U-4C-3CR versus U-5C-4CR and stereochemical outcomes using suitable bicyclic β-amino acid derivatives as bifunctional components in the Ugi reaction

Article abstract of DOI:10.1016/j.tetlet.2003.10.193

Intramolecular Ugi reactions with bicyclic β-amino acids have been performed and the effects of the configuration and N-alkylation have been studied. We have proven that preferential ring contraction or nucleophilic attack by the solvent depend not only o

Full text of DOI:10.1016/j.tetlet.2003.10.193

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 587–590
U-4C-3CR versus U-5C-4CR and stereochemical outcomes using
suitable bicyclic b-amino acid derivatives as bifunctional
components in the Ugi reaction
*
*
Andrea Basso, Luca Banfi, Renata Riva and Giuseppe Guanti
Dipartimento di Chimica e Chimica Industriale, Universit ꢀa degli Studi di Genova, Via Dodecaneso 31, 16146 Genova, Italy
Received 9 September 2003; revised 24 October 2003; accepted 30 October 2003
Abstract—Intramolecular Ugi reactions with bicyclic b-amino acids have been performed and the effects of the configuration and
N-alkylation have been studied. We have proven that preferential ring contraction or nucleophilic attack by the solvent depend not
only on the presence of N-alkylation but also on the relative disposition of the carboxyl group and the amine. Excellent results in
terms of stereoselectivity have been obtained in the case of N-alkyl-3-exo-amino-7-oxabicyclo[2.2.1]-2-endo-carboxylic acids.
Ó 2003 Elsevier Ltd. All rights reserved.
The Ugi four-component reaction (U-4CR) is a valuable
tool in organic chemistry for generating a-amino acid
derivatives in a very straightforward manner by con-
densing an aldehyde, an amine, a carboxylic acid and an
It has been reported that a-amino acids can react in an
intramolecular version of the Ugi reaction (Ugi-5-cen-
3a
tre-4-component reaction, U-5C-4CR) via a similar
mechanism; in this case the six-membered ring inter-
1
3
isocyanide in one pot. Intramolecular versions of the
mediate (Fig. 1, R ¼ H, n ¼ 1) cannot evolve via a ring
Ugi reaction have also been reported, where two of the
four functional groups are present on the same mole-
cule. The possibility of generating b-lactam rings using
b-amino acids as bifunctional compounds is known as
contraction but reacts with a nucleophile, such as
methanol used as the solvent, to give, a,a -imino dicar-
boxylic acid derivatives with very high conversions and
0
3a–f
good diastereoselectivities.
This reaction has been
2a–f
the Ugi-4-centre-3-component reaction (U-4C-3CR).
reported with various a-amino acids, mainly with pri-
3b;f
This reaction evolves through a seven-membered ring
2c
mary amino groups, although proline is also reported
to react in the same way.
3
intermediate (Fig. 1, R ¼ H, n ¼ 2), to give the
b-lactam derivative via a ring-contraction step.
We recently became interested in the synthesis of
pharmacologically relevant molecules via the Ugi multi-
component reaction and therefore we have investigated
both the classical condensation and its intramolecular
versions. In this communication we report the results
that we have obtained performing the intramolecular
Ugi reaction with racemic b-amino acid derivatives of
general formula 1 (Fig. 2), where the amino group can
be either primary or secondary and the carboxyl group
either exo or endo. The alkylated amine, reacting with
an aldehyde, would form an iminium zwitter ionic
species analogous to that formed when proline is
employed in the same reaction, while the primary
amine would react like any other amino acid. The
choice for compounds of formula 1 was made in order
to have a rigid scaffold, able in principle to exert more
influence on the stereoselectivity than would flexible
counterparts.
Figure 1. Cyclic intermediate for Ugi intramolecular reactions with
a- and b-amino acids.
Keywords: Multicomponent reactions; Intramolecular Ugi reaction;
b-Amino acids; Chiral auxiliary; Stereoselective Ugi reaction; Ugi with
secondary amines.
*
Corresponding authors. Tel.: +39-010-3536117; fax: +39-010-3536-
18 (A.B.), tel./fax: +39-010-3536105 (G.G.); e-mail addresses:
andreab@chimica.unige.it; guanti@chimica.unige.it
1
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.193

