Enantio- and diastereodivergent synthetic route to multifarious cyclitols from D-xylose via ring-closing metathesis

Article abstract of DOI:10.1055/s-2008-1067260

Short stereoselective syntheses of various cyclitols, including the derivatives of conduritol B, conduritol F, myo-inositol, and chiro-inositol have been accomplished. The key steps in the syntheses are a ring-closing metathesis process and a diastereodiv

Full text of DOI:10.1055/s-2008-1067260

3142
SPECIAL TOPIC
Enantio- and Diastereodivergent Synthetic Route to Multifarious Cyclitols
from D-Xylose via Ring-Closing Metathesis
S
ynthesis of Cycli
i
tols from
o
D
-Xylosevanni Luchetti,a Kejia Ding,b Marc d’Alarcao,*b Alexander Kornienko*a
a
Department of Chemistry, New Mexico Institute of Mining and Technology, Socorro, NM 87801, USA
Fax +1(575)8355364; E-mail: akornien@nmt.edu
b
Department of Chemistry, San José State University, One Washington Square, San José, CA 95192-0101, USA
Fax +1(408)9244945; E-mail: mdalarcao@science.sjsu.edu
Received 20 May 2008
Dedicated to Professor E. J. Corey on the occasion of his 80th birthday
availability in optically pure form and stereochemically
complex oxygenation patterns that can be relayed to their
target destinations in the desired cyclitols. Thus, D-glu-
cose,9 D-galactose,10 D-mannitol,11 and L-iditol,12 among
others, have served as starting points in efficient syntheses
of cyclitol derivatives. One of our research groups has re-
cently reported an enantiodivergent synthesis of (+)- and
(–)-cyclophellitol from D-xylose.13 Utilizing the latent
plane of symmetry present in the starting carbohydrate, al-
dehydes 1 and ent-1 were prepared as key intermediates
for this enantiodivergent strategy (Scheme 1). In this pa-
per, we show that this chemistry has a much broader scope
and provide a full account of the investigation resulting in
the development of synthetic pathways to diverse cycli-
tols starting from D-xylose and utilizing a ring-closing
metathesis reaction for carbocycle formation.14,15
Abstract: Short stereoselective syntheses of various cyclitols, in-
cluding the derivatives of conduritol B, conduritol F, myo-inositol,
and chiro-inositol have been accomplished. The key steps in the
syntheses are a ring-closing metathesis process and a diastereodi-
vergent organometallic addition to a D-xylose-derived aldehyde.
Key words: conduritol, inositol, Grignard, stereochemistry model,
chelation, Felkin–Anh, cyclophellitol, latent symmetry
The realization that inositols (hexahydroxycyclohexanes),
conduritols (tetrahydroxycyclohexenes) and their numer-
ous derivatives play important biological roles has made
their study an important endeavor in health-related scien-
ces.1 Thus, myo-inositol phosphates have been intensively
investigated for their role in intracellular signal transduc-
tion and calcium mobilization.1d,2 Both myo- and chiro-
inositols have been studied as components of inositol-
phosphoglycans (IPGs), believed to be important in insu-
lin signaling.3 It was discovered that various conduritols
act as modulators of insulin release4 and possess antifeed-
ant, antibiotic, anticancer, and growth-regulating activi-
ties.5 Conduritol epoxides, and more prominently fungal
metabolite cyclophellitol, are potent glycosidase inhibi-
tors and are under investigation as inhibitors of HIV infec-
tion and cancer metastasis.6
OBn
OBn
OBn
BnO
HO
OBn
O
BnO
O
OBn
BnO
OBn
O
ent-1
1
D-xylose
pro-enantiotopic
functionality
OH
OH
These and related research activities have generated con-
siderable synthetic effort directed at developing practical
preparations of the numerous biologically important cy-
clitols and their derivatives. Commercially available, in-
expensive myo-inositol has been a common starting point
in the syntheses of myo-inositol derivatives,7 while signif-
icantly more expensive naturally occurring methylated
chiro-inositols, pinitol, and quebrachitol, have been uti-
lized to prepare cyclitols with D- and L-chiro-inositol ste-
reochemical configurations, respectively.8 However,
labor-intensive selective hydroxyl protection/deprotec-
tion strategies and the necessity of optical resolution of ra-
cemic myo-inositol derivatives have led to utilization of
chiral pool starting materials for cyclitol syntheses. Of
these, carbohydrates represent a logical choice due to their
HO
OH
HO
OH
OH
O
O
OH
(+)-cyclophellitol
(−)-cyclophellitol
Scheme 1 Enantiodivergent strategy utilized in the synthesis of (+)-
and (–)-cyclophellitol from D-xylose
Transformation of aldehyde 1 to biologically important
conduritols and inositols can be achieved using a short
synthetic sequence that starts with a Grignard addition of
a vinylmetal reagent to generate an inseparable epimeric
mixture of alcohols 2 and 3 (Scheme 2). The ratio of the
two is highly dependent on the nature of the vinylmetal re-
agent, solvent and the presence of chelating salts. The
highest selectivity for syn-alcohol 2 (2:3 = 4.3:1) is at-
tained using vinylmagnesium bromide in CH2Cl2 at –78
°C,16 whereas a preponderance of anti-alcohol 3 is ob-
SYNTHESIS 2008, No. 19, pp 3142–3147
x
x.
