J . Org. Chem. 1997, 62, 2669-2670
2669
precursors for natural products.9 The hydroxyl groups
of mannitol diacetonide 310 were derivatized as tosylates
using p-tosyl chloride in pyridine to provide ditosylate
411 in quantitative yield. The acetonide groups of crude
tosylate 4 were hydrolyzed to give tetraol 5 in 65% overall
yield after recrystallization from ethanol. The reaction
of tetraol 5 with p-tosyl chloride in pyridine at 0 °C gave
tetratosylate 6 and tritosylate 7 in 50 and 49% yield,
respectively.12 The yield of the desired tetratosylate 6
was improved to 77% when 7 was further subjected to
tosylation using 1 equiv of p-tosyl chloride in pyridine.
Finally, the reduction of tetratosylate 6 with LAH gave
the target diol 1 in 60% yield.13 In conclusion, a simple
three-step sequence, suitable for multigram preparation,
provided 1 in 30% overall yield.
A P r a ctica l Syn th esis of
(2R,5R)-2,5-Hexa n ed iol
P. Saravanan, Sushil Raina, T. Sambamurthy, and
Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology,
Kanpur, India - 208 016
Received November 18, 1996
C2 Symmetric chiral nonracemic ligands have found
an important place in asymmetric synthesis as the
presence of its axis reduces the number of possible
competing diastereomeric transition states.1,2 Some of
the notable examples of such chiral ligands are trans-
2,5-disubstituted pyrrolidines,3 tetrahydrofuran,4 phos-
pholanes,5 and borolanes.6 Acquisition of these ligands
depends upon availability of 2,5-hexanediol (1) in opti-
cally active form. As a part of our program in enanti-
oselective deprotonation reactions,7 we needed to syn-
thesize (2S,5S)-2,5-dimethylpyrrolidine (2). The most
obvious precursor for 2 is the diol 1 which has mainly
been synthesized using enzymatic methods.3b,8 The only
nonenzymatic method for the diol 1, to the best of our
knowledge, is via asymmetric reduction of methyl ac-
etoacetate using Noyori’s BINAP chemistry followed by
electrochemical Kolbe coupling of the corresponding
acid.5c Although the method is good, the needed equip-
ment for Kolbe coupling reaction may not be available
in every laboratory. In view of this difficulty, we herein
describe a simple, convenient, and practical synthesis of
1 from readily available D-mannitol.
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded on 60
and 80 MHz spectrometers. Chemical shifts are expressed in
ppm downfield from TMS as internal standard, and coupling
constants are reported in hertz. Routine monitoring of reactions
was performed by TLC using silica gel G obtained from Acme.
All the column chromatographic separations were done by using
silica gel (Acme’s, 60-120 mesh). p-Tosyl chloride was recrysal-
lized before use. Petroleum ether used was of boiling range 60-
80 °C. Reactions which needed anhydrous conditions were run
under an atmosphere of dry nitrogen or argon using flame-dried
glassware. The organic extracts were dried over anhydrous
sodium sulfate. Evaporation of solvents was performed at
reduced pressure. Tetrahydrofuran (THF) was distilled from
sodium benzophenone ketyl under nitrogen. Dichloromethane
and pyridine were distilled from CaH2. The rt refers to 20-25
°C.
3,4-Di-O-p-tolu en esu lfon yl-D-m a n n itol (5). Solid p-tosyl
chloride (45 g, 237 mmol) was added to a solution of 1,2:5,6-Di-
O-isopropylidene-D-mannitol 310 (25 g, 95.4 mmol) in pyridine
(70 mL) at rt. Triethylamine (53 mL, 380 mmol) was added,
and the solution was stirred at the same temperature for 48 h.
