Allylated monosaccharides as precursors in triple reductive amination strategies: Synthesis of castanospermine and swainsonine

Article abstract of DOI:10.1021/jo001447t

The feasibility of the triple-reductive amination reaction for the synthesis of complex indolizidine frameworks is illustrated by application to the potent glycosidase inhibitors castanospermine and swainsonine. The target compounds were obtained from known carbohydrate precursors in yields of 23 and 14%, over nine and 13 steps, respectively. The iodoetherification reaction of allylated monosaccharides was shown to be a practical reaction for the synthesis of the tricarbonyl precursors for the key triple reductive amination reactions.

Full text of DOI:10.1021/jo001447t

J . Org. Chem. 2001, 66, 1761-1767
1761
Allyla ted Mon osa cch a r id es a s P r ecu r sor s in Tr ip le Red u ctive
Am in a tion Str a tegies: Syn th esis of Ca sta n osp er m in e a n d
Sw a in son in e
Hang Zhao, Sunej Hans, Xuhong Cheng, and David R. Mootoo*
Department of Chemistry, Hunter College, 695 Park Avenue, New York, New York 10021
Dmotoo@shiva.hunter.cuny.edu
Received October 6, 2000
The feasibility of the triple-reductive amination reaction for the synthesis of complex indolizidine
frameworks is illustrated by application to the potent glycosidase inhibitors castanospermine and
swainsonine. The target compounds were obtained from known carbohydrate precursors in yields
of 23 and 14%, over nine and 13 steps, respectively. The iodoetherification reaction of allylated
monosaccharides was shown to be a practical reaction for the synthesis of the tricarbonyl precursors
for the key triple reductive amination reactions.
The polyhydroxindolizidine alkaloids, of which castano-
spermine 11 and swainsonine 22 are two of the more
prominent derivatives, are noted for their potent glycosi-
dase inhibitory activity3 (Figure 1). Analogues have been
used as biochemical tools and have been examined as
chemotherapeutic agents against diabetes,4 cancer,5 and
HIV.6 Their activity is believed to a result of their ability
to mimic the transition state involved in substrate
hydrolysis.3 For example, the activity of castanospermine
F igu r e 1.
against glucosidases has been tied to the similarity of
the six-membered ring to the glucosyl cation.7 In a less
nine has been related to the resemblance of the five-
membered ring to the mannosyl cation.8 It has been
suggested that their rigid, bicyclic structures are respon-
sible for their potent activity.9 In connection with the
design of more fine-tuned analogues, numerous syntheses
of 1 and 2 and their diastereomers have been reported.10-13
The majority of syntheses are sugar-based, although,
with the advancement in technologies for enantioselective
synthesis, non-carbohydrate syntheses are becoming
increasingly popular. Carbohydrate approaches capitalize
on the easy availability of diastereomeric starting ma-
terials and generally involve introduction of one or more
new carbinol centers in a sugar precursor, thence conver-
obvious way, the anti-mannosidase activity of swainso-
(1) Castanospermine: (a) Hohenschutz, L. D.; Bell, E. A.; J ewess,
P. J .; Leworth, D. P.; Pryce, R. J .; Arnold, E.; Clardy, J . Phytochemistry
1981, 20, 811-814. (b) Nash, R. J .; Fellows, L. E.; Dring, J . V.; Stirton,
C. H.; Carter, D.; Hegarty, M. P.; Bell, E. A. Phytochemistry 1988, 27,
1403-1406.
(2) (a) Swainsonine: Guengerich, F. P.; DiMari, S. J .; Broquist, H.
P. J . Am. Chem. Soc. 1973, 95, 2055-2056. (b) Colegate, S. M.; Dorling,
P. R.; Huxtable, C. R. Aust. J . Chem. 1979, 32, 2257-2264. (c)
Schneider, M. J .; Ungemach, F. S.; Broquist, H. P.; Harris, T. M.
Tetrahedron 1983, 39, 29-32. (d) Molyneux, R. J .; McKenzie, R. A.;
O’Sullivan, B. M.; Elbein, A. D. J . Nat. Prod. 1995, 58, 878-886.
(3) For leading reviews, see: (a) Asano, N.; Nash, R. J .; Molyneux,
R. J .; Fleet, G. W. J . Tetrahedron: Asymmetry 2000, 11, 1645-1680.
(b) Elbein, A. D.; Molyneux, R. J . Alkaloid Glycosidase Inhibitors. In
Comprehensive Natural Products Chemistry; Barton, D., Nakanishi,
K., Meth-Cohn, O., Eds.; Elsevier: Oxford, 1999; Vol. 3, p 129. (c) Sears,
P.; Wong, C.-H. Chem. Commun. 1998, 1161-1170. (d) Ganem, B. Acc.
Chem. Res. 1996, 29, 340-347. (e) Dwek, R. A. Chem. Rev. 1996, 96,
683-720. (f) Kaushal, G. P.; Elbein, A. D. Methods Enzymol. 1994,
230, 316. (g) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res.
1993, 26, 182-190. (h) Legler, G. Adv. Carbohydr. Chem. Biochem.
1990, 48, 319-384. (i) Sinnot, M. L Chem. Rev. 1990, 90, 1171-1202.
(4) (a) Platt, F. M.; Neises, G. R.; Reinkensmeier, G.; Townsend, M.
J .; Perry, V. H.; Proia, R. L.; Winchester, B.; Dwek, R. A.; Butters, T.
D. Science 1997, 276, 428-431. (b) Witczak, Z. J . Carbohydrates as
New and Old Targets for Future Drug Design. In Carbohydrates in
Drug Design; Witczak, Z. J ., Ed.; Marcel Dekker Inc.: New York, 1997;
p 1. (c) Robinson, K. M.; Begovic, M. E.; Rhinehart, B. L.; Heinke, E.
W.; Ducep, J .-B.; Kastner, P. R.; Marshall, F. N.; Danzin, C. Diabetes
1991, 40, 825. (d) Anzeveno, P. B.; Creemer, L. J .; Daniel, J . K.; King,
C.-H.; Liu, P. S. J . Org. Chem. 1989, 54, 2539- 2542.
(8) Tulsiani, R. P.; Harris, T. M.; Touster, O. J . Biol. Chem. 1982,
257, 7936-7939.
(9) Hempel, A.; Camerman, N.; Mastropaolo, D.; Camerman, A. J .
Med. Chem. 1993, 36, 4082-4086.
(10) For a recent review on the synthesis of polyhydroxindolizidines,
see: Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045-4066, and
ref 3d,g.
(11) For a recent synthesis of castanospermine and a comprehensive
listing of syntheses since 1992, see: Denmark, S. E.; Martinborough,
E. A. J . Am. Chem. Soc. 1999, 121, 3046-3056.
(12) Recent syntheses of swainsonine: (a) de Vicente, J .; Go´mez
Arraya´s, R.; Can˜ada, J .; Carretero, J . C. Synlett 2000, 53-56. (b)
Mukai, C.; Sugimoto, Y.; Miyazawa, K.; Yamaguchi, S.; Hanaoka, M.
J . Org. Chem. 1998, 63, 6281-6287. (c) Hunt, J . A.; Roush, W. R. J .
Org. Chem. 1997, 62, 1112-1124. (d) Ferreira, F.; Greck, C.; Geneˆt,
J . P. Bull. Soc. Chim. Fr. 1997, 134, 615-000. (e) For a comprehensive
listing of syntheses before 1996, see: Pearson, W. H.; Hembre, E. J .
