HETEROCYCLES

Communication | Special issue | Vol. 82, No. 2, 2011, pp. 1113-1118
Received, 28th June, 2010, Accepted, 16th August, 2010, Published online, 17th August, 2010.
DOI: 10.3987/COM-10-S(E)76

■ Concise Substrate-Controlled Asymmetric Total Synthesis of (+)-3-(Z)-Dihydrorhodophytin

Byungsook Kim, Te-ik Sohn, Sanghee Kim, Deukjoon Kim,* and Jongkook Lee

The Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Shillim-Dong, San 56-1, Kwanak-Gu, Seoul 151-742, Korea

Abstract

The first asymmetric total synthesis of (+)-3-(Z)-dihydrorhodophytin (1) has been accomplished in 15 steps in 17% overall yield from readily available starting material 6 in a substrate-controlled manner. Key steps in our synthesis are a highly stereoselective dianion alkylation for the synthesis of the α,α’-anti-RCM substrate and a strategy for the introduction of the chlorine function.

(+)-3-(Z)-Dihydrorhodophytin (1) was isolated from the sea hare Aplysia braziliana in 1979 and was shown to possess fish antifeedant activity.1 The structure and absolute stereochemistry of this C15 nonisoprenoid metabolite were elucidated by a combination of spectroscopic analysis and X-ray crystallography.1 Reported herein is a completely substrate-controlled asymmetric synthesis of this interesting α,α'-trans-oxocene marine natural product based upon a highly stereoselective dianion alkylation for the synthesis of an α,α’-anti-RCM substrate.
As shown in Scheme 1, we envisaged that (+)-3-(Z)-dihydrorhodophytin (1) could be elaborated from key a,a’-trans-disubstituted chloro oxocene 2, which in turn could be prepared from chloro diene 3 by a ring-closing metathesis. It should be emphasized that it is critical to introduce the chlorine atom at C(7) of diene alcohol 4 prior to the RCM step (vide infra). We further envisioned that key α,α’-anti-diene alcohol 4 could be stereoselectively secured by our dianion alkylation methodology2 using hydroxy amide 5. Further analysis indicated that hydroxy amide 5 should be readily available from known epoxy alcohol 6.

The synthesis commenced by preparing key alkylation substrate 5 from known alcohol 63 in four steps as shown in Scheme 2. Thus, protection of alcohol 6 with a PMB group, followed by opening of the resultant epoxide 7 with (benzyloxy)methyllithium,4 afforded the one-carbon homologated alcohol 8 in 70% yield for the two steps. Williamson etherification of alcohol 8 with N,N-dimethyl α-chloroacetamide and oxidative removal of the PMB group from the resulting α-alkoxy amide 9 with wet DDQ5 then provided the required alkylation precursor 5 in a highly efficient manner (94%, two steps). To our satisfaction, the crucial dianion alkylation of hydroxy amide 5 by successive treatment with LiHMDS and then allyl iodide produced the desired α,α’-anti-diene 4 as virtually a single stereoisomer in 85% yield. It is interesting to note that the observed diastereoselectivity in the dianion alkylation of C(6)/C(7)-anti-isomer 5 is far superior to that of the previously reported syn-isomer 5’ (>50:1 vs. 6:1).2a

With α,α’-anti-diene alcohol 4 available in multigram quantities, we directed our attention to synthesis of key chloro oxocene 2. Chlorination of the acyclic secondary homoallylic alcohol 4 with inversion of configuration by the Hooz protocol,6 followed by RCM7 of the resultant chloro diene 3 with the first-generation Grubbs’ Ru catalyst, afforded key oxocene 2 in 79% overall yield for the two steps (Scheme 3). Our extensive experience in this field suggested that α,α’-trans, C(6)/C(7)-anti system such as 10 represents the worst substrate for halogenation with inversion of configuration among the four possible diastereomeric oxocene alcohols. This result is probably due to steric hindrance to backside approach of the incoming chloride in the preferred syn-conformation A of 10.8-10 In fact, chlorination of α,α’-trans-alcohol 10, prepared by RCM of diene alcohol 4, led to complete elimination, even under the improved chlorination conditions of Boeckman,9a to give diene 11 as the sole product (83%).

