Total Synthesis of 3′,5′-C-Branched Nucleosides

Article abstract of DOI:10.1021/ol035619v

(Formula presented). A novel total synthesis of 3′,5′-C- branched uridine azido acid has been accomplished using stereoselective aldehyde alkynylation, Ireland-Claisen rearrangement, and iodolactonization as the key reactions. Compared to traditional rout

Full text of DOI:10.1021/ol035619v

ORGANIC
LETTERS
2003
Vol. 5, No. 21
3999-4001
Total Synthesis of 3′,5′-C-Branched
Nucleosides
Eriks Rozners* and Qun Xu
Department of Chemistry and Chemical Biology, Northeastern UniVersity,
Boston, Massachusetts 02115
e.rozners@neu.edu
Received August 26, 2003
ABSTRACT
A novel total synthesis of 3′,5′-C-branched uridine azido acid has been accomplished using stereoselective aldehyde alkynylation, Ireland−
Claisen rearrangement, and iodolactonization as the key reactions. Compared to traditional routes that start from carbohydrates, the present
methodology is more efficient, flexible for future optimization, and provides access to both enantiomers of the products. Because the key
chemistry does not involve the 3′- and 5′-C substituents, our route is a general approach to 3′,5′-C alkyl nucleoside analogues.
Biopolymer mimics possessing controllable folding into well-
defined structures represent a broad and active research area.1
Among biopolymers, RNA is unique because it exhibits the
two functions most important for life: information storage
and catalysis. RNA mimics with improved chemical stability,
folding, and catalytic function will be extremely useful in
biomedicine, materials science, and industrial applications.
Our recent work suggests that replacement of the negatively
charged phosphates by a neutral amide backbone will create
RNA mimics with promising biophysical properties.2 How-
ever, synthetic challenges, in particular, poor access to
monomeric amino acid equivalents 1 (Figure 1), have so far
hindered full exploration of amide-linked RNA.
bonds in a highly functionalized and sensitive molecule and
would be an inherently complicated and inefficient task.6
Recently, we proposed a new total synthesis approach to
related 3′-C-branched azido acids.7 In this communication,
we report the total synthesis of uridine azido acid 1a using
a novel and general approach to 3′,5′-C-branched ribonucleo-
sides.
Our retrosynthetic analysis of 1 (Figure 1) first disconnects
the heterocyclic base and after functional group adjustment
identifies lactone 2 as the first key intermediate. Opening of
the five-membered tetrahydrofuran ring (iodolactonization)
reveals the unsaturated carboxylic acid 3. These disconnec-
tions reduce the complexity from two heterocycles and four
Despite some progress3 in synthesis and structural studies
on amide linkages in DNA4 and RNA,5 azido acids 1 and
the corresponding oligoamides have not been prepared. The
3′,5′-C-branched nucleosides are particularly difficult to make
using the traditional carbohydrate chemistry. Synthesis from
nucleosides requires formation of two new carbon-carbon
(1) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893-4011.
(2) (a) Rozners, E.; Stro¨mberg, R. Nucleosides Nucleotides 1997, 16,
967-970. (b) Rozners, E.; Katkevica, D.; Bizdena, E.; Stro¨mberg, R. J.
Am. Chem. Soc. 2003, 125, in press.
(3) For reviews, see: (a) Freier, S. M.; Altmann, K. H. Nucleic Acids
Res. 1997, 25, 4429-4443. (b) De Mesmaeker, A.; Waldner, A.; Lebreton,
J.; Fritsch, V.; Wolf, R. M. In Carbohydrate Modifications in Antisense
Research; Sanghvi, Y. S., Cook, P. D., Eds.; American Chemical Society:
Washington, DC, 1994; pp 24-39.
Figure 1. Retrosynthetic analysis of 3′,5′-C-branched nucleosides.
