Development of a generic stereocontrolled pathway to fully hydroxylated spirocarbocyclic nucleosides as a prelude to RNA targeting

Article abstract of DOI:10.1055/s-2005-918472

Osmylation of the enantiopure conjugated enones 4 and 15 proceeded predominantly or exclusively from the α-face to give the 2′,3′-diols 6 and 16. Ensuing conversion into the acetonide allowed for sequential stereocontrolled reduction with L-Selectride, an

Full text of DOI:10.1055/s-2005-918472

PAPER
3209
Development of a Generic Stereocontrolled Pathway to Fully Hydroxylated
Spirocarbocyclic Nucleosides as a Prelude to RNA Targeting
A
G
eneric Stereo
y
controlledPathwaytoF
n
ully
H
ydroxylated
E
Spirocarbocycl
.
ic
N
ucleoside
H
s
artung, Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210, USA
Fax +1(614)2921685; E-mail: paquette.1@osu.edu
Received 12 February 2005
In celebration of a 35-year professional relationship with Steve Ley, during which time he has established for himself a stellar career
marked by many significant contributions to organic chemistry.
R2 R1
R2 R1
Abstract: Osmylation of the enantiopure conjugated enones 4 and
15 proceeded predominantly or exclusively from the a-face to give
the 2¢,3¢-diols 6 and 16. Ensuing conversion into the acetonide al-
lowed for sequential stereocontrolled reduction with L-Selectride,
and esterification with triflic anhydride was utilized to form triflates
11 and 19. The heightened electrophilicity of these intermediates
made possible SN2 displacements with several nucleobases as pro-
moted with potassium hydride in N,N-dimethylformamide at room
temperature. Suitable deprotection measures led to the targeted
compounds.
B
B
OH
1
2
R2 R1
B
HO
OH
Key words: spirocarbocycles, nucleosides, triflate displacements,
osmylation, acetonides
3
a, R1 = H, R2 = OH; b, R1 = OH, R2 = H
Figure 1
As a direct consequence of the potent antitumor and anti-
viral properties of select naturally occurring carbocyclic
nucleosides,1 many ingenious inroads have been made
into maximizing the structural diversity of synthetic ana-
logues.2 The innovative modifications have focused on
the alteration of anomeric substituents,3 the desaturation
of the cyclopentane pseudosugar, and various means to
achieve rigidification of the molecular architecture.4 Our
own efforts in this area have given consideration to spiro-
cyclic restriction.5 Successful synthetic approaches to the
syn and anti epimers defined by 16 and 27 (Figure 1) have
heretofore been reported. As yet unexplored has been a
strategy for generating the maximally functionalized
members of the class specified by 3, which is of particular
interest because of their structural relationship to aristero-
mycin.8 The present report fills this gap by providing the
details surrounding a synthetic protocol applicable to the
efficient stereocontrolled introduction of both pyrimidine
and purine nucleobases to generate the spirocyclic carba-
nucleosides.
that b-elimination had to be avoided. Recourse to 2,2-
dimethoxypropane and a catalytic quantity of p-toluene-
sulfonic acid positively addressed this issue, giving rise to
8a in 94% yield. Equivalent success was realized in for-
mation of the benzylidene acetal 8b (benzaldehyde di-
methyl acetal, PTSA; 99% yield), siloxane 8c [1,3-dichloro-
1,1,3,3-tetraisopropyldisiloxane (TIPDSCl2), AgNO3, py,
THF; 98% yield],9 and carbonate 8d (phosgene, DMAP,
CH2Cl2; 80% yield). The first three of these protected
variants could be successfully reduced with L-Selectride
in tetrahydrofuran and efficaciously transformed further
into mesylates 9a–c (R¢ = Ms). The reduction of 8d war-
rants comment. In contrast to 8a–c, which were converted
exclusively into their a-carbinols 9a–c (R¢ = H), 8d exhib-
ited reversed stereoselectivity when reduced with sodium
borohydride in MeOH and produced a carbinol mixture
rich in the b-anomer [(a/b) 1:3]. The significantly reduced
levels of steric shielding on the a-face of 8d are consid-
ered responsible for this crossover.
Preliminary Evaluation of SN2 Reactivity Levels
In atypical fashion,6 mesylates 9a–c (R¢ = Ms) proved to-
tally unreactive to SN2 displacement involving adenine in
N,N-dimethylformamide at 80 °C as the test conditions.
Experiments with carbonate 9d (R¢ = Ms) showed it to be
subject to degradation when comparably treated. The ap-
proach taken to rectify the obviously low reactivity levels
was to involve the triflate derivative instead. Acetonide 11
was accessed without difficulty and its adaptability in the
present setting is presented below.
As depicted in Scheme 1, our initial efforts were focused
on the use of readily available cyclopentenone 46,7 as the
building block of choice. Typical osmylation conditions
resulted in its smooth conversion into the diols 5 and 6, fa-
voring the latter by a factor of 5. After chromatographic
separation, the search for a suitable protecting group was
initiated. When two sets of O-allylation conditions were
applied to 6 and found to deliver only 7, it was made clear
Enabling Technology for the 5¢-b Analogs
SYNTHESIS 2005, No. 19, pp 3209–3218
Advanced online publication: 17.11.2005
DOI: 10.1055/s-2005-918472; Art ID: C04505SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
5
The direct and selective introduction of several nucleo-
base units into 11 proceeded slowly without total con-

3210
R. E. Hartung, L. A. Paquette
PAPER
TBSO
TBSO
TBSO
OsO4, H2O,
acetone
B
HO
OH
TBAF
THF
KH, base
DMF, r.t.
O
O
O
+
11
py; H2S
(62%)
O
O
(1 : 5)
4
5
H3C
CH3
TBSO
TBSO
12
I
,
K2CO3,
a: uracil (37% conv, 76% yield)
b: cytosine (93% conv, 85% yield)
c: thymine (23% conv, 83% yield)
d: adenine (55% conv, 97% yield)
e: 2-amino-6-
DMF (80%)
O
or
(i-Pr)2NEt,
O
HO
OH
I
,
DMF
7
6
(80%)
chloropurine (33% conv, 88% yield)
HO
HO
B
1. L-Selectride,
THF or
NaBH4, MeOH
B
TBSO
TBSO
MeOH
(PTSA)
O
O
O
OH
HO
2. MsCl, Et3N,
CH2Cl2
OR'
O
O
O
O
H3C
CH3
R
R
13
14
8
9
CH3
a: uracil (60%)
a: uracil (82%)
R' = H, Ms
a, R =
b, R =
C
C
b: cytosine (98%)
c: thymine (96%)
d: adenine (82%)
e: 2-amino-6-
chloropurine (100%)
f: guanine (100%)
b: cytosine (62%)
c: thymine (99%)
d: adenine (80%)
e: guanine (93%)
CH3
Ph
1. L-Selectride,
THF (95%)
H
see text
c, R = (i-Pr)2SiOSi(i-Pr)2
2. Tf2O, py
i
CH2Cl2 (100%)
d, R =
C
O
conditions (i):
SH
NaOMe, HO
, MeOH, 80 °C
TBSO
TBSO
B
Scheme 2
OTf
O
O
O
O
ately. Thus, unlike 4 which experiences attack by osmium
tetraoxide from both of its olefinic surfaces, 15 undergoes
the analogous reaction in an entirely stereoselective man-
ner to furnish only 16. The corresponding acetonide 17
was expected as before to be compatible with the reaction
conditions that were to follow, and to prove amenable to
scale-up should such action become necessary. Under the
conditions of L-Selectride reduction, 17 was converted
into alcohol 18 from which the triflate 19 was crafted. The
reactivity observations made during the course of the SN2
displacements on 19 by the five nucleobases are in full
agreement with the notion that the conformation adopted
by the second five-membered ring interferes sterically
with the trajectory normally operative in bimolecular dis-
placement processes. In addition, the shelf stability of 19
is significantly less than that of 11. Utilization of two con-
secutive deblocking maneuvers then led via 21a–f to triols
22a–e.
R
CH3
H3C
11
10
Scheme 1
sumption of the triflate. Notwithstanding, unreacted
starting material could be readily separated from the re-
sulting protected nucleosides, such that the adjusted yields
were quite acceptable (76–97%, Scheme 2). The level of
throughput was highly variable, ranging from a low of
23% conversion for thymine to a high of 93% for cy-
tosine. The guanine subunit was introduced indirectly as
has become customary. Thus, initial displacement of the
triflate with configurational inversion to give 12e and de-
silylation with the generation of 13e was followed by a hy-
drolytic removal of the chlorine substituent with 2-
sulfanylethanol and sodium methoxide in hot MeOH.7,10
The final chemoselective hydrolysis of the acetonide
functionality in MeOH containing p-toluenesulfonic acid
needed no optimization.
In summary, an enantioselective synthesis of ten spirocar-
bocyclic nucleosides was developed, allowing for the two
different configurations at C-5¢. Unprecedented involve-
ment of triflate intermediates was relied upon to gain suf-
ficient reactivity for effecting installation of the purine or
pyrimidine bases with high fidelity at the anomeric center.
