Bull. SOC. Chim. Belg. vol. 105 I no 5 I 1996 SHORT COMMUNICATION

00374646 196 1 $2.00 + 0.00 0 1996 Cornit6 van Beheer van her Bulletin V.Z.W.

FIRST TOTAL SYNTHESIS OF (&)-(lE,3E,1 IE)-CEMBRA-I ,3,11-TRIEN-6-0NE

Jing Li, Xiangjun Yue, Ying Li, Liming Hou, Weidong Li and Yulin Li* State Key Laboratory of Applied Organic Chemistry and Institute of Organic Chemistry, Lanzhou University,

Lanzhou 730000, P.R. China

Received : 15/09/1995 -Accepted : 11/03/1996

ABSTRACT

flurclpa cdyclata, was first synthesized in 12 steps starting from citronellal. (f)-(lE,3E,11E)-Cembra-l,3,1l-trien-6-one, an important marine cembrane ketone isolated from

INTRODUCTION in 1991 from the Caribbean sea whip flunczk~ Cembranoids , 14- membered cyclic diterpenes d ~ l a t a ~ ~ ~ . The geometrical structure of 1 has been

from marine sources, are of interest to synthetic confirmed by spectral methods. As far as we know, ‘chemists and biologists due to their unusual the total synthesis of this compound have not been structural features and wide range of biological reported yet. Herein we report the total synthesis of

( l E , 3E, 11E )- Cembra- 1, 3 , 11- trien- 6- one ( 1 ) ,a marine cembranoid , was isolated

1 from citronella1 2.

-“tu 7

8b 8a X = I ““slf 11

TBDPSO

@ 9

10 12 1

scheme

a ) MeSiCN, KCN/18-crown-6, O‘C, 30 min, 100%; b) LiN(SiMeS)z, O”C, 20 min, then 4 , r. t. , THF, 28%; c ) n-Bu4N+F-, 10% aq. THF, 25‘C, Zh, 93%; d ) 1. NaBH4, MeOH; 2. TBDPSCI, imidazole, DMF, r. t. , Zh, 96%; e ) SeO,, t-BuOOH, CHzClz, 15h, 56% ; f ) I,, PPh3, imidazole, EtzO/CH3CN. 100% i g) methyl isopropyl ketone, LDA, - 78”C, Zh, 56 % ; h ) 1. p-TsOH, MeOH, r. t. , 2h; 2. MnO,, 11-hexane, r. t. , ZOh, 93%; i ) Zn/TiCId, Py, DME, reflux 30h, 62% ; j) n-Bu@+F-in THF ( l M ) , r. t. , :’Ah, 91%; k) PCC, silica gel, CH2C12, r . t. , 10 min, 90%

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EXPERZMENTAL Citronellal 2 was first converted to the

cyanohydrin trimethylsilyl ether 3 by addition of Me3SiCN in the presence of a catalytic amount of KCN/18-crown-6 complex. Compound 3 was treated with 1. 25 equiv of UN (SiMe312 in THF and then coupled with 4 to afford the desired compound 5 in 28% yield, which was converted into ketone 6 by reaction with a catalytic amount of n-Bu4 N+F- in 10% aqueous THF at 25°C for 2h under argon atm~sphere'''~.

The ketone 6 was reduced with NaBH4 to give a corresponding alcohol, which then was protected with TBDPSCl to afford silyl ether 7c5). The high regioselective akylation of 8b was carried out with 5 equiv Li-enolates of methyl isopropyl ketone in dry THF at - 78 "C under argon atmosphere in 56 % yieldc6' .

The last key step was intramolecular macrocyclization induced by low valent titaniumc73. Highly diluted solution and slowly addition of 9 were essential conditions in order to ensure the Occurance of intramolecular reaction. After cyciization product 1 0 had been deprotected with 1M n- BudN+F- in THF@'and then oxidized by PCC in C H Z C ~ ~ ~ ~ ) , the title compound ( f. )-1 was obtained as a clear oil.

The spectral data of key intermediates 6,10,11 was compatible with the assigned structures.

- 1.35 (2H, m, CHZ), 1.58, 1.67 (each 3H,s ,

(9H,rn,ICHz,CH), 2. 21-2. 43(2H,ddd,CH~),

6 r)H(CDC13,4OOMHz): 0.87(3H,d(CH3), 1.15

(CHs)zC=), 1 . 6 8 ( 3 H , ~ , C H 3 ) , 1 .71-2.00

3. 09 ( 2H , s CHz ) 3.50 - 3.90 ( 2H , dt , CHzO ) , 4.03 - 4.28 (ZH, ddd, CH20), 4.62 ( l H , t , OCHO), 5.07(1H,t,CH=),5. 47(1H,t,CH=). ni/n(EIMS): 3 2 2 ( M f , l % ) , 238,220,153,135,

1 444,1364,1107,102 lcm- '. 109,85,69,55,41. V,,(IR) : 2944,2a71,1724,

10 b(CDCl3, 400MHz): 0*87(3H,d,CHs) 1. 08 (9H,s , (CH3)3C), 1. 07-1. 09(6H9d,2CH3), 1.51,1.69(each 3H,d,CH3), 1.20-1.40(2H, m , CHp), 1.65 - 2.60 (lOH, m, 4CH2, ZCH), 2.75-3.15(2H,dd,CHZ), 4.OO(lH,m,CHO), 5 . 1 8 ( 1 H , t , C H = ) , 5 . 9 7 ( 1 H , d , C H = ) , 6.12 < l H , d , C H = ) , 7 .39(5H,m,ArH), 7.69(5H,

m,ArH). m/z(EIMS): 528(MT,9%), 471,377,

2958,2930,2858,1457,1427,1377,1109,1041, 821,737,703cm-'.

359, 335, 293, 199, 183, 136, 121. v,, (IK):

11 bi(CDCl3,4OOMHz): 0.61(3H,d,CH3), 1. 04 (9H,s , (CHs)3C) 1.09- 1.12 (6H, d , 2CH3) , 1.55 , l . 66(each 3H,d,CH3), 1. 27-Z2.65(20H, m, 9CH2, ZCH), 3.50 - 3.93 (ZH, dt, CH20), 3.85(1H,m,CHO), 3.90-4. 10(2H,d,CH20), 4.58(1H,t,OCHO), 5. 06(1H,rn,CH=), 5.33 ( l H , m , C H = ) , 7 .39(5H,m,ArH), 7.71(5H, m,ArH). m/z(EIMS): 589,505,487,477,419,

2857,1710,1465,1427,1108,1023,704crn-1. 283, 221, 199,135,85. V ~ X (ZR): 2962, 2931,

ACKNOWLEDGEMENTS The project was financially supported by the

National Natural Science Foundation of China and by the Special Research Grant for Doctoral Sites in Chinese Universities.

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