Stereospecific conversion of (1R*,3S*)- And (1R*,3A*)-3-cyclohexyl-l-phenylpropane-l,3-diol into the corresponding 2,4-disubstituted oxetanes

Article abstract of DOI:10.1039/a909163g

Conversion of two diastereoisomeric 1,3-dioIs (3-cyclohexyl-l-phenylpropane-l,3-diol) into orthoesters was followed' by treatment with acetyl bromide. The 1,3-bromo acetates (acetic acid 3-bromo-l-cycIohexyl-3-phenyIpropyl esters) were obtained with complete inversion of configuration at a benzylic site. Methanolysis of the bromo acetates, followed by ring-closure, resulted in a second inversion of configuration at a benzylic site to give the corresponding oxetanes with overall retention of configuration. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/a909163g

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Stereospecific conversion of (1R*,3S*)- and (1R*,3R*)-3-
cyclohexyl-1-phenylpropane-1,3-diol into the corresponding
2,4-disubstituted oxetanes
1
Tajassus Aftab,a Christabel Carter,a Martin Christlieb,b Jennifer Harta and Adam Nelson*a
a School of Chemistry, University of Leeds, Leeds, UK LS2 9JT
b University Chemical Laboratories, Lensfield Road, Cambridge, UK CB2 1EW
Received (in Cambridge, UK) 19th November 1999, Accepted 14th January 2000
Published on the Web 9th February 2000
Conversion of two diastereoisomeric 1,3-diols (3-cyclohexyl-1-phenylpropane-1,3-diol) into orthoesters was followed
by treatment with acetyl bromide. The 1,3-bromo acetates (acetic acid 3-bromo-1-cyclohexyl-3-phenylpropyl esters)
were obtained with complete inversion of configuration at a benzylic site. Methanolysis of the bromo acetates,
followed by ring-closure, resulted in a second inversion of configuration at a benzylic site to give the corresponding
oxetanes with overall retention of configuration.
Introduction
There are a number of synthetic methods in which the stereo-
chemistry of the product is controlled by two inversions of
configuration in a reaction sequence. For example, conversion
of the diol 1 into the corresponding orthoester, and reaction
with acetyl bromide, gave an 88:12 mixture of regioisomeric
acetoxy bromides 3 and 4; the bromides 3 and 4 were converted
into the epoxide 5 by methanolysis of the acetate group and
ring closure (Scheme 1).1 The success of the strategy lies in the
Scheme 2
of the aziridinium ion 9 with aqueous methylamine gave the
diamine 10.
The transformation of the epoxide 11 into the cyclopropyl
ketone 14 is another reaction sequence which involves inversion
at both ends of an epoxide.3 The epoxide 11 was opened with
the lithium derivative of methyldiphenylphosphine oxide and
the resulting alcohol was benzoylated (→12) (Scheme 3).
Scheme 1
two inversion reactions: one of the stereogenic centres of 1
is inverted twice (stereochemically equivalent to retention of
configuration) and the other centre is untouched. The regio-
selectivity of the ring opening 2→3 ϩ 4 is inconsequential
because both regioisomers 3 and 4 are converted into the same
stereoisomer 5 and, therefore, the enantiomeric excess of the
starting material is not compromised.
A similar strategy can be exploited in the synthesis of optic-
ally active compounds with only one stereogenic centre. Styrene
oxide was opened with pyrrolidine to give a 70:30 mixture of
the amino alcohols 7 and 8 (Scheme 2).2 Mesylation of the
alcohols 7 and 8 and participation of the nitrogen atom resulted
in inversion at the other end of the original epoxide; both 7 and
8 gave the same enantiomer of the aziridinium ion 9. Treatment
Scheme 3
DOI: 10.1039/a909163g
J. Chem. Soc., Perkin Trans. 1, 2000, 711–722
711
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Intramolecular acylation of the benzoate 12, and treatment
with potassium tert-butoxide in tert-butyl alcohol, initiated
a cascade of reactions, including a second inversion 13→14,
leading to the formation of the cyclopropyl ketone 14. The
geometry of the epoxide 11 was therefore reflected in the
product 14.
With compounds with three or more stereogenic centres, at
least one of the stereogenic centres remains untouched and acts
as a “reference” centre. At the start of our investigation, we
planned a synthesis of oxetanes 20 from 1,3-diols 15 which
would result in net retention of all of the stereogenic centres
of 15. Conversion of 1,3-diols such as 15 into the correspond-
ing orthoesters 16, and reaction with acetyl bromide, was
expected to give the regioisomeric acetoxy bromides 18 and
19 with inversion of configuration at one of the stereogenic
centres (Scheme 4). Hydrolysis of the acetates of 18 and 19, and
Scheme 4
ring-closure, would then invert the configuration of the same
stereogenic centre to give a single oxetane 20. The aim of
the proposed research was to develop a general synthesis
of oxetanes (e.g. 20) which could be used to synthesise any
diastereoisomer at will.
Oxetanes are most usually synthesised using the Paterno–
Büchi cycloaddition4 of aldehydes and alkenes and, although
this reaction is often highly stereoselective, it is often limited to
the synthesis of one of the possible diastereomeric products.
The oxetane ring is found in a number of biologically active
molecules such as the β-amino acid oxetin5 ((2R,3S)-3-amino-
oxetane-2-carboxylic acid) 21, the antifungal triazole6 22, the
antiviral nucleoside7 23 and the anticancer compound, Taxol.8
In syntheses of these, and related compounds, a number of
different approaches have been adopted including the Paterno–
Büchi reaction,9 the ring contraction of a γ-lactone10 and
iodoetherification.11
Scheme 5
syn-25 and syn-27 as single diastereoisomers. However,1,3 anti-
selective reduction of the aldol 24, by delivery of the reducing
agent to the ketone using tetramethylammonium triacetoxy-
borohydride,13 was rather less selective, yielding the diols anti-
25 as a 86:14 mixture of diastereoisomers.
The aldols 28 were synthesised, as a 65:35 mixture of
diastereoisomers, by treating the lithium enolate of propio-
phenone with cyclohexanecarbaldehyde and were separated by
careful chromatography (Scheme 6). The aldols syn- and anti-28
were treated with diethylmethoxyborane at Ϫ78 ЊC in THF–
methanol,12 and sodium borohydride was added to the resulting
chelates (entries 1 and 3; Table 1). The aldol syn-28 was reduced
cleanly to give the diol 29 as a single diastereoisomer. Reduc-
tion of the aldol anti-28 was, however, extremely sluggish and
less diastereoselective; the diols 31 and 32 were obtained as a
78:22 mixture of diastereoisomers in a combined yield of 19%
along with 13% recovered starting material. Reduction of the
aldols syn- and anti-28 was also investigated using sodium
borohydride in ethanol (entries 2 and 4; Table 1).
Results and discussion
Synthesis of starting materials
The aldols 24 and 26 were synthesised by reacting the lithium
enolate of acetophenone with cyclohexanecarbaldehyde and 2-
methylpropanal respectively (Scheme 5).1,3 syn-Selective reduc-
tion of the aldols 24 and 26 was achieved using the method12 of
Prasad and co-workers; reduction of the chelated aldols with
sodium borohydride at Ϫ78 ЊC in THF–methanol gave the diols
The relative stereochemistry of the diols syn-25 and 29 was
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Table 1 Reductions of the aldols 28
Starting
material
Entry
Conditions
Products
Ratio
Yield (%)
1
2
3
4
syn-28
syn-28
anti-28
anti-28
1. Et2BOMe, Ϫ78 ЊC; 2. NaBH4
NaBH4, EtOH, 0 ЊC
1. Et2BOMe, Ϫ78 ЊC; 2. NaBH4
NaBH4, EtOH, 0 ЊC
29
>98:2
85:15
78:22
>90:10
71a
87b
19a,c
66b
29 ϩ 30
31 ϩ 32
31
a Yield of major isomer. b Yield of mixture of isomers. c Starting material recovered in 13% yield.
Table 2 Diagnostic spectroscopic data for the acetonides 33 and 34
3J(HaxHax)/Hz
3J(HaxHeq)/Hz
δC
Acetonide
HA
HB
HA
HB
MeC,MeD
CMeCMeD
33
34
11.6
—
11.5
—
2.7
2.4
1.3
2.0
20.2, 28.3
20.0, 26.1
99.3
99.5
Scheme 7
the two substrates for the borane catalyst. We believe that the
chelate 35 is more stable than 36 because 36 suffers from two
unfavourable gauche interactions (Ph↔Me; cHex↔Me) (the
axial methyl group of 35 does not suffer from any 1,3-diaxial
interactions).† Reduction of 35 occurs from an axial direc-
tion to give the borate 37. In the previous section, we have
Scheme 6
proved by conversion into the corresponding acetonides 33 and
34 (Scheme 7). The 13C chemical shifts of MeC, MeD and the
acetal carbon were characteristic14 of acetonides formed from
syn-1,3-diols and the coupling constants were typical15 of six-
membered rings adopting chair-like conformations (Table 2).
