Asymmetric Construction of Quaternary Centers by Enantioselective Allylation: Application to the Synthesis of the Serotonin Antagonist LY426965

Article abstract of DOI:10.1021/ol025971t

(Matrix Presented) Catalytic enantioselective allylation with a chiral bisphosphoramide was applied to the synthesis of LY426965, a serotonin antagonist. The key step, addition of a 3,3-disubstituted allyltrichlorosilane to benzaldehyde, provided the addu

Full text of DOI:10.1021/ol025971t

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1951-1953
Asymmetric Construction of Quaternary
Centers by Enantioselective Allylation:
Application to the Synthesis of the
Serotonin Antagonist LY426965
Scott E. Denmark* and Jiping Fu
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received April 4, 2002
ABSTRACT
Catalytic enantioselective allylation with a chiral bisphosphoramide was applied to the synthesis of LY426965, a serotonin antagonist. The key
step, addition of a 3,3-disubstituted allyltrichlorosilane to benzaldehyde, provided the adduct containing a stereogenic quaternary center with
excellent diastereoselectivity and enantioselectivity.
The enantioselective addition of allylmetal reagents to
aldehydes is well established as a powerful and general
method for stereoselective carbon-carbon bond formation.1
This reaction has seen wide application in organic synthesis,
particularly in the total synthesis of polypropionate-derived
natural products.1b However, few applications of this method
in the construction of quaternary carbon centers have been
reported.2,3 The challenges of performing such a reaction are
the following: (1) synthesis of geometrically pure 3,3-
disubstituted allylmetal reagents; (2) correlation of the
geometrical purity of allylmetal reagents to the diastereomeric
composition of the product; (3) control of asymmetric
induction with internal chiral auxiliaries or external chiral
catalysts. Recently, we reported the first application of
catalytic, enantioselective allylation to generate quaternary
carbon centers.2a The addition of geometrically defined 3,3-
disubstituted allylic trichlorosilanes to aldehydes is ef-
fectively catalyzed by chiral phosphoramides and provides
allylation products containing quaternary centers with excel-
lent diastereoselectivities and enantioselectivities (Scheme
1). The ease of preparation of allylic trichlorosilanes and
catalyst makes this method very attractive for use in
Scheme 1
(1) For recent review on allylmetal additions, see: (a) Denmark, S. E.;
Almstead, N. G. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000; Chapter 10. (b) Chelmer, S. R.; Roush, W. R. In
Modern Carbonyl Chemistry; Otera, J.; Ed.; Wiley-VCH: Weinheim, 2000;
Chapter 11. (c) StereoselectiVe Synthesis, Methods of Organic Chemistry
(Houben-Weyl), Edition E21; Helmchen, G., Hoffmann, R., Mulzer, J.,
Schaumann, E., Eds.; Thieme; Stuttgart, 1996; Vol. 3, pp 1357-1602. (d)
Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207.
10.1021/ol025971t CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/07/2002

