Asymmetric dihydroxylation and regioselective C-3 indole coupling routes to the anticoccidial antibiotic (+)-diolmycin A2

Article abstract of DOI:10.1016/S0040-4020(01)01219-4

A highly enantioselective synthesis of (+)-diolmycin A2 starting from 4-hydroxybenzaldehyde and employing the Sharpless asymmetric dihydroxylation and CH₃NO₂ solvent assisted regioselective C-3 coupling of indole as the key steps is described.

Full text of DOI:10.1016/S0040-4020(01)01219-4

TETRAHEDRON
Pergamon
Tetrahedron 58 '2002) 1223±1227
Asymmetric dihydroxylation and regioselective C-3 indole
coupling routes to the anticoccidial antibiotic ꢀ1)-diolmycin A2
Rodney A. Fernandes, Mandar S. Bodas and Pradeep Kumarp
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 26 August 2001; accepted 13December 2001
AbstractÐA highly enantioselective synthesis of '1)-diolmycin A2 starting from 4-hydroxybenzaldehyde and employing the Sharpless
asymmetric dihydroxylation and CH3NO2 solvent assisted regioselective C-3coupling of indole as the key steps is described. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
With a search for new anticoccidial agents, Omura and
co-workers isolated diolmycins A1, A2, B1 and B2 '1±4)
from a fermentation broth of Streptomyces sp. WK-2955.1
Diolmycin A1 showed anticoccidial activity at concen-
trations ranging above 0.02 mg/mL and diolmycin A2 at
0.2 mg/mL. Diolmycins B1 and B2 showed poor anticoc-
cidial activity in comparison.2 The coupling constants
between the vicinal protons of the two chiral carbons of 1
and 2 were 5.4 and 2.2 Hz, respectively, suggesting an
erythro con®guration for 1 and a threo con®guration for 2.
Omura et al.2 reported the ®rst total synthesis of the race-
mate, which further con®rmed the presence of an erythro
vicinal diol moiety in 1. Subsequently an asymmetric syn-
thesis of diolmycin A1 1 was also reported by Omura et al.3
by exploiting the principle of kinetic resolution of an allylic
alcohol via the Sharpless asymmetric epoxidation. The
use of chiral pool material, such as l-tartaric acid for
2. Results and discussion
the preparation of diolmycin A2 has recently been reported
by Kotsuki et al.4 The key step in this report involves
ytterbium'III) tri¯uoromethanesulfonate catalyzed high-
pressure ring opening of an intermediate epoxide with
Scheme 1 summarizes the synthesis of the intermediate
epoxide 12, from the commercially available 4-hydroxy-
benzaldehyde 5. The hydroxyl protection of 5 with benzyl
indole. As part of our research program aimed at developing
enantioselective synthesis of naturally occurring lactones5a,b
and amino alcohols,5c±e the Sharpless asymmetric dihydroxyl-
ation6 'SAD) and subsequent transformation of diols via
cyclic sul®tes/sulfates were envisaged as powerful tools
offering considerable opportunities for synthetic manipula-
tions. Herein we report a new and highly enantiocontrolled
total synthesis of '1)-diolmycin A2 2 employing the SAD
and CH3NO2 solvent assisted regioselective C-3coupling of
indole as the key steps.
bromide in DMF gave 6 in essentially quantitative yield.
The subsequent Wittig ole®nation furnished 77 in 78%
yield, which on hydroboration oxidation afforded the
alcohol 8 in 88% yield. Compound 8 was subjected to
Swern oxidation to furnish the corresponding aldehyde
which on treatment with 'ethoxycarbonylmethylene) tri-
phenylphosphorane gave the trans Wittig product 98 in
72% yield. DIBAL-H reduction of 9 '93% yield) followed
by NBS bromination gave the allylic bromide 11 in 83%
yield. Compound 11 was treated with osmium tetroxide and
potassium ferricyanide as co-oxidant in the presence of
1,4-bis'dihydroquinin-9-O-yl)-phthalazine ['DHQ)2PHAL]
ligand under the SAD reaction conditions6 to give the
diol, which on subsequent treatment with K2CO3 in dry
Keywords: asymmetric synthesis; dihydroxylation; epoxide; regioselective
alkylation; indole; anticoccidial antibiotic.