10.1021/ol035619v CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/19/2003

Scheme 1. Total Synthesis of Racemic 3′,5′-Branched
Scheme 2. Synthesis of 3′,5′-Branched Uridine from Glucosea
Uridinea
a Conditions: (a) TBDPSCl, imidazole, DMF, rt, 24 h; (b) NaOH,
iso-PrOH, 70 °C, 30 min, 77% (two steps); (c) MeSO2Cl, NEt3,
CH2Cl2, 0 °C to rt, overnight; (d) NaN3, DMF, 60 °C, 20 h, 76%
(two steps); (e) BCl3, CH2Cl2/hexanes (6/1), -78 °C, 20 min; (f)
Ac2O/pyridine (1/1), rt, 24 h, 61% (two steps); (g) 2,4-O,O′-
bis(trimethylsilyl)uracil, TMSOTf, CH2Cl2, rt, 1.5 h, 86%.
a Conditions: (a) n-BuLi, THF, -78 °C then 6, THF, -78 °C,
4 h, 81%; (b) Lindlar catalyst, H2, MeOH, rt, 2 h 15 min; (c) 7,
DCC, DMAP, CH2Cl2, 0 °C to rt, 3 h, 92% (two steps); (d)
LHMDS, TMSCl, THF, -78 °C to rt, 3.5 h; (e) I2, NaHCO3, THF/
H2O (5/12), 0 °C, 3 h, 66% (two steps and recycling); (f) Zn, NH4Cl,
H2O/ethyl acetate, rt, 2.5 h; (g) Bu3SnH, AIBN, toluene, 95 °C, 1
h 25 min, 96%; (h) TFA, Et3SiH, CH2Cl2, 0 °C, 30 min, 81%; (i)
MeSO2Cl, NEt3, CH2Cl2, 0 °C to rt, overnight, 93%; (j) NaN3,
DMF, 60 °C, 4 h, 94%; (k) BCl3, CH2Cl2/hexanes (10/1), -78 to
-20 °C, 3 h, 91%; (l) DIBAL-H, THF, -85 °C, 3 h, 65%
(recycling); (m) Ac2O/pyridine (1/1), 24 h, rt, 94%; (n) 2,4-O,O′-
bis(trimethylsilyl)uracil, TMSOTf, CH2Cl2, rt, 2 h, 86%.
stereoselectivity in the iodolactonization step could be
alleviated by recycling of the cis isomer: treatment with Zn
powder in aqueous NH4Cl followed by iodolactonization
increased the combined yield of 9 to 60 and 66% after one
and two recyclings, respectively. Structural assignment of
the trans and cis isomers of 9 was initially performed using
NOESY experiments and later confirmed by independent
synthesis of 16.
Reductive removal of iodine, installation of the azido
function, and removal of the benzyl protecting group gave
the azido lactone 13. Selective reduction of the lactone9 in
13 was somewhat capricious, possibly because of the
spatially close azide function. The best result was achieved
when the reaction was stopped and the products were
separated at approximately 30% conversion. Recycling of
recovered starting material gave 14rac in acceptable yield.
Acylation of the free hydroxyl groups and standard nucleo-
side synthesis proceeded uneventfully to complete the total
synthesis of 3′,5′-C-branched uridine 16rac in 13 steps and
16% overall yield from 5 and 6.
stereogenic centers in 1 to only two stereogenic centers in
the acyclic 3. Acid 3 can be obtained from allylic ester 4
via Ireland-Claisen rearrangement. Further disconnection
reveals simple organic compounds: alkyne 5, aldehyde 6,
and carboxylic acid 7 as the starting materials.
