Highly β-selective C-allylation of a ribofuranoside controlling steric hindrance in the transition state

Article abstract of DOI:10.1021/ol8018743

(Graph Presented) A highly β-selective C-allylation oi 2,3-O-(3-pentylidene)-D-ribofuranosyl fluoride is described. This strategy will provide a new concept for synthesizing β-C-ribosides by controlling the effect of steric hindrance in the transition state.

Full text of DOI:10.1021/ol8018743

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5107-5110
Highly ꢀ-Selective C-Allylation of a
Ribofuranoside Controlling Steric
Hindrance in the Transition State
Satoshi Ichikawa,* Ryoko Hayashi, Shinpei Hirano, and Akira Matsuda*
Faculty of Pharmaceutical Sciences, Hokkaido UniVersity, Kita-12, Nishi-6, Kita-ku,
Sapporo 060-0812, Japan
matuda@pharm.hokudai.ac.jp; ichikawa@pharm.hokudai.ac.jp
Received August 12, 2008
ABSTRACT
A highly ꢀ-selective C-allylation of 2,3-O-(3-pentylidene)-D-ribofuranosyl fluoride is described. This strategy will provide a new concept for
synthesizing ꢀ-C-ribosides by controlling the effect of steric hindrance in the transition state.
Stereoselective C-ribosylation is an important reaction that
is often employed to obtain biologically relevant molecules
such as saccharides, nucleosides, and natural products
containing the tetrahydrofuran moiety and is of great interest
in stereocontrolled synthesis.1-5 Since Lewis acid-promoted
nucleophilic substitution of ribosyl donors is generally
believed to proceed via an oxocarbenium ion intermediate,6
an understanding of the stereoselective reactions of oxocar-
benium ions would imply consideration of the preferred
conformation of the charged intermediate.7,8 Some C-
ribosylations, e.g., allylation of 2,3,5-tri-O-benzyl-D-ribo-
furanosyl donors, are known to give R-C-ribosides in a highly
stereoselective manner.9 Among the arguments for stereo-
chemical control,9a,10-12 Woerpel et al. in extensive studies
elegantly explained that the stereoselectivity of C-glycosy-
lation reactions, including that of pentofuranoside cases, is
also largely governed by a stereoelectronic effect.13 Thus, a
stereoelectronically preferred inside attack on the lowest
(9) (a) Araki, Y.; Kobayashi, N.; Ishido, Y.; Nagasawa, J. Carbohydr.
Res. 1987, 171, 125–139. (b) Mukaiyama, T.; Kobayashi, S. Carbohydr.
Res. 1987, 171, 81–87. (c) Mukaiyama, T.; Kobayashi, S.; Shoda, S. Chem.
Lett. 1984, 1529–1530. (d) Tomooka, K.; Matsuzawa, K.; Suzuki, K.;
Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 6339–6342.
(1) Levy, D. E.; Tang, C. The Chemistry of C-Glycosides; Pergamon:
Tarrytown, NY, 1995; Vol. 13
(2) Postema, M. H. D. C-Glycoside Synthesis; CRC Press: Boca Raton,
.
(10) Jaouen, V.; Jegou, A.; Lemee, L.; Veyrieres, A. Tetrahedron 1999,
FL, 1995
.
55, 9245–9262.
(3) Du, Y.; Linhardt, R. J.; Vlahov, I. R. Tetrahedron 1998, 54, 9913–
(11) Nishiyama, Y.; Katoh, T.; Deguchi, K.; Morimoto, Y.; Itoh, K. J.
Org. Chem. 1997, 62, 9339–9341
9959
.
.
(4) Wu, Q.; Simons, C. Synthesis 2004, 1533–1553
.
(12) (a) Schmitt, A.; Reissig, H.-U. Synlett 1990, 10, 1–94. (b) Schmitt,
A.; Reissig, H.-U. Chem. Ber. 1995, 128, 871–876. (c) Schmitt, A.; Reissig,
H.-U. Eur. J. Org. Chem. 2000, 3893–3901. (d) Schmitt, A.; Reissig, H.-
(5) Harmange, J.-C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4,
1711–1754
.
(6) It has also been reported that O-glycosylation of furanosyl triflates
occurs with inversion of configuration via an SN2-type mechanism: Callam,
C. S.; Gadikota, R. R.; Krein, D. M.; Lowary, T. L. J. Am. Chem. Soc.
2003, 125, 13112–13119.
U. Eur. J. Org. Chem. 2001, 116, 9–1174.
(13) (a) Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 1997, 62, 6706–
6707. (b) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12208–12209. (c) Smith, D. M.; Tran, M. B.;
Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 14149–14152. (d) Smith,
D. M.; Woerpel, K. A. Org. Lett. 2004, 6, 2063–2066. (e) Larsen, C. H.;
Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel, K. A. J. Am. Chem.
Soc. 2005, 127, 10879–10884.
(7) (a) Stevens, R. V.; Lee, A. W. M. J. Am. Chem. Soc. 1979, 101,
7032–7035. (b) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289–296
.
(8) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon: New York, 1983; pp 209-221.
10.1021/ol8018743 CCC: $40.75
Published on Web 10/18/2008
2008 American Chemical Society

