An expeditious approach to trisubstituted chiral tetrahydrofurans

Article abstract of DOI:10.1515/znb-2000-3-413

Ozonolysis of 3,6-anhydro-4-O-(p-toluenesulphonyl)-D-glucal (9), obtained in four steps from D-glucose, provided the target compound 11. The structure and configurations of 9 and 11 have been determined by spectral studies and X-ray crystallography. Simil

Full text of DOI:10.1515/znb-2000-3-413

An Expeditious Approach to Trisubstituted Chiral Tetrahydrofurans
Fazila Iqbal3, M oham m ed Saleh Shekhani3*, A bdul M alik3 *, M asood Parvezb,
U zm a R iaz3, Zulfiqar A li3, and K halid M oham m ed K han3
a HEJ Research Institute of Chemistry, University of Karachi, Karachi 75270 Pakistan
b Department of Chemistry University of Calgary, 2500-University Drive N.W; Calgary,
Alberta Canada T2 N 1N4
Reprint request to Prof. Dr. A. Malik. E-mail: hejric@digicom.net.pk and hej@digicom.net.pk
Z. Naturforsch. 55b, 317-320 (2000); received September 20, 1999
Chiral Tetrahydrofurans, Asymmetric Synthesis, D-Glucose, D-Galactose
Ozonolysis of 3,6-anhydro-4-0-(/?-toluenesulphonyl)-D-glucal (9), obtained in four steps
from D-glucose, provided the target compound 11. The structure and configurations of 9 and
11 have been determined by spectral studies and X-ray crystallography. Similar strategy with
D-galactose provided the corresponding derivatives 10 and 12, respectively.
Introduction
Results and Discussion
F ive-m em bered oxygen heterocycles which are
the m ost com m on structures in biologically active
com pounds have been isolated from a variety of
terrestrial and m arine sources. The stable form of
m any sugars, including antineoplastic and antiviral
agents, contain polyhydroxylated tetrahydrofu-
rans. The entire class of com pounds called ino-
phores [1 ] and annonaceous acetogenins [2 ], in-
clude at least one tetrahydrofuran ring. The
polyether antibiotics have attracted considerable
attention because of their ion chelating ability to
transport m etal ions across lipid bilayers [1,3].
N aturally occurring com pounds having polysubsti-
tuted tetrahydrofuran rings display a wide range
of biological activities including antim icrobial, cy-
totoxic, antitum or, antim alarial, antifeedant, pesti-
cidal and im m unosuppressive effects [4,5], Thus,
there is a current interest in the synthesis of this
class of com pounds [5]. Synthetic m ethods which
w ould afford these com pounds bearing chem odif-
ferentiable substituents in optically pure form are
relatively few. Thus, highly flexible and short syn-
thesis of chiral polysubstituted tetrahydrofurans
bearing functionalized side chains rem ain elusive.
H erein we describe a short and novel asym m etric
synthesis of trisubstituted chiral tetrahydrofurans
11 and 12 using the cheap and readily available D-
glucose and D -galactose as the staring m aterial.
Synthesis of D-glucal (7) is achieved from D-
glucose (1 ), which upon treatm ent with acetic an-
hydride and perchloric acid in the presence of red
phosphorus follow ed by the dropw ise addition of
brom ine at -2 0 °C affords 2,3,4,6-tetra-O -acetyl-
a-D -brom oglucopyranoside (3) [7] in 91% yield,
m.p. 8 8 -8 9 °C. It is converted into tri-O -acetyl-D -
glucal (5) [7] after reduction w ith zinc in the pres-
ence of sodium acetate. H ydrolysis of 5 by using a
m ixture of m ethanol-w ater-triethylam ine (5:4:1)
[8 ] provides D-glucal (7) in 80% yield (Schem e 1).
