Stereoselective solvent induced 1,3-proton transfer of an allylic alkoxide to a homoallylic alkoxide catalysed by a chiral lithium amide

Article abstract of DOI:10.1039/b111676b

Stereoselective rearrangements of e.g. meso-epoxides by chiral lithium amides yield chiral allylic alcohols in high enantiomeric excess. Such products are useful synthetic intermediates. Lithium (S)-2-(pyrrolidin-1-ylmethyl)-pyrrolidide Li-2 has been foun

Full text of DOI:10.1039/b111676b

View Article Online / Journal Homepage / Table of Contents for this issue
Stereoselective solvent induced 1,3-proton transfer of an allylic
alkoxide to a homoallylic alkoxide catalysed by a chiral lithium
amide†
2
Maria Hansson, Per I. Arvidsson,‡ Sten O. Nilsson Lill and Per Ahlberg*
Organic Chemistry, Department of Chemistry, Göteborg University, SE-412 96 Göteborg,
Sweden. E-mail: Per.Ahlberg@oc.chalmers.se; Fax: ϩ46 31 772 2908; Tel: ϩ46 31 772 2899
Received (in Cambridge, UK) 2nd January 2002, Accepted 31st January 2002
First published as an Advance Article on the web 28th February 2002
Stereoselective rearrangements of e.g. meso-epoxides by chiral lithium amides yield chiral allylic alcohols in high
enantiomeric excess. Such products are useful synthetic intermediates. Lithium (S)-2-(pyrrolidin-1-ylmethyl)-
pyrrolidide Li-2 has been found to deprotonate cyclohexene oxide 1 in tetrahydrofuran (THF) to yield the
allylic lithium alkoxide of (S)-cyclohex-2-en-1-ol (S)-Li-3 in 80% ee. Upon changing solvent from THF to
2,5-dimethyltetrahydrofuran (2,5-DMTHF) a 1,3-proton transfer of (S)-Li-3 is induced yielding the lithium
alkoxide of (S)-cyclohex-3-en-1-ol (S)-Li-4. Thus the reaction gives access to the homoallylic alcohol 4. This
rearrangement has previously been shown to take place with retention of the stereocenter and intramolecularly.
We here report further results on the stereochemistry of this isomerisation. For this purpose a synthesis of
the deuterium labelled compound, (S)-2-deuterio-3-methylcyclohex-2-en-1-ol (S)-2H-5, has been developed.
Solvent induced isomerisation of the lithium alkoxide of (S)-2H-5 in 2,5-DMTHF gave after isolation only the
rearrangement product (1S,2R)-2-deuterio-3-methylcyclohex-3-en-1-ol (1S,2R)-2H-6 as shown by NMR and
computational modelling. No trace of the isotopomer and diastereoisomer (1S,2S)-2H-6 could be detected.
Thus it is concluded that the rearrangement stereoselectively protonates the C-2 carbon anti to the alkoxide
oxygen to yield the product. Further details of the reaction mechanism are currently under investigation.
Introduction
Lithium organic compounds are among the most useful
reagents in synthesis. But surprisingly little is known about their
reaction mechanisms. To explore the full potential of this
chemistry detailed knowledge about the reaction mechanisms
is needed including the stereochemistry and the role of aggre-
gation and the solvent in the reactions.
Scheme 1 Enantioselective deprotonation of the epoxide 1 by the
lithium amide Li-2 in 2,5-DMTHF and subsequent solvent induced
isomerisation of the allylic alkoxide (S)-Li-3 into the homoallylic
alkoxide (S)-Li-4.
Chiral lithium amides for enantioselective deprotonation of
e.g. meso-epoxides into allylic alcohols in high enantiomeric
excess (ee) are being developed and used.1–3 For example, the
lithium (S)-2-(pyrrolidin-1-ylmethyl)pyrrolidide Li-2 depro-
tonates cyclohexene oxide 1 in tetrahydrofuran (THF) to (S)-
cyclohex-2-en-1-ol (S)-3 in 80% ee.4–7 It has previously been
shown that upon changing the solvent from THF to a more
sterically demanding solvent, e.g. 2,5-dimethyltetrahydrofuran
(2,5-DMTHF) or diethyl ether (DEE), isomerisation of the
allylic lithium alkoxide (S)-Li-3 to the homoallylic lithium
alkoxide of (S)-cyclohex-3-en-1-ol (S)-Li-4 is induced (Scheme
1).8 This observation suggests that such reactions might find
general use for preparation of chiral homoallylic alcohols
which are important starting materials for making other optic-
ally active compounds. A number of drugs, pheromones and
other biologically active compounds may be synthesized using
this type of building block.9–12
methyl group at the double bond effectively prevents the
homoallylic lithium alkoxide Li-6 from further rearrangements
(Scheme 2).
