Stereoselective total synthesis of (-)-aspinolide B from (R)-2,3-O-isopropylideneglyceraldehyde

Article abstract of DOI:10.1055/s-2007-990824

A stereoselective total synthesis of (-)-aspinolide B by a convergent strategy is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990824

PAPER
3627
Stereoselective Total Synthesis of (–)-Aspinolide B from
(R)-2,3-O-Isopropylideneglyceraldehyde
S
tereoselectiv
a
T
otal Syn
l
thesis
o
a
f
(–)-Aspin
k
olide
B
odety Radha Krishna,* M. Narsingam
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 24 July 2007; revised 17 August 2007
Abstract: A stereoselective total synthesis of (–)-aspinolide B by a
convergent strategy is reported.
OMOM
OBn
OBn
O
OH
O
Key words: (R)-2,3-O-isopropylideneglyceraldehyde, Jacobsen
hydrolytic kinetic resolution, Sharpless asymmetric epoxidation,
1,2-anti selective reduction, Yamaguchi lactonization
O
O
OH
OH
OBn
O
2
OH
1
OTPS
4
OH
OBn
Aspinolide B and the aspinonene/aspyrone co-metabolites,
named trienediol, isoaspinonene, dihydroaspyrone, and
dienetriol were discovered by chemical screening meth-
ods in the cultures of Aspergillus ochraceus1 (DSM-7428)
under altered fermentation conditions and the structures
were established by detailed spectroscopic analysis. Other
representative members of this class of lactones are deca-
restrictine D,2 phoracantolide I,3 and achaetolide4 possess-
ing varied biological activities. Generally cyclizations of
medium ring lactones with n = 8–11 (n = number of at-
oms in the lactone ring) are more difficult due to both en-
thalpic and entropic factors.5 Notwithstanding the
difficulty, to date, only one synthesis of (–)-aspinolide B
(1) has been reported by Pilli et al.6 through Nozaki–
Hiyama–Kishi reaction as the key step, albeit in low ste-
reoselectivity.
As part of our interest in the synthesis of natural products7
and in continuation of our earlier work on the synthesis of
decarestrictin D,2 herein we wish to communicate a ste-
reoselective total synthesis of (–)-aspinolide B (1). A con-
vergent strategy (Scheme 1) is used in which both the
intermediates are derived from common, inexpensive
starting materials, namely, (R)-2,3-O-isopropylidene-
glyceraldehyde and propylene oxide.
OBn
(R)-2,3-O-isopropylidene-
glyceraldehyde
OTPS
OPMB
OBn
3
propylene oxide
OPMB
CHO
5
Scheme 1
O
O
O
a
O
OH
OTPS
6
7
Ph
H
b
O
OH
OTPS
8
O
c
OTPS
HO
9
d
e
OBn
OBn
MeO
OTPS
HO
OTPS
10
11
O
f
OBn
OBn
g
O
HO
OTPS
HO
OTPS
The synthesis of 1 was initiated with the known8 com-
pound 6 (Scheme 2), readily obtained from (R)-2,3-O-iso-
propylideneglyceraldehyde. Thus, 6 was silylated to give
TBDPS ether 7 (90%), which on exposure to PTSA in
MeOH for 10 minutes afforded diol 8 (85%). Diol 8 was
converted into the benzylidene derivative 9 in 83% yield,
which on subsequent regioselective reductive ring-open-
ing reaction with DIBAL-H in CH2Cl2 afforded the free
primary alcohol 10 (85%). Later, alcohol 10 was subject-
13
12
h
OBn
i
4
OTPS
14
OH
Scheme 2 Reagents and conditions: (a) TBDPSCl, imidazole,
CH2Cl2, 0 °C to r.t., 3 h; (b) PTSA, MeOH, 10 min; (c) a,a-di-
methoxytoluene, PTSA, CH2Cl2, 0 °C to r.t., 3 h; (d) DIBAL-H,
CH2Cl2, 0 °C to r.t., 4 h; (e) i. (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C,
2 h, ii. Ph3P=CHCO2Me, CH2Cl2, 0 °C to r.t., 4 h; (f) DIBAL-H,
CH2Cl2, 0 °C to r.t., 4 h; (g) (+)-DIPT, Ti(Oi-Pr)4, cumene hydroper-
oxide, CH2Cl2, –20 °C, 12 h; (h) i. CCl4, Ph3P, NaHCO3, reflux, 1 h,
ii. LDA, THF, –78 to –40 °C, 2 h; (i) BnBr, NaH, THF–DMF, 0 °C to
r.t., 2 h.
SYNTHESIS 2007, No. 23, pp 3627–3634
x
x.
x
x
.
2
0
0
7
Advanced online publication: 10.10.2007
DOI: 10.1055/s-2007-990824; Art ID: P09107SS
© Georg Thieme Verlag Stuttgart · New York

3628
P. Radha Krishna, M. Narsingam
PAPER
ed to Swern oxidation followed by a Wittig olefination re- In order to prepare the propargylic alcohol 3, alkyne 4
action to afford a chromatographically separable trans (Scheme 4) was treated with n-BuLi in THF at –78 °C and
a,b-unsaturated ester 11 and its cis-isomer in a 9:1 ratio the resulting acetylenic anion was quenched with alde-
(80% combined yield). The reduction of the trans-ester 11 hyde 5 to furnish 18 (69%) as a diastereomeric mixture
with DIBAL-H in CH2Cl2 at 0 °C to room temperature for (20% de).
four hours afforded the alcohol 12 (86%) and then expo-
In order to increase the diastereoselectivity in favor of the
sure of the ensuing allylic alcohol 12 to Sharpless epoxi-
requisite stereocenter (anti to the existing one), we resort-
dation afforded epoxy alcohol 13 (84%). Epoxide 13 was
ed to an oxidation–reduction protocol. Thus, hydroxy-
alkyne 18 was first oxidized (Dess–Martin periodinane,
CH2Cl2) to its corresponding keto compound 19 (92%).
chlorinated (CCl4, Ph3P, reflux) followed by a base-in-
duced double elimination to afford propargylic alcohol 14
(85%). Later, the propargylic hydroxyl group was protect-
For selective reduction of the keto group, we screened two
ed as its benzyl ether to furnish alkyne 4 (86%).
reducing reagents, i.e., Red-Al and Zn(BH4)2.10 Red-Al
For accessing aldehyde 5 (Scheme 3), the known9 diol 15, was chosen primarily to effect the reduction of the keto
obtained from Jacobsen’s hydrolytic kinetic resolution of functionality as well as the partial reduction of the acety-
propylene oxide, was converted into p-methoxyben- lenic group to afford allylic alcohol 20 in one-pot. On the
zylidene derivative 16 (82%), which on subsequent regio- contrary, reduction of the keto compound with Red-Al
selective reductive ring-opening reaction with DIBAL-H gave low diastereomeric excesses (50% de). However,
in CH2Cl2 afforded the free primary alcohol 17 (84%). Zn(BH4)2 in diethyl ether at –30 °C for 4 hours resulted in
Compound 17 on oxidation under Swern conditions gave compound 3 (82%) (74% de) as a separable diastereomer-
aldehyde 5 (90%).
ic mixture. Hence, Red-Al mediated keto reduction was
discounted and a stepwise reduction of keto group
[Zn(BH4)2] and the acetylenic bond (Red-Al) was adopt-
ed. Also, the undesired isomer was recycled to 3 by an
oxidation-reduction protocol under similar reaction con-
ditions to enhance its chemical and optical yield.
O
H
OPMB
OH
O
a
b
c
O
5
OH
OH
17
15
16
1
The diastereomeric excess was calculated from the H
Scheme 3 Reagents and conditions: (a) 4-methoxybenzaldehyde
dimethyl acetal, PTSA, CH2Cl2, r.t., 6 h; (b) DIBAL-H, CH2Cl2, 0 °C
to r.t., 4 h; (c) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C, 2 h.
