Flexible and simple route for the stereoselective synthesis of trisubstituted γ-butyrolactones: Total synthesis of (+)-blastomycinone and its analogs

Article abstract of DOI:10.1055/s-2004-829173

A flexible route for the stereoselective synthesis of trisubstituted γ-butyrolactones, namely (+)-blastomycinone and its analogs, is devised by the Sharpless asymmetric epoxidation and the regioselective ring opening reaction with dibutylcopper lithium as

Full text of DOI:10.1055/s-2004-829173

PAPER
2107
Flexible and Simple Route for the Stereoselective Synthesis of Trisubstituted
g-Butyrolactones: Total Synthesis of (+)-Blastomycinone and its Analogs1
S
tereoselectiv
a
e
T
otal Syn
l
thesis
o
a
f
T
risubsti
k
tute
d
-Butyro
o
lactones dety Radha Krishna,* V. V. Ramana Reddy, G. V. M. Sharma
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91(40)27160387; E-mail: prkgenius@iict.res.in
Received 14 April 2004; revised 21 May 2004
Many syntheses4 of natural trisubstituted lactones have
Abstract: A flexible route for the stereoselective synthesis of
been directed at (+)-blastomycinone (1) and less attention
has been given to the synthesis of analogs such as 2 and 3.
trisubstituted g-butyrolactones, namely (+)-blastomycinone and its
analogs, is devised by the Sharpless asymmetric epoxidation and
To the best of our knowledge only a few flexible
approaches5 for the synthesis of all possible isomers were
reported. In this paper we describe stereoselective synthe-
sis of trisubstituted g-butyrolactones mainly (+)-blasto-
mycinone (1), 2 and (–)-3-epi-blastomycinone (3)6 by
making use of Sharpless asymmetric epoxidation7 and the
regioselective ring opening reaction protocols8 of the re-
spective epoxides for installing the requisite stereochem-
istries.
(S)-O-Benzyllactaldehyde (4),9 prepared from ethyl L-lac-
tate in two steps, on reaction with (ethoxycarbonyl-
methelene)triphenylphosphorane in MeOH at 0 °C gave
the cis-olefin 5a along with trans product in a ratio 95:5
in 77% yield, while the same reaction when carried out in
benzene at reflux gave trans-olefin 5b (75%) as an exclu-
sive product (Scheme 1). Treatment of 5a and 5b with
DIBAL-H at –20 °C in anhydrous CH2Cl2 led to allylic
alcohols 6a and 6b in good yields. When 6a was subjected
to Sharpless asymmetric epoxidation it was found to be
inert. It was reported in literature10 that the sterically hin-
dered cis allylic alcohols are resistant to epoxidation with
DIPT. Consequently, drawing analogy from the litera-
ture,11 the use of (–)-DET was contemplated. Accord-
the regioselective ring opening reaction with dibutylcopper lithium
as the key steps to introduce the requisite alkyl chain.
Key words: (+)-blastomycinone,
(–)-3-epi-blastomycinone,
Sharpless asymmetric epoxidation, dibutylcopper lithium, Wittig
olefination
(+)-Blastomycinone2 (1, Figure 1) is a degradation prod-
uct of the macrocyclic dilactone (+)-Antimycinone A3, an
anti-fungal antibiotic isolated from several members of
the Streptomyces species. Similar structurally related bio-
active trisubstituted butyrolactones like NFX-2,3a a Vir-
ginamycin inducing factor, NFX-4,3a (+)-antimycinone,3b
and lipid metabolites3c are other isolates from different or-
igins with different alkyl chain lengths.
Figure 1
OBn
OBn
MeOH, 0 °C
DIBAL-H
COOEt
OH
dry CH2Cl2
5a
OBn
OBn
CHO
6a
OBn
Ph3P=CHCOOEt
4
C6H6, reflux
OBn
DIBAL-H
dry CH2Cl2
COOEt
OH
5b
6b
(–)-DET, Ti(OiPr)4
cumene hydroperoxide,
4 Å MS, dry CH2Cl2
OBn
O
O
6a
OH
OH
+
7a
7b
OBn
(–)-DIPT, Ti(OiPr)4
O
6b
cumene hydroperoxide,
4 Å MS, dry CH2Cl2
OH
7c
Scheme 1
SYNTHESIS 2004, No. 13, pp 2107–2114
x
x.
x
x
.
2
0
0
4
Advanced online publication: 27.07.2004
DOI: 10.1055/s-2004-829173; Art ID: P03604SS
© Georg Thieme Verlag Stuttgart · New York

2108
P. R. Krishna et al.
PAPER
ingly, when 6a was subjected to SAE with (–)-DET, it and 86% respective yields. The spectral data of 1 and 3
gave 7a (55%) and 7b (17%) in 19:6 ratio along with some were comparable with the known data.6d The spectral data
amount of starting material. However, 6b indeed under- of the new isomer 2 was thoroughly analyzed and its
went a facile conversion when subjected to SAE with (–)- structure was unequivocally established as reported in
DIPT and gave 7c (71%).
here.
Compounds 7a, 7b and 7c (Scheme 2) on reaction with In conclusion, we have described a flexible and efficient
dibutylcopper lithium in anhydrous Et2O at –20 °C lead to route for the preparation of biologically active trisubstitut-
the regioselective opening of epoxides to give 1,3-diols ed g-butyrolactones by using Sharpless asymmetric ep-
8a, 8b and 8c respectively as major products. The traces oxidation reaction and the regioselective ring opening
of 1,2-diol products were eliminated by using oxidative reaction of the epoxides with ‘dibutylcopper lithium’ as
cleavage with NaIO4 to obtain pure alcohols 8a, 8b and 8c the main strategy for efficient installation of the stereo-
in 75%, 73% and 80% yields, respectively. The primary centers. Cis- and trans-olefins along with the choice of
alcohols were selectively protected as silyl ethers with Sharpless chiral ligands offers the flexibility and general-
TBSCl to give 9a, 9b and 9c in 80–83% yields. The re- ity to the synthetic strategy for the preparation of a variety
maining secondary alcohols were acylated with isovaleryl of such natural products and their analogs by simple selec-
chloride to obtain isovaleryl esters. The next step was to tion or change of reagents.
deblock the silyl ether for further elaboration to acid.
However, 1,3-acyl migration was observed while attempt-
Solvents were dried over standard drying agents and freshly dis-
tilled prior to use. 1H NMR (200 MHz and 300 MHz) and 13C NMR
(50 MHz and 75 MHz) spectra were measured with a Varian Gem-
ini FT-200 M Hz (21 °C) spectrometer and Bruker Avance-300
MHz spectrometers with 7–10 mM solutions in CDCl3 and TMS as
internal standards. J values are given in Hz. Optical rotations were
measured with a JASCO DIP-300 instrument and [a]D values are
given in units of 10–1 deg cm2 g–1at 25 °C. IR spectra were taken
with a Perkin-Elmer 1310 spectrometer. Mass spectra were record-
ed on CEC-21-11013 or Finnigan Mat 1210 double focusing mass
spectrometers operating at a direct inlet system and FAB–MS was
measured using VG AUTOSPEC mass spectrometers at 5k or 7k
resolution using perfluorokerosene as an internal reference. Ele-
mental analysis was recorded on ELEMENTAR (Vario EL, Germa-
ny). Organic solutions were dried over anhyd Na2SO4 and
concentrated below 40 °C in vacuo. The software ACD/Name Ver-
sion 1.0, developed by M/s Advanced Chemistry Development Inc.,
Toronto, Canada, assisted nomenclature used in the experimental
section.
