Highly functionalised cyclobutanols via samarium(II) iodide-induced pinacol cyclisations of carbohydrate-derived 1,4-diketones

Article abstract of DOI:10.1016/j.carres.2005.02.006

d-Ribofuranose and d-arabinofuranose derivatives were converted in a few steps into their 1,4-diketone derivatives, which were pinacol cyclised under the action of SmI₂ to form the corresponding chiral cyclobutanediol products. These products can potentially be applied to the synthesis of anti-viral agents, some of whose structures incorporate chiral cyclobutanediol moieties.

Full text of DOI:10.1016/j.carres.2005.02.006

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 1301–1309
Highly functionalised cyclobutanols via samarium(II) iodide-induced
pinacol cyclisations of carbohydrate-derived 1,4-diketones
D. Bradley G. Williams,* Judy Caddy and Kevin Blann
Department of Chemistry, University of Johannesburg, PO Box 524, Auckland Park, 2006, South Africa
Received 31 May 2004; received in revised form 11 February 2005; accepted 11 February 2005
Available online 23 March 2005
Abstract—D-Ribofuranose and D-arabinofuranose derivatives were converted in a few steps into their 1,4-diketone derivatives,
which were pinacol cyclised under the action of SmI2 to form the corresponding chiral cyclobutanediol products. These products
can potentially be applied to the synthesis of anti-viral agents, some of whose structures incorporate chiral cyclobutanediol moieties.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Carbocycles; Carbohydrates; Radical reactions; Samarium
1. Introduction
small rings, especially chiral 1,2-diols. We herein de-
scribe the conversion of some carbohydrate derivatives
(of D-ribose and D-arabinose) into chiral cyclobutane-
1,2-diol products.
The pinacol coupling reaction is a well-known process,1
which continues to be employed in the synthesis of com-
plex organic molecules.2 Its intramolecular version pro-
vides a direct route to cyclic 1,2-diols, which can be
further elaborated into a range of functional groups. A
number of metal reducing agents promote pinacol
coupling reactions,3 but of these samarium(II) iodide is
frequently superior in terms of chemical yield, and chemo-
and stereoselectivity.4 The SmI2-induced conversion of
carbohydrates into carbocycles has become well
documented in the past few years,5 and some chiral
cyclopentane-4b,5h and cyclohexanediols2b,c,5h have
been prepared using the Sm2+-mediated pinacol
coupling reaction. The same reaction to prepare cyclobu-
tanediols from carbohydrates has, to our knowledge,
not been reported. Chiral, non-racemic cyclobutanols
are highly desirable from a pharmaceutical/medicinal
perspective, since such materials form integral parts of
various anti-viral agents6 and sedatives.7 Our work on
Sm(II)-induced 4-exo-trig cyclisations8 of carbohydrate
derivatives into chiral cyclobutane derivatives suggested
that a pinacol reaction might also be employed to form
2. Results and discussion
Hoffmann and co-workers9 have previously described a
1,4-pinacolisation methodology employing SmI2 that is
useful for the production of strained unfunctionalised
systems containing a 1,2-cyclobutanediol moiety. We
believed that a SmI2-mediated pinacolisation would be
an appropriate technology for preparing functionalised
chiral cyclobutane derivatives, and, in keeping with
our continued interest in SmI2-promoted transforma-
tions,5a,b,8,10 we turned our attention to carbohydrate-
derived 1,4-diketones. These diketone substrates were
readily accessible by treatment of the appropriate lactol
precursors with Grignard- or lithium reagents, and the
diols so obtained were smoothly oxidised directly to
the diketones using Swern methodology (see Experimen-
tal section).
The investigation was initiated with the synthesis of
the diketone 2 from the isopropylidene-protected 5-
deoxy-D-ribose derivative 1 (prepared from D-ribose,
see Ref. 11) using straightforward transformations.
*
Corresponding author. Tel.: +27 11 489 3431; fax: +27 11 489 2819;
e-mail: dbgw@rau.ac.za
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.02.006

1302
D. B. G. Williams et al. / Carbohydrate Research 340 (2005) 1301–1309
The substrate 2 was treated with SmI2 using a variety of
conditions, including those discussed by Hoffmann,9
which involved addition of the substrate in THF to a
soln of SmI2 in THF at reflux. After some experimenta-
tion, a best yield of 55% of the desired cyclobutanol
derivative 3 was obtained when treating the substrate
diketone 2 with SmI2 in THF at ꢀ78 ꢁC (Scheme 1).
The assigned stereochemistry of cyclobutanediol 3
was based on extensive NOE NMR studies. The assign-
ment took into account the fact that the cis relative
stereochemistry of the diol moiety is certain since the
provide products in which the diol is ÔupÕ on the product,
since the sterically demanding chelated Sm(III) ion and
its attendant ligands (lanthanide complexes demonstrate
high co-ordination numbers12) prefer an orientation
trans with respect to the bulky isopropylidene group in
the transition state, as shown in Chart 2. We have pre-
viously observed this effect in the preparation of cyclobu-
tanes via a ketyl-olefin radical cyclisation, in which the
products of cyclisation were also predominantly those
in which the cyclisation was effected with the samarium
ion trans with respect to the isopropylidene group.8
The pinacol cyclisation step was not as successful for
other diketone substrates, including those structurally
similar to 3 and others that were more highly function-
alised. For example, diketones 4 and 5 (Scheme 1) were
subjected to SmI2-mediated pinacol cyclisation under
conditions described above, without success. However,
the addition of HMPA as co-solvent (1 equiv) allowed
successful reactions, affording diols 6 (12%) and 7
Sm-mediated pinacol reaction is
a stereospecific
reaction,2c,5g,h,9a together with the known absolute
(and cis relative) stereochemistry at the isopropylidene
ring system (Chart 1).
The ÔdirectionÕ of cyclisation (i.e., whether the diol
moieties are ÔupÕ or ÔdownÕ on the product as drawn) is
primarily determined by the relative size/steric bulk of
the chelated samarium ion versus that of the terminal
functional groups adjacent to the carbonyl functionality
in the starting material, together with the presence/ab-
sence of a ring system or other bulky group on the ring
which would enhance the directing effect. For example,
the isopropylidene-tethered ribose derivatives typically
13
(10%), respectively. This co-solvent activates SmI2
but also inhibits pinacol reactions,12 as chelation of
the samarium by the diketone14 is prevented due to
the presence of a stable Sm-HMPA complex. Nonethe-
less, studies in our laboratories have shown that 1 equiv
of HMPA activates SmI2 while still allowing pinacolisa-
tion reactions.15
O
O
OH
HO
O
O
OH
1. RLi
Other D-ribose derivatives investigated included dike-
tones 11 and 12 (Scheme 2). Diketone 11 failed alto-
gether to demonstrate the cyclisation reaction under a
wide range of reaction conditions, providing instead
products indicative of a-elimination (see Scheme 3 for
representative structures), indicated primarily by signals
corresponding to aliphatic CH3 and CH2 moieties in the
respective NMR spectra. (For a complete discussion on
Sm(II)-mediated elimination reactions, see Ref. 16.)
