From 2,2'-methylenedifuran to all stereomeric pentadecane-1,3,5,7,9,11,13,15-octols.

Full text of DOI:10.1021/jo010172u

J . Org. Chem. 2001, 66, 7869-7872
7869
syn11 aldol reductions with Mitsunobu reaction12 allow
to prepare, in principle, 16 diastereomeric pentadecane-
1,3,5,7,9,11,13,15-octols (e.g., (-)-5) and analogues (Scheme
1). If the syn relationship between the 4-methoxyben-
zoates at C-3 and C-13 (atom numbering of (-)-5) could
be changed into an anti relative configuration, all possible
stereomeric pentadecane-1,3,5,7,9,11,13,15-octols could
be reached in both enantiomeric forms. We report here
a solution to that problem.
F r om 2,2′-Meth ylen ed ifu r a n to All
Ster eom er ic
P en ta d eca n e-1,3,5,7,9,11,13,15-octols
Marc-Etienne Schwenter and Pierre Vogel*
Section de Chimie, Universite´ de Lausanne, BCH,
CH-1015 Lausanne-Dorigny, Switzerland
As already described,8 diol (-)-4 was converted (Scheme
2) into tetrol (-)-6 in 75% overall yield. Treatment of
(-)-6 with (MeO)2CMe2 in acetone under acidic conditions
(pyridinium paratoluenesulfonate) gave acetonide (-)-7
in 92% yield. Heating (-)-7 in acetonitrile in the presence
of 12 equiv of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
induced the isomerization of (-)-7 into the primary
paramethoxybenzoate (-)-8. Equilibrium ([(-)-8]/[(-)-7]
) 3.0) was reached after 4 h at 80 °C, and (-)-8 could be
isolated in 70% yield (Scheme 2). This result can be
interpreted in terms of acyl group migration from the C-3
to the C-1 position (atom numbering of (-)-5; IUPAC
numbering: 2′′′,4′′′, see (-)-8), the primary ester (-)-8
being more stable than (-)-7 for steric reasons. Also for
steric reasons, the intramolecular migration of the
paramethoxybenzoyl group from the 1-oxy position to the
6-hydroxy group of the cycloheptenol moiety is forbidden.
Attempts to displace the acyclic secondary alcohol at C-3
(atom numbering of (-)-5; IUPAC: 2′′′) using the Mit-
sunobu reaction ((EtOOC)2N2, PPh3, 4-NO2C6H4COOH)12
were not met with success. They led to complex mixtures.
Selective sulfonylation of the acyclic alcohol at C-3
(IUPAC: 2′′′) with CH3SO2Cl and p-TsCl (pyridine, Et3N)
also led to intractable mixtures.
Selective methanolysis of the acyclic paramethoxyben-
zoate at C-3 (IUPAC: 6′) was possible on treating (-)-7
in MeOH containing 7.2 equiv of Mg(OMe)2 (40 °C, 8 h).
This furnished triol (-)-9 in 68% yield, together with 12%
of (-)-8. Dihydroxylation of the cycloheptene moiety of
(-)-9 with (N-methylmorpholine N-oxide, cat. OsO4, CCl4)
followed by oxidative cleavage of the vicinal diol with Pb-
(OAc)4 provided (+)-10 (3:2 mixture of anomers) in 92%
yield. Treatment of (+)-10 with (i-prop)3SiCl and imida-
zole (DMF, 20 °C, 48 h) led to selective double silylation
of the pyranose and primary alcoholic functions, leaving
the secondary alcohol at C-3 (IUPAC: 2′′′) unprotected.
