Asymmetric synthesis and Lewis acid mediated type II carbonyl ene cyclisations of (R)-2-isopropyl-5-methylhex-5-enal

Article abstract of DOI:10.1016/S0957-4166(00)00316-5

The asymmetric synthesis of (R)-2-isopropyl-5-methylhex-5-enal in 98% ee is described. It was discovered that the key alkylation step employing an Evans chiral auxiliary and 3-methylbut-3-en-1-yl trifluoromethanesulphonate as the alkylating agent led to significant competing O-alkylation, a phenomenon not previously reported. Type II carbonyl ene cyclisation of the aldehyde with a range of Lewis acids led to either the (R,R)- or (R,S)-5-methylidenecyclohexanols without concurrent racemisation of the alpha stereogenic centre of the aldehyde. Conditions for effecting the easy racemisation of a model enantiomerically pure aldehyde, (S)-2-methylbutanal, were developed. In an effort to secure a dynamic kinetic resolution procedure, these conditions were applied to (R)-2-isopropyl-5-methylhex-5-enal. However, a competing and dominant Prins cyclisation occurred instead leading to a mixture of all possible cycloadducts, all of which were obtained in 98% ee. Any unreacted aldehyde was found to be enantiomerically pure. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00316-5

TETRAHEDRON:
ASYMMETRY
1
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3591–3607
Asymmetric synthesis and Lewis acid mediated type II
carbonyl ene cyclisations of
(R)-2-isopropyl-5-methylhex-5-enal
D. Christopher Braddocka,* and John M. Brownb
aDepartment of Chemistry, Imperial College of Science Technology and Medicine, South Kensington,
London SW 7 2AY, UK
bDyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK
Received 25 July 2000; accepted 11 August 2000
Abstract
The asymmetric synthesis of (R)-2-isopropyl-5-methylhex-5-enal in 98% ee is described. It was discov-
ered that the key alkylation step employing an Evans chiral auxiliary and 3-methylbut-3-en-1-yl tri-
fluoromethanesulphonate as the alkylating agent led to significant competing O-alkylation, a phenomenon
not previously reported. Type II carbonyl ene cyclisation of the aldehyde with a range of Lewis acids led
to either the (R,R)- or (R,S)-5-methylidenecyclohexanols without concurrent racemisation of the alpha
stereogenic centre of the aldehyde. Conditions for effecting the easy racemisation of a model enantiomer-
ically pure aldehyde, (S)-2-methylbutanal, were developed. In an effort to secure a dynamic kinetic
resolution procedure, these conditions were applied to (R)-2-isopropyl-5-methylhex-5-enal. However, a
competing and dominant Prins cyclisation occurred instead leading to a mixture of all possible cycload-
ducts, all of which were obtained in 98% ee. Any unreacted aldehyde was found to be enantiomerically
pure. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
We have recently defined the intimate stereochemical course (cis vs trans) of the type II
carbonyl ene cyclisation of ( )-2-isopropyl-5-methylhex-5-enal 1 with various alkylaluminium
mediated reagents by recourse to the use of deuterium labelled aldehyde ( )-(E)-[2H] 1a.1 This
study was in agreement with Snider’s original model2 for the transition state A leading to the cis
adduct 2 with sterically undemanding aluminium reagents (e.g. Me2AlCl). Yamamoto’s bulky
alkylaluminium reagent methylaluminium bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR)
gives the trans adduct 33 via a previously unrecognised boat conformation B.1 A similar
boat-like transition state has been proposed for the type I ene cyclisation of citronellal using
bulky molybdenum(II) Lewis acid catalysts.4
* Corresponding author. E-mail: c.braddock@ic.ac.uk
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00316-5

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D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
During the course of these studies it became apparent that a fast racemisation of aldehyde 1
coupled to a chiral Lewis acid catalysed asymmetric ene cyclisation would give rise to
enantiomerically enriched cyclohexenols (Scheme 1). This provided an incentive to study the
feasibility of this dynamic kinetic resolution.5 Inherent to this is the need to also control
diastereoselectivity to provide either the cis or trans cycloadducts 2 and 3. Clearly, any proposed
racemisation reagent must be compatible with the Lewis acidic catalyst; the solvent system must
also be selected with care such as not to destroy the Lewis acid (i.e. a non-protic solvent).
Surprisingly, there is very little known about racemisation of a-chiral aldehydes in non-protic
solvents6 and, to the best of our knowledge, no information on the racemisation of a-chiral
aldehydes in the presence of Lewis acids. Moreover, asymmetric Lewis acid catalysts for
intramolecular type II ene cyclisations are still in the early stages of development.7,8 To
circumvent the need to discover a novel asymmetric Lewis acid catalyst, we therefore chose to
examine our postulated dynamic kinetic resolution in the reverse sense: are there conditions
under which enantiomerically pure aldehyde 1 can be successfully enolised (and therefore
racemised) and also undergo in situ ene cyclisation? Herein we describe the asymmetric synthesis
of aldehyde (R)-1, its stereoselective Lewis acid mediated carbonyl ene cyclisation to either
(1R,2R)-2 or (1S,2R)-3, and report on our efforts to secure a dynamic kinetic resolution. We
also report on the action of catalytic quantities of titanocene ditriflate9 on (R)-1 to provide
enantiomerically pure endocyclic ene adducts (1R,2R)-4 and (1S,2R)-5. We also note that all the
carbonyl ene cyclisation adducts 2–5 may be hydrogenated with high diastereoselectivity using
Crabtree’s catalyst.10
Scheme 1.

D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
3593
2. Results and discussion
2.1. Synthesis and diastereoselective carbonyl ene cyclisation of aldehyde (R)-1
Enantiomerically pure aldehyde (R)-1 was accessed using Evans chiral auxiliary
methodology11 (Scheme 2). N-Acylation of (1S,2R)-(+)-norephedrine derived oxazolidinone 612
with isovaleryl chloride provided the previously reported N-acyloxazolidinone 7.13 In the
synthesis of racemic aldehyde 114 4-iodo-2-methylbut-1-ene had served as an effective elec-
trophile in the alkylation of N-(3-methylbutylidene)cyclohexylamine (a masked aldehyde equiv-
alent) employing LDA as the base. However, when employed as the electrophile for alkylation
of 7 (LDA, THF, −78°C) no carbonꢀcarbon bond formation was observed. Moving to the
highly electrophilic triflate derivative 8 and LDA in THF at −78°C, alkylation proceeded
smoothly to provide an approximately 3:1 mixture of compounds which could be separated by
chromatography. The major compound proved to be the desired C-alkylated product 9,
1
essentially as a single diastereoisomer (>98:2) as judged by H NMR, with the predicted R
Scheme 2. Reagents and conditions: (i) n-BuLi, isovaleryl chloride, THF, −78°C“0°C, 2 h (86%); (ii) LDA,
MeC(ꢁCH2)CH2CH2OTf 8, THF, −20°C, 2 h (50%; 9); (iii) rt; (iv) MeO(Me)NH2Cl, Me3Al, CH2Cl2, 0°C, 1 h (82%);
(v) LiAlH4, THF, −78°C“0°C (39%; 12, 33%; 13); (vi) LiOH, H2O2, THF:H2O 3:1 rt, 16 h (75%); (vii) LiAlH4, Et2O,
reflux, 1 h (98%); (viii) DMSO, oxalyl chloride, Et3N, CH2Cl2, −30°C, 0.5 h (71%)

