A chiral β,δ-dioxo-ε-sulfinyl ester in a convergent enantioselective synthesis towards the C1-C13 polyol fragment of amphotericin B

Article abstract of DOI:10.1002/(SICI)1099-0690(199911)1999:11<3021::AID-EJOC3021>3.0.CO;2-R

This paper describes an efficient stereocontrolled and convergent approach towards the C₁-C₁₃ polyol fragment of amphotericin B. The strategy is based on the stereoselective reduction of a chiral β,γ-dioxo- ε-sulfinyl ester to obtain anti-or syn-1,3-diols.

Full text of DOI:10.1002/(SICI)1099-0690(199911)1999:11<3021::AID-EJOC3021>3.0.CO;2-R

FULL PAPER
A Chiral β,δ-Dioxo-ε-sulfinyl Ester in a Convergent Enantioselective Synthesis
towards the C1–C13 Polyol Fragment of Amphotericin B
[a]
[a]
[a]
´
Guy Solladie,* Nicole Wilb, and Claude Bauder
Keywords: Natural products / Antibiotics / Macrolides / Asymmetric synthesis / Chiral sulfoxide
This paper describes an efficient stereocontrolled and
convergent approach towards the C1–C13 polyol fragment of
amphotericin B. The strategy is based on the stereoselective
reduction of a chiral β,γ-dioxo-ε-sulfinyl ester to obtain anti-
or syn-1,3-diols.
The antibiotic macrolide Amphotericin B is a natural com- on the stereoselective reduction of a chiral β,δ-dioxo-ε-sulf-
pound produced by Streptomyces nodosus. It is character- inyl ester[12,13,15] to obtain anti-or syn-1,3-diols.
ised by a rigid macrolactone ring bearing on one side a
As shown in the retrosynthetic Scheme (Scheme 1), the
hydrophilic polyol, the C1ϪC13 fragment, and on the other polyol 1 can be obtained by condensation of the two syn-
a hydrophobic heptaene, the C20ϪC33 part. The structure diols (Ϫ)-(3S, 5S)-2 and (ϩ)-(2R, 4R)-3, which can be pre-
of Amphotericin B was established by X-ray crystallo- pared by reduction of the β,δ-dioxo-ε-sulfinyl esters (Ϫ)-
graphic analysis.[1]
(S)-4 and (ϩ)-(R)-4 in a similar way to our previous
work.[13Ϫ16]
Figure 1
This antibiotic agent attracted considerable attention for
its potent antifungal properties. Unfortunately its use in
fungicide treatment has been attenuated by serious side-ef-
fects.[2] Some recent papers describe analogs of Ampho-
tericin B with the same antimycotic action but a reduced
toxicity.[3]
Several reports on the synthesis of Amphotericin B have
been published including the first total synthesis by Nico-
laou,[4] the formal synthesis of Masamune[5] and the ap-
proach of McGarvey using the oxazoline methodology.[6]
Many other groups have described the synthesis of the po-
lyol fragment of Amphotericin B starting from natural
products such as amino acids (-aspartic acid, -glutamic
acid)[6a,7] or modified sugars.[8] We also reported the syn-
thesis of the different stereogenic centers of this polyol unit,
using the chiral induction of sulfoxides.[9]
Scheme 1
The sulfoxides (Ϫ)-4 or (ϩ)-4 were readily obtained in
one step from the corresponding dioxo ester 5, prepared on
a multigram scale from commercially available dehy-
droacetic acid.[17] The trianion of 5, obtained at 0°C with
NaH (1 equiv.) and tBuLi (2 equiv.) in THF, was added to
the corresponding pure menthyl-p-toluenesulfinate (R or S)
to give the compounds (Ϫ)-4 or (ϩ)-4, respectively (Scheme
2). As shown in our previous studies,[12,13,15] the δ-carbonyl
in (Ϫ)-4 or (ϩ)-4 is totally enolized (1H-NMR spectroscopy
showed enol signals at δ ϭ 14.5 and 5.6). Consequently,
two equivalents of DibalϪH in THF at Ϫ78°C were re-
quired for the stereoselective reduction of the β-carbonyl;
one to quench the δ-carbonyl enolate and one to reduce the
β-carbonyl. Thus, the reduction of (Ϫ)-4 or (ϩ)-4 (Scheme
3) was carried out without any protection of the δ-carbonyl
More recently, Carreira[10] reported the synthesis of the
C1ϪC13 fragment by asymmetric aldolisation of a dienolate
on furfural induced by a chiral BINAP catalyst. This publi-
cation prompted us to report our own results and describe
a novel and efficient stereocontrolled convergent approach
towards the C1ϪC13 polyol fragment 1 of Amphotericin B
that involves similar intermediates.[11] Our strategy is based
[a]
´ ´
´
Laboratoire de Stereochimie associe au CNRS Ϫ
´
Universite Louis Pasteur, ECPM
25 rue Becquerel, F-67087-Strasbourg Cedex 2, France
Eur. J. Org. Chem. 1999, 3021Ϫ3026
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1434Ϫ193X/99/1111Ϫ3021 $ 17.50ϩ.50/0
3021

´
G. Solladie, N. Wilb, C. Bauder
FULL PAPER
and with no significant reduction of the terminal ester func-
The synthesis of the alkyne (Ϫ)-2 (Scheme 4) started with
tion. As expected, the 1H-NMR analysis of the crude mate- the reduction of the ester in the β,δ-dihydroxy-ε-sulfinyl es-
rial showed only one diastereomer (de > 95%). The re- ter (ϩ)-8 to the alcohol (ϩ)-9 (76%) in dilute conditions
sulting pure β-hydroxy-δ-oxo-ε-sulfinyl esters (Ϫ)-6 and with DibalϪH (4.5 equiv.), followed by protection of the
(ϩ)-6 were isolated after chromatography on metal-free sil- free hydroxyl with a benzyl group to give (ϩ)-10 (55%). A
ica gel.[18]
Pummerer rearrangement (NaOAc in boiling Ac2O) gave,
in 86%, the O,S-acetal 11 as a mixture of diastereomers.
The aldehyde (Ϫ)-12 was obtained in one step (89%) by
adding, at 0°C, the O,S-acetal 11 to an excess of sodium
methanolate (6 equiv.) in MeOH. This procedure does not
give any isomerization of the chiral center α to the aldehyde
because the six-membered acetonide derived from the syn-
diol is thermodynamically more stable (equatorial aldehyde)
than that made from the anti-diol. In the anti configuration
it would have been necessary to use the following three steps
for the transformation of the Pummerer intermediate into
the aldehyde to avoid any racemization: desulfurization of
the O,S-acetal (Raney Ni), acetate hydrolysis (MeONa) and
oxidation of the alcohol to the aldehyde.[15,16a,b] Finally, the
alkyne (Ϫ)-2 was obtained in mild conditions from the alde-
hyde (Ϫ)-12 following an improved one-pot procedure, de-
veloped by Bestmann,[21] using dimethyl diazomethylphos-
phonate generated in situ from the corresponding 1-acyl-
phosphonate. Other attempts, like the CoreyϪFuchs
method, gave only poor results.[22]
Scheme 2
Scheme 4
The other aldehyde, (ϩ)-3 (Scheme 5), was obtained from
the syn-β,δ-dihydroxy-ε-sulfinyl ester (Ϫ)-8 by ester group
reduction with DibalϪH (4 equiv.) in the same conditions
as described above. The resulting alcohol, (Ϫ)-9 (96%
Scheme 3
The δ-carbonyl in (Ϫ)-6 was reduced with diethylmeth- yield), was silylated and the protected product (Ϫ)-13 was
oxyborane and borohydride[19] to obtain exclusively, and in submitted to a Pummerer reaction with trifluoroacetic an-
nearly quantitative yield, the syn-diol (Ϫ)-7 (de > 95%), hydride in acetonitrile.[23] This procedure allows a mild one-
which was finally transformed into the corresponding ace- pot conversion of the sulfoxide to the aldehyde (ϩ)-3 in
tonide (Ϫ)-8. The same protocol applied to the compound 68% yield.
