A practical synthesis of (-)-swainsonine

Full text of DOI:10.1021/jo961101b

J . Org. Chem. 1996, 61, 7217-7221
7217
Sch em e 1. Retr osyn th etic An a lysis of
(-)-Sw a in son in e: Red u ctive Cycliza tion of a n
Azid e Bea r in g Tw o Rem ote Electr op h ilic Sites
A P r a ctica l Syn th esis of (-)-Sw a in son in e
William H. Pearson* and Erik J . Hembre
Department of Chemistry, The University of Michigan,
Ann Arbor, Michigan 48109-1055
Received J une 11, 1996
The indolizidine alkaloid (-)-swainsonine (1) is of long-
standing interest due to its diverse biological activity.1,2
It may be considered an azasugar analog of mannose and
is indeed a potent inhibitor of many mannosidases
including the glycoprotein-processing enzyme mannosi-
dase II.3-7 Swainsonine is the first glycoprotein-process-
ing inhibitor to be selected for clinical testing as an
anticancer drug,8,9 but its high cost has hindered clinical
trials.10 Apparently, there is still no cost-effective way
to either isolate swainsonine from natural sources or to
prepare it synthetically. While a great deal of effort has
been expended on developing synthetic routes to swain-
sonine,11 there is still a need for a practical synthesis of
this important alkaloid. Perhaps the most practical
routes developed to date are those reported by the
research groups of Fleet11m,r and Cha.11n The shortest
synthetic route, developed in our group, has not proven
amenable to scale-up.11o Recent efforts in our laborato-
ries directed toward preparing analogs of swainsonine
have led to the development of a practical route to this
important alkaloid. We report herein a synthesis of (-)-
swainsonine that is relatively short and efficient and uses
simple reactions that allow good reproducibility and
material throughput. Multigram quantities of the pure
alkaloid were easily prepared using small-scale labora-
tory equipment.
to a derivative of D-erythrose. We have previously used
the reductive double-cyclization of an azide bearing two
remote electrophilic centers for the synthesis of other
bioactive alkaloids and their analogs.12,13
(11) (a) Suami, T.; Tadano, K.; Iimura, Y. Chem. Lett. 1984, 513-
516. (b) Ali, M. H.; Hough, L.; Richardson, A. C. J . Chem. Soc., Chem.
Commun. 1984, 447-448. (c) Fleet, G. W. J .; Gough, M. J .; Smith, P.
W. Tetrahedron Lett. 1984, 25, 1853-1856. (d) Yasuda, N.; Tsutsumi,
H.; Takaya, T. Chem. Lett. 1984, 1201-1204. (e) Adams, C. E.; Walker,
F. J .; Sharpless, K. B. J . Org. Chem. 1985, 50, 420-422. (f) Suami, T.;
Tadano, K. Iimura, Y. Carbohydr. Res. 1985, 136, 67-75. (g) Ali, M.
H.; Hough, L. Richardson, A. C. Carbohydr. Res. 1985, 136, 225-240.
(h) Setoi, H.; Takeno, H.; Hashimoto, M. J . Org. Chem. 1985, 50, 3948-
3950. (i) Ikota, N.; Hanaki, A. Chem. Pharm. Bull. 1987, 35, 2140-
21433. (j) Ikota, N.; Hanaki, A. Heterocycles 1987, 26, 2368. (k) Bashyal,
B. P.; Fleet, G. W. J .; Gough, M. J .; Smith, P. W. Tetrahedron 1987,
43, 3083. (l) Dener, J . M.; Hart, D. J . Ramesh, S. J . Org. Chem. 1988,
53, 6022-6030. (m) Carpenter, N. M.; Fleet, G. W. J .; diBello, I. C.;
Winchester, B.; Fellows, L. E.; Nash, R. J . Tetrahedron Lett. 1989, 30,
7261-7264. (n) Bennett, R. B., III; Choi, J .-R.; Montgomery, W. D.;
Cha, J . K. J . Am. Chem. Soc., 1989, 111, 2580-2582. (o) Pearson, W.
H.; Lin, K.-C. Tetrahedron Lett., 1990, 31, 7571. (p) Miller, S. A.;
Chamberlin, A. R. J . Am. Chem. Soc., 1990, 112, 8100-8112. (q) Ikota,
N.; Hanaki, A. Chem. Pharm. Bull. 1990, 38, 2712. (r) Fleet, G. W. J .
U. S. Patent 5,023,340, 1991. (s) Naruse, M.; Aoyagi, S.; Kibayashi, C.
J . Org. Chem., 1994, 59, 1358-1364. (t) Hunt, J . A.; Roush, W. R.
Tetrahedron Lett. 1995, 36, 501-504. (u) Kang, S. H.; Kim, G. T.
Tetrahedron Lett. 1995, 36, 5049-5052. For a synthesis of the non-
natural (+)-enantiomer of swainsonine, see: (v) Oishi, T.; Iwakuma,
T.; Hirama, M.; Ito, S. Synlett 1995, 404-406. Formal syntheses: (w)
Gonzalez, F. B.; Barba, A. L.; Espina, M. R. Bull. Chem. Soc. J pn. 1992,
65, 567-574. (x) Honda, T.; Hoshi, M.; Kanai, K.; Tsubuki, M. J . Chem.
Soc., Perkin Trans. 1 1994, 2091-2101. (y) Angermann, J .; Homann,
K.; Reissig, H.-U.; Zimmer, R. Synlett 1995, 1014-1016. (z) Zhou, W.-
S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.-F. Tetrahedron Lett. 1995, 36, 1291-
1294. (aa) Zhou, W.-S.; Xie, W.-G.; Lu, Z.-H.; Pan, X.-F. J . Chem. Soc.,
Perkin Trans. 1 1995, 2599-2604.
(12) Slaframine: (a) Pearson, W. H.; Bergmeier, S. C. J . Org. Chem.