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D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
configuration at the newly created stereogenic centre11 (vide infra). Surprisingly, the minor
adduct proved to be the product of O-alkylation: enol ether 10. To the best of our knowledge,
competing O-alkylation in Evans chiral auxiliary methodology had not previously been
observed. The formation of quantities of enol ether 10 can be rationalised by noting that triflate
8 is a hard electrophile thus favouring O-alkylation.15 Fortuitously, enol ether 10 was found to
decompose back to N-acyloxazolidinone 7 (with concomitant loss of isoprene) on standing
(t1/2:24 h), which could be recovered and re-alkylated.
Chiral auxiliary removal proved troublesome. Attempted transamination to the Weinreb
amide16 resulted in complete endocyclic ring cleavage leading to amide 11. Reductive cleavage
with LAH11 led to approximately 1:1:1 mixtures of the recovered auxiliary 6, endocylic cleaved
amide 12 and the desired alcohol 13, which could be isolated by chromatography (33%, 98%
ee†). A more satisfactory auxiliary cleavage was achieved with lithium hydroxide and hydrogen
peroxide in a THF/water mixture17 to provide carboxylic acid 14 in 75% yield after distillation
in 98% ee.† The auxiliary 6 could be recovered in moderate yield (48%) by recrystallisation from
toluene. Straightforward functional group manipulation ensued: LAH reduction of acid 14 to
alcohol 13 (98% yield, 98% ee†) followed by Swern oxidation18 provided aldehyde (R)-1 in 71%
yield, 98% ee.†
The action of 1 equivalent of dimethylaluminium chloride on aldehyde (R)-1 in
dichloromethane solution at −78°C brought about smooth cyclisation to the cycloadducts 2 and
3 in the same diastereomeric ratio as observed for the racemic case2 (33:1 2:3, 98% yield). The
two cycloadducts were formed in 98% ee† and were assigned as (1R,2R)-2 and (1S,2R)-3. This
was confirmed by chemical correlation via directed hydrogenation19 of (1R,2R)-2 with
Crabtree’s catalyst10 (vide infra).‡ Similarly, the MABR3 mediated cyclisation of (R)-1 proceeded
with the expected reversal of diastereomeric ratio (1:17 2:3) yielding both cycloadducts in 98%
ee. We have previously shown that a catalytic quantity (4 mol%) of titanocene ditriflate9 cleanly
converts ( )-1 into the endocyclic double bond adducts ( )-4 and ( )-5.1 When (R)-1 was
employed as the substrate the expected cycloadducts (1R,2R)-4 and (1S,2R)-5 were also
obtained in 98% ee.† These results firmly establish that the a-stereogenic centre of aldehyde 1 is
configurationally stable under the typical Lewis acidic conditions required to bring about type
II carbonyl ene cyclisation.
2.2. Racemisation studies
Having established that the a-stereogenic centre in aldehyde 1 is configurationally stable
under prototypical Lewis acidic conditions, we set about finding reagents that would induce
racemisation, but that would also be compatible with the Lewis acid. Rapid equilibration of the
two enantiomeric forms of a-stereogenic carbonyl compounds is well known in polar solvents
with either acid20 or base,21 but there is little or no literature precedent for this type of process
in non-coordinating solvents.
† Enantiomeric excesses were determined by chiral GC analysis by comparison with the corresponding racemic
compound (Table 3, Section 4).
‡ The resulting reduction product proved to have an equal and opposite optical rotation {[h]D=−17.3 (c 0.70,
CHCl3)} to that of the naturally occuring (1S,2S,5R)-neomenthol {[h]D=+17.6 (c 0.70, CHCl3)} and was thus
assigned as (1R,2R,5S)-neomenthol.

D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
3595
(S)-2-Methylbutanal 15, prepared by oxidation of (S)-2-methylbutan-1-ol,22 was chosen as a
model compound for the racemisation studies. Racemic aldehyde ( )-15 was also prepared in
analogous manner from ( )-2-methylbutan-1-ol. Owing to the volatility of aldehyde 15 (bp
88–90°C), an in situ ee determination was developed: diastereomeric imines 16 and 17 were
formed rapidly and quantitatively by treating a solution of ( )-15 in chloroform-d with 1.05
1
equivalents of (R)-(+)-a-methylnaphthylamine. Inspection of the H NMR spectrum obtained
at 300 MHz revealed that the triplet resonances for the 4-H methyl protons of the two
diastereomers 16 and 17 (lH 0.96 and 0.86 ppm, respectively) were sufficiently separated to
allow meaningful integration of these signals. No signals pertaining to the Z imines were
1
observed in the H NMR spectrum. When this method was applied to freshly prepared (S)-15
a 20:1 mixture of imines 16:17 was obtained, setting the benchmark at 90% ee prior to
racemisation. The major diastereomer 16 was found to epimerise slowly in chloroform-d into
the minor diastereomer 17 and after 7 days the diastereomeric ratio was found to be 35:65 (17
major). As a consequence of this finding all NMR acquisitions were performed immediately
after imine formation.
The racemisation of (S)-15 in water–dioxane and water–ethanol mixtures with hydrogen
chloride has been studied by Badin and Pascu.20 These aqueous conditions are clearly incompa-
tible with alkyl aluminium Lewis acids, but it was thought that other reagents in non coordinat-
ing organic solvents may well bring about the same effect.
Triethylamine and 2,6-di-tert-butylpyridine (Table 1, entries 1–2) were found to be ineffective
for the racemisation of (S)-15 in chloroform-d and the use of nitrogen bases was abandoned.
(S)-15 was also found to be stable in the presence of acetic acid in chloroform-d for 24 h (entry
3) but with the stronger p-toluenesulphonic acid approximately 56% racemisation had occurred
after 20 h at room temperature (entry 4). The NMR analysis avoided any evaporative
procedure: the mixture was quenched with dilute aqueous base, the organic phase separated,
dried and filtered and then treated directly with 1.05 equivalents of (R)-(+)-a-methylnaphthyl-
1
amine. The resulting imine mixture in chloroform-d was subjected to H NMR analysis.
Various commercially available resins with basic and acidic properties were also examined as
possible racemisation reagents. The use of the basic Amberlyst 27 resin (entry 5) was found to
have no effect on (S)-15. In contrast, strongly acidic Amberlyst 15 resin resulted in partial
racemisation (entry 6) after 4 h at room temperature.
Molecular sieves (MS) are known to be compatible with Lewis acids.23,24 While 4 A MS were
,
found to have no effect on (S)-15 (entry 7), the use of 13X MS resulted in slow racemisation
,
(entry 8). A possible rationale invokes the ability of 13X MS (pore size:10 A) to accommo-
date aldehyde 15 in the cavity where the effective proton concentration is much increased, but
,
not in the 4 A MS cavities. In contrast, 13X MS had no effect on (R)-1 after 24 h at room
temperature, where presumably the C10-aldehyde is too bulky to enter the molecular frame-
,
work of the sieves. Control experiments with 4 A MS gave the same negative and expected
result.

