Synthesis of the C15-C23 fragment of dictyostatin using a highly stereoselective Carreira alkynylation

Article abstract of DOI:10.1016/j.tet.2007.01.067

A straightforward synthesis of the C15-C23 fragment of dictyostatin has been achieved by a highly stereoselective Carreira alkynylation between alkyne 1 and aldehyde 2, followed by three chemoselective reductions.

Full text of DOI:10.1016/j.tet.2007.01.067

Tetrahedron 63 (2007) 5873–5878
Synthesis of the C15–C23 fragment of dictyostatin using a highly
stereoselective Carreira alkynylation
*
Ofer Sharon, Chiara Monti and Cesare Gennari
Dipartimento di Chimica Organica e Industriale, Centro di Eccellenza C.I.S.I., Universitaꢀ degli Studi di Milano, via Venezian 21,
I-20133 Milano, Italy
Received 1 December 2006; revised 29 January 2007; accepted 30 January 2007
Available online 2 February 2007
Abstract—A straightforward synthesis of the C15–C23 fragment of dictyostatin has been achieved by a highly stereoselective Carreira
alkynylation between alkyne 1 and aldehyde 2, followed by three chemoselective reductions.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
The development of a practical and flexible synthesis of dic-
tyostatin is still an important goal, particularly as the natural
supply is extremely scarce. With the recent withdrawal of
discodermolide from clinical development,13 the importance
of dictyostatin increases further.
The sponge-derived macrolide dictyostatin (Fig. 1) has been
reported to exhibit paclitaxel-like effects on cellular micro-
tubules and to inhibit human cancer cell proliferation at low
nanomolar concentrations and with activity superior to
discodermolide (ED50 0.38 nM, P338 leukemia cells).1
The structure of dictyostatin with full stereochemical assign-
ments was recently established,2 and four total syntheses
were completed by Paterson and co-workers (2004),3 Curran
and co-workers (2004),4 and more recently by Phillips and
O’Neil (2006),5 and Ramachandran and co-workers (2007).6
Curran and co-workers published a fluorous mixture synthe-
sis of (ꢀ)-dictyostatin and three of its diastereomers,7 a syn-
thesis of (ꢀ)-16-normethyldictyostatin,8 while syntheses of
discodermolide–dictyostatin hybrids were reported by both
the Curran9 and the Paterson groups.10 The syntheses of var-
ious fragments (typically the C1–C9, the C11–C23, and the
C10–C23 segments) have also been described,11 and a grow-
ing number of research groups has been recently involved in
targeting this interesting natural product.12
2. Results and discussion
Our synthetic efforts toward dictyostatin were initially fo-
cused on the preparation of the C15–C23 fragment of the
macrolide, containing five of its eleven stereocenters (Fig. 1).
Alkyne 1 was prepared from methyl (R)-3-benzyloxy-2-
methylpropionate following a procedure described by Trost
and Papillon in 2004 (Scheme 1).14 DIBAL-H reduction in
dichloromethane gave an aldehyde, which was not isolated
but treated sequentially in situ with methanol (to quench
the excess DIBAL-H), the Bestmann–Ohira reagent,15,16
and sodium methoxide in THF,17 to afford alkyne 1 in
78% isolated yield.
OH
Alkyne 1 was treated with n-BuLi in THF at ꢀ78 ꢁC and then
with aldehyde 2 (prepared according to Smith III and co-
workers, Scheme1)18 to affordamixtureof thetwo diastereo-
meric propargylic alcohols 3 and 4 in a 6:4 ratio (49% yield,
Scheme2). Alternatively, aCarreiraasymmetricalkynylation
(Zn(OTf)2, Et3N, toluene, RT)19 was carried outwith eitherof
the two enantiomers of N-methyl-ephedrine: the reaction
with (+)-(1S,2R)-N-methyl-ephedrine (mismatched pair)
gave the addition product in 33% yield, with a diastereomeric
ratio of 9:1 in favor of the undesired R-alcohol 4. On the con-
trary, the Carreira coupling with (ꢀ)-(1R,2S)-N-methyl-
ephedrine (matched pair)20 gave the desired S-alcohol 3 in
96% yield as a single diastereomer (Scheme 2).
