Checked by Joseph P. Bullock and Louis S. Hegedus.
1. Procedure
B.
(+)-2-O-Benzyl-L-threitol.
2 A
2-L, three-necked, round-bottomed flask is oven-dried (140°C) and flushed with
nitrogen. The flask is equipped with an
efficient mechanical stirrer, a
250-mL pressure-equalizing addition funnel, and a
reflux condenser equipped with a mineral oil bubbler that is connected to a
nitrogen source. A slight pressure of gas is maintained in the apparatus throughout the course of the reaction. The flask is charged with
16.5 g (434 mmol) of lithium aluminum hydride (Note
7), and cooled to −30°C using an
isopropyl alcohol-dry ice bath. Then
167 mL of dry diethyl ether (Note
8) is added with vigorous stirring and a solution of
57.8 g (434 mmol) of aluminum chloride in
134 mL of dry diethyl ether (Note
8), (Note
9) is added dropwise during 40 min. Dry
dichloromethane (134 mL) (Note
10) is placed in the addition funnel and added rapidly, while the temperature is allowed to rise to 0°C. A solution of
64.7 g (220 mmol) of diethyl (−)-2,3-O-benzylidene-L-tartrate in dry
dichloromethane (134 mL) is added dropwise during 30 min (Note
11). The mixture is stirred for 1 hr at room temperature and heated to reflux for an additional 2 hr. The mixture is cooled to −20°C as above, and 14 mL of de-ionized water, followed by a solution of
31.5 g (561 mmol) of potassium hydroxide in 46 mL of de-ionized water, is added cautiously. The cooling bath is removed and the mixture is stirred at room temperature until the grey color (probably due to unreacted
lithium aluminum hydride) has completely disappeared (Note
12). Efficient stirring is required throughout to ensure good yields. The mixture is filtered through a glass-sintered funnel containing a
2-cm pad of Celite, and the inorganic precipitate is extracted with
0.5 L of dichloromethane in a
Soxhlet apparatus for 3 days. The combined extracts and filtrate are evaporated under reduced pressure (30 mm, 30°C). After drying over
phosphorus pentoxide (P
4O
10) in an evacuated (1 mm)
desiccator,
42.4 g (
91%) of colorless crystals, mp
71–73°C, are obtained and used as such for step C. Recrystallization from
dichloromethane (Note
10) gives
37.4 g (
80%) of
(+)-2-O-benzyl-L-threitol, mp
75–76°C (Note
13).
D.
Ethyl (−)-[R-(E)]-4-O-benzyl-4,5-dihydroxy-2-pentenoate. To a
500-mL, round-bottomed, two-necked flask, fitted with a
nitrogen inlet (Note
19) and a stopper, is added
3.32 g of a suspension of sodium hydride in paraffin, containing
65% sodium hydride. The suspension is washed three times with 40 mL and once with
20 mL of hexanes (Note
20) to remove the paraffin. The residue is freed from remaining hexanes under vacuum (0.01 mm) to give ca.
2.16 g (ca. 90 mmol) of sodium hydride. The flask is fitted with a
magnetic stirring bar and the stopper is exchanged for a septum. Then
100 mL of tetrahydrofuran (Note
21) is added and the suspension is cooled to 0°C.
Triethyl phosphonoacetate (22.87 g, 102 mmol) (Note
22) is added to the stirred
sodium hydride/
tetrahydrofuran suspension by means of a
50-mL syringe over a period of 20 min. The mixture is cooled to −78°C (
acetone/dry ice) and a solution of
10.81 g (60 mmol) of (−)-2-O-benzyl-L-glyceraldehyde in
80 mL of tetrahydrofuran (Note
21) is added by means of a syringe over 20 min. (The checkers transferred this solution via a cannula.) The mixture is stirred for an additional 15 min at −78°C. The temperature is allowed to rise to 0°C within 30 min, and finally is kept at room temperature for an additional 45 min. The reaction is quenched with
150 mL of saturated ammonium chloride solution and extracted three times with
ether (500, 200, 200 mL). The combined organic layers are washed with a mixture of saturated
sodium bicarbonate/brine (1:1, 160 mL). The aqueous layer is washed with
ether (3 × 100 mL). The combined organic layers are dried over
magnesium sulfate, filtered, and evaporated to dryness to give a pale yellow oil. The crude product is purified by column chromatography over silica gel (Note
23) with
petroleum ether/ethyl acetate 1/1 as eluent (Note
24), to yield
11.7 g (
78%) of analytically pure
ethyl (−)-[R-(E)]-4-O-benzyl-4,5-dihydroxy-2-pentenoate (Note
25).
