Investigation of an unexpected addition reaction that occurs when 2,3:4,5-di-O-isopropylidene-D-ribose diethyl dithioacetal is treated with mercuric oxide and mercuric chloride

Full text of DOI:10.1021/jo001782h

J . Org. Chem. 2001, 66, 4405-4408
4405
Notes
Treatment of the dithioacetal 1 with mercuric chloride
and yellow mercuric oxide in aqueous acetone (95:5) at
room temperature for 20 h afforded a crude product that
displayed a proton NMR spectrum with two peaks at δ
9.72 and 9.68, suggesting the presence of two compounds
that were both aldehydes. This mixture of products
proved to be extremely difficult to separate, and it was
therefore reduced with sodium borohydride in aqueous
ethanol to yield a mixture of alcohols that could be
separated chromatographically. The minor product, ob-
tained in 22% overall yield, could be assigned the
structure of 2,3:4,5-di-O-isopropylidene-D-ribitol (3) by
comparison of its spectral data with those reported
previously.1
The NMR and IR spectra of the major product, which
was obtained in 50% overall yield, were generally indica-
tive of what one would expect for an isopropylidenated
carbohydrate derivative, but they did not allow a definite
structural assignment. The low-resolution electrospray
ionization mass spectrum (ESIMS) run in the positive-
ion mode displayed a protonated molecular ion (M + H+)+
of m/z 463, while the ESIMS run in the negative ion mode
showed a deprotonated molecular ion (M - H+)- of m/z
461, indicating a molecular weight of 462. Since the
molecular weight of 3 is 232, the molecular weight 462
observed for the product would be consistent with a
compound formed from two molecules of 3 by covalent
bonding and loss of two protons.
In vestiga tion of a n Un exp ected Ad d ition
Rea ction Th a t Occu r s w h en
2,3:4,5-Di-O-isop r op ylid en e-D-r ibose Dieth yl
Dith ioa ceta l Is Tr ea ted w ith Mer cu r ic
Oxid e a n d Mer cu r ic Ch lor id e
Thota Sambaiah,† Phillip E. Fanwick,‡ and
Mark Cushman*,†
Department of Medicinal Chemistry and Molecular
Pharmacology, and Department of Chemistry,
Purdue University, West Lafayette, Indiana 47907
cushman@pharmacy.purdue.edu
Received December 26, 2000
A mixture of mercuric chloride and mercuric oxide in
aqueous acetone is commonly used to hydrolyze dithio-
acetals in di-O-isopropylidenated pentoses to afford the
corresponding aldehydes.1-5 For example, treatment of
2,3:4,5-di-O-isopropylidene-D-ribose diethyl dithioacetal
(1) with mercuric chloride and mercuric oxide in aqueous
acetone has been reported to provide the expected alde-
hyde 2 in 70% yield.1 In attempting to repeat this
reaction, we recently encountered an unexpected reaction
product in addition to 2. The structure and formation of
this novel reaction product are the subject of the present
paper.
To determine the structure of the product, attempts
were made to crystallize it for X-ray analysis. After
considerable effort, it was found that the compound could
be crystallized in colorless plates by dissolving it in a
minimum amount of methylene chloride and then adding
hexane. The crystals were suitable for X-ray crystal-
lography, and the resulting ORTEP drawing is provided
in the Supporting Information. The solid-state structure
and Fischer projection of the product can be represented
as two structures, both of which are labeled as “4”. The
solid state conformation of 4 is readily apparent from
examination of the stereodiagram shown in Figure 1,
which is programmed for walleyed (relaxed) viewing.
Figure 1 was generated using the Sybyl 6.6 program, and
the coordinates were obtained from X-ray crystallogra-
phy.
Deprotection of the product 4 was investigated under
acidic conditions. When treated with Amberlite IR-120
(H+) resin in refluxing aqueous acetone, the expected
carbohydrate derivative 5 was obtained in 97% yield.1
On the other hand, the primary alcohol present in
compound 4 was oxidized selectively in the presence of
the secondary alcohol with pyridinium chlorochromate
in methylene chloride to afford the corresponding alde-
(2) Cha, J . K.; Christ, W. J .; Kishi, Y. Tetrahedron Lett. 1983, 37,
* To whom correspondence should be addressed. Phone: 765-494-
1465. Fax: 765-494-6790.
3943-3946.
