Synthesis of enantiomerically pure 4-substituted riboses

Article abstract of DOI:10.1055/s-2007-1000822

An efficient and flexible synthesis of 4-substituted ribose analogues is described. The key step involves the simple addition of a Grignard reagent to a ketone derived from a commercially available ribose. The addition of a range of Grignard reagents proc

Full text of DOI:10.1055/s-2007-1000822

LETTER
3149
Synthesis of Enantiomerically Pure 4-Substituted Riboses
S
ynthesis of Enant
d
iomerically
P
r
ure 4-S
i
ubstitut
a
e
d
Ribosesn Maddaford,a Thierry Guyot,a David Leese,a Rebecca Glen,a James Hart,a Xiurong Zhang,a Ray Fisher,a
Donald S. Middleton,b Cheryl L. Doherty,c Nick N. Smith,b David C. Pryde,*b Scott C. Suttond
a
Peakdale Molecular Ltd., Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak, SK23 0PG, UK
Discovery Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, CT13 9NJ, UK
b
E-mail: David.Pryde@pfizer.com
Material Sciences, Pfizer Global Research and Development, Ramsgate Road, Sandwich, CT13 9NJ, UK
Lead Discovery, Pfizer Global Research and Development, 10777 Science Centre Drive, San Diego, CA 92121, USA
c
d
Received 5 October 2007
O
NH2
N
Abstract: An efficient and flexible synthesis of 4-substituted ribose
analogues is described. The key step involves the simple addition of
a Grignard reagent to a ketone derived from a commercially avail-
able ribose. The addition of a range of Grignard reagents proceeded
in high yield and with complete stereocontrol, to provide a single
enantiomer in every case, the identity of which was confirmed by
single-crystal X-ray crystallography. This addition is unaffected by
substitution at the 2-position of the starting ribose.
Me
O
NH
O
N
HO
N
HO
O
O
N3
1
2
NH2
N
O
Key words: ribose, deoxyribose, nucleosides, antivirals, stereocon-
trol
Me
O
NH
O
N
HO
N
HO
O
O
N
Nucleoside analogues based on ribose and ribose deriva-
tives currently form an important part of the chemothera-
peutic arsenal for a variety of viral diseases.1 For example,
3¢-azido-3¢-deoxythymidine (AZT; 1) and 2¢,3¢-dideoxy-
cytidine (ddC; 2) are both components of highly active
anti-retroviral therapy (HAART) HIV therapy (Figure 1),
and have been for many years. The emergence of resis-
tance and/or toxicities associated with HAART has in-
spired continuing efforts to seek new potent nucleoside
analogues to improve or replace agents such as 1 and 2.2
More recently, nucleosides which feature a substituent in
the 4¢-position have been shown to possess promising
anti-HCV (3)3 and anti-HIV (4)4 activity. This helped fo-
cus our attention on developing a flexible method of ac-
cessing various nucleoside analogues with a range of
functionality at the 4¢-position.
In the preceding paper in this series,5 we introduced a ro-
bust and flexible method for the synthesis of 4¢-substitut-
ed nucleosides where the substituent could be chosen
from alkyl, alkenyl, alkynyl, cycloalkyl or aryl. The key
step of this synthesis involved the stereoselective addition
of a Grignard reagent to a ketone (5, PG = protecting
group, Scheme 1) to give diastereomerically pure addition
N
N
HO
OH
HO
3
4
Figure 1 Examples of clinically precedented nucleosides
products 6, which ultimately allowed rapid and efficient
access to racemic versions of 4-substituted 2-deoxyribos-
es 7.
The simplicity and flexibility of this route attracted us to
further develop this methodology to allow access to ribose
analogues 8 (Scheme 2), and more importantly extend the
method to access enantiomerically pure analogues. We
were also interested in determining whether the presence
of substituents elsewhere on the target ribose would inter-
fere with the diastereoselectivity of the Grignard addition
process. The previous methodology relied on a four-step
synthesis starting from isopropyl acetate to construct the
pivotal ketone 5. To access ribose analogues, we needed
access to a similar ketone of structure 10 in an orthogonal-
ly protected form, to which the substituent that would ul-
timately become the 4¢-group would be added to provide
9. We envisaged 10 to be simply accessed from ribose it-
O
OPG
PGO
O
O
OPG
OR
O
OPG
O
OPG
OH
O
PGO
5
6
7
Scheme 1 Our previous methodology to access 4-substituted 2-deoxyribose analogues5
SYNLETT 2007, No. 20, pp 3149–3154
x
x
.x
x
.2
0
0
7
Advanced online publication: 03.12.2007
DOI: 10.1055/s-2007-1000822; Art ID: D31707ST
© Georg Thieme Verlag Stuttgart · New York

