Biosci. Biotechnol. Biochem., 70 (10), 2564–2566, 2006 Note Enantioselective Synthesis of the (1S,5R)-Enantiomer of Litseaverticillols A and B

y Akira MORITA, Hiromasa KIYOTA, and Shigefumi KUWAHARA

Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan

Received May 8, 2006; Accepted May 31, 2006; Online Publication, October 7, 2006 [doi:10.1271/bbb.60253]

An enantioselective synthesis of the (1S,5R)-enan- which have recently culminated in the first enantiose- tiomer of litseaverticillols A and B was accomplished in lective total synthesis of (1R,5S)-()-1 and (1R,5S)-()- line with our previously reported synthetic pathway for 2.4) In this note, we describe the synthesis of their their (1R,5S)-enantiomer. The use of ‘‘EtSCeCl2’’ pre- enantiomers directed toward an evaluation of the differ- pared from EtSLi and CeCl3, instead of previously ence in biological activity between the enantiomers of employed EtSLi itself, for the formation of thiol ester litseaverticillols A and B. intermediates prevented any undesirable epimerization Our synthesis of (1S,5R)-1 and (1S,5R)-2 basically occurring in the process. followed our previous synthesis of their corresponding enantiomers, (1R,5S)-1 and (1R,5S)-2, respectively,4) Key words: litseaverticillol; enantioselective synthesis; except that (R)-4-benzyloxazolidin-2-one was employed sesquiterpenoid; anti-HIV as the source of chirality, instead of its (S)-form used in the previous synthesis. Homogeranic acid (E=Z = ca. Litseaverticillols A and B (1 and 2, respectively; see 3:1)5) was converted via its mixed anhydride form into Scheme 1), monocyclic sesquiterpenoids possessing a N-acyloxazolidinone derivative 3.Thesyn-selective novel carbon framework designated as litseane, were Evans asymmetric aldol reaction6) of 3 with aldehyde isolated together with their congeners (litseaverticillols 47,8) afforded a mixture of (E)- and (Z)-5 which could be C–H) from leaves and twigs of the perennial shrub, readily separated by silica gel column chromatography Litsea verticillata Hance, collected in Vietnam.1) The to furnish (E)- and (Z)-5 in isolated yields of 41% and terpenoids (1 and 2) exhibited considerably high anti- 10%, respectively. The chiral auxiliary of (E)-5 was HIV activity (IC50, 5.0 and 2–3 mg/ml, respectively) by substituted by an ethylthio group to give (E)-6 without inhibiting the replication of HIV-1, but they also showed any epimerization at the position to the carbonyl by 2) cytotoxicity against HOG.R5 cells (a reporter cell line) using ‘‘EtSCeCl2’’ prepared by mixing EtSLi and CeCl3 with CC50 values of 13.2 and 5.7 mg/ml, respectively. in a ratio of 1:1; this seems to be the first example, to our Quite interestingly, these natural products were obtained knowledge, of utilizing the ‘‘RSCeCl2’’ species for the as racemic mixtures (i.e., their specific rotation values preparation of thiol esters. In our previous synthesis of were both zero). This unusual observation as natural the (1R,5S)-isomer of 1 and 2, we employed EtSLi products, coupled with their unprecedented carbon itself,4,9) which resulted, although only occasionally, in skeleton and medicinally important bioactivity, have a small degree of undesirable epimerization at the - attracted the interest of organic chemists. A series of position to give (E)-6 with a reduced 88% diastereo- synthetic studies on litseaverticillols has recently been meric excess (de) in the worst case when we failed to reported by Vassilikogiannakis et al. which led to the keep the reaction