Baker's yeast mediated reduction of dihydroxyacetone derivatives

Article abstract of DOI:10.1016/S0957-4166(99)00415-2

Several monoprotected dihydroxyacetone derivatives 4a-d and their acetates 5a-d were prepared and subjected to biotransformation with baker's yeast. The simple chemical modification of the substrates (i.e. transforming the relatively small hydrophilic hyd

Full text of DOI:10.1016/S0957-4166(99)00415-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4017–4028
Baker’s yeast mediated reduction of dihydroxyacetone
derivatives
József Bálint,a Gabriella Egri,a Attila Kolbert,a,b Csilla Dianóczky,b Elemér Fogassy,a
Lajos Novák b and László Poppe c,∗
aDepartment of Organic Chemical Technology, Technical University of Budapest, H-1111 Budapest, Müegyetem rkp 3,
Hungary
bInstitute for Organic Chemistry, Technical University of Budapest, H-1111 Budapest, Gellért tér 4, Hungary
cChemical Research Center, Institute for Chemistry, Hungarian Academy of Sciences, H-1525 Budapest, PO Box 17, Hungary
Received 7 September 1999; accepted 15 September 1999
Abstract
Several monoprotected dihydroxyacetone derivatives 4a–d and their acetates 5a–d were prepared and subjected
to biotransformation with baker’s yeast. The simple chemical modification of the substrates (i.e. transforming
the relatively small hydrophilic hydroxymethyl group into a larger hydrophobic acetoxymethyl moiety) inverted
the sense of enantiotope selectivity of these reductions yielding optically active diols 6a–d, or their enantiomeric
acetates (7a–d) and diols (ent-6a–d), respectively. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Recently, the synthesis of optically active molecules has attracted interest due to the different effects
of enantiomers. In pharmacy, these differences can be observed in therapeutic effects1 and also in
adsorption, metabolism and excretion.2 Since biological systems are asymmetric catalysts by their nature,
biocatalytic methods are widely applied for the preparation of optically active compounds.3
In the preparation of homochiral biologically active molecules, such as PAF (platelet-activating
factor),4 phospholipids,5 phospholipase A2 inhibitors,6 and many others,7 chiral glycerol derivatives
of high enantiomeric purity might be useful C3 building blocks. Enantiomer selective biocatalytical
methods, e.g. hydrolase-catalyzed kinetic resolution of racemic glycerol derivatives such as glycerol
acetonide,8,9 or glycerol-2,3-carbonate,10 provided moderate selectivity and 50% theoretical limit of the
desired enantiomer.
∗
Corresponding author. E-mail: poppe.szk@chem.bme.hu
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00415-2

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Enantiotope selective reduction of prochiral ketones theoretically enables the total conversion of
the substrate into a single enantiomer of the product chiral secondary alcohol. Such prochiral ketone
precursors of chiral C3 building blocks are protected dihydroxyacetone derivatives. Accordingly, several
chiral C3 derivatives have already been prepared by chiral ruthenium complex-catalyzed asymmetric
reductions.11–13 The enantiotope selective baker’s yeast reduction might be considered as a convenient
biocatalytic alternative to these methods. The 3-methoxy-,14 3-benzoyloxy- and 3-(4-nitrobenzoyl)-
oxy-15 1-hydroxyacetone derivatives and the 3-benzoyloxy-15 and 3-aryloxy-16 1-acetoxyacetone de-
rivatives were reduced by baker’s yeast with various results. Although methods from 3-O-protected
dihydroxyacetone derivatives leading to opposite enantiomeric forms may increase the synthetic value
of the process, baker’s yeast reduction of the 1-hydroxy- and 1-acetoxy-derivatives of 3-O-protected
dihydroxyacetones with the same protective group has never been performed.
