Synthesis of (+)-(1R,2R,4R,6S)-1,6-epoxy-4-benzyloxycyclohexan-2-ol, a key precursor to inositol monophosphatase inhibitors, from (-)-quinic acid

Article abstract of DOI:10.1039/a909292g

A new and efficient route to homochiral (+)-(1R,2R,4R,6S)-1,6-epoxy-4-benzyloxycyclohexan-2-ol and its 2-benzyl ether derivative is described, starting from (-)-quinic acid. The compounds are key intermediates in the solution-phase and solid-phase synthesis of inhibitors for inositol monophosphatase. The pivotal step involves a La³⁺-induced reversal of the diastereoselectivity for the borohydride reduction of an intermediate cyclohexan-4-one. (1R,2R,4R,6R)-(O⁶-Propyl)cyclohexane-1,2,4,6-tetraol 1-phosphate, predicted to be a submicromolar competitive inhibitor of inositol monophosphatase, was prepared from the title epoxide in 5 steps in good overall yield. The compound proved to be a competitive inhibitor and displayed the expected potency confirming the stereochemical requirements for inhibition. The O²-benzylated epoxide derivative could be stereospecifically alcoholysed using either BF₃·(OEt)₂ or Yb(III)(OTf)₃ as catalysts without appreciable levels of benzyl ether protecting group cleavage. The preparation of the alcoholysis products (1S,2R,4S,6R)-2,4-bis(benzyloxy)-6-isopropyloxycyclohexanol and (1S,2R,4S,6R)-2,4-bis(benzyloxy)-6-(phenethyloxy)cyclohexanol, and the synthesis and evaluation of the inhibitor (1R,2R,4R,6R,2′S)-6-(1′-hydroxy-3′-phenylpropan-2-yloxy)-2,4-d ihydroxycyclohexyl phosphate and its diastereomer (1R,2R,4R,6R,2′R)-6-(1′-hydroxy-3′-phenylpropan-2-yloxy)-2,4-d ihydroxycyclohexyl phosphate are described.

Full text of DOI:10.1039/a909292g

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Synthesis of (؉)-(1R,2R,4R,6S)-1,6-epoxy-4-benzyloxycyclohexan-
2-ol, a key precursor to inositol monophosphatase inhibitors, from
(؊)-quinic acid1
1
Jürgen Schulz,a Martin W. Beatona and David Gani*ab
a School of Chemistry, The University, St Andrews, Fife, UK KY16 9ST
b School of Chemistry, The University of Birmingham, Edgbaston, Birmingham, UK B15 2TT
Received (in Cambridge, UK) 24th November 1999, Accepted 3rd February 2000
A new and efficient route to homochiral (ϩ)-(1R,2R,4R,6S)-1,6-epoxy-4-benzyloxycyclohexan-2-ol and its
2-benzyl ether derivative is described, starting from (Ϫ)-quinic acid. The compounds are key intermediates in the
solution-phase and solid-phase synthesis of inhibitors for inositol monophosphatase. The pivotal step involves a
La3ϩ-induced reversal of the diastereoselectivity for the borohydride reduction of an intermediate cyclohexan-4-one.
(1R,2R,4R,6R)-(O6-Propyl)cyclohexane-1,2,4,6-tetraol 1-phosphate, predicted to be a submicromolar competitive
inhibitor of inositol monophosphatase, was prepared from the title epoxide in 5 steps in good overall yield. The
compound proved to be a competitive inhibitor and displayed the expected potency confirming the stereochemical
requirements for inhibition. The O2-benzylated epoxide derivative could be stereospecifically alcoholysed using
either BF3ؒ(OEt)2 or Yb()(OTf)3 as catalysts without appreciable levels of benzyl ether protecting group cleavage.
The preparation of the alcoholysis products (1S,2R,4S,6R)-2,4-bis(benzyloxy)-6-isopropyloxycyclohexanol and
(1S,2R,4S,6R)-2,4-bis(benzyloxy)-6-(phenethyloxy)cyclohexanol, and the synthesis and evaluation of the inhibitor
(1R,2R,4R,6R,2ЈS)-6-(1Ј-hydroxy-3Ј-phenylpropan-2-yloxy)-2,4-dihydroxycyclohexyl phosphate and its diastereomer
(1R,2R,4R,6R,2ЈR)-6-(1Ј-hydroxy-3Ј-phenylpropan-2-yloxy)-2,4-dihydroxycyclohexyl phosphate are described.
Introduction
Inositol monophosphatase is a key enzyme in brain secondary
messenger systems.2 The role of the enzyme is to provide free
inositol which is used to form the secondary messenger pre-
cursor phosphatidylinositol 1,4,5-trisphosphate.2,3 Over-activity
of this cycle is believed to contribute to manic depression in
humans, a debilitating chronic condition with no known cure.
The current treatment of manic depression with lithium salts
has serious drawbacks and thus there has been much interest
and research into useful alternatives. Inositol monophos-
phatase is widely accepted to be the target for lithium ions in
manic depression therapy and has been the focus of much
research effort over the last twelve years.4–9
The enzyme is responsible for the hydrolysis of each of the
monophosphates of -myo-inositol phosphorylated in the 1,3,4
or 6 positions.10 Blocking the enzyme reduces the pool of
inositol available for the biosynthesis of the lipid phosphat-
idylinositol 4,5-bisphosphate which is the precursor for two
secondary messengers, diacyl glycerol and inositol 1,4,5-tris-
phosphate. Lithium ion is now known to inhibit the enzyme by
binding to a ternary enzymeؒMg2ϩ phosphate product com-
plex in the site vacated by a second Mg2ϩ ion,7 see discussion
below. This interaction gives rise to uncompetitive inhibition
with respect to the substrate4 in the millimolar range, but is
difficult to mimic given the simple structure of the Liϩ cation.
Moreover, the action of Liϩ in vivo is augmented by the high
levels of phosphate dianion, a synergistic product inhibitor,
present in the brain.4 The design of inhibitors, therefore, has
focussed on understanding the way in which the cyclitol
hydroxy groups and phosphate ester moiety interact with the
protein and with the bound magnesium ions. Such interactions
within the active site have now been examined and rationalised
for a range of substrates and inhibitors.6,7,11,12 One group
of inhibitors shows Ki values of ~1 µM or lower.11,12 These
compounds are based on 6-substituted cyclohexane-1,2,4-triol
1-phosphates 1 whereby the 6-substituent, if large enough, or
hydrophobic enough, inhibits by disrupting the coordination
sphere of the second of two magnesium cofactors, Mg2ϩ2.7,12
It is now known that Mg2ϩ2 should be hydrated in the active
complex such that the associated water molecule can H-bond to
the 6-OH group in structures that are substrates, e.g. cyclitol
phosphate 2.13 It is also apparent that the terminal hydroxy
group of the 6-hydroxyethyloxy side-chain of inhibitor 1 (R =
OCH2CH2OH) can access the coordination sphere of Mg2ϩ2.7,12
A potential second route to the design of inhibitors lies in
taking advantage of a hydrophobic binding pocket formed by
Val-40 and Leu-42 which lies near the top of the active site
cleft.7,9 It was reasoned that 6-cyclitol substituents that can
interact with both sites should be very tight binding inhibitors
and, indeed, some examples are known.11,12
The absolute stereochemical requirements of the cyclitol ring
for optimal inhibition in 6-substituted cyclohexane-1,2,4-triol
1-phosphate-type inhibitors was already established for a few
examples.11,12 Given that we expected that these requirements
should not change with the nature of the 6-substituent, we set
out to devise a synthesis of suitable homochiral precursors that
would be amenable to simple elaboration to give a range of
DOI: 10.1039/a909292g
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954
This journal is © The Royal Society of Chemistry 2000
943

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Scheme 1 Reagents and conditions: i. Cyclohexanone, H3PO4 (2 drops), 155 ЊC, 30 min; ii. NaBH4, EtOH, 0 ЊC→rt, 12 h; iii. NaIO4, H2O, pH 5–6,
0 ЊC→rt, 6 h, 81% over 3 steps; iv. LaCl3ؒ5H2O, NaBH4, MeOH, Ϫ78 ЊC→rt, 12 h, 95%; v. tBuSiPh2Cl, Et3N, DMAP, DCM, 0 ЊC→rt, 16 h, 48%;
vi. TsCl, Et3N, DMAP, 0 ЊC→rt, 3 days, 67%; vii. TBAF, THF, rt, 6 h, 100%; viii. BnBr, NaH, DMF, Ϫ40 ЊC→rt, 12 h, 80%; ix. TFA(cat.), MeOH, rt,
2 days, 78%; x. K2CO3, MeOH, rt, 30 min, 90%; xi. KH, BnBr, DCM, 12 h, Ϫ78 ЊC→rt, 12 h, 93%.
Table 1 Reduction of ketone 7
Ketone concn./ NaBH4 concn./
LaCl3ؒ7H2O concn./ CaCl2 concn./
Ti(O-iPr)4 concn./
mmol dmϪ3
Entry mmol dmϪ3
mmol dmϪ3
Solvent
T/ЊC
mmol dmϪ3
mmol dmϪ3
Selectivitya
1
2
3
4
5
6
7
8
9
25
25
25
100
100
100
200
200
200
200
200
400
150
50
Et2O
Et2O
reflux
room temp.
room temp.
0
0
—
—
—
—
—
—
—
—
—
—
400
—
—
—
—
30
—
—
—
—
—
—
—
—
—
100:0
83:17
75:25
34:66
50:50
12:88
34:66
88:12
14:86
10:90
12:88
EtOH
MeOH
EtOH
MeOH
EtOH
MeOH
MeOH
MeOH
MeOH
200
200
200
200
200
200
150
50
400
400
400
400
—
800
150
50
Ϫ60
Ϫ60
Ϫ60
Ϫ60
Ϫ60
Ϫ60
10
11
a Selectivity = undesired trans-diol 9:desired cis-diol 8.
homochiral 6-substituted variants.1 Previous syntheses had
utilised the racemic 1,6-epoxy-4-benzyloxycyclohexan-2-ol,
( )-3, which was obtained from cyclohexane-1,4-diol in an
overall yield of 6.6%. Reaction of the 2-O-benzyl derivative
with C- and O-nucleophiles gave the racemic 1-alcohols with
inversion of configuration at C-6.11,12 These were resolved as
their (Ϫ)-(1S,4R)-camphanate esters, which facilitated X-ray
crystallographic analysis of the structures and the determin-
ation of the absolute stereochemistry of the cyclitol moieties,
prior to saponification and phosphorylation at the O1-position.
In these studies it was, of course, necessary to have access to
both enantiomers of each inhibitor in order to probe the
geometry of the active site of the enzyme and correlate
biological potency with the absolute stereochemistry.11,12
Since this key epoxide seemed to be an ideal starting point
for introducing structural diversity, a synthesis of the homo-
chiral (1R,2R,4R,6S)-1,6-epoxy-4-benzyloxycyclohexan-2-ol
form starting from (Ϫ)-quinic acid was explored.
Reduction of the lactone 5 with sodium borohydride in ethanol
gave the vicinal diol 6 which was, without further purification,
converted to the ketone 7 in 95% overall yield using sodium
periodate,15,16 Scheme 1. This sequence was much more efficient
than the reported literature preparations of the ketone 7 which
used lithium aluminium hydride to reduce the acetylated form
of lactone 5.14–17
The diequatorial 4,6-diol (Ϫ)-8 had been required previously
for the synthesis of -(ϩ)-2,6-dideoxystreptamine and it was
reported that the reduction of the 4-keto group of (ϩ)-7 with
lithium borohydride in dimethoxyethane gave a 50:50 mixture
of the epimeric C-4-equatorial and axial alcohols, (Ϫ)-8 and
(ϩ)-9 respectively.16 While these could be separated16,18
we sought conditions to significantly improve the yield of the
4-equatorial alcohol (Ϫ)-8.
The use of sodium borohydride in refluxing ether gave the
4-axial alcohol (ϩ)-9 exclusively (Table 1, entry 1). Under
similar conditions but at 20 ЊC, either in ether, or in ethanol,
or at Ϫ60 ЊC in methanol, the axial alcohol 9 was still the
predominant product (Table 1, entries 2, 3 and 8). This is
expected because the approach of borohydride from the 4-re-
face of the ketone (ϩ)-7 is hindered by the cyclohexylidene
moiety. As it seemed possible that the 4-re-face of the ketone
Results and discussion
(Ϫ)-Quinic acid 4 was converted to the cyclohexylidene lactone
5 in 85% yield following the procedure of Shing and Tai.14
944
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954