2. Notes
1.
Diethyl L-tartrate (99%) was obtained from Janssen Chimica, Brüggen, Germany or Aldrich Chemical Company, Inc.
2.
Benzaldehyde (99+%) from Aldrich Chemical Company, Inc., was used as received.
4. The mixture becomes homogeneous at reflux temperature. The reaction usually takes about 16 hr at an 0.5 mole-scale as indicated by the amount of water separated.
6. The spectral properties of
diethyl (−)-2,3-O-benzylidene-L-tartrate are as follows:
1H NMR (250 MHz, CDCl
3) δ: 1.32, 1.35 (2 t, 6 H, J = 7.1, 2 CH
2CH
3), 4.23, 4.28 (2 q, 4 H, J = 7.1, 2 CH
2CH
3), 4.83, 4.95 (2 d, 2 H, J = 4.0, 2 CHO), 6.16 (s, 1 H, CHPh), 7.40, 7.58 (2 m, 5 H, C
6H
5),
4 [α]D20 −30.7° (CHCl
3,
c 2.20),
5 mp
45°C.
4,5
7.
Lithium aluminum hydride was obtained in 25-g samples (98%) from Merck-Schuchardt, Hohenbrunn, Germany or Aldrich Chemical Company, Inc.
12. The reaction mixture is heated to reflux with
200 mL of tetrahydrofuran; the precipitate then obtained is very easy to filter off.
13. The spectral properties of
(+)-2-O-benzyl-L-threitol are as follows:
1H NMR (250 MHz, CDCl
3) δ: 2.58, 2.76, 2.98 (bs, 3 H, 3 OH), 3.44–3.88 (m, 6 H, 2 CH
2OH, H-2, H-3), 4.56, 4.69 (AB, 2 H, J = 11.6, CH
2C
6H
5), 7.16–7.34 (m, 5 H, C
6H
5),
[α]D25 +17.5° (EtOH,
c 1.14).
5
14. In several experiments it was found that the yield of
(−)-2-O-benzyl-L-glyceraldehyde is somewhat lower when the reaction is performed on a larger scale.
15.
Sodium periodate (98%) was obtained from Fluka Feinchemikalien GmbH, Neu-Ulm, Germany or from Fisher Scientific Company.
16. The pH was controlled with Merck Universal-Indikatorpapier or pHydrion Vivid 1–11 Jumbo pH paper, Micro Essential Laboratory, Brooklyn, NY, USA.
17. A
silicone-oil bath is preheated to 160°C (the checkers used a
sand bath). The flask of the evacuated apparatus filled with the crude product is immersed totally in the bath until no more distillate is collected. For optimum results, the distillation should be performed within 10 to 15 min. Slower distillation leads to lower yields because of thermal decomposition.
18. It is not possible to give exact spectral properties of
(−)-2-O-benzyl-L-glyceraldehyde because of rapid di- and/or oligomerization. In order to check the optical purity of the product, it is convenient to compare the equilibrium value of specific rotation, as obtained after 6 days in
ethanol solution at room temperature;
[α]D22 −33.2° (EtOH,
c 0.083). In succeeding reactions (see Discussion and Step D), it was determined from NMR shift experiments that these products [e.g., (i) the Z-selective Wittig enoate product (with
ethoxycarbonylmethylene-triphenylphosphorane) and the
penten-5-olide therefrom (after acid-catalyzed lactonization,
4,6] and (ii) the E-enoate (Horner product)
4,6 contained enantiomers in ratios of >96:4.
