Ugi four component condensations using aldehydes with an asymmetric centre at C-2

Article abstract of DOI:10.1016/S0040-4039(00)01389-7

Epimerisation of an aldehyde possessing a hydrocarbon substituent α to the carbonyl occurs in the Ugi four component condensation whereas, with either a benzyl or TBDMS ether at C-2 the stereochemical integrity is maintained. A deuterium isotope effect is observed and by carrying out the reaction in methanol-OD, deuterium can be introduced efficiently into C-3 of the condensation products. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01389-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8001–8005
Ugi four component condensations using aldehydes with an
asymmetric centre at C-2
Clare L. Kelly,a Kenneth W. M. Lawrie,b Paul Morgana and Christine L. Willisa,*
aSchool of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
bSynthetic Isotope Chemistry, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue,
Harlow CM19 5AW, UK
Received 27 June 2000; revised 9 August 2000; accepted 16 August 2000
Abstract
Epimerisation of an aldehyde possessing a hydrocarbon substituent a to the carbonyl occurs in the Ugi
four component condensation whereas, with either a benzyl or TBDMS ether at C-2 the stereochemical
integrity is maintained. A deuterium isotope effect is observed and by carrying out the reaction in
methanol–OD, deuterium can be introduced efficiently into C-3 of the condensation products. © 2000
Elsevier Science Ltd. All rights reserved.
The Ugi four component condensation reaction (4CC)1 has been used to good effect in the
synthesis of a range of organic compounds including natural products.2 Armstrong and Keating
have increased the utility of the reaction by the design of a ‘convertible’ isonitrile in which the
resultant cyclohexenyl amide condensation product may be readily converted to a range of other
functional groups.3 In addition, Linderman and coworkers have developed an alternative easily
hydrolysable isonitrile which can be applied to the asymmetric Ugi reaction.4 Recently the
application of the Ugi reaction to the synthesis of combinatorial libraries has generated much
interest since the use of a multicomponent reaction is a good way of generating the diversity
required for such libraries.5
The vast majority of examples of 4CC reactions involve the use of an aldehyde without an
asymmetric centre at C-2. However, early studies by Ugi and coworkers6 indicate that (S)-2-
methylbutanal may be used to prepare amino acids with an asymmetric centre at C-3 such as
L
-
and -isoleucine. In addition, isomers of the antibiotic furanomycin have been prepared via a
D
4CC reaction of trans-aldehyde 1 which gives a 1:1 mixture of 2 and 3 in 55% overall yield
(Scheme 1).7 We now report the results of our investigations on four component condensations
using aldehydes with a stereogenic centre at C-2 which have led to an efficient method for the
incorporation of deuterium labels at C-3 of the adducts.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01389-7

8002
Scheme 1.
It has been shown that the stereochemical outcome of the Ugi reaction may be affected by
temperature, solvent, and concentration. Consequently, in our studies, we maintained a standard
set of conditions using (R)-a-methylbenzylamine, benzoic acid and tert-butyl isocyanide in
methanol at room temperature and simply varied the aldehyde component. In a control
experiment,8 isobutylaldehyde gave two products which were readily separated by flash chro-
matography (Scheme 2). The less polar product (obtained in 28% yield) was assigned as the
1
R,S-diastereomer 4 from its H NMR spectrum9 and the more polar product, isolated in 71%
yield, was the R,R-diastereomer 5. To confirm the stereochemistry at C-2, the minor product 4
was converted to -valine by hydrogenolysis of the a-methylbenzyl group and acid catalysed
L
hydrolysis of the amides, giving
the literature value.10
L
-valine with [h]D+29.4 (c 2, 6M HCl) in good agreement with
Scheme 2.
Having reproduced conditions for the four component condensation, next the fate of an
asymmetric centre at C-2 of an aldehyde was investigated. (R)-2-Methyl-3-phenylpropanal 6 was
prepared using Evans’ valine derived oxazolidinone11 and, when used in the Ugi reaction, four
products were formed in 86% overall yield as shown in Scheme 3. Purification by flash
chromatography gave a mixture of the (2S,3R)- and (2S,3S)-diastereomers 7 and 8 followed by
the (2R,3R)- and (2R,3S)-adducts 9 and 10 which co-eluted. These pairs of diastereomers were
separated by normal phase HPLC giving a ratio of ca. 2:8:5:6 of diastereomers (least to more
polar).
In contrast to the results of Ugi and coworkers,6 the formation of the four products 7–10
indicates that the stereochemical integrity at C-2 of the aldehyde (C-3 in the adducts) has been
lost during the four component condensation. One obvious difference between the two reactions
was the aldehyde: we used (R)-2-methyl-3-phenylpropanal 6 whereas in the earlier studies
(R)-2-methylbutanal 11 was used as a precursor to
L
- and -isoleucine. We repeated the reaction
D
with (R)-2-methylbutanal and again four products were obtained in a ratio 2:8:5:6 (least polar
to most polar) and in 72% overall yield (Scheme 3). Purification by flash chromatography gave
a crystalline mixture of the (2S,3R)- and (2S,3S)-diastereomers 12 and 13 followed by the
(2R,3R)- and (2R,3S)-adducts 14 and 15 also as a crystalline solid. These products could be
further purified by normal phase HPLC.

