Scientifica Acta 2, No. 2, 17 – 20 (2008)
Chemistry
New synthetic route for the preparation of carbocyclic nucleosides through aza-Diels-Alder reactions
Andrea Piccanello
Dipartimento di Chimica Organica, Università di Pavia, Viale Taramelli 10, 27100, Pavia, Italy
[email protected]
A rapid access to carbocyclic nucleosides containing a fused isoxazoline ring is proposed through the Grieco
cycloaddition of cyclopentadiene to iminium salts. The prolific elaboration of the isoxazoline cycloadducts
allowed for the preparation of the target aminols through the unmasking of the hydroxymethylene group at
the C3 level of the azanorbornene structure. The heterocyclic aminols are readily converted into nucleosides
via the linear construction of purine heterobases.
1 Introduction
The preparation of carbocyclic and heterocyclic nucleoside analogues is extensively pursued due to the
importance in the development of new antiviral drugs.[1] New efforts are constantly made to propose
attractive synthetic strategies towards new compounds, with potentially increased biological activities and
decreased toxicities.
In this contest, we have recently developed a synthesis of the isoxazoline-carbocyclic nucleosides 5 by
the linear construction of the desired purine and pyrimidine bases on the regioisomeric aminols 4 (Scheme
1) obtained through elaboration of the hetero Diels-Alder (HDA) cycloadducts 2 of cyclopentadiene 1 to
the nitrosocarbonyl intermediates (RCONO).[2] On pursuing our studies on nucleoside syntheses, we detail
here the first synthesis of a class of racemic purine-carbocyclic nucleosides containing a fused isoxazole
ring and having an hydroxymethylene (HO-CH2 ) group in the side chain of the carbocyclic unit.
[Ph-C ONO]
C OPh
N
1,3-dipolar
Cycloaddition
HDA Cycloaddition
O
2
1
HO
b
NH 2
c
N
a
C OPh
a
O
c
=
PhC
O
o
a
c
b
4
N
b
a
N
Hydrolysis
N-O B ond Cleavage
3
HO
b
5
N
O
c
C Ph
Scheme 1
© 2008 Università degli Studi di Pavia
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Scientifica Acta 2, No. 2 (2008)
1
H C OH
Ph-C H 2-NH 2 . H C l
[Ph-C H 2-NH =C H 2C l]
H 2O
t.a., 48h
6
7
Ph
Ph
N
+
C
N
8
Cl
E t3N
OH
O
Ph
+
C H 2C l 2
t.a., 48h
9
N
O
N
N
10a
Ph
10b
Ph
(49% )
N
(43% )
Ph
Scheme 2
HO
NH C OC H 3
d
O
N
N
14a
Ph
O
c
Ph
N
e
CHO
NH C OC H 3
13a
O
HO
NH 2
H
OE t
OE t
NH C OC H 3
Ph
12a
N
O
N
a
Ph
N
10a
H 3C
Br
Ph
b
H 3C
O
c
N
O
N
15a
Ph
a. NB S, A I B N, C C l 4, ∆
b. NaH C O 3/E tOH , ∆, 10gg
c. A cOH /H 2O 3: 7, t.a., 48h
d. NaB H 4/M eOH , t.a., 24h
e. H C l 3M , M eOH , ∆, 18h
N
11a
O
O
O
C H (OE t) 2
H
NH 2
Ph
H
12a'
NH C OC H 3
HO
N
c
O
O
CHO
H
N
15a'
Ph
Ph
H
13a'
e
NH C OC H 3
NH C OC H 3
d
HO
Scheme 3
O
N
14a'
Ph
2 Results
The N-benzyl-2-azanorborn-5-ene b was prepared by addition of freshly distilled cyclopentadiene 1 to
an aqueous solution of benzylamine hydrochloride 6 and 37% aqueous formaldehyde in an aza-DielsAlder (ADA) reaction according to the well-known procedure.[3] The 1,3-dipolar cycloaddition of benzonitrile oxide (BNO) to 8 was performed by adding the benzhydroximoyl chloride 9 to a dichloromethane
(CH2 Cl2 ) solution of a slight excess of the dipolarophile 1 (1.2 equivs.) and a slight excess of Et3 N
(1.1 equivs.) (Scheme 2). After stirring at room temperature for 48h, from the reaction mixture the two
regioisomeric isoxazoline cycloadducts 10a,b were isolated in 49% and 43% yields, respectively.
The two regioisomeric isoxazoline cycloadducts 10a and 10b were transformed into the stereodefined
regioisomeric anti aminols through a complex but straightforward synthetic elaboration whose steps are
reported in the Scheme 3 and 4, respectively.
By adapting the known procedures,[4] the regioisomeric aminols 15a,b have been converted into the
pyrimidine derivatives 16a,b through condensation with the 5-amino-4,6-dichloropyrimidine and then into
the chloropurines 17a,b with orthoformates under HCl catalysis (Scheme 5). The pyrimidine derivatives
16a,b were obtained in good yields (17a, 72%; 17b 75%) by heating a solution of the aminols 16a,b and
5-amino-4,6-dichloropyrimidine (2 equiv.) in n-BuOH at reflux (bp 117 ˚C) in the presence of an excess of
i-Pr2 NEt (5 equiv.) for 48 h. The epimeric aminol 15a’ was also converted into the pyrimidine derivatives
16a’ (79%) and this latter into the chloropurines 17a’ (82%) under the same conditions.
