Studies toward the synthesis of iejimalides A-D: Preparation of the C3-11 and C12-C24 fragments

Article abstract of DOI:10.1055/s-0033-1340083

The convergent synthesis of the C3-C11 and C12-C24 fragments of the iejimalides A-D is described. The C3-C11 fragment is obtained by a cross-metathesis reaction, while the C12-C24 fragment is derived from a Still-Gennari modified Horner-Wadsworth-Emmons o

Full text of DOI:10.1055/s-0033-1340083

110▌
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paper
Studies toward the Synthesis of Iejimalides A–D: Preparation of the C3–11 and
C12–C24 Fragments
Studies toward the Synthesis of Iejimalides A–D
Gowravaram Sabitha,* Ch. Gurumurthy, Jhillu Singh Yadav
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91(40)27160512; E-mail: gowravaramsr@yahoo.com; E-mail: sabitha@iict.res.in
Received: 30.07.2013; Accepted after revision: 10.10.2013
unique and intriguing molecular architecture, renders
Abstract: The convergent synthesis of the C3–C11 and C12–C24
these natural products attractive synthetic targets, which
fragments of the iejimalides A–D is described. The C3–C11 frag-
has prompted us to study the synthesis of these natural
ment is obtained by a cross-metathesis reaction, while the C12–C24
products. In this connection, we herein report our prelim-
inary studies on the synthesis of the C3–C11 and C12–
C24 fragments of iejimalides A–D.
fragment is derived from a Still–Gennari modified Horner–
Wadsworth–Emmons olefination.
Key words: iejimalides, macrolides, cross-metathesis, Horner–
Wadsworth–Emmons, fragment synthesis
R1
O
H
29
23
1
34
N
H
O
MeO
N
H
24
Iejimalides A–D (1a–d)1 are four novel polyene macro-
lides, isolated by Kobayashi and co-workers from the
methanol extracts of the tunicate, Eudistoma cf. rigida,
collected off Ie island, Okinawa province, Japan. Structur-
ally, the iejimalides consist of a 24-membered polyene
macrolide core structure containing five stereogenic cen-
ters, four conjugated diene units and an N-formyl-L-serine
terminus (Figure 1). The iejimalides show potent growth
inhibitory activity2 against a range of human tumor cell
lines, with iejimalide B being especially potent. Accord-
ing to the data disclosed by the National Cancer Institute
(NCI), iejimalide A shows remarkable potency, with GI50
values as low as 13 nM (MDA-MB-231/ATCC breast
cancer cell line), and total growth inhibition (TGI) values
as low as 40 nM (M14 melanoma cell line), whilst ieji-
malide B is cytostatic (GI50) at <5 nm against 40 of the 60
standard human cancer cell lines tested.3 In addition, the
iejimalides show selective V-ATPase inhibition.4 The
overall structures of the iejimalides were first determined
by Kobayashi in 1988, through degradation and NMR
studies.1a However, the specific stereochemistry of only
one of the six stereogenic centers (i.e., C32, the others be-
ing located at C4, C9, C17, C22, and C23 ) was deter-
mined. After isolation of the iejimalides in relatively large
3
5
O
O
R2O
11
19
OMe
1a: iejimalide A; R1 = R2 = H
1b: iejimalide B; R1 = Me, R2 = H
1c: iejimalide C; R1 = H, R2 = SO3Na
1d: iejimalide D; R1 = Me, R2 = SO3Na
Figure 1 The structures of iejimalides A–D
Scheme 1 outlines our retrosynthetic analysis of ieji-
malides A–D. The C3–C11 fragment 2 could be assem-
bled by a cross-metathesis reaction between alkenes 4 and
5. The subunit 4 was envisioned to originate from but-3-
yn-1-ol (homopropargylic alcohol), while synthon 5 could
be derived from (S)-Roche ester. The C12–C24 fragment
could arise from a Still–Gennari modified Horner–
Wadsworth–Emmons olefination reaction between phos-
phonate 6 and aldehyde 7. The subunit 6, in turn, could be
prepared from γ-butyrolactone and the aldehyde 7 could
be obtained from but-2-yn-1,4-diol via successive
Sharpless epoxidation and Gillman reaction.
amounts from Cystodytes sp.,5 Kobayashi et al. (in 2003) Synthetic Strategy for the C3–C11 Fragment (2)
published revised structures for the iejimalides, with com-
plete determination of the absolute configurations at the
The synthesis of the C5–C11 conjugated diene fragment 4
began from the known epoxy alcohol 8 (Scheme 2), pre-
six stereogenic centers. They also reported a change in the
pared from homopropargylic alcohol as reported previ-
olefin geometry at C13 (Z rather than E), following exten-
ously.9 The epoxy alcohol 8 was converted into allylic
sive 2D NMR investigations, distance geometry calcula-
alcohol 10 by a two-step process involving initial transfor-
mation into iodide 9, which on refluxing with activated
zinc in ethanol afforded the allylic alcohol 10 (76% yield).
Compound 10 was converted into the corresponding O-
methyl ether 11 by methylation using methyl iodide in the
presence of sodium hydride. Next, 11 was subjected to a
tions and degradation studies.6 So far, three total
syntheses7 and two syntheses of fragments8 have been re-
ported. The distinctive biological properties of the ieji-
malides and their scarcity (0.0003–0.0006% of the
tunicate wet weight) in Nature, combined with their
one-pot dihydroxylation and oxidative cleavage of the re-
sulting diol to furnish the corresponding aldehyde, fol-
lowed by a three-carbon Wittig olefination to provide α,β-
unsaturated ester 12. This ester was converted into the
SYNTHESIS 2014, 46, 0110–0118
Advanced online publication: 07.11.2013
DOI: 10.1055/s-0033-1340083; Art ID: SS-2013-Z0529-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

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Studies toward the Synthesis of Iejimalides A–D
111
R1
O
H
N
H
O
MeO
N
H
O
O
R2O
OMe
1a–d
COOEt
OTBDPS
MeO
OBn
2
OMe
C12–C24 fragment
OMOM
3
C3–C11 fragment
OPMB
OMe
OTBDPS
TBSO
+
OMOM
OBn
O
PMBO
OEt
OHC
+
P
4
5
OEt
O
7
6
O
OH
OH
HO
MeOOC
OH
O
homopropargylic
alcohol
γ-butyrolactone
but-2-yn-1,4-diol
(S)-Roche ester
Scheme 1 Retrosynthetic analysis of iejimalides A–D
corresponding aldehyde by reduction with diisobutylalu- The synthesis of the olefinic fragment 5 began with the
minum hydride (DIBAL-H), followed by pyridinium known aldehyde 1410 prepared from (S)-(+)-Roche ester.
chlorochromate (PCC) oxidation. This aldehyde was sub- The aldehyde 14, on homologation with (methylene)tri-
jected to one-carbon Wittig olefination (n-BuLi, phenylphosphorane in anhydrous tetrahydrofuran using
CH3PPh3I, anhydrous THF) to produce the C5–C11 con- n-butyllithium (1.6 M) produced the terminal alkene 5 in
jugated diene fragment 4.
75% yield (Scheme 3).
O
b
ref. 9
ref. 10
OH
OTBDPS
PMBO
R
HO
OHC
EtO2C
8; R = OH
9; R = I
14
homopropargylic alcohol
a
(S)-Roche ester
OR
OMe
a
OTBDPS
d
e
PMBO
PMBO
CO2Et
5
12
10; R = H
11; R = Me
c
Scheme 3 Reagents and conditions: (a) MePPh3I, n-BuLi, anhy-
drous THF, –50 °C to r.t., 5 h, 75%.