(3) Horton, D.; Varela, O. Carbohydr. Res. 1984, 134, 205-214.
† Department of Medicinal Chemistry and Molecular Pharmacology.
(4) Ramage, R.; MacLeod, A. M.; Rose, G. W. Tetrahedron 1991, 47,
‡ Department of Chemistry.
(1) Aslani-Shotorbani, G.; Buchanan, J . G.; Edgar, A. R.; Shahidi,
P. K. Carbohydr. Res. 1985, 136, 37-52.
5625-5636.
(5) Dondoni, A.; Marra, A.; Massi, A. J . Org. Chem. 1997, 62, 6261-
6267.
10.1021/jo001782h CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/23/2001

4406 J . Org. Chem., Vol. 66, No. 12, 2001
Notes
F igu r e 1. Stereodiagram generated from the X-ray coordinates obtained from compound 4. The figure is programmed for walleyed
(relaxed) viewing.
Sch em e 1
Sch em e 2
hyde 6. The structure of the product is consistent with
the m/z 483 peak observed for the sodium adduct (M +
Na+)+ in the ESIMS and with the one-proton aldehyde
1
singlet observed at δ 9.91 in the H NMR spectrum.
The product 4 obviously arises from sodium borohy-
dride reduction of the aldehyde 6 that is formed on
treatment of the protected ribose derivative 1 with
mercuric chloride and mercuric oxide in aqueous acetone.
Since the aldehyde 2 was also detected as a minor
reaction product, the question arises as to whether the
product 4 is formed from 2 by an aldol reaction involving
the mercuric enolate 7, followed by sodium borohydride
reduction. Although mercuric enolates are not common,
they have been documented in several reports,6,7 and
some of them involve addition of the mercuric enolate to
an aldehyde.8 For example, the well-known Ferrier
transformation of 6-deoxy-5-enopyranosyl compounds
(e.g. 8, Scheme 1) involves hydroxymercuration of the
double bond and fragmentation of the ring in the result-
ing intermediate 9 to afford the mercuric enolate 10,
which carries out an intramolecular nucleophilic addition
to the aldehyde to afford 11. By analogy, one can imagine
that intermolecular addition of the mercuric enolate 7
to the aldehyde 2, both of which could be formed from
the dithioacetal 1 in the presence of mercuric oxide and
mercuric chloride in aqueous acetone, would result in the
formation of the aldehyde 6, which would then be reduced
by sodium borohydride to yield the final product 4. To
further investigate this possibility, the aldehyde 2 was
subjected to the same reaction conditions as had been
applied to the dithioacetal 1, and this resulted in the
formation of the product 4 in 15% yield, as opposed to
the 50% yield of 4 starting from the dithioacetal 1. This
result shows that the aldehyde 6 does in fact form from
2 in the presence of mercuric chloride and mercuric oxide
in aqueous acetone, but the lower yield (15% vs 50%)
suggests that additional mechanistic pathways involving
sulfur-containing intermediates may be operating in the
addition reaction when the dithioacetal 1 is employed.
A possible mechanism for the participation of sulfur-
containing intermediates is outlined in Scheme 2. Reac-
tion of the dithioacetal 1 with mercuric chloride would
be expected to result in the formation of the complex 12
having a positively charged sulfur atom.9,10 Elimination
of a proton and (ethylthio)mercuric chloride would result
in the thioenol ether 13, which could undergo oxymer-
curation to afford the hemithioacetal 14.9,11-13 Reaction
(9) J ensen, J . L.; Maynard, D. F.; Shaw, G. R.; Smith, T. W., J r. J .
Org. Chem. 1992, 57, 1982-1986.
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N. G. J . Am. Chem. Soc. 1981, 103, 7727-7734.
