Synthesis of (+)-(2R,3S,4R)-2,3,4-trihydroxycyclohexanone from D-glucose

Article abstract of DOI:10.1016/j.carres.2003.10.010

We have described the synthesis of (+)-(2R,3S,4R)-2,3,4- trihydroxycyclohexanone by the reduction of a keto-conduritol derivative, the latter being prepared in five steps from (-)-(2S,3R,4S,5S)-2,3,4-tribenzyloxy-5- hydroxycyclohexanone, which is in turn

Full text of DOI:10.1016/j.carres.2003.10.010

Carbohydrate
RESEARCH
7
Carbohydrate Research 339 (2004) 361–365
Synthesis of (+)-(2R,3S,4R)-2,3,4-trihydroxycyclohexanone
from -glucose
D
Ivone Carvalho* and Eduardo B. de Melo
Departamento de Ci^encias Farmac^euticas, Faculdade de Ci^encias Farmac^euticas de Ribeir~ao Preto,
Universidade de S~ao Paulo, Av. do Cafeꢀ s/n, Monte Alegre, 14040-903 Ribeir~ao Preto, SP, Brazil
Received 16 August 2003; received in revised form 16 October 2003; accepted 20 October 2003
Abstract—We have described the synthesis of (+)-(2R,3S,4R)-2,3,4-trihydroxycyclohexanone by the reduction of a keto-conduritol
derivative, the latter being prepared in five steps from ())-(2S,3R,4S,5S)-2,3,4-tribenzyloxy-5-hydroxycyclohexanone, which is in
turn readily synthesized from D-glucose.
Ó 2003 Elsevier Ltd. All rights reserved.
Keywords: (+)-(2R,3S,4R)-2,3,4-Trihydroxycyclohexanone; Perbenzylated ())-keto-conduritol; Conduritol B
1. Introduction
and we now wish to report a convenient synthesis of one
such compound, (+)-(2R,3S,4R)-2,3,4-trihydroxy-
cyclohexanone (1), a compound in which the spatial
Hydroxycyclohexanes and their derivatives have an
important place in biology. Hexahydroxycyclohexanes
(inositols) and tetrahydroxycyclohexenes (conduritols)
occur naturally and monoketo inositol derivatives
(inososes) occur as biosynthetic intermediates in the
formation of inositols. myo-Inositol 1,4,5-triphosphate
is crucially involved in cellular regulation;1 and ino-
samines, in which one or two hydroxy groups are
replaced by amino groups, are important constituents of
some antibiotics.2 Related compounds are involved in
insulin modulation3 and conduritol derivatives can dis-
rupt glycoprotein processing through site-direct irre-
versible glycosidase inhibition4 and represent potential
therapeutic agents for treatment of metabolic disorders
such as GaucherÕs disease, diabetes, cancer and viral
infection.5 As carba-sugars, hydroxycyclohexanes have
a methylene group replacing the ring oxygen of normal
sugars, and many of this class show interesting biolog-
ical activity. Therefore, new synthetic procedures, which
produce enantiomerically pure representatives of these
types of compounds, are of considerable general interest
disposition of the 2,3,4-hydroxy groups mimics that of the
2,3,4-hydroxy groups in D-glucose. Ketone 1 was pre-
pared by regioselective conversion of ())-(2S,3R,4S,
5S)-2,3,4-tribenzyloxy-5-hydroxycyclohexanone (3), a com-
pound which may be prepared from
D
-glucose,6a into
the perbenzylated ())-keto-conduritol B (2) in five steps,
followed by a combined hydrogenation–hydrogenolysis
reaction. A retrosynthetic analysis is depicted in
Scheme 1.
2. Discussion
While perbenzylated (+)-(2S,3R,4S)-keto-conduritol (4)
can be easily prepared by elimination of water from
ketone 3,6 the synthesis of the ())-(2R,3S,4R)-enantiomer
Ketone 1 has previously been obtained7 by the action of Acetobacter
suboxydans on 1,4/2,3-cyclohexane-1,2,3,4-tetrol in admixture with
(2S,3S,4R)-2,3,4-trihydroxycyclohexanone, from which it was sepa-
rated by paper chromatography. The latter ketone is the primary
product of oxidation and is reversibly transformed into ketone 1 in
the ferment medium. However, no physical data for 1 were reported
except for its UV spectrum.
