Novel Route to L-Hexoses from L-Ascorbic Acid: Asymmetric Synthesis of L-Galactopyranose and L-Talopyranose. Preliminary Communication

Article abstract of DOI:10.1002/hlca.200390302

A novel route with L-ascorbic acid as a single common starting material to asymmetric synthesis of all eight diastereomers of L-hexoses is described. Assessment of this new approach is demonstrated by the expedient synthesis of L-galactopyranose and L-tal

Full text of DOI:10.1002/hlca.200390302

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Novel Route to l-Hexoses from l-Ascorbic Acid:
Asymmetric Synthesis of l-Galactopyranose and l-Talopyranose
Preliminary Communication
by Ludmila Ermolenko, N. Andre¬ Sasaki*, and Pierre Potier
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, F-91198 Gif-sur-Yvette
(phone: ‡ 330169823101; fax: ‡ 330169077247; e-mail: andre.sasaki@icsn.cnrs.gif.fr)
Dedicated to Professor Duilio Arigoni on the occasion of his 75th birthday
A novel route with l-ascorbic acid as a single common starting material to asymmetric synthesis of all eight
diastereomers of l-hexoses is described. Assessment of this new approach is demonstrated by the expedient
synthesis of l-galactopyranose and l-talopyranose derivatives. Key steps involve stereoselective preparation of
chiral (E)- and (Z)-g-hydroxy-a,b-unsaturated esters and their stereo-controlled dihydroxylation by OsO4.
Introduction. l-Sugars often play an essential role in physiological events of
biologically active compounds, even though their occurrence in nature is rather rare
compared with natural d-homologues [1][2]. However, limited natural sources and few
efficient synthetic methods for this class of compounds have long hindered research on
oligosaccharides and glycoconjugates of the l-sugars, in particular, l-hexoses (for recent
asymmetric syntheses of l-hexoses, see [3]). Therefore, it is of great interest to develop
a practical methodology that provides any one of the eight diastereoisomers. In this
preliminary communication, we report a novel protocol for the synthesis of enantiomeri-
cally pure hexoses of l-configuration from l-ascorbic acid as a single starting material.
Results and Discussions.
General Strategy. Recently, we demonstrated that
enantiomerically pure l-2-amino-2-deoxy hexoses can easily be prepared from (2S)-
2,3-O-isopropylideneglyceraldehyde and l-serine-derived 2-amino-3-(phenylsulfonyl)-
propan-1-ol derivatives (Scheme 1) [4].
Scheme 1. Synthesis of l-2-Amino-2-deoxy Sugars
TBDMS ˆ (t-Bu)Me2Si
A similar approach is conceivable for the synthesis of l-hexoses when the ester 1 is
transformed into g-hydroxy-a,b-unsaturated ester A, a key chiral intermediate with
specific (E)- or (Z)-configuration via a Wittig reaction or a HornerÀEmmons reaction,
respectively. It is reported that 1 is easily available from l-ascorbic acid in three steps,
and that inversion at C(3) of 1 via the Mitsunobu reaction provides its (2S,3S)-
diastereoisomer B [5]. In principle, stereoselective catalytic dihydroxylation of A

