1,2;3,4-Di-O-isopropylidene-l-galactose synthesis from its d-enantiomer

Article abstract of DOI:10.1016/j.tetlet.2012.02.091

Easy procedure was devised to obtain di-O-isopropylidene-l-galactose from di-O-isopropylidene-d-galactose.

Full text of DOI:10.1016/j.tetlet.2012.02.091

Tetrahedron Letters 53 (2012) 2253–2256
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Tetrahedron Letters
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1,2;3,4-Di-O-isopropylidene-L-galactose synthesis from its D-enantiomer
⇑
Bogdan Doboszewski , Piet Herdewijn
Rega Institute for Medical Research, Laboratory of Medicinal Chemistry, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
Easy procedure was devised to obtain di-O-isopropylidene-
L-galactose from di-O-isopropylidene-
D-
Received 30 November 2011
Revised 14 February 2012
Accepted 20 February 2012
Available online 28 February 2012
galactose.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
L
-Galactose
-Galactose
Acetyl migration
D
D
-Galactose is an easily available hexose whose alditol has a
Our initial approach to get
Scheme 2.
The known 6-O-t-butyldiphenylsilyl-
L
-Gal from
D
-Gal is shown in the
plane of symmetry. This implies an enantiotopic relation between
both terminal hydroxymethyl groups in galactitol, and enables a
D
-galactopyranose 323,24
transformation of
shown in the Scheme 1. The same applies to other sugars like
erythrose, xylose, ribose, and allose.
D
-galactose into
L
-galactose or vice versa as
was sequentially reduced with NaBH4 (?4) and conventionally
acetylated (?5). Apparently simple desilylation with Bu4NF for
20 min at rt furnished 1,2,3,5,6-penta-O-acetyl-D-galactitol 7 as
Transformation of
D
-Gal into
L
-Gal based on this principle is
the only product. Evidently, under slightly basic conditions acetyl
group migration took place in initially formed 6 presumably via a
chair-like conformation 8 which approximates 6-OH group and
the carbonyl group of the 4-OAc. The position of the acetates
was established by heteronuclear multiple bond correlation
(HMBC) spectrum, which shows no cross-peak joining the signal
of the H4 and a carbonyl group via three bonds. It should be stressed
that in the substrate 5, there is no correlation between the signals
of both –CH2-OSitBuPh2 hydrogen atoms and a carbonyl group
which proves that no silicon migration took place during either a
reduction (?4) or during acetylation (?5). As a point of interest:
bulky tBuPh2Si– prefers primary versus secondary positions by ca
8–9 kJ/mol.25 Migrations of the acetyl (acyl) groups are a known
phenomenon which can take place in basic, acidic, or neutral med-
ium,26 occur in acyclic27,28 or cyclic compounds,29–35 and can be
either intra- or intermolecular.32 Such migrations are a frequent
nuisance during desilylations using tetrabutylammonium fluoride
(TBAF) due to the presence of water which makes it basic and
promotes migrations via transient orthoesters.27,28,31,32 Neutraliza-
tion of TBAF with acetic acid is known to suppress this process36–38
but due to variable quantities of water in commercial reagents, this
is rather inconvenient. It should be firmly stressed that acetyl
migrations are known even in neutral medium.26 Anhydrous
organic sources of the fluoride anion are known, for example,
tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF),39
tetrabutylammonium tetra(t-butanol) fluoride40 or genuinely
known1–4 and requires sodium amalgam as a critical reducer.
Due to current environmental concerns, the use of large quantities
of mercury is unacceptable. Consequently we searched for an alter-
native method of synthesis of
-Galactose can be obtained from natural sources (flaxseed,5
galactogen6, or seaweeds7), from -ascorbic acid,8 from 1-deoxy-
L-Gal starting from D-Gal.
L
L
1-nitro-
L
-galactitol9 (obtainable from
L
-xylose), from 1-
L
-(À)-2-O-
methyl-chiroinositol (quebrachitol),10 via total synthesis using
either furfural11 or allyl alcohol,12 or via enzymatic processes which
use either galactitol13–15 or
of
into
dene-
carbohydrates in general have been reviewed.20–22
Our interest in -galactose results from a possibility to use it as a
source of the C3 chiral fragment 1, as shown in the Figure 1. Since
enantiomeric 2 can be obtained from -galactose, the procedure
L
-sorbose16 as substrates. Dithioacetals
D
-Gal were used to mask the carbonyl function during conversion
-Gal,17,18 and finally 6,7-dideoxy-1,2;3,4;-di-O-isopropyli-
-galacto-hept-6-enose was used.19 Total syntheses of
L
a
-D
L
D
would be stereospecific and would allow accessing both 1 and 2
via uniform procedures.