The known examples for enantiotope selective reduction of hydroxymethyl ketones or their acetates by
baker’s yeast14,17–19 showed that ketones with the relatively small and hydrophilic hydroxymethyl group
were reduced similarly in a geometrical sense (as a result of the sequence rules, however, the products
may have different configuration labels). On the other hand, acetoxymethyl ketones were reduced with
the opposite sense of enantiotopic preference. This inversion in the sense of enantiomeric preference
was demonstrated by baker’s yeast reduction of phenacyl alcohols and their acetates.19–21 It should be
mentioned here that reduction of hydroxymethyl ketones and their acetates by Geotrichum sp. 38 was
reported to proceed without inversion of the sense of the enantiotopic selectivity.22
Since the monoprotected dihydroxyacetone derivatives are precursors of chiral C3 building blocks,
and their acetates could presumably be reduced by baker’s yeast with opposite enantiopreference, we
thought it worthwhile investigating the bioreduction of these compounds. Here we report the baker’s
yeast reduction of several synthetically useful monoprotected dihydroxyacetone derivatives 4a–d and
their acetates 5a–d.
2. Results and discussion
The preparation of the monoprotected dihydroxyacetone derivatives 4a–d and their acetates 5a–d
was straightforward starting from dihydroxyacetone 1 as outlined in Fig. 1. Ketones 4a15 and 4b
were prepared by monoacylation of the dihydroxyacetone (1, existing mostly in dimeric form) by
benzoyl chloride and pivaloyl chloride, respectively. The benzyloxymethyl ketone 4c was obtained11
from the dimethyl ketal of dihydroxyacetone 2 by subsequent benzylation and acidic deketalization.
Monosilylation23 of dihydroxyacetone 1 provided the ketone 4d smoothly. The acetoxymethyl ketones
5a–d were obtained from their hydroxymethyl precursors (4a–d, respectively) by simple acetylation.
Since stereoselectivity of baker’s yeast-catalyzed reactions may depend considerably on the reaction
conditions (pH, solvent, additives, etc.), it was desirable to find the optimum. Hence, reaction conditions
of the baker’s yeast reduction of 1-benzoyloxy-3-hydroxypropan-2-one 4a were investigated (Table 1).
The different reaction conditions were chosen by analogies with published modifications of reaction
conditions increasing the stereoselectivity of carbonyl-reductions by baker’s yeast. Reductions in apolar
hydrocarbons with ‘non-fermenting’ baker’s yeast resulted in increased selectivities.24,25 Such selectivity
enhancement was obtained by using N2-atmosphere and cosolvent like DMSO.15 Some sulfur-containing
additives, such as L-cysteine or cysteamine, also produced significant selectivity enhancement in the
reductions of 1-acetoxyalkan-2-ones.26 It should be noted, however, that these additives were also used
to suppress the hydrolysis of the ester function in these reactions. Ethanolamine as a possible substitute
for the L-cysteine or cysteamine was also tested as an additive.

J. Bálint et al. / Tetrahedron: Asymmetry 10 (1999) 4017–4028
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Figure 1. Preparation of hydroxymethyl ketones 4a–d and their acetates 5a–d. Reagents and solvents: (i) trimethyl orthoformate
in MeOH; (ii) BnBr, NaH in THF; (iii) 3 M HCl; (iv) BzCl, cat. DMAP, pyridine (for 4a), PivCl, cat. DMAP, pyridine (for 4b)
or TBDMSCl, imidazole in THF (for 4d); (v) Ac2O, cat. DMAP, Et3N in ethyl acetate (for 5a,c,d) or AcCl, cat. DMAP, Et3N
in THF (for 5b)
Although alcohol dehydrogenases can operate in ethanol as solvent, no reduction was observed in
neat ethanol (Entry 1). Reactions with the traditional ‘non-fermenting’ yeast (Entry 2) or with ‘non-
fermenting’ yeast in the presence of ethanol as coupled substrate in cofactor regeneration under N2
(Entry 3) proceeded with moderate selectivities. The low isolated yields in hexane (Entries 4, 5 and
8) indicated low productivity/conversion without significant increase in selectivity. The productivities
and selectivities of systems containing glucose were better (Entries 6–9). The best selectivity yielding
homochiral diol 6a was achieved by ‘fermenting’ baker’s yeast under anerobic conditions with ethanol
as cosolvent and L-cysteine as an additive (Entry 9).