3150
A. Maddaford et al.
LETTER
HO
HO
R
OH OH
OH OH
O
O
OH
OR
OH
OH
OH
R
OH
OH
O
OH
HO
OH
HO
ribose (11)
9
10
8
Scheme 2 Proposed retrosynthetic route to enantiomerically pure 4-substituted riboses
self, or indeed from a 2- or 3-substituted ribose, for which Swern conditions and treated with acetic anhydride to
there are many syntheses well documented in the litera- give the anomeric acetate ribose 19 ready for base attach-
ture.1
ment.
In the forward sense (Scheme 3), we chose a simple ace- A range of other Grignard reagents were also used in a
tonide group to protect the 2,3-hydroxyl groups of ribose, similar reaction with 16, and the results from these exper-
which was accomplished using standard conditions of iments are summarised in Table 1. In every case, the addi-
acetone and catalytic H2SO4. The 5-hydroxyl was then tion of aryl, alkyl or cycloalkyl Grignard nucleophiles
protected as its trityl ether, and the ribose ring subsequent- proceeded stereoselectively to generate a single com-
ly opened by sodium borohydride reduction in ethanol to pound 17 in good to excellent yield. The assignment of the
give the diol 14. The free primary hydroxyl generated in absolute stereochemistry of the newly created centre was
this reaction was then protected as its tert-butyldimethyl- made initially by analogy to the study previously pub-
silyl ether and the remaining secondary hydroxyl group lished by Marco et al.,6 and was unequivocally assigned
was oxidised under Swern conditions to provide the key by obtaining a single-crystal X-ray structure of a final nu-
intermediate ketone 16.
cleoside product, which is shown below in Figure 2.
Then, a range of Grignard additions to 16 were carried out There are many effective methods for the attachment of
at –78 °C in Et2O and the reaction mixtures were allowed the sugar to base units of nucleosides,7 any of which
to warm to room temperature overnight. Initially, cyclo- would have been applicable to the ribose analogue 19.
propyl magnesium chloride was used as a test reagent, and Given the effectiveness of the acetonide group in directing
pleasingly, this afforded the addition product 17a as a sin- the Grignard attack on the ketone 16, it was preferable to
1
gle diastereoisomer by H NMR. Subsequent TBAF re- test the ability of the acetonide group to direct the base ad-
moval of the primary TBDMS group furnished the alcohol dition in 19. We chose the persilylation conditions of Vor-
18 in excellent yield, which was then oxidised under brueggen to attach cytosine to 19 via its benzoylated
HO
TrO
O
O
HO
O
OH
OH
i
ii
OH
OH
ribose (11)
O
O
O
O
HO
12
13
iii
TrO
O
TrO
TrO
O
O
iv
v
HO
HO
OTBDMS
OTBDMS
OH
O
vi
O
O
O
16
15
14
TrO
TrO
O
TrO
O
HO
OAc
HO
vii
viii, ix
OH
OTBDMS
O
O
O
O
O
19
18
17a
Scheme 3 Reagents and conditions: (i) acetone, H2SO4, reflux, 24 h; (ii) TrCl, pyridine, r.t., 24 h; (iii) NaBH4, EtOH, r.t., 3 h, 56% over three
steps from ribose; (iv) TBDMSCl, imidazole, CH2Cl2, r.t., 16 h; (v) (COCl)2, Et3N, DMSO, CH2Cl2, –78 °C → r.t., 16 h; (vi) cyclopropylma-
gnesium choride, Et2O, 3 h, –78 °C → r.t., 65% over three steps from 14; (vii) TBAF, THF, r.t., 1 h, 90%; (viii) (COCl)2, Et3N, DMSO, CH2Cl2,
–78 °C → r.t., 16 h, 91%; (ix) Ac2O, Et3N, CH2Cl2, 1 h, 72%.
