Enantioselective synthesis of (R)-(-)-mevalonolactone via cyclic sulfate methodology

Article abstract of DOI:10.1016/S0957-4166(99)00496-6

An asymmetric synthesis of (R)-(-)-mevalonolactone is described using the Sharpless asymmetric dihydroxylation and the regioselective nucleophilic opening of a cyclic sulfate as key steps. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00496-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4349–4356
Enantioselective synthesis of (R)-(−)-mevalonolactone via cyclic
sulfate methodology†
Rodney A. Fernandes and Pradeep Kumar ∗
Division of Organic Chemistry: Technology National Chemical Laboratory, Pune-411008, India
Received 4 October 1999; accepted 2 November 1999
Abstract
An asymmetric synthesis of (R)-(−)-mevalonolactone is described using the Sharpless asymmetric dihydroxyl-
ation and the regioselective nucleophilic opening of a cyclic sulfate as key steps. © 1999 Elsevier Science Ltd. All
rights reserved.
1. Introduction
Mevalonic acid or mevalonolactone is the biosynthetic precursor of most terpenoids, steroids, ca-
rotenoids, isoprenoids and pentanoids,1 and therefore, it has been a synthetic target of considerable
interest. In connection with our studies on the synthesis of some naturally occurring lactones,2 mainly by
stereoselective transformation of diols via cyclic sulfates, we became interested in developing a simple
and concise route to (R)-(−)-mevalonolactone.
Mevalonolactone was first discovered and synthesized via resolution by Folkers and co-workers.3
Since then a number of asymmetric syntheses of this molecule has been published, the most popular of
which involves the enantioselective synthesis provided by the Sharpless epoxidation of a suitable allylic
alcohol.4 The chiral pool materials such as linalool,5 quinic acid,6 2-methyl-2-hydroxy-γ-butyrolactone,7
and more recently a chiral equivalent of cyclohexa-2,5-dienone,8 and the chiral template 1,2:5,6-di-
O-isopropylidene-α-D-glucofuran-3-ulose9 were reported to be the best sources for the preparation of
mevalonolactone. Other interesting synthetic methodologies involve the use of chiral sulfoxides,10 1,3-
oxathianes11 and axially dissymmetric binaphthyldiamines.12 In addition, several enzymatic syntheses
starting from achiral precursors have been known in the literature.13 However, some of these methods
suffer either from poor enantiomeric purity10,12 or low chemical yield,14 and therefore, an expeditious
synthesis of the target molecule is highly desirable. Herein we report a new and enantiocontrolled five
∗
†
Corresponding author. E-mail: tripathi@dalton.ncl.res.in
This paper is cordially dedicated to Dr. T. Ravindranathan on the occasion of his 60th birthday.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00496-6
tetasy 3131

4350
R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4349–4356
step strategy for the synthesis of (R)-(−)-mevalonolactone 6. The Sharpless asymmetric dihydroxylation
of an appropriate olefin 2 and the regioselective nucleophilic opening of a cyclic sulfate 4 were employed
as key steps in the synthesis.
2. Results and discussion
Our synthetic strategy for the synthesis of (R)-(−)-mevalonolactone was envisioned through the
retrosynthetic route as shown in Scheme 1. The β-hydroxy acid was visualized as an ultimate precursor
for the target molecule which in turn could be obtained from the cyanide opening of the corresponding
cyclic sulfate and subsequent hydrolysis. Thus, the essential feature of our retro-analysis was the
presumption that the nucleophilic opening of the cyclic sulfate would occur in a regioselective manner at
the terminal carbon. Another feature of this synthetic strategy was the formation of the cyclic sulfate with
an acid sensitive group present and the chemoselective hydrolysis of the sulfate ester in order to furnish
the desired β-hydroxy acid.
Scheme 1.
