Aflexible synthesis of cyclopentitol derivatives based on ring-closing metathesis of carbohydrate-derived 1,6-dienes

Article abstract of DOI:10.1039/b207509a

Four partially protected stereoisomeric cyclopentenetriols 5, 10, 15 and 21 have been prepared by ring-closing metathesis of carbohydrate-derived 1,6-dienes. The presence of a differentiated allylic alcohol in the cyclopentenetriols allows a variety of synthetic transformations, underlining the synthetic use of the prepared cyclopentenetriol derivatives as chiral building blocks.

Full text of DOI:10.1039/b207509a

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A flexible synthesis of cyclopentitol derivatives based on ring-
closing metathesis of carbohydrate-derived 1,6-dienes
Huib Ovaa, Bas Lastdrager, Jeroen D. C. Codée, Gijs A. van der Marel, Herman S. Overkleeft
and Jacques H. van Boom*
1
Leiden Institute of Chemistry, Gorlaeus Laboratories, P. O. Box 9502, 2300 RA Leiden,
The Netherlands. E-mail: j.boom@chem.leidenuniv.nl; Fax: (31)715274307;
Tel: (31)715274274
Received (in Cambridge, UK) 1st August 2002, Accepted 9th September 2002
First published as an Advance Article on the web 8th October 2002
Four partially protected stereoisomeric cyclopentenetriols 5, 10, 15 and 21 have been prepared by ring-closing
metathesis of carbohydrate-derived 1,6-dienes. The presence of a differentiated allylic alcohol in the cyclo-
pentenetriols allows a variety of synthetic transformations, underlining the synthetic use of the prepared
cyclopentenetriol derivatives as chiral building blocks.
Introduction
Cyclopentitols, hydroxylated cyclopentane derivatives of vary-
ing nature and complexity, form an integral part of a broad
class of natural products. Relevant examples are the glycosidase
inhibitors mannostatin A, allosamidin and trehalostatin,1 the
cancer therapeutic agent neplanocin2 and the hypermodified
nucleoside queuosine3 (nucleoside Q). The remarkable bio-
logical activities exerted by cyclopentitol derivatives have
inspired several research laboratories to explore their chemical
synthesis, resulting in various successful total syntheses.4
The target-oriented approaches generally applied, however,
normally exclude the rapid generation of synthetic analogues
of naturally occurring cyclopentitols. The development of
methodologies that ensure an easy access to cyclopentitols
Scheme 1
varying in stereochemistry and substitution pattern should
eventually lead to synthetic analogues of natural products with
ment with triethylorthoformate led, after acid catalysed
thermal rearrangement10 to the isolation of 2 in 93% yield over
the three steps. Anomeric debenzoylation (2 to 3, 96%) and
consecutive Wittig olefination gave, after purification by distil-
lation, diene 4 in an overall yield of 84% based on 1. RCM of 4
under the influence of Grubbs’ ruthenium alkylidene catalyst
(Cl2(PCy3)2Ru=CHPh)11 gave the homogeneous (3R,4S,5R)-
3,4-O-isopropylidenecyclopentene-3,4,5-triol (5)12 in 95% yield.
In a related sequence of transformations, (3R,4S,5S )-3,4-O-
cyclohexylidenecyclopentene-3,4,5-triol (10) was prepared. The
required key intermediate 8 proved to be readily accessible by
adaptation of the literature procedure,13 starting from 2,3-O-
hexylidene--ribofuranose 6. Treatment of 6 with excess vinyl
magnesium bromide afforded (3S,4S,5R,6R)-4,5-O-cyclohexyl-
idene-3,4,5,6,7-pentahydroxyhex-1-ene (7), which, upon reac-
tion with sodium periodate, led to the formation of compound
8 in 78% yield over the two steps. Subjection of 8 to anomeric
Wittig olefination and exposure of the resulting 1,6-diene 9 to
Grubbs’ catalyst afforded the desired partially protected cyclo-
pentene 10 in 70% yield over the last two steps. The synthesis
of (3S,4S,5R)-3,4-O-benzylcyclopentene-3,4,5-triol (15) was
accomplished as follows. Treatment of the known14 3-O-benzyl-
5,6-dideoxy-1,2-O-isopropylidene-α--xylo-hex-5-enofuranose
(11) with ethanolic HCl followed by benzylation of the result-
ing free hydroxy function furnished the anomeric mixture of
ethyl furanosides 12. Subsequent liberation of the anomeric
hydroxy was effected by treatment with acetic acid at 65 ЊC for
three days, affording hemiacetal 13 in 79% over the three steps.
favourable properties in terms of activity, toxicity and bioavail-
ability. In this respect, we have recently demonstrated the use-
fulness of carbohydrate-derived dienes, in combination with
ring-closing metathesis (RCM),5 in the construction of a
variety of highly functionalised hetero- and carbocycles.6,7,8 As
an extension of these studies, we here present the results on the
transformation of four easily accessible and cheap carbo-
hydrate derivatives into the four partially protected cyclopen-
tenetriols 5, 10, 15 and 21, respectively. We further demonstrate
the feasibility of a selected cyclopentenetriol (i.e. cyclopentene
derivative 5) for the ensuing introduction of additional hetero-
(nitrogen, sulfur) and carbon functionalities through well-
established synthetic procedures.
Results and discussion
The general synthetic strategy is outlined in Scheme 1. In the
first step, a suitably protected monosaccharide is transformed
into the corresponding, orthogonally protected 3,4,5-tri-
hydroxy-1,6-diene I. Ensuing ring-closing metathesis affords
3,4,5-trihydroxycyclopentene II, the orthogonal functionalis-
ation of which allows synthetic modifications leading to the
introduction of additional functionalities onto the cyclo-
pentene scaffold, as in III.
In Scheme 2, the synthesis of partially protected cyclo-
pentenetriols 5, 10, 15 and 21 is presented. Regioselective
removal of the 5,6-isopropylidene group in benzoyl 2,3:5,6-di-
O-isopropylidene-α--mannofuranose (1),9 followed by treat-
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J. Chem. Soc., Perkin Trans. 1, 2002, 2370–2377
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b207509a

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Scheme 2 Reagents and conditions: a) 1. 80% HOAc, 40 ЊC, 2. HC(OEt3), HOAc, 80 ЊC, 3. Ph3CCO2H (cat), neat, 170 ЊC; b) KOtBu, MeOH; c)
Ph3PϩCH3BrϪ, n-BuLi, THF, Ϫ20 ЊC to rt; d) Cl2(PCy3)2Ru=CHPh (0.5–5 mol%), CH2Cl2; e) vinylmagnesium bromide (5 eq.), THF, Ϫ50 ЊC to rt; f )
NaIO4 (2 eq.), MeOH–H2O 85 : 15; g) Ph3PϩCH3BrϪ (2.1 eq.), KOtBu (2.1 eq.), THF–HMPA, Ϫ78 ЊC to rt; h) 1. EtOH, HCl, 2. NaH, BnBr, DMF;
i) HOAc–H2O 3 : 1, 3 days; j) 1. KOtBu, MeOH, 2. TBDPSCl, pyridine, 3. dimethoxypropane, p-TsOH (cat), 4. pMeOBnCl, NaH, DMF, 5. TBAF,
THF; k) imidazole, triiodoimidazole, Ph3P, toluene, reflux; l) 1. Zn, EtOH–H2O, reflux, 2. Ph3PϩCH3BrϪ, n-BuLi, THF, Ϫ20 ЊC to rt; m) DDQ,
CH2Cl2–H2O.
Subjection of 13 to the two-step sequence as outlined for the
conversion of 3 to 5 proceeded smoothly to give cyclopentene
derivative 15 in 39% yield based on 11.
