Diastereocontrolled synthesis of unit A of cryptophycin

Article abstract of DOI:10.1016/S0040-4020(01)00689-5

Cryptophycin fragment A was prepared in 11 steps from protected methyl (R)-mandelate 4. A diastereoselective addition of magnesium acetylide to methyl mandelate and a Sharpless epoxidation followed by regioselective opening of the resulting epoxide allowe

Full text of DOI:10.1016/S0040-4020(01)00689-5

TETRAHEDRON
Pergamon
Tetrahedron 57 '2001) 7163±7167
Diastereocontrolled synthesis of unit A of cryptophycin
p
Ã
Cyrille Pousset, Mansour Haddad and Marc Larcheveque
Á Â
Laboratoire de Synthese Organique, associe au CNRS, ENSCP, 11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
Received 21 March 2001; revised 15 June 2001; accepted 26June 2001
AbstractÐCryptophycin fragment A was prepared in 11 steps from protected methyl 'R)-mandelate 4. A diastereoselective addition of
magnesium acetylide to methyl mandelate and a Sharpless epoxidation followed by regioselective opening of the resulting epoxide allowed
the synthesis of this intermediate in high diastereomeric purity. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
This strategy allowed the preparation of a diol precursor of
cryptophycin 1 with a good control of stereochemistry but in
a rather moderate yield. However, it would be more ef®cient
to introduce the diol moiety at the beginning of the syn-
thesis. For this purpose, the protected triol 3 'Fig. 2) is a
specially interesting synthon because, once incorporated in
the ®nal structure, it allows the access both to cryptophycin
1 1 and to cryptophycin 8 2 which contains a chlorhydrin
unit10 and shows an even better in vivo biological activity
than cryptophycin 1 itself.3,11
Cryptophycins are cytotoxic, macrocyclic depsipeptides
isolated in 1990 from blue-green algae.1,2 Cryptophycin 1
1 has been shown by Moore and co-workers to be a potent in
vivo tumor-selective cytotoxin 'Fig. 1).2,3 Moreover, it was
not an effective substrate for the P-glycoprotein ef¯ux
mechanism in multiple-drug resistant cells.4 It presents a
broad spectrum of antitumor activity and its exceptional
antiproliferative effects are believed to be derived from
reversible high af®nity binding to microtubules.5
We wish to report here a method which allows the stereo-
selective synthesis of such a protected polyhydroxy unsatu-
rated ester 3 with high enantiomerical purity by asymmetric
epoxidation of an allylic alcohol derived from mandelic
acid.
Following the ®rst report on the synthesis of arenastatin
'cryptophycin 24) in 19946 and cryptophycin 1 in 1995,7
several syntheses of cryptophycin 1 itself or more stable
analogues were reported.8 A common strategy running
through the majority of these syntheses has been the intro-
duction of the epoxide pharmacophore in the last step of
the synthesis by epoxidation of an ethylenic compound
'cryptophycin 3). However, this reaction affords a 2:1 dia-
stereoselectivity and necessitates a tedious HPLC separation
for isolating the required major isomer. An alternative route
using a Sharpless asymmetric dihydroxylation of the same
compound was recently reported.9
2. Results and discussion
We have previously reported that the condensation of a
magnesium acetylide derived from a protected propargylic
alcohol with the aluminium salt obtained by reaction at low
temperature of Dibal-H with O-protected methyl mandelate
Figure 1.
Keywords: depsipeptide; diastereoselective epoxidation; polyol.
Corresponding author. Fax: 133-1-43-25-79-75; e-mail: larchm@ext.jussieu.fr
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020'01)00689-5

7164
C. Pousset et al. / Tetrahedron 57 +2001) 7163±7167
selectively reprotected as an acetonide to give the alcohol 8
'Scheme 1).
In contrast with the alcohol 6, the alcohol 8 was easily
epoxidised with t-butylhydroperoxide in the presence of
'1)-diisopropyl l-tartrate to give as a 95:5 mixture of two
diastereomers from which the compound 9 was isolated in
76% yield. This epoxide was then reacted with trimethyl-
aluminium, a reagent which is known to favour the opening
of 1-hydroxy-2,3-epoxides in 3 position14 and we were
pleased to isolate after hydrolysis, the 1-2 diol 10 exclu-
sively. In order to access the unsaturated ester 15, the
aldehyde 14 was required. For this purpose, the diol 10
was converted to epoxide using the Sharpless conditions
'trimethyl orthoacetate followed by trimethylsilyl
chloride).15 After cyclisation of the intermediate chlor-
hydrin with potassium carbonate, the resulting epoxide 11
was opened with potassium cyanide in the presence of
lithium perchlorate16 to give the hydroxy nitrile 12 '70%
yield). This one was protected as a t-butyl-dimethylsilyl
ether and the resulting nitrile 13 was reduced with
DIBAL-H at low temperature to afford the aldehyde 14.