Scheme 2 Isomerisation of the allylic lithium alkoxide Li-5 into the
homoallylic alkoxide Li-6 by the lithium amide Li-2.
With this substrate it was shown that the solvent induced
isomerisation is 100% stereospecific i.e. the configuration at the
stereogenic carbon center is conserved during the rearrange-
ment. The 1,3-proton transfer was also shown to be close to
100% intramolecular.13
In our previous mechanistic studies of the isomerisation13
the substrate seudenol (a sex pheromone of the Douglas fire
beetle), 3-methylcyclohex-2-en-1-ol 5, has been used. The
We now wish to report on the stereoselectivity of the solvent
induced chiral lithium amide catalysed 1,3-proton transfer reac-
tion. There are four possible modes for this isomerisation. It
may take place suprafacially either on the side of the ring syn to
the oxygen or the ring-side anti to the oxygen. If on the other
hand the 1,3-proton transfer takes place antarafacially the
proton may be abstracted by the base from one or the other side
† Electronic supplementary information (ESI) available: 1H NMR,
1H,1H-COSY NMR and 1H,1H-NOESY NMR spectra of 6; 1H NMR
2
spectra of 5 and (S)-2H-5; H NMR spectrum of (S)-2H-5. See http://
www.rsc.org/suppdata/p2/b1/b111676b/
‡ Present address: Institute of Chemistry, Department of Organic
Chemistry, Uppsala University, Box 531, SE-751 21 Uppsala, Sweden.
DOI: 10.1039/b111676b
J. Chem. Soc., Perkin Trans. 2, 2002, 763–767
This journal is © The Royal Society of Chemistry 2002
763

View Article Online
of the ring and delivered to the opposite side of the ring syn or
anti to the oxygen, respectively. Results are presented on the
determination of the absolute stereochemistry of the isolated
rearrangement product, the homoallylic alcohol. For this
purpose a deuterium labelled seudenol has been designed and
synthesised and used in the isomerisation reaction. Using two-
dimensional NMR-investigations and computational chemistry
it is concluded that the abstracted proton from the lithium
alkoxide of deuterated seudenol is delivered to the 2-carbon
anti with respect to the oxygen to yield only one of the stereo-
isomers of the deuterium labelled homoallylic alcohols after
isolation.
co-workers for enantioselective reduction of unsymmetrical
ketones was employed.16,17 The chiral oxazaborolidine (R)-
tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-
oxazaborole18 (R)-11 was used together with BH3ؒTHF and the
product contained (S)-10 in 80–86% ee as determined by chiral
gas chromatography (GC). The crude product was purified by
flash column chromatography. Typically, the overall yield from
starting material was 45%. After repeated recrystallisations
(typically 3 times) from hexane pure 10 containing (S)-10 in
>99.5% ee was obtained.
To introduce the deuterium and obtain the final product a
procedure by Wu and Okamura19 was tried in which tert-
butyllithium (tBuLi) in DEE is used for lithium–bromine
2
exchange of (S)-10 followed by quenching with H2O. Using
Results and discussion
Below the design, synthesis and application of mono-deuterium
labelled seudenol are presented together with results from the
NMR-studies and computational studies.
this method (S)-2-deuterio-3-methylcyclohex-2-en-1-ol (S)-2H-
5 was obtained, but the deuterium content was only 92 atom%
1
at C-2 as determined by H-NMR. Deuterium was only found
to be introduced at C-2 as determined by 1D 2H-NMR.
