as that observed in previous studies, thus confirming the fact
that alkylidene carbenes are excellent synthetic tools for
establishing nitrogen-bearing quaternary stereocenters.
Table 2. 3-Pyrroline Synthesis from N-Protected Precursors
We were very pleased by these results, and as a corollary
we performed a preliminary study on the use of N-protected
cyclization precursors. We reasoned that if protecting groups
were tolerated during the cyclization process, then the
isolated yields of the resulting 3-pyrrolines may be improved
as these compounds would no longer suffer the handling and
purification problems of materials possessing basic nitrogens.
Suitable cyclization precursors were readily synthesized
from the corresponding primary amines by protection (Boc
or Ts) and subsequent alkylation of the nitrogen with 1,3-
dibromo-2-methylpropene.13 The resulting 1-bromo-1-alkene
precursors (Table 2) were then subjected to the alkylidene
carbene forming conditions (KHMDS, Et2O, rt); the results
of the cyclization reactions are summarized in Table 2.14
In contrast to the results obtained for the free amine
versions (Table 1), we observed quite a range of yields for
the formation of the 3-pyrroline products. In general, the
highest yields were obtained for insertions into methylene
C-H bonds, and as for the free amine cases, insertions into
aliphatic and benzylic positions appear to occur with equal
ease. With the exception of 22 f 23, the formation of
quaternary centers by insertion into tertiary C-H bonds
appears to be much less facile than was observed in the free
amine examples (cf. Table 1). At first glance, these results
seem to be at odds with the accepted order (tertiary >
secondary > primary)15 for the ease of CH-insertion into
different bond types, but we believe that steric hindrance in
the transition state (due to bulky protecting group) accounts
for these apparently anomalous results.
a Reaction conditions: KHMDS (2.0 equiv), Et2O, rt. b Isolated yields.
c 3-Pyrroline has >95% ee as judged by chiral HPLC.
(11) For a selection of alternative approaches to 3-pyrrolines, see: (a)
Donohoe, T. J.; Harji, R. R.; Cousins, R. P. C. Tetrahedron Lett. 2000, 41,
1331. (b) Donohoe, T. J.; Ace, K. W.; Guyo, P. M.; Helliwell, M.; McKenna,
J. Tetrahedron Lett. 2000, 41, 989. (c) Xu, Z.; Lu, X. J. Org. Chem. 1998,
63, 5031. (d) Donohoe, T. J.; Guyo, P. M.; Beddoes, R. L.; Helliwell, M.
J. Chem. Soc., Perkin Trans. 1 1998, 667. (e) Koskinen, A. M. P.;
Schwerdtfeger, J.; Edmonds, M. Tetrahedron Lett. 1997, 38, 5399. (f)
Balasubramanian, T.; Hassner, A. Tetrahedron Lett. 1996, 37, 5755. (g)
Boruah, A.; Baruah, B.; Prajapati, D.; Sandhu, J. S.; Ghosh, A. C.
Tetrahedron Lett. 1996, 37, 4203. (h) Huwe, C. M.; Blechert, S. Tetrahedron
Lett. 1995, 36, 1621. (i) Burley, I.; Hewson, A. T. Synthesis 1995, 1151.
(j) Baldwin, J. E.; Field, R. A.; Lawrence, C. C.; Lee, V.; Robinson, J. K.;
Schofield, C. J. Tetrahedron Lett. 1994, 35, 4649. (k) Ketcha, D. M.;
Carpenter, K. P.; Zhou, Q. J. Org. Chem. 1991, 56, 1318. (l) Anderson, W.
K.; Milowsky, A. S. J. Org. Chem. 1985, 50, 5423. We thank one referee
for supplying useful additional references in this area.
In summary, we have shown that the alkylidene carbene
1,5-CH insertion reaction can be used for the synthesis of a
range of 3-pyrrolines and that precursors derived from
primary amines can be used in this process. It has not escaped
our notice that the 3-pyrroline 17 represents the core carbon
skeleton of lactacystin, and we are currently examining the
application of this methodology to the total synthesis of this
natural product.
Acknowledgment. The Authors thank the EPSRC (GR/
M74696) and GlaxoSmithKline (CASE for M.P.G.) for
generous financial support.
(12) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165.
(13) For full details see Supporting Information.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new products. This
material is available free of charge via the Internet at
(14) We did not observe the formation of alkyne-containing side products
(cf. 5) in these cyclization reactions (as judged by IR, TLC, and H NMR
analysis of the crude reaction mixtures). At present we are unable to account
adequately for this observation, and further studies are underway to explain
these results.
(15) Gilbert, J. C.; Giamalva, D. H.; Weerasooriya, U. J. Org. Chem.
1983, 48, 5251.
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