This provided (+)-11 in 73% yield as a single â-pyrano-
side.13 Sulfonylation of the secondary alcohol (+)-11 with
CH3SO2Cl (pyridine, DMAP cat.) gave the corresponding
mesylate that was not purified but used directly in the
next step. Heating this mesylate in benzene containing
anhydrous CsOAc and 18-crown-6 ether led to a 3:2
mixture of the product of SN2 substitution (+)-12 and of
unreacted mesylate. This could not been pushed to
completion as decomposition completed with the substi-
tution. Acetate (+)-12 was isolated in 63% yield, together
with unreacted mesylate (32%), after column flash chro-
pierre.vogel@ico.unil.ch
Received February 13, 2001
A great variety of natural products of biological interest
includes polyketides (1,3-polyoxo, 1,3-polyols, aldols).1
Several approaches for their synthesis have been pro-
posed.2,3 Inspired by the work of Lautens4 and Hoffmann
and co-workers,5 who have converted 8-oxabicyclo[3.2.1]-
oct-6-en-3-one into 7-carbon-1,3-polyols and analogues,6
and by that of Kaku et al.,7 who have transformed
cyclohept-3-ene-1,6-diol into 1,3-polyols, we have pro-
posed a new, noniterative asymmetric synthesis of long-
chain 1,3-polyols starting from the now readily available
2,2′-methylenedifuran (1).8 The method imployed the
double [3+4]-cycloaddition of the 1,1,3-trichloro-2-oxyallyl
cation to 1. After reductive workup, a 45:55 mixture of
meso-2 and (()-threo-2 was obtained in 55% yield and
separated by fractional crystallizations. The meso com-
pound was converted into meso-3, which was desymme-
trized into diol (-)-4 by means of the Sharpless asym-
metric dihydroxylation.9 Further transformations im-
ploying the combinations of Evans’ anti10 and Nasaraka’s
(1) Omura, S, Tanaka, H. Macrolide Antibiotics: Chemistry, Biology,
and Pratice., Academic Press: New York, 1984. See also: Rychnovsky,
S. D.; Griesgraber, G.; Schlegel, R. J . Am. Chem. Soc. 1995, 117, 197.
Richardson, T. I.; Richardson, T. I.; Rychnovsky, S. D. J . Org. Chem.
1996, 61, 4219. Lipschutz, B. H.; Ullman, B.; Lindsley, C.; Recchi, S.;
Buzard, D. J .; Dickson, D. J . Org. Chem. 1998, 63, 6092. Pawlak, J .;
Sowinski, P., P.; Borowski, E.; Garibaldi, P. J . Antibiot. 1995, 48, 1034.
McGarvey, G. J .; Mathys, J . A.; Wilson, K. J .; Overly, K. O.; Buonova,
P. T.; Spours, P. G. J . Am. Chem. Soc. 1995, 60, 7778. Mukhopadhyay,
T.; Vijayakumar, E. K. S.; Nadkarni, S. R.; Fehlhaber, H.-W.; Kogler,
H.; Petry, S. J . Antibiot. 1998, 57, 582.
(2) See ref 2 and 3 of ref 8.
(3) For recent proposals, see, e.g.: Schneider, C. Angew. Chem., Int.
Ed. 1998, 37, 1375. Rychnovsky, S. D.; Fryszman, O.; Khine, U. R.
Tetrahedron Lett. 1999, 40, 41. Schneider, C.; Rehfeuter, M. Chem.
Eur. J . 1999, 5, 2850. J ørgensen, K. B.; Suenaga, T.; Nakata, T.
Tetrahedron Lett. 1999, 40, 8855. Enders, D.; Hundertmark, T.
Tetrahedron Lett. 1999, 40, 4169. Smith, A. B. III.; Pitram, S. M. Org.
Lett. 1999, 1, 2001. McGarvey, G. J .; Mathys, J . A.; Wilson, K. J .
Tetrahedron Lett. 2000, 41, 6011. Greer, P. B.; Donaldson, W. A.
Tetrahedron Lett. 2000, 41, 3801. Wender, P. A.; Lippa, B. Tetrahedron
Lett. 2000, 41, 1007. Kiegiel, J .; J o´zwik, J .; Wozniak, K.; J urczak, J .
Tetrahedron Lett. 2000, 41, 4959. Barrett, A. G. M.; Braddock, D. C.;
deKoning, P. D.; White, A. J . P.; Williams, D. J . J . Org. Chem. 2000,
65, 375. Sarraf, S. T.; Leighton, J . L. Org. Lett. 2000, 2, 1209. Zacuto,
M. J . Leighton, J . L. J . Am. Chem. Soc. 2000, 122, 8587. Kiyoota, S-i.;
Hena, M. A.; Yabukami, T.; Murai, K.; Goto, F. Tetrahedron Lett. 2000,
41, 7511.
(4) See, e.g.: Lautens, M.; Ma, S.; Yee, A. Tetrahedron Lett. 1995,36,
4185.
(5) See, e.g.: Lampe, T. F. J .; Hoffmann, H. M. R. J . Chem. Soc.,
Chem. Commun. 1996, 1931. Dunke, R.; Hoffmann, H. M. R. Tetra-
hedron 1999, 55, 8385. Dunkel, R.; Mentzel, M.; Hoffmann, H. M. R.
