Synthesis of harzialactone A and its isomers from D-glucose and assignment of absolute stereochemistry

Article abstract of DOI:10.1016/S0957-4166(00)00389-X

The synthesis of the marine metabolite (3R,5R)-harzialactone A 1 from D-glucose is described. Syntheses of all the isomers (3S,5R)-2, (3R,5S)-3 and (3S,5S)-4 of 1 are also described and the absolute stereochemistry for the natural product 1 is assigned un

Full text of DOI:10.1016/S0957-4166(00)00389-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4071–4081
Synthesis of harzialactone A and its isomers from
D-glucose
and assignment of absolute stereochemistry
Hari Babu Mereyala,* Maju Joe and Rajendrakumar Reddy Gadikota
Organic Chemistry Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 28 July 2000; accepted 18 September 2000
Abstract
The synthesis of the marine metabolite (3R,5R)-harzialactone A 1 from
D
-glucose is described.
Syntheses of all the isomers (3S,5R)-2, (3R,5S)-3 and (3S,5S)-4 of 1 are also described and the absolute
stereochemistry for the natural product 1 is assigned unambiguously. © 2000 Elsevier Science Ltd. All
rights reserved.
1. Introduction
Marine microorganisms have been a rich source of bioactive metabolites, especially those with
novel structural features that might represent possible leads in the new drug discovery process.1
Numata et al. have previously isolated antitumour and cytotoxic compounds from microorgan-
isms living in the marine environment.2 Trichoderma harzianum OUPS-N115 strain that was
initially isolated from the sponge Halichondria okadai collected in the Tanabe Bay of Japan and
crude metabolites extracted were shown to exhibit cytotoxic activity against the P388
lymphocytic leukaemia test system in cell cultures.2 Fractionation of the crude culture filtrate
resulted in the isolation of harzialactone A 1 among other lactones. The absolute stereochem-
1
istry for 1 was established using H NMR spectra by comparison of the observed coupling
constants and NOE data with those of related compounds.2
Due to our interest in the design and synthesis of oxygenated lactones3 as cytotoxic agents, we
targeted the synthesis of harzialactone A 1 and its isomers for studying structure–activity
relationships. We have earlier reported the synthesis of harzialactone A 1 by a chiron approach
and revised the absolute stereochemistry as 3R and 5R configurations.4 Now, we report the
synthesis of all possible stereoisomers of harzialactone A 1, viz. (3S,5R)-2, (3R,5S)-3 and
(3S,5S)-4, respectively, by a similar chiron approach and unambiguously assign the absolute
configuration for the natural harzialactone A 1 as 3R and 5R.
* Corresponding author. E-mail: haribabu@iict.ap.nic.in
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00389-X

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2. Results and discussion
Retrosynthetic analysis of (3R,5R)-1 indicates that it could be derived from diol 5 by
regioselective oxidation of the lactol (Scheme 1). Diol 5 in turn could be derived from
diacetone-
hydroxyfuranolactone (3R,5S)-3, which is an antipode of 2, could be derived from diol 8 by a
similar sequence of reactions via intermediates 9 and 10 derived from -glucose by inverting the
D
-glucose 7 having the appropriate stereogenic centres at C-2 and C-4. The isomeric
D
configuration at C-4. The hydroxylactones (3S,5R)-2 and (3S,5S)-4 could be derived by
inverting the configuration at C-3 of 1 and 3, respectively.
Scheme 1.
Thus, for the synthesis of 1, diacetone- -glucose 7 was transformed into the diol 6 in good
D
yield by well established methods5 (Scheme 2). Compound 6 was converted to the methyl
xanthate derivative 11 by reaction with NaHꢀCS2ꢀMeI in THF and subjected to radical
deoxygenation (BU3SnH/cat. AIBN)6 in refluxing toluene to obtain the dideoxy derivative 12 in
1
an overall yield of 25% from
D
-glucose. Compound 12 was characterised from the H NMR
spectrum by the appearance of H-3 protons (2H) between l 1.40 and 1.60 (m, 1H, overlapped)

H. B. Mereyala et al. / Tetrahedron: Asymmetry 11 (2000) 4071–4081
4073
and at l 2.00 (ddd, 1H, J3,3% 13.0 Hz, J3,2 3.5 Hz, J4,3% 4.5 Hz) and benzylic protons at l 2.80 (dd,
1H, Jgem 13.0 Hz, J1%,4 6.0 Hz) and l 3.02 (dd, 1H, Jl%%,4 5.0 Hz). Compound 12 was subjected to
deprotection of the acetonide with aqueous acetic acid containing a catalytic amount of conc.
H2SO4 to obtain the diol 5 as a crystalline solid, mp 91–93°C. Regioselective oxidation of the
diol 5 with pyridinium dichromate in CH2Cl2 at reflux temperature gave the required lactone 1
in 10% yield. However, oxidation of 5 by use of Ag2CO3/Celite7 in benzene:N,N-dimethylfor-
mamide (DMF) (8:1) at reflux temperature resulted in the isolation of the lactone 1 in 71% yield.
