Clerodane, synthesis

Tokoroyama T. Synthesis of Clerodane Diterpenoids and Related Compounds -Stereoselective Construction of the DecaUn Skeleton With Multiple Contiguous Stereogenic Centers Synthesis 2000 611-633... 

The copper-catalyzed conjugate addition of methyhnagnesium iodide to cyclohexenone and trapping of the resulting enolate as its trimethylsilyl enolate, followed by TrSbCle-catalyzed Mukaiyama reaction, are the first steps of an elegant synthesis of enantiomeri-caUy pure clerodanes (equation 45). 

The copper-catalyzed conjugate addition of methyl magnesium iodide to cyclohexenone and trapping the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloro-antinomate-catalyzed Mukaiyama reaction, is apphed to / -(—jcarvone. C-2, C-3 functionalized chiral cyclohexanones are converted into their a-cyano ketones, which are submitted to Robinson annulation with methyl vinyl ketone. Highly functionalized chiral decalones are obtained that can be used as starting compounds in the total synthesis of enantiomerically pure clerodanes (equation 70). 

METHODOLOGY VALIDATION AND STRUCTURE CORRECTION BY TOTAL SYNTHESIS THE CASE OF THE CLERODANE DITERPENOID, SACACARIN... 

For the synthesis of an antibacterial clerodane 262, ozonolysis of a substituted optically pure (-)-2-decalone 261 with (57 ,97 ,1070-configuration was the starting step (Scheme 80) <1995J(P1)757>. 

The first total synthesis of the clerodane alkaloid solidago alcohol was achieved in the laboratory of H.-S. Liu, using a highly diastereoselective DIels-Alder cycloaddition as the key step. The installation of the 3-furyl side chain required the conversion of the bicyclic primary alkyl bromide to the corresponding aldehyde. This was accomplished by the modified Kornblum oxidation, which employed silver tetrafluoroborate to activate the substrate. 

Ly, T. W., Liao, J.-H., Shia, K.-S., Liu, H.-J. A highly effective Diels-Alder approach to cis-clerodane natural products First total synthesis of... 

Tokoroyama T (2000) Synthesis of clerodane diterpenoids and related compounds - stereoselective construction of the decalin skeleton with multiple contiguous stereogenic centers. Synthesis 611-633... 

Tokoroyama, T., Tsukamoto, M., Asada, T., and lio, H., One-pot stereospecific construction of cis-clerodane skeleton by means of doubly stereocontrolled cyclization. Total synthesis of hnaridial. Tetrahedron Lett., 28, 6645, 1987. 

Efremov, L, and Paquette, L.A., First synthesis of a rearranged ec>-clerodane diterpenoid. Development of totally regioselective trisubstituted furan ring assembly and medium-ring alkylation tactics for efficient access to (—)-teubrevin G, J. Am. Chem. Soc., 122, 9324, 2000. 

For the synthesis of clerodane diterpenoids, Tokoroyama and co-workers examined another version of the intramolecular Hosomi-Sakurai reaction (108). Substrates 55.1 and 55.4 were cyclized to yield adducts 55.2-55.3 and 55.5-55.6, respectively (Scheme 55). 

An approach towards the synthesis of the clerodanes has afforded the intermediate (140). The copper-catalysed 1,6-addition of a benzyl Grignard (142) to the dienone (141) affords an unsaturated ketone (143) which is readily cyclized to the ring c aromatic diterpenoid intermediate (144), providing an efficient route to this system. 

A number of these compounds have insect antifeedant activity. The total synthesis of the substituted c/s-decalin (26) as an antifeedant has been reported. Clerodanes have previously been detected in Salvia (Labiatae) species. The gesnerohlins A and B, obtained from S. gesneraefolia, have been assigned the structures (27) and (28) although their absolute stereochemistry was not determined. A further series of clerodanes of uncertain stereochemistry has been isolated from Baccharis species, including bacrispine (29) from B. crispa and the malonate ester (30) from B. tricuneata. ... 

An interesting cascade of two sigmatropic rearrangements followed by an ene reaction was developed for the synthesis of the weo-clerodane skeleton that is a part of the natural product teucroUvin A (Scheme 6.14). Promoted by microwave heating, the precursor 66, which is easily available by the attack of a lithiumorganyl... 

Paquette and Efremov used a ring-closing metathesis strategy in their first total synthesis of the rearranged neo-clerodanes, teubrevin G and teubrevin These compounds feature a cycloctanene core fused and... 

The enantiomerically homogeneous substance 3 has been employed as an intermediate for the synthesis of hans-clerodane diterpenoids ... 

Similar processes have been designed and utilized extensively by Barriault and coworkers for efforts in natural product synthesis. An impressive example of this strategy was utilized for the synthesis of the neo-clerodane skeleton of teucrolivin A. Thermal rearrangement of 92 under microwave irradiation results in a tandem sequence featuring an oxy-Cope rearrangement, followed by the Claisen rearrangement and subsequent ene reaction to give 93. 

SYNTHESIS OF CLERODANE DITERPENES VIA LEWIS ACID CATALYZED CYCLOADDITIONS... 

The ability to access either stereochemistry should have application to not only the synthesis of the Clerodane diterpenes but to other natural products as well. Especially in the case where the opposite stereochemistry to that of the Qerodanes was obtained. There are natural products which have this reversed stereochemistry. For example, the natural product siphonodictyal D (40) a metablolite possessing antimicrobial activity which was... 

Almstead, J.I., Demuth, T.P. and Ledoussal, B. (1998) An investigation into the total synthesis of deroddin stereoselective synthesis of clerodane intermediate. Tetrahedron Asymmetry, 9, 3179-3183. 

Nakano, T., and A. Martin Synthesis of labda-8(17),13(14)-diene-15,16-olide and 15,16-epoxy-labda-8(17),13(16)-14-triene and their rearrangement to clerodane derivatives. Tetrahedron 38, 1217 (1982). 

Scheme 1.33 Asymmetric Morita-Baylis-Hillman reaction/Lewis acid promoted annulation reaction for the synthesis of Clerodane decalin core.

Schaus and coworkers have developed a general route to the Clerodane diter-pene core by the use of previously developed B rousted acid catalyzed asymmetric Morita-Baylis-Hillman (MBH) reaction/Lewis acid mediated ring-annulation process (Scheme 1.33) [31]. Excellent diastereoselectivity was achieved in the key MBH reaction in the presence of 10mol% of the chiral BINOL derivative (29), affording the key intermediate for the synthesis of Clerodane decalin core. 

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