2876 J . Org. Chem., Vol. 67, No. 9, 2002
Suzuki et al.
Sch em e 1
deprotection, similar reaction conditions provided 15 in
75% yield (entry 9). The use of (+)-BINAP gave slightly
lower yield (entry 10). It should be noted that when the
coupling reaction was terminated at 0.5 h, the anomeric
ratio was significantly altered (entry 11).
The structures of the coupling products were estab-
lished by 1H NMR analysis. The major isomer of 15
showed its anomeric proton at δ 5.76 as a broad singlet,
whereas that of the minor isomer appeared at δ 6.40
(broad s). When the broad signal at δ 7.01 (NH of the
â-anomer, exchangeable with D2O) was irradiated, the
signal of the anomeric proton sharpened, implying the
connectivity of the C-1′ carbon in mannose to the amino
group at C-6 of the adenine moiety. The observed NOEs
in the major isomer between H-1′ and H-3′, H-1′ and H-5′,
and H-1′ and H-2′ clearly showed it to be in the â-manno
configuration. Treatment of 15 (R/â mixture) with BBr3
in CH2Cl2 at -78 °C resulted in global deprotection23 to
provide, after recrystallization from water, â-D-mannopy-
ranosylamino-9H-purine 16 in 97% yield. The coupling
constants (J 1′,2′ < 1 Hz, J 2′,3′ ) 3.2 Hz, J 3′,4′ ) 9.4 Hz, J 4′,5′
) 9.4 Hz) and NOEs observed in the 1H NMR again
supported the â-manno configuration.
Whereas an anomerically pure â-mannopyranosy-
lamine 13 was employed as the starting material, the
coupling products 14 and 15 were obtained as anomeric
mixtures, and the ratio of anomers varied by reaction
time. Furthermore, the deprotected product 16 was
isolated as a single â-anomer in high yield despite the
starting material 15 being a 1:5 anomeric mixture. These
phenomenon suggested that the anomerization of 14-
16 had occurred during the reaction and/or purification
processes. With interest to the anomeric behavior of the
N-glycosides, a kinetic analysis of anomerization of 15
was carried out (Scheme 2). Compound 15, consisting of
R-anomer and â-anomer in a ratio of 30.3:69.7, was
dissolved in toluene (5 mg/mL), and the solution was
heated at 100 °C in a sealed tube. The time course of the
anomeric ratios was followed by HPLC (Figure 3a). From
these experiments, it was found that the N-glycoside 15
showed thermal anomerization and reached equilibrium
at R:â ) 10.3:89.7 after 300 h. It was also shown that
the R-anomer, which would arise from anomerization of
pyranosylamine 13 during the coupling process,24 is the
kinetic product and the â-anomer is the thermodynamic
one. With application of eq 1,25 simple first-order kinetics
were observed (Figure 3b) in the anomerization of 15.
Similar reactions were carried out at 105 and 110 °C,
and the resulting rate constants obtained from eqs 1 and
2 are summarized in Table 2. Arrhenius plots shown in
Figure 3c demonstrated well-fitted linearity, and the
activation energies of anomerization of 15 in toluene were
estimated to be 28.2 kcal/mol (from R-anomer to â-ano-
mer) and 32.0 kcal/mol (â-anomer to R-anomer), respec-
tively. The deprotected compound 16 was found to show
much more rapid anomerization than 15, even at room
BuOH, reflux) employed for the successful coupling of
aliphatic amines with 5a 16 led only to the decomposition
of 13, presumably due to the instability of the pyrano-
sylamine as well as the reduced nucleophilicity of the
amino group by the presence of an endocyclic oxygen. At
this juncture we turned our attention to the Pd-catalyzed
conditions,17 which have been recently reported by Buch-
wald,18 Hartwig,19 and Tanaka20 to be efficient procedures
for the coupling of aliphatic and aromatic amines with
aryl halides or triflates. Although the reaction of 13 with
5a under the conditions reported by Tanaka20 (Table 1,
entry 1) gave no coupling products, we were delighted to
find that use of 9-protected 6-chloropurine21 5b afforded
the coupling product 14, though in only 25% yield (entry
2), as an inseparable mixture of R- and â-anomers (ca.
1:5). The dependence on various reaction parameters was
then examined. While use of 6-iodopurine22 derivative 5c
(entry 4) and Hartwig’s conditions19a (entry 6) did not
offer much improvement, Buchwald’s conditions18a using
an excess amount of 9-PMB-6-chloropurine (5b) gave 14
in considerably enhanced yield (entry 8). With SEM-
protected purine 5d , which was expected to undergo facile
(16) Fujii, T.; Ohba, M.; Kawamura, H.; Haneishi, T.; Matsubara,
S. Chem. Pharm. Bull. 1993, 41, 1362.
(17) For recent reviews of Pd-catalyzed amination of aryl halides
and triflates, see: Yang, B. H.; Buchwald, S. L. J . Organomet. Chem.
1999, 576, 125. Hartwig, J . F. Angew. Chem., Int. Ed. 1998, 37, 2046.
Hartwig, J . F. Synlett. 1997, 329.
(18) (a) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc.
1996, 118, 7215. (b) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997,
62, 1264. (c) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348. (d) Wagaw, S.; Rennels, R. A.;
Buchwald, S. L. J . Am. Chem. Soc. 1997, 119, 8451. (e) Wolfe, J . P.;
Buchwald, S. L. J . Org. Chem. 1997, 62, 6066.
(19) (a) Louie, J .; Driver, M. S.; Hamann, B. C.; Hartwig, J . F. J .
Org. Chem. 1997, 62, 1268. (b) Driver, M. S.; Hartwig, J . F. J . Am.
Chem. Soc. 1996, 118, 7217. (c) Louie, J .; Hartwig, J . F. Tetrahedron
Lett. 1995, 36, 3609. (d) Paul, F.; Patt, J .; Hartwig, J . F. J . Am. Chem.
Soc. 1994, 116, 5969.
(20) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807.
(21) Compounds 5b,d were prepared from commercially available
6-chloropurine by essentially the same procedure as that reported for
the preparation of 9-benzyl-6-chloropurine; see: Gundersen, L.-L.;
Bakkestuen, A. K.; Aasen, A. J .; Overas, H.; Rise, F. Tetrahedron 1994,
50, 9743.
(23) Attempted deprotection of compounds 14 and 15 under hydro-
genolytic conditions (H2, Pd catalyst) was unsuccessful; hydrogenation
of the heterocyclic moiety was observed. Treatment of 14 with BBr3/
CH2Cl2 resulted in the formation of many unidentified products, and
no desired product was obtained.
(24) Anomerization of pyranosylamine 13 during the acylation with
2-chlorobenzoyl chloride in pyridine, which resulted in the formation
of R-amide and â-amide in a ratio of 1:4.7, has been observed by Fraser-
Raid; see ref 14.
(25) Hough, L.; Richardson, A. C. In Rodd’s Chemistry of Carbon
Compounds, 2nd ed.; Coffey, S., Ed.; Elsevier: Amsterdam, 1967; Vol.
I, Part F, Chapter 23, p 173.
(22) McKenzie, T. C.; Epstein, J . W. J . Org. Chem. 1982, 47, 4881.