The realization of this plan started with the synthesis of
propargyl alcohol 8 (Scheme 1) that was further subjected
to Lindlar reduction and acylation with 7 to give allylic ester
4. Ireland-Claisen rearrangement of 4 and iodolactonization
were performed in the same reaction mixture without
isolation of the unsaturated carboxylic acid 3.8 Silica gel
chromatography yielded pure trans-lactone 9 (42%) and
some cis isomer (34%) as the major byproduct. The two-
step one-pot procedure (4 to 9) was remarkably efficient in
building structural complexity. The problem of the low
To confirm the structure of 16rac and to gauge the
efficiency of the total synthesis we also designed a traditional
carbohydrate route to 16 (Scheme 2). We started from the
advanced intermediate 17 prepared as reported by Huang et
al. from diacetone-D-glucose in eight steps and 24% yield.10
Protecting group manipulation followed by installation of
the azide function gave 21. The challenging selective
cleavage of the acetonide protection in 21 was achieved using
boron trichloride11 and followed by acetylation and nucleo-
side synthesis to give 16 as a single enantiomer in 15 steps
and 7% overall yield from diacetone-D-glucose. In accord
(4) (a) Idziak, I.; Just, G.; Damha, M.; Giannaris, P. A. Tetrahedron
Lett. 1993, 34, 5417-5420. (b) Lebreton, J.; Waldner, A.; Lesueur, C.; De
Mesmaeker, A. Synlett 1994, 137-140. (c) Mesmaeker, A.; Waldner, A.;
Lebreton, J.; Hoffmann, P.; Fritsch, V.; Wolf, R. M.; Freier, S. M. Angew.
Chem., Int. Ed. Engl. 1994, 33, 226-229. (d) De Mesmaeker, A.; Lesueur,
C.; Bevierre, M.-O.; Waldner, A.; Fritsch, V.; Wolf, R. M. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2790-2794. (e) De Mesmaeker, A.; Lebreton, J.;
Jouanno, C.; Fritsch, V.; Wolf, R. M.; Wendeborn, S. Synlett 1997, 1287-
1290.
(5) (a) Robins, M. J.; Doboszewski, B.; Nilsson, B. L.; Peterson, M. A.
Nucleosides, Nucleotides Nucleic Acids 2000, 19, 69-86. (b) Robins, M.
J.; Doboszewski, B.; Timoshchuk, V. A.; Peterson, M. A. J. Org. Chem.
2000, 65, 2939-2945.
(6) Lebreton, J.; Waldner, A.; Fritsch, V.; Wolf, R. M.; De Mesmaeker,
A. Tetrahedron Lett. 1994, 35, 5225-5228.
(7) Rozners, E.; Liu, Y. Org. Lett. 2003, 5, 181-184.
1
with our initial structural assignments, the H spectra of 16
and 16rac were identical, whereas the spectrum of the
putative cis isomer of 16rac independently prepared from
cis-9 following the chemistry outlined in Scheme 1 was
distinctly different (see Supporting Information).
(9) (a) Herdeis, C.; Schiffer, T. Tetrahedron 1996, 52, 14745-14756.
(b) Mukaiyama, T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron Lett.
1990, 46, 265-276.
(8) For relevant precedents, see: Bartlett, P. A.; Myerson, J. J. Am. Chem.
Soc. 1978, 100, 3950-3952. Konno, T.; Kitazume, T. Tetrahedron:
Asymmetry 1997, 8, 223-230. Okamura, H.; Kuroda, S.; Ikegami, S.;
Tomita, K.; Sugimoto, Y.; Sakaguchi, S.; Ito, Y.; Katsuki, T.; Yamaguchi,
M. Tetrahedron 1993, 49, 10531-10554.
(10) Huang, Z.; Schneider, K. C.; Benner, S. A. J. Org. Chem. 1991,
56, 3869-3882.
(11) Nicolaou, K. C.; Daines, R. A.; Uenishi, J.; Li, W. S.; Papahatjis,
D. P.; Chakraborty, T. K. J. Am. Chem. Soc. 1988, 110, 4672-4685.
4000
Org. Lett., Vol. 5, No. 21, 2003

Scheme 3. Synthesis of Uridine Azido Acida
Scheme 4. Enantioselective Synthesis of Propargyl Alcohol 8a
a Conditions: (a) 24, Zn(OSO2CF3)2, NEt3, toluene, rt, 2 h, 50%.
a Conditions: (a) HCl, methanol, rt, 5 days, 91%; (b) TEMPO,
[bis(acetoxy)iodo]benzene, CH3CN/H2O (1:1), rt, 27 h; (c) TESCl,
pyridine, rt, 24 h, 65% (two steps).
important for development of enantioselective ribozyme
catalysts. Seelig et al.14 showed that artificially selected
ribozymes built of D- and L-nucleosides catalyzed Diels-
Alder reactions yielding enantiomeric products.