Evaluation of the biological properties of 14 and 22 is in
progress.
Synthesis of the 5¢-a Nucleoside Diastereomers
Advantage was taken of the lessons derived from the ac-
quisition of 14a–e for the preparation of those spirocar-
bocyclic nucleosides epimeric at C-5¢ (Scheme 3).
Nevertheless, differences in reactivity surfaced immedi-
Synthesis 2005, No. 19, 3209–3218 © Thieme Stuttgart · New York

PAPER
A Generic Stereocontrolled Pathway to Fully Hydroxylated Spirocarbocyclic Nucleosides
3211
5
TBSO
TBSO
OsO4, H2O,
CH3COCH3
White solid.
O
O
Yield: 90 mg (12%).
Mp 105 °C.
py; H2S
(66%)
OH
HO
15
[a]D20 +7.7 (c 1.0, CHCl3).
IR (CH2Cl2): 3555, 1754, 1471 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.33 (d, J = 3.8 Hz, 1 H), 4.21–
4.18 (m, 1 H), 4.15 (t, J = 4.8 Hz, 1 H), 2.36–1.45 (series of m, 8 H),
0.91 (s, 9 H), 0.12 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 215.2, 80.1, 78.2, 75.0, 49.5, 42.4,
33.8, 32.4, 25.6 (3C), 20.2, 17.8, –4.3, –5.1.
ES HRMS: m/z [M + Na]+ calcd for C15H28O4Si: 323.1649; found:
16
TBSO
1. L-Selectride,
THF, –78 °C (98%)
(CH3)2C(OCH3)2
O
(p-TsOH)
(99%)
2. Tf2O, py,
CH2Cl2 (82%)
O
O
H3C
CH3
17
323.1653.
TBSO
TBSO
B
KH,
6
TBAF
base
White solid.
OR
DMF,
r.t.
THF
O
O
O
O
Yield: 0.34 g (50%).
H3C
H3C
CH3
CH3
Mp 84–85 °C.
18, R = H
19, R = Tf
20
[a]D20 –38.5 (c 1.1, CHCl3).
IR (CH2Cl2): 3557, 1751, 1471 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.49 (dd, J = 4.6, 1.6 Hz, 1 H),
4.35 (d, J = 4.5 Hz, 1 H), 3.91 (t, J = 5.8 Hz, 1 H), 2.32–1.51 (series
of m, 8 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.05 (s, 3 H).
a: uracil (60% conv, 10% yield)
b: cytosine (40% conv, 61% yield)
c: thymine (68% conv, 14% yield)
d: adenine (44% conv, 41% yield)
e: 2-amino-6-
chloropurine (66% conv, 41% yield)
13C NMR (125 MHz, CDCl3): d = 216.1, 80.7, 78.0, 71.7, 51.1, 43.0,
33.1, 31.2, 25.8 (3C), 19.8, 17.9, –4.3, –4.9.
HO
HO
ES HRMS: m/z [M + Na]+ calcd for C15H28O4Si: 323.1649; found:
323.1655.
B
B
MeOH
(PTSA)
O
O
16
HO
OH
White solid.
H3C
CH3
21
Yield: 0.10 g (66%).
22
a: uracil (70%)
a: uracil (88%)
Mp 102 °C.
b: cytosine (93%)
c: thymine (92%)
d: adenine (96%)
e: 2-amino-6-
chloropurine (96%)
f: guanine (72%)
b: cytosine (100%)
c: thymine (90%)
d: adenine (85%)
e: guanine (95%)
[a]D20 +14.7 (c 1.6, CHCl3).
IR (CH2Cl2): 3552, 1750 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.41 (dd, J = 4.5, 1.6 Hz, 1 H),
4.00–3.97 (m, 2 H), 2.74–1.49 (series of m, 8 H), 0.83 (s, 9 H), 0.04
(s, 3 H), 0.03 (s, 3 H).
i
13C NMR (125 MHz, CDCl3): d = 216.7, 78.3, 77.4, 76.7, 51.0, 39.0,
33.6, 32.1, 25.7 (3C), 19.6, 17.8, –4.0, –5.1.
conditions (i):
SH
NaOMe, HO
, MeOH, 80 °C
ES HRMS: m/z [M + Na]+ calcd for C15H28O4Si: 323.1649; found:
323.1647.
Scheme 3
Protocol To Give Acetonides 8a and 17; General Procedure
Keto diols 6 or 16 (32 mg, 0.1 mmol), 2,2-dimethoxypropane (2
mL), and PTSA (2 mg, 0.01 mmol) were combined and heated to 80
°C. The mixture was stirred for 2 h, allowed to cool to r.t., quenched
with sat. NaHCO3 soln, and extracted with Et2O (3 × 30 mL). The
combined organic phases were dried (Na2SO4) and concentrated in
vacuo, and the residue was purified by column chromatography (sil-
ica gel, hexanes–EtOAc 20:1).
Infrared Spectra were recorded on a Perkin Elmer 1600 Series FT-
IR spectrophotometer. 1H NMR spectra were measured on a Bruker
DPX-500 in the indicated solvent. Mass spectra were recorded at
The Ohio State University Campus Chemical Instrumentation Cen-
ter or at Chemistry Department Mass Spectrometry Facility. Col-
umn chromatographic purifications were performed on silica gel
(230–400 mesh). All reactions were performed under N2 unless oth-
erwise noted.
8a
Keto Diols 5, 6, and 16; General Procedure
Yield: 34 mg (94%).
[a]D20 –106.5 (c 1.0, CHCl3).
IR (neat): 1759, 1472, 1271 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.65 (d, J = 5.4 Hz, 1 H), 4.28 (d,
J = 5.4 Hz, 1 H), 3.85 (t, J = 7.8 Hz, 1 H), 2.76–1.54 (series of m, 8
H), 1.44 (s, 3 H), 1.37 (s, 3 H), 0.86 (s, 9 H), 0.07 (s, 3 H), 0.06 (s,
3 H).
a,b-Unsaturated ketone 4 or 15 (0.62 g, 2.3 mmol), H2O (6.3 mL),
acetone (63 mL), py (0.4 mL, 4.7 mmol), and OsO4 (0.65 g, 2.6
mmol) were combined and stirred for 2 h. H2S was bubbled through
the solution until reduction of the osmate ester was complete by
TLC. The solution was filtered through a pad of Celite, and the fil-
trate was quenched with sat. NaHCO3 soln prior to extraction with
Et2O (3 × 150 mL). The combined organic phases were dried
(Na2SO4) and concentrated in vacuo, and the residue was purified
by column chromatography (silica gel, hexanes–EtOAc 5:1).
Synthesis 2005, No. 19, 3209–3218 © Thieme Stuttgart · New York

3212
R. E. Hartung, L. A. Paquette
PAPER
13C NMR (125 MHz, CDCl3): d = 212.6, 110.9, 81.4, 79.9, 79.3,
1H NMR (500 MHz, CDCl3): d = 4.37 (d, J = 5.0 Hz, 1 H), 4.27 (d,
J = 5.0 Hz, 1 H), 3.95 (t, J = 8.1 Hz, 1 H), 2.48–1.39 (series of m, 8
H), 1.39 (s, 3 H), 1.33 (s, 3 H), 0.82 (s, 9 H), 0.06 (s, 3 H), 0.02 (s,
3 H).
13C NMR (125 MHz, CDCl3): d = 213.3, 111.1, 85.3, 79.6, 79.0,
50.3, 40.7, 32.0, 30.8, 26.9, 25.6 (3C), 25.0, 19.6, 17.8, –4.1, –5.0.
50.4, 43.9, 31.9, 28.5, 26.8, 25.8 (3C), 19.1, 17.9, –4.6, –5.1.
EI HRMS: m/z [M]+ calcd for C18H32O4Si: 340.2064; found:
340.2097.
17
Yield: 104 mg (99%).
[a]D20 –77.6 (c 1.7, CHCl3).
ES HRMS: m/z [M + Na]+ calcd for C18H32O4Si: 363.1962; found:
363.1967
IR (neat): 1758, 1251, 1086 cm–1.