OMe
OMe
f
OH
With practical routes to coupling partners 4 and 5 estab-
lished, we turned our attention to the key cross-metathesis
coupling in the presence of Grubbs’ second generation
(Grubbs II) catalyst11 (Scheme 4). Thus, cross-metathesis
of alkenes 4 and 5 in the presence of Grubbs II catalyst (1
mol%) in toluene at reflux temperature gave coupled
product 2 in 65% yield, without isolating any by-products.
Cleavage of the p-methoxybenzyl (PMB) group and oxi-
dation into the corresponding aldehyde set the stage for
the Wittig olefination.
PMBO
PMBO
13
4
Scheme 2 Reagents and conditions: (a) imidazole, PPh3, I2, THF,
0 °C–r.t., 30 min, 81%; (b) Zn, EtOH, reflux, 30 min, 76%; (c) MeI,
NaH, THF, 2 h, 75%; (d) (i) OsO4, NMO, acetone–H2O (4:1); (ii)
NaIO4, THF–H2O (2:1); (iii) Ph3P=C(CH3)CO2Et, benzene, reflux, 4
h, 71% over 3 steps; (e) DIBAL-H, CH2Cl2, 0 °C, 1 h, 77%; (f) (i)
PCC, CH2Cl2, Celite, 0 °C, 1 h, 98%; (ii) n-BuLi, CH3PPh3I, anhy-
drous THF, –50 °C to r.t., 5 h, 68%.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 110–118

112
G. Sabitha et al.
MeO
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diol 17 in 69% yield, possessing anti-stereochemistry at
the two stereocenters.13 Protection of the primary alcohol
as the tert-butyldimethylsilyl ether 18, followed by pro-
tection of the secondary hydroxy group with methoxy-
methyl chloride (MOMCl) provided methoxymethyl ether
19 in quantitative yield. Next, the tert-butyldimethylsilyl
group was removed and the resulting alcohol 20 was oxi-
dized into the corresponding aldehyde and subsequent
Wittig olefination provided α,β-unsaturated ester 21. Re-
duction of this ester provided the alcohol 22 and subse-
quent Swern oxidation gave the desired aldehyde 7, which
was used in the next step without purification.
OTBDPS
a
4 + 5
OPMB
2
C3–C11 fragment
Scheme 4 Reagents and conditions: (a) Grubbs II, toluene, reflux, 3
h, 65%.
Synthetic Strategy for the C12–C24 Fragment (3)
The synthesis of aldehyde 7 started with readily available
but-2-yn-1,4-diol (Scheme 5). Accordingly, but-2-yn-1,4-
diol was converted into the known allylic alcohol 15 as re-
ported earlier,12 by selective monobenzylation and partial
reduction of the triple bond in a very good yield (90%).
The alcohol 15 was subjected to Sharpless asymmetric ep-
oxidation [(–)-DIPT, Ti(Oi-Pr)4, TBHP, –25 °C, 24 h] to
afford epoxy alcohol 16 in 76% yield. Epoxide opening
proceeded smoothly with high regioselectivity by treat-
ment of 16 with lithium dimethylcuprate (Me2CuLi) to
give the expected 1,3-diol accompanied by the undesired
1,2-diol (6:1). The minor isomer was readily removed by
treating the mixture with sodium periodate to yield 1,3-
The synthesis of phosphonate ester 6 (Scheme 6) com-
menced from commercially available γ-butyrolactone, as
reported,14 by deprotonation of methyl diethylphospho-
nate with n-butyllithium, followed by treatment with
γ-butyrolactone and protection of the resulting alcohol as
a tert-butyldimethylsilyl ether.
The Subsequent Horner–Wadsworth–Emmons reaction
between β-ketophosphonate 6 and the aldehyde 7
(Scheme 7), using Paterson’s conditions,15 afforded 24 in
80% yield. The absolute configuration at C21 was set by
a Corey–Bakshi–Shibata (CBS) reduction16 of the enone
a
ref. 11
HO
OBn
a
OH
HO
6 + 7
OBn
OMOM
TBSO
15
OR1 OR2
but-2-yn-1,4-diol
O
24
O
f
b
OBn
OBn
HO
d
b
16
OBn
OMOM
TBSO
17; R1 = R2 = H
18; R1 = TBS, R2 = H
19; R1 = TBS, R2 = MOM
20; R1 = H, R2 = MOM
OMOM
c
OR
d
e
25 R = H
26 R = Me
c
OMOM
g
e
OBn
OBn
EtO2C
OBn
OMOM
HO
HO
OMe
O
P
O
OMe
22
21
O
OEt
27
O
OMOM
OBn
h
OMe
OHC
EtOOC
S-I
OBn
OMOM
7
OMe
Scheme 5 Reagents and conditions: (a) Ti(Oi-Pr)4, (–)-DIPT,
TBHP, anhydrous CH2Cl2, –25 °C, 24 h, 76%; (b) CuI, MeLi, Et2O,
0 °C to –40 °C, 3.5 h, 69%; (c) TBSCl, imidazole, THF, 0 °C, 30 min,
91%; (d) MOMCl, DIPEA, CH2Cl2, 0 °C–r.t., 2 h, 94%; (e) TBAF,
THF, 0 °C to r.t., 1 h, 92%; (f) (i) (COCl)2, CH2Cl2, DMSO, Et3N, 2.5
h, –78 °C; (ii) Ph3P=CHCO2Et, benzene, 2 h, 79%; (g) DIBAL-H,
CH2Cl2, 0 °C, 1 h, 92%; (h) (COCl)2, CH2Cl2, DMSO, Et3N, 2.5 h,
–78 °C, 94%.
28
Scheme 7 Reagents and conditions: (a) Ba(OH)2·8H2O, anhydrous
THF, r.t., 2 h, 80%; (b) (R)-CBS, BH3·DMS, anhydrous THF, –40 °C,
2 h, 71%; (c) MeI, NaH, anhydrous THF, 2 h, 78%; (d) (i) TBAF,
THF, 0 °C–r.t., 1 h, 67%; (e) (i) (COCl)2, CH2Cl2, DMSO, Et3N,
–78 °C, 92%; (e) S-I, NaH, 18-crown-6, anhydrous THF, –78 °C, 3 h,
75%.
O
O
O
ref. 14
OEt
OEt
OEt
OEt
a
O
TBSO
P
HO
P
O
O
6
γ-butyrolactone
23
Scheme 6 Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2, 0 °C, 30 min, 94%.
Synthesis 2014, 46, 110–118
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Studies toward the Synthesis of Iejimalides A–D
113
(S)-1-[(3-Methoxypenten-4-yloxy)methyl]-4-methoxybenzene
(11)
To a suspension of NaH (0.68 g, 28.6 mmol) in anhydrous THF, was
added alcohol 10 (2.77 g, 12.4 mmol) at 0 °C. The mixture was
stirred for 30 min, MeI (1 mL, 16.2 mmol) was added slowly, and
24, which delivered the corresponding allylic alcohol 25
in 71% yield after chromatographic separation of the mi-
nor diastereomer (crude product dr = 9:1, determined by
1H NMR spectroscopy). Methylation of the hydroxy
group provided the methyl ether 26, which was followed the mixture was stirred at r.t. for 2 h. After completion of the reac-
tion (monitored by TLC), it was quenched by the dropwise addition
of ice-cold H2O. The organic layer was separated and the aq layer
extracted with EtOAc (2 × 25 mL). The combined organic layers
were dried over Na2SO4. The solvents were evaporated under vacu-
by cleavage of the tert-butyldimethylsilyl ether and subse-
quent oxidation of the resulting alcohol to afford the cor-
responding aldehyde. This was then subjected to a Still–
Gennari modified Horner–Wadsworth–Emmons17 reac-
um and the residue was purified by column chromatography
tion using sodium hydride and phosphonate salt S-I in an-
hydrous tetrahydrofuran at –78 °C to afford the cis α,β-
unsaturated ester 28 in 75% yield after column chroma-
tography. The phosphonium bromide coupling partner
could be prepared via ester reduction to give the corre-
sponding alcohol, and then bromination.