The detailed information regarding the reagents, solvents and reaction conditions followed by usual
work up is provided in Schemes 2 and 3 and in the Experimental. Our synthesis of target molecule 6
started from 3-methyl-3-butene-1-ol 1, a readily available starting material.15 Thus, treatment of 1 with
ethyl vinyl ether in the presence of a catalytic amount of p-toluenesulfonic acid gave 2 in 93% yield.
The dihydroxylation of olefin 2 using the Sharpless asymmetric dihydroxylation procedure16 gave the
20
diol 3,17 [α]D +1.95 (c 1, CHCl3), in 97% yield. Diol 3 was then treated with thionyl chloride and
triethylamine to obtain the cyclic sulfite which was further oxidized using NaIO4 and a catalytic amount
of ruthenium trichloride to furnish the corresponding cyclic sulfate18 4 in 92% yield. The cyclic sulfate
4 on reaction with sodium cyanide followed by chemoselective hydrolysis of sulfate ester under mild
conditions19 furnished the desired compound 5 in 85% yield.
Alternatively, 5 could be obtained from the diol 3 following a sequence of reactions as depicted
in Scheme 3. The diol 3 on treatment with p-toluenesulfonyl chloride in the presence of pyridine at
room temperature afforded 8 in 96% yield. The nucleophilic displacement of tosylate with sodium

R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4349–4356
4351
Scheme 2. (i) Ethyl vinyl ether, PTSA (cat.), 0°C, 1 h (93%); (ii) (DHQD)2-PHAL, OsO4 (cat.), K3Fe(CN)6, K2CO3,
t-BuOH:H2O (1:1), 0°C, 24 h (97%); (iii) (a) SOCl2, Et3N, CH2Cl2, 0°C, 20 min; (b) RuCl3·H2O, NaIO4, CCl4:CH3CN:H2O
(1:1:1.5), 0°C, 2 h (92%); (iv) NaCN, DMF, 80°C, 8 h, then THF, concd H2SO4:H2O (2:1), rt, 6 h (85%); (v) NaCN, DMF,
80°C, 8 h, then concd H2SO4 (2 equiv.), EtOH:H2O (1:2), reflux, 18 h (60%); (vi) 3N NaOH, 70°C, 3 h, then MeOH, pH 2
(concd HCl), acetone, PTSA (cat.), rt, 8 h (70%)
Scheme 3. (i) TsCl, pyridine, rt, 18 h (96%); (ii) NaCN, EtOH:H2O (3:2), rt, 18 h (97%); (iii) 3N NaOH, 70°C, 3 h, then MeOH,
pH 2 (concd HCl), acetone, PTSA (cat.), rt, 8 h (70%)
cyanide in aqueous ethanol furnished the desired compound 5 in essentially quantitative yield. The
physical and spectroscopic data for this compound exactly matched the one prepared from the cyclic
sulfate. The enantiomeric excess of 5 was determined by converting it into the (+)-MTPA ester.20 The
diastereomeric excess (89%) as determined by 1H NMR spectroscopy of the resulting (+)-MTPA ester is
based on the integration of the characteristic methylene resonance α to the cyano group (doublet in the
2.59–2.61 ppm region) due to the MTPA ester portion. The cyano compound 5 on treatment with aqueous
sodium hydroxide furnished the corresponding β-hydroxy acid which without any further isolation and
purification was subsequently lactonized with p-toluenesulfonic acid to afford the target molecule 6 in
70% yield having [α]D20 –19.1 (c 0.4, EtOH) [lit. [α]D20 –21.6 (c 1.565, 95% EtOH),21 [α]D25 –19.0 (c
2.15, CHCl3)13b].
