Approaches to the synthesis of (+)- and (-)-epibatidine

Article abstract of DOI:10.1039/b002980g

Synthetic approaches to the powerful analgesic alkaloids (+)- and (-)-epibatidine are described. The starting material employed was natural (-)-quinic acid from which chiral enones and α-iodoenones were prepared. Stille coupling afforded suitable substrat

Full text of DOI:10.1039/b002980g

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Approaches to the synthesis of (؉)- and (؊)-epibatidine†
M. Teresa Barros,a Christopher D. Maycock*b and M. Rita Venturab
a Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa,
Departamento de Química, 2825 Monte da Caparica, Portugal
1
b Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa,
Rua da Quinta Grande 6, Apartado 127, 2780-156 Oeiras, Portugal
Received (in Cambridge, UK) 13th April 2000, Accepted 30th October 2000
First published as an Advance Article on the web 21st December 2000
Synthetic approaches to the powerful analgesic alkaloids (ϩ)- and (Ϫ)-epibatidine are described. The starting
material employed was natural (Ϫ)-quinic acid from which chiral enones and α-iodoenones were prepared. Stille
coupling afforded suitable substrates for completion of the syntheses. A key step in this process was the diastereo-
selective reduction of a cyclohexanone with sodium borohydride and DMSO which sets up the stereochemistry
necessary for the formation of the bicycloheptane system. The synthesis of a previously reported enone intermediate
has also been improved.
Introduction
Epibatidine 1 is an alkaloid, first isolated from the skin of
the Ecuadorian poisonous frog Epipedobates tricolor by Daly
and co-workers in 1992.1 Its low natural abundance (less than
1 mg obtained from about 750 frogs), and its strong non-opioid
analgesic activity, greater than 200 times more potent than
morphine and devoid of addictive effects has stimulated
many synthetic efforts.2–7,8 Epibatidine is an extremely potent
nicotinic acetylcholine receptor agonist (Fig. 1),9 and these
receptors are involved in the mediation of several human
disorders such as Alzheimer’s and Parkinson’s diseases.
Interestingly, (ϩ) and (Ϫ) enantiomers of epibatidine are nearly
equipotent in analgesic tests. The effect of molecular chirality
on other, perhaps undesirable, physiological activity is not
known so non-racemic synthesis is still a valid target.
Fig. 1
Here we report our approaches to the enantioselective
synthesis of both enantiomers of epibatidine from (Ϫ)-quinic
acid‡ 2 (Fig. 1) which incorporates all the functionality of
epibatidine before the formation of the azabicyclo[2.2.1]-
heptane system.
Results and discussion
A retrosynthetic analysis for both enantiomers from known
precursors derived from (Ϫ)-quinic acid indicated that intro-
duction of the pyridine unit via a substrate controlled 1,4-
addition to an α,β-unsaturated ketone could furnish both
enantiomers. Trost and Cook3 have already attempted some
1,4-addition strategies without success and we extended his
study to a variety of organocopper derivatives also without
success. We then turned our attention to the use of palladium
catalysed coupling of the pyridine moiety to a suitable α-
iodoenone which could also provide a route to both enantio-
mers depending upon the substrate 6 or 21.
Our original strategy (Scheme 1) was based upon the
2,3-dimethoxybutane-2,3-diyldioxy acetal trans diol protecting
group which created a rigid trans-decalin structure. The first
two steps are already described in the literature.8,10,11 Compound
† Experimental data for compounds 28a, 29a, 30a and 31a are avail-
able as supplementary data. For direct electronic access see http://
www.rsc.org/suppdata/p1/b0/b002980g/
‡ The IUPAC name for quinic acid is 1,3,4,5-tetrahydroxycyclo-
hexanecarboxylic acid.
Scheme 1 Reagents and conditions: (a) DIBAL-H, Et2O, Ϫ78 ЊC/0 ЊC.
(b) NaIO4, H2O, rt (97%, 2 steps). (c) Ac2O, (i-Pr)2NEt, DMAP,
CH2Cl2, 0 ЊC, 94%. (d) I2, DMAP, pyridine–CCl4 (1:1), 0 ЊC/rt, 96%.
(e) Bu3SnC5H3NCl, Pd2(dba)3ؒCHCl3, AsPh3, CuI, THF, rt/60 ЊC, 85%.
(f) K-Selectride, THF, Ϫ78 ЊC, 99%.
166
J. Chem. Soc., Perkin Trans. 1, 2001, 166–173
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b002980g

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Scheme 2 Reagents and conditions: (a) CF3COOH, CH2Cl2, H2O, ∆, 90%.
Scheme 3 Reagents and conditions: (a) Ac2O, (i-Pr)2NEt, DMAP, CH2Cl2, 0 ЊC, 67%. (b) BzCl, (i-Pr)2NEt, DMAP, CH2Cl2, 0 ЊC.
3 was obtained via a transacetalisation with 2,2,3,3-tetrameth-
oxybutane,24 in good yield. Reduction of the methyl ester with
DIBAL-H afforded the very polar triol 4 (98%) which was not
normally isolated but was oxidised directly to β-hydroxyketone
5 with NaIO4. Enone 6 was obtained in 94% yield, by acetyl-
ation of 5 followed by elimination with diisopropylethyl-
amine.8,10,11 Finally, applying Johnson’s method14 but using
DMAP to accelerate the elimination, iodoenone 7 was obtained
Fig. 2
in 96% yield.
A range of reaction conditions were tested to obtain 8 from
7, using the Stille cross-coupling reaction with (2-chloro-5-
pyridyl)tributyltin15–17 to afford ketone 8 in 85% yield. A large
rate enhancement was observed with triphenylarsine as the
palladium ligand. The use of co-catalytic Cu() in this coupling
reaction was also essential.18 It has been reported3,18 that with
ligands, such as AsPh3, the addition of CuI displayed little
effect on the reaction rate, but with our system the presence
of CuI was absolutely necessary, and Johnson14,23 also used this
combination in similar reactions.
sodium methoxide induced the elimination reaction but 1,4-
addition of methanol to the enone occurred to give the mixture
of epimers 20 (Fig. 2).
After the failure of our initial approach we concentrated on
one which depended upon a stereoselective carbonyl reduction
reaction (Schemes 4 and 5). The first three steps are already
described in the literature.8,10,21 K-Selectride was used to reduce
the double bond of 21 chemoselectively, and the next two steps,
as well as for enone 21, were carried out using the published
method.8 Direct α-iodination of enone 23 afforded α-iodoenone
24, in good yield (82%) and a Stille cross-coupling reaction
introduced the chloropyridyl ring to form enone 25 (90%)
(Scheme 4).
Conjugate reduction of the enone 8 with K-Selectride 19
afforded the epimer 9, in quantitative yield. This high stereo-
selectivity is explained by the preference for the pyridine sub-
stituent to attain the equatorial position α to the enolisable
ketone. Unfortunately, after cleavage of this acetal (Scheme 2)
with trifluoroacetic acid, the rigidity of the molecule was lost,
enolisation occurred and a mixture of the two epimers 10 and
11 (82%) was obtained in about a 1:1 ratio, along with a minor
quantity (9%) of the two expected epimers of the eliminated
products, 12 and 13 (2.1:1 respectively). The use of harsher
conditions resulted in some decomposition but no increase in
the amount of eliminated product.