In order to increase the deuterium content several modi-
fications were made to the above procedure. In the Wu and
Okamura procedure the tBuLi is used in 4.2 times molar excess
over alcohol and added dropwise at Ϫ78 ЊC to the vinyl
bromide dissolved in diethyl ether. A reverse procedure with the
vinyl bromide dissolved in diethyl ether and addition to the
tBuLi solution was tried, but the deuterium content of the final
product remained unchanged. A larger excess (42 times molar
excess over alcohol) of tBuLi was also used but under these
conditions the deuterium content at C-2 in the product dropped
to 80 atom%. In order to reach improvement the hydroxylic
protons in the starting alcohol were exchanged by deutrons by
exchange with 2H2O or C2H3O2H, prior to reaction with tBuLi.
However, the deuterium content of the isolated product
remained essentially unchanged. The quenching procedure was
also modified e.g. the reaction was quenched by C2H3O2H at
Ϫ78 ЊC, but the deuterium content of the product did not
increase significantly. These results suggest that the protium
contamination of the product could be due to the fact that tert-
butyl bromide, formed from tBuLi in the lithium–bromine
exchange, partially undergoes a β-elimination by reaction with
vinyllithium in a reaction intermediate 12 (Scheme 5).
Therefore an alkyllithium reagent yielding in the halogen–
lithium exchange a bromide that undergoes no or slower
elimination was employed. However, no lithium–bromine
exchange was detected with methyllithium. But when tBuLi was
exchanged for nBuLi, which would give a much less stabilized
alkene, and therefore a presumably much slower elimination,
(S)-2H-5 with a deuterium content of >99 atom% at C-2 was
obtained. The ee of (S)-2H-5 was >99.5% and the crude yield
was up to 99%. This product was used as a substrate in the 1,3-
proton transfer reactions presented below for determination of
the stereochemistry.
Design and synthesis of a deuterium labelled substrate
For the determination of the product stereochemistry of the
reaction, i.e. to answer the question whether the 1,3-proton
transfer has delivered the proton to the C-2 carbon syn or anti
to the oxygen on the ring, the deuterium labelled substrate, (S)-
2-deuterio-3-methylcyclohex-2-en-1-ol (S)-2H-5, was designed
and synthesised. It was predicted that after isomerisation
of (S)-Li-2H-5 by Li-2 into lithium (1S,2X)-2-deuterio-3-
methylcyclohex-3-en-1-ol (1S,2X)-Li-2H-6 (X = R or S), X
could be determined by NMR (Scheme 3).
Scheme 3 Isomerisation of (S)-Li-2H-5 by Li-2 yielding (1S,2S)-Li-
2H-6 and/or (1S,2R)-Li-2H-6.
The labelled seudenol (S)-2H-5 was synthesized from com-
mercially available 3-ethoxycyclohex-2-enone 7 following the
procedure shown in Scheme 4.
Interpretation of the 1H NMR spectrum of 6
Assignment of the NMR signals to the carbons and hydrogens
in 6 was made by heteronuclear two-dimensional shift corre-
lation NMR—the heteronuclear single quantum correlation
experiment (1H,13C-HSQC) and the proton–proton correlation
experiment (1H,1H-COSY). To be able to differentiate the two
1
hydrogens at C-2 in 6 a homonuclear two-dimensional H,1H-
Scheme 4 Synthetic procedure used for preparation of (S)-2H-5.
NOESY experiment was performed and NOEs between the
protium at C-1 and the protiums at C-2 were determined, as
well as NOEs between the protiums at C-2 and C-6. A much
stronger NOE was found between the protium at C-2 with the
chemical shift 2.26 ppm and the protium at C-1 with the chem-
ical shift 3.98 ppm, than between the other protium at C-2 with
the chemical shift 1.95 ppm and the protium at C-1. A weak
NOE was also found between the protium at C-2 with the chem-
ical shift 1.95 ppm and the protium at C-6 with the chemical
shift 1.57 ppm. No NOE was observed between the protiums at
In the first step the ketone 7 was brominated in the dark by
N-bromosuccinimide (NBS) and 2-bromo-3-ethoxycyclohex-
2-enone 8 was obtained following a procedure by Belmont
and Paquette.14,15 In the next step the bromoketone 8 was
reacted with methyllithium in THF, following a published
procedure14,15 and 2-bromo-3-methylcyclohex-2-enone 9 was
obtained in up to 73% crude yield from 7.
