Mitsunobu coupling of nucleobases and alcohols: An efficient, practical synthesis for novel nonsugar carbon nucleosides

Article abstract of DOI:10.1021/jo070515+

(Chemical Equation Presented) A simple facile synthesis of substituted purine derivatives has been developed by using Mitsunobu conditions for an alcohol and a respective nucleobase. A wide range of alcohols produces good to excellent yield (>90%). The resulting purine analogues show good regioselectivity with N-9 substitution as the dominant products in most of the cases. Application of diastereospecific alcohols reveals a complete inversion of the carbon stereogenic center giving a single diastereomer. More than two dozen novel nucleobase derivatives have been prepared in high yield.

Full text of DOI:10.1021/jo070515+

Mitsunobu Coupling of Nucleobases and
Alcohols: An Efficient, Practical Synthesis for
Novel Nonsugar Carbon Nucleosides
steps and typically gives higher overall yields. However, all
the reported approaches do not work efficiently with electron-
enriched purines such as guanine due to side reactions. Three
6
methods have been reported regarding the formation of the
carbon-base bond for the synthesis of nucleoside analogues:
Weibing Lu, Sujata Sengupta, Jeffrey L. Petersen,
Novruz G. Akhmedov, and Xiaodong Shi*
(
a) palladium-catalyzed displacement of an allylic ester or
carbonate; (b) direct nucleophilic displacement of halides or
activated alcohols; and (c) Mitsunobu coupling. The first two
strategies often encounter considerable competition at the N-9
C. Eugene Bennett Department of Chemistry, West Virginia
UniVersity, Morgantown, West Virginia 26506
7
and N-7 positions of the purine base and the reactions give
8
xiaodong.shi@mail.wVu.edu
ReceiVed March 15, 2007
modest yields (usually lower than 60%).
The well-studied Mitsunobu reaction involves two sequential
reactions: the activation of primary or secondary alcohols by
dialkylazodicarboxylate followed by nucleophilic substitution.9
It was believed that acidic nucleophiles are necessary, since the
dialkylazodicarboxylate must be protonated during the course
of the reaction. Therefore, this reaction was usually applied in
the synthesis of esters, phenyl ethers, thioethers, and amines
(
from the nucleophilic addition of phthalimide or hydrogen
10
azide). The Mitsunobu coupling of allylic and benzylic alcohol
with adenine and 6-chloro-2-aminopurine has been reported
11
previously with good N-9 selectivity. However, poor to modest
yield (20-60%) and limited substrate scope were observed,12
which significantly limits the application of this method.
Currently, there is no detailed study regarding the Mitsunobu
coupling between a nucleobase and an alcohol available in the
literature. Moreover, in all these methods, direct coupling of
guanine with a nonsugar carbon substrate was unsuccessful. The
only successful synthesis of guanine nucleosides was achieved
by the coupling of 6-chloro-2-aminopurine with carbon sub-
strates followed by nucleophilic aromatic substitution as shown
in Scheme 1. The poor overall yields and harsh reaction
conditions make the synthesis of nonsugar guanine analogues
a big challenge.
Our interest in developing novel self-assembled nucleoside
molecular architectures extends our need for facile synthesis of
A simple facile synthesis of substituted purine derivatives
has been developed by using Mitsunobu conditions for an
alcohol and a respective nucleobase. A wide range of
alcohols produces good to excellent yield (>90%). The
resulting purine analogues show good regioselectivity with
N-9 substitution as the dominant products in most of the
cases. Application of diastereospecific alcohols reveals a
complete inversion of the carbon stereogenic center giving
a single diastereomer. More than two dozen novel nucleobase
derivatives have been prepared in high yield.
13
Nucleosides are one of the most important fundamental
building blocks in biological systems. Various nucleoside
analogues have been used in many different research fields to
provide remarkable chemical and biological functions. Some
selected examples include peptide nucleic acid (PNA) mimick-
(
4) (a) Bookser, B. C.; Raffaele, N. B. J. Org. Chem. 2007, 72, 173-
79. (b) Dolores, V.; Wu, T.; Renders, M.; Laflamme, G.; Herdewijn, P.
Tetrahedron 2007, 63, 2634-2646.
