Diastereoselective synthesis of γ-lactams by a one-pot, four-component reaction

Article abstract of DOI:10.1021/ol701911u

A new one-pot, four-component reaction (4CR) between amines, maleic anhydrides, aldehydes, and thiols has been discovered to form tetra-and pentasubstituted γ-lactams with high diastereoselectivity. Each component is independently variable and employed in

Full text of DOI:10.1021/ol701911u

ORGANIC
LETTERS
2007
Vol. 9, No. 20
4077-4080
Diastereoselective Synthesis of
-Lactams by a One-Pot,
γ
Four-Component Reaction
Jingqiang Wei and Jared T. Shaw*,†
Broad Institute of HarVard and MIT, 7 Cambridge Center,
Cambridge, Massachusetts 02142
shaw@chem.ucdaVis.edu
Received August 6, 2007
ABSTRACT
A new one-pot, four-component reaction (4CR) between amines, maleic anhydrides, aldehydes, and thiols has been discovered to form tetra-
and pentasubstituted -lactams with high diastereoselectivity. Each component is independently variable and employed in equivalent
γ
stoichiometry, producing only water as a byproduct.
Multicomponent reactions (MCRs) are an important class
of chemical transformations for the efficient synthesis of
natural products and screening compounds for the discovery
of biological probes and drugs.1 The Hantsch2 and Biginelli3
reactions are important for the synthesis of heterocycles,
whereas the Passerini,4 Ugi,5 and Petasis6 MCRs are useful
methods for preparing R-hydroxy and R-amino carboxylic
acid derivatives.7 To date, few four-component reactions
(4CRs) have been reported to form multiple stereogenic
centers with a high level of diastereoselection.8 Herein, we
disclose the first 4CR for the diastereoselective synthesis of
γ-lactams wherein either two or three stereocenters are
formed with high selectivity.
Our recent discovery of the formal cycloaddition of imines
to 2-arylthiosuccinic anhydrides9 prompted us to probe the
mechanism of this reaction. Of particular interest was the
high regioselectivity in the attack of the imine on the
anhydride. The opening of 2-substituted succinic anhydrides
by amine nucleophiles is known to be unselective,10 presum-
ably due to competing steric and stereoelectronic effects.11
On the basis of the high regioselectivity required for the
yields that we observe, we reasoned that the reactions of
anhydride 2 with imines must be reversible (Scheme 1) and
that only the isomer with the R-thioaryl substituent (5a) was
sufficiently enolizable to proceed on to the observed product
6.
† Current Address: Department of Chemistry, University of California,
One Shields Ave., Davis, CA 95616.
(1) (a) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem.-Eur.
J. 2000, 6, 3321-3329. (b) Zhu, J., Bienayme, H., Eds. Multicomponent
Reactions; Wiley-VCH: Weinheim, Germany, 2005; p 468.
(2) (a) Hantzsch, A. Liebigs Ann. Chem. 1882, 215, 1-82. (b) Simon,
C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957-4980.
(3) (a) Biginelli, P. Ber. Dtsch. Chem. Ges. 1891, 24, 2962-2967. (b)
Kappe, C. O.; Stadler, A. Org. React. (NY) 2004, 63, 1-116.
(4) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181-189. (b) Banfi,
L.; Riva, R. Org. React. (NY) 2005, 65, 1-140.
(5) (a) Ugi, I.; Meyr, R.; Fetzer, U.; Steinbruckner, C. Angew. Chem.
1959, 71, 386. (b) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168-3210. (c) Do¨mling, A. Chem. ReV. 2006, 106, 17-89.
(6) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583-
586. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445-
446.
The reversibility of imine attack on anhydride 2 was tested
using alternate conditions to access intermediates 3 and 5a.
The reaction of benzylamine with anhydride 2 produces the
(8) For direct comparison, we are limiting our description of 3CRs and
4CRs to those in which all of the components can be independently varied.
The Hantzsch, Biginelli, Passerini, and Petasis 3CRs and the Ugi 4CR are
all examples of MCRs in which each component can, to a certain extent,
be varied independently. For a comprehensive discussion of many MCRs
discovered to date, see ref 1.
(9) Ng, P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999-4002.
(10) Stephani, R.; Cesare, V.; Sadarangani, I.; Lengyel, I. Synthesis 2002,
47-52.
(11) (a) Rosenfield, R. E., Jr.; Dunitz, J. D. HelV. Chim. Acta 1978, 61,
2176-2189. (b) Kayser, M. M.; Wipff, G. Can. J. Chem. 1982, 60, 1192-
1198.
(7) (a) For an example of a five-component reaction in which hexasub-
stituted benzenes are produced in a one-pot sequential process, see: Janvier,
P.; Bienayme, H.; Zhu, J. Angew. Chem., Int. Ed. 2002, 41, 4291-4294.
(b) For an example of a seven-component reaction, see: Do¨mling, A.; Ugi,
I. Angew. Chem., Int. Ed. 1993, 32, 563-564.
10.1021/ol701911u CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/31/2007

