The art of total synthesis through cascade reactions

Abstract

The growing importance of cascade reactions reflects and imparts advances in the state of the art of organic synthesis and underscores the desire of synthetic chemists to achieve higher levels of elegance and efficiency. Besides their esthetic appeal, cascade processes offer economical and environmentally friendly means for generating molecular complexity. Because of their many advantages, these reactions have found numerous applications in the synthesis of complex molecules, both natural and designed. In this tutorial review, we highlight the design and execution of cascade reactions within the context of total synthesis as demonstrated with selected examples from these laboratories.

Figure 1

Molecular structures of endiandric acid A (1), hybocarpone (2), thiostrepton (3), 2,2′-epi-cytoskyrin A (4), biyouyanagin A (5), and BE-43472B (6).

Figure 2

Molecular structures of endiandric acids A–D (1, 7–9).

Figure 3

Molecular structure of hybocarpone (2).

Figure 4

Molecular structure of thiostrepton (3).

Figure 5

Molecular structures of 2,2′-epi-cytoskyrin A (4), rugulosin (58), and the proposed structure of rugulin (59).

Figure 6

Retrosynthetic analysis of 2,2′-epi-cytoskyrin A (4), rugulosin (58), and the proposed structure of rugulin (59).

Figure 7

Originally proposed (a) and revised (b) structures of biyouyanagin A.

Figure 8

Retrosynthetic analysis of the proposed structures for biyouyanagin A.

Figure 9

Molecular structure of BE-43472B (6).

Figure 10

Retrosynthetic analysis of BE-43472B (6).

Scheme 1

Black’s hypothesis for the biosynthesis of the endiandric acids.

Scheme 2

Biomimetic cascade total synthesis of endiandric acids A (21), D (19), and E (20) methyl esters.

Scheme 3

Biomimetic cascade total synthesis of endiandric acids B (25), C (26), F (23), and G (24) methyl esters.

Scheme 4

Proposed biosynthesis of hybocarpone (2) from 6-methylchristazarin (27).

Scheme 5

Highlights of the photoenolization/Diels–Alder synthesis of 6-methylchristazarin (27)

Scheme 6

Oxidative radical dimerization of 33 and total synthesis of hybocarpone (2).

Scheme 7

Proposed biosynthesis of the dehydropiperidine core of thiostrepton.

Scheme 8

Precedent for the proposed aza-Diels–Alder dimerization reaction.

Scheme 9

Biomimetic aza-Diels–Alder dimerization cascade and construction of the dehydropiperidine core of thiostrepton (49).

Scheme 10

Competing amide formation pathways and completion of the total synthesis of thiostrepton (3).

Scheme 11

Cascade synthesis of cage-like compounds 82, 83, and 60.

Scheme 12

Completion of the total syntheses of 2,2′-epi-cytoskyrin A (4), rugulosin (58), and the proposed structure of rugulin (59).

Scheme 13

Palladium-catalyzed cascade synthesis of spirocycle 98.

Scheme 14

Highlights of the completion of the total synthesis of biyouyanagin A (5).

Scheme 15

Diels–Alder/S_N(Ar) cascade synthesis of the BE-43472B skeleton (99 and 107).

Scheme 16

Photoisomerization and completion of the total synthesis of BE-43472B (6).