Chemoenzymatic synthesis of trans-dihydrodiol derivatives of monosubstituted benzenes from the corresponding cis-dihydrodiol isomers

Article abstract of DOI:10.1039/b616100f

Enantiopure trans-dihydrodiols have been obtained by a chemoenzymatic synthesis from the corresponding cis-dihydrodiol metabolites, obtained by dioxygenase-catalysed arene cis-dihydroxylation at the 2,3-bond of monosubstituted benzene substrates. This gen

Full text of DOI:10.1039/b616100f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Chemoenzymatic synthesis of trans-dihydrodiol derivatives of monosubstituted
benzenes from the corresponding cis-dihydrodiol isomers†
Derek R. Boyd,*a,b Narain D. Sharma,a,b Nuria M. Llamas,a Gerard P. Coen,a Peter K. M. McGeehina and
Christopher C. R. Allenc
Received 6th November 2006, Accepted 8th December 2006
First published as an Advance Article on the web 4th January 2007
DOI: 10.1039/b616100f
Enantiopure trans-dihydrodiols have been obtained by a chemoenzymatic synthesis from the
corresponding cis-dihydrodiol metabolites, obtained by dioxygenase-catalysed arene cis-dihydroxylation
at the 2,3-bond of monosubstituted benzene substrates. This generally applicable, seven-step synthetic
route to trans-dihydrodiols involves a regioselective hydrogenation and a Mitsunobu inversion of
configuration at C-2, followed by benzylic bromination and dehydrobromination steps. The method has
also been extended to the synthesis of both enantiomers of the trans-dihydrodiol derivatives of toluene,
through substitution of a vinyl bromine atom of the corresponding trans-dihydrodiol enantiomers
derived from bromobenzene. Through incorporation of hydrogenolysis and diMTPA ester
diastereoisomer resolution steps into the synthetic route, both trans-dihydrodiol enantiomers of
monohalobenzenes were obtained from the cis-dihydrodiols of 4-haloiodobenzenes.
Introduction
Mammalian metabolism of arenes A, in common with fungal
biodegradation, often involves monooxygenase-catalysed oxida-
tion to yield phenols. The corresponding arene oxides B1,2, B2,3
and B3,4 have been proposed as initial metabolites on the basis
of their detection or isolation, e.g. from benzene1 (A, R = H)
to yield benzene oxide (B1,2 = B2,3 = B3,4, R = H) or from methyl
benzoate2 (A, R = CO2Me), to give the 1,2-oxide B1,2 (R = CO2Me,
Scheme 1). Substituted benzene oxide intermediates, e.g. B2,3 (R =
Br), synthesised from enantiopure cis-dihydrodiol precursors, were
found to spontaneously racemise via the corresponding oxepin
valence tautomers.3 Further examples of arene oxide intermediates
have been isolated from mammalian liver metabolism of polycyclic
arenes, e.g. naphthalene4 and quinoline,5 but these arene oxides do
not equilibrate with the corresponding oxepins and are generally
more stable. Arene oxide intermediates B1,2, B2,3 and B3,4, derived
from substituted monocylic arenes A, are often unstable, and thus
difficult to isolate, due to their rapid isomerisation to phenols.
However, further evidence for the intermediacy of arene oxides
can be obtained from their epoxide hydrolase-catalysed hydrolysis,
to yield the corresponding trans-dihydrodiols C1,2, C2,3 and C3,4.
A relatively small number of trans-dihydrodiol metabolites have
been isolated from benzene (C1,2 = C2,3 = C3,4 where R =
H) and from other monosubstituted benzene substrates (C3,4
where R = Cl, Br) as well as non-aromatic precursors (C2,3
where R = CO2H).6–10 trans-Dihydrodiols are commonly found
as metabolites of polycyclic arenes, e.g. benzo[a]pyrene, and these
Scheme 1
have been extensively studied, in order to elucidate their role in
carcinogenesis induced by polycyclic aromatic hydrocarbons.11
Comprehensive studies of the alternative dioxygenase-catalysed
metabolism pathway of mono- and poly-cyclic arenes in bacteria,
have been carried out in these and other laboratories and, as a
result, several hundred examples of cis-dihydrodiol metabolites
are now available as synthetic precursors.12–22 The corresponding
range of trans-dihydrodiols, however, cannot yet be obtained in
significant yields by direct biotransformation methods (exclud-
ing the trans-dihydrodiols from benzoic acid).7,8 We have been
interested in exploring potential methods for the synthesis of
trans-dihydrodiols, from the readily available corresponding cis-
dihydrodiols.23 This has resulted in the development of a generally
aSchool of Chemistry and Chemical Engineering, Queen’s University Belfast,
Belfast, UK BT9 5AG. E-mail: dr.boyd@qub.ac.uk; Fax: 02890 323321;
Tel: 02890 974421
bCenTACat, Queen’s University Belfast, Belfast, UK BT9 5AG
cSchool of Biological Sciences, Queen’s University Belfast, Belfast, UK BT9
5AG
† Electronic supplementary information (ESI) available: Further experi-
mental details. See DOI: 10.1039/b616100f
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applicable synthetic route from cis-dihydrodiol metabolites 2a–2e
(Scheme 2) to the corresponding regioisomeric trans-dihydrodiols
C3,4 (R = Cl, Br, I, Scheme 3).24 A similar approach was
also applied to the synthesis of an alternative trans-dihydrodiol
regioisomer C1,2 (R = Me) but could not be used to synthesise any
member of the regioisomeric trans-dihydrodiol series C2,3.24 The
present study, based on an earlier preliminary communication,3
provides an alternative complementary chemoenzymatic route to
the trans-dihydrodiols C2,3, from the corresponding cis-dihydrodiol
precursors (Scheme 2). The chemoenzymatic routes reported in
this and the earlier paper3 provide access to all the possible
types of trans-dihydrodiol regioisomers (C1,2, C2,3, C3,4) from
monosubstituted benzenes which are required in our laboratories
as (i) synthetic precursors, (ii) substrates for biological screening
programmes and (iii) subjects for comparative aromatisation
studies.
Results and discussion
The enantiopure (>98% ee) cis-dihydrodiol metabolites 2a–2e,
derived from biotransformation of the monosubstituted benzene
substrates, chlorobenzene (1a), bromobenzene (1b), iodobenzene
(1c), 1,1,1-trifluorotoluene (1d) and toluene (1e) were available
from earlier studies, using toluene dioxygenase (TDO) present in
whole cells of Pseudomonas putida UV4 (Scheme 2).25
A generally applicable seven-step synthetic sequence, from cis-
dihydrodiols 2a–2d to the corresponding trans-dihydrodiols of
type C2,3, has been developed (Scheme 3). The steps involve
selective hydrogenation at the less substituted alkene bond (2 →
3), a regioselective Mitsunobu inversion at an allylic centre (3 →
4), hydrolysis (4 → 5), protection (5 → 6), allylic bromination
(6 → 7), dehydrobromination (7 → 8) and deprotection (8 → 9).
