A practical approach to synthesize the C(9)-C(24) fragment of (+)-discodermolide

Article abstract of DOI:10.1002/cjoc.201090240

A practical and stereoselective synthesis of the C(9)-C(24) subunit of (+)-discodermolide has been achieved. The strategy featured the construction of the key intermediate Z-trisubstituted vinyl iodide 12 from the dibromoolefin 6 via an efficient modified

Full text of DOI:10.1002/cjoc.201090240

FULL PAPER
A Practical Approach to Synthesize the C(9)—C(24) Fragment
of (＋)-Discodermolide
Yin, Zengshenga(尹增升)
Yue, Xuyib(乐旭义)
Deng, Xiangjuna(邓向君)
Qing, Fengling*,a,b(卿凤翎)
a College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu,
Shanghai 201620, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China
A practical and stereoselective synthesis of the C(9)—C(24) subunit of (＋)-discodermolide has been achieved.
The strategy featured the construction of the key intermediate Z-trisubstituted vinyl iodide 12 from the dibromo-
olefin 6 via an efficient modified Tanino-Miyashita’s approach. The union of the two fragments was carried out
through a Suzuki cross-coupling reaction.
Keywords (＋)-discodermolide, Z-trisubstituted vinyl iodide, Suzuki cross-coupling reaction
Introduction
developed several generations total synthesis to opti-
mize their synthetic routes. Furthermore, Novartis
Pharmaceuticals achieved the large scale synthesis of
(＋)-discodermolide utilizing a hybridized Novartis-
Smith-Paterson synthetic route via a common precur-
sor.6k For all the synthetic strategies mentioned above,
the C(9)—C(24) fragment is a key and synthetic chal-
lenging intermediate (Scheme 1).
Discodermolide (1, Scheme 1) was firstly isolated
from the deep sea marine sponge Discodermia dissolute
by Gunasekera and co-workers in 1990.1 Preliminary
biological evaluations suggested that (＋)-discoder-
molide was a potent immunosuppressive agent, both in
vivo and in vitro, as well as displaying antifungal
activity. It was later demonstrated that discodermolide
showed potent antimitotic activity, the mechanism of
action, similar to that of the clinically proven anticancer
drug Taxol, entails binding and stabilization of micro-
tubules, leading to cell cycle arrest in the G2/M-phase
and ultimately apoptosis.2 More importantly, discoder-
molide displays stronger bind ability to microtubule
than Taxol3 and low nanomolar antiproliferative activity
against multi-drug resistant (MDR) cell lines which are
resistant to Taxol.4 Further bioactive studies suggest that
the presence of low concentrations of Taxol amplified
the toxicity of discodermolide by 20-fold, this synergy
was not observed in other microtubule-stabilizing agent
such as epothilones.4,5 Due to the excellent bioactivity
and the limited availability of ( ＋)-discodermolide
(0.002% w/w isolation yield)1 from natural sources, or-
ganic chemists have developed lots of methods toward
the total synthesis of discodermolide6 and its analogues
for the demand of clinical trial.7
Based on the Smith’s synthetic strategy, the C(9)—
C(24) subunit 2 could be disconnected into fragment 3
[C(9)—C(14)] and fragment 4 [C(15)—C(24)] (Scheme
2). For the preparation of C(9)—C(14) subunit, the con-
struction of C(13)—C(14) cis-trisubstituted double bond
was one of the difficult reactions for scale up, although
a number of strategies for the construction of this
cis-trisubstituted double bond have been developed.
Smith8 and Novartis9 introduced the cis-trisubstituted
double bond via Zhao-Wittig olefination (Scheme 3).
Paterson6h described a route to the construction of a
trisubstituted olefin by Claisen rearrangement (Scheme
4). Panek10 constructed the double bond through a
strategy involving acetylene chemistry, followed by a
Negishi coupling, and iodidation of the resulting silyl
function group (Scheme 5). Unfortunately none of the
aforementioned methods was deemed suitable for the
scale-up construction of the cis-trisubstituted double
bond primarily either because of the low yield of
Zhao-Wittig olefination, or the toxicity of the selenium
chemistry and the use of the expensive Schwarz reagent.
Herein we describe the highly efficient construction of
the C(13)—C(14) cis-trisubstituted double bond from
the dibromoolefin 6 by modified Tanino and
Since Schreiber and co-workers reported the first
total synthesis of unnatural (－)-discodermolide in
1993,6a several groups had described their total
synthesis of discodermolide in the following years.6
Among them, Smith’s group and Paterson’s group
*
E-mail: flq@mail.sioc.ac.cn; Fax: 0086-021-64166128
Received November 20, 2009; revised March 22, 2010; accepted April 9, 2010.
Project supported by the National Natural Science Foundation of China (Nos. 20672020, 20832008) and Shanghai Municipal Scientific Committee.
1400
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1400— 1408

A Practical Approach to Synthesize the C(9)—C(24) Fragment of (＋)-Discodermolide
Scheme 1 Structure of (＋)-discodermolide and C(9)— C(24) subunit
Scheme 2 Retrosynthetic analysis of the C(9)— C(24) fragment of (＋)-discodermolide
Scheme 3 Novartis’ and Smith’s strategy for the preparation of the C(13)— C(14) cis-trisubstituted double bond
Scheme 4 Paterson’s approach to C(13)— C(14) cis-trisubstituted double bond
Chin. J. Chem. 2010, 28, 1400— 1408
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1401

Yin et al.