13
19
OH
O
15
13
17
21
23
HO
HO
11
O
O
O
5
7
OH NH2
1
9
7
1
OH
O
Dictyostatin
Discodermolide
OH OH
O
Figure 1. Marine cytotoxic agents discodermolide and dictyostatin.
Keywords: Alkynylation; Antitumor agents; Dictyostatin; Stereocontrol.
* Corresponding author. Tel.: +39 0250314091; fax: +39 0250314072;
e-mail: cesare.gennari@unimi.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.067

5874
O. Sharon et al. / Tetrahedron 63 (2007) 5873–5878
1) DIBAL-H, CH2Cl2-PhCH3 (88:12), -78 °C
2) MeOH, -78 °C, RT
BnO
CO2Me
3) CH3(CO)CHN2P(O)(OMe)2, MeONa,
THF, - 78 °C
4) Work-up and chromatography (78%)
OBn
1
(R)-3-benzyloxy-2-
methylpropionate
1) PMBO(C=NH)CCl3
PPTS, CH2Cl2-CyH
Swern [O]
OPMB
OH
HO
OPMB
OPMB
MeO2C
OHC
2) LiAlH4, THF
(64%, 2 steps)
(S)-3-hydroxy-2-
methylpropionate
Bn
N
n-Bu2OTf, Et3N
(89%, 2 steps)
Me
HN(Me)OMe-HCl
AlMe3, THF (89%)
N
O
OPMB
Bn
MeO
O
OH
O
O
OH
O
N
O
O
Me
N
LiAlH4, THF
(quant.)
DDQ, CH2Cl2
(86%)
H
MeO
O
O
O
O
O
O
2
PMP
PMP
Scheme 1. Synthesis of alkyne 1 and aldehyde 2.
H
1
OBn
OH
O
O
OH
O
O
+
O
O
O
OBn
3
OBn
PMP
PMP
2
4
PMP
n-BuLi, THF
3:4 ratio = 6:4
3:4 ratio = 1:9
Yield = 49%
Yield = 33%
Yield = 96%
(+)-(1S,2R)-N-methyl-ephedrine
Zn(OTf)2, Et3N, toluene
(-)-(1R,2S)-N-methyl-ephedrine
Zn(OTf)2, Et3N, toluene
3:4 ratio > 99:1
Scheme 2. Stereoselective Carreira alkynylation.
Hydrogenation of alcohol 3 in the presence of a catalytic
amount (10%) of Wilkinson’s catalyst21 in benzene, gave
the desired saturated compound in a low yield (30%), which
was then cleaved with DIBAL-H in dichloromethane18 to
give diol 7 (85%) (Scheme 3). Alternatively, acetal 3 was
cleaved with DIBAL-H to generate diol 5 in 86% yield.
When diol 5 was first silylated (TBSOTf, 2,6-lutidine,
CH2Cl2) and then reduced (H2, Pd/C, EtOAc), Z-alkene 6
was obtained cleanly, with concomitant benzyl removal,
but could not be further reduced to the corresponding alkane
(Scheme 3). Hydrogenation of propargylic alcohol 5 with
Wilkinson’s catalyst21 gave the saturated compound 7 in
a much improved 82% yield (Scheme 4).
Double protection of diol 7, by reaction with TBSOTf in the
presence of 2,6-lutidine, gave compound 8 in 82% yield. Se-
lective removal of the benzyl group over the PMB group (H2,
Raney-Ni, EtOH),22 gave alcohol 9 in 85% yield. Finally,
alcohol 9 was treated with I2, PPh3, imidazole23 to give
iodide 10 (C15–C23) in a quantitative yield, ready for further
elongation of the carbon chain.
DIBAL-H
CH2Cl2
86%
O
O
OH
H2
OH
O
PMB
OH
OBn
3
OBn
PMP
5
TBSOTf
2,6-lutidine
CH2Cl2
30%
85%
cat. (PPh3)3RhCl
benzene
100%
Preliminary experiments with the Myers’ alkylation24 re-
vealed a very poor reactivity of iodide 10; long reaction
times and forcing reaction conditions (elevated tempera-
tures, huge excess of the enolate and use of DMPU as co-
solvent) did not help so far. These problems might be due to
the bulky (although remote!) protective groups, as recently
discussed by Crimmins and Slade.25 Further studies are
currently in progress.
