Total regioselective control of tartaric acid

Article abstract of DOI:10.1021/jo101001s

An efficient strategy to synthesize tartaric acid building blocks for totally regioselective transformations or derivatizations was disclosed. Starting from l-tartaric acid or l-dimethyl tartrate, respectively, we obtained type I and II building blocks with orthogonal sets of protecing groups (4-8 steps, 38-56% overall yield).

Full text of DOI:10.1021/jo101001s

The Total Regioselective Control of Tartaric Acid
Jan Spengler,a,b* Ana I. Fernández-Llamazares,a,b Javier Ruiz-Rodríguez,a,b Klaus Burgerc and
Fernando Albericioa,b,d*
aInstitute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10 , 08028-Barcelona,
Spain; bCIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine,
Barcelona Science Park, Baldiri Reixac 10, 08028-Barcelona, Spain; cInstitut für Organische Chemie,
d
Universität Leipzig, Johannisallee 29, D-04103 Leipzig (Germany); Department of Organic Chemistry,
University of Barcelona, Martí i Franqués 1-11, 08028-Barcelona, Spain.
jan.spengler@irbbarcelona.org; fernando.albericio@irbbarcelona.org
SUPPORTING INFORMATION
TABLE OF CONTENTS
I. GENERAL REMARKS (Abbreviations, reagents, analytical methods) (page SI02)
II. GENERAL PROCEDURES (pages SI02-04)
III. COMPOUND SYNTHESIS AND CHARACTERIZATION (The compounds have the same
numbers as in the article and appear in numerical order. For compounds 1, 2, 9a-c see experimental
section in the article) (pages SI04-13).
IV. X-RAY STRUCTURE OF COMPOUND 4 (pages SI14-15)
V. COPIES OF 1H AND 13C NMR OF COMPOUNDS 1-6 (pages SI16-21)
SI1

I: GENERAL REMARKS
Abbreviations: AcCl, acetyl chloride; ACN, acetonitrile; AcOEt, ethyl acetate; AcOH, acetic acid;
DCM, dichloromethane; DMA, N,N-dimethylacetamide; DMF, N,N-dimethylformamide; HOAc, acetic
acid; TEBAC, triethylbenzylammonium chloride; TLC, thin layer chromatography.
All commercial reagents and solvents were used as received unless otherwise indicated. TLC was
performed with TLC aluminium sheets coated with silica gel 60 F254. Spots were observed with UV or
after staining as indicated and heating [KMnO4 staining solution: 6 g KMnO4, 40 g K2CO3 and 5 mL
NaOH in 600 mL water]. For column chromatography, Silice 35-70 ꢀm was used.
1H-NMR spectra were acquired at 400.125 MHz, 13C at 100.625 MHz with TMS as internal reference,
and 19F at 376.494 MHz. The following abbreviations are used to indicate multiplicity: s, singlet; d,
doublet, dd, double doublet; t, triplet; dt, double triplet; m, multiplet, br s, broad signal. Chemical shifts
(δ) are expressed in parts per million downfield from tetramethylsilyl chloride. Concentrations for
optical rotation values are given in g*100mL-1. Melting points are uncorrected. High resolution mass
spectroscopy (HRMS) was performed with the electrospray (ion spray) (ESI-MS) method in positive or
negative mode (as indicated).
II. GENERAL PROCEDURES
The general procedure A (Reaction of tartaric acid and derivatives with hexafluoroacetone) and all
products are described in the experimental section of the article.
O
HO
HO
CO2H
OH
O
CF3
CF3
HO2C
O
HO2C
SI2

General procedure B: Esterification of (5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl)-acetic
acids with diazomethane
R
R
O
O
O
O
O
O
CF3
CF3
CF3
CF3
MeO2C
O
O
HO2C
CAUTION: Diazomethane is a toxic and explosive gas. All operations must be performed in a
well-ventilated fume hood with properly protection of skin and eyes in the absence of open fire or
sparks.
To a solution of 1 or 9 (2 mmol) in diethyl oxide (20 mL) was added a solution of excess of
diazomethane (approx. 5 equiv.) in diethyl ether (50 mL). After 15 min the solution was dried (MgSO4).
The diethyl ether was removed in vacuo to give the methyl esters 5 and 11, respectively.
General procedure C: Nucleophilic ring opening of the dioxolanones
R
R
O
O
O
CO2Me
OH
O
CF3
CF3
O
HO2C
HO2C
The dioxolane (1.5 mmol) was stirred in DCM/MeOH 1:1 (20 mL) for the preparation of methyl esters
or, for the preparation of the carboxylic acid in 2-PrOH/H2O 2:1 (20 mL), until complete conversion of
starting material (approx. 15 h, TLC control). Then, the solvents were removed in vacuo and the residue
was purified by flash chromatography with DCM/MeOH/AcOH 10:1:0.5. The fractions with product
were pooled and the solvents were removed in vacuo. Then, the remaining acetic acid was removed by
co-evaporation with toluene. For the preparation of the sodium salt, the oily residue was stirred with a
SI3