* Corresponding author. Tel.: +55-16-6024283; fax: +55-16-6331941;
e-mail: carronal@usp.br
0008-6215/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2003.10.010

362
I. Carvalho, E. B. de Melo / Carbohydrate Research 339 (2004) 361–365
O
O
6
BnO
BnO
2
BnO
BnO
1
BnO
BnO
4
5
HO
HO
3
O
OH
BnO
OBn
OBn
HO
O
4
1
2
3
Scheme 1. Retrosynthetic analysis for preparation of cyclohexanone 1 from 3 via the protected ())-keto-conduritol (2).
(2) is not so straightforward and requires a regioselective
O
functional group transformation at the C-1 and C-5
positions of compound 3, with an accompanying change
in the position of the double bond, as outlined in
Scheme 1.
O
6
BnO
2
b
BnO
BnO
1
4
5
3
BnO
BnO
OR
OTBS
In our synthesis we prepared the starting material 3
from methyl 2,3,4-tri-O-benzyl-6-deoxy-a-D-xylo-hex-5-
enopyranoside as a 5S,5R diasteroisomeric mixture
6
3 R= H
5 R= TBS
a
1
Scheme 2. Reagents and conditions: (a) TBSCl, imidazole, DMF; (b)
piperidine.
(ratio 4:1 determined by H NMR integration of CH2-6
hydrogens), as described by McAuliffe and Stick.6a The
stereochemistry at C-5 is irrelevant for the proposed
synthesis, but we carried out our experiments exclusively
with the major 5S-isomer to render the NMR spectra
more clear, and the formula for 3 in Scheme 2 reflects
this fact.
To circumvent the problem caused by this undesired
elimination, the preparation of 2 was investigated by a
second approach (Scheme 3). In this modified approach,
in which the order of introducing the alkenic function
and keto group would be reversed, the carbonyl group
would first be reduced in the hope of improving the
regioselectivity of the double bond formation.
Two different approaches were explored for conver-
sion of compound 3 into ())-(2R,3S,4R)-2,3,4-triben-
zyloxycyclohex-5-enone (2). In the first approach we
intended to initially convert the carbonyl group of 5
[prepared from 3 in almost quantitative yield by reaction
with tert-butyldimethylsilyl chloride (TBSCl)] into the
corresponding enamine,8 followed by hydrogenolysis of
C–N bond to produce the alkene.9 It was envisaged that
de-O-silylation and oxidation would give compound 2.
However, rather surprisingly, piperidine acted exclu-
sively as base on compound 5, resulting in the elimina-
tion of the 3-OBn group, possibly by an E1cb
mechanism, and producing the undesired compound 6,
which was characterized on the basis of its spectral
Contrary to our expectations, neither lithium alu-
minium hydride nor DIBAL gave satisfactory results on
attempted reduction of 5; partial deprotection of the
silylated alcohol or poor product yields resulted. On the
other hand, reduction of ketone 5 with sodium boro-
hydride in methanol gave only one product as shown by
the fact that only a single set of signals were evident in
the 13C spectrum of the alcohol produced (shown by
NMR spectroscopy to be 7––see below) and in sub-
sequent transformation products. That the conforma-
tion of 5 is as indicated is supported by the observed
coupling constants J2;3 9.2, J3;4 8.5, and J4;5 2.2 Hz, and
this places the bulky tert-butyldimethylsilyloxy group in
b-axial orientation with respect to the carbonyl group. It
is well recognized10 that a bulky group in a cyclohexa-
none occupying a b-axial position with respect to the
carbonyl function leads to Ôsteric approach controlÕ on
carbonyl reduction with sodium borohydride, leading to
1
properties (Scheme 2). The H NMR spectrum of this
compound showed the alkene hydrogen H-3 at d 5.73 (J
5.4 Hz), resonances for H-4, H-5, H-60, H-6, respec-
tively, centred on d 4.21, 4.26, 3.04, 2.58 and two sets of
signals characteristic of O-benzyl groups. The structure
of 6 was further confirmed by its 13C NMR spectrum,
with a carbonyl and an alkenic carbon at d 192.09 and
113.75, respectively.
