Synlett 2017; 28(19): 2655-2659
DOI: 10.1055/s-0036-1588518
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the Verapamil Intermediate through the Quaternary Carbon-Constructing Allylic Substitution

Yuichi Kobayashi*, Ryohei Saeki, Yutaro Nanba, Yuta Suganuma, Masao Morita, Keita Nishimura
  • Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan   Email: ykobayas@bio.titech.ac.jp
This work was supported by JSPS KAKENHI Grant Number 26410111 and the Kobayashi International Scholarship
Further Information

Publication History

Received: 08 May 2017

Accepted after revision: 04 July 2017

Publication Date:
08 August 2017 (eFirst)

Abstract

In the present study, the key secondary allylic picolinate was synthesized via Pd(PPh3)4-catalyzed coupling of the TBS ether of (R,Z)-4-iodo-5-methylhex-3-en-2-ol with allyl-MgBr. Allylic substitution of the picolinate with the copper reagent derived from 3,4-(MeO)2C6H3MgBr and Cu(acac)2 in a 2:1 ratio afforded the anti SN2′ product with complete chirality transfer and 91% regioselectivity. Synthetic manipulation of the olefin moiety led to the nitrile group, generating the intermediate for the synthesis of (S)-verapamil.

Supporting Information

 
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  • 21 To an ice-cold suspension of Cu(acac)2 (437 mg, 1.67 mmol) in THF (10 mL) was added a solution of 3,4-3,4-(MeO)2C6H3MgBr (20, 0.46 M in THF, 7.12 mL, 3.28 mmol) dropwise. The mixture was stirred at 0 °C for 30 min and cooled to –40 °C. A THF solution (2 mL) of picolinate 19 (107 mg, 0.273 mmol) derived from (R)-16 of 96% ee was added to the mixture, which was warmed to –20 °C over 2 h, stirred at –20 °C overnight, and diluted with sat. NH4Cl. The product 21 was extracted with EtOAc three times and passed through a short silica gel column (hexane/EtOAc) to afford 21. 1H NMR (400 MHz, CDCl3): δ = 0.71 (d, J = 6.8 Hz, 3 H), 0.84 (d, J = 6.8 Hz, 3 H), 1.81 (d, J = 5.1 Hz, 3 H), 3.46 (t, J = 6.3 Hz, 2 H), 5.52 (dq, J = 16.0, 5.1 Hz, 1 H), 5.58 (d, J = 16.0 Hz, 1 H). Further conversion of 21 into 2 (28 mg, 37% from picolinate 19) was described in the Supporting Information: [α]D 20 –11 (c 0.56, CHCl3); cf. lit.10b [α]D 20 –12.6 (c 3.84, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.80 (d, J = 6.8 Hz, 3 H), 1.19 (d, J = 6.8 Hz, 3 H), 1.20–1.50 (m, 2 H), 1.55–1.68 (m, 1 H), 1.92 (ddd, J = 13.6, 12.0, 4.4 Hz, 1 H), 2.08 (sept, J = 6.8 Hz, 1 H), 2.21 (ddd, J = 13.6, 12.0, 4.4 Hz, 1 H), 3.59 (dt, J = 2.0, 6.0 Hz, 2 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 6.84 (d, J = 8.4 Hz, 1 H), 6.86 (s, 1 H), 6.92 (dd, J = 8.4, 2.4 Hz, 1 H). 13C-APT NMR (100 MHz, CDCl3): δ = 18.6 (+), 19.0 (+), 29.0 (–), 34.3 (–), 38.0 (+), 53.3 (–), 55.97 (+), 56.04 (+), 62.3 (–), 109.6 (+), 111.1 (+), 118.8 (+), 121.5 (–), 130.5 (–), 148.3 (–), 149.1 (–). The 1H NMR and 13C NMR spectra of 2 were consistent with those reported.10d