J . Org. Chem. 1996, 61, 7217-7221. (f) Zhou, W.-S.; Xie, W.-G.; Lu,
Z.-H.; Pan, X.-F. Tetrahedron Lett. 1995, 36, 1291-1294. (g) Naruse,
M.; Aoyagi, S.; Kibayashi, C. J . Org. Chem. 1994, 59, 1358-1364.
(13) For recent examples of related, designed polyhydroxylated
azaheterocycles, see: (a) Le, V. D.; Wong, C.-H. J . Org. Chem. 2000,
65, 2399-2409. (b) Heightman, T. D.; Vasella, A. T. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 750-770.
(5) For a review, see: Gross, P. E.; Baker, M. A.; Carver, J . P.;
Dennis, J . W. Clin. Cancer Res. 1995, 1, 935-944.
(6) (a) Ratner, L.; Heyden, N. V.; Dedera, D. Virology 1991, 181,
180-192. (b) Wikler, D. A.; Holan, G. J . Med. Chem. 1989, 32, 2084-
2089. (c) Karpas, A.; Fleet, G. W. J .; Dwek, R. A.; Petursson, S.;
Namgoog, S. K.; Ramsden, N. G.; J acob, G. S.; Rademacher, T. W. Proc.
Natl. Acad. Sci. U.S.A. 1988, 85, 9229-9233.
(7) Szumilo, T.; Kaushal, G. P.; Elbein, A. D. Arch. Biochem. Biophys.
1986, 247, 261-271.
10.1021/jo001447t CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/15/2001

1762 J . Org. Chem., Vol. 66, No. 5, 2001
Zhao et al.
Sch em e 1
allylated glucoside 10 was prepared through the White-
sides allylation procedure on 919,20 and benzylation of the
major product (9:1 ratio of epimers). Compound 10 was
converted to the alkenyl-acetal-alcohol 11 in 74% overall
yield, via the two-step iodoetherification-reductive elimi-
nation reaction sequence. Swern oxidation of 11 to the
ketone 12, ozonolysis of 12, and acid hydrolysis of the
resulting keto aldehyde led to 13′, the structure of which
1
was assigned on the basis of the H and 13C NMR and
mass data. There was no evidence for the tautomeric bis-
aldehyde structure 13.
Sch em e 2a
Treatment of 13 (13′) in anhydrous methanol in the
presence of freshly activated, powdered molecular sieves,
with 1.5 equiv of ammonium formate and 1.5 equiv of
sodium cyanoborohydride, over 24 h, led to the formation
of a major compound 14 in 78% yield. There was no
evidence for formation of the C8a epimeric product.
Reactions performed under conditions that were not
strictly anhydrous required large excesses of sodium
cyanoborohydride and resulted in much lower yields.
Hydrogenolysis of 14 provided a semisolid product (80%)
that yielded castanospermine 1 on recrystallization from
ethanol. The product was essentially identical to natural
castanospermine1 (mp, 1H and 13C NMR, RD). The overall
yield from 9 was 23% over nine steps.
The efficiency of the TRA suggests that initial amina-
tion on 13 occurs at one of the carbonyl groups (more
likely one or other of the two aldehydes), and the
resulting carbinolamine I or II undergoes sequential
intramolecular reactions with the remaining carbonyl
groups, at an appreciably faster rate than competing
intermolecular processes (Scheme 4). Attempts to isolate
the intermediate products were not successful. Reduction
in the amount of sodium cyanoborohydride or shorter
reaction times led to varying amounts of the final product
and a complex mixture of more polar components which
were not separable. Following this mechanism, the C8
stereogenic center in the indolizidine product could arise
via the hydride reduction of any one or more of the mono-
and bicyclic iminium ions IV, V, and VI. These species
are all expected to undergo preferred, R-face, nucleophilic
attack. Stereoselective hydride delivery anti to the ben-
zyloxy substituent of five-membered iminium ions such
as IV is documented.21 Nucleophilic addition to cyclic six-
membered iminium ions such as V is expected to occur
via a half chair 15 in which the benzyloxy substituents
are in pseudoequatorial positions (Scheme 5). Addition
of hydride in an axial trajectory to give 16 is favored
because this results in a chairlike transition-state geom-
etry, as opposed to equatorial attack which leads to a
boatlike geometry.22,23 Application of this model to the
bicyclic species VI would give the same facial bias. The
congruence of these individual stereoselectivities means
that the relative contributions of IV, V, and VI in the
reaction manifold is likely to be of little effect on the
overall stereoselectivity of the TRA.
a
Key: (a) IDCP, H2O or MeOH, CH2Cl2; (b) Zn.
sion to the bicyclic indolizidine framework. Many of the
published procedures suffer from poor stereoselectivity,
and inefficient protecting group chemistry, especially
with respect to handling of the amino residue. We have
recently described the synthesis of castanospermine via
a novel triple-reductive amination strategy on a carbo-
hydrate-derived tricarbonyl precursor 3 (Scheme 1).14-16
The C6-allylated pyranoside 4 afforded easy access to 3,
and the overall strategy benefits from the fact that the
amino residue is introduced at a late stage in the
synthesis, with concomitant formation of the indolizidine
framework. Herein, we illustrate the application of this
methodology to castanospermine and swainsonine.
Studies from this laboratory have shown that C6-
allylated monosaccharides (e.g., 5) on treatment with
halonium ion undergo a facile, high-yielding reaction to
the halo-THF aldehyde 6 (Scheme 2).17 When the reaction
is performed under anhydrous conditions, in the presence
of an alcohol, the acetal 7 is obtained. This suggested a
route to the requisite tricarbonyl precursors because the
hydroxy alkene 8 obtainable by reductive opening of 7
can be regarded as a masked keto-dialdehyde. Since the
halocyclization reaction is general for monosaccharides,
this approach may be used to access diastereomeric
tricarbonyl derivatives.
The tricarbonyl compound for castanospermine was
obtained from the readily available aldehyde 9,18 as
decribed in our preliminary report (Scheme 3).14 The
(14) Zhao, H.; Mootoo, D. R. J . Org. Chem. 1996, 61, 6762-6763.
(15) To the best of our knowledge, the triple reductive amination
has not been previously reported. Double-reductive amination strate-
gies are well documented: (a) Abe, K.; Okumura, T.; Tsugoshi, T.;
Nakamura, N. Synthesis 1984, 597-598. (b) Zou, W.; Szarek, W. A.
Carbohydr. Res. 1993, 242, 311-314. (c) Baxter, E. W.; Reitz, A. B. J .
Org. Chem. 1994, 59, 3175-3185. (d) Martin, O. R.; Saavedra, O. M.
J . Org. Chem. 1996, 61, 6987-6993.
(16) For related one-pot double cyclizations: (a) Alkylation-lactam-
ization: ref 12e and references cited (b) Reductive amination-
lactamization or reductive amination-alkylation: Denmark, S. E.;
Thorarensen, A.; Middleton, D. S. J . Org. Chem. 1995, 60, 3574-3576
and ref 11. (b) Double-alkylation, Bell, A. A.; Pickering, L.; Watson,
A. A.; Nash, R. J .; Griffiths, R. C.; J ones, M.; Fleet, G. W. J .
Tetrahedron Lett. 1996, 37, 8561-8564.
(19) Kim, E.; Gordon, D. M.; Schmid, W.; Whitesides, G. M. J . Org.