FULL PAPER
Scheme 5 Panek’s approach to C(13)— C(14) cis-trisubstituted
double bond
separated. The aqueous layer was extracted with CH2Cl2
(200 mL×3) and the combined organic layers were
dried over anhydrous MgSO4. Flash chromatography
(ethyl acetate/petroleum ether ＝ 1/4, V/V) provided 7
(28.79 g, 83% yield for two steps) as a colorless oil
whose spectroscopic data are identical with those in the
literature.21 1H NMR (CDCl3, 300 MHz) δ: 7.36—7.20
(m, 7H), 6.86 (d, J＝8.4 Hz, 2H), 4.69—4.61 (m, 1H),
4.44 (s, 2H), 4.20—4.11 (m, 2H), 3.95—3.92 (m, 1H),
3.89—3.85 (m, 1H), 3.79 (s, 3H), 3.60—3.48 (m, 2H),
3.32 (dd, J＝13.5, 2.7 Hz, 1H), 2.76 (dd, J＝13.5, 9.9
Hz, 1H), 2.01—1.92 (m, 1H), 1.25 (d, J＝6.9 Hz, 3H),
0.94 (d, J＝7.2 Hz, 3H).
(R)-3-((2R,3S,4S)-5-(4-Methoxybenzyloxy)-3-
(methoxymethoxy)-2,4-dimethylpentanoyl)-4-benzyl-
oxazolidin-2-one (10) A solution of alcohol 7 (0.83 g,
1.87 mmol) in CH2Cl2 (20 mL) was treated with DIPEA
(0.70 mL, 3.7 mmol), then cooled to 0 ℃ and MOMCl
(0.21 mL, 2.8 mmol) was added dropwise. After stirring
for 5 h at room temperature, additional MOMCl (0.21
mL, 2.8 mmol) was added. The reaction was monitored
by TLC and quenched with saturated NH4Cl solution
(10 mL), the aqueous layer was extracted with CH2Cl2
(15 mL×3). The combined organic layers were concen-
trated and diluted with Et2O (30 mL), then washed with
H2O (20 mL), saturated aqueous NaHCO3 (20 mL),
brine (20 mL) and dried over anhydrous MgSO4. Flash
chromatography (ethyl acetate/petroleum ether＝1/4, V/V)
provided 10 (0.90 g, 99% yield) as a colorless oil. [α]D25
Miyashita’s approach (Scheme 2). In addition, the ter-
minal C(21)—C(24) diene was installed before the un-
ion of the fragments 3 and 4, which is in contrast to the
reported synthetic strategies that the terminal C(21)—
C(24) diene was installed after the union of the two seg-
ments 3 and 4.
Experimental section
Reagents and apparatus
All reagents were used as received from commercial
sources, unless specified otherwise, or prepared as de-
scribed in the literature. Dichloromethane and DMF
1
were distilled from CaH2. H NMR and 13C NMR spec-
tra were recorded on a Bruker AM300 spectrometer.
Melting points are uncorrected.
1
－54.5 (c 1.6, CHCl3). H NMR (CDCl3, 300 MHz) δ:
(R)-4-Benzyl-3-((2R,3S,4S)-3-hydroxy-5-(4-meth-
oxybenzyloxy)-2,4-dimethylpentanoyl)oxazolidin-2-
one (7) To a solution of oxalyl chloride (13.6 mL,
0.16 mol) in CH2Cl2 (150 mL) at －78 ℃ was added
DMSO (28.3 mL, 0.39 mol). After stirring at this tem-
perature for 30 min, a solution of alcohol 9 (16.53 g,
78.6 mmol) in CH2Cl2 (50 mL) was added dropwise.
The reaction mixture was stirred at －78 ℃ for a fur-
ther 30 min before the addition of Et3N (54.5 mL, 0.39
mol). After 15 min, the reaction mixture was warmed to
room temperature and quenched with NaHSO4 solution
and extracted with Et2O (200 mL×3). The combined
organic extracts were washed with dilute NaHSO4 aque-
ous solution (50 mL), H2O (80 mL), saturated aqueous
NaHCO3 (80 mL), brine (80 mL), dried over anhydrous
MgSO4, filtered and concentrated in vacuo to afford the
corresponding aldehyde which can be used for the next
step without further purification.
7.31—7.18 (m, 7H), 6.83 (d, J＝8.4 Hz, 2H), 4.61—
4.54 (m, 2H), 4.49—4.42 (m, 1H), 4.38—4.36 (m, 2H),
4.17—3.98 (m, 2H), 3.95—3.89 (m, 1H), 3.82—3.78 (m,
1H), 3.76 (s, 3H), 3.49 (dd, J＝9.3, 5.1 Hz, 1H), 3.34—
3.24 (m, 2H), 3.32 (s, 3H), 2.77—2.70 (m, 1H), 2.02—
1.98 (m, 1H), 1.25 (d, J＝7.2 Hz, 3H), 1.05 (d, J＝6.9
Hz, 3H). 13C NMR (CDCl3, 100.7 MHz) δ: 175.4, 159.1,
153.1, 135.6, 130.6, 129.4, 129.1, 128.9, 127.3, 113.7,
98.8, 82.7, 72.7, 71.7, 66.1, 56.4, 55.9, 55.2, 41.0, 37.7,
37.3, 14.7, 11.9; IR (KBr) ν: 2972, 2937－, 1779, 1702,
1
1612, 1585, 1513, 1455, 1383, 1032 cm . MS (ESI)
＋
m/z: 508.4 (M ＋ Na) ; HRMS (ESI) calcd for
C27H35NNaO7 (M＋Na)＋ 508.2306, found 508.2301.
(2S,3R,4S)-5-(4-Methoxybenzyloxy)-3-(methoxy-
methoxy)-2,4-dimethylpentan-1-ol (11) At －30 ℃,
a solution of imide 10 (2.623 g, 5.4 mmol) in THF (30
mL) was treated with EtOH (0.64 mL, 10.8 mmol).
－1
Then LiBH4 (2.0 mol•L in THF, 5.4 mL, 10.8 mmol)
Titanium(IV) chloride (10.4 mL, 94.3 mmol) was
added dropwise to a solution of (R)-4-benzyl-3-
propionyloxazolidin-2-one (20.15 g, 86.47 mmol) in
CH2Cl2 (200 mL) at 0 ℃ and the resulting mixture was
stirred for 5 min. Subsequently, TMEDA (29.4 mL, 0.20
mol) was added to the yellow slurry. The dark red
enolate solution was stirred for 20 min at 0 ℃ before a
solution of the aldehyde in CH2Cl2 (150 mL) was added
dropwise and the mixture was stirred for 1 h at 0 ℃.