However, attempts to achieve the one-pot cyclic sulfate opening, hydrolysis of the sulfate ester
and cyano group hydrolysis to the corresponding acid followed by deprotection of the hydroxyl and
subsequent lactonization to the target molecule 6 in strongly acidic media22 failed. Thus, when the cyclic
sulfate 4 was heated with sodium cyanide in dimethylformamide at 80°C followed by solvent removal

4352
R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4349–4356
and treatment of the residual sulfate ester with aqueous ethanolic solution of concd sulfuric acid [concd
H2SO4 (2 equiv.), EtOH:H2O, 1:2] under reflux, it gave only the anhydromevalonolactone 7, presumably
by facile dehydration of the β-hydroxy group (Scheme 2). Compound 7 was fully characterized by its
spectroscopic data which were found to be in full agreement with the literature data.2a,23
3. Conclusion
In conclusion, an asymmetric synthesis of (R)-mevalonolactone has been realized using the Sharpless
asymmetric dihydroxylation as the source of chirality for the first time. Thus, the results described herein
constitute a short and efficient synthesis of natural isomer of mevalonolactone. The unnatural enantiomer
can be synthesized via α-dihydroxylation of 2 and following the reaction sequence as shown in Schemes
2 and 3. The synthetic strategy (retrosynthetic analysis, Scheme 1) described here has significant potential
of further extension to chiral substituted β-hydroxy acids24 which serve as important synthons for several
naturally occurring and biologically active molecules.
4. Experimental
4.1. General information
The solvents were purified and dried by standard procedures before use; petroleum ether of boiling
range 60–80°C was used. Optical rotations were measured using sodium D line on a JASCO-181 digital
polarimeter. Infrared spectra were recorded on an ATI MATTSON RS-1 FT-IR spectrometer. 1H NMR
and 13C NMR were recorded on Bruker AC-200 and MSL 300 NMR spectrometers, respectively. Mass
spectra were obtained with a Finnigan MAT-1020 B-70 eV mass spectrometer. Elemental analyses were
carried out on a Carlo Erba CHNS-O analyzer. Enantiomeric excess was determined by 1H NMR spectra
and by Chirasil-Val-D gas chromatograph.
4.2. 4-(1-Ethoxyethoxy)-2-methyl-1-butene 2
To a stirred solution of ethyl vinyl ether (30 mL) containing p-toluenesulfonic acid (60 mg) was added
3-methyl-3-butene-1-ol 1 (8.6 g, 100 mmol) dropwise at 0°C. After stirring for 1 h, the reaction mixture
was warmed to room temperature and diluted with petroleum ether (100 mL). Filtration through a short
pad of neutral alumina and removal of solvent gave a yellowish liquid which was distilled in vacuo to
give 2 (14.65 g, 93%) as a colorless liquid, bp 60°C/10 torr: TLC (silica gel, petroleum ether:EtOAc,
1
1:1): Rf=0.89; IR (neat) 3025, 2976, 1648, 1399, 1132, 1096, 830 cm−1; H NMR (CDCl3) δ 1.19 (t,
J=7 Hz, 3H), 1.30 (d, J=6.5 Hz, 3H), 1.73 (s, 3H), 2.27 (t, J=6.5 Hz, 2H), 3.3–3.65 (m, 4H), 4.69 (q,
J=6.5 Hz, 1H), 4.76 (d, J=3 Hz, 2H); 13C NMR (CDCl3) δ 14.78. 19.27, 22.14, 37.64, 60.10, 63.18,
99.06, 110.9, 142.31; MS (EI), m/z (%) 158 [M+] (0.8), 143 (3.8), 129 (4.3), 113 (40.6), 103 (32.5), 89
(22.7), 73 (97.4), 69 (100), 53 (29.5). Anal. calcd for C9H18O2 (158.23): C, 68.31; H, 11.47. Found: C,
68.26; H, 11.62.

