Synthesis of antitumor marine steroid aragusterols

Twohedron

L&/m.

Vol. 36. No. 45. pp. 8231-8234. 1995 Elsevw Science Ltd Printed in Great Britain 0040-4039195 $9.50+0.00

0040-4039(95)01772-O

Synthesis of Antitumor

Hidemichi

Milome,

Hiroaki

Miyaoka,

Marine Steroid Aragusterols

Masakazu

Nakano

School ol Pharmacy, Tokyo Univcwty of Pharmacy and Me Horinouchi, Hmhioji. Tokyo 192-03. Japan

and

Yasuji

Yamada*

Science,

A

bsrracf : The synthcw of amilumor mxinc swroid araguswols A, B. C and D WZLYsuccessfully carried out. The synthesis involved swcosclcctive consuuction of side chain segment 8, coupling of 8 wilh 20.kcto slcrold 1 I giving aragustcrol B rrwl conversion of aragustcrol B into araguslerols A. C and D.

Aragusterols A, B, C and D ’ (xestokerol C 2). isolated from the Okinawan marine sponge genus, Xesrospongia, are snucturally unique marine steroids each possessing a rare 26, 27-cycle structure in the side chain. Aragusterols are also important for their biological activity. Aragusterols A and C very strongly inhibit the proliferation of KB cells at IC,, 0.042 and 0.041 &ml, respectively, and express potent in vivo antitumor activity against Ll210 leukemia in mice (T/C 220 8 and 257 %, at 1.6 mg/kg).“*” For more detailed pharmacological research on aragusterols A and C, both compounds must be available in greater amounts. On this study it was decided to conduct this synthesis using hecogenin, a readily available material. The synthesis was conducted by initially obtaining from hecogenin aragusterol B, a natural resource more abundantly present in nature than either aragusterols A or C. This mode of synthesis is presented in detail in the following.

Cl OH y+’ HO ..\H H : : i0xFl aragusterol

A

arqusterol

C

823 I

8232

The synthesis involves the stereoselective formation of side chain segment 8 present in ail aragusterols, stereoselective coupling of 8 with 20.keto steroid I 1 leading to aragusterol B and the conversion of aragusterol B to aragusterols A, C and D. Side chain segment 8 was synthesized in the manner shown in Scheme 1. The hydroxy group of (R)-Shydroxymethyl-2(5H)-furanone (1) p readily available from L-ascorbic acid, was protected as the TBS ether to give 24 (92 % yield). Reaction of butenolide 2 with lithium dimethylcuprate in EGO at -78°C gave lactone 3 with high stereoselectivity in 90% yield.’ Reduction of the lactone carbonyl in 3 with LiAIHa, followed by deprotection of TBS ether with 80% AcOH gave trio1 4 in 89% yield (two steps), which was then converted to allylic alcohol 5 in the following four steps: 1) Pb(OAc), oxidation of 1,2-diol to give aldehyde, 2) Wittig reaction of the aldehyde to give a, p - unsaturated ester, 3) protection of the primary hydroxyl group as silyl ether and 4) diisobutylaluminum hydride (DIBAH) reduction of the ester. Diastereoselective cyclopropanation was successfully conducted according to the recent method of Charette.6 Treatment of allylic alcohol 5 with CH& in the presence of EtzZn and the n-butylboron complex of (S,S)-(-)-N,N,N’,N’-tetramethyltartaide (9) gave the requisite cyclopropane derivative 6’ as the sole product in 99% yield. Compound 6 was converted to alcohol 7* ([a],** -36.6” (c 1.28, CHCla)) in three steps: 1) bromination of the hydroxy group, 2) reduction of the bromide with LiAIH, and 3) deprotection of the silyl group with “Bu,NF. Finally bromide 8, a segment of the side chain, was obtained by treating alcohol 7 with Ph,P-NBS in 75% yield. Scheme I

