Asymmetric synthesis of 4′-quaternary 2′-deoxy-3′- and -4′-epi-β-C- and -N-nucleosides

Article abstract of DOI:10.1055/s-2008-1072577

A versatile and efficient route to both enantiomers of 4′-quaternary 2′-deoxy-3′- and -4′-epi-β-C- and -N-nucleosides is described. The asymmetric synthesis involves the SAMP/RAMP-hydrazone α-alkylation methodology and diastereoselective nucleophilic 1,2-

Full text of DOI:10.1055/s-2008-1072577

PAPER
1545
Asymmetric Synthesis of 4¢-Quaternary 2¢-Deoxy-3¢- and -4¢-epi-b-C- and
-N-Nucleosides
A
symmetric Synth
i
esis of
e
4
¢
-Quatern
t
ary N
u
e
leoside
A
n
r
alogues Enders,* Antje Hieronymi, Gerhard Raabe
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: Enders@rwth-aachen.de
Received 14 February 2008
In connection with these investigations, we envisaged to
develop an asymmetric synthesis of 4¢-quaternary C- as
well as N-nucleoside analogues. We now wish to disclose
our results in detail, partially based on a recent communi-
Abstract: A versatile and efficient route to both enantiomers of 4¢-
quaternary 2¢-deoxy-3¢- and -4¢-epi-b-C- and -N-nucleosides is de-
scribed. The asymmetric synthesis involves the SAMP/RAMP-
hydrazone a-alkylation methodology and diastereoselective nucleo-
philic 1,2-additions. Manipulation of the substituents in the anomer- cation.9
ic position leads to the thermodynamically more stable b-anomers
of excellent diastereo- and enantiomeric purity (>99% de and ee).
The syntheses of both the C- and N-nucleoside analogues
involve the TBS-protected lactone intermediates 4, which
could be obtained by a six-step reaction sequence
(Scheme 1). Starting with the a-alkylation of 2,2-dimeth-
yl-1,3-dioxan-5-one (1),10 the use of the SAMP/RAMP-
hydrazone methodology11 yielded the tert-butyl keto es-
ters (R)-2 (via RAMP) and (S)-2 (via SAMP) in 57% and
64% yield, respectively, over three steps with virtually
complete asymmetric inductions (≥ 99% ee). The diaste-
reoselectivity of the subsequent Grignard addition reac-
tion with alkyl and aryl groups was good to excellent (70–
98%) and the major syn-diastereomers could be separated
Key words: nucleoside analogues, asymmetric synthesis, hydra-
zones, quaternary stereocentres, diastereoselective reduction
A great number of nucleoside analogues have been syn-
thesised and studied recently. Among them, C- as well as
N-nucleosides have been investigated with regard to their
biological activity,1 their behaviour in oligonucleotides,2
and their ability to replace their natural archetypes,3 with
many of them showing promising bioactivity.
A variety of nucleoside analogues have been synthesised, easily by column chromatography, leading to diastereo-
with modifications of the sugar moiety4 as well as of the and enantiomerically pure hydroxy esters 3a–e in 65–98%
aglyconic unit.3,5–7 To our knowledge, no asymmetric and yields (≥ 99% de and ee) (Scheme 1, Table 1).
direct route to 4¢-quaternary 2¢-deoxy-3¢/4¢-epi-nucleo-
Hydroxy esters 3 were subjected to acidic acetonide
sides (Figure 1) has been published so far, although nu-
cleavage and cyclisation in hydrochloric acid–methanol
cleosides close to these targets have been investigated and
(Scheme 1), and this gave access to the corresponding lac-
reported. For example, Matsuda et al.1a studied the bio-
tone diols in excellent yields, with all stereocentres kept
logical activities of 4¢-quaternary thymidines and found
intact. The lactone intermediates 5a–e could be recrystal-
that some of them possess antileukaemic and antiviral ac-
tivity. The investigations of Marx et al. on the same ana-
O
logues with DNA polymerases proved the methyl-
substituted thymidine to be superior to the natural thy-
midines concerning efficiency as well as selectivity.2
Moreover, Naegli et al. inserted 4¢-epi-nucleoside ana-
logues in DNA templates and showed them to have the
potential to stop DNA polymerases, which could be useful
in anticancer drug targeting.8
R
O
TBSO
O
O
O
Me Me
TBSO
(R,R)-4
1
57%
(64%)
80–98%
(59–99%)
c,d
a
R1
R1
HO
HO
O
O
R2
R2
O
R
OH
Ot-Bu
Ot-Bu
b
HO
HO
O
O
O
O
O
O
4'-quaternary 2'-deoxy-
3'-epi-β-nucleoside
4'-quaternary 2'-deoxy-
4'-epi-β-nucleoside
65–98%
(67–92%)
Me Me
Me Me
Figure 1 4¢-Quaternary 2¢-deoxy-3¢- and -4¢-epi-b-nucleosides
(R,R)-3 de, ee ≥ 98%
ee ≥ 99%
(R)-2
R = Me, Et, Ph, 4-FC6H4, allyl
Scheme 1 Reagents and conditions: (a) 1. RAMP (or SAMP), ben-
zene, reflux; 2. t-BuLi, THF, –78 °C; 3. O3, CH2Cl2, –78 °C; (b) 1.
RMgBr, THF, –78 °C or –100 °C; 2. column chromatography; (c) 3
N HCl, MeOH, r.t.; (d) TBSOTf, py, THF, 0 °C. (Yields in brackets
are those of the enantiomeric series based on the SAMP auxiliary.)
SYNTHESIS 2008, No. 10, pp 1545–1558
Advanced online publication: 07.04.2008
DOI: 10.1055/s-2008-1072577; Art ID: Z04408SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
8

1546
D. Enders et al.
PAPER
H3C
H3C
Table 1 Synthesis of TBS-Protected Lactones 4a–e
O
O
TBSO
HO
O
R
R
3
Yield (%)
(R,R)-3 (S,S)-3 of 3
de,a eeb (%) 4
Yield (%)
37–56%
(13–36%)
TBSO
(R,R)-4a
HO
(R,R)-4 (S,S)-4
(R,R,R)-8
ee ≥ 99%
Me
Et
3a
3b
3c
87
66
88
98
66
89
75
92
67
80
≥ 99, ≥ 99 4a
≥ 99, ≥ 99 4b 98
≥ 99, ≥ 99 4c 89
≥ 99, ≥ 99 4d 80
≥ 99, ≥ 99 4e 90
85
88
59
99
74
74
82–100%
(54–100%)
60–65%
(35–54%)
c
a
H3C OH
Ph
H3C
O
TBSO
R
R
b
4-FC6H4 3d
allyl 3e
OTBS OTBS O
70–93%
(66–69%)
TBSO
(R,R)-6
(R,R,R)-7
a Determined by GC (CP-Sil-8) after column chromatography.
b Determined by CSP-GC (Chiral-dex, Chirasil L-Val).
R = Ph, Naph
Scheme 2 Reagents and conditions: (a) CeCl3, RLi, THF, –110 to
–99 °C; (b) Me4N+[HB(OAc)3]–, MeCN, AcOH, –30 °C; (c) TFA–
CHCl3 (4:1), CHCl3, 0 °C. [Yields in brackets are those of the oppo-
site enantiomeric series, starting from (S,S)-4a.]
lised from tetrahydrofuran–n-pentane. For lactone 5b
(R = Et), we were able to perform an X-ray crystal struc-
ture analysis to determine the absolute configuration
(Figure 2).
was achieved with diisobutylaluminum hydride, resulting
in the corresponding lactols, which were acylated without
preliminary purification to lead to lactol esters 9a–e in
yields ranging from 54% to 95% (Scheme 3, Table 3). It
is noteworthy that under these reduction conditions the a-
anomers formed exclusively.
Outright substitution with silylated bases by the Vor-
brüggen methodology5 failed, and therefore lactol esters 9
were exposed to nucleophilic substitution with trimeth-
yl(phenylsulfanyl)silane,15 which led to an anomeric mix-
ture of thioglycosides 10a–e (Scheme 3). These
Figure 2 Structure of (S,S)-5b as determined by X-ray
crystallography12
CH3
O
For the ongoing synthesis, however, most lactone diols
were directly protected by reaction with tert-butyldimeth-
ylsilyl trifluoromethanesulfonate and pyridine to give the
doubly TBS-protected lactones 4a–e in good to excellent
yields (Scheme 1, Table 1).
R
R
O
O
TBSO
TBSO
O
N
NH
O
TBSO
(R,R)-4
TBSO
(R,R,R)-11
ee ≥ 99%
For the preparation of C-nucleosides, lactone 4a was
treated with freshly prepared organocerium reagents13 to
give the open doubly protected keto triol 6 in good to
quantitative yields (Scheme 2). Subsequent reduction of 6
with tetramethylammonium triacetoxyborohydride14 gave
rise exclusively to b-anomers 7 of the protected nucleo-
sides in good to very good yields (Scheme 2, Table 2). Fi-
nally, deprotection of 7 could be achieved by treatment of
7 with trifluoroacetic acid in chloroform; this gave free C-
nucleosides 8 (Scheme 2). The enantiomeric excess
(≥ 99% ee) was maintained throughout the synthesis, and
could be verified in the final products 8a,b (Table 2).
R = Me, Et, Ph, 4-FC6H4
54–74%
(62–95%)
a, b
76–95%
(53–88%)
d
R
O
TBSO
OAc
R
O
TBSO
SPh
c
76–99%
(65–99%)
TBSO
(R,R,R)-9
TBSO
(R,R,R/S)-10
R = Me, Et, Ph, 4-FC6H4, allyl
Scheme 3 Reagents and conditions: (a) DIBAL-H, CH2Cl2, –78 °C;
(b) Ac2O, py, r.t.; (c) TMSSPh, BF3·OEt2, n-hexane, –95 °C to r.t.; (d)
bis-TMS-thymine, NBS, 4-Å MS, CH2Cl2, –78 to –26 °C. [Yields in
brackets are those of the opposite enantiomeric series, starting from
(S,S)-4.]
The synthesis of N-nucleosides first required the reduc-
tion of the TBS-protected lactones 4a–e (Scheme 3). This
Table 2 Preparation of C-Nucleosides 8a,b
R
6
Yield (%)
7
Yield (%)
8
Yield (%)
(R,R)-6
(S,S)-6
54
(R,R,R)-7
(S,S,S)-7
69
(R,R,R)-8
(S,S,S)-8
35
Ph
6a
6b
82
7a
7b
70
93
8a
8b
65
60
1-Naph
100
100
66
54
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 4¢-Quaternary Nucleoside Analogues
1547
Table 3 Synthesis of Protected N-Nucleosides 11a–e
R
9
Yield (%)
10
Yield (%)
11
Yield (%)
(R,R,R)-11 (S,S,S)-11
(R,R,R)-9
(S,S,S)-9
(R,R,R)-10 (S,S,S)-10
Me
9a
9b
9c
9d
9e
54
54
62
74
64
74
62
95
64
74
10a
10b
10c
10d
10e
98
97
89
99
76
86
99
98
65
68
11a
11b
11c
11d
11e
77
95
87
76
77
88
73
53
Et
Ph
4-FC6H4
allyl
a
a
–
–
a Derivatives 11e were unstable and could not be purified.
intermediates turned out to be excellent substrates for the (Table 4). The diastereomers could be separated easily by
N-bromosuccinimide-activated
silyl-Hilbert–Johnson column chromatography and were obtained in 77% and
reaction16 to give the thermodynamically more stable b- 83% combined yields.
anomers of thymidines 11a–d in high diastereoselectivity
In summary, we have demonstrated an efficient and flex-
and good to excellent yields (Scheme 3, Table 3). Only
the allyl derivatives 11e turned out to be unstable and
could not be purified (Table 3).
ible synthetic route towards diastereomerically and enan-
tiomerically pure 4¢-quaternary 3¢- and -4¢-epi-C- and -N-
nucleosides. The free C-nucleosides 8a,b were synthe-
The deprotection of thymidine (S,S,S)-11a was performed sised in nine steps and overall yields of 7–24%. TBS-pro-
as in the case of the C-nucleosides with trifluoroacetic tected N-nucleosides 11a–d and 12–15 were prepared in
acid in chloroform, and gave the unprotected nucleoside 8–34% overall yield, following a ten-step synthetic se-
analogue in 66% yield. Moreover, further nucleobases quence.
were attached to 10a by use of N-bromosuccinimide and
the corresponding silylated heterocycles in dichlo-
All chemicals were purchased from commercial sources and used
romethane; this led to the formation of 4¢-methyl-2¢-
deoxy-3¢- and -4¢-epi-b-N-nucleosides 12–15 (Scheme 4,
Table 4).
without further treatment unless otherwise indicated. Solvents were
dried by standard procedures, and reactions requiring anhydrous
conditions were performed under argon. All melting points were
measured on a Büchi 510 (Dr. Tottoli system) melting point appa-
ratus and are uncorrected. Optical rotations were measured on a
Perkin-Elmer P241 polarimeter. NMR spectra were recorded on a
Varian VXR 300, Varian Gemini 300, Varian Inova 400, or Varian
Unity 500 spectrometer; TMS was used as an internal standard. IR
spectra were recorded on a Perkin-Elmer FT/IR 1760 spectrometer.
