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

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

• References and Notes

• 1 Kakeya H, Takahashi I, Okada G, Isono K, Osada H. J. Antibiot. 1995; 48: 733
• 2 Kakeya H, Onozawa C, Sato M, Arai K, Osada H. J. Med. Chem. 1997; 40: 391
• 3 Mizushina Y, Kobayashi S, Kuramochi K, Nagata S, Sugawara F, Sakaguchi K. Biochem. Biophys. Res. Commun. 2000; 273: 784
• 4 Nakai J, Kawada K, Nagata S, Kuramochi K, Uchiro H, Kobayashi S, Ikekita M. Biochim. Biophys. Acta 2002; 1581: 1
• 5 Mizushina Y, Kuramochi K, Ikawa H, Kuriyama I, Shimazaki N, Takemura M, Oshige M, Yoshida H, Koiwai O, Sugawara F, Kobayashi S, Sakaguchi K. Int. J. Mol. Med. 2005; 15: 785
• 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
• 6b Kuramochi K, Sunoki T, Tsubaki K, Mizushina Y, Sakaguchi K, Sugawara F, Ikekita M, Kobayashi S. Bioorg. Med. Chem. 2011; 19: 4162

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
• 8b Hayashi Y, Kanayama J, Yamaguchi J, Shoji M. J. Org. Chem. 2002; 67: 9443
• 8c Kuramochi K, Itaya H, Nagata S, Takao K, Kobayashi S. Tetrahedron Lett. 1999; 40: 7367
• 8d Kuramochi K, Itaya H, Nagata S, Takao K, Kobayashi S. Tetrahedron Lett. 1999; 40: 7371
• 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
• 10a Tago K, Kogen H. Org. Lett. 2000; 2: 1975
• 10b Tago K, Kogen H. Tetrahedron 2000; 56: 8825
• 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.
• 12 Massad SK, Hawkins LD, Baker DC. J. Org. Chem. 1983; 48: 5180
• 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.
• 17a Johnson MR, Kishi Y. Tetrahedron Lett. 1979; 20: 4347
• 17b Kogen H, Nishi T. J. Chem. Soc., Chem. Commun. 1987; 311
• 18 Katsuki T, Sharpless KB. J. Am. Chem. Soc. 1980; 102: 5974
• 19 Wang Z.-X, Tu Y, Frohn M, Zhang J.-R, Shi Y. J. Am. Chem. Soc. 1996; 119: 11224
• 20 Sharpless KB, Michaelson RC. J. Am. Chem. Soc. 1973; 95: 6136
• 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.