Total synthesis of (-)- and ent-(+)-vindoline and related alkaloids

Abstract

A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as N-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).

Figure 1

Natural products and related structures.

Figure 2

Key cycloaddition cascade.

Scheme 1

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Scheme 3

Figure 3

Absolute configuration of natural products.

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Scheme 8

Figure 4

Competing transition states.

Scheme 9

Scheme 10

Figure 5

Cyclobutene epoxides as potential intermediates.

Scheme 11

Scheme 12

Figure 6

Additional tethered dienophiles examined.

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Figure 7

Highlights of the approach.