Angewandte
Chemie
oriented synthesis are 1) the tandem
ring closing–opening–closing metathesis
reaction[30] (reaction o, step 3) to give
skeletally diverse tricyclic products (7-5-
7, 7-5-8) and 2) the formation of cis-
fused [3.2.1] bicyclic amines by oxidative
cleavage and tandem reductive amina-
tion with primary amines (reaction p,
step 4). In order to discover a new
antibiotic with a novel mode of action,
the diversity-oriented synthesis was
designed to populate new areas of
chemical space so that several of the
scaffolds generated are either rare or
have no known representation in nature
(e.g. the cis–trans-fused 7-5-7 tricycle
resulting from reaction o). Using the
chemistry shown in Scheme 1 and a
limited number of structurally diverse
building blocks, the diversity-oriented
synthesis was achieved of 242 small
molecules that have 18 molecular frame-
works among other unique structural
features. The library was made using
parallel synthetic techniques leading to
1–20 mg of each final product (molec-
ular-weight range 153–857, mean value
379 gmolꢀ1). All library members were
assessed for their identity and quality
and purified if necessary by recrystalli-
zation, chromatography, or extraction to
ensure greater than 90% purity of final
products (as determined by 1H NMR
spectroscopy, HPLC, and LCMS). Full
characterization of the majority (63%)
of the final compounds was undertaken;
1H NMR spectroscopy and LCMS char-
acterized the rest.
Scheme 1. Diversity-oriented synthesis of 242 compounds based on 18 discrete molecular
frameworks. Reagents and conditions: a) LiBr, 1,8-diazabicyclo[5.4.0]undec-7-ene, R1CHO,
MeCN; b) (R)-QUINAP, AgOAc, iPr2NEt, THF, ꢀ788C!258C; c) AD-mix, (DHQD)PHAL, THF/
H2O (1:1); d) chiral bis(oxazoline), Cu(OTf)2, 3 M.S., CH2Cl2, C5H6; e) R2COCl, DMAP,
pyridine, CH2Cl2; f) R3CHO, BH3·pyridine, MeOH; g) SOCl2, pyridine, CH2Cl2, 408C; h) R4Br,
Ag2O, CH2Cl2, 408C; i) R5C(O)R5, TsOH, DMF, 658C; j) R6CHO, TsOH, DMF, 658C; k) NaN3,
DMF, 1008C then dimethyl acetylenedicarboxylate, PhMe, 658C; l) mCPBA, CH2Cl2 then MeOH,
=
=
658C; m) CH2 CHCO2Bn, PhMe, 1208C, Grubbs II, CH2 CH2; n) OsO4, NMO, CH3C(O)CH3/
H2O (10:1); o) RNH2, Me2AlCl, PhMe 1208C; then NaH, R11X, DMF, THF; then PhMe, 1208C,
To assess the degree of overall
diversity obtained in this diversity-ori-
ented synthesis, we compared[24] the
structural diversity of our library to the
chemical space spanned by “benchmark
collections”: 1) known pharmacologi-
cally active small molecules (MDL
Drug Data Report database with a
molecular-weight cutoff of 650 gmolꢀ1
to compare size-independent diver-
7
=
Grubbs II, CH2 CH2; p) NaIO4, THF/H2O (1:1); then R NH2, NaB(OAc)3H, CH2Cl2; q) NaIO4,
THF/H2O (1:1); then R8NHR8, NaB(OAc)3H, CH2Cl2; r) R9CHO, DMF, TsOH, 608C;
s) R10C(O)R10, DMF, TsOH, 608C. DMF=N,N-dimethylformamide, THF=tetrahydrofuran,
DMAP=N,N-dimethylaminopyridine, (DHQD)PHAL=hydroquinidine 1,4-phthalazinediyl
diether, mCPBA=meta-chloroperbenzoic acid, Ts=para-toluenesulfonyl, Grubbs II=1,3-(bis-
(mesityl)-2-imidazolidinyl-idene) dichloro (phenylmethylene) (tricyclohexylphosphine) ruthe-
nium, NMO=4-methylmorpholine-N-oxide, OTf=CF3SO3, Bn=benzyl, QUINAP=1-(2-diphe-
nylphosphino-1-naphthyl)isoquinoline.
work. Later steps involved complexity-generating reactions to
diversify the molecular frameworks further and to release
divergently the compounds from the solid support. For
example, reaction b (step 2) involved the enantioselective
1,3-dipolar cycloaddition of 2 with a wide range of azome-
thine ylides complexed to Ag+ and (R)- or (S)-QUINAP and
subsequent acylation or alkylation of the resultant pyrrolidine
(reactions e and f, respectively),[27] and cleavage (step 4).
Norbornenes could be synthesized using Evansꢀs asym-
metric Diels–Alder methodology (reaction d)[29] and used in
divergent reactions l–o. Two highlights in the diversity-
sity),[31] 2) 3762 compounds marked as “antibacterials” in
the MDDR database,[32] and 3) a focused library (conven-
tional combinatorial chemistry).[33] A visual representation of
the diversity of the collections in “chemical space” is depicted
in Figure 1, and corresponding data are given in Table 1.
Describing each compound by a series of physicochemical
properties, followed by principal component analysis (PCA),
enables quantitative estimation of the diversity achieved on a
per-compound basis. Using this dataset, the DOS library,
numerically, is even more diverse than the MDDR com-
pounds, that is, 22 (relative) units for the DOS library, 19 for
Angew. Chem. Int. Ed. 2008, 47, 2808 –2812
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim