Synthesis of N-glycosides. An alternative approach based on diastereoselective base coupling and SN2 cyclization

Article abstract of DOI:10.1021/ol016991i

Chemical equation presented Acyclic diastereoselection is achieved for the formation of thioaminyl acetals. The highly intramolecular stereocontrolled S_N2 displacement of the thioaminyls allows for the formation of cyclic nucleoside derivatives

Full text of DOI:10.1021/ol016991i

ORGANIC
LETTERS
2002
Vol. 4, No. 2
241-244
Synthesis of N-Glycosides. An
Alternative Approach Based on
Diastereoselective Base Coupling and
SN2 Cyclization
Yvan Guindon,* Marc Gagnon, Isabelle Thumin, Daniel Chapdelaine,
Grace Jung, and Brigitte Gue´rin
Institut de recherches cliniques de Montre´al (IRCM), Bio-organic Chemistry
Laboratory, 110 aVenue des Pins Ouest, Montre´al, Que´bec, Canada H2W 1R7, and
Department of Chemistry and Department of Pharmacology, UniVersite´ de Montre´al,
C.P. 6128, succursale Centre-Ville, Montre´al, Que´bec, Canada H3C 3J7
guindoy@ircm.qc.ca
Received November 1, 2001
ABSTRACT
Acyclic diastereoselection is achieved for the formation of thioaminyl acetals. The highly intramolecular stereocontrolled SN2 displacement of
the thioaminyls allows for the formation of cyclic nucleoside derivatives. This versatile approach may provide easy access to a large variety
of N-glycosides.
N-Glycosides and their acyclic derivatives are compounds
of great medicinal interest.1 The synthesis of nucleosides1,2
Scheme 1
generally involves both SN1 and SN2 displacements of a
leaving group by a silylated purine or pyrimidine (the
Vorbru¨ggen modification2b) at the anomeric carbon of a five-
membered ring carbohydrate derivative (Scheme 1). SN1-
type processes occur more frequently because the presence
of an oxygen on the carbon bearing the leaving group
generally allows for the stabilization of any developing
carbon-centered positive charge through the formation of an
oxonium ion. In the SN1-type process, facial differentiations
can be achieved using, for example, the anchimeric assistance
of neighboring groups2b or internal base delivery.3
The SN2-type process2b has been observed in approaches
such as fluoride displacement or electrophilic addition
involving glycals. The intermediates formed in the latter
reaction include glucal epoxides,4 iodonium ions,5 and
(1) (a) Vorbru¨ggen, H.; Ruh-Pohlenz, C. In Organic Reactions; Paquette,
L. A., et al., Eds.; John Wiley & Sons: New York, 2000; Vol. 55, pp 3-111.
(b) Wilson, L. J.; Hager, M. W.; El-Kattan, Y.; Liotta, D. C. Synthesis
1995, 1465. (c) Lukevics, E.; Tablecka, A. In Nucleoside Synthesis
Organosilicon Methods; Horwood, E., Ed.; New York, 1991.
(2) (a) Mukaiyama, T.; Katsurada, M.; Takashima, T. Chem. Lett. 1991,
985. (b) Anchimeric assistance of neighboring groups: Vorbru¨ggen, H.;
Kroilkiewicz, K.; Bennua, B. Chem. Ber. 1981, 114, 1234. (c) Mukaiyama,
T.; Matsubara, K.; Suda, S. Chem. Lett. 1991, 891. (d) Paulsen, H.; Tietz,
H. Angew. Chem. 1985, 97, 118; Angew. Chem., Int. Ed. Engl. 1985, 24,
128. (e) Nicolaou, K. C.; Sietz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.
1983, 105, 2430. (f) Kahne, D.; Walker, S.; Cheng, Y.; Van Engen, D. J.
Am. Chem. Soc. 1989, 111, 6881. (g) Ratcliffe, A. J.; Konradsson, P.; Fraser-
Reid, B. J. Am. Chem. Soc. 1990, 112, 5665.
(3) Sujino, K.; Sugimura, H. Tetrahedron Lett. 1994, 35, 1883.
(4) Chow, K.; Danishefsky, S. J. Org. Chem. 1990, 55, 4211.
(5) Kim, C. U.; Misco, P. F. Tetrahedron Lett. 1992, 34, 5733.
10.1021/ol016991i CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/21/2001

