Synthesis and reactions of enantiopure substituted benzene cis-hexahydro-1,2-diols

Article abstract of DOI:10.1002/adsc.200900818

Enantiopure dis-dihydro-1,2-diol metabolites, obtained from toluene dioxygenase-catalysed dis-dihydroxylation of six monosubstituted benzene substrates, have been converted to their corresponding dis-hexahydro-1,2-diol derivatives by catalytic hydrogenation via their dis-tetrahydro-1,2-diol intermediates. Optimal reaction conditions for total catalytic hydrogenation of the dis-dihydro-1,2-diols have been established using six heterogeneous catalysts. The relative and absolute configurations of the resulting benzene dis-hexahydro-1,2-diol products have been unequivocally established by X-ray crystallography and NMR spectroscopy. Methods have been developed to obtain enantiopure dis-hexahydro-1,2diol diastereoisomers, to desymmetrise a meso-cishexahydro-1,2-diol and to synthesise 2-substituted cyclohexanols. The potential of these enantiopure cyclohexanols as chiral reagents was briefly evaluated through their application in the synthesis of two enantiomerically enriched phosphine oxides from the corresponding racemic phosphine precursors.

Full text of DOI:10.1002/adsc.200900818

FULL PAPERS
DOI: 10.1002/adsc.200900818
Synthesis and Reactions of Enantiopure Substituted Benzene
cis-Hexahydro-1,2-diols
D. R. Boyd,a N. D. Sharma,a M. V. Berberian,a,b K. S. Dunne,c C. Hardacre,a,b,*
M. Kaik,a,c B. Kelly,c J. F. Malone,a S. T. McGregor,a and P. J. Stevensona,*
a
School of Chemistry and Chemical Engineering, Queenꢀs University, Belfast BT9 5AG, U.K.
Fax : (+44)-28-9097-4687; e-mail: c.hardacre@qub.ac.uk or p.stevenson@qub.ac.uk
CenTACat, Queenꢀs University, Belfast BT9 5AG, U.K.
Celtic Catalysts, Nova UCD, University College Dublin, Belfield, Dublin, Ireland
b
c
Received: November 24, 2009; Published online: March 12, 2010
Abstract: Enantiopure cis-dihydro-1,2-diol metabo- developed to obtain enantiopure cis-hexahydro-1,2-
lites, obtained from toluene dioxygenase-catalysed diol diastereoisomers, to desymmetrise a meso-cis-
cis-dihydroxylation of six monosubstituted benzene hexahydro-1,2-diol and to synthesise 2-substituted
substrates, have been converted to their correspond- cyclohexanols. The potential of these enantiopure cy-
ing cis-hexahydro-1,2-diol derivatives by catalytic hy- clohexanols as chiral reagents was briefly evaluated
drogenation via their cis-tetrahydro-1,2-diol inter- through their application in the synthesis of two
mediates. Optimal reaction conditions for total cata- enantiomerically enriched phosphine oxides from the
lytic hydrogenation of the cis-dihydro-1,2-diols have corresponding racemic phosphine precursors.
been established using six heterogeneous catalysts.
The relative and absolute configurations of the re-
sulting benzene cis-hexahydro-1,2-diol products have Keywords: catalytic hydrogenation; chemoenzymatic
been unequivocally established by X-ray crystallog- synthesis; desymmetrization; cis-dihydrodiols; cis-
raphy and NMR spectroscopy. Methods have been hexahydro-1,2-diols; phosphine oxides
Introduction
(>95% ee) in asymmetric allylic hydroxylation and
cyclopropanation reactions.[17] A further range of che-
Over forty years have now elapsed since the first moenzymatically-derived polyhydroxylated 2,2’-bipyr-
report of the isolation and identification of a cis-dihy- idines has recently been used as ligands in the asym-
drodiol bacterial metabolite 2 (R=H) from benzene metric aminolysis of meso-epoxides to yield amino al-
1, (Scheme 1).[1] Recent reviews[2–11] indicate that cohols (>80% ee).[18] Mono- and di-N-oxide deriva-
more than 400 arene cis-dihydrodiol metabolites have tives of chiral 2,2’-bipyridine ligands have also been
been isolated, with most being enantiopure. Despite used as chiral ligands in asymmetric allylation reac-
the wide range of chiral cis-dihydrodiols now avail- tions to yield allyl alcohols in greater than 85% ee.[18]
able, to date, only a very small proportion has been
Two different heterogeneous catalysts have been
used as synthetic precursors and these have generally used in the disproportionation of benzene cis-dihydro-
been utilised in natural product synthesis.[3–16] The rel- diols 2 [R=H, F, Cl, Br, CN, Me, t-Bu, CF3,
ative instability of many arene-cis-dihydrodiols 2 has, CH(OH)CF3] to yield both the corresponding cis-tet-
however, limited their value as synthetic precursors.
rahydrodiols 5 and catechols 4 (Pd-C),[19] and in the
Partial hydrogenation to yield the corresponding partial hydrogenation of halogenated benzene cis-di-
cis-tetrahydrodiols 5 has maintained most of the func- hydrodiols 2 (R=F, Cl, Br, I, CF3) to give the cis-tet-
tionality with a marked improvement in stability. The rahydrodiol derivatives 5 (Rh-Al2O3).[20] However,
potential of substituted cis-tetrahydro-1,2-diol precur- problems were encountered due to the instability of
sors in asymmetric synthesis has been of recent inter- some cis-dihydrodiols, e.g., 2 (R=I),[20] resulting in
est in our laboratories. Thus, chiral 2,2’-bipyridine li- the formation of the corresponding o- or m-phenols 3.
gands, derived from the cis-dihydrodiol metabolites of Improved methods have recently been developed to
chloroquinolines, and the corresponding cis-tetrahy- minimise phenol formation and to optimise the yields
dro-1,2-diols, have recently proved to be useful chiral of cis-tetrahydrodiols 5 from the regioselective cata-
ligands resulting in high enantiomeric excess values
Adv. Synth. Catal. 2010, 352, 855 – 868
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
855

D. R. Boyd et al.
FULL PAPERS
Results and Discussion
Catalytic Hydrogenation to Yield Benzene cis-
Hexahydrodiols 6 and 7
A preliminary screening programme for catalytic hy-
drogenation was undertaken using a Baskerville
multi-cell autoclave reactor containing ten vessels of
10-mL capacity each and a range of heterogeneous
catalysts. Standard reaction conditions were adopted
using the metabolite 2b, derived from toluene 1b, as a
typical cis-dihydrodiol and the products analysed
using GC-MS (Table 1) and identified using NMR
spectroscopy.
Both partial (to yield 5b) and total hydrogenation
(to yield 6b/7b), dehydration (to yield 3b) and dehy-
drogenation (to yield 4b) products were observed
(Scheme 1). In terms of optimal activity and selectivi-
ty for production of the desired benzene cis-hexahy-
drodiols 6b/7b, rhodium on graphite (5% Rh/G) was
generally found to be the preferred catalyst (97%
yield, Table 1).
When a wider range of substituted benzene cis-di-
hydrodiols 2c–2g was studied with these catalysts
under the same reaction conditions, 5% Rh/G was
again found to be the most efficient for the produc-
tion of cis-hexahydrodiols 6c–6e, 6g, and 7c–7e. Al-
though the corresponding cis-tetrahydrodiols 5f and
5h were readily obtained by partial catalytic hydroge-
nation, we did not succeed in producing the corre-
sponding cis-hexahydrodiols (6f/7f or 6h/7h) under
standard conditions. A different catalyst and harsher
conditions were required to produce cis-hexahydro-
diols 6f/7f. Total hydrogenation of the cis-dihydrodiol
2f to yield cis-hexahydrodiol 6f/7f could only be ach-
Scheme 1. Catalytic hydrogenation of cis-dihydrodiols 2 to
yield the corresponding cis-tetrahydro-5 and diastereoiso-
meric cis-hexahydrodiols 6 and 7.
lytic hydrogenation of the corresponding cis-dihydro- ieved by using a Pd/G catalyst, a higher pressure
diols 2 (R=Br, I, unpublished data). (60 bar) and a much longer reaction time (30 h).
While cis-tetrahydrodiols 5 (R=Cl, Br, I), derived Using all of the six catalysts under the conditions
from monosubstituted halobenzenes by partial hydro- specified in Table 1, compound 5h was found to un-
genation of the corresponding cis-dihydrodiols 2, have
proved to be very useful synthetic precursors, relative-
ly little attention has been paid to the corresponding
products obtained from total hydrogenation, i.e.,
Table 1. Relative yields of cis-hexahydrodiols 6b/7b, cis-tet-
rahydrodiol 5b, phenols 3b and catechol 4b derived from hy-
drogen and catalysts supported on graphite (G), after com-
arene cis-hexahydrodiols 6 and 7. Thus, despite the
large number of arene cis-dihydrodiols 2 available, it
was surprising to find that reports of their exhaustive
hydrogenation, to yield cis-hexahydrodiols 6 and 7,
were confined to those derived from toluene 2 (R=
Me),[21–24] and biphenyl 2 (R=Ph).[25] To the best of
our knowledge, none of these chiral cis-hexahydro-
1,2-diols have been used in synthesis. The first com-
prehensive study of the factors that influence the cat-
alytic hydrogenation of substituted benzene cis-dihy-
drodiols 2 to yield the corresponding cis-hexahydro-
diols 6 and 7, and examples of their synthetic value as
chiral auxiliaries or ligands, is discussed herein.
plete conversion of toluene cis-dihydrodiol 2b.
Catalyst
Selectivity [%] (after 6 h of reaction)[a]
(5% wt metal) 6b/7b[b]
5b
3b
4b
Pd/G
Pt/G
Pd-Pt/G
Ir/G
Ru/G
Rh/G
40
60
29
3
32
97
0
46
21
47
91
4
14
9
7
0
0
10
17
6
64
0
3
0
[a]
Reaction conditions: 0.050 g compound 2b, 0.005 g of cat-
alyst, 5 mL methanol, 3 bar of hydrogen pressure, room
temperature, stirring rate 1000 rpm.
[b]
Isomers 6b/7b did not separate during GLC-MS analysis.
856
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 855 – 868

