Syntheses of 5- and 6-[2,3]-dihydrobenzofuran β-amino acids

Article abstract of DOI:10.1016/S0040-4039(00)00965-5

Efficient stereoselective syntheses of 5- and 6-[2,3]-dihydrobenzofuran β-amino acids are described. These 3-aryl β-amino acids are aspartic acid mimetics that are structurally related to known benzodioxole systems. In many cases, the benzodioxole can inhibit and induce cytochrome P-450; neither of these dihydrobenzofuran β-amino esters is a potent inhibitor of several human P-450 enzymes. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00965-5

Tetrahedron Letters 41 (2000) 5803±5806
Syntheses of 5- and 6-[2,3]-dihydrobenzofuran b-amino acids
Paul J. Coleman,a,* John H. Hutchinson,a Cecilia A. Hunt,a Ping Lu,b
Enock Delaporteb and Tom Rushmoreb
aDepartment of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
bDepartment of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA
Received 6 April 2000; accepted 20 May 2000
Abstract
Ecient stereoselective syntheses of 5- and 6-[2,3]-dihydrobenzofuran b-amino acids are described. These
3-aryl b-amino acids are aspartic acid mimetics that are structurally related to known benzodioxole
systems. In many cases, the benzodioxole can inhibit and induce cytochrome P-450; neither of these
dihydrobenzofuran b-amino esters is a potent inhibitor of several human P-450 enzymes. # 2000 Elsevier
Science Ltd. All rights reserved.
b-Amino acids are constituents of many naturally-occurring peptides, terpenes and macrolides.
As synthetic intermediates, b-amino acids serve as important precursors to b-lactams. In the
course of synthesizing novel RGD (Arg-Gly-Asp) peptidomimetics containing 3-aryl-b-amino
acids, we1 and others2 have investigated the utility of 3-[5-(benzo-1,3-dioxole)]-b-alanine 1 as an
aspartic acid mimetic. While incorporation of b-amino acid 1 into RGD peptidomimetics can
lead to potent integrin receptor antagonists, the benzodioxole moiety in 1 has shown a propensity
to irreversibly bind to cytochrome P-450 isozymes via formation of a metallocarbene complex
between the dioxymethylene and the heme functions.3 Because of the potential metabolic lability
of the benzodioxole bicycle, we were interested in designing syntheses of the dihydrobenzofuran
b-alanines 2 and 3 as isosteric replacements for 1. Presumably, deletion of one of the two oxygen
atoms of the benzodioxole would prevent formation of P-450 carbene complexes. In this paper,
we describe ecient syntheses of the dihydrobenzofuran aspartic acid replacements 2a and 3a,
and evaluate their potential to inhibit cytochrome P-450.
* Corresponding author. Tel: 215 652 4618; fax: 215 652 7310; e-mail: paul_coleman@merck.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00965-5

5804
We planned to synthesize b-amino acid esters 2a and 3a by a diastereoselective heteroconjugate
addition of (R)-(+)-N-benzyl-a-methylbenzylamine to the b-benzofuranyl acrylates in accordance
with the Davies protocol (vide infra).4 This strategy required the syntheses of both the 5- and 6-
substituted benzofurans. Initially, we attempted to prepare the 6-bromobenzofuran 5 by cyclo-
dehydration of the 3-bromophenoxyacetaldehyde acetal 4 with polyphosphoric acid in re¯uxing
benzene (Scheme 1).5 This led to an inseparable mixture (ratio 1:1) of the 6- and 4-bromobenzo-
furans. The use of other Lewis acids (BF3±OEt2, BCl3, TiCl4) led to decomposition of 4 and none
of the desired cyclization products.
Scheme 1.
An alternative strategy for the selective synthesis of the 6-substituted benzofuran was pursued
(Scheme 2). Silylation of commercially available 6-hydroxybenzofuranone6 7 gave 8 with minimal
formation of the undesired enol silane.7 Reduction of the benzofuranone with diisobutylalumi-
num hydride provided the intermediate 3-hydroxy-6-silyloxy-[2,3]-dihydrobenzofuran, which was
heated in aqueous HCl/THF to e€ect dehydration of the benzylic hydroxyl group and subsequent
desilylation to give 6-hydroxybenzofuran 9. Phenol 9 was transformed to the tri¯ate 10 under
standard conditions. Heck coupling between 10 and ethyl acrylate with catalytic Pd(Ph3P)2Cl2
provided the 3-(6-[2,3]-dihydrobenzofuran)-2-propenoic acid ethyl ester 11. Heteroconjugate
addition of (R)-(+)-N-benzyl-a-methylbenzylamine via the Davies procedure a€orded 13 with
Scheme 2. Conditions: (a) TBSCl, Et3N, MeCN, 93%; (b) iBu2AlH, CH2Cl2, ^78ꢀC, then HCl/H2O/THF, 80%; (c) N-
PhNTf2, Et3N, CH2Cl2, 96%; (d) ethyl acrylate, Pd(Ph3P)2Cl2, Et3N, DMF, 90ꢀC, 62%; (e) R-(+)-benzyl-a-methyl-
benzylamine, n-BuLi, THF, ^78ꢀC, 72%; (f) Pd(OH)2, AcOH/H2O/EtOH, H2 (1 atm), then HCl/EtOAc/CH2Cl2, 75%