MS spectra were measured on a Finnigan SSQ7000, and HRMS
spectra on a Finnigan MAT95 mass spectrometer. Elemental
analyses were obtained with a Heraeus CHN-O-Rapid analyser. For
preparative column chromatography, silica gel 60 (particle size
0.040–0.063 mm, Merck) was used. For analytical TLC, pre-coated
silylated
nucleobase,
NBS, CH2Cl2
H3C
H3C
O
O
TBSO
TBSO
SPh
R
TBSO
(R,R,R/S)-10a
TBSO
(R,R,R)-12–15
Scheme 4 Introduction of other nucleobases onto 10a
Table 4 Preparation of Further Nucleoside Analogues from 10a
F
254 silica gel 60 plates (Merck, Darmstadt) were used.
R
Product
Yield (%)
Yield (%)
Hydroxy Esters 3a–d; General Procedure (GP1)
(R,R,R)
(S,S,S)
The Grignard reagent RMgBr (2 equiv) was slowly added to a 0.1
M soln of keto ester 2 in anhyd THF at –100 °C (–78 °C for R =
Me). After 4 h, the reaction was stopped by the addition of sat. aq
NH4Cl (5 mL/mmol). After the mixture had warmed to r.t., the pre-
cipitate was dissolved by dilution with distilled H2O. The aqueous
phase was extracted with Et2O (50 mL/mmol) and the combined or-
ganic layers were washed with brine and dried (MgSO4). The prod-
ucts were purified by column chromatography.
cytosine
12
13
14
15
48
50
N-Ac-guanine
xanthine
37
46
42
76
6-chloropurine
35 (a) + 42 (b)
28 (a) + 55 (b)
(4S,5S)-tert-Butyl 2-(5-Hydroxy-2,2,5-trimethyl-1,3-dioxan-4-
yl)acetate [(S,S)-3a]
According to GP1, keto ester (S)-2 (1.247 g, 5.10 mmol) was treated
with MeMgBr at –78 °C. After workup and column chromatogra-
phy (n-pentane–Et2O, 1:1), hydroxy ester (S,S)-3a was obtained as
colourless crystals.
In contrast to all the other cases, the reaction with silylated
adenine gave only poor results (15% and 16% yield). For
this reason we decided to introduce the less polar adenine
precursor 6-chloropurine into the system, which could be
transformed into adenine by amination in an additional
step. This provided an access to the desired nucleoside an-
alogues 15. Exclusively in this case, a considerable
amount of the a-anomer was found in the reaction mixture
25
Yield: 1.164 g (88%); mp 67 °C; [a]D –9.8 (c 1.10, CHCl3);
Rf = 0.1 (n-pentane–Et2O, 4:1).
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

1548
D. Enders et al.
PAPER
25
IR (KBr): 3559, 3495, 2981, 2941, 1724, 1384, 1369, 1311, 1288,
1263, 1205, 1151, 1062, 1038, 968 cm–1.
Yield: 0.149 g (92%); mp 108 °C; [a]D +12.2 (c 1.00, CHCl3);
Rf = 0.51 (n-pentane–Et2O, 2:1).
1H NMR (300 MHz, C6D6): d = 0.69 (s, 3 H, CH3COH), 1.25 (s, 3
H, CH3CCH3), 1.34 (s, 3 H, CH3CCH3), 1.37 [s, 9 H, C(CH3)3], 2.50
(dd, J = 15.8, 4.0 Hz, 1 H, CH2CO), 2.62 (dd, J = 15.8, 8.7 Hz, 1 H,
CH2CO), 2.92 (s, 1 H, OH), 3.30 (d, J = 11.8 Hz, 1 H, CH2O), 3.41
(d, J = 11.8 Hz, 1 H, CH2O), 4.15 (dd, J = 8.7, 4.0 Hz, 1 H,
CH2CHO).
13C NMR (75 MHz, C6D6): d = 18.4, 18.9, 28.1, 29.7, 36.1, 66.3,
70.3, 73.8, 79.9, 98.7, 170.3.
MS (CI): m/z (%) = 261 (3) [M + H+].
IR (KBr): 3449, 2989, 2921, 1727, 1494, 1450, 1406, 1384, 1371,
1307, 1284, 1256, 1198, 1164, 1092, 1075, 1030, 978, 949, 936,
900, 859, 829, 765, 746, 706 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.37 [s, 9 H, C(CH3)3], 1.50 (s, 3
H, CH3CCH3), 1.63 (s, 3 H, CH3CCH3), 2.08 (dd, J = 15.9, 2.8 Hz,
1 H, CH2CO), 2.41 (dd, J = 15.9, 9.6 Hz, 1 H, CH2CO), 3.48 (s, 1
H, OH), 3.57 (d, J = 12.0 Hz, 1 H, CH2O), 4.20 (d, J = 12.0 Hz, 1
H, CH2O), 4.67 (dd, J = 9.6, 2.8 Hz, 1 H, CH2CHO), 7.20–7.50 (m,
5 H, HAr).
13C NMR (75 MHz, CDCl3): d = 18.3, 28.0, 29.6, 35.8, 70.6, 70.7,
73.3, 80.4, 99.4, 125.2, 127.7, 128.5, 138.7, 170.6.
MS (CI): m/z (%) = 267 (100), 323 (10) [M + H+].
Anal. Calcd for C13H24O5: C, 59.98; H, 9.29. Found: C, 60.38; H,
9.64.
(4R,5R)-tert-Butyl 2-(5-Hydroxy-2,2,5-trimethyl-1,3-dioxan-4-
yl)acetate [(R,R)-3a]
According to GP1, keto ester (R)-2 (1.221 g, 5.00 mmol) was treat-
ed with MeMgBr at –78 °C. After workup and column chromatog-
raphy (n-pentane–Et2O, 1:1), hydroxy ester (R,R)-3a was obtained
as colourless crystals.
Anal. Calcd for C18H26O5: C, 67.06; H, 8.13. Found: C, 66.56; H,
8.62.
(4R,5R)-tert-Butyl 2-(5-Hydroxy-2,2-dimethyl-5-phenyl-1,3-di-
oxan-4-yl)acetate [(R,R)-3c]
According to GP1, keto ester (R)-2 (0.279 g, 1.14 mmol) was treat-
ed with PhMgBr at –100 °C. After workup and column chromatog-
raphy (n-pentane–Et2O, 2:1), (R,R)-3c was obtained as colourless
crystals.
25
Yield: 1.127 g (87%); [a]D +10.2 (c 0.94, CHCl3); all other data
correspond with those of (S,S)-3a.
(4S,5S)-tert-Butyl 2-(5-Ethyl-5-hydroxy-2,2-dimethyl-1,3-di-
oxan-4-yl)acetate [(S,S)-3b]
According to GP1, keto ester (S)-2 (0.122 g, 0.50 mmol) was treated
with EtMgBr at –100 °C. After workup and column chromatogra-
phy (n-pentane–Et2O, 4:1) (S,S)-3b was obtained as colourless crys-
tals.
25
Yield: 0.323 g (88%); [a]D –12.6 (c 1.00, CHCl3); all other data
correspond with those of (S,S)-3c.
(4S,5S)-tert-Butyl 2-[5-(4-Fluorophenyl)-5-hydroxy-2,2-di-
methyl-1,3-dioxan-4-yl]acetate [(S,S)-3d]
According to GP1, keto ester (S)-2 (0.370 g, 1.51 mmol) was treated
with 4-FC6H4MgBr at –100 °C. After workup and column chroma-
tography (n-pentane–Et2O, 2:1), (S,S)-3d was obtained as colour-
less crystals.
25
Yield: 0.104 g (75%); mp 47 °C; [a]D –11.0 (c 1.00, CHCl3);
Rf = 0.3 (n-pentane–Et2O, 2:1).
IR (KBr): 3452, 2985, 2949, 2875, 1715, 1473, 1369, 1329, 1295,
1253, 1203, 1164, 1114, 1091, 1072, 1053, 1038, 1003, 980, 946,
906, 866, 832, 587, 537, 519 cm–1.
25
Yield: 0.345 g (67%); mp 112 °C; [a]D +11.8 (c 0.98, CHCl3);
Rf = 0.6 (n-pentane–Et2O, 2:1).
1H NMR (300 MHz, CDCl3): d = 0.91 (t, J = 7.6 Hz, 3 H, CH3CH2),
1.40 (s, 3 H, CH3CCH3), 1.44 [s, 9 H, C(CH3)3], 1.46 (s, 3 H,
CH3CCH3), 2.39 (dd, J = 15.6, 8.8 Hz, 1 H, CH2CO), 2.50 (dd,
J = 15.6, 3.8 Hz, 1 H, CH2CO), 3.06 (s, 1 H, OH), 3.58 (d, J = 11.9
Hz, 1 H, CH2O), 3.85 (d, J = 11.9 Hz, 1 H, CH2O), 4.22 (dd, J = 8.8,
3.8 Hz, 1 H, CH2CHO).
13C NMR (75 MHz, CDCl3): d = 6.9, 18.3, 25.9, 28.1, 29.4, 35.8,
67.8, 68.2, 72.8, 80.4, 98.8, 170.9.
MS (CI): m/z (%) = 275 (9) [M + H+].
IR (KBr): 3432, 2985, 2927, 2868, 1713, 1605, 1513, 1384, 1369,
1332, 1310, 1280, 1256, 1226, 1192, 1157, 1130, 1085, 1036, 983,
959, 936, 907, 867, 830, 748, 597, 560, 539 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.38 [s, 9 H, C(CH3)3], 1.50 (s, 3
H, CH3CCH3), 1.64 (s, 3 H, CH3CCH3), 2.08 (dd, J = 16.1, 3.0 Hz,
1 H, CH2CO), 2.41 (dd, J = 16.1, 9.4 Hz, 1 H, CH2CO), 3.55 (d,
J = 12.1 Hz, 1 H, CH2O), 3.68 (s, 1 H, OH), 4.17 (d, J = 12.1 Hz, 1
H, CH2O), 4.67 (dd, J = 9.4, 3.0 Hz, 1 H, CH2CHO), 7.05 (dd,
J = 8.9, 8.7 Hz, 2 H, FCCH), 7.50 (dd, J = 8.9, 8.7 Hz, 2 H,
CCHCH).
13C NMR (100 MHz, CDCl3): d = 18.3, 28.0, 29.4, 35.7, 70.4, 70.4,
73.1, 80.3, 99.3, 115.2 (d, JC–F = 20.6 Hz, 2 C, FCCH), 126.9 (d,
JC–F = 7.6 Hz, 2 C, CCHCH), 134.5 (d, JC–F = 3.1 Hz, 1 C, CCOH),
162.0 (d, JC–F = 246.4 Hz, 1 C, CF), 170.3.
Anal. Calcd for C14H26O5: C, 61.29; H, 9.55. Found: C, 61.17; H,
9.94.
