An expedient one-step preparation of (S)-2,3-O-isopropylidene-glyceraldehyde

Article abstract of DOI:10.1055/s-2001-17459

One-step PCC oxidation of (R)-2,3-O-isopropylideneglycerol in dichloromethane provides (S)-2,3-O-isopropylideneglyceraldehyde 2 in 30% yield after its separation from ester 3 by careful distillation. The same procedure with (S)-2,3-O-isopropylideneglycerol affords (R)-2,3-O-isopropylideneglyceraldehyde.

Full text of DOI:10.1055/s-2001-17459

LETTER
1565
An Expedient One-Step Preparation of (S)-2,3-O-Isopropylidene-
glyceraldehyde
O
ne-St e
p
Prepa
u
rat ion of
(
S
)
-
d
2,3-
O
-
Isopro
m
pylideneglyceralde
i
hyde la Ermolenko, N. André Sasaki,* Pierre Potier
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur Yvette, France
Fax +33(1)69077247; E-mail: andre.sasaki@icsn.cnrs-gif.fr
Received 25 June 2001
practical difficulty associated with aqueous solubility and
volatility of the product. However, oxidation of 1 to 2 by
these and several other reagents suffers from a concomi-
tant side reaction due to fast hemiacetal formation and its
further oxidation to ester 3 (Scheme).21
Abstract: One-step PCC oxidation of (R)-2,3-O-isopropylideneg-
lycerol in dichloromethane provides (S)-2,3-O-isopropylideneglyc-
eraldehyde 2 in 30% yield after its separation from ester 3 by careful
distillation. The same procedure with (S)-2,3-O-isopropylideneg-
lycerol affords (R)-2,3-O-isopropylideneglyceraldehyde.
Key words: (R)-2,3-O-isopropylideneglycerol, (S)-2,3-O-isopro-
pylideneglycerol, (S)-2,3-O-isopropylidenegylceraldehyde, (R)-
2,3-O-isopropylidenegylceraldehyde, PCC oxidation
Optically pure (S)- and (R)-2,3-O-isopropylideneglyceral-
dehydes are widely used as key chiral building blocks in
enantioselective syntheses of a variety of natural products.
Whereas (R)-2,3-O-isopropylideneglyceraldehyde is con-
ventionally obtained from D-mannitol,1–6 the preparation
of (S)-enantiomer 2 by known methods is much less prac-
tical due to limited availability of starting materials, na-
ture of reagents used, length of the syntheses, capricious
steps, or low overall yields.7–13 The high solubility of iso-
propylideneglyceraldehyde in water and its volatility re-
sult in significant loss of the product during its isolation.
Rapid polymerization of isopropylideneglyceraldehyde
on standing, even at low temperature, creates handling
and storage problems.
Scheme
In connection with our efforts on the synthesis of L-2-ami-
no-2-deoxy sugars,14,15 we needed (S)-2,3-O-isopropy-
lideneglyceraldehyde 2 in pure form. Although an
efficient one-step preparation of 2 has been reported,16 its
rather too costly starting material, 5,6-O-isopropylidene-
L-gulonic acid -lactone, has made this method prohibi-
tive for us. After several other known methods of its prep-
aration had been tried and found unsatisfactory, we turned
our attention to oxidation of commercially available (R)-
2,3-O-isopropylideneglycerol.17 Swern oxidation of (R)-
2,3-O-isopropylideneglycerol 1 to (S)-2 and its further re-
action, without isolation, has been reported.18 However,
our attempts to obtain pure 2 in good yield by Swern,
Dess-Martin periodinane, Ley perruthenate, or TEMPO
oxidation methods were unsuccessful. Finally, a practical
route to 2 was found by oxidation of (R)-2,3-O-isopropy-
lideneglycerol 1 with PCC.
The representative results given in the Table clearly indi-
cate that PCC is the oxidant of choice in terms of the alde-
hyde to ester ratio (2:3), presumably due to the faster
oxidation rate (entry 1 vs. 3). Attempts to increase the rate
of alcohol oxidation with PDC by addition of AcOH22 led
to decomposition of the products (entry 2). The use of mo-
lecular sieves23 in the PCC oxidation reaction was found
to be beneficial (entry 6 vs. 9).24 On the contrary, addition
of AcONa augmented the accumulation of ester (entry 5
vs. 6). Finally, it was demonstrated that high dilution (en-
try 6 vs. 7) and slow addition of the alcohol to the oxidant
(entry 4 vs. 6) increased the aldehyde to ester ratio (2:3),
certainly because of the low alcohol concentration main-
tained during oxidation.
In spite of the modest yield, the present procedure com-
pares favorably to most of the known methods in overall
efficiency and provides an expeditious access to (S)-2,3-
O-isopropylideneglyceraldehyde 2 as well as its more
common (R)-isomer.