NMR spectrum of 3 by comparing the relative integration
of the methoxy protons of the PMB group. The stereo-
chemical assignment of the newly created stereogenic hy-
droxyl group was assigned by analogy.10 Further, reaction
OH
OBn
a
4
OTPS
OPMB
18
OBn
b
O
c
d
OBn
3
OTPS
OPMB
19
OBn
OMOM
OH
OBn
OBn
e
OTPS
OTPS
OPMB
OBn
20
OPMB
OBn
21
f
OMOM
OBn
OMOM
OBn
g
OH
OH
OPMB
OBn
O
23
22
OBn
OPMB
h
2
Scheme 4 Reagents and conditions: (a) n-BuLi, 5, THF, –78 °C, 3 h; (b) Dess–Martin periodinane, CH2Cl2, 0 °C to r.t., 4 h; (c) Zn(BH4)2,
Et2O, –30 °C, 4 h; (d) Red-Al, Et2O, 0 °C to r.t., 2 h; (e) MOMCl, DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 6 h; (f) TBAF, THF, 0 °C to r.t., 8 h;
(g) i. Dess–Martin periodinane, CH2Cl2, 0 °C to r.t., 4 h, ii. NaClO2, NaH2PO4·2H2O, t-BuOH–2-methylbut-2-ene (3:1), 0 °C to r.t., 10 h; (h)
DDQ, CH2Cl2/H2O (9:1), 0 °C to r.t., 2 h.
Synthesis 2007, No. 23, 3627–3634 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of (–)-Aspinolide B
3629
Toronto, Canada, assisted nomenclature used in the experimental
section.
of 3 with Red-Al in diethyl ether gave the corresponding
olefin 20 (90%), and the resulting allylic hydroxyl group
was protected as its MOM-ether to afford 21 (92%).
TBDPS deprotection of compound 21 (TBAF, THF, r.t.)
afforded primary alcohol 22 (92%), which was oxidized
to the corresponding acid by a two-step process; firstly to
an aldehyde under Dess–Martin periodinane reaction con-
ditions and then on sodium chlorite oxidation to the acid
23 (85% over two steps). Treatment of 23 with DDQ in
CH2Cl2/H2O afforded the seco acid 2 (86%), which on
Yamaguchi macrolactonization11 (Scheme 5) yielded
macrolide 24 (48%). Later, deprotection (PPTS, BuOH,
reflux, 2 h) of MOM ether in 24 afforded compound 25
(87%), followed by esterification with trans-crotonic acid
under Yamaguchi reaction conditions gave the crotonyl
derivative 26 (93%).
tert-Butyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]propoxy-
diphenylsilane (7)
To a stirred solution of alcohol 6 (6 g, 37.5 mmol) in CH2Cl2 (60
mL) were added sequentially imidazole (7.65 g, 112.5 mmol) and
TBDPSCl (10.7 mL, 41.25 mmol) and the stirring was continued for
3 h at r.t. The mixture was diluted with H2O (30 mL), and extracted
with CH2Cl2 (2 × 40 mL). The combined organic layers were
washed with brine (30 mL), dried (Na2SO4), concentrated, and the
residue was purified by column chromatography (silica gel, 60–120
mesh, EtOAc–hexane, 1:9) to afford 7; colorless liquid; yield: 13.44
g (90%); [a]D25 +15.3 (c 0.5, CHCl3).
IR (neat): 750, 1250, 1275, 1850, 2900, 3020 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.05 (s, 9 H, t-C4H9Si), 1.30, 1.35
(2 s, 6 H, 2 × CH3), 1.49–1.82 (m, 4 H, H-2, 2¢, H-3, 3¢), 3.40–3.48
(m, 1 H, H-5), 3.64–3.70 (m, 2 H, H-1), 3.83–4.12 (m, 2 H, H-4, H-
5¢), 7.31–7.41 (m, 6 H, ArH), 7.60–7.69 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 19.2, 24.79, 26.38, 26.9, 27.5, 28.6,
64.3, 65.6, 69.8, 109.8, 128.3, 128.6, 134.2, 135.6.
O
O
b
a
O
O
2
MOMO
OBn
HO
OBn
ESI-MS: m/z = 399 (M+ + 1).
24
OBn
25
OBn
Anal. Calcd for C24H34O3Si: C, 72.32; H, 8.60; Si, 7.05. Found: C,
72.26; H, 8.54; Si, 7.02.
O
d
c
O
1
(2S)-5-[1-(tert-Butyl)-1,1-diphenylsilyl]oxypentane-1,2-diol (8)
PTSA (cat.) was added to a stirred solution of 7 (12 g, 30.15 mmol)
in MeOH (60 mL) and the stirring was continued for 10 min at r.t.
The mixture was quenched with Et3N (4 mL) and stirred for 5 min.
The mixture was concentrated and diluted with EtOAc (100 mL).
The organic layer was washed with H2O (20 mL), brine (20 mL),
dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by column chromatography (60–120 sil-
ica gel, EtOAc–hexane, 2:3) to obtain 8; colorless liquid; yield: 9.17
g (85%); [a]D25 +3.3 (c 0.15, CHCl3).
O
O
OBn
26
OBn
Scheme 5 Reagents and conditions: (a) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF, 0 °C to r.t., 4 h, then DMAP, toluene, reflux, 12
h; (b) PPTS, BuOH, reflux, 2 h; (c) trans-crotonic acid, 2,4,6-trichlo-
robenzoyl chloride, Et3N, THF, 0 °C to r.t., 1 h, then 25, DMAP,
toluene, r.t.,2 h; (d) TiCl4, CH2Cl2, 0 °C to r.t., 2 h.
IR (neat): 750, 1250, 1275, 1850, 2900, 3020, 3450 cm–1.
Finally, global debenzylation (TiCl4, CH2Cl2, 0 °C to r.t.)
afforded the target compound 1 (69%). The physical and
spectroscopic data of 112 were in excellent agreement with
those reported in the literature.1,6
1H NMR (200 MHz, CDCl3): d = 1.04 (s, 9 H, t-C4H9Si), 1.40–1.71
(m, 4 H, H-2, 2¢, H-3, 3¢), 3.34–3.40 (m, 1 H, H-5), 3.54–3.59 (m, 1
H, H-5¢), 3.64–3.69 (m, 3 H, H-1, 1¢, H-4), 7.31–7.41 (m, 6 H, ArH),
7.61–7.64 (m, 4 H, ArH).
In conclusion, a stereoslective total synthesis of 1 has
been accomplished by a convergent strategy wherein (R)-
2,3-O-isopropylideneglyceraldehyde and the chiral diol
ESI-MS: m/z = 376 (M+ + 18).
Anal. Calcd for C21H30O3Si: C, 70.35; H, 8.43; Si, 7.83. Found: C,
derived from propylene oxide were used as the starting 70.27; H, 8.38; Si, 7.78.
materials for the ready access of both the advanced inter-
mediates, their coupling, and subsequent elaboration.
tert-Butyl(diphenyl)-3-[(4S)-2-phenyl-1,3-dioxolan-4-yl]prop-
oxysilane (9)
To a stirred solution of compound 8 (9.0 g, 25.14 mmol) in anhyd
CH2Cl2 (90 mL) was added benzaldehyde dimethylacetal (4.52 mL,
30.17 mmol) followed by PTSA (cat.) at 0 °C and the mixture was
allowed to stir at r.t. for 3 h. The mixture was worked up as de-
scribed for 8 and the residue purified by column chromatography
(silica gel, 60–120 mesh, EtOAc–hexane, 1:3) to afford compound
9; light yellow syrup; yield: 9.3 g (83%); [a]D25 +30.41 (c = 0.325,
CHCl3).
