Stemodin synthesis

Stereoselective reaction with ketones. The reaction of ketone 1 with methyl-lithium, trimethylaluminum, and lithium letramethylaluminate shows no stcrco-specificity. The reaction with mcthylmagncsium bromide gives the two possible adducts in the ratio 2.4 1. The best stereospccificity is observed with dimethylsulf-oxonium methylide, which converts 1 into 2 and 3 in a ratio about 5 1. Reduction of the epoxides with lithium triethylborohydride gives the desired tertiary alcohols. This reaction was used in a synthesis of ( ) stemodin (4).2... 

The biological activity of the diterpenoids of the aphidicolin-stemodin series makes these compounds attractive targets. The total synthesis of stemodin (96) has been described.172 The key spiro-centre at C-9 was constructed by the internal aldol condensation of the keto-aldehyde (97) to afford (98). Several stereoselective syntheses of aphidicolin have been reported with different solutions to the problem... 

Cycloaddition (cf. 12,163). In the presence of CpCo(CO)2, the monocyclic enync (Z)-l cyclizcs to the tetracyclic diene (2) as a 2 1 mixture of epimers. The product has the carbon skeleton present in the ditcrpenc stemodin (3), and can be converted in three steps to an intermediate in a total synthesis of the diterpene. This cycloaddition fails with (E)-l. 

Two different syntheses of aphidicolin (106) were reported in 1979. Corey and his co-workers have now completed a third.A key feature of their route is the base-induced conversion of (104) to (105). It was found that the desired alkylation occurred only under carefully controlled reaction conditions (lithium di-t-butylamide at —102 C), the alternative a-alkylation product predominating under most other conditions. A closely related approach has resulted in the synthesis of ( )-stemodin (107) and ( )-stemodinone (108). The Kametani route to the aphidocolanes has been described earlier in this chapter. 

The first is an attempted Claisen rearrangement of a vinyl ether to give a precursor to aphidicolin [28], and the second is an attempted Claisen rearrangement of a vinyl ether to give an intermediate in the synthesis of stemodin [29]. 

A one-step construction of the stemodane framework that resulted in a formal synthesis of the diterpene stemodin (185) was realized by the cobalt-mediated intramolecular cyclization of ene-diyne 182 (Scheme 7.40) [55], Three stereocenters in 183, two of them quaternary, were produced with complete specificity during this [2 - - 2 + 2] cycloaddition. 

Notably, only the Z-isomer 182 furnished the polycyclic product 183, whereas the corresponding -isomer retarded any intramolecular cycloaddition. Cycloaddition product 183 was thereafter transformed into the dione 184, which already served in another total synthesis of stemodin (185) [56]. 

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