The reaction was quenched with half-saturated aqueous
NH4Cl solution (100 mL) and the organic layer was
was added over 15 min. After stirring at 0 ℃ for 1 h
and at room temperature for 12 h, the mixture was di-
luted with ether (30 mL), quenched carefully with
－1
aqueous NaOH (1.0 mol•L , 10 mL). And then satu-
rated NH4Cl solution (10 mL) was added dropwise, the
aqueous layer was extracted with Et2O (20 mL×3). The
combined organic layers were washed with brine (50
mL), dried over anhydrous MgSO4, filtered and concen-
trated. The crude product was purified by flash chroma-
tography (ethyl acetate/petroleum ether＝1/2, V/V) to af-
1402
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1400— 1408

A Practical Approach to Synthesize the C(9)—C(24) Fragment of (＋)-Discodermolide
ford 11 (1.41 g, 84% yield) as a colorless oil. [α]2D5 47.8
(c 1.8, CHCl3). H NMR (300 MHz, CDCl3) δ: 7.26 (d,
tion was cooled to －78 ℃, and a solution of 6 (490
1
mg, 1.06 mmol) in Et2O (6 mL) was added. After
stirring for 30 min at －78 ℃, a solution of I2 (1.609 g,
6.336 mmol) in THF (10 mL) was added dropwise. The
reaction mixture was warmed to 0 ℃ and stirred for 30
min, then quenched with aqueous NH4Cl solution. The
aqueous layer was extracted with diethyl ether (20 mL
×3). The combined organic layers were washed with
dilute aqueous Na2S2O3, saturated aqueous NaHCO3 (30
mL), brine (30 mL), dried over anhydrous MgSO4.
Flash chromatography (5% ethyl acetate/petroleum ether)
provided 13 (393 mg, 83% yield) whose spectroscopic
data are identical with those in the literature.6i 1H NMR
(CDCl3, 300 MHz) δ: 7.26 (d, J＝9.0 Hz, 2H), 6.87 (d,
J＝8.4Hz, 2H), 5.37 (d, J＝9.0 Hz, 1H), 4.62—4.59 (m,
2H), 4.42 (s, 2H), 3.8 (s, 3H), 3.54—3.49 (m, 1H), 3.41
—3.31 (m, 5H), 2.61—2.54 (m, 1H), 2.46 (s, 3H), 2.02
—1.94 (m, 1H), 1.04 (d, J＝6.9 Hz, 3H), 0.98 (d, J＝6.3
Hz, 3H). MS (ESI) m/z: 471.0 (M＋Na)＋.
J＝8.4 Hz, 2H), 6.86 (d, J＝8.7 Hz, 2H), 4.61 (Abq, JAB
＝6.6 Hz, ∆υAB＝28.2 Hz, 2H), 4.41 (s, 2H), 3.78 (s,
3H), 3.66 (dd, J＝9, 1.8 Hz, 1H), 3.50—3.44 (m, 4H),
3.38 (s, 3H), 3.3 (br, 1H), 1.90 (m, 2H), 0.96 (d, J＝6.9
Hz, 3H), 0.78 (d, J＝6.9 Hz, 3H). 13C NMR (100.7 MHz,
CDCl3) δ: 159.1, 130.5, 129.2, 113.7, 98.6, 80.5, 72.7,
72.1, 64.9, 56.1, 55.2, 36.6, 14.6, 9.5. IR (KBr) ν: 3462,
2964, 2935, 1613, 1586, 1514, 1464, 1363, 1248, 1173,
＋
－1
1091 cm . MS (ESI) m/z: 335.4 (＋M＋Na) . HRMS
(ESI) calcd for C17H28NaO5 (M＋Na) 335.1829, found
335.1827.
1-(((2S,3R,4S)-6,6-Dibromo-3-(methoxymethoxy)-
2,4-dimethylhex-5-enyloxy)methyl)-4-methoxy-
benzene (6) To a solution of oxalyl chloride (0.47 mL,
5.48 mmol) in CH2Cl2 (10 mL) at －78 ℃ was added
DMSO (0.97 mL, 13.70 mmol). After stirring at this
temperature for 30 min, a solution of alcohol 11 (0.86 g,
2.74 mmol) in CH2Cl2 (3 mL) was added dropwise. The
reaction mixture was stirred at －78 ℃ for a further 30
min before the addition of Et3N (1.90 mL, 13.70 mmol).
After 15 min, the reaction mixture was warmed to room
temperature and quenched with NaHSO4 solution, ex-
tracted with Et2O (20 mL×3). The combined organic
extracts were washed with dilute NaHSO4 aqueous solu-
tion (30 mL), H2O (30 mL), saturated aqueous NaHCO3
(30 mL), brine (30 mL), dried over MgSO4, filtered and
concentrated in vacuo to afford the corresponding alde-
hyde which can be used for next step without further
purification.
(5R,6S)-5-((1R)-1-((4S,5S)-2-(4-Methoxyphenyl)-5-
methyl-1,3-dioxan-4-yl)ethyl)-2,2,3,3,6,9,9,10,10-
nonamethyl-4,8-dioxa-3,9-disilaundecane (5) To a
solution of alcohol 17 (2.872 g, 6.6 mmol) in CH2Cl2
(20 mL) was added imidazole (892 mg, 13.1 mmol) and
TBSCl (1.492 g, 9.9 mmol). The mixture was stirred for
1 h at room temperature, then quenched with a brine
solution, extracted with CH2Cl2 (15 mL×3), and
washed with H2O (10 mL). The organic layers were
dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. Flash chromatography (ethyl acetate/petroleum
ether＝1/40, V/V) provided 5 (3.16 g, 87% yield).