Tetrahedron 1997, 53, 13929.
(6) See also: Montan˜a, A. M.; Garcia, F.; Grima, P. M. Tetrahedron
1999, 40, 1375.
(7) Kaku, H.; Tanaka, M.; Norimine, Y.; Miyashita, Y.; Suemune,
H.; Sakai, K. Tetrahedron: Asymmetry 1997, 8, 195.
(8) Schwenter, M.-E.; Vogel, P. Chem. Eur. J . 2000, 6, 4091.
(9) Sharpless, K. B.; Kolb, H. C.; Van Nieuwenhze, M. S. Chem. Rev.
1994, 94, 2483.
(10) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560.
(11) Nasaraka, K.; Pai, F. G. Tetrahedron Lett. 1984, 40, 2233. Chen,
K. N.; Hardtmann, G. E.; Prasad, K.; Repe`ic, O.; Shapiro, M. J .
Tetrahedron Lett. 1987, 28, 155.
(12) Mitsunobu, O. Synthesis 1981, 1.
(13) Structure confirmed by 3J (H-6,H-5) ) 7.4 Hz.
10.1021/jo010172u CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/24/2001

7870 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
Sch em e 1
Sch em e 2
Exp er im en ta l Section
Gen er a l Rem a r k s. See ref 15. Flash column chromatography
(FC) was performed on Merck silica gel (230-400 mesh, no.
9385). Thin-layer chromatography (TLC) was carried out on
silica gel (Merck aluminum foils). 1H NMR signals assignments
were confirmed by double irradiation experiments and, when
required, by 2D NOESY and COSY spectra. J values are given
in hertz.
(-)-(1R,6R)-6-H yd r oxy-4-[[(4R,6S)-6-[(2S)-4-h yd r oxy-2-
[(4-m eth oxyben zoyl)oxy]bu tyl]-2,2-d im eth yl-1,3-d ioxa n -4-
yl]m eth yl]cycloh ep t-3-en -1-yl 4-Meth oxyben zoa te ((-)-7).
A mixture of (-)-68 (0.95 g, 1.66 mmol), acetone (20 mL), 2,2-
dimethoxypropane (9.5 mL), and pyridinium paratoluene-
sulfonate (45 mg) was stirred at 0 °C for 4 h. The solvent was
evaporated to dryness and the residue taken in CH2Cl2 (20 mL).
After the temperature was maintained at 20 °C for 2 h with
pyridinium paratoluenesulfonate (5 mg), NaHCO3 (100 mg) was
added under vigorous stirring. The solvent was evaporated and
the residue purified by FC (CH2Cl2/MeOH 97:3) giving 935 mg
matography on silica gel. According to the NMR data, it
was a different product than that of acetylation of (+)-
10 with Ac2O/pyr./DMAP.
(92%) of (-)-7, colorless, amorphous solid: [R]25 ) -17 (c )
D
Selective monodesilylation of (+)-12 with Bu4NF (THF,
-78 to -50 °C) liberated the pyranose without desilyla-
tion of the primary alcoholic moiety. This furnished (+)-
13 in 85% yield. Reduction of (+)-13 under Evans’
conditions10 (Me4NBH(OAc)3/AcOH/CH3CN, 0-2 °C, 15
h) provided triol (-)-14 isolated in 44% yield. Its structure
was confirmed by the 13C NMR spectra14 of the corre-
sponding tetraacetonide (-)-15 obtained by desilylation
of (-)-14 with Bu4NF (THF, 20 °C), followed by metha-
nolysis of the ester (MeOH/MeOK) and treatment with
(MeO)2CMe2/acetone under acidic conditions.
This paper together with our previous report8 demon-
strates that meso-1,1′-methylenedi[(1R,1′S,5S,5′R)-3-oxo-
8-oxabicyclo[3.2.1]oct-6-ene] (meso-2) obtained readily
from furan and furfuryl alcohol can be converted, in
principle, into all possible stereomeric pentadecane-
1,3,5,7,9,11,13,15-octols with high stereoselectivity and
enantiomeric purity. This realizes a flexible, noniterative
approach to the total asymmetric synthesis of long-chain
polyketides. The success of this approach relies on well-
established reactions such as Evans’ anti10 and Nasara-
ka’s syn11 reductions of aldols, SN2 substitution12 and on
our ability to differentiate between the reactivity of
alcohols on aliphatic and on cycloheptene or tetrahydro-
pyran rings. The method permits the synthesis of
polyketides bearing various protective groups, thus en-
hancing its flexibility.