energy E3 conformer in an oxocarbenium ion of D-furano-
sides with a 3-C-alkoxy substituent gives predominantly R-C-
furanosides. Since, unlike O-ribosylation, neighboring group
participation14 is not usually effective in C-ribosylation
reactions,15,16 it is quite difficult to synthesize ꢀ-C-ribosides
by a Lewis acid-promoted direct alkylation of ribosyl
donors.17-19 We recently developed highly ꢀ-selective
O-ribosylation by using a cyclic ketal protecting group at
the 2,3-hydroxyl groups. Density functional theory (DFT)
quantum mechanical calculations at the B3LYP/6-31G**
level suggested that the lowest-energy conformation of
intermediated oxocarbenium ions protected with the cyclic
ketal is the E3 conformer, which is ca. 11 kcal/mol more
ribosylation reaction would be applicable to ꢀ-C-ribosides.
Herein, we describe the highly ꢀ-selective direct C-allylation
of D-ribofuranosides.
As a preliminary study, some reactions were examined
with different types of nucleophiles. Initially, the cyanation
of 5-O-benzyl-2,3-O-(3-pentylidene)-D-ribofuranosyl fluoride
121 was carried out.24 Treatment of 1 with TMSCN (2.0
equiv) and BF3·OEt2 (0.5 equiv) and molecular sieves 4 Å
(MS4Å) in CH2Cl2 at 0 °C resulted in the rapid formation
of the corresponding cyano derivative 2a in 71% yield (Table
1
1, entry 1). H NMR (500 MHz) analysis of the product
3
stable than the corresponding E conformer. Inside attack
Table 1. C-Ribosylation of 3-Pentylidene-Protected Ribosyl
Fluoride
of the nucleophile would suffer significant steric interactions
from one of the alkyl groups of the cyclic ketal moiety in
its transition state. Increasing the size of the alkyl substituents
such as ethyl groups in the 3-pentylidene group would result
in severe steric repulsion on the R-face, leading to outside
attack with complete reversal of stereoselectivity to give
ꢀ-ribosides (Figure 1).20,21 A cyclic ketal group is removed
Figure 1. Schematic representation of the ꢀ-stereoselectivity of the
nucleophilic attack to oxocarbenium ions of 3-pentylidene-protected
ribofuranoside.
by acidic conditions; this enabled us to synthesize the base-
sensitive nucleoside natural products, caprazol and FR-
900493.22,23 If this reaction could be extended to carbon
nucleophiles, as we expected, then our stereoselective
(14) Jung, K.; Muller, M.; Schmidt, R. Chem. ReV. 2000, 100, 4423–
4442.
(15) Kozikowski, A. P.; Sorgi, K. L. Tetrahedronn Lett. 1983, 24, 1563–
1566
.
(16) McDevitt, J. P.; Lansbury, P. T. J. Am. Chem. Soc. 1996, 118, 3818–
3828
.
(17) Alternatively, ꢀ-C-furanosides can be stereoselectively prepared by
a two-step sequence involving nucleophilic addition of a suitably protected
ribonic γ-lactone followed by Lewis acid-promoted silane reduction. For
examples, see: (a) Gudmundsson, K. S.; Drach, J. C.; Townsend, L. B. J.
Org. Chem. 1997, 62, 3453–3459. (b) Calzada, E.; Clarke, C. A.; Roussin-
Bouchard, C.; Wightman, R. H. J. Chem. Soc., Perkin Trans. 1 1995, 517–
a Combined isolated yields after column chromatography. b Anomeric
1
ratio determined from H NMR integration values of selected protons.
518
(18) Keck, G. E.; Enholm, E. J.; Kachensky, D. F. Tetrahedron Lett.
1984, 25, 1867–1870
(19) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba, A. J. Org. Chem. 2006,
71, 8516–8522
(20) Hirano, S.; Ichikawa, S.; Matsuda, A. Angew. Chem., Int. Ed. 2005,
44, 1854–1856
.
revealed a ꢀ/R ratio of 97/3 and good ꢀ-selectivity as
expected. A Mukaiyama-aldol-type reaction using a silyl
enol ether of acetophenone also proceeded well, and the
desired 2b was obtained in 94% yield with good ꢀ-selectivity
(ꢀ/R ) 97/3, entry 2). Next, a Sakurai-Hosomi-type
.
.
.
(21) Hirano, S.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2007, 72,
9936–9946
(22) Hirano, S.; Ichikawa, S.; Matsuda, A. Tetrahedron 2007, 63, 2798–
.
2804
.
(24) ꢀ-Fluoride was used in this study to clarify the reaction conditions.
The reaction with the corresponding R-fluoride gave the similar results
although not optimized.
(23) Hirano, S.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2008, 73, 569–
577
.
5108
Org. Lett., Vol. 10, No. 22, 2008

