Synthesis of C13-C23 fragment of Iriomoteolide-1a

Article abstract of DOI:10.1055/s-0029-1218152

Highly efficient asymmetric conjugate addition of MeMgBr to α,β-unsaturated esters catalyzed by CuI/To1-BINAP, Paterson aldol, organocatalytic aldol, and cross-metathesis reactions were applied in the synthesis of C13-C23 fragment of Iriomoteolide-la.

Full text of DOI:10.1055/s-0029-1218152

PAPER
3557
Synthesis of C13–C23 Fragment of Iriomoteolide-1a
Synthesis of
C
h
13–C23 Frag
u
ment of Irio
n
moteolide-1a-Yi Wang, Yen-Jin Chin, Teck-Peng Loh*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
Fax +65(6513)8203; E-mail: teckpeng@ntu.edu.sg
Received 8 September 2009
macrolide 1 has interesting structure, containing a 20-
Abstract: Highly efficient asymmetric conjugate addition of
membered ring, nine stereogenic centers, of which two of
MeMgBr to a,b-unsaturated esters catalyzed by CuI/Tol-BINAP,
them are quartenary centers, a cis-conjugated ester, four
Paterson aldol, organocatalytic aldol, and cross-metathesis reac-
hydroxy groups, and six methyls. Due to its interesting
biological activities and challenging structures, it has been
a popular target of total synthesis. Very recently, the
Yang’s group reported a short synthesis of C1–C12 frag-
ment of 1.5
tions were applied in the synthesis of C13–C23 fragment of Iriomo-
teolide-1a.
Key words: asymmetric conjugate addition, organocatalytic aldol,
cross-metathesis, Iriomoteolide-1a
Our retrosynthetic analysis of Iriomoteolide-1a is outlined
in Scheme 1. We envisioned a metal-mediated allylation
of aldehyde 3 using allylic metal generated species from 4
followed by oxidation allowing the formation of 2. Sub-
unit 3 could be obtained from 5. Disconnection of the ole-
finic position of 5 by olefin cross metathesis (CM) will
result in two key fragments 6 and 7. Herein, we report a
successful synthesis of 5 using a strategy based on our
group’s asymmetric conjugate addition,6–10 Paterson al-
Iriomoteolide-1a (1),1 -1b, and -1c2 were isolated from the
sea of Iriomote Island, Japan by Tsuda’s group in 2007.
These macrolides belong to the class of amphidinolides
obtained from Amphidinium sp.3,4 Iriomoteolide-1a has
been shown to exhibit potent cytotoxic activity against hu-
man B lymphocyte DG-75 cells (IC50: 0.002 mg/mL), of
which the cytotoxicity has been shown to be equal to that
of amphidinolide H.3This new type of potent cytotoxic
OH
OH
OTBDPS
OH
20
12
16
19
21
13
14
18
22
OH15
17
11
23
O
O
O
10
O
O
O
1
9
H
6
5
SETO
2
8
4
3
7
OH
TBSO
OH
2
Iriomoteolide-1a
1
OTBDPS
O
OTBDPS
OH
O
(S)
(S)
(R)
(R)
(R)
(S)
(S)
PMBO
+
H
O
PMBO
3
5
X
O
OTES
OH
TBSO
O
OTBDPS
OH
4
(R)
(S)
(S)
(S)
(R)
(S)
(R)
+
O
6
PMBO
7
Scheme 1 Retrosynthetic analysis of Iriomoteolide-1a
SYNTHESIS 2009, No. 21, pp 3557–3564
x
x.
x
x
.
2
0
0
9
Advanced online publication: 07.10.2009
DOI: 10.1055/s-0029-1218152; Art ID: C13509SS
© Georg Thieme Verlag Stuttgart · New York

3558
S.-Y. Wang et al.
PAPER
OTBDPS
this catalytic system.6,7 Subsequently, DIBAL-H reduction
of the b-methyl ester 11 afforded the corresponding alde-
hyde 12 in 85% yield.
OH
1) DIBAL-H, hexanes
EtO
TBSDPCl, imidazole
EtO
–78 °C
DMF, 0 °C to r.t., 24h
(S)
2) Ph3P=CHCO2Me, THF
65%
O
O
99%
Next, we investigated the Paterson aldol reaction of 12
with (S)-ethyl lactate (8)-derived ethyl ketone 13
(Table 1).11 With minor modification of the reported con-
ditions, the desired aldol product 14 was obtained in 85%
yield with high level of diastereoselectivity (>95% de)
(Table 1, entry 4).
9
8
(E/Z = 4:1)
OTBDPS
OTBDPS
MeMgBr
MeO
MeO
CuI, (R)-Tol-BINAP
–20 °C
O
O
60%
10
11
Table 1 Synthesis of 14
(S)
BzO
DIBAL-H, hexanes
–78 °C
OTBDPS
O
H
O
13
OTBDPS
85%
1) (c-HexB)2Cl, Me2NEt
(S)
(R)
–78 °C then 0 °C
12
(S)
(S)
+
(R)
BzO
2) –22 °C, 20 h
O
OH
Scheme 2 Synthesis of 12 using asymmetric conjugate addition of
OTBDPS
MeMgBr as the key step
14
(S)
H
(S)
dol, organocatalytic aldol, and an intermolecular olefin
cross-metathesis reaction.
O
12
First, we focused on the synthesis of the key fragment 7.
Our synthesis commenced from the commercially avail-
able (S)-ethyl lactate (8) (Scheme 2). Protection of the lac-
tate 8 using TBDPSCl, followed by a one-pot DIBAL-H
reduction and Wittig olefination afforded the desired
conjugated ester 10 (E/Z = 4:1) in 65% yield over three
steps (Scheme 2). With the E-enoate 10 in hand, we ex-
plored the CuI/Tol-BINAP catalyzed asymmetric conju-
gate addition (ACA) of 10 with MeMgBr. To our delight,
the reaction of 10 with MeMgBr in the presence of 2
mol% CuI and 3 mol% (R)-Tol-BINAP at –20 °C afford-
ed the desired b-methyl ester 11 in 60% isolated yield
with more than 98:2 diastereoselectivity. The absolute
configuration of the newly generated C21 stereogenic
center was assigned as S by analogy to that reported for
Entry
12/13/Me2NEt/(c-HexB)2Cl
1.0:1.0:2.0:2.0
Yield (%)a
1
2
3
4
40
1.0:1.5:2.0:2.0
45
1.0:1.0:1.5:1.5
40
1.3:1.0:1.5:1.5
85 (>95%)b
a Isolated yields.
b The percentage de was determined on the crude product by NMR
spectroscopy.
Subsequently, the hydroxy group was protected by PMB-
TCA catalyzed by 3 mol% Sc(OTf)3 to afford the desired
compound 15 in 64% yield.12 After PMB protection, alde-
OR1
OR1
OR1
PMBTCA
DIBAL-H, CH2Cl2
Sc(OTf)3 (3 mol%)
–78 °C
HO
THF, 0 °C
BzO
BzO
OH OR2
OR2
64%
O
OH
14
O
16
15
OR1
OR1
Ph3PCH2OMeCl
LiHDMS, THF
0 °C to r.t.
