6′-Oxa analogs of S-adenosylhomocysteine

Article abstract of DOI:10.1016/j.tet.2011.10.063

S-Adenosylmethionine (AdoMet) is a ubiquitous cofactor in biomethylations and, in that role, becomes S-adenosylhomocysteine (AdoHcy), which serves as a biofeedback inhibitor of the methylation process. In seeking to avail unexplored structural variations

Full text of DOI:10.1016/j.tet.2011.10.063

Tetrahedron 68 (2012) 65e71
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
60-Oxa analogs of S-adenosylhomocysteine
*
Weikuan Li, Wei Ye, Stewart W. Schneller
Molette Laboratory for Drug Discovery, Department of Chemistry and Biochemistry, Auburn University, Auburn, AL 36849-5312, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2011
Received in revised form 17 October 2011
Accepted 17 October 2011
Available online 23 October 2011
S-Adenosylmethionine (AdoMet) is a ubiquitous cofactor in biomethylations and, in that role, becomes
S-adenosylhomocysteine (AdoHcy), which serves as a biofeedback inhibitor of the methylation process.
In seeking to avail unexplored structural variations of AdoHcy for biological studies, its 60-oxa analog and
two corresponding carbocyclic nucleosides (based on aristeromycin and neplanocin) have been prepared
via common convergent syntheses.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
S-Adenosylhomocysteine
Aristeromycin
Neplanocin
€
Schollkopf auxiliary
1. Introduction
adenosine and homocysteine, thereby increasing the presence of
AdoHcy for feedback control.5 On the other hand, less6 attention has
Biological methylation is a prominent feature for the successful
metabolism of numerous small molecules and those that fall into the
oligomer and polymer categories.1 It is not surprising, then, that one
approach to chemotherapeutic agent design is to prevent this
considered analogs of AdoHcy itself, particularly at its side chain
sulfur center,7 as a more direct means of inhibiting the demands cast
upon AdoMet. For this purpose, this report describes the synthesis of
the 60-oxa analog of AdoHcy (3) and its carbocyclic partners based on
aristeromycin (4) and neplanocin (5).
methylation from occurring in pathogen driven circumstances.2
A
fruitful outcome in this direction has been to interfere with the
methyl donating capabilities of S-adenosylmethionine (AdoMet, 1,
Fig.1), a ubiquitous cofactor intheaforementioned biomethylations.3
One approach has been to exploit the feedback inhibitory effects4 of
S-adenosylhomocysteine (AdoHcy, 2), which arises from the AdoMet
donation reaction. Numerous laboratories have focused on this
consequence by inhibiting the hydrolase that converts AdoHcy into
2. Results
A convergent approach to targets 3e5 was envisioned that
would begin with a bis-homologated ribofuranose derivative (6 for
the preparation of target compound 3) and a cyclopentyl/cyclo-
pentenyl frame (7a and 7b for 4 and 5, respectively) (Fig. 1). These
units would then be suitably functionalized for introducing (1) the
NH2
N
NH2
N
NH2
N
€
Schollkopf auxiliary as the protected amino acid at the arrow-
N
N
N
N
N
N
designated carbon in Fig. 2 and (2) the requisite adenine unit at
the C-1 center. The initial objective thus became the preparation of
the five-membered ring participants 6, 7a, and 7b for this purpose
(Schemes 1 and 2).
N
N
N
Y
H3C
O
O
X
S
+
HO OH
HO
CO2H
OH
HO
CO2H
OH
CO2H
H2N
H2N
ROH2C
H2N
1
O
OTBS
ROH2C
ROH2C
1
1
1
2, X=S: Y=O
3, X=Y=O
4, X=O;Y=CH2
5
OTBS
OTBS
O
O
O
O
O
O
Fig. 1. S-Adenosylmethionine, S-adenosylhomocysteine, and targer analogs.
7b
7a
for 6, 7, and 8, R=CH2CH2OTs
Fig. 2. Requisite five-membered ring partners in target syntheses.
6
* Corresponding author. Tel.: þ1 334 844 6947; fax: þ1 334 844 0239; e-mail
address: schnest@auburn.edu (S.W. Schneller).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.063

66
W. Li et al. / Tetrahedron 68 (2012) 65e71
OPMB
O
O
OPMB
OH
O
OY
HO
HO
O
O
O
b
a
c
O
O
O
O
O
O
O
O
X
8
9
8
10
X=OH, Y=PMB, 11
X=OTs, Y=PMB, 12
X=OTs, Y=H, 13
d
e
f
PMB= p-methoxybenzyl TBS=Si(t-Bu)Me2
X=OTs, Y=TBS, 6
Scheme 1. Reagents and conditions: a, PMBCI, NaH, 67%, b, NaH, allylBr, 79%; c, (i) NMO, OsO4; (ii) NalO4; (iii) NaBH4, 75% after three steps; d, TsCl, TEA, DABCO (cat.), 82%; e, DDQ,
77%; f, TBSCl, imidazole, 66%.
OTBS
O
b
a
1
O
O
O
O
2
HO
OTBS
9
15
14
O
O
O
TBSO
TBSO
a series, 1/2 single bond
b series, 1/2 double bond
Ref. 13
OH
c
16a
16b
O
O
O
O
Ref. 12
18
17
D-ribose
O
O
e for 19a
f for 19b
d
OTBS
OTBS
O
O
O
O
X
19a
19b
X=OH, 20a, 20b
X=OTs, 7a, 7b
g
Scheme 2. Reagents and conditions: a (i) vinylMgBr, CuBr$SMe2, TMSCl; (ii) NaBH4, CeCl3$7H2O; (iii) TBSCl, imadazole, 42% after three steps; b, (i) NMO, OsO4; (ii) NalO4; (iii)
NaBH4, CeCl3$7H2O, 84% after three steps; c, (i) same as step a (iii); (ii) TBAF, ꢀ40 ꢁC, 63% after two steps; d, NaH, allylBr, 83% for 19a, 85% for 19b; e, same as step b, 86%; f, (i) AD-
mix-b; same as steps (ii) and (iii) within step b, 96%; g, TsCl, DABCO (cat.), 83% for 7a, 83% for 7b.
The synthesis of 6 (Scheme 1) began with allylation of the pri-
mary hydroxyl substituent of the protected ribose derivative 9
(obtained from 2,3-isopropylidene ribose 88) to afford 10. Glycoli-
zation followed by oxidative cleavage and subsequent reduction
converted 10 into 11, which was, then, tosylated to 12. To avoid any
future difficulties in removing the PMB group under oxidative cir-
cumstances, it was removed at this time to give 13. Protection of the
resultant anomeric hydroxyl of 13 as a TBS silyl ether gave 6.
Achieving 7a/7b (Scheme 2) began (for 7a) with a vinylic Mi-
chael addition to enone 149 that was followed by a Luche re-
duction10 and subsequent silylation of the newly formed secondary
alcohol to produce 15. Oxidative cleavage of the olefinic center of 15
followed by reduction afforded 16a.11 Preparation of the relevant
cyclopentenyl unit 7b commenced with, first, silylation of allylic
alcohol 17 (available from ribose via enone 18, Scheme 2)12,13 and
removal of the primary tert-butyldimethylsilyl group to provide
16b. Both 16a and 16b were allylated at their primary hydroxyl
center to result in 19a/19b. Glycolization of these products followed
by periodate oxidative cleavage and sodium borohydride reduction
resulted in 20a and 20b (as in the 15 to 16a procedure), which were
transformed into the requisite derivatives 7a and 7b by tosylation.
