Enantioselective synthesis of C2-symmetric hexols from β-δ- diketosulfoxides

Article abstract of DOI:10.1016/S0957-4166(98)00301-2

An enantioselective synthesis of (1,2S,4S,8S,10S,11)- hexahydroxyundecane, a C₂-symmetric hexol precursor of the alkaloid (-)- lythranidine, is described. This convergent synthesis was based on the stereoselective reduction of two different β-δ

Full text of DOI:10.1016/S0957-4166(98)00301-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3081–3094
Enantioselective synthesis of C2-symmetric hexols from
β,δ-diketosulfoxides
Guy Solladié,∗ Françoise Colobert and Donatienne Denni
Université Louis Pasteur (ECPM), Laboratoire de Stéréochimie associé au CNRS, 1 rue Blaise Pascal, 67008 Strasbourg,
France
Received 20 July 1998; accepted 28 July 1998
Abstract
An enantioselective synthesis of (1,2S,4S,8S,10S,11)-hexahydroxyundecane, a C2-symmetric hexol precursor of
the alkaloid (−)-lythranidine, is described. This convergent synthesis was based on the stereoselective reduction of
two different β,δ-diketosulfoxides. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Following our previous results on the asymmetric synthesis of enantiomerically pure 2,6-disubstituted
pyridines,1 we were interested in the piperidine alkaloid (−)-lythranidine2,3 which has never been
synthesized in enantiomerically pure form.
A possible precursor of this macrocycle could be the tetrahydroxylated piperidine derivative A which
can be obtained from the enantiomerically pure hexol 1 by the methodology we have already described1
for the synthesis of simple piperidine derivatives. We report in this paper a convergent synthesis of
the hexol 1 from the two diketosulfoxides 4 and 5 which can be made from (+)-(R)-menthyl p-
toluenesulfinate or (−)-(S)-methyl-p-tolylsulfoxide (Scheme 1).
2. Results and discussion
The sulfinyl diketoester 5 was prepared from the diketoester 6 which was obtained in one step
from commercially available dehydroacetic acid by a known procedure.4 Condensation of the trianion
of 6, prepared in THF with 1 equiv. of NaH and 2 equiv. of t-BuLi at 0°C, to (+)-menthyl (R)-p-
toluenesulfinate5 afforded in 80% yield the (S)-diketosulfoxide 5 (Scheme 2).
∗
Corresponding author. Fax: 33 3 88 61 65 31; e-mail: solladie@chimie.u-strasbg.fr
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00301-2
tetasy 2450 Article

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Scheme 1.
Scheme 2.
Similarly the (S)-diketosulfoxide 4 was prepared by condensation of the dianion of the β-
ketosulfoxide6 7 (prepared from (−)-(S)-methyl-p-tolylsulfoxide and ethyl acetate in 90% yield) with
the ethyl benzyloxyglycolate. The 1H NMR spectrum of compounds 4 and 5 showed as expected7 that
only the δ-carbonyl was entirely enolized (Scheme 3).
Following our previous results,7 the diastereoselective reduction of the β-carbonyl of the (S)-β,δ-
dicarbonyl sulfoxides 4 and 5 was carried out with 2 equiv. of DIBAL in THF at −78°C. Only one
1
diastereomer of the resulting β-hydroxy-δ-ketosulfoxides 8 and 9 was detected from the 200 MHz H
NMR spectrum of the crude product. The absolute configuration of the compounds 8 and 9 was deduced
from our previous results.7 The large non-equivalence (∆ν=61 and 71 Hz) of the two methylenic protons
α to the sulfinyl group was always observed for a (SS,3R) relative configuration. Yields of the isolated
product (compared to our previous results7) were improved by using purification by crystallization
followed by washing the solids 8 and 9 with ether instead of the usual purification by chromatography
on metal-free silica gel which decomposed the products.
8
In the next step, the δ-carbonyl was reduced to the anti-diol with (Me)4NHB(OAc)3 in good yields:

G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
3083
Scheme 3.
75% for compound 10 and 95% for compound 11 (de >98%). The hydroxylic groups were protected with
2,2-dimethoxypropane (DMP) and the resulting acetonides 10a and 11a were submitted to a Pummerer
rearrangement with acetic anhydride and sodium acetate (Scheme 4).
The intermediate 13 was reduced with lithium aluminium hydride in ether. The six-membered
acetonide was then isomerized in an acidic medium to the thermodynamically more stable9 five-
membered ketal 15.
Protection of the secondary OH with tert-butyl dimethylsilylchloride and debenzylation of the primary
alcohol gave the compound 17 in 88% yield.
The other Pummerer intermediate 12 was desulfurized with Raney nickel and the resulting acetate was
hydrolyzed under mild conditions (K2CO3) followed by thermodynamic isomerization of the acetonide
in an acidic medium affording the alcohol 14 in 55% overall yield. The ester 14 was then transformed by
reduction with lithium aluminium hydride into the corresponding diol 16.
Finally, the two synthons 16 and 17 were modified for coupling via a Wittig reaction: the alcohol
16 was transformed into the phosphonium salt 3 in 60% yield, and the aldehyde 2 obtained from the
alcohol 17 by a Swern oxidation (Scheme 5). The Wittig reaction between the phosphonium salt 3 and
the aldehyde 2 was carried out in the presence of 2 equiv. of BuLi and lithium bromide to give the
olefin 18 in 50% yield. Reduction of the double bond and deprotection of the silylated ether afforded the
C2-symmetric pure hexol 1 in 77% yield.
This procedure could be very easily applied to the preparation of all the other stereoisomers just by
changing the absolute configuration of the starting sulfoxide and forming either the syn- or anti-diol by
known procedures.8,10
3. Experimental
3.1. Ethyl benzyloxyglycolate
To a cold (0°C) solution of ethyl glycolate (7.3 ml, 76.84 mmol) in dry THF (120 ml) was added
sodium hydrate (1.87 g, 77.86 mmol), tetrabutylammonium iodide (2.84 g, 7.864 mmol) and benzyl
bromide (9.2 ml, 77.35 mmol). The reaction mixture was then stirred at room temperature until no more
starting material was detected by TLC (hexane:AcOEt=6:1). The reaction mixture was then cooled and
hydrolyzed with a saturated ammonium chloride solution (100 ml). The aqueous layer was extracted with
AcOEt (3×100 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and
evaporated. Chromatography on silica gel of the residue (hexane and then gradient hexane/AcOEt) gave
benzyloxyglycolate as a pale yellow oil (10.59 g, 71%); Rf 0.40 (hexane:AcOEt=6:1); 1H NMR (CDCl3,

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Scheme 4.
200 MHz): δ 1.30 (t, 3H, H-4), 4.10 (s, 2H, OCH2Ph), 4.24 (q, 2H, H-3), 4.65 (s, 2H, H-1), 7.36 (m, 5H,
H arom.); 13C NMR (CDCl3): δ 14.15 (C-4), 60.80 (C-3), 67.18 (OCH2Ph), 73.27 (C-1), 127.95, 128.02,
128.43 (C-H arom.), 137.07 (Cq arom.), 170.28 (C-2); IR (CHCl3) 2860–2980, 1720–1760, 1630–1600,
1520–1490 cm−1. Anal. calcd for C11H14O3: C, 68.02; H, 7.26. Found: C, 68.16; H, 7.28.