R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4349–4356
4353
4.3. 4-(1-Ethoxyethoxy)-2-methyl-(2R)-butane-1,2-diol 3
To a mixture of K3Fe(CN)6 (4.8 g, 14.6 mmol), K2CO3 (2.02 g, 14.6 mmol) and (DHQD)2-PHAL (38
mg, 48.8 µmol) in t-BuOH–H2O (1:1, 30 mL) cooled at 0°C was added osmium tetroxide (100 µL, 0.1
M solution in toluene). After stirring for 5 min at 0°C, the olefin 2 (0.75 g, 4.74 mmol) was added in one
portion. The reaction mixture was stirred at 0°C for 24 h and then quenched with solid sodium sulfite (7
g). The stirring was continued for an additional 45 min and then the solution was extracted with EtOAc
(3×20 mL). The combined organic phases were dried (Na2SO4) and concentrated. Silica gel column
chromatography of the crude product using petroleum ether:EtOAc (3:2) as eluent gave 3 (0.884 g, 97%)
as a colorless liquid: TLC (silica gel, EtOAc): Rf=0.62; [α]D20 +1.95 (c 1, CHCl3); IR (neat) 3430, 2977,
2931, 1451, 1381, 1343, 1132, 1089, 1054, 938 cm−1; 1H NMR (CDCl3) δ 1.18 (t, J=7 Hz, 3H), 1.28 (s,
3H), 1.30 (d, J=6.5 Hz, 3H), 1.72 (m, 1H), 1.87 (m, 1H), 2.17 (br s, 1H), 2.97 (br s, 1H), 3.43 (m, 2H),
3.5–3.8 (m, 4H), 4.67 (q, J=6.5 Hz, 1H); 13C NMR (CDCl3) δ 15.00, 19.65, 23.86, 37.70, 61.09, 61.70,
69.70, 72.16, 99.78; MS (EI), m/z (%) 147 [M+−OCH2CH3] (6), 115 (69), 103 (16.7), 89 (29), 85 (86.3),
73 (100), 57 (37). Anal. calcd for C9H20O4 (192.25): C, 56.22; H, 10.48. Found: C, 56.19; H, 10.46.
4.4. 5-(1-Ethoxyethoxy) ethyl-5-methyl-(5R)-1,3,2-dioxathiolane-2-dioxide 4
To a stirred solution of the diol 3 (0.3 g, 1.56 mmol) in dry CH2Cl2 (10 mL) cooled at 0°C were added
Et3N (0.436 g, 0.6 mL, 4.3 mmol) and a solution of SOCl2 (0.278 g, 0.17 mL, 2.34 mmol) in CH2Cl2
(5 mL) over a period of 10 min. Stirring was continued for 20 min at 0°C and then the solution was
quenched by addition of water (5 mL) followed by addition of CH2Cl2 (30 mL). The organic layer was
separated, washed with cold water (2×10 mL) and brine (20 mL), dried (Na2SO4) and filtered through a
pad of silica gel. The filtrate was concentrated to give a yellow liquid. To this was added a cold solution
of CCl4 (3 mL) and CH3CN (3 mL). The reaction flask was cooled in an ice bath and cold water (4.5
mL) was added. RuCl3·H2O (4.5 mg, 0.021 mmol) and NaIO4 (0.535 g, 2.5 mmol) were added at once
and the reaction mixture was stirred vigorously at 0°C. The progress of reaction was monitored by TLC.
After 2 h, ether (20 mL) was added and the layers were separated. The aqueous layer was extracted with
ether (3×10 mL) and the combined organic layers were washed with brine (20 mL), dried (Na2SO4) and
passed through a silica gel column. The filtrate was concentrated and the crude product was purified by
silica gel column chromatography using petroleum ether:EtOAc (9:1) as eluent to give 4 (0.365 g, 92%)
20
as a yellow liquid: TLC (silica gel, petroleum ether:EtOAc, 4:1): Rf=0.51; [α]D –1.3 (c 0.3, MeOH);
IR (neat) 3027, 2979, 1447, 1399, 1207, 1131, 1091, 1059, 955, 787 cm−1; 1H NMR (CDCl3) δ 1.21 (t,
J=7 Hz, 3H), 1.26 (d, J=6.5 Hz, 3H), 1.39 (s, 3H), 1.92 (m, 1H), 2.21 (m, 1H), 3.4–3.8 (m, 4H), 4.4–4.6
(m, 2H), 4.65 (q, J=6.5 Hz, 1H); 13C NMR (CDCl3) δ 15.07, 19.68, 24.93, 38.87, 60.45, 60.76, 74.48,
87.1, 99.72; MS (EI), m/z (%) 208 [M+−HOCH2CH3] (0.3), 165 (1), 100 (3), 85 (67), 73 (100), 55 (4).
