Plain text is unavailable for this page.

1. Introduction After numerous near-discoveries of the [4��2] cycloaddition reaction by several luminaries in the field of organic chemistry during the early part of the 20th century,[1, 2] the keen insight of Professor Otto Diels[3] and his student, Kurt Alder,[4] in properly identifying the products (4 and 6, Scheme 1) arising from the reaction of cyclopentadiene (1) with quinone (2) denotes a historic event in the field of chemistry for which these two individuals were rewarded with a reaction that would henceforth bear their names.[5] With prophetic fore- sight, Diels and Alder clearly anticipated the importance of this discovery in their landmark 1928 paper, particularly as applied to natural product synthesis, through the following remark: ���Thus it appears to us that the possibility of synthesis of complex compounds related to or identical with natural products such as terpenes, sesquiterpenes, perhaps even alkaloids, has been moved to the near prospect.��� However, in an intriguing moment of scientific territoriality, which might appear slightly off-color or even amusing to a contem- Scheme 1. The discovery of the Diels �� Alder reaction in 1928, a reaction for which the namesakes would receive the Nobel Prize in Chemistry in 1950: Diels the professor, Alder the student.[5] porary audience, the authors issued the following ominous warning to those researchers interested in applying their discovery to total synthesis: ���We explicitly reserve for ourselves the application of the reaction developed by us to the solution of such problems.���[2] The Diels �� Alder Reaction in Total Synthesis K. C. Nicolaou,* Scott A. Snyder, Tamsyn Montagnon, and Georgios Vassilikogiannakis The Diels �� Alder reaction has both enabled and shaped the art and science of total synthesis over the last few decades to an extent which, arguably, has yet to be eclipsed by any other transformation in the current synthetic repertoire. With myriad applications of this magnificent pericyclic reaction, often as a crucial element in elegant and programmed cascade sequences facilitating complex molecule con- struction, the Diels �� Alder cycloaddi- tion has afforded numerous and un- paralleled solutions to a diverse range of synthetic puzzles provided by nature in the form of natural products. In celebration of the 100th anniversary of Alder��s birth, selected examples of the awesome power of the reaction he helped to discover are discussed in this review in the context of total synthesis to illustrate its overall versatility and underscore its vast potential which has yet to be fully realized. Keywords: biomimetic synthesis �� cycloaddition �� Diels ��Alder reaction �� molecular diversity �� total synthesis [*] Prof. Dr. K. C. Nicolaou, S. A. Snyder, Dr. T. Montagnon, Dr. G. Vassilikogiannakis Department of Chemistry and The Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, CA 92037 (USA) Fax: (��1)858-784-2469 E-mail: kcn@scripps.edu and Department of Chemistry and Biochemistry University of California San Diego 9500 Gilman Drive, La Jolla, CA 92093 (USA) REVIEWS Angew. Chem. Int. Ed. 2002, 41, 1668�� 1698 �� WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1433-7851/02/4110-1669 $ 20.00+.50/0 1669

REVIEWS K. C. Nicolaou et al. Up to the time of their receipt of the Nobel Prize in 1950 it seems that, for the most part, the synthetic community heeded the demand of Diels and Alder, as their cycloaddition reaction did not feature prominently in any total synthesis prior to the stereocontrolled generation of cantharidin[6] by Stork et al. in 1951, or the first synthesis of morphine[7] reported a few months later in which Gates and Tschudi employed the pericyclic process. The apparent delay in applying the Diels �� Alder reaction, or ���diene synthesis��� as it was known at the time, to total synthesis was likely the consequence of a variety of factors. First, with few exceptions, total synthesis during that period played a role inclined more towards structure verification than as its own unique vehicle to advance the field of organic synthesis, as it is practiced today. As such, in a discipline defined by converting known materials by existing methods into other compounds, practitioners would not likely have regarded being the ���first��� to employ a particular transformation in a synthesis as an important contribution, and the number of compounds in which the Diels ��Alder reaction had been demonstrated was limiting in terms of potential synthetic targets. Moreover, the founders of the reaction, while they certainly made significant forays in the 1670 