Stereoselective synthesis of the C10-C18 fragment of iriomoteolide-3a

Article abstract of DOI:10.1055/s-0032-1318141

An efficient synthesis of the highly stereogenic centered C10-C18 fragment of iriomoteolide-3a has been accomplished. Key steps include Sharpless asymmetric dihydroxylation and epoxidation for generation of the desired stereocenters. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318141

PAPER
▌673
paper
Stereoselective Synthesis of the C10–C18 Fragment of Iriomoteolide-3a
Synthesis of the C10–C18 Fragment of Iriomoteolide-3a
Chada Raji Reddy,* Gajula Dharmapuri
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: rajireddy@iict.res.in
Received: 26.10.2012; Accepted after revision: 09.01.2013
In continuation of our work on the synthesis of macro-
lides, including iriomoteolide-3a,3,6 we initiated an alter-
native strategy towards various analogues of 1 for
biological evaluation. In this paper, we report the synthe-
sis of the C10–C18 fragment, a key subunit of iriomote-
olide-3a (1) having five stereocenters.
Abstract: An efficient synthesis of the highly stereogenic centered
C10–C18 fragment of iriomoteolide-3a has been accomplished.
Key steps include Sharpless asymmetric dihydroxylation and epox-
idation for generation of the desired stereocenters.
Key words: macrolide, total synthesis, iriomoteolide-3a, ortho-
Claisen rearrangement, Sharpless dihydroxylation
As shown in Scheme 1, our synthetic strategy for iriomo-
teolide-3a is convergent and involves a late-stage assem-
bly of macrocyclic core 3 and side chain 4. The
macrocycle 3 can be obtained from epoxy subunit 5 and
sulfone 6 through a Julia–Kocienski olefination (C9–C10
bond formation) followed by Yamaguchi macrolactoniza-
tion. The formation of the C9–C10 bond in all earlier ap-
proaches was accomplished using ring-closing
metathesis.
In 2008, Tsuda and co-workers isolated a potent cytotoxic
macrolide, iriomoteolide-3a (1, Figure 1), from a marine
benthic dinoflagellate Amphidinium sp. (strain HYA024),
which was monoclonally separated from sea sand collect-
ed off Iriomote Island, Japan.1 Iriomoteolide-3a (1) is a
15-membered macrolide having a novel carbon frame-
work comprising eight stereogenic centers including an
allyl epoxide, four hydroxy groups and two methyl
branches. Compound 1 represents a unique and novel 15-
membered macrolide class compared to the other known
15-membered macrolides. Further, the initial in vitro
screening showed that iriomoteolide-3a (1) and its 7,8-O-
isopropylidene derivative 2 (Figure 1) exhibit potent cyto-
toxicity against human B lymphocyte DG-75 and Raji
cells in the low nanomolar range. The unique structural
features of iriomoteolide-3a coupled with its potent cyto-
toxicity have attracted the attention of synthetic organic
chemists. In 2009, Nevado and co-workers reported the
first total synthesis of 1 along with biological evaluation
of its analogues.2 At the same time, we demonstrated the
synthesis of the macrocyclic core of iriomoteolide-3a.3
Later, the total synthesis of 7,8-O-isopropylidene iriomo-
teolide-3a was accomplished by Zhao and co-workers,4
while synthesis of the C1–C9 fragment of 2 has been re-
ported by Chang.5
iriomoteolide-3a (1)
Julia–Kocienski
olefination
O
N
9
H
MOMO
N
O
O
S
N
14
OH
O
+
N
10
18
H
Ph
1
O
O
Yamaguchi
4
macrolactonization
O
3
Ph
N
N
N
O
S
O
N
O
O
O
+
HO
O
O
O
OTBS
C10–C18 fragment, 5
OH
R1O
6
H
OH
O
Scheme 1 Retrosynthetic analysis of iriomoteolide-3a
R2O
H
O
The synthesis of epoxy segment 5 (C10–C18 fragment)
was carried out as shown in Scheme 2, starting from pro-
pane-1,3-diol (7). Monoprotection of diol 7 as the tert-bu-
tyldiphenylsilyl ether provided compound 8 in 98% yield.