To obtain the chiral bromoalcohol (S)-2-bromo-3-
methylcyclohex-2-en-1-ol (S)-10 a method by Corey and
764
J. Chem. Soc., Perkin Trans. 2, 2002, 763–767

View Article Online
the hydroxy group in the equatorial position is the main con-
former, so that the protium at C-2 with the chemical shift 1.95
ppm and the protium at C-6 with the chemical shift 1.57 ppm
are in proximity. The explanation for the observed NOE
between the protium with the chemical shift 1.95 ppm (H-2syn)
and the proton at 3.98 ppm (H-1) is that conformers with
the hydroxy group in an axial position are also present. This
assignment is in agreement with other examples showing that
the axial hydrogens at positions C-2 and C-6 have lower
chemical shifts than the equatorial ones.
A detailed interpretation of the results has been performed
using predictions of the coupling constants, based on DFT
calculations (B3LYP/6-31ϩG(d)). The calculations show that
the conformer with an equatorial hydroxy group is more
stable by 0.74 kcal molϪ1. Thus these gas-phase calculations
predict that 78% of the conformers have their hydroxy groups
in equatorial positions at 298 K.
The vicinal coupling constants for the two different con-
formers have been calculated using the Karplus equation:20
3J = A ϩ B cos φ ϩ C cos 2φ
(1)
where 3J is the vicinal coupling constant, φ is the dihedral
angle and A, B and C are constants given the values 4.22, Ϫ0.5,
and 4.5 respectively.20 Using the dihedral angles, obtained from
the DFT calculations, the vicinal coupling constants in (S)-6E
(Fig. 2) were calculated to be 8.5 Hz between H-1 and H-2syn
and 3.3 Hz between H-1 and H-2anti, respectively. The vicinal
coupling constants in (S)-6A (Fig. 2) were calculated to be 0.7
Hz between H-1 and H-2syn and 3.72 Hz for the coupling
between H-1 and H-2anti, respectively. The weighted averages
of the vicinal coupling constants, i.e. assuming a 78 : 22 distri-
bution between the conformers as suggested by the calculations,
were calculated to be 6.8 Hz (6.4 Hz) between H-1 and H-2syn
and 3.4 Hz (3.5 Hz) for the coupling between H-1 and H-2anti.
The experimentally observed values are shown in parentheses.
If the influence of the electronegativity of substituents is also
taken into account slightly lower vicinal coupling constants are
predicted.
Scheme 5 A mechanism for the formation of the deuterated product is
shown together with a possible route to proton contaminated product
when using tBuLi.
1.95 and 2.26 ppm and the protium at 1.81 ppm. The vicinal
coupling constants between the protium at C-1 with the chem-
ical shift 3.98 ppm and the protiums at C-2 with the chemical
shifts 1.95 and 2.26 ppm were found to be 6.4 and 3.5 Hz,
respectively.
In the conformer with the hydroxy group in the equatorial
position (Fig. 1) NOE between the protiums H-2anti and H-1 is
The result of the interpretation is shown in Fig. 2.
Fig. 2 Assigned NMR chemical shifts to the carbons and hydrogens
in 6 based on 1H,13C-HSQC and 1H,1H-COSY NMR experiments and
DFT calculations.
Fig.
1
Geometry optimized (B3LYP/6-31ϩG(d)) structures of
conformers of (S)-6 with the hydroxy group in an equatorial position
((S)-6E) and an axial position ((S)-6A).
The stereochemistry of the isomerisation product
predicted, but a negligible one between H-2syn and H-1. A
weak NOE is also expected between H-2syn and H-6syn. In
addition one would expect to find a large vicinal coupling con-
stant between H-1 and H-2syn and a smaller one between H-1
and H-2anti.
On the other hand for the conformer with the hydroxy group
in an axial position (Fig. 1) large NOEs are predicted between
H-1 and H-2syn as well as H-2anti and a weak one between
H-2anti and H-6anti. Moreover for this conformer the vicinal
coupling constants between H-1 and H-2syn and H-2anti are
predicted to be similar.