8003
Scheme 3.
Our results demonstrate that an aldehyde with an asymmetric centre a to the carbonyl group
and hydrocarbon side-chains e.g. 6 and 11 can undergo epimerisation in the four component
condensation. These observations are not too surprising as the acidic reaction conditions might
be expected to induce isomerisation via either an enol or an intermediate enamine. Indeed this
proposed tautomerism can be turned to our advantage to incorporate deuterium into a range of
compounds for use as mass spectral internal standards. Thus (R)-2-methyl-3-phenylpropanal 6
was reacted with (R)-a-methylbenzylamine-ND2, benzoic acid-OD and tert-butyl isocyanide in
methanol–OD giving the four adducts 7–10 with >80% incorporation of deuterium at C-3. This
exchange process is quite general and when the reaction was repeated using hydrocinnam-
aldehyde 16 or phenylacetaldehyde 19 the deuterated adducts (17/18 and 20/21) were isolated
with a high incorporation of deuterium (Scheme 4).
Scheme 4.
Interestingly when the reaction was repeated using a 2-deuterated aldehyde component such
as [2-D]-(R)-2-methyl-3-phenylpropanal (with 90% incorporation of deuterium) in the presence
of protio reagents and solvent, the adducts retained 50% incorporation of deuterium. The
mechanism of the four component condensation is complex but this result indicates that
deuterium at C-2 of the aldehyde induces a deuterium isotope effect such that enol or enamine
formation is less favourable. Using [2,2-D2]-hydrocinnamaldehyde in the 4CC reaction with
protio reagents and solvent, adducts 17 and 18 were isolated, retaining >80% incorporation of
deuterium at C-3, whereas in the case of [2,2-D2]-phenyacetaldehyde in which the a-protons

8004
(deuterons) would be more acidic, a higher degree of exchange was apparent and the products
20 and 21 retained only 30% incorporation of deuterium.
Substituents other than a hydrocarbon a to the carbonyl would also effect the acidity of the
a-proton and may reduce the propensity for epimerisation at this site, and to investigate this
(S)-2-benzyloxypropanal 22 was prepared from methyl (S)-lactate. Reaction of 22 with (R)-a-
methylbenzylamine, benzoic acid and tert-butyl isocycanide in methanol gave a 1:2 mixture of
just two products 23 and 24, which were separated by flash chromatography (Scheme 5).
Similarly, on repeating the reaction with (S)-tertbutyldimethylsilyloxypropanal 25 only two
products 26 and 27 were obtained confirming that no isomerisation had occurred. These results,
combined with the example shown in Scheme 1, reveal that the stereochemical integrity of an
a-oxygenated aldehyde is maintained during the Ugi reaction and therefore has potential for the
synthesis of a range of b-hydroxy-a-amino acids such as threonine and allothreonine as well as
3-oxygenated unnatural amino acids.
Scheme 5.
Acknowledgements
We are grateful to the EPSRC and SmithKline Beecham for funding (to C.L.K and P.M.).
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