Methyl homosecodaphniphyllate

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. 

Of seven structurally known daphniphylline-type alkaloids, the structure of daphniphylline (1) was first elucidated by an X-ray crystallographic analysis of the corresponding hydrobromide (4). Further X-ray crystallographic studies on daphmacrine methiodide revealed it to have the absolute configuration depicted as 18 (5). Methyl homosecodaphniphyllate (29) has also been proved to have the same absolute configuration as that of daphmacrine (6). Therefore, the... 

Scheme III. Chemical corelation between secodaphniphylline and methyl homosecodaphniphyllate.

On the basis of the above results, coupled with the stereostructures of daphnilactone-B (36) and methyl homosecodaphniphyllate (29), the former can be derived from the latter (29) (Scheme XIII). 

Scheme XIII. Possible pathway from methyl homosecodaphniphyllate to daphnil-actone-B.

Two secodaphnane-type alkaloids (Figure 18.2), secodaphniphylline (8) [19,21,22] and methyl homosecodaphniphyllate (11) [19,21,22], were isolated by Yamamura and Hirata, and their structures were elucidated by X-ray analysis of methyl N-bromoa-cetyl homosecodaphniphyllate and chemical correlations between 8 and 11. The structures of the two related alkaloids, daphniteijsmine (9) [23] and daphniteijsma-nine (10) [24], were elucidated by spectroscopic analysis coupled with an exhaustive comparison of the NMR data of secodaphniphylline and methyl homosecodaphniphyllate (11). 

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. 

Two other interesting compounds found in the plant were methyl homo-daphniphyllate (164) and methyl homosecodaphniphyllate (165). 

Another interesting reaction observed in the series was the oxidation of methyl homosecodaphniphyllate (165). Lead tetra-acetate in benzene converted this... 

Daphniphyllum Alkaloids.—Secodaphniphylline and Methyl Homosecodaphni-phyllate. These alkaloids have been isolated from Daphniphyllum macropodum Miquel. Secodaphniphylline, C30H47NO3, m.p. 130 °C, has been chemically correlated with methyl homosecodaphniphyllate, C23H37NO2, m.p. 103 °C, via (52) as outlined in Scheme... 

A heavy-atom X-ray crystal-structure analysis of methyl IV-bromoacetyl-homosecodaphniphyllate (53) established the structures of secodaphniphylline and methyl homosecodaphniphyllate as (54) and (55), respectively. " The absolute configuration of this derivative was determined by anomalous dispersion procedures. These alkaloids are members of another new group of alkaloids isolated from Daphniphyllum macropodum. 

An interesting oxidation reaction yielding an imine that violates Bredt s rule was discovered in these studies. Methyl homosecodaphniphyllate on oxidation with lead tetra-acetate in dry benzene at room temperature afforded a product, C23H35NO2, which was assigned structure (56) on the basis of chemical... 

Presumably, daphnilactone-B (4) and isodaphnilactone-B (34) are both produced from a common intermediate such as methyl homosecodaphniphyllate... 

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. 

Most of the other known daphniphyllum alkaloids do not yet appear to have been rigorously correlated with daphmacrine or methyl homosecodaphniphyllate [ 7]. 

Methyl homosecodaphniphyllate, K26 Methyl isopulegene, A39 0-methyllactic acid, A1 Methyllanthionine, A9 jS-methylmalic acid, YS Methylmalonyl coenzyme-A, A28... 

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