The determination of the configuration at C-2 in the isomeris-
ation product is based upon the chemical shift assignments of
the protons at C-2 in 6. The pure enantiomer (S)-2H-5 from the
synthesis described above was used in the 1,3-proton transfer
reaction with the chiral lithium amide Li-2 to determine
whether the proton is delivered to the C-2 carbon syn or anti to
the oxygen (Scheme 3). After 240 h reaction the mixture of
starting material and product was purified by flash chrom-
atography giving a 35 : 65 mixture of (S)-2H-5 and (1S,2X)-
2H-6. The isolated yield was 83%. The alcohols were separated
1
2
Thus our results suggest that the protium at C-2 with the
chemical shift 2.26 ppm is on the same side of the ring as
the protium at C-1. They also suggest that the conformer with
by HPLC and analyzed by H- and H-NMR. All deuterium
was found at C-2 in (S)-2H-5 and (1S,2X)-2H-6, respectively.
Only one deuterium signal at 1.95 ppm was detected for the
J. Chem. Soc., Perkin Trans. 2, 2002, 763–767
765

View Article Online
Experimental
Synthesis of 2-bromo-3-ethoxycyclohex-2-enone 8
A procedure by Belmont and Paquette was followed with the
following modification.14,15 Crystals of recrystallised NBS were
added very slowly in portions (up to 2.5 hours). The bromo-
ketone 8 was obtained in up to 99% yield.
Synthesis of 2-bromo-3-methylcyclohex-2-enone 9
A procedure by Belmont and Paquette was followed.14,15 The
crude 9 was obtained in up to 74% yield and used in the next
step without further purification.
Synthesis of (S)-2-bromo-3-methylcyclohex-2-en-1-ol (S)-10
To the catalyst (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-
pyrrolo[1,2-c][1,3,2]oxazaborole (R)-11 (185 µl, 0.28 mmol) was
added BH3ؒTHF (2.77 ml, 1.0 M) with stirring under N2. A
solution of 9 (5.23 g, 27.7 mmol) in THF (10 ml) and a solution
of BH3ؒTHF (13.8 ml, 13.8 mmol, 1.0 M) were added dropwise
simultaneously to the catalyst solution with stirring at 30 ЊC
under N2 (addition rate 0.5 ml minϪ1). The mixture was stirred
for 3 hours at 30 ЊC and quenched by the addition of methanol
(8 ml) at 0 ЊC. To the resulting solution was added HCl (15 ml,
2 M) and water (15 ml). The mixture was extracted with diethyl
ether (3 × 75 ml). The combined ether phases were washed with
brine (50 ml), saturated aqueous sodium bicarbonate solution
(50 ml), brine (50 ml), and dried over MgSO4. Removal of the
solvent under reduced pressure gave crude (S)-10 as a yellow
oil. The yield of product was up to 5.24 g (99%). 1H NMR (400
MHz, C2HCl3): δ 4.27 (m, 1 H), 2.13 (m, 2 H), 1.88 (m, 2 H),
1.85 (s, 3 H), 1.79 (m, 1 H), 1.64 (m, 1 H). The ee of the crude
product was 80% as determined by GC analysis. The product
was purified by flash column chromatography (TLC silica gel
60H, eluent gradient hexane–DEE), giving white crystals of
(S)-10 after evaporation of solvent. Typical yield after chrom-
atography was 2.4 g (45%). The ee of (S)-10 was improved
by repeated recrystallisations from hexane. The final ee was
>99.5% of (S)-10.
Fig. 3 a) 1H NMR spectrum of 6 recorded at 600 MHz and 25 ЊC
Synthesis of (S)-2-deuterio-3-methylcyclohex-2-en-1-ol (S)-2H-5
1
(72 mM in C2HCl3). b) H NMR spectrum of (1S,2R)-2H-6 recorded
2
at 600 MHz and 25 ЊC (66 mM in C2HCl3). c) H NMR spectrum of
nBuLi (11 ml, 22 mmol, 2.0 M) was added dropwise to a solu-
tion of (S)-10 (1.0 g, 5.2 mmol) in dry DEE (100 ml) with
stirring at Ϫ78 ЊC under N2. The reaction mixture was stirred
for 1 hour at Ϫ78 ЊC and for 1 hour at 0 ЊC. 2H2O (2.5 ml) was
added at 0 ЊC and the mixture was allowed to stir for 30 min at
rt. Water (40 ml) was added and the mixture was extracted with
diethyl ether (3 × 100 ml). The combined ether phases were
dried over MgSO4 and the solvent was removed under reduced
pressure. The product was obtained as a yellow oil in yields up
to 0.58 g (>99%) and used in the isomerisation without further
(1S,2R)-2H-6 recorded at 92 MHz and 25 ЊC (95 mM in CHCl3).
isolated homoallylic alcohol i.e. no trace of deuterium in the
2anti position was detected (Fig. 3).
