First Stereocontrolled Synthesis of the (3S,5R,7R,10R,11R)-C1-C13 Fragment of Nystatin A1

Article abstract of DOI:10.1021/jo990245y

A convergent stereoselective synthesis of the (3S,5R,7R,10R,11R)-C1-C13 fragment of Nystatin A₁ is reported in this paper. This fragment contains an all-syn-1,3,5-triol subunit and a syn-1,2-diol moiety. The main features of the synthesis are the enzymatic desymmetrization of a meso diol to obtain an enantiomerically pure syn-4,6-dihydroxy-2-keto-phosphonate, chiral sulfoxide chemistry to prepare an α-(R)-hydroxyaldehyde and 2-trimethylsilyl thiazole reagent to synthesize a synα,β-(R,S)-dihydroxy aldehyde.

Full text of DOI:10.1021/jo990245y

J . Org. Chem. 1999, 64, 5447-5452
5447
F ir st Ster eocon tr olled Syn th esis of th e (3S,5R,7R,10R,11R)-C1-C13
F r a gm en t of Nysta tin A1
Guy Solladie´,* Nicole Wilb, and Claude Bauder
Laboratoire de Ste´re´ochimie associe´ au CNRS, Universite´ Louis Pasteur, Ecole Europe´enne de Chimie,
Polyme`res et Mate´riaux (ECPM). 25 rue Becquerel, 67087-Strasbourg-Cedex 2, France
Carlo Bonini,* Licia Viggiani, and Lucia Chiummiento
Dipartimento di Chimica, Universita` degli Studi della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
Received February 9, 1999
A convergent stereoselective synthesis of the (3S,5R,7R,10R,11R)-C1-C13 fragment of Nystatin
A1 is reported in this paper. This fragment contains an all-syn-1,3,5-triol subunit and a syn-1,2-
diol moiety. The main features of the synthesis are the enzymatic desymmetrization of a meso diol
to obtain an enantiomerically pure syn-4,6-dihydroxy-2-keto-phosphonate, chiral sulfoxide chemistry
to prepare an R-(R)-hydroxyaldehyde and 2-trimethylsilyl thiazole reagent to synthesize a syn-
R,â-(R,S)-dihydroxy aldehyde.
Nystatin A1 is a macrolide antibiotic produced by
Streptomyces noursei and was discovered in 1950.1 It is
one of the most commonly used in antifungal therapy.
The molecular structure of this macrolide is an all-trans
polyene part with six conjugated double bonds and a
polyol moiety containing eight chiral hydroxylic centers.
2-4
The gross structure of Nystatin A1
was confirmed in
19705 and 1971,6 and the absolute configuration of the
chiral centers was assigned more recently by controlled
degradation7,8 and partial synthesis9,10 (Figure 1).
Until now, only the synthesis of Nystatin A1’s C1-C10
fragment, containing three chiral hydroxylic centers, has
been reported by Nicolaou9 (via a Sharpless epoxidation)
to confirm the absolute configuration and by Beau10 from
6-O-silylated-D-glucal as the starting material. Bonini,
after a preliminary work11 to obtain the C1-C10 frag-
ment in racemic form, reported a synthesis of the
enantiomerically pure triol unit from 3-benzyloxypropa-
nal using a chemioenzymatic approach.12,13 More recently,
Schneider14 published the synthesis of the C1-C10 polyol
fragment via a Cope rearrangement. We report in this
paper the first convergent highly stereoselective synthe-
sis of the C1-C13 fragment 1 in the natural configura-
tion (3S, 5R, 7R, 10R, 11R).
F igu r e 1.
As shown in the retrosynthesis (Scheme 1), the C1-
C13 fragment 1 (we used the atom numbering of the
macrocycle for the synthesized fragments) can be discon-
nected in two parts: a chiral ketophosphonate 2 contain-
ing a 1,3-diol unit and a chiral aldehyde 3 with a 1,2-
diol moiety. The phosphonate 2 could be obtained from
the acetonide 4 we had already prepared12 in high
enantiomeric excess (>98%) by desymmetrization of the
corresponding meso-3,5-O-isopropylidene-1,7-heptanediol
by transesterification with vinyl acetate and PFL
(Pseudomonas fluorescens lipase).15 The aldehyde 3 can
be prepared, according to Dondoni’s methodology,16 by
condensation of 2-trimethylsilyl thiazole to the R-hy-
droxy-aldehyde 14, which can be made by the use of
chiral sulfoxides.17
(1) Hazen, E. L.; Brown, R. Science 1950, 112, 423.
(2) Dutcher, J . D.; Walters, D. R.; Wintersteiner, O. J . Org. Chem.
1963, 28, 995.
(3) Saltza, M.; Dutcher, J . D.; Reid, J .; Wintersteiner, O. J . Org.
Chem. 1963, 28, 999.
(4) Manwaring, D. G.; Rickard, R. W.; Golding, B. T. Tetrahedron
Lett. 1969, 5319.
(5) Chong, C. N.; Rickard, R. W. Tetrahedron Lett. 1970, 5145.
(6) Borowski, E.; Zielinski, J .; Falkowski, L.; Ziminski, T.; Golik,
J .; Kolodziejczyk, P.; J ereczek, E.; Gdulewicz, M.; Shenin, Y.; Kotienko,
T. Tetrahedron Lett. 1971, 685.
(3S,5R)-7-Acetoxy-1-hydroxy-3,5-O-isopropylidene-hep-
tane (4), readily obtained from meso-3,5-O-isopropyl-
idene-1,7-heptanediol with lipase,12,15 was protected by
a TBS group to afford the compound 5, and then the
acetate was hydrolyzed with Na/MeOH. The resulting
primary alcohol 6 was oxidized to the corresponding acid,
which was then immediately esterified with diazomethane
to give the ester 7 with an overall yield of 82% from 4
(Scheme 2). The phosphonate 2 was then obtained in 65%
(7) Lancelin, J .-M.; Paquet, F.; Beau, J .-M. Tetrahedron Lett. 1988,
29, 2827.
(8) Lancelin, J .-M.; Beau, J .-M. Tetrahedron Lett. 1989, 30, 4521.
(9) Nicolaou, K. C.; Ahn, K. H. Tetrahedron Lett. 1989, 30, 1217.
(10) Prandi, J .; Beau, J .-M. Tetrahedron Lett. 1989, 30, 4517.
(11) Bonini, C.; Righi, G.; Rossi, L. Tetrahedron 1992, 48, 9801.
(12) Bonini, C.; Racioppi, R.; Viggiani, L., Righi, G.; Rossi, L.
Tetrahedron: Asymmetry 1993, 4, 793.
(13) Bonini, C.; Giugliano, A.; Racioppi, R.; Righi, G. Tetrahedron
Lett. 1996, 37, 2487.
(14) Schneider, C.; Rehfeuter, M. Tetrahedron Lett. 1998, 39, 9.