x
x
.
2
0
0
8
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067260; Art ID: C03508SS
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of Cyclitols from D-Xylose
3143
Scheme 2 Syntheses of benzylated derivatives of conduritol B, conduritol F, myo-inositol, and chiro-inositol
served in the presence of 3 equivalents of MgBr2·OEt2 un- and 9 are consistent with those previously reported for
der the otherwise similar conditions (2:3 = 1:8).
these compounds by us18 and others.19
The stereochemical assignment of the syn and anti addi- We also found that conduritols 4 and 5 are excellent sub-
tion products was confirmed by their conversion into the strates for Mitsunobu inversion. Thus, the yield of a de-
corresponding tetrabenzyl ethers, whose NMR analysis sired conduritol, regardless of whether it is 4 or 5, can be
revealed the symmetry of the syn-alcohol-derived com- further improved by treating the minor unwanted epimer
pound. Although 2 and 3 can in principle be separated, for with Ph3P, p-nitrobenzoic acid (PNB), and diisopropyl
example, by converting them into the corresponding TIPS azodicarboxylate (DIAD) in diethyl ether to afford 4-ni-
ethers and then desilylating,17 direct treatment of their
mixture with the first-generation Grubbs’ ruthenium cata-
lyst gives chromatographically separable conduritols B
(4) and F (5). The facility of the metathesis process is re-
OBn
BnO
LiOH
Ph3P, DIAD
markable. TLC monitoring of the reaction progress re-
veals complete conversion seconds after the catalyst is
added to the reaction mixture. The overall yields of the
conduritol mixtures from aldehyde 1 are in the range of
85–90%, but the individual yields vary depending on the
conditions used to perform the Grignard reaction and they
are dependent on the ratio of intermediate alcohols 2 and
3.
BnO
5
4
THF–H2O
97%
PNB
89%
O
O
O2N
10
OBn
BnO
Conduritols 4 and 5 are further benzylated and dihydrox-
ylated to give myo- and chiro-inostiol derivatives 8 and 9
in good yields. While the C2-symmetry of 6 accounts for
the formation of only one possible cis-dihydroxy com-
pound 8, the facial preference of the dihydroxylation reac-
tion leading to the exclusive formation of 9 is noteworthy.
Evidently, the two vicinal benzyloxy substituents flanking
the olefin in 7 provide a strong steric bias resulting in the
observed stereochemical outcome. The NMR spectra of 8
Ph3P, DIAD
PNB
LiOH
BnO
5
4
O
THF–H2O
95%
94%
O
O2N
11
Scheme 3 Mitsunobu inversion interconverting conduritols 4 and 5
Synthesis 2008, No. 19, 3142–3147 © Thieme Stuttgart · New York

3144
G. Luchetti et al.
SPECIAL TOPIC
trobenzoates 10 and 11, which are smoothly hydrolyzed to Macdonald, Reetz, and more recently Evans and co-work-
5 and 4 respectively (Scheme 3).