ing the TBS group deprotection with TBAF in anhydrous
CH2Cl2. Consequently, it was planned to introduce the es-
ter functionality later in the synthesis. Hence, the 2° alco-
hols of 9a, 9b and 9c were converted to benzyl ethers
(reaction conditions: NaH, BnBr, DMF, r.t.) 10a, 10b and
10c in 88%, 84% and 85% yields, respectively. The TBS
deprotection was carried out with PTSA in MeOH to give
11a, 11b and 11c in 82%, 84% and 80% yields, respec-
tively. The primary alcohols 11a, 11b and 11c were then
oxidized to acids in a 2-step process, first with pyridinium
chlorochromate to give aldehydes, which were later con-
verted (reaction conditions: NaClO2, H2O2, t-BuOH–
H2O)12 to acids 12a, 12b and 12c (82%, 82% and 85%),
respectively. Deprotection of the benzyl groups [Pd(OH)2
under H2 atmosphere] in 12a–12c results in simultaneous
release of the hydroxy functionality with concomitant lac-
tonization leading to (–)-blastomycinolactol 13a, (–)-3-
epi-blastomycinolactol 13b and 13c in 86%, 82% and
87% yields, respectively. Finally, the esterification on
13a–13c was carried out with isovaleryl chloride as re-
ported in the literature5a to obtain 1, 2 and 3 in 89%, 91%
Ethyl-4-benzyloxy-(Z,4S)-2-pentenoate (5a); Typical Procedure
To a stirred solution of 4 (4 g, 24.3 mmol) in MeOH (60 mL) at
0 °C was added (ethoxycarbonylmethylene)-triphenylphosphorane
(10.2 g, 29.2 mmol) portion-wise. The reaction mixture was stirred
OBn R
OBn R
R'
TBSCl, Imidazole
CH2Cl2, r.t.
(n-C4H9)2CuLi
Bn-Br, NaH
DMF, r.t.
7b, 7b and 7c
OH
OTBS
dry ether, –20 °C
R'
C4
C4
C4
H
H
H
9, R '=
9, R' =
9, R' =
8a R =
OH
9a R =
9b R =
9c R =
C4H9, R' =
OH
OH
OH
8b R =
8c R =
OH
OH
C4H9, R' =
C4H9, R' =
1. PCC, AcONa,
CH2Cl2, r.t.
OBn R
OBn R
OBn R
PTSA (cat.)
MeOH, r.t.
Pd (OH)2
OH
OTBS
COOH
2. NaClO2, 30% H2O2,
t-BuOH:H2O (7:3), r.t.
OBn
OBn
OBn
MeOH, r.t.
R'
R'
R'
10a R =
C4
C4
C4
H
H
H
9, R' =
9, R' =
9, R' =
OBn
OBn
OBn
11a R =
11b R =
11c R =
C4H9, R' =
C4H9, R' =
C4H9, R' =
12a R =
12b R =
12c R =
C4H9, R' =
OBn
OBn
OBn
10b R =
10c R =
C4H R' =
9,
H
C4
9, R' =
O
O
O
O
O
isovaleryl
chloride
O
O
O
DMAP, CH2Cl2
r.t.
O
O
R
O
R'
13a R =
13b R =
13c R =
C4H9, R' =
OH
OH
OH
O
O
O
C4
C4
H
9, R' =
9, R' =
H
1
2
3
Scheme 2
Synthesis 2004, No. 13, 2107–2114 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of Trisubstituted g-Butyrolactones
2109
at 0 °C for 3 h. The reaction mixture was concentrated under re-
duced pressure and was purified by column chromatography (silica
gel 60–120; EtOAc–hexane, 1:50) to obtain 5a (4.3 g, 77%) as a
colorless liquid; [a]D –40.5 (c = 1.25, CHCl3).
13C NMR (75 MHz, CDCl3): d = 18.29, 57.16, 59.27, 60.77, 70.53,
71.84, 127.74, 127.89, 128.48.
FAB–MS: m/z (%) = 231 (34) [M+ + 23], 207 (100), 181 (30), 154
(50), 137 (74).
IR (neat): 2940, 1720, 1240, 1180 cm–1.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.43; H,
7.87.
1H NMR (300 MHz, CDCl3): d = 1.25–1.33 (m, 6 H, 2 × CH3), 4.14
(m, 2 H, OCH2CH3), 4.45 (dd, J = 12, 23 Hz, 2 H, OCH2Ph), 5.13
(m, 1 H, CHOBn), 5.82 (d, J = 1.2 Hz, 1 H, CH=CHCOOEt), 6.20
(dd, J = 8.2, 11.7 Hz, 1 H, CH=CHCOOEt), 7.27 (br s, 5 H, ArH).
Compound 7b
[a]D –3.5 (c = 0.5, CHCl3).
FAB–MS: m/z = 235 (72) [M+ + 1], 154 (20), 137 (20), 127 (74), 91
IR (neat): 3400, 2980, 1710, 1340, 1080 cm–1.
(100).
1H NMR (300 MHz, CDCl3): d = 1.23 (d, J = 6.4 Hz, 3 H, CH3), 3.05
(m, 2 H, epo-H), 3.46 (m, 1 H, CHOBn), 3.60 (dd, J = 10.2, 15.3 Hz,
1 H, CHHOH), 3.78 (dd, J = 5.1, 15.1 Hz, 1 H, CHHOH), 4.58 (d,
J = 12.7 Hz, 1 H, OCHHPh), 4.75 (d, J = 12.7 Hz, 1 H, OCHHPh),
7.30 (br s, 5 H, ArH).
13C NMR (50 MHz, CDCl3): d = 17.58, 54.61, 60.50, 71.07, 73.39,
127.45, 127.61, 128.22.
Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.89; H,
7.92.
4-Benzyloxy-(Z,4S)-2-penten-1-ol (6a); Typical Procedure
DIBAL-H (13.8 mL, 19.4 mmol, 20% solution in toluene) was add-
ed dropwise to a solution of 5a (3.8 g, 16.2 mmol) in anhyd CH2Cl2
(40 mL) at –20 °C and stirred for 30 min. After the completion of
the reaction MeOH (15 mL) was added, followed by sat. sodium po-
tassium tartrate solution (15 mL), filtered and washed with EtOAc
(2 × 100 mL). Organic layer was dried (Na2SO4), concentrated un-
der reduced pressure and the residue was subjected to column chro-
matography (silica gel 60–120; EtOAc–hexane, 1:4) to obtain 6a
(2.5 gm, 81%) as a colorless liquid; [a]D –20.9 (c = 1.0, CHCl3).
FAB–MS: m/z (%) = 231 (34) [M+ + 23], 207 (100), 181 (30), 154
(50), 137 (74).
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.13; H,
7.63.
4-Benzyloxy-2-butyl-(2S,3R,4S)-pentane-1,3-diol (8a); Typical
Procedure
IR (neat): 3400, 3000, 1480, 1080 cm–1.
To a stirred solution of copper(I) iodide (0.27 g, 1.4 mmol) in anhyd
Et2O (10 mL) was added n-BuLi (1.8 mL, 2.8 mmol, 1.6 M solution
in n-hexane) at –20 °C and stirred for 30 min. Compound 7a (0.15
g, 0.72 mmol) in anhyd Et2O (10 mL) was added and stirred for 1 h.