Table 1 Characterization of Products
20
Product Mp
[a]D
1H NMR
(500 MHz), d
13C NMR
(125 MHz), d
ES or EI HRMS,
m/z
(°C) (c, solvent)
Acetonides 12a–e and 20a–e
12a
185
205
166
–47.8
(c 0.7, CHCl3) 5.73 (dd, J = 8.0, 2.2 Hz, 1 H), 4.77 (d, J = 6.7 102.5, 82.5, 78.7, 78.3, 62.7, 52.9,
Hz, 1 H), 4.69–4.65 (m, 2 H), 3.81 (t, J = 7.4 39.3, 32.2, 30.4, 26.7, 25.8 (3C),
(CDCl3) 8.46 (s, NH), 7.17 (d, J = 8.1 Hz, 1 H), (CDCl3) 162.7, 150.4, 141.8, 113.5, [M + Na]+ calcd for
C22H36N2O5Si:
459.2285; found:
459.2274
Hz, 1 H), 2.30–1.27 (series of m, 8 H), 1.56 (s, 25.0, 19.4, 18.0, –4.2, –4.9
3 H), 1.33 (s, 3 H), 0.94 (s, 9 H), 0.09 (s, 6 H)
12b
–33.1
(CDCl3) 8.07 (d, J = 5.7 Hz, 1 H), 6.09 (d, J = (CDCl3) 164.6, 157.7, 110.3, 99.2,
[M + Na]+ calcd for
C22H37N3O4Si:
458.2476; found:
458.2445
(c 1.0, CHCl3) 5.7 Hz, 1 H), 5.17–5.15 (m, 1 H), 4.89 (s, NH2), 85.5, 82.6, 81.7, 60.3, 57.6, 39.9,
4.84 (d, J = 6.1 Hz, 1 H), 4.59 (d, J = 6.0 Hz, 1 34.1, 32.0, 26.5, 25.8 (3C), 24.2,
H), 4.23–4.22 (m, 1 H), 2.23–1.43 (series of m, 21.0, 20.6, 18.0, –4.3, –4.9
8 H), 1.51 (s, 3 H), 1.33 (s, 3 H), 0.90 (s, 9 H),
0.07 (s, 3 H), 0.05 (s, 3 H)
12c
12d
–36.8
(CDCl3) 8.19 (s, NH), 6.98 (s, 1 H), 4.77 (d, J = (CDCl3) 163.2, 150.5, 137.7, 113.4, [M + Na]+ calcd for
(c 0.6, CHCl3) 6.3 Hz, 1 H), 4.70–4.66 (m, 2 H), 3.80 (t, J = 7.6 111.0, 82.5, 78.7, 78.3, 62.2, 52.8,
Hz, 1 H), 2.30–1.27 (series of m, 8 H), 2.06 (s, 39.3, 32.1, 30.4, 26.7, 25.8 (3C),
3 H), 1.56 (s, 3 H), 1.33 (s, 3 H), 0.95 (s, 9 H), 25.0, 19.4, 18.0, 12.4, –4.1, –4.9
0.10 (s, 6 H)
C23H38N2O5Si:
473.2442; found:
473.2435
–37.3
(CDCl3) 8.31 (s, 1 H), 7.83 (s, 1 H), 5.77 (s,
(CDCl3) 155.4, 152.7, 150.2, 139.5, [M + Na]+ calcd for
120.3, 113.5, 83.8, 78.9, 77.9, 60.9, C23H37N5O3Si:
(c 1.1, CHCl3) NH2), 5.00 (dd, J = 7.4, 6.1 Hz, 1 H), 4.94 (d,
J = 7.6 Hz, 1 H), 4.76–4.71 (m, 1 H), 3.85 (t, J = 53.3, 40.6, 32.3, 30.3, 26.7, 25.8
7.8 Hz, 1 H), 2.35–1.33 (series of m, 8 H), 1.57 (3C), 24.9, 19.4, 18.0, –4.2, –5.0
(s, 3 H), 1.33 (s, 3 H), 0.95 (s, 9 H), 0.09 (s, 3
H), 0.08 (s, 3 H)
482.2557; found:
482.2576
12e
20a
20b
20c
–23.1
(CDCl3) 7.80 (s, 1 H), 5.10 (s, NH2), 4.98–4.96 (CDCl3) 158.6, 153.7, 151.4, 141.6, [M + Na]+ calcd for
(c 1.1, CHCl3) (m, 1 H), 4.91 (d, J = 7.7 Hz, 1 H), 4.64–4.58
126.0, 113.7, 83.2, 78.6, 77.7, 60.9, C23H36ClN5O3Si:
(m, 1 H), 3.84 (t, J = 8.2 Hz, 1 H), 2.66 (t, J = 53.1, 40.1, 32.2, 30.2, 26.6, 25.9
516.2168; found:
516.2157
12.7 Hz, 1 H), 2.34–2.29 (m, 1 H), 1.93–1.30
(series of m, 6 H), 1.57 (s, 3 H), 1.34 (s, 3 H),
0.97 (s, 9 H), 0.10 (s, 6 H)
(3C), 24.9, 19.3, 18.1, –4.1, –4.9
+3.7
(CDCl3) 8.48 (s, NH), 7.22 (d, J = 8.1 Hz, 1 H), (CDCl3) 162.7, 150.5, 142.0, 113.6, [M + Na]+ calcd for
(c 0.9, CHCl3) 5.73 (dd, J = 8.0, 2.4 Hz, 1 H), 4.77–4.67 (m, 2 102.5, 83.0 (2C), 79.2, 62.4, 53.8,
H), 4.68 (d, J = 5.9 Hz, 1 H), 3.95 (t, J = 6.9 Hz, 35.2, 32.2, 29.6, 26.5, 25.8 (3C),
1 H), 1.98–1.26 (series of m, 8 H), 1.55 (s, 3 H), 25.0, 19.9, 18.0, –4.2, –4.7
1.31 (s, 3 H), 0.92 (s, 9 H), 0.10 (s, 3 H), 0.08
C22H36N2O5Si:
459.2285; found:
459.2316
(s, 3 H)
143
142
+29.2
(CDCl3) 8.01 (d, J = 5.7 Hz, 1 H), 6.05 (d, J = (CDCl3) 164.7, 164.6, 157.6, 111.2, [M + Na]+ calcd for
(c 1.0, CHCl3) 5.7 Hz, 1 H), 5.27–5.24 (m, 1 H), 4.85 (s, NH2), 99.1, 85.6, 83.2, 80.0, 78.0, 57.6,
4.65 (d, J = 6.4 Hz, 1 H), 4.14 (d, J = 6.5 Hz, 1 34.7, 33.2, 29.4, 26.3, 25.7 (3C),
H), 3.93–3.92 (m, 1 H), 2.24–1.24 (series of m, 24.5, 20.2, 17.9, –4.2, –5.0
8 H), 1.48 (s, 3 H), 1.29 (s, 3 H), 0.79 (s, 9 H),
C22H37N3O4Si:
458.2445; found:
458.2442
0.05 (s, 3 H), –0.01 (s, 3 H)
+3.5
(CDCl3) 8.12 (s, NH), 7.01 (d, J = 0.9 Hz, 1 H), (CDCl3) 163.2, 150.5, 137.8, 113.6, [M + Na]+ calcd for
(c 0.4, CHCl3) 4.76–4.68 (m, 2 H), 4.39 (d, J = 7.1 Hz, 1 H),
111.0, 82.89, 82.87, 79.1, 61.9, 53.6, C23H38N2O5Si:
3.96 (t, J = 7.1 Hz, 1 H), 2.42–1.23 (series of m, 35.0, 32.2, 29.4, 26.5, 25.8 (3C),
8 H), 1.94 (s, 3 H), 1.55 (s, 3 H), 1.32 (s, 3 H), 25.1, 19.9, 18.0, 12.4, –4.1, –4.8
0.93 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H)
473.2442; found:
473.2440
Synthesis 2005, No. 19, 3209–3218 © Thieme Stuttgart · New York

PAPER
A Generic Stereocontrolled Pathway to Fully Hydroxylated Spirocarbocyclic Nucleosides
3213
Table 1 Characterization of Products (continued)
20
Product Mp
[a]D
1H NMR
(500 MHz), d
13C NMR
(125 MHz), d
ES or EI HRMS,
m/z
(°C) (c, solvent)
20d
20e
198 +15.5
(CDCl3) 8.32 (s, 1 H), 7.84 (s, 1 H), 5.81 (s,
(CDCl3) 155.5, 152.7, 150.2, 139.5, [M + Na]+ calcd for
(c 1.7, CHCl3) NH2), 5.02 (dd, J = 7.5, 5.5 Hz, 1 H), 4.80–4.75 120.3, 113.8, 84.1, 82.9, 79.0, 60.4, C23H37N5O3Si:
(m, 1 H), 4.53 (d, J = 7.5 Hz, 1 H), 4.00 (t, J = 54.3, 36.7, 32.5, 29.3, 26.5, 25.7
6.7 Hz, 1 H), 2.10–1.41 (series of m, 8 H), 1.55 (3C), 24.9, 20.1, 18.0, –4.1, –4.9
(s, 3 H), 1.30 (s, 3 H), 0.90 (s, 9 H), 0.09 (s, 3
482.2557; found:
482.2530
H), 0.06 (s, 3 H)
–19.5
(c 1.2, CHCl3) (m, 1 H), 4.67–4.62 (m, 1 H), 4.49 (d, J = 7.5