5) Barnes, M. J.; Cooper, N.; Davenport, R. J.; Dyke, H. J.; Galleway,
1
(
F. P.; Galvin, F. C. A.; Gowers, L.; Haughan, A. F.; Lowe, C.; Meissner,
J.; Montana, J. G.; Morgan, T.; Picken, C. L.; Watson, R. J. Bioorg. Med.
Chem. Lett. 2001, 11, 1081-1083.
(6) Hughes, D. L. The Mitsunobu reaction. In Organic Reactions;
Oxford: New York, 1992; Vol. 42, pp 335-656.
1
ing helical DNA, carbocyclic nucleosides as antitumor and
2
antiviral agents, and lipophilic nucleosides in the formation of
3
ion channel and ion carriers. The involvement of diverse
(
7) (a) Chen, H.; Li, S. J. Phys. Chem. A 2006, 110, 12360-12362. (b)
research efforts and the strong potential of interesting chemical
and biological properties produce a great need for the effective
synthesis of novel nucleoside analogues. Currently, two ap-
proaches are applied for the preparation of nucleoside ana-
Robins, M. J.; Zhong, M. J. Org. Chem. 2006, 71, 8901-8906. (c) Garner,
P.; Yoo, J. U.; Sarabu, R. Tetrahedron 1992, 48, 4259-4270.
(8) Chen, W.; Flavin, M. T.; Filler, R.; Xu, Z. Nucleosides Nucleotides
1
996, 15, 1771-1778.
9) Kurti, L.; Czako, B. Strategic Applications of Named Reactions in
Organic Synthesis; Elsevier: Boston, MA, 2005; p p294-295.
10) (a) Mitsunobu, O. Synthesis 1981, 1, 1-28. (b) Hughes, D. L.
Organic Reactions; Wiley: New York, 1992; Vol. 42, pp 335-656.
11) (a) Kitade, Y.; Ando, T.; Yamaguchi, T.; Hori, A.; Nakanishi, M.;
(
4
logues: direct coupling of a base with a carbon substrate and
(
construction of purines and pyrimidines from respective ami-
5
noalkanes. In general, the first route usually involves fewer
(
Ueno, Y. Bioorg. Med. Chem. 2006, 14, 5578-5583. (b) Yang, M.;
Schneller, S. W.; Korba, B. B. J. Med. Chem. 2005, 48, 5043-5046. (c)
Yin, X.; Li, W.; Schneller, S. W. Tetrahedron Lett. 2006, 47, 9187-9189.
(12) (a) Yang, M.; Ye, W.; Schneller, S. W. J. Org. Chem. 2004, 69,
3993-3996. (b) Dyatkina, N. B.; Theil, F.; Von Janta-Lipinski, M.
Tetrahedron 1995, 51, 761-772. (c) Iyer, M. S.; Palomo, M.; Schilling,
K. M.; Xie, Y.; Formanskii, L.; Zembower, D. E. J. Chromatogr., A 2002,
944, 263-267.
(
1) (a) Porcheddu, A.; Giacomelli, G. Curr. Med. Chem. 2005, 12, 2561-
599. (b) Nielsen, P. E. Peptide Nucleic Acids, 2nd ed.; Horizon Bio-
science: Norfolk, 2004; pp 207-226.
2) (a) De Clercq, E. Int. J. Antimicrob. Agents 2001, 18, 309-328. (b)
Nord, L. D.; Dalley, N. K.; McKernan, A.; Robins, R. K. J. Med. Chem.
987, 30, 1044-1054.
3) (a) Davis, J. T. Angew. Chem., Int. Ed. 2004, 43, 668-698. (b) Ma,
L.; Iezzi, M. A.; Kaucher, M. S.; Davis, J. T. J. Am. Chem. Soc. 2006, 128,
5269-15277.
