Catalytic asymmetric C-H activation by methyl thiophen-3-yldiazoacetate applied to the synthesis of (+)-cetiedil

Article abstract of DOI:10.1016/S0040-4039(02)00956-5

Dirhodium tetraprolinate catalyzed reaction of methyl thiophen-3-yldiazoacetate results in intermolecular allylic C-H activation by means of rhodium carbenoid induced C-H insertion. The reaction with 1,4-cyclohexadiene was applied to the asymmetric synthesis of (+)-cetiedil.

Full text of DOI:10.1016/S0040-4039(02)00956-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4981–4983
Catalytic asymmetric C–H activation by methyl
thiophen-3-yldiazoacetate applied to the synthesis of (+)-cetiedil
Huw M. L. Davies,* Abbas M. Walji and Robert J. Townsend
Department of Chemistry, University at Buffalo, State University of New York, Buffalo, NY 14260-3000, USA
Received 15 March 2002; revised 9 May 2002; accepted 14 May 2002
Abstract—Dirhodium tetraprolinate catalyzed reaction of methyl thiophen-3-yldiazoacetate results in intermolecular allylic C–H
activation by means of rhodium carbenoid induced C–H insertion. The reaction with 1,4-cyclohexadiene was applied to the
asymmetric synthesis of (+)-cetiedil. © 2002 Elsevier Science Ltd. All rights reserved.
Intermolecular C–H activation by means of a rhodium
carbenoid induced C–H insertion offers attractive new
synthetic strategies for the preparation of complex
molecules.1 The original studies of C–H insertions with
carbenoids derived from diazoacetates, diazoketones
and diazoacetoacetates demonstrated that such reac-
tions were feasible but were only generally useful when
the reactions were carried out intramolecularly.2 The
main difficulties associated with these carbenoids were
their tendency to undergo dimerization and their lim-
ited chemoselectivity in intermolecular C–H insertions.2
Recently, it has been demonstrated that rhodium car-
benoids derived from diazo compounds functionalized
with both donor and acceptor groups (1) are capable of
undergoing highly efficient intermolecular C–H inser-
tions.3 When these reactions are catalyzed by Rh2(S-
DOSP)4 (2) high asymmetric induction can be
achieved.4–8 The potential of this chemistry as a new
strategic approach for synthesis has been illustrated by
examples where the C–H activation is a surrogate of
some of the classic reactions of organic synthesis, such
as the Claisen rearrangement,5 the Michael reaction,6
the Mannich reaction7 and the aldol reaction.8
A critical requirement for the successful outcome of
these asymmetric intermolecular C–H insertions is the
presence of a donor substituent on the carbenoid.1
Consequently, the vast majority of the published
examples1,4–8 have been conducted with substituted
phenyldiazoacetates. In order for this chemistry to
become broadly useful, it will be necessary to expand
the range of functionality that can act as the donor
group. As an extension to the use of vinyl (1a) and
substituted phenyl (1b) as donor groups, we recently
reported the use of heteroaryldiazoacetates in asymmet-
ric cyclopropanation.9 An illustrative example is the
Rh2(S-DOSP)4-catalyzed cyclopropanation of methyl
thiophen-3-yldiazoacetate 3 to form cyclopropane 4, in
87% yield, 95% de and 89% ee (Eq. (1)).9 In this paper
we describe our exploratory studies to determine if 3
will undergo C–H activation chemistry and to illustrate
the utility of this chemistry by a short asymmetric
synthesis of (+)-cetiedil 5.10 Cetiedil is an effective K+
channel blocker,11 possesses several therapeutic activi-
(1)
Keywords: C–H activation; rhodium carbene; C–H insertion; diazo
compounds.
* Corresponding author. Tel.: 716-645-6800, ext. 2186; fax: 716-645-
6547; e-mail: hdavies@acsu.buffalo.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00956-5