G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
3085
Scheme 5.
3.2. (−)-S(S) 5-Benzyloxy-2,4-dioxo-1-(p-tolylsulfinyl) pentane, 4
To a solution of LDA (161.7 mmol) in THF (290 ml) cooled at 0°C, was added a solution of (−)-(S)-1-
(p-tolylsulfinyl)-2-propanone6 7 (15.62 g, 79.5 mmol) in THF (190 ml). After stirring for 30 min at 0°C
this solution was dropwise added to a solution of ethyl benzyloxyglycolate (4.98 g, 25.67 mmol) in THF
(190 ml) cooled at 0°C. The reaction mixture was stirred at room temperature for 30 min, hydrolyzed
with water (150 ml) and acidified to pH 3–4 with an aqueous 5% H2SO4 solution. The aqueous layer
was extracted with AcOEt (3×200 ml). The combined organic layers were washed with brine, dried
(MgSO4) and concentrated. The crude product was purified by column chromatography on metal-free
silica gel (gradient hexane:AcOEt=8:1 to hexane:AcOEt=5:5) to afford the (−)-S(S)-5-benzyloxy-2,4-
dioxo-1-(p-tolylsulfinyl) pentane as an orange oil (6.19 g, 70%); Rf 0.44 (AcOEt 100%); [α]D=−208
1
(c 2.0, acetone); H NMR (CDCl3, 200 MHz): δ 2.40 (s, 3H, Me p-Tol), 3.68 (AB, 2H, JAB=0.06 Hz,
∆ν=0.38 Hz, H-1), 4.07 (s, 2H, OCH2Ph), 4.21 (s, 2H, H-5), 5.88 (s, 1H, H-3), 7.5 (m, 9H, H arom.);
13C NMR (CDCl3): δ 19.01 (Me p-Tol), 62.63 (C-1), 68.71 (OCH2Ph), 72.46 (C-5), 97.08 (C-3), 121.64,
125.42, 125.62, 126.10, 127.58 (C-H arom.), 134.58, 137.34, 139.77 (Cq arom.), 177.80 (C-4), 191.80
(C-2); IR (CHCl3) 3690, 2840–3020, 1695, 1038 cm−1. Anal. calcd for C19H20O4S: C, 66.25; H, 5.85.
Found: C, 66.35; H, 6.02.
3.3. (−)-[2(R),S(S)]-5-Benzyloxy-2-hydroxy-4-oxo-1-(p-tolylsulfinyl) pentane, 9
To a solution of the β,δ-diketosulfoxide 4 (3.24 g, 9.4 mmol) in THF (300 ml) was dropwise added
at −78°C a solution of DIBAL-H (18.3 ml of a 1 M solution in toluene; 18.8 mmol). Stirring was
continued for 30 min before adding MeOH (150 ml) and then the solution was stirred for 30 min at
room temperature. The solvent was evaporated and the residue was dissolved in AcOEt (200 ml), and
saturated disodium L-tartrate dihydrate (200 ml) was added. The stirring was continued until a clear
phase-separation occurred. The aqueous layer was acidified to pH=5–6 with a 10% solution of HCl and
extracted with AcOEt (3×200 ml). The combined organic layers were washed with brine (200 ml), dried
(MgSO4), and concentrated to afford a solid residue. The crude product was washed with ether (4×20

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G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
ml) to afford the β-hydroxy-δ-ketosulfoxide 9 as an ivory solid (1.66 g, 51%); Rf 0.48 (AcOEt 100%);
1
[α]D=−176 (c 2.0, acetone); H NMR (CDCl3, 200 MHz): δ 2.41 (s, 3H, Me p-Tol), 2.62 (d, 2H, H-
3), 2.90 (AB of ABX, 2H, JAB=13.8 Hz; JAX=3.2 Hz; JBX=9.7 Hz, ∆ν=61.2 Hz, H-1), 4.05 (s, 2H,
OCH2Ph), 4.28 (d, 1H, OH), 4.55 (s, 2H, H-5), 4.60 (m, 1H, H-2), 7.53 (m, 9H, H arom.); 13C NMR
(CDCl3): δ 21.53 (Me p-Tol), 45.37 (C-3), 61.49 (C-1), 63.22 (C-2); 73.50 (C-6), 75.44 (C-5), 127.09,
128.02, 128.19, 128.64, 130.22 (C–H arom.), 136.99, 139.46, 141.82, 207.57 (Cq arom.); IR (CHCl3)
3400, 2860–2980, 1700–1720, 1595–1570, 1460–1510 cm−1. Anal. calcd for C19H22O4S: C, 65.87; H,
6.40. Found: C, 65.95; H, 6.60.
3.4. (−)-[2(R),4(R),S(S)]-5-Benzyloxy-2,4-dihydroxy-1-(p-tolylsulfinyl) pentane, 11
A solution of tetramethylammonium triacetoxyborohydride (10.10 g, 38.33 mmol) in anhydrous acetic
acid (67 ml) was stirred at ambient temperature for 30 min. The mixture was cooled at 0°C, and a solution
of β-hydroxy-δ-ketosulfoxide 9 (1.66 g, 4.80 mmol) in acetic acid (80 ml) was added via cannula. The
mixture was stirred at room temperature for 2 h. The reaction was quenched at 0°C with water (100
ml) and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic
layers were washed with a saturated solution of sodium hydrogenocarbonate, brine, dried (MgSO4),
and concentrated to afford a solid residue. The crude product was washed with ether to afford the
β,δ-dihydroxysulfoxide 11 as an ivory solid (1.59 g, >95%); Rf 0.29 (AcOEt 100%); [α]D=−134 (c
1
0.5, DMSO); H NMR (CDCl3, 200 MHz): δ 1.60 (m, 2H, H-3), 2.42 (s, 3H, Me p-Tol), 2.92 (AB
of ABX, 2H, JAB=13.6 Hz; JAX=9.6 Hz; JBX=2.1 Hz, ∆ν=88.5 Hz, H-1), 3.42 (AB of ABX, 2H,
J
AB=9.4 Hz; JAX=7.2 Hz; JBX=4.0 Hz, ∆ν=21.2 Hz, H-5), 4.04 (m, 1H, H-4), 4.50 (m, 1H, H-2), 4.52
(s, 2H, OCH2Ph), 7.40 (m, 9H, H arom.); 13C NMR (CDCl3): δ 21.43 (Me p-Tol), 39.26 (C-1), 61.03
(C-3), 64.81 (C-4), 67.58 (C-2), 73.39 (OCH2Ph), 74.15 (C-5), 124.04, 127.76, 128.49, 130.13 (C–H
arom.), 137.80, 139.00, 141.65 (Cq arom.); IR (CHCl3) 3330, 2840–2900, 1020 cm−1. Anal. calcd for
C19H24O4S: C, 65.5; H, 7.28. Found: C, 65.36; H, 6.90.
3.5. Methyl 3,5-dioxohexanoate, 6
Magnesium turnings (7.8 g, 0.32 mol) were dissolved in 1.5 l methanol and dehydroacetic acid (36 g,
0.21 mol) in methanol (300 ml) was added. The reaction mixture was heated under reflux for 10 h, after
which the solvent was distilled under reduced pressure. The residue was dissolved in ethyl acetate and
acidified with aqueous 1 M HCl (650 ml) and extracted with ethyl acetate (5×200 ml). The combined
organic layers were washed with brine, dried over MgSO4 and concentrated. The crude product was
distilled under reduced pressure (91°C/0.6 mmHg) to afford a colorless liquid (27 g, 80%); Rf 0.82
(AcOEt:CH2Cl2=5:5). The 1H NMR spectrum indicated the presence of 83% of an enol form, 1H NMR
(CDCl3, 200 MHz): enol, δ 2 (s, 3H, H-6), 3.27 (s, 2H, H-2), 3.66 (s, 3H, OMe), 5.54 (s, 1H, H-4);
ketone: 2.17 (s, 3H, H-6), 3.50 (s, 2H, H-2), 3.66 (s, 3H, OMe), 3.68 (s, 2H, H-4); 13C NMR (CDCl3):
enol, δ 23.4 (C-6), 44.1 (C-2), 51.5 (OMe), 99.9 (C-4), 167.3 (C-1), 186.9 (C-5), 189.5 (C-3); ketone:
29.9 (C-6), 48.5 (C-2), 51.5 (OMe), 56.4 (C-4), 166.8 (C-1), 196.7 (C-5), 201.4 (C-3).
3.6. (−)-S(S) Methyl 3,5-dioxo-6-(p-tolylsulfinyl) hexanoate, 5
To a suspension of NaH (1.82 g, 75.8 mmol) in dry THF (250 ml) at 0°C was added dropwise a solution
of methyl 3,5-dioxohexanoate (11.86 g, 75 mmol) in THF (50 ml). The mixture rapidly became a thick
white suspension. At 0°C, tert-butyllithium (100 ml of a 1.5 M pentane solution; 0.15 mol) was then

