Asymmetric Bronsted acid catalysis: Catalytic enantioselective synthesis of highly biologically active dihydroquinazolinones

Article abstract of DOI:10.1002/anie.200804770

(Chemical Equation Presented) Surprisingly straightforward: A metal-free, highly enantioselective Bronsted acid catalyzed condensation/addition reaction has been developed for the construction of 2,3-dihydroquinazolinones starting from 2-aminobenzamide an

Full text of DOI:10.1002/anie.200804770

Communications
DOI: 10.1002/anie.200804770
Asymmetric Synthesis
Asymmetric Brønsted Acid Catalysis: Catalytic Enantioselective
Synthesis of Highly Biologically Active Dihydroquinazolinones**
Magnus Rueping,* Andrey P. Antonchick, Erli Sugiono, and Konstantin Grenader
Dihydroquinazolinones are important heterocyclic com-
pounds which influence numerous cellular processes. They
display a broad range of biological, medicinal, and pharma-
cological properties and are constituents of antitumor, anti-
biotic, antidefibrillatory, antipyretic, analgesic, antihyper-
tonic, diuretic, antihistamine, antidepressant, and vasodilating
agents.[1]
materials, 2-aminobenzamide and the corresponding alde-
hydes [Eq. (1)]. We report herein the asymmetric, organo-
catalytic synthesis of these valuable enantiopure 2,3-dihydro-
quinazolinones by a one-step procedure using easily acces-
sible or commercially available starting materials.
In addition, 2,3-dihydroquinazolinones of type 1 have
been shown to act as potent tubulin inhibitors with impressive
On the basis of our previous successes in the field of
asymmetric ion-pair catalysis,[6] we started our investigations
with the Brønsted acid catalyzed reaction of 2-aminobenza-
mide (2) with various aldehydes 3 (Table 1). Initial studies
showed that the reaction can be carried out successfully using
phosphoric acid diesters as the catalyst. Therefore we decided
to explore chiral phosphoric acid diesters[7–10] 4a in this
transformation. This would then not only be the first example
of an asymmetric condensation/amine addition sequence of 2-
antiprolivative activity against several human cancer cell
lines, with IC50 values in the nanomolar concentration range.[2]
They act analogously to the antimitotic agent colchicine,[3] as
efficient inhibitors of tubulin polymerization.[4] In addition,
the 2,3-dihydroquinazolinones inhibit the binding of cholchi-
cine to a,b-tubulin.[5] In general, racemic mixtures of 1 have
been assayed; however, it has been shown recently that the S
enantiomer (S)-1 has significantly higher activity in the
inhibition of cholchinine binding and tubulin assembly. As
the S enantiomer could be prepared only by a multistep
diasteroselective synthesis sequence,[2] further investigations
into these highly efficient antitumoral agents were severely
restricted.
Table 1: Brønsted acid catalyzed enantioselective synthesis of 2,3-
dihydroquinazolinones in various solvents.
Given the importance of these valuable 2,3-dihydro-
quinazolinones[1–5] and in view of the significantly higher
activity of the S enantiomer, as well as the lack of efficient
methods for the preparation of these important active agents,
the development of a new catalytic asymmetric synthesis of
these compounds appeared to be of great importance. In this
context, we decided to investigate a metal-free, catalytic
enantioselective approach starting from the simplest starting
Entry[a]
R
Solvent
e.r. (S/R)[b]
1[c]
2[c]
H
H
H
H
H
H
H
OH
OH
OH
THF
Bu2O
72:28
81:18
87:13
84:16
86:14
93:7
92:8
99:1
99:1
93:7
3[c]
MTBE
benzene
toluene
CHCl3
CH2Cl2
toluene
CHCl3
CHCl3
4[c]
5[c]
6[c]
7[c]
[*] Prof. Dr. M. Rueping, Dr. A. P. Antonchick, Dr. E. Sugiono,
Dipl.-Chem. K. Grenader
8[d]
9[d]
10[c]
Degussa Endowed Professorship, Institute for Organic Chemistry
and Chemical Biology, Goethe-University Frankfurt
Max-von-Laue Strasse 7, 60438 Frankfurt am Main (Germany)
Fax: (+49)69-798-29248
[a] Reaction conditions: 2-Aminobenzamide (2), aldehyde 3a/b
(1.1 equiv), 4a (10 mol%), solvent (0.05m), and 3 ꢀ molecular sieves
at room temperature. [b] Enantiomeric ratios were determined by HPLC
on a chiral phase. [c] Enantiomeric ratios of the reaction mixtures after
column chromatography. [d] Enantiomeric ratio of the reaction solution.