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excellent diastereoselectivity (>95:5).8 We have found the Davies procedure to be a highly
practical method for the diastereoselective synthesis of 3-aryl-b-amino acids. Hydrogenolysis of
the benzyl groups of 13 with Pearlman's catalyst occurred with concomitant furan reduction
to give the desired b-amino acid 2a.9 Alternatively, partial reduction of 13 under transfer
hydrogenation conditions (1,4-cyclohexadiene, Pd/C, AcOH) e€ected debenzylation of the amine
13 without saturation of the [2,3]-benzofuran.
Synthesis of the corresponding 5-[2,3]-dihydrobenzofuran b-amino acid 3a was accomplished
by an analogous synthetic sequence commencing with commercially available 5-benzofuran
carboxaldehyde.10
By our measurements (shown in Table 1), benzodioxole 1a is an inhibitor of human CYP3A4
(IC50=800 nM). As hoped, dihydrobenzofuran b-amino esters 2a and 3a display diminished
inhibitory potency for several human P-450 enzymes (CYP3A, CYP2C9, CYP2D6) compared to
1a.11
Table 1
Inhibition of human recombinant P-450 isozymes
Ecient syntheses of the isomeric b-amino esters 2a and 3a have been described. Oxygen atom
deletion from benzodioxole 1 provides isosteric dihydrobenzofuran b-amino esters 2a and 3a as
aspartic acid mimetics that are not potent P-450 inhibitors. Benzofuran b-alanines 2 and 3 should
have considerable utility in the syntheses of new integrin antagonists.
Acknowledgements
We thank Mark Duggan for helpful comments and Joy Hartzell for manuscript preparation.
References
1. Duggan, M. E.; Hartman, G. D.; Ho€man, W. F.; Meissner, R. S.; Perkins, J. J.; Askew, B. C.; Coleman, P. J.;
Hutchinson, J. H.; Naylor-Olsen, A. D. US Patent 5,981,546, 9 November 1999.
2. (a) Zablocki, J. A.; Rico, J. G.; Garland, R. B.; Rogers, T. E.; Williams, K.; Schretzman, L. A.; Rao, S. A.; Bovy,
P. R.; Tjoeng, F. S.; Lindmark, R. J.; Toth, M. V.; Zupec, M. E.; McMackins, D. E.; Adams, S. P.; Miyano, M.;
Markos, C. S.; Milton, M. N.; Paulson, S.; Herin, M.; Jacqmin, P.; Nicholson, N. S.; Panzer-Knodle, S. G.; Haas,
N. F.; Page, J. D.; Szalony, J. A.; Taite, B. B.; Salyers, A. K.; King, L. W.; Campion, J. G.; Feigen, L. P. J. Med.
Chem. 1995, 38, 2378±2394. (b) Stilz, H. U.; Jablonka, B.; Just, M.; Knolle, J.; Paulus, E. F.; Zoller, G. J. Med.
Chem. 1996, 39, 2118±2122. (c) Hoekstra, W. J.; Maryano€, B. E.; Andrade-Gordon, P.; Cohen, J. H.; Constanzo,
M. J.; Damiano, B. P.; Haertlein, B. J.; Harris, B. D.; Kau€man, J. A.; Keane, P. M.; McComsey, D. F.; Villani,
F. J.; Yabut, S. C. Bioorg. Med. Chem. Lett. 1996, 6, 2371±2376.