Synthesis and Reactions of Enantiopure Substituted Benzene cis-Hexahydro-1,2-diols
dergo both hydrogenolysis and hydrogenation to give three organic solvents, methanol, toluene and tetrahy-
the unsubstituted achiral benzene cis-hexahydrodiol drofuran. Each solvent resulted in similar activities
6a/7a and unreacted starting diol 5h.
for the hydrogenation of 2b, however, the relative se-
Solvent studies, based on the Rh/G-catalysed hy- lectivity for the corresponding cis-hexahydrodiols 6b/
drogenation of cis-dihydrodiol 2b, were performed in 7b, was 97% with only 3% of phenol 3b and no diol
5b in methanol. In toluene, diol 2b was converted into
the corresponding phenol 3b (8%), cis-tetrahydrodiol
Table 2. Comparison of initial rates and time required for
5b (5%) and cis-hexahydrodiols 6b/7b (87%) after a
total conversion (100%) of cis-dihydrodiols 2a–2g to the cor-
responding cis-tetrahydrodiols 5a–5g and cis-hexahydrodiols
drofuran, 29% of diol 5b was formed together with
6a–6g/7a–7g using a 5% Rh/G catalyst in methanol.
6 h reaction. For the same reaction time, in tetrahy-
2% phenol 3b and cis-hexahydrodiols 6b/7b (69%).
Initial rates ( mMminÀ1)[a]
Conv. Formation
6a–6g/7a–7g
The diastereoselectivity, ratio 6b/7b, showed no signif-
icant variation with these solvents. Based on these re-
sults, a kinetic study of the relative rates of total hy-
drogenation of the corresponding cis-dihydrodiols 2a–
2g with 5% Rh/G in MeOH was carried out using
stirred tank reactors where the gas pressure, hydrogen
uptake, temperature and stirrer rate were controlled
to provide standard conditions; the results obtained
are shown in Table 2 and Figure 1.
The reaction was found to proceed by an initial fast
hydrogenation of the less substituted alkene bond to
give cis-tetrahydrodiols 5a–5g. This was followed by a
significant decrease in the conversion rates of these
intermediates to form the corresponding cis-hexahy-
drodiols 6a–6g/7a–7g. The nature and size of substitu-
Diene
Time (min)
2a–2g
5a–5g
2a
2b
2c
2d
2e
2f
2g
3
90
32.4
17.3
7.1
7.8
–
–
21.6
10.3
0.9
1.1
2.0
–
12.6
7.2
8.1
–
2.3
5.1
600
300
25
30[b]
480
2.5
6.5
1.2
[a]
Reaction conditions: 0.250 g of cis-dihydrodiol 2, 0.025 g
of 5% Rh/G (0.005=Rh/substrate), 50 mL methanol,
3 bar of H2 pressure, 258C, stirring rate of 1400 rpm.
Time required for partial hydrogenation to give com-
pound 5f only.
[b]
Figure 1. Comparison of kinetic profiles for the formation of cis-hexahydrodiols 6a–6e/7a–7e and 6g from the corresponding
cis-dihydrodiols 2a–2e and 2g.
Adv. Synth. Catal. 2010, 352, 855 – 868
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
857

D. R. Boyd et al.
FULL PAPERS
ent R was found to have a significant effect on reac- pure samples of 6c and 7d were isolated by formation,
tion time for total hydrogenation which followed the chromatographic separation, and hydrolysis of the iso-
sequence H>CN>Me>Ph>CH(OH)CF3 >t-Bu> meric mixture of the corresponding monobenzoates
CF3. In general, with increasing steric hindrance asso- 8c/9c or 8d/9d using the reported method for the iso-
ciated with the substituent R, the hydrogenation rate mers 8b/9b (Scheme 1).[22,24]
decreased. This is likely to be due to the adsorption
The relative and absolute configurations of the cis-
geometry being such that the substituent forces the hexahydrodiol derivatives, derived from toluene
substituted double bond away from the surface of the (1S,2R,3R)-6b[24] and biphenyl (1S,2R,3S)-6d,[25] had
catalyst. However, it is evident from these results that been assigned earlier by stereochemical correlation
the difficulty experienced in the total hydrogenation procedures, while the other cis-hexahydrodiols (6c, 6e,
of cis-tetrahydrodiol 5f, to give compounds 6f/7f, 6f and 6g) have not been reported in the literature.
cannot be rationalised as solely due to the steric ef- X-Ray crystallographic analyses of the benzene cis-
fects or on the basis of a simple electronic effect.
hexahydrodiols 6c (as the benzoate derivative 8c), 6e
and 6g (Figure 2) now provide unequivocal evidence
for: (i) the preferred chair conformation having equa-
torial R substituents [t-Bu, CN, CH(OH)CF3] and the
Preferred Conformations and Configurations of
Substituted Benzene cis-Hexahydrodiols 6b–6g/7b–7f
The relative proportions of the two diastereoisomeric
benzene cis-hexahydrodiol products 6a–6g/7a–7f, ob-
tained by hydrogenation, were determined by
1H NMR spectroscopic analysis of the crude reaction
mixtures (Table 3). The signals for H-1 and H-2 in
both diastereoisomers were distinctive and were used
for the quantification of the diastereoisomeric mix-
tures. Proton H-2 had a higher chemical shift than
proton H-1 for compounds 6b–6g; for compounds 7b–
7f, H-1 usually had a higher chemical shift than H-2
with 7d being the only exception to this trend. The
major diastereoisomers 6b, 7c, 6d–6g (80 –>95%)
could be obtained in pure form by fractional crystalli-
sation of the diastereoisomeric mixtures using
hexane-CHCl3 as solvent. Relatively small propor-
tions of the minor diastereoisomers 6c (20%) and 7d
(13%) were formed following hydrogenation of the
corresponding cis-dihydrodiols 2c and 2d. However,
Table 3. Product composition, and vicinal coupling constants
J2,3 of 2,3-cis- (6) and 2,3-trans- (7) hexahydrodiols produced
by total hydrogenation of cis-dihydrodiols 2 with 5% Rh/G
in methanol.
6
%
J2,3 (Hz)
7
%
J2,3 (Hz)
b
c
85
20
87
95
82
>95
2.8
2.9
2.4
3.0
2.9
2.4
b
c
d
e
f
15
80
13
5
18
<5
9.0
11.4
11.4
9.6
d
e
f[a]
g
10.2
[b]
g
–
[a]
[b]
Catalyst 5% Pd/G in methanol at 60 bar.
This isomer was not detected by H NMR spectroscopy.
Figure 2. X-Ray crystal structures for compounds 6e, 6g and
8c.
1
858
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 855 – 868

Synthesis and Reactions of Enantiopure Substituted Benzene cis-Hexahydro-1,2-diols
hydroxy groups on C-1 and C-2 adopting equatorial may contribute to the unexpected outcome of these
and axial positions, respectively, (ii) the 2,3-cis-rela- reactions.
tive configurations for compounds 6c, 6e and 6g with
The effect of an acetonide protecting group on the
À
À
À
the H C-2 C-3 H torsion angle in the range +558 to diastereoselectivity of the reduction was briefly inves-
+668 and (iii) the (1S,2R,3S)-, (1S,2R,3S)-, and tigated. The acetonide 10c, derived from diol 5c, was
(1’R,1S,2R,3R)- absolute configurations for the cis- much less reactive than the parent diol and a much
hexahydrodiols 6c, 6e and 6g, respectively, based on higher hydrogen pressure (40 bar) was required for
the already established absolute configurations of cis- hydrogenation, which occurred from the more accessi-
dihydrodiol precursors 2c, 2e and 2g.[17,26]
ble face to give compound 11c as the major product
Having firmly established the absolute configura- (94%, Scheme 2). Deprotection, followed by recrys-
tions for the diastereoisomers 6b–6e and 6g by stereo- tallization, gave a pure sample of tert-butylbenzene
chemical correlation or X-ray crystallography, cis-hexahydrodiol 6c. The reversal in diastereoselec-
1H NMR analysis of the relative magnitudes of vicinal tivity on hydrogenation in going from the diol 2c to
scalar coupling constants between H-2 and H-3 were the acetonide 10c was gratifying and allowed easy
examined to confirm the conformation in solution access to both diastereoisomers 6c and 7c by hydroge-
and to correlate the known relative configurations to nation procedures. It should be noted that the tert-
the, as yet unknown, relative configuration of 6f butyl substituent was unique in hydrogenation of a
(Table 3).
cis-dihydrodiol substrate 2c to give the 2,3-trans dia-
In the pure diastereoisomers 6b–6g the vicinal cou- stereoisomer 7c as the major product. The reversal in
pling constants (J2,3) between the H atoms on C-2 diastereoselectivity was not observed during hydroge-
(equatorial) and C-3 (axial) were readily measured by nation of the other cis-tetrahydro-1,2-diol acetonides,
analysis of the multiplets corresponding to H-2 and having smaller substituents. In these cases both the
these were within the range (2.4–3.0 Hz) indicative of diols and acetonides gave the 2,3-cis-diols 6 as the
a cis-relationship between the substituent and the hy- major product, with comparable diastereoselectivities,
droxy group. These values were also consistent with on hydrogenation followed by deprotection of the
the torsion angles (+558 to +598) between the vicinal acetonide group.
H atoms on C-2 and C-3 as observed from the X-ray
In the hydrogenation of 2,3-dimethylcyclohexenes
crystal structures of 8c, 6e and 6g. Conversely com- either cis or trans diastereoisomers may be the pre-
pounds (7b–7f) showed much larger coupling con- dominant product depending on the catalyst and the
stants (J2,3 =9.0–11.4 Hz) as anticipated for a diaxial hydrogen pressure. These results can be rationalised
relationship and a dihedral angle of ca. 1808 between using the Horiuti–Polanyi model.[29] In this model the
vicinal protons on C-2 and C-3 in a trans relationship. alkene and hydrogen are separately chemisorbed onto
With all structures and NMR spectra unambiguous- the catalyst surface and hydrogenation then proceeds
ly assigned, some comment on formation of benzoates in a stepwise manner by replacing the carbon-metal
8c, 8d and 9c, 9d is warranted. Initially it was assumed bonds with carbon-hydrogen bonds. When alkene
that the hydroxy group on C-1 would be the most re- chemisorption is rate-determining this leads to the
active due to its distance from substituent R. This cis-diastereoisomer.[30] The rationale for this is that
indeed turned out to be the case with diastereoiso- alkene-catalyst binding preferentially occurs from the
mers 6b (or 6c) giving 8b (or 8c), respectively. How- face opposite to the 3-substituent and, on hydrogena-
ever, with diastereoisomers 7b (or 7c) the chemose- tion, the 2-substituent ends up cis to the 3-substituent,
lectivity between the two hydroxy groups reversed
and the hydroxy group at C-2 was selectively benzoy-
lated to give diastereoisomers (9b or 9c). This was ob-
1
vious from the H NMR spectrum where the chemical
shift of H-2 increased in value and was confirmed fur-
ther by nOe difference spectroscopy. Hence satura-
tion of the methyl groups within the tert-butyl group
of 9c gives nOe enhancements of 14.4% to H-2, and
9.0% to the ortho-proton on the aromatic ring, con-
firming the assignment. It initially seemed odd that
the C-2 hydroxy, in close proximity to the bulky tert-
butyl group, should be the more reactive than the hy-
droxy on C-1. However, it is well documented that in
reactions which lead to an increase in steric strain the
groups in equatorial positions react faster than groups
in axial positions.[27,28] In compounds 7b (or 7c) the
hydroxy groups on C-2 are indeed equatorial and this Scheme 2. Synthesis of 2,3-cis-hexahydrodiol 6c.
Adv. Synth. Catal. 2010, 352, 855 – 868
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
859

