Synthesis of a γ-lactam library via formal cycloaddition of imines and substituted succinic anhydrides

Article abstract of DOI:10.1021/co2001873

Formal cycloaddition reactions between imines and cyclic anhydrides serve as starting point for the synthesis of diverse libraries of small molecules. The synthesis of succinic anhydrides substituted with electron-withdrawing groups is facilitated by new mild conditions for alkylation of aryl-substituted acetyl esters with ethyl bromoacetate. These anhydrides are then used in formal cycloaddition reactions with imines to produce γ-lactams. 2-Fluoro-5-nitrophenylsuccinic anhydride reacts efficiently with imines to provide lactams that are further diversified by conversion of the nitro group to either an aniline and an azide for subsequent reactions with acylating agents and alkynes, respectively. The synthesis of cyanosuccinic anhydride is reported for the first time, and the use of this compound in reactions with imines and subsequent functionalization of the resultant lactams is demonstrated.

Full text of DOI:10.1021/co2001873

Research Article
pubs.acs.org/acscombsci
Synthesis of a γ-Lactam Library via Formal Cycloaddition of Imines
and Substituted Succinic Anhydrides
Darlene Q. Tan, Amy L. Atherton, Austin J. Smith, Cristian Soldi, Katherine A. Hurley, James C. Fettinger,
and Jared T. Shaw*
Department of Chemistry, One Shields Ave, University of California, Davis, California 95616, United States
S
* Supporting Information
ABSTRACT: Formal cycloaddition reactions between imines
and cyclic anhydrides serve as starting point for the synthesis of
diverse libraries of small molecules. The synthesis of succinic an-
hydrides substituted with electron-withdrawing groups is facili-
tated by new mild conditions for alkylation of aryl-substituted
acetyl esters with ethyl bromoacetate. These anhydrides are then
used in formal cycloaddition reactions with imines to produce
γ-lactams. 2-Fluoro-5-nitrophenylsuccinic anhydride reacts effi-
ciently with imines to provide lactams that are further diversified by conversion of the nitro group to either an aniline and an
azide for subsequent reactions with acylating agents and alkynes, respectively. The synthesis of cyanosuccinic anhydride is
reported for the first time, and the use of this compound in reactions with imines and subsequent functionalization of the
resultant lactams is demonstrated.
KEYWORDS: imine-anhydride formal cycloaddition, cyanosuccinic anhydrides, γ-lactams, spirooxindole
compounds made from this reaction. We set out to develop
better conditions for preparing substituted succinic anhydrides.
2-Fluoro-5-nitrophenylsuccinic anhydride (2a) allows for a
variety of subsequent transformations, including the formation
of spirooxindoles. Cyanosuccinic anhydride (2b) was unknown
in the literature at the outset of our studies and was anticipated
to require much shorter reaction times than previously ob-
served in the imine-anhydride reaction. 2-Benzothiazolesuccinic
anhydride (2c) would install a heterocycle on the 4-position of
the lactam, which has not previously been achieved. Although
this last variant was unsuccessful, we document our attempts to
prepare the requisite anhydride. The choice of these anhydrides
enables the synthesis of products that will have rigid core struc-
tures with several points of diversity derived from the aldehyde,
amine, and subsequent functionalization of the carboxylic acid.
In addition, further diversification of the nitro group and nitrile
is possible for cores 3 and 4. Importantly, the low molecular
weight of the core ensures that the final compounds retain, at
least to a rough approximation, “drug-like”24 and “lead-like”25
molecular properties.
INTRODUCTION
■
γ-Lactams represent important substructures for the synthesis
of natural products1−5 and biologically important compounds
in drug discovery.6−9 In addition, spirobicyclic lactams are also
found in a number of biologically active natural products.10−12
The prevalence of these structures has resulted in the
development of many efficient syntheses,13−18 which have led
to the production of diverse libraries of small molecules for
biological evaluation.9,19,20
Previous work in our laboratory has employed the formal
cycloaddition reaction of imines and anhydrides13,21,22 in the
synthesis of a diverse collection of polycyclic lactams using
solid-phase, split-pool synthesis.9 A portion of that library
resulted from imine-anhydride reactions of substituted phenyl-
succinic anhydrides.23 As part of that study, we documented the
superior reactivity of phenylsuccinic anhydrides that were
substituted with electron-withdrawing groups, which we believe
emanates from increased enolate stabilization of the cyclization
intermediate. As a complement to those investigations, we
wanted to develop solution-based strategies for the preparation
of these complex molecules for high-throughput screening
studies after purification by preparative HPLC. In addition, we
wanted syntheses that were amenable to immediate execution
on larger scale for follow-up studies, establishment of structure-
activity relationships, and other experiments necessary for optimiz-
ing potency and selectivity against a biological target.