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Table 2 13C-NMR shifts of ketone 7 (125 mmol dmϪ3) in CD3OD
solution and in the presence of LaCl3ؒH2O (135 mmol dmϪ3
change in the environment of the C-3 and C-5 methylene
protons as the temperature is decreased.
)
The La3ϩ assisted reduction of ketone 7 to give a 6:1 to 9:1
mixture of alcohols 8 and 9 could be performed successfully on
a 20 g scale. Direct separation of the isomers16,18 was difficult
on such a large scale but treatment with TBDPS-Cl (which
demands an accessible nucleophile)21 gave a mixture of mono-
silylated products, containing predominantly the desired 4-silyl
ether 10. The required silyl ether could be isolated easily in pure
form by column chromatography on silica in 46% overall yield
from the ketone 7. [Note that the remaining material could be
recycled via the sequence: desilylation, reaction with TBDPS-Cl
and chromatographic resolution of the isomers to give further
quantities of 4-silyl ether 10.] Tosylation of the free 6-OH
group of the 4-silyl ether 10 to give 11 was achieved in 67% yield
using tosyl chloride in the presence of a catalytic amount of
DMAP. The removal of the silyl group with TBAF gave the
4-hydroxycyclohexane 6-tosylate 12 in quantitative recovery
and benzylation of the 6-tosylate afforded the 4-benzyl ether
13 in 80% yield after chromatographic purification on silica.
Solvolysis of the cyclohexylidene ketal protection over 2 days
in methanol containing a catalytic amount of TFA gave the 1,2-
diol 14 in 78% yield together with some recovered starting
material. In subsequent reactions the 1,2-diol was not isolated
but the solvent methanol and TFA were removed and the diol
was redissolved in methanol and then treated with potassium
carbonate, in the same “pot”, to give the required homochiral
1,6-epoxy-4-benzyloxycyclohexan-2-ol (ϩ)-3 in 90% yield, 14%
overall yield from (Ϫ)-quinic acid, Scheme 1. Reaction of the
isolated pure diol 14 with methanolic potassium carbonate gave
the epoxide 3 in 90% yield after chromatographic purification
on silica. Compound (ϩ)-3 {mp 64–65 ЊC, [α]D ϩ56.4 (c 0.33 in
MeOH), [α]D ϩ19.2 (c 0.21 in CHCl3) {lit.,22 for 87% ee material
obtained as an oil, [α]D ϩ18.6 (c 4.4 in CHCl3)} and all of its
synthetic intermediates were fully characterised and showed the
expected properties, see Experimental section.
δ with
LaCl3ؒH2O
δ without
LaCl3ؒH2O
C-Atom
∆δa
4-C
1Ј-C
1-C
2-C
6-C
210.70
109.08
74.38
71.84
67.31
41.07
40.05
35.94
32.84
24.89
23.60
23.21
210.22
109.38
74.88
72.21
67.71
41.36
40.24
36.28
33.14
25.25
23.92
23.54
ϩ0.48
Ϫ0.30
Ϫ0.50
Ϫ0.37
Ϫ0.40
Ϫ0.29
Ϫ0.19
Ϫ0.34
Ϫ0.30
Ϫ0.36
Ϫ0.32
Ϫ0.33








3-C, 5-C
2Ј-C, 3Ј-C, 4Ј-C
4Ј-C, 5Ј-C
a ∆δ = chemical shift of C-atoms of ketone 7 with LaCl3ؒH2O Ϫ
chemical shift without LaCl3ؒH2O.
might be better exposed to the reductant if the 4-carbonyl
O-atom and the 6-OH group could be persuaded to occupy
axial positions through chelation to a highly charged metal ion,
reductions were repeated in the presence of various lanthanide
ions.19
At Ϫ60 to Ϫ78 ЊC in methanol in the presence of La3ϩ or
Ce3ϩ over a range of conditions and concentrations, boro-
hydride reduction gave a mixture of the required 4-equatorial
alcohol 8 and 4-axial alcohol 9 in 95% recovery where the
required alcohol 8 constituted up to 80–90% of the total
product mixture (as determined by 1H- and 13C-NMR spectro-
scopy) (see Table 1). On some occasions as much as 95% of the
required alcohol 8 was obtained. Similar reductions performed
in the presence of Pr3ϩ, Er3ϩ and Nd3ϩ ions were less successful
and, interestingly, Ca2ϩ ions were totally ineffective in redirect-
ing the face selectivity of the reduction. The use of Nd3ϩ and
Sm3ϩ ions resulted in the formation of extremely viscous slur-
ries at Ϫ60 ЊC which were very difficult to stir. The proportions
of the required alcohol 8 obtained in these reactions were lower
than for the La3ϩ assisted reduction, as judged by NMR spectro-
scopy. The use of ethanol in place of methanol also gave higher
proportions of the axial alcohol 9.
In order to test the stereochemical requirements for inhibi-
tion of inositol monophosphatase and verify the validity of the
concept, see above, we wished to prepare a single enantiomer
of the 6-propyloxycyclohexane-1,2,4-triol 1-phosphate (Ϫ)-19.
We had previously prepared the phosphate ester ( )-19 in
racemic form12 and had shown that it behaved as a competitive
inhibitor and possessed a Ki value of 1.28 µM. Accordingly,
using chemistry previously optimised for the synthesis of
racemic inhibitors,12 the epoxy alcohol (ϩ)-3 was benzylated
to give the bis(benzyl ether) (ϩ)-15 {[α]D ϩ72.6 (c 0.208 in
MeOH)} in 93% yield. The fully protected cyclitol epoxide
15 was treated with propanol in the presence of boron
trifluoride–diethyl ether to give the 6-propyl ether (Ϫ)-16a {[α]D
Ϫ34.1 (c 0.18 in MeOH)} in 60% yield from epoxide (ϩ)-3,
Scheme 2.
In an attempt to improve the yield of this reaction we also
performed the same experiment using ytterbium() triflate as
a catalyst.23 A 20% molar equivalent of the Lewis acid in reflux-
ing 1,2-dichloroethane gave an identical product (Ϫ)-16b to
the boron trifluoride–diethyl ether method although in an
improved yield of 98%. To explore the practical value of this
catalyst the fully protected cyclitol epoxide 15 was also cleaved
with two other hindered alcohols, namely isopropanol and
2-phenylethanol. Yields of 99% and 65% were obtained for
each of the required isolated products, the isopropyl ether (Ϫ)-
20 and the phenethyl ether (Ϫ)-21, respectively.
Ca2ϩ and La3ϩ ion assisted borohydride reductions have been
utilised for the partially selective reduction of other ketones
but, as yet, the structures of the transition state complexes for
such systems are not well understood.19,20 Preliminary studies to
determine the cause for reversed selectivity for reduction of the
ketone 7 observed here were performed in methanol, in the
absence and presence of La3ϩ ions. 1H- and 13C-NMR spectro-
scopic data indicated that the 4-carbonyl O-atom of ketone 7
binds directly to the lanthanide ion and that there are no gross
changes in the conformation of the ketone 7 (see Table 2 for
13C-NMR shifts). It would seem quite possible that a small
proportion of the equilibrium mixture of bound complexes
in methanolic solution exist with the La3ϩ ion bound to the
4-carbonyl O-atom and, simultaneously, with the 6-OH group
H-bonded to one of the methanol molecules of solvation, such
that the ion resides on the carbonyl 4-si-face. An alternative
structure might exist as a ketone dimer in which both
4-carbonyl O-atoms bind to a single La3ϩ ion such that the two
6-OH groups interact through an H-bond. Low temperature
1H-NMR spectroscopic analysis at Ϫ60 ЊC did not provide
unequivocal evidence in favour of either of these two possibil-
ities but clearly indicated that there is a large and increasing
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954
945

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The 1-hydroxy group of the cyclitol 6-propyl ether 16 was
phosphorylated using diphenyl chlorophosphate and the phos-
phate triester was transesterified, as described previously for the
racemic material,12 to give the dibenzyl phosphate triester (Ϫ)-
18. Deprotection of all four benzyl groups was achieved using
sodium in liquid ammonia and the required (1R,2R,4R,6R)-6-
propyloxycyclohexane-1,2,4-triol 1-phosphate (Ϫ)-19 was isol-
ated as its bis(cyclohexylammonium) salt {mp >200 ЊC
(decomp.), [α]D Ϫ37.8 (c 0.53 in H2O)} after purification by ion
exchange chromatography in 40% yield from the cyclitol 6-
propyl ether 16. The compound and all of its intermediates
displayed identical spectral properties to those for the racemic
material.12
inhibitor and its interactions with the protein had been
modelled.7,12 Thus, it appeared that the O6-(2Ј-hydroxyethyl)-
cyclitol 1-phosphate 1 could be useful in providing a framework
for inhibitor design.
The introduction of a lipophilic group to create a branch
point in the C-6 appended ω-hydroxyalkyl moiety produces a
new chiral centre. It was determined that a benzyl group would
be first introduced into the 1Ј-position of the 2Ј-hydroxyethyl
side chain of compound 1 (R = OCH2CH2OH) to give the
(2ЈS)- and (2ЈR)-epimers 25 and 29, respectively; Scheme 3.
The reason that we wished to examine the introduction of a
benzyl group at C-1Ј of the parent 2Ј-hydroxyethyl compound 1
(R = OCH2CH2OH) first was because the synthesis of the
precursor alcohols (2R)- and (2S)-1-benzyloxy-3-phenyl-
propan-2-ol required for the formation of the (2ЈR)- and (2ЈS)-
epimers 29 and 25 was much easier, starting from homochiral
phenyllactic acids, than the synthesis of the isomeric (2R)- and
(2S)-2-benzyloxy-3-phenylpropan-1-ols. To prepare the 2-benz-
yloxy-3-phenylpropan-1-ols would require reduction of the
carboxy groups, selective protection of the primary OH groups,
benzylation of the secondary OH groups and unmasking of the
orthogonal primary OH group protection such that the alcohol
could serve as a nucleophile in epoxide alcoholysis reactions.
The latter primary alcohols were expected to react better with
the epoxide (ϩ)-15 than the secondary alcohols investigated
here and, therefore, we did not believe that there would be any
additional problems in the synthesis if we could demonstrate
that the secondary (2R)- and (2S)-1-benzyloxy-3-phenyl-
propan-2-ols could be used as nucleophiles. It should be noted
that modelling suggested that the influence of a C-1Ј-tethered
benzyl group in the isomeric (1ЈR)- and (1ЈS)-epimers of com-
pounds 25 and 29 would also be worthy of biological evaluation
in the future.
In order to access both the coordination sphere of Mg2ϩ2
and the hydrophobic pocket it was necessary to conceive of a
molecule that possessed a C-6 appended ω-hydroxyalkyl moiety
and also, a lipophilic moiety suitably disposed to interact with
the side chains of Val-40 and Leu-42 in the protein. Since it
was possible that this might be achieved by introducing a
lipophilic group at a branched position on a C-6 appended
ω-hydroxyalkyl moiety, the effectiveness of such a strategy was
examined. (1R,2R,4R,6R)-O6-(2Ј-Hydroxyethyl)cyclohexane-
1,2,4,6-tetraol 1-phosphate 1 (R = OCH2CH2OH) contains a
pendant 2-hydroxyethyloxy group attached to C-6 and the
synthesis of the parent compound had been previously
described.12 The compound was a submicromolar competitive
Analysis of the structure of the inhibited complex of O6-(2Ј-
hydroxyethyl)cyclitol 1-phosphate 1 had indicated that the
2Ј-hydroxy group and the phosphate ester O-atoms should
interact with Mg2ϩ2 to form an eight-membered metallocycle.
One face of this fused cyclitol-metallocycle is exposed to the
solvent in the upper part of the active site cleft, whereas, the
other, lower face (upon which the 2-OH group of the cyclitol
ring resides) is buried in the protein. The introduction of a
bulky benzyl moiety into the O6-(2Ј-hydroxyethyl) side chain to
give the (2ЈS)-epimer 25 was expected to position the benzyl
moiety above the metallocycle in solvent-filled space and, there-
fore, it was expected that the (2ЈS)-epimer 25 should be a better
inhibitor than the (2ЈR)-epimer 29. Indeed, it was expected that
the (2ЈR)-epimer 29 would be either a very poor inhibitor, or
not active at all.
Scheme 2 Reagents and conditions: i, ClP(O)(OPh)2, Et3N, DMAP,
DCM, rt, 12 h, 92%; ii, NaH, BnOH, THF, 0 ЊC→rt, 2 h, 67%; iii, Na,
NH3(l), 0 ЊC→rt, 2 h, 65%.
Scheme 3 Reagents and conditions: i, ClP(O)(OPh)2, Et3N, DMAP, DCM, rt, 12 h, 83–90%; ii, NaH, BnOH, THF, 0 ЊC→rt, 2 h, 62–67%; iii, Na,
NH3(l), 0 ЊC→rt, 2 h, 60–62%.
946
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954

