Stereoselective conversion of sugar derivatives into C-nucleosides

Article abstract of DOI:10.1021/jo301031t

A two-step process for the transformation of readily available carbohydrate derivatives into acyclic C-nucleosides is described. The carbohydrate undergoes a scission process that is followed by the addition of aryl ketone derivatives, allowing the introduction of a variety of aryl rings. The resulting acyclic C-nucleosides are transformed into 2-deoxy cyclic pyranosides in good yield and excellent stereoselectivity.

Full text of DOI:10.1021/jo301031t

Note
pubs.acs.org/joc
Stereoselective Conversion of Sugar Derivatives into C‑nucleosides
Javier Miguelez, Venkateswara Rao Batchu, and Alicia Boto*
́
́
Instituto de Productos Naturales y Agrobiología del CSIC, Avda. Astrofísico Francisco Sanchez 3, 38206-La Laguna, Tenerife, Spain
S
* Supporting Information
ABSTRACT: A two-step process for the transformation of
readily available carbohydrate derivatives into acyclic C-nucleo-
sides is described. The carbohydrate undergoes a scission process
that is followed by the addition of aryl ketone derivatives,
allowing the introduction of a variety of aryl rings. The resulting
acyclic C-nucleosides are transformed into 2-deoxy cyclic
pyranosides in good yield and excellent stereoselectivity.
he preparation of C-nucleosides has attracted much
Scheme 1. Retrosynthetic Approach for the Preparation of
C-Nucleosides from Carbohydrate Derivatives
T
interest1 since many of these compounds display a potent
biological activity. For instance, the acyclic nucleosides 1
(Figure 1) present antibiotic and anti-inflammatory activity,2
2) and the ribofuranose 9.6d Following our previously reported
radical scission−oxidation procedure,6d substrates 8 and 9 were
treated with (diacetoxyiodo)benzene (DIB) and iodine under
irradiation with visible light to give the oxycarbenium
intermediates 10 and 11, respectively. These intermediates
were trapped by acetate from the reagent (DIB), affording the
acetoxy acetals 12 or 13. The rhamnose-derived acetal 12 was
treated with silyl enol ethers to give the arylketone derivatives
14 (89%), 15 (80%), and 16 (46%). In a similar way, the
ribose-derived acetal 136d was transformed into ketone 17
(48%). In all cases, the stereocontrol exerted by the substituted
dioxolane ring provided the acyclic C-nucleosides with excellent
1,2-trans stereoselectivity (dr >98:2).
The introduction of halogenated aromatic rings is particularly
interesting since they often display potent biological activities
and are also precursors of other aryl systems.8 For instance,
compound 14 can be transformed into product 15 by sp2−sp2
coupling.
Also interesting is the introduction of methoxy-substituted
phenyl rings, since they are found in bioactive nucleoside
Figure 1. Bioactive C-nucleosides.
while cyclic products tiazofurin 21a,3 and dapagliflozin 34 are
cytostatic and antidiabetic drugs, respectively. The stability of
C-nucleosides to in vivo hydrolysis is an important advantage
for their therapeutical use.
Therefore, the development of stereoselective routes to these
compounds has attracted the interest of medicinal chemists and
the pharmaceutical industry.5 Herein we report a highly
stereoselective route to C-nucleosides from readily available
carbohydrates. In the example shown in Scheme 1, the cyclic C-
nucleosides 4 are obtained by reduction and cyclization of the
acyclic precursors 5, which are formed by addition of aryl
ketones or their silyl enol ethers to the acetals 6. These acetals
are formed from carbohydrate derivatives 7 using a sequential
radical scission−oxidation process.6 These steps proceed under
mild conditions and good yields.
The conversion of carbohydrate derivatives into acyclic C-
Received: May 18, 2012
Published: August 16, 2012
nucleosides was studied with rhamnose derivative 87 (Scheme
© 2012 American Chemical Society
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Note
Scheme 2. Study of the Scission and Alkylation Process
Scheme 3. New Conditions for the Alkylation Reaction and
Intramolecular Cyclization To Give C-Nucleoside 20
was carried out by reduction of the ketone and treatment of the
resulting alcohol 19 with a Lewis acid12 to afford the 2-deoxy
1,5-cis C-nucleoside 20 in excellent yield and stereoselectivity
(95%, dr >98:2).13 The causes for this high stereolectivity will
be discussed later. Although some examples of this cyclization
procedure have been reported with simpler diols,12 the result
described herein is noteworthy because of the high
functionalization of substrate 20 and the conformational
constraints imposed by the dioxolane ring.
With this result in hand, other C-nucleosides were prepared
(Scheme 4). Thus, compound 13 was treated with commercial
methyl biphenyl ketone to give the acyclic nucleoside 21
(67%). The one-pot hydrolysis of the formate and the
reduction of the ketone were carried out, affording the
dihydroxy compound 22. On treatment with boron trifluoride
at −20 °C, the cyclization12,13 and deprotection of the
isopropylidene group took place to give the C-nucleoside 23
in good yield and excellent diastereomeric ratio (78%, dr
>98:2).
In a similar way, compound 13 and commercial methyl 2-
naphthyl ketone reacted to give the acyclic C-nucleoside 24 in
good yield (72%) as a single isomer (1,2-trans product). The
one-pot formate hydrolysis and ketone reduction provided
compound 25, which underwent the cyclization reaction.
Because of solubilty problems of compound 25, the cyclization
under the previous conditions (BF3OEt2, MeCN, −20 °C)
proceeded in moderate yields (38%). Therefore, the solvent
was changed to MeNO2, and after some optimization, the
temperature was slightly increased (−10 °C) and boron
trifluoride was replaced by TMSOTf. Under these conditions,
the cyclization proceeded with excellent stereoselectivity to give
compound 26 (71%, dr >98:2).13 The introduction of
polycyclic aryl rings in nucleoside and oligonucleotide
analogues has been explored recently in order to develop
new materials such as fluorescent sensors and biological
probes.14
analogues such as chaetiacandin,9a papulacandin,9a and the
hypotensive agent codonopsin.9b However, the acyclic nucleo-
sides 16 and 17, containing the p-methoxyphenyl rings, were
obtained in moderate yield (46% and 48% respectively),
probably because of the reagent’s degradation. Therefore, an
alternative procedure was explored using ketones as the
nucleophiles in the presence of an amine base and a Lewis
acid (Scheme 3). Although these conditions were described for
the nucleophilic addition to aldehydes,10 their application to
highly functionalized acetoxy acetals such as 13 is new.
