A formal total synthesis of fostriecin by a convergent approach

Article abstract of DOI:10.1055/s-0030-1258187

A formal total synthesis of fostriecin has been accomplished in 20 steps. Our method features the derivation of two of the four chiral centers from commercial diethyl d-(+)-malate. The key steps involve the Julia-Kocienski olefination, the Sharpless asymmetric dihydroxylation, and the Stille coupling.

Full text of DOI:10.1055/s-0030-1258187

PAPER
3325
A Formal Total Synthesis of Fostriecin by a Convergent Approach
T
otal
S
ynthesis of
e
Fostriecin yao Li,a Yu Zhao,a Liu Ye,a Chaonan Chen,a Jiancun Zhang*a,b
a
Guangzhou Institutes of Biomedicine and Health, CAS, 190 Kaiyuan Avenue, Science Park, Guangzhou 510530, P. R. of China
State Key Laboratory of Respiratory Diseases, Guangzhou Medical College, Guangzhou 510120, P. R. of China
Fax +86(20)32015323; E-mail: Zhang_jiancun@gibh.ac.cn
b
Received 30 April 2010; revised 2 June 2010
ic stability and other pharmaceutical properties. Herein
we report a stereocontrolled route to fostriecin by using
diethyl D-(+)-malate as the starting material.
Abstract: A formal total synthesis of fostriecin has been accom-
plished in 20 steps. Our method features the derivation of two of the
four chiral centers from commercial diethyl D-(+)-malate. The key
steps involve the Julia–Kocienski olefination, the Sharpless asym-
metric dihydroxylation, and the Stille coupling.
In the total synthesis of natural product, chiral pools are
often used to introduce chiral centers. As shown in
Scheme 1, the chiral centers at C5 and C11 were both in-
troduced from diethyl D-(+)-malate, making it a distinc-
tive feature of our approach; while the other chiral centers
at C8 and C9 were controlled via a Sharpless asymmetric
dihydroxylation reaction. A Julia–Kocienski olefination
was applied to construct the C6–C7 double bond, and the
conjugated Z,Z,E-trienol unit was expected to be built up
by Stille coupling of vinyl iodide and a stannane.5b–g,7
Key words: fostriecin, chiral pool, Julia–Kocienski olefination,
Sharpless asymmetric dihydroxylation, Stille coupling
Fostriecin (1, CI-920), isolated from Streptomyces pulver-
aceus, is the most selective serine/threonine protein phos-
phatase 2A (PP2A) inhibitor known to date (PP2A/PP4 vs
PP1 selectivity 104).1 It displays potent cytotoxic activity
in vitro against a range of cancer cell lines, and in vivo an-
titumor activity toward lymphoid leukemias.2 The Phase I
clinical trial of fostriecin had been investigated at NCI,
but the study was later halted due to the issues involving
purity and stability.3 However, its remarkable biological
activity has attracted the interest of many researchers in
search of more potent and stable analogues.
As envisaged, the synthesis began with the reduction of
diethyl D-(+)-malate (2) to diol 3 with sodium acetoxy-
borohydride8 in 82% yield (Scheme 2). Protection of the
resulting diol 3 with TBSCl led to the formation of silyl
ether 4. But when 4 was treated with lithium aluminum
hydride, diol 5¢ was obtained instead of the desired alco-
hol 5, while the reduction of 4 with Red-Al at –70 to –40 °C
resulted in the formation of 5 in excellent yield (95%).
Since the stereochemistry of fostriecin was established in
1997,4 several excellent total synthesis had been reported
along with a number of synthetic studies.5 Preliminary
structure–activity relationship (SAR) studies of fostrecin
were also undertaken by Boger6 and others.5f As a part of
our chemical biology program, we aim to further optimize
the structural aspects of fostriecin to improve its metabol-
Alcohol 5 was transformed to alcohol 6 according to the
reported procedure.9 Compound 6 was converted into sul-
fone 7 (87% for 2 steps) through a Mitsunobu reaction fol-
lowed by oxidation with hydrogen peroxide in the
presence of a catalytic amount of Na2WO4.10
3
2
NaHO3PO
8
OH
OR OR
x
5
9
OH
O
O
13
11
O
O
6
12
OH
fostriecin (1)
OR
OR
O
O
OR
S
i-PrO
O
i-PrO
O
O
R
OH
H
OR
OEt
OR
EtO
O
O
diethyl D-(+)-malate
Scheme 1 Retrosynthetic analysis
SYNTHESIS 2010, No. 19, pp 3325–3331
x
x.
x
x
.
2
0
1
0
Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1258187; Art ID: F07610SS
© Georg Thieme Verlag Stuttgart · New York

3326
D. Li et al.
PAPER
O
OH
Table 1 Optimization of Julia–Kocienski Olefination Conditions
O
OR
c
a
OEt
OR
OH
KHMDS
EtO
EtO
11
–78 °C
3 R = H
OTBS
O
O
b
O
diethyl D-(+)-malate (2)
OTBS
S
4 R = TBS
i-PrO
O
i-PrO
O
R
OR
12
d, e
f
OTBS
Ph
HO
N
N
N
i-PrO
O
N
5 R = TBS
5′ R = H
7 R =
8 R =
N
6
S
O
O
Entry
R
Solvent
DME
DME
THF
Temp (°C) E/Za
Yield(%)b
S
i-PrO
O
BT
1
2
3
PT
BT
BT
–78
–78
–78
5:1
7:1
36
76
82
7
Scheme 2 Reagents and conditions: (a) NaBH4, AcOH, THF, 0 °C
to r.t., 82%; (b) TBSCl, imidazole, DMF, 86%; (c) Red-Al, THF, –70
to –40 °C, 95%; (d) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C; (e) ref.
9; (f) (1) DIAD, Ph3P, BT-SH, THF; (2) Na2WO4, H2O2, MeCN, 89%
for 2 steps.
15:1
a Determined by 1H NMR spectroscopy.
b Isolated yield.
Meanwhile, the a,b-unsaturated ester 9 was synthesized
from alcohol 5 via Swern oxidation followed by Wittig re-
action in 90% yield and excellent selectivity (E/Z = 50:1
bulky TBS group in compound 12 was replaced with an
acetal by treating 12 with TBAF and acetalizing the re-
sulting diol 13 with 2-methoxypropene (MOP) in isopro-
pyl alcohol. The acetalized intermediate 14 was then
oxidized using PCC. Since the a,b-unsaturated lactone
tend to decrease the election density at the C6–C7 double
bond,13we expected a desired formation of the diol 16
from dihydroxylation of 15 using (DHQD)2PHAL as a
chiral ligand. Indeed, the reaction achieved excellent re-
gioselectivity (95:5, determined by HPLC) and a very
good yield (85%) (Scheme 4).
1
determined by H NMR spectroscopy) (Scheme 3). Re-
duction of ester 9 with lithium aluminum hydride at 0 °C
gave the allyl alcohol 10,5ewhich was then subjected to
Swern oxidation to afford the a,b-unsaturated aldehyde
11 in nearly quantitative yield (98%).