The reaction conditions for the further compounds were optimized in a similar way. The reductions of
these ketones 4b–d and 5a–d were conducted under the conditions which gave the highest enantiotopic
selectivities, as listed in Table 2. The results achieved by the baker’s yeast reduction of the hydroxymethyl
ketones 4a–d and their acetates 5a–d confirmed the previous findings19–21 and our expectations: the
geometrical sense of the enantiotopic preference altered in all the cases when the hydroxymethyl ketones
4a–d versus their acetates 5a–d were reduced.
In the case of reduction of acetates 5a–d, however, substantial amounts of diols ent-6a–d were also
produced. Configuration of these diols ent-6a–d was opposite to the diols 6a–d from reduction of
the hydroxymethyl ketones 4a–d. These data confirmed that diols ent-6a–d were produced mostly by
reduction of the acetoxymethyl ketones 5a–d followed by an enzymatic hydrolysis, and were consistent
with our previous results on baker’s yeast reduction of 1-acetoxy-3-aryloxypropan-2-ones,16 where the
geometrical sense of enantiotopic preference was the same as for the present ketones 5a–d and different
amounts of hydrolyzed products from enzymatic hydrolysis were also obtained.27
Since the hydroxymethyl ketones 4a–d were reduced substantially slower and with opposite enantio-
topic preferences than the acetoxymethyl ketones 5a–d, our results further support the hypothesis19–21
assuming that these two classes of ketones are reduced mostly by different enzymes of the baker’s yeast
system.

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Table 1
Dependence of the stereoselectivity on the reaction conditions in reduction of ketone 4a
3. Conclusions
Our results showed that the monoprotected dihydroxyacetone derivatives 4a–d and their acetates 5a–d
are synthetically useful precursors of different chiral C3 building blocks. In accordance with the previous
findings, these hydroxymethyl 4a–d and acetoxymethyl 5a–d ketones were reduced by baker’s yeast
oppositely in a geometrical sense, yielding optically active diols 6a–d, or monoacetates 7a–d and the
enantiomeric diols ent-6a–d, respectively.
4. Experimental
1
The H NMR spectra were recorded on a Bruker AW-250 spectrometer operating at 250 MHz. For
enantiomeric excess determinations, a Bruker DRX-500 spectrometer operating at 500 MHz was used.
All spectra were taken in CDCl3 solution and chemical shifts are expressed in ppm values from TMS as
internal standard on δ scale. IR spectra of thin film samples were taken on a Specord 2000 spectrometer.
Optical rotations were determined on a Perkin–Elmer 241 polarimeter. Thin layer chromatography was
carried out using Merck Kieselgel 60 F254 alumina sheets (using hexane:acetone, 10:4, if not stated

J. Bálint et al. / Tetrahedron: Asymmetry 10 (1999) 4017–4028
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Table 2
Results for baker’s yeast reduction of monoprotected dihydroxyacetone derivatives 4a–d and their
acetates 5a–d
otherwise). Spots were visualized by treatment with 5% ethanolic phosphomolybdic acid solution and
heating of the dried plates. Preparative chromatographic separations were performed using vacuum-
chromatography28 on a Merck Kieselgel 60 (0.063–0.200 mm). Chemicals were products of Fluka
or Aldrich. All solvents used were freshly distilled. Baker’s yeast manufactured by Budafok factory,
Budapest, was obtained from a local store.
4.1. 1-Benzoyloxy-3-hydroxypropan-2-one 4a15
The reaction15 starting from 1,3-dihydroxyacetone (1, 20 g, 222 mmol) yielded the desired ketone (4a,
14 g, 32%) as a colorless crystalline solid. Mp: 92–93°C (lit.:15 95–97°C); IR (KBr): 3430 (br), 1718,
1
1602, 1452, 1376, 1278, 1180, 1111, 1072, 924, 811, 709 cm−1; H NMR: 4.50 (s, 2H, O-CH2), 5.03

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(s, 2H, CH2-OBz), 5.53 (br s, 1H, OH), 7.47 (t, 2H, m-ArH), 7.58 (t, 1H, p-ArH), 8.10 (d, 2H, o-ArH).
Calcd for C10H10O4: C, 61.85; H, 5.19. Found: C, 61.66; H, 5.21.