Conjugate reduction of enone 25 with K-Selectride, gave
the two epimers 26 and 27 in a 1:1 ratio. Trost and Cook3
observed some selectivity with a similar system (NHBoc group
instead of a OTBDMS group) and obtained the cis and trans
products in a ratio of 4:1 respectively. The epimers 26 and 27
were very difficult to separate and since the pyridyl group was
attached to an enolisable carbon atom, we reduced the carbonyl
group of the compounds in the mixture (Table 1).
Esterification of 10 and 11 gave the desired α,β-unsaturated
ketones 16 and 19, in low yields. Efforts to acetylate or benz-
oylate the hydroxy groups of 10 and 11 in the presence of
Hunigs base (ethyldiisopropylamine) afforded, as the major
products, the enol esters 14 and 17 respectively, indicating
the ease with which this ketone enolises in the direction of the
2-(5-pyridyl) group (Scheme 3). Benzoylating conditions were
particularly efficient at forming the enol ester 17. Even in the
presence of the less basic pyridine, esterification of the enolate
also occurred. For all of these attempts the principal com-
ponent of the small quantities of mixtures of eliminated
epimers, was the cis isomer (15 or 18). Attempts to hydrolyse
the enol acetate 15 with methanol, and to force the elimination
with diisopropylethylamine were unrewarding. The use of
For the reduction of the mixture of 26 and 27 a variety of
conditions were tested, and some interesting results obtained.
L-Selectride gave only the two cis diastereoisomers 28 and 29,
and both were the axial alcohols.20 There were no significant
differences between the ratios obtained with NaBH4 and
NaBH4 with CeCl3ؒ7H2O, however, when the reduction was
performed with NaBH4 in the presence of DMSO the yield of
the desired diastereoisomer 30 increased, and at Ϫ20 ЊC this
improved further. However, simple borohydride reduction of
this system at Ϫ20 ЊC afforded only slightly lower, selectivities.
Since the yield of the required diastereoisomer is higher than
expected from the ratio of the ketones 26 and 27, we assume
that 26 is being reduced more rapidly than 27 and that 27 is
equilibrating with 26 via an enol under the reaction conditions.
J. Chem. Soc., Perkin Trans. 1, 2001, 166–173
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Table 1 Reduction of the carbonyl group of epimers 26 and 27a
Selectivity/%
Conditions/yield
28
30
29
31
L-Selectride, Ϫ78 ЊC/50%
DIBAL-H, Ϫ78 ЊC/67%
NaBH4, 0 ЊC/99%
NaBH4, CeCl3ؒ7H2O, 0 ЊC/97%
NaBH4, DMSO (1 eq.), 0 ЊC/79%
NaBH4, DMSO (2 eq.), 0 ЊC/95%
NaBH4, Ϫ20 ЊC/98%
32
25
31
25
17
11
8
0
20
16
18
49
55
58
62
68
20
16
13
13
9
0
35
37
44
21
25
24
26
10
4
NaBH4, DMSO (2 eq.), Ϫ20 ЊC/96%
8
a Pyr is 2-chloro-5-pyridyl.
Scheme 4 Reagents and conditions: (a) K-Selectride, THF, Ϫ78 ЊC.
(b) NaOH 0.5 M, THF, 0 ЊC. (c) TBDMSCl, (i-Pr)2NEt, DMAP,
CH2Cl2, 0 ЊC/rt (51%, 3 steps). (d) I2, DMAP, pyridine–CCl4 (1:1),
0 ЊC/rt, 82%. (e) Bu3SnC5H3NCl, Pd2(dba)3ؒCHCl3, AsPh3, CuI, THF,
rt/60 ЊC, 90%. (f) K-Selectride, THF, Ϫ78 ЊC, 88%.
Scheme 5 Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 ЊC,
99%. (b) Bu4NF, THF, rt, 88%. (c) PPh3, HN3, DEAD, THF, 0 ЊC/rt,
94%.
shift than 29, 31, 29a and 31a, which have this group below the
plane of the molecule. The H-1 and H-4 signals are singlets if
the protons are in an equatorial position and multiplets if they
are in an axial position, which correlates well with the expected
values for the coupling constants between axial–equatorial,
equatorial–equatorial and axial–axial protons in a chair con-
formation for cyclohexanes. Fortunately, the major diastereo-
isomer 30 obtained from the later attempts was that with
the correct configuration for completion of the synthesis
(Scheme 5).
Mesylation of 30 afforded 32 in quantitative yield, and
removal of the TBDMS group was achieved with anhydrous
TBAF.10 By applying the Mitsunobu azide modification to
compound 33, azide 34 was obtained which presented a proton
NMR spectrum identical to that previously reported.5 The
conversion of the racemic form of azide 34 to epibatidine has
already been reported in two syntheses.4,5
Our assignment of the configurations to the various diastereo-
isomers produced was made by comparing the proton NMR
spectra both of the reduction products and of their benzoates.
The nature of this selectivity enhancement by DMSO is not
understood although it must increase the rate of the equilibra-
tion reaction or the stereoselectivity of the reduction reaction.
In our analysis the only way to explain the collected NMR
data was by assuming that the pyridine moiety would control
the conformation of the molecule by always adopting an
equatorial position, in spite of the bulky OTBS group. Thus,
on one hand, we could clearly see that compounds with cis
H-1 and H-2, 28, 29, 28a and 29a, show a doublet for H-2, and
the trans compounds 30, 31, 30a and 31a present a H-2 dt
(Table 2). On the other hand, compounds 28, 30, 28a and 30a,
all with the pyridine group above the plane of the molecule and
the same chair conformation, have a lower field H-2 chemical
168
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Scheme 6 Reagents and conditions: (a) DEAD, HN3, PPh3, THF,
0 ЊC/rt, 74%.
Another feasible route to (ϩ)-epibatidine was tested (Scheme
6). Azide 36 was formed by a Mitsunobu azide reaction on
enone 22. After reduction of azide 36 and protection as the
Boc amide, we expected to obtain the enantiomer of one of
Trost’s precursors in his epibatidine synthesis.3 Attempted
Staudinger reduction of azide 36 to the respective amine using
standard conditions (triphenylphosphine TPP), resulted in
severe destruction of the reagents. It is interesting to note that
Trost, in a similar azide reduction, used a Staudinger reaction
with the unusual trimethylphosphine.
The enone 39 has previously been reported12 from the cyclo-
hexane acetal 37. As mentioned earlier the acid treatment of 9
afforded very low yields of unsaturated product 12. Treatment
of the readily available diacetal 38 with acid, however, afforded
very good yields (85%) of the enone 39 which was immediately
protected as its TBDMS ether 40 (Scheme 7). This method
of preparing 40 is considerably easier than that described in
the literature.12 Tetramethoxybutane is readily obtained from
inexpensive biacetyl. The protection of the trans diol using this
reagent was high yielding and highly selective. The product
resulting from the hydrolysis or acid elimination of the acetal
was biacetyl which is yellow and acts as an indicator. Biacetyl
is easily removed from the product either by washing or
by evaporation. Cyclohexane-1,2-dione is expensive and the
products formed by the hydrolysis or elimination from 37
are not volatile and not easily removed from the product. The
rigidity of the acetal formed from biacetyl appears to be the
same as that for the cyclohexanedione. The yield of product
obtained from acetal 38 is very much higher than that reported
for the cyclohexane acetal 37. From enone 40 the iodoenone
41 could be prepared and provided an analoguous route to
(Ϫ)-epibatidine.