RESULTS AND DISCUSSION
■
To more fully exploit the reactivity of substituted succinic
anhydrides, we developed a milder and more easily scaled up
synthesis of these compounds. Previous syntheses rely on amide
bases for enolate generation and were often low yielding for
substrates that we required.23,26 We found that nitrophenylsuccinic
We selected three different substituted succinic anhydrides
to demonstrate the utility of the imine-anhydride reaction
in library synthesis (Figure 1). One liability associated with
the substituted succinic anhydrides emanates from difficulties
in their preparation, thus limiting the structural diversity of
Received: November 8, 2011
Revised: January 4, 2012
Published: January 6, 2012
© 2012 American Chemical Society
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Research Article
Figure 1. Summary of library strategy based on the formal cycloaddition of imines with substituted succinic anhydrides.
Table 1. Optimization of the Alkylation of Substituted
Phenylacetic Acid Esters
Scheme 1. Alkylation of Cyano- and 2-Benzothiazole Acetic
Esters
entry
substrate
solvent/base
temp.
yield
1
6a
6a
6a
6a
6a
6a
6b
6c
6d
6d
6e
CH3CN/Cs2CO3
CH3CN/Cs2CO3
DMF/Cs2CO3
DMF/Cs2CO3
THF/Cs2CO3
23 °C
80 °C
23 °C
100 °C
23 °C
reflux
13%
87%
38%
49%
14%
33%
77%
<10%
8%
2
3
4
5
6
THF/Cs2CO3
7
CH3CN/Cs2CO3
CH3CN/Cs2CO3
CH3CN/Cs2CO3
CH3CN/Cs2CO3
CH3CN/Cs2CO3
23 °C
80 °C
23 °C
80 °C
80 °C
8
9
10
11
34%
71%
anhydrides were the most useful substrates with respect to reactivity
and subsequent conversion to more complex substructures.27
Given that these anhydrides were ultimately derived from the
corresponding nitrophenylacetic esters, we reasoned that the
requisite alkylation should be possible under mildly basic
conditions. Screening a variety of bases and solvents revealed
that the combination of Cs2CO3 with acetonitrile resulted in
the highest yields of alkylation products (eqs 1 and 2; Table 1,
entries 2, 7, 10−11).28 Although the reaction fails for 6c
and gives poor conversion for 6d, this reaction works well for
arylacetic esters with electron-withdrawing groups attached
(6a−b, e), which corresponds to the expected enolate anion
stability conferred by delocalization into the ring.
Scheme 2. Conversion of Diesters to Substituted Succinic
Anhydrides
We attempted to apply the mild alkylation conditions for the
two additional substrates (Scheme 1). When ethyl cyanoacetate (8)
was used as a substrate, dialkylation became the major observable
product. Various combinations of NaOEt and NaOt-Bu in
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Scheme 3. Imine-Anhydride Reactions of 2a Followed by Ester and Amide Formation
Scheme 4. Spirocyclization Reactions of 19, 20, and 22
THF/H2O cleaved the diesters to their corresponding diacids.
Subsequent dehydration to the anhydrides was best achieved
with trifluoroacetic anhydride. Residual TFAA and trifluoro-
acetic acid were removed by azeotropic removal with toluene,
1
and the resultant anhydrides were generally >90% pure by H
NMR spectroscopy. Although this sequence worked well for
the conversion of diesters 7a and 9 to anhydrides 2a and 2b,
respectively, attempts to prepare anhydride 2c from benzothiazole
12 were unsuccessful because of degradation of the diacid
during the dehydration. Similar results were observed with
acetic anhydride and with the neutral dehydration agent 15,
which was developed by Kita et al. for the express purpose of
preparing heterocycle-fused glutaric anhydrides.29 There are
currently no known heterocycle-substituted succinic anhydrides
related to 2c, and we are continuing to examine ways of achiev-
ing this difficult dehydration to prepare these potentially useful
substrates.