Synlett 2007, No. 20, 3149–3154 © Thieme Stuttgart · New York

LETTER
Synthesis of Enantiomerically Pure 4-Substituted Riboses
3151
hindered
approach
Table 1 Addition of Grignard Reagents to 16
TrO
TrO
TBSO
OTr
HO
R
O
OTBDMS
OTBDMS
RMgX
O
H
O
O
O
O
O
O
H
Mg
Br Nu
favoured
approach
16
17a–e
Yield (%)a
Figure 3 Proposed model of attack of nucleophiles onto ketone 16
R
Product
cyclopropyl
allyl
17a
17b
17c
17d
17e
100
100
88
Table 2 Coupling Reaction of Various Bases with 19
TrO
O
HO
O
OAc
Base
methyl
phenyl
i, ii
77
O
O
O
O
19
20a–d
ethynyl
79
a All products were obtained as a single diastereoisomer by crude 1H
NMR.
Base
Producta
20a
Anomeric ratio (a/b)b Yield (%)c
Bz-cytosine
uracil
1:1
1:2
1:1
1:2
61
60
25
60
20b
chloropurine
thymine
20c
20d
a The products were obtained using identical persilylation reaction
conditions as detailed in Scheme 4. Reaction conditions: (i) Bz-cy-
tosine, bis(trimethylsilyl)acetamide, MeCN, TMSOTf, reflux, 1.5 h,
31% (+ 30% a-anomer); (ii) NH3, MeOH.
b Determined by crude 1H NMR spectroscopy. Individual characteri-
sation of each anomer was carried out following silica gel chroma-
tographic separation.
c Yield of isolated, purified products.
HCl to remove the acetonide.8 This gave the enantiomeri-
cally pure 4¢-cyclopropyl-substituted nucleoside 21 in
64% yield, thus completing the synthesis in approximate-
ly 5% overall yield from ribose.
A single-crystal X-ray structure of 219 was obtained
(Figure 2), which confirmed that the initial Grignard addi-
tion to the ketone 16 proceeded as predicted from the si
face to yield the 4¢-S configuration.
Figure 2 Single-crystal X-ray structure of nucleoside product 21;
there are two molecules in the asymmetric unit, which have been
drawn independently for clarity (residue 1 on the left and residue 2 on
the right)
derivative (Scheme 4).7 This provided the protected nu-
cleoside analogue 20a in approximately 30% yield, along
with the corresponding a-anomer in a similar yield. De-
spite the apparently crowded vicinity of the lower face of
9, the acetonide was confirmed as poorly directive of the
base condensation. During the base attachment the trityl
group was also cleaved and the resulting 20a was then ful-
ly deprotected using firstly ammonia in methanol to re-
move the benzoyl group, and secondly in situ generated
A plausible model for the addition is shown in Figure 3, in
which chelation-controlled addition of the nucleophile to
the ketone 16 occurs from the si face to give the observed
stereochemical outcome.6
Several other bases were also coupled to 19 in a manner
similar to that shown in Scheme 4, and the results are
shown in Table 2. In each case, the base coupled to the
NHBz
TrO
HO
O
NH2
O
HO
N
OAc
O
ii, iii
i
N
N
N
O
O
O
O
O
O
HO
OH
19
20a
21
Scheme 4 Reagents and conditions: (i) Bz-cytosine, bis(trimethylsilyl)acetamide, MeCN, TMSOTf, reflux, 1.5 h, 31% (+ 30% a-anomer);
(ii) NH3, MeOH; (iii) NaOMe, MeOH then AcCl, r.t., 48 h, 64% over two steps.
Synlett 2007, No. 20, 3149–3154 © Thieme Stuttgart · New York

3152
A. Maddaford et al.
LETTER
sugar in modest isolated yield to produce the desired b- tained in enantiomerically pure form from ribose itself.
anomer along with an equimolar amount or less of the a- One could envisage this method being applied to many
anomer. However, in every case the anomers were easily other ribose analogues, featuring a range of substitution
separated by column chromatography. Changing the ace- patterns in the 2,3-positions, provided the presence of this
tonide group in each of the starting substrates 19 for an es- additional functionality does not affect the diastereoselec-
ter, such as acetate or benzoate, would be expected to tivity of the key Grignard addition step.
improve the anomeric ratio of the coupled products signif-
icantly, a strategy which was explored in the second phase
of this work described below.