NaIO4, MeOH–H2O
0 °C to r.t.
6 N HCl, EtOAc
two steps, 63%
MeO
H
two steps, 78%
OR2
O
OR2
17
18
NH
OR1
Ph3PMeBr
n-BuLi, THF
–78 °C to r.t.
OR1
O
O
CCl3
(S)
(R)
(S)
(S)
H
MeO
PMBTCA
80%
OR2
OR2
R1 = TBDPS
2 = PMB
19
7
R
Scheme 3 Synthesis of 7
Synthesis 2009, No. 21, 3557–3564 © Thieme Stuttgart · New York

PAPER
Synthesis of C13–C23 Fragment of Iriomoteolide-1a
3559
catalyzed by 5 mol% camphorsulfonic acid (CSA) to gen-
erate 23 in 90% yield. Next, the mixture of tertiary allylic
alcohol diasteromer was obtained in 84% yield by treating
23 with excess of vinylmagnesium bromide (dr = 5:1).
The favored desired diastereomer (R,R,R)-6, could be eas-
ily separated by column chromatography on silica gel
(70% yield). After PMB protection of 6, the olefin 24 was
obtained in 88% yield.
O
OH
O
21
HO
MeO
OMe
CHO
(R)
(R)
D-proline, DMSO
63%
OH
CSA (5 mol%)
CH2Cl2, r.t.
90%
20
22
O
OH
O
O
(S)
(R)
With the tertiary allylic alcohol in hand, the cross-meta-
thesis of 7 and 24 catalyzed by the Hoveyda–Grubbs 2nd
generation catalyst 25 was attempted.14 Unfortunately, we
failed to get the cross-metathesis (CM) product for the
bulky-protected tertiary alcohol. Fortunately, the desired
CM product 5 was formed in 60% yield (based on recov-
ered starting material) with excellent stereoselectivity
(>95% E-isomer) when 7 was subjected to cross metathe-
sis with 2.0 equivalents of the free allylic alcohol 6 under
identical conditions (Scheme 5).15
BrMg
(R)
(S)
(R)
O
THF, 0 °C
70% (dr = 5:1)
O
6 (major product)
23
O
OPMB
NaH, PMBCl
DMF, 0 °C to r.t., 24 h
(S)
(R)
(R)
O
88%
In conclusion, we have successfully synthesized C13–
C23 fragment of Iriomoteolide-1a (1) using the efficient
and enantioselective CuI/Tol-BINAP catalyzed ACA of
MeMgBr to a,b-unsaturated esters, Paterson’s aldol, List
aldol, and cross-metathesis reaction. Further investiga-
tions will be directed towards the syntheses of fragment 4
and completion of the total synthesis of 1 and analogues.
Studies along these lines are in progress.
24
Scheme 4 Synthesis of 24
hyde 17 was then generated via DIBAL-H reduction fol-
lowed by oxidative cleavage (78% from 15).
Subsequently, aldehyde 17 was subjected to Wittig ho-
mologation using methoxymethylenetriphenylphospho-
rane by employing LiHMDS as the base to generate the
methyl ether 18. Treatment of 18 with aqueous 6 N HCl in
ethyl acetate furnished the desired aldehyde 19 in 63%
yield over two steps. Another one-carbon homologation
of 19 afforded 7 in 80% yield (Scheme 3).
Experiments involving moisture- or air-sensitive components were
performed in oven-dried glassware under a positive pressure of ni-
trogen using freshly distilled solvents. Commercial grade solvents
and reagents were used without further purification unless other-
wise indicated. Infrared spectra were recorded on a Bio-Rad FTS
165 FTIR spectrometer. The oil samples were examined under neat
conditions. High-resolution mass spectra (HRMS) were obtained
using Finnigan MAT95XP GC/HRMS (Thermo Electron Corpora-
tion). NMR spectra were recorded on a Bruker Avance DPX 300, a
Bruker AMX 400 or a Bruker AMX 500 spectrophotometer (CDCl3
as solvent). Chemical shifts for NMR spectra are reported as d in
units of parts per million (ppm) downfield from SiMe4 (d = 0.0
For the synthesis of enantiomerically enriched fragment
of 6, we employed the List aldol reaction of cyclohexane-
carboxaldehyde (20) with hydroxyacetone (21) catalyzed
by D-proline (Scheme 4).13 The desired aldol product
(R,R)-22 was obtained in high diastereoselectivity (dr
>20:1) and high ee (>99%). Subsequently, the dihydroxy
function of 22 was protected by 2,2-dimethoxypropane
N
N
Cl
Ru
O
Cl
Hoveyda-Grubbs 2nd generation catalyst 25
O
OR
(S)
(R)
(R)
O
O
OTBDPS
OR
R = PMB, 24
R = H, 6
25 (8 mol%)
CH2Cl2, reflux
O
PMBO
+
OTBDPS
R = PMB, no desired product
R = H, 5, yield: 38% (based on recovered S.M. 60%)
PMBO
7
Scheme 5 Synthesis of 5
Synthesis 2009, No. 21, 3557–3564 © Thieme Stuttgart · New York

3560
S.-Y. Wang et al.
PAPER
Methyl (3S,4S)-4-(tert-Butyldiphenylsilyloxy)-3-methylpen-
ppm) and relative to the signal of chloroform-d (d = 7.2600 ppm,
singlet, for 1H NMR; d = 77.0 ppm, triplet, for 13C NMR). Coupling
constants are reported as a J value in Hz. The proportion of diaste-
reomers and geometric isomers was determined from the integra-
tion of 1H NMR and 13C NMR spectra.
tanoate (11)
In a round-bottomed flask equipped with a septum and a stirring bar,
(R)-Tol-BINAP (0.408 g, 0.6 mmol) and CuI (0.076 g, 0.4 mmol)
were stirred in CH2Cl2 (10 mL) for 20 min, concentrated in vacuo,
and then stirred in t-BuOMe (80 mL) till a bright yellow suspension
was observed. The mixture was then cooled to –20 °C and MeMgBr
(20.0 mL, Aldrich 3.0 M solution in Et2O, 60.0 mmol) was added
carefully. After stirring for 15 min, a solution of E-10 (7.37 g, 20
mmol) in t-BuOMe (24 mL) was added dropwise over 10 h via a sy-
ringe pump. After stirring at –20 °C for an additional 1 h, the mix-
ture was quenched with MeOH (30 mL) and sat. aq NH4Cl (100
mL). The aqueous layer was extracted with Et2O (3 × 100 mL) and
the combined organic extracts were dried (Na2SO4), filtered, and
concentrated in vacuo. The resulting residue was purified by flash
chromatography (100:1 hexanes–EtOAc) to afford the desired prod-
uct 11 as a colorless oil (4.61 g, 60%); Rf = 0.73 (EtOAc–hexanes,
1:4); [a]D20 –8.4 (c = 1.2, CHCl3).