Chem. 1993, 58, 5500-5507.
(20) The configuration of the new carbinol center was tentatively
assigned by comparison of 1H NMR of both epimers with those of
related chain extended gluco derivatives: ref 17b.
(21) (a) Choi, J .-R.; Han, S.; Cha, J . K. Tetrahedron Lett. 1991, 32,
6469-6472. (b) Pearson, W. H.; Bergmeier, S. C.; Williams, J . P. J .
Org. Chem. 1992, 57, 3977-3987.
(17) Khan, N.; Xiao, H.; Cheng, X.; Mootoo, D. R. Tetrahedron 1999,
55, 8303-8312.
(18) (a) Hashimoto, H.; Asano, K.; Fuji, F.; Yoshimura, J . Carbohydr.
Res. 1982, 104, 87-00. (b) Czernecki, S.; Horns, S.; Valery, J .-M. J .
Org. Chem. 1995, 60, 650-655.
(22) The double reductive amination on 5-ketoglucose and benzy-
hydrylamine proceeds with high stereoselectivity for the 2,5-imino-D-
glucitol: ref 15c.
(23) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289-296.

Synthesis of Castanospermine and Swainsonine
J . Org. Chem., Vol. 66, No. 5, 2001 1763
Sch em e 3a
a
Key: (a) allyl bromide, Sn, CH3CN-H2O (10:1), ultrasound; (b) BnBr, NaH, n-Bu4NI, DMF; (c) IDCP, CH2Cl2-MeOH; (d) Zn, 95%
EtOH, 4; (e) Swern oxidation; (f) O3, CH2Cl2, -78 °C then Ph3P; (g) THF-9 M HCl; (h) NH4HCO2, NaCNBH3, MeOH; (i) 10% Pd-C,
MeOH-HCOOH.
Sch em e 4
furanoside derivative of 20 (Scheme 7).24 Reaction of 20
Sch em e 5
with allyltrimethylsilane in the presence of BF3‚OEt2
gave the (R) alcohol 21 (79%) and the (S)-epimer (3%).
The stereochemistry was tentatively assigned on the
basis of the reported stereoselectivity of these allylation
conditions on related aldehydes.25 The desired alcohol 21
was converted to the benzyl ether 18, which was treated
according to the standard iodocyclization-THF opening
sequence to give the hydroxyalkene 22. Hydroboration
of 22 followed by oxidation of the diol product led to the
ketoaldehyde 23. DDQ-mediated removal of the p-meth-
It follows from the foregoing discussion that systems
oxybenzyl, in the presence of triethylamine,26 provided
in which the individual iminium ions are expected to have
a mixture of two compounds, for which the physical data
the same stereochemical bias are good candidates for
supported isomeric structures 24a ,b. For example, the
highly stereoselective TRAs. Accordingly, stereoselective
major, more polar component 24a showed an IR absorp-
synthesis of swainsonine should be possible from a
tion at 3454 cm-1 but no peaks for free carbonyl groups.
tricarbonyl derivative such as 17, since hydride attack
1HNMR signals were observed at δ 3.57 (s, 3H), 5.04 (d,
on the associated iminium ions VII, VIII, and IX is
1H) and 5.17 (m, 1H) corresponding to the OMe and
expected to occur preferentially from the â-direction. We
acetal hydrogens, respectively. No signals for carbonyl
envisaged the synthesis of an appropriate tricarbonyl
precursor from the C5-allylated 2,3-O-isopropylidene-
furanose 18 (Scheme 6).
(24) Schmidt, O. In Methods in Carbohydrate Chemistry; Academic
Press Inc.: London, 1963; Vol. II, pp 319-325.
(25) Danishefsky, S. J .; DeNinno, M. P.; Phillips, G. B.; Zelle, R. E.;
Lartey, P. A. Tetrahedron 1986, 42, 2809-2819.
(26) Li, P.; Hung-J ang, G.; Sun, L.; Zhao, K. J . Org. Chem. 1998,
The aldehyde 20 was prepared from 2,3:5,6-di-O-
mannofuranose 19 in 80% overall yield, via modification
of the procedure which was developed for the methyl
63, 366-369. J . Org. Chem. 1992, 57, 3977-3987.

1764 J . Org. Chem., Vol. 66, No. 5, 2001
Zhao et al.
Sch em e 6
of the benzyl ether provided a product which was es-
sentially identical with natural swainsonine.2c,12g (mp, 1H
and 13C NMR, RD). The overall yield of swainsonine from
19 was approximately 14% over 13 steps.
In summary, the TRA strategy appears to be well
suited to stereochemically defined indolizidine motifs.
The synthesis of castanospermine and swainsonine il-
lustrates that allylated monosaccharides are practical
precursors for the key tricarbonyl intermediates required
for this methodology. A wide range of analogue structures
will be possible in view of the number of easily accessible
monosaccharide precursors of different configurations
and constitution. It should be also possible to extend
these principles to bicyclo [m.n.0] frameworks which are
embedded in other classes of alkaloids. These directions
are being pursued and will be reported in due course.
Exp er im en ta l Section
Gen er a l P r oced u r es. TLC was performed on aluminum
sheets precoated with silica gel 60 (HF-254, E. Merck) to a
thickness of 0.25 mm. Flash column chromatography (FCC)
was performed using Kieselgel 60 (230-400 mesh, E. Merck)
and employed a stepwise solvent polarity gradient, correlated
with TLC mobility. The spots were visualized by UV, charring
with a solution of ammonium molybdate (VI) tetrahydrate
(12.5 g) and cerium (IV) sulfate tetrahydrate (5.0 g) in 10%
aqueous H2SO4 (500 mL), or in the case of amine derivatives,
with a solution of 0.3% ninhydrin and 0.3% acetic acid in
butanol. Unless otherwise stated, 1H and 13C NMR spectra
were recorded at 300 and 75.5 MHz, respectively. Elemental
analysis were performed by Schwarzkopf Microanalysis Labo-
ratory. High-resolution mass spectroscopy was carried out at
the Mass Spectral Facility at the University of Illinois at
Urbana-Champaign. Melting points are reported uncorrected.
carbons were observed in the 13C NMR, but resonances
at δ 92.3, 104.3, 106.0, and 113.1, corresponding to acetal
carbons were present. The mass spectrometry data were
also in agreement with 24a . Careful 2D COSY analysis
of the acetal protons and the respective vicinal protons
favored 24a over the methyl pyranoside regioisomer (in
which the OH and MeO substituents in 24a are juxta-
posed). The minor compound 24b showed very similar
physical characteristics to 24a .