MTBE=methyl tert-butyl ether.
[**] We acknowledge Evonik Degussa and the DFG (Priority Programme
Organocatalysis) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804770.
908
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 908 –910

Angewandte
Chemie
Table 3: Substrate scope[a,b] of the organocatalytic enantioselective syn-
aminobenzamide 2 and aldehydes 3, but also the first efficient
access to various enantioenriched 3-dihydroquinazolinones 1.
Indeed, our initial investigations proved that 2,3-dihydroqui-
nazolinone 1a and 1b could be obtained in very good
enantiomeric ratios (up to e.r. 99:1)[11] when the reactions
were performed in aromatic or halogenated solvents and in
the presence of chiral Brønsted acid 4a (Table 1, entries 4–
10). A detailed inspection of the reaction showed that a
heterogeneous reaction mixture was formed in the reaction of
2 with 3b. When the precipitate was removed by filtration or a
sample was taken from the supernatant for analysis, almost
enantiopure product was obtained (Table 1, entries 8 and 9).
Subsequent analysis of the precipitate revealed this corre-
sponded to product 1 with a lower enantiomeric ratio. The
unified and completely dissolved reaction mixture of 1b
thesis of dihydroquinazolinones 1.[13]
1a: e.r. 93:7, 86%
1 f: e.r. 90:10 (e.r. 99:1)[c], 93%
formed
, therefore, in lower overall enantioselectivity
1b: e.r. 93:7 (e.r. 99:1)[c,d], 86%
1g: e.r. 96:4, 85%
(Table 1, entry 10).[12,13] We decided to perform further
experiments in chloroform because of the generally better
solubility of both reactants and products. For most reaction
mixtures we observed homogeneous solutions, and typically,
better enantioselectivities could be obtained.
1c: e.r. 96:4, 87%
1h: e.r. 93:7 (e.r. 99:1)[d], 92%
To further optimize the reaction conditions, in addition to
the variation in temperature and catalyst loading, the chiral
phosphoric acid diesters 4a–f were tested (Table 2). The best
results with regard to selectivity and reactivity were obtained
using the Brønsted acid 4a in chloroform at room temper-
ature. At either lower temperatures or lower catalyst loading
(1 mol% 4a) similar enantioselectivity was obtained but the
reaction time was prolonged. With the optimized reaction
conditions in hand, we investigated the substrate scope of the
reaction. In general, for the first time, a number of different
aliphatic and aromatic aldehydes with electron-donating and
-withdrawing substituents were successfully applied in the
reaction with 2-aminobenzamide. The corresponding (S)-2,3-
dihydroquinazolinones 1a–1j were isolated in good yields
and excellent enantioselectivity (up to e.r. 99:1; Table 3).
1d: e.r. 93:7, 93%
1e: e.r. 90:10, 90%
1i: e.r. 93:7[c], 73%
1j: e.r. 90:10, 93%
[a] Reaction conditions: 2-Aminobenzamide (2), aldehyde 3a–j
(1.1 equiv), 4a (10 mol%), CHCl3 (0.05m), and 3 ꢀ molecular sieves at
room temperature. [b] Yield of isolated product after column chroma-
tography of reaction mixtures. Enantiomeric ratios were determined by
HPLC on a chiral phase. [c] Enantiomeric ratio of the chloroform reaction
solution. [d] Enantiomeric ratio of the toluene reaction solution.
Table 2: Evaluation of chiral Brønsted acids as catalysts in the new
reaction.