5

6 9 Reagents : A. TBSCI, imidazolc, DMF, r.t., 92%; B. MczCuLi, Et20, -78OC, 90%; C. i) LiAlb, THF, 0°C. ii) 80% AcDH, r.t.. 89% (2 steps); D. i) Pb(OAc)4, KzC@, benzene, r.t., ii) PhsP=CHC@Me, benzene, r.t., 67% (2 Steps), iii) TBDPSCI. imidazole, DMF. r.t.. iv) DIBAH. CH2C12, -78°C. 91% (2 steps); E. CH212, EtzZn. 9. CHzcI2, r.t., 99%; F. i) PhsP, CBr4, CH2C12, r.t., ii) LiAIb, THF-Et20, r.t., iii) “Bu,$VF, THF, r.t., 88% (3 Steps); G. PbP. NBS, CH2CI2, r.t.. 75%. Aragusterol B was synthesized via stereoselective coupling of side chain segment 8 with 20-keto steroid 11 (Scheme 2). The hydroxy groups of steroid IO, prepared from (+)-hecogenin acetate in five steps: were protected as triethylsilyl (TES) ether to give 20-keto steroid 1 1. Reaction of 20-keto steroid 11 with dkyllithium, prepared from bromide 8 with lithium naphthalenide in THF at 0°C followed by deprotection of TES ether with “Bu,NF at room temperature gave alcohol 12 with high stereoselectivity (2O.S:2OR = 26:1).“.” The regioselective Oppenauer oxidation of C-3 hydroxyl group of 12 afforded aragusterol B (mp 194-195”C, [a]o24 +4.7” (c 0.22, CHC13)). Aragusterols A, C and D were synthesized from aragusterol B by chemical modification of the side chain. Ketalization and dehydration of aragusterol B by treatment with ethylene glycol andp-toluenesulfonic acid in

8233

Scheme 2

o&q

aragusterol A

i

15

H

aragusterol C

aragusterol D

Reagenrs : A. TESCI, imidalolc, DMF, r.1.. 8.5%; B. i) 8, lithium naphthalenide, THF, O”C, ii) “Bu&F, THF, r.t., 93% (2 steps): C. Ai(O’Buh, cyclohcxanonc, tolucnc, rcllux, 66%; D. ethylene glycol, TsOH, bcnzcne, rcflux. 79%: E. ‘BuOOH, VO(ac:rc)2. CHzCI2. r.t., 78%; F. i) ‘PrzNMgBr, THF, r.t., 93%, ii) 80%AcOH, I.[.. 98%: G. mCPBA, NQHPOJ, C’HlClz, O”C, 54%; H. Li2CuCb. THF, r.t., 90%; I. PDC, 4AMS. CH2Cl2, r.1.. qu:mt.

benzene gave 20(22)E olefin 13 and the 20(22)Z isomer in a 1O:l ratio with the concomitant formation of a trace amount of the 20(21) isomer. Epoxidation of & olefin 1 3 with ‘B&OH in the presence of vanadium (III) acetylacetonate” gave @OR, 22R) epoxide 14 along with a trace amount of (20X, 22s) isomer in 26: 1 ratio” in 81% yield.13 Epoxide 14 was converted to allylic alcohol 1 5 by treatment with jPr,NMgBr,14 prepared from diisopropylamine and methylmrrgnesiuln bromide, followed by acid hydrolysis of the ketal with 80% A&H at room temperature. The stereoselective epoxidation of allylic alcohol 15 with mCPBA at 0°C provided aragusterol A (mp IS&161’C, {a],,“’ +3X.0” (c 0.1 1~ CHCIS)).” Reaction of aragusterol A with dilithium tetrachlorocuprate’6 at room temperature afforded exclusively aragusterol C (mp 203-205°C. [c~]~*’ +19.4’ (c 0.27, CHC13)) in 90% yield. The selective oxidation of the hydroxy group at C-22 of allylic alcohol 15 with pyridinium dichromate (PDC) at room temperature gave aragusterol D (mp 151-152”C, [alDz6 -59.2” (c 0.15, CHQ)) in quantitative yield. Physical data for the synthetic aragusterols obtained above showed agreement with those of the corresponding natural aragusterol\ ” Acknowledgments: This work was supposed in part by a Grant-in-Aid for Scientific Research (Grant No.066721 14 and No.06282106) from the blinistry of Education, Science and Culture of Japan.