(ϩ)-6 stereoselectively gave the syn-diol (ϩ)-7 (de > 95%)
Finally, the alkyne (Ϫ)-2 was metallated with nBuLi at
and then the acetonide (ϩ)-8.[15] The large nonequivalence 0°C and added at Ϫ75°C to the aldehyde (ϩ)-3 to give, in
of the two methyl groups of the acetonide in the 13C-NMR 57% yield, a mixture of two C-8 isomers 1a/1b in a 24:76
spectrum confirmed the relative configuration of the diols: ratio as determined by 1H-NMR spectroscopy (from the
δ ϭ 20.0 and 30.2 for the acetonide (ϩ)-8 and δ ϭ 20.3 and C8 hydroxyl group signal), a similar result to the previous
30.4 for the acetonide (Ϫ)-8, which are characteristic of a attempts to synthesize this fragment[7][10] (Scheme 6). We
syn-diol acetonide.[20] Typical values for the anti-diol ace- assigned the configuration of 1b to the major isomer by
tonide methyl groups are δ ϭ 24 and 25.5.[20,13,16c]
comparison with the literature results.[7][10]
3022
Eur. J. Org. Chem. 1999, 3021Ϫ3026

Convergent Enantioselective Synthesis towards the C1ϪC13 Polyol Fragment of Amphotericin B
FULL PAPER
Methyl (؊)-(S)-3,5-Dioxo-6-(p-tolylsulfinyl)hexanoate (4): To a sus-
pension of NaH (2.2 g, 1.2 equiv.) in dry THF (250 mL) was added
dropwise at 0°C a solution of methyl 3,5-dioxohexanoate (5)[17]
(12.11 g, 0.0765 mol) in THF (25 mL). To the resulting thick, white
mixture was added by cannula at 0°C, over a period of 15 min,
tert-butyllithium (100 mL of a 1.5  solution in pentane, 2.04
equiv.). The solution turned from yellow/orange to deep red during
the addition. (ϩ)-Menthyl (R)-p-tolylsulfinate (11.31 g, 0.5 equiv.)
in THF (35 mL) was then added dropwise over 20 min. Stirring at
0°C was continued for an additional 40 min until all sulfinate was
consumed (tlc). The reaction was quenched with saturated NH4Cl
(10 mL) and diluted with AcOEt (250 mL), and then acidified to
pH 1 with 1  HCl (170 mL) and conc. H2SO4. The aqueous layer
was extracted with AcOEt (3 ϫ 150 mL). The combined organic
extracts were washed with brine (100 mL), dried over MgSO4 and
filtered before being concentrated. The crude oily residue was puri-
fied by rapid chromatography on treated silica gel[18] (hexane and
CH2Cl2) to give (Ϫ)-4 as an orange oil (7.85 g, 69%), which was
used directly in the next step. An analytical sample was obtained
by crystallization (CH2Cl2/diethyl ether). This product exists en-
Scheme 5
20
tirely in the enol form. [α]D ϭ Ϫ268 (c ϭ 0.89, CHCl3). m.p.
1
58°C. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 14.56 (br. s, 1 H, OH
enol), 7.55 (A part of AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ
41 Hz), 7.34 (B part of AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ
41 Hz), 5.52 (s, 1 H, H enol), 3.75 (s, 3 H, OCH3), 3.69 (A part of
AB, 1 H, 6-CH2, JAB ϭ 10 Hz, ∆ν ϭ 20 Hz), 3.58 (B part of AB,
1 H, 6-CH2, JAB ϭ 10 Hz, ∆ν ϭ 20 Hz), 3.37 (s, 2 H, CH2), 2.42 (s,
3 H, CH3-Ar). Ϫ 13C NMR (CDCl3): δ (CO) ϭ 189.6 (CϭO), 180.2
(CϭO enol form), 167.4 (CO2CH3); C 143.1, 139.6; CH 130.7,
Scheme 6
The natural configuration at C8, as shown in 1a, could be
obtained from 1b as described previously by a Mitsunobu 124.7, 103.4 (enol); CH2 65.5, 45.9; CH3 53.2 (OCH3), 22.2
reaction.[7] However, the C11ϪC13 fragment 1 of Ampho-
(ArCH3). Ϫ C14H16O5S (296.33): calcd. C 56.74, H 5.44; found C
56.93, H 5.48.
tericin B could be obtained directly from the mixture 1a/1b
by reduction of the triple bond, oxidation of the carbinol
Methyl (؊)-[5R,S(S)]-5-Hydroxy-3-oxo-6-(p-tolylsulfinyl)hexanoate
[10]
at C8
and stereoselective reduction of the C8 ketone by (6): To a solution of (Ϫ)-4 (6.0 g, 22.2 mmol) in THF (400 mL) was
-Selectride .[4a,6a,10]
added dropwise (over 15 min) at Ϫ 78°C a solution of DibalϪH
(45 mL 1  in toluene, 2 equiv.). Stirring was continued for a
further 15 min before adding MeOH (90 mL). After 1 h stirring the
solution was kept for 0.5 h at room temperature and the solvent
was evaporated to afford an orange powder, which was dissolved
in AcOEt (300 mL) and treated with sat. disodium -tartrate dihy-
drate (200 mL). This mixture was stirred overnight at room tem-
perature and then acidified to pH 4 with conc. HCl. The aqueous
layer was extracted with AcOEt (2 ϫ 150 mL) and saturated with
brine before extraction with AcOEt (150 mL). The combined or-
ganic extracts were washed with brine, dried (MgSO4) and concen-
trated to afford a solid residue. The crude product was purified by
rapid chromatography on treated silica gel[18] (AcOEt/CH2Cl2, 1:1)
and the resulting solid was recrystallized (CH2Cl2/diethyl ether) to
give (Ϫ)-6 as colorless crystals (3.10 g, 47%, de > 95%) containing
In conclusion, we have reported an efficient convergent
synthesis of a known precursor of the C11ϪC13 polyol frag-
ment of Amphotericin B from the chiral β,δ-dioxo-ε-sulfi-
nyl ester. It has been demonstrated that this highly func-
tionalized dioxo sulfoxide is a powerful tool for the stereo-
selective synthesis of natural products containing syn- or
anti-1,3-diol and 1,2-diol units
Experimental Section
General: Melting points were determined with a Reichert micro-
scope. Ϫ 1H- and 13C-NMR spectra were recorded at 200 and
50 MHz in CDCl3 on a Bruker AC 200 SY spectrometer. Chemical
shifts are reported in δ units (ppm). Peak multiplicities are abbrevi-
ated as: singlet, s; doublet, d; triplet, t; multiplet, m. Ϫ Optical
rotations were recorded using a PerkinϪElmer 241MC polarimeter
at 25°C (λ ϭ 589 nm). Ϫ Thin layer chromatography (TLC) was
performed using precoated sheets of silica gel 60 (230Ϫ400 mesh)
from Merck. Eluting solvents are indicated in the text. Dry THF
was distilled from sodium/benzophenone. Diisopropylamine was
freshly distilled over potassium hydroxide. Ϫ Apparatus for all
experiments carried out under an inert atmosphere was dried by
flaming under pressure and was then filled with argon. Treated
silica gel was prepared according to literature[18] by washing silica
gel (1 kg) with two liters of dilute HCl (10%) and then rinsed sev-
eral times with water until neutral pH. Finally, silica gel was filtered
and dried for one week under air before use.