solution of NaHCO3 (1.0 molar equiv. corresponding to the amount of oily product obtained) in
acetone/water 1:1 (20 mL) for 30 min. After solvent removal at 50°C the white residue was suspended
in 2-PrOH and dried on a filter plate.
General procedure D: Saponification of the dimethyltartrates
R
R
O
CO2H
OH
O
CO2Me
OH
HO2C
MeO2C
To a solution of the dimethyltartrate 7a-c, 18 (approx. 5 mmol) in dioxane (15 mL) was added an
aqueous solution of 2.1 equiv. LiOH (10 mL). After complete conversion of starting material (1-2 h with
stirring, TLC), the solvents were evaporated and the residue was dissolved in water (15 mL). The
solution was extracted with DCM (2 x 5 mL). Then, conc. aqueous HCl (5 mL) was added (check for
acidic pH) and it was extracted with AcOEt (3 x 25 mL). The organic phase was dried with MgSO4,
filtered and concentrated in vacuo to give 8a-c or 19, respectively.
III: COMPOUND SYNTHESIS AND CHARACTERIZATION
(2R)-Acetoxy-{(4R)-5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl}-acetic acid (3): 3.15 g
(10.55 mmol) of 1 was stirred in AcCl (25 mL) under exclusion of moisture for 15 h. Then, the volatiles
were evaporated (CAUTION). The residue was dissolved in DCM (100 mL), washed with cold water (3
x 20 mL), and dried over MgSO4. Removal of the solvent gave 3.0 g (84 %) of 3 as crystalline product.
1
Mp.: 151-152 °C (recryst. from CHCl3); H NMR (acetone-d6): δ = 2.14 (s, 3H), 5.70 (d, J = 1.9 Hz,
1H), 5.91 (d, J = 1.8 Hz, 1H) ppm; 13C NMR (acetone-d6): δ = 20.9, 70.6, 77.3, 98.7 (m), 120.8 (q, J =
19
286 Hz), 121.6 (q, J = 288 Hz), 166.2, 167.0, 170.6 ppm; F NMR (acetone-d6): δ = -82.23 (m, 3F), -
SI4

80.96 (m, 3F) ppm; IR (KBr): ν = 1851, 1778, 1741, 1708 cm-1; αD20 +37.6 (c 2.0, acetone); HRMS (ES-
): calc. for [C9H6F6O7 – H]- 338.9939, found 338.9944.
(2R,3R)-3-O-Acetyl-1-methyl tartrate (4): Following the general procedure C, 0.94 g (2.76 mmol) of
3 gave 4 (510 mg, 90 %) as oil [Rf = 0.1 (KMnO4: yellow)]. A small portion was converted into the
sodium salt (quantitative yield). Mp. (sodium salt): 181 °C (decomposition); 1H NMR (CDCl3): δ = 2.15
(s, 3H), 3.83 (s, 3H), 4.81 (d, J = 2.1 Hz, 1H), 5.49 (d, J = 2.2 Hz, 1H) ppm; 13C NMR (sodium salt in
D2O): δ = 19.9, 53.3, 70.3, 73.8, 170.6, 172.3, 172.8 ppm; IR (sodium salt, KBr): ν = 1730, 1626, 1394
20
cm-1; αD (sodium salt) -5.1 (c 2.0, H2O); HRMS (ES-): calc. for [C7H10O7 – H]- 205.0348, found
205.0347.
(2R)-(Acetyoxy)-{(4R)-5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl}-methylacetate
(5):
Following the general procedure B with 1.09 g (3.2 mmol) 3 gave 5 (0.99 g, 88 %) as slowly
crystallizing oil. Mp. (recryst. from toluene): 82-84 °C; 1H NMR (CDCl3): δ = 2.15 (s, 3H), 3.86 (s, 3H),
13
5.25 (d, J = 1.8 Hz, 1H), 5.56 (d, J = 2.0 Hz, 1H) ppm; C NMR (CDCl3): δ = 19.8, 53.5, 68.9, 74.9,
97.9 (m), 118.5 (q, J = 187 Hz), 119.5 (q, J = 189 Hz), 164.1, 164.9, 168.8 ppm; 19F NMR (CDCl3): δ =
-81.34 (q, J = 8.0 Hz, 3F), -80.07 (q, J = 8.0 Hz, 3F) ppm; IR (KBr): ν = 1855, 1760, 1441, 981 cm-1;
αD20 +42.2 (c 2.5, CHCl3); HRMS (ES+): calc. for [C10H8F6O7 + Na]+ 377.0072, found 377.0073.
(2R,3R)-2-O-Acetyl-1-methyl tartrate (6): Following the general procedure C, 0.61 g (1.72 mmol) of
5 gave 6 (280 mg, 79 %) as oil [Rf = 0.1 (KMnO4: yellow)]. 1H NMR (CDCl3): δ = 2.16 (s, 3H), 3.83 (s,
3H), 4.82 (m, 1H), 5.51 (m, 1H) ppm; 13C NMR (CDCl3): δ = 20.2, 53.1, 70.2, 72.9, 167.6, 170.3, 173.2
ppm, IR (film): ν = 1750, 1221, 1074 cm-1; αD20 -34.5 (c 2.0, CHCl3); HRMS (ES-): calc. for [C7H10O7 –
H]- 205.0348, found 205.0341.
L-O-Mono-benzylated-dimethyltartrates (7a-c): The compounds 7a-c were obtained from dimethyl
L-tartrate (typically in 10 g - scale) in 96 (7a), 82 (7b) and 80 % (7c) yield according to published
procedure [S. Nakamura, Y. Hirata, T. Kurosaki, M. Anada, O. Kataoka, S. Kitagaki, S. Hashimoto,
SI5

