A practical synthesis of the C1-C9 fragment of dictyostatin

Article abstract of DOI:10.1055/s-2008-1067149

A stereoselective synthesis of the C1-C9 fragment of (-)-dictyostatin has been achieved by use of a titanium(IV) chloride mediated chelation-controlled Mukaiyama aldol reaction and two modified Horner-Wadsworth-Emmons olefinations (Roush-Masamune and Stil

Full text of DOI:10.1055/s-2008-1067149

2158
PAPER
A Practical Synthesis of the C1–C9 Fragment of Dictyostatin
Synthesis of the
C
h
1–C9 Fragm
i
ent of
a
D
ictyostati
r
n
a Zanato, Luca Pignataro, Zhongyan Hao, Cesare Gennari*
Dipartimento di Chimica Organica e Industriale, Centro di Eccellenza C.I.S.I., Università degli Studi di Milano,
Via G. Venezian 21, 20133 Milan, Italy
Fax +39(02)50314072; E-mail: cesare.gennari@unimi.it
Received 5 March 2008
Dedicated with respect and admiration to Professor Reinhard W. Hoffmann, on the occasion of his 75th birthday
Roush–Masamune
Abstract: A stereoselective synthesis of the C1–C9 fragment of
(–)-dictyostatin has been achieved by use of a titanium(IV) chloride
mediated chelation-controlled Mukaiyama aldol reaction and two
modified Horner–Wadsworth–Emmons olefinations (Roush–
Masamune and Still–Gennari).
(E/Z > 100:1)
1
MeO
O
(R)-Roche ester
9
2
OH OTBS
Still–Gennari
(Z/E > 100:1)
chelation-controlled
aldol (>95:5)
Key words: antitumor agents, stereoselective synthesis, aldol reac-
tions, titanium, olefination
26
OH
23
HO
The sponge-derived macrolide (–)-dictyostatin (1,
Scheme 1) has been reported to exhibit paclitaxel-like ef-
fects on cellular microtubules and to inhibit human cancer
cell proliferation at low nanomolar concentrations, with
activity somewhat superior to the already very active dis-
codermolide (ED50 0.38 nM, P338 leukemia cells).1
Moreover, (–)-dictyostatin (1) is also extremely active
against paclitaxel-resistant cancer cell lines. The structure
of (–)-dictyostatin (1) with full stereochemical assign-
ment was established by Paterson and co-workers fairly
recently (2004),2 and four total syntheses were completed
in the period 2004–2007.3 A growing number of research
groups have recently been involved in targeting this inter-
esting natural product, and the syntheses of several ana-
logues (e.g., normethyldictyostatins, epi-dictyostatins),4
discodermolide/dictyostatin hybrids,5 and various frag-
ments and synthetic intermediates6 have been described.
The development of a practical and flexible synthesis of
(–)-dictyostatin (1) is still an important goal, particularly
as the natural supply is extremely scarce. With the recent
withdrawal of discodermolide from clinical develop-
ment,7 the importance of dictyostatin (1) further increases.
O
O
1
10
9
OH OH
(–)-dictyostatin (1)
Evans aldol
(>98:2)
(S)-Roche ester
(S)-Roche ester
Myers
alkylation
(>98:2)
OTBS
19
TBSO
TBSO
OPMB23
3
12
Marshall–
Tamaru
addition
(>98:2)
Carreira alkynylation
(>100:1)
10
Scheme 1 Retrosynthetic approach to fragments C1–C9 (2) and
C10–C23 (3)6j of (–)-dictyostatin (1), with key reactions involved and
associated diastereomeric ratios
ed aldehyde 5 in quantitative yield, and, without
purification, aldehyde 5 was immediately subjected to a
titanium(IV) chloride mediated chelation-controlled Mu-
kaiyama aldol reaction with 1-(tert-butyldimethylsiloxy)-
1-(tert-butylsulfanyl)ethene (Scheme 2).10 The aldol
product 6 was isolated in 94% yield and a 97:3 diastereo-
meric ratio in favor of the desired stereoisomer. Although
it was reported that the two diastereomers could be sepa-
rated by two consecutive purifications by flash chroma-
tography,10a we still observed the presence of some isomer
(£3%) in the 13C NMR spectrum of 6. However, we decid-
ed to continue our synthesis as planned, confident that the
minor isomer would be removable at a later stage of the
sequence.