Thus it is concluded that deuterium is syn to the oxygen in
the deuterium labelled homoallylic alcohol product i.e. the
1,3-proton transfer has delivered the proton anti with respect
to the oxygen as shown in Fig. 4 i.e. selectively to yield the
1
purification. H NMR (600 MHz, C2HCl3): δ 4.18 (m, 1 H),
1.95 (m, 1 H), 1.88 (m, 1 H), 1.79 (m, 1 H), 1.75 (m, 1 H), 1.70
(s, 3 H), 1.57–1.60 (m, 2 H), 1.38 (m, 1 H). The deuterium
content in the product was analyzed by 1H- and 2H-NMR and
was found to be >99 atom% in position 2. The ee was >99.5%.
Isomerisation
Glassware and syringes used in the isomerisation reaction were
dried at 50 ЊC in a vacuum oven overnight. 2,5-DMTHF was
distilled from sodium–benzophenone ketyl in a nitrogen
atmosphere before use. All manipulations concerning the iso-
merisation reactions were carried out in a glove box (Mecaplex
GB 80 equipped with a gas purification system that removes
oxygen and moisture) using gas-tight syringes.
Fig. 4 The stereochemistry of the rearranged product is shown. The
rearranged proton is found at C-2 in a position anti with respect to the
oxygen.
enantiomer (1S,2R)-2H-6 as the product. No trace of the stereo-
isomer (1S,2S)-2H-6 could be detected. It is not yet clear
whether a monomer or a dimer of the lithium amide (Li-2)
is carrying out the 1,3-proton transfer and whether the
rearrangement is suprafacial or antarafacial; experiments to
address this question are currently underway.
Racemic 3-methylcyclohex-3-en-1-ol 6
Isomerisation of racemic Li-5 into racemic Li-6 was performed
on up to a gram scale according to the following general
766
J. Chem. Soc., Perkin Trans. 2, 2002, 763–767

View Article Online
protocol for isomerisations: nBuLi (227 µl, 0.34 mmol, 1.5 M in
hexane) was added to a solution of 5 (20.0 µl; 0.17 mmol) and 2
(28.0 µl; 0.17 mmol) in 2,5-DMTHF (1.00 ml) maintained at
0 ЊC. The flask was then moved to a thermostat held at 30.0
0.02 ЊC. The reaction was monitored by withdrawing 50.0 µl of
the reaction mixture using a dry syringe. The sample was trans-
ferred to a vial containing diethyl ether (1.0 ml) and saturated
NH4Cl (0.50 ml), and the mixture was shaken. The aqueous
layer was removed and the ether phase was dried over Na2SO4
prior to GC analysis. After 72 h the reaction mixture contained
5 and 6 in about 35 : 65 ratio. Typical yield was 90%. For
workup the organic layer was washed with a solution of NH4Cl
(1 M) followed by brine, prior to drying (Na2SO4) and evapor-
ation of the solvent. The alcohol mixture was purified by silica
gel flash chromatography (eluent 75 : 25 hexane–DEE) giving
hexane : DEE) giving a 35 : 65 mixture of (S)-2H-5 and
(1S,2R)-2H-6 in 83% yield (0.39 g). The mixture was separated
by HPLC-separation following the procedure cited above,
giving 0.22 g of (1S,2R)-2H-6.
Acknowledgements
We thank the Swedish Research Council for financial support
and Charlotta Damberg at the Swedish NMR Centre for NMR
assistance.
References
1 P. J. Cox and N. S. Simpkins, Tetrahedron: Asymmetry, 1991, 2, 1.
2 D. M. Hodgson, A. R. Gibbs and G. P. Lee, Tetrahedron, 1996, 52,
14361.
3 P. O’Brien, J. Chem. Soc., Perkin Trans. 1, 1998, 1439.
4 M. Asami, Chem. Lett., 1984, 829.
5 M. Asami and H. Kirihara, Chem. Lett., 1987, 389.
6 M. Asami, Bull. Chem. Soc. Jpn., 1990, 63, 721.
7 M. Asami, T. Ishizaki and S. Inoue, Tetrahedron: Asymmetry, 1994,
5, 793.