1
Angew. Chem. Int. Ed. 2003, 42, 5351-5355]. The H NMR data are identical with those reported [N.
Nagashima, M. Ohno, Chem. Pharm. Bull. 1991, 39, 1972-1982.].
L-O-Monobenzyl tartaric acid (8a): Following the general procedure D, 1.48 g (5.52 mmol) 7a gave
1
1.30 g 8a as white crystalline solid (89 %). Mp.: 128-129 °C; H NMR (acetone-d6): δ = 4.51 (m, 2H),
4.66 (d, J = 2.5 Hz, 1H), 4.86 (d, J = 11.5 Hz, 1H), 7.31 (m, 5H) ppm; 13C NMR (acetone-d6): δ = 73.9,
20
74.6, 81.1, 129.4, 129.6, 139.8, 172.0, 173.9 ppm; IR (KBr): ν = 1741, 1707, 1379 cm-1; αD +54.1 (c
2.0, acetone); HRMS (ES-): calc. for [C11H12O6 – H]- 239.0556, found 239.0557.
L-O-Mono-(4-nitrobenzyl) tartaric acid (8b): Following the general procedure D, 5.73 g (18.29
mmol) 7b gave 4.31 g 8b as yellow crystalline solid (82 %). Mp.: 197-198 °C; 1H NMR (acetone-d6): δ
= 4.57 (m, 1H), 4.68 (m, 2H), 5.03 (d, J = 13.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 8.20 (d, J = 8.8 Hz,
2H) ppm; 13C NMR (acetone-d6): δ = 73.3, 73.9, 81.6, 125.0, 129.9, 147.8, 149.2, 171.8, 173.9 ppm; IR
(KBr): ν = 1724, 1674, 1518, 1343 cm-1; αD20 +52.7 (c 2.0, acetone); HRMS (ES-): calc. for [C11H11NO8
– H]- 284.0406, found 284.0415.
L-O-Mono-(4-methoxybenzyl) tartaric acid (8c): Following the general procedure D, 6.54 g (21.92
mmol) 7c gave 4.57 g 8c as white crystalline solid (77 %). Mp.: 174-176 ºC; 1H NMR (DMSO-d6): δ =
3.32 (br s, 1H), 3.74 (s, 3H), 4.27 (d, J = 11.2 Hz, 1H), 4.31 (d, J = 2.8 Hz, 1H), 4.38 (d, J = 2.8 Hz,
1H), 4.64 (d, J = 11.2 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 12.78 (br s, 2H) ppm;
13C NMR (DMSO-d6): δ = 55.0, 71.6, 71.8, 79.2, 113.4, 129.3, 129.8, 158.69, 170.9, 172.7 ppm; IR
20
(KBr): ν = 3302, 1744, 1710, 1612, 1511, 1382, 1255, 1241, 1134, 1078 cm-1; αD +48.0 (c 2.0,
acetone); HRMS (ES-): calc. for [C12H14O7 – H]- 269.0661, found 269.0669.
Sodium (2R,3R)-3-O-benzyl-1-methyl tartrate (10a): Following the general procedure C with 9a
(585 mg, 1.51 mmol), the free acid was obtained after flash chromatography (Rf = 0.3, KMnO4: yellow),
which was transformed into the sodium salt to give 10a (340 mg, 81 %) as white powder. Mp.: 186 °C
(decomposition); 1H NMR (D2O): δ = 3.60 (s, 3H), 4.13 (d, J = 2.8 Hz, 1H), 4.36 (d, J = 12.1 Hz, 1H),
SI6

4.61 (d, J = 2.8 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 7.41 (m, 5H) ppm; 13C NMR (D2O): δ = 52.9, 72.3,
72.7, 79.9, 128.5, 128.8, 129.0, 137.2, 174.1, 176.3 ppm; IR (KBr): ν = 1746, 1596, 1399, 1128, 702
cm-1; αD20 +69.3 (c 2.0, H2O); HRMS (ES-): calc. for [C12H14O6 – H]- 253.0712, found 253.0717.
Sodium (2R,3R)-3-O-(4-nitrobenzyl)-1-methyl tartrate (10b): Following the general procedure C
with 9b (1.0 g, 2.31 mmol), the free acid was obtained after flash chromatography (Rf = 0.2, UV), which
was transformed into the sodium salt to give 10b (700 mg, 98 %) as white scales. Mp.: 216 °C
(decomposition); 1H NMR (D2O): δ = 3.50 (s, 3H), 4.04 (d, J = 2.8 Hz, 1H), 4.37 (d, J = 13.1 Hz, 1H),
4.52 (d, J = 2.8 Hz, 1H), 4.76 (d, J = 13.1 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H)
ppm; 13C NMR (D2O): δ = 52.8, 71.3, 72.7, 81.0, 123.8, 129.0, 145.4, 147.3, 174.1, 176.0 ppm; IR
20
(KBr): ν = 1738, 1603, 1515, 1352, 1090 cm-1; αD +66.3 (c 2.0, H2O); HRMS (ES-): calc. for
[C12H13NO8 – H]- 298.0563, found 298.0570.
(2R,3R)-3-O-(4-methoxybenzyl)-1-methyl tartrate (10c): Following the general procedure C with 9c
(0.38 g, 0.92 mmol), the free acid 10c (0.24 g, 92%) was obtained as a yellowish oil after purification by
flash chromatography (DCM/MeOH/AcOH 20:1:1, Rf = 0.25, UV). 1H NMR (CDCl3): δ = 3.66 (s, 3H),
3.80 (s, 3H), 4.35 (d, J = 2.0 Hz, 1H), 4.37 (d, J = 11.7 Hz, 1H), 4.63 (d, J = 1.8 Hz, 1H), 4.77 (d, J =
11.6 Hz, 1H), 6.32 (br s, 2H), 6.87 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H) ppm; 13C NMR
(DMSO-d6): δ = 52.7, 55.2, 72.1, 72.6, 77.3, 113.8, 128.4, 130.1, 159.6, 171.4, 173.5 ppm; IR (film): ν
= 3180, 2955, 1748, 1612, 1515, 1251, 1135, 1090, 1031 cm-1; αD20 +20.0 (c 1.0, CHCl3); HRMS (ES-):
calc. for [C13H16O7 – H]- 283.0818, found 283.0823.
Methyl-(2R)-(benzyloxy)-{(4R)-5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl}-acetate (11a):
Following the general procedure B, 9a (0.88 g, 2.21 mmol) gave 11a (0.84 g, 95 %) as dense yellowish
oil. 1H NMR (CDCl3): δ = 3.86 (s, 3H), 4.38 (d, J = 2.4 Hz, 1H), 4.56 (d, J = 11.3 Hz, 1H), 4.88 (d, J =
11.3 Hz, 1H), 5.10 (d, J = 2.3 Hz, 1H), 7.32 (m, 5H) ppm; 13C NMR (CDCl3): δ = 53.0, 74.0, 74.9, 76.5,
98.2 (m), 118.4 (q, J = 287 Hz), 119.7 (q, J = 289 Hz), 128.2, 128.3, 128.4, 135.7, 165.0, 167.7 ppm;
19F NMR (CDCl3): δ = -81.4 (q, J = 7.9 Hz), -79.8 (q, J = 8.1 Hz) ppm; IR (film): ν = 1854, 1766, 1320,
SI7