2
(
1
(
(13) Besada, P.; Gonzalez-Moa, M. J.; Teran, C.; Santana, L.; Uriarte,
E. Synthesis 2002, 16, 2445-2449.
1
10.1021/jo070515+ CCC: $37.00 © 2007 American Chemical Society
5
012
J. Org. Chem. 2007, 72, 5012-5015
Published on Web 05/25/2007

TABLE 1. Screening of Reaction Conditions between Guanine and Primary Alcohola
entry
method
ROH (equiv)
purine base (equiv)
solvent
temp (°C)
yield (%)b
1
2
1
2
3
4
5
6
7
8
9
A
A
A
A
A
A
A
A
B
B
B
B
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3.0
2.0
2.0
2.0
2.0
1.0 equiv, R ) R ) H
THF
THF
THF
THF
DMF
CH3CN
DCE
THF
DMF
CH3CN
DCE
THF
70
70
70
70
70
70
70
70
70
70
70
70
0
0
0
1
2
1.0 equiv, R ) R ) Ac
1
2
1.0 equiv, R ) R ) COCF3
1
2
1.0 equiv, R ) Ac; R ) CONPh2
58
47
38
36
62
65
57
43
93
1
2
1.0 equiv, R ) Ac; R ) CONPh2
1
2
1.0 equiv, R ) Ac; R ) CONPh2
1
2
1.0 equiv, R ) Ac; R ) CONPh2
1
2
1.0 equiv, R ) Ac; R ) CONPh2
1
2
1.0 equiv, R ) Ac; R ) CONPh2
1
2
1
1
1
0
1
2
1.0 equiv, R ) Ac; R ) CONPh2
1 2
1.0 equiv, R ) Ac; R ) CONPh2
1
2
1.0 equiv, R ) Ac; R ) CONPh2
a
Method A: A mixture of guanine or protected guanine (1 equiv), alcohol (1.05 equiv), PPh3 (1.05 equiv), and DIAD (1.05 equiv) was stirred in the
designated solvent (0.1 M) at 70 °C for 12 h. Method B: A mixture of 2d (1.0 equiv), alcohol (1.0 equiv), PPh3 (1.05 equiv), and DIAD (1.05 equiv) in
anhydrous THF (0.1 M) with N2 protection was stirred at 70 °C for 6 h. Then alcohol (1.0 equiv), PPh3 (1.05 equiv), and DIAD (1.05 equiv) were added
sequentially and the resulting mixture were heated at 70 °C for another 6 h. b Isolated yields.
overall yield),16 is found to be the best protecting group,
producing the desired coupling product in a moderate yield
SCHEME 1. Literature Reported Synthesis of Nonsugar
Guanine Analogues
(entry 4). Notably, only the desired N-9 substituted product is
observed in this coupling reaction.
During reflux in anhydrous THF, all of the alcohol is
consumed within 4 h while some of the protected guanine
remains unreacted. It is reasonable to hypothesize that the
activated alcohol undergoes significant decomposition side
reactions, which causes the low yield of the coupling product.
An increase in the amount of alcohol and DIAD also increases
the rate of the side reactions, resulting in only slight improve-
ment of the desired guanine coupling (entry 8). A different
reaction condition includes the addition of one more equivalent
of the activated alcohol after 6 h of reaction (method B). This
modification significantly increases the yield of the guanine
product by consuming all the purines. Screening of the solvents
reveals that THF is the best solvent for the desired reaction.
Compound 3d can then be readily converted to the desired
nonsugar guanine analogue 4a by treatment with a 1:1 mixture
different nonsugar guanine analogues.14 Herein, we report an
efficient and practical synthesis of nonsugar nucleosides using
optimized Mitsunobu coupling of guanine and a variety of
alcohols with excellent N-9 selectivity and good-to-excellent
yield. The reaction between a simple primary alcohol, TBS-
protected ethylene glycol, and guanine derivatives was first
studied and the results are summarized in Table 1.
It is known that alcohol can be activated by dialkylazodi-
carboxylate even at low temperature. Both guanine and protected
guanine have poor solubility in nonpolar organic solvents such
as anhydrous THF, which is usually considered to be the best
solvent for the Mitsunobu reaction. Since purines are not great
nucleophiles for activated alcohols, dilution of the reaction
causes significant increase in the reaction time and leads to a
16
of ammonia and methanol solution at 60 °C with >95% yield.
To the best of our knowledge, this method is the first example
in the literature that directly couples alcohols with guanine
nucleophiles. Compared to the current approach in the literature
15
poor yield of the desired coupling product. To increase the
purine base solubility, the reaction is carried out at 70 °C, where
both guanine and protected guanine are partially soluble. As
shown in Table 1, both guanine and diacetyl guanine (entry 2)
do not generate the coupling product. To increase the acidity
of the nucleophile, trifluoroacetate-protected guanine is used
in the coupling reaction (entry 3). However, no coupling product
is observed. The O-carbamate-N-acetate protected guanine,
which can be readily prepared from guanine in two steps (>90%
(Scheme 1), this new strategy will yield the nonsugar carbon-
guanine analogue in a more efficient way with much higher
overall yield. Therefore, this method provides a very practical
synthesis of novel guanine nucleosides. The substrate scope of
alcohols is summarized in Table 2.