However, the more reactive aromatic-conjugated keto-
ne10a 12, when subjected to SmI2-mediated cyclisation
R
R
SmI2, THF
-78 o
O
O
O
CMe2
O
O
CMe2
C
2. Swern
oxidation
CMe2
(1.0 eq. HMPA)
1
2: R = thiophen-2-yl 3: R = thiophen-2-yl
4: R = Bu
5: R = P h
6: R = Bu
7: R = P h
Scheme 1.
H
H
OH
OH
O
O
CH3
CH3
CH
3
R
S
S
Sm
H
CH3
O
S
S
O
O
O
H
O
O
vs.
O
H
CH3
O
I
R
CH3
CH3
CH3
CH3
I
Sm
S
S = solvent or HMPA
S
S
NOE effects observed
Chart 1.
Chart 2.
TBDMSO
HO
O
OH
R
TBDMSO
i)
TBDMSO
TBDMSO
SmI2, THF
OHOH
O
O
O
OH
R
R
Swern
O
CMe2
O
reflux
O
O
O
O
CMe2
O
oxidation
CMe2
CMe2
9: R = Bu
10: R = thiophen-2-yl
13: R = thiophen-2-yl
11: R = Bu
12: R = thiophen-2-yl
8
Scheme 2. (i) BuMgBr, Et2O or thiophen-2-yllithium, THF.

D. B. G. Williams et al. / Carbohydrate Research 340 (2005) 1301–1309
1303
BnO
BnO
BnO
Swern
O
OHOH
Bu
O
OH
O
HO
OH
BnO
SmI2, THF
reflux
i)
Bu
OBn
17: R = butyl
R
OBn
BnO
oxidation
OBn
15: R = butyl
16: R = thiophen-2-yl 18: R = thiophen-2-yl
BnO
BnO
OBn
BnO
19: R = butyl
20: R = thiophen-2-yl
14
O
O
O
O
Bu
Bu
+
OBn
OBn
BnO
α-elimination products
Scheme 3. (i) BuMgBr, Et2O or thiophen-2-yllithium, THF.
allowed isolation of product 13 (Scheme 2) in a yield of
8%, again affording multiple products of a-elimination.
Diketone substrates for the pinacol cyclisation step
bearing different stereochemistry to those described
above, namely 17 and 18, were readily prepared from
tri-O-benzyl D-arabinose (Scheme 3). These diketones
were subjected to reaction with SmI2 in THF under re-
flux, affording cyclic products 19 and 20 in yields of
15% and 20%, respectively. These reactions clearly dem-
onstrated that the rotational restriction imposed by the
isopropylidene ring of the corresponding ribose deriva-
tives was not a prerequisite for pinacol coupling reac-
tions, in contradistinction to the 4-exo-trig reactions
that generate chiral cyclobutanes but which specifically
require a rotationally restrictive molecular make-up.8
This outcome rests with the fact that the pinacolisation
requires both ketone oxygens of the molecule to be
simultaneously complexed to the Sm-ion (see Chart 2),
which, in the event, imposes a specific conformation
on the ketyl-radical intermediates.
Pinacol coupling designed to prepare small rings is,
this research demonstrates, not as general as one might
expect after reviewing HoffmannÕs work since in no case
in that work did a substrate possess leaving groups a to
the carbonyls. What the present work has established is
that, in the presence of a leaving group, elimination of
that group is frequently preferred over a pinacol reac-
tion that will generate a strained ring system. It is there-
fore important to bear this in mind when planning a
synthesis involving this methodology.
3. Experimental
3.1. General
Thin layer chromatography (TLC) was conducted quan-
titatively on Merck GF254 pre-coated silica gel glass
plates (0.25 layer). Visualisation was achieved under
UV light (254 nm) and/or after spraying the TLC plate
with a chromic acid soln followed by heating. ÔFlash col-
umn chromatographyÕ refers to column chromatography
under nitrogen pressure (ca. 50 kPa). The columns were
loaded with E. Merck Kieselgel 60 (230–400 mesh) and
eluted with appropriate solvent mixtures in a vol/vol
ratio. Acetone was dried over anhyd K2CO3 for 24 h.
The salt was filtered off and the solvent subsequently
˚
distilled from 3 A molecular sieves and stored under
N2. THF was pre-dried over freshly ground KOH, which
was then filtered off and the solvent was dried using so-
dium-benzophenone under N2. The solvent was distilled
under N2 immediately prior to use. Dichloromethane
was heated over CaH2 under N2 with subsequent distilla-
˚
tion. MeOH was distilled from Mg/I2 and stored over 3 A
molecular sieves. Ethyl acetate was distilled from
K2CO3 using a Vigreux distillation column. Hexanes
were simply distilled prior to use. HMPA was heated
over CaH2 under an argon atmosphere for one week
prior to its use. The solvent was only used if freshly dis-
tilled. Pyridine was pre-dried over anhyd CaCl2 and then
˚
distilled from 3 A molecular sieves. NMR spectra were
recorded using a Varian Gemini 2000, 300 MHz spec-
trometer. The samples were usually made up in CDCl3.
The 1H NMR data are referenced to the residual solvent
peak of CDCl3 [d = 7.24 ppm]. The relative stereochem-
istry was determined after studying nuclear Overhauser
effect spectra. 13C NMR data are referenced to the sol-
vent peak of CDCl3 (d = 77.0 ppm). The compilation
of fragmentation determinations were recorded on a
Finnigan Matt 8200 spectrometer at an electron impact
of 70 eV, while FAB-HRMS spectra were recorded on
a Varian E7070 using glycerol or nitrobenzylalcohol as
the matrix. A Perkin–Elmer 881 spectrometer was used
to record IR spectra using dry chloroform as the solvent.
In conclusion, we have developed a procedure for the
conversion of D-ribose and D-arabinose derivatives into
highly functionalised, chiral, non-racemic cyclobutanes,
and have exposed some limitations of this reaction as
applied to multifunctional substrates. The success of
the cyclisation reaction is rather dependent upon the
nature of the functionality a to the carbonyl groups
(i.e., aromatic vs aliphatic ketones) and to a larger ex-
tent on the presence or absence of a leaving group a
to the carbonyl. Additionally, it has been found that
small amounts of HMPA additive were beneficial to
especially difficult reactions.

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D. B. G. Williams et al. / Carbohydrate Research 340 (2005) 1301–1309
A Jasco model DIP-730 spectropolarimeter having a cell
with a 10 mm path length was used to determine optical
rotations. The concentration c indicates the concentra-
tion of the sample in grams per 100 mL of soln. Melting
points were determined using a Reichert Thermopan
microscope together with a Koffler hot-stage and are
uncorrected. All reactions were performed in flamed
out glass apparatus using dry solvents unless otherwise
stated. All samarium diiodide reactions were carried
out under argon using degassed solvents while standard
chemistry was done under an atmosphere of nitrogen.
Room temperature refers to a temperature ranging from
20 to 25 ꢁC. The standard work-up procedure involved
adding water to the reaction mixture and extracting it
repeatedly with EtOAc. The organic layer was then sepa-
rated and rinsed with brine and finally with water. After
separation and drying of the organic phase with anhyd
MgSO4, the solvent was removed under diminished pres-
sure at a temperature of ca. 40 ꢁC. The crude product
was then purified by flash column chromatography.