Varian Gemini 200 MHz, Bruker Avance-300 MHz, Varian 400
MHz, 500 MHz, 600 MHz spectrometers were used for NMR mea-
surement with 7–10 mM solutions in CDCl3 with tetramethylsilane
as internal standard. J values are given in Hz. Optical rotations were
measured with a JASCO P-1020 instrument and [a]D values are in
units of 10–1 deg cm2 g–1at 25 °C. IR spectra were taken with a
Perkin-Elmer 1310 spectrometer. Mass spectra were recorded on
CEC-21-11013 or Finnigan Mat 1210 double focusing mass spec-
trometers operating at a direct inlet system, FABMS and HRMS
was measured using VG AUTOSPEC mass spectrometers at 5 or 7
k resolution using perflurokerosene 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.,
IR (neat): 750, 1250, 1275, 1850, 2900, 3015 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.04 (s, 9 H, t-C4H9Si), 1.40–1.71
(m, 4 H, H-2, 2¢, H-3, 3¢), 3.38–3.43 (m, 1 H, H-5), 3.58–3.62 (m, 1
H, H-5¢), 3.66–3.74 (m, 3 H, H-1, 1¢, H-4), 5.42 (s, 1 H, OCHPh),
7.31–7.41 (m, 11 H, ArH), 7.61–7.64 (m, 4 H, ArH).
ESI-MS: m/z = 464 (M+ + 18).
Anal. Calcd for C28H34O3Si: C, 75.29; H, 7.67; Si, 6.29. Found: C,
75.22; H, 7.56; Si, 6.21.
Synthesis 2007, No. 23, 3627–3634 © Thieme Stuttgart · New York

3630
P. Radha Krishna, M. Narsingam
PAPER
(2S)-2-(Benzyloxy)-5-[1-(tert-butyl)-1,1-diphenylsilyl]oxy-
pentan-1-ol (10)
1H NMR (200 MHz, CDCl3): d = 1.03 (s, 9 H, t-C4H9Si), 1.56–1.71
(m, 4 H, H-2, 2¢, H-3, 3¢), 3.59–3.82 (m, 3 H, H-1,1¢, H-4), 4.11–
4.13 (m, 2 H, H-7, 7¢), 4.33 (d, J = 11.94 Hz, 1 H, OCH2Ph), 4.53
(d, J = 11.94 Hz, 1 H, OCH2Ph), 5.5–5.84 (m, 2 H, olefinic), 7.25–
7.42 (m, 11 H, ArH), 7.59–7.62 (m, 4 H, ArH).
DIBAL-H (28.65 mmol, 20% solution in toluene) was added drop-
wise to a solution of 9 (9.0 g, 20.18 mmol) in anhyd CH2Cl2 (45 mL)
at 0 °C and the mixture was stirred for 4 h. After the completion of
the reaction, MeOH (5 mL) was added, followed by sat. aq sodium
potassium tartrate solution (10 mL). The mixture was filtered and
the filtrate was extracted with EtOAc (2 × 100 mL). The combined
organic layers were dried (Na2SO4), concentrated under reduced
pressure, and the residue subjected to column chromatography (60–
120 silica gel, EtOAc–hexane, 1:4) to obtain 10; light yellow syrup;
yield: 7.68 g (85%); [a]D25 –5.3 (c 0.1, CHCl3).
ESI-MS: m/z = 475 (M+ + 1).
Anal. Calcd for C30H38O3Si: C, 75.90; H, 8.07; Si, 5.92. Found: C,
75.86; H, 8.01; Si, 5.87.
[(2R,3S)-3-((1S)-1-(Benzyloxy)-4-[1-(tert-butyl)-1,1-diphenyl-
silyl]oxybutyl)oxiran-2-yl]methanol (13)
To a stirred and cooled (–20 °C, CCl4/CO2) suspension of molecular
sieves (4 Å, dried under N2) in anhyd CH2Cl2 (10 mL) under N2
were added sequentially (+)-DIPT (0.346 g, 1.47 mmol) in anhyd
CH2Cl2 (5 mL), Ti(Oi-Pr)4 (0.22 mL, 0.74 mmol) and cumene hy-
droperoxide (1.7 g, 11.07 mmol, 80% solution) with an interval of
15 min. After 20 min, the resulting mixture was treated dropwise
with a solution of 12 (3.5 g, 7.38 mmol) in anhyd CH2Cl2 (20 mL)
and the mixture was stirred for 12 h at –20 °C. The mixture was
quenched with 10% aq NaOH, saturated with NaCl (30 mL) at r.t.,
stirred for 1 h, filtered through Celite, and extracted with EtOAc
(4 × 50 mL). Evaporation of solvent and purification of the residue
by column chromatography (silica gel, 60–120 mesh, EtOAc–hex-
ane, 1.5:3.5) furnished 13; colorless syrup; yield: 3.04 g (84%);
[a]D25 –30.25 (c 0.45, CHCl3).
IR (neat): 750, 1050, 1250, 1275, 1850, 2900, 3015, 3450 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.04 (s, 9 H, t-C4H9Si), 1.55–1.72
(m, 4 H, H-2, 2¢, H-3, 3¢), 3.41–3.51 (m, 1 H, H-5), 3.58–3.69 (m, 4
H, H-1, 1¢, H-4, H-5¢), 4.43–4.60 (m, 2 H, OCH2Ph), 7.25–7.43 (m,
11 H, ArH), 7.61–7.64 (m, 4 H, ArH).
ESI-MS: m/z = 449 (M+ + 1).
Anal. Calcd for C28H36O3Si: C, 74.95; H, 8.09; Si, 6.26. Found: C,
74.89; H, 8.01; Si, 6.21.
Methyl (E,4S)-4-(Benzyloxy)-7-[1-(tert-butyl)-1,1-diphenyl-
silyl]oxyhept-2-enoate (11)
To a stirred solution of oxalyl chloride (1.47 mL, 17.18 mmol) in
anhyd CH2Cl2 (30 mL) was added DMSO (2.44 mL, 34.37 mmol)
at –78 °C and the stirring was continued at the same temperature for
0.5 h. A solution of the alcohol 10 (7 g, 15.63 mmol) in CH2Cl2 (40
mL) was added at –78 °C and the mixture was stirred for 1.5 h at the
same temperature. Et3N (20.48 mL, 146.61 mmol) was added at
0 °C and the whole was stirred for an additional 30 min. The mix-
ture was diluted with H2O (30 mL) and extracted with CH2Cl2
(2 × 50 mL). The combined organic layers were washed with brine
(20 mL), dried (Na2SO4), and concentrated to give aldehyde (6.55
g) in 94% yield as a pale yellow syrup which was used as such in
the next reaction. To a stirred solution of (methoxycarbonylmethyl-
ene)triphenylphosphorane (5.62 g, 16.14 mmol) in CH2Cl2 (60 mL)
was added the above obtained aldehyde (6.0 g, 13.45 mmol) at 0 °C
and the stirring was continued for 4 h at r.t. The mixture was con-
centrated, purified by column chromatography (silica gel, 60–120
mesh, EtOAc–hexane, 1:9) to give 11; pale yellow syrup; yield: 5.4
g (80%); [a]D25 –9.13 (c 0.3, CHCl3).
IR (neat): 750, 820, 1175, 1250, 1513, 2263, 2900, 3440 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.04 (s, 9 H, t-C4H9Si), 1.59–1.91
(m, 4 H, H-2, 2¢, H-3, 3¢), 2.85 (dd, J = 2.22, 5.31 Hz, 1 H, H-6),
2.99–3.06 (m, 1 H, H-5), 3.19–3.34 (m, 1 H, H-4), 3.48 (dd,
J = 4.21, 12.64 Hz, 1 H, H-7), 3.57–3.64 (m, 2 H, H-1, 1¢), 3.75 (dd,
J = 2.74, 12.63 Hz, 1 H, H-7¢), 4.42–4.60 (m, 2 H, OCH2Ph), 7.25–
7.40 (m, 11 H, ArH), 7.59–7.62 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 19.0, 26.6, 28.1, 28.8, 56.7, 56.9,
61.2, 63.2, 76.4, 127.1, 127.8, 128.0, 129.6, 130.1, 133.4, 133.9,
135.2, 136.2.
