J. Org. Chem. 1994,59, 715-717
715
Synthetic Studies toward Ciguatoxin. Stereocontrolled Construction of the KLM Ring Fragment Makoto Sasaki, Masayuki Inoue, and Kazuo Tachibana' Department of Chemistry, School of Science, T h e University of Tokyo, Bunkyo-ku, Tokyo 113, J a p a n Received November 15, 1 9 9 9
of the a-oriented methyl group at the C50 position7 was realized with complete stereocontrol by a two-step sequence of reactions [(l)LDA, THF, -78 O C ; MeI; (2) LDA, THF, -78 "C; saturated aqueous NH4C11 in 76% yield. Dithiane alcohol 6, obtained by treatment of 5 with 1,3Ciguatoxin (1) and its congeners are the toxic principles propanedithiol (TMSOTf, CH2Cl2, 0 "C, 96%), was of ciguatera, which is known as the most widespread among converted to its TBDMS ether 7 in quantitative yield. sea food poisonings of dinoflagellate origin (Figure 1l.I Cleavage of the dithiane 7 with 5 equiv of N-iodosuccinThe toxin molecule 1 is one of the most potent neurotoxins imide (NIS)in aqueous acetonitrile8 and subsequent and binds to the same site of voltage-dependent sodium Homer-Emmons olefination gave the a,&unsaturated channels as structurally similar brevetoxins.2 However, ester 8 in 92% overall yield. Kabuki-Sharpless asymita very limited availability from natural sources has metric epoxidationg of allylic alcohol 9, prepared from 8 prevented further studies including precise conformational by a three-step protocol (74% overall), was followed by analysis, characterization of the interaction with sodium protection of the primary alcohol to afford MOM ether 10 channels, and development of a highly specific immuin high yield. DIBALH reduction of the lactone 10 and noassay for its detection in food sources. Thus, ita protection of the resulting hemiacetal according to the synthetic supply is urgently needed.3 In this paper, we method of Sinou'O provided allyl ether 11 as a 3 2 anomeric report the first stereoselective synthesis of the KLM ring mixture in 91% overall yield. After removal of the fragment of this molecule, which appears to be well-suited TBDMS group (94%), treatment of epoxy alcohol 12with for a haptenic epitope of anti-ciguatoxin a n t i b ~ d y .The ~ dimsylpotassium (THF, rt, 3 h) resulted in the predompresent synthesis is based on the 7-endo selective cyclizainant formation of fully substituted oxepane 13 accomtion of the epoxy alcohol as a key step for the efficient panied by tetrahydropyran 14 in 80% total yield. In this construction of the fully substituted oxepane ring K. cyclization, 7-endo cyclization proceeded preferentially The synthesis of the KLM ring fragment started with in spite of the absence of an activator group such as an methyl 4,6-O-benzylidene-2-deoxy-2-C-methyl-a-~-altroelectron-rich olefin for the selective cleavage of the pyranoside (2),5,6whose configurations at C 2 4 5 correepoxide." The presence of the trans-fused five-membered spond to those at C46449 of ciguatoxin,respectively. The ring is presumed to be responsible for the observed alcohol 2 was transformed into nitrile 3 in 68% overall selectivity, although the extent of ita contribution is unclear.12 Difference in the regioselectivity of the cyyield by the following sequence (Scheme 1): (1)benzylclization was observed between the two diastereomers, ation, (2) acid hydrolysis of the benzylidene group, (3) i.e., the 518 allyl ether selective tosylation of the primary hydroxyl, and (4) provided only the desired treatment with sodium cyanide in DMSO. DIBALH oxepane 138,whereas the 51a allyl ether 12d3produced an inseparable 1.7:l mixture of oxepane 13a and tetrahyreduction of 3 followed by NaClO2 oxidation led to the dropyran 14. hydroxy carboxylic acid, which was treated with phenylsulfonyl chloride and triethylamine to give the trans-fused In order to construct the L ring, we needed one-carbon bicyclic lactone 4 in 51% overall yield from 3. Introduction homologation for 13 (Scheme 2). Thus, protection of the hydroxyl group of the mixture of 13 and 14 as the TIPS
Summary: The first stereoselectivesynthesis of the KLM ring fragment of ciguatoxin is reported including as a key step 7-endo selective cyclization of epoxy alcohol to construct a fully substituted oxepane ring (12 13).