DIBAL-H
CH2Cl2
H2, Pd-C
EtOAc
72%
OH
OBn
OH
O
PMB
OH
O
O
PMB
OTBS
TBS
7
6
Scheme 3. Problematic routes to the C15–C23 fragment.

O. Sharon et al. / Tetrahedron 63 (2007) 5873–5878
5875
H2
TBSOTf
2,6-lutidine
cat. (PPh3)3RhCl
benzene
CH2Cl2
82%
OBn
OH
OH
O
PMB
OH
O
PMB
OH
OH
82%
OBn
OBn
5
7
H2
Raney-Ni
I2, Ph3P,
imidazole
CH3CN-Et2O, 0°C
100%
EtOH
85%
O
O
PMB
OTBS
O
O
PMB
OTBS
TBS
8
TBS
9
Me
O
Ph
N
I
23
OH Me
15
Poor yields
O
O
PMB
OTBS
LDA, LiCl, THF
TBS
10
Scheme 4. Synthesis of the C15–C23 fragment of dictyostatin.
3. Experimental
3.1.1. ((S)-2-Methyl-but-3-ynyloxymethyl)-benzene (1).
A solution of DIBAL-H (1.5 M in toluene, 3.52 mL,
5.28 mmol) was added dropwise (over 30 min) to a cold
(ꢀ78 ꢁC), stirred solution of methyl (R)-3-benzyloxy-2-
methyl-propionate (957 mg, 4.60 mmol) in CH2Cl2
(25.0 mL). After 30 min, methanol (0.25 mL, 6.21 mmol)
was added. The cooling bath was removed and the mixture
[containing (R)-3-benzyloxy-2-methyl-propionaldehyde]
was allowed to warm to room temperature. A solution of so-
dium methoxide (25 wt % in methanol, 3.0 mL, 13.10 mmol)
in THF (9.0 mL) was added dropwise (over 15 min) to a
stirred solution of (1-diazo-2-oxo-propyl)-phosphonic acid
dimethyl ester15–17 CH3(CO)CHN2P(O)(OMe)2 (2.5 g,
13.10 mmol) in THF (45.0 mL) at ꢀ78 ꢁC, followed by can-
nulation of the aldehyde solution over 5 min. The cooling
bath was removed and after 30 min a saturated aqueous solu-
tion of Rochelle’s salt (90.0 mL) was added. The mixturewas
vigorously stirred for a further 30 min and the two phases
were separated; the aqueous phase was extracted twice
with diethyl ether and the combined organic phases were
dried over Na2SO4. Purification of the crude product by flash
chromatography (n-hexane/EtOAc, 9.5:0.5) afforded alkyne
1 (625 mg, 78%) as a colorless oil. Rf¼0.25 (n-hexane/
EtOAc, 9.5:0.5); [a]2D0 ꢀ5.1 (c 1, in CHCl3); 1H NMR
(400 MHz, CDCl3): d¼7.36 (br s, 5H), 4.61 (s, 2H), 3.58
(dd, 1J¼9.0 Hz, 2J¼6.3 Hz, 1H), 3.43 (dd, 1J¼9.0 Hz,
2J¼7.3 Hz, 1H), 2.78–2.75 (m, 1H), 2.12 (d, J¼2 Hz, 1H),
1.27 ppm (d, J¼7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d¼138.9, 129.1, 128.3, 87.1, 74.5, 73.8, 69.7,
27.3, 18.3 ppm; FTIR (CCl4): n¼3313, 3030, 2963, 1548,
1261, 1217 cmꢀ1; HRMS (ESI): calcd for C12H14NaO:
197.09369 [M+Na]+; found: 197.09361 (resolution 46,900).
3.1. General procedures
All reactions were carried out in flame-dried glassware un-
der argon atmosphere. All commercially available reagents
were used as received. The solvents were dried by distilla-
tion over the following drying agents and were transferred
under nitrogen: CH3CN (CaH2), CH2Cl2 (CaH2), (CH2Cl)2
(CaH2), MeOH (CaH2), Et3N (CaH2), i-Pr2EtN (CaH2),
HN(TMS)2 (CaH2), THF (Na), Et2O (Na), benzene (Na), tol-
uene (Na), n-hexane (Na). Organic extracts were dried over
anhydrous Na2SO4. Reactions were monitored by analytical
thin-layer chromatography (TLC) using silica gel 60 F254
precoated glass plates (0.25 mm thickness) or basic alumina
supported on aluminum foils. TLC Rf values are reported.