Compounds 24a ,b were individually subjected to the
TRA since the reaction conditions are expected to lead
to insitu formation of the tricarbonyl derivative. Indeed,
the identical indolizidine product 2512f,g was obtained as
a single stereoisomer in 69 and 66% yields from 24a and
24b, respectively. Since 25 has previously been converted
to swainsonine, this constitutes a formal synthesis.12g
Hydrolysis of acetonide in 25 followed by hydrogenolysis
Meth yl 7,8,9-Tr id eoxy-2,3,4,6-tetr a -O-ben zyl-L-glycer o-
r-D-glu co-n on -8-en o-p yr a n osid e (10). Tin powder (121 mg,
1.02 mmol, 100 mesh) and allyl bromide (0.136 mL, 1.53 mmol)
were added to a solution of aldehyde 9 (236 mg, 0.51 mmol) in
a mixture of 10:1 CH3CN-H2O (11 mL). The reaction was
placed in an ultrasonic bath for 16 h. NaOH (6 M) was then
added to the reaction mixture to pH 8, and the resulting slurry
was filtered through a Celite pad. The filtrate was extracted
with ether (3 × 30 mL), and the organic phase was washed
with brine (30 mL), dried (Na2SO4), filtered, and evaporated
Sch em e 7a
a
Key: (a) PMBCL, NaH, n-Bu4NI, DMF; (b) HOAc; (c) NaIO4; (d) allyltrimethylsilane, BF3‚OEt2; (e) BnBr, NaH, n-Bu4NI, DMF; (f)
IDCP, CH2Cl2-MeOH; (g) Zn, 95% EtOH, 4; (h) BH3, THF, then Na2O2; (i) Swern oxidation; (j) DDQ, Et3N, CH2Cl2-H2O; (k) NH4HCO2,
NaCNBH3, MeOH; (l) 10% Pd-C, MeOH-HCOOH; (m) HCl, THF-H2O.

Synthesis of Castanospermine and Swainsonine
J . Org. Chem., Vol. 66, No. 5, 2001 1765
in vacuo. 1H NMR analysis of the crude product indicated a
9:1 ratio of products. FCC afforded a major (193 mg, 75%) and
a minor product (20 mg, 8%).
3.48 (s, 3H), 3.55 (m, 1H), 3.72 (m, 2H), 3.87 (m, 1H), 4.02 (t,
1H, J ) 9.3 Hz), 4.32 (d, 1H, J ) 11.1 Hz), 4.37 (d, 1H, J )
11.7 Hz), 4.67 (m, 3H), 4.79 (ABq, ∆δ ) 0.02 ppm, J ) 10.5
Hz, 2H), 4.89 (d, 1H, J ) 11.4 Hz), 4.99 (d, 1H, J ) 10.5 Hz),
5.13 (m, 2H), 5.81 (m, 1H), 7.32 (m, 20H); 13C NMR (CDCl3) δ
34.5, 55.8, 71.1, 72.0, 73.6, 74.8, 75.8, 76.0, 80.1, 82.7, 98.6,
117.8, 127.7-128.6 (several lines), 134.8, 138.2, 138.3, 138.8.
Anal. Calcd for C39H46O7: C, 74.74; H, 7.40; O, 17.86. Found:
C, 74.35; H, 7.43; O, 18.22.
For major product: Rf ) 0.70 (40% EtOAc-petroleum
ether); IR (CHCl3) 3528, 1640, 1606 cm-1; 1H NMR (CDCl3) δ
2.23 (m, 1H), 2.36 (m, 1H), 3.32 (s, 3H), 3.46 (dd, 1H, J ) 3.6,
9.6 Hz), 3.50 (d, 1H, J ) 9.3 Hz), 3.65 (t, 1H, J ) 9.3 Hz), 3.86
(m, 1H), 3.95 (t, 1H, J ) 9.3 Hz), 4.55 (d, 1H, J ) 3.6 Hz),
4.69 (ABq, ∆δ ) 0.15 ppm, 2H, J ) 12.0 Hz), 4.76 (ABq, ∆δ )
0.22 ppm, 2H, J ) 10.8 Hz), 4.87 (ABq, ∆δ ) 0.15 ppm, 2H, J
) 10.8 Hz), 5.07 (m, 2H), 5.78 (m, 1H), 7.25-7.32 (m, 15H);
13C NMR (CDCl3) δ 38.8, 55.5, 68.1, 71.8, 73.6, 75.3, 75.9, 77.8,
80.0, 82.3, 98.6, 118.0, 127.7, 127.9, 128.1, 128.3, 128.6, 135.0,
138.3, 138.5, 139.0.
Keton e-Alk en e (12). DMSO (0.88 mL, 13 mmol) was
slowly added at -78 °C to a mixture of oxalyl chloride (0.90
mL, 11 mmol) and anhydrous CH2Cl2 (10 mL). The reaction
mixture was stirred at this temperature for 20 min, at which
time a solution of 11 (2.1 g, 3.4 mmol) in CH2Cl2 (15 mL) was
slowly introduced. After an additional 20 min, Et3N (2.9 mL,
21 mmol) was slowly added. The reaction mixture was then
warmed to room temperature and diluted with ether (50 mL).
The resulting suspension was washed with saturated NaHCO3
(25 mL) and the aqueous layer extracted with ether (3 × 25
mL). The combined organic phase was washed with brine (25
mL), dried (Na2SO4), filtered and evaporated in vacuo. FCC
of the residual syrup afforded ketone 12 (2.0 g, 95%): Rf )
For minor product: Rf ) 0.65 (40% EtOAc-petroleum
ether); 1H NMR (CDCl3) δ 2.20 (m, 2H), 2.28 (br, 1H), 2,70 (br
d, 1H, J ) 5.0 Hz, D2O ex), 3.31 (s, 3H), 3.43 (m, 2H), 3.62
(dd, 1H, J ) 4.5, 9.9 Hz), 3.77 (m, 1H), 3.96 (t, 1H, J ) 9.3
Hz), 4.50 (d, 1H, J ) 3.6 Hz), 4.65 (ABq, ∆δ ) 0.13 ppm, 2H,
J ) 11.7 Hz), 4.74 (ABq, ∆δ ) 0.32 ppm, 2H, J ) 11.1 Hz),
4.84 (ABq, ∆δ ) 0.22 ppm, 2H, J ) 10.8 Hz), 5.00 (m, 2H),
5.79 (m, 1H), 7.15-7.36 (m, 15H); 13C NMR (CDCl3) δ 36.8,
55.4, 71.7, 71.8, 73.4, 74.8, 75.8, 79.8, 80.4, 82.5, 98.0, 117.4,
127.7-128.5 (several lines), 135.3, 137.9, 138.2, 138.7.
0.6 (20% EtOAc-petroleum ether); [R]23 -17° (c ) 4.1,
D
1
CHCl3); IR (film) 1725, 1641, 1606 cm-1; H NMR (CDCl3) δ
n
NaH (0.50 g, 60% suspension in oil, 12.5 mmol) and Bu4NI
2.30 (m, 1H), 2.45 (m, 1H), 3.38 (s, 3H), 3.45 (s, 3H), 3.85 (dd,
1H, J ) 3.9, 6.3 Hz), 4.15 (m, 2H), 4.32 (d, 1H, J ) 5.7 Hz),
4.40 (m, 2H), 4.55 (m, 2H), 4.71 (m, 4H), 4.79 (d, 1H, J ) 11.1
Hz), 4.98 (m, 2H), 5.72 (m, 1H), 7.25 (m, 20H); 13C NMR
(CDCl3) δ 36.5, 54.4, 55.8, 71.9, 73.4, 74.3, 74.8, 77.8, 79.7,
80.8, 81.7, 105.5, 117.6, 127.5-128.8 (several lines), 133.9,
137.9, 138.2, 138.4, 138.9, 207.9; HRMS (FAB) calcd for
(0.22 g, 0.38 mmol) was added to a solution of the major
product from the previous step (4.8 g, 9.5 mmol) in dry THF
(40 mL), at 0 °C. The slurry was stirred at this temperature
for 20 min, at which time benzyl bromide (2.70 mL, 22.7 mmol)
was added. The reaction was warmed to room temperature
and stirred for 16 h. The temperature was then lowered to 0
°C, and MeOH (1 mL) was added. After an additional 15 min,
the mixture was diluted with water (100 mL) and extracted
with ether (3 × 50 mL). The combined organic phase was
washed with brine (50 mL), dried (Na2SO4), and filtered.
