Catalytic enantioselective conjugate addition of carbamates

Article abstract of DOI:10.1021/ja047004e

Catalytic, asymmetric conjugate addition of carbamates to enoyl systems has been realized for the first time, providing a two-step access to virtually enantiopure N-protected β-amino acids. Copyright

Full text of DOI:10.1021/ja047004e

Published on Web 07/09/2004
Catalytic Enantioselective Conjugate Addition of Carbamates
Claudio Palomo,* Mikel Oiarbide, Rajkumar Halder, Michael Kelso, Enrique Go´mez-Bengoa, and
Jesu´s M. Garc´ıa†
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, UniVersidad del Pa´ıs Vasco,
Apdo. 1072, 20080 San Sebastia´n, Spain
Received May 21, 2004; E-mail: qoppanic@sc.ehu.es
Table 1. Reaction of R′-Hydroxy Enone 1a [R1 ) PhCH2CH2] with
Benzylcarbamate 2 Promoted by Representative
Bis(oxazoline)-Metal Complexes
Interest in the synthesis of optically active â-amino acids1 arises
due to their presence in a variety of natural products,2 including
â-lactams,3 and because of the promise shown by â-peptides as
biostable peptidomimetics.4 While the Mannich-type reaction
between azomethines and enolates is a powerful method for
constructing this functionality,5 the conjugate addition of amines
and their synthetic equivalents to R,â-unsaturated carbonyls con-
stitutes another practical, direct, and flexible strategy toward this
goal.1,6 Recent advances in this direction include the conjugate
addition of amines,7 aldoximes,8 and masked forms of ammonia
such us hydrazoic acid,9 trimethylsilyl azide,10 and hydroxylamines11
promoted by catalytic quantities of certain chiral metal complexes7-11
and even simple peptides.9 Catalytic activation of R,â-unsaturated
carbonyls toward reaction with weaker nitrogen nucleophiles such
as carbamates has, however, proven to be more difficult, and indeed
it was only very recently that this reaction could be realized
catalytically through the use of certain Brønsted12 and Lewis acids.13
While these recent methods directly afforded useful N-protected
â-amino carbonyl adducts, asymmetric variants of this reaction,
which are of potentially great practical importance, have until now
remained elusive. Here we report the first highly enantioselective
conjugate addition reactions of carbamates to enones catalyzed by
chiral Lewis acids.
It has been postulated that a major obstacle to the development
of Lewis acid-catalyzed enantioselective conjugate additions of
carbamates is the possibility for alternative nonselective pathways
to be catalyzed by Brønsted acids (protons) resulting from hydroly-
sis of Lewis acids in reaction media.14 We surmised that one way
of minimizing these competing pathways might be to use chelating
R,â-unsaturated carbonyl templates capable of preferentially co-
ordinating to oxophilic metal centers rather than protons.15 We
recently hypothesized that R′-hydroxy enones coordinate to Lewis
acids (i.e., Evans bis-(oxazoline)-copper complexes) in a very
efficient manner, probably through a 1,4-metal binding pattern, and
successfully applied this principle to enantioselective Diels-Alder
reactions.16 Accordingly, it was expected that this sytem might be
equally effective in the context of asymmetric conjugate addition
reactions of carbamates.
product 11a
a
b
catalyst
R
MX
n
time, h
yield, %
ee, %
6
7
8
9
tBu
tBu
Ph
Mg(OTf)2
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
144
144
72
no reactionc
no reactionc
49d
86
83
96
98
tBu
72
10
40
90
a Isolated yield after column chromatography. bDetermined by HPLC.
d
cStarting material recovered. Not optimized.
Table 2. Enantioselective Conjugate Addition of Carbamates to
R′-Hydroxy Enones 1 Catalyzed by Complex 9a
time
(h)
yield
(%)b
ee
(%)c
1
compd 1
R
carbamate
product
a
Ph(CH2)2
2
3
4
5
2
3
2
2
71
18
118
142
62
18
66
68
22
67
96
100
96
11a
12a
13a
14a
11b
12b
11c
11d
12d
11e
11f
86
92
51d
74
66
76
83
71
87
53
57
85
65
96
88
99
96
92
96
96
96
98
98
94
91
94
b
CH3(CH2)5
c
d
CH3CH2
(CH3)2CHCH2
3
e
f
(CH3)2CH
c-C6H11
2e
2e
3
12f
11g
g
(CH3)3C
2f
a Reactions performed on a 2 mmol scale with a ratio of 1:carbamate:9
c
) 1:2:0.1. bIsolated yield after column chromatography. Determined by
HPLC using Chiralpak AD, AS, and Chiralcell OD columns (see Supporting
d
e
Information for details). Volatile compound. Performed with 20 mol %
f
catalyst. Reaction carried out at refluxing conditions.
and branched aliphatic chains) in the presence of 10 mol % catalyst
9 affords the corresponding N-protected â-amino carbonyls 11 in
regularly high yields and excellent enantioselectivities. Other alkyl
carbamates such as 3-5 were also reactive under these conditions,
