A structurally diverse library of polycyclic lactams resulting from systematic placement of proximal functional groups

Article abstract of DOI:10.1002/anie.200503341

(Chemical Equation Presented) A short, linear sequence for the synthesis of complex small polycyclic lactams (see picture) is presented. The sequence, which is applied to the synthesis of a library of 529 compounds, is based on a catalytic, enantioselective cycloaddition between an oxazole and an aldehyde, so that the resultant compounds are enantiomerically pure and readily prepared in either stereochemical series.

Full text of DOI:10.1002/anie.200503341

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Combinatorial Chemistry
DOI: 10.1002/anie.200503341
A Structurally Diverse Library of Polycyclic
Lactams Resulting from Systematic Placement of
Proximal Functional Groups**
Judith M. Mitchell and Jared T. Shaw*
The chemical synthesis of small molecules en masse has
emerged as a powerful tool to facilitate discoveries in biology
and medicine.[1] Screening in chemical biology often involves
the discovery of new cellular processes without prior knowl-
edge of the protein targets. As such, libraries of small
molecules that contain extensive skeletal and stereochemical
diversity will offer the greatest opportunity for discovery
across a variety of biological screens. Combinatorial techni-
ques using split/pool chemistry[2] have been widely employed
for the synthesis of small molecules, while advances in
chemical automation and other new techniques have enabled
the synthesis of large numbers of compounds in a parallel
fashion.[3] Despite many advances in library synthesis, the
efficient preparation of compounds with different core-atom
connectivity within the same library remains an important
challenge.[4]
We have addressed the challenge of synthesizing structur-
ally diverse small molecules by designing efficient linear
synthetic sequences that rely on the strategic manipulation of
a single functional group to determine the three-dimensional
array of the library members (Figure 1B). Synthetic
approaches that employ branching pathways[5] and “libraries
from libraries” (Figure 1A) have proven to be extremely
useful for the synthesis of complexlibraries employing a
variety of interesting transformations.[6] Our linear strategy
(Figure 1B) was developed to produce libraries of compara-
ble complexity by using fewer chemical manipulations.
Furthermore, our strategy complements “folding” processes[7]
by producing compounds with a comparable level of struc-
tural diversity from a single solid-phase starting material.
To demonstrate the efficacy of this strategy, we designed a
short, linear sequence that exploits a key bond construction
Figure 1. Schematic diagram that compares two strategies for the
production of structurallycomplex libraries.
between proximal functional groups (Scheme 1). The first
step employs an enantioselective variant of the addition of a
methoxy-substituted oxazole to an aromatic aldehyde. In this
step, the aldehyde may be substituted at the ortho position
with an azido or azidomethyl substituent. Next, the oxazoline
products are alkylated at the position a to the carbonyl group,
thus offering a second opportunity to incorporate an azido
substituent. The substrates bearing pendant azides are sub-
jected to a Staudinger-type reduction that results in sponta-
neous cyclization to the corresponding spirocyclic or fused
lactams. N-alkylation of the various lactams in a split/pool
manner affords the final products. In addition to the four
distinct structures produced by the divergent cyclization, we
envisioned the conversion of methyl ester 5 into a series of
amides 8 to produce a variety of structures that complement
the complexity of 7a–d.
Since many biological screening experiments are often
conducted without prior knowledge of the protein target, the
best chance for discovery emanates from libraries that present
a high level of structural diversity.[8] The importance of three-
dimensional shape on “biorelevant” structural diversity has
been predicted statistically[9] and demonstrated in a compar-
ison of cyclic and acyclic structures derived from carbohy-
drates.[10] To assess the overall structural diversity of the
structures in our library, we examined a scatter plot of the two
variable dihedral angles of the PM5-minimized structures of 7
and 8 (Figure 2). For each compound, the two dihedral angles
y and f of the oxazoline substituents are plotted on x and
y axes, respectively. Enantiomers are scored with equal and
opposite signs for y and f to account for the differential
interactions that might occur with a biological target.
Although 7 and 8 possess two stereocenters, only one
diastereomer is produced by our synthetic sequence.
[*] Dr. J. M. Mitchell, Dr. J. T. Shaw
Department of Chemical Biology
Broad Institute of Harvard and MIT
320 Bent Street, Cambridge, MA 02141 (USA)
Fax: (+1)617-324-9601
E-mail: shaw@broad.harvard.edu
[**] This work was conducted under the aegis of the Harvard Center for
Methodologyand LibraryDevelopment (NIGMS P50 GM069721).
J.T.S. thanks Amgen Pharmaceuticals for a New FacultyAward. We
thank Prof. Nabi Magomedov (Rochester University), Dr. Jacob
Janey(Merck), Prof. TimothyJ. Mitchison (Harvard Medical
School), and Professor Stuart Schreiber (Broad Institute) for
insightful discussions. The authors thank Max Narovlyansky for the
preparation of the solid support, Dr. Nicola J. Tolliday(Broad
Institute) for facilitation of screening, and Dr. Ralph Mazitschek
(Broad Institute) for assistance with molecular modeling.
The incorporation of acyclic 8, fused 7b,c, and spirocyclic
7a,d products in this library results in wide coverage of three-
dimensional space. The boatlike conformation adopted by
seven-membered ring lactams 7c and 7d results in signifi-
