Efficient lactam synthesis

Details Efficient lactam synthesis Efficient lactam synthesis

2002-12-18

2004-02-10

Kifle, Bruck (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06689890

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to synthetic methods for the preparation of lactams. More particularly, the present invention relates to efficient and economic synthetic methods for the preparation of optionally substituted lactams by intramolecular C—H insertion reactions of &agr;-diazoamides, in which the &agr;-diazoamides are activated for intramolecular C—H insertion, for example by sulfone substitution, and to compounds and libraries of compounds derived therefrom.
BACKGROUND OF THE INVENTION
Lactacystin, an exemplary chiral pyrrolidinone, possesses structural motifs common to a number of biologically active natural products such as kainic acid and epolactaene. These molecules, or their synthetic precursors, contain lactam cores (specifically, &ggr;-lactam cores) that are highly functionalized. Numerous medicinal applications of such &ggr;-lactam systems are known, encompassing applications as diverse as, for example, anticancer agents, psychotropic agents, neuromuscular transmission blockers, immunoregulators, neurological excitants, protease inhibitors, and antidepressants. Therefore, a general, efficient and economic synthesis of such chiral pyrrolidinones would facilitate ongoing and future health related research.
The pyrrolidinone functionality is a prevalent theme in various syntheses, and serves as a crucial intermediate in the synthesis of numerous natural products. Although a large number of synthetic methods have been reported to date (see, for example, DiCosimo, R., Gavagan, J. E., Fager, S. K., Fallon, R. D., Folsom, P. W., Herkes, F. E., Eisenberg, A., and Hann, E. C. “Chemoenzymatic Production of Lactams from Aliphatic &agr;,&ohgr;-Dinitriles” 1998, J. Org. Chem. 63:4792), the reported asymmetric syntheses are inefficient, lengthy, and costly (see, for example, Meyers, A. I. and Burgess, L. E. “Asymmetric Synthesis of &ggr;,&ggr;-Dialkyl-&ggr;-aminobutyric Acid Analogues and 2,2-Disubstituted Pyrrolidines” 1991, J. Am. Chem. Soc. 113:9858 ).
Due to their biological activities and interesting structural features, it is also desirable to develop improved synthesis of lactacystin and clasto-lactacystin &bgr;-lactone. New methodology for the construction of the lactam core in order to carry out targeted synthesis efficiently is also desirable.
For example, the biological activity of lactacystin and clasto-lactacystin &bgr;-lactone (FIG.
1
), is relevant to the regulation of apoptosis, an active research area for the development of anti-cancer treatments. The process of apoptosis (programmed cell death), which is regulated by the oncoprotein BcI-2, is targeted through the inhibition of the 20S proteasome, which overcomes the BcI-2 protective function and thereby induce cell death. Thus, specific inhibition of the 20S proteasome has been proposed for the selective destruction of cancerous cells but not normal cells. As a well-known specific inhibitor of the targeted proteasome, lactacystin has attracted considerable attention from synthetic chemists. Lactacystin is a natural product obtained from microbial metabolites, which induces neurite outgrowth in neuroblastoma cells as well as inhibits progression of human osteosarcoma cells. This natural product and its analog, clasto-lactacystin &bgr;-lactone, also induce apoptosis in human monoblast cells. Because of scarcity and significant bioactivity, there is a need for economic total syntheses of these chiral pyrrolidinone compounds.
For synthesis of such chiral pyrrolidinones, amino acids are potential versatile starting materials. To effect the chiral pyrrolidinone synthesis, these amino acids require a ring closure reaction. In one approach, initramolecular C—H insertion reactions of &agr;-diazoamide are used, catalyzed by rhodium salts. However, &agr;-diazoamides are poor substrates in ring closures through C—H insertions, mainly due to competing side reactions, poor regioselectivities, and poor stereoselectivities (Table 1).