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D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
Table 1
Racemisation of (S)-2-methylbutanal 15a
Entry
Reagent
Time/h
16:17b,c
1
2
3
4
5
6
7
8
Triethylamined
2,6-di-tert-Butylpyridined
Acetic acidd
48
48
24
20
24
4
95:5 (0)
95:5 (0)
95:5 (0)
67:33 (56)
95:5 (0)
56:44 (78)
95:5 (0)
73:27 (44)
p-Tosic acidd
Amberlyst 27e
Amberlyst 15e
e,f
,
4 A MS
24
24
13X MSe,f
a All reactions performed in freshly distilled chloroform-d with 0.5 mmol of (S)-15.
b Imines 16 and 17 formed by addition of 0.53 mmol (R)-(+)-a-methylnaphthylamine to the isolated solution of
aldehyde 15 and the diastereomeric ratio determined immediately by integration of the 4-H methyl resonances in the
1H NMR spectrum.
c Figures in parenthesis indicate percentage racemisation of (S)-15.
d 5 mol%.
e 200 mg solid reagent.
f Molecular sieves were powdered and activated prior to use at 300°C under vacuum for 0.5 h.
When ( )-aldehyde 1 was treated with p-tosic acid or Amberlyst 15 resin in chloroform-d a
complex mixture of inseparable products resulted with at least seven resonances in the double
1
bond region of the H NMR spectrum (lH 6.0–4.5 ppm). The relative ratios of products was
approximately the same in both cases. The chemical shifts of the resonances and their
relative ratios are tabulated below (Table 2). The products were identified as the exocyclic
adducts 2 and 3 and endocyclic adducts 4 and 5. The two broad singlets resonating at lH
4.71 and 4.68 ppm were tentatively assigned as the 6-H resonances for the alternative inter-
nal double bond isomers (1R*,2R*)-2-isopropyl-5-methylcyclohex-5-en-1-ol 18 and (1S*,2R*)-
2-isopropyl-5-methylcyclohex-5-en-1-ol 19. The appearance of two sets of resonances as
apparent AB quartets in this region of the spectrum suggests the formation of conjugated
dienes 20 and 21.
The various cycloadducts are postulated to result from direct intramolecular Prins-
addition1 of the terminus of the double bond to the protonated carbonyl group of ( )-1.
Non-selective intermolecular b-hydrogen abstraction follows to produce the complex mixture
of double bond isomers. The dienes 20 and 21 presumably result from acid-catalysed elimina-
tion of water from the already formed cyclohexenols.
(R)-1 was treated with p-tosic acid in chloroform-d in an attempt to measure the relative
rates of Prins-type cyclisation versus acid catalysed enolisation of the a-stereogenic centre.
1
The reaction was monitored by H NMR and was quenched with aqueous base at approxi-
mately 50% conversion. Chiral GC analysis revealed that the unreacted aldehyde 1 had not
undergone any racemisation (i.e. 98% ee) and all the cyclohexenols 2–5, 18, 19 so produced
were formed in 98% ee† by comparison with the GC traces from the experiment with p-tosic
acid and ( )-aldehyde 1.

D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
3597
Table 2
1H NMR analysis of product distribution resulting from effect of p-tosic acid on (9)-1
lH/ppm
Relative ratioa
Assignment
5.46 br s
5.32 br s
4.85 br s and 4.75 br s
4.71 br s
4.68 br s
57
23
17
32
31
6
4; 4-H
5; 4-H
2; 7-H×2
18; 6-Hb,c
19; 6-Hb
6.13 and 5.78 AB quartet; J=10.2 Hz
5.5.8 2nd order AB quartet
20; 3-H, 4-Hd
21; 2-H, 3-Hd
13
1
a As determined by integration of the corresponding signals in the H NMR spectrum.
b The assignments are interchangeable.
c This resonance obscures the expected signal for the 7-H trans cycloadduct 3 proton: relative ratio 3 by integration
of the 1-H resonance at lH 3.48 ppm.
d The assignments are interchangeable.
2.3. Diastereoselective hydrogenation
Yamamoto previously confirmed the relative stereochemistry of the trans cycloadduct ( )-3
obtained from the ene cyclisation of ( )-1 with MABR by its hydrogenation to ( )-menthol 21
with hydrogen gas over 10% Pd/C in methanol.3 In our hands, hydrogenation of ( )-3 under
these conditions gave a 2:1 mixture of ( )-menthol 21 and ( )-isomenthol 22 (43% combined
yield). Similarly, the hydrogenation of cycloadduct ( )-2 with palladium-on-carbon gave a 1:1
mixture of ( )-neomenthol 23 and ( )-isoneomenthol 24 (53% combined yield) confirming the cis
relationship between the hydroxyl and isopropyl groups.
Crabtree’s catalyst {[PCy3(py)Ir(COD)]PF6} has been used to great effect in hydroxyl-directed
hydrogenations of cyclohexenols.19,25 Hydrogenation of cis cycloadduct ( )-2 in
dichloromethane in the presence of 5 mol% of the catalyst was complete within 0.5 h giving
( )-neomenthol 23 as the exclusive product (87% yield). Directed hydrogenation with Crabtree’s
catalyst of the racemic cis endocyclic adduct ( )-4 was similarly effective again giving rise
exclusively to ( )-neomenthol 23. Furthermore, hydrogenation of the either exocyclic or
endocyclic trans cycloadducts ( )-3 or ( )-5 with Crabtree’s catalyst gave ( )-isomenthol 22 in 92
and 88% yield, respectively.

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D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
Since we have shown that enantiomerically pure cyclohexenols (1R,2R)-2 and (1S,2R)-3 are
available by diastereoselective carbonyl ene cyclisation of (R)-1, we have thus also completed
formal asymmetric syntheses of (1R,2R,5S)-neomenthol 23 and (1S,2R,5R)-isomenthol 22.
3. Conclusion
We have demonstrated that the Lewis acid mediated type II carbonyl ene-cyclisation of the
a-stereogenic enantiomerically pure aldehyde (R)-1 proceeds without configurational compro-
mise giving direct access to enantiomerically pure menthol skeletons. We have also used (R)-1
to probe the possibility of effecting a dynamic kinetic resolution process. In these experiments
any acid source employed to facilitate enolisation leads instead to competing and dominant
Prins reactivity and leaves the original configuration untouched.
4. Experimental
4.1. Materials and methods
THF, PhMe and Et2O were distilled from Na/Ph2CO. CH2Cl2, NEt3 and diisopropylamine
were distilled from CaH2. Tf2O was distilled from P2O5. DMF, DMSO, CH3NO2, isovaleric
chloride, pyridine and oxalyl chloride were distilled immediately prior to use. n-Butyllithium was
titrated against freshly recrystallised diphenylacetic acid immediately prior to use.26 (4R,5S)-4-
Methyl-5-phenyl-2-oxazolidinone 6 was prepared by the method of Evans.12 4-Bromo-2,6-di-
tert-butylphenol was prepared from 2,6-di-tert-butylphenol using Br2 in CCl4.
(S)-(+)-2-Methylbutanal 1522 {[h]D +27.0 (neat) (lit.,22 +28.5 (neat))}, pyridinium dichromate,27
Cp2Ti(OTf)2 and Crabtree’s catalyst10,25 were prepared using published procedures. Racemic
9
samples of alcohol 13, aldehyde 1 and cycloadducts 2–5 were prepared according to our
previously published methods.14 All other materials were used as purchased. All manipulations
of air or moisture sensitive materials were carried out under a dry argon atmosphere using
standard vacuum line and Schlenk techniques.
Analytical thin layer chromatography (tlc) was performed on Merck plastic-backed plates
coated with 0.2 mm silica gel 60 F254. Product spots were visualised by quenching of ultraviolet
fluorescence (umax=254 nm) or by staining with acidic potassium permanganate. Column
chromatography was performed on Merck silica gel 60H, 230–300 mesh using the flash
chromatographic technique of Still.28
Melting points were recorded on a Reichert–Koffler block and are uncorrected. Boiling point
values recorded for short path distillations were obtained using a Bu¨chi GKR-51 Ku¨gelrohr
oven. The value quoted is the uncorrected pot temperature. Elemental microanalyses were
performed by Mrs. V. Lamburn in the Dyson Perrins Laboratory using a Carlo Erba 1106
elemental analyser. Specific rotations ([h]D) were recorded at 24°C on a thermostatted Perkin–
Elmer 241 polarimeter. Infrared spectra were recorded on a Perkin–Elmer 1750 Fourier
Transform spectrometer. Samples were prepared as thin films on sodium chloride plates or as
1
potassium bromide disks. H and 13C NMR spectra were recorded on Varian Gemini 200,