20
+ +
1132 cm-1; αD +81.4 (c 2.5, CHCl3); HRMS (ES+): calc. for [C15H12F6O6 + NH4 ] 420.0882, found
420.0882.
Methyl-(2R)-(4-nitrobenzyloxy)-{(4R)-5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl}-acetate
(11b): Following the general procedure B, 9b (0.82 g, 1.89 mmol) gave 11b (0.75 g, 83 %) as dense
yellowish oil. 1H NMR (CDCl3): δ = 3.90 (s, 3H), 4.45 (d, J = 2.3 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H),
5.00 (d, J = 12.0 Hz, 1H), 5.17 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 8.22 (d, J = 8.7 Hz, 2H)
ppm; 13C NMR (CDCl3): δ = 53.2, 72.9, 75.8, 76.4, 98.1 (m), 116.2 (m), 121.9 (m), 123.6, 128.1, 143.3,
19
147.7, 165.0, 167.1 ppm; F NMR (CDCl3): δ = -81.3 (q, J = 7.8 Hz), -79.8 (q, J = 8.0 Hz) ppm; IR
20
(film): ν = 2961, 1855, 1766, 1608, 1525 cm-1; αD +64.3 (c 2.5, CHCl3); HRMS (ES+): calc. for
[C15H11F6NO8 + Na+]+ 470.0287, found 470.0285.
Methyl-(2R)-(4-methoxybenzyloxy)-{(4R)-5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl}-
acetate (11c): Following the general procedure B, 9c (0.72 g, 1.58 mmol) gave 11c (0.55 g, 81 %) as
dense yellowish oil. 1H NMR (CDCl3): δ = 3.81 (s, 3H), 3.85 (s, 3H), 4.35 (d, J = 2.4 Hz, 1H), 4.50 (d, J
= 11.1 Hz, 1H), 4.80 (d, J = 11.1 Hz, 1H), 5.08 (d, J = 2.3 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.22 (d, J =
13
8.6 Hz, 2H) ppm; C NMR (CDCl3): δ = 52.8, 55.1, 73.6, 74.4, 76.5, 98.1 (m), 113.7, 118.4 (q, J =
287.0 Hz), 119.7 (q, J = 289.1 Hz), 127.7, 129.9, 159.7, 165.0, 167.7 ppm; 19F NMR (CDCl3): δ = -81.4
(q, J = 8.1 Hz, 3F), -79.8 (q, J = 7.9 Hz, 3F) ppm; IR (film): ν = 1853, 1765, 1516, 1320, 1244, 1193,
20
+ +
1132, 983, 722 cm-1; αD +30.3 (c 1.0, CHCl3); HRMS (ES+): calc. for [C16H14F6O7 + NH4 ]
450.0987, found 450.0966.
(2R,3R)-2-O-Benzyl-1-methyl tartrate (12a): Following the general procedure C, 11a (0.73 g, 1.81
mmol) gave 12a (460 mg, 100 %) as crystalline solid. Rf = 0.2 (UV); Mp.: 96-97 °C; 1H NMR (CDCl3):
δ = 3.83 (s, 3H), 4.43 (d, J = 2.3 Hz, 1H), 4.49 (d, J = 11.5 Hz, 1H), 4.64 (d, J = 2.3 Hz, 1H), 4.85 (d, J
13
= 11.5 Hz, 1H), 7.29 (m, 5H) ppm; C NMR (CDCl3): δ = 52.6, 72.0, 73.3, 77.9, 128.2, 128.3, 128.4,
136.1, 169.9, 174.8 ppm; IR (KBr): ν = 1756, 1454, 1104 cm-1; αD20 +82.7 (c 2.0, CHCl3); HRMS (ES-):
calc. for [C12H14O6 – H]- 253.0712, found 253.0710.
SI8