ESI-MS: m/z = 491 (M+ + 1).
Anal. Calcd for C30H38O4Si: C, 73.43; H, 7.81; Si, 5.72. Found: C,
73.39; H, 7.76; Si, 5.66.
(3R,4S)-4-(Benzyloxy)-7-[1-(tert-butyl)-1,1-diphenylsilyl]oxy-
hept-1-yn-3-ol (14)
IR (neat): 750, 1250, 1275, 1713, 2900, 3010 cm–1.
To a stirred solution of the epoxide 13 (3.0 g, 6.12 mmol) in anhyd
CCl4 (15 mL) were added Ph3P (2.41 g, 9.18 mmol) and NaHCO3
(0.6 g, 0.2 g for 1 g of starting material) and the mixture was heated
to reflux for 1 h. The CCl4 was evaporated under reduced pressure
and the obtained residue was purified by column chromatography
(silica gel, 60–120 mesh, EtOAc–hexane, 1:9) to afford the corre-
sponding chloro compound (2.87 g) in 92% yield as a colorless syr-
up. Due to the instability of this compound, it was used in the next
step without delay. To a stirred mixture of (i-Pr)2NH (2.19 mL, 16.5
mmol) in anhyd THF (10 mL) was added n-BuLi (6.6 mL, 16.5
mmol, 2.5 M solution in n-hexane) at –78 °C and the stirring was
continued for 1 h. A solution of the above-obtained chloro com-
pound (2.8 g, 5.5 mmol) in anhyd THF (20 mL) was added to the
above-prepared LDA at –40 °C and the mixture was stirred for 2 h
at the same temperature. The mixture was quenched with aq NH4Cl
(10 mL) and allowed to stir for 15 min. The organic layer was sep-
arated and the aqueous layer was washed with EtOAc (2 × 20 mL).
The combined organic layers were washed with H2O (2 × 10 mL),
brine (10 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude product was purified by column chromatogra-
phy (silica gel 60–120 mesh, EtOAc–hexane, 1:4) to give 14; light
yellow syrup; yield: 2.2 g (85%); [a]D25 –16.96 (c 0.28, CHCl3).
1H NMR (300 MHz, CDCl3): d = 1.04 (s, 9 H, t-C4H9Si), 1.55–1.74
(m, 4 H, H-2, 2¢, H-3, 3¢), 3.61 (t, J = 6.04 Hz, 2 H, H-1), 3.74 (s, 3
H, OCH3), 3.88–3.93 (m, 1 H, H-4), 4.3 (d, J = 12.08 Hz, 1 H,
OCH2Ph), 4.53 (d, J = 12.08 Hz, 1 H, OCH2Ph), 5.95 (d, J = 15.86
Hz, 1 H, olefinic), 6.80 (dd, J = 6.79, 15.86 Hz, 1 H, olefinic), 7.22–
7.39 (m, 11 H, ArH), 7.59–7.62 (m, 4 H, ArH).
ESI-MS: m/z = 503 (M+ + 1).
Anal. Calcd for C31H38O4Si: C, 74.06; H, 7.62; Si, 5.59. Found: C,
73.98; H, 7.56; Si, 5.50.
(E,4S)-4-(Benzyloxy)-7-[1-(tert-butyl)-1,1-diphenylsilyl]oxy-
hept-2-en-1-ol (12)
To a stirred solution of 11 (4.50 g, 8.96 mmol) in anhyd CH2Cl2 (30
mL) was added DIBAL-H (12.75 mL, 17.93 mmol, 2 M solution in
toluene) at 0 °C and the stirring continued for 4 h at r.t. The mixture
was worked up as described for 10 and the residue purified by col-
umn chromatography (silica gel, 60–120 mesh, EtOAc–hexane,
1:4), to afford 12; colorless syrup; yield: 3.66 g (86%); [a]D25 –32.0
(c 0.3, CHCl3).
IR (neat): 750, 1250, 1275, 1670, 2900, 3390 cm–1.
IR (neat): 750, 1250, 2900, 3010, 3310 cm–1.
Synthesis 2007, No. 23, 3627–3634 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of (–)-Aspinolide B
3631
25
1H NMR (200 MHz, CDCl3): d = 1.04 (s, 9 H, t-C4H9Si), 1.52–1.85
(m, 4 H, H-2, 2¢, H-3, 3¢), 2.39 (d, J = 2.03, 1 H, H-7), 3.44–3.55 (m,
1 H, H-4), 3.64 (t, J = 6.12 Hz, 2 H, H-1), 4.35–4.44 (m, 1 H, H-5),
4.58 (br s, 2 H, OCH2Ph), 7.28–7.42 (m, 11 H, ArH), 7.59–7.62 (m,
4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 19.3, 27.1, 27.7, 28.4, 63.9, 70.8,
73.0, 75.2, 80.4, 81.2, 127.5, 127.8, 128.2, 129.7, 134.1, 135.5,
138.1, 138.7.
hexane, 1:4) to afford 17; colorless syrup; yield: 2.5 g (84%); [a]D
–70.92 (c 0.27, CHCl3).
IR (neat): 850, 1050, 1250, 2900, 3010, 3450 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.16 (d, J = 6.25 Hz, 3 H, CH3),
3.37–3.67 (m, 3 H, H-1, H-1¢, H-2), 3.79 (s, 3 H, OCH3), 4.35–4.62
(m, 2 H, OCH2Ph), 6.85 (d, J = 8.02 Hz, 2 H, ArH), 7.24 (d, J = 8.02
Hz, 2 H, ArH).
ESI-MS: m/z = 197 (M+ + 1).
ESI-MS: m/z = 490 (M+ + 18).
Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.25; H,
8.16.
Anal. Calcd for C30H36O3Si: C, 76.23; H, 7.68; Si, 5.94. Found: C,
76.12; H, 7.59; Si, 5.86.
(2R)-2-[(4-Methoxybenzyl)oxy]propanal (5)
tert-Butyl[(4S,5R)-4,5-di(benzyloxy)hept-6-ynyl]oxydiphenyl-
silane (4)
To a stirred solution of oxalyl chloride (0.96 mL, 11.22 mmol) in
anhyd CH2Cl2 (10 mL) was added DMSO (1.59 mL, 22.44 mmol)
at –78 °C and the stirring was continued at the same temperature for
0.5 h. A solution of the alcohol 17 (2 g, 10.20 mmol) in CH2Cl2 (10
mL) was added at –78 °C and the mixture was stirred for 1.5 h at the
same temperature. Et3N (8.6 mL, 61.22 mmol) was added at 0 °C
and the mixture was stirred for an additional 30 min. The mixture
was worked up as described for 11 and the residue was purified by
column chromatography (silica gel, 60–120 mesh, EtOAc–hexane,
1:5) to afford 5; colorless syrup; yield: 1.78 g (90%).
To a cooled (0 °C) suspension of NaH (0.25 g, 10.59 mmol, 60%
w/w dispersion in paraffin oil) in THF (15 mL) and DMF (1 mL)
was added portionwise a solution of 14 (3.5 g, 9.11 mmol) in THF
(10 mL). After 15 min, BnBr (0.6 mL, 5.08 mmol) was added drop-
wise at 0 °C and stirred for 1.5 h at r.t. Sat. aq NH4Cl (10 mL) was
added dropwise at 0 °C followed by EtOAc (50 mL). The organic
layer was washed with H2O (20 mL), brine (20 mL), dried
(Na2SO4), and evaporated. The obtained residue was purified by
column chromatography (silica gel, 60–120 mesh, EtOAc–hexane,
1:9) to give 4; light yellow syrup; yield: 2.05 g (86%); [a]D
–115.92 (c 0.18, CHCl3).
