A regio- and stereocontrolled approach to pyranosyl C-nucleoside synthesis

Article abstract of DOI:10.1021/ol801183e

(Chemical Equation Presented) Six novel diastereomerically pure C-nucleosides have been synthesized from nonchiral starting materials, using the ene/intramolecular Sakurai cyclization reaction demonstrating a simple, general, and stereocontrolled approach to pyranosyl C-nucleosides.

Full text of DOI:10.1021/ol801183e

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3323-3326
A Regio- and Stereocontrolled Approach
to Pyranosyl C-Nucleoside Synthesis
Philip Redpath,† Simon Macdonald,‡ and Marie E. Migaud*,†
Respiratory CEDD, SteVenage, SG1 2NY, U.K., and School of Chemistry and
Chemical Engineering, Queen’s UniVersity Belfast, Stranmillis Road,
Belfast BT9 5AG, Northern Ireland
m.migaud@qub.ac.uk
Received May 23, 2008
ABSTRACT
Six novel diastereomerically pure C-nucleosides have been synthesized from nonchiral starting materials, using the ene/intramolecular Sakurai
cyclization reaction demonstrating a simple, general, and stereocontrolled approach to pyranosyl C-nucleosides.
C-Nucleosides form a unique class of nucleosides in which the
glycosidic C-C bond between the sugar moiety (usually ribose)
and heterocycle is resistant to chemical and enzymatic cleavage.
C-Nucleosides, such as benzamide riboside 1 and tiazofurin 2
(Figure 1), are precursors to inhibitors of nicotinamide adenine
dinucleotide (NAD) dependent enzymes such as oxidoreduc-
tases1 and glycohydrolases,2,3 being converted to dinucleotide
cofactor analogues such as 3 (Figure 1).4
For instance, inosine monophosphate dehydrogenase (IM-
PDH), the enzyme which catalyzes the NAD-dependent
conversion of inosine 5′-monophosphate (IMP) to guanosine
5′-monophosphate (GMP), is key to the synthesis of guanine
† Queen’s University Belfast.
‡ Respiratory CEDD.
Figure 1. Known antiproliferative agents.
(1) Jager, W.; Salamon, A.; Szekeres, T. Cur. Med. Chem. 2002, 9, 781.
(2) Migaud, M. E.; Pederick, R. L.; Bailey, V. C.; Potter, B. V. L.
Biochemistry 1999, 38, 9105
(3) Batoux, N. E.; Paradisi, F.; Engel, P. C.; Migaud, M. E. Tetrahedron
2004, 60, 6609
(4) Gharehbaghi, K.; Grunberger, W.; Jayaram, H. N. Curr. Med. Chem.
2002, 9, 743.
.
nucleotides.5 It has been discovered that human IMPDH
exists as two isoforms, types I and II. The level of IMPDH
activity is much greater in several tumors as compared with
.
10.1021/ol801183e CCC: $40.75
Published on Web 07/04/2008
2008 American Chemical Society