Furthermore, a mutual NOE interaction was observed between
HA and HB in each case.
already noted that the reduction of anti-28 with sodium boro-
hydride in the presence of one equivalent of diethylmethoxy-
borane was extremely sluggish. Previously, substoichiometric
quantities of alkoxyboranes have been used in 1,3syn-selective
reductions without significant loss of stereoselectivity,12,17
though stereoselective reductions with as little as 10 mol%
alkoxyborane have not, to our knowledge, been previously
reported.
Kinetic separation of the diastereomeric aldols 28
The diastereomeric aldols 28 could also be separated using a
remarkable kinetically controlled separation. Treatment of a
65:35 mixture of syn- and anti-28 with 10 mol% diethyl-
methoxyborane and sodium borohydride at Ϫ78 ЊC in THF–
methanol gave the diol 29 (63% yield) and the aldol anti-28
(31% yield), both as single diastereoisomers (Scheme 6). We
have rationalised this result in terms of competition between
Optimisation of the conversion of 1,3-diols into acyloxy halides
As a starting point for our investigation,18 we treated the
† For a remarkable conformational effect which results from a steric
repulsion between equatorial substituents, see ref. 16.
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Scheme 8
diastereomeric diols syn- and anti-25 with 45% hydrogen
spectroscopy. The orthoester 40 was, however, rather unstable,
and attempted aqueous work-up of this reaction gave the
regioisomeric acetates 44 and 45. In separate experiments,
bromide in acetic acid;19 the same 25:75 mixture of compounds
was obtained in each case (Scheme 8). At this stage of the
investigation, it was unclear whether these compounds were
stereo- or regioisomers. In fact, the products were shown to be
the diastereomeric acetoxy bromides 38 and 39 since both com-
pounds exhibited an HMBC crosspeak between the carbonyl
carbon and the benzylic proton. Under these reaction condi-
tions, therefore, the transformation was not stereospecific since
both diols were converted into the same mixture of acetoxy
bromides 38 and 39.
An alternative strategy involved the treatment of the ortho-
esters, derived from the diols 25, with acetyl bromide (Scheme
9).1 Accordingly, the diols 25 were treated with trimethyl
treatment of the orthoesters 40 and 42, derived from syn-
and anti-25, with acetyl bromide at Ϫ78 ЊC gave the acetoxy
bromides 38 and 39 respectively. The ratio of products obtained
under these reaction conditions reflected the starting mixture
of diols 25, indicating that nucleophilic substitution of the
dioxonium ions (41 and 43) was stereospecific. In a similar vein,
the diol syn-27 was converted into the acetoxy bromide 47 with
complete inversion of configuration at the benzylic site (Scheme
10). The acetoxy bromides 38 and 39 epimerised slowly on
Scheme 10
standing in diffuse light, a process which presumably involved
the intermediacy of the benzylic radical 46.‡
Similarly, the diol syn-25 was converted into the correspond-
ing bromo formate 49 (Scheme 11). The formation of the ortho-
formate 48 was much slower than that of the orthoester 40 and
the kinetic mixture of orthoester epimers (ca. 15:85 mixture
after five minutes, together with unreacted starting material)
slowly equilibrated over two hours to give a thermodynamic
60:40 mixture of epimeric orthoformates. Once again, treat-
ment of the orthoformates 48 with acetyl bromide was stereo-
specific yielding the bromo formate 49 as a >90:10 mixture of
diastereoisomers.
Intriguingly, the diols 25 could be converted into acetoxy
bromides simply by treatment with acetyl bromide in dichloro-
methane at Ϫ78 ЊC (Scheme 12). Presumably, participation
(e.g. 50 arrows) is faster than acetylation of the intermediate
hydroxy acetate.§ The process was, however, incompletely stereo-
specific; syn-25 was converted into a 91:9 mixture of 38 and 39,
and the diol anti-25 gave a 48:52 mixture of products.
Scheme 9
‡ For a rearrangement which proceeds via a similar intermediate, see
ref. 20.
§ Treatment of a 37:63 mixture of the hydroxy acetates 44 and 45 gave
only the acetoxy bromide 38.
orthoacetate and catalytic pyridinium toluene-p-sulfonate in
deuterochloroform and the formation of the corresponding
1
orthoesters (40 and 42) was observed by 500 MHz H NMR
714
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Table 3 Diagnostic coupling constants for oxetane products
Oxetane
3JHH (cis)/Hz
3JHH (trans)/Hz
52
54
57
8.1, 8.1
8.5, 8.5
8.0
6.9, 6.9
6.2, 6.2
6.0
Scheme 11
Scheme 13
Scheme 12
Fig. 2 Transition states leading to the oxetanes 52 and 54.
Fig. 1 Diagnostic NOEs in the oxetane 52.
stituted oxetane 54 was higher than that of 52, presumably
because the cyclisation with substituents on opposite sides of
the forming ring (Fig. 2) was better able to compete with
fragmentation (55 arrows) than the cyclisation leading to 52
(Fig. 2).¶
Synthesis of 2,4-disubstituted oxetanes
The acetoxy bromides 38 and 39 were converted into the
hydroxy bromides 51 and 53 by reduction with diisobutyl-
aluminium hydride (Scheme 13). A range of reaction conditions
(K2CO3, methanol; tBuOK, DMSO;21 tBuOK, hexane;22
BuLi, THF23) were screened for the conversion of the hydroxy
bromides 51 and 53 into the oxetanes 52 and 54; although the
phase-transfer catalysed24 (Bu4NHSO4, NaOH) ring closure of
51 was reasonably high yielding, a mixture of the diastereo-
meric oxetanes was obtained, perhaps as a result of competing
Walden25 inversion. The best method involved the treatment of
the hydroxy bromides 51 and 53 with sodium hydride in reflux-
ing THF. The relative stereochemistry of the oxetanes 52 and 54
was determined by measurement of their coupling constants
(Table 3);15 52 exhibited a mutual NOE enhancement between
the protons HA and HB (Fig. 1). The yield of the trans disub-
The stereospecificity of the transformations 51→52 and
53→54 was assessed by analysis of the crude reaction mixtures
1
by 300 MHz H NMR (Scheme 13). The hydroxy bromide 51
1
¶ The products of the fragmentation of 55 were observed in H NMR
spectra of crude reaction mixtures.
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Scheme 14
3
57 was determined by analysis15 of JHH coupling constants
(Table 3) and the absence of an NOE enhancement between HA
and HB. Cyclisation via the benzylic cation 59 is presumably
Table 4 Two-pot conversion of 1,3-diols 25 into oxetanes 52 and 54
Starting
material
Yielda
Bromoester Oxetane (%)
Entry
Reagent
1
2
3
4
syn-25
syn-25
anti-25
anti-25
(MeO)3CMe
(MeO)3CH
(MeO)3CMe
(MeO)3CH
38
49
39
56
52
54
52
54
21
15
51
47
a Yield over two steps.
competitive with the usual SN2 reaction pathway; other cyclis-
ation reactions suffer loss of stereospecificity in particularly
unfavourable cases.3,10a
gave the oxetane 52 as a >95:5 mixture of diastereoisomers and
an 86:14 mixture of 53 and 51 gave the oxetanes 54 and 52 as an
88:12 mixture of isomers; the cyclisation of the hydroxy brom-
ides 51 and 53 proceeded with a high level of stereospecificity.
Under the optimised reaction conditions, therefore, both form-
ation of the acetoxy bromide (→38 or 39) and cyclisation (→52
or 54) proceeded with inversion of configuration as was
required by the strategy outlined in the introduction.
Conclusion
We have developed a convenient two-pot procedure for the
formal dehydration of the 1,3-diols syn- and anti-25 to give the
oxetanes 52 and 54. The method proceeds with overall retention
at both of the stereogenic centres and should be applicable to
the synthesis of optically active, as well as racemic, oxetanes.
Development of a convenient preparation of oxetanes
Although we had developed a conversion of 1,3-diols into
oxetanes which proceeded with overall retention of configur-
ation (Scheme 13), the method was rather cumbersome because
it involved three separate reactions including a reduction with
diisobutylaluminium hydride (→51 or 53) which was difficult to
work up. We therefore developed a reaction sequence which was
more convenient.
Reaction conditions were screened for the direct conversion
of the bromo acetates 38 and 39 and the bromo formates 49 and
56 into the oxetanes 52 and 54. The optimum method involved
treatment of the crude bromo esters with one equivalent of
methanol and three equivalents of sodium hydride in refluxing
THF; deacylation by sodium methoxide was followed by cyclis-
ation to the oxetanes 52 and 54 (Scheme 14). Yields for this
transformation are summarised in Table 4; the bromo acetates
38 and 39 (entries 1 and 3) gave a higher yield of the oxetanes
52 and 54 than did the bromo formates 49 and 56 (entries 2
and 4). Other reaction conditions investigated (e.g. K2CO3,
MeOH; NaOMe, MeOH) resulted in greater fragmentation of
the intermediate alkoxide 55.