Hz, 1 H), 3.99–3.97 (m, 1 H), 2.81–1.23 (series 54.0, 36.0, 32.4, 29.2, 26.5, 25.8
of m, 8 H), 1.54 (s, 3 H), 1.30 (s, 3 H), 0.91 (s, (3C), 24.9, 20.0, 18.0, –4.1, –4.9
9 H), 0.09 (s, 3 H), 0.06 (s, 3 H)
(CDCl3) 7.80 (s, 1 H), 5.19 (s, NH2), 4.95–4.92 (CDCl3) 158.8, 153.7, 151.3, 141.6, [M + Na]+ calcd for
125.9, 113.9, 83.5, 82.7, 78.8, 60.5, C23H36ClN5O3Si:
516.2168; found:
516.2163
Protected Hydroxy Nucleosides 13a–e and 21a–e
13a
217 –24.3
(c 1.0, CHCl3) 5.73 (d, J = 8.0 Hz, 1 H), 4.86 (d, J = 6.7 Hz, 1 102.4, 83.7, 79.5, 78.7, 62.3, 53.2,
(CDCl3) 8.87 (s, NH), 7.85 (d, J = 8.1 Hz, 1 H), (CDCl3) 163.2, 151.0, 143.6, 112.9, [M + Na]+ calcd for
C16H22N2O5:
345.1420; found:
345.1438
H), 4.80–4.72 (m, 2 H), 3.96 (t, J = 6.9 Hz, 1 H), 40.0, 32.2, 31.3, 26.9, 25.2, 19.9
2.47–1.55 (series of m, 8 H), 1.53 (s, 3 H), 1.30
(s, 3 H)
13b
149 –11.4
(CDCl3) 8.05 (d, J = 5.9 Hz, 1 H), 6.15 (d, J = (CDCl3) 164.8, 163.7, 157.6, 109.6, [M + Na]+ calcd for
(c 0.8, CHCl3) 5.7 Hz, 1 H), 5.22 (d, J = 5.6 Hz, 1 H), 5.10 (s, 99.9, 81.5, 81.3, 79.7, 55.5, 52.2,
C16H23N3O4:
344.1565; found:
344.1580
NH2), 4.70 (d, J = 5.3 Hz, 1 H), 4.59 (dd, J =
5.5, 1.7 Hz, 1 H), 4.09 (t, J = 7.4 Hz, 1 H), 2.32–
1.22 (series of m, 8 H), 1.48 (s, 3 H), 1.33 (s, 3
H)
39.9, 33.0, 31.6, 26.4, 25.1, 24.1
13c
13d
256 –34.3
(CDCl3) 8.96 (s, NH), 7.06 (d, J = 1.2 Hz, 1 H), (CDCl3) 163.7, 150.7, 139.7, 113.2, [M + Na]+ calcd for
(c 1.0, CHCl3) 4.90 (dd, J = 7.0, 5.4 Hz, 1 H), 4.83 (d, J = 7.1 111.0, 82.9, 80.0, 79.7, 65.4, 54.2,
Hz, 1 H), 4.45–4.40 (m, 1 H), 3.94 (t, J = 6.1 39.4, 32.6, 30.7, 26.7, 25.0, 19.9,
C17H24N2O5:
359.1577; found:
359.1574
Hz, 1 H), 2.30–1.39 (series of m, 8 H), 1.93 (dd, 12.3
J = 1.0 Hz, 3 H), 1.56 (s, 3 H), 1.34 (s, 3 H)
>300 –29.7
(CD3OD) 8.26 (s, 1 H), 8.21 (s, 1 H), 5.08 (t, J = (CD3OD) 155.9, 152.1, 149.1, 140.2, [M + H]+ calcd for
(c 0.6, CHCl3) 7.0 Hz, 1 H), 4.94 (d, J = 7.1 Hz, 1 H), 4.93–
4.86 (m, 1 H), 3.90 (t, J = 6.4 Hz, 1 H), 2.48–
113.1, 84.1, 79.8, 78.1, 60.8, 53.8,
40.5, 31.7, 30.1, 25.7, 23.8, 19.1,
C17H23N5O3:
346.1873; found:
346.1875
1.41 (series of m, 8 H), 1.57 (s, 3 H), 1.34 (s, 3 12.4
H)
13e
21a
>300 –48.0
(c 1.6, py)
(py-d5) 8.44 (s, 1 H), 5.32–5.29 (m, 2 H), 5.03– (py-d5) 160.6, 154.6, 151.0, 141.8,
[M + Na]+ calcd for
4.99 (m, 1 H), 4.06 (t, J = 6.2 Hz, 1 H), 2.69–
1.44 (series of m, 8 H), 1.59 (s, 3 H), 1.30 (s, 3 54.1, 40.8, 33.2, 30.8, 26.8, 24.9,
H) 20.0
125.4, 112.9, 84.2, 80.1, 77.6, 60.8, C17H22ClN5O3:
402.1303; found:
402.1297
–3.0
(c 0.5, CHCl3) 5.74 (d, J = 7.9 Hz, 1 H), 4.81 (t, J = 5.7 Hz, 1 102.4, 83.6, 83.3, 78.77, 64.7, 54.5, C16H22N2O5:
(CDCl3) 9.01 (s, NH), 7.36 (d, J = 8.1 Hz, 1 H), (CDCl3) 163.2, 150.7, 143.2, 113.3, [M + Na]+ calcd for
H), 4.61–4.57 (m, 1 H), 4.39 (d, J = 6.9 Hz, 1
H), 4.01 (t, J = 5.5 Hz, 1 H), 2.50–1.57 (series
of m, 8 H), 1.55 (s, 3 H), 1.32 (s, 3 H)
34.9, 32.8, 30.6, 26.7, 25.0, 20.4
345.1420; found:
345.1417
21b
21c
273 +13.4
(c 1.0, CHCl3) 5.7 Hz, 1 H), 5.39 (s, NH2), 5.15–5.14 (m, 1 H), 99.8, 85.2, 83.9, 80.7, 76.5, 59.1,
(CDCl3) 8.02 (d, J = 5.7 Hz, 1 H), 6.08 (d, J = (CDCl3) 164.9, 164.1, 157.5, 110.3, [M + Na]+ calcd for
C16H23N3O4:
344.1580; found:
344.1588
4.58 (d, J = 5.6 Hz, 1 H), 4.03 (d, J = 5.5 Hz, 1 33.9, 33.6, 30.0, 26.3, 24.0, 22.0
H), 3.84 (d, J = 5.7 Hz, 1 H), 2.11–1.47 (series
of m, 8 H), 1.79 (s, 3 H), 1.61 (s, 3 H)
248 –5.5
(c 0.2, CHCl3) 4.83 (dd, J = 6.8, 5.4 Hz, 1 H), 4.57–4.53 (m, 1 110.9, 83.6, 83.2, 78.9, 64.5, 54.5,
(CDCl3) 8.48 (s, NH), 7.13 (d, J = 0.9 Hz, 1 H), (CDCl3) 163.4, 150.1, 139.1, 113.4, [M + Na]+ calcd for
C17H24N2O5:
359.1577; found:
359.1580
H), 4.39 (d, J = 6.9 Hz, 1 H), 4.02 (t, J = 5.8 Hz, 35.0, 32.9, 30.6, 29.7, 26.7, 25.0,
1 H), 2.51–1.19 (series of m, 8 H), 1.94 (d, J = 12.3
0.8 Hz, 3 H), 1.56 (s, 3 H), 1.32 (s, 3 H)
Synthesis 2005, No. 19, 3209–3218 © Thieme Stuttgart · New York

3214
R. E. Hartung, L. A. Paquette
PAPER
Table 1 Characterization of Products (continued)
20
Product Mp
[a]D
1H NMR
(500 MHz), d
13C NMR
(125 MHz), d
ES or EI HRMS,
m/z
(°C) (c, solvent)
21d
21e
>300 –36.2
(py-d5) 8.63 (s, 1 H), 8.61 (s, 1 H), 8.18 (s,
NH2), 5.33 (1 H not seen), 5.19–5.15 (m, 1 H), 120.5, 112.9, 85.0, 84.0, 77.9, 60.9, C17H23N5O3:
4.72 (d, J = 7.1 Hz, 1 H), 4.21 (t, J = 4.8 Hz, 1 55.6, 36.6, 33.3, 30.4, 26.6, 24.8,
H), 3.19–1.33 (series of m, 8 H), 1.61 (s, 3 H), 20.9
1.33 (s, 3 H)
(py-d5) 157.1, 153.0, 150.3, 140.1,
[M + Na]+ calcd for
(c 1.0, py)
368.1693; found:
368.1684
–1.5
(c 1.6, py)
(py-d5) 8.63 (s, 1 H), 7.60 (s, NH2), 5.22 (dd,
J = 6.6, 4.5 Hz, 1 H), 5.03–4.99 (m, 1 H), 4.59 125.3, 112.6, 85.0, 84.1, 77.4, 60.7, C17H22ClN5O3:
(py-d5) 160.6, 154.7, 150.8, 141.8,
[M + Na]+ calcd for
(d, J = 6.8 Hz, 1 H), 4.11 (s, 1 H), 3.06–3.01 (m, 56.0, 35.9, 33.5, 30.3, 26.7, 24.8,
1 H), 2.38–1.62 (series of m, 7 H), 1.59 (s, 3 H), 20.9
1.32 (s, 3 H)
402.1303; found:
402.1280
Spironucleosides 14a–e and 22a–e