Swern oxidation of alcohol to aldehyde followed by Gri-
gnard reaction with vinylmagnesium bromide afforded
the allyl alcohol 9 in 86% yield over two steps.7 Treatment
of 9 with triethyl orthoacetate in the presence of propanoic
acid at 140 °C for four hours gave the γ,δ-unsaturated es-
ter 10 via ortho-Claisen rearrangement.8 At this stage, the
requisite chiral dihydroxy functionality on C14–C15 was
achieved using Sharpless asymmetric dihydroxylation.
O
R1 = R2 = H, iriomoteolide-3a (1)
R1–R2 = CMe2, 7,8-O-isopropylidene derivative 2
Figure 1 Structure of iriomoteolide-3a and its 7,8-O-isopropylidene
derivative
SYNTHESIS 2013, 45, 0673–0677
Advanced online publication: 07.02.2013
DOI: 10.1055/s-0032-1318141; Art ID: SS-2012-Z0839-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

674
C. R. Reddy, G. Dharmapuri
PAPER
i) (COCl)2, Et3N
DMSO, CH2Cl2, –78 °C
MeC(OEt)3
propanoic acid
TBDPSO
TBDPSCl, imidazole
HO
OTBDPS
HO
OH
CH2Cl2, 30 min
98%
ii)
140 °C, 4 h, 96%
, THF
–78 °C to r.t., 12 h
MgBr
OH
7
8
9
86% (over two steps)
O
O
AD-mix-α
TBDPSO
OEt
O
MeSO2NH2
O
O
TBSOTf, 2,6-lutidine
CH2Cl2, 30 min 98%
TBDPSO
TBDPSO
t-BuOH–H2O (1:1)
0 °C, 24 h, 80%
10
OH
OTBS
11
12
O
LiHMDS (1 M in THF)
MeI
OH
O
LiBH4
Me2C(OMe)2, CSA (cat.)
CH2Cl2, 30 min, 96%
TBDPSO
OH
TBDPSO
THF, MeOH
30 min, 98%
THF, –78 °C, 2 h, 85%
OTBS
OTBS
14
13
i) py·SO3, Et3N
CH2Cl2, 0 °C, 2 h
O
O
O
NH4F, MeOH
O
O
O
TBDPSO
HO
EtO
0 °C to r.t., 36 h, 95%
ii) Ph3P=CHCO2Et
benzene, 0 °C to r.t., 12 h
(88% over two steps)
OTBS
15
OTBS
16
O
OTBS
17
O
O
O
DIBAL-H
(+)-DIPT, t-BuOOH, Ti(Oi-Pr)4
O
O
HO
HO
MS (4 Å), CH2Cl2, –20 °C
12 h, 84%
CH2Cl2, –78 °C to r.t.
1 h, 94%
OTBS
OTBS
18
5
Scheme 2 Synthesis of the C10–C18 fragment 5
Thus, exposure of 10 to AD-mix-α in the presence of asymmetric epoxidation reaction conditions [(+)-DIPT,
methanesulfonamide provided the hydroxy γ-lactone 11 Ti(Oi-Pr)4, t-BuOOH, CH2Cl2, –20 °C]16 to produce frag-
through a one-pot dihydroxylation followed by in situ lac- ment 5 in 84% yield with good stereoselectivity. Epoxide
tonization.9 The enantiomeric purity of this lactone 11 fragment 5 was fully characterized by mass spectrometry
was confirmed at a later stage (intermediate 13).10 The and 1H NMR, 13C NMR and IR spectroscopy.
free secondary alcohol of 11 was protected as the tert-bu-
tyldimethylsilyl ether 12. Then, the introduction of the
C17-methyl group was accomplished through a stereose-
lective methylation of lactone 12 under lithium hexameth-
In summary, asymmetric synthesis of the protected C10–
C18 fragment having five stereogenic carbons of iriomo-
teolide-3a has been accomplished. Sharpless asymmetric
dihydroxylation, stereoselective methylation and
Sharpless asymmetric epoxidation reactions are the key
steps to obtain the requisite stereocenters of the fragment.