The reaction mixture was quenched with sat. NH4Cl (2 mL), treated
with NH3 solution (2 mL) and allowed to stir for 15 min. The organ-
ic layer was separated and the water layer was washed with EtOAc
(2 × 10 mL). The combined organic layers were washed with water
(2 × 5 mL), brine (1 × 5 mL), dried (Na2SO4) and concentrated un-
der reduced pressure. The crude product was purified by column
chromatography (silica gel 60–120, EtOAc–hexane, 1:5) to obtain
8a (0.143 g, 75.5%) as a colorless liquid; [a]D +11.6 (c = 0.5,
CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.30 (d, J = 8.6 Hz, 3 H, CH3), 1.70
(d, 1 H, OH), 4.12 (t, J = 8.5 Hz, 2 H, CH2OH), 4.20–4.38 (m, 1 H,
CHOBn), 4.45 (dd, J = 10.4, 34.7 Hz, 2 H, OCH2Ph), 5.50 (dd, J =
7.8, 13 Hz, 1 H, CH=CHCH2OH), 5.77 (dt, J = 7.8, 13 Hz, 1 H,
CH=CHCH2OH), 7.27 (br s, 5 H, ArH).
FAB–MS: m/z = 215 (72) [M+ + 23], 193 (100) [M+ + 1], 175 (32),
154 (38), 91 (54).
Anal. Calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 74.83; H,
8.27.
3-[1-Benzyloxy-(1S)-ethyl]-(2R,3S)-oxiran-2-yl Methanol (7a)
and 3-[1-Benzyloxy-(1S)-ethyl]-(2S,3R)-oxiran-2-yl Methanol
(7b); Typical Procedure
IR (neat): 3420, 2930, 1560 1050, 760 cm–1.
To stirred anhyd CH2Cl2 (10 mL) were added (–)-diethyl tartrate
(1.287 g, 6.2 mmol) in CH2Cl2 (5 mL) at –20 °C followed by titani-
um isopropoxide (1.55 mL, 5.2 mmol) and stirred for 20 min.
Cumene hydroperoxide (2 mL, 10.3 mmol, 80% solution) was add-
ed to the reaction mixture and allowed to stir for 20 min. A solution
of 6a (1.0 g, 5.2 mmol) in CH2Cl2 (10 mL) was added and allowed
to stir at –20 °C for 15 d. The reaction mixture was quenched with
NaOH in aq sat Na2SO4 solution (1 g in 10 mL) and stirred for 2 h.
The reaction mixture was filtered through celite; the residue washed
with EtOAc (4 × 100 mL), the organic layer was washed with water
(2 × 50 mL), brine (2 × 50 mL), dried (Na2SO4) and concentrated
under reduced pressure. The crude product was subjected to column
chromatography (silica gel 60–120; EtOAc–hexane, 1:5). The first
eluted compound was 6a (0.25 g) the second elute was the 7a (0.450
g, 55.5%), the third elute was 7b (0.140 g, 17%).
1H NMR (300 MHz, CDCl3): d = 0.897 (t, J = 6.78, 3 H, CH2CH3),
1.16–1.27 (m, 10 H), 1.76 (m, 1 H, CHC4H9), 3.57 (m, 1 H,
CHOBn), 3.66–3.79 (m, 3 H, CH2OH, CHOH), 4.42 (d, J = 11.7 Hz,
1 H, OCH2Ph), 4.62 (d, J = 11.7 Hz, 1 H, OCH2Ph), 7.27 (br s, 5 H,
ArH).
13C NMR (75 MHz, CDCl3): d = 14.06, 15.39, 23.04, 24.07, 29.76,
40.82, 64.34, 70.62, 75.31, 77.08, 127.63, 127.79, 128.34, 138.31.
FAB–MS: m/z (%) = 289 (34) [M+ + 23], 267 (100) [M+ + 1], 157
(94), 141 (50), 91 (54).
Anal. Calcd for C16H26O3: C, 72.14; H, 9.84. Found: C, 72.37; H,
9.92.
1-[1-Benzyloxy-(1S)-ethyl]-2-tert-butyldimethyl Silyloxy Meth-
yl-(1R,2S)-hexyl Alcohol (9a); Typical Procedure
To a stirred solution of 8a (0.18 g, 0.67 mmol) in CH2Cl2 (4 mL),
imidazole (0.092 g, 1.3 mmol) and t-butyl dimethylsilyl chloride
(0.121 g, 0.8 mmol) were added and allowed to stir at r.t. for 1 h.
The reaction mixture was concentrated under reduced pressure and
subjected to column chromatography (silica gel 60–120; EtOAc–
hexane, 1:50) to obtain 9a (0.22 g. 81%) as a colorless liquid; [a]D
+19.6 (c = 0.6, CHCl3).
IR (neat): 3510, 2960, 2850, 1490, 1280 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.01 [s, 6 H, -Si(CH3)2], 0.864–
0.91 [br s, 12 H, Si(t-C4H9), CH3], 1.10–1.45 (m, 9 H, CH3, 3 ×
Compound 7a
[a]D +4.37 (c = 0.5, CHCl3).
IR (neat): 3400, 2980, 1710, 1340, 1080 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.38 (d, J = 6.4 Hz, 3 H, CH3), 2.91
(dd, J = 4.15, 7.54 Hz, 1 H, epo-H), 3.15 (dd, J = 4.15, 5.6 Hz, 1 H,
epo-H), 3.30 (m, 1 H, CHOBn), 3.83 (m, 2 H, CH2OH), 4.48 (d, J =
12.0 Hz, 1 H, CHHPh), 4.57 (d, J = 12.0 Hz, 1 H, CHHPh), 7.27 (br
s, 5 H, ArH).
Synthesis 2004, No. 13, 2107–2114 © Thieme Stuttgart · New York

2110
P. R. Krishna et al.
PAPER
CH2), 1.71–1.77 (m, 1 H, CHC4H9), 3.47–3.55 (m, 1 H, CHOH),
3.68 (dd, J = 2.64, 10.2 Hz, 2 H, CH2OTBS), 3.77 (dd, J = 3.77, 9.82
Hz, 1 H, CHOBn), 4.38 (d, J = 11.7 Hz, 1 H, OCH2Ph), 4.60 (d, J =
11.7 Hz, 1 H, OCH2Ph), 7.27 (br s, 5 H, ArH).
FAB–MS: m/z (%) = 381 (14) [M+ + 1], 273 (100), 255 (8), 215
(20), 141 (30).
To a stirred solution of aldehyde (0.065 g, 0.18 mmol) in t-BuOH–
H2O (7:3, 1 mL), were added sodium chlorite (0.024 g, 0.27 mmol)
and H2O2 (0.11 mL, 0.98 mmol, 30% aq. sol.), and stirred at r.t. for
6 h. The reaction mixture was concentrated, residue dissolved in
EtOAc (10 mL), washed with water (1 × 5 mL), brine (1 × 5 mL),
dried (Na2SO4) and concentrated under reduced pressure. The crude
product was purified by column chromatography (silica gel 60–120:
EtOAc–hexane, 3:20) to obtain 12a (0.055 g, 82%) as a colorless
liquid; [a]D +8.0 (c = 0.5, CHCl3).
Anal. Calcd for C22H40O3Si: C, 69.42; H, 10.59. Found: C, 69.55;
H, 10.63.
IR (neat): 3300–3000 (br), 2930, 1710, 1280 cm–1.
