The first total synthesis of the natural enantiomer of the insect-antifeedant dihydroclerodin ( 1 ) and lupulin C ( 268 ) has been achieved in 18 and 17 steps respectively starting from R-(-)-carvone ( 2 ). A new strategy was developed in which the hexahydrofuro[2,3- b ]furan fragment was introduced in the beginning of the synthesis, via a remarkably diastereoselective Mukaiyama reaction of silyl enol ether 135 with 2-methoxy-hexahydrofuro[2,3- b ]furan ( 156 ), which gave only two of the possible eight diastereoisomers. After separation of the two diastereoisomers, ketone 142 with the correct configuration at C9, C11, C13, and C16 was obtained in an easy procedure (chapter 2). For the annulation of ketone 142 , the Robinson annulation was investigated first, but this did not give good results due to steric hindrance (chapter 4). To reduce the steric congestion, the isopropenyl group was transformed into a double bond by ozonolysis, followed by treatment of the ozonide with Cu(OAc) 2 and FeSO 4 to give enone 146 . A 1,2-addition of 3-(1,3-dioxolan-2-yl)-propyllithium to this enone, followed by an oxidative rearrangement yielded enone 249 . Catalytic reduction of this enone with palladium took place from the b-side and thus gave the correct stereochemistry at C10. Deprotection of the aldehyde, followed by an aldol reaction led to decalone 144 .
( a ) MeMgI, CuBroMe 2 S, TMSCl;
( b ) TrClO 4 , 156 ;
( c ) separation of diastereoisomers;
( d ) i) O 3 , ii) Cu(OAc) 2 , FeSO 4 ;
( e ) t -BuLi, 246 ;
( f ) PCC;
( g ) Pd/C, H 2 ;
( h ) PPTS, H 2 O; ( k ) PPTS, D.
The conjugate addition of vinylmagnesium bromide to 144 and trapping of the enolate with a solution of monomeric formaldehyde introduced the last carbon atoms of the clerodane skeleton and established the desired stereochemistry at C5. The hydroxyl group was protected as its silyl ether ( 253 ) to ensure a selective reduction of the carbonyl function to give a diol with the desired configuration at C6. The obtained diol was protected as its acetonide, followed by ozonolysis of the double bond, and subsequent reduction of the ozonide gave alcohol 260 .
( a ) i) vinylMgBr, CuBroMe 2 S, ii) CH 2 O;
( b ) TBDMSiCl, imidazole;
( c ) LiAlH 4 ;
( d ) MeO 2 CMe 2 , PPTS;
( e ) i) O 3 , ii) NaBH 4 .
To obtain an exocyclic double bond at C4, the hydroxyl group in compound 260 was transformed into its xanthate ester 264 . Elimination of this ester at 216øC gave the desired 265 (Chugaev reaction). After careful deprotection of the acetonide, an epoxidation of the double bond by m -CPBA was carried out. Acetylation of the hydroxyl groups then gave dihydroclerodin ( 1 ) and epi -dihydroclerodin ( 268 ) which could be separated by flash column chromatography. The measured [a] D fitted well with reported optical rotations of dihydroclerodin isolated from natural sources, which proved that we had synthesized the natural enantiomer of dihydroclerodin. Acetylation of diol 266 completed the synthesis of lupulin C (chapter 5).
( a ) i) NaH, CS 2 , ii) MeI;
( b ) 216øC;
( c ) CF 3 CO 2 H;
( d ) m -CPBA;
( e ) Ac 2 O, pyridine, DMAP.
overall yield of 0.35% in 18 steps
|Qualification||Doctor of Philosophy|
|Award date||10 May 2000|
|Place of Publication||S.l.|
|Publication status||Published - 2000|
- insect control