(15) The transesterification reaction with PPL has been greatly
improved with a chemical yield of 96 to 98%, manuscript in prepration.
(16) (a) Dondoni, A.; Fogagnolo, M., Medici, A.; Pedrini, P. Tetra-
hedron Lett. 1985, 26, 5477. Dondoni, A.; Fantin, G.; Fogagnolo, M.,
Pedrini, P. J . Org. Chem. 1990, 55, 1439. (b) Dondoni, A.; Orduna, J .;
Merino, P. Synthesis 1992, 201.
(17) Solladie´, G.; Almario, A. Tetrahedron: Asymmetry 1994, 5,
1717.
10.1021/jo990245y CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/26/1999

5448 J . Org. Chem., Vol. 64, No. 15, 1999
Solladie´ et al.
Sch em e 1
Sch em e 3
Sch em e 2
Sch em e 4
yield by condensation of the dimethyl methylphosphonate
anion to the methyl ester 7 (we observed the formation,
in 25 to 30% yield of the R,â-unsaturated ester resulting
from the elimination of the â-oxygen and the acetonide
opening in a basic medium).
quickly as possible to prevent the migration of the silyl
group from the secondary to the primary alcohol).
The crucial point at this stage was to prepare a pure
syn-1,2-diol from 14. The known Dondoni’s method,16a
using the addition of 2-trimethylsilyl thiazole (2-TST) to
R-hydroxyaldehyde usually gives mainly the anti-1,2-diol.
However, previous work in our laboratory18 as well as a
more recent report from Dondoni16b showed indeed that
mainly the syn-1,2-diol could be also obtained. When we
treated the aldehyde 14 with 2-TST, we got only the pure
syn-1,2-diol 15 in 72% yield (Scheme 3).
The enantiomerically pure aldehyde 14 was prepared
by a method we already reported17 in seven steps with
25% overall yield from the dianion of tert-butyl acetoac-
etate and (+)-menthyl-(R)-p-toluenesulfinate (Scheme 3).
The â-ketosulfoxide 8 was first stereoselectively reduced
to the (R)-configuration17 with DIBAL in 67% (de >98%),
and the resulting alcohol 9 was protected by a TBS group
to give the compound 10 in 88% yield. After a Pummerer
rearrangement, the product 11 was subjected to desulfu-
rization with Raney Nickel to get the compound 12 in
63% overall yield. We finally reduced the acetate with
DIBAL and oxidized the resulting primary alcohol 13 by
a Swern oxidation to the aldehyde 14 in 81% overall yield
(during the reduction of 12 with DIBAL, it was important
to neutralize and hydrolyze the reaction medium as
The relative configuration of 15 was assigned by
removing the silyl-protecting group with TBAF (93%) in
THF and preparing the acetonide 17 (dimethoxypropane,
1
acetone, pTsOH cat., 92%) (Scheme 4). In H NMR, the
coupling constants H4-H3 (J ) 8 Hz) as well as the
chemical shift in 13C NMR of the two methyl groups R
(18) Almario, A. Thesis, Universite´ Louis Pasteur, Strasbourg, 1994.

C1-C13 Fragment of Nystatin A1
J . Org. Chem., Vol. 64, No. 15, 1999 5449
Sch em e 5
aluminum hydride-lithium iodide, entry 1), we observed
good syn selectivity (77:23) but only a 50% conversion.
With L-Selectride or Super-Hydride,21 we had a moderate
syn selectivity and a good yield. Finally, the use of NaBH4
at 0 °C afforded compound 21 with good syn selectivity
(72:28) and a complete conversion. This diastereofacial
selectivity, in nonchelating hydride addition on a carbo-
nyl â to a chiral center, can be explained by a preferential
conformation in an open chain model.21,22
After separation of the two diastereomers of 21, the
absolute configuration of the C7 center was determined
by Mosher’s ester using MTPA-Cl in pyridine;23 the (S)-
and (R)-MTPA esters were prepared from the main
diastereomer 21, and the 1H NMR spectra were recorded.
The ∆δ values for the vinylic signals were characteristic
of an S configuration at C7 in the isomer 21.
Finally, the fragment C1-C13 1 of Nystatin was
obtained by double bond hydrogenation of 21 over pal-
ladium on charcoal.
In conclusion, we have reported the first stereocon-
trolled synthesis of the C1-C13 polyol moiety of Nystatin
in the natural (3S,5R,7R,10R,11R) configuration, using
a convergent synthesis with a combination of biocatalytic
chemistry and sulfoxide-mediated asymmetric induction
to create the chiral centers.
Ta ble 1. Red u ction Con d ition s of th e Ca r bon yl of
Com p ou n d 20
Exp er im en ta l Section
temperature
(°C)
conversion
entry
hydride
solvent
syn:antia
(%)
(-)-(3S,5R)-7-Acetoxy-1-O-(ter t-bu tyld im eth ylsilyl)-3,5-
1
2
3
4
5
LiAlH4-LiI
L-Selectride
L-Selectride
Super-Hydride THF
NaBH4 MeOH
Et2O
THF
THF
-100
-78
-100
-78
0
77:23
66:34
65:35
53:47
72:28
50
100
100
100
100
O-isop r op ylid en e-h ep ta n e (5). In
a two-necked round-
bottomed flask with a nitrogen inlet and while stirring,
compound 412 (0.1 g, 0.41 mmol) and imidazole (0.041 g, 0.6
mmol) were added to freshly distilled CH2Cl2 (25 mL). The
reaction mixture was cooled in ice for 20 min and TBDMSCl
(0.09 g, 0.60 mmol) and catalytic DMAP (4-(dimethylamino)-
pyridine) were added. After 20 h (TLC monitoring), the
mixture was diluted with CH2Cl2 and washed with brine. The
organic layers are dried on Na2SO4 and evaporated in vacuo,
Syn:anti ratios were determined by 1H NMR (200 MHz, CDCl3)
a
analysis.
and R′ (27.9 and 27.3 ppm, respectively) are characteristic
of a trans configuration for 17.19 Finally, we observed an
NOE between H4 and H2. These results confirmed a syn
relative configuration for the diol 15, which is, therefore,
the (RS) enantiomer.
The free hydroxylic function in 15 was then protected
by TBS in 89% yield (with tert-butyl dimethylsilyl triflate;
no reaction was observed with TBDMSCl), and the
thiazole group was hydrolyzed in the usual conditions16
in 88% yield to get the pure aldehyde 19 in 78% overall
yield from 15 (Scheme 4).