D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
3599
Bruker WH 300 or Bruker AM 500 spectrometers. Chemical shifts (l) are quoted in parts per
million relative to residual internal chloroform and J values are given in Hz. 19F spectra were
recorded on a Bruker AM 250 (235.2 MHz) spectrometer. Chemical shifts (lF) are quoted in
ppm and are externally referenced to fluorotrichloromethane [lF=0.0]. Mass spectra were
recorded on a Trio-1 GCMS spectrometer.
4.2. (4R,5S)-(+)-3-[3-Methyl-1-oxobut-1-yl]-4-methyl-5-phenyl-2-oxazolidinone 7
n-Butyllithium (1.6 M in hexanes, 45.2 ml) was added to a solution of oxazolidinone 6 (12.8
g, 72 mmol) in dry THF at −78°C until the red colour persisted. Isovaleryl chloride (9.5 ml, 78
mmol) was added immediately and the colour discharged. The pale yellow solution was allowed
to warm to 0°C over 2 h, stirred for 1 h, and quenched with saturated aqueous sodium hydrogen
carbonate solution (30 ml). The resulting two phase mixture was stirred vigorously for 1 h and
the THF removed under reduced pressure. The organics were extracted with Et2O (3×100 ml),
washed with 1 M NaOH solution (3×100 ml), water (100 ml) and brine (100 ml). The pale yellow
solution was dried (MgSO4), filtered and evaporated to give a pale yellow oil. This material
solidified on standing and was recrystallised from pentane (two crops) to give the acyloxazolid-
inone 7 (16.2 g, 86%) as a white solid; mp 53–55°C (lit.,13 52–53°C); [h]D +47.9 (c 1.3 in CHCl3);
(found: C, 68.80; H, 7.37; N, 5.33. C15H19NO3 requires C, 68.94; H, 7.33; N, 5.36%). wmax (KBr
disk)/cm−1 2962m, 2873m, 1779vs (CꢁO), 1703s (CꢁO); lH (500 MHz; CDCl3) 7.47–7.27 (5H, m,
Ph), 5.67 (1H, d, J 7.3, PhCH), 4.78 (1H, dq, J 7.3, 6.6, NCH), 2.92 (1H, dd, J 15.9, 6.7,
COCHH), 2.79 (1H, dd, J 15.9, 7.2, COCHH), 2.22 (1H, ddqq, J 7.2, 6.7, 6.4, 6.4, (CH3)2CH),
1.02 (3H, d, J 6.4, CH3CHCH3), 1.01 (3H, d, J 6.4, CH3CHCH3), 0.91 (3H, d, J 6.6, 4-Me); lC
(50.3 MHz; CDCl3) 172.8 (COCH2), 159.3 (OCON), 133.6 (ipso-C), 128.9 (ArꢀCH), 125.9
(ArꢀCH), 79.9 (PhCH), 54.7 (NCHCH3), 44.0 (COCH2), 25.0 (CH3CHCH3), 22.4
(CH3CHCH3), 22.3 (CH3CHCH3), 14.4 (NCHCH3); m/z (CI+; NH3) 279 (M+18+, 95%), 262
(M+1+, 100), 244 (4),.218 (12), 195 (5), 175 (4), 159 (4), 134 (13), 116 (15), 105 (4), 91 (5), 85 (7),
69 (3).
4.3. 3-Methylbut-3-en-1-yl trifluoromethanesulphonate 8
Using the general method of Stang29 a solution of Tf2O (6.7 ml, 40 mmol) in CH2Cl2 (50 ml)
was added dropwise to a stirred solution of 3-methylbut-3-en-1-ol (4.0 ml, 40 mmol) and
pyridine (3.9 ml, 48 mmol) in CH2Cl2 (50 ml) at −78°C. A white precipitate was formed
immediately in a colourless solution. After complete addition of Tf2O the resulting black
solution was stirred at 0°C for a further 2 h, poured onto ice, washed with ice-cold 1 M HCl
solution (3×50 ml), water (50 ml), dried (MgSO4), filtered and partially evaporated (ca 20 ml) to
give a dilute solution of the thermally sensitive triflate 8 in CH2Cl2. This solution was stored at
−26°C under argon. An aliquot of this solution (1.0 ml) was withdrawn and evaporated to
dryness to give a spectroscopically pure black oil (205 mg, 0.94 mmol, 0.94 M solution; 22 ml,
20.6 mmol, 52%); wmax (thin film)/cm−1 3085w, 2980m, 2923m, 1815w (CꢁC), 1414s, 1247s, 1208s,
1147s, 946s, 810s; lH (200 MHz; CDCl3) 4.94 (1H, br s, CꢁCHH), 4.83 (1H, br s, CꢁCHH), 4.63
(2H, t, J 6.8, OCH2), 2.54 (2H, br t, J 6.8, OCH2CH2), 1.79 (3H, br s, 3-Me); lC (50.3 MHz;
CDCl3) 138.7 (CꢁCH2), 118.6 (q, J 319, CF3), 114.2 (CꢁCH2), 75.2 (OCH2), 37.1 (OCH2CH2),
22.0 (CH3); lF (235.2 MHz; CDCl3) −75.5 (3F, s, CF3).

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D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
4.4. (4R,5S)-(+)-3-[(2R)-2-Isopropyl-5-methyl-1-oxohex-5-en-1-yl]-4-methyl-5-phenyl-
2-oxazolidinone 9
n-Butyllithium (1.6 M, 12.4 ml, 19.8 mmol) was added dropwise to a solution of diisopropyl-
amine (3.3 ml, 23.4 mmol) in THF (40 ml) at −20°C and stirred for 0.5 h. The straw yellow
solution was cooled to −78°C and added dropwise to a stirred solution of acyloxazolidinone 7
(4.7 g, 18.0 mmol) in THF (80 ml) at −78°C. The bright yellow solution was stirred at −78°C
for 0.5 h and a solution of triflate 8 in CH2Cl2 (0.94 M, 22.0 ml, 20.6 mmol) was added
dropwise. The bright yellow colour discharged and the pale yellow solution was warmed to
−20°C and stirred for 2 h. The solution was allowed to warm to room temperature and
quenched with a phosphate buffer (50 ml, pH 7). The solvent was removed under reduced
pressure and the organics extracted with Et2O (3×100 ml), dried (MgSO4), filtered and the
solvent evaporated to give a dark orange oil. Purification by flash chromatography on silica gel
(5% ethyl acetate in pentane) gave first the title compound 9 (2.95 g, 50%) as a single
diastereomer as a colourless oil which solidified on standing mp 66–68°C; [h]D +23.3 (c 1.1 in
CHCl3) (found: C, 72.92; H, 8.05; N, 4.04. C20H27NO3 requires C, 72.92; H, 8.26; N, 4.25%);
wmax (thin film)/cm−1 3072w, 2964m, 2878, 1781vs (CꢁO), 1697vs (CꢁO), 1650w (CꢁC); lH (500
MHz; CDCl3) 7.44–7.21 (5H, m, Ph), 5.63 (1H, d, J 7.2, PhCH), 4.81 (1H, dq, J 7.2, 6.6, NCH),
4.69 (1H, br s, CꢁCHH), 4.67 (1H, br s, CꢁCHH), 3.76 (1H, ddd, J 10.1, 6.8, 3.5, COCH),
2.01–1.88 (4H, m, CH2CH2), 1.72–1.67 (1H, m, CH3CHCH3), 1.71 (3H, br s, 5%-Me), 1.00 (3H,
d, J 6.8, CH3CHCH3), 0.98 (3H, d, J 6.8, CH3CHCH3), 0.91 (3H, d, J 6.6, 4-Me); lC (50.3 MHz;
CDCl3) 176.3 (COCH), 159.2 (OCON), 145.7 (CꢁCH2), 135.5 (ipso-C), 128.9 (ArꢀCH), 125.8
(ArꢀCH), 110.6 (CꢁCH2), 78.7 (PhCH), 55.0 (NCH), 48.3 (COCH), 35.4, 30.7, 26.7, 22.1, 20.7,
19.0, 14.3; m/z (CI+; NH3) 347 (M+18+, 7%), 330 (M+1+, 100), 286 (10), 261 (6), 246 (2), 202 (3),
153 (3), 134 (9), 118 (8), 109 (3) and second (4R,5S)-(+)-3-[(Z)-2,8-dimethyl-5-oxanona-1,6-dien-
6-yl]-4-methyl-5-phenyl-2-oxazolidinone 10 as a thermally unstable colourless oil: lH (300 Hz,
CDCl3) 7.45–7.28 (5H, m, Ph), 5.65 (1H, d, J 7.4, PhCH), 4.87 (1H, br s, CꢁCHH), 4.84 (1H,
d, J 8.5, OCꢁCH), 4.82 (1H, br s, CꢁCHH). 4.27 (1H, dq, J 7.4, 6.6, NCH), 3.95 (1H, dt, J 9.5,
7.4), 3.83 (1H, dt, J 9.5, 7.4), 2.78 (1H, dqq, J 8.5, 6.8, 6.8,), 2.42 (1H, br t, J 7.4), 1.80 (3H,
br s), 1.07 (3H, d, J 6.8), 1.01 (3H, d, J 6.8), 0.80 (3H, d, J 6.6, 4-Me).
4.5. Attempted transamination of 9
Following the method of Evans et al.16 a solution of trimethylaluminium in toluene (2 M, 0.33
ml, 0.66 mmol) was added dropwise to a stirred suspension of N,O-dimethylhydroxylamine (64
mg, 0.66 mmol) in dry dichloromethane (2 ml) under argon at 0°C. Effervescence occurred and
the white suspension solubilised to give a colourless solution in 0.5 h. A solution of oxazolid-
inone 9 (72 mg, 0.22 mmol) in dry dichloromethane (1 ml) was added via a double ended needle
and the yellow solution was stirred at 0°C. After 1 h the mixture was partitioned between
ice-cold 1 M HCl (10 ml) and dichloromethane (10 ml). The layers were separated and the
aqueous phase extracted with dichloromethane (2×10 ml). The combined organic layers were
dried (MgSO4), filtered and evaporated to give a pale yellow oil. This material was purified by
flash chromatography on silica gel (30% ethyl acetate in pentane) to give (1S,2R,5R)-(+)-N,O-
dimethyl-3-aza-2,8-dimethyl-5-(1-methylethyl)-4-oxo-1-phenyl-8-nonenyl
hydroxyl
carboxy