Imine-anhydride reactions of anhydride 2a with imines
16 and 17 proceeded in high yield at room temperature
(Scheme 3). Imine 16 is commercially available, whereas 17 was
prepared from isobutylamine and benzaldehyde and used without
purification. The resultant acids were converted directly to
either the corresponding methyl esters 19 or the amides 20−22.
Analysis of the diastereoselectivity at the amide stage showed
that mixtures varying from 63:37 to 67:33 were generally
formed. Although this lack of diastereoselectivity would be a
liability for a target-directed synthesis, it is an advantage for
diversity-oriented synthesis, provided that the diastereomers are
easily separated. At this point isobutyl amides 20a and 20b
could be separated into their constituent diastereomers by
recrystallization or column chromatography, whereas 21a
and 21b exhibited poor solubility and, as a result, were not
separable by chromatography. We decided to replace 21 with
22, which had much better solubility, consistent with 20,
indicating that the amide NH2 was problematic. Ester 19b
was also easily separated and the major diastereomer formed
crystals suitable for X-ray diffraction, confirming the relative
configuration of the aromatic rings as 4,5-syn. A similar result
was observed for the major diastereomer of amide (20b), and
both structures are consistent with previous observations from
our laboratory.23
several different solvents invariably resulted in mixtures of
unreacted 8 and the mono and dialkylation products 9 and 10.
This result is probably due to the highly electron-withdrawing
nature of the cyano group paired with the low steric demand when
compared to phenyl. Ultimately, the use of NaOEt and ethanol
enabled multigram quantities of 9 to be isolated by vacuum
distillation. Analogously, mono and dialkylation products 12
and 13, respectively, were competitive when the phenyl ring
was replaced by 2-benzothiazole for the alkylation substrate (11).
Given the ease with which 9 could be prepared and purified, con-
version of this material to the required benzothiazole-substituted
succinate ester 12 was more practical.
Succinate esters were cleanly converted to anhydrides in two
steps (Scheme 2). Saponification with lithium hydroxide in
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Figure 2. Diversity reagents employed in Scheme 6.
Table 2. Optimization of Imine Anhydride Reaction Using
Cyanosuccinic Anhydride
Table 3. Imine Anhydride Reactions of Cyanosuccinic
Anhydride 2b
entry
solvent
dr
conversion (isolated yield)
a
entry
imine ; R1, R2
product, yield
1
2
3
4
5
6
CHCl3
ACN
DCM
THF
79:21
78:22
75:25
93:7
96%
b
1
2
3
4
5
6
7
16 , CH3, H
34, 65%
35, 63%
36, 69%
37, 84%
38, 60%
39, 86%
40, 83%
41, 65%
93%
17, i-Bu, H
>98%
>98% (76%)
96%
28, i-Pr, H
29, CyCH2, H
DMF
PhMe
66:34
63:37
30, HCCCH2, H
31, p-ClC6H5CH2, H
32, p-ClC6H5CH2, OCH3
33, p-ClC6H5CH2, CN
>98%
Two strategies for preparing spirooxindoles from imine-
anhydride products 19, 20, and 22 were examined (Scheme 4,
Figure 2). Amides 20 and 22 were cyclized under basic conditions.
In each case, the spirooxindole products were formed in high
yield. Both substrates were reduced to the corresponding
anilines using either SnCl2 and HCl or hydrogen and palladium
on carbon. Both sets of conditions produced the anilines in
similar yields, and the latter method was generally cleaner and
more scaleable. Although there is some precedent for one-step
aminolysis and cyclization of methyl esters related to 19,30 this
transformation proved to be inefficient for our substrates as
exemplified by the low yield of 23b obtained from 19b.
8
a
Imines were formed using 1 equiv of amine, 1 equiv of aldehyde, and
1.6 equiv of HC(OEt)3 in THF. Commercially available imine.
b
Scheme 5. Reduction and Acylation of 40
Cyanosuccinic anhydride 2b reacts with various imines at
ambient temperature with high diastereoselectivity (Table 2).
Reactions are almost instantaneous and also proceed at reduced
temperature. A survey of various solvents revealed conversions
were universally high and that reactions in THF proceeded with
the highest diastereoselectivity. Using this method, acid 27 was
isolated by trituration and filtration in 76% yield as a single
detectable diastereomer. The scope of this substrate was
explored by using imines formed in situ from amines and
aldehydes using triethyl orthoformate as a dehydrating agent
(Table 3). The reaction tolerates various substituents on nitrogen
(entries 1−6), as well as electron-donating or withdrawing groups
on the aldehyde (entries 7 and 8). Isolated yields after conversion
to the corresponding methyl esters ranged from 63 to 86%, and
in all cases the observed diastereoselectivity was excellent.