Concentration of the filtrate in vacuo gave a brown oil, which
when subjected to FCC provided pyranoside alkene 10 (5.50
g, 97%): Rf ) 0.80 (20% EtOAc-petroleum ether); [R]23D -20°
(c ) 5.7, CHCl3); 1H NMR (CDCl3) δ 2.58 (m, 2H), 3.41 (s, 3H),
3.59 (dd, 1H, J ) 3.6, 9.9 Hz), 3.72 (m, 2H), 3.89 (dd, 1H, J )
5.4, 8.4 Hz), 4.02 (t, 1H, J ) 9.6 Hz), 4.34 (d, 1H, J ) 11.1
Hz), 4.38 (d, 1H, J ) 11.7 Hz), 4.69 (m, 2H), 4.81 (ABq, ∆δ )
0.02 ppm, 2H, J ) 10.5 Hz), 4.96 (d, 1H, 10.5 Hz), 5.01 (d, 1H,
J ) 10.5 Hz), 5.14 (m, 2H), 5.86 (m, 1H), 7.34 (m, 20H); 13C
NMR (CDCl3) δ 34.5, 55.8, 71.1, 72.0, 73.6, 74.7, 75.7, 76.0,
80.1, 82.6, 98.6, 117.8, 127.6-128.6 (several lines), 134.8,
138.2, 138.4, 138.8; HRMS (FAB) calcd for C38H42O6Na (M +
Na) 617.2879, found 617.2876.
C
39H44O7Na (M + Na) 647.2985, found 647.2985.
Tr ica r bon yl P r ecu r sor 13 (13′). O3 was bubbled at -78
°C through a solution of 12 (1.83 g, 2.94 mmol) in a mixture
of CH2Cl2 (15 mL) and MeOH (3 mL). The progress of the
reaction was monitored by TLC until complete disappearance
of the starting material. The reaction mixture was then purged
with argon and warmed to room temperature. Methanol (15
mL) and Ph3P (1.2 g, 4.6 mmol) were added, and stirring was
continued under an argon atmosphere for 1 h. Concentration
of the reaction mixture followed by FCC of the residual slurry
afforded the ketoaldehyde derivative (1.73 g, 95%): Rf ) 0.35
(20% EtOAc-petroleum ether); IR (film) 1709 (broad), 1603
1
cm-1; H NMR (CDCl3) δ 2.45 (ddd, 1H, J ) 2.1, 8.4, 14 Hz),
2.61 (dd, 1H, J ) 3.6, 14 Hz), 3.38 (s, 3H), 3.43 (s, 3H), 3.82
(dd, 1H, J ) 4.5, 5.7 Hz), 4.15 (m, 2H), 4.31 (d, 1H, J ) 5.7
Hz), 4.35 (d, 1H, J ) 11.4 Hz), 4.51-4.82 (m, 8H), 7.26 (m,
20H), 9.41 (d, 1H, J ) 0.9 Hz); 13C NMR (CDCl3) δ 45.2, 54.9,
56.0, 72.6, 73.8, 74.4, 75.3, 77.8, 78.0, 80.0, 81.0, 105.8, 127.7-
128.7 (several lines), 137.5, 137.7, 138.1, 138.8, 199.4, 208.1.
HCl (9 M, 15 mL) was added to a solution of the material
obtained from the previous step (1.73 g, 2.78 mmol), in THF
(45 mL). The reaction mixture was stirred at room temperature
for 1 h and then carefully neutralized by addition of saturated
aqueous NaHCO3. The resulting mixture was extracted with
ether (3 × 50 mL), and the combined organic phase was
washed with brine (50 mL). The organic layer was dried (Na2-
SO4), filtered, and evaporated in vacuo. FCC of the semisolid
residue afforded 13′ as an amorphous, white solid (1.66 g).
Recrystalliztion from EtOAc-petroleum ether afforded white
needles (0.70 g, 40%), mp 147-148 °C. FCC of the mother
liquor afforded a second crop of crystals (0.72 g, 41%): Rf )
7,8,9-Tr id eoxy-2,3,4,6-tetr a -O-ben zyl-L-glycer o-D-glu co-
n on -8-en ose Dim eth yl Aceta l (11). IDCP (3.2 g, 6.9 mmol)
was added to a solution of pyranoside alkene 10 (2.7 g, 4.6
mmol) in a mixture of CH2Cl2 (50 mL) and MeOH (0.75 mL,
23 mmol) under argon. The reaction mixture was stirred at
room temperature for 1 h, poured into 10% aqueous Na2S2O3,
and extracted with ether (3 × 50 mL). The organic phase was
washed with brine (50 mL), dried (Na2SO4), filtered, and
concentrated in vacuo to give a brown oil. This material was
used directly in the next step. For characterization purposes,
a sample was purified by FCC: Rf ) 0.50 (20% EtOAc-
1
petroleum ether); H NMR (CDCl3) δ 1.65, 2.19, 2.43 (all m,
2H), 3.21 (m, 2H), 3.27, 3.31, 3.46, 3.51 (s, 6H), 3.95 (m, 3H),
4.21-4.38 (m, 5H), 4.50 - 4.92 (m, 7H), 7.34 (m, 20H); 13C
NMR (CDCl3) δ 10.1, 12.5, 35.6, 37.9, 54.5, 54.7, 56.1, 56.3,
71.0, 71.1, 74.1, 74.4, 74.9, 75.0, 75.4, 76.3, 76.7, 78.6, 79.1,
80.1, 81.7, 82.5, 83.6, 85.7, 106.1, 106.3, 127.3-128.5 (several
lines), 138.0, 138.2, 138.9, 139.1, 139.4, 139.5.
0.3 (30% EtOAc-petroleum ether); [R]23 +16.5° (c 1.80,
D
CHCl3); IR (CHCl3) 3387 cm-1; 1H NMR (CDCl3) δ 1.99, 2.13,
2.39 (all m, 2H), 3.56 (m, 2H), 3.90 (m, 2H), 4.18-4.50 (m,
4H), 4.70-5.03 (m, 4H), 5.17-5.53 (m, 2H), 7.25 (m, 20H); 13
C
The crude material from the previous step was dissolved in
95% ethanol (50 mL) and stirred with freshly activated zinc
powder (11 g) at reflux for 1 h. The suspension was then
diluted with ether and filtered through a short column of
florisil. Concentration of the filtrate under reduced pressure
followed by FCC of the residual, dark brown oil afforded
hydroxyalkene 11 (2.1 g, 74% from 10): Rf ) 0.5 (20% EtOAc-
NMR (CDCl3) δ 37.4, 37.8, 72.4, 74.9, 75.3, 75.4, 75.9, 76.0,
76.7, 78.1, 78.2, 82.0, 82.2, 83.7, 93.7, 93.9, 97.3, 98.1, 103.5,
103.7, 127.7-128.7 (several lines), 137.5, 137.6, 138.0, 138.6,
138.7; MS (CI-NH3) 598 (M - H2O + NH4+). Anal. Calcd for
13′ C36H38O8: C, 72.22; H, 6.40; O, 21.38. Found: C, 71.96; H,
6.58; O, 21.46.