20
9% of enol. Ϫ [α]D ϭ Ϫ206 (c ϭ 0.82, CHCl3). Ϫ M.p. 123°C.
Ϫ
1H NMR (200 MHz, CDCl3): δ ϭ 7.53 (A part of AAЈBBЈ, 2
H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 33 Hz), 7.36 (B of AAЈBBЈ), 2 H, pTol,
JAB ϭ 8 Hz, ∆ν ϭ 33 Hz), 4.62 (m, 1 H, Hx of ABX), 4.11 (d, 1
H, OH, J ϭ 3.4 Hz), 3.74 (s, 3 H, OCH3), 3.48 (s, 2 H,
CH2CO2Me), 2.92 (ABX, 2 H, 6-CH2, JAB ϭ 13.4 Hz, JAX
9.5 Hz, JBX ϭ 3.8 Hz, ∆ν ϭ 75 Hz), 2.80 (d, 2 H, 4-CH2, J
ϭ
ϭ
6 Hz), 2.42 (s, 3 H, CH3-Ar). Ϫ 13C NMR (CDCl3): δ CO ϭ 202.2
(CO), 167.9 (CO2CH3); C, 142.5, 139.8; CH 130.9, 124.7, 64.3
(CHOH); CH2 60.8, 50.3, 49.7; CH3 53.2 (OCH3), 22.1 (ArCH3).
Ϫ C14H18O5S (298.34): calcd. C 56.36, H 6.08; found C 56.07, H,
6.03.
Methyl (؊)-[3S,5R,S(S)]-syn-3,5-Dihydroxy-6-(p-tolylsulfinyl)hex-
anoate (7): A solution of (Ϫ)-6 (3.04 g, 10 mmol) in THF/MeOH
Eur. J. Org. Chem. 1999, 3021Ϫ3026
3023

´
G. Solladie, N. Wilb, C. Bauder
FULL PAPER
(100 mL/20 mL, 5:1) was cooled at Ϫ78°C. After rapid addition (B of AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 21 Hz), 4.48 (m, 1 H,
(2 min) of a solution of Et2BOMe (1  in THF, 11.2 mL, 1.1 equiv.)
a white precipitate was formed. Stirring was continued during
20 min before adding NaBH4 (0.5 g, 1.3 equiv.) in one portion,
which led to a homogeneous solution. After 4 h at Ϫ78°C, AcOH
(20 mL) and then sat. NaHCO3 (100 mL) were added at room tem-
perature until pH 7 was reached. The aqueous layer was extracted
with AcOEt (3 ϫ 150 mL) and the combined organic extracts were
dried (MgSO4) and concentrated. The yellow oil was then azeo-
tropically distilled with MeOH (3 ϫ 50 mL). The product was puri-
fied by rapid chromatography on treated silica gel[18] (AcOEt) to
afford the light yellow oil (Ϫ)-7, which crystallized at low tempera-
H-2), 4.15 (m, 1 H, H-4), 3.71 (t, 2 H, H-6, J ϭ 4.8 Hz), 2.74 (m,
2 H, H-1), 2.38 (s, 3 H, CH3ϪAr), 1.69 (q, 2 H, H-5, J ϭ 4.8 Hz),
1.52 (s, 3 H, CH3, acetonide), 1.43 (dt, 1 H, Heq-3, Jgem ϭ 23.4 Hz,
3J ϭ 2.9 Hz), 1.41 (s, 3 H, CH3, acetonide), 1.28 (m, 1 H, Hax-3).
Ϫ
13C NMR (CDCl3): δ ϭ 142.1 (C arom.), 141.8 (C arom.), 130.6
(CH arom.), 124.4 (CH arom.), 100.0 (C, acetonide), 69.1 (CH-2),
65.4 (CH2-6), 64.1 (CH-4), 60.8 (CH2-1), 38.8 (CH2-3), 36.9 (CH2-
5), 30.6 (CH3, acetonide), 22.0 (CH3, pTol), 20.5 (CH3, acetonide).
Ϫ C16H24O4S (312.43): calcd. C 61.50, H 7.74; found C 61.42, H
7.80.
(؊)-[2R,4R,S(S)]-6-(tert-Butyldimethylsilyloxy)-syn-2,4-(isopropyl-
idenedioxy)-1-(p-tolylsulfinyl)hexane (13): The alcohol (Ϫ)-9
(483 mg, 1.55 mmol) was dissolved at 0°C under argon in dry
DMF (15 mL). Imidazole (274 mg, 4.02 mmol, 2.6 equiv.) and then
tert-butyldimethylsilyl chloride (350 mg, 2.32 mmol, 1.5 equiv.)
were successively added. After 15 h at room temperature the reac-
tion was hydrolyzed with water (20 mL) and diluted with ether
(15 mL). Stirring was continued until clear separation of the layers
was observed. The aqueous layer was extracted with ether
(3 ϫ 15 mL) and the combined organic extracts were successively
washed with water (5 ϫ 15 mL) and brine (20 mL) before being
dried over MgSO4. Evaporation of the solvent gave a crude oil,
which was purified by rapid chromatography on silica gel to obtain
20
ture (4°C) (2.9 g, 97%, de > 95%). Ϫ [α]D ϭ Ϫ198 (c ϭ 1.15,
1
CHCl3). Ϫ M.p. 91°C. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 7.50
(A of AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 37 Hz), 7.31 (B of
AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 37 Hz), 4.96 (br. s, 1 H,
OH), 4.47 (m, 1 H, Hx of ABX), 4.29 (m, 1 H, Hx of ABX), 4.17
(br. s, 1 H, OH), 3.65 (s, 3 H, OCH3), 2.86 (ABX, 2 H, 6-CH2,
JAB ϭ 13.2 Hz, JAX ϭ 9.8 Hz, JBX ϭ 2.4 Hz, ∆ν ϭ 49 Hz), 2.47
(m, ABX type, 2 H, CH2CO2Me), 2.39 (s, 3 H, CH3ϪAr),
1.80Ϫ1.53 (m, 2 H, 4-CH2). Ϫ 13C NMR (CDCl3): δ ϭ CO 173.1
(CO2CH3); C 142.3, 140.2; CH 130.7, 124.6, 68.2 (CHOH), 66.7
(CHOH); CH2 63.9, 42.7, 42.1; CH3 54.1 (OCH3), 22.0 (ArCH3).
