טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentAbramovich Adi
SubjectConvergent Preparation of Chiral Polysubstituted
Cyclopropanes
DepartmentDepartment of Chemistry
Supervisor Professor Ilan Marek
Full Thesis textFull thesis text - English Version


Abstract

Enantiomerically enriched chiral three-member ring are important building blocks in organic chemistry, and can be found in many organic molecules with biological, and in some cases with pharmaceutical activities.

We would like to present a new approach for the preparation of diastereo- and enantiomerically pure 1,2-di- and 1,2,2-trialkylated cyclopropanes based on the synthesis of homochiral 1,1-bismetallated cyclopropane.

We found that our desired homochiral 1,1-bismetallated cyclopropane can be easily obtained from the corresponding homochiral 1,1-bissulfinylcyclopropane by means of the well known sulfoxide-lithium exchange reaction. This transformation can be either done stepwise, by a first and second sulfoxide-lithium exchange followed by reaction with alkylating reagents, or by a double sulfoxide-lithium exchange reaction.

First, we studied the selectivity of the sulfoxide-lithium exchange reaction and we found that the best conditions were when the bissulfinyl cycloproanes was treated with three equiv of n-BuLi in THF at -80 oC. The (trans)-1-alkyl-2-sulfinylcyclopropane was obtained in good yield and as a unique diastereomer. The stereochemistry of the cyclopropane was compared with literature data. It was found that the measured J coupling indicates that the sulfoxide syn to the alkyl chain was selectively removed. This observation was again proved by an X-ray analysis of the oxidized monosulfinyl cyclopropane.

The scope of the reaction was investigated. Both reactive electrophiles such as benzyl bromide or allyl bromide, and non reactive electrophiles such as methyl or butyl iodide can be used in that reaction and the (syn)-di-alkylated monosulfinylcyclopropanes can be obtained in moderate to good yields and as a single diastereoisomer.

Then, the removal of the second sulfoxide was investigated. After screening for the best conditions to overcome the problem associated with tertiary cyclopropylmetal, we found that two equiv of t-BuLi in toluene at -80 oC followed by reaction with electrophiles produced the desired either 1,2-di- or 1,2,2-trialkylated cyclopropanes with excellent diastereoselectivity in moderate to good yields. By changing the addition order of the electrophilic reagents, both diastereoisomers can be obtained at will in excellent diastereoselectivity.

Moreover, some preliminary results show that we were able to obtain the first example of chiral 1,1-bislithiated cyclopropane. By deuterolysis of the reaction mixture, one of the smallest possible chiral cyclopropane, namely 1-decyl-2,2-dideuterocyclopropane, can be obtained in 80% yield.