At this stage, having easy access to partially protected
cyclopentenetriols of different stereochemistry, we set out to
demonstrate their potential usefulness as synthetic inter-
mediates. To this end, we selected compound 5, which we have
subjected to various synthetic transformations. For instance,
installation of a xanthate ester was readily accomplished by
reaction of 5 with carbon disulfide followed by methylation to
afford 22 (Scheme 3). Subsequent thermal rearrangement led
to the stereoselective formation of mixed dithiocarbonate 23
in 62% yield over the two steps. In a related synthetic sequence
of reactions, compound 5 was transformed into protected
aminocyclopentenediol 25. Reaction of 5 with trichloro-
acetonitrile in the presence of the base DBU afforded trichloro-
acetimidate 24, which, upon heating in xylenes under reflux,
rearranged to give target compound 25 in high yield.18 The
synthetic potential of 25 is further demonstrated by subse-
quent epoxidation (25 to 26) in good yield and excellent stereo-
selectivity. It is of interest to note that both (unprotected)
aminocyclopentenediols 25 and 26 are found as an integral part
of hypermodified nucleosides of the queuosine family.19
The results presented so far comprise the facile transform-
ation of -sugars to a set of three diastereoisomeric, orthogon-
ally protected cyclopentenetriols 5, 10 and 15. The flexibility
of our strategy is further illustrated by the conversion of -
galactose into (3S,4R,5S )-3,4-O-isopropylidenecyclopentene-
3,4,5-triol (21) (the enantiomer of 5). To this end, the known15
peracetylated p-methoxyphenyl-α--galactopyranoside 16 was
converted into the primary iodide 18 via the following six step
sequence (see Scheme 2): Saponification of the acetate groups
and subsequent regioselective silylation, introduction of the
isopropylidene protective group, protection of the remaining
hydroxy function as the p-methoxybenzyl ether, deprotection of
the t-butyldiphenylsilyl group and treatment of the resulting 17
with 2,4,5-triiodoimidazole and triphenylphosphine according
to the method of Garegg and Samuelsson.16 Ensuing reductive
rearrangement17 of 18 proceeded smoothly to give the open-
chain aldehyde, which was subjected to Wittig olefination to
provide orthogonally protected 1,6-diene 19 in good yield (45%
based on 16). RCM and subsequent DDQ-mediated oxidative
cleavage of the p-methoxybenzyl protecting group in 20 gave
the desired partially protected cyclopentenetriol 21 ([α]2D0
ϩ110.4) in 85% over the last two steps. The NMR spectra of 21
(both proton and carbon) proved to be identical to those of
enantiomeric 5 ([α]2D0 Ϫ110.0).
Apart from the successful [3,3]-sigmatropic rearrangements
of compounds 22 and 24 to allow the introduction of hetero-
atoms onto the cyclopentene scaffold, it was realised that 5
would also be amenable to the stereoselective installation of a
hydroxymethylene functionality. As a first example, attention
was focused on the installation of a hydroxymethyl substituent
via a [2,3]-Wittig–Still20 rearrangement. Condensation of 5
J. Chem. Soc., Perkin Trans. 1, 2002, 2370–2377
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were determined at 20 ЊC, in units of 10Ϫ1 deg cm2 gϪ1by means
of a Propol automatic polarimeter at the sodium D-line. Mass
spectrometry was performed on a PE/SCIEX API 165 equipped
with an ion spray interface. Column chromatography was per-
formed on Baker silica gel (0.063–0.200 mm) or on Merck silica
gel (0.040–0.063 mm) column. TLC analysis was conducted on
DC-fertigfolien (Schleicher and Schüll F1500 LS254) or Merck
silica 60 F245 coated aluminum sheets. Toluene, CH2Cl2, tri-
ethylamine and xylenes were boiled under reflux with CaH2 for
3 hours, distilled and stored over molecular sieves (4 Å). THF
and Et2O were distilled from LiAlH4 prior to use. HMPA was
distilled directly before use under high vacuum. All other
solvents (Baker, pro analysis) were stored over molecular sieves
(4 Å) except for methanol and acetonitrile (Rathburn, HPLC
grade), which were stored over molecular sieves (3 Å). Methyl
triphenylphosphonium bromide was dried over KOH under
high vacuum at 140 ЊC for 24 hours prior to use. Grubbs’
catalyst Cl2(PCy3)2Ru=CHPh was prepared according to the
literature procedure.11 n-BuLi (1.6 M in hexanes, Aldrich) and
vinylmagnesium bromide (1 M in THF, Aldrich), were used as
received.
Scheme 3 Reagents and conditions: a) 1. NaH, CS2, toluene, 2. MeI,
DMF; b) xylenes, reflux; c) DBU, CCl3CN, CH2Cl2, 0 ЊC; d) 3-methyl-3-
trifluoromethyldioxirane, CH3CN.
Benzoyl 2,3-O-isopropylidene-ꢀ-D-lyxo-hex-5-enofuranose (2)
Benzoyl 2,3:5,6-di-O-isopropylidene-α--mannofuranose (1)
(28.7 g, 78.76 mmol) was dissolved in HOAc (175 mL) and
heated to 40 ЊC. Water (75 mL) was added and stirring was
continued for 135 minutes after which time TLC analysis
showed complete conversion (Rf 0.55, EtOAc). Solvents were
evaporated and the remainder was coevaporated with toluene
(2 × 50 mL). The residue was taken up in (EtO)3CH, heated to
80 ЊC and HOAc was added (1.5 mL). The reaction was
complete within 30 minutes (Rf 0.60, EtOAc–petroleum ether
30 : 70). The solution was concentrated and heated to 170 ЊC
in an open flask. Triphenyl acetic acid (100 mg, 0.347 mmol,
0.44 mol%) was added and after 4 hours all starting material
had been transformed into a higher running product (Rf 0.55,
EtOAc–petroleum ether, 2 : 8). The resulting clear oil was
allowed to cool to room temperature. Column chromatography
(20% EtOAc in petroleum ether) gave the homogeneous title
compound (21.5 g, 93%). 13C-NMR (50.1 MHz, CDCl3): δ 24.7,
25.9 (2 × CH3, isopr.), 76.4, 77.0, 77.6 (C-2, C-3, C-4), 101.0
Scheme 4 Reagents and conditions: a) Bu3SnCH2I, KH, dibenzo-18-
crown-6, THF, 0 ЊC; b) n-BuLi, THF, Ϫ78 ЊC; c) ClSiMe2CH2Br,
CH2Cl2, Et3N; d) 1. Bu3SnH (1.5 eq.), AIBN (cat), benzene, reflux, 2.
H2O2 (30%, aq.), Na2CO3, THF–MeOH, 5 ЊC.
with tributyliodomethylstannane (Scheme 4), followed by trans-
metallation of 27 with n-butyllithium afforded the expected
hydroxymethylated species 28 in 68% yield, together with 20%
recovery of 5. Alternatively, introduction of an α-halosilylether
provides a handle for radical cyclisation while the silylether
functions as a masked hydroxy moiety. The latter Stork21
radical cyclisation approach generates a hydroxymethyl sub-
stituent cis relative to the original alcohol.22 Silylation of 5 with
bromomethyldimethylsilyl chloride afforded 29 in 83% yield
(Scheme 4). 5-Exo-trig radical cyclisation of 29 followed by
in situ hydrogen peroxide-mediated oxidation afforded 1,2-O-
isopropylidene-4a-carba-β--xylofuranose 30 in 73% yield over
two steps.