4.2. 1-Hydroxy-3-pivaloyloxypropan-2-one 4b
To a stirred solution of 1,3-dihydroxyacetone (1, 6.75 g, 75 mmol) and 4-(dimethylamino)pyridine
(0.1 g) in pyridine (45 ml) pivaloyl chloride (6.1 ml, 50 mmol) was added dropwise at 24–25°C. After
stirring the resulting mixture at room temperature overnight pyridine was evaporated in vacuo. The
residue was diluted with ethyl acetate (100 ml) and washed with 5% HCl (2×20 ml). The aqueous phase
was re-extracted with ethyl acetate (2×30 ml). The combined organic phases were washed with saturated
NaHCO3 solution (30 ml) and brine (30 ml). After drying over MgSO4 the solvent was evaporated and
the residual solid was recrystallized from hexane to yield a crystalline product (4b, 3.75 g, 43%). IR
(KBr): 3408, 2960, 2930, 1735, 1725, 1470, 1360, 1280, 1170, 1070, 880 cm−1; 1H NMR: 1.25 (s, 9H,
3 CH3), 4.37 (s, 2H, O-CH2), 4.73 (s, 2H, CH2-OPiv). Calcd for C8H14O4: C, 55.16; H, 8.10. Found: C,
55.40; H, 8.07.
4.3. 1-Benzyloxy-3-hydroxypropan-2-one 4c11
Preparation of the monobenzylated dihydroxyacetone 4a11 started from 1,3-dihydroxyacetone (1, 2.25
1
g, 25 mmol) and via the intermediates 2,2-dimethoxypropane-1,3-diol [2, 90%, H NMR: 3.31 (s, 6H,
2 OCH3), 3.67 (s, 4H, 2 CH2O] and 1-benzyloxy-2,2-dimethoxypropan-3-ol [3, 52%, 1H NMR: 3.27 (s,
6H, 2 OCH3), 3.53 (s, 2H, CH2-OBn), 3.70 (s, 2H, O-CH2), 4.58 (s, 2H, OCH2Ph), 7.32 (m, 5H, ArH)]
resulted in a homogeneous oily product (4c, 1.74 g, 39% overall). IR: 3440 (br), 2869, 1731, 1496,
1434, 1209, 1103, 1028, 741 cm−1; 1H NMR: 4.19 (s, 2H, CH2-OBn), 4.47 (s, 2H, O-CH2), 4.60 (s, 2H,
OCH2Ph), 7.35 (m, 5H, ArH). Calcd for C10H10O4: C, 66.65; H, 6.71. Found: C, 66.33; H, 6.73.
4.4. 1-(tert-Butyldimethylsilyl)oxy-3-hydroxypropan-2-one 4d23
Silylation23 from 1,3-dihydroxyacetone (1, 2.0 g, 22.2 mmol) provided the desired ketone (4d, 1.39 g,
60%) as a colorless oil. IR: 3430 (br), 2970, 2940, 2890, 2870, 1740, 1490, 1270, 1105, 855, 795 cm−1;
1H NMR: 0.03 (s, 6H, 2 CH3-Si), 0.91 (s, 9H, 3 CH3), 4.30 (s, 2H, CH2-OTBDMS), 4.49 (s, 2H, O-CH2).
Calcd for C9H20O3Si: C, 52.90; H, 9.87. Found: C; 52.73; H, 9.88.
4.5. Acetylation of hydroxymethyl ketones 4a–d
Method A (for 4a, 4c and 4d): To a stirred solution of hydroxymethyl ketone (4a, 7 g, 36 mmol),
triethylamine (7 ml, 50 mmol) and 4-(dimethylamino)pyridine (0.1 g) in ethyl acetate (70 ml) acetic
anhydride (4 ml, 42 mmol) was added dropwise at room temperature and the resulting mixture was
stirred for 90 min. The reaction mixture was washed with 10% HCl (2×140 ml), 1 M Na2CO3 (140 ml)
and dried over Na2SO4. Evaporation of the solvent resulted in an oil. The same procedure was used for
ketones 4c (1.1 g, 6 mmol) and 4d (1.70 g, 8.32 mmol).