(2R,3R)-2-O-(4-Nitrobenzyl)-1-methyl tartrate (12b): Following the general procedure D, 11b (0.52
g, 1.16 mmol) gave 12b (290 mg, 83 %) as crystalline solid, Rf = 0.3 (UV). Mp.: 118-119 °C; 1H NMR
(acetone-d6): δ = 3.77 (s, 3H), 4.60 (d, J = 2.6 Hz, 1H), 4.64 (d, J = 2.6 Hz, 1H), 4.68 (d, J = 13.1 Hz,
1H), 5.00 (d, J = 13.1 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H) ppm; 13C NMR
(acetone-d6): δ = 53.3, 73.3, 73.8, 81.9, 125.0, 129.9, 147.8, 149.2, 171.4, 173.7 ppm; IR (KBr): ν =
20
1751, 1719, 1545, 1531 cm-1; αD +50.1 (c 2.0, acetone); HRMS (ES-): calc. for [C12H13NO8 – H]-
298.0563, found 298.0564.
(2R,3R)-2-O-(4-Methoxybenzyl)-1-methyl tartrate (12c): Following the general procedure D, 11c
(0.30 g, 0.69 mmol) gave 12c (173 mg, 88 %) as yellowish solid after purification by flash
1
chromatography with DCM/MeOH/AcOH 10:0.5:0.5 (Rf = 0.23, UV). Mp: 116-118 ºC; H NMR
(CDCl3): δ = 3.78 (s, 3H), 3.83 (s, 3H), 4.40 (d, J = 2.4 Hz, 1H), 4.42 (d, J = 11.5 Hz, 1H), 4.62 (d, J =
2.4 Hz, 1H), 4.77 (d, J = 11.3 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H) ppm; 13C NMR
(CDCl3): δ = 52.6, 55.2, 72.0, 73.0, 77.5, 113.9, 128.2, 130.1, 159.6, 170.1, 174.5 ppm; IR (film): ν =
20
3150, 2922, 1724, 1610, 1512, 1249, 1137, 1089, 1029 cm-1; αD +8.1 (c 2.0, MeOH); HRMS (ES-):
calc. for [C13H16O7 – H]- 283.0818, found 283.0824.
(2R,3R)-3-O-(4-Methoxybenzyl)-1-allyl tartrate (13): The dioxolane 9c (0.199 g, 0.48 mmol) was
dissolved in DCM/allyl alcohol 1:1 (10 mL). After stirring the reaction mixture for 15 h at room
temperature, it was heated under reflux until complete conversion of starting material (2 h, TLC
control). Then, the solvents were removed in vacuo, and the residue was purified by flash
1
chromatography with Hx/AcOEt 1:1 (Rf = 0.15, UV) to give 13 (0.100 g, 93%) as a colourless oil. H
NMR (CDCl3): δ = 3.80 (s, 3H), 4.38 (d, J = 2.1 Hz, 1H), 4.41 (d, J = 11.5 Hz, 1H), 4.50 (m, 1H), 4.64
(d, J = 2.0 Hz, 1H), 4.67 (m, 1H), 5.29 (m, 1H), 5.30 (m, 1H), 5.81 (m, 1H), 6.87 (d, J = 8.6 Hz, 2H),
13
7.20 (d, J = 8.6 Hz, 2H) ppm; C NMR (CDCl3): δ = 55.2, 66.6, 72.1, 72.8, 77.5, 113.9, 119.4, 128.3,
130.1, 131.1, 159.7, 170.6, 172.8 ppm; IR (film): ν = 1032, 1092, 1136, 1250, 1514, 1612, 1748, 2929,
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20
3450 cm-1; αD +14.9 (c 2.0, CHCl3); HRMS (ES-): calc. for [C15H18O7 – H]- 309.0974, found
309.0980.
Allyl-(2R)-(4-methoxybenzyloxy)-{(4R)-5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl}-acetate
(14): The dioxolane 9c (0.710 g, 1.70 mmol) was dissolved in oxalyl chloride (2.5 mL) under N2
atmosphere. A drop of DMF was added and the reaction mixture was stirred for 15 min. Then, the
solvents were removed in vacuo to give the corresponding acid chloride (0.742 g) as a yellowish oil.
This intermediate was dissolved in dry diethyl ether (5 mL) and the allyl alcohol (0.115 mL, 1.70 mmol)
was added dropwise at room temperature. The reaction mixture was stirred until complete conversion of
starting material (4 h, TLC control). Then, the solvents were removed in vacuo and the residue was
purified by flash cromatography with Hx/AcOEt 9:1 (Rf = 0.2, UV) to give the ester 14 (0.600 g, 95 %)
1
as a colourless oil. H NMR (CDCl3): δ = 3.81 (s, 3H), 4.36 (d, J = 2.4 Hz, 1H), 4.52 (d, J = 11.1 Hz,
1H), 4.75 (dt, J = 5.7 Hz, 1.3 Hz, 2H), 4.80 (d, J = 11.1 Hz, 1H), 5.09 (d, J = 2.3 Hz, 1H), 5.31 (ddt, J =
10.5 Hz, 2.3 Hz, 1.1 Hz, 1H), 5.36 (ddt, J = 17.2 Hz, 2.8 Hz, 1.4 Hz, 1H), 5.93 (ddt, J = 17.0 Hz, 10.5
13
Hz, 5.7 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H) ppm; C NMR (DMSO-d6): δ =
55.2, 66.5, 73.6, 74.4, 76.6, 97.8 (m), 113.8, 118.5 (q, J = 287.0 Hz), 119.2, 119.7 (q, J = 289.0 Hz),
127.7, 130.0, 130.9, 159.7, 165.0, 167.0 ppm; 19F NMR (CDCl3): δ = -81.4 (q, J = 8.0 Hz, 3F), -79.8 (q,
20
J = 8.1 Hz, 3F) ppm; IR (film): ν = 1132, 1192, 1245, 1320, 1515, 1613, 1764, 1856, 2957 cm-1; αD
+ +
+29.3 (c 2.0, CHCl3); HRMS (ES+): calc. for [C18H16F6O7 + NH4 ] 476.1144, found 476.1128.
(2R,3R)-2-O-(4-Methoxybenzyl)-1-allyl tartrate (15): Following the general procedure D, 0.244 g
(0.65 mmol) of 13 gave 15 (143 mg, 97 %) as yellowish oil after purification by flash chromatography
with Hx/AcOEt 1:1 (Rf = 0.15, UV). 1H NMR (CDCl3): δ = 3.77 (s, 3H), 4.42 (d, J = 2.1 Hz, 1H), 4.43
(d, J = 10.9 Hz, 1H), 4.64 (d, J = 2.3 Hz, 1H), 4.72 (dt, J = 5.8 Hz, 1.3 Hz, 2H), 4.78 (d, J = 11.3 Hz,
1H), 5.29 (m, 1H), 5.37 (m, 1H), 5.94 (m, 1H), 6.83 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H) ppm;
13C NMR (CDCl3): δ = 55.2, 66.2, 72.9, 77.5, 113.8, 119.0, 128.3, 130.1, 131.3, 159.5, 169.1, 174.6,
SI10