In conclusion, partially protected 1,6-heptadiene-3,4,5-triols,
which are easily accessible from suitably functionalised mono-
saccharides, proved to be excellent starting compounds for
the RCM-mediated construction of partially protected, chiral
cyclopentenetriols. The cyclopentenetriols are useful assets in
the preparation of higher functionalised cyclopentane deriv-
atives. The latter is demonstrated by the transformation of
cyclopentenetriol 5 into highly versatile structural entities,
including side-chain modifications of nucleoside Q (25 and 26)
and the carba--xylofuranose derivative 30.
(C-1), 112.9 (Cq, isopr.), 119.6 (C-6), 128.2, 129.4, 131.3, 133.2
1
(CHarom Bz, C-5), 164.7 (C᎐O). H NMR (200 MHZ, CDCl ):
᎐
3
δ 1.36 (s, 3H, CH3, isopr.), 1.39 (s, 3H, CH3, isopr.), 4.64 (m,
1H), 4.86 (m, 2H) (H-2, H-3, H-4), 5.40 (m, 2H, H-6), 5.98 (m,
1H, H-5), 6.42 (s, 1H, H-1), 7.41–8.04 (m, 5H, CHarom Bz).
2,3-O-Isopropylidene-ꢀ-D-lyxo-hex-5-enofuranose (3)
Compound 2 (21.0 g, 72.3 mmol) was dissolved in MeOH
(100 mL), 100 mg KOtBu was added and the solution was
stirred for 24 h. TLC analysis revealed total conversion into a
lower running product (Rf 0.65, EtOAc–petroleum ether 1 : 1).
Dowex-W50X4-Hϩ was added until neutral pH, the resin was
filtered and the filtrate was concentrated under reduced pres-
sure. Column chromatography (30% EtOAc in petroleum
ether) gave pure 3 (12.95 g, 96%) as a clear oil. 13C-NMR (50.1
MHz, CDCl3): δ 24.7, 25.8 (2 × CH3, isopr.), 81.2, 81.3, 85.7
(C-2, C-3, C-4), 100.7 (C-1), 112.5 (Cq isopr.), 119.2 (C-6), 132.0
(C-5). 1H NMR (200 MHz, CDCl3): δ 1.32 (s, 3H, CH3 isopr.),
1.48 (s, 3H, CH3 isopr.), 3.38 (br s, 1H, OH), 4.63 (m, 2H), 4.74
(m, 1H) (H-2, H-3, H-4), 5.31–5.45 (m, 2H, H-6), 5.95 (m, 1H,
H-5).
Experimental
General methods and materials
(3R,4S,5R)-3,4-Isopropylidenehepta-1,6-diene-3,4,5-triol (4)
1H- and 13C-NMR spectra were recorded on a Jeol JNM-FX-
200 (200/50.1 MHz) or on a Bruker DPX-300 (300/75.1 MHz).
NMR shifts are reported in ppm (δ) relative to tetramethyl-
silane, coupling constants J are given in Hz. Optical rotations
Methyltriphenylphosphonium bromide (4.22 g, 11.81 mmol)
was dissolved in 50 mL of THF and cooled to Ϫ20 ЊC. n-BuLi
(1.6 M in hexanes, 7 mL, 11.8 mmol) was added and the solu-
tion was allowed to warm to rt, stirred for 30 minutes, and
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cooled to Ϫ20 ЊC. A solution of 998 mg (5.36 mmol) of 3 in
THF (5 mL) was slowly added to the reaction mixture via the
cold wall of the flask and the reaction mixture was allowed to
warm to rt and stirred overnight. TLC analysis revealed the
appearance of a higher running spot (Rf 0.60, EtOAc–
petroleum ether 1 : 1). A little sat. aq. NH4Cl was added and the
solution was concentrated to a small volume. The residue was
taken up in Et2O (100 mL), extracted with sat. aq. NH4Cl
and water. The organic phase was dried (MgSO4), filtered and
concentrated. Little Et2O and petroleum ether were added after
which a white solid precipitated. The precipitate was filtered off
over Celite, rinsed with ice-cold Et2O and the filtrate was con-
centrated. Column chromatography (20% EtOAc in petroleum
ether) gave pure 4 (0.96 g, 98%). 13C-NMR (50.1 MHz, CDCl3):
δ 24.9, 27.3 (2 × CH3, isopr.), 70.4, 78.8, 80.6 (C-3, C-4, C-5),
108.4 (Cq, isopr.), 116.9, 119.0 (C-1, C-7), 134.0, 136.5 (C-2,
C-6). 1H NMR (200 MHz, CDCl3): δ 1.41 (s, 3H, CH3, isopr.),
1.55 (s, 3H, CH3, isopr.), 4.08 (m, 2H), 4.62 (dd, J 7.6, J 7.8 Hz,
1H) (H-3, H-4, H-5), 5.22–5.43 (m, 4H, H-1, H-7), 5.78–6.12
(m, 2H, H-2, H-6). MS (CI): m/z 207.0 [M ϩ Na]ϩ.
H-4), 5.15–5.43 (m, 2H, H-6), 5.49 (d, J 3.0 Hz, 1H, H-1), 5.92–
6.10 (m, 1H, H-5).
(3R,4S,5S )-3,4-O-Cyclohexylidenehepta-1,6-diene-3,4,5-triol
(9)
To methyl triphenylphosphonium bromide, 3.40 g (9.53 mmol)
in THF (8 mL) and HMPA (2 mL) was added at Ϫ78 ЊC,
KOtBu (1.97 g, 9.5 mmol). The resulting solution was stirred
for an additional hour at Ϫ20 ЊC. A solution of 8 (980 mg,
4.33 mmol) in THF (2 mL) was added and the solution was
allowed to warm to room temperature. After 14 hours all
starting material had been transformed into a slightly higher
running product as indicated by TLC (Rf 0.60, EtOAc–
petroleum ether 4 : 6). The reaction mixture was quenched with
aq. sat. NH4Cl (50 mL) and extracted with Et2O (100 mL).
The ether layer was dried (MgSO4), filtered and concentrated.
Column chromatography (5% 15% EtOAc–petroleum ether)
gave homogeneous 9 (0.83 g, 85%). 13C-NMR (50.1 MHz,
CDCl3): δ 23.6, 23.9, 25.0, 34.6, 37.4 (5 × CH2, Cy), 70.8, 78.2,
80.2 (C-3, C-4, C-5), 109.4 (Cq, Cy), 115.9, 118.0 (C-1, C-7),
1
134.2, 137.7 (C-2, C-6). H-NMR (200 MHz, CDCl3): δ 1.17–
(3R,4S,5R)-3,4-O-Isopropylidenecyclopentene-3,4,5-triol (5)
1.68 (m, 10H, 5 × CH2, Cy), 1.81 (d, J 4.4 Hz, 1H, OH), 4.02
(m 1H), 4.18 (m, 1H), 4.80 (m,1H) (H-3, H-4, H-5), 5.21–5.49
(m, 4H, H-1, H-7), 5.97–6.15 (m, 2H, H-1, H-6).