D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
3601
imide 11 (42 mg, 82%) as a white solid: mp 123–125°C (found: C, 67.39; H, 8.78. C22H34N2O4
requires C, 67.66; H, 8.78%); [h]D +5.9 (c 0.38 in CHCl3); wmax (KBr disk)/cm−1 3317m (NH),
3074w, 2959m, 2873, 1722s (CꢁO), 1641s (CꢁO); lH (500 MHz; CDCl3) 7.39–7.28 (5H, m, Ph),
5.78 (1H, d, J 4.0, PhCH), 5.57 (1H, br d, J 8.7, NH), 4.70 (1H, br s, CꢁCHH), 4.64 (1H, br
s, CꢁCHH), 4.54 (1H, ddq, J 8.7, 6.9, 4.0, NCH), 3.75 (3H, s, OMe), 3.19 (3H, s, NMe), 2.02
(1H, ddd, J 15.0, 8.1, 4.7, CH2CHHCꢁC), 1.89 (1H, ddd, J 15.0, 7.6, 7.6, CH2CHHCꢁC), 1.77
(1H, dqq, J 6.7, 6.7, 6.6, MeCHMe), 1.75–1.61 (3H, m, COCHCH2CH2), 1.69 (3H, br s,
CꢁCMe), 1.13 (3H, d, J 6.9, NCHMe), 0.91 (3H, d, J 6.7, MeCHMe), 0.86 (3H, d, J 6.7,
MeCHMe); lC (125.6 MHz; CDCl3) 174.6 (NHCO), 156.2 (NCOO), 145.7 (CꢁCH2), 137.6
(ipso-C), 128.7 (ArꢀCH), 128.3 (ArꢀCH), 126.5 (ArꢀCH), 110.6 (CꢁCH2), 79.4 (PhCO), 61.8
(OCH3), 54.2 (NCHMe), 48.6, 35.6, 35.6, 30.6), 27.5, 22.0, 20.7, 20.2, 15.5; m/z (CI+; NH3) 391
(M+18+, 12%) 304 (4), 288 (5), 287 (21), 286 (100), 270 (7), 217 (3), 196 (8), 164 (5), 134 (5), 62
(6).
4.6. Attempted reduction of 9 to alcohol 13
A solution of oxazolidinone 9 (164 mg, 0.5 mmol) in dry THF (5 ml) was added dropwise to
a stirred suspension of lithium aluminium hydride (190 mg, 5 mmol) in dry THF (10 ml) under
argon at −78°C. The grey suspension was allowed to warm to 0°C and quenched by the
successive addition of water (0.2 ml), 4 M NaOH solution (0.2 ml) and water (1 ml). The
resulting white suspension was filtered through a pad of Celite, washed with diethyl ether (3×10
ml), dried (MgSO4), filtered and the solvent evaporated to give a yellow oil. The material was
purified by flash chromatography on silica gel (30% ethyl acetate in pentane) to give first
(2R)-N-2-((1S,2R)-2-methyl-1-phenylethoxy)-5-methyl-2-(1-methylethyl)-5-hexenyl amide 12 (60
mg, 39%) as a white solid: lH (300 MHz; CDCl3) 7.38–7.29 (5H, m, Ph), 5.52 (1H, br d, J 8.4,
NH), 4.89 (1H, d, J 4.2, PhCH), 4.71 (1H, br s, CꢁCHH), 4.65 (1H, br s, CꢁCHH), 4.38 (1H,
ddq, J 8.4, 6.9, 4.2, HNCH), 3.33 (1H, br s, OH), 2.11–1.55 (6H, m, Me2CHCHCH2CH2), 1.69
(3H, br s, CꢁCMe), 1.11 (3H, d, J 6.9, NCHMe), 0.97 (3H, d, J 6.7, MeCHMe), 0.96 (3H, d,
J 6.7, MeChMe); lC (50.3 MHz; CDCl3) 176.3 (CꢁO), 145.6 (CꢁCH2), 141.0 (ipso-C), 128.3
(ArꢀCH), 127.7 (ArꢀCH), 126.6 (ArꢀCH), 110.7 (CꢁCH2), 76.5 (PhCH), 54.1 (NHC), 50.7
(COC), 35.6, 30.6, 27.5, 22.0, 21.0, 20.2, 14.6; m/z (CI+; NH3) 304 (M+1+, 11%), 290 (13), 288
(75), 286 (M+1+−H20, 100), 270 (7), 218 (4), 202 (4), 170 (5), 134 (8), 118(3); recovered auxiliary
6 (22 mg, 25%) and alcohol 13 (26 mg, 33%) as a colourless oil, [h]D +9.04 (c 1.2, CHCl3); wmax
(thin film)/cm−1 3600–3100br s (OH), 3074w, 2959s, 2943s, 2874s, 1650m (CꢁC), 1454m, 1387m,
1370m, 1037m, 886m; lH (500 MHz; CDCl3) 4.72 (1H, br s, CꢁCHH), 4.70 (1H, br s, CꢁCHH),
3.61 (2H, m, HOCH2), 2.09 (1H, ddd, J 14.7, 10.9, 5.9), 2.03 (1H, ddd, J 14.7, 9.3, 6.1), 1.83
(1H, dqq, J 6.9, 6.9, 4.7), 1.74 (3H, br s, 5-Me), 1.50 (1H, dddd, J 13.8, 10.9, 6.1, 5.0), 1.40 (1H,
dddd, J 3.8, 9.3, 7.8, 5.9), 1.34 (1H, ddddd, J 7.8, 5.0, 5.0, 5.0, 4.7) 0.92 (3H, d, J 6.9,
CH3CHCH3), 0.91 (3H, d, J 6.9, CH3CHCH3); lC (50.3 MHz; CDCl3) 146.5 (CꢁCH2), 110.0
(CꢁCH2), 63.4 (HOCH2), 46.0, 35.8, 27.7, 25.6, 22.3, 19.6, 19.0; m/z (CI+; NH3) 174 (M+18+,
7%), 157 (M+1+, 100), 138 (13), 123 (47), 109 (10), 95 (83), 82 (94), 69 (67), 55 (38).
4.7. (R)-(+)-2-Isopropyl-5-methylhex-5-ene-1-carboxylic acid 14
Hydrogen peroxide (7.6 ml, 30% by volume, 54.0 mmol) was added dropwise to a stirred
solution of oxazolidinone 9 (2.95 g, 9.0 mmol) in water (45 ml) and THF (135 ml) followed by