1
0.94, CHCl3); H NMR (400 MHz, CDCl3) δ 8.01-7.94 (m, 4H),
6.94-6.88 (m, 4H), 5.63 (t, 1H, J ) 6.6 Hz), 5.46 (dddd, 1H, J )
9.8, 9.7, 3.2, 3.1 Hz), 5.16 (dddd, 1H, J ) 9.7, 9.6, 3.9, 3.8 Hz),
4.06 (m, 1H), 3.99 (m, 1H), 3.91 (m, 1H), 3.86 (s, 3H), 3.84 (s,
3H), 3.79-3.55 (m, 2H), 2.91 (br.s, 1H), 2.53 (br.s, 1H), 2.51-
2.42 (m, 4H), 2.26-2.09 (m, 4H), 1.98-1.87 (m, 2H), 1.81-1.72
(m, 2H), 1.64 (ddd, 1H, J ) 21.7, 12.8, 8.9 Hz), 1.63 (ddd, 1H, J
) 21.7, 12.8, 9.0 Hz), 1.31 (s, 3H), 1.14 (s, 3H). Anal. Calcd for
C34H44O10 (612.716): C, 66.65; H, 7.24. Found: C, 66.51; H, 7.36.
(-)-(1R,6R)-6-Hyd r oxy-4-[[(4R,6S)-6-[(2S)-4-[(4-m eth oxy-
b en zoyl)oxy]-2-h yd r oxyb u t yl]-2,2-d im et h yl-1,3-d ioxa n -4-
yl]m eth yl]cycloh ep t-3-en -1-yl 4-Meth oxyben zoa te ((-)-8).
A mixture of (-)-7 (0.1 g, 0.16 mmol), anhyd CH3CN (4 mL),
and DBU (0.3 g, 1.97 mmol) was heated to 80 °C for 4 h. After
being cooled to -78 °C, the solution was poured dropwise into
1% aqueous HCl solution, cooled to 0 °C under vigorous stirring,
and extracted with EtOAc (10 mL, three times). The combined
organic extracts were dried (MgSO4). After filtration (Celite),
NaHCO3 (20 mg) was added and the solvent evaporated to
dryness. FC (CH2Cl2/MeOH 98:2, Rf ((-)-7) ) 0.22, Rf ((-)-8) )
0.27) gave (-)-7 (22 mg, 22%) and (-)-8 (70 mg, 70%): colorless
1
oil; [R]25 ) -51 (c ) 1.10, CHCl3); H NMR (400 MHz, CDCl3)
D
δ 8.01-7.95 (m, 4H), 6.94-6.89 (m, 4H), 5.67 (t, 1H, J ) 6.8
Hz), 5.18 (m, 1H), 4.53 (ddd, 1H, J ) 11.1, 8.2, 5.5 Hz), 4.40
(ddd, 1H, J ) 11.1, 5.7, 5.6 Hz), 4.18 (m, 1H), 4.11 (m, 1H), 4.03
(m, 2H), 3.86 (s, 6H), 2.53-2.48 (m, 4H), 2.27-2.15 (m, 4H), 1.69
(t, 2H, J ) 5.8 Hz), 1.75-1.68 (m, 1H), 1.61 (ddd, 1H, J ) 13.0,
9.1, 6.0 Hz), 1.37 (s, 3H), 1.36 (s, 3H). Anal. Calcd for C43H44O10
(612.72): C, 66.65; H, 7.24. Found: C, 66.52; H, 7.24.
(-)-(1R,6R)-6-Hyd r oxy-4-[[(4R,6R)-6-[(2S)-2,4-d ih yd r oxy-
bu tyl]-2,2-d im eth yl-1,3-d ioxa n -4-yl]m eth yl]cycloh ep t-3-en -
(14) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
(15) Kraehenbuehl, K.; Picasso, S.; Vogel, P. Helv. Chim. Acta 1998,
81, 1439.