1
Compound 1 was characterised from the H NMR spectrum by the appearance of an H-3
proton at l 3.95 (td, 1H, J3,4 8.3 Hz, J3,4% 8.3 Hz, JOH 1.9 Hz) and from the characteristic IR
absorption of g-lactone at 1769 cm−1 and hydroxyl at 3500 cm−1. Compound 1 exhibited a
1
specific rotation of +38.0 (c 0.3, CHCl3). 13C, H NMR and specific rotation data of (3R,5R)-1
were in complete agreement with the data reported for the natural product that was earlier
assigned (3S,5S)-configuration.2 In order to assign unambiguously the absolute stereochemistry
of 1, syntheses of its antipode (3S,5S)-42 and the other two isomers 2 and 3 were also
considered. Synthesis of (3S,5R)-hydroxylactone 2 was planned from 1 involving the inversion
of configuration at C-3 by Mitsunobu reaction8 of 1. Thus, reaction of 1 with DEAD/p-
NO2C6H4CO2H/Ph3P in THF gave the p-nitrobenzoate 13. Formation of 13 was evident from
1
the H NMR spectrum by the appearance of H-3 at l 5.73 (dd, J3,4 6.5 Hz, J3,4% 9.0 Hz) shifted
downfield due to esterification. Compound 13 on reaction with a catalytic amount of NaOMe
in methanol:dichloromethane (1:1) strictly at −20°C resulted in the isolation of (3S,5R)-2 as a
1
crystalline solid, mp 94–97°C, [h]D −8.5 (c 1.1, CHCl3). Compound 2 was characterised from H
NMR by the appearance of H-3 at l 4.40–4.70 (m, 1H) merged with H-5 and the IR spectrum
from the characteristic g-lactone absorption at 1772 cm−1.
Scheme 2. Reagents and conditions: i, NaH, CS2, MeI, THF, 0°C“rt; ii, nBu3SnH, AIBN, toluene, reflux; iii, 60% aq.
CH3COOH, cat. H2SO4, 45°C; iv, Ag2CO3–Celite, C6H6:DMF (8:1), reflux; v, p-NB acid, Ph3P, DEAD, THF,
0°C“rt; vi, NaOCH3, MeOH:CH2Cl2 (1:1), −20°C

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Synthesis of hydroxylactone (3R,5S)-3 was achieved starting from diacetone- -glucose 7.
D
Compound 7 was converted to the 3-deoxy diol derivative 14 by literature methods9a and
reacted with sodium metaperiodate to obtain the corresponding aldehyde that was immediately
reacted with phenylmagnesium bromide to isolate the alcohol 9 (Scheme 3). Compound 9 was
converted to the methyl xanthate ester 15 and deoxygenated to obtain the dideoxyfuranose
derivative 16 in good yield. Reaction of 16 with aq. acetic acid containing a catalytic amount of
conc. H2SO4 resulted in the isolation of diol 8, that on further regioselective oxidation with
Ag2CO3/Celite in benzene:DMF (8:1) at reflux temperature gave the hydroxylactone (3R,5S)-3
as a crystalline solid in good yield, mp 101–103°C, [h]D +8.7 (c 1.1, CHCl3). Compound 3 was
1
characterised by H NMR spectrum from the appearance of H-3 at l 4.40–4.70 (m, 1H) merged
1
along with H-5. (3R,5S)-3 was identical to (3S,5R)-2 in the H and 13C NMR spectra, except it
exhibited the opposite sign of the specific rotation. Thus, 3 is an enantiomer of 2.