temperature below 15 C. Diaster- first synthesis of ()-1 and ()-2 and also provided a eomerically pure thiol ester (E)-6 was then subjected to clear explanation for their formation as racemic mix- the Liebeskind–Srogl esterification reaction10) at 80 C tures.3) We became interested in these racemic sesqui- under microwave irradiation to give an almost quanti- terpenes of natural origin from another viewpoint that tative yield (96%) of (E)-7.4) The slightly improved there could be a possibility that one enantomer might chemical yield in the present case (96%) as compared have only anti-HIV activity and the other cytotoxicity. to that in our previous synthesis of (1R,5S)-1 (90%)4) In that case, the anti-HIV enantiomer with no cytotox- would be ascribable to the reduced microwave-irradi- icity could be a promising lead compound for practical ation time (15 min 2); the reaction mixture was anti-HIV agents. This presumption prompted our syn- irradiated at 80 C for 60 min in total (15 min 4)in thetic efforts on the optically active forms of 1 and 2 the previous synthesis. Finally, (E)-7 was exposed to a

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Bn (Z)-5 was transformed into (1S,5R)-2 with 95% de 23 4) 23 a) {½D þ150 (c 0.17, CHCl3); lit. ½D 151 (c homogeranic acid O N 0.10, CHCl ) for (1R,5S)-1}. An evaluation of the (E/Z = ca. 3:1) 3 biological activity of (1S,5R)-1 and (1S,5R)-2, as well as O O 3 their previously obtained enantiomers, is now being OTES conducted by Prof. Fong (University of Illinois at b) R3Sn Chicago). Xp α nBu3Sn CHO 4 O (E)-5 Experimental IR, 1H- and 13C-NMR, and mass spectra were OTES recorded by using the same spectrometers and condi-

R3Sn tions as those reported in Ref. 4. Silica gel column Xp chromatography and the microwave experiments were O (Z)-5 conducted in a similar manner to those described in 1 13 OTES Ref. 4. The IR, and H- and C-NMR spectra of OTES compounds 3,(E)- and (Z)-5,(E)- and (Z)-6,(E)- and c) R Sn d) H (E)-5 3 (Z)-7,(1S,5R)-1, and (1S,5R)-2 were identical with those EtS R' R' reported for the corresponding enantiomers in Ref. 4. O (E)-6 O (E)-7 (R)-4-Benzyl-3-(4,8-dimethyl-3,7-nonadienoyl)oxazo- e) lidin-2-one (3). Compound 3 (E=Z-mixture, 2.21 g, 55% OH 1 yield) was obtained as a colorless oil from 2.15 g (11.8 H 5) 5 mmol) of homogeranic acid (E=Z = ca. 3:1) and 2.21 g (12.5 mmol) of (R)-4-benzyloxazolidin-2-one O (1S,5R)-1 according to the procedure reported in Ref. 4. HR- þ FABMS m=z (½M þ H ): calcd. for C21H28NO3, OH 342.2069; found, 342.2073. c) d) e) (Z)-5 (Z)-6 (Z)-7 H (R)-4-Benzyl-3-{(2R,3E)-4,8-dimethyl-2-[(1R,2Z)-3- (tributylstannyl)-1-(triethylsilyloxy)-2-butenyl]-3,7-non- O (1S,5R)-2 adienoyl}oxazolidin-2-one [(E)-5], and its (3Z)-isomer Bn [(Z)-5]. Compounds (E)-5 (329 mg, 41% yield) and (Z)- 5 (82.9 mg, 10% yield) were obtained as colorless oils Xp = R = nBu O N R' = (CH2)2CH=CMe2 from 0.339 g (0.992 mmol) of 3 and 0.517 g (1.44 mmol) O of 4 according to the procedure reported in Ref. 4. (E)- 22 5: ½D 37:6 (c 1.33, CHCl3); HR-FABMS m=z þ Scheme 1. Synthesis of the (1S,5R)-Enantiomer of Litseaverticillols (½M þ H ): calcd. for C43H74NO4SiSn, 814.4409; A and B [(1S,5R)-1 and (1S,5R)-2, respectively]. 