Brugia Malayi - Clark Science Center - Smith College

Purification and Synthesis of 2,6-dimethylcyclohexanol and Similar
Cyclohexanol Analogues for Application as General Anesthetics
Kelly Smith
This research in collaboration with the Adam Hall Laboratory focuses on the importance of cyclohexanol derivatives as possible
general anesthetics. Cyclohexanol compounds have a similar structure to propofol, a common anesthetic (Figure 1). Adam
Hall has studied the effects of various cyclohexanols on GABAA (γ-aminobutyric acid type A), a receptor known to play a role
in propofol activity. As a result, they discovered that 2,6-diisopropylcyclohexanol and 2,6-dimethylcyclohexanol were most
effective (afterpropofol) as modulators of GABAA followed by cyclohexanol compounds with bulkier side chains. This research
was conducted using a mixture of isomers for all compounds, but current research in this field points to the importance of
stereochemistry in relation to a compounds effectiveness with GABAA and in the human body.
The three diastereomers of 2,6-dimethylcyclohexanol were separated via column chromatography, but the separation is
extremely difficult we never attempted to separate enantiomers (3 and 4), (Figure 2). Therefore, asymmetric syntheses were utilized
toselectively make trans,trans (2) as well as cis,trans (3) and trans, cis(4)
From (Z) and (E) 2,6-dimethylcyclohexanone (5 and 6). The diastereomers of 2,6-dimethylcyclohexanone were separated
via column chromatography. The synthesis of 2 involves reduction with sodium borohydride mediated by β-cyclodextrin,
which complexes with 5 to permit only axial attack to produce2 (Figure 3). This complex uses host-guest interactions to promote
axial attack. In comparison, 6 was reduced with sodium borohydride without need for β-cyclodextrin to synthesize isomers 3 and 4
(Figure 4). Isomer1 can be readily isolated from the mixture of isomers of 2,6-dimethylcyclohexanol by column chromatography.
The next phase of this project involves synthesizing other 2,6-disubstituted cyclohexanol stereoisomers, including
2,6-diisopropylcylcohexanol and 2,6-diethylcyclohexanol, individually making all of the stereoisomers. These chiral molecules can
then be studied for their individual effectiveness as anesthetics to generate new and different anesthetic molecules. (Supported by
the Howard Hughes Medical Institute)
Advisor: Kevin Shea
2012
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