TLC: Rf 0.58 (2:1 hexanes–EtOAc); IR (CHCl3); mmax
3620, 3440, 3040, 1710, 1422 cmꢀ1; 1H NMR: (300 MHz,
CDCl3) dH 7.88 (dd, 1H, J 3.9 and 1.2 Hz, H20), 7.68 (dd,
1H, J 5.1 and 1.2 Hz, H40), 7.12 (dd, 1H, J 5.1 and
3.9 Hz, H30), 5.42 (d, 1H, J 6.8 Hz, H2), 4.70 (d, 1H, J
6.8 Hz, H3), 2.28 (s, 3H, H5a, b and c), 1.54 (s, 3H,
CH3-isopropylidene), 1.45 (s, 3H, CH3-isopropylidene);
13C NMR: (75 MHz, CDCl3) dC 206.2 (C4), 188.0 (C1),
141.3 (C10), 135.1 (C30), 134.3 (C20), 128.2 (C40), 112.5
(acetal-C), 82.2 (C3), 80.8 (C2), 27.7 (C5), 26.9 (CH3-iso-
propylidene), 25.7 (CH3-isopropylidene); HRMS:
Found 254.3140. Calculated for C12H14SO4 254.3146;
EIMS: m/z 254 (M+, 28%), 136 (100%).
3.3. (1R,2S,3R,4S)-2-Methyl-3,4-O-isopropylidene-1-
(thiophen-2-yl)-cyclobutane-1,2,3,4-tetraol (3)
The diketone 2 (100 mg, 0.394 mmol) in THF (8 mL)
was added dropwise to a soln of SmI2 (1.18 mmol,
3.0 equiv) in THF (12 mL) at ꢀ78 ꢁC under argon.
The reaction mixture was allowed to warm to room tem-
perature over 24 h and then quenched by exposure to
the atmosphere. The mixture was filtered through a thin
pad of silica and chromatographed, affording the desired
product as an oil (55 mg, 0.215 mmol, 55%).
3.2. (2R,3S)-2,3-Dihydroxy-2,3-O-isopropylidene-1-
(thiophen-2-yl)-1,4-pentanedione (2)
To a soln of thiophene (505 mg, 6.00 mmol) in THF
(20 mL) was added n-butyllithium (1.0 equiv, 1.6 M hex-
ane soln) dropwise at 0 ꢁC. The soln was allowed to
warm to room temperature and stirred for a further
hour. This soln was added dropwise to a soln of 1
(348 mg, 2.00 mmol) in THF (9 mL) at 0 ꢁC. After stir-
ring at room temperature for 3 h, the reaction mixture
was quenched with H2O, the solvent was removed under
diminished pressure and a CH2Cl2/water extraction was
carried out.
[a]D: ꢀ16.4 (c 1, EtOAc); TLC: Rf 0.57 (2:1 hexanes–
EtOAc); IR (CHCl3); mmax 3600, 3440, 3040, 1660 cmꢀ1
;
1H NMR: (300 MHz, CDCl3) dH 7.26–7.23 (m, 2H, H30,
H40), 6.98 (dd, 1H, J 4.8 and 3.9 Hz, H20), 4.61 (d, 1H, J
5.9 Hz, H2), 4.52 (d, 1H, J 5.9 Hz, H3), 3.86 (br s, 1H,
OH), 3.05 (br s, 1H, OH), 1.58 (s, 3H, CH3-isopropylid-
ene), 1.31 (s, 3H, CH3-isopropylidene), 1.16 (s, 3H,
CH3); 13C NMR: (75 MHz, CDCl3) dC 142.0 (C10),
126.6 (C40), 125.7 (C30), 125.0 (C20), 115.2 (acetal-C),
82.0 (C2), 80.4 (C1), 79.7 (C4), 74.2 (C3), 25.7 (CH3-iso-
propylidene), 25.4 (CH3-isopropylidene), 20.1 (CH3);
HRMS: Found 256.0768. Calculated for C12H16SO4
256.0769; EIMS: m/z 256 (M+, 7%), 136 (100%).
The crude product diol was partially purified on a sil-
ica column (this material was found to be somewhat
unstable) and directly subjected to Swern oxidation as
follows:
A soln of trifluoroacetic anhydride (TFAA, 1.41 mL,
10.00 mmol) in CH2Cl2 (2.0 mL) was added dropwise
to a soln of Me2SO (0.71 mL, 10.00 mmol) in CH2Cl2
(9.0 mL) at ꢀ78 ꢁC and stirred for 1 h at the same tem-
perature. To the stirring mixture was added dropwise a
soln of the crude product from the directly preceding
reaction in CH2Cl2 (6.0 mL) at ꢀ78 ꢁC, and thereafter
the reaction mixture was stirred for an additional 2 h
at the same temperature. A soln of Et3N (2.23 mL,
16.00 mmol) in CH2Cl2 (4.0 mL) was added dropwise,
and the stirring continued for 0.5 h at ꢀ78 ꢁC. The reac-
tion mixture was removed from cooling bath and al-
lowed to reach room temperature with stirring. The
reaction mixture was partitioned between CH2Cl2 and
ice water, and the product was purified by column chro-
matography (5:1 hexanes–EtOAc), and isolated as a
light yellow oil (150 mg, 0.591 mmol, 30% over two
steps).
3.4. (3S,4R)-3,4-Dihydroxy-3,4-O-isopropylidene-2,5-
nonanedione (4)
Magnesium (103 mg, 4.25 mmol) was added to a flamed
out two-neck flask fitted with a reflux condenser and a
dropping funnel. A soln of butyl bromide (0.46 mL,
4.28 mmol) in THF (4 mL) was added dropwise to the
magnesium with constant stirring. A small iodine crystal
was added to initiate the reaction. An ice bath was used
to cool the reaction mixture to prevent excessive boiling.
After addition of the butyl bromide soln, the reaction
mixture was heated to 50 ꢁC for 15 min.
Both Grignard reagent (see above) and ribose deriva-
tive 1 (74 mg, 0.425 mmol) in THF (2 mL) were cooled
to 0 ꢁC, and the Grignard reagent was added dropwise
to the substrate soln with constant stirring. The reaction
mixture was allowed to warm to room temperature, the

D. B. G. Williams et al. / Carbohydrate Research 340 (2005) 1301–1309
1305
solvent was removed under diminished pressure and the
residue washed with NaHCO3 and extracted with
EtOAc. The general Swern oxidation procedure (see 2)
was carried out to oxidise the diol precursor, affording
the requisite diketone after purification by column chro-
matography (10:1 hexanes–EtOAc) (35 mg, 0.154 mmol,
36% over two steps).
ꢀ78 ꢁC under argon. The mixture was allowed to warm
to room temperature over 24 h and the reaction mixture
was quenched by exposure to the atmosphere. The mix-
ture was filtered through a thin pad of silica and chro-
matographed. The desired product was obtained as an
oil (8 mg, 0.035 mmol, 12%).