This intermediate was rather unstable and it was imme-
diately reacted with trimethylphosphonoacetate in the
presence of tetramethylguanidine as a base to give the
required unsaturated ester 15 in 78% yield.
Figure 2.
4 allowed the obtention of the acetylenic protected triol 5 in
high diasteomeric purity.12 Further reduction of the triple
bond under Denmark conditions13 'Red-Alw at 2208C in
order to prevent the O±Si bond cleavage) afforded the E
allylic alcohol 6 stereospeci®cally. It appeared that such
an allylic alcohol could be a good synthon for building the
fragment A of cryptophycins. We envisaged introducing
the methyl at position 3 via the regioselective opening of
an epoxyalcohol of appropriate stereochemistry 'in anti
position vs diol moiety). Thus, we decided to investigate
the epoxidation of 6. We thought that the presence of a
free hydroxy function would allow the obtention of the
required anti epoxide stereoselectively. However, this
secondary allylic alcohol was found unreactive towards
the Sharpless epoxidation. Moreover, the reaction with
t-butyl hydroperoxide in the presence of a catalytic amount
of VO'acac)3 afforded the required anti diastereomer in 40%
diastereomeric excess only. As the opening reaction of this
epoxide with dimethylcuprate was found very dif®cult
probably because of steric hindrance, we decided to modify
our strategy. In this order, compound 6 was completely
deprotected in acidic medium and the resulting triol 7 was
In conclusion, an ef®cient synthesis of cryptophycin unit A
has been completed from mandelic acid. Introduction of
the diol moiety in the benzylic position provides an
ef®cient method for installing the epoxide pharmacophore.
Scheme 1. 'a) Dibal-H hexane, 2788C then magnesium acetylide; 'b) Red-Alw, Et2O, 2208C, 'c) 2 M HCl MeOH, 408C; 'd) acetone, CuSO4, cat. APTS;
'e) t-BuOOH, l-'1)-Diisopropyl-tartrate, Ti'O-i-Pr)4, CH2Cl2; 'f) Me3Al, hexane, rt; 'g) CH3C'OMe)3, Me3SiCl, CH2Cl2, 08C, then K2CO3 MeOH, rt; 'h) KCN,
LiClO4, CH3CN, 708C 'i) t-BuMe2SiOTf, 2,6-lutidine, CH2Cl2; 'j) Dibal-H toluene, 2788C; 'k) trimethylphosphonoacetate, tetramethylguanidine, THF.

C. Pousset et al. / Tetrahedron 57 +2001) 7163±7167
7165
Experiments are currently underway for the total synthesis
of cryptophycin 1 and analogues.
500 mL, round-bottomed ¯ask ®tted with mechanical
stirrer, thermometer, addition funnel, and argon inlet was
placed the acetylenic alcohol 5 '4.75 g, 10 mmol) in 100 mL
of anhydrous Et2O. The solution was cooled to 2258C and
treated via a syringe with a 3.2 M solution of bis'methoxy-
ethoxy) aluminium hydride in toluene '4.8 mL, 15 mmol).