Compound 4 (3.10 g, 16.8 mmol) was dissolved in CH2Cl2
(50 mL), the solution was degassed by passing through a
stream of argon for 15 min and 69 mg (0.5 mol%) of Grubbs’
catalyst (PCy3)2Cl2Ru=CHPh was added under an atmosphere
of argon. After 5 hours TLC analysis revealed complete con-
version (Rf 0.40, EtOAc–petroleum ether 4 : 6). The reaction
mixture was exposed to air and purified by column chroma-
tography (40% EtOAc in petroleum ether) to yield 2.61 g
(95%) of homogeneous 5. 13C-NMR (75.1 MHz, CDCl3):
δ 25.3, 26.8 (2 × CH3 isopr.), 80.0 (C-5), 83.9 (C-4), 85.4
(3R,4S,5S )-3,4-O-Cyclohexylidenecyclopentene-3,4,5-triol (10)
Compound 9 (275 mg, 1.23 mmol) was dissolved in CH2Cl2
(25 mL). This solution was degassed by bubbling through
nitrogen for 10 minutes and 51 mg (5 mol%) of Cl2(PCy3)2-
Ru=CHPh was added. The reaction mixture was stirred
overnight in a sealed flask, after which time TLC (EtOAc–
petroleum ether 1 : 4) indicated total conversion of starting
material into a lower running product (Rf 0.40, EtOAc–
petroleum ether 1 : 4). The reaction mixture was exposed to air,
concentrated and purified by column chromatography. Column
chromatography (15% EtOAc in petroleum ether) gave 192 mg
(80%) of homogeneous 10 as a colourless oil. 13C-NMR (50.1
MHz, CDCl3): δ 23.6, 23.8, 24.8, 35.9, 37.2 (5 × CH2, Cy), 74.0,
1
(C-3),111.2 (Cq isopr.), 134.4, 134.6 (C-1, C-2). H-NMR (300
MHz, CDCl3): δ 1.35 (s, 3H, CH3 isopr.), 1.40 (s, 3H, CH3
isopr.), 1.80 (br s, OH) 4.53 (d, H-3 J 5.5 Hz, 1H), 4.80 (s,
1H, H-5), 5.30 (m, 1H, H-4), 5.92 (m, 1H), 6.03 (m, 1H),
(H-1, H-2). MS (ESI): m/z 157.2 [M ϩ H]ϩ; [α]2D0 Ϫ110 (c=1,
CHCl3).
1
76.5, 83.1 (C-3, C-4, C-5), 132.0, 136.2 (C-1, C-2). H-NMR
2,3-O-Cyclohexylidene-ꢀꢁ-L-ribo-hex-5-enofuranose (8)
(300 MHz, CDCl3): δ 1.28–1.66 (m, 10H, CH2 Cy), 2.77 (d,
J 9.9 Hz, 1H), 4.53 (dd, J 5.9 Hz, J 9.9 Hz, 1H, H-5), 4.74 (t,
J 5.9 Hz, 1H, H-3), 5.02 (dd, J 1 Hz, J 5.5 Hz, 1H, H-4), 5.88
(m, 2H, H-1, H-2). MS (CI): m/z (M ϩ Na)ϩ 219.0; [α]2D0 Ϫ9.6
(c=1, CHCl3).
2,3-O-Cyclohexylidene--ribose (6) (3.47 g,15.1 mmol) was dis-
solved in THF (30 mL) and cooled to Ϫ50 ЊC. Vinylmagnesium
bromide (75 mL, 1 M in THF) was slowly added via the cold
wall of the flask maintaining the temperature at Ϫ50 ЊC. After
addition the solution was allowed to warm to room tempera-
ture and stirred overnight after which all starting material had
been transformed into a lower running product (Rf 0.60,
EtOAc–petroleum ether 7 : 3). The solution was cooled to
0 ЊC, and 5 g of solid NH4Cl was added, followed by the slow
addition of sat. aq. NH4Cl (20 mL). THF was evaporated
under reduced pressure and EtOAc (200 mL) was added
followed by saturated aqueous NH4Cl (100 mL). The EtOAc
layer was collected and concentrated, providing crude 7 as an
oil which was used in the next step without further purification.
Thus, 7 was dissolved in 85 mL of MeOH and cooled to 0 ЊC.
Water (15 mL) was added followed by NaIO4 (6.62 g, 31 mmol).
The solution was allowed to warm to room temperature and
was stirred for 45 minutes after which the reaction was complete
(Rf 0.80, EtOAc–petroleum ether 6 : 4) as judged by TLC.
Solids were filtered over Celite and the filtrate was washed with
Et2O. Solvents were removed under reduced pressure and the
residue was taken up in Et2O (200 mL) and washed with water
(200 mL). The organic phase was dried (MgSO4), filtered and
concentrated. Column chromatography (20 40% EtOAc in
petroleum ether) gave 2.64 g (78%) of homogeneous 8 as an oil.
13C-NMR (50.1 MHz CDCl3): δ 23.3, 23.6, 24.7, 34.1, 35.9
(5 : CH2, Cy), 82.0, 84.4, 86.0 (C-2, C-3, C-4), 101.2 (C-1),
Ethyl 2,3-di-O-benzyl-ꢀꢁ-D-xylo-hex-5-enofuranoside (12)
3-O-benzyl-5,6-dideoxy-αβ--xylo-hex-5-enofuranose12
11
(7.1 g, 29.6 mmol) was dissolved in absolute EtOH (100 mL)
and cooled to 0 ЊC, then a 3 M HCl solution in EtOH (5 mL)
was added and the mixture was allowed to warm to rt. After
3 hours all starting material had been transformed into two new
spots (Rf 0.30 and 0.40, EtOAc–petroleum ether 7 : 3). Sat. aq.
NaHCO3 was added (3 mL) and the resulting suspension was
reduced to a small volume, taken up in EtOAc (200 mL) and
washed with water (2 × 100 mL). The EtOAc layer was dried
(MgSO4), filtered and concentrated to give 7.74 g (99%) of the
ethyl glycosides as a mixture of anomers, which were used in the
next reaction without further purification. Thus, the ethyl
glycosides (7.28 g, 27.6 mmol) were dissolved in DMF (100 mL)
and cooled to 0 ЊC. NaH (2.0 g, 50 mmol, 60% in mineral oil)
was added followed by benzylbromide (4.75 mL, 40 mmol).
After 1 hour TLC analysis revealed complete transformation
into two higher running products (Rf 0.50 and 0.55, EtOAc–
petroleum ether 1 : 9). Methanol (2 mL) was added and the
solution was stirred for a further 30 minutes. The mixture
was poured into Et2O (300 mL) and washed with water
(2 × 500 mL). The organic layers were dried (MgSO4),
filtered and concentrated. Column chromatography (EtOAc–
1
112.7 (Cq Cy), 116.4 (C-6), 142.3 (C-5). H-NMR (200 MHz,
CDCl3): δ 1.61 (m, 10H, 5 × CH2, Cy), 4.65 (m, 3H, H-2, H-3,
J. Chem. Soc., Perkin Trans. 1, 2002, 2370–2377
2373

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petroleum ether 15 : 85) gave 9.87 g (99%) of the title com-
pound as an anomeric mixture. 13C-NMR (50.1 MHz, CDCl3):
δ 14.8, 14.9 (2 × CH3,,OEt), 63.1, 63.4 (2 × CH2, OEt), 71.5,
71.7, 71.8, 72.1 (4 × CH2, Bn), 78.2, 81.6, 82.3, 82.4, 83.4, 87.0
(C-2, C-3, C-4), 99.0, 106.3 (C-1), 117.8, 117.9 (C-6), 127.3,
127.4, 127.5, 127.7, 128.0, 128.1 (CHarom Bn), 134.1, 134.9
(C-5), 137.6 (Cq Bn).
p-Methoxyphenyl 2-O-(p-methoxybenzyl)-3,4-O-isopropylidene-
ꢁ-D-galactopyranoside (17)
A. Synthesis of p-methoxyphenyl 6-O-tert-butyldiphenylsilyl-
ꢁ-D-galactopyranoside. To a solution of compound 16 (13.8 g,
30.4 mmol) in methanol (400 mL) was added 33.6 mg
(0.3 mmol) KOtBu. The solution was stirred for three hours,
after which time the solution was brought to neutral pH with
Dowex-Hϩ. The mixture was filtered and concentrated,
coevaporated with pyridine and taken up in pyridine (300 mL).