Anal. calcd for C9H18O6S (254.29): C, 42.51; H, 7.14; S, 12.61. Found: C, 42.60; H, 7.20; S, 12.58.
4.5. 4-(1-Ethoxyethoxy)-2-hydroxy-2-methyl-(2S)-butylcyanide 5
To a solution of cyclic sulfate 4 (0.25 g, 0.983 mmol) in dry DMF (8 mL) was added NaCN (0.08 g,
1.63 mmol) and stirred under argon for 8 h at 80°C. The solvent was removed under reduced pressure.
The residue was suspended in dry THF (5 mL) and concd H2SO4 (0.05 mL) and water (0.025 mL)
were added to the stirred suspension. The hydrolysis was monitored by TLC. After 6 h, excess NaHCO3
was added and stirred for 15 min. Filtration through Celite and concentration of the filtrate under reduced
pressure gave the crude product which was purified by silica gel column chromatography using petroleum

4354
R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4349–4356
ether:EtOAc (3:2) as eluent to give 5 (0.168 g, 85%) as a colorless oil: TLC (silica gel, EtOAc): Rf=0.825;
20
[α]D +1.3 (c 0.8, EtOH); IR (neat) 3470, 2979, 2933, 2250, 1451, 1382, 1345, 1131, 1092, 1058, 950
cm−1; 1H NMR (CDCl3) δ 1.21 (t, J=7 Hz, 3H), 1.32 (d, J=6.5 Hz, 3H), 1.40 (s, 3H), 1.92 (m, 2H), 2.58
(d, J=2 Hz, 2H), 3.4–3.65 (m, 2H), 3.65–3.9 (m, 3H), 4.69 (dq, J=3, 6.5 Hz, 1H); 13C NMR (CDCl3) δ
15.01, 19.62, 26.76, 31.13, 39.55, 61.24, 61.39, 70.32, 99.62, 117.54; MS (EI), m/z (%) 186 [M+−15]
(5.34), 156 [M+−OCH2CH3] (13.24), 115 (13.9), 112 (21.36), 94 (27.35), 73 (100), 71 (53.84), 55 (3.84).
Anal. calcd for C10H19NO3 (201.25): C, 59.68; H, 9.52; N, 6.96. Found: C, 59.62; H, 9.56; N, 6.95.
4.6. (R)-(−)–Mevalonolactone 6
To the cyano compound 5 (100 mg, 0.497 mmol) was added an aqueous solution of NaOH (3N, 1.2
mL) and the mixture was stirred at 70°C for 3 h. The suspension was cooled in an ice bath followed by
addition of MeOH (4 mL). The solution was acidified to pH 2 with concd HCl. MeOH was stripped off
and the residue was dissolved in acetone (5 mL). To this was added p-toluenesulfonic acid (100 mg) and
the mixture stirred at room temperature for 8 h. Et3N was added and the solvent removed under reduced
pressure. The residue was purified by silica gel column chromatography using petroleum ether:EtOAc
20
(1:4) as eluent to give 6 (45 mg, 70%) as a pale yellow oil; TLC (silica gel, EtOAc): Rf=0.29; [α]D
–19.1 (c 0.4, EtOH) [lit. [α]D –21.6 (c 1.565, 95% EtOH),21 [α]D –19.0 (c 2.15, CHCl3)13b]; IR
(neat) 3400, 3018, 2976, 1732, 1265, 1215, 1190, 754 cm−1; 1H NMR (CDCl3) δ 1.39 (s, 3H), 1.91 (m,
2H), 2.5 (d, J=18 Hz, 1H), 2.6 (br s, 1H), 2.7 (d, J=18 Hz, 1H), 4.36 (m, 1H), 4.62 (m, 1H); MS (EI), m/z
(%) 131 [M++1] (4.48), 130 [M+] (2.56), 115 (4.9), 85 (14.95), 71 (100), 58 (16.66).
