Facile enantiospecific synthesis of dihydroconduritols E and F

Article abstract of DOI:10.1055/s-2008-1067261

An enantiospecific synthesis of cyclohexane-1,2,3,4-tetrols was accomplished from L-(+)-tartaric acid. Pivotal steps in the synthetic sequence include zinc-mediated Boord-type fragmentation of an acetonide, ring-closing metathesis (RCM), and osmium-mediat

Full text of DOI:10.1055/s-2008-1067261

SPECIAL TOPIC
3155
Facile Enantiospecific Synthesis of Dihydroconduritols E and F
F
acile Synthesis of
a
D
ihydroco
v
nduritol E an
i
d
F
rayani R. Prasad,* Amit B. Pawar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Fax +91(80)23600529; E-mail: prasad@orgchem.iisc.ernet.in
Received 15 May 2008
OH
OH
OH
OH
OH
Abstract: An enantiospecific synthesis of cyclohexane-1,2,3,4-
tetrols was accomplished from L-(+)-tartaric acid. Pivotal steps in
the synthetic sequence include zinc-mediated Boord-type fragmen-
tation of an acetonide, ring-closing metathesis (RCM), and osmi-
HO
OH
OH
HO
HO
OH
OH
HO
HO
OH
OH
HO
OH
OH
um-mediated dihydroxylation.
cyclohexanetetrol
conduritol
quercitol
inositol
Key words: cyclitols, ring-closing metathesis, tartaric acid, Boord
fragmentation
OH
OH
OH
OH
OH
HO
HO
HO
HO
OH
OH
OH
Owing to their diverse biological activity and importance
as synthetic intermediates in organic synthesis, cyclitols
have been a topic of interest in recent years.1 Naturally oc-
curring cyclohex-5-ene-1,2,3,4-tetrols (conduritols) are
inhibitors of glycosidases and a number of derivatives of
conduritols have been found to possess biological activi-
ty.2 Considerable effort from a number of synthetic
groups has been directed towards the asymmetric synthe-
sis of conduritols including constrained analogues
(Figure 1).3 While racemic synthesis of these compounds
is reported either by oxidation of cyclohexadienes,4 or by
the reduction of the epoxy peroxides derived from cyclo-
hexadienes,5 very few approaches are reported in the liter-
ature for the enantioselective synthesis of dihydro-
conduritols. Methods for the asymmetric synthesis of cy-
clohexanetetrols include the direct reduction of conduri-
tols,6 ring opening of chiral oxabicycles,7 stereoselective
oxyselenylation of cyclohexenyl ethers,8 and the
OH
OH
OH
OH
1
2
3: conduritol F
4: conduritol E
1: dihydroconduritol F
2: dihydroconduritol E
Figure 1 Conduritols and dihydroconduritols
OMOM
OMOM
O
R2
HO
R1
I
1, 2
O
OMOM
5a R1 = OH, R2 = H
5b R1 = H, R2 = OH
6
7
O
O
O
O
Me
N
MeO
MeO
N
N
Me
OMe
Me
O
OH
8
O
O
9
chemoenzymatic synthesis reported by Hudlicky et al.9 Scheme 1 Retrosynthesis of cyclitols 1 and 2
Herein, we disclose our efforts towards the enantiospecif-
ic synthesis of dihydroconduritols.
Protection of the hydroxy group as the methoxymethyl
ether 11, followed by reduction of the Weinreb amide in
11 with sodium borohydride furnished the alcohol 12 in
94% yield. Treatment of 12 with triphenylphosphine/imi-
dazole and iodine afforded the iodide 7 in 86% yield. Re-
action of 7 with zinc in refluxing ethanol cleanly produced
the diene 6 in 94% yield (Scheme 2).
Our approach to the synthesis of dihydroconduritols 1 and
2 was based on the dihydroxylation of the cyclohexene
derivative 5. The synthesis of 5 was anticipated from ring-
closing metathesis (RCM) of diene 6. Formation of the di-
ene 6 was envisioned by Boord-type fragmentation10 of
the acetonide iodide 7. g-Hydroxybutyramide 8, derived
from the bis-Weinreb amide of tartaric acid 9, was identi-
fied as the precursor for the synthesis of iodide 7
(Scheme 1).
Protection of the free hydroxy group in 6 as the corre-
sponding silyl ether 13 was affected with tert-butyldi-
methylsilyl triflate in presence of pyridine. Ring-closing
metathesis12 of 13 with the Grubbs 1st generation catalyst
furnished the cyclohexene 14 in 84% yield. Osmium-
mediated dihydroxylation of 14 afforded the correspond-
ing diol 15 in good yield. Deprotection of the silyl group
as well as the methoxymethyl group in 15 with trifluoro-
acetic acid resulted in the cyclitol 1 (dihydroconduritol F)
in 93% yield. Spectral and physical data of the compound
is in agreement with that reported in literature7
(Scheme 3).