The reaction, monitored by HPLC [column: Merck
Lichrocart 250-4, 100RP-18.5 mm], was generally complete
within 5 h. The solution was quenched by dropwise addition
of 1 M H2SO4 '30 mL). The organic layer was separated and
washed with H2O '50 mL£2) and brine '50 mL). After
drying 'MgSO4), the ethereal phase was concentrated
under reduced pressure and the residual oil was chromato-
graphed 'cyclohexane/AcOEt 4:1) to afford the ethylenic
3. Experimental
3.1. General procedure
Products were puri®ed by distillation or by medium pressure
liquid chromatography on a Jobin±Yvon Modulprep
'Kieselgel 60H Merck) or by ¯ash chromatography
'Kieselgel 60 Merck: 230±400 Mesh; solvent: cyclo-
hexane/EtOAc) and analysed by GC 'Chrompack BP5,
25 m capillary column) or by TLC 'Merck silica gel 60F
254). Carbonated silica gel was obtained from Kieselgel
Merck which was percolated with a 1 M aqueous solution
of sodiumhydrogenocarbonate, washed with water until
neutrality, then washed twice with methanol, dried and
activated at 1108C for two days. NMR spectra were
recorded on a Bruker AC at 200 MHz for 1H- and
20
compound 6 '3.43 g, 72%): ‰aŠ ˆ240.8 'c 1.24, CHCl3);
D
IR '®lm) n 3445, 2955, 2930, 2890, 2855, 1700, 1425 cm21
;
1H NMR '200 MHz, CDCl3) d 1.12 's, 9H), 3.16±3.24 'm,
1H), 3.48 's, 3H), 4.18±4.52 'm, 3H), 4.58 'd, Jˆ7.6Hz,
1H), 4.71 's, 2H), 5.71±6.01 'm, 2H), 7.33±7.56 'm, 10H),
7.65±7.82 'm, 5H); 13C NMR '50 MHz, CDCl3) d 19.0,
26.6, 55.7, 63.3, 75.1, 82.3, 94.3, 126.8, 127.5, 127.8,
128.0, 128.2, 129.5, 131.2, 133.4, 135.3, 137.9; MS 'CI,
NH3) m/z 'relative intensity) 494 'M1NH41, 18%), 342
'100%); Anal. Calcd for C29H36SiO4: C, 73.07; H, 7.60.
Found: C, 73.37; H, 7.75.
1
50 MHz for 13C NMR or on a Bruker 400 Avance for H.
CDCl3 was used as solvent with TMS as internal standard.
IR spectra were recorded on a Perkin±Elmer 599 spectro-
photometer. Mass spectra were recorded on a Ribermag
R10-10C instrument at 70 eV ionising voltage; ammonia
was used for chemical ionisation. Optical rotations were
measured on a Jasco P-1010 polarimeter.
3.1.3. (1R,2R,3E)-1-Phenyl-pent-3-en-1,2,5-triol (7).
Conc. HCl '0.2 mL) was added to a solution of 5 '7.2 g,
15 mmol) in methanol '50 mL) and stirred at 408C for two
days. Methanol was removed in vacuo and the residue was
diluted in diethyl ether and washed with saturated aqueous
NaHCO3. After drying 'MgSO4), the ethereal phase was
concentrated under reduced pressure and the residual oil
was chromatographed 'CH2Cl2/MeOH 9:1) to afford the
3.1.1.
methoxy-1-phenyl-pent-3-yn-2-ol (5). Compound
(1R,2R)-5-(t-Butyldiphenylsilyloxy)-1-methoxy-
4
'3.15 g, 15 mmol) was dissolved in Et2O/pentane '1:1,
60 mL) under an argon atmosphere, cooled to 2788C, and
treated dropwise with 18 mL of DIBAL-H '1 M in hexanes).
The mixture was stirred for 1 h before addition, through
cannula, of a Grignard solution of magnesium acetylide,
prepared as followed: an ethereal solution '30 mL) of
protected propargyl alcohol '6.62 g, 22.5 mmol) was treated
with 15.46mL of n-BuLi '1.6M in hexanes) at 2208C
under an argon atmosphere; the mixture was stirred for
1 h at this temperature, warmed to 08C, and recooled to
2308C; an ethereal magnesium bromide solution, obtained
from magnesium '1.44 g, 60 mmol) and 1,2-dibromoethane
'11.16g, 60 mmol), was then cannulated and the reaction
was allowed to reach 238C, while stirring was continued
overnight. The next day, the solution was cooled to
2208C and quenched by addition of a 10% HCl solution
'30 mL) and diluted with water '50 mL). The organic
extract was washed with brine, dried over MgSO4 and
concentrated under reduced pressure. Flash chromatography
'cyclohexane/EtOAc 4:1) gave 5 '6.2 g, 87%) as an oil:
1
20
D
triol 7 '2.7 g; 92%). ‰aŠ ˆ 111:2 'c 1.20, MeOH); H
NMR '200 MHz, CDCl3) d 2.98 'm, 1H), 3.55±3.67 'm,
1H), 3.89±4.24 'm, 3H), 4.41±4.56'm, 2H), 5.52 'dd, 1H,
Jˆ5.6, 15.7 Hz), 5.63±5.79 'm, 1H), 7.23±7.33 'm, 5H);
13C NMR '50 MHz, CDCl3) d 62.1, 75.8, 77.1, 126.5,
126.9, 127.7, 128.1, 131.6, 132.3, 140.3; MS 'CI, NH3)
m/z 'relative intensity) 212 'M1NH41, 100%), 194 'M,
4%).
