Reserpine, synthesis

Table 4.27 Summary of reaction metrics and synthesis tree parameters for reserpine synthesis plans ranked according to overall kernel (maximum) RME. ...

Mehta, G. Reddy, D.S. (1998) Reserpine Synthesis A Protocol for the Stereoselective Construction of the Densely Functionalized Ring-E. Journal of the Chemical Society Perkin Transactions I, 2125-2126. 

Scheme (11). The final stages of Woodward s reserpine synthesis.

The synthetic scheme used by Woodward in his famous reserpine synthesis has been adapted for a synthesis of racemic apoyohimbine (Chart IV). The aldehyde LIXa, precursor of rings D-E of apoyohimbine, was prepared together with its epimer (LIXb) by 0s04/Ba(C103)2 oxidation of the key intermediate (LVIII) (cf. reserpine synthesis. Volume VIII, p. 316). Condensation of LIXa with tryptamine, followed by the conventional steps, yielded the racemic lactone LXIV, which was subsequently hydrolyzed and esterified to LXV, isomeric with corynan-thine. Racemic apoyohimbine (LXVI) was then secured by tosylation of LXV followed by basic treatment of the 18-tosylate (39a). 

Uracil has been used to functionalize olefins in a modified de Mayo reaction (Scheme 29) this sequence is an integral part of a new reserpine synthesis. 

The control of the stereochemical changes taking place in a reaction is a vital part of modern synthetic organic chemistry. A most interesting example of a controlled reaction leading to a c/5-hydroisoquinoline precursor for reserpine synthesis is shown in Scheme 45. Three contiguous asymmetric centres were set up in one reaction by the application of this Cope rearrangement. 

The silyl-tethered compound 69 undergoes a tandem radical cyclization followed by desilylation and oxidation of the sulfide and elimination to give bicyclic 70 further elaborations (by way of 71) convert this intermediate to cyclohexane derivative 72, transformed in five steps to 73, an intermediate in Woodward s reserpine synthesis (Scheme 13). PCC oxidation of the enol ether function of 72 yielded 74. 

A final synthetic effort in the yohimbine alkaloid area concerns the studies reported by Loewenthal and his coworkers (Scheme 3.92) (143). The aim was to develop an efficient method to prepare the bicyclic enone 21, which serves as a key intermediate in the Woodward reserpine synthesis strategy (19). The route for preparation of 21 began with Friedel Crafts reaction of 2-methoxynaphthalene (523) with the oxalyl chloride equivalent 524, a process which afforded the acenaphthenoquinone 525. Oxidative-decarboxylation of 525 yielded the naphthalene-carboxylic acid 526 which was transformed by Birch reduction and esterification to the dihydro-derivative 527. Carboxyla-tion then provided geminal diester 528 which was epoxidized. Sequential lactonization and methylation afforded tricyclic lactone 529. Ester cleavage with subsequent decarboxylation gave lactone 530 which was demethylated to provide 531. While no further effort was given to the development of this... 

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