[a]D: ꢀ14.7 (c 1.0, CHCl3); TLC: Rf 0.42 (2:1 hexanes–
TLC: Rf 0.42 (5:1 hexanes–EtOAc); IR (CHCl3); mmax
1766, 1759, 1745, 1727, 1658, 1640, 1241, 1081,
EtOAc); IR (CHCl3); mmax 3601, 3455, 3040, 3033, 1701,
1
1664 cmꢀ1; H NMR: (300 MHz, CDCl3) dH 4.32 (d,
869 cmꢀ1
;
1H NMR: (300 MHz, CDCl3) dH 4.71 (d,
1H, J 5.5 Hz, H3), 4.18 (d, 1H, J = 5.5 Hz, H4), 2.81
(s, 1H, OH), 1.54 (s, 3H, CH3), 1.35–1.23 (m, 6H,
(CH2)3CH3), 1.29 (s, 1H, 3H, CH3-isopropylidene),
1.24 (s, 3H, CH3-isopropylidene), 0.90 (t, 3H, J 6.6 Hz,
(CH2)3CH3); 13C NMR: (75 MHz, CDCl3) dC
114.2 (acetal-C), 81.7 (C1), 79.6 (C4), 77.7 (C3), 72.2
(C2), 31.1 (CH2CH2CH2CH3), 29.6 (CH2CH2CH2CH3),
25.4 (CH3-isopropylidene), 24.9 (CH3-isopropylidene),
23.2 (CH2CH2CH2CH3), 20.5 (CH3), 14.0 (CH2CH2-
CH2CH3); HRMS: Found 230.1511. Calculated for
C12H22O4 230.1518; CIMS: 231 (MH+, 11%), 230 (M+,
3%), 215 (M+ꢀCH3, 24%), 201 (M+ꢀCH2CH3, 16%),
173 (M+ꢀBu, 3%), 155 (M+ꢀBuꢀH2O, 18%).
1H, J 7.5 Hz, H4), 4.66 (d, 1H, J 7.5 Hz, H3), 2.53
(td, 2H, J 7.5 and 4.2 Hz, H6a and b), 2.19 (s, 3H,
H1a, b and c), 1.54 (s, 3H, CH3-isopropylidene), 1.53–
1.01 (m, 4H, CH2(CH2)2CH3), 1.37 (s, 3H, CH3-isopro-
pylidene), 0.86 (t, 3H, J 7.5 Hz, (CH2)3CH3); 13C NMR:
(75 MHz, CDCl3) dC 207.6 (C2), 205.8 (C5), 111.8 (ace-
tal-C), 82.0 (C4), 81.8 (C3), 39.9 (C6), 27.7 (C1), 26.7
(C7), 25.3 (CH3-isopropylidene), 24.9 (CH3-isopropylid-
ene), 22.1 (C8), 13.8 (C9); HRMS: Found 228.1359. Cal-
culated for C12H20O4 228.1362; CIMS: 229 (MH+,
100%), 211 (M+ꢀOH, 8%), 199 (M+ꢀCH2CH3, 6%),
185, (M+ꢀCH2CH2CH3, 22%), 171 (M+ꢀbutyl, 5%).
3.5. (2R,3S)-2,3-Dihydroxy-2,3-O-isopropylidene-1-phen-
yl-1,4-pentanedione (5)
3.7. (3R,4S)-2-Methyl-1-phenyl-3,4-O-isopropylidene-
cyclobutane-1,2,3,4-tetraol (7)
Dione 5 was prepared from 1 (48 mg, 0.76 mmol) by
reaction with phenylmagnesium bromide (7.60 mmol)
according to the Grignard method as described above
for 4, followed by Swern oxidation according to the gen-
eral method described for 2. The product was purified
by column chromatography (4:1 hexanes–EtOAc) pro-
viding the diketone as a clear oil (43 mg, 0.172 mmol,
62% over two steps).
The diketone (60 mg, 0.242 mmol) was subjected to the
same cyclisation reaction conditions as the butyl ana-
logue (6) to form the desired cyclobutane product as
an oil (6 mg, 0.024 mmol, 10%).
[a]D: ꢀ3.1 (c 1.0, CHCl3); TLC: Rf 0.41 (3:1 hex-
anes–EtOAc); IR (CHCl3); mmax 3610, 3454, 3450,
3030, 3032, 1700, 1660 cmꢀ1 1H NMR: (300 MHz,
;
CDCl3) dH 7.52 (dd, 2H, J 8.4 and 1.6 Hz, aromatics),
7.37–7.29 (m, 3H, aromatics), 4.73 (d, 1H, J 5.1 Hz,
H4), 4.54 (d, 1H, J 5.1 Hz, H3), 2.73 (br s, 1H, OH),
1.91 (br s, 1H, OH), 1.51 (s, 3H, CH3), 1.43 (s, 1H,
3H, CH3-isopropylidene), 1.35 (s, 3H, CH3-isopropyl-
idene); 13C NMR: (75 MHz, CDCl3) dC 136.7 (ipso)
128.6 (ortho), 128,2 (meta), 128.0 (para), 109.7 (ace-
tal-C), 81.5 (C2), 77.5 (C4), 76.2 (C3), 66.6 (C1), 25.5
(CH3-isopropylidene), 25.4 (CH3-isopropylidene), 21.4
(CH3); HRMS: Found 250.1207. Calculated for
C14H18O4 250.1205; CIMS: 251 (MH+, 24%), 250
(M+, 4%), 233 (M+ꢀOH, 2%).
TLC: Rf 0.39 (4:1 hexanes–EtOAc); IR (CHCl3); mmax
2671, 1735, 1706, 1700, 1602, 1520, 1498, 1453, 1099,
1
1027, 864 cmꢀ1; H NMR: (300 MHz, CDCl3) dH 7.97
(d, 2H, J 7.5 Hz, ortho aromatics), 7.58 (t, 1H, J
7.2 Hz, para aromatics), 7.46 (dd, 2H, J 7.5 and
7.25 Hz, meta aromatics), 5.65 (d, 1H, J 6.6 Hz, H2),
4.73 (d, 1H, J = 6.6 Hz, H3), 2.36 (s, 3H, H5a, b and
c), 1.49 (s, 3H, CH3-isopropylidene), 1.48 (s, 3H, CH3-
isopropylidene); 13C NMR: (75 MHz, CDCl3) dC 206.8
(C4), 194.4 (C1), 134.9 (ipso), 133.7 (para), 129.1 (ortho),
128.6 (meta), 112.3 (acetal-C), 82.0 (C2), 80.1 (C3), 27.7
(C5), 27.0 (CH3-isopropylidene), 25.8 (CH3-isopropylid-
ene); HRMS: Found 248.1048. Calculated for C14H16O4
248.1049; EIMS: m/z 249 (MH+, 0.02%), 122
(M+ꢀC7H9O2, 33%), 105 (M+ꢀC7H5O, 100%).
3.8. 5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-D-
ribose (8)
A
soln of 2,3-O-isopropylidene-D-ribose16 (75 mg,
3.6. (3R,4S)-1-(1-Butyl)-2-methyl-3,4-O-isopropylidene-
cyclobutane-1,2,3,4-tetraol (6)
0.40 mmol) and imidazole (10% m/m) in pyridine
(1 mL) was cooled to 0 ꢁC. To this soln was added
tert-butyldimethylsilylchloride (67 mg, 0.43 mmol), after
which the soln was allowed to warm to room tempera-
ture and stirred at this temperature for 6 h. The solvent
was removed under diminished pressure, and the residue
The diketone (70 mg, 0.302 mmol) in THF (4 mL) was
added dropwise to a soln of SmI2 (0.906 mmol,
3.0 equiv) and HMPA (1 equiv/Sm) in THF (12 mL) at

1306
D. B. G. Williams et al. / Carbohydrate Research 340 (2005) 1301–1309
purified by flash chromatography to afford the silyl ether
as an oil (85 mg, 0.28 mmol, 70%).
