Synthesis of cyclitols via cyclopropanation/palladium-catalyzed ring opening

Article abstract of DOI:10.1055/s-2008-1067262

The stereoselective syntheses of three cyclitols, 5a-carba-α-D- rhamnopyranose, 5a-carba-β-D-digitoxopyranose, and 5a-carba-α-L- rhamnopyranose, have been achieved. The routes rely upon a Simmons-Smith cyclopropanation and diastereospecific ring opening of cyclopropanol under Pd/C hydrogenation conditions to prepare the α-methyl ketone. A sequence of diastereoselective reduction, dihydroxylation, and/or Myers' reductive 1,3-rearrangement were used to install the desired stereochemistry. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067262

SPECIAL TOPIC
3171
Synthesis of Cyclitols via Cyclopropanation/Palladium-Catalyzed Ring
Opening
Synthesis of Cyclitols ingde Shan, George A. O’Doherty*
Department of Chemistry, West Virginia University, Morgantown, WV 26506, USA
Fax +1(304)2934904; E-mail: George.ODoherty@mail.wvu.edu
Received 28 May 2008
R
Abstract: The stereoselective syntheses of three cyclitols, 5a-car-
ba-a-D-rhamnopyranose, 5a-carba-b-D-digitoxopyranose, and 5a-
carba-a-L-rhamnopyranose, have been achieved. The routes rely
upon a Simmons–Smith cyclopropanation and diastereospecific
R
O
arenes
ring opening of cyclopropanol under Pd/C hydrogenation condi-
tions to prepare the a-methyl ketone. A sequence of diastereoselec-
tive reduction, dihydroxylation, and/or Myers’ reductive 1,3-
rearrangement were used to install the desired stereochemistry.
butadienes
R
bicycloheptenones
Key words: cyclitol, carbasugar, cyclopropanol, Pd/C hydrogena-
tion, ring opening
HO
COOH
OH
OH
OH
OH
HO
HO
R
HO
HO
O
OH
HO
C-Glycosides are carbohydrates wherein one of the acetal
oxygens has been replaced with a methylene group.1
These nonhydrolyzable sugar mimics have long been rec-
ognized as an important pharmacophore.2 Cyclitols are an
important subset of the C-glycoside structural motif
where the endo-acetal ring oxygen has been replaced with
a methylene group.3 In particular, polyhydroxylated cy-
clohexane cyclitols that mimic pyranosugars are ubiqui-
tous in biologically important natural products (e.g.,
aminoglycosides, validamycins, acarbose, pyralomicins,
pancratistatin).3
OH
OH
D-(–)-quinic acid
sugars
D-cyclitol
pyranose sugar
O
OH
O
O
quinones
cylclohexenol
furans
Because of their pharmacological importance, there has
Scheme 1
been
a
myriad of approaches to the cyclitols
(Scheme 1).3,4 These various routes have used both chiral
(e.g., sugars and quinic acid) and achiral (e.g., arenes,
furans, dienes) molecules as starting materials, with car-
bohydrates dominating this list of starting materials.3,4
O
OH
OH
R
HO
HO
R
O
R
O
O
For the last ten years, we have been interested in develop-
ing de novo approaches to pyranose sugars using di-
enoates and furans as starting materials.5 The dienoate
route uses an iterative Sharpless asymmetric dihydroxyla-
tion to prepare galacto-lactones. The furan route uses
asymmetric catalysis to a furan alcohol 3, followed by an
Achmatowicz rearrangement to a pyranone 2, which in
turn can be converted into various pyranose sugars 1
(Scheme 2).6 Of these two approaches, the route that uses
furans as starting materials has the advantage of being
more flexible in terms of substitution pattern and ste-
reochemistry.
OH
OH
D-pyranose sugar
D-pyranones
furan alcohols
1
2
3
Scheme 2
sired a new approach to cyclitol sugars. In particular, we
were interested in developing an approach to the cyclitols
that had the same structural flexibility as our furan ap-
proach. In particular, we desired a route that uses enones
as cyclitol pyranone analogues that could similarly be
converted into various cyclitol stereoisomers. While we
ultimately want to develop a de novo asymmetric ap-
proach, we chose to use quinic acid (5) as our starting ma-
terial, because it was already known to be easily converted
into pseudoenantiomeric enones 4 and 6 (Scheme 3).
Herein, we describe our approach to cyclitol sugars 7, 8,
ent-7 from known enones 4 and 6 (Figure 1).7
As part of our continuing efforts to develop new ap-
proaches to biologically important carbohydrates, we de-
SYNTHESIS 2008, No. 19, pp 3171–3179
x
x.
x
x
.
2
0
0
8
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067262; Art ID: C03708SS
© Georg Thieme Verlag Stuttgart · New York

3172
M. Shan, G. A. O’Doherty
SPECIAL TOPIC
O
OH
O
OH
OH
HO
COOH
HO
HO
HO
HO
O
O
OH
HO
HO
OMe
O
OH
O
OH
OH
OH
MeO
8
7
ent-7
D-(–)-quinic acid
4
5
6
Figure 1 Cyclitol sugars 7, 8, ent-7
Scheme 3
We envisioned that the stereochemistry of methylation
could be controlled by the other substituents in the ring.
Finally, the desired sugar stereochemistry could be estab-
lished by subsequent transformation, akin to our pyranone
to sugar chemistry.5,6
Our initial plan to install the methyl group for these target
molecules was to use enolate chemistry to introduce a
methyl group at the a-position of a,b-unsaturated ketone
either through in situ generated enolate or silyl enol ether.
HO
HO
O
HO
COOH
OH
i) RhCl(PPh)3
PhMe2SiH
H
H
4 steps
60%
+
ii) Et2Zn, CH2I2
iii) TsOH
O
HO
O
O
O
O
OH
O
83%
(3 steps)
5
4
9b
9a
O
O
Pd(OAc)2, py
9a
+
80 °C
86%
O
O
O
O
O
O
10a/10b
1:2
10a
10b
O
Pd(OAc)2, py
quinone, 80 °C
9a
or Pd/C, r.t.
O
10a
O
O
H2, Pd/C
88%
10a
+
O
11a/11b
3:1
O
O
11b
O
11a
O
H2, Pd/C
89%
10b
+
O
O
11a/11b
1:10
O
O
11a
11b
O
O
0.5 M NaOH, THF
+
11a/b
0 °C
85%
OH
OH
12a/12b
2:3
12a
12b
Scheme 4
Synthesis 2008, No. 19, 3171–3179 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Cyclitols
3173
Our synthesis started with enone 4, which was easily pre- 80% yield (Scheme 5). Deprotection of 11a under acidic
pared from D-quinic acid (5) in four steps with 60% over- conditions (10% HCl, THF) produced diol 13. Alterna-
all yield.8 Unfortunately, all attempts at 1,4-reduction and tively, the diol could be achieved as a single diastereomer
direct alkylation of enone 4 were unsuccessful. For in- by first deprotection of acetonide in 9a (10% HCl, THF,
stance, the Tsuda–Saegusa catalytic copper hydride 1,4- 82%), then followed by the isomerization of the resulting
reduction proceeded smoothly, but the in situ alkylation of triol 14 under the same hydrogenation conditions (Pd/C,
the enolate intermediate with methyl iodide failed to H2,82%). 1H NMR analysis of 11a and 13 confirmed their
cleanly give the desired a-methyl ketones 11a/b stereochemistry, clearly demonstrating the formation of
(Scheme 4).9 The in situ use of Stryker’s reagent for 1,4- a-methyl ketone.
hydrosilyation of 4 also proved to be problematic.10
O
O
HO
Alternatively, we envisioned that a cyclopropanation and
ring-opening process could lead to the formation of a-
methyl ketone.11 Thus, the one-pot hydrosilylation of
enone 4 [RhCl(PPh3)3, PhMe2SiH, 60 °C]12 followed by
Simmons–Smith cyclopropanation (ZnEt2, CH2I2)13 of the
resulting silyl enol ether at 0 °C gave an inseparable mix-
ture of cyclopropanol silyl ethers which, when desilylated
under acidic conditions (TsOH, MeOH), furnished two
readily separable diastereoisomers 9a/b in 83% overall
yield with a dr ratio of ~1:1 (Scheme 4). With the cyclo-
propanol in hand, we next turned our attention to its ring
opening.