2,3-Di(benzyloxy)-4-tert-butyldimethyl Silyloxy-(2S,3R,4S)-oc-
tane (10a); Typical Procedure
1H NMR (300 MHz, CDCl3): d = 0.86 (t, J = 6.79 Hz, 3 H, CH3),
1.20–1.33 (m, 9 H), 1.62–1.72 (m, 1 H, CH2C3H7), 2.51–2.59 (m, 1
H, CHCOOH), 3.49–3.55 (m, 1 H, CHOBn), 3.77 (dd, J = 4.53,
7.17 Hz, 1 H, CHOBn), 4.43–4.73 (m, 4 H, OCH2Ph), 7.27 (br s, 10
H, ArH).
FAB–MS: m/z (%) = 371 (10) [M+ + 1], 263 (14), 154 (32), 136
(28), 91(100).
Sodium hydride (0.02 g, 0.51 mmol, 60% dispersion in paraffin oil)
was added to a stirred solution of 9a (0.2 g, 0.51 mmol) in anhyd
DMF (1 mL) at 0 °C and stirred for 15 min. Benzyl bromide (0.065
mL, 0.51 mmol) was added to the reaction mixture and stirred at r.t.
for additional 30 min. The reaction mixture was quenched with sat.
NH4Cl (2 mL) and stirred for 10 min, extracted with Et2O (3 × 10
mL), dried (Na2SO4) and concentrated under reduced pressure. The
crude product was subjected to column chromatography (silica gel
60–120; EtOAc–hexane, 1:50) to afford 10a (0.22 g, 88%) as a col-
orless liquid; [a]D –2.0 (c = 0.5, CHCl3).
Anal. Calcd for C23H30O4: C, 74.57; H, 8.16. Found: C, 74.42; H,
8.03.
3-Butyl-4-hydroxy-5-methyl-(3R,4R,5S)-tetrahydro-2-fura-
none [(–)-Blastmycinolactol] (13a); Typical Procedure
IR (neat): 2960, 2850, 1570, 1250, 1100 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.06 [s, 6 H, Si(CH3)2], 0.89–0.97
[br s, 12 H, Si (t-C4H9), CH3], 1.18–1.34 (m, 9 H, CH3, 3 × CH2),
1.72 (m, 1 H, CHC4H9), 3.58 (t, J = 5.127 Hz, 2 H, CH2OTBS), 3.67
(t, J = 4.39 Hz, 1 H, CHOBn), 3.75 (dd, J = 4.39, 5.86 Hz, 1 H,
CHOBn), 4.48–4.82 (m, 4 H, OCH2Bn), 7.27 (br s, 10 H, ArH).
FAB–MS: m/z (%) = 471 (12) [M+ + 1], 255 (18), 215 (48) 181 (16)
91 (100).
Pd(OH)2 (cat.) was added to a stirred solution of 12a (0.045 g, 0.12
mmol) in MeOH (0.5 mL) and stirred under H2 atmosphere for 24 h
at r.t. The reaction mixture was filtered, filtrate concentrated under
reduced pressure and purified by column chromatography (silica
gel 60–120, EtOAc–hexane, 1:4) to obtain 13a (0.018 g, 86%) as a
colorless solid: mp 50–51 °C [Lit.8 mp 49.5–50.5 °C]; [a]D –17.56
(c = 1.0, CHCl3) {Lit.8 [a]D –18.0 (c = 1.25, CHCl3}.
IR (neat): 3400, 1770, 1190 cm–1.
Anal. Calcd for C29H46O3Si: C, 73.99; H, 9.85. Found: C, 71.08; H,
9.95.
1H NMR (300 MHz, CDCl3): d = 0.93 [t, J = 6.6, 3 H, (CH2)3CH3],
1.35–1.64 (m, 8 H), 1.80–1.92 (m, 1 H), 2.53 (ddd, J = 3.77, 7.93
Hz, 1 H, CHC4H9), 3.78 (t, J = 6.68 Hz, 1 H, CHCH3), 4.00–4.22
(m, 1 H, CHOH).
2-[1,2-Di(benzyloxy)-(1R,2S)-propyl]-(2S)-hexan-1-ol (11a);
Typical Procedure
PTSA (cat.) was added to a stirred solution of 10a (0.2 g, 0.42
mmol) in MeOH (2 mL) and stirred at r.t. for 30 min. Reaction mix-
ture was quenched with Et3N (0.2 mL) and stirred for 5 min. The re-
action mixture was concentrated and diluted with EtOAc (10 mL).
The organic layer was washed with water (5 mL), brine (5 mL),
dried (Na2SO4) and concentrated under reduced pressure. The crude
product was purified by column chromatography (silica gel 60–120;
EtOAc–hexane, 1:10) to obtain 11a (0.122 g, 82%) as a liquid; [a]D
+12.5 (c = 0.5, CHCl3).
13C NMR (75 MHz, CDCl3): d = 13.79, 18.17, 22.52, 28.08, 28.75,
48.53, 78.77, 80.23, 178.4.
FAB–MS: m/z (%) = 173 (10) [M+ + 1], 99 (63), 82 (48), 71 (26),
57 (84).
Anal. Calcd for C9H16O3: C, 62.76; H, 9.36. Found: C, 63.05; H,
9.10.
4-Butyl-2-methyl-5-oxo-(2S,3R,4R)-tetrahydro-3-furan-yl
3-Methylbutanoate [(+)-Blastomycinone] (1); Typical Proce-
dure
IR (neat): 2960, 2850, 1570 1250, 1190 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.876 (t, 3 H, J = 7.17 Hz, CH3),
1.22–1.31 (br s, 9 H), 1.80–1.89 (m, 1 H, CHC4H9), 3.51–3.64 (m,
3 H, CHOBn, CH2OH), 3.67–3.74 (m, 1 H, CHOBn), 4.43–4.7 (m,
4 H, CH2Ph), 7.28 (br s, 10 H, ArH).
FAB–MS: m/z (%) = 357 (26) [M+ + 1], 327 (26), 249 (38), 157
(100), 141 (64).
To a mixture of 13a (0.050 g, 0.29 mmol) in CH2Cl2 (2 mL) and
dimethylaminopyridine (0.014 g, 1.16 mmol), isovaleryl chloride
(0.21 mL, 1.7 mmol) was added at r.t. and stirred for 24 h. The re-
action mixture was quenched with sat. aq NaHCO3 solution (1 mL)
and stirred for 15 min and diluted with CH2Cl2 (5 mL). The organic
layer was washed with water (2 × 5 mL), brine (2 × 5 mL), dried
(Na2SO4) and residue obtained was purified by column chromatog-
raphy (silica gel 60–120; EtOAc–hexane, 1:10) to obtain 1 (0.065 g,
89%) as a colorless liquid; [a]D +11.0 (c = 1.2, CHCl3) {Lit.8 [a]D
+11.5 (c = 1.2, CHCl3)}.
Anal. Calcd for C23H32O3: C, 77.49; H, 9.05. Found: C, 77.63; H,
9.22.
2-[1,2-Di(benzyloxy)-(1R,2S)-propyl]-(2R)-hexanoic Acid
(12a); Typical Procedure
IR (neat): 3400, 1770, 1190 cm–1.
To a stirred solution of 11a (0.075 g, 0.21 mmol) in CH2Cl2 (2 mL)
was added pyridininum chlorochromate (0.068 g, 0.31 mmol) and
NaOAc (0.034 g, 0.42 mmol), and allowed to stir at r.t. for 45 min.