(4R,5R)-tert-Butyl 2-(5-Ethyl-5-hydroxy-2,2-dimethyl-1,3-di-
oxan-4-yl)acetate [(R,R)-3b]
According to GP1, keto ester (R)-2 (0.222 g, 0.91 mmol) was treat-
ed with EtMgBr at –100 °C. After workup and column chromatog-
raphy (n-pentane–Et2O, 4:1), (R,R)-3b was obtained as colourless
crystals.
19F NMR (376 MHz, CDCl3): d = –114.72.
MS (CI): m/z (%) = 209 (100), 285 (20).
Anal. Calcd for C18H25FO5: C, 63.51; H, 7.40. Found: C, 63.28; H,
7.91.
25
Yield: 0.164 g (66%); [a]D +11.2 (c 1.05, CHCl3); all other data
correspond with those of (S,S)-3b.
(4R,5R)-tert-Butyl 2-[5-(4-Fluorophenyl)-5-hydroxy-2,2-di-
methyl-1,3-dioxan-4-yl]acetate [(R,R)-3d]
According to GP1, keto ester (R)-2 (0.270 g, 1.11 mmol) was treat-
ed with 4-FC6H4MgBr at –100 °C. After workup and column chro-
matography (n-pentane–Et2O, 2:1), (R,R)-3d was obtained as
colourless crystals.
(4S,5S)-tert-Butyl 2-(5-Hydroxy-2,2-dimethyl-5-phenyl-1,3-di-
oxan-4-yl)acetate [(S,S)-3c]
According to GP1, keto ester (S)-2 (0.122 g, 0.50 mmol) was treated
with PhMgBr at –100 °C. After workup and column chromatogra-
phy (n-pentane–Et2O, 2:1), (S,S)-3c was obtained as colourless
crystals.
Yield: 0.369 g (98%); [a]D25 –9.6 (c 0.99, CHCl3); all other data cor-
respond with those of (S,S)-3d.
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 4¢-Quaternary Nucleoside Analogues
1549
(4S,5S)-tert-Butyl 2-(5-Allyl-5-hydroxy-2,2-dimethyl-1,3-diox-
an-4-yl)acetate [(S,S)-3e]
Yield: 0.315 g (99%); mp 80 °C; [a]D25 –2.87 (c 1.05, MeOH). The
resulting lactone (0.083 g, 0.57 mmol) was treated with TBSOTf
and py as described in GP2. The product (S,S)-4a could be obtained
after column chromatography (n-pentane–Et2O, 4:1) as colourless
crystals.
ZnBr2 (0.137 g, 0.60 mmol, 1.2 equiv) was dried under vacuum and
dissolved in anhyd THF (5 mL/mmol) and the mixture was cooled
to –78 °C. AllMgBr (0.6 mL, 0.6 mmol, 1.2 equiv) was added slow-
ly and the mixture was allowed to stir for 30 min. It was then cooled
to –100 °C and (S)-2 (0.122 g, 0.50 mmol, 1.0 equiv) in anhyd THF
(5 mL/mmol) was added. After 1 h, the reaction was quenched by
the addition of H2O (10 mL/mmol). After workup as described in
GP1 and column chromatography (n-pentane–Et2O, 1:1), (S,S)-3e
was obtained as colourless crystals.
25
Yield: 0.195 g (89%); mp 44 °C; [a]D +23.9 (c 1.15, CHCl3);
Rf = 0.4 (n-pentane–Et2O, 4:1).
IR (KBr): 2955, 2932, 2893, 2860, 1777, 1470, 1258, 1230, 1117,
1001, 955, 915, 879, 840, 777, 671 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.06 (s, 3 H, SiCH3), 0.07 (s, 3 H,
SiCH3), 0.08 (s, 3 H, SiCH3), 0.09 (s, 3 H, SiCH3), 0.89 [s, 9 H,
C(CH3)3], 0.90 [s, 9 H, C(CH3)3], 1.30 (s, 3 H, CH3C), 2.66 (dd,
J = 17.0, 7.7 Hz, 1 H, CH2CO), 2.75 (dd, J = 17.0, 7.7 Hz, 1 H,
CH2CO), 3.61 (d, J = 10.6 Hz, 1 H, CH2OSi), 3.91 (d, J = 10.6 Hz,
1 H, CH2OSi), 4.23 (dd, J = 7.7, 7.7 Hz, 1 H, CHCH2CO).
13C NMR (75 MHz, CDCl3): d = –5.7, –5.6, –5.2, –4.7, 17.9, 18.2,
21.2, 25.6, 25.8, 39.0, 65.4, 74.5, 87.4, 174.3.
MS (CI): m/z (%) = 243 (100), 377 (2) [M + H+].
Yield: 0.114 g (80%); mp 49 °C; [a]D25 0 (c 1.00, CHCl3); Rf = 0.6
(n-pentane–Et2O, 1:1).
IR (KBr): 3439, 2981, 2936, 2874, 1715, 1641, 1370, 1314, 1280,
1258, 1204, 1158, 1088, 1063, 1030, 973, 955, 909, 883, 831, 752,
739, 620, 585, 529 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 3 H, CH3CCH3), 1.45 [br,
12 H, CH3CCH3, C(CH3)3], 2.07 (ddd, J = 14.4, 8.2, 1.0 Hz, 1 H,
CH2COH), 2.22 (ddd, J = 14.4, 6.7, 1.2 Hz, 1 H, CH2COH), 2.41
(dd, J = 15.6, 8.9 Hz, 1 H, CH2CO), 2.54 (dd, J = 15.6, 3.7 Hz, 1 H,
CH2CO), 3.07 (d, J = 1.2 Hz, 1 H, OH), 3.52 (d, J = 11.9 Hz, 1 H,
CH2O), 3.83 (d, J = 11.9 Hz, 1 H,CH2O), 4.22 (dd, J = 8.9, 3.7 Hz,
1 H, CH2CHO), 5.07–5.14 (m, 2 H, CH2CHCH2), 5.75–5.89 (m, 1
H, CH2CHCH2).
13C NMR (75 MHz, CDCl3): d = 18.3, 28.0, 29.3, 35.8, 38.1, 67.9,
68.3, 72.5, 80.5, 98.9, 118.8, 131.6, 170.7.
MS (CI): m/z (%) = 231 (100), 287 (8) [M + H+].
HRMS: m/z [M – CH3]+ calcd for C14H23O5: 271.154; found:
Anal. Calcd for C18H38O4Si: C, 57.70; H, 10.22. Found: C, 57.55;
H, 10.53.
(4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-methyldihydrofuran-2(3H)-one [(R,R)-4a]
The hydroxy ester (R,R)-3a (0.825 g, 3.38 mmol) was cyclised ac-
cording to GP2. Recrystallisation afforded the free lactone as co-
lourless crystals.
Yield: 0.493 g (99%); [a]D23 +2.96 (c 1.02, MeOH).
The resulting lactone (0.157 g, 1.08 mmol) was treated with TB-
SOTf and py as described in GP2. The product (R,R)-4a could be
obtained after column chromatography (n-pentane–Et2O, 4:1) as
colourless crystals.
271.154.
(4R,5R)-tert-Butyl 2-(5-Allyl-5-hydroxy-2,2-dimethyl-1,3-diox-
an-4-yl)acetate [(R,R)-3e]
25
ZnBr2 (0.639 g, 2.8 mmol, 1.2 equiv) was dried under vacuum and
dissolved in anhyd THF (5 mL/mmol) and the mixture was cooled
to –78 °C. AllMgBr (2.8 mL, 2.8 mmol, 1.2 equiv) was added slow-
ly and the mixture was allowed to stir for 30 min. It was then cooled
to –100 °C and (R)-2 (0.570 g, 2.33 mmol, 1.0 equiv) in anhyd THF
(5 mL/mmol) was added. After 1 h, the reaction was quenched by
the addition of H2O (10 mL/mmol). After workup as described in
GP1 and column chromatography (n-pentane–Et2O, 1:1), (R,R)-3e
was obtained as colourless crystals.
Yield: 0.345 g (86%); [a]D –24.0 (c 1.02, CHCl3); all other data
correspond with those of (S,S)-4a.
(4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-ethyldihydrofuran-2(3H)-one [(S,S)-4b]
The hydroxy ester (S,S)-3b (0.137 g, 0.50 mmol) was cyclised ac-
cording to GP2. Recrystallisation afforded the free lactone as co-
lourless crystals.
Yield: 0.079 g (99%); mp 112 °C; [a]D25 +5.7 (c 1.04, MeOH).
Yield: 0.437 g (65%); [a]D25 –0.7 (c 1.20, CHCl3); all other data cor-
respond with those of (S,S)-3e.
The resulting lactone (0.061 g, 0.38 mmol) was treated with
TBSOTf and py as described in GP2. The product (S,S)-4b could be
obtained after column chromatography (n-pentane–Et2O, 4:1) as
colourless crystals.
TBS-Protected Lactones 4a–e; General Procedure (GP2)
The appropriate hydroxy ester, one of 3a–e, was dissolved in
MeOH (3 mL/mmol) and treated with 3 N HCl in aq MeOH (12 N
aq HCl–MeOH, 1:4; 3 mL/mmol). The mixture was stirred until
TLC indicated complete conversion of the starting material. All sol-
vents were evaporated under reduced pressure and the products
were recrystallised from THF–n-pentane. The free lactones (1
equiv) were then dissolved in THF (10 mL/mmol) and py (6 equiv)
was added at 0 °C. After slow addition of TBSOTf (3 equiv), the re-
action mixture was stirred for 4 h and then quenched with H2O (5
mL/mmol), extracted with Et2O (50 mL/mmol), washed with brine,
and dried (MgSO4). Column chromatography gave pure products
4a–e.
25
Yield: 0.088 g (60%); mp 43 °C; [a]D +22.6 (c 0.97, CHCl3);
Rf = 0.8 (n-pentane–Et2O, 2:1).
IR (KBr): 2954, 2933, 2891, 2859, 1763, 1468, 1256, 1227, 1171,
1103, 1079, 1037, 1004, 926, 843, 777 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.06–0.09 (4 s, 12 H, SiCH3),
0.89–0.90 [2 s, 18 H, C(CH3)3], 0.95 (t, J = 7.4 Hz, 3 H, CH3CH2),
1.64 (q, J = 7.4 Hz, 2 H, CH3CH2), 2.66 (dd, J = 17.0, 8.2 Hz, 1 H,
CH2CO), 2.78 (dd, J = 17.0, 8.2 Hz, 1 H, CH2CO), 3.65 (d, J = 10.7
Hz, 1 H, CH2OSi), 3.95 (d, J = 10.7 Hz, 1 H, CH2OSi), 4.32 (dd,
J = 8.2, 8.2 Hz, 1H, H-3).
13C NMR (100 MHz, CDCl3): d = –5.7, –5.6, –5.2, –4.5, 7.6, 17.9,
(4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-methyldihydrofuran-2(3H)-one [(S,S)-4a]
The hydroxy ester (S,S)-3a (0.573 g, 2.16 mmol) was cyclised ac-
cording to GP2. Recrystallisation afforded the free lactone as co-
lourless crystals.
18.2, 25.6, 25.8, 26.9, 39.1, 64.0, 71.9, 89.4, 174.2.
MS (CI): m/z (%) = 331 (100), 390 (6) [M + H+].
HRMS: m/z [M – C4H9]+ calcd for C15H31O4Si2: 331.176; found:
331.176.
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

1550
D. Enders et al.
PAPER
(4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-ethyldihydrofuran-2(3H)-one [(R,R)-4b]
The hydroxy ester (R,R)-3b (0.164 g, 0.60 mmol) was cyclised ac-
cording to GP2. Recrystallisation afforded the free lactone as co-
lourless crystals.
obtained after column chromatography (n-pentane–Et2O, 6:1) as
colourless crystals.
25
Yield: 0.155 g (74%); mp 90 °C; [a]D +9.64 (c 0.98, CHCl3);
Rf = 0.6 (n-pentane–Et2O, 6:1).
IR (KBr): 2954, 2933, 2891, 2858, 1781, 1511, 1469, 1254, 1226,
1177, 1133, 1082, 950, 929, 841, 779 cm–1.
Yield: 0.095 g (99%); [a]D25 –7.16 (c 1.02, MeOH).
