Total Syntheses of Potent Glycosidase Inhibitors
J. Am. Chem. Soc., Vol. 121, No. 13, 1999 3047
In view of the therapeutic potential of the indolizidine
alkaloids and the opportunity to gain insights into the mechanism
by which glycosidases process oligosaccharides, considerable
efforts have been directed toward the syntheses of 1, its
stereoisomers, and its analogues.11 Because of their highly
oxygenated architecture, most of the reported syntheses of (+)-1
and (+)-2 use the intrinsic chirality of carbohydrate precursors
to establish four of the five contiguous stereogenic centers of
targeted indolizidine alkaloids.11a-c,e The stereochemical con-
figurations at C(6), C(7), C(8), and C(8a) of castanospermine
and 6-epicastanospermine correspond to those of D-glucose and
D-mannose, respectively. As a result, the carbohydrate-based
syntheses of 1 and 2 use these hexoses or their derivatives as
starting materials. In contrast to the indolizidine alkaloids, the
pyrrolizidines 3-5 have attracted much less synthetic attention.12
Australine, (+)-3, and 1-epiaustraline, (+)-5, have been prepared
using a carbohydrate-based approach beginning with an ap-
propriate pyranose, analogous to the transformations leading to
(+)-1 and (+)-2.12a,d-f 3-Epiaustraline ((+)-4) has not yet, to
our knowledge, been synthesized. Although the use of sugar
precursors in the construction of alkaloids 1-5 minimizes the
need to create the requisite stereocenters and introduce oxygen
functionality, the syntheses highlighting this approach are often
linear, limited in their flexibility, and, in some cases, fail to
demonstrate high levels of stereocontrol. Indeed, few methods
exist for the preparation of the targeted alkaloids outside of these
carbohydrate-based approaches. Of the twenty-four reported
syntheses of 1, 2, 3, and 5, only six syntheses involve the de
novo creation of the requisite functional groups and attendant
stereogenic centers.11d,11g,12b,13
Over the past eight years, we have extensively developed the
tandem [4 + 2]/[3 + 2] cycloaddition of nitroalkenes as a
general method for the synthesis of pyrrolidine- and pyrrolizi-
dine-containing compounds.14-17 We now wish to demonstrate
both the utility and the versatility of the enantioselective tandem
[4 + 2]/[3 + 2] nitroalkene cycloaddition reaction in the
preparation of enantiomerically pure castanospermine ((+)-1),
6-epicastanospermine ((+)-2), australine ((+)-3), and 3-epiaus-
traline ((+)-4).
The syntheses of these four alkaloids would provide several
new challenges for the tandem cycloaddition method. In contrast
to our previously reported syntheses, a hydroxymethyl group
would need to be incorporated at C(3) rather than at C(1) for
the construction of pyrrolizidines 3 and 4.15 In addition,
preparation of indolizidine alkaloids 1 and 2 requires a one-
carbon homologation to access 5,6- rather than 5,5-bicyclic
structures. This paper describes a novel, unified strategy which
allows for the rapid and stereoselective syntheses of all four
alkaloids in enantiopure form from a single common precursor.
Synthetic Strategy
(11) Syntheses of castanospermine ((+)-1) published since 1992: (a)
Zhao, H.; Mootoo, D. R. J. Org. Chem. 1996, 61, 6762. (b) Overkleeft, H.
S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547. (c) Grassberger, V.;
Berger, A.; Dax, K.; Fechter, M.; Gradnig, G.; Stuetz, A. E. Liebigs Ann.
Chem. 1993, 379. (d) Kim, N. S.; Choi, J. R.; Cha, J. K. J. Org. Chem.
1993, 58, 7096. (e) For a review of published syntheses of 1, 2, and
analogues up to 1992 see: Burgess, K.; Henderson, I. Tetrahedron 1992,
48, 4045. For analogues of 1 and 2 published since 1992 see: (f) Michael,
J. P. Nat. Prod. Rep. 1997, 21. (g) Furneaux, R. H.; Gainsford, G. J.; Mason,
J. M.; Tyler, P. C. Tetrahedron 1994, 50, 2131. (h) Carretero, J. C.; Gomez,
A. J. Org. Chem. 1998, 63, 2993. (i) Izquierdo, I.; Plaza, M. T.; Robles,
R.; Mota, A. J. Tetrahedron: Asymmetry 1998, 9, 1015. (j) Xu, Y.-M.;
Zhou, W.-S. Chin. J. Chem. 1998, 16, 34. (k) Holmes, A. B.; Bourdin, B.;
