Pierre Deslongchamps

Stereoelectronic control in the cleavage of tetrahedral intermediates in the hydrolysis of esters and amides

Abstract A new stereoelectronic theory for the cleavage of the tetrahedral intermediate in the hydrolysis of esters and amides is presented. In this new theory, the precise conformation of the intermediate hemi-orthoester or hemi-orthoamide controls the nature of the hydrolysis products. It is postulated that the breakdown of a conformer of a tetrahedral intermediate depends upon the orientation of the lone pair orbitals of the hetero-atoms. Specific cleavage of a carbon-oxygen or a carbon-nitrogen bond in any conformer is allowed only if the other two hetero-atoms (oxygen or nitrogen) each have an orbital oriented antiperiplanar to the leaving O-alkyl or N-alkyl group. Experimentally, the oxidation of acetals by ozone and the acid hydrolysis of a series of cyclic orthoesters demonstrates clearly that there is indeed a stereoelectronic control in the cleavage of hemiorthoesters. Similarly, a study of the basic hydrolysis of a variety of N,N-dialkylated imidate salts shows that the same stereoelectronic control is operating in the cleavage of hemiorthoamides.

The Relative Rate of Hydrolysis of a Series of Acyclic and Six-Membered Cyclic Acetals, Ketals, Orthoesters, and Orthocarbonates

Abstract The relative rate of hydrolysis of these compounds is rationalized by considering the influence of steric, inductive and stereoelectronic effects on the hydrolysis reaction mechanism.

A Highly Efficient Access to Spiroketals, Mono-unsaturated Spiroketals, and Furans: Hg(II)-Catalyzed Cyclization of Alkyne Diols and Triols

Hg(II) salts are identified as highly efficient catalysts for the versatile construction of spiroketals from alkyne diols in aqueous conditions. Monounsaturated spiroketals and furans were accessed with equal ease when propargylic triols (or propargylic diols) were subjected to similar conditions. Even the semiprotected alkyne diols gave the corresponding spiroketals with the same ease in a cascade manner. The reactions are instant and high yielding at ambient temperatures. Regioselectivity issues are well addressed.

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 (enantio- and diastereo- selectivity). 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 de- protection). 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.

Synthesis of the Antiproliferative Agent Hippuristanol and Its Analogues via Suarez Cyclizations and Hg(II)-Catalyzed Spiroketalizations

A full account of the synthesis of hippuristanol and its analogues is described. Hecogenin acetate was identified as a suitable and economical starting material for this work, and substrate-controlled stereoselection was obtained throughout the construction of the key spiroketal unit. Suárez cyclization was first used, but Hg(II)-catalyzed spiroketalization of the 3-alkyne-1,7-diol motif was finally identified as the most convenient strategy.

One-step construction of a 13α-methyl 14α-hydroxy steroid via a new anionic polycyclization method

Abstract The base-catalyzed reaction of 2-carbomethoxy-2-cyclohexenone (6) with the substituted Nazarov reagent 5 yields directly the tetracyclic β-ketoester 8 which upon decarboalkoxylation gives 13α-methyl-14α-hydroxy steroid 9.

Intramolecular Michael addition of cyclic β-ketoester on conjugated acetylenic ketone.

Abstract A study on the base-catalyzed intramolecular Michael addition of β-ketoester-ynone 1 (n′ = 1–2, n = 0–3) is reported.

Efficient Synthetic Approach to Potent Antiproliferative Agent Hippuristanol via Hg(II)-Catalyzed Spiroketalization

The steroidal natural product hippuristanol targets eukaryotic translation initiation factor (eIF)4A which plays a pivotal role in translation in eukaryotic cells. Now an efficient synthesis of hippuristanol from 11-ketotigogenin is reported. The synthesis features a rapid construction of a spiroketal unit via Hg(OTf)(2)-catalyzed oxidation/spiroketalization of the 3-alkyn-1,7-diol motif.

Synthesis of cis-decalin via Diels-Alder and double Michael cycloaddition with substituted Nazarov reagent

Abstract The base-catalyzed cycloaddition of the methyl substituted Nazarov reagent 2 with 2-carbomethoxy-2-cyclohexenone ( 1 ) yielding cis-decalin products is reported.

A Convenient Synthesis OF 2-Carbomethoxycyclohexanone

Abstract In connection with a synthetic problem of our laboratory, it became necessary to have pure 2-carbomethoxycyclohexanone (1). A search of the chemical literature revealed that the known procedures for the preparation of this compound do not give good yields.