Formal enantioselective synthesis of (-)-carbovir and (-)-abacavir: An application of the rhodium(I)-catalysed tandem hydrosilylation-intramolecular aldol reaction

Article abstract of DOI:10.1055/s-2005-918423

An efficient synthesis of the highly potent anti-HIV carbocyclic nucleosides (-)-carbovir and (-)-abacavir has been accomplished from D-(-)-ribose using a rhodium(I)-catalysed tandem hydrosilylation-intramolecular aldol strategy to access a key intermediate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918423

PAPER
3079
Formal Enantioselective Synthesis of (–)-Carbovir and (–)-Abacavir:
An Application of the Rhodium(I)-Catalysed Tandem Hydrosilylation–
Intramolecular Aldol Reaction
a
a
b
E
M
nantioselective Synth
a
e
sis of (–)-
r
Carbovir
t
and (–
a
)-Abacavir Freiría,* Andrew J. Whitehead, William B. Motherwell
a
Chemical Development Division, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire,
SG1 2NY, UK
Fax +44(143)8764869; E-mail: marta.x.freiria@gsk.com
Christopher Ingold Laboratories, Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, UK
b
Received 1 June 2005
Abstract: An efficient synthesis of the highly potent anti-HIV car-
bocyclic nucleosides (–)-carbovir and (–)-abacavir has been accom-
plished from D-(–)-ribose using a rhodium(I)-catalysed tandem
hydrosilylation-intramolecular aldol strategy to access a key inter-
mediate.
Key words: asymmetric synthesis, carbocyclic nucleosides, aldol
reaction, hydrosilylation, rhodium
Figure 1 Structure of carbocyclic nucleosides
Development of efficient synthetic routes to carbocyclic
nucleoside analogues has attracted considerable attention
in recent years, not only as a consequence of their interest-
ing biological activities but also because of the constant
challenge associated with stereoselective construction of
material has the clear advantage of being very inexpen-
sive, a major disadvantage is the subsequent necessity for
introduction of chirality into the carbocyclic ring, often
involving classical resolution, enzymatic resolution or de-
symmetrisation of a meso intermediate. Only very few
syntheses have involved a stereoselective cyclisation
method for generation of the cyclopentyl moiety and most
of these rely on either a ring closing metathesis or alky-
lidene carbene insertion strategy and on the use of chiral
auxiliaries to establish the absolute configuration of the
5
-membered ring carbocycles. Since the first racemic syn-
thesis of the carbocyclic analogue of adenosine by Shealy
1
and Clayton in 1966 and the subsequent isolation of its
2
(
(
–)-enantiomer, the antifungal antibiotic aristeromycin 1
Figure 1) from Streptomyces citricolor, interest in this
class of compounds has continued to grow rapidly. In par-
ticular, (–)-carbovir 2, which was first prepared by
3
Vince’s group in 1988, was shown to efficiently combat
6
pseudo-sugar. In this context, Crimmins has reported an
efficient and general strategy based on an asymmetric al-
dol/ring closing metathesis sequence for the synthesis of
acquired immunodeficiency syndrome (AIDS) by selec-
tively inhibiting human immunodeficiency virus (HIV)
reverse transcriptase. It was however removed from a
clinical trial test due to its pharmacokinetic and toxicolog-
ical deficiencies. More recently, a prodrug of (–)-carbovir,
7
(
–)-carbovir and (–)-abacavir. Tanimori has described a
different approach based on intramolecular cyclopropana-
tion of a chiral a-diazo-b-ketoester which takes advantage
once again of the asymmetry induced by a chiral auxiliary.
4
known as (–)-abacavir or Ziagen 3, with higher oral bio-
availability and the capacity to penetrate the central ner-
vous system, has been approved by the Food and Drug
Administration (FDA) for treatment of AIDS (Figure 1).