Method B (for 4b): To a stirred solution of 1-hydroxy-3-pivaloyloxypropan-2-one (4a, 2 g, 11.5 mmol),
triethylamine (1.75 g, 13.8 mmol) and 4-(dimethylamino)pyridine (50 mg) in THF (25 ml) acetyl chloride
(1.08 g, 13.8 mmol) was added dropwise and the mixture was stirred for 90 min. Ethyl acetate (100 ml)
and 5% HCl solution (15 ml) were added to the mixture and the forming layers were separated. The
aqueous layer was extracted with ethyl acetate (50 ml). The combined organic phases were washed with

J. Bálint et al. / Tetrahedron: Asymmetry 10 (1999) 4017–4028
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saturated NaHCO3 solution (25 ml), saturated Na2CO3 solution and dried over Na2SO4. After removal
of the solvent, preparative vacuum column chromatography of the residue yielded an oil 5b.
4.6. 1-Acetoxy-3-benzoyloxypropan-2-one 5a
Yield: 6.3 g, 75%. IR: 3069, 2991, 2939, 1737, 1729, 1601, 1451, 1417, 1372, 1277, 1228, 1177,
1
1101, 1052, 1025, 977, 834, 715 cm−1; H NMR: 2.20 (s, 3H, CH3-CO), 4.86 (s, 2H, CH2-OAc), 5.01
(s, 2H, CH2-OBz), 7.46 (t, 2H, m-ArH), 7.58 (t, 1H, p-ArH), 8.09 (d, 2H, o-ArH). Calcd for C12H12O5:
C, 61.01; H, 5.12; Found: C, 61.21; H, 5.10.
4.7. 1-Acetoxy-3-pivaloyloxypropan-2-one 5b
Yield: 1.9 g, 77%. IR: 2970, 1735, 1730, 1725, 1470, 1360, 1470, 1360, 1280, 1215, 1150, 1130, 1055
cm−1; 1H NMR: 1.22 (s, 9H, 3 CH3), 2.12 (s, 3H, CH3-CO), 4.69 (s, 2H, O-CH2), 4.70 (s, 2H, O-CH2).
Calcd for C10H16O5: C, 55.55; H, 7.46; Found: C, 55.45; H, 7.48.
4.8. 1-Acetoxy-3-benzyloxypropan-2-one 5c
Yield: 1.23 g, 92%. IR: 3032, 2937, 2860, 1739, 1732, 1455, 1410, 1374, 1235, 1104, 1071, 1027,
742, 700 cm−1; 1H NMR: 2.21 (s, 3H, CH3-CO), 4.19 (s, 2H, CH2-OBn), 4.63 (s, 2H, OCH2Ph), 4.94 (s,
2H, CH2-OAc), 7.38 (m, 5H, ArH). Calcd for C12H14O4: C, 64.85; H, 6.35; Found: C, 65.00; H, 6.33.
4.9. 1-Acetoxy-3-(tert-butyldimethylsilyl)oxypropan-2-one 5d
Yield: 1.90 g, 93%. IR: 2965, 2940, 2895, 2870, 1755, 1740, 1490, 1420, 1390, 1270, 1250, 1110,
1090, 855, 795 cm−1; 1H NMR: 0.03 (s, 6H, 2 CH3-Si), 0.87 (s, 9H, 3 CH3), 2.08 (s, 3H, CH3-CO), 4.19
(s, 2H, CH2-OTBDMS), 4.87 (s, 2H, CH2-OAc). Calcd for C11H22O4Si: C, 53.63; H, 9.00; Found: C,
53.81; H, 9.02.
4.10. Baker’s yeast-catalyzed stereoselective reduction of ketones 4a–d, 5a–d
4.10.1. General method
Yeast was added to the media as indicated in Table 2. After stirring the resulting cell suspension for
30 min, the corresponding ketone (4a–d, 5a–d; 500 mg) was added. When indicated, the substrate was
previously dissolved in ethanol (2–4 ml). The reaction mixture was stirred (time given in Table 2). The
resulting mixture was extracted with ethyl acetate (2×150 ml), the combined ethyl acetate layers were
washed with brine, dried over MgSO4, and the solvent was evaporated in vacuo. The residue was purified
by preparative vacuum column chromatography (hexane:acetone, 10:1) to give oily product(s) in yields
indicated in Table 2.