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affords pentol C, which can be reduced into aldehyde D, followed by the regioselective
removal of 5,6-O-protection to give hexose E. Alternatively, the pentol C can be
cyclized to lactone F and in turn be reduced to hexose E (Scheme 2).
Scheme 2. Retrosynthetic Plan for l-Hexoses
Synthesis of l-Galactopyranose. Treatment of the ester 1 with TBDPSCl provided
the TBDPS-protected ester 2 in 98% yield (Scheme 3). Reduction of 2 to the 1,2-O-
isopropylidene tetrol 3 with LiBH4 in anhydrous Et2O was easily accomplished in 95%
yield. Subsequent Swern oxidation of 3, followed by the Wittig reaction with
[(ethoxycarbonyl)methylidene]triphenylphosphorane (Ph3PˆCHCO2Et) furnished
a,b-unsaturated ester 5 in 80% yield (for two steps) as a single (E)-isomer. Having
prepared the desired olefin 5 in ca. 75% overall yield, attention was turned to the
stereoselective dihydroxylation. From our earlier experience, we anticipated that
osmium-catalyzed dihydroxylation without a chiral auxiliary might proceed with high
stereoselectivity and reaction rate [4]. To our delight, treatment of 5 with a catalytic
amount of OsO4 in the presence of 4-methylmorpholine N-oxide as the re-oxidant in
the mixture of THF/H2O 9 :1 afforded the pentol 6 in 98% yield. The anti/syn ratio was
1
ca. 50 :1 judging from H-NMR. The major anti-diastereoisomer was easily separated
from its syn-isomer by silica-gel chromatography. The pentol 6 was then treated with
2,2-dimethoxypropane in acetone in the presence of a catalytic amount of TsOH to
afford the fully protected pentol 7 in 90% yield. Reduction of the ester function of the
pentol 7 with DIBAL in toluene at À788 gave the aldehyde 8 in 95% yield.
Regioselective removal of the 2,3-isopropylidene group of 8 by TFA in CH2Cl2,
followed by treatment with Ac2O, provided the l-galactopyranose 9 as a single b-
anomer in 60% yield (for two steps)1). The configuration of the lactone 10, obtained by
heating the pentol 6 in AcOH/H2O 4 :1 at 508 for 24 h, was established by X-ray
crystallography as depicted in the Figure.
1
)
Data for l-galactopyranose 9: [a]D ˆ ‡35.7 (c ˆ 1.65). IR (neat): 3480, 3073, 2934, 2859, 1753, 1590, 1472,
1428, 1371, 1227, 1155, 1114, 1088, 1059, 1013, 955, 935, 822, 757, 703, 608. 1H-NMR 7.75 (m, 2 H); 7.65
(m, 2 H); 7.40 (m, 6 H); 5.90 (d, J ˆ 7.4, HÀC(1)); 4.70 (dd, J ˆ 7.4, 9.6, HÀC(2); 4.35 (dd, J ˆ 3.0, 2.2,
HÀC(5)); 4.25 (m, HÀC(3), HÀC(4)); 4.05 (d, J ˆ 14.0, HÀC(6)); 3.68 (dd, J ˆ 2.2, 14.0, HÀC(6)); 2.18
(s, 3 H); 1.92 (s, 3 H); 1.46 (s, 3 H); 1.42 (s, 3 H); 1.14 (s, 9 H). 13C-NMR 170.3; 169; 136.2; 135.9; 130.2;
130.0; 127.9; 111.2; 95.2 (C(1)); 76.2 (C(3)); 74.4 (C(2)); 71.9 (C(5)); 69.3 (C(4)); 60.1 (C(6)); 27.1; 27.0;
‡
‡
26.6; 21.4; 20.8; 19.4. ESI-MS: 579 ([M ‡ K] ), 565 ([M ‡ Na] ), 505.

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Scheme 3. Synthesis of 1,6-O-Diacetyl-2,3-O-isopropylidene-4-O-(tert-butyldiphenylsilyl)-l-galactopyranose 9
t
a) BuPh2SiCl (TBDPSCl), 1H-imidazole, DMF; 98%. b) LiBH4, THF, 08; 95%. c) (COCl)2, DMSO, Et3N,
CH2Cl2, À788. d) Ph3PˆCHCO2Et, CH2Cl2; 80% (from 3). e) OsO4 (cat.), 4-methylmorpholine N-oxide
(NMO), THF, 90 h; 98%. f) Me2C(OMe)2, TsOH (cat.), acetone; 90%. g) (Me2CHCH2)2AlH (DIBAL),
toluene, À788; 95%. h) CF3COOH (TFA)/CH2Cl2, 08, 15 min. i) Ac2O, Et3N, 4-(dimethylamino)pyridine,
CH2Cl2; 60% from 8. j) AcOH/H2O 4 :1, 508, 24 h; 50%.
Figure. X-Ray crystal structure of lactone 10

