Synthesis and Purification of 2,6-dimethylcyclohexanol for Application
as a General Anesthetic
K. Smith, M.J. Kim, R. Sinha, and K. M. Shea*
Smith College, Chemistry Department, Northampton, MA 01063
kshea@smith.edu
Project Goal
Synthesize trans,trans-2,6-dimethylcyclohexanol using selective methods.
Background
•  Propofol, a common anesthetic, has been shown to act on the
GABAA receptor.
•  Like many anesthetics, mysteries still remain
•  about propofol’s action.
•  Push to develop new anesthetics to:
Propofol
o uncover anesthetics with fewer side effects.
o allow for more testing to understand the anesthetic action
and mechanisms of action for anesthetics in general.
•  Based on previous study of propofol analogs, Adam Hall’s
neuroscience lab investigated various cyclohexanols due to
their structure similarity to propofol, cyclohexanols being fully
hydrogenated propofol analogs.
•  A few of the cyclohexanol derivatives that showed anesthetic
potency:
Isomerization
Past Work
•  The initial goal of this project was separating the stereoisomers for
testing by the Hall lab of the individual stereoisomers.
•  These separations, based on chromatographic techniques, were
completed last year by Alex Page for her honors thesis.
•  These separations, after many attempts at optimization, failed to
separate the stereoisomers, except for separation of the cis,cis isomer in
large quantities.
•  Preliminary testing by the Hall lab showed the trans,trans isomer
to be most potent of the isomers.
•  As a result, this current project switched to synthesizing
trans,trans-2,6-dimethylcyclohexanol.
trans,trans
Both reduction and isomerization can occur in these reactions dictating the
stereochemical outcome..
OH
OH
O
O
cis
O
trans
`
1)  Reaction with β-cyclodextrin: poor yields after various attempts at
optimization
Example of host-guest chemistry
O
OH
OH
B‐CD,
Na2CO3(0.2
M),
NaBH4
rt,
24
hrs
5‐23%
2
91‐99%
1
1‐9%
HO
OH
OH
3
2
22%
1
19%
59%
4
O K
O
KH (in pentane)
0˚C-->25˚C (4-7h )--> 0˚C
OH
O
OH
1
52‐54%
2
46‐48%
OH
OH
O
25˚C (2-4 h)
O
1. MeI
1 hr (-10˚C)
2. EtOTf
16 h (25˚C)
O
58%
EtOTf (2 Eqv)
OH
70%
• Test individual stereoisomers as potential anesthetics.
3
98%
4
1
cis,cis
0˚C (1 h) --> 25˚C (16 h)
LiAlH4,
THF
1
hr,
rt
33%
OH
n-BuLi (in hexane)
LiAlH4,
THF
1
hr,
rt
57‐81%
Resolution of
diastereomers was
confirmed with 1D
1H NMR. Unique 1H
NMR peaks are
represented with
isomer assignments.
Future Approaches
OH
OH
4
• Synthesize cyclohexanone precursors, asymmetric and
symmetric, that likely can be reduced using LiAlH4 with
separation of stereoisomers via column chromatography:
3) Simple Reducing Agents: used to synthesize all isomers
Separation of isomer 1 from 2 using column chromatography
Isomers 3 and 4 left as enantiomeric mixture
O
3
By using common reducing agents, all isomers could be
separated (the mixture of enantiomers were not separated).
Further experimentation by the Hall lab revealed cis,cis-2,6dimethylcyclohexanol as the most potent isomer.
OH
OH
OH
75˚C
for
2
hrs,
then
45˚C,
24
hrs
51%
OH
Unlikely Discovery
2) Reaction with metal complex reducing agent (MCRA)
Example of aggregate activation
MCRA synthesized from NaH, Ni(OAc)2, and 2,6-dimethyl-2,5-hexanediol
Produced mixtures of isomers that can’t be separated by column
ooochromatography
Ni(OAc)2,
NaH
THF
2
1
OH
NMR Analysis
Reactions
Reduction reactions of 2,6-dimethylcyclohexanone:
O
•  2,6-dimethylcyclohexanol was selected for further studies in
this project because it has a strong anesthetic potency and is
available commercially.
•  Due to the chirality of the body, single stereoisomers act
differently in environments within the body.
•  This compound exists as two diastereomers and a set of
enantiomers (box above).
•  Testing with cyclohexanol derivatives pictured above used
mixtures of isomers.
Li
2
2%
Funding: Tomlinson Fund