4.10.2. 1-Benzoyloxypropane-2,3-diol 6a
1
IR: 3400 (br), 2952, 1714, 1602, 1452, 1379, 1316, 1278, 1178, 1117, 1071, 1027, 712 cm−1; H
NMR: 3.50–3.80 (m, 2H, O-CH2), 4.12 (m, 1H, O-CH), 4.37 (m, 2H, CH2-OBz), 7.43 (t, 2H, m-ArH),
7.54 (t, 1H, p-ArH), 8.02 (d, 2H, o-ArH).

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4.10.3. 1-Pivaloyloxypropane-2,3-diol 6b
IR: 3450, 2980, 2960, 1730, 1480, 1460, 1370, 1280, 1170, 1045 cm−1; 1H NMR: 1.22 (s, 9H, 3 CH3),
3.59 and 3.69 (2 dd, 2H, O-CH2), 3.94 (m, 1H, O-CH), 4.16 (m, 2H, CH2-OPiv).
4.10.4. 1-Benzyloxypropane-2,3-diol 6c
IR: 3385 (br), 2924, 2867, 1646, 1496, 1453, 1364, 1207, 1074, 925, 865, 738, 698 cm−1; 1H NMR:
3.50–3.78 (m, 4H, O-CH2), 3.87 (m, 1H, O-CH), 4.55 (s, 2H, OCH2Ph), 7.35 (m, 5H, ArH).
4.10.5. 1-(tert-Butyldimethylsilyl)oxypropane-2,3-diol 6d
IR: 3400, 2970, 2945, 2895, 2865, 1485, 1275, 1250, 1130, 1090, 850, 795 cm−1; 1H NMR: 0.03 (s,
3H, CH3-Si), 0.06 (s, 3H, CH3-Si), 0.88 (s, 9H, 3 CH3), 3.55–3.75 (m, 5H, 2 O-CH2 and O-CH).
4.10.6. 1-Acetoxy-3-benzoyloxypropan-2-ol 7a
IR: 3462 (br), 3065, 2958, 1727, 1721, 1606, 1452, 1375, 1316, 1276, 1178, 1116, 1071, 1047, 1027,
713 cm−1; 1H NMR: 2.11 (s, 3H, CH3-CO), 4.25 (m, 3H, CH2-OAc and O-CH), 4.42 (m, 2H, CH2-OBz),
7.44 (t, 2H, m-ArH), 7.58 (t, 1H, p-ArH), 8.03 (d, 2H, o-ArH).
4.10.7. 1-Acetoxy-3-pivaloyloxypropan-2-ol 7b
IR: 3400 (br), 2980, 2960, 1730, 1725, 1475, 1450, 1370, 1280, 1170, 1045 cm−1; 1H NMR: 1.23 (s,
9H, 3 CH3), 2.09 (s, 3H, CH3-CO), 4.05–4.25 (m, 5H, 2 O-CH2 and O-CH).
4.10.8. 1-Acetoxy-3-benzyloxypropan-2-ol 7c
1
IR: 3445, 3063, 3030, 1738, 1496, 1454, 1369, 1244, 1098, 1045, 740, 699 cm−1; H NMR: 2.08
(s, 3H, CH3-CO), 3.52 (m, 2H, CH2OBn), 4.05 (m, 1H, O-CH), 4.16 (m, 2H, CH2OAc), 4.56 (s, 2H,
OCH2Ph), 7.33 (m, 5H, ArH).
4.10.9. 1-Acetoxy-3-(tert-butyldimethylsilyl)oxypropan-2-ol 7d
IR: 3460, 2960, 2935, 2895, 2860, 1755, 1735, 1480, 1405, 1380, 1270, 1250, 1120, 1050, 850, 795
cm−1; 1H NMR: 0.02 (s, 3H, CH3-Si), 0.05 (s, 3H, CH3-Si), 0.86 (s, 9H, 3 CH3), 2.04 (s, 3H, CH3-CO),
3.58 (m, 2H, CH2-OTBDMS), 3.76–4.01 (m, 2H, CH2-OAc), 4.09 (m, 1H, O-CH).