The 4CR of thiols, amines, and aldehydes with maleic
anhydride works well for a variety of substrates (eq 2, Figure
1). Alkyl primary amines can be R- or â-branched, as
Scheme 1. Reversibility of the Imine-Anhydride Reaction
hemi-acid products 7a and 7b in a 55:45 ratio (eq 1). The
mixture of amides 7a and 7b was allowed to react with
benzaldehyde in refluxing toluene under dehydrating condi-
tions. Nearly quantitative conversion to lactam 8 was
observed. In addition, 7a and 7b were prepared, separated,
and carried on to 8 in independent reactions.12 These results
are consistent with the intermediacy of N-acyl iminium ion
5a in the formation of lactam 8. A three-component reaction
(3CR) whereby benzylamine, anhydride 2, and benzaldehyde
were combined in a single operation also produced lactam
8 in high yield.
Figure 1. One-pot, four-component syntheses of tetrasubstituted
γ-lactams (p-tol ) p-C6H4CH3). All reactions were conducted by
combining the four components in equimolar ratios and heating to
reflux in toluene for 24 h. Yields are reported for conversion to
the methyl ester and purification by flash chromatography (see
Supporting Information).
The demonstration that amides 7a and 7b produce the
same product as the imine anhydride reaction by a completely
different mechanism prompted us to attempt a four-
component reaction (4CR). We hypothesized that the thiol
could react with an initially formed maleic amide to form
amides 7a and 7b and thus enable a four-component reaction.
We were delighted to find that combining benzyl amine,
maleic anhydride (9), p-thiocresol (10), and benzaldehyde
in toluene at reflux produced lactam 11 in high yield (Scheme
2). Benzaldehyde dimethyl acetal can be used in place of
previously reported for the imine-anhydride reaction, and
in this case, anilines now produce N-aryl lactams in excellent
yields. Although the reaction is limited to nonenolizable
aldehydes due to enamide formation, the successful reaction
of cyclopropane carboxaldehyde demonstrates that enoliza-
tion only needs to be energetically suppressed and not
completely prevented. The thiol component can be aryl- or
alkyl-substituted, though in the latter case the diastereose-
lectivity is reduced.13 Ortho-substitution on the thiols is well
tolerated, opening the possibility for asymmetric induction
from a substituent with a stereogenic center. Given the
importance of γ-lactams in drug discovery and natural
Scheme 2. One-Pot, Four-Component Reaction (4CR)
(12) See Supporting Information. A related 3CR with homophthalic
anhydride has been observed: Yadav, J. S.; Reddy, B. V. S.; Saritha Raj,
K.; Prasad, A. R. Tetrahedron 2003, 59, 1805-1809.
(13) The S-aryl compounds are useful substrates for radical reactions.
See: (a) Ikeda, M.; Hamada, M.; Yamashita, T.; Matsui, K.; Sato, T.;
Ishibashi, H. J. Chem. Soc., Perkin Trans. 1999, 1, 1949-1956. (b) Alibes,
R.; Bayon, P.; De March, P.; Figueredo, M.; Font, J.; Marjanet, G. Org.
Lett. 2006, 8, 1617-1620. (c) Ghosh, S.; Sinha, S.; Drew, M. G. B. Org.
Lett. 2006, 8, 3781-3784.
benzaldehyde, but the yield is lower. In each case, >95%
selectivity for the 4,5-syn isomer was observed.
4078
Org. Lett., Vol. 9, No. 20, 2007