H
Pd/C
10% HCl
H2
O
THF
77%
HO
O
80%
O
OH
O
9a
11a
HO
13
H
Pd/C
10% HCl
13
9a
H2
THF
82%
HO
82%
OH
14
Unfortunately, all attempts to open the three-membered
ring using acid or base failed to give the desired a-methyl
ketone.14 The ring opening promoted by Pd(OAc)2 in the
presence of pyridine at 80 °C resulted in a mixture of sep-
arable exo- and endo-a,b-unsaturated ketone 10a/10b
(1:2) in 86% yield.15 When this reaction was carried out
under similar conditions with the addition of two equiva-
lents of quinone, 10a was the only enone product pro-
duced in 70% yield along with 10% recovered starting
material, which could prevent the palladium(0)-catalyzed
isomerization of 10a to 10b. Interestingly, the cyclopro-
panol could also be opened by stoichiometric Pd/C at
room temperature to afford 10a exclusively.
O
OH
i) Boc2O
DMAP
LiAlH4
13
–78 °C
ii) Et3N
83%
91%
dr 11:1
OBoc
OBoc
15
16
OH
OH
HO
HO
HO
HO
LiAlH4
83%
OsO4, NMO
87%
16
OBoc
OH
7
17
With access to enones 10a and 10b, we next explored
their hydrogenation to prepare the a-methyl ketones 11a/
b. Thus, hydrogenation of 10a under typical conditions
(H2, Pd/C) afforded an inseparable diastereomeric mix-
ture of a-methyl ketone 11a/11b in 88% yield (dr 3:1),
while hydrogenation of 10b under the same conditions
produced 11a/11b in 89% yield with opposite diastereose-
lectivity (dr 1:10). In order to skirt the separation problem
at this point, we continued our synthesis with the diaste-
reomeric mixture of 11a/b. Base promoted b-elimination
of 11a/11b (dr 3:1) (0.5 M NaOH, THF, 0 °C) furnished a
mixture of allylic alcohol 12a/12b (dr 2:3) in 85% yield,16
which were also difficult to separate. These results forced
us to reinvestigate the cyclopropanol ring-opening pro-
cess.
Scheme 5
With the methyl group having been set, we next tried to
install the a-D-rhamnose stereochemistry. Thus, the diol
13 was acylated with Boc-anhydride followed by b-elim-
ination to afford enone 15 in 83% yield over two steps.
The carbonyl group of 15 was diastereoselectively re-
duced with LiAlH4 at –78 °C to provide the allylic alco-
hol 16 in 91% yield (dr 11:1) with easy removal of the
minor diastereomer by column chromatography. Dihy-
droxylation of cyclohexene 16 under Upjohn conditions18
produced triol 17 as a single diastereomer in good yield
(87%). Reductive removal of the tert-butyl carbonate
group with LiAlH4 resulted in 5a-carba-a-D-rhamnopyr-
anose (7) in 83% yield (Scheme 5).
We thought a direct hydrogenation with Pd/C of the cy-
clopropanol ring could avoid formation of the enone inter-
mediate 10a by preventing b-hydride elimination. That is
to say, we hoped the Pd-homoenolate intermediate might
be trapped by the Pd-bound hydrogen.17 To our delight,
hydrogenation of 9a with Pd/C under balloon pressure of
H2 resulted in 11a as a single diastereomer (dr >100:1) in
In order to prepare the b-D-carbasugar, we switched the
starting material to enone 6 (Scheme 6). Enone 6 could
also be readily prepared from D-quinic acid (5) in five
steps in 50% yield.19 As with enone 4 (cf. Scheme 4), a
one-pot hydrosilylation and cyclopropanation of 6, fol-
lowed by desilylation under acidic conditions gave a dia-
Synthesis 2008, No. 19, 3171–3179 © Thieme Stuttgart · New York

3174
M. Shan, G. A. O’Doherty
SPECIAL TOPIC
stereomeric mixture of cyclopropanol 18a/b (dr ~1:1) in rangement conditions to provide olefin 21 in good yield
85% overall yield. Although these two cyclopropanol iso- (73%, two steps).20 Dihydroxylation of the olefin 21 under
mers were inseparable, a direct cyclopropanol ring open- the Upjohn dihydroxylation conditions (OsO4, NMO) af-
ing of this mixture by Pd/C under hydrogenation forded an inseparable diastereomeric mixture of diol (dr
conditions (balloon pressure of H2, 6 h, r.t.) afforded a 11:1), which was derivatized as an acetonide 22 (81% for
diastereomeric mixture of a-methyl ketones 19a/19b two steps), with the minor diastereomer removed by chro-
(63% yield, dr 2:1) along with some recovered cyclopro- matography. Finally, reduction of the Boc-carbonate by
panol 18b (20%, as a single diastereomer). The mixture of LiAlH4 and removal of acetonide in acid conditions (10%
19a and 19b could be separated by a combination of crys- HCl, THF) afforded 5a-carba-b-D-digitoxopyranose 8 in
tallization and silica gel chromatography resulting in a di- 85% yield.
astereomerically enriched mixture of 19a (dr >13:1) and
Our efforts toward the L-carbasugars, commenced with
1
diastereomerically pure 19b. H NMR coupling constant
the synthetic transformations of a-methyl ketone 19a
analysis of 19b confirmed its stereochemistry.
(Scheme 7). Acid hydrolysis of the bis-ketal in 19a (dr
With the a-methyl ketone 19b in hand, we next turned our ~10:1) afforded diol 23 in 70% yield with the minor dia-
attention to install the b-D-digitoxose stereochemistry. stereomer removed by silica gel chromatography. It was,
Thus, deprotection of 19b in acidic conditions (90% however, difficult to prevent some epimerization of the
TFA–H2O) gave crude diol (albeit with some C-5 epimer- axial methyl group in 23 under the reaction conditions (dr
ization, dr ~15:1), which underwent acylation with Boc- ~8:1 for crude 23). The diol 23 subsequently underwent
anhydride, and subsequent b-elimination to afford enone acylation with Boc-anhydride and b-elimination under ba-
20 (79% yield from 19b, dr ~15:1). While pure isomer 20 sic conditions to furnish enone ent-15 (90% overall yield,
could be obtained by careful chromatography, the diaste- two steps). Thus, this enantiomer of 15 could be converted
reomeric mixture of 20 could be directly used in the dia- into 5a-carba-a-L-rhamnopyranose ent-7 using the same
stereoselective reduction (LiAlH4 at –78 °C). The minor 3-step reaction sequence for the conversion of 15 to 7.