8 A. Z.-Q. Khan, P. I. Arvidsson and P. Ahlberg, Tetrahedron, 1996, 7,
399.
1
a pure mixture of 5 and 6 in 45% yield as shown by H NMR
and GC. The isomers were separated on an analytical and
semi-preparative scale using HPLC (Dynamax silica column,
solvent: 75 : 25 cyclohexane–EtOAc (analytical 1.2 ml minϪ1,
semipreparative 5.5 ml minϪ1)) with refractive index detection.
1H NMR (600 MHz, C2HCl3): δ 5.38 (br, 1 H), 3.98 (m, 1 H),
2.26 (m, 1 H), 2.16 (m, 1 H), 2.07 (m, 1 H), 1.95 (m, 1 H), 1.81
(m, 1 H), 1.67 (s, 3 H), 1.57 (m, 2 H), 1.53 (br s, 1 H); 13C{1H}
NMR (100 MHz, C2HCl3): δ 23.2, 23.4, 29.4, 38.5, 66.9, 120.0,
131.0.
9 J. S. Sabol and R. J. Cregge, Tetrahedron Lett., 1989, 30, 3377.
10 M. Asami, J. Takahashi and S. Inoue, Tetrahedron: Asymmetry,
1994, 5, 1649.
11 L. F. Tietze, K. Schiemann, C. Wegner and C. Wulff, Chem. Eur. J.,
1998, 4, 1862.
12 S. Barrett, P. O’Brien, H. C. Steffens, T. D. Towers and M. Voith,
Tetrahedron, 2000, 56, 9633.
13 P. I. Arvidsson, M. Hansson, A. Z.-Q. Khan and P. Ahlberg, Can. J.
Chem., 1998, 76, 795.
14 L. A. Paquette and G. Zon, J. Am. Chem. Soc., 1974, 96, 224.
15 D. T. Belmont and L. A. Paquette, J. Org. Chem., 1985, 50,
4102.
16 E. J. Corey, R. K. Bakshi and S. Shibata, J. Am. Chem. Soc., 1987,
109, 5551.
17 E. J. Corey, R. K. Bakshi, S. Shibata, C.-P. Chen and V. K. Singh,
J. Am. Chem. Soc., 1987, 109, 7925.
18 D. J. Mathre, T. K. Jones, L. C. Xavier, T. J. Blacklock, R. A.
Reamer, J. J. Mohan, T. T. Jones, K. Hoogsteen, M. W. Baum and
E. J. J. Grabowski, J. Org. Chem., 1991, 56, 751.
19 K.-M. Wu and W. H. Okamura, J. Org. Chem., 1990, 55, 4025.
20 H. Günther, NMR Spectroscopy—Basic Principles, Concepts, and
Applications in Chemistry, John Wiley & Sons, 1995.
Isomerisation of the lithium alkoxide of (S)-2-deuterio-3-
methylcyclohex-2-en-1-ol Li-(S)-2H-5 to the lithium alkoxide of
(1S,2R)-2-deuterio-3-methylcyclohex-3-en-1-ol (1S,2R)-Li-2H-6
(S)-2-(Pyrrolidin-1-ylmethyl)pyrrolidine 2 (474 µl, 2.91 mmol)
and (S)-2-deuterio-3-methylcyclohex-2-en-1-ol (S)-2H-5 (0.47 g,
4.15 mmol) were dissolved in 2,5-DMTHF (13.95 ml) in the
reaction vessel inside the glove box. The vessel was transferred
out of the glove box and nBuLi (2.08 ml, 5.0 mmol, 2.4 M
in hexane) was added under N2. The vessel was transferred
from the glove box to a thermostat (Heto Birkeröd) held at 30
0.02 ЊC. After 240 h the reaction was quenched by addition of
a saturated solution of NH4Cl in water (10 ml). The organic
layer was washed with brine (2 × 5 ml) before drying over
Na2SO4 and evaporation of the solvent. The residue was puri-
fied by flash chromatography (silica gel TLC 60H, eluent 75 : 25
J. Chem. Soc., Perkin Trans. 2, 2002, 763–767
767