Two-step stereocontrolled synthesis of densely functionalized cyclic β-aminoesters containing four stereocenters, based on a new cerium(IV) ammonium nitrate catalyzed sequential three-component reaction

Article abstract of DOI:10.1021/ol801738d

(Chemical Equation Presented) The cerium(IV) ammonium nitrate (CAN)-catalyzed sequential, one-pot reaction between alkylamines, β-ketoesters, and chalcones afforded cis-4,6-disubstituted 2-alkylaminocyclohexene-1-carboxylic esters with complete diastereoselectivity. The carbon-carbon double bond of these compounds was reduced with sodium triacetoxyborohydride, again with complete diastereoselectivity. This novel two-step route allows the transformation of very simple acyclic starting materials into tetrasubstituted cyclohexane derivatives bearing four functional groups, including a cis-β-aminoester moiety, and generates four stereocenters, three of which are adjacent and one of which is quaternary.

Full text of DOI:10.1021/ol801738d

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4303-4306
Two-Step Stereocontrolled Synthesis of
Densely Functionalized Cyclic
ꢀ-Aminoesters Containing Four
Stereocenters, Based on a New
Cerium(IV) Ammonium Nitrate Catalyzed
Sequential Three-Component Reaction
Vellaisamy Sridharan and J. Carlos Mene´ndez*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia,
UniVersidad Complutense, 28040 Madrid, Spain
josecm@farm.ucm.es
Received July 29, 2008
ABSTRACT
The cerium(IV) ammonium nitrate (CAN)-catalyzed sequential, one-pot reaction between alkylamines, ꢀ-ketoesters, and chalcones afforded
cis-4,6-disubstituted 2-alkylaminocyclohexene-1-carboxylic esters with complete diastereoselectivity. The carbon-carbon double bond of these
compounds was reduced with sodium triacetoxyborohydride, again with complete diastereoselectivity. This novel two-step route allows the
transformation of very simple acyclic starting materials into tetrasubstituted cyclohexane derivatives bearing four functional groups, including
a cis-ꢀ-aminoester moiety, and generates four stereocenters, three of which are adjacent and one of which is quaternary.
ꢀ-Amino acids and their esters have attracted much attention
in recent years1 due to their biological and pharmacological
relevance. Although they are less widely distributed than their
R counterparts, a considerable number of bioactive natural
products contain ꢀ-amino acid moieties, including, among
many others, the ꢀ-lactam antibiotics,2 antitumor compounds
such as taxol,3 cryptophycin 1,4 and dolastatin 11,5 the
antibiotics nodularin and microcistin,6 the marine antifungal
agent jasplakinolide,7 and the aminopeptidase inhibitors
bestatin and amastatin.8 In addition, ꢀ-amino acids are very
important in medicinal chemistry because they allow the
creation of peptidomimetics that not only have potent
biological activity but also are resistant to proteolysis9,10 and
hence have improved pharmacokinetic properties with regard
(2) For some representative reviews on ꢀ-lactam antibiotics, see: (a)
Go´mez-Gallego, M.; Manchen˜o, M. J.; Sierra, M. A. Tetrahedron 2000,
56, 5743. (b) Singh, G. S. Mini-ReV. Med. Chem. 2004, 4, 69. (c) Singh,
G. S. Mini-ReV. Med. Chem. 2004, 4, 96. (d) See also the periodical reviews
published in the series Amino Acids, Peptides and Proteins (Royal Society
of Chemistry).
(3) (a) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int.
Ed. Engl. 1994, 33, 15. (b) Blagosklonny, M. V.; Fojo, T. Int. J. Cancer
1999, 83, 151. (c) Gue´ritte, F. Curr. Pharm. Des. 2001, 7, 1229.
(4) Shih, C.; Gossett, L. S.; Gruber, J. M.; Grossman, C. S.; Andis, S. L.;
Schultz, R. M.; Worzalla, J. F.; Corbett, T. H.; Metz, J. T. Bioorg. Med.
Chem. Lett. 1999, 9, 69.
(1) For reviews, with emphasis on synthetic aspects, see: (a) Cole, D. C.
Tetrahedron 1994, 50, 9517. (b) Sewald, N. Amino Acids 1996, 11, 397.
(c) Abdel-Magid, A. F.; Cohen, J. H.; Maryanoff, C. A. Curr. Med. Chem.
1999, 6, 955. (d) Juaristi, E.; Lo´pez-Ruiz, H. Curr. Med. Chem. 1999, 6,
983. (e) Liu, M.; Sibi, M. P. Tetrahedron 2003, 58, 7991. For a monograph,
see: (f) Juaristi, E.; Soloshonok, V. A. EnantioselectiVe Synthesis of Beta-
Amino Acids, 2nd ed.; John Wiley and Sons: New York, 2005.
10.1021/ol801738d CCC: $40.75
Published on Web 09/09/2008
2008 American Chemical Society