yldisilazide/iodomethane conditions at –78 °C to afford
exclusively 13 in 85% yield,11 which was confirmed by
NOE studies.10,12
Reduction of lactone 13 using lithium borohydride pro-
vided the 1,4-diol 14 in 98% yield, which was protected
as the seven-membered acetonide 15 under 2,2-dimeth-
oxypropane/10-camphorsulfonic acid reaction condi-
tions.13 Next, the tert-butyldiphenylsilyl group of 15 was
selectively deprotected to alcohol 16 using ammonium
fluoride in methanol (95% yield).14 The next step in-
volved the two-carbon extension by employing Parikh–
Doering oxidation (py·SO3, CH2Cl2)15 to the correspond-
ing aldehyde followed by a Wittig homologation with
Ph3P=CHCO2Et to obtain the α,β-unsaturated ester 17 in
88% yield over two steps as the E-isomer (>98%). Reduc-
tion of the ester 17 using diisobutylaluminum hydride at
–78 °C afforded the allylic alcohol 18 in 94% yield. The
desired chiral epoxide was introduced under Sharpless
1H and 13C NMR spectra were recorded in CDCl3 solvent at 300 and
75 MHz, respectively, on a Bruker Avance spectrometer at r.t. The
chemical shifts (δ) are reported in ppm on a scale downfield from
TMS as internal standard. Coupling constants J are in hertz (Hz).
FTIR spectra were recorded as KBr thin films on a Perkin-Elmer
683 spectrophotometer. High resolution mass spectra (HRMS) were
recorded on a quadrupole time-of-flight (Q-TOF) mass spectrome-
ter (Agilent Technologies, classic G6510A) equipped with an ESI
source [voltage: 80 V; capillary at 3000–3500 V; skimmer at 60 V;
nitrogen as drying (300 °C; 9 L/min) and nebulizing (45 psi) gas];
m/z ratios are reported as values in atomic mass units. All the re-
agents and solvents were reagent grade and used without further pu-
rification, unless specified otherwise. Technical grade EtOAc and
hexanes used for column chromatography were distilled prior to
use. Column chromatography was carried out using silica gel (60–
120 mesh) packed in glass columns. All reactions were performed
under an atmosphere of nitrogen in flame-dried or oven-dried glass-
ware with magnetic stirring.
Synthesis 2013, 45, 673–677
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of the C10–C18 Fragment of Iriomoteolide-3a
IR (KBr): 3458, 1773, 1219, 1111, 918, 772 cm–1.
675
5-(tert-Butyldiphenylsilyloxy)pent-1-en-3-ol (9)
A soln of DMSO (9.0 mL, 127.3 mmol) in CH2Cl2 (50 mL) was
added to a soln of oxalyl chloride (5.51 mL, 63.6 mmol) in CH2Cl2
(50 mL) cooled at –78 °C. After 5 min, a soln of 8 (10.0 g, 31.8
mmol) in CH2Cl2 (83 mL) was added dropwise to the cold mixture
over 5 min. After 20 min, Et3N (17.7 mL, 127.3 mmol) was added,
and the mixture was allowed to reach r.t. and poured into H2O (125
mL). The organic phase was separated and the aqueous phase was
extracted with CH2Cl2 (2 × 100 mL). The collected organic phases
were washed with brine (50 mL), dried (Na2SO4) and concentrated
to give the crude aldehyde as a yellow oil, which was used in the
next step without further purification.
1H NMR (300 MHz, CDCl3): δ = 7.69–7.60 (m, 4 H), 7.45–7.32 (m,
6 H), 4.38 (dt, J = 6.7, 3.0 Hz, 1 H), 3.95–3.77 (m, 3 H), 3.10 (br s,
1 H), 2.70–2.56 (m, 1 H), 2.50–2.35 (m, 1 H), 2.27–2.15 (m, 2 H),
1.98–1.82 (m, 1 H), 1.74–1.61 (m, 1 H), 1.05 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 177.6, 135.5, 133.0, 129.9, 127.8,
82.7, 72.6, 62.1, 34.6, 28.5, 26.8, 23.9, 19.0.
HRMS (ESI): m/z [M + Na]+ calcd for C23H30O4SiNa: 421.2078;
found: 421.2101.
(S)-5-[(S)-2,2,3,3,10,10-Hexamethyl-9,9-diphenyl-4,8-dioxa-
3,9-disilaundecan-5-yl]dihydrofuran-2(3H)-one (12)
To a soln of the crude aldehyde in distilled THF (150 mL) at –78 °C
was added 1 M vinylmagnesium bromide in THF (38.1 mL, 38.1
mmol), and the mixture was stirred at that same temperature for 1 h.