Accordingly, the synthetic sequence commenced with the
controlled addition of but-3-enylmagnesium bromide to
the bis-Weinreb amide 9,11 resulting in the g-oxobutyr-
amide 10 in 90% yield. Stereoselective reduction of the
keto group in 10 with K-Selectride furnished alcohol 8.
SYNTHESIS 2008, No. 19, pp 3155–3159
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067261; Art ID: C03308SS
x
x.
x
x
.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

3156
K. R. Prasad, A. B. Pawar
SPECIAL TOPIC
OMOM
OMOM
Ph3P, PNBA, DIAD, THF
O
O
PO
HO
O
O
Me
N
Grubbs catalyst
CH2Cl2, r.t., 2 h
94%
MgBr
THF, −15 °C
MeO
MeO
N
N
0 °C to r.t., 1 h, 60%
P = p-nitrobenzoyl
OMe
0.5 h, 90%
Me
O
O
Me
O
9
O
16
6
10
O
O
OH
MOMO
MOMO
PO
MOM-Cl, DIPEA
i) K2CO3, MeOH
r.t., 0.5 h, 90%
ii) Amberlyst-15
MeOH, r.t.
OsO4, NMO
K-Selectride
THF, −78 °C
2 h
MeO
HO
HO
PO
N
DMAP, CH2Cl2, 40 °C, 6 h
70% for two steps
THF–H2O
0 °C to r.t.
24 h, 92%
Me
O
OH
8
HO
17
OH
2
OH
18
4 h, 88%
O
O
O
NaBH4, MeOH
MeO
Scheme 4 Synthesis of dihydroconduritol E (2)
N
HO
0 °C to r.t., 2 h, 94%
Me
O
OMOM
11
O
OMOM
12
OMOM
O
HO
Zn dust
Ph3P, Imidazole
I2, toluene, ∆
4 h, 86%
I
EtOH, ∆, 5 h
O
OMOM
94%
6
7
Scheme 2 Synthesis of 3-hydroxy-4-(methoxymethoxy)octa-1,7-
diene 6
OMOM
OMOM
HO
PO
Grubbs catalyst
CH2Cl2, r.t., 6 h
84%
TBDMSOTf
pyridine, CH2Cl2
0 °C, 1 h, 92%
Figure 2
13
6
P = TBDMS
Column chromatography was performed on silica gel (Acme grade
100–200 mesh), petroleum ether = PE. TLC plates were visualized
either with UV, or in an I2 chamber, or with phosphomolybdic acid
spray, unless noted otherwise. Unless stated otherwise, all reagents
were purchased from commercial sources and used without addi-
tional purification. THF was freshly distilled over Na/benzophe-
none ketyl. Melting points were uncorrected. Unless stated
otherwise, all the reactions were performed under an inert atmo-
sphere.
OH
OMOM
OsO4, NMO
THF–H2O
OMOM
HO
PO
HO
PO
TFA
0 °C to r.t., 24 h
92%
CH2Cl2, r.t.
4 h, 93%
HO
OH
1
14
OH
15
Scheme 3 Synthesis of dihydroconduritol F (1)
(4R,5R)-N-Methoxy-N,2,2-trimethyl-5-(pent-4-enoyl)-1,3-diox-
olane-4-carboxamide (10)
After successfully accomplishing the synthesis of dihy-
droconduritol F (1), synthesis of dihydroconduritol E (2),
was undertaken. Thus, the reaction of 6 under Mitsunobu
conditions13 proceeded smoothly to afford the 4-nitroben-
zoyl ester 16 in 60% yield. Ring-closing metathesis of 16
with the Grubbs 1st generation catalyst furnished the cy-
clohexene 17 in excellent yield. Osmium-mediated dihy-
droxylation of the diene gave the diol 18 in 92% yield; the
stereochemistry of 18 was further proved by X-ray crystal
structure analysis (Figure 2).14 Deprotection of the 4-ni-
trobenzoyl ester and the methoxymethyl ether provided
dihydroconduritol E (2) in 79% yield for two steps
(Scheme 4).
In an oven-dried, two-neck, 50-mL round-bottom flask equipped
with magnetic stirrer bar and argon inlet was placed the bis-Wein-
reb amide 9 (0.5 g, 1.8 mmol) dissolved in THF (6 mL). The soln
was cooled to –15 °C and 1 M but-3-enylmagnesium bromide in
THF (3 mL, 3 mmol) was added dropwise under argon. The mixture
was stirred for 30 min, quenched with sat. NH4Cl (3 mL) and ex-
tracted with Et2O (2 × 15 mL). The combined ethereal layers were
washed with brine, dried (Na2SO4), and the solvent was evaporated.
The residue was purified by column chromatography (PE–EtOAc,
7:3) to afford 10 (0.44 g, 90%) as a colorless oil.
[a]D +4.4 (c 3.6, CHCl3).