Conversion of key chloro oxocene intermediate 2 to (+)-3-(Z)-dihydrorhodophytin (1) was accomplished in an uneventful sequence similar to that employed for our synthesis of (+)-3-(Z)-pinnatifidenyne,9b as summarized in Scheme 4. Our direct ketone synthesis protocol9b on α-alkyloxy amide 2 with ethylmagnesium bromide, followed by L-Selectride reduction6b,11 of the resulting ethyl ketone in a Felkin-Ahn sense, provided secondary alcohol 12 as a single isomer in 88% yield for the two steps. Introduction of the bromine functionality at C(13) with inversion of configuration in the presence of the chlorine atom under the Hooz conditions completed elaboration of the C(12) side chain to give bromide 13 in 93% yield.
Next, we turned our attention to incorporation of the (Z)-enyne side chain to complete the synthesis. For this purpose, removal of the benzyl group in bromide 13 by exposure to wet DDQ afforded alcohol 14 in 67% yield. Dess-Martin periodinane oxidation12 of primary alcohol 14 and subsequent Stork-Zhao olefination13 of the resulting aldehyde produced (Z)-vinyl iodide 15 as a single isomer in 84% yield from alchohol 14. Sonogashira coupling reaction14 of (Z)-vinyl iodide 15 with (trimethylsilyl)acetylene in the presence of (Ph3P)4Pd/CuI provided the desired (Z)-enyne 16 (98%). Finally, removal of the trimethylsilyl protecting group with TBAF delivered (+)-3-(Z)-dihydrorhodophytin (1) in 84% yield. Spectral data and specific rotation of the synthetic material were in good agreement with those of the natural product.15

In summary, a concise and highly stereoselective asymmetric total synthesis of (+)-3-(Z)-dihydrorhodophytin (1) has been accomplished in 15 steps in 17% overall yield from readily available starting material 6 in a completely substrate-controlled manner. Our synthesis features a highly stereoselective dianion alkylation, a strategy for the demanding introduction of the chlorine function into the oxocene skeleton, and an RCM as key steps.

ACKNOWLEDGEMENTS
Dedicated to Professor Dr. Albert Eschenmoser on the occasion of his 85th birthday. This research was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea Government (MEST) (No. 20100001710).

References

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15. Rf 0.38 (n-hexane/ethyl acetate, 20/1); [α]25D +61.7 (c 0.1, CHCl3; lit.,1: [α ]25D +74.8); 1H NMR (500 MHz, CDCl3) δ 6.03 (ddd, J = 8.0, 8.0, 11.0 Hz, 1 H), 5.79-5.90 (m, 2 H), 5.58 (ddd, J = 1.0, 1.0, 11.0 Hz, 1 H), 4.21 (dd, J = 6.5, 8.0 Hz, 1 H), 4.06-4.10 (m, 2 H), 3.90 (ddd, J = 2.5, 7.5, 11.0 Hz, 1 H), 3.16 (d, J = 2.0 Hz, 1 H), 2.55-2.70 (m, 5 H), 2.46 (ddd, J = 7.5, 11.0, 14.5 Hz, 1 H), 2.19 (ddddd, J = 3.0, 7.0, 7.0, 7.0, 14.5 Hz, 1 H), 1.74-1.83 (m, 1 H), 1.08 (t, J = 7.0 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 140.3, 130.2, 127.6, 111.5, 82.8, 80.1, 79.6, 73.4, 64.2, 60.3, 35.3, 33.5, 30.13, 30.14, 12.2; HRMS (CI) found 331.0460 [calcd for C15H21OBrCl(M+H)+ 331.0464].