Stereoselective total synthesis of ophiocerin D from d-xylose

Article abstract of DOI:10.1016/j.tetasy.2008.08.016

A stereoselective total synthesis of ophiocerin D is reported by a combination of a 'chiron' approach and an asymmetric synthesis, from d-xylose. Of the four stereogenic centers, the vic diols C3/C4 and C5/C6 were obtained by Sharpless asymmetric dihydroxylation and from d-xylose, respectively.

Full text of DOI:10.1016/j.tetasy.2008.08.016

Tetrahedron: Asymmetry 19 (2008) 2092–2095
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Stereoselective total synthesis of ophiocerin D from D-xylose
*
Gangavaram V. M. Sharma , Krishna Damera
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 August 2008
Accepted 19 August 2008
A stereoselective total synthesis of ophiocerin D is reported by a combination of a ‘chiron’ approach and
an asymmetric synthesis, from
D-xylose. Of the four stereogenic centers, the vic diols C3/C4 and C5/C6
were obtained by Sharpless asymmetric dihydroxylation and from
D-xylose, respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Accordingly, the known7 alcohol 5 on protection with benzyl
bromide gave 6 (87%). Diacetonide 6 on acid (5% H2SO4, THF) cat-
alyzed hydrolysis at room temperature gave diol 7, which on oxi-
dative cleavage (H5IO6 in aq EtOAc) at room temperature
afforded the aldehyde 8. Wittig olefination of aldehyde 8 furnished
the ester 9 in 75% yield. Treatment of 9 with TBDMSCl and imidaz-
The chemical investigations on freshwater aquatic fungi by
Gloer et al.1 resulted in the isolation of tetrahydropyran derivatives
ophiocerins A–C and ophiocerin D 1 from Ophioceras venezuelense
(Magnaporthaceae).2 The structural analysis of ophiocerin A–D
was arrived at by Gloer et a1.1 from spectroscopic studies, while
the absolute stereochemistry was assigned by CD spectrometry
by the use of the excitation chirality method.3 These new tetra-
hydropyran derivatives4 appear to be the first isolated natural
products from the above genus. The substituted tetrahydropyran
moiety is a part structure of a wide variety of natural products with
diversified biological functions.5 In continuation of our efforts
on the synthesis of natural products6 from carbohydrates,
ole in CH2Cl2 gave TBS ether 10 (92%), [
Asymmetric dihydroxylation8 of ester 10 with AD-mix-
diol 11 (62%), which on protection with MOMCl in the presence
a]
D = À12.8. (c 1.2, CHCl3).
a
gave the
of DIPEA afforded the MOM ether 12 in 91% yield, [a]D = +41.6 (c
2.2, CHCl3).
Having established all the four stereocenters, next it was aimed
at the cyclization and introduction of an isocrotonyl side chain at
the C-5 OH group. Accordingly, ester 12 on reduction with LAH
in THF at room temperature gave the alcohol 13 (89%), which on
further reaction with p-TsCl (Et3N, CH2Cl2) furnished tosylate 14
(68%). Tosylate 14 was exposed to TBAF9 at room temperature to
result in desilylation and concomitant cyclization in one-pot to
give the cyclized product 15 in 78% yield. TBAF in the present study
acted as a desilylating agent, as well as a base to promote a facile
cyclization reaction (Scheme 2).
herein, we report the total synthesis 1 from a D-xylose derivative
(Scheme 1).
OH
2'
4
O
OH
3
1'
3'
5
O
4'
2
For the introduction of the side chain, the benzyl group in 15
was removed by hydrogenation using Pd(OH)2 in MeOH to give
O
1
6
7
the alcohol 2 (87%), [
a
]
D = À2.7 (c 2.0, CHCl3). Further, acylation
1
ophiocerin D
2. Results and discussion
of 2 with 2-butynoic acid 3 under Yamaguchi10 reaction conditions
gave 16 in 79% yield, which on selective hydrogenation in the pres-
ence of Lindlar catalyst afforded 17 in 75% yield, [a]D = +34.4 (c 0.2,
CHCl3). Finally, PPTS catalyzed deprotection of the MOM groups in
17 furnished ophiocerin D 1 in 71% yield. The specific rotation va-
lue [a]D = +38.4 (c 0.1, CHCl3) of synthetic 1 was matching with
that of the natural product [a]D = +40 (c 0.1, CHCl3).