The reaction mixture was concentrated under reduced pressure,
Et2O (50 mL) was added and the ether layer was passed through a
column (silica gel 60–120), to give aldehyde (0.065 g, 87%) as syr-
up. The aldehyde thus obtained was subjected to the next reaction
without further purification or characterization.
1H NMR (300 MHz, CDCl3): d = 0.91–0.98 (m, 9 H), 1.24–1.42 (m,
4 H), 1.45 (d, J = 6.8 Hz, 3 H, CH3), 1.56–1.67 (m, 1 H), 1.78–1.9
(m, 1 H), 2.00–2.14 (m, 1 H), 2.19 (d, J = 6.8 Hz, 2 H, OCOCH2),
2.58–2.65 (m, 1 H, CHC4H9), 4.33 (dq, J = 4.8, 6.8 Hz, 1 H,
CHCH3), 4.92 (t, J = 5.2 Hz, 1 H, CHOH).
13C NMR (50 MHz, CDCl3): d = 13.7, 19.42, 22.31, 25.7, 28.92,
29.04, 43.13, 46.46, 78.44, 79.3, 172.34, 175.78.
Synthesis 2004, No. 13, 2107–2114 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of Trisubstituted g-Butyrolactones
2111
FAB–MS: m/z (%) = 173 (10) [M+ + 1], 99 (63), 82 (48), 71 (26),
2-[1,2-Di(benzyloxy)-(1S,2S)-propyl]-(2R)-hexan-1-ol (11b);
57 (84).
Typical Procedure
PTSA (cat.) was added to a solution of 10b (0.4 g, 0.84 mmol) in
MeOH (4 mL) at r.t. and stirred for 30 min. To the reaction mixture
Et3N was added and stirred for 5 min. Workup and chromatography
as described for 11a gave 11b (0.25 g, 84%) as a liquid; [a]D +12.6
(c = 1.0, CHCl3).
Anal. Calcd for C14H24O4: C, 67.57; H, 9.92. Found: C, 67.61; H,
9.78.
4-Benzyloxy-2-butyl-(2R,3S,4S)-pentane-1,3-diol (8b); Typical
Procedure
To a stirred solution of copper(I) iodide (0.237 g, 1.25 mmol) in an-
hyd Et2O (10 mL) was added n-BuLi (1.6 M solution in n-hexane,
1.56 mL, 4 mmol) at –20 °C and stirred for 30 min. To this 7b (0.13
g, 0.625 mmol) in anhyd Et2O (10 mL) was added and stirred for 1
h. Workup and chromatography as described for 8a gave 8b (0.12
g, 73%) as a colorless liquid; [a]D +11.5 (c = 0.5, CHCl3).
IR (neat): 2960, 2850, 1570 1250, 1190 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 7.4 Hz, 3 H, CH3),
1.22–1.34 (br d, 9 H), 1.60–1.72 (m, 1 H, CHC4H9), 3.40–3.54 (m,
2 H, CH2OH), 3.67 (dd, J = 2.97, 11.15 Hz, 1 H, CHOBn), 3.77 (t,
J = 6.69 Hz, 1 H, CHOBn), 4.45–4.70 (m, 4 H, 2 × CH2Ph), 7.28 (br
s, 10 H, ArH).
FAB–MS: m/z (%) = 357 (26) [M+ + 1], 327 (26), 249 (38), 157
(100), 141 (64).
IR (neat): 3420, 2930, 1560 1050, 760 cm–1
1H NMR (200 MHz, CDCl3): d = 0.910 (t, J = 6.9 Hz, 3 H,
CH2CH3), 1.16–1.60 (m, 11 H), 3.53–3.71 (m, 4 H, CHOBn,
CH2OH, CHOH), 4.42 (d, J = 11.89 Hz, 1 H, OCH2Ph), 4.66 (d,
J = 11.89 Hz, 1 H, OCH2Ph), 7.27 (br s, 5 H, ArH).
13C NMR (75 MHz, CDCl3): 14.01, 15.32, 22.96, 23.72, 29.75,
40.95, 64.18, 70.93, 78.06, 96.04, 127.74, 128.41, 137.99.
Anal. Calcd for C23H32O3: C, 77.49; H, 9.05; C, 77.67; H, 9.25.
2-[1,2-Di(benzyloxy)-(1S,2S)-propyl]-(2S)-hexanoic Acid (12b);
Typical Procedure
To a stirred solution of 11b (0.25 g, 0.70 mmol) in CH2Cl2 (5 mL)
were added pyridininum chlorochromate (0.23 g, 1.0 mmol) and
NaOAc (0.172 g, 2.1 mmol), and allowed to stir at r.t. for 45 min.
The reaction mixture was concentrated under reduced pressure and
Et2O was added (50 mL) and the ether layer was passed through col-
umn (silica gel 60–120) to obtain aldehyde (0.23 g, 93%) as syrup,
which was used as such for the next reaction.
FAB–MS: m/z (%) = 289 (34) [M+ + 23], 267 (100) [M+ + 1], 157
(94), 141 (50), 91 (54).
Anal. Calcd for C16H26O3: C, 72.14; H, 9.84. Found: C, 72.37; H,
9.96.
1-[1-Benzyloxy-(1S)-ethyl]-2-tert-butyldimethylsilyloxymethyl-
(1S,2R)-hexyl Alcohol (9b); Typical Procedure
To a stirred solution of the aldehyde (0.23 g, 0.65 mmol) in t-
BuOH–water (7:3, 2.5 mL), were added sodium chlorite (0.088 g,
1.5 mmol) and H2O2 (0.4 mL, 3.25 mmol, 30% aq solution) and
stirred at r.t. for 6 h. Workup and chromatography as described for
12a gave 12b (0.055 g, 82%) as a colorless liquid; [a]D +11.0 (c =
0.5, CHCl3).
To a stirred solution of 8b (0.54 g, 2.03 mmol) in CH2Cl2 (10 mL),
imidazole (0.276 g, 4.0 mmol) and t-butyl dimethylsilyl chloride
(0.365 g, 2.4 mmol) were added and stirred at r.t. for 1 h. Workup
and chromatography as described for 9a gave 9b (0.63 g, 80%) as a
colorless liquid; [a]D +20.8 (c = 0.6, CHCl3).
IR (neat): 3300–3000 (br), 2930, 1710, 1280 cm–1.
IR (neat): 3510, 2960, 2850, 1490, 1280 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.86 (t, J = 6.6 Hz, 3 H, CH3), 1.19
(d, J = 5.8 Hz, 3 H, CH3), 1.25–1.30 (br d, 6 H), 1.60–1.72 (m, 1 H,
CH2C3H7), 2.63 (q, 1 H, CHCOOH), 3.60–3.73 (m, 2 H, CHOBn),
4.51 (d, J = 23 Hz, 4 H, OCH2Ph), 7.27 (br s, 10 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.41, 15.90, 23.94, 28.17, 30.27,
47.34, 72.47, 74.59, 82.65, 129.07, 139.54, 179.98.
1H NMR (300 MHz, CDCl3): d = 0.01 [s, 6 H, -Si(CH3)2], 0.88 [s,
12 H, Si(t-C4H9), CH3], 1.15 (d, J = 5.28 Hz, 3 H, CH3), 1.17–1.36
[br s, 6 H, (CH2)3], 1.46–1.52 (m, 1 H, CHC4H9), 3.53–3.66 (m, 4
H, CHOH, CHOBn, CH2OTBS), 4.47 (d, J = 11.33 Hz, 1 H,
OCH2Ph), 4.67 (d, J = 11.3 Hz, 1 H, OCH2Ph), 7.27 (br s, 5 H,
ArH).
