Multicomponent assembly strategies for the synthesis of diverse tetrahydroisoquinoline scaffolds

Article abstract of DOI:10.1021/ol201739u

Several novel multicomponent assembly processes have been developed for the rapid and efficient assembly of various heterocyclic scaffolds bearing a tetrahydroisoquinoline core, each of which allows for facile derivatization to access a diverse array of compounds. This work led to the serendipitous discovery of a new method for the synthesis of a fused quinazolone ring system, which was applied to a one-step total synthesis of the quinazolinocarboline alkaloid rutaecarpine.

Full text of DOI:10.1021/ol201739u

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4542–4545
Multicomponent Assembly Strategies for the
Synthesis of Diverse Tetrahydroisoquinoline
Scaffolds
Brett A. Granger, Kyosuke Kaneda, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The Texas Institute for Drug and
Diagnostic Development, The University of Texas at Austin, Austin, Texas 78712,
United States
sfmartin@mail.utexas.edu
Received June 28, 2011
ABSTRACT
Several novel multicomponent assembly processes have been developed for the rapid and efficient assembly of various heterocyclic scaffolds
bearing a tetrahydroisoquinoline core, each of which allows for facile derivatization to access a diverse array of compounds. This work led to the
serendipitous discovery of a new method for the synthesis of a fused quinazolone ring system, which was applied to a one-step total synthesis of
the quinazolinocarboline alkaloid rutaecarpine.
The identification of potent and selective modulators of
biological pathways is a key step in studying fundamental
biology and discovering drug leads. Efforts to facilitate
access to such compounds have fueled the development
of several approaches for the generation of small mole-
cule libraries.1 Collections of small molecules containing
privileged scaffolds, which are skeletal frameworks that
bind to multiple receptors and display a wide range of
biological activities,2,3 often exhibit relatively high hit rates
in screening assays. Initial hits can then be modified by
introducing potency and selectivity enhancing substituents
to give derivatives that exhibit favorable physiochemical
properties.
We recently reported the design and development of a
novel strategy for diversity-oriented synthesis (DOS) that
featured a Mannich-type multicomponent assembly pro-
cess (MCAP), followed by various cyclization reactions
that were enabled by selective functional group pairing to
construct substituted heterocyclic ring systems.4À6 This
approach has been extended to the synthesis and diversi-
fication of compounds based on the benzodiazepine,
(1) (a) Brenner, S.; Lerner, R. A. Proc. Natl. Acad. Sci. U.S.A. 1992,
89, 5381–5383. (b) Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X. -Y.;
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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.
(4) For the first example of this process, see: Martin, S. F.; Benage,
B.; Hunter, J. E. J. Am. Chem. Soc. 1988, 110, 5925–5927.
(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.
(3) For leading references to privileged substructures, see: (a) Welsch,
M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14,
347–361. (b) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow,
J. W.; Pippin, D. A. Comb. Chem. High Throughput Screening 2004, 7,
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r
10.1021/ol201739u
Published on Web 08/11/2011
2011 American Chemical Society