O
OTBS
a
b
OTBS
5
EtO
9
OH
O
H
OTBS
OTBS
a
b
c
12
OH
c
OTBS
OTBS
i-PrO
O
HO
13
10
11
O
Scheme 3 Reagents and conditions: (a) (COCl)2, DMSO, Et3N,
CH2Cl2, –78 °C; then Ph3P=CMeCO2Et, 0 °C, 90%; (b) LiAlH4, 0 °C,
Et2O, 96%; (c) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C, 98%.
O
i-PrO
O
14
O
Having obtained both the fragments 7 and 11, the feasibil-
ity of using the Julia–Kocienski olefination to construct
the E-olefin at C6–C7 was investigated by examining sev-
eral reaction conditions.11 It was found that the R group
and solvent influenced the E/Z selectivity and yield as
shown in Table 1. When the R group was 1-phenyl-1H-
tetrazol-5-yl (PT) and DME was used as solvent at –78
°C, conjugated diene 12 was obtained with a 5:1 E/Z ratio
and a low yield (36%) (Table 1, entry 1). Changing the R
group from PT to benzothiazol-2-yl (BT), a good yield
(76%) was achieved accompanied by a slight increase in
E/Z ratio (7:1) (entry 2). However, when THF instead of
DME was used as the solvent, a satisfactory selectivity
(E/Z = 15:1) was obtained in very good yield (82%) (entry
3).
O
d
O
O
15
O
OH
O
O
O
OH
16
Scheme 4 Reagents and conditions: (a) TBAF, THF, 92%; (b) 2-
methoxypropene, PPTS, i-PrOH, 91%; (c) PCC, CaCO3, CH2Cl2, 0
°C, 62%; (d) (DHQD)2PHAL, K2OsO2(OH)4, K3Fe(CN)6, K2CO3,
NaHCO3, MeSO2NH2, t-BuOH–H2O, 0 °C, 85%.
It is worth noting that compound 15 was acid-sensitive.
This was verified in an alternative approach to compound
15 (Scheme 5). Silyl ether 12 was converted into the a,b-
unsaturated lactone 17 by using PCC as oxidant. Treat-
ment of lactone 17 with HF in acetone in dark gave acetal
15¢ as a diasteromeric mixture. The 13C NMR signals (d =
The stereocenters at C8 and C9 were built by a Sharpless
asymmetric dihydroxylation reaction (AD). Since Sharp-
less AD reaction was prone to occur at the most electron-
rich and sterically less hindered olefin,5c,12 the sterically
Synthesis 2010, No. 19, 3325–3331 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Fostriecin
3327
137.93 and 137.81 for C7, 129.22 and 129.13 for C6, In conclusion, we have accomplished a formal synthesis
78.37 and 78.28 for C5, 32.67–32.61 for C4) and a low of fostriecin using diethyl D-(+)-malate to introduce two
25
25
optical rotation value {[a]D +5 vs [a]D +45.5 for 15} of the four chiral centers. The total synthesis and the bio-
suggested a racemization of 15¢ at C5.
logical evaluation of fostriecin analogues are currently in
progress in our laboratory.
OTBS
a
b
12
OTBS
Reagent and solvents were purchased from commercial suppliers
and purified by standard techniques when necessary. Petroleum
ether (PE) refers to the fraction boiling in the range 60–90 °C. Ox-
ygen-sensitive and moisture-sensitive reactions were carried out un-
der argon or N2. Optical rotations were measured on a precision
O
O
17
4
O
7
O
1
5
automated polarimeter. H NMR spectra were recorded on a 400
*
O
MHz NMR spectrometer and 13C NMR on a 100 MHz NMR spec-
trometer with complete proton decoupling. Low- and high-resolu-
tion mass spectra were recorded using electrospray ionization (ESI)
and electron impact (EI) mode, and samples were used as MeOH so-
lutions and M+ refers to the molecular ion peak.
O
6
15′
Scheme 5 Reagents and conditions: (a) PCC, CaCO3, CH2Cl2, 0 °C,
53%; (b) HF, acetone, 85%.
Diol 3
After deprotection of the acetonide of compound 16, a ful-
ly protected compound 18 was provided by selectively
protecting the primary hydroxy group with triethylchlo-
rosilane (TESCl),14 the C11 secondary hydroxy groups
with TBSOTf, and the remaining two hydroxy groups
with TESOTf. According to a modification of Imanishi’s
procedure,5e 18 was subjected to Swern oxidation,15 fol-
lowed by an iodomethylenation reaction16 to yield the vi-
nyl iodide 19 with the Z-isomer as the major product
To a suspension of NaBH4 (127 mg, 3.4 mmol) in anhyd THF (30
mL) was added dropwise a solution of AcOH (0.24 mL, 3.4 mmol)
in anhyd THF (0.6 mL) at 0 °C over a period of 10 min and the mix-
ture was stirred for 1 h. A solution of ester 2 (0.5 g, 2.6 mmol) in
anhyd THF (2 mL) was added dropwise at 0 °C over a period of 10
min. The resulting mixture was stirred at 5–10 °C for 2 h. The mix-
ture was quenched by slow addition of MeOH (10 mL) and evapo-
rated to dryness on a rotary evaporator under reduced pressure. The
residue was dissolved in MeOH (20 mL) and evaporated to dryness
again. This process was repeated twice. The residue was treated
with EtOAc (20 mL) and filtered. The solid was washed with
EtOAc (25 mL). The filtrate was evaporated to dryness and purified
by silica gel chromatography eluting with PE–EtOAc (1:1 to 1:2) to
yield 3 (0.32 g, 82%) as a colorless oil; [a]D25 +16.4 (c 7.5, CHCl3).
1
(Z/E = 9:1 determined by H NMR spectroscopy) (58%
isolated yield for 2 steps). Selective removal of the more
labile TES group at C9 position with PPTS in methanol at
5 °C led to the formation of vinyl iodide 20 under 80%
yield.5e Stille coupling of compound 20 with stannane
2217 under ligand-free condition furnished the key inter-
mediate 21 (Scheme 6). Further, the optical rotation and
the spectral data of 21 were in agreement with those re-
ported in the literatures,5b–e,n while the conversion of 21
into fostriecin has been confirmed by Jacobsen,5b
Hatakeyama,5c Imanishi,5e and McDonald.5n Thus, the for-
mal total synthesis of fostriecin (1) was completed.
1H NMR (400 MHz, CDCl3): d = 4.16 (q, J = 7.2 Hz, 2 H), 4.13–
4.09 (m, 1 H), 3.67 (dd, J = 3.4, 11.4 Hz, 1 H), 3.52 (dd, J = 6.2,
11.4 Hz, 1 H), 3.27 (br s, 2 H), 2.54 (dd, J = 8.4, 16.4 Hz, 1 H), 2.47
(dd, J = 4.0, 16.4 Hz, 1 H), 1.26 (t, J = 7.2 Hz, 3 H).
MS (ESI): m/z = 149.1 (M + H)+.
