Novel synthesis of chiral, enantiomerically pure thiodiglycols and diglycols

Article abstract of DOI:10.1016/S0957-4166(98)00224-9

Natural α-hydroxy acids have been converted in a sequence of O- protection, reduction, O-activation, thioether and ether formation and deprotection to chiral, non-racemic β,β'-dihydroxy thioethers 1a, 1b and ether 1c. Overall yields are excellent (75%). In an attempt to synthesize the respective dihydroxy ether 1d derived from mandelic acid 1,3-dioxolane derivatives 7 were obtained.

Full text of DOI:10.1016/S0957-4166(98)00224-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2349–2357
Novel synthesis of chiral, enantiomerically pure thiodiglycols and
diglycols
Jens Christoffers ∗ and Ulrich Rößler
Technische Universität Berlin, Institut für Organische Chemie, Sekretariat C 3, Straße des 17. Juni 135, D-10623 Berlin,
Germany
Received 6 May 1998; accepted 29 May 1998
Abstract
Natural α-hydroxy acids have been converted in a sequence of O-protection, reduction, O-activation, thioether
and ether formation and deprotection to chiral, non-racemic β,β0-dihydroxy thioethers 1a, 1b and ether 1c. Overall
yields are excellent (75%). In an attempt to synthesize the respective dihydroxy ether 1d derived from mandelic
acid 1,3-dioxolane derivatives 7 were obtained. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Whereas chiral bidentate ligands have become ubiquitous in catalytic asymmetric synthesis over the
past decades,1,2 other multidentate3–6 ligands have rarely found applications in this field. In particular,
we are interested in the development of chiral metal catalysts with C2-symmetric tridentate ligands of
the general type 1 with different donor sets, e.g. X=N, P, S, O; Y=S, O (Scheme 1).7 In this context
we planned to synthesize the chiral thiodiglycols 1a and 1b as well as chiral diglycols 1c8,9 and 1d.
These enantiopure compounds 1a–d, which have already been synthesized in different ways as racemic
materials,10–13 shall serve for the complexation of alkali and alkali earth metals in the catalysis of base
mediated processes (aldol and Michael reactions).14,15 Moreover, 1a–d are useful intermediates for the
preparation of other tripodal ligands of the general type 1, since the transformations OH-→SR0 and
OH-→PR02 (R0=aryl, alkyl) have readily been performed.3
∗
Corresponding author. Tel: +49 30/314-23189; fax: +49 30/723-1233; e-mail: jchr@wap0105.chem.tu-berlin.de
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00224-9

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Scheme 1. C2-Symmetric tripodal ligands 1, chiral thiodiglycoles 1a and 1b, chiral diglycoles 1c and 1d, retrosynthesis from
ethyl lactate (2a) and ethyl mandelate (2b)
2. Results and discussion
Reasonable starting materials for the preparation of 1a–d are (S)-ethyl lactate (2a, R=Me) and (S)-ethyl
mandelate (2b, R=Ph), because the stereoinformation is derived from the chiral pool and the oxygen
functionalities are preexisting. The synthesis of 1a,b reported in this work is summarized in Scheme 2.
After introduction of the protecting group (EE=ethoxyethyl) by stirring the esters 2 in ethyl vinyl ether
as solvent and a catalytic amount of TosOH,16 reduction of the intermediate ethyl carboxylates 3 with
17,18
LiAlH4
furnished the primary alcohols 4. Subsequently, the hydroxy functions were activated by
tosylate formation with TosCl–pyridine.19 Acidic workup in this step cleanly removed the ethoxyethyl
protective group,20 and the resulting tosylates 521–23 were converted to the corresponding thioethers 1a
and 1b by SN reaction with Na2S in acetone. Interestingly, although an excess of Na2S was applied to
achieve good conversion of the tosylates 5, no thiol formation was detectable. Obviously, intermediate
thiolates are significantly more nucleophilic than sulfide under our reaction conditions. Thanks to
excellent yields in all four synthetic steps the overall yields from esters 2 were 77% for 1a and 76%
for 1b.
Scheme 2. Synthesis of chiral thiodiglycoles 1a (R=Me) and 1b (R=Ph); reagents, conditions, and yields: (i) H2C_CHOEt, cat.
TosOH·H2O, 3a: 98%, 3b: 100%; (ii) LiAlH4, Et2O, 4a: 95%, 4b: 98%; (iii) 1. TosCl, pyridine, 2. HCl–H2O, 5a: 91%, 5b:
94%; (iv) Na2S, acetone, 70°C, 1a: 88%, 1b: 82%; EE=EtO(Me)CH, Tos=pMeC6H4SO2
Scheme 3 outlines our synthetic strategy leading to the chiral β,β0-dihydroxy ethers 1c and 1d.
Tosylates 5 were first re-protected with ethyl vinyl ether–cat. TosOH,24 and the resulting compounds
6 were converted with the deprotonated primary alcohols 4 in DMF. Acidic workup directly cleaved the
protective groups and furnished the diol 1c in good yield.