cantly different dihedral angles y and f relative to their six-
membered ring analogues 7a and 7b. In the cases of the
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Scheme 1. Summaryof the synthetic pathwaythat produces a libraryof complex products from oxazole 1. (
) indicates a split/pool step in
which multiple building blocks are incorporated.
acyclic 8 and spirocyclic 7a,d compounds, free rotation about
the C5–phenyl bond is restricted by the dense substitution at
C4 of the oxazoline ring.[11] Although a small molecule may
not bind to its target in the ground-state conformation, these
molecules are all sufficiently rigid that the comparison of the
dihedral angles y and f provides a starting point for the
evaluation of their structural diversity. Based on the broad
range of biological activities observed for oxazolines and
polycyclic lactams,[12] we expect this library of structurally
complexcompounds to provide interesting results in a variety
of biological screens.[13]
Our efforts commenced with development of a solid-
phase[14] variant of the Suga–Ibata reaction (Table 1).[15]
Several aluminum complexes were examined, and triflate
(OTf) complex 9 offered the best overall performance. While
À
the analogous SbF6 complexemployed by Evans and
others[15,16] is more reactive, a study of the temperature
profile[17] of this catalyst suggests that it degrades under the
higher reaction temperatures that are required for the solid-
phase reaction. The reactions of several standard substrates
(entries 1 and 4–6) and two azido aldehydes (entries 2 and 3)
proceeded in high yield and selectivity. The modest diaste-
reoselectivity (d.r.) of this reaction is alleviated in the
subsequent alkylation step (see below). Although our pre-
liminary studies were conducted with (R)-9, production of the
final library employs each enantiomer of this catalyst to
maximize the diversity of the products.
Alkylation of the oxazoline intermediates was achieved in
high yield and diastereoselectivity using strong, neutral
phosphazene bases (BEMP or BTPP) and reactive electro-
Figure 2. Structural diversityof compounds 7 and 8 as revealed bya
scatter plot that compares the dihedral angles y and f of (R)- and (S)-
7a–d and 8.
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Table 1: Suga–Ibata reactions of solid-phase oxazole 1.
A cyclization reaction between the strategically placed
azide and ester functional groups establishes the core-atom
connectivity of the final products. This key reduction/cycliza-
tion sequence was achieved under Staudinger-type conditions
with added base to facilitate ring closure (Scheme 2).[19]
A
1
EntryR
R2
R3 Conversion [%][a] ee [%][b] dr
1
2
3
4
5
6
H
N3
CH2N3
Br
Cl
H
H
H
H
H
OCH3
H
H
H
H
Cl
H
100
100
100
100
100
100
99
97
95
91:9[b]
88:12[b]
86:14[b]
84:16[a]
88:12[a]
88:12[a]
[c]
–
–
[c]
[c]
H
–
[a] Based on LCMS. [b] Based on chiral HPLC comparison to a racemic
reference compound prepared in solution. [c] Not determined.
Scheme 2. Cyclization of azido esters. Conversion of >95% (LCMS) is
observed in all cases. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
single set of conditions was developed that produced all of the
possible fused and spirocyclic lactams in > 95% conversion.
The full potential of our strategy was realized by employ-
ing the diverse lactam products 6a–d in a mix-and-split
alkylation of the amide NH functionality presented by all of
the core structures (Table 3). Once again, we found that the
philes (see Table 2).[18] Allylic and benzylic halides both
exhibit high conversion rates. Michael-type additions were
possible with phenyl vinyl sulfone or tert-butyl acrylate, while
2-nitrostyrene was not suitable. In all cases, > 94% diaster-
eoselection was observed, and the conditions were suitable
for both oxazoline and electrophile substrates containing the
azido or azidomethyl substituent.
Table 3: N-Acylation and alkylation of lactams 6a–d.[a]
Table 2: Alkylation of oxazoline 3 with various electrophiles.[a]
Lactam[a]
Electrophile
6a
50
100
100
6b
6c
75
100
100
6d
Ac2O[b]
PhCOCl[b]
PhCH2Br
–
62
100
100
100
100
EntryConversion
[%]
R1, R4, R5
E
100
100
100
76
CH3I
nPrBr
60
100
100
100
21
8
10
10
1[a]
2[a]
3
4
5
100
80
R1 =H, R4 =H, R5 =H
R1 =H, R4 =H, R5 =Br
R1 =H, R4 =Br, R5 =H
R1 =H, R4 =H, R5 =N3
R1 =H, R4 =H, R5 =CH2N3
R1 =N3, R4 =H, R5 =H
R1 =CH2N3, R4 =H, R5 =H
100
100
100
100
100
100
100
100
100
[a] Conversion (%) based on LCMS. [b] Base=Et3N, all others used
BTPP (see Table 2). NMP=1-methyl-2-pyrrolidone.
6
7
8[a]
9
100
86
R1 =H, R4 =H
R1 =H, R4 =Ph
neutral phosphazene bases were optimal for lactam alkyla-
tion, whereas more traditional conditions that employed
triethylamine were useful for acylation.[20] While each of the
four core structures exhibits a range of reactivity in the
alkylation and acylation reactions, successful reactions were
observed in 21 out of the 28 possible lactam/electrophile
combinations.[21]
10
11
12
100
100
<5
R1 =H, R4 =H, R5 =SO2Ph
R1 =H, R4 =H, R5 =CO2tBu
R1 =H, R4 =Ph, R5 =NO2
[a] BEMP used as the base, all others employed BTPP.
While the bulk of the structural complexity of this library
results from systematic placement of an azide substituent, the
esters 5 lacking an azide could be converted into a series of
amides in high yield (Scheme 3). The methyl ester was cleanly
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effective. This transformation yields compounds that comple-
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[11] Use of semiempirical calculations (PM5) to generate an energy
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variants of this linker were recently described which feature
Received: September 20, 2005
Published online: February 15, 2006
Keywords: asymmetric synthesis · combinatorial chemistry ·
.
lactams · synthetic methods
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