In summary, asymmetric routes have been developed for the
synthesis of (ϩ)- and (Ϫ)-epibatidine from readily available
materials using mild reaction conditions. The other approaches
to (Ϫ)-epibatidine reported here revealed important aspects
of the reactivity of trans vicinal diols, and allowed us to prepare
some potentially useful cyclohexane derivatives.
Experimental
General
Melting points were determined with a capillary apparatus and
1
are uncorrected. H NMR spectra were obtained at 300 MHz
in CDCl3 with chemical shift values (δ) in ppm downfield
from tetramethylsilane and at 300 K, and 13C NMR spectra
were obtained at 100.61 MHz in CDCl3. DEPT, CH-COSY and
J. Chem. Soc., Perkin Trans. 1, 2001, 166–173
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Scheme 7 Reagents and conditions: (a) Pearlman’s catalyst, AcOEt, H2 (50 psi), quantitative. (b) CF3COOH, H2O, CH2Cl2, reflux, 85%.
(c) TBDMSCl, (i-Pr)2NEt, DMAP, CH2Cl2, 0 ЊC/rt, 98%.
HH-COSY were used as an aid to structure elucidation and
carbon assignments but these data are not reported here.
Microanalyses were performed by the ITQB analytical services
using a combustion apparatus. IR (ν/cmϪ1): measured on
an FTIR spectrophotometer. Medium pressure preparative
column chromatography: silica gel Merck 60 H. Preparative
TLC: silica gel Merck 60 GF254. Analytical TLC: Aluminium-
backed silica gel Merck 60 F254. Specific rotations ([α]tD) were
measured on an automatic polarimeter and values are given
in 10Ϫ1 deg cm2 gϪ1. Reagents and solvents were purified and
dried according to ref. 22. All the reactions were carried out
in an inert atmosphere (argon or nitrogen), unless otherwise
indicated.
(1H, d, J = 10.0 Hz, H-2), 4.49 (1H, dt, J = 9.0, 2.1 Hz, H-4),
4.09–4.00 (1H, m, H-5), 3.32 (3H, s, OCH3), 3.26 (3H, s,
OCH3), 2.74 (1H, dd, J = 16.7, 5.2 Hz, H-6), 2.48 (1H, dd,
J = 16.4, 13.4 Hz, H-6), 1.37 (3H, s, CH3), 1.33 (3H, s, CH3).
δC (100.61 MHz; CDCl3; Me4Si) 196.8 (C-1), 148.5, 130.1 (C-2,
C-3), 100.8, 99.7 (2 × C(CH3)OCH3), 69.2, 68.1 (C-4, C-5),
48.1, 48.0 (2 × OCH3), 42.0 (C-6), 17.6 (2 × CH3).
(4R,5R)-2-Iodo-4,5-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyldioxy]cyclohex-2-en-1-one (7)
To a solution of enone 6 (0.992 g, 4.09 mmol) in pyridine–CCl4
(10 mL:10 mL), at 0 ЊC, was added I2 (2.604 g, 10.2 mmol) in
pyridine–CCl4 (6 mL:6 mL) and a catalytic amount of DMAP.
The reaction mixture was stirred at rt for 24 h, and then 20%
aqueous Na2S2O3 solution (15 mL) was added. The mixture was
extracted with diethyl ether (3 × 10 mL), the combined organic
extracts were dried (MgSO4) and concentrated to afford an
orange solid which was purified by column chromatography.
Elution with AcOEt–hexane 5:95 furnished 7 (1.448 g, 96%) as
white crystals. Mp 190–192 ЊC. [α]D20 ϩ60.9 (c 0.63 in CH2Cl2).
Anal. calc. for C12H17O5I: C 39.15, H 4.65. Found: C 39.32,
H 4.58%. νmax (KBr)/cmϪ1: 2958, 2947, 2918, 2860, 2833 (all
(3R,4R,5R)-5-Hydroxy-3,4-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyldioxy]cyclohexan-1-one (5)
To a solution of 324 (1.5 g, 4.68 mmol) in diethyl ether (40 mL)
at Ϫ78 ЊC was slowly added DIBAL-H (diisobutylaluminium
hydride 1.0 M solution in hexanes, 23.4 mL, 0.023 mmol). The
reaction was stirred for 15 min at Ϫ78 ЊC and for a further
15 min at 0 ЊC. Water (30 mL) was added and the resulting gel
was filtered and washed with water three times. To the aqueous
filtrate containing triol 4, was added NaIO4 (1.71 g, 8.0 mmol)
and the mixture was stirred at rt for 1 h, and then it was
extracted with ethyl acetate (3 × 30 mL), the combined organic
extracts were dried (MgSO4) and the solvent evaporated to
afford 5 (1.180 g, 97% from 3) as white crystals. Compound 5:
mp 163–165 ЊC. [α]D20 ϩ159.8 (c 0.59 in CH2Cl2). Anal. calc.
for C12H20O6: C 55.37, H 7.74. Found: C 55.15, H 7.75%.
νmax (KBr)/cmϪ1: 3481 (O–H), 3009, 2993, 2968, 2953, 2885 (all
C–H), 1682 (C᎐O, α,β-unsat. ketone). δ (300 MHz; CDCl3;
᎐
H
Me4Si) 7.63 (1H, d, J = 1.2 Hz, H-3), 4.49 (1H, d, J = 2.9 Hz,
H-4), 4.08–4.01 (1H, m, H-5), 3.31 (3H, s, OCH3), 3.26 (3H, s,
OCH3), 2.98 (1H, dd, J = 16.4, 4.7 Hz, H-6), 2.61 (1H, dd,
J = 16.1, 13.4 Hz, H-6), 1.36 (3H, s, CH3), 1.32 (3H, s, CH3).
δC (100.61 MHz; CDCl3; Me4Si) 189.9 (C-1), 156.8 (C-3), 103.7
(C-2), 101.0 and 99.8 (2 × C(CH3)OCH3), 71.2 and 67.6
(C-4, C-5), 48.2 and 48.1 (2 × OCH3), 39.9 (C-6), 17.6, 17.5
(2 × CH3).
C–H), 1726 (C᎐O, sat. ketone). δ (300 MHz; CDCl3; Me4Si)
᎐
H
4.25–4.23 (2H, m, H-3, H-5), 3.88 (1H, dd, J = 10.1, 2.4 Hz,
H-4), 3.31 (3H, s, OCH3), 3.23 (3H, s, OCH3), 2.69–2.63
(3H, m, 2 × (H-2 and/or H-6) and/or OH), 2.54–2.46 (2H,
m, 2 × (H-2 and/or H-6) and/or OH), 1.35 (3H, s, CH3), 1.31
(3H, s, CH3). δC (100.61 MHz; CDCl3; Me4Si) 205.4 (C-1),
100.2, 99.2 (2 × C(CH3)OCH3), 72.2, 67.6, 63.2 (C-3, C-4,
C-5), 48.1, 47.9 (2 × OCH3), 46.2, 44.7 (C-2, C-6), 17.6, 17.5
(2 × CH3).