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Table 3 Inhibition constants for substituted cyclohexane-1,2,4,6-tetraols
Entry
Compound
R
RЈ
Ki/µmol dmϪ3
Mode of inhibition
2Ϫ
1
2
3
4
5
6
7
8
9
( )
-PO32Ϫ
-PO3
-C2H4OH
-C2H4OH
-Cyclic P
-CH3
-C3H7
-C3H7
-2Ј-CH-{2ЈS)-2Ј-CH2Ph}CH2OH
-2Ј-CH-{2ЈR)-2Ј-CH2Ph}CH2OH
-H
-H
1.8
Competitive12b
Competitive12b
Competitive12b
Competitive12b
Competitive12b
Competitive
(Ϫ)-(1R,2R,4R,6R)
( )
( )
0.5
160.0
2.5
1.2
0.87
100.0
310.0
3.0
-Cyclic P
2Ϫ
-PO32Ϫ
( )
-PO32Ϫ
-PO32Ϫ
-PO32Ϫ
-PO32Ϫ
-PO32Ϫ
-PO3
(Ϫ)-(1R,2R,4R,6R)-19
(Ϫ)-(1R,2R,4R,6R,2ЈS)-25
(Ϫ)-(1R,2R,4R,6R,2ЈR)-29
(Ϫ)-(1S,2R,4S)-2
(ϩ)-(1R,2S,4R)-2
Competitive
Competitive
Competitive12b
Weak substrate12b
10
Weak substrate
The synthesis of the (2ЈS)-epimer 25 started from key
epoxide (ϩ)-15. Treatment of the epoxide with 1.5 equivalents
of (2S)-(Ϫ)-1-benzyloxy-3-phenylpropan-2-ol (which was itself
obtained in two steps from commercially available -(Ϫ)-
phenyllactic acid) in the presence of boron trifluoride–diethyl
ether12,24 gave the 1-alcohol 22 in an acceptable 50% yield after
chromatographic purification on silica. The use of less than 1.5
equivalents of (2S)-(Ϫ)-1-benzyloxy-3-phenylpropan-2-ol gave
rise to much lower isolated yields. The exclusion of moisture
was also found to be particularly important when using lower
excesses of the alcohol nucleophile. Phosphorylation of the
1-OH group with diphenyl chlorophosphate, gave the diphenyl
phosphate triester 23 in 90% yield. Transesterification in the
presence of sodium benzyl oxide gave 24 in 67% yield and
reductive deprotection of each of the five benzyloxy groups
afforded the required 1-phosphate (Ϫ)-25 in 62% yield after ion
exchange chromatographic purification and conversion to the
bis(cyclohexylammonium) salt.
Exactly the same methodology was used for the synthesis of
the epimeric (Ϫ)-(1ЈR)-cyclitol 1-phosphate 29 except the key
epoxide [(ϩ)-15] was treated, under Lewis acid catalysed con-
ditions, with (2R)-(ϩ)-1-benzyloxy-3-phenylpropan-2-ol which
was itself obtained in two steps from commercially available
-(ϩ)-phenyllactic acid.
When tested for biological activity using standard enzyme
assays4 compounds (Ϫ)-19, 25 and 29 behaved as competitive
inhibitors for inositol monophosphatase (see Table 3). The
observed Ki value of 0.87 µM for (Ϫ)-19 was lower than that
for the racemic material12 indicating that the (1R,2R,4R,6R)-
antipode is the most active enantiomer. This result is in accord
with predictions based upon earlier modelling work7 and
supports the notion that the same absolute (1R,2R,4R,6R)-
configuration in the cyclitol ring should be optimal for the
design of more elaborate inhibitors.
Compounds 25 and 29 were both competitive inhibitors and
gave Ki values of 100 µM and 310 µM respectively. These values
are much higher than that of 0.5 µM observed for the inhibitor
without an additional benzyl moiety (see Table 3; entry 2). The
relative potency of the two 2Ј-epimers is qualitatively consistent
with expectations in that the (2ЈS)-epimer 25 binds tighter. The
C-2Ј branch point in the (2ЈS)-epimer is very close to the posi-
tion of the side chain carboxylate group of Asp-220 which
interacts with Mg2ϩ2 and it is quite likely that the position of
Asp-220 is disturbed by the benzylic C-atom. Therefore, it may
be worthwhile to assess the comparative potency of the (1ЈS)-
and (1ЈR)-epimers of the isomeric cyclitol phosphates where the
branch point is moved further away from the O6-atom, see
above. The use of the homochiral epoxide 3 will be valuable in
the synthesis of such inhibitors and, evidently, will allow access
to a wide range of C-6 elaborated inhibitors. The recent finding
that 6-aminocyclitol 1-phosphates can serve as substrates and
can be prepared using ytterbium triflate catalysed aminolysis of
epoxide 3 will help significantly in the design of inhibitors.13,25
A major objective is now to prepare compounds that can simul-
taneously recognise both the hydrophilic and hydrophobic
binding sites on the enzyme proximal to C-6 of the substrate 2.
The further recent finding that the epoxide can be immobilised
on polystyrene resins for the solid-phase synthesis of inhibitors
should speed progress in this and related areas considerably.26,27
Experimental
Elemental microanalyses were performed in the departmental
micro-analytical laboratory. NMR spectra were recorded on a
Bruker AM-300 spectrometer (1H, 300 MHz; 13C, 75.4 MHz;
31P, 121.5 MHz), Varian Gemini 300 spectrometer (1H, 300
MHz; 13C, 75.4 MHz) and a Varian Unity Plus 500 spec-
trometer (1H, 500 MHz; 13C, 125.6 MHz). Chemical shifts are
described in parts per million downfield from SiMe4 and are
reported consecutively as position (δH or δC), relative integral,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
dd = double of doublets, sep = septet, m = multiplet, and br =
broad), coupling constant (J/Hz) and assignment (numbering
according to the IUPAC nomenclature for the compound). 1H-
2
NMR spectra were referenced internally on HOH (δ 4.68),
CHCl3 (δ 7.27) or (CH3)2SO (δ 2.47). 13C-NMR spectra were
referenced on CH3OH (δ 49.9), C2HCl3 (δ 77.5) or (CH3)2SO
(δ 39.70) and 31P NMR spectra to external H3PO4 (δ 0). IR
spectra were recorded on a Perkin-Elmer 1710 FT-IR spec-
trometer. The samples were prepared as Nujol mulls, solutions
in chloroform or thin films between sodium chloride discs. The
frequencies (ν) as absorption maxima are given in wavenumbers
(cmϪ1) relative to a polystyrene standard. Mass spectra and
accurate mass measurements were recorded on a VG 70-250 SE,
a Kratos MS-50 or by the SERC service at Swansea using a VG
AZB-E. Fast atom bombardment spectra were recorded using
glycerol as a matrix. Major fragments were given as percentages
of the base peak intensity (100%). UV–VIS optical densities
were measured on a CamSpec M302 spectrophotometer. Flash
chromatography was performed according to the method of
Still et al.28 using Fluka Kieselgel C60 (40–60 µm mesh) silica
gel. Analytical thin layer chromatography was carried out on
0.25 mm precoated silica gel plates (Whatman PE SIL G/UV)
and compounds were visualised using UV fluorescence, iodine
vapour, ethanolic phosphomolybdic acid, aqueous potassium
permanganate or ninhydrin. Melting points were taken on an
Electrothermal melting point apparatus and are uncorrected.
Optical rotations were measured at 23 ЊC on an Optical Activity
AA-1000 polarimeter using 10 or 20 cm path length cells and
are given in units of 10Ϫ1 deg cm2 gϪ1.
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954
947

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Inositol 1-phosphates were prepared from myo-inositol as
described previously29 using the method of Billington et al.,30
while other substrates were prepared as described below.
Amberlite IR 118H ion exchange resin was obtained from BDH
(Poole, Dorset, UK). Phosphorylating agents were obtained
from the Aldrich Chemical Co. Ltd. (Gillingham, Dorset, UK).
The solvents used were either distilled or of Analar quality and
light petroleum ether refers to that portion boiling between
40–60 ЊC. Solvents were dried according to literature pro-
cedures.31 Ethanol and methanol were dried using magnesium
turnings. DMF, CH2Cl2, diisopropylamine and triethylamine,
were distilled over CaH2. THF and diethyl ether were dried over
sodium–benzophenone and distilled under nitrogen.
cm3) and ethyl acetate (100 cm3) and the aqueous phase was
extracted with ethyl acetate (2 × 100 cm3). The combined
organic layers were dried (MgSO4) and then concentrated under
reduced pressure to give 13 g of a crude mixture of the cis-diol
(Ϫ)-8 and the trans-diol (ϩ)-9 in a ratio of 5:1, as judged by 1H-
NMR spectroscopy. For analytical purposes a small amount of
the diol mixture was chromatographed on silica (ethyl acetate–
petroleum ether; 2:1) where the less polar trans-4,6 diol (ϩ)-9
was eluted first.
For the trans-diol (ϩ)-9: mp 129–130 ЊC; [α]D ϩ6 (c 0.16 in
MeOH); δH(300 MHz; C2HCl3) 1.33–1.83 (10 H, m, cyclohexyl-
2
3
idene), 1.90 (1 H, ‘dt’, JH-H 15.4, JH-H 4.1, secondary-H),
2.03–2.14 (1 H, m, secondary-H), 2.20–2.30 (1 H, m,
3
secondary-H), 2.58 (1 H, d, JH-H 8.0, OH), 3.30–3.70 (1 H,
3
(؉)-(1S,2R,6R)-1,2-Cyclohexylidenedioxy-4-oxocyclohexan-6-
broad, OH), 3.90 (1 H, ‘t’, JH-H 5.6, 1-H), 4.07–4.20 (2 H, m,
ol 714
4-H and 6-H) and 4.35–4.44 (1 H, m, 2-H); δC(75.4 MHz;
C2HCl3) 23.56, 23.93, 24.83, 33.07, 34.98, 37.17 and 38.36
(5 × C secondary of cyclohexylidene, 3-C and 5-C), 65.96 (4-C),
68.43 (6-C), 73.98 (2-C), 80.02 (1-C) and 109.75 (C quaternary
of cyclohexylidene); m/z (CI) 229 (100%, [M ϩ H]ϩ), 211 (38,
[M ϩ H Ϫ H2O]ϩ) and 99 (4, C6H11Oϩ).
For cis-diol (Ϫ)-8: mp 119–120 ЊC (Found: C, 62.65; H, 9.1.
C12H20O4 requires C, 63.1; H, 8.8%) (HRMS: found: [M ϩ H]ϩ,
229.1432. C12H21O4 requires 229.1440); [α]D Ϫ70.6 (c 0.16 in
MeOH); δH(300 MHz; C2HCl3) 1.30–1.70 (11 H, m, cyclohex-
ylidene and 5-H), 1.75 (1 H, ddd, 2JH-H 14.3, 2JH-H 9.33 and 4.7,
3-H), 2.04–2.13 (1 H, m, 5-H), 2.24–2.33 (1 H, m, 3-H), 3.77–
3.85 (1 H, m, 6-H), 3.86–3.92 (1 H, ‘t’, 3JH-H 6.3 and 5.2, 1-H),
4.02–4.14 (1 H, m, 4-H) and 4.34–4.41 (1 H, m, 2-H); δC(75.4
MHz; C2HCl3) 23.61, 23.94, 24.90 and 35.10 (4 × C secondary
of cyclohexylidene), 35.70 (3-C), 38.07 (C secondary of
cyclohexylidene), 38.11 (5-C), 65.31 (4-C), 70.8 (6-C), 72.66
(2-C), 79.62 (1-C) and 109.59 (C quaternary of cyclohex-
ylidene); m/z (CI) 229 (100%, [M ϩ H]ϩ), 211 (44, [M ϩ
H Ϫ H2O]ϩ) and 99 (10, C6H11Oϩ).
(Ϫ)-Quinic acid (Ϫ)-4 (30 g, 156 mmol) and cyclohexanone
(48.6 cm3, 46 g, 470 mmol) were treated with conc. phosphoric
acid (3 drops) and heated under reflux for 30 min. The water
produced was removed by distillation for 1–2 h and the reaction
mixture was allowed to cool to room temperature whereupon
it solidified. The crude solid was recrystallised from dichloro-
methane to remove most of the cyclohexanone and the crude
lactone (Ϫ)-5 was collected by filtration. The crude lactone (Ϫ)-
5 was dissolved in ethanol (300 cm3) and the solution cooled in
an ice bath. NaBH4 (3.8 g, 100 mmol) was added in 4 batches
with vigorous stirring and the mixture was allowed to warm
to room temperature with stirring overnight. The solvent was
removed under reduced pressure and the residue was dissolved
in water (300 cm3). The pH of the solution was adjusted to pH 6
by the dropwise addition of conc. phosphoric acid. The weakly
acidic solution was cooled in an ice bath and NaIO4 (33.4 g, 156
mmol) was added slowly in batches over a period of 30 min
with stirring. After a further 5 h, the mixture was extracted with
diethyl ether (2 × 150 cm3) followed by ethyl acetate (150 cm3).
The combined organic phases were dried (MgSO4) and concen-
trated under reduced pressure. The residual oil solidified upon
drying in vacuo and the crude solid was recrystallised (ethyl
acetate–petroleum ether; 1:10) to give ketone (ϩ)-7 as a white
solid (27.5 g, 78%); work-up of the mother liquor by chromato-
graphy on silica (ethyl acetate–petroleum ether; 1:2) afforded
further quantities of the ketone (ϩ)-7 (1.1 g, 3%), mp 97–98 ЊC
(Found: C, 63.9; H, 8.1. C12H18O4 requires C, 63.7; H, 8.0%);
[α]D ϩ100.3 (c 0.44 in MeOH); νmax(Nujol)/cmϪ1 3775 s, 1720 s,
1471 s, 1386 s and 1092 s; δH(300 MHz; C2HCl3) 1.30–1.45 (2 H,
br s, cyclohexylidene), 1.5–1.70 (8 H, m, cyclohexylidene), 2.00–
(؊)-(1S,2R,4S,6R)-1,2-Cyclohexylidenedioxy-4-(tert-butyldi-
phenylsilyl)cyclohexan-6-ol 10
The above described crude mixture of cis- and trans-4,6 diols
(Ϫ)-8 and (ϩ)-9 (10 g, 43.86 mmol) was dissolved in dry
dichloromethane (100 cm3), and DMAP (1.22 g, 10 mmol) and
dry TEA (6.26 cm3, 4.55 g, 45 mmol) were added. The mixture
was cooled in an ice bath and tert-butyldiphenylsilyl chloride
(11.7 cm3, 12.37 g, 45 mmol) was added dropwise with vig-
orous stirring. The mixture was stirred for a further 16 h at
room temperature and then extracted with water (100 cm3). The
aqueous phase was extracted with dichloromethane (3 × 100
cm3) and the pooled organic phases were dried (MgSO4) and
concentrated under reduced pressure. The residual oil was
chromatographed on silica (ethyl acetate–petroleum ether; 10:1
and then 5:1) to give the silylated compound (Ϫ)-10 as a white,
sticky foam (9.9 g, 48%) (Found: C, 71.9; H, 8.15. C28H38O4Si
requires C, 72.05; H, 8.2%) (HRMS: found: [M ϩ H]ϩ,
467.2608. C28H39O4Si requires 467.2618); [α]D Ϫ23.0 (c 0.398 in
MeOH); νmax(Nujol)/cmϪ1 3404 s; δH(300 MHz; C2HCl3) 1.06
(9 H, s, tbutyl), 1.30–1.40 (1 H, br s, 3-H), 1.45–1.60 (10 H, m,
cyclohexylidene), 1.65–1.75 (1 H, m, 5-H), 1.78–1.93 (2 H, m,
3-H and 5-H), 3.07–3.16 (1 H, br s, 6-OH), 3.73–3.84 (1 H, br s,
2
3
2.25 (1 H, broad, OH), 2.43 (1 H, ddd, JH-H 17.85, JH-H 3.85
and 1.9, 5-H), 2.63–2.73 (2 H, m, 3-H and 5-H), 2.80 (1 H, dd,
2JH-H 17.6, 3JH-H 3.85, 3-H), 4.21–4.26 (1 H, br s, 6-H), 4.27–4.33
(1 H, m, 1-H) and 4.66–4.72 (1 H, m, 2-H); δC(75.4 MHz;
C2HCl3) 23.39, 23.77, 25.01, 33.17, 36.15, 40.17 and 41.59
(5 × C secondary of cyclohexylidene, 3-C and 5-C), 68.21 (6-C),
71.71 (2-C), 74.61 (1-C), 109.52 (C quaternary of cyclohexylid-
ene) and 208.66 (4-C); δC(75.4 MHz; C2H3O2H) 23.21, 23.59,
24.92, 32.81, 35.95, 39.91 and 41.03 (5 × C secondary of
cyclohexylidene, 3-C and 5-C), 67.38 (6-C), 71.89 (2-C), 74.55
(1-C), 109.05 (C quaternary of cyclohexylidene) and 209.89
(4-C); m/z (CI) 227 (35%, [M ϩ H]ϩ), 129 (56, [M ϩ H Ϫ
C6H10O]ϩ) and 99 (100, C6H11Oϩ).
3
6-H), 4.0 (1 H, ‘t’, 1-H, JH-H 5.3), 4.06–4.16 (1 H, m, 4-H),
4.36–4.44 (1 H, m, 2-H), 7.30–7.50 (6 H, m, SiPh2) and 7.60–
7.70 (4 H, m, SiPh2); δC(75.4 MHz; C2HCl3) 18.92 [C(CH3)3],
23.58, 23.88 and 24.30 (3 × C secondary of cyclohexylidene),
26.84 [C(CH3)3], 35.19 (C secondary of cyclohexylidene), 35.72
(3-C), 36.55 (5-C), 38.06 (C secondary of cyclohexylidene),
68.02 (4-C), 69.93 (6-C), 71.81 (2-C), 78.79 (1-C), 109.26 (C
quaternary of cyclohexylidene) and 127.78, 127.81, 129.89,
129.95, 133.49, 135.78, 135.81 and 135.84 (Ar-CH and Ar-C
quaternary of SiPh2); m/z (CI) 467 (100%, [M ϩ H]ϩ), 369
(33, [M ϩ H Ϫ C6H10O]ϩ), 211 (29, [M Ϫ OSiC16H19]ϩ) and 99
1,2-Cyclohexylidenedioxycyclohexane-4,6-diol
(؊)-(1S,2R,4S,6R)-8 and (؉)-(1S,2R,4R,6R)-915,16
To a stirred solution of the ketone (ϩ)-7 (13.56 g, 60 mmol) in
methanol (700 cm3) was added LaCl3ؒ7H2O (22.3 g, 60 mmol)
and the suspension was cooled to Ϫ78 ЊC. NaBH4 (2.66 g, 70
mmol) was added in small batches whilst maintaining vigorous
stirring. The mixture was allowed to warm slowly to room tem-
perature over 12 h and the solvent was removed under reduced
pressure. The residual oil was partitioned between water (100
948
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954