ers, have reached similar conclusions in their investiga-
tions of Li- and Ti-based organometallic addition
reactions to a,b-dialkoxy aldehydes.20b,22 Literature re-
ports indicate that the selectivity can be switched from
anti to syn by replacing organolithium reagents with their
organomagnesium counterparts.20b,23 Due to the higher
chelating ability of Mg2+ the operative transition state for
these addition reactions should be D and the results of our
experiments with aldehyde 1 (entries 5, 6) are consistent
with this proposal. The replacement of Lewis basic ethe-
real solvents with CH2Cl2 should further strengthen the
metal coordination in transition state D and this is also
well-precedented in the literature.22a,24 Indeed complete
removal of THF from the commercial vinylmagnesium
bromide reagent and its substitution by CH2Cl2 gives the
highest syn selectivity we have been able to attain (entry
9).16
The diastereodivergence of this synthetic pathway arises
from the stereocontrol in the Grignard reaction of alde-
hyde 1 with vinylmagnesium bromide. Before the condi-
tions favoring the formation of 2 over 3 and vice versa
were found, extensive experimentation had been per-
formed and the observed general trends warrant a discus-
sion. Factors controlling the stereochemistry of
organometallic addition reactions with a-alkoxy, and
even a,b-dialkoxy aldehydes have been investigated in
some detail.20 However, such processes are considerably
more complicated in the case of carbohydrate-derived al-
dehydes, which may contain additional alkoxy groups ca-
pable of chelation.
Generally, researchers have interpreted the stereochemi-
cal outcomes of such reactions in terms of Felkin–Anh
(Figure 1a, transition state A), a-chelation (Figure 1b,
transition state C), and b-chelation (Figure 1c, transition
state E) models.20a When applied to aldehyde 1, these
models will be represented by transition states B, D and F,
which will lead to the formation of anti-, syn- and anti-
alcohols 3, 2, and 3, correspondingly.
Finally, we propose that the syn to anti switch that occurs
with increasing amounts of MgBr2·OEt2 (entries 10–12),
should be interpreted in terms of the b-chelation con-
trolled transition state E. Here, the second metal coordina-
tion event with the participation of a- and g-alkoxyl
groups leads to the reactive conformer F, in which the per-
pendicular geometry of Ca–OBn bond and coordination
of this a-alkoxyl to the metal would enhance the ‘Anh ef-
fect’. This hypothesis is in agreement with the results re-
ported by Martin and co-workers, who found that the
selectivity of organometallic addition to a a,b,g-trialkoxy-
aldehyde was crucially dependent on the protecting group
on the g-oxygen.25 The reaction stereochemistry was com-
pletely reversed when the nonchelating g-TBDPS ether
was replaced by the benzyloxy moiety, arguing in favor of
an a- to b-chelation switch similar to the one proposed in
this work.
OBn
(a)
OR'
O
H
3
H
O
OBn
H
H
R
BnO
Nu
Li
A
B
(b)
X
X
Mg
BnO
O
M
RO
O
H
BnO
2
RO
H
H
Although we found that the highest selectivities favoring
both syn- and anti-alcohols 2 and 3 are obtained in
CH2Cl2, the practicality of these procedures, especially
performed on a large scale, are somewhat undermined by
the side-reaction of the Grignard reagent with the solvent
and, therefore, the necessity to use a large excess of the re-
agent (20 equiv). The procedures involving the use of vi-
nyllithium in diethyl ether (2:3 = 1:3.5) and
vinylmagnesium bromide in CH2Cl2–THF (5:1)
(2:3 = 3:1) may be recommended for large-scale prepara-
tions.