⇑
Corresponding author. Tel.: +32 16 337387; fax: +32 16 337340.
E-mail address: piet.herdewijn@rega.kuleuven.be (P. Herdewijn).
Permanent address: Departamento de Química, Universidade Federal Rural de
Pernambuco, 52171-900 Recife, PE, Brazil.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.091

2254
B. Doboszewski, P. Herdewijn / Tetrahedron Letters 53 (2012) 2253–2256
1
OH
OH
6
OH
OH
RO
HO
HO
HO
O
O
1
HO
HO
HO
HO
OH
OH
OH
HO
HO
OH
OR
OH
OH
-Galactose
6
CHO
6-O-protected
1-O-protected
D
-galactitol=
D
L-Galactose
L-galactitol
Scheme 1. Transformation of
D-galactose into L-galactose.
Isopropylidene groups in the known 6-O-benzyl-diisopropylid-
ene-
-galactose 1045 were hydrolyzed by treatment with 80%
trifluoroacetic acid, and without characterization the resulting 11
H
RHN
O
D
O
OH
OH
RHN
O
was reduced (NaBH4) and conventionally acetylated to furnish
O
O
1,2,3,4,5-penta-O-acetyl-6-O-benzyl-
pound can be also named 2,3,4,5,6-penta-O-acetyl-1-O-benzyl-
galactitol, but we prefer the former name to stress the origin of this
D-galactitol 13. This com-
1
L-
L
-Galactose
´
D-galactose. Hydrogenation over Adams catalyst
compound from
furnished the overreduced cyclohexylmethyl ether 14 together
with the expected 1,2,3,4,5-penta-O-acetyl- -galactitol 6, which
RHN
O
O
RHN
D
O
OH
OH
can be easily separated by flash chromatography. No acetyl migra-
tion in 6 took place during handling or chromatography as evi-
denced by the HBMC spectrum: the –CH2OH protons do not
correlate with any of the carbonyl groups present. A structure of
6 was submitted to X-ray analysis and will be published in due
course. Subsequent Dess–Martin periodinane oxidation by analogy
to a published procedure46 (?15), followed by Zemplén deacetyla-
tion (?16) and final isopropylidenation furnished the target
H
O
O
D-Galactose
2
Figure 1. Application of L- and G-galactose derivatives as a source of chiral C3
fragments.
anhydrous tetrabutylammonium fluoride41 prepared from hexaflu-
orobenzene, and tetrabutylammonium cyanide (see Ref. 42 for the
results of attempted drying of Bu4NF Â H2O). These reagents are
rather inconvenient due to their hygroscopic nature, or a necessity
to prepare them before use. Considering these factors the use of 4
as a starting material to obtain the target 17 was abandoned.
Compound 7 co-crystallized upon mixing with triphenylphos-
phine oxide43,44 and was submitted to X-ray analysis.
1,2;3,4-di-O-isopropylidene-
13C and optical rotation) match those of the compound obtained
by direct acetonation of
-galactose.47
In conclusion, easy conversion48 of commercial diisopropylid-
ene- -galactose into diisopropylidene- -galactose was devised,
L
-galactose 17, whose properties (1H,
L
D
L
which complements the existing methods described in the Refs.
17–19, and which avoids toxic mercury1–4 or badly smelling sulfur
compounds.17,18
Since pivaloyl groups are less prone to migrate,26 we tried to ob-
tain 6-O-t-butyl-diphenylsilyl-1,2,3,4,5-penta-O-pivaloyl-D-galac-
Acknowledgments
titol. Nevertheless, attempts to get this compound by reaction of
4 with pivaloyl chloride in pyridine and DMAP resulted in complex
mixtures.
The disappointing result presented above prompted us to exam-
ine an alternative strategy as shown in the Scheme 3.
ProfessorEveline Lescrinier and Professor Jef Rozenski, Labora-
tory of Medicinal Chemistry, Rega Institute, are thanked for
500 MHz and exact mass measurements, respectively, Professor
OR
OR
1
2
OAc
OAc
tBuPh2SiO
HO
O
Bu4NF 2eq
20min, rt
NaBH4
RO
RO
3
4
AcO
AcO
OH
HO
OR
OSitBuPh2
5
6
OAc
OH
OH
323,24
4
R=H
R=Ac
49% for two steps
6
Ac2O, Py
5
1
OAc
OAc
2
AcO
OAc
AcO
HO
O
3
possibly via:
4
O
OAc
H3C
5
OAc
OAc
O
OAc
6
H
8
7
, 44%
-galactitol (1,2,4,5,6-penta-O-acetyl-L-galactitol) 7 during desilylation of 5.
