Facile and unified approach to skeletally diverse, privileged scaffolds

Article abstract of DOI:10.1021/ol200709h

A novel strategy has been developed to generate a diverse array of privileged scaffolds from readily available tetrahydropyridine precursors that may be prepared by a multicomponent assembly process followed by a ring-closing metathesis. The functionality embedded in these key intermediates enables their facile elaboration into more complex structures of biological relevance by a variety of ring-forming processes and refunctionalizations.

Full text of DOI:10.1021/ol200709h

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2590–2593
Facile and Unified Approach to Skeletally
Diverse, Privileged Scaffolds
James J. Sahn, Justin Y. Su, and Stephen F. Martin*
Department of Chemistry and Biochemistry and The Texas Institute for Drug and
Diagnostic Development, The University of Texas at Austin, Austin Texas 78712,
United States
sfmartin@mail.utexas.edu
Received March 16, 2011
ABSTRACT
A novel strategy has been developed to generate a diverse array of privileged scaffolds from readily available tetrahydropyridine precursors that
may be prepared by a multicomponent assembly process followed by a ring-closing metathesis. The functionality embedded in these key
intermediates enables their facile elaboration into more complex structures of biological relevance by a variety of ring-forming processes and
refunctionalizations.
The demand to identify new, selective agents to treat
human diseases and to serve as tools to interrogate biolo-
gical function has led to various approaches for generating
molecular libraries for biological screening. Although
traditional combinatorial synthesis has been employed to
produce large numbers ofnovelcompounds, these libraries
have historically suffered from low hit rates and poor
specificity, a consequence that has been attributed to poor
physiochemical properties and insufficient structural di-
versity, coupled with a lack of stereocenters and molecular
rigidity.1 Accordingly, recent efforts in library design have
focused upon developing more effective strategies. For
example, libraries based on so-called privileged substruc-
tures typically exhibit higher hit rates in a variety of
biological assays.1,2 A single privileged scaffold can be
easily modified via manipulation of either functional
groups or ring substitution patterns. Because such altera-
tions often induce marked changes in potency and target
affinity, libraries based upon privileged scaffolds are well-
suited for identifying new lead compounds for drug
discovery.
(1) (a) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin.
Chem. Biol. 2010, 14, 347–361. (b) Feher, M.; Schmidt, J. M. J. Chem.
Inf. Comput. Sci. 2003, 43, 218–227.
We recently became interested in designing new strate-
gies for diversity-oriented synthesis (DOS)3 to prepare
collections of biologically active small molecules having
(2) For leading references to privileged substructures, see: (a) Evans,
B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel,
K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235–2246.
(b) Pippin, D. A.; Darrow, J. W.; Mitchell, S. A.; Currie, K. S.;
DeSimone, R. W. Comb. Chem. High Throughput Screening 2004, 7,
473–493. (c) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893–930. (d) Constantino, L.; Barlocco, D. Curr. Med. Chem.
2006, 13, 65–85.
(3) See for example: (a) Burke, M. D.; Schreiber, S. L. Angew. Chem.,
Int. Ed. 2004, 43, 46–58. (b) Tan, D. S. Nat. Chem. Biol. 2005, 1, 74–84.
(c) Spandl, R. J.; Bender, A.; Spring, D. R. Org. Biomol. Chem. 2008, 6,
1149–1158.
(4) For the first example of this process, see: Martin, S. F.; Benage,
B.; Geraci, L. S.; Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc. 1991,
113, 6161–6171.
r
10.1021/ol200709h
Published on Web 04/22/2011
2011 American Chemical Society