20
174.7 ppm; IR (film): ν = 1032, 1091, 1131, 1250, 1515, 1612, 1747, 2938, 3450 cm-1; αD +33.0 (c
2.0, CHCl3); HRMS (ES-): calc. for [C15H18O7 – H]- 309.0974, found 309.0976.
(2R,3R)-2-O-Acetyl-3-O-benzyl-1-methyl tartrate (16): 10a (0.424 g, 1.67 mmol) was stirred in
AcCl (7 mL) with a catalytic amount of DMAP until complete conversion (2 h, TLC, UV). Then, the
solvent was removed in vacuo (CAUTION!) and the residue was purified by flash chromatography with
DCM/AcOH 10:0.5. The fractions with product (Rf = 0.55, UV) were pooled and the solvents were
removed in vacuo. Then, the remaining acetic acid was removed by co-evaporation with toluene to give
16 (474 mg, 96 %) as yellowish oil. 1H NMR (CDCl3): δ = 2.17 (s, 3H), 3.66 (s, 3H), 4.54 (d, J = 11.8
Hz, 1H), 4.70 (d, J = 2.8 Hz, 1H), 4.87 (d, J = 11.8 Hz, 1H), 5.56 (d, J = 2.8 Hz, 1H), 7.34 (m, 5H) ppm;
13C NMR (CDCl3): δ = 20.4, 52.7, 72.4, 73.7, 75.9, 128.4, 128.5, 135.9, 166.8, 170.1, 172.9 ppm; IR
20
(film): ν = 700, 749, 1013, 1088, 1138, 1219, 1375, 1438, 1455, 1755, 1956, 3214 cm-1; αD +55.9 (c
2.0, CHCl3); HRMS (ES-): calc. for [C14H16O7 – H]- 295.0818, found 295.0819.
(2R,3R)-3-O-Acetyl-2-O-benzyl-1-tert-butyl-4-methyl tartrate (17): To a solution of 16 (476 mg,
1.60 mmol) and TEBAC (274 mg, 1.60 mmol) in DMA (20 mL) was added dried K2CO3 (5.75 g, 41.6
t
mmol) followed by BuBr (10.52 g, 76.8 mmol). The mixture was stirred at 55 ºC for 24 h and, after
cooling, cold H2O (100 mL) was added. The product was extracted into AcOEt (75 mL). The organic
layer was separated, washed with H2O (2 x 40 mL), dried over MgSO4 and concentrated under reduced
pressure. The resulting residue was purified by flash chromatography with Hx/AcOEt 4:1 (Rf = 0.41,
UV), to give 17 (451 mg, 80 %) as yellowish oil after removal of solvents. 1H NMR (CDCl3): δ = 1.47
(s, 9H), 2.16 (s, 3H), 3.64 (s, 3H), 4.41 (d, J = 3.1 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 5.57 (d, J = 3.0
13
Hz, 1H), 4.90 (d, J = 12.0 Hz, 1H), 7.32 (m, 5H) ppm; C NMR (CDCl3): δ = 20.3, 27.8, 52.3, 72.7,
73.2, 76.3, 82.6, 127.9, 128.21, 128.24, 136.5, 166.9, 167.0, 169.7 ppm; IR (film): ν = 700, 742, 799,
20
845, 1028, 1088, 1142, 1224, 1372, 1437, 1455, 1754, 2978 cm-1; αD +67.0 (c 2.0, CHCl3); HRMS
+ +
(ES+): calc. for [C18H24O7 + NH4 ] 370.1866, found 370.1862.
SI11