G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
3087
quickly added with a cannula over a period of 15 min. The solution turned yellow, orange, and finally
deep red as the addition progressed. The (+)-menthyl (R)-p-toluenesulfinate5 (11.04 g, 37.5 mmol) in
solution in THF (45 ml) was then added dropwise within 20 min. Stirring at 0°C was continued for
2 h until all the sulfinate was consumed (TLC). The reaction was quenched with a saturated solution
of NH4Cl (120 ml), diluted with AcOEt (100 ml), and then acidified to pH 3 with a 10% solution of
H2SO4. The aqueous layer was extracted with AcOEt (4×200 ml). The combined organic layers were
washed with brine (200 ml), dried over MgSO4, and filtered before being concentrated. The crude oily
residue was purified by rapid chromatography on metal-free silica gel (hexane and CH2Cl2) to give an
orange oil which was crystallized (diethyl ether) to afford (−)-S(S) methyl 3,5-dioxo-6-(p-tolylsulfinyl)
hexanoate 5 as pale yellow prisms (7.8 g, 70%); Rf 0.42 (AcOEt:CH2Cl2=5:5); [α]D=−262 (c 1, CHCl3);
1
mp=51–53°C; H NMR (CDCl3, 200 MHz): δ 2.39 (s, 3H, Me p-Tol), 3.34 (s, 2H, H-2), 3.62 (AB of
ABX, 2H, JAB=8 Hz, ∆ν=17 Hz, H-6), 3.71 (s, 3H, OMe), 5.64 (s, 1H, H-4), 7.40 ((AB)2, 4H, JAB=8
Hz, ∆ν=39 Hz, H arom.), 14.4 (s, 1H, H enol); 13C NMR (CDCl3): δ 21.4 (Me p-Tol), 45.1 (C-2), 52.5
(OMe), 64.7 (C-6), 102.7 (C-4), 123.99, 130 (C–H arom.), 139.5, 142.3 (Cq arom.), 167.3 (C-1), 179.5
(C-3), 188.8 (C-5).
3.7. (−)-[5(R)S(S)] Methyl 5-hydroxy 3-oxo-6-(p-tolylsulfinyl) hexanoate, 8
To a solution of the β,δ-diketosulfoxide 5 (1 g, 3.39 mmol) in THF (100 ml) at −78°C was added
dropwise a solution of DIBAL-H (6.77 ml of a 1 M solution in toluene, 6.78 mmol). Stirring was
continued for 30 min before adding MeOH (30 ml) and then the solution was stirred 30 min at
room temperature. The solvent was evaporated and the residue was dissolved in AcOEt (30 ml), and
saturated disodium L-tartrate dihydrate (30 ml) was added. The stirring was continued until a clear
phase-separation occurred. The aqueous layer was acidified to pH=5–6 with a 10% solution of HCl and
extracted with AcOEt (3×50 ml). The combined organic layers were washed with brine (50 ml), dried
(MgSO4), and concentrated to afford a solid residue. The crude product was washed with ether (4×10
ml) to afford the β-hydroxy-δ-ketosulfoxide 8 as an ivory solid (0.61 g, 60%); Rf 0.44 (AcOEt 100%);
[α]D=−202 (c 0.82, CHCl3); 1H NMR (CDCl3, 200 MHz): δ 2.43 (s, 3H, Me p-Tol), 2.74 (A of ABX,
1H, JAB=13.6 Hz; JAX=2.5 Hz, ∆ν=70.9 Hz, H-6), 2.81 (d, 2H, H-4), 3.07 (B of ABX, 1H, JAB=13.6 Hz;
J
BX=9.5 Hz, ∆ν=70.9 Hz, H-6), 3.48 (s, 2H, H-2), 3.72 (s, 3H, OMe), 4.21 (d, 1H, OH), 4.63 (m, 1H,
H-5), 7.44 (AB, 4H, JAB=8.2 Hz, ∆ν=34.1 Hz, H arom.); 13C NMR (CDCl3): δ 21.52 (Me p-Tol), 49.09
(C-2), 49.67 (C-4), 52.58 (OMe), 60.53 (C-6), 63.57 (C-5), 124.07, 130.25, (C-arom.), 139.26, 141.76
(Cq arom.), 173.65 (C-1), 201.60 (C-3); IR (CHCl3) 1700–1735, 2940–3020, 3400 cm−1. Anal. calcd for
C14H18O5S: C, 56.36; H, 5.78. Found: C, 56.33; H, 5.78.
3.8. (−)-[5(R)3(R)S(S)] Methyl-3,5-dihydroxy 6-(p-tolylsulfinyl) hexanoate, 10
A solution of tetramethylammonium triacetoxyborohydride (6.35 g, 24.13 mmol) in anhydrous acetic
acid (44 ml) was stirred at ambient temperature for 30 min. The mixture was cooled at 0°C, and a solution
of β-hydroxy-δ-ketosulfoxide 8 (900 mg, 3.02 mmol) in acetic acid (45 ml) was added via cannula. The
mixture was stirred at room temperature for 2 h. The reaction was quenched at 0°C with water (100
ml). The aqueous layer was extracted with dichloromethane (3×100 ml). The combined organic layers
were washed with a saturated solution of sodium hydrogenocarbonate and with brine, dried (MgSO4),
and concentrated to afford a solid residue. The crude product was washed with ether to afford the β,δ-
dihydroxysulfoxide 10 as an ivory solid (680 mg, 75%); Rf 0.18 (AcOEt 100%); [α]D=−172 (c 1.0,
DMSO); 1H NMR (CDCl3, 200 MHz): δ 1.60–1.74 (m, 2H, H-4), 2.42 (s, 3H, Me p-Tol), 2.50 (m, 2H,

