Synthesis and proof of stereostructure of a new (+)-isomenthone-derived homochiral 1,3-diol

Article abstract of DOI:10.1016/S0957-4166(98)00013-5

Diastereopure (+)-isomenthone-derived ketoalcohol 2 was converted to the homochiral 1,3-diol 6 either by direct reduction or reduction of silyl protected derivatives. The diastereomeric preference of the reduction was the same in all cases. Reduction of 2

Full text of DOI:10.1016/S0957-4166(98)00013-5

Pergamon
Tetrahedron: Asymmetry 9 (1998) 599–606
Synthesis and proof of stereostructure of a new (+)-isomenthone-
derived homochiral 1,3-diol
John M. Gardiner,a,∗ Jameel H. Chughtai a and Ian H. Sadler b
aDepartment of Chemistry, University of Manchester Institute of Science and Technology (UMIST), PO Box 88, Manchester
M60 1QD, UK
bUltra-High Field NMR Centre, Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ,
UK
Received 3 December 1997; accepted 12 January 1998
Abstract
Diastereopure (+)-isomenthone-derivedketoalcohol 2 was converted to the homochiral 1,3-diol 6 either by direct
reduction or reduction of silyl protected derivatives. The diastereomeric preference of the reduction was the same
in all cases. Reduction of 2 with NaBH4 gave essentially a single diastereomer, while reduction with LiAlH4 gave
∼6:1 selectivity in favour of the same diastereomer. Reduction of the silyl protected substrates 7 and 8 gave, after
column chromatography, 98% yield of a single diastereomer, desilylation of which established this to be the same
diastereomer as obtained through hydride reductions of unprotected 2. The structure of diol 6 was proven through
coupling data and NOE experiments at 600 MHz. Overall, two stereochemistry introducing steps have elaborated
the two stereogenic centres of (+)-isomenthone to the five contiguous stereogenic centres of 6. © 1998 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Terpenones and terpenols are a valuable source of chiral materials for the synthesis of a range of
chiral controllers.1 While menthone has seen many successful applications, the epimeric isomenthone
system has been far less utilized. In 1990 we proposed C2 or pseudo-C2 chiral cyclic ketones (derived by
asymmetric synthesis or from carbohydrate or terpene starting materials) as precursors for asymmetric
epoxidation through the intermediacy of dioxiranes derived from such ketones.2 During the synthesis
of one target class of pseudo-C2 chiral cyclic ketones, ketoalcohols 2 and/or 3 were synthesized from
(+)-isomenthone 1. The diastereomeric outcome of the aldol reactions providing these ketoalcohols was
shown to be influenced by choice of reaction conditions, with Si-face addition being kinetically preferred
∗
Corresponding author. E-mail: john.gardiner@umist.ac.uk
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00013-5

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with a range of aldehyde substrates.3 Since there are relatively few applications of (+)-isomenthone as
a chiral pool source of chiral controllers, we are also interested in exploring these aldol derivatives as
intermediates for synthesis of various types of novel bifunctional homochiral compounds with potential
applications in asymmetric synthesis. We thus considered the elaboration of these ketoalcohols to new
chiral 1,3-diols, and report here the synthesis of the diastereopure homochiral 1,3-diol 6 which contains
five contiguous stereogenic centres and proof of its stereochemistry through NMR experiments at 600
MHz.
2. Results and discussion
The reduction of the cyclohexanones of types 2 or 3 (alternate conformers shown) could be influenced
by a number of factors, including the ring conformation and the stereoelectronic preferences of axial ver-
sus equatorial reduction, coupled with the steric requirements of the C2 (and C6 if present) substituents
in the reactive conformation. Additionally, with some reducing agents the influence of the free OH on
reagent direction could be considered. X-Ray structures of several of the ketoalcohols of types 2 and 3 all
indicate that the ketoalcohols in the solid state adopt the conformation with the isopropyl equatorial, as
shown for 2a and 3a.3,4 However, NMR analyses indicate a trans-diaxial H1–H2 relationship suggesting
that in solution the ketoalcohols adopt the alternate cyclohexyl conformer with an axial isopropyl. We
proceeded with ketoalcohol 4 (which has the stereochemistry of generic diastereomer 2) as the substrate
for further elaboration through reduction. The NMR-derived conformational evidence for the solution
structure of 4 leads to an anticipation of axial hydride delivery being sterically and stereoelectronically
preferred anti to the (axial) isopropyl, generating a diol product with trans disposed C1 hydroxyl and C2
hydroxyalkyl substituents, i.e., diol 6.