The retrosynthetic analysis of 1 indicated that it could be pre-
pared from 2 and butynoic acid 3, while 2 could in turn be pre-
pared from
D-xylose derivative 4. Thus, the synthetic strategy
would be to (a) deoxygenate C-5 to a methyl group, (b) retention
of C3/C4 for C5/C6 of 1, and (c) introduction of a C3/C4 diol on
the Wittig product made from the 1,2-diol of 4.
3. Conclusion
Thus, the present study describes the total synthesis of ophioc-
erin D 1 by a combination of a chiron approach and an asymmetric
synthesis, wherein the C3/C4 and C5/C6 stereocenters were
* Corresponding author.
E-mail address: esmvee@iict.res.in (G. V. M. Sharma).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.016

G. V. M. Sharma, K. Damera / Tetrahedron: Asymmetry 19 (2008) 2092–2095
2093
Yamaguchi
protocol
Deoxygenation
O
OMOM
OMOM
OH
HO
O
OH
O
O
O
O
O
O
O
2
4
1
Wittig/dihydroxylation
+
COOH
3
Scheme 1.
O
O
OH
OH
OH
O
O
O
c
a
CHO
d, e
b
O
BnO
O
BnO
HO
OBn
8
7
6
5
TBSO
OMOM
TBSO
OR
O
OMOM
OR
O
RO
OMOM
OR
OMe
OMe
OBn OMOM
OBn OR
O
OBn
13
14
11 R = H
12 R = MOM
R = H
R = Ts
9 R = H
10 R =TBS
15
2
R = Bn
R = H
OMOM
OMOM
OMOM
OMOM
O
O
n
m
1
O
O
O
O
17
16
Scheme 2. Reagents and conditions: (a) BnBr, NaH, THF, 0 °C–rt; (b) 5% H2SO4, THF, 40 °C; (c) H5IO6, EtOAc/H2O, rt; (d) Ph3P@CHCO2Me, benzene, reflux; (e) TBDMSCl,
imidazole, CH2Cl2, rt; (f) AD-mix- , t-BuOH/H2O, 0 °C–rt; (g) MOMCl, DIPEA, CH2Cl2, rt; (h) LAH, THF, 0 °C–rt; (i) p-TsCl, Et3N, CH2Cl2, 0 °C–rt; (j) TBAF, THF, rt; (k) H2, Pd(OH)2,
MeOH, rt; (l) 2-butynoic acid, 2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, rt; (m) Lindlar catalyst, MeOH, rt; (n) PPTS, t-BuOH, 70 °C.
a
obtained by asymmetric dihydroxylation and from
D
-xylose,
4.1.1. (3aR,5R,6S,6aR)-2,2,5-Trimethyl perhydrofuro[2,3-d]-
[1,3]-dioxol-6-yl-benzyl ether 6
respectively. Furthermore, TBAF acted as a mild base to afford a
one-pot desilylation/cyclization. Thus, this strategy is adoptable
for the generation of a library of stereoisomers.
To a cooled (0 °C) suspension of NaH (0.82 g, 34.4 mmol, 60% w/
w dispersion in paraffin oil) in THF (15 mL), a solution of 5 (5 g,
28.7 mmol) in THF (10 mL) was added dropwise. After 15 min,
BnBr (4.9 g, 28.7 mmol) was added at 0 °C and stirred at room tem-
perature for 6 h. The reaction mixture was quenched with satd aq
NH4Cl solution (20 mL) and extracted with EtOAc (2 Â 50 mL). The
combined organic layers were washed with water (50 mL), brine
(50 mL), dried (Na2SO4), and evaporated. The crude product was
purified by column chromatography (silica gel, 60–120 mesh,
EtOAC/hexane, 2:8) to afford 6 (6.2 g, 87%) as a light yellow syrup.
4. Experimental
4.1. General methods
Solvents were dried over standard drying agents and freshly
distilled prior to use. Chemicals were purchased and used without
further purification. All column chromatographic separations were
performed using silica gel (Acme’s, 60–120 mesh). Organic solu-
tions were dried over anhydrous Na2SO4 and concentrated below
40 °C in vacuo. 1H NMR (200 MHz, 300 MHz, and 400 MHz) and
13C NMR (50 MHz and 75 MHz) spectra were measured with a Var-
ian Gemini FT-200 MHz spectrometer, Bruker Avance 300 MHz,
Unity 400 MHz, and Inova-500 MHz with tetramethylsilane as an
internal standard for solutions in deuteriochloroform. J values are
given in hertz. IR spectra were recorded on at Perkin–Elmer IR-
683 spectrophotometer with NaCl optics. Optical rotations were
measured with JASCO DIP 300 digital polarimeter at 25 °C. Mass
spectra were recorded on CEC-21-11013 or Fannigan Mat 1210
double focusing mass spectrometers operating at a direct inlet sys-
tem or LC/MSD Trap SL (Agilent Technologies).