(1S,6S,7R,8R,8a R)-1,6,7,8-Tetr a ben zyloxyocta h yd r oin -
d olizid in e (14). To a mixture of 13 (80 mg, 0.14 mmol),
ammonium formate (16 mg, 0.23 mmol), and freshly activated,
petroleum ether); [R]23 +27° (c ) 4.1, CHCl3); IR (film) 3476,
D
1641, 1605 cm-1; 1H NMR (CDCl3) δ 2.55 (m, 2H), 3.37 (s, 3H),

1766 J . Org. Chem., Vol. 66, No. 5, 2001
Zhao et al.
powdered 3A molecular sieves in anhydrous MeOH (2 mL) was
added NaCNBH3 (63 mg, 0.30 mmol). The reaction mixture
was stirred for 24 h at room temperature and then filtered
through a bed of Celite. The filtrate was diluted with CH2Cl2
(10 mL), washed succesively with saturated aqueous NaHCO3
(4 mL) and brine (2 mL), dried (Na2SO4), filtered, and
evaporated in vacuo. FCC of the crude residue provided 14
compound 10. Benzyl ether 18 (1.7 g, 97%) was obtained: Rf
) 0.60 (10% EtOAc-petroleum ether); [R]23 +34.3° (c 1.90,
D
CHCl3); 1H NMR (CDCl3) δ 1.32 (s, 3H), 1.45 (s, 3H), 2.39 (m,
1H), 2.61 (m, 1H), 3.79 (s, 3H), 3.90 (m, 2H), 4.47 (ABq, ∆δ )
0.17 ppm, J ) 11.1 Hz, 2H), 4.59 (d, 1H, J ) 6.0 Hz), 4.65 (m,
2H), 4.82 (dd, 1H, J ) 3.3, 6.0 Hz), 5.05 (s, 1H), 5.18 (m, 2H),
6.02 (m, 1H), 6.86 (d, 2H, J ) 8.4 Hz), 7.23 (d, 2H, J ) 8.4
Hz), 7.35 (m, 5H); 13C NMR (CDCl3) δ 25.2, 26.4, 36.4, 55.5,
68.6, 72.7, 76.0, 80.0, 80.6, 85.2, 105.2, 112.4, 114.1, 117.6,
127.7, 128.2, 128.4, 129.7, 130.0, 134.8, 139.0, 159.5; HRMS
(FAB) calcd for C26H31O6 (M - H) 439.2121, found 439.2119.
(63 mg, 78%): Rf ) 0.5 (15% EtOAc-toluene); [R]23 +32° (c
D
1
1.0, CHCl3); H NMR (C6D6) δ 1.73 (m, 3H), 1.91 (t, 1H, J )
10.2 Hz), 2.00 (dd, 1H, J ) 5.1, 9.6 Hz), 2.89 (m, 1H), 3.15
(dd, 1H, J ) 4.8, 10.2 Hz), 3.68 (t, 1H, J ) 8.7 Hz), 3.80 (m,
1H), 3.93 (m, 1H), 4.18 (t, 1H, J ) 8.7 Hz), 4.20 (ABq, ∆δ )
0.22 ppm, 2H, J ) 11.7 Hz), 4.50 (ABq, ∆δ ) 0.05 ppm, 2H, J
) 11.7 Hz), 4.94 (ABq, ∆δ ) 0.25 ppm, 2H, J ) 11.7 Hz), 5.00
(ABq, ∆δ ) 0.16 ppm, 2H, J ) 11.4 Hz), 7.23 (m, 20H); 13C
NMR (C6D6) δ 31.2, 53.2, 55.3, 70.9, 72.4, 73.1, 74.9, 76.0, 78.5,
78.6, 80.2, 88.7, 127.6-128.9 (several lines), 139.5, 139.9,
140.4, 140.9. Anal. Calcd for C36H39O4N: C, 78.66; H, 7.15; O,
11.64; N, 2.55. Found: C, 78.45; H, 7.37; O, 11.69; N, 2.49.
Ca sta n osp er m in e (1). HCOOH (1 mL) was added to a
mixture of 14 (120 mg, 0.22 mmol), 10% Pd-C (500 mg), and
MeOH (4 mL) under an argon atmosphere. The suspension
was was stirred for 2 h and then filtered through a pad of
Celite. The filter cake was washed several times with MeOH
and then concentrated in vacuo. The residual syrup was
dissolved in ethanol and stirred with Amberlite IRA-(OH) ion-
exchange resin (500 mg) for 30 min. The mixture was filtered
through Celite and the filtrate concentrated in vacuo to give
a semisolid residue (33 mg, 80%). Recrystallization from
ethanol afforded white prisms (29 mg, 70%): mp 202-208 °C
6,7,8-Tr id eoxy-5-O-ben zyl-2,3-O-(1-m eth yleth ylid en e)-
D-m a n n o-oct -7-en ose p -m et h oxyb en zyl Met h yl Acet a l
(22). Treatment of compound 18 (9.3 g, 21.1 mmol) following
the two-step iodoetherification-reductive elimination sequence
that was used for the synthesis of 11 (see the Supporting
Information), provided 22 (7.8 g, 78%): Rf ) 0.50 (20% EtOAc-
petroleum ether); [R]23D -41.3° (c ) 2.7, CHCl3); IR (film) 3510,
1640, 1612 cm-1; 1H NMR (CDCl3) δ 1.32 (s, 3H), 1.49 (s, 3H),
2.33 (d, 1H, J ) 11.7 Hz, D2O ex), 2.34 (m, 1H), 2.56 (m, 1H),
3.42 (s, 3H), 3.42 (m, 1H, partially buried under s at δ 3.70),
3.70 (s, 3H), 3.77 (t, 1H, J ) 9.0 Hz), 4.25 (t, 1H, J ) 7.2 Hz),
4.46 (m, 3H), 4.60 (m, 2H), 4.94 (d, 1H, J ) 7.2 Hz), 5.08 (m,
2H), 5.88 (m, 1H), 6.79 (d, 2H, J ) 8.7 Hz), 7.22 (d, 2H, J )
8.7 Hz), 7.27 (m, 5H); 13C NMR (CDCl3) δ 24.5, 26.8, 34.9, 53.4,
55.2, 69.3, 72.0, 74.8, 76.0, 79.2, 101.1, 108.3, 113.9, 117.3,
127.5, 127.7, 128.3, 129.5, 129.8 (several lines), 134.7, 138.6,
159.4. Anal. Calcd for C27H36O7: C, 68.62; H, 7.68. Found: C,
68.24; H, 8.01.
Ketoa ld eh yd e 23. 9-BBN in THF (74 mL of a 0.5 M
solution, 37 mmol) was added at 0 °C to a solution of 22 (5.8
g, 12 mmol) in dry THF (250 mL). After 1 h, the reaction was
warmed to room temperature and maintained at this temper-
ature for 18 h. The reaction was then cooled to 0 °C, and a
mixture of 30% H2O2 (55 mL) and 30% NaOH (55 mL) was
slowly added. The solution was extracted with ether (3 × 200
mL). The organic phase was washed with brine (200 mL), dried
(Na2SO4), filtered, and evaporated in vacuo. FCC of the residue
gave the diol derivative (5.2 g, 86%): Rf ) 0.30 (50% EtOAc-
dec (lit.1a mp 212-215 °C dec); [R]23 +70° (c 0.33, H2O) [lit.1a
D
[R]D +79.7° (c ) 0.93, H2O)]; Rf ) 0.25 (30% MeOH-CHCl3);
1H NMR and TLC data were identical with those of a
commercial sample of castanospermine;27 1H NMR (D2O) δ
1.0.69 (m, 1H), 2.03 (m, 1H), 2.20 (m, 1H), 2.32 (m, 1H), 3.07
(dt, 1H, J ) 2.1, 9.6 Hz), 3.16 (dd, 1H, J ) 5.1, 11.1 Hz), 3.59
(m, 1H), 4.40 (m, 1H); 13C NMR (D2O) δ 31.7, 50.6, 54.4, 68.0,
68.6, 69.1, 70.4, 78.0; MS (ES) m/z 190 (M + H).
p-Meth oxyben zyl 6,7,8-Tr id eoxy-5-O-ben zyl-2,3-O-(1-
m eth yleth ylid en e)-r-D-m a n n o-oct-7-en ofu r a n osid e (18).