Scheme 2. Formation of 1,2,3,5,6-penta-O-acetyl-
D

B. Doboszewski, P. Herdewijn / Tetrahedron Letters 53 (2012) 2253–2256
2255
OR
OR
RO
BnO
HO
HO
O
O
O
80% CF3CO2H
NaBH4
RO
RO
O
OH
O
OR
OBn
O
OH
D-Galactose
11
12
13
54% from
9
R=H
R=Ac
R=H
R=Bn
94%
BnBr, KOH
Bu4NHSO4
Ac2O, Py
10
1045
HO
OAc
OAc
OAc
OAc
O O
O
PtO2, H2
EtOAc, EtOH
AcO
AcO
AcO
AcO
+
O
Di-O-isopropylidene-
O
-
L
-galactose
OAc
OAc
OH
17
75% from 6
acetone, cat. H2SO4
14
25%
6
59%
OR
OR
Dess-Martin
periodinane, CH2Cl2
RO
RO
OR
O
H
R= Ac15
R= H 16
Na+-OMe
MeOH
Scheme 3. Synthesis of di-O-isopropylidene-L-galactose 17 from its enantiomer 9.
33. Roslund, M. U.; Aitio, O.; Wärnå, J.; Maaheimo, H.; Murzin, D. Y.; Leino, R. J. Am.
Chem. Soc. 2008, 130, 8769–8772.
34. Yoshimoto, K.; Tsuda, Y. Chem. Pharm. Bull. 1983, 31, 4324–4334.
Wim De Borggraeve, Department of Chemistry, Katholieke Univer-
siteit Leuven for access to the medium pressure Parr hydrogena-
tion facilities, and Chantal Biernaux and Christiane Callebaut for
editorial work.
ˇ
35. Kovac, P.; Glaudemans, C. P. J. Carbohydr. Res. 1985, 140, 313–318.
36. DiLauro, A. M.; Seo, W.; Philips, S. T. J. Org. Chem. 2011, 76, 7352–7358.
37. Wu, X.; Zhou, J.; Snider, B. B. Angew. Chem., Int. Ed. 2009, 48, 1283–1286.
38. Siegel, D. S.; Piizi, G.; Piersanti, G.; Movassaghi, M. J. Org. Chem. 2009, 74, 9292–
9304.
References and notes
39. Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey, D. S.; Roush, W. R.
J. Org. Chem. 1998, 63, 6436–6437.
40. Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M. H. Angew. Chem., Int. Ed. 2008, 47,
8404–8406.
41. Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127, 2050–2051.
42. Sharma, R. K.; Fry, J. L. J. Org. Chem. 1983, 48, 2112–2114.
43. Etter, M. C.; Baures, P. W. J. Am. Chem. Soc. 1988, 110, 639–640.
44. Etter, M. C. Acc. Chem. Res. 1990, 23, 120–126.
1. Glatthaar, C.; Reichstein, T. Helv. Chim. Acta 1937, 20, 1537–1541.
2. Frush, H. L.; Isbell, H. S. Methods Carbohydr. Chem. 1962, 1, 127–131. Whistler.
3. Pizzarello, R. A.; Freudenberg, W. J. Am. Chem. Soc. 1939, 61, 611–613.
4. Binch, H.; Stangier, K.; Thiem, J. Carbohydr. Res. 1998, 306, 409–419.
5. Anderson, E. J. Biol. Chem. 1933, 100, 249–253.
6. May, F.; Wieland, H. Hoppe Seylers Z. Physiol. Chem. 1954, 296, 154–166.
7. Nunn, J. R.; von Holdt, H. H. J. Chem. Soc. 1957, 1094–1097.
8. Kim, K. S.; Cho, B. H.; Shin, I. Bull. Korean Chem. Soc. 2002, 23, 1193–1194.
9. Kubala, J.; Caplovic, J.; Svec, J. Czechoslovak Patent CS 227527 (B1), 1985; Chem.
Abstr. 1985, 106, 176796.