Reduction of ketoalcohol 4 with sodium borohydride (at ambient temperature, MeOH) afforded, with
high selectivity, one of the two possible diols 5 or 6 [6 is represented in the ring conformation with three
equatorial groups (related to the NMR-derived conformation of precursor 4 shown) and 5 represents
equatorial hydride addition to conformer 4]. Analogous reduction of 4 with lithium aluminium hydride
(between 0°C and r.t., THF) provided a mixture of diol diastereomers but favouring (∼6:1 ratio) the
same diastereomer as obtained by reduction with NaBH4. To evaluate the effect of any free hydroxyl
involvement, reductions were also carried out using the two silyl ether protected derivatives 7 and 8.
Reduction of both 7 and 8 provided single diastereomeric products in 98% purified yield, and desilylation
provided a diol product which was identical to that formed from reduction of the unprotected ketoalcohol
with a hydride reagent. We thus wished to establish the diol as being 6 or 5.
Proof of whether the stereostructure of the diol was not trivial by NMR. There is extensive signal
overlap, and the connectivity, via the C6 proton, between protons on the two hydroxyl bearing carbons
is complicated both by this fact and by the rotational options for the side chain and conformational
possibilities for the ring (although predicted conformations for 5 and 6 are shown, this is perhaps less
certain in 5 than 6).5

J. M. Gardiner et al. / Tetrahedron: Asymmetry 9 (1998) 599–606
601
Fig. 1. Key NOE effects establishing diastereostructure
To resolve the diastereomeric assignment by NMR methods, we prepared the isopropylidine acetal
derivative of the diol obtained, to freeze out rotational effects about the important C–C bond to C6, and
restrict the conformational freedom of the cyclohexyl ring by forming a decalin-type bicycle. Diol 5
would give rise to acetal 9, and diol 6 to acetal 10. The isopropylidine acetal derivative is thus either 9
or 10. Decoupling experiments indicated that both Ha and Hb are coupled to a third proton, Hc (at 1.34
ppm) which appears as a ddd with couplings of 9.5, 10.2 and 10.5 Hz. This is consistent with the three
diaxial couplings expected for Hc in 10, but inconsistent with the expected pattern for Hc in 9 (which
would have one diaxial coupling of ∼10 Hz, and two equatorial–axial couplings of ∼3 Hz).
NOE experiments (Fig. 1) further confirm the structure, with large NOEs between Ha, Hb and the axial
isopropylidene acetal methyl group, and a 6% NOE between Hc and the isopropyl hydrogen (Fig. 1). In
the alternative diastereomer 9, Ha and Hb are on opposite faces of the bicyclic system, and Hc and the
isopropyl group are 1,3-diequatorial, and thus key observed NOEs would be impossible in this alternative.
Further confirmation of the structure is provided by all the NMR data (Table 1 and Fig. 2). Thus, NMR
unambiguously establishes that reduction of 4, or its hydroxyl-protected analogues, with NaBH4 or
LiAlH4 gives good or essentially complete diastereoselectivity in favour of diastereomeric 1,3-diol 6.
Additionally, the monosilylated diol products from 7 and 8 can thus be unambiguously identified as 11
and 12 respectively.
In summary, overall, the two stereogenic centres of (+)-isomenthone have been elaborated to 6 (in two
stereochemistry introducing steps) which has five contiguous stereogenic centres, the configurations of
all centres now unambiguously established through a combination of X-ray determinations3,4 and NMR.
