An efficient synthesis of (3R,4R)-O-isopropylidene-1,6-Hexanediol

Article abstract of DOI:10.1081/SCC-100104048

(3R,4R)-O-isopropylidene-1,6-Hexanediol 1 has been synthesized from a readily available D-mannitol derivative in few steps.

Full text of DOI:10.1081/SCC-100104048

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AN EFFICIENT SYNTHESIS
OF (3R,4R)-O-
ISOPROPYLIDENE-1,6-
HEXANEDIOL
P. Saravanan a & Vinod K. Singh b
a Department of Chemistry , Indian Institute of
Technology , Kanpur, 208 016, India
b Department of Chemistry , Indian Institute of
Technology , Kanpur, 208 016, India
Published online: 09 Nov 2006.
To cite this article: P. Saravanan & Vinod K. Singh (2001) AN EFFICIENT SYNTHESIS
OF (3R,4R)-O-ISOPROPYLIDENE-1,6-HEXANEDIOL, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:9, 1383-1388, DOI: 10.1081/SCC-100104048
To link to this article: http://dx.doi.org/10.1081/SCC-100104048
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SYNTHETIC COMMUNICATIONS, 31(9), 1383–1388 (2001)
AN EFFICIENT SYNTHESIS OF (3R,4R)-
O-ISOPROPYLIDENE-1,6-HEXANEDIOL
P. Saravanan and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology,
Kanpur, India - 208 016
ABSTRACT
(3R,4R)-O-isopropylidene-1,6-Hexanediol 1 has been synthe-
sized from a readily available D-mannitol derivative in few
steps.
The growing importance of asymmetric synthesis involving C2 sym-
metric molecules as chiral directors provides an impetus for the preparation
of such compounds.1–3 Optically active diols with a C2 axis of symmetry
play a significant role as chiral auxiliaries in the synthesis of biologically
active compounds.4–9 (3R,4R)-O-Isopropylidene-1,6-Hexanediol 1 is one
such important diol, which is useful for the preparation of synthetic receptor
molecules for peptides10 and cyclo-BINOL ligand 211,12 for asymmetric syn-
thesis. While working on a part of our program on design, synthesis, and
application of chiral non-racemic diols13–15 and diamines,16,17 we realized
that, by changing the strategy of protection and deprotection, it is possible
to synthesize the diol 1 in an efficient manner from D-mannitol. In this
paper, we delineate our efforts in this direction.18
* Corresponding author.
1383
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1384
SARAVANAN AND SINGH
The mannitol-3,4-monoacetonide tetraol 319 was selectively protected
as benzoate at the primary hydroxyl position using benzoyl chloride in
pyridine in 29% yield. The resulting dibenzoate diol 4 was subjected to
tosylation using p-TsCl in pyridine-Et3N to give the desired ditosyl dibenzo-
ate 5 in quantitative yield.19 Deoxygenation of tosylates and removal of the
benzoate groups were performed in one step using LiAlH4 as reducing agent
in THF-ether to give the tethered C2 symmetric diol 1 in 60% yield.
Although the final diol 1 was synthesized in just three steps, lower yield
(29%) in the first step of benzoylation reaction forced us to explore an alter-
native method for the protection of primary hydroxyl groups. Thus, the pri-
mary hydroxyl groups of the tetraol 3 were selectively protected as TBDMS
ethers in 94% yield. The secondary hydroxyl groups of TBDMS ether 6 were
converted into ditosylates 7, followed by removal of TBDMS ethers using
CAN/MeOH20 to give 8. It is worth mentioning here that other reagents
such as FeCl3/MeOH or aq HCl/THF failed to give the clean deprotection of
Figure.