Regioselective catalytic hydrogenation (H2, 5% Rh–Al2O3) of
cis-dihydrodiols 2a–2d, under pressure in THF solution, yielded
the corresponding cis-tetrahydrodiols 3a–3d, generally, in high
yield (80–90%). The partial hydrogenation of cis-dihydrodiol
metabolite 2c of iodobenzene proved difficult. It required careful
monitoring of the progress of the reaction, to minimise the
competing aromatization to ortho-iodophenol. cis-Tetrahydrodiol
3c could only be obtained in ca. 50% yield. The selective hydro-
genation of cis-dihydrodiol metabolite 2e of toluene also proved
to be more difficult and an alternative approach was adopted for
the synthesis of trans-dihydrodiol 9e of toluene (Scheme 4).
Scheme 2
Scheme 3 Reagents: i H2, Rh–Al2O3; ii PPh3, DEAD, 4-NO2·C6H4·CO2H; iii K2CO3, H2O, MeOH; iv Ac2O, pyridine; v NBS, CCl4; vi LiCl, Li2CO3,
HMPA.
Scheme 4 Reagents: i TBDMSTf, Et3N, DCM; ii NBS, AIBN, CCl4; iii Li2CO3, LiCl, HMPA; iv MeMgBr, Ni(acac)2, Et2O; v TBAF, THF.
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Due to the general instability of cis-dihydrodiols 2a–2d, at-
tempts to carry out the Mitsunobu inversion reaction on these
parent diols did not succeed; the corresponding phenols were
the only products formed. However, using standard conditions,
their stable cis-tetrahydrodiol derivatives 3a–3d were found to
undergo inversion of the hydroxyl group at the allylic carbon
centre. Thus, reaction of tetrahydrodiols 3a–3d, with a mixture of
triphenylphosphine, diethyldiazodicarboxylate (DEAD) and para-
nitrobenzoic acid (p-NBA), in benzene, resulted in the exclusive
inversion of configuration at C-2 to yield the monoesters 4a–
4d. The progress of the reaction was monitored by TLC and the
in compound 12 to be replaced with a methyl group (to give
intermediate 13 using a Grignard reagent), before deprotection
to yield the trans-dihydrodiol of toluene 9e, in a total of eight
steps from cis-dihydrodiol 2b.
All of the trans-dihydrodiols 9a–9e, obtained using the method
shown in Schemes 3 and 4, were single enantiomers having
(1S) absolute configurations. The synthesis of trans-dihydrodiol
enantiomers 9aꢀ–9cꢀ and 9eꢀ of (1R) configuration, was also carried
out using two different methods.
The first synthetic approach was based on the Mitsunobu inver-
sion of the non-allylic (C-1) chiral centre in a cis-tetrahydrodiol,
using a suitably protected derivative. The cis-tetrahydrodiol of
bromobenzene 3b was thus selectively protected as a monoTB-
DMS derivative 14, taking advantage of the less sterically hindered
position of the C-1 hydroxyl group (Scheme 5). The remaining
hydroxyl group at C-2 was then protected as the less sterically
demanding allyl ether 15. Removal of the TBDMS group yielded
the required non-allylic alcohol 16 which was easily converted into
para-nitrobenzoate 17 via a Mitsunobu inversion process. Alkaline
hydrolysis of ester 17 gave alcohol 18 which on deprotection
(RhCl(Ph3P)3, DABCO, EtOH, H2O) yielded the (1R)-trans-1,2-
tetrahydrodiol 5bꢀ. The remaining steps in the synthesis of (1R)
enantiomer 9eꢀ were identical to those used for (1S)-trans-1,2-
dihydrodiol 9e (Scheme 4). The latter method requires a twelve
step synthesis from cis-1,2-dihydrodiol 2b.
1
identification of compounds 4a–4d was carried out by H-NMR
spectroscopic analyses of small samples, after workup. The major
portion of each of the crude reaction mixtures was hydrolysed,
in situ, using K2CO3 in aq. MeOH, to give trans-tetrahydrodiols
5a–5d in an overall yield of 58–64% from the corresponding cis-
tetrahydrodiol precursors 3a–3d.
trans-Tetrahydrodiols 5a–5d were protected, as diacetates 6a–
6d (Ac2O–pyridine) in 93–96% yield prior to allylic bromination,
using N-bromosuccinimide in CCl4, to give the corresponding
bromides 7a–7d. The latter compounds were found to exist
as isomeric mixtures that showed evidence of decomposition,
during attempted purification by chromatography. These relatively
unstable bromides 7a–7d were, therefore, used without purification
in the next dehydrobromination step (Li2CO3 and LiCl in HMPA)
which gave the corresponding trans-dihydrodiol diacetates 8a–
8d (74–93% yields from the diacetate precursors 6a–6d). The
final hydrolysis step of diacetates 8a–8d with K2CO3 in aq.
MeOH yielded the target molecules, trans-dihydrodiols 9a–9d (94–
98%). The versatility of this synthetic route, from cis-dihydrodiol
precursors 2a–2d to the corresponding trans-dihydrodiols 9a–
9d, is demonstrated by its application to other members of the
substituted benzene cis-dihydrodiol series and also to the opposite
enantiomers, after suitable modification (Schemes 4–6).
The original synthetic sequence (Scheme 3) shows the con-
version of the trans-tetrahydrodiol of bromobenzene 5b to the
corresponding trans-dihydrodiol 9b in four steps, using acetate
protecting groups (6b, 7b and 8b). trans-Tetrahydrodiol 5b was
also converted to the trans-dihydrodiol 9b using a similar synthetic
sequence but using diTBDMS protecting groups (10, 11 and 12
respectively, Scheme 4). This approach allowed the bromine atom
A shorter alternative synthetic approach to enantiomers 9aꢀ–
9cꢀ was also examined (Scheme 6). In contrast to the enantiopure
cis-dihydrodiol metabolites 2a–2e, derived from the correspond-
ing monosubstituted benzene substrates 1a–1e, para-substituted
iodobenzenes 19a–19c on biotransformation (P. putida UV4) gave
mixtures of cis-dihydrodiol enantiomers 20a/20aꢀ (from 19a)26 and
20b/20bꢀ (from 19b)26 and an achiral cis-dihydrodiol 20c = 20cꢀ
(from 19c) (Scheme 6). Controlled hydrogenolysis to remove only
an iodine atom, in each case, produced an enantiomeric mixture
of monosubstituted benzene cis-dihydrodiols 2a/2aꢀ (35 : 60),
2b/2bꢀ (39 : 61), 2c/2cꢀ (50 : 50) in 40–70% yields. The partial
hydrogenolysis of achiral cis-dihydrodiol 20c = 20cꢀ required
careful monitoring of the progress of the reaction, to minimise
the loss of both iodine atoms. Partial hydrogenation of the
enantiomeric mixtures of cis-dihydrodiols 2a–2c/2aꢀ–2cꢀ, to yield
the corresponding cis-tetrahydrodiols 3a–3c/3aꢀ–3cꢀ and their
=
Scheme 5 Reagents: i TBDMSTf, Et3N, DCM; ii BrCH2CH CH2, BaO, DMF, H2O; iii TBAF, THF; iv Ph3P, DEAD, 4-NO2·C6H4·CO2H, THF;
v K2CO3, MeOH; vi RhCl(Ph3P)3, DABCO, H2O, EtOH; vii NBS, CCl4; viii Li2CO3, LiCl, HMPA; ix MeMgBr, Et2O; x TBAF, THF.
