Total synthesis of (+)-superstolide A

Abstract

A convergent and highly stereocontrolled total synthesis of the cytotoxic macrolide (+)-superstolide A is described. Key features of this synthesis include the use of bimetallic linchpin 36b for uniting the C(1)-C(15) (43) and the C(20)-C(27) (38) fragments of the natural product, a late-stage Suzuki macrocyclization of 49, and a highly diastereoselective transannular Diels-Alder reaction of macrocyclic octaene 4. In contrast, the intramolecular Diels-Alder reaction of pentaenal 5 provided the desired cycloadduct with lower stereoselectivity (6:1:1).

Figure 1

Superstolides A and B

Figure 2

¹H nOe interactions in the IMDA adduct 23

Scheme 1

Retrosynthetic Analysis

Scheme 2

Synthesis of Allylic Alcohols 7a–b

Scheme 3

Synthesis of Trienyl Iodide 20

Scheme 4

Synthesis of the IMDA precursor 22

Scheme 5

IMDA of Pentaenal 5

Scheme 6

Elaboration of the IMDA adduct 23

Scheme 7

Synthesis of iodide 6

Scheme 8

Revision of the Synthetic Strategy

Scheme 9

Unexpected Z/E isomerization during Takai olefination of 32

Scheme 10

Second Generation Retrosynthesis of Superstolide A

Scheme 11

Studies on the Synthesis of a Bimetallic Linchpin

Scheme 12

Synthesis of Bimetallic Linchpin 36b

Scheme 13

Synthesis and Wittig coupling of 35a and aldehyde 37a

Scheme 14

Synthesis of the C(16)-C(27) Fragment 47

Scheme 15

Fragment Assembly Strategies

Scheme 16

Macrolactonization Pathway for Superstolide Synthesis

Scheme 17

Synthesis of carboxylic acid 53

Scheme 18

Completion of the Total Synthesis of Superstolide A