Diversity-oriented synthesis of drug-like macrocyclic scaffolds using an orthogonal organo- and metal catalysis strategy

Article abstract of DOI:10.1002/anie.201406865

Small-molecule modulators of biological targets play a crucial role in biology and medicine. In this context, diversity-oriented synthesis (DOS) provides strategies toward generating small molecules with a broad range of unique scaffolds, and hence three-dimensionality, to target a broad area of biological space. In this study, an organocatalysisderived DOS library of macrocycles was synthesized by exploiting the pluripotency of aldehydes. The orthogonal combination of multiple diversity-generating organocatalytic steps with alkene metathesis enabled the synthesis of 51 distinct macrocyclic structures bearing 48 unique scaffolds in only two to four steps without the need for protecting groups. Furthermore, merging organocatalysis and alkene metathesis in a onepot protocol facilitated the synthesis of drug-like macrocycles with natural-product-like levels of shape diversity in a single step.

Full text of DOI:10.1002/anie.201406865

Angewandte
Chemie
DOI: 10.1002/anie.201406865
Synthetic Methods
Diversity-Oriented Synthesis of Drug-Like Macrocyclic Scaffolds
Using an Orthogonal Organo- and Metal Catalysis Strategy**
Andrꢀ Grossmann, Sean Bartlett, Matej Janecek, James T. Hodgkinson, and David R. Spring*
Dedicated to Professor Dieter Enders on the occasion of his retirement
Abstract: Small-molecule modulators of biological targets
play a crucial role in biology and medicine. In this context,
diversity-oriented synthesis (DOS) provides strategies toward
generating small molecules with a broad range of unique
scaffolds, and hence three-dimensionality, to target a broad
area of biological space. In this study, an organocatalysis-
derived DOS library of macrocycles was synthesized by
exploiting the pluripotency of aldehydes. The orthogonal
combination of multiple diversity-generating organocatalytic
steps with alkene metathesis enabled the synthesis of 51 distinct
macrocyclic structures bearing 48 unique scaffolds in only two
to four steps without the need for protecting groups. Further-
more, merging organocatalysis and alkene metathesis in a one-
pot protocol facilitated the synthesis of drug-like macrocycles
with natural-product-like levels of shape diversity in a single
step.
demonstrating a variety of concepts and hit discoveries.[17–24]
Recent work in this field has sought to increase the scaffold
diversity of libraries, as this is considered the most significant
principle component of diversity (others being appendage,
functional group, and stereochemical diversity).[8,9] In this
regard, the build/couple/pair (B/C/P) algorithm has been
established as a popular strategy[25–29] for the generation of
diverse scaffolds, while other methods such as oxidative ring
expansion,[30,31] fragment-based domain shuffling,[32] two-
directional synthesis,[33] and multi-dimensional coupling
have also been reported.[34] Very recently, these strategies
have been applied to the synthesis of macrocycles,[26–28,31–34]
which constitute attractive and underrepresented targets in
drug discovery. Macrocycles exhibit unique properties such as
conformational pre-organization as well as higher affinity and
selectivity for biological targets.[35]
In the outlined work, we report a new B/C/P-based
strategy (Scheme 1a) toward natural-product-like macrolac-
tones 5, utilizing building blocks 6–11 with self-orthogonal
handles for organo- and metal catalysis (Schemes 1b and 2).
We envisaged that the aldehydes and their organocatalytic
coupling partners (termed “alophile” building blocks) could
be prepared in one or two steps from commercially available
starting materials (Scheme 2). In this context, each “alophile”
group of molecules sharing a building block core was
synthesized from the same aldehyde precursor, introducing
structural diversity in the outlined synthetic approach as early
as in the build phase (Scheme 2a). For example, aldehyde 10
was transformed into enal 11, alcohol 13, b-ketoester 15, and
chalcone derivative 16 in moderate to excellent yields (55–
99%). In the build phase, six different classes of building
blocks were synthesized, ranging from aromatic (10–11, 13,
15, and 16) and heteroaromatic (17–20, and 23) to aliphatic
core structures (21 and 22).
