Triple reductive amination approach to polyhydroxyindolizidine alkaloids: A total synthesis of castanospermine

Full text of DOI:10.1021/jo961208z

6762
J . Org. Chem. 1996, 61, 6762-6763
Sch em e 1
Tr ip le Red u ctive Am in a tion Ap p r oa ch to
P olyh yd r oxyin d olizid in e Alk a loid s: A Tota l
Syn th esis of Ca sta n osp er m in e
Hang Zhao and David R. Mootoo*
Department of Chemistry, Hunter College, 695 Park Avenue,
New York, New York 10021
Received J une 27, 1996
The polyhydroxindolizidine alkaloids, of which castano-
spermine 1 is one of the more prominent derivatives, are
noted for their powerful glycosidase inhibitory activity.1
Analogs have been used as biochemical tools and have
been examined as chemotherapeutic agents in the treat-
ment of several disorders,2 including cancer3 and HIV-
I.4 It is commonly believed that their enzyme inhibitory
activity is related to their carbohydrate-like structure.5
The variation of enzyme specificity with stereochemistry
appears to be consistent with this hypothesis, and this
has led to considerable interest in analog design and
synthesis.5-7
Several syntheses center on the introduction of one or
more new carbinol centers in a sugar template, leading
to conversion to the bicyclic indolizidine framework.
Noncarbohydrate approaches are becoming increasingly
popular with the advancement in methodologies for
enantio- and stereoselective synthesis of polyhydroxy-
lated compounds. Many of the published procedures
suffer from poor stereoselectivity and inefficient protect-
ing group chemistry, especially with respect to handling
of the amino residue. In view of the latter we envisaged
a strategy in which a carbohydrate-derived tricarbonyl
precursor 2 is converted in a single step to the target
indolizidine skeleton via a triple reductive amination
reaction (Scheme 1).5,8,9 Notwithstanding questions of
stereoselectivity and the formation of di- and triaminated
products, this approach capitalizes on the use of a
carbohydrate precursor and on the fact that the amino
residue is introduced at a late stage in the synthesis and
with concomitant formation of the indolizidine frame-
work. Herein we illustrate the general features of this
strategy by the synthesis of castanospermine.
be identified in a D-glucose precursor.10 The remaining
carbinol center at C1 would have to be introduced at an
‘off-ring’ position of a monosaccharide template. A more
challenging proposition was the practical preparation of
the tricarbonyl functionality. Toward this goal, we
anticipated the use of a pyranoside alkene precursor 4.
The alkenyl residue serves as a novel protecting group
device since treatment of 4 with halonium ions in the
presence of an alcohol gives the iodotetrahydrofuran-
acetal product 3, which is primed for transformation to
the desired tricarbonyl precursor, under relatively mild
conditions.11
The synthesis begins with the known aldehyde 5,
which is available on a large scale and in four straight-
forward steps from methyl R-D-glucopyranoside.12 Ally-
lation of 5 under the conditions developed by Whitesides
(allyl bromide, Sn, CH3CN/H2O, ultrasound) led to a 9:1
ratio of alcohol epimers in 83% yield.13,14 Chromato-
graphic separation and benzylation of the major product
gave 6, which was smoothly converted within 30 min, on
treatment with iodonium dicollidine perchlorate (IDCP)/
CH2Cl2/MeOH, to a mixture of iodo-THF’s. Zinc-medi-
ated reductive elimination of the crude product led to the
alkenyl acetal-alcohol 7 in 74% overall yield from the
pyranoside alkene 6. The conversion of 7 to the requisite
tricarbonyl intermediate was achieved in 90% yield via
a three-step sequence of reactions: alcohol oxidation
using the Swern’s procedure to the ketone 8, followed by
alkene ozonolysis and acetal hydrolysis. 1H and 13CNMR
analysis of the product showed no evidence of the free
bis-aldehyde 9; instead, the mass spectrum and the
presence of several acetal resonances suggested a mixture
of lactol isomers (e.g., 9′) and/or hydrate formation
(Scheme 2).
In common with previous sugar based syntheses, the
three carbinol centers C6, C7, and C8 in the target may
(1) For a recent review, see: Elbein, A. D.; Molyneux, R. J . In
Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.;
Wiley: New York, 1987; Vol. 5, pp 1-54.
Treatment of the presumed bis-aldehyde derivative in
anhydrous methanol, with 1.5 equiv of ammonium for-
mate and 30 equiv of sodium cyanoborohydride over 24
h, led to the formation of a major compound 10 in 53%
yield together with an intractable mixture of several
minor, highly polar components (∼20%). Within the
(2) Elbein, A. D. Crit. Rev. Biochem. 1984, 16, 21.
(3) (a) Humphries, M. J .; Matsumoto, K.; White, S. L.; Olden, K.
Cancer Res. 1986, 46, 5215. (b) Dennis, J . W. Cancer Res. 1986, 46,
5131. (c) Ahrens, P. B.; Ankel, H. J . Biol. Chem. 1987, 262, 7575.
(4) (a) Walker, B. D.; Kowalski, M.; Goh, W. C.; Kozarsky, K.;
Krieger, M.; Rosen, C.; Rohrschneider, L; Haseltine, W. A.; Sodroski,
J . Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 8120. (b) Ruprecht, R. M.;
Mullaney, S.; Andersen, J .; Bronson, R. J . Acquired Immune Defic.