The resulting lactone (0.108 g, 0.67 mmol) was treated with
TBSOTf and py as described in GP2. The product (R,R)-4b could
be obtained after column chromatography (n-pentane–Et2O, 4:1) as
colourless crystals.
1H NMR (300 MHz, CDCl3): d = 0.01 (s, 3 H, SiCH3), 0.03 (s, 3 H,
SiCH3), 0.09 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3), 0.87 [s, 9 H,
C(CH3)3], 0.96 [s, 9 H, C(CH3)3], 2.68 (dd, J = 16.8, 7.9 Hz, 1 H,
CH2CO), 2.85 (dd, J = 16.8, 7.7 Hz, 1 H, CH2CO), 3.72 (d, J = 10.6
Hz, 1 H, CH2OSi), 4.21 (d, J = 10.6 Hz, 1 H, CH2OSi), 4.51 (dd,
J = 7.7, 7.9 Hz, 1 H, CHCH2CO), 7.04 (m, 2 H, FCCH), 7.43 (m, 2
H, CCHCH).
25
Yield: 0.258 g (99%); [a]D –18.0 (c 0.99, CHCl3); all other data
correspond with those of (S,S)-4b.
(4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-phenyldihydrofuran-2(3H)-one [(S,S)-4c]
The hydroxy ester (S,S)-3c (0.156 g, 0.49 mmol) was cyclised ac-
cording to GP2. Recrystallisation afforded the free lactone as co-
lourless crystals.
13C NMR (75 MHz, CDCl3): d = –5.8, –5.7, –5.1, –4.3, 17.9, 18.2,
25.7, 25.8, 38.9, 66.1, 75.0, 89.4, 115.3 (d, JC–F = 21.6 Hz, 2 C,
FCCH), 126.4 (d, JC–F = 7.7 Hz, 2 C, CCHCH), 135.9 (d, JC–F = 3.0
Hz, CCHCH), 162.5 (d, JC–F = 47.2 Hz, 1 C, CF), 173.6.
19F NMR (282 MHz, CDCl3): d = –114.0.
MS (CI): m/z (%) = 203 (100), 456 (5) [M + H+].
Yield: 0.101 g (99%); mp 125 °C; [a]D25 –6.9 (c 0.95, MeOH).
The resulting lactone (0.110 g, 0.53 mmol) was treated with
TBSOTf and py as described in GP2. The product (S,S)-4c could be
obtained after column chromatography (n-pentane–Et2O, 4:1) as
colourless crystals.
Anal. Calcd for C23H39FO4Si2: C, 60.75; H, 8.64. Found: C, 60.77;
H, 9.08.
(4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-(4-fluorophenyl)dihydrofuran-2(3H)-one
[(R,R)-4d]
25
Yield: 0.232 g (100%); mp 61 °C; [a]D +13.4 (c 0.83, CHCl3);
Rf = 0.7 (n-pentane–Et2O, 4:1).
IR (KBr): 2953, 2933, 2890, 2859, 1791, 1468, 1402, 1256, 1136,
1112, 1026, 938, 839, 781, 756, 705 cm–1.
The hydroxy ester (R,R)-3d (0.371 g, 1.09 mmol) was cyclised ac-
cording to GP2. Recrystallisation afforded the free lactone as co-
lourless crystals.
Yield: 0.245 g (99%); [a]D23 +8.3 (c 1.00, MeOH).
1H NMR (300 MHz, CDCl3): d = 0.00–0.02 (2 s, 6 H, SiCH3), 0.09–
0.11 (2s, 6 H, SiCH3), 0.87 [s, 9 H, C(CH3)3], 0.97 [s, 9 H, C(CH3)3],
2.66 (dd, J = 16.8, 7.9 Hz, 1 H, CH2CO), 2.88 (dd, J = 16.8, 7.9 Hz,
1 H, CH2CO), 3.75 (d, J = 10.6 Hz, 1 H, CH2OSi), 4.26 (d, J = 10.6
Hz, 1 H, CH2OSi), 4.53–4.58 (dd, J = 7.9, 7.9 Hz, 1 H, CHCH2CO),
7.31–7.47 (m, 5 H, HAr).
13C NMR (75 MHz, CDCl3): d = –5.8, –5.7, –5.1, –4.3, 17.9, 18.2,
25.7, 25.8, 39.0, 66.1, 75.0, 89.8, 124.5, 128.0, 128.4, 140.0, 173.9.
MS (CI): m/z (%) = 203 (100), 437 (17) [M + H+].
The resulting lactone (0.130 g, 0.58 mmol) was treated with
TBSOTf and py as described in GP2. The product (R,R)-4d could
be obtained after column chromatography (n-pentane–Et2O, 4:1) as
colourless crystals.
23
Yield: 0.214 g (81%); [a]D –9.85 (c 1.02, CHCl3); all other data
correspond with those of (S,S)-4d.
(4S,5S)-5-Allyl-4-(tert-butyldimethylsiloxy)-5-[(tert-butyl-
dimethylsiloxy)methyl]dihydrofuran-2(3H)-one [(S,S)-4e]
The hydroxy ester (S,S)-3e (0.141 g, 0.49 mmol) was cyclised ac-
cording to GP2. Recrystallisation afforded the free lactone as co-
lourless crystals.
Anal. Calcd for C23H40O4Si2: C, 63.25; H, 9.23. Found: C, 63.51; H,
9.29.
(4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-phenyldihydrofuran-2(3H)-one [(R,R)-4c]
The hydroxy ester (R,R)-3c (0.324 g, 1.00 mmol) was cyclised ac-
cording to GP2. Recrystallisation afforded the free lactone as co-
lourless crystals.
Yield: 0.084 g (99%); mp 69 °C; [a]D26 +2.8 (c 1.00, MeOH).
The resulting lactone (0.067 g, 0.39 mmol) was treated with
TBSOTf and py as described in GP2. The product (S,S)-4e could be
obtained after column chromatography (n-pentane–Et2O, 10:1) as
colourless crystals.
Yield: 0.208 g (99%); [a]D24 +9.6 (c 0.99, MeOH).
The resulting lactone (0.210 g, 1.00 mmol) was treated with
TBSOTf and py as described in GP2. The product (R,R)-4c could be
obtained after column chromatography (n-pentane–Et2O, 4:1) as
colourless crystals.
Yield: 0.390 g (89%); [a]D25 –9.1 (c 0.98, CHCl3); all other data cor-
respond with those of (S,S)-4c.
25
Yield: 0.118 g (75%); mp 47 °C; [a]D +11.96 (c 1.13, CHCl3);
Rf = 0.31 (n-pentane–Et2O, 10:1).
IR (KBr): 2957, 2933, 2896, 2859, 1788, 1469, 1257, 1231, 1134,
1071, 933, 883, 839, 777 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.06 (2s, 3 H, SiCH3), 0.07 (s, 3
H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.89 [s, 9 H, C(CH3)3], 0.90 [s, 9
H, C(CH3)3], 2.36 (d, J = 7.2 Hz, 2 H, CH2CHCH2), 2.65 (dd,
J = 17.1, 7.9 Hz, 1 H, CH2CO), 2.75 (dd, J = 17.1, 7.9 Hz, 1 H,
CH2CO), 3.62 (d, J = 10.6 Hz, 1 H, CH2OSi), 3.94 (d, J = 10.6 Hz,
1 H, CH2OSi), 4.35 (dd, J = 7.9, 7.9 Hz, 1 H, CHCH2CO), 5.10–
5.19 (m, 2 H, CH2CHCH2), 5.71–5.82 (m, 1 H, CH2CHCH2).
(4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-(4-fluorophenyl)dihydrofuran-2(3H)-one
[(S,S)-4d]
The hydroxy ester (S,S)-3d (0.188 g, 0.55 mmol) was cyclised ac-
cording to GP2. Recrystallisation afforded the free lactone as co-
lourless crystals.
13C NMR (75 MHz, CDCl3): d = –5.7, –5.6, –5.1, –4.5, 17.9, 18.2,
25.6, 25.8, 38.4, 38.9, 64.6, 71.6, 88.6, 119.7, 131.6, 174.3 (C-1).
Yield: 0.124 g (99%); mp 140 °C; [a]D25 –5.9 (c 0.97, MeOH).
The resulting lactone (0.104 g, 0.46 mmol) was treated with
TBSOTf and py as described in GP2. The product (S,S)-4d could be
MS (CI): m/z (%) = 269 (100), 403 (2) [M + H+].
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 4¢-Quaternary Nucleoside Analogues
1551
25
Anal. Calcd for C20H40O4Si2: C, 59.95; H, 10.06. Found: C, 59.52;
H, 10.13.
Yield: 0.372 g (82%); [a]D –13.3 (c 1.07, CHCl3); all other data
correspond with those of (S,S)-6a.
(4R,5R)-5-Allyl-4-(tert-butyldimethylsiloxy)-5-[(tert-butyl-
dimethylsiloxy)methyl]dihydrofuran-2(3H)-one [(R,R)-4e]
Hydroxy ester (R,R)-3e (0.437 g, 1.53 mmol) was cyclised accord-
ing to GP2. Recrystallisation afforded the free lactone as colourless
crystals.
(3S,4S)-3,5-Bis(tert-butyldimethylsiloxy)-4-hydroxy-4-methyl-
1-(1-naphthyl)-pentan-1-one [(S,S)-6b]
According to GP3, lactone (S,S)-4a (0.0.375 g, 1.00 mmol) was
treated with 1-NaphLi [freshly prepared by addition of t-BuLi (2
equiv) to a soln of 1-BrNaph in anhyd THF (5 mL/mmol) at –78 °C]
and CeCl3. Workup and column chromatography (n-pentane–Et2O,
6:1) gave pure product (S,S)-6b as a colourless oil.
Yield: 0.265 g (99%); [a]D24 –2.4 (c 1.03, MeOH).
The resulting lactone (0.830 g, 0.48 mmol) was treated with
TBSOTf and py as described in GP2. The product (R,R)-4e could be
obtained after column chromatography (n-pentane–Et2O, 4:1) as
colourless crystals.
23
Yield: 0.502 g (100%); [a]D –33.2 (c 1.57, CHCl3); Rf = 0.5 (n-
pentane–Et2O, 6:1).
IR (film): 2951, 2890, 2859, 1683, 1467, 1365, 1255, 1087, 839,
765, 670 cm–1.
22
Yield: 0.175 g (91%); [a]D –9.52 (c 1.04, CHCl3); all other data
correspond with those of (S,S)-4e.
1H NMR (400 MHz, CDCl3): d = 0.02 (s, 3 H, SiCH3), 0.07 (2s, 6
H, SiCH3), 0.19 (s, 3 H, SiCH3), 0.88 [s, 9 H, C(CH3)3], 0.91 [s, 9
H, C(CH3)3], 1.16 [s, 3 H, C(CH3)3], 2.62 (s, 1 H, OH), 3.16 (dd,
J = 17.3, 6.0 Hz, 1 H, CH2CO), 3.49 (dd, J = 17.3, 5.0 Hz, 1 H,
CH2CO), 3.54 (s, 2 H, CH2OSi), 4.67 (dd, J = 6.0, 5.0 Hz, 1 H,
CHCH2CO), 7.48–8.65 (m, 7 H, HAr).
13C NMR (100 MHz, CDCl3): d = –5.5, –5.4, –4.9, –4.1, 18.2, 18.2,
21.3, 25.9, 26.0, 45.6, 67.3, 71.8, 74.4, 124.1, 125.7, 126.2, 127.2,
127.7, 127.8, 128.2, 132.5, 130.0, 133.8, 136.0, 201.7.