Visualization was accomplished by irradiation with a UV
lamp and/or staining with ceric ammonium molybdate
(CAM) solution. Flash column chromatography was per-
˚
formed using silica gel 60 A, particle size 40–64 mm, follow-
ing the procedure by Still and co-workers.26 Proton NMR
spectra were recorded on 400, 300, or 200 MHz spectrome-
ters. Proton chemical shifts are reported in parts per million
(d) with the solvent reference relative to tetramethylsilane
(TMS) employed as the internal standard (CDCl3,
d 7.26 ppm; DMSO-d6, d 2.50 ppm). The following abbrevi-
ations are used to describe spin multiplicity: s¼singlet,
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, br¼broad
signal, dd¼doublet of doublet, dt¼doublet of triplet,
ddd¼doublet of doublet of doublet. Carbon NMR spectra
were recorded on 400 (100 MHz), 300 (75 MHz) or 200
(50 MHz) spectrometers with complete proton decoupling.
Carbon chemical shifts are reported in parts per million (d)
relative to TMS with the respective solvent resonance as
the internal standard (CDCl3, d 77.0 ppm). Infrared spectra
were recorded on a standard infrared spectrophotometer;
peaks are reported in cmꢀ1. Optical rotation values were
measured on an automatic polarimeter at the sodium D
line. High resolution mass spectra (HRMS) were performed
on a hybrid quadrupole time-of-flight mass spectrometer
equipped with an ESI ion source. A reserpine solution
100 pg/ml (about 100 count/s), 0.1% HCOOH/CH3CN 1:1,
was used as reference compound (Lock Mass).
3.1.2. (2S,3S,6S)-7-Benzyloxy-2-[(2S,4S,5S)-2-(4-meth-
oxy-phenyl)-5-methyl-[1,3]dioxan-4-yl]-6-methyl-hept-
4-yn-3-ol (3). Zinc triflate (1.42 g, 3.91 mmol) was dried
in a two-necked flask while heating under vacuum. (ꢀ)-N-
Methylephedrine (532 mg, 2.97 mmol) was then added,
and the vessel was purged with argon for 15 min. Toluene
(3.0 mL) was added, followed by triethylamine (0.41 mL,
2.97 mmol) and the mixture was stirred at room temperature
for 2 h. The mixture was then treated with a solution of
alkyne 1 (518 mg, 2.97 mmol) in dry toluene (0.9 mL),

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O. Sharon et al. / Tetrahedron 63 (2007) 5873–5878
stirred for a further 15 min, and then with a solution of alde-
hyde 218 (246 mg, 0.93 mmol) in toluene (1.2 mL). The
reaction progress was monitored by TLC. After 24 h the re-
action mixture was diluted with diethyl ether and quenched
with a saturated NH4Cl solution (15.0 mL). The organic
phase was separated and the aqueous layer was extracted
with ether (3ꢂ20 mL). The combined organic extracts were
washed with brine and dried over Na2SO4. Purification of the
crude product by flash chromatography (n-hexane/EtOAc,
8:2) afforded diastereoisomerically pure propargylic alcohol
3 (392 mg, 96%) as a colorless oil. Rf ¼0.21 (n-hexane/
EtOAc, 8:2); [a]D20 +34.6 (c 1, in CHCl3); 1H NMR
(400 MHz, CDCl3): d¼7.39–7.28 (m, 7H), 6.89 (d,
J¼8.4 Hz, 2H), 5.47 (s, 1H), 4.59–4.57 (m, 3H), 4.12 (dd,
(s, 3H), 3.55 (dd, 1J¼9.2 Hz, 2J¼6.0 Hz, 2H), 3.50 (t,
J¼10.8 Hz, 1H), 3.40 (dd, 1J¼8.8 Hz, 2J¼7.2 Hz, 1H),
2.85–2.78 (m, 1H), 2.71 (br s, 1H), 2.11–2.07 (m, 1H),
2.00–1.98 (m, 1H), 1.24 (d, J¼7.2 Hz, 3H), 1.19 (d,
J¼6.8 Hz, 3H), 0.77 ppm (d, J¼6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d¼160.5, 138.8, 131.5, 129.0, 128.7,
128.2, 127.8, 114.2, 101.6, 87.9, 86.4, 81.7, 74.6, 73.7,
67.4, 55.9, 41.0, 31.1, 27.3, 18.5, 8.5 ppm; FTIR (CCl4):
n¼3619, 3540, 3065, 3030, 2973, 2931, 2842, 2228, 1623,
1519, 1465, 1369, 1303, 1254, 1169, 1123 cmꢀ1; HRMS
(ESI): calcd for C27H34NaO5: 461.22985 [M+Na]+; found:
461.22909 (resolution 25,200).