€
butoxylcarbonyl) protected adenine to yield 23. Deprotection of 23
resulted in the desired target compound 3.
Similarly, 7a and 7b were converted to 4 and 5 (Scheme 3)
through 24e26.
3. Experimental section
3.1. General
1H and 13C NMR spectra were recorded on either a Bruker AC 250
spectrometer (250 MHz for proton and 62.5 MHz for carbon) or
a Bruker AV 400 spectrometer (400 MHz for proton and 100 MHz for
carbon), referenced to internal tetramethylsilane (TMS) at 0.0 ppm.
The mass spectral data were obtained using a Waters Micromass
QTOF Premier mass spectrometer. The reactions were monitored
by thin-layer chromatography (TLC) using 0.25 mm Whatman
Diamond silica gel 60-F254 precoated plates with visualization by
irradiation with a Mineralight UVGL-25 lamp. Column chromatog-
ꢀ
raphy was performed on Whatman silica, 230e400 mesh, and 60 A
using elution with the indicated solvent system. Yields refer to
chromatographically and spectroscopically (1H and 13C NMR) ho-
mogeneous materials.
Coupling of
6
with the Schollkopf reagent7d,14 gave 21
(Scheme 3). Removal of the silyl protection of 21 gave 22. In-
stallation of the adenine component was achieved by converting 22
to its C-1 chloro derivative (HMPT/CCl4) followed by a nucleophilic
substitution reaction involving the anion of N6,N6-bis-(tert-
3.1.1. ((3aR,4R,6R,6aR)-6-(4-Methoxybenzyloxy)-2,2-dimethyl-tetra-
hydrofuro[3,4-d]-[1,3]dioxol-4-yl)methanol
(9). Compound
86
(2.98 g, 16.6 mmol) was dissolved in DMF. The solution was

W. Li et al. / Tetrahedron 68 (2012) 65e71
67
N(Boc)2
ROH2C
O
X
N
N
N
N
c
d
3
on 22
ROH2C
O
O
O
O
O
X=OTBS, 21
X=OH, 22
23
b
a
6, 7a, 7b
N(Boc)2
1
N
N
N
ROH C
2
2
X
N
d
ROH2C
e
4, 5
O
O
on 24a, 24b
N
EtO
O
O
OEt
N
X=OTBS, 24a, 24b
X=OH, 25a, 25b
(CH2)2
OEt
26a, 26b
b
N
Schöllkopf
reagent
EtO
R=
a series, 1/2 single bond
N
b series, 1/2 double bond
€
Scheme 3. Reagents and conditions: a, Schollkopf reagent, n-BuLi, 68% for 21, 89% for 24a, 81% for 24b; b, TBAF, 60% for 22, 60% for 25a, 90% for 25b, c, (i) HMPT, CCl4, (ii) NaH,
Ad(Boc)2, 25% for two steps; d, (i) TFA/H2O; (ii) K2CO3, yields for two steps, 61% for 3, 46% for 4, 71% for 5; e, Ph3P, DIAD, Ad(Boc)2, 57% for 26a, 73% for 26b.
cooled to 0 ꢁC and NaH (0.68 g, 60% in mineral oil, 17 mmol) was
added portionwise. The mixture was stirred at this same temper-
ature for 1 h; p-methoxybenzyl chloride (2.76 mL, 20.4 mmol) was
then added. The solution was warmed to room temperature and
stirred overnight. The solvent was removed under reduced pres-
sure and the residue partitioned between H2O and EtOAc. The
aqueous phase was extracted with EtOAc (3ꢂ30 mL). The combined
organic layers were washed with brine, dried (Na2SO4), and con-
centrated. The residue was purified by silica gel column chroma-
tography (hexanes/EtOAc¼2:1) to give 9 as a colorless oil (3.38 g,
the column rinsed with EtOAc. The combined organic liquids were
concentrated. The residue was dissolved in CH2Cl2/H2O (1:1, 30 mL)
and NaIO4 (6.40 g, 30.0 mmol) added at room temperature. The
mixture was stirred 3 h. The organic layer was diluted with CH2Cl2
(100 mL), separated, washed with H2O (20 mL), dried (Na2SO4), and
concentrated. The residue was dissolved in MeOH (30 mL) at 0 ꢁC
and NaBH4 (1.80 g, 48.6 mmol) added portionwise. The mixture was
stirred at the same temperature for 30 min. Saturated NH4Cl so-
lution (30 mL) was added and the mixture filtered through Celite.
The filtrate was removed under reduced pressure and the residue
was purified by silica gel column chromatography (hexanes/
EtOAc¼3:1 to 1:1) to give 11 as a colorless oil (5.41 g, 75.2%). 1H
65.6%). 1H NMR (400 MHz, CDCl3)
d 7.26 (m, 2H), 6.89 (m, 2H), 5.16
(s, 1H), 4.83 (d, J¼6.0 Hz, 1H), 4.69 (d, J¼11.2 Hz, 1H), 4.62 (m, 2H),
4.50 (d, J¼11.2 Hz, 1H), 4.43 (m, 1H), 3.80 (s, 3H), 3.68 (m, 2H), 1.47
NMR (CDCl3, 400 MHz) d 7.25 (m, 2H), 6.88 (m, 2H), 5.14 (s,1H), 4.69
(s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
159.7, 130.0, 128.6,
(d, J¼6.0 Hz,1H), 4.62e4.65 (m, 2H), 4.36e4.40 (m, 2H), 3.80 (s, 3H),
114.1, 112.1, 107.7, 88.4, 86.0, 81.5, 69.9, 55.3, 26.4, 24.7. Calcd HRMS
for C16H22O6: 310.1416; found: 310.1409.
3.72 (m, 2H), 3.54e3.60 (m, 4H), 2.38 (m, 1H), 1.47 (s, 3H), 1.31 (s,
3H); 13C NMR (CDCl3, 100 MHz)
d 159.6, 129.9, 129.3, 114.1, 112.6,
107.5, 85.7, 85.5, 82.3, 72.6, 72.4, 69.2, 61.9, 55.5, 26.7, 25.2. Calcd
3.1.2. (3aR,4R,6R,6aR)-4-(Allyloxymethyl)-6-(4-methoxybenzyloxy)-
2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxole (10). The just de-
scribed 9 (10.02 g, 32.32 mmol) was dissolved in DMF (50 mL) and
NaH (1.54 g, 38.5 mmol, 60% in mineral oil) added in portions. Allyl
bromide (5.50 mL, 64.1 mmol) was then added dropwise via a sy-
ringe. The mixture was stirred at room temperature (12 h) followed
by the addition of H2O (10 mL) to quench the reaction. The mixture
was extracted with Et2O (3ꢂ100 mL). The combined organic layers
were washed with H2O (3ꢂ20 mL), brine (50 mL), dried (Na2SO4),
and concentrated. The residue was purified by silica gel column
chromatography (hexanes/EtOAc¼20:1) to give 10 as a colorless oil
HRMS for C18H26O7 (MꢀCH3): 339.1444; found: 339.1444.