DIOL FROM D-MANNITOL
1385
TBDMS ethers, and there was always some concomitant cleavage of acetonide
group. The LAH reduction of the tosylate 8 gave the final diol 1 in an overall
yield of 50%. In conclusion, a simple and short synthetic route for a chiral diol
1 was developed from cheap and commercially available D-mannitol.
GENERAL METHODS
1H NMR spectra were recorded on 60 and 400 MHz spectrometers.
Chemical shifts are expressed in ppm downfield from TMS as internal stan-
dard, 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 recrystallized before use.
Petroleum ether used was of boiling range 60ꢀ–80ꢀC. Reactions that
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 sulphate. Evaporation of solvents was performed at
reduced pressure. Tetrahydrofuran (THF) was distilled from sodium benzo-
phenone ketyl under nitrogen. Dichloromethane and pyridine were distilled
from CaH2 Room temperature (rt) refers to 25ꢀ–30ꢀC.
1,6-Di-O-benzoyl-3,4-O-isopropylidene-D-mannitol (4)
To a solution of tetraol 3 (2.2 g, 10 mmol) in pyridine (10 mL) was
added benzoyl chloride (2.8 g, 20 mmol) at 0ꢀC and stirred for 3 h. The
reaction mixture was diluted with CH2C12 (50 mL), washed with water,
brine, and dried. Removal of the solvent under reduced pressure gave
crude product. Purification over silica gel column afforded the pure product
as a crystalline solid (1.2 g, 29%); m.p. 92ꢀ–93ꢀC (lit.19 m.p. 94ꢀC; Rf 0.40
25
25
(25% EtOAc in petroleum ether); ½aŠD þ13ꢀ (c 3.3, CHCl3) {lit.19 ½aŠD þ24.1ꢀ
(c 1.45, Pyridine)}; IR (KBr) 3450, 1710, 1590, 760 cm–1; H NMR (CCl4,
1
60 MHz) ꢀ 1.32 (s, 6H), 3.90 (m, 4H), 4.1–4.80 (m 6H), 7.20–7 80 (m, 10H).
1,6-Di-O-benzoyl-3,4-O-isopropylidene-2,5-Di-O-
p-toluenesulphonyl-D-mannitol (5)
To a solution of Dibenzoate 4 (1 g, 2.4 mmol) in (CH2Cl2 (10 mL) was
added triethylamine (665 ml, 4.8 mmol) and pyridine (10 mL) at rt. The reac-
tion mixture was cooled to 0ꢀC and solid p-tosyl chloride (1.1 g, 6 mmol) was

1386
SARAVANAN AND SINGH
added. The pink solution was stirred for 48 h (0ꢀC to rt). The reaction
mixture was diluted with CH2Cl2 (50 mL), washed with water, and brine.
The organic layer was dried and condensed. The crude product was purified
over silica gel column to provide the pure product 5 as a crystalline solid
(1.46 g, 91%); m.p. 96ꢀ –98ꢀC (lit.19 m.p. 99ꢀC; Rf 0.80 (25% EtOAc in
25
25
D
petroleum ether); ½aŠD þ25ꢀ (c 1.0, CHCl3) {lit.19 ½aŠ þ27ꢀ (c 3.0, CHCl3)};
IR (KBr) 1710, 1580, 840. 760 cm–1; H NMR (CDCl3, 400 MHz) ꢀ 1.39
1
(s, 6H), 2.28 (s, 6H), 4.35–4.61 (m, 6H), 5.0 (m, 2H), 7.14 (d, J ¼ 8.5 Hz, 4H),
7.40 (t, J ¼ 6.5 Hz, 5H), 7.54 (m, 1H), 7.75 (d, J ¼ 8 Hz, 4H) 7.95 (d, J ¼ 8 Hz,
4H); 13C NMR (CDCl3 100 MHz) ꢀ 22.2, 28.0, 63.5, 78.0, 79.1, 112, 128.5,
128.9, 130.0, 130.4, 130.5, 133.8, 134.3, 145.6, 166.6; MS (FAB, m/z): 738
(Mþ). Anal. calc. for (C37H38O12S2: C, 60.16; H, 5.14; S, 8.67. Found: C,
59.78; H, 5.28; S, 8.79.
1,6-Di-O-tert-butyldimethylsilyl-3,4-O-isopropylidene-D-mannitol (6)
To a solution of tetraol 3 (2 g, 10 mmol), triethylamine (3.5 mL,
25 mmol), and DMAP (catalytic) in CH2Cl2 (50 mL) was added
TBDMSCl (3.1 g, 20 mmol) at rt, and the reaction mixture was stirred for
8 h. It was diluted with CH2Cl2 (25 mL), washed with water, brine, and
dried. Removal of the solvent under reduced pressure gave the crude prod-
uct, which was purified over silica gel column to provide the pure product 6
as a colorless oil (3.8 g, 94%); Rf 0.50 (10% EtOAc in petroleum ether);
25
½aŠD þ21.2ꢀ (c 1.0, CHCl3); IR (neat) 3450, 1210, 1050 cm–1; 1H NMR
(CDCl3, 400 MHz) ꢀ 0.03 (s, 12H), 0.82 (s, 18H), 1.29 (s, 6H), 3.35 (bs,
2H, OH), 3.56–3.84 (m, 8H); MS (FAB, m/z): 450 (Mþ), 434, 392, 334,
298 (base peak). Anal. calc. for C12H46O6Si2: C, 56.01; H, 10.22. Found:
C, 56.24; H, 9.68.
1,6-Di-O-tert-butyldimethylsilyl-2,5-Di-O-p-toluenesulphonyl-3,
4-O-isopropylidene-D-mannitol (7)
To a stirred solution of the diol 6 (3 g, 6.7 mmol) in CH2Cl2 (20 mL)
was added pyridine (20 mL) and triethylamine (1.9 mL, 13.5 mmol) at rt and
the reaction mixture was cooled to 0ꢀC p-Tosyl chloride (2.5 g, 13.5 mmol)
was added in portions to give the pink solution, which was allowed to warm
to rt, and stirring was continued for 24 h. After completion of the reaction
(by TLC), the mixture was diluted with some more CH2Cl2 (50 mL), washed
several times with water, brine, and dried. Removal of the solvent gave
crude product, which was purified over silica gel to afford the pure product

