DOI: 10.1002/cmdc.201100339
Application of Barluenga Boronic Coupling (BBC) to the Parallel Synthesis
of Drug-like and Drug Fragment-like Molecules
Shoko Nakagawa,*[a] Katie A. Bainbridge,[a] Ken Butcher,[a] Dave Ellis,[a] Wolfgang Klute,[a] and
Thomas Ryckmans*[a, b]
Library and array synthesis has proven an invaluable tool for
medicinal chemists to quickly assess key structure–activity rela-
tionships against a biological target. The main requirements
for the adoption of a given synthetic protocol are: 1) the avail-
ability of a diverse set of monomers (building blocks), 2) the re-
action should be adapted to the preparation of drug-like mole-
cules and thus should tolerate a wide range of functional
groups, and 3) the process should ideally be air- and moisture-
tolerant. As a consequence, the protocols used for library syn-
thesis have traditionally been biased toward polar bond forma-
tion, such as amide couplings.
However, emerging CÀC bond formation methodologies are
often crucial to establish new synthetic methods and discon-
nections, but publications in this field often focus on simplified
Figure 1. Distribution of synthetic protocols used for the synthesis of over
1300 libraries included in this survey, representing ~90000 compounds
substrates, yielding products of high lipophilicity (i.e., high
cLogP) and few functionalities such as hydrogen bond donors
or acceptors (i.e., low topological polar surface area (TPSA)).
High cLogP and low TPSA values are correlated with a range
of preclinical issues such as low solubility, promiscuity, and tox-
icity,[1] and have emerged as a key descriptors of drug-like-
ness[2,3] and drug fragment-likeness.[4–6] For these reasons, me-
dicinal chemists often find recently published CÀC bond for-
mation reactions ill-suited to generate new compounds with
good drug-like (“rule-of-five”) and drug fragment-like (“rule-of-
three”) properties. In a recent review, MacDonald et al.[7] ele-
gantly demonstrate that there is limited overlap between the
“synthetic space” described in recent synthetic communica-
tions and the “drug-like space” defined by the “rule-of-five”
and related approaches. To assess the diversity of reactions
used in parallel chemistry at our Pfizer research facility in Sand-
wich, we analyzed the protocols used for the preparation of
more than 1300 libraries over the last 18 months (2010–2011).
The protocols were pooled by bond-type formation (Figure 1).
N-Acylation reactions (in which we included amide, sulfona-
mide, urea, and carbamate formation) accounted for a signifi-
cant number (30%) of protocols. CÀN bond formation (includ-
ing N-alkylation, N-arylation, and reductive aminations) repre-
successfully prepared; overall success rate: 60%.
sented 18% of protocols. Heterocycle formation accounted for
9% of protocols, while CÀC bond formation (which includes
Suzuki and Stille couplings) was only used in 8% of protocols.
The category “other” (31%) captures both seldom-used reac-
tions and multistep reactions: for example, a combination of
the above protocols with protection/deprotection steps. These
results are roughly comparable to data gathered from the me-
dicinal chemistry literature, which show that CÀC bond forma-
tion reactions account for ~11% of the methods used to pre-
pare drug candidates.[8]
Interestingly, the overall success rates of CÀC bond forma-
tion protocols (67% success rate) used in our parallel synthesis
were similar to N-acylation (73% success rate) and CÀN (66%
success rate) bond formation protocols. Assuming all protocols
yield compounds with similar drug-like properties, these results
demonstrate that although robust CÀC bond formation proto-
cols are now available, this type of reaction is still underused
by medicinal chemists for the preparation of library com-
pounds.
In this context, the Barluenga boronic coupling[9] (BBC) re-
cently caught our attention. This novel reaction involves the
formation of a CÀC bond between a diazo compound (gener-
ated in situ from a para-toluenesulfonyl (tosyl) hydrazone) and
a boronic acid through a reductive coupling (Scheme 1). Of
special interest to us was the fact that a small number of ex-
amples (four out of 27) included polar functional groups such
as anilinic NH2 and NÀH heterocycles, and the synthesis of a
single small, highly polar drug-like molecule (compound 1)
was indeed exemplified. The average isolated yields are consis-
tently high (>80%) with only two examples <60% (two of
27). Given the ease of preparation of tosylhydrazones from a
[a] S. Nakagawa,+ K. A. Bainbridge, K. Butcher, Dr. D. Ellis, Dr. W. Klute,
Dr. T. Ryckmans+
Pfizer Worldwide Medicinal Chemistry
Ramsgate Road, Sandwich CT139NJ Kent (UK)
[b] Dr. T. Ryckmans+
Lundbeck A/S, Building G1/0345 Ottiliavej 9, 2500 Valby (Denmark)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
compounds 5–7, 8a–g, 9a–g, and 10a–g including analytical data.
ChemMedChem 2012, 7, 233 – 236
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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