Silyl Ether 4
To a solution of alcohol 3 (4.0 g, 27.0 mmol) and imidazole (5.5 g,
81.0 mmol) in DMF (15 mL) was added TBDMSCl (10.2 g, 67.5
mmol) at r.t. After the disappearance of the starting material (TLC),
the reaction mixture was diluted with Et2O (70 mL) and washed
with H2O (3 × 25 mL), sat. aq NaHCO3 (2 × 25 mL), and brine (30
mL). The organic layer was dried (MgSO4) and concentrated. The
residue was loaded on a silica gel column and eluted with PE–
TESO
OTBS
a, b
c
16
OTES
O
O
OTES
25
18
EtOAc (10: 1) to yield 4 (8.77 g, 86%) as a colorless oil; [a]D
+24.3 (c 10, CHCl3).
RO
OTBS
e
I
1H NMR (400 MHz, CDCl3): d = 4.20–4.06 (m, 3 H), 3.58 (dd,
J = 5.2, 9.8 Hz, 1 H), 3.41 (dd, J = 7.0, 9.8 Hz, 1 H), 2.62 (dd,
J = 4.3, 14.8 Hz, 1 H), 2.35 (dd, J = 8.0, 14.8 Hz, 1 H), 1.25 (t,
J = 7.2 Hz, 3 H), 0.88 (d, J = 2.9 Hz, 9 H), 0.86–0.84 (m, 9 H), 0.06
(d, J = 2.9 Hz, 3 H), 0.04 (d, J = 2.2 Hz, 9 H).
SnBu3
22
OTBDPS
O
O
OTES
19 R = TES
20 R = H
d
TBS
O
MS (ESI): m/z = 377.2 (M + H)+.
HO
1
OTBDPS
O
O
Alcohol 5
OTES
To a solution of Red-Al (1.14 g, 70% in toluene) in THF (20 mL)
was added dropwise a solution of silyl ether 4 (1.0 g, 2.65 mmol) in
THF (5 mL) slowly at –70 °C. After the addition, the temperature of
the mixture was gradually raised to –40 °C and stirred overnight. Aq
NH4OH (0.6 mL) was added to quench the reaction. The resulting
mixture was allowed to warm to r.t. and filtered. The filtrate was
evaporated to dryness and loaded on a silica gel column and eluted
21
Scheme 6 Reagents and conditions: (a) MeOH, cation resin; (b)
TESCl, TBSOTf, TESOTf, 2,6-lutidine, CH2Cl2, –78 °C, 79% for 2
steps; (c) 1. (COCl)2, DMSO, i-Pr2NEt, CH2Cl2; 2. ICH2Ph3P+I–,
NaHMDS, HMPA, THF, 58% for 2 steps; (d) PPTS, MeOH, 5 °C,
80%; (e) Pd(MeCN)2Cl2, 22, DMF, 80%.
Synthesis 2010, No. 19, 3325–3331 © Thieme Stuttgart · New York

3328
D. Li et al.
PAPER
with PE–EtOAc (20:1) to yield 5 (0.84 g, 95%) as a colorless oil;
[a]D25 +15.8 (c 5.0, CHCl3).
3.92 (dd, J = 7.6, 14.2 Hz, 1 H), 3.86 (dd, J = 4.4, 14.2 Hz, 1 H),
3.79 (hept, J = 6.2 Hz, 1 H), 2.15–2.06 (m, 2 H), 1.06 (d, J = 6.0 Hz,
3 H), 1.04 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 154.1, 133.0, 131.5, 129.7, 126.8,
126.2, 125.3, 91.7, 68.7, 61.1, 60.3, 29.5, 23.3, 21.1.
1H NMR (400 MHz, CDCl3): d = 3.90–3.84 (m, 1 H), 3.79–3.69 (m,
2 H), 3.59 (dd, J = 4.8, 10.0 Hz, 1 H), 3.49 (dd, J = 7.2, 10.0 Hz, 1
H), 2.78 (t, J = 5.4 Hz, 1 H), 1.87 (m, 1 H), 1.72 (m, 1 H), 0.88 (s,
9 H), 0.87 (s, 9 H), 0.08 (s, 3 H), 0.075 (s, 3 H), 0.06 (s, 3 H), 0.05
(s, 3 H).
MS (ESI): m/z = 287.1 (M + Na)+.
HRMS (EI): m/z calcd for C16H20O4N4S: 364.1204; found:
364.1200.
MS (ESI): m/z = 335.1 (M + H)+.
Alcohol 69
Ester 9
Alcohol 6 was prepared from 5 according to the reported proce-
To a solution of oxalyl chloride (0.58 mL, 6.8 mmol) in CH2Cl2 (20
mL) was added dropwise a solution of DMSO (0.63 mL, 8.8 mmol)
in CH2Cl2 (4 mL) at –78 °C. After 15 min, alcohol 5 (1.35 g, 4.0
mmol) in CH2Cl2 (5 mL) was added slowly. The white slurry was
stirred for 1 h at –78 °C before Et3N (2.45 mL, 17.6 mmol) was add-
ed slowly. The solution was allowed to warm to r.t. and stirred for
an additional 30 min. The Wittig reagent 2-(triphenyl-5-phospha-
nylidene)propionic acid ethyl ester (PPh3=CMeCO2Et) (1.34 g, 4.0
mmol) was added to the reaction mixture, and stirred at 0 °C for 1
h. The mixture was diluted with Et2O (50 mL), and the Et2O layer
was washed with H2O (3 × 20 mL), sat. aq NaHCO3 (2 × 20 mL),
and brine (30 mL), dried (MgSO4), and concentrated. The residue
was purified by using silica gel chromatography eluting with PE–
Et2O (50:1) to yield 9 (1.52 g, 90%) as a colorless oil; [a]D25 +14 (c
5.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.85 (t, J = 7.2 Hz, 1 H), 4.18 (q,
J = 7.2 Hz, 2 H), 3.80–3.72 (m, 1 H), 3.55 (dd, J = 4.8, 10.0 Hz, 1
H), 3.40 (dd, J = 6.8, 10.0 Hz, 1 H), 2.48 (ddd, J = 5.2, 6.8, 15.2 Hz,
1 H), 2.28 (dt, J = 7.2, 15.2 Hz, 1 H), 1.84 (s, 3 H), 1.28 (t, J = 7.2
Hz, 3 H), 0.89 (s, 9 H), 0.87 (s, 9 H), 0.05 (s, 12 H).
13C NMR (100 MHz, CDCl3): d = 168.0, 138.9, 129.0, 72.4, 67.1,
60.3, 33.9, 25.9, 25.8, 18.3, 18.1, 14.3, 12.5, –4.5, –4.8, –5.4, –5.4.
dure;9 [a]D25 +38.2 (c 0.5, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.00 (dd, J = 5.2, 10.0 Hz, 1 H),
5.72 (d, J = 10.0 Hz, 1 H), 5.10 (s, 1 H), 4.08 (m 1 H), 4.00 (hept,
J = 6.0 Hz, 1 H), 3.73 (m 1 H), 3.60 (m, 1 H), 2.14 (m, 1 H), 1.93–
1.85 (m, 2 H), 1.25 (d, J = 6.0 Hz, 3 H), 1.18 (d, J = 6.0 Hz, 3 H).
