Synthesis of pyrrolidine C-nucleosides via Heck reaction.

Article abstract of DOI:10.1021/ol007029s

[figure: see text] A novel method for the synthesis of pyrrolidine C-nucleosides has been developed. The key step of the synthesis is the palladium(0)-mediated coupling of a disubstituted N-protected 2-pyrroline and 5-iodouracil. C-Nucleoside 14 and its N

Full text of DOI:10.1021/ol007029s

ORGANIC
LETTERS
2001
Vol. 3, No. 3
489-492
Synthesis of Pyrrolidine C-Nucleosides
via Heck Reaction
Adrian Ha1berli and Christian J. Leumann*
Department of Chemistry and Biochemistry, UniVersity of Bern, Freiestrasse 3,
3012 Bern, Switzerland
leumann@ioc.unibe.ch
Received December 20, 2000
ABSTRACT
A novel method for the synthesis of pyrrolidine C-nucleosides has been developed. The key step of the synthesis is the palladium(0)-mediated
coupling of a disubstituted N-protected 2-pyrroline and 5-iodouracil. C-Nucleoside 14 and its N-methyl derivative 15 can easily be converted
to the corresponding phosphoramidite building blocks for DNA synthesis.
In the context of our ongoing research on the synthesis and
properties of oligonucleotide analogues, we became inter-
ested in an efficient access to pyrrolidine C-nucleoside
building blocks for DNA synthesis.
bond formation was performed by the addition of the lithium
or Grignard reagents of the heterocycles to the corresponding
substituted γ-lactams or related compounds.4-7 Abasic pyr-
rolidine 2′-deoxy-C-nucleoside and pyrrolidine 2′-deoxyad-
enosine with an additional CH2-unit between C-1′ and the
base were incorporated into DNA by Verdine and co-
workers. These oligomers were tested as inhibitors for
glycosidase II and base-excision DNA repair enzymes.8,9
Starting from 2-deoxy-D-ribose, Kim et al. synthesized
N-acetyl-pyrrolidine-2′-deoxy-â-D-pseudouridine in 19 steps
in an overall yield of 3.4% via Staudinger-aza-Wittig
cyclization of a 2,4-di-O-benzylpyrimidin-5-yl-substituted
γ-azido ketone.10
Several pyrrolidine C-nucleosides with aromatic (hetero)-
cycles, such as substituted phenyls, imidazoles, or 9-deaza-
guanine, as aglycons were synthesized as transition state
inhibitors for nucleoside hydrolases or nucleoside phos-
phatases by Schramm and co-workers. The aglycon was
introduced via addition of the corresponding aryl-lithium or
aryl-Grignard reagents to the imine function of substituted
3,4-dihydro-2H-pyrroles.1-3 Yokoyama and co-workers syn-
thesized different stereoisomers of pyrrolidine C-nucleosides,
pyrrolidine 2′-deoxy-C-nucleosides, and pyrrolidine 2′,3′-
dideoxy-C-nucleosides as glycosidase inhibitors. The C-C
Palladium-mediated coupling reactions of furanoid glycals
with appropriate aglycon derivatives were successfully
employed for the regio- and stereospecific formation of
(1) Horenstein, B. A.; Zabinski, R. F.; Schramm, V. L. Tetrahedron Lett.
1993, 34, 7213.
(2) Furneaux, R. H.; Limberg, G.; Tyler, P. C.; Schramm, V. L.
Tetrahedron 1997, 53, 2915.
(3) Evans, G. B.; Furneaux, R. H.; Gainsford, G. J.; Schramm, V. L.;
Tyler, P. C. Tetrahedron 2000, 56, 3053.
(8) Scha¨rer, O. D.; Ortholand, J.-Y.; Ganesan, A.; Ezaz-Nikpay, K.;
Verdine, G. L. J. Am. Chem. Soc. 1995, 117, 6623.
(9) Deng, L.; Scha¨rer, O. D.; Verdine, G. L. J. Am. Chem. Soc. 1997,
119, 7865.
(4) Yokoyama, M.; Ikeue, T.; Ochiai, Y.; Momotake, A.; Yamaguchi,
K.; Togo, H. J. Chem. Soc., Perkin Trans. 1 1998, 2185.
(5) Momotake, A.; Mito, J.; Yamaguchi, K.; Togo, H.; Yokoyama, M.
J. Org. Chem. 1998, 63, 7207.
(6) Momotake, A.; Togo, H.; Yokoyama, M. J. Chem. Soc., Perkin Trans.
1 1999, 1193.
(10) Kim, D. C.; Yoo, K. H.; Kim, D. J.; Chung, B. Y.; Park, S. W.
Tetrahedron Lett. 1999, 40, 4825.
(11) Farr, R. N.; Outten, R. A.; Cheng, J. C.; Daves, G. D. Organo-
metallics 1990, 9, 3151.
(12) Hsieh, H.-P.; McLaughlin, L. W. J. Org. Chem. 1995, 60, 5356.
(13) Zhang, H.-C.; Brakta, M.; Daves, G. D. Nucleosides Nucleotides
1995, 14, 105.
(7) Yokoyama, M.; Ikenogami, T.; Togo, H. J. Chem. Soc., Perkin Trans.
1 2000, 2067.
(14) Coleman, R. S.; Madaras, M. L. J. Org. Chem. 1998, 63, 5700.
10.1021/ol007029s CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/17/2001