Methyl (؊)-[3S,5R,S(S)]-syn-3,5-(Isopropylidenedioxy)-6-(p-tolyl-
sulfinyl)hexanoate (8): The dihydrosulfoxide (Ϫ)-7 (1.3 g, 4.33
mmol) and a catalytic amount of pTsOH (65 mg) were dissolved in CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 7.51 (A of AAЈBBЈ,
20
(Ϫ)-13 as a yellow oil (597 mg, 91%). Ϫ [α]D ϭ Ϫ123 (c ϭ 1.29,
1
acetone (65 mL) and 2,2-dimethoxypropane (6.5 mL). Stirring at
room temperature (3 h) was maintained until starting material had
disappeared (tlc). The solvents were removed and the crude product
2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 44 Hz), 7.29 (B of AAЈBBЈ, 2 H, pTol,
AB ϭ 8 Hz, ∆ν ϭ 44 Hz), 4.51Ϫ4.41 (m, 1 H, H-2), 4.14Ϫ4.03 (m,
1 H, H-4), 3.76Ϫ3.55 (m, 2 H, H-6), 2.74 (m, 2 H, H-1), 2.38 (s, 3
J
was then diluted in CH2Cl2 (100 mL) and sat. NaHCO3 (10 mL) H, CH3ϪAr), 1.65Ϫ1.54 (m, 2 H, H-5), 1.51 (s, 3 H, CH3, aceton-
3
was added. The mixture was stirred for 15 min at room temperature
and diluted with water (50 mL). The aqueous layer was extracted
ide), 1.49 (dt, 1 H, Heq-3, Jgem ϭ 10.0 Hz, J ϭ 2.5 Hz), 1.41 (s, 3
H, CH3, acetonide), 1.31Ϫ1.13 (m, 1 H, Hax-3), 0.86 (s, 9 H, SitBu),
with CH2Cl2 (2 ϫ 50 mL) and the combined organic extracts were 0.13 (s, 6 H, SiMe2). Ϫ 13C NMR (CDCl3): δ ϭ 142.1 (C, arom.),
washed with water (100 mL), dried (MgSO4) and concentrated to 141.9 (C, arom.), 130.6 (CH, arom.), 124.4 (CH, arom.), 99.9 (C,
20
afford (Ϫ)-8 as sharp, colorless needles (1.43 g, 97%). [α]D
ϭ
acetonide), 66.1 (CH-2), 65.6 (CH2-6), 64.1 (CH-4), 59.2 (CH2-1),
39.9 (CH2-3), 37.3 (CH2-5), 30.7 (CH3, acetonide), 26.5 (CH3, tBu),
Ϫ172 (c ϭ 0.97, CHCl3). Ϫ M.p. 92Ϫ95°C. Ϫ 1H NMR (200 MHz,
CDCl3): δ ϭ 7.46 (A of AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 22.0 (CH3, pTol), 20.5 (CH3, acetonide), 18.9 (C, SitBu), Ϫ4.8
41 Hz), 7.25 (B of AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 41 Hz), (CH3, SiMe2). Ϫ C22H38O4SiS (426.69): calcd. C 61.93, H 8.98;
4.6Ϫ4.4 (m, 1 H), 4.35Ϫ4.26 (m, 1 H), 3.61 (s, 3 H, OCH3), 2.70 found C 61.72, H 8.87.
(m, ABX type, 2 H, 6-CH2), 2.40 (ABX, 2 H, CH2CO2Me, JAB
ϭ
(؉)-(2R,4R)-6-(tert-Butyldimethylsilyloxy)-syn-2,4-(isopropyl-
idenedioxy)hexanal (3): To a cooled (0°C) solution of the sulfoxide
(Ϫ)-13 (122 mg, 0.29 mmol) in dry acetonitrile (3 mL) were added
2,4,6-collidine (76 µL, 0.57 mmol, 2 equiv.) and then trifluoroacetic
anhydride (81 µL, 0.57 mmol, 2 equiv.). When no more starting
material was detected (0.5 h, tlc), the reaction was quenched at 0°C
with aqueous NaHCO3 (150 mg, 1.75 mmol, 6 equiv in 3 mL H2O).
The mixture was stirred for a further 2 h at room temperature be-
fore being diluted with ether (5 mL) and water (5 mL). The aque-
15.0 Hz, JAX ϭ 7 Hz, JBX ϭ 6.8 Hz, ∆ν ϭ 38 Hz), 2.34 (s, 3 H,
CH3ϪAr), 1.56 (dt, 1 H, 4-Heq, Jgem ϭ 14 Hz, J3 ϭ 2.4 Hz), 1.48
[s, 3 H, C(Me)2], 1.35 [s, 3 H, C(Me)2], 1.29Ϫ1.12 (m, 1 H, 4-Hax).
Ϫ
13C NMR (CDCl3): δ CO ϭ 171.5 (CO2CH3); C 142.0, 141.9,
100.1 [C(Me)2]; CH 130.5, 124.3, 66.2 (CHOH), 63.9 (CHOH);
CH2 65.3, 41.5, 36.4; CH3 52.2 (OCH3), 30.4 (CH3), 21.9 (ArCH3),
20.3(CH3). Ϫ C17H24O5S (340.42): calcd. C 59.98, H 7.11; found
C 60.06, H 6.89.
(؊)-[2R,4R,S(S)]-6-Hydroxy-syn-2,4-(isopropylidenedioxy)-1-(p- ous layer was extracted with ether (2 ϫ 5 mL) and the combined
tolylsulfinyl)hexane (9): The ester (Ϫ)-8 (25 mg, 0.07 mmol) was
dissolved in dry THF (6 mL) at Ϫ78°C. A solution of DibalϪH (1
 in toluene, 0.3 mL, 0.3 mmol, 4 equiv.) was added dropwise and
the evolution of the reaction was monitored by tlc and the tempera-
ture rose slowly. After 7 h the reaction was hydrolyzed by adding
sat. NH4Cl (6 mL). Water (6 mL) and AcOEt (6 mL) were added
and the aqueous layer was acidified with 5% aqueous H2SO4 and
was then extracted with AcOEt (3 ϫ 10 mL). The combined or-
ganic extracts were washed with brine (20 mL) and dried (MgSO4).
Evaporation of the solvent afforded a pale yellow oil, which was
purified by column chromatography on silica gel (AcOEt; AcOEt/
organic extracts were successively washed with 1  HCl (5 mL), sat.