TBDPSCl (8.6 mL) was added, and the mixture was stirred for
two hours. TLC analysis revealed the disappearance of starting
compound and formation of a new product (Rf 0.90, EtOAc–
EtOH 9 : 1). Methanol was added and the mixture was con-
centrated. The residue was taken up in EtOAc (400 mL)
and washed with 1 M HCl and water. The organic layer was
separated, dried on MgSO4 to give the crude title compound,
which was used in the next step without further purification.
13C-NMR (50.1 MHz, in CDCl3): δ 19.0 (Cq, tBu), 26.7 (CH3,
tBu), 55.5 (OMe), 63.6 (C-6), 69.2, 71.3, 73.7, 75.2 (C-2, C-3,
C-4, C-5), 102.5 (C-1), 114.4, 118.6 (CH, MP), 127.7, 129.7,
135.5 (CH, Ph), 133.0 (Cq, Ph), 151.3, 155.2 (Cq, MP).
2,3-Di-O-benzyl-D-xylo-hex-5-enofuranose (13)
Compound 12 (0.65 g, 1.80 mmol) was dissolved in HOAc
(7.5 mL), heated to 65 ЊC and water (2.5 mL) was slowly added.
The solution was kept at 65 ЊC for three days. TLC analysis
indicated complete conversion (Rf 0.40, EtOAc–petroleum
ether 3 : 7). Toluene (10 mL) was added and the solution was
evaporated to dryness, and coevaporated with toluene (2 ×
3 mL). Column chromatography (EtOAc–petroleum ether
25 : 75) gave homogeneous 13 (0.48 g, 81%) as an anomeric
mixture. 13C-NMR (50.1 MHz, CDCl3): δ 71.5, 71.8, 72.0, 72.5
(4 × CH2Bn), 79.2, 81.6, 81.7, 82.2, 82.7, 85.2 (C-1, C-2, C-3),
95.3, 100.8 (C-1), 118.0, 118.2 (C-6), 127.3, 127.4, 127.6, 127.7,
127.8, 128.1, 128.2 (CHarom Bn), 133.5, 134.0 (C-5), 136.9,
1
137.1, 137.4 (Cq Bn). H-NMR (200 MHz, CDCl3): δ 3.97 (m,
2H), 4.49–4.68 (m, 5H) (2 × CH2Bn, H-2, H-3, H-4), 5.25–5.53
(m, 3H, H-6, H-1), 5.89–6.17 (m, 1H, H-5), 7.22–7.43 (m, 10H,
CHarom Bn).
B. Synthesis of p-methoxyphenyl 6-O-tert-butyldiphenylsilyl-
3,4-O-isopropylidene-ꢁ-D-galactopyranoside. The crude galacto-
side from the previous step was dissolved in acetone (250 mL),
and dimethoxypropane (18.5 mL) and a catalytic amount of
p-TsOH were added. The reaction was stirred for one hour,
after which it was neutralised with a little sat. Na2HCO3 and
concentrated in vacuo. The residue was taken up in EtOAc
(250 mL), washed with water and dried on MgSO4. Column
chromatography (10 50% EtOAc in petroleum ether) gave the
title compound (17.2 g) in 99% yield over the two steps.
13C-NMR (50.1 MHz, in CDCl3): δ 18.9 (Cq, tBu), 26.0 (CH3,
isopr.), 26.5 (CH3, tBu), 27.8 (CH3, isopr.), 55.2 (OMe), 62.7
(C-6), 72.9, 73.7, 78.8 (C-2, C-3, C-4, C-5), 101.7 (C-1), 109.9
(Cq, isopr.), 114.2, 118.4 (CH, MP), 127.4, 129.5, (CH, Ph),
132.9 (Cq, Ph), 151.1, 155.0 (Cq, MP).
(3R,4S,5R)-3,4-O-Benzylhepta-1,6-diene-3,4,5-triol (14)
A solution of 4.2 mmol of ylide was prepared by the addition
of 1 eq. of n-BuLi in hexanes to methyl triphenylphosphonium
bromide in THF (20 mL) at Ϫ78 ЊC until all solids had dis-
solved. The resulting solution was allowed to warm to Ϫ20 ЊC
and was stirred for one hour. Compound 13 (0.45 g, 1.38 mmol)
in THF (1 mL) was added by syringe via the cold wall of the
flask at Ϫ20 ЊC. The resulting solution was allowed to warm to
rt and was stirred overnight. TLC analysis revealed a higher
running spot (Rf 0.85, EtOAc–petroleum ether 1 : 1). The solu-
tion was quenched with sat. aq. NH4Cl (100 mL) and extracted
with ether (100 mL). The ether layer was dried (MgSO4),
filtered and concentrated. Purification by column chroma-
tography (10% 25% EtOAc in petroleum ether) gave homo-
geneous 14 (0.31g, 72%). 13C-NMR (50.1 MHz, CDCl3): δ 70.5,
75.0 (2 × CH2Bn), 71.9, 81.6, 83.8 (C-3, C-4, C-5), 115.6, 119.2
(C-1, C-7), 127.4, 127.6, 127.7, 128.0 (CHarom Bn), 135.2, 138.3
(C-2, C-6), 138.1 (Cq Bn). 1H-NMR (200 MHz, CDCl3): δ 2.47
(d, J 7.3 Hz, 1H, OH), 3.43 (dd, J 3.7 Hz, J 6.2 Hz, 1H), 4.07
(dd, J 5.8, J 7.7 Hz, 1H ) (H-3, H-4), 4.27 (m, 1H, H-5), 4.38
(d, J 11.7 Hz, 1H), 4.61 (d, J 11.7 Hz, 1H, CH2 Bn), 4.66 (d, AB,
J 11.3 Hz, 1H), 4.84 (d, AB, J 11.3 Hz, 1H, CH2 Bn), 5.12–5.44
(m, 4H, H-1, H-7), 5.79–5.96 (m, 2H, H-2, H-6), 7.24–7.35 (m,
10H, CHarom Bn).
C. Synthesis of p-methoxyphenyl 2-O-( p-methoxybenzyl)-
6-O-tert-butyldiphenylsilyl-3,4-O-isopropylidene-ꢁ-D-galacto-
pyranoside. The galactoside from the previous step (4.38 g, 7.76
mmol) was dissolved in DMF (100 mL), brought to 0 ЊC and
NaH (466 mg, 60% in oil, 11.6 mmol) was added, followed by
p-methoxybenzyl chloride (1.26 mL, 9.28 mmol). The solution
was stirred for two days, after which time methanol was added
and the solution was stirred for a further 30 minutes. Et2O
was added (250 mL) and the solution was washed with water
(2 × 200 mL). The organic phase was dried on MgSO4, filtered
and concentrated. Column chromatography (0 30% EtOAc in
1
petroleum ether) gave the title compound (4.25 g, 80%). H-
NMR (200 MHz, CDCl3): δ 1.08 (s, 9H, CH3, tBu), 1.34 (s, 3H,
CH3, isopr.), 1.41 (s, 3H, CH3, isopr.), 3.76 (s, 3H, OMe), 3.80
(s, 3H, OMe), 3.65 (m, 1H), 3.95 (m, 3H), 4.24 (m, 2H) (H-2,
H-3, H-4, H-5, H-6), 4.78 (m, 1H, H-1), 4.85 (s, 2H, CH2, Bn),
6.68 (m, 2H, CH, MP), 6.88 (m, 2H, CH, MBn), 7.05 (m, 2H,
CH, MP), 7.35–7.47 (m, 8H, CH, MBn, Ph), 7.69–7.72 (m,
4H, Ph).