Scheme 3. Synthesis of chiral diglycol 1c; reagents, conditions, and yields: (i) H2C_CHOEt, cat. TosOH·H2O, 6a
(R=Me): 97%, 6b (R=Ph): 97%; (ii) 1. 4a, NaH, DMF, 2. H+ (ion exchanger resin), CH2Cl2, 1c: 41%; EE=EtO(Me)CH,
Tos=pMeC6H4SO2
However, compound 1d was not accessible by this method. Presumably due to steric reasons we were
not able to achieve any conversion of 4b with 6b. Consequently, we decided to enhance reactivity of
the electrophile 6 by choosing a different leaving group. Following a literature strategy25 we converted
a stoichiometric mixture of 4b and pyridine with 0.5 equivalents of triflic anhydride. Below 0°C the

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2351
starting material 4b converted cleanly to a mixture of two diastereomeric products, which were separable
by chromatography. Their constitution was elucidated by standard spectroscopic means to be the 1,3-
dioxolane derivatives 7a and 7b. These racemic materials are known in the literature as dimers of styrene
oxide26,27 (Scheme 4). Target compound 1d was not detectable in the reaction mixture. The relative
configuration of 7a and 7b was established by NOE experiments: whereas 2-CH showed a NOE to one
of the 5-CH protons in isomer 7a only, in compound 7b a NOE was detected between 2-CH and 4-CH
as well as to one 5-CH proton. Consequently, phenyl and benzyl substituents are situated trans to one
another in 7a, and compound 7b is the cis isomer. A mechanistic rationale for the formation of 7a and 7b
suggests a cyclic arenium ion (phenonium ion)28–30 as an intermediate resulting from an intramolecular
substitution of the triflate leaving group. This three membered ring intermediate can be opened by a
deprotonated equivalent of 4b under either retention or inversion of the configuration, thus leading to two
diastereomeric products. The absolute configuration of the 4,5-C2 fragments is assumed to be retained in
the reaction sequence. Loss of the ethoxyethyl protective function is thought to be caused by pyridinium
triflate present in the reaction mixture.
Scheme 4. Formation of dioxolane derivatives 7a and 7b from 4b; reagents, conditions, and yields: (i) 0.5 equiv. (CF3SO2)2O,
1.0 equiv. pyridine, THF, −30°C, 45 min, 7a: 19%, 7b: 17%
The final products 1a–c and 7a and 7b, as well as all intermediates, were fully characterized, and 1a–c
showed only one set of signals in their NMR spectra, which was important with respect to enantiomeric
excess: partially racemic starting materials would have caused formation of a certain amount of (S,R)-
diastereoisomers, which were not detectable in samples of 1a–c.
In summary, the conversion of α-hydroxy esters derived from (S)-lactic 2a and (S)-mandelic acid 2b
to chiral, C2-symmetric thiodiglycoles 1a and 1b and diglycol 1c in excellent overall yields was reported.
In attempts to synthesize a dihydroxy ether derived from mandelic acid 1,3-dioxolane derivatives 7a and
7b were obtained.
3. Experimental†
3.1. General
1
Column chromatography was accomplished with Merck silica gel (Type 60, 0.063–0.200 mm). H
NMR spectra were recorded on a Bruker AM 400 (400 MHz), and reported in parts per million (ppm)
using the residual proton solvent peak of CDCl3 at 7.26 ppm as an internal standard, with coupling
constants (J) in hertz (Hz). NOE experiments were performed on a Bruker AC 200 (200 MHz). 13C
NMR spectra were recorded on a Bruker AC 200 (50 MHz), and reported in parts per million (ppm)
using the solvent triplet of CDCl3 at 77.0 ppm as an internal standard. Assignments were made using
DEPT experiments. MS spectra were obtained with Varian MAT 711 and MAT 955Q (high resolution)
spectrometers. IR spectra were recorded on a Nicolet Magna IR 750 spectrophotometer. Elemental
†
Abbreviations: ATR: attenuated total reflection; MTB: tert-butyl methyl ether; Tos: p-tolylsulfonyl.

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J. Christoffers, U. Rößler / Tetrahedron: Asymmetry 9 (1998) 2349–2357
analyses were obtained with an Analytik Jena Vario EL. Optical rotations were measured with a
Perkin–Elmer polarimeter 341. Melting points were measured with a Leica Galen III and are uncorrected.
Reagents and starting materials were purchased from common commercial suppliers and used as re-
ceived. (S)-(+)-Ethyl mandelate was synthesized according to the literature procedure from commercially
available (S)-(+)-mandelic acid.31 Et2O was freshly distilled from sodium.
3.2. (S)-(−)-Ethyl 2-(1-ethoxyethoxy)propanoate 3a
TosOH·H2O (95 mg, 0.50 mmol) was added to a solution of (S)-(−)-ethyl lactate 2a (11.8 g, 100
mmol) in ethyl vinyl ether (30 ml) at −20°C, and stirred for 45 min. The mixture was diluted with
MTB (50 ml), washed with a saturated solution of NaHCO3 (3×50 ml), and dried over MgSO4.
Evaporation of all volatile materials gave 3a (18.6 g, 97.8 mmol, 98%) as a colorless oil (mixture of
20
20
two diastereoisomers; 1:1 by 1H NMR). [α]D −80 (c 4.1, CHCl3), lit.24 [α]D −78.9 (c 4.4, CHCl3).