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Synthesis of l-Talopyranose. Preparation of (Z)-a,b-unsaturated ester 11 was
carried out by treatment of aldehyde 4 with bis(2,2,2-trifluoroethyl)(methoxycar-
bonylmethyl)phosphonate (CF3CH2O)2POCH2CO2Me (Horner Emmons condition)
in the presence of 18-crown-6 and KN(TMS)2 in THFat À788 to afford 11 in 85% yield
(Scheme 4). Although (Z)-configured alkenes are reported to give higher levels of anti-
selectivity than (E)-isomers [6], the same oxidation conditions used for the preparation
of 6 provided a mixture of pentols 12a and 12b with a rather disappointing anti/syn ratio
of 2.3 :1 in 87% yield. The major anti-diastereoisomer was separated from its syn-
diastereoisomer with ease by silica-gel chromatography, affording the pure anti-12a in
54% yield. The desired diastereoisomer 12a was converted to the fully protected pentol
ester 13 that was, in turn, reduced to the aldehyde 14 with DIBAL in toluene at À788
(77% yield for two steps). Formation of the pyranose system was accomplished by
treatment of 14 with catalytic amount of TFA in CH2Cl2 at 08 for 3 h, followed by
acetylation. The last two-step sequence provided the l-talopyranose derivative 15 as a
single b-anomer in 60% yield2).
Scheme 4. Synthesis of 1,2,3,6-Tetra-O-acetyl-4-O-[(tert-butyl)diphenylsilyl]-l-talopyranose 15
a) (CF3CH2O)2POCH2CO2CH3, 18-crown-6, KN(TMS)2, THF, À788; 85%. b) OsO4 (cat.), NMO, THF, 90 h;
54% (anti-14). c) Me2C(OMe)2, TsOH (cat.), acetone; 85%. d) (Me2CHCH2)2AlH, toluene, À788; 95%. e)
TFA/CH2Cl2, 08, 15 min. f) Ac2O, Et3N, 4-(dimethylamino)pyridine, CH2Cl2; 60% from 14.
Conclusions. We have developed an expedient route to asymmetric synthesis of l-
hexoses starting from the ascorbic acid-derived ester 1. The versatility of our method
for the syntheses of the different l-hexopyranoses is demonstrated simply by changing
the reagents used for the preparation of (E)- and (Z)-a,b-unsaturated esters, 5 and 11,
respectively. Furthermore, it is noteworthy that stereoselective dihydroxylation of the
2
)
Data for l-talopyranose 15: [a]D ˆ ‡24.8 (c ˆ 1.6): IR (neat): 3481, 3073, 3019, 2934, 2860, 1755, 1473,
1428, 1370, 1228, 1138, 1113, 1073, 925, 822, 757, 704, 667, 611. 1H-NMR 7.65 (m, 4 H); 7.40 (m, 6 H); 5.95
(d, J ˆ 7.3, HÀC(1)); 5.37 (d, J ˆ 3.2, HÀC(2)); 5.33 (dd, J ˆ 3.2, 7.7, HÀC(3)); 4.20 (dd, J ˆ 7.9, 11.1,
HÀC(6)); 4.05 (ddd, J ˆ 1.3, 4.3, 7.6, HÀC(5)); 3.95 (dd, J ˆ 4.3, 11.1, HÀC(6)); 3.82 (dd, J ˆ 1.3, 4.3,
HÀC(4)); 2.15 (s, 3 H); 1.97 (s, 3 H); 1.92 (s, 6 H), 1.13 (s, 9 H): 13C-NMR: 170.5; 169.2; 136.1; 132.1; 130.2;
130.1; 127.9; 90.4 (C(1)); 73.4 (C(5)); 69.9 (C(2)); 68.7 (C(4)); 67.5 (C(3)); 63.1 (C(6)); 27.1; 27.0; 21.1; 21.4;
‡
20.8; 20.7; 20.6; 19.5. ESI-MS: 609 ([M ‡ Na] ).

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a,b-unsaturated esters such as 5 and 11 with the free OH group at C(4) in syn-selective
manner can widen the scope of the present approach [7].
¡
The authors thank Angele Chiaroni for the X-ray analysis.
REFERENCES
[1] T. Takita, Y. Muraoka, T. Nakatani, A. Fujii, Y. Umezawa, H. Naganawa, H. Umezawa, J. Antibiot. 1978,
31, 801.
[2] A. S. Swierzko, A. S. Shashkov, S. N. Senchenkova, F. V. Toukach, A. Ziolkowski, M. Cedzynski, N. A.
Paramonov, W. Kaca, Y. A. Knirel, FEBS Lett. 1996, 398, 297.
[3] a) M. Bednarski, S. Danishefski, J. Am. Chem. Soc. 1986, 108, 7060; b) S. Y. Ko, A. W. M. Lee, S.
Masamune, L. A. Reed III, K. B. Sharpless, F. J. Walker, Tetrahedron 1990, 46, 245; c) L. F. Tietze, A.
Montenbruck, C. Schneider, Synlett 1994, 509; d) A. Dondoni, A. Marra, A. Massi, J. Org. Chem. 1997, 62,
6261; e) M. Takeuchi, T. Taniguchi, K. Ogasawara, Synthesis, 1999, 341; f) M. Adinolfi, G. Barone, F. De
¬
¬
Lorenzo, A. Iadonisi, Synlett 1999, 336; g) J. Hajko, A. Liptak, V. Pozsgay, Carbohydr. Res. 1999, 321, 116;
h) H. G. Bazin, M. W. Wolff, R. J. Linhardt, J. Org. Chem. 1999, 64, 144; i) J. M. Harris, M. D. Keranen
G. A. O×Doherty, J. Org. Chem. 1999, 64, 2982; j) J. M. Harris, M. D. Ker‰nen, H. Nguyen, V. G. Young,
G. A. O×Doherty, Carbohydr. Res. 2000, 328, 17; k) S.-C. Hung, C.-C. Wang, S. R. Thopate, Tetrahedron
Lett. 2000, 41, 3119; l) H. Takahashi, Y. Hitomi, Y. Iwai, S. Ikegami, J. Am. Chem. Soc. 2000, 122, 2995.
[4] L. Ermolenko, N. A. Sasaki, P. Potier, J. Chem. Soc., Perkin Trans. 1 2000, 2465.
[5] E. Abushanab, P. Vemishetti, R. W. Leiby, H. K. Singh, A. B. Mikkilineni, D. C.-J. Wu, R. Saibaba, R.
Panzica, J. Org. Chem. 1988, 53, 2598.
[6] J. K. Cha, W. J. Christ, Y. Kishi, Tetrahedron Lett. 1983, 24, 3943.
[7] T. Donohoe, M. J. Waring, N. J. Newcomb, Synlett 2000, 149.
Received August 14, 2003