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Scheme 6 Reagents: i H2, Pd–C; ii H2, Rh–Al2O3; iii PPh3, DEAD, 4-NO2·C6H4·CO2H; iv NaOH, H2O,MeOH; v (−)-MTPACl, pyridine; vi Ac2O,
pyridine; vii NBS, CCl4; viii LiCl, Li2CO3, HMPA.
conversion to the corresponding trans-tetrahydrodiols 5a–5c/5aꢀ–
Conclusion
5cꢀ, was carried out as described (Scheme 3).
The syntheses of trans-(1S,2R)-dihydrodiols (9a–9c) and trans-
Earlier studies from these laboratories have shown that the
abnormal (1R)-cis-dihydrodiol enantiomers 2aꢀ–2cꢀ can be ob-
tained via a second biotransformation, using an enzyme-catalysed
kinetic resolution method.27 In this further biotransformation,
with naphthalene diol dehydrogenase enzymes present in whole
cells of wild type (e.g. P. putida NCIMB 8859) or recombinant
(e.g. E. coli nar B) strains,27,28 only the normal (1S)-cis-dihydrodiol
enantiomers 2a–2c were found to be the substrates and were
converted to the corresponding catechols. The residual abnormal
(1R)-cis-dihydrodiol enantiomers 2aꢀ–2cꢀ were then separated from
the catechols by chromatography. An alternative method to the
second biotransformation procedure, using a chemical resolution
process, is also presented in this study.
The enantiomeric mixtures of trans-tetrahydrodiol enan-
tiomers 5a/5aꢀ–5c/5cꢀ were treated with (−)-(R)-a-methoxy-a-
(trifluoromethyl)phenylacetyl (MTPA) chloride in pyridine so-
lution, to yield the corresponding diMTPA diastereoisomers
21a/21aꢀ–21c/21cꢀ which were separated by preparative layer
chromatography (PLC) (Scheme 6). Hydrolysis of the sepa-
rated diMTPA ester diastereoisomers under alkaline condi-
tions, produced single enantiomers of the corresponding trans-
tetrahydrodiol enantiomers 5a–5c and 5aꢀ–5cꢀ which were, in turn,
converted in four steps to the corresponding trans-dihydrodiols
9a–9c and 9aꢀ–9cꢀ, using the method discussed earlier (Schemes 3
and 6). This route, to the synthesis of trans-1,2-dihydrodiol
enantiomers 9aꢀ–9cꢀ, from cis-1,2-dihydrodiol precursors 20aꢀ–
20cꢀ, is slightly shorter than the one used for trans-dihydrodiol
9eꢀ (Schemes 4 and 5). Furthermore, both trans-(1S,2R)-(9a–9c)
and trans-(1R,2S)-dihydrodiols (9aꢀ–9cꢀ) were synthesised from
metabolites produced by a single biotransformation.
(1S,2S)-dihydrodiol (9d) enantiomers from enantiopure cis-
dihydrodiol precursors have been carried out through a generally
applicable chemoenzymatic method. A modification of this route
has been used in the synthesis of both trans-(1S,2R)-(9a–9c)
and the reverse trans-(1R,2S)-dihydrodiol enantiomers (9aꢀ–9cꢀ).
Thus, cis-dihydrodiol metabolites of 4-substituted iodobenzenes
containing both enantiomers (20a/20aꢀ–20c/20cꢀ) were converted
to the corresponding trans-tetrahydrodiols (5a/5aꢀ–5c/5cꢀ) and
resolved via their diMTPA esters (21a/21aꢀ–21c/21cꢀ). Replace-
ment of a bromine atom with a methyl group in the diTBDMS
derivatives of trans-tetrahydrodiol enantiomers 5b and 5bꢀ pro-
vided a synthetic route to the corresponding trans-dihydrodiols
enantiomers 9e and 9eꢀ.
Expermental
NMR (1H and 13C) spectra were recorded on Bruker Avance
DPX-300 and DPX-500 instruments and mass spectra were run
at 70 eV, on a VG Autospec Mass Spectrometer, using a heated
inlet system. Accurate molecular weights were determined by the
peak matching method, with perfluorokerosene as the standard.
Elemental microanalyses were carried out on a PerkinElmer 2400
CHN microanalyser. For optical rotation ([a]D) measurements
◦
(ca. 20 C, 10−1 deg cm2 g−1), a PerkinElmer 341 polarimeter
was used. Flash chromatography and PLC were performed on
Merck Kieselgel type 60 (250–400 mesh) and PF254/366 respec-
tively. Merck Kieselgel type 60F254 analytical plates were used
for TLC. cis-Dihydrodiols (1S,2S)-2a–2c (>98% ee), (1S,2R)-
2d and 2e (>98% ee), (1R,2S)-20a/(1S,2R)-20aꢀ (ca. 25% ee),
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(1R,2S)-20b/(1S,2R)-20bꢀ (ca. 22% ee) and the achiral cis-
dihydrodiol 20c were available from earlier work,25,26 were used
for this study.
the filtrate concentrated under reduced pressure. The residue was
partitioned by extraction, with a mixture of ethyl acetate (50 cm3)
and saturated aq. NaCl solution (30 cm3). The EtOAc layer was
separated, dried (Na2SO4), and concentrated. Further purification
of the product, by flash chromatography (15% → 50% EtOAc in
hexane) yielded trans-tetrahydrodiol 5a–5d/5aꢀ–5cꢀ.
Hydrogenolysis of cis-dihydrodiols 20a–20c/20aꢀ–20cꢀ to yield the
corresponding cis-dihydrodiols 2a–2c/2aꢀ–2cꢀ
A solution of cis-1,2-dihydroxycyclohexa-3,5-diene enantiomers
20a–20c/20aꢀ–20cꢀ (3.0 mmol), in MeOH (20 cm3) containing
NaOAc·3H2O (0.272 g, 6.0 mmol) and quinoline (50 ll), was
stirred, at room temperature under H2 (1 atm.) in the presence
of Pd/C (3%, 0.1 g) until the hydrogenolysis was complete (2–
4 h). Removal of the catalyst by filtration and concentration of
the filtrate yielded the crude mixture of enantiomers 2a–2c/2aꢀ–
2cꢀ that was purified (40–70% yield) by PLC (Rf 0.3 to 0.5, 50%
EtOAc in hexane).
trans-(1S,2R)- 5a and trans-(1R,2S)-1,2-Dihydroxy-3-chloro-
cyclohex-3-ene 5aꢀ. Enantiomer 5a, white crystals (0.53 g, 65%);
mp 69–70 ◦C (CHCl3–hexane), [a]D +79 (c 1.77, MeOH); (Found:
C, 48.5; H, 6.1. C6H9ClO2 requires C 48.5; H, 6.1%); dH (500 MHz,
CDCl3) 1.74 (1 H, m, 6-H), 1.95 (1 H, m, 6ꢀ-H), 2.20 (2 H, m, 5-H,
5ꢀ-H), 3.85 (1 H, m, 1-H), 4.07 (1 H, d, J2,1 6.5, 2-H), 5.92 (1 H, dd,
J4,5 = J4,5 4.0, 4-H); m/z (EI) 150 (M+, 1%), 148 (3), 132 (1), 132
ꢀ
(3), 106 (36), 104 (100), 95 (5), 69 (7), 65 (5), 41 (18). Enantiomer
5aꢀ: [a]D −72 (c 1.62, MeOH).
