A ring-closing olefin metathesis approach to bridged azabicyclic structures

Article abstract of DOI:10.1016/S0040-4039(02)00100-4

A facile and general entry to functionalized bridged bicyclic nitrogen heterocycles has been developed that involves the ring-closing metathesis (RCM) of cis-2,6-dialkenyl-N-acyl piperidines that were readily prepared from glutarimide or 4-methoxypyridine

Full text of DOI:10.1016/S0040-4039(02)00100-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1779–1782
A ring-closing olefin metathesis approach to bridged azabicyclic
structures
Christopher E. Neipp and Stephen F. Martin*
Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA
Received 5 November 2001; accepted 17 December 2001
Abstract—A facile and general entry to functionalized bridged bicyclic nitrogen heterocycles has been developed that involves the
ring-closing metathesis (RCM) of cis-2,6-dialkenyl-N-acyl piperidines that were readily prepared from glutarimide or 4-
methoxypyridine. © 2002 Elsevier Science Ltd. All rights reserved.
Bridged bicyclic alkaloids containing a nitrogen atom
in the one-atom bridge of a [n.3.1] core found in the
general structures 1–4 constitute an important class of
natural products, many members of which exhibit
potent and useful biological activity.1 Consequently,
there has been considerable interest in the synthesis of
compounds that incorporate this structural motif,2 and
the development of new and general routes to construct
these systems efficiently would be of considerable value.
In the context of a program directed toward developing
strategies for alkaloid synthesis, it occurred to us that
ring-closing metathesis (RCM)3 might allow facile
access to structures such as 1–4 and hence provide a
useful alternative to existing methodologies. We now
report some of our initial results in this area.
the use of such constructions to elaborate bridged
bicyclic systems,8 and the synthesis of azabicyclo [n.3.1]
ring systems of types 1–4 have not been reported. In
this context, we envisioned that cis-2,6-disubstituted
piperidines would be ideal candidates for cyclization via
RCM to give these heterocycles (Scheme 1). This
hypothesis was based upon the well-known preference
for cis-2,6-disubstituted N-acyl piperidines 5 to exist in
the chair conformer 6 wherein the substituents in the 2
and 6 positions are axially oriented in order to avoid
A1,3 strain with the N-acyl group.9 The alkenyl groups
are thus properly disposed to undergo facile RCM to
give the desired bridged azabicyclic compounds 7.
Prior to examining the feasibility of the key RCM
reaction, it was first necessary to establish a general
entry to the requisite cis-2,6-disubstituted piperidines,
and two approaches were developed that involved
sequential stereoselective additions to N-acyl iminium
ions or Michael acceptors.10 In the first, glutarimide
(10) was employed as a starting material (Scheme 2).
Although reduction of 10 with NaBH4 in ethanol in the
presence of acid gave the ethoxy lactam 11, several
attempts to react this intermediate with organometallic
reagents to introduce the first alkenyl side chain were
either unsuccessful or proceeded in poor yield. This was
somewhat surprising, as such reactions for pyrrolidine
derivatives of 11 have been reported.11 On the other
hand, we found that the sulfone 12 reacted smoothly
with either vinylmagnesium bromide or 3-butenylmag-
nesium bromide to provide the lactams 13a and 13c in
74% and 68% yield, respectively.12 The allyl lactam 13b
was prepared according to a literature procedure.13 The
amide nitrogen atoms of 13a–c were protected by
acylation with benzylchloroformate (Cbz-Cl) to provide
Early work in our laboratories validated the efficacy of
RCM reactions for the formation of fused nitrogen
heterocycles,4 and we subsequently exploited RCM
cyclizations as key steps in the syntheses of the complex
anticancer alkaloids manzamine A and FR900482.5,6
Other groups have since reported applications of RCM
to the synthesis of a variety of fused bicyclic nitrogen
heterocycles.7 Despite the prolific use of RCM for the
preparation of monocyclic and fused bicyclic carbocy-
cles and heterocycles, there are but a few examples of
* Corresponding author. E-mail: sfmartin@mail.utexas.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00100-4

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C. E. Neipp, S. F. Martin / Tetrahedron Letters 43 (2002) 1779–1782
Scheme 1.
the imides 14a–c (74–92%). The DIBAl-H reduction of
the lactam carbonyl groups of 14a–c followed by
stereoselective reaction of the crude N-acyl hemiami-
nals with allyltrimethylsilane in the presence of
BF3·OEt2 furnished inseparable mixtures of the requi-
site cis-2,6-dialkenylpiperidines 15a–c together with
small amounts of their trans isomers (cis/trans=17–
24:1 based upon GC analysis). To our delight, 15a–c
underwent facile and efficient RCM at room tempera-
ture in the presence of the Grubbs catalyst 8 to give the
bicyclic nitrogen heterocycles 16a–c.14,15
were encountered in applying the tactics depicted in
Scheme 2 to the stereoselective preparation of the req-
uisite cis-2,6-divinyl piperidines. However, we found
that chemistry that had been developed by Comins was
nicely applicable to the problem at hand.16 Thus, reac-
tion of 4-methoxypyridine (17) with vinyl magnesium
bromide in the presence of Cbz-Cl followed by hydroly-
sis of the intermediate methoxydiene gave 18 in excel-
lent yield (Scheme 3). When 18 was allowed to react
with vinyl cuprates,17 the cis-2,6-divinyl piperidines 19a
and 19b were formed together with their respective
trans isomers from which they were inseparable. The
cis/trans ratios were determined to be 15:1 and 9:1,
respectively, as determined by integration of the pro-
tons at C(2) and C(6) in the 1H NMR spectrum.
Although 19a underwent RCM with the catalyst 8 at
room temperature, cyclization of 19b was slow and
inefficient using 8, and 20b was isolated in only 43%
yield together with recovered starting material even
after prolonged heating at 40°C and further addition of
portions of catalyst 8. However, when the more reactive
RCM catalyst 9 was employed, cyclization of 19b pro-
ceeded readily at room temperature to give 20b in 89%
yield.14
We were also interested in applying RCM to the syn-
thesis of the tropane core structure 1, but difficulties
Scheme 2.
Scheme 3.

C. E. Neipp, S. F. Martin / Tetrahedron Letters 43 (2002) 1779–1782
1781
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Scheme 4.
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We were intrigued by the possibility that this RCM
approach to the tropane skeleton might be readily
applied to compounds of biological interest. Toward
this goal, we found that the copper enolate derived
from conjugate addition of a vinyl cuprate to 18 could
be trapped with methyl cyanoformate to give 21, which
1
was determined by H NMR to exist predominantly as
the enol tautomer (Scheme 4). Compound 21 under-
went facile RCM to provide 22,14 the conversion of
which into cocaine (23) and other related tropane com-
pounds may be envisioned.
In summary, we have developed a concise and general
entry to functionalized azabicyclo[n.3.1]alkenes via the
RCM of 2,6-cis-dialkenyl piperidines, which were read-
ily prepared from glutarimide or 4-methoxypyridine.
Various applications of this methodology to the synthe-
sis of biologically active alkaloids are the subject of
current investigation, the results of which will be
reported in due course.
Acknowledgements
We thank the National Institutes of Health (GM
25439), the Robert A. Welch Foundation, Pfizer, Inc.,
and Merck Research Laboratories for their generous
support of this research. We are also grateful to Bristol-
Myers Squibb for a predoctoral fellowship to C.E.N.
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