5806
3. (a) Wilkinson, C. F.; Murray, M.; Marcus, C.; Dube, C. In Pestic. Chem.: Hum. Welfare Environ., Proc. 5th Int.
Congr. Pestic. Chem., Meeting Date 1982; Miyamoto, J.; Kearney, P. C., Eds.; Dept. Entomol., Cornell Univ.,
Ithaca, NY, USA. Pergamon: Oxford, 1983; Vol. 3, pp. 463±468. (b) Dahl, A. R.; Brezinski, D. A. Inhal. Toxicol.
Res. Inst., Albuquerque, NM, USA. Biochem. Pharmacol. 1985, 34(5), 631±636.
4. (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183. (b) Davies, S. G.; Garrido, N. M.; Ichihara,
O.; Walters, I. A. S. J. Chem. Soc., Chem. Commun. 1993, 1153.
5. Barker, P.; Finke, P.; Thompson, K. Synth. Commun. 1989, 19, 257±265.
6. Available from Lancaster Synthesis.
7. Silylation of the phenolic oxygen in 8 allows dissolution of 9 in organic solvents. Without protection, the metal
alkoxide derived from deprotonation of 8 is highly insoluble.
8. The stereoassignment of 12 as the (S)-diastereomer is based on the Davies precedent (see Ref. 3).
25
1
9. Data for ester 2a (HCl salt): ‰ꢀŠ +9.4 (c 0.02; MeOH); H NMR (300 MHz, MeOD) ꢁ 7.27 (d, J=7.5 Hz, 1H),
D
6.89 (dd, J=7.5, 1.8 Hz, 1H), 6.84 (d, J=1.8 Hz, 1H), 4.59 (m, 3H), 4.15 (q, J=7.5 Hz, 2H), 3.20 (t, J=8.4 Hz,
2H), 2.99 (m, 2H), 1.21 (t, J=7.5 Hz, 3H) ppm.
10. Commercially available 5-benzofuran carboxaldehyde (Maybridge Chemical Company) was (a) ole®nated
(carboethoxytriphenylphosphorane, 95%), followed by (b) heteroconjugate addition (R-(+)-benzyl-a-methyl-
benzylamine, n-BuLi, THF, 51%), and (c) hydrogenolysis (Pd(OH)2, H2, 91%) to provide ester 3a.
25
D
1
Data for ester 3a (HCl salt): ‰ꢀŠ +5.10 (c 0.05; MeOH); H NMR (300 MHz, MeOD) ꢁ 7.29 (s, 1H), 7.14 (dd,
J=8.1, 1.5 Hz, 1H), 6.73 (d, J=8.1 Hz, lH), 4.55 (t, J=8.7 Hz, 2H), 4.52 (m, 1H), 4.12 (q, J=7.5 Hz, 2H), 3.24 (t,
J=8.7 Hz, 2H), 2.92 (m, 2H), 1.19 (t, J=7.5 Hz, 3H) ppm.
11. Compounds 1a, 2a and 3a were incubated with 5±10 pmol of human recombinant CYP3A4, -2C9 and -2D6 in
phosphate bu€er (pH 7.4) containing an NADPH-generating system and isozyme-selective ¯uorogenic probes.
The probe substrates included 7-benzyloxy-4-(trimethyl)-coumarin at 20 mM for CYP3A4, 7-benzyloxy-4-
(trimethyl)-coumarin at 50 mM for CYP2C9 and 3-[2-(N,N-diethyl-N-methylamino)ethyl]-7-methoxy-4-
methylcoumarin at 1 mM for CYP2D6. The substrate concentrations correspond to the Km for the respective
isozyines. The reactions were carried out so that product formation was linear with protein concentration and
incubation time at 37ꢀC, and terminated by adding 75 ml of 80% acetonitrile/20% 0.5 M Tris. The ¯uorescent
products were quantitated with a SPECTRAmax1 Gemini Dual-Scanning Microplate Spectro¯uorometer
(Molecular Devices, Sunnyvale, CA) and the IC50 values obtained from a four-parameter logistic curve plotted
with Data Assistant (Microsoft Excel1).