Unfortunately, the Horner-Wadsworth-Emmons cou-
pling between the phosphonate 2 and the aldehyde 19
gave only 12% yield in the desired product and important
degradation products. The lack of reactivity was probably
due to the bulky TBS group in 19. So, we hydrolyzed the
thiazole group in the acetonide 17 to obtain the aldehyde
18 in 50% yield. This time, the Horner-Wadsworth-
Emmons reaction between the phosphonate 2 and the
aldehyde 18 gave, in 68% yield, the protected polyol 20
(Scheme 5).
affording pure compound 5 (0.148 g, 0.41 mmol; 100%): [R]20
D
) -1.7 (c ) 1.00, CHCl3); 1H NMR (CDCl3) δ ) 4.30-4.15 (m,
2H), 4.14-3.90 (m, 2H), 3.80-3.60 (m, 2H), 2.09 (s, 3H), 1.85-
1.70 (m, 2H), 1.70-1.60 (m, 2H), 1.40 (s, 3H), 1.38 (s, 3H),
1.30-1.10 (m, 2H), 0.90 (s, 9H), 0.00 (s, 6H); 13C NMR (CDCl3)
δ ) 171.3, 99.7, 65.9, 65.5, 60.9, 58.7, 39.4, 37.1, 35.3, 30.1,
25.9, 20.9, 19.7, -5.4. Anal. Calcd for C18H36O5Si (360.21): C,
60.01; H, 9.99. Found: C, 60.12; H, 9.87.
(-)-(3S,5R)-1-O-(ter t-Bu tyld im eth ylsilyl)-3,5-O-isop r o-
p ylid en e-h ep ta n ol (6). Compound 5 (0.148 g, 0.41 mmol) was
dissolved in MeOH (20 mL) with a catalytic amount of Na.
After the mixture was stirred for 4 h, the solvent was
evaporated. The crude mixture was diluted with CHCl3 and
was filtered on Celite. After evaporation of the solvent, the
crude product was chromatographed on silica gel (petroleum
ether/EtOAc 75:25 as eluent) to afford pure 6 (0.121 g; 93%):
1
[R]20 ) -8.2 (c ) 1.10, CHCl3); H NMR (CDCl3) δ ) 4.15-
D
4.00 (m, 2H), 3.80-3.70 (m, 2H), 3.68-3.58 (m, 2H), 2.60 (bs,
1H), 1.80-1.70 (m, 2H), 1.70-1.61 (m, 2H), 1.45 (s, 3H), 1.37
(s, 3H), 1.40-1.28 (m, 2H), 0.89 (s, 9H), 0.00 (s, 6H); 13C NMR
(CDCl3) δ ) 98.6, 65.5, 60.9, 58.7, 39.4, 38.1, 36.9, 30.2, 25.9,
19.9, 18.3, -5.4. Anal. Calcd for C16H34O4Si (318.2): C, 60.39;
H, 10.68. Found: C, 60.52; H, 11.01.
The crucial step was the reduction of the carbonyl
function C7 of 20 with a syn selectivity. We tried several
reaction conditions (Table 1) with different reducing
agents. In the conditions developed by Suzuki20 (lithium
Meth yl (-)-(3S,5R)-1-O-(ter t-Bu tyld im eth ylsilyl)-3,5-O-
isop r op ylid en e-h ep t a n -7-oa t e (7). NaIO4 (1.21 g, 5.66
mmol) was added to a biphasic solution of compound 6 (0.6 g,
1.89 mmol) in CCl4 (9 mL), MeCN (9 mL), and phosphate
buffer (pH 7, 0.4 M, 13.5 mL). After the mixture was stirred
(19) (a) Rychnovsky, S. D.; Skalitzky, D. J . Tetrahedron Lett. 1990,
31, 945. (b) Dana, G.; Danechpajouh, H. Bull. Soc. Chim. Fr. 1980,
395.
(20) (a) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron
Lett. 1988, 29, 5419. (b) Mori, Y.; Kuhara, M.; Takeuchi, A.; Kageyama,
H.; Suzuki, M. Tetrahedron Lett. 1988, 29, 5423.
(21) Evans, D. A.; Dart, M. J .; Duffy, J . L. Tetrahedron Lett. 1994,
35, 8541.
(22) Bonini, C.; Esposito, V.; D’Auria, M.; Righi, G. Tetrahedron
1997, 53, 13419 and references therein.
(23) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.

5450 J . Org. Chem., Vol. 64, No. 15, 1999
Solladie´ et al.
for 5 min, RuCl3‚3H2O (10.5 mg, 4.7 mmol) was added to the
mixture, which was vigorously stirred for 6 h at room tem-
perature. Then, CH2Cl2 (30 mL) was added, and the organic
layer was separated. After drying on Na2SO4, the organic
solution was concentrated in vacuo, diluted with ether, filtered
through a Celite pad, and concentrated in vacuo, affording the
crude acid (0.6 g). The acid was then diluted in ether (30 mL)
and treated with CH2N2 in ether, until the solution became
yellow. The solution was then evaporated in vacuo with a trap
of acetic acid; the crude residue was then purified by flash
chromatography (petroleum ether/EtOAc 75:25 as eluent),
AB system, 0.3H, enol, J AB ) 9 Hz, ∆ν ) 36.3 Hz), 3.36 (B
part of an AB system, 0.3H, enol, J AB ) 9 Hz, ∆ν ) 36.3 Hz),
3.46 (A part of an AB system, 0.7H, ketone, J AB ) 13 Hz, ∆ν
) 12.3 Hz), 3.40 (B part of an AB system, 0.7H, ketone, J AB
)
13 Hz, ∆ν ) 12.3 Hz), 2.39 (s, 3H), 1.45 (s, 6.3H, ketone), 1.42
(s, 2.7H, enol); 13C NMR (CDCl3) δ ) 195.3, 172.1, 166.0, 165.9,
142.7, 142.5, 140.6, 139.9, 130.6, 130.4, 124.5, 96.3, 82.9, 82.1,
68.0, 64.1, 52.4, 28.6, 28.4, 21.9. Anal. Calcd for C15H20O4S
(296.38): C, 60.79; H, 6.80. Found: C, 60.89; H, 6.65.
ter t-Bu tyl (-)-(3R,SS)-3-Hyd r oxy-4-p -tolylsu lfin yl-bu -
ta n oa te (9). Dibal-H, 1 M in toluene (12.6 mL; 1.43 equiv),
was added dropwise at -75 °C to a solution of 8 (2.61 g; 8.8
mmol) in THF (65 mL). After 45 min, the solution was
quenched at -70 °C with MeOH (3 mL) and stirred for 1 h
affording pure compound 7 (0.580 g; 88%): [R]20 ) -13.3 (c
D
) 0.98, CHCl3); 1H NMR (CDCl3) δ ) 4.40-4.28 (m, 1H, X
part of an ABX syst), 4.10-4.00 (m, 1H), 3.70 (s, 3H), 3.80-
3.60 (m, 2H), 2.46 (AB part of an ABX syst, 2H, J AB ) 15.5
Hz, J AX ) 6.9 Hz, J BX ) 6.2 Hz, ∆ν ) 39.9 Hz), 1.70-1.60 (m,
2H), 1.46 (s, 3H), 1.38 (s, 3H), 1.30-1.15 (m, 2H), 0.90 (s, 9H),
0.05 (s, 6H); 13C NMR (CDCl3) δ ) 173.0, 99.0, 66.5, 65.5, 58.0,
51.5, 41.5, 39.5, 37.0, 31.0, 26.0, 20.0, 18.5, -5.0. Anal. Calcd
for C17H34O5Si (346.20): C, 58.97; H, 9.8. Found: C, 59.12; H,
10.12.
and then treated with
a saturated solution of disodium
L-tartrate dihydrate (10 mL). The mixture was left overnight
at room temperature. The aqueous layer was acidified to pH
) 5 with HCl concentrated, then extracted with AcOEt (3 ×
60 mL). The combined organic layers were washed with brine
(40 mL), dried over MgSO4, and concentrated to an orange oil.