diastereomers of the resulting allylic alcohol (82% yield)
could be readily removed by chromatography, and the
major isomer was then treated in Myer’s reductive rear-
Alternatively, the L-series of carbasugar could also be pre-
pared from cyclopropanol 9b (Scheme 4). We first depro-
O
OH
HO
COOH
i) RhCl(PPh3)3
PhMe2SiH
H
5 steps
50%
O
O
ii) Et2Zn, CH2I2
iii) TsOH
OMe
OMe
OH
HO
O
O
OH
85%
MeO
MeO
dr ~1:1
6
5
18a/b
O
O
Pd/C
H2
18a/b
+
O
O
OMe
OMe
63%
19a/19b
(2:1)
O
O
MeO
MeO
19a
19b
O
i) LiAlH4
–78 °C
i) 90% TFA, H2O
19b
ii) (Boc)2O, DMAP
ii) Et3N
ii) DIAD, Ph3P
NBSH
OBoc
OBoc
73%
79%
21
20
O
OH
O
HO
i) LiAlH4
i) OsO4, NMO
21
ii) 10% HCl
THF
ii) DMP, TsOH
81%
OBoc
22
OH
85%
8
Scheme 6
Synthesis 2008, No. 19, 3171–3179 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Cyclitols
3175
O
O
O
Me
Me
Me
i) (Boc)2O
DMAP
90% TFA–H2O
70%
O
HO
ii) Et3N
90%
OMe
O
OBoc
OH
MeO
23
ent-15
19a
HO
HO
O
i) (Cl3CO)2CO
DMAP
H
Me
H
Pd/C
10% HCl
H2
THF
82%
O
ii) Et3N
73%
HO
OH
HO
80%
O
OH
24
9b
25
OH
O
O
Me
Me
Me
DIAD, Ph3P
LiAlH4
p-nitrobenzoic acid
95%
–78 °C
90%
OPNBz
27
OH
OPNBz
12b
26
OH
HO
OH
Me
HO
HO
Me
LiOH
85%
OsO4, NMO
94%
27
HO
OPNBz
28
OH
(ent)-7
Scheme 7
tected the acetonide of 9b under acidic conditions (10% were also used to install the desired carbasugar stereo-
HCl, THF) to give the triol 24 in 82% yield (Scheme 7). chemistry.
Exposure of the cyclopropanol 24 to typical hydrogena-
tion conditions (Pd/C, H2) as before afforded the a-methyl
1H and 13C NMR spectra were recorded on 600 M or 270 M NMR
spectrometers. Chemical shifts were reported relative to CDCl3 (d =
7.26) or CD3OD (d = 3.31) for 1H, and CDCl3 (d = 77.0) or CD3OD
(d = 49.15) for 13C. Optical rotations were measured with a digital
polarimeter in the solvent specified. IR spectra were obtained on a
FT-IR spectrometer. Melting points are uncorrected. Rf values were
obtained by elution of TLC plates in the stated solvent ratios (v/v).
Toluene, Et2O, THF, CH2Cl2, and Et3N were dried by passing
through activated alumina column under a positive pressure of ar-
gon. Commercial reagents were used without purification, unless
otherwise noted. Air and/or moisture-sensitive reactions were car-
ried out under argon using oven/flamed-dried glassware and stan-
dard syringe/septa techniques. Only new procedures and physical
data for new compounds were reported in this experimental sec-
tion.7
ketone 25 in 80% yield as a single diastereomer. Once
1
again H NMR analysis clearly demonstrated the stereo-
chemistry of the a-methyl ketone. Dehydration of diol 25
through carbonate formation and b-elimination furnished
the allylic alcohol 12b in 73% yield over two steps. In or-
der to prepare the a-sugar, we need to invert the stereo-
chemistry of the C-1 hydroxy group. Thus, Mitsunobu
reaction of 12b with p-nitrobenzoic acid in the presence of
DIAD and PPh3 gave the ester 26 in excellent yield (95%)
with desired inverted stereochemistry.21 Diastereoselec-
tive reduction of the enone 26 (LiAlH4, –78 °C) afforded
the allylic alcohol 27 in 90% yield (dr 11:1) with the mi-
nor isomer easily removed by chromatography. Dihy-
droxylation of 27 produced the triol 28 in 94% yield with
complete stereocontrol. Saponification of ester 28 under
basic conditions (LiOH, MeOH) afforded 5a-carba-a-L-
rhamnopyranose ent-7 in 85% yield.22
(3aR,7aS)-Tetrahydro-2,2-dimethyl-6-methyleneben-
zo[d][1,3]dioxol-5(6H)-one (10a) and (3aR,7aS)-3a,4-Dihydro-
2,2,6-trimethylbenzo[d][1,3]dioxol-5(7aH)-one (10b)
To a solution of 9a (139 mg, 0.76 mmol) in toluene (6 mL) was add-
ed pyridine (128 mL, 1.59 mmol) and Pd(OAc)2 (178 mg, 0.79
mmol). The mixture was heated up to 80 °C and kept stirring for 3
h. Then it was cooled to r.t., and filtered through a filter paper, rins-
ing with Et2O–hexane (1:1, 50 mL). The solution was washed with
aq 0.5 M NaHSO4 (1 mL) at 0 °C, then with aq sat. NaHCO3 (1 mL)
and brine (1 mL), and dried (Na2SO4). The solution was concentrat-
ed under reduced pressure and the residue was purified by silica gel
column chromatography. Elution with hexane–EtOAc (7:1) afford-
In conclusion, three carbasugars in D/L and a/b forms
have been successfully synthesized starting from D-(–)-
quinic acid (5). This synthesis highlights a novel diaste-
reospecific Pd/C catalyzed cyclopropanol ring opening,
diastereoselective reduction, and dihydroxylation. Mit-
sunobu reaction and Myers’ reductive rearrangement
Synthesis 2008, No. 19, 3171–3179 © Thieme Stuttgart · New York

3176
M. Shan, G. A. O’Doherty
SPECIAL TOPIC
ed two pure compounds 10a (42 mg, 31%) and 10b (75 mg, 55%).
To a solution of 9a (10 mg, 0.05 mmol) in toluene (0.5 mL) was
added pyridine (8.7 mL, 0.11 mmol), quinone (12 mg, 0.10 mmol),
and Pd(OAc)2 (14 mg, 0.06 mmol). The mixture was heated up to
80 °C and kept stirring for 3 h. Then it was cooled to r.t. and filtered
through a filter paper rinsing with Et2O–hexane (1:1, 5 mL). The so-
lution was concentrated under reduced pressure and directly loaded
onto a silica gel column. Elution with hexane–EtOAc (5:1) afforded
compounds 10a (7 mg, ~70%) and 9a (1 mg, ~10% recovery). To a
solution of 9a (1.6 mg, 0.009 mmol) in THF–EtOH (1:1, 0.6 mL)
was added 10% Pd/C (11 mg, 0.01 mmol Pd). The mixture was
stirred at r.t. for 24 h and filtered through a filter paper. The solution
was concentrated under reduced pressure to give a residue that was
shown by crude 1H NMR spectroscopy to be exclusively 10a.
dried (Na2SO4). The solution was concentrated under reduced pres-
sure. The H NMR spectrum of the residue showed that it was a
mixture of 12a/b [dr (12a/12b) 2:3]; yield: 85%. The two isomers
12a and 12b were inseparable on silica gel column.