The mixture was further stirred overnight while the solution was al-
lowed to warm to r.t. Sat. aq NH4Cl (150 mL) was added into the
white turbid solution chilled in an ice bath. The aqueous phase was
extracted with EtOAc (3 × 100 mL) and the combined organic ex-
tracts were washed with H2O (50 mL) and brine (2 × 50 mL), dried
(Na2SO4) and concentrated under reduced pressure to give a yellow
syrup. Purification by flash column chromatography (hexanes–
EtOAc, 15:1) afforded 9 (9.30 g, 86%) as a slightly yellow oil.
To a cooled (0 °C) soln of hydroxy lactone 11 (3.0 g, 7.6 mmol) in
CH2Cl2 (25 mL) were added TBSOTf (2.11 mL, 9.20 mmol) and
2,6-lutidine (2.22 mL, 19.2 mmol). The mixture was stirred at r.t.
for 30 min and was then diluted with CH2Cl2 (15 mL). The organic
phase was washed with sat. aq NaHCO3 (20 mL) and brine (15 mL),
dried (Na2SO4) and concentrated. The residue was purified by flash
chromatography (2→5% EtOAc in hexanes) to give the silylated
lactone 12 (3.85 g, 98%) as a colorless oil.
[α]D25 +10.2 (c 2.0, CHCl3).
IR (KBr): 2956, 2889, 1782, 1470, 1255, 1110, 704 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.60–7.50 (m, 4 H), 7.39–7.21 (m,
6 H), 4.35 (dt, J = 6.7, 2.2 Hz, 1 H), 3.85 (q, J = 6.0 Hz, 1 H), 3.71
(t, J = 6.7 Hz, 2 H), 2.49–2.24 (m, 2 H), 2.16–2.01 (m, 1 H), 1.92–
1.53 (m, 3 H), 1.00 (s, 9 H), 0.81 (s, 9 H), 0.05 (s, 3 H), 0.00 (s, 3 H).
IR (KBr): 3444, 2930, 2857, 1427, 1390, 1111, 923, 822 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.69–7.63 (m, 4 H), 7.44–7.33 (m,
6 H), 5.91–5.80 (m, 1 H), 5.30 (dt, J = 11.3, 17.1 Hz, 1 H), 5.12 (dt,
J = 1.8, 10.3 Hz, 1 H), 4.42 (dd, J = 5.4, 11.3 Hz, 1 H), 3.94–3.78
(m, 2 H), 3.05 (br s, 1 H), 1.83–1.73 (m, 2 H), 1.07 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 177.1, 135.4, 133.4, 129.6, 127.6,
81.7, 71.4, 59.9, 35.3, 28.5, 26.8, 25.7, 23.8, 19.1, 17.9, –4.5, –4.6.
13C NMR (75 MHz, CDCl3): δ = 140.5, 135.4, 132.9, 129.7, 127.7,
HRMS (ESI): m/z [M + Na]+ calcd for C29H44O4Si2Na: 535.2800;
found: 535.2805.
114.2, 72.0, 62.5, 38.2, 26.7, 18.9.
HRMS (ESI): m/z [M + Na]+ calcd for C21H28O2SiNa: 363.1751;
found: 363.1738.
(3R,5S)-5-[(S)-2,2,3,3,10,10-Hexamethyl-9,9-diphenyl-4,8-di-
oxa-3,9-disilaundecan-5-yl]-3-methyldihydrofuran-2(3H)-one
(13)
Ethyl (E)-7-(tert-Butyldiphenylsilyloxy)hept-4-enoate (10)
A mixture of 9 (5.0 g, 14.7 mmol), triethyl orthoacetate (24.3 mL,
132.3 mmol) and a catalytic amount of propanoic acid (1.0 mL, 13.5
mmol) was refluxed for 4 h, followed by the removal of triethyl or-
thoacetate. The residues were dissolved in EtOAc (80 mL) and the
mixture was washed with brine (2 × 30 mL), dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (hexanes–EtOAc, 25:1) to afford 10
(5.78 g, 96%) as a yellow syrup.