privileged ring systems as well as substructures found in
natural products. One such strategy combines a multi-
component assembly process (MCAP) involving three or
more reactants to prepare pivotal intermediates that are
transformed into heterocyclic scaffolds by various ring-
forming reactions that are directed by selective pairing of
functional groups.4ꢀ6 We have now developed a useful
extension of this strategy, wherein tetrahydropyridines,
which are accessed via a MCAP and a subsequent ring-
closing metathesis (RCM), are transformed into a number
of privileged scaffolds. We now present some of the details
of these investigations.
and biarylisoindolinones similar to 5ꢀ7 exhibit KDR
inhibitory activity.12 Indeed, biaryls are privileged scaf-
folds that are present in 4.3% of all known drugs.1,13
Scheme 2. Synthesis of Isoindolinone Scaffold 4 and Subsequent
Suzuki Cross-Coupling
To develop this new approach to scaffold generation, a
suitably functionalized tetrahydropyridine, such as 3, was
needed. Accordingly, reaction of 2-bromo-6-chlorobenzal-
dehyde (1),7 allylamine, CbzꢀCl, and allylzinc bromide in a
Mannich-like MCAP gave diene 2 in 89% yield (Scheme 1).
Cyclization of 2 via a RCM reaction delivered the pivotal
intermediate 3. Tactics for its elaboration into various
heterocyclic scaffolds, especially privileged substructures,
were then explored.
Tetrahydropyridine 3 underwent facile Heck cyclization
under Jeffrey’s conditions14 and microwave irradiation to
provide the enecarbamate 10, a versatile intermediate that
is nicely functionalized for a number of diversification
reactions (Scheme 3). For example, electron-rich enecar-
bamates are excellent inputs in imino DielsꢀAlder reac-
tions, such as the Povarov reaction.15,16 Although Povarov
reactions involving substrates having the structural com-
plexity of 10 are not known, we discovered that the
reaction of 10 with p-toluidine and ethyl glyoxylate in the
presence of Sc(OTf)3 gave a readily separable mixture
(1.2:1.0) of diastereomeric tetrahydroquinolines 11 and
12 in 84% yield. Formation of a mixture of stereoisomers
was not unexpected because Povarov reactions often
proceed with low stereoselectivity. The relative stereo-
chemistry of 11 was verified by single X-ray crystallo-
graphic analysis, whereas the structure of 12 was
Scheme 1. Synthesis of Tetrahydropyridine 3
The isoindolinone ring system, which is found in the
potent antiviral natural product stachyflin,8 is one impor-
tant member of the family of privileged scaffolds.9 Intri-
gued by the possibility of preparing isoindolinones from 3
via a Parham cyclization,10 we found that treatment of 3
with n-BuLi at ꢀ100 °C gave isoindolinone 4 in 60% yield
(Scheme 2). To illustrate possible tactics for diversifying 4,
it was subjected to Suzuki cross-coupling reactions with
electron-rich and electron-deficient arylboronic acids to
give biaryls 5 and 6; hydrogenation of 5 provided saturated
amide 7. Relative to possibilities for biological activity, it is
notable that cyclohexyl-fused isoindolinones similar to 4
possess potent urotensin-II receptor antagonist activity,11
tentatively assigned on the basis of a value of JH2ꢀH3
=
3.4 Hz, which is consistent with the proposed stereochem-
istry and not with the trans-diaxial relationship expected
for the C(3)-epimer.17 The indanyl quinoline 14, the
structure of which was secured by X-ray crystallography,
was also isolated in 5ꢀ10% yield; 14 is presumably
(5) For a review of such strategies, see: Sunderhaus, J. D.; Martin,
S. F. Chem.;Eur. J. 2009, 15, 1300–1308.
(6) (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett.
2007, 9, 4223–4226. (b) Sunderhaus, J. D.; Dockendorff, C.; Martin,
S. F. Tetrahedron 2009, 65, 6454–6469.
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Steinman, D. H.; Holmes, J. H.; Bousquet, P. J.; Cunha, G. A.; Moskey,
M. D.; Ahmed, A. A.; Pease, L. J.; Glaser, K. B.; Stewart, K. D.;
Davidsen, S. K.; Michaelides, M. R. Bioorg. Med. Chem. Lett. 2004, 14,
4505–4509.
(7) Rawalpally, T.; Ji, Y.; Shankar, A.; Edward, W.; Allen, J.; Jian,
Y.; Cleary, T. P.; Pierce, M. E. Org. Process Res. Dev. 2008, 12, 1293–
1298.
(8) Minagawa, K.; Kouzuki, S.; Kamigauchi, T. J. Antibiot. 2002, 55,
165–171.
(13) Hajduk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W. J. Med.
Chem. 2000, 43, 3443–3447.
(14) Jeffrey, T. Tetrahedron Lett. 1985, 26, 2667–2670.
(15) For reviews on the Povarov reaction, see: (a) Povarov, L. S.
Russ. Chem. Rev. 1967, 36, 656–670. (b) Glushkov, V. A.; Tolstikov,
A. G. Russ. Chem. Rev. 2008, 77, 137–159. (c) Kouznetsov, V. V.
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(9) Zhu, J.; Nueville, L.; Salcido, A. J. Org. Chem. 2008, 73, 3600–
3603.
(10) Parham, W. E.; Bradsher, C. K. Acc. Chem. Res. 1982, 15, 300–
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(11) Lawson, E. C.; Luci, D. K.; Ghosh, S.; Kinny, W. A.; Reynolds,
C. H.; Qi, J.; Smith, C. E.; Wang, Y.; Minor, L. K.; Haertlein, B. J.;
Parry, T. J.; Damiano, B. P.; Maryanoff, B. E. J. Med. Chem. 2009, 52,
7432–7445.
(16) (a) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913–2916. (b)
Yadav, J. S.; Reddy, B. V.; Sunitha, V.; Reddy, S. K.; Ramakrishna,
K. V. Tetrahedron Lett. 2004, 45, 7947–7950. (c) Hu, Y. J.; Tomaszewski,
M.; Walpole, C. PCT Int. Appl. WO 075476 A1 20050818, 2005.
(17) Adduct 12 undergoes spontaneous oxidation to 13 and could not
be isolated in pure form.
Org. Lett., Vol. 13, No. 10, 2011
2591