1
tert-Butyl (1S,5S)-5-Methyl-4-oxocyclohex-2-enyl Carbonate
(15)
Diol 13 (250 mg, 1.74 mmol) was dissolved in CH2Cl2 (15 mL) at
r.t., into which DMAP (24 mg, 0.2 mmol) was added, followed by
the addition of a solution of Boc2O (1.2 g, 5.6 mmol) in CH2Cl2 (5
mL). The mixture was stirred at r.t. for 2 h, cooled down to 0 °C, di-
luted with Et2O (30 mL), and then quenched with aq sat. NaHCO3
(10 mL). The mixture was stirred at 0 °C for another 1 h and then
extracted with hexane–Et2O (1:2, 2 × 50 mL). The combined organ-
ic layers were washed with brine (15 mL) and dried (Na2SO4). The
solution was concentrated under reduced pressure and the residue
was redissolved in CH2Cl2 (9 mL) at 0 °C. To this solution was
slowly added Et3N (1.8 mL, 12.9 mmol). The mixture was then
stirred overnight at 0 °C and the stirring was continued for another
2 h at r.t. Then it was cooled back to 0 °C, diluted with hexane–Et2O
(1:1, 50 mL) and then quenched with aq 0.5 M NaHSO4 (30 mL) at
0 °C. The aqueous layer was extracted with hexane–Et2O (1:1,
2 × 100 mL). The combined organic layers were washed with aq sat.
NaHCO3 (20 mL), brine (20 mL), and dried (Na2SO4). The solution
was concentrated under reduced pressure to afford a residue which
was purified by column chromatography over silica gel. Elution
with hexane–EtOAc (10:1) gave enone 15 (325 mg, 83% for two
steps) as a white solid; mp 36.8–38.2 °C; Rf = 0.49 (hexane–EtOAc,
4:1); [a]D20 –175.19 (c 1.54, CHCl3).
10a
White solid; mp 58.3–60.3 °C; Rf = 0.45 (1:1, hexane–EtOAc);
[a]D20 +16.36 (c 0.33, CHCl3).
IR (film): 2991, 2917, 1709, 1671, 1627, 1431, 1384, 1363, 1286,
1274, 1243, 1207, 1163, 1081, 1062, 1038, 950 cm–1.
1H NMR (270 MHz, CDCl3): d = 6.17 (dd, J = 2.0, 2.0 Hz, 1 H),
5.32 (dd, J = 2.2, 1.7 Hz, 1 H), 4.69 (ddd, J = 6.7, 3.2, 3.2 Hz, 1 H),
4.60 (ddd, J = 7.4, 3.2, 3.2 Hz, 1 H), 2.79 (dd, J = 15.3, 2.7 Hz, 1
H), 2.77 (dd, J = 15.8, 3.0 Hz, 1 H), 2.64 (dddd, J = 15.3, 3.7, 2.2,
2.2 Hz, 1 H), 2.58 (dd, J = 15.8, 3.5 Hz, 1 H), 1.34 (s, 3 H), 1.33 (s,
3 H).
13C NMR (67.5 MHz, CDCl3): d = 197.3, 138.9, 123.5, 108.0, 73.1,
72.4, 42.0, 34.9, 26.0, 24.1.
HRMS (ESI): m/z calcd for [C10H14O3 + H]+: 183.1016; found:
183.1016.
IR (film): 2991, 2969, 2930, 2879, 1731, 1686, 1627, 1454, 1369,
1343, 1274, 1252, 1195, 1156, 1121, 1079, 1067, 1046, 965 cm–1.
1H NMR (270 MHz, CDCl3): d = 6.86 (dd, J = 10.2, 4.2 Hz, 1 H),
6.04 (dd, J = 9.9, 1.0 Hz, 1 H), 5.29 (ddd, J = 4.5, 4.5, 4.2 Hz, 1 H),
2.77 (dqd, J = 9.6, 7.2, 4.9 Hz, 1 H), 2.25 (dddd, J = 13.9, 4.9, 4.9,
1.0 Hz, 1 H), 2.06 (ddd, J = 13.9, 9.4, 4.5 Hz, 1 H), 1.49 (s, 9 H),
1.15 (d, J = 6.9 Hz, 3 H).
13C NMR (67.5 MHz, CDCl3): d = 201.0, 152.8, 143.3, 131.2, 82.9,
68.1, 37.7, 35.4, 27.7, 14.9.
10b
20
Colorless oil; Rf = 0.55 (1:1, hexane–EtOAc); [a]D +71.42 (c
1.89, CHCl3).
IR (film): 2986, 2926, 1679, 1450, 1380, 1368, 1243, 1223, 1155,
1063, 1038, 1012, 967 cm–1.
1H NMR (270 MHz, CDCl3): d = 6.39 (dq, J = 4.7, 1.5 Hz, 1 H),
4.69 (dddd, J = 4.5, 3.0, 3.0, 1.5 Hz, 1 H), 4.63 (ddq, J = 4.9, 3.0,
2.0 Hz, 1 H), 2.92 (dd, J = 17.3, 2.7 Hz, 1 H), 2.65 (dd, J = 17.3, 3.9
Hz, 1 H), 1.80 (dd, J = 1.5, 1.5 Hz, 3 H), 1.36 (s, 3 H), 1.34 (s, 3 H).
tert-Butyl (1S,4R,5S)-4-Hydroxy-5-methylcyclohex-2-enyl
Carbonate (16)
To a solution of enone 15 (69 mg, 0.30 mmol) in THF (6 mL) at
–78 °C was added LiAlH4 (40 mg, 0.92 mmol) in several portions.
The mixture was stirred at –78 °C for 30 min, then acetone (2 mL)
was added dropwise at –78 °C and the mixture was stirred for an-
other 20 min to quench the reaction. Then it was diluted with EtOAc
(30 mL) and aq sat. NH4Cl (6 mL) was added. The mixture was
warmed up and stirred at 0 °C for 15 min and then the aqueous layer
was extracted with EtOAc (2 × 30 mL). The combined organic lay-
ers were washed with aq sat. NH4Cl (5 mL), brine (5 mL), and dried
(Na2SO4). The solution was concentrated under reduced pressure to
give a residue that was then purified by chromatography on a silica
gel column. Elution with hexane–EtOAc (5:1) afforded the allylic
alcohol 16 (60 mg, 90%) as a white solid; mp 81.6–83.6 °C;
Rf = 0.27 (hexane–EtOAc, 4:1); [a]D20 –130.66 (c 1.05, CHCl3).
13C NMR (67.5 MHz, CDCl3): d = 195.7, 140.6, 135.5, 109.6, 73.6,
71.6, 39.1, 27.8, 26.6, 15.8.
HRMS (ESI): m/z calcd for [C10H14O3 + H]+: 183.1016; found:
183.1016.
Hydrogenation of 10a and 10b
To a solution of enone 10a (or 10b) (40 mg, 0.22 mmol) in THF–
EtOH (1:1, 3 mL) was added 10% Pd/C (20 mg). The mixture was
degassed using vacuum and refilled with H2 at ~ –30 °C for three
times and then was stirred under a balloon pressure of H2 at r.t. for
2 h. The mixture was filtered through a filter paper and the solution
was concentrated under reduced pressure. A crude 1H NMR spec-
trum of the residue showed that it was a diastereomeric mixture of
a-methyl ketone 11a/11b with dr (11a/11b) 3:1 for 10a [or dr (11a/
11b) 1:10 for 10b]. The two isomers 11a and 11b were inseparable
on silica gel column and a mixture of isomers 11a/b was obtained
in 88% yield from 10a (or 89% from 10b).
