Application of Assembly-line Synthesis to Conformationally Designed Cyclic and Acyclic Molecules
Final Report Abstract
Assembly-line synthesis of boronic ester by iterative homologations is a robust method that can be easily automated due to its high level of efficiency and stereochemical fidelity. A main drawback of the current assembly-line synthesis is that only a methyl substituent on α-stannyl benzoates is accessible in enantiopure form. With different substituents rather than methyl, α-stannyl benzoates are generally liquid and enantiomeric ratio cannot be enhanced by recrystallization. Therefore, discovering alternative precursors to chiraI carbenoids was required to apply assembly-line synthesis to a broad range of molecules. In this project, synthesis of α-sulfinyl benzoates and their application as chiral carbenoid precursors were studied. A range of enantiopure α-sulfinyl benzoates were prepared by either the sulfinylation of α-magnesiated benzoates or the alkylation of unsubstituted α-sulfinyl benzoates. Application of α-sulfinyl benzoates as chiral metal carbenoid precursors in the homologation of boronic esters were demonstrated. Three consecutive iterations of homologation of boronic esters was also performed. However, further iterations failed due to the increase in the steric hindrance of boronic esters. Therefore, α-sulfinyl benzoates are not suitable precursors for assembly-line synthesis of long hydrocarbons. This work was published in the Journal of American Chemical Society. Flexible acyclic molecules that adopt defined shapes were designed by diamond-lattice analysis and molecular mechanics. The use of diamond-lattice analysis alone was misleading because the flexibility of the backbone was overshadowed. Proposed structures were revisited and also analyzed using molecular mechanics. Synthesis of target compounds that contain seven or eight stereocenter was succeeded by nine or ten consecutive iterative homologations of boronic esters. Due to the lack of a suitable assembly-line synthesis, homologation with carbenoids generated by an enantioselective deprotonation of benzoates was performed to introduce long side chains to the hydrocarbon backbone which produces other minor diastereomers as well. Target helical compounds were then separated from their minor diastereomers by preparative HPLC. Preliminary analysis indicated that the conformation control on such flexible long hydrocarbon chain is indeed possible. In future, NMR analysis and DFT calculations of target compounds will be completed in the research groups of Prof. Aggarwal and Prof. Butts. Design, synthesis, and analysis of molecules with other defined shapes will be performed by the same research groups at University of Bristol.
Publications
- “α-Sulfinyl Benzoates as Precursors to Li- and Mg Carbenoids for the Stereoselective Iterative Homologation of Boronic Esters” J. Am. Chem. Soc. 2017, 139, 11877–11886
Casoni, G.; Kucukdisli, M.; Fordham, J. M.; Burns, M.; Myers, E. L.; Aggarwal, V. K.
(See online at https://doi.org/10.1021/jacs.7b05457)
