Methyl homosecodaphniphyllate synthesis

Guided by the desire to preserve the squalene chain for as long as possible, Heathcock s strategy for the synthesis of methyl homosecodaphniphyllate (1) defers the formation of a carbon-carbon bond between positions 2 and 3 to a late stage in the synthesis... 

With a secure route to pentacyclic amine 2, the completion of the total synthesis of 1 requires only a few functional group manipulations. When a solution of 2 in ethanol is exposed to Pd-C in an atmosphere of hydrogen, the isopropenyl double bond is saturated. When a small quantity of HCI is added to this mixture, the hydro-genolysis of the benzyl ether is accelerated dramatically, giving alcohol 15 in a yield of 96%. Oxidation of the primary alcohol in 15 with an excess of Jones reagent, followed by Fischer esterification, gives ( )-methyl homosecodaphniphyllate [( )-1] in an overall yield of 85 % from 2. 

An asymmetric total synthesis of (—)-secodaphniphylline was carried out using a mixed Claisen condensation between (—)-methyl homosecodaphniphyllate (11) and a carboxylic acid derivative 154 with the characteristic 2,8-dioxabicyclo[3.2.1]octane structure commonly found in the daphniphyllum alkaloids (Scheme 18.23) [68,69]. The necessary chirality was secured by an asymmetric Michael addition reaction of... 

C.H. Heathcock and co-workers devised a highly convergent asymmetric total synthesis of (-)-secodaphniphylline, where the key step was a mixed Claisen condensation. In the final stage of the total synthesis, the two major fragments were coupled using the mixed Claisen condensation] the lithium enolate of (-)-methyl homosecodaphniphyllate was reacted with the 2,8-dioxabicyclo[3.2.1]octane acid chloride. The resulting crude mixture of (3-keto esters was subjected to the Krapcho decarboxylation procedure to afford the natural product in 43% yield for two steps. 

C. H. Heathcock, M. M. Hansen, R. B. Ruggeri, J. C. Kath, Daphniphyllum alkaloids.il. Biomimetic total synthesis of methyl homosecodaphniphyllate. Development of the tetracylization reaction, J. Org. Chem. 57 (1992) 2544-2553. 

Diels-Alder reaction to give 226 as an intennediate. When 226 was subjected to healing, an aza-Prins reaction followed by loss of a proton afforded 228 in 77 % overall yield for the entire sequence commencing with diol 224. This late-stage intermediate was readily utilized to complete the total synthesis of the squalene-derived natural product methyl homosecodaphniphyllate (229) [114]. This masterful synthesis qualifies, without doubt, as one of the all-time triumphs in natural products synthesis [116],... 

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