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7871
Sch em e 3
1-yl 4-Meth oxyben zoa te ((-)-9). A 0.6 M solution of Mg(OMe)2
in anhyd MeOH (6 mL, 3.6 mmol) was added dropwise to a
stirred solution of (-)-7 (305 mg, 0.5 mmol) in anhyd MeOH (10
mL). The mixture was stirred at 40 °C for 8 h (TLC, SiO2, CH2-
Cl2/MeOH 95:5, Rf ((-)-7) ) 0.35, Rf ((-)-8) ) 0.40, Rf ((-)-9) )
0.19). After being cooled to 0 °C, the mixture was neutralized
with 0.5 M anhyd oxalic acid solution in MeOH. The solvent was
evaporated and the residue purified by FC (CH2Cl2/MeOH 95:
(m, 2H), 6.92 (m, 2H), 5.48 (tt, 0.6H, J ) 11.4, 4.9 Hz), 5.44 (br.s,
0.6H), 5.31 (tt, 0.4H, J ) 11.4, 4.9 Hz), 4.87 (br d, 0.4H, J ) 8.6
Hz), 4.65 (m, 0.6H), 4.34 (m, 1H), 4.16 (m, 2H), 4.04 (m, 0.4H),
3.87 (m, 2H), 3.86 (s, 3H), 2.88 (dd, 0.4H, J ) 16.5, 8.3 Hz), 2.74,
2.54 (2m, 3.6H), 2.45-2.07 (m, 2H), 1.85-1.38 (m, 8H), 1.36 (s,
6H). Anal. Calcd for C26H38O10 (510.78): C, 61.16; H, 7.50.
Found: C, 61.22; H, 7.56.
(+)-(2S,4S,6S)-2-[3-[(4S,6S)-6-[(2S)-2-Hyd r oxy-4-[(tr iiso-
p r op ylsilyl)oxy]bu tyl]-2,2-d im eth yl-1,3-d ioxa n -4-yl]-2-oxo-
p r op yl]t et r a h yd r o-6-[(t r iisop r op ylsilyl)oxy]-2H -p yr a n -4-
yl 4-Meth oxyben zoa te ((+)-11). A mixture of (+)-10 (124 mg,
0.24 mmol), anhyd DMF (6 mL), imidazole (185 mg, 2.72 mmol),
and (i-Pr)3SiCl (0.25 mL, 227 mg, 1.18 mmol) was stirred at 20
°C for 48 h (TLC, SiO2, CH2Cl2/MeOH 95:5, Rf ((+)-11) ) 0.50).
The mixture was neutralized by addition of a saturated aqueous
solution of NaHCO3 (15 mL) and extracted with EtOAc (5 mL,
three times). The combined organic extracts were dried (MgSO4),
and the solvent was removed. FC (Et2O/light petroleum ether
5) giving (-)-8 (37 mg, 12%) and (-)-9 (162 mg, 68%): colorless
1
oil; [R]25 ) -52 (c ) 1.05, CHCl3); H NMR (400 MHz, CDCl3)
D
δ 7.96 (m, 2H), 6.90 (m, 2H), 5.66 (t, 1H, J ) 6.8 Hz), 5.17 (tt,
1H, J ) 8.4, 3.5 Hz), 4.22-4.00 (m, 4H), 3.89-3.80 (m, 2H), 3.86
(s, 3H, OMe), 2.50 (m, 4H), 2.24 (m, 3H), 2.14 (ddd, 1H, J )
13.6, 8.8, 3.2 Hz), 1.80-1.59 (m, 6H), 1.38, 1.37 (2s, 6H). Anal.
Calcd for C26H38O8 (478.58): C, 65.25; H, 8.00; found: C, 65.19;
H, 8.03.
(+)-(2S,4S,6S an d 6R)-2-[3-[(4S,6S)-6-[(2S)-2,4-Dih ydr oxy-
bu tyl]2,2-dim eth yl-1,3-dioxan -4-yl]-2-oxopr opyl]tetr ah ydr o-
6-h yd r oxy-2H-p yr a n -4-yl 4-Meth oxyben zoa te ((+)-10). A
mixture of (-)-9 (135 mg, 0.28 mmol), acetone (1.3 mL), H2O
(0.2 mL), N-methylmorpholine N-oxide (65 mg, 0.48 mmol), and
a 0.1 M solution of OsO4 in CCl4 (0.13 mL) was stirred at 20 °C
for 15 h. Na2S2O5 (0.1 g) was added and the mixture stirred at
20 °C for 30 min and extracted with EtOAc (2 mL, five times);
the combined extracts were dried (MgSO4) and the solvent
evaporated to dryness. The residue was taken in dioxane (2 mL).
