A concise and convenient synthesis of DL-proto-quercitol and DL-gala-quercitol via ene reaction of singlet oxygen combined with [2 + 4] cycloaddition to cyclohexadiene

Article abstract of DOI:10.1021/jo962092+

Photooxygenation of 1,4-cyclohexadiene afforded hydroperoxy endoperoxides 3 and 4 in a ratio of 88:12. Reduction of 3 with LiAlH₄ or thiourea followed by acetylation of the hydroxyl group and KMnO₄ oxidation of the double bond gave proto-quercitol 10b. Application of the same reaction sequences to 4 resulted in the formation of gala-quercitol 14. Quercitols were easily obtained by ammonolysis of acetate derivatives in MeOH. The outcome of dihydroxylation reactions were supported by conformational analysis.

Full text of DOI:10.1021/jo962092+

J . Org. Chem. 1997, 62, 2453-2457
2453
A Con cise a n d Con ven ien t Syn th esis of DL-pr oto-Qu er citol a n d
DL-ga la -Qu er citol via En e Rea ction of Sin glet Oxygen Com bin ed
w ith [2 + 4] Cycloa d d ition to Cycloh exa d ien e†
Emine Salamci, Hasan Sec¸en, Yasar Su¨tbeyaz, and Metin Balci*,‡
Department of Chemistry, Faculty of Arts and Sciences, Atatu¨rk University, 25240-Erzurum, Turkey
Received November 8, 1996X
Photooxygenation of 1,4-cyclohexadiene afforded hydroperoxy endoperoxides 3 and 4 in a ratio of
88:12. Reduction of 3 with LiAlH4 or thiourea followed by acetylation of the hydroxyl group and
KMnO4 oxidation of the double bond gave proto-quercitol 10b. Application of the same reaction
sequences to 4 resulted in the formation of gala-quercitol 14. Quercitols were easily obtained by
ammonolysis of acetate derivatives in MeOH. The outcome of dihydroxylation reactions were
supported by conformational analysis.
Stereospecific [4 + 2] Diels-Alder addition of singlet
oxygen to cyclic dienes followed by opening of the result-
ing peroxide linkage by appropriate reducting reagents
is a reaction which has as yet no equivalent in the
synthetic methodology to form cyclic 1,4-dihydroxyl com-
pounds in a cis configuration. Recently, we have applied
this methodology to the stereospecific synthesis of the
highly hydroxylated cyclohexane derivatives1 and syn-
thesized conduritols and their derivatives2 in a short and
stereospecific way. Parallel to the execution of efficient
design of conduritol derivatives we embarked on a
general synthetic approach to cyclopentols. For this
reason we applied for the first time singlet oxygen ene
reaction combined with the singlet oxygen [2 + 4]
addition successfully to the synthesis of proto-quercitol.3
Only three optically active forms have been found in
nature and only in plants.5
So far, 10 possible diastereoisomers of quercitols have
been synthesized by different methods.2d The synthesis
of proto-quercitol was accomplished by McCasland4b using
(-)-chiro-inositol, by Suami6a using DL-1,2-anhydro-5,6-
O-cyclohexylidene-chiro-inositol, and by Cambie6b using
conduritol-A. In all previously reported syntheses, start-
ing materials have been natural products or compounds
which required many steps to synthesize. Herewith, we
describe a concise and convenient three step synthesis
of proto- and gala-quercitols starting from cyclohexadi-
ene.
In our previous study, we successively used 1,3-
cyclohexadiene for stereospecific synthesis of conduritol-
A1c and conduritol-F.1d,e In our synthesis, 1,4-oxygen
functional groups were incorporated to cyclohexane ring
by singlet oxygen. Besides these, transformations using
singlet oxygen for synthesis of cyclitol derivatives have
been described.7,8
Resu lts a n d Discu ssion
Tetraphenylporphyrin-sensitized photooxygenation of
1,4-cyclohexadiene in methylene chloride at room tem-
perature resulted in the formation of the bicyclic endo-
peroxides 3 and 4 in a ratio of 88:12 (Scheme 1). The
Quercitol has been used as a generic term for cyclo-
hexanepentols. The family of quercitols is one of the
largest all-known family of diastereoisomers in organic
chemistry.4 Cyclohexanepentols can exist in 16 stereo-
isomeric forms, of which four are symmetric, the 12
others being grouped in six pairs of optical mirror images.