MgX
H
Nu
OBn
C
D
(c)
MgX
Nu
X
R
Mg
O
3
Bn
M
O
O
X
O
O
O
OR
Mg X
X
Bn
Bn
R
F
E
In conclusion, a short synthetic route to a diverse group of
cyclitol derivatives has been developed. The synthesis is
enantiodivergent and allows for the preparation of various
derivatives of conduritols B and F as well as myo- and
Figure 1 Possible transition states governing the stereocontrol in
vinylmetal addition to aldehyde 1
It appears that the reaction can be channeled through B, D, chiro-inositols in both enantiomeric series. In addition,
or F by adjusting the chelating power of the reaction me- conduritol B derivative ent-4 served as a penultimate in-
dium.21 Nonchelating reagents would be expected to react termediate in the synthesis of (+)-cyclophellitol by Trost
through the Felkin–Anh transition state B, leading to the and co-workers.26 Therefore, our route provides another
selective formation of anti-alcohol 3. Our results with vi- strategy for an enantiodivergent synthesis of this inten-
sively researched anti-HIV and antimetastic agent and,
nyllithium (Table 1, entries 1–4) are consistent with this
more importantly, a library of its analogues in both enan-
interpretation and can be explained by the low chelating
ability of organolithium reagents in ethereal solvents. tiomeric series. Finally, we believe that our studies of the
Synthesis 2008, No. 19, 3142–3147 © Thieme Stuttgart · New York

SPECIAL TOPIC
Synthesis of Cyclitols from D-Xylose
3145
Table 1 Stereoselectivities of Vinylmetal Addition to Aldehyde 1
Entry
1
Vinylmetal reagent
vinyllithium
Solvent
Additive
Chelation
low
anti:syn 3:2
THF
12-crown-4
1.5:1
2.2:1
2.6:1
3.5:1
1:2
2
vinyllithium
THF
none
low
3
vinyllithium
THF
Me2S
low
4
vinyllithium
Et2O
none
low
5
vinylmagnesium bromide
vinylmagnesium bromide
vinylmagnesium bromide
vinylmagnesium bromide
vinylmagnesium bromide
vinylmagnesium bromide
vinylmagnesium bromide
vinylmagnesium bromide
THF–Et2O (1:1)
THF
none
medium
medium
medium
medium
medium
high
6
none
1:2
7
CH2Cl2–THF (1:1)
CH2Cl2–THF (5:1)
CH2Cl2
none
1:2
8
none
1:3
9
none
1:4.3
1:1
10
11
12
CH2Cl2
MgBr2·OEt2 (1 equiv)
MgBr2·OEt2 (2 equiv)
MgBr2·OEt2 (3 equiv)
CH2Cl2
high
2:1
CH2Cl2
high
8:1
(3S,4R,5R)-Tribenzyloxy-(6R)-hydroxycyclohexene (5)
stereochemical outcome of the vinylmetal addition to a
carbohydrate-derived aldehyde shed more light on these
generally poorly understood processes.
To a solution of aldehyde 1 (0.5 g, 1.2 mmol) in CH2Cl2 (11 mL)
was added MgBr2·OEt2 (0.92 g, 3.6 mmol) in one portion and the
mixture was stirred at r.t. for 30 min. To a cold (–78 °C) mixture
was added vinylmagnesium bromide in CH2Cl2 (24 mL of 1 M so-
lution, 24 mmol) over a period of 30 min. The mixture was stirred
at –78 °C for 3 h after which time MeOH (10 mL) was added. The
mixture was allowed to warm up to r.t. and treated with aq 1 M
NH4Cl (25 mL). The aqueous layer was extracted with CH2Cl2 (2 ×
25 mL) and the combined organic extracts were washed with H2O
(40 mL), brine (40 mL), and dried (MgSO4). The residue consisted
of a 1:8.5 (based on the integration of doublets at 2.61 and 3.15
ppm) mixture of 2 and 3, which was chromatographed (hexanes–
EtOAc, 6:1). To a solution of 2 and 3 (0.44 g, 1:8.5) in CH2Cl2 (40
mL) was added (Cy3P)2RuCl2(CHPh) (56 mg, 0.068 mmol) at r.t.
The mixture was stirred for 15 min and opened to the atmosphere
for 4 h. The solvent was evaporated and the residue chromato-
graphed (hexanes–Et2O, 1:1 → 1:2) to give 0.39 g (79%) of 5, pre-
ceded by 50 mg (10%) of 4; [a]D20 +39.3 (c 0.9, CHCl3).
Unless otherwise noted all commercially obtained reagents were
used without purification. THF was distilled from sodium ben-
zophenone ketyl prior to use. CH2Cl2 was distilled from CaCl2. Re-
actions were carried out under N2 in oven-dried glassware using
standard syringe, cannula, and septa techniques. Reactions were
monitored by TLC (Silica Gel 60 F254, 250 mm) and visualized with
UV light and ceric ammonium molybdate solution. Flash chroma-
tography was performed on silica gel (32–63 mm). Optical rotations
1
were measured with an Autopol III automatic polarimeter. H and
13C NMR spectra were recorded on Jeol 300 MHz spectrometer.