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(41, C6H11Oϩ). A mixture of two silylated cyclohexanetetraols
(6.1 g, 30% no further characterisation), arising from the
presence of an overall three equatorial OH groups and one
axial OH group in the mixture of trans- and cis-diol (ϩ)-9
and (Ϫ)-8 respectively, which was used for the silylation reac-
tion, was eluted from the column after the desired compound
(Ϫ)-10.
(؊)-(1R,2R,4R,6R)-1,2-Cyclohexylidenedioxy-4-benzyl-6-(4Ј-
methylphenylsulfonyloxy)cyclohexane 13
Under an atmosphere of N2, a solution of alcohol (Ϫ)-12 (5 g,
12 mmol) in dry DMF (100 cm3) was treated with benzyl brom-
ide (2.8 cm3, 4.1 g, 24 mmol). The solution was cooled to
Ϫ50 ЊC and NaH (600 mg, 15 mmol; 60% dispersion in oil) was
added with continued stirring. The mixture was allowed to
slowly warm up to room temperature and then water (100 cm3)
was cautiously added. The mixture was extracted with diethyl
ether (2 × 100 cm3) and the combined organic layers were
dried (MgSO4) and concentrated under reduced pressure.
The residual oil was chromatographed on silica (ethyl acetate–
petroleum ether; 1:5) to give, after recrystallisation from
methanol, the benzyl ether (Ϫ)-13 as a white solid (4.53 g, 80%);
mp 83–84 ЊC (Found: C, 65.8; H, 6.9. C26H32O6S requires C,
66.1; H, 6.8%) (HRMS: found: Mϩ, 472.1927. C26H32O6S
(؊)-(1R,2R,4S,6R)-1,2-Cyclohexylidenedioxy-4-(tert-butyl-
diphenylsilyl)-6-(4Ј-methylphenylsulfonyloxy)cyclohexane 11
To a stirred solution of the silylated compound (Ϫ)-10 (9 g,
19.3 mmol) in dry dichloromethane (100 cm3) was added
DMAP (488 mg, 4 mmol) and dry TEA (3.01 cm3, 2.18 g,
21.6 mmol). The mixture was cooled in an ice bath and 4-
methylbenzenesulfonyl chloride (4.78 g, 25.1 mmol) was added
with vigorous stirring. Stirring was continued for three days
at room temperature and then water (100 cm3) was added.
The two phases were separated and the aqueous phase was
extracted with dichloromethane (3 × 100 cm3). The combined
organic layers were dried (MgSO4) and the solvent removed
under reduced pressure. The residual oil was chromatographed
on silica (ethyl acetate–petroleum ether; 1:10) to give the
tosylate (Ϫ)-11 as a white, sticky foam, which solidified upon
treatment with MeOH (8 g, 67%), and some unreacted starting
material (Ϫ)-10 (710 mg, 8%); mp 98–99 ЊC (Found: C, 67.75;
H, 6.8. C35H44O6SSi requires C, 67.7; H, 7.1%) (HRMS:
found: Mϩ, 620.2638. C35H44O6SSi requires 620.2628); [α]D
Ϫ51.5 (c 0.68 in MeOH); δH(300 MHz; C2HCl3) 1.0 (9 H, s,
tbutyl), 1.10–1.50 (10 H, m, secondary-H of cyclohexylidene),
1.52–1.66 (1 H, m, 5-H), 1.68–1.74 (1 H, m, 3-H), 2.12–2.26
(2 H, m, 3-H and 5-H), 2.4 (3 H, s, tosyl-CH3), 3.88–4.02 (2 H,
m, 1-H and 4-H), 4.08–4.29 (2 H, m, 2-H and 6-H), 7.23–7.28
(2 H, m, Ar-H), 7.33–7.47 (6 H, m, Ar-H), 7.60–7.65 (4 H, m,
requires 472.1920); [α]D Ϫ85.3 (c 0.214 in MeOH); νmax
-
(CH2Cl2)/cmϪ1 3063 s, 2946 s, 1605 s, 1444 s, 1346 s, 1273 s, 1183
s, 942 s, 816 s and 742 s; δH(300 MHz; C2HCl3) 1.25–1.52 (10 H,
m, cyclohexylidene), 1.52–1.61 (1 H, m, 5-H), 1.71 (1 H, ddd,
3
2JH-H 13.6, JH-H 10.4 and 4.7, 3-H), 2.43 (3 H, m, tosyl-CH3),
2.46–2.56 (1 H, m, 3-H and 5-H), 3.70–3.81 (1 H, m, 4-H), 3.97
(1 H, dd, 3JH-H 5.5 and 7.1, 1-H), 4.32–4.37 (1 H, m, 2-H), 4.46
3
2
(1 H, ddd, JH-H 11.8, 7.1 and 4.4, 6-H), 4.49 (1 H, d, JH-H
2
11.5, one of OCH2Ph), 4.55 (1 H, d, JH-H 11.5, one of
OCH2Ph), 7.20–7.30 (7 H, m, Ar-H) and 7.82 (2 H, d, JH-H
3
8.3, Ar-H); δC(75.4 MHz; C2HCl3) 21.47 (tosyl-CH3), 23.44,
23.72, 24.83, 32.5, 34.71, 35.18 and 37.41 (5 × C secondary of
cyclohexylidene, 3-C and 5-C), 70.71 (OCH2Ph), 70.97 (4-C),
72.98 (2-C), 76.42 (6-C), 81.43 (1-C), 109.72 (C quaternary of
cyclohexylidene), 127.52, 127.69, 128.05, 128.45 and 129.64
(Ar-CH) and 134.10, 138.2 and 144.56 (Ar-C quaternary); m/z
(EI) 472 (31%, Mϩ), 382 (7, [M ϩ H Ϫ C7H7]ϩ) and 91 (100,
ϩ
C7H7 ).
3
Ar-H) and 7.72 (2 H, d, JH-H 8.25, tosyl-H); δC(75.4 MHz;
C2HCl3) 18.94 [C(CH3)3], 21.48 (tosyl-CH3), 23.39, 23.68 and
24.84 (3 × C secondary of cyclohexylidene), 26.76 [C(CH3)3],
34.62, 35.34, 37.22 and 38.19 (2 × C secondary of cyclohexyl-
idene, 3-C and 5-C), 65.46 (4-C), 72.94 (2-C), 76.11 (6-C), 81.21
(1-C), 109.51 (C quaternary of cyclohexylidene) and 127.69,
127.76, 128.05, 129.61, 129.77, 129.84, 133.71, 133.94, 135.72,
135.76 and 144.4 (Aryl-CH and Ar-C quaternary); m/z (EI)
620 (3%, Mϩ), 353 (100) and 193 (17, [M Ϫ C7H7SO3 Ϫ
C16H19OSi]ϩ).
(؊)-(1R,2R,4R,6R)-4-Benzyloxy-6-(4Ј-methylphenylsulfonyl-
oxy)cyclohexane-1,2-diol 14
To a stirred solution of the ketal (Ϫ)-13 (4 g, 8.5 mmol) in
MeOH (50 cm3) was added TFA (0.1 cm3). After 2 days, the
solvent was removed under reduced pressure and the residual
oil was chromatographed on silica (ethyl acetate–petroleum
ether; 2:1) to give diol (Ϫ)-14 as a colourless oil (2.6 g, 78%)
and some unreacted starting material (Ϫ)-13 (0.6 g, 15%)
(Found: C, 60.8; H, 6.6. C20H24O6S requires C, 61.2; H, 6.2%)
(HRMS: found: [M ϩ H]ϩ, 393.1382. C20H25O6S requires
393.1372); [α]D Ϫ42.0 (c 0.67 in MeOH); νmax(neat)/cmϪ1 3472,
2926, 1600, 1444, 1361 and 1084; δH(300 MHz; C2HCl3) 1.37–
1.48 (1 H, m, 3-H), 1.49–1.61 (1 H, m, 5-H), 2.24–2.39 (2 H, m,
3-H, 5-H), 2.46 (3 H, m, tosyl-CH3), 2.54–2.62 (1 H, broad,
OH), 3.06–3.14 (1 H, broad, OH), 3.63 (1-H, dd, 3JH-H 8.8 and
2.8, 1-H), 3.75–3.86 (1 H, m, 4-H), 4.12–4.17 (1 H, m, 2-H),
4.46 (2 H, s, OCH2Ph), 4.70 (1 H, ddd, 3JH-H 11.8, 9.05 and 4.95,
6-H) and 7.20–7.30 (7 H, m, Ar-H) and 7.82 (2 H, d, 3JH-H 8.3,
tosyl-H); δC(75.4 MHz; C2HCl3) 21.62 (tosyl-CH3), 35.48 (3-
C), 36.16 (5-C), 68.59 (2-C), 70.86 (OCH2Ph), 70.95 (4-C),
73.61 (1-C), 80.42 (6-C), 127.59, 127.75, 127.94, 128.48 and
130.05 (Ar-CH) and 133.42, 138.25 and 145.34 (Ar-C quater-
nary); m/z (CI) 393 (67%, [M ϩ H]ϩ), 221 (63, [M ϩ H Ϫ
C7H8O3S]ϩ), 203 (51, [MH Ϫ C7H8O3S Ϫ H2O]ϩ), 113 (100)
(؊)-(1R,2R,4R,6R)-1,2-Cyclohexylidenedioxy-6-(4Ј-methyl-
phenylsulfonyloxy)cyclohexan-4-ol 12
To a stirred solution of the tosylate (Ϫ)-11 (8 g, 12.9 mmol) in
THF was added TBAF (15 cm3 of a 1 mol dmϪ3 solution in
THF, 15 mmol) and the resulting mixture was stirred at room
temperature for 16 h. The solvent was concentrated under
reduced pressure and the residual oil was chromatographed on
silica (ethyl acetate–petroleum ether; 1:1) to give alcohol (Ϫ)-
12 as a white solid (dihydrate: 5.39 g, 100%); mp 140–142 ЊC
(Found: C, 55.0; H, 6.6. C19H26O6Sؒ2H2O requires C, 54.5; H,
6.3%); [α]D Ϫ88.5 (c 0.3 in MeOH); νmax(Nujol)/cmϪ1 3394 s,
1464 s and 1381 s; δH(300 MHz; C2HCl3) 1.22–1.70 (12 H, m,
cyclohexylidene, 3-H and 5-H), 2.32–2.45 (5 H, m, 3-H, 5-H
and tosyl-CH3), 3.95 (1 H, dd, 1-H, 3JH-H 6.9 and 5.3), 3.99–4.10
(1 H, m, 4-H), 4.30–4.35 (1 H, m, 2-H), 4.45 (1 H, ddd, 6-H,
3JH-H 11.5, 7.1 and 4.4), 7.29 (2 H, d, 3JH-H 8.3, Ar-H) and 7.80
ϩ
and 91 (22, C7H7 ).
3
(2 H, d, JH-H 8.3, Ar-H); δC(75.4 MHz; C2HCl3) 21.53 (tosyl-
(؉)-(1S,2R,4R,6R)-4-Benzyloxy-1,6-epoxycyclohexan-2-ol 322
CH3), 23.49, 23.76, 24.86, 34.72, 35.0, 37.44 and 38.25 (5 ×
C secondary of cyclohexylidene, 3-C and 5-C), 63.94 (4-C),
73.07 (2-C), 76.16 (6-C), 81.29 (1-C), 109.65 (C quaternary of
cyclohexylidene), 128.10 and 129.75 (Ar-CH) and 134.04 and
144.71 (Ar-C quaternary); m/z (EI) 383 (100%, [M ϩ H]ϩ), 285
(11, [M ϩ H Ϫ C6H10O]ϩ), 211 (33, [M ϩ H Ϫ C7H8O3S]ϩ) and
99 (34, C6H11Oϩ).
To a stirred solution of the diol (Ϫ)-14 (2.5 g, 6.4 mmol) in
MeOH (30 cm3) was added K2CO3 (1.77 g, 12.8 mmol) in small
portions. The viscous reaction mixture was stirred at room tem-
perature for 30 min, filtered, and the pad washed thoroughly
with diethyl ether followed by ethyl acetate. The combined
organic solutions were concentrated under reduced pressure
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954
949