[
a
]
D = À50.9 (c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.32 (d,
3H, J = 6.2 Hz, –CH3), 1.41 (s, 3H, –CH3), 1.50 (s, 3H, –CH3) 4.21–
4.26 (m, 1H, –CH), 3.62 (d, 1H, J = 2.9 Hz, –CH), 4.51 (d, 1H,
J = 12.4 Hz, –CHC6H5) 4.55 (d, 1H, J = 3.6 Hz, –CH), 4.65 (d, 1H,
J = 12.4 Hz, –CHC6H5) 5.80 (d, 1H, J = 4.0 Hz, –CH), 7.20–7.31 (m,
5H, –C6H5); IR (neat): 2978, 2920, 2870, 1453, 1064 cmÀ1; ESIMS:
271 [M+Na]+.
4.1.2. (4R,5R,E)-Methyl 4-(benzyloxy)-5-hydroxyhex-2-enoate 9
To a solution of 6 (6.0 g, 24.1 mmol) in THF (30 mL), 5% H2SO4
(30 mL) was added and the reaction mixture stirred at 40 °C for
10 h. The reaction mixture was neutralized with solid NaHCO3
(30 g) and extracted with EtOAc (3 Â 100 mL). The combined

2094
G. V. M. Sharma, K. Damera / Tetrahedron: Asymmetry 19 (2008) 2092–2095
organic layers were dried (Na2SO4) and evaporated. The crude was
filtered through 60–120 mesh silica gel (1:1 EtOAc/hexane) to
afford (3R,4R,5R)-4-(benzyloxy)-5-methyltetrahydro-2,3-furandiol
7 (3.5 g, 71%) as a yellow syrup.
To a stirred solution of 7 (3.0 g, 13.3 mmol) in EtOAc/water (1:1,
10 mL), periodic acid (6.0 g, 26.7 mmol) was added at 0 °C and stir-
red for 2 h at room temperature. The reaction mixture was
extracted with EtOAc (2 Â 50 mL) and washed with water
(2 Â 50 mL). The combined organic layers were dried (Na2SO4)
and evaporated under reduced pressure to afford (2S,3R)-2-(benz-
yloxy)-3-hydroxybutanal 8 which was used as such for the next
reaction.
A solution of aldehyde 8 (2.8 g, 8.1 mmol) in benzene was added
to a solution of (methoxycarbonylmethylene)triphenyl phosphor-
ane (3.1 g, 9.7 mmol) in benzene (30 mL) at reflux and stirred for
5 h. The solvent was evaporated and residue purified by column
chromatography (silica gel, 60–120 mesh, EtOAc/hexane, 1:4) to
OCH3), 3.91 (t, 1H, J = 1.5, 3.0 Hz, –CH), 4.01 (dd, 1H, J = 4.1,
6.4 Hz, –CH), 4.06–4.09 (m, 1H, –CH), 4.32 (br s, 1H, –OH), 4.68
(d, 1H, J = 11.3 Hz, –CHC6H5), 4.53 (d, 1H, J = 11.3 Hz, –CHC6H5),
7.22–7.31 (m, 5H, –C6H5); 13C NMR (75 MHz, CDCl3): d À4.53,
18.48, 25.76, 27.17, 52.61, 61.77, 69.99, 72.29, 73.63, 80.85,
127.89, 128.42, 129.97, 137.77, 173.38; IR (neat): 3444, 3065,
2927, 1761, 1252 cmÀ1; HRMS m/z [M+Na]+; calcd 399.2202, found
399.2209 for C20H35O6Si.