8
More recently, Florent has used (S)-ethyl lactate from the
chiral pool in an enantioselective formal total synthesis of
(
–)-carbovir. The two key steps of this route involved a
As a consequence of their biological activity, a consider-
able number of synthetic approaches to (–)-carbovir and
its related analogue (–)-abacavir have been developed,5
and such molecules have proven to be an excellent test
bed in the search for alternative and perhaps more effi-
cient stereoselective strategies for the preparation of car-
bocyclic nucleosides. A considerable majority of the
above syntheses have relied on the use of cyclopentadiene
as the preformed carbocyclic core. Although this starting
Claisen [3,3]-sigmatropic rearrangement and a rutheni-
um-catalysed ring closing metathesis. Unfortunately,
however, a 1:1 mixture of diastereomers was generated in
the very last step of the synthesis. Since we have recently
reported that the rhodium(I)-catalysed tandem hydrosily-
9
lation-intramolecular aldol reaction is a very promising
approach for construction of functionalised carbocycles
from the chiral pool, and in view of the ongoing interest in
the synthesis of carbocyclic nucleosides, we therefore en-
visaged the application of this sequence to the syntheses
of (–)-carbovir and its related analogue (–)-abacavir. Our
strategy, as depicted in the retrosynthetic analysis of
Scheme 1, utilises the stereoselective rhodium(I)-catal-
SYNTHESIS 2005, No. 18, pp 3079–3084
x
x.
x
x
.
2
0
0
5
Advanced online publication: 12.10.2005
DOI: 10.1055/s-2005-918423; Art ID: P07105SS
Georg Thieme Verlag Stuttgart · New York
©

3
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M. Freiría et al.
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ysed tandem hydrosilylation–aldol cyclisation to form the The key highly functionalised carbocyclic intermediate 4
pseudo-sugar ring with the appropriate relative stereo- required for our synthetic approach was obtained in four
chemistry for the Trost asymmetric allylic alkylation pro- steps from commercially available D-(–)-ribose
tocol (AAA). Furthermore, the absolute stereochemistry (Scheme 2).9
10
would be generated from the chiral pool, through selec-
Thus, protection of D-(–)-ribose as its isopropylidene de-
tion of the cheap and readily available D-ribose
Scheme 1).
rivative 5 using 2,2-dimethoxypropane and a catalytic
quantity of p-toluenesulfonic acid proceeded in 76%
yield. Subsequent Wittig olefination with Ph PCHCO Me
(
3
2
Scheme 1 Retrosynthetic analysis
Scheme 2 Reagents and conditions: (a) 2,2-Dimethoxypropane, p-toluenesulfonic acid, acetone, 0 °C, 1 h; (b) Ph PCHCO Me, CH Cl , r.t.,
3
2
2
2
5
h; (c) NaIO , CH Cl , H O, r.t., 5 h; (d) Et SiH, 1 mol% RhH(PPh ) , toluene, 50 °C, 16 h
4 2 2 2 3 3 4
Synthesis 2005, No. 18, 3079–3084 © Thieme Stuttgart · New York

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Enantioselective Synthesis of (–)-Carbovir and (–)-Abacavir
3081
afforded diol 6 in 60% yield. Oxidative cleavage of diol 6 forded diol 10 in 86% yield, which was quantitatively
with NaIO then furnished the aldehydic cyclisation pre- converted to the diacetate 11. Selective deprotection of
4
cursor 7 in 68% yield. Finally, rhodium(I)-catalysed the relatively robust acetonide protecting group was then
tandem hydrosilylation–intramolecular aldol reaction of a required. In the first instance, attempted deprotection by
Z/E mixture of 6-oxo-2-hexenoate 7 using our preferred acidic hydrolysis with 2.0 M HCl led to removal of both
catalyst, RhH(PPh ) , led to the highly substituted five- acetate-protecting groups whereas the isopropylidene
3
4
membered ring carbocycle 4 in 81% yield as a mixture of functionality remained intact. In the event, however, use
diastereomers in a 5.4:4.0:2.0:1.0 ratio, which were sepa- of a mixture of TFA–H O (9:1) gave the desired syn-diol
2
rated by column chromatography. The moderate yield ob- 8 in 92% yield.
tained in the Wittig olefination of lactol 5 is due to the
propensity of unsaturated ester 6 to participate in an in-
With ready access to the syn-diol 8, several possible
routes to the cyclopentene were investigated. Although a
tramolecular Michael addition to afford the corresponding
variety of methods are known to effect deoxygenation of
tetrahydrofuran derivative. The Wittig reaction of sugar
lactols with stabilised ylides such as alkoxycarbonylmeth-
ylene triphenylphosphoranes has been intensively investi-
13
the 2¢–3¢ vicinal diol to the corresponding alkene, this
transformation proved to be problematic in the present
13i,j
case. The Garegg–Samuelsson
procedure using I2,
1
1
gated, and this behaviour has previously been noted.
