Efficient synthesis of carbovir and its congener via π-allylpalladium complex formation by ring strain-assisted C-N bond cleavage

Full text of DOI:10.1021/jo962416u

1580
J . Org. Chem. 1997, 62, 1580-1581
Sch em e 1
Efficien t Syn th esis of Ca r bovir a n d Its
Con gen er via π-Allylp a lla d iu m Com p lex
F or m a tion by Rin g Str a in -Assisted C-N
Bon d Clea va ge
Nobuya Katagiri,* Masahiro Takebayashi,
Hideaki Kokufuda, Chikara Kaneko,
Kouichi Kanehira,† and Masahiro Torihara†
Pharmaceutical Institute, Tohoku University, Aobayama,
Aoba-ku, Sendai 980-77, J apan, and NIC Research and
Development Department, Kuraray Co., Ltd., Kurashiki-cho,
Nakajo-machi, Kitakanbaragun, Niigata, J apan
Sch em e 2a
Received December 30, 1996
The recent finding that modified nucleosides such as
dideoxynucleosides are potentially effective therapeutic
agents for the treatment of the acquired immune defi-
ciency syndrome (AIDS) has triggered explosive new
developments in the chemistry of these compounds and
their analogs.1 To date, AZT (3′-azido-3′-deoxythymi-
dine), ddI (2′,3′-dideoxyinosine), ddC (2′,3′-dideoxycyti-
dine), d4T (2′,3′-didehydro-3′-deoxythymidine), and 3TC
(â-L-(-)-2′-deoxy-3′-thiacytidine) belonging to dideoxy-
nucleosides are the approved drugs for the treatment of
AIDS. However, a number of other modified nucleosides
have gone through at least preliminary clinical studies.
For example, carbovir (1a ),2 carbocyclic 2′,3′-didehydro-
2′,3′-dideoxyguanosine, has been found to show signifi-
cant anti-HIV activity, and its congener (1b) having a
higher oral bioavailability than carbovir is currently
undergoing clinical trials for the treatment of HIV
infection.3
a
Key: (a) (i) nBuLi, THF, -78 °C, (ii) (o-NO2)C6H4SO2Cl or
(PhO)2POCl; (b) (i) Pd[P(OiPr)3]4 (0.1 equiv), THF or NMP, rt, (ii)
6-chloropurine (Na+ salt or Bu4N+ salt) or 2-(formylamino)-6-
chloropurine (Bu4N+) salt.
clic nucleosides. All previous synthetic methods of 1 from
2 () A) involve cyclopentenylamines (B) as intermediates
formed by 2,3-bond fission (Scheme 1, cleavage-a).2,6
Previously, we reported a synthesis of cyclopentenyl-
amine from 2 by NaBH4-mediated reductive amido bond
cleavage reaction (cleavage-a) and a conversion of the
cyclopentenylamine to carbocyclic nucleosides.7 How-
ever, these reported methods have a crucial drawback
because of their time-consuming reaction steps concomi-
tant with purine ring construction resulting in low total
yield.
Although considerable literature is available concern-
ing the synthesis of 1a , most of these papers deal with
synthetic methods via cyclopentene derivatives as syn-
thetic precursors.4 2-Azabicyclo[2.2.1]hept-5-en-3-one (2,
ABH)5 produced industrially is one of the most versatile
reagents for the synthesis of 1a as well as other carbocy-
In this paper, we report an efficient synthesis of 1 from
2, which involves a novel π-allylpalladium complex
formation (C) by ring strain-assisted 1,2-bond fission
(cleavage-b) of 2, and would provide a more practical
method for the synthesis of 1.
† Kuraray Co., Ltd.
(1) For recent reviews, see: (a) Huryn, D. M.; Okabe, M. Chem. Rev.
1992, 92, 1745. (b) Dueholm, K. L.; Pedersen, E. B. Synthesis 1992, 1.
(2) (a) Vince, R.; Hua, M. J . Med. Chem. 1990, 33, 17. (b) Vince, R.;
Brownell, J . Biochem. Biophys. Res. Commun. 1990, 168, 912.
(3) (a) Kimberlin, D. W.; Coen, D. M.; Biron, K. K.; Cohen, J . I.;
Lamb, R. A.; McKinlay, M.; Emini, E. A.; Whitley, R. J . Antiviral Res.
1995, 26, 369. (b) Good, S. S.; Daluge, S. M.; Ching, S. V.; Ayers, K.
M.; Mahony, W. B.; Faletto, M. B.; Domin, B. A.; Owens, B. S.; Dornsife,
R. E.; McDowell, J . A.; LaFon, S. W.; Symonds, W. T. Antiviral Res.
1995, 26, A229.