45. Ballou, C. E.; Fischer, H. O. L. J. Am. Chem. Soc. 1954, 76, 3188–3193.
46. Hajkó, J.; Liptak, A.; Pozsgay, V. Carbohydr. Res. 1999, 321, 116–120.
´
47. Pedatella, S.; Guaragna, A.; DAlonzo, D.; De Nisco, M.; Palumbo, G. Synthesis
10. Chida, N.; Suzuki, M.; Suwama, M.; Ogawa, S. J. Carbohydr. Chem. 1989, 8, 319–
332.
2006, 305–308.
48. 6-O-tButyldiphenylsilyl-D-galactopyranose 3: D-galactose (18.0 g; 100 mmol)
11. Takeuchi, T.; Taniguchi, T.; Ogasawara, K. Synthesis 1999, 341–354.
12. Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A., III; Sharpless, K. B.; Walker, F.
J. Tetrahedron 1990, 46, 245–264.
13. Yadav, K. K.; Vernwal, S. K.; Afaq, Z.; Yadav, K. D. S. Indian J. Chem. Techn. 2002,
9, 218–222.
was silylated in dry DMF (1800 mL) using tBuPh2SiCl, (27.2 mL; 28.9 g;
105 mmol) and Et3N (19.4 mL; 14.1 g; 140 mmol) under argon during 20 h.
Extraction (EtOAc-brine), drying, evaporation, and chromatography (gradient
CH2Cl2–MeOH 100:11?100:14 furnished a colorless foam (32.6 g; 78%; Rf 0.26
CH2Cl2–MeOH); aD +15.6° (c 5.1; MeOH; not reported in Refs. 23,24).
1H(300 MHz, DMSO-d6 after exchange with D2O): 7.68–7.40(two groups of
signals), 4.25 (d, J = 7.2 Hz), 3.96(t, J = 6.5 Hz), 3.87–3.72(unresolved signal
superimposed on HOD), 3.64–3.46(m), 3.30 (dd, J = 3.1 Hz, 9.6 Hz), 3.24(dd,
J = 7.1 Hz, 9.5 Hz), 0.96(s, 9H). 13C (75 MHz, DMSO-d6): 135.07, 135.02, 133.12,
133.07, 133.04, 129.78,127.84, 97.49, 92.69, 74.51, 73.43, 71.99, 70.14, 69.38,
3876, 68.67, 68.09, 63.00, 62.95, 26.64, 18.79.
14. Yadav, K. K.; Vernwal, S. K.; Afaq, Z.; Yadav, K. D. S. J. Sci. Ind. Res. India 2002, 61,
361–365.
15. Woodyer, R. D.; Christ, T. N.; Deweese, K. A. Carbohydr. Res. 2010, 345, 363–368.
16. Leang, K.; Maekawa, K.; Menavuvu, B. T.; Morimoto, K.; Granström, T. B.;
Takada, G.; Izumori, K. J. Biosci. Bioeng. 2004, 97, 383–388.
17. González, F. S.; Baer, H. H. Carbohydr. Res. 1990, 202, 33–47.
18. Brackhagen, M.; Boye, H.; Vogel, C. J. Carbohydr. Chem. 2001, 20, 31–43.
19. Lay, H.; Lehmann, J.; Ziser, L.; Reutter, W. Carbohydr. Res. 1989, 195, 145–149.
1,2,3,4,5-Penta-O-acetyl-6-O-tbutyldiphenylsiyl-D-galactitol 5: Compound 3
(8.14 g; 19.5 mmol) in techn. EtOH (60 mL) was cooled in ice-water bath and
NaBH4, 0.89 g, 23.5 mmol was added with magnetic stirring. After 1 h, more
NaBH4 was added (0.83 g) and water bath was removed. After a total of 6 h the
mixture was partitioned between EtOAc, brine, and aq. (NH4)2SO4. Aqueous
phase was extracted second time with EtOAc. Combined organic phases were
washed with H2O, dried, evaporated, and co-evaporated with MeOH (500 mL)
twice. Final drying furnished 5 as a foam, 8.39 g evidently contaminated
(theoretical yield is 8.18 g). Exact mass (electrospray): calc. for
´
20. DAllonzo, D.; Guaragna, G.; Palumbo, G. Curr. Org. Chem. 2009, 13, 71–98.
21. Vogel, P.; Robina, I. Synthesis of Monosaccharides and Analogs In
Comprehensive Glycoscience; Camerling, J. P., Ed.; Elsevier, 2007; Vol. 1, pp
489–582. chapter 1.13.
22. Zamojski, A.; Banaszek, A.; Grynkiewicz, G. Adv. Carbohydr. Chem. Biochem.
1982, 40, 1–129.
