The essence of total synthesis

Abstract

For the past century, the total synthesis of natural products has served as the flagship of chemical synthesis and the principal driving force for discovering new chemical reactivity, evaluating physical organic theories, testing the power of existing synthetic methods, and enabling biology and medicine. This perspective article seeks to examine this time-honored and highly demanding art, distilling its essence in an effort to ascertain its power and future potential.

Fig. 1.

Structures of quinine (1), progesterone (2), penicillin (3), prostaglandin F_2α (4), and cobyric acid (5), natural products whose total synthesis inspired and resulted in the development of manifold advances in chemistry, biology, and medicine.

Scheme 1.

Insights into the synthetic efficiency of nature: total synthesis of trichodimerol (12) through a dimerization event based on a double Michael/ketalization sequence. A different pathway from 6 led to bisorbicillinol (13) and bisorbibutenolide (14).

Scheme 2.

The brevetoxins: ornate architectures whose unique ring systems demanded the development of several novel synthetic technologies before yielding to total synthesis.

Scheme 3.

The CP-molecules: a serendipitous discovery during their total synthesis, in what was expected to be a routine oxidation, served as the catalyst for the design and development of a series of new synthetic technologies.

Scheme 4.

The diazonamide A studies: confirming structural assignments and discovering new chemical reactivity.

Scheme 5.

Calicheamicin γ₁^I and the enediynes: an opportunity to make fundamental discoveries in chemical synthesis, physical organic chemistry, molecular design, and chemical biology.

Fig. 2.

Taxol: total synthesis met the challenge through a convergent strategy using two Diels–Alder reactions.

Scheme 6.

Vancomycin: a synthetic target whose novel architecture afforded the opportunity to develop new chemistry, such as a triazene-driven method for bisaryl ether formation and a cross-metathesis reaction in water to form dimeric vancomycin analogs with activity greater than that of the natural product.

Scheme 7.

The epothilones: use of new solid-phase technology combined with an olefin metathesis-based cyclorelease strategy rapidly generated a number of structural analogs, ultimately culminating in a drug candidate (82) for cancer chemotherapy.