phenylselenium ions.6 Dominant in the approaches used to
date for the synthesis of N-glycosides has been the fact that
the base is always introduced on the cyclic sugar. Acyclic
N-glycosides have even been prepared from cyclic inter-
mediates through ring cleavage of the sugar.7
Lacking in literature have been strategies involving a base
coupling step that precedes a cyclization as illustrated in
Scheme 2. A rare example of such an approach is Liotta’s
speaking, an electron-withdrawing group should be present
on the nitrogen to render the nitrogen electron deficient,
making more energy demanding the creation of an iminium
ion intermediate in a competitive SN1-like process. We
hypothesized that silylated purines and pyrimidines would
be judicious choices of amines and that an intramolecular
SN2 displacement of the sulfur on the thioaminyl by the
hydroxyl group at C4 should lead to N-glycosides (Scheme
2b).9 The preliminary results of our study are depicted herein.
Dithioacetal 1 was used to evaluate the reactivity of
different thiol activating reagents in the silylated base
coupling step. Hg(OAc)2/TMSOTf 10 and dimethyl(meth-
ylthio)sulfonium tetrafluoroborate (Me2S(SMe)BF4)11 have
both proven to be successful conditions as seen in Table 1.
Promising ratios of 4:1 and 13:1 were obtained in favor of
syn product 2a when silylated uracil was used (Table 1,
entries 1 and 2). Replacing the methyl with a silyl ether
(OTBS) resulted in a significant increase in diastereoselec-
tivity (cf. entries 1 and 3 as well as entries 2 and 4, Table
1).12 Similarly, excellent diastereoselectivity and yield were
obtained when thioacetal 3 was treated with either thymine
(Table 1, entries 5 and 6) or cytosine (Table 1, entries 7 and
8). The silylated adenine was coupled effectively with
dithioacetal 3 using Hg(OAc)2/TMSOTf (Table 1, entry 9).13
Scheme 2
Substrates bearing a primary or secondary alkoxy group
at C4 were also considered. With the exception of 12 (Table
1, entry 12),14,15 all substrates tested gave excellent results
(Table 1, entries 10, 11, 13, and 14).16
synthesis of AZT (R1 ) OBz, R3 ) N3, R4 ) H, X)OBn),
wherein an SN1 pathway is responsible for the anomeric
stereochemistry (Scheme 2a).8 The challenging strategy we
propose (Scheme 2b) is based on a diastereoselective
introduction of the silylated base to an acyclic dithioacetal
intermediate and a subsequent SN2-like intramolecular dis-
placement.
A few years ago, we became interested in inducing on
acyclic molecules stereogenic centers bearing a C-N bond.
One of the approaches we have developed in this context is
based on a diastereoselective transformation of thioacetals.
The first step of the approach to be depicted herein involves
the formation of a thionium ion intermediate to which an
amine is added in order to generate the thioaminyl acetal
(Scheme 3).
A couple of conclusions can be drawn at this point. The
use of Hg(OAc)2/TMSOTf and Me2S(SMe)BF4 in the first
step was effective in selectively activating the sulfur.
Additionally, the presence of an alkoxy group (OR1, 1,2-
induction, Scheme 3) on the stereogenic center R to the
dithioacetal17 during addition of the silylated base was
successful in promoting excellent diastereoselectivity. Two
(9) The synthesis of disaccharide proposed by Hindsgaul bears a similarity
to our approach in that cyclization occurs as the final step: McAuliffe, J.
C.; Hindsgaul, O. J. Org. Chem. 1997, 62, 1234.
(10) Bra˚nalt, J.; Kvarnstro¨m, I.; Niklasson, G.; Svensson, S. C. T.;
Classon, B.; Samuelsson, B. J. Org. Chem. 1994, 59, 1783.
(11) Trost, B. M.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529.
(12) Proof of the structure was obtained through crystallization of 4a
followed by X-ray analysis. See Supporting Information.
(13) The coupling of this base was less successful in the presence of
Me2S(SMe)BF4, giving complex mixtures of thioaminyl acetals. Similar
results were obtained with guanine in the presence of either thiol activating
reagent, an issue that will have to be revisited with modified purine bases.
Regioselectivity in the synthesis of purine nucleosides is discussed in ref
1a. Additional approaches such as the blocking of nitrogen functions were
not considered in this study.
Scheme 3
(14) Bernardi et al. have shown that allylmagnesium bromide addition
to 2,3-syn- and 2,3-anti-dialkoxy aldehydes also takes place with different
degrees of stereocontrol, the syn substrate giving the highest ratio: Bernardi,
R.; Fuganti, C.; Grasselli, P. Tetrahedron Lett. 1981, 22, 4021.
(15) A mixture of SEt/SMe compounds was obtained from 12. A control
experiment involving cyclization of the corresponding isolated SEt and SMe
products in the presence of Me2S(SMe)BF4 gave products 23a:23b with
similar ratios, indicating that the SMe/SEt exchange does not occur after
the introduction of thymine and is not responsible for the erosion of
diastereoselectivity.
(16) The 1,2-anti relative stereochemistry of 9b was confirmed by X-ray
analysis. See Supporting Information.
(17) For more on the use of dithioacetals in diastereoselective processes,
see: (a) Shibata, N.; Fujita, S.; Gyoten, M.; Matsumoto, K.; Kita, Y.
Tetrahedron Lett. 1995, 36, 109. (b) Mori, I.; Bartlett, P. A.; Heathcock,
C. H. J. Org. Chem. 1990, 55, 5966.
Diastereoselectivity is induced through the transfer of
stereochemical information originating from the stereogenic
center adjacent to the thioacetal (1,2-induction). The resulting
thioaminyl acetal is further transformed through an SN2-type
process to preserve chirality. For the latter to occur, tactically
(6) (a) D´ıaz, Y.; El-Laghdach, A.; Matheu, M. I.; Castillo´n, S. J. Org.
Chem. 1997, 62, 1501. (b) D´ıaz, Y.; El-Laghdach, A.; Castillo´n, S.
Tetrahedron 1997, 53, 10921.
(7) Elkattan, Y.; Gosselin, G.; Imbach, J. L. J. Chem. Soc., Perkin Trans.
1 1994, 10, 1289.
(8) Hager, M. W.; Liotta, D. C. J. Am. Chem. Soc. 1991, 113, 5117.
242
Org. Lett., Vol. 4, No. 2, 2002