Scheme 3. Reagents and conditions: i, NaIO4, CH2Cl2:MeOH:sat. aq. NaHCO3, 0°C“rt; ii, phenylmagnesium
bromide, THF, 0°C; iii, NaH, CS2, MeI, THF, 0°C“rt; iv, Bu3SnH, AIBN, toluene, reflux; v, 60% aq. CH3COOH,
cat. H2SO4, 45°C; vi, Ag2CO3–Celite, C6H6:DMF (8:1), reflux; vii, p-NB acid, Ph3P, DEAD, THF, 0°C“rt; viii,
NaOCH3, MeOH:CH2Cl2 (1:1), −20°C
The synthesis of hydroxylactone (3S,5S)-4 was achieved from 3 by inverting the configuration
at the C-3 hydroxyl. Thus, the Mitsunobu reaction of 3 (DEAD/p-NO2C6H4CO2H/Ph3P) gave
the p-nitrobenzoyl ester derivative 17 that on further reaction with a catalytic amount of
NaOMe in MeOH and dichloromethane (1:1) at −20°C gave (3S,5S)-4 in good yield, as a
crystalline solid, mp 71–74°C, [h]D −38.0 (c 0.3, CHCl3). (3S,5S)-4 was characterised as the
enantiomer of (3R,5R)-1 due to the negative sign of specific rotation and superimposable 1H and
13C NMR spectra. Thus, natural harzialactone A was unambiguously assigned the structure
(3R,5R)-1 and not (3S,5S) as was assigned earlier.2
In order to prepare a large number of structural analogues of 1 for studying structure–activity
relationships, we have developed an alternative, high yielding and concise synthetic route

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4075
starting from
D
-xylose. Thus, reaction of 1,2-O-isopropylidene-a- -xylofuranose with p-toluene-
D
sulphonyl chloride gave the mono tosylate 18 in good yield9a,b (Scheme 4). Compound 18 on
Grignard reaction with phenylmagnesium bromide gave 19. Compound 19 was converted to the
methyl xanthate ester 20 and then deoxygenated (Bu3SnH/AIBN) to obtain the advanced
intermediate 12 in an overall yield of 40% from
D
-xylose. Syntheses of 1 and 2 from 12 have
been carried out as described in Scheme 2. In order to synthesise 3 and 4 from the intermediate
19 it was required to deoxygenate the C-3 hydroxyl group and invert the configuration at C-2
(Scheme 4). Compound 19 was converted to the 3-O-triflate 21 and reacted with DBU in
benzene to obtain unsaturated furan derivative 22 in good yield. Compound 22 was character-
ised from the 1H NMR spectrum by the appearance of a double bond proton H-3 at l 5.95–6.18
merged with H-1. However, hydrogenation of 22 with Raney Ni in ethanol at 1 atm pressure of
H2 to obtain 16 resulted in decomposition of 22. Hence, it was not possible to prepare hydroxy-
lactones 3 and 4 by this route.
Scheme 4. Reagents and conditions: i, phenylmagnesium bromide, THF, 0°C“rt; ii, NaH, CS2, MeI, THF, 0°C“rt;
iii, Bu3SnH, AIBN, toluene, reflux; iv, trifluoromethanesulphonic anhydride, pyridine, CH2Cl2, 0°C; v, DBU, THF,
60°C; vi, (W4)-Raney Ni, EtOH, 1 atm H2
In conclusion syntheses of all four stereoisomers 1–4 of harzialactone A have been achieved
by a chiron approach starting from
D
-glucose. The naturally occurring harzialactone A 1 was
unambiguously assigned the correct absolute stereochemistry.
3. Experimental
1H NMR spectra were measured with a Varian Gemini 200 MHz spectrometer with
tetramethylsilane as internal standard for solutions in deuteriochloroform. J values are given in

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Hertz. 13C NMR spectra were recorded on a Varian Gemini 50 MHz spectrometer with
CDCl3 as the internal standard (lC 77.0) for solutions in deuteriochloroform. Optical rota-
tions were measured with a JASCO DIP-370 instrument and [h]2D5 values are in units of 10−1
deg cm2 g−1. All melting points are uncorrected. IR spectra were recorded on a Perkin–Elmer
1310 spectrometer. All organic solvents were freshly distilled prior to use. Air sensitive
reactions were generally performed under a positive pressure of nitrogen within the glassware,
which had been flame-dried under vacuum.
3.1. A mixture of 1-[2,2-dimethyl-(6S)-O-(S-methyl dithiocarbonyl)-(3aR,5R,6aR)perhydrofuro-
[2,3-d][1,3]dioxol-5-yl]-phenylmethyl-(1R/S)-O-(S-methyl dithiocarbonate) 11
To a solution of compound 65 (3.5 g, 13.2 mmol) in dry THF was added hexane washed
sodium hydride (0.8 g, 33.0 mmol) at 0°C and the mixture was stirred for 15 min. To the
above reaction mixture at 0°C was added carbon disulphide (2.0 mL, 33.0 mmol) and this
was stirred for 15 min. This was followed by the addition of iodomethane (2.1 mL, 33.0
mmol) at 0°C and the reaction mixture was brought to room temperature and stirred. When
the reaction was complete, excess sodium hydride was quenched with a few drops of acetic
acid and concentrated to obtain a residue, which was dissolved in dichloromethane (100 mL),
washed with water (2×40 mL), dried (Na2SO4), filtered and concentrated to a residue which
was filtered on a bed of silica gel [60–120 mesh, hexane:ethyl acetate (4:1)] to obtain a
diastereomeric mixture (3:1) of the title compound 11 (5.5 g, 94%) as a colourless syrup. lH
(200 MHz; CDCl3) 1.30, 1.50, 1.60 (6H, 3s, 2×Me), 2.50, 2.54, 2.60, 2.64 (6H, 4s, 2×SMe),
4.58, 4.64 (1H, 2d, J 4.7, H-6a), 4.75–4.92 (1H, m, H-5), 5.34, 5.90 (1H, 2d, J 2.3, 4.5, H-6),
6.00, 6.14 (1H, 2d, J 2.3 4.5 H-3a) 6.60, 6.71 (1H, 2d, J 10.0 C6H5CH6 ) and 7.25–7.50 (5H, m,
ArH); found: C, 48.59; H, 4.82%; C18H22O5S4 requires: C, 48.41; H, 4.97%.