3.1.4. 2-(((3aR,4R,6R,6aR)-6-(4-Methoxybenzyloxy)-2,2-dimethyl-
tetrahydrofuro[3,4-d]-[1,3]dioxol-4-yl)methoxy)ethyl 4-
methylbenzenesulfonate (12). Compound 11 (6.05 g, 17.0 mmol),
TEA (20 mL), TsCl (3.90 g, 20.5 mmol), and DABCO (50 mg) were
mixed in CH2Cl2 (100 mL) and this mixture stirred at room tem-
perature for 30 min. Water (10 mL) was added and the organic layer
separated, washed with brine (20 mL), dried (Na2SO4), and con-
centrated. The residue was purified by silica gel column chroma-
tography (hexanes/EtOAc¼5:1) to give 12 as an orange oil (7.15 g,
(8.97 g, 79.5%). 1H NMR (CDCl3, 250 MHz)
d
7.22 (m, 2H), 6.89 (m,
82.3%). 1H NMR (CDCl3, 400 MHz)
d 7.80 (m, 2H), 7.31 (m, 2H), 7.22
2H), 5.85e5.92 (m, 1H), 5.13e5.31 (m, 3H), 4.61e4.68 (m, 3H),
4.37e4.46 (m, 2H), 4.02 (m, 2H), 3.82 (s, 3H), 3.50 (m, 2H), 1.48 (s,
(m, 2H), 6.87 (m, 2H), 5.10 (s, 1H), 4.55e4.60 (m, 3H), 4.37 (d,
J¼11.6 Hz,1H), 4.24 (m,1H), 4.09e4.16 (m, 2H), 3.80 (s, 3H), 3.67 (m,
2H), 3.43 (m, 2H), 2.43 (s, 3H), 1.47 (s, 3H), 1.30 (s, 3H); 13C NMR
3H), 1.30 (s, 3H); 13C NMR (CDCl3, 62 MHz)
d 159.4, 134.6, 129.8,
129.2, 117.3, 113.8, 112.3, 106.9, 85.3, 85.2, 82.2, 72.2, 71.0, 68.8, 55.3,
26.4, 24.9. Calcd HRMS for C19H26O6 (MꢀCH3): 335.1495; found:
335.1499.
(CDCl3, 100 MHz) d 159.6, 145.0, 133.2, 130.0, 129.9, 129.4, 128.2,
114.1, 112.6, 107.2, 85.5, 85.1, 82.3, 72.4, 69.3, 69.0, 68.9, 55.5, 26.6,
25.1, 21.8. Calcd HRMS for C25H32O9S: 508.1767; found: 508.1774.
3.1.3. 2-(((3aR,4R,6R,6aR)-6-(4-Methoxybenzyloxy)-2,2-dimethyl-
tetrahydrofuro[3,4-d]-[1,3]dioxol-4-yl)methoxy)ethanol
(11). Compound 10 (7.11 g, 20.31 mmol) was dissolved in THF
(50 mL) and to this NMO (7.20 mL, 50% in H2O, 31.2 mmol) was
added followed by OsO4 (20 mg, 0.078 mmol). The reaction mixture
was stirred at room temperature overnight. Sodium thiosulfate
(10 g) was added. The mixture was stirred for another 2 h. The
mixture was filtered through a short silica gel column (5 cm) and
3.1.5. 2-(((3aR,4R,6R,6aR)-6-Hydroxy-2,2-dimethyl-tetrahydrofuro
[3,4-d][1,3]dioxol-4-yl)methoxy)ethyl 4-methylbenzenesulfonate
(13). Derivative 12 (4.87 g, 9.59 mmol) was dissolved in CH2Cl2/
H2O (20:1, 30 mL) and to this DDQ (1.10 g, 4.85 mmol) was added.
The mixture was stirred vigorously at room temperature for 3 h.
The resulting precipitate was removed by filtration. The filtrate was
diluted with CH2Cl2 (100 mL) and washed with saturated NaHCO3
solution (3ꢂ30 mL). The organic layer was dried (Na2SO4), and

68
W. Li et al. / Tetrahedron 68 (2012) 65e71
concentrated. The residue was purified by silica gel column chro-
added NMO (3.6 mL, 50% in H2O, 16 mmol) followed by OsO4
(20 mg, 0.078 mmol). The resulting mixture was stirred at room
temperature overnight. Sodium thiosulfate (5 g) was then added
and the mixture stirred for an additional 2 h. This mixture was
filtered through a short silica gel column followed by rinsing the
column with EtOAc. The combined organic phases were concen-
trated. The residue was dissolved in CH2Cl2/H2O (1:1, 30 mL) and
NaIO4 (2.1 g, 9.9 mmol) then added at room temperature. The
mixture was stirred 3 h. The organic layer was diluted with
CH2Cl2 (90 mL), separated, washed with H2O (20 mL), dried
(Na2SO4), and concentrated. The residue was dissolved in MeOH
(30 mL) at 0 ꢁC and to this NaBH4 (0.30 g, 6.4 mmol) was added,
portionwise. This mixture was stirred at the same temperature for
30 min. Saturated NH4Cl solution (30 mL) was added and the
mixture was filtered through Celite. The solvent was removed
under reduced pressure and the residue purified by silica gel
column chromatography (hexanes/EtOAc¼3:1 to 1:1) to give 16a
as a colorless oil (2.1 g, 84%). The NMR spectrum was consistent
with the literature.11
matography (hexanes/EtOAc¼3:1) to give 13 as an orange oil (
b/
a
¼6:1, 2.88 g, 77.4%). 1H NMR (CDCl3, 400 MHz) for the
b isomer
d
7.82 (m, 2H), 7.37 (m, 2H), 5.27 (d, J¼10.8 Hz, 1H), 4.71 (m, 1H),
4.45 (d, J¼5.6 Hz, 1H), 4.32 (m, 1H), 4.11e4.20 (m, 3H), 3.72e3.78
(m, 2H), 3.55e3.65 (m, 2H), 2.45 (s, 3H), 1.48 (s, 3H), 1.31 (s, 3H); 13C
NMR (CDCl3, 100 MHz) for the
b isomer d 145.2, 132.6, 129.9, 128.0,
112.1, 103.9, 87.2, 85.3, 81.8, 72.6, 69.1, 68.2, 26.4, 24.8, 21.7. Calcd
HRMS for C17H24O8S (MþNH4): 406.1537; found: 406.1536.