3.1.4.
(1R,2R,3E)-1,2-Di-O-isopropylidene-1-phenyl-
pent-5-ene-1,3,5-triol (8). Anhydrous CuSO4 '4.5 g,
28 mmol) and PTSA '30 mg) were added to a solution of
7 '2.7 g, 14 mmol) in acetone '100 mL). After stirring for
two days at room temperature, acetone was evaporated in
vacuo and the residue was dissolved in CH2Cl2, washed with
saturated aqueous NaHCO3 and dried 'MgSO4). After
concentration under reduced pressure 2.9 g of pure aceto-
20
‰aŠ ˆ266 'c 0.7, CHCl3); IR '®lm) n 3430 'br), 2955,
D
20
2930, 2890, 2860, 1425 cm21
;
1H NMR '200 MHz,
nide 8 was obtained as an oil '91%). ‰aŠ ˆ 14:8 'c 3.0,
D
CHCl3); H NMR '200 MHz, CDCl3) d 1.55 and 1.60 '2s,
1
CDCl3) d 1.07 's, 9H), 2.72 'd, Jˆ5 Hz, 1H), 3.41 's,
3H), 4.25±4.38 'm, 2H), 4.48±4.58 'm, 1H), 4.62±4.80
'm, 3H), 7.26±7.50 'm, 10H), 7.65±7.80 'm, 5H); 13C
NMR '50 MHz, CDCl3) d 19.1, 26.6, 52.5, 55.8, 66.5,
80.8, 82.5, 84.9, 94.7, 127.6, 127.9, 128.2, 128.3, 129.7,
132.9, 135.6, 137.1; MS 'CI, NH3) m/z 'relative intensity)
492 'M1NH41, 22%), 198 '100%). Anal. Calcd for
C29H34SiO4: C, 73.38; H, 7.21. Found: C, 73.10; H, 7.29.
2£3H), 2.46'br s, 1H), 4.10 'br s, 2H), 4.25 'dd, 1H, Jˆ5.6,
8.4 Hz), 4.69 'd, 1H, Jˆ14.2 Hz), 5.74±5.88 'm, 2H), 7.32±
7.40 'm, 5H); 13C NMR '50 MHz, CDCl3) d 26.9, 27.0,
62.5, 82.9, 83.6, 109.2, 126.4, 128.1, 128.4, 134.5, 136.7;
MS 'CI, NH3) m/z 'relative intensity) 252 'M1NH41, 29%),
194 '100%). Anal. Calcd for C14H18O3: C, 71.80; H, 7.74.
Found: C, 71.56; H, 7.75.
3.1.5. (1R,2R,3R,4R)-1,2-Di-O-isopropylidene-3,4-epoxy-
1-phenyl-pentan-1,2,5-triol (9). Ti'O-i-Pr)4 '1.8 mL,
3.1.2. (1R,2R,3E)-5-(t-Butyldiphenylsilyloxy)-1-methoxy-
methoxy-1-phenyl-pent-3-ene-2-ol (6). In a four-necked,

7166
C. Pousset et al. / Tetrahedron 57 +2001) 7163±7167
6mmol) and l-'1)-diisopropyltartrate '1.3 mL, 6mmol)
were successively added to a 2208C cooled suspension of
4.8 Hz), 2.74 't, 1H, Jˆ4.9 Hz), 2.80±2.88 'm, 1H), 4.04
'dd, 1H, Jˆ4.0, 8.6Hz), 4.84 'd, 1H, Jˆ8.6Hz), 7.29±7.45
'm, 5H); 13C NMR '50 MHz, CDCl3) d 10.3, 26.8, 26.9,
37.0, 45.9, 57.3, 79.9, 83.8, 108.5, 126.7, 128.0, 128.2,
137.5; MS 'CI, NH3) m/z 'relative intensity) 266
'M1NH41, 100%), 249 '45%), 208 '90%). Anal. Calcd
for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.85; H, 8.19.