I
n biology and medicine, small molecules are critical, for
example, in the study of signaling pathways and as potential
therapeutics.[1–6] However, the identification of small-mole-
cule modulators for a particular protein target, especially if its
structure is unknown, is nontrivial. The enormous size of
chemical space (estimated as more than 1060 stable small
molecules)[7] precludes the testing of all possible compounds
in a screening campaign, and the absence of structural
guidelines leads to debate over suitable selection criteria for
small-molecule libraries. In this respect, scaffold diversity,[8–11]
structural complexity,[6,8,12] and the fraction of sp3-hybridized
carbon atoms (Fsp3)[12–15] have been identified as important
selection. The efficient access to such structurally diverse
small molecules has been termed diversity-oriented synthesis
(DOS).[2–6,9,16]
Since the pioneering work of Schreiber,[16] many groups
have focused on the development of novel DOS strategies—
In the couple phase, considering the extensive number of
reported methodologies in the field of organocatalysis,[36] we
chose to focus on the use of N-heterocyclic carbenes (NHCs)
34–36 as organocatalysts. NHCs exhibit some unusual proper-
ties, enabling the “umpolung” of functional groups, for
example the conversion of the carbon atom in a or g position
of an aldehyde into a nucleophile.[37] Using this transforma-
tion to our advantage, ten unique coupling motifs were
accessible from aldehyde 10 or enal 11, as is demonstrated for
the phenolate building block (Scheme 3), which was subjected
to single-step transformations such as benzoin (24),[38] Stetter
(25),[39] or different redox-esterification reactions (27–29, 32,
and 33)[40–44] and cascade processes (30 and 31).[45,46] We found
that all coupling reactions gave the desired products in
[*] Dr. A. Grossmann, S. Bartlett, M. Janecek, Dr. J. T. Hodgkinson,
Prof. D. R. Spring
Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge CB2 1EW (UK)
E-mail: spring@ch.cam.ac.uk
Homepage: http://www-spring.ch.cam.ac.uk/
[**] Our work was supported by the European Union, Engineering and
Physical Sciences Research Council, Biotechnology and Biological
Sciences Research Council, Medical Research Council, Cancer
Research UK, and the Wellcome Trust. A.G. thanks the German
Research Foundation for a postdoctoral fellowship (GR 4429/1-1).
S.B. thanks the Herchel Smith Fund for a Ph.D. studentship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406865.
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Scheme 2. Building blocks. A) Diversification of aldehyde 10 toward
“alophile” components. B) Building blocks with different cores. Reac-
tion conditions: a) 12 (3 equiv), NaOMe, DMF/MeOH 2:1, reflux,
55%; b) NaBH4, NaHSO4, H2O, CH3CN, 81%; c) 14 (1 equiv), 4-NO2-
C6H4-B(OH)2 (2.5 mol%), toluene, 79%; d) acetophenone, EtOH/
SOCl2 10:1, 99%. DMF=N,N-dimethylformamide.
Scheme 1. Diversity through organo- and metal catalysis. A) The B/C/P
algorithm in the proposed strategy. B) Building blocks with pluripotent
and orthogonal functional groups.
synthetically useful yields (22–86%) prior to the optimization
of reaction conditions.
In order to access macrocycles that possess larger ring
sizes and hence, higher skeletal diversity in the DOS library,
self-orthogonal building blocks were used as branching points
(Scheme 4). In this context, diol 6, nitrostyrene 7, and
aldehyde 8 were modified regioselectively under NHC
catalysis and thus without the need for protection. Therefore,
after installation of the first coupling motif, the building block
chains in the intermediates 39, 42, and 9 were directly
extended according to a formal B/C/C algorithm. Moreover,
in the particular case of hydroxamic acid 9, the outlined
protocol was repeated a third time demonstrating a B/C/C/C
algorithm.
Scheme 3. Macrocycles with different coupling motifs accessible
through organocatalysis followed by ring-closing metathesis. For
clarity, only examples with the phenolate core and the major stereoiso-
mer are presented. Yields are shown of the purified product (organo-
catalytic coupling; ring-closing metathesis). Mes=mesityl. TMS=tri-
methylsilyl.