Our laboratory recently reported a highly stereoselective
synthesis of the C10–C23 fragment 3 of (–)-dictyostatin
(1) (Scheme 1).6j We now report on a practical synthesis
of the C1–C9 fragment 2 (Scheme 1), containing two of
its eleven stereocenters and the (2Z,4E)-2,4-dienoate unit.
We started our synthesis from commercially available
methyl (R)-3-hydroxy-2-methylpropionate [(R)-Roche
ester] (Scheme 2). Conversion of the (R)-Roche ester into
its benzyl ether with benzyl trichloroacetimidate was fol-
lowed by lithium aluminum hydride reduction of the ester
to give alcohol 4 in 89% overall yield8 (Scheme 2). Oxi-
dation of alcohol 4 with Dess–Martin periodinane9 afford-
Reduction (LAH) of 6 gave diol 7 in 98% yield, and sub-
sequent double silylation of diol 7 led to fully protected
triol 8 (98%) (Scheme 2). Benzyl removal was accom-
plished by hydrogenolysis with Raney nickel in ethanol11
SYNTHESIS 2008, No. 14, pp 2158–2162
Advanced online publication: 18.06.2008
DOI: 10.1055/s-2008-1067149; Art ID: C00408SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

PAPER
Synthesis of the C1–C9 Fragment of Dictyostatin
2159
shifts are reported relative to TMS and the solvent resonance was
employed as the internal standard (CDCl3, d = 7.26). The 13C NMR
spectra were recorded with complete proton decoupling, with chem-
ical shifts reported relative to TMS and the solvent resonance as the
internal standard (CDCl3, d = 77.0). Infrared spectra were recorded
on a standard FT/IR spectrophotometer. Optical rotation values
were measured on an automatic polarimeter with a 1-dm cell, at the
sodium D line. HRMS was performed on a hybrid quadrupole TOF
mass spectrometer equipped with an ESI ion source. A reserpine
soln (100 pg/mL, about 100 counts/s, 0.1% HCO2H–MeCN, 1:1),
was used as reference compound (Lock Mass). All reactions were
carried out in oven- or flame-dried glassware under a N2 atmo-
sphere, unless stated otherwise. All commercially available re-
agents were used as received. All solvents were dried by standard
procedures before use. Organic extracts were dried over anhyd
Na2SO4. Reactions were magnetically stirred and monitored by
TLC on silica gel 60 F254 precoated glass plates (0.25 mm thick-
ness). Visualization was accomplished by irradiation with a UV
lamp and/or staining with a ceric ammonium molybdate or KMnO4
solution. Flash chromatography was performed on silica gel (60 Å,
particle size 0.040–0.062 mm) by the procedure of Still and co-
workers.16 Yields refer to chromatographically and spectroscopical-
ly pure compounds, unless stated otherwise.
a
c
MeO
O
b
H
OH
OH OBn
O
OBn
e
4
5
t-BuS
O
d
OH
OBn
HO OH OBn
6
7
f
g
TBSO
O
OBn
TBS
TBSO
O
OH
TBS
8
9
OMe
h
i
N Me
H
TBSO
O
O
TBSO
OTBS
O
TBS
10
11
COOMe
j
H
(R)-3-(Benzyloxy)-2-methylpropionaldehyde (5)
A soln of alcohol 48 (0.4 g, 2.2 mmol) in anhyd CH2Cl2 (12.3 mL)
was treated at 0 °C with py (0.45 mL, 5.5 mmol) and DMP (1.12 g,
2.64 mmol). The reaction mixture was warmed to r.t. and stirred for
1 h. After completion of the reaction, sat. aq NaHCO3 (38.0 mL) and
Na2S2O3 (3.99 g, 16.1 mmol) were added. After the mixture had
stirred for 30 min, the phases were separated, and the aqueous phase
was extracted with Et2O (3 × 40 mL). The combined organic ex-
tracts were washed with brine (2 × 50 mL), dried (Na2SO4), and
evaporated under reduced pressure; this gave crude aldehyde 5,
which was used without further purification.
