טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentSmirnov Polina
SubjectStereoselective Synthesis via a Zn-Brook Rearrangement
Followed by an Ene-Allene Carbocyclization
Reaction
DepartmentDepartment of Chemistry
Supervisor Professor Ilan Marek
Full Thesis textFull thesis text - English Version


Abstract

One of the major challenges in organic synthesis is the design of new and efficient reaction systems which will enable the creation of functionalized organic molecules from relatively simple starting materials. Particularly relevant are synthetic methodologies that create several carbon-carbon bonds in a single-pot operation, introducing higher complexity to the reaction system. Another important goal is the ability to develop enantioselective methods for the construction of new stereogenic centers. Combining these two targets, creation of several new bonds and stereogenic centers, in a single pot-operation would be extremely useful in organic synthesis and will pave the way to new approaches for synthetic transformations.

In previously studied cases, multicomponent reactions were developed leading to the creation of new stereodefined compounds in highly efficient, single pot reactions. However, the introduction of selectivity control in acyclic systems was mostly achieved by using stoichiometric amounts of chiral auxiliaries. The goal of this study was the development of a new, highly efficient, methodology that will utilize asymmetric catalysis in a single-pot reaction systems leading to the formation of several new bonds and stereogenic centers in acyclic systems.

In this research work we were able to obtain diastereoisomerically pure (dr >99:1) and enantiomerically enriched (er up to 98:2) substituted propargyl diols possessing a tertiary hydroxyl group from simple acylsilanes. This process combines several transformations; catalytic enantioselective alkynylation of acylsilanes followed by an allenyl-Zn-Brook rearrangement and a Zn-ene-allene (or Zn-yne-allene) cyclization reaction, in a single pot operation. Following, a Tamao-Fleming oxidation, the final acyclic products were obtained with excellent control of the stereochemistry of all stereogenic centers.

Density functional theory (DFT) studies showed that in our newly developed systems the Brook rearrangement proceeds through an interesting allenyl-Zn-Brook rearrangement instead of the classic [1,2]-Zn-Brook rearrangement, due to a significantly lower activation barrier. This mode of reaction explains the transfer of chirality in the allenyl-Zn-Brook rearrangement. This novel methodology produces sophisticated molecular frameworks through asymmetric catalysis, while complying with synthetic efficiency, by creating three new bonds and two new stereogenic centers in a single-pot reaction sequence.