Enantioselective synthesis of β-amino esters and its application to the synthesis of the enantiomers of the antidepressant Venlafaxine

Article abstract of DOI:10.1039/b605047f

β-Amino esters are readily formed from the rhodium(ii) prolinate-catalyzed intermolecular C-H insertion between methyl aryldiazoacetates and a bis-silyl protected methylamine. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605047f

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Enantioselective synthesis of b-amino esters and its application to the
synthesis of the enantiomers of the antidepressant Venlafaxine{
Huw M. L. Davies* and Aiwu Ni
Received (in Bloomington, IN, USA) 6th April 2006, Accepted 21st May 2006
First published as an Advance Article on the web 14th June 2006
DOI: 10.1039/b605047f
b-Amino esters are readily formed from the rhodium(II)
prolinate-catalyzed intermolecular C–H insertion between
methyl aryldiazoacetates and a bis-silyl protected methylamine.
The development of practical C–H activation methods are of
considerable current interest because they can lead to new strategic
reactions for synthesis. One effective C–H activation process has
been the C–H insertion chemistry of metal carbenoids. In recent
years, donor/acceptor-substituted carbenoids have been shown to
be capable of highly regioselective and stereoselective C–H
activation.1 C–H bonds adjacent to nitrogen are especially
Fig. 1 Protected amines capable of C–H activation.
silyl-protected methylamine (4), a systematic study was conducted
by using phenyldiazoacetate (7a) as the carbenoid source
(Scheme 2). A major advantage of using the bis-silyl protecting
group is that it is stable under carbenoid reaction conditions and
appears to sterically protect the amino group from the electrophilic
carbenoid. Under mildly acidic conditions, however, the protecting
group is very labile and the b-amino ester is released and readily
isolated as its hydrochloride salt. When the bis-silylamine 4 was
favorable sites for functionalization, and from
a strategic
perspective this is a significant transformation because it is a
surrogate of the Mannich reaction (Scheme 1).2
Over the last few years, we have been exploring what types of
nitrogen functionality are compatible with intermolecular C–H
activation chemistry. A site that is too nucleophilic will tend to
react with the carbenoid or poison the catalyst,3 while unprotected
N–H bonds will be prone to N–H insertion.4 So far, we have
found that N-Boc protected cyclic amines 1,2a,c,d N-Boc-N-alkyl-
N-methylamines 22b and N,N-dimethylanilines 32e are effective
substrates for intermolecular C–H activation (Fig. 1).2
In this paper, we describe how N-methyl-1-aza-2,5-disilacyclo-
pentane (4)5 (Fig. 2) is a useful substrate for the C–H activation
chemistry. It can be effectively used for the direct enantioselective
synthesis of b-amino esters 5,6 and in a three-step synthesis of the
enantiomers of the antidepressant Venlafaxine (6).7
The dominant chiral catalyst for enantioselective reactions of
donor/acceptor-substituted carbenoids has been the dirhodium(II)
prolinate, Rh2(S-DOSP)4.8 In order to explore the feasibility of
the Rh2(S-DOSP)4-catalyzed reactions of aryldiazoacetates with
Fig. 2 N-methyl-1-aza-2,5-disilacyclopentane (4) as a substrate for C–H
activation.
Scheme 1
Department of Chemistry, University at Buffalo, State University of
New York, Buffalo, NY 14260-3000, USA.
E-mail: hdavies@buffalo.edu; Fax: 716-645-6547;
Tel: 716-645-6900 X2186
{ Electronic Supplementary Information (ESI) available: Experimental
details for the synthesis of all new compounds. See DOI: 10.1039/b605047f
Scheme 2
3110 | Chem. Commun., 2006, 3110–3112
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Table 1 Optimization studies for C–H functionalization of 4
Table 2 Enantioselective synthesis of b-amino esters 5a
Compound
Ar
Yield (%) (Conditions) ee (%)
a
53 (A)
97
Catalyst
Entry Equiv. 7a Temperature/uC loading (%)
Yield
(%)a
ee
(%)
b
c
d
e
53 (A)
94
(a)
(b)
(c)
2
2
0.5
25
240
240
1
1
2
73
68
53
84
93
97
a
Yield is based on the limiting reagent.
62 (B)
63 (B)
55 (B)
93
85
71
used as the limiting reagent, the reaction, conducted at room
temperature, gave the b-amino ester 5a in 73% yield and 84% ee
(Table 1, entry a). The enantioinduction could be improved to
93% ee, without much loss in yield by conducting the reaction at
240 uC (Table 1, entry b). Even higher enantioinduction (97% ee)
could be obtained by making 7a the limiting reagent, but the yield
was lower (53%) in this case (Table 1, entry c).
Having developed optimized conditions for the C–H activation
chemistry, the reaction was then extended to a series of
