Robins et al.
hexopyranoside32 (12a) (91%), and hydrolysis gave 2,6-dideoxy-
R-D-ribo-hexopyranose32,33 (digitoxose) (12c). Treatment of 11b
with LTBD gave methyl 2,6-dideoxy-3-deuterio-R-D-ribo-
hexopyranoside (12b). The same stereochemical outcome in the
presence or absence of protection at O4 and O6 precludes
participation or directive effects by the hydroxyl groups. Hydride
attack occurred at the less hindered â-face.
General Procedure B: Deoxygenative [1,2]-Hydride Shift
Rearrangement. LTBH (1 M in THF; 15 mL, 15 mmol) [Note20]
was added by syringe into a stirred solution of 2a (421 mg, 1.00
mmol) in dried DMSO (15 mL) under N2 at ambient temperature,
and stirring was continued for 18 h. H2O (5 mL) was added
cautiously, and the solution was concentrated. The residue was
chromatographed [(Dowex 1 × 2 (OH-), H2O] and recrystallized
(MeOH) to give 9-(2-deoxy-â-D-threo-pentofuranosyl)adenine3,6a
(3a) (247 mg, 98%): mp 220-221 °C [Note35] (lit.6a mp 218-
1
220 °C); H NMR δ 2.26 (d, J ) 14.6 Hz, 1H), 2.75-2.82 (m,
Summary and Conclusions
1H), 3.58-3.63 (m, 1H), 3.71-3.76 (m, 1H), 3.88-3.92 (m, 1H),
4.31-4.36 (m, 1H), 4.70 (t, J ) 5.4 Hz, 1H), 5.99 (d, J ) 5.4 Hz,
1H), 6.26 (d, J ) 8.3 Hz, 1H), 7.36 (br s, 2H), 8.15, 8.35 (2 × s,
2 × 1H); 13C NMR δ 40.7, 59.9, 69.2, 82.4, 85.2, 119.0, 140.0,
148.5, 152.2, 156.1; FAB-MS m/z 252 ([M + H+], 10), 157 (100);
HRMS (C10H14N5O3) calcd 252.1091, found 252.1090.
Deuterium Labeling. Treatment of 2a with LTBD20 according
to general procedure B gave 3′[2H]3a: 1H NMR δ 2.26 (d, J )
14.6 Hz, 1H), 2.79 (dd, J ) 8.8, 14.6 Hz, 1H), 3.58-3.64 (m, 1H),
3.71-3.76 (m, 1H), 3.88-3.92 (m, 1H), 4.71 (t, J ) 5.6 Hz, 1H),
5.98 (s, 1H), 6.26 (d, J ) 8.8 Hz, 1H), 7.38 (br s, 2H), 8.16, 8.36
(2 × s, 2 × 1H); 13C NMR δ 40.7, 60.0, 68.9 (reduced intensity),
82.5, 85.2, 119.0, 140.1, 148.5, 152.3, 156.1; FAB-MS m/z 253
([M + H+], 100); HRMS (C10H13DN5O3) calcd 253.1154, found
253.1155.
Tosylation of 2′[2H]1a16 at O2′ by general procedure A followed
by treatment of 2′[2H]2a with LTBH20 according to general
procedure B gave 2′(R)[2H]3a: 1H NMR δ 2.26 (d, J ) 2.0 Hz,
1H), 3.55-3.63 (m, 1H), 3.71-3.76 (m, 1H), 3.87-3.91 (m, 1H),
4.31-4.36 (m, 1H), 4.64 (t, J ) 5.4 Hz, 1H), 5.93 (d, J ) 5.0 Hz,
1H), 6.25 (d, J ) 1.9 Hz, 1H), 7.31 (br s, 2H), 8.14, 8.34 (2 × s,
2 × 1H); 13C NMR δ 40.4 (reduced intensity), 59.9, 69.2, 82.4,
85.2, 118.9, 140.0, 148.5, 152.2, 156.1; FAB-MS m/z 253 ([M +
H+], 10), 141 (100); HRMS (C10H13DN5O3) calcd 253.1154, found
253.1152.
Tosylation of 3′[2H]1a16 at O2′ by general procedure A followed
by treatment of 3′[2H]2a with LTBH20 according to general
procedure B gave 2′(S)[2H]3a: 1H NMR δ 2.77 (dd, J ) 5.9, 8.8
Hz, 1H), 3.57-3.63 (m, 1H), 3.71-3.76 (m, 1H), 3.88-3.91 (m,
1H), 4.33 (dt, J ) 3.4, 5.4 Hz, 1H), 4.70 (t, J ) 5.6 Hz, 1H), 5.98
(d, J ) 5.9 Hz, 1H), 6.25 (d, J ) 8.3 Hz, 1H), 7.35 (br s, 2H),
8.15, 8.35 (2 × s, 2 × 1H); 13C NMR δ 40.4 (reduced intensity),
59.9, 69.2, 82.5, 85.2, 119.0, 140.1, 148.6, 152.3, 156.1; FAB-MS
m/z 253 ([M + H+], 100); HRMS (C10H13DN5O3) calcd 253.1154,
found 253.1153.
Treatment of 2b-e gave 3b [70% (H2O); Dowex 1 × 2 (OH-),
50 mM aqueous Et3NH‚HCO3 with data as reported4c], 3c [74%;
Dowex 1 × 2 (OH-) H2O f 30% MeOH/H2O; with data as
reported5], 3d [82% (diffusion crystallization MeOH/Et2O)], and
3e [71%; Dowex 1 × 2 (OH-), H2O f H2O/MeOH, 1:1],
respectively.