(EtOAc–hexane, 1:9) to afford methyl ether 11 (2.1 g, 75%) as a
colorless oil.
[α]D25 +6.33 (c 0.6, CHCl3).
IR (neat): 3489, 3074, 2932, 2859, 1737, 1611, 1513, 1247, 1092,
1035, 926, 821, 772, 515 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.21 (d, J = 9.0 Hz, 2 H), 6.82 (d,
J = 9.0 Hz, 2 H), 5.67–5.57 (m, 1 H), 5.20–5.14 (m, 2 H), 4.38 (s, 2
H), 3.78 (s, 3 H), 3.71–3.64 (m, 1 H), 3.54–3.47 (m, 1 H), 3.46–3.39
(m, 1 H), 3.23 (s, 3 H), 1.86–1.77 (m, 1 H), 1.74–1.65 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 138.3, 130.5, 129.2, 117.2,
113.6, 79.8, 72.5, 66.2, 56.2, 55.2, 35.5.
MS (ESI): m/z = 259 [M + Na]+.
In summary, the synthesis of the C3–C11 and C12–C24
fragments of iejimalides A–D have been accomplished in
a short and convergent manner. Investigations on the as-
sembly of the macrolactone, the preparation of the side
chain and the completion of the synthesis are currently un-
derway and will be reported in due course.
(S,E)-Ethyl 6-(4-Methoxybenzyloxy)-4-methoxy-2-methylhex-
2-enoate (12)
All reagents and catalysts were purchased from Sigma-Aldrich. Re-
actions were conducted under N2 in anhydrous solvents (CH2Cl2,
THF and EtOAc). All reactions were monitored by TLC (Merck 60
F-254 silica gel plates; samples were made visual under UV light).
Column chromatography was performed on silica gel (60–120
mesh) supplied by Acme Chemical Co., India. n-Hexane (bp 60–
80 °C) and EtOAc (bp 76–78 °C) were used for silica gel column
chromatography. Yields refer to those of chromatographically and
spectroscopically (1H and 13C NMR) homogeneous materials. Air-
sensitive reagents were transferred via a syringe or a cannula. Evap-
oration of solvents was performed under reduced pressure on a Bu-
chi rotary evaporator. Optical rotations were recorded using a
JASCO DIP-370 polarimeter. IR spectra were obtained using a
NMO (1.3 g, 11.4 mmol) and the alkene 11 (2.07 g, 8.7 mmol) were
dissolved in acetone–H2O (4:1, 18 mL). A solution of OsO4 (0.02
M) in toluene (2 mL) was added and the mixture stirred overnight
at r.t., then cooled in an ice bath. The reaction was quenched by the
addition of sat. aq Na2SO3 solution (15 mL). Most of the acetone
was removed by rotary evaporation, and the aq mixture was extract-
ed with EtOAc (3 × 30 mL). The combined extracts were concen-
trated under reduced pressure, and the crude diol was used in the
next step without further purification. NaIO4 (2.4 g, 11.4 mmol) was
added to the crude diol (2.07 g, 7.6 mmol) in THF–H2O (2:1, 20
mL) at r.t. The reaction was complete within 30 min. After filtra-
tion, the two layers were separated and the aq layer was extracted
with EtOAc (2 × 50 mL), dried over Na2SO4 and concentrated to
give the corresponding crude aldehyde, which was used in the next
step without further purification. The crude aldehyde was immedi-
ately dissolved in benzene (30 mL) and treated with
Ph3P=C(CH3)CO2Et (3.8 g, 10.6 mmol). The mixture was heated at
reflux temperature for 4 h, and then allowed to cool to r.t. The sol-
vent was removed under reduced pressure and the residue was puri-
fied by silica gel column chromatography (EtOAc–hexanes, 10–
15%) to afford 12 (1.6 g, 71%) as a yellow oil.
1
Perkin-Elmer Infrared-683 spectrophotometer. H and 13C NMR
spectra of samples in CDCl3 were recorded on Varian FT-400 MHz,
Bruker UXNMR FT-300 MHz (Avance) and Avance-500 MHz
spectrometers. Chemical shifts (δ) are reported relative to TMS
(δ = 0.0) as an internal standard. Mass spectra were obtained on a
Finnigan MAT1020B or micromass VG 70-70H spectrometer oper-
ating at 70 eV, using a direct inlet system.
(S)-5-(4-Methoxybenzyloxy)pent-1-en-3-ol (10)
A stirred suspension of iodide 9 (9 g, 23.9 mmol) and Zn powder
(7.8 g, 119.6 mmol) in anhydrous EtOH (75 mL) was heated at re-
flux temperature for 30 min. The mixture was filtered through a
Celite pad, concentrated under reduced pressure, and the crude res-
idue purified by column chromatography (EtOAc–PE, 3:7) to fur-
nish alcohol 10 (4 g, 76%) as a light yellow liquid.
[α]D25 +8.80 (c 0.3, CHCl3).
IR (neat): 2932, 1712, 1612, 1513, 1462, 1249, 1098, 1034, 822,
749, 541 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.19 (d, J = 8.3 Hz, 2 H), 6.81 (d,
J = 8.3 Hz, 2 H), 6.51 (d, J = 9.0 Hz, 1 H), 4.38 (ABq, J = 11.3 Hz,
2 H), 4.23–4.13 (m, 3 H), 3.77 (s, 3 H), 3.57–3.47 (m, 1 H), 3.43–
3.34 (m, 1 H), 3.23 (s, 3 H), 1.95–1.81 (m, 1 H), 1.87 (s, 3 H), 1.73–
1.61 (m, 1 H), 1.31 (t, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 167.5, 159.0, 141.4, 130.4, 130.3,
129.1, 113.6, 74.5, 72.5, 65.7, 60.6, 56.5, 55.1, 34.8, 14.1, 12.7.
[α]D25 +4.66 (c 0.1, CHCl3).
IR (neat): 3443, 2934, 2861, 1612, 1512, 1246, 1092, 819 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.20 (d, J = 8.0 Hz, 2 H), 6.82 (d,
J = 8.0 Hz, 2 H), 5.85–5.77 (m, 1 H), 5.22 (d, J = 17.0 Hz, 1 H),
4.42 (s, 2 H), 4.33–4.26 (m, 1 H), 3.77 (s, 3 H), 3.66–3.60 (m, 1 H),
3.59–3.53 (m, 1 H), 3.19 (br s, 1 H), 1.85–1.71 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H26O5Na: 345.1672;
found: 345.1683.
13C NMR (75 MHz, CDCl3): δ = 159.2, 140.0, 129.6, 129.3, 114.6,
113.7, 72.9, 72.0, 67.8, 55.1, 35.9.
MS (ESI): m/z = 245 [M + Na]+.
