Checked by Gregory P. Brengel and Albert I. Meyers.
1. Procedure
B.
(1R)-2,3-Di-O-isopropylidene-1-(2-thiazolyl)-D-glycitol. A
100-mL, three-necked, round-bottomed flask, containing a magnetic stirring bar, is equipped with a
50-mL pressure-equalizing dropping funnel and a low-temperature thermometer (Note
1). The dry apparatus is filled with
argon and kept under an inert gas pressure of ca. 100 mm for the entire reaction time. The flask is charged with
2.0 g (0.0154 mol) of D-glyceraldehyde acetonide (Note
9) in
25 mL of dichloromethane (Note
10) and the dropping funnel is filled with
2.4 g (0.0153 mol) of 2-TST in
25 mL of dichloromethane (Note
10). The reaction flask is cooled to 0°C in an
ice bath. While the solution is stirred, 2-TST is added dropwise over a period of 15 min. After the reaction is stirred for 12 hr at room temperature, it is complete as shown by TLC (silica,
diethyl ether –
petroleum ether 1:1).
Dichloromethane (ca. 40 mL) is removed under reduced pressure and the residue is treated with
tetrabutylammonium fluoride (
14 mL of a 1.1 M solution in tetrahydrofuran, 0.0154 mol) (Aldrich Chemical Company, Inc.) Desilylation is complete as shown by TLC (silica,
diethyl ether –
petroleum ether, 1:1) in 10 min. Volatile material is removed under reduced pressure and the residue is treated with 50–60 mL of water. The mixture is extracted with
dichloromethane (3 × 50 mL) and the combined
dichloromethane solutions are dried with anhydrous
sodium sulfate. The solvent is removed under reduced pressure and the solid residue (3.14 g) is flash chromatographed (silica,
diethyl ether –
petroleum ether, 3:2) to give
2.85 g (
84%) of the alcohol as a white solid, mp
114–116°C (from
dichloromethane-
hexane) (Note
11).
D.
Thiazolyl-to-formyl deblocking. The protected
1-(2-thiazolyl)-D-glycitol (3.5 g, 0.0115 mol) is dissolved in
70 mL of acetonitrile (Note
17),
methyl iodide (24.7 g, 0.173 mol, purified by passing through neutral alumina) is added and the resulting mixture is heated to reflux until N-methylation of
thiazole is complete (at least 24 hr) as shown by TLC (Note
15) and (Note
18). The solvent is removed under reduced pressure and the residue (Note
19) is dissolved in at least
70 mL of methanol. The solution is cooled to 0°C in an ice bath and
sodium borohydride (0.65 g, 0.0172 mol) is added in portions while the solution is stirred vigorously. After the solution is stirred for 30 min at 0°C, it is treated with
2 mL of acetone, and the solvent is removed under reduced pressure. The residue is treated with a saturated solution of
sodium chloride (50 mL) and extracted with
dichloromethane (3 × 50 mL). The combined extracts are dried over anhydrous
sodium sulfate and the solvent is removed under reduced pressure. The resulting oil (Note
20) is dissolved in
acetonitrile (5 mL) and the solution is slowly added to a vigorously stirred solution of
mercury chloride (3.7 g, 0.0136 mol) in a 4:1 mixture of
acetonitrile – water (50 mL). After being stirred at room temperature for 15 min, the reaction mixture is filtered on a
Büchner funnel through Celite and the sticky inorganic residue is rinsed with
diethyl ether. The combined ethereal extracts are added to the filtered solution and the mixture is concentrated to ca. 10 mL by evaporation of the solvent under reduced pressure. The residue is treated with a saturated solution of
potassium chloride (KCI) (50 mL), extracted with
dichloromethane (3 × 50 mL), and the combined extracts are dried over anhydrous
sodium sulfate (Note
21). Removal of volatile material under reduced pressure gives an oil that is flash chromatographed (silica,
diethyl ether –
petroleum ether 1:1) to afford
1.77 g (
62%) of
2-O-benzyl-3,4-isopropylidene-D-erythrose (Note
22).
2. Notes
1. The glass components of the apparatus were dried overnight in a 150°C-oven and allowed to cool in a
desiccator over a drying agent before assembly.
3. A 1.5 M solution of
butyllithium in hexane was purchased from Aldrich Chemical Company, Inc. Aliquots were transferred to a
100-mL graduated cylinder, stoppered with a
rubber septum using a
15-gauge cannula and
argon.
5.
2-Bromothiazole, available from Aldrich Chemical Company, Inc., was distilled prior to use.
7. The Claisen distillation head was filled with glass wool to avoid formation of foam. The checkers found that constant heating of the distillation apparatus with a heat gun greatly facilitates the rate of distillation and minimizes the column holdup.
8. The product showed the following spectroscopic properties:
1H NMR (80 MHz, CDCl
3, TMS) δ: 0.40 (s, 9 H), 7.40 (d, 1 H, J = 3.0), 8.01 (d, 1 H, J = 3.0);
13C NMR (75.5 MHz, CDCl
3, TMS) δ: −1.20 (q), 121.3 (d), 145.8 (d), 174.3 (s). Other physical properties includes n
22.5D 1.4975 and d = 0.987.
9. The aldehyde was freshly distilled material prepared according to the
Organic Syntheses procedure.
2
11. This product (anti-adduct) was ≥95% diastereomerically pure based on comparison of the
1H NMR spectrum with that of the syn-adduct.