Experimental
All solvents were distilled before use. THF and Et2O were
freshly distilled from lithium aluminium hydride whilst CH2Cl2
and toluene were freshly distilled from calcium hydride. Ether
refers to diethyl ether and petrol refers to petroleum spirit (bp
40–60 ЊC) unless otherwise stated. Diisopropylamine was puri-
fied prior to use by distillation from calcium hydride. Solvents
were removed under reduced pressure using a Büchi rotary
evaporator at water aspirator pressure. Triphenylmethane was
used as indicator for THF. n-Butyllithium was titrated against
diphenylacetic acid before use. All non-aqueous reactions were
carried out under argon using oven-dried glassware.
Flash column chromatography was carried out using silica
(35–70 µm particles) according to the method of Still et al.26
Thin-layer chromatography was carried out on commercially
available pre-coated plates (Merck silica Kieselgel 60F254).
Unless otherwise stated, Rf values were measured with ethyl
acetate as eluant. Proton and carbon NMR spectra were
recorded on a Bruker WM 250, DPX 300 or DRX 500 Fourier
transform spectrometer using an internal deuterium lock.
Chemical shifts are quoted in parts per million downfield of
tetramethylsilane and values of coupling constants (J) are given
in Hz. The symbol * after the proton NMR chemical shift
indicates that the signal disappears after a D2O “shake”.
Carbon NMR spectra were recorded with broad band proton
decoupling and Attached Proton Test. The symbols ϩ and
Ϫ after the carbon NMR chemical shift indicate odd and even
numbers of attached protons respectively.
In a similar way, it was expected that the diol 29 would be
transformed into the oxetane 58. This transformation is a
particularly stern test of stereospecificity because all three sub-
stituents would be on the same face of the forming ring. In fact,
the product of the reaction was not the expected oxetane 58 but
the oxetane 57 (Scheme 15). The relative stereochemistry of
Melting points were determined on a Reichert hot stage
apparatus and are uncorrected. Infrared spectra were recorded
on a Nicolet Avatar 360 FT-IR ESP infrared spectrophoto-
meter and signals were referenced to the polystyrene 1601 cmϪ1
Scheme 15
716
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absorption. Mass spectra were recorded on a VG autospec mass
spectrometer, operating at 70 eV, using both the electron impact
and fast atom bombardment methods of ionisation. Accurate
molecular weights were obtained by peak matching using per-
fluorokerosene as a standard. Electron Impact was used unless
Fast Atom Bombardment (ϩFAB) is indicated. Microanalyses
were carried out by the staff of the School of Chemistry using
a Carlo Erba 1106 automatic analysers. Optical rotations
were recorded on a Perkin-Elmer 241 polarimeter (using the
sodium D line; 589 nm) and [α]D20 are given in units of 10Ϫ1 deg
eluting with 20% EtOAc in petrol, gave the aldol syn-28 (1.83 g,
16%, syn:anti >95:5) as yellow needles, mp 44–46 ЊC; Rf 0.30
(20% EtOAc in petrol) (Found: C, 78.2; H, 9.25; C16H22O2
requires C, 78.0; H, 9.00%); νmax/cmϪ1 (Nujol) 3402 (br, OH),
2852, 1673 (C᎐O), 1278 and 1112; δ (300 MHz, CDCl3) 7.92
᎐
H
(2 H, d, J 7.1, ortho-Ph), 7.59 (1 H, t, J 7.5, para-Ph), 7.47 (2 H,
app t, J 7.2, meta-Ph), 3.68 (2 H, m, CHOH and CHMe), 3.07
(1 H, d, J 2.5, OH), 2.10 (1 H, br d, J 12.8) and 2.0–0.9 (14 H,
m); δC (300 MHz, CDCl3) 206.3, 136.3, 133.7, 129.2, 128.8,
75.7, 41.7, 40.6, 29.9, 29.6, 26.8, 26.5, 26.2 and 10.9; m/z
(EI) 247 (11%, MHϩ), 163 (31), 134 (65), 105 (100, PhCO), 77
(61, Ph), 55 (52) and 41 (41).
cm2 gϪ1
.
Also obtained were the aldols 28 (4.58 g, syn:anti 52:48,
41%).
3-Cyclohexyl-3-hydroxy-1-phenylpropan-1-one 24
Butyllithium (1.6 M in hexanes, 57.5 ml, 92 mmol) was added
to a stirred solution of diisopropylamine (13.45 ml, 96 mmol)
in dry THF (200 ml) and the reaction mixture was stirred for
15 minutes at 0 ЊC. The reaction mixture was then cooled to
Ϫ78 ЊC, acetophenone (9.73 ml, 83 mmol) in dry THF (40 ml)
was added dropwise and the reaction mixture was stirred for
a further 30 minutes. Cyclohexanecarbaldehyde (12.1 ml, 100
mmol) in dry THF (40 ml) was added dropwise and the reaction
mixture was stirred for 30 minutes at Ϫ78 ЊC. The reaction mix-
ture was quenched with saturated aqueous ammonium chloride
(100 ml) and was slowly warmed to room temperature. The
reaction mixture was diluted with water (100 ml) and extracted
with ethyl acetate (3 × 100 ml). The combined organic extracts
were dried (MgSO4), filtered and evaporated under reduced
pressure to yield a crude product which was purified by flash
chromatography, eluting with 1:9 ethyl acetate–petrol to give
the aldol 24 (16.91 g, 88%) as yellow needles, mp 42.8–44.4 ЊC;
Rf 0.30 (20% EtOAc in petrol) (Found: C, 77.9; H, 8.95;
C15H20O2 requires C, 77.5; H, 8.70%); νmax/cmϪ1 (Nujol) 3470
Kinetic separation of the aldols 28. Diethylmethoxyborane
(1.0 M in THF, 626 µl) was added to the aldols 28 (1.46 g, 5.93
mmol, syn:anti 65:35) in THF (60 ml) and methanol (15 ml) at
Ϫ78 ЊC. The reaction was stirred for 30 minutes, sodium boro-
hydride (262 mg, 6.89 mmol) added, and the mixture stirred for
a further 16 h at Ϫ78 ЊC. Acetic acid (15 ml) and aqueous
sodium hydroxide solution (2 M, to pH 10) were added, and the
mixture was extracted with EtOAc (3 × 400 ml). The combined
organic extracts were dried (MgSO4), filtered and evaporated
under reduced pressure to give a crude product which was puri-
fied by flash chromatography, eluting with 10% EtOAc in petrol
to give the diol 29 (0.91 g, 63%) as pale yellow needles, mp
96–98 ЊC; Rf 0.26 (20% EtOAc in petrol) (Found: Mϩ Ϫ H2O,
230.11659; C16H24O2 requires M Ϫ H2O 230.1670); νmax/cmϪ1
(Nujol) 3330 (OH), 1460 and 1376; δH (300 MHz, CDCl3) 7.36–
7.21 (5 H, m, Ph), 4.98 (1 H, d, J, 2.7, PhCHOH), 3.57 (1 H, dd,
J 9.2 and 1.7, CHOH), 3.50 (1 H, br s, OH), 2.73 (1 H, br s,
OH), 1.95 (1 H, m, CHMe), 1.82–0.80 (11 H, m) and 0.78 (3 H,
d, J 7.1, Me); δC (300 MHz, CDCl3) 143.9, 128.5, 127.3, 126.1,
81.7, 79.2, 41.4, 41.0, 30.1, 29.2, 26.7, 26.3, 26.2 and 4.6; m/z
(EI) 247 (0.5%, Mϩ), 231 (3), 213 (1), 124 (83), 118 (77), 107
(86), 82 (83), 82 (76), 79 (91), 77 (88), 67 (62) and 55 (100).
Also obtained was the aldol anti-28 (0.46 g, 31%) as white
needles, mp 32–35 ЊC; Rf 0.30 (20% EtOAc in petrol) (Found: C,
77.8; H, 9.30; C16H22O2 requires C, 78.0; H, 9.00%); νmax/cmϪ1
(OH), 1683 (C᎐O), 1317 and 1099; δ (300 MHz, CDCl3) 7.9
᎐
H
(2 H, d, J 7.1, ortho-Ph), 7.6 (1 H, t, J 7.4, para-Ph), 7.5 (2 H,
app t, J 7.7, meta-Ph), 4.0–3.96 (1 H, m, CHOH), 3.2–3.1 (2 H,
m, CHAHB and OH), 3.05 (1 H, dd, J 9.3 and 8.2, CHAHB) and
2.2–1.0 (11 H, m); δC (300 MHz, CDCl3) 201.7, 137.3, 134.8,
129.1, 128.6, 72.2 (CHOH), 43.5, 42.6, 29.4, 28.7, 26.9, 26.6
and 26.5; m/z (EI) 232 (4%, Mϩ), 214 (M Ϫ H2O), 163 (53,
M Ϫ C5H9), 149 (37, M Ϫ C6H10), 134 (17, C7H12O), 105 (100,
PhCO), 77 (47, C6H5) and 41 (19).