Thus, compound 13 was treated with methyl p-methox-
yphenyl ketone, triethylamine, and TMSOTf, affording
compound 17 in good yield (73% versus 48% with the
previous procedure) and excellent stereoselectivity. This
method not only increased the yields but also simplified the
addition procedure, avoiding the preparation of the silyl enol
ether. In addition, production costs are reduced, since many
methylaryl ketones are commercial and relatively inexpensive
products.
The formate group of compound 17 was selectively
hydrolyzed, affording hydroxy ketone 18.6b The reductive
cyclization of this compound was tried using different
conditions,8a,b,11 but side products (dihydroxy derivatives,
furan rings, etc) were often isolated. A change in the procedure
A possible explanation of the high stereoselectivity of the
intramolecular cyclization is given in Scheme 5. On treatment
of substrate 19 with the Lewis acid, an intermediate 27 could be
formed, followed by generation of a cation stabilized by the p-
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Note
Scheme 4. Conversion of Acetoxy Acetal 13 into C-
Nucleosides 23 and 26
Scheme 5. Mechanism for the Intramolecular Cyclization of
Compound 19 To Give C-Nucleoside 20
substrates. Using our radical scission−oxidation protocol,
followed by the addition of C-nucleophiles (aryl ketones or
their silyl enol ethers), a variety of 1,2-trans-substituted acyclic
C-nucleosides were produced in good yields and high
stereoselectivities and under mild conditions.
The resulting acyclic C-nucleosides were transformed into
cyclic 2-deoxy C-nucleosides in just two steps, in good global
yields and excellent diastereoselectivity, to give the 1,5-cis
products. The application of this cyclization procedure to
substrates with high functionalization and conformational
constraints, to give the unprotected sugar cores, is remarkable
and allows the preparation of potential cytotoxic and antiviral
C-nucleosides.
EXPERIMENTAL SECTION
■
General Methods. General Remarks. Melting points were
determined with a hot-stage apparatus and are uncorrected. Optical
rotations were measured at the sodium line at ambient temperature
(26 °C) in CHCl3 solutions. NMR spectra were determined at 500 or
1
400 MHz for H and 125.7 or 100 MHz for 13C in the presence of
TMS as internal standard, unless otherwise stated. Mass spectra and
HRMS were determined with electronic impact (EI) at 70 eV. Merck
silica gel 60 PF254 and 60 (0.063−0.2 mm) were used for preparative
thin-layer chromatography and column chromatography, respectively.
All reactions involving air- or moisture-sensitive materials were carried
out under a nitrogen atmosphere. The spray reagent for TLC analysis
was 0.5% vanillin in H2SO4−EtOH (4:1), and the TLC was heated
until development of color.
General Procedure for the Radical Scission−Oxidation. To a
solution of the carbohydrate substrate (compounds 8 or 9, 2.0 mmol)
in dry dichloromethane (20 mL) were added iodine (540 mg, 2.11
mmol) and (diacetoxyiodo)benzene (DIB) (820 mg, 2.54 mmol). The
reaction mixture was stirred for 75 min at room temperature (26 °C)
under irradiation with visible light (80-W tungsten filament lamp).
The reaction mixture was then poured into 10% aqueous Na2S2O3 and
extracted with CH2Cl2. The organic layer was dried over sodium
sulfate and filtered, and the solvent was removed under vacuum. The
residue was purified by chromatography on silica gel (hexanes/EtOAc)
to afford the acetoxy acetals (products 12 or 13).
methoxyphenyl group (resonance structure 28 shown).15 Due
to the strain of the trans-substituted dioxolane ring, a deformed
chair conformation, with two equatorial oxygen functions and
equatorial 1-aryl and 5-alkyl substituents, would be adopted. In
this conformation, the 5-OH group could get close to the
benzylic cation, and the subsequent cyclization would give the
1,5-cis isomer.13b The cleavage of the isopropylidene protecting
group would reduce the strain of the system, yielding the final
product 20.
In the cyclization of related alcohols 22 and 25, the
intermediate cation could be stabilized by resonance with the
biphenyl or the naphthyl groups. The cyclization would be
similar to the one shown for intermediate 28 to give the cis-
products 23 or 26.
(1R)-1-Acetoxy-3-O-acetyl-5-deoxy-4-O-formyl-1,2-O-iso-
propylidene-L-arabinitol (12). Obtained from 3-acetyl-1,2-di-O-
isopropylidene-L-rhamnopyranose (8) (492 mg, 2.0 mmol) according
to the general procedure for the radical scission−oxidation. After
column chromatography (hexanes/EtOAc 70:30), compound 12 (553
mg, 91%) was isolated as a solid: mp 101−103 °C (EtOAc/hexane);
IR (CHCl3) 3026, 2993, 2939, 1748, 1725 cm−1; 1H NMR (500 MHz,
In conclusion, a short, highly stereoselective process for the
conversion of readily available carbohydrate derivatives into
acyclic and cyclic C-nucleosides was carried out. Different 2,3-
O-isopropylidene carbohydrate derivatives were used as
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Note
CDCl3) δH 1.28 (3H, d, J = 6.0 Hz), 1.45 (3H, s), 1.46 (3H, s), 2.06
(3H, s), 2.11 (3H, s), 4.38 (1H, dd, J = 2.0, 3.3 Hz), 5.17−5.21 (2H,
m), 6.06 (1H, d, J = 2.1 Hz), 8.02 (1H, s); 13C NMR (125.7 MHz,
CDCl3) δC 15.8, 20.7, 21.1, 26.7, 27.2, 68.8, 71.9, 80.8, 96.8, 113.8,
159.8, 169.9, 170.0; HRMS (EI) calcd for C12H17O8 [M+ − CH3]
289.0923, found 289.0929. Anal. Calcd for C13H20O8: C, 51.32; H,
6.62. Found: C, 51.07; H, 6.58.
1-Acetoxy-4-O-benzoyl-3-O-formyl-1,2-O-isopropylidene-D-
erythritol (13). Obtained from 5-benzoyl-2,3-di-O-isopropylidene-D-
ribofuranose (9) (588 mg, 2.0 mmol) according to the general
procedure for the radical scission−oxidation. After column chroma-
tography (hexanes/EtOAc 70:30), compound 13 was obtained as a
separable mixture of the (1R)-13 (479 mg, 68%) and the (1S)-13 (127
mg, 18%) isomers (global yield, 86%), which have been previously
reported.6d
General Procedure for the Preparation of Silyl Enol Ethers.