3 Physical properties and spectral data are as follows:
[α]D −1.2° to −1.5° (MeOH,
c 1.0)
1H NMR (80 MHz, CDCl
3-D
2O, TMS) δ: 1.40 (s, 3 H), 1.47 (s, 3 H), 4.0 (m, 2 H), 4.45 (m, 1 H), 5.07 (d, 1 H, J = 5.1), 7.30 (d, 1 H, J = 3.2), 7.73 (d, 1 H, J = 3.2);
13C NMR (75.5 MHz, CDCl
3, TMS) δ: 25.16 (q), 26.69 (q), 65.38 (t), 71.77 (d), 78.42 (d), 110.54 (s), 120.33 (d), 142.96 (d), 170.95 (s).
13.
Benzyl bromide was purchased from Aldrich Chemical Company, Inc., and purified by passing through neutral alumina.
14.
Sodium hydride, 60% dispersion in mineral oil from Aldrich Chemical Company, Inc., was used as obtained.
15. The reaction appeared complete by TLC (silica,
diethyl ether –
petroleum ether, 1:1); R
f alcohol = 0.15, R
f O-benzyl derivative = 0.27.
16. Physical properties and spectral data are as follows:
[α]D +53.7° to +59.6° (CHCl
3,
c 1.66);
1H NMR (270 MHz, CDCl
3, TMS) δ: 1.34 (s, 3 H), 1.39 (s, 3 H), 4.02 (dd, 1 H, J = 4.9, 1.2), 4.52–4.70 (m, 3 H), 4.83 (d, 1 H, J = 5.5), 7.33–7.35 (m, 5 H), 7.39 (d, 1 H, J = 3.2), 7.81 (d, 1 H, J = 3.2);
13C NMR (75.5 MHz, CDCl
3, TMS) δ: 25.39 (q), 26.54 (q), 56.31 (t), 72.81 (t), 78.65 (d), 79.09 (d), 110.67 (s), 120.73 (d), 128.74 (d), 128.86 (d), 129.20 (d), 138.0 (s), 143.5 (s) 170.55 (s).
17.
Reagent grade acetonitrile from Carlo Erba was used as obtained.
19. A sample of this material obtained in a separate experiment was crystallized from
methanol –
diethyl ether to give the pure
N-methylthiazolium iodide as white crystals, mp
181–183°C (dec);
1H NMR (80 MHz, CD
3OD, TMS) δ: 1.33 (s, 3 H), 1.51 (s, 3 H), 3.95–4.51 (m, 3 H), 4.17 (s, 3 H), 4.79 (br d, 2 H), 5.36 (d, 1 H, J = 7.2), 7.34 (s, 5 H), 8.27 (m, 2 H).
20. A sample of this material obtained in a separate experiment was purified by chromatography (silica,
dichloromethane –
diethyl ether 85:5) to give the pure
thiazolidine as 1:1 mixture of diastereoisomers : oil;
1H NMR (80 MHz, CDCl
3, TMS) δ: 1.36 (s, 3 H), 1.42 (s, 3 H), 2.31 (s, 1.5 H), 2.33 (s, 1.5 H), 2.77–3.25 (m, 4 H), 3.66 (m, 1 H), 3.90–4.55 (m, 4 H), 4.77 (s, 2 H), 7.32 (s, 5 H).
21. The solid residue contains mercury salts and should be disposed of by procedures used for heavy metal residues.
22. The product showed the following properties: oil;
[α]D +36.8° to +37.1° (CHCl
3,
c 1.70); IR (film) cm
−1: 2720, 1734;
1H NMR (270 MHz, CDCl
3, TMS) δ: 1.35 (s, 3 H), 1.43 (s, 3 H), 3.81 (dd, 1 H, J = 6.8, 2.5), 3.92 (dd, 1 H, J = 6.1, 9.6), 4.07 (dd, 1 H, J = 9.2, 7.3), 4.35 (m, 1 H), 4.67 (AB quartet, 2 H, J = 11.6), 7.3–7.38 (m, 5 H), 9.70 (d, 1 H, J = 2.5);
13C NMR (75.5 MHz, CDCl
3, TMS) δ: 25.22 (q), 26.55 (q), 66.37 (t), 73.51 (t), 75.22 (d), 83.31 (dd), 110.24 (s), 128.38 (d), 128.75 (d), 137.23 (s), 201.4 (d).
3. Discussion
The procedure presented here illustrates the use of 2-TST as a one-carbon homologating reagent of a chiral α,β-dialkoxy aldehyde.
3,7 The protocol is based on three essential key operations, i.e., the anti-stereoselective addition (ds ≥ 95%) of 2-TST to the aldehyde (Step B), the protection of the
hydroxy group at the newly formed stereogenic center (Step C), and the liberation of the formyl group from the thiazole ring (Step D). This step involves a sequence of three reactions (N-methylation of the thiazole ring, reduction, and hydrolysis) that occurs under almost neutral conditions and leaves unaltered the asymmetric centers in the chiral compounds. The procedure for the N-methylation appears more practical than an earlier method
8 employing
trimethyloxonium fluoroborate in liquid
sulfur dioxide.
9 Overall, 2-TST appears to serve as an equivalent to the formyl anion synthon. The iterative application of this principle over several consecutive cycles produces a series of homologues of
D-glyceraldehyde up to a nine-carbon chain and with an all-
anti configuration of the vicinal hydroxy groups.
3 This linear iterative one-carbon extension technology was successfully applied to
L-threose acetonide,
3 dialdoses,
3,10 and α-amino aldehydes.
11
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