View Article Online
and the residual oil was chromatographed on silica (ethyl
acetate–petroleum ether; 1:1) to give epoxy alcohol (ϩ)-3 as a
white solid (1.27 g, 90%), mp 64–65 ЊC (Found: C, 70.7; H, 7.2.
C13H16O3 requires C, 70.9; H, 7.3%); [α]D ϩ56.4 (c 0.329 in
MeOH); δH(300 MHz; C2HCl3) 1.56 (1 H, ddd, 2JH-H 13.7, 3JH-H
9.3 and 2.0, 3-H), 1.90–2.10 (3 H, m, 2 × 5-H and 3-H), 3.32–
3.42 (2 H, m, 1-H and 6-H), 3.62–3.71 (1 H, m, 4-H), 4.26–4.38
(1 H, br s, 2-H), 4.42 (1 H, d, 2JH-H 11.7, one of OCH2Ph), 4.50
and 6-C), 76.73 (1-C), 127.67 and 128.46 (Ar-CH) and 138.62
(Ar-C quaternary); m/z (CI) 371 (26%, [M ϩ H]ϩ) and 107
(100). [Note that synthesis of racemic 16 has previously been
reported.12]
(؊)-(1S,2R,4S,6R)-1-(Diphenoxyphosphoryloxy)-2,4-bis(benz-
yloxy)-6-propyloxycyclohexane 17
Under an atmosphere of N2, a stirred solution of alcohol (Ϫ)-
16 (340 mg, 0.92 mmol) in dry dichloromethane (50 cm3) was
treated with DMAP (37 mg, 0.3 mmol) and dry TEA (0.17 cm3,
121 mg, 1.2 mmol) followed by diphenyl chlorophosphate
(0.31 cm3, 403 mg, 1.5 mmol). After stirring at room temper-
ature for 3 h, water (50 cm3) was added and the two phases
separated. The aqueous phase was extracted with dichloro-
methane (50 cm3) and the combined organic phases were
dried (MgSO4) and then concentrated under reduced pressure.
The residual oil was chromatographed on silica (ethyl acetate–
petroleum ether; 1:5) to give phosphate triester (Ϫ)-17 as a
colourless oil (510 mg, 92%) (HRMS: found: [M ϩ H]ϩ,
603.2504. C35H40O7P requires 603.2512); [α]D Ϫ37.7 (c 0.17 in
2
(1 H, d, JH-H 11.7, one of OCH2Ph) and 7.25–7.50 (5 H, m,
Ar-H); δC(75.4 MHz; C2HCl3) 29.14 and 32.50 (3-C and 5-C),
54.05 and 55.40 (1-C and 6-C), 64.83 (2-C), 70.13 (OCH2Ph),
71.63 (4-C), 127.51, 127.70 and 128.49 (Ar-CH) and 138.39
(Ar-C quaternary); m/z (CI) 221 (65%, [M ϩ H]ϩ), 203 (100,
[M ϩ H Ϫ H2O]). Epoxy alcohol (ϩ)-3 was also obtained
directly from compound (Ϫ)-13 in a one-pot reaction, simply
by adding K2CO3 (2.5 equivalents) to the reaction mixture of
compound (Ϫ)-13 in methanol, following the treatment with
TFA, after 3 days. An overall yield of 78% of (ϩ)-11 was
obtained together with 6% of recovered (Ϫ)-13. [Note that the
synthesis of racemic epoxy alcohol ( )-311,12 and spectroscopic
data thereof have been reported previously,12 and limited data
of (ϩ)-3 have also been reported previously.22]
3
MeOH); δH(300 MHz; C2HCl3) 0.84 (3 H, t, JH-H 7.8, OCH2-
CH2CH3), 1.38–1.55 (4 H, m, OCH2CH2CH3, 3-H and 5-H),
2.22–2.32 (1 H, m, secondary-H), 2.40–2.49 (1 H, m,
secondary-H), 3.36–3.50 (2 H, m, OCH2CH2CH3), 3.72–3.82
(2 H, m, 4-H and 6-H), 3.07–4.12 (1 H, m, 2-H), 4.41 (1 H, d,
(؉)-(1S,2R,4R,6R)-2,4-Bis(benzyloxy)-1,6-epoxycyclohexane
15
2
Under an atmosphere of N2, a solution of epoxy alcohol (ϩ)-3
(1.1 g, 5 mmol) in dry THF (50 cm3) was cooled in an ice bath
and benzyl bromide (0.66 cm3, 940 mg, 5.5 mmol) and then KH
(washed with petroleum ether prior to use, 220 mg, 5.5 mmol)
were added with stirring. Stirring was continued at room
temperature for 3 h and then water was added cautiously. The
mixture was extracted with diethyl ether (2 × 50 cm3), and
the organic phases were combined, dried (MgSO4) and then
concentrated under reduced pressure. The residual oil was
chromatographed on silica (ethyl acetate–petroleum ether; 1:5)
to give epoxide (ϩ)-15 as a colourless oil (1.44 g, 93%); [α]D
ϩ72.6 (c 0.208 in MeOH); δH(300 MHz; C2HCl3) 1.68–1.72
(1H, m, 3-H), 2.00–2.10 (3 H, m, 3-H and 2 × 5-H), 3.29–3.32
(1 H, m, 6-H), 3.42–3.46 (1 H, m, 1-H), 3.70–3.77 (1 H, m, 4-H),
4.15–4.23 (1 H, m, 2-H), 4.45 (2 H, s, OCH2Ph), 4.70 (1 H, d,
2JH-H 11.4, OCH2Ph), 4.45 (1 H, d, JH-H 12.3, OCH2Ph), 4.46
(1 H, d, 2JH-H 11.4, OCH2Ph), 4.52 (1 H, d, 2JH-H 12.3, OCH2Ph),
4.51–4.59 (1 H, m, 1-H) and 7.10–7.40 (20 H, m, Ar-H); δC(75.4
MHz; C2HCl3) 10.35 (OCH2CH2CH3), 23.09 (OCH2CH2CH3),
33.89 and 35.53 (3-C and 5-C), 70.60 (OCH2Ph), 71.07 (4-C),
71.78 (OCH2CH2CH3), 72.19 (OCH2Ph), 74.47 (C tertiary, 3JC-P
3
2
6.6), 75.35 (C tertiary, JC-P 2.8), 82.85 (1-C, JC-P 7.6), 120.12,
120.18, 120.20, 120.28, 125.15, 125.22, 127.55, 127.58, 127.61,
127.67, 128.35, 128.39, 128.44, 128.47 and 129.70 (Ar-CH),
138.51 and 138.59 (Ar-C quaternary) and 150.87 (Ar-C quater-
nary); δP(121.5 MHz; C2HCl3) Ϫ12.32; m/z (EI) 603 (16), 341
(13), 251 (56), 140 (43) and 91 (100). [Note that synthesis of
racemic 17 has previously been reported.12]
(؊)-(1S,2R,4S,6R)-1-[Bis(benzyloxy)phosphoryloxy]-2,4-bis-
(benzyloxy)-6-propyloxycyclohexane 18
2
2JH-H 12.1, OCH2Ph), 4.74 (1 H, d, JH-H 12.1, OCH2Ph) and
7.25–7.50 (10 H, m, Ar-H); δC(75.4 MHz; C2HCl3) 28.60
and 29.09 (3-C and 5-C), 52.25 and 53.12 (1-C and 6-C), 70.04
and 70.50 (OCH2Ph), 71.12 (4-C), 72.09 (2-C), 127.48, 127.62,
127.75 and 128.39 (Ar-CH) and 138.36 and 138.58 (Ar-C
quaternary); m/z (CI) 221 (8%, [M ϩ 2H Ϫ C7H7]ϩ) and 91
Under an atmosphere of N2, a stirred, cooled solution of the
phosphate triester (Ϫ)-17 (480 mg, 0.8 mmol) and benzyl
alcohol (0.165 cm3, 172 mg, 1.6 mmol) in dry THF (50 cm3) was
treated with NaH (60% dispersion in oil, 76 mg, 1.9 mmol). The
solution was allowed to warm to room temperature over 3 h
and then water (50 cm3) was added with caution. The mixture
was extracted with diethyl ether (2 × 50 cm3) and the organic
phases were combined and then dried (MgSO4) and concen-
trated under reduced pressure. The residual oil was chromato-
graphed on silica (ethyl acetate–petroleum ether) to give
phosphate triester (Ϫ)-18 as a white solid (340 mg, 67%), mp
68–69 ЊC (Found: C, 70.9; H, 7.1. C37H43O7P requires C, 70.5;
H, 6.9%) (HRMS: found: [M Ϫ C7H7]ϩ, 539.2204. C30H36O7P
requires 539.2199); [α]D Ϫ33.4 (c 0.155 in MeOH); δH(300 MHz;
C2HCl3) 0.86 (3 H, t, 3JH-H 7.4, OCH2CH2CH3), 1.34–1.46 (2 H,
m, 3-H and 5-H), 1.48–1.58 (2 H, m, OCH2CH2CH3), 2.09–2.29
(1 H, m, secondary-H), 2.38–2.47 (1 H, m, secondary-H),
3.4–3.54 (2 H, m, OCH2CH2CH3), 3.70–3.82 (2 H, m, 4-H and
6-H), 4.07–4.12 (1 H, m, 2-H), 4.28–4.36 (1 H, m, 1-H), 4.45
ϩ
(100, C7H7 ).
(؊)-(1S,2R,4S,6R)-2,4-Bis(benzyloxy)-6-propyloxycyclohex-
anol 16a
To an ice cooled, stirred solution of the epoxide (ϩ)-15 (620
mg, 2 mmol) and propan-1-ol (0.37 cm3, 300 mg, 5 mmol) in dry
toluene (5 cm3) was added BF3ؒOEt2 (3 drops of a 1:15 mixture
in dry toluene). After stirring at room temperature for 3 h the
solvent was removed under reduced pressure and the residual
oil chromatographed on silica (ethyl acetate–petroleum ether;
1:2) to give alcohol (Ϫ)-16 as a colourless oil (380 mg, 65%)
(HRMS: found: [M ϩ H]ϩ 371.2214. C23H31O4 requires
371.2222); [α]D Ϫ34.1 (c 0.18 in MeOH); δH(300 MHz; C2HCl3)
0.92 (3 H, t, 3JH-H 7.4, OCH2CH2CH3), 1.23–1.43 (2 H, m, 3-H
and 5-H), 1.54–1.67 (2 H, m, OCH2CH2CH3), 2.31–2.40 (1 H,
m, secondary-H), 2.45–2.53 (1 H, m, secondary-H), 3.39–3.61
(4 H, m, OCH2CH2CH3, 1-H and 6-H), 3.68–3.8 (1 H, m, 4-H),
2
2
(1 H, d, JH-H 11.5, OCH2Ph), 4.49 (1 H, d, JH-H 11.8,
OCH2Ph), 4.52 (1 H, d, 2JH-H 11.8, OCH2Ph), 4.58 (1 H, d, 2JH-H
11.8, OCH2Ph), 5.03–5.12 (4 H, m, 2 × POCH2Ph) and 7.20–
7.40 (20 H, m, Ar-H); δC(75.4 MHz; C2HCl3) 10.40 (OCH2-
CH2CH3), 23.22 (OCH2CH2CH3), 33.95 and 35.37 (3-C and
2
3.93–3.98 (1 H, m, tertiary-H), 4.46 (1 H, d, JH-H 12.8,
2
OCH2Ph), 4.53 (1 H, d, JH-H 12.8, OCH2Ph), 4.60 (2 H, s,
2
2
OCH2Ph) and 7.20–7.50 (10 H, m, Ar-H); δC(75.4 MHz;
C2HCl3) 10.49 (OCH2CH2CH3), 23.24 (OCH2CH2CH3), 34.05
and 35.31 (3-C and 5-C), 70.60 (OCH2Ph), 71.17 (OCH2-
CH2CH3), 71.67 (4-C), 72.02 (OCH2Ph), 75.59 and 76.18 (2-C
5-C), 69.00 (POCH2Ph, JC-P 5.4), 69.11 (POCH2Ph, JC-P 6.5),
70.59 (OCH2Ph), 71.20 (4-C), 71.65 (OCH2CH2CH3), 72.31
(OCH2Ph), 74.65 (C tertiary, 3JC-P 6.5), 75.24 (C tertiary), 81.36
2
(1-C, JC-P 6.6), 127.56, 127.61, 127.65, 127.82, 127.89, 128.32,
950
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954