1991, 56, 1976-1978. (b) Pearson, W. H.; Bergmeier, S. C.; Williams,
J . P. J . Org. Chem. 1992, 57, 3977-3987. Australine and alexine
stereoisomers: (c) Pearson, W. H.; Hines, J . V. Tetrahedron Lett. 1991,
32, 5513-5516. Ring-expanded analogs of swainsonine: (d) Pearson,
W. H.; Hembre, E. J . Tetrahedron Lett. 1993, 34, 8221-8224. (e)
Pearson, W. H.; Hembre, E. J . J . Org. Chem., 1996, 61, 5537-5545.
Ring-expanded analogs of australine and alexine: (f) Pearson, W. H.;
Hembre, E. J . J . Org. Chem., 1996, 61, 5546-5556.
(13) For related one-pot double cyclizations using azido epoxides or
amino epoxides, see references 11h,m and: (a) Kim, Y. G.; Cha, J . K.
Tetrahedron Lett. 1989, 30, 5721-5724. (b) Ina, H.; Kibayashi, C. J .
Org. Chem. 1993, 58, 52-61. (c) J irousek, M. R.; Cheung, A. W.-H.;
Babine, R. E.; Sass, P. M.; Schow, S. R.; Wick, M. M. Tetrahedron Lett.
1993, 34, 3671-3674. (d) Kim, N.-S.; Choi, J .-R.; Cha, J . K. J . Org.
Chem. 1993, 58, 7096-7099. (e) Poitout, L.; Le Merrer, Y.; Depezay,
J .-C. Tetrahedron Lett. 1994, 35, 3293-3296. (f) Lohray, B. B.;
J ayamma, Y.; Chatterjee, M. J . Org. Chem. 1995, 60, 5958-5960.
Our strategy for the synthesis of swainsonine is shown
in Scheme 1. The lactam A may arise from a reductive
double-cyclization of the azido lactone B, which should
be available by dihydroxylation of C. The γ,δ-unsatur-
ated carboxylic acid derivative C was proposed to be
available by a Claisen rearrangement of the allylic
alcohol D derived by addition of a vinyl organometallic
(1) Isolation from the fungus Rhizoctonia leguminicola: (a) Guenger-
ich, F. P.; DiMari, S. J .; Broquist, H. P. J . Am. Chem. Soc. 1973, 95,
2055. (b) Schneider, M. J .; Ungemach, F. S.; Broquist, H. P.; Harris,
T. M. Tetrahedron 1983, 39, 29-32. From the fungus Metarhizium
anisopliae: (c) Hino, M.; Nakayama, O.; Tsurumi, Y.; Adachi, K.;
Shibata, T.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J . Antibiot.
1985, 35, 926-935. (d) Patrick, M. S.; Adlard, M. W.; Keshavarz, T.
Biotechnol. Lett. 1995, 17, 433-438. From the legume Swainsona
canescens: (e) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J .
Chem. 1979, 32, 2257-64. From the locoweed Astragalus lentigino-
sus: (f) Molyneux, R. J .; J ames, L. F. Science 1982, 216, 190-191. From
Weir vine: (g) Molyneux, R. J .; McKenzie, R. A.; O’Sullivan, B. M.;
Elbein, A. D. J . Nat. Prod. 1995, 58, 878-886.
(2) For a review of the synthesis and biological activity of swainso-
nine and other glycosidase inhibitors, see: Nishimura, Y. In Studies
in Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Am-
sterdam, 1992; Vol. 10, pp 495-583.
(3) Elbein, A. D. Annu. Rev. Biochem 1987, 56, 497-534.
(4) Cenci Di Bello, I.; Fleet, G.; Namgoong, S. K.; Tadano, K.;
Winchester, B. Biochem. J . 1989, 259, 855-861.
(5) Elbein, A. D. FASEB J . 1991, 5, 3055-3063.
(6) Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2, 199-210.
(7) Kaushal, G. P.; Elbein, A. D. Methods Enzymol. 1994, 230, 316-
329.
(8) Goss, P. E.; Baker, M. A.; Carver, J . P.; Dennis, J . W. Clin.
Cancer Res. 1995, 1, 935-944.
(9) Das, P. C.; Roberts, J . D.; White, S. L.; Olden, K. Oncol. Res.
1995, 7, 425-433.
(10) For example, Sigma Chemical Co. sells 1 mg of (-)-swainsonine
isolated from Rhizoctonia leguminicola for ca. $100 (1995 catalog).
Toronto Research Chemicals sells 1 mg of synthetic (-)-swainsonine
for ca. $40.
S0022-3263(96)01101-2 CCC: $12.00 © 1996 American Chemical Society

7218 J . Org. Chem., Vol. 61, No. 20, 1996
Sch em e 2. Syn th esis of (-)-Sw a in son in e
Notes
limits of detection by high-field 1H-NMR. Without
purification, 4 was submitted to the Sharpless dihy-
droxylation procedure,19,20 affording the lactones 5R and
5â in 70% and 9% yields, respectively, after separation.21
Removal of the silyl protecting group from 5R gave the
diol 6, which was smoothly converted to the crystalline
dimesylate 7. Selective displacement of the less hindered
mesylate of 7 with sodium azide afforded 8. Palladium-
catalyzed hydrogenolysis of 8 to the amine followed by
filtration of the catalyst and treatment of the filtrate with
sodium methoxide caused cyclization to the known
crystalline bicyclic lactam 9 in 75% yield. Reduction22
of 9 with borane-methyl sulfide complex gave a 94%
yield of crystalline 10, also a known compound,11h,k,n,s
which was hydrolyzed to swainsonine (1) in 96% yield.
While not the shortest synthesis,11o this route involves
simple, reproducible steps that work well on a substantial
scale. Using this method, 4.5 g of swainsonine was
prepared in 20% overall yield from the lactone 2, requir-
ing 11 steps involving three chromatographic separations
and five crystallizations.
To summarize, a simple route to the clinically useful
anticancer agent (-)-swainsonine (1) has been developed.
Given the current scarcity and high cost of this material,
this preparation may be useful to researchers in this
area. Finally, the possibility of preparing analogs of
swainsonine substituted at C(6) and C(7) arises by simple
modifications in the Claisen rearrangement step. This
strategy has recently been reduced to practice in our
laboratories. The preparation of these analogs and their
biological activity will be reported separately.