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G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
H-2), 2.93 (AB of ABX, 2H, JAB=13.4 Hz; JAX=9.9 Hz; JBX=2.1 Hz, ∆ν=71.1 Hz, H-6), 3.69 (s, 3H,
H-5), 3.77 (d, 1H, J=3.53 Hz, MeO), 4.33 (m, 1H, OH), 4.52 (m, 1H, H-5), 4.65 (d, 1H, J=3.4 Hz), 7.43
((AB)2, 4H, JAB=8.1 Hz, ∆ν=34.4 Hz, H arom.); 13C NMR (CDCl3): δ 21.44 (Me p-Tol), 41.30 (C-4),
42.44 (C-2), 51.80 (OMe), 61.88 (C-6), 64.01 (C-3), 64.93 (C-5), 124.04, 130.17 (C–H arom.), 139.26,
147.77 (Cq arom.), 172.66 (C-1); IR (CHCl3) 3420, 2960–3040, 1725 cm−1. Anal. calcd for C14H20O5S:
C, 55.98; H, 6.71. Found: C, 55.92; H, 6.70.
3.9. (−)-[2(R)4(R)S(S)]-5-Benzyloxy-2,4-(isopropylidenedioxy)-1-(p-tolylsulfinyl)-pentane, 11a
The dihydroxysulfoxide 11 (1.46 g, 4.20 mmol) and catalytic p-TsOH (80 mg, 0.42 mmol) were
dissolved in dimethylformamide (154 ml) and dimethoxypropane (6.20 ml). Stirring at room temperature
was continued until all starting material disappeared (TLC). The reaction mixture was diluted in AcOEt
(50 ml) and saturated NaHCO3 (50 ml) was added. The reaction was stirred at room temperature to obtain
a white precipitate. The aqueous layer was extracted with AcOEt (3×50 ml). The combined organic
layers were washed with a saturated solution of NH4Cl (50 ml) and with brine (50 ml), dried over MgSO4,
and filtered before being concentrated. The crude product was purified by column chromatography
on silica gel (CH2Cl2:AcOEt=6:4) to give a yellow oil (1.55 g, 95%); Rf 0.50 (CH2Cl2:AcOEt=6:4);
1
[α]D=−110 (c 2.0, CHCl3); H NMR (CDCl3, 200 MHz): δ 1.43 (s, 3H, Me acetal), 1.49 (s, 3H, Me
acetal), 1.60 (m, 2H, H-3), 2.40 (s, 3H, Me p-Tol), 2.78 (AB of ABX, 2H, JAB=13.2 Hz; JAX=9.1 Hz;
JBX=4.0 Hz, ∆ν=19.3 Hz, H-1), 3.48 (AB of ABX, 2H, JAB=10.3 Hz; JAX=4.5 Hz; JBX=6.2 Hz, ∆ν=23.6
Hz, H-5), 4.09 (m, 1H, H-4), 4.45 (m, 1H, H-2), 4.57 (AB, 2H, JAB=12 Hz, ∆ν=11.9 Hz, OCH2Ph), 7.31
(m, 9H, H arom.); 13C NMR (CDCl3): δ 21.28 (Me p-Tol), 24.54–24.82 (C-8 and C-7), 33.98 (C-1),
60.95 (C-4), 64.01 (C-3), 66.12 (C-2), 72.30 (OCH2Ph), 73.27 (C-5), 101.06 (C-6), 123.68, 127.54,
127.58, 128.26, 129.66 (C arom.), 136.04, 141.26, 141.42 (Cq arom.); IR (CHCl3) 2840–2910, 1010
cm−1. Anal. calcd for C22H28O4S: C, 68; H, 7.21. Found: C, 67.9; H, 7.21.
3.10. [2(R)4(R)]-1-Acetoxy-5-benzyloxy-2,4-(isopropylidenedioxy)-1-(p-tolylthio)-pentane, 13
Anhydrous sodium acetate (0.15 g, 1.81 mmol) was added to the preceding sulfoxide (58.5 mg, 0.15
mmol). Acetic anhydride (5 ml) was then added, and the mixture was refluxed (135°C) until all the
sulfinate was consumed (TLC). After cooling, the solvent was removed by azeotropic distillation with
toluene to obtain a deep brown solid which was diluted in CH2Cl2 and filtered through Celite. The crude
product was purified by column chromatography on silica gel (hexane:AcOEt=9:1) to afford 13 as a
yellow oil (45.4 mg, 70%), a mixture of the two isomers at the C1 position which were not separated.
1H NMR (CDCl3, 200 MHz): major isomer, δ 1.36 (s, 3H, H-7), 1.40 (s, 3H, H-8), 1.77 (m, 2H, H-3),
2.07 (s, 3H, MeCOO), 2.33 (s, 3H, Me p-Tol), 3.46 (m, 2H, H-5), 4.08 (m, 2H, H-2 and H-4), 4.58 (AB,
2H, JAB=12.3 Hz, ∆ν=11 Hz, OCH2Ph), 7.26 (m, 9H, H arom.); minor isomer, δ 1.36 (s, 3H, H-7), 1.40
(s, 3H, H-8), 1.77 (m, 2H, H-3), 2.05 (s, 3H, MeCOO), 2.33 (s, 3H, Me p-Tol), 3.46 (m, 2H, H-5), 4.08
(m, 2H, H-5), 4.58 (AB, 2H, JAB=12.3 Hz, ∆ν=11 Hz, OCH2Ph), 7.26 (m, 9H, H arom.); 13C NMR
(CDCl3): δ 19.69 (Me p-Tol), 21.32 (MeOAc), 24.64, 24.96 (C-7 and C-8), 31.48 (C-3), 66.46 (C-4),
68.33 (C-2), 72.43 (OCH2Ph), 73.59 (C-5), 82.11 (C-1), 101.27 (C-6), 127.83, 128.51, 129.94, 133.87,
134.04, 134.40 (C arom.), 138.26, 138.63, 138.72, 169.89 (Cq arom.); IR (CHCl3) 2880–3000, 1750,
1015 cm−1. Anal. calcd for C24H30O5S: C, 66.95; H, 7.02. Found: C, 67.10; H, 7.20.