The outcomes are consistent with axial reduction of conformers with an axial isopropyl group. This can

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Table 1
1 H NMR resonances and assignments for 10
Fig. 2. Site numbers and labels for NMR data in Table 1
be rationalized by considering that the alternate hydride addition on conformer 4 is hindered by an axial
isopropyl and two axial hydrogens.
Having established the diastereomeric outcome of the reduction as affording the novel diol 6, the
diol can now be employed for synthesis of chiral controllers, or could be used directly as a 1,3-diol
ligand. The use of 1,3-bifunctional ligands such as 6 or derivatives, is of interest because these could
form 6-membered chelates which would be able to adopt the trans-decalin type conformation seen for
the isopropylidine acetal. Functionalization is also available by hydroxyl derivatizations, for example, to
provide bifunctional ligands such as bis(diarylphosphinites).6 The synthesis of other bifunctional ligands
from 1,3-diols analogous to 6, and evaluation as catalysts are planned.

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603
3. Experimental
3.1. General methods and materials
Nuclear magnetic spectra (1H and 13C) were recorded using Bruker AC-200 and AC-300 (UMIST)
instruments. 600 MHz NMR data were obtained through the EPSRC Ultra-High Field NMR Service at
Edinburgh University. Spectra were recorded in deuterated chloroform (CDCl3) with tetramethylsilane
as the internal standard. Chemical shifts (δ) are reported in ppm. 13C substitutions are assigned with
the aid of DEPT experiments where indicated. Infrared spectra were obtained using a Perkin–Elmer
1600 FTIR instrument. Chemical ionisation (c.i.) spectra and fast atom bombardment (FAB) spectra
were obtained on VG 70/70 Hybrid, or Kratos MS-50TC [FAB] spectrometers. Microanalyses were
performed at UMIST microanalysis service. UV spectra were recorded using a Perkin–Elmer Lambda
15 UV/VIS ultraviolet spectrophotometer and infra-red spectra were obtained using Perkin–Elmer 1605
FTIR and 783 instruments. Optical rotations were measured at 589 nm in a 2 mL cell using an AA100
optical activity polarimeter; concentrations are given in g/100 mL of CH2Cl2 at 24°C. Thin layer
chromatography (tlc) was performed on Merck 60 F254 aluminium backed plates and viewed under a UV
lamp or visualised by immersion in either p-anisaldehyde or phosphomolybdic acid solutions and heating
with a hot gun. Flash column chromatography employed Prolabo silica gel (70–230 mesh). THF was
distilled from sodium metal/benzophenone immediately prior to use, and dichloromethane and hexane
were distilled prior to use in column chromatography.
3.2. (10R,1S,2R,3R,6R)-2-(10-Hydroxypropyl)-6-isopropyl-3-methylcyclohexanol 6
3.2.1. Method (a): reduction of 4 with NaBH4
(10R,2R,3R,6R)-2-(10-Hydroxypropyl)-6-isopropyl-3-methylcyclohexanone 4 (500 mg, 4.7 mmol)
was dissolved in distilled methanol (10 mL), to this was added sodium borohydride (247 mg, 6.5 mmol)
and the reaction stirred at room temperature for 24 h. The contents of the flask were then transferred to a
separatory funnel and diluted with CH2Cl2 (60 mL). The organic layer was washed with saturated sodium
chloride solution (3×5 mL) and water (3×5 mL), dried (MgSO4), filtered and the solvent removed in
vacuo to afford the crude diol 6, which was purified by flash column chromatography (3:1 Hex:Et2O) to
afford 481 mg (95% yield) of the diol as a white solid.