Syndr. 1989, 2, 149.
(5) Kajimoto, T.; Liu, K. K.-C.; Pederson, R. L.; Zhong, Z.; Ichikawa,
Y.; Porco, J . A.; Wong, C.-H. J . Am. Chem. Soc. 1991, 113, 6187.
(6) Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045.
(7) Rajeswari, S.; Chandrasekharan, S.; Govindachari, T. R. Het-
erocycles 1987, 25, 659.
(8) Although double reductive amination strategies have been
reported, the triple reductive amination approach is not known; see:
(a) Reference 5. (b) Baxter, E. W.; Reitz, A. B. J . Org. Chem. 1994, 59,
3175. (c) Martin, O. R.; Saavedra, O. M. Tetrahedron Lett. 1995, 36,
799.
(10) (a) Bernotas, R. C.; Ganem, B. Tetrahedron Lett. 1984, 25, 165.
(b) Anzeveno, P. B.; Creemer, L. J . Tetrahedron Lett. 1990, 31, 2085.
(11) (a) Elvey, S. P.; Mootoo, D. R. J . Am. Chem. Soc. 1992, 114,
9685. (b) Wilson, P.; Shan, W.; Mootoo, D. R. J . Carbohydr. Chem, 1994,
13, 113. (c) Shan, W.; Wilson, P.; Liang, W.; Mootoo, D. R. J . Org. Chem.
1994, 59, 7986.
(12) Hashimoto, H.; Asano, K.; Fuji, F.; Yoshimura, J . J . Carbohydr.
Res. 1982, 104, 87.
(13) Kim, E.; Gordon, D. M.; Schmid, W.; Whitesides, G. M. J . Org.
Chem. 1993, 58, 5500.
(9) A conceptually similar strategy to the pyrrolidizidine alkaloids
involving a double reductive amination-lactam formation sequence
has recently been described: Denmark, S. E.; Thorarensen, A.;
Middleton, D. S. J . Org. Chem. 1995, 60, 3574.
(14) 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: Czernecki, S.; Horns, S.;
Valery, J .-M. J . Org. Chem. 1995, 60, 650.
S0022-3263(96)01208-X CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 20, 1996 6763
Sch em e 2a
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, ∆; (e) Swern oxidation; (f) O3, CH2Cl2, -78 °C then Ph3P; (g) THF-9 M HCl; (h) 1.3 equiv of NH4HCO2, 30 equiv of NaCNBH3,
MeOH; (i) 10% Pd/C, MeOH-HCOOH.
Sch em e 3
Sch em e 4a
a
Key: (a) O3, CH2Cl2, -78 °C then Ph3P; (b) THF-9 M HCl;
(c) 1.3 equiv of NH4HCO2, 30 equiv of NaCNBH3, MeOH.
the difference in reactivity of 11 vs 12 appears to be more
in agreement with a pathway through the six-membered
iminium ion IV, i.e., 9 f III f IV f 10, rather than one
which involves the five membered intermediate II, i.e.,
9 f I f II f 10 (Scheme 3).
limits of NMR detection less than 5% of the C8a epimer
was observed. Hydrogenolysis of 10 gave a product that
was identical with natural castanospermine15 (mp, IR,
NMR, RD). The overall yield from 5 was 22% over nine
steps.
In addition to its synthetic significance, this result has
biosynthetic implications, since it has been proposed that
the variation in the configuration at C8a is related to the
timing of reduction of a cyclic iminium ion relative to
introduction of the C1-alcohol.17 The application of these
results to the synthesis of other polyhydroxyindolizidines
and of related alkaloid ring systems is currently under-
way and will be reported in due course.
The preponderance of monoamination vs di- and tri-
aminated products suggests that initial reductive ami-
nation on 9 occurs preferentially at one of the aldehyde
groups and the resulting primary amine undergoes
stereoselective cyclization to the pyrrolidine or piperidine,
giving the indolizidine, before appreciable di- and tri-
amination occurs, i.e., 9 f III f IV f 10 or 9 f I f II
f 10 (Scheme 3). Therefore, comparison of the double
reductive amination of 11 and 12 with regard to the
facility and stereoselectivity of the reaction might be
insightful as to the preferred sequence (Scheme 4).
Substrates 11 and 12 were obtained via ozonolysis or
hydrolysis, respectively, on the ketone 8, used in the
previous sequence. Each was individually subjected to
the identical amination conditions used on the tricarbonyl
substrate 9. The reaction of 11 was sluggish and gave
an intractable mixture of products. On the other hand,
12 behaved in a fashion similar to 9. A single product
13 of identical C8a configuration to 10 was obtained in
54% yield over 24 h.16 This stereochemical result and
Ack n ow led gm en t . This investigation was sup-
ported in part by a “Research Centers in Minority
Institutions” award, RR-03037, from the Division of
Research Resources, National Institutes of Health.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and NMR spectra for 1 and 6-13 (20 pages).
J O961208Z
(16) The related double reductive cyclization on 5-ketoglucose
derivatives has also been shown to proceed with high stereoselectivity
for the 2,5-imino-D-glucitol: see refs 5 and 8.
(17) Schneider, M. J .; Ungemach, F. S.; Broquist, H. P.; Harris, T.
M. J . Am. Chem. Soc. 1982, 104, 6863.
(15) Availabe from Tocris Cookson, Inc., St. Louis, MO 63146.