This crude product was purified by rapid chromatography on
silica gel, and the resulting pale yellow crystals were recrystal-
lized (ether/hexane) to obtain 9 as white crystals (1.71 g;
66.6%): mp ) 94 °C; [R]20D ) -207 (c ) 1.04, CHCl3); 1H NMR
(200 MHz, CDCl3) δ ) 7.53 (A fragment of an (AB)2 system,
2H, J AB ) 8 Hz, ∆ν ) 39 Hz), 7.34 (B fragment of an (AB)2
system, 2H, J AB ) 8 Hz, ∆ν ) 39 Hz), 4.56 (m, 1H, Hx of an
ABX system), 4.07 (d, 1H, OH, J ) 3.5 Hz), 2.88 (AB part of
ABX system, 2H, J AB ) 13.5 Hz, J AX ) 10 Hz, J BX ) 2.5 Hz,
∆ν ) 61 Hz), 2.45 (d, 2H, J ) 6 Hz), 2.42 (s, 3H), 1.41 (s, 9H);
13C NMR (CDCl3) δ ) 170.7, 141.7, 139.9, 130.2, 124.0, 81.7,
63.8, 61.8, 42.1, 28.1, 21.5. Anal. Calcd for C15H22O4S (298.40):
C, 60.38; H, 7.43. Found: C, 60.53; H, 7.35.
ter t-Bu tyl (-)-(3R,SS)-3-ter t-Bu tyld im eth ylsilyloxy-4-
p -tolylsu lfin yl-bu ta n oa te (10). The alcohol 9 (4.98 g; 16.6
mmol) was dissolved at 0 °C under argon in dry DMF (80 mL).
Imidazole (3 g; 2.65 equiv) and tert-butyldimethylsilyl chloride
(3.8 g; 1.51 equiv) were added successively. After 15 h at room
temperature, the reaction was hydrolyzed with water (100 mL)
and diluted with ether (100 mL). The aqueous layer was
extracted with ether (5 × 15 mL). The combined organic layers
were washed with brine (20 mL), dried (MgSO4), and concen-
trated. The crude orange oil was purified by rapid chroma-
Dim eth yl (+)-(3S,5S)-1-ter t-Bu tyld im eth ylsilyloxy-3,5-
isop r op ylid en ed ioxy-7-oxo-octyl-8-p h osp h on a te (2). A 1.5
M solution of n-BuLi in hexane (0.5 mL; 2.0 equiv) was added
at -78 °C to dimethyl methyl phosphonate (0.1 mL; 2.5 equiv)
in dry THF (2 mL). After 50 min, the ester 7 (129.7 mg; 0.373
mmol) in dry THF (2 mL) was dropwise added to the solution.
Two hours later, the colorless mixture was hydrolyzed with a
saturated solution of NH4Cl (10 mL) and stirred at room
temperature for 1 h. Water (10 mL) and CH2Cl2 (15 mL) were
added, and the solution was acidified to pH 4 with HCl 10%
(1 mL). The aqueous layer was extracted with CH2Cl2 (3 × 10
mL), and the organic layers were dried over MgSO4 and
concentrated. The crude product was then purified by chro-
matography on silica gel (AcOEt/CH2Cl2 1:1) to afford 2 as a
colorless liquid (106 mg; 64.7%): [R]20 ) +4.5 (c ) 0.88,
D
1
CHCl3); H NMR (200 MHz, CDCl3) δ ) 4.39-4.26 (m, 1H, X
part of an ABX syst), 4.10-3.95 (m, 1H), 3.795 (d, 3H, P-OMe,
J ) 11 Hz), 3.792 (d, 3H, P-OMe, J ) 11 Hz), 3.70-3.55 (m,
2H), 3.22, 3.14, 3.11 and 3.03 (AB syst coupled with P, 2H,
J AB ) 14 Hz, J H-P ) 22.5 Hz, ∆ν ) 8 Hz), 2.70 (AB part of an
ABX syst, 2H, J AB ) 16 Hz, J AX ) 7 Hz, J BX ) 5 Hz, ∆ν ) 37.5
Hz), 1.65-1.56 (m, 2H), 1.58 (dt, 1He´q, J ) 2.5 Hz, J ) 12.5
Hz), 1.24-1.06 (m, 1Hax), 0.86 (s, 9H, Si-C(CH3)3), 0.02 (s,
6H, Si-CH3); 13C NMR (CDCl3) δ ) 200.9 (d, CO, J C-P ) 6.5
Hz), 99.4 (C(Me)2), 66.0 (CH-O), 66.3 (CH-O), 59.3 (CH2 ),
53.7 (d, P-OCH3, J C-P ) 6.5 Hz), 51.0 (CH2 ), 44.1 (d, P-CH2,
J C-P ) 127.6 Hz), 40.0 (CH2 ), 37.3 (CH2 ), 30.7 (C(Me)2), 26.6
(Si-C(CH3)3), 20.4 (C(Me)2), 18.9 (Si-C(CH3)3), -4.7 (Si-CH3).
Anal. Calcd for C19H39O7SiP (438.57): C, 52.03; H, 8.96.