We discovered that successive treatm ent of 7
with excess of N aH and 2.5 equivalents of p-tolu-
enesulphonylim idazole in D M F affords the bicy-
clic com pound
9
as
a
crystalline product
(Schem e 1). Its structure is established by spectro-
scopic m ethods and further confirm ation is p ro-
vided by single crystal X -ray crystallographic
analysis. The com pound 9 can be perceived as con-
cealed trisubstituted chiral tetrahydrofuran which
will be unraveled upon cleavage along the carbon-
carbon double bond. The com pound 9 is subjected
to ozonolysis under a variety of tem perature and
solvent conditions. In m ost cases it yields com pli-
cated m ixture of several products. A fter num ber
of attem pts it was finally discovered that the ozo-
nolysis is best carried out in dichlorom ethane at -
90 °C, and if the resulting product is im m ediately
subjected to sodium borohydride reduction, a sin-
gle crystalline product 11 is obtained. The
spectrospcopic analysis as well as single crystal X-
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D
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318
F. Iqbal et al. ■A n E xpeditious A pproach to Trisubstituted C hiral T etrahydrofurans
1) CH3COOH, CH3COONa
CUSO4, Zn, 0°C
2) Na2C03>MeOH
3 Ri=OAc, RrH
1 Ri=OH, R2=H
4
R != H ,
R ,= O A c
2 Rj=H, R2=OH
1) O3, CH2C12,-90oC
2) S(CH3)2,NaBH4, 0°C
OH
HO
5 Ri=R3=OAc, R^ h
6 Ri=H, R2=R3=OAc
11 R=a OT s
12 R=ß OT s
9 Ri=OTs,I%=H
10 Ri=H, I^=OTs
7 Ri=R3=OH, %=H
8 Rj=H R2=R3=OH
Scheme 1.
Fig. 1. X-ray diagram (ORTEP) of compound 9. The
configuration shown is orbitarily selected based on the
known sterochemistry of D-glucal.
Fig. 2. X-ray diagram (ORTEP) of compound 11. The
configuration shown is orbitarily selected based on the
known stereochemistry of D-glucal.
ray crystallographic data confirm ed the structure
of target com pound 11. The com puter draw n p e r-
spective of com pounds 9 and 11 are show n in Fig-
ures 1 and 2 .
Experimental
IR spectra were recorded in CHC13 on Shi-
m adzu IR-460 spectrom eter. The ‘H -N M R (400
and 300 M Hz) and 13C N M R (100 and 75 M Hz)
spectra were recorded on B ruker AM -400 or
B ruker AM -300 spectrom eters with CDC13 as a
The 3ß-epim er 12 was obtained from D -galactal
8. obtained from D -galactose 2, following sim ilar
m ethodology as for 11 (Schem e 1).
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319
F. Iqbal et al. • A n E xpeditious A pproach to Trisubstituted C hiral T etrahydrofurans
6.21 (1H, d, 7=5.6 Hz, 1-/7), 5.23 (1H , br. s, 4-H),
4.91 (dd, 1H, 7=6.3, 5.6 Hz, 2-77), 4.53 (1H, br. d,
7=4.0 Hz, 5-77), 4.23 (1H, d, 7=10.8 Hz, 6-77), 4.20
(1H, d, 7=6.3 Hz, 3-/7), 4.13 (1H, dd, 7=10.8, 4.0
Hz, 6'-H), 2.46 (3H, s, C //3); 13C N M R (C D C I3, 75
M H z): (3 145.2 (C -l), 145.3, 130.5 (A rC ), 130.1,
127.9 (A rC H ), 101.6 (C-2), 79.4 (C-5), 77.5 (C-4),
73.9 (C-6 ), 71.8 (C-3), 21.7 (C H 3); IR (C H C I3),
vmax: 3020,1630, 1580, 1360, 1180 cm "1; H RM S: m /
z 282.05616 (M )+ (C n H 14O sS requires 282.05619).
solvent. The chem ical shifts are in ppm from in-
ternal TMS. O ptical rotations were m easured on a
Schm idt and H aensch Polartronic D polarim eter.
M ass spectra w ere obtained either on a MAT-312
or on a JE O L JM S-H X 110 instrum ent. M elting
points w ere determ ined on Btichi 535 m elting
point apparatus and are uncorrected. A nalytical
TLC was carried out on precoated M erck silicagel
60 F254 (0.25 m m thickness) plates Flash chrom a-
tography was perform ed on silica gel 60 (70-230
m esh). T H F was distilled from sodium benzophe-
none ketyl just before use. D ichlorom ethane, pyri-
dine, D M F w ere distilled on C aH 2. All reactions
w ere executed in flam e-dried glassware under an
atm osphere of dry argon.