Benzene (5 mL) was added and the solution cooled to 0 °C. Pb-
(OAc)4 (dried under vacuum, 10-3 Torr, 20 °C) was added (185
mg, 0.42 mmol) portionwise under stirring. Stirring was con-
tinued at 0 °C for 15 min (TLC, SiO2, CH2Cl2/MeOH 9:1, Rf
(intermediate diol) ) 0.12, Rf ((+)-10) ) 0.26) and a saturated
aqueous solution of NaHCO3 (2 mL) was added under vigorous
stirring. The mixture was extracted with EtOAc (3 mL, five
times). The combined extracts were dried (MgSO4), the solvent
was evaporated, and the residue was purified by FC (CH2Cl2/
MeOH 95:5) yielding (+)-10 (132 mg, 92%) as a colorless oil:
[R]25D ) +8 (c ) 0.51, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.98
3:2) yielded (+)-11 (146 mg, 73%) as a colorless oil: [R]25 ) +5
D
(c ) 1.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.96 (m, 2H),
6.90 (m, 2H), 5.14 (tt, 1H, J ) 11.4, 4.7 Hz), 4.86 (dd, 1H, J )
7.4, 1.9 Hz), 4.27 (m, 1H), 4.12 (m, 1H), 4.07-3.87 (m, 4H), 3.86
(s, 3H), 3.62 (br d, 1H, J ) 2.3 Hz), 2.85 (dd, 1H, J ) 16.5, 7.6
Hz), 2.72 (br dd, 1H, J ) 16.4, 8.2 Hz), 2.53 (br dd, 1H, J )
16.5, 4.8 Hz), 2.47 (br dd, 1H, J ) 16.4, 4.5 Hz), 2.32 (br d, 1H,
J ) 9.0 Hz), 2.08 (br d, 1H, J ) 12.1 Hz), 1.73-1.45 (m, 7H),
1.41 (br d, 1H, J ) 11.8 Hz), 1.34, 1.33 (2s, 6H), 1.15-0.97 (m,
42H). Anal. calcd for C44H78O10Si2 (823.26): C, 64.19; H, 9.55.
Found: C, 64.22; H, 9.61.
(+)-(2S,4S,6S)-2-[3-[(4S,6S)-6-[(2R)-2-Acetoxy-4-[(tr iisopr o-
p y l)o x y ]b u t y l]-2,2-d i m e t h y l-1,3-d i o x a n -4-y l]-2-o x o -
p r op yl]tetr a h yd r o-6-[(tr iisop r op ylsilyl)oxy]-2H-p yr a n -4-yl
4-Met h oxyb en zoa t e ((+)-12). A mixture of (+)-11 (140 mg,
0.17 mmol), CH2Cl2 (4 mL), anhyd pyridine (0.4 mL), MeSO2Cl
(0.2 mL, 295 mg, 2.57 mmol), and 4-(dimethylamino)pyridine
(10 mg) was stirred at 20 °C for 4 h. A saturated aqueous
solution of NaHCO3 (4 mL) was added and the mixture stirred

7872 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
at 20 °C for 30 min. The mixture was extracted with CH2Cl2 (5
mL, three times). The combined organic extracts were dried
(MgSO4) and evaporated to dryness (20 °C, 10-3 Torr). The
residue was taken in anhyd benzene (4 mL). Cesium acetate (520
mg, 2.7 mmol) and 18-crown-6 ether (160 mg, 0.6 mmol) were
added, and the mixture was heated to 80 °C for 6 h. After the
mixture was heated to 20 °C, a saturated aqueous solution of
NaHCO3 (2 mL) was added and the mixture extracted with
EtOAc (2 mL, twice). The combined organic extracts were dried
(MgSO4), and the solvent was evaporated. FC (Et2O/light
petroleum ether 3:2) yielded (+)-12 (94 mg, 63%) as a colorless
oil (Rf ) 0.52) and 35 mg of the intermediate mesylate (22%)
that can be used in a second batch for the displacement reaction.
(TLC, SiO2, CH2Cl2/MeOH 9:1, Rf ((+)-13) ) 0.64, Rf ((-)-14) )
0.47), the solvent was evaporated to dryness (10-3 Torr, 20 °C),
and a saturated aqueous solution of NaHCO3 (3 mL) was added.