19.
Nitrogen was dried by means of a Sicapent® (E. Merck) drying tube. The checkers used
argon.
20. The checkers used
hexanes (technical grade) distilled over 3 Å molecular sieves. The submitters used
pentane distilled from
sodium.
22.
Triethyl phosphonoacetate was purified by distillation (bp
143°C, 9 mm). The checkers obtained this compound (99%) from Aldrich Chemical Company, Inc., and used it as received.
23. The submitters used
28 g of Kieselgel 60, E. MERCK, 0.040–0.063 mm (250–400 mesh); column: 28 cm × 2.5 cm. The checkers used
100 g of silica gel, 0.032–0.063 mm, Selecto Scientific, Norcross, GA, USA, catalog # 162824; column: 40 cm × 5.5 cm.
24.
Ethyl acetate and petroleum ether (technical grade; boiling range 40–80°C) were purified by distillation. The checkers used
ethyl acetate/
hexanes 10/90 followed by
ethyl acetate/
hexanes 35/65 as eluent;
ethyl acetate (HPLC grade) was obtained from Mallinckrodt Specialty Chemicals Company, Paris, KY, USA and hexanes (technical grade) were distilled over 3 Å molecular sieves.
25. The analytical data (after chromatography) were as follows: Calcd. for C
14H
18O
4 (250.29): C, 67.18; H, 7.25. Found: C, 67.00; H. 7.20. The E/Z ratio was found to be >97:3 (determined by HPLC). Rt
E = 3.72 min; Rt
Z = 4.28 min, eluent
petroleum ether/
ethyl acetate 6/4 (
LiChrosorb Si 60 column, E. Merck]. TLC: R
f = 0.34 (
petroleum ether/
ethyl acetate 1/1). GLC analysis:
Column PS086/.32 mm × 20 m glass capillary, 95:5
methyl/
phenylsilicone. Program: T
1, 40°C/(1 min), rate 10°C/min, T
2, 300°C, 0.5 bar hydrogen pressure; Rt
Z = 16.47 min; Rt
E = 17.25 min. E/Z ratio was found to be >97:3 (determined by GLC).
[α]D22 −75.8° (CHCl
3,
c 1.192, E/Z >97:3), bp
125–130°C (0.001 mm).
13C NMR (63 MHz, CDCl
3) δ: 14.2 (OCH
2CH
3), 60.7 (OCH
2CH
3), 64.6 (C-5), 71.5 (CH
2Ph), 79.0 (C-4), 123.9 (C-2), 127.9, 128.0, 128.3, 128.6, 137.6 (C
6H
5), 144.3 (C-3), 165.9 (C-1);
1H NMR (250 MHz, CDCl
3), δ: 1.30 (t, 3 H, J = 7.1, CH
3), 2.32 (dd, 1 H, J = 5.2, 7.9, OH), 3.65 (m, 2 H, CH
2OH), 4.14 (m, 1 H, 4-H), 4.22 (q, 2 H, J = 7.1, OCH
2CH
3), 4.41, 4.45 (AB, 2 H, J = 11.6, CH
2Ph), 6.11 (dd, 1 H, J = 1.3, 15.8, 2-H), 6.85 (dd, 1 H, J = 6.1, 15.8, 3-H), 7.34 (m, 5 H, C
6H
5).
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995 and "Neue Datenblätter für gefährliche Arbeitsstoffe nach der Gefahrstoffverordnung", Welzbacher, U. (Ed.); WEKA Fachverlage, Kissing, 1991.
3. Discussion
Both enantiomers of
2 are readily available from
D-mannitol and from
L-gulonolactone, respectively, and have been used in many reactions in a straightforward manner, because of the free aldehyde and the protected hydroxy functions. Unfortunately,
2 tends to trimerize and partial racemization has often been encountered on prolonged storage, thus preventing shipping/commercialization.
16 A recent paper on large-scale preparation of
glyceraldehyde acetonide 2, however, indicates suitable stability even at room temperature when certain precautions are met.