Boron trifluoride etherate (4.9 mL, 39.4 mmol) was added to
a solution of aldehyde 20 (8.1 g, 26 mmol) in dry CH2Cl2 (300
mL), at -78 °C. The solution was stirred at this temperature
for 20 min, at which time allyltrimethylsilane (5.0 mL, 31
mmol) was added. The reaction mixture was maintained at
-78 °C for 2 h and then poured into saturated aqueous
NaHCO3 (300 mL). The mixture was extracted with ether (3
× 200 mL), and the organic phase was washed with brine (200
mL), dried (Na2SO4), filtered, and evaporated in vacuo. FCC
of the residue provided 21 (7.2 g, 77%) and a minor product
(0.3 g, 3%).
petroleum ether); IR (CHCl3) 3450, 1613 cm-1 1H NMR
;
(CDCl3) δ 1.32 (s, 3H), 1.50 (s, 3H), 1.60 (m, 3H), 1.80 (m, 1H),
2.69 (d, 1H, J ) 8.7 Hz), 2.90 (br s, 1H, D2O ex), 3.42 (s, 3H),
3.42 (m, buried under s at δ 3.42), 3.55 (m, 2H), 3.68 (s, 3H),
3.78 (t, 1H, J ) 8.1 Hz), 4.27 (t, 1H, J ) 7.5 Hz), 4.45 (m, 3H),
4.62 (d, 1H, J ) 10.8 Hz), 4.97 (d, 1H, J ) 7.2 Hz), 6.80 (d,
2H, J ) 8.7 Hz), 7.26 (m, 7H); 13C NMR (CDCl3) δ 24.3, 26.4,
26.5, 27.3, 53.2, 55.0, 62.5, 69.1, 71.7, 74.9, 75.8, 79.2, 100.9,
108.1, 113.8, 127.4, 127.5, 128.1, 129.4, 129.6, 138.4.
The Swern oxidation procedure which was used for the
preparation of 12 was applied to a sample of the diol from the
previous step (2.3 g, 4.7 mmol), using DMSO (2.0 mL, 28
mmol), oxalyl chloride (2.1 mL, 24 mmol) and Et3N (6.8 mL,
47 mmol). Ketoaldehyde 23 (1.9 g, 84%) was obtained as a
For 21: Rf ) 0.50 (20% EtOAc-petroleum ether); [R]23
D
+66.9° (c ) 0.75, CHCl3); IR (CHCl3) 3492, 1642 cm-1; 1H NMR
(CDCl3) δ 1.32 (s, 3H), 1.47 (s, 3H), 2.34 (m, 1H), 2.55 (m, 1H),
2.80 (br d, 1H, J ) 5.1 Hz, D2O ex), 3.78 (s, 3H), 3.88 (dd, 1H,
J ) 3.6, 8.1 Hz), 4.01 (m, 1H), 4.53 (ABq, ∆δ ) 0.18 ppm, J )
11.4 Hz, 2H), 4.62 (d, 1H, J ) 6.0 Hz), 4.83 (dd, 1H, J ) 5.7,
3.6 Hz), 5.14 (s, 1H), 5.18 (m, 2H), 5.95 (m, 1H), 6.91 (d, 2H,
J ) 8.4 Hz), 7.27 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3) δ 24.6,
25.9, 38.9, 55.1, 68.5, 69.0, 80.0, 81.4, 84.9, 104.9, 112.4, 113.8,
117.6, 129.3, 129.7, 134.5, 159.3. Anal. Calcd for C19H26O6: C,
65.13; H, 7.48. Found: C, 65.06; H, 7.48.
yellow oil: Rf ) 0.75 (50% EtOAc-petroleum ether); [R]23
D
-17.2° (c 7.10, CHCl3); IR (CHCl3) 1709 (broad), 1613 cm-1
;
1H NMR (CDCl3) δ 1.32 (s, 3H), 1.54 (s, 3H), 1.76 (m, 1H),
1.96 (m, 1H), 2.32 (m, 2H), 3.37 (s, 3H), 3.71 (s, 3H), 3.92 (dd,
1H, J ) 8.1, 3.9 Hz), 4.28 (m, 2H), 4.42 (t, 1H, J ) 6.6 Hz),
4.52 (m, 2H), 4.63 (d, 1H, J ) 6.0 Hz), 4.79 (d, 1H, J ) 6.6
Hz), 6.78 (d, 2H, J ) 8.4 Hz), 7.17 (d, 2H, J ) 8.4 Hz), 7.24-
7.26 (m, 7H), 9.50 (s, 1H); 13C NMR (CDCl3) δ 23.1, 25.4, 27.0,
39.7, 54.2, 55.2, 68.7, 72.5, 76.7, 78.2, 81.9, 100.5, 110.6, 113.8,
127.9, 128.2, 128.4, 129.4, 129.7, 137.4, 159.3, 201.4, 205.1;
HRMS (FAB) calcd for C27H33O8 (M - H) 485.2175, found
485.2176.
For minor product: Rf ) 0.55 (20% EtOAc-petroleum
1
ether); H NMR (CDCl3) δ 1.29 (s, 3H), 1.46 (s, 3H), 2.43 (m,
2H), 3.13 (br s, 1H, D2O ex), 3.78 (s, 3H), 3.89 (dd, 1H, J )
5.1, 3.6 Hz), 4.10 (q, 1H, J ) 5.1 Hz), 4.51 (ABq, ∆δ ) 0.15
ppm, J ) 11.4 Hz, 2H), 4.63 (d, 1H, J ) 5.7 Hz), 4.73 (dd, 1H,
J ) 5.7, 3.6 Hz), 5.14 (m, 3H), 5.91 (m, 1H), 6.87 (d, 2H, J )
8.7 Hz), 7.27 (d, 2H, J ) 8.7 Hz); 13C NMR (CDCl3) δ 24.5,
25.9, 37.9, 55.2, 68.7, 69.5, 80.5, 81.1, 85.5, 104.7, 112.6, 113.9,
117.5, 129.3, 129.8, 134.5, 159.4.
Tr ica r bon yl P r ecu r sor 24a ,b. DDQ (135 mg, 0.595 mmol)
was added at 0 °C, to a mixture of 23 (102 mg, 0.209 mmol),
in Et3N (0.03 mL, 0.22 mmol), CH2Cl2 (10 mL), and H2O (1
mL). After 20 min, the reaction mixture warmed to room
temperature and stirred at this temperature for an additional
3 h. The reaction mixture was then poured into saturated
NaHCO3 (20 mL) and extracted with CH2Cl2 (3 × 25 mL). The
combined organic phase was washed with brine (25 mL), dried
(Na2SO4), filtered and evaporated in vacuo. FCC of the residue
A portion of the product from the previous step (1.4 g, 4.3
mmol) was benzylated following the procedure used for
(27) Purchased from Tocris Cookson, Inc.