to the natural peptides. Peptides composed of ꢀ-amino acids
(ꢀ-peptides) fold into three-dimensional structures similar
to those of the natural peptides and often exhibit important
pharmacological properties. For example, some peptides
related to the general structure 1 (Figure 1) are antibiotics,
Table 1. CAN-Catalyzed Preparation of
2-Alkylamino-1-cyclohexene-1-carboxylic Esters
entry compd
R1
R2
Ar
time, h yield, %
1
2
3
4
5
6
7
8
9
10
11
12
13
5a
5a
5b
5c
5d
5e
5f
5g
5h
5ia
5ia
5ja
5ja
nBu
nBu
nBu
nBu
nBu
nC6H13
nC7H15
nC6H13
nC7H15
(()-2-Me-Bu Et Ph
(S)-2-Me-Bu Et Ph
(()-sec-Bu
(R)-sec-Bu
Et Ph
Et Ph
Et 4-ClC6H4
tBu Ph
tBu 4-ClC6H4
Et Ph
Et Ph
Et 4-ClC6H4
Et 4-ClC6H4
30
42
42
42
42
45
45
42
42
45
48
96
96
63
77
73
80
81
71
73
68
72
71
74
74
72
Figure 1. Example of a biologically active ꢀ-peptidic structure.
Et Ph
Et Ph
and most interestingly, they have shown activity against
vancomycin-resistant bacteria.11
a As a 1:1 diastereomeric mixture.
In spite of the importance of cyclic ꢀ-amino acid deriva-
tives, exemplified by the components of 1, there are relatively
few methods that allow their preparation. We present here a
new procedure for the synthesis of highly substituted and
functionalized derivatives of 2-amino-1-cyclohexene-1-car-
boxylic acid bearing up to four stereocenters, three of which
are adjacent and the fourth which is quaternary. This method
involves a new three-component reaction12 from acyclic
precursors, catalyzed by cerium(IV) ammonium nitrate, for
the diastereoselective construction of a tetrasubstituted cy-
clohexene derivative containing an unsaturated ꢀ-aminoester
moiety, followed by the stereoselective reduction of a double
bond within the initial (cyclized) reaction product.
did not lead to any observable enantioselection, as shown
by the absence of optical rotation and the comparison of the
products arising from the racemic and enantiomerically pure
amines (e.g., entries 10 and 11 and 12 and 13),15 which were
studied by NMR techniques and also by HPLC with
conventional and chiral columns. All attempts to extend the
scope of the reaction by using R,ꢀ-unsaturated ketones
different from chalcones or γ-substituted ꢀ-ketoesters have
been unsuccessful so far. The structural and stereochemical
assignment of compound 5 was based on spectroscopic data
and confirmed by the single-crystal X-ray diffraction study
of 5c (Figure 2).
As shown in Scheme 1 and Table 1, the reaction at room
temperature between primary amines 2, ꢀ-ketoesters 3, and
Scheme 1. Sequential Three-Component Reaction between
Primary Amines, ꢀ-Ketoesters, and Chalcones
Figure 2. X-ray diffraction structure of compound 5c.
chalcones 4, in the presence of a catalytic amount (5 mol
%) of cerium(IV) ammonium nitrate (CAN), afforded
2-aminocyclohex-1-ene-1-carboxylic esters 513 in good
yields, with a molecule of water as the only byproduct. The
reaction proceeded with complete selectivity in favor of the
diastereoisomer having a cis-arrangement for the aryl sub-
stituents at C-4 and C-6, with both substituents placed in an
equatorial position. The choice of CAN as the catalyst was
based on its low oxophilicity in comparison to other Lewis
acids,14 which prevented loss of the hydroxyl group by
elimination. The use of chiral amines as starting materials
Cyclohexene derivatives 5 are proposed to arise from an
initial CAN-catalyzed reaction16 between amines 2 and
ꢀ-ketoesters 3 to give ꢀ-enaminones 6, followed by a Michael
addition to the enone system in substrates 4 to give 7,
imine-enamine tautomerism to 8, and a final cyclization
step, where the tendency of both aromatic substituents to sit
in equatorial positions controls the stereochemistry of the
final products (Scheme 2). In agreement with this hypothesis,
a control experiment run from an isolated enaminone 6
4304
Org. Lett., Vol. 10, No. 19, 2008