1
To a solution of PPh3 (2.872 g, 10.96 mmol) in
CH2Cl2 (15 mL) was added CBr4 (1.82 g, 5.48 mmol) at
0 ℃. After stirring for 15 min, a solution of the alde-
hyde and 2,6-lutidine (638 µL) in CH2Cl2 (5 mL) was
added. After stirring for 4 h, the reaction mixture was
quenched with saturated NH4Cl solution and extracted
with CH2Cl2 (20 mL×3). The combined organic ex-
tracts were dried over anhydrous MgSO4. Flash chro-
matography (ethyl acetate/petroleum ether＝1/20, V/V)
provided 6 (0.99 g, 78% yield for two steps) as a color-
[α]2D8 27.4 (c 2.4, CHCl3). H NMR (CDCl3, 300 MHz)
δ: 7.38 (d, J＝8.7 Hz, 2H), 6.86 (d, J＝9.0 Hz, 2H), 5.40
(s, 1H), 4.09 (dd, J＝11.4, 4.8 Hz, 1H), 3.87 (d, J＝7.2
Hz, 1H) 3.80 (s, 3H), 3.55 (d, J＝9.6 Hz, 1H), 3.52—
3.34 (m, 3H), 2.07—1.99 (m, 1H), 1.93—1.86 (m, 2H),
1.00 (d, J＝7.2 Hz, 3H), 0.90 (s, 9H), 0.84 (s, 9H), 0.80
(d, J＝6.6 Hz, 3H), 0.73 (d, J＝6.3 Hz, 3H), 0.03 (d,
J＝1.5 Hz, 6H), －0.03 (d, J＝4.5 Hz, 6H). IR (KBr) ν:
2950, 2930, 2857, 1618, 1560, 1518, ＋1461, 1249, 1125
－1
cm . MS (ESI) m/z: 575.3 (M＋Na) . Anal. calcd for
1
less oil. [α]2D5 24.6 (c 2.1, CHCl3). H NMR (300 MHz,
C30H56O5Si2: C 65.17, H 10.21; found C 65.32, H 10.25.
(2S,3S,4R,5R,6S)-5,7-bis(tert-butyldimethylsilyl-
oxy)-3-(4-methoxybenzyloxy)-2,4,6-trimethylheptan-
1-ol (19) To a solution of 5 (1.02 g, 1.85 mmol) in
toluene (47 mL) was added dropwise a solution of DI-
CDCl3) δ: 7.26 (d, J＝8.7 Hz, 2H), 6.88 (d, J＝8.7 Hz,
2H), 6.40 (d, J＝9.9 Hz, 1H), 4.60 (ABq, JAB＝6.3 Hz,
∆υAB＝12.3 Hz, 2H), 4.42 (s, 2H), 3.81 (s, 3H), 3.51—
3.48 (m, 3H), 3.38 (s, 3H), 2.74—2.63 (m, 1H), 2.01—
1.93 (m, 1H), 1.03 (d, J＝5.1 Hz, 3H), 1.01 (d, J＝4.8
Hz, 3H). 13C NMR (CDCl3, 100.7 MHz) δ: 159.0, 142.0,
130.5, 129.2, 113.7, 98.0, 87.9, 82.7, 72.7, 71.7, 56.0,
55.2, 40.1, 36.7, 14.5, 13.5. IR (KBr) ν: 2971, 2934,
2885, 1612, 1586, 1513, 1462, 1362, 1＋247, 1172, 1091
－1
BAL (9.24 mL 1.0 mol•L solution in toluene, 9.24
mmol) at －15 ℃ within 30 min. The reaction mixture
was warmed to 0—5 ℃ and stirred for 1 h. Ethyl ace-
tate (40 mL) was then added, maintaining the tempera-
ture at 0 ℃, followed by saturated sodium potassium
tartrate (30 mL). The mixture was warmed to 25 ℃
and stirred for an additional 1 h. The organic layer was
separated. The aqueous phase was extracted with ethyl
acetate (40 mL). The combined organic extracts were
washed with H2O (20 mL) and brine (20 mL), dried
over anhydrous MgSO4. Flash chromatography (ethyl
acetate/petroleum ether＝1/10, V/V) provided 19 (0.785 g,
77% yield) as a colorless oil. [α]2D5 3.5 (c 1.2, CHCl3).
－1
cm . MS (ESI) m/z: 487.0 (M＋Na) . HRMS (ESI)
calcd for C18H26Br2NaO4 (M＋Na)＋ 487.0090, found
487.0090.
1-(((2S,3R,4S,Z)-6-Iodo-3-(methoxymethoxy)-2,4-
dimethylhept-5-enyloxy)methyl)-4-methoxybenzene
(13) To a suspension of CuI (605 mg, 3.17 mmol) in
Et2O (10 mL) was added MeLi (3.96 mL, 6.34 mmol,
－1
1.6 mol•L in Et2O) at 0 ℃. The resulting clear solu-
Chin. J. Chem. 2010, 28, 1400—1408
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1403

Yin et al.
FULL PAPER
1H NMR (CDCl3, 300 MHz) δ: 7.26 (d, J＝8.4 Hz, 2H),
6.87 (d, J＝8.7 Hz, 2H), 4.52 (ABq, JAB＝10.2 Hz,
∆υAB＝42.3 Hz, 2H), 3.88 (dd, J＝6.9, 1.8 Hz, 1H), 3.80
(s, 3H), 3.71 (dd, J＝11.1, 3.3 Hz, 1H), 3.58 (dd, J＝
11.1, 6.0 Hz, 1H), 3.53—3.36 (m, 3H), 2.11 (br, 1H),
1.93 (m, 3H), 1.02 (d, J＝6.0 Hz, 3H), 1.00 (d, J＝6.0
Hz, 3H), 0.92 (s, 9H), 0.87 (s, 9H), 0.83 (d, J＝6.9 Hz,
3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.03 (s, 6H). IR (KBr) ν:
3483, 2955, 2929, 2857, 1613, 1587, 1514, 1471, 1389,
0.02 (s, 6H). 13C NMR (CDCl3, 100.7 MHz) δ: 159.0,
135.1, 132.5, 131.3, 129.1, 117.3, 113.6, 84.2, 74.7,
73.0, 66.0, 55.2, 40.6, 40.4, 35.9, 26.3, 26.1, 26.0, 18.6,
18.4, 11.6, 11.0, －3.4, －3.7. MS (ESI) m/z: 599.5 (M＋
Na)＋. HRMS (ESI) calcd for C33H60NaO4Si (M＋Na)＋
599.3922, found 599.3942.