(5) For the isolation and synthesis of proto-quercitol, see: (a)
Braconnot, H. Annals. Chim. Phys. 1849, 27, 392. (b) Posternak, T.
The Cyclitols, French ed., Hermann: Paris, 1965. (c) Plouvier, V. C.
R. Se´ances Acad. Sci., Paris 1955, 240, 113. (d) Plouvier, V. C. R.
Se´ances Acad. Sci., Paris 1961, 253, 3047.
(6) (a) Suami, T.; Ogawa, S.; Ueda, T.; Uchino, H. Bull. Chem. Soc.
J pn. 1972, 45, 3226. (b) Cambie, R. C., Renner, N. D., Rutledge, P. S.,
Woodgate, P. D. Aust. J . Chem. 1990, 43, 1597.
† Dedicated to Professor Waldemar Adam on the occasion of his 60th
birthday.
‡ Fulbright Scholar for 1996-1997 in the Department of Chemistry,
Auburn University, Alabama.
X Abstract published in Advance ACS Abstracts, April 1, 1997.
(1) (a) Akbulut, N.; Balci, M. Doga, Turk. J . Chem. 1987, 11, 47. (b)
Akbulut, N.; Balci, M. J . Org. Chem. 1988, 53, 3338. (c) Su¨tbeyaz, Y.;
Sec¸en, H.; Balci, M. J . Chem. Soc., Chem. Commun. 1988, 1330. (d)
Sec¸en, H.; Su¨tbeyaz, Y.; Balci, M. Tetrahedron Lett. 1990, 31, 1323.
(e) Sec¸en, H.; Gu¨ltekin, S.; Su¨tbeyaz, Y.; Balci, M. Synth. Commun.
1994, 24, 2103. (f) Kara, Y.; Balci, M.; Borne, S. A.; Watson, W. H.
Tetrahedron Lett. 1994, 35, 3349.
(2) For reviews, see: (a) Balci, M.; Su¨tbeyaz, Y.; Sec¸en, H. Tetra-
hedron 1990, 46, 3715. (b) Brown, S. M.; Hudlicky, T. In Organic
Synthesis: Theory and Practice; Hudlicky, T., Ed.; J AI Press: Green-
wech, CT, 1992. (c) Carless, A. J . Tetrahedron: Asymmetry 1992, 795.
(d) Hudlicky, T.; Cebulak, M. Cyclitols and Derivatives; VCH: New
York, 1993. (e) Balci, M. Pure Appl. Chem. 1997, 69, 97.
(3) Sec¸en, H.; Salamci, E.; Su¨tbeyaz, Y.; Balci, M. Synlett 1993, 609.
(4) (a) McCasland, G. E. Adv. Carbohydr. Chem. 1965, 20, 11. (b)
McCasland, G. E.; Naumann, M. O.; Durham, L. J . J . Org. Chem. 1968,
33, 4220.
(7) For application of singlet oxygen to the synthesis of cyclitols
see: (a) Wasserman, H. H.; Ives, J . L. Tetrahedron 1981, 37, 1825. (b)
Carless, H. A. J .; Billinge, J . R.; Oak, O. Z. Tetrahedron Lett. 1989,
30, 3113. (c) Hudlicky, T.; Price, J . D.; Luna, H.; Andersen, C. M.
Synlett 1990, 309. (d) Carless, H. A. J .; Busia, K. Tetrahedron Lett.
1990, 31, 1617. (e) Carless, H. A. J .; Malik, S. S. Tetrahedron:
Asymmetry 1992, 3, 1135. (f) Adam, W.; Schuhmann, R. M. J . Org.
Chem. 1996, 61, 874.
(8) (a) Wassermann, H. H.; Murray, R. W., Eds. Organic Chemis-
try: A Series of Monographes, Singlet Oxygen; Academic Press: New
York, 1979. (b) Frimer, A. A., Ed. Singlet Oxygen; CRC Press: Boca
Raton, FL, 1985. (c) Hudlicky, T.; Luna, H.; Olivo, H. F.; Andersen,
C.; Nugent, T.; Price, J . D. J . Chem. Soc., Perkin Trans. 1 1991, 2907.
(d) J ohnson, C. R.; Patrick, A. P.; Adams, J . P. J . Chem. Soc., Chem.
Commun. 1991, 1006. (e) Hudlicky, T.; Rulin, F.; Tsunoda, F. Luna,
H.; Andersen, C.; Price, J . D. Isr. J . Chem. 1991, 31, 229. (f) J ohnson,
C. R.; Adams, J . P.; Collins, M. A. J . Chem. Soc., Perkin Trans. 1 1993,
1.