O
BnO
BnO
BnO
BnO
BnO
BnO
d
a
e
1
BnO
R'O
BnO
O
OBn
OTBS
OR
5
7 R= TBS, R'= H
8 R= TBS, R'= Ms
9 R= H, R'= Ms
2
b
c
Scheme 3. Reagents and conditions: (a) NaBH4, MeOH; (b) MsCl, DMAP, pyridine; (c) water–THF–AcOH; (d) oxalyl chloride, Me2SO, CH2Cl2;
(e) cyclohexene–EtOH (2:1), Pd black.

I. Carvalho, E. B. de Melo / Carbohydrate Research 339 (2004) 361–365
363
1
an axial alcohol being produced. The H NMR spec-
trum of the reduction product 7 is in full accord with the
structure and conformation shown for this compound,
with J1;2 3.3, J2;3 and J3;4 9.3, J4;5 2.7, J5;6 and J1;6 2.5 and
achieved; CH2Cl2 was obtained anhydrous by distilling
from calcium hydride; methanol was dried by distilling
from the alkoxide (formed by reaction with activated
ꢁ
magnesium) and storage over powdered 3 A molecular
0
0
J5;6 and J1;6 3.7 Hz.
sieves; N,N-dimethylformamide (DMF) and triethyl-
amine were dried by distilling from calcium hydride
immediately prior to use; pyridine was obtained anhy-
drous by distillation from calcium hydride and storage
over potassium hydroxide pellets. Organic solns were
dried over anhyd MgSO4. Reactions were maintained at
)78 °C by means of a dry ice–acetone bath, and at 0 °C
by means of an ice bath.
Mesylation of 7 gave the mesylate 8 (87%) as an un-
stable oil. Hydrolysis of the O-silyl protective group of 8
was initially performed under mildly acidic conditions,
and this provided product 9 in a reasonable yield (72%),
but the reaction was slow. On the other hand, catalytic
Bu4NþFꢀ in THF mediated O-silyl deprotection of 8
proceeded quite efficiently to furnish alcohol 9 in 85%
yield.11
Swern oxidation12 of compound 9 directly produced
compound 2 in 73% yield, suggesting that the b-O-mesyl
group was eliminated during the triethylamine quench-
3.1. ())-(2S,3R,4R,5S)-2,3,4-Tribenzyloxy-5-(tert-butyl-
dimethylsilyloxy)cyclohexanone (5)
ing of the oxidation mixture. Compound 2 exhibited ½aꢁ
tert-Butyldimethylsilyl chloride (697 mg; 4.62 mmol) was
added to a stirred soln of ())-(2S,3R,4S,5S)-2,3,4-tri-
benzyloxy-5-hydroxycyclohexanone (3) (1.0 g, 2.31mmol)
in DMF (4.6 mL), under argon atmosphere, and imid-
azole (773 mg, 11.36 mmol) at room temperature and the
mixture was allowed to react for 9 h, when monitoring
by TLC showed completion. The mixture was then
poured into a separatory funnel containing crushed ice,
water and diethyl ether. The organic layer thus obtained
was washed with brine and then dried and concentrated
under diminished pressure. Silica gel chromatography
[1:1 EtOAc–hexane] gave 5 as a colourless oil, which
solidified (1.25 g, 2.28 mmol, 99%); mp 39.0–41.0 °C;
D
)64.7, a rotation very similar but opposite in sign to that
of the known (+)-isomer. The synthesis of ketone 1 was
completed by combined hydrogenation and hydro-
genolysis of the protected 2 by hydrogen transfer from
cyclohexene, which resulted in simultaneous O-benzyl
deprotection and double bond reduction, to give the
desired product in 86% yield.