The choice of Cr(VI) reagents, PCC and PDC, in
dichloromethane19,20 allows the circumvention of the
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1565,1566,ftx,en;G13001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1566
L. Ermolenko et al.
LETTER
Table Oxidation of (R)-2,3-O-Isopropylideneglycerol 1 by
Chromium (VI) Reagents
(11) De Wilde, H.; De Clercq, P.; Vandewalle, M. Tetrahedron
Lett. 1987, 28, 4757.
(12) Marco, J. L.; Rodriguez, B. Tetrahedron Lett. 1988, 29,
1997.
(13) Bisseret, P.; Rohmer, M. J. Org. Chem. 1989, 54, 2958.
(14) Ermolenko, L.; Sasaki, N. A.; Potier, P. Tetrahedron Lett.
1999, 40, 5187.
(15) Ermolenko, L.; Sasaki, N. A.; Potier, P. J. Chem. Soc.,
Perkin Trans. 2000, 2465.
(16) Hubschwerlen, C.; Specklin, J.-L.; Higelin, J. Org. Syn.
1995, 72, 1.
(17) (R)- and (S)-2,3-O-Isopropylidene glycerols are available in
kg scale from CHEMI S. p. A., Via dei Lavoratori 54, 20092
Cinisello Balsamo (MI), Italy.
(18) Janson, M.; Kvarnstroem, I.; Svensson, S. C. T.; Classon, B.;
Samuelsson, B. Synthesis 1993, 129.
(19) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 5, 399.
(20) Piancatelli, G.; Scettri, A.; D’Aura, M. Synthesis 1982, 245.
(21) Representative data for 3: colorless liquid, bp 100 °C/0.2
mm; [ ]D20 -7.3 (c 2.4, CHCl3); IR(neat): 3510(br), 2988,
2939, 2887, 1761, 1683, 1456, 1373, 1214, 1155, 1103,
1070, 841 cm-1; 1H NMR (400 MHz, CDCl3) = 4.64 (1 H,
dd, J = 5.0, 7.5 Hz), 4.40–4.05 (6 H, m), 3.76 (1 H, dd,
J = 5.0, 7.5 Hz), 1.51 (3 H, s), 1.44 (3 H, s), 1.41 (3 H, s),
1.36 (3 H, s); 13C NMR (50 MHz, CDCl3) = 170.9, 111.2,
109.6, 73.8, 73.2, 67.1, 66.0, 65.1, 26.5, 25.7, 25.4, 25.1; m/
z (ESI) 299 [M+K]+, 283 [M+Na]+, 261 [M+H]+, 202. Anal.
Calcd. for C12H20O6: C, 55.37; H, 7.74. Found: C, 55.07; H,
7.96.
Entry
1
Reagent
Ratio (GC)a Notes
2:3
PDC 1.5 equiv, molec- 1:5
ular sieves
2
3
PDC 1.5 equiv, AcOH
decomposition
PCC 1.5 equiv, molec- 1:2
ular sieves
4
5
6
PCC 2 equiv, 0 °C,
molecular sieves
1: 50
alcohol was add-
ed in one portion
PCC 2 equiv, AcONa, 1:3
molecular sieves
PCC 2 equiv, molecu- 5:2
lar sieves
20 mL of
CH2Cl2 /g of
PCC
7
PCC 2 equiv, molecu- 1:4
lar sieves
10 mL of
CH2Cl2 /g of
PCC
8
9
PCC 3 equiv, molecu- 1:1
lar sieves
PCC 2 equiv
2:3
(22) Czernecki, S.; Georgoulis, C.; Stevens, C. L.;
Vijayakumaran, K. Tetrahedron Lett. 1985, 26, 1699.
(23) Herscovici, J.; Antonakis, K. J. Chem. Soc., Chem. Comm.
1980, 561.
a GC analyses were performed on a Varian 3400 instrument using
DB-5 column (25 m 0.25 mm, temperature programmed 50–
200 °C heating at 10 °C/min).
(24) Procedure: In a 2 L round bottom flask equipped with a
magnetic stirring bar, reflux condenser and dropping funnel,
PCC (Fluka) (43 g, 0.2 mol) was suspended in anhydrous
CH2Cl2 (600 mL) and stirred vigorously. After 30 min,
freshly activated molecular sieve (UOP Type 4A, Fluka) (40
g) were added in one portion. (R)-2,3-O-Isopropylidene-
glycerol (13.2 g, 0.1 mol) in anhydrous CH2Cl2 (200 mL)
was added drop wise over 4 h and stirring was continued for
additional 1 h. Celite (50 g) followed by dry diethyl ether
(800 mL) was added to the stirred reaction mixture. After 30
min the supernatant liquid was decanted from a black gum.
The insoluble residue was washed with dry diethyl ether
(3 200 mL), the combined organic solutions were filtered
through a pad of Florisil and concentrated at atmospheric
pressure. Distillation of the residue, by recovering the
fraction distilling between 64 °C and 65 °C (35 mbar),
afforded the (S)-2,3-O-isopropylideneglyceraldehyde as a
colorless liquid (ca. 4 g, 30%); [ ]D20 -64.5 (c 3.5, benzene),
[lit. -63.510/–67.91/–69.79/–75.414(benzene, c 8/8/2.22/8)].
References and Notes
(1) Baer, E.; Fischer, H. O. L. J. Am. Chem. Soc. 1939, 61, 761.
(2) Baker, S. B. J. Am. Chem. Soc. 1952, 74, 827.
(3) Jung, M. E.; Show, T. J. J. Am. Chem. Soc. 1980, 102, 6304.
(4) Schmid, C. R.; Bryant, J. D. Organic Synthesis 1993, 72, 6.
(5) Schmid, C. R.; Bradley, D. A. Synthesis 1992, 587.
(6) Earle, M. J.; Abdur-Rashid, A.; Priestley, N. D. J. Org.
Chem. 1996, 61, 5697.
(7) Rokach, J.; Yong, R. N.; Kakushima, M. Tetrahedron Lett.
1981, 22, 979.
(8) Heathcock, C. H.; White, C. T.; Morrison, J. J.; VanDerveer,
D. J. Org. Chem. 1981, 46, 1296.
(9) MaloneyHuss, K. E. Synth. Comm. 1985, 15(4), 273.
(10) Hubschwerlen, C. Synthesis 1986, 962.
Synlett 2001, No. 10, 1565–1566 ISSN 0936-5214 © Thieme Stuttgart · New York