p
Corresponding author. Tel.: 191-20-5893300; fax: 191-20-5893614;
e-mail: tripathi@dalton.ncl.res.in
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020'01)01219-4

1224
R. A. Fernandes et al. / Tetrahedron 58 ,2002) 1223±1227
Scheme 3. Alkylation of the complex indole±SnCl4.
employing the regioselective C-3coupling reaction with
indole as the key step. Although, the 3-position is the
most reactive site for electrophilic attack, low yields are
usually encountered due to the competitive formation of
1-alkylated and/or 1,3-dialkylated products often associated
with self polymerization of indole as a side product.10
However, a recent report about an improved synthesis of
3-acylindoles by Ottoni et al.11 prompted us to explore the
Lewis acid catalyzed regioselective C-3coupling of indole
with epoxide 12 for diolmycin synthesis. It has been
observed that in C-3acylation of indole using Lewis acid,
the addition of CH3NO2 as co-solvent greatly increases the
solubility of the solid indole±Lewis acid complex in the
reaction media, shortening the reaction time and raising
the yields signi®cantly.11 Indeed following the above pro-
cedure, the treatment of epoxide 12 with indole in a mixture
of CH2Cl2 and CH3NO2 '4:3) in the presence of SnCl4 as the
Lewis acid gave the C-3coupled product in good yield. A
probable mechanism of this reaction is depicted in Scheme
3. Presumably the Lewis acid SnCl4 complexes at 3-position
of indole, being the most reactive site for electrophilic
attack. The intermediate thus formed would then collapse
in a nucleophilic attack toward the epoxide eventually
leading to the C-3coupled indole. The subsequent deprotec-
tion of benzyl group with 10% Pd±C in EtOH under H2
Scheme 1. 'i) BnBr, K2CO3, DMF, TBAI 'cat), rt, 24 h, '99%);
'ii) Ph3PvCH2, THF, rt, 24 h, '78%); 'iii) 'a) BH3´DMS, THF, rt, 4 h,
'b) NaOH in EtOH/H2O '2:1), then 30% aq. H2O2, 08C, 3h '88%);
'iv) 'a) 'COCl)2, DMSO, CH2Cl2, 2788C, Et3N, 2608C, 1 h,
'b) Ph3PvCHCO2Et, THF, rt, 24 h '72%); 'v) DIBAL-H, Et2O, 08C,
1 hÐrt, 30 min '93%); 'iv) NBS, Ph3P, CH2Cl2, 2308C, 4 h '83%);
'vii) 'a) K3Fe'CN)6, K2CO3, 'DHQ)2PHAL, OsO4 'cat), NaHCO3,
MeSO2NH2, t-BuOH/H2O '1:1), 08C, 18 h, 'b) MeOH, K2CO3, rt, 10 h '73%).
methanol afforded the epoxide 129 [a]D ˆ111.07 'cˆ1,
20
CHCl3) [lit. 111.2 'cˆ0.98, CHCl3)4] in 73% yield.
Alternatively the epoxide 12 could be obtained from 9
following the reaction steps as shown in Scheme 2. The
dihydroxylation of ole®n 9 using the SAD procedure gave
20
the diol 13 [a]D ˆ229.8 'cˆ1, CHCl3) in 91% yield.
The dihydroxyl protection of 13 was carried out with
2,2-dimethoxypropane in presence of catalytic amount of
p-TSA to give the acetonide 14 in quantitative yield. Ester
group reduction of 14 with lithium aluminium hydride gave
the alcohol 159 [a]D ˆ211.00 'cˆ1.2, CHCl3) in 97%
20
yield. The primary hydroxyl group was then converted
into the tosylate 16 in 90% yield. Deprotection of the
acetonide was effected with 3N HCl in MeOH followed
by subsequent treatment with K2CO3 in dry MeOH to
20
atmosphere furnished diolmycin A2 2 [a]D ˆ146.32
'cˆ0.2, MeOH) [lit. 149.2 'cˆ0.24, MeOH)4] in 53% yield.
furnish the epoxide 129 [a]D ˆ111.12 'cˆ1, CHCl3) in
20
85% yield.
3. Conclusion
With the enantiomerically pure epoxide 12 in hand, we
then proceeded for the total synthesis of diolmycin A2 2
In conclusion a highly enantioselective synthesis of
'1)-diolmycin A2 2 from readily accessible starting
material by a simple and operationally feasible procedure
was achieved. The versatility of the route employed lies in
the fact that all the diolmycins A1, A2, B1, B2 can be
synthesized by employing either a or b-dihydroxylation
and using either cis or trans ole®n for step 'vii) and 'i) in
Schemes 1 and 2, respectively.