3. Experimental
1H NMR spectra were recorded at 300 or 400 MHz on a
Bruker DPX300 FT or Bruker DRX 400FT spectro-
meters, respectively, in CDCl3 unless stated otherwise,
with Me4Si as internal standard. 13C NMR spectra were
similarly recorded at 75 or 100 MHz on a Bruker
DPX300 FT or Bruker DRX 400FT spectrometers, re-
spectively. Coupling constants (J values) are given in
Hz. Where appropriate, signal assignments were de-
½aꢁ )11.4° (c 1, CH2Cl2). IR (cmꢀ1/film) mmax 1735
D
(C@O); 1254 [Si(Me)2]; 1107 (SiO); 836 [Si(Me)3]; 777
1
(SiO). H NMR (300 MHz): d 0.06 (s, 6H, Si(CH3)2);
0
0
0.87 (s, 9H, SiC(CH3)3); 2.42 (dd, 1H, J6;6 11.8, J5;6
2.5 Hz, H-60); 2.51 (dd, 1H, J5;6 4.1 Hz, H-6); 3.68 (dd,
1H, J4;5 2.2, J3;4 8.5 Hz, H-4); 4.01 (d, 1H, J2;3 9.3 Hz H-
2); 4.08 (br t, 1H, H-3); 4.31 (m, 1H, H-5); 4.58, 4.94 (2d,
each 1H, JAB 11.7 Hz, PhCH2O); 4.75 (s, 2H, PhCH2O),
4.83, 4.88 (2d, each 1H, J 10.8 Hz, PhCH2O) 7.25–7.39
(m, 15H, ArH). 13C NMR (75 MHz): d )5.09; )4.58
(Si(CH3)2); 18.11 (SiC(CH3)3); 25.71 (SiC(CH3)3); 45.11
(C-6); 67.90 (C-5); 73.11 (PhCH2O); 73.49 (PhCH2O);
75.75 (PhCH2O); 81.89 (C-3); 82.30 (C-4); 85.79 (C-2);
127.67; 127.79; 128.22; 128.38; 128.43 (Ar-C); 138.5,
138.3, 138.2 (Ar-Cq); 203.8 (CO); Anal. Calcd for
C33H42O5Si: C, 72.49; H, 7.74. Found: C, 72.46; H, 8.09.
m=z (EI) Found: [M]þ 546.1, C33H42O5Si, requires
546.28.
1
duced by DEPT 135, COSY H–1H NMR experiments.
Optical rotations were measured at ambient temperature
with a Schmidt Haensch Polartronic HH8 polari-
meter for solns in CHCl3 unless stated otherwise and ½aꢁ
D
values are given in 10ꢀ1 degꢂcm2ꢂgꢀ1. IR spectra were
ꢀ ꢀ
recorded on a Nicolet Protege FT460 spectrophotome-
ter. Low resolution mass spectra and elemental analyses
were performed by Mr. A. W. R. Saunders at the Uni-
versity of East Anglia. TLC was performed on silica gel
(E. Merck) SIL G-25UV254 and compounds on devel-
oped plates were detected either by viewing with a UV
lamp (254 nm), or by spraying with a 10% sulfuric acid,
1.5% molybdic acid, 1% ceric sulfate spray followed by
heating to 150 °C. Column chromatography was per-
formed on Kieselgel 60 (70–230 mm mesh, E. Merck).