(3S,4S,5R)-3,4-O-Benzylcyclopentene-3,4,5-triol (15)
Compound 14 (240 mg, 0.73 mmol) was dissolved in CH2Cl2
(75 mL). The solution was degassed by bubbling through nitro-
gen for 10 minutes, 31 mg (5 mol%) of Cl2(PCy3)2Ru=CHPh
was added and the reaction mixture was stirred for 3 days in a
sealed flask. TLC analysis (25% EtOAc in petroleum ether)
revealed total transformation of starting material into a lower
running product and higher running, unidentified products.
The lower running compound was isolated by column chroma-
tography (10% 20% EtOAc in petroleum ether) to give 150
mg (68%) of homogeneous 15. 13C-NMR (50.1 MHz, CDCl3):
δ 71.3, 72.1 (2 × CH2Bn), 79.7, 86.1, 93.8 (C-3, C-4, C-5), 127.7,
127.9, 128.3 (CHarom Bn), 131.7, 134.5 (C-1, C-2), (138.1 Cq
Bn). 1H-NMR (300 MHz, CDCl3): δ 1.78 (d, J 8.1 Hz, 1H, OH),
4.01 (t, J 3.9 Hz, 1H, H-4), 4.45 (m, 1H, H-3), 4.58 (app. s, 2H,
CH2 Bn), 4.63 (m, 1H, H-5), 4.74 (d, AB, J 11.8 Hz, 2H, CH2
Bn), 5.84–5.92 (m, 2H, H-1, H-2), 7.27–7.43 (m, 10H, CHarom
Bn); [α]2D0 29.5 (c=1, CHCl3).
D. Synthesis of p-methoxyphenyl 2-O-p-methoxybenzyl-3,4-
O-isopropylidene-ꢁ-D-galactopyranoside (17). The galactoside
from the previous step (2.49 g, 3.63 mmol) was dissolved in
40 mL THF, and 4.0 mL 1 M TBAF in THF was added. After
45 minutes the reaction was complete, Et2O was added, and the
mixture was washed with water, dried on MgSO4 and concen-
trated in vacuo. Column chromatography yielded 1.53 g (94%)
of the title compound. 1H NMR (200 MHz, CDCl3): δ 1.35 (s,
3H, CH3, isopr.), 1.41 (s, 3H, CH3, isopr.), 3.78 (s, 3H, OMe),
3.80 (s, 3H, OMe), 3.64 (dd, 1H, J 6.6 Hz, J 8.0 Hz), 3.81 (m,
1H), 3.93 (m, 2H), 4.23 (m, 2H) (H-2, H-3, H-4, H-5, H-6), 4.79
2374
J. Chem. Soc., Perkin Trans. 1, 2002, 2370–2377

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(d, AB, 1H, CH2, MBn, J 11.7 Hz), 4.84 (d, 1H, H-1), 4.85 (d,
AB, 1H, CH2, MBn, J 11.7 Hz), 6.86 (m, 4H, CH, MP, MBn),
6.97 (m, 2H, CH, MP), 7.53 (m, 2H, CH, MBn).
according to TLC. The solution was filtered over Celite. The
filtrate was washed subsequently with water (50 mL) and
aqueous NaHCO3. The organic phase was dried (MgSO4) fil-
tered and concentrated. Column chromatography (20% 50%
EtOAc in petroleum ether) afforded 132 mg (86%) of 21, the
p-Methoxyphenyl 6-deoxy-6-iodo-2-O-(p-methoxybenzyl)-3,4-
O-isopropylidene-ꢁ-D-galactopyranoside (18)
NMR spectra of which were identical to those of enantiomer 5.
ϩ
20
MS (CI): m/z 157.2 [M ϩ H] ; [α] ϩ110.4 (c=1, CHCl3).
D
Compound 17 (1.53 g, 3.42 mmol), imidazole (0.46 g, 6.8
mmol), and 1,4,5-triiodoimidazole (2.43 g, 5.45 mmol) were
dissolved in toluene (50 mL). Triphenylphospine (3.58 g,
13.6 mmol) was added and the slurry solution was brought to
reflux temperature. After one hour the reaction was complete,
the mixture was cooled to rt, Et2O (50 mL) was added and the
mixture was washed with aqueous saturated Na2S2O3 (50 mL),
saturated aqueous NaHCO3 (50 mL) and water (50 mL),
dried on MgSO4, and concentrated in vacuo. Et2O (50 mL) was
added and the mixture was filtered over Celite. Column
chromatography (0 50% EtOAc in petroleum ether) yielded
1.53 g (95%) of iodide 18. 1H NMR (200 MHz, CDCl3): δ 1.35
(s, 3H, CH3, isopr.), 1.40 (s, 3H, CH3, isopr.), 3.40 (m, 2H, H-6),
3.78 (s, 3H, OMe), 3.79 (s, 3H, OMe), 3.62 (dd, 1H, J 6.5 Hz,
J 8.0 Hz), 3.97 (m, 1H), 4.26 (m, 2H) (H-2, H-3, H-4, H-5), 4.77
(d, 1H, H-1, J1,2 7.3 Hz), 4.78 (d, AB, 1H, CH2, MBn, J 11.7
Hz), 4.85 (d, AB, 1H, CH2, MBn, J 11.7 Hz), 6.85 (m, 4H, CH,
MP, MBn), 7.08 (m, 2H, CH, MP), 7.33 (m, 2, CH, MBn).
S-Methyl O-(3R,4S,5R)-4,5-O-isopropylidenedioxycyclo-
penten-3-yl dithiocarbonate (22)
Alcohol 5 (180 mg, 1.12 mmol) was dissolved in toluene (5 mL),
NaH (60% in mineral oil, 90 mg, 2.25 mmol) was added and the
solution was heated to 50 ЊC for 10 min and cooled to 0 ЊC.
CS2 (0.24 mL, 0.31 g, 4 mmol) was added and the solution was
allowed to warm to rt and stirred for 3 hours. The solution was
cooled to 0 ЊC and then MeI (0.25 mL, 0.45 mmol) was added,
immediately followed by the addition of 5 mL of DMF. After
an additional 15 min all starting material had been transformed
into a higher running product according to TLC (Rf 0.80,
EtOAc–petroleum ether 25 : 75). The reaction mixture was
poured into Et2O (50 mL) and washed with water (2 × 50 mL).
The organic phase was dried (MgSO4), filtered and concen-
trated. Column chromatography (0 25% EtOAc in petroleum
ether) gave homogeneous 22 (177 mg, 64%). 13C-NMR (75.1
MHz, CDCl3): δ 19.2 (CH3, SMe), 25.8, 27.3 (2 × CH3 isopr),
82.5, 83.9 (C-4, C-5), 90.9 (C-3), 112.4 (Cq isopr.), 130.2, 139.1
(3S,4R,5S )-3,4-O-Isopropylidene-5-O-p-methoxybenzylhepta-
1,6-diene-3,4,5-triol (19)
1
(C-1, C-2). H-NMR (300 MHz, CDCl3): δ 1.37 (s, 3H, CH3
isopr), 1.44 (s, 3H, CH3 isopr), 2.58 (s, 3H, SMe), 4.73 (d, J 5.8
Hz, 1H), 5.32 (m, 1H) (H-4, H-5), 6.03 (m, 1H), 6.23 (m, 1H)
(H-1, H-2), 6.35 (m, 1H, H-3); [α]2D0 Ϫ248.6 (c=1, CHCl3).
