alpha;-Carbonyl radical cyclization approach toward spiro4.4nonene: total synthesis of dimethyl gloiosiphone A

摘要

O RO RO O OMe OH 1 R = H 2 R = Me O MeO MeO 2 3 4 O I 5 O O NNMe2 O O I O i iv 7 5 4 8 6 ii iii O I O HO I O MeO I O MeO MeO 9 10 i 11 3 ii 8 iv iii a-Carbonyl radical cyclization approach toward spiro4.4nonene: total synthesis of dimethyl gloiosiphone A Chin-Kang Sha* and Wen-Yueh Ho Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, ROC. E-mail: cksha@chem.nthu.edu.tw Received (in Cambridge, UK) 2nd November 1998, Accepted 9th November 1998 The total synthesis of dimethyl gloiosiphone A 2 was achieved via an a-carbonyl radical spirocyclization.Gloiosiphone A 1 and its dimethyl derivative 2 were isolated from red marine algae Gloiosiphonia verticillaris.1 Crude lipid collections of Gloiosiphonia verticillaris were found to exhibit profound antimicrobial activity against several Staphylococcus, Bacillus and Salmonella species. Since the causative agent 1 was not stable enough for isolation, the crude collections were treated with CH2N2 to furnish the more stable dimethyl derivative 2.Compounds 1 and 2 comprise a new structural class featuring a highly oxygenated spiro4.4nonene system. Due to their potential antimicrobial activity and novel molecular skeleton, these compounds are challenging synthetic targets. The first total synthesis of dimethyl gloiosiphone A 2 has been achieved recently by Paquettersquo;s group.2 As an extension of our work on the a-carbonyl radical cyclization reaction,3 we report herein the total synthesis of 2 using an a-carbonyl radical cyclization as the key step.The retrosynthetic analysis is outlined in Scheme 1. The spirononene structure in 2 could be produced by an a-carbonyl radical cyclization followed by appropriate oxidation (4?3). The radical precursor iodo ketone 4 would be generated according to our method4 from 5, which in turn could be prepared from cyclopentanone 6 according to Yamashitarsquo;s procedure.5 Treatment of cyclopentanone 6 with N,N-dimethylhydrazine in the presence of TFA as catalyst furnished hydrazone 7 (Scheme 2).Deprotonation of 7 with BunLi at 0 deg;C followed by alkylation with 5-iodopent-1-yne and hydrolysis yielded the required ketone 5. Ketone 5 was sequentially treated with HMDS/TMSI and NaI/MCPBA in THF to afford iodo ketone 4. Treatment of 4 with Bu3SnH under standard conditions furnished the required spirocyclic compound 8 in 50 yield. To improve the yield, an atom transfer radical reaction was adopted.6 Thus, irradiation of a benzene solution of ketone 4 at reflux with a sun lamp in the presence of (Bu3Sn)2 (0.1 equiv.) followed by reduction of the resulting vinyl iodide with Bu3SnH (1.05 equiv.) using AIBN as initiator furnished spiro compound 8 in 87 overall yield.We then focused our attention on the introduction of enol ether moieties into 8. First, iodo ketone 9 was generated from 8 by the same method used for the transformation of 5?4 (Scheme 3).3 The iodo ketone 9 was then converted into unsaturated ketone 10 via a modified version of Satorsquo;s method.7 Accordingly, 9 was oxidized with DMSO at 70 deg;C followed by addition of I2 (1 equiv.) to provide 10.Compound 10 was subsequently methylated with NaH and MeI to give methoxy iodo enone 11. Nucleophilic displacement of iodide in 11 with NaOMe then furnished dimethoxy enone 3. Allylic oxidation of 3 with SeO2 gave diketone 12 (60) (Scheme 4). Treatment of 12 with a catalytic amount of OsO4 with NMO as the co-oxidant gave dihydroxy ketone 13.Finally, selective methylation of the primary alcohol with dimethyl sulfate in presence of excess K2CO3 (10 equiv.) afforded Scheme 1 Scheme 2 Reagents and conditions: i, H2NNMe2, 90; ii, BunLi, 0 deg;C, 5-iodopent-1-yne, then 10 HCl, 1 h, 80; iii, HMDS, TMSI, CH2Cl2, then NaI, MCPBA, THF, 82; iv, (Bu3Sn)2 (0.1 equiv.), sun lamp, C6H6, 1.5 h, then Bu3SnH (1.05 equiv.), AIBN, C6H6, 87. Scheme 3 Reagents and conditions: i, HMDS, TMSI, CH2Cl2, then NaI, MCPBA, THF, 82; ii, DMSO, I2, 86; iii, NaH, MeI, DMF, 95; iv, NaOMe (10 equiv.), MeOH, 92.Chem. Commun., 1998, 2709ndash;2710 2709O MeO MeO O OH OH O MeO MeO O 3 12 13 2 i ii iii dimethyl gloiosiphone A 2. All spectral data for 2 are in good agreement with those reported in the literature.1,2 In summary, a total synthesis of dimethyl gloiosiphone A 2 has been accomplished in a stereoselective manner in which an a-carbonyl radical cyclization reaction was employed to facilitate the construction of the key spiro4.4nonene skeleton.Application of this versatile a-carbonyl radical cyclization methodology toward the total synthesis of more complex natural products is under current investigation. We thank the National Science Council of the Republic of China for financial support (NSC87-2113-M-007-043). Notes and references 1 J. L. Chen, M. F. Moghaddam and W. H. Gerwick, J. Nat. Prod., 1993, 56, 1205. 2 L. A. Paquette, C. F. Sturino and P. Doussot, J. Am. Chem. Soc., 1996, 118, 9456; C. F. Sturino, P. Doussot and L. A. Paquette, Tetrahedron, 1997, 53, 8913. 3 C.-K. Sha, C.-Y. Shen, T.-S. Jean, R.-T. Chiu and W.-H. Tseng, Tetrahedron Lett., 1993, 34, 7641; C.-K. Sha, R.-T. Chiu, C.-F. Yang, N.-T. Yao, W.-H. Tseng, F.-L. Liao and S.-L. Wang, J. Am. Chem. Soc., 1997, 119, 4130; C.-K. Sha, K. C. Santhosh and S.-H. Lih, J. Org. Chem., 1998, 63, 2699. 4 C.-K. Sha, T.-S. Jean and D.-C. Wang, Tetrahedron Lett., 1990, 31, 3745. 5 T. Mino, S. Masuda, M. Nishio and M. Yamashita. J. Org. Chem., 1997, 62, 2633. 6 D. P. Curran, Synthesis, 1988, 417 and 489; D. P. Curran, in Free Radicals in Synthesis and Biology, ed. F. Minisci, Kluwer, Dordrecht, 1988, p. 37. 7 K. Sato, Y. Kojima and H. H. Sato, J. Org. Chem., 1970, 35, 2374. Communication 8/08455F Scheme 4 Reagents and conditions: i, SeO2, dioxane, reflux, 60; ii, OsO4, NMO, ButOH, THF, H2O, 87; iii, K2CO3 (10 equiv.), Me2SO4, 75. 2710 Chem. Commun., 1998, 2709ndash;2710