4.1.5. (2R,3S,4R,5R)-Methyl 4-(benzyloxy)-5-(isopropyldimethy-
lsilyloxy)-2,3-bis-(methoxymethoxy)hexanoate 12
To a cooled (0 °C) solution of 11 (2.0 g, 5.0 mmol) in CH2Cl2
(10 mL), DIPEA (3.9 mL, 30.3 mmol) and MOM-Cl (0.813 g,
10.1 mmol) were added sequentially and stirred at room tempera-
ture for 6 h. The reaction mixture was evaporated and purified the
residue by column chromatography (silica gel, 60–120 mesh,
EtOAc/hexane, 1:5) to afford 12 (2.2 g, 91%) as a yellow syrup.
afford 9 (2 g, 75%) as a pale yellow syrup. [
a
]
D = À22.8 (c 0.5,
[a]
D = +41.6 (c 2.2, CHCl3); 1H NMR (200 MHz, CDCl3): d 0.04 (s,
CHCl3); 1H NMR (CDCl3, 300 MHz): d 1.15 (d, 3H, J = 5.8 Hz,
ÀCH3), 2.56 (br s, 1H, OH), 3.64–3.69 (m, 2H, 2 Â –CH), 3.76 (s,
3H, –OCH3), 4.34 (d, 1H, J = 11.3 Hz, –CH–C6H5), 4.63 (d, 1H,
J = 11.3 Hz, CH–C6H5), 6.01 (d, J = 15.7 Hz, olefinic), 6.79 (dd, 1H,
J = 6.9, 15.7 Hz, olefinic), 7.21–7.30 (m, 5H, –C6H5); 13C NMR
(75 MHz, CDCl3): 166.19, 144.56, 137.31, 128.01, 124.26, 83.32,
71.54, 69.52, 51.74, 18.25; IR (neat): 3403, 2926, 2864, 1706,
1451 cmÀ1; HRMS m/z [M+Na]+ calcd 273.1102 found 273.1108
for C14H18O4Na.
6H, 2 Â –CH3), 0.87 (s, 9H, 3 Â –CH3), 1.26 (d, 3H, J = 6.6 Hz,
–CH3), 3.29 (s, 3H, –OCH3), 3.36 (s, 3H, –OCH3), 3.41 (dd, 1H,
J = 3.6, 5.8 Hz, –CH), 3.67 (s, 3H, –OCH3), 4.05 (dd, 1H, J = 3.6,
6.6 Hz, –CH), 4.18 (dd, 1H, J = 2.9, 5.8 Hz, –CH) 4.39 (d, 1H, J =
2.9 Hz, –CH), 4.54–4.58 (m, 2H, –OCH2), 4.62 (d, 1H, J = 11.7 Hz,
–CHC6H5), 4.66–4.70 (m, 2H, –OCH), 4.72 (d, 1H, J = 11.7 Hz,
–CHC6H5), 7.21–7.30 (m, 5H, –C6H5); 13C NMR (75 MHz, CDCl3): d
À4.2, 21.12, 25.01, 52.41, 56.21, 68.41, 73.25, 75.82, 79.08, 82.54,
97.12, 127.12, 128.72, 128.48, 138.24, 173.8; IR (Neat): 2210,
1750, 1440, 1223, 1032, 867 cmÀ1; HRMS: m/z [M+Na]+ calcd
509.2546, found 509.2540 for C24H42O8Na.
4.1.3. (4R,5R,E)-Methyl 4-(benzyloxy)-5-(isopropyldimethyl-
silyloxy)-hex-2-enoate 10
To a stirred solution of 9 (1.8 g, 7.2 mmol) in anhydrous CH2Cl2
(20 mL) imidazole (0.55 g, 6.4 mmol) was added at 0 °C. After
15 min, TBDMSCl (1.08 g, 7.2 mmol) was added and reaction mix-
ture stirred at room temperature for 5 h. The reaction mixture was
quenched with satd aq NH4Cl (25 mL) and extracted with CH2Cl2
(2 Â 25 mL). The organic layer was washed with water (2 Â
25 mL), dried (Na2SO4), evaporated, and the residue purified by
column chromatography (silica gel, 60–120 mesh, EtOAC/hexane,
4.1.6. (2R,3R,4R,5R)-4-(Benzyloxy)-5-(isopropyldimethyl-
silyloxy)-2,3-bis(methoxymethoxy)hexan-ol 13
To a stirred suspension of LAH (0.19 g, 5.1 mmol) in dry THF
(5 mL) at 0 °C, a solution of 12 (1.5 g, 3.0 mmol) in dry THF
(15 mL) was added. After 1 h, satd aq Na2SO4 solution (30 mL)
was added to the reaction mixture and stirred for an additional
30 min. It was filtered through Celite and the residue was washed
with EtOAc (2 Â 70 mL). The filtrate was evaporated and the resi-
due purified by column chromatography (silica gel, 60–120 mesh,
1:5 EtOAc/hexane) to afford 13 (1.7 g, 89%) as a pale yellow liquid.