23. Fylaktakidou, K. C.; Duarte, C. D.; Koumbis, A. E.; Nicolau, C.; Lehn, J.-M.
ChemMedChem 2011, 6, 153–168.
C
22H32O6Si+Na+ = 443.1866, found: 443.1852. This material was acetylated
24. Boto, A.; Hernández, D.; Hernández, R.; Suárez, E. J. Org. Chem. 2006, 71, 1938–
1948.
25. Muzler, J.; Schöllhorn, B. Angew. Chem., Int. Ed. Engl. 1990, 29, 431–432.
overnight using pyridine (150 mL), Ac2O (70 mL), and DMAP (0.5 g).
Conventional extractive work-up and co-evaporation with xylenes followed
by chromatography in hexane-EtOAc 3:1 furnished 5 (6.0 g; 49% for two steps)
which spontaneously crystallized. Mp. 105–120°, Rf 0.41 (hexane–EtOAc 3:1),
aD À18.2° (c 2.7; CHCl3), exact mass (electrospray): calc. for
´
´
´
26. Tomic, S.; Petrovic, V.; Matanovic, M. Carbohydr. Res. 2003, 338, 491–494.
27. Stamatov, S. D.; Stawin´ ski, J. Org. Biomol. Chem. 2010, 8, 463–477.
28. Stamatov, S. D.; Stawin´ ski, J. Org. Biomol. Chem. 2007, 5, 3787–3800.
29. Angyal, S. J.; Melrose, G. J. H. J. Chem. Soc. 1965, 6494–6500.
30. Nkambule, C. M.; Kwezi, N. W.; Kinfe, H. H.; Nokwequ, M. G.; Gammon, D. W.;
Oscarson, S.; Karlsson, E. Tetrahedron 2011, 67, 618–623.
C
32H42O11Si+Na+ = 653.2394, found: 653.2393. 1H (500 MHz, CDCl3,
connectivity established by COSY): 7.615–7.365 (H aromatic), 5.450 (dd,
J = 1.8 Hz, 9.9 Hz, 1H, H4), 5.314 (dd, J = 1.9 Hz, 9.9 Hz, 1H, H3), 5.24–5.20
(unresolved, 2H, H2,5), 4.275 (dd, J = 4.9 Hz, 11.7 Hz, 1H, H1a), 3.851 (dd,
J = 11.7 Hz, 11.7 Hz, 1H, H1b), 3.595 (d, J = 10.8 Hz, 1H), 3.559 (d, J = 11.0 Hz,
1H), 2.113, 2.080, 2.026, 2.015, 1.951(five s, total 15H). 13C (75 MHz, CDCl3):
170.60, 170.43, 170.31, 169.99, 169.59, 135.80, 135.69, 133.12, 133.04, 129.99,
31. Hamdouchi, C.; Jaramillo, C.; Lopez-Prados, J.; Rubio, A. Tetrahedron Lett. 2002,
43, 3875–3879.
32. Chevallier, O. P.; Migaud, M. E. Beilstein. Org. Chem. 2006, 2.

2256
B. Doboszewski, P. Herdewijn / Tetrahedron Letters 53 (2012) 2253–2256
129.95, 127.88, 70.18, 67.98, 67.85, 67.37, 62.39, 61.74, 26.84, 20.97, 20.84,
20.80, 20.59, 19.24.
1,2,3,5,6-Penta-O-acetyl-
128.51, 127.94, 127.92, 73.52, 68.44, 67.91, 67.85, 67.78, 62.40, 20.97, 20.86,
20.73.