3.2.2. Method (b): reduction of 4 with LiAlH4
A 25 mL round bottomed flask equipped with a stir bar was flame-dried and cooled under a stream of
argon. The flask was charged with LiAlH4 (40 mg, 1.05 mmol), sealed and flushed with argon. Freshly
distilled THF (10 mL) was added and the flask cooled to 0°C in an ice–water bath. (10R,2R,3R,6R)-2-
(10-Hydroxypropyl)-6-isopropyl-3-methylcyclohexanone 4 (202 mg, 0.95 mmol) was dissolved in THF
(5 mL) and added dropwise to the LiAlH4/THF over 10 minutes and the reaction allowed to stir at
ambient temperature overnight. The reaction was quenched with water (5 mL) and the contents of the
flask transferred to a separatory funnel and diluted with ether (60 mL). The organic layer was washed
with water (3×5 mL) and saturated sodium chloride solution (3×5 mL), dried (MgSO4), filtered and the
solvent removed in vacuo to afford the crude diol. Purification by flash column chromatography afforded
two diastereomers (Rf 1:1 Hex:Et2O, 0.23, 0.2; 18 mg (9%) and 120 mg (59%) respectively. The major
component being diol 6 (as obtained from NaBH4 reduction).

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3.2.3. Method (c): desilylation of 11 and 12
The silyl protected diol (11 or 12) (100 mg, 0.3 mmol) was dissolved in distilled THF (5 mL) and
to this was added t-butyl ammonium fluoride (0.6 mL, 0.6 mmol) and the mixture allowed to stir at
room temperature for 3 h. The reaction was transferred to a separatory funnel and diluted with ether (30
mL) and washed with saturated NaCl solution (2×5 mL) and water (2×5 mL). The organic layer was
separated, dried (MgSO4), filtered and the solvent removed in vacuo to afford the diol 6 as a white solid
(95 mg, 94% yield): mp 52–55°C; 1H NMR (300 MHz, CDCl3) δ 4.30–4.28 (m, 1H, CHOH), 3.62–3.56
(m, 1H, CHOH), 1.71–1.59 (m, 3H), 1.57–1.23 (m, 6H), 1.22–1.18 (m, 4H), 1.08 (d, 3H, J=6.6 Hz),
1.0–0.95 (m, 5H), 0.93 (d, 3H, J=6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 73.6 (CHOH), 70.2 (CHOH),
52.3 (CH), 44.6 (CH), 29.5 (CH2), 29.3 (CH2), 29.2, 28.7, 21.5, 21.4, 21.3, 21.1, 10.2; FAB MS m/z 214
(M+), 213 (M−H+), 197 (M–OH); anal. calcd for C13H26O2: C, 72.9; H, 12.2; found: C, 73.0; H, 12.3;
IR νmax 3438 (br, OH), 2939, 2876, 1452, 1281, 1053, 912, 732 cm−1; [α]D −15 (c 0.65, CH2Cl2, 24°C).
3.3. (10R,2R,3R,6R)-(10-Triethylsilyloxypropyl)-6-isopropyl-3-methyl-2-cyclohexanone 7
To sodium hydride (101 mg, 4.0 mmol) suspended in freshly distilled THF (10 mL) was added
triethylsilyltriflate (710 mg, 2.68 mmol) and the flask cooled to −78°C. To this mixture 4 (570 mg,
2.68 mmol) dissolved in THF (5 mL) was added dropwise and the mixture was stirred at −78°C for 1 h
and then allowed to warm to room temperature. The reaction was diluted with ether (60 mL), transferred
to a separatory funnel and washed with saturated sodium chloride solution (2×5 mL), dried (MgSO4),
filtered and the solvent removed in vacuo. Flash column chromatography (10:1 Hex:Et2O, 1% Et3N)
yielded the title compound 7 as a colourless oil in 85% yield (760 mg): 1H NMR (300 MHz, CDCl3) δ
4.10 (dt, 1H, J=5.8, 11.5 Hz, –CHOSiEt3), 2.26–2.10 (m, 1H), 2.05–1.87 (m, 3H), 1.81–1.62 (m, 2H),
1.58–1.38 (m, 5H), 1.35–1.10 (m, 6H), 0.97–0.73 (m, 14H), 0.63–0.47 (m, 6H); 13C NMR (75 MHz
CDCl3) δ 207.1 (C=O), 73.8 (–CHOSiEt3), 60.7 (CH), 55.1 (CH), 33.8, 29.0 (CH2), 27.5 (CH2), 26.7,
25.2 (CH2), 21.1, 20.6, 19.0, 8.6, 6.6 (3×CH3), 5.3 (3×CH2); HRMS m/z calcd for C19H38O2Si (MH+):
327.2719; found 327.2725; anal. calcd: C, 69.9; H, 11.6; S, 8.6; found: C, 69.7; H, 11.8; S, 8.3; IR νmax
2958, 2923, 1706, 1445, 1388, 1154 1058, 984 cm−1; [α]D +98 (c 0.35, CH2Cl2, 24°C).