Partial hydrogenation of cis-dihydrodiols 2a–2d/2aꢀ–2cꢀ to yield
cis-tetrahydrodiols 3a–3c/3aꢀ–3cꢀ
For compounds 5b, 5bꢀ, 5c, 5cꢀ and 5d see ESI.†
Acetylation of trans-tetrahydrodiols 5a–5d/5aꢀ–5cꢀ to yield
trans-tetrahydrodiol diacetates 6a–6d/6aꢀ–6cꢀ
Typical procedure: cis-1,2-Dihydroxycyclohexa-3,5-diene 2a–
2d/2aꢀ–2cꢀ (5 mmol) was dissolved in THF (15 cm3) and the
solution poured into a hydrogenation bottle containing catalyst
(0.5 g) Rh–Al2O3 (5%). The bottle filled with H2 [25 psi (2a/2aꢀ),
40 psi (2b/2bꢀ), 75 psi (2c/2cꢀ), 20 psi (2d)]was mechanicallyshaken
until hydrogenation was complete [ca. 3 h (2a/2aꢀ), 6 h (2b/2bꢀ),
16 h (2c/2cꢀ), 2 h (2d)]. The catalyst was removed by filtration,
the filtrate concentrated, and the crude hydrogenated compound
purified by flash chromatography (5% MeOH in CHCl3 or 40%
EtOAc in hexane) to give cis-tetrahydrodiol 3a–3d/3aꢀ–3cꢀ.
Typical procedure: A solution of trans-tetrahydrodiol 5a–5d/5aꢀ–
5cꢀ (3.5 mmol), in anhydrous pyridine (0.5 cm3), was treated with
Ac2O (10 mmol), and the mixture heated at 50 ◦C for 4 h. The crude
product obtained, after removal of excess of Ac2O and pyridine
under reduced pressure, was purified by flash chromatography
(hexane → 30% Et2O in hexane) to yield diacetate 6a–6d/6aꢀ–6cꢀ.
trans-(1S,2R)- 6a and trans-(1R,2S)-1,2-Diacetoxy-3-chloro-
cyclohex-3-ene 6aꢀ. Enantiomer 6a, white crystals (0.78 g, 96%);
mp 43–45 ◦C (CHCl3–hexane), [a]D +97 (c 1.53, CHCl3); (Found:
C, 51.5; H, 5.6. C10H13ClO4 requires C 51.6; H, 5.6%); dH
(300 MHz, CDCl3) 1.91 (2 H, m, 6-H, 6ꢀ-H), 2.06 (3 H, s, OCOMe),
2.12 (3 H, s, OCOMe), 2.25 (2 H, m, 5-H, 5ꢀ-H), 5.05 (1 H, m, H-1),
5.40 (1 H, d, J2,1 6.0, 2-H), 6.14 (1 H, dd, J4,5 = J4,5ꢀ 3.9, 4-H); m/z
(EI) 234 (M+, 1%), 232 (1), 197 (5), 174 (4), 172 (12), 132 (35), 130
(84), 112 (45), 95 (25), 77 (14), 43 (100). Enantiomer 6aꢀ: [a]D −100
(c 1.40, CHCl3).
cis-(1S,2S)- 3a and cis-(1R,2R)-1,2-Dihydroxy-3-chlorocyclo-
hex-3-ene 3aꢀ. Enantiomer 3a, white crystalline solid (0.64 g,
86%); mp 111–112 ◦C (CHCl3–hexane); [a]D −158 (c 1.06, MeOH);
(Found: C, 48.5; H, 5.9. C6H9ClO2 requires C 48.5; H, 6.1%); dH
(500 MHz, CDCl3) 1.79 (2 H, m, 6-H, 6ꢀ-H), 2.14 (1 H, m, 5-H),
2.30 (1 H, m, 5ꢀ-H), 3.93 (1 H, m, 1-H), 4.16 (1 H, d, J2,1 3.5, 2-H),
5.99 (1 H, dd, J4,5 = J4,5 4.1, 4-H); m/z (EI) 150 (M+, 1%), 148 (4),
ꢀ
106 (30), 104 (100), 95 (7), 69 (16), 65 (18). Enantiomer 3aꢀ: [a]D
+154 (c 1.11, MeOH).
For compounds 6b, 6bꢀ, 6c, 6cꢀ and 6d see ESI.†
For compounds 3b, 3bꢀ, 3c, 3cꢀ and 3d see ESI.†
Mitsunobu inversion reaction with cis-tetrahydrodiols
3a–3d/3aꢀ–3cꢀ to yield the 4-nitrobenzoates of trans-tetrahydrodiol
4a–4d/4aꢀ–4cꢀ and their hydrolysis to produce
Benzylic bromination of the trans-tetrahydrodiol diacetates
6a–6d/6aꢀ–6cꢀ to yield trans-tetrahydrodiol bromodiacetates
7a–7d/7aꢀ–7cꢀ
trans-tetrahydrodiols 5a–5d/5aꢀ–5cꢀ
Typical procedure: Freshly crystallised N-bromosuccinimide
(3.7 mmol) and a,a-azoisobisbutyronitrile (AIBN) (ca. 2 mg)
were added to a solution of trans-tetrahydrodiol diacetate 6a–
6d/6aꢀ–6cꢀ (3.4 mmol) dissolved in carbon tetrachloride (10 cm3).
The reaction mixture was gently refluxed, under nitrogen, using
a heat lamp. The reaction, monitored by TLC, was complete
after 1.5 h of refluxing. The reaction mixture was cooled to
room temperature, the precipitated succinimide filtered off, and
the solvent removed in vacuo. The crude product 7a–7d/7aꢀ–7cꢀ,
identified as a diastereoisomeric mixture of bromides of tetra-
Typical procedure: To a stirring solution of cis-tetrahydrodiols 3a–
3d/3aꢀ–3cꢀ (5.5 mmol) and Ph3P (6 mmol), in anhydrous benzene
(20 cm ) containing dry 3 A molecular sieves (1 g), DEAD
3
˚
(6 mmol) was added drop-wise, at room temperature. After stirring
the reaction mixture for 30 min, p-nitrobenzoic acid (5.4 mmol)
was added, the mixture was stirred for a further 30 min, and then
refluxed at 90 ◦C until the reaction was complete (ca. 3 h, by TLC).