4. Experimental
4.1. General information
Solvents were puri®ed and dried by standard procedures
before use; petroleum ether of boiling range 60±808C was
used. Melting points are uncorrected. Optical rotations were
measured using sodium D line on a JASCO P-1020 micro-
processor based polarimeter. Infrared spectra were recorded
Scheme 2. 'i) K3Fe'CN)6, K2CO3, 'DHQ)2PHAL, OsO4 'cat), MeSO2NH2,
t-BuOH/H2O '1:1), 08C, 24 h '91%); 'ii) 2,2-DMP, p-TSA 'cat), 'CH3)2CO,
rt, overnight '99%); 'iii) LiAlH4, Et2O, 08C to rt, overnight '97%);
'iv) p-TSCl, Pyridine, CH2Cl2, rt, 12 h '90%); 'v) 'a) 3N HCl, MeOH, rt,
12 h, 'b) K2CO3, MeOH, rt, 10 h '85%); 'vi) 'a) Indole, SnCl4, CH2Cl2/
CH3NO2 '4:3), 08CÐrt, 12 h, 'b) 10% Pd±C, EtOH, H2, rt, 18 h, '53%).
1
on ATI MATTSON RS-1 FT-IR spectrometer. H and 13C
NMR spectra were recorded on Bruker AC-200 spectro-
meter. Mass spectra were obtained with a TSQ 70,

R. A. Fernandes et al. / Tetrahedron 58 ,2002) 1223±1227
1225
Finningen MAT mass spectrometer. Elemental analyses
were carried on a Carlo Erba CHNS±O analyzer.
69.95, 114.91, 127.26, 127.70, 128.36, 129.79, 130.86,
137.07, 157.36; MS 'EI), m/e '%): 228 [M1] '29), 210
'1.2), 107 '6.6), 91 '100), 65 '5.4); Anal. Calcd for
C15H16O2 '228.28): C, 78.91; H, 7.06. Found: C, 79.12; H,
6.95.
4.1.1. 4-Benzyloxybenzaldehyde ꢀ6). To a stirred suspen-
sion of K2CO3 '34 g, 246 mmol) in dry DMF '200 mL) at
room temperature was added 4-hydroxybenzaldehyde 5
'20 g, 163.93 mmol) and TBAI 'cat). The mixture was
stirred for 30 min and then benzylbromide '28.5 g,
166.6 mmol) was added. The reaction mixture was stirred
at room temperature for 24 h and then quenched with water
and extracted with EtOAc '3£100 mL). The combined
organic extracts were washed with water '2£100 mL),
brine, dried 'Na2SO4) and concentrated. Silica gel column
chromatography of the crude product using petroleum ether/
EtOAc '85:15) as eluent gave 6 '34.41 g, 99%) as a white
solid; mp 78±798C; IR 'CHCl3): nmax 2728, 1690, 1601,
4.1.4. Ethyl-4-ꢀ40-benzyloxyphenyl)but-2-enoate ꢀ9). To a
solution of oxalyl chloride '5.48 g, 46 mmol) in dry CH2Cl2
'50 mL) at 2788C was added dropwise DMSO '6.53mL,
91.98 mmol) in CH2Cl2 '5 mL) over 15 min. The reaction
mixture was stirred for 30 min and a solution of 8 '7 g,
30.66 mmol) in CH2Cl2 '20 mL) was added dropwise over
15 min. The reaction mixture was stirred for 30 min at
2788C and 30 min at 2608C and then Et3N '15 mL) in
CH2Cl2 '10 mL) was added dropwise and stirred for 1 h.
The reaction mixture was poured into 10% aq. HCl
'100 mL) and the organic layer separated. The aqueous
layer was extracted with EtOAc '3£50 mL) and the
combined organic layers were washed 'brine), dried
'Na2SO4) and concentrated to give the crude aldehyde.
This was used for the next step without further puri®cation.
1
1578, 832, 758 cm21; H NMR 'CDCl3): d 5.16 's, 2H),
7.1 'd, Jˆ8 Hz, 2H), 7.3'm, 5H), 7.85 'd, Jˆ8 Hz, 2H),
9.9 's, 1H); MS 'EI), m/e '%): 212 [M1] '4.3), 91 '100), 65
'9.5); Anal. Calcd for C14H12O2 '212.3): C, 79.23; H, 5.69.