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6756.
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(6) Matsui, S. Bull. Chem. Soc. J pn. 1987, 60, 1853-1865.
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3437.
(8) Paquette, L. A.; Annis, G. D.; Schostarez, H. J . Am. Chem. Soc.
1982, 104, 6646-6653.

Notes
J . Org. Chem., Vol. 66, No. 12, 2001 4407
of 14 with the aldehyde 2 would then afford intermediate
15. The hemithioacetal 15 would be expected to decom-
pose to the aldehyde 6, which would be reduced to the
corresponding alcohol 4 in the presence of sodium boro-
hydride. Alternatively, the hemiacetal 14 could decom-
pose to form the aldehyde 7,9,11 which could then react
to form 6 and then 4.
Since the mercuric chloride and mercuric oxide system
is used widely for the conversion of the dithioacetal
derivatives of di-O-isopropylidinated pentoses to the
expected aldehydo pentoses, and coupling products have
not been reported before, a limited scope of the present
coupling reaction might be expected.1-5 It was previously
reported that the treatment of 1 with mercuric chloride
and mercuric oxide in aqueous acetone affords a 70%
yield of 2, which does not agree with our present
observation.1 However, the exact volume of aqueous
acetone employed was not specified, and the reaction time
was provided as “overnight”, so it is difficult to make an
exact comparison. One would logically expect that the
coupling reaction observed here would be minimized in
a more dilute solution of the reactants.
Recent interest in the aldol reaction as an approach
to the synthesis of complex carbohydrates has focused
on aldolase-catalyzed reactions14-18 as well as on base-
catalyzed aldol reactions involving nonidentical reaction
partners.19-25 The latter approach has typically involved
the addition of a ketone enolate to an aldehyde,19,20,24,25
although enolates derived from aldehydes21 and esters22,23
have also been employed. Much less attention has been
given to aldol reactions starting from identical carbohy-
drate derivatives. The use of the mercuric chloride and
mercuric oxide system as employed here could therefore
potentially be a general method of carbohydrate coupling
that could be employed in the synthesis of novel carbo-
hydrate derivatives. However, preliminary studies on a
limited number of potential reactants suggest that the
method may not be wide in scope. Both the 2,5:3,4-di-O-
isopropylidenated dithioacetal derivative 16 of ribose,1
as well as the corresponding aldehydo ribose derivative
17,1 failed to provide any carbohydrate coupling product
when subjected to the mercuric chloride and mercuric
oxide system. Likewise, both the dithioacetal derivative
18 of xylose and the corresponding aldehydo sugar
derivative 19 did not yield any coupling product. In these
cases, the aldehydes 17 and 19 were recovered un-
changed, and the dithioacetals 16 and 18 were converted
cleanly to 17 and 19.1,26,27
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected. Proton
nuclear magnetic resonance spectra (1H NMR) were recorded
on 300 and 500 MHz spectrometers, as noted. The chemical shift
values are expressed in ppm (parts per million) relative to
tetramethylsilane as internal standard: s ) singlet, d ) doublet,
m ) multiplet, bs ) broad singlet. The 13C NMR spectra were
recorded at 75 MHz. Microanalyses were performed at the
