isolated crude. To facilitate isolation and purification, the amine
was protected with Boc anhydride to give bis-protected,
bifunctional azaspiro[3.3]heptane intermediate 10 in good yield
over the two steps. The benzyl group was then removed under
transfer hydrogenation conditions to give alcohol 11 in good
yield. Finally, oxidation of compound 11 with Dess-Martin
periodinane (DMP) gave the desired Boc-protected 6-oxo-2-
azaspiro[3.3]heptane 1 in good yield.
This sequential route provides access to compound 1 in eight
steps and 19% overall yield, as well as synthetically useful,
orthogonally protected 2-azaspiro[3.3]heptane 10 in six steps and
30% yield and related 2-azaspiro[3.3]heptane analogs 2 and 11.
Confirmation of the structure of 6-oxo-2-azaspiro[3.3]heptane
1 was obtained by X-ray crystallographic analysis of crystals
obtained from ethyl acetate and heptane (Figure 4).
zinc-copper couple in 1,2-dimethoxyethane on similar
cycloadditions to generate spirocyclobutanes,12 we were only
successful using zinc powder11,13 in dioxane. It is important
to note that a slow exotherm develops while the reaction is
slowly warmed from 0 to 25 °C.14 In order to maintain
efficient reaction conversion, it is important to maintain the
reaction temperature between room temperature and 30 °C.
If the reaction temperature exceeds 30 °C, significant loss
of the Boc group is observed.
Without further purification, the crude dichloroketone 13 was
dechlorinated in the presence of zinc and acetic acid10 to give the
desired 2-azaspiro[3.3]heptane 1 in modest yield after chromatog-
raphy. This concise route provided 51 g of compound 1 in three
steps and 21% overall yield. Notably, the cycloaddition chemistry
was successfully carried out on 100 g scale in 2.5 L of solvent
and could be further optimized to improve the yield.
In conclusion, two scaleable syntheses of the novel 6-oxo-
2-azaspiro[3.3]heptane ring system exemplified by compound
1 have been described. The first route, depicted in Scheme 1,
is very practical, beginning with inexpensive epibromohydrin,
and permits access to several 2-azaspiro[3.3]heptane intermedi-
ates in reasonable yield. The second route, depicted in Scheme
2, provides rapid and scaleable access to compound 1 in just
three steps from readily available but considerably more
expensive N-Boc-azetidin-3-one. Compound 1 and related
intermediates 2, 10, and 11 described herein are useful for further
selective derivation on the azetidine and cyclobutane rings provid-
ing access to novel 2,5- and 2,6-disubsituted compounds accessing
chemical space complementary to piperidine, homopiperidine, and
4-methylenepiperidine ring systems.
Acknowledgment. We would like to thank Jon Bordner
and Ivan Samardjiev of Pfizer Global Research & Develop-
ment for determination of the X-ray crystal structure of
compound 1. We would also like to thank Joseph Moon of
Pfizer Global Research & Development for molecular
modeling of 1 and piperidine surrogates and James Blinn of
Pfizer Global Research & Development for helpful discussion
around the crystal structure of 1.
Figure 4. X-ray plot of 6-oxo-azaspiro[3.3]heptane 1.
A more concise, but similarly yielding, three-step synthesis
of 2-azaspiro[3.3]heptane 1 utilizing a [2 + 2] cycloaddition
with dichloroketene is shown in Scheme 2.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds. This material
Scheme 2. Synthesis of 1 via [2 + 2] Cycloaddition
OL901325S
(11) (a) Hyatt, J. A.; Raynolds, P. W. Ketene cycloadditions. In Organic
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Wittig reaction of N-Boc-azetidin-3-one 12 proceeded in
modest yield to give olefin 6. Initial attempts to carry out
the subsequent [2 + 2] cycloaddition reaction were unsuc-
cessful. Generation of the dichloroketene from dichloroacetyl
chloride and triethylamine11 gave complicated reaction
mixtures with no evidence of the cycloaddition product 13.
Despite successful reports using trichloroacetyl chloride and
(13) (a) Bak, D. A.; Brady, W. T. J. Org. Chem. 1979, 44, 107. (b)
Erden, I.; Sorenson, E. M. Tetrahedron Lett. 1983, 24, 2731. (c) Gruhn,
A. G.; Reusch, W. Tetrahedron 1993, 49, 8159. (d) Baldwin, J. E.; Shukla,
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Tetrahedron Lett. 2000, 41, 9441
.
(14) We have noticed in similar [2 + 2] reactions using zinc-copper
couple that a violent exotherm may develop, especially when using THF
as the solvent.
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