Diasteroselective synthesis of new spiropiperidine scaffolds from the CN(R,S) building block

Article abstract of DOI:10.1021/jo050258d

A methodology allowing the construction of spiropiperidine scaffolds similar to those found in naturally occurring alkaloids has been developed. This approach begins with the well-established CN(R,S) strategy, the spiro-center being built by way of an int

Full text of DOI:10.1021/jo050258d

Diasteroselective Synthesis of New Spiropiperidine Scaffolds from
the CN(R,S) Building Block
Emmanuel Roulland, Fabrice Cecchin, and Henri-Philippe Husson*
Laboratoire de Chimie The´rapeutique, UMR 8638 associe´e au CNRS et a` l’Universite´ Rene´ Descartes
(Paris 5), Faculte´ des Sciences Pharmaceutiques et Biologiques, 4, Avenue de l’Observatoire,
75270 Paris Cedex 06, France
henri-philippe.husson@univ-paris5.fr
Received February 8, 2005
A methodology allowing the construction of spiropiperidine scaffolds similar to those found in
naturally occurring alkaloids has been developed. This approach begins with the well-established
CN(R,S) strategy, the spiro-center being built by way of an intramolecular attack of a nitrile function
by an organolithium species obtained by a halogen/lithium exchange reaction mediated by either
t-BuLi or lithium naphthalenide.
Introduction
as a leaving group. In this event, our approach encom-
passed the ring closure of the functions borne at the
quaternary stereogenic center (Figure 1).
Thus, preparation of 1,7-diazaspiro[5,5]undecane de-
rivatives 34 was based upon the facile generation of
iminium salts by hydride reduction or organometallic
attack at the CN group and subsequent easy intra-
molecular nucleophilic alkylation.
The unique structure of the spiropiperidine framework
serves as an important constituent of simple or complex
alkaloids (e.g., histrionicotoxins, nitraria, or pinnaic acid
alkaloids) as well as non-natural biologically active
compounds. As a consequence, many efforts have been
directed toward the development of synthetic strategies
for alkaloids in 2- and 3-spiropiperidine series. However,
of the many methods available there have been very few
solutions for polyfunctionalized systems1 and more frus-
trating for enantiomerically pure products.2 Some years
ago, we initiated a project based upon the CN(R,S)
strategy3 to extend the pharmacological scope of this
series. Indeed, efficient stereocontrolled formation of a
quaternary aminonitrile center by alkylation of (-)-
5-cyano-3-phenylhexahydro-5H-[1,3]oxazolo[3,2-a]-
pyridine 1 allowed different routes to the target mol-
ecules. In specific cases depending on experimental
conditions, instead of behaving as an iminium equivalent,
the nitrile group of the aminonitrile function can be
engaged in the reaction as an electrophile rather than
On the other hand, addition of a methyl Grignard to 4
led to a ketone precursor of spiro derivative 55 through
a subsequent aldol reaction.
Finally, we reported in a preliminary communication
the spiroannulation of a piperidine ring via a facile
alkyllithium intramolecular nucleophilic attack onto the
nitrile group in derivative 2a.6 In this work, we wish to
report the extension of this unique approach to the
synthesis of chiral nonracemic substituted [5,6]- and [6,6]-
spiropiperidines of type A or B, respectively (Figure 1).
With respect to the noteworthy stereoselectivity4 of the
formation of the first chiral center at the C2 position of
the piperidine ring, it appeared interesting to be able to
perform further stereocontrolled functionalization at the
C6 position.
(1) Dake, G. R.; Fenster, M. D. B.; Hurley, P. B.; Patrick, B. O. J.
Org. Chem. 2004, 69, 5668-5675 and references herein cited.
(2) (a) Bahajaj, A. A.; Moore, M. H.; Vernon, J. M. Tetrahedron 2004,
60, 1235-1246. (b) Carson, M. W.; Kim, G.; Hentemann, M. F.;
Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4450-
4452. (c) Carson, M. W.; Kim, G.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 4453-4456 (d) Francois, D.; Lallemand, M.-C.; Selkti,
M.; Tomas, A.; Kunesch, N.; Husson, H.-P. Angew. Chem., Int. Ed.
1998, 37, 104-105.
(4) Zhu, J.; Quirion, J.-C.; Husson, H.-P. J. Org. Chem. 1993, 58,
6451-6456.
(5) Zhu, J.; Royer, J.; Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett.
1991, 32, 2485-2488.
(6) Ribeiro, C. M. R.; de Melo, S. J.; Bonin, M.; Quirion, J.-C.;
Husson, H.-P. Tetrahedron Lett. 1994, 35, 7227-7230.
(3) Husson, H.-P.; Royer, J. Chem. Soc. Rev. 1999, 28, 383-394.
10.1021/jo050258d CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/05/2005
4474
J. Org. Chem. 2005, 70, 4474-4477