Where mixed solvents were used, the ratios given are in
v/v. Tetrahydrofuran and diethyl ether were pre-dried
by storage over sodium wire and obtained anhydrous by
distillation from sodium metal and benzophenone once
the blue colouration due to the ketyl radical had been
3.2. (+)-(1R,2R,3S,4R,5S)-2,3,4-Tribenzyloxy-5-(tert-
butyldimethylsilyloxy)cyclohexanol (7)
())-(2S,3R,4R,5S)-2,3,4-Tribenzyloxy-5-(tert-butyldi-
methylsilyloxy)cyclohexanone (5) (390 mg, 0.714 mmol)
was dissolved in methanol (2 mL) and to the cooled soln
(4 °C) NaBH4 (39 mg) was added portionwise. The
mixture was stirred for 10 min at 4 °C and then 24 h at

364
I. Carvalho, E. B. de Melo / Carbohydrate Research 339 (2004) 361–365
room temperature. TLC [1:4 EtOAc–hexane] indicated
the reaction was complete and the soln was concentrated
and the mixture was partitioned between water and di-
ethyl ether. The organic phase was separated, the aq
layer further extracted with ether, and the combined
organic extracts were dried and concentrated under di-
minished pressure to give a white solid that was chro-
matographed [1:4 EtOAc–hexane] to yield the
compound 7 as a colourless crystals (302 mg, 0.55 mmol,
C34H46O7SSi: C, 65.14; H, 7.40. Found: C, 65.32; H,
7.62. m=z (EI) Found: [M)C7H7]þ 535.1; C27H39O7SSi,
requires 535.22.
3.4. ())-(1S,2S,3R,4S,5R)-2,3,4-Tribenzyloxy-5-
mesyloxycyclohexanol (9)
Method A: Compound 8 (214 mg; 0.34 mmol) was added
to a mixture of 3:1:1 AcOH–water–THF (7.0 mL). After
being stirred 8 days at room temperature, the mixture
was concentrated and the residue partitioned between
water and diethyl ether. The separated aq layer was
further extracted with diethyl ether and the combined
organic phases were dried, concentrated and the residue
was purified by silica gel column chromatography
[2:3 EtOAc–hexane] to give the compound 9 as an oil
that spontaneously crystallized on storage at 4 °C
77%); mp 90.0–92.0 °C; ½aꢁ +5.2° (c 1, CH2Cl2). IR
D
(cmꢀ1/film) mmax 3480 (OH). 1H NMR (300 MHz): d 0.07
(s, 6H, Si(CH3)2); 0.89 (s, 9H, SiC(CH3)3); 1.43 (dt, 1H,
0
0
0
J6;6 14.8, J1;6 ¼ J5;6 2.5 Hz, H-6); 2.14 (dt, 1H, J5;6 ¼ J1;6
3.7 Hz, H-60); 3.29 (dd, 1H, J4;5 2.7, J3;4 9.3 Hz, H-4);
3.35 (dd, 1H, J1;2 3.3, J2;3 9.3 Hz, H-2); 4.08 (m, 2H, H-5,
OH); 4.15 (t, 1H, H-3); 4.26 (m, 1H, H-1); 4.68, 4.77 (2d,
each 1H, JAB 11.8 Hz, PhCH2O); 4.74 (s, 2H, PhCH2O);
4.85, 4.95 (2d, each 1H, JAB 10.7 Hz, PhCH2O); 7.24–
7.40 (m, 15H, ArH). 13C NMR (75 MHz): d )4.57, )5.44
(Si(CH3)2); 18.14 (SiC(CH3)3); 25.78 (SiC(CH3)3); 33.32
(C-6); 68.62 (C-5); 71.68 (C-1); 72.32 (PhCH2O); 73.78
(PhCH2O); 75.92 (PhCH2O); 79.14 (C-3); 82.59 (C-2);
83.23 (C-4); 127.56, 127.65, 127.66, 127.86, 127.95,
128.05, 128.09, 128.11, 128.13, 128.23, 128.30, 128.32,
128.32, 128.38, 128.41, 128.43 (Ar-C); 138.68, 139.07
(Ar-Cq); Anal. Calcd for C33H44O5Si: C, 72.22; H, 8.08.
Found: C, 72.38; H, 8.20. m=z (EI) Found: [M]þ 548.2,
C33H44O5Si, requires 548.30.