Hydroxy Ketones 6a,b; General Procedure (GP3)
First, CeCl3·7H2O (2 equiv) was dried without stirring at 130 °C in
vacuo (ca. 0.05 mbar) for 1 h. It was subsequently ground by stirring
under these conditions for another 1 h. After cooling to r.t., the flask
was filled with argon, and anhyd THF (4 mL/mmol CeCl3) was add-
ed. The suspension was stirred for at least 1 h and then placed in an
ultrasound bath for another 1 h. The mixture was cooled to –78 °C,
and RLi in (n-Bu)2O (R = Ph) or n-pentane–THF (R = Naph) (2
equiv) was added dropwise. After the mixture had stirred at low
temperature for 2 h, a bright yellow colour indicated the formation
of the active cerium reagent. The mixture was then cooled to
–105 °C and lactone 4a was added in anhyd THF (5 mL/mmol),
while the temperature was carefully kept below –100 °C. After 30
min, the reaction mixture was allowed to warm to –99 °C and
quenched with H2O (10 mL/mmol). Extraction with CH2Cl2 (100
mL/mmol), followed by treatment with brine and drying (MgSO4)
provided the desired product 6, which could be purified by column
chromatography.
MS (CI): m/z (%) = 353 (100), 488 (6).
HRMS: m/z [M – OH]+ calcd for C28H45O3Si2: 485.291; found:
485.291.
Anal. Calcd for C28H46O4Si2: C, 66.88; H, 9.22. Found: C, 67.29; H,
9.03.
(3R,4R)-3,5-Bis(tert-butyldimethylsiloxy)-4-hydroxy-4-methyl-
1-(1-naphthyl)pentan-1-one [(R,R)-6b]
According to GP3, lactone (R,R)-4a (0.375 g, 1.00 mmol) was treat-
ed with 1-NaphLi [freshly prepared by addition of t-BuLi (2 equiv)
to a soln of 1-BrNaph in anhyd THF (5 mL/mmol) at –78 °C] and
CeCl3. Workup and column chromatography (n-pentane–Et2O, 6:1)
gave the pure product (R,R)-6b as a colourless oil.
Yield: 0.502 g (100%); [a]D25 +19.5 (c 2.09, CHCl3); all other data
correspond with those of (S,S)-6b.
(3S,4S)-3,5-Bis(tert-butyldimethylsiloxy)-4-hydroxy-4-methyl-
1-phenylpentan-1-one [(S,S)-6a]
According to GP3, lactone (S,S)-4a (0.375 g, 1.00 mmol) was treat-
ed with PhLi and CeCl3. Workup and column chromatography (n-
pentane–Et2O, 6:1) gave pure product (S,S)-6a as a colourless oil.
Yield: 0.246 g (54%); [a]D24 +5.6 (c 0.65, CHCl3); Rf = 0.6 (n-pen-
tane–Et2O, 4:1).
TBS-Protected C-Nucleosides 7a,b; General Procedure (GP4)
A suspension of Me4N+[HB(OAc)3]– (3 equiv) in anhyd MeCN (5
mL/mmol) was treated with anhyd AcOH (5 mL/mmol) under an
argon atmosphere. The resulting soln was cooled to –30 °C and add-
ed to a soln of the appropriate hydroxy ketone 6 in anhyd MeCN
(2.5 mL/mmol). The reaction was left overnight at –26 °C. Quench-
ing of the reaction with a soln of Na/K tartrate in H2O (10 mL/
mmol) led to a precipitate, which was dissolved by the addition of
sat. aq Na2CO3. The aqueous phase was extracted with Et2O (100
mL/mmol) and the combined organic layers were washed with brine
and dried (MgSO4). The cyclised products 7 were purified by col-
umn chromatography.
IR (film): 2932, 2859, 1689, 1468, 1367, 1255, 1088, 941, 838, 778,
691, 672 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.08 (s, 6 H, SiCH3), 0.15 (s, 3 H,
SiCH3), 0.16 (s, 3 H, SiCH3), 0.92 [s, 9 H, C(CH3)3], 1.00 [s, 9 H,
C(CH3)3], 1.20 (s, 3 H, CCH3), 2.69 (s, 1 H, OH), 3.11 (dd, J = 17.3,
6.3 Hz, 1 H, CH2CO), 3.49 (dd, J = 17.3, 4.4 Hz, 1 H, CH2CO), 3.59
(d, J = 9.6 Hz, 1 H, CH2OSi), 3.63 (d, J = 9.6 Hz, 1 H, CH2OSi),
4.67 (dd, J = 6.3, 4.4 Hz, 1 H, CHCH2CO), 7.52–7.55 (m, 2 H,
CCHCH), 7.62–7.65 (m, 1 H, CCHCHCH), 8.04–8.06 (m, 2 H,
CCHCH).
13C NMR (100 MHz, CDCl3): d = –5.5, –5.4, –4.9, –4.3, 18.1, 21.1,
25.9, 26.0, 42.0, 67.3, 71.6, 74.4, 128.0, 128.4, 132.8, 137.1, 198.1.
(2S,3S,5S)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-methyl-5-phenyltetrahydrofuran [(S,S,S)-7a]
The hydroxy ketone (S,S)-6a (0.074 g, 0.16 mmol) was treated with
Me4N+[HB(OAc)3]– according to GP4. The pure TBS-protected C-
nucleoside (S,S,S)-7a was obtained as a colourless oil after workup
and column chromatography (n-pentane–Et2O, 40:1).
MS (CI): m/z (%) = 435 (100), 437 (12).
Anal. Calcd for C24H44O4Si2: C, 63.66; H, 9.80. Found: C, 63.95; H,
10.05.
(3R,4R)-3,5-Bis(tert-butyldimethylsiloxy)-4-hydroxy-4-methyl-
1-phenylpentan-1-one [(R,R)-6a]
Yield: 0.046 g (69%); [a]D25 +7.2 (c 1.40, CHCl3); Rf = 0.5 (n-pen-
tane–Et2O, 40:1).
According to GP4, lactone (R,R)-4a (0.375 g, 1.00 mmol) was treat-
ed with PhLi and CeCl3. Workup and column chromatography (n-
pentane–Et2O, 6:1) gave pure product (R,R)-6a as a colourless oil.
IR (film): 2932, 2888, 2858, 1466, 1363, 1255, 1098, 1028, 941,
838, 777, 698, 673 cm–1.
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

1552
D. Enders et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 0.01 (s, 6 H, SiCH3), 0.07 (s, 6 H,
SiCH3), 0.86 [s, 9 H, C(CH3)3], 0.91 [s, 9 H, C(CH3)3], 1.21 (s, 3 H,
CH3), 1.99 (ddd, J = 12.9, 7.4, 5.4 Hz, 1 H, CCHCH2CH), 2.58
(ddd, J = 12.9, 7.7, 5.7 Hz, 1 H, CCHCH2CH), 3.69 (d, J = 10.1 Hz,
1 H, CH2OSi), 3.82 (d, J = 10.1 Hz, 1 H, CH2OSi), 4.16 (dd, J = 5.7,
5.7 Hz, 1 H, CCHCH2CH), 5.02 (dd, J = 7.7, 7.7 Hz, 1 H,
CCHCH2CH), 7.20–7.46 (m, 5 H, HAr).
evaporation with MeOH. Column chromatography gave pure prod-
ucts 8.
(2S,3S,5S)-2-(Hydroxymethyl)-2-methyl-5-phenyltetrahydro-
furan-3-ol [(S,S,S)-8a]
As described in GP5, silyl ether (S,S,S)-7a (0.046 g, 0.11 mmol)
was desilylated in TFA–CHCl3. After column chromatography
(Et2O), the free nucleoside (S,S,S)-8a was obtained as a colourless
foam.
13C NMR (75 MHz, CDCl3): d = –5.4, –5.1, –4.7, 18.0, 18.5, 21.5,
25.7, 26.1, 43.9, 66.2, 77.0, 78.2, 85.3, 126.2, 128.1, 127.0, 143.8.
Yield: 0.008 g (35%); the analytical data correspond with those of
(R,R,R)-8a.
MS (EI): m/z (%) = 231 (100), 437 (1) [M + H+].
Anal. Calcd for C24H44O3Si2: C, 66.00; H, 10.15. Found: C, 65.65;
H, 10.15.
(2R,3R,5R)-2-(Hydroxymethyl)-2-methyl-5-phenyltetrahydro-
furan-3-ol [(R,R,R)-8a]
(2R,3R,5R)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-methyl-5-phenyltetrahydrofuran [(R,R,R)-7a]
The hydroxy lactone (R,R)-6a (0.158 g, 0.35 mmol) was treated
with Me4N+[HB(OAc)3]– according to GP4. The pure TBS-protect-
ed C-nucleoside (R,R,R)-7a was obtained as a colourless oil after
workup and column chromatography (n-pentane–Et2O, 40:1).
As described in GP5, the silyl ether (R,R,R)-7a (0.111 g, 0.25
mmol) was desilylated in TFA–CHCl3. After column chromatogra-
phy (Et2O), the free nucleoside (R,R,R)-8a was obtained as a colour-
less foam.
Yield: 0.034 g (65%); [a]D23 +17.0 (c 0.24, CHCl3); Rf = 0.5 (Et2O).
IR (KBr): 3502, 3363, 2920, 2868, 1496, 1457, 1370, 1209, 1067,
1009, 938, 906, 753, 698, 619 cm–1.
Yield: 0.108 g (70%); [a]D25 –6.8 (c 1.03, CHCl3); all other data cor-
respond with those of (S,S,S)-7a.
1H NMR (400 MHz, CDCl3): d = 1.24 (s, 3 H, CH3), 1.97 (ddd,
J = 12.9, 9.6, 4.9 Hz, 1 H, CH2CH), 2.67 (s, 1 H, OH), 2.70 (dd,
J = 12.9, 6.3 Hz, 1 H, CH2CH), 3.79 (s, 2 H, CH2OH), 4.28 (dd,
J = 14.0, 7.1 Hz, 1 H, CHOH), 4.94 (dd, J = 9.6, 6.3 Hz, 1 H,
CHCH2CHOH), 7.26–7.42 (m, 5 H, HAr)
13C NMR (100 MHz, CDCl3): d = 21.9, 44.7, 66.9, 76.7, 79.8, 83.5,
126.0, 127.7, 128.3, 141.2.
(2S,3S,5S)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-methyl-5-(1-naphthyl)tetrahydrofuran
[(S,S,S)-7b]
The hydroxy lactone (S,S)-6b (0.328 g, 0.67 mmol) was treated with
Me4N+[HB(OAc)3]– according to GP4. The pure TBS-protected C-
nucleoside (S,S,S)-7b was obtained as a colourless oil after workup
and column chromatography (n-pentane–Et2O, 40:1).
MS (EI): m/z (%) = 177 (100), 209 (1) [M + H+].
HRMS: m/z [M]+ calcd for C12H16O3: 208.110; found: 208.110.
25
Yield: 0.215 g (66%); [a]D –42.1 (c 1.06, CHCl3); all other data
correspond with those of (R,R,R)-7b.
(2S,3S,5S)-2-(Hydroxymethyl)-2-methyl-5-(1-naphthyl)tetra-
hydrofuran-3-ol [(S,S,S)-8b]
As described in GP5, the silyl ether (S,S,S)-7b (0.215 g, 0.44 mmol)
was desilylated in TFA–CHCl3. After column chromatography
(Et2O), the free nucleoside (S,S,S)-8b was obtained as colourless
crystals.
(2R,3R,5R)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-methyl-5-(1-naphthyl)tetrahydrofuran
[(R,R,R)-7b]
The hydroxy lactone (R,R)-6b (0.502 g, 1.00 mmol) was treated
with Me4N+[HB(OAc)3]– according to GP4. The pure TBS-protect-
ed C-nucleoside (R,R,R)-7b was obtained as a colourless oil after
workup and column chromatography (n-pentane–Et2O, 40:1).
Yield: 0.061 g (54%); [a]D22 –25.0 (c 0.96, CHCl3); all other analyt-
ical data correspond with those of (R,R,R)-8b.
Yield: 0.451 g (93%); [a]D24 +43.9 (c 0.95, CHCl3); Rf = 0.5 (n-pen-
tane–Et2O, 40:1).
(2R,3R,5R)-2-(Hydroxymethyl)-2-methyl-5-(1-naphthyl)tetra-
hydrofuran-3-ol [(R,R,R)-8b]
As described in GP5, the silyl ether (R,R,R)-7b (0.240 g, 0.49
mmol) was desilylated in TFA–CHCl3. After column chromatogra-
phy (Et2O), the free nucleoside (R,R,R)-8b was obtained as colour-
less crystals.