To a stirred soln of lactone 12 (2.0 g, 3.90 mmol) in THF (20 mL)
at –78 °C was added 1 M LiHMDS in THF (4.6 mL, 4.60 mmol).
After 1 h, MeI (0.79 mL, 15.6 mmol) was added and the reaction
mixture was stirred for an additional 1 h at –78 °C. The reaction was
quenched with sat. aq NH4Cl (20 mL) and the mixture was extracted
with EtOAc (2 × 20 mL). The organic layer was dried (Na2SO4) and
concentrated, and the crude product was purified by flash column
chromatography (2→5% EtOAc in hexanes) to afford 13 (1.77 g,
85%) as a colorless liquid.
IR (KBr): 2930, 2857, 1737, 1427, 1159, 1111, 1040, 823 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.69–7.59 (m, 4 H), 7.43–7.30 (m,
6 H), 5.47–5.40 (m, 2 H), 4.09 (q, J = 7.5 Hz, 2 H), 3.63 (t, J = 6.7
Hz, 2 H), 2.36–2.16 (m, 6 H), 1.23 (t, J = 7.5 Hz, 3 H), 1.03 (s, 9 H).
[α]D25 +8.5 (c 1.0, CHCl3).
IR (KBr): 2956, 2858, 1778, 1467, 1180, 838, 704 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.66–7.60 (m, 4 H), 7.45–7.32 (m,
6 H), 4.42–4.34 (m, 1 H), 3.91 (q, J = 6.0 Hz, 1 H), 3.76 (t, J = 6.0
Hz, 2 H), 2.72–2.56 (m, 1 H), 2.24–2.12 (m, 1 H), 1.90–1.60 (m, 3
H), 1.24 (d, J = 7.5 Hz, 3 H), 1.06 (s, 9 H), 0.87 (s, 9 H), 0.10 (s, 3
H), 0.06 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 173.1, 135.5, 133.9, 130.1, 129.4,
127.8, 127.5, 63.7, 60.1, 35.9, 34.2, 27.9, 26.8, 19.1, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C25H34O3SiNa: 433.2561;
found: 433.2560.
13C NMR (75 MHz, CDCl3): δ = 180.2, 135.5, 133.5, 129.7, 127.6,
79.0, 71.5, 60.0, 35.5, 34.2, 32.1, 26.8, 25.7, 19.1, 17.9, 16.4, –4.5,
–4.6.
HRMS (ESI): m/z [M + Na]+ calcd for C30H46O4Si2Na: 549.2827;
found: 549.2809.
(S)-5-[(S)-3-(tert-Butyldiphenylsilyloxy)-1-hydroxypropyl]di-
hydrofuran-2(3H)-one (11)
Into a 250-mL round-bottom flask were added t-BuOH (29 mL),
H2O (29 mL), AD-mix-α (8.19 g, 1.4 g/mmol) and methanesulfon-
amide (556 mg, 5.8 mmol). The mixture was stirred at r.t. for 5 min
and then cooled to 0 °C. To this cooled solution was added com-
pound 10 (2.4 g, 5.8 mmol), and the mixture was stirred for 24 h at
0 °C. The reaction was quenched with sat. aq Na2SO3 soln at r.t. The
mixture was diluted with EtOAc (50 mL) and, after separation of the
layers, the aqueous layer was further extracted with EtOAc (2 × 50
mL). The combined organic layers were washed with brine (40 mL)
and dried (Na2SO4). The crude mixture was purified by flash col-
umn chromatography (20→30% EtOAc in hexanes) to give 11
(1.87 g, 80%) as a colorless oil.
(2R,4S,5S)-5-(tert-Butyldimethylsilyloxy)-7-(tert-butyldiphe-
nylsilyloxy)-2-methylheptane-1,4-diol (14)
To a stirred soln of lactone 13 (4.6 g, 8.7 mmol) in THF (42 mL) at
0 °C were sequentially added MeOH (0.35 mL) and LiBH4 (230
mg, 10.4 mmol). After 30 min, the reaction was quenched with sat.
aq NH4Cl (50 mL), and the mixture was extracted with Et2O (2 × 40
mL). The extracts were dried (Na2SO4) and concentrated under re-
duced pressure, and the crude product was purified by column chro-
[α]D25 +20.1 (c 1.0, CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 673–677

676
C. R. Reddy, G. Dharmapuri
PAPER
matography (10→20% EtOAc in hexanes) to afford 14 (4.54 g,
98%) as a colorless oil.