IR (neat): 750, 1250, 2900, 3010, 3310 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.03 (s, 9 H, t-C4H9Si), 1.47–1.86
(m, 4 H, H-2, 2¢, H-3, 3¢), 2.44 (d, J = 2.03, 1 H, H-7), 3.52–3.66 (m,
3 H, H-1, 1¢, H-4), 4.07–4.15 (m, 1 H, H-5), 4.44–4.55 (m, 2 H,
OCH2Ph), 4.67–4.90 (m, 2 H, OCH2Ph), 7.24–7.37 (m, 16 H, ArH),
7.59–7.62 (m, 4 H, ArH).
IR (neat): 850, 1050, 1250, 1707, 2900, 3010 cm–1.
25
1H NMR (200 MHz, CDCl3): d = 1.18 (d, J = 6.25 Hz, 3 H, CH3),
3.92–3.99 (m, 1 H, H-2), 3.79 (s, 3 H, OCH3), 4.39–4.62 (m, 2 H,
OCH2Ph), 6.85 (d, J = 8.02 Hz, 2 H, ArH), 7.24 (d, J = 8.02 Hz, 2
H, ArH), 9.82 (br s, 1 H, CHO).
(2R,6R,7S)-6,7-Di(benzyloxy)-10-[1-(tert-butyl)-1,1-diphenyl-
silyl]oxy-2-[(4-methoxybenzyl)oxy]dec-4-yn-3-ol (18)
To a stirred mixture of compound 4 (1.5 g, 2.67 mmol) in anhyd
THF (10 mL) was added n-BuLi (2.14 mL, 5.34 mmol, 2.5 M solu-
tion in n-hexane) at –78 °C and the stirring was continued for 1 h.
A solution of 5 (0.62 g, 3.2 mmol) in anhyd THF (10 mL) was added
at –78 °C and the mixture was stirred for 2 h at the same tempera-
ture. The mixture was quenched with aq NH4Cl (10 mL) and al-
lowed to stir for 15 min. The organic layer was separated and the
aqueous layer was washed with EtOAc (2 × 20 mL). The combined
organic layers were washed with H2O (2 × 10 mL), brine (10 mL),
dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by column chromatography (silica gel
60–120 mesh, EtOAc–hexane, 1:4) to give 18; light yellow syrup;
yield: 1.39 g (69%).
13C NMR (75 MHz, CDCl3): d = 19.2, 27.1, 27.6, 28.6, 63.8, 70.8,
71.2, 73.0, 75.2, 80.4, 81.0, 127.4, 127.8, 128.2, 129.7, 134.1,
135.3, 137.9, 138.8.
ESI-MS: m/z = 585 (M+ + 23).
HRMS (ESI): m/z calcd for C37H42O3Si + Na: 585.2800; found:
585.2822.
(4R)-2-(4-Methoxyphenyl)-4-methyl-1,3-dioxolane (16)
To a stirred solution of 15 (2.0 g, 26.32 mmol) in anhyd CH2Cl2 (20
mL) was added anisaldehyde dimethylacetal (5.74 g, 31.57 mmol)
followed by PTSA (cat.) at 0 °C and the stirring was continued for
6 h at r.t. The mixture was neutralized with aq NaHCO3 (10 mL) and
extracted with CH2Cl2 (3 × 20 mL). The combined organic layers
were washed with brine (10 mL), dried (Na2SO4), and concentrated.
The crude residue was purified by column chromatography (silica
gel, 60–120 mesh, EtOAc–hexane, 1:9) to afford 16; light yellow
syrup; yield: 4.2 g (82%); [a]D25 –30.13 (c 0.1, CHCl3).
IR (neat): 750, 850, 1250, 2210, 2900, 3010 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.03 (s, 9 H, t-C4H9Si), 1.21–1.30
(m, 3 H, CH3), 1.52–1.81 (m, 4 H, H-2, 2¢, H-3, 3¢), 3.44–3.74 (m,
4 H, H-1, 1¢, H-4, H-9), 3.75 (s, 1.8 H, OCH3), 3.79 (s, 1.2 H,
OCH3), 4.45–4.58 (m, 6 H, H-5, H-8, 2 × OCH2Ph), 4.68–4.86 (m,
2 H, OCH2Ph), 6.74–6.84 (m, 2 H, ArH), 7.18–7.36 (m, 18 H, ArH),
7.59–7.62 (m, 4 H, ArH).
IR (neat): 850, 1250, 2900, 3010 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.36 (d, J = 3.13 Hz, 3 H, CH3),
3.46–3.59 (m, 1 H, H-1), 3.79 (s, 3 H, OCH3), 4.01–4.21 (m, 1 H,
H-1¢), 4.22–4.37 (m, 1 H, H-2), 5.77 (s, 1 H, OCHPh), 6.85 (d,
J = 8.02 Hz, 2 H, ArH), 7.25 (d, J = 8.02 Hz, 2 H, ArH).
LC–MS: m/z = 779 (M+ + 23).
(2R,6R,7S)-6,7-Di(benzyloxy)-10-[1-(tert-butyl)-1,1-diphenyl-
silyl]oxy-2-[(4-methoxybenzyl)oxy]dec-4-yn-3-one (19)
ESI-MS: m/z = 195 (M+ + 1).
To a stirred solution of 18 (1.2 g, 1.58 mmol) in anhyd CH2Cl2 (15
mL) was added Dess–Martin periodinane reagent (1.01 g, 2.38
mmol) at 0 °C and the stirring was continued for 4 h at r.t. The mix-
ture was quenched with a 1:1 ratio of aq sat. NaHCO3 and aq
Na2S2O3 (15 mL), allowed to stirred for 30 min and extracted with
CH2Cl2 (2 × 20 mL). The combined organic layers were washed
with H2O (10 mL), dried (Na2SO4), and concentrated. The crude
residue was purified by column chromatography (silica gel 60–120
mesh, EtOAc–hexane, 1:9) to give 19; colorless syrup; yield: 1.1 g
(92%); [a]D25 –128.66 (c 0.05, CHCl3).
Anal. Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 67.91; H,
7.17.
(2R)-2-[(4-Methoxybenzyl)oxy]propan-1-ol (17)
To a stirred solution of 16 (3.0 g, 15.46 mmol) in anhyd CH2Cl2 (20
mL) was added DIBAL-H (21.9 mL, 30.92 mmol, 2 M solution in
toluene) at 0 °C and the stirring was continued for 4 h at r.t. The
mixture was worked up as described for 10 and the residue was pu-
rified by column chromatography (silica gel, 60–120 mesh, EtOAc–
Synthesis 2007, No. 23, 3627–3634 © Thieme Stuttgart · New York

3632
P. Radha Krishna, M. Narsingam
PAPER
IR (neat): 750, 890, 1250, 1680, 2200, 2900, 3010 cm–1.
Anal. Calcd for C48H58O6Si: C, 75.95; H, 7.70; Si, 3.70. Found: C,
75.89; H, 7.64; Si, 3.66.
1H NMR (300 MHz, CDCl3): d = 1.03 (s, 9 H, t-C4H9Si), 1.36 (d,
J = 6.79 Hz, 3 H, CH3), 1.52–1.82 (m, 4 H, H-2, 2¢, H-3, 3¢), 3.57–
3.67 (m, 3 H, H-1, 1¢, H-4), 3.73 (s, 3 H, OCH3), 3.82–3.94 (m, 1 H,
H-9), 4.24 (d, J = 4.53, 1 H, H-5), 4.32–4.83 (m, 6 H, CH2Ph), 6.76
(d, J = 8.68 Hz, 2 H, ArH), 7.18–7.36 (m, 18 H, ArH), 7.59–7.62
(m, 4 H, ArH).
tert-Butyl[(4S,5R,6E,8S,9R)-4,5-di(benzyloxy)-9-[(4-methoxy-
benzyl)oxy]-8-(methoxymethoxy)dec-6-enyl]oxydiphenylsilane
(21)
To a stirred and cooled (0 °C) solution of alcohol 20 (0.7 g, 0.92
mmol) in CH2Cl2 (7 mL) was added DIPEA (0.32 mL, 1.85 mmol)
followed by methoxymethyl chloride (0.08 mL, 1.38 mmol) and a
catalytic amount of DMAP at 0 °C and the stirring was continued
for 6 h at r.t. After the completion of the reaction, the mixture was
extracted with CH2Cl2 (2 × 10 mL). The combined organic layers
were washed with H2O (5 mL), brine (5 mL), dried (Na2SO4), and
concentrated. The crude residue was purified by column chroma-
tography (silica gel, 60–120 mesh, EtOAc–n-hexane, 0.8:9.2) to af-
ford 21; colorless syrup; yield: 0.68 g (92%); [a]D25 –10.40 (c 0.53,
CHCl3).