Ê
4 A molecular sieves '1.2 g) in CH2Cl2 '30 mL). After
stirring for 10 min, a solution of the ethylenic compound
8 '1.00 g, 4.3 mmol) in CH2Cl2 '10 mL) was slowly added
and stirred for 5 min at the same temperature. Anhydrous
t-butylhydroperoxide '2 mL, 9 mmol) was then added and
the resulting mixture was stirred for 4 days at 2208C. After
hydrolysis with 2 M aqueous tartaric acid, the solution was
extracted with CH2Cl2. The organic phase was dried
'MgSO4) and concentrated under reduced pressure; the
3.1.8. (2S,3S,4R,5R)-5-Cyano-1,2-di-O-isopropylidene-3-
methyl-1-phenyl-pentan-1,2,4-triol (12). To a solution of
epoxide 11 '124 mg, 0.5 mmol) in anhydrous acetonitrile
'15 mL) was added anhydrous LiClO4 '80 mg, 0.75 mmol)
and KCN '49 mg, 0.75 mmol). The suspension was stirred
at 708C for 6h and hydrolysed at room temperature with
water. The reaction mixture was extracted with diethyl ether
and the organic layer was dried over MgSO4. The solvent
was removed under reduced pressure and the residue was
puri®ed by column chromatography on silica gel using 7:3
cyclohexane/AcOEt as eluent to give 12 as a colorless oil
residual oil was chromatographed 'cyclohexane/AcOEt
20
6:4) to afford the epoxide 9 '812 mg, 76%): ‰aŠ
ˆ
D
1
233:4 'c 1.90, CHCl3); H NMR '200 MHz, CDCl3) d
1.55 and 1.58 '2s, 2£3H), 2.00 's, 1H), 2.97±3.16'm,
1H), 3.25±3.27 'dd, 1H, Jˆ2.2, 5.1 Hz), 3.66±3.84 'm,
2H), 3.96'dd, 1H, Jˆ2.4, 10.4 Hz), 4.96'd, 1H, Jˆ
8.0 Hz); 13C NMR '50 MHz, CDCl3) d 26.6, 26.8, 54.5,
56.2, 60.8, 81.1, 81.6, 109.9, 126.5, 128.4, 137.4. MS 'CI,
NH3) m/z 'relative intensity) 268 'M1NH41, 100%), 251
'15%). Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found:
C, 67.88; H, 7.19.
1
20
D
'96mg, 70% yield). ‰aŠ ˆ 212:4 'c 1.98, CH2Cl2); H
NMR '200 MHz, CDCl3) d 1.06'd, 3H, Jˆ7.1 Hz), 1.51
and 1.58 '2d, 2£3H), 1.90±2.02 'm, 1H), 2.47 'dd, 1H, Jˆ
4.4, 16.8 Hz), 2.62 'dd, 1H, Jˆ7.3, 16.8 Hz), 3.00 'd, 1H,
Jˆ6.1 Hz), 3.85±4.00 'm, 1H), 4.03 'dd, 1H, Jˆ2.2,
8.8 Hz), 4.83 'd, 1H, Jˆ8.9 Hz), 7.28±7.48 'm, 5H); 13C
NMR '50 MHz, CDCl3) d 9.7, 23.7, 26.7, 27.1, 36.5,
70.7, 79.6, 82.4, 109.0, 117.8, 126.6, 128.6, 136.9; MS
'CI, NH3) m/z 'relative intensity) 293 'M1NH41, 100%),
276'12%), 235 '95%). Anal. Calcd for C 16H21NO3: C,
69.78; H, 7.68; N, 5.10. Found: C, 69.31; H, 8.03; N, 4.99.
3.1.6. (1R,2R,3S,4R)-1,2-Di-O-isopropylidene-3-methyl-
1-phenyl-pentan-1,2,4,5-tetrol (10). Compound
9
'550 mg, 2.2 mmol) was dissolved in a 5:1 mixture of
hexane/CH2Cl2 '5 mL) and slowly added under an argon
atmosphere to a solution of trimethylaluminium '6.6
mmol) in hexane '6mL) cooled to 2108C. After one
hour, the mixture was warmed up and stirred for 20 h at
room temperature. After hydrolysis with 0.1 M aqueous
tartaric acid, the reaction mixture was extracted with diethyl
ether. The organic phase was washed with brine, dried on
MgSO4 and concentrated under reduced pressure. After
column chromatography on carbonated silica gel 'cyclo-
hexane/AcOEt 6:4), pure compound 10 was isolated as an
oil '210 mg) in addition to 100 mg '18%) of the starting
3.1.9. (3S,4S,5R,6R)-3-t-Butyldimethylsilyloxy-5,6-di-O-
isopropylidenedioxy-4-methyl-6-phenyl-hexanal
(14).