IR (CHCl3): 2953, 2931, 2886, 2858, 1467, 1255, 1217, 1100, 840,
760 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.12 (s, 3 H, SiCH3), 0.17 (s, 3 H,
SiCH3), 0.23 (s, 6 H, SiCH3), 0.91 [s, 9 H, C(CH3)3], 1.06 [s, 9 H,
C(CH3)3], 1.48 (s, 3 H, CH3), 2.01 (ddd, J = 12.8, 7.2, 5.6 Hz, 1 H,
CCHCH2CH), 2.90 (ddd, J = 12.8, 7.6, 6.0 Hz, 1 H, CCHCH2CH),
3.83 (d, J = 10.2 Hz, 1 H, CH2OSi), 3.94 (d, J = 10.2 Hz, 1 H,
CH2OSi), 4.28 (dd, J = 6.0, 5.6 Hz, 1 H, CCHCH2CH), 5.81 (dd,
J = 7.6, 7.2 Hz, 1 H, CCHCH2CH), 7.46–7.99 (m, 7 H, HAr).
13C NMR (100 MHz, CDCl3): d = –5.3, –5.3, –5.1, –4.7, 17.9, 18.4,
21.5, 25.6, 26.0, 42.9, 65.9, 74.4, 78.0, 85.0, 122.6, 122.9, 124.8,
125.3, 125.5, 126.9, 128.6, 129.8, 133.3, 139.3.
25
Yield: 0.076 g (60%); mp 118 °C; [a]D +26.3 (c 0.99, CHCl3);
Rf = 0.5 (Et2O).
IR (KBr): 3517, 3325, 2962, 2913, 2862, 1508, 1435, 1373, 1340,
1283, 1220, 1101, 1055, 1016, 939, 913, 860, 778, 490 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.35 (s, 3 H, CH3), 2.05 (ddd,
J = 12.9, 9.3, 6.6 Hz, 1 H, CH2CH), 2.42 (t, J = 6.2 Hz, 1 H,
CH2OH), 2.91 (ddd, J = 12.9, 6.6, 6.3 Hz, 1 H, CH2CH), 2.99 (d,
J = 14.5 Hz, 1 H, CHOH), 3.87 (d, J = 6.2 Hz, 2 H, CH2OH), 4.36
(dd, J = 14.5, 6.59 Hz, 1 H, CHOH), 5.67 (dd, J = 9.3, 6.3 Hz, 1 H,
CHCH2CHOH), 7.45–7.99 (m, 7 H, HAr).
MS (CI): m/z (%) = 167 (100), 488 (4) [M + H+].
Anal. Calcd for C28H46O3Si2: C, 69.08; H, 9.52. Found: C, 69.50; H,
9.71.
13C NMR (100 MHz, CDCl3): d = 22.0, 43.7, 66.9, 73.3, 79.7, 83.6,
121.7, 123.1, 125.4, 125.9, 127.9, 128.6, 130.5, 133.5, 137.1.
MS (EI): m/z (%) = 258 (100), 259 (17) [M + H+].
Free C-Nucleosides 8a,b; General Procedure (GP5)
A TFA–CHCl3 mixture (4:1, 2.5 mL/mmol) was slowly added to
the appropriate TBS-protected nucleoside 7 in CHCl3 (6 mL/mmol)
at 0 °C. When the reaction was completed, the solvent was evapo-
rated under reduced pressure. Traces of TFA were removed by co-
Anal. Calcd for C16H18O3: C, 74.39; H, 7.02. Found: C, 74.36; H,
7.19.
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 4¢-Quaternary Nucleoside Analogues
1553
Acylated Lactols 9a–e; General Procedure (GP6)
13C NMR (100 MHz, CDCl3): d = –5.5, –5.4, –5.0, –4.5, 7.7, 17.9,
The appropriate lactone, one of 4a–e, was dissolved in anhyd
CH2Cl2 (10 mL/mmol), and at –78 °C DIBAL-H (1.05 equiv) was
added dropwise. After the reaction was completed, it was quenched
with a sat. soln of Na/K tartrate in H2O (20 mL/mmol) and a pH 7
buffer (20 mL/mmol). After extraction of the mixture with CH2Cl2,
treatment with brine, and drying (MgSO4), the oily residue was dis-
solved in py, and Ac2O was added at r.t. Stirring overnight and sub-
sequent evaporation of the solvents led to products 9a–e, which
could be purified by column chromatography.
18.2, 21.4, 25.7, 25.9, 27.1, 41.3, 64.3, 73.3, 88.6, 97.3, 170.2.
MS (CI): m/z (%) = 241 (100), 432 (0.1) [M]+.
Anal. Calcd for C21H44O5Si2: C, 58.29; H, 10.25. Found: C, 58.58;
H, 10.39
(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-ethyltetrahydrofuran-2-yl Acetate [(R,R,R)-
9b]
According to GP6, lactone (R,R)-4b (0.260 g, 0.67 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (R,R,R)-9b was obtained as a co-
lourless oil.
(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-methyltetrahydrofuran-2-yl Acetate [(S,S,S)-
9a]
Yield: 0.156 g (54%); [a]D22 +35.3 (c 1.43, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-9b.
According to GP6, lactone (S,S)-4a (0.331 g, 0.87 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (S,S,S)-9a was obtained as a co-
lourless oil.
(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-phenyltetrahydrofuran-2-yl Acetate [(S,S,S)-
9c]
According to GP6, lactone (S,S)-4c (0.192 g, 0.44 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (S,S,S)-9c was obtained as a co-
lourless oil.
25
Yield: 0.270 g (74%); [a]D +30.15 (c 1.28, CHCl3); Rf = 0.5 (n-
pentane–Et2O, 10:1).
IR (film): 2954, 2894, 2859, 1746, 1468, 1372, 1253, 1113, 1011,
974, 843, 774 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.05 (2 s, 6 H, SiCH3), 0.07 (s, 3
H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.89 [s, 18 H, C(CH3)3], 1.23 (s, 3
H, CCH3), 2.04 (s, 3 H, CH3CO), 2.16 (ddd, J = 13.2, 6.9, 1.9 Hz, 1
H, CH2CH), 2.40 (ddd, J = 13.2, 6.9, 5.8 Hz, 1 H, CH2CH), 3.56 (d,
J = 10.2 Hz, 1 H, CH2OSi), 3.64 (d, J = 10.2 Hz, 1 H, CH2OSi),
4.20 (dd, J = 6.9, 6.9 Hz, 1 H, CHOH), 6.29 (dd, J = 5.8, 1.9 Hz, 1
H, CHCH2CHOH).
13C NMR (100 MHz, CDCl3): d = –5.5, –5.4, –5.0, –4.7, 18.0, 18.3,
21.4, 22.7, 25.7, 25.9, 41.5, 65.8, 76.2, 86.7, 97.6, 170.2.
MS (CI): m/z (%) = 227 (100), 421 (2) [M + 2]+.
Yield: 0.200 g (95%); [a]D24 –19.2 (c 1.17, CHCl3); Rf = 0.4 (n-pen-
tane–Et2O, 10:1).
IR (film): 2954, 2932, 2891, 2858, 1748, 1468, 1367, 1253, 1113,
1010, 959, 940, 841, 777, 703 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.07 (s, 6 H, SiCH3), 0.16 (s, 3 H,
SiCH3), 0.18 (s, 3 H, SiCH3), 0.92 [s, 18 H, C(CH3)3], 2.06 (s, 3 H,
CH3CO), 2.16 (ddd, J = 12.6, 6.9, 1.7 Hz, 1 H, CH2CH), 2.62 (ddd,
J = 12.6, 8.2, 5.4 Hz, 1 H, CH2CH), 3.71 (d, J = 10.4 Hz, 1 H,
CH2OSi), 4.07 (d, J = 10.4 Hz, 1 H, CH2OSi), 4.65 (dd, J = 8.2, 6.9
Hz, 1 H, CHOSi), 6.53 (dd, J = 5.4, 1.7 Hz, 1 H, CHCH2CHOSi),
7.32–7.52 (m, 5 H, HAr).
Anal. Calcd for C20H42O5Si2: C, 57.37; H, 10.11. Found: C, 57.31;
H, 10.13.
13C NMR (100 MHz, CDCl3): d = –5.6, –5.0, –4.3, 17.9, 18.2, 21.3,
25.7, 25.9, 41.0, 66.7, 77.2, 89.4, 97.5, 124.8, 126.9, 127.6, 143.2,
170.2.
(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-methyltetrahydrofuran-2-yl Acetate [(R,R,R)-
9a]
According to GP6, lactone (R,R)-4a (3.057 g, 8.16 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (R,R,R)-9a was obtained as a co-
lourless oil.
MS (CI): m/z (%) = 289 (100), 479 (1) [M – H+].
Anal. Calcd for C25H44O5Si2: C, 62.45; H, 9.22. Found: C, 62.80; H,
8.91.
Yield: 1.843 g (54%); [a]D25 –21.54 (c 1.28, CHCl3); all other ana-
lytical data correspond with those of (S,S,S)-9a.
(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-phenyltetrahydrofuran-2-yl Acetate [(R,R,R)-
9c]
According to GP6, lactone (R,R)-4c (0.380 g, 0.87 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (R,R,R)-9c was obtained as a co-
lourless oil.
Yield: 0.261 g (62%); [a]D24 +27.5 (c 1.44, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-9c.
(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-ethyltetrahydrofuran-2-yl Acetate [(S,S,S)-9b]
According to GP6, lactone (S,S)-4b (0.191 g, 0.49 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (S,S,S)-9b was obtained as a co-
lourless oil.
25
Yield: 0.132 g (62%); [a]D –34.38 (c 1.44, CHCl3); Rf = 0.3 (n-
(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-(4-fluorophenyl)tetrahydrofuran-2-yl Acetate
[(S,S,S)-9d]
According to GP6, lactone (S,S)-4d (0.049 g, 0.11 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (S,S,S)-9d was obtained as a co-
lourless oil.
pentane–Et2O, 10:1).
IR (film): 2935, 2892, 2859, 1747, 1468, 1371, 1253, 1114, 988,
958, 884, 843, 775 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.04 (2 s, 6 H, SiCH3), 0.07 (s, 3
H, SiCH3), 0.08 (s, 3 H, SiCH3), 0.89 [m, 21 H, C(CH3)3, CH3CH2],
1.55 (m, 2 H, CH3CH2), 2.03 (s, 3 H, CH3CO), 2.12 (ddd, J = 12.9,
7.7, 1.2 Hz, 1 H, CH2CH), 2.43 (ddd, J = 12.9, 7.7, 5.5 Hz, 1 H,
CH2CH), 3.53 (d, J = 10.3 Hz, 1 H, CH2OSi), 7.37 (d, J = 10.3 Hz,
1 H, CH2OSi), 4.30 (dd, J = 7.7, 7.7 Hz, 1 H, CHOSi), 6.27 (dd,
J = 5.5, 1.2 Hz, 1 H, CHCH2CHOSi).
Yield: 0.035 g (64%); [a]D22 –22.9 (c 0.72, CHCl3); Rf = 0.3 (n-pen-
tane–Et2O, 10:1).
IR (CHCl3): 2952, 2893, 2860, 1749, 1604, 1510, 1468, 1369, 1251,
1113, 1011, 942, 844, 778, 670, 558 cm–1.
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

1554
D. Enders et al.
PAPER
1H NMR (400 MHz, CDCl3): d = 0.07 (s, 6 H, SiCH3), 0.16 (s, 3 H,
SiCH3), 0.18 (s, 3 H, SiCH3), 0.91 [s, 9 H, C(CH3)3], 1.03 [s, 9 H,
C(CH3)3], 2.07 (s, 3 H, CH3CO), 2.16 (ddd, J = 12.6, 6.9, 1.7 Hz, 1
H, CH2CH), 2.59 (ddd, J = 12.6, 8.0, 5.2 Hz, 1 H, CH2CH), 3.71 (d,
J = 10.4 Hz, 1 H, CH2OSi), 4.00 (d, J = 10.4 Hz, 1 H, CH2OSi),
4.60 (dd, J = 8.0, 6.9 Hz, 1 H, CHOSi), 6.52 (dd, J = 5.2, 1.7 Hz, 1
H, CHCH2CHOSi), 7.04–7.09 (m, 2 H, FCCHCH), 7.45–7.49 (m, 2
H, FCCH).