Found: C, 52.16; H, 9.22.
tography on silica gel to afford the clear yellow oil 10 (6.05 g;
1
88.3%): [R]20 ) -138 (c ) 0.94, CHCl3); H NMR (200 MHz,
D
CDCl3) δ ) 7.48 (A fragment of an (AB)2 system, 2H, J AB ) 8
Hz, ∆ν ) 41 Hz), 7.28 (B fragment of an (AB)2 system, 2H,
J AB ) 8 Hz, ∆ν ) 41 Hz), 4.58 (m, 1H, Hx of the two ABX
system), 2.94 (AB of an ABX system, 2H, J AB ) 13 Hz, J AX
)
8.5 Hz, J BX ) 4 Hz, ∆ν ) 21 Hz), 2.46 (AB of an ABX system,
2H, J AB ) 15 Hz, J AX ) 6 Hz, J BX ) 4 Hz, ∆ν ) 19 Hz), 2.37
ter t-Bu t yl (-)-(SS)-3-Oxo-4-p -t olylsu lfin yl Bu t a n oa t e
(8). To a solution of diisopropylamine (29.7 mL; 0.226 mmol;
2.17 equiv) in THF (400 mL) was added n-BuLi (1.42 M in
hexane; 148 mL; 2.1 equiv) at -40 °C. After 30 min, tert-butyl
acetoacetate (17.2 mL; 0.104 mol) was added slowly via
cannula at -65 °C. The cold bath was removed, and the
solution was stirred for 1 h before adding a solution of (+)-
menthyl-(SR)-p-toluenesulfinate (15.37 g; 0.0522 mol; 0.5 equiv)
in THF (120 mL) at -75 °C. When the reaction was completed
(TLC), saturated NH4Cl (100 mL) was added, and the pH was
adjusted to 1 with diluted HCl. The aqueous layer was
extracted with AcOEt (3 × 100 mL). The combined organic
layers were washed with brine (100 mL), dried over MgSO4,
filtered, and concentrated to a deep yellow oil. This crude
unstable product was purified by rapid chromatography on
silica gel to afford a clear yellow unstable oil 8 (11.93 g; 77%),
(s, 3H), 1.39 (s, 9H), 0.90 (s, 9H), 0.20 (s, 3H), 0.12 (s, 3H); 13
C
NMR (CDCl3) δ ) 170.0, 142.0, 141.8, 130.5, 124.3, 81.5, 67.0,
64.7, 44.1, 28.7, 26.4, 21.5, 18.7, -3.9, -4.2. Anal. Calcd for
C
21H36O4SSi (412.66): C, 61.12; H, 8.79. Found: C, 61.33; H,
8.63.
ter t-Bu tyl (3R)-3-ter t-Bu tyld im eth ylsilyloxy-4-a cetoxy-
4-p -tolylsu lfen yl-bu ta n oa te (11). Anhydrous sodium acetate
(8.7 g; 14 equiv) was added to the sulfoxide 10 (3.88 g; 9.4
mmol). Acetic anhydride (230 mL) was then added and the
mixture was refluxed for 14 h at 135 °C. After the solution
was cooled, the brown heterogeneous solution was filtered, and
the solvent was removed by azeotropic distillation with toluene
(6 × 50 mL). The resulting deep brown residue was diluted
with CH2Cl2 (20 mL) and filtered on Celite. The crude product
was purified by column chromatography on silica gel (CH2-
Cl2/hexane 1:3) to afford 11 as a colorless oil (3.32 g; 78%).
We obtained two stereoisomers at the C4 position in a ratio of
56:44 which were not separated: 1H NMR (200 MHz, CDCl3)
2 diastereomers (56/44) δ ) 7.38 (A fragment of an (AB)2
system, 2H, J AB ) 8 Hz, ∆ν ) 55 Hz), 7.10 (B fragment of an
(AB)2 system, 2H, J AB ) 8 Hz, ∆ν ) 55 Hz), 6.15 (d, 0.56H, J
) 6 Hz, one dia), 6.10 (d, 0.44H, J ) 2 Hz, other dia), 4.40 (m,
0.44H, Hx of an ABX system, one dia), 4.32 (q, 0.56H, Hx of
an ABX system, J ) 6 Hz, other dia), 2.64 (2 superposed ABX
which must be immediately used in the next reaction: [R]20
D
1
) -204 (c ) 1.4, CHCl3); H NMR (200 MHz, CDCl3) ketone/
enol (70: 30), δ ) 12.10 (broad s, 0.3H, enol), 7.52 (A part of
an (AB)2 system, 0.7H, J AB ) 6.5 Hz, ∆ν ) 39 Hz), 7.32 (B
part of an (AB)2 system, 2H, J AB ) 6.5 Hz, ∆ν ) 39 Hz), 4.99
(s, 0.3H, enol), 4.00 (A part of an AB system, 0.7H, ketone,
J AB ) 13.5 Hz, ∆ν ) 17.8 Hz), 3.91 (B part of an AB system,
0.7H, ketone, J AB ) 13.5 Hz, ∆ν ) 17.8 Hz), 3.54 (A part of an

C1-C13 Fragment of Nystatin A1
J . Org. Chem., Vol. 64, No. 15, 1999 5451
systems, 2H), 2.32 (s, 3H), 2.05 (s, 1.32H,one dia), 2.04 (s,
1.68H, other dia), 1.44 (s, 9H), 0.88 (s, 3.96H, one dia), 0.87
(s, 5.04H,other dia), 0.09 (s, 1.32H), 0.08 (s, 1.32H), 0.07 (s,
1.68H), 0.06 (s, 1.68H); 13C NMR (CDCl3) δ ) 170.5, 169.9,
138.9, 138.6, 134.4, 133.9, 130.3, 129.9, 128.9, 86.5, 84.3, 81.3,
71.9, 70.6, 41.0, 40.6, 28.6, 26.3, 23.2, 21.7, 21.5, 18.6, 18.5,
-4.1, -4.2, -4.3. Anal. Calcd for C23H38O5SSi (454.70): C,
60.76; H, 8.42. Found: C, 61.02; H, 8.31.
(20 mL). The solution was then diluted with ether (80 mL),
and the aqueous layer was extracted with ether (3 × 30 mL).
The organic layers were combined, washed with brine (50 mL),
dried over MgSO4, and concentrated. The crude product was
purified by column chromatography on silica gel (AcOEt/
hexane 2:8) to afford 15 as a colorless oil (954 mg; 72%): [R]20
D
1
) +6 (c ) 0.87, CHCl3); H NMR (200 MHz, CDCl3) 7.75 (d,
1H, J ) 3 Hz), 7.26 (d, 1H, J ) 3 Hz), 4.94 (dd, 1H, J ) 7.5
Hz, J ) 2.5 Hz), 4.65 (m, 1H, Hx of an ABX system), 3.85 (d,
ter t-Bu tyl (+)-(3R)-3-ter t-Bu tyld im eth ylsilyloxy-4-a c-
etoxy-bu ta n oa te (12). Freshly actived Raney nickel was
added by portions to a solution of compound 11 (0.573 g; 1.26
mmol) in MeOH (30 mL). The reaction at room temperature
was monitored by TLC (AcOEt/hexane 1:9). The mixture was
carefully filtered on Celite, and the cake was washed abun-
dantly with MeOH. After the solvent was evaporated, the
product was purified by rapid chromatography on silica gel
(AcOEt/hexane 1:9) to afford a colorless liquid 12 (339 mg;
1H, OH, J ) 7.5 Hz), 2.55 (AB of an ABX system, 2H, J AB
)
16 Hz, J AX ) 7 Hz, J BX ) 5.5 Hz, ∆ν ) 74 Hz), 1.43 (s, 9H),
0.80 (s, 9H), 0.02 (s, 3H), -0.25 (s, 3H); 13C NMR (CDCl3) 173.8,
171.0, 143.0, 119.8, 81.9, 74.7, 72.2, 40.5, 28.8, 26.3, 18.6, -4.3,
-4.7. Anal. Calcd for C17H31NO4SSi (373.58): C, 54.66; N 3.75,
H, 8.36. Found: C, 54.87; N, 3.12, H, 8.34.