Under Argon, t-butyldimethylsilyltri¯ate '90 mL, 0.36
mmol) was added at 08C to a solution of 12 '65 mg,
0.24 mmol) and 2,6-lutidine '60 mL, 5 mmol) in CH2Cl2
'5 mL). After stirring for 3 h, the reaction mixture was
hydrolysed with water and the organic layer was extracted
with CH2Cl2 and dried over MgSO4. The solvent was
removed under reduced pressure and the residue was
puri®ed by column chromatography on silica gel using 9:1
cyclohexane/AcOEt as eluent to give 13 '85 mg, 92%
yield). This one was dissolved into anhydrous toluene
'10 mL) and cooled to 2788C. 1 M DIBAL-H in toluene
'450 mL, 0.45 mmol) was added and the resulting mixture
was stirred for 2.5 h at the same temperature. The reaction
was quenched with anhydrous methanol '0.8 mL) followed
by 0.5N H2SO4 and vigorously stirred for 1 h. The reaction
mixture was extracted with diethyl ether and the organic
layer was washed with brine and dried over MgSO4. The
solvent was removed under reduced pressure and the residue
was puri®ed by column chromatography on silica gel using
92:8 cyclohexane/AcOEt as eluent to give 14 as an unstable
20
D
compound: 44% yield. ‰aŠ ˆ 268:0 'c 2.59, CH2Cl2);
1H NMR '200 MHz, CDCl3) d 1.02 'd, 3H, Jˆ7.0 Hz),
1.52 and 1.58 '2s, 2£3H), 1.88±2.06'm, 1H), 2.95 'br s,
1H), 3.45±3.55 'm, 1H), 3.87±3.92 'm, 1H), 4.09 'dd, 1H,
Jˆ2.2, 9.0 Hz), 4.83 'd, 1H, Jˆ9.0 Hz), 7.35±7.40 'm, 5H);
13C NMR '50 MHz, CDCl3) d 10.1, 27.1, 30.1, 64.5, 74.6,
79.5, 83.1, 108.7, 126.7, 128.4, 128.5, 137.3; MS 'CI, NH3)
m/z 'relative intensity) 284 'M1NH41, 100%), 267 '18%).
3.1.7. (1R,2R,3S,4R)-1,2-Di-O-isopropylidene-4,5-epoxy-
3-methyl-1-phenyl-pentan-1,2-diol (11). Trimethylsilyl
chloride '87 mg, 0.8 mmol) and trimethylorthoacetate
'97 mg, 0.8 mmol) were added at 08C to a solution of 10
'173 mg, 0.65 mmol) in CH2Cl2 '3 mL). The solution was
stirred for one hour, concentrated under reduced pressure
and dissolved in anhydrous methanol '5 mL). K2CO3
'225 mg, 1.6mmol) was then added and the resulting
suspension was vigorously stirred for 2 h before hydrolysis.
The reaction mixture was extracted with diethyl ether and
the organic layer was dried over MgSO4. The solvent was
removed under reduced pressure and the residue was puri-
®ed by column chromatography on silica gel using 95:5
cyclohexane/AcOEt as eluent to give 11 as a colourless
1
compound '50 mg, 58%). H NMR '200 MHz, CDCl3) d
0.10 's, 6H), 0.82 's, 9H), 1.12 'd, 3H, Jˆ7.0 Hz), 1.50
and 1.56'2s, 2 £3H), 1.80±1.92 'm, 1H), 2.46±2.55 'm,
2H), 3.86'dd, 1H, Jˆ2.4, 8.9 Hz), 4.07±4.15 'm, 1H),
4.70 'd, 1H, Jˆ8.9 Hz), 7.29±7.39 'm, 5H), 9.75 't, 1H,
Jˆ2.2 Hz); 13C NMR '50 MHz, CDCl3) d 24.8, 7.8, 17.8,
25.6, 27.0, 27.1, 38.8, 47.3, 70.3, 80.5, 82.9, 108.9, 126.6,
128.3, 128.5, 137.6, 202.0.