DIOL FROM D-MANNITOL
1387
7 as a viscous liquid (4.6 g, 91%); Rf 0.80 (10% EtOAc in petroleum ether);
25
1
½aŠD þ11.9ꢀ (c 18, CHCl3; IR (neat) 1590, 1360, 1180, 1060 cm–1; H NMR
(CDCl3, 400 MHz) ꢀ 0.02 (s, 12H), 0.82 (s, 18H), 1.30 (s, 6H), 2.39 (s, 6H),
3.7 2–3.87 (m, 4H), 4.40 (m, 2H), 4.70 (m, 2H), 7.30 (d, J ¼ 8.5 Hz, 4H), 7.82
(d, J ¼ 8.5 Hz, 4H); MS (FAB, m/z): 759 (Mþþ1), 637. Anal. calc. for
C35H58O10S2Si2: C, 55.40; H, 7.65; S, 8.44. Found: C, 55.62; H, 7.54.
2,5-Di-O-p-toluenesulphonyl-3,4-O-isopropylidene-D-mannitol (8)
To a stirred solution of ditosylate 7 (4 g, 5.3 mmol) in MeOH (40 mL),
was added ceric ammonium nitrate (6.4 g, 11.6 mmol) at 0ꢀC. The reaction
mixture was stirred at that temperature for 12 h. Solvent was removed in
vacuo at rt and the resulting oily material was diluted with ether (50 mL),
washed with saturated aqueous sodium bicarbonate, water, brine, and dried.
Solvent removal gave the crude product, which was purified over silica gel to
afford the pure product 8 as a viscous oil (2.32 g, 83%); Rf 0.50 (50% EtOAc
in petroleum ether); ½aŠ þ15.2ꢀ (c 1.25, CHCl3; IR (neat) 3380, 1360,
25
D
1
1060 cmꢁ1; H NMR (CDCl3, 400 MHz) ꢀ 1.29 (s, 6H), 2.46 (s, 6H), 3.72
(d, J ¼ 10 Hz, 2H), 3.83 (d, J ¼ 10 Hz, 2H), 4.15 (m, 2H), 4.62 (m, 2H), 7.35
(d, J ¼ 8 Hz, 4H), 7.80 (d, J ¼ 8 Hz, 4H); 13C NMR (CDCl3, 100 MHz)
ꢀ 21.7, 27.1, 61.6, 76.3, 81.6, 111.3, 128.0, 129.8, 133.0, 145.0. Anal. calc.
for C23H30O10S2: C, 52.07; H, S.66: S, 12.07. Found: C, 51.89; H, 5.68.
(3R,4R)-O-isopropylidene-1,6-hexanediol (1)
(From 5): To a suspension of LAH (630 mg, 16.5 mmol) in ether
(80 mL), ditosylate 5 (1.5 g, 2.0 mmol) in THF (10 mL) was added at 0ꢀC,
and stirred for 24 h (0ꢀC to rt). Excess LAH was destroyed by the addition
of EtOAc (0.5 mL). It was worked up by adding water (0.5 mL), followed by
the same amount of 4N aq. NaOH. It was stirred for 5 m, water (0.5 mL) was
introduced, and the mixture was further stirred for 20 m. Resulting white
precipitate was filtered through celite. The filtrate was dried, concentrated
in vacuo, and the resulting material was purified by column chromatography
using petroleum ether/ethy acetate as an eluent on silica gel to afford the final
diol 1 as a low melting solid (225 mg, 60%): Rf 0.20 (50% EtOAC in petro-
25
D
leumether);½aŠ þ22.0ꢀ (c3.4, CHCl3);IR(film)3450 cm–1;1HNMR(CDCl3,
400 MHz) ꢀ 1.38 (s, 6H), 1.74–1.86 (m, 4H), 2.55 (bs, 2H, OH), 3.78–3.83 (m,
4H), 3.84–3.85 (m, 2H); 13C NMR (CDCl3, 100 MHz) ꢀ 27.1, 34.3, 60.4, 79.6,
108.7; Anal. calc. for C9H18O4: C, 56.84; H, 9.47. found: C, 56.92; H, 9.38.

1388
SARAVANAN AND SINGH
(From 8): To a suspension of LAH (600 mg, 16.0 mmol) in ether
(60 mL) the compound 8 (2.1 g, 4.0 mmol) in THF(10 mL) was added at
0ꢀC, and stirred for 24 h (0ꢀC to rt). It was worked up as above to provide
the final diol 1 (520 mg, 71%) as a low melting solid.
ACKNOWLEDGMENTS
We thank CSIR, New Delhi, for a research grant (to V.K.S.) and a
senior research fellowship (to P.S.).
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Received in the USA June 14, 2000