Purdue Microanalysis Laboratory, and all values were within
(0.4% of the calculated compositions. Silica gel used for column
chromatography was 230-400 mesh. Compounds 1, 2, 3, 16, 17,
18, and 19 were prepared as described in the literature.1,26,27
[5-((4R)-2,2-Dim et h yl(1,3-d ioxola n -4-yl))(4R,5R)-4-h y-
d r oxym eth yl)-2,2-d im eth yl(1,3-d ioxola n -4-yl)][5-((4R)-2,2-
d im eth yl(1,3-d ioxola n -4-yl))(4S,5S)-2,2-d im eth yl(1,3-d ioxo-
la n -4-yl)](1S)-m eth a n -1-ol (4). The dithioacetal 1 (3.54 g, 10.5
mmol) in aqueous acetone (95:5, 30 mL) was stirred with yellow
mercuric oxide (8.37 g) while a solution of mercuric chloride (7.54
g, 27.4 mmol) in acetone (20 mL) was added dropwise. After
being stirred for 20 h, the mixture was filtered through Celite
and concentrated in vacuo. The residue was extracted with
CHCl3 (3 × 20 mL), and the CHCl3 layer was washed with
saturated KI solution (2 × 10 mL) and then water (20 mL), dried
(Na2SO4), and concentrated to give a mixture of compounds
assumed to be 2 and 6 (2.33 g). Without further purification,
this mixture in 50% aqueous ethanol (170 mL) was treated with
sodium borohydride (4.05 g, 107 mmol) at room temperature for
3 h. Extraction of the reaction mixture with chloroform (2 × 50
mL) yielded a syrup (2.11 g). The mixture was separated by flash
chromatography (30 g, 2 × 25 cm column of SiO2, 230-400
mesh), eluting with light petroleum ether-diethyl ether (7:3),
to afford compound 3 (0.527 g, 22%) and compound 4 (1.19 g,
50%) in pure form. The structure of 2,3:4,5-di-O-isopropylidene-
D-ribitol (3) was characterized by comparing its spectral data
with those reported earlier.1 Compound 4: mp 96-101 °C; IR
(KBr) 3512, 3412, 2990 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.63
(d, J ) 6 Hz, 2 H), 4.48 (m, 1 H), 4.35 (m, 3 H), 4.18 (m, 2 H),
4.07 (m, 2 H), 3.92 (m, 2 H), 3.64 (d, J ) 12 Hz, 1 H), 3.12 (d, J
) 6 Hz, 1 H), 1.44 (s, 3 H), 1.43 (s, 6 H), 1.40 (s, 6 H), 1.35 (s, 6
H), 1.30 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 110.11, 109.31,
108.86, 108.47, 85.26, 78.78, 78.63, 74.04, 72.40, 68.71, 67.90,
66.98, 62.51, 28.40, 26.89, 26.77, 26.30, 26.20, 25.37, 25.14, 24.56;
positive-ion ESIMS (M - H+)- m/z 463; negative-ion ESIMS (M
+ H+)+ m/z 461. Anal. Calcd for C22H38O10: C, 57.14; H, 8.22.
Found: C, 57.19; H, 8.32.
(13) Yur′ev, Y. K.; Makarov, N. V. Zh. Obshch. Khim. 1958, 28, 885-
891.
(14) Durrwachter, J . R.; Sweers, H. M.; Nozaki, K.; Wong, C.-H.
Tetrahedron Lett. 1986, 27, 1261-1264.
(15) Schultz, M.; Waldman, H.; Kunz, H.; Vogt, W. Liebigs Ann.
Chem. 1990, 1019-1024.
(16) Fessner, W.-D.; Sinerius, G. Angew. Chem., Int. Ed. Engl. 1994,
33, 209-212.
(17) Look, G. C.; Fotsch, C. H.; Wong, C.-H. Acc. Chem. Res. 1993,
26, 182-290.
(4S ,5S ,2R ,3R ,6R ,7R ,8R )-4-(H y d r o x y m e t h y l)n o n a n e -
1,2,3,4,5,6,7,8,9-n on a ol (5). A solution of compound 4 (0.400 g,
0.865 mmol) in 50% aqueous acetone (25 mL) was heated at
reflux for 3 h with Amberlite IR-120 (H+) resin (2.40 g).
Filtration and concentration yielded a syrup that was dissolved
(18) Henderson, I.; Sharpless, K. B.; Wong, C.-H. J . Am. Chem. Soc.
1994, 116, 558-561.
(19) Yu, K.-L.; Fraser-Reid, B. J . Chem. Soc., Chem. Commun. 1989,
1442-1445.
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1991, 47, 189-204.
(21) Noe, C.; Knollmu¨ller, M.; Ettmayer, P.; Freissmuth, J . Liebigs
Ann. Chem. 1994, 611-613.