3.1.6. 2-(((3aR,4R,6S,6aR)-6-(tert-Butyldimethylsilyloxy)-2,2-
dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)ethyl 4-
methylbenzenesulfonate (6). To 13 (1.54 g, 3.97 mmol) dissolved in
dry CH2Cl2 (60 mL) was added DMAP (20 mg). The solution was
treated with imidazole (0.68 g, 10.4 mmol) and TBSCl (1.21 g,
8.07 mmol) at 0 ꢁC. The solution was then warmed to room tem-
perature and stirred for 2 h. Water (20 mL) was added to quench
the reaction. The organic layer was separated, washed with brine,
dried (Na2SO4), and concentrated under reduce pressure. The res-
idue was purified by silica gel column chromatography (hexanes/
EtOAc¼5:1) to give 6 as a colorless oil (1.32 g, 66.2%). 1H NMR
3.1.9. ((3aR,6S,6aR)-6-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-
6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol
(16b). Compound 1712,13 (0.85 g, 2.8 mmol) was dissolved in
CH2Cl2 (30 mL) and to this were added TBSCl (0.85 g, 5.6 mmol)
and imidazole (0.36 g, 5.6 mmol) at room temperature. The mix-
ture was stirred at this temperature for 5 h. Water (10 mL) was
added to quench the reaction. The organic layer was separated,
dried (Na2SO4), and filtered through a short silica gel column. The
filtrate was concentrated under reduced pressure (H2O bath
temperature: 80 ꢁC). The resulting colorless oil was dissolved in
THF and cooled to ꢀ78 ꢁC. To this TBAF (2.8 mL, 1.0 M in THF,
2.8 mmol) was added. The solution was slowly warmed to room
temperature. Saturated NH4Cl solution (10 mL) was added. The
resulting mixture was extracted with EtOAc (3ꢂ50 mL). The
combined organic layers were washed with brine (3ꢂ20 mL),
dried (Na2SO4), and concentrated. The residue was purified with
silica gel column chromatography (hexanes/EtOAc¼2:1) to give
16b as a colorless oil (0.54 g, 63%). 1H NMR (CDCl3, 400 MHz)
(CDCl3, 400 MHz) d 7.79 (m, 2H), 7.35 (m, 2H), 5.34 (s, 1H), 4.65 (dd,
J¼6.0, 0.4 Hz, 1H), 4.49 (d, J¼6.0 Hz, 1H), 4.13 (m, 3H), 3.66 (m, 2H),
3.43 (m, 2H), 2.45 (s, 3H), 1.47 (s, 3H), 1.32 (s, 3H), 0.87 (s, 9H), 0.10
(s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 144.8, 132.9, 129.9,
128.0, 112.3, 103.3, 87.2, 84.9, 82.5, 72.6, 69.1, 68.7, 26.5, 25.7, 25.1,
21.7, 17.9, ꢀ4.3, ꢀ5.4. Calcd HRMS for C23H38O8SSi (MþNH4):
520.2406; found: 520.2400.
3.1.7. tert-Butyl((3aR,4S,6R,6aR)-2,2-dimethyl-6-vinyl-tetrahydro-
3aH-cyclopenta-[d]-[1,3]dioxol-4-yloxy)dimethylsilane
(15). Vinylmagnesium bromide (25 mL, 1.0 M in THF, 25 mmol) was
added to a suspension of CuBr$SMe2 (0.41 g, 2.0 mmol) in THF
(30 mL) at ꢀ78 ꢁC. The mixture was stirred at this temperature for
1 h. To this were added, dropwise, enone 148 (3.0 g, 19 mmol),
HMPA (10 mL), and TMSCl (3.2 mL, 25 mmol) at ꢀ78 ꢁC. The
resulting mixture was warmed to room temperature and stirred
overnight. Saturated NH4Cl solution (30 mL) was then added to
quench the reaction. The mixture was extracted with Et2O
(3ꢂ100 mL). The combined organic phases were washed with brine
(100 mL), dried (Na2SO4), and concentrated. The residue was dis-
solved in MeOH (100 mL) and CeCl3$7H2O (7.4 g, 20 mmol) added at
d
5.67 (m, 1H), 4.89 (m, 1H), 4.64e4.67 (m, 2H), 4.30e4.38 (m, 2H),
2.05 (br, 1H), 1.42 (s, 3H), 1.37 (s, 3H), 0.92 (s, 9H), 0.14 (s, 3H), 0.12
(s, 3H); 13C NMR (CDCl3, 100 MHz)
143.7, 130.5, 112.4, 83.2, 79.1,
d
74.5, 60.2, 27.4, 26.7, 25.9, 18.5, ꢀ4.4, ꢀ4.7. Calcd HRMS for
0
ꢁC. This was followed by the portionwise addition of NaBH4
C15H28O4Si (MþH): 301.1835; found: 301.1825.
(0.74 g, 20 mmol). The resulting mixture was stirred at this tem-
perature for 1 h. Saturated NH4Cl solution (20 mL) was added to
quench the reaction. The mixture was filtered through Celite and
the filtrate concentrated. The residue was extracted with Et2O
(3ꢂ100 mL) and the combined organic phases dried (Na2SO4), and
filtered through a short silica gel column (10 cm). The filtrate was
concentrated and the residue dissolved in CH2Cl2 (100 mL). TBSCl
(3.0 g, 20 mmol) and imidazole (2.0 g, 31 mmol) were then added to
this solution at room temperature. The mixture was stirred for 3 h
and H2O (10 mL) was added to quench the reaction. The organic
layer was separated, washed with H2O (20 mL), dried (Na2SO4), and
concentrated. The residue was purified by silica gel column chro-
matography (hexanes/EtOAc¼20:1) to give 15 as a colorless oil
3.1.10. ((3aR,4S,6R,6aR)-6-(Allyloxymethyl)-2,2-dimethyl-tetrahy-
dro-3aH-cyclopenta–[d][1,3]dioxol-4-yloxy)(tert-butyl)dimethylsi-
lane (19a). To compound 16a (1.6 g, 5.3 mmol) dissolved in DMF
(50 mL) was added NaH (0.25 g, 6.3 mmol, 60% in mineral oil) in
portions. Allyl bromide (1.1 mL, 12 mmol) was then added to this
mixture, dropwise, via a syringe. The mixture was stirred at room
temperature for 12 h. Water (10 mL) was added to quench the re-
action. The mixture was extracted with Et2O (3ꢂ100 mL). The
combined organic phases were washed with H2O (3ꢂ20 mL), brine
(50 mL), dried (Na2SO4), and concentrated. The residue was purified
by silica gel column chromatography (hexanes/EtOAc¼20:1) to give
19a as a colorless oil (1.6 g, 83%). 1H NMR (CDCl3, 400 MHz)
d 5.89
(2.5 g, 43% in three steps). 1H NMR (CDCl3, 400 MHz)
d
5.76 (m, 1H),
(m, 1H), 5.14e5.26 (m, 2H), 4.38 (m, 2H), 4.19 (m, 1H), 3.94 (m, 2H),
3.37 (m, 1H), 3.30 (m, 1H), 2.24 (m, 1H), 2.05 (m, 1H), 1.68 (m, 1H),
1.48 (s, 3H), 1.31 (s, 3H), 0.91 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C
5.02e5.08 (m, 2H), 4.37 (m, 2H), 4.07 (m, 1H), 2.66 (m, 1H), 2.03 (m,
1H), 1.73 (m, 1H), 1.49 (s, 3H), 1.31 (s, 3H), 0.91 (s, 9H), 0.09 (s, 6H);
13C NMR (CDCl3, 100 MHz)
d
139.1, 114.7, 111.3, 84.1, 80.1, 72.5, 44.3,
NMR (CDCl3, 100 MHz) d 134.8, 116.7, 111.3, 82.5, 80.9, 77.3, 72.9,
35.6, 26.3, 25.7, 24.7 18.4, ꢀ4.4, ꢀ4.7. Calcd HRMS for C16H30O3Si
72.0, 42.3, 34.8, 26.6, 26.1, 24.9, 18.5, ꢀ4.4, ꢀ4.7. Calcd HRMS for
(MþH): 299.2042; found: 299.2043.
C18H34O4Si (MþH): 343.2305; found: 343.2312.