aryldiazoacetates (Table 2). The b-amino esters were isolated as
their hydrochloride salts, which eliminated the need for chromato-
graphic purification. In the case of aryldiazoacetates lacking
electron donating groups, the reactions were conducted at 240 uC
with an excess of protected N-methylamine 4 (conditions A). The
carbenoids from more electron rich aryldiazoacetates, such as 7c
and 7e, are less reactive and their reactions are best conducted at
0 uC with the slow addition of a two-fold excess of the
aryldiazoacetate (conditions B). The b-amino esters 5 are produced
in moderate to high enantioselectivity (65–97% ee). Particularly
interesting are the reactions with the bromide 7b, triflate 7d or
boronate 7e derivatives, which lead to the possibility of making
various analogs through Suzuki coupling.
f
30 (A)
54 (A)
65
95
g
After establishing the C–H functionalization of 4 as an effective
method for the synthesis of b-amino esters, the methodology was
extended to the enantioselective synthesis of the antidepressant
Venlafaxine (6) (Effexor2). This pharmaceutical agent has been
commercialized as a racemic mixture, even though both enantio-
mers have significant biological activity. (S)-6 is a relatively
selective serotonin reuptake inhibitor, while (R)-6 is more selective
for the norepinephrine transporter.7a The required C–H insertion
product, 5c, was generated in 62% yield and 93% ee. The published
Eschweiler–Clarke conditions7a for the N,N-dimethylation of
racemic 5c to 8 were not suitable because epimerization occurred
under the rather harsh conditions. HCHO/NaBH(OAc)3 was
found to be a suitable alternative, as it resulted in the effective
conversion of 5c to 8 in 82% yield at room temperature with no
loss of ee being found. Finally, conversion of 8 to (S)-Venlafaxine
was achieved by reaction with pentyl-1,5-dimagnesium bromide.9
The optimum conditions required slow parallel addition of
solutions of both the Grignard reagent and the ester to the
reaction vessel. After the work-up of the reaction, formation of the
h
75 (B)
80
a
Conditions A: 240 uC, 0.5 equiv. 7, 2% catalyst, 2 h addition.
Conditions B: 0 uC, 2 equiv. 7, 2% catalyst, 5 h addition.
HCl salt and enrichment by recrystallization, (S)-6 was obtained in
49% yield and 99% ee. (R)-6 was prepared in similar way from a
reaction sequence beginning with a Rh2(R-DOSP)4-catalyzed
reaction.
In summary, the C–H insertion reactions of the bis-silylmethyl-
amine 4 with various aryldiazoacetates afforded b-amino esters in
good yields and with high enantioselectivity. Using this method,
the enantiomers of the antidepressant Venlafaxine were synthe-
sized in three simple steps with high enantioselectivity.
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4 M. Doyle, M. McKervey and T. Ye, Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides,
John Wiley & Sons, Inc., New York, 1998, pp. 433–445.
5 S. Djuric, J. Venit and P. Magnus, Tetrahedron Lett., 1981, 22,
1787.
This work was supported by the National Institutes of Health
(DA15225 and DA06634) and the National Science Foundation
(CHE-030536).
6 For reviews on the synthesis of b-amio acids, see: (a) G. Cardillo and
C. Tomasini, Chem. Soc. Rev., 1996, 117; (b) G. Lelais and D. Seebach,
Biopolymers, 2004, 76, 206.
7 (a) J. P. Yardly, G. E. M. Husbands, G. Stack, J. Butch, J. Bicksler,
J. A. Moyer, E. A. Muth, T. Andree, H. Fletcher, III, M. N. G. James
and A. R. Sielecki, J. Med. Chem., 1990, 33, 2899; (b) D. Han and
E. C. Y. Wang, PharmacoEconomics, 2005, 23, 567; (c) N. J. Phelps and
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G. L. Stimmel and J. Y. Aiso, Clin. Ther., 2003, 2138.
8 (a) H. M. L. Davies and J. Nikolai, Org. Biomol. Chem., 2005, 3, 4176; (b)
H. M. L. Davies and O. Loe, Synthesis, 2004, 16, 2595.
9 C. A. Aguilar, J. B. Llado´, P. C. Garcia, M. C. Q. Miguel and
N. S. Madrid, US Pat., 6 506 941, 2001.
Notes and references
1 H. M. L. Davies and R. E. J. Beckwith, Chem. Rev., 2003, 103, 2861.
2 (a) H. M. L. Davies and T. Hansen, J. Am. Chem. Soc., 1999, 121, 6509;
(b) H. M. L. Davies and C. Venkataramani, Angew. Chem., Int. Ed.,
2002, 41, 2197; (c) H. M. L. Davies, C. Venkataramani, T. Hansen and
D. W. Hopper, J. Am. Chem. Soc., 2003, 125, 6462; (d) H. M. L. Davies,
D. W. Hopper, T. Hansen, X. Liu and S. R. Childers, Bioorg. Med.
Chem. Lett., 2004, 14, 1799; (e) H. M. L. Davies and Q. Jin, Org. Lett.,
2004, 6, 1769.
3 M. Doyle, M. McKervey and T. Ye, Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides,
John Wiley & Sons, Inc., New York, 1998, pp. 355–432.
3112 | Chem. Commun., 2006, 3110–3112
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