General procedure for the preparation o f
tetrahydrofurans 11 and 12
A
solution of 9 (1 m m ol, 0.282 g) in dichloro-
m ethane (30 ml) was cooled to -9 0 °C and ozone
was bubbled through the solution until it devel-
oped a light-blue color. D im ethylsulfide (1 ml) was
added to the reaction m ixture. It was w arm ed to
rt and evaporated in vacuo. The residue was dis-
solved in ethanol (10 ml), and cooled to 0 °C. To
this cooled solution was added a solution of so-
dium borohydride (1 m m ol, 0.032 g) in w ater
(5 m l), with constant stirring. A fter 2 m in, the so-
lution was neutralized by addition of glacial acetic
acid. A fter partial concentration in vacuo, the mix-
ture was lyophilized and the residue repeatedly
extracted with hot ethyl acetate. The solution so
obtained was evaporated in vacuo and purified by
flash chrom atography using hexane-ethyl acetate
(50:50) to afford pure 11 (white solid) and 12 (col-
orless oil).
General procedure for the preparation o f bicyelie
compounds 9 and 10
To
a
suspension of oil-free N aH (4 mmol,
0.096 g) in anhydrous D M F (6 ml) under argon at
5 °C was added a solution of D-glucal (1 mmol,
0.146 g) in D M F (10 ml) and the m ixture was
stirred at rt for 30 min. It was diluted with D M F
(15 m l), cooled to -2 5 °C and treated with a solu-
tion of /?-toluenesulphonylim idazole (2.5 mmol,
0.555 g) in D M F (15 ml). The m ixture was stirred
at -2 5 °C for 1 h and further at 5 °C for 12 h. The
reaction was quenched with moist ether, filtered
through a bed of celite, repeatedly w ashed with
w ater, dried (N a2S 0 4), concentrated and purified
by flash chrom atography using either hexane-chlo-
roform (1:9) or hexane-ethyl acetae (85:15) as
eluent. The resulting product was recrystallized
from C H C l3-hexane to afford pure 9 and 10 as
w hite crystalline solid.
(2R,3R,4R)-2-Hydroxymethyl-3-0-tosyl-4-
hydroxy-tetrahydrofuran (11):
84% ; m.p. 7 6 -
78 °C; ' [ ö ] d
=
+10° (c=0.4, CHC13); >H N M R
(CDCI3, 300 M Hz): (3 7.82 (2H , d, 7=8.4 H z, A r/7),
7.34 (2H, d, 7=8.4 Hz, A r//), 5.01 (1H, dd, 7=6.9,
5.0 Hz, 3 -//), 4.22 (1H, dt, 7=5.0, 4.0 Hz, 2-H), 4.11
(1H, td, 7=6.9, 4.2 Hz, 4-H), 3.86 (1H, dd, 7=9.9,
4.2 H z, 5 -//), 3.80 (1H , dd, 7=9.9, 4.2 Hz, 5’-//),
3.75 (1H, dd, 7=12.1, 4.2 Hz, 6 -//), 3.66 (1H, dd,
3.6-Anhydro-4-0-(p-toluenesulfonyl)-D-glucal
(9): 75% ; m.p. 5 7 -5 8 °C; [a ß 5
= + 9.0° (c=l,
CHC13); lH N M R (C D C I3, 400 M Hz): d 7.82 (2H,
d, 7=8.4 H z, A rH), 7.36 (2H, d, 7=8.4 Hz, A rH),
6.41 (1H , d, 7=5.7 Hz, 1-//), 4.88 (1H, dt, 7=5.7,
1.4 Hz, 2-H), 4.69 (1H, ddd, 7=5.7, 3.9, 1.4 Hz, 4- 7=12.1, 4.2 Hz, 6 ’-//), 2.45 (3H, s, C//3); 13C N M R
H), 4.44 (1H , t, 7=3.9 Hz, 5-7/), 4.18 (1H, d, 7=11.1
Hz, 6-77), 4.11 (1H , dd, 7=11.1, 3.9 Hz, 6’-77), 4.06
(1H, t, 7=5.7 Hz, 3-77), 2.45 (3H, s, C //3); 13C N M R
(C D C I3, 100 M H z): <3 146.3 (C -l), 146.4, 130.4
(A rC), 130.0, 128.0 (A rC H ) , 99.5 (C-2), 74.3 (C-
6 ), 73.9 (C-5), 70.5 (C-4), 67.2 (C-3), 21.7 (C H 3);
IR (C H C I3), vmax: 3030, 1620, 1590, 1350, 1180
c m -1; H R M S: m /z 282.05617 (M )+ (C 13H 140 5S re-
quires 282.05619).