product synthesis, we anticipate that the wide substrate
tolerance will enable the preparation of useful synthetic
intermediates.
Scheme 3. Mechanism of the One-Pot, 4CRa
Pentasubstituted lactams can be prepared from 3-substi-
tuted maleic anhydrides (eq 3, Table 1) with high (>83%)
Table 1. 3-Substituted Maleic Anhydrides
a Iminium ion 3 (path B) equilibrates with iminium ion 5a (path
A) to proceed on to product.
entry
(product)
R1
i-Pr
Bn
o-BrC6H5
i-Pr
R2
R4
yielda,b
ds
at either terminus (paths A and B, Scheme 3) of the double
bond of unsymmetrical maleic amides, depending on the
conditions.16 Condensation with the aldehyde results in the
formation of the iminium zwitterions 5a and 3, from paths
A and B, respectively. In the case of path A, iminium ion
5a can tautomerize at the thio-substituted carboxylate to form
enolate 5b, which proceeds on to product. In the case of
path B, iminium ion intermediate 3 intermediate can partition
to imine 1 and anhydride 2, which can recombine to iminium
ion 5a and proceed on to the observed product. The
mechanism for the formation of the pentasubstituted lactam
products is complicated by regioselectivity of the reactions
of substituted maleic anhydrides,17 and further control
experiments will be required to fully dissect this process.
1 (24)
2 (25)
3 (26)
4 (27)
5 (28)
Ph
Ph
CH3
CH3
i-Bu
i-Bu
i-Bu
70%
65%
49%e
68%
62%
86%c
83%d
f
o-BrC6H5
Ph
-
83%d
f
Bn
Ph
-
a Combined yield of product mixture after conversion to the methyl ester
(see Supporting Information). bMajor isomer out of the mixture of up to
c
four isomers. Based on GC analysis of the unpurified mixture of methyl
esters. dLower limit based on analysis of 1H NMR spectroscopy. eYield of
isolated major diastereomer based on conversion of the intermediate acid
to benzyl amide 29 and isolation of the major diastereomer (see Supporting
Information). fBaseline resolution of a minor isomer was not possible using
GC or HPLC.
diastereoselectivity for the formation of one of the four
possible diastereomers. Methyl and isobutyl14 substituents
both exhibit high selectivity. The configuration of acid 26
(entry 3) was determined by conversion to benzyl amide 29
and X-ray crystallographic analysis. We are currently
investigating the origin of the high diastereoselectivity
observed in this reaction.
The products of the 4CR are useful precursors to stereo-
chemically defined trisubstituted lactams. Radical reductive
desulfurization yields the corresponding disubstituted carboxy
lactam syn-34 in high yield and with high diastereoselection
(Scheme 4).18 The 4,5-anti diastereomer of 34 is easily
(16) The conjugate addition of thiols to maleic monoamides has been
reported to occur at the â-carbon of the amide: (a) Augustin, M.; Mueller,
W. Z. Chem. 1985, 25, 61-62. (b) Neumann, R.; Ringsdorf, H. J. Am.
Chem. Soc. 1986, 108, 487-490. The presence of the other regioisomers
is not ruled out in either report. For related studies on thiol conjugate addition
to mixed amide/ester and ester/acid maleates, see: (c) Augustin, M.;
Koehler, M. Tetrahedron 1976, 32, 2141-2145. (d) Tomioka, K.; Muraoka,
A.; Kanai, M. J. Org. Chem. 1995, 60, 6188-6190. (e) Kamimura, A.;
Murakami, N.; Kawahara, F.; Yokota, K.; Omata, Y.; Matsuura, K.; Oishi,
Y.; Morita, R.; Mitsudera, H.; Suzukawa, H.; Kakehi, A.; Shirai, M.;
Okamoto, H. Tetrahedron 2003, 59, 9537-9546. (f) Kamimura, A.;
Murakami, N.; Yokota, K.; Shirai, M.; Okamoto, H. Tetrahedron Lett. 2002,
43, 7521-7523. (g) Schmidt, T. J.; Ak, M.; Mrowietz, U. Bioorg. Med.
Chem. 2007, 15, 333-342.
(17) (a) Mehta, N. B.; Phillips, A. P.; Lui, F. F.; Brooks, R. E. J. Org.
Chem. 1960, 25, 1012-1015. (b) Baydar, A. E.; Boyd, G. V.; Aupers, J.;
Lindley, P. F. J. Chem. Soc., Perkin Trans. 1981, 1, 2890-2894. Mehta et
al. report that primary amines react unselectively with 3-methylmaleic
(citraconic) anhydride, whereas secondary amines were reported to react
with >95% regioselectivity. The subsequent report from Baydar demon-
strates that these findings were incorrect and that both primary and secondary
amines exhibit 50:50 to 78:22 regioselectivity.
The mechanism of this new 4CR relies on the ability of
both regioisomers of the initially formed maleic amide to
converge on a single regioisomer of the iminium ion capable
of proceeding to the lactam product (Scheme 3). Reaction
of amine 30 with maleic anhydride is rapid at ambient
temperature, while the subsequent conjugate addition of the
thiol to the amide in the absence of base15 is slower and
proceeds at elevated temperatures. Thiols are known to react
(14) Alkyl-substituted maleic anhydrides are easily prepared from
Grignard reagents and dimethylacetylene dicarboxylate: (a) Scholte, A. A.;
Eubanks, L. M.; Poulter, C. D.; Vederas, J. C. Bioorg. Med. Chem. 2004,
12, 763-770.
(15) See refs 16a and 16b. The reaction of the thiol with the anhydride
in the presence of base is rapid at room temperature: Zienty, F. B.; Vineyard,
B. D.; Schleppnik, A. A. J. Org. Chem. 1962, 27, 3140-3146. When the
thiol, amine, and anhydride are combined at rt, some of the thio-substituted
anhydride could form since the addition of the amine to the anhydride is
probably competitive with the base-mediated conjugate addition of the thiol.
Compounds 31-33 are all observed in the crude reaction mixture before
the reaction mixture is heated to induce the condensation with the aldehyde.
(18) (a) Natsugari, H.; Matsushita, Y.; Tamura, N.; Yoshioka, K.; Ochiai,
M. J. Chem. Soc., Perkin Trans. 1983, 1, 403-411. (b) Kametani, T.;
Kawamura, K.; Honda, T. J. Am. Chem. Soc. 1987, 109, 3010-3017.
Org. Lett., Vol. 9, No. 20, 2007
4079