(3S,4R,5R)-Tribenzyloxy-(6S)-hydroxycyclohexene (4)
To a 1 M solution of vinylmagnesium bromide in CH2Cl2 (23 mL)
was added aldehyde 1 (0.5 g, 1.2 mmol) in CH2Cl2 (7 mL) dropwise
during 30 min at –78 °C. The mixture was stirred at that temperature
for 3 h, and MeOH (2 mL) was added to quench the excess of the
Grignard reagent. The mixture was warmed up to r.t. and washed
with H2O (10 mL), aq 1 M NH4Cl (10 mL), H2O (10 mL), and brine.
The organic layer was dried (MgSO4) and evaporated to dryness.
The residue consisted of a 4.3:1 (based on the integration of dou-
blets at 2.64 and 3.25 ppm) mixture of 2 and 3, which was chro-
matographed (hexanes–EtOAc, 6:1). To a solution of 2 and 3 (0.46
g, 4.3:1) in CH2Cl2 (40 mL) was added (Cy3P)2RuCl2(CHPh) (56
mg, 0.068 mmol) at r.t. The mixture was stirred for 15 min and
opened to the atmosphere for 4 h. The solvent was evaporated and
the residue chromatographed (hexanes–Et2O, 1:1 → 1:2) to give
0.35 g (70%) of 4, followed by 80 mg (16%) of 5; [a]D20 +123.3 (c
0.8, CHCl3).
1H NMR (CDCl3): d = 7.35–7.25 (m, 15 H), 5.88 (d, J = 1.9 Hz, 2
H), 4.94–4.66 (m, 6 H), 4.29 (m, 1 H), 4.10 (d, J = 7.4 Hz, 1 H), 4.50
(dd, J = 7.2, 9.7 Hz, 1 H), 3.56 (dd, J = 4.1, 9.7 Hz, 1 H), 2.71 (d,
J = 2.5 Hz, 1 H).
13C NMR (CDCl3): d = 138.8, 138.6, 138.2, 131.0, 128.6, 128.5,
128.1, 128.0, 127.8, 127.7, 127.0, 79.7, 79.1, 79.0, 75.2, 73.2, 72.0,
65.7.
HRMS (ESI): m/z calcd for C27H28O4 + Na (M + Na)+: 439.1885;
found: 439.1885.
(3S,4R,5R,6S)-Tetrabenzyloxycyclohexene (6)19
To a solution of 4 (7 mg, 0.017 mmol) in DMF (0.6 mL) was added
NaH (4 mg of 60% dispersion in mineral oil, 0.1 mmol) at 0 °C. The
mixture was stirred for 15 min after which time BnBr (5 mL, 0.04
mmol) was added and the resulting solution was stirred overnight.
Et2O (3 mL) was added and the excess of NaH was quenched with
aq 1 M NH4Cl (2 mL). The organic layer was washed with H2O (2
× 2 mL), dried (MgSO4), and evaporated. The residue was subjected
to a preparative chromatography plate (hexanes–EtOAc, 9:1) to
give 7.5 mg (88%) of 6, whose 1H NMR spectrum was identical to
that reported previously.19
1H NMR (CDCl3): d = 7.25–7.36 (m, 15 H), 5.70 (m, 2 H), 5.03 (d,
J = 11.3 Hz, 1 H), 4.92–4.25 (m, 5 H), 4.32–4.25 (m, 2 H), 3.79 (dd,
J = 7.4, 10.2 Hz, 1 H), 3.53 (dd, J = 8.0, 10.1 Hz, 1 H), 2.22 (d,
J = 3.9 Hz, 1 H).
13C NMR (CDCl3): d = 138.7, 138.3, 129.5, 128.7, 128.6, 128.5,
128.1, 128.0, 127.9, 127.8, 127.1, 84.4, 83.4, 80.6, 75.4, 72.4, 72.0.
HRMS (ESI): m/z calcd for C27H28O4 + Na (M + Na)+: 439.1885;
found: 439.1884.
Synthesis 2008, No. 19, 3142–3147 © Thieme Stuttgart · New York

3146
G. Luchetti et al.
SPECIAL TOPIC
(3S,4R,5R,6R)-Tetrabenzyloxycyclohexene (7)27
Hydrolysis of Esters 10 and 11
To a solution of 5 (8 mg, 0.019 mmol) in DMF (0.6 mL) was added
NaH (4 mg of 60% dispersion in mineral oil, 0.1 mmol) at 0 °C. The
mixture was stirred for 15 min after which time BnBr (5 mL, 0.04
mmol) was added and the resulting solution was stirred overnight.
