SPECIAL FEATURE: PERSPECTIVE The essence of total synthesis K. C. Nicolaou* and Scott A. Snyder Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037; and Department of Chemistry and Biochemistry, University of California, 9500 Gilman Drive, La Jolla, CA 92093 Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved July 1, 2004 (received for review May 27, 2004) 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. Essence (e´s’ns) n. the most signifi- cant part of a thing’s nature; the sum of the intrinsic properties without which a thing would cease to be what it is, and which are not affected by accidental modifications. (The New Lexicon Webster’s Dictionary) lthough the practice of total synthesis and the rationale be- hind its pursuit have changed A throughout the course of its history, its most fundamental property has not. At its core, in its most essential form, natural product total synthesis is a vehicle for discovery, one that is per- haps unparalleled by any other endeavor in the realm of chemical synthesis (1–3). The reason follows: every natural prod- uct type isolated from the seemingly limitless chemical diversity in nature provides a unique set of research oppor- tunities deriving from its distinctive Fig. 1. Structures of quinine (1), progesterone (2), penicillin (3), prostaglandin F2␣ (4), and cobyric acid three-dimensional architecture and bio- (5), natural products whose total synthesis inspired and resulted in the development of manifold advances logical properties. For instance, in the in chemistry, biology, and medicine. early part of the 20th century, efforts directed toward the synthesis of the an- timalarial agent quinine (1) (Fig. 1) led designed penicillins with activity profiles This brief synopsis drawing from just to a sizeable body of knowledge regard- superior to the parent natural product, five examples barely scratches the sur- ing the construction of heteroaromatic and revolutionized the entire peptide- face of the rich history of scientific systems and the unique physical proper- synthesis field. In the 1960s and 1970s, breakthroughs in this field and the po- ties of quinoline and piperidine rings. In members of the eicosanoid family of tential for making fundamental ad- more recent times, its structure has natural products, such as prostaglandin vances. Here, we offer several additional served as the basis for the design of sev- F2a (4), served as the artistic canvas on examples from our own experiences in eral new classes of antimalarial drugs which E. J. Corey was inspired to create the hope that they will illustrate the true that have saved thousands of lives (4). the first catalysts capable of orchestrat- wealth of discoveries that can emanate Similarly, attempts to construct steroids ing asymmetric Diels–Alder reactions. It from more contemporary endeavors in such as progesterone (2) before World also was the arena in which he and his total synthesis. War II provided insights into how car- group developed the now ubiquitous bon–carbon bonds could both be forged Selected Total Synthesis Endeavors family of silyl-based protecting groups, and cleaved, with their partial or total one of the most general and powerful If the past few decades have taught us synthesis ultimately rendering them methods for the catalytic asymmetric anything about the power of our syn- available in quantities that are sufficient thetic tools, it is that we have yet to to propel them into useful drugs, such reduction of ketones (Corey–Bakshi– Shibata reduction), and a series of reach a level of efficiency and deftness as the birth control pill, which is now commensurate to that possessed by na- used by millions of women around the prostaglandin analogs used for various purposes (7). During the same era, the ture. Yet, although we cannot exactly world (5). In the 1950s, the highly sensi- emulate the master chemical artisan, tive ␤-lactam ring of penicillin (3) unique structures possessed by mole- served as the impetus for John Sheehan cules like vitamin B12 and cobyric acid (6) to develop carbodiimide-based re- (5) served as the testing ground for new This paper was submitted directly (Track II) to the PNAS agents for the formation of peptide reactions and fundamental physical or- office. bonds. This discovery capped the first ganic principles, such as the Eschen- *To whom correspondence should be addressed. E-mail: practical synthesis of this essential me- moser corrin synthesis (8) and the [email protected]. dicinal agent, enabled the synthesis of Woodward–Hoffman rules (9). © 2004 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0403799101 PNAS ͉ August 17, 2004 ͉ vol. 101 ͉ no. 33 ͉ 11929–11936 Downloaded by guest on September 26, 2021 synthetic chemists can come close when they develop synthetic strategies toward natural products based on biogenetic considerations because what often re- sults is a concise and elegant construc- tion of molecular complexity. As an added benefit, such approaches also af- ford insights into how reactions can be combined productively into novel cas- cade events. Historical examples of such successes include W. S. Johnson’s syn- thesis of progesterone by means of a series of cation-␲ cyclizations and our own construction of several members of the endiandric acid family of natural products by means of a cascade se- quence that combined electrocycliza- tions and Diels–Alder reactions (10). A more recent entry comes from our research program directed toward se- lected members of the bisorbicillinoid family of natural products (11). For in- stance, although the cage-like natural product trichodimerol (12) (Scheme 1) seemed hopelessly complex on initial inspection based on its dense array of chiral centers and unusual ring frame- work, closer analysis suggested that its entire architecture could arise in a sin- gle step from a far simpler, but highly reactive, intermediate: quinol 7 and its tautomer 8. The operations required to bring about this tantalizing proposal, however, were relatively complex be- cause they involved a dimerization-based domino sequence comprised of two Mi- chael reactions and two ketalizations. After careful experimentation, we were able to accomplish this ambitious series of events in the laboratory by carefully cleaving the acetate group within 6 un- der basic conditions to generate the re- Scheme 1. Insights into the synthetic efficiency of nature: total synthesis of trichodimerol (12) through active monomers and then quenching ͞ the reaction with NaH PO ⅐H O. A sim- a dimerization event based on a double Michael ketalization sequence. A different pathway from 6 led 2 4 2 to bisorbicillinol (13) and bisorbibutenolide (14). ilar strategy protocol was employed by Barnes-Seeman and Corey in their suc- cessful synthesis of trichodimerol (12). when targeting a complex natural prod- the power to forge such strained struc- Amazingly, if this protocol was altered uct with a unique conglomeration of tural domains in highly functionalized just slightly, we could also convert 7 and structural motifs. Indeed, rare and chal- settings. By using this gap in methodol- 8 into two other members of the family, lenging molecular features within sec- ogy as an opportunity for discovery, we 13 bisorbicillinol ( ) and bisorbibutenolide ondary metabolites have long presented developed a series of synthetic reactions (14), by coaxing them to participate in synthetic chemists with golden opportu- based on the power of heteroatoms (i.e., an intermolecular Diels–Alder union nities for invention, whether simply by sulfur and phosphorous) to drive these instead (11). Whether or not nature cre- inspiring creative strategies and tactics, entropically disfavored ring closures; ates these natural products in the same way is unknown, but it is difficult to or serving as a stringent testing ground four of these methods are shown in conceive that nature would employ a that reveals weaknesses in the power of Scheme 2. Apart from finding wide- pathway that is any less expedient. In existing methodology to fashion such spread applicability to a range of other any case, these sequences point to one complexity effectively. The brevetoxins synthetic problems, these unique ap- of the key directions for the future of (15, 16) (Scheme 2), the toxic agents proaches were critical to the completion chemical synthesis as pressure increases responsible for the ‘‘Red Tide’’ phenom- of both of these formidable targets, ac- to generate molecular complexity rap- ena, certainly fit this bill with their ex- complishments that have more recently idly through efficient and atom-econom- quisite array of trans-fused ether rings inspired a host of researchers to attempt ical processes that produce minimal of various sizes (13). Of particular chal- the total synthesis of other cyclic poly- chemical waste. lenge were their medium-sized cyclic ethers, some of even greater size and Similar levels of beauty, challenge, ethers because the technology that was complexity (14–20). and opportunity for discovery also