MS (ESI): m/z = 195.1 (M + Na)+.
Sulfone 7
To a solution of alcohol 6 (0.200 g, 1.16 mmol), benzothiazol-2-thi-
ol (BT-SH) (0.233 g, 1.39 mmol), and Ph3P (0.365 g, 1.39 mmol) in
anhyd THF (15 mL) was added DEAD (0.3 mL, 1.5 mmol) at 0 °C.
After 1 h, the temperature was raised to r.t., and the reaction mixture
was stirred for 5 h. The mixture was concentrated, and the residue
was treated with Et2O (15 mL) and filtered. The filtrate was evapo-
rated to dryness. The residue was then dissolved in MeCN (10 mL)
and treated with a mixture of Na2WO4·2H2O (57 mg, 0.17 mmol)
and 30% aq H2O2 (1.4 g, 11.6 mmol). After 24 h, the mixture was
diluted with CH2Cl2 (20 mL). The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 15 mL). The com-
bined organic phases were dried (Na2SO4), filtered, and concentrat-
ed under reduced pressure. Purification by chromatography on
silica gel (PE–EtOAc, 5:1) provided 7 (0.367 g, 89%) as a colorless
syrup; [a]D25 +15.6 (c 3.3, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.19 (ddd, J = 0.8, 1.2, 8.0 Hz, 1
H), 8.00 (ddd, J = 0.8, 1.2, 8.0 Hz, 1 H), 7.63 (ddd, J = 1.2, 7.2, 8.0
Hz, 1 H), 7.58 (ddd, J = 1.2, 7.2, 8.0 Hz, 1 H), 5.96–5.89 (m, 1 H),
5.67 (ddd, J = 2.0, 4.8, 10.0 Hz, 1 H), 4.98 (d, J = 2.0 Hz, 1 H), 4.63
(ddd, J = 4.8, 7.6, 14.4 Hz, 1 H), 4.00 (hept, J = 6.0 Hz, 1 H), 3.90
(dd, J = 7.6, 14.8 Hz, 1 H), 3.73 (dd, J = 4.8, 14.8 Hz, 1 H), 2.19–
2.13 (m, 2 H), 1.16 (d, J = 6.0 Hz, 3 H), 1.07 (d, J = 6.0 Hz, 3 H).
MS (ESI): m/z = 439.2 (M + Na)+.
HRMS (ESI): m/z calcd for C21H44O4Si2 + Na (M + Na)+: 439.2670;
found: 439.2679.
Alcohol 10
To a mixture of LiAlH4 (1.1 g, 28.8 mmol) and Et2O (60 mL) was
added dropwise a solution of ester 9 (10.0 g, 24.0 mmol) in Et2O (20
mL) at 0 °C. After stirring for 2.5 h, the reaction mixture was
quenched by slowly adding H2O (1 mL) followed by 10% aq NaOH
(5 mL). The resulting mixture was filtered. The filtrate was evapo-
rated and the residue was purified by silica gel chromatography
eluting with PE–EtOAc (1:1) to yield 10 (8.68 g, 96%) as a colorless
syrup; [a]D25 +7.4 (c 5.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.52–5.45 (m, 1 H), 4.01 (d,
J = 6.0 Hz, 2 H), 3.72–3.67 (m, 1 H), 3.50 (dd, J = 5.2, 10.0 Hz, 1
H), 3.41 (dd, J = 6.4, 10.0 Hz, 1 H), 2.32 (ddt, J = 0.8, 6.0, 14.4 Hz,
1 H), 2.17 (dt, J = 7.2, 14.4 Hz, 1 H), 1.67 (s, 3 H), 1.26 (t, J = 6.0
Hz, 1 H), 0.89 (s, 9 H), 0.88 (s, 9 H), 0.05–0.04 (m, 12 H).
13C NMR (100 MHz, CDCl3): d = 166.6, 152.6, 136.7, 128.0, 127.6,
127.1, 126.2, 125.4, 122.4, 91.8, 68.8, 61.1, 59.2, 30.0, 23.4, 21.2.
MS (ESI): m/z = 376.1 (M + Na)+.
HRMS (ESI): m/z calcd for C16H19NO4S2 + Na (M + Na)+:
376.0648; found: 376.0657.
Compound 8
To a solution of alcohol 6 (0.2 g, 1.16 mmol), PT-SH (0.269 g, 1.5
mmol), and Ph3P (0.396 g, 1.5 mmol) in THF (15 mL) was added
DEAD (0.322 mL, 1.624 mmol) at 0 °C. After stirring for 1 h, the
reaction mixture was warmed to r.t. and stirred for 5 h. The resulting
mixture was evaporated and treated with Et2O (5 mL) and filtered.
The filtrate was evaporated to dryness. The residue was dissolved in
MeCN (10 mL) and treated with a mixture of Na2MoO4·2H2O (56
mg, 0.23 mmol) and 30% aq H2O2 (1.4 g, 11.6 mmol) overnight and
then diluted with CH2Cl2 (20 mL). The organic layer was separated,
and the aqueous phase was extracted with CH2Cl2 (3 × 15 mL). The
combined organic phases were dried (Na2SO4), filtered, and con-
centrated. Purification on a silica gel column (PE–EtOAc 5:1) pro-
13C NMR (100 MHz, CDCl3): d = 134.3, 120.4, 71.2, 66.9, 65.0,
30.6, 24.0, 23.9, 16.4, 16.2, 11.9, –6.4, –6.7, –7.3, –7.3.
MS (ESI): m/z = 397.2 (M + Na)+.
HRMS (ESI): m/z calcd for C19H42O3Si2 + Na (M + Na)+: 397.2565;
found: 397.2560.
Aldehyde 11
To a solution of oxalyl chloride (2.0 mL, 23.6 mmol) in CH2Cl2 (150
mL) was added dropwise a solution of DMSO (2.58 mL, 36.28
mmol) in CH2Cl2 (5 mL) at –78 °C. After 30 min, alcohol 10 (6.8 g,
18.14 mmol) in CH2Cl2 (10 mL)was added slowly. The white slurry
was stirred for 1 h at –78 °C before Et3N (8.8 mL, 63.49 mmol) was
added slowly. The solution was allowed to warm to r.t. and washed
25
vided 8 (0.19 g, 45%) as a colorless syrup; [a]D +3.6 (c 1.8,
CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.63–7.53 (m, 5 H), 5.90 (m, 1 H),
5.64 (ddd, J = 2.2, 4.6, 10.0 Hz, 1 H), 4.92 (s, 1 H), 4.61 (m, 1 H),
Synthesis 2010, No. 19, 3325–3331 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Fostriecin
3329
with H2O (3 × 30 mL), sat. aq NaHCO3 (2 × 30 mL), and brine (50
mL), dried (MgSO4), and concentrated. The residue was purified by
silica gel chromatography eluting with PE–Et2O (50:1 to 20:1) to
yield 11 (6.65 g, 98%) as a colorless oil; [a]D25 +9.5 (c 9.0, CHCl3);
1H NMR (400 MHz, CDCl3): d = 9.40 (s, 1 H), 6.61 (ddd, J = 1.2,
7.2, 8.0 Hz, 1 H), 3.87–3.80 (m, 1 H), 3.56 (dd, J = 5.2, 10.0 Hz, 1
H), 3.39 (dd, J = 7.6, 10.0 Hz, 1 H), 2.61 (ddt, J = 0.8, 6.4, 14.8 Hz,
1 H), 2.51 (dt, J = 7.2, 14.8 Hz, 1 H), 1.74 (s, 3 H), 0.87 (s, 9 H),
0.86 (s, 9 H), 0.05 (s, 3 H), 0.03 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 195.1, 151.3, 140.5, 72.0, 66.8,
34.1, 25.9, 25.8, 18.3, 18.0, 9.4, –4.4, –4.8, –5.4, –5.4.