3.4. (10R,2R,3R,6R)-2-(10-t-Butyldimethylsilyloxypropyl)-6-isopropyl-3-methylcyclohexanone 8
To a solution of 4 (100 mg, 0.47 mmol) and DMAP (3 mg) in pyridine (5 mL) was added t-
butyldimethylsilyl triflate (137 mg, 0.52 mmol). The reaction was stirred at room temperature under
argon overnight. The reaction was diluted with ether (15 mL) and transferred to a 100 mL separatory
funnel and further diluted with ether (60 mL), washed with saturated copper sulphate (4×5 mL) and
water (3×5 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in
vacuo to afford the crude product which was purified by flash column chromatography (10:1 Hex:Et2O)
to afford the silylated compound 8 as a colourless oil (130 mg, 85% yield): 1H NMR (300 MHz, CDCl3) δ
4.05–3.95 (m, 1H, CHOTBDMS), 2.22–2.12 (m, 2H), 2.08–1.95 (m, 2H), 1.81–1.62 (m, 3H), 1.55–1.34
(m, 3H), 1.0 (d, 3H, J=6.6 Hz), 0.93–0.81 (m, 18H), 0.00 and 0.02 (2 singlets for Si(Me)2, 6H); 13C NMR
(75 MHz, CDCl3) δ 215.0 (C=O), 73.3 (CHOTBDMS), 60.2 (CH), 55.2 (CH), 33.8, 28.9 (CH2), 26.9
(CH2), 26.6, 25.7, 25.1 (CH2), 21.8, 21.7, 18.9, 17.8, 9.7, −4.6 (CH3), −4.7 (CH3); HRMS m/z calcd for
C19H38O2Si (MH+): 327.2719; found: 327.2717; IR νmax 2956, 2360, 2348, 1701 (C=O), 1382, 1254,
1167, 1094, 867 cm−1; [α]D +94 (c 0.54, CH2Cl2, 24°C).

J. M. Gardiner et al. / Tetrahedron: Asymmetry 9 (1998) 599–606
605
3.5. (1S,5R,6R,7R,10R)-2,4-Dioxa-5-ethyl-10-isopropyl-3,3,7-trimethyl-trans-bicyclo[4.4.0]decane 10
To the 1,3 diol 6 (300 mg, 1.4 mmol) in acetone (10 mL) was added CSA (32 mg 0.14 mmol) followed
by 2,2-dimethoxypropane (160 mg, 1.54 mmol) and the mixture stirred at room temperature for 24 h. The
reaction was quenched with water (5 mL), transferred to a separatory funnel and diluted with ether (60
mL). The organic layer was washed with water (3×5 mL), dried over anhydrous (MgSO4), filtered and
the solvent removed in vacuo to afford the crude product. Flash column chromatography (10:1 Hex:Et2O)
afforded the acetonide 10 in 75% yield (269 mg) as a colourless oil: 1H NMR (600 MHz, CDCl3) δ 3.75
(dd, 1H, Ha, J=4.1, 10.5 Hz), 3.49 (ddd, 1H, Hb, J=2.8, 7.9, 9.3 Hz), 1.91 (ds, 1H, Hiprop, J=6.7, 9.0 Hz),