In summary, we report on the development of a new
metal-free, highly enantioselective, Brønsted acid catalyzed
condensation/amine addition reaction for the synthesis of 2,3-
dihydroquinazolinones starting from the simplest and most
readily available starting materials. Thus, a highly efficient
and general approach to valuable enantiomerically enriched
2,3-dihydroquinazolinones with preference for the more
active S enantiomers has been established. This extremely
simple and practical protocol is not only of great importance
and considerable interest for additional drug design and
development of dihydroquinazolinones, but it also simplifies
further examination of tubulin polymerization inhibition in
antitumor research. This in turn may provide insights into the
mechanism of the ligand binding at the colchicine binding site.
Moreover, certain dihydroquinazolinones show an inherent
fluorescence which allows explicit intracellular localization.
Entry[a]
Cat.
Ar
e.r. (S/R)[b]
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4 f
9-anthracenyl
1-naphthyl
2-naphthyl
9-phenanthryl
phenyl
93:7
73:27
58:42
72:28
55:45
75:25
53:47
4-biphenyl
3,5-(CF3)C6H3
4g
[a] Reaction conditions: 2-Aminobenzamide (2), benzaldehyde 3a
(1.1 equiv), 4 (10 mol%) CHCl3 (0.05m) and 3 ꢀ molecular sieves at
room temperature. [b] Enantiomeric ratios were determined by HPLC on
a chiral phase.
Angew. Chem. Int. Ed. 2009, 48, 908 –910
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
909

Communications
5356; c) S. Hoffmann, A. M. Seayad, B. List, Angew. Chem. 2005,
117, 7590; Angew. Chem. Int. Ed. 2005, 44, 7424; d) R. I. Storer,
D. E. Carrera, Y. Ni, D. W. C. MacMillan, J. Am. Chem. Soc.
2006, 128, 84; e) M. Terada, K. Sorimachi, D. Uraguchi, Synlett
2006, 133; f) M. Terada, K. Machioka, K. Sorimachi, Angew.
Chem. 2006, 118, 2312; Angew. Chem. Int. Ed. 2006, 45, 2254;
g) S. Mayer, B. List, Angew. Chem. 2006, 118, 4299; Angew.
Chem. Int. Ed. 2006, 45, 4193; h) J. Itoh, K. Fuchibe, T. Akiyama,
Angew. Chem. 2006, 118, 4914; Angew. Chem. Int. Ed. 2006, 45,
4796; i) S. Hoffmann, M. Nicoletti, B. List, J. Am. Chem. Soc.
2006, 128, 13074; j) N. J. A. Martin, B. List, J. Am. Chem. Soc.
2006, 128, 13368; k) T. Akiyama, H. Morita, K. Fuchibe, J. Am.
Chem. Soc. 2006, 128, 13070; l) H. Liu, L.-F. Cun, A.-Q. Mi, Y. Z.
Jiang, L. Z. Gong, Org. Lett. 2006, 8, 6023; m) M. Terada, K.
Sorimachi, J. Am. Chem. Soc. 2007, 129, 292; n) Q. Kang, Z.-A.
Zhao, S.-L. You, J. Am. Chem. Soc. 2007, 129, 1484; o) G. B.
Rowland, E. B. Rowland, Y. Liang, J. A. Perman, J. C. Antilla,
Org. Lett. 2007, 9, 2609; p) J. Zhou, B. List, J. Am. Chem. Soc.
2007, 129, 7498; q) G. Li, G. B. Rowland, E. B. Rowland, J. C.
Antilla, Org. Lett. 2007, 9, 4065; r) M. J. Wanner, R. N. S.
van der Haas, K. R. de Cuba, J. H. van Maarseveen, H. Hiem-
stra, Angew. Chem. 2007, 119, 7629; Angew. Chem. Int. Ed. 2007,
46, 7485; s) J. Jiang, J. Yu, X.-X. Sun, Q.-Q. Rao, L.-Z. Gong,
Angew. Chem. 2008, 120, 2492; Angew. Chem. Int. Ed. 2008, 47,
2458; t) S. Xu, Z. Wang, X. Zhang, X. Zhang, K. Ding, Angew.