1H NMR: (300 MHz, CDCl3) dH 7.27–7.23 (m, 1H, aro-
matic), 7.12–7.09 (m, 1H, aromatic), 6.99–6.94 (m, 1H,
aromatic), 5.13 (dd, 1H, J 9.3 and 2.4 Hz, H1), 4.78
(d, 1H, J 3.0 Hz, OH), 4.34 (dd, 1H, J 9.6 and 5.4 Hz,
H3), 4.14 (dd, 1H, J 9.3 and 5.4 Hz, H2), 3.96–3.65
(m, 3H, H4, H5a and b), 3.42 (d, 1H, J 3.3 Hz, OH),
1.38 (s, 3H, CH3-isopropylidene), 1.29 (s, 3H, CH3-iso-
propylidene), 0.91 (s, 9H, C(CH3)3), 0.10 (s, 6H,
SiCH3 · 2); 13C NMR: (75 MHz, CDCl3) dC 144.9
(C10), 126.4 (C30), 124.9 (C20), 124.6 (C40), 109.0 (ace-
tal-C), 81.5 (C3), 77.2 (C2), 69.3 (C5), 68.0 (C1), 64.2
(C4), 28.1 (CH3-isopropylidene), 25.9 (C(CH3)3), 25.4
(CH3-isopropylidene), 18.4 (C(CH3)3), ꢀ5.27 (SiCH3),
ꢀ5.33 (SiCH3); HRMS: Found 388.1751. Calculated
for C18H32O5SSi 388.1740; EIMS: m/z 388 (M+, 2%),
275 (M+ꢀthiophenylꢀC2H6, 13%), 73 (100%).
TLC: Rf 0.80 (3:1 hexanes–EtOAc); 1H NMR:
(300 MHz, CDCl3) dH 5.26 (d, 1H, J 12.0 Hz, H1),
4.72 (d, 1H, J 12.0 Hz, OH), 4.67 (d, 1H, J 5.7 Hz,
H2), 4.48 (d, 1H, J 5.7 Hz, H3), 4.34 (br s, 1H, H4),
3.73–3.75 (m, 2H, H5), 1.47 (s, 3H, CH3-isopropylid-
ene), 1.30 (s, 3H, CH3-isopropylidene), 0.91 (s, 9H,
C(CH3)3), 0.12 (s, 6H, SiCH3 · 2); 13C NMR:
(75 MHz, CDCl3) dC 112.0 (acetal C), 103.4 (C1), 87.6
and 87.0 (C3, C2), 81.7 (C4), 64.8 (C5), 26.5 (CH3-iso-
propylidene), 25.8 (C(CH3)3), 25.0 (CH3-isopropylid-
ene), 18.3 (C(CH3)3), ꢀ5.6 (SiCH3 · 2); HRMS:
Found 304.1711. Calculated for C14H28O5Si 304.1706;
EIMS: m/z 289 (M+ꢀCH3, 15%), 247 (M+ꢀt-Bu,
65%), 189 (M+ꢀTBDMS, 65%), 75 (100%).
3.9. 1-(1-Butyl)-5-O-tert-butyldimethylsilyl-2,3-O-isopro-
pylidene-D-ribitol (9)
3.10.2. Diastereomer 2. TLC: Rf 0.34 (5:1 hexanes–
EtOAc); IR (CHCl3); mmax 3451, 2902, 1252,
1
1073 cmꢀ1; H NMR: (300 MHz, CDCl3) dH 7.27–7.22
A Grignard reaction (see compound 4) of 8 (500 mg,
1.645 mmol) using butylmagnesium bromide (16.45
mmol) afforded the desired diol as a colourless oil after
chromatography (8:1 hexanes–EtOAc) (420 mg, 1.159
mmol, 70%).
(m, 1H, aromatic), 7.07–7.05 (m, 1H, aromatic), 7.98–
6.94 (m, 1H, aromatic), 5.39 (dd, 1H, J 7.8 and
1.7 Hz, H1), 4.70 (dd, 1H, J 6.3 and 2.4 Hz, H3), 4.13
(dd, 1H, J 9.3 and 6.3 Hz, H2), 4.15–4.01 (m, 1H,
H4), 3.82 (dd, 1H, J = 10.2 and 3.3 Hz, H5a), 3.69
(dd, 1H, J 10.2 and 5.1 Hz, H5b), 3.11 (d, 1H, J
7.8 Hz, OH), 2.75 (d, 1H, J 5.7 Hz, OH), 1.53 (s, 3H,
CH3-isopropylidene), 1.36 (s, 3H, CH3-isopropylidene),
0.89 (s, 9H, C(CH3)3), 0.08 (s, 6H, SiCH3 · 2); 13C
NMR: (75 MHz, CDCl3) dC 145.9 (C10), 126.4 (C30),
125.0 (C20), 124.4 (C40), 108.7 (acetal-C), 80.0 (C3),
76.3 (C2), 69.3 (C5), 67.5 (C1), 64.3 (C4), 26.9 (CH3-iso-
propylidene), 25.9 (C(CH3)3), 24.7 (CH3-isopropylid-
ene), 18.4 (C(CH3)3), ꢀ5.27 (SiCH3), ꢀ5.38 (SiCH3);
HRMS: Found 388.1748. Calculated for C18H32O5SSi
388.1740; EIMS: m/z 275 (M+ꢀthiophenylꢀC2H6,
13%), 43 (100%).
TLC: Rf 0.39 (8:1 hexanes–EtOAc); IR (CHCl3); mmax
3600, 3340, 3040, 2960, 1710, 1680 cmꢀ1 1H NMR:
;
(300 MHz, CDCl3) dH 4.09 (br s, 1H, OH), 4.02–3.95
(m, 2H, H2 and H4), 3.87–3.75 (m, 2H, H1 and H3),
3.85 (dd, 1H, J 9.9 and 3.3 Hz, H5a), 3.60 (dd, 1H, J
9.9 and 7.2 Hz, H5b), 3.29 (br s, 1H, OH), 1.80–1.30
(m, 6H, (CH2)3CH3), 1.34 (s, 3H, CH3-isopropylidene),
1.30 (s, 3H, CH3-isopropylidene), 0.89 (s, 12H, C(CH3)3,
(CH2)3CH3), 0.07 (s, 6H, SiCH3 · 2); 13C NMR:
(75 MHz, CDCl3) dC 108.4 (acetal-C), 81.1 (C2), 77.4
(C3), 69.3 (C4), 68.9 (C1), 64.4 (C5), 33.8 (C10), 28.1
(CH3-isopropylidene), 27.5 (CH3-isopropylidene), 25.9
(C(CH3)3), 25.5 (C20), 22.9 (C30) 18.4 (C(CH3)3), 14.2
(C40), ꢀ5.29 (SiCH3), ꢀ5.34 (SiCH3); HRMS: Found
362.2491 Calculated for C18H38O5Si 362.2489; EIMS:
m/z 362 (M+, 20%), 331 (M+ꢀC2H7, 100%).