S0022-3263(96)02092-0 CCC: $14.00 © 1997 American Chemical Society

2454 J . Org. Chem., Vol. 62, No. 8, 1997
Salamci et al.
Sch em e 1
F igu r e 1. Optimized geometries for isomers 3 and 4.
Ta ble 1. Resu lts fr om AM1 Ca lcu la tion s
substrate
∆Hf (kcal/mol)
dipole moments (Debye)
3
4
5
6
7
8
-5.177
-8.810
-1.147
-1.241
-40.32
-42.45
2.48
3.45
3.18
2.99
1.65
3.71
reaction mixture was chromatographed on silica gel
column with ether/petroleum ether (1:1) as eluant.
The structures of 3 and 4 were assigned by 1H and 13C
NMR. The most conspicuous features in the 1H NMR
spectra of the endoperoxides 3 and 4 are two distinct AB
systems which correspond to two olefinic and two meth-
ylenic protons. Olefinic protons of 3 resonating at δ
6.56-6.73 show further splitting with adjacent bridge-
head protons. Methylenic protons resonate as an AB
system δ 2.54 and 1.20 and gave most useful information
for the structure of these endoperoxides. The B part of
the AB system (low field resonance, H6exo) is split into a
doublet of doublets of doublets (J ) 14.2, 8.1, and 3.7
Hz). The large splitting originates from the geminal
coupling where the second doublet splitting (8.21 Hz)
arises from the vicinal hydrogen which is attached to the
C5 carbon atom. The high-field part of the AB system
resonates as triplets of doublet. The coupling constant
between H6endo and bridgehead proton is J ) 2.3 Hz.
Bridgehead proton H1 has a larger coupling to H6exo
proton than to H6endo proton. Geometry optimization
calculations (AM1) show a dihedral angle of 71° for H1-
H6endo and 48.5° for H1-H6exo, which is consistent with
our assignments. Unequivocal assignment of these meth-
ylene signals permitted identification of H4 (δ 5.08), H8
(δ 6.56), H7 (δ 6.73), H1 (δ 4.58), and H5 (δ 4.50) by
observation of the diagonal cross peaks between ap-
propriate protons in the COSY spectrum. The relative
stereochemistry of the hydroxy peroxide group at C5 was
determined from the coupling constants between protons
H4 and H5. The assignments for the syn isomer 4 were
based on a series of homonuclear decoupling experiments.
13C NMR spectral data are also in agreement with the
proposed structures.
to isolate any trace of 2 were unsuccessful. We believe
that the rate of addition of singlet oxygen to the diene
system 2 is much faster than the rate of the ene reaction.
In order to rationalize the formation of these isomers,
we have carried out some AM1 calculations.10
The optimized geometrys of these isomers 3 and 4
(Figure 1) were calculated using the AM1 method.
Results from AM1 calculations show that the minor
isomer 4 has a lower heat of formation (-8.810 kcal/mol)
than the major isomer (-5.177 kcal/mol) which indicates
that the minor isomer is thermodynamically the most
stable one (Table 1). This can be rationalized by the
existence of a hydrogen-bonding interaction between
hydroperoxide hydrogen and peroxide linkage, which can
also be seen from the short distance (2.1 Å). For
comparison, we have calculated the heats of formation
of the corresponding ethyl and hydroxymethyl derivatives
5-8. Ethyl derivatives 5 and 6 show similar heats of
For the mechanism of formation of these interesting
endoperoxides containing hydroperoxide groups, we as-
sume that 1,4-cyclohexadiene first undergoes an ene
reaction8a,b with the double-activated methylene groups
to give the hydroperoxide 2. Because of the unfavorable
arrangement of double bonds, a [2 + 4] cycloaddition can
be excluded. On the other hand, formation of dioxetane
by addition of singlet oxygen to one of these double bonds
can occur only with certain activated double bonds.8a
Addition of singlet oxygen to a diene9 unit results in the
formation of the isolated products 3 and 4. Since the
hydroperoxide 2 has no plane of symmetry, singlet oxygen
approaches the diene unit in 2 preferentially from the
sterically less crowded face of the molecule. All efforts
formation as they have no hydrogen bonding to the
peroxide linkage. On the other hand, hydroxymethyl
derivatives 7 and 8 show an energy difference of ∆HF
)
2 kcal/mol where syn isomer 8 is energetically favored,
as expected. These results support the stabilization of
the exo isomer 4 by the hydrogen bond interactions. The
fact that the kinetically controlled product is formed as
the major product indicates the steric factors in the
transition state determine the course of the cycloaddition
reaction of singlet oxygen to the diene unit.