Collins, I.; Davison, E. C.; Rudge, A. J.; Stork, T. C.; Warner, J. A. Pure
Appl. Chem. 1997, 69, 531. (l) Landmesser, N. G.; Tsui, H.-C.; King, C.-
H. R.; Paquette, L. A. Synth. Commun. 1996, 26, 2213. (m) Furneaux, R.
H.; Gainsford, G. J.; Mason, J. M.; Tyler, P. C.; Hartley, O.; Winchester,
B. G. Tetrahedron 1995, 51, 12611. (n) Herczegh, P.; Kovacs, I.; Szilagyi,
L.; Sztaricckai, F.; Berecibar, A.; Riche, C.; Chiaroni, A.; Olesker, A.;
Lukacs, G. Tetrahedron 1995, 51, 2969. (o) Martin, S. F.; Chen, H.-J.;
Lynch, V. M. J. Org. Chem. 1995, 60, 276. (p) Kefalas, P.; Husson, H.-P.;
Grierson, D. S. Nat. Prod. Lett. 1993, 3, 313. (q) Furneaux, R. H.; Gainsford,
G. J.; Mason, J. M.; Tyler, P. C. Tetrahedron Lett. 1994, 35, 3143. (r)
Casiraghi, G.; Ulgheri, F.; Spanu, P.; Rassu, G.; Pinna, L.; Gasparri Fava,
G.; Belicchi Ferrari, M.; Pelosi, G. J. Chem. Soc., Perkin Trans. 1 1993,
2991. (s) Jirousek, M. R.; Cheung, A. W. H.; Babine, R. E.; Sass, P. M.;
Schow, S. R.; Wick, M. M. Tetrahedron Lett. 1993, 34, 3671. (t) Kefalas,
P.; Grierson, D. S. Tetrahedron Lett. 1993, 34, 3555. (u) Martin, S. F.;
Chen, H. J.; Yang, C. P. J. Org. Chem. 1993, 58, 2867. (v) Maggini, M.;
Prato, M.; Ranelli, M.; Scorrano, G. Tetrahedron Lett. 1992, 33, 6537. (w)
Burgess, K.; Chapling, D. A. Tetrahedron Lett. 1992, 33, 6077. (x) Lee, C.
K.; Sim, K. Y.; Zhu, J. Tetrahedron 1992, 48, 8541. (y) Siriwardena, A.
H.; Chiaroni, A.; Riche, C.; Grierson, D. S. J. Org. Chem. 1992, 57, 5661.
(z) Gallagher, T.; Giles, M.; Subramanian, R. S.; Hadley, M. S. J. Chem.
Soc., Chem. Commun. 1992, 166. (aa) St.-Denis, Y.; Chan, T. H. J. Org.
Chem. 1992, 57, 3078. (bb) Mulzer, J.; Dehmlow, H.; Bushchmann, J.;
Luger, P. J. Org. Chem. 1992, 57, 3194. (cc) Pearson, W. H.; Hembre, E.
J. Tetrahedron Lett. 1993, 34, 8221. (dd) Brandi, A.; Cicchi, S.; Cordero,
F. M.; Frignoli, R.; Goti, A.; Picasso, S.; Vogel, P. J. Org. Chem. 1995,
60, 6806.
In formulating the synthetic plan for these four natural
products, we recognized that the absolute configurations at C(1),
C(8a), C(8), and C(7) of 1 and 2 are the same as the
configurations at the corresponding centers C(7), C(7a), C(1),
and C(2) of 3 and 4, namely S, R, R, and R, respectively, Scheme
1. We envisioned that these four common stereogenic centers
would originate from the tandem [4 + 2]/[3 + 2] cycloaddition
process, thus allowing the syntheses to diverge from a common
cycloadduct. Meanwhile, the remaining stereogenic center, C(6)
of 1 and 2 and C(3) of 3 and 4, would have to be independently
set in a postcycloaddition modification.
A successful design strategy leading to the preparation of all
four alkaloids (1-4) must incorporate the ability to access both
5,5- and 5,6-fused bicyclic systems. All our previous synthetic
efforts have relied on N-acylations for the formation of the
C(3)-N bond, resulting in the closure of one of the rings of
the pyrrolizidine subunits. We now wished to explore the
potential of N-alkylations to accomplish a similar structural
objective but with the added flexibility of readily adjusting the
ring size. This strategy is illustrated in Scheme 1 for the
preparation of castanospermine ((+)-1) and australine ((+)-3)
via indolizidine 6 and pyrrolizidine 7. Hydrogenolysis of nitroso
(13) (a) Reymond, J. L.; Pinkerton; A. A.; Vogel, P. J. Org. Chem. 1991,
56, 2128. (b) Bhide, R.; Martezaei, R.; Scilimati, A. Sih, C. J. Tetrahedron
Lett. 1990, 31, 4827. (c) Ina, H.; Kibayashi, C. Tetrahedron Lett. 1991, 32,
54147.
(14) For a review of the asymmetric tandem [4 + 2]/[3 + 2] cycloaddition
of nitro olefins see the following: Denmark, S. E.; Thorarensen, A. Chem.
ReV. 1996, 96, 137.
(15) For the synthesis of 7-epiaustraline: Denmark, S. E.; Herbert, B.
J. Am. Chem. Soc. 1998, 120, 7357.
(16) (a) Denmark, S. E.; Thorarensen, A. J. Org. Chem. 1994, 59, 5672.
(b) Denmark, S. E.; Thorarensen, A. J. Am. Chem. Soc. 1997, 119, 125. (c)
Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J. Am. Chem. Soc. 1996,
118, 8266. (d) Denmark, S. E.; Marcin, L. R. J. Org. Chem. 1997, 62,
1675.
(17) Denmark, S. E.; Hurd, A. R.; Sacha, H. J. J. Org. Chem. 1997, 62,
1668.
(12) Reported syntheses of (+)-australine ((+)-3): (a) Pearson, W. H.;
Hines, J. V. Tetrahedron Lett. 1991, 32, 5513. (b) White, J. D.; Hrnciar,
P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998, 120, 7359. (c) Reference
11g. For syntheses of 1-epiaustraline (5): (d) Ikota, N. Tetrahedron Lett.
1992, 33, 2553. (e) Choi, S.; Bruce, I.; Fairbanks, A. J.; Fleet, G. W.; Jones,
A. H.; Nash, R. J.; Fellows, L. E. Tetrahedron Lett. 1991, 32, 5517. (f) For
a review of the reported syntheses of hydroxylated pyrrolizidine alkaloids
see: Giovanni, C.; Zanardi, F.; Rassu, G.; Pinna, L. In AdVances in the
StereoselectiVe Synthesis of Hydroxylated Pyrrolizidines.