Ribose nucleosides that contain a 2¢-CMe substituent have
recently attracted much attention due to their anti-HCV
activity.10 Several syntheses of 2-CMe ribose and the re-
The ketone addition methodology had thus demonstrated lated 2-CMe ribonolactone template are known in the lit-
that a variety of 4-substituted riboses could be readily ob- erature,11 which in our view made this template a good
HO
TrO
O
O
HO
O
O
O
O
i
ii
O
O
O
O
HO
OH
23
24
22
iii
TrO
O
TrO
TrO
O
O
iv
v
HO
HO
OTBDMS
OTBDMS
OH
O
O
O
O
27
26
25
vi
TrO
TrO
O
TrO
O
O
HO
HO
vii
viii
OH
OTBDMS
O
O
O
O
O
30
29
28
ix, x
BzO
BzO
BzO
O
O
O
OBz
O
O
xiii, xiv
xi, xii
BzO
OBz
O
O
BzO
OBz
31
33
32
xv
N
N
BzO
HO
O
NHBz
O
N
NH2
N
xvi
N
N
N
N
BzO
OBz
HO
OH
34
35
Scheme 5 Reagents and conditions: (i) acetone, H2SO4, reflux, 24 h, 100%; (ii) TrCl, pyridine, CH2Cl2, r.t., 24 h; (iii) LiAlH4, THF, r.t., 3 h,
100% over two steps; (iv) TBDMSCl, imidazole, CH2Cl2, r.t., 16 h, 93%; (v) (COCl)2, Et3N, DMSO, CH2Cl2, r.t., 16 h; (vi) MeMgBr, Et2O, –
78 °C → r.t., 91% over two steps; (vii) TBAF, THF, r.t., 2 h; (viii) TPAP, NMO, CH2Cl2, r.t., 3 h, 66% over two steps; (ix) TFA, CH2Cl2, r.t.,
16 h; (x) BzCl, Et3N, 85% over two steps; (xi) TFA, H2O, r.t., 16 h; (xii) BzCl, pyridine, r.t., 16 h, 78% over two steps; (xiii) LiAl(i-BuO)3H,
THF, r.t., 4 h; (xiv) BzCl, CH2Cl2, r.t., 16 h, 74% over two steps; (xv) BSA, TMSOTf, MeCN, N6-Bz-adenine, reflux, 6 h, 67%; (xvi) NH3 in
MeOH, excess, r.t., 3 d, 56%.
Synlett 2007, No. 20, 3149–3154 © Thieme Stuttgart · New York

LETTER
Synthesis of Enantiomerically Pure 4-Substituted Riboses
3153
choice as a starting point to further test our methodology. detailed in the reference section.13–15 Further disclosures
By closely following the route of Schemes 3, 2-CMe ri- of analogues prepared using this methodology and their
bonolactone 22 was uneventfully converted into the ke- utility will follow in due course.
tone 27 in good yield (Scheme 5). Our only concession to
the presence of the ribonolactone functionality was the
use of LiAlH4 in the reduction step, rather than NaBH4,
References and Notes
(1) Dan, A.; Iino, T.; Yoshimura, Y.; Minakawa, N.; Tanaka,
M.; Saraki, T. In Nucleosides and Nucleotides as Anti-
Tumor and Anti-Viral Agents; Chu, C.; Baker, D. C., Eds.;
Plenum Publishing Co.: New York, 1993, .
(2) (a) See, for example: el Kouni, M. H. Curr. Pharm. Des.
2002, 8, 581; and references therein. (b) For a recent review
of ribose-modified nucleosides, see: Ichikawa, E.; Kato, K.
Synthesis 2002, 1.
(3) Klumpp, K.; Leveque, V.; Le Pogam, S.; Ma, H.; Jiang, W.-
R.; Kang, H.; Granycome, C.; Singer, M.; Laxton, C.; Hang,
J. Q.; Sarma, K.; Smith, D. B.; Heindl, D.; Hobbs, C. J.;
Merrett, J. H.; Symons, J.; Cammack, N.; Martin, J. A.;
Devos, R.; Najera, I. J. Biol. Chem. 2006, 281, 3793.