NaHCO3 (5 mL) and then with water (3 ϫ 5 mL) before being
dried over MgSO4. The crude product obtained after removal of
the solvent was purified by chromatography on silica gel to give
the pure aldehyde (ϩ)-3 as a colorless oil (59 mg, 68%). Ϫ [α]D20 ϭ
1
ϩ55 (c ϭ 1.30, CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 9.58
(s, 1 H, CHO), 4.31 (dd, 1 H, H-2, J ϭ 12.2 Hz, J ϭ 2.9 Hz),
4.18Ϫ4.05 (m, 1 H, H-4), 3.79Ϫ3.59 (m, 2 H, H-6), 1.75 (dt, 1 H,
Heq-3, Jgem ϭ 12.9 Hz, 3J ϭ 2.8 Hz), 1.69Ϫ1.60 (m, 2 H, H-5), 1.46
(s, 6 H, CH3, acetonide), 1.42Ϫ1.24 (m, 1 H, Hax-3), 0.89 (s, 9 H,
SitBu), 0.04 (s, 6 H, SiMe2). Ϫ 13C NMR (CDCl3): δ ϭ 202.0
MeOH, 9:1) to give (Ϫ)-9 as a light yellow oil (22 mg, 96%). Ϫ (CHO), 99.8 (C, acetonide), 74.8 (CH-2), 65.7 (CH-4), 59.2 (CH2-
[α]D20 ϭ Ϫ152 (c ϭ 0.55, CHCl3). Ϫ 1H NMR (200 MHz, CDCl3):
δ ϭ 7.48 (A of AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 21 Hz), 7.32
6), 39.9 (CH2-3), 31.9 (CH2-5), 30.5 (CH3, acetonide), 26.6 (CH3,
tBu), 20.2 (CH3, acetonide), 19.0 (C, tBu), Ϫ4.7 (CH3, SiMe2). Ϫ
3024
Eur. J. Org. Chem. 1999, 3021Ϫ3026

Convergent Enantioselective Synthesis towards the C1ϪC13 Polyol Fragment of Amphotericin B
C15H30O4Si (302.49): calcd. C 59.56, H 10.00; found C 59.60, H, (CH-4), 37.1 (CH2-3), 37.0 (CH2-5), 30.4 (CH3, acetonide), 21.1
FULL PAPER
10.13.
(CH3, pTol), 20.0 (CH3, acetonide). Ϫ C23H30O4S (402.55): calcd.
C 68.63, H 7.51; found C 65.76, H 7.04.
(؉)-[2S,4S,S(R)]-6-Hydroxy-syn-2,4-(isopropylidenedioxy)-1-(p-
tolylsulfinyl)hexane (9): DibalϪH in toluene (10 mmol, 4.5 equiv.)
was added dropwise to a solution at Ϫ78°C of the ester (ϩ)-8[15]
(760 mg, 2.23 mmol) in dry THF (150 mL). After stirring for 4 h
(monitored by tlc) the reaction was quenched with sat. NH4Cl
(10 mL) and then diluted with AcOEt (30 mL) and water (40 mL).
The aqueous layer was acidified with 5% H2SO4 and extracted with
AcOEt (2 ϫ 50 mL). The combined organic extracts were washed
with brine (50 mL), dried (MgSO4), filtered and evaporated. The
resulting crude product was purified by column chromatography
on silia gel (AcOEt; AcOEt/MeOH, 9:1) to afford the alcohol (ϩ)-
(2S,4S)-1-Acetoxy-6-benzyloxy-syn-2,4-(isopropylidenedioxy)-1-(p-
tolylthio)hexane (11): Anhydrous sodium acetate (200 mg, 10
equiv.) followed by acetic anhydride (6 mL) were added to the sul-
foxide (ϩ)-10 (98 mg, 0.24 mmol). The mixture was refluxed for
10 h at 135°C then stirred for 2 h at room temperature. The brown
heterogeneous solution was filtered through Celite and washed with
CH2Cl2. The solvents were removed by azeotropic distillation with
toluene (4 ϫ 5 mL). The resulting crude product was purified by
chromatography on silica gel (AcOEt/hexane) to give the pure
product 11 as a yellow oil (93 mg, 86%) along with a 70/30 mixture
20
1
9 as a light yellow oil (530 mg, 76%). Ϫ [α]D ϭ ϩ165 (c ϭ 1.73,
of diastereomers at C-1. Ϫ H NMR (200 MHz, CDCl3): δ ϭ 7.40
1
CHCl3). Ϫ H NMR (200 MHz, CDCl3): δ ϭ 7.51 (A of AAЈBBЈ,
(A of AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 57 Hz), 7.33 (m, 5 H,
Ph), 7.11 (B of AAЈBBЈ, 2 H, ITol, JAB ϭ 8 Hz, ∆ν ϭ 57 Hz), 6.06
(d, 0.7 H, H-1, J ϭ 5.6 Hz, major isomer), 5.94 (d, 0.3 H, H-1,
J ϭ 5.6 Hz, minor isomer), 4.52 [A of AB, 1 H, CH2 (OBn), JAB ϭ
2 H, pTol, JAB ϭ 8 Hz, ∆ν ϭ 42 Hz), 7.30 (B of AAЈBBЈ, 2 H, pTol,
JAB ϭ 8 Hz, ∆ν ϭ 42 Hz), 4.56Ϫ4.43 (m, 1 H, H-2), 4.22Ϫ4.04 (m,
1 H, H-4), 3.73 (t, 2 H, H-6, J ϭ 5.6 Hz), 2.81Ϫ2.65 (m, 2 H, H-
1), 2.38 (s, 3 H, CH3-Ar), 1.74Ϫ1.66 (m, 2 H, H-5), 1.53 (s, 3 H,
CH3, acetonide), 1.48Ϫ1.19 (m, 2 H, H-3), 1.41 (s, 3 H, CH3, ace-
tonide). Ϫ 13C NMR (CDCl3): δ ϭ 142.1 (C arom.), 141.9 (C
arom.), 130.6 (CH arom.), 124.4 (CH arom.), 100.0 (C, acetonide),
69.2 (CH-2), 65.5 (CH2-6), 64.1 (CH-4), 60.9 (CH2-1), 38.8 (CH2-
3), 36.9 (CH2-5), 30.6 (CH3, acetonide), 22.0 (CH3, pTol), 20.5
(CH3, acetonide). Ϫ C16H24O4S (312.43): calcd. C 61.50, H 7.74;
found C 62.10, H 7.69.
12.1 Hz, ∆ν ϭ 6 Hz], 4.49 [B of AB, 1 H, CH2 (OBn), JAB
ϭ
12.1 Hz, ∆ν ϭ 6 Hz], 4.17Ϫ3.99 (m, 2 H, H-2 ϩ H-4), 3.66Ϫ3.48
(m, 2 H, H-6), 2.33 (s, 3 H, CH3-Ar), 2.05 (s, 3 H, OAc), 1.82Ϫ1.72
(m, 2 H, H-5), 1.61 (dt, 1 H, H-3eq, Jgem ϭ 15.3 Hz, 3J ϭ 2.4 Hz),
1.50Ϫ1.21 (m, 1 H, H-3ax), 1.40 (s, 3 H, CH3, acetonide), 1.37 (s,
3 H, CH3, acetonide). Ϫ 13C NMR (CDCl3): δ ϭ 170.4 (CO), 170.3
(CO), 139.1 (C arom.), 134.9 (CH arom.), 134.4 (CH arom.), 130.4
(CH arom.), 130.3 (CH arom.), 129.0 (CH arom.), 128.6 (C arom.),
128.3 (C arom.), 99.8 (C, acetonide), 83.7 (CH-1), 83.5 (CH-1),
73.7 (CH2, OBn), 71.2 (CH-2), 70.6 (CH-2), 66.6 (CH2-6), 66.3
(CH-4), 37.1 (CH2-5), 33.8 (CH2-3), 33.2 (CH2-3), 30.6 (CH3, ace-
tonide), 21.9 (CH3, OAc), 21.6 (CH3, pTol), 20.3 (CH3, acetonide).
