A concise asymmetric synthesis of the pheromone 1-methylcyclohex-2-enol via a 'merged substitution-elimination reaction'

Article abstract of DOI:10.1039/a701756a

The title compound is prepared (> 94% ee) by a three step synthesis from 1-methylcyclohexene via a 'merged substitution-elimination reaction' involving a phenylselenide ion.

Full text of DOI:10.1039/a701756a

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A concise asymmetric synthesis of the pheromone 1-methylcyclohex-2-enol via
a ‘merged substitution-elimination reaction’
David P. G. Hamon*† and Kellie L. Tuck
Chemistry Department, University of Adelaide, S.A. 5005, Australia
The title compound is prepared ( > 94% ee) by a three step
synthesis from 1-methylcyclohexene via a ‘merged substitu-
tion-elimination reaction’ involving a phenylselenide ion.
enantiomer,‡ can nevertheless be fractionally recrystallised to
high enantiomeric purity (94% ee after four recrystallisations
from diethyl ether–hexane, 37% yield, the racemate is less
soluble).
One of the constituents of the pheromone system of the beetle
Dendroctonus pseudotsugae Hopkins, an economically impor-
tant pest of the Douglas fir tree, is the aggregation pheromone
1-methylcyclohex-2-enol 1. Previous syntheses of the optically
active pheromone 1 have involved the conversion of optically
active intermediates, prepared by classical resolution,1 enzy-
mically,2,3 from the chiral pool,4 or by multistep asymmetric
syntheses.5,6
Treatment of the tosylate 3 with NaSePh (PhSeSePh, NaBH4,
EtOH10), in boiling EtOH, did not give the sought after
substitution reaction. Rather surprisingly an elimination reac-
tion occurred instead. The initial reaction gave a mixture of the
alcohol 1 and the ketones 6 and 7. It had been assumed from the
outset that base treatment of the tosylate 3 would give the
ketones 6 and 7, by a negative-ion pinacol rearrangement,11 and
this was confirmed by treatment of the tosylate with KOBut (in
THF at room temperature, 6:7 = 8:1, 90%). Selenide ion is too
weak a base to abstract a proton from an alcohol and it was
likely that ketones 6 and 7 were artifacts formed from
adventitious sources of base. A wash of the glassware with
NH4Cl solution prior to the reaction of tosylate 3 with NaSePh,
obviates the formation of these ketones and the volatile alcohol
(S)-(2)-1§ is isolated, in 78% yield, by fractional distillation.
The enantiomeric purity of the tertiary allylic alcohol 1 could
not be obtained directly by chiral shift NMR experiments and
we did not have access to complexation GC.1 Conversion of the
alcohol to the epoxide 8 (with slow addition of MCPBA to
alcohol 1, NaHCO3, Et2O, 0 °C, 70%, the diastereomer is not
formed) and chiral shift NMR experiments‡ on this (94% ee)
confirmed that the enantiomeric purity from the tosylate had
been maintained.
The mechanism for the elimination reaction observed is
intriguing. The reaction of the tosylate 3 with NaSePh in EtOH
is not an E1 mechanism since the qualitative observation is that
the half-life for the reaction is concentration dependent; because
no products from pinacol rearrangement are observed when care
is taken to remove adventitious base; and because the tosylate is
recovered unchanged after reflux in EtOH. The question arises,
therefore, as to why selenide anion, a powerful nucleophile to
carbon but non-nucleophilic to hydrogen attached to the oxygen
of an alcohol, should suddenly change allegiance and become a
nucleophile to hydrogen attached to carbon. Winstein, in a
paper published in 1956,8 first drew attention to the dichotomy
of weak bases but good nucleophiles which promote elimination
reactions when he wrote about merged substitution-elimination
reactions. Since then there has been considerable debate12,13 as
to the veracity of his suggestion but, in our opinion, no clear
RO
OH
O
HO
SePh
1
2
4
If asymmetric syntheses are to become important for
industrial preparations it is necessary to illustrate that they can
be made simple and short. However, this is not necessarily a
trivial exercise. With this pedagogical principle in mind, we
sought to modify our earlier route5 in the hope that the separate
enantiomers might be more readily prepared. Serendipity has
played an important role in providing a simple solution to this
problem and we disclose a three step asymmetric synthesis of
this pheromone which is applicable to the synthesis of either
enantiomer, and which gives the constituent in an enantiomeric
purity exceeding 94% ee. Ironically the aggregation pheromone
found naturally is only 10% ee7 but the challenge of the
asymmetric synthesis has been pedagogically both useful and
exciting. A key step in our earlier synthesis5 of this pheromone
involved nucleophilic substitution of the epoxide 2. Although
both the leaving groups in the epoxide 2 and the tosylate 3 are
in a pseudo neopentyl location, a study of models suggests that
tosylate 3 is considerably more hindered to nucleophilic attack
than the epoxide 2. However, it was considered that with the
powerful nucleophile NaSePh, tosylate 3 might also, like
epoxide 2, react to give in this case the selenide 4. Thermal
elimination of the selenoxides5 derived from 4 would give the
pheromone 1. Asymmetric dihydroxylation of 1-methylcyclo-
hexene should give the optically active diol 5 from which the
tosylate 3 could be prepared.
After this work had commenced, Sharpless reported,9 as a
footnote, the ee (52%, by chiral HPLC) for the asymmetric
dihydroxylation (AD b mix) of 1-methylcyclohexene to the diol
5, but no experimental details for the preparation were provided.
Owing to the water solubility and considerable volatility of the
diol 5, we have found it necessary to modify, somewhat, the
standard work-up procedures for this reaction by removal of the
KOH wash normally used to remove methanesulfonamide. The
product is then isolated, in 85% yield, by fractional distillation
of all solvents, chromatography and sublimation (50 °C/0.5
Torr). Conversion of the diol 5 to the mono secondary tosylate
3 (85% yield, 94% yield for the racemate on a larger scale) gives
material which, although it is initially only 75% of the major
OH
OH
OH
OTs
(S)-(–)-1
5
6
3
O
OH
O
HA
+
O
HB
7
8
Scheme 1
Chem. Commun., 1997
941