normal tissue5 with the up-regulation of the type II isoform
in these rapidly replicating cells. Selective inhibition of this
dominant species, with reduced toxicity toward type I, would
be antiproliferative. Agents, such as benzamide riboside 1,
are very potent antiproliferatives but also display high
cytotoxic activity toward healthy cells.4 Consequently, it is
essential to synthesize novel C-nucleosides that possess
structural diversity to increase specific recognition in order
to optimize enzyme and cell selectivity and maintain high
levels of inhibition. Our focus is therefore on obtaining
benzamide riboside analogues that will be incorporated as
nicotinamide adenine dinucleotide mimics with potential to
be selective inhibitors of IMPDH. Although a number of
routes exist for the preparation of C-nucleosides, their scope
is very limited and lengthy.6–10 Herein, we report our initial
results in the establishment of a novel and stereocontrolled
route for the construction of a range of diastereomerically
pure pyranosyl C-nucleosides.
conditions. The latter uses n-butyllithium and tetramethyl-
ethyldiamine as base to deprotonate methallyl alcohol 4 and
traps the resulting carbanion with chlorotrimethylsilane.17
Allylsilane 5 was obtained in modest yields, with media
polarity critically affecting the outcome. Introduction of a
triisopropylsilyl (TIPS) moiety on compound 6 was required
in order to achieve higher yields in the subsequent synthetic
steps. The ene-reaction of allylsilane 6a with 3-cyanoben-
zaldehyde 7, promoted by diethylaluminium chloride
(Et2AlCl) led to the (Z)-homoallylic alcohol 8a with complete
control of the double bond geometry (Scheme 2).11
Scheme 2. Ene Reaction
Recently, Marko´ developed an efficient procedure for the
preparation of diastereomerically pure exo-methylene pyrans,
using the tandem ene/intramolecular Sakurai cyclization
(IMSC) of aldehydes with an allylsilane or an allylcarbam-
ate.11–15 This route, which offers great potential to a wide
range of D/L nucleoside analogues incorporating the essential
C-C glycosidic bond, has never before been applied to the
preparation of nucleoside mimetics (Scheme 1).16
Subsequent condensation with an appropriate second
aldehyde thereafter provided the framework for the desired
C-nucleoside (Scheme 3) due to the pseudoequatorial posi-
tions adopted by the silyloxy and cyanoaromatic ring in the
Scheme 1. Generic Structures of Synthetic Targets
Scheme 3. IMSC with Crotonaldehyde
Starting from the allyl alcohol 4, our initial strategy
involved the synthesis of allylsilane 5 in bulk using Trost’s
(5) Chen, L.; Petrelli, R.; Felczak, K.; Gao, G.; Bonnac, L.; Yu, J. S.;
Bennett, E. M.; Pankiewicz, K. W. Curr. Med. Chem. 2008, 15, 650.
(6) Krohn, K.; Dorner, H.; Zukowski, M. Curr. Med. Chem. 2002, 9,
727
.
oxycarbonium chairlike transition state.11 However, the
hydroxymethylene moiety that would be introduced at the
C5-position of the exo-methylene pyrans could not directly
be set in place in good yields due to the lack of reactivity of
R-hydroxyaldehydes toward the IMSC.11
(7) Ramesh, N. G.; Balasubramanian, K. K. Eur. J. Org. Chem. 2003,
23, 4477
(8) Schramm, V. L.; Tyler, P. C. Curr. Top. Med. Chem. 2003, 3, 525
(9) Franchetti, P.; Cappellacci, L.; Grifantini, M.; Jayaram, H. N.;
.
.
Goldstein, B. M. ACS Symp. Ser. 2003, 839, 212
.
(10) Shaban, M. A. E.; Nasr, A. Z. AdV. Heterocycl. Chem. 1997, 68,
223
.
(11) Marko´, I. E.; Dumeunier, R.; Leclercq, C.; Leroy, B.; Plancher,
J. M.; Mekhalfia, A.; Bayston, D. J. SynthesissStuttgart 2002, 958
.
(15) Leroy, B.; Marko´, E. I. J. Org. Chem. 2002, 67, 8744.
(16) For clarity purposes, carbohydrate numbering has been used in the
text C-1 corresponding to the etheral carbon linked to benzamide.
(17) Trost, B. M.; Chan, M. D. T.; Nanninga, T. N. Org. Synth. 1984,
62, 58.
(12) Leroy, B.; Marko´, E. I. Tetrahedron Lett. 2001, 42, 8685
(13) Leroy, B.; Marko´, E. I. Tetrahedron Lett. 2000, 41, 7225
.
.
(14) Pospisil, J.; Kumamoto, T.; Marko, I. E. Angew. Chem., Int. Ed.
2006, 45, 3357
.
3324
Org. Lett., Vol. 10, No. 15, 2008