allylation9,15,16,25 was conducted. The reaction of 1 with
allyltrimethylsilane (2.0 equiv) in the presence of BF3·OEt2
(0.5 equiv) and MS 4Å in CH2Cl2 at 0 °C gave 2c. The
reaction proceeded smoothly within 10 min, and the desired
C-allylriboside 2c was obtained in 86% yield with excellent
ꢀ-selectivity (ꢀ/R > 98/2, entry 3). The stereochemistry at
the 1-position was determined by 500 MHz NOE experi-
ments, as shown in Figure 2. In addition, the coupling
Table 2. C-Allylation of 3-Pentylidene-Protected Ribosyl
Fluoride with Various Substituted Allyltrimethylsilanes
Figure 2. Key NOE correlations of the ꢀ-C-allylribosides.
constants of H-2, for all the C-allylribosides obtained in this
study, were 4.6 and 6.9 Hz, indicative that they had the same
stereochemistry at the anomeric position. The stereoselec-
tivity was not influenced by other activators such as SnCl4
or TiCl4, although the yield of 2c was reduced (entries 4
and 5). As for the cyanation and Mukaiyama-aldol-type
reactions, it cannot be completely excluded that the R-ano-
mers undergo epimerization to give the ꢀ-anomers, in
equilibrium. However, the products never interconvert in the
Sakurai-Hosomi-type allylation, and so the ꢀ-riboside must
be the kinetically controlled product. In the absence of MS
4Å, a large amount of 1-O-(ꢀ-D-ribofuranosyl)-ꢀ-D-ribofura-
noside 3, which is a C-2 symmetric dimer, was obtained as
a byproduct. Presumably, the dimer was obtained by ribo-
sylation of 5-O-benzyl-2,3-O-(3-pentylidene)-D-ribofuranose
generated by partial hydrolysis of the fluoride 1. It is
important to note that the stereogenic centers at the anomeric
positions of 3 were both in the ꢀ-configuration, and the other
possible diastereomers were not obtained at all. Namely,
ꢀ-selective O-ribosylation occurred to produce only the dimer
3 in this case.
With these promising results in hand, we expanded our
study of the reaction with various substituted allyltrimeth-
ylsilane derivatives (Table 2). Introduction of a substituent
at the R-position to the TMS group of allyltrimethylsilane
such as methyl 3-trimethylsilyl-4-pentenoate gave the desired
(25) Wilcox, C. S.; Otoski, R. M. Tetrahedron Lett. 1986, 27, 1011–
1014
.
(26) Hosomi, A.; Hashimoto, H.; Sakurai, H. Tetrahedron Lett. 1980,
21, 951–954.
(27) This was prepared by a cross-metathesis reaction of methyl acrylate
and allyltrimethylsilane in a manner similar to the procedure previouly
reported.29
a Combined isolated yields after chromatography. b Anomeric ratio
determined from 1H NMR integration values of selected protons. c Reaction
time was 1 h.
(28) Evans, D. A.; Aye, Y.; Wu, J. Org. Lett. 2006, 8, 2071–2073.
(29) Blanco, O. M.; Castedo, L. Synlett 1999, 5, 557–558.
Org. Lett., Vol. 10, No. 22, 2008
5109