Angew. Chem. Int. Ed. 2002, 41, 1668 �� 1698 Professor K. C. Nicolaou, born in Cyprus and educated in England and the US, is currently Chairman of the Department of Chemistry at The Scripps Research Institute, where he holds the Darlene Shiley Chair in Chemistry and the Aline W. and L. S. Skaggs Professorship in Chemical Biology, as well as Professor of Chemistry at the University of California, San Diego. His impact on chemistry, biology, and medicine flows from his works in chemical synthesis and chemical biology described in over 500 publications and 70 patents and his dedication to chemical education, as evidenced by his training of more than 400 graduate students and postdoctoral fellows. His recent book titled Classics in Total Synthesis, which he co- authored with Erik J. Sorensen, is used around the world as a teaching tool and source of inspiration for students and practitioners of organic synthesis. Scott A. Snyder, born in Palo Alto, California in 1976, spent his formative years in the suburbs of Buffalo, New York. He received his B.A. in Chemistry (summa cum laude) from Williams College, Williamstown, Massachusetts, in 1999, where he explored the hetero-Diels ��Alder reaction with Prof. J. Hodge Markgraf. He then began graduate studies with Prof. K. C. Nicolaou, where he has devoted his attention to the chemistry and biology of the marine-derived antitumor agent diazonamide A. He is the recipient of a Barry M. Goldwater Fellowship in Science and Engineering, a National Science Foundation Predoctoral Fellowship, and a Graduate Fellowship from Pfizer, Inc. His research interests include complex natural product synthesis, reaction mechanism and design, and application of these fields to chemical biology. Tamsyn Montagnon was born in Hong Kong in 1975. She received her B.Sc. in Chemistry with Medicinal Chemistry from the University of Leeds, UK, which was followed by a move to the University of Sussex where she obtained a D.Phil in 2000 for research conducted under the supervision of Professor P. J. Parsons, towards the synthesis of complex natural products, including the squalestatins and triptoquinone C. She was awarded a GlaxoWellcome post-doctoral fellowship and joined Professor K. C. Nicolaou��s group in January 2001. Her research interests include natural product synthesis, medicinal chemistry, and reaction methods and mechanisms. Georgios E. Vassilikogiannakis was born in Iraklion, Crete, Greece in 1970. He received his B.Sc. in Chemistry in 1993 and his Ph.D. in 1998 from the University of Crete under the guidance of Professor Michael Orfanopoulos exploring the mechanisms of the electrophilic additions of singlet oxygen, tetracyanoethylene, triazolinediones, and fullerenes to alkenes and dienes. He joined Professor K. C. Nicolaou��s group in 1999, and was involved in the total syntheses of bisorbicillinol, bisorbibutenolide, trichodimerol, and colombiasin A. He was recently appointed Assistant Professor of chemistry at the University of Crete, Greece. His primary research interests involve the synthesis of natural products as an enabling endeavor for the discovery of new chemical knowledge and its application to chemical biology. T. Montagnon K. C. Nicolaou S. A. Snyder G. E. Vassilikogiannakis

REVIEWS The Diels �� Alder Reaction in Total Synthesis area of terpene synthesis,[8] became diverted by other research concerns of greater interest to them, particularly in regard to understanding the mechanistic underpinnings of the reaction they had discovered.[9] Significantly, these efforts ultimately resulted in such important advances as the Alder endo rule that governs the stereochemical outcome of the typical Diels �� Alder reaction.[10] The most dominant reason for the delay in the incorporation of the Diels �� Alder cycloaddition into total synthesis, however, might be attributed to World War II and its aftermath, a period for which no analysis can properly estimate the challenges to conducting research in organic synthesis, particularly in Germany. As such, the truly visionary application of the Diels �� Alder reaction to total synthesis would have to await the imagina- tion of chemical artists such as R. B. Woodward, who would apply new levels of creativity to the reaction at hand through some highly elegant and instructive syntheses. In 1952, Woodward et al. disclosed their historic routes to the steroids cortisone and cholesterol (12 and 13, respectively, Scheme 2) Scheme 2. The pioneering adoption of a quinone-based Diels�� Alder reaction by Woodward et al. in 1952 as the key step in the total synthesis of the steroid hormones cortisone (12) and cholesterol (13).