C-glycosidic bonds.11-14 Zhang et al. used Heck chemistry
for the synthesis of 2′-deoxypseudouridine15 (Scheme 1). Less
Scheme 2. Synthesis of N-CBz Enamine 5a
Scheme 1. Retrosynthesis of 2′-Deoxypseudouridine (1) by
Zhang et al.15 and of the C-Aza-furanose Nucleoside 4a
a CBz, benzyloxycarbonyl; TBDMS, tert-butyldimethylsilyl.
a (a) Fmoc-Cl, dioxane, 5% aq. NaHCO3 soln, 0 °C f rt, 9 h;
(b) BH3‚(CH3)2S, THF, reflux, 2 h; (c) TBDMS-Cl, imidazole, THF,
rt, 2 h; (d) piperidine, THF, rt, 12 h; (e) NCS (N-chlorosuccinimide),
hexane, rt, 1 h; (f) LTMP (lithium 2,2,6,6-tetramethylpiperidide),
THF, -78 °C, 2 h; (g) benzyl chloroformate, NEt3, THF, -78 °C
f rt, 8 h.
is known about the palladium-catalyzed reactions to form a
C-C bond between N-protected enamines and hetero-
cycles.16,17 In this communication we report on the regio-
and stereospecific synthesis of pyrrolidine-2′-deoxypseudo-
uridine and of its N-1-methyl derivative (pyrrolidine-
pseudothymidine) using Heck chemistry, as well as their
elaboration into phosphoramidite building blocks for DNA
synthesis. As a key step the palladium-mediated coupling
of CBz-protected enamine 5 and 5-iodouracil (3) was chosen
(Scheme 1).
As starting material the commercially available trans-3-
hydroxy-L-proline (6) was chosen, which already possesses
the correct stereochemistry at C(2) and C(3). The amino
group was protected as Fmoc carbamate, followed by the
selective reduction of the carboxylic acid of 7 with the
BH3‚S(CH3)2 complex in almost quantitative yield to give
diol 8.18 In a one-pot reaction, both hydroxy groups were
protected as TBDMS ethers, followed by the cleavage of
the Fmoc group with piperidine (f 9). To introduce the
enamine functionality, 9 was N-chlorinated with NCS
followed by the LTMP-mediated elimination of HCl at -78
°C, after a procedure by Schramm and co-workers.2 NMR
data of the intermediate 3,4-dihydro-2H-pyrrole derivative,
which can be isolated by FC, proved that the deprotonation
occurred exclusively at the C(5) position. CBz-protected
enamine 5 was obtained after the addition of benzyl
chloroformate and NEt3 to the in situ formed imine at low
temperature. Overall yield of 5 from 6 was 52% (Scheme
2).
(10b, synthesized from 10a by Br-Li exchange, followed
by the reaction with I2, entries 3-7) were unsuccessful. The
coupled product 11 was only obtained in the reaction of 5
and 10b in low yields of less than 5% using Pd(OAc)2 as
catalyst with PPh3 or bppp as ligand and NBu3 as base and
carrying out the reaction in CHCl3 at 60 °C for several days
(entries 8 and 9).11 Higher temperatures and longer reaction
times led to the decomposition of the starting materials.
Iodide 10b was then replaced by the commercially available,
unprotected 5-iodouracil (3). The Heck reaction of 5 and 3
using PPh3, bppp, or P(C6F5)3 as ligands led to unreacted
Scheme 3. Palladium-Mediated Heck Couplinga
Our initial experiments on the palladium(0)-catalyzed
coupling of enamine 5 with 5-bromo- (10a,19 Scheme 3,
Table 1 entries 1 and 2) or 5-iodo-2,4-di-O-benzylpyrimidine
(15) Zhang, H.-C.; Daves, G. D. J. Org. Chem. 1992, 57, 4690.
(16) Gurjar, M. K.; Pal, S.; Rao, A. V. R. Heterocycles 1997, 45, 231.
(17) Nilsson, K.; Hallberg, A. J. Org. Chem. 1990, 55, 2464.
(18) Jordis, U.; Sauter, F.; Siddiqi, S. M.; Ku¨enburg B.; Bhattacharya
K. Synthesis 1990, 925.
a Experimental conditions, see Table 1. TBDMS, tert-butyldi-
methylsilyl.
(19) Schinazi, R. F.; Prusoff, W. H. J. Org. Chem. 1985, 50, 841.
490
Org. Lett., Vol. 3, No. 3, 2001