and indeed when tert-butyl carbamate 3 was used, the Boc-protected
adducts were produced after considerably shorter reaction times
and the yields even increased slightly. Reactions were generally
carried out at ambient temperature in methylene chloride,17 although
for enone 1g, which bears the bulky tert-butyl group, refluxing
conditions were required. Interestingly, no detrimental effect on
enantioselectivity was observed in this instance. Unfortunately,
enones bearing â-aryl substituents proved to be unreactive even
under forcing conditions.18
Initial screening reactions carried out with R′-hydroxy enone 1a
and benzyl carbamate 2 in the presence of 10 mol % of several
chiral Lewis acids, Table 1, revealed that using catalyst 9 â-amino-
protected carbonyl adduct 11a was indeed formed in an impressive
86% isolated yield and, most notably, with 96% ee. Significant
changes were not observed with catalyst 10, but catalysts 6-8 were
found to be less efficient in terms of either reactivity or enan-
tioselectivity.
To assess the key role played by the achiral template in these
reactions, complementary assays using enoyl derivatives 15 and
16, two typical substrates used in enantioselective conjugate addition
reactions, were performed. While enone 1c reacted with benzyl-
carbamate 2 in the presence of catalyst 9 to provide 11c in 83%
Table 2 shows that reacting carbamate 2 (2 mol equiv) with a
variety of â-alkyl-substituted R′-hydroxy enones (bearing both linear
† Current address: Departamento de Qu´ımica Aplicada, Universidad Pu´blica
de Navarra, Campus de Arrosad´ıa, 31006 Pamplona, Spain.
9
9188
J. AM. CHEM. SOC. 2004, 126, 9188-9189
10.1021/ja047004e CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Chemical Elaboration of Adducts onto Optically Pure
N-Protected â-Amino Acids
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unreactive. The alkyledene malonate 16 was more reactive, and
under the above conditions the corresponding addition product could
be obtained in 80%, albeit in racemic form.
The excellent enantioselectivity observed in these reactions is
of particular interest in that it provides, through oxidative cleavage
of the acyloin moiety, optically pure N-protected â-alkyl-â-amino
acids. For example, treatment of Cbz adducts 11a and 11d with
sodium metaperiodate in a methanol-water mixture afforded 17a
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acids 18a and 18d in 99 and 92% yields. Of considerable practical
importance is the fact that these transformations yield acetone as
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the methyl ester derivatives 19d, 20a, and 20d was determined by
comparison of the optical rotations with published values and by
chemical correlation.19 The configuration for the remaining adducts
was assigned by analogy.
In conclusion, we have demonstrated for the first time that
asymmetric catalytic conjugate addition of carbamates with high
enantiocontrol is feasible. In particular, chiral bis(oxazoline)copper
complexes catalyze the addition reaction of carbamates and R′-
hydroxy enones to yield products with ees uniformly above 92%.20
Further work to expand this catalytic system to other asymmetric
reactions is under investigation.
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(17) In acetonitrile, which is the solvent of choice for Cu(II)-catalyzed conjugate
additions of carbamates (see ref 13b), the asymmetric reaction did not
proceed. THF was also found to be ineffective (<5% conversion after 2
days). Diethyl ether generally showed results comparable to those attained
in methylene chloride, although in certain instances the enantioselectivity
was essentially perfect (for example, product 11a 92% yield, g99% ee;
11b, 95% yield, g99% ee).
Acknowledgment. We thank The University of the Basque
Country and Ministerio de Ciencia y Tecnologia (MCYT, Spain)
for financial support. A grant to M. Kelso from MCYT is
acknowledged.
(18) For problems inherent to the conjugate addition of N-nucleophiles to â-aryl
enoyl systems, and a solution to them, see: ref 11c. Also see: ref 11e-
g.
(19) See Supporting Information for details.
Supporting Information Available: Complete experimental pro-
cedures, determination of stereoisomeric mixtures, 1H and 13C spectra,
and HPLC chromatograms (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) At the present stage, proposals for consistent catalytic cycle and transition-
state models seem premature. One reviewer has suggested an eight-
membered transition state involving copper coordination.
JA047004E
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J. AM. CHEM. SOC. VOL. 126, NO. 30, 2004 9189