(25) Haines, A. H.; Lamb, A. J . Carbohydr. Res. 2000, 325, 323-
(22) Grandel, R.; Kazmaier, U. Tetrahedron Lett. 1997, 38, 8009-
339.
8012.
(26) Yadav, J . S.; Chander, M. C.; Rao, C. S. Tetrahedron Lett. 1989,
(23) Haag, D.; Chen, X.-T.; Fraser-Reid, B. Chem. Commun. (Cam-
bridge) 1998, 2577-2578.
(24) Majewski, M.; Nowak, P. J . Org. Chem. 2000, 65, 5152-5160.
30, 5455-5458.
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1538.

4408 J . Org. Chem., Vol. 66, No. 12, 2001
Notes
in methanol and precipitated with diethyl ether to provide 5
SCALEPACK29 was applied. Transmission coefficients ranged
from 0.735 to 0.972 with an average value of 0.907. A secondary
extinction correction was applied.30 The final coefficient, refined
in least-squares, was 0.0470000 (in absolute units). Intensities
of equivalent reflections were averaged. The agreement factor
for the averaging was 5.0% based on intensity.
(0.253 g, 97%) as a semisolid: IR (neat) 3358, 2941 cm-1 1H
;
NMR (300 MHz, CD3OD) δ 4.23 (s, 2 H), 4.02 (d, J ) 7.2 Hz, 2
H), 3.93 (s, 4 H), 3.82-3.61 (m, 14 H); 13C NMR (75 MHz, CD3-
OD) δ 78.73, 74.53, 73.29, 73.07, 72.90, 71.97, 71.48, 64.75, 64.15;
ESIMS (M + H+)+ m/z 303. Anal. Calcd for C10H22O10: C, 39.73;
H, 7.28. Found: C, 38.70; H, 7.38.
Str u ctu r e Solu tion a n d Refin em en t. The structure was
solved by direct methods using SIR97.31 The remaining atoms
were located in succeeding difference Fourier syntheses. Hydro-
gen atoms were included in the refinement but restrained to
ride on the atom to which they are bonded. The structure was
refined by full-matrix least-squares methods where the function
5-((4R)-2,2-Dim et h yl(1,3-d ioxola n -4-yl))-4-[[5-((4R)-2,2-
d im eth yl(1,3-d ioxola n -4-yl))(4S,5S)-2,2-d im eth yl(1,3-d ioxo-
la n -4-yl)](1S)-h yd r oxym eth yl](4R,5R)-2,2-d im eth yl-1,3-d i-
oxola n e-4-ca r ba ld eh yd e (6). Compound 4 (0.317 g, 0.685
mmol) was dissolved in dry CH2Cl2 (10 mL), pyridinium chlo-
rochromate (0.295 g, 1.37 mmol) was added, and the mixture
was stirred at room temperature for 8 h under argon atmo-
sphere. After 8 h, additional pyridinium chlorochromate (0.295
g, 1.37 mmol) was added, and stirring was continued for 24 h.