(S,E)-6-(4-Methoxybenzyloxy)-4-methoxy-2-methylhex-2-en-1-
ol (13)
To a solution of compound 12 (1.57 g, 4.8 mmol) in CH2Cl2 (15
mL) at 0 °C was added DIBAL-H (6 mL, 9.7 mmol, 1.6 M in hex-
ane). The mixture was stirred for 1 h, and was then quenched by the
addition of sat. potassium sodium tartrate solution. The mixture was
© Georg Thieme Verlag Stuttgart · New York
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114
G. Sabitha et al.
PAPER
warmed to r.t. and stirred for 4 h until two clear layers were ob-
served. The layers were separated and the aq layer was extracted
with CH2Cl2 (3 × 25 mL). The combined organic layers were dried
over Na2SO4, the solvent was evaporated, and the residue was puri-
fied by column chromatography (10–15% EtOAc–hexane) to afford
allylic alcohol 13 (1 g, 77%) as a colorless oil.
mmol, 1.6 M in hexane) was slowly added and the mixture allowed
to stir for 1 h. During this time the mixture turned yellow which in-
dicated the formation of the ylide. This yellow solution was cooled
to –50 °C and the aldehyde was added. The resulting solution was
slowly warmed to r.t. and stirred at the same temperature for 5 h.
The mixture was quenched with sat. NH4Cl solution (5 mL). The or-
ganic compound was extracted with Et2O (2 × 10 mL) and the com-
bined organic layer washed with brine (3 × 10 mL), dried over
anhydrous Na2SO4, and evaporated under reduced pressure. Silica
gel column chromatography (8% EtOAc–hexane) afforded the de-
sired alkene 5 (0.15 g, 75%) as a colorless liquid.
[α]D25 +0.88 (c 0.75, CHCl3).
IR (neat): 3421, 2927, 2862, 1612, 1513, 1457, 1247, 1177, 1096,
821, 763, 517 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.19 (d, J = 9.0 Hz, 2 H), 6.82 (d,
J = 9.0 Hz, 2 H), 5.24 (d, J = 9.0 Hz, 1 H), 4.37 (s, 2 H), 4.08 (q,
J = 7.0 Hz, 1 H), 3.96 (s, 2 H), 3.78 (s, 3 H), 3.52–3.46 (m, 1 H),
3.44–3.36 (m, 1 H), 3.20 (s, 3 H), 1.90–1.82 (m, 1 H), 1.68 (s, 3 H),
1.66–1.59 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 139.1, 130.5, 129.2, 125.5,
113.6, 74.1, 72.6, 68.0, 66.3, 55.9, 55.2, 35.5, 14.0.
[α]D25 +4.78 (c 0.8, CHCl3).
IR (neat): 3071, 2959, 2859, 1641, 1467, 1426, 1386, 1258, 739,
703 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.74–7.63 (m, 4 H), 7.47–7.34 (m,
6 H), 5.80 (ddd, J = 17.3, 10.5, 6.7 Hz, 1 H), 5.07–4.96 (m, 2 H),
3.60–3.45 (m, 2 H), 2.47–2.34 (m, 1 H), 1.11–1.01 (m, 12 H).
13C NMR (75 MHz, CDCl3): δ = 141.3, 135.6, 133.9, 129.5, 127.5,
114.0, 68.4, 40.2, 26.8, 19.3, 16.1.
HRMS (ESI): m/z [M + Na]+ calcd for C16H24O4Na: 303.1566;
found: 303.1575.
MS (ESI): m/z = 342 [M + NH4]+.
(S,E)-1-Methoxy-4-[(3-methoxy-5-methylhepta-4,6-dienyl-
oxy)methyl]benzene (4)
PCC (1.15 g, 5.3 mmol) and Celite (1 g) were added to a solution of
alcohol 13 (1 g, 3.5 mmol) in CH2Cl2 (30 mL). After stirring the
mixture at 25 °C for 1 h, i-PrOH (5 mL) was added and the solvent
was removed under reduced pressure. The residue was filtered
through a Celite pad and the filter cake rinsed with Et2O. The organ-
ic layer was washed with dil HCl (2 mL), H2O (5 mL) and brine (5
mL), and then dried (Na2SO4). Removal of the solvent afforded a
gummy material, which was purified by silica gel column chroma-
tography (EtOAc–hexane, 2:8) to afford the corresponding alde-
hyde (0.97 g, 54.1, 98%) as an oil.
[(2R,3E,5E,7S)-9-(4-Methoxybenzyloxy)-7-methoxy-2,5-di-
methylnona-3,5-dienyloxy](tert-butyl)diphenylsilane (2)
A mixture of alkene 4 (0.1 g, 0.36 mmol), alkene 5 (0.140 g, 0.43
mmol) and Grubbs-II catalyst (1 mol%) under an N2 atm in toluene
(10 mL) was stirred at reflux temperature. After completion of the
reaction as indicated by TLC (3 h), the mixture was concentrated
under reduced pressure and the residue subjected to silica gel col-
umn chromatography (EtOAc–hexane, 3:7) to give pure cross-
metathesis product 2 (0.13 g, 65%), as a colorless liquid.
[α]D25 +10.44 (c 0.15, CHCl3).
The aldehyde (0.77 g, 2.75 mmol) was dissolved in anhydrous THF
(3 mL) under N2. In another round-bottomed flask, methyltriphe-
nylphosphonium iodide (4.5 g, 11.0 mmol) in anhydrous THF (20
mL), under an N2 atm, was cooled to –30 °C. n-BuLi (2.7 mmol, 1.6
M in hexane) was slowly added and the mixture allowed to stir for
1 h. During this time the mixture turned yellow, which indicated
formation of the ylide. This yellow solution was cooled to –50 °C
and treated with the above solution of the aldehyde. The resulting
solution was slowly warmed to r.t. and stirred at the same tempera-
ture for 5 h. The mixture was quenched with sat. NH4Cl solution (10
mL). The organic compound was extracted with Et2O (2 × 10 mL),
the combined organic layers washed with brine (3 × 10 mL), dried
over anhydrous Na2SO4, and evaporated under reduced pressure.
Silica gel column chromatography of the residue (8% EtOAc–hex-
ane) afforded the desired diene 4 (0.48 g, 1.7 mmol, 68%) as a yel-
low liquid.
IR (neat): 3449, 2926, 2856, 1669, 1609, 1513, 1248, 1101, 1053,
823, 704 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.66 (d, J = 7.5 Hz, 4 H), 7.46–
7.31 (m, 6 H), 7.25 (d, J = 8.3 Hz, 2 H), 6.87 (d, J = 8.3 Hz, 2 H),
6.10 (d, J = 15.8 Hz, 1 H), 5.61 (dd, J = 15.8, 7.5 Hz, 1 H), 5.21 (d,
J = 9.8 Hz, 1 H), 4.41 (ABq, J = 5.2, 3.7 Hz, 2 H), 3.81–3.77 (m, 4
H), 3.60–3.38 (m, 4 H), 3.21 (s, 3 H), 2.53–2.42 (m, 1 H), 1.99–1.65
(m, 5 H), 1.07 (d, J = 6.7 Hz, 3 H), 1.05 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 159.9, 140.8, 137.0, 135.5, 133.4,
132.8, 131.9, 130.5, 129.5, 129.4, 129.1, 127.5, 113.6, 74.4, 72.6,
66.3, 60.3, 56.0, 55.2, 35.6, 26.7, 19.7, 14.0, 12.1.