Chem. 2008, 120, 2882; Angew. Chem. Int. Ed. 2008, 47, 2840;
u) M. Sickert, C. Schneider, Angew. Chem. 2008, 120, 3687;
Angew. Chem. Int. Ed. 2008, 47, 3631; v) D. S. Giera, M. Sickert,
C. Schneider, Org. Lett. 2008, 10, 4259; w) C. Baudequin, A.
Zamfir, S. B. Tsogoeva, Chem. Commun. 2008, 4637.
Additional studies on these aspects and further applications
of this reaction are topics of current investigations.
Received: September 30, 2008
Published online: December 19, 2008
Keywords: antitumor agents · inhibitors · organocatalysis ·
.
phosphoric acid diester
[1] a) H. L. Yale, M. Kalkstein, J. Med. Chem. 1967, 10, 334; b) G. L.
Neil, L. H. Li, H. H. Buskirk, T. E. Moxlcy, Cancer Chemother.
1972, 56, 163; c) G. Bonola, P. Da Re, M. J. Magistretti, E.
Massarani, I. Setnikar, J. Med. Chem. 1968, 11, 1136; d) Rexall
Drug Co. , K.S. Patent 3,257,397, 1966 [Chem. Abstr. 1966, 66,
8933b]; e) C. H. Boehringer Sohn, French Patent M 2588, 1964
[Chem. Abstr. 1964, 61, 16075h]; f) R. J. Alaimo, H. E. Russel, J.
Med. Chem. 1972, 15, 335; g) E. Cohen, B. Klarberg, J. R.
Vaughan, J. Am. Chem. Soc. 1959, 81, 5508; h) K. Okumura, T.
Oine, Y. Yamada, G. Hayashi, M. Nakama, J. Med. Chem. 1968,
11, 348; i) Instituto De Angeli S.p.A. , French Patent M 1893,
1963 [Chem. Abstr. 1964, 60, 3956]; j) J. I. Levin, P. S. Chan, T.
Bailey, A. S. Katocs, A. M. Venkatesan, Bioorg. Med. Chem.
Lett. 1994, 4, 1141.
[2] G. M. Chinigo, M. Paige, S. Grindrod, E. Hamel, S. Dakshana-
murthy, M. Chruszcz, W. Minor, M. L. Brown, J. Med. Chem.
2008, 51, 4620.
[3] For an excellent review of the synthesis of colchicine: T.
Graening, H.-G. Schmalz, Angew. Chem. 2004, 116, 3292;
Angew. Chem. Int. Ed. 2004, 43, 3230.
[8] VAPOL-phosphate catalyzed reaction: a) G. B. Rowland, H.
Zhang, E. B. Rowland, S. Chennamadhavuni, Y. Wang, J. C.
Antilla, J. Am. Chem. Soc. 2005, 127, 15696; b) Y. Liang, E. B.
Rowland, G. B. Rowland, J. A. Perman, J. C. Antilla, Chem.
Commun. 2007, 4477; c) G. Li, Y. Liang, J. C. Antilla, J. Am.
Chem. Soc. 2007, 129, 5830; d) E. B. Rowland, G. B. Rowland, E.
Rivera-Otero, J. C. Antilla, J. Am. Chem. Soc. 2007, 129, 12084.
[9] a) D. Nakashima, H. Yamamoto, J. Am. Chem. Soc. 2006, 128,
9626; b) P. Jiao, D. Nakashima, H. Yamamoto, Angew. Chem.
2008, 120, 2445; Angew. Chem. Int. Ed. 2008, 47, 2411; c) C. H.
Cheon, H. Yamamoto, J. Am. Chem. Soc. 2008, 130, 9246; d) D.
Enders, A. A. Narine, F. Toulgoat, T. Bisschops, Angew. Chem.
2008, 120, 5744; Angew. Chem. Int. Ed. 2008, 47, 5661.
[10] a) M. Rueping, W. Ieawsuwan, A. P. Antonchick, B. J. Nacht-
sheim, Angew. Chem. 2007, 119, 2143; Angew. Chem. Int. Ed.
