Pergamon Tmahrdron Leners. Vol. 36, No. 49, pp 9003-9006. 1995

Elsewer Science Ltd Printed m Great Britain

0040.40?9/95 $9.50+0.00

0040-4039(95 10 197 I-S

Diastereo- and Enantio-Controlled Synthesis of Sandalwood Constituents

(-)-p-Santalene and (+)-Epi-jbsantalene Starting from

the Same (+)-Norcamphor

Masanori Saito, Mitsuhiro Kawamura, and Kunio Ogasawara*

East Indian sandalwood constituents. (-I-p-santalene’ (1) and (+)-epi-p-santalene’ (2), are of interest not

only for their fragrant odor character but also for the fact that then absolute structures. except for the

diastereomeric quaternary stereogemc center. have been found to be enantiomeric with respect to the core

bicyclo[2.2.l]heptane framework. Although the problem in racernlc synthesis’ is merely the matter of

diastereoselecnve control. an additlonal problem needs to be solved m chiral synthesis when only one particular

enantiomer is av;ulable as the precursor Namely. a divergent route making the particular enantiomer utilizable

has to be devrsed.“’ We wish to report here one such example which allowed use of the same (+)-norcamphor

(3) as the chiral startmg material for the dlasterecl- and enantio-controlled construction of either (-)-p-santalene

(1) or (+i-epl-a-santalene (2) (Scheme 1).

I,-)-fi-santalene (1) \ A 0

Lb (+)-norcamphor (3)

(+)-epi-p-santalene (2)

Scheme 1

(+)-Norcamphor (31. the only accessible enantmmer in >OS% cy: at present from commercially available

(+)-endo-norborneol.’ was transformed mto the keto-ester 4 in satisfactory yield by exactly following the

established procedure for the racemic substrate ’ To mtroduce the methyl group, 4 was first treated with

diphenyl chlorophosphate m the presence of sodium hydride to give the enol phosphate” (5), [a],” -30.4 (c

I .O. CHCI,). This compound was next reacted with tnmethylaluminum in the presence of a catalytic amount of

9004

tetrakis(triphenylphosphine)paJladium in I .2-dichloroethane- at 80 “C to furnish the cross-coupling product 6,

[a],,” -1 I I .6 (U 0.3, CHCI,), m excellent yield without difficulty. It is noted that the ester function of both the

substrate and the product was stable and remained so throughout this transformation (Scheme 2).

CO,Me CO,Me bO,Me 4 5 6

Scheme 2

Reqenr.\ and r~onduron.\ II ref 7 II) haH. (PhO),PIO)C‘I. THF (X5% I 111) Me,AI. Pd(PPh,), (cat ). CICH,CH,CI, 80 “C (85%).

In order to synthesize (-)-p-santalene (1). 6 w’as reduced with diisobutylahrminum hydride (DIBAH) to

give the allylic alcohol 7, [a],,” -5 I .6 (i’ 0.6. CHCI,) Smce neither the direct Claisen rearrangement using

ethyl vinyl ether in the presence of mercury(I1) acetate nor its Johnson modification’ using triethyl orthoacetate

in the presence of acid catalyst was successful m fumishmg the corresponding [3,3]-sigmatropic rearraugement

products satisfactorily. 7 was first treated with phenyl vmyl sulfoxide’ in the presence of sodium hydride to

give the P-allyloxyethyl phenyl sulfoxide (8) which, wsithout purification, was heated at 150 “C in decalin to

give the expected aldehyde 10. [a],,‘” -64.3 ((, 0.4, CHCI,). in 57% overall yield as a single product via the

vinyl ether (9) by concurrent p-elimination and sigmatropic rearrangement. Although the stereochemistry of the

product 10 could not be determined at this stage. subsequent transformation revealed that the p-carboethyl

group was introduced diastereoselectively from the C.UI face of the intermediate 9 as anticipated.

10 v4

11 X=OH

vi & 12.X=OTs 13 : X=CN

“ii G,4 X=CHO

Scheme 3

Reuwxs rind condrfwn.x I I DIBAH, CH,CI,. -78 ‘C (89%) II) PhSlO)CH=CH?. NaH. THF, room temp. iii) decalin. 150 “c (57% from 7) 1~) NaBH,. MeOH. v){+TsCI. Et,N. 4-(NN-dlmrthylamtno)pyndine (DMAP) (cat.), CH,CII. vi) KCN, DMSO. vii) DIBAH. CH,CI,. 45 “C. then dtl. H,SO, vill) I-PrPPh,l. ~-B&I, THF. -30 “C (23% from 10).