As indicated by Table 2, a large group of different alcohols
produce the carbon-guanine products with use of the optimized
conditions, including primary alcohols, secondary alcohols,
allylic alcohols, propargyl alcohols, benzylic alcohols, etc. tert-
Butyl alcohol was also reacted with protected guanine, but no
coupling product was observed due to steric hindrance on the
tertiary carbon. With all these substrates, the carbon-guanine
(
14) (a) Shi, X.; Fettinger, J. C.; Davis, J. T. Angew. Chem., Int. Ed.
001, 40, 2827-2831. (b) Shi, X.; Mullaugh, K. M.; Fettinger, J. C.; Jiang,
Y.; Hofstadler, S. A.; Davis, J. T. J. Am. Chem. Soc. 2003, 125, 10830-
0841.
15) When 2d and 1 were reacted at room temperature under diluted
2
1
(
conditions, 3d was obtained in less than 10% isolated yield even after
running the reaction for 16 h.
(16) (a) Zou, R.; Robbins, M. J. Can. J. Chem. 1987, 65, 1436. (b) Choo,
H.; Chong, Y.; Chu, C. K. Org. Lett. 2001, 3, 1471-1473.
J. Org. Chem, Vol. 72, No. 13, 2007 5013

TABLE 2. Reaction Substrate Scope in the Guanine-Alcohol
TABLE 3. Investigation of Purine Basesa
a
Coupling
a
Same reaction condition as in Table 2. b Isolated yields. c Structure was
a
Reaction condition: A reaction mixture of 2d (1.0 equiv), alcohol (1.05
confirmed by X-ray crystallography.
equiv), PPh3 (1.05 equiv), and DIAD (1.05 equiv) in anhydrous THF (0.1
M) with N2 protection was stirred at 70 °C for 6 h, then alcohol (1.05
equiv), PPh3 (1.05 equiv), and DIAD (1.05 equiv) were added sequentially
and the resulting mixture was heated at 70 °C for another 6 h. Isolated
yields. Structure was confirmed by X-ray crystallography.
b
c
products were prepared in good-to-excellent yields by using this
two-step combination.
It is known in the literature that 6-chloropurine, 2,6-
dichloropurine, and 6-chloro-2-aminopurine are able to couple
with selected alcohols under Mitsunobu conditions. However,
the alcohols are limited to allylic and benzylic positions and
reaction yields are not satisfactory in all of the cases (20-50%).
The chloropurines are much more soluble in THF than guanine
derivatives. Therefore, the reaction can take place at room
temperature. However, low yields of the coupling products are
observed due to the side reactions associated with the poor
nucleophilicity of purines. Different purines have been inves-
tigated as the nucleophile by using the optimized reaction
conditions (Table 3).
FIGURE 1. Preparation of diaminopurine derivatives from compounds
7
. Reaction condition: the mixture of compound 7 (1.0 equiv) and
NaN (2.5 equiv) in EtOH/H O (5/1 volume ratio) was refluxed for 2
3
2
h, then the solvent was removed under reduced pressure, and the
resulting crude product was hydrogenated in EtOH in the presence of
Pd/C (10 mol %). Yield: 86% for 8a and 88% for 8b in two steps,
respectively.
with specific more reactive alcohols. These results may be due
to the poor solubility of the bases. An easy conversion of the
chloropurine to the respective aminopurine compounds has been
developed and the target aminopurine carbon nucleoside is
1
7
As shown in Table 3, the more soluble purines indeed
generate the desired coupling products in good yields under the
optimized reaction condition. For 6-chloropurine, only N-9
coupled compounds are obtained, while for 2,6-dichloropurine,
N-7 compounds are observed as the minor products in some
cases. This observation can be attributed to the lower electron
density of 2,6-dichloropurine, which results in competition of
the nucleophilicity at the N-9 and N-7 positions. These two
regioisomers can be separated by column chromatography and
the structures are determined by X-ray crystallography (Sup-
porting Information).
obtained in excellent overall yield. Therefore, the substrate
scope of this reaction can be extended even further.
