ment, which would also define the olefin geometry. This
strategy had previously been employed in a similar system
to give the aldehyde 1411 (Scheme 2) that should easily be
Scheme 1
Scheme 2
unsaturated-2-azaallylstannanes and their use in the genera-
tion and cycloaddition of 2-azapentadienyl anions and
azomethine ylides.8,9 Cycloaddition of the anions gives
products that result from the all-trans-2-azapentadienyl anion
(the “W” conformation; vide infra). We predicted that the
resultant pyrrolidines would be synthetically useful because
they contain an alkenyl group in the 2-position that provides
a handle for further functionalization.
According to the retrosynthetic analysis shown in Scheme
1, it was recognized that 6b should be attainable using fairly
simple precursors. As illustrated, the ketone 6b should be
accessible by reduction of the diene in 7 and oxidation of
the corresponding alcohol that results after deprotection. The
tricyclic diene 7 would be assembled by an intramolecular
Heck reaction involving the vinyl iodide 8. This bicyclic
amine 8 should result from an intramolecular cycloaddition
of the R,â-unsaturated-2-azaallylstannane 9. The vinylsilane
functionality was incorporated into the molecule because it
is a much better anionophile than a simple alkene.10 Further,
desilylation should be possible at the stage of the oxidation
of the secondary alcohol to an R-silyl ketone.
transformed into the key intermediate 9 after some functional
group manipulation. To this end, the acetal 11 was formed
by protection of 2-bromoacrolein 10 using the conditions
reported by Smith (Scheme 2).12 Multigram quantities of 11
were easily prepared and, following distillation, found to have
an excellent shelf life when stored cold. To form the alcohol
12 lithium-halogen exchange was carried out using n-
butyllithium and the resulting organolithium was quenched
with excess acetaldehyde. Depezay’s Johnson ortho ester
Claisen conditions were used to give the ethyl ester 13.11
Although Depezay reported isolating exclusively the Z
isomer, in our hands the E/Z ratio was batch dependent.
Fortunately, upon deprotection of the acetal, the aldehyde
isomerized to the E-R,â-unsaturated aldehyde 14. Reduction
with sodium borohydride in methanol then gave the allylic
alcohol 15 in five steps and 73% yield from 11. After
protection of the alcohol as the tert-butyldimethylsilyl ether
and adjusting the ester oxidation state, the aldehyde 16 was
formed in good yield.
The key acyclic imine 9 should be accessible from the
corresponding aldehyde and amine by condensation. Exami-
nation of the requisite aldehyde suggested the possibility of
installing the carbonyl functionality by a Claisen rearrang-
(5) (a) Stork, G.; Dolfini, J. E. J. Am. Chem. Soc. 1963, 85, 2872. (b)
Stork, G. Pure Appl. Chem. 1966, 9, 131.
(6) (a) Ban, Y.; Sato, Y.; Inoue, I.; Nagai, M.; Oishi, T.; Terashim, M.;
Yonemits, O.; Kanaoka, Y. Tetrahedron Lett. 1965, 2261. (b) Ban, Y.; Ikuo,
I.; Inoue, I.; Akagi, M.; Oishi, T. Tetrahedron Lett. 1969, 25, 2067. (c)
Kuehne, M. E.; Bayha, C. Tetrahedron Lett. 1966, 1311. (d) Stevens, R.
V.; Fitzpatrick, J. M.; Kaplan, M.; Zimmerman, R. L. Chem. Commun.
1971, 857. (e) Martin, S. F.; Desai, S. R.; Phillips, G. W.; Miller, A. C. J.
Am. Chem. Soc. 1980, 102, 3294. (f) Wu, P. L.; Chu, M.; Fowler, F. W. J.
Org. Chem. 1988, 53, 963. (g) Meyers, A. I.; Berney, D. J. Org. Chem.
1989, 54, 4673. (h) Iyengar, R.; Schildknegt, K.; Aube, J. Org. Lett. 2000,
2, 1625. (i) Iyengar, R.; Schildknegt, K.; Morton, M.; Aube, J. J. Org. Chem.
2005, 70, 10645. (j) Banwell, M. G.; Smith, J. A. J. Chem. Soc., Perkin
Trans. 1 2002, 2613. (k) Fukuda, Y.; Shindo, M.; Shishido, K. Org. Lett.
2003, 5, 749.
With a good source of 16 in hand, we set out to advance
to a suitably protected version of 9 and test the key
cycloaddition (Scheme 3). To this end, 1-lithio-1-trimethyl-
silylethylene was added to the aldehyde 16, and the resultant
alcohol was protected as the BOM ether to give 17 in 86%
yield. The BOM protecting group was chosen because it
should be cleaved at the same time the diene of 7
(7) For a review, see: Pearson, W. H.; Stoy, P. Synlett 2003, 903.
(8) (a) Pearson, W. H.; Jacobs, V. A. Tetrahedron Lett. 1994, 35, 7001.
(b) Pearson, W. H.; Barta, N. S.; Kampf, J. W. Tetrahedron Lett. 1997, 38,
3369.
(9) Mi, Y. Ph.D. Thesis, University of Michigan, Ann Arbor, MI, 1999.
(10) Pearson, W. H.; Szura, D. P.; Postich, M. J. J. Am. Chem. Soc.
1992, 114, 1329.
(11) Depezay, J. C.; LeMerrer, Y. Tetrahedron Lett. 1975, 16, 3469.
(12) Smith, A. B., III; Levenberg, P. A.; Jerris, P. J.; Scarborough, R.
M.; Wovkulich, P. M. J. Am. Chem. Soc. 1981, 103, 1501-1513.
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