methyl-hept-4-yn-3-ol (4). n-BuLi (1.6 M solution in hex-
ane, 0.094 mL, 0.15 mmol) was added slowly to a stirred so-
lution of alkyne 1 (21 mg, 0.12 mmol) in THF (2.0 mL) at
ꢀ78 ꢁC. The yellowish solution was stirred for 90 min at
ꢀ78 ꢁC. A solution of aldehyde 218 (26.4 mg, 0.10 mmol)
in THF (0.5 mL) was added dropwise and the solution
became colorless. The reaction was stirred overnight at
ꢀ78 ꢁC. A saturated NH4Cl aqueous solution was then
added, the layers were separated, and the aqueous phase ex-
tracted with ether (3ꢂ4 mL). The combined organic extracts
were dried over Na2SO4. Purification of the crude product
by flash chromatography (n-hexane/EtOAc, 8:2) afforded
a mixture of diastereomeric propargylic alcohols 3 and 4
in a 6:4 ratio (21.5 mg, 49%) as a colorless oil. The
diastereomeric ratio was determined by NMR. Rf ¼0.21
(n-hexane/EtOAc, 8:2).
2
1J¼11.2 Hz, J¼4.8 Hz, 1H), 3.82 (d, J¼4.4 Hz, 1H), 3.81
3.1.5. (2S,3S,4S,5S,8S)-9-Benzyloxy-3-(4-methoxy-benz-
yloxy)-2,4,8-trimethyl-non-6-yne-1,5-diol (5). A solution
of DIBAL-H (1.5 M in toluene, 2.28 mL, 3.42 mmol) was
added to a solution of acetal 3 (298 mg, 0.68 mmol) in
CH2Cl2 (10 mL) at ꢀ78 ꢁC. After stirring for 20 min at
ꢀ78 ꢁC, for 1 h at 0 ꢁC, and for 30 min at room temperature,
the reaction mixture was quenched with methanol (5 mL) at
ꢀ78 ꢁC. The mixture was filtered through a pad of Celite,
rinsed with CH2Cl2 (3ꢂ50 mL), and the resulting solution
evaporated to give a yellowish solid. Purification of the crude
product by flash chromatography (n-hexane/EtOAc, 6:4)
afforded diol 5 (258 mg, 86%) as a colorless oil. Rf ¼0.23
3.1.3. (2S,3R,6S)-7-Benzyloxy-2-[(2S,4S,5S)-2-(4-meth-
oxy-phenyl)-5-methyl-[1,3]dioxan-4-yl]-6-methyl-hept-
4-yn-3-ol (4). Zinc triflate (153 mg, 0.42 mmol) was dried
in a two-necked flask while heating under vacuum. (+)-N-
Methylephedrine (57 mg, 0.32 mmol) was then added and
the vessel was purged with argon for 15 min. Toluene
(1.0 mL) was added, followed by triethylamine (0.045 mL,
0.32 mmol) and the mixture was stirred at room temperature
for 2 h. The mixture was then treated with a solution of
alkyne 1 (56 mg, 0.32 mmol) in dry toluene (0.2 mL), stirred
for a further 15 min, and then with a solution of aldehyde 218
(26.4 mg, 0.10 mmol) in toluene (0.2 mL). The reaction
progress was monitored by TLC. After 48 h the reaction
mixture was diluted with diethyl ether and quenched with
a saturated NH4Cl solution (3 mL). The organic phase was
separated and the aqueous layer was extracted with ether