(126 mg, 0.25 mmol, 72%); mp 161.0–163.0 °C; ½aꢁ
D
)26.3° (c 1, CH2Cl2). IR (cmꢀ1/film): 3510 (OH). H
1
NMR (300 MHz): d 1.63 (dt, 1H, J6;6 15.0 Hz, H-60);
0
2.39 (dt, 1H, J5;6 5.1 Hz, H-6); 2.93 (s, 3H, CH3SO2–);
3.39 (dd, 1H, J1;2 3.5 Hz, J2;3 8.1 Hz, H-2); 3.48 (dd, 1H,
J4;5 2.7 Hz, J3;4 8.0 Hz, H-4); 3.95 (t, 1H, H-3); 4.01 (m,
1H, H-1); 4.55, 4.60 (2d, each 1H, J 11.7 Hz, PhCH2O);
4.66 (s, 2H, PhCH2O); 4.66, 4.72 (2d, each 1H, J
11.7 Hz, PhCH2O); 5.02 (m, 1H, H-5); 7.18–7.28 (15H,
m, ArH). 13C NMR (75 MHz): d 31.41 (C-6); 38.84
(CH3SO2–); 66.38 (C-1); 72.60 (PhCH2O); 73.25
(PhCH2O); 75.11 (PhCH2O); 77.27 (C-3, C-5); 78.83 (C-
4); 80.72 (C-2); 127.76, 127.81, 127.92, 128.05, 128.14,
128.39, 128.46, 128.49 (Ar-C); 137.66, 137.87, 138.26
(Ar-Cq). Anal. Calcd for C28H32O7S: C, 65.60; H, 6.29.
Found: C, 65.90; H, 6.63. m=z (EI) found: [M+H2O]þ
530.2; C28H34O8S, requires 530.20.
Method B: A soln of 8 (200 mg, 0.32 mmol) in tetra-
hydrofuran (4 mL) was treated with 1.0 M soln of tetra-
n-butylammonium fluoride in tetrahydrofuran (0.15 mL).
The reaction mixture was stirred at room temperature
for 3 h, when monitoring by TLC [2:3 EtOAc–hexane]
showed completion. The soln was dried, concentrated
and the residue was subjected to silica gel column
chromatography [EtOAc–hexane (2:3)] to give the title
compound 9 (138 mg, 0.27 mmol, 85%).
3.3. (+)-(1S,2R,3R,4S,6R)-1,2,3-Tribenzyloxy-4-tert-
butyldimethylsilyloxy-6-mesyloxycyclohexane (8)
(+)-(1R,2R,3S,4R,5S)-2,3,4-Tribenzyloxy-5-(tert-butyl-
dimethylsilyloxy)cyclohexanol (7) (271 mg, 0.49 mmol)
was dissolved in pyridine (4.2 mL), and mesyl chloride
(0.1 mL; 1.32 mmol) and DMAP (8.4 mg) were added.
The mixture was allowed to react for 8 h, when moni-
toring by TLC [3:7 EtOAc–hexane] showed completion.
The reaction was quenched with crushed ice and the
product extracted with diethyl ether, dried over MgSO4
and concentrated. The residue was purified by silica gel
column chromatography [3:7 EtOAc–hexane] to give 8
as an oil (269 mg, 0.43 mmol, 87%); ½aꢁ +3.0° (c 1,
D
CH2Cl2). IR (cmꢀ1/film): 1352, 1174 (S@O); 900 (S–O).