(2R,3R)-2-O-Benzyl-1-tert-butyl tartrate (18): Following general procedure D, 17 (0.693 g, 1.97
mmol) gave after flash chromatography with Hx/AcOEt/AcOH 75:25:1 (Rf = 0.38, UV) 18 (0.572 g,
1
98%) as white solid. Mp: 101-102 ºC; H NMR (CDCl3): δ = 1.52 (s, 9H), 4.31 (br s, 1H), 4.50 (d, J =
11.4 Hz, 1H), 4.57 (br s, 1H), 4.82 (d, J = 11.4 Hz, 1H), 7.34 (m, 5H) ppm; 13C NMR (CDCl3): δ = 28.0,
72.2, 73.1, 78.1, 83.0, 128.1, 128.3, 128.3, 136.4, 168.4, 173.3 ppm; IR (film): ν = 698, 740, 844, 1095,
20
1159, 1256, 1370, 1456, 1748, 2926, 3200 cm-1; αD +65.8 (c 2.0, CHCl3); HRMS (ES-): calc. for
[C15H20O6 – H]- 295.1182, found 295.1195.
(2R,3R)-3-O-Acetyl-2-O-benzyl-1-methyl tartrate (19): 12a (0.724 g, 2.84 mmol) was stirred in
AcCl (7 mL) a catalytic amount of DMAP until complete conversion (2 h, TLC, UV). Then, the valatiles
were removed in vacuo (CAUTION!) and the residue was purified by flash chromatography with
DCM/AcOH 10:0.5. The fractions with product (Rf = 0.55, UV) were pooled and the solvents were
removed in vacuo. Then, the remaining acetic acid was removed by co-evaporation with toluene to give
20 (0.793 g, 94 %) as yellowish oil. 1H NMR (CDCl3): δ = 2.16 (s, 3H), 3.79 (s, 3H), 4.52 (d, J = 11.8
Hz, 1H), 4.55 (d, J = 2.9 Hz, 1H), 4.90 (d, J = 11.8 Hz, 1H), 5.58 (d, J = 2.9 Hz, 1H), 7.31 (m, 5H) ppm;
13C NMR (CDCl3): δ = 20.4, 52.6, 72.3, 73.6, 75.9, 128.3, 128.4, 136.0, 168.8, 170.0, 171.9 ppm; IR
20
(film): ν = 700, 747, 1026, 1080, 1146, 1226, 1375, 1437, 1455, 1758, 2956, 3214 cm-1; αD +59.4 (c
2.0, CHCl3); HRMS (ES-): calc. for [C14H16O7 – H]- 295.0818, found 295.0819.
(2R,3R)-2-O-Acetyl-3-O-benzyl-1-tert-butyl-4-methyl tartrate (20): To a solution of 19 (0.401 g,
1.35 mmol) and TEBAC (251 mg, 1.35 mmol) in DMA (20 mL) was added dried K2CO3 (4.85 g, 35.1
t
mmol) followed by BuBr (8.88 g, 64.8 mmol). The mixture was stirred at 55 ºC for 24 h and, after
cooling, cold H2O (100 mL) was added. The product was extracted into AcOEt (75 mL). The organic
layer was separated, washed with H2O (2 x 40 mL), dried over MgSO4 and concentrated under reduced
pressure. The resulting residue was purified by flash chromatography (Hx/AcOEt 3:1, Rf = 0.43, UV), to
give 20 (0.414 g, 87 %) as yellowish oil. 1H NMR (CDCl3): δ = 1.42 (s, 9H), 2.14 (s, 3H), 3.77 (s, 3H),
4.52 (d, J = 11.5 Hz, 1H), 4.57 (d, J = 3.2 Hz, 1H), 4.86 (d, J = 11.5 Hz, 1H), 5.45 (d, J = 3.2 Hz, 1H),
SI12

13
7.31 (m, 5H) ppm; C NMR (CDCl3): δ = 20.4, 27.7, 52.2, 72.8, 73.5, 76.8, 82.9, 128.0, 128.2, 136.3,
165.1, 169.0, 169.8 ppm; IR (film): ν = 700, 746, 800, 845, 1020, 1087, 1160, 1227, 1371, 1437, 1456,
20
+ +
1756, 2978 cm-1; αD +49.3 (c 2.0, CHCl3); HRMS (ES+): calc. for [C18H24O7 + NH4 ] 370.1866,
found 370.1865.
(2R,3R)-3-O-Benzyl-1-tert-butyl tartrate (21): To a solution of 20 (0.300 g, 0.85 mmol) in THF/H2O
3:1 (18 mL) was added at 0 ºC with 30% H2O2 (0.700 mL, 6.80 mmol) followed by LiOH (0.144 g, 3.40
mmol). The resulting mixture was stirred at 0 ºC for 2 h and then at room temperature for 15 h. Then, at
0 ºC an 1.5 M solution of Na2SO3 (5.0 mL, 7.48 mmol) was added to quench the excess of peroxide.
After stirring at 0 ºC for 15 min, the mixture was buffered to pH 9-10 with sat. aqu. NaHCO3 and the
THF was evaporated under reduced pressure. The aqueous phase was acidified to pH 1-2 with conc.
aqueous HCl and the product was extracted with AcOEt (3 x 20 mL). The organic phase was dried with
MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography
1
(Hx/AcOEt/AcOH 75:25:1, Rf = 0.31, UV), to give 21 (0.244 g, 97 %) as a colourless oil. H NMR
(CDCl3): δ = 1.44 (s, 9H), 4.40 (d, J = 2.1 Hz, 1H), 4.48 (d, J = 11.3 Hz, 1H), 4.52 (d, J = 2.2 Hz, 1H),
4.80 (d, J = 11.3 Hz, 1H), 7.33 (m, 5H) ppm; 13C NMR (CDCl3): δ = 27.8, 72.2, 73.2, 78.5, 83.4, 128.2,
128.2, 128.4, 136.4, 169.9, 173.9 ppm; IR (film): ν = 698, 747, 844, 1095, 1159, 1258, 1370, 1456,
20
1738, 2934, 2979 cm-1; αD +43.8 (c 2.0, CHCl3); HRMS (ES-): calc. for [C15H20O6 – H]- 295.1182,
found 295.1189.
SI13