Ethyl (S)-2-(tert-Butyldiphenylsilyloxy)propanoate (9)
To a solution of ethyl (S)-(+)-lactate (8; 10.40 g, 100.0 mmol) in
DMF (200 mL) was added imidazole (10.20 g, 150 mmol), followed
by the addition of TBDPSCl (14.5 g, 96.1 mmol) in one portion at
0 °C. The reaction mixture was warmed to r.t. and stirred for 24 h.
After cooling to 0 °C, the mixture was poured into aq 0.5 N HCl
(50 mL) and extracted with EtOAc (3 × 100 mL). The combined or-
ganic extracts were successively washed with H2O (150 mL) and
brine (80 mL), and dried (MgSO4). The solvent was removed under
reduced pressure to give 35.60 g (quant) of crude silyl ether 9 as a
colorless liquid. The material was used in the next step after purifi-
cation through a pad of silica gel (EtOAc–hexanes, 1:10); Rf = 0.75
(EtOAc–hexanes, 1:4); [a]D20 –47.6 (c = 1.3, CHCl3).
FTIR (KBr, neat): 3070, 2960, 2929, 1737 (C=O), 1280, 1109, 702
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.66–7.82 (m, 4 H), 7.36–7.44 (m,
6 H), 7.79–3.82 (m, 1 H), 3.65 (s, 3 H), 2.61–2.65 (m, 1 H), 2.04–
2.16 (m, 2 H), 1.07 (s, 9 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.88 (d,
J = 6.5 Hz, 3 H).
FTIR (KBr, neat): 3070, 2980, 2958, 2893, 2858, 1753 (C=O),
1427, 1136, 1111, 702 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.66–7.67 (m, 4 H), 7.35–7.43 (m,
6 H), 4.25 (q, J = 6.5 Hz, 1 H), 4.02 (dq, J = 7.5, 1.5 Hz, 2 H), 1.37
(d, J = 6.5 Hz, 2 H), 1.15 (d, J = 7.5 Hz, 2 H), 1.10 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 173.8 135.9, 135.7, 133.6, 133.2,
13C NMR (125 MHz, CDCl3): d = 174.1, 135.9, 134.7, 133.9, 129.6,
129.4, 127.6, 127.4, 72.0, 51.4, 51.4, 37.1, 36.8, 27.0, 19.3, 19.1,
14.9.
129.7, 127.6, 127.5, 69.0, 60.6, 26.8, 21.2, 19.2, 14.0.
HRMS: m/z calcd for C21H29O3Si [M + 1]: 379.1705; found:
379.1716.
HRMS: m/z calcd for C23H33O3Si [M + 1]: 385.2199; found:
385.2206.
Methyl (S,E)-4-(tert-Butyldiphenylsilyloxy)pent-2-enoate (10)
In a round-bottomed flask equipped with a stirring bar, ester 9
(19.11 g, 50.0 mmol) was dissolved in hexanes (50 mL) and cooled
to –78 °C. DIBAL-H (Aldrich 1 M solution in heptane, 52.5 mL,
52.5 mmol), precooled to –78 °C, was added carefully over several
portions. After stirring for another 1.0 h, MeOH (6.5 mL), pre-
cooled to –78 °C, was added carefully in one portion and stirred for
a further 0.5 h till a white suspension was observed. Methyl (tri-
phenylphosphoranylidene)acetate (25.0 g, 75.0 mmol) was added in
one portion, followed by THF (50 mL) and the reaction mixture was
allowed to warm to r.t. and then allowed to reflux for an additional
6 h. The mixture was then cooled to r.t., carefully diluted with
EtOAc (100 mL) and sat. aq potassium sodium tartrate (200 mL),
and stirred vigorously at r.t. till a clear biphasic separation was ob-
served. The aqueous layer was extracted with EtOAc (2 × 200 mL)
and the combined organics were dried (Na2SO4), filtered, and con-
centrated in vacuo. The Ph3PO was removed by filtering through a
short silica plug using hexanes. The filtrate was concentrated and
purified by flash chromatography (hexanes to 200:1 hexanes–
EtOAc) to afford the desired E-enoate 10 as a colorless oil (12.42 g,
65%; 81% for the mixture of E/Z-isomers, 80:20); Rf = 0.72
(EtOAc–hexanes, 1:4); [a]D20 –41.8 (c = 0.9, CHCl3).
(3S,4S)-4-(tert-Butyldiphenylsilyloxy)-3-methylpentanal (12)
In a round-bottomed flask equipped with a stirring bar, the ester 11
(3.84 g, 10.0 mmol) was dissolved in hexanes (10 mL) and cooled
to –78 °C. DIBAL-H (Aldrich 1 M solution in heptane, 11.0 mL,
11.0 mmol), precooled to –78 °C, was added carefully. After stir-
ring for another 1.0 h, the reaction was quenched with sat. aq potas-
sium sodium tartrate (50 mL), warmed to r.t., and stirred vigorously
till a clear biphasic separation was observed. The aqueous layer was
extracted with EtOAc (2 × 200 mL), and the combined organics
were dried (Na2SO4), filtered, and concentrated in vacuo. The resi-
due was purified by flash chromatography (hexanes to 50:1 hex-
anes–EtOAc) to afford the desired 12 as a colorless oil (3.00 g,
85%); Rf = 0.70 (EtOAc–hexanes, 1:4); [a]D20 –10.5 (c = 0.8,
CHCl3).
FTIR (KBr, neat): 3070, 2959, 2929, 2891, 2858, 1722 (C=O),
1110, 702 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.73 (s, 1 H), 7.68–7.70 (m, 4 H),
7.38–7.45 (m, 6 H), 3.84–3.86 (m, 1 H), 2.65–2.67 (m, 1 H), 2.18–
2.25 (m, 2 H), 1.08 (s, 9 H), 0.97 (d, J = 6.5 Hz, 3 H), 0.87 (d,
J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 202.8, 135.9, 135.8, 134.4, 133.8,
129.7, 129.6, 127.6, 127.4, 72.1, 46.2, 34.9, 27.0, 19.2, 18.4, 15.6.
FTIR (KBr, neat): 3070, 2954, 2927, 1703 (C=O), 1427, 1112, 700
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.64–7.71 (m, 4 H), 7.36–7.45 (m,
6 H), 6.93 (dd, J = 15.5, 4.4 Hz, 1 H), 6.93 (dd, J = 15.5, 1.5 Hz, 1
H), 4.45–4.51 (m, 6 H), 1.14 (d, J = 10.5 Hz, 3 H), 1.10 (s, 9 H).
13C NMR (125 MHz, CDCl3): d = 167.2, 151.8, 135.8, 135.7, 134.0,
133.3, 129.8, 127.6, 127.6, 118.6, 68.6, 51.5, 27.0, 23.3, 19.2.
HRMS: m/z calcd for C22H31O2Si [M + 1]: 355.2093; found:
355.2092.