After successful isolation and characterization of en-
doperoxides 3 and 4, we turned our attention to the
reduction of both peroxide linkages in 3 and 4. The
(9) For similar reaction, see: Saito, I.; Tamoto, K.; Katsumura, A.;
Sugiyama, H.; Matsuura, T. Chem. Lett. 1978, 127.
(10) Dewar, M. J . S.; Zoebisch, E. G.; Healy, E. F. Stewart, J . J . P.
J . Am. Chem. Soc. 1985, 107, 3902.

Synthesis of Quercitol
J . Org. Chem., Vol. 62, No. 8, 1997 2455
Sch em e 2
F igu r e 2. Lowest energy conformation of 9b.
Sch em e 3
peroxide linkage is highly susceptible to reductive cleav-
age by a variety of reductants.11 Bicyclic endoperoxides
can be readily reduced by catalytic hydrogenation to the
corresponding cis-diols. Under the conditions for forming
cis-diols, any double bonds present are also reduced.
Selective reduction of both peroxide linkages in 3 was
performed with either thiourea or LiAlH4 under very mild
conditions to give the cyclohexenetriol 9a (Scheme 2).
Since only the oxygen-oxygen bonds break in this
reaction, it preserves the configuration at all three carbon
atoms. For further structural proof, 9a was converted
to the corresponding acetate 9b which has been fully
characterized from the spectroscopic data.
Cyclohexenetriacetate 9b is an ideal substrate for the
synthesis of quercitols and aminoquercitols. By com-
parison of the configuration of this triacetate with the
configuration of proto-quercitol, it can easily be seen that
the three hydroxyl groups have been incorporated in the
six-membered ring correctly as desired for the synthesis
of proto-quercitol. In the next step, the double bond has
to be oxidized in a cis fashion. The oxidation of olefins
with permanganate is not commonly used as a prepara-
tive method because of its typically low selectivity.12
However, we chose to examine the oxidation of triacetate
9b with permanganate with the intention of introducing
the two hydroxyl groups in a cis configuration to the
double bond to complete the synthesis of proto-quercitol.
Treatment of 9b with KMnO4 (-15 °C, H2O) gave to our
surprise only one diol 10a in an isolated yield of 66%.
Careful NMR studies did not reveal the formation of any
trace of the other diastereoisomer. For characterization
of the product, we converted 10a to DL-proto-quercitol
pentaacetate 10b.13 Deacetylation of 10b with ammonia
in methanol afforded DL-proto-quercitol 11 in quantitative
yield. The spectral data of 10b and 11 were identical
with those reported in the literature.14
In order to explain the formation of one isomer during
KMnO4 oxidation, we have carried out conformational
analysis using the AM1 method on the triacetate 9b. This
analysis indicates clearly that anti attack to the double
bond should be favored since acetoxyl groups bonded to
C1 and C2 are sterically more demanding and block the
syn face of the molecule (Figure 2).
The same methodology was applied to the synthesis
of gala-quercitol 14 starting from the minor isomer 4
(Scheme 3). Successful reduction of peroxide linkages in
4 followed by acetylation of formed triol 12a using acetic
anhydride-pyridine resulted in the formation of the
corresponding triacetate 12b. For cis hydroxylation of
the double bond in 12b, an OsO4-NMO oxidation15
method was applied. Thus, the formed triacetoxy diol
13a was converted to the acetate derivative13b 13b for
further characterization.
gala-Quercitol 14 itself was readily and quantitatively
obtained by ammonolysis of gala-quercitol pentaacetate
13b, which was characterized by comparison of its
physical data with those reported13,16 in the literature.
In summary, with relatively little synthetic effort we
have achieved the stereospecific synthesis of DL-proto-
quercitol and DL-gala-quercitol in three steps starting
from commercially available 1,4-cyclohexadiene and in-
troduced the complex stereochemistry in a very simple
(11) Balci, M. Chem. Rev.. 1981, 81, 91.
(12) (a) Fatiadi, A. J . Synthesis 1987, 85. (b) Hudlicky, M. Oxidation
in Organic Chemistry; American Chemical Society: Washington, DC,
1990; p 86.