TBSO
OTBS
12
O
TBSO
OTBS
13
1COOMe
k
9
OH OTBS
2
Scheme 2 Reagents and conditions: (a) Ref. 8, 89%; (b) DMP,
CH2Cl2, r.t., 100%; (c) (t-BuS)(TBSO)C=CH2, TiCl4, CH2Cl2,
–80 °C, 94%, dr 97:3; (d) LAH, THF, r.t., 98%; (e) TBSOTf, 2,6-lu-
tidine, CH2Cl2, –20 °C, 98%; (f) H2, Raney-Ni, EtOH, r.t., 80%; (g)
DMP, CH2Cl2, r.t., 100%; (h) (EtO)2P(O)CH2C(O)N(Me)OMe, LiCl,
DBU, MeCN, r.t., 90%; (i) DIBAL-H, THF, –78 °C, 91%; (j)
(F3CCH2O)2P(O)CH2CO2Me, KHMDS, THF, 18-crown-6, –78 °C,
90%; (k) HF·py, THF–py, r.t., 86%.
Yield: 0.39 g (100%); pale yellow oil; Rf = 0.77 (hexanes–EtOAc,
6:4).
1H NMR (400 MHz, CDCl3): d = 1.17 (d, J = 7.2 Hz, 3 H, CH3),
2.65–2.73 (m, 1 H, H–2), 3.66 (dd, J = 4.8, 9.2 Hz, 1 H, H-3), 3.72
(dd, J = 6.8, 9.2 Hz, 1 H, H-3), 4.55 (s, 2 H, CH2Ph), 7.10–7.36 (m,
5 H, Ph), 9.75 (s, 1 H, H-1).
S-tert-Butyl (3S,4R)-5-(Benzyloxy)-3-hydroxy-4-methylpen-
tanethioate (6)
(80%), and the resulting primary alcohol 9 was oxidized
(DMP) to furnish aldehyde 10 in quantitative yield
(Scheme 2). Aldehyde 10 was not purified and immedi-
A stirring solution of aldehyde 5 (392 mg, 2.2 mmol) in anhyd
CH2Cl2 (5.0 mL) was treated at –80 °C with TiCl4 (0.49 mL, 2.2
mmol). After a few seconds, a solution of 1-(tert-butyldimethylsi-
loxy)-1-(tert-butylsulfanyl)ethene10 (814 mg, 3.3 mmol) in anhyd
CH2Cl2 (2.5 mL) was slowly added. After stirring for 2 h at –80 °C,
the mixture was quenched with 1 M KOH (18.0 mL). The organic
phase was washed with brine (2 × 3 mL), dried (Na2SO4), filtered,
and evaporated under reduced pressure. The crude product was pu-
rified by flash chromatography (hexanes–EtOAc, 85:15); this gave
6 (dr 97:3) as a colorless oil. Further purification by flash
chromatography10a (benzene–Et2O, 95:5) did not improve the dr.
ately subjected to
a
Horner–Wadsworth–Emmons
reaction with diethyl (N-methoxy-N-methylcarbamoyl-
methyl)phosphonate12 under Roush–Masamune condi-
tions.13 The olefination reaction afforded the Weinreb
amide 11 in 90% yield as a single E-isomer (E/Z >100:1)
(Scheme 2). Diisobutylaluminum hydride reduction gave
aldehyde 12 (91%), which was subjected to a Still–
Gennari olefination14 to afford methyl (2Z,4E)-2,4-di-
enoate 13 in 90% yield as a single isomer (2Z/2E >100:1)
(Scheme 2).4d,15 The minor (7R)-isomer (£3%), which
originated during the Mukaiyama aldol reaction, was re-
moved at this stage by flash chromatography. Finally, re-
moval of the primary tert-butyldimethylsilyl group
(HF·py, THF–py) furnished the desired C1–C9 fragment
2 of (–)-dictyostatin in good yield (Scheme 2).4d
Yield: 642 mg (94%); [a]D20 –23.0 (c 0.75, CH2Cl2); Rf = 0.42 (hex-
anes–EtOAc, 85:15).