(S)-3-Oxopentan-2-yl Benzoate (13)
To a cooled (–20 °C) mixture of ethyl (S)-lactate (8; 8.0 g, 67.6
mmol) and MeON(Me)H·HCl (16.4 g, 168 mmol) in THF (200 mL)
was added a 2 M solution of i-PrMgCl in Et2O (168 mL) dropwise
over 30 min. The reaction mixture was stirred at –20 °C for 30 min
and at 0 °C for a further 30 min before sat. aq NH4Cl (500 mL) was
added. The mixture was extracted with Et2O (4 × 150 mL), fol-
lowed by CH2Cl2 (4 × 150 mL). The combined organic extracts
were dried (MgSO4), concentrated in vacuo, and the residue was pu-
HRMS: m/z calcd for C22H28O3Si + Na [M + Na]: 391.1705; found:
391.1729.
Synthesis 2009, No. 21, 3557–3564 © Thieme Stuttgart · New York

PAPER
Synthesis of C13–C23 Fragment of Iriomoteolide-1a
3561
rified by column chromatography (EtOAc–hexanes, 50:50) to give
the intermediate Weinreb amide (7.19 g, 80%) as a colorless oil. To
a cooled (0 °C) solution of this amide (2.0 g, 15.0 mmol) in THF (30
mL) was added a 3 M solution of EtMgBr in Et2O (16 mL) and the
reaction mixture was allowed to warm to r.t. After 1 h, sat. aq
NH4Cl (80 mL) was added and the mixture was extracted with Et2O
(40 mL), followed by CH2Cl2 (2 × 40 mL). The combined organic
extracts were dried (MgSO4) and concentrated. Then, CH2Cl2 (100
mL) was added. To this solution was added Bz2O (5.11 g, 22.6
mmol), DMAP (0.20 g, 1.64 mmol), and i-Pr2NEt (5.0 mL, 28.6
mmol). After stirring for 14 h, excess Bz2O was removed by the ad-
dition of ethylenediamine (1.0 g, 16.6 mmol). H2O (80 mL) was
added, the mixture extracted with Et2O (4 × 40 mL); the combined
organic extracts were dried (MgSO4), and concentrated to an oil.
Column chromatography (20% EtOAc in hexanes) afforded (S)-13
(2.17 g, 70%) as a colorless oil; Rf = 0.52 (EtOAc–hexanes, 1:4);
[a]D20 +24.4 (c = 0.6, CHCl3) {Lit.11b [a]D20 +25.1 (c = 4.6,
CHCl3)}.
equiv) and PMBTCA (0.423g, 1.5 mmol, 1.5 equiv) in THF (20
mL) at 0 °C. After stirring for 12 h, the reaction was quenched by
the addition of aq NaHCO3 (20 mL) and the phases were separated.
The aqueous phase was extracted with EtOAc (3 × 20 mL) and the
combined organic phases were dried (MgSO4), and concentrated in
vacuo. Flash column chromatography of the residue (hexanes–
EtOAc, gradient elution, 50:1 to 20:1) afforded PMB ether 15
(0.435 g, 64%) as a pale yellow oil; Rf = 0.62 (EtOAc–
hexanes, 1:4); [a]D20 –15 (c = 0.7, CHCl3).
FTIR (KBr, neat): 3068, 2962, 2931, 2893, 2858, 1722 (C=O), 1714
(C=O), 1265, 1111, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.09 (d, J = 7.6 Hz, 2 H), 7.67–
7.69 (m, 4 H), 7.56–7.60 (m, 1 H), 7.35–7.48 (m, 8 H), 7.16 (d,
J = 8.8 Hz, 2 H), 6.83 (d, J = 8.8 Hz, 2 H), 5.38 (q, J = 6.8 Hz, 3
H), 4.21 (d, J = 10.8 Hz, 1 H), 4.18 (d, J = 10.8 Hz, 1 H), 3.79–3.81
(m, 1 H), 3.77 (s, 3 H), 3.66–3.71 (m, 1 H), 2.99–3.07 (m, 1 H), 1.94
(dt, J = 14.4, 4.8 Hz, 1 H), 1.64–1.70 (m, 1 H), 1.44 (d, J = 7.2 Hz,
3 H), 1.24–1.33 (m, 2 H), 1.11 (d, J = 7.2 Hz, 3 H), 1.05 (s, 9 H),
0.94 (d, J = 6.6 Hz, 3 H), 0.90 (d, J = 6.4 Hz, 3 H).
13C NMR (100.0 MHz, CDCl3): d = 209.6, 165.7, 159.0, 135.9,
135.8, 134.8, 134.1, 133.2, 130.5, 129.8, 129.4, 129.3, 128.4, 127.6,
127.4, 113.7, 113.5, 79.7, 74.9, 72.4, 72.3, 55.1, 48.3, 36.7, 35.1,
27.0, 19.7, 19.3, 15.8, 15.2, 13.7.
FTIR (KBr, neat): 3062, 2981, 2939, 1720 (C=O), 1716 (C=O),
1452, 1269, 1109, 1026, 711 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.05–8.07 (m, 2 H), 7.41–7.59 (m,
3 H), 5.33 (q, J = 7.2 Hz, 2 H), 2.46–2.68 (m, 2 H), 1.51 (d, J = 7.0
Hz, 2 H), 1.07 (t, J = 7.2 Hz, 3 H).
13C NMR (75.4 MHz, CDCl3): d = 208.4, 165.8, 133.3, 129.7,
129.4, 128.4, 75.0, 31.4, 16.4, 7.1.
HRMS: m/z calcd for C42H52O6Si + Na [M + Na]: 703.3431; found:
703.3442.
HRMS: m/z calcd for C12H15O3 [M + 1]: 207.1013; found:
207.1021.
(2S,4S,5R,7S,8S)-8-(tert-Butyldiphenylsilyloxy)-5-(4-methoxy-
benzyloxy)-4,7-dimethylnonane-2,3-diol (16)
(2S,4R,5R,7S,8S)-8-(tert-Butyldiphenylsilyloxy)-5-hydroxy-4,7-
dimethyl-3-oxononan-2-yl Benzoate (14)
In a round-bottomed flask equipped with a stirring bar, the ester 15
(1.36 g, 2.0 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to
–78 °C. DIBAL-H (Aldrich 1 M solution in heptane, 6.0 mL, 6.0
mmol), precooled to –78 °C, was added dropwise. After stirring for
another 1.0 h, the reaction was quenched with sat. aq potassium so-
dium tartrate (50 mL), warmed to r.t., and stirred vigorously till a
clear biphasic separation was observed. The aqueous layer was ex-
tracted with CH2Cl2 (3 × 15 mL), and the combined organic were
dried (Na2SO4), filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (5:1 hexanes–EtOAc) to af-
ford the desired diol 16 as a colorless oil (0.98 g); Rf = 0.13 and 0.14
(EtOAc–hexanes, 1:4); [a]D20 –7.7 (c = 1.2, CHCl3).
To a stirred solution (–78 °C) of 13 (2.06 g, 10.0 mmol) in Et2O (40
mL) was added chlorodicyclohexylborane (15.0 mL, 1 M in hex-
anes, 15.0 mmol) and Me2NEt (1.5 mL, 15 mmol). The mixture was
warmed to 0 °C, stirred for 2 h, and then recooled to –78 °C. A so-
lution of aldehyde 12 (4.60 g, 13.0 mmol) in Et2O (10 mL) was add-
ed dropwise over 2 min. After 2 h, the reaction mixture was kept in
the freezer (–24 °C) for 20 h. The mixture was warmed to 0 °C and
quenched by dropwise addition of MeOH (30 mL), pH 7 phosphate
buffer (30 mL), and 35% H2O2 (30 mL), and stirred for 1 h at r.t.