View Article Online
128.38, 128.41, 128.45, 128.54 and 128.60 (Ar-CH) and 138.64
(Ar-C quaternary); δP(121.5 MHz; C2HCl3) Ϫ1.55; m/z (EI) 539
(21), 279 (26), 261 (25) and 91 (100). [Note that synthesis of
racemic 18 has previously been reported.12]
(؊)-(1S,2R,4S,6R)-2,4-Bis(benzyloxy)-6-isopropoxycyclohex-
anol 20
This compound was prepared in a manner identical with that
described for the 6-propoxy compound 16b using isopropanol
(40 mg, 0.05 cm3, 0.64 mmol) to give the protected tetraol 20 as
a light brown oil which did not require any further purification
(110 mg, 99%) (HRMS: found: [M ϩ H]ϩ, 370.2157. C23H30O4
requires 370.2144); [α]D Ϫ25.6 (c 0.31 in EtOAc); νmax(neat)/
cmϪ1 3481 s, 2935 s, 1731 s and 1080 s; δH(300 MHz; C2HCl3)
1.00–1.15 (6 H, m, 2 × CH3), 1.17–1.97 (2 H, m, secondary-H),
2.22–2.42 (3 H, m, secondary-H and OH), 3.37–3.40 (1 H, m,
6-H), 3.46–3.57 (1 H, m, 1-H), 3.61–3.76 (2 H, m, 1Ј-CH and
4-H), 3.86–3.89 (1 H, m, 2-H), 4.36–4.60 (4 H, m, 2 × CH2Ph)
and 7.17–7.37 (10 H, m, Ar-H); δC(75 MHz; C2HCl3) 22.33 and
23.35 (CH3), 34.12 (3-C), 36.51 (5-C), 70.44 (1Ј-C), 70.53
(OCH2Ph), 71.66 (4-C), 72.09 (OCH2Ph), 74.49 (6-C), 75.64
(2-C), 75.28 (2-C), 76.14 (1-C), 127.62, 127.65 and 128.44
(Ar-CH) and 138.68 and 138.71 (Ar-C quaternary); m/z (EI)
370 (3%, [M ϩ H]ϩ), 279 (23), 205 (11) and 91 (100).
(؊)-(1R,2R,4R,6R)-6-Propoxy-2,4-dihydroxycyclohexyl bis-
(cyclohexylammonium) phosphate [bis(cyclohexylammonium)
salt of 19]
Under an atmosphere of N2, gaseous ammonia (15–20 cm3) was
condensed at Ϫ78 ЊC, and sodium metal (110 mg, 4.8 mmol)
was added. A solution of phosphate triester (Ϫ)-19 (300 mg,
0.48 mmol) in dry THF (0.5 cm3) was added to the blue solution
through a septum. After stirring at Ϫ78 ЊC for 30 min, meth-
anol (2 cm3) was added and the mixture allowed to warm up to
room temperature. The solvents were removed under reduced
pressure and the residual white solid was subjected to ion
exchange chromatography (Amberlite IR-118H), eluting
with water. The acidic fractions containing the product
were collected and an excess of freshly distilled cyclohexyl-
amine was added and stirring at room temperature continued
for 4 h. The aqueous layer was extracted with diethyl ether
(3 × 50 cm3) to remove the excess of cyclohexylamine, and
lyophilised. The crude white solid was recrystallised from
water–acetone to give phosphate (Ϫ)-19 as a white solid (84 mg,
65%); mp >200 ЊC (decomp.); [α]D Ϫ37.7 (c 0.526 in MeOH);
(؊)-(1S,2R,4S,6R)-2,4-Bis(benzyloxy)-6-(2-phenylethoxy)-
cyclohexanol 21
This compound was prepared in a manner identical with that
described for the 6-propoxy compound 16b using 2-phenyl-
ethanol (0.04 g, 0.04 cm3, 0.32 mmol) to give a light brown oil
which was purified by silica column chromatography (ethyl
acetate–petroleum ether; 1:5) to afford the 6-(2-phenylethyl)
protected tetraol 21 as a colourless oil (90 mg, 65%); [α]D Ϫ70.6
(c 0.34 in EtOAc); δH(300 MHz; C2HCl3) 1.19–1.29 and 2.18–
2.41 (4 H, m, 2 × secondary-H), 2.80 (2 H, m, CH2Ph), 3.34–3.42
(2 H, m, 1-H and 6-H), 4.03–4.06 (1 H, m, 2-H), 3.58–3.80 (3 H,
m, 4-H and -OCH2CH2), 3.83 (1 H, m, 2-H), 4.33–4.57 (4 H, m,
2 × OCH2Ph) and 7.03–7.35 (15 H, m, Ar-H); δC(75 MHz;
C2HCl3) 33.91 (3-C), 35.11 (5-C), 36.53 (8-CH2), 70.20 (7-CH2),
70.49 (OCH2Ph), 71.51 (4-CH), 71.92 (OCH2Ph), 75.42 (6-C),
76.01 (2-C), 77.01 (1-C), 126.26, 127.55, 127.61, 127.63, 128.38,
128.41 and 128.90 (Ar-CH) and 138.54 and 138.91 (Ar-C
quaternary).
2
3
δH(500 MHz; H2O) 0.74 (3 H, t, JH-H 7.41, OCH2CH2CH3),
0.94–1.12 (2 H, m, 2 × 4-H of Cha†), 1.12–1.30 (9 H, m,
2 × {2 × 2-H and 3-H of Cha} and 5-H), 1.36–1.54 (5 H,
m, OCH2CH2CH3, 2 × 4-H of Cha and 3-H), 1.58–1.70 [4 H,
m, 2 × (2 × 3-H of Cha)], 1.79–1.88 [4 H, m, 2 × (2 × 2-H
of Cha)], 1.9–2.0 (1 H, m, 3-H), 2.12–2.20 (1 H, m, 5-H), 2.94–
3.06 (2 H, m, 2 × 1-H of Cha), 3.40–3.60 (3 H, m, OCH2-
CH2CH3 and 6-H), 3.80–3.91 (2 H, m, 1-H and 4-H) and
2
4.16–4.22 (1 H, m, 2-H); δC(75.4 MHz; H2O) 9.40 (OCH2-
CH2CH3), 22.08 (OCH2CH2CH3), 23.42 (3-C of Cha), 23.91
(4-C of Cha), 29.97 (2-C of Cha), 36.68 (5-C), 36.95 (3-C), 50.0
(1-C of Cha), 64.08 (4-C), 67.13 (2-C), 71.72 (OCH2CH2CH3),
2
75.12 (1-C, JC-P 6.6) and 77.29 (6-C, broad); δP(121.4 MHz;
2H2O) ϩ3.11. [Note that synthesis of racemic 19 has previously
been reported.12]
(؊)-(1R,2R,4S,6S,2ЈS)-2,4-Bis(benzyloxy)-6-(1Ј-benzyloxy-3Ј-
phenylpropan-2-yloxy)cyclohexanol 22
(؊)-(1S,2R,4S,6R)-2,4-Bis(benzyloxy)-6-propyloxycyclohexanol
16b
A stirred solution of the epoxide (ϩ)-15 (620 mg, 2 mmol) and
(2S)-1-benzyloxy-3-phenylpropan-2-ol (726 mg, 3 mmol) in dry
toluene (5 cm3) was cooled in an ice bath. BF3ؒEt2O (0.1 cm3 of
a 1:15 mixture of BF3ؒEt2O in dry toluene) was added drop-
wise, and stirring at room temperature was continued for 1 h.
The solvent was then removed under reduced pressure and the
residual oil chromatographed on silica (ethyl acetate–petroleum
ether; 1:2) to give alcohol (Ϫ)-22 as a colourless oil (550 mg,
50%) (HRMS: found: [M ϩ H]ϩ, 553.2947. C36H41O5 requires
553.2954); [α]D Ϫ24.0 (c 0.14 in MeOH); νmax(neat)/cmϪ1 3462 s,
2916 s, 1463 s and 1093 s; δH(300 MHz; C2HCl3) 1.08–1.21 (1 H,
m, 5-H), 1.21–1.34 (1 H, m, 3-H), 1.85–1.95 (1 H, m, 5-H),
2.18–2.28 (1 H, m, 3-H), 2.72 (1 H, dd, 2JH-H 13.6, 3JH-H 7.7, 3Ј-
H), 2.80 (1 H, dd, 2JH-H 13.6, 3JH-H 5.5, 3Ј-H), 3.47–3.64 (5 H, m,
1-H, 4-H, 6-H and 2 × 1Ј-H), 3.91 (1 H, br s, 2-H), 3.95–4.5
(1 H, m, 2Ј-H), 4.31 (1 H, d, 2JH-H 11.7, one of OCH2Ph), 4.40
To a stirred solution of the epoxide (ϩ)-15 (180 mg, 0.58 mmol)
in 1,2-dichloroethane (25 cm3) was added Yb()(OTf)3 (128
mg, 0.08 mmol) followed by propan-1-ol (1.28 mmol, 80 mg, 0.1
cm3). The mixture was refluxed for 3 h, and then the solvent was
removed under reduced pressure. The residue was then washed
with water (10 cm3) and then extracted with ethyl acetate
(2 × 10 cm3). The combined organic layers were dried (Na2SO4)
and the solvent removed under reduced pressure to give a light
coloured oil (0.21 g, 98%) (HRMS: found: [M ϩ H]ϩ, 371.2229.
C36H41O5 requires 371.2222); [α]D Ϫ25.0 (c 1.1 in EtOAc);
νmax(neat)/cmϪ1 3490 s, 2975 s, 1728 s and 1090 s; δH(300 MHz;
C2HCl3) 0.85 (3 H, t, JH-H 7.42, OCH2CH2CH3), 1.16–1.34 (2 H,
m, secondary-H), 1.47–1.58 (2 H, qt, OCH2CH2CH3), 2.25–
2.49 (3 H, m, 2 × secondary-H and OH), 3.32–3.63 (4 H, m,
OCH2CH2CH3, 4-H and 6-H), 3.64–3.88 (2 H, m, 1-H and
2-H), 4.37–4.60 (4 H, m, 2 × OCH2Ph), 7.17–7.27 (10 H, m,
Ar-H); δC(75 MHz; C2HCl3) 23.33 (CH3), 34.10 (3-C), 35.38
(5-C), 70.67 (OCH2Ph), 71.24 (7-CH2), 71.74 (4-C), 72.10
(OCH2Ph), 75.66 (6-C), 76.26 (2-CH), 76.82 (1-C), 76.01 (2-C),
77.01 (1-C), 127.80, 128.57 and 138.76 (Ar-CH), 138.73 (Ar-C
quaternary); m/z (CI) 371 (100%, [M ϩ H]ϩ), 281 (49), 263 (31),
107 (78) and 91 (20).
2
2
(1 H, d, JH-H 11.7, one of OCH2Ph), 4.53 (1 H, d, JH-H 12.3,
2
one of OCH2Ph), 4.56 (2 H, s, OCH2Ph), 4.71 (1 H, d, JH-H
12.3, one of OCH2Ph) and 7.20–7.50 (20 H, m, Ar-H); δC(75.4
MHz; C2HCl3) 34.86 and 36.92 (3-C and 5-C), 39.55 (3Ј-C),
70.39 (OCH2Ph), 71.87 (4-C), 72.42 (OCH2Ph), 73.04 (1Ј-C),
73.50 (OCH2Ph), 76.25 (C tertiary), 77.10 (C tertiary), 78.75
(2Ј-C), 81.26 (1-C), 126.49, 127.36, 127.45, 127.58, 127.68,
127.92, 127.97, 128.28, 128.38, 128.42, 128.53 and 129.70 (Ar-
CH) and 137.46, 138.21, 138.78 and 139.32 (Ar-C quaternary);
m/z (CI) 553 (100%, [M ϩ H]ϩ) and 462 (8, [MH Ϫ C7H7]ϩ);
m/z (FAB-MS) 553 (16%, (M ϩ H]ϩ) and 181 (100).
† Cha = cyclohexylammonium.
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954
951