(4R,5R)-2-(2-Chloro-5-pyridyl)-4,5-[(2S,3S)-2,3-dimethoxy-
butane-2,3-diyldioxy]cyclohex-2-en-1-one (8)
To a solution of 7 (0.800 g, 2.17 mmol) in THF (12 mL) was
added AsPh3 (0.068 g, 10 mol%), Pd2(dba)3ؒCHCl3 (0.056 g,
2.5 mol%) and CuI (0.040 g, 10 mol%). The suspension was
stirred for 10 min, and (2-chloro-5-pyridyl)tributyltin (1.138 g,
2.82 mmol) in THF (2 mL) was added. After stirring at 60 ЊC
for 24 h, 10% aqueous Na2SO3 solution (5 mL) was added to
the cooled (rt) suspension. The mixture was washed with 10%
aqueous KF solution (10 mL) and extracted with diethyl ether
(3 × 10 mL), the combined organic layers were dried (MgSO4)
and the solvent evaporated to give an orange solid residue.
Purification by column chromatography (AcOEt–hexane 1:9)
afforded 8 (0.653 g, 85%) as white crystals. Mp 147–149 ЊC.
[α]D20 ϩ61.5 (c 0.66 in CH2Cl2). Anal. calc. for C17H20O5NCl:
C 57.71, H 5.70, N 3.96. Found: C 57.79, H 5.93, N 4.00%.
(4R,5R)-4,5-[(2S,3S)-2,3-Dimethoxybutane-2,3-diyldioxy]-
cyclohex-2-en-1-one (6)
To a solution of 5 (1.180 g, 4.53 mmol) in CH2Cl2 (4.8 mL),
at 0 ЊC, was added a catalytic amount of DMAP, diisopropyl-
ethylamine (1.59 mL, 9.5 mmol) and acetic anhydride (0.512
mL, 5.4 mmol). After stirring for 1 h at 0 ЊC all the starting
material had been consumed. The reaction mixture was washed
with saturated aqueous NaHCO3 solution (10 mL) and
extracted with CH2Cl2 (3 × 10 mL). The organic layer was
dried (MgSO4) and concentrated. Purification by column
chromatography (AcOEt–hexane 2:8) gave enone 6 (1.035 g,
94.2%) as white crystals. Mp 182–184 ЊC. [α]D20 ϩ64.4 (c 0.39 in
CH2Cl2). Anal. calc. for C12H18O5: C 59.49, H 7.49. Found: C
59.39, H 7.46%. νmax (KBr)/cmϪ1: 3003, 2966, 2955, 2930, 2856,
νmax (KBr)/cmϪ1: 2991 and 2947 (C–H), 1678 (C᎐O, α,β-unsat.
᎐
ketone). δH (300 MHz; CDCl3; Me4Si) 8.34 (1H, d, J = 3.0 Hz,
pyr H-6), 7.66 (1H, dd, J = 9.0, 3.0 Hz, pyr H-4), 7.32
(1H, d, J = 9.0 Hz, pyr H-3), 7.00 (1H, s, H-3), 4.65 (1H, dd,
J = 9.0, 3.0 Hz, H-4), 4.16 (1H, m, H-5), 3.36 (3H, s, OCH3),
3.30 (3H, s, OCH3), 2.93 (1H, dd, J = 15.0, 3.0 Hz, H-6),
2.66 (1H, dd, J = 15.0, 12.0 Hz, H-6), 1.40 (3H, s, CH3), 1.36
(3H, s, CH3).
2839 (all C–H), 1680 (C᎐O, α,β-unsat. ketone). δ (300 MHz;
᎐
H
CDCl3; Me4Si) 6.85 (1H, dd, J = 10.1, 1.4 Hz, H-3), 6.00
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(2R,4R,5R)-2-(2-Chloro-5-pyridyl)-4,5-[(2S,3S)-2,3-dimethoxy-
butane-2,3-diyldioxy]cyclohexan-1-one (9)
layer was dried (MgSO4) and concentrated. Purification by pre-
parative TLC (AcOEt–hexane 4:6) gave a mixture of epimers
15 and 16 (0.015 g, 37%, 2.7:1 15–16) and 14 (0.017 g, 30%),
both fractions as colourless oils. Compound 14: δH (300 MHz;
CDCl3; Me4Si) 8.30 (1H, d, J = 3.0 Hz, pyr H-6), 7.51 (1H,
dd, J = 9.0, 3.0 Hz, pyr H-4), 7.30 (1H, d, J = 9.0 Hz, pyr
H-3), 5.24–5.21 (2H, m, H-4, H-5), 2.86–2.81 (2H, m, 2 × (H-3
and/or H-6)), 2.57–2.50 (2H, m, 2 × (H-3 and/or H-6)), 2.09
(6H, s, 2 × OC(O)CH3), 1.99 (3H, s, OC(O)CH3). Compound
15: δH (300 MHz; CDCl3; Me4Si) 8.20 (1H, d, J = 3.0 Hz, pyr
H-6), 7.45 (1H, dd, J = 5.7, 2.4 Hz, pyr H-4), 7.33 (1H, d,
J = 8.1 Hz, pyr H-3), 6.92 (1H, dt, J = 10.5, 2.1 Hz, H-3),
5.86–5.81 (1H, m, H-4), 3.70 (1H, dd, J = 14.4, 4.2 Hz, H-6),
2.64–2.58 (1H, m, H-5), 2.42–2.34 (1H, m, H-5), 2.14 (3H, s,
OC(O)CH3). Compounds 15 and 16: m/z (EI): 265 ([M]ϩ,
0.04%), 223 (10.24), 205 (23.16), 142 (37), 140 (100), 126 (9.44),
84 (44.34), 77 (5.83), 55 (5.33).
To a solution of 8 (0.682 g, 1.93 mmol) in THF (12 mL) at
Ϫ78 ЊC was slowly added K-Selectride (1.92 mL, 1.92 mmol).
The reaction was stirred at this temperature for 1 h, and it was
quenched with saturated aqueous NH4Cl (10 mL). The aqueous
layer was extracted with ethyl acetate (3 × 6 mL), the combined
organic extracts were dried (MgSO4) and concentrated to yield
a viscous residue which was purified by column chromato-
graphy (AcOEt–hexane 2.5:7.5). Compound 9 (0.679 g, 99%)
was obtained as white crystals. Mp 156–158 ЊC. [α]D20 ϩ137.7
(c 0.48 in CH2Cl2). Anal. calc. for C17H22O5NCl: C 57.39, H
6.23, N 3.94. Found: C 57.29, H 6.09, N 3.82%. νmax (KBr)/
cmϪ1: 3013, 2993, 2951, 2883, 2835 (al C–H), 1720 (C᎐O, sat.
᎐
ketone), 1591 (C᎐C). δ (300 MHz; CDCl3; Me4Si) 8.12 (1H,
᎐
H
d, J = 3.0 Hz, pyr H-6), 7.38–7.31 (2H, m, pyr H-3 and H-4),
4.13–4.08 (1H, m, H-4 or H-5), 3.93–3.86 (1H, m, H-4 or H-5),
3.64 (1H, dd, J = 13.8, 5.7 Hz, H-2), 3.35 (3H, s, OCH3), 3.28
(3H, s, OCH3), 2.78–2.70 (2H, m, 2 × H-6), 2.31–2.24 (1H, m,
H-3), 1.98 (1H, dt, J = 12.9 Hz, H-3), 1.53 (6H, s, 2 × CH3).