Phenyl Sulfides 10a–e; General Procedure (GP7)
BF3·OEt2 (5.0 equiv) and TMSSPh (10.0 equiv) were slowly added
to a soln of the appropriate acylated lactol, one of 9a–e, in n-hexane
at –95 °C. The mixture was warmed to r.t. overnight and subse-
quently quenched with sat. aq NaHCO3 (10 mL/mmol). Extraction
with Et2O (50 mL/mmol), treatment with brine, and drying
(MgSO4) gave products 10a–e as anomeric mixtures, which were
purified by column chromatography.
13C NMR (100 MHz, CDCl3): d = –5.6, –5.0, –4.3, 17.9, 18.2, 21.3,
25.7, 25.9, 41.0, 66.6, 76.8, 89.2, 97.5, 114.4 (d, JC–F = 20.6 Hz, 2
C, FCCH), 126.6 (d, JC–F = 7.6 Hz, 2 C, FCCHCH), 139.0 (d,
JC–F = 3.0, 1 C, FCCHCHC), 161.78 (d, JC–F = 244.1, 1 C, FC),
170.1.
(2S,3S,5R)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-methyl-5-(phenylsulfanyl)tetrahydrofuran
[(S,S,R)-10a]
The nucleophilic substitution was carried out with lactol (S,S,S)-9a
(0.468 g, 1.12 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (S,S,R)-10a was character-
ised.
MS (CI): m/z (%) = 307 (100), 497 (1) [M – H+].
Anal. Calcd for C25H43FO5Si2: C, 60.20; H, 8.69. Found: C, 60.35;
H, 8.88.
Yield: 0.452 g (86%); Rf = 0.4 (n-pentane–Et2O, 20:1).
(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimethyl-
siloxy)methyl]-5-(4-fluorophenyl)tetrahydrofuran-2-yl Acetate
[(R,R,R)-9d]
IR (film): 3639, 2936, 2860, 1470, 1255, 1099, 1010, 938, 839,
777, 744 cm–1.
According to GP6, lactone (R,R)-4d (0.222 g, 0.49 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (R,R,R)-9d was obtained as a co-
lourless oil.
Yield: 0.180 g (74%); [a]D22 +28.8 (c 0.94, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-9d.
1H NMR (500 MHz, CDCl3): d = 0.07 (s, 6 H, SiCH3), 0.89 (s, 3 H,
SiCH3), 0.10 (s, 3 H, SiCH3), 0.92 [s, 9 H, C(CH3)3], 0.94 [s, 9 H,
C(CH3)3], 1.19 (s, 3 H, CH3C), 2.15 (ddd, J = 13.4, 4.6, 4.3 Hz, 1 H,
CH2CH), 2.69 (ddd, J = 13.4, 7.6, 6.1 Hz, 1 H, CH2CH), 3.78 (d,
J = 10.2 Hz, 1 H, CH2OSi), 3.85 (d, J = 10.2 Hz, 1 H, CH2OSi),
4.07 (dd, J = 6.1, 4.3 Hz, 1 H, CHOSi), 5.57 (dd, J = 7.6, 4.6 Hz, 1
H, CHCH2CHOSi), 7.19 (m, 1 H, HAr), 7.25–7.53 (m, 4 H, HAr).
(2S,4S,5S)-5-Allyl-4-(tert-butyldimethylsiloxy)-5-[(tert-butyl-
dimethylsiloxy)methyl]tetrahydrofuran-2-yl Acetate [(S,S,S)-
9e]
According to GP6, lactone (S,S)-4e (0.205 g, 0.51 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (S,S,S)-9e was obtained as a co-
lourless oil.
13C NMR (75 MHz, CDCl3): d = –5.3, –5.1, –4.6, 15.3, 18.5, 22.5,
25.8, 29.1, 42.3, 66.0, 77.0, 86.1, 87.6, 126.4, 128.7, 130.7, 135.0.
MS (CI): m/z (%) = 227 (100), 469 (0.2) [M]+.
Anal. Calcd for C24H44O3SSi2: C, 61.48; H, 9.46. Found: C, 61.74;
H, 9.69.
(2R,3R,5S)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-methyl-5-(phenylsulfanyl)tetrahydrofuran
[(R,R,S)-10a]
Yield: 0.167 g (74%); [a]D22 –33.5 (c 2.32, CHCl3); Rf = 0.4 (n-pen-
tane–Et2O, 10:1).
IR (film): 2954, 2932, 2892, 2858, 1751, 1469, 1371, 1254, 1115,
1002, 963, 841, 778 cm–1.
The nucleophilic substitution was carried out with lactol (R,R,R)-9a
(0.848 g, 2.03 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (R,R,S)-10a was character-
ised; all analytical data correspond with those of (S,S,R)-10a.
1H NMR (300 MHz, CDCl3): d = 0.05 (s, 6 H, SiCH3), 0.62 (s, 3 H,
SiCH3), 0.72 (s, 3 H, SiCH3), 0.89 [s, 9 H, C(CH3)3], 0.90 [s, 9 H,
C(CH3)3], 2.04 (s, 3 H, CH3CO), 2.12 (ddd, J = 12.9, 7.2, 1.2 Hz, 1
H, CH2CHOSi), 2.29 (m, 2 H, CCH2CHCH2), 2.42 (ddd, J = 12.9,
8.2, 5.7 Hz, 1 H, CH2CHOSi), 3.52 (d, J = 10.6 Hz, 1 H, CH2OSi),
3.69 (d, J = 10.6 Hz, 1 H, CH2OSi), 4.33 (dd, J = 8.2, 7.2 Hz, 1 H,
CHOSi), 5.10 (m, 2 H, CCH2CHCH2), 5.81 (m, 1 H, CCH2CHCH2),
6.28 (dd, J = 5.7, 1.2 Hz, 1 H, CHCH2CHOSi).
Yield: 0.933 g (98%).
(2S,3S,5R)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-ethyl-5-(phenylsulfanyl)tetrahydrofuran
[(S,S,R)-10b]
The nucleophilic substitution was carried out with lactol (S,S,S)-9b
(0.132 g, 0.31 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (S,S,R)-10b was character-
ised.
13C NMR (75 MHz, CDCl3): d = –5.5, –5.0, –4.5, 17.9, 18.3, 21.4,
25.7, 26.0, 39.3, 41.2, 65.0, 73.4, 87.9, 97.4, 117.9, 133.6, 170.30.
MS (CI): m/z (%) = 253 (100), 445 (1) [M + H+].
Anal. Calcd for C22H44O5Si2: C, 59.41; H, 9.97. Found: C, 59.47; H,
9.94.
Yield: 0.148 g (99%); Rf = 0.5 (n-pentane–Et2O, 20:1).
IR (film): 3420, 2932, 2858, 1583, 1469, 1385, 1255, 1097, 1040,
917, 842, 777, 741, 690, 485 cm–1.
(2R,4R,5R)-5-Allyl-4-(tert-butyldimethylsiloxy)-5-[(tert-butyl-
dimethylsiloxy)methyl]tetrahydrofuran-2-yl Acetate [(R,R,R)-
9e]
According to GP6, lactone (R,R)-4e (0.146 g, 0.36 mmol) was re-
duced and acylated. After workup and column chromatography (n-
pentane–Et2O, 10:1), pure product (R,R,R)-9e was obtained as a co-
lourless oil.
1H NMR (400 MHz, CDCl3): d = 0.06 (s, 6 H, SiCH3), 0.08 (s, 3 H,
SiCH3), 0.09 (s, 3 H, SiCH3), 0.91 [s, 9 H, C(CH3)3], 0.89 (t, J = 7.2
Hz, 3 H, CH3CH2), 0.93 [s, 9 H, C(CH3)3], 1.56 (m, 2 H, CH3CH2),
2.13 (ddd, J = 13.5, 4.5, 4.0 Hz, 1 H, CH2CHOSi), 2.62 (ddd,
J = 13.5, 7.4, 6.0 Hz, 1 H, CH2CHOSi), 3.75 (d, J = 10.7 Hz, 1 H,
CH2OSi), 3.92 (d, J = 10.7 Hz, 1 H, CH2OSi), 4.16 (dd, J = 6.1, 4.0
Hz, 1 H, CHOSi), 5.54 (dd, J = 7.4, 4.5 Hz, 1 H, CHCH2CHOSi),
7.18–7.54 (m, 5 H, HAr)
Yield: 0.102 g (64%); [a]D22 +40.1 (c 0.89, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-9e.
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 4¢-Quaternary Nucleoside Analogues
1555
13C NMR (100 MHz, CDCl3): d = –5.3, –5.1, –4.5, 8.3, 18.0, 18.4,
25.7, 26.0, 27.3, 42.7, 64.0, 74.7, 86.0, 89.9, 126.1, 128.4, 130.4,
137.3.
MS (CI): m/z (%) = 241 (100), 482 (0.1) [M]+.
HRMS: m/z [M – C4H9]+ calcd for C21H37O3SSi2: 425.200; found:
1H NMR (400 MHz, CDCl3): d = 0.02 (s, 3 H, SiCH3), 0.05 (s, 3 H,
SiCH3), 0.28 (s, 3 H, SiCH3), 0.29 (s, 3 H, SiCH3), 0.98 [s, 9 H,
C(CH3)3], 1.11 [s, 9 H, C(CH3)3], 2.22 (ddd, J = 12.9, 6.9, 5.2 Hz, 1
H, CH2CHOSi), 2.65 (ddd, J = 12.9, 6.9, 4.7 Hz, 1 H, CH2CHOSi),
3.94 (d, J = 10.2 Hz, 1 H, CH2OSi), 4.29 (d, J = 10.2 Hz, 1 H,
CH2OSi), 4.63 (dd, J = 6.9, 5.2 Hz, 1 H, CHOSi), 6.03 (dd, J = 6.9,
6.9 Hz, 1 H, CHS), 7.14–7.77 (m, 9 H, HAr).
425.200.
13C NMR (100 MHz, CDCl3): d = –5.8, –5.6, –5.0, –4.5, 18.0, 18.3,
25.7, 25.9, 41.5, 66.3, 76.8, 85.6, 90.6, 114.1 (d, JC–F = 20.6 Hz, 2
C, FCCH), 126.5, 127.3 (d, JC–F = 8.4 Hz, 2 C, FCCHCH), 128.7,
130.4, 135.8, 138.4 (d, JC–F = 3.1 Hz, 1 C, FCCHCHC), 162.8 (d,
JC–F = 244.9 Hz, 1 C, FC).
(2R,3R,5S)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-ethyl-5-(phenylsulfanyl)tetrahydrofuran
[(R,R,S)-10b]
The nucleophilic substitution was carried out with lactol (R,R,R)-9b
(0.156 g, 0.36 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (R,R,S)-10b was character-
ised; all analytical data correspond with those of (S,S,R)-10b.
MS (CI): m/z (%) = 307 (100), 549 (1) [M]+.
Anal. Calcd for C29H45FO3SSi2: C, 63.46; H, 8.26. Found: C, 63.47;
H, 8.15.
Yield: 0.169 g (97%).
(2R,3R,5S)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-(4-fluorophenyl)-5-(phenylsulfanyl)tetrahy-
drofuran [(R,R,S)-10d]
The nucleophilic substitution was carried out with lactol (R,R,R)-9d
(0.180 g, 0.36 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (R,R,S)-10d was character-
ised; all analytical data correspond with those of (S,S,R)-10d.
(2S,3S,5R)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-phenyl-5-(phenylsulfanyl)tetrahydrofuran
[(S,S,R)-10c]
The nucleophilic substitution was carried out with lactol (S,S,S)-9c
(0.030 g, 0.06 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (S,S,R)-10c was character-
ised.
Yield: 0.197 g (99%).
Yield: 0.033 g (99%); Rf = 0.7 (n-pentane–Et2O, 20:1).