ter t-Bu tyl (+)-(3R,4S)-3,4-Dih yd r oxy-4-(2-th ia zolyl)-bu -
ta n oa te (16). Tetrabutylammonium fluoride, 1 M in THF
(0.165 mL; 1.1 equiv), was added to a solution of protected
alcohol 15 (56 mg; 0.15 mmol) in dry THF (5 mL) at 0 °C. After
the TLC had shown that the reaction was complete, the
reaction was quenched by adding a spatula of silica. The
solution was stirred on for 30 min before evaporating the
solvent under reduced pressure. The crude compound kept on
the silica was purified by chromatography on silica gel (AcOEt/
81%): [R]20 ) +8 (c ) 1.84, CHCl3); 1H NMR (200 MHz,
D
CDCl3) δ ) 4.26 (m, 1H), 4.01 (d, 2H, J ) 5.5 Hz), 2.40 (d, 2H,
J ) 6 Hz), 2.05 (s, 3H), 1.43 (s, 9H), 0.85 (s, 9H), 0.08 (s, 3H),
0.07 (s, 3H); 13C NMR (CDCl3) δ ) 171.4, 170.8, 81.4, 68.4,
68.0, 41.8, 28.8, 26.4, 21.5, 18.7, -4.0, -4.2. Anal. Calcd for
C16H32O5Si (332.51): C, 57.80; H, 9.70. Found: C, 57.89; H, 9.50.
ter t-Bu tyl (+)-(3R)-3-ter t-Bu tyld im eth ylsilyloxy-4-h y-
d r oxy-bu ta n oa te (13). The ester 12 (1.38 g; 4.15 mmol) was
dissolved in THF (100 mL) at -75 °C and Dibal-H, 1 M in
toluene (9.2 mL; 2.2 equiv), was added dropwise. The colorless
solution was stirred for 4 h, and the temperature was allowed
to rise 5 °C. The reaction was then quenched with aqueous
saturated NH4Cl (30 mL), and the cold bath was removed. The
solution was diluted with AcOEt (25 mL) and water (25 mL)
and acidified to pH ) 1 with HCl 1 N (6 mL). The aqueous
layer was extracted with AcOEt (2 × 30 mL). The combined
organic layers were washed with brine (50 mL), filtered, and
concentrated. The crude colorless oily product was purified by
rapid chromatography on silica gel (AcOEt/hexane 1:9) to
hexane 1:3) to afford a light yellow oil 16 (36 mg; 93%): [R]20
D
1
) +7 (c ) 0.96, CHCl3); H NMR (200 MHz, CDCl3) 7.68 (d,
1H, J ) 3 Hz), 7.29 (d, 1H, J ) 3 Hz), 4.90 (d, 1H, J ) 4 Hz),
4.39 (dt, 1H, Hx of an ABX system, J ) 8 Hz, J ) 4 Hz), 3.96
(m, 2H, 2 × OH), 2.59 (AB of an ABX system, 2H, J AB ) 16.5
Hz, J AX ) 5 Hz, J BX ) 7 Hz, ∆ν ) 22 Hz), 1.45 (s, 9H); 13C
NMR (CDCl3) 172.9, 172.3, 142.9, 120.1, 82.1, 74.1, 71.5, 39.2,
28.7. Anal. Calcd for C11H17NO4S (259.32): C, 50.95; H, 6.61;
N, 5.40. Found: C, 50.78; H, 6.62; N, 5.12.
ter t-Bu t yl (+)-(3R,4S)-3,4-Isop r op ylid en ed ioxy-4-(2-
th ia zolyl)-bu ta n oa te (17). 2,2-Dimethoxypropane (0.15 mL;
4 equiv) and p-toluenesulfonic acid (30 mg; 0.5 equiv) were
added successively to a solution of diol 16 (81 mg; 0.31 mmol)
in acetone (5 mL). The solution was stirred overnight at room
temperature and then evaporated to dryness under reduced
pressure. The resulting yellow oil was dissolved in CH2Cl2 (4
mL), and saturated NaHCO3 (4 mL) was added. The solution
was stirred for 2 h, and then the aqueous layer was extracted
with CH2Cl2 (3 × 7 mL). The organic layers were washed with
brine (20 mL), dried over MgSO4, and concentrated. The crude
compound was purified on silica gel (AcOEt/hexane 1:3) to
afford a colorless liquid of 13 (1.05 g; 87%): [R]20 ) +3 (c )
D
1
1.3, CHCl3); H NMR (200 MHz, CDCl3) δ ) 4.15 (m, 1H, Hx
of an ABX system), 3.55 (m, 2H), 2.45 (AB of an ABX system,
2H, J AB ) 15.5 Hz, J AX ) 6.5 Hz, J BX ) 6 Hz, ∆ν ) 17 Hz),
2.07 (broad t, J ) 6.5 Hz, 1H, OH), 1.43 (s, 9H), 0.87 (s, 9H),
0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3) 171.4, 81.3, 70.3,
66.8, 41.2, 28.7, 26.4, 18.6, -4.1, -4.2. Anal. Calcd for
C
14H30O4Si (290.48): C, 57.89; H, 10.41. Found: C, 57.63; H,
10.32.
ter t-Bu tyl (+)-(3R)-3-ter t-Bu tyldim eth ylsilyloxy-3-for m -
afford 17 as a yellow oil (86 mg; 92%): [R]20 ) +13 (c ) 0.92,
D
1
yl-p r op a n oa te (14). DMSO (165 mL) was added dropwise at
-78 °C to a solution of oxalyl chloride (0.52 mL; 2.6 equiv) in
CH2Cl2 (20 mL). After 15 min, the alcohol 13 (663 mg; 2.28
mmol) diluted in CH2Cl2 (7 mL) was slowly added. The reaction
was stirred for 40 min and cooled at -70 °C. Then, NEt3 (2
mL; 6.5 equiv) was added, and the mixture was stirred for 1
h in the cold bath and 40 min at room temperature. After
completion, (TLC) the reaction was first quenched with CH2-
Cl2 (10 mL) and water (20 mL) and then neutralized with 1 N
HCl (1 mL). The organic layer was washed with water (4 ×
80 mL) and brine (60 mL) and then dried (MgSO4). Evapora-
tion of the solvent afforded 14 as a light yellow oil (292 mg;
93%), which was used in the next step without further
purification: [R]20D ) +30 (c ) 1.04, CHCl3); 1H NMR (200 MHz,
CDCl3) 9.64 (s, 1H), 4.24 (t, 1H, J ) 5.5 Hz), 2.63 (AB part of
ABX system, 2H, J AB ) 16.5 Hz, J AX ) 5.4 Hz, J BX ) 5.5 Hz,
∆ν ) 0.4 Hz), 1.38 (s, 9H), 0.85 (s, 9H), 0.06 (s, 3H), 0.04 (s,
3H); 13C NMR (CDCl3) 203.7, 169.7, 81.9, 74.9, 40.6, 28.6, 26.2,
18.6, -4.2, -4.4. Anal. Calcd for C14H28O4Si (288.46): C, 58.29;
H, 9.78. Found: C, 58.35; H, 9.72.
