J. Am. Chem. Soc. 1998, 120, 7359-7360
7359
Scheme 1a
Tandem Ring-Closing Metathesis Transannular
Cyclization as a Route to Hydroxylated
Pyrrolizidines. Asymmetric Synthesis of
(+)-Australine
James D. White,* Peter Hrnciar, and Alexandre F. T. Yokochi
Department of Chemistry, Oregon State UniVersity
CorVallis, Oregon 97331-4003
ReceiVed April 6, 1998
The family of pyrrolizidine alkaloids continues to provide novel
structures with interesting and potentially valuable biological
properties.1 The alexines,2 represented by the parent alkaloid (1),
australine (2),3 and the pentahydroxypyrrolizidine casuarine (3),4
are powerful inhibitors of glucosidase and exhibit antiviral5
including anti-HIV activity.6 Although a variety of de noVo
approaches to the construction of simple pyrrolizidines is avail-
able,7 none is directly applicable to the asymmetric synthesis of
structures such as 1-3. Indeed, pathways to these systems have
a Key: (i) CH2dCH(CH2)2NCO, i-Pr2NEt, C6H6, ∆, 93%; (ii) t-BuOK,
THF, 0 °C, 96%; (iii) Amberlyst-15, Me2CO, rt, 62% (98% based on
recovered 6); (iv) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 90%; (v)
Ph3P+Me Br-, KHMDS, THF, -78 °C f rt, 76%; (vi) 10, CH2Cl2, rt,
97%; (vii) m-CPBA, CH2Cl2, rt, 82%.
generally pursued routes involving transmutation of carbohydrates
from the chiral pool.8 Herein we describe a new synthesis of
pyrrolizidines based on ring-closing metathesis in conjunction with
transannular cyclization. The method is potentially applicable
not only to polyhydroxylated pyrrolizidines such as 1-3 but to
important indolizidines, such as swainsonine9 and castanosper-
mine,10 as well.
Ring-closing metathesis (RCM) has established itself as a
valuable method for the elaboration of medium-sized rings,11
including heterocyclic variants.12 In tandem with transannular
cyclization (TC),13 RCM affords convenient access to a fused
bicyclic system from an acyclic precursor. The practicality of a
RCM-TC strategy is illustrated here by its application to an
efficient stereocontrolled synthesis of (+)-australine (2),14
a
tetrahydroxypyrrolizidine isolated from the rainforest tree Castano-
spermum australe.3
The known epoxy alcohol 415 was reacted with 4-butenyl
isocyanate, prepared from 4-pentenoic acid via Curtius rearrange-
ment of the corresponding azide and used in situ, to give the
urethane 5 (Scheme 1). Exposure of 5 to potassium tert-butoxide
afforded the oxazolidinone 6 which readily underwent acetonide
migration in the presence of Amberlyst resin to give the internal
ketal 7. Swern oxidation of primary alcohol 7 followed by a
Wittig reaction of the resultant aldehyde 8 with methylenetriph-
enylphosphorane furnished diene 9.
(1) Liddell, J. R. Nat. Prod. Rep. 1996, 13, 187.
(2) (a) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.; Derome,
A. E.; Hamor, G. W. J.; Scofield, A. M.; Watkin, D. J. Tetrahedron Lett.
1988, 29, 2487. (b) Nash, R. J.; Fellows, L. E.; Dring, J. V.; Fleet, G. W. J.;
Girdhar, A.; Ramsden, N. G.; Peach, J. M.; Hegarty, M. P.; Scofield, A. M.
Phytochemistry 1990, 29, 111. (c) Nash, R. J.; Fellows, L. E.; Plant, A. C.;
Fleet, G. W. J.; Derome, A. E.; Baird, P. D.; Hegarty, M. P.; Scofield, A. M.
Tetrahedron 1988, 44, 5959.
Ring-closing metathesis of 9 with Grubbs catalyst 10 produced
the azacyclooctene derivative 11 in virtually quantitative yield.
Conformational analysis of 11 using an AM1 algorithm led to
the prediction that epoxidation of this olefin should occur with
high stereoselectivity at the face opposite the transannular alkyl
substituent, and when 11 was treated with m-chloroperoxybenzoic
acid (m-CPBA) , a single epoxide was the result. An X-ray
crystallographic analysis revealed the configuration of this epoxide
to be as shown in 12. Although an azacyclooctane could be
liberated from oxazolidinone 12, intramolecular attack by nitrogen
at the epoxide to form a pyrrolizidine was impeded by the trans-
fused acetonide in this structure. Unfortunately, attempts to
(3) Molyneux, R. J.; Benson, M. J.; Wong, R. Y. J. Nat. Prod. 1988, 51,
1198.
(4) Nash, R. J.; Thomas, P. I.; Waigh, R. D.; Fleet, G. W. J.; Wormald,
M. R.; de Q. Lilley, P. M.; Watkin, D. J. Tetrahedron Lett. 1994, 35, 7849.
(5) Elbein, A. D.; Tropea, J. E.; Molyneux, R. J. US Pat. Appl. US 289,-
907; Chem. Abstr. 1990, 113, P91444p.
(6) Fellows, L. E.; Nash, R. J. PCT Int. Appl. WO GB Appl. 89/7951;
Chem. Abstr. 1991, 114, 143777c.
(7) For a recent review of this area, see: Dai, W.-M.; Nagao, Y.; Fujita,
E. Heterocycles 1990, 30, 1231.
(8) Casiraghi, G.; Zanardi, F.; Rassu, G.; Pinna, L. Org. Prep. Proc. Intl.
1996, 28, 641.
(9) For a recent summary, see: Hunt, J. A.; Roush, W. R. J. Org. Chem.
1997, 62, 1112-1124.
(14) (a) A synthesis by Pearson targeted at australine was reported as a
synthesis of (+)-7-epiaustraline (Pearson, W. H.; Hines, J. V. Tetrahedron
Lett. 1991, 32, 5513) due to erroneous NMR data in the literature. The errors
have now been corrected (Wormald, M. R.; Nash, R. J.; Hrnciar, P.; White,
J. D.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry, in press),
and it has been confirmed that Pearson’s synthesis is indeed that of (+)-
australine. (b) A different synthesis of 2 has been reported utilizing ring
contraction of castanospermine (Furneaux, R. H.; Gainsford, G. J.; Mason, J.
M.; Tyler, P. C. Tetrahedron 1994, 50, 2131).
(10) (a) Hohenschutz, L. D.; Bell, E. A.; Jewess, P. J.; Leworthy, D. P.;
Pryce, R. J.; Arnold, E.; Clardy, J. Phytochemistry 1981, 20, 811. (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.
(11) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28,
446. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans 1 1998, 371.
(12) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 7324.
(13) Harrowven, D. C.; Pattenden, G. In ComprehensiVe Organic Synthesis;
Trost, B. M., Ed.; Pergamon Press: Oxford, UK, 1991; Vol. 3, p 379.
(15) Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 1109.
S0002-7863(98)01140-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/29/1998