Further improvements in the yield of this transformation
could presumably be achieved by replacement of the stan-
dard Wittig reagent with a more bulky phosphorane (tert-
butyl or benzyl groups), as recently reported by Clive.12
With the appropriate carbocyclic precursor 4a in hand,
preparation of the selectively protected syn-diol 8 was
then achieved (Scheme 3).
PPh and imidazole was attempted for the direct conver-
3
sion of the syn-diol 8 to the olefin. Unfortunately, no reac-
tion was observed. Since the direct conversion of the 1,2-
diol into the corresponding alkene was unsuccessful, we
therefore elected to convert it into the bistriflate derivative
13f
in order to attempt the Tipson–Cohen protocol. Al-
though syn-diol 8 was readily converted to the corre-
sponding bistriflate by reaction with triflic anhydride,
Thus, deprotection of the triethylsilyl ether was accom- pyridine and DMAP, exposure to NaI and Na S O in
2
2
3
plished with n-Bu NF in THF at room temperature, lead- DMF at 85 °C led to a complex mixture of compounds
4
ing to the corresponding cyclopentanol 9 in 97% yield. with no evidence of the expected cyclopentene. In view of
Subsequent reduction of the methyl ester using LiAlH af- the fact that the most promising protocols failed with this
4
Scheme 3 Reagents and conditions: (a) n-Bu NF, THF, r.t., 1 h; (b) LiAlH , THF, 0 °C, 2 h; (c) Ac O, Et N, DMAP, CH Cl , 0 °C, 2 h; (d)
4
4
2
3
2
2
TFA, H O, 0 °C, 0.5 h; (e) pentafluorophenylchlorothionoformate, pyridine, DMAP, r.t., 5 h; (f) 1,3-dimethyl-2-phenyl-1,3-diazaphospholi-
2
dine, THF, 40 °C, 4 h
Synthesis 2005, No. 18, 3079–3084 © Thieme Stuttgart · New York

3
082
M. Freiría et al.
PAPER
sensitive substrate, a milder method was therefore re- troleum ether (30–40 °C)–EtOAc, 9:1] to afford the silyl-protected
1
4
cyclopentanol 4 (4.95 g, 81%) as four diastereomers 4a:4b:4c:4d in
quired. In the event, the Corey–Hopkins procedure was
found to be the most effective. Thus, cyclic thionocarbon-
ate 12 was readily accessed from diol 8 by exposure to
pentafluorophenylchlorothionoformate, pyridine and
DMAP in toluene at room temperature in 78% yield. Sub-
sequent treatment of 12 with 3 equivalents of 1,3-dimeth-
yl-2-phenyl-1,3-diazaphospholidine in anhydrous THF at
a 5.4:4:2:1 ratio.
(
[
1S,2S,3S,4S)-Isomer (4a)
20
a] –20.7 [c = 0.50, CHCl –MeOH (9:1)].
D
3
–
1
FTIR (film): 2936, 2878, 1733, 1439, 1376, 1262, 902 cm .
1
H NMR (500 MHz, CDCl ): d = 0.51 (q, J = 7.7 Hz, 6 H), 0.86 (t,
3
J = 7.7 Hz, 9 H), 1.21 (s, 3 H), 1.35 (s, 3 H), 1.89 (dd, J = 6.3, 13.8
Hz, 1 H), 2.24 (ddd, J = 5.4, 10.7, 13.8 Hz, 1 H), 3.02 (ddd, J = 4.0,
4
0 °C, afforded the desired cyclopentene 13 in 65% yield
after column chromatography (Scheme 3).
6
.3, 10.7 Hz, 1 H), 3.60 (s, 3 H), 4.20 (d, J = 5.4 Hz, 1 H), 4.28 (d,
6
a
J = 4.0 Hz, 1 H), 4.67 (t, J = 5.4 Hz, 1 H).
As previously described by Crimmins, palladium-cata-
1
3
lysed coupling of the allylic acetate 13 with 2-amino-6-
chloropurine and 2-amino-6-(cyclopropylamino)purine 50.4, 76.8, 78.2, 84.9, 108.9, 171.1.