IR (neat): 3079, 2987, 1720, 1670, 1457, 1442, 1382, 1157, 1081,
995 cm–1.
In conclusion, facile synthesis of dihydroconduritol F and
dihydroconduritol E was accomplished from tartaric acid.
Pivotal reactions include Boord-type fragmentation of an
iodo acetonide to afford a 3,4-dihydroxyocta-1,7-diene
and subsequent ring-closing metathesis of the diene. The
approach described is amenable for the synthesis of higher
analogues such as cycloheptane- and cyclooctanetetrols.
1H NMR (300 MHz, CDCl3): d = 5.82 (ddt, J = 16.8, 10.5, 6.3 Hz,
1 H), 5.10–4.95 (m, 3 H), 4.83 (d, J = 4.5 Hz, 1 H), 3.71 (s, 3 H),
3.24 (s, 3 H), 2.83 (dt, J = 18.0, 7.2 Hz, 1 H), 2.70 (dt, J = 18.0, 7.2
Hz, 1 H), 2.42–2.29 (m, 2 H), 1.49 (s, 3 H), 1.44 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 207.4, 169.6, 136.6, 115.3, 112.7,
82.1, 73.8, 61.6, 38.3, 32.4, 26.9, 26.6, 26.1.
HRMS: m/z [M + Na]+ calcd for C13H21NNaO5: 294.1317; found:
294.1309.
Synthesis 2008, No. 19, 3155–3159 © Thieme Stuttgart · New York

SPECIAL TOPIC
Facile Synthesis of Dihydroconduritols E and F
3157
(4R,5S)-N-Methoxy-5-[(R)-1-(methoxymethoxy)pent-4-enyl]-
N,2,2-trimethyl-1,3-dioxolane-4-carboxamide (11)
(0.78 g, 3.1 mmol) at r.t. and the mixture was stirred under reflux
for 4 h. When the reaction was complete (TLC), the mixture was
cooled to r.t., poured into H2O (10 mL), and extracted with Et2O
(3 × 20 mL). The combined organic layers were washed with brine
(30 mL) and sat. Na2S2O3 (10 mL), dried (Na2SO4), and the solvent
was evaporated. Column chromatography of the residue (silica gel,
PE–Et2O, 96:4) gave the iodide 7 (0.49 g, 86%) as a colorless oil.
[a]D –14.2 (c 1, CHCl3).
IR (neat): 2933, 1641, 1452, 1371, 1218, 1033, 917, 887, 772 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.86 (ddt, J = 16.7, 10.5, 6.7 Hz,
1 H), 5.14–5.00 (m, 2 H), 4.77, 4.72 (2 d, J = 6.8 Hz, 2 H), 4.01–
3.85 (m, 2 H), 3.81–3.70 (m, 1 H), 3.47–3.40 (m, 1 H), 3.45 (s, 3 H),
3.32 (dd, J = 10.4, 4.9 Hz, 1 H), 2.30–2.14 (m, 2 H), 1.83–1.64 (m,
2 H), 1.50 (s, 3 H), 1.47 (s, 3 H).
To a soln of 10 (0.8 g, 2.9 mmol) in anhyd THF (8 mL) at –78 °C
was added 1 M K-Selectride in THF (4.4 mL, 4.4 mmol) dropwise
over 10 min under argon and the mixture was stirred at –78 °C for
2 h. When the reaction was complete (TLC), it was cautiously
quenched by addition of MeOH and then poured into H2O (10 mL)
and extracted with EtOAc (2 × 15 mL). The combined organic lay-
ers were washed with brine, dried (Na2SO4), and the solvent was
evaporated. The residue was purified by column chromatography
(silica gel, PE–EtOAc, 6:4) afforded the alcohol 8 (0.65 g, 80%) as
a colorless oil. The alcohol was isolated with traces of K-Selectride
impurity and was used as such in the next step.
To a soln of alcohol 8 (0.6 g, 2.2 mmol) in anhyd CH2Cl2 (15 mL)
at 0 °C were added DIPEA (1.14 mL, 6.6 mmol), DMAP (54 mg,
0.44 mmol), and MOMCl (0.32 mL, 4.4 mmol). The mixture was
stirred at 0 °C for 15 min and then heated to 40 °C and stirred for 6
h. When the reaction was complete (TLC), it was cooled to r.t.,
poured into H2O (15 mL), and extracted with Et2O (3 × 25 mL). The
combined ethereal extracts were washed with brine (30 mL), dried
(Na2SO4), and the solvent was evaporated. The residue was subject-
ed to column chromatography (silica gel, PE–EtOAc, 7:3) to give
11 (0.6 g, 86%) as a colorless oil.
13C NMR (100 MHz, CDCl3): d = 137.9, 115.3, 109.4, 96.7, 82.0,
76.0, 75.7, 56.2, 30.1, 29.9, 27.5, 27.2, 7.2.
