Scheme 3 Synthesis of the GPR40 receptor agonists.
Indeed such an approach was used in the total synthesis of
cyclopropyl alkanoic derivatives 30 and 31 developed as
human GPR40 receptor agonists (active at low nanomolar
concentrations).10 Cyclopropyl ester 27 was produced from
4-(tert-butoxycarbonylamino)benzaldehyde 26 in 84% yield
using our novel one-pot process (Scheme 3). Cleavage of the
Boc group, followed by reductive amination and saponifica-
tion under standard reaction conditions, provided the GPR40
receptor agonist 31 in 51% overall yield. It is also possible to
prepare the unprotected cyclopropyl ester 27 from the
(4-nitrophenyl)cyclopropyl ester 11 (Table 1, entry 13), by
reduction of the nitro group under pressure of hydrogen in
presence of PtO2 (49% for two steps). Finally cyclopropyl
amide 30 was also synthesized, as carboxamide derivatives
were found to be equally active as GPR40 agonists. The same
synthetic strategy was used and cyclopropyl amide 30 was
produced in 58% overall yield from aldehyde 26 in 3 steps.
In conclusion, we have developed the first multicatalytic
approach for the synthesis of trans-cyclopropyl compounds
from aldehydes. The copper-catalyzed olefination reaction was
directly followed by the palladium-catalyzed cyclopropana-
tion reaction, which was clearly not affected by the olefination
residual by-products and catalyst still present in the reaction
mixture. The one-pot process produced a variety of cyclopropyl
derivatives in good to excellent yields, while the isolation of the
alkene intermediate was not required. The one-pot methodology
allows the formation of three new C–C bonds and was applied
to the synthesis of GPR40 small molecule agonists.
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This work was supported by NSERC (Canada), the Canada
Foundation for Innovation, Boehringer Ingelheim (Canada)
Ltee, Merck Frosst, and the Universite de Montreal.
´ ´ ´
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ꢁc
This journal is The Royal Society of Chemistry 2008
4976 | Chem. Commun., 2008, 4974–4976