1H NMR (300 MHz): d 0.09 (s, 6H, Si(CH3)2); 0.94 (s,
3.5. ())-(2R,3S,4R)-2,3,4-Tribenzyloxycyclohex-5-enone
(2)
9H, SiC(CH3)3); 1.70 (d, 1H, J5;5 14.3 Hz, H-50); 2.38 (d,
0
1H, H-5); 2.92 (s, 3H, CH3SO2–); 3.36 (d, 1H, J 5.7 Hz,
H-3); 3.56 (br s, 1H, H-1); 4.06 (t, 1H, H-2); 4.18 (m,
1H, H-4), 4.65–4.78 (m, 6H, PhCH2O); 5.13 (br s, 1H,
H-6); 7.30–7.36 (m, 15H, ArH). 13C NMR (75 MHz):
d )4.77, )4.88 (Si(CH3)2); 18.20 (SiC(CH3)3); 25.94
(SiC(CH3)3); 33.42 (C-5); 38.79 (CH3SO2–); 68.09 (C-4);
73.25 (PhCH2O); 73.70 (PhCH2O); 74.98 (PhCH2O);
77.26 (C-2); 77.40 (C-6); 79.66 (C-1); 81.74 (C-3); 127.56,
127.81, 127.95, 128.33, 128.38, 128.49, 128.52 (Ar-C);
138.10, 138.58, 138.88 (Ar-Cq); Anal. Calcd for
A soln of oxalyl chloride (42 mg, 0.03 mL, 0.324 mmol)
in CH2Cl2 (0.8 mL) was cooled to )78 °C and dimethyl
sulfoxide (63 mg, 0.06 mL, 0.803 mmol), in CH2Cl2
(0.3 mL) was added dropwise from a syringe over 5 min.
The mixture was then stirred for 10 min at )78 °C and
then the mesylate 9 (96 mg, 0.187 mmol), dissolved in
CH2Cl2 (0.3 mL) was added dropwise over 5 min. Stir-
ring was continued at )78 °C for 30 min after which
triethylamine (1.6 mL, 11.6 mmol) was added. After 2 h

I. Carvalho, E. B. de Melo / Carbohydrate Research 339 (2004) 361–365
365
0
the cooling bath was removed and water (3.6 mL) was
added at room temperature. Stirring was continued for
10min and the organic layer was then separated. The aq
phase was extracted with CH2Cl2 (3ꢃ5 mL) and the
combined organic layers were washed successively with
brine (5 mL), 1% aq HCl (5 mL), water (4 mL), 5% aq
Na2CO3 (5 mL) and water (4 mL). The soln was dried,
concentrated and the residue was subjected to silica gel
column chromatography [3:7 EtOAc–hexane] to give the
title compound 2 as white crystals (57 mg, 0.137 mmol,
(ddd, 1H, J6;6 14.5 Hz, H-60); 2.54 (ddt, 1H, J2;6 1.2 Hz,
H-6); 3.25 (dd, 1H, J2;3 9.8, J3;4 9.0 Hz, H-3); 3.81 (ddd,
1H, H-4); 4.04 (dd, 1H, H-2). 13C NMR (100 MHz,
CD3OD) d 29.97 (C-5); 36.52 (C-6); 72.55 (C-4); 79.43
(C-2); 80.95 (C-3); 209.14 (CO). Anal. Calcd for
C6H10O4: C, 49.31; H, 6.90. Found: C, 49.74; H, 7.09.
Acknowledgements
73%); mp 61.4–63.0 °C, lit.6a 61–62 °C; ½aꢁ )64.7° (c 1,
We thank FAPESP (Brazil) for financial support and
ꢀ
Dr. Alan H. Haines and Prof. Dr. Maurıcio Gomes
Constantino for valuable comments on this article.
D
CH2Cl2), lit.6a for enantiomer ½aꢁ +64° (c 1, CH2Cl2).
D
IR (cmꢀ1/film): 1700 (C@O conjugated to C@C), 1610
1
(C@C). H NMR (300 MHz): d 3.96 (dd, 1H, J2;3 10.7,
J3;4 7.7 Hz, H-3); 4.04 (d, 1H, H-2); 4.36 (dt, 1H, J4;5
2.3 Hz, H-4); 4.73, 4.82 (2d, each 1H, J 11.5 Hz,
PhCH2O); 4.74, 5.08 (2d, each 1H, J 11.3 Hz, PhCH2O);
4.80, 4.96 (2d, each 1H, J 10.9 Hz, PhCH2O); 6.03 (dd,
1H, J5;6 10.4, J4;6 2.3 Hz, H-6); 6.80 (dd, 1H, H-5); 7.25–
7.44 (15H, m, ArH). 13C NMR (75 MHz): d 71.74
(PhCH2O); 72.65 (PhCH2O); 73.84 (PhCH2O); 78.88 (C-
3); 83.76 (C-4); 84.62 (C-2); 125.99, 126.04, 126.13,
126.25, 126.31, 126.42, 126.60, 126.77 (Ar-C, C-6);
135.84, 136.00, 136.41 (Ar-Cq); 146.29 (C-5); 195.73
(CO); Anal. Calcd for C27H26O4: C, 78.24; H, 6.32.