3.1.8. ((3aR,4R,6S,6aR)-6-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-
3.1.11. ((3aR,4S,6aR)-6-(Allyloxymethyl)-2,2-dimethyl-4,6a-dihydro-
3aH-cyclopenta[d][1,3]dioxol-4-yloxy)(tert-butyl)dimethylsilane
(19b). Following the same procedure given for 19a, 16b (0.50 g,
tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol
(16a). To
compound 15 (2.5 g, 8.4 mmol) dissolved in THF (50 mL) was

W. Li et al. / Tetrahedron 68 (2012) 65e71
69
1.7 mmol) resulted in 19b as a colorless oil (0.48 g, 85%). 1H NMR
(CDCl3, 400 MHz) 5.85e5.95 (m, 1H), 5.70 (m, 1H), 5.26 (m,
residue was purified by silica gel column chromatography (hex-
anes/EtOAc¼5:1) to give 7 as an orange oil (0.24 g, 83%). 1H NMR
d
J¼17.2 Hz, 1H), 5.19 (m, J¼10.4 Hz, 1H), 4.88 (d, J¼4.8 Hz, 1H),
(CDCl3, 400 MHz) d 7.80 (m, 2H), 7.33 (m, 2H), 4.31 (m, 2H), 4.13 (m,
4.65 (m, 2H), 4.13 (m, 2H), 4.03 (m, 2H), 1.39 (s, 3H), 1.37 (s, 3H),
3H), 3.62 (m, 2H), 3.37 (m, 1H), 3.28 (m, 1H), 2.45 (s, 3H), 2.18 (m,
1H), 2.05 (m, 1H), 1.53 (m, 1H), 1.47 (s, 3H), 1.30 (s, 3H), 0.90 (s, 9H),
0.91 (s, 9H), 0.12 (s, 6H); 13C NMR (CDCl3, 100 MHz)
d 141.8, 134.6,
131.6, 117.2, 112.2, 82.8, 78.9, 74.6, 71.9, 66.5, 27.5, 26.8, 25.9,
0.08 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 144.9, 133.0,
18.5, ꢀ4.4, ꢀ4.7.
129.9, 127.9, 111.4, 82.2, 80.9, 77.2, 73.2, 72.9, 69.1, 68.5, 68.0, 42.2,
34.6, 26.6, 25.6, 24.9, 21.7, 18.5, ꢀ4.4, ꢀ4.7. Calcd HRMS for
C24H40O7SSi (MþH): 501.2342; found: 501.2338.
3.1.12. 2-(((3aR,4R,6S,6aR)-6-(tert-Butyldimethylsilyloxy)-2,2-
dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methoxy)
ethanol (20a). Allyl derivative 19a (0.80 g, 2.3 mmol) was dissolved
in THF (50 mL) and to this NMO (0.90 mL, 50% in H2O, 4.0 mmol)
was added, which was followed by OsO4 (10 mg, 0.039 mmol) ad-
dition. The mixture was stirred at room temperature overnight at
which time Na2S2O3 (2 g) was added. This new mixture was stirred
for another 2 h. The mixture was then filtered through a short silica
gel column. The column was rinsed with EtOAc/MeOH (5:1, 100 mL)
and the combined organic phases concentrated. The residue was
dissolved in MeOH/H2O (1:1, 30 mL) and to this solution NaIO4
(0.73 g, 3.4 mmol) was added at room temperature. The mixture
was stirred for 3 h at this temperature following, which time the
mixture was cooled to 0 ꢁC and NaBH4 (0.30 g, 6.4 mmol) added
portionwise. The mixture was stirred at the same temperature for
30 min. Saturated NH4Cl solution (30 mL) was added and the
mixture was filtered through Celite. The solvent was removed un-
der reduced pressure and the residue purified by silica gel column
chromatography (hexanes/EtOAc¼3:1 to 1:1) to give 20a as a col-
3.1.15. 2-(((3aR,6S,6aR)-6-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-
6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methoxy)ethyl 4-
methylbenzenesulfonate (7b). Following the same process for
obtaining 7a, derivative 20b (0.24 g, 0.70 mmol) provided 7b as an
orange oil (0.33 g, 95%). 1H NMR (CDCl3, 400 MHz)
d 7.80 (m,
J¼8.4 Hz, 2H), 7.34 (m, J¼8.4 Hz, 2H), 5.64 (d, J¼1.2 Hz, 1H), 4.80 (d,
J¼4.0 Hz, 1H), 4.63 (m, 2H), 4.08e4.18 (m, 4H), 3.64e3.67 (m, 2H),
2.44 (s, 3H), 1.37 (s, 3H), 1.36 (s, 3H), 0.92 (s, 9H), 0.13 (s, 3H), 0.12 (s,
3H); 13C NMR (CDCl3, 100 MHz)
d 144.8, 141.2, 133.0, 132.0, 129.9,
128.0, 112.2, 82.7, 78.9, 74.5, 69.1, 68.2, 67.6, 27.4, 26.8, 25.9, 21.7,
18.2, ꢀ4.4, ꢀ4.7. Calcd HRMS for C24H38O7SSi (MꢀCH3): 483.1873;
found: 483.1865.
3.1.16. (2S,5R)-2-(2-(((3aR,4R,6S,6aR)-6-(tert-Butyldimethylsily-
loxy)-2,2-dimethyl-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)
ethyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (21). (R)-3,6-
Diethoxy-2-isopropyl-2,5-dihydropyrazine (1.50 mL, 7.04 mmol)
was dissolved in THF (3 mL) and this solution cooled to ꢀ78 ꢁC n-
BuLi (3.00 mL, 2.5 M in hexanes, 7.50 mmol) was then added in
dropwise. The mixture was stirred at ꢀ78 ꢁC for 1 h. To this was
added 6 (2.76 g, 5.49 mmol) dissolved in THF (5 mL) in a dropwise
manner using a syringe. The mixture was slowly warmed to ꢀ30 ꢁC
and kept 2 h at this temperature followed by warming to room
temperature and then stirring overnight. Water (10 mL) was added
to quench the reaction. The mixture was extracted with Et2O
(3ꢂ50 mL) and the combined organic layers washed with brine
(30 mL), dried (Na2SO4), and concentrated. The residue was purified
by silica gel column chromatography (hexanes/EtOAc¼10:1) to give
21 as an orange oil, which was contaminated with (R)-3,6-
diethoxy-2-isopropyl-2,5-dihydropyrazine (2.03 g). This product
was used directly in next step without further purification. 1H NMR
orless oil (0.60 g, 86%). 1H NMR (CDCl3, 400 MHz)
d 4.38 (m, 2H),
4.14 (m, 1H), 3.72 (m, 2H), 3.55 (m, 2H), 3.42 (m, 1H), 3.35 (m, 1H),
2.29 (br, 1H), 2.03 (m, 2H), 1.62 (m, 1H), 1.49 (s, 3H), 1.31 (s, 3H), 0.91
(s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d 111.6,
82.3, 80.9, 73.0, 72.9, 72.2, 61.8, 42.4, 34.6, 26.5, 26.0, 24.9, 18.5,
ꢀ4.4, ꢀ4.8. Calcd HRMS for C17H34O5Si (MþH): 347.2254; found:
347.2249.