(Nujol) 3402 (br, OH), 2852, 1673 (C᎐O), 1278 and 1112;
᎐
δH (300 MHz, CDCl3) 7.97 (2 H, d, J 7.1, ortho-Ph), 7.59 (1 H, t,
J 7.4, para-Ph), 7.48 (2 H, app t, J 7.7, meta-Ph), 3.71 (1 H, qd,
J 5.5 and 7.2, CHMe), 3.57 (1 H, app q, J 8.0, CHOH), 3.00
(1 H, J 8.0, OH), 2.0–1.0 (11 H, m) and 1.29 (3 H, d, J 7.2, Me);
δC (300 MHz, CDCl3) 206.8, 136.9, 133.8, 129.2, 128.7, 79.2,
42.1, 41.7, 32.3, 30.6, 30.1, 29.7 and 16.5; m/z (EI) 247 (11%,
MHϩ), 163 (31), 134 (65), 105 (100, PhCO), 77 (61, Ph), 55 (52)
and 41 (41).
3-Hydroxy-4-methyl-1-phenylpentan-1-one 26
By the same general method, acetophenone (1.94 cm3, 16.7
mmol) and isobutyraldehyde (1.44 cm3, 15.8 mmol) gave a
crude product which was purified by column chromatography,
eluting with 4:1 petrol–ether, to give the aldol 26 (2.33 g, 73%)
as white needles, Rf 0.30 (4:1 petrol–ether 4:1) (Found: MHϩ,
193.1216; C12H17O2 requires M, 193.1228); νmax(CHCl3)/cmϪ1
3422 (OH), 1725 (C᎐O) and 1599 (C᎐C); δ (400 MHz; CDCl )
᎐
᎐
H
3
(1R*,3S*)-3-Cyclohexyl-1-phenylpropane-1,3-diol syn-25
7.95 (2 H, d, J 7.1, Ph ortho-H), 7.58 (1 H, t, J 7.4, Ph para-H),
7.48 (2 H, t, J 7.8, Ph meta-H), 3.98 (1 H, ddd, J 11.8, 5.7 and
2.3, CHOH), 3.15 (1 H, dd, J 17.5 and 2.4, CH2), 3.02 (1 H,
ddd, J 17.5, 9.5 and 2.0, CH2), 1.78 (1 H, dq, J 13.4 and 6.7,
CHMe2), 1.10 (3 H, d, J 6.8, Me) and 0.80 (3 H, d, J 6.8, Me);
δC (101 MHz; CDCl3) 201.4Ϫ (CO), 137.0Ϫ (Ph ipso-C), 133.5ϩ,
128.7ϩ, 128.1ϩ, 72.4ϩ (COH), 41.9Ϫ (CH2), 33.1ϩ (CHMe2),
18.6ϩ (Me) and 17.9ϩ (Me); m/z (ϩCI) 193.0 (89%, M ϩ 1),
175.0 (37, M Ϫ OH), 149.0 (10, MH Ϫ iPr), 105.0 (100, M Ϫ
PhCO) and 77.0 (15, Ph).
Diethylmethoxyborane (1.0 M in THF, 950 µl, 0.95 mmol) was
added to a stirred solution of the 3-cyclohexyl-3-hydroxy-1-
phenylpropan-1-one 24 (200 mg, 0.86 mmol) in dry THF (40
ml) and methanol (10 ml). The reaction was stirred for 15 min-
utes at Ϫ78 ЊC and sodium borohydride (36 mg, 0.95 mmol)
was added. The reaction mixture was stirred for 2 hours at
Ϫ78 ЊC. The reaction mixture was quenched with acetic acid
(5 ml) and slowly warmed to room temperature. The reaction
mixture was diluted with ethyl acetate (50 ml) and washed with
saturated aqueous sodium bicarbonate solution (3 × 50 ml).
The combined organic extracts were dried (MgSO4), filtered
and evaporated under reduced pressure to give the crude prod-
uct, which was purified by flash chromatography, eluting with
1:9 ethyl acetate–petrol, and repeated dissolution in methanol
(15 × 30 ml) and removal of volatile components under reduced
pressure, to give the diol syn-25 (124 mg, 62%) as colourless
plates, mp 118.5–220.8 ЊC; Rf 0.20 (20% EtOAc in petrol)
(Found: C, 76.8; H, 9.50; C15H22O2 requires C, 76.9; H, 9.45%);
(2R*,3S*)-3-Cyclohexyl-3-hydroxy-2-methyl-1-phenylpropan-1-
one 28
By the same general method, propiophenone (5.5 ml, 45.4
mmol) and cyclohexanecarbaldehyde (6.05 ml, 45.6 mmol)
gave a crude product which was purified by column chromato-
graphy, eluting with 10% EtOAc in petrol, to give the aldols 28
(6.82 g, 62%, syn:anti 65:35). Careful column chromatography,
J. Chem. Soc., Perkin Trans. 1, 2000, 711–722
717

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νmax/cmϪ1 (Nujol) 3328 (OH), 1462 and 1376; δH (300 MHz,
CDCl3) 7.39–7.26 (5 H, m, Ph), 4.93 (1 H, br dd, J 7.7 and 4.5,
PhCHOH), 3.75 (1 H, m, CHOH), 3.39 (1 H, br s, OH), 2.7 (1
H, d, J 3.1, OH) and 1.84–1.00 (13 H, m); δC (300 MHz, CDCl3)
145.1, 128.4, 127.4, 126.2, 81.8, 79.3, 40.8, 40.5, 30.2, 29.2, 26.7,
26.3 and 26.2; m/z (EI) 234 (6%, Mϩ), 216 (26, M Ϫ H2O), 133
(89), 107 (100, PhCHOH), 79 (63) and 41 (32).
solution of the aldol syn-28 (190 mg, 0.77 mmol) in ethanol
(5 ml) at 0 ЊC. The mixture was stirred for 16 h and the ethanol
evaporated off under reduced pressure. The residue was dis-
solved in dichloromethane (5 ml), poured into water and
extracted with dichloromethane (3 × 5 ml). The combined
organic extracts were dried (MgSO4), filtered and evaporated
under reduced pressure to give a crude product. The crude
product was dissolved in THF (5 ml), glycerol (5 ml) and aque-
ous sodium hydroxide solution (2 M, 5 ml) and the mixture
stirred vigorously for 2 h. The reaction was quenched with
water and extracted with dichloromethane (3 × 10 ml) and the
combined organic extracts were dried (MgSO4), filtered and
evaporated under reduced pressure to give the diol 29 (166 mg,
87%, 29:30 85:15 mixture), spectroscopically identical to that
obtained previously.
(1S*,3R*)-4-Methyl-1-phenylpentane-1,3-diol syn-27
By the same general method, the aldol 26 (0.6 g, 3.125 mmol)
gave a crude product which was purified by flash chromato-
graphy, eluting with 1:1 petrol–ether to give the diol syn-27
(340 mg, 56%) as a colourless oil, Rf 0.31 (petrol–EtOAc, 1:1)
(Found: Mϩ, 194.1306; C12H18O2 requires M, 194.1306);
νmax(CHCl3)/cmϪ1 3608 (OH), 3488 (OH) and 1605 (C᎐C);
᎐
δH (400 MHz, CDCl3) 7.42–7.25 (5 H, m, Ph), 4.92 (1 H, dd,
J 9.0 and 3.7, CHOHPh), 3.75 (1 H, ddd, J 7.6, 5.2 and 2.4,
CHOH), 3.38 (1 H, s, OH), 2.81 (1 H, s, OH), 1.85–1.55 (3 H,
m, CH2 and CHMe2), 0.92 (3 H, d, J 6.8, Me) and 0.91 (3 H, d,
J 6.8, Me); δC (101 MHz, CDCl3) 144.7Ϫ (Ph ipso-C), 128.5ϩ,
127.6ϩ, 125.7ϩ, 77.7ϩ (CHOH), 75.7ϩ (CHOH), 42.1Ϫ (CH2),
34.3ϩ (CHMe2), 18.2ϩ (Me) and 17.4ϩ (Me); m/z (ϩEI) 194.0
(28%, Mϩ), 176.0 (52, M Ϫ H2O), 133.0 (53, M Ϫ Pr) and 107.0
(100, PhCHOH).
(1R*,2R*,3R*)-1-Cyclohexyl-2-methyl-3-phenylpropane-1,3-
diol 31
By the same general method, the aldol anti-28 (190 mg, 0.77
mmol) gave the diol 31 (127 mg, 0.52 mmol, 31:32 >90:10
mixture), spectroscopically identical to that obtained
previously.