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D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
lithium hydroxide monohydrate (750 mg, 18 mmol) at 0°C. The solution was allowed to warm
to room temperature and stirred for 16 h. Aqueous sodium sulphite solution (1.5 M, 40 ml, 10%
excess based on H2O2) was added to the milky solution to give a colourless alkaline solution (pH
9). The neutral organics were extracted with CH2Cl2, dried (MgSO4), filtered and the solvent
evaporated to give an off-white solid. Recrystallisation from toluene gave white crystals of
(4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone 6 (0.77 g, 48%), [h]D +168.4 (c 1.1 in CHCl3).
The aqueous phase was acidified to pH 1 with 1 M HCl, extracted with EtOAc (3×50 ml) dried
(MgSO4), filtered and the solvent evaporated to give a pale yellow oil. Purification by short path
distillation in base-washed glassware (160°C, 0.1 mmHg) gave carboxylic acid 14 (1.15 g, 75%)
as a colourless oil, [h]D +5.3 (c 1.2 in CHCl3); wmax (thin film)/cm−1 3400–2400s (OH), 3076w,
2965s, 2943s, 2877, 1704s (CꢁO), 1651m (CꢁC), 1452m, 1421m, 1391m, 1374m, 1287m, 1229m,
889m; lH (500 MHz; CDCl3) 4.73 (1H, br s, CꢁCHH), 4.70 (1H, br s, CꢁCHH), 2.17 (1H, ddd,
J 10.6, 7.1, 3.9, HO2CCH), 2.08 (1H, br ddd, J 14.8), 2.00 (1H, ddd, J 14.8, 9.6, 6.6), 1.93 (1H,
dqq, 7.1, 6.8, 6.8, CH3CHCH3), 1.77 (1H, dddd, J 13.9, 10.6, 9.6, 5.4), 1.72 (3H, s, 5-Me), 1.67
(1H, dddd, J 13.9, 10.2, 6.6, 3.9), 0.99 (6H, d, J 6.8, CH(CH3)2); lC (50.3 MHz; CDCl3) 182.6
(HO2C), 145.2 (CꢁCH2), 110.6 (CꢁCH2), 51.9 (H2OCCH), 35.7, 30.3, 26.9, 22.2, 20.2, 19.0; m/z
(CI+; NH3) 188 (M+18+, 20%), 171 (M+1+, 100), 153 (20), 137 (8), 127 (10), 109 (12), 95 (3), 83
(6), 69 (14), 58 (13). Racemic carboxylic acid ( )-14 for chiral GC analysis (Table 3) was
prepared by PDC oxidation of ( )-aldehyde 1:14 Pyridinium dichromate (7.52 g, 20 mmol) was
added in portions to a stirred solution of ( )-aldehyde 1 (1.54 g, 10 mmol) in DMF (20 ml)
under argon at room temperature. After 16 h the dark mixture was poured into water (200 ml)
and extracted with Et2O (3×50 ml). The combined organics were washed with 1 M HCl (3×100
ml), water (3×100 ml), dried (MgSO4), filtered and the solvent evaporated to give a dark red oil.
Purification by short path distillation (160°C, 0.1 mmHg) gave ( )-14 (1.3 g, 76%) as a
colourless oil identical in all respects to the enantiomerically pure material prepared above.
4.8. (R)-(+)-2-Isopropyl-5-methylhex-5-en-1-ol 13
Carboxylic acid (R)-(+)-14 (800 mg, 4.7 mmol) was dropped as a solution in Et2O (30 ml) into
a finely divided suspension of LiAlH4 (800 mg, 20 mmol) in Et2O (60 ml) at room temperature.
The grey suspension was refluxed for 1 h, cooled to room temperature and quenched by the
successive addition of water (1 ml), 4 M NaOH solution (1 ml) and water (3 ml). The white
solids were filtered at the pump, the ethereal solution dried (MgSO4), filtered and the solvent
evaporated to give alcohol 13 (722 mg, 98%) as a colourless oil, [h]D +9.12 (c 1.2 in CHCl3); all
other data identical to the material prepared above. For enantiomeric excess determination, see
Table 3.
4.9. (R)-(−)-2-Isopropyl-5-methylhex-5-enal 1
Dimethyl sulphoxide (127 ml, 1.8 mmol) was added as a solution in CH2Cl2 (2 ml) to a stirred
solution of oxalyl chloride (155 ml, 1.8 mmol) in CH2Cl2 (2 ml) at −78°C. Effervescence
occurred, the colourless solution was stirred for 1 h at −78°C and alcohol (R)-(+)-13 (139 mg,
0.89 mmol) was added as a solution in CH2Cl2 (4 ml). The resulting colourless solution was
stirred at −78°C for 1 h. Triethylamine (625 ml, 4.5 mmol) was added and a white precipitate was
immediately formed in the colourless solution. The solution was allowed to warm to −30°C over
0.5 h and quenched with 4 M aqueous sodium hydrogen sulphate solution (6.0 ml). The organics