(4) For recent reviews of the synthesis of carbocyclic nucleosides,
see: (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
(b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.;
Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. For recent
syntheses of carbovir, see: (c) Martinez, L. E.; Nugent, W. A.; J acobsen,
E. N. J . Org. Chem. 1996, 61, 7963. (d) Trost, B. M.; Stenkamp, D.;
Pulley, S. R. Chem. Eur. J . 1995, 1, 568. (e) Berranger, T.; Langlois,
Y. Tetrahedron Lett. 1995, 36, 5523. (f) Campbell, J . A.; Lee, W. K.;
Rapoport, H. J . Org. Chem. 1995, 60, 4602. (g) Park, K. H.; Rapoport,
H. J . Org. Chem. 1994, 59, 394. (h) Handa, S.; Earlam, G. J .; Geary,
P. J .; Hawes, J . E.; Phillips, G. T.; Pryce, R. J .; Ryback, G.; Shears, J .
H. J . Chem. Soc., Perkin Trans. 1 1994, 1885.
To facilitate the cleavage of the 1,2-bond by Pd0, an
electron-withdrawing group was introduced to the 2-posi-
tion of 2. Compound 2 was treated with BuLi followed
by o-nitrobenzenesulfonyl chloride in THF at -78 °C to
give the desired compound 3a (mp 94 °C) in 83% yield
(Scheme 2). In a similar manner, a diphenylphosphoryl
group was also introduced to the 2-position by using
diphenyl chlorophosphate to give 3b (mp 51 °C) in almost
quantitative yield.
(6) (a) Csuk, R.; Dorr, P. Tetrahedron 1995, 51, 5789. (b) Taylor, S.
J . C.; McCague, R.; Wisdom, R.; Lee, C.; Dickson, K.; Ruecroft, G.;
O’Brien, F.; Littlechild, J .; Bevan, J .; Roberts, S. M.; Evans, C. T.
Tetrahedron: Asymmetry 1993, 4, 1117.
(5) J agt, J .; Van Leusen, A. J . Org. Chem. 1974, 39, 564. (b) Daluge,
S.; Vince, R. J . Org. Chem. 1978, 43, 2311.
(7) Katagiri, N.; Muto, M.; Kaneko, C. Tetrahedron Lett. 1989, 30,
1645.
S0022-3263(96)02416-4 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 6, 1997 1581
Sch em e 3a
Next, we carried out the coupling reaction of 3 with
6-chloropurines (5) in the presence of Pd0. Compound
3a was reacted with 6-chloropurine tetrabutylammonium
salt (5a )8 in the presence of Pd[P(OiPr)3]4 (0.1 equiv) in
THF at rt for 1 h to give 6 (mp 212 °C) in 60% yield.9
The fact that 6 was obtained as the major product in this
reaction shows that the Pd0 catalyst approaches from the
exo-side of 3a to form the π-allylpalladium complex (4),
which reacted stereoselectively with 5a to give 6. Com-
pound 3b did not react with 5a under the same reaction
conditions. Therefore, 3b was treated with the sodium
salt (5b) instead of 5a under the same catalyst in NMP
(N-methylpyrrolidone) at rt for 1 h to give 7 (mp 187 °C)
in 55% yield. In order to obtain a synthetic intermediate
of 1, we then examined the reaction of 3a with 2-(formyl-
amino)-6-chloropurine tetrabutylammonium salt (5c).
The reaction was performed under the same reaction
conditions for the preparation of 6 to give the required
coupling product 8 in 55% yield.
The synthesis of carbocyclic nucleosides by direct
introduction of purine bases to cyclopentene derivatives
via a π-allylpalladium complex was initially pioneered
by Trost and his co-workers.10 Later, this method was
applied by several other groups to the synthesis of
carbocyclic nucleosides including 1.11 In these reactions,
cyclopentenyl carbonates, and the epoxide,10a were used
as efficient substrates for the formation of the π-allylpal-
ladium complex because the allylic oxygen functional
group is a good leaving group for the nucleophilicity of
palladium in its zero oxidation state.12 Recently, J ung
and his co-worker have reported the synthesis of 1a via
a π-allylpalladium complex formed by the reaction of the
3-(N,N-ditosylimido)cyclopentene derivative obtained from
2 in four steps with Pd0, in which the ditosylimido group
acts as a leaving group.13 In our reaction, it is notewor-
thy to mention that π-allylpalladium complex (4) is
formed by C-N bond cleavage (cleavage-b in Scheme 1)
in the ring of bicyclic amide 3, in which the N-sulfonyl-
or N-phosphorylamido group behaves as an intramolecu-
lar leaving group. This may be due to the 5-membered
bicyclic ring strain. The fact that 6-membered bicyclic
compound 914 no longer reacts with 6-chloropurine in the
presence of Pd0 and results in the quantitative recovery
of the starting material may be additional proof of this
mechanism.