HRMS (ESI): m/z [M + Na]+ calcd for C36H48O4NaSi: 595.32141;
found: 595.32345.
{(2R,3R)-3-[(Benzyloxy)methyl]oxiran-2-yl}methanol (16)
In a two-neck 250 mL, round-bottomed flask, anhydrous CH2Cl2
(20 mL) was added to activated powdered 4 Å MS and the suspen-
sion cooled to –20 °C. Ti(Oi-Pr)4 (1.9 mL, 6.74 mmol) and (–)-
DIPT (1.44 g, 6.74 mmol) in anhydrous CH2Cl2 (10 mL) were
added with stirring, and the resulting mixture stirred for 30 min at
–24 °C. Compound 15 (6 g, 33.7 mmol) in anhydrous CH2Cl2 (20
mL) was added and the mixture stirred for another 30 min at –24 °C.
TBHP (8.0 mL, 40.4 mmol) was added and the mixture stirred at the
same temperature for 24 h. After warming to 0 °C, the reaction was
quenched by the addition of H2O (3.5 mL) and stirred for 1 h at r.t.
Next, an aq solution of NaOH (20%) sat. with NaCl was added and
the mixture was stirred vigorously for another 30 min at r.t. The re-
sulting mixture was filtered through Celite and the residue rinsed
with CH2Cl2. The organic phase was separated and the aq phase ex-
tracted with CH2Cl2 (3 × 30 mL). The combined organic phase was
washed with brine (20 mL) and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure and the residue puri-
fied by silica gel column chromatography (EtOAc–hexane, 4:6) to
afford epoxide 16 (4.8 g, 76%) as a viscous liquid.
[α]D25 +4.10 (c 0.19, CHCl3).
IR (neat): 2927, 2859, 1714, 1610, 1248, 1175, 1100, 1035, 821
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.3 Hz, 2 H), 6.87 (d,
J = 8.3 Hz, 2 H), 6.40 (dd, J = 17.4, 10.6 Hz, 1 H), 5.32 (d, J = 9.0
Hz, 1 H), 5.20 (d, J = 17.4 Hz, 1 H), 5.06 (d, J = 10.6 Hz, 1 H), 4.41
(s, 2 H), 4.21 (dt, J = 9.0, 6.8 Hz, 1 H), 3.80 (s, 3 H), 3.59–3.49 (m,
1 H), 3.47–3.36 (m, 1 H), 3.23 (s, 3 H), 1.99–1.88 (m, 1 H), 1.81 (d,
J = 1.5 Hz, 3 H), 1.78–1.64 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 140.8, 137.0, 132.8, 130.5,
129.1, 113.6, 112.6, 74.4, 72.5, 66.2, 55.9, 55.1, 35.5, 12.1.
MS (ESI): m/z = 299 [M + Na]+.
(R)-tert-Butyl[(2-methylbut-3-enyl)oxy]diphenylsilane (5)
The aldehyde 14 (0.2 g, 0.6 mmol) was dissolved in anhydrous THF
(2 mL) under N2. In another round-bottomed flask, methyltriphe-
nylphosphonium iodide (1.01 g, 2.4 mmol) was taken in anhydrous
THF (10 mL) under an N2 atm and cooled to –30 °C. n-BuLi (1.8
Synthesis 2014, 46, 110–118
© Georg Thieme Verlag Stuttgart · New York

PAPER
Studies toward the Synthesis of Iejimalides A–D
115
IR (neat): 3421, 2926, 2862, 1739, 1638, 1454, 1368, 1102, 1026,
871, 745, 699, 609 cm–1.
[(2S,3S)-4-(Benzyloxy)-3-(methoxymethoxy)-2-methylbut-
oxy](tert-butyl)dimethylsilane (19)
To a solution of the alcohol 18 (4.77 g, 14.7 mmol) in CH2Cl2 (35
mL) was added DIPEA (6.33 mL, 36.8 mmol). After 1 h, the solu-
tion was cooled to 0 °C and MOMCl (1.77 mL, 22.07 mmol) was
added under N2 using a syringe. The resulting mixture was stirred at
r.t. for 6 h and then quenched by adding sat. NaHCO3 solution. The
product was extracted with CH2Cl2 (2 × 100 mL) and the combined
organic layers concentrated under reduced pressure. The residue
was purified on a silica gel column using (10% EtOAc–hexane) to
yield 19 (5 g, 94%) as a bright yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.27 (m, 5 H), 4.58 (ABq,
J = 11.3 Hz, 2 H), 3.92 (dd, J = 12.8, 2.2 Hz, 1 H), 3.77 (dd,
J = 12.0, 3.0 Hz, 1 H), 3.72 (d, J = 4.5 Hz, 1 H), 3.64 (dd, J = 12.8,
3.7 Hz, 1 H), 3.52 (ddd, J = 6.0, 3.0, 1.5 Hz, 1 H), 3.23 (q, J = 5.2
Hz, 1 H), 3.12–3.07 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 137.5, 128.3, 127.6, 126.8, 73.2,
69.5, 61.0, 55.8, 54.2.
(2S,3S)-4-(Benzyloxy)-2-methylbutane-1,3-diol (17)
[α]D25 = +9.74 (c 0.65, CHCl3).
To a stirred suspension of CuI (14.7 g, 74.2 mmol) in anhydrous
Et2O (147 mL) at 0 °C was added slowly MeLi (92.7 mL, 0.148
mmol, 1.6 M in Et2O) under an N2 atm, and the resulting solution
was stirred for 15 min at 0 °C. Epoxy alcohol 16 (4.8 g, 24.7 mmol)
in anhydrous Et2O (20 mL) was then added dropwise at –40 °C.
Once the addition was complete, the mixture was stirred at 0 °C for
3 h. The reaction was quenched by the careful addition of sat. aq
NH4Cl solution. The mixture was filtered through a pad of Celite,
and the salts were washed several times with Et2O. The combined
organic layers were washed with brine (2 × 20 mL) and dried over
Na2SO4. Concentration of the Et2O extract under reduced pressure
provided 4.9 g (23.4 mmol, 94%) of a pale yellow oil, which was a
6:1 mixture of the regioisomeric diols. This mixture was dissolved
in THF (60 mL) and treated with H2O (30 mL) containing NaIO4
(7.4 g, 34.7 mmol) with stirring to cleave the 1,2-diol. The reaction
was complete in 1 h. After the layers were separated, the aq layer
was extracted with Et2O (3 × 30 mL) and the combined extracts
dried over Na2SO4 and concentrated in vacuo. The residue was sub-
jected to silica gel column chromatography (EtOAc–hexane, 4:6) to
afford diol 17 (3.5 g, 69%) as a pale yellow liquid.
IR (neat): 2954, 2930, 2887, 2858, 2212, 1709, 1464, 1253, 1102,
1037, 838, 775, 738, 697 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 4.83–4.68 (m,
2 H), 4.54 (ABq, J = 12.0 Hz, 2 H), 3.76–3.67 (m, 1 H), 3.66–3.51
(m, 4 H), 3.37 (s, 3 H), 2.06–1.92 (m, 1 H), 0.93–0.87 (m, 12 H),
0.02 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 138.3, 128.2, 127.6, 127.4, 96.6,
78.1, 73.2, 71.1, 64.5, 55.5, 37.7, 25.8, 18.2, 13.3, –5.4.
HRMS (ESI): m/z [M + Na]+ calcd for C20H36O4NaSi: 391.2275;
found: 391.2288.