D. R. Boyd et al.
FULL PAPERS
i.e., the thermodynamically less stable diastereoiso- 7c. Another complicating factor, in all of these hydro-
mer. It should be noted that this classical model is genations, is that internal polar groups may have an
over simplistic in that it ignores the additional inter- attractive interaction with the heterogeneous catalyst
nal torsional and angle strain caused by the conforma- surface and guide chemisorption towards the most
tional reorganisation in the substrate on chemisorp- hindered face, with alcohols being particularly effec-
tion.[31,32] In cases where reduction of the ꢂhalf hydro- tive in that respect.[36] The effect of this complication
genatedꢀ intermediate becomes rate-limiting, all prior may be reduced in a polar solvent, such as methanol,
intermediates in the catalytic cycle can equilibrate due to solvation effects but nevertheless may still in-
leading ultimately to the thermodynamically more fluence the chemisorption geometry.
stable trans-diastereoisomer on hydrogenation.[33]
While total catalytic hydrogenation of the enantio-
Herein, in the hydrogenation of dienes 2b–2g, in all pure arene cis-dihydrodiols 2b–2g gave the corre-
examples, with the exception of diene 2c which has a sponding arene cis-hexahydrodiols 6b–6g and 7b–7f,
tert-butyl group, there is a marked preference for for- having three (or four) chiral centres, under similar
mation of the 2,3-cis diastereoisomer 6. For the conditions, compound 2h gave only the parent achiral
dienes which follow this general trend, alkene chemi- benzene hexahydrodiol 6a. The possibility of transfer-
sorption is likely to be the rate-determining step in ring the chirality, originally present in the cis-dihydro-
the hydrogenation. X-ray crystallographic studies of diol metabolite of chlorobenzene 2h, into a desym-
the structures of cis-dihydrodiol 2g,[26,34] and 2,3-cis- metrised form of the parent cis-hexahydrodiol 6a was
hexahydrodiol derivatives 6e and 6g (Figure 2), show examined. The cis-tetrahydrodiol 5h, obtained earlier
the OH group on C-2 in a pseudoaxial or axial posi- by partial hydrogenation of compound 2h,[19] was con-
tion. This is also likely to be an indication of the con- verted mainly to a mixture of the corresponding
formational preference in solution. On the assump- monoACHTUNTRGNEUNGbenzyl ethers 12h:13h (4:1) using benzyl bro-
tion that the catalytic hydrogenation of the monosub- mide and NaH in DMF. This mixture was readily sep-
stituted benzene cis-dihydrodiols 2b–2g proceeds en- arated by PLC, (Scheme 3). The structures of 12h and
tirely via the corresponding cis-tetrahydrodiols 5b–5g, 13h were assigned by NMR spectroscopy. The posi-
the marked preference for the 2,3-cis-diastereoiso- tion of O-benzylation was confirmed both by nOe dif-
mers 6b, 6d–6g may be due to the delivery of hydro- ference spectroscopy and HMBC correlations. It is
gen to the less hindered alkene face opposite to the noteworthy that, under these conditions, the sterically
pseudoaxial hydroxy group (Figure 3).
hindered pseudo axial hydroxy on C-2 was more reac-
The reversal in diastereoselectivity during hydroge- tive than the hydroxy on C-1. Since this reaction was
nation of the tert-butyl-substituted diol (2c) was intri- base-mediated, a possible explanation for the ob-
guing and out of line with the other examples. Clearly served selectivity may be due to the difference in the
the size of the substituent is playing a role. It is note- pKa values between the allylic and homoallylic alco-
worthy that in the catalytic hydrogenation of 2-alkyl- hols. In general, as a result of the increased electrone-
phenols, to yield 2-alkylcyclohexanols, the tert-butyl- gativity of the unsaturated substituent, the pKa values
phenol also gives the opposite diastereoselectivity to of alcohols, in which the OH group is adjacent to an
the methylphenol,[35] indicating that the size of the alkene group, are lower than those of the correspond-
substituent can reverse diastereoselectivity. Formally ing saturated alcohols.[37]
hydrogen has added from the more hindered face of
Hydrogenolysis and hydrogenation of compounds
alkene to give the thermodynamically more stable 12h and 13h using a Pd/C catalyst in methanol yielded
2,3-trans-diastereoisomer 7c as the major product. It the corresponding enantiomers (1S,2R)-14a and
appears that in this case chemisorption of the alkene (1R,2S)-14a as desymmetrised derivatives of the
is not rate-determining and that equilibration of the parent cis-hexahydrodiol 6a. These enantiomers
initially chemisorbed adducts ultimately leads to diol proved to be indistinguishable from those obtained
Figure 3. Preferred conformations during hydrogenation of cis-tetrahydrodiols 5 to yield 2,3-cis-6 and 2,3-trans-hexahydro-
diols 7.
860
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 855 – 868

Synthesis and Reactions of Enantiopure Substituted Benzene cis-Hexahydro-1,2-diols
the less hindered axial oxygen on C-1 was selectively
tosylated to give the desired regioisomers 16c, 16d.
Reductive removal of the tosylate group by treatment
with lithium aluminium hydride yielded the corre-
sponding enantiopure cyclohexanols 17c, 17d, 18c,
and 18d in three steps from the corresponding cis-di-
hydrodiols 2c and 2d.
The structural similarity between enantiopure cy-
clohexanols 17c, 17d, 18c, 18d and menthol (2-isopro-
pyl-5-methylcyclohexanol) prompted us to briefly
compare their potential as chiral auxiliaries in the for-
mation of P-chiral phosphine oxides (S)-21, (R)-21
and (S)-22, (R)-22 from the corresponding racemic
phosphines (19 and 20) via a process of dynamic ki-
netic resolution (Scheme 5). The process was carried
Scheme 3. Conversion of cis-tetrahydrodiol 5h to cis-hexahy-
drodiol derivatives (1S,2R)-14a and (1R,2S)-14a).
earlier via a stereoselective lipase-catalysed acylation
of the benzyl ethers.[38]
Synthesis of 2-substituted cyclohexanols (1S,2S)-
17c, (1S,2S)-17d, (1S,2R)-18c and (1S,2R)-18d was un-
dertaken as part of our programme to investigate the
potential of enantiopure arene cis-dihydrodiols 2, and
derivatives, e.g., cis-tetrahydrodiols 5 and phenols 3
as precursors of chiral ligands[17,18,39] scaffolds,[40] re-
solving agents[34] and now, auxiliaries, (Scheme 3 and
Scheme 4).
The cis-hexahydrodiols 6c, 6d, 7c, and 7d were con-
verted to the corresponding monotosylates 15c, 15d,
16c, and 16d using the method of Martinelli[41] which
employed a catalytic quantity of Bu2SnO and was re-
ported to be chemoselective for monotosylation.
Good yields (80–85%), after purification by PLC,
were obtained. It is well known that in the stoichio-
metric reaction of preformed cyclic stannylene acetals
the equatorial oxygen is more reactive towards elec-
trophiles than the axial oxygen[42–45] and as expected
the tosylates 15c, 15d were the major products de-
rived from diols 6c, 6d. However, surprisingly, on re-
Scheme 5. Enantioselective synythesis of chiral phosphine
oxides (S)-21/(R)-21 and (S)-22/(R)-22 from the correspond-
action of diols 7c, 7d, under the Martinelli conditions, ing racemic phosphines 19 and 20
Scheme 4. Conversion of 2,3-cis- (6c or 6d) and 2,3-trans-hexahydrodiols (7c or 7d) into 2-substituted cyclohexanols (17c or
17d; 18c or 18d).
Adv. Synth. Catal. 2010, 352, 855 – 868
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
861

D. R. Boyd et al.
FULL PAPERS
out using essentially the same method that was re- comparable ee for phosphine oxide 21 (68%) and a
cently reported.[46]
superior ee value (80%) for phosphine oxide 22.
A mechanism for this reaction, involving the initial
stereoselective formation of one of two rapidly equili-
brating pentacoordinate phosphorus intermediates Conclusions
(phosphoranes), followed by their collapse to yield
preferentially one of the two diastereoisomeric alkox- This study has shown that optimal conditions have
yphosphonium salts and the resulting phosphine oxide been obtained for the total hydrogenation of a range
enantiomers (R/S)-21 or (R/S)-22, has been pro- of cis-dihydrodiol metabolites of monosubstituted
posed.[46]
benzene substrates (2b–2g) to yield the corresponding
The racemic phosphines, phenyl-ortho-tolylmethyl- cis-hexahydrodiol diastereoisomers (6b–6g and 7b–
phosphine 19 and phenyl-ortho-anisylmethylphos- 7f). The monohalogenated benzene cis-dihydrodiol 2h
phine 20, were available from the earlier studies[46] was partially hydrogenated to yield the cis-tetrahydro-
where optimal stereoselectivity in phosphine oxide diol 5h. This compound was in turn protected as the
synthesis was observed (Scheme 5), using (1S,2S,5R)- corresponding monobenzyl ethers (12h and 13h)
menthol as the chiral secondary alcohol and the which were separated and hydrogenolysed/hydrogen-
oxygen atom source. The comparative results ob- ated to yield the desymmetrised enantiomers
tained using (1S,2S,5R)-menthol, and the chemoenzy- [(1S,2R)-14a and (1R,2S)-14a] of benzene cis-hexahy-
matically-derived 2-substituted cyclohexanols 17c, drodiol 6a.
17d, 18c and 18d, under standard reaction conditions
(<À788C in a solution of hexachloroacetone in tolu- three steps to the corresponding 2-substituted cyclo-
ene), are shown in Table 4. hexanols 17c, 17d, 18c and 18d. These cyclic monols,
The cis-dihydrodiols 2c and 2d were converted in
The dramatic effect of substituent selection on ste- obtained by chemoenzymatic synthesis, have been
reoselectivity is evident from replacement of the tert- used as chiral reagents in a dynamic kinetic resolution
butyl group (18c) with a phenyl group (18d) where a process to yield the enantioenriched P-chiral phos-
marked decrease in ee value was observed.
phine oxides (e.g., 21 and 22) having potential value
The wide range of results (16–80% ee), shown in in chiral ligand synthesis.
Table 4, emphasises the importance of the structure of
the chiral secondary alcohol on both the enantiopuri-
ty and absolute configurations of the phosphine oxide
Experimental Section
products. Thus the standard for comparison, (À)-men-
thol, provided optimal stereoselectivity during the for-
1H NMR and 13C NMR spectra were recorded on Bruker
mation of phenyl-ortho-tolylmethylphosphine oxide
21 (70% ee). In general the alcohols in which the
alkyl/aryl and hydroxy groups were in cis positions,
e.g., alcohols 17c and 17d, gave phosphine oxides with
Avance DPX-300 and DRX-500 instruments and mass spec-
tra were run at 70 eV, on an AE1-MS90 mass spectrometer
updated by VG Autospec, using a heated inlet system. Ac-
curate molecular weights were determined, by the peak
poor ee values. Of the 2-substituted cyclohexanols matching method, with perfluorokerosene as standard. Ele-
mental microanalyses were carried out on a Perkin–Elmer
2400 CHN microanalyser. For optical rotation ([a]D) meas-
urements (ca. 208C, 10À1 deg cm2 gÀ1) a Perkin–Elmer 214
polarimeter was used. Flash column chromatography and
PLC were performed on Merck Kieselgel type 60 (250–400
mesh) and PF254/366, respectively. Merck Kieselgel type 60F254
analytical plates were used for TLC. Samples of cis-dihydro-
diols 2a–2h,[26] cis-tetrahydrodiols 5c and 5h,[19,20] and the
phosphines 22 and 23[46] were available from earlier studies.
The cis-dihydrodiols 2a–2h had earlier been established as
single enantiomers, i.e., enantiopure, (>98% ee) by
CSPHPLC and NMR analysis methods.[26] All catalysts were
obtained from Johnson Matthey. For the heterogeneously
catalysed hydrogenations, the reactions were monitored by
evaluated, compound trans-18c, derived from the
major diastereoisomer 7c (Table 3), was structurally
most similar to ent-(+)-menthol. The stereochemistry
of the secondary alcohol controls the configuration at
phosphorus and, not surprisingly, the stereoselectivity
was opposite to that found using (À)-menthol, with a
Table 4. Enantiopurity values (% ee) and absolute configu-
rations of phosphine oxides 21 and 22.
Cyclic alcohol
Phosphine oxide, ee and absolute con-
1
figuration %
regular sample analysis using H NMR, GC (Hewlett Pack-
21
22
ard 6890 instrument fitted with a ZB-5 column 30 m,
0.25 mm diameter) and GC-MS (Perkin–Elmer Clarus 500
instrument with a PE-5MS column 30 m, 0.25 mm diameter).
The percentage of conversion/selectivity was determined by
comparing the retention times with known standards, using
a calibration plot for each product and reactant. The stan-
dard solutions in methanol were prepared at known concen-
A
E
E
ACHTUNGTRENNUNG
66 (R)
38(S)
80 (S)
18 (S)
20 (S)
ACHTUNGTRENNUNG
862
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 855 – 868