Iodide 18 (367 mg, 0.684 mmol) was dissolved in 96% EtOH
(8 mL), 1 g of activated powdered zinc was added and the
mixture was boiled under reflux. After 75 minutes, TLC indi-
cated total conversion into a lower running product. The
solution was filtered over Celite, washed with a little EtOH and
concentrated. Sat. aq. Na2S2O3 (1 ml) and CH2Cl2 (10 ml) were
added. The organic phase was separated, dried (MgSO4) and
concentrated. The product was subjected directly to Wittig
olefination as described for the synthesis of 14 (using 2.2 eq. of
freshly prepared ylide) to give after column chromatography
(5 10% EtOAc in petroleum ether) 152 mg (73%) of the title
compound as an oil. 13C-NMR (75.1 MHz, CDCl3): δ 25.6, 27.4
(2 × CH3 isopr.), 55.1 (CH3, OMe MBn), 69.6 (CH2 MBn),
78.3, 79.0, 80.6 (C-3, C-4, C-5), 109.0 (Cq isopr.), 113.5 (CHarom
MBn), 118.7, 119.4 (C-1, C-7), 128.9 (CHarom MBn), 130.4 (Cq
S-Methyl S-(3S,4S,5S )-4,5-O-isopropylidenedioxycyclo-
penten-3-yl dithiocarbonate (23)
Compound 22 (170 mg, 0.68 mmol) was dissolved in xylenes
(5 mL) and brought to reflux for 20 minutes after which time
the starting material had been transformed into a slightly
higher running product (Rf 0.60, EtOAc–toluene 4 : 96). Solv-
ents were removed under vacuum and column chromatography
gave 165 mg (97%) of 23 as a clear oil. 13C-NMR (75.1 MHz,
CDCl3): δ 13.0 (SMe), 25.9, 27.3 (2 × CH3 isopr), 54.8, 84.6,
84.9 (C-3, C-4, C,5), 111.4 (Cq isopr.), 130.4, 135.3 (C-1, C-2),
188.6 (C᎐O). 1H-NMR (300 MHz, CDCl ): δ 1.36 (s, 3H), 1.42
᎐
3
(s, 3H), 2.45 (s, 3H), 4.67 (d, J 5.8 Hz, 1H), 5.27 (m, 2H), 5.98
1
MBn), 134.3, 134.5 (C-2, C-6). H-NMR (300 MHz, CDCl3):
(m, 1H), 5.77 (m, 1H); [α]2D0 ϩ188 (c=1, CHCl3).
δ 1.39 (s, 3H, CH3 isopr.), 1.52 (s, 3H, CH3 isopr.), 3.81 (m, 4H),
4.17 (t, J 6.6 Hz, 1H), 4.48 (AB, J 11.7 Hz, 2H), 4.59 (d, J 7.3
Hz, 1H) (H-3, H-4, H-5, CH2 MBn), 5.26 (m 4H, H-1, H-7),
5.86 (m, 2H, H-2, H-6), 6.86 (d, J 8.8 Hz, 2H, CHarom MBn),
7.29 (d, J 8.8 Hz, 2H, CHarom MBn).
(3R,4R,5R)-3-O-Trichloroacetimidoyl-4,5-O-isopropylidene-
cyclopentene-3,4,5-triol (24)
Compound 5 (917 mg, 5.87 mmol) was dissolved in CH2Cl2
(15 mL) and cooled to 0 ЊC. DBU, (1.05 mL, 6.8 mmol) was
added followed by trichloroacetonitrile (0.88 mL, 8.8 mmol).
The reaction was complete after 10 minutes as judged by TLC
(Rf 0.90, EtOAc–petroleum ether 1 : 1). The reaction mixture
was poured into sat. aq. NH4Cl (10 mL). The organic layer was
collected and washed with water (10 mL), dried (Na2SO4), fil-
tered and concentrated. Column chromatography (30% EtOAc
in petroleum ether) gave 1.74 g (99%) of pure 24 as white
needles. 13C-NMR (75.1 MHz, CDCl3): δ 25.7, 27.2 (2 × CH3,
isopr.), 82.7, 83.9, 87.5 (C-3, C-4, C-5), 112.4 (Cq isopr.), 130.6,
138.3 (C-1, C-2), 161.9 (C=NH). 1H-NMR (300 MHz, CDCl3):
δ 1.38 (s, 3H, CH3 isopr.), 1.45 (s, 3H, CH3 isopr.), 4.70 (d, J 5.8
Hz, 1H, H-5), 5.33 (m, 1H, H-4), 5.76 (s, 1H, H-3), 6.04 (m,
1H), 6.22 (m, 1H), (H-1, H-2). MS (ESI): m/z 321.8 [M ϩ Na]ϩ,
m/z 323.8 [M ϩ Na ϩ 2]ϩ, m/z 325.9 [M ϩ Na ϩ 4]; [α]2D0 Ϫ121.0
(c=1, CHCl3).
(3S,4R,5S )-3,4-O-Isopropylidene-5-O-p-methoxybenzylcyclo-
pentene-3,4,5-triol (20)
Compound 19 (92 mg, 0.30 mmol) was subjected to RCM using
the same conditions as described for the synthesis of 15 to give
82 mg (99%) of the title compound. 13C-NMR (75.1 MHz,
CDCl3): δ 25.5, 27.1 (2 × CH3 isopr.), 55.1 (CH3, OMe MBn),
71.2 (CH2 MBn), 83.2, 84.1, 87.7 (C-3, C-4, C-5), 109.0 (Cq
isopr.), 113.7 (CHarom MBn), 129.3 (CHarom MBn), 129.8 (Cq
1
MBn), 133.1, 135.4 (C-1, C-2). H-NMR (300 MHz, CDCl3):
δ 1.37 (s, 3H, CH3 isopr.), 1.41 (s, 3H, CH3 isopr), 3.82 (m, 4H),
4.47 (m, 3H), 5.28 (m, 1H, H-3, H-4, H-5, CH2 MBn), 5.91 (m,
1H), 6.03 (m, 1H) (H-1, H-2), 6.88 (m, 2H, CHarom MBn), 7.29
(m, 2H, CHarom MBn).
(3S,4R,5S )-3,4-O-Isopropylidenecyclopentene-3,4,5-triol (21)
(3S,4R,5S )-5-(N-Trichloroacetylamino)-3,4-O-isopropylidene-
cyclopentene-3,4-diol (25)
Compound 20 (272 mg, 0.98 mmol) was dissolved in CH2Cl2
(8 mL), water (0.5 mL) was added and cooled to 0 ЊC. DDQ
(446 mg, 1.97 mmol) was added. After 2 hours all starting
material had been transformed into a lower running product
Compound 24 (1.45 g, 4.82 mmol) was dissolved in xylenes
(25 mL) and heated until reflux. After 5 hours all starting
J. Chem. Soc., Perkin Trans. 1, 2002, 2370–2377
2375

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material had been transformed into a lower running product
(Rf 0.25, EtOAc–petroleum ether, 0.75 : 0.25). Solvents were
evaporated and column chromatography (20% EtOAc in
petroleum ether) gave 1.29 g, 89% of homogeneous 24 as a
white solid. 13C-NMR (75.1 MHz, CDCl3): δ 25.6, 27.2 (2 ×
into sat. aq. NH4Cl (20 mL) and extracted with EtOAc (2 × 25
mL). The combined organic layers were dried (MgSO4), filtered
and concentrated. Column chromatography (10 50% EtOAc
in petroleum ether) gave 64 mg (0.38 mmol) of 28 (68%) yield
and 16 mg recovery (20%) of 5. 13C-NMR (75.1 MHz, CDCl3):
δ 25.4, 27.2 (2 × CH3 isopr.), 63.4 (CH2OH), 54.6, 81.3, 84.2
CH3, isopr.), 63.0 (C-5), 83.5 (C-4), 84.3 (C-3), 92.2 (Cq, CCl3),
1
1
111.6 (C , isopr.), 130.4, 136.7 (C-1, C-2), 161.5 (C᎐O). H-
(C-3, C-4, C-5), 109.9 (Cq isopr.), 132.9, 133.5 (C-1, C-2). H-
᎐
q
NMR (300 MHz, CDCl3): δ 1.36 (s, 3H, CH3, isopr.), 1.44 (s,
3H, CH3, isopr.), 4.57 (d, 1H, H-3, J 5.0 Hz), 4.84 (m, 1H, H-4),
5.33 (m, 1H, H-5), 5.58 (m, 1H), 6.15 (m, 1H), (H-1, H-2),
6.58 (bd, 1H, NH, J 6.0 Hz.). MS (CI): m/z 321.8 [M ϩ Na]ϩ,
m/z 323.8 [M ϩ Na ϩ 2]ϩ, m/z 325.9 [M ϩ Na ϩ 4]ϩ; [α]2D0
ϩ130.8 (c=1, CHCl3).
