Pergamon Tetrahedron Letters, Vol. 37, No. 33, pp. 5929-5930, 1996

Copyright © 1996 Elsevier Science Ltd Printed in Great Britain. All rights reserved

PII: S0040-4039(96)01279-8 0040-4039/96 $15.00 + 0.00

8-Endo Cyclization of (Alkoxycarbonyl)methyl Radicals: Stereoselective Synthesis of (-)-Clavukerin A

and (-)-11-Hydroxyguaiene

Eun Lee* and Cheol Hwan Yoon

Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea

Abstract : (-)-Clavukerin A was synthesized from (+)-limonene oxide via 8-endo radical cyclization. (-)-I l-Hydroxyguaiene was also synthesized, but its spectroscopic data did not match with those reported for the natural product. Copyright © 1996 Elsevier Science Ltd

Clavukerin A (1) was isolated from the Okinawan soft coral Clavularia koellikeri by Kitagawa and

coworkers. ~ Considerable amount of work was directed towards synthesis of this trinorguaiane

sesquiterpene, 2 but the known syntheses of the natural enantiomer are lengthy and inefficient. 2~'2d

We reported some time ago that 8-endo cyclization is the preferred mode of reaction for

(alkoxycarbonyl)methyl radicals generated from bromoacetates. 3 In the present study, this unique reaction

was utilized in the synthesis of (-)-clavukerin A.

The bromoacetate 4, prepared from the known aldehyde 3, 4 reacted with tributylstannane under the

standard high dilution conditions to yield the heptanolactone 5 as the only cyclization product. (Scheme 1)

O • 1) cat. HClO4, aq. THF ~ H 2) NalO4, aq. THF 1) LAH, Ether, 0 °C

3) Piperidine, Ether; 2) BrCH2CO2H AcOH, Reflux O DCC, DCM, 0 °C

2 75 % 3 89 % 4 Br (+)-Limonene oxide 0

1.2 eq. Bu3SnH 0.05 eq. AIBN Benzene (0.025 M) Reflux, 5 h (Syringe Pump, 4 h) 68 %

TiCI4, Zn ~ THF, Reflux 1) LAH, Ether

Reverse Addition 0 2)Swern Oxid. 0 (Syringe Pump, 16 h) 0 88 %

1 8 5 % 6 5 (-)-Clavukerin A

Scheme 1

The lactone 5 was reduced to a diol via lithium aluminum hydride t~eduction, and subsequent oxidation

led to the isolation of the dialdehyde a ) c (-)-Clavukerin A (1) 5 was obtained via intramolecular McMurry-

type coupling reaction using titanium chloride and zinc metal. 6

5929

5930

The heptanolactone 5 was also envisaged as a good intetvnediate for the synthesis of 11-hydroxy-

guaiene (11) isolated by Bohlmann from the roots of Parthenium hysterophorus. 7 Basic methanolysis of the

lactone 5, THP protection of the resulting primary alcohol, and subsequent lithium aluminum hydride

reduction led to the preparation of the mono-protected diol 7. The ketone 8 was isolated upon tosylation of

7, cyanide substitution, and addition of methyllithium. (Scheme 2)

1) NaOMe, MeOH

cat. p-TsOH "- 2) NaCN, DMSO, 90 °C

O 3) LAH, Ether, 0 °C OH 3) MeLi, THF, -78 °C 79 % OTHP 67 % OTHP

5 7 8

1) cat. p-TsOH MeOH

2) PCC, NaOAc 4A MS, DCM

8 5 %

MeLi, THF, -78 °C Dibenzo-18-c-6

90 % Benzene, Reflux O 82 % O

9

[trio 2° = -47 °

Scheme 2 The ketoaldehyde 9 was prepared via deprotection of 8 and PCC oxidation. Intramolecular aldol

condensation of 9 provided the dienone 10 in good yield, which gave the desired dienol 11 upon addition of

methyllithium. The product 11, however, was found to possess different spectroscopic characteristics 8 from

those reported by Bohlmann. It appears that the structure of 11-hydroxyguaiene reported by Bohlmann has

to be revised. Acknowledgements : This research was supported by the Ministry of Education (BSR1-94-3416) and the Organic Chemistry Research Center (KOSEF).

REFERENCES 1. Kobayashi, M.; Son, B. W.; Kido, M.; Kyogoku, Y.; Kitagawa, I. Chent Pharm. Bull. 1983, 31,

2160-2163. 2. a) Kim, S. K.; Pak, C. S. J. Org. ChelrL 1991, 56, 6829-6832.

b) Asaoka, M.; Kosaka, T.; Itahana, H.; Takei, H. Chem. Left. 1991, 1295-1298. c) Shimizu, I.; Ishikawa, T. Tetrahedron Lett. 1994, 35, 1905-1908. d) Honda, T.; Ishige, H.; Nagase, H. J. ChenL Soc. Perkin Trans. 1 1994, 3305-3310.

3. Lee, E.; Yoon, C. H.; Lee, T. H. J. Ant ChenL Soc. 1992, 114, 10981-10982. 4. Wolinsky, J.; Slabaugh, M. R.; Gibson, T. J. Org. Chem. 1964, 29, 3740-3742. 5. 13C NMR (50.3 MHz, CDCIa) ~5 138.6, 135.0, 128.7, 123.8, 54.52, 37.81, 34.47, 34.30, 27.23, 26.73,

14.44, 11.48; [CX]D24=-50 °(C 0.55, CHC13). 6. (-)-Clavukerin A(1) was obtained in 9 steps from (+)-limonene oxide (34 % overall yield). This is by

far the most efficient synthesis. 7. Bohlmann, F; Zdero, C.; Lonitz, M. Phytochemistry, 1977, 16, 575-577. 8. ~H NMR (200 MHz, CDC! 3) ~ 0.78 (d, 3H, J = 6.6 Hz), 1.36 (s, 6H), 1.74 (s, 3H), 3.15 (1H), 6.39

(s, 1H); ~3C NMR (20.1 MHz, CDC13)~5 147.7, 137.9, 134.2, 117.7, 74.35, 50.94, 37.92, 35.77, 34.83, 29.06, 28.86, 26.88, 25.47, 14.54, 14.41; MS (El) 220 (M ÷, 30), 205 (76), 202 (100), 187 (33), 177 (20), 159 (62), 145 (70), 131 (54), 119 (30), 105 (36), 91 (31), 77 (16), 55 (23), 43 (68); [tX]D2°=-47 o (C 0.34, CC14). Reported value 7 for 11-hydroxyguaiene; [Ct]D24=+34 °(C 2.5, CHCI3).

(Received in Japan 21 May 1996; revised 21 Jane 1996; accepted 26 June 1996)