Synthesis of Bicyclic Rings with Quaternary Centers through Sequential Birch Reduction-Alkylation and Cycloisomerization

Mentor: Dr. Bill Malachowski

1The focus of this research project will be the synthesis of bicyclic ring systems with quaternary centers, using sequential Birch reduction-alkylation and metal-catalyzed cycloisomerization (Scheme 1).  There are relatively few previous examples of bicyclic ring synthesis via metal-catalyzed cycloisomerization reactions, most of which involve malonate type derivatives, ethers, or disubstituted amines. The collection of substrates for this process, therefore, has been relatively limited. Birch reduction-alkylation is an excellent way to synthesize precursors for cycloisomerization reactions, and there is no precedent of employing this method to enantioselectively synthesize bicyclic rings. The Malachowski group has long been focused on studying Birch reduction-alkylation reactions and utilizing them, in combination with other reactions, to make structurally interesting compounds that can serve as important intermediates on the path to complex biologically active molecules. ,


Scheme 1. Overall scheme of the Birch reduction-alkylation and cycloisomerization sequence.

2I will initially focus on generating 1 (Scheme 2) and 3 (Scheme 3) via Birch reduction-alkylation using alkenyl and alkynyl alkylating agents, which will introduce a pi system capable of undergoing cycloisomerization.



Scheme 2. Synthesis of cyclohexadiene substrates using alkynyl and alkenyl alkylating agents via Birch reduction-alkylation reaction.

Scheme 3. Synthesis of dihydrofuran substrates using alkynyl and alkenyl alkylating agents via Birch reduction-alkylation reaction.

              Using the substrates generated from the Birch reduction-alkylation step, I will then focus on synthesizing bicyclic rings through cycloisomerization reactions with Pd(II) and Ru(II) catalysts. If successful, this step will illustrate the applicability of metal catalyzed cycloisomerization to the construction of more complex bicyclic structures.

V. Michelet et al. Angew. Chem. Int. Ed. 2008, 47, 4268 – 4315, and references therein.

T. Paul, W.P. Malachowski, J. Lee, Org. Lett. 2006, 8, 4007.

W.P. Malachowski, T. Paul, S. Phounsavath, J. Org. Chem.200772 (18),6792–6796.