The nucleophiles were prepared from their corresponding methyl aryl
ketones. Thus, a solution of TMSOTf (0.67 mL, 3.5 mmol) in
dichloromethane (3 mL) was added dropwise to a solution of the
starting methyl ketone (3.5 mmol) and triethylamine (1.1 mL) in
dichloromethane (15 mL), cooled at 0 °C. The mixture was stirred at
0−5 °C for 30 min and then was allowed to reach 26 °C and stirred
for 1 h. It was diluted with hexanes and washed with saturated aqueous
NaHCO3 solution and water. The organic layer was dried over
anhydrous sodium sulfate, filtered, and evaporated under vacuum to
afford the silyl enol ether, which was used without further purification
in the next step. The starting amounts for each ketone were as follows:
methyl 4-bromophenyl ketone (697 mg, 3.5 mmol), methyl 4-
(phenyl)phenyl ketone (686 mg, 3.5 mmol), and methyl 4-
methoxyphenyl ketone (525 mg, 3.5 mmol).
General Procedure for Addition of Silyl Enol Ethers. To a
solution of the acetoxy acetals (products 12 or 13, 0.33 mmol) in dry
dichloromethane (3 mL) at 0 °C were added the silyl enol ether (1.33
mmol) and boron trifluoride etherate (81 μL, 0.66 mmol). The
mixture was stirred until disappearance of the starting material (about
3 h) and then was poured into saturated aqueous NaHCO3 and
extracted with CH2Cl2. After usual solvent drying and evaporation, the
residue was purified by column chromatography on silica gel
(hexanes/EtOAc) to afford the aryl ketones 14−17.
= 8.3 Hz), 8.03 (2H, d, J = 8.5 Hz), 8.04 (1H, s); 13C NMR (125.7
MHz, CDCl3) δC 16.0, 20.7, 26.6, 27.5, 41.7, 69.8, 71.0, 72.9, 79.0,
109.7, 127.2, 128.3, 128.9, 135.3, 139.8, 146.0, 160.1, 170.3, 196.4;
HRMS (EI) calcd for C24H25O7 [M+ − Me] 425.1600, found
425.1611. Anal. Calcd for C25H28O7: C, 68.17; H, 6.41. Found: C,
68.52; H, 6.30.
(1R)-3-O-Acetyl-4-O-formyl-1,2-O-isopropylidene-1-[2-oxo-
2-(4-methoxyphenyl)ethyl]-5-deoxy-D-arabinitol (16). Obtained
from the acetoxy acetal 12 (100 mg, 0.33 mmol) according to the
general procedure for the addition of silyl enol ethers. After column
chromatography (hexanes/EtOAc 85:15), compound 16 (60 mg,
46%) was obtained as a syrup: [α]D −1.10 (c 0.002, CHCl3); IR
(CHCl3) 3019, 1727, 1677, 1605 cm−1; 1H NMR (500 MHz, CDCl3)
δH 1.34 (3H, d, J = 6.4 Hz), 1.38 (3H, s), 1.41 (3H, s), 2.16 (3H, s),
3.14 (1H, dd, J = 4.6, 16.4 Hz), 3.28 (1H, dd, J = 7.3, 16.4 Hz), 3.86
(3H, s), 4.03 (1H, dd, J = 2.6, 7.7 Hz), 4.38 (1H, ddd, J = 4.6, 7.4, 7.4
Hz), 5.21 (1H, dd, J = 2.6, 5.8 Hz), 5.28 (1H, dddd, J = 5.8, 6.1, 6.3,
6.5 Hz), 6.93 (2H, d, J = 6.9 Hz), 7.93 (2H, d, J = 6.9 Hz), 8.03 (1H,
s); 13C NMR (125.7 MHz, CDCl3) δC 16.0, 20.8, 26.7, 27.6, 41.4, 55.5,
69.9, 71.2, 73.1, 79.1, 109.7, 113.8, 129.9, 130.6, 160.1, 163.8, 170.3,
195.3; HRMS (EI) calcd for C19H23O8 [M+ − Me] 379.1393, found
379.1383. Anal. Calcd for C20H26O8: C, 60.90; H, 6.64. Found: C,
60.68; H, 6.58.
(1R)-4-O-Benzoyl-3-O-formyl-1,2-O-isopropylidene-1-[2-
oxo-2-(4-methoxyphenyl)ethyl]-D-erythritol (17). Obtained from
the acetoxy acetal 13 (116 mg, 0.33 mmol) according to the general
procedure for the addition of silyl enol ethers. After column
chromatography (hexanes/EtOAc 60:40), compound 17 (70 mg,
48%) was obtained as a clear oil: 1H NMR (500 MHz, CDCl3) δH 1.44
(3H, s), 1.46 (3H, s), 3.20 (1H, dd, J = 4.8, 16.5 Hz), 3.40 (1H, dd, J =
7.0, 16.6 Hz), 3.87 (3H, s), 4.10 (1H, dd, J = 6.8, 7.1 Hz), 4.50 (1H,
dd, J = 6.8, 12.3 Hz), 4.67 (1H, ddd, J = 4.8, 7.1, 7.2 Hz), 4.76 (1H, dd,
J = 2.9, 12.3 Hz), 5.50 (1H, ddd, J = 2.9, 6.9, 7.1 Hz), 6.94 (2H, d, J =
8.8 Hz), 7.44 (2H, dd, J = 7.5, 7.9 Hz), 7.57 (1H, dd, J = 7.4, 7.5 Hz),
7.95 (2H, d, J = 8.9 Hz), 8.02 (2H, d, J = 8.4 Hz), 8.07 (1H, s); 13C
NMR (125.7 MHz, CDCl3) δC 26.9, 27.3, 42.4, 55.5, 63.2, 71.5, 75.1,
78.9, 110.2, 113.8, 128.5, 129.6, 129.7, 130.6, 133.2, 159.9, 163.8,
166.1, 195.1; HRMS (EI) calcd for C24H27O8 [M+ + H] 443.1706,
found 443.1697.