>300 –39.6
14a
14b
14c
14d
14e
22a
22b
(py-d5) 7.95 (d, J = 8.0 Hz, 1 H), 5.84 (d, J = 7.9 (py-d5) 164.6, 152.6, 143.0, 102.0,
Hz, 1 H), 5.54–5.48 (m, 1 H), 5.10–5.08 (m, 1 79.8, 75.5, 72.9, 62.2, 54.0, 37.7,
H), 4.88 (d, J = 4.8 Hz, 1 H), 4.30 (t, J = 5.6 Hz, 33.0, 32.0, 20.2
1 H), 2.73–1.33 (series of m, 8 H)
[M + Na]+ calcd for
C13H18N2O5:
305.1107; found:
305.1115
(c 1.4, py)
>300 –20.0
(c 0.8, py)
(py-d5) 8.05 (d, J = 3.8 Hz, 1 H), 7.75 (s, NH2), (py-d5) 166.1, 154.6, 143.3, 99.8,
6.43–6.41 (m, 1 H), 5.86–5.84 (m, 1 H), 4.98– 82.5, 79.3, 78.4, 74.8, 55.4, 41.2,
4.97 (m, 2 H), 4.28 (m, 1 H), 2.69–1.53 (series 33.6, 32.4, 20.8
of m, 8 H)
[M + Na]+ calcd for
C13H19N3O4:
304.1267; found:
304.1256
>300 –36.0
(CD3OD) 7.47 (s, 1 H), 4.70–4.64 (m, 1 H),
(CD3OD) 163.6, 150.4, 138.0, 108.4, [M + Na]+ calcd for
77.9, 72.7, 70.6, 60.5, 51.9, 34.7,
(c 0.8, MeOH) 4.40–4.37 (m, 1 H), 4.06 (d, J = 5.0 Hz, 1 H),
C14H20N2O5:
319.1264; found:
319.1254
3.90 (t, J = 5.4 Hz, 1 H), 2.18–1.37 (series of m, 30.3, 29.5, 17.7, 9.41
8 H), 1.86 (s, 3 H)
>300 –40.0
(c 0.7, py)
(py-d5) 8.55 (s, 1 H), 8.48 (s, 1 H), 8.14 (s,
(py-d5) 157.0, 152.6, 150.0, 140.9,
[M + Na]+ calcd for
C14H19N5O3:
328.1380; found:
328.1377
NH2), 5.75–5.25 (not seen, 1 H), 4.94 (d, J = 3.9 128.0, 80.0, 76.8, 73.6, 61.3, 54.8,
Hz, 1 H), 4.49–4.44 (m, 2 H), 2.77–1.61 (series 38.7, 32.8, 32.1, 20.1
of m, 8 H)
>300 –42.2
>300 –14.3
>300 –27.4
(DMSO-d6) 7.78 (s, 1 H), 7.48 (s, NH2), 4.76– (DMSO-d6) 157.3, 153.7, 152.0,
[M + Na]+ calcd for
(c 0.5, DMSO) 4.75 (m, 1 H), 4.49 (m, 1 H), 3.99–3.96 (m, 1
136.1, 114.3, 78.8, 75.8, 72.2, 58.1, C14H19N5O4:
H), 3.81 (d, J = 4.5 Hz, 1 H), 2.09–1.23 (series 53.6, 32.6, 32.0, 31.4, 19.9
of m, 8 H)
344.1329; found:
344.1313
(DMSO-d6) 7.76 (d, J = 8.0 Hz, 1 H), 5.62 (d, (DMSO-d6) 163.6, 151.9, 142.7,
[M + Na]+ calcd for
C13H18N2O5:
305.1107; found:
305.1103
(c 0.3, DMSO) J = 8.0 Hz, 1 H), 4.83–4.76 (m, 2 H), 4.59 (d,
101.8, 77.4, 76.8, 74.9, 59.6, 53.3,
J = 4.2 Hz, 1 H), 3.49 (t, J = 4.3 Hz, 1 H), 1.87– 33.2, 32.6, 32.1, 19.9
1.36 (series of m, 8 H)
(py-d5) 8.06 (d, J = 3.8 Hz, 1 H), 7.68 (s, NH2), (py-d5) 166.4, 156.8, 114.3, 99.5,
6.26 (d, J = 3.9 Hz, 1 H), 5.91–5.86 (m, 1 H),
[M + Na]+ calcd for
C13H19N3O4:
(c 1.2, py)
82.5, 77.6, 77.4, 76.3, 54.9, 34.5,
4.85 (t, J = 5.4 Hz, 1 H), 4.31 (d, J = 5.8 Hz, 1 33.4, 31.4, 20.4
H), 4.24 (t, J = 6.2 Hz, 1 H), 2.73–1.53 (series
of m, 8 H)
304.1267; found:
304.1275
22c
22d
22e
>300 –7.8
(c 0.14, MeOH) (m, 1 H), 4.34 (dd, J = 9.0, 6.9 Hz, 1 H), 3.88 (t, 77.8, 76.9, 74.9, 60.7, 53.5, 32.4,
(CD3OD) 7.72 (d, J = 1.0 Hz, 1 H), 4.93–4.88 (CD3OD) 165.0, 152.1, 139.1, 110.0, [M + Na]+ calcd for
C14H20N2O5:
319.1264; found:
319.1275
J = 7.2 Hz, 1 H), 3.71 (d, J = 4.9 Hz, 1 H), 2.06– 31.5, 31.3, 19.2, 11.0
1.52 (series of m, 8 H), 1.90 (d, J = 1.0 Hz, 3 H)
>300 –36.4
(c 1.0, py)
(py-d5) 8.60 (s, 1 H), 8.53 (s, 1 H), 8.17 (s,
(py-d5) 157.3, 152.7, 150.2, 140.7,
[M + Na]+ calcd for
C14H19N5O3:
328.1380; found:
328.1368
NH2), 5.48–5.42 (m, 1 H), 5.22 (dd, J = 8.5, 4.3 121.0, 77.7, 77.6, 75.1, 61.3, 55.1,
Hz, 1 H), 4.27 (t, J = 6.5 Hz, 1 H), 4.24 (d, J = 45.7, 34.0, 32.4, 20.7
4.3 Hz, 1 H), 3.96–1.13 (series of m, 8 H)
>300 –14.1
(DMSO-d6) 7.79 (s, 1 H), 6.63 (s, NH2), 4.93 (d, (DMSO-d6) 157.2, 153.9, 152.0,
[M + Na]+ calcd for
(c 0.5, DMSO) J = 11.1, 5.1 Hz, 1 H), 4.65 (d, J = 4.1 Hz, 1 H), 135.9, 116.9, 77.2, 76.6, 76.3, 58.2, C14H19N5O4:
4.33–4.29 (m, 1 H), 3.55 (t, J = 4.3 Hz, 1 H),
2.05–1.23 (series of m, 8 H)
53.8, 34.7, 33.4, 31.9, 20.2
344.1329; found:
344.1323
Synthesis 2005, No. 19, 3209–3218 © Thieme Stuttgart · New York

PAPER
A Generic Stereocontrolled Pathway to Fully Hydroxylated Spirocarbocyclic Nucleosides
3215
Reduction of Acetonides 8a and 17; General Procedure
dried (Na2SO4) and concentrated in vacuo, and the residue was pu-
rified by column chromatography (silica gel, hexanes–EtOAc 30:1)
to give 8b as a colorless oil.
A solution of acetonide 8a or 17 (34 mg, 0.1 mmol) and THF (1.4
mL) was cooled to –78 °C and L-Selectride (0.11 mL, 0.11 mmol)
was added. The mixture was stirred for 20 min, quenched with sat.
NaHCO3 soln, transferred to a separatory funnel, and extracted with
Et2O (3 × 30 mL). The combined organic phases were dried
(Na2SO4) and concentrated in vacuo, and the residue was purified
by column chromatography (silica gel, hexanes–EtOAc 20:1).
Yield: 50 mg (99%).
[a]D20 –68.9 (c 1.3, CHCl3).
IR (neat): 1737, 1461, 1365 cm–1.
1H NMR (CDCl3, 500 MHz): d = 7.47–7.45 (m, 2 H), 7.41–7.37 (m,
3 H), 5.86 (s, 1 H), 4.76 (d, J = 5.7 Hz, 1 H), 4.43 (d, J = 5.7 Hz, 1
H), 3.90 (t, J = 7.9 Hz, 1 H), 2.85 (d, J = 18.0 Hz, 1 H), 2.28–1.58
(series of m, 7 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.04 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 211.2, 136.1, 129.6, 128.3 (2C),
126.8 (2C), 105.0, 81.5, 81.2, 80.0, 50.7, 44.0, 31.9, 28.4, 25.8 (3C),
19.1, 17.9, –4.5, –5.1.