H2O (100 mL) was added, the organic layer was separated and the
aqueous layer extracted with Et2O (3 × 80 mL). The combined or-
ganics were washed with brine (60 mL), dried (MgSO4), filtered,
and evaporated in vacuo. Silica gel chromatography (hexanes–
EtOAc, gradient elution, 50:1 to 20:1) afforded alcohol 14 in 85%
yield (4.76 g, 8.5 mmol) as a colorless solid; Rf = 0.48 (EtOAc–
hexanes, 1:4); [a]D20 +9.6 (c = 0.9, CHCl3).
FTIR (KBr, neat): 3417, 3072, 2962, 2989, 1651, 1643, 1247, 1109,
665 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.68 (m, 10 H), 7.29 (d,
J = 8.4 Hz, 0.68 H), 7.16 (d, J = 8.4 Hz, 1.32 H), 6.85 (d, J = 8.4
Hz, 0.68 H), 6.81 (d, J = 8.4 Hz, 1.32 H), 4.68–4.70 (m, 2 H), 4.27–
4.44 (m, 2 H), 3.55–3.58 (m, 1 H), 2.72 (s, 0.33 H), 2.48 (s, 0.67 H),
2.23 (s, 0.67 H), 2.20 (s, 0.33 H), 1.53–1.90 (m, 4 H), 1.11 (d,
J = 7.0 Hz, 2 H), 1.06 (4) (s, 3 H), 1.05 (7) (s, 6 H), 1.04 (d, J = 7.0
Hz, 1 H), 0.97 (d, J = 7.0 Hz, 2 H), 0.90–0.93 (m, 5 H), 0.81 (d,
J = 7.2 Hz, 2 H).
13C NMR (100.0 MHz, CDCl3): d = 159.3, 159.1, 136.0, 135.9,
134.7, 134.6, 130.4, 130.1, 129.5, 129.4, 128.5, 127.6, 127.5, 127.4,
127.0, 113.8, 113.7, 83.4, 80.2, 76.2, 75.1, 72.6, 72.3, 72.2, 71.0,
68.9, 68.0, 65.3, 55.2 (5), 55.2 (2), 38.6, 37.0, 36.4, 34.6, 33.2, 27.0,
21.0, 20.0, 19.4, 19.3, 18.4, 15.8, 15.5, 14.5, 13.5, 12.0, 11.4.
FTIR (KBr, neat): 3522, 3047, 2962, 2931, 2893, 2856, 1722
(C=O), 1714 (C=O), 1379, 1267, 1111, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.11 (d J = 7.6 Hz, 2 H), 7.37–
7.69 (m, 13 H), 5.42 (q, J = 6.8 Hz, 1 H), 3.82–3.89 (m, 2 H), 2.80
(s, 1 H), 2.76–2.78 (m, 1 H), 1.73–1.95 (m, 2 H), 1.56 (d, J = 7.2
Hz, 3 H), 1.24–1.30 (m, 1 H), 1.23 (d, J = 7.2 Hz, 3 H), 1.07 (s, 9
H), 0.97 (d, J = 6.4 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3 H).
13C NMR (75.4 MHz, CDCl3): d = 211.7, 165.8, 135.9, 135.9,
135.7, 134.4, 133.8, 133.2, 129.7, 129.6, 129.5, 129.5, 128.4, 127.6,
127.4, 74.7, 72.2, 72.0, 48.8, 37.4, 36.4, 27.0, 19.2, 18.8, 16.8, 15.6,
14.4.
HRMS: m/z calcd for C35H51O5Si [M]: 579.3506; found: 579.3521.
HRMS: m/z calcd for C34H45O5Si [M + 1]: 561.3036; found:
561.3011.
(2R,3R,5S,6S)-6-(tert-Butyldiphenylsilyloxy)-3-(4-methoxyben-
zyloxy)-2,5-dimethylheptanal (17)
To a stirred solution (0 °C) of the diol 16 (0.98 g, 1.7 mmol) in
MeOH (16 mL) and H2O (16 mL) was added NaIO4 (2.16 g, 10.2
mmol) in small portions. After complete addition, the mixture was
stirred for 2 h. H2O (80 mL) was added and the mixture was extract-
ed with Et2O (4 × 80 mL). The combined organics were washed
(2S,4R,5R,7S,8S)-8-(tert-Butyldiphenylsilyloxy)-5-(4-methoxy-
benzyloxy)-4,7-dimethyl-3-oxononan-2-yl Benzoate (15)
Sc(OTf)3 (30.0 mg, 0.06 mmol, 0.06 equiv) was added to a stirred
solution of freshly azeotroped alcohol 14 (0.560, 1.0 mmol, 1.0
Synthesis 2009, No. 21, 3557–3564 © Thieme Stuttgart · New York

3562
S.-Y. Wang et al.
PAPER
with brine (80 mL), dried (MgSO4), filtered, and evaporated in
vacuo. Silica gel chromatography (hexanes–EtOAc, 20:1) afforded
aldehyde 17 as a colorless oil (0.83 g, over two steps, 78%);
Rf = 0.58 (EtOAc–hexanes, 1:4); [a]D20 –26.6 (c = 1.3, CHCl3).
100:1) afforded pure 7 as pale yellow oil (80%); Rf = 0.75 (EtOAc–
hexanes, 1:4); [a]D20 –1.9 (c = 1.0, CHCl3).
FTIR (KBr, neat): 3070, 2960, 2929, 2856, 1514, 1427, 1247, 1111
cm–1.
FTIR (KBr, neat): 3062, 2960, 2931, 2856, 1722 (C=O), 1514,
1247, 1037, 740 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.66–7.69 (m, 4 H), 7.31–7.42 (m,
6 H), 7.18 (d, J = 8.4 Hz, 2 H), 6.82 (d, J = 8.4 Hz, 2 H), 5.72–5.80
(m, 1 H), 4.98–5.01 (m, 2 H), 4.40 (d, J = 13.9 Hz, 1 H), 4.26 (d,
J = 13.9 Hz, 1 H), 3.75–3.81 (m, 4 H), 3.24–3.26 (m, 1 H), 2.05–
2.22 (m, 3 H), 1.71–1.83 (m, 3 H), 1.25–1.32 (m, 2 H), 1.05 (s, 9 H),
0.84–1.02 (m, 9 H).
13C NMR (125.0 MHz, CDCl3): d = 159.0, 137.9, 135.0, 134.3,
131.2, 129.5, 129.4, 115.5, 113.8, 81.5, 72.4, 72.3, 77.8, 55.2, 38.5,
37.4, 36.8, 35.4, 32.4, 30.3, 27.0, 19.8, 19.3, 17.2, 15.7, 14.7.