IR (film): 3354, 2974, 1732, 1455, 1397, 1370, 1340, 1281, 1256,
1155, 1058, 1035, 945 cm–1.
1H NMR (600 MHz, CDCl3): d = 5.95 (ddd, J = 9.6, 1.8 Hz, 1 H),
5.85 (dddd, J = 10.2, 4.2, 1.8, 1.8 Hz, 1 H), 4.99 (m, 1 H), 3.70 (ddd,
J = 9.0, 3.6, 1.8 Hz, 1 H), 1.91 (dddd, J = 14.4, 3.0, 3.0, 1.8 Hz, 1
H), 1.82 (ddqd, J = 12.0, 9.6, 6.6, 3.0 Hz, 1 H), 1.57 (ddd, J = 15.0,
12.0, 4.8 Hz, 1 H), 1.48 (s, 9 H), 1.07 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CDCl3): d = 153.2, 136.9, 125.4, 82.1, 73.2,
69.1, 34.2, 32.8, 27.8, 18.0.
b-Elimination of 11a/b
To a solution of a mixture of 11a/11b (dr 3:1, 18 mg, 0.1 mmol) in
THF (6 mL) at 0 °C was added aq 0.5 M NaOH (3 drops) and the
mixture was stirred at 0 °C for 30 h. Then, aq sat. NH4Cl (10 drops)
was added and the mixture diluted with EtOAc (20 mL). The organ-
ic layer was washed with aq sat. NH4Cl (1 mL), brine (1 mL), and
Synthesis 2008, No. 19, 3171–3179 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Cyclitols
3177
HRMS (ESI): m/z calcd for [C12H20O4 + Na]+: 251.1254; found:
19a
251.1254.
White solid; mp 92.0–93.0 °C; dr (19a/19b) = 18:1; Rf = 0.31 (hex-
ane–EtOAc, 4:1).
tert-Butyl (1S,2S,3S,4R,5S)-2,3,4-Trihydroxy-5-methylcyclo-
hexyl Carbonate (17)
IR (film): 3016, 2949, 2911, 2840, 1731, 1461, 1430, 1364, 1277,
1204, 1108, 1073, 1039, 1025, 971 cm–1.
To a solution of olefin 16 (37 mg, 0.16 mmol) in t-BuOH–acetone–
aq 50% NMO (1:1:1; 1.5 mL) was added a small piece of crystalline
OsO4 at 0 °C. The mixture was stirred at 0 °C for overnight, then aq
sat. Na2S2O4 (1.5 mL) was added and stirred at 0 °C for another 2 h.
The mixture was passed through a pad of sand/silica gel/Celite and
rinsed with EtOAc–MeOH (10:1). The effluent was dried (Na2SO4)
and concentrated under reduced pressure to give a residue that was
purified on a silica gel column. Elution with hexane–EtOAc (1:2)
gave the triol 17 (37 mg, 87%) as a colorless oil: Rf = 0.27 (hexane–
EtOAc, 1:3); [a]D20 +10.31 (c 1.9, MeOH).
1H NMR (600 MHz, CDCl3): d = 4.00 (ddd, J = 12.0, 9.6, 4.8 Hz, 1
H), 3.74 (ddd, J = 13.2, 10.2, 5.4 Hz, 1 H), 3.28 (s, 3 H), 3.21 (s, 3
H), 2.61 (dd, J = 15.0, 12.6 Hz, 1 H), 2.58 (m, 1 H), 2.48 (ddd,
J = 15.0, 5.4, 1.2 Hz, 1 H), 1.84 (ddd, J = 13.2, 12.0, 6.6 Hz, 1 H),
1.74 (ddd, J = 13.8, 6.6, 3.0 Hz, 1 H), 1.29 (s, 3 H), 1.28 (s, 3 H),
1.20 (d, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): d = 210.7, 99.7, 99.3, 68.8, 66.3, 48.0,
47.9, 43.3, 41.5, 32.2, 17.9, 17.7, 17.6.
HRMS (ESI): m/z calcd for [C13H22O5 + Na]+: 281.1359; found:
281.1360.
IR (film): 3388, 2933, 1740, 1457, 1369, 1277, 1255, 1157, 1051,
960 cm–1.
1H NMR (600 MHz, CD3OD): d = 4.69 (ddd, J = 3.6, 3.0, 1.8 Hz, 1
H), 3.92 (ddd, J = 3.6, 3.6, 1.2 Hz, 1 H), 3.48 (dd, J = 9.6, 3.6 Hz, 1
H), 3.29 (ddd, J = 9.0, 9.0, 1.8 Hz, 1 H), 1.67 (m, 3 H), 1.46 (s, 9 H),
1.02 (d, J = 5.4 Hz, 3 H).
13C NMR (150 MHz, CD3OD): d = 154.4, 83.1, 76.4, 76.3, 74.5,
72.2, 33.8, 33.2, 28.2, 18.4.
19b
White crystals; mp 174–175 °C; Rf = 0.33 (hexane–EtOAc, 4:1);
[a]D20 +145.40 °C (c 0.37, CHCl3).
IR (film): 2987, 2951, 2913, 2884, 2833, 1703, 1468, 1444, 1431,
1377, 1277, 1231, 1220, 1202, 1156, 1112, 1081, 1054, 1037, 928
cm–1.
1H NMR (600 MHz, CDCl3): d = 3.96 (ddd, J = 12.0, 9.6, 4.8 Hz, 1
H), 3.71 (ddd, J = 13.2, 9.6, 5.4 Hz, 1 H), 3.32 (s, 3 H), 3.23 (s, 3
H), 2.60 (dd, J = 13.8, 5.4 Hz, 1 H), 2.53 (ddd, J = 13.2, 13.2, 1.2
Hz, 1 H), 2.41 (ddqd, J = 12.6, 6.6, 6.6, 1.2 Hz, 1 H), 2.08 (ddd,
J = 12.6, 6.6, 4.2 Hz, 1 H), 1.43 (ddd, J = 13.2, 12.6, 12.0 Hz, 1 H),
1.32 (s, 3 H), 1.31 (s, 3 H), 1.07 (d, J = 6.0 Hz, 3 H).
13C NMR (150 MHz, CDCl3): d = 208.0, 99.6, 99.4, 69.6, 69.4, 48.0,
47.9, 44.5, 43.0, 34.5, 17.7, 17.6, 14.0.
HRMS (ESI): m/z calcd for [C13H22O5 + H]+: 259.1540; found:
259.1540.
HRMS (ESI): m/z calcd for [C12H22O6 + Na]+: 285.1309; found:
285.1309.