G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
3089
3.11. [2(R)4(R)]-5-Benzyloxy-2,4-(isopropylidenedioxy)-pentanol, 13a
To a solution of the acetoxy 13 (31.7 mg, 0.07 mmol) in dry ether (2.4 ml) at 0°C was added LiAlH4
(14 mg, 0.37 mmol). The reaction mixture was stirred at room temperature until all the starting material
was consumed (TLC). After quenching with a saturated solution of Na2SO4, the reaction was stirred
at room temperature to obtain a white suspension. The mixture was dried over MgSO4, filtered over
Celite, washed with hot ether and the solvent flash evaporated. The crude product was purified by
column chromatography on silica gel (ether:hexane=8:2) to give a pale yellow oil (15.3 mg, 82%); Rf
0.47 (CH2Cl2:AcOEt=6:4); [α]D=+28 (c 2.5, CHCl3); 1H NMR (CDCl3, 200 MHz): δ 1.40 (s, 6H, H-7
and H-8), 1.61 (m, 2H, H-3), 2.03 (m, 1H, OH), 3.56 (m, 4H, H-1 and H-5), 4.01 (m, 2H, H-2 and H-4),
4.58 (AB, 2H, JAB=12.2. Hz, ∆ν=10.5 Hz, OCH2Ph), 7.31 (m, 5H, H arom.); 13C NMR (CDCl3): δ
24.96–25.05 (C-7 and C-8), 30.01 (C-3), 65.46 (C-1), 66.36 (C-2), 67.55 (C-4), 72.61 (OCH2Ph), 73.44
(C-5), 100.72 (C-6), 127.74, 127.79, 128.47 (C arom.), 138.31 (Cq arom.); IR (CHCl3) 3600, 2880–3000,
1015 cm−1. Anal. calcd for C15H22O4: C, 67.65; H, 8.39. Found: C, 67.61; H, 8.39.
3.12. [2(R)4(R)]-5-Benzyloxy-4-hydroxy-1,2-(isopropylidenedioxy)-pentane, 15
To a solution of the preceding acetonide 13a (988 mg, 3.79 mmol) in acetone (172 ml) was added at
room temperature p-toluenesulfinic acid (36 mg, 0.19 mmol). The reaction mixture was stirred at room
temperature and monitored by TLC. After quenching with a saturated solution of NaHCO3, the aqueous
layer was extracted with AcOEt (3×100 ml). The combined organic layers were washed with brine, dried
over MgSO4 and the solvent evaporated. The crude product was purified by column chromatography on
silica gel (CH2Cl2:AcOEt=6:4) to afford a colorless oil (939 mg, 93%); Rf 0.46 (CH2Cl2:AcOEt=6:4);
[α]D=−5 (c 1.0, CHCl3); 1H NMR (CDCl3, 200 MHz): δ 1.34 (s, 3H, H-7), 1.39 (s, 3H, H-8), 1.67 (m,
2H, H-3), 2.93 (s, 1H, OH), 3.41 (AB of ABX, 2H, JAB=9.5 Hz; JAX=7.2 Hz; JBX=3.8 Hz, ∆ν=65.9
Hz, H-5), 3.53 (A of ABX, 1H, JAB=7.9 Hz; JAX=7.7 Hz, ∆ν=225.1 Hz, H-1), 3.97 (X of ABX, m,
1H, H-4), 4.06 (B of ABX, 1H, JAB=7.9 Hz; JBX=6.0 Hz, ∆ν=225.1 Hz, H-1), 4.29 (X of ABX, m, 1H,
H-2); 4.53 (s, 2H, OCH2Ph), 7.32 (m, 5H, H arom.); 13C NMR (CDCl3): δ 25.68–26.91 (C-7 and C-8),
36.77 (C-3), 67.77 (C-2), 69.68 (OCH2Ph), 73.25 (C-5), 73.39 (C-4), 74.41 (C-1), 108.63 (C-6), 127.67,
127.72, 128.39 (C arom.), 137.89 (Cq arom.); IR (CHCl3) 3570, 2840–2980, 1059 cm−1. Anal. calcd for
C15H22O4: C, 67.65; H, 8.27. Found: C, 67.50; H, 8.27.
3.13. [2(R)4(R)]-5-Benzyloxy-4-(tert-butyldimethylsilyloxy)-1,2-(isopropylidenedioxy)-pentane, 15a
To a solution of the alcohol 15 (49.6 mg, 0.19 mmol) in DMF (1 ml) was added at 0°C imidazole
(38 mg, 0.56 mmol) and tert-butyldimethylsilyl chloride (56.2 mg, 0.37 mmol). The reaction mixture
was stirred at room temperature overnight and hydrolyzed with a saturated solution of NH4Cl. After
extraction with ether (3×50 ml), the organic layers were washed with brine (50 ml) and dried over
MgSO4. After evaporating the solvent, the crude product was purified by column chromatography on
silica gel (CH2Cl2:AcOEt=6:4) to afford a colorless oil (68 mg, 96%); Rf 0.39 (hexane:AcOEt=9:1);
1
[α]D=+9 (c 1.5, CHCl3); H NMR (CDCl3, 200 MHz): δ 0.09 (s, 3H, Me2Si), 0.12 (s, 3H, Me2Si),
0.92 (s, 9H, t-BuSi), 1.36 (s, 3H, H-7), 1.42 (s, 3H, H-8), 1.74 (m, 2H, H-3), 3.41 (AB of ABX, 2H,
JAB=9.6 Hz; JAX=5.5 Hz; JBX=2.2 Hz, ∆ν=48.5 Hz, H-5), 3.51 (A of ABX, 1H, JAB=7.7 Hz; JAX=7.7
Hz, ∆ν=231.1 Hz, H-1), 4.05 (B of ABX, 1H, JAB=7.7 Hz; JBX=7.7 Hz, ∆ν=231.1 Hz, H-1), 4.11 (m,
1H, H-4); 4.25 (m, 1H, H-2), 4.53 (s, 2H, OCH2Ph), 7.34 (m, 5H, H arom.); 13C NMR (CDCl3): δ −4.83
((CH3)2Si), −4.34 ((CH3)2Si), 16.12 (C-3), 25.62 (C-7 and C-8), 25.90 (C(CH3)3Si), 27.06 (C(CH3)3Si),