IR (CHCl3): 3470, 2962, 2926, 2860, 1681, 1455, 1364, 1253, 1101
cm–1.
1H NMR (400 MHz,CDCl3): d = 0.96 (d, J = 7.2 Hz, 3 H, CH3),
1.50 (s, 9 H, t-BuS), 1.89–1.97 (m, 1 H, H-4), 2.65 (dd, J = 8.0, 15.2
Hz, 1 H, H-2), 2.70 (dd, J = 4.0, 15.2 Hz, 1 H, H-2), 3.52 (dd,
J = 6.4, 9.6 Hz, 1 H, H-5), 3.58 (dd, J = 4.8, 9.6 Hz, 1 H, H-5), 4.04
(ddd, J = 4.0, 8.0, 6.4 Hz, 1 H, H-3), 4.50 (s, 2 H, CH2Ph), 7.28–
7.39 (m, 5 H, Ph).
1H (400.13 MHz) and 13C (100.58 MHz) NMR spectra were record-
1
ed on a Bruker Avance-400 spectrometer. The H NMR chemical
Synthesis 2008, No. 14, 2158–2162 © Thieme Stuttgart · New York

2160
C. Zanato et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 11.8 (epimer at C-3, £3%), 14.5,
30.4, 38.3 (epimer at C-3, £3%), 38.6, 49.0, 49.9, 70.8 (epimer at C-
3, £3%), 73.0, 74.1, 74.4, 126.7, 127.2, 128.7, 138.6, 200.7.
and the mixture was degassed and then purged with H2 (3×). After
stirring for 72 h at r.t., the reaction mixture was filtered through a
short pad of Celite, washed with EtOAc (2 × 100 mL), and evapo-
rated under reduced pressure. The crude product was purified by
flash chromatography (hexanes–EtOAc, 10:1).
ESI-HRMS: m/z calcd for C17H26NaO3S: 333.4400; found:
333.4425.
20
Yield: 441 mg (80%); colorless oil; [a]D –4.0 (c 1.11, CH2Cl2);
(3S,4R)-5-(Benzyloxy)-4-methylpentane-1,3-diol (7)
Rf = 0.16 (hexanes–EtOAc, 10:1).
A solution of 6 (500 mg, 1.6 mmol) in anhyd THF (4.0 mL) was
added to a cold (0 °C) suspension of LAH (122 mg, 3.2 mmol) in
anhyd THF (4.0 mL). The mixture was warmed to r.t. and stirred for
an additional 2 h. The solution was cooled to 0 °C and then
quenched with H2O (0.7 mL), 2 M NaOH (1.4 mL), and H2O (1.4
mL). After vigorously stirring for 1 h, the mixture was dried
(Na2SO4), filtered, and evaporated under reduced pressure. The
crude product was purified by flash chromatography (hexanes–
EtOAc, 6:4).
IR (CHCl3): 3366, 2956, 2929, 2885, 2858, 1472, 1255, 1094, 836,
775 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.07 (s, 6 H, Me2Si), 0.12 (s, 6 H,
Me2Si), 0.91 (s, 9 H, t-BuSi), 0.92 (s, 9 H, t-BuSi), 1.04 (d, J = 7.2
Hz, 3 H, CH3), 1.71–1.82 (m, 3 H, H-2, H-4), 2.61 (br s, 1 H, OH),
3.55 (dd, J = 5.6, 11.2 Hz, 1 H, H-5), 3.68 (t, J = 6.4 Hz, 2 H, H-1),
3.80 (dd, J = 4.0, 11.2 Hz, 1 H, H-5), 3.90–3.94 (m, 1 H, H-3).
13C NMR (100 MHz, CDCl3): d = –4.7, –4.0, –3.8, 13.1 (epimer at
C-3, £3%), 14.9, 18.6, 18.9, 26.5, 26.6, 38.2, 39.3, 40.5 (epimer at
C-3, £3%), 60.4, 65.9, 73.4 (epimer at C-3, £3%), 74.8.
23
Yield: 352 mg (98%); colorless oil; [a]D –21.6 (c 0.87, CH2Cl2);
Rf = 0.50 (hexanes–EtOAc, 6:4).