588
A. Basso et al. / Tetrahedron Letters 45 (2004) 587–590
group; in fact compound 2, when treated with sodium
hydride in the absence of methyl iodide, epimerised only
after prolonged exposure, since in this case the more
acidic proton is the NH, and epimerisation can only
occur via the dianionic species.
Figure 2. General formula for b-amino acid derivatives employed in
the Ugi intramolecular reactions.
Before looking for alternative procedures to obtain the
cis compound, we decided to investigate the reactivity of
amino acid 1b, obtained from 5 in two steps by analogy
with 1a, in the Ugi reaction. We found that this
N-alkylated-amino acid reacted smoothly with isovaleric
aldehyde and tert-butyl isocyanide and after 24 h at
room temperature the main product was found to be the
methyl ester 6a. In this case the postulated cyclic inter-
mediate (Fig. 1, R ¼ alkyl, n ¼ 2), being unable to
undergo intramolecular ring contraction to the corre-
sponding b-lactam, preferably reacted intermolecularly
with methanol, in analogy with a-amino acids, to
generate the corresponding methyl ester (Scheme 2).
Compound 1a was obtained from methyl 3-exo-(benzyl
oxycarbonyl)amino-7-oxabicyclo[2.2.1]-2-exo-carboxyl-
ate 2 in two steps and was reacted with different com-
binations of aldehydes and isocyanides to give, as
expected, the corresponding bicyclic b-lactams 3a–f
(
Scheme 1). However, an examination of the diastereo-
meric ratio, determined by NMR analysis, revealed that
the deÕs were disappointingly not higher than 42%
4
(
Table 1). We recently came across a paper by Ful o€ p
5
and co-workers where they reported similar results with
analogous bicyclic amino acids.
However, the most interesting outcome of this reaction
was that, after an accurate NMR analysis, only one
diastereoisomer was detected, while compound 1a, with
the same aldehyde and isocyanide, gave two diastereo-
isomers with dr 2:1.
We then attempted the synthesis of the N-methylated cis
amino acid, but when we treated compound 2 with
sodium hydride and methyl iodide, we isolated, as the
sole product, the endo N-methyl epimer 5 (Scheme 2).
This epimerisation is most likely taking place on the
methylated product 4, by deprotonation of the more
acidic carbon, that is the one alpha to the carboxyl
Stimulated by this very promising result and in order to
test the generality of the method, we decided to inves-
tigate the reaction with a wide combination of aldehydes
and isocyanides. We were delighted to find that all the
reactions were clean and reached a satisfying conversion
within 72 h at room temperature and in all cases, even
when extremely unbulky aldehydes and isocyanides were
6
employed, only one diastereoisomer could be detected,
within the limits of the NMR sensitivity (Table 2),
4
meaning that this N-methylated trans amino acid could
completely control the stereochemistry of the newly
formed stereocentre.
Scheme 1. Synthesis of amino acid 1a and subsequent Ugi reactions.
Table 1. Results obtained in the Ugi reaction with scaffold 1a
With these extremely interesting results in hand, we
decided to investigate if the observed stereoselectivity
was due mainly to the trans configuration or to the
presence of an N-alkyl group, or to the combination of
the two effects. To this end we synthesised the trans
amino acid 1c and the corresponding N-propylated cis
derivative 1d: the first was obtained by prolonged
exposure of 2 with sodium hydride, followed by ester
hydrolysis and Cbz deprotection, and the latter was
obtained from compound 1a by reductive amination
with propanal (Scheme 3). Both compounds were sub-
1
2
Compound
R
R
Yield (%)
Dr
3a
3b
3c
3d
3e
3f
i-Pr
i-Pr
Ph
t-Bu
n-Bu
t-Bu
n-Bu
t-Bu
n-Bu
96
84
78
84
95
90
67:33
68:32
71:29
71:29
52:48
50:50
Ph
Bn
Bn
Scheme 2. Synthesis of amino acid 1b and subsequent Ugi reactions.