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G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
36.63 (C(CH3)3Si), 66.72 (C-2), 69.95 (C-5), 72.66 (C-4), 73.30 (OCH2Ph), 75.06 (C-1), 106.55 (C-6),
126.32, 127.55, 127.62 (C arom.), 136.32 (Cq arom.); IR (CHCl3) 2960–2840, 1100 cm−1. Anal. calcd
for C21H36O4Si: C, 66.27; H, 9.53. Found: C, 66.14; H, 9.69.
3.14. [2(R)4(R)]-4-(tert-Butyldimethylsilyloxy)-1,2-(isopropylidenedioxy)-5-pentanol, 17
A solution of the preceding benzyl ether 15a (245 mg, 0.65 mmol) and 5% Pd/C (one spatula) in
tetrahydrofuran (20 ml), under a hydrogen atmosphere (10 atm), was stirred at room temperature for 5
h. The catalyst was then removed by filtration over Celite, washed with tetrahydrofuran and the solvent
evaporated. The crude product was purified by column chromatography (hexane:AcOEt=9:1) to afford
a colorless oil (0.16 g, 88%); Rf 0.46 (hexane:AcOEt=9:1); [α]D=+5 (c 1.5, CHCl3); 1H NMR (CDCl3,
200 MHz): δ 0.10 (s, 6H, Me2Si), 0.90 (s, 9H, t-BuSi), 1.34 (s, 3H, H-7), 1.39 (s, 3H, H-8), 1.72 (m, 2H,
H-3), 2.07 (t, 1H, OH), 3.49 (A of ABX, 1H, JAB=7.7 Hz; JAX=7.7 Hz, ∆ν=118.5 Hz, H-1), 3.59 (m, 2H,
H-5), 3.95 (m, 1H, H-2), 4.05 (B of ABX, 1H, JAB=7.7 Hz; JBX=7.7 Hz, ∆ν=118.5 Hz, H-1), 4.17 (m,
1H, H-4); 13C NMR (CDCl3): δ −4.45 ((CH3)2Si), −4.66 ((CH3)2Si), 18.13 (C-3), 25.90 (C-7 and C-8),
27.10 (C(CH3)3Si), 38.36 (C(CH3)3Si), 67.20 (C-1), 69.90 (C-5), 70.43 (C-2), 72.84 (C-4), 109.00 (C-
6); IR (CHCl3) 3450–3540, 2870–3000 cm−1. Anal. calcd for C14H30O4Si: C, 57.89; H, 10.41. Found:
C, 57.92; H, 10.35.
3.15. [2(R)4(R)]-4-tert-Butyldimethylsilyloxy)-1,2-(isopropylidenedioxy)-5-pentanal, 2
To a stirred solution of oxalyl chloride (0.14 ml, 1.58 mmol) in dichloromethane (3 ml) at −78°C was
added dimethyl sulfoxide (0.23 ml, 3.17 mmol). After 15 min, a solution of alcohol 17 (0.15 mg, 0.53
mmol) in CH2Cl2 (3.7 ml) was slowly added to the reaction mixture via a cannula. After stirring at −78°C
during 1.5 h, triethylamine was added (0.88 ml, 6.33 mmol). After stirring at −78°C for 30 min and at
0°C for 1 h, the reaction was quenched with a saturated solution of NH4Cl (10 ml). The combined organic
layers were washed with brine, dried (MgSO4) and the solvent flash evaporated. The crude product was
purified by column chromatography (hexane:AcOEt=9:1) to afford a colorless oil (0.13 g, 82%); Rf 0.39
(hexane:AcOEt=9:1); [α]D=+18 (c 2.0, CHCl3); 1H NMR (CDCl3, 200 MHz): δ 0.095 (s, 3H, Me2Si),
0.10 (s, 3H, Me2Si), 0.93 (s, 9H, t-BuSi), 1.34 (s, 3H, H-7), 1.39 (s, 3H, H-8), 1.78 (m, 2H, H-3), 3.54
(AB of ABX, 2H, JAB=7.7 Hz; JAX=7.7 Hz; JBX=5.9 Hz, ∆ν=106.7 Hz, H-1), 4.06 (A of ABX, 1H,
J
AB=7.7 Hz; JAX=7.7 Hz, ∆ν=106.7 Hz, H-1), 4.23 (m, 2H, H-2 and H-4); 13C NMR (CDCl3): δ −5.05
((CH3)2Si), −4.55 ((CH3)2Si), 18.26 (C(CH3)3Si), 25.81 (C-7 and C-8), 27.09 (C(CH3)3Si), 36.19 (C-3),
69.60 (C-1), 71.78 (C-2), 75.30 (C-4), 109.04 (C-6.); IR (CHCl3) 2920–3040, 2860–2900, 1750 cm−1
.
3.16. (−)-[3(R)5(R)S(S)]-3,5-(Isopropylidenedioxy)-6-(p-tolylsulfinyl)methyl hexanoate, 10a
The dihydroxysulfoxide 10 (1.5 g, 5.33 mmol) and catalytic p-TsOH (0.11 g, 0.53 mmol) were
dissolved in acetone (270 ml) and dimethoxypropane (27 ml). Stirring at room temperature was continued
until all starting material disappeared (TLC). The reaction mixture was diluted in AcOEt (100 ml) and
saturated NaHCO3 (100 ml) was added. The reaction was stirred at room temperature to obtain a white
precipitate. The aqueous layer was extracted with AcOEt (3×100 ml). The combined organic layers were
washed with a saturated solution of NH4Cl (100 ml) and with brine (100 ml), dried over MgSO4, and
filtered before being concentrated. The crude product was purified by column chromatography on silica
gel (AcOEt:CH2Cl2=6:4) to give a yellow oil (1.72 g, 95%); Rf 0.44 (AcOEt:CH2Cl2=6:4); [α]D=−119
(c 1.0, CHCl3); 1H NMR (CDCl3, 200 MHz): δ 1.40 (s, 3H, H-8), 1.44 (s, 3H, H-9), 1.71 (m, 2H, H-4),

G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
3091
2.39 (s, 3H, Me p-Tol), 2.51 (AB of ABX, 2H, JAB=15.87 Hz; JAX=5.6 Hz; JBX=7.9 Hz, ∆ν=33 Hz,
H-6), 2.78 (m, 2H, H-2), 3.66 (s, 3H, MeO), 4.35 (m, 1H, H-3), 4.42 (m, 1H, H-5), 7.42 ((AB)2, 4H,
J
AB=8 Hz, ∆ν=42.4, H arom.); 13C NMR (CDCl3): δ 21.37 (Me p-Tol), 24.36–24.61 (C-8 and C-9),
37.07 (C-4), 40.31 (C-2), 51.66 (MeO), 60.94 (C-3), 63.33 (C-5), 64.05 (C-6), 101.43 (C-7), 123.77,
129.99 (C arom.), 141.41 (Cq arom.), 171.15 (C-1); IR (CHCl3) 3000–2860, 1720 cm−1. Anal. calcd for
C17H24O5S: C, 59.97; H, 7.11. Found: C, 60.17; H, 6.98.
3.17. (−)-[3(R)5(R)S(S)]-6-Acetoxy-3,5-(isopropylidenedioxy)-6-(p-tolylthio)-methyl hexanoate, 12
Anhydrous sodium acetate (1.45 g, 17.62 mmol) was added to the preceding sulfoxide 10a (500 mg,
1.47 mmol). Acetic anhydride (100 ml) was then added, and the mixture was refluxed (135°C) until all
the sulfoxide was consumed (TLC). After cooling, the solvent was removed by azeotropic distillation
with toluene to obtain a deep brown solid which was dissolved in CH2Cl2 and filtered on Celite. The
crude product was purified by column chromatography on silica gel (hexane:AcOEt=8:2) to afford 12 as
a yellow oil (528 mg, 94%), a mixture of the two isomers at the C6 position which were not separated. 1H
NMR (CDCl3, 200 MHz): major isomer, δ 1.28 (s, 3H, H-8), 1.34 (s, 3H, H-9), 1.69 (m, 2H, H-4), 1.96
(s, 3H, MeCOO), 2.37 (s, 3H, Me p-Tol), 2.58 (m, 2H, H-2), 3.66 (s, 3H, MeO), 4.00 (m, 1H, H-3), 4.23
(m, 1H, H-5), 6.03 (m, 1H, H-6), 7.23 (AB, 4H, JAB=8 Hz, ∆ν=55.5 Hz, H arom.); minor isomer, 1.37
(s, 3H, H-8), 1.41 (s, 3H, H-9), 1.69 (m, 2H, H-4), 1.92 (s, 3H, MeCOO), 2.37 (s, 3H, Me p-Tol), 2.58
(m, 2H, H-2), 3.66 (s, 3H, MeO), 4.00 (m, 1H, H-3), 4.23 (m, 1H, H-5), 6.03 (m, 1H, H-6), 7.23 (AB,
4H, JAB=8 Hz, ∆ν=55.5 Hz, H arom.); 13C NMR (CDCl3): δ 21.02 (MeCOO), 24.56 (Me p-Tol), 34.53
(C-4), 40.35 (C-2), 51.66 (MeO), 63.42 (C-3), 67.74 (C-5), 81.90 (C-6), 101.26 (C-7), 129.85, 133.95 (C
arom.), 138.54, 138.63 (Cq arom.), 169.68 (COMe), 171.06 (C-1). Anal. calcd for C19H26O6S: C, 59.67;
H, 6.85. Found: C, 59.74; H, 6.78.
3.18. (+)-[3(R)5(R)] Methyl-6-acetoxy-3,5-(isopropylidenedioxy) hexanoate, 12a
Raney nickel was added in portions to a solution of compound 12 (1.8 g, 207 mmol) in MeOH (25
ml). The reaction was stirred at room temperature for 25 h. The mixture was carefully filtered through
Celite and the solid washed with MeOH. After evaporating the solvent, the product was purified by
rapid chromatography on silica gel (hexane:AcOEt=8:2) to afford a colorless oil (527 mg, 75%); Rf 0.41
(hexane:AcOEt=6:4); [α]D=+17 (c 1.5, CHCl3); 1H NMR (CDCl3, 200 MHz): δ 1.27 (s, 3H, H-8), 1.30
(s, 3H, H-9), 1.61 (m, 2H, H-4), 2.00 (s, 3H, MeCOO), 2.44 (AB of ABX, 1H, JAB=15.7 Hz; JAX=7.7 Hz;
J
AX=5.5 Hz, ∆ν=25.9 Hz, H-2), 3.61 (s, 3H, H-6 and H-3), 45.22 (m, 1H, H-5); 13C NMR (CDCl3): δ
20.88 (CH3COO), 24.49, 24.54 (C-8 and C-9), 33.67 (C-2), 40.38 (C-4), 51.65 (CH3OCO), 63.26 (C-3),
64.84 (C-5), 66.13 (C-6), 100.88 (C-7), 170.91 (C-1), 171.13 (CH3COO); IR (CHCl3) 2940–2980, 1725
cm−1. Anal. calcd for C12H20O6: C, 55.37; H, 7.74. Found: C, 55.44; H, 7.97.
3.19. [3(R)5(R)] Methyl 3,5-(isopropylidenedioxy)-3-hydroxy-hexanoate, 14
(1) An aqueous solution of K2CO3 (1.56 g, 11.28 mmol/72 ml) was added dropwise to a stirred solution
of the preceding acetoxyester 12a (1.174 g, 4.51 mmol) in MeOH (144 ml). The reaction mixture was
stirred at room temperature for 20 min and then hydrolyzed with a saturated solution of NH4Cl (100 ml).
The aqueous layer was extracted with AcOEt (3×100 ml). The combined organic layers were washed
with brine, dried over MgSO4 and evaporated.