The solution was filtered through Celite and silica gel and then
concentrated to afford a liquid. The resulting residue was
purified by flash chromatography (20 g, 2 × 40 cm column of
SiO2, 230-400 mesh), eluting with hexanes-ethyl acetate (8:
2), to afford compound 6 (0.097 g, 31%): IR (neat) 3448, 2987,
2
2
minimized was Σw(|Fo| - |Fc| )2 and the weight w is defined as
w ) 1/[σ2(Fo2) + (0.0378P)2 + 0.4390P] where P ) (Fo + 2Fc2)/
2
3. Scattering factors were taken from the International Tables
for Crystallography.32 A total of 5478 reflections were used in
the refinements. However, only reflections with Fo > 2σ(Fo2) were
used in calculating R. The final cycle of refinement included 300
variable parameters and converged (largest parameter shift was
0.00 times its esd) with unweighted and weighted agreement
2
factors of: R1 ) Σ |Fo - Fc|/Fo ) 0.045, R2 ) SQRT (Σw(Fo
-
Fc2)2/Σw(Fo2)2) ) 0.089. The standard deviation of an observation
of unit weight was 1.07. The highest peak in the final difference
Fourier had a height of 0.40 e/A3. The minimum negative peak
had a height of -0.30 e/A3. The factor for the determination of
the absolute structure33 refined to -0.70. Refinement was
performed on a Alpha Server 2100 using SHELX-97.34 Crystal-
lographic drawings were done using programs ORTEP35 and
PLUTON.36
2937, 1737 cm-1 1H NMR (500 MHz, CDCl3) δ 9.91 (s, 1 H),
;
4.55 (d, J ) 11.09 Hz, 1 H), 4.51 (q, J ) 4.28 Hz, 1 H), 4.44 (m,
1 H), 4.34 (d, J ) 7.05 Hz, 1 H), 4.14 (q, J ) 6.09 Hz, 2 H), 4.09
(t, J ) 1.76 Hz, 1 H), 4.04 (t, J ) 8.67 Hz, 1 H), 3.90 (m, 2 H),
3.25 (d, J ) 11.14 Hz, 1 H), 1.52 (s, 3 H), 1.47 (s, 3 H), 1.42 (s,
3 H), 1.41 (s, 3 H), 1.40 (s, 6 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.31
(s, 3 H), 1.30 (s, 3 H); ESIMS (M + Na+)+ m/z 483. Anal. Calcd
for C22H36O10: C, 57.39; H, 7.82. Found: C, 57.66; H, 7.63.
X-r a y Cr ysta llogr a p h y of Com p ou n d 4. Da ta Collection .
A colorless plate of compound 4 having approximate dimensions
of 0.50 × 0.50 × 0.30 mm was mounted on a glass fiber in a
random orientation. Preliminary examination and data collection
were performed with Mo KR radiation (λ ) 0.71073 Å) on a
Nonius KappaCCD. Cell constants and an orientation matrix
for data collection were obtained from least-squares refinement,
using the setting angles of 12991 reflections in the range 4 < θ
< 27°. The orthorhombic cell parameters and calculated volume
are as follows: a ) 10.8892(4) Å, b ) 22.2696(2) Å, c ) 9.7366(9)
Å, V ) 2361.1(2) Å3. For Z ) 4 and FW ) 462.54, the calculated
density is 1.30 g/cm3. The space group was determined by the
program ABSEN.28 From the systematic presences of h00 h )
2n, 0k0 k ) 2n, and from least-squares refinement, the space
group was determined to be P21212 (#18). The data were collected
at a temperature of 173 ( 1 K. Data were collected to a
maximum 2θ of 55.8°.
Ack n ow led gm en t. This research was made possible
by NIH Grant GM51469.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallogra-
phy data for compound 4, including an ORTEP diagram. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O001782H
(29) Otwinowski, Z.; Minor, Z. Methods Enzymol. 1997, 276, 307-
326.
(30) Sheldrick, G. M. SHELEX97, Program for the Refinement of
Crystal Structures; University of Go¨ttingen: 1997.
(31) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G.; Polidori, G.; Spagna,
R. J . Appl. Crystallogr. 1999, 32, 115-119.
(32) International Tables for Crystallography; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 1992; Vol. C.
(33) Flack, H. D. Acta Crystallogr. 1983, A39, 876-881.
(34) Sheldrick, G. M.; Schneider, T. R. Methods Enzymol. 1997, 277
(Macromolecular Crystallography, Part B), 319-343.
(35) J ohnson, C. K. OrtepII Report ORNL-5138; Oak Ridge National
Laboratory: Oak Ridge, TN, 1976.
Da ta Red u ction . A total of 12991 reflections were collected,
of which 5512 were unique. Lorenz and polarization corrections
were applied to the data. The linear absorption coefficient is 1.0/
cm for Mo K radiation. An empirical absorption correction using
(36) Spek, A. L. PLUTON. Molecular Graphics Program; University
of Ultrecht: Ultrecht, The Netherlands, 1991.
(28) McArdle, P. J . Appl. Crystallogr. 1966, 29, 306.