(4) Summerer, D.; Marx, A. Bioorg. Med. Chem. Lett. 2005, 15,
869.
(5) Wainwright, P.; Maddaford, A.; Bissell, R.; Fisher, R.;
Leese, D.; Lund, A.; Runcie, K.; Dragovich, P. S.; Gonzalez,
J.; Kung, P.; Middleton, D. S.; Pryde, D. C.; Stephenson, P.
T.; Sutton, S. C. Synthesis 2007, 1378.
(6) Alberto, M. J.; Miguel, C.; Florenci, G.; Santiago, R.;
Encarna, C.; Juan, M. J. Org. Chem. 1998, 63, 698.
(7) Vorbrueggen, H.; Ruh-Pohlenz, C. In Handbook of
Nucleoside Synthesis; John Wiley & Sons, Inc.: Chichester
(UK), 2001.
(8) For a range of protection/deprotection methods and primary
references, see: Greene, T. W.; Wuts, P. G. M. In Protecting
Groups in Organic Synthesis, 3rd ed.; John Wiley & Sons,
Inc.: New Jersey (USA), 1999.
(9) Crystal data for 21: C12H17N3O5, orthorhombic, P212121, a =
15.1487(16), b = 24.363(3), c = 6.9867(8) Å, Z = 8, V =
2578.6(5) Å3, Dc = 1.459 Mg/m3, Mo–Ka radiation, l =
0.71073 Å, 5.4 2q 44.6. Bruker AXS SMART-APEX
diffractometer was used to collect the data; 21867 reflections
were collected of which 5995 unique reflections [I >2s(I)]
were used for refinement (401 parameters), converging to
R = 0.058 and Rw = 0.1297. The configuration of 21 was
determined relative to the known configuration of the
starting material and was not determined directly from the
X-ray diffraction data. CCDC 662745 contains the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK, fax: +44(1223)336033.
(10) See, for example: Eldrup, A. B.; Prhavc, M.; Brooks, J.;
Bhat, B.; Prakash, T. P.; Song, Q.; Bera, S.; Bhat, N.; Dande,
P.; Cook, P. D.; Bennett, C. F.; Carroll, S. S.; Ball, R. G.;
Bosserman, M.; Burlein, C.; Colwell, L. F.; Fay, J. F.;
Flores, O. A.; Getty, K.; LaFemina, R. L.; Leone, J.;
MacCoss, M.; McMasters, D. R.; Tomassini, J. E.; Von
Langen, D.; Wolanski, B.; Olsen, D. B. J. Med. Chem. 2004,
47, 5284; and references therein.
which proceeded in excellent yield. Methylmagnesium
bromide was then chosen as our test nucleophile for this
system. The Grignard reaction pleasingly provided the ad-
dition product 28 once again as a single compound and in
excellent yield. This answered our initial query as to the
effect a 2-substituent would have on the key addition re-
action, which pleasingly was none. We then sought to
convert 28 into a nucleoside.
Upon removal of the TBS group in 28, we found that by
carrying out the oxidation reaction of the resulting alcohol
29 using tetrapropylammonium perruthenate (TPAP)–
NMO,12 the conversion led directly to the formation of the
ribonolactone 30, which although not desired, was signif-
icantly better than a range of other oxidation methods
which tended to cause decomposition of 29. We therefore
sought to transform the newly formed carbonyl group of
30 to a suitable leaving group for the base attachment pro-
cess. To our surprise, it was found that further derivatisa-
tion of 30 suffered from problems of messy and
incomplete reactions, possibly due to the crowded nature
of the ribose skeleton in 30. Initial attempts to remove
concurrently the trityl ether and the acetonide protecting
groups gave a product which was very difficult to isolate
due to its highly polar nature. Instead we opted for a step-
wise process in which the trityl ether was first removed
using TFA in CH2Cl2 and replaced with a benzoate ester,
prior to hydrolysing the acetonide with TFA in water.
Subsequent benzoylation then gave the protected ribono-
lactone 32 in overall 64% yield from 30.