(2S,3S)-4-(Benzyloxy)-3-(methoxymethoxy)-2-methylbutan-1-
ol (20)
To a stirred solution of compound 19 (4.97 g, 13.5 mmol) in anhy-
drous THF (20 mL), TBAF (16.2 mL, 16.2 mmol, 1 M solution in
THF) was added slowly at 0 °C. After completion of the reaction as
indicated by TLC, the mixture was concentrated under reduced
pressure and the residue purified by column chromatography
(EtOAc–hexane, 3:7) to yield alcohol 20 (3.15 g, 92%) as a color-
less liquid.
[α]D25 –6.78 (c 0.55, CHCl3).
IR (neat): 3386, 3030, 2923, 2829, 1636, 1454, 1098, 1024, 771,
697, 602 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.41–7.27 (m, 5 H), 4.57 (ABq,
J = 11.8 Hz, 2 H), 3.75 (td, J = 7.0, 3.2 Hz, 1 H), 3.67 (d, J = 5.6 Hz,
2 H), 3.61 (dd, J = 9.4, 3.0 Hz, 1 H), 3.49–3.42 (m, 2 H), 2.91 (br s,
2 H), 0.87 (d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 137.6, 128.4, 127.8, 127.7, 75.3,
73.3, 72.8, 67.0, 37.3, 13.5.
MS (ESI): m/z = 233 [M + Na]+.
[α]D25 +62.80 (c 0.5, CHCl3).
IR (neat): 3440, 3030, 2922, 1651, 1453, 1366, 1201, 1101, 1032,
916, 739, 699, 605 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.27 (m, 5 H), 4.81 (d,
J = 6.6 Hz, 1 H), 4.65 (d, J = 6.6 Hz, 1 H), 4.55 (ABq, J = 12.0 Hz,
2 H), 3.78–3.51 (m, 5 H), 3.40 (s, 3 H), 2.04–1.90 (m, 1 H), 1.81 (br
s, 1 H), 0.97 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 137.8, 128.3, 127.6, 127.5, 96.6,
79.8, 73.5, 70.9, 64.9, 55.7, 37.0, 13.8.
MS (ESI): m/z = 254 [M]+.
(2S,3S)-1-(Benzyloxy)-4-[(tert-butyldimethylsilyl)oxy]-3-meth-
ylbutan-2-ol (18)
To a stirred solution of the diol 17 (3.47 g, 16.5 mmol) in CH2Cl2
(30 mL), imidazole (2.24 g, 32.9 mmol) was added at 0 °C, and the
resulting mixture stirred for 15 min. TBSCl (2.23 g, 14.87 mmol)
was added to the mixture at 0 °C, which was stirred for a further 1
h. After completion of the reaction as indicated by TLC, the mixture
was concentrated under reduced pressure and the residue subjected
to column chromatography (EtOAc–hexane, 1:9) to yield pure
product 18 (4.8 g, 91%) as a colorless liquid.
(E,4S,5S)-Ethyl 6-(Benzyloxy)-5-(methoxymethoxy)-4-methyl-
hex-2-enoate (21)
Oxalyl chloride (1.54 mL, 17.8 mmol) was added dropwise at
–78 °C to a solution of DMSO (2.5 mL, 35.7 mmol) in anhydrous
CH2Cl2 (20 mL). The mixture was stirred for 25 min at this temper-
ature and then a solution of alcohol 20 (2.28 g, 8.93 mmol) in anhy-
drous CH2Cl2 (2 mL) was added. The mixture was stirred for 1 h at
–78 °C. After addition of Et3N (7.4 mL, 53.6 mmol), the mixture
was stirred for 15 min at –78 °C and then for 20 min at 0 °C. The
reaction mixture was then diluted with H2O (15 mL) and CH2Cl2
(30 mL). The organic layer was separated and washed with brine
(20 mL), dried over Na2SO4, and concentrated in vacuo to afford a
crude aldehyde, which was used in the next step without purifica-
tion. The crude aldehyde was immediately dissolved in benzene (15
mL) and treated with Ph3P=CHCO2Et (2.28 g, 9.0 mmol). The mix-
ture was heated at reflux temperature for 1 h, and then allowed to
cool to r.t. The solvent was removed under reduced pressure and the
residue was purified by silica gel chromatography to afford alkene
21 (2.2 g, 79%) as a pale yellow liquid.
[α]D25 +4.88 (c 0.3, CHCl3).
IR (neat): 3469, 3065, 3037, 2955, 2930, 2857, 1635, 1467, 1362,
1253, 1097, 1028, 837, 766, 698, 603 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H), 4.57 (ABq,
J = 11.8 Hz, 2 H), 3.79 (dd, J = 9.8, 4.5 Hz, 2 H), 3.64–3.47 (m, 3
H), 2.62 (s, 1 H), 1.94–1.82 (m, 1 H), 0.92–0.87 (m, 12 H), 0.06 (s,
6 H).
13C NMR (75 MHz, CDCl3): δ = 138.2, 128.3, 127.7, 127.6, 74.3,
73.3, 72.7, 66.8, 37.1, 25.8, 18.1, 13.3, –5.6.
HRMS (ESI): m/z [M + H]+ calcd for C18H33O3Si: 325.2193; found:
325.2204.
[α]D25 +50.86 (c 0.5, CHCl3).
IR (neat): 2932, 1718, 1653, 1453, 1368, 1265, 1103, 1036, 918,
863, 739, 699 cm–1.
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Synthesis 2014, 46, 110–118

116
G. Sabitha et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 6.98 (dd,
J = 15.6, 8.1 Hz, 1 H), 5.83 (dd, J = 15.8, 1.1 Hz, 1 H), 4.78 (d,
J = 6.7 Hz, 1 H), 4.63 (d, J = 6.7 Hz, 1 H), 4.52 (s, 2 H), 4.18 (q,
J = 6.9 Hz, 2 H), 3.69 (q, J = 5.0 Hz, 1 H), 3.57–3.45 (m, 2 H), 3.37
(s, 3 H), 2.78–2.65 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 1.10 (d,
J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 166.5, 150.2, 137.9, 128.4, 128.3,
127.5, 121.6, 96.4, 79.2, 73.3, 70.6, 60.1, 55.7, 38.4, 15.8, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C18H26O5Na: 345.1672;
found: 345.1681.
HRMS (ESI): m/z [M + Na]+ calcd for C15H33O5PNaSi: 375.1727;
found: 375.1741.
(5S,6S,7E,9E)-5-[(Benzyloxy)methyl]-6,16,16,17,17-pentameth-
yl-2,4,15-trioxa-16-silaoctadeca-7,9-dien-11-one (24)
To a solution of β-ketophosphonate 6 (2.3 g, 6.5 mmol) in THF (30
mL) was added Ba(OH)2·8H2O (1.0 g, 6.0 mmol) at r.t., which had
been preactivated by heating at 110 °C for 1 h and dried under vac-
uum. The mixture was stirred for 30 min, then crude aldehyde 7 (1.6
g, 5.4 mmol) in THF–H2O (9:1, 15 mL) was added. The mixture
was stirred for 1.5 h and then quenched with sat. NH4Cl solution (15
mL). The organic compound was extracted with EtOAc (2 × 30
mL) and the combined organic layer washed with brine (3 × 15
mL), dried over anhydrous Na2SO4, and evaporated to dryness un-
der reduced pressure. The residue was purified by silica gel column
chromatography (8% EtOAc–hexane) to afford the desired ketone
24 (1.3 g, 80%) as a pale yellow oil.