R
1
R
2
Z
Yield (7:8)
i
Pr
i
Pr
CH
3
CO
89% (>99:<1)
i
Pr
i
Pr
H
95% (81:19)
i
Bu
i
Bu
CH
3
CO
92% (37:63)
i
Bu
i
Bu
H
95% (<1:>99)
PMP
i
Bu
CO
2
Me
76% (8:92)
i
Bu
PhCH
2
CH
2
CH
3
CO
94% (49:51)
i
Bu
PhCH
2
CH
2
H
85% (<1:32)
PMP
PhCH
2
CH
2
CO
2
Me
84% (<1:>99)
i
Pr
i
Pr
CH
3
CO
89% (>99:<1)
i
Pr
i
Pr
H
95% (81:19)
i
Bu
i
Bu
CH
3
CO
92% (37:63)
i
Bu
i
Bu
H
95% (<1:>99)
PMP
i
Bu
CO
2
Me
76% (8:92)
i
Bu
PhCH
2
CH
2
CH
3
CO
94% (49:51)
i
Bu
PhCH
2
CH
2
H
85% (<1:32)
PMP
PhCH
2
CH
2
CO
2
Me
84% (<1:>99)
Common alternative methods employ the use of &agr;-diazoacetamides, &agr;-diazoacetoacetamides, and &agr;-diaomalonamides, which also give rise to regiochemical mixtures. Such reactions are performed at elevated temperature, and often provide low diastereoselectivities. Thus, each reaction gives poor yields and/or a complicated mixture of products, as illustrated below in Scheme A:
It is a further object of the prevent invention to provide a means for synthesis bioactive compounds including, but not limited to, pramanicin, statine, AHPPA, kainic acid, rolipram, and eoplactaene.
The above and other features and advantages are achieved through the use of a novel synthetic method as herein disclosed. In accordance with one embodiment of the present invention, there is provided a method of synthesizing a lactam, the method comprising firstly providing an &agr;-diazoacetamide of structure (I),
in which R
1-6
are substituents that can include H, halo, N
3
, CN, NC, (C
1
-C
22
)alkyl, (C
6
-C
10
)aryl, (C
3
-C
8
)cycloalkyl, (C
2
-C
22
)alkenyl, (C
5
-C
8
)cycloalkenyl, (C
7
-C
32
)aralkyl, (C
7
-C
32
)alkylaryl, (C
9
-C
32
)aralkenyl, (C
9
-C
32
)alkenylaryl, OR, SR, N(R)
2
, NH(R), CO
2
R, C(O)R, P(O)(OR)
2
, COR, CF
3
, S(O)R, or SO
2
R, wherein each R is independently H, (C
1
-C
22
)alkyl, (C
6
-C
10
)aryl, (C
3
-C
8
)cycloalkyl, (C
2
-C
22
)alkenyl, (C
5
-C
8
)cycloalkenyl, (C
7
-C
32
)aralkyl, (C
7
-C
32
)alkylaryl, (C
9
-C
32
)aralkenyl, or (C
9
-C
32
)alkenylaryl; or R
2
and R
3
together comprise (C
1
-C
22
)alkyl, (C
2
-C
22
)alkenyl, (C
7
-C
32
)alkylaryl, (C
9
-C
32
)alkenylaryl, —C(CH
3
)
2
—O—CH
2
—, —(CH
2
)
n
—O—C(O)—, —C(X)—O—CH
2
— or —C(X)—CH
2
—O—, where n=0-10, and X is (C
6
-C
10
)aryl or (C
7
-C
32
)alkylaryl.
Secondly, the &agr;-diazoacetamide is reacted under conditions that promote intramolecular C—H insertion, whereby a lactam is synthesized.
In accordance with another embodiment of the present invention, lactams synthesized by the foregoing method are provided. An exemplary lactam compound synthesized according to the method of the present invention is clasto-lactacystin &bgr;-lactone.
In accordance with another embodiment of the present invention, a library of lactams synthesized by the foregoing method is provided, where such a library may be used, for example, in to screen for compounds having a desired biological activity.
Accordingly, a general synthetic method is desired that affords optionally substituted lactams in high yield, using economical conditions and reagents, comprising synthetic steps that cleanly provide product having the correct stereochemistry.
In addition, synthetic methods are also desired that economically provide libraries of chemically distinct lactams or compounds derived by further synthesis from lactams, for use, for example, in screening to identify biologically active lead compounds.
SUMMARY OF THE INVENTION
It is therefore a feature and advantage of the present invention, for example, to provide de novo methodology for the synthesis of the lactam core embedded in lactacystin and to refine this technology for general use. As depicted, for example, below, the C—H insertion reaction of diazo compound 4 can lead to the formation of a &ggr;-lactam, which is functionalized at every center. By varying substituents and structures, this method is expanded to formulate a large library of biologically significant lactams and compounds derived therefrom by further synthesis.
It is another feature and advantage of the present invention to provide the synthetic

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