MS (ESI): m/z = 373.2 (M + Na)+.
HRMS (ESI): m/z calcd for C19H40O3Si2 + Na (M + Na)+: 395.2408;
Acetal 14
To a solution of diol 13 (0.55 g, 1.95 mmol) and 2-methoxypropene
(MOP) (0.9 mL, 9.7 mmol) in i-PrOH (40 mL) was added PPTS (95
mg, 0.39 mmol) at r.t. The reaction mixture was stirred for 1.5 h at
r.t. before Et3N (0.3 mL) was added to quench the reaction. The re-
sulting mixture was evaporated, and the residue was loaded on a sil-
ica gel column and eluted with PE–EtOAc (20:1) to give 14 (0.57 g,
91%) as a colorless oil; [a]D25 +24 (c 1.8, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.28 (d, J = 16.0 Hz, 1 H), 5.99
(dd, J = 5.6, 10.0 Hz, 1 H), 5.71 (d, J = 10.0 Hz, 1 H), 5.63 (dd,
J = 6.4, 16.0 Hz, 1 H), 5.48 (t, J = 7.4 Hz, 1 H), 5.10 (s, 1 H), 4.51–
4.42 (m, 1 H), 4.14 (pent, J = 6.4 Hz, 1 H), 4.04–3.97 (m, 2 H), 3.55
(t, J = 7.4 Hz, 1 H), 2.53–2.46 (m, 1 H), 2.41–2.34 (m, 1 H), 2.11
(dd, J = 10.8, 18.0 Hz, 1 H), 2.01 (dt, J = 4.4, 18.0 Hz, 2 H), 1.76 (s,
3 H), 1.41 (s, 3 H), 1.34 (s, 3 H), 1.23 (d, J = 6.0 Hz, 3 H), 1.16 (d,
J = 6.0 Hz, 3 H).
found: 395.2401.
13C NMR (100 MHz, CDCl3): d = 135.52, 135.48, 128.4, 127.4,
127.2, 126.1, 109.0, 93.1, 75.5, 69.4, 69.1, 66.8, 32.7, 30.9, 26.9,
25.6, 23.9, 22.0, 12.6.
Compound 12
To a solution of the sulfone 7 (5.78 g, 16.4 mmol) and the aldehyde
11 (5.30 g, 14.2 mmol) in anhyd THF (300 mL) at –78 °C was added
KHMDS (0.5 M in toluene, 34.1 mL, 17.1 mmol) over a period of
1 h. The resulting mixture was stirred for an additional 3 h at this
temperature, and then allowed to warm to r.t. and evaporated. The
residue was loaded on silica gel column and eluted with PE–EtOAc
MS (ESI) m/z = 345.1 (M + Na)+.
HRMS (EI): m/z calcd for C19H30O4: 322.2157; found: 322.2139.
25
(50:1 to 20:1) to give 12 (6.03 g, 82%) as a pale-yellow syrup; [a]D
+24.5 (c 1.05, CHCl3).
Lactone 15
A mixture of PCC (10.0 g, 46.5 mmol), CaCO3 (20.0 g), and CH2Cl2
(100 mL) was stirred for 30 min before a solution of acetal 14 (3.0
g, 9.3 mmol) in CH2Cl2 (150 mL) was added at 5 °C. The reaction
mixture was stirred overnight at this temperature and filtered. The
filtrate was evaporated, and the residue was loaded on a silica gel
column and eluted with PE–EtOAc (4:1) to give 15 (1.6 g, 62%) as
a pale-yellow syrup; [a]D25 +45.5 (c 0.6, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.86 (dt, J = 4.4, 10.0 Hz, 1 H),
6.33 (d, J = 15.6 Hz, 1 H), 6.01 (d, J = 10.0 Hz, 1 H), 5.64 (dd,
J = 6.8, 15.6 Hz, 1 H), 5.53 (t, J = 7.2 Hz, 1 H), 4.94 (dd, J = 7.0,
15.0 Hz, 1 H), 4.12 (pent, J = 6.4 Hz, 1 H), 4.00 (dd, J = 6.0, 7.6 Hz,
1 H), 3.53 (t, J = 7.6 Hz, 1 H), 2.51–2.33 (m, 4 H), 1.74 (s, 3 H),
1.39 (s, 3 H), 1.32 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 6.28 (d, J = 16.0 Hz, 1 H), 6.00
(dd, J = 5.2, 10.0 Hz, 1 H), 5.72 (ddt, J = 1.2, 2.8, 10.0 Hz, 1 H),
5.59 (dd, J = 6.4, 16.0 Hz, 1 H), 5.56 (t, J = 7.6 Hz, 1 H), 5.11 (s, 1
H), 4.51–4.46 (m, 1 H), 4.01 (hept, J = 6.4 Hz, 1 H), 3.74–3.68 (m,
1 H), 3.50 (dd, J = 5.2, 10.0 Hz, 1 H), 3.41 (dd, J = 6.4, 10.0 Hz, 1
H), 2.41 (dt, J = 6.4, 14.4 Hz, 1 H), 2.26 (dt, J = 7.2, 14.4 Hz, 1 H),
2.12–2.08 (m, 1 H), 2.05–1.99 (m, 1 H), 1.75 (s, 3 H), 1.23 (d,
J = 6.4 Hz, 3 H), 1.17 (d, J = 6.4 Hz, 3 H), 0.88 (s, 9 H), 0.87 (s, 9
H), 0.04–0.02 (m, 12 H).
13C NMR (100 MHz, CDCl3): d = 136.2, 134.3, 129.7, 128.6, 126.3,
126.1, 93.3, 73.2, 69.5, 67.1, 67.0, 33.4, 31.0, 26.0, 25.9, 23.9, 22.1,
18.3, 18.1, 12.5, –4.5, –4.8, –5.3, –5.4.
MS (ESI): m/z = 533.3 (M + Na)+.