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explanation has been given for what is actually occurring in
these reactions. Since our example appears to be one of the more
extreme examples of this phenomenon, we would like to present
our observations in the hope that they will rekindle debate on
this subject.
Under the same conditions, with NaSePh, as when the
tosylate 3 gives only the elimination product 1, both the racemic
isomeric trans-tosylate 9 and the racemic mesylate 10 undergo
clean substitution reactions to give the selenide derivatives
11¶14 and 12 respectively. It has been shown15 that for the
We thank Rebecca Kennedy for the experiments referred to
in ref. 14.
Footnotes
† E-mail: dhamon@chemistry.adelaide.edu.au
‡ All chiral shift NMR experiments were run in 15% C6D6 in CCl4 with
Eu(hfc)3. Racemic tosylate 6. dH (200 MHz, CDCl3) 1.14 (s, 3 H, CH3),
1.2–1.8 (complex, 8 H, methylene envelope), 1.59 (s, 1 H, OH), 2.45 (s,
1 H, Ar-CH3), 4.36 (dd, 1 H, J 4.04, 9.94 Hz, H1), 7.34 (d, 2 H, J 8.22 Hz,
Ar-H), 7.80 (d, 2 H, J 8.22 Hz, Ar-H). The doublet originally at d 7.80
separates, to baseline, into two doublets with the shift reagent. Racemic
epoxide 8. dH (200 MHz, CDCl3) 1.2–2.1 (complex, 6 H, methylene
envelope), 1.33 (s, 3 H, CH3), 2.40 (br s, 1 H, OH), 3.10 (d, 1 H, J 4.0 Hz,
H2), 3.36 (m, 1 H, H3). The multiplet originally at d 3.36 separates, to
baseline, into two broadened singlets with the shift reagent.
OCH2CH2Ph
OH
OH
OTs
OMs
SePh
§ Pheromone 1. dH (200 MHz, CDCl3) 1.29 (s, 3 H, CH3), 1.5–1.8
(complex, 4 H, methylene envelope), 2.0 (m, 2 H, H4), 5.60 (br d, 1 H, J
10.0 Hz, H2), 5.75 (td, 1 H, J 4.0, 10.0 Hz, H3). dC (75.5 MHz, CDCl3) 19.5,
25.0, 29.3, 37.8, 67.9, 128.9, 133.7.
¶ A referee has suggested that this compound might have the structure 4 if
it arose through double inversion via the epoxide. However, optically active
compound 4 is already known5 and the spectral data are different.
∑ A study of a model (axial leaving group down) shows that the reacting
centre can move up smoothly towards the nucleophile as overlap of the
orbitals takes place. This would give the product in the boat conformation.
No such smooth pathway exists for the equatorial leaving group. We believe
that this requirement would also account for the known trans-diaxial
opening of cyclic epoxides.
10
9
11
PhSe
R2
R3
R2
X
OCH2CH2Ph
SePh
H
R1
OSO2R
12
13
4-tert-butylcyclohexyl derivatives the axial tosylate reacts
faster than the equatorial tosylate in SN2 reactions. Conforma-
tional mobility is clearly demonstrated for the tosylate 3, even at
room temperature, since it is likely that the compounds 6 and 7
come from two different chair conformers. From a study of
models it is seen that when the leaving group is axial not only
is the rear-side attack less hindered but, the nucleophile, the
reaction centre and the leaving group can stay co-linear
throughout the reaction.∑ Perhaps herein lies an explanation for
our observations. It is likely that the selenide ion follows a
trajectory co-incident with the dipole axis of the molecule and
that in both the compounds 9 and 10 the propensity for carbon
nucleophilicity is not thwarted by steric barriers since only lone
pairs (see 13) would hinder the approach. In the case of the
tosylate 3, however, the methyl group would clearly present an
obstacle to rear-side attack and the deflected nucleophile might
then encounter the hydrogen atom, held in an antiperiplanar
relationship to the leaving group, with sufficient energy to
overcome the barrier to elimination and this then becomes the
lower energy process.
In conclusion, therefore, we have developed a three step
asymmetric synthesis of the pheromone, from achiral starting
materials. The route is probably far more efficient than any to
date and will be extremely efficient if further developments to
the Sharpless procedure allows a more enantioselective prepara-
tion of the diol 5. Furthermore the synthesis has revealed an
intriguing elimination reaction which may help to unravel the
paradoxes arising in the mechanism of weak-base elimination
reactions.
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Received in Cambridge, UK, 13th March 1997; Com.
7/01756A
942
Chem. Commun., 1997