Found: C, 79.18; H, 5.74.
4.1.2. 4-Benzyloxystyrene ꢀ7). To a mixture of triphenyl-
methylphosphonium iodide '24 g, 59.35 mmol) and sodium
amide '3.48 g, 89.23 mmol) was added dry THF '150 mL)
and stirred for 12 h at room temperature. The yellow super-
natant liquid was added through a syringe to the solution of
6 '10 g, 47.11 mmol) in dry THF '20 mL). The reaction
mixture was stirred for 24 h at room temperature and then
quenched with 2% aq. HCl and extracted with EtOAc
'3£100 mL). The combined organic extracts were washed
with water '2£100 mL), brine, dried 'Na2SO4) and con-
centrated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc '95:5) as eluent gave
7 '7.72 g, 78%) as a white solid; mp 71±728C 'lit. 68±
To a solution of 'ethoxycarbonylmethylene)triphenyl phos-
phorane '10.5 g, 30.14 mmol) in dry THF '30 mL) was
added a solution of the above aldehyde in dry THF
'10 mL). The reaction mixture was stirred at room tempera-
ture for 24 h. It was then concentrated and puri®ed by silica
gel column chromatography using petroleum ether/EtOAc
'9:1) as eluent to give 9 '6.54 g, 72%) as a pale yellow oil;
IR 'neat): nmax 1713, 1651, 1609, 1509, 910, 733 cm21; 1H
NMR 'CDCl3): d 1.30 't, Jˆ8 Hz, 3H), 3.50 'd, Jˆ6 Hz,
2H), 4.23'q, Jˆ8 Hz, 2H), 5.07 's, 2H), 5.85 'dt, Jˆ16,
2 Hz, 1H), 6.98 'd, Jˆ8 Hz, 2H), 7.14 'm, 3H), 7.4 'm,
5H); 13C NMR 'CDCl3): d 14.07, 37.41, 59.98, 70.02,
115.12, 122.10, 127.25, 127.73, 128.39, 129.64, 130.00,
137.10, 147.35, 157.65, 159.52, 166.25; MS 'EI), m/e
'%): 296 [M1] '13.7), 251 '1.8), 127 '10.7), 91 '100), 65
'2.9); Anal. Calcd for C19H20O3 '296.35): C, 77.00; H, 6.80.
Found: C, 77.02; H, 6.72.
1
698C12); IR 'CHCl3): nmax 1606, 1510, 836, 759 cm21; H
NMR 'CDCl3): d 5.09 's, 2H), 5.59 's, 1H), 5.68 's, 1H), 6.7
'm, 1H), 6.95 'd, Jˆ8 Hz, 2H), 7.35±7.44 'm, 7H); 13C
NMR 'CDCl3): d 69.94, 111.6, 114.9, 127.36, 127.84,
128.46, 130.7, 136.18, 136.95, 158.57; MS 'EI), m/e '%):
210 [M1] '38), 91 '100), 65 '3.6); Anal. Calcd for C15H14O
'210.26): C, 85.67; H, 6.71. Found: C, 85.49; H, 6.86.
4.1.5. 4-ꢀ40-Benzyloxyphenyl)-but-2-ene-1-ol ꢀ10). To a
stirred solution of 9 '1.5 g, 5.06 mmol) in dry ether
'75 mL) at 08C was added DIBAL-H '12.7 mL, 12.7
mmol, 1 M solution in toluene) dropwise over 15 min.