Reduction of the carbonyl group then proceeded in good
yield with lithium tri(isobutoxy)aluminium hydride to
furnish the ribose derivative, which was simply protected
as its benzoyl ester to provide the base-coupling partner
33 as a direct analogue of the derivative 19 used in the
above coupling reactions of Table 2. This time, persilyla-
tion of N-benzoyladenine followed by TMSOTf-mediated
addition of 33 furnished, as expected, the protected nucle-
oside 34 as a single anomer in 67% yield. To complete the
synthesis, 34 was finally deprotected using ammonia in
methanol to provide the nucleoside derivative 35 in good
yield.
The utility of our methodology has thus been demonstrat-
ed to access a 2¢,4¢-dialkyl-substituted nucleoside.
In summary, we have further developed our earlier meth-
odology to access 4-substituted riboses by demonstrating
a method to produce a range of enantiomerically pure 4-
substituents. We have shown that the method may be ap-
plied to a variety of substituents and to the synthesis of
2,4-dialkyl containing riboses with no loss of stereochem-
ical integrity in the key step where the 4-substituent is in-
troduced. Representative experimental procedures are
(11) (a) Bio, M. M.; Xu, F.; Waters, M.; Williams, J. M.; Savary,
K. A.; Cowden, C. J.; Yang, C.; Buck, E.; Song, Z. J.;
Tschaen, D. M.; Volante, R. P.; Reamer, R. A.; Grabowski,
E. J. J. J. Org. Chem. 2004, 69, 6257. (b) Girardet, J.-L.;
Gunic, E.; Esler, C.; Cieslak, D.; Pietrzkowski, Z.; Wang, G.
J. Med. Chem. 2000, 43, 3704. (c) Punzo, F.; Watkin, D. J.;
Hotchkiss, D.; Fleet, G. W. J. Acta Crystallogr., Sect. E:
Synlett 2007, No. 20, 3149–3154 © Thieme Stuttgart · New York

3154
A. Maddaford et al.
LETTER
Struc. Rep. Online 2006, 62, o98. (d) Jenkinson, S. F.;
Jones, N. A.; Moussa, A.; Stewart, A. J.; Heinz, T.; Fleet, G.
W. J. Tetrahedron Lett. 2007, 48, 4441.
CH2Cl2 to provide 34 (1.6 g, 67%) as a white foam; Rf = 0.41
(2% MeOH–CH2Cl2). 1H NMR (CDCl3): d = 1.62 (s, 3 H),
1.66 (s, 3 H), 4.76 (dd, 2 H), 6.27 (s, 1 H), 6.81 (s, 1 H), 7.30–
7.60 (m, 12 H), 7.96–8.10 (m, 8 H), 8.30 (s, 1 H), 8.86 (s, 1
H), 9.33 (br s, 1 H, NH).
(12) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 2004, 639.
(13) Representative Experimental Procedure for the
Preparation of 30: To a solution of 27 (19.9 g, 36 mmol) in
THF (300 mL) at –78 °C, was added a 3 M solution of
MeMgBr in THF (17.8 mL, 53 mmol) over 10 min. The
reaction mixture was stirred for 15 min and allowed to self
warm to r.t. After 30 min, the reaction mixture was quenched
with MeOH and diluted with EtOAc. The mixture was
washed with 1 N HCl, dried over MgSO4 and evaporated to
give 28 (18.7 g, 91%). This was used crude without further
purification; Rf = 0.55 (hexane–EtOAc, 8:1). To a solution of
28 (18.7 g, 32 mmol) in THF (200 mL) was added a 1 M
solution of TBAF in THF (35.7 mL, 35 mmol). The mixture
was stirred for 3 h at r.t., diluted with EtOAc and washed
with brine–H2O (1:1, 3 ×). The organics were dried over
MgSO4, filtered and evaporated to give 29 (15.6 g) which
was used without further purification; Rf = 0.34 (hexane–
EtOAc, 2:1). To a solution of 29 (15.6 g, 34 mmol) in
CH2Cl2 (600 mL) was added NMO (13.8 g, 120 mmol),
TPAP (0.25 g, 0.7 mmol) and 4 Å MS (100 g). The mixture
was then stirred for 6 h at r.t., filtered and washed with H2O.