(13) (a) Posternak, T.; Schopfer, W. H. Helv. Chim. Acta 1950, 33,
343. (b) McCasland, G. E.; Furuta, S.; J ohnson, L. F.; Shoolery, J . N.
J . Am. Chem. Soc. 1961, 83, 2335. (c) Nakajima, M.; Kurihara, N.
Chem. Ber. 1961, 94, 515. (d) For most recent gala-quercitol synthesis,
see: Angelaud, R.; Landais, Y. J . Org. Chem. 1996, 61, 5202.
(14) (a) Pachaly, P.; Khosravian, H. Planta Med. 1988, 54, 516. (b)
Ruangrungsy, N.; Lange, G. L.; Lee, M. J . Nat. Prod. 1986, 49, 253.
(c) Angyal, S. J .; Odier, L. Carbohydr. Res. 1982, 101, 209. (d) Angyal,
S. J .; Odier, L. Carbohydr. Res. 1982, 100, 43. (e) Angyal, S. J .; Gilham,
P. T. J . Chem. Soc. 1957, 3691.
(15) Van Rheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 1973.
(16) Nakajima, M.; Kurihara, N. Chem. Ber. 1961, 95, 515.

2456 J . Org. Chem., Vol. 62, No. 8, 1997
Salamci et al.
yield 55% from LiAlH4 reaction, 50% from thiourea reaction;
colorless solid; mp 95-96 °C from ethanol; 1H-NMR (200 MHz,
D2O) δ 5.76 (br s, 2H), 4.21 (dd, J ) 9.7, 6.1 Hz, 1H), 4.0 (m,
1H), 3.61 (dt, J ) 12.2, 3.7 Hz, 1H), 1.96 (m, 1H), 1.56 (dt, J
) 14.1, 12.2, 9.7 Hz, 1H); 13C-NMR (50 MHz, D2O) δ 37.8, 69.6,
70.8, 71.3, 131.6, 138.9; IR (KBr) 3390, 2950, 1472, 1270. Anal.
Calcd for C6H10O4: C, 49.31; H, 6.90. Found: C, 49.67; H, 6.62.
(2,5/1)-Tr ia cetoxy-3-cycloh exen e (9b). To a magnetically
stirred solution of triol 9a (400 mg, 3.07 mmol) in 5 mL of
pyridine was added Ac2O (1.25 g, 12.25 mmol). The reaction
mixture was stirred at rt for 6 h. The mixture was cooled to
0 °C and 200 mL of 1 N HCl solution added, and the mixture
was extracted with ether (3 × 100 mL). The combined organic
extracts were washed with NaHCO3 solution (25 mL) and
water (10 mL) and then dried (Na2SO4). Removing of the
solvent under reduced pressure and recrystallization of product
from ethyl acetate/n-hexane gave 9b (525 mg, 67%, colorless
solid, mp 30-31 °C): 1H-NMR (200 MHz, CDCl3) δ 5.89 (br
dd, J ) 10.0, 2.9 Hz, 1H), 5.75 (dd, J ) 10.0, 2.5 Hz, 1H), 5.31
(m, 2H), 5.17 (ddd, J ) 11.1, 6.9, 4.4 Hz, 1H), 2.20-1.90 (m,
10H); 13C-NMR (50 MHz, CDCl3) δ 21.4, 21.5, 21.6, 31.5, 66.7,
69.1, 70.6, 129.2, 129.4, 170.6, 170.8, 170.9; IR (KBr) 2940,
1740, 1430. Anal. Calcd for C12H16O6: C, 56.25; H, 6.29.
Found: C, 55.93; H, 6.52.
way. Further studies of the chemistry of the double bond
in 9 and 13 directed toward the synthesis of other
quercitols and aminoquercitols are currently in progress.
Exp er im en ta l P a r t
Gen er a l. Melting points were determined on a melting
apparatus. Solvents were concentrated at reduced pressure.
Infrared spectra were obtained from KBr pellets on an infrared
recording spectrophotometer. 1H-NMR spectra were recorded
on 60, 200, and 400 MHz spectrometer and are reported in δ
units with SiMe4 as internal standard. All column chroma-
tography was performed on silica gel (60 mesh).