Final steps toward the azido acid 1a starting from the
enantiomerically pure material 16 are shown in Scheme 3.
Deprotection of both silyl and acetyl groups under acidic
conditions gave diol 22. Selective oxidation of the primary
alcohol12 in diol 22 followed by protection of the secondary
2′-OH with triethylsilyl group gave the target azido acid 1a
as a highly crystalline material. Because the 2′-OH in 23
was clearly more hindered than in nonmodified nucleosides,
we chose the 2′-O-triethylsilyl protection instead of the more
traditional 2′-O-tert-butyldimethylsilyl group. The protecting
groups in 1 will have to be later optimized during synthesis
of amide-linked RNA.
Our racemic synthesis in Scheme 1 can be rendered
asymmetric using any reaction that reliably controls the
absolute stereochemistry of alcohol 8, for example, the zinc
acetylide chemistry developed by Carreira and co-workers.13
In preliminary experiments, reaction of 5 and 6 in the
presence of zinc triflate and N-methylephedrine 24 gave the
nonracemic 8 in 50% yield and 92% ee (Scheme 4). The
use of bulky trityl and TBDPS protecting groups was
important; the reaction between MOM-protected propargyl
alcohol and TBS-protected aldehyde gave the target product
in low yield (>10%) and ca. 80% ee. The stereochemistry
of 8 synthesized using (1S,2R)-N-methylephedrine 24 was
assigned as (S)- on the basis of analogy with literature
precedents.13 Because both enantiomers of 24 are inexpensive
and readily available, the total synthesis approach has the
advantage that both enantiomers of 1 can be prepared by
choosing the appropriate chiral catalyst, thereby providing
access to both enantiomers of amide-linked RNA. This is
In summary, we have developed a novel total synthesis
approach to 3′,5′-C-branched nucleosides that culminates in
preparation of the uridine azido acid 1a. Although relatively
small in size, these highly functionalized compounds are
difficult to prepare using the traditional routes of carbohy-
drate chemistry. Currently, the total synthesis of 1a is
somewhat more efficient (overall 16 steps, 9% yield,
Schemes 1 and 3) than the traditional carbohydrate approach
(overall 18 steps, 4% yield, Schemes 2 and 3). However,
the former is more flexible for further improvement. Because
the total synthesis does not depend on a particular starting
material, it can be readily optimized using most current
developments in synthetic organic chemistry, e.g., improved
variants of iodolactonization15 and alternative syntheses of
3 and other key intermediates.
Another feature of our synthesis in Scheme 1 is the
generality. Because the key substituents in the modified
nucleoside, the 3′-C and the 5′-C alkyl branches, do not
directly participate in the chemical transformations, our route
can be used to prepare other analogues having different 3′
and 5′ substituents.
Acknowledgment. We thank Northeastern University
(startup funds and RSDF grant to E.R.) and the donors of
the Petroleum Research Fund, administered by the American
Chemical Society (37599-AC1), for support of this research.
Supporting Information Available: Experimental pro-
cedures, spectral data, and copies of 1H and 13C NMR data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293-295.
(b) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi. A.; Piancatelli, G. J.
Org. Chem. 1997, 62, 6974-6977. (c) For a review, see: de Nooy, A. E.
J.; Besemer, A. C.; van Bekkum, H. Synthesis 1996, 1153-1174.
(13) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806-1807. (b) Frantz, D. E.; Fa¨ssler R.; Tomooka, C. S.;
Carreira, E. M. Acc. Chem. Res. 2000, 33, 373-381.
OL035619V
(14) Seelig, B.; Keiper, S.; Stuhlmann, F.; Jaschke, A. Angew. Chem,
Int. Ed. 2000, 39, 4576-4579.
(15) Kang, S. H.; Kim, M. J. Am. Chem. Soc. 2003, 125, 4684-4685.
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