1H NMR (400 MHz, CDCl3): δ 1.16 (3H, t, J=6.9 Hz), 1.18 (3H, t, J=6.8 Hz), 1.21–1.32 (9H, m),
1.34–1.66 (9H, m), 3.43–3.71 (4H, m), 4.14–4.22 (5H, m), 4.33 (1H, q, J=6.9 Hz), 4.77 (1H, q, J=5.3
Hz), 4.78 (1H, q, J=5.3 Hz). 13C NMR (50 MHz, CDCl3) δ 13.94 (2CH3), 14.83 (CH3), 15.03 (CH3),
18.65 (2CH3), 19.45 (CH3), 19.75 (CH3), 59.98 (CH2), 60.48 (2CH2), 60.83 (CH2), 69.43 (CH), 69.63
(CH), 99.01 (CH), 99.17 (CH), 173.07 (C), 173.35 (C). IR (ATR): 3513 (w), 2981 (s), 2936 (m), 2903
(m), 2876 (m), 1759 (vs), 1736 (s), 1604 (w), 1447 (m), 1373 (m), 1341 (w), 1299 (m), 1271 (m), 1194
(s), 1174 (s), 1145 (s), 1096 (vs), 1081 (vs), 1055 (s), 1027 (m), 966 (m), 925 (w), 889 (w), 853 (w), 757
(w), 702 (w). MS (EI, 70 eV) m/z (%)=175 (5), 145 (25), 117 (9), 102 (10), 73 (100). HRMS: mol. mass
calcd 189.1127 (for C9H17O4), found 189.1132 (M−H+).
3.3. (S)-(+)-Ethyl 2-(1-ethoxyethoxy)-2-phenylethanoate 3b
TosOH·H2O (190 mg, 1.00 mmol) was added to a solution of (S)-(+)-ethyl mandelate 2b (18.0 g, 100
mmol) in ethyl vinyl ether (60 ml) at 0°C, and stirred for 1 h. The mixture was diluted with MTB (50
ml), washed with a saturated solution of NaHCO3 (3×50 ml), and dried over MgSO4. Evaporation of all
volatile materials gave 3b (25.2 g, 100 mmol, 100%) as a colorless oil (mixture of two diastereoisomers;
1:1 by 1H NMR). [α]D20 +62 (c 3.7, CHCl3). 1H NMR (400 MHz, CDCl3): δ 1.13 (6H, t, J=7.1 Hz), 1.18
(3H, t, J=7.2 Hz), 1.19 (3H, t, J=7.2 Hz), 1.35 (6H, d, J=5.4 Hz), 3.40–3.66 (4H, m), 4.00–4.21 (4H, m),
4.78 (1H, q, J=5.4 Hz), 4.93 (1H, q, J=5.4 Hz), 5.16 (1H, s), 5.23 (1H, s), 7.18–7.37 (6H, m), 7.42–7.48
(4H, m). 13C NMR (50 MHz, CDCl3): δ 13.67 (2CH3), 14.77 (2CH3), 19.37 (CH3), 19.63 (CH3), 60.10
(CH2), 60.33 (CH2), 60.63 (2CH2), 74.85 (CH), 75.01 (CH), 98.41 (CH), 98.79 (CH), 126.70 (2CH),
126.81 (2CH), 127.94 (CH), 128.08 (3CH), 128.14 (2CH), 136.61 (C), 136.94 (C), 170.76 (2C). IR
(ATR): 3090 (w), 3065 (w), 3032 (w), 2980 (s), 2935 (m), 2902 (m), 1751 (vs), 1733 (s), 1603 (w), 1587
(w), 1496 (w), 1478 (w), 1454 (m), 1386 (m), 1370 (m), 1338 (m), 1298 (m), 1267 (m), 1205 (s), 1176
(s), 1155 (s), 1137 (s), 1081 (vs), 1056 (vs), 1029 (s), 951 (m), 933 (m), 900 (w), 867 (m), 860 (m), 815
(w), 730 (m), 698 (s). MS (EI, 70 eV) m/z (%)=207 (6), 179 (53), 163 (82), 145 (5), 135 (20), 118 (8),
107 (29), 90 (19), 79 (25), 73 (100). HRMS: mol. mass calcd 252.1362 (for C14H20O4), found 252.1367
(M+). Anal. calcd for C14H20O4 (252.31): C 66.65, H 7.99, found C 66.47, H 7.93.