FAB–MS: m/z (%) = 381 (14) [M+ + 1], 273 (100), 255 (8), 215
FAB–MS: m/z (%) = 371 (10) [M+ + 1], 263 (14), 154 (32), 136
(20), 141 (30).
(28), 91(100).
Anal. Calcd for C22H40O3Si: C, 69.42; H, 10.59. Found: C, 69.27;
H, 10.45.
Anal. Calcd for C23H30O4: C, 74.57; H, 8.16. Found: C, 74.62; H,
8.22.
2,3-Di(benzyloxy)-4-tert-butyldimethylsilyloxymethyl-
(2S,3S,4R)-octane (10b); Typical Procedure
3-Butyl-4-hydroxy-5-methyl-(3S,4S,5S)-tetrahydro-2-fura-
none (13b); Typical Procedure
Sodium hydride (0.037 g, 1.56 mmol, 60% dispersion in paraffin
oil) was added to a stirred solution of 9b (0.6 g, 1.5 mmol) in anhyd
DMF (3 mL) at 0 °C and stirred for 15 min. To this benzyl bromide
(0.203 mL, 1.7 mmol) was added and stirred at r.t. for 30 min.
Workup and chromatography as described for 10a gave 10b (0.620
g, 84%) as a colorless liquid; [a]D –9.3 (c = 0.5, CHCl3).
Pd(OH)2 (cat.) was added to a stirred solution of 12b (0.12 g, 0.32
mmol) in MeOH (1 mL) under H2 atmosphere for 24 h at r.t. Work-
up and chromatography as described for 13a gave 13b (0.45 g,
82%) as a syrup; [a]D –52.5 (c = 0.5, CHCl3).
IR (neat): 3400, 1770, 1190 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.93 (t, J = 7.17 Hz, 3 H, CH3),
1.25–1.60 (m, 8 H), 1.65–1.74 (m, 1 H), 2.49 (ddd, J = 3.77, 7.93
Hz, 1 H, CHC4H9), 4.13 (t, J = 4.53 Hz, 1 H, CHCH3), 4.59 (dq, J =
6.4, 11.7 Hz, 1 H, CHOH).
13C NMR (75 MHz, CDCl3): d = 13.8, 22.39, 28.06, 29.26, 49.2,
73.81, 78.73, 178.4.
IR (neat): 2960, 2850, 1570, 1250, 1100 cm–1.
1H NMR: d = 0.01 [s, 6 H, Si(CH3)2], 0.90 (br s, 12 H), 1.15–1.38
(m, 9 H, CH3, 3 × CH2), 1.59–1.69 (m, 1 H, CHC4H9), 3.53 (d, J =
6.79 Hz, 2 H, CH2OTBS), 3.63 (dd, J = 3.02, 7.55 Hz, 1 H,
CHOBn), 3.70 (t, J = 6.42 Hz, 1 H, CHOBn), 4.50–4.82 (m, 4 H,
OCH2Bn), 7.27 (br s, 10 H, ArH).
FAB–MS: m/z (%) = 471 (12) [M+ + 1], 255 (18), 215 (48) 181 (16)
91 (100).
FAB–MS: m/z (%) = 173 (10) [M+ + 1], 99 (63), 82 (48), 71 (26),
57 (84).
Anal. Calcd for C9H16O3: C, 62.77; H, 9.36. Found: C, 62.85; H,
9.47.
Anal. Calcd for C29H46O3Si: C, 73.99; H, 9.85. Found: C, 74.12; H,
9.95.
Synthesis 2004, No. 13, 2107–2114 © Thieme Stuttgart · New York

2112
P. R. Krishna et al.
PAPER
4-Butyl-2-methyl-5-oxo-(2S,3S,4S)-tetrahydro-3-furanyl
3-Methylbutanoate (2); Typical Procedure
the reaction mixture was then added a 80% solution of cumene hy-
droperoxide (1.6 mL, 8.3 mmol) and stirred for 20 min, followed by
the addition of 6b (0.8 g, 8.3 mmol) dissolved in CH2Cl2 (10
mL)and a further stirring at –20 °C for 12 h. Workup and chroma-
tography as described for 7a gave 7c (0.61 g, 71%) as a colorless
liquid; [a]D –0.7 (c = 1.0, CHCl3).
To a mixture of 13b (0.02 g, 0.116 mmol) in CH2Cl2 (2 mL) and
dimethylaminopyridine (0.056 g, 0.46 mmol), isovaleryl chloride
(0.085 mL, 0.69 mmol) were added at r.t. and stirred for 24 h. Work-
up and chromatography as described for 1 gave 2 (0.026 g, 91%) as
a colorless liquid; [a]D –31.1 (c = 1.0, CHCl3).
IR (neat): 3400, 2980, 1710, 1340, 1080 cm–1.
IR (neat): 3400, 1770, 1190 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.25 (d, J = 5.8 Hz, 3 H, CH3), 2.92
(m, 1 H, epo-H), 3.05 (dd, J = 2.5 Hz, 7.6 Hz, 1 H, epo-H), 3.34 (m,
1 H, CHOBn), 3.91 (dd, J = 3, 10 Hz, 2 H, CH2OH), 4.58 (d, J = 9.1
Hz, 1 H, CH2Ph), 4.72 (d, J = 9.1 Hz, 1 H, CH2Ph), 7.30 (br s, 5 H,
ArH).
FAB–MS: m/z (%) = 231 (34) [M+ + 23], 207 (100), 181 (30), 154
(50), 137 (74).
1H NMR (200 MHz, CDCl3): d = 0.91–0.99 (br s, 9 H), 1.30–1.47
(m, 8 H), 1.62–1.79 (m, 1 H, CHC3H7), 2.03–2.16 (m, 1 H,
CHC3H7), 2.21 (d, J = 5.86 Hz, 2 H, COCH2), 2.52 (ddd, J = 2.93,
8.78 Hz, 1 H, CHC4H9), 4.72 (m, 1 H, CHCH3), 5.12 (dd, J = 2.93,
4.39 Hz, 1 H, CHOCO).
13C NMR (75 MHz, CDCl3): d = 13.72, 14.26, 22.32, 25.56, 28.18,
29.07, 43.04, 47.13, 75.22, 76.69, 172.21, 176.63.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 69.43; H,
7.83.
FAB–MS: m/z (%) = 256 (10) [M+], 200 (16), 184 (2.6), 155 (10),
99 (34), 85 (100).
4-Benzyloxy-2-butyl-(2S,3S,4S)-pentane-1,3-diol (8c); Typical
Procedure
Anal. Calcd for C14H24O4: C, 65.60; H, 9.44. Found: C, 65.78; H,
9.11.
To a stirred solution of copper(I) iodide (1g, 5.2 mmol) in anhyd
Et2O (10 mL) was added n-BuLi (1.6 M solution in n-hexane, 6.5
mL, 10.5 mmol) at –20 °C and stirred for 30 min. To this solution,
7c (0.55 g, 2.6 mmol) in anhyd Et2O (10 mL) was added and stirred
for 1 h. Workup and chromatography as described for 8a gave 8c
(0.56 g, 80%) as a colorless liquid; [a]D +25.6 (c = 1.0, CHCl3).
