Studies in fulvene cycloadditions and in optical resolutions

Abstract

This thesis entitled "Studies in Fulvene Cycloadditions and in Optical Resolutions" presents, in two parts and five chapters, the following: Studies on the 1,3-dipolar cycloaddition reaction of 6,6-diphenylfulvene with various nitrones (Part I), and a novel example of a spontaneous optical resolution-that of 1-(4-methoxyphenyl)-2-phenyl-1-propanone-as also related stereochemical and synthetic studies (Part II).

Part I Chapter 1 reports studies on the 1,3-dipolar cycloaddition reaction between 6,6-diphenylfulvene and C,N-diphenylnitrone. The structure of the product, isolated in 85% yield, was determined by NOESY and X-ray diffraction to be 1 (Scheme I). It is argued that both concerted and stepwise (diradical) mechanisms are possible for this reaction, the latter being based on the plausible stability of the intermediate diradical. The rate of the above reaction showed a slight inverse dependence on solvent polarity, as is known for many other 1,3-dipolar cycloadditions. Chapter 2 reports studies on the 1,3-dipolar cycloaddition reaction between 6,6-diphenylfulvene and various nitrones (Scheme II). It appears the above cycloaddition reaction is sensitive to steric effects, but not much to electronic effects, as seen by substitution on the C-phenyl ring of the nitrone; regiochemistry of cycloaddition was insensitive to para and meta, but not to ortho, substitution. Also, the above cycloaddition was found to be highly accelerated when performed in the neat melt.

Part II Chapter 1 reports the spontaneous generation of optical activity when 1-(4-methoxyphenyl)-2-phenyl-1-propanone (2) was crystallized in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Scheme III). The above ketone was chosen because of two properties: Firstly, it was known to exist as a conglomerate, i.e., a mechanical mixture of the enantiomeric crystals (as opposed to a racemate, in which the enantiomers share the same lattice), and secondly, the mutual interconversion of the enantiomers in solution was possible in the presence of a strong base (DBU), via the enolate anion. Crystalline 1-(4-methoxyphenyl)-2-phenyl-1-propanone with enantiomeric excess values of about 70% could be obtained by this method. The term "Preferential Spontaneous Resolution" has been proposed for phenomena such as the above, wherein optical activity is generated spontaneously—i.e., without the use of any optically active agent.

Chapter 2 reports two crystallization techniques which improve Pasteur's mechanical-manual technique for resolution of conglomerates. Many grams of 1-(4-methoxyphenyl)-2-phenyl-1-propanone could be obtained by these methods in optical purities of about 90%. Chapter 3 reports efforts to use 1-(4-methoxyphenyl)-2-phenyl-1-propanone as a starting material for the synthesis of interesting natural products, especially steroids, in view of the success in optically enriching this ketone reported in Chapters 1 and 2. Notably, the above ketone (racemic as well as optically enriched to an e.e. of 83%) has been converted by the multi-step process shown below (Scheme IV), to a bicyclic tetralone derivative (3). Also, diastereoselectivity in the hydroboration-oxidation of the styrene derivative (4) shown below was studied using various hydroborating reagents, and explanations have been proposed for the results (Scheme V).