Ϫ C25H32O5S (444.59): calcd. C 67.54, H 7.25; found C 67.50, H
7.10.
(؉)-[2S,4S,S(R)]-6-Benzyloxy-syn-2,4-(isopropylidenedioxy)-1-(p-
tolylsulfinyl)hexane (10): Sodium hydride (9 mg, 0.36 mmol, 1.3
equiv.) was added to a solution of the alcohol (ϩ)-9 (87 mg,
0.28 mmol) at 0°C in dry THF (3 mL). The suspension was stirred
for 30 min before adding tetrabutylammonium iodide (15 mg,
0.04 mmol, 0.15 equiv.) and benzyl bromide (66 µL, 0.56 mmol, 2
equiv.). After stirring overnight at room temperature, water (5 mL)
and then CH2Cl2 (10 mL) were added to the reaction mixture. The
aqueous layer was extracted with CH2Cl2 (2 ϫ 5 mL). The com-
bined organic extracts were washed with water (5 ϫ 10 mL), brine
(100 mL) and dried over MgSO4 before being filtered and concen-
trated. The crude oily residue was purified by rapid chromatogra-
phy on silica gel to give the protected alcohol (ϩ)-10 as a yellow
(؊)-(2S,4S)-6-Benzyloxy-syn-2,4-(isopropylidenedioxy)hexanal (12):
Sodium methanolate (53 mg, 0.99 mmol, 6 equiv.) was added to a
solution at 0°C of the O,S-acetal 11 (73 mg, 0.16 mmol) in MeOH
(5 mL). The reaction was stirred at 0°C until no more starting ma-
terial was detected by tlc (3 h). The reaction was then quenched
with sat. NH4Cl (3 mL) and water (3 mL). After dilution with
CH2Cl2 (5 mL) the aqueous layer was acidified to pH 5 with a few
drops of 10% HCl and then extracted with CH2Cl2 (3 ϫ 5 mL).
The combined organic extracts were washed with water (10 mL),
brine (10 mL) and dried over MgSO4. The solvent was removed
and the crude product was purified by chromatography on silica
gel to afford aldehyde (Ϫ)-12 as a pale yellow oil (40 mg, 89%). Ϫ
20
oil (55%). Ϫ [α]D ϭ ϩ141 (c ϭ 0.99, CHCl3). Ϫ 1H NMR
(200 MHz, CDCl3): δ ϭ 7.53 (A of AAЈBBЈ, 2 H, pTol, JAB
ϭ
8.2 Hz, ∆ν ϭ 46 Hz), 7.30 (B of AAЈBBЈ, 2 H, pTol, JAB ϭ 8.2 Hz,
∆ν ϭ 46 Hz), 7.38Ϫ7.21 (m, 5 H, Ph), 4.55Ϫ4.41 (m, 1 H, H-2),
4.47 (d, 2 H, OCH2Ph, J ϭ 0.86 Hz), 4.17Ϫ4.04 (m, 1 H, H-4),
3.63Ϫ3.45 (m, 2 H, H-6), 2.80Ϫ2.65 (m, 2 H, H-1), 2.39 (s, 3 H,
CH3-Ar), 1.79Ϫ1.68 (m, 2 H, H-5), 1.51 (s, 3 H, CH3, acetonide),
20
1
[α]D ϭ Ϫ38 (c ϭ 1.02, CHCl3). Ϫ H NMR (200 MHz, CDCl3):
4
δ ϭ 9.58 (d, 1 H, H-1, J ϭ 0.5 Hz), 7.40Ϫ7.28 (m, 5 H, Ph), 4.52
3
1.50 (dt, 1 H, H-3eq, Jgem ϭ 12.6 Hz, J ϭ 2.6 Hz), 1.41 (s, 3 H,
[A of AB, 1 H, CH2 (OBn), JAB ϭ 12.1 Hz, ∆ν ϭ 5 Hz], 4.49 [B of
AB, 1 H, CH2 (OBn), JAB ϭ 12.1 Hz, ∆ν ϭ 5 Hz], 4.30 (ddd, 1 H,
CH3, acetonide), 1.31Ϫ1.14 (m, 2 H, H-3ax). Ϫ 1H NMR
(200 MHz, C6D6): δ ϭ 7.75 (A of AAЈBBЈ, 2 H, pTol, JAB ϭ 8 Hz,
∆ν ϭ 11 Hz), 7.38Ϫ7.12 (m, 5 H, Ph), 6.64 (B of AAЈBBЈ, 2 H,
pTol, JAB ϭ 8 Hz, ∆ν ϭ 11 Hz), 4.62Ϫ4.49 (m, 1 H, H-2),
4.44Ϫ4.31 (m, 2 H, OCH2Ph), 3.99Ϫ3.86 (m, 1 H, H-4), 3.60Ϫ3.39
(m, 2 H, H-6), 2.66Ϫ2.48 (m, 2 H, H-1), 2.02 (s, 3 H, CH3-Ar),
1.87Ϫ1.66 (m, 2 H, H-5), 1.59 (s, 3 H, CH3, acetonide), 1.45 (s, 3
H, CH3, acetonide), 1.56Ϫ0.95 (m, 2 H, H-3). Ϫ 13C NMR
(CDCl3): δ ϭ 142.1 (C arom.), 141.9 (C arom.), 139.0 (C arom.),
130.6 (CH arom.), 129.0 (CH arom.), 128.2 (CH arom.), 124.4 (CH
arom.), 99.9 (C, acetonide), 73.6 (OCH2Ph), 66.6 (CH2-6), 66.5
3
3
4
H-2, J ϭ 12.2 Hz, J ϭ 3.1 Hz, J ϭ 0.5 Hz), 4.15Ϫ4.06 (m, 1 H,
H-4), 3.66Ϫ3.50 (m, 2 H, H-6), 1.83Ϫ1.70 (m, 3 H, H-5 ϩ H-3eq),
1.46 (s, 6 H, CH3, acetonide), 1.41Ϫ1.23 (m, 1 H, H-3ax). Ϫ 13C
NMR (CDCl3): δ ϭ 201.9 (CHO), 139.2 (C arom.), 129.1 (CH
arom.), 128.3 (CH arom.), 99.8 (C, acetonide), 74.7 (CH2, OBn),
73.7 (CH-2), 66.4 (CH2-6), 66.1 (CH-4), 37.1 (CH2-2), 31.7 (CH2-
5), 30.5 (CH3, acetonide), 20.2 (CH3, acetonide). Ϫ C16H22O4
(278.35): calcd. C 69.04, H 7.97; found C 67.59, H 7.82.