General Procedure for the Addition of Aryl Ketones. To a
stirred solution of acetoxy acetal 13 (400 mg, 1.14 mmol) in dry
dicloromethane (6 mL) was added the ketone (4.8 mmol) and
triethylamine (325 μL, 4.64 mmol). Then TMSOTf (518 μL, 5.7
mmol) was added dropwise for 20 min at 0 °C and the mixture was
stirred for 3 h at the same temperature. The reaction mixture was
diluted with a saturated aqueous NaHCO3 solution and extracted with
CH2Cl2. After usual drying and solvent removal, the residue was
purified by flash chromatography on silica gel (hexanes/EtOAc) to
afford the ketone.
(1R)-4-O-Benzoyl-3-O-formyl-1,2-O-isopropylidene-1-[2-
oxo-2-(4-methoxyphenyl)ethyl]-D-erythritol (17). Obtained from
the acetoxy acetal 13 (400 mg, 1.14 mmol) and methyl 4-
methoxyphenyl ketone (930 mg, 4.8 mmol) according to the general
procedure for the addition of aryl ketones. After column
chromatography (hexanes/EtOAc 60:40), compound 17 (362 mg,
73%) was isolated as a clear oil.
(1R)-3-O-Acetyl-4-O-formyl-1,2-O-isopropylidene-1-[2-oxo-
2-(4-bromophenyl)ethyl]-5-deoxy-D-arabinitol (14). Obtained
from the acetoxy acetal 12 (100 mg, 0.33 mmol) according to the
general procedure for the addition of silyl enol ethers. After column
chromatography (hexanes/EtOAc 90:10), compound 14 (130 mg,
89%) was obtained as a solid: mp 99−101 °C (EtOAc/hexane); [α]D
−7.6 (c 0.002, CHCl3); IR (CHCl3) 3015, 1726, 1688, 1588 cm−1; 1H
NMR (500 MHz, CDCl3) δH 1.34 (3H, d, J = 6.6 Hz), 1.36 (3H, s),
1.39 (3H, s), 2.16 (3H, s), 3.16 (1H, dd, J = 4.5, 16.7 Hz), 3.26 (1H,
dd, J = 7.4, 16.7 Hz), 4.01 (1H, dd, J = 2.3, 7.6 Hz), 4.32 (1H, ddd, J =
4.1, 7.6, 7.6 Hz), 5.18 (1H, dd, J = 2.6, 6.0 Hz), 5.27 (1H, dddd, J =
6.3, 6.6, 6.6, 6.7 Hz), 7.60 (2H, d, J = 8.5 Hz), 7.81 (2H, d, J = 8.9 Hz),
8.02 (1H, s); 13C NMR (125.7 MHz, CDCl3) δC 16.0, 20.7, 26.5, 27.4,
41.5, 69.8, 70.9, 72.6, 78.9, 109.7, 128.6, 129.8, 131.9, 135.4, 160.0,
170.3, 195.8; HRMS (EI) calcd for C14H12O381Br [CH2C(OCHO)-
CHCHCHCHCOC6H4-p-Br]+ 308.9949, found 308.9955; calcd
for C14H12O379Br 306.9970, found 306.9985. Anal. Calcd for
C19H23O7Br: C, 51.48; H, 5.23. Found: C, 51.57; H, 5.10.
(1R)-3-O-Acetyl-4-O-formyl-1,2-O-isopropylidene-1-[2-oxo-
2-(biphenyl-4-yl)ethyl]-5-deoxy-D-arabinitol (15). Obtained from
the acetoxy acetal 12 (100 mg, 0.33 mmol) according to the general
procedure for the addition of silyl enol ethers. After column
chromatography (hexanes/EtOAc 90:10), compound 15 (116 mg,
80%) was obtained as a white solid: mp 136−138 °C (EtOAc/
hexane); [α]D −2.75 (c 0.002, CHCl3); IR (CHCl3) 3019, 1731, 1687,
1605 cm−1; 1H NMR (500 MHz, CDCl3) δH 1.36 (3H, d, J = 6.4 Hz),
1.40 (3H, s), 1.42 (3H, s), 2.17 (3H, s), 3.24 (1H, dd, J = 4.5, 16.6
Hz), 3.36 (1H, dd, J = 7.4, 16.6 Hz), 4.06 (1H, dd, J = 2.5, 7.7 Hz),
4.40 (1H, ddd, J = 4.5, 7.5, 7.5 Hz), 5.24 (1H, dd, J = 2.5, 5.8 Hz), 5.30
(1H, dddd, J = 5.7, 6.5, 6.6, 6.7 Hz), 7.40 (1H, dd, J = 7.1, 7.4 Hz),
7.47 (2H, dd, J = 7.6, 8.0 Hz), 7.62 (2H, d, J = 8.2 Hz), 7.68 (2H, d, J
(1R)-4-O-Benzoyl-1,2-O-isopropylidene-1-[2-oxo-2-(4-
methoxyphenyl)ethyl]-D-erythritol (18). Obtained from aryl
ketone 17 (350 mg, 0.79 mmol) by treatment with NaHCO3 (663
mg, 7.9 mmol) in methanol (5 mL). After column chromatography
(hexanes/EtOAc 60:40), compound 18 (308 mg, 94%) was obtained
as a syrup: [α]D +8 (c 0.54, CHCl3); IR (CHCl3) 3435, 1720, 1677,
1
1601 cm−1; H NMR (500 MHz, CDCl3) δH 1.42 (6H, s), 3.38 (1H,
dd, J = 5.4, 17.0 Hz), 3.43 (1H, dd, J = 6.3, 17.0 Hz), 3.85 (1H, dd, J =
7.2, 8.3 Hz), 3.87 (3H, s), 4.09 (1H, m), 4.44 (1H, dd, J = 6.4, 11.8
Hz), 4.67 (1H, dd, J = 2.8, 11.7 Hz), 4.68 (1H, m), 6.93 (2H, d, J = 9.0
Hz), 7.44 (2H, dd, J = 7.6, 8.1 Hz), 7.57 (1H, dd, J = 7.4, 7.5 Hz), 7.97
(2H, d, J = 9.0 Hz), 8.07 (2H, d, J = 7.5 Hz); 13C NMR (125.7 MHz,
CDCl3) δC 27.0, 27.3, 42.8, 55.5, 67.1, 72.3, 76.2, 80.5, 109.5, 113.8,
128.4, 129.7, 129.8, 130.7, 133.1, 163.8, 167.1, 196.9; HRMS (EI)
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Note
calcd for C22H23O7 [M+ − Me] 399.1444, found 399.1433. Anal. Calcd
for C23H26O7: C, 66.65; H, 6.32. Found: C, 66.77; H, 6.16.