1:10) to afford 10 (2.4 g, 92%) as
a light yellow syrup.
[a
]
D = À12.8 (c 1.2, CHCl3); 1H NMR (CDCl3, 300 MHz): d 0.23 (s,
6H, 2 Â –CH3), 0.82 (s, 9H, 3 Â –CH3), 1.01 (d, 3H, J = 5.8 Hz,
–CH3), 3.73 (s, 3H, –OCH3), 3.75–3.82 (m, 2H, –CH), 4.41 (d, 1H,
J = 12.1 Hz, –CHC6H5), 4.62 (d, 1H, J = 12.1 Hz, –CHC6H5) 6.07 (d,
1H, J = 16.1 Hz, olefinic), 6.81 (dd, 1H, J = 4.7, 16.1 Hz, olefinic),
7.22–7.32 (m, 5H, –C6H5); 13C NMR (75 MHz, CDCl3): 166.67,
145.64, 138.01, 128.33, 127.96, 122.61, 81.79, 71.56, 69.70, 51.56,
[a]
D = À30.4 (c 2.4, CHCl3); 1H NMR (CDCl3, 200 MHz): 0.06 (s, 6H,
2 Â –CH3), 0.91 (s, 9H, 3 Â –CH3), 1.25 (d, 3H, J = 6.6 Hz, –CH2),
3.41(s, 6H, 2 Â –OCH3), 3.41–3.44 (m, 1H, –CH), 3.71–3.73 (m,
2H, 2 Â –CH), 3.82–3.85 (m, 1H, –CH), 3.91–3.94 (m, 1H, –CH),
4.11–4.14 (m, 1H, –CH), 4.59–4.63 (m, 2H, –OCH2), 4.71 (s, 2H,
–CH2C6H5), 4.73–4.81 (m, 2H, –OCH2), 7.25–7.32 (m, 5H, –C6H5);
13C NMR (75 MHz, CDCl3): d À4.29, 20.70, 25.88, 55.72, 62.66,
68.90, 71.12, 73.24, 81.03, 83.95, 97.08, 97.48, 127.34, 128.15,
25.76, 18.74, À4.80; IR (neat): 2926, 2864, 1716, 1251, 889 cmÀ1
;
ESIMS: 365 [M+H]+.
128.21, 138.12; IR (neat): 3446, 2923, 2853, 1643, 1102 cm–1
HRMS m/z [M+Na]+ calcd 481.2597, found 481.2594 for
C23H42O7NaSi.
;
4.1.4. (2R,3R,4R,5R)-Methyl 4-(benzyloxy)-2,3-dihydroxy-5-
(isopropyldimethylsily-loxy)hexanoate 11
A well-stirred solution of AD-mix-a (5.8 g, 7.5 mmol) in t-
BuOH/H2O (1:1, 20 mL) was treated with methane sulfonamide
(0.35 g, 3.7 mmol) at room temperature. After 30 min, the clear
yellow solution was cooled to 0 °C and a solution of ester 10
(1.5 g, 3.7 mmol) in t-BuOH (5 mL) was added. The reaction mix-
ture was stirred vigorously at 0 °C for 27 h and then quenched with
solid Na2SO4 (5 g). It was warmed to room temperature and stirred
for an additional 1 h. The resultant reaction mixture was extracted
with CH2Cl2 (3 Â 100 mL), and the combined extracts were dried
(Na2SO4), filtered, and evaporated to give a crude residue, which
was purified by column chromatography (silica gel, 60–120 mesh,
30:70% EtOAc/hexane) to afford 11 (1.0 g in 62%) as a yellow syrup.