3.11. (3S,4R)-1-O-tert-Butyldimethylsilyl-1,3,4-trihy-
droxy-3,4-O-isopropylidene-2,5-nonanedione (11)
The general Swern oxidation method (see compound 2)
was used to oxidise 9 (362 mg, 1.000 mmol). The prod-
uct was purified by column chromatography (5:1 hex-
anes–EtOAc) to afford the dione as an oil (257 mg,
0.718 mmol, 72%).
3.10. 5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-1-
(thiophen-2-yl)-D-ribitol (10)17
The general procedure to introduce a thiophene group
using thiophene (505 mg, 6.00 mmol) and n-BuLi (see
compound 2) was carried out with the protected ribose
derivative 8 (608 mg, 2.000 mmol). The crude product
was then purified on a silica column. Two diastereomers
could be isolated as light yellow oils (total yield 460 mg,
1.186 mmol, 59%), which were combined and used as a
mixture in the following step.
TLC: Rf 0.42 (5:1 hexanes–EtOAc); IR (CHCl3); mmax
3600, 3440, 3040, 2960, 1720 cmꢀ1
;
1H NMR:
(300 MHz, CDCl3) dH 4.91 (d, 1H, J 6.9 Hz, H3), 4.83
(d, 1H, J 6.9 Hz, H4), 4.43 (d, 1H, J 17.7 Hz, H1a),
4.29 (d, 1H, J 17.7 Hz, H1b), 2.66–2.47 (m, 2H,
CH2(CH2)2CH3), 1.57–1.23 (m, 4H, CH2(CH2)2CH3),
1.51 (s, 3H, CH3-isopropylidene), 1.40 (s, 3H, CH3-iso-
propylidene), 0.89–0.87 (m, 12H, (CH2)3CH3, C(CH3)3),
0.07 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3); 13C NMR:
(75 MHz, CDCl3) dC 208.2 (C5), 204.7 (C2), 111.1
3.10.1. Diastereomer 1. TLC: Rf 0.40 (5:1 hexanes–
EtOAc); IR (CHCl3); mmax 3452, 2902, 1251, 1073 cmꢀ1
;

D. B. G. Williams et al. / Carbohydrate Research 340 (2005) 1301–1309
1307
(acetal-C), 82.0 (C4), 79.8 (C3), 68.3 (C1), 39.3 (C6),
26.9 (CH3-isopropylidene), 25.8 (C(CH3)3), 25.4 (CH3-
isopropylidene), 25.0 (C7) 22.2 (C8), 18.4 (C(CH3)3),
13.9 (C9), ꢀ5.4 (SiCH3), ꢀ5.6 (SiCH3); HRMS: Found
358.2167. Calculated for C18H34O5Si 358.2176; EIMS:
m/z 343 (M+ꢀCH3, 2%), 301 (M+ꢀBu, 6%), 243
(M+ꢀTBDMS, 15%), 85 (100%).
idene), 1.30 (s, 3H, CH3-isopropylidene), 0.73 (s, 9H,
C(CH3)3), ꢀ0.08 (s, 3H, SiCH3), ꢀ0.24 (s, 3H, SiCH3);
13C NMR: (75 MHz, CDCl3) dC 143.0 (C10), 126.5
(C30), 124.8 (C20), 124.6 (C40), 114.8 (acetal-C), 80.7
(C1), 80.1 (C2), 79.2 (C3), 73.4 (C4), 61.0 (C5), 25.7
(CCH3), 25.2 (CH3-isopropylidene · 2), 18.1 (C(CH3)3),
ꢀ5.79 (SiCH3), ꢀ5.95 (SiCH3); HRMS: Found
386.157993. Calculated for C18H30SSiO5 386.158325;
EIMS: m/z 386 (M+, 17%), 136 (100%).
3.12. (3S,4R)-1-O-tert-Butyldimethylsilyl-1,3,4-trihy-
droxy-3,4-O-isopropylidene-1-(thiophen-2-yl)-2,5-pentane-
dione (12)17
3.14. 2,3,5-Tri-O-benzyl-1-(1-butyl)-D-arabinitol (15)
The general procedure to perform a Swern oxidation
(see compound 2) was carried out to oxidise 10
(393 mg, 1.013 mmol), and the product was purified by
column chromatography (5:1 hexanes–EtOAc) to yield
a yellow oil (203 mg, 0.529 mmol, 52%).
A
Grignard reaction (see compound 4) using
butylmagnesium bromide (7.10 mmol) on tri-O-benzyl-
D-arabinofuranose (commercially available from Sigma–
Aldrich, 299 mg, 0.711 mmol) afforded the desired
product as a colourless oil after chromatography (3:1
hexanes–EtOAc) (326 mg, 0.682 mmol, 96%).
TLC: Rf 0.28 (3:1 hexanes–EtOAc); IR (CHCl3); mmax
3582, 2956, 2880, 1396, 1368, 1142, 1100, 1027,
916 cmꢀ1; H NMR: (300 MHz, CDCl3) dH 7.38–7.31
(m, 15H, aromatics), 4.82–4.55 (m, 6H, OCH2Ph),
4.16–4.11 (m, 1H, H2), 3.96–3.56 (m, 5H, H1a, H1b,
H3, H4, H5), 3.40 (br s, OH), 3.35 (d, OH), 2.99 (d,
OH, J 5.4 Hz), 2.87 (br s, OH), 1.70–1.15 (m, 6H,
(CH2)3CH3), 0.94 (t, 3H, J 7.1 Hz, (CH2)3CH3); 13C
NMR: (75 MHz, CDCl3) dC (major and minor isomers)
137.8 (ipso), 137.7 (ipso), 137.6 (ipso), 137.5 (ipso), 137.4
(ipso), Aromatics—128.1, 128.0, 127.9, 127.8, 127.7,
127.6, 127.5, 127.5, 127.4, 81.0 (C4), 80.4 (C4), 78.3
(C3), 77.8 (C3), 74.2 (C2), 73.5 (C5), 73.1 (C1 and
C2), 73.0 (C5), 72.9 (C1), 71.0 (OCH2Ph), 70.9
(OCH2Ph), 70.7 (OCH2Ph), 70.7 (OCH2Ph), 70.4
(OCH2Ph), 70.1 (OCH2Ph), 33.9 (C6), 33.3 (C6), 27.8
(C7), 27.7 (C7), 22.6 (C8), 22.5 (C8), 14.0 (C9), 13.9
(C9); HRMS: Found 479.2796. Calculated for
C30H39O5 479.2797; FABMS: 479 (MH+).
TLC: Rf 0.28 (5:1 hexanes–EtOAc); IR (CHCl3); mmax
2903, 1721, 1651, 1402, 1240 cmꢀ1
;
1H NMR:
(300 MHz, CDCl3) dH 7.94 (dd, 1H, J 3.9 and 1.2 Hz,
H20), 7.67 (dd, 1H, J 5.0 and 1.2 Hz, H40), 7.12 (dd,
1H, J = 4.8 and 3.9 Hz, H30), 5.54 (d, 1H, J 6.5 Hz,
H3), 4.89 (d, 1H, J 6.5 Hz, H2), 4.50 (d, 1H, J
17.6 Hz, H5a), 4.31 (d, 1H, J 17.6 Hz, H5b), 1.45 (s,
3H, CH3-isopropylidene), 1.43 (s, 3H, CH3-isopropylid-
ene), 0.82 (s, 9H, C(CH3)3), ꢀ0.02 (s, 3H, SiCH3), ꢀ0.05
(s, 3H, SiCH3); 13C NMR: (75 MHz, CDCl3) dC 203.5
(C1), 188.2 (C4), 140.8 (C10), 135.1 (C30), 134.7 (C20),
128.1 (C40), 111.5 (acetal-C), 80.8 (C3), 80.4 (C2), 68.2
(C5), 27.0 (CH3-isopropylidene), 25.8 (C(CH3)3), 25.8
(CH3-isopropylidene), 18.4 (C(CH3)3), ꢀ5.5 (SiCH3),
ꢀ5.7 (SiCH3); HRMS: Found 384.1427. Calculated for
C18H28SSiO5 384.1427; EIMS: m/z 384 (M+, 32%), 154
(100%).