Exp er im en ta l Section
Gen er a l Meth od s. All commercial reagents (if liquid) were
distilled prior to use. All other solid reagents were used as
obtained. Tetrahydrofuran was distilled from sodium/benzophe-
none ketyl. Toluene, dichloromethane, dimethyl sulfoxide, and
triethylamine were distilled from calcium hydride. Dimethyl-
formamide was distilled from barium oxide at reduced pressure.
Methanol and ethanol were distilled from calcium oxide. All
reactions were conducted under an atmosphere of dry nitrogen.
Analytical thin layer chromatography (TLC) was conducted on
precoated silica gel plates (Kieselgel 60 F254, 0.25 mm thickness,
manufactured by E. Merck & Co., Germany). For visualization,
TLC plates were either stained with iodine vapor or phospho-
molybdic acid solution. Flash column chromatography was
performed according to the general procedure described by Still23
using flash grade Merck Silica Gel 60 (230-400 mesh). Gas
chromatographic (GC) analyses were performed using a 530 µm
methylpolysiloxane column (3 µm film thickness, 5 m length)
using flame ionization detection. A standard temperature
program of 100 °C for 2 min followed by a 40 °C/min ramp to
200 °C was used. Elemental analyses were performed by the
University of Michigan Department of Chemistry CHN/AA
Services Branch. High resolution mass spectrometric (HRMS)
The synthesis of swainsonine (Scheme 2) began with
2,3-O-isopropylidene-D-erythronolactone (2), which is
commercially available (Aldrich) or may be prepared in
large quantities from inexpensive D-isoascorbic acid.14,15
Reduction of 2 with diisobutylaluminum hydride16 pro-
vided 2,3,-O-isopropylidene-D-erythrose. Addition of vi-
nylmagnesium bromide17 followed by selective monopro-
tection of the resulting diol afforded the allylic alcohol 3
(97:3 anti/ syn) in 73% yield from 2. Separation of the
diastereomeric mixture was possible; however, it was
unnecessary, since both allylic alcohols 3 produce the
same γ,δ-unsaturated ester 4 when subjected to J ohnson
orthoester Claisen rearrangement conditions.18 The
rearrangement produced only the E-isomer within the
(19) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, 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.
(20) For similar oxidative lactonizations, see: (a) Wang, Z.-M.;
Zhang, X.-L.; Sharpless, K. B. Tetrahedron Lett. 1992, 33, 6407-6410.
(b) Keinan, E.; Sinha, S. C.; Sinha-Bagchi, A.; Wang, Z.-M.; Zhang,
X.-L.; Sharpless, K. B. Tetrahedron Lett. 1992, 33, 6411-6414.
(21) Alternatively, Cha’s method might be used to transform 4 into
swainsonine. Cha and co-workers made a compound similar to 4 (ethyl
ester, Z-alkene, free hydroxy instead of (tert-butyldimethylsilyl)oxy)
by a Wittig route.
(14) Cohen, N.; Banner, B. L.; Laurenzano, A. J .; Carozza, L. In
Organic Syntheses; Freeman, J . P., Ed.; Wiley: New York, 1990; Coll.
Vol. IV, pp 297-301.
(15) Dunigan, J .; Weigel, L. O. J . Org. Chem. 1991, 56, 6225-6227.
(16) Cohen, N.; Banner, B. L.; Lopresti, R. J .; Wong, F.; Rosenberger,
M.; Liu, Y. Y.; Thom, E.; Liebman, A. A. J . Am. Chem. Soc 1983, 105,
3661-3672.
(17) Mekki, B.; Singh, G.; Wightman, R. H. Tetrahedron Lett. 1991,
32, 5143-5146.
(18) J ohnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brocksom,
T. J .; Li, T.; Faulkner, D. J .; Petersen, M. R. J . Am. Chem. Soc. 1970,
92, 741-743.
(22) While the reduction of 9 to 10 has been reported by Fleet using
BH3‚Me2S,11m their procedure involves isolation of the borane complex
of 10. Our procedure is adapted from a similar one by Keck which was
used to make an epimer of swainsonine: Keck, G. E.; Romer, D. R. J .
Org. Chem. 1993, 58, 6083-6089.
(23) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem 1978, 43, 2923-
2925.

Notes
J . Org. Chem., Vol. 61, No. 20, 1996 7219
measurements are accurate to within 2.2 ppm (electron impact,
EI), 3.9 ppm (chemical ionization, CI), or 3.3 ppm (fast-atom
bombardment, FAB), based on measurement of the performance
of the mass spectrometer on a standard organic sample.
(3S,4S,5R)-6-[(ter t-Bu t yld im et h ylsilyl)oxy]-4,5-(isop r o-
p ylid en ed ioxy)-1-h exen -3-ol (3). The reduction of 2,3-O-
isopropylidene-D-erythronolactone (2) was performed using a
modified version of Cohen’s procedure.16 Diisobutylaluminum
hydride (101 mL of a 1.5 M solution in toluene, 152 mmol) was
added in a dropwise fashion via an addition funnel to a cold (-78
°C) solution of 2,3-O-isopropylidene-D-erythronolactone (2)14
(20.0 g, 126 mmol) in CH2Cl2 (360 mL). After 2 h, methanol (20
mL) was added, followed by brine (10 mL). After warming to
room temperature, the mixture was diluted with ether (500 mL),
and MgSO4 (150 g) was added. After stirring vigorously for 4
h, the mixture was filtered with suction through a sintered glass
funnel, and the filter cake was washed with ether (100 mL). The
filtrate was concentrated to give 17.0 g (84%) of crude 2,3-O-
isopropylidene-D-erythrose as a pale yellow oil that was used
without further purification.
The addition of vinylmagnesium bromide to 2,3-O-isopropy-
lidene-D-erythrose was carried out according to Mekki et al.17,24
The crude lactol was dissolved in THF (380 mL) and cooled to
-78 °C, and vinylmagnesium bromide (315 mL of a 1 M solution
in THF, 315 mmol) was added in a dropwise fashion via an
addition funnel. The mixture was then warmed to 0 °C. After
6 h, the reaction was quenched by the addition of saturated
aqueous NH4Cl (100 mL). The resulting mixture was diluted
with water (200 mL) and extracted with EtOAc (3 × 200 mL).
