Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
6434 J . Org. Chem. 1999, 64, 6434-6442
En a n tiosp ecific Syn th esis of (-)-Sla fr a m in e a n d Rela ted
Hyd r oxyla ted In d olizid in es. Utiliza tion of a Nu cleop h ilic Ala n in ol
Syn th on Der ived fr om Ser in e1
Mukund P. Sibi* and J ames W. Christensen
Department of Chemistry, North Dakota State University, Fargo, North Dakota 58105-5516
Received May 25, 1999
A general methodology for the synthesis of indolizidine alkaloids δ-coniceine (12), 1-hydroxyin-
dolizidine (20), desacetoxy slaframine (24), slaframine (34), and an analogue (37) has been developed.
This convergent approach utilizes the available chirality in proline and serine and is conceptually
different from other approaches. A highly stereoselective coupling of the prolinals with a nucleophilic
alaninol synthon provides the precursors for the key cyclization. A novel thermolytic annulation of
an oxazolidinone is the key step in the formation of the six-membered piperidine ring. Further
elaboration provides the target natural products 24, 34, and 37 in good overall yields.
Hydroxylated indolizidine alkaloids have gained inter-
deficiency virus (HIV) responsible for the disease AIDS.7
Its potential for use as an anti-viral and anti-cancer agent
has also been proposed.8 The wide range of bioactivity of
these indolizidines makes them ideal targets for the
development of new strategies for their efficient synthe-
sis.
est as synthetic targets due to their diverse and potent
biological activities.2 Of the many naturally occurring
members of this family, slaframine, swainsonine, and
castanospermine have received notable attention. The
A variety of methods have been reported for the
synthesis of indolizidine alkaloids.9 The objective of this
study was to develop a general synthetic methodology
whereby a host of related indolizidine alkaloids could be
prepared by a common route. In particular the synthesis
of the parent indolizidine δ-coniceine,10 1-hydroxyin-
dolizidine,11 and slaframine12,13 were of primary concern.
Our convergent approach which uses the available chiral-
ity in proline and serine is conceptually different from
other approaches and involves the annulation of the six-
(7) (a) Gruters, R. A.; Neefjes, J . J .; Tersmette, M.; De Goede, R. E.
Y.; Tulp, A.; Huisman, H. G.; Midema, F.; Ploegh, H. L. Nature
(London) 1987, 330, 74. (b) Sunkara, P. S.; Bowlin, T. L.; Liu, P. S.;
Sjoerdsma, A. Biochem. Biophys. Res. Commun. 1987, 148, 206.
(8) Humphries, M. J .; Matsumoto, K.; White, S. L.; Olden, K. Cancer
Res. 1986, 46, 5215.
(9) Angle, S. R.; Breitenbucher, J . G. In Studies in Natural Products
Chemistry; Stereoselective Synthesis; Atta-ur-Rahman, Ed.; Elsevier:
New York, 1995; Vol. 16, Part J , pp 453-502.
alkaloid slaframine, a mycotoxin produced by the fungus
Rhizoctonia leguminicola, and swainsonine have been
shown to arise from a common biosynthetic precursor.3
These two compounds are involved in “slobbers syn-
drome”,4 a process which leads to excess salivation in
cattle when they graze on fungus-infested feeds.5 Swain-
sonine has also been found to be a potent R-mannosidase
inhibitor.6 Castanospermine, an alkaloid isolated from a
variety of legumes as well as the Moreton Bay chestnut
Castanospermum australe, is one of the actively studied
targets due to its ability to interrupt the functions of the
glycoprotein envelope surrounding the human immuno-
(10) Coniceine Isolation: Roberts, M. F.; Brown, R. T. Phytochem-
istry 1981, 20, 447. Racemic synthesis: (a) Martin-Lopez, M. J .;
Bermejo-Gonzalez, F. Tetrahedron Lett. 1994, 35, 4235. (b) J ung, M.