4.11. Determination of enantiomeric excess and absolute configuration of the diols (6a–d, ent-6a–d) and
monoacetates 7a–d
4.11.1. Enantiomeric excess determination
4.11.1.1. (A) MTPA derivatization of the optically active monoacetates 7a–d. A sample of each
monoacetate (7a–d, 50 µmol, ca.12 mg) with measured optical rotation was converted into its (R)-MTPA
ester [350 µl of 5% (R)-MTPA-Cl solution in carbon tetrachloride, pyridine (25 µl), DMAP (2 mg), 50°C,
3 h]. A similar reaction was carried out with the racemic monoacetates rac-7a–d. The diastereomer ratio
referring to the enantiomeric excess of the monoacetates 7a–d was determined from the 1H NMR spectra
of the MTPA ethers [500 MHz, CH3CO signals: (R,R)-7a-MTPA: 2.07 ppm, (R,S)-7a-MTPA: 2.01 ppm,
(R,R)-7b-MTPA: 2.08 ppm, (R,S)-7b-MTPA: 2.02 ppm, (R,S)-7c-MTPA: 2.03 ppm, (R,R)-7c-MTPA:
1.97 ppm, (R,R)-7d-MTPA: 2.05 ppm, (R,S)-7d-MTPA: 1.98 ppm].
4.11.1.2. (B) Preparation of diacetates 8a–d from monoacetates 7a–d and diols 6a–d or ent-6a–d.
Another aliquot of each sample 7a–d used in the MTPA ee determination was acetylated [7a–d: 0.1 g,

J. Bálint et al. / Tetrahedron: Asymmetry 10 (1999) 4017–4028
4025
Et3N (1.4 mmol), DMAP (10 mg), Ac2O (1.1 mmol) in EtOAc (1 ml), at rt, 90 min; purified yields over
90%] to give the corresponding oily diacetate 8a–d with known enantiomeric excess value.
Diacetates 8a–d or ent-8a–d were also prepared from the optically active diols [6a–d or ent-6a–d: 0.1
g, Et3N (2.8 mmol), DMAP (15 mg), Ac2O (2.2 mmol) in EtOAc (1 ml), at rt, 90 min; purified yields
over 90%] as well. Optical rotations of these diacetates 8a–d or ent-8a–d compared to the rotation data
of the diacetates 8a–d with known enantiomeric purities refer to the enantiomeric composition of the
corresponding parent diol 6a–d or ent-6a–d.
4.11.2. 1-Benzoyloxy-2,3-diacetoxypropane 8a
IR: 3065, 2962, 1753, 1747, 1735, 1602, 1452, 1372, 1316, 1260, 1224, 1178, 1115, 1071, 1051, 1026,
713 cm−1; 1H NMR: 2.11 (s, 3H, CH3-CO), 2.13 (s, 3H, CH3-CO), 4.20–4.65 (m, 4H, 2 O-CH2), 5.43
(m, 1H, CH-OAc), 7.45 (t, 2H, m-ArH), 7.58 (t, 1H, p-ArH), 8.04 (d, 2H, o-ArH).
4.11.3. 2,3-Diacetoxy-1-pivaloyloxypropane 8b
IR: 2970, 1745, 1735, 1725, 1470, 1360, 1280, 1220, 1145, 1040 cm−1; 1H NMR: 1.20 (s, 9H, 3 CH3),
2.06 (s, 3H, CH3-CO), 2.08 (s, 3H, CH3-CO), 4.12–4.35 (m, 4H, 2 O-CH2), 5.28 (m, 1H, CH-OAc).
4.11.4. 1-Benzyloxy-2,3-diacetoxypropane 8c
IR: 3010, 2925, 2835, 1744, 1727, 1496, 1450, 1365, 1240, 1100, 1030, 950, 735, 695 cm−1; 1H NMR:
2.00 (s, 3H, CH3-CO), 2.04 (s, 3H, CH3-CO), 3.56 (m, 2H, CH2-OBn), 4.23 (m, 2H, CH2-OAc), 4.50 (s,
2H, OCH2Ph), 5.18 (m, 1H, CH-OAc), 7.29 (m, 5H, ArH).