Et2O (3 mL) was added and the excess of NaH was quenched with
aq 1 M NH4Cl (2 mL). The organic layer was washed with H2O (2
× 2mL), dried (MgSO4), and evaporated. The residue was subjected
to preparative TLC (hexanes–EtOAc, 9:1) to give 9 mg (94%) of 7,
To a stirred solution of 10 or 11 (20 mg, 0.035 mmol) in THF (0.5
mL) was added aq 1 M LiOH (0.5 mL). The reaction mixture was
stirred for 3 h at rt. The solvent was evaporated and the residue chro-
matographed (hexanes–EtOAc, 9:1) to yield pure 5 (14.1 mg, 97%)
or 4 (13.8 mg, 95%).
Acknowledgment
1
whose H NMR spectrum was identical to that reported previous-
ly.27
A.K. would like to acknowledge the financial support from the US
National Institutes of Health (RR-16480 and CA-99957) under the
BRIN/INBRE and AREA programs. M.D. acknowledges the finan-
cial support from the National Institutes of Health (DK-44589 and
GM-84819). The content is solely the responsibility of the authors
and does not necessarily represent the official views of the National
Institutes of Health.
3,4,5,6-Tetra-O-benzyl-D-myo-inositol (8)19
To a solution of 6 (6 mg, 0.012 mmol) and NMO (2 mg, 0.017
mmol) in acetone–H2O (9:1, 0.6 mL) was added a catalytic amount
of OsO4. The mixture was stirred for 3 d at r.t. and treated with Et2O
(3 mL). The organic layer was washed with aq 10% Na2S2O3 (2
mL), H2O (2 mL), dried (MgSO4), and evaporated. The residue con-
sisted of 8, which was >98% pure by TLC and 1H NMR spectrosco-
References
1
py (5.8 mg, 89%). H NMR spectrum of 8 was identical to that
reported previously.19
(1) (a) Posternak, T. Chemistry of the Cyclitols – The Cyclitols;
Hermann: Paris, 1965. (b) Hudlicky, T.; Cebulak, M.
Cyclitols and Derivatives. A Handbook of Physical, Spectral
and Synthetic Data; VCH: Weinheim, 1993. (c) Ferrier, R.
J.; Middleton, S. Chem. Rev. 1993, 93, 2779. (d)Billington,
D. C. The Inositol Phosphates – Chemical Synthesis and
Biological Significance; VCH: Weinheim, 1993.
(e) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A.
J. Chem. Rev. 1996, 96, 1195. (f) Gültekin, M. S.;Çelik, M.;
Balci, M. Curr. Org. Chem. 2004, 8, 1159.
1,2,3,4-Tetra-O-benzyl-L-chiro-inositol (9)18
To a solution of 7 (6 mg, 0.012 mmol) and NMO (2 mg, 0.017
mmol) in acetone–H2O (9:1, 0.6 mL) was added a catalytic amount
of OsO4. The mixture was stirred for 2 h at r.t. and treated with Et2O
(3 mL). The organic layer was washed with aq 10% Na2S2O3 (2
mL), H2O (2 mL), dried (MgSO4), and evaporated. The residue con-
1
sisted of 9, which was >98% pure by TLC and H NMR (5.9 mg,
93%). 1H NMR spectrum of 9 was identical to that reported previ-
ously.18
(2) Potter, B. V. L.; Lampe, D. Angew. Chem., Int. Ed. Engl.
1995, 34, 1933.
(3) See: Chakraborty, N.; d’Alarcao, M. Bioorg. Med. Chem.
2005, 13, 6732; and references cited therein.
(4) Billington, D. C.; Perron-Sierra, F.; Beaubras, S.; Duhault,
J.; Espinal, J.; Challal, S. Bioorg. Med. Chem. Lett. 1994, 4,
2307.
(5) (a) Balci, M.; Sütbeyaz, Y.; Seçen, H. Tetrahedron 1990, 46,
3715. (b) Balci, M. Pure Appl. Chem. 1997, 69, 97; and
references cited therein.