synthesis. We report herein an application of this method to
asymmetric synthesis of 5-hydroxytryptamine1A antagonists
24 (Scheme 2) which bear stereogenic quaternary centers.
sioned that the enantioselective allylation reaction would
provide an alternative and efficient approach to this type of
structure.
Scheme 3
Scheme 2
(S)-1,2-Diphenyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]-
2-methyl-1-butanone (2a) and (S)-1-cyclohexyl-4-[4-(2-
methoxyphenyl)-1-piperazinyl]-2-methyl-2-phenyl-1-buta-
none (2b) (LY426965) belong to a family of arylpiperazines
that are effective pharmaceutical agents for the treatment of
conditions related to or affected by the serotonin 1A
receptor.4 In particular, LY426965 (2b) is a full antagonist
of the serotonin 1A receptor and has no partial agonist
properties. Preclinical studies indicated that LY426965 is a
selective, full 5-HT1A antagonist that may have clinical use
as pharmacotherapy for smoking cessation and depression
related disorders. Structurally, these compounds contain
quaternary centers R to a carbonyl group, the synthesis of
which represents a long-standing challenge.3 A common
approach to this problem involves asymmetric alkylation of
corresponding enolate.5 However, this method has not found
success with acyclic substrates presumably because of the
difficulties in controlling the enolate geometry. We envi-
The retrosynthetic analysis of 2 shown in Scheme 2
identifies two key disconnections. The first is construction
of the C-N bond by combining keto aldehyde 3 with
commercially available arylpiperazine 4 by a reductive
amination. The second is the construction of the quaternary
center by addition of allyltrichlorosilane 5 to the appropriate
aldehyde. In this case, the allylation adduct, homoallyl
alcohol 6, contains all the necessary carbon units for synthesis
of 2 as well as functionalilty for further manipulations.
Because the hydroxyl group in 6 will be oxidized to provide
the carbonyl group in the final product 2, its configuration
in the allylation adduct, although highly controlled, is
irrelevant for this application. Therefore, the requisite S
configuration of the quaternary center can be obtained by
combination of (E)-trichlorosilane (E)-5 and catalyst (S,S)-1
or (Z)-trichlorosilane (Z)-5 with catalyst (R,R)-1. Preliminary
studies from these laboratories revealed that substituents on
the double bond significantly affect the reactivity and
selectivity of the allylic trichlorosilane. For example, it was
found a Z-methyl substituent has a beneficial effect on the
enantioselectivity, as evidenced by highly selective syn-
butenylation and prenylation process.2a On the other hand, a
Z-phenyl substituent is deleterious for the reaction. Under
standard allylation conditions, the addition of (Z)-cinnamyl-
trichlorosilane to benzaldehyde resulted in only a trace
amount of the desired adduct. Accordingly, we selected the
combination of (E)-trichlorosilane (E)-5 and catalyst (S,S)-1
for the synthesis of 6.
(2) For the most recent advance in chiral Lewis-base-catalyzed enanti-
oselective allylation, see: (a) Denmark, S. E.; Fu, J. J. Am. Chem. Soc.
2001, 123, 9488 and reference therein. While this manuscript was in
preparation, Hall reported the generation of quaternary centers using chiral
allylboronate reagents. (b) Kennedy, J. W. J.; Hall, D. G. J. Am. Chem.
Soc. 2002, 124, 898.
(3) For reviews on enantioselective construction of quaternary stereo-
centers, see: (a) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed. 2001,
40, 4591. (b) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998,
37, 388. (c) Fuji, K. Chem. ReV. 1993, 93, 2037. (d) Martin, S. F.
Tetrahedron 1980, 36, 419.
(4) (a) Rasmussen, K.; Calligaro, D. O.; Czachura, J. F.; Dreshfield-
Ahmad, L. J.; Evans, D. C.; Hemrick-Luecke, S. K.; Kallman, M. J.;
Kendrick, W. T.; Leander, J. D.; Nelson, D. L.; Overshiner, C. D.;
Wainscott, D. B.; Wolff, M. C.; Wong, D. T.; Branchek, T. A.; Zgombick,
J. M.; Xu, Y.-C. J. Pharmacol. Exp. Ther. 2000, 294, 688. (b) Kohlman,
T. D.; Xu, Y.-C.; Godfrey, A. G.; O′Toole, J. C.; Zhang, T. Y. Eur. Pat.
Appl. 1999, 47pp.
(5) For recent examples, see: (a) Hamada, T.; Chieffi, A.; Ahman, J.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261. (b) Saito, S.; Nakadai,
M.; Yamamoto, H. Synlett 2000, 1107.
The synthesis of 2a (Scheme 3) commences with carbo-
metalation of phenylacetylene 7 followed by trapping the
vinylalane with formaldehyde to provide the allylic alcohol
8 in geometrically pure form and modest yield.6 Alcohol 8
(6) Okudado, N.; Negishi, E.-I. Tetrahedron Lett. 1978, 27, 2357.
Org. Lett., Vol. 4, No. 11, 2002
1952