Synthesis and Reactions of Enantiopure Substituted Benzene cis-Hexahydro-1,2-diols
trations and peak responses were plotted as a function of
concentration leading to linear plots. All the reactions were
performed in duplicate and the results averaged. Research
grade hydrogen was supplied by BOC.
Typical Conditions for Catalytic Hydrogenation of
cis-Dihydrodiols 2b–2g to Yield cis-Hexahydrodiols
6b–6g and 7b–7f
Diols 2b–2e, 2g were hydrogenated to give the correspond-
ing substituted benzene cis-hexahydrodiols 6b/7b–6e/7e and
6g using the conditions given in Table 2 (5% Rh/G, MeOH,
3 bar H2, 1400 rpm). Hydrogenation of compound 2f to
yield the cis-hexahydrodiols 6f/7f required the use of a 5%
Pd/G catalyst, MeOH solvent, and hydrogen under higher
pressure (60 bar). Yields of cis-hexahydrodiols obtained
after hydrogenation were generally >95% by GLC analyses.
General Procedure for the Heterogeneous Catalysed
Hydrogenations of 3-Substituted Benzene cis-
Dihydrodiols 2a–2g
Screening experiments were conducted using a Baskerville
multi-cell autoclave reactor at room temperature and 3 bar
of hydrogen pressure. Catalyst (0.005 g), substrate (0.050 g)
and solvent (5 mL) were added to each reaction vessel. The
autoclave was purged with hydrogen gas and the pressure
was set to 3 bar. The catalytic runs were carried out with
continuous stirring (1000 rpm) for 6 h. At the end of each
experiment, the reaction mixture was filtered to remove the
catalyst and to stop further reaction. The sample was subse-
quently analysed by 1H NMR spectroscopy and GC.
AHCTUNGTREG(NNUN 1S,2R,3R)-3-Methylcyclohexane-1,2-diol (6b): Major dia-
stereoisomer (85%); viscous oil; [a]D: À25 (c 1.1, CHCl3),
1
(Lit.[22] [a]D: À25, CHCl3); H NMR (500 MHz, CDCl3): d=
0.84 (3H, d, J=6.8 Hz, Me), 1.08–1.14 (2H, m, 5-H), 1.34–
1.37 (2H, m, 4-H), 1.49–1.51 (2H, m, 6-H), 1.87 (1H, ddd,
J=2.8, 5.3, 9.1 Hz, 3-H), 2.25 (2H, bs, OH), 3.38 (1H, ddd,
J=2.8, 5.8, 11.4 Hz, 1-H), 3.58 (1H, t, J=2.8 Hz, 2-H); MS
(EI): m/z=130 (M+, 20%), 112 (67), 97 (100), 71 (63).
AHCTUNGTREG(NNUN 1S,2R,3S)-3-Methylcyclohexane-1,2-diol (7b): Minor dia-
Kinetic Studies
stereoisomer (15%); viscous oil; [a]D: +27 (c 0.8, CHCl3)
1
(Lit.[21] [a]D: +35, CHCl3); H NMR (500 MHz, CDCl3): d=
Reaction kinetic experiments were performed in a stirred
tank reactor. The reactor was heated to 258C, and the
system purged with hydrogen. The hydrogen pressure was
maintained at 3 bar and the stirrer set at 1400 rpm. These
parameters were kept throughout the experiment. Under
these conditions, the reactions were under kinetic control.
All the reactions were performed in duplicate and the re-
sults averaged.
0.98 (3H, d, J=6.5 Hz, Me), 1.06–1.51 (6H, m, 4-H, 5-H, 6-
H), 1.87 (1H, m, 3-H), 3.20 (1H, dd, J=3.0, 9.0 Hz, 2-H),
3.95 (1H, m, 1-H).
Synthesis of the Monobenzoates 8c, 8d, 9c and 9d
The monobenzoates were synthesised by a general proce-
dure involving treatment of the mixture of corresponding
cis-hexahydrodiols 6c, 6d, 7c, and 7d (1.88 mmol) in pyridine
(ca. 2 mL) with 239 mL (2 mmol) benzoyl chloride. The mix-
ture was stirred for 12 h, the pyridine removed under re-
duced pressure, and the residue purified by PLC (EtOA-
c:hexane, 1:4) to give pure samples of two monobenzoate
isomers.
Aliquots of the reaction (approximately 0.5 mL) were reg-
ularly removed to monitor the reactant/products distribution
with time. In each case the sample was removed from the
reaction medium, filtered to extract the catalyst and subse-
quently analysed by GC and GC-MS. In addition, at the end
of each experiment, the composition of the reaction mixture
1
was analysed by H NMR spectroscopy.
AHCTUNGTREG(NNUN 1S,2R,3S)-1-Benzoyloxy-3-tert-butyl-2-hydroxycyclohex-
ane (8c): Using the general procedure cis-hexahydrodiol 6c
was converted to the corresponding monobenzoate 8c;
yield: 16%; mp 95–978C (EtOAc/hexane); [a]D: +7 (c 0.82,
CHCl3); HR-MS: m/z=276.1707, calcd. for C17H24O3 (M+):
276.1725; 1H NMR (300 MHz, CDCl3): d=0.95 (9H, s,
CMe3), 1.84–2.08 (3H, m, 4-H, 6-H), 4.32 (1H, t, J=2.6 Hz,
2-H), 4.98 (1H, ddd, J=13.3, 5.0, 2.6 Hz, 1-H), 7.45 (2H, t,
J=8.0 Hz, Ar-H), 7.58 (1H, t, J=8.0 Hz, Ar-H), 8.06 (2H,
d, J=8.0 Hz, Ar-H); 13C NMR (125 MHz): d=20.3, 24.3,
25.5, 3ꢃ29.1, 30.1, 33.1, 50.4, 69.9, 2ꢃ128.8, 2ꢃ130.0, 130.8,
133.4, 166.0; MS (I): m/z=276 (M+., 2%), 261 (3), 154.13
(47), 105 (100), 98 (95).
Characterisation of the 3-Substituted Cyclohexene
and Cyclohexane-cis-diols
cis-Cyclohexenediols 5a (R=H), 5b (R=Me), 5c (R=t-Bu),
5e (R=CN), 5f (R=CF3), 5g [R=CH(OH)CF3], 5h (R=
Cl), generated by the heterogeneous catalysed hydrogena-
tions of the corresponding 3-substituted benzene cis-dihy-
drodiols 2 showed identical GC-MS and spectroscopic char-
acteristics to those reported earlier.[19] Compound 5d was
obtained by partial hydrogenation of the corresponding cis-
dihydrodiol 2d using 3% Pd/C in EtOAc solvent under H2;
1
its H NMR was identical to the reported spectrum.[47]
Isomers 6c or 6d, 7c or 7d obtained pure, after separation
from diastereoisomeric mixtures of monobenzoates, were
fully characterised. Compounds 6e–6g were purified by crys-
tallisation and the minor isomers 7e, 7f were only identified
by 1H NMR analysis of the enriched mixtures and com-
pound 7g was not observed in any hydrogenation experi-
ments. Cyclohexane-1,2-diol 6a was commercially available
while compounds 6b and 7b had been reported earlier.[22]
Crystal data for 8c: C17H24O3, M=276.4, monoclinic, a=
8.967(2), b=5.847(1), c=15.058(4) ꢄ, b=94.21(1)8, U=
787.4(3) ꢄ3, T=293(2) K, Mo-Ka radiation, l=0.71073 ꢄ,
space group P21 (no. 4), Z=2,
FACTHNGUTERNUN(G 000)=300, Dx =
1.166 gcmÀ3, m=0.08 mmÀ1, Bruker SMART diffractometer,
f/w scans, 2.78<2q<56.18, measured/independent reflec-
tions: 7698/3273, direct methods solution, full-matrix least
2
squares refinement on Fo , anisotropic displacement parame-
ters for non-hydrogen atoms; hydrogens located in a differ-
ence Fourier synthesis but included at positions calculated
from the geometry of the molecules using the riding model,
with isotropic vibration parameters. Final R1 =0.058 for
2490 data with Fo > 4s(Fo), 185 parameters, wR2 =0.130 (all
Adv. Synth. Catal. 2010, 352, 855 – 868
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
863