Ethyl (E,S)-5-(tert-Butyldimethylsilyloxy)-5-[(4S,6R)-2,2,6-tri-
methyl-1,3-dioxepan-4-yl]pent-2-enoate (17)
To a soln of alcohol 16 (1.5 g, 4.51 mmol) in CH2Cl2–DMSO (3:1
v/v, 30 mL) at 0 °C were added Et3N (3.16 mL, 22.5 mmol) and
py·SO3 (3.59 g, 22.5 mmol). After being stirred at 0 °C for 2 h, the
reaction mixture was diluted with Et2O (30 mL), washed with H2O
(20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrat-
ed under reduced pressure. The residual crude aldehyde was used in
the next step without further purification.
[α]D25 +1.2 (c 2.0, CHCl3).
IR (KBr): 3299, 2954, 2931, 2858, 1466, 1249, 1086, 835, 775
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.69–7.57 (m, 4 H), 7.46–7.32 (m,
6 H), 3.81–3.65 (m, 3 H), 3.65–3.57 (m, 1 H), 3.55–3.38 (m, 2 H),
2.66 (br s, 1 H), 2.46 (br s, 1 H), 1.98–1.76 (m, 2 H), 1.71–1.60 (m,
1 H), 1.57–1.36 (m, 2 H), 1.06 (s, 9 H), 0.94 (d, J = 6.5 Hz, 3 H),
0.88 (s, 9 H), 0.09 (s, 3 H), 0.05 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 135.4, 133.4, 129.6, 127.6, 72.7,
70.2, 67.4, 60.3, 37.4, 36.3, 32.4, 26.7, 25.8, 19.0, 18.0, 17.0, –4.3,
–4.6.
To a soln of the crude aldehyde in benzene (10 mL) at 0 °C was add-
ed Ph3P=CHCO2Et (3.10 g, 9.03 mmol) and the reaction mixture
was allowed to warm to r.t. After being stirred at r.t. for 12 h, the
reaction mixture was concentrated under reduced pressure. Purifi-
cation by flash chromatography (2→3% EtOAc in hexanes) afford-
ed α,β-unsaturated ester 17 (1.59 g, 88%) as a colorless oil.
[α]D25 –60.2 (c 0.5, CHCl3).
IR (KBr): 2928, 2857, 1718, 1654, 1167, 1042, 774 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C30H51O4Si2: 531.3320;
found: 531.3342.
(S)-2,2,3,3,10,10-Hexamethyl-9,9-diphenyl-5-[(4S,6R)-2,2,6-tri-
methyl-1,3-dioxepan-4-yl]-4,8-dioxa-3,9-disilaundecane (15)
To a soln of diol 14 (2.2 g, 4.15 mmol) in CH2Cl2 (20 mL) at 0 °C
were added 2,2-dimethoxypropane (1.01 mL, 8.29 mmol) and CSA
(48 mg, 0.20 mmol), and the mixture was stirred at r.t. for 30 min.
Then, the reaction was quenched by adding sat. aq NH4Cl soln and
the resulting mixture was extracted with CH2Cl2 (2 × 20 mL). The
combined organic layers were washed with brine (20 mL), dried
(Na2SO4), filtered and concentrated, and the residue was purified by
column chromatography (2→5% EtOAc in hexanes) to afford ace-
tonide 15 (2.28 g, 96%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 7.01–6.86 (m, 1 H), 5.80 (d, J =
15.4 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.88–3.73 (m, 2 H), 3.71–
3.59 (m, 1 H), 3.40–3.27 (m, 1 H), 2.54–2.34 (m, 1 H), 2.28–2.10
(m, 1 H), 1.92–1.76 (m, 1 H), 1.63–1.20 (m, 11 H), 1.01 (d, J = 6.0
Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H), 0.02 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 165.6, 146.8, 123.3, 100.5, 73.5,
69.7, 65.9, 59.7, 34.6, 34.0, 30.9, 26.0, 25.2, 25.0, 18.1, 17.0, 14.5,
–4.1, –4.4.