a
Key: (a) MeOH, PPh3-DEAD, THF-CH2Cl2 (1:1), rt; (b)
NaBH4, MeOH, 0 °C; (c) (i) NaH (2.2 equiv), THF, 0 °C, (ii) tBoc2O,
rt f 50 °C, (iii) MeI, rt; (d) NaBH4, MeOH, 0 °C f rt; (e) AcOH,
50 °C.
direct conversion by using reductive reagents such as
NaBH4 in the presence of a metal salt was unsuccessful.
Therefore, compound 6 was transformed to the N-
methylated derivative 10 (mp 215-217 °C) by the Mit-
sunobu reaction (Scheme 3). 10 was then treated with
NaBH4 to give the known hydroxymethyl product 1115
in almost quantitative yield, concomitant with the forma-
tion of N-methyl-o-nitrobenzenesulfonamide. The trans-
formation of 8 to 15 was carried out as follows. That is,
t
8 was treated with NaH (2 equiv) and reacted with Boc2O
and MeI successively to give 13, which was subjected to
reductive amido bond cleavage reaction by NaBH4 to form
the hydroxymethyl derivative 14. Finally, removal of the
tBoc group by acetic acid at 50 °C for 8 h gave the known
compound 15 (mp 160-162 °C (lit.2a mp 145-147 °C) for
C11H12ClN5O‚3/4H2O) in 72% total yield from 8 leading
to 1a and 1b.
In summary, we have found that formation of the
π-allylpalladium complex from the 2-azabicyclo[2.2.1]-
hept-5-en-3-one having an electron-withdrawing group
at the 2-position in the presence of Pd0 leads to an
efficient synthesis of carbovir (1a ) and its congener (1b).
Since chiral 2 is now commercially available, our method
is also applicable to the synthesis of optically active 1a
and 1b.
Next, to obtain 1 and its congener 11 from 8 and 6,
respectively, we investigated conversion of the sulfonyl
amide groups of 6 and 8 to the hydroxymethyl group. The
(8) Bisacchi, G. S.; Singh, J .; Godfrey J r. J . D.; Kissick, T. P.; Mitt,
T.; Malley, M. F.; Di Marco, J . D.; Gougoutas, J . Z.; Mueller, R.; Zahler,
R. J . Org. Chem. 1995, 60, 2902.
(9) A trace amount (about 5%) of 7-substituted 6-chloropurine
derivative was also obtained as a minor product.
(10) (a) Trost, B. M.; Kuo, G.-H.; Benneche, T. J . Am. Chem. Soc.
1988, 110, 621. (b) Trost, B. M.; Li, L.; Guile, S. D. J . Am. Chem. Soc.
1992, 114, 8745.
(11) (a) Nokami, J .; Matsuura, H.; Nakasima, K.; Shibata, S. Chem.
Lett. 1994, 1071. (b) Roberts, S. M.; Shoberu, K. A. J . Chem. Soc.,
Perkin Trans. 1 1991, 2605. (c) Gundersen, L.-L.; Benneche, T.;
Undheim, K. Tetrahedron Lett. 1992, 33, 1085.
(12) For an excellent review concerning the formation of π-allylpal-
ladium complexes and their reactions, see: Godleski, S. A. Nucleophiles
with Allyl-Metal Complexes. In Comprehensive Organic Synthesis;
Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 4, Chapter 3.3, pp
585-661.
(13) J ung, M. E.; Rhee, H. J . Org. Chem. 1994, 59, 4719.
(14) Compound 9 (mp 138-139 °C) was obtained in 66% yield by
the same procedure given for the preparation of 3a .
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for compounds 3a ,b, 6-8, 10, 11, and 15 and H-NMR
spectra for compounds 3a ,b, 6-8, 10, 11, 13, and15 (13 pages).
1
J O962416U
(15) Vince, R.; Hua, M.; Brownell, J .; Daluge, S.; Lee, F.; Shannon,
W.; Lavelle, G.; Qualls, J .; Weislow, O.; Kiser, R.; Canonico, P.; Schultz,
R.; Narayanan, V.; Mayo, J .; Shoemaker, R.; Boyd, M. Biochem.
Biophys. Res. Commun. 1988, 156, 1046.