1.78 (ddq, 1H, H(CH2), J=2.8, 7.3, 14.3 Hz), 1.78 (dm, 1H, Hf, J=4 Hz), 1.49 (ddq, 1H, H(CH2), J=7.3,
7.9, 14.3 Hz), 1.44 (m, 1H, Hd), 1.38 (s, 3H, Mea), 1.38 (m, 1H, Hg), 1.35 (s, 3H, Mee), 1.35 (ddd, 1H,
Hc, J=9.3, 10.2, 10.5 Hz), 1.28 (m, 1H, He), 1.26 (m, 1H, Hh), 1.20 (dq, 1H, Hj, J=4, 10.5 Hz), 1.06
(d, 3H, Meisoprop, J=6.7 Hz), 0.98 (t, 3H, Me5, J=6.2 Hz), 0.92 (t, 3H, Meethyl, J=7.3 Hz), 0.88 (d, 3H,
Meisoprop, J=6.7 Hz); 1H NMR (300 MHz, CDCl3) δ 3.76 (dd, 1H, J=3.9, 10.3 Hz, CHOH), 3.53–3.46
(m, 1H, CHOH), 1.95–1.73 (m, 3H), 1.58–1.40 (m, 5H), 1.38 (s, 3H), 1.36 (s, 3H), 1.07 (d, 3H, J=6.6
Hz), 0.99 (d, 3H, J=5.7 Hz), 0.95–0.90 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 76.5 (CHOH), 75.1
(CHOH), 43.9, 43.6, 33.9, 31.7 (CH2), 30.3, 28.8 (CH2), 27.2 (CH2), 25.9, 23.2, 22.3, 22.0, 19.6, 9.8;
HRMS m/z for C16H30O2 (MH+): calcd: 255.2246; found: 255.2247; IR νmax 2939, 2876, 1452, 1281,
1053, 912, 732 cm−1; [α]D +10 (c 0.19, CH2Cl2, 24°C).
3.6. (10R,1S,2R,3R,6R)-2-(10-Triethylsilyloxypropyl)-6-isopropyl-3-methylcyclohexanol 11
To 7 (200 mg, 0.6 mmol) in dry methanol (5 mL) was added sodium borohydride (47 mg, 1.2 mmol)
and the mixture allowed to stir at room temperature for 2 h. The reaction was diluted with CH2Cl2 (50
mL), transferred to a separatory funnel and washed with water (2×5 mL) and saturated sodium chloride
solution (2×5 mL). The organic layer was separated, dried over anhydrous magnesium sulphate, filtered
and the solvent removed in vacuo to afford the crude product which was purified by passing through a
pad of silica (CH2Cl2, 1% Et3N) to afford the pure product 11 in 98% yield as a colourless oil (198 mg):
1H NMR (300 MHz, CDCl3) δ 4.02–3.90 (m, 1H), 3.70–3.61 (m, 1H), 1.83–1.80 (m, 1H), 1.61–1.32
(m, 7H), 1.30–1.11 (m, 3H), 0.98–0.84 (m, 11H), 0.83–0.78 (m, 9H), 0.58–0.42 (m, 6H). 13C NMR (75
MHz, CDCl3) δ 74.3 (CH), 71.4 (CH), 50.8 (CH), 44.0 (CH), 30.3 (CH), 29.6 (CH2), 29.5 (CH2), 28.4,
23.2, 21.7, 21.5, 20.8, 9.4, 6.9, 5.5 (CH2); FAB MS m/z 329 (MH+), 311 (M+−OH); anal. calcd for
C19H40O2Si: C, 69.9; H, 11.6; Si 8.6; found: C, 69.7; H, 11.8; Si, 8.3; IR νmax 2958, 2923, 1445, 1388,
1154 1058, 984 cm−1; [α]D +44 (c 0.45, CH2Cl2, 24°C).