(2S,3R,4R,5S,6S,Z)-3-(tert-Butyldimethylsilyloxy)-
5-(4-methoxybenzyloxy)-2,4,6-trimethyldeca-7,9-
dien-1-ol (21) Bis-TBS alcohol 20 (184 mg, 0.32
mmol) was dissolved in a 1% HCl/EtOH solution (3 mL)
(37% HCl solution∶EtOH＝1∶99), stirred for 1 h and
keeping the internal temperature at 15—20 ℃. The
mixture was then neutralized with saturated NaHCO3
solution, extracted with CH2Cl2 (10 mL×3), and the
combined organic layers were dried over anhydrous
MgSO4. Flash chromatography (ethyl acetate/petroleum
ether＝1/5, V/V) provided 21 (145 mg, 98%) as a color-
less oil whose spectroscopic data are identical with
those in the literature.6m 1H NMR (CDCl3, 300 MHz) δ:
7.27 (d, J＝8.1 Hz, 2H), 6.86 (d, J＝8.1 Hz, 2H), 6.68—
6.55 (m, 1H), 6.03 (t, J＝10.8 Hz, 1H), 5.57 (t, J＝10.8
Hz, 1H), 5.20 (d, J＝17.1 Hz, 1H), 5.12 (d, J＝10.5 Hz,
1H), 4.51 (ABq, JAB＝10.5 Hz, ∆υAB＝30.0 Hz, 2H),
3.80 (s, 3H), 3.70 (t, J＝4.2 Hz, 1H), 3.54 (dd, J＝10.5,
7.2 Hz, 1H), 3.40 (dd, J＝10.5, 6.3 Hz, 1H), 3.22 (dd,
J＝6.3, 4.5 Hz, 1H), 3.02—2.95 (m, 1H), 1.89—1.74 (m,
2H), 1.66 (br, 1H), 1.08 (d, J＝6.6 Hz, 3H), 1.02 (d, J＝
6.6 Hz, 3H), 0.93 (s, 9H), 0.83 (d, J＝6.6 Hz, 3H), 0.08
(d, J＝5.4 Hz, 6H).
－1
1361, ＋1251, 1173, 1037 cm . MS (ESI) m/z: 577.5 (M
＋Na) . Anal. calcd for C30H58O5Si2: C 64.93, H 10.53;
found C 65.48, H 10.62.
(5R,6S)-5-((2R,3S,4S,Z)-3-(4-Methoxybenzyloxy)-
4-methylocta-5,7-dien-2-yl)-2,2,3,3,6,9,9,10,10-
nonamethyl-4,8-dioxa-3,9-disilaundecane (20) To a
solution of oxalyl chloride (0.17 mL, 1.94 mmol) in
CH2Cl2 (5 mL) at －78 ℃ was added DMSO (0.35
mL, 4.85 mmol). After stirring at this temperature for 30
min, a solution of alcohol 19 (0.538 g, 0.97 mmol) in
CH2Cl2 (3 mL) was added dropwise. The reaction mix-
ture was stirred at －78 ℃ for a further 30 min before
the addition of Et3N (0.67 mL, 4.85 mmol). After 15
min, the reaction mixture was warmed to room tem-
perature and quenched with NaHSO4 solution, extracted
with Et2O (20 mL×3). The combined organic extracts
were washed with dilute NaHSO4 aqueous solution (20
mL), H2O (20 mL), saturated aqueous NaHCO3 (30 mL),
brine (20 mL), dried over anhydrous MgSO4, filtered
and concentrated in vacuo to afford the corresponding
aldehyde which can be used next without further purifi-
cation.
Results and discussion
To a suspension of CrCl2 (478 mg, 3.88 mmol) in
THF (8 mL) was added a solution of the aldehyde and
(1-bromoallyl)trimethylsilane (1.13 g, 5.83 mmol) in
THF (4 mL) at 0 ℃, warmed to room temperature and
stirred for 20 h. The resultant deep purple suspension
was partitioned between pH 7 buffer (10 mL) and
EtOAc (15 mL), separated and the aqueous layer was
extracted with EtOAc (10 mL×3), the combined
organics was washed with brine and dried over anhy-
drous MgSO4, concentrated in vacuo. The residue was
dissolved in THF (5 mL) and added to a suspension of
NaH (186 mg, 7.77 mmol) in THF (5 mL) dropwise.
After 2 h, the reaction was cooled to 0 ℃, quenched
with NaHCO3 solution carefully and extracted with
Et2O (10 mL×3). The combined organic extracts were
dried over anhydrous MgSO4. Flash chromatography
(ethyl acetate/petroleum ether＝1/60, V/V) provided 20
As shown in Scheme 2, the C(14)—C(15) bond in
C(9)—C(24) subunit could be formed through a Suzuki
cross-coupling reaction between the vinyl iodide 4 and
the iodide 3. The iodide 3 could be synthesized from
compound 5.6h The Z-trisubstituted vinyl iodide 4 was
intended to be prepared from the dibromoolefin 6 by a
modified Tanino and Miyashita’s approach. Fragments
5 and 6 were envisioned to arise from a common pre-
cursor 7 possessing three contiguous stereogenic centers
(Scheme 2).
Synthesis of the C(9)—C(14) fragment 4 began with
the commercial available Roche ester 8 (Scheme 6).