D. R. Boyd et al.
FULL PAPERS
data), GoF=1.17, D1min,max =À0.12/0.20 eꢄÀ3. CCDC
737846 contains the supplementary crystallographic data for
this compound. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
85–868C);[21] [a]D: +65 (c 1.1, MeOH); (Lit. [a]D: +53 and
+73, MeOH);[21] 1H NMR (300 MHz, CDCl3): d=1.25–1.40
(2H, m, 5-H), 1.40–1.70 (2H, m, 4-H), 1.71–1.92 (2H, m, 6-
H), 2.61 (1H, ddd, J=2.1, 3.3, 10.8 Hz, 3-H), 3.59 (1H, ddd,
J=2.1, 4.8, 11.5 Hz, 1-H), 3.93 (1H, t, J=2.4 Hz, 2-H), 7.23–
7.35 (5H, m, Ar); 13C NMR (125 MHz): d=23.81, 24.01,
28.84, 47.56, 72.85, 74.28, 126.98, 127.36, 128.28, 143.36.
ACHTUNGTRENNUNG(1S,2R,3R)-2-Benzoyloxy-3-tert-butyl-1-hydroxycyclohex-
ane (9c): White crystalline solid; yield: 65%; mp 117–1188C
(EtOAc/hexane); [a]D: + 68 (c, 1.08, CHCl3); HR-MS: m/
AHCTUNGTREG(NNUN 1S,2R,3R)-3-tert-Butylcyclohexane-1,2-diol (7c): White
crystalline solid; yield: 80%; mp 74–768C (Et2O/hexane);
1
z=276.1723, calcd. for C17H24O3 (M+): 276.1725); H NMR
(500 MHz, CDCl3): d=0.95 (9H, s, CMe3), 1.11 (1H, qd, J=
12.8, 4.0 Hz, 5-Hax), 1.54 (2H, 2m, 5-H, 4-H), 1.68 (1H, m,
6-H), 1.93 (2H, 2m, 4-H, 6-H), 2.01 (1H, td, J=11.4, 3.8 Hz,
3-H), 4.11 (1H, m, 1-H), 5.13 (1H, dd, J=10.9, 2.5 Hz, 2-H),
7.45(2H, t, J=7.9 Hz, Ar-H), 7.58 (1H, t, J=7.9 Hz, Ar-H),
8.09 (2H, d, J=7.9 Hz, Ar-H); 13C NMR (125 MHz): d=
19.8, 26.8, 3ꢃ29.5, 31.3, 33.0, 44.5, 69.7, 78.3, 2ꢃ128.9, 2ꢃ
130.2, 130.7, 133.6, 165.8.
[a]D: +39 (c 0.9, CHCl3); HR-MS: m/z=172.1461, calcd. for
1
C10H20O2 (M+): 172.1463; H NMR (500 MHz, CDCl3): d=
0.99 [9H, s, C(Me)3], 1.12 (1H, m, 5-H), 1.40–1.60 (4H, m,
4-H, 5-H, 6-H), 1.70 (2H, m, 6-H), 1.80 (1H, m, 3H), 2.28–
2.12 (2H, bs, OH), 3.52 (1H, ddd, J=2.8, 4.8, 11.5 Hz, 2-H),
3.95 (1H, q, J=2.9 Hz, 1-H); 13C NMR (125 MHz): d=
20.04, 26.37, 28.63, 31.75, 33.13, 47.08, 72.24, 74.98; MS (EI):
m/z=172 (M+, 12%), 157 (M+ÀMe, 30), 154 (M+ÀH2O, 5),
98 (100).
ACHTUNGTRENNUNG(1S,2R,3S)-1-Benzoyloxy-2-hydroxy-3-phenylcyclohexane
(8d): White crystalline solid; yield: 82%; mp 118–1228C
(EtOAc/hexane); [a]D: +8 (c 0.5, CHCl3); HR-MS: m/z=
296.1400, calcd. for C19H20O3 (M+): 296.1412; 1H NMR
(500 MHz, CDCl3): d=1.52–1.60 (3H, m, 4-H, 5-H,), 1.91–
2.17 (3H, m, 4-H, 6-H), 2.85 (1H, dt, J=12.9, 2 Hz, 3-H),
4.23 (1H, m, 2-H), 5.18 (1H, dq, J=11.5, 2.6 Hz, 1-H), 7.23–
7.56 (8H, m, Ar-H), 8.06 (2H, d, J=7.3 Hz, Ar-H);
13C NMR (125 MHz): d=23.9, 24.0, 25.3, 47.4, 72.4, 76.6,
127.1, 2ꢃ128.4, 4ꢃ128.8, 2ꢃ130.0, 130.8, 133.7, 143.1, 166.5;
MS (EI): m/z=296.14 (M+., 18%), 278.13 (100), 279.13 (22).
AHCTUNGTREG(NNNU 1S,2R,3R)-3-Phenylcyclohexane-1,2-diol (7d): White
solid; yield: 13%; mp 95–978C (EtOAc/hexane), (Lit.[25] mp
90–918C); [a]D: +50 (c 0.50, MeOH); (Lit. [a]D: À75 (ent),
1
and +81, MeOH)[25]; H NMR (300 MHz, CDCl3): d=1.55–
1.58 (2H, m, 5-H), 1.76–177(2H, m, 4-H), 2.05–2.10 (2H, m,
6-H), 2.91 (1H, ddd, J=11.4, 11.0, 3.5 Hz, 3-H), 3.67 (1H,
m, 1-H), 4.11 (1H, dd, J=2.8, 11.4 Hz, 2-H), 7.24–7.35 (5H,
m, Ar); 13C NMR (125 MHz): d=22.71, 23.48, 28.12, 46.31,
71.91, 75.16, 126.98, 127.36, 128.28, 143.36.
AHCTUNGTREG(NNUN 1S,2R,3S)-3-Cyanocyclohexane-1,2-diol (6e): Colourless
ACHTUNGTRENNUNG(1S,2R,3R)-2-Benzoyloxy-1-hydroxy-3-phenylcyclohexane
crystalline solid; yield: 90%; mp 135–1378C (CHCl3/
hexane); [a]D: À7 (c 1.02, MeOH); HR-MS: m/z=141.0776,
calcd. for C7H11NO2 (M+): 141.0790); 1H NMR (500 MHz,
CDCl3): d=1.20 (1H, m, 5-H), 1.55–1.65 (3H, m, 6-H, 6’-H,
4-H), 1.72 (1H, m, 5’-H), 1.80 (1H, m, 4-H), 2.16 (1H, s br,
OH), 2.59 (1H, ddd, J=3.8, 7.0, 10.7 Hz, 3-H), 2.76 (1H, s
br, OH), 3.54 (1H, ddd, J=3.0, 4.8, 8.5 Hz, 1-H), 3.94 (1H,
dd, J=3.0 3.8 Hz, 2-H); 13C NMR (125 MHz, CDCl3): d=
21.48, 24.05, 28.69, 33.81, 69.33, 70.58, 120.69; IR (KBr):
nmax =3307.06 (OH), 2248.3 cmÀ1 (CN); MS (EI): m/z=141
(M+., 14%), 70 (100).
(9d): Colourless crystalline solid; yield: 18%; mp 120–1268C
(EtOAc/hexane); [a]D: +92 (c 0.6, CHCl3); HR-MS: m/z=
296.1400, calcd. for C19H20O3 (M+): 296.1412; 1H NMR
(500 MHz, CDCl3): d=1.61–1.76 (3H, m, 4-H, 5-H), 1.84–
2.08 (3H, m, 4-H, 6-H), 3.37 (1H, td, J=11.8, 3.4 Hz, 3-H),
4.43 (1H, q, J=1.8 Hz, 1-H), 5.28 (1H, dd, J=11.5, 2.7 Hz,
2-H), 7.12–7.41 (4H, m, Ar-H), 7.80 (2H, d, J=7.7 Hz, Ar-
H); 13C NMR (125 MHz): d=19.8, 31.5, 33.9, 43.3, 68.5,
79.2, 126.9, 2ꢃ128.0, 2ꢃ128.7, 2ꢃ128.8, 2ꢃ129.9, 130.4,
133.3, 143.1, 166.3; MS (EI): m/z=296.14 (100).
Crystal data for 6e: C7H11NO2, M=141.2, orthorhombic,
a=6.609(1), b=10.432(2), c=21.956(4) ꢄ, U=1513.8(5) ꢄ3,
T=293(2) K, Cu-Ka radiation, l=1.54178 ꢄ, space group
General Procedure for the Hydrolysis of
Monobenzoates 8c, 8d and 9c, 9d
P212121 (no. 19), Z=8, FACHTNUTGRNEUNG
(000)=608, Dx =1.239 gcmÀ3, m=
0.75 mmÀ1, Siemens P3 diffractometer, w scans, 8.08<2q<
110.08, measured/independent reflections: 7824/1891, direct
methods solution, full-matrix least squares refinement on
A solution of monobenzoate (0.23 mmol) in a mixture of
water (0.5 mL) and MeOH (5 mL) was stirred with K2CO3
(0.5 g) at room temperature for 12 h. The solvents were re-
moved under reduced pressure, the residue extracted with
EtOAc (20 mL) and the extract concentrated. Purification
of the concentrate by PLC (EtOAc:hexane, 1:1) yielded the
corresponding cis-hexahydrodiols 6c, 6d, 7c,7d.
2
Fo , anisotropic displacement parameters for non-hydrogen
atoms; hydrogens located in a difference Fourier synthesis
but included at positions calculated from the geometry of
the molecules using the riding model, with isotropic vibra-
tion parameters. The asymmetric unit consists of two crystal-
lographically independent, but configurationally equivalent,
molecules. Final R1 =0.042 for 1758 data with Fo > 4s(Fo),
186 parameters, wR2 =0.113 (all data), GoF=1.11,
D1min,max =À0.10/0.21 eꢄÀ3. CCDC 737844 contains the sup-
plementary crystallographic data for this compound. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
ACHTUNGTRENNUNG(1S,2R,3S)-3-tert-Butylcyclohexane-1,2-diol (6c): White
crystalline solid; yield: 20%; mp 76–788C (Et2O/hexane);
[a]D: +4.0 (c 0.80, CHCl3); HR-MS: m/z=172.1462, calcd.
1
for C10H20O2 (M+): 172.1464; H NMR (500 MHz, CDCl3):
d=0.98 [9H, s, C(Me)3], 1.12–1.90 (6H, m, 4-H, 5-H, 6-H),
1.70–1.80 (1H, m, 3-H), 3.49 (1H, td, J=3.0, 11.4 Hz, 1-H),
4.12 (1H, dd, J=4.2, 2.1 Hz, 2-H); 13C NMR (125 MHz): d=
20.25, 24.30, 29.01, 29.22, 33.04, 50.58, 71.55, 73.77; MS
(ES+): m/z=173 [(M+H)+, 13%), 172 (100), 158 (16), 149
(12), 114 (15).
AHCTUNGTREG(NNUN 1S,2R,3R)-3-Cyanocyclohexane-1,2-diol (7e): Minor dia-
G
(6d):
White
stereoisomer; yield: ca 5% in enriched mixture; 1H NMR
(300 MHz, CDCl3): d=1.30–1.55 (6H, m, 4-H, 5-H, 6-H),
864
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 855 – 868