A. Basso et al. / Tetrahedron Letters 45 (2004) 587–590
589
a
Table 2. Results obtained in the Ugi reaction with scaffold 1b
In order to study in more detail the surprising results
obtained with compound 1b, we looked also for alter-
native N-alkyl groups that could be removed at the end
of the condensation (e.g., by hydrogenolysis). Com-
pound 2 was treated with benzyl bromide and sodium
hydride and the resulting trans derivative 10 was
hydrolysed and selectively hydrogenolysed (Scheme 4).
Also in this case, after condensation of 11 with different
isocyanides and aldehydes, only one diastereoisomer
could be detected by NMR, although yields were found
to be lower, probably due to the higher steric hindrance
1
2
Compound
R
R
Yield (%)
6
6
6
6
6
6
6
6
6
6
6
6
a
b
c
d
e
f
i-Pr
i-Pr
i-Pr
i-Pr
i-Bu
i-Bu
Et
t-Bu
n-Bu
Bn
50
90
70
90
60
96
50
60
50
94
58
93
(CH
t-Bu
Bn
2 2 2
) CO Me
g
h
i
t-Bu
n-Bu
t-Bu
n-Bu
t-Bu
n-Bu
Et
Bn
j
Bn
Ph
4
of the benzyl group (Table 4).
k
l
Ph
In a final series of experiments a Ugi reaction was
performed on the unsaturated derivative 13, prepared by
modifying a literature procedure, and the sole dia-
stereoisomer obtained (14) was subjected to retro Diels–
Alder reaction and enamine hydrolysis to give the amino
acid derivative 16 (Scheme 5). These results proved that
a
In all cases the dr was higher than 95:5.
7
compounds such as 13, in their optically active form,
could be efficiently used as chiral auxiliaries in the
stereoselective synthesis of a-amino amides via multi-
component Ugi reactions.
Scheme 3. Synthesis of amino acids 1c and 1d and subsequent Ugi
reactions.
Scheme 4. Synthesis of amino acid 11 and subsequent Ugi reactions.
jected to Ugi reactions with various aldehydes and iso-
cyanides and in these cases not only were the diastereo-
selectivities lower but also the conversion yields fell
a
Table 4. Results obtained in the Ugi reaction with scaffold 11
4
(
Table 3).
1
2
Compound
R
R
Yield (%)
1
1
1
1
2a
2b
2c
2d
i-Pr
Bn
Ph
t-Bu
n-Bu
t-Bu
t-Bu
11
55
30
49
Particularly interesting was the case of compound 1c,
although the amino group was not alkylated, the trans
configuration did not allow ring contraction, and a
methyl ester was isolated in analogy with 1b. In a recent
Bn
a
5
In all cases the dr was higher than 95:5.
paper it was reported that trans cyclic b-amino acids
did not react at all in such a reaction. Only in the case of
the reaction with tert-butyl isocyanide and isobutyr-
aldehyde was the expected methyl ester 8a not obtained,
while a small amount of a compound with an NMR
spectrum consistent with a trans b-lactam was isolated.
Table 3. Results obtained in the Ugi reaction with scaffolds 1c and 1d
1
2
Compound
R
R
Yield (%)
Dr
8a
8b
8c
9a
9b
9c
i-Pr
i-Pr
i-Bu
i-Pr
i-Pr
i-Bu
t-Bu
n-Bu
Bn
See text
––
26
56
5
>95:5
>76:24
>95:5
>89:11
>75:25
t-Bu
n-Bu
Bn
28
47
Scheme 5. Ugi reaction with an unsaturated bicyclic amino acid and
subsequent removal of the chiral auxiliary.