We have demonstrated that a completely stereoselective and
chemically efficient deoxygenative [1,2]-hydride shift rear-
rangement occurred upon treatment of several ribonucleoside
and mannopyranoside cis-vicinal diol monotosylates with LT-
BH(D). Deuterium labeling showed that the process occurred
with inversion of stereochemistry at both carbinol carbons. This
is consistent with abstraction of the hydroxyl proton by hydride,
generation of a carbonyl group with a concomitant [1,2]-hydride
shift to the backside of the vicinal carbon, and displacement of
the tosylate group. Attack of borohydride at the less hindered
face generated the inverted alcohol. The process also occurred
with bromide and chloride leaving groups with an SN2-like rate
order of OTs ≈ Br . Cl for these semipinacol rearrangements.
The nucleobase and sugar substituents had negligible effects.
Mechanistic similarities exist between the [1,2]-hydride shift
process of the semipinacol rearrangements and the [1,2]-electron
shift that occurs during reduction of ribonucleotides to 2′-
deoxynucleotides at the active site of ribonucleotide reductases
(RNRs). Radical-induced deoxygenations catalyzed by RNRs
result in double retention of stereochemistry at C2′ and C3′, in
contrast with the doubly inverted semipinacol products. Analo-
gous results with mannopyranoside tosylates provide ready
access to deoxyallose and digitoxose sugars.
Experimental Section34
General Procedure A: Preparation of 2′-O-Tosylnucleosides14
(2). The nucleoside 1 (1.0 mmol) was stirred under reflux in
absolute MeOH (25 mL) with Bu2SnO (275 mg, 1.1 mmol) until
the suspension became a clear solution [1c,d (∼45 min); 1a,e (∼1
h); 1b (∼2 h)]. The solution was cooled to ambient temperature,
and Et3N (2.1 mL, 1.52 g, 15 mmol) and then TsCl (2.85 g, 15
mmol) were added. Stirring was continued until tosylation was
virtually complete (TLC) [1c (∼5 min); 1b,d (∼10 min); 1a (∼15
min); 1e (∼45 min)]. Volatiles were evaporated, and the residue
was partitioned [Et2O (50 mL)/H2O (50 mL)]. Volatiles were
evaporated from the aqueous phase, and the residue was recrystal-
lized to give 2a14 (73%), 2b4c (52%), 2c5 (79%), 2d (67%), and 2e
(52%).
2d: 1H NMR δ 2.29 (s, 3H), 3.59 (m, 2H), 4.01 (m, 1H), 4.29
(t, J ) 5.0 Hz, 1H), 5.38 (dd, J ) 7.5, 5.0 Hz, 1H), 5.77 (t, J ) 5.0
Hz, 1H), 5.94 (d, J ) 5.0 Hz, 1H), 6.08 (d, J ) 7.5 Hz, 1H), 6.43
(d, J ) 3.5 Hz, 1H), 7.14 (br s, 2H), 7.16 (d, J ) 3.5 Hz, 1H), 7.91
(s, 1H). Anal. Calcd for C18H20N4O6S (420.4): C, 51.42; H, 4.79;
N, 13.33. Found: C, 51.35; H, 4.85; N, 13.32.
4-Amino-7-(2-deoxy-â-D-threo-pentofuranosyl)pyrrolo[2,3-d]-
pyrimidine (3d). Mp 202-203 °C; UV max 272 nm (ꢀ 11 900),
min 239 nm (ꢀ 2300); 1H NMR δ 2.14 (dd, J ) 14.6, 2.9 Hz, 1H),
2.72-2.77 (ddd, J ) 14.6, 8.8, 5.9 Hz, 1H), 3.56-3.82 (m, 3H),
4.29-4.32 (m, 1H), 4.62 (t, J ) 5.6 Hz, 1H), 5.98 (d, J ) 5.9 Hz,
1H), 6.32 (dd, J ) 8.7, 3.4 Hz, 1H), 6.56 (d, J ) 3.9 Hz, 1H), 7.05
(br s, 2H), 7.46 (d, J ) 3.4 Hz 1H), 8.06 (s, 1H); 13C NMR δ
157.5, 151.3, 149.0, 123.1, 102.9, 99.2, 84.2, 82.5, 69.4, 60.0, 40.8;
HRMS (C11H14N4O3) calcd 250.1066, found 250.1074. Anal. Calcd
for C11H14N4O3‚0.25H2O (254.7): C, 51.86; H, 5.74; N, 21.99.
Found: C, 51.74; H, 5.42; N, 21.65.
2e: 1H NMR δ 2.27 (s, 3H), 3.60 (m, 2H), 4.02 (m, 1H), 4.31
(m, 1H), 5.23 (dd, J ) 7.5, 5.0 Hz, 1H), 6.07 (d, J ) 7.5 Hz, 1H),
5.70 (br s, 2H), 7.36, 7.86 (2 × s, 2 × 1H), 7.40 (br s, 2H), 7.96,
8.32 (2 × s, 2 × 1H). Anal. Calcd for C19H21N5O7S (463.5): C,
49.24; H, 4.57; N, 15.11. Found: C, 49.23; H, 4.53; N, 15.03.
4-Amino-5-carboxamido-7-(2-deoxy-â-D-threo-pentofurano-
syl)pyrrolo[2,3-d]pyrimidine (3e). Mp 236-237 °C; UV max 280
(32) Cheung, T. M.; Horton, D.; Weckerle, W. Carbohydr. Res. 1977,
58, 139-151.
(33) Roush, W. R.; Brown, R. J. J. Org. Chem. 1983, 48, 5093-5101.
(34) Experimental details are in the Supporting Information.
(35) X-ray quality crystals of 3a were obtained by diluting a concentrated
solution of 3a in DMSO with MeOH and allowing the resulting solution to
stand overnight. Large crystals of 3a that formed were separated, washed
with MeOH, and dried under vacuum.
8220 J. Org. Chem., Vol. 72, No. 22, 2007