4982
H. M. L. Da6ies et al. / Tetrahedron Letters 43 (2002) 4981–4983
ties,12 and is a potent blocker of acetylcholine and
choline fluxes.13 The reported synthesis of the pure
enantiomers of 5 required resolution by fractional crys-
tallization of a chiral precursor to 5.10
dicted to be R in analogy to the product derived from
the reaction with methyl phenyldiazoacetate.5a The
cyclopropanation product 8 was formed in 73% ee.
One of the most notable features of the C–H activation
chemistry of donor–acceptor substituted rhodium car-
benoids is that they are often highly regioselective.1,4–8
In order to explore whether the carbenoid from 3 has
similar characteristics, the Rh2(S-DOSP)4 catalyzed
reaction of 3 with 1-methyl-1-cyclohexene was exam-
ined (Eq. (4)). A high level of regioselectivity was
observed as C–H insertion occurred only at the least
crowded allylic methylene site. The C–H insertion
product 10 was formed in 40% yield, 50% de and 94%
ee.
The major challenge in extending the reaction of 3 from
cyclopropanation chemistry to C–H activation chem-
istry is to ensure effective trapping of the carbenoid.
The initial studies with cyclohexane were not promis-
ing. Rh2(S-DOSP)4-catalyzed reaction of 3 in cyclohex-
ane as solvent gave no C–H insertion product, even
under reflux conditions, which usually enhances the
C–H activation chemistry.4 Only carbene dimerization
was observed. In order to improve the chances of an
intermolecular C–H insertion, the reaction of 3 with
N-Boc-pyrrolidine was examined because N-Boc-pyrro-
lidine has been shown to be 2000 times more reactive
towards C–H insertion than cyclohexane.4 In this case
the C–H insertion product 6 was effectively formed in
64% yield with 91% de and 67% ee (Eq. (2)). This result
compares favorably with the parallel reaction reported
for methyl phenyldiazoacetate.7a The absolute stereo-
chemistry of 6 has not been determined but it is pre-
dicted to be (2S,2¦S) in analogy to the reaction with
methyl phenyldiazoacetate.7a
(4)
A more efficient C–H insertion was achieved on reac-
tion of 3 with 1,4-cyclohexadiene. As is typical of
Rh2(S-DOSP)4-catalyzed reactions,14 the highest enan-
tioselectivity was obtained when the reaction was car-
ried out in hydrocarbon solvent. The C–H insertion
product 11 was formed in 65% ee when
dichloromethane was used as solvent and in 88% ee
when hexane was used as solvent.
(2)
C–H Insertion was also possible at other activated
positions. The reaction of 3 with 1,3-cyclohexadiene
resulted in the formation of C–H insertion product 7
and cyclopropanation product 8 in a combined yield of
52% (Eq. (3)). The C–H insertion product 7 was formed
as an inseparable mixture of diastereomers, and so in
order to determine the extent of asymmetric induction,
7 was reduced to the cyclohexane 9 which was formed
in 70% ee. The absolute stereochemistry of 7 is pre-
(5)
A practical utility of this heteroaryldiazoacetate inter-
molecular C–H insertion was envisioned in the asym-
metric synthesis of (+)-cetiedil 5. Even though the direct
C–H activation of cyclohexane with thiophen-3-yldia-
zoacetates is not feasible, the reaction of thiophen-3-
yldiazoacetates with cyclohexadienes followed by
reduction would be a rapid asymmetric entry into the
cetiedil core. In order to limit the number of synthetic
steps after the C–H activation step, the reaction was
conducted on the 2-chloroethyl ester derivative (Scheme
1). Diazoacetate 14 was synthesized by standard ester-
ification of the commercially available acid 12 to 13
(92% yield), followed by diazo transfer using p-acetami-
dobenzenesulfonyl azide (p-ABSA)15 and DBU (88%
yield). C–H insertion of 1,4-cyclohexadiene with dia-
zoacetate 14 catalyzed by Rh2(R-DOSP)4 formed the
(3)

H. M. L. Da6ies et al. / Tetrahedron Letters 43 (2002) 4981–4983
4983
Foundation (CHE 0092490) and the National Institutes
of Health (GM57425) is gratefully acknowledged.
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precursor (+)-15 (55% yield and 88% ee). Catalytic
hydrogenation (97% yield) followed by introduction of
the hexamethyleneimine functionality furnished (+)-
cetiedil 5 in 94% yield with 88% ee.16
10. Roxburgh, C. J.; Ganellin, C. R.; Shiner, M. A. R.;
Benton, D. C. H.; Dunn, P. M.; Ayalew, Y.; Jenkinson,
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Innothe´ra. US Patent. 3 377 592, 1983.
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In summary, the intermolecular C–H activation chem-
istry of methyl thiophen-3-yldiazoacetate 3 is not as
general as that reported for substituted phenyldiazoac-
etates. However, C–H activation by means of C–H
insertion can be carried out at allylic positions and a to
nitrogen. The synthetic potential of this chemistry was
illustrated by a short asymmetric synthesis of (+)-
cetiedil.
13. Morot Gaudrry-Talarmain, Y.; Diebler, M. F.; Robba,
M.; Lancelot, J. C.; Lesbats, B.; Israe¨l, M. Eur. J. Phar-
macol. 1989, 166, 327.
Supplementary material. Detailed experimental condi-
tions for the synthesis of compounds 3–16.
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Acknowledgements
16. In analogy to 9, the absolute stereochemistry of (+)-5 is
predicted to be S.
Financial support of this work by the National Science