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(؊)-(1R,2R,4S,6S,2ЈS)-1-(Diphenoxyphenylphosphoryloxy)-
2,4-bis(benzyloxy)-6-(1Ј-benzyloxy-3Ј-phenylpropan-2-yloxy)-
cyclohexane 23
C2HCl3) Ϫ1.49; m/z (FAB-MS) 813 (5%, [M ϩ H]ϩ), 279 {25,
[(PhCH2O)2PO2H2]ϩ} and 181 (100).
(؊)-(1R,2R,4R,6R,2ЈS)-2,4-Dihydroxy-6-(1-hydroxy-3-phenyl-
propan-2-yloxy)cyclohexyl bis(cyclohexylammonium) phosphate
[bis(cyclohexylammonium) salt of 25]
Alcohol (Ϫ)-22 (500 mg, 0.9 mmol), DMAP (244 mg, 0.2
mmol) and dry TEA (0.14 cm3, 101 mg, 1 mmol) were dissolved
in dry dichloromethane (50 cm3) under an atmosphere of N2,
and cooled in an ice bath. Diphenyl chlorophosphate (0.31 cm3,
403 mg, 1.5 mmol) was added dropwise and stirring at room
temperature was continued for 16 hours. Water (50 cm3) was
added and the two phases separated. The aqueous phase was
extracted with dichloromethane (50 cm3) and the combined
organic phases were dried (MgSO4) and then concentrated
under reduced pressure. The residual oil was chromatographed
on silica (ethyl acetate–petroleum ether; 1:2) to give phosphate
triester (Ϫ)-23 as a colourless oil (660 mg, 90%); [α]D Ϫ22.6
(c 0.2825 in MeOH); νmax(neat)/cmϪ1 2936 s, 1600 s, 1498 s, 1463
s, 1361 s, 1283 s, 1190 s, 1059 s and 957 s; δH(300 MHz; C2HCl3)
Under an atmosphere of nitrogen, ammonia gas was condensed
(15–20 cm3) at Ϫ78 ЊC and sodium metal (103.5 mg, 4.5 mmol)
was added. A solution of phosphate triester (Ϫ)-24 (350 mg,
0.43 mmol) in dry THF (1 cm3) was added to the blue solution
through a septum. After stirring at Ϫ78 ЊC for 30 minutes,
methanol (5 cm3) was added to quench the reaction, followed
by water (2 cm3) and the mixture allowed to warm up to room
temperature. The solvents were removed under reduced
pressure and the residual solid was subjected to ion exchange
chromatography (Amberlite IR-118H), eluting with water. The
acidic fractions containing the product were collected and an
excess of cyclohexylamine was added and stirring at room
temperature continued for 1 h. The aqueous solution was then
lyophilised and the residual white solid was dissolved in water
(5 cm3). Dichloromethane (10 cm3) was added to the mixture
and after stirring for 15 min, the aqueous phase was pipetted
off and lyophilised to give phosphate (Ϫ)-25 as a white solid
(149 mg, 62%); mp >200 ЊC (decomp.) (HRMS: found:
[MH2 Ϫ C6H14N]ϩ, 462.2243. C21H37NO8P requires 462.2257);
[α]D Ϫ40.9 (c 0.3535 in MeOH); δH(500 MHz; 2H2O) 0.99–1.08
(1 H, m, 5-H), 1.08–1.70 (2 H, m, 2 × 4-H of Cha), 1.22–1.34
[8 H, m, 2 × (2 × 2-H and 2 × 3-H of Cha)], 1.38–1.44 (1 H, m,
3-H), 1.56–1.62 (2 H, m, 2 × 4-H of Cha), 1.70–1.79 [5 H, m,
2 × (2 × 3-H of Cha) and 5-H], 1.89–1.96 [4 H, m, 2 × (2 × 2-H
of Cha)], 1.95–2.0 (1 H, m, 3-H), 2.76 (1 H, dd, 2JH-H 13.4, 3JH-H
7.8, 3Ј-H), 2.81 (1 H, dd, 2JH-H 14.5, 3JH-H 5.6, 3Ј-H), 3.00–3.14
(2 H, m, 2 × 1-H of Cha), 3.49 (1 H, dd, 2JH-H 12.2, 3JH-H 4.45,
1Ј-H), 3.55–3.62 (1 H, m, 6-H), 3.71 (1 H, dd, 2JH-H 12.2, 3JH-H
3.3, 1Ј-H), 3.73–3.79 (1 H, m, 4-H), 3.82–3.88 (2 H, m, 2Ј-H and
1-H), 4.19–4.24 (1 H, m, 2-H) and 7.10–7.30 (5 H, m, Ar-H);
3
0.98–1.12 (1 H, m, 5-H), 1.34–1.45 (1 H, ‘t’, JH-H 13.8, 3-H),
1.94–2.04 (1 H, m, 5-H), 2.15–2.25 (1 H, m, 3-H), 2.61 (1 H, dd,
2JH-H 16.5, 3JH-H 9.3, 3Ј-H), 2.90 (1 H, dd, 2JH-H 16.5, 3JH-H 6.0,
2
3
3Ј-H), 3.34 (1 H, dd, JH-H 9.6, JH-H 5.8, 1Ј-H), 3.50 (1 H, dd,
3
2JH-H 9.6, JH-H 4.7, 3Ј-H), 3.55–3.65 (1 H, m, 4-H), 3.72–3.82
(1 H, m, 2Ј-H), 3.85–3.94 (1 H, m, 6-H), 4.09–4.15 (1 H, m,
2
2-H), 4.28 (1 H, d, JH-H 11.5, one of OCH2Ph), 4.38 (1 H, d,
2JH-H 11.5, one of OCH2Ph), 4.37–4.44 (4 H, m, 2 × OCH2Ph),
4.45–4.56 (1 H, m, 1-H) and 7.20–7.50 (20 H, m, Ar-H); δC(75.4
MHz; C2HCl3) 33.88 (3-C), 35.16 (5-C), 39.17 (3Ј-C), 70.3
(OCH2Ph), 70.79 (4-C), 71.95 (OCH2Ph), 72.25 (1Ј-C), 73.27
3
(OCH2Ph), 73.89 (6-C, JC-P 7.5), 75.12 (2-C), 78.89 (2Ј-C),
3
82.46 (1-C, JC-P 6.0), 120.10, 120.18, 120.26, 125.14, 125.22,
126.16, 127.48, 127.61, 127.67, 128.14, 128.29, 128.32, 128.39,
129.71 and 129.79 (Ar-CH), 138.42, 138.54 and 138.92 (Ar-C
2
quaternary), 150.70 (Ar-C quaternary, JC-P 6.5) and 150.90
(Ar-C quaternary, 2JC-P 7.0); δP(121.5 MHz; C2HCl3) Ϫ12.29.
(؊)-(1R,2R,4S,6S,2ЈS)-1-[Bis(benzyloxy)phosphoryloxy]-2,4-
bis(benzyloxy)-6-(1Ј-benzyloxy-3Ј-phenylpropan-2-yloxy)cyclo-
hexane 24
2
δC(75.4 MHz; H2O) 24.41 and 24.91 (3-C and 4-C of Cha),
30.96 (2-C of Cha), 38.21 (3-C), 38.31 (3-C), 39.17 (5Ј-C), 51.0
(1-C of Cha), 63.75 (1Ј-C), 64.5 (4-C), 68.54 (2-C), 76.19 (6-C,
3JC-P 5.4), 78.96 (1-C, 2JC-P 5.4), 83.08 (2Ј-C), 127.24, 129.29 and
130.34 (Ar-CH) and 139.41 (Ar-C quaternary); δP(121.5 MHz;
2H2O) 1.16; m/z (FAB-MS) 462 (72%, [MH2 Ϫ C6H14N]ϩ),
385 (40, [MH2 Ϫ C6H14N Ϫ C7H7]ϩ), 363 (15, [MH3 Ϫ 2 ×
C6H14N]ϩ) and 105 (100).
Under an atmosphere of N2, a stirred, cooled solution of the
phosphate triester (Ϫ)-23 (610 mg, 0.69 mmol) and benzyl
alcohol (0.14 cm3, 151 mg, 1.4 mmol) in dry THF (50 cm3) was
treated with NaH (60% dispersion in oil, 60 mg, 1.5 mmol). The
mixture was stirred at room temperature for a further 2 h and
then quenched with water (20 cm3). The mixture was extracted
with diethyl ether (2 × 50 cm3) and the organic phases were
combined, dried (MgSO4), and then concentrated under
reduced pressure. The residual oil was chromatographed on
silica (ethyl acetate–petroleum ether; 1:1) to give phosphate
triester (Ϫ)-24 as a colourless oil (375 mg, 67%) (Found: C,
73.6; H, 6.45. C50H53O8P requires C, 73.9; H, 6.6%); [α]D Ϫ27.1
(c 0.3425 in MeOH); δH(300 MHz; C2HCl3) 1.00–1.11 (1 H, m,
5-H), 1.27–1.40 (1 H, m, 3-H), 1.95–2.04 (1 H, m, 5-H), 2.12–
(؊)-(1R,2R,4S,6S,2ЈR)-2,4-Bis(benzyloxy)-6-(1Ј-benzyloxy-3Ј-
phenylpropan-2-yloxy)cyclohexanol 26
This compound was prepared in a manner identical with that
described for the alcohol (Ϫ)-(1R,2R,4S,6S,2ЈS)-22, using
epoxide (ϩ)-15 (620 mg, 2 mmol) and (2R)-1-benzyloxy-3-
phenylpropan-2-ol (726 mg, 3 mmol) to give alcohol (Ϫ)-26 as
a colourless oil (500 mg, 45%) (HRMS: found: [M ϩ H]ϩ,
553.2959. C36H41O5 requires 553.2954); [α]D Ϫ12.7 (c 0.5 in
MeOH); νmax(neat)/cmϪ1 3570 s, 3472 s, 2935 s, 2868 s, 1610 s,
1502 s, 1449 s, 1347 s, 1244 s, 1093 s and 918 s; δH(300 MHz;
2
3
2.42 (1 H, m, 3-H), 2.67 (1 H, dd, JH-H 12.7, JH-H 8.0, 3Ј-H),
2
3
2
2.92 (1 H, dd, JH-H 13.5, JH-H 4.7, 3Ј-H), 3.43 (1 H, dd, JH-H
9.9, 3JH-H 5.75, 1Ј-H), 3.53 (1 H, dd, 2JH-H 9.9, 3JH-H 5.4, 1Ј-H),
3.57–3.65 (1 H, m, 4-H), 3.72–3.88 (2 H, m, 2Ј-H and 6-H),
4.10–4.15 (1 H, m, 2-H), 4.22–4.29 (1 H, m, 1-H), 4.30 (1 H, d,
3
C2HCl3) 1.26–1.43 (2 H, m, 3-H and 5-H), 2.07 (1 H, d, JH-H
4.5, OH), 2.22–2.32 (1 H, m, 3-H), 2.38–2.47 (1 H, m, 5-H), 2.84
(1 H, dd, 2JH-H 12.7, 3JH-H 7.7, 3Ј-H), 2.92 (1 H, dd, 2JH-H 14.0,
3JH-H 5.8, 3Ј-H), 3.36–3.43 (1 H, m, 1-H), 3.5 (2 H, ‘d’, JH-H 5.5,
2 × 1Ј-H), 3.54–3.64 (1 H, m, 6-H), 3.65–3.73 (1 H, m, 4-H),
3.82–3.87 (1 H, m, 2-H), 3.88–3.97 (1 H, m, 2Ј-H), 4.36 (1 H, d,
2
2JH-H 11.4, one of OCH2Ph), 4.38 (1 H, d, JH-H 11.4, one of
OCH2Ph), 4.42 (2 H, s, OCH2Ph), 4.47 (1 H, d, 2JH-H 12.0, one
2
of OCH2Ph), 4.56 (1 H, d, JH-H 12.0, one of OCH2Ph), 4.97–
5.12 (4 H, m, 2 × POCH2Ph) and 7.15–7.45 (30 H, m, Ar-H);
δC(75.4 MHz; C2HCl3) 34.0 and 35.21 (3-C and 5-C), 39.16 (3Ј-
2JH-H 11.8, one of OCH2Ph), 4.45 (1 H, d, JH-H 11.5, one of
2
2
2
C), 68.97 (POCH2Ph, JC-P 5.4), 69.08 (POCH2Ph, JC-P 5.4),
70.31 (OCH2Ph), 70.90 (4-C), 71.93 (OCH2Ph), 72.18 (1Ј-C),
OCH2Ph), 4.50 (1 H, d, 2JH-H 12.1, one of OCH2Ph), 4.55 (2 H,
s, OCH2Ph), 4.58 (1 H, d, 2JHH 12.1, one of OCH2Ph) and 7.20–
7.50 (20 H, m, Ar-H); δC(75.4 MHz; C2HCl3) 34.40 and 36.91
(3-C and 5-C), 38.97 (3Ј-C), 70.52 (OCH2Ph), 71.88 (4-C), 72.12
(OCH2Ph), 72.83 (1Ј-C), 73.37 (OCH2Ph), 75.93 (C tertiary),
76.18 (C tertiary), 77.16 (2Ј-C), 79.55 (1-C), 126.50, 127.51,
127.54, 127.57, 127.62, 127.68, 128.33, 128.40, 128.43, 128.51
3
73.24 (OCH2Ph), 74.05 (6-C, JC-P 7.5), 75.06 (2-C), 78.93
(2Ј-C), 81.10 (1-C), 126.18, 127.49, 127.60, 127.66, 127.78,
127.82, 127.85, 127.98, 128.14, 128.29, 128.32, 128.36, 128.41,
128.51, 128.57, 128.59, 128.6 and 129.78 (Ar-CH) and 138.42,
138.58, 138.68 and 138.85 (Ar-C quaternary); δP(121.5 MHz;
952
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954