3.7. (10R,1S,2R,3R,6R)-(10-t-Butyldimethylsilyloxypropyl)-6-isopropyl-3-methyl-2-cyclohexanol 12
To 8 (200 mg, 0.6 mmol) dissolved in methanol (5 mL) was added sodium borohydride (47 mg,
1.2 mmol) and the mixture stirred at room temperature for 2 h. The reaction mixture was diluted with
CH2Cl2 (50 mL), transferred to a separatory funnel and washed with water (2×5 mL) and saturated
sodium chloride solution (2×5 mL). The organic layer was separated, dried (MgSO4), filtered and the
solvent removed in vacuo to afford the crude product which was purified by passing through a pad of
1
silica to afford 12 in 98% yield as a colourless oil (198 mg): H NMR (300 MHz, CDCl3) δ 4.07 (dd,
1H, J=3, 5 Hz, –CHCHOH), 3.76–3.74 (m, 1H, CHOTBDMS), 1.70–1.36 (m, 9H), 1.33–1.18 (m, 3H),
0.96 (d, 3H, J=6.4 Hz), 0.91 (d, 3H, J=5.0 Hz), 0.90–0.86 (m, 14H), 0.06 (s, 3H, CH3SiCH3), 0.05 (s,
3H, CH3SiCH3); 13C NMR (75 MHz, CDCl3) 74.2 (CH), 71.6 (CH), 50.9 (CH), 44.0 (CH), 30.9, 30.3

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J. M. Gardiner et al. / Tetrahedron: Asymmetry 9 (1998) 599–606
(CH2), 29.7 (CH2), 28.4, 25.9, 23.4, 21.7, 21.5, 18.5 (quat, CCH3), 9.5, −4.4, −4.7; HRMS m/z calcd for
C19H40O2Si (MH+): 329.2876; found: 329.2872; IR (neat) 3512 (OH br), 2973, 2960, 1455, 1334, 1128,
1045, 946 cm−1; [α]D +20 (c 0.6, CH2Cl2, 24°C).
Acknowledgements
We thank the EPSRC for an Earmarked Studentship (JHC) and associated Research Grant GR/K01728
and for supporting the EPSRC Ultra-High Field NMR Centre, Edinburgh University, where 600 MHz
NMR experiments were performed.
References
1. (a) Chiral pool materials as sources for enantioselective catalysts and chiral auxiliaries: Blaser, H.-U. Chem. Rev. 1992,
92, 935. (b) Uses of terpenes, including menthone, as chiral pool materials: Ho, T.-L. Enantioselective Synthesis: Natural
Products from Chiral Terpenes; Wiley: New York, 1992. (c) For examples of chiral ligands derived from menthone/menthol:
Catalytic Asymmetric Synthesis; ed. I. Ojima, VCH: New York, 1993.
2. We are aware of one other group who have since adopted the same general target strategy: Armstrong, A.; Hayter, B. R.
Tetrahedron: Asymmetry 1997, 8, 1677.
3. Chughtai, J. H.; Gardiner, J. M.; Harris, S. G.; Parsons, S.; Rankin, D. W. H.; Schwalbe, C. H. Tetrahedron Lett. 1997, 38,
9043.
4. Gardiner, J. M.; Koehl, M.; Chughtai, J. H.; Harris, S. G.; Parsons, S.; Rankin, D. W. H.; Schwalbe, C. H. submitted.
5. In 5 axial hydroxypropyl (branched) and methyl groups would replace the axial isopropyl and hydroxyl groups of compound
6. Replacing an axial methyl with an axial hydroxyl would be expected to only be favoured by a few (∼3.5) KJ mol−1, so
the conformational preference for 5 will be largely determined by the direction and magnitude of the energy difference
between the isopropyl and hydroxyalkyl groups. In the case of 6, the alternative ring conformer would have three axial
groups.
6. Preliminary example: The bisphosphinite derivative 13 has been prepared, and synthetic details and applications will be
reported in due course. [α]D24=33 (c 0.34, CH2Cl2).