ESI-MS: m/z = 772 (M+ + 18).
Anal. Calcd for C48H54O6Si: C, 76.36; H, 7.21; Si, 3.72. Found: C,
76.31; H, 7.17; Si, 3.66.
(2R,3S,6R,7S)-6,7-Di(benzyloxy)-10-[1-(tert-butyl)-1,1-diphe-
nylsilyl]oxy-2-[(4-methoxybenzyl)oxy]dec-4-yn-3-ol (3)
To a stirred solution of compound 19 (1.0 g, 1.32 mmol) in anhyd
Et2O (10 mL) was added Zn(BH4)2 (0.6 mL, 2.65 mmol, 4.4 M so-
lution in n-hexane) at –30 °C and the stirring was continued for 4 h.
The mixture was quenched with aq NH4Cl (6 mL) and allowed to
stir for 15 min. The organic layer was separated and the aqueous
layer was washed with EtOAc (2 × 20 mL). The combined organic
layers were washed with H2O (2 × 10 mL), brine (10 mL), dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified by column chromatography (silica gel 60–120
mesh, EtOAc–hexane, 1:4) to give 3; colorless syrup; yield: 0.822
g (82%, with 74% de); [a]D25 –59.0 (c 0.5, CHCl3).
IR (neat): 750, 890, 970, 1250, 1670, 2900, 3010 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.03 (s, 9 H, t-C4H9Si), 1.18 (d,
J = 6.42 Hz, 3 H, CH3), 1.49–1.62 (m, 4 H, H-2, 2¢, H-3, 3¢), 3.3 (s,
3 H, OCH3), 3.48–3.62 (m, 3 H, H-1, 1¢, H-4), 3.74 (s, 3 H, OCH3),
3.77–3.80 (m, 1 H, H-9), 4.06–4.13 (m, 1 H, H-8), 4.28–4.34 (m, 1
H, H-5), 4.45–4.67 (m, 8 H, OCH2OCH3, 3 × OCH2Ph), 5.64–5.75
(m, 2 H, olefinic), 6.76 (d, J = 8.50 Hz, 2 H, ArH), 7.18–7.36 (m, 18
H, ArH), 7.59–7.62 (m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.3, 19.4, 26.9, 27.5, 28.4, 55.3,
55.7, 63.8, 70.6, 71.1, 72.6, 73.9, 78.3, 81.3, 82.8, 95.3, 113.6,
127.7, 127.8, 128.4, 128.4, 128.9, 129.4, 129.6, 130.0, 133.4, 135.2,
138.6, 139.0, 159.4.
IR (film): 750, 850, 1250, 2210, 2900, 3010 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.02 (s, 9 H, t-C4H9Si), 1.24 (d,
J = 6.3 Hz, 3 H, CH3), 1.53–1.76 (m, 4 H, H-2, 2¢, H-3, H-3¢), 2.34
(d, J = 5.59 Hz, 1 H, OH), 3.54–3.63 (m, 3 H, H-1, 1¢, H-4), 3.75 (s,
3 H, OCH3), 4.13–4.16 (m, 1 H, H-9), 4.38–4.56 (m, 6 H, H-5, H-8,
2 × OCH2Ph), 4.63–4.86 (m, 2 H, OCH2Ph), 6.78 (d, J = 8.65 Hz, 2
H, ArH), 7.26 (m, 18 H, ArH), 7.61 (d, J = 7.57 Hz, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.8, 19.2, 27.1, 27.6, 28.8, 55.4,
63.9, 65.3, 70.7, 71.4, 72.8, 76.7, 80.7, 82.9, 85.2, 113.9, 127.5,
127.9, 128.2, 128.3, 129.2, 129.5, 130.2, 134.0, 135.5, 137.8, 138.6,
159.3.
ESI-MS: m/z = 803 (M+ + 1).
Anal. Calcd for C50H62O7Si: C, 74.78; H, 7.78; Si, 3.50. Found: C,
74.70; H, 7.69; Si, 3.45.
(4S,5R,6E,8S,9R)-4,5-Di(benzyloxy)-9-[(4-methoxybenzyl)oxy]-
8-(methoxymethoxy)dec-6-en-1-ol (22)
To a stirred solution of 21 (0.6 g, 0.748 mmol) in anhyd THF (6 mL)
was added Bu4NF in THF (1.51 mL, 1.496 mmol) at 0 °C and the
stirring was continued for 8 h at r.t. The mixture was concentrated
and the crude residue was purified by column chromatography (sil-
ica gel, 60–120 mesh, EtOAc–hexane, 3:7) to afford 22; light yel-
low syrup, yield: 0.388 g (92%); [a]D25 –50.65 (c 0.53, CHCl3).
LC–MS: m/z = 779 (M + Na)+.
HRMS (ESI): m/z calcd for C48H56O6Si + Na: 779.3743; found:
779.3734.
(2R,3S,4E,6R,7S)-6,7-Di(benzyloxy)-10-[1-(tert-butyl)-1,1-
diphenylsilyl]oxy-2-[(4-methoxybenzyl)oxy]dec-4-en-3-ol (20)
To a solution of 3 (0.8 g, 1.06 mmol) in anhyd Et2O (10 mL) was
added dropwise Red-Al reagent (0.63 mL, 3.17 mmol, 70% solution
in toluene) at 0 °C and stirred for 2 h at the same temperature. The
mixture was quenched with sat. aq NH4Cl solution (6 mL) and ex-
tracted with EtOAc (3 × 15 mL). The organic layer was washed
with H2O (10 mL), brine (10 mL), dried (Na2SO4), and concentrat-
ed. The crude residue was purified by column chromatography (sil-
ica gel, 60–120 mesh, EtOAc–hexane, 1:4) to furnish 20; light
yellow syrup; yield: 0.72 g (90%); [a]D25 –138.94 (c 0.3, CHCl3).
IR (neat): 750, 890, 970, 1250, 1670, 2910, 3010, 3400 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19 (d, J = 6.04 Hz, 3 H, CH3),
1.42–1.61 (m, 4 H, H-2, 2¢, H-3, 3¢), 3.3 (s, 3 H, OCH3), 3.49–3.59
(m, 3 H, H-1, 1¢, H-4), 3.76 (s, 3 H, OCH3), 3.84–3.89 (m, 1 H, H-
9), 4.05–4.12 (m, 1 H, H-8), 4.30–4.37 (m, 1 H, H-5), 4.48–4.69 (m,
8 H, OCH2OCH3, 3 × OCH2Ph), 5.64–5.73 (m, 2 H, olefinic), 6.79
(d, J = 8.30 Hz, 2 H, ArH), 7.18–7.31 (m, 12 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.9, 27.6, 28.7, 55.4, 55.8, 63.9,
70.6, 71.1, 72.6, 73.9, 78.4, 81.3, 82.8, 95.3, 113.8, 127.8, 128.2,
128.4, 128.6, 129.4, 130.0, 138.8, 139.0, 159.4.
IR (neat): 750, 890, 970, 1250, 1665, 2900, 3010 cm–1.
ESI-MS: m/z = 565 (M+ + 1).