D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
3603
were extracted with CH2Cl2 (3×10 ml), combined, washed with water (10 ml), dried (MgSO4),
filtered and the solvent evaporated to give a pale yellow oil. Purification by flash chromatogra-
phy on silica gel (3% ethyl acetate in pentane) gave aldehyde (R)-1 (98 mg, 71%) as a colourless
oil, [h]D −40.9 (c 0.43 in CHCl3) (found: C, 77.60; H, 12.06. C10H18O requires C, 77.87; H,
11.76%); wmax (thin film)/cm−1 3075m, 2963s, 2921s 2837s, 1724s (CꢁO), 1650m (CꢁC), 1456s; lH
(500 MHz; CDCl3) 9.66 (1H, d, J 3.2, CHO), 4.74 (1H, br s, CꢁCHH), 4.69 (1H, br s, CꢁCHH),
2.10 (1H, dddd, J 9.4, 6.2, 3.6, 3.2, OHCCH), 2.03 (1H, dqq, J 6.8, 6.8 6.2), 2.02 (1H, br ddd,
J 14.8, 10.1, 5.5), 1.95 (1H, br ddd J 14.8, 9.4, 6.6), 1.81 (1H, dddd, J 13.6, 9.4, 9.4, 5.5), 1.72
(3H, br s, 5-Me), 1.61 (1H, dddd, J 13.6, 10.1, 6.6, 3.6), 0.99 (3H, d, J 6.8, CH3CHCH3), 0.98
(3H, d, J 6.8, CH3CHCH3); lC (50.3 MHz; CDCl3) 206.1 (CHO), 145.3 (CꢁCH2), 110.7
(CꢁCH2), 57.5 (OHCCH), 35.5, 28.2, 23.6, 22.2, 20.1, 19.5; m/z (CI+; NH3) 172 (M+18+, 23%),
155 (M+1+, 10), 137 (100), 121 (15), 111 (23), 93 (18), 81 (33), 69 (31). For enantiomeric excess
determination, see Table 3.
4.10. (1R,2R)-2-Isopropyl-5-methylidenecyclohexan-1-ol 2
A solution of dimethylaluminium chloride in hexane (0.33 ml, 1 M, 1.1 mmol) was added
dropwise to a solution of aldehyde (R)-1 (46 mg, 0.3 mmol) in CH2Cl2 (2 ml) at −78°C. The
colourless solution was stirred for 0.5 h and then quenched with 1 M sulphuric acid (2 ml). The
organics were extracted with CH2Cl2 (3×5 ml), dried (MgSO4), filtered and the solvent
evaporated to give a pale yellow oil (44 mg, 98%). Purification by flash chromatography on silica
gel (10% ethyl acetate in pentane) gave the title compound 2 (37 mg, 80%) as a colourless oil,
[h]D −18.0 (c 0.35 in CHCl3); wmax (thin film)/cm−1 3700–3100s (OH), 3072w, 2941vs, 2870s,
1654m (CꢁC stretch); lH (500 MHz; CDCl3) 4.85 (1H, br s, CꢁCHH), 4.75 (1H, br s, CꢁCHH),
4.14 (1H, br s, HOCH), 2.40 (1H, br dd, J 13.6, 3.4), 2.33 (1H, dddd, J 13.2, 4.4, 2.4, 2.2), 2.29
(1H, br dd, J 13.6, 2.9), 2.01 (1H, br ddd, J 13.3, 13.3, 4.4), 1.81 (1H, br d, J 13.3), 1.60 (1H,
dqq, J 8.9, 6.7, 6.7), 1.30 (1H, dddd, J 13.3, 13.2, 12.7, 4.2), 1.28 (1H, d, J 8.1, OH), 1.09 (1H,
dddd, 12.7, 8.9, 3.9, 2.2), 0.99 (3H, d, J 6.7, CH3CHCH3), 0.93 (3H, d, J 6.7, CH3CHCH3); lC
(50.3 MHz; CDCl3) 145.3 (CꢁCH2), 111.2 (CꢁCH2), 68.3 (HCOH) 47.9, 42.9, 34.5, 29.1, 25.9,
20.9, 20.8; m/z (CI+; NH3) 137 (M+1−H2O+, 58%), 136 (54), 121 (26), 107 (12), 93 (100). For
enantiomeric excess determination, see Table 3.
4.11. (1S,2R)-2-Isopropyl-5-methylidenecyclohexan-1-ol 3
Following the procedure of Yamamoto3 a solution of trimethylaluminium in toluene (0.9 ml,
2 M, 1.8 mmol) was added dropwise to a solution of 4-bromo-2,6-di-tert-butylphenol (1.0 g, 36
mmol) in toluene (2 ml) with vigorous effervescence at 0°C. After 1 h the red solution was
cooled to −78°C and added dropwise to a solution of (R)-2-isopropyl-5-methylhex-5-enal 1 (140
mg, 0.9 mmol) in toluene (1 ml). The solution was stirred for 1 h and then allowed to warm to
−40°C. After 2 h the mixture was quenched with 1 M sulphuric acid (2 ml), the organics were
extracted with CH2Cl2 (3×5 ml), dried (MgSO4), filtered and the solvent evaporated to give a
dark brown residue. Purification by flash chromatography on silica gel (pentane followed by
15% ethyl acetate in pentane) gave the title compound 3 (110 mg, 78%) as a colourless oil; wmax
(thin film)/cm−1 3600–3100m (OH), 3074m, 2937s, 2875s, 1654 (CꢁC stretch); lH (500 MHz;
CDCl3) 4.69 (1H, br s, CꢁCHH), 4.68 (1H, br s, CꢁCHH), 3.46 (1H, ddd, J 10.0, 9.6, 4.6,
HOCH), 2.61 (1H, ddd, 12.5, 4.6, 1.5), 2.27 (1H, ddd, J 13.3, 4.1, 3.7, 1.5), 2.17 (1H, dqq, J 7.0,
6.9, 3.4), 2.05 (1H, br dd, J 12.5, 10.0), 1.95 (1H, br ddd, J 13.3, 13.2, 3.7), 1.72 (1H, dddd, J

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D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
13.0, 3.7, 3.7, 3.4), 1.31 (1H, dddd, J 13.1, 9.6, 3.4, 3.4), 1.06 (1H, dddd, J 13.2, 13.1, 13.0, 4.1),
0.96 (3H, d, J 6.9, CH3CHCH3), 0.83 (3H, d, J 7.0, CH3CHCH3); lC (50.3 MHz; CDCl3) 146.9
(CꢁCH2), 108.9 (CꢁCH2), 72.0 (HOCH), 49.8, 44.2, 33.8, 25.6, 23.7, 20.9, 16.2; m/z (CI+; NH3)
137 (M+1−H2O+, 32%), 121 (19), 107 (11), 93 (100). 4-Bromo-2,6-bis(1,1-dimethylethyl)phenol
was recovered as a bright yellow solid (0.9 g, 86%). For enantiomeric excess determination, see
Table 3.
4.12. (1R,2R)-2-Isopropyl-5-methylcyclohex-4-en-1-ol 4 and (1S,2R)-2-isopropyl-5-
methylcyclohex-4-en-1-ol 5
Aldehyde (R)-1 (198 mg, 1.3 mmol) was added to a solution of titanocene ditriflate (12 mg,
0.03 mmol) in nitromethane (2 ml). After 10 minutes the orange solution was passed through a
pad of silica and washed through with Et2O. The combined organics were evaporated and the
yellow residue purified by flash chromatography on silica gel (10% ethyl acetate in pentane) to
give first (1R,2R)-4 (112 mg, 56%) as a colourless oil. wmax (thin film)/cm−1 3600–3100s (OH),
3070w, 2960s, 2926, 1474m, 1383m, 1215m; lH (500 MHz; CDCl3) 5.46 (1H, br s, CꢁCH), 4.18
(1H, br s, HOCH), 2.16 (1H, br d, J 16.8), 2.16 (1H, br d, J 16.8), 2.06 (1H, d, J 17.8), 1.83 (1H,
br dd, J 16.8, 10.5), 1.68 (3H, br s, 5-Me), 1.62 (1H, dqq, J 9.4, 6.7, 6.7), 1.36 (1H, d, J 7.5,
OH), 1.14 (1H, dddd, J 10.5, 9.4, 5.8, 1.0), 0.99 (3H, d, J 6.7, CH3CHCH3), 0.93 (3H, d, J 6.7,
CH3CHCH3); lC (50.3 MHz; CDCl3) 129.9 (CꢁCH), 120.7 (CꢁCH), 66.1 (HOCH), 44.1, 39.5,
29.3, 25.1, 23.5, 20.8; m/z (CI+, NH3) 172 (M+18+, 36%), 153 (22), 137 (100), 136 (85), 121 (68),
93 (38), 81 (40); and second (1S,2R)-5 (49 mg, 25% as a colourless oil). wmax (thin film)/cm−1
3600–3100s (OH), 3074w, 2961s, 2943s, 2863, 1463m, 1302m, 1218m; lH (500 MHz; CDCl3) 5.39
(1H, br s, CꢁCH), 3.84 (1H, ddd, J 9.6, 8.5, 5.4, HOCH), 2.32 (1H, br dd, J 17.0, 5.4), 2.13 (1H,
dqq, J 6.9, 6.9, 4.6), 2.05 (2H, m), 1.89 (1H, br dd, J 17.0, 8.5), 1.70 (3H, br s, 5-Me), 1.53 (1H,
dddd, J 9.8, 9.6, 5.5, 4.6), 0.98 (3H, d, J 6.9, CH3CHCH3), 0.92 (3H, d, J 6.9, CH3CHCH3); lC
(50.3 MHz; CDCl3) 131.1 (CꢁCH), 120.4 (CꢁCH), 69.1 (HOCH), 45.3, 39.6, 25.9, 23.9), 23.1,
20.6, 16.6; m/z (CI+, NH3) 172 (M+18+, 19%), 154 (11), 137 (100), 136 (55), 121 (30), 93 (53),
81 (62). For enantiomeric excess determination, see Table 3.
Table 3
Retention times from chiral GC analysis for enantiomeric excess determinationa,b
Compound
T/°Cc
Retention time/mind
14
13
1
120
75
50
47.3 (R)*, 49.4 (S)
159.6 (S), 169.5 (R)*
167.5 (S), 172.7 (R)*
2
3
4
5
80
100
85
77.3 (1S,2S), 81.4 (1R,2R)*
47.6 (1R,2S), 50.2 (1S,2R)*
103.7 (1S,2S), 113.2 (1R,2R)*
157.8 (1R,2S), 161.9 (1S,2R)*
85
a All runs were performed on a Fisons GC 8130 gas chromatograph fitted with a flame ionisation detector and a
3390A Hewlett Packard Integrator. Helium was used as the carrier gas at a pressure of 10 psi using a 25QC2/Cydex-b
0.25 column (SGE).
b All runs utilised racemic compounds to establish retention times, followed by a separate injection with the
corresponding compound in the chiral series; in all cases the chiral compounds displayed a 98% ee.
c Oven temperature.
d Major enantiomer marked with an asterisk.