C-allylriboside 2d in high yield and with excellent selectivity
(entry 1). Next, the reaction with ꢀ-substituted allytrimeth-
ylsilanes was examined. The reaction with methallyltrim-
ethylsilane gave 2e in a highly ꢀ-stereoselective manner
(entry 2). Acetoxymethyl and chloromethyl substitutions had
no influence on either the yield or the stereoselectivity, and
the corresponding C-allylribosides 2f and 2g were obtained
in a ꢀ-selective manner (ꢀ/R ) 97/3 for 2f, >98/2 for 2g)
in 88% and 93% yields (entries 3 and 4), respectively.
However, the presence of an electron-withdrawing substituent
such as an ester or a halogen at the ꢀ-position to the TMS
group required a long reaction time,26 and the yields of the
corresponding C-allylribosides 2h and 2i were decreased,
although the same high level of stereoselectivity remained
(entries 5 and 6).
heteroatom nucleophiles, the reaction generally tends to
proceed by addition to the activated sp2 center or stabilized
carbocation via an SN1 mechanism. Therefore, it is presumed
that the reaction pathways, including a direct SN2 substitution
of the fluoride 1 or its contact ion pair, might be suppressed,
and the reaction via the oxocarbenium ion is much more
dominant. This could partially account for the increased
ꢀ-selectivity in this study. The steric effect in the transition
state would contribute significantly to afford excellent
ꢀ-selectivity resulting in an unusual outside attack with
complete reversal of the stereoselectivity compared to a
general inside attack mechanism (Figure 1). This strategy
provides a new concept for the synthesis of ꢀ-C-ribosides,
where controlled steric hindrance in the transition state
determines the stereochemistry of C-glycosylation.
The effect of the substituent at the γ position to the TMS
group was also examined. Reaction of 1 with methyl
4-trimethylsilyl-2-butenoate27 did not proceed at all because
the electron-withdrawing nature of the ester at the γ position
strongly reduced the electron density at the nucleophilic γ
position of the allyltrimethylsilane (entry 7). An allyltrim-
ethylsilane with a phenyl28 or a benzyl group29 at the
γ-position smoothly reacted with 1 to provide the corre-
sponding branched C-allylribosides 2k and 2l in good yields
as a mixture of diastereomers at the additionally formed
stereocenter (entries 8 and 9). Furthermore, reaction with
propargyltrimethylsilane gave the corresponding allene de-
rivative 2m in an excellent ꢀ-selective manner (ꢀ/R ) 97/3,
entry 10).
In conclusion, we report herein a highly ꢀ-selective access
to C-allylribosides from 2,3-O-(3-pentylidene)-D-ribofura-
nosyl fluoride. The influence of this type of reaction in
synthetic and biological chemistry has been limited due to
the tendency for R-selective substitutions of ribosyl donors
promoted by Lewis acids. Our method now allows for the
convenient synthesis of biologically relevant molecules such
as C-nucleosides or natural products.
Acknowledgment. This work was supported by grants-
in-aid for scientific research from the Ministry of Education,
Science, Sports, and Culture. We thank Ms. S. Oka and Ms.
A. Tokumitsu (Center for Instrumental Analysis, Hokkaido
University) for measurement of the mass spectra.
As previously reported,21 high ꢀ-selectivity in a ribosy-
lation reaction could be explained by steric hindrance in the
transition state. Compared to our previous studies where
alcohols were employed as the nucleophiles (ꢀ/R ) 82/
18-97/3), nearly complete ꢀ-selectivity was observed when
carbon nucleophiles were used. Because of the inherently
weaker nucleophilic character of carbon nucleophiles versus
Supporting Information Available: Experimental pro-
cedures, 1H NMR, and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL8018743
5110
Org. Lett., Vol. 10, No. 22, 2008