The mixture was filtered, the filtrate concentrated under reduced
pressure, and the concentrate dissolved in MeOH (15 cm3). Water
(1 cm3) and K2CO3 (15 mmol) were added, and the reaction
mixture stirred at room temperature. When the hydrolysis was
complete (ca. 3 h), the inorganic material was filtered off, and
1
hydrodiol diacetate, by H-NMR spectroscopy, was used imme-
diately in the next step without purification due to its unstable
nature.
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trans-(1S,2R)- 7a and trans-(1R,2S)-1,2-Diacetoxy-3-chloro-5-
bromocyclohex-3-ene 7aꢀ. Enantiomers 7a and 7aꢀ, light yellow
oil (1.01 g, 95%); dH (500 MHz, CDCl3) 2.10 (3 H, s, OCOMe),
2.12 (3 H, s, OCOMe), 2.41 (1 H, m, 6-H), 2.51 (1 H, m, 6ꢀ-H),
4.78 (1 H, m, 5-H), 5.33 (1 H, m, 1-H), 5.55 (1 H, m, 2-H), 6.35
(1 H, m, 4-H).
For compounds 9b, 9bꢀ, 9c, 9cꢀ and 9d see ESI.†
(1R,6S)- 10 and [(1S,6R)-2-Bromo-6-{[1-(tert-butyl)-1,1-
dimethylsilyl]oxy}-2-cyclohexenyl)oxy] (tert-butyl)-
dimethylsilane 10ꢀ
A stirring solution of trans-tetrahydrodiol 5b (0.135 g, 0.7 mmol)
and Et3N (0.4 cm3, 2.8 mmol) in dry CH2Cl2 (10 cm3) was treated,
under N2 at 0 ◦C, with TBDMSTf (0.37 cm3, 1.6 mmol), and the
reaction mixture was allowed to come to room temperature. After
stirring for 1 h, the reaction was quenched by the addition of 5%
aq. NaHCO3 solution. The organic layer was separated and the
aq. layer extracted with CH2Cl2 (10 cm3). The combined solution
was dried (Na2SO4) and the solvent evaporated. Purification of the
residue by flash chromatography (hexane) yielded pure diTBDMS
derivative 10 as a colourless semisolid (0.28 g, 95%); [a]D +76
(c 0.73, CHCl3); (Found: M+–C4H9, 363.0798. C14H28BrO2Si2
requires 363.0811); dH(500 MHz, CDCl3) 0.06, 0.07, 0.13, 0.20
[3 H each, s, 2 × –Si(Me)2], 0.87, 0.91 [9 H each, s, 2 × –C(Me)3],
1.57–1.63 (1H, m, 5-H), 1.80–1.86 (1 H, m, 5ꢀ-H), 1.94–2.00 (1 H,
m, 4-H), 2.24–2.31 (1 H, m, 4ꢀ-H), 3.84 (1 H, d, J1,6 2.9, 1-H),
For compounds 7b, 7bꢀ, 7c, 7cꢀ and 7d see ESI.†
Dehydrobromination of trans-tetrahydrodiol bromodiacetates
7a–7d/7aꢀ–7cꢀ to yield trans-dihydrodiol diacetates 8a–8d/8aꢀ–8cꢀ
Typical procedure: Anhydrous lithium chloride (8 mmol) and
anhydrous lithium carbonate (7 mmol) were added with stirring
to a solution of trans-tetrahydrodiol bromodiacetates 7a–7d/7aꢀ–
7cꢀ (2.9 mmol) in freshly distilled HMPA (2 cm3). The reaction
mixture was heated (2 h) at 95 ◦C under N2 with stirring. The
mixture was then cooled to 0 ◦C, diluted with Et2O (25 cm3), and
aq. HCl solution (1 M, 15 cm3) was added to it drop-wise. After
shaking the mixture in a separating funnel, the Et2O layer was
separated and the aq. layer was again extracted with Et2O (2 ×
15 cm3). The combined Et2O extract was washed with aq. NaHCO3
solution (2.5%, 20 cm3), dried (Na2SO4), and concentrated in
vacuo. Purification of the residue by PLC (50% Et2O in hexane, Rf
∼0.50,) yielded the trans-dihydrodioldiacetate 8a–8d/8aꢀ–8cꢀ.
ꢀ
3.89 (1 H, m, 6-H), 6.16 (1 H, dd, J3,4 2.5, J3,4 5.5, 3-H); m/z (EI)
363 (M+–C4H9, 27%), 263 (18), 233 (21), 205 (24), 189 (16), 147
(100), 79 (11) and 73 (62). Enantiomer 10ꢀ was similarly prepared
from trans-tetrahydrodiol 5bꢀ (0.220 g, 1.14 mmol), as a colourless
semisolid (0.44 g, 92%); [a]D −75 (c 0.87, CHCl3).
trans-(1S,2R)- 8a and trans-(1R,2S)-1,2-Diacetoxy-3-chloro-
cyclohexa-3,5-diene 8aꢀ. Enantiomer 8a, white crystals (0.63 g,
93%); mp 53–54 ◦C, (EtOAc–hexane); [a]D +437 (c 1.03, CHCl3);
(Found: C, 51.9; H, 4.7. C10H11ClO4 requires C 52.1; H, 4.8%); dH
(500 MHz, CDCl3) 2.08 (3 H, s, OCOMe), 2.13 (3 H, s, OCOMe),
5.34 (1 H, dd, J1,2 4.0, J1,6 4.6, 1-H), 5.66 (1 H, d, J2,1 4.0, 2-H),
5.90(1 H, dd, J6,1 4.6, J6,5 9.5, 6-H), 6.09 (1 H, dd, J5,4 6.2, J5,6 9.5,
5-H), 6.29 (1 H, d, J4,5 6.2, 4-H); m/z (EI) 232 (M+, 3%), 230 (7),
195 (13), 130 (22), 128 (57), 43 (100). Enantiomer 8aꢀ: [a]D −435
(c 0.75, CHCl3).
(1R,6S)- 12 and [(1S,6R)-2-Bromo-6-[{1-(tert-butyl)-1,1-
dimethylsilyl}oxy]-2,4-cyclohexenyl)oxy](tert-butyl)-
dimethylsilane 12ꢀ
DiTBDMS derivative 10 (0.172 g, 0.41 mmol) was converted into
the corresponding diastereomeric mixture of bromo compounds
11 with N-bromosuccinimide, using the typical procedure for
bromination mentioned earlier. The crude brominated mixture (ca.
0.220 g) was dissolved in HMPA (0.5 cm3), and treated with an-
hydrous Li2CO3 (0.06 g, 0.82 mmol) and LiCl (0.03 g, 0.82 mmol)
according to the typical procedure mentioned earlier. Purification
of the crude product by PLC (hexane) gave compound 12 as a
colourless oil (0.07 g, 43%); [a]D +303 (c 0.88, CHCl3); (Found M+,
418.1344. C18H35BrO2Si2 requires 418.1359); dH(500 MHz, CDCl3)
0.07, 0.11, 0.17, 0.19, (3 H each, s, 2 × –Si(Me)2) 0.88, 0.90 (9 H
each, s, 2 × –C(Me)3), 4.14 (1 H, dd, J6,1 2.5, J6,5 6.0, 6-H), 4.17
(1 H, d, J1,6 2.5, 1-H), 5.87 (1 H, dd, J5,4 9.3, J5,6 6.0, 5-H), 5.89
(1H, dd, J4,5 9.3, J4,3 5.3, 4-H), 6.34 (1 H, d, J3,4 4.5, 3-H); m/z (EI)
418 (M+, 45%), 339 (47), 305 (8), 225 (15), 189 (18), 147 (100), 115
(6), 73 (84) and 59 (8).