P h otooxygen a tion of 1,4-Cycloh exa d ien e. To a stirred
solution of 1,4-cyclohexadiene (1.0 g, 12.5 mmol) in 100 mL of
CH2Cl2 was added 20 mg of tetraphenylporphyrin (TPP). The
resulting mixture was irradiated with a projection lamp (150
W) while oxygen was being passed through solution and the
mixture was stirred for 48 h at room temperature. The 1H-
NMR spectrum of the mixture showed that the ratio of 3:4
was 88:12. Evaporation of the solvent (30 °C, 20 mmHg) and
chromatography of the residue on a silica gel column (100 g)
eluting with hexane/ether (1:1) gave as the first fraction
endoperoxide 3 (1.15 g, 63%) and as the second fraction
endoperoxide 4 (0.12 g, 7%).
a n ti-2,3-Dioxa bicyclo[2.2.2]oct-7-en -5-yl h yd r op er ox-
id e (3): colorless solid; mp 131-132 °C from CHCl3/ether; 1H-
NMR (200 MHz, CDCl3) δ 8.85 (br s, 1H), 6.73 (ddd, J ) 8.3,
6.3, 1.8 Hz, 1H), 6.56 (ddd, J ) 8.3, 6.9, 1.4 Hz, 1H), 5.08 (m,
1H), 4.69 (m, 1H), 4.60 (ddd, J ) 8.1, 4.0, 2.5 Hz, 1H), 2.54
(ddd, J ) 14.2, 8.1, 3.7 Hz, 1H), 1.20 (dm, J ) 14.2, 1H); 13C-
NMR (50 MHz, CDCl3) δ 29.8, 71.1, 71.3, 75.2, 129.5, 134.3;
IR (KBr) 3380, 2920, 1280, 1210. Anal. Calcd for C6H8O4: C,
50.01; H, 5.59. Found: C, 49.45; H, 5.34.
syn -2,3-Dioxa bicyclo[2.2.2]oct-7-en -5-yl h yd r op er oxid e
(4): colorless solid; mp 98-100 °C, from CHCl3/petroleum
ether; 1H-NMR (200 MHz, CDCl3) δ 8.82 (br s, 1H), 6.74 (ddd,
J ) 8.2, 5.8, 1.7 Hz, 1H), 6.63 (ddd, J ) 8.2, 6.2, 1.8 Hz, 1H),
5.06 (dq, J ) 6.2, 1.7 Hz, 1H), 4.64 (m, 1H), 4.21 (ddd, J )
9.9, 4.3, 1.9 Hz, 1H), 1.96 (ddd, J ) 14.3, 9.9, 2.4 Hz, 1H),
1.83 (dt, J ) 14.3, 4.0 Hz, 1H); 13C-NMR (50 MHz, CDCl3) δ
27.4, 70.9, 72.5, 77.6, 130.1, 135.1; IR (KBr) 3230, 2980, 1446,
1370. Anal. Calcd for C6H8O4: C, 50.01; H, 5.59. Found: C,
49.35; H, 5.26.
(2,5/1)-Cycloh ex-3-en etr iol (9a ). (a ) By r ed u ction of 3
w ith LiAlH4. To a magnetically stirred slurry of 261 mg (6.87
mmol) of LiAlH4 in 50 mL of THF was added a solution of 450
mg (3.13 mmol) of endoperoxide 3 in 25 mL of THF at 0 °C
under nitrogen, during 3 h. The reaction mixture was stirred
at rt for 1 h, and 20 g of silica gel was added. After 12 h of
stirring at rt, 50 mL of methanol was added and the solution
was filtered. The solvents were rotoevaporated (at 40 °C, 20
mmHg), and the residue was purified by column chromatog-
raphy (35 g of basic alumina), eluting with CHCl3/methanol
(95:5), affording pure (2,5/1)-cyclohex-3-enetriol 9a (163 mg,
40%).