9a (R¢ = H)
Yield: 33 mg (95%).
[a]D20 –33.7 (c 1.2, CHCl3).
IR (neat): 3543, 1472, 1371 cm–1.
1H NMR (CDCl3, 500 MHz): d = 4.53 (d, J = 5.6 Hz, 1 H), 4.45 (t,
J = 5.7 Hz, 1 H), 4.21–4.16 (m, 1 H), 3.82 (t, J = 7.2 Hz, 1 H), 2.05–
1.38 (series of m, 8 H), 1.49 (s, 3 H), 1.38 (s, 3 H), 0.89 (s, 9 H),
0.06 (s, 3 H), 0.05 (s, 3 H).
ES HRMS: m/z [M + Na]+ calcd for C22H32O4Si: 411.1962; found:
411.1950.
Ketone 8b (23 mg, 0.06 mmol) and THF (1 mL) were combined and
cooled to –78 °C, at which point a 1 M solution of L-Selectride in
THF (66 mL, 0.07 mmol) was added. The mixture was stirred for 20
min, quenched with sat. aq NaHCO3, warmed to r.t., transferred to
a separatory funnel, and extracted with Et2O (3 × 15 mL). The com-
bined organic phases were dried (Na2SO4) and concentrated to leave
a residue that was purified by column chromatography (silica gel,
hexanes–EtOAc 10:1) to give 9b (R¢ = H) as a white solid.
13C NMR (125 MHz, CDCl3): d = 109.9, 81.3, 80.8, 79.5, 70.4, 52.8,
43.0, 29.9, 26.1, 25.8 (3C), 24.2, 20.2, 17.8, –4.1, –5.0.
ES HRMS: m/z [M + Na]+ calcd for C18H34O4Si: 365.2118; found:
365.2117.
18
Yield: 100 mg (98%).
[a]D20 +29.9 (c 1.7, CHCl3).
Yield: 23 mg (100%).
IR (neat): 3495, 1471, 1372 cm–1.
Mp 66 °C.
1H NMR (CDCl3, 500 MHz): d = 4.46 (t, J = 5.7 Hz, 1 H), 4.14–4.11
(m, 1 H), 4.06 (d, J = 5.5 Hz, 1 H), 3.64 (t, J = 5.7 Hz, 1 H), 2.26–
1.34 (series of m, 8 H), 1.49 (s, 3 H), 1.34 (s, 3 H), 0.89 (s, 9 H),
0.04 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 110.4, 85.4, 79.3, 78.0, 70.9, 54.3,
37.8, 33.3, 30.1, 26.0, 25.8 (3C), 24.3, 20.2, 17.9.
[a]D20 –5.8 (c 1.0, CHCl3).
IR (neat): 3565, 1460, 1402 cm–1.
1H NMR (CDCl3, 500 MHz): d = 7.55–7.53 (m, 2 H), 7.43–7.42 (m,
3 H), 5.82 (s, 1 H), 4.61 (d, J = 5.9 Hz, 1 H), 4.55 (t, J = 5.9 Hz, 1
H), 4.35–4.30 (m, 1 H), 3.89 (t, J = 7.6 Hz, 1 H), 2.19–1.49 (series
of m, 8 H), 0.93 (s, 9 H), 0.10 (s, 3 H), 0.08 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 136.5, 129.7, 128.4 (2C), 126.9
(2C), 104.0, 82.7, 81.0, 80.4, 70.8, 53.1, 43.4, 34.0, 30.0, 22.9 (3C),
20.2, 17.8, –4.1, –5.0.
ES HRMS: m/z [M + Na]+ calcd for C18H34O4Si: 365.2118; found:
365.2102.
Mesylation of 9a (R¢ = H)
ES HRMS: m/z [M + Na]+ calcd for C22H34O4Si: 413.2118; found:
413.2117.
To a solution of 9a (20 mg, 0.06 mmol) in CH2Cl2 (2 mL) at 0 °C
was added Et3N (25 mL, 0.18 mmol) followed by MsCl (14 mL, 0.18
mmol). The mixture was allowed to warm to r.t. over a period of 3
h, and then was quenched with sat. NaHCO3 soln and extracted with
Et2O (3 × 20 mL). The combined organic phases were dried
(Na2SO4) and concentrated in vacuo, and the residue was purified
by column chromatography (silica gel, hexanes–EtOAc 10:1).
A solution of alcohol 9b (R¢ = H) (7.0 mg, 0.02 mmol) in CH2Cl2
(1.0 mL) was cooled to 0 °C and treated with Et3N (15 mL, 0.11
mmol) followed by MsCl (8.4 mL, 0.11 mmol). The mixture was al-
lowed to warm to r.t., stirred for 36 h, quenched with sat. NaHCO3
soln, and extracted with Et2O (3 × 20 mL). The combined organic
phases were dried (Na2SO4) and concentrated, and the residue was
purified by column chromatography (silica gel, hexanes–EtOAc
3:1) to give 9b (R¢ = Ms) as a colorless oil.
Yield: 28 mg (100%).
[a]D20 –50.1 (c 1.3, CHCl3).
IR (neat): 1457, 1360, 1252 cm–1.
1H NMR (CDCl3, 500 MHz): d = 5.11–5.07 (m, 1 H), 4.64 (t, J =
5.4 Hz, 1 H), 4.51 (d, J = 5.4 Hz, 1 H), 3.87 (t, J = 7.6 Hz, 1 H), 3.07
(s, 3 H), 2.20 (t, J = 11.9 Hz, 1 H), 2.08–1.35 (series of m, 7 H), 1.50
(s, 3 H), 1.36 (s, 3 H), 0.91 (s, 9 H), 0.11 (s, 3 H), 0.07 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 110.7, 81.1, 80.6, 78.5, 78.0, 52.3,
38.9, 38.7, 33.4, 29.3, 26.1, 25.8 (3C), 24.4, 19.8, 17.7, –4.2, –5.0.
ES HRMS: m/z [M + Na]+ calcd for C19H36O6SSi: 443.1894; found:
443.1897.
Yield: 8 mg (96%).
[a]D20 –43.3 (c 1.0, CHCl3).
IR (neat): 1470, 1360, 1256 cm–1.
1H NMR (CDCl3, 500 MHz): d = 7.55 (dd, J = 6.7, 3.8 Hz, 2 H),
7.43–7.40 (m, 3 H), 5.80 (s, 1 H), 5.25–5.20 (m, 1 H), 4.73 (t, J =
5.7 Hz, 1 H), 4.59 (d, J = 5.8 Hz, 1 H), 3.93 (t, J = 8.1 Hz, 1 H), 3.02
(s, 3 H), 2.41–1.21 (m, 8 H), 0.94 (s, 9 H), 0.15 (s, 3 H), 0.10 (s, 3
H).
13C NMR (125 MHz, CDCl3): d = 136.3, 129.7, 128.3 (2C), 127.1
(2C), 104.6, 82.2, 81.2, 79.0, 78.1, 52.6, 38.7, 33.4, 31.5, 25.8 (3C),
22.6, 19.9, 17.8, –4.1, –5.0.
Formation of Mesylate 9b (R¢ = Ms)
A solution of 6 (40 mg, 0.13 mmol) and PTSA (2.5 mg, 0.01 mmol)
in neat PhCH(OMe)2 (0.5 mL) was stirred at 80 °C for 1 h. The mix-
ture was cooled to r.t., quenched with sat. NaHCO3 soln, and ex-
tracted with Et2O (3 × 20 mL). The combined organic phases were
ES HRMS: m/z [M + Na]+ calcd for C23H36O6SSi: 491.1894; found:
491.1902.
Synthesis 2005, No. 19, 3209–3218 © Thieme Stuttgart · New York

3216
R. E. Hartung, L. A. Paquette
PAPER
Formation of Mesylate 9c (R¢ = Ms)
Formation of Mesylate 9d (R¢ = Ms)
A solution of 6 (64 mg, 0.22 mmol), py (140 mL, 1.7 mmol), and
AgNO3 (150 mg, 0.86 mmol) in THF (12 mL) was stirred in the
dark for 1 h, at which point TIPDSCl2 (137 mL, 0.43 mmol) was
added in one portion. The mixture was stirred for 2 h and filtered
through a pad of Celite. The filtrate was transferred to a separatory
funnel and extracted with Et2O (3 × 30 mL). The combined organic
phases were dried (Na2SO4) and concentrated to leave a residue that
was purified by column chromatography (silica gel, hexanes–
EtOAc 20:1) to give 8c as a colorless oil.
Diol 6 (20 mg, 0.07 mmol) and DMAP (82 mg, 0.7 mmol) were dis-
solved in CH2Cl2 (2 mL), the solution was brought to 0 °C, and a 1-
M solution of phosgene in toluene (0.6 mL, 0.6 mmol) was added.
The mixture was stirred for 16 h while warming to r.t., quenched
carefully with sat. NaHCO3 soln, and extracted with Et2O (3 × 20
mL). The combined organic phases were dried (Na2SO4) and con-
centrated, and the residue was purified by column chromatography
(silica gel, hexanes–EtOAc 10:1) to give 8d as a colorless oil.