Mitsunobu Inversion of Conduritols 4 and 5
To a stirred solution of 4 or 5 (30 mg, 0.072 mmol) in Et2O (1.25
mL) was added PPh3 (19 mg, 0.072 mmol) and 4-nitrobenzoic acid
(12 mg, 0.072 mmol) at r.t. After the material had dissolved, DIAD
(17.7 mL, 0.074 mmol) was added to the mixture. After stirring for
17 h at r.t., the mixture was concentrated under reduced pressure
and the residue was chromatographed (hexanes–EtOAc, 9:1) to
yield pure 10 (37 mg, 89%) or 11 (39 mg, 94%).
(6) (a) Legler, G.; Herrchen, M. FEBS Lett. 1981, 135, 139.
(b) Atsumi, S.; Iinuma, H.; Nosaka, C.; Umezawa, K.
J. Antibiot. 1990, 43, 1579. (c) Atsumi, S.; Umezawa, K.;
Iinuma, H.; Naganawa, H.; Nakamura, H.; Iitaka, I.;
Takeuchi, T. J. Antibiot. 1990, 43, 49.
(7) Sureshan, K. M.; Shashidhar, M. S.; Praveen, T.; Das, T.
Chem. Rev. 2003, 103, 4477.
(8) Kiddle, J. J. Chem. Rev. 1995, 95, 2189.
(9) See, for example: Saito, S.; Shimazawa, R.; Shirai, R. Chem.
Pharm. Bull. 2004, 52, 727.
(10) See, for example: Dubreuil, D.; Cleophax, J.; de Almeida,
M. V.; Verre-Sebrié, C.; Liaigre, J.; Vass, G.; Géro, S. D.
Tetrahedron 1997, 53, 16747.
(11) See, for example: Chiara, J. L.; Martín-Lomas, M.
Tetrahedron Lett. 1994, 35, 2969.
(12) See, for example: Guidot, J. P.; Le Gall, T.; Mioskowski, C.
Tetrahedron Lett. 1994, 35, 6671.
(13) Kireev, A. S.; Breithaupt, A. T.; Collins, W.; Nadein, O. N.;
Kornienko, A. J. Org. Chem. 2005, 70, 742.
(14) For preliminary account of this work, see: Kornienko, A.;
d’Alarcao, M. Tetrahedron: Asymmetry 1999, 10, 827.
(15) For other examples of utilization of ring-closing metathesis
in cyclitol synthesis, see: (a) Verhelst, S. H. L.; Wennekes,
T.; van der Marel, G. A.; Overkleeft, H. S.; van Boeckel, C.
A. A.; van Boom, J. H. Tetrahedron 2004, 60, 2813.
(b) Andersen, T. L.; Skytte, D. M.; Madsen, R. Org. Biomol.
Chem. 2004, 2, 2951. (c) Heo, J. N.; Holson, E. B.; Roush,
(1R,4S,5R,6R)-4,5,6-Tris(benzyloxy)cyclohex-2-enyl 4-Nitro-
benzoate (10)
[a]D20 –114.3 (c 0.1, CHCl3).
1H NMR (CDCl3): d = 8.28 (d, J = 8.5 Hz, 2 H), 8.18 (d, J = 8.5, 2
H), 7.36–7.23 (m, 15 H), 6.04–5.87 (m, 3 H), 4.99–4.67 (m, 6 H),
4.16–4.04 (m, 2 H), 3.73 (dd, J = 3.0, 9.9 Hz, 1 H).
13C NMR (CDCl3): d = 164.3, 150.6, 138.6, 138.2, 138.0, 135.7,
134.2, 131.0, 128.8, 128.6, 128.4, 128.2, 128.0, 127.8, 123.6, 123.1,
79.8, 78.4, 77.9, 77.3, 75.3, 72.8, 68.3.
HRMS (ESI): m/z calcd for C34H31NO7 + Na (M + Na)+: 588.1998;
found: 588.1982.
(1S,4S,5R,6R)-4,5,6-Tris(benzyloxy)cyclohex-2-enyl 4-Nitro-
benzoate (11)
[a]D20 +156.8 (c 0.05, CHCl3).