δC (100.61 MHz; CDCl3; Me4Si) 203.8 (C-1), 150.5 (pyr C-2),
149.6 (pyr C-6), 139.0 (pyr C-4), 131.5 (pyr C-5), 124.0 (pyr
C-3), 99.8 and 99.5 (2 × C(CH3)OCH3), 69.3 and 68.0 (C-4,
C-5), 51.6 (C-2), 48.2 and 48.1 (2 × OCH3), 44.7 and 33.4 (C-3,
C-6), 17.6 (2 × CH3).
(4R,5R)-1,4,5-Tris(benzoyloxy)-2-(2-chloro-5-pyridyl)cyclohex-
1-ene (17) and (4R,6R)-4-benzoyloxy-6-(2-chloro-5-pyridyl)-
cyclohex-2-en-1-one (18) and (4R,6S)-4-benzoyloxy-6-(2-chloro-
5-pyridyl)cyclohex-2-en-1-one (19)
To a suspension of 10 and 11 (0.032 g, 0.13 mmol) in CH2Cl2
(1 mL), at 0 ЊC, was added a catalytic amount of DMAP,
diisopropylethylamine (0.069 mL, 0.40 mmol) and benzoyl
chloride (0.031 mL, 0.026 mmol). After stirring for 3 h at 0 ЊC
all the starting material had been consumed. The reaction
mixture was washed with saturated aqueous NaHCO3 solution
(3 mL) and extracted with CH2Cl2 (3 × 3 mL). The organic
layer was dried (MgSO4) and concentrated. Purification by pre-
parative TLC (AcOEt–hexane 4:6) gave a mixture of epimers
18 and 19 (0.004 g, 10%, 2:1 18–19) as a colourless oil and 17
(0.066 g, 90%) as white crystals. Compound 17: mp 52–54 ЊC.
[α]D20 Ϫ40.9 (c 0.94 in CH2Cl2). Anal. calc. for C32H24O6NCl:
C 69.38, H 4.37, N 2.53. Found: C 69.40, H 4.07, N 2.58%.
νmax (KBr)/cmϪ1: 3063 (C–H), 1724 (C᎐O, ester). δ (300 MHz;
(2R/S,4R,5R)-2-(2-Chloro-5-pyridyl)-4,5-dihydroxycyclohexan-
1-one (10 and 11) and (4R,6R)-6-(2-chloro-5-pyridyl)-4-hydroxy-
cyclohex-2-en-1-one (12) and (4R,6S)-6-(2-chloro-5-pyridyl)-4-
hydroxycyclohex-2-en-1-one (13)
To a solution of 9 (0.183 g, 0.51 mmol) in CH2Cl2 (5.6 mL) was
added CF3COOH (0.282 mL, 3.7 mmol) and water (0.056 mL).
The reaction was refluxed for 5 h, and then it was cooled. The
solvent was evaporated, the viscous residue was redissolved
in AcOEt (5 mL) and solid NaHCO3 was added. The sus-
pension was filtered and the solvent evaporated again to afford
a viscous residue. Purification by column chromatography
(AcOEt–hexane 7:3) afforded a mixture of epimers 12 and 13
(0.010 g, 8.7%, 2.1:1 12–13) and a mixture of epimers 10 and 11
(0.102 g, 82%, in almost 1:1 ratio), both as colourless viscous
oils. Epimers 10 and 11: δH (300 MHz; CDCl3; Me4Si) 8.18
(d, J = 3.0 Hz), 8.14 (d, J = 3.0 Hz), 7.50 (dd, J = 9.0, 3.0 Hz),
7.41 (m), 7.34–7.30 (m), 4.41 (br s), 4.19–4.05 (m), 3.80 (m),
3.68 (dd), 3.14 (dd, J = 15.0, 3.0 Hz), 2.90 (t, J = 6.0 Hz),
2.69–1.91 (m). m/z (EI): 241 ([M]ϩ, 5.12%), 207 (12.77), 205
(38.28), 170 (24.47), 168 (10.56), 152 (21.51), 142 (45.30), 140
(100), 127 (16.32), 115 (10.65), 104 (14.33), 84 (17.40), 77 (10).
Compound 12: δH (300 MHz; CDCl3; Me4Si) 8.20 (1H, d,
J = 2.4 Hz, pyr H-6), 7.57 (1H, dd, J = 8.4, 2.4 Hz, pyr H-4),
7.33 (1H, d, J = 8.1 Hz, pyr H-3), 7.03 (1H, d, J = 10.0 Hz,
H-3), 6.13 (1H, dd, J = 10.5, 2.4 Hz, H-2), 4.83 (1H, m, H-4),
3.62 (1H, dd, J = 14.4, 3.9 Hz, H-6), 2.62–2.55 (1H, m, H-5),
2.36–2.28 (1H, m, H-5). Compounds 12 and 13: m/z (EI): 223
([M]ϩ, 4.90%), 219.90 (24.48), 140 (86.76), 104 (14.27), 84 (100),
77 (12.84), 55 (29.17).
᎐
H
CDCl3; Me4Si) 8.48 (1H, s, Ar or pyr H), 8.07–8.01 (5H, m,
Ar and pyr H), 7.95–7.93 (2H, d, J = 6.0 Hz, Ar and/or pyr H),
7.59–7.28 (10H, 2m, Ar and pyr H), 5.73 (2H, s, H-4, H-5),
3.25–3.14 (2H, m, 2 × (H-3 and/or H-6)), 3.25–3.14 (2H, m,
2 × (H-3 and/or H-6)). Epimers 18 and 19: δH (300 MHz;
CDCl3; Me4Si) 8.24 (d, J = 2.4 Hz, pyr H-6 18), 8.08–8.04 (m),
7.59 (m), 7.51–7.45 (m), 7.46 (d, J = 8.1 Hz), 7.06 (d, J = 10.5
Hz, H-3 18), 6.26 (dd, J = 10.2, 2.1 Hz, H-2 18), 6.09 (m, H-4
18), 5.78 (m, H-4 19), 4.10 (dd, J = 10.5, 5.1 Hz, H-6 18), 3.79
(dd, J = 14.4, 4.2 Hz, H-6 18), 2.80–2.49 (m). νmax (KBr)/cmϪ1:
1718 (C᎐O, ester), 1685 (C᎐O, α,β-unsat. ketone), 1564 (C᎐C).
᎐
᎐
᎐
m/z (EI): 327 ([M]ϩ, 0.53%), 309 (2.25), 205 (6.85), 140 (2.70),
105 (100), 77 (17.72).
(4S)-4-[(tert-Butyldimethylsilyl)oxy]-2-iodocyclohex-2-en-1-one
(24)
To a solution of enone 23 (1.032 g, 4.56 mmol) in pyridine–
CCl4 (6 mL:6 mL), at 0 ЊC, was added I2 (2.89 g, 11.4 mmol) in
pyridine–CCl4 (5 mL:5 mL) and a catalytic amount of DMAP.
