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Synlett 2006(18): 3037-3040  
DOI: 10.1055/s-2006-951522
LETTER
© Georg Thieme Verlag Stuttgart · New York

Structural Factors Governing Stereoselective Heck Reaction for the ­Construction of the Oxindole Portion of TMC-95A

Masayuki Inoue*a,b,c, Tomoaki Takahashia, Hidetomo Furuyamaa, Masahiro Hiramaa
a Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Fax: +81(22)7956566; e-Mail: inoue@ykbsc.chem.tohoku.ac.jp;
b Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
c PRESTO, Japan Science and Technology Agency, Sendai 980-8578, Japan
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Publication History

Received 23 March 2006
Publication Date:
25 October 2006 (online)

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Abstract

In our total synthesis of the potent proteasome inhibitor TMC-95A, we reported an efficient Z-selective Mizoroki-Heck reaction to produce a 3-alkylideneoxindole structure. In this paper, we investigated in detail the structural factors influencing this remarkable Z-selectivity using various structurally modified versions of the original substrate.

Key words

palladium - Heck reaction - cyclizations - indoles - peptides

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All the substrates described in this paper were prepared by a route similar to that published in ref. 2a.

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Typical Procedure (Entry 1, Table 1).
To a solution of (E)-2 (1.43 g, 2.36 mmol) and Et3N
(3.30 mL, 23.6 mmol) in THF (23.6 mL) was added Pd2(dba)3·CHCl3 (495 mg, 0.473 mmol) and NMP (23.6 mL). After being stirred for 5 min, the reaction mixture was diluted with EtOAc and quenched with H2O. The organic phase was separated and washed with H2O, sat. NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified with flash column chromatography to give (Z)-3 (1.04 g, 1.98 mmol, E/Z = 1:25, 84%). [α]D 25 -6.81 (c 1.65, MeOH). FT-IR (film): ν = 1731, 1574, 1470, 1371 cm-1. 1H NMR (500 MHz, CDCl3): δ = 1.33 (9 H, s, Boc), 1.49 (3 H, s, acetonide), 1.55 (3 H, s, acetonide), 1.64 (9 H, s, Boc), 3.81 (1 H, d, J = 9.5 Hz, H25), 4.32 (2/3 H, dd, J = 9.5, 8.5 Hz, H25), 4.38 (1/3 H, J = 9.5, 8.5 Hz, H25), 5.73 (1/3 H, dd, J = 9.5, 8.5 Hz, H8), 5.85 (2/3 H, dd, J = 9.5, 8.5 Hz, H8), 6.79 (2/3 H, d, J = 9.5 Hz, H7), 6.90 (1/3 H, d, J = 9.5 Hz, H7), 7.00 (1 H, dd, J = 8.0, 8.0 Hz, H3), 7.39 (1 H, d, J = 8.0 Hz, H4), 7.45 (1/3 H, d, J = 8.0 Hz, H2), 7.48 (2/3 H, d, J = 8.0 Hz, H2). 13C NMR (125 MHz, CDCl3): δ = 23.8, 24.8, 26.9, 27.7, 27.9, 28.5, 54.3, 56.0, 68.5, 69.0, 80.5, 80.9, 85.6, 94.2, 94.8, 106.8, 118.6, 119.1, 124.9, 125.2, 125.3, 125.8, 134.1, 134.3, 137.8, 144.1, 145.9, 148.2. 152.0, 165.5. HRMS (ESI): m/z calcd for C24H31BrN2NaO6 [M + Na]+: 545.1258; found: 545.1263.

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Addition of the palladium hydride to (Z)-3 would generate either C6-Pd or C7-Pd species. Isomerization of the olefin geometry is possible through syn-elimination of C6-Pd/C7-H or C7-Pd/C8-H and following reconjugation of the olefin.