(1R)-4-O-Benzoyl-1-[2-hydroxy-2-(biphenyl-4-yl)ethyl]-1,2-
O-isopropylidene-D-erythritol (22). Obtained from compound 21
(390 mg, 0.8 mmol) using the general reduction procedure. After
purification by chromatography (hexanes/EtOAc, 70:30), compound
22 was obtained as a 1:1 diastereomer mixture (299 mg, 81%). Syrup:
IR (CHCl3) 3509, 1720, 1605 cm−1; 1H NMR (500 MHz, CDCl3) δH
1.43/1.45 (3H, s), 1.46/1.49 (3H, s), 2.08/2.11 (1H, m), 2.22/2.29
(1H, [ddd, J = 3.3, 3.3, 14.3 Hz/ddd, J = 3.8, 10.3, 13.9 Hz]), 3.80/
3.84 (1H, [dd, J = 7.6, 7.6 Hz/dd, J = 7.6, 7.7 Hz]), 4.02/4.03 (1H,
m), 4.30/4.36 (1H, [br ddd, J = 3.2, 7.9, 9.5 Hz/ddd, J = 3.8, 7.9, 9.5
Hz]), 4.41 (1H, dd, J = 6.5, 11.8 Hz), 4.62/4.63 (1H, m/m), 5.02/5.06
(1H, [dd, J = 3.2, 9.6 Hz/br d, J = 9.5 Hz]), 7.36 (1H, dd, J = 7.5, 7.8
Hz), 7.42−7.47 (6H, m), 7.56−7.59 (5H, m), 8.04−8.07 (2H, m); 13C
NMR (125.7 MHz, CDCl3) δC 27.0, 27.3, 42.8/43.5, 66.9/67.1, 71.5/
72.9, 72.2/72.1, 77.6/79.3, 80.0/80.3, 109.3/109.7, 126.0, 126.2,
127.0/127.1, 127.1/127.2, 128.5, 128.7, 129.7, 133.3/133.4, 140.4,
140.8/140.9, 142.9/143.2, 167.2; HRMS (EI) calcd for C27H27O6 [M+
− Me] 447.1808, found 447.1824. Anal. Calcd for C28H30O6: C, 72.71;
H, 6.54. Found: C, 72.80; H, 6.77.
(1R)-4-O-Benzoyl-3-O-formyl-1,2-O-isopropylidene-1-[2-
oxo-2-(biphenyl-4-yl)ethyl]-D-erythritol (21). Obtained from the
acetoxy acetal 13 and methyl 4-biphenyl ketone (930 mg, 4.76 mmol)
according to the general procedure for the addition of aryl ketones.
After column chromatography (hexanes/EtOAc 70:30), compound 21
(368 mg, 67%) was obtained as a syrup: [α]D +20.4 (c 0.19, CHCl3);
IR (CHCl3) 1731, 1685, 1605 cm−1; 1H NMR (500 MHz, CDCl3) δH
1.46 (3H, s), 1.47 (3H, s), 3.29 (1H, dd, J = 4.6, 16.7 Hz), 3.48 (1H,
dd, J = 7.1, 16.8 Hz), 4.13 (1H, dd, J = 6.6, 7.2 Hz), 4.53 (1H, dd, J =
6.7, 12.2 Hz), 4.72 (1H, ddd, J = 4.6, 7.2, 7.2 Hz), 4.79 (1H, dd, J =
2.9, 12.3 Hz), 5.53 (1H, m), 7.40−7.48 (5H, m), 7.56 (1H, dd, J = 7.4,
7.5 Hz), 7.62 (2H, d, J = 8.0 Hz), 7.68 (2H, d, J = 8.2 Hz), 8.03−8.05
(4H, m), 8.10 (1H, brs); 13C NMR (125.7 MHz, CDCl3) δC 26.9,
27.3, 42.7, 63.1, 71.5, 74.9, 78.9, 110.2, 127.2, 128.3, 128.5, 128.8,
128.9, 129.5, 129.7, 133.2, 135.3, 139.7, 146.1, 159.8, 166.1, 196.2;
HRMS (EI) calcd for C28H25O7 [M+ − Me] 473.1600, found
473.1586. Anal. Calcd for C29H28O7: C, 71.30; H, 5.78. Found: C,
71.18; H, 5.80.