3.6-Anhydro-4-0-(p-toluenesulphonyl)-D-galac-
tal (10): 78% ; m.p. 8 2 -8 3 °C; [a ]^ = -3 8 ° (c=0.22,
C H C I3); 'H N M R (C D C I3, 400 M Hz): 6 7.81 (2H,
d, 7=8.3 Hz, A r/7), 7.31 (d, 2H, 7=8.3 Hz, A r/7).
(C D C L, 75 M H z): (3 145.6, 129.8 (A rC ), 130.1,
128.0 (A rC H ), 79.2 (C-4), 78.2 (C-3), 72.4 (C-5),
70.3 (C-2), 60.7 (C-6 ), 21.6 (q, C H 3); Positive FAB-
H RM S: m/z 289.07455 (M + H )+ (C 12H 170 6S re-
quires 289.07458).
(2R,3S,4R)-2-Hydroxymethyl-3-0-tosyl-4-
hydroxy-tetrahydrofuran (12): 80% ; [oc]d
= -56°
(c=0.22, CHCI3); ]H N M R (CDCI3, 400 M Hz): (3
7.77 (2H , d, 7=8.3 H z, A r//), 7.35 (2H , d, 7 = 8.3
Hz, A r//), 4.71 (1H, br. s, 3 -//), 4.21 (1H , br. s, 2-
H), 4.01 (1H, q, 7=2.7 Hz, 4-H), 3.89 (2H , d, 7=2.7
Hz, 5-H), 3.73 (1H , dd, 7=11.9, 2.8 H z, 6-H), 3.57
(1H, dd, 7=11.9, 2.7 Hz, 6 ’-//), 2.44 (s, C //3); 13C
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320
F. Iqbal et al. ■A n E xpeditious A pproach to T risubstituted C hiral T etrahydrofurans
P 21212 1), with unit cell param eters a - 9.647(3),
b = 19.103(7), c = 6.963(2) A , V = 1283.2(6) A 3,
Z = 4, D x = 1.492 g cm “3, p = 2.72 c irr \ F(000) =
608.867 observed reflections [/> 3 .0 0 6 a (I)] w ere
N M R (C D C I3, 125 M Hz): <3 145.7, 133.2 (A rC ),
130.1, 127.9 (A rC H ), 85.8 (d, C-3), 83.6 (d, C-2),
75.2 (C-4), 74.2 (C-5), 61.5 (C -6 ), 21.7 (C H 3); IR
(CHCU), r max: 3070, 1625, 1350, 1170 c m -1; Posi-
tive
FA B -H R M S:
m /z
289.07456
(M + H )+ used for refinem ent; R = 0.038 and R w = 0.037.
(C i2H 170 6S requires 289.07458).
In order to establish the absolute configuration
Crystaliographic data for com pounds 9 and 11
w ere collected on a R igaku A F C 6 S diffractom eter
with graphite m onochrom atized M o-K a radiation
(A = 0.71069 A ). The structure of 9 (C ^H ^O ^S ,
Mw. 282.31) was determ ined from an orthorhom -
bic crystal of dim ensions 0.65 x 0.50 x 0.30 mm
(space group P212 12 1), with unit cell param eters
a = 13.208(1), b = 15.975(1), c = 6.155(1) A , V =
of the two structures, parallel refinem ent of the
inverted structures were carried out tow ards the
end of the full-m atrix, least-squares calculations,
yielding Flack param eter [9] of -1.05(9) and
0.50(4) for C 13H 140 5S and C 12H 160 6S, respec-
tively, and were therefore, rejected as the absolute
structures present in the crystals; the Flack p aram -
eter for the structures reported in this paper
w ere -0.11(9) and -0.02(4), respectively. F u rth er
details of the x-ray structure determ ination are d e-
posited at the Cam bridge C rystallographic D ata
C entre (U. K.) and can be obtained by quoting the
num bers C C D C 137228 and C C D C 137229, the
authors and the citation.
1298.8(3) A 3, Z = 4, D x = 1.444 g cm “3,
= 2.62
cm -1, F(000) 592. 1045 observed reflections
=
[/> 3 .0 0 5 a (I)] w ere used for refinem ent; R = 0.034
and R w = 0.039.
The structure of 11 (C 12H 160 6S, Mw. 288.31)
was determ ined from an orthorhom bic crystal of
dim ensions 0.50 x 0.28 x 0.19 mm (space group
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