5a-Carba-a-D-rhamnopyranose (7)
To a solution of the carbonate 17 (26 mg, 0.10 mmol) in THF (2
mL) at 0 °C was added LiAlH4 (26 mg, 0.68 mmol). The mixture
was warmed up and stirred at r.t. for 1 h, then it was diluted with
EtOAc (10 mL) and aq sat. NaHCO3 (2 mL) was added. The mix-
ture was stirred for another 20 min to quench the reaction and then
was passed through a pad of sand/silica gel/Celite, eluting with
EtOAc–MeOH (10:1). The effluent was dried (Na2SO4) and con-
centrated under reduced pressure to give a residue which was puri-
fied by chromatography over silica gel column. Elution with
EtOAc–MeOH (10:1) afforded the cyclitol 7 (13 mg, 83%) as a col-
5a-Carba-b-D-digitoxopyranose (8)
To a solution of carbonate 22 (16 mg, 0.06 mmol) in THF (2 mL) at
0 °C was added LiAlH4 (16 mg, 0.42 mmol). The mixture was
warmed up to r.t. and stirred for 1 h. The mixture was diluted with
EtOAc (5 mL) and aq sat. NaHCO3 (1.5 mL) was added. The mix-
ture was stirred for another 20 min to quench the reaction and then
passed through a pad of sand/silica gel/Celite, eluting with EtOAc.
The effluent was dried (Na2SO4) and concentrated under reduced
pressure to give a residue. The residue was redissolved in THF–aq
10% HCl (1:1, 1.5 mL) and the solution was stirred at r.t. for 30 min.
It was then cooled down to 0 °C, and diluted with EtOAc (5 mL).
Then aq sat. NaHCO3 (1 mL) and solid NaHCO3 (250 mg) were
slowly added to quench the reaction. The mixture was concentrated
to a residue that was directly loaded to a silica gel column. Elution
with EtOAc–MeOH (20:1) gave cyclitol 8 (7 mg, 85%) as a color-
20
orless oil; Rf = 0.24 (EtOAc–MeOH, 5:1); [a]D –17.24 (c 0.58,
MeOH).
IR (film): 3315, 2922, 1404, 1377, 1281, 1240, 1186, 1154, 1052,
1003, 964 cm–1.
1H NMR (600 MHz, CD3OD): d = 3.87 (dd, J = 3.6, 3.0 Hz, 1 H),
3.83 (ddd, J = 3.6, 3.0, 3.0 Hz, 1 H), 3.61 (dd, J = 9.6, 3.0 Hz, 1 H),
3.26 (dd, J = 9.6, 9.6 Hz, 1 H), 1.78 (ddqd, J = 10.2, 9.6, 6.6, 6.6 Hz,
1 H), 1.59 (m, 2 H), 1.01 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CD3OD): d = 76.9, 75.0, 74.3, 71.1, 35.9, 33.1,
18.6.
Separation of (2S,3S,4aR,7R,8aR)-Hexahydro-2,3-dimethoxy-
2,3,7-trimethylbenzo[b][1,4]dioxin-6(7H)-one (19a) and
(2S,3S,4aR,7S,8aR)-Hexahydro-2,3-dimethoxy-2,3,7-trimethyl-
benzo[b][1,4]dioxin-6(7H)-one (19b)
A diastereomeric mixture of 19a/19b (6.5 g, dr ~2:1) was recrystal-
lized from hexane–Et2O several times, resulting in diastereomeri-
cally enriched 19a [~3.3 g, dr (19a/19b) ~10:1] in the mother
liquors and 19b [~2.0 g, dr (19b/19a) >20:1] as the crystal form, as
well as other small amounts of mixtures (dr ratio range from 4:1 to
1:4). The 19a enriched part and the 19b enriched part were further
purified, respectively, by silica gel column chromatography, eluting
with hexane–EtOAc (6:1) to give more enriched 19a (2.6 g, dr
~18:1, 40% recovery from original mixture) and pure 19b (1.8 g,
28% recovery from the original mixture).
20
less oil; Rf = 0.44 (EtOAc–MeOH, 5:1); [a]D +32.50 (c 0.64,
CHCl3).
IR (film): 3353, 2975, 2950, 2930, 1454, 1417, 1370, 1307, 1184,
1141, 1094, 1047, 980 cm–1.
1H NMR (600 MHz, CD3OD): d = 3.95 (ddd, J = 3.0, 3.0, 2.4 Hz, 1
H), 3.94 (dddd, J = 11.4, 11.4, 4.2, 4.2 Hz, 1 H), 3.06 (dd, J = 10.2,
3.0 Hz, 1 H), 2.11 (dddd, J = 13.2, 3.6, 3.6, 3.0 Hz, 1 H), 1.88 (dddd,
J = 12.0, 3.6, 3.6, 2.4 Hz, 1 H), 1.83 (ddqd, J = 10.2, 10.2, 6.6, 3.6
Hz, 1 H), 1.39 (ddd, J = 13.2, 11.4, 2.4 Hz, 1 H), 1.01 (ddd,
J = 12.6, 12.6, 11.4 Hz, 1 H), 1.00 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CD3OD): d = 78.3, 71.7, 66.1, 43.4, 41.5, 32.4,
19.2.
HRMS (ESI): m/z calcd for [C7H14O3 – H]–: 145.0870; found:
145.0871.
Synthesis 2008, No. 19, 3171–3179 © Thieme Stuttgart · New York

3178
M. Shan, G. A. O’Doherty
SPECIAL TOPIC
(2R,4R,5R)-4,5-Dihydroxy-2-methylcyclohexanone (23)
13C NMR (150 MHz, CDCl3): d = 200.9, 152.9, 143.3, 131.2, 82.9,
A sample of bisketal 19a (500 mg, 1.94 mmol, dr ~10:1) was placed
in a 250 mL flask at 0 °C. A solution of TFA–H2O (5:1, 3.7 mL) was
added to the contents of the flask at 0 °C while stirring. The mixture
was stirred at 0 °C for 20 min and diluted with EtOAc (30 mL). Aq
sat. NaHCO3 (10 mL) and solid NaHCO3 (6 g) were slowly added
to the mixture to quench the reaction. The mixture was run through
a pad of sand/silica gel/Celite, rinsing with EtOAc–MeOH (10:1),
and the effluent was dried (Na2SO4). The solution was concentrated
under reduced pressure to give a residue. The crude 1H NMR spec-
trum showed that a little isomerization on the a-methyl group had
happened, which lowered the dr to ~8:1. The residue was then puri-
fied by chromatography over a silica gel column. Elution with hex-
ane–EtOAc (1:3) gave the pure diol 23 (195 mg, 70%) with the
minor isomer removed; white solid; mp 67.9–69.2 °C; Rf = 0.50
(EtOAc–MeOH, 10:1); [a]D20 –12.99 (c 2.6, CHCl3).
68.1, 37.7, 35.4, 27.7, 14.9.
HRMS (ESI): m/z calcd for [C12H18O4 + Na]+: 249.1097; found:
249.1097.
(1R,2R,3R,4S,5R)-2,3,4-Trihydroxy-5-methylcyclohexyl
4-Nitrobenzoate (28)
To a solution of the olefin 27 (30 mg, 0.11 mmol) in t-BuOH–ace-
tone–aq 50% NMO (1:1:1 1.5 mL) was added a small piece of crys-
talline OsO4 at 0 °C. The mixture was stirred overnight at 0 °C, then
aq sat. Na2S2O4 (1.5 mL) was added and stirred at 0 °C for another
2 h. The mixture was passed through a pad of sand/silica gel/Celite,
rinsed with EtOAc–MeOH (10:1). The effluent was dried (Na2SO4)
and concentrated under reduced pressure to give a residue that was
purified by silica gel column. Elution with EtOAc–MeOH (20:1)
gave the triol 28 (32 mg, 94%) as a white solid; mp 203–204 °C;
Rf = 0.20 (hexane–EtOAc, 1:2); [a]D20 –32.59 (c 0.54, MeOH).