3.4. (S)-(+)-2-(1-Ethoxyethoxy)-1-propanol 4a
A solution of 3a (18.6 g, 97.8 mmol) in Et2O (40 ml) was added dropwise to a suspension of LiAlH4
(2.97 g, 78.2 mmol) in Et2O (40 ml) at −20°C, the mixture was stirred over night, and hydrolyzed with

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2353
water (20 ml). The organic layer was decanted, and the solids were washed twice with MTB (each 50
ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), and dried over
MgSO4. Evaporation of the solvents gave 4a (13.8 g, 93.1 mmol, 95%) as a colorless oil (mixture of two
20
29
diastereoisomers; 1:1 by 1H NMR). [α]D +41 (c 6.2, CHCl3), lit.17 [α]D +42.2 (c 5.87, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 1.12 (3H, d, J=6.3 Hz), 1.17 (3H, d, J=6.4 Hz), 1.21 (3H, t, J=7.0 Hz), 1.22
(3H, t, J=7.1 Hz), 1.32–1.38 (6H, m), 2.39 (1H, br s), 3.19 (1H, br s), 3.42–3.61 (7H, m), 3.67–3.73 (1H,
m), 3.77–3.84 (2H, m), 4.72 (1H, q, J=5.3 Hz), 4.80 (1H, q, J=5.3 Hz). 13C NMR (50 MHz, CDCl3): δ
15.04 (2CH3), 17.00 (CH3), 17.39 (CH3), 20.23 (CH3), 20.45 (CH3), 60.42 (CH2), 60.73 (CH2), 66.46
(CH2), 66.83 (CH2), 72.86 (CH), 75.31 (CH), 99.36 (2CH). IR (ATR): 3453 (br s), 2976 (s), 2933 (m),
2875 (m), 1725 (w), 1706 (w), 1446 (m), 1376 (s), 1336 (m), 1173 (m), 1127 (vs), 1099 (vs), 1052 (vs),
968 (s), 923 (m), 884 (w), 844 (w). MS (EI, 70 eV) m/z (%)=133 (3), 117 (7), 103 (17), 73 (100). HRMS:
mol. mass calcd 147.1021 (for C7H15O3), found 147.1019 (M−H+).
3.5. (S)-(+)-2-(1-Ethoxyethoxy)-2-phenyl-1-ethanol 4b
A solution of 3b (25.2 g, 100 mmol) in Et2O (40 ml) was added dropwise to a suspension of LiAlH4
(3.40 g, 89.5 mmol) in Et2O (40 ml) at −20°C, the mixture was stirred over night, and hydrolyzed with
water (30 ml). The organic layer was decanted, and the solids were washed twice with MTB (each 50
ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), and dried over
MgSO4. Evaporation of the solvents gave 4b (20.6 g, 97.8 mmol, 98%) as a colorless oil (mixture of two
1
20
1
diastereoisomers; 1:1 by H NMR). [α]D +140 (c 4.9, CHCl3). H NMR (400 MHz, CDCl3): δ 1.02
(3H, t, J=7.1 Hz), 1.21 (3H, t, J=7.1 Hz), 1.30–1.36 (6H, m), 2.36 (1H, dd, J=3.9 Hz, J=9.4 Hz), 2.70
(1H, dd, J=3.5 Hz, J=9.4 Hz), 3.20–3.29 (1H, m), 3.52–3.74 (7H, m), 4.58–4.67 (2H, m), 4.74–4.81 (2H,
m), 7.25–7.39 (10H, m). 13C NMR (50 MHz, CDCl3): δ 14.65 (CH3), 15.09 (CH3), 20.12 (CH3), 20.27
(CH3), 60.39 (CH2), 60.57 (CH2), 66.90 (CH2), 67.08 (CH2), 78.51 (CH), 79.67 (CH), 98.32 (CH), 99.52
(CH), 126.62 (2CH), 126.67 (2CH), 127.59 (CH), 127.73 (CH), 128.09 (2CH), 128.20 (2CH), 138.83
(C), 139.68 (C). IR (ATR): 3442 (br vs), 3086 (w), 3063 (w), 3031 (w), 2978 (s), 2932 (m), 2877 (m),
1604 (w), 1586 (w), 1453 (m), 1386 (s), 1340 (m), 1311 (w), 1226 (w), 1128 (vs), 1093 (vs), 1078 (vs),
1047 (vs), 1027 (vs), 954 (s), 918 (m), 957 (m), 849 (m), 759 (s), 701 (vs). MS (EI, 70 eV) m/z (%)=179
(45), 134 (9), 121 (99), 107 (20), 103 (44), 91 (37), 79 (22), 77 (37), 73 (100). HRMS: mol. mass calcd
179.1072 (for C11H15O2), found 179.1072 (M−CH2OH+). Anal. calcd for C12H18O3 (210.27): C 68.55,
H 8.63, found C 68.18, H 8.80.
3.6. (S)-(+)-2-Hydroxy-1-propyl tosylate 5a
TosCl (13.9 g, 73.1 mmol) was added to a solution of 4a (7.22 g, 48.7 mmol) in pyridine (70 ml), and
stirred over night at room temperature. Water (50 ml) and CH2Cl2 (50 ml) were added, and the mixture
was stirred for 30 min. The layers were separated, and the aqueous layer was extracted with CH2Cl2
(3×100 ml). The combined organic layers were washed five times with hydrochloric acid (18%, each
100 ml), then with water (200 ml) and brine (200 ml). The solution was dried over MgSO4, evaporated,
and the crude product was chromatographed (SiO2, MTB, Rf=0.45) to give 5a (10.2 g, 44.4 mmol, 91%)
as a colorless solid (mp 34°C, lit.19 36°C). [α]D20 +11 (c 5.4, CHCl3), lit.19 [α]D +10.3 (c 4.57, CHCl3).