After the mixture was stirred at 20 °C for 10 min, more NaHCO3
was added until neutralization. The mixture was extracted with
EtOAc (3 mL, five times). The combined organic extracts were
dried (MgSO4), and the solvent was evaporated. FC (CH2Cl2/
MeOH 97:3) yielded (-)-14 (10 mg, 44%) as a colorless oil: [R]25
D
) -14 (c ) 0.60, CHCl3); 1H NMR (400 MHz, CDCl3): δ 7.99
(m, 2H), 6.92 (m, 2H), 5.51 (tt, 1H, J ) 8.4, 4.2 Hz), 5.14 (quint,
1H, J ) 6.7 Hz), 4.09 (m, 2H), 3.92 (m, 2H), 3.87 (s, 3H), 3.71 (t,
2H, J ) 6.5 Hz), 3.67 (m, 2H), 2.02 (s, 3H), 2.05-1.40 (m, 14H),
1.36, 1.31 (2s, 6H), 1.05 (m, 21H). Anal. Calcd for C37H64O11Si
(712.99): C, 62.33; H, 9.05. Found: C, 62.22; H, 9.09.
Data for (+)-12: [R]25 ) +5 (c ) 0.95, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 7.97 (m, 2H), 6.91 (m, 2H), 5.15 (m, 1H), 4.86
(br dd, J ) 9.1, 1.8, 1H), 4.26 (m, 1H), 3.98 (m, 1H), 3.89 (m,
1H), 3.86 (s, 3H), 3.72 (t, 2H, J ) 6.5 Hz), 2.85 (dd, 1H, J )
16.5, 7.6 Hz), 2.71 (dd, 1H, J ) 16.4, 8.4 Hz), 2.53 (dd, 1H, J )
16.5, 4.8 Hz), 2.46 (dd, 1H, J ) 16.4, 4.3 Hz), 2.33 (br d, 1H, J
) 11.0 Hz), 2.08 (m, 1H), 2.03 (s, 3H), 1.90-1.80 (m, 3H), 1.74-
1.56 (m, 4H), 1.46-1.30 (m, 1H), 1.33, 1.29 (2s, 6H), 1.05 (m,
42H). Anal. Calcd for C46H80O11Si2 (865.30): C, 63.85; H, 9.32.
Found: C, 63.85; H, 9.27.
(-)-(4S,6R)-4-[[(4R)-2,2-Dim eth yl-1,3-dioxan -4-yl]m eth yl]-
6-[[(4S,6R)-6-[[(4R)-2,2-d im et h yl-1,3-d ioxa n -4-yl]m et h yl]-
2,2-d im et h yl-1,3-d ioxa n -4-yl]m et h yl]-2,2-d im et h yl-1,3-d i-
oxa n ((-)-15) (or 1,3:5,7:9,11:13,15-Tetr a -O-isop r op ylid en e-
(3R ,5R ,7S ,9R ,11S ,13R )-p e n t a d e ca n e -1,3,5,7,9,11,13,15-
octol). A mixture of (-)-14 (10 mg, 0.014 mmol), anhyd THF (1
mL), and 1 M Bu4NF in anhyd THF (0.03 mL) was stirred at 20
°C for 2.5 h. The solvent was evaporated to dryness (10-3 Torr,
20 °C) and the residue taken in anhyd MeOH (2 mL). After the
addition of MeOK (20 mg), the solution was stirred at 20 °C for
15 h. AcOH was added until neutralization (bromothymol blue),
and SiO2 (200 mg) was added. The solvent was evaporated and
the residue purified by FC (CH2Cl2/MeOH 9:1, then 7:3). The
main fraction was dissolved in acetone (3 mL), and 2,2-
dimethoxypropane (2 mL), pyridinium paratoluenesulfonate (3
mg), and anh. CuSO4 (50 mg) were added. The mixture was
stirred at 40 °C for 15 h (TLC, SiO2, Et2O/light petroleum ether
3:2, Rf ((-)-15) ) 0.32). A saturated aqueous solution of NaHCO3
(0.5 mL) was added, and the solvent was evaporated to dryness
(10-3 Torr, 20 °C). The residue was taken with H2O (2 mL) and
extracted with EtOAc (2 mL, five times). The combined organic
extracts were dried (MgSO4), and the solvent was evaporated.