Hence, 8a was cyclized with crotonaldehyde 9 activated by
BF3·OEt2, which was the most proficient Lewis acid at
catalyzing this synthetic step. The diastereomerically pure silyl-
protected exo-methylene tetrahydropyran 10a was obtained
along with the free alcohol 10b. Deprotection using tetrabuty-
lammonium fluoride (TBAF) and subsequent reprotection (for
handling purposes) of the crude mixture using acetic anhydride
in pyridine led to dialkene 11. The amide functionality was then
introduced by base-mediated hydrolysis of the nitrile in 11
(Scheme 3). The hydroxyl groups at C-6 and C-3 were
introduced by oxidative cleavage of the alkenes in 12 followed
by reduction of the dicarbonyl intermediate. Subsequent acety-
lation of these hydroxyls, purification, and acetyl removal then
yielded the final C-nucleoside 13 in 20% overall yield over four
steps (Scheme 4).18
etaldehyde 14 underwent the ene reaction with allylsilane
6b to give the (Z)-alkene intermediate 20 in satisfactory
yields. The benzamide pyrans 21a and 21b were then
obtained by IMSC with 3-cyanobenzaldehyde 7 (Scheme 6).
Scheme 6. Synthesis of Regioisomer 18
Scheme 4. Synthesis of Benzamide Riboside Analogue 13
Repetition of the procedures used for the synthesis of the
previous analogues, including selective reduction of a ketone
using sodium borohydride and cerium trichloride yielded the
C-nucleoside 18 (Scheme 6). The 2,3-syn-triol 19 was also
obtained quite readily (Scheme 7).
The IMSC was attempted with R-benzyloxyacetaldehyde 14,
knowing that the electron-withdrawing nature of the R-hydroxy
substituent would hinder the cyclization pathway.11 Indeed, as
anticipated, the IMSC reaction did occur in low yields and
provided a mixture of silylated and desilylated material. In situ
removal of the tert-butyldimethylsilyl (TBDMS) moiety pro-
vided the exo-methylene tetrahydropyran 15 in 25% yield over
two steps. This tetrahydropyran was then ozonized to give an
isolable ketone intermediate that was selectively reduced with
LS-Selectride; hydration of the nitrile occurred during workup
to produce 16. Cleavage of the benzyl ether at O-6 with TMSI
yielded the syn-configured C-nucleoside 17 (Scheme 5).
Scheme 7. Synthesis of Regioisomer 19
Attention now turned to constructing the 1,2-syn and 4,5-
syn stereoisomers 23 and 24 (Figure 2). Using the described
ene-silyl chemistry, these isomers were not obtainable, as
this methodology was exclusive to the (Z)-isomer, as
described by Marko´.
Scheme 5. Stereocomplementary Syn-Configuration 17
Figure 2. 1,2-syn-23 and 4,5-syn-24 stereoisomers.
Instead, Marko´’s group adopted an allyl-metalation pro-
tocol to achieve this type of stereochemistry.15 Using this
In order to access the regioisomers 18 and 19, the sequence
of aldehyde addition was exchanged. The R-benzyloxyac-
(18) Stereochemistry determined by NOE studies and J values from 1H
NMR.
Org. Lett., Vol. 10, No. 15, 2008
3325

procedure, allylsilane 5 was condensed with diisopropylcar-
bamoyl chloride to obtain 25. The lithiated species 26 was
treated with titanium tetraisopropoxide followed by benzal-
dehyde or R-benzyloxyacetaldehyde to access 27 and 28,
respectively (Scheme 8). The enol carbamates 27 and 28 were
the carbamate-promoted ene-ICMS chemistry to access the
benzamide riboside derivatives from 23 and 24. Alternative
synthetic sequences and oxazoline chemistry are currently
under investigation to overcome this difficulty. Compound
32 possessing a 3,4-syn stereochemistry, and its counterpart,
compound 33 possessing a 2,3-syn stereochemistry were two
isomers synthesized using this sequence. Work is currently
being carried out to obtain the anti-configured isomers
(Scheme 10).
Scheme 8. Ene-ICMS Strategy Using Carbamate Intermediate
Scheme 10. Synthesis of Isomers 32 and 33
isolated as single geometric (E)-isomers that smoothly
underwent IMSC with crotonaldehyde 9 to give 29 and with
1
benzaldehyde 30 to give 31, respectively. H NMR assign-
ments helped support the nature of each stereoisomer; they
were consistent with the literature, and the geometries of
the starting enol ethers (Scheme 9).11–15 Ozonolysis and
Scheme 9. Pyran 29 and 31 via IMSC
In summary, we have applied an established methodology
to a new synthetic purpose: the preparation of racemic D/L
pyranosyl C-nucleosides. Consequently, the first simple,
general, and stereocontrolled approach to these nucleosides
has been realized. With ongoing work, this approach should
broaden the methodologies available for novel C-nucleoside
synthesis. Notwithstanding their racemic nature, these ben-
zamide riboside analogues have potential antiproliferative
activity. Those best mimicking nicotinamide riboside are
likely to offer crucial information on enzyme-NAD recogni-
tion processes and enhance our knowledge of their biological
and conformational importance and assist in future rational
drug design.
reduction of the exo-cyclic alkenes in carbamates 29 and 31
proceeded much more efficiently compared with the corre-
sponding silyl derivatives. Unfortunately, lithium aluminum
hydride was the only reagent that could effectively remove
the carbamate protecting group from the C-2 or C-4 position
of the tetrahydropyrans. It is, however, incompatible with
nitrile functionality.15
Acknowledgment. This work was supported by DEL and
GSK.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
As a consequence, the amide functionality was difficult
to introduce or maintain throughout the synthesis when using
OL801183E
3326
Org. Lett., Vol. 10, No. 15, 2008