(1R*,3R*)-3-Cyclohexyl-1-phenylpropane-1,3-diol anti-25
Acetic acid (20 ml) was added to a stirred solution of tetra-
methylammonium triacetoxyborohydride (11.6 g, 44 mmol) in
dry acetonitrile (20 ml) and the reaction was stirred for 30 min.
The reaction was cooled to Ϫ40 ЊC and a solution of the aldol
24 (1.22 g, 5.54 mmol) in acetonitrile (10 ml) was added. The
reaction was stirred for 4 h, left for three days at Ϫ18 ЊC,
quenched with aqueous sodium potassium tartrate solution
(0.5 M, 40 ml) and stirred for 30 min. Dichloromethane (100
ml) and saturated aqueous sodium bicarbonate solution (100
ml) were added, the layers separated, the aqueous fraction
extracted with dichloromethane (3 × 50 ml) and the combined
organic fractions were washed with saturated aqueous sodium
bicarbonate solution (3 × 50 ml), dried (MgSO4), filtered and
evaporated under reduced pressure to give the crude product.
The crude product was dissolved in a mixture of THF (30 ml),
glycerol (20 ml) and aqueous sodium hydroxide solution (2 M,
20 ml), stirred for 2 h, quenched with water, extracted with
dichloromethane (2 × 50 ml), dried (MgSO4), filtered and evap-
orated under reduced pressure to give the crude product which
was purified by flash chromatography, eluting with 1:4 ethyl
acetate–petrol, to give the diol anti-25 (760 mg, 62%; anti:syn
86:14) as colourless plates, mp 89–91 ЊC; Rf 0.20 (20% EtOAc
in petrol) (Found: C, 76.65; H, 9.60; C15H22O2 requires C,
76.9; H, 9.45%); νmax/cmϪ1 (Nujol) 3330 (OH), 1462 and 1376;
δH (300 MHz, CDCl3) 7.39–7.26 (5 H, m, Ph), 5.06 (1 H, t, J 5.8,
PhCHOH), 3.75 (1 H, q, J 6.2, CHOH), 3.35 (1 H, br s, OH),
2.73 (1 H, br s, OH) and 1.84–1.00 (13 H, m); δC (300 MHz,
CDCl3) 145.1, 128.8, 127.6, 125.9, 73.8, 72.2, 44.0, 42.0, 29.3,
28.6, 26.8, 26.5 and 26.4; m/z (EI) 234 (Mϩ, 3%), 216
(M Ϫ H2O, 30), 133 (85), 107 (100), 79 (85), 55 (70) and 41 (65).
(1R*,2R*,3R*)-1-Cyclohexyl-2-methyl-3-phenylpropane-1,3-
diol 31
By the same general method, diethylmethoxyborane (6 ml, 1 M
in THF), anti-28 and sodium borohydride (191 mg, 5.01 mmol)
gave a crude product to which was added THF (50 ml), glycerol
(50 ml) and aqueous sodium hydroxide solution (2 M, 50 ml).
The mixture was stirred vigorously for 2 h, quenched with water
and extracted with dichloromethane (3 × 200 ml). The com-
bined organic extracts were dried (MgSO4), filtered and evapor-
ated to give a crude product which was purified by flash
chromatography, eluting with 5→15% EtOAc in petrol to give
starting material (144 mg, 13%) and a crude product. The crude
product was further purified by flash chromatography, eluting
with 15% EtOAc in petrol to give the diol 31 (211 mg, 19%,
31:32 78:22) as a colourless oil; Rf 0.19 (15% EtOAc in petrol)
(Found: Mϩ Ϫ H2O, 230.11659; C16H24O2 requires M Ϫ H2O
230.1670); νmax/cmϪ1 (CDCl3 solution) 3420 (O–H), 2925, 2856,
1451 and 1108; δH (300 MHz, CDCl3) 7.37–7.21 (5 H, m, Ph),
4.95 (1 H, d, J 2.7, PhCH), 3.55 (1 H, dd, J 9.2, 1.7, CHChex),
2.06–1.87 (1 H, m, CHMe), 1.78–0.63 (11 H, m, Chex) and 0.77
(3 H, d, J 7.1, Me); δC (300 MHz, CDCl3) 143.9, 128.5, 127.3,
126.2, 87.1 (CHChex), 79.2 (PhCH), 41.0, 30.2, 29.2, 26.7, 26.3,
26.2, 10.7 and 4.6 (Mesyn); m/z (EI) 230 (0.75%, M Ϫ H2O), 124
(53), 118 (96), 117 (100), 91 (50), 82 (51), 55 (83) and 41 (51).
Also obtained was recovered starting material (144 mg, 13%).
(1R*,2S*,3R*)-3-Cyclohexyl-2-methyl-1-phenylpropane-1,3-diol
29
By the same general method, the aldol syn-28 (503 mg, 2.53
mmol) gave a crude product. The crude product was dissolved
in THF (10 ml), glycerol (10 ml) and aqueous sodium hydroxide
solution (2 M, 10 ml), and the mixture was stirred vigorously
for 2 h, quenched with water and extracted with dichloro-
methane (3 × 50 ml). The combined organic extracts were dried
(MgSO4), filtered and evaporated under reduced pressure to
give a crude product which was purified by flash chromato-
graphy, eluting with 20% EtOAc in petrol, to give the diol 29
(360 mg, 71%), spectroscopically identical to that obtained
previously.
(4R*,6S*)-6-Cyclohexyl-2,2-dimethyl-4-phenyl-1,3-dioxane 33
(1R*,3S*)-3-Cyclohexyl-1-phenylpropane-1,3-diol syn-25 (40
mg, 0.17 mmol) was dissolved in dichloromethane (2 ml) and
2,2-dimethoxypropane (40 µl, 0.34 mmol) and pyridinium
toluene-p-sulfonate (PPTS, 4 mg) were added. The reaction
mixture was stirred for 1 hour at room temperature. The reac-
tion mixture was quenched with ammonium chloride and
extracted with dichloromethane (3 × 5 ml). The combined
organic layers were dried (MgSO4), filtered and evaporated to
give a crude product which was purified by flash chromato-
graphy eluting with 90:9:1 petrol–ethyl acetate–triethylamine
to yield the acetonide 33 (45 mg, 97%) as an oil; Rf 0.35 (10%
EtOAc in petrol) (Found: C, 78.4, H, 9.8; C18H26O2 requires C,
(1R*,2S*,3R*)-1-Cyclohexyl-2-methyl-3-phenylpropane-1,3-diol
29
Sodium borohydride (32 mg, 0.85 mmol) was added to a stirred
718
J. Chem. Soc., Perkin Trans. 1, 2000, 711–722

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78.6, H, 9.6%); νmax/cmϪ1 (Nujol) 2918, 1450 and 1384; δH (500
MHz, CDCl3) 7.40–7.23 (5 H, m, Ph), 4.86 (1 H, dd, J 11.6 and
2.7, PhCH), 3.7 (1 H, ddd, J 11.5, 7.0 and 1.3), 2.17 (3 H, m,
Me), 1.97 (1 H, m) and 1.7–0.9 (15 H, m); δC (500 MHz, CDCl3)
143.2, 128.8, 127.9, 126.5, 99.3, 73.9, 72.3, 43.2, 37.0, 31.4, 30.1,
29.7, 29.4, 29.3, 28.3 and 20.2; m/z (EI) 273 (Mϩ Ϫ H, 11%),
105 (60) and 95 (100). The stereochemistry of the molecule was
confirmed by the observation of a mutual NOE between 4-H
and 6-H.
M Ϫ HOAc, 216.1514); νmax/cmϪ1 (Nujol) 3403 (OH), 2931 and
1732 (C᎐O); δ (300 MHz, CDCl ) 7.36–7.26 (5 H, m, Ph), 5.94
᎐
H
3
(1 H, dd, J 7.9 and 6.7, PhCHOHmin), 4.75 (2 H, m, CHOAc
and PhCHOHmaj), 3.23 (1 H, ddd, 5.4, 4.3 and 2.6, CHOHmaj),
2.07 (3 H, s, Memin), 2.00 (3 H, s, Memaj) and 2.1–0.9 (16 H, m);
δC (300 MHz, CDCl3) 171.4maj, 170.2min, 144.2maj, 140.2min
75.9maj, 75.2min, 73.3min, 72.6maj, 44.0min, 41.8maj, 40.8maj, 40.6min
30.9majϩmin, 28.8min, 28.6maj, 27.9maj, 27.6min, 26.4min, 26.3maj
,
,
,
26.2min, 26.0maj, 21.4min and 21.2maj; m/z (EI) 216 (40%,
Mϩ Ϫ H2O), 133 (100) and 105 (70).