Synthesis of Castanospermine and Swainsonine
J . Org. Chem., Vol. 66, No. 5, 2001 1767
afforded unreacted 23 (10 mg), 24a (41 mg, 59% based on
recovered 23) and 24b (14 mg, 20% based on recovered 23).
for 2 h, then filtered through a pad of Celite. The filter cake
was washed several times with methanol and then concen-
trated in vacuo. The residue was dissolved in a mixture of 6
N HCl (1 mL) and THF (3 mL) and stirred at room tempera-
ture for 2 h. The volatiles were then removed under reduced
pressure. The residual syrup was dissolved in ethanol and
stirred with Amberlite IRA-(OH) ion-exchange resin (500 mg)
for 30 min. The mixture was filtered through Celite and the
filtrate concentrated in vacuo to give a semisolid residue 2 (39
mg, 80%). Recrystallization from CHCl3-MeOH-Et2O af-
forded needles: mp 138-142 °C (lit.2c mp 144-145 °C, lit.12g
For 24a : Rf ) 0.25 (15% EtOAc-petroleum ether); [R]23
D
-68.8° (c 3.50, CHCl3); IR (CHCl3) 3454 cm-1; 1H NMR (CDCl3)
δ 1.35, 1.48 (both s, 3H ea), 1.65-1.95 (m, 4H), 2.75 (d, J )
10.8 Hz, 1H, D2O ex), 3.56 (s, 3H), 3.60 (m, 1H), 4.60 (m, 3H),
4.75 (m, 1H), 5.04 (d, J ) 3.0 Hz, 1H), 5.17 (m, 1H), 7.35 (m,
5H); 13C NMR (CDCl3) δ 22.7, 25.4, 26.1, 28.1, 58.5, 70.8, 71.9,
78.4, 83.0, 92.2, 104.2, 106.0, 113.1, 127.3, 128.2, 128.4, 138.5;
HRMS (FAB) calcd for C19H26O7Na (M + Na), 389.1576, found
389.1581.
1
For 24b: Rf ) 0.40 (15% EtOAc-petroleum ether); IR
mp 141-143 °C); H NMR and TLC data were identical with
1
(CHCl3) 3454 cm-1; H NMR (CDCl3) δ 1.32, 1.42 (both s, 3H
those for a commercial sample of swainsonine;28 Rf ) 0.30 (30%
CH3OH-EtOAc); [R]23 -86° (c 0.30, CH3OH) [lit.2c [R]25
ea), 1.70-1.95 (m, 4H), 2.88 (br d, J ) 10 Hz, 1H, D2O ex),
3.45 (s, 3H), 3.58 (m, 1H), 4.65 (s, 2H), 4.73 (m, 2H), 4.95 (s,
1H), 5.10 (m, 1H), 7.30 (m, 5H). 13C NMR (CDCl3) δ 22.9, 25.6,
26.9, 27.7, 56.8, 71.2, 72.1, 84.4, 85.2, 92.4, 111.6, 112.5, 112.6,
127.7, 128.3, 128.5, 138.5; HRMS (FAB): calcd for C19H24O6
(M - OH), 349.1651, found 349.1651.
D
D
-87.2° (c ) 1.03, CH3OH), lit.12g [R]26 -82.6° (c ) 1.03, CH3-
D
OH)]; 1H NMR (D2O) δ 1.21 (m, 1H), 1.49 (m, 1H), 1.66 (broad,
1H), 1.86 (dd, 1H, J ) 3.6, 9.0 Hz), 1.93 (dd, 1H, J ) 2.7, 14.3
Hz), 2.02 (m, 1H), 2.49 (dd, 1H, J ) 13.2, 9.8 Hz), 2.83 (dd,
1H, J ) 13.2, 2.1 Hz), 2.87 (broad, 1H), 3.76 (dt, 1H, J ) 3.9,
10.2 Hz), 4.19 (dd, 1H, J ) 3.9, 5.7 Hz), 4.30 (m, 1H); 13C NMR
(D2O) δ 23.6, 32.9, 52.0, 61.3, 66.8, 69.4, 70.0, 73.3; MS (ES)
m/z 174 (M + H).
(1S,2R,8R,8aR)-8-(Ben zyloxy)-1,2-(isopr opyliden edioxy)-
octa h yd r oin d olizid in e (25). A mixture of 24a (110 mg, 0.30
mmol), ammonium formate (40 mg, 0.60 mmol), NaCNBH3
(280 mg, 2.6 mmol), freshly activated, powdered 4A molecular
sieves, and anhydrous MeOH (3 mL) was stirred at room
temperature for 24 h. The reaction mixture was then processed
as described for the preparation of 14. FCC of the crude residue
provided 25 (67 mg, 69%). Rf ) 0.30 (50% EtOAc-petroleum
ether); [R]23 -67° (c 3.1, CHCl3) [lit.12f [R]20 -64.2° (c 0.50,
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (NIH), General Medical Sciences (GM
57865), for their support of this research. “Research
Centers in Minority Institutions” award RR-03037 from
the National Center for Research Resources of the NIH,
which supports the infrastructure (and instrumentation)
of the Chemistry Department at Hunter, is also ac-
knowledged. The contents are solely the responsibility
of the authors and do not necessarily represent the
official views of the NCRR/NIH.
D
D
CHCl3), lit.12g [R]26 -58.9° (c 0.27, CHCl3)]; 1H NMR (CDCl3)
D
δ 1.14-1.26 (m, 1H), 1.35 (s, 3H), 1.51 (s, 3H), 1.51-1.65 (m,
2H), 1.69 (dd, 1H, J ) 4.0, 8.8 Hz), 1.83 (dt, J ) 3.0, 11.0 Hz,
1H), 2.09 (dd, J ) 4.4, 10.6 Hz, 1H), 2.10 (m, 1H), 2.97 (bd, J
) 10.6 Hz, 1H), 3.12 (d, J ) 10.6 Hz, 1H), 3.64 (ddd, 1H, J )
4.4, 8.8, 11.0 Hz, 1H), 4.59 (dd, 4.4, 6.2 Hz, 1H), 4.68 (s, 2H),
4.73 (dd, 1H, J ) 4.3, 6.2 Hz, 1H), 7.20-7.42 (m, 5H); 13C NMR
(CDCl3) δ 24.3, 25.3, 26.3, 30.9, 51.9, 60.5, 71.6, 72.6, 74.5,
78.2, 79.6, 111.0, 127.4, 127.9, 128.3, 139.4; HRMS (FAB) calcd
for C18H26NO3 (M + H) 304.1912, found 304.1916.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 1, 2, 10, 12-14, 18, and 20-25 and detailed
procedures for 20 and 22. This material is available free of
charge via the Internet at http://pubs.acs.org.
Treatment of 24b (30 mg, 0.085 mmol) according to the
procedure described for 24a provided 25 (17 mg, 66%).
Sw a in son in e (2). HCOOH (1 mL) was added to a mixture
of 25 (86 mg, 0.22 mmol), 10% Pd-C (500 mg), and MeOH (4
mL) under an argon atmosphere. The suspension was stirred
J O001447T
(28) Purchased from Sigma, Inc.