[11] where, in the initial step, reaction of quinone 7 with butadiene in benzene at 100 8C for 96 hours effected a smooth Diels �� Alder cycloaddition to form bicyclic adduct 9 via the intermediacy of endo transition state 8.[11] Several features of this particular [4��2] cycloaddition reaction are of note. First, Woodward recognized that by using a differentiated quinone nucleus it would be possible to effect regioselective control of the intermolecular Diels �� Alder union, as the more electron-rich methoxy-substituted olefin would be less dieno- philic than its methyl-substituted counterpart. An equally insightful design element was the anticipation that even though a cis-fused adduct would arise from the Diels ��Alder reaction, conversion into the requisite thermodynamically more stable trans-fused system present in the targeted natural products would be relatively simple to achieve. Thus, in the next synthetic operation, base-induced epimerization readily provided the coveted trans-fused ring system (10), thus setting the stage for an eventual ring-contraction process that would allow completion of this region of the steroid nucleus.[12] Similar levels of synthetic ingenuity are reflected in the total synthesis of reserpine (17, Scheme 3) by Woodward et al. in 1956,[13] where again an opening Diels ��Alder reaction forged the critical bicyclic system (16) that would serve as the Scheme 3. Application of the Diels �� Alder reaction in the total synthesis of reserpine (17) by Woodward et al. in 1956.[13] scaffold for the ensuing synthetic sequence.[14] This use of a Diels �� Alder strategy to form an initial array of rings and stereocenters, elements which pave the way for subsequent stereocontrolled elaboration to the final target molecule, represents a distinctive hallmark of Woodward��s synthetic acumen. Moreover, these two examples from Woodward��s research group are illustrative of a new school of thought that emerged in the 1950s which involved approaching the syn- thesis of complex molecules by rational synthetic strategies, and they admirably demonstrated the inherent strength of the Diels �� Alder reaction to solve challenging synthetic puzzles which might otherwise have remained hopelessly complex. In this review, we hope to highlight didactic exemplars of the Diels ��Alder reaction in the context of natural product total synthesis representing work which has decisively ad- vanced both the power and scope of this pericyclic process beyond the pioneering applications of Woodward. In selecting our case studies, we accepted the fact that any review of such a widely used reaction with nearly three-quarters of a century of history could not possibly be comprehensive. Our aspiration is that the delineated examples will sufficiently cover the various areas in which Diels ��Alder methodology represents an indispensable tool for the art of total synthesis, and will reflect key paradigm shifts in the field through novel and inventive approaches to this classic reaction. We hope that these discussions will inspire you not only to further explore the literature in terms of syntheses not expounded upon here, but also to create even more fantastic applications of the Diels �� Alder reaction in your own research. Angew. Chem. Int. Ed. 2002, 41, 1668�� 1698 1671

REVIEWS K. C. Nicolaou et al. 2. Regiocontrol and Beyond: Achieving Stereoselection The early total syntheses by Woodward described above amply illustrate the ability of the Diels �� Alder reaction to create molecular complexity. Not only is a cyclohexene ring generated through the formation of two new s bonds, but up to four contiguous stereocenters are also concomitantly fashioned in the process. Fortunately, as a result of the regio- and stereospecific nature of the Diels �� Alder reaction (always a cis addition) and the diastereoselectivity of the union based on the Alder endo rule[10] (where a more sterically crowded and seemingly less thermodynamically stable transition state results when the dienophile possesses a suitable conjugating substituent), the formation of these chiral elements is often predictable in a relative sense. However, new principles and approaches to the Diels �� Alder reaction would be needed beyond those delineated in the syntheses of reserpine and cholesterol if absolute control of stereochemistry is required. In addition, although Woodward��s Diels �� Alder reactions elegantly achieved regioselectivity, results which can be rationalized successfully on the basis of frontier molecular orbital theory,[15] these examples do not reflect the challenges faced in attempting to achieve such control in certain