(4R*,5S*,6R*)-6-Cyclohexyl-2,2,5-trimethyl-4-phenyl-1,3-
dioxane 34
(4S*,6R*)-6-Cyclohexyl-2-methoxy-2-methyl-4-phenyl-1,3-
dioxane 42 and (1R*,3S*)-acetic acid 3-bromo-1-cyclohexyl-3-
phenylpropyl ester 39
By the same general method, (1R*,2S*,3R*)-3-cyclohexyl-2-
methyl-1-phenylpropane-1,3-diol 29 (150 mg, 0.60 mmol) gave
a crude product which was purified by flash chromatography,
eluting with 90:9:1 petrol–ethyl acetate–triethylamine, to yield
the acetonide 34 (127 mg, 72%) as an oil; Rf 0.35 (10% EtOAc
in petrol) (Found: C, 79.0, H, 9.7; C19H28O2 requires C, 79.1, H,
9.8%); νmax/cmϪ1 (Nujol) 2920, 1495, 1450 and 1384; δH (500
MHz, CDCl3) 7.35–7.20 (5 H, m, Ph), 5.03 (1 H, d, J 2.4,
PhCH), 3.66 (1 H, dd, J 9.6 and 2.0), 2.10 (1 H, br d, J 14.1),
1.8–0.8 (11 H, m), 1.52 (3 H, s, Me), 1.48 (3 H, s, Me) and 0.61
(3 H, d, J 6.9, Me); δC (500 MHz, CDCl3) 141.8, 128.3, 127.1,
126.0, 99.5, 78.2, 75.5, 39.1, 35.4, 30.6, 30.4, 27.9, 27.1, 26.3,
26.1, 20.0 and 5.4; m/z (EI) 287 (Mϩ Ϫ H, 15%), 105 (60) and
95 (100). The stereochemistry of the molecule was confirmed
by the observation of a mutual NOE between 4-H and 6-H.
Trimethyl orthoacetate (16 µl, 0.16 mmol) and pyridinium
toluene-p-sulfonate (1 mg) were added to a solution of the diol
anti-25 (22 mg, 0.10 mmol) in deuterochloroform (1.5 ml) in an
NMR tube. After 2 min, the orthoacetates (64:36 mixture of
1
epimers) were observed by H NMR, δH (250 MHz, CDCl3)
7.40–7.2 (5 H, m, Ph), 5.03 (1 H, dd, J 9.0 and 6.2, PhCHmaj),
4.78 (1 H, dd, J 9.9 and 3.7, PhCHmin), 3.82 (1 H, q, 7.2,
CHOHmaj), 3.59 (1 H, m, CHOHmin), 3.28 (3 H, s, OMe), 1.62
(3 H, s, Memin), 1.48 (3 H, s, Memaj) and 2.3–0.9 (13 H, m).
The reaction mixture was cooled to Ϫ78 ЊC and acetyl brom-
ide (22 µl, 0.16 mmol) was added. The reaction mixture was
stirred overnight, poured into saturated aqueous sodium
bicarbonate solution, extracted with dichloromethane (3 × 3
ml), dried (MgSO4), filtered and evaporated to give the acetoxy
bromide 39 (28 mg, 99%; 39:38 85:15) as a colourless oil;
Rf 0.70 (20% EtOAc in petrol) (Found: Mϩ Ϫ HOAc Ϫ Br,
199.1480; C17H23BrO2 requires M Ϫ HOAc Ϫ Br, 1991486);
νmax/cmϪ1 (Nujol) 2931, 1730 (C᎐O) and 1454; δ (500 MHz,
(2R*,4R*,6S*)- and (2R*,4S*,6R*)-2-Methoxy-4-cyclohexyl-6-
phenyl-1,3-dioxane 48
By the same general method trimethyl orthoformate (14 µl, 0.13
mmol) and pyridinium toluene-p-sulfonate (1 mg) were added
to a solution of the diol syn-25 (20 mg, 0.09 mmol) in deutero-
chloroform. The progress of this reaction was monitored by
NMR; after 5 minutes the reaction mixture consisted of a
60:40 mixture of starting material–orthoesters (<10:90 mix-
ture of epimers) and after 12 minutes the reaction mixture
consisted of a 20:80 mixture of starting material–orthoesters
(38:62 mixture of epimers). After 2 h, the reaction mixture
consisted of the orthoesters 48 (60:40 mixture of epimers), δH
(250 MHz, CDCl3) 7.39–7.27 (5 H, m, Ph), 5.59 (1 Hmaj, s,
CHOMe), 5.34 (1 Hmin, s, CHOMe), 5.12 (1 Hmaj, dd, J 16.7 and
6.3, PhCH), 4.75 (1 Hmin, dd, J 16.7 and 6.3, PhCH), 3.98
(1 Hmaj, ddd, J 16.7, 8.3 and 6.3, ChexCH), 3.72 (3 Hmin, s, Me),
3.62 (1 Hmin, ddd, J 16.7, 8.3 and 6.3, ChexCH), 3.54 (3 Hmaj, s,
Me) and 2.05–0.90 (13 H, m).
᎐
H
CDCl3) 7.41–7.24 (5 H, m, Ph), 4.88 (1 H, dd, J 9.7 and 5.7,
CHBr), 4.39 (1 H, ddd, J 12.3, 5.5 and 3.8, CHOAc), 2.50 (2 H,
m), 1.96 (3 H, s, Me) and 1.7–0.9 (11 H, m); δC (500 MHz,
CDCl3) 169.5, 140.0, 127.8, 127.7, 126.4, 74.7, 49.8, 40.8, 40.3,
27.4, 26.8, 25.2, 25.0 and 20.0; m/z (EI) 278 (Mϩ Ϫ HOAc, 2%),
199 (95), 117 (90) and 43 (100). The regioselectivity of the reac-
tion was proved by the observation of an HMBC crosspeak
between OAc and CHOAc.
(1R*,3R*)-Acetic acid 3-bromo-1-cyclohexyl-3-phenylpropyl
ester 38
Trimethyl orthoacetate (40 µl, 0.33 mmol) and pyridinium
toluene-p-sulfonate (1 mg) were added to a stirred solution of
the diol syn-25 (100 mg, 0.43 mmol) in dichloromethane (2 ml).
The reaction mixture was stirred for 10 minutes at room tem-
perature, cooled to Ϫ78 ЊC and acetyl bromide (58 µl, 0.75
mmol) was added dropwise. The reaction was stirred for 16 h,
quenched with saturated sodium bicarbonate solution,
extracted with dichloromethane (3 × 5 ml), dried (MgSO4),
filtered and evaporated to give the acetoxy bromide 38 (90 mg,
99%; 38:39 >98:2) as a colourless oil; Rf 0.70 (20% EtOAc
in petrol) (Found: Mϩ Ϫ HOAc Ϫ Br, 199.1483; C17H23BrO2
requires M Ϫ HOAc Ϫ Br, 199.1486); νmax/cmϪ1 (Nujol) 2931,
(1R*,4S*,6R*)-6-Cyclohexyl-2-methoxy-2-methyl-4-phenyl-1,3-
dioxane 40, (1R*,3S*)-acetic acid 3-cyclohexyl-3-hydroxy-1-
phenylpropyl ester 44 and (1R*,3S*)-acetic acid 1-cyclohexyl-3-
hydroxy-3-phenylpropyl ester 45
Trimethyl orthoacetate (10 µl, 0.10 mmol) and pyridinium
toluene-p-sulfonate (1 mg) were added to a solution of the diol
syn-25 (40 mg, 0.17 mmol) in deuterochloroform (1.5 ml) in an
NMR tube. After 2 min, the orthoacetate 40 was observed by
1H NMR, δH (500 MHz, CDCl3) 7.40–7.25 (5 H, m, Ph), 5.03
(1 H, dd, J 11.7 and 2.7, PhCH), 3.7 (1 H, ddd, J 11.5, 7.4 and
1.4), 3.26 (3 H, s, OMe), 1.95 (1 H, m), 1.7–1.55 (5 H, m), 1.54
(3 H, s, Me) and 1.4–0.9 (6 H, m); δC (500 MHz, CDCl3) 141.9,
128.4, 127.6, 126.1, 113.0, 73.0, 71.1, 49.7, 42.4, 28.8, 28.0, 26.6,
26.1, 26.0 and 22.8. The stereochemistry of the molecule was
proved by the observation of a mutual NOE between 4-H and
6-H.