Diasteroselective Synthesis of Spiropiperidine Scaffolds
FIGURE 1. Spiropiperidine frameworks from the CN(R,S) building block 1.
SCHEME 1. Diastereoselective Alkylation of the CN(R,S) Building Block 1
pentane at low temperature.7 A possible mechanism for
the formation of the tricyclic system 10a,b is presented
in Scheme 2. The putative intermediate ketimine 8a,b
rearranged into enamines 10a or 10b along with opening
of the oxazolidine ring. We postulate 8a,b as plausible
intermediates since similar nonspiranic but stable com-
pounds are produced in high yield by nucleophilic attack
of organolithium (nBuLi or PhLi) on aminonitrile 1.8
It is noteworthy that we obtained the cyclobutane
derivative 9a6 using lithium di-tert-butylbiphenilide
(LiDBB) instead of lithium naphthalenide. Compound 9a
resulted from a reductive cleavage of the tertiary nitrile
function of 2a followed by an intramolecular halogen
substitution. This alternative spirocyclization example
demonstrated that the reduction of the aminonitrile
function was fast enough to compete with a halogen/
lithium exchange reaction on the alkyl chloride chain.
Those observations must be compared with the recent
results published by Rychnovsky et al.9 for 2-cyano-
tetrahydropyrans. In their case, they observed that
chloronitrile derivatives (closely related to compound 2b)
exhibited similar selectivity when reacting with LiDBB;
the nitrile function was the quicker to react, and no
chloride/lithium exchange was seen. The selectivity
SCHEME 2. Halogen/Lithium Exchange and
Spiroannulation Reaction
Results and Discussion
The chloro and bromo compounds 2a-c were used as
starting materials for the synthesis. Cyclization precur-
sors 2a and 2b were obtained as single diastereomers
by alkylation of 1 with 1-chloro-3-iodopropane and 1-chlo-
ro-4-iodobutane, respectively, while compound 2c was
obtained by alkylation of 1 with 3-bromopropanol yielding
alcohol 6 which was subsequently brominated (Scheme
1).
The annulation reaction took place when the halogen
was exchanged by a lithium atom leading to intermedi-
ates 7a or 7b (Scheme 2). The first type of metal/halogen
exchange was attempted with chlorinated compounds 2a4
or 2b. In these cases, the exchange was performed using
3 equiv of preformed lithium naphthalenide in THF at
-78 °C under argon (Scheme 2). Lithiation of compound
2c was cleanly performed by using t-BuLi in ether/
(7) Ashby, E. C.; Pham, T. N.; Park, B. Tetrahedron Lett. 1985, 26,
4691-4694.
(8) Froelich, O.; Desos, P.; Bonin, M.; Quirion, J.-C.; Husson, H.-P.;
Zhu, J. J. Org. Chem. 1996, 61, 6700-6705.
(9) (a) Rychnovsky, S. D.; Takaoka, L. R. Angew. Chem., Int. Ed.
2003, 42, 818-820. (b) Wolckenhauer, S. A.; Rychnovsky S. D.
Tetrahedron 2005, 61, 3371-3381.
J. Org. Chem, Vol. 70, No. 11, 2005 4475