1
3.13. (3S,4S)2-tert-Butyldimethylsilyloxymethyl-3,4-O-
isopropylidene-1-(thiophen-2-yl)-cyclobutane-1,2,3,4-tet-
raol (13)
3.15. 2,3,5-Tri-O-benzyl-1-(thiophen-2-yl)-D-arabinitol
(16)
The diketone 12 (120 mg, 0.313 mmol) in THF (2 mL)
was added dropwise to a soln of SmI2 (0.938 mmol,
3.0 equiv) in THF (12 mL) at ꢀ78 ꢁC under argon.
The reaction mixture was allowed to warm to room tem-
perature over 24 h and then quenched by opening the
flask to the atmosphere. The mixture was filtered
through a thin pad of silica and then chromatographed
to afford the cyclobutane derivative as a light yellow oil
(10 mg, 0.026 mmol, 8%).
Reaction of tri-O-benzyl-D-arabinofuranose (288 mg,
0.686 mmol) with thiophen-2-yllithium (2.058 mmol,
prepared from 173 mg thiophene and 1.0 equiv of n-
BuLi) according to the procedure described for com-
pound 2 afforded the product 16 as a colourless oil
(335 mg, 0.665 mmol, 97%).
TLC: Rf 0.33 (3:1 hexanes–EtOAc); IR (CHCl3); mmax
3560, 2880, 1459, 1396, 1358, 1097, 1069, 1031, 920,
[a]D: ꢀ3.7 (c 1, EtOAc); TLC: Rf 0.42 (5:1 hexanes–
1
1
EtOAc); IR (CHCl3); mmax 3600, 3440, 3040 cmꢀ1; H
833 cmꢀ1; H NMR: (300 MHz, CDCl3) dH 7.40–7.23
NMR: (300 MHz, CDCl3) dH 7.27 (dd, 1H, J 3.6 and
1.2 Hz, H20), 7.19 (dd, 1H, J 5.1 and 1.2 Hz, H40),
6.95 (dd, 1H, J 5.1 and 3.6 Hz, H30), 6.66 (d, 1H, J
5.9 Hz, H3), 6.62 (d, 1H, J 5.9 Hz, H2), 4.54 (s, 1H,
OH), 3.89 (s, 1H, OH), 3.79 (d, 1H, J 10.5 Hz, H5a),
3.75 (d, 1H, J 10.5 Hz, H5b), 1.58 (s, 3H, CH3-isopropyl-
(m, 30H, aromatics), 7.21–7.17 (m, 2H, thiophene aro-
matics), 7.04–6.93 (m, 4H, thiophene aromatics), 5.28
(br s, 1H), 5.23 (t, 1H, J 5.5 Hz), 4.67–4.50 (m, 12H),
4.35 (dd, 2H, J 34.8 and 11.1 Hz), 4.10–4.09 (m, 2H,
H4), 3.98 (t, 1H, J 4.1 Hz), 3.89 (d, 1H, J 6.9 Hz),
3.73–3.59 (m, 4H), 3.45 (d, 1H, J 4.5 Hz, OH), 2.95 (d,

1308
D. B. G. Williams et al. / Carbohydrate Research 340 (2005) 1301–1309
1H, J 5.7 Hz, OH), 1.80 (br s, OH · 2); 13C NMR:
(75 MHz, CDCl3) dC (major and minor isomers) 145.9
(C10), 145.8 (C10), 137.8 (ipso), 137.7 (ipso · 2), 137.6
(ipso), 137.5 (ipso), 137.4 (ipso), Aromatics—128.3,
128.3, 128.2, 128.1, 127.9, 127.8, 127.7, 127.6, 126.6
(C30), 126.5 (C30), 124.7 (C20), 124.6 (C20), 124.2
(C40), 124.2 (C40), 83.3 (C3), 81.8 (C3), 78.5 (C2), 78.0
(C2), 73.7 (C4 and C4), 73.6 (C1), 73.5 (C1), 73.3 (C5
and C5), 70.9 (OCH2Ph), 70.8 (OCH2Ph), 70.7
(OCH2Ph), 70.1 (OCH2Ph), 69.9 (OCH2Ph), 69.7
(OCH2Ph); HRMS: Found 504.1971. Calculated for
C30H32O5S: 504.1970; FABMS: 504 (M+).
(OCH2Ph), 74.1 (OCH2Ph), 73.5 (OCH2Ph), 73.3 (C5);
HRMS: Found 501.1735. Calculated for C30H29SO5:
501.1736.
3.18. (3R,4R)-3,4-Di-O-benzyl-2-[(benzyloxy)methyl]-1-
butyl-cyclobutane-1,2,3,4-tetraol (19)
(3R,4R)-1,3,4-Tri-(benzyloxy)-2,5-nonanedione (67 mg,
0.21 mmol) was dissolved in degassed THF (5 mL) and
the solvent removed by vacuum distillation to ensure
an oxygen-free system. The residue was dissolved in
THF (6 mL) and added dropwise with stirring to a
freshly prepared soln of SmI2 in THF (6.3 mL of
0.1 M soln, 0.63 mmol, 3.0 equiv) at room temperature.
The mixture was heated under reflux for 6 h, after which
it was diluted with EtOAc (20 mL) and filtered through
a thin pad of silica gel. The solvent was removed under
diminished pressure and the residue purified by column
chromatography, providing the product as an oil
(15 mg, 0.032 mmol, 15%).
[a]D: ꢀ29.6 (c 3.0, CHCl3); TLC: Rf 0.75 (3:1 hexanes–
EtOAc); IR (CHCl3); mmax. 3070, 3016, 2934, 2872, 1723,
1704, 1685, 1458, 1272, 1109, 1026, 913 cmꢀ1; 1H NMR:
(300 MHz, CDCl3) dH 7.32–7.24 (m, 15H, aromatics),
4.65–4.43 (m, 6H, OCH2Ph · 3), 3.83 (dd, 2H, J 33.3
and 6.0 Hz), 3.65 (dd, 2H, J 28.8 and 9.9 Hz), 2.85 (s,
1H, OH), 2.67 (s, 1H, OH), 1.41–1.24 (m, 6H,
(CH2)3CH3), 0.87 (t, 3H, J 6.9 Hz, (CH2)3CH3); 13C
NMR: (75 MHz, CDCl3) dC 138.0 (ipso), 137.7 (ipso),
137.4 (ipso), 128.4 (meta), 128.3 (meta), 128.3 (meta),
127.9 (ortho and para), 127.8 (ortho), 127.7 (para and
ortho), 127.6 (para), 81.7 (C3), 80.2 (C4), 76.2 (C1),
75.8 (C2), 73.7 (CH2OBn), 72.1 (OCH2Ph), 72.0
(OCH2Ph) 71.8 (OCH2Ph), 34.0 (CH2CH2CH2CH3),
25.5 (CH2CH2CH2CH3), 23.2 (CH2CH2CH2CH3), 14.1
3.16. (3S,4S)-1,3,4-Tri-(benzyloxy)-2,5-nonanedione
(17)17
Swern oxidation of 15 (50 mg, 0.105 mmol, see com-
pound 2 for procedure) followed by column chromato-
graphy (5:1 hexanes–EtOAc) afforded the dione 17 as
a white solid material (48 mg, 0.103 mmol, 98%).