C NMR (125 MHz, CDCl ): d = 3.7, 5.7, 22.8, 25.1, 30.8, 46.2,
3
then leads respectively, after subsequent hydrolysis, to
–)-carbovir 2 and (–)-abacavir 3.
LRMS (FAB): m/z = 331, 301, 241, 211, 187.
(
HRMS–FAB: m/z [M + H]+ calcd for C H O Si: 331.19406;
1
6
31
5
In summary, an efficient formal asymmetric synthesis of found: 331.19408.
the potent and highly selective inhibitors of human immu-
Methyl (1S,2S,3S,4S)-2-Hydroxy-3,4-isopropylidenedioxy-
cyclopentane Carboxylate (9)
To a solution of methyl (1S,2S,3S,4S)-2-triethylsilyloxy-3,4-isopro-
nodeficiency virus, (–)-carbovir and (–)-abacavir, has
been accomplished from D-ribose using the rhodium(I)-
catalysed tandem hydrosilylation–intramolecular aldol re-
pylidenedioxycyclopentane carboxylate 4a (300 mg, 0.9 mmol) in
action as the key step for stereoselective cyclopentanoid anhyd THF (3 mL), was added dropwise 1.0 M TBAF in THF (2
formation.
mL, 2.0 mmol) and the reaction mixture was stirred at r.t. for 1 h.
After diluting with water (5 mL), the resulting solution was extract-
ed with CH Cl (2 × 5 mL). The combined organic extracts were
2
2
Melting points were determined using a Reichert hot stage appara-
tus and are uncorrected. Optical rotations were recorded on a Per-
kin-Elmer 241 polarimeter (using the sodium D line; 589 nm) and
dried over MgSO , filtered and concentrated. Purification by flash
4
column chromatography [petroleum ether (30–40 °C)–EtOAc, 8:2]
afforded cyclopentanol 9 (190 mg, 97%) as a white solid.
T
–1
2
–1
[
a] are given in units of 10 deg dm g . IR spectra were record-
D
2
0
Mp 102–104 °C; [a] –21.2 [c = 0.40, CHCl –MeOH (9:1)].
ed on a Perkin-Elmer 1605 FT-IR spectrometer as thin films on
D
3
–
1
NaCl or as KBr discs and are reported in cm . Mass spectra were
recorded on a Micromass 70-SE spectrometer using a cesium ion
gun for FAB. Elementary analyses and accurate mass measure-
ments were performed at Christopher Ingold Laboratories, Univer-
sity College London. NMR spectra were recorded using a Bruker
AMX-300 or a Bruker AMX-400 or a Bruker Avance 500 spec-
FTIR (film): 3463, 2988, 2936, 1730, 1440, 1375, 1269, 1211, 1028
–
1
cm .
1
H NMR (400 MHz, CDCl ): d = 1.29 (s, 3 H), 1.43 (s, 3 H), 2.09–
3
2
4
.24 (m, 2 H), 3.08 (ddd, J = 4.0, 8.0, 12.0 Hz, 1 H), 3.74 (s, 3 H),
.30 (d, J = 8.0 Hz, 1 H), 4.44 (d, J = 5.6 Hz, 1 H), 4.78 (t, J = 5.6
Hz, 1 H).
trometer. Chemical shifts (d) are quoted in ppm relative to TMS.
13C NMR (100 MHz, CDCl
): d = 23.7, 26.1, 33.4, 44.9, 52.1, 76.1,
1
The H NMR spectra are referenced to the residual CHCl peak at
3
3
3
.26 ppm. Coupling constants (J) are reported in Hz. 1 C NMR
7
9.2, 84.9, 109.4, 174.9.
7
spectra were fully decoupled and are referenced to the middle peak
LRMS (ES): m/z = 239, 217.
of CHCl at 77.0 ppm. Splitting patterns are designated as s, singlet;
3
+
HRMS–ES: m/z [M + Na] calcd for C H O Na: 239.0892; found:
1
0
16
5
d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; or a combi-
nation of these. Column chromatography was performed using
BDH silica gel (40–60 mm). Analytical TLC was performed on pre-
coated aluminium-backed plates (Merck Kieselgel 60 F ) and vi-
2
39.0895.