HRMS (ESI): m/z calcd for C28H54O4Si2 + Na (M + Na)+: 533.3453;
13C NMR (100 MHz, CDCl3): d = 164.0, 144.7, 137.8, 134.8, 129.1,
123.5, 121.6, 109.0, 78.5, 75.3, 68.9, 53.4, 32.6, 29.9, 26.9, 25.6,
12.5.
found: 533.3478.
MS (ESI): m/z = 279.1 (M + H)+.
Diol 13
HRMS (ESI): m/z calcd for C16H22O4 + Na (M + Na)+: 301.1410;
found: 301.1423.
A solution of the TBS-protected diol 12 (5.5 g, 10.76 mmol) in THF
(50 mL) was treated with a 1.0 M solution of TBAF in THF (24.7
mL, 24.7 mmol) at r.t. The reaction mixture was stirred overnight at
r.t. and then evaporated. The residue was loaded on a silica gel col-
umn and eluted with PE–EtOAc (2:1 to 1:1) to afford 13 (2.8 g,
92%) as a pale-yellow oil; [a]D25 +46 (c 2.3, CHCl3).
1H NMR (400 MHz, CD3OD): d = 6.32 (d, J = 15.6 Hz, 1 H), 6.02–
5.98 (m, 1 H), 5.68 (dd, J = 2.0, 10.0 Hz, 1 H), 5.62 (dd, J = 6.4,
15.6 Hz, 1 H), 5.59 (t, J = 7.2 Hz, 1 H), 5.10 (s, 1 H), 4.45–4.30 (m,
1 H), 3.99 (hept, J = 6.0 Hz, 1 H), 3.65 (pent, J = 6.0 Hz, 1 H), 3.50
(dd, J = 4.4, 11.2 Hz, 1 H), 3.44 (dd, J = 6.0, 11.2 Hz, 1 H), 2.39 (dt,
J = 6.4, 15.2 Hz, 1 H), 2.27 (dt, J = 7.6, 15.2 Hz, 1 H), 2.06–2.04
(m, 2 H), 1.77 (s, 3 H), 1.20 (d, J = 6.0 Hz, 3 H), 1.16 (d, J = 6.0 Hz,
3 H).
Compound 16
A mixture of (DHQD)2PHAL (220 mg, 0.28 mmol), K2OsO2 (OH)4
(42 mg, 0.113 mmol), K3Fe(CN)6 (3.95 g, 12.0 mmol), K2CO3 (1.66
g, 12.0 mmol), NaHCO3 (1.01 g, 12.0 mmol), and MeSO2NH2
(0.393 g, 4.13 mmol) in t-BuOH–H2O (1:1, 37 mL) was stirred at
r.t. till both phases were clear, and then the reaction mixture was
cooled to 0 °C. A solution of the lactone 15 (1.05 g, 3.76 mmol) in
t-BuOH (4 mL) was added. The resulting mixture was stirred vigor-
ously for 10 h at this temperature and treated with 2 M aq citric acid
(10 mL, 20 mmol) and Na2SO3 (5.6 g). The resulting mixture was
extracted with EtOAc (4 × 50 mL). The combined organic phases
were dried (Na2SO4) and concentrated. The residue was loaded on
a silica gel column and eluted with PE–EtOAc (2:1 to 1:1) to afford
16 (0.855 g, 85%) as a colorless syrup. The unreacted starting ma-
terial was recovered (100 mg); [a]D25 +78.5 (c 0.9, CHCl3).
1H NMR (400 MHz, CD3OD): d = 7.04 (ddd, J = 2.8, 5.6, 10.0 Hz,
1 H), 6.00 (ddd, J = 1.2, 2.4, 10.0 Hz, 1 H), 5.98 (dd, J = 0.8, 15.6
Hz, 1 H), 5.89 (dd, J = 6.0, 15.6 Hz, 1 H), 5.04–4.98 (m, 1 H), 4.29–
4.23 (m, 1 H), 4.06 (dd, J = 6.0, 8.0 Hz, 1 H), 3.56 (dd, J = 1.6, 10.8
Hz, 1 H), 3.53 (t, J = 7.6 Hz, 1 H), 2.56 (dddd, J = 1.2, 4.8, 5.6, 18.4
Hz, 1 H), 2.45 (ddt, J = 2.8, 10.8, 18.4 Hz, 1 H), 1.87 (ddd, J = 1.6,
13C NMR (100 MHz, CD3OD): d = 135.6, 134.6, 128.6, 128.1,
126.4, 125.8, 93.3, 71.9, 69.6, 67.1, 65.48, 32.1, 30.7, 22.8, 21.0,
11.3.
MS (ESI): m/z = 305.1 (M + Na)+.
HRMS (EI): m/z calcd for C16H26O4: 282.1826; found: 282.1811.
Synthesis 2010, No. 19, 3325–3331 © Thieme Stuttgart · New York

3330
D. Li et al.
PAPER
8.0, 14.0 Hz, 1 H), 1.41 (ddd, J = 4.8, 10.8, 14.0 Hz, 1 H), 1.35 (s,
3 H), 1.32 (s, 3 H), 1.28 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 165.2, 146.6, 137.7, 126.2,
120.1, 108.2, 78.2, 74.4, 74.1, 74.0, 69.6, 35.1, 29.4, 26.0, 24.7,
23.1.
MS (ESI): m/z = 335.1 (M + Na)+.
HRMS (ESI): m/z calcd for C16H24O6 + Na (M + Na)+: 335.1465;
in CH2Cl2 (0.2 mL) at –78 °C. Ten min later, silyl ether 18 (26 mg,
0.035 mmol) in CH2Cl2 (0.3 mL) was added slowly. After stirring
for 10 min at –78 °C, the temperature of the reaction mixture was
allowed to rise to –40 °C and stirred at this temperature for 1.5 h.
The mixture was then cooled to –78 °C and DIPEA (0.45 mL, 2.59
mmol) was added. The mixture was allowed to warm to r.t. and di-
luted with Et2O (30 mL), washed with a phosphate buffer (pH 6.86)
(3 × 5 mL). The organic phase was dried (MgSO4) and concentrated
to give the intermediate crude aldehyde, which was used in next step
without further purification. To a mixture of ICH2Ph3P+I– (218 mg,
0.41 mmol) and anhyd THF (5 mL) was added a 2 M solution of
NaHMDS in THF (0.185 mL, 0.37 mmol) at r.t. and stirred for 3
min. The resulting mixture was cooled to –60 °C, and HMPA (0.1
mL) was added. The mixture was cooled to –78 °C and the alde-
hyde, prepared as described above, in THF (1 mL) was added. The
reaction mixture was stirred at this temperature for 2 h and then di-
luted with Et2O (40 mL), the Et2O layer was washed with a phos-
phate buffer (pH 6.86) (15 mL). The organic phase was dried
(MgSO4) and concentrated. The residue was purified by preparative
TLC on silica gel plates (PE–EtOAc, 5:1) to yield 19 (15 mg, 58%)
as a colorless oil together with the E-isomer 19¢ (2 mg, 8%).
found: 335.1473.