View Article Online
and 129.57 (Ar-CH) and 138.21, 138.61, 138.75 and 138.91
(Ar-C quaternary); m/z (CI) 553 (44%, [M ϩ H]ϩ), 463 (100,
[MH2 Ϫ C7H7]ϩ), 373 (64, [MH3 Ϫ 2 × C7H7]ϩ) and 91 (20,
[C7H7]ϩ).
m, 2 × 4-H of Cha), 1.02–1.15 [8 H, m, 2 × (2 × 2-H and 2 ×
3-H of Cha)], 1.30–1.43 (4 H, m, 2 × 4-H of Cha, 3-H, 5-H),
1.50–1.59 [4 H, m, 2 × (2 × 3-H of Cha)], 1.65–1.76 [5 H, m,
2 × (2 × 2-H of Cha) and 5-H], 1.81–1.89 (1 H, m, 3-H), 2.80
(1 H, dd, 2JH-H 13.5, 3JH-H 7.5, 3Ј-H), 2.92 (1 H, dd, 2JH-H 13.5,
3JH-H 6.0, 3Ј-H), 3.07–3.13 (2 H, m, 2 × 1-H of Cha), 3.46 (1 H,
dd, 2JH-H 11.5, 3JH-H 6.0, 1Ј-H), 3.59–3.65 (1 H, m, 1Ј-H), 3.76–
3.81 (1 H, br s, 2-H), 3.86–3.92 (1 H, m, 2Ј-H), 3.92–4.04 (3 H,
m, 4-H, 2-H and 1-H) and 7.10–7.30 (5 H, m, Ar-H); δC(75.4
MHz; 2H2O) 24.40 and 24.90 (3-C and 4-C of Cha), 30.96 (2-C
of Cha), 34.60 (3-C, broad), 36.82 (5-C), 37.58 (3Ј-C), 51.01
(1-C of Cha), 62.85 (1Ј-C), 66.36 (C tertiary), 66.63 (C tertiary),
(؊)-(1R,2R,4S,6S,2ЈR)-1-(Diphenoxyphosphoryloxy)-2,4-bis-
(benzyloxy)-6-(1Ј-benzyloxy-3Ј-phenylpropan-2-yloxy)cyclo-
hexane 27
This compound was prepared in a manner identical with that
described for the phosphate triester (Ϫ)-(1R,2R,4S,6S,2ЈS)-23,
using alcohol (Ϫ)-26 (450 mg, 0.82 mmol) to give phosphate
triester (Ϫ)-27 as a colourless oil (530 mg, 83%) (HRMS:
found: [M ϩ H]ϩ, 785.3253. C48H50O8P requires 785.3243); [α]D
Ϫ2.1 (c 0.6125 in MeOH); δH(300 MHz; C2HCl3) 1.45–1.61
(2 H, m, 3-H and 5-H), 2.19–2.29 (1 H, m, secondary-H), 2.36–
2.46 (1 H, m, secondary-H), 2.74 (1 H, dd, 2JH-H 13.7, 3JH-H 8.2,
3Ј-H), 2.94 (1 H, dd, 2JH-H 13.7, 3JH-H 5.2, 3Ј-H), 3.35 (1 H, dd,
2JH-H 10.2, 3JH-H 6.0, 1Ј-H), 3.43 (1 H, dd, 2JH-H 10.2, 3JH-H 3.6,
1Ј-H), 3.67–3.78 (1 H, m, 4-H), 3.87–3.96 (1 H, m, 2Ј-H), 3.98–
4.08 (1 H, m, 6-H), 4.04–4.20 (1 H, m, 2-H), 4.33 (1 H, d, 2JH-H
11.8, one of OCH2Ph), 4.39–4.45 (3 H, m, 1.5 of OCH2Ph),
4.48 (2 H, s, OCH2Ph), 4.52–4.60 (1 H, m, 1-H) and 7.2–7.5 (20
H, m, Ar-H); δC(75.4 MHz; C2HCl3) 33.71 (3-C), 35.84 (5-C,
broad), 38.27 (3Ј-C), 70.47 (OCH2Ph), 71.26 (4-C), 71.88
(OCH2Ph), 72.12 (1Ј-C), 73.23 (OCH2Ph), 73.80 (6-C, 3JC-P 6.5),
74.92 (2-C), 79.94 (2Ј-C), 82.59 (1-C, broad), 120.11, 120.19,
120.25, 120.30, 125.27, 126.11, 127.49, 127.52, 127.55, 127.58,
127.6, 128.29, 128.35, 128.39, 129.53, 129.63, 129.71 and 129.76
(Ar-CH), 138.36, 138.43, 138.55 and 138.66 (Ar-C quaternary),
150.73 (Ar-C quaternary, 2JC-P 7.6) and 150.8 (Ar-C quaternary,
2JC-P 2.1); δP(121.5 MHz; C2HCl3) Ϫ12.22; m/z (FAB-MS) 785
(15%, [M ϩ H]ϩ) and 251 (100, [(PhO)2PO2H2]ϩ).
3
75.30 (1-C, broad), 75.37 (6-C, JC-P 5.4), 80.02 (2Ј-C), 127.25,
129.45 and 130.26 (Ar-CH) and 139.29 (Ar-C quaternary);
δP(121.5 MHz; 2H2O) 3.0.
Acknowledgements
The authors thank the BBSRC and EPSRC for grants J29893
and K35792, the Wellcome Trust for grant 040331, the EPSRC
for a studentship for M. W. B. and Dr Mahmoud Akhtar for
scientific support.
References
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2 D. Gani, C. P. Downes, I. Batty and J. Bramham, Biochem. Biophys.
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5 R. Bone, J. P. Springer and J. R. Atack, Proc. Natl. Acad. Sci.
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(؊)-(1R,2R,4S,6S,2ЈR)-1-[Bis(benzyloxy)phosphoryloxy]-2,4-
bis(benzyloxy)-6-(1Ј-benzyloxy-3Ј-phenylpropan-2-yloxy)cyclo-
hexane 28
6 (a) A. G. Cole and D. Gani, J. Chem. Soc., Chem. Commun., 1994,
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This compound was prepared in a manner identical with that
described for the phosphate triester (Ϫ)-(1R,2R,4S,6S,2ЈS)-24,
using the phosphate triester (Ϫ)-27 (500 mg, 0.64 mmol) to give
phosphate triester (Ϫ)-28 as a colourless oil (322 mg, 62%)
(Found: C, 73.65; H, 7.25. C50H53O8P requires C, 73.9; H,
6.6%); [α]D Ϫ3.5 (c 0.405 in MeOH); δH(300 MHz; C2HCl3)
1.38–1.55 (2 H, m, 3-H and 5-H), 2.13–2.23 (1 H, m, secondary-
H), 2.32–2.42 (1 H, m, secondary-H), 2.78 (1 H, dd, 2JH-H 13.7,
3JH-H 8.0, 3Ј-H), 2.96 (1 H, dd, 2JH-H 13.7, 3JH-H 4.9, 3Ј-H), 3.32
(1 H, dd, 2JH-H 10.2, 3JH-H 5.8, 1Ј-H), 3.40 (1 H, dd, 2JH-H 10.2,
3JH-H 3.6, 1Ј-H), 3.66–3.76 (1 H, m, 4-H), 3.83–3.91 (1 H, m, 2Ј-
H), 3.92–3.42 (1 H, m, 6-H), 4.09–4.15 (1 H, m, 2-H), 4.24–4.32
(1 H, m, 1-H), 4.33 (1 H, d, 2JH-H 11.8, one of OCH2Ph), 4.41–
4.48 (3 H, m, 1.5 of OCH2Ph), 4.53 (1 H, d, 2JH-H 11.5, one of
OCH2Ph), 5.00–5.10 (4 H, m, 2 × POCH2Ph) and 7.10–7.40
(30 H, m, Ar-H); δC(75.4 MHz; C2HCl3) 33.82 (3-C), 35.60
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2
(5-C, broad), 38.21 (3Ј-C), 69.09 (POCH2Ph, JC-P 5.4), 69.23
2
(POCH2Ph, JC-P 5.4), 70.48 (OCH2Ph), 71.42 (4-C), 72.0
(OCH2Ph), 72.11 (1Ј-C), 73.23 (OCH2Ph), 74.34 (6-C, 3JC-P 7.5),
74.85 (2-C), 79.59 (2Ј-C), 81.18 (1-C, broad), 126.12, 127.53,
127.57, 127.63, 127.92, 128.32, 128.36, 128.42, 128.46, 128.50,
128.56, 129.67 and 129.77 (Ar-CH) and 138.32, 138.45 and
138.72 (Ar-C quaternary); δP(121.5 MHz; C2HCl3) Ϫ1.33.
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(؊)-(1R,2R,4R,6R,2ЈR)-2,4-Dihydroxy-6-(1-hydroxy-3-phenyl-
propan-2-yloxy)cyclohexyl bis(cyclohexylammonium) phosphate
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This compound was prepared in a manner identical with that
described for the phosphate (Ϫ)-(1R,2R,4R,6R,2ЈS)-25, using
the triester (Ϫ)-28 (300 mg, 0.37 mmol) to give phosphate (Ϫ)-
29 as a white solid (124 mg, 60%); mp >200 ЊC (decomp.); [α]D
Ϫ12.4 (c 0.335 in MeOH); δH(500 MHz; 2H2O) 0.87–0.98 (2 H,
J. Chem. Soc., Perkin Trans. 1, 2000, 943–954
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