(3ꢂ5 mL). The combined organic extracts were washed
with brine and dried over Na2SO4. Purification of the crude
product by flash chromatography (n-hexane/EtOAc, 8:2) af-
forded a mixture of diastereomeric propargylic alcohols 3
and 4 in a 1:9 ratio (14.5 mg, 33%) as a colorless oil. The dia-
stereomeric ratio was determined by NMR. Data for 4: Rf ¼
0.21 (n-hexane/EtOAc, 8:2); [a]2D0 ꢀ18.6 (c 1, in CHCl3);
1H NMR (400 MHz, CDCl3): d¼7.38–7.28 (m, 7H), 6.88
(d, J¼7.5 Hz, 2H), 5.48 (s, 1H), 4.59–4.57 (m, 3H), 4.11
1
(n-hexane/EtOAc, 6:4); [a]2D0 +14.7 (c 1, in CHCl3); H
NMR (400 MHz, CDCl3): d¼7.36–7.27 (m, 7H), 6.88 (d,
J¼8.5 Hz, 2H), 4.56 (m, 4H), 4.41 (d, J¼6.6 Hz, 1H), 3.82
(s, 3H), 3.72 (dd, 1J¼7.5 Hz, 2J¼3.1 Hz, 1H), 3.65 (d,
1
2
J¼5.2 Hz, 2H), 3.53 (dd, J¼9 Hz, J¼6.3 Hz, 1H), 3.40
1
2
(dd, J¼8.7 Hz, J¼7.1 Hz, 1H), 2.80–2.90 (m, 1H), 2.64
(br s, 1H), 2.52 (br s, 1H), 2.01–1.99 (m, J¼9 Hz, 1H),
1.95–1.85 (m, 1H), 1.24 (d, J¼6.9 Hz, 3H), 1.12 (d,
J¼6.9 Hz, 3H), 0.94 ppm (d, J¼7 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d¼160.0, 138.8, 131.1, 130.1, 129.1,
128.4, 128.3, 114.6, 89.3, 85.2, 82.1, 75.1, 74.7, 73.7,
71.9, 66.7, 66.4, 55.9, 43.6, 38.9, 27.5, 18.4, 15.4,
10.7 ppm; FTIR (CCl4): n¼3619, 3520, 3065, 3030, 2966,
2936, 2877, 2238, 1619, 1521, 1461, 1254, 1100,
1051 cmꢀ1
;
HRMS (ESI) calcd for C27H36NaO5:
463.24550 [M+Na]+; found: 463.24487 (resolution 25,500).
3.1.6. (2S,3S,4S,5R,8S)-9-Benzyloxy-3-(4-methoxy-benz-
yloxy)-2,4,8-trimethyl-nonane-1,5-diol (7). A solution of
propargylic diol 5 (198 mg, 0.45 mmol) in dry benzene
(12 mL) was added to a dried two-necked flask. One neck
was sealed and the other was fitted with a three-way stop-
cock connected to an atmospheric pressure hydrogenation
apparatus and a vacuum pump. The solution was accurately
degassed and purged with hydrogen, then Wilkinson’s cata-
lyst Rh(PPh3)3Cl (42 mg, 0.045 mmol) was added and the
mixture was stirred overnight. Silica gel was added and the
solvent was evaporated. Purification of the crude product
by flash chromatography (n-hexane/EtOAc, from 9:1 to
8:2) afforded diol 7 (164 mg, 82%) as a yellowish oil.
Rf ¼0.23 (n-hexane/EtOAc, 85:15); [a]2D0 +11.1 (c 1, in
1
2
(dd, J¼10.5 Hz, J¼4.6 Hz, 1H), 3.82 (d, J¼4.4 Hz, 1H),
3.81 (s, 3H), 3.57–3.50 (m, 3H), 3.40 (dd, 1J¼9.1 Hz,
2J¼6.8 Hz, 1H), 2.86–2.80 (m, 1H), 2.68 (br s, 1H), 2.11–
2.07 (m, 1H), 2.00–1.98 (m, 1H), 1.25 (d, J¼7.1 Hz, 3H),
1.15 (d, J¼7.2 Hz, 3H), 0.75 ppm (d, J¼7.2 Hz, 3H).