17 18 19
Glyceraldehyde derivatives with one protected and one free hydroxy function could, in principle offer new options because 2O/3O are more strongly differentiated, and further, since the free hydroxy group does or may cause different regio- and stereoselectivity in the next or subsequent steps.
2-O-Benzylglyceraldehyde,
3, because of its di- or oligomeric form, is configurationally stable at room temperature.
6 The
D-form has previously been prepared from
D-mannitol in four steps, with an overall yield of 5%,
20 or in 9 steps with 4%,
21 and from
D-glucose in six steps with an overall yield of 50%.
22
As described here, both enantiomers of
3 can be prepared in three steps from commercially available
diethyl D- and L-tartrate in up to 70% over-all yield.
2,3,4,6 Procedures to obtain the
benzylidene acetal,
23,24 with the ensuing reduction step,
23,24 are based on previous literature reports. Both enantiomers of
3 have been used in highly stereoselective nitroaldol additions.
4,25 Imines, nitrones, oximes, and nitrile oxides derived therefrom were recently employed in a variety of additions/cycloadditions.
26 27 28,29 30 31 32 33 (−)-2-O-Benzyl-L-glyceraldehyde has further been used for the preparation of protected
(2S,4R)-4-hydroxyornithine, via a Horner-Emmons reaction to the corresponding α,β-didehydroamino acid derivatives and subsequent diastereoselective hydrogenation.
34 Transformation of aldehyde
3 in Z-selective Wittig or E-selective Horner reactions
4,6,35 (see Step D
36), formation of the
dimethyl acetal5,37 or of the corresponding nitro compound by oxidation of the oxime,
5,37 represent further recent uses of
3.
Appendix
Compounds Referenced (Chemical Abstracts Registry Number)
petroleum ether
hexanes
brine
dimethyl acetal
glyceraldehyde acetonide
(−)-2-O-BENZYL-L-GLYCERALDEHYDE
ETHYL (R,E)-4-O-BENZYL-4,5-DIHYDROXY-2-PENTENOATE
Diethyl (−)-2,3-O-benzylidene-L-tartrate
Ethyl (−)-[R-(E)]-4-O-benzyl-4,5-dihydroxy-2-pentenoate
sodium hydride in paraffin
penten-5-olide
diethyl D- and L-tartrate
benzylidene acetal
methylsilicone
phenylsilicone
ethanol (64-17-5)
potassium carbonate (584-08-7)
ethyl acetate (141-78-6)
ether,
diethyl ether (60-29-7)
ammonium chloride (12125-02-9)
sodium bicarbonate (144-55-8)
nitrogen (7727-37-9)
cyclohexane (110-82-7)
benzaldehyde (100-52-7)
acetone (67-64-1)
aluminum chloride (3495-54-3)
potassium hydroxide (1310-58-3)
Benzophenone (119-61-9)
sodium (13966-32-0)
Pentane (109-66-0)
d-Glucose (492-62-6)
dichloromethane (75-09-2)
magnesium sulfate (7487-88-9)
Tetrahydrofuran (109-99-9)
lithium aluminum hydride (16853-85-3)
sodium hydride (7646-69-7)
potassium bicarbonate (298-14-6)
argon (7440-37-1)
triethyl phosphonoacetate (867-13-0)
Sodium periodate (7790-28-5)
diethyl L-tartrate
ethoxycarbonylmethylene-triphenylphosphorane (1099-45-2)
phosphorus pentoxide (1314-56-3)
D-mannitol (69-65-8)
p-toluenesulfonic acid monohydrate (6192-52-5)
2-O-Benzylglyceraldehyde
Propanal, 3-hydroxy-2-(phenylmethoxy)-, (R)-
2-Pentenoic acid, 5-hydroxy-4-(phenylmethoxy)-, ethyl ester, [R-(E)]- (119770-84-2)
(+)-2-O-Benzyl-L-threitol
2,3-O-isopropylideneglyceraldehyde (22323-80-4)
L-gulonolactone
(2S,4R)-4-hydroxyornithine
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