HRMS (ESI): m/z [M + Na]+ calcd for C21H40O5SiNa: 423.2537;
found: 423.2543.
[α]D25 –25.2 (c 2.0, CHCl3).
(E,S)-5-(tert-Butyldimethylsilyloxy)-5-[(4S,6R)-2,2,6-trimethyl-
1,3-dioxepan-4-yl]pent-2-en-1-ol (18)
IR (KBr): 2931, 2858, 1465, 1251, 1103, 999, 833, 703 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.68–7.60 (m, 4 H), 7.42–7.29 (m,
6 H), 3.91–3.63 (m, 5 H), 3.36–3.27 (m, 1 H), 1.93–1.72 (m, 2 H),
1.57–1.33 (m, 3 H), 1.32–1.22 (m, 6 H), 1.05 (s, 9 H), 1.03 (d, J =
6.0 Hz, 3 H), 0.85 (s, 9 H), 0.07 (s, 3 H), 0.00 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 135.5, 133.9, 129.4, 127.5, 100.3,
70.2, 69.6, 66.1, 60.9, 34.2, 33.6, 30.7, 26.8, 25.8, 25.0, 24.9, 19.2,
17.8, 16.8, –4.2, –4.8.
To a stirred soln of conjugated ester 17 (1.2 g, 3.0 mmol) in CH2Cl2
(15 mL) cooled to –78 °C was added a 20% soln of DIBAL-H in tol-
uene (4.26 mL, 6.0 mmol) dropwise. The solution was stirred at
–78 °C for 1 h, and the reaction was quenched by the addition of sat.
aq potassium sodium tartrate soln (20 mL). Then, the mixture was
warmed to r.t. and filtered through a pad of Celite®, and the residue
was washed with sat. aq NaCl. The resulting mixture was extracted
with CH2Cl2 (25 mL). The organic extract was concentrated to ob-
tain the crude product, which was purified by column chromatogra-
phy (5→10% EtOAc in hexanes) to give 18 (1.0 g, 94%) as a
colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C33H54O4Si2Na: 593.3453;
found: 593.3480.
(S)-3-(tert-Butyldimethylsilyloxy)-3-[(4S,6R)-2,2,6-trimethyl-
1,3-dioxepan-4-yl]propan-1-ol (16)
[α]D25 –34.0 (c 1.0, CHCl3).
To a cooled (0 °C) stirred soln of 15 (2.45 g, 4.29 mmol) in MeOH
(15 mL) was added NH4F (1.5 g, 42.1 mmol), and the mixture was
stirred for 36 h. The reaction was quenched with sat. aq NaHCO3,
and the mixture was extracted with CH2Cl2 (2 × 15 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy (5→10% EtOAc in hexanes) to provide 16 (1.32 g, 95%) as
a colorless oil; 15 (50 mg) was recovered.
IR (KBr): 3464, 2930, 2854, 1218, 1075, 970, 834, 772 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.78–5.58 (m, 2 H), 4.05 (q, J =
4.5 Hz, 2 H), 3.89–3.69 (m, 2 H), 3.63–3.52 (m, 1 H), 3.37–3.27 (m,
1 H), 2.36–2.24 (m, 1 H), 2.13–1.98 (m, 1 H), 1.90–1.75 (m, 1 H),
1.60–1.35 (m, 2 H), 1.29 (s, 6 H), 1.01 (d, J = 6.7 Hz, 3 H), 0.89 (s,
9 H), 0.06 (s, 3 H), 0.02 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 131.0, 130.4, 100.4, 74.0, 69.9,
66.0, 63.7, 34.8, 34.2, 30.7, 25.8, 25.0, 24.9, 17.9, 16.8, –4.2, –4.5.
[α]D25 –25.0 (c 1.0, CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C19H38O4SiNa: 381.2432;
found: 381.2439.
IR (KBr): 3415, 2935, 1466, 1381, 1219, 1165, 1071, 835, 775
cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.90–3.54 (m, 5 H), 3.42–3.30 (m,
1 H), 2.43 (br s, 1 H), 1.95–1.77 (m, 2 H), 1.68–1.37 (m, 3 H), 1.31
(s, 6 H), 1.03 (d, J = 6.0 Hz, 3 H), 0.90 (s, 9 H), 0.09 (s, 3 H), 0.08
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 100.6, 72.9, 69.8, 66.2, 60.3, 34.6,
33.7, 30.6, 25.7, 25.0, 24.6, 17.8, 16.7, –4.4, –4.9.