For compounds 8b, 8bꢀ, 8c, 8cꢀ and 8d see ESI.†
Hydrolysis of trans-dihydrodiol diacetates 8a–8d/8aꢀ–8cꢀ to yield
trans-dihydrodiols 9a–9d/9aꢀ–9cꢀ
Typical procedure: To a stirring solution of trans-dihydrodiol
diacetate 8a–8d/8aꢀ–8cꢀ (2.65 mmol) in MeOH (10 cm3), was
added water (1 cm3) and K2CO3 (8 mmol). On completion of the
hydrolysis (ca. 3 h, by TLC), the potassium salts were filtered off
and the filtrate concentrated under reduced pressure. The crude
product was dissolved in EtOAc (25 cm3), the solution washed
with brine solution (10 cm3), dried (Na2SO4), and concentrated in
vacuo. Purification of the residue by PLC (50% EtOAc in hexane)
yielded trans-dihydrodiol 9a–9d/9aꢀ–9cꢀ.
Bromo diTBDMS derivative 12ꢀ was similarly prepared from
compound 10ꢀ (0.2 g, 0.55 mmol), as a colourless semisolid
(0.092 g, 40%); [a]D +295 (c 0.68, CHCl3).
tert-Butyl(1R,6R)- 13 and tert-butyl[(1S,6S)-6-
{[1-(tert-butyl)-1,1-dimethylsilyl]oxy}-2-methyl-2,
4-cyclohexadienyl)oxy] dimethylsilane 13ꢀ
trans-(1S,2R)- 9a and trans-(1R,2S)-1,2-Dihydroxy-3-chloro-
cyclohexa-3,5-diene 9aꢀ. Enantiomer 9a, white crystals (0.38 g,
98%); mp 94–96 ◦C (MeOH–CHCl3); [a]D +504 (c 0.66, MeOH);
(Found: M+, 146.0138. C6H7ClO2 requires 146.0135; dH (500 MHz,
CDCl3) 4.42 (1 H, dd, J2,1 9.1, J2,6 3.4, 2-H), 4.52 (1 H, m, 1-H),
5.92 (2 H, m, 5-H, 6-H), 6.12 (1 H, m, 4-H); m/z (EI) 146 (M+,
54%), 130 (8), 128 (125), 117 (24), 111 (12), 100 (100), 93 (14), 81
(48), 65 (77), 53 (65). Enantiomer 9aꢀ: [a]D −489 (c 0.59, MeOH).
A solution of compound 12 (0.34 g, 0.81 mmol) in dry THF
(7 cm3), containing nickel(II) acetylacetonate (0.01 g, 0.04 mmol),
was treated drop-wise with a solution of MeMgBr (3 M in Et2O,
2.0 mmol, 0.68 cm3), under a N2 atmosphere. The reaction mixture
was refluxed at 60 ◦C (3 h), left stirring at room temperature
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(10 h), cooled (0 ◦C), and then treated with aq. NH4Cl solution to
terminate the reaction. Ether (30 cm3) was added to the mixture
and the organic layer separated. The remaining aq. layer was
extracted with Et2O (2 × 10 cm3). The combined organic extract
was dried (Na2SO4), concentrated under reduced pressure, and
the residue purified by PLC (hexane). DiTBDMS derivative 13 was
obtained as a colourless semisolid (0.245 g, 85%); [a]D +275 (c 0.98,
CHCl3); (Found: M+, 354.2400. C19H38O2Si2 requires 354.2410);
dH(500 MHz, CDCl3) 0.026, 0001, 0006, 0.024 [3 H each, s, 2 ×
–Si(Me)2], 0.79, 0.80 [9 H each, s, 2 × –C(Me)3], 1.75 (3 H, s, –Me),
3.94 (1 H, d, J1,6 5.5, 1-H), 4.01 (1 H, dd, J6,1 5.5, J6,5 5.0, 6-H),
5.59–5.62 (2 H, m, 4-H, 6-H), 5.78 (1 H, dd, J4,5 5.0, J4,3 3.2, 4-H);
m/z (EI) 354 (M+, 100%), 165 (13), 147 (46), 137 (20), 133 (8), 91
(13), 84 (35) and 73 (70).
249 [M+–C(Me)3, 8%], 211 (15), 197 (94), 184 (100), 170 (7), 150
(3), 90 (10) and 43 (5).
(1S,2S)-2-[{(Allyloxy)-3-bromo-3-cyclohexenyl}oxy]-
(tert-butyl)dimethylsilane 15
MonoTBDMS ether 14 (0.06 g, 0.2 mmol) was dissolved in DMF
(0.5 cm3) and BaO (0.06 g, 0.4 mmol), allyl bromide (0.045 cm3,
0.52 mmol) and water (0.25 cm3) were added to the solution.
The reaction mixture was stirred at room temperature. When the
starting material had been consumed (∼48 h), the barium salts
were filtered off and the filtrate concentrated in vacuo. Purification
of the residue by flash chromatography (10% ether in hexane) gave
the allyloxy TBDMS derivative 15 as a colourless oil (0.061 g,
90%); [a]D −284 (c 0.40, CHCl3); (Found: M+–C(Me)3, 289.9944.
C11H18BrO2Si requires 289.9960); dH(500 MHz, CDCl3) 0.07, 0.09
[3 H each, s, –Si(Me)2], 0.91 [9 H, s, –C(Me)3], 1.58–1.62 (1 H, m,
6-H), 1.91–1.98 (1 H, m, 6ꢀ-H), 2.00–2.09 (1 H, m, 5ꢀ-H), 2.17–
2.23 (1 H, m, 5-H), 3.85–3.87 (1 H, m, 1-H), 3.90 (1 H, d, J2,1
3.5, 2-H), 4.23–4.27 (1 H, ddt, J 14, J 7.5, J 1.5, –OCH2CHCH2),
4.40–4.44 (1 H, ddt, J 14.0, J 7.5, J 1.5, –OCH2CHCH2), 5.15–
5.18 (1 H, ddd, J 10.5, J 3.0, J 1.5, –OCH2CHCH2), 5.27–5.31
(1 H, ddd, J 17.5, J 5.0, J 1.5, –OCH2CHCH2), 5.98–6.06 (1 H,
Enantiomer 13ꢀ was similarly obtained from compound 12ꢀ
(0.290 g, 0.7 mmol) as a colourless semisolid (0.17 g, 70%); [a]D
−270 (c 0.60, CHCl3).