The reaction mixture was stirred for 1 h at 08C and 30 min
at room temperature. It was cooled again to 08C and
quenched with 2N HCl. The resulting gel was dissolved
by adding 6N HCl. The organic layer was separated and
aqueous layer extracted with CH2Cl2 '3£20 mL). The
combined organic layers were washed with brine, dried
'Na2SO4) and concentrated. Silica gel column chroma-
tography of the crude product using petroleum ether/
EtOAc '9:1) as eluent gave 10 '1.2 g, 93%) as a colorless
liquid; IR 'neat): nmax 3339, 1611, 1600, 1510, 811,
4.1.3. 2-ꢀ40-Benzyloxyphenyl) ethanol ꢀ8). To a solution of
7 '10 g, 47.56 mmol) in dry THF '100 mL) at 08C under
argon atmosphere was added BH3.DMS '24 mL, 48 mmol,
2 M solution in THF) and the reaction mixture was allowed
to warm to room temperature and stirred for 4 h. The reac-
tion ¯ask was cooled to 08C and then a solution of NaOH
'24 g, 96 mmol) in EtOH/H2O '2:1, 60 mL), followed by
H2O2 '16.4 mL, 144 mmol, 30% w/v solution in water)
were added dropwise over 30 min. It was then allowed to
stir at room temperature for 3h. The product was taken up in
EtOAc and the aqueous layer extracted with EtOAc
'3£25 mL). The combined organic layers were washed
with brine, water, dried 'Na2SO4) and concentrated. Silica
gel column chromatography of the crude product using
petroleum ether/EtOAc '8:2) as eluent gave 8 '9.55 g,
88%) as a white solid; mp 85±868C; IR 'CHCl3): nmax
1
755 cm21; H NMR 'CDCl3): d 2.15 'br s, 1H), 3.35 'd,
Jˆ6 Hz, 2H), 4.15 'm, 2H), 5.06 's, 2H), 5.62±5.93'm,
2H), 6.95 'd, Jˆ8 Hz, 2H), 7.31 'd, Jˆ8 Hz, 2H), 7.4±
7.48 'm, 5H); 13C NMR 'CDCl3): d 37.52, 62.96, 69.98,
114.90, 127.17, 127.62, 128.28, 128.31, 130.08, 131.29,
132.36, 137.14, 157.17; MS 'EI), m/e '%): 254 [M1]
'7.4), 228 '1.9), 91 '100), 77 '6.0), 65 '20.7); Anal. Calcd
for C17H18O2 '254.3): C, 80.29; H, 7.13. Found: C, 80.52; H,
7.01.
1
3402, 1611, 1511, 824, 757 cm21; H NMR 'CDCl3): d
1.72 'br s, 1H), 2.82 't, Jˆ6 Hz, 2H), 3.83 't, Jˆ6 Hz,
2H), 5.07 's, 2H), 6.95 'd, Jˆ8 Hz, 2H), 7.2 'd, Jˆ8 Hz,
2H), 7.3±7.4 'm, 5H); 13C NMR 'CDCl3): d 38.12, 63.45,

1226
R. A. Fernandes et al. / Tetrahedron 58 ,2002) 1223±1227
4.1.6. 4-ꢀ40-Benzyloxyphenyl)-1-bromo-but-2-ene ꢀ11).
To a solution of 10 '1 g, 3.93 mmol) in dry CH2Cl2
'15 mL) cooled at 2308C was added Ph3P '1.237 g,
4.72 mmol) followed by NBS '0.84 g, 4.72 mmol). After
4 h of stirring, the reaction mixture was diluted with water
'10 mL). The organic layer was separated and aqueous layer
extracted with CH2Cl2 '2£15 mL). The combined organic
layers were washed with brine, dried 'Na2SO4) and concen-
trated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc '24:1) gave 11
'1.03g, 83%) as a pale yellow liquid; IR 'neat): nmax
0.1 M solution in toluene, 0.4 mol%), followed by
methanesulfonamide '0.964 g, 10.12 mmol). After stirring
for 5 min at 08C, the ole®n 9 '3g, 10.13mmol) was added in
one portion. The reaction mixture was stirred at 08C for 24 h
and then quenched with solid Na2SO3 '5 g). The stirring was
continued for an additional 45 min and then the solution was
extracted with EtOAc '5£30 mL). The combined organic
layers were washed with 10% KOH, brine, dried 'Na2SO4)
and concentrated. Silica gel column chromatography of the
crude product using petroleum ether/EtOAc '9:3) as eluent
gave 13 '3.05 g, 91%) as a white solid; mp 104±1068C;
1
20
1608, 1508, 1454, 825, 736, 695 cm21; H NMR 'CDCl3):
[a]D ˆ229.8 'cˆ1, CHCl3); IR 'CHCl3): nmax 3488,
1
d 3.39 'd, Jˆ7 Hz, 2H), 4.00 'd, Jˆ8 Hz, 2H), 5.07 's, 2H),
5.8±5.97 'm, 2H), 6.95 'd, Jˆ8 Hz, 2H), 7.14 'd, Jˆ8 Hz,
2H), 7.38±7.48 'm, 5H); 13C NMR 'CDCl3): d 37.46, 53.45,
70.03, 115.05, 127.37, 127.77, 128.47, 129.24, 129.5,
131.63, 134.10, 135.01, 137.26, 157.47; MS 'EI), m/e
'%): 318 [M111] '6.0), 317 [M1] '5.0), 292 '1.5), 236
'5.0), 196 '1.6), 91 '100), 77 '5.0), 65 '24.4), 57 '8.8);
Anal. Calcd for C17H17BrO '317.3): C, 64.35; H, 5.40.