3.1.4. (2S,3S,6S)-7-Benzyloxy-2-[(2S,4S,5S)-2-(4-meth-
oxy-phenyl)-5-methyl-[1,3]dioxan-4-yl]-6-methyl-hept-
4-yn-3-ol (3) and (2S,3R,6S)-7-benzyloxy-2-[(2S,4S,5S)-
2-(4-methoxy-phenyl)-5-methyl-[1,3]dioxan-4-yl]-6-
1
CHCl3); H NMR (400 MHz, CDCl3): d¼7.37–7.29 (m,
7H), 6.89 (d, J¼8.6 Hz, 2H), 4.61 (A part of an AB system,
J¼10.5 Hz, 1H), 4.57 (B part of an AB system, J¼10.5 Hz,

O. Sharon et al. / Tetrahedron 63 (2007) 5873–5878
5877
1H), 4.52 (s, 2H), 3.81 (s, 3H), 3.76–3.66 (m, 5H), 3.56 (dd,
81.5, 74.7, 74.6, 68.9, 65.3, 56.0, 40.1, 39.5, 36.8, 32.1,
29.0, 26.7, 26.7, 18.8, 17.4, 10.8, ꢀ3.4, ꢀ3.6 ppm; HRMS
(ESI): calcd for C32H62NaO5Si2: 605.40280 [M+Na]+;
found: 605.39994 (resolution 23,100).
2
1J¼6.9 Hz, J¼3.9 Hz, 1H), 3.38–3.28 (m, 2H), 2.52 (br s,
2H), 2.06 (m, 1H), 1.81–1.78 (m, 2H), 1.55–1.49 (m, 2H),
1.01–0.96 ppm (m, 9H); 13C NMR (100 MHz, CDCl3):
d¼160.1, 139.4, 130.8, 130.3, 129.5, 129.0, 128.2, 128.1,
114.6, 87.4, 76.5, 75.6, 74.9, 73.7, 66.2, 55.9, 40.2, 38.4,
34.2, 33.2, 30.8, 17.9, 15.5, 8.1 ppm; FTIR (CCl4):
n¼3640, 3526, 2934, 2875, 1613, 1515, 1455, 1362, 1250,
3.1.9. 1-{(1S,2R,3R,6S)-3-(tert-Butyl-dimethyl-silanyl-
oxy)-1-[(S)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-
ethyl]-7-iodo-2,6-dimethyl-heptyloxymethyl}-4-
methoxy-benzene (10). Imidazole (46 mg, 0.67 mmol), tri-
phenylphosphine (176 mg, 0.67 mmol), and iodine (140 mg,
0.55 mmol) were added sequentially to a solution of alcohol
9 (100 mg, 0.172 mmol) in a mixture of diethyl ether/aceto-
nitrile 2:1 (4.5 mL). The reaction mixture was stirred for
1.5 h at room temperature and then quenched with an aque-
ous solution of sodium thiosulfate. The organic phase was
separated and the aqueous layer extracted with ether
(3ꢂ20 mL). The combined organic extracts were washed
with brine and dried over Na2SO4. Purification of the crude
product by flash chromatography (n-hexane/EtOAc, 99:1)
afforded iodide 10 (119 mg, 100%) as a colorless oil.
Rf ¼0.21 (n-hexane/EtOAc, 99:1); 1H NMR (300 MHz,
CDCl3): d¼7.23 (d, J¼11 Hz, 2H), 6.85 (d, J¼11 Hz, 2H),
4.56 (A part of an AB system, J¼14.7 Hz, 1H), 4.45 (B
part of an AB system, J¼14.7 Hz, 1H), 3.79 (s, 3H), 3.68–
3.61 (m, 3H), 3.48–3.46 (m, 2H), 3.16–3.08 (m, 2H),
1.87–1.76 (m, 2H), 1.45–1.20 (m, 3H), 0.97–0.67 (m,
27H), 0.125–0.00 ppm (m, 13H); HRMS (ESI): calcd for
C32H61NaIO4Si2: 715.30453 [M+Na]+; found: 715.30311
(resolution 16,000).
1216, 1174, 817 cmꢀ1
;
HRMS (ESI): calcd for
C27H40NaO5: 467.27680 [M+Na]+; found: 467.27637 (reso-
lution 24,900).