HRMS: m/z [M + Na]+ calcd for C13H23INaO4: 393.0539; found:
393.0538.
(3R,4R)-4-(Methoxymethoxy)octa-1,7-dien-3-ol (6)
To a soln of iodide 7 (0.45 g, 1.21 mmol) in abs EtOH (20 mL) was
added Zn dust (0.63 g, 9.7 mmol) at r.t. and the mixture was stirred
at 80 °C for 5 h (TLC monitoring). When the reaction was complete,
the mixture was filtered through a short pad of Celite and the Celite
pad was washed with Et2O (2 × 15 mL) and the solvent was evapo-
rated. Column chromatography of the residue (silica gel, PE–
EtOAc, 7:3) furnished 6 (0.21 g, 94%) as a colorless oil.
[a]D –4.8 (c 1.1, CHCl3).
IR (neat): 2986, 2938, 1668, 1455, 1371, 1256, 1216, 1032, 917
cm–1.
1H NMR (400 MHz, CDCl3): d = 5.81 (ddt, J = 16.9, 10.2, 6.6 Hz,
1 H), 5.07–4.95 (m, 2 H), 4.80–4.72 (m, 1 H), 4.75, 4.65 (2 d,
J = 6.8 Hz, 2 H), 4.61–4.52 (m, 1 H), 3.75 (s, 3 H), 3.75–3.67 (m, 1
H), 3.39 (s, 3 H), 3.22 (s, 3 H), 2.26–2.08 (m, 2 H), 1.71–1.60 (m, 2
H), 1.47 (s, 3 H), 1.44 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.5, 138.1, 115.0, 111.2, 96.7,
79.4, 76.6, 73.2, 61.8, 55.9, 32.3, 30.4, 29.6, 27.0, 26.2.
[a]D –10.7 (c 1, CHCl3).
IR (neat): 3460, 2931, 1641, 1443, 1215, 1033, 995, 918, 837 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.92–5.72 (m, 2 H), 5.40–5.19 (m,
2 H), 5.06–4.95 (m, 2 H), 4.74, 4.68 (2 d, J = 6.8 Hz, 2 H), 4.04 (t,
J = 6.2 Hz, 1 H), 3.42 (s, 3 H), 3.25 (br s, 1 H), 2.26–2.05 (m, 2 H),
1.74–1.50 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 138.0, 137.2, 116.9, 114.9, 97.4,
83.0, 74.7, 55.8, 30.4, 29.4.
HRMS: m/z [M + Na]+ calcd for C10H18NaO3: 209.1154; found:
209.1155.
HRMS: m/z [M + Na]+ calcd for C15H27NNaO6: 340.1736; found:
340.1750.
(4S,5S)-4-(Hydroxymethyl)-5-[(R)-1-(methoxymethoxy)pent-4-
enyl]-2,2-dimethyl-1,3-dioxolane (12)
To a soln of 11 (0.55 g, 1.73 mmol) in MeOH (5 mL) cooled to 0 °C
was added NaBH4 (0.13 g, 3.5 mmol) portionwise over a period of
15 min and the mixture was stirred at r.t. for 2 h. It was quenched
by cautious addition of H2O (5 mL), poured into H2O (10 mL), and
extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with brine (30 mL), dried (Na2SO4), and the solvent
was evaporated. Column chromatography of the residue (silica gel,
PE–EtOAc, 7:3) afforded 12 (0.43 g, 94%) as a colorless oil.
(3R,4R)-3-(tert-Butyldimethylsiloxy)-4-(methoxymethoxy)octa-
1,7-diene (13)
To a precooled (0 °C) soln of alcohol 6 (0.1 g, 0.53 mmol) in anhyd
CH2Cl2 (2 mL) was added pyridine (0.11 mL, 1.3 mmol) and
TBDMSOTf (0.15 mL, 0.63 mmol) and the mixture was stirred at 0
°C for 1 h. The mixture was then poured into H2O (10 mL) and ex-
tracted with Et2O (3 × 15 mL). Combined ethereal extracts were
washed with brine (20 mL), dried (anhyd Na2SO4) and the solvent
was evaporated. Column chromatography of the residue (silica gel,
PE–EtOAc, 95:5) afforded 13 (0.15 g, 92%) as a colorless oil.
[a]D +4.7 (c 1, CHCl3).
IR (neat): 3488, 2931, 1641, 1442, 1379, 1250, 1034, 916, 883, 740
cm–1.
1H NMR (400 MHz, CDCl3): d = 5.83 (ddt, J = 16.9, 10.3, 6.7 Hz,
1 H), 5.10–4.98 (m, 2 H), 4.77, 4.70 (2 d, J = 6.8 Hz, 2 H), 4.05 (dt,
J = 8.3, 4.1 Hz, 1 H), 3.98 (dd, J = 8.3, 4.5 Hz, 1 H), 3.84–3.65 (m,
3 H), 3.43 (s, 3 H), 2.57 (br s, 1 H), 2.32–2.11 (m, 2 H), 1.80–1.59
(m, 2 H), 1.44 (s, 3 H), 1.42 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 137.9, 115.1, 108.9, 97.0, 78.7,
77.3, 76.6, 62.6, 56.0, 29.9, 29.8, 27.1, 27.0.