ESI-HRMS: m/z calcd for C18H42O3NaSi2: 385.2565; found:
385.2564.
IR (CHCl3): 3388, 2958, 2924, 2877, 1454, 1364, 1071, 1057, 1028
cm–1.
1H NMR (400 MHz,CDCl3): d = 0.90 (d, J = 6.8 Hz, 3 H, CH3),
1.73–1.82 (m, 2 H, H-2), 1.90–2.00 (m, 1 H, H-4), 2.98 (br s, 2 H,
OH), 3.50 (t, J = 9.2 Hz, 1 H, H-5), 3.66 (dd, J = 4.0, 9.2 Hz, 1 H,
H-5), 3.79–3.89 (m, 3 H, H-1 and H-3), 4.55 (s, 2 H, CH2Ph), 7.28–
7.42 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): d = 12.1 (epimer at C-3, £3%), 14.3,
35.8 (epimer at C-3, £3%), 36.6, 39.1, 62.3, 74.2, 75.0 (epimer at C-
3, £3%), 75.9, 77.5, 128.4, 128.6, 129.2, 138.3.
(2S,3S)-3,5-Bis(tert-butyldimethylsiloxy)-2-methylpentanal (10)
A solution of alcohol 9 (0.4 g, 1.1 mmol) in anhyd CH2Cl2 (7.0 mL)
was treated at 0 °C with pyridine (0.22 mL, 2.8 mmol) and DMP
(0.56 g, 1.3 mmol). The reaction mixture was warmed to r.t., and
stirred for 2 h. After completion of the reaction, sat. aq NaHCO3
(18.0 mL) and Na2S2O3 (2.0 g, 8.0 mmol) were added. After the
mixture had stirred for 30 min, the phases were separated, and the
aqueous phase was extracted with Et2O (3 × 20 mL). The combined
organic extracts were washed with brine (2 × 25 mL), dried
(Na2SO4), and evaporated under reduced pressure; this gave crude
aldehyde 10, which was used without further purification.
ESI-HRMS: m/z calcd for C13H20NaO3: 247.1347; found: 247.1301.
{[(2R,3S)-3,5-Bis(tert-butyldimethylsiloxy)-2-methylpentyl-
oxy]methyl}benzene (8)
Yield: 397 mg (100%); pale yellow oil; Rf = 0.56 (hexanes–EtOAc,
A solution of diol 7 (350 mg, 1.56 mmol) in anhyd CH2Cl2 (39 mL)
was treated at –20 °C with 2,6-lutidine (1.5 mL, 12.5 mmol), fol-
lowed by TBSOTf (2.7 mL, 3.12 mmol). After stirring for 1 h, the
mixture was quenched with sat. aq NH4Cl (40 mL). The phases
were separated, and the aqueous phase was extracted with CH2Cl2
(2 × 40 mL). The combined organic extracts were washed with
brine (2 × 50 mL), dried (Na2SO4), and evaporated under reduced
pressure. The crude product was purified by flash chromatography
(hexanes–EtOAc, 95:5).
9:1).
1H NMR (400 MHz, CDCl3): d = 0.07 (s, 6 H, Me2Si), 0.10 (s, 6 H,
Me2Si), 0.90 (s, 9 H, t-BuSi), 0.91 (s, 9 H, t-BuSi), 1.10 (d, J = 7.2
Hz, 3 H, CH3), 1.75–1.82 (m, 2 H, H-4), 2.58–2.59 (m, 1 H, H-2),
3.70–3.73 (m, 2 H, H-5), 4.17–4.19 (m, 1 H, H-3), 9.76 (d, J = 1.6
Hz, 1 H, H-1).