The reaction mixture was stirred at rt for 4 h, and then 20%
aqueous Na2S2O3 solution (15 mL) was added. The mixture was
extracted with diethyl ether (3 × 10 mL), the combined organic
extracts were dried (MgSO4) and concentrated to afford an
orange residue which was purified by column chromatography.
Elution with AcOEt–hexane 5:95 furnished 24 (1.317 g, 82%)
as a colourless liquid. [α]D20 Ϫ44.4 (c 1.68 in CH2Cl2). νmax (film)/
(4R,5R)-1,4,5-Triacetoxy-2-(2-chloro-5-pyridyl)cyclohex-1-ene
(14) and (4R,6R)-4-acetoxy-6-(2-chloro-5-pyridyl)cyclohex-2-en-
1-one (15) and (4R,6S)-4-acetoxy-6-(2-chloro-5-pyridyl)cyclo-
hex-2-en-1-one (16)
To a suspension of 10 and 11 (0.037 g, 0.15 mmol) in CH2Cl2
(1 mL), at 0 ЊC, was added a catalytic amount of DMAP,
diisopropylethylamine (0.080 mL, 0.46 mmol) and acetic
anhydride (0.029 mL, 0.030 mmol). After stirring for 3 h at
0 ЊC all the starting material had been consumed. The reaction
mixture was washed with saturated aqueous NaHCO3 solution
(3 mL) and extracted with CH2Cl2 (3 × 3 mL). The organic
cmϪ1: 2954, 2931, 2885, 2856 (all C–H), 1693 (C᎐O, α,β-unsat.
᎐
ketone), 1589 (C᎐C). δ (300 MHz; CDCl3; Me4Si) 7.61 (1H,
᎐
H
s, H-3), 4.51 (1H, m, H-4), 2.83 (1H, dt, J = 16.8, 4.5 Hz, H-5
or H-6), 2.56–2.44 (1H, m, H-5 or H-6), 2.28–2.22 (1H, m,
H-5 or H-6), 2.07–2.03 (1H, m, H-5 or H-6), 0.91 (9H, s,
SiC(CH3)3), 0.13 (3H, s, SiCH3), 0.12 (3H, s, SiCH3).
J. Chem. Soc., Perkin Trans. 1, 2001, 166–173
171

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(4S)-4-[(tert-Butyldimethylsilyl)oxy]-2-(2-chloro-5-pyridyl)cyclo-
hex-2-en-1-one (25)
H-4), 3.27 (1H, d, J = 12.9 Hz, H-2), 2.18 (2H, dt, J = 11.4 Hz,
2 × H-3 or 2 × H-5 or 2 × H-6), 1.91–1.52 (4H, m, 2 × H-3
and/or 2 × H-5 and/or 2 × H-6), 0.90 (9H, s, SiC(CH3)3), 0.07
(3H, s, SiCH3), 0.04 (3H, s, SiCH3). Compound 29: [α]D20 Ϫ61.2
(c 0.25 in CH2Cl2). νmax (film)/cmϪ1: 3450 (O–H), 2891 and
2856 (C–H). δH (300 MHz; CDCl3; Me4Si) 8.27 (1H, d, J = 1.8
Hz, pyr H-6), 7.64 (1H, dd, J = 8.1, 2.4 Hz, pyr H-4), 7.28 (1H,
d, J = 8.4 Hz, pyr H-3), 3.89 (1H, s, H-1), 3.71 (1H, m, H-4),
2.75 (1H, d, J = 13.2 Hz, H-2), 2.13–1.68 (6H, m, 2 × H-3,
2 × H-5, 2 × H-6), 0.90 (9H, s, SiC(CH3)3), 0.08 (3H, s, SiCH3),
0.07 (3H, s, SiCH3). Compound 30: mp 79–80 ЊC. [α]D20 Ϫ10.6
(c 0.32 in CH2Cl2). Anal. calc. for C17H28O2NSiCl: C 59.71, H
8.25, N 4.10. Found: C 59.80, H 8.62, N 4.12%. νmax (film)/cmϪ1:
3375 (O–H), 2955, 2943, 2926, 2899, 2856 (all C–H). δH (300
MHz; CDCl3; Me4Si) 8.28 (1H, s, pyr H-6), 7.54 (1H, dd,
J = 8.1, 2.1 Hz, pyr H-4), 7.29 (1H, d, J = 8.7 Hz, pyr H-3), 4.09
(1H, s, H-4), 3.70–3.62 (1H, m, H-1), 3.04 (1H, dt, J = 11.7,
3.0 Hz, H-2), 1.94–1.59 (6H, m, 2 × H-3, 2 × H-5, 2 × H-6),
0.92 (9H, s, SiC(CH3)3), 0.07 (3H, s, SiCH3), 0.05 (3H, s,
SiCH3). Compound 31: [α]D20 Ϫ7.00 (c 0.74 in CH2Cl2).
νmax (film)/cmϪ1: 3358 (O–H), 2933, 2885, 2857 (all C–H).
δH (300 MHz; CDCl3; Me4Si) 8.25 (1H, s, pyr H-6), 7.56 (1H,
dd, J = 8.4, 2.4 Hz, pyr H-4), 7.29 (1H, d, J = 8.4 Hz, pyr
H-3), 3.77–3.72 (1H, m, H-1), 3.67–3.60 (1H, m, H-4), 2.57
(1H, dt, J = 11.4, 3.0 Hz, H-2), 2.15–1.97 (4H, m, 2 × H-3
and/or 2 × H-5 and/or 2 × H-6 or OH), 1.70–1.48 (3H,
m, 2 × H-3 and/or 2 × H-5 and/or 2 × H-6), 0.87 (9H, s,
SiC(CH3)3), 0.07 (3H, s, SiCH3), 0.05 (3H, s, SiCH3).
To a solution of 24 (0.883 g, 2.5 mmol) in THF (6 mL) was
added AsPh3 (0.076 g, 10 mol%), Pd2(dba)3ؒCHCl3 (0.064 g,
2.5 mol%) and CuI (0.048 g, 10 mol%). The suspension was
stirred for 10 min, and (2-chloro-5-pyridyl)tributyltin (1.304
g, 3.24 mmol) was added. After stirring at 60 ЊC for 24 h, 10%
aqueous Na2SO3 solution (5 mL) was added to the cooled
suspension. The mixture was washed with 10% aqueous KF
solution (10 mL) and extracted with diethyl ether (3 × 10 mL),
the combined organic layers dried (MgSO4) and the solvent
evaporated to give an orange liquid residue. Purification by
column chromatography (AcOEt–hexane 0.5:9.5) afforded 25
(0.762 g, 90%) as a yellowish oil. [α]D20 Ϫ50.8 (c 1.13 in CH2Cl2).
νmax (film)/cmϪ1: 2955, 2930, 2885, 2858 (all C–H), 1685 (C᎐O,
᎐
α,β-unsat. ketone), 1581 (C᎐C). δ (300 MHz; CDCl3; Me4Si)
᎐
H
8.34 (1H, d, J = 1.5 Hz, pyr H-6), 7.70 (1H, dd, J = 8.7, 2.4 Hz,
pyr H-4), 7.33 (1H, d, J = 8.1 Hz, pyr H-3), 6.94 (1H, s, H-3),
4.69 (1H, m, H-4), 2.77 (1H, dt, J = 12.6, 4.2 Hz, H-5 or H-6),
2.52 (1H, dt, J = 12.9, 4.2 Hz, H-5 or H-6), 2.34–2.29 (1H,
m, H-5 or H-6), 2.14–2.10 (1H, m, H-5 or H-6), 0.93 (9H, s,
SiC(CH3)3), 0.16 (3H, s, SiCH3), 0.15 (3H, s, SiCH3).