(؊)-(3S,5S)-1-Benzyloxy-syn-3,5-(isopropylidenedioxy)hept-6-yne
(CH-2), 65.6 (CH2-1), 64.1 (CH-4), 37.2 (CH2-3), 37.1 (CH2-5), (2): The aldehyde (Ϫ)-12 (92 mg, 0.33 mmol) was diluted with dry
30.6 (CH3, acetonide), 22.0 (CH3, pTol), 20.5 (CH3, acetonide). Ϫ MeOH (1.5 mL). Successively, potassium carbonate (91 mg,
13C NMR (C6D6): δ ϭ 143.8 (C arom.), 140.5 (C arom.), 139.4 (C 0.66 mmol, 2 equiv.) and a solution of dimethyl diazo-1-oxo-2-pro-
arom.), 130.0 (CH arom.), 123.9 (CH arom.), 99.4 (C, acetonide),
pylphosphonate (88 mg, 0.46 mmol, 1.4 equiv.) in dry MeOH
73.1 (OCH2Ph), 66.4 (CH2-6), 66.3 (CH-2), 65.8 (CH2-1), 63.9 (1 mL) were added. The reaction was stirred during 3 h at room
Eur. J. Org. Chem. 1999, 3021Ϫ3026
3025

´
G. Solladie, N. Wilb, C. Bauder
FULL PAPER
[1]
P. Ganis, G. Avitabile, W. Mechlinski, C. P. Schaffner, J. Am.
Chem. Soc. 1971, 93, 4560Ϫ4564.
temperature and then diluted with ether (5 mL) before being
quenched with sat. NaHCO3. This mixture was stirred at room
temperature for 1 h and then diluted with water (5 mL). The aque-
ous layer was acidified to pH 1 with 20% HCl and then extracted
with AcOEt (2 ϫ 5 mL). The combined organic extracts were
washed with brine (15 mL), dried (MgSO4), filtered and evapo-
rated. The crude residue was purified by chromatography on silica
gel (AcOEt/hexane, 2:8) to obtain the alkyne (Ϫ)-2 as a colorless
[2] [2a]
J. M. Brown, A. E. Derome, S. J. Kimber, Tetrahedron Lett.
[2b]
1985, 26, 253Ϫ256. Ϫ
B. DeKruijff, R. A. Demmel, Bi-
ochim. Biophys. Acta 1974, 339, 57Ϫ70.
[3a] A. W. Taylor, D. T. MacPherson, Tetrahedron Lett. 1994, 35,
[3]
5289Ϫ5292. Ϫ [3b] B. J. Costello, M. J. Driver, W. S. McLachlan,
[3c]
A. W. Taylor, J. Chem. Soc., Perkin I 1993, 1829Ϫ1830. Ϫ
D. F. Corbett, D. K. Dean, A. R. Greenlees, D. T. McPherson,
J. Antibiot. 1995, 48, 509.
[4] [4a]
20
1
K. C. Nicolaou, R. A. Daines, J. Uenishi, W. S. Li, D. P.
oil (58 mg, 64%). Ϫ [α]D ϭ Ϫ19 (c ϭ 1.16, CHCl3). Ϫ H NMR
(200 MHz, CDCl3): δ ϭ 7.37Ϫ7.28 (m, 5 H, Ph), 4.66 (dt, 1 H, H-
Papahatjis, T. K. Chakraborty, J. Am. Chem. Soc. 1988, 110,
4672Ϫ4685. Ϫ [4b] K. C. Nicolaou, R. A. Daines, T. K. Chakra-
borty, Y. Ogawa, J. Am. Chem. Soc. 1988, 110, 4685Ϫ4696. Ϫ
[4c] K. C. Nicolaou, R. A. Daines, Y. Ogawa, T. K. Chakraborty,
J. Am. Chem. Soc. 1988, 110, 4696Ϫ4705.
5, 3J ϭ 11.1 Hz, 4J ϭ 2.7 Hz), 4.50 [d, 2 H, CH2 (OBn), J
ϭ
1.6 Hz], 4.12Ϫ3.99 (m, 1 H, H-3), 3.66Ϫ3.47 (m, 2 H, H-1), 2.46
(d, 1 H, H-7, J ϭ 2.1 Hz), 1.81Ϫ1.60 (m, 4 H, H-2 ϩ H-4), 1.45
(s, 3 H, CH3, acetonide), 1.43 (s, 3 H, CH3, acetonide). Ϫ 1H NMR
(200 MHz, C6D6): δ ϭ 7.29Ϫ7.06 (m, 5 H, Ph), 4.36 (dt, 1 H, H-
5, 3J ϭ 11.7 Hz, 4J ϭ 2.4 Hz), 4.27 [d, 2 H, CH2 (OBn), J ϭ
3.3 Hz], 4.20Ϫ3.69 (m, 1 H, H-3), 3.50Ϫ3.24 (m, 2 H, H-1), 2.04
(d, 1 H, H-7, J ϭ 2.1 Hz), 1.77Ϫ1.48 (m, 3 H, H-2 ϩ H-4ax), 1.46
[5] [5a]
D. Boschelli, T. Takemasa, Y. Nishitani, S. Masamune,
Tetrahedron Lett. 1985, 26, 5239Ϫ5242. Ϫ [5b] P. Ma, V. S. Mar-
tin, S. Masamune, K. B. Sharpless, S. M. Viti, J. Org. Chem.
1982, 47, 1378Ϫ1380. Ϫ [5c] R. M. Kennedy, A. Abiko, T. Take-
masa, H. Okumoto, S. Masamune, Tetrahedron Lett. 1988, 29,
[5d]
451Ϫ454. Ϫ
S. Masamune, P. Ma, H. Okumoto, J. W. El-
lingboe, Y. Ito, J. Org. Chem. 1984, 49, 2834Ϫ2837.
3
[6] [6a]
(s, 3 H, CH3, acetonide), 1.34 (dt, 1 H, H-4eq, J ϭ 12.9 Hz, J ϭ
G. J. McGarvey, J. A. Mathys, K. J. Wilson, K. R. Overly,
2.7 Hz), 1.33 (s, 3 H, CH3, acetonide). Ϫ 13C NMR (CDCl3): δ ϭ
139.1 (C arom.), 129.1 (C arom.), 128.3 (CH arom.), 99.9 (C, ace-
tonide), 83.3 (C-6), 75.3 (CH2, OBn), 73.7 (CH-7), 66.5 (CH2-1),
66.2 (CH-5), 60.9 (CH-3), 37.9 (CH2-4), 36.9 (CH2-2), 30.8 (CH3,
acetonide), 20.1 (CH3, acetonide). Ϫ C17H22O3 (274.36): calcd. C
74.42, H 8.08; found C 72.86, H 7.87.
P. T. Buonora, P. G. Spoors, J. Org. Chem. 1995, 60,
[6b]
7778Ϫ7790. Ϫ
G. J. McGarvey, J. A. Mathys, K. J. Wilson,
[6c]
J. Org. Chem. 1996, 61, 5704Ϫ5705. Ϫ
G. J. McGarvey, J.
M. Williams, R. N. Hiner, Y. Matsubara, T. Oh, J. Am. Chem.
Soc. 1986, 108, 4943Ϫ4952.
[7]
S. Hanessian, S. P. Sahoo, M. Botta, Tetrahedron Lett. 1987, 28,
1143Ϫ1146. This type of approach was also used by Carreira et
al., see ref.[10]
[8] [8a]
(3S,5S,9R,11R)-1-Benzyloxy-13-(tert-butyldimethylsilyloxy)-8-
hydroxy-syn-3,5:9,11-(diisopropylidenedioxy)tridec-6-yne (1a and
1b): BuLi (36 µmol, 1.05 equiv.) was added to a solution of the
alkyne (Ϫ)-2 (9.5 mg, 35 µmol) at Ϫ75°C in dry THF (0.5 mL).