Table 1. Reaction Conditions and Yields of the Heck Coupling of 5 with 3 or 10 to 11 or 12a
entry
aglycon
catalyst
base
ligand
PPh3
additive
solvent
temp
yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
10a
10a
10b
10b
10b
10b
10b
10b
10b
3
Pd(Ph3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
P d (OAc)2
P d (OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
P d (OAc)2
NEt3
CH3CN
DMF
CHCl3
CH3CN
DMF
80 °C
rt
K2CO3
NBu3
NBu3
Ag2CO3
NBu3
NaHCO3
NEt3
NBu 3
NBu3
NBu3
NBu3
NBu3
NBu 3
Bu4NCl
PPh3
PPh3
PPh3
60 °C
80 °C
80 °C
90 °C
60 °C
60 °C
60 °C
60 °C
60 °C
65 °C
65 °C
65 °C
Na-acetate
Bu4NCl
DMF
DMF
P P h 3
bp p p
PPh3
bppp
PPh3
CHCl3
CHCl3
CHCl3
CHCl3
DMF
<5%
<5%
3
3
3
3
P(C6F5)3
AsP h 3
DMF
DMF
50-58%
a Scheme 3, catalyst concentration 10-33 mol %. If no coupling product was observed, the reactions were stopped after 2 days. bppp,
1,3-bis(diphenylphosphino)propane.
starting material or to decomposition at higher temperatures.
No product arising from Heck coupling could be isolated
(entries 10-13). Finally, 12 was obtained in a yield of 58%
after replacement of the phosphine ligands by the “soft”
ligand AsPh320 and by using DMF as the solvent (entry 14).
As expected,11-15 the double bond flipped to the 3,4-position
of the pyrrolidine ring. The R-configuration of the new
stereocenter was proven at a later stage.
Both silyl ethers of 12 were cleaved with TBAF under
mild acidic deprotection conditions. At -15 °C the obtained
keto group was stereoselectively reduced with NaB-
(OAc)3H.15 Diol 4 was separated by FC from a minor
stereoisomer (<5%), which was not further analyzed. The
corresponding N-1-Me compound 13 was obtained in 77%
yield after reaction of the tetrasilyl derivative of 4, which
was prepared in situ, with CH3I for 70 h.21 Pd-catalyzed
hydrogenation of the CBz group of 4 and 13 was achieved
at a H2 pressure of 1 bar. For determination of the relative
configuration, amine 14 was converted into the N-acetyl
compound 16. The NMR data of 16 were identical with those
reported for the same compound in the literature10 and proved
the expected (2R,4S,5R)-configuration (independent confir-
mation by NOE experiments). For the remaining part of the
synthesis, 14 and 15 were N-protected with the Fmoc group
that was shown earlier to be compatible with standard
oligonucleotide synthesis.8 The phosphoramidite building
blocks 19 and 20 were obtained by dimethoxy-tritylation of
the primary alcohol of 17 and 18, respectively, followed by
Scheme 4. Synthesis of Phosphoramidites 19 and 20a
a (a) AcOH, TBAF, THF, -15 °C f rt, 37 h; (b) NaB(OAc)3H, AcOH, CH3CN, -15 °C f rt, 20 min; (c) BSA, CH3I, CH2Cl2, rt, 70
h; (d) H2, Pd/C, MeOH, rt, 4 h; (e) Ac2O, MeOH, H2O, 0 °C f rt, 2.5 h; (f) Fmoc-OSu, THF, dioxane, 5% aq. NaHCO3 soln, rt, 3 h; (g)
DMT-Cl, pyridine, rt, 2 h; (h) (iPr2N)(NCCH2CH2O)PCl, iPr2NEt, THF, rt, 2 h.
Org. Lett., Vol. 3, No. 3, 2001
491

reaction with 2-cyanoethyl N,N-diisopropylchlorophosphora-
midite. The amidites 19 and 20 can be directly used for
standard cyanoethyl phosphoramidite oligonucleotide syn-
thesis. The total yields of 19 and 20 from 6 were 14% and
6%, respectively (Scheme 4).
In conclusion, an efficient method for the syntheses of
the pyrrolidine-2′-deoxypseudouridine phosphoramidite build-
ing block 19 and its N-1-methyl derivative 20 (pyrrolidine-
pseudothymidin) was developed. It was shown that Heck-
type reactions can be employed to build up pyrrolidine
C-nucleosides from the corresponding N-protected enamines
and functionalized heterocycles. However, the reaction
conditions, especially the tuning of the electronic properties
of the ligand, are critical for the success of the Pd-catalyzed
coupling. AsPh3 as a “soft” ligand of monodentate donicity
proved to be appropriate.
The incorporation of the new phosphoramidites into
oligonucleotides and the evaluation of their biophysical and
biological properties are in progress.
Acknowledgment. This work was supported by a re-
search grant from the Swiss National Science Foundation
and a Ph.D. grant from Novartis.
Supporting Information Available: Experimental pro-
cedure for the synthesis of all compounds and their spec-
troscopic characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) Kojima, A.; Honzawa, S.; Boden, C. D. J.; Shibasaki, M. Terahedron
Lett. 1997, 38, 3455.
(21) Bhattacharya, B. K.; Devivar, R. V.; Revankar, G. R. Nucleosides
Nucleotides 1995, 14, 1269.
OL007029S
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Org. Lett., Vol. 3, No. 3, 2001