Found: C, 64.50; H, 5.72.
1732, 1611, 1514, 757 cm21; H NMR 'CDCl3): d 1.30 't,
Jˆ7 Hz, 3H), 2.70 'br s, 2H), 2.90 'd, Jˆ8 Hz, 2H), 4.12 'm,
2H), 4.3'q, Jˆ7 Hz, 2H), 5.06 's, 2H), 6.95 'd, Jˆ8 Hz,
2H), 7.22 'd, Jˆ8 Hz, 2H), 7.4 'm, 5H); 13C NMR 'CDCl3):
d 13.9, 38.9, 61.6, 69.8, 71.9, 73.5, 114.86, 127.17, 127.65,
128.28, 129.89, 130.23, 136.99, 157.43, 159.41, 173.38; MS
'EI), m/e '%): 330 [M1] '14), 312 '9), 239 '25.6), 197 '14),
107 '16.6), 91 '100), 65 '2.5); Anal. Calcd for C19H22O5
'330.36): C, 69.07; H, 6.71. Found: C, 68.85; H, 6.82.
4.1.7. ꢀ2S,3S)-4-ꢀ40-Benzyloxyphenyl)-1,2-epoxy-3-hydroxy-
butane ꢀ12). To a mixture of K3Fe'CN)6 '1.55 g,
4.727 mmol), K2CO3 '0.653g, 4.727 mmol), 'DHQ) 2PHAL
'12.27 mg, 15.75 mmol, 1 mol%) and NaHCO3 '0.4 g,
4.727 mmol) in t-BuOH/H2O '1:1, 20 mL) at 08C was
added osmium tetroxide '79 mL, 0.1 M solution in toluene,
0.5 mol%), followed by methanesulfonamide '0.150 g,
1.575 mmol). After stirring for 2 min at 08C, the allylic bro-
mide 11 '0.5 g, 1.575 mmol) was added in one portion. The
reaction mixture was stirred at 08C for 18 h and then
quenched with solid sodium sul®te '1 g). The stirring was
continued for additional 15 min and then the solution was
extracted with EtOAc '3£20 mL). The combined organic
phases were washed with 10% KOH and brine, dried
'Na2SO4) and concentrated. To the residue was added dry
MeOH '10 mL) and K2CO3 '0.262 g, 1.9 mmol) and the
mixture stirred at room temperature for 10 h. Water
'20 mL) and EtOAc '20 mL) were added. The organic
layer was separated and aqueous layer extracted with
EtOAc '2£20 mL). The combined organic layers were
washed with brine, dried 'Na2SO4) and concentrated. Silica
gel column chromatography of the crude product using
petroleum ether/EtOAc '4:1) as eluent gave 12 '0.310 g,
4.1.9. Ethyl-ꢀ2R,3S)-4-ꢀ40-benzyloxyphenyl)-2,3-O-iso-
propylidenedioxybutanoate ꢀ14). To a solution of 13
'2.5 g, 7.56 mmol) and p-TSA 'cat) in dry acetone
'75 mL) was added 2,2-dimethoxypropane '1.2 g, 1.4 mL,
11.35 mmol) and stirred overnight. A pinch of NaHCO3 was
added and stirred for 10 min. The reaction mixture was
®ltered through a short pad of neutral alumina and concen-
trated. Column chromatography of the crude product using
petroleum ether/EtOAc as eluent '9:1) gave 14 '2.77 g,
20
99%) as a colorless oil; [a]D ˆ217.74 'cˆ1, CHCl3); IR
'neat): nmax 1752, 1611, 1512, 1382, 1297, 1024, 757 cm21
;
1H NMR 'CDCl3): d 1.27 't, Jˆ7 Hz, 3H), 1.44 's, 3H), 1.48
's, 3H), 2.98±3.10 'm, 2H), 4.15±4.22 'm, 3H), 4.38 'm,
1H), 5.06 's, 2H), 6.95 'd, Jˆ8 Hz, 2H), 7.30 'd, Jˆ8 Hz,
2H), 7.47 'm, 5H); 13C NMR 'CDCl3): d 13.7, 25.47, 26.8,
38.0, 60.6, 69.65, 77.5, 79.35, 110.49, 114.5, 126.95,
127.39, 128.06, 128.9, 130.26, 136.95, 137.03, 157.43,
170; MS 'EI), m/e '%): 370 [M1] '9), 312 '6.4), 239
'12.8), 173 '23), 155 '15.4), 91 '100), 65 '3.8); Anal.
