Transannular Diels-Alder reaction on macrocycles. A general strategy for the synthesis of polycyclic compounds

Various aspects of the transannular Diels-Alder reaction are examined in order to eventually develop a general method for the synthesis of a large variety of polycyclic compounds related to the diterpenes, mterpenes and steroids. Emphasis is made on the control of the relative and absolute configuration of the polycyclic products. Preliminary work towards the synthesis of some specific target natural products is also presented. The great contribution of R.B. Woodward and his contemporaries to the field of organic synthesis was the demonstration that organic chemists were capable of synthesizing in the laboratory highly complex organic substances. In those days, it was known that synthesis had to be carried out with functional groups, but since chemical reactivity was poorly understood, the synthetic planning had to be very general in nature, and each step had essentially to be discovered along the way by studying the reactivity of each intermediate. Later on, the reactivity of functional groups became better understood, and it became possible to put more logic in the synthetic planning. It is on that basis that E.J. Corey and his contemporaries were able to demonstrate the value of the principle of retrosynthetic analysis which is based principally on the chemical reactivity of functional groups. Nowadays, progress in organic synthesis is presently achieved through the discoveries of new chemical reactions (methods, etc), new reaction conditions with an emphasis on asymmetric synthesis and new synthetic strategies. It is recognized that a good synthetic plan should have a high degree of control on the chemical reactivity (chemoselectivity), regioselectivity and stereoselectivity (enantioand diastereoselectivity). Furthermore, a good plan ought to be simple minimizing as much as possible bond forming processes, and specially functional group manipulations (transformation, activation, protection and deprotection). Returning to synthetic strategy, it is also recognized that a chemical process can be classified in three different categories. It can either be intermolecular or intramolecular in nature, and the later can be subdivided in two different ways, i.e. formation of a bond via a simple cyclization reaction or via a transannular process (ref. 1). Transannular processes ought to be very powerful synthetically. Indeed, being carried out on macrocycles, there is in such cases, a high degree of conformational restriction and as a result, proximity effects become operative and very often, these effects will increase the rate of one reaction and slow down others which are normally competing. The total synthesis of ryanodol (ref. 2) which was analyzed from the point of view of strategy, was described as one of the rare examples where transannular processes are used as key steps. In this synthesis, the formation of the required macrocycles for one of the transannular processes was produced indirectly via the cleavage of a small ring. If transannular processes had not been used frequently in synthesis before it was mainly because this approach requires the use of macrocycles. However, if direct methods for the formation of large rings would become available, synthetic chemists would be in a position to develop new innovative strategies of molecular construction. Our work showed that it should be relatively easy to construct macrocycles using a simple and direct method of cyclization. One condition had however to be respected namely, the acyclic precursor should have some unsaturations appropriately located along the chain in order to cut down degrees of freedom while eliminating at the same time most of the transannular steric repulsion during the cyclization step. Preliminary results (ref. 3) from our laboratory demonstrated that 10-membered rings could indeed be produced under medium dilution conditions via the direct displacement of an allylic or propargylic chloride