Yield: (17 mg, 80%).
Yield: 116 mg (98%).
[a]D20 –134.8 (c 1.3, CHCl3).
IR (neat): 1825, 1804, 1766, 1471 cm–1.
1H NMR (CDCl3, 500 MHz): d = 5.15 (d, J = 6.7 Hz, 1 H), 4.67 (d,
J = 6.8 Hz, 1 H), 3.93 (t, J = 8.5 Hz, 1 H), 2.78 (d, J = 18.3 Hz, 1
H), 2.23 (d, J = 18.4 Hz, 1 H), 2.19–1.65 (series of m, 6 H), 0.86 (s,
9 H), 0.05 (s, 3 H), 0.01 (s, 3 H).
[a]D20 –47.2 (c 1.2, CHCl3).
IR (neat): 1765, 1464, 1251 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.68–4.64 (m, 2 H), 3.83 (dd, J =
5.5, 4.1 Hz, 1 H), 2.26–1.44 (m, 8 H), 1.12–0.90 (m, 28 H), 0.89 (s,
9 H), 0.07 (s, 3 H), 0.04 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 212.4, 80.8, 79.7, 75.2, 52.0, 43.4,
33.9, 32.5, 25.7 (3C), 19.7, 17.8, 17.4–12.8 (12C), –4.2, –4.9.
13C NMR (125 MHz, CDCl3): d = 205.5, 153.8, 81.7, 80.4, 78.1,
52.4, 43.5, 31.5, 27.8, 25.7 (3C), 19.0, 17.8, –4.6, –5.2.
ES HRMS: m/z [M + Na]+ calcd for C27H54O5Si3: 565.3171; found:
ES HRMS m/z [M + Na]+ calcd for C16H26O5Si: 349.1441; found:
565.3191.
349.1434.
Ketone 8c (116 mg, 0.21 mmol) was dissolved in THF (3 mL),
cooled to –78 °C, treated with L-Selectride (235 mL, 0.23 mmol),
and stirred for 10 min prior to quenching with sat. NaHCO3 soln and
extraction with Et2O (3 × 30 mL). The combined organic phases
were dried (Na2SO4) and concentrated, and the residue was purified
by column chromatography (silica gel, hexanes–EtOAc 20:1) to
give 9c (R¢ = H) as a colorless oil.
A solution of 8d (41 mg, 0.13 mmol) in MeOH (4 mL) was cooled
to 0 °C and NaBH4 (4.8 mg, 0.13 mmol) was added. The mixture
was quenched after 5 min with sat. NaHCO3 soln, transferred to a
separatory funnel, and extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were dried (Na2SO4) and concentrated,
and the residue was purified by column chromatography (silica gel,
hexanes–EtOAc 5:1) to give 9d (R¢ = H) and its b-epimer, both as
colorless oils.
Yield: 100 mg (86%).
9d (R¢ = H)
[a]D20 –0.5 (c 1.3, CHCl3).
IR (CH2Cl2): 3574, 1464, 1250 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.47 (d, J = 4.4 Hz, 1 H), 4.26 (t,
J = 4.4 Hz, 1 H), 4.03 (dd, J = 11.4, 6.0 Hz, 1 H), 3.73 (t, J = 7.1 Hz,
1 H), 2.34–1.35 (m, 8 H), 1.12–1.06 (m, 28 H), 0.89 (s, 9 H), 0.05
(s, 6 H).
13C NMR (125 MHz, CDCl3): d = 80.8, 77.2, 74.5, 71.2, 54.5, 43.2,
33.8, 32.3, 25.8 (3C), 19.6, 17.9, 17.5–13.0 (12C), –4.3, –4.9.
ES HRMS: m/z [M + Na]+ calcd for C27H56O5Si3: 567.3327; found:
Yield: 7 mg (17%).
[a]D20 –35.7 (c 1.8, CHCl3).
IR (neat): 3420, 1804, 1471 cm–1.
1H NMR (CDCl3, 500 MHz): d = 5.00 (d, J = 6.6 Hz, 1 H), 4.87 (t,
J = 6.2 Hz, 1 H), 4.46–4.42 (m, 1 H), 3.89 (t, J = 7.7 Hz, 1 H), 2.11–
1.50 (series of m, 8 H), 0.90 (s, 9 H), 0.087 (s, 3 H), 0.082 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 154.8, 82.0, 81.1, 80.8, 71.3, 54.4,
33.8, 31.5, 29.9, 25.8 (3C), 20.2, 17.7, –4.1, –5.0.
567.3316.
ES HRMS: m/z [M + Na]+ calcd for C16H28O5Si: 351.1598; found:
To a solution of 9c (R¢ = H) (54 mg, 0.1 mmol) in CH2Cl2 (3.4 mL)
at 0 °C was added Et3N (42 mL, 0.3 mmol) followed by MsCl (23
mL, 0.3 mmol). The mixture was allowed to warm to r.t., quenched
after 6 h with sat. NaHCO3 soln, and extracted with Et2O (3 × 30
mL). The combined organic phases were dried (Na2SO4) and con-
centrated to leave a residue that was purified by column chromatog-
raphy (silica gel, hexanes–EtOAc 10:1) to give 9c (R¢ = Ms) as a
colorless oil.
351.1599.
b-epimer
Yield: 26 mg (63%).
[a]D20 +13.5 (c 1.5, CHCl3).
IR (neat): 3512, 1794, 1471 cm–1.
1H NMR (CDCl3, 500 MHz): d = 5.05–4.99 (m, 1 H), 5.03 (d, J =
4.7 Hz, 1 H), 4.20 (d, J = 4.8 Hz, 1 H), 3.87 (t, J = 5.1 Hz, 1 H),
2.29–1.45 (series of m, 8 H), 0.91 (s, 9 H), 0.107 (s, 3 H), 0.105 (s,
3 H).
13C NMR (125 MHz, CDCl3): d = 154.9, 82.3, 80.3, 78.8, 74.2, 54.5,
40.3, 33.0, 27.8, 25.8 (3C), 21.2, 17.9, –4.3, –4.9.
ES HRMS: m/z [M + Na]+ calcd for C16H28O5Si: 351.1598; found:
351.1601.
Yield: 56 mg (90%).
[a]D20 –4.8 (c 1.7, CHCl3).
IR (CH2Cl2): 1464, 1360, 1250 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.88 (dd, J = 10.8, 6.4 Hz, 1 H),
4.49 (d, J = 4.3 Hz, 1 H), 4.35 (t, J = 4.4 Hz, 1 H), 3.75 (t, J = 7.6
Hz, 1 H), 2.99 (s, 3 H), 2.41–1.20 (series of m, 8 H), 1.12–1.08 (m,
28 H), 0.90 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 80.9, 79.8, 76.3, 73.1, 54.4, 39.6,
38.2, 32.5, 31.2, 25.8 (3C), 19.6, 17.9, 17.5–17.1 (8C), 13.5, 13.4,
13.1, 13.0, –4.3, –4.8.
To a solution of 9d (R¢ = H) (26 mg, 0.08 mmol) in CH2Cl2 (3.3 mL)
at 0 °C was added Et3N (33 mL, 0.24 mmol) followed by MsCl (19
mL, 0.24 mmol). The mixture was allowed to warm to r.t. over a pe-
riod of 3 h, quenched with sat. NaHCO3 soln, and extracted with
Et2O (3 × 20 mL). The combined organic phases were dried
(Na2SO4) and concentrated, and the residue was purified by column
chromatography (silica gel, hexanes–EtOAc 3:1) to give 9d (R¢ =
Ms) as a colorless oil.
ES HRMS: m/z [M + Na]+ calcd for C28H58O7SSi3: 645.3103;
found: 645.3121.
Synthesis 2005, No. 19, 3209–3218 © Thieme Stuttgart · New York

PAPER
A Generic Stereocontrolled Pathway to Fully Hydroxylated Spirocarbocyclic Nucleosides
3217
Yield: 28 mg (87%).
purified by column chromatography (silica gel, 6% MeOH in
CH2Cl2).
[a]D20 –71.4 (c 1.4, CHCl3).
IR (neat): 1810, 1471, 1362 cm–1.
1H NMR (CDCl3, 500 MHz): d = 5.30–5.26 (m, 1 H), 5.07 (t, J =
6.0 Hz, 1 H), 4.97 (d, J = 6.5 Hz, 1 H), 3.94 (t, J = 7.7 Hz, 1 H), 3.12
(s, 3 H), 2.20–1.54 (series of m, 8 H), 0.91 (s, 9 H), 0.13 (s, 3 H),
0.09 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 154.3, 81.37, 81.32, 78.8, 75.7,
54.2, 38.7, 38.2, 33.2, 29.1, 25.7 (3C), 19.9, 17.7, –4.2, –5.0.
ES HRMS: m/z [M + Na]+ calcd for C17H30O7SSi: 429.1373; found:
429.13919.