Ethyl 4-benzyloxy-(E,4S)-2-pentenoate (5b); Typical Procedure
To a stirred solution of (ethoxycarbonylmethylene)-triphenylphos-
phorane (12.7 g, 36.5 mmol) in benzene (30 mL) at reflux was add-
ed 4 (5.0 g, 30.4 mmol) in benzene (20 mL) and allowed to reflux
for 1 h. Workup and chromatography as described for 5a gave 5b
(5.3 g, 75%) as a colorless liquid; [a]D –40.6 (c = 1.25, CHCl3).
IR (neat): 3420, 2930, 1560 1050, 760 cm–1.
IR (neat): 2940, 1720, 1240, 1180 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.90 (t, J = 6.1, 3 H, CH2CH3),
1.21 [d, J = 4.1 Hz, 3 H, CH(OBn) CH3], 1.27–1.53 (m, 8 H), 2.33
(br s, 1 H, OH), 3.46 (dd, J = 3.4, 6.8 Hz, 1 H, CHOH), 3.54–3.8 (m,
3 H, CH2OH, CHOBn), 4.42 (d, J = 10.3 Hz, 1 H, OCH2Ph), 4.70
(d, J = 10.3 Hz, 1 H, OCH2Ph), 7.31 (br s, 5 H, ArH).
13C NMR (75 MHz): d = 13.97, 15.65, 22.83, 28.74, 29.44, 40.9,
78.62, 127.83, 128.46, 138.0.
1H NMR (300 MHz, CDCl3): d = 1.20–1.30 (m, 6 H, 2 × CH3), 4.02
(m, 1 H, CHOBn), 4.12 (m, 2 H, COOCH2CH3), 4.35 (d, 1 H, J =
13 Hz, CH2Ph), 4.50 (d, J = 13 Hz, 1 H, CH2Ph), 5.90 (d, J = 17.3
Hz, 1 H, CHCOOEt), 6.78 (dd, J = 6.9, 17 Hz, 1 H, CH=CHCOO-
Et), 7.23 (br s, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.21, 20.6, 60.4, 70.67, 73.83,
121.3, 127.5, 127.6, 128.39.
FAB–MS: m/z (%) = 289 (34) [M+ + 23], 267 (100) [M+ + 1], 157
(94), 141 (50), 91 (54).
FAB–MS: m/z = 235 (72) [M+ + 1], 154 (20), 137 (20), 127 (74), 91
(100).
Anal. Calcd for C16H26O3: C, 72.14; H, 9.84. Found: C, 72.33; H,
9.79.
Anal. Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.47; H,
7.67.
1-[1-Benzyloxy-(1S)-ethyl]-2-tert-butyldimethylsilyloxymeth-
yl(1S,2S)-hexyl Alcohol (9c); Typical Procedure
4-Benzoloxy-(E, 4S)-2-penten-1-ol (6b); Typical Procedure
DIBAL-H (12 mL, 16.9 mmol, 20% solution in toulene) was added
to a solution of 5b (2 g, 8.5 mmol) in ahnyd CH2Cl2 (20 mL) at –20
°C dropwise and stirred for 30 min. Workup and chromatography as
described for 6a gave 6b (1.4 g, 85%) as a colorless liquid; [a]D
–39.2 (c = 1.0, CHCl3).
To a stirred solution of 8c (0.50 g, 1.8 mmol) in CH2Cl2, imidazole
(0.25 g, 3.7 mmol) and t-butyldimethylsilyl chloride (0.31 g, 2.0
mmol) were added and stirred at r.t. for 1 h. Workup and chroma-
tography as described for 9a gave 9c (0.59 g, 83%) as a colorless
liquid; [a]D +24.5 (c = 1.0, CHCl3).
IR (neat): 3510, 2960, 2850, 1490, 1280 cm–1.
IR (neat): 3400, 3000, 1480, 1080 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.01 [s, 6 H, -Si(CH3)2], 0.86 [br
s, 12 H, Si(t-C4H9), CH3], 1.18 (d, J = 4.5 Hz, 3 H, CH3), 1.25 (br s,
5 H, 2 × CH2, CH), 1.60 (m, 1 H, CHC4H9), 2.82 (br s, 1 H, OH),
3.40 (m, 1 H, CHOH), 3.56 (dd, J = 5.9, 11.8 Hz, 2 H, CH2OTBS),
3.69 (dd, J = 5.9, 11.8 Hz, 2 H, CH2OTBS), 4.40 (d, J = 11.15 Hz,
1 H, CHHPh), 4.64 (d, J = 11.15 Hz, 1 H, CHHPh), 7.27 (br s, 5 H,
ArH).
1H NMR (300 MHz, CDCl3): d = 1.25 (d, J = 4.6 Hz, 3 H, CH3), 1.51
(br s, 1 H, OH), 3.91 (t, J = 10.3, 14.8 Hz, 1 H, CHOBn), 4.12 (d,
J = 4.6 Hz, 2 H, CH2OH), 4.38 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.52
(d, J = 11.5 Hz, 1 H, CH2Ph), 5.60 (dd, J = 9.2, 12.6 Hz, 1 H,
CH=CHCH2OH), 5.73–5.82 (m, 1 H, CH=CHCH2OH), 7.23 (br s,
5 H, ArH).
FAB–MS: m/z = 215 (72) [M+], 193 (100) [M+ + 1], 175 (32), 154
(38), 91 (54).
FAB–MS: m/z (%) = 381 (14) [M+ + 1], 273 (100), 255 (8), 215
(20), 141 (30).
Anal. Calcd for C12H16O2: C, 74.97; H, 8.39. Found: C, 74.85; H,
8.45.
Anal. Calcd for C22H40O3Si: C, 69.42; H, 10.59. Found: C, 69.39;
H, 10.74.
3-[1-Benzyloxy-(1R)-ethyl]-(2R)-oxiran-2-yl Methanol (7c);
Typical Procedure
To stirred anhyd CH2Cl2 (10 mL) was added (–)-diisopropyl tartrate
(1.07 g, 4.5 mmol) in CH2Cl2 (5 mL) at –20 °C. Later titanium iso-
propoxide (1.18 g, 4.15 mmol) was added and stirred for 20 min. To
2,3-Di(benzyloxy)-4-tert-butyldimethylsilyloxy-(2S,3S,4S)-oc-
tane (10c); Typical Procedure
Sodium hydride (0.02 g, 0.5 mmol, 60% dispersion in paraffin oil)
was added to a solution of 9c (0.2 g, 0.53 mmol) in anhyd DMF (1
Synthesis 2004, No. 13, 2107–2114 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of Trisubstituted g-Butyrolactones
2113
mL) at 0 °C and stirred for 15 min. To this solution, benzyl bromide
(0.109 g, 0.64 mmol) was added and stirred at r.t. for further 30 min.
Workup and chromatography as described for 10a gave 10c (0.21 g,
85%) as a colorless liquid; [a]D +2.1 (c = 1.0, CHCl3).
1H NMR: d = 0.01 [s, 6 H, -Si(CH3)2], 0.86 (br s, 12 H, t-C4H9,
CH3), 1.18 (d, J = 6.15 Hz, 3 H, CH3), 1.22–1.32 [br s, 6 H, (CH3)3],
1.72 (m, 1 H, CHC4H9), 3.28 (dd, J = 4.6, 10.6 Hz, 1 H, CHOBn),
3.53 (dd, J = 5.2, 11.2 Hz, 1 H, CHOBn), 3.68–3.84 (m, 2 H,
CH2OTBS), 4.44–4.82 (m, 4 H, OCH2Bn), 7.27 (br s, 10 H, ArH).
Anal. Calcd for C23H30O4: C, 74.57; H, 8.16. Found: C, 74.39; H,
8.07.