(
1R,2S,3S,4S)-2-Hydroxy-1-(hydroxymethyl)-3,4-isopro-
2
54
pylidenedioxycyclopentane (10)
sualised by 254 nm UV or by staining with basic KMnO solution
4
To a solution of cyclopentanol 9 (170 mg, 0.79 mmol) in anhyd
THF (10 mL) was added 1.0 M LiAlH in Et O (1.73 mL, 1.73
followed by heat. All cyclisations and air- and/or moisture-sensitive
4
2
reactions were carried out in oven-dried glassware under a N atmo-
2
mmol) at 0 °C under a N atmosphere. After 2 h, the reaction was
2
sphere using standard Schlenk techniques. Unless otherwise noted,
chemicals were commercially available and used without further
purification. Toluene was distilled from sodium. THF was distilled
from sodium-benzophenone ketyl. CH Cl was distilled from CaH .
quenched with a 10% aq NaOH solution (3.5 mL). EtOAc (10 mL)
was added and the layers were separated. The aqueous phase was
extracted with EtOAc (4 × 5 mL) and the combined organic extracts
2
2
2
were dried over MgSO , filtered and concentrated. Purification by
4
flash column chromatography [petroleum ether (30–40 °C)–EtOAc,
1:1] afforded the desired product 10 (127 mg, 86%) as a clear oil.
Methyl 2-Triethylsilyloxy-3,4-isopropylidenedioxycyclopen-
tane Carboxylate (4)
Triethylsilane (4.6 g, 39 mmol) was added slowly to a stirred solu-
tion of methyl (4R,5S)-6-oxo-4,5-isopropylidenedioxy-2-hexenoate
9
2
0
[a] –21.7 [c = 1.60, CHCl –MeOH (9:1)].
D 3
FTIR (film): 3411, 2987, 2935, 1376, 1265, 1210, 1029 cm–1.
7
(4.0 g, 19 mmol) and tetrakis(triphenylphosphine) rhodium hy-
1
H NMR (400 MHz, CDCl ): d = 1.30 (s, 3 H), 1.43 (s, 3 H), 1.77
dride (220 mg, 0.19 mmol, 1 mol%) in anhyd degassed toluene (0.4
M in substrate) at ambient temperature. The resulting solution was
heated for 16 h at 50 °C and then cooled to r.t. The reaction mixture
was diluted with 2 M aq NaOH (10 mL) and extracted with CH Cl
3
(
dd, J = 6.4, 13.6 Hz, 1 H), 2.02 (td, J = 5.2, 13.6 Hz, 1 H), 2.31–
2
1
.38 (m, 1 H), 2.52 (s, 1 H), 3.13 (s, 1 H), 3.83 (dd, J = 6.0, 11.0 Hz,
H), 4.03 (dd, J = 3.6, 11.0 Hz, 1 H), 4.22 (d, J = 5.2 Hz, 1 H), 4.37
2
2
(
d, J = 5.6 Hz, 1 H), 4.78 (t, J = 5.62 Hz, 1 H).
(
2 × 10 mL). The combined organic extracts were dried over
MgSO , filtered and the filtrate concentrated under reduced pres-
13
4
C NMR (100 MHz, CDCl ): d = 23.8, 26.1, 31.6, 41.4, 61.8, 78.0,
3
sure. The resulting oil was purified by column chromatography [pe-
7
9.7, 86.3, 109.7.
Synthesis 2005, No. 18, 3079–3084 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of (–)-Carbovir and (–)-Abacavir
3083
LRMS (ES): m/z = 211, 189.
mg, 0.03 mmol), and the reaction mixture was stirred at r.t. for 5 h.
The reaction was quenched with 5% aq HCl and the layers were sep-
arated. The organic phase was washed with a sat. aq solution of
NaHCO (2 × 15 mL) and the organic phase was dried over MgSO ,
+
HRMS–ES: m/z [M + Na] calcd for C H O Na: 211.0946; found:
9
16
4
2
11.0946.
3
4
filtered and concentrated. Purification by flash column chromatog-
raphy [petroleum ether (30–40 °C)–EtOAc, 6:4] afforded the de-
sired thiocarbonate 12 (64 mg, 78%) as a clear oil.
(
1R,2S,3S,4S)-2-Acetoxy-1-(acetoxymethyl)-3,4-isopro-
pylidenedioxycyclopentane (11)
To a solution of diol 10 (280 mg, 1.49 mmol) in anhyd CH Cl (10
mL) was added Et N (0.45 mL, 3.28 mmol) at 0 °C under a N at-
mosphere. Ac O (0.42 mL, 4.47 mmol) was then added dropwise
2
2
2
0
[a] –21.0 (c = 0.65, CH Cl ).