(b) By r ed u ction of 3 w ith Th iou r ea . To a magnetically
stirred slurry of 1.06 g (13.88 mmol) of thiourea in 25 mL of
methanol was added a solution of 1.00 g (6.94 mmol) of
endoperoxide 3 in 50 mL of methanol at 25 °C. After
completion of addition (ca. 10 min), the mixture was stirred
for 1 h, the solids were removed by filtration, methanol was
rotoevaporated (at 35 °C, 20 mmHg), and the residue was
purified by column chromatography on silica gel (100 g) elution
with CHCl3/methanol (97:3) and afforded the pure (2,5/1)-
cyclohex-3-enetriol 9a (630 mg, 70%): colorless solid; mp 76-
78 °C from absolute methanol; 1H-NMR (200 MHz, D2O) δ 5.75
(br d, J ) 10.5 Hz, 1H), 5.66 (dd, J ) 10.5, 1.8 Hz, 1H), 4.28
(br q, J ) 3.8 Hz, 1H), 3.91 (ddd, J ) 7.2, 1.7, 1.4 Hz, 1H),
3.73 (ddd, J ) 11.9, 7.2, 4.7 Hz, 1H), 1.82 (m, 2H); 13C-NMR
(50 MHz, D2O) δ 38.7, 67.1, 71.4, 74.3. 132.3, 133.8; IR (KBr)
3350, 2920, 1440, 1190. Anal. Calcd for C6H10O4: C, 49.31;
H, 6.90. Found: C, 49.01; H, 6.71.
(1,2,5)-Tr ia cetoxy-3-cycloh exen e (12b). The same pro-
cedure was applied as described above: yield 50%; colorless
1
solid; mp 92-93 °C from chloroform/n-hexane; H-NMR (200
MHz, CDCl3) δ 5.90 (AB system, J ) 10.1, 2.8, 1.4 Hz, 2H),
5.40 (m, 2H), 5.01 (dt, J ) 10.6, 3.9 Hz, 1H), 2.20-1.90 (m,
10H); 13C-NMR (50 MHz, CDCl3) δ 21.3, 21.4, 21.5, 29.3, 65.8,
67.2, 68.0, 126.5, 132.6, 170.4, 170.6, 170.8; IR (KBr) 3004,
1778, 1395. Anal. Calcd for C12H16O6: C, 56.25; H, 6.29.
Found: C, 56.63; H, 6.41.
DL-pr oto-Qu er citol P en ta a ceta te (10b). To a magneti-
cally stirred ethanol solution (100 mL) of triacetate 9b (4.0 g,
15.63 mmol) was added a solution of KMnO4 (2.46 g, 15.63
mmol) and MgSO4 (1.87 g, 15.63 mmol) in water (40 mL) at
-5 °C for 7 h. After the addition was complete, the reaction
mixture was stirred for additional 15 h at the given temper-
ature and then filtered. The precipitate was washed several
times with hot water. The combined filtrates were concen-
trated to 20 mL by rotoevaporation. The aqueous solution was
extracted with ethyl acetate (3 × 30 mL), and the extracts were
dried (Na2SO4). Evaporation of the solvent gave triacetoxy diol
10a (3.00 g, 66%), which was submitted to acetylation as
described above: 2.81 g, 73%; colorless solid; mp 115-116 °C
(lit.9,13a mp 114-116.5 °C, lit.13b mp 124-125 °C) from ethyl
1
acetate/n-hexane; H-NMR (400 MHz, CDCl3) δ 5.37 (t, J )
10.0 Hz, 1H), 5.33 (dd, J ) 4.0, 3.2 Hz, 1H), 5.23 (dd, J ) 10.0,
3.2 Hz, 1H), 5.16 (ddd, J ) 14.4, 9.2, 5.2 Hz, 1H), 5.08 (br q,
J ) 3.6 Hz, 1H); 2.23 (br dt, J ) 14.4, 5.2, 3.6 Hz, 1H), 2.14
(br s, 6H), 2.04 (br s, 6H), 2.00 (m, 1H), 2.00 (s, 3H); 13C-NMR
(100 MHz, CDCl3) δ 20.5, 20.6, 20.7, 20.8, 20.8, 29.7, 67.4, 68.2,
68.8, 69.3, 70.7, 169.1, 169.7, 169.8, 169.9; IR (KBr) 2960, 1740,
1440.
DL-pr oto-Qu er citol (11). Pentaacetoxycyclohexane (10b)
(300 mg, 0.802 mmol) was dissolved in 15 mL of absolute
methanol. While dry NH3 was passed through solution, the
mixture was stirred for 2 h at room temperature. Evaporation
of methanol and formed acetamide gave proto-quercitol 11 in
nearly quantitative yield (132 mg): mp 228-229 °C (lit. mp
1
227 °C,14b 228-230 °C,13b 237 °C6) from absolute EtOH; H-
NMR (200 MHz, D2O) δ 3.94 (br q, J ) 3.3 Hz, 1H), 3.83 (dd,
J ) 3.3, 3.5 Hz, 1H), 3.70 (ddd, J ) 11.4, 9.3, 5.1 Hz, 1H),
3.62 (dd, J ) 9.6, 3.3 Hz, 1H), 3.47 (t, J ) 9.3, 9.6 Hz, 1H),
1.89 (br ddd, J ) 14.0, 5.1, 3.9 Hz, 1H), 1.72 (ddd, J ) 14.0,
11.4, 2.9 Hz, 1H); 13C-NMR (50 MHz, D2O) δ 36.2, 71.5, 71.8,
73.9, 75.2, 77.5; IR (KBr) 3300, 2900, 1420.