Mp: 64–66 ꢁC; TLC: Rf 0.31 (5:1 hexanes–EtOAc); IR
(CHCl3); mmax 3081, 3026, 2993, 2880, 1793, 1740, 1695,
1
140, 1333 1100, 1034, 913 cmꢀ1; H NMR: (300 MHz,
CDCl3) dH 7.42–7.16 (m, 15H, aromatics), 4.62–4.21
(m, 10H, OCH2Ph · 3, H1a, H1b, H3, H4), 2.56 (dt,
1H, J 18.3 and 7.5 Hz, H6a), 2.29 (dt, 1H, J 18.3 and
7.5 Hz, H6b), 1.49–1.39 (m, 2H, CH2CH2CH2CH3),
1.30–1.15 (m, 2H, (CH2)2CH2CH3), 0.84 (t, 3H, J
7.4 Hz, (CH2)3CH3); 13C NMR: (75 MHz, CDCl3) dC
210.0 (C2), 206.6 (C5), 136.9 (ipso), 136.4 (ipso), 136.1
(ipso), Aromatics—128.5, 128.4, 128.3, 128.2, 128.2,
127.8, 84.5 (C4), 83.7 (C3), 74.3 (OCH2Ph · 2), 74.2
(OCH2Ph), 73.3 (C1), 39.4 (C6), 24.9 (C7), 22.2 (C8),
13.8 (C9); HRMS: Found 475.2485. Calculated for
C30H35O5 475.2484; FABMS: 475 (MH+).
(CH2CH2CH2CH3);
HRMS:
Found
476.2566.
3.17. (2S,3S)-2,3,5-Tri-(benzyloxy)-1-(thiophen-2-yl)-1,4-
pentanedione (18)
Calculated for C30H36O5 476.2563; EIMS: m/z 477
(MH+, 46%), 368 (M+ꢀC7H8O, 16%), 296 (M+ꢀC8H12Oꢀ
C4H9, 58%), 85 (100%).
The general procedure to perform a Swern oxidation
(see compound 2) was carried out to oxidise 16
(53 mg, 0.105 mmol), and the product was purified by
column chromatography (3:1 hexanes–EtOAc) affording
the title compound as an oil (36 mg, 0.072 mmol, 68%).
TLC: Rf 0.44 (3:1 hexanes–EtOAc); IR (CHCl3); mmax
3074, 2873, 1733, 1692, 1688, 1660, 1500, 1413, 1358,
3.19. (3R,4R)-3,4-Di-O-benzyl-2-[(benzyloxy)methyl]-1-
(thiophen-2-yl)-cyclobutane-1,2,3,4-tetraol (20)
(2R,3R)-2,3,5-Tri-(benzyloxy)-1-(thiophen-2-yl)-1,4-
pentanedione (69 mg, 0.21 mmol) was subjected to iden-
tical cyclisation conditions as 19. The residue was puri-
fied by column chromatography (4:1 hexanes–EtOAc),
affording the desired product as a colourless oil
(21 mg, 0.042 mmol, 20%).
133, 1139, 1104, 1034, 920, 864 cmꢀ1
;
1H NMR:
(300 MHz, CDCl3) dH 7.89 (dd, 1H, J 3.8 and 1.1 Hz,
H30), 7.66 (dd, 1H, J 5.1 and 1.2 Hz, H20), 7.35–6.94
(m, 16H, aromatics), 4.89 (d, 1H, J 3.0 Hz), 4.72 (d,
1H, J 11.4 Hz), 4.32 (t, 1H, J 2.4 Hz), 4.66–4.22 (m,
7H); 13C NMR: (75 MHz, CDCl3) dC 205.9 (C4),
190.1 (C1), 141.1 (C10), 136.9 (ipso), 136.5 (ipso), 135.9
(ipso), 134.8 (C20), 134.1 (C40), Aromatics—128.4,
128.3, 128.3, 128.2, 128.1, 128.0, 128.0, 127.9, 127.8,
127.7, 127.6, 126.6 (C30), 83.8 (C2), 83.3 (C3), 74.4
[a]D: ꢀ11.1 (c 0.5, CHCl3); TLC: Rf 0.27 (4:1 hexanes–
EtOAc); IR (CHCl3); mmax 3441, 3038, 2930, 2879, 1538,
1523 1458, 1263, 1099 cmꢀ1 1H NMR: (300 MHz,
;
CDCl3) dH 7.37–7.20 (m, 15H, aromatics), 7.05 (dd,
1H, J 3.6 and 3.3 Hz, H30), 7.01 (d, 1H, J 3.6 Hz,
H20), 6.98 (d, 1H, J 3.3 Hz, H40), 4.75–4.49 (m,
6H,OCH2Ph · 3), 4.43 (d, 1H, J 6.6 Hz, H4), 4.04 (d,

D. B. G. Williams et al. / Carbohydrate Research 340 (2005) 1301–1309
1309
Lett. 1991, 32, 5097–5100; (i) Hoffmann, H. M. R.; El-
Khawaga, A. M.; Oehlerking, H.-H. Chem. Ber. 1991, 124,
2147.
1H, J 6.6 Hz, H3), 3.71 (s, 2H, CH2OBn), 3.41(s, 1H,
OH), 2.89 (s, 1H, OH); 13C NMR: (75 MHz, CDCl3)
dC 138.6 (ipso), 137.9 (ipso), 137.5 (C10), 137.0 (ipso),
Aromatics—128.5, 128.4, 128.3, 128.2, 128.0, 127.9,
127.8, 127.7, 127.6, 126.9, 126.8 (C40), 125.1 (C20),
124.6 (C30), 83.4 (C4), 79.5 (C3), 75.0 (C2), 73.6 (C1),
72.6 (OCH2Ph), 72.4 (OCH2Ph · 2), 70.6 (CH2OBn);
HRMS: Found 502.1821. Calculated for C30H30O5S
502.2753; EIMS: m/z 502 (M+, 34%), 501 (M+-H,
100%), 484 (M+ꢀH2O, 35%).
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Acknowledgements
8. (a) Williams, D. B. G.; Blann, K. Eur. J. Org. Chem. 2004,
3286–3291; (b) Williams, D. B. G.; Blann, K.; Holzapfel,
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¨
We gratefully acknowledge the financial assistance from
the NRF (South Africa, through GUN2053664) and the
RAU which made this work possible.
mann, H. M. R. Tetrahedron 1996, 52, 11799–11810.
10. For a review on samarium-mediated fragmentation reac-
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