(1S,2S)- 9e and (1R,2R)-3-Methyl-3,5-cyclohexadiene-1,2-diol 9eꢀ
Tetrabutylammonium fluoride solution (1.0 M in THF, 1.7 cm3)
was added to a cooled (0 ◦C) solution of diTBDMS derivative 13
(0.17 g, 0.48 mmol) in THF (3 cm3). After stirring the reaction
mixture at 0 ◦C (10 min.) and then room temperature (3 h),
the solvent was removed under reduced pressure and the residue
purified by PLC (50% EtOAc in hexane). trans-Dihydrodiol 9e
was obtained as a white crystalline solid (0.04 g, 67%); Rf 0.26
(45% EtOAc in hexane); mp 90–92 ◦C (from EtOAc–hexane); [a]D
+310 (c 0.40, MeOH); (Found: M+, 126.0679. C7H10O2 requires
126.0681); dH(500 MHz, CDCl3) 1.91 (3 H, s, –Me), 4.22 (1 H, d,
J1,2 10.5, J6,1 1.5, 1-H), 4.37 (1 H, d, J2,1 10.5, 2-H), 5.70 (1 H,
dd, J6,5 11.5, J6,1 1.5, 6-H), 5.80 (1 H, dd, J4,5 10.5, 4-H), 5.89
(1 H, ddd, J5,6 11.5, J5,4 3.0, J5,1 1.5, 5-H); dC(125 MHz, CDCl3)
18.94, 73.76, 76.36, 119.85, 124.93, 126.57, 126.99; m/z (EI) 126
(M+, 66%), 111 (22), 108 (63), 97 (41), 80 (100), 77 (36), 69 (27),
65 (56) and 55 (54). trans-Dihydrodiol 9eꢀ was similarly obtained
from compound 13ꢀ (0.17 g, 0.48 mmol) as a white solid (0.042 g,
70%); [a]D −301 (c 0.47, MeOH).
ꢀ
m, –OCH2CHCH2), 6.10 (1 H, dd, J4,5 5.0, J4,5 2.5, 4-H); m/z (EI)
290 [M+–C(Me)3, 17%], 231 (28), 200 (13), 156 (34), 122 (43), 87
(21), 43 (100) and 23 (66).
(1S,2S)-2-(Allyloxy)-3-bromo-3-cyclohexen-1-ol 16
Allyloxy monoalcohol 16 was prepared from compound 15 (0.22 g,
0.63 mmol) using the procedure described for the synthesis of
compound 9e. Purification by flash chromatography (20% Et2O
in hexane) afforded allyloxy monoalcohol 16 as a colourless oil
(0.125 g, 84%); [a]D −235 (c 0.26, CHCl3); (Found: M+, 232.0097.
C9H13BrO2 requires 232.0099); dH(500 MHz, CDCl3) 1.76–1.80
(2 H, m, 6-H), 2.02–2.08 (1 H, m, 5-H), 2.24–2.31 (1 H, m, 5ꢀ-H),
2.47 (1 H, d, J 8.0, –OH), 3.87–3.92 (1 H, m, 1-H), 3.95 (1 H, d, J2,1
4.5, 2-H), 4.26–4.29 (1 H, ddt, J 13.7, J 7.0, J 1.5, –OCH2CHCH2),
4.44–4.85 (1 H, ddt, J 13.7, J 7.0, J 1.5, –OCH2CHCH2), 5.22–
5.25 (1 H, ddd, J 10.5, J 4.0, J 1.0, –OCH2CHCH2), 5.32–5.37
(1 H, ddd, J 17.5, J 4.0, J 1.0, –OCH2CHCH2), 5.96–6.03 (1 H,
(1S,6S)-2-Bromo-6-[{1-(tert-butyl)-1,1-dimethylsilyl}oxy]-2-
ꢀ
m, –OCH2CHCH2), 6.22 (1 H, t, J4,5 = J4,5 4.0, 4-H); m/z (EI)
cyclohexen-1-ol 14
232 (M+, 3%), 190 (98), 188 (100), 160 (22), 162 (24), 119 (13), 109
To a solution of tetrahydrodiol 3b (2 g, 10.4 mmol) in dry
pyridine (4 cm3), TBDMSCl (1.9 g, 12.6 mmol) and DMAP
(5 mol%, 0.063 g) were added and the reaction mixture was stirred
overnight at room temperature. Excess of pyridine was removed
in vacuo, the residue extracted with EtOAc (50 cm3), the extract
washed with water (2 × 15 cm3) and dried (Na2SO4). Removal of
solvent under reduced pressure yielded crude monoTBDMS 14.
Purification by flash chromatography (10% EtOAc in hexane) gave
monoTBDMS 14 as a colourless oil (2.94 g, 92%); (Found: M+–
C(Me)3, 248.9944. C8H14BrO2Si requires 248.9947); [a]D −51
(c 1.0, CHCl3); dH(500 MHz, CDCl3) 0.006, 0.008 [3 H each, s,
–Si(Me)2], 0.79 [9 H, s, –C(Me)3], 1.49–1.53 (1 H, m, 5-H), 1.68–
1.76 (1 H, m, 5ꢀ-H), 1.89–1.97 (1 H, m, 4-H), 2.07–2.14 (1 H, m,
(25), 97 (43), 81 (61), 67 (58) and 55 (41).
(1R,2S)-2-(Allyloxy)-3-bromo-3-cyclohexenyl (4-nitrophenyl)
carbonate 17
Monoalcohol 16 (0.12 g, 0.52 mmol) was converted into p-
nitrobenzoate derivative 17 using the typical procedure described
earlier for the Mitsunobu reaction. Purification by flash chro-
matography (20% Et2O in hexane) yielded p-nitrobenzoate 17
as white needles (0.128 g, 65%); Rf 0.38 (15% Et2O in hexane);
mp 104–105 ◦C (from hexane); [a]D −137 (c 0.88, CHCl3);
(Found: M+–C3H5, 339.9870. C13H11BrNO5 requires 339.9821);
dH(500 MHz, CDCl3) 2.02–2.09 (2 H, m, 6-H), 2.21–2.26 (1 H, m,
5-H), 2.29–2.35 (1 H, m, 5ꢀ-H), 3.90 (1 H, d, J2,1 2.5, 2-H), 4.27–4.35
(2 H, m, –OCH2CHCH2), 5.23 (1 H, d, J 10.5, –OCH2CHCH2),
4ꢀ-H), 2.66 (1 H, d, J 3.7, –OH), 3.83 (1 H, ddd, J6,5 10.5, J6,5 4.0,
ꢀ
J6,1 3.5, 6-H), 3.99 (1 H, d, J1,6 3.5, 1-H), 6.09 (1 H, dd, J3,4 4.9
ꢀ
J3,4 3.4, 3-H); dC(125 MHz, CDCl3) −4.84, −4.50, 17.28, 25.23,
5.34–5.37 (1 H, m, –OCH2CHCH2), 5.41 (1 H, dt, J1,2 2.5, J1,6
=
ꢀ
25.45, 25.47, 25.80, 25.84, 70.80, 72.33, 121.84, 132.35; m/z (EI)
J1,6 5.0, 1-H), 5.95–6.03 (1 H, m, –OCH2CHCH2), 6.38 (1 H, m,
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ꢀ
4,6 5.0, J4,6 3.06, 4-H), 8.16–8.18 (2 H, d, J 8.5, Ar–H), 8.29–8.31
J
6ꢀ-H), 2.15 (1 H, m, 5-H), 2.17 (1 H, m, 5ꢀ-H), 3.54 (3 H, s, OMe),
3.56 (3 H, s, OMe), 5.36 (1 H, m, 1-H), 5.60 (1 H, d, J2,1 3.3, 2-H),
6.12 (1 H, m, 4-H), 7.40–7.58 (10 H, m, Ar–H).