D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
3605
4.13. Reaction of ( )-2-methylbutanal 15 with (R)-(+)-1-methyl-1-(1-naphthyl)ethylamine
(R)-(+)-1-Methyl-1-(1-naphthyl)ethylamine (85 mg, 0.53 mmol) was added dropwise to a
solution of ( )-2-methylbutanal 15 (43 mg, 0.50 mmol) stirring in CDCl3 (0.5 ml). The
solution immediately turned milky to give a 1:1 mixture of the diastereomeric imines 16 and
1
17, which were analysed directly by H NMR; lH (300 MHz; CDCl3) 8.14 (2H, d, J 8.2,
ArꢀH, 16 and 17), 7.89 (1H, d, J 7.3, ArꢀH, 16), 7.86 (1H, d, J 7.3, ArꢀH, 17), 7.75 (2H, d,
J 8.1, ArꢀH, 16 and 17), 7.72 (2H, d, J 8.2, ArꢀH, 16 and 17), 7.62 (1H, d, J 6.0, HCꢁN,
16), 7.61 (1H, d, J 6.1, HCꢁN, 17), 7.51 (4H, m, ArꢀH, 16 and 17), 5.13 (1H, q, J 7.1,
CꢁNCH 16), 5.12 (1H, q, J 7.1, CꢁNCH 17), 2.33 (2H, dddq, J 7.3, 7.1, 6.9, 6.0), 1.67 (6H,
d, J 7.1), 1.53 (2H, ddq, J 14.0, 7.4, 7.3, 8), 1.41 (2H, ddq, J 14.0, 7.4, 7.1), 1.11 (3H, d, J
6.9, 2-Me 17), 1.08 (3H, d, J 6.9, 2-Me 16), 0.96 (3H, t, J 7.4, CH3CH2 16), 0.86 (3H, t, J
7.4, CH3CH2 17); lC (50.3 MHz; CDCl3) 168.8 (CꢁN, 16 and 17), 141.4 (ArꢀC, 16 and 17),
134.2 (ArꢀC, 16 and 17), 130.1 (ArꢀC, 16 and 17), 129.2 (ArꢀCH, 16 and 17), 127.5
(ArꢀCH, 16 and 17), 126.0 (ArꢀCH×2, 16 and 17), 125.6 (ArꢀCH, 16 and 17), 124.0
(ArꢀCH, 16 and 17), 123.7 (ArꢀCH, 16 and 17), 65.1 (CꢁNCH, 16 and 17), 41.0, 27.0, 24.5,
24.4, 17.1 (2-Me, 16 and 17).
4.14. Reaction of (S)-(+)-2-methylbutanal 15 with (R)-(+)-1-methyl-1-(1-naphthyl)ethylamine
As for the method above for the reaction of ( )-2-methylbutanal (15) with 1-methyl-1-(1-
naphthyl)ethylamine to give a 95:5 ratio of 16:17, respectively, by integration of the 4-H
1
diasteromeric resonances in the H NMR spectrum (lH 0.96, 0.86 ppm; 16,17).
4.15. General procedure for the attempted racemisation of (S)-(+)-2-methylbutanal 15 with
organic bases (Table 1, entries 1–2)
(S)-(+)-2-Methylbutanal 15 (43 mg, 0.50 mmol) was treated with an organic base (5 mol%) for
48 h in dry CDCl3 (1 ml). The mixture was quenched with saturated aqueous ammonium
chloride solution (1 ml) and extracted with CDCl3 (2×1 ml). The combined organics were dried
(MgSO4), filtered and then treated with (R)-(+)-1-methyl-1-(1-naphthyl)ethylamine (85 mg, 0.53
mmol). The mixture was analysed directly by integration of the 4-H diasteromeric imine
1
resonances in the H NMR spectrum (lH 0.96, 0.86 ppm; 16,17).
4.16. General procedure for the attempted racemisation of (S)-(+)-2-methylbutanal 15 with
organic acids (Table 1, entries 3–4)
(S)-2-Methylbutanal 15 (43 mg, 0.50 mmol) was treated with an organic acid (5 mol%) for
20–24 h in dry CDCl3 (1 ml). The mixture was quenched with saturated aqueous sodium
hydrogen carbonate solution (1 ml) and extracted with CDCl3 (2×1 ml). The combined organics
were dried (MgSO4), filtered and then treated with (R)-(+)-1-methyl-1-(1-naphthyl)ethylamine
(85 mg, 0.53 mmol). The mixture was analysed directly by integration of the 4-H diasteromeric
1
imine resonances in the H NMR spectrum (lH 0.96, 0.86 ppm; 16,17).

3606
D. C. Braddock, J. M. Brown / Tetrahedron: Asymmetry 11 (2000) 3591–3607
4.17. General procedure for the attempted racemisation of (S)-(+)-2-methylbutanal with solid
reagents (Table 1, entries 5–8)
(S)-2-Methylbutanal (15) (43 mg, 0.50 mmol) and activated molecular sieves (200 mg) or an
Amberlyst resin (200 mg) were stirred vigorously for 24 h in dry CDCl3 (1 ml). The mixture was
filtered and (R)-(+)-1-methyl-1-(1-naphthyl)ethylamine (85 mg, 0.53 mmol) was added. The
mixture was analysed directly by integration of the 4-H diasteromeric imine resonances in the 1H
NMR spectrum (lH 0.96, 0.86 ppm; 16,17).
4.18. General procedure for hydrogenations with Crabtree’s catalyst
A vigorously stirred mixture of cycloadduct 2, 3, 4 or 5 (154 mg, 1 mmol) and Crabtree’s
catalyst10,26 (41 mg, 5 mol%) in degassed CH2Cl2 (2 ml) was exposed to hydrogen gas (1
atmosphere). The extent of reaction was monitored by the uptake of hydrogen on a gas burette.
The hydrogen atmosphere was removed and the solvent was evaporated under reduced pressure.
The residue was triturated with hot pentane, and the combined organics filtered. The solvent
1
was removed under reduced pressure and the products analysed by H NMR and GCMS. In all
cases the menthol isomer produced was identical to an authentic sample.
Acknowledgements
We thank the EPSRC and Quest International for joint support of a Studentship (to D.C.B.)
under the CASE Scheme, and Dr. Charles S. Sell for his interest and support. We thank K. K.
Hii for extensive NMR experiments.
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