(2S,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2-(2-chloro-5-pyridyl)-
cyclohexan-1-one (26) and (2R,4S)-4-[(tert-butyldimethylsilyl)-
oxy]-2-(2-chloro-5-pyridyl)cyclohexan-1-one (27)
To a solution of 25 (0.200 g, 0.59 mmol) in THF (3 mL)
at Ϫ78 ЊC was slowly added K-Selectride (1 M in THF,
0.588 mL, 0.59 mmol). Saturated aqueous NH4Cl solution
(5 mL) was added and the temperature was allowed to rise
to rt. The mixture was extracted with ethyl ether (3 × 5 mL),
the combined organic extracts were dried (MgSO4) and con-
centrated to yield a residue that was purified by column
chromatography (AcOEt–hexane 1:9). A mixture of the two
epimers 26 and 27 was obtained (0.177 g, 88%, 1:1) as a colour-
less liquid. δH (300 MHz; CDCl3; Me4Si) 8.13 (2H, d, J = 1.8
Hz, 2 × pyr H-6), 7.47–7.28 (4H, m, 2 × pyr H-4, 2 × pyr H-3),
4.30 (1H, s, H-4 26), 4.21 (1H, m, H-4 27), 3.68 (1H, dd,
J = 13.5, 5.4 Hz, H-2 26), 2.95 (1H, dt, J = 13.5, 5.7 Hz, H-2
27), 2.56–1.80 (12H, m, 4 × H-3, 4 × H-5, 4 × H-6), 0.96 (9H, s,
SiC(CH3)3), 0.89 (9H, s, SiC(CH3)3), 0.14 (3H, s, SiCH3), 0.12
(3H, s, SiCH3), 0.11 (3H, s, SiCH3), 0.10 (3H, s, SiCH3).
(1R,2R,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2-(2-chloro-5-
pyridyl)-1-[(methylsulfonyl)oxy]cyclohexane (32)
To a solution of 30 (0.085 g, 0.25 mmol) in CH2Cl2 (3 mL) at
0 ЊC was added triethylamine (0.085 mL, 0.60 mmol) and mesyl
chloride (0.030 mL, 0.38 mmol). When all the starting mat-
erial had been consumed (10 min), saturated aqueous NH4Cl
solution (5 mL) was added and the mixture was extracted
with CH2Cl2 (3 × 5 mL). After drying (MgSO4) the combined
organic layers, the solvent was evaporated to afford 32 (0.103 g,
99%) as a viscous liquid. [α]D20 Ϫ18.6 (c 0.42 in CH2Cl2).
νmax (KBr)/cmϪ1: 2951, 2935, 2887, 2858 (C–H). δH (300 MHz;
CDCl3; Me4Si) 8.28 (1H, d, J = 1.8 Hz, pyr H-6), 7.58 (1H, dd,
J = 8.1, 2.4 Hz, pyr H-4), 7.32 (1H, d, J = 8.4 Hz, pyr H-3), 4.66
(1H, dt, J = 10.5, 5.4 Hz, H-1), 4.11 (1H, s, H-4), 3.32 (1H, m,
H-2), 2.53 (3H, s, OSO2CH3), 2.24–2.17 (2H, m, H-3 and/or
H-5 and/or H-6), 1.93–1.65 (4H, m, 2 × H-3 and/or 2 × H-5
and/or 2 × H-6). m/z (EI): 420.10 ([M ϩ 1]ϩ, 0.22%), 362
(7.46), 192 (100), 153 (84.45), 126 (53), 117 (16.44). HRMS
found: Mϩ Ϫ Clpyr Ϫ TBDMS 192.045601, C7H12O4S requires
192.045631.
νmax (film)/cmϪ1: 2953, 2930, 2887 (all C–H), 1720 (C᎐O, sat.
᎐
ketone), 1566 (C᎐C). m/z (EI): 339 ([M]ϩ, 1.93%), 282 (100),
᎐
240 (42.65), 226 (34.43), 190 (10.47), 140 (12.78), 115 (10.40),
75 (48.99).
(1R,2R,4S)-4-[(tert-Butyldimethylsilyl)oxy]-2-(2-chloro-5-
pyridyl)cyclohexan-1-ol (30) and (1S,2R,4S)-4-[(tert-butyldi-
methylsilyl)oxy]-2-(2-chloro-5-pyridyl)cyclohexan-1-ol (28) and
(1R,2S,4S)-4-[(tert-butyldimethylsilyl)oxy]-2-(2-chloro-5-
pyridyl)cyclohexan-1-ol (29) and (1S,2S,4S)-4-[(tert-butyldi-
methylsilyl)oxy]-2-(2-chloro-5-pyridyl)cyclohexan-1-ol (31)
(1S,3R,4R)-3-(2-Chloro-5-pyridyl)-4-[(methylsulfonyl)oxy]-
cyclohexan-1-ol (33)
To a solution of 32 (0.109 g, 0.26 mmol) in THF (2 mL) at rt
was added Bu4NF (0.085 mL, 0.60 mmol). The mixture was
stirred at rt until all the starting material had been consumed
(24 h). The reaction was diluted with ethyl acetate (2 mL) and
water (2 mL) was added. After stirring for 5 min, the mixture
was quenched with saturated NaCl (5 mL) and extracted with
ethyl acetate (3 × 5 mL). Evaporation of the solvent afforded
a viscous residue which was purified by preparative TLC
(AcOEt–hexane 7:3) to yield 33 (0.070 g, 88%) as a white solid.
Mp 108–109 ЊC. [α]D20 Ϫ45.0 (c 0.28 in CH2Cl2). νmax (KBr)/cmϪ1:
To a solution of 26 and 27 (0.293 g, 0.86 mmol) in methanol
(6 mL) at Ϫ20 ЊC, was added DMSO (dimethyl sulfoxide, 0.161
mL, 1.72 mmol) and NaBH4 (0.151 g, 3.44 mmol). The reaction
was stirred until all the starting material had been consumed.
Saturated aqueous NH4Cl solution (10 mL) was added and
the mixture was extracted with diethyl ether (8 mL) and ethyl
acetate (2 × 8 mL). The combined organic extracts were dried
(MgSO4) and the solvent evaporated to give a viscous residue,
which was purified by column chromatography (AcOEt–hexane
1:9) and it afforded the four diastereoisomers 28, 29, 30 and
31 (0.283 g, 96%) 2:1:15.5:6.5, respectively. Compound 28:
[α]D20 ϩ32.0 (c 0.325 in CH2Cl2). νmax (film)/cmϪ1: 3353 (O–H),
2951, 2928, 2884, 2856 (C–H). δH (300 MHz; CDCl3; Me4Si)
8.29 (1H, s, pyr H-6), 7.61 (1H, dd, J = 8.4, 2.1 Hz, pyr H-4),
7.27 (1H, d, J = 7.8 Hz, pyr H-3), 4.21 (1H, s, H-1), 4.01 (1H, s,
3394 (O–H), 2957, 2935, 2895 (all C–H), 1587 (C᎐C). δ (300
᎐
H
MHz; CDCl3; Me4Si) 8.30 (1H, s, pyr H-6), 7.60 (1H, dd,
J = 9.0, 3.0 Hz, pyr H-4), 7.32 (1H, d, J = 9.0 Hz, pyr H-3),
4.66 (1H, m, H-4), 4.20 (1H, s, H-1), 3.40–3.30 (1H, m, H-3),
2.54 (3H, s, OSO2CH3), 2.21–1.76 (6H, m, 2 × H-2, 2 × H-5,
2 × H-6). m/z (EI): 305 ([M]ϩ, 0.16%), 209 (7.38), 191 (100),
165 (21), 140 (15.47), 126 (16.15), 104 (10.81), 79 (9.72).