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G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
(2) To a solution of the resulting crude hydroxyester in acetone (90 ml) was added p-toluenesulfonic
acid (85.77 mg, 0.45 mmol). The reaction mixture was stirred at room temperature overnight. The reac-
tion was quenched with a saturated solution of NaHCO3 (50 ml). The aqueous layer was extracted with
AcOEt (3×50 ml). The combined organic layers were washed with brine, dried over MgSO4 and con-
centrated. The crude product was purified by column chromatography on silica gel (hexane:AcOEt=5:5)
to afford a yellow oil (817 mg, 83%); Rf 0.38 (hexane:AcOEt=5:5); [α]D=−12 (c 2.0, CHCl3); 1H NMR
(CDCl3, 200 MHz): δ 1.34 (s, 3H, H-8), 1.39 (s, 3H, H-9), 1.73 (t, 2H, H-2), 2.51 (m, 2H, H-4), 3.37 (A
of ABX, 1H, JAB=8 Hz; JAX=7.7 Hz, ∆ν=111.8 Hz, H-6), 3.70 (s, 3H, CH3OCO), 3.90 (B of ABX, 1H,
J
AB=8 Hz; JBX=6.1 Hz, ∆ν=111.8 Hz, H-6), 4.22 (m, 2H, H-5 and H-3); 13C NMR (CDCl3): δ 25.73,
26.97 (C-8 and C-9), 40.40 (C-4), 41.40 (C-2), 51.76 (MeO), 65.51 (C-3), 69.52 (C-6), 74.49 (C-5),
108.81 (C-7), 172.92 (C-1); IR (CHCl3) 3730, 3030–2930, 1750 cm−1. Anal. calcd for C10H18O5: C,
55.83; H, 8.31. Found: C, 55.89; H, 8.39.
3.20. (+)-[3(R)5(S)]-5,6-(Isopropylidendioxy)-1,3-hexanediol, 16
To a solution of lithium aluminium hydride (195.4 mg, 5.15 mmol) in ether (76 ml) at −25°C was
added a solution of the ester 14 (1.12 g, 5.15 mmol) in ether (7.6 ml) at −25°C. The reaction mixture
was stirred at −25°C until all the starting material was consumed (TLC). The reaction was quenched
with a saturated solution of sodium sulfate, filtered over Celite and the solvent flash evaporated. The
crude product was purified by silica gel chromatography (AcOEt 100%) to afford a colorless oil (833
mg, 85%); Rf 0.21 (AcOEt 100%); [α]D=+3 (c 0.5, CHCl3); 1H NMR (CDCl3, 200 MHz): δ 1.36 (s, 3H,
H-9), 1.42 (s, 3H, H-8), 1.76 (m, 4H, H-4), 2.67 (m, 1H, OH), 3.31 (m, 1H, OH), 3.58 (td, 2H, H-1), 3.58
(A of ABX, 1H, JAB=8 Hz; JAX=7.5 Hz, ∆ν=104 Hz, H-6), 3.94 (m, 1H, H-6), 3.86 (m, 2H, H-1), 4.09
(m, 2H, H-6 and H-3), 4.27 (m, 1H, H-5); 13C NMR (CDCl3): δ 25.72, 26.96 (C-8 and C-9), 38.82 (C-1),
40.54 (C-2), 61.06 (C-4), 68.63 (C-5), 69.55 (C-6), 73.50 (C-3), 108.89 (C-7); IR (CHCl3) 3730–3660,
3030–2920 cm−1. Anal. calcd for C9H18O4: C, 56.82; H, 9.54. Found: C, 56.78; H, 9.56.
3.21. (−)-[3(R)5(S)]-1-Iodo-5,6-(isopropylidenedioxy)-3-hexanol, 3a
A solution of diol 16 (100 mg, 0.53 mmol) in ether (2.4 ml) and acetonitrile (1 ml) at 0°C was treated
with imidazole (78.73 mg, 1.16 mmol), triphenylphosphine (151.66 mg, 0.58 mmol) and iodine (146.76
mg, 0.58 mmol). The reaction mixture was stirred at room temperature until no more starting material
was detected by TLC (hexane:AcOEt=5:5). A saturated solution of NaHCO3 (2 ml) was added and the
mixture stirred for 10 min. To the resulting mixture was added iodine in small portions until a persistent
red-colored organic layer was obtained. Stirring was continued for another 10 min. After addition of
a sodium thiosulfate solution (2 ml), the mixture was extracted with ether (3×10 ml) and the combined
organic layers washed with brine prior to drying (MgSO4) and solvent evaporation. Silica gel chromatog-
raphy of the residue (hexane:AcOEt=5:5) provided (−)-[3(R)5(S)]-1-iodo-5,6-(isopropylidenedioxy)-3-
hexanol as a colorless oil (102 mg, 64%); Rf 0.53 (hexane:AcOEt=5:5); [α]D=−23 (c 1.0, CHCl3); 1H
NMR (CDCl3, 200 MHz): δ 1.35 (s, 3H, H-9), 1.41 (s, 3H, H-8), 1.72 (t, 2H, H-4), 1.95 (m, 2H, H-2),
2.71 (d, 1H, OH), 3.29 (td, 2H, H-1), 3.58 (A of ABX, 1H, JAB=8 Hz; JAX=7.5 Hz, ∆ν=104 Hz, H-6),
3.94 (m, 1H, H-5), 4.07 (B of ABX, 1H, JAB=8 Hz; JBX=6 Hz, ∆ν=104 Hz, H-6), 4.30 (m, 1H, H-3); 13
C
NMR (CDCl3): δ 2.55 (C-1), 25.65, 26.93 (C-8 and C-9), 39.39 (C-2), 40.91 (C-4), 68.93 (C-5), 69.32
(C-6), 73.36 (C-3), 109.10 (C-7). Anal. calcd for C9H17O3I: C, 36; H, 5.71. Found: C, 35.92; H, 5.70.