[(2S,3S)-3-{(S)-2-(tert-Butyldimethylsilyloxy)-2-[(4S,6R)-2,2,6-
trimethyl-1,3-dioxepan-4-yl]ethyl}oxiran-2-yl]methanol (5)
To a stirred mixture of powdered molecular sieves (4 Å, 4.0 g) and
Ti(Oi-Pr)4 (0.083 mL, 0.27 mmol) in CH2Cl2 (10 mL) cooled at
–20 °C was added (+)-DIPT (0.22 mL, 0.94 mmol). The mixture
was stirred at –20 °C for 10 min and a soln of allylic alcohol 18 (1.4
g, 3.9 mmol) in CH2Cl2 (12 mL) and 4 M t-BuOOH in toluene (3.8
mL, 15.6 mmol) were added successively. The resulting mixture
was stirred at –20 °C for 12 h, then the reaction was quenched with
H2O (0.02 mL) and 20% aq NaOH (0.015 mL). The mixture was
stirred at r.t. for 45 min, then the organic layer was separated and
the reaction mixture was filtered. The aqueous layer was extracted
with CH2Cl2 (2 × 25 mL). The organic layer and the extracts were
HRMS (ESI): m/z [M + Na]+ calcd for C17H36O4SiNa: 355.2275;
found: 355.2290.
Synthesis 2013, 45, 673–677
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of the C10–C18 Fragment of Iriomoteolide-3a
677
combined, washed with brine (25 mL), dried (Na2SO4) and concen-
trated. The residual oil was purified by column chromatography
(10→15% EtOAc in hexanes) to give 5 (1.22 g, 84%) as a colorless
oil.
[α]D25 –55.5 (c 1.0, CHCl3).
IR (KBr): 3230, 2930, 2858, 1378, 1219, 1083, 836, 774 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.92–3.69 (m, 4 H), 3.60–3.46 (m,
1 H), 3.36–3.22 (m, 1 H), 3.05–2.98 (m, 1 H), 2.90–2.85 (m, 1 H),
1.89–1.73 (m, 1 H), 1.67–1.51 (m, 2 H), 1.44–1.19 (m, 8 H), 1.00
(d, J = 7.5 Hz, 3 H), 0.88 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H).
(9) (a) Evans, A. P.; Roseman, J. D. Tetrahedron Lett. 1997, 38,
5249. (b) Mandel, A. L.; Bellosta, V.; Curran, D. P.; Cossy,
J. Org. Lett. 2009, 11, 3282.
(10) Compound 13 was converted into a known compound 13a
(Scheme 3). A comparison of specific rotations {observed
for 13a: [α]D30 +16.3 (c 1.0, CHCl3), Lit.3: [α]D30 +16.6 (c
1.0, CHCl3)} showed that the enantiomeric excess in the
Sharpless dihydroxylation was >95%, and also confirmed
the exclusive formation of 13 from 12 (by NOE studies on
13a12).
13C NMR (75 MHz, CDCl3): δ = 100.4, 71.2, 69.3, 66.0, 61.6, 59.2,
53.7, 33.5, 30.6, 25.7, 25.0, 24.7, 21.6, 17.8, 16.7, –4.2, –4.9.
HRMS (ESI): m/z [M + Na]+ calcd for C19H38O5SiNa: 397.2381;
found: 397.2378.
i) NH4F
MeOH
O
O
0 °C to r.t.
O
30 h
O
TBSO
TBDPSO
ii) TBSCl
imidazole
OTBS
OTBS
DMF, r.t.
8 h
13a
13
Acknowledgment
84%
G.D. thanks the Council of Scientific and Industrial Research
(CSIR), New Delhi for a research fellowship.
Scheme 3
(11) Mohapatra, D. K.; Sahoo, G.; Sankar, K.; Gurjar, M. K.
Tetrahedron: Asymmetry 2008, 19, 2123.
(12) NOE experiments were carried out on compound 13a and
the enhancements are shown in Figure 2.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 673–677