The combined organic layers were washed with brine, dried
(MgSO4), filtered, and concentrated to give 19.5 g of a yellow oil
that was used without further purification. Purification of a
small sample by chromatography (3:1 to 2:1 hexane/EtOAc
gradient) provided an analytically pure sample of the pure anti-
diol, (2R,3S,4S)-2,3-O-isopropylidene-1,2,3,4-tetrahydroxy-5-hex-
ene:24 Rf ) 0.14 (3:1 hexane/EtOAc); bp 94-100 °C at 0.25
mmHg; [R]23D -42.5° (c 1.53, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 5.99 (ddd, J ) 5.6, 10.6, 17.3 Hz, 1H), 5.38 (dt, J ) 1.4, 17.3
Hz, 1H), 5.27 (dt, J ) 1.4, 10.5 Hz, 1H), 4.3 (m, 2H), 4.05 (dd, J
) 5.8, 8.4 Hz, 1H), 4.02 (m, 1H), 3.8 (m, 3H), 1.43 (s, 3H), 1.35
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.5, 116.5, 108.4, 79.6,
77.3, 70.6, 60.7, 27.7, 25.3: IR (neat) 3383 (s), 2987 (s), 2937
(m), 1456 (w), 1382 (m), 1220 (s), 1048 (s); MS (CI, CH4) m/ z
(rel intensity) 189 [(M + H)+, 40], 173 (22), 131 (80), 113 (100);
HRMS (CI, CH4) calcd for C9H16O4H [(M + H)+] 189.1127, found
189.1122. Anal Calcd for C9H16O4: C, 57.43; H, 8.57. Found:
C, 57.44; H, 8.60.
(ddd, J ) 5.2, 10.6, 17.2 Hz, 1H), 5.40 (dt, J ) 1.7, 17.2 Hz, 1H),
5.22 (dt, J ) 1.6, 10.6 Hz, 1H), 4.37 (m, 1H), 4.21 (td, J ) 4.4,
6.7 Hz, 1H), 4.13 (dd, J ) 4.0, 6.5 Hz, 1H), 3.96 (dd, J ) 7.0,
10.7 Hz, 1H), 3.76 (dd, J ) 4.4, 10.7 Hz, 1H), 3.01 (d, J ) 5.8
Hz, 1H), 1.49 (s, 3H), 1.37 (s, 3H), 0.91 (s, 9H), 0.10 (s, 6H); 13
C
NMR (CDCl3, 90 MHz) δ 137.7, 115.8, 108.2, 79.6, 77.3, 67.0,
61.7, 27.2, 25.8, 24.9, 18.3, -5.6; IR (neat) 3475 (br, m) 2931
(s), 1858 (s), 1472 (m), 1381 (m) cm-1; MS (CI, NH3) m/ z (rel
intensity) 303 [(M + H)+, 1.5], 287 (6), 245 (100), 227 (26), 117
(41); HRMS (CI, NH3) calcd for C15H30O4SiH [(M + H)+]
303.1992, found 303.1983. Anal. Calcd for C15H30O4Si: C,
59.56; H, 10.00. Found: C, 59.61; H, 10.01.
Meth yl (E)-(6S,7R)-8-[(ter t-Bu tyld im eth ylsilyl)oxy]-6,7-
(isop r op ylid en ed ioxy)-4-octen oa te (4). Trimethyl orthoac-
etate (77 mL, 640 mmol) and propionic acid (1.9 mL, 26 mmol)
were added to a solution of the allylic alcohol 3 (27.9 g, 92.3
mmol) in toluene (500 mL). The flask was fitted with
a
distillation head, and the mixture was heated at reflux, distilling
off methanol as it formed. GC was used to monitor the
disappearance of starting material (tR ) 4.0 min) and the
appearance of product (tR ) 5.2 min, see General Methods above
for GC conditions). After 24 h, the mixture was cooled to room
temperature and concentrated to give 32.7 g (99%) of the title
compound 4 as a pale yellow oil that was used without further
purification. Purification of a small sample by chromatography
(10:1 hex/EtOAc) provided an analytically pure sample. Rf )
0.40 (6:1 hex/EtOAc); [R]23 -0.9° (c 1.08, CHCl3); 1H NMR
D
(CDCl3, 360 MHz) δ 5.77 (m, 1H), 5.57 (dd, J ) 7.7, 15.4 Hz,
1H), 4.58 (t, J ) 7.1 Hz, 1H), 4.15 (dd, J ) 6.1, 12.2 Hz, 1H),
3.68 (s, 3H), 3.59 (m, 2H), 2.41 (m, 4H), 1.46 (s, 3H), 1.36 (s,
3H), 0.89 (s, 9H), 0.06 (s, 6H); 13C NMR (CDCl3, 90 MHz) δ 173.3,
132.8, 126.5, 108.3, 78.6, 78.3, 62.3, 51.6, 33.4, 27.9, 27.6, 25.8,
25.4, 18.2, -5.4; IR (neat) 2930 (s), 2857 (m), 1743 (s), 1438 (m),
1375 (m) cm-1; MS (CI, NH3) m/ z (rel intensity) 376 [(M +
NH4)+, 12], 318 (87), 301 (100), 271 (29), 186 (32), 169 (29), 151
(28); HRMS (CI, NH3) calcd for C18H34O5SiNH4 [(M + NH4)+]
376.2519, found 376.2519. Anal. Calcd for C18H34O5Si: C,
60.30; H, 9.56. Found:: C, 60.12; H 9.61.