3.1.13. 2-(((3aR,6S,6aR)-6-(tert-Butyldimethylsilyloxy)-2,2-dimethyl-
6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methoxy)ethanol
(20b). Compound 19b (0.35 g, 1.0 mmol) was dissolved in t-BuOH/
H2O (1:1, 10 mL) and to this AD-mix-
b (1.4 g) was added. The
mixture was stirred at room temperature for 24 h. Sodium thio-
sulfate (2.0 g) was added to quench the reaction. The mixture was
extracted with EtOAc (3ꢂ50 mL) and the combined organic layers
washed with brine (30 mL), dried (Na2SO4), and concentrated. The
residue was dissolved in MeOH/H2O (1:1, 10 mL) and then NaIO4
(0.26 g, 1.2 mmol) was added. The mixture was stirred at room
temperature for 3 h followed by the portionwise addition of NaBH4
(0.24 g, 5.1 mmol). The mixture was stirred at room temperature for
30 min. Saturated NH4Cl solution (10 mL) was added to quench the
reaction. The mixture was extracted with EtOAc (3ꢂ100 mL) and
the combined organic layers washed with brine (30 mL), dried
(Na2SO4), and concentrated. The residue was purified by a silica gel
column chromatography (hexanes/EtOAc¼2:1) to produce 20b as
(CDCl3, 400 MHz)
d 5.35 (s, 1H), 4.72 (m, 1H), 4.51 (m, 1H),
3.85e4.25 (m, 6H), 3.42e3.65 (m, 4H), 2.25 (m, 2H), 2.15 (m, 1H),
1.85 (m, 1H), 1.47 (s, 3H), 1.25 (m, 9H), 1.03 (d, J¼6.8 Hz, 3H), 0.89 (s,
9H), 0.77 (d, J¼6.8 Hz, 3H), 0.11 (s, 3H), 0.09 (s, 3H). Calcd HRMS for
C27H50N2O7Si: 542.3387; found: 542.3379.
3.1.17. (3aR,4R,6R,6aR)-6-((2-((2S,5R)-3,6-Diethoxy-5-isopropyl-2,5-
dihydropyrazin-2-yl)ethoxy)methyl)-2,2-dimethyl-tetrahydrofuro
[3,4-d][1,3]dioxol-4-ol (22). Compound 21 (1.72 g mixture from the
previous step) was dissolved in THF (5 mL) and to this was added
TBAF (10.0 mL, 1 M in THF). This mixture was stirred at room
temperature for 1 h. The solvent was removed under reduced
pressure and the residue purified by silica gel column chromatog-
raphy (hexanes/EtOAc¼3:1) to give 22 as a colorless oil (0.81 g,
a colorless oil (0.34 g, 96%). 1H NMR (CDCl3, 400 MHz)
d 5.69 (m,
1H), 4.89 (d, J¼5.2 Hz, 1H), 4.65 (m, 2H), 4.19 (m, 2H), 3.75 (m, 2H),
3.59 (m, 2H), 1.41 (s, 3H), 1.37 (s, 3H), 0.92 (s, 9H), 0.14 (s, 3H), 0.13
(s, 3H); 13C NMR (CDCl3, 100 MHz)
d
141.6, 131.9, 112.3, 82.9, 78.9,
60%). 1H NMR (CDCl3, 250 MHz)
d
5.28 (d, J¼11.0 Hz, 1H), 4.95 (d,
74.5, 71.9, 67.5, 61.8, 27.4, 26.7, 25.9,18.5, ꢀ4.4, ꢀ4.7. Calcd HRMS for
J¼11.0 Hz, 1H), 4.75 (d, J¼6.0 Hz, 1H), 4.37 (m, 1H), 4.00e4.22 (m,
5H), 3.85e3.95 (m, 1H), 3.55e3.72 (m, 4H), 2.35e2.45 (m, 1H),
2.15e2.30 (m, 2H), 1.78e1.90 (m, 1H), 1.48 (s, 3H), 1.28 (m, 9H), 1.03
(d, J¼6.8 Hz, 3H), 0.71 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3, 60 MHz)
C17H32O5Si (MþH): 345.2097; found: 345.2095.
3.1.14. 2-(((3aR,4R,6S,6aR)-6-(tert-Butyldimethylsilyloxy)-2,2-
dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methoxy)
ethyl 4-methylbenzenesulfonate (7a). Compound 20a (0.20 g,
0.58 mmol), TEA (2 mL), TsCl (0.20 g, 1.1 mmol), and DABCO (5 mg)
were mixed in CH2Cl2 (20 mL) and stirred at room temperature
30 min. Water (5 mL) was added and the organic layer separated,
washed with brine (20 mL), dried (Na2SO4), and concentrated. The
d
163.6,162.9,111.9,103.8, 87.5, 85.6, 81.9, 71.9, 68.8, 60.8, 53.9, 52.3,
33.6, 29.2, 26.4, 24.8, 20.8, 19.1, 16.8, 14.4, 14.3. Calcd HRMS for
C21H36N2O7: 428.2523; found: 428.2518.
3.1.18. 9-((3aR,4R,6R,6aR)-6-((2-((2S,5R)-3,6-Diethoxy-5-isopropyl-
2,5-dihydropyrazin-2-yl)ethoxy)methyl)-2,2-dimethyl-

70
W. Li et al. / Tetrahedron 68 (2012) 65e71
tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-6-bis(tert-butox-
ylcarboxyl)aminopurine (23). Compound 22 (0.61 g, 1.4 mmol) was
dissolved in THF (10 mL) and then CCl4 (0.20 mL, 2.0 mmol) was
added. At ꢀ78 ꢁC, HMPT (0.35 mL, 2.0 mmol) was introduced
dropwise. The mixture was stirred at the same temperature for 1 h
then warmed to 0 ꢁC followed by additional stirring for 1 h. The
solution was again re-cooled to ꢀ78 ꢁC and the sodium salt of
Ad(Boc)2 in DMF (10 mL) (prepared by addition of 260 mg 60% NaH
in mineral oil to 1.80 g Ad(Boc)2 in 10 mL DMF) added dropwise.
The mixture was warmed to room temperature and stirred over-
night. Water (20 mL) was added to quench the reaction. The mix-
ture was extracted with EtOAc (3ꢂ50 mL) and the combined
organic fractions washed with brine (3ꢂ30 mL), dried (Na2SO4),
and concentrated. The residue was purified by silica gel column
chromatography (hexanes/EtOAc¼3:1) to give 23 as a yellow oil
4.85 (m, 1H), 4.64 (m, 2H), 4.05e4.16 (m, 7H), 3.89 (m, 1H), 3.63 (m,
1H), 3.55 (m, 1H), 2.15e2.25 (m, 2H), 1.85 (m, 1H), 1.39 (s, 3H), 1.36
(s, 3H), 1.25 (m, 6H), 1.00 (d, J¼6.8 Hz, 3H), 0.92 (s, 9H), 0.72 (d,
J¼6.8 Hz, 3H), 0.13 (s, 3H), 0.12 (s, 3H); 13C NMR (CDCl3, 100 MHz)
d
163.5, 163.3, 142.3, 131.5, 112.3, 83.0, 79.1, 74.8, 67.8, 67.4, 60.9,
60.8, 60.7, 52.8, 34.4, 32.1, 27.6, 27.1, 26.1, 19.3, 18.7, 16.9, 14.5, ꢀ4.2,
ꢀ4.6. Calcd HRMS for C28H50N2O6Si (MþH): 539.3516; found:
539.3506.