[a]D +58.7 (c 1.1, CHCl3).
IR (neat): 2954, 2932, 1641, 1472, 1254, 1136, 1034, 920, 862 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.93–5.85 (m, 1 H), 5.81 (ddt,
J = 16.9, 10.4, 6.9 Hz, 1 H), 5.29–5.13 (m, 2 H), 5.05–4.92 (m, 2 H),
4.80, 4.65 (2 d, J = 6.7 Hz, 2 H), 4.24 (t, J = 5.2 Hz, 1 H), 3.51–3.40
(m, 1 H), 3.40 (s, 3 H), 2.24–2.17 (m, 1 H), 2.14–2.02 (m, 1 H),
1.73–1.60 (m, 1 H), 1.46–1.34 (m, 1 H), 0.90 (s, 9 H), 0.06 (s, 3 H),
0.04 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 138.6, 137.3, 115.7, 114.6, 97.4,
81.0, 74.7, 55.7, 30.0, 29.1, 25.8, 18.2, –4.7, –4.9.
HRMS: m/z [M + Na]+ calcd for C16H32NaO3Si: 323.2018; found:
323.2022.
HRMS: m/z [M + Na]+ calcd for C13H24NaO5: 283.1521; found:
283.1518.
(4R,5S)-4-(Iodomethyl)-5-[(R)-1-(methoxymethoxy)pent-4-
enyl]-2,2-dimethyl-1,3-dioxolane (7)
To a soln of 12 (0.4 g, 1.53 mmol) in anhyd toluene (20 mL) was
added Ph3P (1.2 g, 4.6 mmol), imidazole (0.31 g, 4.6 mmol), and I2
Synthesis 2008, No. 19, 3155–3159 © Thieme Stuttgart · New York

3158
K. R. Prasad, A. B. Pawar
SPECIAL TOPIC
(3R,4R)-3-(tert-Butyldimethylsiloxy)-4-(methoxymethoxy)cy-
clohex-1-ene (14)
(3S,4R)-4-(Methoxymethoxy)-3-(4-nitrobenzoyl)octa-1,7-diene
(16)
To a soln of 13 (0.13 g, 0.43 mmol) in anhyd CH2Cl2 (10 mL) was
added Grubbs 1st generation catalyst (36 mg, 0.043 mmol) under
argon. The mixture was stirred at r.t. for 6 h until completion (TLC).
The mixture was passed through a short pad of silica gel. The silica
gel pad was washed with Et2O (2 × 15 mL) and the solvent was
evaporated. The crude residue was subjected to column chromatog-
raphy (silica gel, PE–Et2O, 9:1) to afford 14 (0.1 g, 84%) as a col-
orless oil.
To a precooled (0 °C) soln of 6 (0.1 g, 0.53 mmol) in anhyd THF (5
mL) was added Ph3P (0.28 g, 1.08 mmol) and 4-nitrobenzoic acid
(0.18 g, 1.08 mmol) under argon and the mixture was stirred for 10
min. DIAD (0.16 mL, 0.8 mmol) was added over a period of 15 min
at 0 °C and then the mixture was warmed up to r.t. and stirred for 1
h. When the reaction was complete (TLC), the volatiles were re-
moved under reduced pressure and the crude residue obtained was
purified by column chromatography (silica gel, PE–EtOAc, 9:1) to
afford 16 (0.11 g, 60%) as a colorless oil.
[a]D –51.0 (c 1, CHCl3).
IR (neat): 2954, 2930, 1472, 1150, 1050, 921, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.76–5.67 (m, 1 H), 5.56–5.47 (m,
1 H), 4.76, 4.70 (2 d, J = 6.7 Hz, 2 H), 4.18–4.08 (m, 1 H), 3.59
(ddd, J = 9.6, 6.1, 3.2 Hz, 1 H), 3.37 (s, 3 H), 2.16–2.04 (m, 2 H),
2.00–1.90 (m, 1 H), 1.72–1.58 (m, 1 H), 0.89 (s, 9 H), 0.09 (s, 3 H),
0.08 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 129.0, 128.6, 96.2, 78.2, 71.2,
55.2, 25.9, 25.8, 23.8, 18.1, –4.6, –4.7.
HRMS: m/z [M + Na]+ calcd for C14H28NaO3Si: 295.1705; found:
297.1700.
[a]D –14.0 (c 1, CHCl3).