4.1.7. (2R,3R,4R,5S)-3-(Benzyloxy)-4,5-bis(methoxymethoxy)-2-
methyl-tetrahydro-2H-pyran 15
To a solution of 13 (1.7 g, 3.7 mmol) in CH2Cl2 (15 mL) at 0 °C,
Et3N (0.7 mL, 5.5 mmol) and tosyl chloride (0.84 g, 4.4 mmol) were
added sequentially and stirred at room temperature for 6 h. The
reaction mixture was washed with water (10 mL), brine (10 mL),
dried (Na2SO4), and evaporated under reduced pressure. The resi-
due was filtered through silica gel (60–120 mesh, EtOAc/hexane,
1:4) to furnish (2R,3R,4S,5R)-4-(benzyloxy)-5-(isopropyldimethyl-
silyloxy)-2,3-di(methoxymethoxy)hexyl 4-methyl-1-benzenesul-
fonate 14 (1.5 g, 68%) as a pale yellow oil.
[a
]
D = +12.8 (c 1.5, CHCl3); 1H NMR (CDCl3, 200 MHz): d 0.03 (s, 6H,
To a stirred solution of 14 (1.5 g, 2.4 mmol) in dry THF (5 mL) at
0 °C, n-Bu4N+FÀ in THF (6.1 mL, 6.1 mmol) was added and then stir-
red at room temperature for 8 h. The reaction mixture was evapo-
2 Â –CH3), 0.86 (s, 9H, 3 Â –CH3), 1.28 (d, 3H, J = 6.4 Hz, –CH3), 2.93
(br s, 1H, –OH), 3.55 (dd, 1H, J = 3.7, 9.4 Hz, –CH), 3.82 (s, 3H,

G. V. M. Sharma, K. Damera / Tetrahedron: Asymmetry 19 (2008) 2092–2095
2095
rated and the residue purified by column chromatography (silica
pressure and purified the residue by column chromatography (sil-
gel, 60–120 mesh, EtOAc/hexane, 6:4) to afford 15 (0.63 g, 78%)
ica gel, 60–120 mesh, EtOAc/hexane, 1:4) to afford 17 (0.015 mg,
as a pale yellow syrup. [
a]
D = À100.7 (c 1.4, CHCl3); 1H NMR (CDCl3,
75%) as a colorless oil, [a]
D = +34.4 (c 0.2, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.14 (d, 3H, J = 6.2 Hz, –CH3), 3.06 (d, 1H, J = 6.2 Hz,
–CH), 3.33 (s, 3H, –OCH3), 3.35–3.38 (m, 1H, –CH), 3.39 (s, 3H,
–OCH3), 3.41–3.47 (m, 1H, –CH), 3.57–3.62 (m, 2H, 2 Â –CH),
4.03 (dd, 1H, J = 5.5, 14.3 Hz, –CH), 4.59 (d, 1H, J = 11.1 Hz,
–CHC6H5), 4.62–4.75 (m, 4H, –OCH2), 4.92 (d, 1H, J = 11.1 Hz
–CHC6H5), 7.46–7.23 (m, 5H, C6H5); 13C NMR (75 MHz, CDCl3): d
17.13, 52.59, 55.66, 69.10, 73.94, 78.07, 80.18, 96.24, 97.29,
127.59, 127.61, 138.51; IR (neat): 2955, 2858, 1521, 1465, 1241
cmÀ1; HRMS m/z [M+Na]+ calcd 349.1627, found 349.1631; for
300 MHz): d 1.10 (d, 3H, J = 6.6 Hz, CH3), 2.15 (dd, 3H, J = 1.8,
7.3 Hz, –CH3), 3.17 (dd, 1H, J = 9.9, 10.6 Hz, –CH), 3.33 (s, 3H,
–OCH3), 3.35 (s, 3H, –OCH3), 3.60 (dd, 1H, J = 6.2, 12.8 Hz, –CH),
3.69 (dd, 1H, J = 3.3, 9.5 Hz, –CH), 3.77 (dd, 1H, J = 5.1, 9.9 Hz,),
4.06 (dd, 1H, J = 5.1, 10.6 Hz, –CH), 4.66 (dq, 4H, J = 6.6 Hz, –CH2),
5.21 (dd, 1H, J = 1.1, 3.3 Hz, –CH), 5.91 (dd, 1H, J = 1.8, 11.3 Hz, ole-
finic), 6.31 (dq, 1H, J = 7.3, 11.3 Hz, olefinic); 13C NMR (75 MHz,
CDCl3): d 15.57, 16.77, 55.44, 55.60, 69.17, 70.40, 72.85, 73.68,
95.09, 97.19, 120.32, 145.92, 166.01; IR (neat): 2980, 2857, 1710,
1097 cmÀ1; HRMS m/z [M+Na]+; calcd 327.1419, found 327.1421
for C24H24O7Na.