3.1.22. (3aS,4S,6R,6aR)-6-((2-((2S,5R)-3,6-Diethoxy-5-isopropyl-2,5-
dihydropyrazin-2-yl)ethoxy)methyl)-2,2-dimethyl-tetrahydro-3aH-
cyclopenta[d][1,3]dioxol-4-ol (25a). The tosylated 24a (0.50 g,
0.92 mmol) was dissolved in THF (10 mL). To this was added, with
the assistance of a syringe, TBAF (2.0 mL,1 M in THF, 2.0 mmol). The
mixture was heated to 60 ꢁC and kept at this temperature for
30 min. The solvent was removed under reduced pressure, and the
residue purified by silica gel column chromatography (hexanes/
EtOAc¼3:1) to afford 25a as an orange oil (0.16 g, 43%). 1H NMR
(0.23 g, 25%). 1H NMR (CDCl3, 400 MHz)
d 8.88 (s, 1H), 8.38 (s, 1H),
6.28 (d, J¼2.8 Hz, 1H), 5.23 (m, 1H), 4.95 (m, 1H), 4.52 (m, 1H),
3.95e4.23 (m, 6H), 3.55e3.65 (m, 4H), 2.25 (m, 1H), 2.28 (m, 1H),
1.82 (m, 1H), 1.65 (s, 3H), 1.38e1.48 (m, 27H), 1.02 (d, J¼7.2 Hz, 3H),
(CDCl3, 400 MHz)
d 4.49 (m, 1H), 4.45 (m, 1H), 4.08e4.21 (m, 5H),
0.70 (d, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d
163.3, 163.0,
3.96 (m, 1H), 3.87 (m, 1H), 3.53 (m, 1H), 3.45 (m, 1H), 3.35 (m, 1H),
3.25 (m, 1H), 2.40 (d, J¼8.4 Hz, 1H), 2.25 (m, 2H), 2.12 (m, 1H), 1.82
(m, 3H),1.49 (s, 3H),1.34 (s, 3H),1.25e1.28 (m, 6H),1.03 (d, J¼6.8 Hz,
152.9, 152.3, 150.4, 150.3, 143.4, 133.6, 137.0, 129.3, 114.2, 91.4, 85.8,
85.1, 83.7, 81.8, 70.9, 68.4, 60.75, 60.71, 60.62, 60.56, 52.6, 33.8, 31.9,
27.8, 27.3, 25.3, 19.1, 14.4, 14.3. Calcd HRMS for C36H55N7O10
745.4010; found: 745.3993.
:
3H), 0.72 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
d 163.2, 163.1,
111.2, 83.1, 79.6, 76.3, 72.2, 67.8, 60.69, 60.65, 60.57, 60.51, 52.7, 42.0,
35.5, 34.2, 31.9, 26.2, 26.1, 14.4, 14.3. Calcd HRMS for C22H38N2O6:
426.2730; found: 426.2733.
3.1.19. (S)-2-Amino-4-(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-
3,4-dihydroxy-tetrahydrofuran-2-yl)methoxy)butanoic acid (3). The
purine derivative 23 (0.10 g, 0.92 mmol) was dissolved in TFA/H2O
(2:1, 2 mL) at ꢀ20 ꢁC. This solution was stirred at 0 ꢁC for 6 h. IRA-67
ion exchange resin was added to neutralize the mixture. The resin
was removed by filtration and the solvent concentrated at reduced
pressure. The residue was dissolved in MeOH/H2O (2:1, 2 mL) and
K2CO3 (0.20 g, 1.4 mmol) was added. The mixture was stirred at
room temperature for 5 h and the solvent removed under reduced
pressure. The residue was purified by silica gel column chroma-
tography (EtOAc/MeOH/NH4OH (29.6%)¼1:1:1) to give 3 as a white
foam (0.03 g, 61%). Mp >210 ꢁC (decomposed). 1H NMR (D2O,
3.1.23. (3aS,4S,6aR)-6-((2-((2S,5R)-3,6-Diethoxy-5-isopropyl-2,5-
dihydropyrazin-2-yl)ethoxy)methyl)-2,2-dimethyl-4,6a-dihydro-
3aH-cyclopenta[d][1,3]dioxol-4-ol (25b). Undertaking the same
process that resulted in 25a, product 24b (0.20 g, 0.37 mmol)
availed 25b as a colorless oil (0.14 g, 90%). 1H NMR (CDCl3, 400 MHz)
d
5.75 (m, 1H), 4.95 (m, 1H), 4.75 (m, 1H), 4.55 (m, 1H), 4.05e4.15
(m, 7H), 3.88 (m, 1H), 3.63 (m, 1H), 3.55 (m, 1H), 2.71 (br, 1H),
2.15e2.25 (m, 2H), 1.85 (m, 1H), 1.42 (s, 3H), 1.39 (s, 3H), 1.35 (m,
6H), 1.00 (d, J¼6.8 Hz, 3H), 0.72 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz) d 163.5,163.3,143.0,131.2,112.6, 83.1, 77.9, 73.5, 67.8, 67.1,
250 MHz)
2H), 4.43 (m, 1H), 4.32 (m, 1H), 3.65e3.85 (m, 4H), 2.15e2.25 (m,
2H). 13C NMR (D2O, 62 MHz)
175.3, 155.8, 152.8, 149.1, 140.7, 118.7,
d
8.35 (s, 1H), 8.22 (s, 1H), 6.07 (d, J¼5.0 Hz, 1H), 4.78 (m,
60.9, 60.8, 60.7, 52.8, 34.8, 32.0, 27.8, 26.7, 19.2, 16.8, 14.6, 14.5. Calcd
HRMS for C22H36N2O6 (MþH): 425.2651; found: 425.2661.
d
88.3, 83.7, 74.2, 71.0, 70.8, 68.8, 54.0, 30.6. Calcd HRMS for
C14H20N6O6 (MþH): 369.1522; found: 369.1525.