(5R)-5-[(1′S,2′R,3′R)-(4′-[(ter t-Bu tyld im eth ylsilyl)oxy]-1′-
h ydr oxy-2′,3′-(isopr opyliden edioxy)bu tyl]tetr ah ydr ofu r an -
2-on e (5r) a n d (5S)-5-[(1′R,2′R,3′R)-4′-[(ter t-Bu t yld im e-
t h y lsily l)o x y ]-1′-h y d r o x y -2′,3′-(iso p r o p y lid e n e d iox y)-
bu tyl]tetr a h yd r ofu r a n -2-on e (5â). The dihydroxylation was
performed using the general procedure reported by Sharpless.19
A solution of the crude alkene 4 (32.0 g, 89.2 mmol) in t-BuOH
(150 mL) was added to a cold (0 °C), mechanically stirred,
biphasic mixture of water (475 mL) and tert-butyl alcohol (300
mL) containing potassium ferricyanide (93 g, 280 mmol), potas-
sium carbonate (39 g, 280 mmol), potassium osmate dihydrate
(0.35 g, 0.95 mmol), (DHQD)2-PHAL (0.75 g, 0.96 mmol),19 and
methanesulfonamide (9.0 g, 94.5 mmol). The solution was
allowed to warm slowly to room temperature. GC was used to
monitor the disappearance of the alkene 4 (tR ) 5.2 min) and
the appearance of the product (tR ) 6.8 min, see General
Methods above for GC conditions). After 18 h, sodium sulfite
(150 g) was added, and the mixture was stirred an additional 1
h. EtOAc (400 mL) was then added, the layers were separated,
and the aqueous layer was extracted with EtOAc (3 × 400 mL).
The combined organic layers were washed with 2 N KOH (400
mL) and then dried (MgSO4) and concentrated. Chromatogra-
phy (10:1 to 3:1 hex/EtOAc gradient) provided 22.6 g (70% from
3) of 5R as a colorless oil followed by 2.98 g (9% from 3) of 5â as
The crude diol mixture was dissolved in THF/DMF (3:1, 400
mL). The solution was cooled to 0 °C, and tert-butyldimethylsilyl
chloride (18.8 g, 125 mmol) and imidazole (17.6 g, 259 mmol)
were added. After 45 min, the mixture was poured into ether
(400 mL), and the organic layer was washed with 1 M HCl (2 ×
200 mL). The combined aqueous layers were back-extracted
with ether (2 × 100 mL). The combined organic layers were
washed with water, 5% NaHCO3, and brine and then dried
(MgSO4), filtered, and concentrated. Chromatography (100:1 to
20:1 hex/EtOAc gradient) provided 27.1 g (71% from 2) of the
anti-allylic alcohol 3 followed by 0.88 g (2% from 2) of the syn-
allylic alcohol diastereomer. Data for 3-anti Rf ) 0.48 (6:1
hexane/EtOAc); [R]23 -36.3° (c 0.58, CHCl3); 1H NMR (CDCl3,
D
300 MHz) δ 6.02 (ddd, J ) 5.2, 10.6, 17.2 Hz, 1H), 5.44 (dt, J )
1.6, 17.2 Hz, 1H), 5.25 (dt, J ) 1.6, 10.6 Hz, 1H), 4.3-4.2 (m,
2H), 4.19 (d, J ) 3.2 Hz, 1H), 4.06 (dd, J ) 5.5, 9.2 Hz, 1H),
3.86 (dd, J ) 9.9, 10.5 Hz, 1H), 3.65 (dd, J ) 3.5, 10.5 Hz, 1H),
1.39 (s, 3H), 1.34 (s, 3H), 0.92 (s, 9H), 0.14 (s, 6H); 13C NMR
(CDCl3, 75 MHz) δ 137.4, 115.7, 108.5, 80.6, 77.2, 69.8, 62.0,
28.0, 25.8, 25.3, 18.3, -5.47, -5.52; IR (neat) 3470 (br m), 2933
(s), 2885 (s), 2859 (s), 1472 (m), 1380 (m), 1077 (s) cm-1; MS
(CI, NH3) m/ z (rel intensity) 303 [(M + H)+, 18], 285 (9), 262
(19), 245 (100), 227 (42), 173 (46); HRMS (CI, NH3) calcd for
a colorless oil. Data for 5R: Rf ) 0.28 (3:1 hex/EtOAc); [R]23
D
-36.3° (c 0.58, CHCl3); 1H NMR (CDCl3, 360 MHz) δ 4.84 (ddt,
J ) 1.4, 5.7, 7.2 Hz, 1H), 4.42 (dd, J ) 5.6, 9.7 Hz, 1H), 4.26
(ddd, J ) 3.6, 5.6, 9.9 Hz, 1H), 4.14 (br d, J ) 3.3 Hz, 1H), 3.77
(m, 2H), 3.65 (dd, J ) 3.5, 10.5 Hz, 1H), 2.72 (m, 1H), 2.44 (m,
1H), 2.32 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H), 0.91 (s, 9H), 0.13 (s,
6H); 13C NMR (CDCl3, 90 MHz) δ 178.0, 108.7, 79.1, 76.6, 76.4,
71.0, 61.8, 28.4, 27.9, 25.7, 25.3, 23.8, 18.2, -5.6, -5.7; IR (neat)
3430 (br w), 2934 (m), 2858 (m), 1778 (s), 1472 (w), 1370 (m)
cm-1; MS (CI, NH3) m/ z (rel intensity) 378 [(M + NH4)+, 52],
361 [(M + H)+, 100], 170 (27), 153 (27); HRMS (CI, CH4) calcd
for C17H32O6SiH [(M + H)+] 361.2046, found 361.2035. Anal.
Calcd for C17H32O6Si: C, 56.64; H, 8.95. Found: C, 56.58; H,
9.04.
C
15H30O4SiH [(M + H)+] 303.1992, found 303.1984. Anal. Calcd
for C15H30O4Si: C, 59.56; H, 10.00. Found: C, 59.29; H, 10.00.
Data for minor isomer (3-syn): Rf ) 0.41 (6:1 hex/EtOAc);
1
[R]23 -3.9° (c 1.05, CHCl3); H NMR (CDCl3, 360 MHz) δ 6.01
D
(24) Since the communication by Mekki et al. does not provide
experimental procedures or spectroscopic data,17 we have chosen to
include these details herein.