C17H26O6Na.
4.1.8. (2R,3S,4S,5S)-4,5-Bis(methoxymethoxy)-2-methyl
tetrahydro-2H-3-pyranol 2
4.1.11. Ophiocerin D: (2R,3R,4S,5S)-4,5-dihydroxy-2-methyl-
tetrahydro-2H-3-pyranyl(Z)-2-butenoate 1
To a solution of 15 (0.3 g, 0.9 mmol) in dry MeOH (5 mL), a cat-
alytic amount of Pd(OH)2 (20%) was added and the reaction mix-
ture stirred at room temperature under hydrogen atmosphere for
5 h. It was filtered and washed with ethyl acetate (20 mL). The fil-
trate was evaporated under reduced pressure and purified by col-
umn chromatography (silica gel, 60–120 mesh, EtOAC/hexane, 3:2)
To a solution of 17 (0.01 g, 0.03 mmol) in t-butanol (2 mL), PPTS
(0.024 g, 0.09 mmol) was added and stirred at 70 °C for 4 h. The
reaction mixture was concentrated and the residue dissolved in
EtOAc (20 mL). It was washed with water (2 mL), brine (2 mL),
and dried (Na2SO4). The solvent was evaporated and the residue
purified by column chromatography (silica gel, 60–120 mesh,
EtOAc/hexane, 1:1) to afford 1 (0.005 g, 71%) as a white solid;
to afford 2 (0.19 g, 87%) as a colorless liquid. [
a
]
D = À2.7 (c 2.0,
CHCl3); 1H NMR (200 MHz, CDCl3): d 1.21 (d, 3H, J = 6.6 Hz,
–CH3), 2.20 (br s, 1H, –OH), 3.09–3.12 (m, 1H, –CH), 3.32 (s, 3H,
–OCH3), 3.40 (s, 3H, –OCH3), 3.45 (dd, 1H, J = 1.1, 5.5 Hz, –CH),
3.75–3.89 (m, 2H, –CH), 4.01 (dd, 1H, J = 5.5, 11 Hz, –CH), 4.80–
4.58 (m, 4H, 2 Â –CH2), 13C NMR (75 MHz, CDCl3): d 16.71, 55.42,
55.64, 68.92, 71.19, 74.42, 80.21, 96.12, 97.2; IR (Neat): 3400,
1180, 1095, 1065 cmÀ1; HRMS: m/z [M+Na]+ calcd for C10H20O6Na:
259.1157; found: 259.1160 for C10H20O6Na.
mp 94–97 °C [lit.1 mp 96–98 °C); [
[a]
a]
D = +38.4 (c 0.1, CHCl3) {lit.1
D = +40 (c 0.1, CHCl3)}; 1H NMR (300 MHz, CDCl3): d 1.17 (d,
3H, J = 6.5 Hz, –CH3), 2.12 (dd, 3H, J = 1.5, 7.3 Hz, –CH3), 3.16 (dd,
1H, J = 10.0, 10.9 Hz, –CH), 3.59–3.67 (m, 2H, 2 Â –CH), 3.86 (ddd,
1H, J = 5.3, 9.2, 10.0 Hz, –CH), 3.99 (dd, 1H, J = 5.3, 10.9 Hz, –CH),
5.14 (dd, 1H, J = 1.1, 3.4 Hz, –CH), 5.87 (dq, 1H, J = 1.5, 11.5 Hz, ole-
finic), 6.45 (dq, 1H, J = 7.3, 11.5 Hz, olefinic); 13C NMR (75 MHz,
CDCl3): d 15.52, 16.61, 67.12, 69.41, 73.71, 75.42, 76.95, 119.61,
147.12, 166.92; IR (neat): 3422, 1710, 1640, 1440, 1181, 1099,
1076 cmÀ1; HRMS: m/z [M+Na]+ calcd for C10H16O5Na: 239.0895;
found 239.0906 for C10H16O5Na.