Roulland et al.
SCHEME 3. Enamine Function Reactivity Studies
SCHEME 4. Reduction of Hemiketal System of
Compound 13
expected hemiketal via an oxonium intermediate that
was trapped by one molecule of water (Scheme 4).
The reduction of 13 with AlH3 cleanly led to a mixture
of diastereomeric and unseparable diols 14 followed by
selective alcohol protection providing secondary alcohol
15 as a mixture of diastereomers.
As far as piperidine scaffolds are concerned it was
necessary to obtain a multifunctional system allowing
substitution at position C6, the C2 positions being
already occupied by the functionalized spiro system. For
this purpose, the enamine functions of 10a and 10b were
protonated as iminium salts which were trapped as stable
aminonitriles by reaction with CN- giving 11a and 11b
(Scheme 3). Only one diastereomer was detectable wherein
the entering nitrile group was in axial disposition anti
with respect to the developing nitrogen electron lone pair.
This reaction occurred under stereoelectronic control that
positioned the CN group axial by stabilization due to an
anomeric effect (n f σ*C-CN). The 13C NMR shift of the
C6 carbon atom is in accordance with the shift typically
observed (δC 45-48 ppm) in other piperidine aminonitrile
compounds with an axial nitrile function.11 The 1H NMR
spectrum of the H6 proton is also typical for an axial
position of the nitrile function since it shows only a small
J3 coupling constant with its neighbors H5a and H5b
(J3 ) 1.6, 4.6 Hz for 11a, 3.2 Hz for 11b). A classical J3
coupling constant for an axial H6 proton would have been
typically around 12 Hz.12
The nitrous deamination reaction was also performed
on 11a leading to hemiketal 16. Finally, the reactivity
of the R-aminonitrile moiety was explored. A vinyl chain
could be regio and stereoselectively introduced using
vinylmagnesium bromide to give 17 having the same
configuration as the nitrile group of 16 (Scheme 5).
This occurred after prior formation of an iminium
species through the complexation of the nitrile function
with one silver cation from AgBF4 and subsequent
precipitation of insoluble AgCN.3 Similarly, an acetate
chain could be introduced on 16 with total selectivity via
a Mukaiyama-like13 reaction with silyl-enol ether of ethyl
acetate 18.14 The stereochemistry at C6 for both com-
pounds 17 and 19 was unambiguously established by 1H
NMR NOESY experiments which showed a strong NOE
confirming the axial position of the acetate and the vinyl
side chains (Scheme 5).
observed could be attributed to the difference of reduction
potential between lithium di-tert-butylbiphenilide and
lithium naphthalenide (-2.14 and -1.98 V, respec-
tively).10
The enamines 10a,b appeared to be too unstable to
allow purification by column chromatography which led
to polymerization products and low yields. Thus, crude
enamines were directly used in the next step (Scheme
3). However, they were fully characterized as stable
piperidines 12a and 12b obtained by reduction using
palladium-catalyzed hydrogenation or using NaBH3CN
in MeOH. Two possible isomers 12a-cis and 12a-trans
can be envisioned in which the ring junction between the
cyclopentane and the morpholine rings could be either
cis or trans, but only one was observed. The same
reasoning could be done for 12b. The skeleton of these
polycyclic compounds being quite rigid, the calculation
of the conformation of lower energy is easy. Thus, the
calculated difference of energy between isomers 12a-cis
and 12a-trans (MM2 Chem3D) is around 16 kcal/mol,
showing unambiguously that the cis-fused ring junction
(12a-cis) was the most likely to be formed (Figure 2).
FIGURE 2. MM2 calculation of the minimum conformational
energy for 12a-trans and 12a-cis.
(11) Bonin, M.; Chiaroni, A.; Riche, C.; Beloeil, J.-C.; Grierson, D.
S.; Husson, H.-P. J. Org. Chem. 1987, 52, 382-385. In this paper, the
13C δ shift observed for compounds bearing an axial nitrile was 48.3
and 50.4 ppm for an equatorial nitrile. We observed δ ) 47.6 ppm for
compound 12a and 46.0 ppm for 12b.
(12) Studies in Organic Chemistry 43, Piperidine; Rubiralta, M.,
Giralt, E., Diez, A., Eds.; Elsevier: New York, 1991; p 297.
(13) Berrien, J.-F.; Billion, M.-A.; Husson, H.-P.; Royer, J.J. Org.
Chem. 1995, 60, 2922-2924.
(14) Rathke M. W.; Sullivan, D. F. Synth. Commun. 1973, 3, 67-
72.
An attempt to perform a classical HCl hydrolysis of
the hemiaminal function of 12b failed to give the
expected hemiketal 13. Surprisingly, the reaction led to
decomposition products. However, a nonclassical but
facile nitrous deamination reaction of 12b afforded the
(10) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924-1930.
4476 J. Org. Chem., Vol. 70, No. 11, 2005

Diasteroselective Synthesis of Spiropiperidine Scaffolds
SCHEME 5. Reactivity Study of 16 Aminonitrile
Function
SCHEME 6. One-Pot, Two-Step Annulation and
Functionalization Process on 2c
As a result, a poor stereoselectivity is observed for the
nucleophile addition step.
We were also interested in trapping the intermediate
that is formed during the spirocyclization step by reaction
with a nucleophile. Thus, allyl derivatives 20 and 21
(1:4) were synthesized according to a one-pot procedure
composed of two various steps (Scheme 6). The first step
is the spirocyclization achieved by lithiation of 2c using
t-BuLi. The second step is addition of allylmagnesium
bromide. The main diastereomer 21 exhibited an axial
stereochemistry at position C6 attested by a strong NOE.
Due to Schlenk equilibrium, MgBr2 was obviously intro-
duced in the reaction medium with the Grignard reagent.
Since it behaves as a Lewis acid, the plausible iminium
intermediate 22 (Scheme 6) might be formed. This
iminium ion has very probably a different geometry
compared with the one obtained from aminonitrile 16.
Conclusion
In summary, starting from the CN(R,S) building block
1, a concise method for the preparation of enantiopure
[5,6]- and [6,6]spiropiperidines has been developed. The
usefulness of R-aminonitriles, generally considered as
protected iminium functions, is thus significantly in-
creased. The use of this strategy for the development of
biologically active compounds having a spiropiperidine
framework is presently being studied.
Supporting Information Available: Details of experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO050258D
J. Org. Chem, Vol. 70, No. 11, 2005 4477