1,2,3,4,5-Penta-O-acetyl-6-O-cyclohexylmethyl-D-galactitol 14 and 1,2,3,4,5-
D
-galactitol (1,2,4,5,6-penta-O-acetyl-
L
-galactitol) 7:
Desilylation of 5 (0.22 g; 0.35 mmol) in THF (12 mL) and 1 M Bu4NF (0.7 mL)
during 20 min at rt, followed by extractive work-up (CH2Cl2–water) and flash
chromatography in hexane–EtOAc 9:11 furnished 7 (0.060 g; 44%) as a syrup
penta-O-acetyl-D-galactitol 6: Compound 13 (1.74 g; 3.6 mmol) was
solubilized in EtOAc (20 mL) and abs. EtOH was added (20 mL) followed by
PtO2 (0.149 g) in a medium pressure vessel and hydrogenation was performed
on a Parr apparatus during 3 h at initial pressure of 45 psi. Tlc sprayed with
Hanessian´ s stain showed strongly charring spot of 14 Rf 0.81 (hexane–EtOAc
which chars very weakly with 2% CrO3 in 10% aq H2SO4 system. aD +1.3° (c 2.1;
CHCl3), Rf 0.37 (hexane–EtOAc 3:1, exact mass (electrospray): calc. for
C16H24O11+Na+ = 415.1211, found: 415.1224. 1H (500 MHz, CDCl3,
connectivity established by COSY): 5.479 (ddd, J = 1.7 Hz, 4.5 Hz, 7.5 Hz, 1H,
H2), 5.175 (ddd, J = 1.7 Hz, 4.7 Hz, 7.7 Hz, 1H, H5), 5.100 (dd, J = 1.7 Hz, 9.9 Hz,
1H, H3), 4.413 (dd, J = 4.7 Hz, 11.7 Hz, 1H, H6a), 4.247 (dd, J = 4.5 Hz, 11.9 Hz,
H1a), 4.154 (dd, J = 7.8 Hz, 11.7 Hz, H6b), 4.20 (dd, J = 7.9 Hz, 11.9 Hz, H1b),
3.755 (ddd, J = 1.5 Hz, 6.9 Hz, 8.7 Hz, H4), 3.479 (d, J = 7.0 Hz, –OH,
exchangeable), 2.168, 2.083, 2.076, 2.047, 2.046 (–OAc, total 15H). 13C
(75 MHz, CDCl3):172.03, 171.07, 170.61, 170.04, 70.02, 69.45, 68.71, 67.82,
63.36, 62.86, 20.93, 20.77.6.
´
9:1) and very weakly charring spot of 6 Rf 0.45; substrates Rf is 0.74. Filtration
through a sintered glass (attention: Pt must not be let dry to avoid potential
self-ignition), evaporation and flash chromatography using a gradient hexane–
EtOAc.
2:1?9:12, gave 14 (0.45 g; 25%) and 6 (0.84 g; 59%). Data of 14: mp 95–97°
(hexane–EtOAc), aD À7.1° (c 2.6; CHCl3), exact mass: calc. for
C
23H36O11+H+ = 489.2330, found: 489.2333. 1H(300 MHz, CDCl3): 5.38–5.21
(m, 4H), 4.28 (dd, J = 4.8 Hz, 11.7 Hz, 1H), 3.85 (dd, J = 7.5 Hz, 1107 Hz, 1H),
3.37 (apparent d, J = 6.1 Hz, 2H), 3.21 (dd, J = 6.6 Hz, 9.0 Hz, 1H), 3.11 (dd,
J = 6.4 Hz, 9.0 Hz, 1H), 2.11, 2.09, 2.08, 2.07, 2.02 five s, total 12H, 1.71–1.51,
1.28–1.11 and 0.93–0.86 three groups of multiplets, total 11H. 13C (75 MHz,
CDCl3): 170.53, 170.39, 170.36, 169.94, 169.79, 77.47, 69.31, 68.47, 67.94,
67.88, 67.77, 62.42, 37.99, 29.94, 26.68, 25.94, 20.94, 20.82, 20.74. Data of 6:
mp. 145–147° (hexane–EtOAc), aD À19.9° (c 4; CHCl3), exact mass: cacl. for
1,2;3,4-Di-O-isopropylidene-6-O-benzyl-
D-galactose 10: To
a
solution of
commercial 1,2;3,4-di-O-isopropylidene-
D-galactose (Acros,
a
D-56.8° 5.9
c
CHCl3) (20.8 g; 80 mmol) in toluene (100 mL) was added KOH (30 g; crushed
in a mortar under protective layer of hexane), benzyl bromide (16.6 mL; 24 g;
140 mmol), and Bu4NHSO4 (0.5 g). This mixture was magnetically stirred on an
oil bath at ca 100°. After ca 30 min most of KOH formed lumps. Water (30 mL)
was added to solubilize KOH and to change a mode of catalysis from solid-
liquid to liquid–liquid. After a total time of 3 h, TLC showed that all substrate Rf
0.21 formed the product Rf 0.64 (hexane–EtOAc 3:1). Organic phase was
separated and washed with dil. HCl, and twice with water. Evaporation and
chromatography (gradient hexane–EtOAc 20:1?20:2?20:3) furnished 10 as
an oil, (26.3 g; 94%) aD À68° (c 6.7; CHCl3), aD was not mentioned in Ref. 45.