2007, 46, 2097; b) M. Rueping, B. J. Nachtsheim, S. M. Moreth,
M. Bolte, Angew. Chem. 2008, 120, 603; Angew. Chem. Int. Ed.
2008, 47, 593; c) M. Rueping, T. Theissmann, A. Kuenkel, R. M.
Koenigs, Angew. Chem. 2008, 120, 6903; Angew. Chem. Int. Ed.
2008, 47, 6798.
[11] The absolute configuration of the products was assigned by
comparison of the optical rotation value of 1a with the value
reported in Ref. [2].
[12] The observation that the precipitate and reaction solution in
heterogeneous mixtures display different enantioselectivities is
not surprising. In such cases it is possible to obtain almost
enantiopure product by simple filtration. However, to determine
the true enantioselectivity of this reaction, we prepared the
HPLC sample from a solution of both the precipitate and the
supernatant.
[4] For an overview of tubulin as a target for anticancer drugs: a) A.
Jordan, J. A. Hadfield, N. J. Lawrence, A. T. McGown, Med. Res.
Rev. 1998, 18, 259; b) M. A. Jordan, L. Wilson, Nat. Rev. 2004, 4,
253; c) M. Arkin, Curr. Opin. Chem. Biol. 2005, 9, 317; d) A.
Nagle, W. Hur, N. S. Gray, Curr. Drug Targets 2006, 7, 305.
[5] M. J. Hour, L. J. Huang, S. C. Kuo, Y. Xia, K. Bastow, Y.
Nakanishi, E. Hamel, K. H. Lee, J. Med. Chem. 2000, 43, 4479.
[6] a) M. Rueping, E. Sugiono, C. Azap, T. Theissmann, M. Bolte,
Org. Lett. 2005, 7, 3781; b) M. Rueping, E. Sugiono, C. Azap,
Angew. Chem. 2006, 118, 2679; Angew. Chem. Int. Ed. 2006, 45,
2617; c) M. Rueping, A. P. Antonchick, T. Theissmann, Angew.
Chem. 2006, 118, 3765; Angew. Chem. Int. Ed. 2006, 45, 3683;
d) M. Rueping, A. P. Antonchick, T. Theissmann, Angew. Chem.
2006, 118, 6903; Angew. Chem. Int. Ed. 2006, 45, 6751; e) M.
Rueping, C. Azap, Angew. Chem. 2006, 118, 7996; Angew. Chem.
Int. Ed. 2006, 45, 7832; f) M. Rueping, E. Sugiono, T. Theiss-
mann, A. Kuenkel, A. Kꢀckritz, A. Pews Davtyan, N. Nemati,
M. Beller, Org. Lett. 2007, 9, 1065; g) M. Rueping, E. Sugiono,
F. R. Schoepke, Synlett 2007, 1441; h) M. Rueping, E. Sugiono,
S. A. Moreth, Adv. Synth. Catal. 2007, 349, 759; i) M. Rueping,
A. P. Antonchick, Angew. Chem. 2007, 119, 4646; Angew. Chem.
Int. Ed. 2007, 46, 4562; j) M. Rueping, A. P. Antonchick, C.
Brinkmann, Angew. Chem. 2007, 119, 7027; Angew. Chem. Int.
Ed. 2007, 46, 6903; k) M. Rueping, A. P. Antonchick, Org. Lett.
2008, 10, 1731; l) M. Rueping, T. Theissmann, S. Raja, J. W. Bats,
Adv. Synth. Catal. 2008, 350, 1001; m) M. Rueping, A. P.
Antonchick, Angew. Chem. 2008, 120, 5920; Angew. Chem. Int.
Ed. 2008, 47, 5836.
[7] For examples of the application of chiral phosphoric acid
diesters, see: a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe,
Angew. Chem. 2004, 116, 1592; Angew. Chem. Int. Ed. 2004, 43,
1566; b) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126,
[13] A detailed experimental procedure and characterization of all
products is given in the Supporting Information.
910
www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 908 –910