Thus, 10 was sequentially reduced. tosylated and substituted to furnish the cyanide 13, [a],” -102.8 (c

1.3. CHCI,) du the alcohol 11, [a],,” -I IO.1 tc 0.7, CHCI,). and the tosylate 12. The cyanide 13 was

reduced partially with DIBAH to give the aldehyde 14 after acid workup which, on Wittig condensation,

9005

afforded (-)-p-santalene (1). ]a],,‘” -124.0 (c 0.4. CHCI,) [lit.“‘: [cI],~‘” -I 12 (c 5.01, CHCI,)], as a single product. Stereochemistry of the intermediate aldehyde 10 was thus determined unambiguously at this point.

Overall yield of 1 from 4 was 8.4% (Scheme 3) We next examined, the transformation of the same key compound 6 into (+)-epi-psantalene (2).

Treatment of 6 with methyl todrde m the presence of lithnrm diisopropylamide (LDA) allowed diastereo- and tegioselective alkylation” to give the exe-methyl product 15. [cI],,‘~ 41.3 (c 0.8, CHCI,), exclusively in excellent yield. The stereochemistry of the product was determined unambiguously by subsequent transformation. Thus, reduction of the ester 15 yielded the primary alcohol 16, [aIt]‘” +95.1 (c 0.6, CHCl,), mp 80.0-8 I.5 “C. Oxidatton of 16 under the Swern condittons yielded the highly volatile aldehyde 17 which, immediately, was transformed into the homologated primary alcohol 20. [a],,“’ +47.3 (c 0.5, CHCI,), in sequential Wtttig condensatton,” acid hydrolysis, and reduction via the vinyl ether 18 and the aldehyde 19.

The primary alcohol was first transformed mto the known cyanide”’ 22, [aIn” +50.8 (c 0.31, CHCl,) [lit.“‘: [a],,” +27.5 ((’ 0.24. CHCI,)], riu the tosylate 21 as above. Finally, the cyanide 22 was reduced partially with DIBAH to give the aldehyde 23 after acid workup. which was condensed with the Wittig reagent

to yield (+)-epi-p-santalene (2). [a],,” +28.1 (c 0.38, CHCI,) [lit.: [al,;’ +25.9 Cc 0.4, CHCI,),‘” [a],‘” +26.4 (c 1.0, CHCI,).” [u],,‘” +27.4 ((’ I .95, CHCI a)‘c] Overall yield of 2 from 4 was 5.5% (Scheme 4).

CO,Me i 15 16 OH

L ‘X

,,Q7:X=O 18 : X=CHOMe

19 ,,,~20 : X=OH viii &21 : X=OTs

22:X=CN IX ~23:xmo

Scheme 4

Rruyenrs md c ~mdllrrm II WA. Mel. THF. -7X (‘ 1x7’11 ii, LlAIH,. THF (88%). 111) Swem oxid (7SrC). iv) MeOCH:PPh,CI. &aH-DMSO. THF. 0 (‘ 1) 10% HCI $11 UaBH,. MeOH (48% from 17). vii) p-T&I, Et,N, DMAP (cat.), CH:CI: viii) KCN. DMSO (hJ% from 201 1x1 DIBAH. C‘ti,CI,. 35 C. then dil H,SO, x1 I-PrPPh,l. n-BuLi. THF, -30 “C (44% from 221.

In concluston. we have devised a dtastereo- and enantio-controlled construction of (-)-b-santalene (1) and (+)-epi-p-santalenc (21. both occurring in East Indian sandalwood oil and having an enantiomeric core

bicyclo[2.2.l]heptane framework. ustng the same (+)-norcamphor (I) as the chiral starting material.

References and Notes I. Chual synthesis of p-santalene, see: a) Hodgson. G. L : MacSweeney, D. F.; Mills, R. W.; Money, T.

J Chertr SOC.. (‘hem C’omntun 1973. 275 b) Eck. C R.; Hodgson, G. L.; MacSweeney, D. F.;

9006

2

3.

4.

5.

6.

7.

8.

9.

10.

11. 12

Mills. R. W.: Money. T J Chem. SOCK.. Per/&l Truns. / 1974. 1938. c) Oppolzer, W.; Chapuis, C.;

Dupuis. D.: Guo. M. Hell Chim. Al,ru 1985, 68, 2100. d) Takano, S.; Inomata, K.; Kurotaki, A.; Ohkawa. T.: Ogasawara, K. J. Gem. Sock.. Chem. Commun. 1987, 1720. e) Sonawane, H. R.; Bellur, N. S.; Ahuja. J. R.; Kulkami, D. G. J. Or,g. Chem. 1991, 56, 1434. f) Krotz. A.; Helmchen, G. Llebig~ Ann. Chem. 1994. 601.