Scheme 3. Imino DielsꢀAlder Reaction of Enecarbamate 10
Scheme 4. Synthesis of Norbenzomorphan Analogues 16ꢀ19
benzoxazocine 23 that featured a ring-closing etherifi-
cation (Scheme 5). We first prepared the piperidine 21 as
a single diastereomer by highly selective vicinal dihy-
droxylation of 20 from the more hindered olefin face
formed from 11 and/or 12 via an elimination-oxidation
sequence.18 Oxidation of the mixture of 11 and 12 with
DDQ furnished 13 in 70% yield. It is noteworthy that
11ꢀ13 embody fused privileged substructures that can be
diversified through elaboration of multiple functional
handles.
Scheme 5. Tetrahydrobenzo[1,5]oxazocine 23 via an Intramo-
lecular Ullmann Etherification
The enecarbamate 10 can be easily converted into a
number of norbenzomorphans, a privileged skeleton whose
members exhibit a range of neurological activities such as
AChE inhibitory19 and codeine-like analgesic activity
(Scheme 4).20 In the event, the olefinic moiety in 10 was
first reduced selectively under ionic conditions to furnish 15
in 94% yield.21 Exemplary cross-coupling reactions of 15
with arylboronic acids and amines gave the biaryls 16 and 17
and the aniline 18 in good yield. In an application of a
known, but rarely used reaction,22 we found that treating 18
with TMSI, followed by workup with aqueous sodium
bicarbonate, yielded benzylamine 19.
Tetrahydrobenzo[1,5]oxazocines are known to exhibit a
diverse array of important biological properties, including
CNS and analgesic activity,23 as well as hepatitis C inhibi-
tory activity.24 Accordingly, we developed a novel entry to
such compounds as exemplified by a facile synthesis of
employing the conditions of Woodward.25 When 21 was
subjected to a copper-catalyzed intramolecular etheri-
fication,26 benzoxazocine 23 was obtained in 87% yield.
With both a free hydroxl group and protected nitrogen,
benzoxazocine 23 is ideally suited for analogue synthe-
sis, as exempified by allyl and benzyl ethers 24 and 25,
respectively.
Compounds containing the 1,2,3,4-tetrahydrobenzo[h]-
[1,6]naphthyridine motif exhibit a wide range of biological
properities, including selective 5-HT4 antagonist activity,27
gastric (Hþ/Kþ)-ATPase inhibition,28 and broad-spectrum
antibacterial activity.29 We thus queried whether we might
be able to access this ring system from 3 via double-bond
(18) For a similar transformation, see: Vincente-Garcıa, E.; Catti, F.;
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A.; Hedberg, K.; Ives, J.; Johnson, J.; Jones, S. J. Med. Chem. 1994, 37,
1996–2000.
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(21) Comins, D. L.; Weglarz, M. A. J. Org. Chem. 1991, 56, 2506–
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(25) Woodward, R. B.; Brutcher, F. V. J. Am. Chem. Soc. 1958, 80,
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(28) Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing, S. M.; Leach,
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(29) Inagaki, H.; Fujisawa, T.; Itoh, M.; Hayakawa, M.; Tsuda, T.
PCT Int. Appl. WO 125808 A1 20091510.
(22) D’Andrea, S. V.; Michalson, E. T.; Freeman, J. P.; Chidester, C.
G; Szmuskzkovicz, J. J. Org. Chem. 1991, 56, 3133–3137.
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S.; Ferreira, M.; Stansfield, I.; Mackay, A.; Conte, I.; Ercolani, C.;
Zaramella, S.; Palumbi, M.; Meuleman, P.; Leroux-Roels, G.; Giuliano,
C.; Fiore, F.; Di Marco, S.; Baiocco, P.; Koch, U.; Migliaccio, G.;
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Org. Lett., Vol. 13, No. 10, 2011