1H NMR (400 MHz, CDCl3): δ 1.16 (3H, d, J=7.3 Hz), 2.03 (1H, br s), 2.45 (3H, s), 3.85 (1H, dd, J=7.3
Hz, J=10.0 Hz), 4.00 (1H, dd, J=3.0 Hz, J=10.0 Hz), 4.02–4.09 (1H, m), 7.34–7.38 (2H, m), 7.78–7.82
(2H, m). 13C NMR (50 MHz, CDCl3): δ 18.94 (CH3), 21.62 (CH3), 65.59 (CH), 74.77 (CH2), 127.92
(2CH), 129.93 (2CH), 132.63 (C), 145.06 (C). IR (ATR): 3065 (w), 3031 (w), 2979 (w), 2932 (w), 2895

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J. Christoffers, U. Rößler / Tetrahedron: Asymmetry 9 (1998) 2349–2357
(w), 2875 (w), 1726 (w), 1598 (w), 1494 (w), 1453 (w), 1361 (s), 1307 (w), 1291 (w), 1189 (s), 1176
(vs), 1129 (m), 1096 (s), 1079 (s), 1055 (m), 1026 (m), 976 (s), 958 (s), 922 (m), 874 (m), 814 (m), 775
(m), 760 (m), 701 (s), 666 (s). MS (EI, 70 eV) m/z (%)=230 (1), 200 (49), 156 (98), 155 (36), 139 (6),
107 (9), 92 (100), 91 (96), 77 (4), 65 (28). HRMS: mol. mass calcd 230.0613 (for C10H14O4S), found
230.0613 (M+). Anal. calcd for C10H14O4S (230.28): C 52.16, H 6.13, found C 52.14, H 6.17.
3.7. (S)-(+)-2-Hydroxy-2-phenyl-1-ethyl tosylate 5b
TosCl (17.2 g, 90.0 mmol) was added to a solution of 4b (12.6 g, 60.0 mmol) in pyridine (75 ml), and
stirred over night at room temperature. Water (150 ml) and CH2Cl2 (50 ml) were added, and the mixture
was stirred for 45 min. The layers were separated, and the aqueous layer was extracted with CH2Cl2
(3×100 ml). The combined organic layers were washed four times with hydrochloric acid (18%, each
200 ml), with water (200 ml), and with brine (200 ml). The solution was dried over MgSO4, evaporated,
and the crude product was chromatographed (SiO2, MTB:hexane 1:1, Rf=0.34) to give 5b (16.4 g, 56.1
mmol, 94%) as a colorless solid (mp 73°C, lit.21 65–66°C). [α]D +55 (c 2.4, CHCl3), lit.21 [α]D
20
25
+51.1 (c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3): δ 2.44 (3H, s), 2.58 (1H, br s), 4.04 (1H, dd, J=8.6
Hz, J=10.4 Hz), 4.14 (1H, dd, J=3.3 Hz, J=10.4 Hz), 4.97 (1H, dd, J=3.3 Hz, J=8.6 Hz), 7.28–7.37 (7H,
m), 7.73–7.79 (2H, m). 13C NMR (50 MHz, CDCl3): δ 21.60 (CH3), 71.85 (CH), 74.27 (CH2), 126.14
(2CH), 127.90 (2CH), 128.44 (CH), 128.60 (2CH), 129.89 (2CH), 132.58 (C), 138.23 (C), 145.03 (C).
IR (ATR): 3523 (br m), 3063 (w), 3031 (w), 2946 (w), 2891 (w), 1597 (w), 1495 (w), 1453 (w), 1401
(w), 1355 (s), 1308 (w), 1293 (w), 1189 (m), 1174 (vs), 1096 (m), 1070 (w), 1019 (w), 968 (s), 917 (w),
867 (m), 814 (m), 774 (m), 759 (w), 700 (m), 667 (s). MS (EI, 70 eV) m/z (%)=275 (40), 262 (14), 217
(4), 155 (57), 139 (4), 120 (7), 107 (100), 91 (75), 79 (26), 77 (19), 73 (35), 65 (17). HRMS: mol. mass
calcd 275.0742 (for C15H15O3S), found 275.0743 (M−OH+). Anal. calcd for C15H16O4S (292.36): C
61.63, H 5.52, found C 61.37, H 5.58.
3.8. (S,S)-(+)-Bis(2-hydroxy-1-propyl) thioether 1a
A mixture of 5a (1.15 g, 5.00 mmol) and Na2S·H2O (65%, 480 mg, 4.00 mmol) in acetone (3 ml)
was stirred in a tightly closed reaction flask over night at 70°C. The mixture was diluted with CH2Cl2
(25 ml), dried over MgSO4, and evaporated to dryness. The crude product was chromatographed (SiO2,
MTB, Rf=0.16) to give 1a (330 mg, 2.20 mmol, 88%) as a colorless oil. [α]D20 +110 (c 3.4, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 1.25 (6H, d, J=6.2 Hz), 2.49 (2H, dd, J=8.4 Hz, J=13.8 Hz), 2.61 (2H, br s),
2.75 (2H, dd, J=3.4 Hz, J=13.8 Hz), 3.84–3.94 (2H, m). 13C NMR (50 MHz, CDCl3): δ 21.98 (2CH3),
41.46 (2CH2), 66.14 (2CH). IR (ATR): 3352 (br vs), 2968 (s), 2913 (m), 1453 (m), 1406 (m), 1371 (s),
1339 (m), 1300 (m), 1328 (w), 1192 (w), 1123 (vs), 1065 (vs), 1030 (vs), 934 (vs), 880 (w), 861 (w),
826 (m). MS (EI, 70 eV) m/z (%)=150 (3), 132 (2), 117 (6), 106 (100), 99 (5), 88 (21), 75 (28), 62 (99).