Table 1. Introduction of the Silylated Base, Model Study
Figure 1. Proposed transition states for the base coupling.
substrate 18a in the presence of Me2S(SMe)BF4 was highly
stereocontrolled, and an excellent yield of trans product 19a
was obtained (Table 2, entry 1). Similarly, the cyclization
of 18b gave exclusively product 19b (Table 2, entry 2).
Mixtures of 1,2-syn/anti thioaminyl acetals were reacted with
Me2S(SMe)BF4. The corresponding trans and cis N-glyco-
sides were obtained in the same ratios as the starting products
(Table 2, entries 3-5).18 This and the reversal of stereo-
Table 2. Cyclization of Various Substrates
a Conditions A: Silylated base, Hg(OAc)2, TMSOTf, CH2Cl2, 23 °C,
24 to 48 h. B: Silylated base, Me2S(SMe)BF4, CH3CN, -20 to 0 °C, 2 to
1
12 h. b Ratios were determined by H NMR spectroscopy. c A mixture of
SEt:SMe (3:1) products was obtained.
transition states involving thionium ions can be proposed to
account for the anti and syn products in the base coupling
step (Figure 1). In the lowest-energy syn-predictive transition
state A, the hydrogen at C2 is almost in the same plane as
the thionium ion,17b and the incoming nucleophile reacts on
the face opposite the alkoxy group.
The second step of the sequence involved the intra-
molecular displacement of the activated SR group by the
hydroxyl group at C4. As seen in Table 2, the cyclization of
a Conditions: Me2S(SMe)BF4, THF, 25 °C, 1 h. b Ratios were determined
by 1H NMR spectroscopy. c SMe thioaminyl acetal was used as the starting
material.
Org. Lett., Vol. 4, No. 2, 2002
243

chemistry observed at the carbon center bearing the hetero-
cycles were strong indicators of the SN2-like character of
this reaction.
scope of these reactions will be studied further as will the
possibility of using other nucleophiles in both intra- and
intermolecular displacements for the second step of the
reaction sequence.
In conclusion, this study shows that reversing the normally
accepted order of carbon heteroatom bond formation (i.e.,
the C-N bond prior to the C-O bond) is as a strategy viable
for the formation of N-glycosides. Also shown is that acyclic
diastereoselection can be achieved for the formation of
thioaminyl acetals, compounds with potential medicinal
significance. The highly stereocontrolled SN2 displacement
of the thioaminyls can allow for the formation of cyclic
nucleoside derivatives. This versatile approach may provide
easy access to different N-glycosides (L, D, R, and â). The
Acknowledgment. The authors thank NSERC for its
financial support as well as Ms. LaVonne Dlouhy for her
assistance in the preparation of this manuscript.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1-33;
determination of the relative configuration for compounds
4a, 9b, 19a, 19b, 21a, 21b, 23a, 23b, 25a, and 25b; and
NMR spectra for compounds 2a, 2b, 3, 5-7, 9a, 11a, 11b,
13-18, 20-25, and 29-32. This material is available free
of charge via the Internet at http://pubs.acs.org.
(18) Relative configuration of the cyclized products was established by
correlation of NMR chemical shifts. See Supporting Information. The NMR
assignments were verified by the X-ray crystallographic structure of 25a
and by NOESY experiments of cyclized products 19a and 19b as well as
23a and 23b.
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Org. Lett., Vol. 4, No. 2, 2002