(2E,4R,5S)-5,7-Bis(tert-butyldimethylsiloxy)-N-methoxy-N,4-
dimethylhept-2-enamide (11)
16
Yield: 692 mg (98%); colorless oil; [a]D –7.1 (c 0.86, CH2Cl2);
Diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate (0.25
mL, 1.2 mmol), DBU (0.2 mL, 1.3 mmol), and, finally, aldehyde 10
(397 mg, 1.1 mmol) were added to a stirred suspension of LiCl
(flame-dried under vacuum before use; 112 mg, 2.6 mmol) in anhyd
MeCN (8.7 mL) at r.t. The mixture was stirred at r.t. for 1.5 h and
then quenched with H2O (18 mL). After 15 min, EtOAc (18 mL)
was added and the mixture was stirred for an additional 30 min. The
two phases were separated, and the aqueous phase was extracted
with EtOAc (3 × 30 mL). The combined organic extracts were dried
(Na2SO4) and evaporated under reduced pressure. The crude prod-
uct was purified by flash chromatography (hexanes–EtOAc, 9:1).
Rf = 0.60 (hexanes–EtOAc, 95:5).
IR (CHCl3): 3113, 2955, 2928, 2856, 1471, 1254, 1092, 835, 774
cm–1.
1H NMR (400 MHz, CDCl3): d = 0.07 (s, 9 H, t-BuSi), 0.89–0.91
(m, 21 H, t-BuSi, Me2Si, Me2Si), 0.95 (d, J = 6.8 Hz, 3 H, CH3),
1.60–1.67 (m, 2 H, H-4), 1.99–2.05 (m, 1 H, H-2), 3.31 (dd, J = 6.8,
9.2 Hz, 1 H, H-1), 3.46 (dd, J = 6.4, 9.2 Hz, 1 H, H-1), 3.63–3.76
(m, 2 H, H-3, H-5), 3.89–3.92 (m, 1 H, H-5), 4.51 (s, 2 H, CH2Ph),
7.30–7.36 (m, 5 H, Ph).
13C NMR (100 MHz, CDCl3): d = –4.6, –3.9, –2.3, 12.2 (epimer at
C-3, £3%), 13.3, 18.8, 19.0, 26.5, 26.6, 36.4, 39.1 (epimer at C-3,
£3%), 39.8, 60.9, 70.3 (epimer at C-3, £3%), 71.1, 73.5, 73.7, 128.0,
128.1, 129.0, 139.4.
23
Yield: 441 mg (90%); colorless oil; [a]D +8.3 (c 0.70, CH2Cl2);
Rf = 0.24 (hexanes–EtOAc, 9:1).
IR (CHCl3): 2955, 2929, 2895, 2886, 2857, 1666, 1636, 1471, 1382,
1255, 1099, 836, 775 cm–1.
ESI-HRMS: m/z calcd for C25H48O3NaSi2: 475.3034; found:
475.3049.
1H NMR (400 MHz, CDCl3): d = 0.05 (s, 6 H, Me2Si), 0.07 (s, 6 H,
Me2Si), 0.90 (s, 9 H, t-BuSi), 0.91 (s, 9 H, t-BuSi), 1.10 (d, J = 7.2
Hz, 3 H, CH3), 1.57–1.69 (m, 2 H, H-6), 2.50–2.59 (m, 1 H, H-4),
3.26 (s, 3 H, NCH3), 3.60–3.70 (m, 2 H, H-7), 3.71 (s, 3 H, NOCH3),
3.83–3.88 (m, 1 H, H-5), 6.40 (d, J = 15.6 Hz, 1 H, H-2), 6.97 (dd,
J = 8.0, 15.6 Hz, 1 H, H-3), 7.05 (dd, J = 7.2, 15.6 Hz, H-3, epimer
at C-5, £3%).
(2R,3S)-3,5-Bis(tert-butyldimethylsiloxy)-2-methylpentan-1-ol
(9)
Raney-Ni11a was washed with H2O until the washings were pH neu-
tral, and then rinsed with absolute EtOH (5 × 100 mL). A solution
of 8 (690 mg, 1.52 mmol) in absolute EtOH (102 mL) was added,
Synthesis 2008, No. 14, 2158–2162 © Thieme Stuttgart · New York

PAPER
Synthesis of the C1–C9 Fragment of Dictyostatin
2161
13C NMR (100 MHz, CDCl3): d = –4.7, –3.8, 15.2 (epimer at C-5,
£3%), 15.6, 18.7, 18.9, 26.6, 26.7, 33.1, 37.5, 43.0, 45.1 (epimer at
C-5, £3%), 60.6, 62.3, 72.8, 73.1 (epimer at C-5, £3%), 119.4,
150.2, 167.6.