IR (film): 3373, 3280, 2969, 2924, 1694, 1437, 1421, 1399, 1380,
1276, 1229, 1165, 1123, 1094, 1071, 1032, 967 cm–1.
IR (film): 3351, 2925, 1715, 1608, 1525, 1408, 1346, 1314, 1275,
1H NMR (600 MHz, CDCl3): d = 4.19 (dddd, J = 4.8, 4.2, 3.6, 3.2
Hz, 1 H), 4.02 (dddd, J = 4.2, 3.6, 3.6, 3.6 Hz, 1 H), 2.91 (ddd,
J = 14.4, 3.6, 0.6 Hz, 1 H), 2.78 (ddq, J = 7.8, 7.2, 6.6 Hz, 1 H), 2.42
(dd, J = 14.4, 4.8 Hz, 1 H), 2.14 (d, J = 3.0 Hz, 1 H), 2.07 (d, J = 3.6
Hz, 1 H), 2.00 (dd, J = 8.4, 4.2 Hz, 1 H), 1.99 (dd, J = 8.4, 3.6 Hz,
1 H), 1.08 (d, J = 6.6 Hz, 1 H).
13C NMR (150 MHz, CDCl3): d = 211.9, 74.0, 69.0, 44.5, 40.1, 36.9,
14.7.
HRMS (ESI): m/z calcd for [C7H12O3 + H]+: 145.0859; found:
145.0859.
1159, 1122, 1102, 1078, 1052, 1009, 952 cm–1.
1H NMR (600 MHz CD3OD): d = 8.33 (d, J = 9.0 Hz, 2 H), 8.22 (d,
J = 9.0 Hz, 2 H), 5.20 (ddd, J = 4.2, 2.4, 2.4 Hz, 1 H), 4.05 (dd,
J = 3.0, 3.0 Hz, 1 H), 3.65 (dd, J = 9.6, 3.6 Hz, 1 H), 3.39 (dd,
J = 9.6, 9.6 Hz, 1 H), 1.82 (m, 3 H), 1.07 (d, J = 6.0 Hz, 3 H).
13C NMR (150 MHz, CD3OD): d = 165.2, 152.3, 137.0, 131.9,
124.9, 76.3, 75.4, 74.8, 72.0, 34.1, 33.1, 18.5.
HRMS (ESI): m/z calcd for [C14H17O7 + Na]+: 334.0897; found:
334.0896.
5a-Carba-a-L-rhamnopyranose (ent-7)
tert-Butyl (1R,5R)-5-Methyl-4-oxocyclohex-2-enyl Carbonate
(ent-15)
To a solution of the ester 28 (25 mg, 0.08 mmol) in MeOH (1.5 mL)
was added LiOH (3.0 mg, 0.12 mmol) at r.t. The mixture was stirred
at r.t. for 4 h. Then aq sat. NH4Cl (0.5 mL) was added. This small
amount of mixture was directly loaded onto a silica gel column.
Elution with EtOAc–MeOH (10:1) afforded cyclitol ent-7 (11 mg,
Diol 23 (142 mg, 1.0 mmol) was dissolved in THF–CH2Cl2 (7.5
mL, 1:2) at r.t., into which DMAP (12 mg, 0.1 mmol) was added,
followed by the addition of a solution of Boc2O (870 mg, 4 mmol)
in CH2Cl2 (2.5 mL). The mixture was stirred at r.t. for 2 h, then
cooled down to 0 °C, diluted with Et2O (30 mL), and was then
quenched with aq sat. NaHCO3 (7 mL). The mixture was stirred at
0 °C for another 2 h and extracted with hexane–Et2O (1:2, 2 × 30
mL). The combined organic layers were washed with brine (7 mL)
and dried (Na2SO4). The solution was concentrated under reduced
pressure and the residue was redissolved in CH2Cl2 (6.5 mL) at
0 °C. To this solution was added Et3N (1.0 mL, 5 mmol) slowly.
The mixture was then stirred overnight at 0 °C and then for another
2 h at r.t. Then it was cooled back to 0 °C, diluted with hexane–Et2O
(1:1, 40 mL), and quenched with aq 0.5 M NaHSO4 (10 mL) at 0 °C.
The aqueous layer was extracted with hexane–Et2O (1:1, 2 × 40
mL). The combined organic layers were washed with aq 0.5 M
NaHSO4 (10 mL) at 0 °C, then washed with aq sat. NaHCO3 (10
mL), brine (10 mL), and dried (Na2SO4). The solution was concen-
trated under reduced pressure to afford a residue that was purified
by silica gel column chromatography. Elution with hexane–EtOAc
(10:1) gave enone ent-15 (200 mg, 90%) as a white solid; mp 37.5–
20
85%) as a colorless oil; Rf = 0.28 (EtOAc–MeOH, 5:1); [a]D
+11.38 (c 0.65, MeOH).
IR (film): 3297, 2922, 1455, 1406, 1377, 1296, 1239, 1186, 1153,
1050, 1002, 964 cm–1.
1H NMR (600 MHz, CD3OD): d = 3.87 (dd, J = 3.6, 3.6 Hz, 1 H),
3.83 (ddd, J = 3.0, 3.0, 3.0 Hz, 1 H), 3.62 (dd, J = 9.6, 3.0 Hz, 1 H),
3.26 (dd, J = 10.2, 9.6 Hz, 1 H), 1.78 (ddqd, J = 9.6, 9.6, 6.6, 6.6 Hz,
1 H), 1.59 (m, 2 H), 1.01 (d, J = 6.6 Hz, 3 H).
13C NMR (150 MHz, CD3OD): d = 76.9, 75.0, 74.3, 71.1, 35.9, 33.1,
18.6.
HRMS (ESI): m/z calcd for [C7H14O4 + Na]+: 185.0784; found:
185.0784.
Acknowledgment
We are grateful to NSF (CHE-0749451) and the ACS-PRF (47094-
AC1) for the support of our research program, and NSF-EPSCoR
(0314742) for a 600 MHz NMR at WVU.
20
38.9 °C; Rf = 0.44 (hexane–EtOAc, 4:1); [a]D +167.84 (c 1.0,
CHCl3).
IR (film): 2980, 2935, 2875, 1735, 1684, 1459, 1369, 1341, 1272,
1252, 1155, 1080, 1044, 965 cm–1.
References
1H NMR (600 MHz, CDCl3): d = 6.86 (dd, J = 10.2, 4.2 Hz, 1 H),
6.03 (d, J = 10.2 Hz, 1 H), 5.29 (ddd, J = 4.8, 4.8, 4.2 Hz, 1 H), 2.76
(dqd, J = 10.2, 7.2, 5.4 Hz, 1 H), 2.25 (dddd, J = 14.4, 4.8, 4.8, 0.6
Hz, 1 H), 2.06 (ddd, J = 14.4, 9.6, 4.8 Hz, 1 H), 1.49 (s, 9 H), 1.15
(d, J = 7.2 Hz, 3 H).
(1) Postema, M. H. D. C-Glycoside Synthesis, 1st ed.; CRC
Press: Boca Raton, 1995.
(2) Carbohydrate Mimics. Concepts and Methods; Chapleur,
Y., Ed.; Wiley-VCH: Weinheim, 1998.