1H NMR (500 MHz, CDCl3): d = 9.73 (d, J = 2.0 Hz, 2 H), 7.69–
7.40 (m, 4 H), 7.37–7.43 (m, 6 H), 7.24 (d, J = 10.5 Hz, 2 H), 7.88
(d, J = 10.5 Hz, 2 H), 4.49 (d, J = 13.5 Hz, 1 H), 4.40 (d, J = 14.0
Hz, 1 H), 3.74–3.86 (m, 4 H), 3.64–3.66 (m, 1 H), 2.64–2.686 (m, 1
H), 1.45–1.76 (m, 3 H), 1.28 (m, 3 H), 1.07 (s, 9 H), 0.98 (d, J = 8.0
Hz, 3 H), 0.84 (d, J = 8.5 Hz, 3 H).
13C NMR (125.0 MHz, CDCl3): d = 204.7, 159.2, 135.9, 135.8,
1334.9, 134.3, 130.3, 129.5, 129.4, 129.3, 127.5, 113.8, 79.5, 72.8,
71.2, 55.2, 49.3, 40.3, 29.1, 27.0, 26.6, 19.3, 19.2, 15.0, 10.2.
HRMS: m/z calcd for C35H48O3Si + Na [M + Na]: 567.3270; found:
567.3260.
HRMS: m/z calcd for C33H45O4Si [M + 1]: 533.3087; found:
533.3092.
(3R,4R)-4-Cyclohexyl-3,4-dihydroxybutan-2-one (22)
To a mixture of DMSO (80.0 mL) and hydroxyacetone (21; 20 mL)
was added the cyclohexanecarbaldehyde (20; 10.0 mmol) followed
by D-proline (0.35 g, 30 mol%), and the resulting homogeneous re-
action mixture was stirred at r.t. for 60 h. Then, half sat. aq NH4C1
(60 mL) and EtOAc (60 mL) were added with vigorous stirring, the
layers were separated, and the aqueous phase was extracted thor-
oughly with EtOAc (3 × 60 mL). Then, the combined organic phas-
es were washed with H2O (100 mL), brine (100 mL), and dried
(MgSO4). The residue obtained by concentration was purified by
flash column chromatography (hexanes–EtOAc, 5:1, 4:1, 2:1, 1:1)
to afford the anti-diol 22 as a white powder (1.17 g, 63%). The ee
of 22 was determined by HPLC analysis (chiral Daicel Chiralpak
AS, hexanes–i-PrOH, 85:15, flow rate 1.0 mL/min, l = 285 nm):
tR = 7.70 min); Rf = 0.50 (EtOAc–hexanes, 1:1); [a]D20 –81.6
(c = 1.0, CHCl3) {Lit.13 [a]D +83 (c = 1.0, CHCl3), for (3S,4S)-4-
cyclohexyl-3,4-dihydroxybutan-2-one}.
(3S,4R,6S,7S)-7-(tert-Butyldiphenylsilyloxy)-4-(4-methoxyben-
zyloxy)-3,6-dimethyloctanal (19)
Methoxymethyltriphenylphosphonium chloride (0.771 g, 2.25
mmol) was dissolved in anhyd THF (8 mL), and to this solution,
cooled to 0 °C, was slowly added LiN(SiMe3)2 (2.1 mL of a 1 M so-
lution in THF). After stirring 1 h at 0 °C, aldehyde 17 (0.532 g, 1.0
mmol) in anhyd THF (5 mL) was added. After stirring the mixture
overnight at r.t., H2O (10 mL) was added and the two phases were
separated. The aqueous layer was extracted with Et2O (3 × 20 mL),
and the combined organic fractions were collected, dried, and evap-
orated. The crude product was purified by silica gel chromatogra-
phy (hexanes–EtOAc, 100:1) to give the methyl ether 18. This
product was dissolved in EtOAc (4 mL) followed by a solution of
aq 6 N HCl (2 mL). The mixture was stirred at r.t. until the disap-
pearance of 18 as monitored by TLC and then sat. aq NaHCO3
(10 mL) was added. The organic phase was separated, and the aque-
ous layer was extracted several times with EtOAc (3 × 20 mL). The
combined organic fractions were collected and dried, and the sol-
vent was evaporated to give crude aldehyde 19. Silica gel chroma-
tography (hexanes–EtOAc, 100:1) afforded aldehyde 19 as a
colorless oil (over two steps, 63%); Rf = 0.59 (EtOAc–
hexanes, 1:4); [a]D20 –16.7 (c = 0.5, CHCl3).
FTIR (KBr, neat): 3381, 2920, 2850, 1697 (C=O), 1421, 1359,
1076, 1039, 983 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.23 (d, J = 5.4 Hz, 2 H), 3.51–
3.54 (m, 2 H), 2.31 (s, 4 H), 1.53–1.93 (m, 6 H), 1.04–1.29 (m, 5 H).
13C NMR (75.4 MHz, CDCl3): d = 209.8, 78.3, 77.6, 39.8, 29.7,
27.7, 27.4, 26.2, 26.1, 25.8.
FTIR (KBr, neat): 2958, 2929, 2856, 1722 (C=O), 1247 cm–1.
HRMS: m/z calcd for C10H19O3 [M + 1]: 187.1329; found:
1H NMR (500 MHz, CDCl3): d = 9.64 (s, 1 H), 7.64–7.67 (m, 4 H),
7.35–7.43 (m, 6 H), 7.16 (d, J = 8.5 Hz, 2 H), 6.83 (d, J = 8.5 Hz,
2 H), 4.32 (d, J = 11.0 Hz, 1 H), 4.28 (d, J = 11.0 Hz, 1 H), 3.76–
3.80 (m, 4 H), 3.15–3.18 (m, 1 H), 2.17–2.36 (m, 3 H), 1.66–1.71
(m, 1 H), 1.32–1.40 (m, 2 H), 0.95 (s, 9 H), 0.941 (d, J = 6.5 Hz, 3
H), 0.940 (d, J = 6.5 Hz, 3 H), 0.89 (d, J = 7.0 Hz, 3 H).
13C NMR (125.0 MHz, CDCl3): d = 202.4, 159.0, 135.9, 135.8,
134.7, 134.2, 130.6, 129.6, 129.4, 129.3, 127.5, 127.3, 113.6, 80.9,
72.11, 71.0, 55.2, 46.6, 36.7, 33.1, 31.1, 27.0, 19.7, 19.3, 16.5, 15.3.
187.1334.
1-[(4R,5R)-5-Cyclohexyl-2,2-dimethyl-1,3-dioxolan-4-yl]eth-
anone (23)
To a mixture of 22 (1.860 g, 10.0 mmol), 2.2-dimethoxypropane
(10.408 g, 100.0 mmol) and CH2Cl2 (20 mL) was added CSA (0.116
g, 0.05 mmol), and the reaction mixture was stirred at r.t. for over-
night. Then, half sat. aq NaHCO3 (30 mL) and CH2Cl2 (20 mL) add-
ed with vigorous stirring, the layers were separated, and the aqueous
phase was extracted with CH2Cl2 (2 × 20 mL). Then, the combined
organic phases were washed with H2O (50 mL), brine (50 mL), and
dried (MgSO4). The residue obtained by concentration was purified
by flash column chromatography (hexanes–EtOAc, 100:1) to afford
23 in 90% yield (2.042 g) as pale yellow oil; Rf = 0.692 (EtOAc–
hexanes, 1:4); [a]D20 +0.87 (c = 1.2, CHCl3).