Compound 17
A mixture of PCC (0.4 g, 1.96 mmol), CaCO3 (2.0 g), and CH2Cl2
(15 mL) was stirred at r.t. Thirty min later, compound 12 (0.2 g,
0.39 mmol) in CH2Cl2 (2 mL) was added dropwise at 15 °C and
stirred overnight. The resulting mixture was filtered. The filtrate
was evaporated and purified by chromatography over silica gel elut-
25
ing with PE–EtOAc (10:1–5:1) to yield 17 (0.1 g, 53%), [a]D
+24.2 (c 0.6, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.89 (td, J = 9.6, 4.2 Hz, 1 H), 6.35
(d, J = 15.6 Hz, 1 H), 6.06 (td, J = 9.6, 1.8 Hz, 1 H), 5.68–5.59 (m,
2 H), 4.98 (dd, J = 14.4, 7.2 Hz, 1 H), 3.75–3.69 (m, 1 H), 3.51 (dd,
J = 10.0, 5.2 Hz, 1 H), 3.39 (dd, J = 10.0, 6.8 Hz, 1 H), 2.50–2.37
(m, 3 H), 2.34–2.24 (m, 1 H), 1.74 (s, 3 H), 0.89 (s, 11 H), 0.87 (s,
9 H), 0.04 (s, 9 H), 0.03 (s, 3 H).
19
[a]D25 +22.5 (c 0.09, CHCl3).
1H NMR (400 MHz, CD3OD): d = 7.02 (ddd, J = 3.2, 5.6, 10.0 Hz,
1 H), 6.36 (d, J = 7.6 Hz, 1 H), 6.21 (t, J = 7.6 Hz, 1 H), 6.00 (d,
J = 10.0 Hz, 1 H), 5.94 (d, J = 15.6 Hz, 1 H), 5.80 (dd, J = 6.0, 15.6
Hz, 1 H), 5.05–5.00 (m, 1 H), 4.53–4.48 (m, 1 H), 3.83 (d, J = 8.4
Hz, 1 H), 2.60–2.52 (m, 1 H), 2.45–2.37 (m, 1 H), 1.94–1.88 (m, 1
H), 1.38 (s, 3 H), 1.14 (ddd, J = 2.8, 8.8, 14.0 Hz, 1 H), 1.03 (t,
J = 8.0 Hz, 9 H), 0.99 (t, J = 8.0 Hz, 9 H), 0.91 (s, 9 H), 0.78 (q,
J = 8.0 Hz, 6 H), 0.65 (q, J = 8.0 Hz, 7 H), 0.16 (s, 3 H), 0.08 (s, 3
H).
13C NMR (100 MHz, CDCl3): d = 164.2, 144.8, 138.5, 133.8, 131.6,
122.6, 121.7, 78.7, 72.9, 66.9, 33.4, 30.1, 26.0, 25.9, 18.4, 18.1,
12.5, –4.4, –4.7, –5.30, –5.34.
MS (ESI): m/z = 489.2 (M + Na)+.
HRMS (ESI): m/z calcd for C25H47O4Si2 (M + H)+: 467.3007;
found: 467.3012.
Silyl Ether 18
13C NMR (100 MHz, CD3OD): d = 164.9, 145.9, 144.7, 137.9,
126.6, 120.3, 79.2, 77.8, 77.7, 75.8, 73.0, 41.2, 29.3, 25.2, 23.2,
17.6, 6.6, 6.5, 6.3, 6.2, 5.6, –4.0, –4.8.
A mixture of acetal 16 (65 mg, 0.21 mmol), cationic exchange resin
[001 × 7 (strong acidic styrene cation exchange resin), 0.1 g] and
MeOH (10 mL) was stirred for 6 h and filtered. The filtrate was
evaporated to dryness, and the residue was dissolved in 2,6-lutidine
(0.5 mL) and CH2Cl2 (10 mL). The mixture was cooled to –78 °C
and TESCl (56 mL, 0.33 mmol) was added. After stirring for 2 h,
TBSOTf (67 mL, 0.29 mmol) was added and after 30 min, TESOTf
(0.42 mL, 1 M in CH2Cl2) was added to the reaction mixture, which
was stirred for 2 h before quenching with sat. aq NaHCO3 (10 mL).
The resulting mixture was extracted with Et2O (3 × 15 mL). The
combined organic phases were dried (MgSO4), filtered, and concen-
trated. The residue was purified on silica gel (PE–EtOAc, 50:1 to
20:1) to give 18 (120 mg, 79%) as a colorless syrup; [a]D25 +19.7 (c
1.07, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.86 (ddd, J = 4.0, 4.4, 10.0 Hz, 1
H), 6.05 (td, J = 1.6, 10.0 Hz, 1 H), 5.89 (dd, J = 1.0, 15.6 Hz, 1 H),
5.73 (dd, J = 6.4, 15.6 Hz, 1 H), 4.96–4.90 (m, 1 H), 3.82–3.76 (m,
1 H), 3.65 (dd, J = 2.8, 8.4 Hz, 1 H), 3.51 (dd, J = 6.0, 10.0 Hz, 1
H), 3.39 (dd, J = 4.8, 10.0 Hz, 1 H), 2.44–2.40 (m, 2 H), 1.67 (ddd,
J = 2.8, 8.8, 14.4 Hz, 1 H), 1.33 (s, 3 H) 1.32 (ddd, J = 1.8, 8.4, 14.4
Hz, 4 H), 0.98–0.92 (m, 27 H), 0.87 (s, 9 H), 0.67–0.55 (m, 18 H),
0.08 (s, 3 H), 0.077(s, 3 H).
19¢
1H NMR (400 MHz, CD3OD): d = 7.03 (ddd, J = 3.2, 5.6, 9.6 Hz, 1
H), 6.55 (dd, J = 7.6, 14.4 Hz, 1 H), 6.35 (d, J = 14.4 Hz, 1 H), 6.03–
5.95 (m, 1 H), 5.94 (d, J = 15.7 Hz, 1 H), 5.81 (dd, J = 6.0, 15.7 Hz,
1 H), 5.06–5.01 (m, 1 H), 4.29–4.24 (m, 1 H), 3.70 (dd, J = 4.0, 6.8
Hz, 1 H), 2.62–2.54 (m, 1 H), 2.46–2.37 (m, 1 H), 1.95 (ddd,
J = 4.0, 8.4, 14.0 Hz, 1 H), 1.39 (s, 3 H), 1.28–1.21 (m, 1 H), 1.01
(t, J = 8.0 Hz, 9 H), 1.00 (t, J = 8.0 Hz, 9 H), 0.90 (s, 9 H), 0.72–
0.63 (m, 12 H), 0.06 (s, 3 H), 0.09 (s, 3 H).
13C NMR (100 MHz, D3OD): d = 166.3, 151.1, 147.3, 138.9, 128.2,
121.7, 79.4, 79.2, 77.8, 77.3, 74.7, 44.2, 30.8, 26.5, 25.6, 19.1, 8.0,
7.6, 7.4, 6.7, –3.4, –3.9.