Calcd for C22H26O5 '370.42): C, 71.33; H, 7.07. Found: C,
71.52; H, 6.97.
4.1.10. ꢀ2S,3S)-4-ꢀ40-Benzyloxyphenyl)-2,3-O-isopropyl-
idenedioxy-butan-1-ol ꢀ15). To a stirred suspension of
LiAlH4 '307 mg, 8.1 mmol) in dry ether '100 mL) at 08C
was added 14 '2 g, 5.4 mmol) in ether '10 mL) dropwise.
The reaction mixture was warmed to room temperature and
stirred overnight. Excess LiAlH4 was destroyed by slow
addition of 5% aq. NaOH followed by addition of EtOAc
'100 mL). The white cake was ®ltered and washed with
EtOAc '3£50 mL) and MeOH '2£20 mL). The ®ltrate
was dried 'K2CO3) and concentrated. Column chroma-
tography of the crude product using petroleum ether/
EtOAc '4:1) gave 15 '1.72 g, 97%) as a white solid; mp
20
73%) as a white solid; mp 67±698C; [a]D ˆ111.07
'cˆ1, CHCl3) 'lit. 111.2 'cˆ0.98, CHCl3)4); IR 'CHCl3):
n
max 3443, 1611, 1511, 1177, 1025, 759, 697, 668 cm21; 1H
NMR 'CDCl3): d 2.09 's, 1H), 2.62±2.65 'dd, Jˆ2, 4 Hz,
1H), 2.77 't, Jˆ4 Hz, 1H), 2.86±2.89 'dd, Jˆ4, 2 Hz, 2H),
3.04 'm, 1H), 3.66 'm, 1H), 5.06 's, 2H), 6.96 'd, Jˆ8 Hz,
2H), 7.18 'd, Jˆ8 Hz, 2H), 7.37±7.48 'm, 5H); 13C NMR
'CDCl3): d 40.02, 44.87, 54.61, 70.09, 72.41, 115.04,
127.32, 127.80, 128.42, 129.60, 130.26, 137.14, 157.68;
MS 'EI), m/e '%): 270 [M1] '10.8), 197 '10.2), 107 '3.4),
91 '100), 77 '5.4), 65 '21.6); Anal. Calcd for C17H18O3
'270.3): C, 75.53; H, 6.71. Found: C, 75.63; H, 6.98.
20
58±598C; [a]D ˆ211.00 'cˆ1.2, CHCl3); IR 'CHCl3):
1
nmax 3468, 1610, 1510, 1216, 1038, 763 cm21; H NMR
4.1.8. Ethyl-ꢀ2R,3S)-4-ꢀ40-benzyloxyphenyl)-2,3-dihydroxy-
butanoate ꢀ13). To a mixture of K3Fe'CN)6 '9.93g,
30.4 mmol), K2CO3 '4.2 g, 30.4 mmol) and 'DHQ)2PHAL
'78.9 mg, 101 mmol, 1 mol%) in t-BuOH/H2O '1:1,
120 mL) at 08C was added osmium tetroxide '411 mL,
'CDCl3): d 1.43's, 6H), 2.8 'm, 1H), 2.99 'm, 1H), 3.15
'br s, 1H), 3.35 'm, 1H), 3.5 'm, 1H), 3.83 'm, 1H), 4.12 'm,
1H), 5.05 's, 2H), 6.95 'd, Jˆ8 Hz, 2H), 7.18 'd, Jˆ8 Hz,
2H), 7.4 'm, 5H); 13C NMR 'CDCl3): d 26.72, 26.94, 38.15,
61.86, 69.69, 77.34, 80.90, 108.35, 114.64, 126.99, 127.43,

R. A. Fernandes et al. / Tetrahedron 58 ,2002) 1223±1227
1227
128.09, 129.31, 129.37, 136.92, 157.32; MS 'EI), m/e '%):
328 [M1] '6.6), 313 [M1215] '2.4), 198 '4.2), 131 '55.4),
91 '100), 65 '3.0), 58 '10.2); Anal. Calcd for C20H24O4
'328.4): C, 73.14; H, 7.36. Found: C, 73.18; H, 7.45.