-
e Abstract
published in Advance ACS Abstracts, February 1, 1994. (1)(a)Murata, M.;Legrand,A.-M.; Ishihhi,Y.;Fukui,M.;Yasumoto, T. J. Am. Chem. SOC.1990,112,4380.(b) Lewis, R. J.; Sellin, M.; Poli, M.A.; Norton,R.S.; MacLeod, J. K.;Sheil, M. M. Toxicon 1991,29,1115. (c)Murata, M.; Legrand, A.-M.; Scheuer, P. J.;Yawmoto, T. Tetrahedron Lett. 1992,33,525.(d) Satake, M.; Murata, M.; Yasumoto,T. Tetrahedron Lett. 1993,34,1975.(e) Lewis, R. J.; Norton, R. S.; Brereton, I. M.; Eccles, C. D. Toxicon 1993,31,637. ( 2 ) Gawley, R. E.; Rein, K. S.; Kinoshita, M.; Baden, D. G. Toxicon 1992,30,780 and references cited therein. (3)For other synthetic works, see: (a) Alvarez, E.; Diaz, M. T.; PBrez, R.; Marth, J. D. Tetrahedron Lett. 1991,32,2241.(b)Alvarez, E.;Zurita, D.;Marth, J. D. TetrahedronLett.1991,32,2245.(c)Zbrraga,M.;Martfn, J.D. Tetrahedron Lett. 1991,32,2249.(d) Alvarez, E.;Rodrfguez, M. L.; Zurita, D.; Marth,J. D. Tetrahedron Lett. 1991,32,2253.(e) Suzuki, T.;
(7)The numbering of compounds used in this paper corresponds to that of ciguatoxin (Figure 1). (8)A variety of reagents were tested for the oxidative hydrolyeis of dithiane in 7,among which 5 equiv of NIS in aqueous acetonitrile at room temperature was found to be the best set of conditions with respect to the yield and ita reproducibility. (9) Katauki, T.; Sharplees, K. B. J. Am. Chem. SOC. 1980,102,5976. (10)Lakhmiri, R.; Lhoste, P.: Sinou, D. Tetrahedron Lett. 1989.30. , , 4669. (11)Nicolaou, K. C.;Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. SOC. 1989,111,5335. (12)Base treatment of epoxy alcohol A gave a mixture of oxepane B and tetrahydropyran C in 21 % and 67% yield, respectively.
Sato,O.;Hirama,M.;Yamamoto,Y.;Murata,M.;Yasumoto,T.;Harada,
N. Tetrahedron Lett. 1991,32,4505. (0Sato, 0.; Hirama, M. Synlett 1992,705.(9) Alvarez, E.; Rico, M.; Rodrfguez, R. M.; Zurita, D.; Marth, J. D. Tetrahedron Lett. 1992,33,3385. (h) Ravelo, J. L.; Regueiro, A.; Martin, J. D. Tetrahedron Lett. 1992,33,3389.(i) Soler, M. A.; Palaz6n, J. M.; Martin, V. S. Tetrahedron Lett. 1993,34,5471. (4)Hokama, Y.;Hong, T. W. P.; Isobe, M.; Ichikawa, Y.; Yasumoto, T. J. Clin. Lab. Anal. 1992,6, 54. (5)Hicks, D. R.;Fraser-Reid, B. Can. J. Chem. 1975,53,2017. (6)The absolute stereochemistry of ciguatoxin was proposed to be one represented by structure 1; see ref 3e.
fi pen
Me
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t
no A
OBn
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(13)A part of the 3 2 mixture of 12a and 128was separated by HPLC (YMC A024 SIL column, 10 X 300 mm; eluent, 25% ethyl acetate in hexane; w 264 nm; flow rate, 3.0 mL/min; t R , 12a,23.6 min; 12424.7 min).
0022-3263~94/1959-0715$04.50/00 1994 American Chemical Society
716 J. Org. Chem., Vol. 59, No. 4, 1994
Communications Scheme la
Me
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HO TBDMS
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i
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6
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:
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0 Key: (a) NaH, BnBr, DMF, rt; (b) TsOH, MeOH, rt; (c) TsCl, EtsN, DMAP, CHzClz, 0 OC; (d) NaCN, DMSO, 70 O C ; (e) DIBAL, CHaClz, NaHzPO4, t-BuOH-HzO, rt; (8) PhSOzC1, EtsN, CHzClz, 0 OC to rt; (h) LDA, MeI, THF, -78 OC; (i) -78 OC; (f) NaC102,2-methyl-2-butene, LDA, NH4C1, THF, -78 OC; 6) HS(CH&SH, TMSOTf, CHZC12,O OC; (k)TBDMSOTf, 2,6-lutidine, CHZC12, rt; (1) NIS, CHsCN-HzO, rt; (m) (i-PrO)zPOCHzCOzEt,KOt-Bu, THF, -78 to 0 OC; (n) PDC, 4 A M s , CHzClz, rt; ( 0 ) NaBH4, MeOH, 0 OC; (p) t-BuOOH, Ti(O-i-Pr)d, (-)-diethyl tartarate, CHzC12, -20 OC; (9)MOMC1, i-PrzNEt, CHzClZ, rt; (r) allylOCOzEt, Pdz(dibenzylideneacetone)&HC13, 1,4-bis(diphenylphoaphino)butane, THF, 65 OC; (e) n-BmNF, THF, rt, (t) KCHzSOCHs, THF, rt.