ter t-Bu tyl (+)-(3R,4S)-3-ter t-Bu tyld im eth ylsilyloxy-4-
h yd r oxy-4-(2-th ia zolyl)-bu ta n oa te (15). 2-Trimethylsilylth-
iazole (0.57 mL; 1 equiv) was added to a solution of aldehyde
13 (1.03 g; 3.57 mmol) in dry CH2Cl2 (40 mL), and the solution
was stirred overnight at room temperature. It was then
evaporated to dryness under reduced pressure, and the result-
ing yellow oil was added to a 5% citric acid in methanol (60
mL). After the mixture was stirred for 4 h at room tempera-
ture, water was added (40 mL) as well as saturated NaHCO3
CHCl3); H NMR (200 MHz, CDCl3) 7.74 (d, 1H, J ) 3 Hz),
7.32 (d, 1H, J ) 3 Hz), 5.00 (d, 1H, J ) 8 Hz), 4.37 (dt, 1H, Hx
of an ABX system, J ) 8 Hz, J ) 3.5 Hz), 2.74 (AB of an ABX
system, 2H, J AB ) 16 Hz, J AX ) 4 Hz, J BX ) 8 Hz, ∆ν ) 42
Hz), 1.53 (s, 3H), 1.51 (s, 3H), 1.42 (s, 9H); 13C NMR (CDCl3)
170.1, 169.7, 143.6, 119.9, 111.2, 81.7, 80.1, 79.0, 38.5, 28.7,
27.9, 27.3. Anal. Calcd for C14H21NO4S (299.38): C, 56.17; H,
7.07; N, 4.68. Found: C, 56.37; H, 6.97; N, 4.47.
ter t-Bu t yl (+)-(3R,4S)-4-F or m yl 3,4-isop r op ylid en e-
d ioxy-bu ta n oa te (18). To a solution of compound 17 (35 mg;
0.12 mmol) in dry acetonitrile (2 mL) were added powdered
activated molecular sieves (200 mg) and methyltriflate (17 µL;
1.3 equiv). The solution was stirred at rt, and the reaction was
followed by TLC. When there was no more starting material
left (∼2 h), the solution was evaporated to dryness under
reduced pressure. The residue was dissolved in dry methanol
(2 mL) and cooled at 0 °C before adding sodium borohydride
(10 mg; 2.2 equiv). After 30 min at 0 °C, the cold bath was
removed and the solution stirred for 30 min at room temper-
ature before quenching with acetone (3 mL). Filtration through
Celite and solvent evaporation led to a light yellow oil, which
was dissolved again in acetonitrile (2 mL), and a solution of
mercury(II) chloride (38 mg; 1.2 equiv) in CH3CN/H2O (5 mL,
4:1) was added dropwise. After the solution was stirred for 15
min, the reaction mixture was filtered through Celite, which
was carefully washed with CH2Cl2 (15 mL). After solvent
evaporation, the residue was dissolved in CH2Cl2 (4 mL) and
brine (4 mL) was added. The biphasic solution was stirred
vigorously for 2 h, and then the two layers were separated.

5452 J . Org. Chem., Vol. 64, No. 15, 1999
Solladie´ et al.
The aqueous layer was extracted with CH2Cl2 (3 × 4 mL), and
the organic layers were combined and dried on MgSO4. After
filtration and evaporation of the solvent, an orange oil was
obtained (37 mg) and used without any purification in the next
step: 1H NMR (200 MHz, CDCl3) 9.74 (d, 1H, J ) 2 Hz), 4.46-
4.39 (m, 1H), 4.10 (dd, 1H, J ) 7.5 Hz, J ) 2 Hz), 2.65 (dd,
2H, J ) 6.5 Hz, J ) 2.5 Hz), 1.47 (s, 3H), 1.45 (s, 9H), 1.42 (s,
3H); 13C NMR (CDCl3) 200.7, 169.8, 112.0, 84.7, 82.2, 73.8,
39.9, 28.7, 27.7, 26.9.
80.5, 77.7, 71.8, 66.1, 59.3, 43.7, 39.9, 38.7, 30.9, 28.8, 27.8,
27.6, 26.6, 20.6, 18.9, -4.7. Anal. Calcd for C29H54O8Si (558.83):
C, 62.33; H, 9.74. Found: C, 62.15; H, 9.52.
ter t-Bu tyl (+)-(3S,5R,7R,10R,11R)-1-ter t-Bu tyld im eth -
ylsilyoxy-7-h yd r oxy-d i-3,5-10,11-isop r op ylid en ed ioxy-
tr id eca n oa te (1). To a solution of alkene 21 (16 mg; 29 µmol)
in AcOEt (0.5 mL) was added Pd/C, and the heterogeneous
solution was stirred for 3 h at room temperature under
hydrogen atmosphere. The palladium was then filtered through
Celite, and the solution was concentrated to a colorless oil.
Purification by TLC (AcOEt/hexane 1:3) gave a colorless oil
ter t-Bu t yl (-)-(3S,5S,R,10R,11R)-1-ter t-Bu t yld im et h -
ylsilyloxy-di-3,5-10,11-isopr opyliden e-dioxy-7-oxo-tr idec-
8-en -13-oa te (20). To a solution of phosphonate 2 (70 mg; 0.16
mmol) in dry DME (1.5 mL) at 0 °C was added sodium hydride
(4 mg; 1.1 equiv). The solution was then heated for 45 min at
55 °C and became bright orange. After the solution was cooled
to -78 °C, a solution of the crude aldehyde 18 (∼35 mg; 1.1
equiv) in dry DME (0.6 mL) was added. The temperature of
the cold bath was allowed to rise slowly to room temperature,
and the reaction was followed on TLC. The reaction was
quenched after 4 h by adding saturated NH4Cl (3 mL). Water
(3 mL) was also added, the two layers were separated, and
the organic layer was washed with saturated NaHCO3 (3 mL)
and brine (3 mL). The aqueous layers were combined, satu-
rated with NaCl, and extracted with ether (3 × 3 mL). The
combined organic layers were dried on MgSO4 and concen-
trated to 82 mg of a yellow oil. Purification on TLC (CH2Cl2/
(8 mg; 50%) of 1: [R]20 ) +9 (c ) 0.57, CHCl3); 1H NMR (200
D
MHz, C6D6) 4.30-4.20 (m, 1H), 4.01-3.58 (m, 6H), 3.39 (s, 1H),
2.46 (AB of an ABX system, 2H, J AB ) 15 Hz, J AX ) 7 Hz, J BX
) 5 Hz, ∆ν ) 26.9 Hz), 1.84-1.51 (m, 9H), 1.41 (s, 6H), 1.39
(s, 12H), 1.35-1.20 (m, 1H), 1.31 (s, 3H), 1.00 (s, 9H), 0.07 (s,
6H); 13C NMR (CDCl3) 170.6, 109.2, 99.4, 81.7, 81.1, 77.7, 71.6,
70.9, 66.3, 59.6, 43.8, 40.0, 39.98, 39.90, 38.1, 34.4, 30.9, 28.8,
28.0, 27.9, 26.6, 20.7, 18.9, -4.7. Anal. Calcd for C29H56O8Si
(560.84): C, 62.11; H, 10.06. Found: C, 61.95; H, 9.97.