in excellent yields. We expect that this very simple protocol
will provide a general method for the displacement of
alkylamino groups in unsaturated ꢀ-aminoesters by ammonia.
Finally, we undertook the study of the reduction of the
CdC double bond in compounds 5 and 9. After some
unsuccesful attempts with other reagents, we found that
sodium triacetoxyborohydride, generated in situ from sodium
borohydride and acetic acid,17 effected the desired transfor-
mation in good to excellent yields, affording compounds 10
as a single diastereoisomer (Scheme 4 and Table 3). The
Scheme 2
.
Mechanism Proposed for the Three-Component
Reaction Leading to Compounds 5
Scheme 4
.
Fully Diastereoselective Reduction of Compounds 5
and 9 by Sodium Triacetoxyborohydride
generated from butylamine 2a and ethyl acetoacetate 3a gave
a result identical to that obtained in the corresponding three-
component reaction (78% yield of compound 5a).
To facilitate the application of this chemistry to the peptide
field, it was important to consider the preparation of
N-unsubstituted analogues of aminoesters 5. After some
experimentation, we found an efficient method leading to
this type of compound, consisting of the displacement of
stereochemical assignment of compounds 10 was based on
that previously established for 5and also on detailed coupling
Scheme 3
.
Displacement of the Alkylamino Group in
Compound 5 by Ammonia
Table 3. Reduction of 2-Amino-1-cyclohexene-1-carboxylic
Esters
starting
entry material
R1
R2
Ar
product yield, %
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
9a
9b
9c
9d
nBu
nBu
nBu
nBu
nC6H13 Et
nC7H15 Et
nC6H13 Et
nC7H15 Et
H
H
H
H
Et
Et
Ph
4-ClC6H4
10a
10b
10c
10d
10e
10f
10g
10h
10i
94
73a
71a
73a
75a
76a
84a
81a
95
tBu Ph
the alkylamino unit of 5 by ammonia through an addition-
elimination mechanism. Thus, as shown in Scheme 3 and
Table 2, exposure of some representative compounds 5 to a
tBu 4-ClC6H4
Ph
Ph
4-ClC6H4
4-ClC6H4
Ph
Et
Et
Table 2. Synthesis of 2-Amino-1-cyclohexene-1-carboxylic
Esters 9 from Compounds 5
10
11
12
4-ClC6H4
10j
10k
10l
94
95
93
tBu Ph
tBu 4-ClC6H4
starting
entry material
a In these cases, compounds 10 were accompanied by small amounts
of side products containing a C3dC4 double bond, presumably arising from
elimination of a molecule of water from 10.
R1
R2
Ar
product yield, %
1
2
3
4
5
6
7
5a
5b
5c
5d
5g
5h
5i
nBu
nBu
nBu
nBu
Et Ph
Et 4-ClC6H4
tBu Ph
tBu 4-ClC6H4
Et 4-ClC6H4
Et 4-ClC6H4
9a
9b
9c
9d
9b
9b
9a
88
87
90
88
85
87
90
constant studies, which are summarized in Scheme 4 for the
case of compound 10d. The conformation proposed for
compounds 10 is probably stabilized by an intramolecular
hydrogen bond between the axial hydroxy and alkylamino
substituents.
nC6H13
nC7H15
(S)-2-Me-Bu Et Ph
solution of ammonium formate in ethanol at room temper-
ature for 5 h gave the desired N-unsubstituted compounds 9
The diastereoselectivity observed in the reduction step can
be explained by the mechanism proposed in Scheme 5. As
Org. Lett., Vol. 10, No. 19, 2008
4305