(E,4S,5S)-6-(Benzyloxy)-5-(methoxymethoxy)-4-methylhex-2-
en-1-ol (22)
To a solution of compound 21 (2.17 g, 6.7 mmol) in CH2Cl2 (20
mL) at 0 °C was added DIBAL-H (8.4 mL, 13.4 mmol, 1.6 M in
hexane). The solution was stirred for 1 h, and was then quenched by
addition of sat. potassium sodium tartrate solution. The resulting so-
lution was warmed to r.t. and then stirred for 4 h until two clear lay-
ers were observed. The layers were separated and the aq layer was
extracted with CH2Cl2 (3 × 30 mL). The combined organic layers
were dried over Na2SO4, the solvent was evaporated, and the resi-
due purified by column chromatography (10–15% EtOAc–hexane)
to afford allylic alcohol 22 (1.8 g, 92%) as a colorless oil.
[α]D25 +28.53 (c 0.5, CHCl3).
IR (neat): 3448, 2922, 2853, 1637, 1460, 1099, 762 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.28 (m, 6 H), 7.18–7.08 (m,
1 H), 6.19–6.14 (m, 1 H), 6.09 (d, J = 15.1 Hz, 1 H), 4.78 (d, J = 6.7
Hz, 1 H), 4.63 (d, J = 6.7 Hz, 1 H), 4.51 (s, 2 H), 3.76–3.58 (m, 3
H), 3.56–3.43 (m, 2 H), 3.37 (s, 3 H), 2.80–2.60 (m, 2 H), 2.58–2.50
(m, 1 H), 1.96–1.74 (m, 2 H), 1.10 (d, J = 6.8 Hz, 3 H), 0.89 (m, 9
H), 0.05 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 200.6, 146.0, 142.6, 137.9, 129.1,
128.5, 128.2, 127.7, 127.5, 96.5, 79.5, 74.9, 73.2, 70.7, 55.6, 39.2,
36.5, 27.3, 25.8, 18.2, 16.3, –5.3.
[α]D25 +37.0 (c 0.5, CHCl3).
IR (neat): 3421, 3030, 2888, 1664, 1453, 1102, 1036, 741, 699 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.27 (m, 5 H), 5.68–5.63 (m,
2 H), 4.78 (d, J = 6.7 Hz, 1 H), 4.65 (d, J = 6.7 Hz, 1 H), 4.51 (ABq,
J = 13.2, 12.2 Hz, 2 H), 4.08 (d, J = 3.0 Hz, 2 H), 3.66–3.63 (m, 1
H), 3.52–3.48 (m, 2 H), 3.38 (s, 3 H), 2.60–2.48 (m, 1 H), 1.06 (d,
J = 6.9 Hz, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C27H45O5Si: 477.3030; found:
477.3039.
13C NMR (75 MHz, CDCl3): δ = 138.0, 133.6, 129.7, 128.2, 127.6,
127.5, 96.5, 79.8, 73.1, 70.9, 63.4, 55.5, 38.2, 16.5.
HRMS (ESI): m/z [M + Na]+ calcd for C16H24O4Na: 303.1566;
found: 303.1575.
(5S,6S,7E,9E,11S)-5-[(Benzyloxy)methyl]-6,16,16,17,17-penta-
methyl-2,4,15-trioxa-16-silaoctadeca-7,9-dien-11-ol (25)
A flame-dried round-bottomed flask (100 mL) was charged with ke-
tone 24 (1.27 g, 2.6 mmol) and anhydrous THF (5 mL), the vessel
was cooled to –20 °C and (R)-methyl-CBS-oxazaborolidine (2.6
mL, 2.6 mmol) was added. BH3·DMS complex (0.75 mL, 8.0
mmol) was slowly added over 10 min, and the mixture was stirred
for 50 min at this temperature before being slowly quenched with
MeOH over a period of about 15 min. The mixture was warmed to
r.t. and after the majority of gas evolution had subsided, the solvents
were evaporated under vacuum and the residue was purified by col-
umn chromatography (EtOAc–hexane, 1:9) to afford alcohol 25
(0.9 g, 71%) as a colorless oil.
(4S,5S,E)-6-(Benzyloxy)-5-(methoxymethoxy)-4-methylhex-2-
enal (7)
Oxalyl chloride (1.0 mL, 12.0 mmol) was added dropwise at –78 °C
to a solution of DMSO (1.7 mL, 24.0 mmol) in anhydrous CH2Cl2
(20 mL). The mixture was stirred for 25 min at this temperature and
then a solution of 22 (1.77 g, 6.0 mmol) in anhydrous CH2Cl2 (5
mL) was added. The mixture was stirred for 1 h at –78 °C. After ad-
dition of Et3N (5.0 mL, 36.1 mmol), the mixture was stirred for 15
min at –78 °C and then for 20 min at 0 °C. The reaction mixture was
then diluted with H2O (10 mL) and CH2Cl2 (25 mL). The organic
layer was separated and washed with brine (15 mL), dried over
Na2SO4, and concentrated in vacuo to afford a crude aldehyde 7,
which was used in the next step without further purification.
[α]D25 +9.75 (c 0.2, CHCl3).
IR (neat): 3447, 2922, 2852, 1638, 1462, 1253, 1098, 1035, 835,
775, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H), 6.30–5.98 (m,
2 H), 5.78–5.44 (m, 2 H), 4.78 (d, J = 6.7 Hz, 1 H), 4.73–4.63 (m, 1
H), 4.51 (s, 2 H), 4.60–4.46 (m, 1 H), 3.71–3.57 (m, 3 H), 3.56–3.45
(m, 2 H), 3.42–3.32 (m, 4 H), 2.63–2.50 (m, 1 H), 1.18–1.11 (m, 2
H), 1.06 (d, J = 6.7 Hz, 3 H), 0.95–0.87 (m, 2 H), 0.91 (s, 9 H), 0.07
(s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 138.2, 135.7, 134.4, 130.4, 130.1,
128.2, 127.5, 127.4, 96.6, 79.9, 73.3, 73.2, 72.2, 63.3, 55.6, 38.8,
34.6, 28.8, 25.9, 18.3, 16.6, –5.3.
Diethyl {5-[(tert-Butyldimethylsilyl)oxy]-2-oxopentyl}phospho-
nate (6)
To a stirred solution of alcohol 23 (1.7 g, 7.1 mmol) in CH2Cl2 (15
mL), imidazole (0.97 g, 14.2 mmol) was added at 0 °C, and the re-
sulting mixture stirred for 15 min. TBSCl (1.6 g, 10.7 mmol) was
added to the mixture at 0 °C, which was then stirred for 1 h. After
completion of the reaction as indicated by TLC, the mixture was
concentrated under reduced pressure and the residue subjected to
column chromatography (EtOAc–hexane, 1:9) to yield the pure
product 6 (2.35 g, 94%) as a colorless liquid.
MS (ESI): m/z = 479 [M + H]+.
IR (neat): 3446, 2928, 2836, 1715, 1254, 1099, 1027, 835, 776 cm–1.