(1R)-4-O-Benzoyl-1-[2-hydroxy-2-(2-naphthyl)ethyl]-1,2-O-
isopropylidene-D-erythritol (25). Obtained from compound 24
(369 mg, 0.8 mmol) using the general reduction procedure. After
purification by chromatography (hexanes/EtOAc, 70:30), compound
25 was obtained (289 mg, 83%) as a 3:2 diastereomer mixture. Syrup:
IR (CHCl3) 3506, 1720, 1277 cm−1; 1H NMR (500 MHz, CDCl3) δH
major isomer: 1.40 (3H, s), 1.44 (3H, s), 2.11 (1H, m), 2.32 (1H, ddd,
J = 3.7, 9.7, 14.6 Hz), 3.82 (1H, dd, J = 7.7, 7.8 Hz), 3.98 (1H, m),
4.36 (1H, m), 4.39 (1H, m), 4.61 (1H, m), 5.14 (1H, dd, J = 2.3, 9.8
Hz), 7.40−7.48 (5H, m), 7.55 (1H, dd, J = 7.6, 7.8 Hz), 7.77−7.84
(4H, m), 8.00−8.06 (2H, m); minor isomer: 1.41 (3H, s), 1.47 (3H,
s), 2.11 (1H, m), 2.25 (1H, ddd, J = 3.5, 3.5, 14.4 Hz), 3.80 (1H, dd, J
= 7.6, 7.7 Hz), 3.97 (1H, m), 4.26 (1H, ddd, J = 3.5, 7.5, 9.0 Hz), 4.39
(1H, m), 4.60 (1H, m), 5.12 (1H, dd, J = 3.7, 9.3 Hz), 7.40−7.48 (5H,
m), 7.56 (1H, dd, J = 7.7, 7.8 Hz), 7.77−7.84 (4H, m), 8.00−8.06
(2H, m); 13C NMR (125.7 MHz, CDCl3) δC 26.9, 27.3, 43.0/43.4,
67.0, 71.9/72.1, 71.8/73.1, 77.6/79.2, 80.0/80.2, 109.2/109.6, 123.8/
124.0, 124.1/124.4, 125.7/125.8, 126.0/126.1, 127.6, 127.9/128.0,
128.1/128.2, 128.4/128.5, 129.6, 129.7, 132.8/132.9, 133.2/133.3,
133.2/133.4, 141.2/141.6, 167.1/167.2; HRMS (EI) calcd for
C26H28O6 [M+] 436.1886, found 436.1889. Anal. Calcd for
C26H28O6: C, 71.54; H, 6.47. Found: C, 71.60; H, 6.70.
General Procedures for the Cyclization Reaction. Method A.
To a solution containing the diol (0.15 mmol) in dry acetonitrile (3
mL) were added active molecular sieves 4 Å (5 mg) and BF3·OEt2 (19
μL, 0.15 mmol) at −40 °C. The mixture was stirred for 20 min and
quenched with aqueous NaHCO3. The aqueous layer was extracted
with EtOAc, dried, filtered, and evaporated to dryness. The residue
was purified by chromatography on silica gel (hexanes/EtOAc) to give
the cyclic C-nucleoside.
Method B. To a solution containing the diol (0.3 mmol) in dry
acetonitrile (3 mL) was added BF3·OEt2 (70 μL, 0.60 mmol) at −20
°C. The mixture was stirred for 60 min, followed by workup and
purification as in method A.
(1R)-4-O-Benzoyl-3-O-formyl-1,2-O-isopropylidene-1-[2-
oxo-2-(2-naphthyl)ethyl]-D-erythritol (24). Obtained from the
acetoxy acetal 13 and methyl 2-naphthyl ketone (816 mg, 4.8 mmol)
according to the general procedure for the addition of aryl ketones.
After column chromatography (hexanes/EtOAc 70:30), compound 24
(378 mg, 72%) was obtained as a syrup: [α]D +30.4 (c 0.17, CHCl3);
IR (CHCl3) 1731, 1685, 1631 cm−1; 1H NMR (500 MHz, CDCl3) δH
1.47 (3H, s), 1.48 (3H, s), 3.40 (1H, dd, J = 4.6, 16.7 Hz), 3.59 (1H,
dd, J = 7.1, 16.6 Hz), 4.17 (1H, dd, J = 6.6, 7.3 Hz), 4.53 (1H, dd, J =
6.6, 12.2 Hz), 4.75 (1H, ddd, J = 4.6, 7.2, 7.2 Hz), 4.79 (1H, dd, J =
2.9, 12.2 Hz), 5.54 (1H, dddd, J = 0.8, 2.9, 6.5, 6.6 Hz), 7.47 (2H, dd, J
= 7.6, 8.1 Hz), 7.61 (2H, m), 7.66 (1H, dd, J = 7.0, 7.9 Hz), 7.93 (2H,
dd, J = 8.9, 9.3 Hz), 8.01 (1H, d, J = 8.1 Hz), 8.07−8.10 (3H, m), 8.14
(1H, brs), 8.52 (1H, d, J = 1.4 Hz); 13C NMR (125.7 MHz, CDCl3)
δC 26.9, 27.3, 42.7, 63.2, 71.6, 75.0, 78.9, 110.3, 123.7, 126.8, 127.8,
128.4, 128.5, 128.7, 129.5, 129.6, 129.7, 130.1, 132.4, 133.2, 134.0,
135.7, 159.9, 166.1, 196.6; HRMS (EI) calcd for C27H26O7 [M+]
462.1679, found 462.1680. Anal. Calcd for C27H26O7: C, 70.12; H,
5.67. Found: C, 70.05; H, 5.74.
General Procedure for the Reduction of Aryl ketones. A
mixture of the ketone (0.80 mmol) and sodium borohydride (61 mg,
1.60 mmol) in anhydrous methanol (5 mL) was stirred at 0 °C for 90
min. Then saturated aqueous NaHCO3 (2 mL) and EtOAc (10 mL)
were added, and the mixture was stirred at 0 °C for 5 min. The
reaction mixture was poured into water and extracted with EtOAc.
After usual drying and solvent removal, the residue was purified by
chromatography (hexanes/EtOAc 70:30) to give the diols.
(1R)-4-O-Benzoyl-1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-
1,2-O-isopropylidene-D-erythritol (19). Obtained from the ketone
18 (331 mg, 0.8 mmol) according to the general reduction procedure.