20
25
4.7. Anhydromevalonolactone 7
To a solution of cyclic sulfate 4 (0.225 g, 0.885 mmol) in dry DMF (8 mL) was added NaCN (0.087
g, 1.77 mmol) and stirred under argon for 8 h at 80°C. The reaction mixture was cooled to room
temperature, washed with brine and extracted with ether (3×15 mL). The ether layer was dried (Na2SO4)
and concentrated. To this was added an aqueous ethanolic solution of concd H2SO4 [concd H2SO4
(0.1 mL, 2 equiv.), EtOH (1 mL) and water (2 mL)] and refluxed for 18 h. The reaction mixture was
cooled, neutralised (NaHCO3) and extracted with CH2Cl2 (3×15 mL), dried (Na2SO4) and concentrated.
Purification of the crude product by silica gel column chromatography using petroleum ether:EtOAc (1:1)
as eluent gave 7 (0.06 g, 60%) as a colorless oil. TLC (silica gel, petroleum ether:EtOAc, 1:1): Rf=0.57;
IR (neat) 2978, 2923, 1721, 1647, 1397, 1267, 1150, 1063, 998 cm−1; 1H NMR (CDCl3) δ 1.99 (s, 3H),
2.33 (t, J=6.5 Hz, 2H), 4.39 (t, J=6.5 Hz, 2H), 5.79 (s, 1H); MS (EI), m/z (%) 112 [M+] (38.1), 99 (2.38),
82 (60.7), 67 (17.26), 54 (100).
4.8. 4-(1-Ethoxyethoxy)-2-hydroxy-2-methyl-(2R)-butyl 4-methyl-1-benzenesulfonate 8
To a solution of diol 3 (0.25 g, 1.3 mmol) in dry pyridine (8 mL) was added p-toluenesulfonyl chloride
(0.324 g, 1.7 mmol) at room temperature and stirred for 18 h. Then aqueous CuSO4 solution (20%,
w/v, 10 mL) and EtOAc (15 mL) were added and stirring was continued for 45 min. The aqueous layer
was extracted with EtOAc (4×20 mL) and combined organic layers were washed with water, brine and
dried (Na2SO4). Removal of solvent gave a pale green liquid which was purified by silica gel column
chromatography using petroleum ether:EtOAc (7:3) as eluent to give 8 (0.432 g, 96%) as a colorless oil:
20
TLC (silica gel, EtOAc): Rf=0.92; [α]D –0.8 (c 0.8, EtOH); IR (neat) 3474, 2979, 2931, 1605, 1359,
1179, 1130, 1094, 1056, 979, 841 cm−1; 1H NMR (CDCl3) δ 1.19 (t, J=7 Hz, 3H), 1.26 (d, J=6.5 Hz,

R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4349–4356
4355
3H), 1.28 (s, 3H), 1.82 (m, 2H), 2.45 (s, 3H), 3.4–3.6 (m, 4H), 3.65–3.9 (m, 3H), 4.64 (dq, J=3, 6.5 Hz,
1H), 7.36 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H); 13C NMR (CDCl3) δ 15.07, 19.62, 21.33, 24.41, 37.04,
61.24, 61.40, 70.74, 75.37, 99.78, 127.77, 129.72, 132.92, 144.71; MS (EI), m/z (%) 257 [M+−89] (0.2),
172 (8.1), 155 (40), 115 (100), 107 (12.5), 91 (90.2), 71 (69.6), 65 (17.85), 57 (3.6). Anal. calcd for
C16H26O6S (346.43): C, 55.47; H, 7.57; S, 9.25. Found: C, 55.48; H, 7.61; S, 9.23.
4.9. Compound 5 via tosyl displacement
To a stirred solution of the tosylate 8 (0.35 g, 1.01 mmol) in EtOH:H2O (3:2 v/v, 5 mL), cooled at 0°C,
was added NaCN (0.174 g, 3.55 mmol). The mixture was slowly allowed to warm to room temperature.
