Studies toward the Second-Generation Synthesis of Epolactaene: Highly Stereoselective Construction of the Epoxy-γ-Lactam Moiety

Kouta Tajima; Yoshifumi Umehara; Kenichi Kobayashi; Hiroshi Kogen

doi:10.1055/s-0034-1378562

Synlett, Table of Contents

Synlett 2014; 25(16): 2337-2340
DOI: 10.1055/s-0034-1378562

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Studies toward the Second-Generation Synthesis of Epolactaene: Highly Stereoselective Construction of the Epoxy-γ-Lactam Moiety

Kouta Tajima

Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan Fax: +81(42)4958633 Email: hkogen@my-pharm.ac.jp

,

Yoshifumi Umehara

Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan Fax: +81(42)4958633 Email: hkogen@my-pharm.ac.jp

,

Kenichi Kobayashi

Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan Fax: +81(42)4958633 Email: hkogen@my-pharm.ac.jp

,

Hiroshi Kogen*

Graduate School of Pharmaceutical Sciences, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan Fax: +81(42)4958633 Email: hkogen@my-pharm.ac.jp

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Abstract

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Abstract

Highly stereoselective synthesis of the epoxy-γ-lactam moiety toward the second-generation total synthesis of epolactaene was achieved via an E-selective Horner–Wadsworth–Emmons reaction using our new reagent and diastereoselective epoxidation of an allyl diol with VO(acac)₂ and TBHP.

Key words

epolactaene - Horner–Wadsworth–Emmons reaction - (E)-α-bromoacrylate - stereoselective synthesis - epoxidation - epoxy-γ-lactam

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References

References and Notes
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6a Kuramochi K, Yukizawa S, Ikeda S, Sunoki T, Arai S, Matsui R, Morita A, Mizushina Y, Sakaguchi K, Sugawara F, Ikekita M, Kobayashi S. Bioorg. Med. Chem. 2008; 16: 5039
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Our previous works on epolactaene:

7a Naruto S, Marumoto S, Kogen H. JP H11-130765, 1999 ; a patent application was filed before Patent Office on October 30, 1997 as a patent filing number of H09-297983
7b Marumoto S, Kogen H, Naruto S. J. Org. Chem. 1998; 63: 2068
7c Marumoto S, Kogen H, Naruto S. Tetrahedron 1999; 55: 7129
7d Marumoto S, Kogen H, Naruto S. Tetrahedron 1999; 55: 7145

Total synthesis of epolactaene by other research groups:

8a Hayashi Y, Narasaka K. Chem. Lett. 1998; 313
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8e Kuramochi K, Nagata S, Itaya H, Matsubara Y, Sunoki T, Uchiro H, Takao K, Kobayashi S. Tetrahedron 2003; 59: 9743
8f Tan Z, Negishi E. Org. Lett. 2006; 8: 2783

9 Marumoto S, Kogen H, Naruto S. Chem. Commun. 1998; 2253

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10c Nakata A, Kobayashi K, Kogen H. Chem. Pharm. Bull. 2013; 61: 108

11 Lactone 5 is actually the enantiomer of the known intermediate in our previous synthesis of unnatural (+)-epolactaene, see ref. 7c.
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13 TBS ether 8b was used in the next step without purification because of its instability.
14 The stereochemistries of the resulting E-configured double bonds were confirmed after reduction to alcohols 7a–c with DIBAL-H by the NOE correlation between the allylic methine proton and methylene protons.
15 Although the Bn and TBS groups had no advantage over TBDPS in the HWE reaction, the subsequent steps were carried out to confirm their influence on the stereoselectivity of the epoxidation.

16a Luche JL. J. Am. Chem. Soc. 1979; 101: 5848
16b TBDPS ether in 13c was derivatized to (R)- or (S)-MTPA ester after protection of 1,3-diol functionality as an acetonide. Since ¹H NMR of each crude product did not show the signals of the other diastereomer, we confirmed no epimerization occurred during the synthesis of 13c.

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21 The low yield is due to the deprotection of the TBS group during the reaction.
22 Procedure for Synthesizing Epoxide 6c (Table 1 Entry 9) To a stirred solution of allyl diol 13c (96 mg, 0.26 mmol) in CH₂Cl₂ (5.0 mL) was added VO(acac)₂ (14 mg, 0.052 mmol) at r.t. After stirring for 10 min, TBHP (5.5 M solution in decane, 0.10 mL, 0.55 mmol) was added, and the mixture was stirred for 6 h. The reaction was quenched by addition of a sat. aq Na₂S₂O₃ solution. The mixture was extracted with CH₂Cl₂ (4 × 20 mL). The combined extracts were dried over Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane–EtOAc, 1:1) to afford epoxide 6c (97 mg, 97%) as a colorless oil. [α]²⁵ _D –9.2 (c 0.99, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.63–7.72 (m, 4 H), 7.35–7.50 (m, 6 H), 3.81 (dd, J = 12.3, 4.8 Hz, 1 H), 3.71 (dq, J = 7.8, 6.0 Hz, 1 H), 3.59 (dd, J = 12.3, 8.1 Hz, 1 H), 3.33 (dd, J = 12.3, 6.3 Hz, 1 H), 3.26 (dd, J = 12.3, 6.3 Hz, 1 H), 3.11 (d, J = 7.8 Hz, 1 H), 1.73 (dd, J = 8.1, 5.1 Hz, 1 H), 1.44 (t, J = 6.3 Hz, 1 H), 1.29 (d, J = 6.0 Hz, 3 H), 1.03 (s, 9 H). ¹³C NMR (100 MHz, CHCl₃): δ = 135.7, 135.6, 133.6, 133.3, 130.1, 130.0, 127.8, 127.7, 66.3, 64.4, 63.9, 63.3, 61.0, 26.7, 21.6, 19.1. IR (CHCl₃): 3588, 2963, 2933, 1472, 1373, 1235, 1111, 952, 822 cm^–1. LRMS (FAB⁺): m/z = 387 [M + H]⁺. Anal. Calcd for C₂₂H₃₀O₄Si·H₂O: C, 65.31; H, 7.97. Found: C, 65.13; H, 7.74.
23 Maruyama K, Ueda M, Sasaki S, Iwata Y, Miyazawa M, Miyashita M. Tetrahedron Lett. 1998; 39: 4517
24 Spectral Data for 4b [α]²² _D –60.4 (c 0.10, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.17 (br s, 1 H), 5.64 (br s, 1 H), 3.81 (m, 1 H), 3.77 (s, 3 H), 3.51 (br s, 1 H), 3.23 (br s, 3 H), 1.33 (d, J = 4.5 Hz, 3 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 167.2, 165.5, 65.8, 64.7, 63.3, 61.6, 32.4, 25.7 (3 C), 21.7, 17.9, –4.7 (2 C). IR (CHCl₃): 3517, 3401, 2932, 1703, 1678, 1572, 1390, 1260, 1216, 1116, 840, 746 cm^–1. HRMS (FAB⁺): m/z calcd for C₁₄H₂₉O₅N₂Si [M + H]⁺: 333.1846; found: 333.1846.