After column chromatography (hexanes/EtOAc 70:30), compound 19
(306 mg, 92%) was obtained as a 3:2 diastereomer mixture. Syrup: IR
(CHCl3) 3509, 1722, 1612, 1516 cm−1; 1H NMR (500 MHz, CDCl3)
δH major isomer 1.41 (3H, s), 1.44 (3H, s), 2.01 (1H, m), 2.23 (1H,
ddd, J = 3.9, 9.8, 14.5 Hz), 3.79 (3H, s), 3.80 (1H, m), 4.00 (1H, m),
4.33 (1H, ddd, J = 3.8, 7.6, 7.6 Hz), 4.39 (1H, m), 4.61 (1H, dd, J =
2.5, 6.3 Hz), 4.95 (1H, br d, J = 9.6 Hz), 6.86 (2H, d, J = 8.7 Hz), 7.28
(2H, d, J = 8.6 Hz), 7.45 (2H, dd, J = 7.0, 7.8 Hz), 7.57 (1H, dd, J =
7.5, 7.8 Hz), 8.06 (2H, d, J = 7.5 Hz); minor isomer 1.42 (3H, s), 1.46
(3H, s), 2.05 (1H, m), 2.14 (1H, ddd, J = 3.6, 3.6, 14.5 Hz), 3.78 (1H,
m), 3.79 (3H, s), 3.99 (1H, m), 4.22 (1H, br ddd, J = 3.0, 7.5, 7.6 Hz),
4.37 (1H, m), 4.60 (1H, dd, J = 2.5, 6.0 Hz), 4.91 (1H, dd, J = 3.6, 9.2
Hz), 6.86 (2H, d, J = 8.7 Hz), 7.29 (2H, d, J = 8.3 Hz), 7.46 (2H, dd, J
= 7.5, 7.9 Hz), 7.59 (1H, dd, J = 7.2, 7.5 Hz), 8.04 (2H, d, J = 7.2 Hz);
13C NMR (125.7 MHz, CDCl3) δC 26.91/27.95, 27.26/27.28, 42.9/
Method C. To a solution containing the diol (0.1 mmol) in dry
nitromethane (1 mL) was added TMSOTf (50 μL, 0.27 mmol) at −10
°C. The mixture was stirred for 60 min, followed by workup and
purification as in method A.
(1R)-6-O-Benzoyl-1-(4-methoxyphenyl)-1,2-dideoxygluco-
pyranose (20). Obtained from compound 19 (62 mg, 0.15 mmol) as
described in the general procedure for cyclization, method A. After
purification by chromatography, compound 20 was obtained (51 mg,
95%) as a syrup: [α]D −43.1 (c 0.93, CHCl3); IR (CHCl3) 3591, 3491,
1707, 1614 cm−1; 1H NMR (500 MHz, CDCl3) δH 1.64 (1H, ddd, J =
11.6, 11.6, 12.9 Hz), 2.13 (1H, ddd, J = 2.0, 4.9, 13.0 Hz), 3.31 (1H,
dd, J = 9.1, 9.2 Hz), 3.53 (1H, m), 3.71 (3H, s), 3.77 (1H, m), 4.39
(1H, dd, J = 1.7, 11.6 Hz), 4.45 (1H, dd, J = 2.2, 12.2 Hz), 4.76 (1H,
dd, J = 3.9, 12.2 Hz), 6.79 (2H, d, J = 8.6 Hz), 7.19 (2H, d, J = 8.7
Hz), 7.36 (2H, dd, J = 7.7, 7.8 Hz), 7.49 (1H, dd, J = 7.3, 7.6 Hz), 8.00
(2H, d, J = 8.0 Hz); 13C NMR (125.7 MHz, CDCl3) δC 40.3, 55.3,
64.4, 72.1, 72.6, 77.4, 78.3, 113.8, 127.2, 128.4, 129.6, 129.9, 133.1,
43.4, 55.2, 67.00/67.06, 71.37/72.66, 72.17/72.00, 77.6/79.1, 80.0/
80.2, 109.2/109.6, 113.8/113.9, 126.8/127.0, 128.4/128.5, 129.5/
129.7, 133.2/133.3, 136.1/136.4, 159.0, 167.1/167.2; HRMS (EI)
calcd for C23H28O7 [M+] 416.1835, found 416.1833. Anal. Calcd for
C23H28O7: C, 66.33; H, 6.78. Found: C, 66.54; H, 6.86.
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The Journal of Organic Chemistry
Note
133.4, 159.2, 167.8; HRMS (EI) calcd for C20H22O6 [M+] 358.1416;
found, 358.1418.
postdoctoral contract, respectively. We thank Dr. J. A. Gallardo
for his cooperation in the synthesis of acetal 8.
(1R)-6-O-Benzoyl-1-(biphenyl-4-yl)-1,2-dideoxyglucopyra-
nose (23). Obtained from compound 22 (139 mg, 0.3 mmol) as
described in the general procedure for cyclization, method B. After
purification by chromatography (hexanes/EtOAc, 60:40), compound
23 was obtained (95 mg, 78%) as a syrup. Compound 22 was also
transformed using method A, but the yields of compound 23 were
lower (57%): [α]D −41.9 (c 0.17, CHCl3); IR (CHCl3) 3487, 1716,
1604, 1490 cm−1; 1H NMR (500 MHz, CDCl3) δH 1.77 (1H, ddd, J =
11.5, 11.6, 13.1 Hz), 2.31 (1H, ddd, J = 2.1, 4.9, 13.1 Hz), 3.40 (1H,
dd, J = 9.1, 9.2 Hz), 3.65 (1H, ddd, J = 2.3, 3.5, 9.6 Hz), 3.91 (1H,
ddd, J = 4.9, 8.7, 11.4 Hz), 4.54 (1H, dd, J = 2.2, 12.2 Hz), 4.60 (1H,
dd, J = 2.0, 11.6 Hz), 4.94 (1H, dd, J = 3.5, 12.3 Hz), 7.34 (1H, dd, J =
7.3, 7.6 Hz), 7.40−7.50 (6H, m), 7.58 (4H, d, J = 7.8 Hz), 7.60 (1H,
dd, J = 7.8, 7.9 Hz), 8.11 (2H, d, J = 8.5 Hz); 13C NMR (125.7 MHz,
CDCl3) δC 40.3, 64.2, 72.0, 72.5, 77.6, 78.4, 126.4, 127.1, 127.2, 127.3,
128.5, 128.7, 129.5, 129.9, 133.4, 139.9, 140.8, 167.9; HRMS (EI)
calcd for C25H24O5 [M+] 404.1624, found 404.1625. Anal. Calcd for
C25H24O5: C, 74.24; H, 5.98. Found: C, 74.54; H, 6.12.