Guanine-Containing Compounds 13f and 21f; General Proce-
dure
A mixture of 13e (30 mg, 0.082 mmol), MeOH (10 mL), 2-sulfa-
nylethanol (0.11 mL, 1.64 mmol), and a 5.25 M solution of NaOMe
in MeOH (0.33 mL, 1.7 mmol) was stirred at 80 °C for 4 h. The re-
action mixture was quenched with sat. NaHCO3 soln, transferred to
a separatory funnel, and extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were dried (Na2SO4) and the residue was
purified by column chromatography (silica gel, 10% MeOH in
CH2Cl2).
Synthesis of Triflates 11 and 19
13f
A solution of 9a (R¢ = H) or 18 (259 mg, 0.76 mmol) and CH2Cl2
(2.2 mL) was cooled to 0 °C, at which point py (0.12 mL, 1.5 mmol)
and Tf2O (0.15 mL, 0.9 mmol) were added. The mixture was stirred
for 40 min, quenched with H2O, transferred to a separatory funnel,
and extracted with CH2Cl2 (3 × 30 mL). The combined organic
phases were dried (Na2SO4) and concentrated, and the residue was
purified by column chromatography (silica gel, hexanes–EtOAc
20:1).
White solid.
Yield: 29 mg (100%).
Mp >300 °C.
[a]D20 –23.5 (c 1.5, DMSO).
1H NMR (500 MHz, DMSO-d6): d = 7.86 (s, 1 H), 6.81 (s, NH2),
4.90–4.80 (m, 3 H), 4.61–4.56 (m, 1 H), 2.79–1.23 (series of m, 8
H), 1.44 (s, 3 H), 1.23 (s, 3 H).
11
13C NMR (125 MHz, DMSO-d6): d = 157.2, 153.9, 151.5, 136.1,
127.8, 112.7, 84.1, 79.5, 77.0, 60.0, 53.8, 41.6, 32.7, 30.5, 27.0,
25.3, 19.8.
EI HRMS: m/z [M + Na]+ calcd for C17H23N5O4: 384.1642; found:
384.1635.
White solid (decomposed upon heating).
Yield: 370 mg (100%).
[a]D20 –29.3 (c 0.7, CHCl3).
IR (neat): 1415, 1246, 1210 cm–1.
1H NMR (CDCl3, 500 MHz): d = 5.29–5.25 (m, 1 H), 4.64 (t, J =
5.5 Hz, 1 H), 4.49 (d, J = 5.3 Hz, 1 H), 3.87 (t, J = 8.4 Hz, 1 H),
2.34–1.32 (series of m, 8 H), 1.51 (s, 3 H), 1.38 (s, 3 H), 0.91 (s, 9
H), 0.09 (s, 3 H), 0.08 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 111.2, 85.2, 81.2, 80.4, 78.4, 52.5,
38.7, 32.9, 28.8, 26.0, 25.7 (3C), 24.4, 19.7, 17.7, –4.1, –5.2.
21f
White solid.
Yield: 24 mg (72%).
Mp >300 °C
[a]D20 +2.4 (c 1.0, DMSO).
1H NMR (500 MHz, DMSO-d6): d = 7.89 (s, 1 H), 6.48 (s, NH2),
4.87 (dd, J = 7.2, 5.1 Hz, 1 H), 4.72 (d, J = 4.4 Hz, 1 H), 4.60–4.56
(m, 1 H), 4.35 (d, J = 7.3 Hz, 1 H), 2.95–1.45 (series of m, 8 H), 1.43
(s, 3 H), 1.22 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 157.2, 153.9, 151.5, 136.1,
117.2, 112.8, 84.7, 83.4, 77.6, 58.5, 55.1, 38.0, 33.0, 26.8, 25.2,
21.0.
19
Yield: 97 mg (82%).
[a]D20 –10.3 (c 0.7, CHCl3).
IR (neat): 1415, 1246, 1209 cm–1.
1H NMR (CDCl3, 500 MHz): d = 5.25–5.21 (m, 1 H), 4.61 (t, J =
5.5 Hz, 1 H), 4.17 (d, J = 5.1 Hz, 1 H), 3.76 (t, J = 7.2 Hz, 1 H),
2.40–1.54 (series of m, 8 H), 1.50 (s, 3 H), 1.34 (s, 3 H), 0.89 (s, 9
H), 0.06 (s, 3 H), 0.05 (s, 3 H).
EI HRMS: m/z [M + H]+ calcd for C17H23N5O4: 384.1642; found:
384.1625.
13C NMR (125 MHz, CDCl3): d = 111.8, 86.3, 85.7, 78.8, 78.1, 53.5,
35.0, 32.5, 30.5, 25.9, 25.6 (3C), 24.7, 19.6, 17.8, –4.3, –5.0.
Ultimate Acetonide Hydrolysis To Give Spirocarbocyclic
Nucleosides 14 and 22; General Procedure
To a solution of 13a–f or 21a–f (20 mg, 0.062 mmol) in MeOH (2.0
mL) was added PTSA (11.8 mg, 0.062 mmol). The mixture was
stirred for 24 h, concentrated, and subjected to column chromatog-
raphy (silica gel, 15% MeOH in CH2Cl2).
SN2 Displacement Involving Triflates 11 and 19; General Proce-
dure
To a solution of the nucleobase (0.33 mmol) in DMF (10 mL) at r.t.
and under N2 was added KH (15 mg, 0.36 mmol). The mixture was
stirred for 10 min prior to the addition of 11 or 19 (60 mg, 0.12
mmol). The mixture was stirred for 48 h, quenched with H2O, trans-
ferred to a separatory funnel, and extracted with Et2O (3 × 30 mL).
The combined organic phases were dried (Na2SO4) and the residue
was purified by column chromatography (silica gel, hexanes–
EtOAc 2:1).
References
(1) (a) Agrofoglio, L. A.; Challand, S. R. Acyclic Carbocyclic
and L-Nucleosides; Kluwer Academic: Dordrecht, 1998.
(b) Marquez, V. E.; Lim, M. I. Med. Res. Rev. 1986, 6, 1.
(2) For reviews consult: (a) Rodriquez, J. B.; Comin, M. J.
Mini-Rev. Med. Chem. 2003, 3, 95. (b) Schneller, S. W.
Curr. Top. Med. Chem. 2002, 2, 1087. (c) Ichikawa, E.;
Kato, K. Curr. Med. Chem. 2001, 8, 385. (d) Crimmins, M.
T. Tetrahedron 1998, 54, 9229. (e) Huryn, D. M.; Okabe,
M. Chem. Rev. 1992, 92, 1745. (f) Borthwick, A. D.;
Biggadike, K. Tetrahedron 1992, 48, 51.
Desilylation of 12a–e and 20a–e; General Procedure
To a solution of 12a–e or 20a–e (0.07 mmol) and THF (1 mL) was
added a 1-M solution of TBAF in THF (0.2 mL, 0.21 mmol). The
mixture was stirred for 24 h, quenched with brine, transferred to a
separatory funnel, and extracted with CH2Cl2 (4 × 30 mL). The
combined organic phases were dried (Na2SO4) and the residue was
(3) Kool, E. T. Chem. Rev. 1997, 97, 1473.
Synthesis 2005, No. 19, 3209–3218 © Thieme Stuttgart · New York

3218
R. E. Hartung, L. A. Paquette
PAPER
(7) Hartung, R. E.; Paquette, L. A. J. Org. Chem. 2005, 70,
(4) For reviews, see: (a) Leumann, C. J. Bioorg. Med. Chem.
2002, 10, 841. (b) Braasch, D. A.; Corey, D. R. Chem. Biol.
2001, 8, 1. (c) Meldgaard, A.; Wengel, J. J. Chem. Soc.,
Perkin Trans. 1 2000, 3539. (d) Wengel, J. Acc. Chem. Res.
1999, 32, 301. (e) Herdewijn, P. Liebigs Ann. 1996, 1337.
(f) Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543.
(5) Paquette, L. A. Aust. J. Chem. 2004, 57, 7.
1597.
(8) Kusaka, T.; Yamamoto, H.; Muroi, M.; Kishi, T. J. Antibiot.
1968, 21, 255.
(9) Haraguchi, K.; Takahashi, H.; Shiina, N.; Horii, C.;
Yoshimura, Y.; Nishihawa, A.; Sasakura, E.; Nakamura, K.
T.; Tanaka, H. J. Org. Chem. 2002, 67, 5919.
(10) (a) Pathak, T.; Bezin, H.; Chattopadhyaya, J. Tetrahedron
1986, 42, 5427. (b) Johnston, T. P.; Holum, L. B.;
Montgomery, J. A. J. Am. Chem. Soc. 1958, 80, 6265.
(6) (a) Paquette, L. A.; Hartung, R. E.; France, D. J. Org. Lett.
2003, 5, 869. (b) Hartung, R. E.; Paquette, L. A.
Heterocycles 2005, in press.
Synthesis 2005, No. 19, 3209–3218 © Thieme Stuttgart · New York