HRMS: mol. mass calcd 150.0715 (for C6H14O2S), found 150.0718 (M+). Anal. calcd for C6H14O2S
(150.24): C 47.97, H 9.39, found C 47.88, H 9.57.
3.9. (S,S)-(+)-Bis(2-hydroxy-2-phenyl-1-ethyl) thioether 1b
A mixture of 5b (1.46 g, 5.00 mmol) and Na2S·H2O (65%, 480 mg, 4.00 mmol) in acetone (3 ml)
was stirred in a tightly closed reaction flask over night at 70°C. The mixture was diluted with CH2Cl2
(25 ml), dried over MgSO4, and evaporated to dryness. The crude product was chromatographed (SiO2,
20
MTB:hexane 1:1, Rf=0.24) to give 1b (562 mg, 2.05 mmol, 82%) as a colorless oil. [α]D +96 (c 1.7,

J. Christoffers, U. Rößler / Tetrahedron: Asymmetry 9 (1998) 2349–2357
2355
1
CHCl3). H NMR (40 MHz, CDCl3): δ 2.77 (2H, dd, J=8.9 Hz, J=14.0 Hz), 2.90 (2H, dd, J=3.7 Hz,
J=14.0 Hz), 3.20 (2H, br s), 4.77 (2H, dd, J=3.7 Hz, J=8.9 Hz), 7.24–7.44 (10H, m). 13C NMR (50 MHz,
CDCl3): δ 41.74 (2CH2), 72.50 (2CH), 125.76 (4CH), 127.88 (2CH), 128.50 (4CH), 142.42 (2C). IR
(ATR): 3402 (br vs), 3085 (w), 3061 (w), 3029 (w), 2954 (w), 2914 (w), 2885 (w), 1700 (w), 1602 (w),
1493 (m), 1453 (m), 1408 (m), 1333 (w), 1298 (w), 1230 (w), 1196 (m), 1156 (w), 1081 (w), 1057 (s),
1028 (m), 1003 (m), 916 (w), 865 (w), 848 (w), 768 (m), 737 (m), 698 (vs). MS (EI, 70 eV) m/z (%)=274
(1), 257 (100), 239 (49), 213 (25), 205 (33), 174 (22), 137 (84), 135 (34), 121 (23), 107 (60), 104 (81),
91 (31), 79 (31), 77 (28). HRMS: mol. mass calcd 274.1028 (for C16H18O2S), found 274.1033 (M+).
3.10. (S)-(−)-2-(1-Ethoxyethoxy)-1-propyl tosylate 6a
TosOH·H2O (19 mg, 0.10 mmol) was added to a solution of 5a (1.15 g, 5.00 mmol) in ethyl vinyl
ether (10 ml) and MTB (10 ml) at −20°C, and stirred for 1 h. The mixture was diluted with MTB (30
ml), washed three times with a saturated solution of NaHCO3 (each 30 ml), dried over MgSO4, and
evaporated to dryness. The crude product was chromatographed (SiO2, MTB:hexane 1:2, Rf=0.35) to
give 6a (1.46 g, 4.83 mmol, 97%) as a colorless oil (mixture of two diastereoisomers; 1:1 by 1H NMR).
[α]D −11 (c 4.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 1.08–1.19 (12H, m), 1.20–1.24 (6H, m), 2.43
20
(6H, s), 3.36–3.46 (2H, m), 3.50–3.60 (2H, m), 3.81–4.01 (6H, m), 4.70 (2H, q, J=5.3 Hz), 7.30–7.36
(4H, m), 7.74–7.80 (4H, m). 13C NMR (50 MHz, CDCl3): δ 15.10 (CH3), 15.15 (CH3), 17.14 (CH3),
17.95 (CH3), 20.29 (2CH3), 21.54 (2CH3), 60.00 (CH2), 60.28 (CH2), 68.59 (CH), 69.55 (CH), 72.89
(2CH2), 98.45 (CH), 99.88 (CH), 127.84 (2CH), 127.88 (2CH), 129.73 (2CH), 129.79 (2CH), 132.87
(2CH), 144.72 (C), 144.80 (C). IR (ATR): 2980 (m), 2935 (m), 2898 (m), 1598 (m), 1495 (w), 1452 (m),
1360 (vs), 1308 (w), 1292 (w), 1211 (w), 1190 (s), 1177 (vs), 1133 (s), 1121 (s), 1097 (s), 1079 (s), 1055
(m), 1020 (w), 990 (s), 963 (s), 931 (m), 828 (s), 815 (s), 792 (m), 706 (w), 688 (w), 667 (s). MS (EI, 70
eV) m/z (%)=302 (1), 287 (2), 257 (5), 217 (6), 213 (21), 200 (15), 173 (4), 156 (33), 155 (58), 139 (3),
107 (5), 92 (50), 91 (81), 73 (100), 65 (21). HRMS: mol. mass calcd 302.1188 (for C14H22O5S), found
302.1191 (M+).
