Skeletally diverse small molecules using a build/couple/pair strategy

Article abstract of DOI:10.1021/ol900173t

Intermolecular couplings of simple building blocks using catalytic, stereoselective cross-Mannich reactions followed by intramolecular functional group-pairing reactions of easily accessed variants of the Mannich products are explored as a route to skelet

Full text of DOI:10.1021/ol900173t

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1559-1562
Skeletally Diverse Small Molecules
Using a Build/Couple/Pair Strategy
Takuya Uchida,† Manuela Rodriquez,†,‡ and Stuart L. Schreiber†,*
Howard Hughes Medical Institute, Broad Institute of HarVard and MIT, 7 Cambridge
Center, Cambridge, Massachusetts 02142, Department of Chemistry and Chemical
Biology, HarVard UniVersity, Cambridge, Massachusetts 02138, and Department of
Pharmacological Sciences, UniVersity of Salerno, Via Ponte don Melillo,
84084 Fisciano, Italy
stuart_schreiber@harVard.edu
Received January 27, 2009
ABSTRACT
Intermolecular couplings of simple building blocks using catalytic, stereoselective cross-Mannich reactions followed by intramolecular functional
group-pairing reactions of easily accessed variants of the Mannich products are explored as a route to skeletally diverse small molecules. The
synthetic pathway yields products having 12 different skeletons using only three steps and has the potential to enable substantial stereochemical
diversification in the future.
Small molecules are widely used as probes in biology and
drugs in medicine.1 One approach to their discovery involves,
in part, an upfront investment in chemistry; specifically, the
complete synthesis of a transformative small-molecule
screening collection.2 The properties of compounds in such
a collection should possess have been discussed elsewhere,
as has a synthesis strategy that might facilitate their produc-
tion.3 We describe an application of this “build/couple/pair”
strategy here, illustrating how intramolecular, functional
group-pairing reactions can facilitate the synthesis of skel-
etally diverse small molecules. A recent application of this
strategy proved effective in generating stereochemically and
skeletally diverse small molecules, but the requirement for
a pre-existing stereogenic center in aldehyde-containing
building blocks, which imparted face selectivity during a
Petasis reaction, limited the diversity of steroisomers. In this
case, only one face of the imine was accessible to the
nucleophile, resulting in anti-diastereoselectivity.4 We rea-
soned that organocatalytic enantioselective additions to
electrophilic imines might increase the degree of stereo-
chemical diversity.5 Here, we explore the use of catalytic,
enantioselective Mannich reactions using achiral aldehydes
as the nucleophile in cross-coupling reactions of highly
electrophilic imines derived from primary amines and ethyl
glyoxylate.5b Although, in principle, recent advances in this
area would provide access to all four steroisomeric products,
we have in this study focused on the syn-diastereomeric
(4) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2006, 45, 3635–3638.
(5) (a) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem.
Soc. 2002, 124, 827–833. (b) Co´rdova, A.; Watanabe, S.; Tanaka, F.; Notz,
W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1866–1867. (c) Hayashi,
Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K. Angew.
Chem., Int. Ed. 2003, 42, 3677–3680. (d) Notz, W.; Tanaka, F.; Watanabe,
S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III.
J. Org. Chem. 2003, 68, 9624–9634. (e) Chowdari, N. S.; Suri, J. T.; Barbas,
C. F., III. Org. Lett. 2004, 6, 2507–2510. (f) Ibrahem, I.; Co´rdova, A. Chem.
Commun. 2006, 1760–1762. (g) Mitsumori, S.; Zhang, H.; Ha-Yeon Cheong,
P.; Houk, K. N.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006,
128, 1040–1041.
† Broad Institute of Harvard and MIT.
‡ University of Salerno.
(1) Schreiber, S. L. Nat. Chem. Biol. 2005, 1, 64–66.
(2) Spiegel, D. A.; Schroeder, F. C.; Duvall, J. R.; Schreiber, S. L. J. Am.
Chem. Soc. 2006, 128, 14766–14767.
(3) (a) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008,
47, 48–56. (b) Schreiber, S. L. Nature 2009, 457, 153–154.
10.1021/ol900173t CCC: $40.75
Published on Web 03/10/2009
2009 American Chemical Society