FC (Et2O/light petroleum ether 1:1) yielded (-)-15 (4 mg, 57%):
(+)-(2S,4S,6S an d 6R)-Tetr ah ydr o-6-h ydr oxy-2-[3-[(4S,6R)-
6-[(2S)-2-a cet oxy-4-[(t r iisop r op ylsilyl)oxy]b u t yl]-2,2-d i-
m eth yl-1,3-dioxan -4-yl]-2-oxopr opyl]-2H-pyr an -4-yl 4-Meth -
oxyben zoa te ((+)-13). A 0.1 M solution of Bu4NF in anhyd THF
(0.4 mL) was added dropwise to a stirred solution of (+)-12 (35
mg, 0.04 mmol) in anhyd THF (6 mL) cooled to -78 °C. The
mixture was stirred at -50 °C for 1 h and was poured into an
ice-cold, saturated aqueous solution of NH4Cl (1 mL) under
vigorous stirring. Stirring at 20 °C was continued for 30 min,
and the mixture was extracted with EtOAc (3 mL, three times).
The combined organic extracts were dried (MgSO4), and the
solvent was evaporated. FC (CH2Cl2/MeOH 97:3) yielded (+)-
13 (24 mg, 85%) as colorless oil: [R]25 ) +8 (c ) 1.10, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 7.97 (m, 2H), 6.91 (m, 2H), 5.48
(tt, 0.6H, J ) 11.3, 4.9 Hz), 5.43 (br.s, 0.6H), 5.16 (m, 1.4 + 0.4H),
4.88 (ddd, 0.4H, J ) 9.6, 5.5, 1.8 Hz), 4.60 (m, 0.6H), 4.29 (m,
1H), 3.97 (m, 0.4H), 3.86 (s, 6H), 3.77 (m, 1H), 3.70 (m, 2H),
2.83 (dd, 0.4H, J ) 14.9, 9.1 Hz), 2.78-2.64 (m, 2H), 2.57-2.39
(m, 2H), 2.38-2.07 (m, 2H), 2.05, 2.03 (2s, 6H), 1.95-1.35 (m,
8H), 1.33, 1.32, 1.30, 1.29 (4s, 6H), 1.05 (m, 21H). Anal. Calcd
for C37H60O11Si (708.96): C, 62.68; H, 8.53. Found: C, 62.56; H,
8.62.
colorless oil; [R]25 ) -19 (c ) 0.35, CHCl3); 13C NMR (100.6
D
MHz, CDCl3): δ 100.4, 100.2 (2s), 98.3, 98.2 (2s), 65.6, 64.9, 63.3,
63.1, 62.7, 62.1 (6d), 60.1, 59.9 (2t), 42.3, 41.8, 38.6, 38.3, 31.7,
30.8 (6t), 30.0, 29.9 (2q), 24.7, 24.7, 24.6, 24.5 (4q), 19.2 (q). Anal.
Calcd for C27H48O8 (500.67): C, 64.77; H, 9.66. Found: C, 64.81;
H, 9.67.
Ack n ow led gm en t. This work was supported by the
Swiss National Science Foundation. We thank also Mrs.
Martial Rey and Francisco Sepulveda for technical help.
(-)-(1R,3R,5R)-3,5-Dih yd r oxy-1-(2-h yd r oxym et h yl)-6-
[ ( 4 R ,6 R ) -6 -[ ( 2 R ) -2 -a c e t o x y -4 -[ ( t r i i s o p r o p y l ) o x y ] -
bu tyl]-2,2-d im eth yl-1,3-d ioxa n -4-yl]h exyl 4-Meth oxyben z-
oa te ((-)-14) (or 3-O-Acetyl-5,7-O-d iisop r op ylid en e-13-O-
(4-m et h oxyb en zoyl)-1-O-(t r iisop r op ylsilyl)-(3R,5S,7R,9R,
11R,13R)-p en ta d eca n e-1,3,5,7,9,11,13,15-octol). A 9:1 mix-
ture of AcOH/CH3CN (1.35 mL) was added dropwise to a stirred
solution of (+)-13 (23 mg, 0.032 mmol) and Me4NBH4 (440 mg)
cooled to 0 °C. After the mixture was stirred at 2 °C for 15 h
1
Su p p or tin g In for m a tion Ava ila ble: Detailed H and 13C
NMR spectra and signal assignments and UV, IR, and MS
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O010172U