reaction should prove useful in the rapid synthesis of
collections of compounds for the discovery of drugs and
biological probes. We are currently pursuing the synthesis
of several natural product targets using this transformation.
Scheme 4. Stereoselective Synthesis of 4,5-syn- and
4,5-anti-γ-Lactams
Acknowledgment. This work was conducted under the
aegis of the Broad Institute Center for Methodology and
Library Development (CMLD, NIGMS P50 GM069721) and
supported by Amgen in the form of a new faculty award to
J.T.S. J.T.S. thanks Prof. Stuart Schreiber (Harvard Univer-
sity, Broad Institute, and Howard Hughes Medical Institute)
and Prof. David Evans (Harvard University) for insightful
discussions. Dr. Richard Staples (Harvard Univserity) is
acknowledged for X-ray crystallographic analysis. X-ray
structures of 29 and 34 were rendered with imol (http://
www.pirx.com/iMol/), and Piotr Rotkiewicz (pirx.com) is
acknowledged for helpful input.
accessed by desulfurization with Raney nickel to a mixture
of diastereomers that can be epimerized with potassium tert-
butoxide at ambient temperature to yield a single isomer of
product.
We have demonstrated that densely substituted γ-lactams
are formed from a remarkable four-component reaction that
forms up to three stereogenic centers in a single step. This
Supporting Information Available: Experimental pro-
cedures for the preparation of all new compounds and X-ray
crystallographic data for 29 and 34. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL701911U
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Org. Lett., Vol. 9, No. 20, 2007