(3) For a review on cyclitol chemistry, see: Arjona, O.; Gomez,
A. M.; Lopez, C.; Plumet, J. Chem. Rev. 2007, 107, 1919.
Synthesis 2008, No. 19, 3171–3179 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Cyclitols
3179
(4) For synthetic approaches to cyclitol published after ref. 3,
see: (a) Ortiz, J. C.; Ozores, L.; Cagide-Fagin, F.; Alonso, R.
Chem. Commun. 2006, 4239. (b) Chiara, J. L.; Garcia, A.;
Sesmilo, E.; Vacas, T. Org. Lett. 2006, 8, 3935.
(10) (a) Lipshutz, B. H.; Chrisman, W.; Noson, K.; Papa, P.;
Sclafani, J. A.; Vivian, R. W.; Keith, J. M. Tetrahedron
2000, 56, 2779. (b) Mahoney, W. S.; Stryker, J. M. J. Am.
Chem. Soc. 1989, 111, 8818.
(11) For a recent review, see: Kulinkovich, O. G. Chem. Rev.
2003, 103, 2597.
(12) (a) Ojima, I.; Kogure, T. Organometallics 1982, 1, 1390.
(b) Tojo, S.; Isobe, M. Synthesis 2005, 1237.
(13) For a review on Simmons–Smith cyclopropanation, see:
(a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev.
1993, 93, 1307. (b) Lautens, M.; Klute, W.; Tam, W. Chem.
Rev. 1996, 96, 49. (c) Lebel, H.; Marcoux, J.-F.; Molinaro,
C.; Charette, A. B. Chem. Rev. 2003, 103, 977.
(14) For acid and base opening, see ref. 11. For examples of acid-
catalyzed opening, see: (a) Schreiber, S. L.; Smith, D. B.;
Schulte, G. J. Org. Chem. 1989, 54, 5994. (b) Paquette, L.
A.; Ross, R. J.; Shi, Y. J. J. Org. Chem. 1990, 55, 1589.
For examples of base-catalyzed opening, see: (c) Barnier, J.
P.; Blanco, L.; Rousseau, G.; Guibe-Jampel, E.; Fresse, I.
J. Org. Chem. 1993, 58, 1570.
(15) Park, S.-B.; Cha, J. K. Org. Lett. 2000, 2, 147.
(16) Tarros, M. T.; Maycock, C. D.; Ventura, M. R. J. Org.
Chem. 1997, 62, 3984.
(17) For examples of the trapping of organometallic
intermediates with hydrogen, see: (a) Ngai, M.-Y.; Kong,
J.-R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063. (b) Iida,
H.; Krische, M. J. Top. Curr. Chem. 2007, 279, 77.
(c) Skucas, E.; Ngai, M.-Y.; Komanduri, V.; Krische, M. J.
Acc. Chem. Res. 2007, 40, 1394.
(c) Chakraborty, C.; Vyavahare, V. P.; Dhavale, D. D.
Tetrahedron 2007, 63, 11984. (d) Lysek, R.; Schutz, C.;
Favre, S.; O’Sullivan, A. C.; Pillonel, C.; Krulle, T.; Jung, P.
M. J.; Clotet-Codina, I.; Este, J.; Vogel, R. Bioorg. Med.
Chem. 2006, 14, 6355. (e) Corsaro, A.; Pistara, V.; Catelani,
G.; D’Andrea, F.; Adamo, R.; Chiacchio, M. A. Tetrahedron
Lett. 2006, 47, 6591. (f) Frigell, J.; Cumpstey, I.
Tetrahedron Lett. 2007, 48, 9073. (g) Sardinha, J.; Guieu,
S.; Deleuze, A.; Fernandez-Alonso, M. C.; Rauter, A. P.;
Sinay, P.; Marrot, J.; Jimenez-Babero, J.; Sollogoub, M.
Carbohydr. Res. 2007, 342, 1689. (h) Plumet, J.; Gomez, A.
M.; Lopez, J. C. Mini-Rev. Org. Chem. 2007, 4, 201.
(5) Zhou, M.; O’Doherty, G. A. Curr. Top. Med. Chem. 2008, 8,
114.
(6) An Achmatowicz reaction is the oxidative rearrangement of
furyl alcohols to 2-substituted 6-hydroxy-2H-pyran-3(6H)-
ones: (a) Achmatowicz, O.; Bielski, R. Carbohydr. Res.
1977, 55, 165. (b) Grapsas, I. K.; Couladouros, E. A.;
Georgiadis, M. P. Pol. J. Chem. 1990, 64, 823. For its use
in carbohydrate synthesis, see: (c) Harris, J. M.; Keranen,
M. D.; O’Doherty, G. A. J. Org. Chem. 1999, 64, 2982.
(d) Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young, V. G.;
O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17. For
examples of oligosaccharides, see: (e) Guo, H.; O’Doherty,
G. A. Angew. Chem. Int. Ed. 2007, 46, 5206. (f) Babu, R.
S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004,
126, 3428. (g) Zhou, M.; O’Doherty, G. A. Org. Lett. 2008,
10, 2283.
(7) The application of this approach to carbasugar 1-phosphates
has been communicated; the full development of this
methodology is reported here, see: Shan, M.; O’Doherty, G.
A. Org. Lett. 2008, 10, 3381.
(8) (a) Federspiel, M.; Fischer, R.; Hennig, M.; Mair, H.-J.;
Oberhauser, T.; Rimmler, G.; Albiez, T.; Bruhin, J.;
Estermann, H.; Gandert, C.; Gockel, V.; Gotzo, S.;
Hoffmann, U.; Huber, G.; Janatsch, G.; Lauper, S.; Rockel-
Stabler, O.; Trussardi, R.; Zwahlen, A. G. Org. Process Res.
Dev. 1999, 3, 266. (b) Trost, B. M.; Romero, A. G. J. Org.
Chem. 1986, 51, 2332. (c) Audia, J. E.; Boisvert, L.; Patten,
A. D.; Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1989,
54, 3738. (d) Barros, M. T.; Maycock, C. D.; Ventura, M. R.
J. Org. Chem. 1997, 62, 3984.
(18) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973.
(19) (a) Montchamp, J.-L.; Tian, F.; Hart, M. E.; Frost, J. W.
J. Org. Chem. 1996, 61, 3897. (b) Barros, M. T.; Maycock,
C. D.; Ventura, M. R. J. Chem. Soc., Perkin Trans. 1 2001,
166.
(20) (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118,
4492. (b) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996,
37, 4841. (c) Myers, A. G.; Zheng, B.; Movassaghi, M.
J. Org. Chem. 1997, 62, 7507. (d) Haukaas, M. H.;
O’Doherty, G. A. Org. Lett. 2002, 4, 1771. (e) Zhou, M.;
O’Doherty, G. A. Org. Lett. 2006, 8, 4339.
(21) (a) Mitsunobu, O.; Yamada, Y. Bull. Chem. Soc. Jpn. 1967,
40, 2380. (b) Mitsunobu, O. Synthesis 1981, 1.
(22) The optical rotations of compounds 7 and ent-7 prepared by
us were significantly higher than reported; however, the
remaining spectral data for compound 7 and ent-7 matched
those of the reported data for ent-7 prepared by Redlich et
al., see: Redlich, H.; Sudau, W.; Szadenings, A. K.;
Vollerthun, R. Carbohydr. Res. 1992, 226, 57.
(9) Tsuda, T.; Satomi, H.; Hayashi, T.; Saegusa, T. J. Org.
Chem. 1987, 52, 439.
Synthesis 2008, No. 19, 3171–3179 © Thieme Stuttgart · New York