1H NMR (300 MHz, CDCl3): d = 1.03 (s, 9 H, t-C4H9Si), 1.36 (d,
J = 6.42 Hz, 3 H, CH3), 1.52–1.82 (m, 4 H, H-2, 2¢, H-3, 3¢), 3.45–
3.61 (m, 3 H, H-1, 1¢, H-4), 3.76 (s, 3 H, OCH3), 3.77–3.80 (m, 1 H,
H-9), 4.20–4.24 (m, 1 H, H-8), 4.30–4.65 (m, 7 H, H-5, 3 ×
OCH2Ph), 5.67–5.73 (m, 2 H, olefinic), 6.76 (d, J = 8.30 Hz, 2 H,
ArH), 7.18–7.36 (m, 18 H, ArH), 7.59–7.62 (m, 4 H, ArH).
Anal. Calcd for C34H44O7: C, 72.31; H, 7.85. Found: C, 72.26; H,
7.80.
(4S,5R,6E,8S,9R)-4,5-Di(benzyloxy)-9-[(4-methoxybenzyl)oxy]-
8-(methoxymethoxy)dec-6-enoic Acid (23)
To a stirred solution of 22 (0.3 g, 0.532 mmol) in anhyd CH2Cl2 (4
mL) was added the Dess–Martin periodinane reagent (0.338 g,
0.797 mmol) at 0 °C and the stirring was continued for 4 h at r.t. The
mixture was worked up as described for 19 and the residue was used
directly in the next step. To a stirred solution of the above obtained
aldehyde (0.27 g, 0.48 mmol) in t-BuOH–2-methylbut-2-ene (2:1, 6
13C NMR (75 MHz, CDCl3): d = 14.2, 19.6, 26.8, 27.2, 28.6, 55.2,
63.8, 70.6, 71.1, 72.6, 73.9, 78.3, 81.3, 81.8, 113.8, 127.8, 127.9,
128.2, 128.4, 128.6, 129.4, 129.7, 130.0, 133.4, 135.4, 138.8, 139.0,
159.4.
ESI-MS: m/z = 776 (M+ + 18).
Synthesis 2007, No. 23, 3627–3634 © Thieme Stuttgart · New York

PAPER
Stereoselective Total Synthesis of (–)-Aspinolide B
3633
mL) were added NaClO2 (0.087 g, 0.96 mmol), NaH2PO4 (0.15 g,
0.96 mmol), and H2O (0.5 mL) and the stirring was continued for 10
h at r.t. The mixture was concentrated and the residue was dissolved
in EtOAc (15 mL). The EtOAc solution was washed with H2O (5
mL), brine (5 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude product was purified by column chromatogra-
phy (silica gel, 60–120 mesh, EtOAc–hexane, 2:3) to afford 23;
light yellow syrup; yield: 0.24 g (85%); [a]D –65.11 (c 0.15,
CHCl3).
IR (neat): 750, 890, 970, 1250, 1670, 2910, 3010, 3585 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.17 (d, J = 6.04 Hz, 3 H, CH3),
1.75–1.90 (m, 2 H, H-3, 3¢), 2.17–2.38 (m, 2 H, H-2, 2¢), 3.32 (s, 3
H, OCH3), 3.49–3.59 (m, 1 H, H-4), 3.75 (s, 3 H, OCH3), 3.81–3.89
(m, 1 H, H-9), 4.05–4.12 (m, 1 H, H-8), 4.28–4.40 (m, 1 H, H-5),
4.48–4.69 (m, 8 H, OCH2OCH3, 3 × OCH2Ph), 5.66–5.74 (m, 2 H,
olefinic), 6.79 (d, J = 8.67 Hz, 2 H, ArH), 7.18–7.31 (m, 12 H,
ArH).
The combined organic layers were washed with H2O (2 × 10 mL),
brine (10 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude product was purified by column chromatogra-
phy (silica gel 60–120 mesh, EtOAc–hexane, 0.8:4.2) to give 24;
light yellow syrup; yield: 0.065 g (48%); [a]D25 +6.0 (c 0.5, CHCl3).
IR (film): 1061, 1098, 1737, 2854, 2927 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 (d, J = 6.79 Hz, 3 H, CH3),
1.72–1.98 (m, 2 H, H-3, 3¢), 2.41–2.7 (m, 2 H, H-2, 2¢), 3.30–3.12
(m, 1 H, H-4), 3.32 (s, 3 H, OCH3), 3.73 (t, J = 9.06 Hz, 1 H, H-8),
4.66–4.30 (m, 5 H, H-5, 2 × OCH2Ph), 4.73 (s, 2 H, OCH2O), 4.92–
4.83 (m, 1 H, H-9), 5.28–5.39 (m, 1 H, olefinic), 5.64 (dd, J = 9.06,
15.86 Hz, 1 H, olefinic), 7.40–7.28 (m, 10 H, ArH).
13C NMR (75 MHz, CDCl3): d = 17.3, 25.1, 33.9, 55.5, 70.9, 71.6,
72.2, 76.3, 82.9, 83.9, 94.9, 127.2, 127.4, 127.5, 127.4, 128.2,
128.4, 129.8, 131.6, 138.3, 138.9, 174.6.
25
ESI-MS: m/z = 463 (M + Na)+.
13C NMR (75 MHz, CDCl3): d = 14.9, 28.6, 32.8, 55.4, 55.8, 63.9,
70.6, 71.4, 72.6, 73.9, 78.4, 81.3, 82.8, 95.3, 113.8, 127.8, 128.5,
128.7, 128.8, 129.2, 129.7, 138.6, 139.1, 159.3, 176.1.
HRMS (ESI): m/z calcd for C26H32O6 + Na: 463.2096; found:
463.2107.
(5S,6R,9S,10R)-5,6-Di(benzyloxy)-9-hydroxy-10-methyl-
3,4,5,6,9,10-hexahydro-2H-2-oxecinone (25)
ESI-MS: m/z = 579 (M+ + 1).
Anal. Calcd for C34H42O8: C, 70.57; H, 7.32. Found: C, 70.51; H,
7.25.
To a stirred solution of 24 (0.05 g, 0.11 mmol) in BuOH (3 mL) was
added PPTS (0.086 g, 0.34 mmol) and refluxed for 2 h. The mixture
was quenched with sat. aq NH4Cl (10 mL). The mixture was con-
centrated and diluted with EtOAc (10 mL). The organic layer was
separated and the aqueous layer was washed with EtOAc (2 × 10
mL). The combined organic layers were washed with H2O (2 × 5
mL), brine (5 mL), dried (Na2SO4), and concentrated under reduced
pressure. The crude product was purified by column chromatogra-
phy (silica gel 60–120 mesh, EtOAc–hexane, 1:4) to give 25; color-
less syrup; yield: 0.039 g (87%); [a]D25 –30.4 (c 0.13, CHCl3).
(4S,5R,6E,8S,9R)-4,5-Di(benzyloxy)-9-hydroxy-8-(methoxy-
methoxy)dec-6-enoic Acid (2)
To a stirred solution of compound 23 (0.22 g, 0.38 mmol) in
CH2Cl2/H2O (19:1, 4.2 mL) was added DDQ (0.13 g, 0.57 mmol)
and the stirring was continued for 2 h at r.t. Sat. aq NaHCO3 (10 mL)
was added and the mixture was extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were washed with H2O (10 mL), brine
(10 mL), dried (Na2SO4), and concentrated. The crude residue was
purified by column chromatography (silica gel, 60–120 mesh,
EtOAc–hexane, 1:1) to afford 2; colorless gummy syrup; yield: 0.15
g (86%); [a]D25 –57.43 (c 0.13, CHCl3).
IR (neat): 750, 1250, 1720, 2910, 3010 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.36 (d, J = 6.43 Hz, 3 H, CH3),
1.67–2.04 (m, 2 H, H-3, 3¢), 2.42–2.75 (m, 2 H, H-2, 2¢), 3.66–3.83
(m, 1 H, H-4), 3.91–4.18 (m, 1 H, H-8), 4.33–4.48 (m, 3 H, H-5,
OCH2Ph), 4.67–4.83 (m, 2 H, OCH2Ph), 5.3 (dd, J = 1.83, 15.62
Hz, 1 H, H-9), 5.52–5.89 (m, 2 H, olefinic), 7.2–7.4 (m, 10 H, ArH).