products. Our initial aim was to establish conditions that
permit (1) the attachment of functional groups to the amine
and aldehyde functionalities and (2) intramolecular, func-
tional group-pairing reactions that would result in products
having diverse skeletons (Scheme 1).
Scheme 2. Cyclizations of N-Alkylated Intermediates
Scheme 1
.
Build/Couple/Pair Strategy Yielding Skeletally
Diverse Small Molecules
We initiated the current research with commercially
available achiral reagents 1, 2, and 3 to minimize the overall
number of synthetic steps (Scheme 2). Stereochemical control
of the coupling step was achieved by using an organocatalytic
asymmetric cross-Mannich reaction.5b (As noted, extensions
of this chemistry should exploit the full potential of
analogous enantio- and diastereoselective Mannich reactions
coupled to analogous derivatization and cyclization reactions.
Such reactions would enable the synthesis of both stere-
ochemically and skeletally diverse products, provided that
the cyclization reactions proceed with both diastereomeric
Mannich products.)
The first reaction was a three-component, cross-Mannich
reaction using a simple aldehyde to afford the syn-product
4 stereoselectively in 72% yield. A one-pot Wittig reaction
proceeded at room temperature and gave E-alkene 5 with
high stereoselectivity in 69% yield. The E-alkene 5 was also
alkylated to give 6, 8, and 11. Benzyl compound 6 was
cyclized by using a Heck reaction to give 6/7-fused bicyclic
compound 7 in 79% yield. Allyl compound 8 was cyclized
by using another Heck reaction to give diene 9 in 42% yield6
or a one-pot Heck/Diels-Alder-cascade sequence to give
tricyclic compound 10 with a 5/6/6-fused ring system.
The structure of 10 was confirmed by X-ray crystal-
lographic analysis. A Pauson-Khand reaction of propargyl
compound 11 proceeded diastereoselectively to give azabi-
cyclo compound 12.7
The E-alkene 5 was further transformed via one-pot
acylations to give 13 and 14 in 57% and 50% yields,
respectively (Scheme 3). Attempts to achieve microwave-
assisted intramolecular Diels-Alder reactions using furans
13 and 14 gave poor results when performed below 200 °C.
Above this temperature only diesters 15 and 16, resulting
(6) Nagasawa, K.; Ishihara, H.; Zako, Y.; Shimizu, I. J. Org. Chem.
1993, 58, 2523–2529.
(7) Gu¨nter, M.; Gais, H.-J. J. Org. Chem. 2003, 68, 8037–8041.
1560
Org. Lett., Vol. 11, No. 7, 2009