4.12. 1-(tert-Butyldimethylsilyl)oxy-2,3-diacetoxypropane 8d
1
IR: 2965, 2940, 2895, 2870, 1755, 1485, 1385, 1270, 1245, 1130, 1060, 850, 795 cm−1; H NMR:
0.03 (s, 3H, CH3-Si), 0.06 (s, 3H, CH3-Si), 0.88 (s, 9H, 3 CH3), 2.05 (s, 3H, CH3-CO), 3.69 (m, 2H,
CH2-OTBDMS), 4.09–4.33 (m, 2H, CH2-OAc), 5.05 (m, 1H, CH-OAc).
4.13. Determination of the absolute configuration of the monoacetates 7a–d and diols 6a–d and ent-
6a–d
Since the absolute configuration of a benzoyloxy 6a,15 and the benzyloxy compounds 6c11,29 and
7c30,31 are known, the diacetates 8a,c prepared either from the monoacetates 7a,c or the diols 6a,c and
ent-6a,c were suitable for determination of the absolute configuration of these compounds.
For determination of the absolute configuration of pivaloyloxy compounds 7b, 6b, and ent-6b, an
optically active sample of (R)-3-acetoxypropane-1,2-diol {[α]D=−9.9 (c 2, pyridine) [lit.:32 [α]D=−9.2,
(c 1.7, pyridine)] obtained by catalytic hydrogenation from (R)-3-acetoxy-1-benzyloxypropan-2-ol ma-
nufactured by PfL catalysis30} was converted to (S)-3-acetoxy-1-pivaloyloxypropane-2-ol ent-7b proving
the absolute configuration of 7b. Configurations of the diols 6b and ent-6b were determined via their
diacetates 8b and ent-8b compared to the diacetate 8b from the monoacetate 7b.
The optical rotation of (R)-1-(tert-butyldimethylsilyl)oxypropane-2,3-diol 6d was reported33 as
[α]D=−0.6 (c 1.31, CHCl3). Since the small specific rotation values of the polar 1,2-diols are often
unreliable,34 absolute configuration of the diols 6d and ent-6d was determined by an independent
method. Silylation of the above (R)-3-acetoxypropane-1,2-diol with TBDMS-Cl (imidazole/THF) gave
(S)-1-acetoxy-3-(tert-butyldimethylsilyl)oxypropan-2-ol {ent-7d, [α]D=−14.1 (c 1, MeOH)}. The yeast

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J. Bálint et al. / Tetrahedron: Asymmetry 10 (1999) 4017–4028
reduction resulted, however, in (R)-monoacetate {7d, [α]D=+17.6 (c 1, MeOH)}. Acylation of this (R)-
monoacetate 7d resulted in (R)-diacetate {(R)-8d, [α]D=+19.8 (c 1, MeOH)}. Since a diol fraction
{ent-6d, [α]D=+0.9 (c 1, CHCl3); [α]D=+9.2, (c 1, methanol)} from another reduction of the acetoxy-
methyl ketone 5d also resulted in (R)-diacetate {(R)-8d, [α]D=+19.1 (c 1, MeOH)}, this diol ent-6d
should have the (R)-configuration. Therefore, the above cited specific rotation data for the (R)-1-(tert-
butyldimethylsilyl)oxypropane-2,3-diol should be revised.
The absolute configurations, enantiomeric excesses and optical rotation values of diols 6a–d and
monoacetates 7a–c prepared by baker’s yeast reduction and their diacetate derivatives 8a–d are given
in Table 3.
Acknowledgements
The Hungarian OTKA Foundation (T014894) is gratefully acknowledged for financial support. J.B.
thanks the Zoltán Magyary Foundation for a postdoctoral fellowship. G.E. thanks the Hungarian OTKA
Foundation for a postdoctoral fellowship (no. D 29445).
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Table 3
Enantiomeric excess, specific rotations and absolute configurations for compounds 6a–d, 7a–d
and 8a–d

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