Synthesis and Reactions of Enantiopure Substituted Benzene cis-Hexahydro-1,2-diols
1
1.87 (1H, m, 3-H), 3.25 (1H, dd, J=3.0, 9.6 Hz, 2-H), 4.10
(M+): 210.1617; H NMR (300 MHz, CDCl3): d=1.14 (9H,
(1H, m, 1-H).
s, CMe3), 1.38 (3H, s, Me), 1.42 (3H, s, Me), 1.61–1.72 (2H,
m, 4-H), 1.86–1.97 (1H, m, 5-H), 2.09–2.25 (1H, m, 5-H),
4.17 (1H, dd, J=5.8, 11.2 Hz, 3a-H), 4.59 (1H, d, J=5.8 Hz,
7a-H), 5.82 (1H, t, J=4.3 Hz, 6-H); 13C NMR (125 MHz):
d=22.25, 26.42, 26.76, 28.56, 30.66, 72.15, 74.55, 107.77,
124.75, 143.85.
A
(6f):
Colourless crystalline solid; yield: 82%; mp 62–648C
(CHCl3/hexane); [a]D: À10 (c 1.0, CHCl3); anal calcd. for
C7H11O3F3: C 29.8, H 3.9%; found: C 29.9, H 3.9: HR-MS:
m/z=184.0708, calcd. for C7H11O2F3 (M+): 184.0711;
1H NMR (500 MHz, CD3Cl): d=1.25–1.36 (1H, m, 5-H),
1.65–1.80 (4H, m, 4-H, 5-H, 6-H), 2.07 (1H, m,, 4-H),
2.08(1H, m, 3-H), 2.30 (1H, s br, OH), 2.18 (1H, s br, OH),
3.55 (1H, ddd, J=2.9, 5.3, 10.5 Hz, 1-H), 4.25 (1H, t, J=
2.9 Hz, 2-H); 13C NMR (125 MHz, CDCl3): d=18.38, 22.74,
28.28, 30.52, 45.54 (q, J=26 Hz), 67.63, 71.78, 127.22(q,
J=283 Hz); MS (EI): m/z=184 (M+., 27%), 166 (34), 138
(31), 97 (39), 70 (100).
(3aR,4S,7aS)-4-tert-Butyl-2,2-dimethyl-hexahydro-
benzo[d]ACTHUNRTGNEUNG[1,3]dioxole (11c)
Hydrogenation of acetonide 10c using 5% Rh/G catalyst
(0.150 g, 40 bar) in MeOH afforded the product 11c as the
major diastereoisomer which, on purification by PLC
(EtOAc:hexane, 1:4), was obtained as a viscous oil; yield:
0.980 g (94%); [a]D: +2.1 (c 1.1, MeOH); HR-MS: m/z=
212.1772, calcd. for C13H24O2 (M+): 212.1776; 1H NMR
(300 MHz, CDCl3): d=0.99 (9H, s, CMe3), 1.0–1.5 (6H, m,
4H, 5H, 6H), 3.97 (1H, ddd, J=4.9, 2.5 Hz, 3a-H), 4.28
(1H, td, J=5.2, 9.3 Hz, 7a-H); 13C NMR (125 MHz): d=
21.27, 22.91, 26.51, 28.69, 29.78, 33.38, 47.78, 74.94, 76.26,
108.22.
A
(7f):
Minor diastereoisomer in enriched mixture; 1H NMR
(500 MHz, CDCl3): d=1.20–1.56 (5H, m, 4-H, 5-H, 6-H),
1.82–1.87 (1H, m, 6-H), 1.96 (1H, m, 3-H), 3.75 (1H, dd, J=
3.0, 10.2 Hz, 2-H), 4.06 (1H, q, J=2.8 Hz, 1-H).
ACHTUNGTRENNUNG(1S,2R,3R)-3-[(1’R)-2’,2’,2’-Trifluoro-1’-hydroxyethyl]cy-
clohexane-1,2-diol (6g): Colourless crystalline solid; yield:
90%; mp 162–1638C (EtOAc); [a]D: À20 (c 1.0, CHCl3);
HR-MS: m/z=214.0816, calcd. for C8H13O3F3 (M+):
Deprotection of acetonide 11c, by heating at 508C over-
night, with a mixture of THF:H2O:TFA (8:2:1), gave cis,cis-
hexahydrodiol 6c.
1
214.0817; H NMR (500 MHz, CD3OD): d=1.60–1.73 (6H,
m, 4-H 5-H, 6-H), 1.78 (1H, m, 3-H), 3.47 (1H, ddd, J=2.5,
5.0, 11.0 Hz, 1-H), 3.97 (1H, quintet, J=7.5 Hz, CHCF3),
4.21 (1H, t, J=2.4 Hz, 2-H); MS (EI): m/z=214 (M+., 4%), Monobenzylation of (1S,2S)-3-Chlorocyclohex-3-ene-
196 (M+ÀH2O, 12), 70 (100).
1,2-diol (5h)
Crystal data for 6g: C8H13F3O3, M=214.2, orthorhombic,
a=5.044(1), b=9.078(1), c=20.920(1) ꢄ, U=957.9(2) ꢄ3,
T=298(2) K, Mo-Ka radiation, l=0.71069 ꢄ, space group
A
solution of (1S,2S)-3-chlorocyclohex-3-ene-1,2-diol 5h
(0.150 g, 1.0 mmol) in DMF (0.5 mL) was added dropwise to
a suspension of NaH (0.065 g, 2.7 mmol) in DMF (0.5 mL)
under an N2 atmosphere. The mixture was stirred at room
temperature for half an hour. It turned green during this
time. Benzyl bromide (0.180 g, 1.05 mmol) was added drop-
wise, to the stirred reaction mixture. After stirring the mix-
ture overnight, at room temperature, it was poured into a
beaker containing NH4Cl/ice mixture. The aqueous reaction
mixture was extracted with EtOAc (2ꢃ20 mL), the extract
dried (Na2SO4) and the solvent evaporated. The residue, on
purification by PLC (hexane:EtOAC, 3:1), afforded two
monobenzylated products. The major, low Rf (0.35), product
was identified as compound 12h and the minor, high Rf
(0.59), as compound 13h.
P212121 (no. 19), Z=4, FACHTNUTGRNEUNG
(000)=448, Dx =1.485 gcmÀ3, m=
0.15 mmÀ1, Marresearch image plate diffractometer, 4.08<
2q<40.78, measured/independent reflections: 3711/908,
direct methods solution, full-matrix least squares refinement
2
on Fo , anisotropic displacement parameters for non-hydro-
gen atoms; hydrogens located in a difference Fourier synthe-
sis but included at positions calculated from the geometry of
the molecules using the riding model, with isotropic vibra-
tion parameters. Final R1 =0.047 for 885 data with Fo >
4s(Fo), 133 parameters, wR2 =0.122 (all data), GoF=1.11,
D1min,max =À0.20/0.19 eꢄÀ3. CCDC 737845 contains the sup-
plementary crystallographic data for this compound. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_-
request/cif.
A
(12h):
Monobenzyl derivative 12h was obtained as a colourless vis-
cous oil; yield: 0.142 g (59%); [a]D: À132 (c 1.13, CHCl3);
anal. calcd. for C13H15O2Cl: C 65.4, H 6.3%; found: C 65.3,
H 6.5; HR-MS: m/z=238.0758, calcd. for C13H15O235Cl
ACHTUNGTRENNUNG
1
(M+): 238.0761); H NMR (500 MHz, CDCl3): d=1.72 (1H,
ACHTUNGTRENNUNG
m, 6-H), 1.78 (1H, m, 6’-H), 2.08 (1H, m, 5-H), 2.20 (1H,
m, 5’-H), 3.86 (1H, td, J=4.0, 10.1 Hz, 1-H), 3.99 (1H, d,
J=4.1 Hz, 2-H), 4.75 (1H, d, J=11.3 Hz, CHH’Ph), 4.98
(1H, d, J=11.3 Hz, CH’HPh), 5.98 (1H, dd, J=3.7, 4.5 Hz,
4-H), 7.31–7.41 (5H, m, ArH); 13C NMR (125 MHz, CDCl3):
d=24.40, 26.10, 69.16, 75.02, 78.85, 128.44, 128.51, 128.94,
129.60, 130.51, 138.27; MS (EI): m/z=92 (18%), 91 (100), 89
(5), 83 (6), 79 (12), 77 (23), 75 (7), 67 (5), 65 (36), 55(9), 54
(9).
p-Toluenesulfonic acid (0.015 g) was added to a stirred solu-
tion of compound 5c (1.23 g, 7.2 mol) in acetone (4 mL) and
2,2-dimethoxypropane (8.0 mL) and the mixture stirred at
ambient temperature for 12 h. The solvents were removed
under reduced pressure, the residue treated with aqueous
K2CO3 solution (25 mL), and the mixture extracted with
EtOAc (2ꢃ40 mL). The extract was dried (MgSO4), the sol-
vent removed under reduced pressure, and the residue puri-
fied by PLC (EtOAc:hexane, 1:4) to give acetonide 10c as a
colourless viscous oil; yield: 1.38 g (92%); [a]D: +82.7 (c
1.1, MeOH); HR-MS: m/z=210.1620, calcd. for C13H22O2
A
(13h):
Monobenzyl derivative 13h was also obtained as a viscous
oil; yield: 0.048 g (20%); [a]D: À134 (c 1.58, CHCl3); HR-
Adv. Synth. Catal. 2010, 352, 855 – 868
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
865