Protection of ester 8 as PMB ether and followed by
direct reduction with LiAlH4 gave alcohol 9 in 86%
yield in two steps.11 Generally, compound 7 was ob-
tained through Aldol reaction of the aldehyde prepared
from oxidation of 8 and (R)-4-benzyl-3-propionyloxa-
zolidin-2-one in the presence of n-Bu2BOTf. But this
reaction must be carried out in strict anhydrous system
and the success of this reaction was largely dependent
on the quality of the n-Bu2BOTf, a large scale synthesis
of aldol product 7 was limited because the yield was
drastically decreased.6k Delightfully, we found that
when TiCl4 was used instead of the n-Bu2BOTf in this
aldol reaction, the large amount of 7 (28.0 g) could be
obtained in 83% yield in two steps and the diastereo-
1
(356 mg, 64% yield). [α]2D8 28.4 (c 1.0, CHCl3). H
NMR (CDCl3, 300 MHz) δ: 7.25 (d, J＝8.7 Hz, 2H),
6.85 (d, J＝8.7 Hz, 2H), 6.68—6.55 (m, 1H), 6.01 (t,
J＝11.1 Hz, 1H), 5.51 (t, J＝10.5 Hz, 1H), 5.18 (d, J＝
17.1 Hz, 1H), 5.09 (d, J＝10.2 Hz, 1H), 4.49 (ABq, JAB
＝10.5 Hz, ∆υAB＝23.7 Hz, 2H), 3.80 (s, 3H), 3.65 (dd,
J＝5.7, 3.9 Hz, 1H), 3.48 (dd, J＝9.6, 6.3 Hz, 1H), 3.30
—3.22 (m, 2H), 3.21—2.92 (m, 1H), 1.79—1.75 (m, 2H),
1.05 (d, J＝6.6 Hz, 3H), 0.96 (d, J＝6.6 Hz, 3H), 0.92 (s,
9H), 0.88 (s, 9H), 0.83 (d, J＝6.9 Hz, 3H), 0.06 (s, 6H),
1404
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1400—1408

A Practical Approach to Synthesize the C(9)—C(24) Fragment of (＋)-Discodermolide
selectivity was retained (no diastereomers was found
1). It was also found that the stirring was very hard
1
according to H NMR analysis).12 To obtain the alde-
when the solution of iodine in Et2O was added to the
reaction mixture, which is a fatal limitation of this reac-
tion for scale-up. To optimize the reaction conditions,
the experiment was carried out at variations in solvents,
Me2CuLi amount and iodide reagent (Table 1). More
amount of Me2CuLi resulted in more byproducts (Table
1, Entry 2), when NIS (N-iodosuccinimide) was used to
replace iodine, more 13a was generated and the 6 was
not converted completely (Table 1, Entry 3). To our de-
light, the reaction proceeded easier to stir when the solu-
tion of iodine in THF was added to the reaction mixture
in Et2O. Furthermore the expected vinyl iodide 13 was
obtained in 83% yield along with only a small amount
of 1,1-dimethylalkene 13a and Z-trisubstituted vinyl
bromide 13b (Table 1, Entry 4). To the best of our
knowledge, this represented the highest yield for the
construction of trisubstituted cis double bond. Removal
of the PMB moiety of 13 under DDQ/H2O oxidative
conditions furnished alcohol 14 in 82% yield, the resul-
tant alcohol 14 reprotected as the TBS ether to give the
C(9)—C(14) fragment 4 in 90% yield (Scheme 6).6m
With the fragment 4 in hand, we focused on the
synthesis of the fragment C(15)—C(24) fragment 3
(Scheme 7). Elaboration of the C(15)—C(24) fragment
3 began with DDQ oxidation of the common precursor 7
to generate acetal 15 in 85% yield. Reductive removal
of the chiral auxiliary by treatment of 15 with LiBH4 in
THF/H2O furnished alcohol 16 in 87% yield.16 Swern
oxidation of 16 led to the corresponding aldehyde,
which underwent syn Evans aldol addition of
hyde 12, Smith and coworkers employed Weinreb
transamidation of 7 in the presence of Me3Al, however,
Me3Al is a dangerous and not readily available reagent
due to its pyrophoric properties.6k To circumvent the
problem, alcohol 7 was protected as MOM ether, then
removal of the chiral auxiliary by treatment of 10 with
LiBH4 afforded alcohol 11 in 84% yield.13 Swern oxida-
tion of 11 gave the aldehyde 12 successfully.
To prepare the Z-trisubstituted vinyl iodide 13,
Smith,8 Marshall6e and the Novartis group9 employed
Zhao-Wittig olefination reaction in moderate yield.
However, in our trial, this olefination step was one of
the most difficult reactions. When the iodoylide pre-
pared in situ from the ethyltriphenylphonium iodide was
treated with aldehyde 12, only 20% yield of the ex-
pected product 13 was obtained and the result was also
hard to reproduce. Recently, we noticed that Tanino and
Miyashita reported the conversion of dibromoolefin to
Z-trisubstituted vinyl iodide in satisfied yield and the
method has been applied successfully in the synthesis of
the C(9)—C(14) subunit of discodermolide.14 We set
our mind to employ Tanino and Miyashita’s method to
improve the efficiency of preparing vinyl iodide 13. Ini-
tially, aldehyde 12 was converted to dibromoolefin 6 via
Corey-Fuchs15 homologation in 78% yield (from 11).
Treatment of 6 with Me2CuLi and iodine afforded the
desired Z-trisubstituted vinyl iodide 13 in 64% yield
along with 1,1-dimethylalkene 13a, Z-trisubstituted vi-
nyl bromide 13b and alkynyl iodide 13c (Table 1, Entry
Scheme 6
Reagents and conditions: a) (i) PMBOH, NaH, Cl3CCN, (＋)-10-CAS, CH2Cl2/cyclohexane (1/2); (ii) LiAlH4, THF, 86% for two steps; b) (i) DMSO,
(ClCO)2, Et3N, －78 ℃; (ii) TiCl4, TMEDA, (R)-4-benzyl-3-propionyloxazolidin-2-one, 0 ℃, 83% for 2 steps; c) MOMCl, DIPEA, 99%; d) LiBH4, EtOH,
84%; e) DMSO, (ClCO)2, Et3N, －78 ℃; f) PPh3, CBr4, Et3N, 0 ℃, 78% for two steps; g) MeLi, CuI, I2, －78 ℃, 83%; h) DDQ, H2O, 82%; i) TBSCl,
imidazole, 90%.