IR (neat): 2939, 1726, 1529, 1350, 1269, 1102, 916 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.30 (d, J = 8.8 Hz, 2 H), 8.23 (d,
J = 8.8 Hz, 2 H), 6.02–5.88 (m, 1 H), 5.82 (ddt, J = 16.8, 10.2, 6.6
Hz, 1 H), 5.68 (dt, J = 6.4, 1.3 Hz, 1 H), 5.45–5.30 (m, 2 H), 5.12–
4.95 (m, 2 H), 4.80, 4.67 (2 d, J = 6.9 Hz, 2 H), 3.85 (dt, J = 7.2, 3.8
Hz, 1 H), 3.37 (s, 3 H), 2.34–2.10 (m, 2 H), 1.81–1.65(m, 2 H).
13C NMR (100 MHz, CDCl3): d = 163.8, 150.6, 137.8, 135.7, 132.0,
130.8, 123.6, 119.4, 115.4, 96.4, 77.9, 77.7, 56.0, 29.9, 29.8.
HRMS: m/z [M + Na]+ calcd for C17H21NNaO6: 358.1267; found:
358.1275.
(1S,2S,3R,4R)-3-(tert-Butyldimethylsiloxy)-4-(methoxy-
methoxy)cyclohexane-1,2-diol (15)
(3S,4R)-4-(Methoxymethoxy)-3-(4-nitrobenzoyl)cyclohex-1-ene
(17)
To a soln of 14 (0.08 g, 0.3 mmol) in THF (1.6 mL) and H2O (0.4
mL) was added a 50% soln of NMO in H2O (0.2 mL, 0.9 mmol) and
OsO4 (3 mg, 0.01 mmol) at 0 °C. The mixture was gradually
warmed up to r.t. and stirred for 24 h. It was then quenched with sat.
Na2SO3 soln (2 mL). EtOAc (2 mL) was then introduced and the re-
sulting mixture was vigorously stirred at r.t. for 30 min and further
extracted with EtOAc (3 × 10 mL). Combined organic layers were
washed with brine (20 mL), dried (anhyd Na2SO4), and the solvent
was evaporated. Column chromatography of the residue (silica gel,
PE–EtOAc, 2:8) afforded 15 (0.084 g, 92%) as a colorless solid; mp
74–76 °C.
To a stirred soln of 16 (90 mg, 0.26 mmol) in anhyd CH2Cl2 (5 mL)
was added Grubbs 1st generation catalyst (22 mg, 10 mol%, 0.03
mmol) at r.t. and the mixture was stirred at r.t. for 2 h (TLC moni-
toring). It was then filtered through a short pad of silica gel and the
silica gel pad washed with Et2O (2 × 15 mL) and the solvent was
evaporated. The residue was subjected to column chromatography
(silica gel, PE–EtOAc, 8:2) to yield 17 (77 mg, 94%) as a colorless
oil.
[a]D +295 (c 0.4, CHCl3).
IR (neat): 2939, 1721, 1607, 1528, 1347, 1272, 1105, 1032, 719
cm–1.
[a]D +19.0 (c 1, CHCl3).
IR (KBr): 3437, 2950, 1472, 1254, 1102, 1041, 963, 836, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.64 (s, 2 H), 3.93–3.78 (m, 2 H),
3.57–3.53 (br m, 1 H), 3.50–3.45 (br m, 1 H), 3.36 (s, 3 H), 1.90–
1.65 (m, 3 H), 1.61–1.48 (m, 1 H), 0.86 (s, 9 H), 0.08 (s, 3 H), 0.06
(s, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.28 (d, J = 9.0 Hz, 2 H), 8.24 (d,
J = 9.0 Hz, 2 H), 6.06 (dt, J = 9.8, 3.5 Hz, 1 H), 5.88–5.78 (m, 1 H),
5.68 (t, J = 4.4 Hz, 1 H), 4.74, 4.66 (2 d, J = 6.9 Hz, 2 H), 4.02 (dt,
J = 10.8, 3.5 Hz, 1 H), 3.33 (s, 3 H), 2.44–2.30 (m, 1 H), 2.29–2.14
(m, 1 H), 2.10–2.00 (m, 1 H), 1.96–1.80 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 96.0, 77.5, 74.8, 72.9, 68.1, 55.5,
25.7, 24.8, 24.3, 17.9, –4.7, –5.0.
13C NMR (100 MHz, CDCl3): d = 164.3, 150.4, 135.9, 134.0, 130.7,
123.4, 122.9, 94.9, 72.3, 68.8, 55.5, 24.4, 23.9.
HRMS: m/z [M + Na]+ calcd for C14H28NaO3Si: 329.1760; found:
HRMS: m/z [M + Na]+ calcd for C15H17NNaO6: 330.0954; found:
329.1758.
330.0949.