3.1.7. 1-{(1S,2R,3R,6S)-7-Benzyloxy-3-(tert-butyl-di-
methyl-silanyloxy)-1-[(S)-2-(tert-butyl-dimethyl-silanyl-
oxy)-1-methyl-ethyl]-2,6-dimethyl-heptyloxymethyl}-4-
methoxy-benzene (8). Freshly distilled 2,6-lutidine
(0.10 mL, 0.86 mmol) and TBSOTf (169 mg, 0.64 mmol)
were added to a stirred solution of diol 7 (93.4 mg,
0.21 mmol) in CH2Cl2 (3.0 mL) at ꢀ78 ꢁC. The reaction
mixture was stirred for 30 min at ꢀ78 ꢁC and then quenched
with a saturated NH4Cl aqueous solution. The organic phase
was separated and the aqueous layer extracted with CH2Cl2.
The combined organic extracts were washed with brine,
dried over Na2SO4, and evaporated. Purification of the crude
product by flash chromatography (n-hexane/EtOAc, 95:5)
afforded compound 8 (116 mg, 82%) as a colorless oil.
Rf ¼0.19 (n-hexane/EtOAc, 95:5); [a]2D0 +2.3 (c 1, in
1
CHCl3); H NMR (400 MHz, CDCl3): d¼7.35 (br s, 5H),
7.29 (d, J¼8.4 Hz, 2H), 6.91 (d, J¼8.4 Hz, 2H), 4.57–4.46
(m, 4H), 3.82 (s, 3H), 3.69–3.50 (m, 3H), 3.50 (dd,
1J¼6.7 Hz, 2J¼4.2 Hz, 1H), 3.33 (dd, 1J¼9.0 Hz,
2J¼6.0 Hz, 1H), 3.23 (dd, 1J¼7.0 Hz, 2J¼9.0 Hz, 1H),
1.92–1.89 (m, 1H), 1.83–1.80 (m, 1H), 1.74–1.71 (m, 1H),
1.14–1.12 (m, 1H), 0.99 (d, J¼6.8 Hz, 3H), 0.95–0.93 (m,
27H), 0.10–0.05 ppm (m, 12H); 13C NMR (100 MHz,
CDCl3): d¼159.6, 139.5, 132.4, 129.6, 129.0, 128.1,
128.0, 114.4, 81.7, 78.0, 77.7, 77.4, 76.7, 74.9, 74.6, 73.7,
65.4, 40.3, 39.6, 34.6, 32.2, 29.7, 26.7, 17.9, 15.9, 10.8,
ꢀ3.5, ꢀ3.9 ppm; FTIR (CCl4): n¼3066, 3032, 1613, 1586,
1549, 1388, 1302, 1181, 1172, 939 cmꢀ1; HRMS (ESI):
calcd for C39H68NaO5Si2: 695.44975 [M+Na]+; found:
695.44742 (resolution 20,000).
Acknowledgements
We thank the European Commission for financial support
(IHP Network grant ‘Design and synthesis of microtubule
stabilizing anticancer agents’ HPRN-CT-2000-00018) and
for a postdoctoral fellowship to O.S. (‘Marie Curie’ MEIF-
CT-2003-500880). We also gratefully acknowledge Merck
Research Laboratories (Merck’s Academic Development
ꢀ
Program Award to C.G.), Ministero dell’Universita e della
Ricerca (PRIN prot. 2006030449), and Universita degli
ꢀ
Studi di Milano for financial support and for a postdoctoral
fellowship (Assegno di ricerca) to C.M.
3.1.8. (2S,5R,6R,7S,8S)-5,9-Bis-(tert-butyl-dimethyl-
silanyloxy)-7-(4-methoxy-benzyloxy)-2,6,8-trimethyl-
nonan-1-ol (9). Raney-nickel was washed with water until
the washings were pH neutral and then rinsed five times
with absolute EtOH. A solution of compound 8 (100 mg,
0.149 mmol) in absolute EtOH (10 mL) was added, the mix-
ture was accurately degassed, and then purged three times
with hydrogen. After stirring for 24 h, the Raney-nickel
was removed by filtration and the filtrate purified by flash
chromatography (n-hexane/EtOAc, 92:8) to afford alcohol
9 (74 mg, 85%) as a colorless oil. Rf ¼0.14 (n-hexane/EtOAc,
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