D 2 2
3
2
2
FTIR (film): 2962, 1747, 1469, 1351, 1222 cm–1.
followed by a catalytic amount of 4,4-dimethylaminopyridine (19.6
mg, 0.15 mmol). After 2 h, the reaction was quenched with 5% aq
HCl and the layers were separated. The aqueous phase was extract-
ed with CH Cl (2 × 5 mL) and the combined organic extracts were
1
H NMR (400 MHz, CDCl ): d = 1.97 (ddd, J = 4.4, 9.6, 14.4 Hz, 1
3
H), 2.06 (s, 3 H), 2.09 (s, 3 H), 2.37 (dd, J = 8.4, 14.4 Hz, 1 H), 2.61–
2
1
.67 (m, 1 H), 4.11 (dd, J = 7.2, 11.2 Hz, 1 H), 4.19 (dd, J = 8.4,
1.2 Hz, 1 H), 5.09 (d, J = 6.7 Hz, 1 H), 5.40–5.44 (m, 2 H).
2
2
washed with aq sat. NaHCO (10 mL), dried over MgSO , filtered
3
4
and concentrated. Purification by flash column chromatography
petroleum ether (30–40 °C)–EtOAc, 6:4] afforded the desired
product 11 (400 mg, 99%) as a clear oil.
13
C NMR (100 MHz, CDCl ): d = 21.0, 34.1, 38.8, 60.9, 75.4, 85.5,
3
[
8
7.8, 169.2, 70.7, 190.4.
LRMS (ES): m/z = 275, 214.
2
0
[
a] –20.0 (c = 0.65, CH Cl ).
D 2 2
+
HRMS–ES: m/z [M + H] calcd for C H O S: 275.0592; found:
1
1
15
6
–
1
FTIR (film): 2984, 2938, 1746, 1439, 1373, 1254, 1159, 1037 cm .
2
75.0589.
1
H NMR (400 MHz, CDCl ): d = 1.21 (s, 3 H), 1.39 (s, 3 H), 1.63
3
(
1R,2R)-2-Acetoxy-1-acetoxymethyl-3-cyclopentene (13)6a
(
td, J = 5.2, 13.6 Hz, 1 H), 1.90 (dd, J = 6.4, 13.6 Hz, 1 H), 1.98 (s,
H), 2.59–2.65 (m, 1 H), 4.01 (dd, J = 3.6, 11.0 Hz, 1 H), 4.08 (dd,
To a solution of thiocarbonate 12 (55 mg, 0.24 mmol) in anhyd THF
6
(
(
1 mL) was added 1,3-dimethyl-2-phenyl-1,3-diazaphospholidine
140 mg, 0.71 mmol), and the reaction mixture was stirred at 40 °C
J = 6.0, 11.0 Hz, 1 H), 4.33 (d, J = 5.2 Hz, 1 H), 4.67 (t, J = 5.2 Hz,
1
H), 5.05 (d, J = 5.6 Hz, 1 H).
for 4 h. The reaction was quenched with 5% aq HCl and the layers
were separated. After concentration of the solvent under reduced
pressure, the crude oil was purified by flash column chromatogra-
phy [CH Cl then petroleum ether (30–40 °C)–EtOAc, 6:4] to af-
1
3
C NMR (100 MHz, CDCl ): d = 20.9, 23.8, 26.0, 33.7, 38.6, 62.1,
3
7
7.4, 79.2, 84.2, 110.4, 170.0, 171.0.
LRMS (ES): m/z = 295, 273, 213.
2
2
+
ford the desired cyclopentene 13 (26 mg, 65%) as a clear oil.
HRMS–ES: m/z [M + H] calcd for C H O : 273.1342; found:
1
3
21
6
2
0
6a
2
73.1338.
[a] –181 (c = 0.45, CH Cl ) [Lit. –178.0 (c = 0.45, CH Cl )].
D
2
2
2
2
–
1
FTIR (film): 2925, 1736, 1438, 1370, 1234 cm .
