This tutorial review provides a survey of syntheses in which an enzymatic step contributed to generating downstream molecular complexity in the target. The first part provides a guide to the types of enzymatic transformations suitable for incorporation into synthetic schemes. The principles of symmetry, especially the concept of "latent symmetry", which are often used to simplify enantiodivergent design of targets, are discussed next. The examples are discussed in the order of a degree of experimental difficulty associated with the execution of a particular biological technique. Lipase resolutions and desymmetrizations are discussed first followed by more advanced protocols involving oxidoreductase enzymes and ending with examples of syntheses that employ pathway engineering and directed evolution of proteins. Future prospects of biocatalytic methods as means of efficient preparation of target compounds are indicated. The authors hope that the review will serve to convince those synthetic chemists reluctant to use biological methods to include enzymatic procedures in their design.

Dedicated to David T. Gibson in honor of his discovery of enzymatic dihydroxylation of aromatic compounds 40 years ago, his subsequent work in the area, and the contributions he has made to chemoenzymatic synthesis.

We became interested in approaches to morphine in the early 1990s following our immersion into the new program on the enzymatic dihydroxylation of aromatics. Larry Kwart, a former classmate of one of us at Rice University, who worked with our group at Virginia Tech in the mid-1980s, introduced to us the use of blocked mutants of Pseudomonas putida (Pp39D) for the production of arene-cis-dihydrodiols. Larry had gained expertise in microbiology from a postdoctoral stay with David Gibson, who discovered this unique enzymatic transformation, and he helped us to establish a strong program in chemoenzymatic synthesis that continues to this day. Without his pioneering effort, none of our accomplishments in chemoenzymatic synthesis, including the various approaches to morphine, would have materialized. Here we trace the evolution of our approaches to morphine alkaloids and some commercial opiate-derived medicinal agents. The design features and chronology of our approaches are discussed in a way that allows the reader to appreciate a number of errors that were made in conception as well as in execution. Experience acquired from many failed or less-than-effective attempts has finally led to an "almost reasonable" total synthesis, the key concept being based on our very first but unsuccessful attempt more than two decades ago. The irony of this accomplishment has not been lost on us. Each section of this Account presents a summary of distinctly different approaches to morphine alkaloids. Each ends with a short and philosophical lesson that was (or should have been) learned in the process. We intend for this Account to offer more than the history of a search for the perfect design solution to a synthetic problem. In today's era of rapid and often careless publication of results, it should serve also as a reminder that the success and the integrity of synthetic ventures depends on perseverance, adjustment of strategy, improvements of previous attempts, and serious attention to the quality of experimental data. Although somewhat satisfied with our latest accomplishment in morphinan synthesis, we plan to improve our design in the hope that a six-step synthesis is no longer in the realm of fantasy. With more than 20 years of effort in this area, our continuing involvement may qualify as obsession.

No abstract

The first documented report of a possible Cope rearrangement was probably that of Baeyer, who prepared eucarvone by hydrobromination of carvone in 1894. Although the transformation was briefly studied at that time, it was not until the 1950s that this and other Cope‐type rearrangements received detailed attention. The thermal isomerization of cis ‐divinylcyclopropane to cycloheptan‐1,4‐diene was reported by Vogel in 1960 during his studies of the Cope rearrangement of 1,5‐hexadienes annulated by a homologous series of carbocyclic rings. Scores of mechanistic studies followed this discovery upon the realization that the rearrangement could be related to the conceptually similar vinylcyclopropane–cyclopentene isomerization discovered a year earlier. It was also recognized that this rearrangement might be operating in the formation of cycloheptatriene from norcaradiene during photolysis of diazomethane in benzene. The topic received considerable attention in the 1960s, an era of mechanistic investigations of various concerted transformations. During the 1970s it enjoyed exploitation in many synthetic strategies, and the following decade the elements of this rearrangement were incorporated into tandem or multistep procedures in a preconceived manner. Many aspects of the various permutations of the Cope rearrangement have been previously reviewed. The purpose of this review is to summarize the mechanistic, stereochemical, and practical results in this area in the context of the evolution of synthetic achievements during the last 40 years. Also described in this chapter are the transformations of several of the simple heteroatom permutations of this rearrangement in order to render appropriate comparisons of various systems. A discussion addresses those rearrangements of cyclopropanes, oxiranes, thiiranes, and aziridine rings substituted with vicinal vinyl groups. Excluded from this review are rearrangements of those divinylsubstituted three‐membered rings that contain more than a single heteroatom within the reacting manifold. Brief mention of these systems along with a guide to the literature is found in the last section of this chapter. The literature is covered through December 1990. Many of the principal researchers in this field have been contacted and many unpublished transformations have been included in the tables.