1H(300 MHz, CDCl3): 7.36–7.25(H aromatic), 5.54 (d, J = 5.0 Hz, 1H), 4.63 (d,
J = 12.0 Hz, 1H), 4.60(dd, J = 2.4 Hz, 7.8 Hz, 1H), 4.55(d, J = 12.1 Hz, 1H),
4.31(dd, J = 2.3 Hz, 5.0 Hz, 1H), 4.27(dd, J = 2.0 Hz, 8.0 Hz, 1H), 4.01(dt,
J = 1.7 Hz, 6.1 Hz, 6.1 Hz, 1H), 3.70(dd, J = 5.9 Hz, 10.0 Hz, 1H), 3.61 (dd,
J = 6.7 Hz, 10.0 Hz, 1H), 1.54, 1.44, 1.34, 1.33(four s, 12H total). 13C (75 MHz,
CDCl3): 138.56, 128.51, 127.91, 127.74, 109.43, 108.74, 96.59, 73.52, 71.40,
70.88, 70.83, 69.10, 67.11, 26.31, 26.20, 25.15, 24.66.
C
16H24O11+Na+ = 415.1211, found: 415.1215. 1H (500 MHz, CDCl3; connectivity
established by COSY): 5.257 (dd, J32 = 2.0 Hz, J34 = 10.0 Hz, H3), 5.235 (ddd,
J23 = 2.0 Hz, J21a = 4.7 Hz, J21b = 7.6 Hz, H2), 5.176 (dd, J45 = 1.8 Hz, J43 = 10.0 Hz,
H4), 4.924 (ddd, J54 = 1.7 Hz, J56 = 6.3 Hz, J56 = 7.3 Hz, H5), 4.158 (dd,
J1a2 = 4.7 Hz, J11 = 11.7 Hz, H1a), 3.742 (dd, J1b2 = 7.6 Hz, J11 = 11.7 Hz, H1b)
3.454–3.407 (m, H6a), [after D2O exchange: dd, J65 = 6.2 Hz, J66 = 11.8 Hz],
3.338–3.301(m, H6b), [after D2O exchange: dd, J65 = 7.7 Hz, J66 = 11.7 Hz],
2.826 (t, J = 5.8 Hz, exchangeable, –OH), 2.018, 1.992, 1.961, 1.903. 13C
(125 MHz, CDCl3):171.17, 170.45, 170.41, 170.25, 169.73, 70.01, 67.76, 67.61,
67.35, 62.24, 59.91, 20.69, 20.57, 20.53, 20.45.
1,2;3,4-Di-O-isopropylidene-L-galactose 17. To a magnetically stirred solution
of 6 (1.34 g; 3.4 mmol) in dry CH2Cl2 (24 mL) was added a solution of Dess–
Martin periodinane (Acros, 15 wt %, 0.35 mmol/mL) (14.6 mL; 5.1 mmol). The
solution became turbid in a few min. After 1 h 20 min aq. sat.NaHCO3 and aq.
Na2S2O3 were added and stirring was continued for 10 min. Extractive work-up
(CH2Cl2-brine) and evaporation of volatiles furnished colorless oil of the
1.2.3.4.5-Penta-O-acetyl-6-O-benzyl-D-galactitol 13: Compound 10 (24.2 g;
69.1 mmol) was mixed with 80% aq CF3CO2H. After 15 min TLC showed that
all the substrates reacted to form a new spot Rf 0.45 (CH2Cl2–MeOH 4:1). The
volatiles were removed by evaporation and the residue was briefly dried on an
oil pump. Water 200 mL was added to a residual oil followed by Amberlite IRA
400 ÀOH until neutrality. The resin was filtered and washed with water 1 L.
Combined filtrates were evaporated and thoroughly dried on an oil pump to
furnish 11 (13.8 g); exact mass: calc. for C13H18O6+Na+ = 293.0996, found:
293.1021. Alternatively 1 M HCl can be used to hydrolyze the acetonides.49 The
crude 11 was solubilized in techn. EtOH (50 mL) and water (180 mL) and after
chilling in ice-bath, NaBH4 (2.8 g; 75 mmol) was added portionwise during ca
10 min while maintaining magnetic stirring. The cooling bath was removed.
After 2 h, more NaBH4 (1.3 g) was added. After a total reduction time of 3 h, dil.