The reaction mixture was diluted with CH2Cl2 (300 mL) and
washed with water and brine. The organic layer was dried (Na2-
SO4) and concentrated on rotary evaporator to give 54 g of crude
ditosylate. This was subjected to the next step without any
purification. A small amount of this material (500 mg) from a
different batch was purified by crystallization using hexane-
CH2Cl2 (3:1) to give the pure 1,2:5,6-Di-O-isopropylidene-3,4-
di-O-p-toluenesulfonyl-D-mannitol (4)11 as a white crystalline
solid for characterization: Rf 0.50 (1:3, EtOAc in petroleum
The strategy, involved in the synthesis, was based on
protection and deprotection of hydroxyl groups of D-
mannitol which is a cheap chiral source for synthesis of
(1) Whitesell, J . K. Chem. Rev. 1989, 89, 1581.
(2) For recent references on the use of C2 symmetric ligands in
asymmetric synthesis, see: (a) DattaGupta, A.; Singh, V. K. Tetrahe-
dron Lett. 1996, 37, 2633. (b) Cowton, E. L. M.; Gibson, S. E.;
Schneider, M. J .; Smith, M. H. Chem. Commun. 1996, 839. (c) Muci,
A. R.; Campos, K. R.; Evans, D. A. J . Am. Chem. Soc. 1995, 117, 9075.
(d) DattaGupta, A.; Bhuniya, D.; Singh, V. K. Tetrahedron 1994, 50,
13725. (e) Burk, M. J .; Gross, M. F. Tetrahedron Lett. 1994, 35, 9363.
(f) Kubota, H.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1993, 34,
8135.
(3) For synthesis, see: (a) Review: Pichon, M.; Figadere, B.
Tetrahedron: Asymm. 1996, 7, 927. (b) Kim, M.-J .; Lee, I. S. Synlett
1993, 767. (c) Zwaagstra, M. E.; Meetsma, A.; Feringa, B. L. Tetrahe-
dron: Asymm. 1993, 4, 2163. (d) Short, R. P.; Kennedy, R. M.;
Masamune, S. J . Org. Chem. 1989, 54, 1755. (e) Schlessinger, R. H.;
Iwanowicz, E. J . Tetrahedron Lett. 1987, 28, 2083. (f) Harding, K. E.;
Burks, S. R. J . Org. Chem. 1981, 46, 3920.
(4) Kim, M.-J .; Lee, I. S. J . Org. Chem. 1993, 58, 6483.
(5) (a) Wiesauer, C.; Kratky, C.; Weissensteiner, W. Tetrahedron:
Asymm. 1996, 7, 397. (b) Burk, M. J .; Gross, M. F. Tetrahedron Lett.
1994, 35, 9363. (c) Burk, M. J .; Feaster, J . E.; Harlow, R. L.
Tetrahedron: Asymm. 1991, 2, 569.
(6) Masamune, S. In Stereochemistry of Organic and Bioorganic
Transaformations; Bartmann, W., Sharpless, K. B., Eds.; VCH: Wein-
heim, 1987; p 49.
(7) (a) Bhuniya, D.; DattaGupta, A.; Singh, V. K. J . Org. Chem. 1996,
61, 6108. (b) Bhuniya, D.; DattaGupta, A.; Singh, V. K. Tetrahedron
Lett. 1995, 36, 2847. (c). Bhuniya, D.; Singh, V. K. Synth. Commun.
1994, 24, 1475. (d) Bhuniya, D.; Singh, V. K. Synth. Commun. 1994,
24, 375.
(9) (a) Raina, S.; Singh, V. K. Tetrahedron 1996, 52, 4479. (b)
Hanessian, S. Total Synthesis of Natural Products: The 'Chiron'
Approach; Pergamon Press Ltd.: New York, 1983.
(10) Vogel, A. I. Text Book of Practical Organic Chemistry, 5th ed.;
ELBS/Longman: Birmingham, AL, 1989; pp 654.
(11) Brigl, P.; Gruner, H. Ber. 1934, 67, 1969.
(12) Merrer, Y. Le; Dureault, A.; Gravier, C.; Languin et, D.;
Depenjay, J . C. Tetrahedron Lett. 1985, 319.
(8) Lieser, J . K. Synth. Commun. 1983, 13, 765.
(13) Krishnamurthy, S. J . Org. Chem. 1980, 45, 2550.
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