Chiral synthesis of epl-p-santalene. see: a) la and lb b) Id. c) Arai, Y.; Yamamoto, M.; Koizumi, T. Bull. Chem Sot. Jpn. 1988. 6/. 467. d) Zhong. G. -F.: Schlosser, M. Synlett 1994, 173. e)

Kamikubo. T.; Ogasawaa, K. Chem. Left. 1995. 95.

Pertinent reviews, see: a) Heathcock. C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.: White, C. T. in The TOM Swthe.sis of Nutural Products Ed. by ApSimon. J Wiley. 1983, 5, 249. b) Fraga, B. M. Naturul Prod. Rep. 1995. 12. 303 and the preceding reports.

Prepared by Jones oxidation of (+)-endo-norhorneol manufactured enzymatically which was kindly supplied by Chisso Corporation, Marunouchi 2-7-3. Chiyoda. Tokyo 100, Japan. Optical purity of 3 wzas determmed to be >9S% ee by HPLC using a chiral column, see: Kawamura, M.; Ogasawara, K. Tetrcthedron Lett. 1995. 36. 3369.

Mander. L N.; Sethi, S. P Tetrahedron Lett. 1983. 24. 5425

Ireland, R. E.: Pfister. G. Tetrahedron Lrtt. 1969. 214.5.

Takai. K.; Oshlma. K.; Nozaki, H. Terrahedron Left. 1980, 21. 2531. Monti, H.; Corr~ol, C.: Bertrand. M. Terrahedron Left. 1982, 23, 947.

Mandai. T : Ueda. M.: Hasegawa, S.: Kawada, M : Tsuji, J.: Saito, S. Tetrahedron Left. 1990, 31,

4041

Bertrand. M Motm, H.; Huong, K. C. Terruhedron Leu. 1979. IS

Corey. E. J.: Nozoe. S J. Am. Chem SM. 1965. 87, 5728.

‘H nmr spectra (300 MHz. CDCI,) of the selected compound5 - 6: 6 3.71 (s, 3H). 3.20 (br s, IH), 2.78 (br s, IH). 2.11 (s. 3H). 1.80-1.64 (m, 2H). 1.47-I 37 (m, IH). 1.27-0.05 (m, 3H). 7: 64.22 (d, IH. J=l2.S Hz), 4.06 (d. IH. J=l2.5 Hz). 2.91 (s, IH). 2.62 (br d, IH, J=O.7 Hz), 1.75-0.85 (m, 7H). 1.69 IS. 3H). 10: 6 9.83 (t. IH. J=3.0 HI). 1.X6 (s. IH). 4.S4 (s, lH), 2.73 (br d, IH, J=2.9,

15.3 Hz). 2.34 (dd, IH. J=3.3, 15.1 HI). 2 26 (br d. IH. J=3.X Hz), 1.80-1.18 (m, 6H), 1.23 (s, 3H). 11: 6 4.7X (s, IH). 4.52 (s. IH). 3.X5-3.6.1 (m. 2H). 2.6X (br d, IH, J=4.0 Hz), 2.10 (br d, lH, J=2.6 Hz), 1.82-1.15 (m. 9H). 1.07 (s, IH). 15: 6 5.02 (s. IH), 4.80 (s. IH), 3.69 (s, IH), 2.74 (br d. IH, I=29 Hz). 7 71 tbr d. IH, J=l.5 Hz). 17X-l I9 cm. 8H). 1.33 (s. 3H). 20: 6 4.75 (s, IH), 4.51 (s. IH). 3.X6-3.60 (tn. 2H). 2.68 (br d. IH. J=4.0 Hz). 1.98 (br d. IH, J=2.9 Hz), 1.80-1.13 (m,

9H). 1.03 i\, 3H, c-)-p-santalene (1): b 5.14-5.03 (m. IH!. 3.72 (s. IH), 4.46 (s, IH). 2.66 (br d, IH, J=2.9 Hz). 2 IS-1 X4 (m. ?H). 1.67 IS, JH). 161 (s. 3H). 1.57-1.08 (m, 8H), 1.04 (s, 3H). (+)- epi-p-santalene (2V65.165.06(m. lH1.4.71 (s. lH).3.47(s, lH).2.67(brd. lH.J=4.1 Hz),2.13- 178 cm. 3H). I.68 (\. {Hi. 1.62 (s. 3H). 1 5X-l 16 (m, 8H). 1.02 (s. 3H).

(Received in Jupun I2 Seprcwhrr 1995; re~~iseci I I fktolwr 1995: accepted 13 October 1995)