4.1.9. (2R,3S,4R,5S)-4,5-Bis(methoxymethoxy)-2-methyl-
tetrahydro-2H-pyran-3-yl but-2-ynoate 16
To a solution of 15 (0.05 g, 0.21 mmol) and Et3N (0.058 g,
0.42 mmol) in dry THF (3 mL) at 0 °C, 2,4,6-trichlorobenzoyl chlo-
ride (0.051 g, 0.21 mmol) was added dropwise and stirred at room
temperature for 2 h. The reaction mixture was evaporated and the
residue dissolved in toluene (2 mL). A solution of 2 (0.017 g,
0.21 mmol) and DMAP (0.051 g, 0.42 mmol) in dry toluene (2 mL)
was added to the reaction mixture and stirred at room temperature
for 12 h. It was filtered through Celite and washed with toluene
(2 Â 5 mL). The filtrate was evaporated and the residue purified
by column chromatography (silica gel, 60–120 mesh, EtOAc/hex-
Acknowledgment
One of the authors (D.K.) thanks the CSIR, New Delhi, India, for
financial support in the form of a fellowship.
References
1. Reategui, R. F.; Gloer, J. B.; Campbell, J.; Shearer, C. A. J. Nat. Prod. 2005, 68, 701–
705.
2. Shearer, C. A.; Crane, J. L.; Chen, W. Mycologia 1999, 91, 145–156.
3. Harada, N.; Nakanishi, K. Acc. Chem. Res. 1972, 5, 257–263.
4. Yadav, J. S.; Lakshmi, P. N.; Harshavardhan, S. J.; Subba Reddy, B. V. Synlett
2007, 1945–1947.
5. (a) Banskota, A. H.; Kadota, S. J. Nat. Prod. 2001, 64, 491–496; (b) Suginome, M.;
Iwanami, T.; Ito, Y. J. Org. Chem. 1998, 63, 6096–6097; (c) Marko, I. E.;
Mekhalfia, A. Tetrahedron Lett. 1992, 33, 1799–1802; (d) Marko, I. E.; Bayston,
D. J. Tetrahedron 1994, 24, 7141–7156.
6. (a) Sharma, G. V. M.; Janardhan Reddy, J.; Laxmi Reddy, K. Tetrahedron Lett.
2006, 47, 6531–6535; (b) Sharma, G. V. M.; Laxmi Reddy, K.; Janardhan Reddy,
J. Tetrahedron Lett. 2006, 47, 6537–6540; (c) Sharma, G. V. M.; Babu, K. V.
Tetrahedron: Asymmetry 2007, 18, 2175–2184; (d) Babu, K. V.; Sharma, G. V. M.
Tetrahedron: Asymmetry 2008, 19, 577–583.
ane, 3:7) to afford 16 (0.05 mg, 79%) [a]D = +13.5 (c 0.2, CHCl3);
1H NMR (CDCl3, 300 MHz): d 1.14 (d, 3H, J = 6.2 Hz, CH3), 2.30 (s,
3H, –CH3), 3.17 (m, 1H, –CH), 3.34 (s, 3H, –OCH3), 3.35 (s, 3H,
–OCH3), 3.65–3.69 (m, 2H, 2 Â –CH), 3.78 (dd, 1H, J = 5.4, 9.7 Hz,
–CH), 4.03 (dd, 1H, J = 5.0, 10.9 Hz –CH), 4.56–4.62 (m, 2H,
–OCH2), 4.67–4.75 (m, 2H, OCH2) 5.28 (dd, 1H, J = 1.7, 3.5 Hz,
–CH), IR (neat) 2931, 2858, 1735, 1515, 1247, 1463 cmÀ1; HRMS
m/z [M+Na]+ calcd 325.1263, found 325.1269; for C14H22O7Na.
4.1.10. (Z)-[(2R,3S,4R,5S)-4,5-Bis(methoxymethoxy)-2-methyl-
tetrahydro-2H-pyran-3-yl]but-2-enoate 17
7. Sharma, G. V. M.; Chandra Mouli, Ch. Tetrahedron Lett. 2002, 43, 9159–9161.
8. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.
S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M. J. Org. Chem. 1992, 57, 2768–2771.
9. (a) Clark, J. H. Chem. Rev. 1980, 80, 429–452; (b) Corey, E. J.; Venkateswarlu, A. J.
Am. Chem. Soc. 1972, 94, 6190–6191.
To a solution of 16 (0.02 mg, 0.625 mmol) in dry MeOH (2 mL),
catalytic amount of Lindlar catalyst was added and the reaction
mixture was stirred at room temperature under a hydrogen atmo-
sphere for 3 h. The reaction mixture was filtered and washed with
ethyl acetate (10 mL). The filtrate was evaporated under reduced
10. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.