After stirring for 18 h, it was diluted with water and extracted with CH2Cl2. The organic layer was washed
with brine and water, dried (Na2SO4) and concentrated. Silica gel column chromatography of the crude
product using petroleum ether:EtOAc (7:3) gave 5 (198 mg, 97%) as a colorless oil: [α]D20 +1.25 (c 0.7,
EtOH). The spectroscopic data were in full agreement with those of the one prepared by the opening of
cyclic sulfate 4 via step iv.
Acknowledgements
One of us (R.A.F.) thanks CSIR, New Delhi, for financial assistance. We are grateful to Dr. T.
Ravindranathan for his support and encouragement. We would like to thank Dr. (Mrs.) A. S. Tambe
and Dr. (Mrs.) S. S. Biswas for GC analysis. This is NCL communication no. 6476.
References
1. For reviews concerning the discovery and role of mevalonolactone, see: (a) Goldstein, J. L.; Brown, M. S. Nature 1990,
343, 425–430. (b) Herbert, R. B. The Biosynthesis of Secondary Metabolites, 2nd ed.; Chapman and Hall: London, 1989. (c)
Caspi, E. Tetrahedron 1986, 42, 3–50. (d) Goodwin, T. W. Natural Substances Formed Biologically from Mevalonic Acid;
Academic Press: New York, 1970; pp. 45–47.
2. (a) Kumar, P.; Saravanan, K. Tetrahedron 1998, 54, 2161–2168. (b) Pais, G. C. G.; Fernandes, R. A.; Kumar, P. Tetrahedron
1999, 55, 13445–13450. (c) Pais, G. C. G. Ph.D. Thesis, National Chemical Laboratory, Pune, India, 1997.
3. (a) Folkers, K.; Shunk, C. H.; Linn, B. O.; Robinson, F. M.; Wittreich, P. E.; Huff, J. W.; Gilfillan, J. L.; Skeggs, H. R.
Discovery and Elucidation of Mevalonic Acid in Ciba Foundation Symposium on the Biosynthesis of Terpenes and Sterols;
Wolstenholme, G. E. W.; O’Connor, M., Eds.; J. S. A. Churchill Ltd: London, 1959; pp. 20–43.
4. (a) Ray, N. C.; Raveendranath, P. C.; Spencer, T. A. Tetrahedron 1992, 48, 9427–9432. (b) Bolitt, V.; Mioskowski, C.; Bhatt,
R. K.; Falck, J. R. J. Org. Chem. 1991, 56, 4238–4240. (c) Ohta, T.; Tabei, N.; Nozoe, S. Heterocycles 1989, 28, 425–432.
(d) Schneider, J. A.; Yoshihara, K. J. Org. Chem. 1986, 51, 1077–1079. (e) Mori, K.; Okada, K. Tetrahedron 1985, 41,
557–559. (f) Bonadies, F.; Rossi, G.; Bonini, C. Tetrahedron Lett. 1984, 25, 5431–5434.
5. (a) Wilson, W. K.; Scallen, T. J.; Morrow, C. J. J. Lipid Res. 1982, 23, 645–652. (b) Cornforth, R. H.; Cornforth, J. W.;
Popjak, G. Tetrahedron 1962, 18, 1351–1354.
6. Eberle, M.; Arigoni, D. Helv. Chim. Acta 1960, 43, 1508–1513.
7. Davis, F. A.; Reddy, G. V.; Chen, B. C.; Kumar, A.; Haque, M. S. J. Org. Chem. 1995, 60, 6148–6153.
8. Shimizu, M.; Kamikubo, T.; Ogasawara, K. Tetrahedron: Asymmetry 1997, 8, 2519–2521.
9. Kishida, M.; Yamauchi, N.; Sawada, K.; Ohashi, Y.; Eguchi, T.; Kakinuma, K. J. Chem. Soc., Perkin Trans 1 1997, 891–895.
