First examples of a highly stereoselective passerini reaction: A new access to enantiopure mandelamides

Article abstract of DOI:10.1055/s-2003-40846

Achiral benzaldehydes and isocyanides could be transformed enantioselectively in a Passerini three-component reaction to chiral mandelamides by using a galacturonic acid derivative as chiral inducer.

Full text of DOI:10.1055/s-2003-40846

1536
LETTER
First Examples of a Highly Stereoselective Passerini Reaction: A New Access
to Enantiopure Mandelamides
A
N
ewAccess to
a
Enantiopu
y
re Mandelam
m
ides ond Frey,a Stuart G. Galbraith,a,1 Sandro Guelfi,a Clemens Lamberth,*a Martin Zellerb
a
Syngenta AG, Research Department, Optimisation Chemistry, Schwarzwaldallee 215, 4002 Basel, Switzerland
Fax +41(61)3238529; E-mail: clemens.lamberth@syngenta.com
b
Syngenta AG, Process Development, Breitenloh 5, 4333 Muenchwilen, Switzerland
Received 2 June 2003
amide, and the Ugi reaction of a carbonyl compound, an
isocyanide, an amine and a carboxylic acid to obtain an a-
acylaminocarboxamide, the prochiral aldehyde produces
the new chiral centre. There are several examples in the
literature for stereoselective multi-component reactions.
Using glycosylamines8 or a-ferrocenylalkylamines,9 high
degrees of diastereoselectivity could be achieved in Ugi
reactions. Also cases have been described, in which the
Passerini reaction was carried out with a chiral aldehyde10
or isocyanide.11 Unfortunately, the stereoselectivity here
is in most of the cases relatively low. During a research
program we required a reliable approach to enantiopure
mandelamides. We decided to perform a Passerini reac-
tion with a chiral acid, which would hopefully transfer
chiral information during the multi-component condensa-
tion, and would be cleaved off afterwards to yield the de-
sired a-hydroxyphenylacetamide. For this purpose, we
investigated several different phenylalanine, proline and
galacturonic acid derivatives as asymmetric inducing
agents from the chiral pool.
Abstract: Achiral benzaldehydes and isocyanides could be trans-
formed enantioselectively in a Passerini three-component reaction
to chiral mandelamides by using a galacturonic acid derivative as
chiral inducer.
Key words: a-hydroxy acid derivative, mandelamide, Passerini
reaction, multi-component reaction
a-Hydroxy acids and their derivatives play an indisput-
ably important role in chemistry and biology.2 Among this
class of chemical compounds, particularly amides of man-
delic acid are gaining in interest because of new opportu-
nities in medicine3 and agriculture.4 The fact that such
molecules contain a chiral centre clearly underlines the
need for an efficient enantioselective synthesis. So far,
the preparation of enantiopure mandelamides from
achiral precursors has been mainly achieved by catalytic
asymmetric hydrogenation of phenylglyoxylamides
(Scheme 1). Hereby, the stereoselective reduction of the
keto function is accomplished using rhodium(I) complex-
es with chiral diphosphine ligands, especially of the
AMPP-5 or BICHEP-type.6
It turned out, that 1,2,3,4-tetra-O-acetyl-a-D-galacturonic
acid13 (5d) gave a Passerini product 6d with high dia-
stereoselectivity, which after cleavage of the ester linkage
led to the mandelamide 7 with impressive enantiomeric
excess (Scheme 2, Table 1).14,15 The analysis of the
stereochemical outcome of the reaction was performed by
HPLC on a chiralpak AD column (20% isopropanol in
hexane as solvent). The correct assignment of the enanti-
omers was obtained by comparison with the coupling
products of commercially available D-(–) and L-(+) man-
delic acids with homoveratrylamine.
Scheme 1
This stereoselectivity is not surprising, because the initial
step of the postulated mechanism of the Passerini reaction
In this paper we present a new two-step approach to enan-
tiopure mandelamides from achiral building blocks by
application of a highly stereoselective multi-component
reaction.
Recently, multi-component reactions received much at-
tention as powerful tool for the generation of molecular
diversity in combinatorial libraries and for the easy as-
sembly of complex chemical structures.7 In both classical
multi-component reactions operating with isocyanides,
the Passerini reaction of a carbonyl compound, an iso-
cyanide and a carboxylic acid to give an a-acyloxycarbox-
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1536,1538,ftx,en;G12403ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

LETTER
A New Access to Enantiopure Mandelamides
1537
Table 1 Passerini Reactions of Benzaldehyde (3) and 2-(3,4-
Dimethoxyphenyl)ethyl Isocyanide12 (4) with Different Chiral Acids
is the formation of a hydrogen-bonded adduct from the
carbonyl and carboxylic acid components.7c,17 A non-isol-
able cyclic intermediate of all three components is then
built by a-addition of the electrophilic carbonyl carbon
atom and the nucleophilic oxygen atom of the carboxylic
acid to the isocyanide carbon atom. This a-adduct rear-
ranges in an intramolecular transacylation to the stable a-
acyloxycarboxamide.7c,17 That means, that the carboxylic
acid takes part in the reaction from the beginning on and
can therefore influence its stereochemical outcome.
Also, other benzaldehydes and isocyanides18 could be
transformed stereoselectively into the corresponding
mandelamides by Passerini reaction with 1,2,3,4-tetra-O-
acetyl-a-D-galacturonic acid (5d) and subsequent ester
hydrolysis. Looking at the results in Table 2, it seems that
the chiral induction does not work in every case, and that
phenethyl isocyanides are preferred as substrates.
Entry
a
5
Yield of 7 er of 7
(%)
(%) (conf.)
76
51:49
(S:R)
b
c
69
72
47:53
(S:R)
52:48
(S:R)
In summary, we have developed a new method for the
asymmetric synthesis of mandelamides. The enantio-
selective preparation of other a-hydroxycarboxamides
should also be possible using this approach. Maybe the
application of other acylated glycuronic acids will result
in even higher enantiomeric excesses.
d
e
63
75
93:7
(S:R)
53:47
(S:R)
Acknowledgement
The authors are very grateful to H. Baumgartner and A. Cicchetti
for their valuable contributions regarding er analysis.
Table 2 Passerini Reactions of 1,2,3,4-tetra-O-Acetyl-a-D-galacturonic Acid13 with Different Aldehydes and Isocyanides18
Entry
1
Aldehyde
Isocyanide
Mandelamide
er (%)
98:2
2
3
4
5
6
94:6
71:29
56:44
91:9
90:10
Synlett 2003, No. 10, 1536–1538 © Thieme Stuttgart · New York

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R. Frey et al.
LETTER
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Synlett 2003, No. 10, 1536–1538 © Thieme Stuttgart · New York