(1S,2S,3S,4R)-Cyclohexane-1,2,3,4-tetrol (Dihydroconduritol
F, 1)
(1R,2R,1S,2R)-4-(Methoxymethoxy)-3-(4-nitrobenzoyl)cyclo-
hexane-1,2-diol (18)
To a soln of 15 (50 mg, 0.16 mmol) in CH2Cl2 (5 mL) at r.t. was
added TFA (1 mL) and the mixture was stirred at r.t. for 2 h. When
the reaction was complete (TLC), the volatiles were removed under
reduced pressure. The residue thus obtained was triturated with
Et2O and the Et2O was evaporated to furnish 1 (22 mg, 93%) as a
thick viscous mass.
[a]D +31.6 (c 0.6, H2O) {Lit.7 [a]D +31 (c 0.7, H2O)}.
IR (KBr): 3400, 2946, 2891, 1535, 1343, 1277, 1051, 985 cm–1.
1H NMR (400 MHz, CD3OD): d = 3.94–3.89 (m, 1 H), 3.51 (t,
J = 8.9 Hz, 1 H), 3.40–3.24 (m, 2 H), 1.83–1.60 (m, 3 H), 1.54–1.42
(m, 1 H).
13C NMR (100 MHz, CD3OD): d = 75.1, 74.7, 72.8, 69.2, 26.8, 26.4.
To a soln of 17 (65 mg, 0.21 mmol) in THF (1.6 mL) and H2O (0.4
mL) was added a 50% soln of NMO in H2O (0.15 mL, 0.63 mmol)
and OsO4 (3 mg, 0.01 mmol) at 0 °C. The mixture was gradually
warmed up to r.t. and stirred for 24 h. When the reaction was com-
plete (TLC), it was quenched by addition of sat. Na2SO3 (2 mL).
The resulting mixture was vigorously stirred at r.t. with EtOAc (2
mL) for 30 min and further extracted with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine (20 mL), dried
(anhyd Na2SO4), and the solvent was evaporated. Column chroma-
tography of the residue (silica gel, PE–EtOAc, 3:7) afforded 18 (66
mg, 92%) as a colorless solid; mp 155–157 °C.
[a]D –54.0 (c 0.5, EtOH).
IR (KBr): 3547, 3457, 2935, 2621, 1713, 1521, 1350, 1290, 1093,
1042, 872 cm–1.
HRMS: m/z [M + Na]+ calcd for C6H12NaO4: 171.0633; found:
171.0627.
Synthesis 2008, No. 19, 3155–3159 © Thieme Stuttgart · New York

SPECIAL TOPIC
Facile Synthesis of Dihydroconduritols E and F
3159
1H NMR (400 MHz, CDCl3, CD3OD): d = 8.30 (d, J = 9.0 Hz, 2 H),
8.26 (d, J = 9.0 Hz, 2 H), 5.34 (dd, J = 8.0, 2.5 Hz, 1 H), 4.67, 4.63
(2 d, J = 6.8 Hz, 2 H), 4.23–4.15 (m, 1 H), 4.17–4.03 (m, 2 H), 3.30
(s, 3 H), 2.02–1.73 (m, 4 H).
13C NMR (100 MHz, CDCl3, CD3OD): d = 164.5, 150.4, 135.5,
130.6, 123.4, 95.3, 75.3, 73.1, 69.7, 69.1, 55.3, 25.2, 23.6.
References
(1) (a) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A.
J. Chem. Rev. 1996, 96, 1195. (b) Kiddle, J. J. Chem. Rev.
1995, 95, 2189. (c) Hudlicky, T.; Cebulak, M. Cyclitols and
Derivatives; VCH: New York, 1993. (d) Chida, N.; Ogawa,
S. Chem. Commun. 1997, 807.
(2) (a) Atsumi, S.; Umezawa, K.; Iinuma, H.; Naganawa, H.;
Nakamura, H.; Iitaka, Y.; Takeuchi, T. J. Antibiot. 1990, 43,
49. (b) Chida, N.; Yamada, K.; Ogawa, S. J. Chem. Soc.,
Chem. Commun. 1991, 588.
(3) (a) For a review on conduritols see: Balci, M.; Sutbeyaz, Y.;
Secen, H. Tetrahedron 1990, 46, 3715. (b) Constrained
conduritol analogues: Mehta, G.; Ramesh, S. S.; Bera, M. K.
Chem. Eur. J. 2003, 9, 2264.
(4) (a) Zelinskii, N. D.; Denisenko, Ya. I.; Eventona, M. S. C. R.
Acad. Sci. URSS 1935, 1, 313. (b) Posternak, T.; Friedli, H.
Helv. Chim. Acta 1953, 36, 251. (c) Sable, H. Z.; Powell, K.
A.; Katchian, H.; Niewoehner, C. B.; Kadlec, S. B.
Tetrahedron 1970, 26, 1509. (d) Tschamber, T.;
Backenstrass, F.; Fritz, H.; Streith, J. Helv. Chim. Acta 1992,
75, 1052; and references cited therein. (e) Huang, C.-Y.;
Cabell, L. A.; Anslyn, E. V. Synth. Commun. 1994, 24,
2757. (f) Gypser, A.; Michel, D.; Nirschl, D. S.; Sharpless,
K. B. J. Org. Chem. 1998, 63, 7322.
HRMS: m/z [M + Na]+ calcd for C15H19NNaO8: 364.1008; found:
364.1006.