D. R. Boyd et al.
FULL PAPERS
MS: m/z=238.0749, calcd. for C13H15O235Cl (M+): 238.0761);
1H NMR (500 MHz, CDCl3): d=1.72 (1H, m, 6-H), 1.83
(1H, m, 6’-H), 1.99 (1H, m, 5-H), 2.18 (1H, m, 5’-H), 2.6
(1H, d, J=4.3 Hz, OH), 3.62 (1H, td, J=3.2, 10.2 Hz, 1-H),
4.16 (1H, dd, J=4.3 Hz, 2-H), 4.53 (1H, d, J=11.8 Hz,
CHH’Ar), 4.58 (1H, d, J=11.8 Hz, CHH’Ar), 5.89 (1H, t,
J=3.5 Hz, 4-H), 7.26 (5H, m, Ar-H); 13C NMR (125 MHz,
CDCl3): d=22.34, 24.36, 69.75, 71.32, 76.77, 128.18, 128.41,
128.65, 128.99, 131.67, 138.15; MS (EI): m/z=240 (M+, 37Cl,
2%), 238 (M+, 35Cl, 6), 196 (9), 194 (39), 159 (7), 116 (6),
114 (30), 92 (47), 91 (100), 65 (64).
33.04, 50.46, 69.84, 85.82, 128.01, 130.26, 134.89, 145.17; MS
(EI); m/z=326 (100%, M+).
Toluene-4-sulfonic acid (1S,2R,3S)-2-hydroxy-3-phenylcy-
clohexyl ester (15d): Viscous oil; [a]D: À29 (c 1.6, CHCl3);
HR-MS: m/z=346.1229, calcd. for C19H22O4S (M+):
1
346.1239; H NMR (300 MHz, CDCl3) d=1.26–1.44 (1H, m,
5-H), 1.52–2.04 (5H, m, 4-H, 5-H, 6-H), 2.44 (3H, s, Me),
2.65 (1H, m, 3-H), 4.15 (1H, m, 2-H), 4.62 (1H, ddd, J=2.5,
4.8, 11.6 Hz, 1-H), 7.23–7.32 (5H, m, Ar), 7.34 (2H, d, J=
8.2 Hz, Ar), 7.81 (2H, d, J=8.1 Hz, Ar); 13C NMR
(125 MHz): d=22.36, 23.97, 23.55, 25.72, 47.64, 72.33, 84.31,
127.28, 128.30, 128.81, 129.03, 130.63, 134.73, 142.62, 145.54;
MS (EI): m/z=346 (100%, M+), 328 (48).
ACHTUNGTRENNUNG(1S,2R)-2-Benzyloxycyclohexan-1-ol (14a)
Toluene-4-sulfonic acid (1S,2R,3R)-3-tert-butyl-2-hydrox-
ycyclohexyl ester (16c): Colourless crystalline solid, mp 93–
1038C (ethyl acetate/hexane); [a]D: À3 (c 1.0, CHCl3); HR-
MS: m/z=326.1550, calcd. for C17H26O4S (M+): 326.1552;
1H NMR (300 MHz, CDCl3): d=0.96 (9H, s, CMe3), 1.32–
1.52 (4H, m, 4-H, 5-H), 1.65( 1H, d, J 10.2, OH), 1.71 (1H,
m, 6-H), 1.75 (1H, m, 6H), 1.93 (1H, m, 3-H), 2.47 (3H, s,
Me), 3.48 (1H, dt, J=2.7, 10.3 Hz, 2-H), 4.79 (1H, m, 1-H),
7.36 (2H, d, J=8.1 Hz, Ar), 7.35 (2H, d, J=8.1 Hz, Ar);
13C NMR (125 MHz): d=19.91, 21.90, 26.25, 29.28, 30.21,
33.24, 48.01, 74.00, 85.21, 128.34, 130.59, 134.41, 145.23; MS
(EI): m/z=326 (100%, M+).
Toluene-4-sulfonic acid (1S,2R,3R)-2-hydroxy-3-phenylcy-
clohexyl ester (16d): Viscous oil, [a]D: +53 (c 1.3, CHCl3);
HR-MS: m/z=346.1233, calcd. for C19H22O4S (M+):
346.1239; 1H NMR (300 MHz, CDCl3): d=1.29–1.68 (4H,
m, 4-H, 5-H, 6-H), 1.81 (1H, m, 4-H’), 2.07 (1H, m, 6-H),
2.37 (1H, s, Me), 2.86 (1H, dt, J=3.9 11.9 Hz, 3-H), 3.66
(1H, d, J=11.9 Hz, 2-H), 4.88 (1H, m, 1-H), 7.06–7.29 (5H,
m, Ar), 7.30 (2H, d, J=8.2 Hz, Ar), 7.77 (2H, d, J=8.1 Hz,
Ar); 13C NMR (125 MHz): d=20.33, 22.58, 30.33, 33.23,
46.46, 60.31, 73.89, 127.36, 128.07, 128.15, 128.31, 129.12,
130.16, 134.45, 142.50, 145.13; MS (EI): m/=346 (100%,
M+), 329 (12), 328 (52).
To a solution of (1S,2S)-2-benzyloxy-3-chlorocyclohex-3-en-
1-ol 12h (0.15 g, 0.63 mmol) in MeOH (10 mL). Et3N
(0.13 mL) and Pd/C (10%, 10 mg) were added and the mix-
ture stirred under a hydrogen atmosphere for 9 h. The solu-
tion was filtered through a pad of celite, the filtrate concen-
trated under vacuum and the crude product purified by PLC
(10% EtOAc in hexane) to afford the title compound as an
oil; yield: 0.11 g (90%); [a]D: À17.3 (c 1.10, CHCl3), (Lit.[35]
[a]D: À16.5); HR-MS: m/z=206.1298, calcd. for C13H18O2
1
(M+): 206.1307; H NMR (500 MHz, CDCl3): d=1.29 (2H,
m, 4-H), 1.55 (2H, m, 5-H), 1.60 (2H, m, 3-H), 1.83 (2H, m,
6-H), 2.26 (1H, d, J=5.1 Hz, OH), 3.51 (1H, td, J=3.2,
8.3 Hz, 2-H), 3.86 (1H, m, 1-H), 4.52 (1H, d, J=11.8 Hz,
CH’HPh), 4.62 (1H, d, J=11.8 Hz, CHH’Ph), 7.28 (1H, m,
ArH), 7.35 (4H, m, ArH); 13C NMR (125 MHz, CDCl3): d=
21.61, 22.50, 26.96, 30.82, 69.16, 70.56, 78.56, 127.95, 128.04,
128.84, 139.01; MS (EI): m/z=207 (M+ +1, 4%), 206 (M+,
7), 115 (9), 108 (13), 107 (60), 97 (18), 93 (5), 92 (63), 91
(100), 82 (17), 79 (26), 69 (14), 67 (14), 65 (17), 57 (6), 55
(6).
ACHTUNGTRENNUNG(1R,2S)-2-Benzyloxycyclohexanol (14a)
ACHTUNGTRENNUNG(1S,2S)-1-Benzyloxy-3-chlorocyclohex-3-en-2-ol 13h (0.13 g,
0.55 mmol) was reacted with hydrogen in a similar manner
to compound 12h to furnish the title compound; yield:
0.11 g (95%); [a]D: +17.1 (c, 1.10 in CHCl3), {Lit.[35] [a]D:
+16.4 (c 1.20, CHCl3)}.
Synthesis of Cyclohexanols 17c, 17d, 18c and 18d
A solution of monotosylate derivative 15c/15d or 16c/16d
(3 mmol) in dry THF (30 mL) was treated with excess of
LiAlH4 (0.25 g) and the mixture refluxed under N2 (12 h).
The reaction was quenched by the careful addition of moist
ether, the precipitated salts removed by filtration through a
pad of celite and the filtrate concentrated under vacuum.
The crude product obtained was purified by column chro-
matography (20% EtOAc in hexane) to furnish the corre-
sponding cyclohexanol 17c/17d, 18c/18d. The compounds
crystallised on standing and were not recrystallised.
Synthesis of Monotosylates 15c, 15d, 16c and 16d
To a solution of cis-hexahydrodiol 6c/6d or 7c/7d (6.9 mmol)
in dry dichloromethane (20 mL) was added p-toluenesulfon-
yl chloride (1.32 g, 6.9 mmol), Et3N (0.98 mL) and Bu2SnO
(0.100 g); the mixture was stirred at ambient temperature
for 12 h. The reaction mixture was then filtered through a
pad of celite and the filtrate concentrated under vacuum.
The crude product obtained was purified by column chro-
matography (20% EtOAc in hexane) to furnish the corre-
sponding monotosylate 15c/15d, 16c/16d; yield: 80–85%.
Toluene-4-sulfonic acid (1S,2R,3S)-3-tert-butyl-2-hydroxy-
cyclohexyl ester (15c): White solid, mp 137–1398C (ethyl
acetate/hexane); [a]D: À38 (c 1.0, CHCl3); HR-MS: m/z=
326.1546, calcd. for C17H26O4S (M+): 326.1552; 1H NMR
(300 MHz, CDCl3): d=0.97 (9H, s, CMe3), 1.20–1.71 (6H,
m, 4-H, 5-H, 6-H), 1.88 (1H, m, 3-H), 2.47 (3H, s, Me), 4.18
(1H, m, 2-H), 4.36 (1H, ddd, J=2.5, 4.8, 11.6 Hz, 1-H), 7.35
(2H, d, J=8.1 Hz, Ar), 7.82 (2H, d, J=8.1 Hz, Ar);
13C NMR (125 MHz): d=19.81, 22.03, 24.20, 26.14, 28.96,
AHCTUNGTREG(NNNU 1S,2S)-2-tert-Butylcyclohexanol (17c): Mp 55–578C,
(Lit.[35] rac. mp 54–558C); [a]D: +21 (c 1, CHCl3), (Lit.[48]
[a]D: +21); 1H NMR (300 MHz, CDCl3) d=1.01 (9H, s,
CMe3), 1.02–1.81 (9H, m, 1-H, 3-H, 4-H, 5-H, 6-H), 4.27
(1H, m, 1-H); 13C NMR (125 MHz): d=20.01, 21.27, 26.81,
28.63, 32.67, 35.15, 51.03, 68.01.
AHCTUNGTRENNUNG
(1S,2S)-2-Phenylcyclohexanol (17d): Mp 24–278C, (Lit.[49]
mp 25–268C); [a]D: +207 (c 1.1, MeOH), (Lit.[49] [a]D:
1
+213); H NMR (300 MHz, CDCl3): d=1.01–2.46 (8H, m,
3-H, 4-H, 5-H, 6-H), 2.62 (1H, m, 2-H), 3.85 (1H, m, 1-H),
7.04–7.24 (5H, m, Ar).
866
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 855 – 868