Found: C, 78.14; H, 6.52. m=z (EI) Found: [M)C7H7]þ
323.1; C20H19O4, requires 323.13.
References
€
1. Dalko, P. I.; Sinay, P. Angew. Chem., Int. Ed. 1999, 38,
773–777.
2. Billington, D. C.; Perron-Sierra, F.; Picard, I.; Beaubras,
S.; Duhault, J.; Espinal, J.; Challal, S. Bioorg. Med. Chem.
Lett. 1994, 4, 2307–2312.
3. Sleight, S.; Wilson, B. A.; Heimark, D. B.; Larner, J.
Biochem. Biophys. Res. Commun. 2002, 295, 561–569.
4. Yu, L.; Cabrera, R.; Ramirez, J.; Malinovskii, V. A.;
Brew, K.; Wang, P. G. Tetrahedron Lett. 1995, 36, 2897–
2900.
5. Falshaw, A.; Hart, J. B.; Tyler, P. C. Carbohydr. Res.
2000, 329, 301–308.
6. (a) McAuliffe, J. C.; Stick, R. V. Aust. J. Chem. 1997, 50,
193–196; (b) Semeria, D.; Philippe, M.; Delaumeny,
J.-M.; Sepulchre, A.-M.; Gero, S. D. Synthesis 1983,
710–713; (c) Miyazaki, H.; Kobayashi, Y.; Shiozaki, M.
J. Org. Chem. 1995, 60, 6103–6109.
3.6. (+)-(2R,3S,4R)-2,3,4-Trihydroxycyclohexanone (1)
A soln of ())-(2R, 3S,4R)-2,3,4-Tribenzyloxycyclohex-5-
enone (2) (100 mg, 0.24 mmol) in cyclohexene–ethanol
(2:1, 7.0 mL) was stirred in the presence of Pd-black
catalyst (35 mg) at 80 °C for 4 h, when TLC showed the
disappearance of the starting material. The mixture was
filtered through a Celite pad and the filtrate was con-
centrated to afford a solid, which was, washed with di-
ethyl ether and the residue dried under diminished pressure
to gave the title compound 1 (30 mg, 0.20 mmol, 86%);
7. Posternak, Th.; Reymond, D. Helv. Chim. Acta 1955, 38,
195–205.
8. Heyl, F. W.; Herr, M. E. J. Am. Chem. Soc. 1953, 75,
1918–1920.
9. Coulter, J. M.; Lewis, J. W.; Lynch, P. P. Tetrahedron
1968, 24, 4489–4500.
10. Dauben, W. G.; Fonken, G. J.; Noyce, D. S. J. Am. Chem.
Soc. 1956, 78, 2579–2582.
11. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
94, 6190–6191.
12. Haines, A. H. Methods for the Oxidation of Organic
Compounds, Alcohols, Alcohol Derivatives, Alkyl Halides,
Nitroalkanes, Alkyl Azides, Carbonyl Compounds, Hydrox-
yarenes and Aminoarenes; Academic Press: London, 1988;
p 117.
½aꢁ +4.6° (c 0.5, MeOH). IR (cmꢀ1/film): 3380 (OH),
D
1722 (C@O). 1H NMR (400 MHz/CD3OD) d 1.48
0
0
(dddd, 1H, J5;6 4.5, J4;5 11.3, J5;5 13.2, J5;6 14.5 Hz, H-5);
2.12 (dddd, 1H, J5 ;6 2.8, J5 ;4 4.8, J5 ;6 6.1 Hz, H-50); 2.34
0
0
0
0