Data for 5â: Rf ) 0.18 (3:1 hex/EtOAc); [R]23 +4.5° (c 0.95,
D
1
CHCl3); H NMR (CDCl3, 300 MHz) δ 4.77 (td, J ) 2.9, 6.6 Hz,

7220 J . Org. Chem., Vol. 61, No. 20, 1996
Notes
1H), 4.31 (t, J ) 6.0 Hz, 1H), 4.18 (ddd, J ) 3.6, 5.8, 8.5 Hz,
1H), 3.94 (ddd, J ) 3.0, 4.1, 6.0 Hz, 1H), 3.83 (dd, J ) 8.5, 10.7
Hz, 1H), 3.66 (dd, J ) 3.6, 10.7 Hz, 1H), 2.85 (d, J ) 4.2 Hz,
1H), 2.69 (m, 1H), 2.46 (m, 1H), 2.28 (m, 2H), 1.45 (s, 3H), 1.36
(s, 3H), 0.89 (s, 9H), 0.08 (s, 6H); 13C NMR (CDCl3, 75 MHz)
177.3, 108.4, 79.8, 77.2, 76.8, 70.6, 61.6, 28.2, 27.6, 25.8, 25.3,
24.1, 18.3, -5.4; IR (neat) 3470 (br, m), 2954 (m), 2858 (m), 1778
(s), 1463 (m), 1381 (m) cm-1; MS (CI, NH3) m/ z (rel intensity)
378 [(M + NH4)+, 100], 361 [(M + H)+, 31], 320 (20), 303, (20),
170 (18), 153 (23); HRMS (CI, NH3 and CH4) calcd for C17H32O6-
SiH [(M + H)+] 361.2046, found 361.2033. Anal. Calcd for
Hz, 1H), 3.53 (dd, J ) 3.5, 13.1 Hz, 1H), 3.47 (dd, J ) 7.2, 13.1
Hz, 1H), 3.22 (s, 3H), 2.69 (m, 1H), 2.56 (dd, J ) 7.1, 9.8 Hz,
1H), 2.3-2.5 (m, 2H), 1.54 (s, 3H), 1.40 (s, 3H); 13C NMR (CDCl3,
90 MHz) δ 175.8, 109.2, 78.8, 78.1, 76.6, 75.8, 51.6, 39.2, 27.6,
27.5, 25.4, 24.2; IR (neat) 2990 (m), 2940 (m), 2105 (s), 1784 (s),
1360 (s) cm-1; MS (CI, NH3) m/ z (rel intensity) 367 [(M + NH4)+,
100], 322 (16), 228 (24); HRMS (CI, NH3) calcd for C12H19N3O7-
SNH4 [(M + NH4)+] 367.1287, found 367.1288. Anal. Calcd for
C
12H19N3O7S: C, 41.26; H, 5.48; N, 12.03. Found: C, 40.97; H,
5.36; N, 11.98.
(1S,2R,8R,8a R)-8-Hyd r oxy-1,2-(isop r op ylid en ed ioxy)in -
d olizid in -5-on e (9). Palladium hydroxide on carbon (1.50 g)
was added to a solution of the azido mesylate 8 (9.75 g, 27.9
mmol) in MeOH (500 mL). The flask was evacuated by aspirator
and purged with hydrogen three times, and the resulting
heterogeneous mixture was stirred under a balloon of hydrogen.
After 6 h, the hydrogen was evacuated and the mixture was
filtered through Celite, rinsing with MeOH (100 mL). Sodium
methoxide (3.20 g, 59.3 mmol) was added, and the solution was
warmed to reflux. The reaction was monitored by IR for the
disappearance of the lactone carbonyl stretch at 1784 cm-1 and
appearance of the lactam carbonyl stretch at 1625 cm-1. After
60 h, the solution was cooled to room temperature and concen-
trated to a volume of ca. 50 mL, causing precipitation of a white
solid. The mixture was diluted with CH2Cl2 (500 mL), florisil
(50 g) was added, and the mixture was stirred at room temper-
ature for 30 min. The suspension was then filtered through
Celite, and the filtrate was concentrated to give an yellow oil
that crystallized upon standing. Recrystallization from EtOAc/
ether (1:2) provided 3.85 g (61%) of lactam 9 as a white
crystalline solid. The mother liquor was concentrated to give a
yellow oil that was purified by chromatography (10% EtOH/
EtOAc) to give another 0.91 g of crystalline 9 [total yield: 4.76
g (75%)]. Rf ) 0.38 (10:1 CHC3/MeOH); mp 129 °C (lit. 126-
C
17H32O6Si: C, 56.64; H, 8.95. Found: C, 56.27; H, 8.91.
(5R)-5-[(1′S,2′R,3′R)-1′,4′-Dih ydr oxy-2′,3′-(isopr opyliden e-
d ioxy)bu tyl]tetr a h yd r ofu r a n -2-on e (6). A solution of tetra-
n-butylammonium fluoride (19.8 g of a 75% w/w solution in
water, 56.7 mmol) in THF (50 mL) was added to a cold (0 °C)
solution of 5R (18.6 g, 51.6 mmol) in THF (250 mL). After 1.5
h, silica gel (25 g) and water (10 mL) were added, and the
mixture was stirred another 10 min. The mixture was then
filtered through Celite, rinsing with ether (300 mL). The filtrate
was dried (MgSO4) and concentrated. Chromatography (30:60:1
to 30:60:10 hex/EtOAc/EtOH gradient) provided 11.7 g (84%) of
the diol 6 as a pale yellow oil. Rf ) 0.25 (20:1 CHCl3/MeOH);
[R]23D -66.9° (c 0.90, CHCl3); 1H NMR (CDCl3, 360 MHz) δ 4.87
(m, 1H), 4.33 (m, 2H), 4.22 (d, J ) 6.3 Hz, 1H), 3.8 (m, 3 H),
3.38 (t, J ) 5.7 Hz, 1H), 2.68 (ddd, J ) 7.2, 9.3, 17.5 Hz, 1H),
2.50 (ddd, J ) 7.3, 10.0, 17.5 Hz, 1H), 2.33 (m, 2H), 1.41 (s, 3H),
1.36 (s, 3H); 13C NMR (CDCl3, 90 MHz) δ 178.5, 108.6, 80.0,
76.8, 76.2, 70.8, 60.7, 28.6, 27.8, 25.2, 23.6; IR (neat) 3390 (br,
s), 2987 (s), 2939 (s), 1770 (s), 1372 (s) cm-1; MS (CI, NH3) m/ z
(rel intensity) 264 [(M + NH4)+, 100], 247 [(M + H)+, 55], 229
(15), 206 (15), 160 (11); HRMS (CI, NH3) calcd for C11H18O6H
[(M + H)+] 247.1182, found 247.1187. Anal. Calcd for
C
11H18O6: C, 53.65; H, 7.37. Found: C, 53.44; H, 7.33.