MS (ESI): m/z = 759.3 (M + Na)+.
HRMS (ESI): m/z calcd for C32H61IO5Si3 + Na (M + Na)+:
759.2764; found: 759.2773.
Vinyl Iodide 20
A solution of 19 (8 mg, 0.01 mmol) and PPTS (16 mg, 0.06 mmol)
in MeOH (3 mL) was stirred at 5 °C for 5 h. After quenching the re-
action with Et3N (0.1 mL), the mixture was evaporated to dryness.
The residue was dissolved in CH2Cl2 (0.1 mL) and purified by pre-
parative TLC on silica gel plates (PE–EtOAc, 5:1) to yield 20 (5 mg,
80%) as a colorless oil. The unreacted starting material was recov-
ered (1.5 mg); [a]D25 +40.0 (c 0.05, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.89 (dt, J = 4.0, 10.0 Hz, 1 H),
6.33 (t, J = 7.6 Hz, 1 H), 6.22 (d, J = 7.6 Hz, 1 H), 6.06 (d, J = 10.0
Hz, 1 H), 5.90 (d, J = 15.6 Hz, 1 H), 5.80 (dd, J = 6.0, 15.6 Hz, 1
H), 4.97 (dd, J = 6.4, 14.8 Hz, 1 H), 4.68–4.63 (m, 1 H), 3.63 (d,
13C NMR (100 MHz, CDCl3): d = 164.1, 144.4, 138.6, 125.8, 121.8,
77.9, 77.8, 77.1, 71.4, 67.8, 38.8, 29.8, 26.0, 24.8, 18.3, 7.2, 7.1, 6.9,
6.8, 5.7, 4.4, –3.6, –4.2.
MS (ESI) m/z = 751.3 (M + Na)+.
HRMS (ESI): m/z calcd for C37H76O6Si4 + Na (M + Na)+: 751.4611;
found: 751.4631.
Vinyl Iodide 19
To a solution of oxalyl chloride (50 mL, 0.59 mmol) in CH2Cl2 (5
mL) was added dropwise a solution of DMSO (65 mL, 0.92 mmol)
Synthesis 2010, No. 19, 3325–3331 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Fostriecin
3331
J = 10.8 Hz, 1 H), 3.01 (s, 1 H), 2.50–2.40 (m, 2 H), 1.71 (dd,
J = 7.6, 14.0 Hz, 1 H), 1.42–1.35 (m, 1 H), 1.34 (s, 3 H), 0.94 (t,
J = 8.0 Hz, 9 H), 0.88 (s, 9 H), 0.58 (q, J = 8.0 Hz, 6 H), 0.11 (s, 3
H), 0.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 163.8, 144.4, 144.2, 138.2, 127.1,
122.1, 79.7, 77.7, 77.5, 75.1, 74.3, 37.5, 29.9, 26.0, 22.8, 18.2, 7.2,
7.1, –4.2, –4.7.
(4) Boger, D. L.; Hikota, M.; Lewis, B. M. J. Org. Chem. 1997,
62, 1748.
(5) (a) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc.
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Chem. Int. Ed. 2001, 40, 3667. (c) Esumi, T.; Okamoto, N.;
Hatakeyama, S. Chem. Commun. 2002, 3042.
(d) Miyashita, K.; Ikejiri, M.; Kawasaki, H.; Maemura, S.;
Imanishi, T. Chem. Commun. 2002, 742. (e) Miyashita, K.;
Ikejiri, M.; Kawasaki, H.; Maemura, S.; Imanishi, T. J. Am.
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MS (ESI): m/z = 645.3 (M + Na)+.
Compound 2217
1H NMR (400 MHz, CDCl3): d = 7.71 (d, J = 6.4 Hz, 4 H), 7.45–
7.37 (m, 6 H), 7.11 (t, J = 12.0 Hz, 1 H), 6.40–6.28 (m, 1 H), 6.08
(d + dd, J = 12.8, 63.2 Hz, 1 H), 5.81 (dt, J = 4.6, 15.2 Hz, 1 H), 4.29
(d, J = 2.8 Hz, 2 H), 1.60–1.42 (m, 6 H), 1.35–1.26 (m, 6 H), 1.10
(s, 9 H), 0.99–0.95 (m, 6 H), 0.89 (t, J = 7.2 Hz, 9 H).
MS (ESI): m/z = 613.1 (M + H)+.
Compound 21
To a solution of 20 (4.0 mg, 0.0064 mmol) and stannane 22 (15 mg,
0.025mmol) in DMF (1 mL), which had been degassed previously,
was added Pd(MeCN)2Cl2 (1.0 mg, 0.0039 mmol). The reaction
mixture was stirred at r.t. in the dark for 24 h. The solvent was re-
moved under reduced pressure, and the resulting residue was dis-
solved in CH2Cl2 (0.1 mL) and purified by preparative TLC on
silica gel plates (PE–CH2Cl2, 1:3) to yield 21 (4.2 mg, 80%) as a
colorless oil; [a]D25 –1.8 (c 0.4, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.68 (d, J = 6.8 Hz, 4 H), 7.44–
7.36 (m, 6 H), 6.89 (dt, J = 4.0, 9.6 Hz, 1 H), 6.76 (dd, J = 12.0, 14.4
Hz, 1 H), 6.34 (t, J = 11.4 Hz, 1 H), 6.15 (t, J = 11.4 Hz, 1 H), 6.07–
6.02 (m, 2 H), 5.91–5.77 (m, 3 H), 5.53 (t, J = 10.0 Hz, 1 H), 4.99–
4.91 (m, 2 H), 4.29 (d, J = 4.8 Hz, 2 H), 3.68 (d, J = 10.8 Hz, 1 H),
3.03 (d, J = 1.6 Hz, 1 H), 2.46–2.43 (m, 2 H), 1.68–1.62 (m, 1 H),
1.38–1.33 (m, 1 H), 1.32 (s, 1 H), 1.07 (s, 9 H), 0.92 (t, J = 8.0 Hz,
9 H), 0.88 (s, 9 H), 0.57 (q, J = 8.0 Hz, 6 H), 0.07 (s, 3 H), 0.03 (s,
3 H).
13C NMR (100 MHz, CDCl3): d = 163.8, 144.2, 138.3, 135.8, 135.8,
134.5, 134.0, 130.3, 129.8, 127.9, 127.1, 124.9, 123.5, 122.6, 122.1,
77.7, 77.4, 75.2, 67.3, 64.5, 39.4, 29.9, 27.1, 26.1, 22.5, 19.5, 18.3,
7.2, 7.0, –4.1, –4.8.
MS (ESI): m/z = 839.3 (M + Na)+.
Acknowledgment
We thank Dr. Fayang Qiu for helpful discussion. Financial support
of this work was provided by the Chinese Academy Science Inno-
vation Grant (grant number: KSCX1-YW-10) and Guangzhou Sci-
ence and Technology Plan Item (item number: 2006Z2-E5011).
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Synthesis 2010, No. 19, 3325–3331 © Thieme Stuttgart · New York