HRMS: m/z calcd for C34H46O4Si + Na [M + Na]: 569.3063; found:
569.3083.
tert-Butyl[(2S,3S,5R,6S)-5-(4-methoxybenzyloxy)-3,6-dimethyl-
non-8-en-2-yloxy]diphenylsilane (7)
Methyltriphenylphosphonium bromide (0.715 g, 2.0 mmol) was
dissolved in anhyd THF (8 mL), and to this solution, cooled to –78 °C,
was slowly added n-BuLi (1.2 mL of a 1.6 M solution in hexanes).
After 1 h at –78 °C, aldehyde 19 (0.546 g, 1.0 mmol) in anhyd THF
(5 mL) was added. The mixture was slowly warmed to r.t. H2O (20
mL) was added and the two phases were separated. The aqueous
layer was extracted several times with Et2O (3 × 20 mL). The organ-
ic fractions were collected, and dried (Na2SO4), and the solvent was
evaporated to give 7. Silica gel chromatography (hexanes–EtOAc,
FTIR (KBr, neat): 2927, 2854, 1708 (C=O), 1450, 1355, 1060 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.32 (d, J = 7.6 Hz, 1 H), 4.02 (dd,
J = 8.8, 7.6, Hz, 1 H), 2.26 (s, 3 H), 1.63–1.87 (m, 5 H), 1.60 (s, 3
H), 1.34 (s, 3 H), 0.92–1.25 (m, 6 H).
13C NMR (100.0 MHz, CDCl3): d = 209.7, 109.4, 82.8, 82.6, 37.6,
29.7, 29.3, 28.4, 26.6, 26.2, 25.4, 24.8.
HRMS: m/z calcd for C13H23O3 [M + 1]: 227.1650; found:
227.1647.
Synthesis 2009, No. 21, 3557–3564 © Thieme Stuttgart · New York

PAPER
Synthesis of C13–C23 Fragment of Iriomoteolide-1a
3563
(R)-2-[(4R,5R)-5-Cyclohexyl-2,2-dimethyl-1,3-dioxolan-4-
yl]but-3-en-2-ol (6)
13C NMR (100.0 MHz, CDCl3): d = 158.9, 139.5, 131.4, 129.4,
117.8, 113.6, 106.6, 83.2, 82.6, 80.1, 64.3, 55.3, 36.3, 31.4, 30.5,
26.9, 26.5, 25.8, 25.2, 25.1, 20.1.
Freshly prepared vinylmagnesium bromide [prepared from Mg
(0.72 g) and 1 M vinyl bromide in THF (30 mL)] was cooled to
0 °C. The ketone 23 (2.26 g, 10.0 mmol) in THF (50 mL) was added
dropwise and the resulting reaction mixture was stirred at 0 °C for
overnight. Then, sat. aq NH4C1 (50 mL) was added carefully with
vigorous stirring, the layers were separated, and the aqueous phase
was extracted thoroughly with Et2O (3 × 50 mL). Then, the com-
bined organic phases were washed with brine (80 mL) and dried
(MgSO4), and concentrated to give a mixture of 6 and 6¢. The mix-
ture was purified by flash column chromatography (hexanes–
EtOAc, 250:1 to 20:1) to afford (R,R,R)-6 (1.78 g, 70%) and
HRMS: m/z calcd for C23H35O4 [M + 1]: 375.2519; found:
375.2535.
(2R,6S,7R,9S,10S,E)-10-(tert-Butyldiphenylsilyloxy)-2-
[(4R,5R)-5-cyclohexyl-2,2-dimethyl-1,3-dioxolan-4-yl]-7-(4-
methoxybenzyloxy)-6,9-dimethylundec-3-en-2-ol (5)
To a solution of 7 (11.2 mg, 19.8 mmol) and allyllic alcohol 6 (10.0
mg, 39.6 mmol) in CH2Cl2 (1.0 mL) was added the 2nd generation
Hoveyda–Grubbs catalyst 25 (1.0 mg, 1.6 mmol) and the mixture
was heated at reflux for 12 h under N2. The mixture was cooled to
r.t. and concentrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (hexanes–EtOAc, 100:1
to 20:1) to afford 5 (5.8 mg, 38%) as a colorless oil and; Rf = 0.53
(EtOAc–hexanes, 1:4); [a]D20 –16.0 (c = 0.5, CHCl3). Recovered
starting material 7: 4.1 mg.
20
(R,R,S)-6¢ (0.35 g, 14%); Rf = 0.60 (EtOAc–hexanes, 1:4); [a]D
–29.1 (c = 1.0, CHCl3).
FTIR (KBr, neat): 3425, 2989, 2927, 2852, 1651, 1381, 1255, 1033,
758 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.05 (dd, J = 23.2, 14.4 Hz, 1 H),
5.34 (dd, J = 23.2, 2.0 Hz, 1 H), 5.16 (dd, J = 14.4, 2.0 Hz, 1 H),
3.95 (d, J = 2.0 Hz, 1 H), 3.87 (dd, J = 12.0, 8.0 Hz, 1 H), 2.23 (s,
1 H), 1.66–2.04 (m, 5 H), 1.50 (s, 3 H), 1.34 (s, 3 H), 1.33 (s, 3 H),
1.23–1.28 (m, 6 H).
13C NMR (100.0 MHz, CDCl3): d = 142.5, 113.3, 106.7, 82.7, 82.4,
74.7, 36.3, 31.7, 30.3, 28.7, 26.4, 25.7, 25.5, 25.4, 25.0.
FTIR (KBr, neat): 3581, 3070, 2958, 2922, 2852, 1612, 1454, 1379,
1249, 1161, 1035 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.73–7.86 (m, 4 H), 7.41–7.54 (m,
6 H), 7.10 (d, J = 8.4 Hz, 2 H), 7.01 (d, J = 8.4 Hz, 2 H), 5.53–5.71
(m, 2 H), 4.30 (d, J = 10.4 Hz, 1 H), 4.12 (d, J = 11.2 Hz, 1 H),
3.90–3.95 (m, 1 H), 3.84–3.87 (m, 1 H), 3.75–3.76 (m, 4 H), 3.26–
3.33 (m, 1 H), 2.11–2.33 (m, 2 H), 1.64–1.98 (m, 4 H), 1.48 (s, 3 H),
1.11–1.41 (m, 15 H), 0.99 (s, 9 H), 0.79–0.97 (m, 9 H).
13C NMR (100.0 MHz, CDCl3): d = 159.0, 136.0, 135.9, 135.3,
135.0, 134.3, 131.1, 129.6, 129.5, 129.4, 129.3, 128.8, 127.5, 127.3,
113.6, 106.6, 83.2, 82.2, 81.8, 74.0, 72.3, 70.9, 55.2, 37.4, 36.4,
35.9, 35.4, 32.7, 31.6, 30.2, 29.7, 27.1, 26.7, 26.4, 25.8, 25.6, 25.5,
25.0, 19.9, 19.4, 15.6, 14.8.