5
90
A. Basso et al. / Tetrahedron Letters 45 (2004) 587–590
385–387; (c) Obrecht, R.; Toure, S.; Ugi, I. Heterocycles
In conclusion this paper reports for the first time the
different reactivities of bicyclic b-amino acids in the
intramolecular Ugi reaction. We have demonstrated that
configuration and N-alkylation can play an important
role in the outcome of the reaction and we have obtained
excellent results in terms of diastereoselectivity with
compound 1b. Finally, we have proven that compounds
such as 13 can be successfully employed as chiral auxil-
iaries and removed at the end of the condensation under
very mild conditions. We are currently preparing opti-
1
1
984, 21, 271–277; (d) Kehagia, K.; Ugi, I. Tetrahedron
995, 51, 9523–9530; (e) D o€ mling, A.; Kehagia, K.; Ugi, I.
Tetrahedron 1995, 51, 9519–9522; (f) Nitta, H.; Hatanaka,
M.; Ishimura, T. J. Chem. Soc., Chem. Commun. 1987, 51–
5
2.
3
. (a) Gokel, G.; L u€ dke, G.; Ugi, I. In Isonitrile Chemistry;
Ugi, I., Ed.; Academic: New York, 1971; p 158; (b)
Demharter, A.; H o€ rl, W.; Herdtweck, E.; Ugi, I. Angew.
Chem., Int. Ed. 1996, 35, 173–175; (c) Ugi, I.; Demharter,
A.; H o€ rl, W.; Schmid, T. Tetrahedron 1996, 52, 11657–
11664; (d) Zimmer, R.; Ziemer, A.; Gruner, M.; Brudgam,
I.; Hartl, H.; Reissig, H. U. Synthesis 2001, 1649–1658; (e)
Park, S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.; Kim, Y.;
Lee, D. H. Tetrahedron Lett. 1998, 39, 7109–7112; (f) Kim,
Y. B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D. H.;
Koh, H. Y.; Kim, Y. S. Org. Lett. 2001, 3, 4149–4152.
. Yields refer to isolated products purified by flash chroma-
tography. All new compounds have been fully characterised
by NMR and MS.
7
cally active compounds such as 1b and 13 in order to
obtain, via an intramolecular Ugi reaction, chiral amino
acid derivatives and we will investigate, on a molecular
basis, with the aid of molecular modelling tools, the
reasons for the high stereoselectivity observed. This will
hopefully clarify some of the obscure points on the
mechanism of the Ugi reaction that are, after about
4
5
0 years from its discovery, still debated.
5
6
. Gedey, S.; Van der Eycken, J.; Ful o€ p, F. Org. Lett. 2002, 4,
1
967–1969.
. To confirm unambiguously the absence of the second
diastereoisomer, the two diastereoisomers of compound 6f
were independently prepared via an alternative procedure
and their NMR spectra were compared with the one of the
crude material of the Ugi reaction of compound 1b with
isobutyric aldehyde and benzyl isocyanide, confirming that
only one diastereoisomer could be detected within the limits
of the NMR sensitivity.
Acknowledgements
The authors wish to thank Dr. Francesca Tarchino for
her precious collaboration with this work and Univer-
sit ꢀa di Genova and MIUR (COFIN 2002) for financial
support.
7
. Optically active 13 and related compounds can be
9
prepared by desymmetrisation of diesters or anhydrides
8
of exo-3,6-epoxy-1,2,3,6-tetrahydro-phthalic acids prior to
the Curtius rearrangement generating the amino acid
moiety.
References and Notes
1
. D o€ mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169–
210.
. (a) Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 2802–
814; (b) Isenring, H. P.; Hofheinz, W. Synthesis 1981,
8. Guanti, G.; Banfi, L.; Narisano, E.; Riva, R.; Thea, S.
Tetrahedron Lett. 1986, 27, 4639–4642.
9. Chen, Y.; McDaid, P.; Deng, L. Chem. Rev. 2003, 103,
2965–2983.
3
2
2