AcOH was added and the opaque solution was passed successively through a
bed of Amberlite IRA 400 ÀOH followed by Amberlite IRC 50 H+. The resins
were washed with MeOH–H2O 9:1 mixture. Combined filtrates were
evaporated, and co-evaporated four times with MeOH (400 mL) to remove
any boron compounds potentially present. After final drying on an oil pump,
the residue was acetylated in pyridine (180 mL), Ac2O (120 mL), and DMAP
(1 g). After overnight reaction TLC showed a spot Rf 0.31 (hexane–EtOAc 7:3),
together with minor impurities. Extractive work-up and chromatography in
hexane-EtOAc 2:1 yielded 13 (13.3 g; 54%) for three steps of oil which
spontaneously crystallized. Mp 112–115°, aD À18.2° (c 1.6; CHCl3). Data for
2,3,4,5,6-penta-O-acetyl-aldehydo-
L-galactose 15 (exact mass: calc. for
C
16H22O11+Na+ = 413.1054, found: 413.1056), which chars intensely with
´
Hanessians stain and has Rf practically the same as that of the substrate 6.
Abs. MeOH (30 mL) was added followed by a piece of Na. The resulting
yellowish oil was kept in a refrigerator overnight. All 15 have disappeared to
form L
-galactose 16 (exact mass: calc. for C6H12O6+Na+ = 203.0526, found:
203.0536). Amberlite IRC 50H+ was added, filtered out, and washed with
MeOH–water. After evaporation of volatiles and drying on an oil pump, the
yellow glassy residue was treated with dry acetone (prepared by shaking of
techn. acetone with P2O5, filtration and distillation) (40 mL) and conc. H2SO4
(1 mL). After stirring for 4 h, TLC showed a spot of 17 Rf 0.36 (hexane-EtOAc
3:2) indistinguishable from commercial D form. Conc. NH4OH was added to
neutralize the mixture. Solid material was filtered out. The residual oil
obtained after evaporation of acetone was purified by chromatography
(hexane-EtOAc 6:5) to yield 17 (0.67 g; 75% for three steps). aD +53°(c 4.4;
CHCl3), lit.47
a
D +57° (c 0.9; CHCl3); for D form: aD À54.5° (c not mentioned)51
and aD À55° (c 3.5; CHCl3).52 Exact mass: calc. for C12H20O6+Na+ = 283.1152,
found: 283.1152. 1H (300 MHz, CDCl3): 5.56 (d, J = 5.0 Hz, 1H), 4.61(dd,
J = 2.3 Hz, 7.9 Hz, 1H), 4.33 (dd, J = 2.4 Hz, 5.0 Hz, 1H), 4.27 (dd, J = 1.5 Hz,
7.9 Hz, 1H), 3.90–3.70 (unresolved, 3H) [after D2O exchange: 3.98–3.79,
unresolved, 2H), 3.71 (dd, J = 4.1 Hz, 11.0 Hz, 1H)], 1.54, 1.45 two s, 3H each,
1.34(s 6H). 13C (75 MHz, CDCl3): 109.55, 108.80, 96.40, 71.58, 70.85, 70.69,
68.39, 62.22, 26.12, 26.04, 25.05, 24.44.
enantiomeric product prepared via dithioacetal of D
-galactose50: mp 107–109°,
aD (+20.3°; c 3.7; CHCl3). Exact mass: calcd for C23H30O11+Na+ = 505.1680,
found: 505.1674. 1H (300 MHz, CDCl3): 7.35-7.27 (H aromatic), 5.42 (dd,
J = 1.8 Hz, 9.9 Hz, 1H), 5.34 (dd, J = 1.9 Hz, 9.9 Hz, 1H), 5.31–5.23 (m, 2H),4.49
(d, J = 11.7 Hz, 1H), 4.42 (d, J = 11.9 Hz, 1H), 4.27 (dd, J = 4.8 Hz, 11.7 Hz, 1H),
3.85(dd, J = 7.5 Hz, 11.6 Hz, 1H),3.45(d, J = 6.1 Hz, 2H), 2.09, 2.08, 2.07, 2.03,
2.01five s, 15H; 13C (75 MHz, CDCl3): 170.53, 170.41, 169.92, 127.91, 137.69,
49. Anet, E. F. L. J. Carbohydr. Res. 1968, 7, 84–85.
50. Zinner, H.; Kleeschätzky, R.; Neels, P. Chem. Ber. 1965, 98, 1492–1497.
´
51. Martins Alho, M. A.; DAccorso, N. B.; Thiel, I. M. E. J. Heterocycl. Chem. 1996, 33,
1339–1343.
52. Schmidt, O. T. Methods Carbohydr. Chem. 1962, 1, 318–325.