טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentSimaan Marwan
SubjectCarbometalation/Oxidation/Ring Opening Sequence As a New
Tool for the Synthesis of Aldehydes Bearing
Quaternary Stereogenic Center
DepartmentDepartment of Chemistry
Supervisor Professor Ilan Marek
Full Thesis textFull thesis text - English Version


Abstract

For the last few decades, we have witnessed a renaissance in chemical manipulations of small rings. Particularly flourishing in that context was the use of cyclopropane derivatives, which has been extensively covered. Among all the possible three-membered ring subunits that have been reported, cyclopropanol derivatives have recently attracted a lot of attention as they are found in many natural products and they may also undergo a large variety of synthetic transformations. Several approaches can yield cyclopropanols, although the synthesis of polysubstituted cyclopropanol derivatives as single diastereomer and enantiomer remains in its complete infancy. So, there is clearly a need for a general and efficient method for the enantio- and diastereoselective synthesis of such complex end products, and in particular, the challenging tri- and tetrasubstituted cyclopropanols.

In this manuscript, we initially describe the diastereoselective carbocupration reaction of alkoxy functionalized cyclopropene derivatives, followed by a subsequent trapping of the cyclopropyl metal species with an electrophilic source of oxygen (oxenoid) to afford various tetrasubstituted cyclopropanol derivatives in high enantiomeric ratios. The diastereoselective carbocupration/oxidation reaction of simpler nonfunctionalized cyclopropenes was also possible and afforded the corresponding nonfunctionalized tri- and tetrasubstituted cyclopropanols in high diastereomeric ratios.

While the preparation of enantiomerically enriched nonfunctionalized cyclopropenes was not yet possible, the asymmetric copper catalyzed carbomagnesiation/oxidation sequence of achiral nonfunctionalized cyclopropenes was successful and afforded the desired trisubstituted cyclopropanols in high diastereo- and enantiomeric excess. Changing the source of the incorporated electrophilic heteroatom from oxygen to nitrogen was highly efficient and afforded a new class of the equally important polysubstituted cyclopropylamine derivatives.

The utilization of the high ring strain of the cyclopropanol unit allowed us to perform two selective ring fragmentation sequences leading eventually to acyclic aldehydes bearing α-all carbon stereogenic centers. First, we could show that the direct ring fragmentation of alkoxy functionalized cyclopropanol derivatives afforded the desired acyclic aldehydes, whereas an indirect Pd-catalyzed distant functionalization of ω-ene nonfunctionalized cyclopropanols triggered a metal-walk and selective ring fragmentation giving also access to acyclic aldehydes. In all cases, the formation of the challenging quaternary carbon stereocenter could be prepared with high enantiomeric ratios.