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chromatography (hexanes/EtOAc, 55:45), compound 26 was obtained
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1
(CHCl3) 3480, 1714, 1605 cm−1; H NMR (500 MHz, CDCl3) δH
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1.81 (1H, ddd, J = 11.5, 11.6, 12.9 Hz), 2.35 (1H, ddd, J = 2.1, 4.9,
13.1 Hz), 3.44 (1H, dd, J = 9.0, 9.2 Hz), 3.68 (1H, br b), 3.69 (1H,
ddd, J = 2.3, 3.6, 9.6 Hz), 3.93 (1H, m), 4.56 (1H, dd, J = 2.1, 12.3
Hz), 4.71 (1H, dd, J = 1.6, 11.5 Hz), 4.94 (1H, dd, J = 3.2, 12.3 Hz),
7.43−7.50 (5H, m), 7.59 (1H, dd, J = 7.3, 7.6 Hz), 7.82 (2H, d, J = 8.9
Hz), 7.83 (2H, d, J = 8.2 Hz), 8.12 (2H, d, J = 7.6 Hz); 13C NMR
(125.7 MHz, CDCl3) δC 40.4, 64.3, 72.1, 72.6, 77.8, 78.5, 124.0, 124.6,
125.9, 126.1, 127.6, 128.0, 128.2, 128.5, 129.6, 130.0, 133.0, 133.2,
133.4, 138.3, 167.9; HRMS (EI) calcd for C23H22O5 [M+] 378.1467,
found 378.1485. Anal. Calcd for C23H22O5: C, 73.00; H, 5.86. Found:
C, 73.27; H, 6.20.
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* Supporting Information
́
́
Carbon and proton shifts and NOESY correlations for
́
1
compounds 14−16, 18, 20, 21, 23, 24, and 26. H and 13C
́
́
́
NMR spectra for products 14−26. Mechanistic considerations
for the cyclization reaction and molecular-modeling studies
with analogues of intermediate 28. This material is available
free of charge via the Internet at http://pubs.acs.org.
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B.; Hocek, M. J. Org.
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Kotora, M. Org. Biomol. Chem. 2011, 9, 5934−5937. (c) Ding, H.;
Greenberg, M. M. J. Org. Chem. 2010, 75, 535−544. (d) Jarchow-
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■
Corresponding Author
*Tel: +34-922-260112 (ext 267). Fax: +34 922260135. E-mail:
alicia@ipna.csic.es.
̌
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Notes
The authors declare no competing financial interest.
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4608−4611 and references cited therein. (b) Oliveira, D. F.; Severino,
E. A. C.; Correia, R. D. Tetrahedron Lett. 1999, 40, 2083−2086.
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Tetrahedron 1984, 40, 1381−1390. (b) Downey, C. W.; Johnson, M.
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therein.
ACKNOWLEDGMENTS
■
This work was supported by the Research Program CTQ2009-
07109 of the Plan Nacional de Investigacio
́
́
Desarrollo e Innovacion
́ ́
Tecnolog
́
Innovacion
́
(11) (a) Moral, J. A.; Moon, S. J.; Rodriguez-Torres, S.; Minehan, T.
also acknowledge financial support from FEDER funds
(European Funds for Regional Development). J.M. and
V.R.B. thank CSIC for a JAE predoctoral fellowship and a
̌
G. Org. Lett. 2009, 11, 3734−3737. See also: (b) Stefko, M.;
Slavetínska, L.; Klepetar va, B.; Hocek, M. J. Org. Chem. 2010, 75,
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442−449. (c) Bonnac, L.; Lee, S. E.; Giuffredi, G. T.; Elphick, L. M.;
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The Journal of Organic Chemistry
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(12) (a) Suzuki, K. Pure Appl. Chem. 1994, 66, 2175−2178.
(b) Hudkins, R. L.; Zulli, A. L.; Underiner, T. L.; Angeles, T. S.;
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Almo, S. C.; Fedorov, A. A.; Ruggeri, B. A. Bioorg. Med. Chem. Lett.
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1
(13) (a) Only one diastereomer was detected, either by H NMR
spectra of the crude reaction mixture or by its subsequent careful
chromatographic purification. Due to the limitations of NMR
detection, the dr is given as >98:2: Wernerova, M.; Hudlicky, T.
Synlett 2010, 2701−2707. (b) The 1,5-cis stereochemistry was
determined according to the coupling constant values in the 1H NMR
spectra and NOESY experiments (see the Supporting Information).
Thus, for cyclic C-nucleoside 20, NOESY spatial correlations were
observed between 1-H (δ 4.39)/3-H (δ 3.77)/5-H (δ 3.53) and 2-Hβ
(1.64)/4-H (δ 3.31). For compound 23, NOESY spatial interactions
were observed between 1-H (δ 4.60)/3-H (δ 3.91)/5-H (δ 3.65), and
4-H (δ 3.40)/6-H2 (δ 4.54/4.94). For compound 26, NOESY spatial
correlations were observed between 1-H (δ 4.71)/3-H (δ 3.93), and 4-
H (δ 3.44)/6-H2 (δ 4.56/4.94).
(14) (a) Teo, Y. N.; Wilson, J. N.; Kool, E. T. J. Am. Chem. Soc. 2009,
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(15) For related mechanism proposals, see: (a) Takeuchi, T.;
Matsuhashi, M.; Nakata, T. Tetrahedron Lett. 2008, 49, 6462−6465.
(b) Spadafora, M.; Mehiri, M.; Burger, A.; Benhida, R. Tetrahedron
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5859.
NOTE ADDED AFTER ASAP PUBLICATION
■
This paper was published ASAP on August 23, 2012. Figure 1
was updated and ref 4a was added. The revised paper was
reposted on September 7, 2012.
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