3.2. 2,2-Dimethyl-5-phenylmethyl-(3aR,5R,6aR)-perhydrofuro[2,3-d][1,3]dioxole 12
To a solution of the dixanthate 11 (5.45 g, 12.2 mmol) in dry toluene (225 mL) were added
tributyltin hydride (8.9 g, 30.5 mmol), AIBN (5 mg) and the mixture was refluxed under a
nitrogen atmosphere for 6 h. After completion of the reaction, solvent was removed under
reduced pressure to obtain a residue which was filtered on a bed of silica gel [60–120 mesh,
hexane:ethyl acetate (6:1)] to obtain the title compound 12 (2.1 g, 74%) as a colourless syrup.
[h]D −18.0 (c 1.3, CHCl3); lH (200 MHz, CDCl3) 1.29, 1.49 (6H, 2s, 2×Me), 1.40–1.60 (1H,
m, H-6, merged), 2.00 (1H, ddd, Jgem 13.0, J6,6a 3.5, J5,6% 4.5, H-6%), 2.80 (1H, dd, Jgem 13.0,
J1%,5 6.0, C6H5CH2
J3a,6a 4.0, J6,6a 4.0, H-6a), 5.80 (1H, d, H-3a), 7.10–7.35 (5H, m, ArH); lC (50 MHz, CDCl3)
25.9, 26.5 (2×CH3), 38.3 (C-6), 40.2 (C6H5CH2), 78.1, 80.2 (C-5, 6a), 105.2 (C-3a), 110.6 (C-2)
6 ), 3.02 (1H, dd, J1%%,5 5.0, C6H5CH6 2), 4.40 (1H, dddd, H-5), 4.65 (1H, t,
6
6
and 126.2–137.5 (aromatic); found: C, 71.94; H, 7.88%; C14H18O3 requires: C, 71.77; H,
7.74%.
Prepared from compound 20 (1.15 g, 3.40 mmol), by reaction with tributyltin hydride (1.2
g, 4.1 mmol) and AIBN (5 mg) as described for the preparation of compound 12 from 11, to
obtain the title compound 12 (0.61 g, 77%) as a colourless syrup. Analytical data obtained
were in complete agreement with the compound obtained from 11.

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3.3. A mixture of 5-phenylmethyl-(2S/R,3R,5R)-tetrahydrofuran-2,3-diol 5
A solution of 12 (2.0 g, 8.5 mmol) in 60% aq. acetic acid (12 mL) and a catalytic amount of
H2SO4 was stirred at 45°C for 6 h. After completion of the reaction, it was neutralised carefully
with solid NaHCO3 and extracted into ethyl acetate (40 mL). The organic phase was separated,
washed with water (2×15 mL), dried (Na2SO4), filtered and concentrated to a residue which was
purified on a bed of silica gel [60–120 mesh, hexane:ethyl acetate (1:2)] to obtain the title
compound 5 (1.4 g, 85%) as a crystalline solid, mp 91–93°C. [h]D +17.0 (c 0.6, CHCl3). lH (200
MHz, CDCl3) 1.80–2.10 (2H, m, H-4,4%), 2.63 (1H, br.s, OH), 2.70–3.20 (2H, m, C6H5CH6 2), 3.80
(1H, br.s, OH), 4.10–4.35 (1H, m, H-5), 4.50–4.75 (1H, m, H-3), 5.27 (0.4H, s, H-2), 5.38 (0.6H,
d, J2,3 3.0, H-2) and 7.20–7.45 (5H, M, ArH); lC (50 MHz, CDCl3) 37.2, 37.7 (C-4), 41.4, 43.3
(C6H5C6 H2), 70.5, 75.8, 76.3, 79.1 (C-3,5), 96.3, 102.6 (C-2) and 125.0–138.5 (aromatic); found:
C, 68.25; H, 7.31%; C11H14O3 requires: C, 68.02; H, 7.27%.
3.4. 3-Hydroxy-5-phenylmethyl-(3R,5R)-tetrahydrofuran-2-one 1
To a solution of 5 (1.3 g, 6.7 mmol) in benzene:N,N-dimethylformamide (20 mL, 8:1) was
added Ag2CO3–Celite (4.8 g, 8.0 mmol) and refluxed for 3 h. After completion of the reaction,
the catalyst was filtered off and concentrated to a residue, which was chromatographed on silica
gel [60–120 mesh, hexane:ethyl acetate (3:1)] to obtain the title compound 1 (0.91 g, 71%) as a
1
white solid, mp 78–79°C (lit.,2 82–84°C). [h]D +38.0 (c 0.3, CHCl3). H NMR, 13C NMR and IR
spectra of 1 were in complete agreement with the reported data.2
3.5. 3-(4-Nitrophenylcarbonyloxy)-5-phenylmethyl-(3S,5R)-tetrahydrofuran-2-one 13
To a solution of compound 1 (0.8 g, 4.0 mmol) in dry THF (30 mL) were added
4-nitrobenzoic acid (1.9 g, 11.6 mmol) and triphenylphosphine (3.7 g, 14.2 mmol) followed by
diethyl azodicarboxylate (2.7 g, 15.6 mmol) in dry THF (5 mL) at 0°C and then the reaction
mixture was brought to room temperature and stirred under a nitrogen atmosphere for 8 h.