Finally, in the pair phase, the macrocyclization of the
constructed linear precursors was achieved through alkene
metathesis in moderate to excellent yield (33-99%), con-
structing 51 distinct polyether macrolactones.[47]
The synthesized DOS library of 51 macrocyclic com-
pounds was analyzed statistically in order to evaluate the
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Figure 1. Mean yields with respect to ring size for organocatalysis and
ring-closing metathesis steps. Numbers above the bars represent the
number of macrocycles of the corresponding ring size in the library.
set of macrocycles with two reference collections: an estab-
lished set of 40 top-selling drugs and 60 natural products.[31,34]
In the PMI analysis, our DOS library exhibited broad shape
diversity and more prominent spherical characteristics (com-
parable to that of the natural product reference set) than the
drug reference set, which is mostly confined to rod- and disc-
like shapes. In addition, PCA illustrated the pronounced
drug-like properties of our DOS library.
To further increase the step economy of the proposed B/
C/P methodology, we envisaged that under certain circum-
stances, the NHC-catalyzed coupling and alkene metathesis
steps could be combined in one pot.[48] However, it is known
that NHCs react quickly with late transition metals, thereby
decreasing their reactivity, and thus this combination of
catalyst types was very rarely investigated previously.[49,50]
Fortunately, we found that the Grubbs II catalyst 38 showed
no appreciable loss in activity in the presence of the NHCs
used. Therefore, we combined the NHC-catalyzed redox-
esterification and Ru-catalyzed alkene metathesis steps in
one pot (Scheme 5) to furnish macrocyclic lactone 50
smoothly and with comparable efficiency to the step-wise
protocol (36% versus 48% overall yield, respectively). It is
noteworthy that 50 strongly resembles natural products, for
example pondaplin (51), a phenyl propanoid with anti-cancer
properties.[51,52]
Scheme 4. Synthesis of macrocyclic scaffolds using B/C/C/P (A,B) and
B/C/C/C/P (C) algorithms. Reaction conditions: a) 35a (10 mol%),
NaOAc, CH2Cl2, 408C; b) 38 (10 mol%), CH2Cl2, reflux; c) PhNO
(1.0 equiv), 35a (10 mol%), TMEDA, CH2Cl2, RT; d) 35b (30 mol%),
KHCO3, toluene/MeOH 10:1, RT; e) 35a (10 mol%), TMEDA, CH2Cl2,
RT. Yields of isolated products (organocatalytic coupling; ring-closing
metathesis) after column chromatography are given in brackets.
TMEDA=N,N,N’,N’-tetramethylethylenediamine
In summary, we have demonstrated the efficient synthesis
of a DOS library of macrocyclic compounds using an
efficiency and diversity achieved using the demonstrated
strategy. First, the yields of all organocatalytic coupling and
alkene metathesis reactions were plotted in a histogram
(Figure 1). These yields were dependent on both the ring size
and functional groups present, with mean yields for each step
in excess of 50%, exemplifying the synthetic utility of the
presented methodology. Subsequently, the shape and chemo-
physical diversity of the DOS library was visualized in the
form of a principal moment-of-inertia plot (PMI; Supporting
Information, Figure S1) and a principal component analysis
plot (PCA; Figure S2) featuring 15 calculated chemo-physical
properties, respectively. In both instances, we compared our
Scheme 5. One-pot synthesis of macrolactone 50 through a combina-
tion of NHC-catalyzed redox-esterification and Grubbs II catalyzed
alkene metathesis. a) Yield of isolated product 50 as a mixture of E/Z
isomers after column chromatography. Comparative yields over two
steps using a stepwise protocol are given in brackets.
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Keywords: carbenes · macrocycles · metathesis ·
organocatalysis · synthetic methods
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Communications
Synthetic Methods
A. Grossmann, S. Bartlett, M. Janecek,
J. T. Hodgkinson,
D. R. Spring*
&&&& — &&&&
Diversity-Oriented Synthesis of Drug-Like
Macrocyclic Scaffolds Using an
Orthogonal Organo- and Metal Catalysis
Strategy
Hand in hand: The outlined diversity-
oriented synthesis of a library of macro-
cycles is based on the orthogonal com-
bination of multiple diversity-generating
organocatalytic steps with alkene meta-
thesis. In total, 51 macrocyclic structures
bearing 48 unique scaffolds, drug-like
chemophysical properties, and natural-
product-like shape diversity were synthe-
sized in only 2 to 4 steps without the need
for protecting groups.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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