Chin. J. Chem. 2010, 28, 1400—1408
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1405

Yin et al.
FULL PAPER
Table 1 Conversion of dibromoolefin 6 to Z-trisubstituted vinyl iodide 13
Entry
Solvent
Et2O
Me2CuLi amount
3 equiv.
Iodide reagent
Byproducta
13a, 13b, 13c
13a, 13b, 13c, 13d
13a, 13bc
Yieldb of 13
1
2
3
4
I2
64%
70%
70%
83%
Et2O
4 equiv.
I2
Et2O
3 equiv.
NIS
Et2O/THF
3 equiv.
I2
13a, 13b
a Determined by MS-ESI. b Isolated yield. c A small amount of 6 was found.
Scheme 7
Reagents and conditions: a) DDQ, CH2Cl2, 85%; b) LiBH4, H2O, －30 ℃ to 0 ℃, 87%; c) (i) DMSO, (ClCO)2, Et3N, －78 ℃; (ii) n-Bu2BOTf, Et3N,
(R)-4-benzyl-3-propionyloxazolidin-2-one, －78 ℃, 85% for 2 steps; d) (i) TBSOTf, 2,6-lutidine, 98%; (ii) LiBH4, H2O, 91%; e) TBSCl, imidazole, 87%; f)
DIBAL-H, 77%; g) (i) DMSO, (ClCO)2, Et3N, －78 ℃; (ii) CrCl2, (1-bromoallyl)trimethylsilane, NaH, 64% for 2 steps; h) HCl/EtOH (1/99), 20 ℃, 98%; i)
PPh3, I2, imidazole, quant.
(R)-4-benzyl-3-propionyloxazolidin-2-one in the pres-
ence of the n-Bu2BOTf to give the aldol product 17 in
85% yield in two steps.6a Compound 17 is not configu-
rationally stable at 0 ℃ or above, protecting hydroxyl
group of 17 as TBS ether immediately was important
and necessary.17 Reductive removal of the chiral auxil-
iary by treatment with LiBH4 in THF/H2O afforded al-
cohol 18 in 91% yield.6a,17
Attention was turned to the installation of the termi-
nal Z diene before the union of the two segments, which
would facilitate the synthesis of C(9)—C(24) subunit.
Thus, protection of 18 as TBS ether furnished the
bis-TBS ether 5 in 87% yield (Scheme 7). Regio-
selective ring opening of the acetal 5 was carried out by
treatment with DIBAL-H to give the alcohol 19 in 77%
yield. Swern oxidation of the alcohol 19 and the
1406
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1400—1408

A Practical Approach to Synthesize the C(9)—C(24) Fragment of (＋)-Discodermolide
resulting aldehyde was subjected to Nazaki-Hiyama
reaction18 and Peterson-type syn elimination19 to provide
the terminal diene compound 20 in moderate yield (64%
from 19). Selective deprotection of the bis-TBS ether 20
by treatment with HCl/EtOH (1/99) at 20 ℃ afforded
primary alcohol 21 in 98% yield.6i Synthesis of the C(15)
—C(24) fragment 3 was completed by iodination of 21
in the presence of PPh3, I2 and imidazole in quantitative
yield.20
the first time. Unfortunately, as described by the Nor-
vartis group, the reaction mixture was complex and the
separation was troublesome. Then we tried the union via
a modified Suzuki cross-coupling reaction (Scheme 8),
employed by Norvartis group and Smith in their
fourth-generation total synthesis. As expected, the union
of fragment 3 and 4 proceeded smoothly to afford C(9)
—C(24) fragment 2 successfully in 67% yield, whose
spectroscopic data are identical with those in the litera-
ture.6m
With the efficient synthetic access to fragment 4 and
3, we tried their union via Negishi coupling reaction at
Scheme 8 Union of fragment 3 and 4
7885.
References
(f) Smith, A. B., III; Kaufman, M. D.; Beauchamp, T. J.;
LaMarche, M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823.
(g) Halstead, D. P. Ph.D. Dissertation, Harvard University,
Cambridge, MA, 1999.
1
Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte,
G. K. J. Org. Chem. 1990, 55, 4912. Correction: J. Org.
Chem. 1991, 56, 1346.
2
(a) Longley, R. E.; Caddigan, D.; Harmony, D.; Gunasekera,
M.; Gunasekera, S. Transplantation 1991, 52, 650.
(b) Longley, R. E.; Caddigan, D.; Harmony, D.; Gunasekera,
M.; Gunasekera, S. Transplantation 1991, 52, 656.
(c) ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.;
Longley, R. E.; Gunasekera, S. P.; Rosenkranz, H. S.; Day,
B. W. Biochemistry 1996, 35, 243.
(d) Hung, D. T.; Chen, J.; Schreiber, S. L. Chem. Biol. 1996,
3, 287.
Kowalsi, R. J.; Fiannakakou, P.; Gunasekera, R. E.; Longley,
R. E.; Day, B. W.; Hamel, E. Mol. Pharmacol. 1997, 52,
613.
(h) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. Angew.
Chem., Int. Ed. 2000, 39, 377.
(i) Smith, A. B., III; Freeze, B. S.; Brouard, I.; Hirose, T.
Org. Lett. 2003, 5, 4405.
(j) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.;
Scott, J. P.; Sereinig, N. Org. Lett. 2003, 5, 35.