22 found, 814.4404. (Z)-5: ½D 26:3 (c 0.455, Reagents and conditions: a) tBuCOCl, Et3N, (R)-4-benzyl-3- CHCl ); HRMS (FAB) m=z (½M þ Hþ): calcd. for lithiooxazolidin-2-one, THF, 78 to 20 C for 4 h (55%); b) (i) 3 nBu BOTf, iPr NEt, CH Cl , 78 C overnight then 0 C 30 min; C43H74NO4SiSn, 814.4409; found, 814.4407. The mag- 2 2 2 2 (ii) TESCl, imidazole, DMF, 20 C overnight [41% for (E)-5, 10% nitude of the specific rotation of (E)-6 (37:6 ) did not for (Z)-5]; c) EtSH, nBuLi, CeCl3, 15 C overnight [80% for (E)-6, correspond to the data previously reported for its 65% for the (Z)-6]; d) PdCl2(PPh3)2, Cu(I) thiophene-2-carboxylate, enantiomer (þ24:8 ).4) This discrepancy seems to be (2-furyl)3P, THF, microwave, 80 C for 15 min 2 (96% for (E)-7, ascribable to a small amount of impurities contained in 91% for (Z)-7); e) TBAF–HF, aq. THF, 0 C for 10 min (quant. for 1, 83% for 2). the previously synthesized enantiomer. S-Ethyl (2R,3E)-4,8-Dimethyl-2-[(1R,2Z)-3-(tributyl- stannyl)-1-(triethylsilyloxy)-2-butenyl]-3,7-nonadiene- solution of TBAF–HF/THF containing a small amount thioate [(E)-6]. To a stirred suspension of anhydrous of water (adjusted to pH 7 to prevent possible loss of CeCl3 (256 mg, 1.04 mmol; prepared from CeCl3.7H2O stereochemical integrity via the retroaldol–aldol process according to the literature protocol11)) in THF (6 ml) and/or keto–enol equilibration)4) to furnish (1S,5R)-1 were successively added EtSH (76 ml, 1.03 mmol) and 23 4) 23 {½D þ120 (c 0.20, CHCl3); lit. ½D 122 (c a solution of nBuLi in hexane (1.6 M, 0.620 ml, 0.992 0.10, CHCl3) for (1R,5S)-1}. Despite careful optimiza- mmol) at 78 C, and the mixture was stirred at 0 C for tion of the reaction conditions in the final deprotection 30 min. A solution of (E)-5 (67.0 mg, 82.2 mmol) in THF step, especially in the reaction time, the slight degree of (1 ml) was then added at 20 C, and the resulting epimerization occurring at the -position could not be mixture was stirred overnight at 15 C. The reaction 4) suppressed, giving the target molecule with 95% de, as was quenched with sat. NH4Cl aq., and the mixture was 1 determined by its H-NMR analysis. By following the extracted with Et2O. The extract was washed with brine, same three-step sequence of reactions as that employed dried (Na2SO4) and concentrated in vacuo. The residue for the conversion of (E)-5 into (1S,5R)-1, compound was chromatographed over silica gel (hexane/EtOAc = 2566 A. MORITA et al. 200:1) to give 48.2 mg (80%) of (E)-6 as a colorless oil. References 22 ½D þ46 (c 0.95, CHCl3); HR-FABMS m=z (½M þ þ H ): calcd. for C35H69O2SSiSn, 699.3804; found, 1) Zhang, H.-J., Tan, G. T., Hoang, V. D., Hung, N. V., 699.3810. Cuong, N. M., Soejarto, D. D., Pezzuto, J. M., and Fong, (3Z)-isomer of (E)-6 [(Z)-6]. Compound (Z)-6 (14.6 H. H. S., Natural anti-HIV agents. Part 3: litseaverticil- mg, 65% yield) was obtained as a pale yellow oil from lols A–H, novel sesquiterpenes from Litsea verticillata. Tetrahedron, 59, 141–148 (2003). 26.3 mg (32.3 mmol) of (Z)-5 and 50 ml (0.675 mmol) 2) Hoang, V. D., Tan, G. T., Zhang, H.-J., Tamez, P. A., of EtSH in the same manner as that described for (E)- 25 Hung, N. V., Cuong, N. M., Soejarto, D. D., Fong, H. H. 6. ½D þ55:8 (c 0.965, CHCl3); HR-FABMS m=z þ S., and Pezzuto, J. M., Natural anti-HIV agents—part I: (½M þ H ): calcd. for C35H69O2SSiSn, 699.3804; (+)-demethoxyepiexcelsin and verticillatol from Litsea found, 699.3807. verticillata. Phytochemistry, 59, 325–329 (2002). (4S,5R)-5-[(E)-2,6-Dimethyl-1,5-heptadienyl]-2-meth- 3) Vassilikogiannakis, G., Margaros, I., Montagnon, T., and yl-4-(triethylsilyloxy)-2-cyclopentenone [(E)-7]. Com- Stratakis, M., Illustrating the power of singlet oxygen pound (E)-7 (11.3 mg, 96% yield) was obtained as a chemistry in a synthetic context: biomimetic syntheses pale yellow oil from 23.7 mg (33.7 mmol) of (E)-6 of litseaverticillols A–G, I and J and the structural according to the procedure reported in Ref. 4, except reassignment of litseaverticillol E. Chem. Eur. J., 11, that the microwave-irradiation time was reduced to 5899–5907 (2005) and references cited therein. 