3.11. (S)-(+)-2-(1-Ethoxyethoxy)-2-phenyl-1-ethyl tosylate 6b
TosOH·H2O (19 mg, 0.10 mmol) was added to a solution of 5b (1.46 g, 5.00 mmol) in ethyl vinyl
ether (10 ml) and MTB (20 ml) at −5°C, and stirred for 1 h. The mixture was diluted with MTB (50
ml), washed three times with a saturated solution of NaHCO3 (each 40 ml), dried over MgSO4, and
evaporated to dryness. The crude product was chromatographed (SiO2, MTB:hexane 1:2, Rf=0.39) to
give 6b (1.77 g, 4.85 mmol, 97%) as a colorless oil (mixture of two diastereoisomers; 1:1 by 1H NMR).
20
1
[α]D +86 (c 2.9, CHCl3). H NMR (400 MHz, CDCl3): δ 0.98 (3H, t, J=7.0 Hz), 1.13 (3H, t, J=7.0
Hz), 1.18–1.26 (6H, m), 2.44 (6H, m), 3.18–3.28 (1H, m), 3.46–3.61 (3H, m), 4.00–4.17 (4H, m), 4.60
(1H, q, J=5.4 Hz), 4.75–4.85 (2H, m), 4.88 (1H, dd, J=4.2 Hz, J=8.0 Hz), 7.22–7.36 (14H, m), 7.69–7.79
(4H, m). 13C NMR (50 MHz, CDCl3): δ 14.81 (CH3), 15.17 (CH3), 20.01 (CH3), 20.40 (CH3), 21.56
(2CH3), 59.29 (CH2), 61.15 (CH2), 72.63 (CH2), 72.99 (CH2), 74.79 (CH), 74.86 (CH), 97.68 (CH),
100.14 (CH), 126.64 (2CH), 127.06 (2CH), 127.83 (4CH), 128.15 (CH), 128.44 (3CH), 128.55 (2CH),
129.69 (2CH), 129.75 (2CH), 132.90 (C), 132.96 (C), 137.45 (C), 138.50 (C), 144.61 (C), 144.69 (C).
IR (ATR): 2979 (w), 2936 (w), 2879 (w), 1597 (w), 1495 (w), 1452 (w), 1400 (w), 1353 (s), 1307 (w),
1291 (w), 1189 (m), 1173 (vs), 1096 (m), 1019 (w), 974 (s), 928 (s), 857 (m), 829 (m), 812 (s), 791 (m),
705 (w), 688 (w), 665 (s). MS (EI, 70 eV) m/z (%)=319 (1), 275 (6), 228 (4), 217 (8), 155 (16), 104 (6),

2356
J. Christoffers, U. Rößler / Tetrahedron: Asymmetry 9 (1998) 2349–2357
91 (27), 77 (4), 73 (100), 65 (6). HRMS: mol. mass calcd 319.1004 (for C17H19O4S), found 319.1006
+
(M−OCH2CH3 ). Anal. calcd for C19H24O5S (364.46): C 62.62, H 6.64, found C 62.29, H 6.61.
3.12. (S,S)-(+)-Bis(2-hydroxy-1-propyl) ether 1c
A solution of 4a (296 mg, 2.00 mmol) and 6a (605 mg, 2.00 mmol) in DMF (1 ml) was added dropwise
to a suspension of NaH (80% dispersion in mineral oil, 120 mg, 4.00 mmol) in DMF (1 ml) under an
atmosphere of Ar. The mixture was stirred over night at room temperature, subsequently hydrolyzed
with water (20 ml), and extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried over
MgSO4 and evaporated to dryness. The residue was taken up in CH2Cl2 (5 ml), stirred over an acidic
ion exchanger resin (88.0 mg, DOWEX 50 W×8) for three days, filtered, and evaporated to dryness.
The residue was chromatographed (SiO2, MTB, Rf=0.18) to give 1a (111 mg, 0.827 mmol, 41%) as a
colorless oil. [α]D +52, [α]365 +148, [α]436 +98, [α]546 +60, [α]578 +53 (c 2.3, CHCl3), lit.9
20
20
20
20
20
[α]Hg +57.62 (c 2.505, CHCl3). 1H NMR (400 MHz, CDCl3): δ 1.15 (6H, d, J=6.3 Hz), 2.45 (2H, br
26
s), 3.32 (2H, dd, J=8.3 Hz, J=9.7 Hz), 3.46 (2H, dd, J=3.0 Hz, J=9.7 Hz), 3.95–4.05 (2H, m). 13C NMR
(50 MHz, CDCl3): δ 18.50 (2CH3), 65.77 (2CH), 76.42 (2CH2). IR (ATR): 3368 (br vs), 2971 (m), 2931
(m), 2866 (s), 1453 (w), 1422 (w), 1376 (m), 1355 (w), 1144 (s), 1103 (vs), 933 (m), 979 (s), 944 (m),
956 (m), 841 (w). MS (EI, 70 eV) m/z (%)=101 (2), 89 (91), 71 (9), 59 (100), 57 (16). HRMS: mol. mass
calcd 89.0603 (for C4H9O2), found 89.0610 [M+−C(OH)HCH3]. Anal. calcd for C6H14O3 (134.17): C
53.71, H 10.52, found C 53.63, H 10.66.