(k) Mickel, S. J.; Niederer, D.; Daeffler, R.; Osmani, A.;
Kuesters, E.; Schmid, E.; Schaer, K.; Gamboni, R.; Chen,
W.; Loeser, E.; Kinder, F. R., Jr.; Konigsberger, K.; Prasad,
K.; Ramsey, T. M.; Repič, O.; Wang, R.-M.; Florence, G.;
Lyothier, I.; Paterson, I. Org. Process Res. Dev. 2004, 8,
122 and references cited therein.
3
4
Martello, L. A.; McDaid, H. M.; Regl, D. L.; Yang, C. P. H.;
Meng, D.; Pettus, T. R. R.; Kaufman, M. D.; Arimoto, H.;
Danishefsky, S. J.; Smith, A. B., III; Horwitz, S. B. Clin.
Cancer Res. 2000, 6, 1978.
(l) Arefolov, A.; Panek, J. S. J. Am. Chem. Soc. 2005, 127,
5596.
(m) Smith, A. B., III; Freeze, B. S.; Xian, M.; Hirose, T.
Org. Lett. 2005, 7, 1825.
5
6
(a) Honore, S.; Kamath, K.; Braguer, D.; Horwitz, S. B.;
Wilson, L.; Briand, C.; Jordan, M. A. Cancer Res. 2004, 64,
4957.
(b) Huang, G. S.; Lopez-Barcons, L.; Freeze, B. S.; Smith,
A. B., III; Gorldberg, G. L.; Horwitz, S. B.; Mcdaid, H. M.
Clin. Cancer Res. 2006, 12, 298.
(a) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber,
S. L. J. Am. Chem. Soc. 1993, 115, 12621.
(b) Hung, D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am.
Chem. Soc. 1996, 118, 11054.
(n) Paterson, I.; Lyothier, I. Org. Lett. 2004, 6, 4933.
(o) Lemos, E. de; Porée, F. H.; Commerçon, A.; Betzer,
J.-F.; Pancrazi, A.; Ardisson, J. Angew. Chem. Int. Ed. 2007,
46, 1917.
7
8
For the review, see:
(a) Shaw, S. J. Mini-Rev. Med. Chem. 2008, 8, 276.
(b) Florence, G. J.; Gardner, N. M.; Paterson, I. Nat. Prod.
Rep. 2008, 25, 342.
(c) Smith, A. B., III; Freeze, B. S. Tetrahedron 2008, 64,
261.
(a) Smith, A. B., III.; Beauchamp, T. J.; LaMarche, M. J.;
Kaufman, M. D.; Qiu, Y. P.; Arimoto, H.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654.
(b) For an investigation of the mechanism of this transfor-
mation, see: Harimoto, H.; Kaufman, M. D.; Kobayashi, K.;
(c) Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J.
Am. Chem. Soc. 1995, 117, 12011.
(d) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J.
Org. Chem. 1997, 62, 6098.
(e) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63,
Chin. J. Chem. 2010, 28, 1400—1408
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1407

Yin et al.
FULL PAPER
Qiu, Y.; Smith, A. B., III. Synlett 1998, 765.
(b) Roche, C.; Roux, R. L.; Haddad, M.; Phansavath, P.;
Genêt, J.-P. Synlett 2009, 573.
15 Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
16 Jassen, D.; Albert, D.; Jansen, R.; Müller, R.; Kalesse, M.
Angew. Chem., Int. Ed. 2007, 46, 4898.
17 Mickel, S. J. Strategies and Tactics in Organic Synthesis
2005, 6, 269.
18 Paterson, I.; Schlapbach, A. Synlett 1995, 498.
19 For a review of Peterson-type eliminations, see: Ager, D.
Org. React. 1990, 38, 1.
20 Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.;
Koch, G.; Kuesters, E.; Daeffler, R.; Osmani, A.; See-
ger-Weibel, M.; Schmid, E.; Hirni, A.; Schaer, K.; Gamboni,
R.; Bach, A.; Chen, S.; Chen, W.; Geng, P.; Jagoe, C. T.;
Kinder, F. R., Jr.; Lee, G. T.; McKenna, J.; Ramsey, T. M.;
Repič, O.; Rogers, L.; Shieh, W. C.; Wang, R. M.; Waykole,
L. Org. Process Res. Dev. 2004, 8, 107.
21 Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.;
Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Koba-
yashi, K. J. Am. Chem. Soc. 2000, 122, 8654.
9
Mickel, S. J.; Sedelmeier, G. H.; Niederer, D.; Schuerch, F.;
Grimler, D.; Koch, G.; Daeffler, R.; Osmani, A.; Hirni, A.;
Schaer, K.; Gamboni, R.; Bach, A.; Chaudhary, A.; Chen, S.;
Chen, W.; Hu, B.; Jagoe, C. T.; Kim, H.-Y.; Kinder, F. R.;
Liu, Y.; Lu, Y.; McKenna, J.; Prashad, M.; Ramsey, T. M.;
Repič, O.; Rogers, L.; Shieh, W. C.; Wang, R. M.; Waykole,
L. Org. Process Res. Dev. 2004, 8, 101.
10 (a) Panek, J. S.; Hu, T. J. Org. Chem. 1997, 62, 4912.
(b) Arefolov, A.; Langille, N. F.; Panek, J. S. Org. Lett.
2001, 3, 3281.
(c) Arefolov, A.; Panek, J. S. Org. Lett. 2002, 4, 2397.
11 Mulzer, J.; Mantoulidis, A.; Öhler, E. J. Org. Chem. 2000,
65, 7456.
12 Herb, C.; Bayer, A.; Maier, M. E. Chem. Eur. J. 2004, 10,
5649.
13 Penning, T. D.; Djuric, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun.
1990, 20, 307.
14 (a) Tanino, K.; Arakawa, K.; Satoh, M.; Iwata, Y.; Miya-
shita, M. Tetrahedron Lett. 2006, 47, 861.
(E0911202 Cheng, F.)
1408
www.cjc.wiley-vch.de
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1400—1408