After completion of the reaction, the solvent was removed in vacuo to obtain a residue which
was purified by column chromatography [SiO2, 60–120 mesh, hexane:ethyl acetate (9:1)] to
obtain the title compound 13 (1.1 g, 79%) as a crystalline solid, mp 123–126°C. [h]D −8.0 (c 1.2,
CHCl3); IR wmax (neat) cm−1 1733, 1796. lH (200 MHz, CDCl3) 2.00–2.30 (1H, m, H-4),
2.70–2.96 (1H, m, H-4%), 3.05 (1H, dd, Jgem 14.0, J1%,5 6.4, C6H5CH2
6 ), 3.22 (1H, dd, J1%%,5 7.0,
C6H5CH2), 4.62–4.88 (1H, m, H-5), 5.73 (1H, dd, J3,4 6.5, J3,4% 9.0, H-3), 7.12–7.50 (5H, m, ArH)
6
and 8.12–8.49 (4H, m, ArH); found: C, 63.41; H, 4.49%; C18H15NO6 requires: C, 63.34; H,
4.43%.
3.6. 3-Hydroxy-5-phenylmethyl-(3S,5R)-tetrahydrofuran-2-one 2
To a solution of compound 13 (0.5 g, 1.5 mmol) in MeOH:CH2Cl2 (8 mL, 1:1) at −20°C was
added a catalytic amount of sodium methoxide and the mixture was stirred for 15 min. After
completion of the reaction, the reaction mixture was neutralised with carbon dioxide and the
solvent was removed in vacuo to obtain a residue which was filtered on a bed of silica gel
[60–120 mesh, hexane:ethyl acetate (4:2)] to obtain the title compound 2 (0.24 g, 83%) as a
crystalline solid, mp 94–97°C. [h]D −8.5 (c 1.1, CHCl3); IR wmax (neat) cm−1 3400, 1772; lH (200

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H. B. Mereyala et al. / Tetrahedron: Asymmetry 11 (2000) 4071–4081
MHz, CDCl3) 1.97 (H, dt, Jgem 12.0, J3,4 11.0, J4,5 11.0, H-4), 2.62 (1H, ddd, J3,4% 4.8, J4%,5 7.1,
H-4%), 2.80–3.00 (3H, m, C6H5CH2 and OH), 3.17 (1H, dd, Jgem 13.3, J1%,5 6.2, C6H5CH2),
4.40–4.70 (2H, m, H-3,5) and 7.10–7.45 (5H, m, ArH); lC (50 MHz, CDCl3) 36.5 (C-4), 41.1
6
6
(C6H5C6 H2), 68.4 (C-3), 77.2 (C-5), 126.9–135.5 (aromatic) and 177.5 (CꢁO); found: C, 68.70; H,
6.22%; C11H12O3 requires: C, 68.74; H, 6.29%. HRMS: M+ 192.0795 (requires M+ 192.0786).
3.7. A mixture of 1-[2,2-dimethyl-(3aR,5R,6aR)-perhydrofuro[2,3-d][1,3]dioxol-5-yl]-phenyl-
methan-(1R/S)-ol 9
To a solution of 14 (3.5 g, 17.2 mmol) at 0°C in CH2Cl2:MeOH:satd aq. NaHCO3 (1:1:0.1, 70
mL) was added in one portion NaIO4 (9.2 g, 43.0 mmol) and the mixture was stirred for 2 h at
room temperature. After completion of the reaction, the reaction mixture was diluted with
dichloromethane (70 mL) and filtered through Celite. The filtrate was concentrated in vacuo to
obtain the aldehyde (2.7 g, 90%) as a thick syrup. The aldehyde was dried under high vacuum
for 1 h at room temperature and reacted with phenylmagnesium bromide [prepared from
bromobenzene (3.6 g, 23.0 mmol) and magnesium (0.56 g, 23.0 mmol)] in dry THF (38 mL)
under a nitrogen atmosphere at 0°C for 20 min. The reaction mixture was stirred for a further
4 h at 0°C and quenched with satd aq. ammonium chloride (7 mL) and filtered through Celite.
The filtrate so obtained was concentrated to a residue and was chromatographed [SiO2, 60–120
1
mesh, hexane:ethyl acetate (4:1)] to obtain a diastereomeric mixture (1:1 by H NMR) of the
title compound 9 (3.1 g, 80%) as a thick syrup. lH (200 MHz, CDCl3) 1.32, 1.62 (6H, 2s,
2×CH3), 1.80–2.35 (2H, m, H-6,6%), 2.80 (1H, br.s, OH), 4.00–4.35 (1H, m, H-5), 4.60–4.75 (1H,
m, H-6a), 4.88 (0.5H, d, J 9.0, C6H5CH6 ), 4.98 (0.5H, d, J 4.5, C6H5CH6 ), 5.72 (0.5H, d, J 3.5,
H-3a), 5.82 (0.5H, d, J 2.5, H-3a) and 7.20–7.50 (5H, m, ArH); found: C, 67.34; H, 7.32%;
C14H18O4 requires: C, 67.18; H, 7.25%.