G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
3093
3.22. (+)-[2(R)4(R)8(S)10(R)]-4-(tert-Butyldimethylsilyloxy)-1,2-10,11-(diisopropylidenedioxy)-8-
hydroxy-5-undecene, 18
(1) [3(R)5(S)]-(5,6-(Isopropylidenedioxy)-3-hexanyl)-phosphonium iodide, 3: A solution of the pre-
ceding iodide 3a (0.27 g, 0.91 mmol) and triphenylphosphine (1.2 g, 4.57 mmol) in dry toluene (10 ml)
was refluxed until no more starting material was detected by TLC (hexane:AcOEt=5:5). After evaporating
the solvent, the phosphonium salt 3 was obtained as a white solid by precipitation from dry ether, filtration
1
and washing with ether (quantitative yield). H NMR (CDCl3, 200 MHz): δ 1.28 (s, 3H, H-8), 1.31 (s,
3H, H-9), 1.81 (m, 4H, H-4 and H-2), 3.50 (A of ABX, 1H, JAB=8 Hz; JAX=8 Hz, ∆ν=116.4 Hz, H-6),
3.88 (m, 1H, H-3), 4.09 (B of ABX, 1H, JAB=8 Hz; JBX=6 Hz, ∆ν=116.4 Hz, H-6), 4.26 (m, 3H, H-5
and H-1), 7.50 (m, 15H, H arom.).
(2) To a slurry of 3 (500 mg, 0.89 mmol) in THF (4 ml) at 0°C was added a solution of n-butyllithium
(1.15 ml, 1.79 mmol, 1.55 M in hexane) dropwise over 2 min. The resulting yellow–orange solution was
stirred vigorously at 0°C for 20 min and then at room temperature for 10 min, after which a solution of
lithium bromide (77.21 mg, 0.89 mmol) in THF (4 ml) was added. The mixture was cooled to −45°C,
and a solution of 2 (171 mg, 0.59 mmol) in THF (4 ml) was added. The reaction mixture was stirred at
−30°C until all the aldehyde was consumed (TLC hexane:ether=6:4). After quenching with a saturated
solution of NH4Cl, the reaction was acidified to pH=5–6 with a 5% solution of HCl. The aqueous layer
was extracted with ether. The combined organic layers were washed with brine, dried (MgSO4) and
the solvent flash evaporated. The crude product was purified by column chromatography on silica gel
(hexane:ether=6:4) to give a colorless oil (105.4 mg, 50%); Rf 0.54 (hexane:ether=5:5); [α]D=+4 (c 2.0,
1
CHCl3); H NMR (CDCl3, 200 MHz): δ 0.02 (s, 3H, (CH3)2Si), 0.05 (s, 3H, (CH3)2Si), 0.87 (s, 9H,
C(CH3)3Si), 1.33 (s, 3H, H-14), 1.35 (s, 3H, H-15), 1.38 (s, 3H, H-17), 1.40 (s, 3H, H-18), 1.70 (m,
4H, H-3 and H-9), 2.23 (m, 2H, H-7), 2.58 (s, 1H, OH), 3.50 (m, 2H, H-1 and H-11), 3.75 (m, 2H, H-2
and H-10), 4.05 (m, 2H, H-1 and H-11), 4.23 (m, 2H, H-4 and H-8), 5.56 (m, 2H, H-5 and H-6); 13C
NMR (CDCl3): δ −4.70 ((CH3)2Si), −4.05 ((CH3)2Si), 18.25 (C(CH3)3Si), 25.96 (C-13, C-14, C-16 and
C-17), 27.00 (C(CH3)3Si), 39.86 (C-7), 40.83, 42.46 (C-3 and C-9), 68.02, 71.46 (C-10 and C-2), 69.92
(C-11 and C-1), 73.12, 73.84 (C-8 and C-4), 108.90 (C-12 and C-15), 125.97 (C-6), 137.86 (C-5). Anal.
calcd for C23H44O6Si: C, 57.95; H, 9.3. Found: C, 57.7; H, 9.24.
3.23. [2(R)4(R)8(S)10(R)]-1,2-10,11-(Diisopropylidenedioxy)-4,8-dihydroxy-undecane, 1
(1) A solution of the unsaturated compound 18 (141 mg, 0.32 mmol) and 10% Pd/C (44 mg) in AcOEt
(6 ml), under a hydrogen atmosphere (5 atm), was stirred at room temperature for 5 h. The catalyst was
removed by filtration over Celite, washed with AcOEt and the solvent evaporated. The crude compond
was purified by silica gel chromatography (hexane:ether=5:5) to afford a colorless oil (138.6 mg, 97%);
Rf 0.54 (hexane:ether=5:5); 1H NMR (CDCl3, 200 MHz): δ 0.05 (s, 3H (CH3)2Si), 0.08 (s, 3H (CH3)2Si),
0.88 (s, 9H, C(CH3)3Si), 1.15 (m, 6H, H-5, H-6 and H-7), 1.3 (s, 3H, H-acetonide), 1.35 (s, 3H, H-
acetonide), 1.38 (s, 3H, H-acetonide), 1.40 (s, 3H, H-acetonide), 1.42 (m, 4H, H-3 and H-9), 3.53 (m,
2H, H-1 and H-11), 3.86 (m, 2H, H-1, H-11 and H-8), 4.38 (m, 1H, H-4).
(2) To a solution of the preceding silyloxy derivative (60.9 mg, 0.14 mmol) in THF (2 ml) was added,
at 0°C, tetrabutylammonium fluoride (0.34 ml of a 1 M solution in THF, 0.34 mmol). The reaction
mixture was stirred at room temperature for 2 days and the solvent evaporated. The residue was dissolved
in AcOEt (5 ml) and acidified with a 10% solution of HCl. The aqueous layer was extracted with
AcOEt (3×5 ml). The combined organic layers were washed with brine, dried (MgSO4), filtered and
concentrated. The crude product was purified by silica gel chromatography (ether:AcOEt=8:2) to afford

3094
G. Solladié et al. / Tetrahedron: Asymmetry 9 (1998) 3081–3094
1
a white solid (42.8 mg, 92%); Rf 0.22 (ether:AcOEt=8:2); H NMR (CDCl3, 200 MHz): δ 1.35 (s, 6H,
H-acetonide), 1.40 (s, 6H, H-acetonide), 1.50 (m, 6H, H-5, H-6 and H-79), 1.63 (m, 4H, H-3 and H-
9), 3.58 (A of ABX, 1H, JAB=7.5 Hz; JAX=5 Hz, ∆ν=107.2 Hz, H-1 and H-11), 3.79 (B of ABX, 1H,
JAB=7.5 Hz; JBX=7.5 Hz, ∆ν=107.2 Hz, H-6), 4.33 (m, 2H, H-4 and H-8).
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