We next investigated a reaction sequence where the
aminoaldehyde 4 was acylated to form a urea in the second
step (Scheme 5).
Scheme 3. Cyclizations of N-Acylated Intermediates
Scheme 5. Cyclizations of N-Acylaminoaldehyde Derivatives
from cyclization, olefin isomerization, and epimerization,
were isolated.8 The stereochemistry of tricyclic compound
15 was confirmed by X-ray crystallographic analysis.
Next, we examined a sequence where the amine moiety
of aminoaldehyde 4 was acylated in the second step (Scheme
4). A hydrazone of 17 was transformed to give lactam 18
Following urea formation and mild acidic treatment,
aminoaldehyde 4 was converted into cyclic compounds 20
and 21. The hemiaminal 20 was obtained as an inseparable
mixture of R-OH and ꢀ-OH (R/ꢀ ) 4.9) and was converted
into compound 21 following treatment with aqueous TFA.
The hemiaminal 20 was also converted into the bridged
bicycle 22 by Weinreb amidation and in situ cyclization.11
Compound 21 was converted into the tricycle 23 by a
Pictet-Spengler reaction under conditions more acidic than
those required to form 21.12 After column chromatography,
23 was obtained as a single isomer in 67% yield. This
structure was confirmed by X-ray crystallographic analysis.
Scheme 4. Cyclizations of N-Acylaminoaldehyde Derivatives
(8) (a) Cooper, J. A.; Cornwall, P.; Dell, C. P.; Knight, D. W.
Tetrahedron Lett. 1988, 29, 2107–2110. (b) Kappe, C. O.; Murphree, S. S.;
Padwa, A. Tetrahedron 1997, 53, 14179–14233.
(9) (a) Snider, B. B.; Conn, R. S. E.; Sealfon, S. J. Org. Chem. 1979,
44, 218–221. (b) Grigg, R.; Dowling, M.; Jordan, M. W.; Sridharan, V.
Tetrahedron 1987, 43, 5873–5886. Lactam 18a was also obtained in 11%
yield. It was probably formed via azo-hydrazo prototropy reaction of 18,
followed by 6-exo-trig cyclization.
presumably via either an intramolecular Michael addition or
an ene reaction.9 A nitrone derived from 17 underwent an
intramolecular 1,3-dipolar cycloaddition to give the fused
isoxazolidine 19 in 65% yield.10 Compound 19 was obtained
as a single isomer, and the assignment of its stereochemistry
was based on NOESY experiments.
Furthermore, a hydrazone of 17 underwent intramolecular 1,3-dipolar
cycloaddition reaction via hydrazone-azomethine imine isomerization to
afford the fused pyrazolidine 18b in 9% yield.
(10) (a) Noguchi, M.; Okada, H.; Tanaka, M.; Matsumoto, S.; Kakehi,
A.; Yamamoto, H. Bull. Chem. Soc. Jpn. 2001, 74, 917–925. (b) Shing,
T. K. M.; Wong, A. W. F.; Ikeno, T.; Yamada, T. J. Org. Chem. 2006, 71,
3253–3263.
Org. Lett., Vol. 11, No. 7, 2009
1561

In conclusion, using a syn-selective cross-Mannich reaction
in the context of the build/couple/pair strategy, we obtained
skeletally diverse small molecules with 12 different skeletons
within three steps starting from commercially available
reagents. In addition to incorporating the compounds now
available by the pathway described here into the Broad
Institute screening collection, we aim to use this strategy
with enantio- and diastereomeric products resulting from syn-
and anti-selective Mannich reactions.5 Results of small-
molecule screens using the compounds synthesized here and
in the future will be made available on the public database
ChemBank.13
research. The authors acknowledge Dr. Douglas M. Ho, Dr.
Jingwei Huang, and Dr. Richard J. Staples of the Department
of Chemistry and Chemical Biology, Harvard University for
X-ray crystallographic analysis. T.U. is a postdoctoral fellow
sponsored by Daiichi Sankyo Co., Ltd. S.L.S. is a Howard
Hughes Medical Institute Investigator.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900173T
Acknowledgment. The NIGMS-sponsored Center of
Excellence in Chemical Methodology and Library Design
(Broad Institute CMLD; P50 GM069721) funded this
(12) Nielsen, T. E.; Meldal, M. J. Comb. Chem. 2005, 7, 599–610.
(13) (a) Strausberg, R. L.; Schreiber, S. L. Science 2003, 300, 294–
295. (b) Seiler, K. P.; George, G. A.; Happ, M. P.; Bodycombe, N. E.;
Carrinski, H. A.; Norton, S.; Brudz, S.; Sullivan, J. P.; Muhlich, J.; Serrano,
M.; Ferraiolo, P.; Tolliday, N. J.; Schreiber, S. L.; Clemons, P. A. Nucleic
Acids Res. 2008, 36, D351–D359.
(11) Lie´by-Muller, F.; Constantieux, T.; Rodriguez, J. J. Am. Chem. Soc.
2005, 127, 17176–17177.
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