(4S,5E,7E,9S,10S)-[11-(Benzyloxy)-4-methoxy-10-(methoxy-
methoxy)-9-methylundeca-5,7-dienyloxy](tert-butyl)dimethyl-
silane (26)
To a suspension of NaH (0.1 g, 4.1 mmol) in anhydrous THF, was
added alcohol 25 (0.87 g, 1.8 mmol) at 0 °C. After stirring for 30
min, MeI (0.14 mL, 2.3 mmol) was added slowly and the mixture
stirred for a further 2 h at r.t. Following completion of the reaction
(monitored by TLC), it was quenched by the addition of ice-cold
1H NMR (300 MHz, CDCl3): δ = 4.19–4.06 (m, 4 H), 3.60 (t,
J = 6.0 Hz, 2 H), 3.11 (s, 1 H), 3.04 (s, 1 H), 2.68 (t, J = 7.1 Hz, 2
H), 1.88–1.73 (m, 2 H), 1.32 (t, J = 6.9 Hz, 6 H), 0.86 (s, 9 H), 0.02
(s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 202.0, 62.5, 62.4, 61.9, 41.5, 40.5,
26.6, 25.8, 18.2, 16.3, 16.2, 5.4.
Synthesis 2014, 46, 110–118
© Georg Thieme Verlag Stuttgart · New York

PAPER
Studies toward the Synthesis of Iejimalides A–D
117
H2O dropwise. The organic layer was separated and the aq layer ex-
tracted with EtOAc (2 × 25 mL). The combined organic layers were
dried over Na2SO4 and the solvents were evaporated under vacuum.
The residue was purified by column chromatography (EtOAc–hex-
ane, 1:9) to afford methyl ether 26 (0.7 g, 78%) as a colorless oil.
IR (neat): 3450, 2927, 1636, 1456, 1257, 1097, 1033, 699 cm–1.
[α]D25 –0.47 (c 0.35, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H), 6.26–5.99 (m,
2 H), 5.72–5.35 (m, 2 H), 4.78 (d, J = 6.7 Hz, 1 H), 4.65 (d, J = 6.7
Hz, 1 H), 4.61–4.45 (m, 1 H), 4.52 (s, 2 H), 4.03–3.79 (m, 2 H),
3.77–3.48 (m, 3 H), 3.38 (s, 3 H), 3.24 (s, 3 H), 2.63–2.51 (m, 1 H),
1.68–1.49 (m, 4 H), 1.08 (d, J = 6.9 Hz, 3 H), 0.89 (s, 9 H), 0.05 (d,
J = 1.5 Hz, 6 H).
[α]D25 –7.52 (c 0.35, CHCl3).
IR (neat): 3452, 2924, 2853, 1711, 1457, 1372, 1224, 1102, 1037,
945, 757, 669 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 7.22–6.98 (m,
1 H), 6.26–5.90 (m, 1 H), 5.91 (t, J = 7.5 Hz, 1 H), 5.72–5.58 (m, 1
H), 5.55–5.35 (m, 1 H), 4.79 (d, J = 6.7 Hz, 1 H), 4.65 (d, J = 6.7
Hz, 1 H), 4.52 (s, 2 H), 4.59–4.47 (m, 1 H), 4.19 (q, J = 7.5 Hz, 2
H), 3.70–3.46 (m, 3 H), 3.38 (s, 3 H), 3.24 (s, 3 H), 2.61–2.41 (m, 3
H), 1.89 (s, 3 H), 1.29 (t, J = 7.5 Hz, 3 H), 1.18–1.13 (m, 2 H), 1.07
(d, J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.1, 140.9, 138.5, 137.0, 135.5,
132.9, 130.6, 129.1, 128.2, 127.5, 126.9, 96.6, 86.0, 74.4, 72.6,
66.3, 60.0, 56.0, 55.2, 39.5, 35.6, 31.9, 29.6, 22.6, 14.2, 12.1.
13C NMR (75 MHz, CDCl3): δ = 138.2, 135.8, 132.0, 130.0, 128.4,
128.2, 127.8, 127.5, 96.6, 82.0, 79.9, 78.3, 73.2, 63.2, 56.8, 55.6,
40.7, 31.9, 29.6, 25.9, 16.5, 14.1, –5.3.
HRMS (ESI): m/z [M + Na]+ calcd for C27H40O6Na: 483.2717;
found: 483.2716.
MS (ESI): m/z = 516 [M + Na]+.
Acknowledgment
(4S,5E,7E,9S,10S)-11-(Benzyloxy)-4-methoxy-10-(methoxy-
methoxy)-9-methylundeca-5,7-dien-1-ol (27)
Ch. G. thanks CSIR, New Delhi for the award of a fellowship.
To a stirred solution of compound 26 (0.67 g, 1.36 mmol) in anhy-
drous THF, TBAF (1.63 mL, 1.6 mmol, 1 M in THF) was added
slowly at 0 °C. After completion of the reaction as indicated by
TLC, the mixture was concentrated under reduced pressure and the
residue subjected to column chromatography (EtOAc–hexane, 3:7)
to yield the pure product 27 (0.34 g, 67%) as a colorless liquid.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
[α]D25 –48.66 (c 0.15, CHCl3).
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IR (neat): 3445, 2923, 2856, 1728, 1632, 1452, 1367, 1147, 1097,
1032, 994, 916, 741, 698 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H), 6.26–6.01 (m,
2 H), 5.72–5.39 (m, 2 H), 4.78 (d, J = 6.6 Hz, 1 H), 4.70–4.60 (m, 1
H), 4.56–4.48 (m, 3 H), 3.69–3.46 (m, 5 H), 3.38 (s, 3 H), 3.24 (s, 3
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38.8, 32.5, 28.8, 16.5.
MS (ESI): m/z = 401 [M + Na]+.
Ethyl (2Z,6S,7E,9E,11S,12S)-13-(Benzyloxy)-6-methoxy-12-
(methoxymethoxy)-2,11-dimethyltrideca-2,7,9-trienoate (28)
Oxalyl chloride (1.3 mL, 1.6 mmol) was added dropwise at –78 °C
to a solution of DMSO (0.23 mL, 3.2 mmol) in anhydrous CH2Cl2
(10 mL). The mixture was stirred for 25 min at this temperature and
then a solution of 27 (0.31 g, 0.8 mmol) in anhydrous CH2Cl2 (3
mL) was added. The mixture was stirred for 1 h at –78 °C. After ad-
dition of Et3N (0.68 mL, 4.9 mmol), the mixture was stirred for 15
min at –78 °C and then for 20 min at 0 °C. The reaction mixture was
then diluted with H2O (10 mL) and CH2Cl2 (20 mL). The organic
layer was separated and washed with brine (10 mL), dried over
Na2SO4, and concentrated in vacuo to afford a crude aldehyde,
which was used in the next step without further purification.
A solution of the phosphonate S-I (0.09 g, 0.23 mmol) in anhydrous
THF (5 mL) was added to an ice-cold suspension of NaH (0.015 g,
0.66 mmol) in THF (5 mL). After the mixture had been stirred for
30 min at 0 °C, it was cooled to –78 °C, and then a solution of the
above aldehyde (0.1 g, 0.26 mmol) in anhydrous THF (6 mL) was
added dropwise along with a catalytic amount of 18-crown-6. The
mixture was stirred for 1 h, diluted with Et2O (5 mL) and quenched
by the slow addition of H2O (4 mL). The layers were separated, and
the aq phase extracted with Et2O (2 × 10 mL). The organic extract
was washed with brine (5 mL), dried over anhydrous Na2SO4 and
concentrated in vacuo. The crude residue was purified by column
chromatography on silica gel (EtOAc–PE, 0.3:9.7) to give α,β-un-
saturated ester 28 (0.09 g, 75%) as a viscous liquid.
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© Georg Thieme Verlag Stuttgart · New York
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Synthesis 2014, 46, 110–118
© Georg Thieme Verlag Stuttgart · New York