3-Butyl-4-hydroxy-5-methyl-(3R,4S,5S)-tetrahydro-2-fura-
none [(–)-3-epi-Blastmycinolactol] (13c)
Pd(OH)2 (cat.) was added to a solution of 12c (0.14 g, 0.395 mmol)
in MeOH (1 mL) at r.t. and stirred under H2 atmosphere for 24 h.
Workup and chromatography as described for 13a gave 13c (0.058
g, 87%) as syrup; mp 100–101 °C [Lit.8 mp 99.5–100 °C]; [a]D
–95.5 (c = 0.5, MeOH); {Lit.8 [a]D –96.0 (c = 0.3, MeOH)].
IR (neat): 2960, 2850, 1570, 1250, 1100 cm–1.
FAB–MS: m/z (%) = 47 (12) [M+ + 1], 255 (18), 215 (48) 181 (16)
IR (neat): 3400, 1770, 1190 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 6.79 Hz, 3 H, CH3),
1.34–1.45 (m, 8 H), 1.71–1.81 (m, 1 H), 2.58 (dt, J = 4.9, 9.8 Hz, 1
H, CHC4H9), 4.32 (dt, J = 4.9, 9.8 Hz, 1 H, CHCH3), 4.43 (dq, J =
3.0, 6.4 Hz, 1 H, CHOH).
91 (100).
Anal. Calcd for C29H46O3Si: C, 73.99; H, 9.85. Found: C, 74.05; H,
9.92.
13C NMR (75 MHz, CDCl3): d = 13.67, 13.86, 22.54, 22.97, 29.71,
2-[1,2-Di(benzyloxy)-(1S,2S)-propyl]-(2S)-hexan-1-ol (11c);
Typical Procedure
PTSA (cat.) was added to a solution of 10c (0.2 g, 0.42 mmol) in
MeOH (2 mL) at r.t. and stirred for 30 min. Workup and chroma-
tography as described for 11a gave 11c (0.12 g, 80%) as a liquid;
[a]D –4.4 (c = 1.0, CHCl3).
47.56, 71.16, 78.97, 178.25.
FAB–MS: m/z (%) = 173 (10) [M+ + 1], 99 (63), 82 (48), 71 (26),
57 (84).
Anal. Calcd for C9H16O3: C, 62.76; H, 9.36. Found: C, 62.55; H,
9.44.
IR (neat): 2960, 2850, 1570 1250, 1190 cm–1.
4-Butyl-2-methyl-5-oxo-(2S,3S,4R)-tetrahydro-3-furanyl
3-Methylbutanoate [(-)-3-epi-Blastomycinone] (3)
1H NMR (200 MHz, CDCl3): d = 0.876 (t, J = 5.9 Hz, 3 H, CH3),
1.17 [d, J = 5.94 Hz, 3 H, CH(OBn)CH3], 1.25–1.63 (br s, 7 H), 3.45
(dd, J = 3.7, 7.4 Hz, 1 H, CHOBn), 3.54 (d, J = 4.45, 11.15 Hz, 1 H,
CHOBn), 3.80 (dd, J = 11.8, 18.5 Hz, 2 H, CH2OH), 4.50–4.85 (m,
4 H, CH2Ph), 7.28 (br s, 10 H, ArH).
FAB–MS: m/z (%) = 357 (26) [M+ + 1], 327 (26), 249 (38), 157
(100), 141 (64).
To a mixture of 13c (0.05 g, 0.29 mmol) and dimethylaminopyri-
dine (0.142 g, 1.16 mmol) in CH2Cl2 (2 mL), isovaleryl chloride
(0.21 mL, 1.7 mmol) was added at r.t. and stirred for 24 h. Workup
and chromatography as described for 1 gave 3 (0.063 g, 86%) as a
colorless solid; mp 49–50 °C [Lit.8 mp 48–49 °C]; [a]D –88.0 (c =
1.0, CHCl3); {Lit.8 [a]D –89.0 (c = 0.9, CHCl3)}.
IR (neat): 3400, 1770, 1190 cm–1.
Anal. Calcd for C23H32O3: C, 77.49; H, 9.05. Found: C, 77.52; H,
9.21.
1H NMR (300 MHz, CDCl3): d = 0.85–0.98 (m, 9 H), 1.26–1.46 (m,
8 H), 1.78–1.84 (m, 1 H), 2.03–2.18 (m, 1 H), 2.24 (d, J = 6.2 Hz, 2
H, OCOCHCH), 2.66 (dt, J = 6.2, 5.6 Hz, 1 H, CHC4H9), 4.54 (dq,
J = 3.2, 6.4 Hz, 1 H, CHCH3), 5.60 (dd, J = 3.2, 5.2 Hz, 1 H,
CHOH).
13C NMR (75 MHz, CDCl3): d = 13.75, 14.07, 22.29, 22.45, 23.39,
25.56, 29.54, 42.95, 45.75, 71.95, 77.38, 172.10, 176.42.
2-[1,2-Di(benzyloxy)-(1S,2S)-propyl]-(2R)-hexanoic Acid (12c);
Typical Procedure
To a stirred solution of 11c (0.1 g, 0.27 mmol) in CH2Cl2 (2 mL)
were added pyridininum chlorochromate (0.088 g, 0.4 mmol) and
NaOAc (0.044 g, 0.54 mmol) and stirring was continued at r.t. for
45 min. The reaction mixture was concentrated under reduced pres-
sure and diluted with Et2O (50 mL) and the ether layer was passed
through column (silica gel 60–120) to obtain aldehyde (0.087 g,
89%) as syrup, which was used as such for the next reaction without
further purification.
FAB–MS: m/z (%) = 256 (10) [M+], 200 (16), 184 (2.6), 155 (10),
99 (34) 85 (100).
Anal. Calcd for C14H24O4: C, 65.60; H, 9.44. Found: C, 65.48; H,
9.31.
To a stirred solution of the above aldehyde (0.087 g, 0.24 mmol) in
t-BuOH–water (7: 3, 1 mL), were added sodium chlorite (0.033 g,
0.36 mmol) and H2O2 (0.13 mL, 1.2 mmol, 30% aq solution) and the
mixture was stirred at r.t. for 6 h. Workup and chromatography as
described for 12a gave 12c (0.076 g, 85%) as a colorless liquid; [a]D
+2.5 (c = 1.0, CHCl3).
Acknowledgment
One of the authors (V. V. R. R.) acknowledges financial support in
the form of a fellowship from the UGC, New Delhi, India.
IR (neat): 3300–3000 (br), 2930, 1710, 1280 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.86 (t, J = 6.69 Hz, 3 H, CH3),
1.23 (d, J = 5.94 Hz, 3 H, CH3), 1.30–1.70 (br s, 7 H), 2.61–2.77 (m,
1 H, CHCOOH), 3.57 (t, J = 4.46 Hz, 1 H, CHOBn), 3.69 (t, J = 6.69
Hz, 1 H, CHOBn), 4.43–4.73 (m, 4 H, OCH2Ph), 7.24–7.28 (br s,
10 H, ArH).
13C NMR (75 MHz, CDCl3): d = 15.28, 16.78, 23.63, 29.58, 31.03,
49.17, 72.48, 75.65, 76.87, 83.79, 128.85, 129.02,129.52, 129.53,
139.53, 139.84, 180.87.
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Synthesis 2004, No. 13, 2107–2114 © Thieme Stuttgart · New York

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P. R. Krishna et al.
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