was converted by the Corey-Kim procedure to the corre-
sponding chloride 9, which was then treated with triethy-
lamine, trichlorosilane, and a catalytic amount of CuCl to
provide allyllic trichlorosilane (E)-5 also in geometrically
pure form and in 81% yield for two steps. The addition of
(E)-5 to benzaldehye in the presence of 10 mol % of (S,S)-1
provided the key intermediate, anti-6, with 99/1 dr and 97/3
er. It was found that addition of 0.2 equiv of n-Bu4N+I-
slightly improved the reaction yield without affecting the
selectivity.7 Hydroboration/oxidation of the vinyl group and
Swern oxidation of the diol 10 provided the keto aldehyde
3a in 80% yield from 6. Finally, the piperazine moiety 4
was appended by reductive amination of 3a with 4 and
sodium triacetoxyborohydride to provide 2a in 86% yield.
The synthesis of LY426965 (2b) required the use of
cyclohexanecarboxaldehyde as the electrophile in the ally-
lation reaction. Unfortunately, when this aldehyde was
employed under the standard allylation conditions, no desired
product was formed. Careful analysis of the reaction mixture
aldehyde were ongoing, we envisioned that 2b could also
be synthesized from diol 10 through selective saturation of
the benzylic alcohol. To this end, diol 10 was subjected to
a variety of hydrogenation conditions, which involved
variations in hydrogen pressure, catalyst, solvent, tempera-
ture, and acid additive. Ultimately, selective hydrogenation
was achieved in 74% yield by a two-step procedure (Scheme
5). The phenyl group at the 1-position was first reduced to
a mixture of cyclohexyl diol 11 and cyclohexenyl diol 12
under 50 psi of hydrogen using Rh/Al2O3 as the catalyst.
Although a prolonged reaction time led to the hydrogenation
of the other phenyl group, the cyclohexenyl diol 12 could
be selective reduced under 300 psi of hydrogen using Pt/
carbon as the catalyst to give 11 in 74% yield. Finally,
oxidation of the diol followed by reductive amination
provided LY426965 (2b).
Scheme 5
1
by H NMR spectroscopy revealed that an R-chloro silyl
ether was formed instead (Scheme 4).8 Previous mechanistic
Scheme 4
In conclusion, the application of a catalytic enantioselective
allylation catalyzed by a chiral phosphoramide has been
demonstrated in the asymmetric synthesis of serotonin
anagonists 2a and 2b (LY426965), which contain R-carbonyl
quaternary carbon centers. These syntheses demonstrated not
only the efficiency of this allylation method in the generation
of quaternary centers but also the versatile functionality
provided in such allylation adducts. Extension of the addition
of allyltrichlorosilanes to other electrophiles and applications
in organic synthesis are currently under investigation.
investigations have found that all reactions of chlorosilanes
studied to date involved ionization of chloride ions to create
cationic silicon species.9 In the reaction with aliphatic
aldehydes, the combination of the chloride ion and the
aldehyde results in the formation of an R-chloro silyl ether
that precludes addition of the allylating agent. While attempts
to solve the problem with aliphatic aldehyde by effecting
the equilibrium between the R-chloro silyl ether and the
Acknowledgment. We are grateful to the National
Science Foundation (NSF CHE 0105205) for the support of
this research. J.F. thanks the Boehringer Ingelheim Pharma-
ceutical Company for a graduate fellowship.
(7) Short, J. D.; Attenoux, S.; Berrisford, D. J. Tetrahedron Lett. 1997,
38, 2351.
(8) Formation of chlorohydrins has also been observed in other reactions
of chlorosilanes with aldehydes: Wynn, T.; Ghosh, S. K. Unpublished
results from these laboratories.
(9) For mechanistic studies, see: (a) Denmark, S. E.; Su, X.; Nishigaichi,
Y. J. Am. Chem. Soc. 1998, 120, 12990. (b) Denmark, S. E.; Fu, J. J. Am.
Chem. Soc. 2000, 122, 12021.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 2-11. This
material is available via the Internet at http://pubs.acs.org.
OL025971T
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