3.8. A mixture of 1-[2,2-dimethyl-(3aR,5R,6aR)-perhydrofuro[2,3-d][1,3]dioxol-5-yl]-phenyl-
methyl-(1R/S)-O-(S-methyl dithiocarbonate) 15
Prepared from the alcohol 9 (3.0 g, 12.0 mmol), sodium hydride (0.43 g, 18.0 mmol), carbon
disulphide (1.1 mL, 18.0 mmol) and iodomethane (1.1 mL, 18.0 mmol) as described for
compound 11 to obtain the title compound 15 (3.9 g, 95%) as a colourless syrup. lH (200 MHz,
CDCl3) 1.34, 1.70, 1.72 (6H, 3s, 2×Me), 1.80–2.40 (2H, m, H-6,6%), 2.56, 2.58 (3H, 2s, SMe),
4.40–4.82 (2H, m, H-5,6a), 5.80, 5.84 (1H, 2d, J 4.0, 3.5, H-3a), 6.68 (1H, d, J 9.0, C6H5ꢀCH6 )
and 7.20–7.50 (5H, m, ArH); found: C, 56.66; H, 6.01%; C16H20O4S2 requires: C, 56.45; H,
5.92%.
3.9. 2,2-Dimethyl-5-phenylmethyl-(3aR,5S,6aR)-perhydrofuro[2,3-d][1,3]dioxole 16
Prepared from the xanthate derivative 15 (3.8 g, 11.2 mmol) by reaction with tributyltin-
hydride (4.1 g, 14.0 mmol) and AIBN (5 mg) as described for compound 12, to obtain the title
compound 16 (2.1 g, 79%) as a colourless syrup. [h]D −26.0 (c 1.1, CHCl3); lH (200 MHz,
CDCl3) 1.36, 1.64 (6H, 2s, 2×Me), 1.90–2.10 (2H, m, H-6,6%), 2.90 (1H, dd, Jgem 14.0, J1%,5 8.0,
C6H5CH6 2), 3.18 (1H, dd, J1%%,5 7.0, C6H5CH6 2), 4.20–4.40 (1H, m, H-5), 4.60–4.80 (1H, m, H-6a),

H. B. Mereyala et al. / Tetrahedron: Asymmetry 11 (2000) 4071–4081
4079
5.76 (1H, d, J3a,6a 4.0, H-3a) and 7.10–7.40 (5H, m, ArH). lC (50 MHz, CDCl3) 25.9, 26.9
(2×CH3) 35.5, 42.3 (C-1%, 6), 80.8, 81.6 (C-6a,5), 106.4 (C-3a), 111.9 (CMe2) and 126.0–138.4
6
(aromatic); found: C, 71.92; H, 7.79%; C14H18O3 requires: C, 71.77; H, 7.74%.
3.10. A mixture of 5-phenylmethyl-(2S/R,3R,5S)-tetrahydrofuran-2,3-diol 8
Prepared from compound 16 (2.0 g, 8.5 mmol) as described for compound 5 to obtain the title
compound 8 (1.36 g, 82%) as a crystalline solid, mp 75–77°C (diastereomeric ratio 3:2). lH (200
MHz, CDCl3) 1.45–1.90 (1H, m, H-4), 2.15–2.55 (1H, m, H-4%), 2.75–3.20 (2H, m, C6H5CH6 2),
3.60 (1H, br.s, OH), 4.00–4.70 (2H, m, H-3,5), 5.19 (0.6H, J2,3 4.5, H-2), 5.30 (0.4H, s, H-2) and
7.10–7.45 (5H, m, ArH); found: C, 68.19; H, 7.38%; C11H14O3 requires: C, 68.02; H, 7.27%.
3.11. 3-Hydroxy-5-phenylmethyl-(3R,5S)-tetrahydrofuran-2-one 3
Prepared from the lactol 8 (1.3 g, 6.7 mmol) and Ag2CO3–Celite (5.0 g, 8.4 mmol) in benzene:
N,N-dimethylformamide (20 mL, 8:1) as described for compound 1 to obtain the title compound
3 (0.85 g, 66%) as a crystalline solid, mp 101–103°C. [h]D +8.7 (c 1.1, CHCl3); lH (200 MHz,
CDCl3) 1.97 (1H, dt, Jgem 12.0, J3,4 11.0, J4,5 11.0, H-4), 2.62 (1H, ddd, Jgem 12.0, J3,4% 4.8, J4%,5
7.1, H-4%), 2.80–3.00 (2H, m, C6H5CH2
C6H5CH2), 4.40–4.70 (2H, m, H-3,5) and 7.10–7.45 (5H, m, ArH); lC (50 MHz, CDCl3) 36.5
(C-4), 41.1 (C6H5C
6
and OH merged), 3.17 (1H, dd, Jgem 13.3, J1%,5 6.2,
6
6
H2), 68.4 (C-3), 77.2 (C-5), 126.9–135.5 (aromatic) and 177.5 (CꢁO); found:
C, 68.89; H, 6.37%; C11H12O3 requires: C, 68.74; H, 6.29%. HRMS: M+ 192.0788 (requires M+
192.0786).