mixture of diastereomers. We initially tried to prepare the
pyridazine 35 from 34 by the acid-promoted removal of the
N-Boc protecting groups followed by oxidation using a
variety of oxidants. However, all of our efforts were
unsuccessful, and the diene 33 was invariably obtained in
near quantitative yield, presumably through a retro
DielsꢀAlder pathway involving extrusion of molecular
nitrogen. While exploring various alternative routes to
generate an aromatic pyridazine ring, we fortuitously
discovered that treatment of 34 with bromine provided
35 via an unprecedented tandem sequence of bromination,
N-Boc deprotection, and aromatization. Pyridazine 35
bears several functional handles for further elaboration
and derivatization.
Scheme 6. Preparation of Hydrobenzonaphthyridines 29 and 30
Scheme 7. Pyridazine 35 via a Tandem Bromination, Depro-
tection, Oxidation Sequence
isomerization, followed by a Povarov reaction. Thermal,
palladium-catalyzed isomerizations of tetrahydropyridines
to enecarbamates are known,30 but we found that heating 3
in the presence of 10% Pd/C using conventional heating
methods gave irreproducible yields of 26; reaction times
were also lengthy. On the other hand, when this reaction
was promoted with microwave heating (300 W, 120 °C), 26
was obtained in 77% yield after only 50 min; it is notable
that there was no observable loss of halogen under these
conditions (Scheme 6). When 26 was allowed to react with
ethyl glyoxylate and either o-bromoaniline or p-chloroani-
line in the presence of Sc(OTf)3, the corresponding tetra-
hydroquinolines 27 and 28 were formed as mixtures of
diastereomers in 80% and 73% yield, respectively. Oxida-
tion of 27 and 28 with DDQ gave the corresponding
tetrahydrobenzonaphthyridines 29 and 30, each of which
has multiple functional handles for further diversification.
Moreover, varying the aniline and aldehyde inputs in the
Povarov MCR would further expand the range of possible
analogues.
Pyridazines display a wide range of biological activities
and have shown promise as 11β-HSD1 inhibitors for
treating type II diabetes31 and as effective antitumor
agents.32 During the course of our efforts to synthesize
novel heterocyclic scaffolds for DOS, we sought to extend
our MCAP/RCM approach to access novel fused pyrida-
zine ring systems such as 35. The synthesis of this scaffold
began by preparing the enyne 32 using propargylamine in
an MCAP reaction (Scheme 7). A subsequent enyne RCM
proceeded in excellent yield to furnish the diene 33, which
underwent a DielsꢀAlder reaction with di-tert-butyl azo-
dicarboxylate to afford cycloadducts 34 as an inseparable
In summary, we have developed a novel strategy for the
diversity-oriented synthesis of a variety of heterocyclic
scaffolds, many of which embody privileged substructures
that are suitably functionalized for further diversification.
The key feature of the approach is a multicomponent
assembly process followed by a ring-closing metathesis to
give substituted tetrahydropyridines. These tetrahydro-
pyridines then serve as pivotal intermediates for the facile
generation of numerous functionalized scaffolds of biolo-
gical relevance. Further applications of this and related
approaches to the syntheses of novel compound libraries
are in progress, and the results of these investigations will
be reported in due course.
Acknowledgment. We thank the National Institutes of
Health (GM 86192) and the Robert A. Welch Foundation
(F-0652) for their generous support of this work. J.Y.S. is
grateful for a Pfizer Summer Undergraduate Research
Fellowship. We also thank Dr. Vince Lynch (The Uni-
versity of Texas) for performing X-ray analyses.
Supporting Information Available. Experimental pro-
1
(30) For example, see: Paintner, F. F.; Wanner, K. T. Tetrahedron
1994, 50, 3113–3122.
cedures, spectral data and copies of H NMR and 13C
(31) Amrein, K.; Hunziker, D.; Kuhn, B.; Mayweg, A. V.; Neidhart,
W.; Hoffmann-La Roche Inc.; U.S. Patent US 0010519 (A1), 2007.
(32) Kuroiwa, S.; Odanaka, J.; Maruyama, S.; Sato, Y.; Tomura, A.;
Sato, H.; Suzuki, Y. U.S. Patent US 7563893 (B2), 2009.
NMR spectra for all new compounds, and X-ray data for
11 and 14. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 10, 2011
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