The Application of the Sequential Birch Reduction Alkylation Cope Rearrangement to the Synthesis of Natural Products

Posted May 10th, 2010 at 2:53 pm.

Iva Yonova
Mentor: Professor Malachowski

One of the greatest challenges in synthetic organic chemistry is creating quaternary carbon centers. Most of the current synthetic tools available to chemists result in a mixture of two stereoisomers, which reduces the effectiveness of the process, as the yield of the desired stereoisomer is automatically halved. Furthermore, the importance of obtaining enantiomericly pure compounds cannot be overstated, as they play a major role in the pharmaceutical industry.

The Malachowski group has been working on utilizing the sequential Birch reduction-allylation and Cope rearrangement (Birch Cope sequence) (Figure 1) as the fundamental tool for the construction of quaternary carbon centers. The group has successfully applied it to the total synthesis of complex natural products such as mesembrine and lycoramine.

Figure 1:


A carbon atom bonded to four more carbon atoms.
Molecules with same structure but different spatial orientation
Only one stereisomer
Most therapeutic agents contain stereocenters (carbon atoms bonded to four different groups) and one of the enantiomers (or mirror images) is the active drug, while the other may be inactive and innocuous or potentially harmful.

The synthesis of all of the above compounds has been initialized by derivatives of ortho anisic acid (Figure 1) with an attached chiral auxiliary(5), which is obtained by the reduction of the common amino acid L-Proline(6) (Figure 2).

Figure 2


The effectiveness of the Birch Cope sequence depends on the type of molecule to which it is applied – different substituents will have different effects on the labiality of the benzene ring, and thus affect the compounds’ reactivity in the process. My current project involves expanding the scope of the Birch Cope sequence and adapting it to a variety of different substrates. Some of the targets of the project involve aniline and anisole derivatives, alpha phenyl imines, and aminobenzoates (Figure 3). The major challenges that will be faced in the project are the synthesis of the substrate molecules and the adaptation of the Birch reaction conditions to match the specific chemical character of each molecule.

Figure 3


(5) A group that contains a chiral center and is thus able to limit the reactivity of the compound so that only one stereoisomer of the product is formed.

(6) One of the twenty amino acids the human body produces; enantiomericaly pure.

Filed under: 2007,Malachowski, Dr. William,Yonova, Iva by Ann Dixon

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