3.12. 3-(4-Nitrophenylcarbonyloxy)-5-phenylmethyl-(3S,5S)-tetrahydrofuran-2-one 17
Prepared from compound 3 (0.7 g, 3.6 mmol) by reaction with 4-nitrobenzoic acid (1.8 g, 10.9
mmol), triphenylphosphine (3.5 g, 13.3 mmol) and diethylazodicarboxylate (2.5 g, 14.5 mmol) as
described for compound 13 to obtain the title compound 17 (0.99 g, 80%) as a crystalline solid,
mp 84–87°C. [h]D −17.0 (c 1.2, CHCl3); IR wmax (neat) cm−1 1722, 1788; lH (200 MHz, CDCl3)
2.40 (1H, ddd, Jgem 15.0, J4,5 12.0, J3,4 7.5, H-4), 2.62 (1H, ddd, J4%,5 10.0, J3,4% 4.0, H-4%), 3.90
(2H, dd, J 12.0, C6H5CH2
(4H, m, ArH). lC (50 MHz, CDCl3) 32.7 (C-4), 41.0 (C6H5C
(aromatic) and 163.4, 171.7 (CꢁO of ester, lactone); found: C, 63.51; H, 4.49%; C18H15NO6
requires: C, 63.34; H, 4.43%.
6
), 4.90–5.10 (2H, m, H-3,5), 7.15–7.50 (5H, m, ArH) and 8.10–8.40
H2), 68.9, 78.1 (C-3,5), 123.4–139.8
6
3.13. 3-Hydroxy-5-phenylmethyl-(3S,5S)-tetrahydrofuran-2-one 4
Prepared from compound 17 (0.5 g, 1.5 mmol) as described for compound 2, to obtain the
title compound 4 (0.2 g, 73%) as a crystalline solid, mp 71–74°C. [h]D −38.0 (c 0. 3, CHCl3); IR
wmax (neat) cm−1 3420, 1771. lH (200 MHz, CDCl3) 2.29 (1H, dt, Jgem 13.2, J3,4 8.3, J4,5 8.3, H-4),
2.38 (1H, ddd, J4%,5 3.5, H-4%), 2.98 (1H, dd, Jgem 15.0, J1%,5 5.50, C6H5CH2
6 ), 3.00 (1H, dd,
C6H5CH2), 3.99 (1H, td, J3,OH 1.9, H-3), 4.92 (1H, dtd, H-5) and 7.20–7.40 (5H, m, ArH). lC (50
6
MHz, CDCl3) 34.3 (C-4), 41.1 (C6H5C6 H2), 67.0 (C-3), 78.1 (C-5), 127.3–135.2 (aromatic) and
177.1 (CꢁO); found: C, 68.79; H, 6.33%; C11H12O3 requires: C, 68.74; H, 6.29%. HRMS: M+
192.0792 (requires M+ 192.0786).

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3.14. 2,2-Dimethyl-5-phenylmethyl-(3aR,5R,6aR)-perhydrofuro[2,3-d][1,3]-dioxol-(6S)-ol 19
To a solution of phenylmagnesium bromide [prepared from bromobenzene (6.5 g, 41.5 mmol)
and magnesium (1.0 g, 41.5 mmol) in dry THF (70 mL)] at 0°C under a nitrogen atmosphere
was added a solution of compound 18 (4.0 g, 11.6 mmol) in dry THF (20 mL) during a period
of 10 min and the reaction mixture was brought to room temperature. The reaction mixture was
stirred overnight at room temperature. After completion of the reaction, it was cooled to 0°C,
quenched with satd aq. ammonium chloride (17 mL) and filtered through Celite. The Celite bed
was washed with ethyl acetate (30 mL) and the combined filtrate was concentrated to a residue
which was chromatographed [SiO2, 60–120 mesh, hexane:ethyl acetate (4:1)] to obtain the title
compound 19 (2.4 g, 83%) as a crystalline solid, mp 125–127°C. [h]D −12.0 (c 1.1, CHCl3); lH
(200 MHz, CDCl3) 1.26, 1.46 (6H, 2s, 2×Me), 1.61 (1H, d, J6,OH 6.0, OH), 2.90 (1H, dd, Jgem
18.0, J1%,5 8.3, C6H5CH2
(1H, ddd, H-5), 4.43 (1H, d, J3a,6a 4.0, H-6a), 5.88 (1H, d, H-3a) and 7.10–7.35 (5H, m, ArH).
lC (50 MHz, CDCl3) 26.0, 26.5 (2×CH3) 33.8 (C6H5CH2), 74.6, 81.1, 85.2 (C-5,6,6a), 104.3
(C-3a), 111.4 (CMe2) and 126.4–137.5 (aromatic); found: C, 67.24; H, 7.27%; C14H18O4 requires:
6 ), 3.02 (1H, dd, J1%%,5 6.0, C6H5CH6 2), 3.90 (1H, dd, J5,6 2.3, H-6), 4.30
6
6
6
C, 67.18; H, 7.25%.