NMR (300 MHz, CDCl3): δ 1.36 (s, 3H, CH3 isopr), 1.42 (s,
3H, CH3 isopr), 2.08 (br s, 2H, 2 × OH), 2.99 (m, 1H, H-5), 3.55
(dd, J 6 Hz, J 11 Hz, 1H, CH2OH), 3.75 (dd, J 5 Hz, J 11.0 Hz,
1H, CH2OH), 4.59 (d, J 6 Hz, 1H, H-3), 5.15 (m, 1H, H-4), 5.76
(m, 1H, H-2), 5.92 (m, 1H, H-1).
(3R,4R,5R)-3-O-Bromomethyldimethylsilyl-4,5-O-isopropyl-
idenecyclopentene-3,4,5-triol (29)
(1R,2R,3S,4R,5S )-5-(N-Trichloroacetylamino)-1,2-epoxy-3,4-
O-isopropylidenecyclopentanediol (26)
Alcohol 5 (123 mg, 0.79 mmol) was dissolved in CH2Cl2 (4 mL)
and triethylamine (0.22 mL) was added followed by bromo-
methyldimethylsilylchloride (0.14 mL, 1.03 mmol). After 1 hour
all starting material had been transformed into a higher
running product (Rf 0.85, EtOAc–petroleum ether 4 : 6). The
suspension was directly poured onto a silica gel column eluting
with 25% EtOAc and 1% Et3N in petroleum ether giving 0.201 g
Compound 5 (100 mg, 0.33 mmol) was dissolved in acetonitrile
and Na2EDTA solution (0.83 mL, 8 M in H2O) was added. The
mixture was cooled to 0 ЊC and 1,1,1-trifluoroacetone (0.33 mL,
3.5 mmol) was added via a pre-cooled syringe. Subsequently,
NaHCO3 (217 mg, 2.55 mmol) and oxone (1.02 g, 1.66 mmol)
were added in portions over a period of 1 h. H2O (0.8 mL) and
EtOH (5 mL) were added and the mixture was brought to pH 7
through the addition of NaHCO3. After two days stirring at rt
TLC analysis revealed the formation of a new product (Rf 0.40,
EtOAc–petroleum ether 2 : 8). The mixture was filtered, taken
up in dichloromethane and washed with water. The organic
phase was separated, dried (MgSO4), filtered and concentrated.
After column chromatography (0 10% EtOAc in petroleum
ether) the title compound was obtained (75 mg, 72%) as a white
solid. 13C-NMR (75.1 MHz, CDCl3): δ 24.5, 26.8 (2 × CH3,
1
of pure 29 (83%). H-NMR (200 MHz, CDCl3): δ 0.31 (s, 3H,
CH3Si), 0.32 (s, 3H, CH3Si), 1.34 (s, 3H, isopr.), 1.40 (s, 3H,
isopr.), 2.48 (s, 2H, -OCH2Si), 4.47 (d, J 6 Hz, 1H), 4.81 (m,
1H), 5.27 (m, 1H) (H-3, H-4, H-5), 5.83 (m, 1H), 6.00 (m, 1H)
(H-1, H-2).
1,2-O-Isopropylidene-4a-carba-ꢁ-L-xylofuranose (30)
Compound 29 (201 mg, 0.66 mmol) was dissolved in benzene
(10 mL) and heated to reflux. A solution of AIBN (2.15 mg,
0.013 mmol, 2 mol%) and Bu3SnH (286 mg, 0.98 mmol) in
benzene (0.7 mL) was added using a syringe pump over a 3 hour
period. By this time, all starting material had disappeared and
volatiles were evaporated off. The resulting solution was taken
up in THF (1 mL) and MeOH (1 mL), 79 mg of Na2CO3 was
added followed by 1.18 mL 30% aqueous H2O2 and the mixture
was heated at 50 ЊC overnight. The resulting suspension was
evaporated to dryness, EtOAc was added and solids were
crushed. The resulting suspension was poured onto a silica gel
column using pure EtOAc as eluent giving 90 mg (74%) of 30.
13C-NMR (75.1 MHz, CDCl3): δ 24.3, 26.6 (2 × CH3 isopr.),
32.4 (C-4a), 42.2 (C-4), 61.8 (C-5), 77.6 (C-3), 80.2 (C-1), 86.8
isopr.), 58.6 (C-5), 59.1 (C-1), 60.2 (C-2), 79.0 (C-3), 86.4 (C-4),
1
112.6 (C , isopr.), 161.5 (C᎐O). H-NMR (300 MHz, CDCl ):
᎐
q
3
δ 1.31 (s, 3H, CH3, isopr.), 1.50 (s, 3H, CH3, isopr.), 3.75 (m,
1H, H-2), 3.81 (m, 1H, H-1), 4.26 (m, 1H, H-4), 4.51 (m, 1H,
H-5), 4.72 (m, 1H, H-3). MS (CI): m/z 338.0 [M ϩ Na]ϩ,
m/z 339.9 [M ϩ Na ϩ 2]ϩ, m/z 341.9 [M ϩ Na ϩ 4]ϩ.
(3R,4S,5R)-3,4-O-Isopropylidene-5-methyltributylstannyl-
cyclopentene-3,4,5-triol (27)
Compound 5 (300 mg, 1.85 mmol) was dissolved in THF
(5 mL) and cooled to 0 ЊC. Potassium hydride (165 mg, 4 mmol)
was added followed by 5 mg of dibenzo-18-crown-6. Bu3-
SnCH2I (0.66 mL, 2.2 mmol) was added and the solution was
allowed to warm to rt. Stirring was continued for 30 min after
which time TLC indicated consumption of all starting material
and that a new compound had been formed (Rf 0.8, EtOAc–
light petroleum 1 : 9 v/v). Water (20 mL) was added followed by
EtOAc (10 mL) and toluene (10 mL). The organic phase was
separated, dried (Na2SO4), filtered and concentrated. Column
chromatography (0 10% EtOAc in toluene) gave pure 27
(787 mg, 91%). 13C-NMR (75.1 MHz, CDCl3): δ 8.9 (SnBu3),
13.6 (SnBu3), 25.5 (2 × CH3 isopr.), 27.2, 29.0 (SnBu3), 60.2
(OCH2Sn), 82.3, 84.2, 92.7 (C-3, C-4, C-5), 111.4 (Cq isopr.),
1
(C-2), 110.4 (Cq isopr.). H-NMR (200 MHz, CDCl3): δ 1.30
(s, 3H, CH3 isopr.), 1.42 (s, 3H, CH3 isopr), 1.74 (m, 1H), 1.92
(m, 1H) (H-4a), 2.39 (m, 1H, H-4), 3.86 (dd, J 5 Hz, J 11 Hz,
1H, H-5a), 4.08 (dd, J 4 Hz, J 11 Hz, 1H, H-5b), 4.24 (d, J 4 Hz,
1H, H-3), 4.37 (d, J 6 Hz, 1H, H-2), 4.79 (t, J 5 Hz, 1H, H-1);
[α]2D0 ϩ16.08 (c=1, CHCl3).
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