The reaction mixture was poured into water, extracted with
dichloromethane (3 × 3 ml), dried (MgSO4), filtered and
evaporated to give the hydroxy acetates 45 and 44 (63:37
mixture of regioisomers, 43 mg, 99%); Rf 0.60 (20% EtOAc
in petrol) (Found: Mϩ Ϫ HOAc, 216.1515; C17H24O3 requires
1732 (C᎐O) and 1454; δ (500 MHz, CDCl ) 7.41–7.24 (5 H, m,
᎐
H
3
Ph), 5.07 (1 H, ddd, J 10.4, 5.3 and 2.4, CHOAc), 4.88 (1 H, dd,
J 9.7 and 5.7, CHBr), 2.49 (1 H, ddd, J 15.1, 9.2 and 2.4), 2.33
(1 H, ddd, J 15.1, 9.7 and 5.3), 1.88 (3 H, s, Me) and 1.8–0.9
(11 H, m); δC (500 MHz, CDCl ) 170.6 (C᎐O), 142.0, 128.8,
᎐
3
128.4, 127.3, 76.1, 52.1 (CBr), 41.8, 41.3, 28.6, 28.1, 26.3, 26.03,
26.02 and 20.8; m/z (EI) 278 (Mϩ Ϫ HOAc, 1%), 199 (85), 117
(100) and 43 (95). The regioselectivity of the reaction was
proved by the observation of an HMBC crosspeak between
OAc and CHOAc.
(1R*,3R*)-Acetic acid 1-bromo-4-methyl-1-phenylpent-3-yl ester
47
The diol syn-27 (340 mg, 1.75 mmol) was dissolved in dry
J. Chem. Soc., Perkin Trans. 1, 2000, 711–722
719

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dichloromethane (15 cm3) and toluene-p-sulfonic acid (33 mg,
0.18 mmol) was added. Trimethyl orthoacetate (0.244 cm3, 1.93
mmol) was added and the mixture stirred at room temperature
for 3 h. The solvent was removed under reduced pressure. The
pressure was further reduced to 0.1 mm Hg and held for 2 min.
The residue was redissolved in dichloromethane (15 cm3) and
acetyl bromide (0.155 cm3, 2.10 mmol) was added at 0 ЊC and
stirred at room temperature overnight. The solvent was
removed under reduced pressure and the residue purified by
column chromatography (petrol–ether, 9:1) to give the bromo
ester 47 (330 mg, 63%) as a colourless oil, Rf 0.24 (petrol–
EtOAc, 2:3) (Found: Mϩ, 299.0659; C12H20O279Br requires
purified by flash chromatography eluting with 1:4 ether–petrol
to yield the acetoxy bromides 38 and 39 (0.14 g, 96%, 38:39
25:75) as a brown oil, spectroscopically identical to that
obtained previously.
(1R*,3R*)- and (1R*, 3S*)-Acetic acid 3-bromo-1-cyclohexyl-3-
phenylpropyl esters 38 and 39
By the same general method, the diol anti-25 (100 mg, 0.43
mmol) gave the acetoxy bromides (0.14 g, 96%, 38:39 25:75)
as a brown oil, spectroscopically identical to that obtianed
previously.
MHϩ, 299.0647); νmax(CHCl3)/cmϪ1 1736 (C᎐O); δH (200 MHz,
᎐
(1R*,3R*)-3-Bromo-1-cyclohexyl-3-phenylpropan-1-ol 51
CDCl3) 7.50 (5 H, m, Ph), 5.05–5.17 (1 H, m, CHCO2Me), 5.02
(1 H, dd, J 7.5 and 5.0, CHBr), 2.60–2.22 (2 H, m, CH2), 1.91
(3 H, s, COMe), 0.94 (3 H, d, J 7.2, Me) and 0.92 (3 H, d, J 7.3,
Me); δC (54 MHz, CDCl3) 170.1Ϫ (CO), 140.2Ϫ (Ph ipso-C),
129.1ϩ, 129.1ϩ, 127.2ϩ, 70.7ϩ (CHOAc), 50.2ϩ (CHBr), 40.1Ϫ
(CH2), 32.0ϩ (COMe), 20.2ϩ (CHMe2), 18.1ϩ (Me) and 18.0ϩ
(Me); m/z (ϩFAB) 299.1 (15, Mϩ).
Diisobutylaluminium hydride (1.5 M in toluene, 0.65 ml, 0.98
mmol) was added to a stirred solution of the acetate 38 (70 mg,
0.22 mmol) in dry dichloromethane (3 ml). The reaction mix-
ture was stirred for 1.5 hours at Ϫ78 ЊC, quenched with satur-
ated ammonium chloride solution (3 ml), filtered through Celite
with dichloromethane and the layers were separated. The aque-
ous fractions were extracted with dichloromethane (3 × 30 ml),
and the combined organic extracts were dried (MgSO4), filtered
and evaporated under reduced pressure to yield the hydroxy
bromide 51 (65 mg, 99%) as a brown oil; Rf 0.30 (20% EtOAc
in petrol) (Found: Mϩ Ϫ H2O Ϫ Br, 199.1482; C17H23BrO2
requires M Ϫ H2O Ϫ Br, 199.1486); νmax/cmϪ1 (Nujol) 3418
(OH), 2931, 1495 and 1450; δH (500 MHz, CDCl3) 7.42–7.24
(5 H, m, Ph), 5.30 (1 H, dd, J 11.5 and 2.7, CHBr), 3.80 (1 H,
ddd, J 10.4, 5.6 and 2.0, CHOH), 2.51 (1 H, ddd, J 14.4, 10.4
and 2.7), 2.38 (1 H, ddd, J 14.4, 11.5 and 2.0) and 2.0–0.9 (11 H,
m); δC (500 MHz, CDCl3) 142.7, 128.6, 128.3, 127.3, 73.9, 54.0,
43.8, 43.9, 29.0, 28.0, 26.3, 26.2 and 26.0; m/z (EI) 278
(Mϩ Ϫ H2O, 1%), 199 (30), 105 (100) and 91 (55).
(1R*,3R*)-Formic acid 3-bromo-1-cyclohexyl-3-phenylpropyl
ester 49
By the same general method, trimethyl orthoformate (21 µl,
0.19 mmol), pyridinium toluene-p-sulfonate (1 mg), acetyl
bromide (36 µl, 0.65 mmol) and the diol anti-25 (31 mg, 0.13
mmol) gave a crude product which was purified by column
chromatography, eluting with 15% EtOAc in petrol, to give the
formate 49 (40 mg, >95%; 49:56 >90:10) as a colourless oil;
Rf 0.75 (20% EtOAc in petrol) (Found: MϩϪBr 245.1538;
C16H21BrO2 requires M Ϫ Br 245.1542); νmax/cmϪ1 (CDCl3 solu-
tion) 3055, 2987, 1645, 1422 and 1266; δH (500 MHz, CDCl3)
8.01 (1 H, s, CHO), 7.46–7.19 (5 H, m, Ph), 5.12 (1 H, ddd,
J 9.6, 5.0 and 2.2, CHOCHO), 4.88 (1 H, dd, J 9.0 and 4.0,
CHBr), 2.44 (1 H, ddd, J 15.0, 9.0 and 2.2), 2.23 (1 H, ddd,
J 15.0, 9.6 and 4.0) and 1.7–0.8 (11 H, m); δC (500 MHz,
(2R*,4S*)-2-Cyclohexyl-4-phenyloxetane 52
Trimethyl orthoacetate (140 µl, 1.10 mmol) and pyridinium
toluene-p-sulfonate (2 mg) were added to a stirred solution
of the diol syn-25 (218 mg, 0.98 mmol) in dichloromethane
(7 ml). The reaction mixture was stirred for 5 minutes at room
temperature, cooled to Ϫ78 ЊC and acetyl bromide (185 µl,
2.50 mmol) was added dropwise. The reaction was stirred for
16 h, quenched with saturated sodium bicarbonate solution,
extracted with dichloromethane (3 × 5 ml), dried (MgSO4),
filtered and evaporated to give a crude product. The crude
product was dissolved in dry dichloromethane (6 ml), cooled
to Ϫ78 ЊC and diisobutylaluminium hydride (2.0 ml of a 1.5 M
solution in dichloromethane, 3.0 mmol) was added. The
reaction was stirred for 1.5 h, saturated aqueous ammonium
chloride added and the reaction mixture filtered through Celite,
eluting with dichloromethane (100 ml). The layers were separ-
ated, the aqueous layer extracted with dichloromethane (3 × 50
ml) and the combined organic extracts were dried (MgSO4),
filtered and evaporated to give a crude product. Analysis of the
crude product by 300 MHz 1H NMR spectroscopy showed that
the hydroxy bromide 51 was present as a >98:2 mixture of
diastereoisomers. The crude product was dissolved in dry THF
(10 ml), sodium hydride (80 mg, 60% dispersion in oil, 2.00
mmol) was added and the reaction was refluxed overnight. The
reaction was quenched with saturated aqueous ammonium
chloride solution, the layers were separated, the aqueous layer
was extracted with dichloromethane (3 × 50 ml) and the
combined organic extracts were dried (MgSO4), filtered and
evaporated to give a crude product which was purified by flash
chromatography, eluting with 10% EtOAc in petrol, to give the
oxetane 52 (55 mg, 26%) as a colourless oil; Rf 0.70 (20% EtOAc
in petrol) (Found: Mϩ Ϫ H, 215.1435; C15H20O requires M Ϫ
H, 215.1435); νmax/cmϪ1 (CDCl3 solution) 2924, 2856, 1451 and
1097; δH (500 MHz, CDCl3) 7.43–7.25 (5 H, m, Ph), 5.66 (1 H,
app t, J 7.8, PhCH), 4.47 (1 H, app q, J 7.9), 2.88 (1 H, dt,
CDCl ) 159.8 (C᎐O), 140.8, 127.7, 127.5, 126.2, 75.6, 50.8
᎐
3
(CBr), 40.8, 40.3, 29.4, 28.7, 25.3 and 25.2 (1 peak missing); m/z
(EI) 278 (Mϩ Ϫ HOCHO, 1%), 245 (M Ϫ Br, 50), 199 (74), 117
(100) and 95 (61).