Reduction of the cyano group of 40 to an aminomethyl group
(Scheme 5) followed by acylation with 3,5-dinitrobenzoyl
chloride produced crystalline amide 42 suitable for analysis by
X-ray diffraction. The origin of the high 4,5-anti diastereose-
lection in this reaction could be thermodynamic or kinetic, and
experiments to probe the factors that influence the stereo-
chemical outcome of this reaction are underway.
The amino-spirooxindoles 25 and 26 were employed as syn-
thetic intermediates for diversification by two different reac-
tions (Scheme 6). 25a and 25b were converted to the corre-
sponding azides that underwent smooth cycloaddition reactions
with alkynes 43 using sodium ascorbate and copper(II) acetate
to form triazoles 44a and 44b. Amines 26a and 26b were
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Scheme 6. Library Synthesis Using 25, 26, 27, 34
CONCLUSION
■
The synthesis of a “pilot scale” library of complex γ-lactams
has been achieved. An optimized protocol for the alkylation
of substituted acetate esters allow the large-scale synthesis
of succinates under mild conditions. The resulting succinic
anhydrides undergo smooth reactions with imines to supply
carboxylic acid-appended γ-lactams that can be used in a variety
of subsequent diversification reactions. Although we had pre-
viously documented the formal cycloaddition reaction for 2-
fluoro-5-nitrophenylsuccinic anhydride succinic anhydride, this
work demonstrates the use of the reaction products in acylation
and azide−alkyne cycloaddition (AAC) reactions. Finally, we
introduce cyanosuccinic anhydride as a new and highly reactive
substrate for the imine-anhydride reaction and show that it also
leads to a variety of complex library members.
Figure 3. Summary of the molecular properties computed for library
members. Calculated partition coefficients (cLogP) are based on the
XLOGP method of Wang.31
ASSOCIATED CONTENT
■
S
* Supporting Information
converted to amides, ureas, and to sulfonamides using 45.
Cyano-substituted lactam 34 was reduced to the amine using
Raney nickel and ammonia, and the resulting amine 49 was also
employed in acylation and sulfonylation reactions with 45.
Acid-substituted lactams 27, produced directly from the imine
anhydride reaction, were diversified using a series of amines and
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hex-
afluorophosphate (HATU). The library members were purified
by mass-directed fractionation to give 85% or greater of the
products in 20−99% yield.
The library produced by the chemistry described above
results in a set of compounds with desirable properties for high-
throughput screening and the discovery of drug leads and
biological probes (Figure 3). The molecular weights range from
200 to 570, which is an ideal range for subsequent modi-
fications by replacing building blocks and/or adding elements
of diversity. In addition, the cLogP31 range is favorable, with the
vast majority of the compounds falling between one and five.
Finally, hydrogen bond donors (0−2) and acceptors (4−9) are
both within the accepted ranges for the development of drugs
and leads.24,25
Detailed experimental procedures, full characterization data,
and purification details for all new compounds, as well as .cif
files for compounds 19b, 20b, and 42. This material is available
free of charge via the Internet at http://pubs.acs.org. In addition,
all library members have been submitted to the National Small
Molecule Repository where they will be made available for high-
throughput screening.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jtshaw@ucdavis.edu.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CAREER award to J.T.S.) and the National Institutes of
Health (NCI/R01CA131458; NIGMS/P41GM089153). J.C.F.
acknowledges support from the NSF (CHE-0840444) for the
purchase of the Bruker SMART DUO diffractometer used for
X-ray crystallography. A.L.A. acknowledges research support in
the form of a UC Davis President’s Undergraduate Fellowship
(PUF). C.S. thanks CAPES (Brazilian Coordination for the
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Research Article
and stereoselective homoenolate equivalents. J. Am. Chem. Soc. 2009,
131, 8805−8814.
Improvement of Higher Education Personnel) for a post-
doctoral fellowship. The authors thank Patrick Porubsky
(University of Kansas) for conducting mass-directed purifica-
tion of all final library members at the Center for Methodology
and Library Development (KU-CMLD), which is funded by
the NIH (NIGMS/P50GM069663). Phillip P. Painter (Tantillo
research group, UC Davis) is acknowledged for calculating the
molecular properties of the library using OpenEye software
(www.eyesopen.com).
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