128 °C,11m 125-127 °C11h); [R]23 +12.6° (c 1.06, MeOH), [lit.
(5R)-5-[(1′S,2′R,3′R)-1′,4′-Bis(m eth a n esu lfon yloxy)-2′,3′-
D
[R]25 +4.3° (c 0.16, MeOH)11h]; 1H NMR (300 MHz, CDCl3) δ
(isop r op ylid en ed ioxy)b u t yl]t et r a h yd r ofu r a n -2-on e (7).
Methanesulfonyl chloride (10.1 mL, 130 mmol) was added to a
cold (0 °C) solution of the diol 6 (10.7 g, 43.3 mmol) and DMAP
(0.265 g, 2.16 mmol) in pyridine (130 mL). The mixture was
stirred for 30 min and then placed in a refrigerator (2 °C). After
16 h, ethyl acetate (400 mL) was added, and the solution was
washed with 10% HCl (3 × 100 mL). The aqueous layers were
back-extracted with ethyl acetate (100 mL). The combined
organic layers were washed with saturated NaHCO3 and brine,
dried (MgSO4), and concentrated to give a foamy yellow solid.
Recrystallization from EtOAc/hex (∼1:1) provided 15.7 g (90%)
of the dimesylate 7 as a pale yellow crystalline solid in three
crops. Rf ) 0.11 (1:1 hex/EtOAc); mp 120-123 °C; [R]23D +39.8°
(c 1.31, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 4.81 (ddd, J )
2.9, 5.9, 7.7 Hz, 1H), 4.52 (td, J ) 3.1, 6.4 Hz, 1H), 4.46 (dd, J
) 3.1, 10.8 Hz, 1H), 4.40 (dd, J ) 4.8, 5.8, 1H), 4.32 (dd, J )
6.6, 10.8 Hz, 1H), 3.25 (s, 3H), 3.08 (s, 3H), 2.74 (m, 1H), 2.58
(m, 1H), 2.44 (m, 2H), 1.54 (s, 3H), 1.40 (s, 3H); 13C NMR (CDCl3,
90 MHz) δ 175.9, 109.4, 78.8, 77.9, 76.1, 75.1, 69.3, 39.2, 37.3,
27.4, 27.3, 25.6, 23.9; IR (neat) 3027 (w), 2989 (m), 2942 (m),
1784 (s), 1462 (w), 1359 (s) cm-1; MS (CI, NH3) m/ z (rel
intensity) 420 [(M + NH4)+, 100], 403 [(M + H)+, 2], 246 (56);
HRMS (CI, NH3) calcd for C13H22O10S2NH4 [(M + NH4)+]
420.0998, found 420.0998. Anal. Calcd for C13H22O10S2: C,
38.80, H, 5.51. Found: C, 38.93; H, 5.63.
(5R)-5-[(1′S,2′R,3′R)-4′-Azid o-2′,3′-(isop r op ylid en ed ioxy)-
1′-(m eth a n esu lfon yloxy)bu tyl]tetr a h yd r ofu r a n -2-on e (8).
Sodium azide (12.1 g, 187 mmol) was added to a solution of the
dimesylate 7 (15.0 g, 37.4 mmol) in DMSO (110 mL), and the
flask was heated at 80 °C (oil bath). After 36 h, the solution
was cooled and poured into water (300 mL) and extracted with
EtOAc (3 × 200 mL). The combined organic extracts were
washed with brine, dried (MgSO4), and concentrated. Crystal-
lization from CHCl3/Et2O provided 8.50 g (65%) of the azido-
mesylate 8 as a white crystalline solid in two crops. The mother
liquor was concentrated and chromatography (2:1 hex/EtOAc to
50:50:1 hex/EtOAc/EtOH gradient) provided 0.99 g (9%) of the
diazide [Rf ) 0.62 (1:1 hex/EtOAc)], followed by an additional
1.33 g of 8 [total yield 9.83 g (75%)], and 0.75 g (5%) of recovered
D
4.81 (dd, J ) 4.5, 6.0 Hz, 1H), 4.75 (t, J ) 5.5 Hz, 1H), 4.19 (d,
J ) 13.5 Hz, 1H), 4.15 (ddd, J ) 4.2, 8.4, 15.5 Hz, 1H), 3.33 (dd,
J ) 4.5, 13.6 Hz, 1H), 2.69 (d, J ) 4.5 Hz, 1H), 2.53 (ddd, J )
2.9, 6.6, 18.0 Hz, 1H), 2.41 (ddd, J ) 6.4, 11.7, 18.0 Hz, 1H),
13
2.13 (m, 1H), 1.87 (m, 1H), 1.43 (s, 3H), 1.34 (s, 3H); C NMR
(CDCl3, 75 MHz) δ 168.2, 112.1, 79.8, 77.6, 77.2, 66.3, 65.4, 50.6,
29.8, 26.4, 24.7; IR (neat) 3361 (br m), 2987 (m), 2938 (m), 2870
(m), 1625 (s), 1471 (m), 1454 (m) cm-1; MS (EI, 70 eV) m/ z (rel
intensity) 227 (M+, 58), 212 (53), 152 (51), 85 (100), 68 (53), 43
(76); HRMS calcd for C11H17NO4 (M+) 227.1157, found 227.1159.