tetrahydropyridine, and aryl piperidine scaffolds.7À9 We
now report a further expansion of this approach for DOS
and the development of several MCAPs that provide ready
access to various privileged structures fused to a tetrahy-
droisoquinoline core, which itself is found in molecules that
exhibit a wide array of biological activities, including antihy-
pertensive,10 antitumor,11 and antimalarial properties.12
We chose the readily available 7-bromodihydroisoqui-
noline (1)13 as the common input for these MCAPs,
because it allows for preparation of various derivatives
via cross-coupling reactions with the aryl bromide moiety
(Scheme 1). Inasmuch as compounds incorporating the
highlighted tricyclic ring system in 7 are known to be
potent R2-adrenoceptor antagonists,14 we sought to devel-
op an efficient entry to this ring system.
condensation with N-methylhydroxylamine gave an inter-
mediate nitrone that underwent facile 1,3-dipolar cycload-
dition to provide isoxazolidine 4 in 66% yield from 1; no
other stereoisomerswere isolated. The relativestereochem-
istry in 4 was unambiguously determined by single crystal
X-ray analysis. Notably, 4 is easily prepared on a multi-
gram scale without column chromatography. Subsequent
reduction of the lactam moiety in 4, followed by a Suzuki
cross-coupling, provided the biaryl isoxazolidine 6. Upon
treatment with nickel boride, 6 underwent N,O-bond
cleavage to give the secondary amine 7 in 90% yield.15
The amino group in 7 is an obvious point for further
diversification as illustrated by its reaction with 2-furoyl
chloride in the presence of triethylamine to furnish amide 8
in 77% yield.
We also wanted to explore methods for elaborating
heterocyclic rings directly onto the parent dihydroisoqui-
noline 1, and it occurred to us that appending a 1,4-
diazepine-2,5-dione ring might be of considerable use.
For example, N,N’-diphenethyl-1,4-diazepine-2,5-diones
(highlighted portion of 12) are of interest as inhibitors of
the UCB13-UEV enzyme complex and hence may be
useful as antitumor agents.16 Since 12 represents a novel,
constrained analog of these systems, we set to the task of
preparing such compounds via our MCAP/cyclization
strategy. In the event, reaction of 1 with silyl ketene acetal
Scheme 1. Synthesis and Diversification of 7
Scheme 2. Synthesis of 1,4-Diazepine-2,5-diones
Accordingly, treatment of 1 with trans-crotonyl chloride
and silyl enol ether 2 in the presence of a catalytic amount
of TMSOTf provided the aldehyde 3, which upon
(7) Donald, J. R.; Martin, S. F. Org. Lett. 2011, 13, 852–855.
(8) Sahn, J. J.; Su, J. Y.; Martin, S. F. Org. Lett. 2011, 13, 2590–2593.
(9) Hardy, S.; Martin, S. F. Org. Lett. 2011, 13, 3102–3105.
(10) Gavras, I.; Vlahakos, D.; Melby, J. C.; Gavras, H. J. Clin.
Pharm. 1984, 24, 343–350.
(11) Asaoka, T.; Yazawa, K.; Mikami, Y.; Takahashi, K. J. Antibiot.
1982, 35, 1708–1710.
(12) Francois, G.; Bringmann, G.; Phillipson, J. D.; Boyd, M. R.;
Assi, L. A.; Schneider, C.; Timperman, G. U.S. Patent No. 5,639,761,
1994.
9 and chloroacetyl chloride in the presence of a catalytic
amount of TMSOTf at À78 °C provided amide 10 in 89%
(13) (a) Worrall, D. E. Org. Synth. 1929, 9, 66. (b) Schumacher,
R. W.; Davidson, B. S. Tetrahedron 1999, 55, 935–942. (c) Mjalli,
A. M. M.; Gohimmukkula, D. R.; Tyagi, S. U.S. Patent No.
7,208,601, 2005.
(14) VanDyke, J. W., Jr.; Havera, H. J.; Johnson, R. D. J. Med.
Chem. 1971, 15, 91–93.
(15) Jones, A. D.; Knight, D. W.; Thornton, S. R. J. Chem. Soc.,
Perkin Trans. 1 1999, 3337–3344.
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Org. Lett., Vol. 13, No. 17, 2011
4543

yield (Scheme 2). When 10 was heated with primary alkyl
€
corresponding N-alkyl 1,4-diazepine-2,5-diones were ob-
tained. For example, reaction of 10 with 11 provided 12 in
69% yield. BuchwaldÀHartwig cross-coupling of 12 with
morpholine (13) gave amine 14 in 72% yield.
Toward incorporating this ring system in fused isoquino-
lines, 1 was first allowed to react with either zinc phenyl-
acetylide or ethynylmagnesium bromide in the presence of
TMSOTf (Scheme 4). The intermediate adducts were then
trapped with o-azidobenzoyl chloride, and upon warming
to room temperature, the amide thus produced readily
underwent a dipolar cycloaddition to furnish the novel
triazolo 1,5-benzodiazepin-2-ones 17 and 18 in 80% and
93% yields, respectively. Subsequent BuchwaldÀHartwig
or Suzuki cross-coupling reactions generated derivatives
21 and 22.
amines in the presence of Hunig’s base in CH3CN the
The molecular framework embodied in 15 and 16 (6,7-
dihydropyrimido[6,1-a]isoquinoline-2,4(3H,11bH)-dione)
is present in compounds that exhibit hypotensive and
diuretic effects.17 We were thus intrigued by the possibility
that we might exploit an MCAP/cyclization sequence to
access this ring system by a route that would be more
expedient than those previously reported.17a,18 Indeed,
sequential treatment of 1 with TMSOTf, the silyl ketene
acetal 9, and phenyl isocyanate provided 15 in 63% yield
(Scheme 3). Because an isocyanate is implemented as the
electrophilic component, this series of reactions represents
a significant expansion of our MCAP chemistry to give
products containing urea functionality. Preliminary stu-
dies using isothiocyanates as electrophilic inputs have not
been as successful. Compound 15 was further elaborated
via a Suzuki cross-coupling to give the aryl substituted
tricyclic scaffold 16 in 92% yield.
Scheme 4. Synthesis of Triazolo 1,5-Benzodiazepin-2-ones
Scheme 3. Synthesis of Dihydropyrimidine-2,4-diones
During initial experiments that were directed toward
developing the sequence outlined in Scheme 4, we dis-
covered that acylation of dihydroisoquinoline 23 with
o-azidobenzoyl chloride at room temperature, followed
by addition of ethynylmagnesium bromide, did not give
the expected amide 26; the benzaldehyde 24 and the
quinazolone 25 were obtained instead (Scheme 5).
Although 25 was isolated as a minor product, its forma-
tion suggested that we had serendipitously uncovered a
new entry to quinazolones, a heterocyclic ring system
present in a variety of pharmaceuticals and biologically
active natural products.3a,23
The 1,5-benzodiazepin-2-one framework is present in
many compounds that bind to multiple targets including
the interleukin-1β converting enzyme (ICE)19 and voltage-
gated potassium channels.20 More specifically, the triazolo
1,5-benzodiazepin-2-one scaffold, highlighted in 17 and
18, is present in compounds reported to inhibit serine
protease21 and to bind to the benzodiazepine receptor.22
(17) (a) Kaneko, H.; Nagatsuka, T. Jpn. Kokai Tokkyo Koho JP
45009467, 1971. (b) Lombardino, J. G.; McLaMore, W. M.; Laubach, G. D.
U.S. Patent No. 3,021,331, 1962.
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(19) Batchelor, M. J.; Bebbington, D.; Bemis, G. W.; Fridman,
W. H.; Gillespie, R. J.; Golec, J. M. C.; Gu, Y.; Lauffer, D. J.;
Livingston, D. J.; Matharu, S. S.; Mullican, M. D.; Murcko, M. A.;
Murdoch, R.; Nyce, P. L.; Robidoux, A. L. C.; Wannamaker, M. W.;
Wilson, K. Y.; Zelle, R. E. U.S. Patent No. 6,008,217, 1999.
(20) Clareman, D. A.; Liverton, N.; Selnick, G. G.; Smith, G. R. U.S.
Patent No. 5,726,171, 1998.
After some optimization, we found that treatment of 1
with o-azidobenzoyl chloride in 1,2-dichloroethane under
reflux provided quinazolone 27 in 62% yield (Scheme 6); no
1
aldehyde was observed in the H NMR spectrum of the
crude reaction mixture. To the best of our knowledge, this
represents the first example of an intramolecular cyclization
(21) Mohapatra, D. K.; Maity, P. K.; Shabab, M.; Khan, M. I.
Bioorg. Med. Chem. Lett. 2009, 19, 5241–5245.
(22) Bertelli, L.; Biagi, G.; Giorgi, I.; Livi, O.; Manera, C.; Scartoni,
V.; Martini, C.; Giannaccini, G.; Trincavelli, L.; Barili, P. L. Farmaco
1998, 53, 305–311.
(23) (a) Hughes, A. N.; Rafi, I.; Griffin, M. J.; Calvert, A. H.; Newell,
D. R.; Calvete, J. A.; Johnston, A.; Clendeninn, N.; Body, A. V. Clin.
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419.
4544
Org. Lett., Vol. 13, No. 17, 2011