The stereochemistry control of this reaction has also been
investigated. In the conventional Mitsunobu reaction, the
nucleophiles are believed to undergo an SN2 mechanism.
Therefore, a complete conversion of the stereogenic center is
expected. Several diastereospecific alcohol derivatives have been
employed to evaluate the stereochemistry of this conversion and
the results are listed in Table 4.
(17) (a) Sznidman, M. L.; Du, J.; Pesyan, A.; Cleory, D. G.; Hurley, K.
P.; Waligora, F.; Almond, M. R. Nucleoside, Nucleotides & Nucleic Acids,
Neither adenine nor 2,6-diaminopurine produces the desired
coupling product with a simple alcohol, although they were
reported as possible purine bases in the Mitsunobu coupling,
2
004, 23, 1875-1887. (b) Tiwari, K. N.; Messini, L.; Montgomery, J. A.;
Secrist, J. A. Nucleoside, Nucleotides & Nucleic Acids 2001, 20, 743-
746.
5
014 J. Org. Chem., Vol. 72, No. 13, 2007

TABLE 4. Stereochemistry Control of the Nucleobase-Mitsunobu
Experimental Section
a-c
Reaction
General Procedure for Mitsunobu Coupling. The substituted
purine or protected guanine (1.0 equiv) was added to a solution of
3
alcohol (1.05 equiv) and PPh (1.05 equiv) in anhydrous THF under
an N atmosphere. The resulting suspension/solution was treated
2
with diisopropyl azodicarboxylate (DIAD, 1.05 equiv) and the
reaction mixture was then stirred at 70 °C for 6 h. Then the second
portions of alcohol (1.05 equiv), PPh (1.05 equiv), and DIAD (1.05
3
equiv) were added to the reaction mixture sequentially. The mixture
was stirred for another 6 h at the same temperature. The mixture
was cooled, treated with saturated sodium chloride, and extracted
with dichloromethane. The combined organic layer was then washed
with water and dried over anhydrous sodium sulfate. The solvent
was removed under reduced pressure. Flash silica gel chromatog-
raphy gave the pure product.
Deprotection of the Protected Guanine 3. The protected
guanine 3 was dissolved in a mixture of ammonia/methanol (1:1).
The resulting solution was heated at 60 °C for 2 h. The solvent
was removed under reduced pressure and the crude product was
purified by flash silica gel chromatography.
a
Same reaction conditions as shown in Table 2. b Isolated yields.
c
Coupling constant between C1-H and C2-H for the determination of
relative stereochemistry. Structure was confirmed by X-ray crystallography.
d
In all the examples, a single diastereomer is obtained. The
relative stereochemistry of all the compounds has been deter-
mined by NMR and the complete inversion of the alcohol
stereogenic center is observed. These results are consistent with
the SN2 mechanism and strongly enhance the application of
the reported method as a general approach for the stereospecific
synthesis of carbon nucleosides.
Synthesis of Diaminopurine 8. A solution of 2,6-dichloropurine
(1.0 equiv) and NaN (2.5 equiv) in EtOH/H O (5/1 volume ratio)
3 2
7
was refluxed for 2 h. Then solvent was removed under reduced
pressure to give the crude product, which was hydrogenated in
EtOH in the presence of Pd/C (10 mol %). The resulting mixture
was passed through celite, concentrated, and purified by flash silica
column chromatography.
In summary, a study of the Mitsunobu reaction between
simple alcohols and nucleobase has been performed. A large
number of nucleobases and alcohols can give the desired
coupling products in good-to-excellent yields under the opti-
mized condition. This approach has a very large substrate scope
with good stereochemistry control, which makes it a very
efficient and practical method for the synthesis of novel carbon
nucleosides. Studies of some novel carbon guanine analogues
as self-assembly building blocks and potential drug candidates
are currently under investigation in our group.
Acknowledgment. We thank the C. Eugene Bennett Depart-
ment of Chemistry, the Eberly College of Arts and Science,
and the WV Nano Initiative at West Virginia University for
financial support.
Supporting Information Available: Experimental procedures,
spectral data for all new compounds, and CIF files for compounds
6e, 6i, 6m, 6q, 6r, 6s, and 8a. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO070515+
J. Org. Chem, Vol. 72, No. 13, 2007 5015