E.; Choi, Y. M. J . Org. Chem. 1991, 56, 6729. (c) Green, D. L. C.;
Thompson, C. M. Tetrahedron Lett. 1991, 32, 5051. (d) Garst, M. E.;
Bonfiglio, J . N.; Marks, J . J . Org. Chem. 1982, 47, 1494. (e) Garst, M.
E.; Bonfiglio, J . N. Tetrahedron Lett. 1981, 2075. (f) Khatri, N. A.;
Schmitthenner, H. F.; Shringarpure, J .; Weinreb, S. M. J . Am. Chem.
Soc. 1981, 103, 6387. (g) Schell, F. M.; Ganguly, R. N. J . Org. Chem.
1980, 45, 4069. (h) Munchof, M. J .; Meyers, A. I. J . Org. Chem. 1995,
60, 7084. (i) Sato, Y.; Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetrahe-
dron 1994, 50, 371. (j) Nukui, S.; Sodeoka, M.; Shibasaki, M. Tetra-
hedron Lett. 1993, 34, 4965. (k) Waldmann, H.; Braun, M. J . Org.
Chem. 1992, 57, 4444. (l) Waldmann, H.; Braun, M. Gazz. Chim. Ital.
1991, 121, 277. (m) Pearson, W. H.; Lin, K.-C. Tetrahedron Lett. 1990,
31, 7571. (n) Danishefsky, S.; Taniyama, E.; Webb II, R. R. Tetrahedron
Lett. 1983, 24, 11. (o) Branchaud, B. P. J . Org. Chem. 1983, 48, 3538.
(p) Arisawa, M.; Takezawa, E.; Niishida, A.; Mori, M.; Nakagawa, M.
Synlett 1997, 1179. (q) Takahata, H.; Kubota, M.; Momose, T.
Tetrahedron: Asymmetry 1996, 7, 3047. (r) De Kimpe, N.; Stanoeva,
E.; Kulinkovich, O. Org. Prep. Proced. Int. 1995, 27, 674. (s) Sa´nchez-
Sancho, F.; Herrado´n, B. Tetrahedron: Asymmetry 1998, 9, 1951.
(11) 1-Hydroxyindolizidine synthesis: (a) Takahata, H.; Banba, Y.;
Momose, T. Tetrahedron: Asymmetry 1990, 1, 763. (b) Takahata, H.;
Tajima, M.; Banba, Y.; Momose, T. Chem. Pharm. Bull. 1989, 37, 2550.
(c) ref 3 a and b. (d) Green, D. L. C.; Kiddle, J . J .; Thompson, C. M.
Tetrahedron 1997, 51, 2865.
(1) Taken in part from the Ph.D. Thesis of J . W. Christensen, North
Dakota State University, 1994.
(2) General reviews on indolizidine alkaloids: Michael, J . P. Nat.
Prod. Rep. 1997, 14, 21, Takahata, H.; Momose, T. In The Alkaloids;
Cordell, G. A., Ed.; Academic: San Diego, 1993; Vol. 44, Chapter 3.
(3) (a) Harris, C. M.; Schneider, M. J .; Ungemach, F. S.; Hill, J . E.;
Harris, T. M. J . Am. Chem. Soc. 1988, 110, 940. (b) Harris, T. M.;
Harris, C. M.; Hill, J . E.; Ungemach, F. S.; Broquist, H. P.; Wickwire,
B. M. J . Org. Chem. 1987, 52, 3094. (c) Harris, C. M.; Campbell, B. C.;
Molyneux, R. J .; Harris, T. M. Tetrahedron Lett. 1988, 29, 4815.
(4) Croom J r, W. J .; Froetschel, M. A.; J ohnson, A. D. J . Anim. Sci.
1995, 73, 1499.
(5) Gardiner, R. A.; Rinehart, J r., K. L.; Snyder, J . J .; Broquist, H.
P. J . Am. Chem. Soc. 1968, 90, 5639.
(6) (a) Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2, 199. (b)
Cenci Di Bello, I.; Fleet, G.; Namgoong, S. K.; Tadano, K.; Winchester,
B. Biochem. J . 1989, 259, 855.
10.1021/jo9908546 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/04/1999