© 2008 Università degli Studi di Pavia
Scientifica Acta 2, No. 2 (2008)
19
Ph
Ph
Ph
N
N
N
O
O
a
N
10b
Br
N
11b
O
H 3C
H
OE t
OE t
NH C OC H 3
O
b
12b
c
O
H 3C
a. NB S, A I B N, C C l 4, ∆
b. NaH C O 3/E tOH , ∆, 10gg
c. A cOH /H 2O 3: 7, t.a., 48h
d. NaB H 4/M eOH , t.a., 24h
e. H C l 3M , M eOH , ∆, 18h
Ph
HO
N
HO
NH C OC H 3
O
CHO
d
NH C OC H 3
13b
NH 2
e
O
N
14b
Ph
N
15b
Ph
O
Scheme 4
Cl
H 2N
Cl
N
N
HO
HO
HN
NH 2
N
N
N
15a
N
b
a
O
N
HO
O
Ph
N
16a
O
Ph
N
17a
Ph
Cl
H 2N
N
HN
NH 2
O
N
15a'
O
N
16a'
HO
Ph
O
N
17a'
Ph
Cl
H 2N
N
N
HN
O
N
N
N
b
a
N
15b
N
HO
NH 2
Ph
Cl
HO
HO
N
b
HO
Ph
N
N
N
a
HO
Cl
N
Ph
N
16b
O
Ph
N
17b
O
a. 5-ammino-4,6-diclor opir imidina (2 eqv.), iPr 2E tN (5 eqv.), nB utOH , ∆, 48h. b. H C (OE t) 3/H C l, t.a., 8gg.
Scheme 5
From the chloro-substituted nucleosides 17a,a’,b a variety of derivatives can be obtained by nucleophilic substitution.[5] On heating MeOH solutions of 17a,a’,b at 50 ˚C in the presence of an excess of
NH3 or other differently substituted amines, the amino derivatives 18a,a’,b(A-D) could easily be obtained
(Scheme 3).
© 2008 Università degli Studi di Pavia
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Scientifica Acta 2, No. 2 (2008)
R
Cl
N
N
N
N
HO
HO
N
N
N
N
a
O
N
17a
O
Ph
a. R NH 2/M eOH , 50 °C , 24 h.
N
18a
Ph
R
Cl
N
R = NH 2
NH M e
NH cPr
OE t
N
N
N
N
N
N
N
a
HO
O
N
17a'
R
Ph
Cl
N
N
HO
N
18a
A
B
C
D
18a'
A
B
C
D
A
B
C
D
18b
Y elds (%)
NH 2
NHMe
NHcPr
OE t
NH 2
NHMe
NHcPr
OE t
NH 2
NHMe
NHcPr
OE t
HO
89
92
90
84
88
95
80
77
72
87
80
80
O
N
18a'
Ph
R
N
N
HO
N
N
N
a
Ph
N
17b
O
Ph
N
18b
O
Scheme 6
References
[1] [1] (a) Y. Mizuno, The Organic Chemistry of Nucleic Acids (Kadansha LTD, Tokyo, 1986); (b) T. Ueda, Chemistry of Nucleosides and Nucleotides (Townsend Ed., Plenum Press, New York, 1988) vol. 1, chap. 1.; (c) P. C.
Srivasta, R. K. Robins, R. B. Jr. Meyer, Chemistry of Nucleosides and Nucleotides (Townsend Ed., Plenum Press,
New York, 1988) vol. 1, chap. 2; (d) G. R. Revenkar, R. K. Robins, Chemistry of Nucleosides and Nucleotides,
(Townsend Ed., Plenum Press, New York, 1988) Vol. 2, Cpt 4.
[2] P. Quadrelli, R. Scrocchi, P. Caramella, A. Rescifina, A. Piperno, Tetrahedron 60, 3643 (2004).
[3] P. A. Grieco, S. D. Larsen, Organic Synthesis 68, 206 (1990).
[4] (a) M. Ishikura, A. Murakami, N. Katagiri, Organic and Biomolecular Chemistry 1, 452 (2003); (b) L. Yu, J. Li,
J. Ramirez, D. Chen,P. G. Weng, Journal of Organic Chemistry 62, 903 (1997); (c) P. Pinho P. G. Andersson,
Chemical Communications 597 (1999).
[5] (a) D. Salvatori, R. Volpini, S. Vicenzetti, A. Vita, S. Costanzi, C. Lambertucci, G. Cristalli, S. Vittori, Bioorganic
and Medicinal Chemistry 10, 2973 (2002); (b) N. Katagiri, Y. Yamatoya, M. Ishikura, Tetrahedron Letters 40,
9069 (1999).
© 2008 Università degli Studi di Pavia