HRMS: m/z calcd for C15H27O3 [M + 1]: 255.1958; found:
255.1960.
(S)-2-[(4R,5R)-5-Cyclohexyl-2,2-dimethyl-1,3-dioxolan-4-
yl]but-3-en-2-ol (6¢)
Rf = 0.63 (EtOAc–hexanes, 1:4); [a]D20 –42.2 (c = 1.5, CHCl3).
FTIR (KBr, neat): 3552, 2893, 2926, 2852, 1614, 1450, 1045 cm–1.
HRMS: m/z calcd for C48H71O6Si [M + 1]: 771.5020; found:
771.5011.
1H NMR (300 MHz, CDCl3): d = 6.01 (dd, J = 17.1, 10.8 Hz, 1 H),
5.40 (dd, J = 17.4, 1.8 Hz, 1 H), 5.34 (dd, J = 10.5, 1.5 Hz, 1 H),
3.90 (d, J = 5.4 Hz, 1 H), 3.80–3.85 (m, 1 H), 2.56 (s, 1 H), 1.61–
2.07 (m, 5 H), 1.37 (s, 3 H), 1.32 (s, 6 H), 1.20–1.31 (m, 6 H).
13C NMR (75.4 MHz, CDCl3): d = 142.7, 112.7, 106.8, 82.7, 81.9,
75.5, 36.0, 31.4, 30.2, 27.0, 26.8, 26.3, 25.6, 25.2, 24.8.
Acknowledgment
We gratefully acknowledge the Nanyang Technological University,
Singapore for Education Academic Research Fund Tier 2 (No.
T206B1221 and T207B1220RS) and Biomedical Research Council
(05/1/22/19/408) for the funding of this research.
HRMS: m/z calcd for C15H27O3 [M + 1]: 255.1953; found:
255.1960.
(4R,5R)-4-Cyclohexyl-5-[(R)-2-(4-methoxybenzyloxy)but-3-en-
2-yl]-2,2-dimethyl-1,3-dioxolane (24)
References
To a mixture of DMF (10.0 mL) and 6 (1.27 g, 5.0 mmol) was added
NaH (0.36 g, 60%; 9.0 mmol) carefully at 0 °C and the mixture was
stirred at the same temperature for 1 h. PMBCl was added dropwise
by a syringe and the mixture was slowly warmed to r.t. and stirred
for 20 h. Then, sat. aq NH4C1 (50 mL) was added carefully with
vigorous stirring, the layers were separated and the aqueous phase
was extracted thoroughly with EtOAc (3 × 50 mL). Then, the com-
bined organic phases were washed with H2O (80 mL), brine
(80 mL), and dried (MgSO4). concentrated and purified by flash
column chromatography (hexanes–EtOAc, 50:1 to 20:1) to afford
24 (1.64 g, 88%) as a pale yellow powder; Rf = 0.70 (EtOAc–
hexanes, 1:4); [a]D20 +7.5 (c = 1.1, CHCl3).
(1) Tsuda, M.; Oguchi, K.; Iwamoto, R.; Okamoto, Y.;
Kobayashi, J.; Fukushi, E.; Kawabata, J.; Ozawa, T.;
Masuda, A.; Kitaya, Y.; Omasa, K. J. Org. Chem. 2007, 72,
4469.
(2) Kawabata, J.; Ozawa, T.; Masuda, A. J. Nat. Prod. 2007, 70,
1661.
(3) (a) Review see: Kobayashi, J.; Tsuda, M. Nat. Prod. Rep.
2004, 21, 77. (b) Kobayashi, J.; Kubota, T. J. Nat. Prod.
2007, 70, 451.
(4) For some selected synthesis of amphidinolides, see: (a) Va,
P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128, 15960.
(b) Kim, C. H.; An, H. J.; Shin, W. K.; Yu, W.; Woo, S. K.;
Jung, S. K.; Lee, E. Angew. Chem. Int. Ed. 2006, 45, 8019.
(c) Jin, J.; Chen, Y.; Li, Y.; Wu, J.; Dai, W.-M. Org. Lett.
2007, 9, 2585.
FTIR (KBr, neat): 3007, 2927, 2852, 1612, 1857, 1369, 1053, 767
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.22 (d, J = 8.4 Hz, 1 H), 6.84 (d,
J = 8.4 Hz, 1 H), 6.19 (dd, J = 17.6, 5.2 Hz, 1 H), 5.35 (ddd,
J = 24.0, 10.8, 1.2 Hz, 1 H), 4.28 (s, 2 H), 3.99 (d, J = 5.6 Hz, 1 H),
3.80–3.82 (m, 4 H), 1.48–2.06 (m, 5 H), 1.43 (s, 3 H), 1.42 (s, 3 H),
0.77–1.37 (m, 9 H).
(5) Fang, L.; Xue, H.; Yang, J. Org. Lett. 2008, 10, 4645.
(6) (a) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc. 2007,
129, 276. (b) Wang, S.-Y.; Lum, T.-K.; Ji, S.-J.; Loh, T.-P.
Adv. Synth. Catal. 2008, 350, 673.
(7) Lum, T.-K.; Wang, S.-Y.; Loh, T.-P. Org. Lett. 2008, 10,
761.
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PAPER
(8) For asymmetric addition of Grignard reagents to a,b-
unsaturated thioesters, see: Macia Ruiz, B.; Geurts, K.;
Fernandez-Ibanez, M. A.; ter Horst, B.; Minnaard, A. J.;
Feringa, B. L. Org. Lett. 2007, 9, 5123.
(9) For asymmetric addition of Grignard reagents to sulfones,
see: Bos, P. H.; Minnaard, A. J.; Feringa, B. L. Org. Lett.
2008, 10, 4219.
(10) Bates, R. W.; Sridhar, S. J. Org. Chem. 2008, 73, 8104.
(11) (a) Paterson, I.; Wallace, D. J.; Velázquez, S. M.
Tetrahedron Lett. 1994, 35, 9083. (b) Paterson, I.; Wallace,
D. J.; Cowden, C. J. Synthesis 1998, 639. (c) Cowden, C. J.;
Paterson, I. Org. React. 1997, 51, 1.
(13) (a) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
(b) The absolute configuration of 22 was determined based
on this reference.
(14) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2000, 122, 8168. (b) Hoye, T. R.;
Zhao, H. Org. Lett. 1999, 1, 1123. (c) Chatterjee, A. K.;
Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc.
2003, 125, 11360.
(15) For an example of CM reactions between olefins bearing a
quartenary carbon atom and an a-olefin in the total synthesis
of a natural product, see: Kanada, R. M.; Itoh, D.; Nagai, M.;
Niijima, J.; Asai, N.; Mizui, Y.; Abe, S.; Kotake, Y. Angew.
Chem. Int. Ed. 2007, 46, 4350.
(12) Private communication with Professor Ian Paterson.
Synthesis 2009, No. 21, 3557–3564 © Thieme Stuttgart · New York