(1R*,3R*)-Acetic acid 3-bromo-1-cyclohexyl-3-phenylpropyl
ester 38
Acetyl bromide (25 µl, 0.40 mmol) was added to a stirred solu-
tion of the diol syn-25 (22 mg, 0.08 mmol) in dry dichloro-
methane at Ϫ78 ЊC. The reaction mixture was stirred overnight,
poured into saturated aqueous sodium bicarbonate solution,
extracted with dichloromethane (3 × 3 ml), dried (MgSO4),
filtered and evaporated to give the acetoxy bromide 38
(26 mg, >98%; 38:39 91:9) as a colourless oil, spectroscopically
identical to that obtained previously.
Treatment of anti-25 with acetyl bromide
By the same general method, the diol anti-25 (33 mg, 0.12
mmol) gave acetoxy bromides 38 and 39 (37 mg, >98%; 38:39
48:52) as a colourless oil, spectroscopically identical to that
obtained previously.
(1R*,3R*)- and (1R*,3S*)-Acetic acid 3-bromo-1-cyclohexyl-3-
phenylpropyl esters 38 and 39
The diol syn-25 (100 mg, 0.43 mmol) was dissolved in 45%
hydrobromic acid in acetic acid (1 ml, 9.93 mmol). The reaction
mixture was stirred for 40 minutes at room temperature. The
reaction mixture was quenched with water (2 ml) and neutral-
ised with saturated sodium bicarbonate solution. The reaction
mixture was extracted with ether (3 × 30 ml). The combined
organic layers were dried (MgSO4), filtered and evaporated
under reduced pressure to give the crude product which was
720
J. Chem. Soc., Perkin Trans. 1, 2000, 711–722

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J 10.8 and 6.9), 2.31 (1 H, dt, J 10.8 and 8.1), 2.01 (1 H, m) and
1.8–0.8 (10 H, m); δC (500 MHz, CDCl3) 143.9, 128.8, 128.0,
125.8, 82.1, 78.5, 45.4, 35.1, 28.3, 26.8, 26.5, 26.0 and 25.8;
m/z (EI) 215 (Mϩ Ϫ H, 25%), 105 (100) and 77 (45). The relative
stereochemistry was confirmed by the observation of a mutual
NOE between 1-H and 3-H.
were added. The vessel was wrapped in foil and the reaction
stirred for 24 h at 60 ЊC, quenched with water and extracted
with EtOAc (3 × 15 ml). The combined organic extracts were
dried (MgSO4), filtered and evaporated to give a crude product
which was purified by flash chromatography, eluting with 10%
ether in petrol, to give the oxetane 52 (39 mg, 21%) as a colour-
less oil spectroscopically identical to that obtained previously.
Analysis of the crude reaction mixture by 300 MHz 1H NMR
spectroscopy showed the oxetane 52 to be present as a >98:2
mixture of diastereoisomers.
(2R*,4R*)-2-Cyclohexyl-4-phenyloxetane 54
By the same general method, trimethyl orthoacetate (93 µl, 0.73
mmol), pyridinium toluene-p-sulfonate (2 mg), acetyl bromide
(112 µl, 1.52 mmol), the diol anti-25 (142 mg, 0.61 mmol),
methanol (27 µl, 0.67 mmol) and sodium hydride (73 mg, 60%
dispersion in oil, 1.82 mmol) gave a crude product which was
purified by flash chromatography, eluting with 5% ether in
petrol to give the oxetane 54 (80 mg, 51%) as a colourless oil,
spectroscopically identical to that obtained previously.
(2R*,4R*)-2-Cyclohexyl-4-phenyloxetane 54
By the same general method, the diol syn-25 (218 mg, 0.98
mmol gave the oxetane 54 (110 mg, 52%) as a colourless oil;
Rf 0.80 (20% EtOAc in petrol) (Found: Mϩ Ϫ H, 215.1434;
C15H20O requires M Ϫ H, 215.1435); νmax/cmϪ1 (CDCl3 solu-
tion) 2925, 2856, 1451 and 1266; δH (500 MHz, CDCl3) 7.43–
7.25 (5 H, m, Ph), 5.58 (1 H, dd, J 8.5 and 6.2, PhCH), 4.49
(1 H, app q, J 6.2), 2.75 (1 H, ddd, J 14.5, 8.5 and 6.2), 2.56
(1 H, ddd, J 14.5, 8.5 and 6.2), 2.02 (1 H, m) and 1.9–0.8 (10 H,
m); δC (500 MHz, CDCl3) 144.2, 128.8, 127.9, 125.7, 84.2, 80.1,
44.6, 34.4, 28.5, 27.1, 27.0, 25.8 and 25.7; m/z (EI) 215
(Mϩ Ϫ H, 20%), 105 (100) and 77 (50).
(2R*,3S*,4S*)-2-Cyclohexyl-3-methyl-4-phenyloxetane 57
By the same general method, trimethyl orthoacetate (123 µl,
0.98 mmol), the diol 29 (200 mg, 0.81 mmol), pyridinium
toluene-p-sulfonate (2 mg), acetyl bromide (149 µl, 2.02 mmol),
methanol (36 µl, 0.89 mmol) and sodium hydride (97 mg, 60%
dispersion in oil, 2.419 mmol) gave a crude product which was
purified by flash chromatography, eluting with 10% EtOAc in
petrol to give the oxetane 57 (26 mg, 13%) as a colourless oil; Rf
0.70 (20% EtOAc in petrol) (Found: Mϩ Ϫ H, 229.1590; C16-
H22O requires M Ϫ H, 229.1593); νmax/cmϪ1 (CDCl3 solution)
2925, 2856, 1451 and 1267; δH (500 MHz, CDCl3) 7.43–7.26
(5 H, m, Ph), 5.08 (1 H, d, J 6.0, PhCH), 4.43 (1 H, dd, J 10.2,
8.0, CHChex), 2.92 (1 H, app. sextet, J 7.2, CHMe), 2.07–0.71
(11 H, m, Chex) and 1.30 (3 H, d, J 7.2, Me); δH (500 MHz,
CDCl3) 143.3, 128.5, 127.6, 125.3 (Ph), 87.2 (PhCH), 85.2
(CHChex), 40.6 (CHMe), 39.0, 28.3, 26.6, 25.6, 25.5 (Chex) and
14.1 (Me); m/z 229 (Mϩ Ϫ H, 30%) and 77 (100).
Analysis of the crude reaction mixture by 300 MHz 1H NMR
showed that the oxetanes 54 and 52 were present as an 88:12
mixture of diastereoisomers.
(2R*,4S*)-2-Cyclohexyl-4-phenyloxetane 52
Trimethyl orthoformate (280 µl, 2.56 mmol) and pyridinium
toluene-p-sulfonate (2 mg) were added to a stirred solution of
the diol syn-25 (500 mg, 2.14 mmol) in dichloromethane (15
ml). The reaction mixture was stirred for 1.5 h at room temper-
ature, cooled to Ϫ78 ЊC and acetyl bromide (385 µl, 5.34 mmol)
was added. The reaction was stirred for 16 h, quenched with
saturated sodium bicarbonate solution, extracted with dichloro-
methane (3 × 15 ml), dried (MgSO4), filtered and evaporated to
give a crude product. The crude product was dissolved in dry
THF (10 ml), and methanol (95 µl, 2.35 mmol) and sodium
hydride (256 mg, 60% dispersion in oil, 6.41 mmol) were added.
The reaction was stirred for 48 h at 60 ЊC, quenched with water
and extracted with EtOAc (3 × 15 ml). The combined organic
extracts were dried (MgSO4), filtered and evaporated to give a
crude product which was purified by flash chromatography,
eluting with 10% ether in petrol, to give the oxetane 52 (69 mg,
15%) as a colourless oil spectroscopically identical to that
obtained previously.
Acknowledgements
We thank the Nuffield foundation for undergraduate bursaries
(to T. A. and J. H.) and Pfizer and the AstraZeneca Strategic
Research Fund for additional support. Dr Stuart Warriner is
thanked for helpful discussions.
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J. Chem. Soc., Perkin Trans. 1, 2000, 711–722