3.1.24. 9-((3aS,4R,6R,6aR)-6-((2-((2S,5R)-3,6-Diethoxy-5-isopropyl-
2,5-dihydropyrazin-2-yl)ethoxy)methyl)-2,2-dimethyl-tetrahydro-
3aH-cyclopenta[d][1,3]dioxol-4-yl)-9H-purin-6-di(tert-butox-
ylcarbonyl)amine (26a). Compound 25a (0.14 g, 0.33 mmol) was
dissolved in THF and to this were added Ph3P (0.17 g, 0.66 mmol)
and Ad(Boc)2 (0.22 g, 0.66 mmol). DIAD (0.13 mL, 0.66 mmol) was
then added, portionwise, via a syringe at 0 ꢁC. The mixture was
warmed to room temperature and stirred overnight. The solvent
was removed under reduced pressure. The residue was purified by
silica gel column chromatography (hexanes/EtOAc¼3:1) to give 26a
3.1.20. (2S,5R)-2-(2-(((3aR,4R,6S,6aR)-6-(tert-Butyldimethylsily-
loxy)-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)
methoxy)ethyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine
(24a). Following
a procedure similar to that for obtaining
21, (R)-3,6-Diethoxy-2-isopropyl-2,5-dihydropyrazine (0.43 mL,
2.0 mmol) and 7a (0.52 g, 1.0 mmol) resulted 24a as an orange oil
(0.50 g, 89%). 1H NMR (CDCl3, 400 MHz)
d 4.28e4.38 (m, 3H), 4.15
(m, 2H), 4.10 (m, 2H), 4.05 (m, 1H), 3.87 (m, 1H), 3.55 (m, 1H), 3.45
(m, 1H), 3.25e3.35 (m, 2H), 2.25 (m, 1H), 2.17 (m, 2H), 2.05 (m, 1H),
1.77 (m, 1H), 1.62 (m, 1H), 1.48 (s, 3H), 1.25e1.32 (m, 9H), 1.03 (d,
J¼6.8 Hz, 3H), 0.91 (s, 9H), 0.72 (d, J¼6.8 Hz, 3H), 0.09 (s, 3H), 0.08
as an orange oil (0.14 g, 57%). 1H NMR (CDCl3, 400 MHz)
d 8.85 (s,
1H), 8.21 (s, 1H), 5.09 (m, 1H), 4.95 (m, 1H), 4.85 (m, 1H), 4.63 (m,
1H), 4.05e4.21 (m, 6H), 3.85 (m, 1H), 3.55 (m, 3H), 2.45 (m, 2H),
2.25 (m, 1H), 2.15 (m, 1H),1.90 (m, 1H),1.55 (s, 3H),1.47 (s,18H),1.35
(s, 3H), 1.27 (m, 6H), 1.03 (d, J¼6.8 Hz, 3H), 0.70 (d, J¼6.8 Hz, 3H);
(s, 3H); 13C NMR (CDCl3, 100 MHz)
d 163.4, 163.0, 111.1, 82.5, 81.1,
73.1, 72.7, 67.7, 61.9, 61.8, 60.6, 60.5, 52.6, 42.3, 31.9, 29.2, 26.6, 26.1,
24.8, 19.1, 18.5, 16.7, 14.7, 14.4, ꢀ4.4, ꢀ4.7. Calcd HRMS for
C28H52N2O6Si: 540.3595; found: 540.3584.
13C NMR (CDCl3, 100 MHz)
d 163.4, 163.2, 153.5, 151.8, 150.6, 150.4,
143.9, 129.4, 113.7, 83.7, 71.8, 67.9, 61.9, 60.6, 60.5, 59.6, 52.7, 43.8,
33.9, 33.7, 31.9, 27.9, 27.8, 27.7, 25.1, 21.9, 21.8, 19.2, 16.8, 14.4, 14.2.
Calcd HRMS for C37H57N7O9: 743.4218; found: 743.4208.
3.1.21. (2S,5R)-2-(2-(((3aR,6S,6aR)-6-(tert-Butyldimethylsilyloxy)-
2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)me-
thoxy)ethyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine
(24b). As with 24a, the procedure used for obtaining 21 was fol-
lowed with (R)-3,6-Diethoxy-2-isopropyl-2,5-dihydropyrazine
(0.32 mL, 1.5 mmol) and 7b (0.25 g, 0.50 mmol) gave 24b as an
3.1.25. 9-((3aS,4R,6aR)-6-((2-((2S,5R)-3,6-Diethoxy-5-isopropyl-2,5-
dihydropyrazin-2-yl)ethoxy)methyl)-2,2-dimethyl-4,6a-dihydro-
3aH-cyclopenta[d][1,3]dioxol-4-yl)-9H-purin-6-bis(tert-butox-
ylcarbonyl)amine (26b). Pursuing the same procedure that gave
26a, 25b (0.12 g, 0.28 mmol) was converted to 26b as an orange oil
orange oil (0.22 g, 81%). 1H NMR (CDCl3, 400 MHz)
d
5.68 (m, 1H),
(0.15 g, 73%). 1H NMR (CDCl3, 250 MHz)
d 8.90 (s, 1H), 7.99 (s, 1H),

W. Li et al. / Tetrahedron 68 (2012) 65e71
71
5.83 (m, 1H), 5.66 (m, 1H), 5.35 (m, J¼8.0 Hz, 1H), 4.73 (m, J¼9.2 Hz,
1H), 4.05e4.15 (m, 7H), 3.90 (m,1H), 3.65 (m, 2H), 2.25 (m, 2H),1.90
(m,1H),1.50 (s, 6H),1.46 (s,18H),1.35 (m, 6H),1.03 (d, J¼6.8 Hz, 3H),
77.1, 73.0, 67.7, 64.4, 53.7, 29.9. Calcd HRMS for C15H20N6O5 (MþH):
365.1573; found: 365.1577.
0.70 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3, 62.9 MHz)
d 163.2, 153.6,
Acknowledgements
153.0, 152.3, 150.6, 150.4, 142.8, 129.3, 121.8, 112.8, 84.4, 83.8, 71.9,
67.9, 67.3, 65.0, 60.7, 60.6, 60.5, 52.6, 34.2, 31.9, 27.8, 27.4, 25.9, 19.1,
16.7, 14.4, 14.3. Calcd HRMS for C37H55N7O9 (MþH): 742.4139;
found: 742.4133.
Partial support of this research was provided by funds from
Department of Health and Human Services (AI 56540). Also, sup-
port from the Molette Fund and Auburn University is appreciated.
3.1.26. (S)-2-Amino-4-(((1R,2R,3S,4R)-4-(6-amino-9H-purin-9-yl)-
2,3-dihydroxycyclopentyl)methoxy)butanoic acid (4). The protected
material 26a (0.13 g, 0.17 mmol) was treated with TFA/H2O (3:1,
3 mL) at room temperature overnight. The solvent was removed
under reduced pressure. The residue was dissolved in MeOH/H2O
(3:1, 10 mL), K2CO3 (0.20 mg, 1.4 mmol) was added. The mixture
was stirred at room temperature for 5 h. The solvent was removed
under reduced pressure and the residue purified by silica gel col-
umn chromatography [(EtOAc/MeOH/NH4OH) (29.6%)¼1:1:1] to
give 4 as a white foam (30 mg, 46%). Mp >200 ꢁC (decomposed). 1H
References and notes
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4.50 (m, 1H), 4.09 (m, 2H), 3.85 (m, 1H), 3.65 (m, 2H), 3.55 (m, 2H),
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100 MHz)
d 173.4, 155.4, 152.0, 149.1, 140.5, 118.7, 74.7, 72.5, 72.2,
67.9, 59.6, 53.7, 42.8, 29.9, 28.9. Calcd HRMS for C15H22N6O5 (MþH):
367.1730; found: 367.1740.
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3.1.27. (S)-2-Amino-4-(((3R,4S,5R)-3-(6-amino-9H-purin-9-yl)-4,5-
dihydroxycyclopent-1-enyl)methoxy)butanoic acid (5). Analogous to
the route that provided 4, compound 26b (0.12 g, 0.16 mmol) gave 5
as a white foam (40 mg, 71%), mp >180 ꢁC (decomposed). 1H NMR
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(D2O, 400 MHz) d 8.17 (s, 1H), 8.14 (s, 1H), 6.10 (m, 1H), 5.54 (m, 1H),
€
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1H), 3.82 (m, 2H), 2.30 (m, 1H), 2.23 (m, 1H); 13C NMR (D2O,
100 MHz) d 174.0, 155.1, 151.9, 148.8, 145.2, 140.8, 127.8, 127.5, 118.6,