30 min (15 min 2). ½ 22 þ126 (c 0.32, CHCl ); 4) Morita, A., and Kuwahara, S., Enantioselective total D 3 synthesis of litseaverticillols A and B. Org. Lett., 8, HR-FABMS m=z (½M þ Hþ): calcd. for C H O Si, 21 37 2 1613–1616 (2006). 349.2563; found, 349.2570. 5) Mori, K., and Funaki, Y., Synthesis of (4E,8E,2S, 0 (1 Z)-isomer of (E)-7 [(Z)-7]. Compound (Z)-7 (7.9 3R,20R)-N-20-hydroxyhexadecanoyl-9-methyl-4,8-sphin- mg, 91% yield) was obtained as a pale yellow oil from gadienine, the ceramide portion of the fruiting-inducing 17.5 mg (25.0 mmol) of (Z)-6 in the same manner as that cerebroside in a basidiomycete Schizophyllum commune, 23 described for (E)-7. ½D þ122 (c 0.34, CHCl3); HR- and its (2R,3S)-isomer. Tetrahedron, 41, 2369–2377 þ FABMS m=z (½M þ H ): calcd. for C21H37O2Si, (1985). 349.2563; found, 349.2564. 6) Evans, D. A., Bartroli, J., and Shih, T. L., Enantiose- (4S,5R)-5-[(E)-2,6-Dimethyl-1,5-heptadienyl]-4-hy- lective aldol condensations. 2. Erythro-selective chiral droxy-2-methyl-2-cyclopentenone [(1S,5R)-1]. Com- aldol condensations via boron enolates. J. Am. Chem. pound (1S,5R)-1 [4.8 mg, quantitative yield; (1S,5R)-1/ Soc., 103, 2127–2129 (1981). 7) Domı´nguez, B., Pazos, Y., and de Lera, A. R., Stereo- (1S,5S)-1 = 43:1] was obtained as a colorless oil from controlled synthesis of 6-s-cis- and 6-s-trans-locked 9Z- 7.0 mg (20 mmol) of (E)-7 according to the procedure retinoids by hydroxy-accelerated Stille coupling of (Z)- reported in Ref. 4, except that the reaction temperature tri-n-butylstannylbut-2-en-1-ol and bicyclic dienyl tri- and the reaction time were respectively reduced to 0 C flates. J. Org. Chem., 65, 5917–5925 (2000). 24 and 10 min. ½D þ120 (c 0.20, CHCl3); HR-FABMS 8) Evano, G., Schaus, J. V., and Panek, J. S., A convergent þ m=z (½M þ H ): calcd. for C15H23O2, 235.1698; found, synthesis of the macrocyclic core of cytotrienins: 235.1698. application of RCM for macrocyclization. Org. Lett., 6, (4S,5R)-5-[(Z)-2,6-Dimethyl-1,5-heptadienyl]-4-hy- 525–528 (2004). droxy-2-methyl-2-cyclopentenone [(1S,5R)-2]. Com- 9) Miyazaki, T., Han-ya, Y., Tokuyama, H., and pound (1S,5R)-2 [4.4 mg, 83% yield; (1S,5R)-2/(1S, Fukuyama, T., New odorless protocols for the synthesis 5S)-2 = 53:1] was obtained as a colorless oil from of aldehydes and ketones from thiol esters. Synlett, 477– 480 (2004). 7.9 mg (23 mmol)of(Z)-7 in the same manner as that 23 10) Wittenberg, R., Srogl, J., Egi, M., and Liebeskind, L. S., described for (1S,5R)-1. ½D þ150 (c 0.17, CHCl3); þ Ketone synthesis under neutral conditions. Cu(I) diphen- HR-FABMS m=z (½M þ H ): calcd. for C15H23O2, ylphosphinate-mediated, palladium-catalyzed coupling 235.1698; found, 235.1700. of thiol esters and organostannanes. Org. Lett., 5, 3033– 3035 (2003). Acknowledgment 11) Takeda, N., and Imamoto, T., Use of cerium(III) chloride in the reactions of carbonyl compounds with organo- This work was financially supported, in part, by a lithiums or Grignard reagents for the suppression of Grant-in-Aid for Scientific Research (B) from the abnormal reactions: 1-butyl-1,2,3,4-tetrahydro-1-naph- Ministry of Education, Culture, Sports, Science and thol. Org. Synth., 76, 228–238 (1998). Technology of Japan (No. 16380075).