Synthesis and Reactions of Enantiopure Substituted Benzene cis-Hexahydro-1,2-diols
A
[5] D. T. Gibson, R. E. Parales, Curr. Opin. Biotechnol.
2000, 11, 236–243.
[6] D. R. Boyd, N. D. Sharma, C. C. R. Allen, Curr. Opin.
(Lit.[50] mp 50–528C); [a]D: +44 (c 1.1, CHCl3), (Lit.[50] [a]D:
+44); H NMR (300 MHz, CDCl3): d=0.09–1.35 (5H, m, 3-
H, 4-H, 5-H), 0.99 (9-H, s, CMe3), 1.80–1.63 (2H, m, 6-H),
1.95 (1H, m, 2-H), 3.47 (1H, dt, J=4.3 10.0 Hz, 1-H);
13C NMR (125 MHz): d=25.19, 26.22, 26.84, 29.41, 33.21,
37.83, 53.57, 73.62.
Biotechnol. 2001, 12, 564–573.
[7] R. A. Johnson, Org. React. 2004, 63, 117.
[8] D. R. Boyd, T. D. H. Bugg, Org. Biomol. Chem. 2006,
4, 181–192.
[9] K. A. B. Austin, M. Matveenko, T. A. Reekie, M. G.
Banwell, Chem. Aust. 2008, 75, 3–7.
[10] T. Hudlicky, J. W. Reed, Synlett 2009, 685–703.
[11] T. Hudlicky, J. W. Reed, Chem. Soc. Rev. 2009, 38,
3117–3132.
[12] D. M. Pinkerton, M. G. Banwell, A. C. Willis, Org. Lett.
2009, 11, 4290–4293.
ACHTUNGTRENNUNG(1S,2R)-2-Phenylcyclohexanol (18d): Crystalline solid, mp
62–638C, (Lit.[51] mp 63–648C), [a]D: +56 (c 1.1, CHCl3),
1
(Lit.[51]; [a]D: +57); H NMR (300 MHz, CDCl3): d=1.25–
1.90 (7H, m, 3-H, 4-H, 5-H, 6-H), 2.01–2.18 (1H, m, 6-H),
2.43 (1H, ddd, J=3.6, 9.9, 12.5 Hz, 2-H), 3.66 (1H, ddd, J=
2.7, 4.2, 9.9 Hz, 1-H), 7.24–7.37 (5H, m, Ar); 13C NMR
(125 MHz): dC =25.23, 26.55, 33.15, 34.61, 53.83, 74.96,
127.47, 128.35, 129.38, 144.04.
[13] A. D. Findlay, A. Gebert, I. A. Cade, M. G. Banwell,
Aust. J. Chem. 2009, 62, 1173–1180.
[14] M. T. Jones, B. D. Schwartz, A. C. Willis, M. G. Ban-
well, Org. Lett. 2009, 11, 3506–3509.
[15] A. D. Findlay, M. G. Banwell, Org. Lett. 2009, 11,
3160–3162.
Asymmetric Oxidation of ortho-Tolylmethylphenyl-
phosphine 19 and ortho-Anisylmethylphenyl-
phosphine 20 to the Corresponding Phosphine Oxides
21 and 22
[16] M. Matveenko, M. G. Banwell, M. Joffe, S. Wan, E.
Fantino, Chem. Biodivers. 2009, 6, 685–691.
[17] D. R. Boyd, N. D. Sharma, L. Sbircea, D. Murphy, T.
Belhocine, J. F. Malone, S. L. James, C. C. R. Allen,
J. T. G. Hamilton, Chem. Commun. 2008, 5535–5537.
[18] D. R. Boyd, N. D. Sharma, L. Sbircea, D. Murphy, J. F.
Malone, S. L. James, C. C. R. Allen, J. T. G. Hamilton,
Org. Biomol. Chem. 2010, 8, 1081–1090.
[19] V. Berberian, C. C. R. Allen, N. D. Sharma, D. R.
Boyd, C. Hardacre, Adv. Synth. Catal. 2007, 349, 727–
739.
[20] D. R. Boyd, N. D. Sharma, N. M. Llamas, G. P. Coen,
P. K. M. McGeehin, C. C. R. Allen, Org. Biomol.
Chem. 2007, 5, 514–522.
[21] H. Ziffer, K. Kabuto, D. T. Gibson, V. M. Kobal, D. M.
Jerina, Tetrahedron 1977, 33, 2491–2496.
[22] H. Ziffer, D. M. Jerina, D. T. Gibson, V. M. Kobal, J.
Am. Chem. Soc. 1973, 95, 4048–4049.
Experimental conditions used for the Appel reaction were
as reported earlier.[46] Typically phosphines 19 (or 20,
0.13 mmol), alcohols 17c (or 17d, 18c, 18d, 0.16 mmol, all
available from earlier studies[46]) and hexachloroacetone
(0.13 mmol) furnished the corresponding phosphine oxides
(S)-21 [or (S)-22, (R)-21, (R)-22]. The absolute configura-
tions of phosphine oxides (S)-21 and (S)-22, (R)-21, (R)-22
had been established earlier.[46] The ee values for phosphine
oxides 21 and 22 were determined by CSP-HPLC analysis
using the following conditions: (i) phosphine oxide 21,
100 mL aliquot in 1.5 mL propan-2-ol, Chiralpak 1 A
column, heptane/ethanol 80:20, flow rate of 1 mLminÀ1, de-
tection at 230 nm; (S)-enantiomer 21:7.1 min, (R)-enantio-
mer 21: 7.9 min and (ii) phosphine oxide 22, 100 mL in
1.5 mL propan-2-ol, Chiralpak 1 A column; heptane/ethanol
90:10, flow rate of 1 mLminÀ1, detection at 254 nm; (R)-
enantiomer 22: 14.1 min, (S)-enantiomer 22: 15.4 min.
[23] T. Hudlicky, H. Luna, G. Barbieri, L. D. Kwart, J. Am.
Chem. Soc. 1988, 110, 4735–4741.
[24] H. Ziffer, J. I. Seeman, R. J. Highet, Sokoloski, J. Org.
Chem. 1974, 39, 3698–3701.
Acknowledgements
[25] K. Kabuto, H. Shindo, H. Ziffer, J. Org. Chem. 1977,
42, 1742–1746.
[26] J. K. Gawronski, M. Kwit, D. R. Boyd, N. D. Sharma,
J. F. Malone, A. F. Drake, J. Am. Chem. Soc. 2005, 127,
4308–4319.
Financial assistance was provided by an EU Marie Curie
Host Fellowship for Transfer of Knowledge, NOVACAT,
Project No. 29846 (MK and KD), a Science Foundation Ire-
land Grant, No. 04/IN3/B581 (NDS) and postgraduate stu-
dentships funded by the European Social Fund (SMcG) and
CenTACat (VB).
[27] E. L. Eliel, Stereochemistry of Carbon Compounds,
McGraw-Hill Book Company, 1962.
[28] S. Winstein, N. J. Holness, J. Am. Chem. Soc. 1955, 77,
5562–5578.
[29] I. Horiuti, M. Polanyi, Trans. Faraday Soc. 1934, 30,
1164.
References
[30] S. Siegel, G. V. Smith, J. Am. Chem. Soc. 1960, 82,
6082–6087.
[31] S. Siegel, J. R. Cozort, J. Org. Chem. 1975, 40, 3594–
3598.
[32] S. Siegel, B. Dmuchovsky, J. Am. Chem. Soc. 1964, 86,
2192–2198.
[1] D. T. Gibson, J. R. Koch, R. E. Kallio, Biochemistry
1968, 7, 2653–2661.
[2] S. M. Resnick, K. Lee, D. T. Gibson, J. Ind. Microbiol.
1996, 17, 438–457.
[3] D. R. Boyd, G. N. Sheldrake, Nat. Prod. Rep. 1998, 15,
309–324.
[33] S. Siegel, G. V. Smith, J. Am. Chem. Soc. 1960, 82,
6087–6090.
[4] T. Hudlicky, D. Gonzalez, D. T. Gibson, Aldrichimica
Acta 1999, 32, 35–62.
Adv. Synth. Catal. 2010, 352, 855 – 868
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
867

D. R. Boyd et al.
FULL PAPERS
[34] D. R. Boyd, N. D. Sharma, V. Ljubez, J. F. Malone,
C. C. R. Allen, 2007, 82, 1072–1081.
[35] E. J. Blanc, H. Pines, J. Org. Chem. 1968, 33, 2035–
2043.
[36] H. W. Thompson, S. Y. Rashid, J. Org. Chem. 2002, 67,
2813–2825.
[42] Y. Demizu, Y. Kubo, H. Miyoshi, T. Maki, Y. Matsu-
mura, N. Moriyama, O. Onomura, Org. Lett. 2008, 10,
5075–5077.
[43] A. B. C. Simas, K. C. Pais, A. A. T. da Silva, J. Org.
Chem. 2003, 68, 5426–5428.
[44] S. David, A. Thieffry, A. Veyrieres, J. Chem. Soc.
[37] E. P. Serjeant, B. Dempsey, IUPAC Chemical Data
Series, Ionization Constants of Organic Acids in Aque-
ous Solution, Pergamon, 1979.
[38] K. Naemura, S. Takeuchi, K. Hirose, Y. Tobe, T.
Kaneda, Y. Sakata, J. Chem. Soc. Perkin Trans. 1 1995,
213–219.
Perkin Trans. 1 1981, 1796–1801.
[45] D. Wagner, J. P. H. Verheyde, J. G. Moffatt, J. Org.
Chem. 1974, 39, 24–30.
[46] E. Bergin, C. T. OꢀConnor, S. B. Robinson, E. M.
McGarrigle, C. P. OꢀMahony, D. G. Gilheany, J. Am.
Chem. Soc. 2007, 129, 9566–9567.
[39] D. R. Boyd, N. D. Sharma, N. I. Bowers, P. A. Good-
rich, M. R. Groocock, A. J. Blacker, D. A. Clarke, T.
Howard, H. Dalton, Tetrahedron: Asymmetry 1996, 7,
1559–1562.
[47] D. Gonzalez, V. Schapiro, G. Seoane, T. Hudlicky, K.
Abboud, J. Org. Chem. 1997, 62, 1194–1195.
[48] K. L. Cheo, T. H. Elliott, R. C. C. Tao, J. Chem. Soc. C
1966, 1988–1989.
[40] L. Sbircea, N. D. Sharma, W. Clegg, R. W. Harrington,
P. N. Horton, M. B. Hursthouse, D. C. Apperley, D. R.
Boyd, S. L. James, Chem. Commun. 2008, 5538–5540.
[41] M. J. Martinelli, R. Vaidyanathan, J. M. Pawlak, N. K.
Nayyar, U. P. Dhokte, C. W. Doecke, L. M. H. Zollars,
E. D. Moher, V. Van Khau, B. Kosmrlj, J. Am. Chem.
Soc. 2002, 124, 3578–3585.
[49] P. Peach, D. J. Cross, J. A. Kenny, I. Mann, I. Houson,
L. Campbell, T. Walsgrove, M. Wills, Tetrahedron 2006,
62, 1864–1876.
[50] C. Djerassi, P. A. Hart, E. J. Warawa, J. Am. Chem.
Soc. 1964, 86, 78–89.
[51] Y. H. She, C. F. Wu, K. S. Shia, J. D. Wu, R. K. Peddin-
ti, H. J. Liu, Synthesis 2005, 749–752.
868
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 855 – 868