contexts where particular unsymmetrical diene and/or dienophile units having specific steric and electronic properties are employed. As such, general solutions would be required to address the problem of selectively incorporating useful sets of diverse functionality in Diels �� Alder cycloaddition products. In this section, we highlight some answers to the issues of regio- and stereoselectivity which have been developed by leading synthetic chemists to provide a qualitative measure of the current state of the art in Diels �� Alder technology. A classical method to enhance regioselectivity is based on the use of Lewis acid catalysts. Upon complexation of such species to the dienophile, the normal demand Diels ��Alder reaction is promoted since the energy gap between the lowest unoccupied molecular orbital (LUMO) of the dienophile and the highest occupied molecular orbital (HOMO) of the diene is reduced, thus decreasing the activation energy required to achieve the cycloaddition. Moreover, as this stabilization is greater for the endo transition state, as a result of beneficial enhancement of secondary orbital overlap that is unobtain- able in an exo mode of reaction, the use of Lewis acids favors an increased ratio of endo:exo products. More valuable synthetically, however, is the fact that Lewis acids can often reverse the regiochemical course of a Diels�� Alder addition and generate products that would not otherwise be observed in a simple, thermally induced reaction.[16] An early and elegant example of this concept is provided by the total synthesis of tetrodotoxin (22, Scheme 4) by Kishi et al.[17] As in the Woodward paradigm, an initial Diels ��Alder union between quinone 18 and butadiene (19) was employed to generate a preliminary set of rings and stereocenters for subsequent elaboration. However, the intriguing feature of this example is that the use of SnCl4 in the Diels ��Alder reaction proved critical for the chemoselective engagement of butadiene with the oxime-bound dienophile to form 20 in the absence of the Lewis acid, the other olefinic bond of quinone Scheme 4. Use of Lewis acid catalysis by Kishi et al. (1972) to achieve chemoselective control in the formation of key intermediate 21 leading to tetrodotoxin (22).[17] 18 reacted exclusively. Although oximes normally behave mesomerically as electron-donating substituents, thus deacti- vating the neighboring olefin for Diels �� Alder reaction, coordination of the Lewis acid reverses this behavior by drawing electron density away from this group, which leads to an adjacent highly competent electron-deficient dienophile.[18] Thus, Lewis acid activation nicely effected regiochemical control in the employed [4��2] cycloaddition that could not have been achieved otherwise. Among other methods introduced to achieve excellent regioselectivity, as well as to incorporate useful functional groups, Danishefsky��s widely applicable diene system (23, Scheme 5a) represents one of the most important advances in this regard within the past quarter century.[19] Initially developed as part of a method to selectively generate pyran rings upon reaction with aldehyde dienophiles,[20] the power of the prototype diene 23 rests in the synergistic effects of the two incorporated oxygen groups, which provide mutually reinforcing electronic contributions to the diene system such that regiospecific formation of a lone endo adduct results upon reaction with most dienophiles. In addition, upon treatment with mild acid after the Diels �� Alder reaction, cleavage of the silyl protecting group residing within the product and the strategic location of the methoxy leaving group enables an ensuing cascade sequence that results in the formation of an a,b-unsaturated system. An early demon- stration of this strategy in total synthesis can be found in the route used by Danishefsky et al. to form disodium prephenate (27, Scheme 5b),[21] where, although the target may not seem to possess great molecular complexity, application of this designed diene technology provided a highly elegant and concise solution to the synthetic problem at hand. As illustrated, after regioselective formation of Diels ��Alder product 25, in situ treatment of this compound with acetic acid formed the desired a,b-unsaturated system which concurrent- ly eliminated phenyl sulfoxide to provide 26, a product which was easily elaborated to the target structure. The versatility of this particular technology is underscored by the wide variety of such dienes that can be employed.[22] For example, use of a Danishefsky-type diene (28, Scheme 5c) 1672 Angew. Chem. Int. Ed. 2002, 41, 1668 �� 1698