(
1R,2S,3S,4S)-2-Acetoxy-1-(acetoxymethyl)-3,4-dihydroxy-
1
H NMR (400 MHz, CDCl ): d = 2.02 (s, 3 H), 2.05 (s, 3 H), 2.22–
cyclopentane (8)
Diacetate 11 (390 mg, 1.43 mmol) was dissolved in TFA (180 mL)
and H O (20 mL) at 0 °C under a N atmosphere. After 30 min, the
3
2
.29 (m, 1 H), 2.46–2.53 (m, 1 H), 2.68–2.73 (m, 1 H), 4.14 (dd,
J = 7.2, 11.2 Hz, 1 H), 4.22 (dd, J = 8.4, 11.2 Hz, 1 H), 5.74 (dd,
J = 2.0, 7.2 Hz, 1 H), 5.84–5.86 (m, 1 H), 6.09–6.11 (m, 1 H).
13
2
2
reaction mixture was concentrated under reduced pressure. EtOAc
2 mL) was then added and the mixture was washed with 5% aq
NaHCO (3 × 2 mL) The aqueous phase was extracted with EtOAc
(
C NMR (100 MHz, CDCl ): d = 21.0, 21.1, 34.7, 39.5, 63.4, 78.1,
3
3
129.4, 136.8, 170.7, 171.1.
(
4 × 2 mL) and the combined organic extracts were dried over
LRMS (ES): m/z = 199, 216.
MgSO , filtered and concentrated. Purification by flash column
chromatography [petroleum ether (30–40 °C)–EtOAc, 1:1] afford-
4
+
HRMS–ES: m/z [M + H] calcd for C10
H
O
: 199.09702; found:
15
4
ed the desired diol 8 (306 mg, 92%) as a clear oil.
199.09712.
2
0
[
a] –23.0 (c = 0.50, CH Cl ).
D 2 2
–
1
FTIR (film): 3419, 2940, 1735, 1435, 1370, 1246, 1099, 1039 cm . Acknowledgment
1
H NMR (400 MHz, CDCl ): d = 1.75 (ddd, J = 4.4, 9.6, 14.4 Hz, 1
3
We wish to thank GlaxoSmithKline for the provision of a stu-
dentship to M.F.
H), 2.01 (ddd, J = 1.6, 8.4, 14.4, Hz, 1 H), 2.05 (s, 3 H), 2.10 (s, 3
H), 2.70 (br, 1 H), 2.89–2.95 (m, 1 H), 3.55 (br, 1 H), 4.00 (t, J = 4.4
Hz, 1 H), 4.08 (dd, J = 6.4, 11.2 Hz, 1 H), 4.15 (dd, J = 6.8, 11.2 Hz,
1
H), 4.22 (t, J = 4.4 Hz, 1 H), 5.01 (dd, J = 4.4, 8.0 Hz, 1 H).
References
1
3
C NMR (100 MHz, CDCl ): d = 21.0, 33.7, 36.7, 63.3, 70.9, 79.3,
3
(1) Shealy, Y.; Clayton, J. J. Am. Chem. Soc. 1966, 88, 3885.
8
1.1, 171.0, 172.4.
(
2) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi,
LRMS (ES): m/z = 233, 173.
T.; Mizuno, K. J. Antibiot. 1968, 21, 255.
(
3) Vince, R.; Hua, M.; Brownell, J.; Daluge, S. M.; Lee, F. C.;
Shannon, W. M.; Lavelle, G. C.; Qualls, J.; Weislow, O. S.;
Kiser, R.; Canonico, P. G.; Schultz, R. H.; Narayanan, V. L.;
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+
HRMS–ES: m/z [M + H] calcd for C H O : 233.1035; found:
1
0
17
6
2
33.1025.
(
1R,2S,3R,4S)-2-Acetoxy-1-(acetoxymethyl)-3,4-di-O-thiono-
carbonyl Cyclopentane (12)
(
To a solution of diol 8 (70 mg, 0.30 mmol) in anhyd toluene (12 mL)
was added pyridine (178 mg, 2.26 mmol) at 0 °C under a N atmo-
sphere. Pentafluorophenylchlorothionoformate (159 mg, 0.60
mmol) was added followed by a catalytic amount of DMAP (3.6
2
Synthesis 2005, No. 18, 3079–3084 © Thieme Stuttgart · New York

3
084
M. Freiría et al.
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Synthesis 2005, No. 18, 3079–3084 © Thieme Stuttgart · New York