The organics were dried over MgSO4 and evaporated to
provide a residue that was purified by flash column
chromatography eluting with CH2Cl2–hexane (7:3) to give
30 (9.8 g, 66% over two steps); Rf = 0.60 (CH2Cl2–hexane,
7:3). 1H NMR (CDCl3): d = 1.40 (s, 3 H), 1.43 (s, 3 H), 1.45
(s, 3 H), 1.47 (s, 3 H), 3.21 (d, 1 H), 3.28 (d, 1 H), 3.72 (s, 1
H), 7.25–7.38 (m, 15 H).
A mixture of 34 (1.6 g, 2.2 mmol) and 16% NH3–MeOH (50
mL) was left standing at r.t. for 3 d. After concentration in
vacuo, the residue obtained was stirred in MeOH–CH2Cl2
(1:1; 15 mL) and the resulting white solid was filtered and
dried to give 35 (0.37 g, 56%) as a white solid. 1H NMR
(D2O): d = 0.78 (s, 3 H), 1.20 (s, 3 H), 3.56 (dd, 2 H), 4.09
(s, 1 H), 6.06 (s, 1 H), 8.05 (s, 1 H), 8.25 (s, 1 H). MS: m/z
(%) = 296.01 [M + H]+. Chemical purity by HPLC: Atlantis
dC18, 3 × 150 mm, 3 mM, 0–50% MeCN over 15 min, then
50–95% MeCN over 5 min then held for 5 min (aqueous
phase containing 0.1% TFA in H2O), 98.43% (257 nm).
(15) Representative Experimental Procedure for the
Preparation of 20a: Bis(trimethylsilyl)acetamide (3.8 mL,
16 mmol) was added to a suspension of N-benzoylcytosine
(1.67 g, 8 mmol) in MeCN (30 mL) under argon and the
reaction mixture was heated at reflux temperature for 30
min. After cooling to r.t., 19 (2.0 g, 4 mmol) was added
followed by TMSOTf (2.1 mL, 12 mmol). The reaction
mixture was then heated at reflux for 1.5 h, allowed to cool,
diluted with EtOAc and sat. NaHCO3 and stirred for 5 min.
The mixture was filtered and the organic phases were
separated, dried over MgSO4 and concentrated in vacuo. The
resulting white foam was further purified by flash silica
chromatography eluting with CH2Cl2–EtOAc–MeOH
(1:1:0.1) to give 20a (0.52 g, 31%) as a white foam and the
corresponding a-anomer (0.49 g, 30%) as a white foam. Data
for b-anomer: Rf = 0.59 (CH2Cl2–EtOAc–MeOH, 1:1:0.1).
1H NMR (MeOD-d3): d = 0.34–0.43 (m, 2 H), 0.50–0.60 (m,
2 H), 0.96–1.06 (m, 1 H), 1.36 (s, 3 H), 1.58 (s, 3 H), 3.68 (s,
2 H), 4.88–4.94 (m, 2 H), 5.85 (d, 1 H), 7.50–7.67 (m, 4 H),
7.96 (d, 2 H), 8.40 (d, 1 H). Data for a-anomer: Rf = 0.40
(CH2Cl2–EtOAc–MeOH, 1:1:0.1). 1H NMR (MeOD-d3): d =
0.41–0.50 (m 2 H), 0.55–0.73 (m, 2 H), 1.10–1.20 (m, 1 H),
1.30 (s, 3 H), 1.35 (s, 3 H), 3.62 (s, 2 H), 4.83–4.87 (m, 1 H),
5.08 (dd, 1 H), 6.34 (d, 1 H), 7.50–7.67 (m, 4 H), 7.95 (d, 2
H), 8.06 (d, 1 H).
(14) Experimental Procedure for the Preparation of 35: A
suspension of N-benzoyladenine (1.6 g, 6.7 mmol) and
bis(trimethylsilyl)acetamide (3.3 mL, 13.4 mmol) in MeCN
(40 mL) was heated at reflux for 40 min. The mixture was
cooled to r.t., and 33 (2.0 g, 3.4 mmol) was added followed
by TMSOTf (1.8 mL, 10 mmol). The resulting mixture was
heated at reflux for 6 h, cooled to r.t., diluted with EtOAc and
washed with sat. NaHCO3. The organics were dried over
MgSO4 and evaporated to give a residue that was purified by
flash column chromatography eluting with 2% MeOH–
Synlett 2007, No. 20, 3149–3154 © Thieme Stuttgart · New York

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