These data are consistent with literature values.11h
(1S,2R,8R,8a R)-8-Hyd r oxy-1,2-(isop r op ylid en ed ioxy)in -
d olizid in e (10).22 Borane-methyl sulfide complex (59 mL of a
2 M solution in THF, 118 mmol) was added over a period of 30
min via an addition funnel to a cooled (0 °C) solution of the
lactam 9 (6.65 g, 29.3 mmol) in THF (725 mL). After 30 min,
the solution was warmed to room temperature. After another
2 h, the reaction was quenched by the slow addition of ethanol
(440 mL, caution: hydrogen evolution) and concentrated to give
a viscous oil which was redissolved in EtOH (700 mL) and heated
at reflux for 2 h. After cooling to room temperature, the solution
was concentrated to give 6.6 g of a colorless, crystalline solid
which was recrystallized from 200 mL of hot hexanes to provide
5.87 g (94%) of the title compound, Rf ) 0.41 (10:1 CHCl3/MeOH);
mp 101-103 °C (lit. mp 104-106° C,11h 106-108 °C,11k 100-
103 °C,11n 101-104 °C11s); [R]23 -81.7° (c 1.10, MeOH), [lit.
D
[R]25 -73.3° (c 0.35, MeOH),11h [R]20 -65.8° (c 0.5, MeOH),11k
D
D
[R]25D -67.3° (c 0.46, MeOH),11s [R]25D -72.76 (c 0.43, MeOH)11n
]
1H NMR (300 MHz, CDCl3) δ 4.70 (dd, J ) 4.6, 6.2 Hz, 1H),
4.61 (dd, J ) 4.2, 6.3 Hz, 1H), 3.83 (m, 1H), 3.15 (d, J ) 10.7
Hz, 1H), 2.99 (dt, J ) 3.0, 10.4 Hz, 1H), 2.33 (br s, 1H), 2.12
(dd, J ) 4.2, 10.7 Hz, 1H), 2.05 (m, 1H), 1.85 (m, 1H), 1.6-1.7
(m, 3H), 1.51 (s, 3H), 1.34 (s, 3H), 1.2-1.3 (m, 1H); 13C NMR
(90 MHz, CDCl3) δ 111.3, 79.1, 78.2, 73.6, 67.3, 59.8, 51.6, 32.9,
25.9, 24.7, 24.0; IR (neat) 3198 (br m), 2980 (m), 2941 (s), 2857
(w), 2792 (m), 1466 (w), 1446 (w), 1371 (m) cm-1; MS (EI, 70
eV) m/ z (rel intensity) 213 (M+, 53), 198 (24), 138 (100), 113
(82), 96 (712), 43 (41); HRMS calcd for C11H19NO3 (M+) 213.1365,
found 213.1367. These data are consistent with those reported
in the literature.11n
starting dimesylate 7. Data for 8: Rf ) 0.33 (1:1 hex/EtOAc);
1
[R]23 +75.0° (c 0.52, CHCl3); mp 136 °C; H NMR (CDCl3, 300
D
MHz) δ 5.01 (dd, J ) 3.8, 6.0 Hz, 1H), 4.81 (ddd, J ) 3.7, 6.1,
7.8 Hz, 1H), 4.43 (ddd, J ) 3.5, 5.9, 7.2 Hz, 1H), 4.35 (t, J ) 5.7
(1S,2R,8R,8a R)-1,2,8-Tr ih yd r oxyin d olizid in e [(-)-Sw a in -
son in e] (1). Prepared according to the published procedure.11n

Notes
J . Org. Chem., Vol. 61, No. 20, 1996 7221
A solution of 10 (5.75 g, 27 mmol) in THF (27 mL) was treated
with 6 N HCl (27 mL) at room temperature for 12 h. The
solution was then concentrated the residue was applied to an
ion exchange column (Dowex 1 × 8 200 OH-, 30 g), which was
eluted with water. The fractions containing 1 were identified
by TLC (iodine stain). These fractions were concentrated to give
a white crystalline solid which was recrystallized from CHCl3/
MeOH/ether to give 4.50 g (96%) of swainsonine (1) in three
crops. Rf ) 0.35 (3:1 CHCl3/MeOH w/1% NH4OH); mp 139-
142 °C (lit. mp 141-143 °C,11k,s 144-145 °C,1b 140-142 °C11n);
[R]23D -74.0° (c 0.98, MeOH) [lit. [R]25D -82.6° (c 1.03, MeOH),11s
[R]25D -73.8° (c 0.21, EtOH),11e [R]25D -75.7° (c 2.33, MeOH)11n];
1H NMR (300 MHz, D2O) δ 4.39 (ddd, J ) 2.8, 5.9, 8.0 Hz, 1H),
4.29 (dd, J ) 3.5, 5.8 Hz, 1H), 3.84 (app td, J ) 4.6, 10.3 Hz,
1H), 3.0 (m, 1H), 2.97 (dd, J ) 2.8, 11.3 Hz, 1H), 2.70 (dd, J )
8.1, 11.3 Hz, 1H), 2.04-2.15 (m, 3H), 1.76 (m, 1H), 1.55 (qt, J )
4.1, 13.2 Hz, 1H), 1.28 (qd, J ) 4.5, 12.3 Hz, 1H); 13C NMR (90
MHz, D2O, MeOH internal standard) δ 72.6, 69.4, 68.9, 66.0,
60.3, 51.6, 32.2, 22.9; IR (neat) 3366 (br s), 2944 (s), 2884 (m),
2804 (m), 2727 (m), 1660 (w), 1378 (m) cm-1; MS (EI, 70 eV)
m/ z (rel intensity) 173 (M+, 16), 155 (30), 113 (73), 96 (73), 83
(100); HRMS calcd for C8H15NO3 (M+) 173.1052, found 173.1052.
These data are consistent with those reported in the literature.11n
Ack n ow led gm en t. This work was funded by the
National Institutes of Health (GM-35572). E.J .H. was
supported in part by National Research Service Award
T32 GM07767.
J O961101B