
in e (14) a n d (1R,2S, 8R,8a R)-8-(P h en ylm eth oxy)-1,2-d i-
a cetoxyin d olizid in e (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,
in 11 was also isolated): [R]24 -96 (c 1.6, CHCl3); MS (CI+)
D
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).
0.576 mmol, 17.1%) as clear oils. 14: [R]25 -108 (c 2.15,
D
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
2S-(1′R-P h en ylm eth oxy-4′-h yd r oxybu tyl)-2,5-d ih yd r o-
p yr r ole (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%)
(s). 15: [R]24 +6 (c 1.0, CHCl3); MS (CI+) m/z 348 (69) (M +
D
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), 2.20-
2.36 (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);
13C 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).
as a clear oil: [R]24 -83 (c 4.0, CHCl3); MS (CI+) m/z 248
D
(100) (M + 1); HRMS (CI+) found 248.165414, calcd for C15H22
-
(3a R,9R,9a R,9b S)-Oct a h yd r o-2,3-d im et h yl-9-(p h en yl-
m eth oxy)-1,3-d ioxolo[4,5-a ]in d olizin e (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
NO2 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
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
HRMS (CI+) found 214.1440, calcd for C11H20NO3 214.1443
1
(M + 1); H 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,8a S)-Oct a h yd r o-1,2,8-in d olizin et r iol [(-)-
Sw a in son in e ] (1). (3aR,9R,9aR,9bS)-Octahydro-2,3-dim-
ethyl-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. Evapo-
ration 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
[R]23 -67 (c 0.3, CHCl3)]; MS (CI+) m/z 304 (100) (M + 1);
spectra to an authentic sample:23 [R]26 -71 (c 0.56, MeOH)
D
D
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).
[lit.12c [R]26 -83 (c 1.03, MeOH)]; MS (CI+) m/z 174 (100) (M
D
+ 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).
(3a R,9R,9a R,9bS)-Octa h yd r o-2,3-d im eth yl-1,3-d ioxolo-
[4,5-a ]in d olizin -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 80-
Ack n ow led gm en t. We thank the Australian Re-
search 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.
Su p p or tin g In for m a tion Ava ila ble: 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.
82 °C (lit.22 100-104 °C); [R]26 -49 (c 0.42, CHCl3) [lit.12c,22
D
[R]26 -67 (c 0.46, CHCl3)]; MS (CI+) m/z 214 (100) (M + 1);
J O025977W
D
7780 J . Org. Chem., Vol. 67, No. 22, 2002