(2 H, d, J 8.5, Ar–H); m/z (EI) 340 (M+–C3H5, 12%), 233 (8), 231
(9), 214 (22), 190 (39), 188 (42), 158 (53), 150 (100), 135 (30), 104
(56), 79 (29) and 65 (15).
For compounds 21b, 21bꢀ, 21c and 21cꢀ see ESI.†
(1R,2S)-2-(Allyloxy)-3-bromo-3-cyclohexen-1-ol 18
Hydrolysis of diMTPA esters 21a–21c/21aꢀ–21cꢀ to
Allyloxy monoalcohol 18 was obtained by the hydrolysis of p-
nitrobenzoate 17 (0.3 g, 0.78 mmol), using the procedure described
earlier. Purification by flash chromatography (5% EtOAc in hex-
ane) afforded alcohol 18 as an off-white semisolid (0.16 g, 87%); Rf
0.18 (20% Et2O in hexane); [a]D −66 (c 0.95, CHCl3); (Found: M+,
232.0090. C9H13BrO2 requires 232.0099); dH(500 MHz, CDCl3)
1.72–1.79 (1 H, m, 6-H), 1.92–1.97 (1 H, m, 6ꢀ-H), 2.09–2.24 (2 H,
m, 5-H), 3.80 (1 H, d, J2,1 5.0, 2-H), 3.97–3.99 (1 H, m, 1-H),
4.18–4.22 (1 H, ddt, J 12.5, J 6.0, J 1.5, –OCH2CHCH2), 4.29–
4.33 (1 H, ddt, J 12.5, J 6.0, J 1.5, –OCH2CHCH2), 5.15–5.24
(1 H, ddd, J 10.0, J 2.5, J 1.0, –OCH2CHCH2), 5.32–5.36 (1 H,
ddd, J 17.5, J 3.0, J 1.5, –OCH2CHCH2), 5.96–6.04 (1 H, m,
trans-tetrahydrodiols 5a–5c/5aꢀ-5cꢀ
Typical procedure: DiMTPA ester 21a–21c/21aꢀ–21cꢀ (2 mmol) in
THF (15 cm3) was treated with a methanolic solution of NaOH
(1 M, 3 cm3) and the reaction mixture was stirred at ambient
temperature (3 h). A saturated aq. solution of NH4Cl (2 cm3)
was added and the solvents were distilled off at normal pressure.
A solution of brine (20 cm3) was added to the residue, the aq.
mixture extracted with EtOAc (2 × 25 cm3), the extract dried
(Na2SO4) and concentrated in vacuo to give trans-tetrahydrodiol
5a–5c/5aꢀ–5cꢀ (ca. 95% yield).
ꢀ
–OCH2CHCH2), 6.21 (1 H, t, J4,5 = J4,5 4.0, 4-H); m/z (EI) 232
(M+, 5%), 190 (97), 188 (100), 153 (15), 146 (22), 109 (29), 97 (40),
Acknowledgements
81 (68), 67 (61) and 55 (53).
This material is based upon work supported by the Science
Foundation Ireland under Grant No. 04/IN3/B581. We also
acknowledge financial support from the HEA North South
Programme for Collaborative Research, and CenTACat (NDS),
the European Social Fund (NMLL) and the Queen’s University
of Belfast (CRO’D). We also wish to thank the EPSRC National
Mass Spectrometry Service Centre at the University of Wales,
Swansea, for providing high resolution mass spectral data.
(1R,2S)-3-Bromo-3-cyclohexene-1,2-diol 5bꢀ
To a solution of compound 18 (0.12 g, 0.51 mmol) in a mixture
of H2O–EtOH (9 : 1, 5 cm3), tris(triphenylphosphine)rhodium(I)
chloride [RhCl(Ph3P)3] (0.034 g,
7 mol equv.) and 1,4-
diazobicyclo[2.2.2]octane (0.015 g, 0.13 mmol) were added. After
refluxing the reaction mixture (3 h), at 100 ◦C under N2, 1 M
aq. HCl solution (2 cm3) was added to quench the reaction. The
solvents were removed under reduced pressure and the residue
purified by PLC (50% EtOAc in hexane), to yield pure trans-
References
◦
tetrahydrodiol 5bꢀ as colourless crystals (0.08 g, 80%); mp 98 C
(from CHCl3); [a]D −77 (c 0.97, MeOH).
1 A. B. Lindstrom, K. Yeowell-O’Connell, S. Waidyanatha, B. T.
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DiMTPA esters 21a–21c/21aꢀ–21cꢀ of trans-tetrahydrodiols
5a–5c/5aꢀ–5cꢀ
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Typical procedure:
A solution of the enantiomeric mix-
ture of trans-tetrahydrodiol 5a–5c/5aꢀ–5cꢀ (2.5 mmol) in
dry pyridine (2 cm3) was treated with (−)-(R)-a-methoxy-a-
(trifluoromethyl)phenylacetyl (MTPA) chloride (1.40 g, 5.5 mmol)
◦
and the reaction mixture was stirred at 60 C overnight. Excess
of pyridine was removed in vacuo and the crude mixture of two
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(1S,2R)-Di-[(S)-2-methoxy-2-phenyl-2-trifluoroacetoxy]-3-chloro-
◦
cyclohex-3-ene 21a. White solid, mp 125–127 C; (Found: M+,
580.1074. C26H2335ClF6O6 requires 580.1087); [a]D +40 (c 1.94,
CHCl3); dH(500 MHz, CDCl3) 1.69 (1 H, m, 6-H), 1.93 (1 H, m,
6ꢀ-H), 2.18 (2 H, m, 5-H, 5ꢀ-H), 3.51 (3 H, s, OMe), 3.60 (3 H, s,
OMe), 5.26 (1 H, m, 1-H), 5.48 (1 H, d, J2,1 2.9, 2-H), 6.18 (1 H,
d, J4,5 4.0, 4-H), 7.41–7.59 (10 H, m, Ar–H).
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Theory and Applications, JAI Press Inc., Greenwich, 1993,
p. 113.
(1R,2S)-Di-[(S)-2-methoxy-2-phenyl-2-trifluoroa◦cetoxy]-3-chloro-
cyclohex-3-ene 21aꢀ. White solid, mp 128–130 C; (Found: M+,
580.1077. C26H2335ClF6O6 requires 580.1087); [a]D −110 (c 1.81,
CHCl3); dH(500 MHz, CDCl3) 1.88 (1 H, m, 6-H), 1.94 (1 H, m,
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