1
20
D
oil '105 mg, 65%). ‰aŠ ˆ 110:9 'c 2.57, CH2Cl2); H
NMR '200 MHz, CDCl3) d 1.12 'd, 3H, Jˆ7.0 Hz), 1.50
and 1.58 '2s, 2£3H), 1.55 'm, 1H), 2.47 'dd, 1H, Jˆ2.6,
3.1.10. (2E,5S,6S,7R,8R)-5-t-Butyldimethylsilyloxy-7,8-

C. Pousset et al. / Tetrahedron 57 +2001) 7163±7167
7167
5. Panda, D.; Himes, R. H.; Moore, R. E.; Wilson, L.; Jordan,
M. A. Biochemistry 1997, 36, 12948±12953.
di-O-isopropylidenedioxy-6-methyl-8-phenyl-octa-2-
enoic acid methyl ester (15)Tetramethylguanidine '23 mL,
0.18 mmol) was added via a syringe to a stirred solution
under argon at 2788C of aldehyde 13 '45 mg, 0.12 mmol)
and trimethylphophonoacetate '33 mg, 0.18 mmol) in
anhydrous THF '10 mL). Stirring was continued for
30 min at 2788C, then the solution was allowed to warm
to room temperature for 4 h. The reaction was quenched
with water '6mL) and extracted with diethyl ether. The
organic layer was dried over MgSO4. The solvent was
removed under reduced pressure and the residue was puri-
®ed by column chromatography on silica gel using 92:8
cyclohexane/AcOEt as eluent to give 15 '42 mg, 78%).
6. Kobayashi, M.; Kurosu, M.; Wang, W.; Kitigawa, I. Chem.
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7. Barrow, R. A.; Hemscheidt, T.; Liang, J.; Paik, S.; Moore,
R. E.; Tius, M. A. J. Am. Chem. Soc. 1995, 117, 2479±2490.
Â
8. Rej, R.; Nguyen, D.; Go, B.; Fortin, S.; Lavallee, J.-F. J. Org.
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Guo, Z.; Sih J. Org. Chem. 1996, 61, 6893±6900. Dhokte,
U. P.; Khau, V. V.; Hutchinson, D. R.; Martinelli, M. J.
Tetrahedron Lett. 1998, 39, 8771±8774. White, J. D.; Hong,
J.; Robarge, L. A. Tetrahedron Lett. 1998, 39, 8779±8782.
White, J. D.; Hong, J.; Robarge, L. A. J. Org. Chem. 1999,
64, 6206±6216. Patel, V. F.; Andis, S. L.; Kennedy, J. H.; Ray,
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Ghosh, A. K.; Bischoff, A. Org. Lett. 2000, 2, 1573±1575.
Eggen, M.; Mossman, C. J.; Buck, S. B.; Nair, S. K.; Bhat,
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‰aŠ ˆ 121:5 'c 2.0, CHCl3); 1H NMR '200 MHz,
20
D
CDCl3) d 20.04 and 0.03 '2s, 2£3H), 0.81 's, 9H), 1.03
'd, 3H, Jˆ6.9 Hz), 1.48 and 1.54 '2s, 2£3H), 1.72±1.76'm,
1H), 2.23±2.32 'm, 2H), 3.62±3.68 'm, 1H), 3.73 's, 3H),
3.95 'dd, 1H, Jˆ2.7, 8.8 Hz), 4.66 'd, 1H, Jˆ8.8 Hz), 5.68
'd, 1H, Jˆ17.7 Hz), 6.82 'dt, 1H, Jˆ7.0, 15.7 Hz), 7.26±
7.38 'm, 5H); 13C NMR '50 MHz, CDCl3) d 24.9, 20.1,
8.5, 17.8, 25.6, 26.8, 27.1, 36.3, 38.8, 51.2, 72.9, 80.7, 82.7,
108.7, 122.8, 126.8, 128.2, 128.5, 137.8, 146.1, 166.1; MS
'CI, NH3) m/z 'relative intensity) 466 'M1NH41, 100%).
Anal. Calcd for C25H40O5Si: C, 66.93; H, 8.98. Found: C,
67.09; H, 9.04.
9. Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org.
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È
12. Haddad, M.; Imogaõ, H.; Larcheveque, M. J. Org. Chem.
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13. Denmark, S. E.; Jones, T. K. J. Org. Chem. 1982, 47, 4595±
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