3.13. trans-(2S,4S)-(+)-2-Benzyl-4-phenyl-1,3-dioxolan 7a and cis-(2R,4S)-(+)-isomer 7b
Pyridine (79 mg, 1.0 mmol) was added to a solution of 4b (210 mg, 1.00 mmol) in THF (1 ml) under
an atmosphere of Ar at −30°C. The mixture was stirred for 30 min, then (CF3SO2)2O (141 mg, 0.500
mmol) was added dropwise, and the resulting mixture was stirred for another 45 min at −30°C. After
hydrolyzation with water (10 ml), the mixture was extracted three times with CH2Cl2 (each 10 ml), and
the combined organic layers were dried over MgSO4. After removal of the solvents, the residue was
chromatographed (SiO2, MTB:hexane 1:10) to give 7a (22.5 mg, 0.0936 mmol, 19%, Rf=0.39) as a
brownish solid (mp 42°C, lit.27 33–34°C) and 7b (20.0 mg, 0.0832 mmol, 17%, Rf=0.33) as a yellowish
oil. 7a: [α]D +45 (c 1.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ 3.04 (1H, dd, J=5.1 Hz, J=14.0 Hz),
20
3.10 (1H, dd, J=4.2 Hz, J=14.0 Hz), 3.68 (1H, dd, J=7.7 Hz, J=8.3 Hz), 4.37 (1H, dd, J=6.3 Hz, J=8.3
Hz), 4.99 (1H, dd, J=6.3 Hz, J=7.7 Hz), 5.49 (1H, dd, J=4.2 Hz, J=5.1 Hz), 7.22–7.46 (10H, m). 13C
NMR (50 MHz, CDCl3): δ 41.24 (CH2), 72.68 (CH2), 77.72 (CH), 105.69 (CH), 125.99 (2CH), 126.59
(CH), 127.99 (CH), 128.31 (2CH), 128.58 (2CH), 129.82 (2CH), 136.00 (C), 139.51 (C). IR (ATR):
3086 (w), 3063 (w), 3029 (w), 2950 (w), 2923 (w), 2870 (m), 1604 (w), 1495 (m), 1454 (m), 1399 (w),
1341 (w), 1306 (w), 1208 (w), 1133 (vs), 1079 (m), 1042 (m), 1029 (m), 987 (s), 939 (w), 908 (w), 842
(w), 754 (s), 698 (vs). MS (EI, 70 eV) m/z (%)=239 (1), 149 (54), 121 (100), 103 (79), 91 (52), 77 (31),
65 (20). HRMS: mol. mass calcd 239.1072 (for C16H15O2), found 239.1076 (M−H+). 7b: [α]D20 +48 (c
1.2, CHCl3). 1H NMR (400 MHz, CDCl3): δ 3.11 (1H, dd, J=4.8 Hz, J=14.0 Hz), 3.17 (1H, dd, J=4.4 Hz,
J=14.0 Hz), 3.70 (1H, dd, J=6.7 Hz, J=7.9 Hz), 4.18 (1H, dd, J=7.0 Hz, J=7.9 Hz), 5.01 (1H, dd, J=6.7
Hz, J=7.0 Hz), 5.31 (1H, dd, J=4.4 Hz, J=4.8 Hz), 7.20–7.44 (10H, m). 13C NMR (50 MHz, CDCl3): δ
40.80 (CH2), 71.98 (CH2), 78.46 (CH), 105.35 (CH), 126.36 (2CH), 126.65 (CH), 128.10 (CH), 128.30
(2CH), 128.49 (2CH), 129.91 (2CH), 135.95 (C), 139.37 (C). IR (ATR): 1/λ=3086 (w), 3063 (w), 3030
(w), 2951 (w), 2924 (w), 2878 (m), 1726 (w), 1605 (w), 1495 (m), 1454 (m), 1404 (w), 1372 (w), 1345
(w), 1307 (w), 1286 (w), 1204 (w), 1134 (vs), 1080 (m), 1042 (m), 1028 (m), 1002 (m), 951 (w), 910

J. Christoffers, U. Rößler / Tetrahedron: Asymmetry 9 (1998) 2349–2357
2357
(w), 844 (w), 823 (w), 754 (s), 697 (vs). MS (EI, 70 eV) m/z (%)=239 (1), 149 (100), 121 (98), 103 (58),
91 (66), 77 (14), 65 (10). HRMS: mol. mass calcd 239.1072 (for C16H15O2), found 239.1071 (M−H+).
Anal. calcd for C16H16O2 (240.30): C 79.97, H 6.71, found C 79.67, H 6.83.
Acknowledgements
Support from Professor S. Blechert and the Institut für Organische Chemie der Technischen Universität
Berlin as well as financial aid from the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged. J. C. also thanks the Fonds der Chemischen Industrie for a
fellowship.
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