3.15. 2,2-Dimethyl-5-phenylmethyl-(3aR,5R,6aR)-perhydrofuro[2,3-d][1,3]dioxol-(6S)-yl-O-(S-
methyl dithiocarbonate) 20
Prepared from the alcohol 19 (1.0 g, 4.0 mmol) by reaction with sodium hydride (0.15 g, 6.0
mmol), carbon disulphide (0.36 mL, 6.0 mmol) and iodomethane (0.37 mL, 6.0 mmol) as
described for compound 11. This gave the title compound 20 (1.26 g, 93%) as a colourless syrup.
[h]D −16.0 (c 1.1, CHCl3); lH (200 MHz, CDCl3) 1.34, 1.54 (6H, 2S, 2×CMe), 2.69 (3H, s, SMe),
3.00 (1H, dd, Jgem 15.0, J1%,5 7.9, C6H5CH6 2), 3.10 (1H, dd, J1%%,5 6.80, C6H5CH6 2), 4.55 (1H, ddd,
J5,6 2.3, H-5), 4.64 (1H, d, J3a,6a 4.0, H-6a), 5.71 (1H, dd, H-6), 5.97 (1H, d, H-3a), 7.10–7.40
(5H, m, ArH); found: C, 56.59; H, 5.98%; C16H20O4S2 requires C, 56.45; H, 5.92%.
3.16. 2,2-Dimethyl-5-phenylmethyl-(3aR,5R,6aR)-perhydrofuro[2,3-d][1,3]dioxol-(6S)-yl-
(trifluoromethanesulphonate) 21
To a solution of 19 (1.0 g, 4.0 mmol) in dry dichloromethane (15 mL) at −10°C under a
nitrogen atmosphere was added dry pyridine (1 mL, 12.0 mmol) followed by trifluoromethane-
sulphonic anhydride (1.4 g, 5.0 mmol). The reaction mixture was stirred at 0°C for 45 min and
diluted with chilled dichloromethane (15 mL). The organic phase was separated and washed
with chilled aq. 2% HCl (15 mL), water (2×25 mL), dried (Na2SO4) and concentrated at reduced
pressure to obtain the title compound 21 (1.4 g, 92%) as a crystalline solid, mp 92–95°C. [h]D
−4.0 (c 1.1, CHCl3); lH (200 MHz, CDCl3) 1.38, 1.51 (6H, 2s, 2×Me), 2.92 (1H, dd, Jgem 13.6,
J1%,5 4.5, C6H5CH6 2), 3.12 (1H, dd, J1%%,5 7.9, C6H5CH6 2), 4.55 (1H, ddd, J5,6 2.3, H-5), 4.75 (1H,
dd, J3a,6a 4.0, H-6a), 5.10 (1H, d, J5,6 2.3, H-6), 6.20 (1H, d, H-3a) and 7.20–7.40 (5H, m, ArH);
found: C, 47.31; H, 4.55%; C15H17F3O6S requires: C, 47.12; H, 4.48%.
3.17. 2,2-Dimethyl-5-phenylmethyl-(3aR,6aR)-dihydrofuro[2,3-d][1,3]dioxole 22
To a solution of compound 21 (1.35 g, 3.5 mmol) in dry THF (25 mL) was added
1,8-diazabicyclo-[5.4.0]undec-7-ene (0.8 g, 5.3 mmol) and the mixture was stirred at 60°C for 7

H. B. Mereyala et al. / Tetrahedron: Asymmetry 11 (2000) 4071–4081
4081
h. After completion of the reaction, the mixture was diluted with chilled water (10 mL) and
diethyl ether (25 mL). The organic phase was separated and the aqueous phase was extracted
with diethyl ether (2×10 mL). The combined organic phase was washed with water (2×10 mL),
dried (Na2SO4) and concentrated to obtain the title compound 22 (0.6 g, 74%) as a crystalline
solid, mp 62–64°C. [h]D −95.0 (c 1.1, CHCl3); lH (200 MHz, CDCl3) 1.42, 1.50 (6H, 2s, 2×Me),
2.80–3.20 (2H, m, C6H5CH6 2), 4.80–5.00 (1H, m, H-6a), 5.95–6.18 (2H, m, H-3a,6) and 7.05–7.40
(5H, m, ArH); found: C, 72.47; H, 6.98%; C14H16O3 requires: C, 72.39; H, 6.91%.
Acknowledgements
M.J. thanks CSIR, New Delhi for financial assistance in the form of a fellowship.
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