in dichloromethane delivered rutaecarpine (30) in 58%
yield (Scheme 7).24a,28
Scheme 5. Formation of Quinazolone 25 as a Minor Side
Product
Scheme 7. Total Synthesis of Rutaecarpine (30)
In summary, we have developed several new MCAPs for
the rapid synthesis of complex heterocyclic scaffolds in which
tetrahydroisoquinolines are fused to 1,4-diazepine-2,5-dione,
dihydropyrimidine-2,4-dione, 1,5-benzodiazepin-2-one, and
quinazolone rings. These heterocycles bear functionality that
may be further exploited in a variety of cross-coupling reac-
tions to generate small compound libraries for submission to
the NIH Molecular Libraries Small Molecule Repository
(MLSMR). An important feature of this approach to DOS
is that the members of these libraries typically have clog P
values in the approximate range of 3.0À4.5; these compounds
thus have excellent promise as potential leads. We also
discovered a novel method to form fused quinazolone rings
and have applied this discovery to a one-step synthesis of the
quinazolinocarboline alkaloid rutaecarpine. Significantly,
these novel reaction sequences can be applied to other imines,
including those that are generated in situ by four-component
assembly processes we have previously reported.6À9 Further
applications of this and related approaches to the syntheses of
unique compound libraries are in progress, and the results of
these investigations will be reported in due course.
of an organic azide onto a putative N-acyliminium ion to
form a quinazolone.24 Subsequent Suzuki cross-coupling of
27 provided the biaryl quinazolone 28 in 94% yield.
Scheme 6. Synthesis of Quinazolones 27 and 28
In order to showcase the utility of this novel route to
quinazolones, we applied it to a one-step synthesis of the
quinazolinocarboline alkaloid rutaecarpine (30). Rutae-
carpine was isolated from the dried, unripe fruit of Evodia
rutaecarpa and displays various biological activities in-
cluding being a potent and selective inhibitor of cyto-
chrome P450 in human liver microsomes.25,26 Simply
treating dihydro-β-carboline hydrochloride (29)27 with
Acknowledgment. We thank the National Institutes of
Health (GM 24539 and 86192) and the Robert A. Welch
Foundation (F-0652) for their generous support of this
work. Wealsothank Dr. Vincent Lynch(The Universityof
Texas at Austin) for performing X-ray crystallography.
Supporting Information Available. Experimental proce-
dures, spectral data and copies of 1H and 13C NMR spectra
for all new compounds, and the CIF file for 4. Thismaterialis
available free of charge via the Internet at http://pubs.acs.org.
€
o-azidobenzoyl chloride in the presence of Hunig’s base
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