(1R,2R,3S,4R)-4-(Methoxymethoxy)cyclohexane-1,2,3-triol
To a MeOH (20 mL) soln of 18 (50 mg, 0.14 mmol) was added
K2CO3 (40 mg, 0.3 mmol) and the mixture was stirred at r.t. for 30
min. When the reaction was complete (TLC), the solvent was re-
moved under reduced pressure and the residue obtained was puri-
fied by column chromatography (silica gel, EtOAc) to afford the
product (25 mg, 90%) as a viscous mass.
[a]D –16.0 (c 1, MeOH).
IR (KBr): 3423, 2925, 2853, 1452, 1150, 1076, 1033, 916 cm–1.
1H NMR (400 MHz, CDCl3, CD3OD): d = 4.53 (s, 2 H), 3.85 (br s,
1 H), 3.75 (br s, 1 H), 3.59 (dd, J = 8.6, 2.2 Hz, 1 H), 3.55 (dd,
J = 8.6, 2.2 Hz, 1 H), 3.23 (s, 3 H), 1.68–1.45 (m, 4 H).
13C NMR (100 MHz, CDCl3, CD3OD): d = 96.1, 76.7, 72.1, 71.1,
68.9, 55.2, 25.2, 23.5.
HRMS: m/z [M + Na]+ calcd for C8H16NaO5: 215.0895; found:
(5) Akbulut, N.; Balci, M. J. Org. Chem. 1988, 53, 3338; and
references cited therein.
215.0900.
(6) Kindl, H.; Kremlicka, G. J.; Hoffmann-Ostenhof, O.
Monatsh. Chem. 1966, 97, 1783.
(7) Drian, C. L.; Vionnet, J.-P.; Vogel, P. Helv. Chim. Acta
1990, 73, 161.
(1R,2R,3R,4R)-Cyclohexane-1,2,3,4-tetrol (Dihydroconduritol
E, 2)
To a soln of triol obtained above (22 mg, 0.11 mmol) in MeOH at
r.t. was added Amberlyst-15 (100 mg) and the mixture was stirred
for 4 h (TLC monitoring). When the reaction was complete, it was
filtered and concentrated under reduced pressure to afford 2 (15 mg,
88%) as a viscous mass.
(8) Lee, Y. J.; Lee, K.; Jung, S. I.; Jeon, H. B.; Kim, K. S.
Tetrahedron 2005, 61, 1987.
(9) Hudlicky, T.; Price, J. D.; Luna, H.; Andersen, C. M. Synlett
1990, 309.
(10) (a) Swallen, L. C.; Boord, C. E. J. Am. Chem. Soc. 1930, 52,
651. For application of this strategy in synthesis of allylic
alcohols see: (b) Pak, C. S.; Lee, E.; Lee, G. H. J. Org.
Chem. 1993, 58, 1523. (c) Rao, A. V. R.; Reddy, E. R.;
Joshi, B. V.; Yadav, J. S. Tetrahedron Lett. 1987, 28, 6497.
(d) Schneider, C.; Kazmaier, U. Synthesis 1998, 1314.
(11) Nugiel, D. A.; Jacobs, K.; Worley, T.; Patel, M.; Kaltenbach,
R. F. III; Meyer, D. T.; Jadhav, P. K.; De Lucca, G. V.;
Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.;
Seitz, S. P. J. Med. Chem. 1996, 39, 2156.
[a]D –35.5 (c 0.9, MeOH).
IR (KBr): 3410, 2909, 1455, 1211, 1080, 898, 847 cm–1.
1H NMR (500 MHz, CD3OD, CDCl3): d = 3.95 (br s, 4 H), 3.70 (br
s, 4 H), 1.82–1.70 (m, 2 H), 1.69–1.55 (m, 2 H).
13C NMR (125 MHz, CD3OD, CDCl3): d = 71.4, 68.6, 24.6.
HRMS: m/z [M + Na]+ calcd for C6H12NaO4: 171.0633; found:
171.0639.
(12) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18. (b) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem.
Res. 1995, 28, 446.
Acknowledgment
(13) Mitsunobu, O. Synthesis 1981, 1.
We thank the Department of Science and Technology (DST), New
Delhi for funding the project and for the CCD facility at IISc. One
of us (A.B.P.) thanks council of scientific and industrial research
(CSIR), New Delhi for a junior research fellowship.
(14) Stereochemistry of 18 was further proved by X-ray crystal
structure analysis. (The crystallographic data has been
deposited with The Cambridge Crystallographic Data
Centre, CCDC687686). This data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via http://www.ccdc.cam.ac.uk/data request/cif.
Synthesis 2008, No. 19, 3155–3159 © Thieme Stuttgart · New York