pared by slow dropwise addition of HF·py (1.3 mL) to a solution of
pyridine (5.0 mL) and THF (10.2 mL)]. The reaction mixture was
warmed to r.t. and stirred for 8 h. After quenching of the reaction by
the addition of sat. aq NaHCO3 (30 mL), the mixture was extracted
with EtOAc (4 × 20 mL). The combined organic extracts were
washed with sat. aq CuSO4 (3 × 15 mL) and brine (2 × 40 mL), dried
(Na2SO4), and evaporated under reduced pressure. Purification by
flash chromatography (hexanes–EtOAc, 2:1) gave 2.
ESI-HRMS: m/z calcd for C22H47NNaO4Si2: 468.2936; found:
468.2328.
(2E,4R,5S)-5,7-Bis(tert-butyldimethylsiloxy)-4-methylhept-2-
enal (12)
18
Yield: 218 mg (86%); colorless oil; [a]D –10.5 (c 1.00, CH2Cl2);
A stirred solution of Weinreb amide 11 (400 mg, 0.9 mmol) in an-
hyd THF (9.4 mL) was treated at –78 °C with 1 M DIBAL-H in hex-
anes (2.7 mL, 2.7 mmol). After being stirred for 90 min at –78 °C,
this solution was poured into a mixture of 1 M aq tartaric acid (12.4
mL) and EtOAc (13.8 mL). After the mixture had stirred for 1 h, the
layers were separated, the aqueous phase was extracted with Et2O
(2 × 20 mL), and the combined organic extracts were washed with
brine (2 × 25 mL), dried (Na2SO4), and evaporated under reduced
pressure; this gave crude aldehyde 12, which was used without fur-
ther purification.
[a]D24 –14.0 (c 0.20, CHCl3) {Lit.4d [a]D20 –14.3 (c = 0.21, CHCl3)};
Rf = 0.20 (hexanes–EtOAc, 8:2).
IR (CHCl3): 3418, 2954, 2929, 2885, 2857, 1719, 1637, 1601, 1439,
1256, 1197, 1176, 1082, 1031, 1005, 837, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.09 (s, 3 H, MeSi), 0.10 (s, 3 H,
MeSi), 0.91 (s, 9 H, t-BuSi), 1.09 (d, J = 6.8 Hz, 3 H, CH3), 1.63–
1.74 (m, 2 H, H-8), 1.98 (br s, 1 H, OH), 2.54–2.59 (m, 1 H, H-6),
3.73 (s, 3 H, CO2CH3), 3.69–3.75 (m, 2 H, H-9), 3.85–3.88 (m, 1 H,
H-7), 5.61 (d, J = 11.2 Hz, 1 H, H-2), 6.02 (dd, J = 8.0, 15.6 Hz, 1
H, H-5), 6.56 (t, J = 11.2 Hz, 1 H, H-3), 7.38 (dd, J = 11.2, 15.6 Hz,
1 H, H-4).
Yield: 317 mg (91%); pale yellow oil; Rf = 0.81 (hexanes–EtOAc,
6:4).
13C NMR (100 MHz, CDCl3): d = –3.9, –3.7, 15.4, 18.7, 26.5, 36.3,
43.3, 51.8, 60.7, 74.4, 116.4, 127.6, 146.0, 147.7, 167.6.
1H NMR (400 MHz, CDCl3): d = 0.06 (s, 6 H, Me2Si), 0.09 (s, 6 H,
Me2Si), 0.90 (s, 9 H, t-BuSi), 0.92 (s, 9 H, t-BuSi), 1.14 (d, J = 7.2
Hz, 3 H, CH3), 1.53–1.60 (m, 1 H, H-6), 1.64–1.73 (m, 1 H, H-6),
2.57–2.67 (m, 1 H, H-4), 3.64–3.67 (m, 2 H, H-7), 3.90–3.91 (m, 1
H, H-5), 6.13 (dd, J = 7.6, 15.6 Hz, 1 H, H-2), 6.87 (dd, J = 7.6, 15.6
Hz, 1 H, H-3), 9.53 (d, J = 7.6 Hz, 1 H, H-1).