8234

References

and

Notes

1. a) Iguchi, K.; Fujita, M.; Nagaoka, H.; Mitome, H.; Yamada, Y. Terra/~&on Lefr., 1993, 34, 6277; b) Iguchi, K.; Shimura, H.; Taira, S.; Yokoo, C.; Matsumoto, K.; Yamada, Y. J. Org. Chem., 1994, 59, 7499; c) Shimura, H.; Iguchi, K.; Yamada, Y.; Nakaike, S.; Yamagishi, T.; Matsumoto, K.; Yokoo, C. Experientia,

1994,

50,

134.

2.

Kobayashi,

3.

Mann, J.; Weymouth-Wilson,

J.; Ishida, K.; Naitoh, K.; Shigemori,

4.

Structural assignments for all stable synthetic intermediates were made based on ‘H-NMR MHz), IR, high resolution mass spectroscopy and/or combustion analysis.

5.

The trans stereochemistry of substituents at C-3 and C-4 positions on lactone 3 was strongly suggested by preferential attack of the reagent from less hinder side. Similar stereoselective reactions have been reported. For example: Hannessian, S.; Murray, P. J.; Sahoo, S. P. Tetrahedron Letr., 1985, 26, 5627: Nagaoka, H.; Iwashima, M.; Abe, H.; Iguchi, K.; Yamada, Y. Chem. Pharm. Bull., 1992, 40, 1742.

6.

Charette, A. B.; Juteau, H. J. Am. Chem. Sot., 1994, Brochu, C.J. Org.Chem., 1995, 60, 1081.

116, 2651: Charette, A. B.; Prescott, S.;

7.

Cyclopropanation of 5 in the absence of dioxsborolane diastcreomeric mixtures at a ratio of 3 : 2.

chiral ligand 9 resulted in the formation of

8.

Alcohol 7 was converted top-nitrobcnzoate shown identical with p-nitrobenzoate ([a],,‘* by chemical degradation.”

([a],,26

9.

Tschesche, R.; Schwinum, E. Chem.

1967.

A. Carbohydr.

Ber.,

Res.,

H. J. Nat. Prod. 1, 216,

199

1993, 56, 1350.

511. (400 or 300

-24.3’ (c 0.29, CHCb) which was subsequently -25. I” (c 0.39, CHCIJ) derived from the natural aragusterol 100,

464.

10.

The ratio of the diastereomers was determined by ‘H-NMR

11.

Similar stereoselective reactions for 20-keto steroids have been reported. For example: Chaudhuri, N. K.; Williams, J. G.; Nickolson, R.; Gut, M. J. Org. Gem.. 1969, 34, 3759: Kametani, T.; Katoh, T.; Tsubuki, M.; Honda, T. J. Am. Chcm. Sot., 1986, 108, 7055.

12.

Sharpless. K. B.; Michaelson,

13.

Diastereoselectivity in the epoxidation of 1 3 can be explained based on the transition state in which vanadium metal is coordinated with hydroxy group at C-12.

14.

Fukuyama, T.; Akasaka, K.; Karanewsky, Sot., 1979, 101, 262.

15.

The stereoselectivity of epoxidation the less hindered side.

16.

Ciaccio, J. A.; Addess, K. J.; Bell, T.W. Tcrrahedron

17.

aragusterol A” mp 157-158”C, [alo +37.6” (c I .06. CHCl3); aragusterol Bib mp 194-195”C, [a], +4.0” (c 1.56, CHCI,); aragusterol C” mp 2042OS”C, [a],, +20.1° (c 0.35, CHCI,); aragusterol Dlb mp 152.5153.5”C, [a], -61.3” (c 0.30, CHC13).

(Received

in Japan

7 August

R. C. J. Am. Chem.

1995; revised

Sot.,

analysis.

1973, 9.5, 6136.

= 6, ‘2
with mCPBA is explained by preferential attack of the reagent from

8 September

Left.,

1995;

1986, 27, 3697.

accepted

14 September

1995)