was separated. The aqueous layer was extracted with
EtOAc '2£15 mL). The combined organic layers were
washed with brine, dried 'Na2SO4) and concentrated to a
syrupy liquid. This was dissolved in dry EtOH '10 mL)
and 10% Pd±C '25 mg) was added carefully. The reaction
mixture was stirred under an atmosphere of H2 ®lled in a
balloon for 18 h at room temperature. The mixture was
®ltered and concentrated under reduced pressure. The
residue was puri®ed by silica gel column chromatography
using CHCl3/MeOH '5:1) as eluent to give diolmycin A2 2
4.1.11. ꢀ2S,3S)-4-ꢀ40-Benzyloxyphenyl)-2,3-O-isopropyl-
idenedioxy-1-p-toluenesulfonyloxybutane ꢀ16). To a solu-
tion of 15 '0.5 g, 1.52 mmol) in dry CH2Cl2 '10 mL) was
added pyridine '1 mL) followed by p-TsCl '435 mg,
2.28 mmol) and stirred at room temperature for 12 h. The
reaction mixture was diluted with EtOAc '50 mL) and
washed with water '2£20 mL), brine, dried 'Na2SO4) and
concentrated. Column chromatography of the crude product
using petroleum ether/EtOAc '9:1) gave 16 '0.66 g, 90%) as
20
'21 mg, 53%) as a thick syrupy liquid; [a]D ˆ146.32
'cˆ0.2, MeOH) [lit. 149.2 'cˆ0.24, MeOH)4]. Spectro-
scopic data are in full agreement with those reported.4
20
a white solid; mp 83±848C 'lit. 83.5±84);4 [a]D ˆ219.62
'cˆ1, CHCl3) [lit. 219.7 'cˆ1.07, CHCl3)4]; IR 'CHCl3):
nmax 1611, 1512, 1370, 1241, 1217, 1177, 1020, 982, 830,
815, 757, 668 cm21; 1H NMR 'CDCl3): d 1.33 's, 3H), 1.37
's, 3H), 2.44 's, 3H), 2.7±3.01 'm, 2H), 3.8±4.06 'm, 4H),
5.07 's, 2H), 6.9 'd, Jˆ8 Hz, 2H), 7.10 'd, Jˆ8 Hz, 2H),
7.3±7.45 'm, 7H), 7.75 'd, Jˆ8 Hz, 2H); 13C NMR 'CDCl3):
d 20.91, 26.31, 26.8, 37.82, 68.88, 69.57, 77.40, 77.62,
108.91, 114.6, 126.88, 127.36, 128.02, 128.72, 129.38,
129.93, 132.76, 136.88, 144.34, 157.35; MS 'EI), m/e
'%): 482 [M1] '12.7), 467 [M1215] '4.0), 285 '8.7), 227
'27.0), 91 '100), 65 '12.7); Anal. Calcd for C27H30O6S
'482.51): C, 67.21; H, 6.27. Found: C, 67.52; H, 6.05.
Acknowledgements
R. A. F. thanks CSIR, New Delhi, for senior research
fellowship. We are grateful to Dr M. K. Gurjar for his
support and encouragement. This is NCL Communication
no. 6616.
References
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brine, dried 'Na2SO4) and concentrated. Silica gel column
chromatography of the crude product using petroleum ether/
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20
solid; mp 67±698C; [a]D ˆ111.12 'cˆ1, CHCl3).
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4.3. Diolmycin A2 ꢀ2)
1
9. The enantiomeric excess is determined by H and 19F NMR
To a stirring solution of indole '21 mg, 179 mmol) in dry
CH2Cl2 '4 mL) under argon atmosphere at 08C was added
SnCl4 '25 mL, 207 mmol). The icebath was removed and the
reaction mixture was stirred for 45 min at room temperature.
The epoxide 12 '40 mg, 148 mmol) was added in small
portions to the suspension, followed by CH3NO2 '3mL).
The mixture was stirred for 10 h at room temperature and
then quenched with cold water '10 mL) and EtOAc
'20 mL). The mixture was ®ltered and the organic layer
spectroscopy of the corresponding '1)-MTPA ester. The
enantiomeric purity was found to be .95%.
10. Sundberg, R. J. The Chemistry of Indoles; Academic: New
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