13C NMR (75 MHz, CDCl3): d = 16.5, 25.3, 33.8, 70.7, 71.6, 72.2,
76.3, 82.9, 83.3, 127.2, 127.4, 127.5, 127.4, 128.2, 128.4, 129.8,
131.6, 138.3, 138.8, 174.3.
IR (neat): 750, 970, 1250, 1670, 2910, 3010, 3585 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.13 (d, J = 6.28 Hz, 3 H, CH3),
1.75–1.90 (m, 2 H, H-3, 3¢), 2.36 (t, J = 7.07 Hz, 2 H, H-2, 2¢), 3.32
(s, 3 H, OCH3), 3.49–3.59 (m, 1 H, H-4), 3.76–3.97 (m, 3 H, H-8,
H-9, OH), 4.33–4.74 (m, 7 H, H-5, OCH2OCH3, 3 × OCH2Ph),
5.66–5.76 (m, 2 H, olefinic), 7.23–7.28 (m, 10 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.4, 28.8, 33.5, 55.8, 63.9, 69.8,
71.4, 72.6, 78.4, 81.3, 82.8, 95.3, 127.8, 127.9, 128.4, 128.6, 129.4,
129.7, 130.2, 133.3, 135.2, 138.8, 139.0, 176.1.
ESI-MS: m/z = 414 (M+ + 18).
Anal. Calcd for C24H28O5: C, 72.70; H, 7.12. Found: C, 72.65; H,
7.05.
ESI-MS: m/z = 481 (M+ + 23).
(2R,3S,6R,7S)-6,7-Di(benzyloxy)-2-methyl-10-oxo-3,6,7,8,9,10-
hexahydro-2H-3-oxecinyl (E)-But-2-enoate (26)
HRMS (ESI): m/z calcd for C26H34O7 + Na: 481.2202; found:
481.2208.
To a stirred solution of trans-crotonic acid (0.013 g, 0.15 mmol) in
anhyd THF (2 mL) was added Et3N (0.04 mL, 0.3 mmol) at r.t. and
the stirring was continued for 1 h. 2,4,6-Trichlorobenzoyl chloride
(0.03 mL, 0.19 mmol) in anyhd THF (1 mL) was then added and the
mixture was stirred for 2 h at r.t. The solvent was evaporated and the
residue was diluted with toluene (3 mL). DMAP (0.037 g, 0.3
mmol) and alcohol 25 (0.03 g, 0.075 mmol) were added and after 6
h, toluene was evaporated and the crude residue was purified by col-
umn chromatography (silica gel, 60–120 mesh, EtOAc–hexane,
1:9) to afford 26; colorless syrup; yield: 0.033 g (93%); [a]D25 –80.0
(c 0.06, CHCl3).
(5S,6R,9S,10R)-5,6-Di(benzyloxy)-9-(methoxymethoxy)-10-
methyl-3,4,5,6,9,10-hexahydro-2H-2-oxecinone (24)
To a stirred solution of 2 (0.14 g, 0.3 mmol) in anhyd THF (5 mL)
was added Et3N (0.42 mL, 3.05 mmol) at r.t. and the stirring was
continued for 0.5 h at r.t. 2,4,6-Trichlorobenzoyl chloride (0.24 mL,
1.53 mmol) in anhyd THF (2 mL) was added and the mixture was
further stirred for 4 h at r.t. The solvent was evaporated, the residue
diluted with toluene (40 mL), and treated with DMAP (0.373 g, 3.05
mmol) in toluene (150 mL) over a period of 12 h using a syringe
pump under reflux condition. After the addition of DMAP, the mix-
ture stirred for another 10 h at reflux conditions. After completion
of the reaction, toluene was removed under reduced pressure, and
EtOAc (50 mL) was added to the crude residue. The mixture was
quenched with sat. aq NH4Cl (20 mL). The organic layer was sepa-
rated and the aqueous layer was washed with EtOAc (2 × 20 mL).
IR (neat): 750, 1250, 1720, 1745, 2910, 3010 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.30 (d, J = 6.05 Hz, 3 H, CH3),
1.80–2.02 (m, 5 H, H-3, 3¢, CH3), 2.44–2.73 (m, 2 H, H-2, 2¢), 3.24–
3.31 (m, 1 H, H-4), 4.36–4.49 (m, 3 H, H-5, OCH2Ph), 4.67–4.74
(m, 2 H, OCH2Ph), 4.88–5.06 (m, 2 H, H-8, H-9), 5.42 (dd, J = 1.76,
15.63 Hz, 1 H, olefinic), 5.63 (ddd, J = 1.76, 8.0, 15.85 Hz, 1 H, ole-
Synthesis 2007, No. 23, 3627–3634 © Thieme Stuttgart · New York

3634
P. Radha Krishna, M. Narsingam
PAPER
finic), 5.84 (dd, J = 1.56, 8.0, 15.43 Hz, 1 H, olefinic), 7.01 (dq,
J = 7.22, 14.94 Hz, 1 H, olefinic), 7.19–7.37 (m, 10 H, ArH).
13C NMR (75 MHz, CDCl3): d = 16.5, 18.4, 27.2, 32.5, 71.3, 71.9,
71.7, 72.9, 75.2, 78.6, 122.2, 127.6, 127.8, 128.2, 128.6, 130.9,
137.7, 145.4, 165.7, 175.2.
ESI-MS: m/z = 307 (M + Na)+.
HRMS (ESI): m/z calcd for C14H20O6 + Na: 307.1157; found:
307.1160.
Acknowledgment
ESI-MS: m/z = 487 (M+ + 23).
One of the authors (M.N.) thanks the CSIR, New Delhi, for finan-
cial support in the form of a fellowship.
HRMS (ESI): m/z calcd for C28H32O6 + Na: 487.2096; found:
487.2107.
(2R,3S,6R,7S)-6,7-Dihydroxy-2-methyl-10-oxo-3,6,7,8,9,10-
hexahydro-2H-3-oxecinyl (E)-But-2-enoate (1)
References
To a stirred solution of 26 (0.025 g, 0.05 mmol) in CH2Cl2 (3 mL)
was added TiCl4 (0.012 mL, 0.107 mmol) in CH2Cl2 (1 mL) at 0 °C
and the stirring was continued for 2 h. Sat. aq NaHCO3 (10 mL) was
added and the mixture was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were washed with H2O (10 mL), brine (10
mL), dried (Na2SO4), and concentrated. The crude residue purified
by column chromatography (silica gel, 60–120 mesh, EtOAc–hex-
ane, 2:3) to afford 1; colorless syrup; yield: 0.0106 g (69%); [a]D
–43.7 (c 0.08, CHCl3).
IR (KBr): 1061, 1670, 1725, 1745, 2920 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.34 (d, J = 6.42 Hz, 3 H, CH3),
1.72–1.81 (m, 1 H, H-3¢), 1.90 (dd, J = 6.79, 1.51 Hz, 3 H, CH3),
1.89–2.34 (m, 4 H, 2 × OH, H-2¢, H-3), 2.47 (ddd, J = 15.48, 9.40,
1.00 Hz, 1 H, H-2), 3.61–3.65 (m, 1 H, H-4), 4.55–4.51 (m, 1 H, H-
5), 4.92–4.98 (m, 1 H, H-9), 5.09 (dq, J = 9.25, 6.23 Hz, 1 H, H-8),
5.57 (ddd, J = 15.86, 7.93, 2.26 Hz, 1 H, olefinic), 5.67 (dd,
J = 16.05, 1.70 Hz, 1 H, olefinic), 5.85 (dd, J = 15.50, 1.70 Hz, 1
H, olefinic), 7.02 (dq, J = 15.48, 6.79 Hz, 1 H, olefinic).
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Synthesis 2007, No. 23, 3627–3634 © Thieme Stuttgart · New York