Wittig olefination provided hydroxy olefins 15 (64%) and 16 (24%). At this stage, the undesired tetrahydropyran 16 was easily removed by silica gel chromatography. Conventional functional group manipulation allowed for the transformation of the pure oxepane 15 to the tramfusedlactone 17 in five steps: [(l) triethylsilylation (86%); (2) hydroboration using 9-BBN (91% 1; (3) oxidation with SOa-Pyr;(4) selective hydrolysis of the triethylsilyl group to form the corresponding hemiacetal, (5) PDC oxidation (83% for the three steps)]. Methylation of the lithium enolate derived from 17 led exclusively to 18 with the d-h desired configuration a t the C51 position in 52% yield j Me OBn (77% based on the recovered starting material) and TIPSO.,,, __ TIPSO.,,, subsequent introduction of the allyl group as a threeI carbon unit for the construction of the spirally attached MOMO MOMO M ring furnished the hemiketall9 in 79% yield. AppliH " H i X H H i Me Me Me cation of the asymmetric osmylation with N,N'-bis(2,4,617X=H 18 trimethylbenzyl) (S,S)1,2-diphenyl-1,2-diaminoiC18: X = Me k,l] ethane15gave the triol (78%),which upon treatment with camphorsulfonic acid (PhH, rt) gave rise to the spiroketal Me OBn Me OH 20 in 97 % yield. Finally, benzylation of the hydroxyl group at C54 gave the protected KLM ring fragment 21 in 91% yield. The stereochemistry at the C52 and C54 positions were assigned on the basis of literature precedent,15 Me differential NOE experiments, and our preceding model 22 study.I6 Compound 21 was converted into 22 by the following sequence in 61% overall yield (1) n-BwNF, Key: (a) TIPSOTf, 2,6-lutidine, CHzC12,O "C to rt; (b) PdClz, THF, rt; (2) KH, MeI, THF, 0 OC to rt, (3) Hz, 20% PdNaOAc, AcOH-HzO, rt, 74% (two steps); (c) P W + C H & r , KHMDS, THF, 0 "C, 15: 64%, 16: 24%; (d) EhSiOTf, 2,6-lutidme, CHZClz, (OH)&, EtOH, rt. Its lH NMR spectrum in pyridine-& 0 OC, 86%; (e) 9-BBN, THF,rt; H a ,NaOH, rt, 915%; (0SOa-PF, matched well with that of ciguatoxin. EtsN, DMSO, CH&la, 0 'C; (0) AcOH-THF-Hz0 (331), rt, (h) The synthesis reported herein has the potential to PDC, 4 A MS, CH&lz, rt, 83% (h steps); (i) LDA, MeI, THFHMPA,-78OC, 52% (77%~ o n t h e ~ v e r e 8 a t a r t i n g m a t e r i a l ) ; provide adequate amounts of a structural fragment of (j)AllylMgBr, THF, -78 .C, 79%;(k)OsOd, NJV'-bis(2,4,&trimethciguatoxinfor further research, including its use as a hapten ylbenzyl)-(S,S)-l,2-dipheoyl-1,2.dk"e ,CH&12, -90 OC; aq NaHS03-THF, reflux, 78%; 0)CSA,PhH,rt,97 % ;(m)NaH, BnBr,
a. 1
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-
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DMF, 0 "C to rt, 90%; (n) n - B a F , THF, rt, 98%; ( 0 ) KH, MeI, 20% Pd(OH)dC, EtOH, rt, 67%. THF, 0 OC to rt, 94%; (p) Hz,
ethers and selective removal of the allyl group with PdC12 under mild condition^'^ (7474 overall yield) followed by
(14) Nakada, T.; Kitajima, T.; Nakahara, Y.; Ogawa,T. Carbohydr. Res. 1992,228, 157. (15) Corey,E. J.; Jardine, D. P.; Virgil, S.; Yuen, P.-W.; Connel, R. D. J. Am. Chem. SOC.1989,111,9243. (16) Sasaki, M.; Hasegawa, A.; Tachibana, K. Tetrahedron Lett. 1993, 34,8489.
Communications
J. Org. Chem., Vol. 59, No.4, 1994 717
Figure 1. Structure and the ring assignment of CiguatOXin (1). of antigens to raise monoclonal antibodies that could recognize the natural toxin. Further studies toward this direction are currently underway. Acknowledgment. We thank Prof. Michio Murata of this department for valuable discussions and advice throughout this work.
Supplementary Material Available: Experimental procedurea and spectrmcopicdata for compounds 3-22(11 paes).
"hiamaterialiecontained in librarieson microfiche,immediately follow thie article in the microfilm addition of the journal, and can be ordered from the ACS; see any current masthead page for
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