ga la -Qu er citol P en ta a ceta te (13b). A 50 mL three-
necked, round-bottomed flask, equipped with a magnetic
stirrer and a nitrogen inlet, was charged with 91 mg (0.67
mmol) of NMO, 1 mL of water, and 0.5 mL of acetone. To
this solution were added ca. 2.0 mg of OsO4 (0.008 mmol) and
170 mg (0.66 mmol) of triacetate 11b. The resulting mixture
was stirred vigorously under nitrogen at rt. During the
overnight stirring, the reaction mixture became homogeneous.
(1,2,5)-Cycloh ex-3-en etr iol (12a ). Reduction of 4 with
LiAlH4 and with thiourea was carried out as described above:

Synthesis of Quercitol
J . Org. Chem., Vol. 62, No. 8, 1997 2457
After 24 h, the reaction was complete. Sodium hydrosulfite
(0.01g) and 0.5 g of Florisil slurried in 2 mL of water were
added, the slurry was stirred for 10 min, and the mixture was
filtered through a pad of 0.5 g of Celite in a 50 mL sintered-
glass funnel. The Celite cake was washed with acetone (3 ×
10 mL). The filtrate was neutralized to pH 7 with H2SO4. The
organic layer was removed in vacuo. The pH of the resulting
aqueous solution was adjusted to pH 5 with sulfuric acid, and
the triacetoxy diol 13a was separated from N-methylmorpho-
line hydrosulfate by extraction with ethyl acetate (4 × 20 mL).
The combined ethyl acetate extracts were washed with 2 mL
of 25% NaCl solution and two or three times with water and
dried (Na2SO4). Evaporation of solvent gave 134 mg of
triacetoxy diol (70%). The same procedure as described above
was applied for acetylation of triacetoxy diol 13a (110 mg, 64%,
mp 116-117 °C (lit. mp 117-118 °C,13b 92 °C15) recrystallized
from absolute 2-propanol): 1H-NMR (200 MHz, CDCl3) δ 5.39
(m, 1H), 5.26 (m, 3H), 5.11 (dt, J ) 8.83, 4.42 Hz, 1H), 1.98-
2.27 (m, 1H), 2.11 (s, 3H), 2.09 (s, 3H), 2.04 (s, 3H), 2.01(s,
3H), 2.00 (s, 3H); 13C-NMR (50 MHz, CDCl3) δ 22.7, 22.8, 22.9,
31.19, 68.79, 69.7, 70.2, 71.8, 171.3, 171.3, 171.7; IR (KBr)
3055, 2980, 1753, 1446.
DL-ga la -Qu er citol (14). 14 was synthesized by ammonoly-
sis of 13b (90 mg, 0.24 mmol) as described above by the
synthesis of proto-quercitol 11 in almost quantitative yield (39
mg, 0.24 mmol): mp13 256-257 °C recrystallized from absolute
1
methanol; H-NMR (200 MHz, D2O) δ 4.66 (m, 1H), 4.02 (m,
2H), 3.76 (dd, J ) 10.2, 4.4 Hz, 1H), 3.66 (dd, J ) 9.1, 3.3 Hz,
1H), 2.07 (m, 1H), 1.72 (dt, J ) 11.4, 10.8 Hz, 1H); 13C-NMR
(50 MHz, D2O) δ 38.0, 71.0, 72.5, 76.2, 76.5, 76.8; IR (KBr)
3410, 2950, 1676, 1421.
Ack n ow led gm en t. The authors are indebted to the
Department of Chemistry (Atatu¨rk University) and the
TBAG-DPT-6 for financial support of this work and
State Planning Organization of Turkey (DPT) for pur-
chasing a 200 MHz NMR spectrometer. M.B. thanks
to Fulbright Scholarship Board for a grant and Professor
Philip Shevlin for helpful discussions during the prepa-
ration of the manuscript.
J O962092+