IV. X-RAY STRUCTURE OF COMPOUND 4
Experimental: A prismatic crystal (0.1x0.1x0.2 mm) was selected and mounted on a MAR345
diffractometer with an image plate detector. Unit-cell parameters were determined from 938 reflections
(3 < θ < 31º) and refined by least-squares method. Intensities were collected with graphite
monochromatized Mo Kα radiation. 10036 reflections were measured in the range 2.83 ≤ θ ≤ 32.42.
3058 of which were non-equivalent by symmetry (Rint(on I) = 0.056 ). 2194 reflections were assumed
as observed applying the condition I > 2σ(I). Lorentz-polarization but no absorption corrections were
made.
The structure was solved by Direct methods, using SHELXS computer program (Sheldrick, G.M.,
(1997), A program for automatic solution of crystal structure. Univer Goettingen, Germany) and refined
by full-matrix least-squares method with SHELX97 computer program (Sheldrick, G.M., (1997), A
program for crystal structure refinement. Univer Goettingen, Germany), using 10036 reflections, (very
negative intensities were not assumed). The function minimized was Σ w │ │Fo│2-│Fc│2│2, where w
= [σ2(I)+(0.0662P)2]-1, and P = (│Fo│2+ 2│Fc│2)/3, f, f' and f" were taken from International Tables of
X-Ray Crystallography (International Tables of X-Ray Crystallography, (1974), Ed. Kynoch press, Vol.
IV, pp 99-100 and 149). 4H atoms were located from a difference synthesis and refined with an overall
isotropic temperature factor and 6H atoms were located from a difference synthesis and refined, using a
riding model, with an isotropic temperature factor equal to 1.2 the equivalent temperature factor of the
atom which are linked. The final R(on F) factor was 0.055, wR(on │F│2) = 0.130 and goodness of fit =
1.150 for all observed reflections. Number of refined parameters was 143. Max. shift/esd = 0.00, Mean
shift/esd = 0.00. Max. and min. peaks in final difference synthesis was 0.162 and -0.162 eÅ-3,
respectively.
Crystal data and structure refinement for 4
Empirical formula
Formula weight
C7 H10 O7
206.15
SI14

Temperature
293(2) K
Wavelength
0.71073 Å
Crystal system, space group
Unit cell dimensions
Monoclinic, P21/c
a = 9.161(6) Å α = 90 º.
b = 9.374(6) Å β = 109.59(3) º.
c = 11.956(5) Å γ = 90 º.
967.3(10) Å3
Volume
Z, Calculated density
Absorption coefficient
F(000)
4, 1.416 Mg/m3
0.130 mm-1
432
Crystal size
Theta range for data collection
Limiting indices
0.2 x 0.09 x 0.09 mm
2.83 to 32.42 º.
-12<=h<=13, -13<=k<=13, -17<=l<=17
10036 / 3058 [R(int) = 0.0564]
99.3 %
Reflections collected / unique
Completeness to theta = 25.00
Absorption correction
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2σ(I)]
R indices (all data)
None
Full-matrix least-squares on F2
3058 / 0 / 143
1.150
R1 = 0.0552, wR2 = 0.1302
R1 = 0.0876, wR2 = 0.1441
0.162 and -0.162 e.Å-3
Largest diff. peak and hole
SI15

V. COPIES OF 1H AND 13C NMR OF COMPOUNDS 1-6
(2R)-(Hydroxy)-{(4R)-5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl}-acetic acid 1
(1H, 13C: acetone-d6)
O
400
HO
O
CF
3
HOC
2
O
CF
3
300
200
100
0
10.0
5.0
0.0
ppm (t1)
10000
5000
0
150
100
50
0
ppm (f1)
SI16

(5-Oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-ylidene)-acetic acid 2
(1H, 13C: acetone-d6)
1000
500
0
O
HO2C
O
O
CF3
F3C
10.0
ppm (t1)
5.0
0.0
15000
10000
5000
0
150
100
50
0
ppm (f1)
SI17

(2R)-Acetoxy-{(4R)-5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl}-acetic acid 3
(1H, 13C: acetone-d6)
700
600
O
AcO
O
CF3
500
HO C
2
O
CF3
400
300
200
100
0
10.0
ppm (f1)
5.0
0.0
10000
5000
0
150
100
50
0
ppm (f1)
SI18

(2R,3R)-3-O-Acetyl-1-methyl tartrate 4
(1H: D2O, 13C: acetone-d6)
AcO
CO2Me
OH
1000
500
0
HO2C
10.0
5.0
0.0
ppm (f1)
25000
20000
15000
10000
5000
0
150
100
50
0
ppm (f1)
SI19

(2R)-(Acetyoxy)-{(4R)-5-oxo-2,2-bis-trifluoromethyl-[1,3]dioxolan-4-yl}-
methylacetate 5 (1H, 13C: CDCl3)
2500
2000
1500
1000
500
O
AcO
O
CF3
MeO2C
O
CF3
0
8.0
ppm (f1)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
15000
10000
5000
0
150
100
50
0
ppm (f1)
SI20

(2R,3R)-2-O-Acetyl-1-methyl tartrate 6 (1H, 13C: CDCl3)
2000
1500
1000
500
0
HO
CO2Me
OAc
HO2C
10.0
5.0
0.0
ppm (f1)
20000
15000
10000
5000
0
150
100
50
0
ppm (f1)
SI21

SI22