ESI-HRMS: m/z calcd for C17H32NaO4Si: 351.1962; found:
351.1957.
Acknowledgment
Methyl (2Z,4E,6R,7S)-7,9-Bis(tert-butyldimethylsiloxy)-
6-methylnona-2,4-dienoate (13)
We thank the Ministero dell’Università e della Ricerca for financial
support (PRIN prot. 2006030449) and for a postdoctoral fellowship
(‘Assegno di ricerca’ to L. Pignataro) and a PhD fellowship (Borsa
di dottorato ‘Progetto giovani’ to C. Zanato). C. Gennari gratefully
acknowledges Merck Research Laboratories for the Merck’s Aca-
demic Development Program Award. Z. Hao (Lanzhou University,
PRC) thanks the China Scholarship Council for a PhD mobility
grant.
A solution of (F3CCH2O)2P(O)CH2CO2Me (0.18 mL, 0.86 mmol)
and 18-crown-6·MeCN (1.20 g, 3.9 mmol) in anhyd THF (15.6
mL) was cooled to –78 °C, and 0.5 M KHMDS in toluene (1.72 mL,
0.86 mmol) was added dropwise. After the mixture had spent a few
min at –78 °C, a solution of aldehyde 12 (300 mg, 0.78 mmol) in an-
hyd THF (6.5 mL) was added dropwise. The mixture was stirred at
–78 °C for 1 h and then treated with sat. aq NH4Cl (20 mL) and Et2O
(20 mL). The layers were separated, the aqueous phase was extract-
ed with Et2O (2 × 30 mL), and the combined organic extracts were
washed with H2O (2 × 40 mL), dried (Na2SO4), and evaporated un-
der reduced pressure. The crude product was purified by flash chro-
matography (hexanes–EtOAc, 100:5).
References
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22
Yield: 319 mg (90%); colorless oil; [a]D –2.7 (c 0.70, CH2Cl2);
24
20
[a]D –6.4 (c 0.35, CHCl3) {Lit.4d [a]D –6.6 (c = 0.36, CHCl3)};
Rf = 0.35 (hexanes–EtOAc, 100:5).
(2) Paterson, I.; Britton, R.; Delgado, O.; Wright, A. E. Chem.
IR (CHCl3): 3408, 2957, 2927, 2856, 2738, 2710, 2360, 2341, 1722,
1639, 1602, 1471, 1438, 1258, 1194, 1176, 1098, 1030, 835, 806,
775 cm–1.
1H NMR (400 MHz,CDCl3): d = 0.05 (s, 6 H, Me2Si), 0.08 (s, 6 H,
Me2Si), 0.90 (s, 9 H, t-BuSi), 0.92 (s, 9 H, t-BuSi), 1.09 (d, J = 6.9
Hz, 3 H, CH3), 1.55–1.67 (m, 2 H, H-8), 2.47–2.57 (m, 1 H, H-6),
3.63–3.68 (m, 2 H, H-9), 3.75 (s, 3 H, CO2CH3), 3.82–3.85 (m, 1 H,
H-7), 5.61 (d, J = 11.3 Hz, 1 H, H-2), 6.06 (dd, J = 8.0, 15.2 Hz, 1
H, H-5), 6.58 (t, J = 11.3 Hz, 1 H, H-3), 7.37 (dd, J = 11.3, 15.2 Hz,
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Curran, D. P. Org. Lett. 2005, 7, 2873. (b) Fukui, Y.;
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ESI-HRMS: m/z calcd for C23H46NaO4Si2: 465.2827; found:
465.2823.
Methyl (2Z,4E,6R,7S)-7-(tert-Butyldimethylsiloxy)-9-hydroxy-
6-methylnona-2,4-dienoate (2)
A solution of compound 13 (338 mg, 0.74 mmol) in THF (3.8 mL)
at 0 °C was treated with a soln of HF·py in THF–py [16.5 mL, pre-
Synthesis 2008, No. 14, 2158–2162 © Thieme Stuttgart · New York

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Synthesis 2008, No. 14, 2158–2162 © Thieme Stuttgart · New York