Acknowledgment. We thank Professor Subbu Perumal
(Madurai Kamaraj University, Madurai, Tamil Nadu, India)
for the X-ray diffraction study of compound 5c. Financial
support from MEC (grant CTQ2006-10930/BQU) and
CAM-UCM (Grupos de Investigacio´n UCM, grant 920234)
is also gratefully acknowledged.
Scheme 5. Mechanistic Proposal for the Diastereoselectivity
Observed in the Reduction of Compounds 5 and 9 to 10
Supporting Information Available: Representative ex-
perimental procedures, characterization data for compounds
5, 9, and 10, X-ray data and cif file for 5c, and spectra of all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL801738D
(6) Namikoshi, M.; Rinehart, K. L.; Dahlem, A. M.; Beasley, V. R.;
Carmichael, W. W. Tetrahedron Lett. 1989, 30, 4349.
(7) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986, 27,
2797.
(8) Roers, R.; Verdine, G. L. Tetrahedron Lett. 2001, 42, 3563.
(9) For a review of ꢀ-amino acid-based peptidominetics, see: Steer, D. L.;
Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M. I. Curr. Med. Chem.
2002, 9, 811.
(10) For a review of the structural and biological characteristices of
peptides containing exclusively ꢀ-amino acids (ꢀ-peptides), see: Gademann,
K.; Hintermann, T.; Schreiber, J. V. Curr. Med. Chem. 1999, 6, 905.
(11) (a) Koert, U. Angew. Chem., Int. Ed. Engl. 1997, 36, 1836. (b)
Porter, E. A.; Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H. Nature
2000, 404, 565. (c) Raguse, T. L.; Jonathan, R.; LePlae, P. R.; Gellman,
S. H. Org. Lett. 2001, 3, 3963.
described in the literature for a related reduction,17 coordina-
tion to boron should take place on the enol tautomer of the
starting material, leading to 11, and the first hydride transfer
step can be expected to take place from the face opposite to
the hydroxyl group, as this would allow an intramolecular
hydrogen bond to develop in the transition state 12. Proto-
nation of the enol moiety in 13 would then take place from
the face opposite to the amino and hydroxyl substituents,
leading to the observed stereochemistry for compounds 10.
In summary, we have developed an experimentally con-
venient, user- and environmentally friendly two-step protocol
that requires simple, inexpensive, and readily available
starting materials, reagents, and catalysts and allows the
efficient and completely diastereoselective synthesis of
tetrasubstituted cyclohexane frameworks bearing four func-
tional groups, including a cis-ꢀ-aminoester moiety and
containing four stereocenters, three of which are adjacent
and a fourth which is quaternary.
(12) For selected reviews and monographs on multicomponent reactions,
see: (a) Do¨mling, A.; Ugi, I. Angew. Chem. Int. Ed. Engl. 2000, 39, 3168.
(b) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.-Eur. J. 2000,
6, 3321. (c) Ugi, A. Pure Appl. Chem. 2001, 73, 187. (d) Ugi, A. Molecules
2003, 8, 53. (e) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471. (f)
Zhu, J. Eur. J. Org. Chem. 2003, 1133. (g) Ramo´n, D. J.; Yus, M. Angew.
Chem., Int. Ed. 2005, 44, 1602. (h) Zhu, J., Bienayme´, H., Eds. Multicom-
ponent Reactions; Wiley-VCH: Weinheim, 2005. (i) Do¨mling, A. Chem.
ReV. 2006, 106, 17. For a symposium in print on this topic, see: Marek, I.,
Ed. Tetrahedron 2005, 67, 11299.
(13) In most reactions, compounds 5 were accompanied by small
amounts (5-10%) of the corresponding 1,3-cyclohexadiene derivatives,
arising from elimination of a molecule of water.
(14) See, for instance: Tsuruta, H.; Yamaguchi, K.; Imamoto, T.
Tetrahedron 2003, 59, 10419.
(15) Although the reaction described here is unprecedented, there is a
literature report of the preparation of 1-acetyl-2-alkylamino-1,3-cyclohexa-
diene derivatives in 0-74% yield from ꢀ-enaminones and chalcones
generated in situ from aryl bromides and propargyl alcohols. See: Schramm,
O. G.; Mu¨ller, T. J. J. Synlett 2006, 1841.
(16) For precedent of the fast generation of enaminones from amines
and ꢀ-ketoesters under CAN catalysis, see: Sridharan, V.; Avendan˜o, C.;
Mene´ndez, J. C. Synlett 2007, 881.
(5) Bates, R. B.; Brusoe, K. G.; Burns, J. J.; Caldera, S.; Cui, W.;
Gangwar, S.; Gramme, M. R.; McClure, K. J.; Rouen, G. P.; Schadow, H.;
Stessman, C. C.; Taylor, S. R.; Vu, V. H.; Yarick, G. V.; Zhang, J.; Pettit,
G. R.; Bontems, R. J. Am. Chem. Soc. 1997, 119, 2111.
(17) Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini, M.
J. Org. Chem. 1994, 59, 5328.
4306
Org. Lett., Vol. 10, No. 19, 2008