1H NMR (CDCl3): d = 8.24 (d, J = 8.8 Hz, 2 H), 8.02 (d, J = 8.8 Hz,
2 H), 7.36–7.10 (m, 15 H), 5.83 (m, 2 H), 5.64 (d, J = 10.5 Hz, 1 H),
4.98–4.67 (m, 6 H), 4.30 (dd, J = 2.8, 4.7 Hz, 1 H), 3.93–3.85 (m, 2
H).
13C NMR (CDCl3): d = 164.1, 150.6, 138.5, 138.1, 135.3, 130.9,
130.0, 128.6, 128.5, 128.4, 128.1, 128.1, 127.9, 127.7, 125.4, 123.5,
83.8, 81.1, 79.8, 77.5, 75.8, 75.7, 72.7.
HRMS (ESI): m/z calcd for C34H31NO7 + Na (M + Na)+: 588.1998;
found: 588.1995.
Synthesis 2008, No. 19, 3142–3147 © Thieme Stuttgart · New York

SPECIAL TOPIC
W. R. Org. Lett. 2003, 5, 1697. (d) Marco-Contelles, J.;
Synthesis of Cyclitols from D-Xylose
3147
(18) Kornienko, A.; Marnera, G.; d’Alarcao, M. Carbohydr. Res.
1998, 310, 141.
de Opazo, E. J. Org. Chem. 2002, 67, 3705. (e) Conrad, R.
M.; Grogan, M. J.; Bertozzi, C. R. Org. Lett. 2002, 4, 1359.
(f) Boyer, F.-D.; Hanna, I.; Nolan, S. P. J. Org. Chem. 2001,
66, 4094. (g) Jorgensen, M.; Iversen, E. H.; Paulsen, A. L.;
Madsen, R. J. Org. Chem. 2001, 66, 4630. (h) Nishikawa,
A.; Saito, S.; Hashimoto, Y.; Koga, K.; Shirai, R.
Tetrahedron Lett. 2001, 42, 9195. (i) Hanna, I.; Ricard, L.
Org. Lett. 2000, 2, 2651. (j) Marco-Contelles, J.; de Opazo,
E. J. Org. Chem. 2000, 65, 5416. (k) Marco-Contelles, J.;
de Opazo, E. Tetrahedron Lett. 2000, 41, 2439.
(19) Yamauchi, N.; Kakinuma, K. J. Antibiot. 1992, 45, 756.
(20) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.
(b) Mead, K.; Macdonald, T. L. J. Org. Chem. 1985, 50, 422.
(21) Both the organometallic reagent and the reaction solvent are
important since Lewis basic solvents such as THF or Et2O
can diminish chelation by strongly coordinating to the metal
species.
(22) (a) Reetz, M. T.; Kesseler, K. J. Org. Chem. 1985, 50, 5436.
(b) Evans, D. A.; Cee, V. J.; Siska, S. J. J. Am. Chem. Soc.
2006, 128, 9433.
(23) Mead, K. T. Tetrahedron Lett. 1987, 28, 1019.
(24) (a) Keck, G. E.; Andrus, M. B.; Romer, D. R. J. Org. Chem.
1991, 56, 417. (b) Guillarme, S.; Haudrechy, A.
Tetrahedron Lett. 2005, 46, 3175.
(25) Martin, S. F.; Chen, H.-J.; Yang, C.-Y. J. Org. Chem. 1993,
58, 2867.
(l) Kapferer, P.; Sarabia, F.; Vasella, A. Helv. Chim. Acta
1999, 82, 645. (m) Sellier, O.; Van de Weghe, P.; Eustache,
J. Tetrahedron Lett. 1999, 40, 5859. (n) Seepersaud, M.;
Al-Abed, Y. Org. Lett. 1999, 1, 1463.
(16) After our original disclosure of these results (ref. 14),
Madsen and co-workers reported that performing this
reaction with vinylmagnesium chloride in toluene leads to a
higher (5:1) syn selectivity (ref. 15b).
(17) Luchetti, G.; Ding, K.; Kornienko, A.; d’Alarcao, M.
Synthesis 2008, 3148.
(26) Trost, B. M.; Hembre, E. J. Tetrahedron Lett. 1999, 40, 219.
(27) Ackermann, L.; Tom, D. E.; Fürstner, A. Tetrahedron 2000,
56, 2195.
Synthesis 2008, No. 19, 3142–3147 © Thieme Stuttgart · New York