ter t-Bu tyl (+)-(3R,4S)-3,4-Di-ter t-bu tyldim eth ylsilyloxy-
4-for m yl-bu ta n oa te (19). Methyl iodide (0.8 mL; 45 equiv)
was added to a solution of thiazole 15 (132 mg; 0.28 mmol) in
dry acetonitrile (5 mL), and the solution was stirred under
reflux (Toil bath ) 95 °C). When the reaction was completed
(TLC, 17 h), the solution was evaporated to dryness under
reduced pressure. The resulting orange oil was dissolved in
dry methanol (5 mL) and sodium borohydride (16 mg; 1.5
equiv) was added at 0 °C. After the reaction was warmed to
at room temperauture, the reaction was followed on TLC.
When all the starting permethylated thiazole had reacted,
acetone was added (0.5 mL). The solution was evaporated
again to dryness, the resulting yellow oil was dissolved in CH2-
Cl2 (5 mL), and water (5 mL) was added. The solution was
stirred for 10 min, and then the aqueous layer was extracted
with CH2Cl2. The organic layers were combined and dried on
MgSO4. The residue was dissolved in acetonitrile (4 mL), and
a solution of mercuric chloride (93 mg; 1.2 equiv) in CH3CN/
H2O (15 mL; 4:1) was added. After the solution was stirred
for 30 min at room temperature, the mixture was filtered over
Celite. The Celite was washed with ether (20 mL). The solution
was concentrated, and the residue was dissolved in CH2Cl2 (6
mL) and brine (8 mL). This solution was stirred overnight at
room temperature, and then the aqueous layer was extracted
with CH2Cl2 (3 × 4 mL). The organic layers were combined
and dried over MgSO4. After evaporation of the solvent under
reduced pressure, an orange oil was obtained (113 mg; 93%),
hexane 1:1) gave a colorless oil (60 mg; 68%) of 20: [R]20
)
D
-7 (c ) 1.02, CHCl3); 1H NMR (200 MHz, CDCl3) 6.75 (dd,
1H, J ) 16 Hz, 3J ) 6 Hz), 6.37 (dd, 1H, J ) 16 Hz, 4J ) 1
Hz), 4.44-4.33 (m, 2H), 4.31-4.01 (m, 2H), 3.78-3.58 (m, 2H),
2.71 (AB of an ABX system, 2H, J AB ) 16 Hz, J AX ) 6.5 Hz,
J BX ) 5 Hz, ∆ν ) 67 Hz), 2.66-2.45 (m, 2H), 1.68-1.62 (m,
3H), 1.58 (s, 6H), 1.45 (s, 12H), 1.34 (s, 3H), 1.25-1.14 (m,
1H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) 198.4, 169.8,
142.6, 132.1, 110.6, 99.4, 82.1, 80.5, 77.5, 66.5, 66.1, 59.4, 47.8,
40.1, 38.9, 37.8, 30.8, 28.8, 27.8, 27.4, 26.6, 20.5, 18.9, -4.7.
Anal. Calcd for C29H52O8Si (556.81): C, 62.56; H, 9.41. Found:
C, 62.31; H, 9.47.
ter t-Bu tyl (+)-(3S,5S,7S,10R,11R)-1-ter t-Bu tyld im eth -
ylsilyloxy-7-h yd r oxy-d i-3,5-10,11-isop r oylid en ed ioxy-
tr id ec-8-en -13-oa te (21). To a solution of ketone 20 (9 mg;
16 µmol) in dry methanol (1 mL) at 0 °C was added sodium
borohydride (3 mg; 4 equiv). The solution was stirred for 30
min in a cold bath, and the reaction was then quenched by
adding saturated NH4Cl (1 mL). The cold bath was removed,
and the aqueous layer was acidified to pH ) 3 and then
extracted with CH2Cl2 (3 × 1 mL). The organic layers were
combined and dried on MgSO4. After filtration and evaporation
1
which was pure enough to be used in the next step: [R]20
)
of the solvent, a colorless oil (10 mg) was obtained. H NMR
D
+45 (c ) 1.04, CHCl3); 1H NMR (200 MHz, CDCl3) 9.72 (d,
1H, J ) 1 Hz), 4.39 (m, 1H, Hx part of an ABX system), 4.09
(dd, 1H, J ) 4.5 Hz, J ) 1 Hz), 2.48 (AB part of an ABX
system, 2H, J AB ) 16 Hz, J AX ) 4.5 Hz, J BX ) 8 Hz, ∆ν ) 94
Hz), 1.43 (s, 9H), 0.91 (s, 9H), 0.85 (s, 9H), 0.09 (s, 3H), 0.07
(s, 3H), 0.06 (s, 3H), 0.04 (s, 3H);13C NMR (CDCl3) 203.4, 171.8,
81.4, 79.8, 39.4, 28.8, 26.4, 18.6, -3.9, -4.0, -4.1, -4.5.
showed a mixture of two diastereomers (72/28), which could
be separated by TLC (AcOEt/hexane 1:3). For the main isomer
1
(6 mg, 64% isolated yield): [R]20 ) +6 (c ) 1.06, CHCl3); H
D
3
NMR (200 MHz, CDCl3) 5.84 (dd, 1H, J ) 15.5 Hz, J ) 4.5
Hz), 5.70 (dd, 1H, J ) 15.5 Hz, 3J ) 6 Hz), 4.36 (m, 1H), 4.17-
3.99 (m, 4H), 3.78-3.58 (m, 2H), 3.46 (s, 1H, OH), 2.47 (d, 2H,
J ) 5.5 Hz), 1.73-1.62 (m, 5H), 1.58 (s, 3H), 1.46 (s, 9H), 1.45
(s, 3H), 1.41 (s, 3H), 1.33-1.21 (m, 1H), 0.89 (s, 9H), 0.04 (s,
6H); 13C NMR (CDCl3) 170.4, 138.0, 126.5, 109.7, 99.4, 81.7,
J O990245Y