172
J. Chem. Soc., Perkin Trans. 1, 2001, 166–173

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HRMSfound:Mϩ Ϫ OMs Ϫ OH Ϫ 2H191.049801,C11H10NCl
liquid residue was purified by preparative TLC (AcOEt–hexane
requires 191.050177.
2:8) to afford compound 40 (0.063 g, 98%) as a colourless oil.
[α]D20 ϩ112.3 (c 0.98 in CHCl3), (lit.21 [α]D Ϫ115.94 (c 1.06 in
CHCl3) for the enantiomer). νmax (KBr)/cmϪ1: 2954, 2930, 2857
(1R,2R,4R)-4-Azido-2-(2-chloro-5-pyridyl)-1-[(methylsulfonyl)-
oxy]cyclohexane (34)
(all C–H), 1690 (C᎐O). δ (300 MHz; CDCl3; Me4Si) 6.83
᎐
H
(1H, dt, J = 10.2, 1.8 Hz, H-3), 5.92 (1H, dd, J = 10.2, 0.6 Hz,
H-2), 4.53 (1H, m, H-4), 2.58 (1H, dt, J = 16.8, 4.5 Hz, H-6),
2.35 (1H, m, H-6), 2.22 (1H, m, H-5), 2.00 (1H, m, H-5), 0.92
(9H, s, SiC(CH3)3), 0.13 (3H, s, SiCH3), 0.12 (3H, s, SiCH3).
To a solution of 33 (0.074 g, 0.24 mmol) in THF (3 mL),
at 0 ЊC, was added triphenylphosphine (0.093 g, 0.36 mmol),
hydrazoic acid (0.84 M in benzene, 1.72 mL, 1.44 mmol) and
DEAD (diethyl azodicarboxylate, 0.058 mL, 0.36 mmol) in
THF dropwise. The reaction mixture was stirred at rt. When
all the starting material had been consumed, the solvent was
evaporated and the residue was purified by column chromato-
graphy (AcOEt–hexane 2:8) to afford a mixture of azide 34
and the eliminated by-product (19:1) as white crystals. Azide
34 was further purified by recrystallisation from ether (0.075 g,
94%). Mp 128–129 ЊC (lit.5 racemic 119–120 ЊC). [α]D20 Ϫ10.1
(c 0.345 in CH2Cl2). νmax (KBr)/cmϪ1: 2964, 2942 (both C–H),
2108 (N3). δH (300 MHz; CDCl3; Me4Si) 8.30 (1H, d, J = 1.8 Hz,
pyr H-6), 7.61 (1H, dd, J = 8.4, 2.1 Hz, pyr H-4), 7.38 (1H, d,
J = 8.4 Hz, pyr H-3), 4.61 (1H, dt, J = 10.8, 4.5 Hz, H-1), 4.52
(1H, m, H-4), 2.90 (1H, m, H-2), 2.53 (3H, s, OSO2CH3), 2.53–
2.49 (1H, m, H-3 or H-5 or H-6), 2.25–2.20 (2H, m, 2 × H-2
and/or 2 × H-5 and/or 2 × H-6), 1.88–1.58 (2H, m, 2 × H-2
and/or 2 × H-5 and/or 2 × H-6). δC (100.61 MHz; CDCl3;
Me4Si) 151.1 (pyr C-2), 149.7 (pyr C-6), 137.6 (pyr C-4), 134.8
(pyr C-5), 124.6 (pyr C-3), 82.1 (C-1), 57.9 (C-4), 44.6 (C-2),
38.1 (OSO2CH3), 37.3, 31.5 and 29.6 (C-3, C-5, C-6). m/z (EI):
205 (100%), 191 (18), 178 (92.53), 166 (30.27), 164 (41.41), 152
(24.24), 140 (35.89), 126 (40.43), 104 (54.22), 78.90 (47.71),
63 (15.17), 51 (21.45). HRMS found: Mϩ Ϫ OMs Ϫ N3 Ϫ 2H
191.050765, C11H10NCl requires 191.050177.
Acknowledgements
We thank Fundação para a Ciência e a Tecnologia for valuable
financial support and a grant (Praxis XXI/BD/4527/94) for
M. R. V.
Notes and references
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(4R,5R)-4,5-[(2S,3S)-2,3-Dimethoxybutane-2,3-diyldioxy]-
cyclohexan-1-one (38)
A Parr hydrogenation flask was charged with enone 6 (0.080 g,
0.33 mmol), ethyl acetate (3 mL) and Pearlman’s catalyst
(palladium hydroxide on carbon, 0.0021 g). This mixture was
hydrogenated (50 psi§) for 15 h. The suspension was filtered
through a pad of Celite and the filtrate was concentrated to
yield 0.080 g (quantitative yield) of the saturated product 38 as
white crystals. [α]D20 ϩ152.6 (c 0.49 in CH2Cl2). νmax (KBr)/cmϪ1:
2955, 2889 (both C–H), 1721 (C᎐O, sat. ketone). δ (300 MHz;
᎐
H
CDCl3; Me4Si) 3.94–3.86 (1H, m, H-3 or H-4), 3.79–3.70 (1H,
m, H-3 or H-4), 3.32 (3H, s, OCH3), 3.24 (3H, s, OCH3), 2.64–
2.30 (4H, m, 2 × H-2 and/or 2 × H-5 and/or 2 × H-6), 2.11–
1.99 (1H, m, H-2 or H-5 or H-6), 1.77–1.61 (1H, m, H-2 or
H-5 or H-6), 1.33 (3H, s, CH3), 1.32 (3H, s, CH3).
(4R)-4-[(tert-Butyldimethylsilyl)oxy]cyclohex-2-en-1-one (40)
To a solution of 38 (0.080 g, 0.33 mmol) in CH2Cl2 (1.5 mL)
was added CF3COOH (0.179 mL, 2.34 mmol) and water (0.034
mL). The reaction was refluxed for 2 h and then it was cooled.
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a catalytic quantity of DMAP and tert-butyldimethylsilyl
chloride (TBDMSCl, 0.092 g, 0.60 mmol) in CH2Cl2 (1 mL)
were added. The reaction was stirred at rt for 18 h. Water
(2 mL) was then added and the mixture was vigorously stirred
for 15 min and extracted with CH2Cl2 (3 × 3 mL). The com-
bined organic extracts were dried (MgSO4) and evaporated. The
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§ 1 psi = 6.89 kPa.
J. Chem. Soc., Perkin Trans. 1, 2001, 166–173
173