The reaction was stirred for 1 h at 0°C and then cooled to Ϫ75°C
again before adding the aldehyde (ϩ)-3 (10 mg, 35 µmol) in solu-
tion in THF (0.5 mL). The reaction was left overnight and the tem-
perature allowed to reach room temperature slowly. The solution
was diluted with ether (3 mL) and the reaction was quenched by
adding sat. NH4Cl (3 mL). The aqueous layer was extracted with
ether (3 ϫ 5 mL) and the combined organic extracts were dried
(MgSO4) and concentrated to give a crude colorless oil (21 mg),
which was purified by tlc to separate the mixture 1a/1b (57%) from
the unchanged aldehyde (ϩ)-3 and alkyne (Ϫ)-2. The mixture (24/
76) of the two isomers 1a (the desired 8R isomer) and 1b (the 8S
isomer) was purified by tlc (triple migration) to afford a pure ana-
D. Liang, B. Fraser-Ried, J. Chem. Soc., Chem. Commun.
1984, 1123Ϫ1125. Ϫ [8b] D. Liang, H. W. Pauls, B. Fraser-Ried,
M. Georges, A. M. Mubarak, S. Jarosz, Can. J. Chem. 1986, 64,
1800Ϫ1809. Ϫ [8c] M. Kinoshita, M. Morioka, M. Tanigughi, J.
[8d]
Shimizu, Bull. Chem. Soc. Jpn. 1987, 60, 4005Ϫ4014. Ϫ
David, A. Malleron, New. J. Chem. 1993, 17, 505Ϫ511. Ϫ
S.
[8e]
A. Fürstner, J. Baumgartner, Tetrahedron 1993, 49, 8541Ϫ8560.
[9]
´
G. Solladie, J. Hutt, Tetrahedron Lett. 1987, 28, 797Ϫ800.
[10]
J. Krüger, E. M. Carreira, Tetrahedron Lett. 1998, 39,
7013Ϫ7016.
[11]
We presented these results in a short communication at 7th
Belgian Organic Synthesis Symposium (BOSS), Louvain-la-
Neuve, Belgium, July 5Ϫ9, 1998; and they are described in the
´
PhD thesis of N. Wilb, Universite Louis Pasteur of Strasbourg,
November 27, 1998.
[12]
´
G. Solladie, N. Ghiatou, Tetrahedron Lett. 1992, 33,
1605Ϫ1608.
[13]
[14]
´
G. Solladie, C. Dominguez, J. Org. Chem. 1994, 59, 3898Ϫ3901.
G. Solladie, N. Ghiatou, Tetrahedron: Asymmetry 1992, 3,
´
33Ϫ38.
20
lytic sample of the 1b isomer {[α]D ϭ ϩ10 (c ϭ 0.19, CHCl3)}.
[15]
´
G. Solladie, C. Bauder, L. Rossi, J. Org. Chem. 1995, 60,
Mixture of two diastereomers: 1H NMR (200 MHz, CDCl3): δ ϭ
7.34 (m, 5 H, Ph), 4.70 (m, 1 H, H-9), 4.52 [A of AB, 1 H, CH2
(OBn), JAB ϭ 12.3 Hz, ∆ν ϭ 7 Hz], 4.49 [B of AB, 1 H, CH2 (OBn),
JAB ϭ 12.3 Hz, ∆ν ϭ 7 Hz], 4.25Ϫ3.90 (m, 3 H, H-3 ϩ H-5 ϩ H-
11), 3.80Ϫ3.46 (m, 4 H, H-1 ϩ H-13), 2.66 (d, 0.76 H, OH of
isomer 8S, J ϭ 3.5 Hz), 2.38 (d, 0.24 H, OH of isomer 8R, J ϭ
4.4 Hz), 1.80Ϫ1.65 (m, 8 H, H-2 ϩ H-4 ϩ H-10 ϩ H-12), 1.58 (s,
3 H, CH3, acetonide), 1.44 (s, 3 H, CH3, acetonide), 1.42 (s, 3 H,
CH3, acetonide), 1.40 (s, 3 H, CH3, acetonide), 0.90 (s, 9 H, SitBu),
0.06 (s, 6 H, SiMe2). Ϫ 13C NMR (CDCl3): δ ϭ 138.5 (C arom.),
128.5 (CH arom.), 127.8 (CH arom.), 99.3 (C, acetonide), 99.1 (C,
acetonide), 85.2 (C-7), 81.4 (C-8), 73.2 (CH2, OBn), 71.5 (CH-6),
65.9 (CH2-13), 66.7 (CH-9), 65.3 (CH-3), 64.8 (CH-5), 60.5 (CH-
11), 58.8 (CH2-1), 39.5 (CH2-2), 37.5 (CH2-4), 36.3 (CH2-10), 30.2
(CH3, acetonide), 30.1 (CH3, acetonide), 30.0 (CH2-12), 26.0 (CH3,
SitBu), 20.1 (CH3, acetonide), 19.5 (CH3, acetonide), 18.4 (C,
SitBu), Ϫ5.3 (SiCH3). Ϫ C32H53O7Si (577.84): calcd. C 66.51, H
9.24; found C 66.38, H 9.19.
7774Ϫ7777.
[16] [16a]
´
G. Solladie, N. Huser, Tetrahedron: Asymmetry 1995, 6,
2679Ϫ2682. Ϫ [16b] G. Solladie, L. Gressot-Kempf, Tetrahedron:
´
Asymmetry 1996, 6, 2679Ϫ2379. Ϫ [16c] G. Solladie, F. Colobert,
´
D. Denni, Tetrahedron: Asymmetry 1998, 9, 3081Ϫ3094.
J. G. Batelaan, Synth. Commun. 1976, 6, 81Ϫ83.
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[17]
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[19] [19a]
[19b]
K. Narasaka, F. C. Pai, Chem. Lett. 1980, 1415Ϫ1418. Ϫ
K. Narasaka, F. C. Pai, Tetrahedron 1984, 40, 2233Ϫ2238.
Ϫ
[19c] K. M. Chen, G. E. Hardtmann, K. Prasad, O. Repic, M.
J. Shapiro, Tetrahedron Lett. 1987, 28, 155Ϫ158.
S. D. Rychnovsky, D. J. Skalitzky, Tetrahedron Lett. 1990, 31,
945Ϫ948.
[20]
[21]
[22]
S. Müller, B. Liepold, G. Roth, H. J. Bestmann, Synlett 1996,
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E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 3769Ϫ3772.
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A. K. Sharma, D. Swern, Tetrahedron Lett. 1974,
[23b]
1503Ϫ1506. Ϫ
thesis 1978, 881. Ϫ
H. Sugihara, R. Tanikaya, A. Kaji, Syn-
[23c]
P. Bravo, M. Frigerio, G. Resnati, J.
Org. Chem. 1990, 55, 4216Ϫ4218.
[O99194]
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Eur. J. Org. Chem. 1999, 3021Ϫ3026