10. Abushanab, E.; Reed, D.; Suzuki, F.; Sih, C. J. Tetrahedron Lett. 1978, 3415–3418.
11. (a) Frye, S. V.; Eliel, E. L. Tetrahedron Lett. 1986, 3223–3226. (b) Frye, S. V.; Eliel, E. L. J. Am. Chem. Soc. 1988, 110,
484–489.
12. Kawakami, Y.; Hiratake, J.; Yamamoto, Y.; Oda, J. J. Chem. Soc., Chem. Commun. 1984, 779–781.
13. (a) Orru, R. V. A.; Osprian, I.; Kroutil, W.; Faber, K. Synthesis 1998, 1259–1263. (b) Lakher, F. J.; Hager, L. P. J. Org.
Chem. 1996, 61, 3923–3925. (c) Ferraboschosi, P.; Grisenti, P.; Casati, S.; Santaniello, E. Synlett 1994, 754–756. (d) Sugai,

4356
R. A. Fernandes, P. Kumar / Tetrahedron: Asymmetry 10 (1999) 4349–4356
T.; Kakeya, H.; Ohta, H. Tetrahedron 1990, 46, 3463–3468. (e) Francis, C. J.; Jones, J. B. J. Chem. Soc., Chem. Commun.
1984, 579–580. (f) Ohta, H.; Tetsukawa, H.; Noto, N. J. Org. Chem. 1982, 47, 2400–2404. (g) Irwin, A. J.; Jones, J. B. J.
Am. Chem. Soc. 1977, 99, 556–561. (h) Huang, F. C.; Lee, L. F. H.; Mittal, R. S. D.; Ravikumar, P. R.; Chan, J. A.; Sih, C.
J.; Caspi, E.; Eck, C. R. J. Am. Chem. Soc. 1975, 97, 4144–4145.
14. Eliel, E. L.; Soai, K. Tetrahedron Lett. 1981, 30, 2859–2862.
15. 3-Methyl-3-butene-1-ol was procured from Aldrich Chemical Company.
16. (a) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35, 448–451. (b) Torii, S.; Liu, P.; Bhuvaneswari, N.;
Amatore, C.; Jutand, A. J. Org. Chem. 1996, 61, 3055–3060. (c) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. Tetrahedron
Lett. 1995, 36, 3481–3484. (d) Tietze, L. F.; Golitzer, J. Synthesis 1998, 873–878. (e) For a review on the asymmetric
dihydroxylation, see: Kolb, H. C.; VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–2547.
17. For the measurement of enantiomeric excess, the diol 3 was converted into the triol 9. The enantiomeric purity of the triol
9 was estimated to be in excess of 89% by GLC using Chirasil-Val-D (25 m×0.32 mm I.D.) at 120°C for 5 min, 10°C/min
to 220°C.
18. For a review on cyclic sulfites and sulfates, see: Lohray, B. B. Synthesis 1992, 1035–1052.
19. For the synthesis of cyclic sulfates from diols containing acid sensitive groups and chemoselective hydrolysis of sulfate
esters, see: Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655–658.
20. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543–2549.
21. Frye, S. V.; Eliel, E. L. J. Org. Chem. 1985, 50, 3402–3404.
22. Gu, J.-X.; Holland, H. L. Synth. Commun. 1998, 28, 3305–3315.
23. (a) Nangia, A.; Madusudan Rao, B.; Prasuna, G. Synth. Commun. 1992, 22, 593–602. (b) Bonadies, F.; Di Fabio, R. J. Org.
Chem. 1984, 49, 1647–1649. (c) Herold, P.; Mohr, P.; Tamm, C. Helv. Chim. Acta 1983, 66, 744–754. (d) White, J. D.;
Carter, J. P.; Kazar III, H. S. J. Org. Chem. 1982, 47, 929–932.
24. Noyori, R.; Ohkuma, T.; Kitamura, M. J. Am. Chem. Soc. 1987, 109, 5856–5858 and references cited therein.