(2S,3S,5R)-2-Allyl-3-(tert-butyldimethylsiloxy)-2-[(tert-butyl-
dimethylsiloxy)methyl]-5-(phenylsulfanyl)tetrahydrofuran
[(S,S,R)-10e]
The nucleophilic substitution was carried out with lactol (S,S,S)-9e
(0.167 g, 0.38 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (S,S,R)-10e was character-
ised.
IR (film): 2953, 2888, 2857, 1582, 1474, 1254, 1191, 1136, 1109,
940, 840, 778, 740, 697 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.00 (s, 3 H, SiCH3), 0.04 (s, 3 H,
SiCH3), 0.27 (s, 3 H, SiCH3), 0.29 (s, 3 H, SiCH3), 0.98 [s, 9 H,
C(CH3)3], 1.11 [s, 9 H, C(CH3)3], 2.25 (ddd, J = 12.9, 6.7, 5.2 Hz, 1
H, CH2CHOSi), 2.67 (ddd, J = 12.9, 6.7, 5.2 Hz, 1 H, CH2CHOSi),
3.99 (d, J = 10.1 Hz, 1 H, CH2OSi), 4.03 (d, J = 10.1 Hz, 1 H,
CH2OSi), 4.66 (dd, J = 5.2, 5.2 Hz, 1 H, CHOSi), 6.04 (dd,
J = 6.7,6.7 Hz 1 H, CHS), 7.37–7.77 (m, 10 H, HAr)
Yield: 0.127 g (68%); Rf = 0.5 (n-pentane–Et2O, 20:1).
IR (film): 2933, 2858, 1469, 1440, 1386, 1255, 1100, 1009, 920,
841, 777, 743, 692 cm–1.
13C NMR (100 MHz, CDCl3): d = –5.8, –5.6, –5.0, –4.5, 18.0, 18.3,
25.8, 25.9, 41.6, 66.5, 76.9, 85.6, 90.8, 125.9, 126.4, 126.8, 127.4,
128.6, 130.5, 137.5, 142.6.
1H NMR (400 MHz, CDCl3): d = 0.06 (s, 9 H, SiCH3), 0.08 (s, 3 H,
SiCH3), 0.92 [s, 9 H, C(CH3)3], 0.93 [s, 9 H, C(CH3)3], 2.11 (ddd,
J = 13.5, 4.5, 4.5 Hz, 1 H, CH2CHOSi), 2.32 (m, 2 H,
CCH2CHCH2), 2.60 (ddd, J = 13.5, 7.1, 6.3 Hz, 1 H, CH2CHOSi),
3.70 (d, J = 10.7 Hz, 1 H, CH2OSi), 3.97 (d, J = 10.7 Hz, 1 H,
CH2OSi), 4.20 (dd, J = 6.3, 4.5 Hz, 1 H, CHOSi), 5.54 (dd, J = 7.1,
4.5 Hz, 1 H, CHS), 5.09 (m, 2 H, CCH2CHCH2), 5.85 (m, 1 H,
CCH2CHCH2), 7.23–7.55 (m, 5 H, HAr).
13C NMR (100 MHz, CDCl3): d = –5.4, –5.3, –5.1, –4.5, 17.9, 18.4,
25.7, 26.0, 39.3, 41.4, 65.1, 74.3, 86.2, 89.1, 117.8, 126.2, 128.4,
130.5, 134.1, 137.1.
MS (CI): m/z (%) = 385 (100), 495 (4) [M + H+].
HRMS: m/z [M – C4H9]+ calcd for C22H37O3SSi2: 437.200; found:
MS (CI): m/z (%) = 289 (100), 531 (1) [M]+.
Anal. Calcd for C29H46O3SSi2: C, 65.61; H, 8.73. Found: C, 65.96;
H, 8.59.
(2R,3R,5S)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-phenyl-5-(phenylsulfanyl)tetrahydrofuran
[(R,R,S)-10c]
The nucleophilic substitution was carried out with lactol (R,R,R)-9c
(0.247 g, 0.51 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (R,R,S)-10c was character-
ised; all analytical data correspond with those of (S,S,R)-10c.
Yield: 0.241 g (89%).
437.201.
(2S,3S,5R)-3-(tert-Butyldimethylsiloxy)-2-[(tert-butyldimethyl-
siloxy)methyl]-2-(4 fluorophenyl)-5-(phenylsulfanyl)tetrahy-
drofuran [(S,S,R)-10d]
(2R,3R,5S)-2-Allyl-3-(tert-butyldimethylsiloxy)-2-[(tert-butyl-
dimethylsiloxy)methyl]-5-(phenylsulfanyl)tetrahydrofuran
[(R,R,S)-10e]
The nucleophilic substitution was carried out with lactol (S,S,S)-9d
(0.035 g, 0.07 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (S,S,R)-10d was character-
ised.
The nucleophilic substitution was carried out with lactol (R,R,R)-9e
(0.102 g, 0.23 mmol) as described in GP7. Column chromatography
(n-pentane–Et2O, 40:1) gave a colourless oil as an anomeric mix-
ture, of which the major diastereomer (R,R,S)-10e was character-
ised; all analytical data correspond with those of (S,S,R)-10e.
Yield: 0.025 g (65%); Rf = 0.7 (n-pentane–Et2O, 20:1).
Yield: 0.087 g (76%).
IR (film): 2953, 2932, 2889, 2857, 1508, 1471, 1255, 1229, 1097,
1043, 940, 838, 778, 743 cm–1.
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

1556
D. Enders et al.
PAPER
TBS-Protected N-Nucleosides 11–15; General Procedure (GP8)
A suspension of phenyl sulfide 10, the appropriate silylated nucleo-
base (2 equiv) and 4-Å MS (125 mg/mmol) in CH2Cl2 (10 mL/
mmol) was prepared and cooled to –78 °C. Then, NBS (1.2 equiv)
was added, and after 1 h, the reaction mixture was warmed to
–26 °C and left at this temperature overnight. The reaction was then
quenched by the addition of 10% aq Na2S2O3 (10 mL/mmol) and fil-
tered. The aqueous phase was extracted with CH2CL2 (50 mL/
mmol), washed with brine, and dried (MgSO4). Column chromatog-
raphy gave the TBS-protected N-nucleosides 11–15.
Hz, 1 H, CH2OSi), 2.77 (dd, J = 5.5, 2.2 Hz, 1 H, CHOSi), 6.13 (dd,
J = 7.7, 3.6 Hz, 1 H, CH2CHNCO), 7.67 (d, J = 1.1 Hz, 1 H, NCH-
CCO), 8.10 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = –5.5, –5.2, –5.1, –4.8, 8.0, 12.6,
18.0, 18.3, 25.7, 15.9, 26.0, 42.0, 61.9, 73.8, 83.8, 90.9, 110.0,
136.0, 150.2, 163.6.
MS (CI): m/z (%) = 241 (100), 500 (17) [M + H+].
HRMS m/z: [M – C4H9]+ calcd for C20H37O5N2Si2: 441.224; found:
441.224.
1-{(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimeth-
ylsiloxy)methyl]-5-methyltetrahydrofuran-2-yl}-5-methylpyri-
midine-2,4(1H,3H)-dione [(S,S,S)-11a]
1-{(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldi-
methylsiloxy)methyl]-5-ethyltetrahydrofuran-2-yl}-5-methyl-
pyrimidine-2,4(1H,3H)-dione [(R,R,R)-11b]
Phenyl sulfide (S,S,R)-10a (0.183 g, 0.39 mmol) was treated with
bis-TMS-thymine according to GP8. After column chromatography
(n-pentane–Et2O, 1:1), product (S,S,S)-11a was obtained as colour-
less crystals.
Phenyl sulfide (R,R,S)-10b (0.169 g, 0.35 mmol) was treated with
bis-TMS-thymine according to GP8. After column chromatography
(n-pentane–Et2O, 1:1), product (R,R,R)-11b was obtained as colour-
less crystals.
Yield: 0.165 g (95%); [a]D21 –11.3 (c 1.07, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-11b.
26
Yield: 0.146 g (77%); mp 153 °C; [a]D +7.5 (c 1.02, CHCl3);
Rf = 0.9 (n-pentane–Et2O, 1:1).
IR (KBr): 2934, 2858, 1713, 1471, 1285, 1258, 1091, 1011, 930,
842, 777 cm–1.
1-{(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimeth-
ylsiloxy)methyl]-5-phenyltetrahydrofuran-2-yl}-5-methylpyri-
midine-2,4(1H,3H)-dione [(S,S,S)-11c]
Phenyl sulfide (S,S,R)-10c (0.033 g, 0.06 mmol) was treated with
bis-TMS-thymine according to GP8. After column chromatography
(n-pentane–Et2O, 1:1), product (S,S,S)-11c was obtained as colour-
less crystals.
1H NMR (300 MHz, CDCl3): d = 0.01 (s, 6 H, SiCH3), 0.06 (s, 3 H,
SiCH3), 0.10 (s, 3 H, SiCH3), 0.89 [s, 9 H, C(CH3)3], 0.93 [s, 9 H,
C(CH3)3], 1.21 (s, 3 H, CH3C), 1.93 (d, J = 1.1 Hz, 3 H, CH3CCO),
1.99 (ddd, J = 14.6, 2.7, 1.9 Hz, 1 H, CH2CHOSi), 2.82 (ddd,
J = 14.6, 7.7, 5.2 Hz, 1 H, CH2CHOSi), 3.75 (d, J = 10.2 Hz, 1 H,
CH2OSi), 3.89 (d, J = 10.2 Hz, 1 H, CH2OSi), 4.09 (dd, J = 5.2, 1.9
Hz, 1 H, CHOSi), 6.21 (dd, J = 7.7, 2.7 Hz, 1 H, CH2CHNCO), 7.66
(d, J = 1.1 Hz, 1 H, NCHCCO), 9.05 (s, 1 H, NH).
23
Yield: 0.024 g (73%); mp 235 °C; [a]D +34.2 (c 0.77, CHCl3);
Rf = 0.2 (n-pentane–Et2O, 1:1).
13C NMR (100 MHz, CDCl3): d = –5.4, –5.2, –5.1, –4.9, 12.6, 18.0,
18.4, 21.3, 25.6, 26.0, 41.7, 65.0, 75.1, 83.8, 88.5, 109.8, 136.5,
150.3, 163.7.
IR (KBr): 3027, 2954, 2858, 1668, 1471, 1272, 1189, 1103, 1065,
1006, 936, 837, 779, 704 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.22 (s, 6 H, SiCH3), 0.38 (s, 3 H,
SiCH3), 0.44 (s, 3 H, SiCH3), 0.98 [s, 9 H, C(CH3)3], 1.16 [s, 9 H,
C(CH3)3], 2.08 (2 m, J = 14.6 Hz, 1 H, CH2CHOSi), 2.18 (d, J = 1.1
Hz, 3 H, CH3CCO), 2.58 (ddd, J = 14.6, 8.2, 5.0 Hz, 1 H,
CH2CHOSi), 4.03 (d, J = 10.2 Hz, 1 H, CH2OSi), 4.43 (d, J = 10.2
Hz, 1 H, CH2OSi), 4.87 (m, 1 H, CHOSi), 6.48 (dd, J = 8.2, 2.5 Hz,
1 H, CH2CHNCO), 7.48–7.64 (m, 5 H, HAr), 8.06 (d, J = 1.1 Hz, 1
H, NCHCCO), 9.58 (s, 1 H, NH).
MS (EI): m/z (%) = 73 (100), 485 (2) [M + H+].
Anal. Calcd for C23H44O5N2Si2: C, 56.98; H, 9.15; N, 5.78. Found:
C, 56.48; H, 8.74; N, 5.46.
1-{(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldi-
methylsiloxy)methyl]-5-methyltetrahydrofuran-2-yl}-5-meth-
ylpyrimidine-2,4(1H,3H)-dione [(R,R,R)-11a]
Phenyl sulfide (R,R,S)-10a (0.100 g, 0.21 mmol) was treated with
bis-TMS-thymine according to GP8. After column chromatography
(n-pentane–Et2O, 1:1), product (R,R,R)-11a was obtained as colour-
less crystals.
13C NMR (100 MHz, CDCl3): d = –6.0, –5.7, –5.0, –4.9, 12.7, 18.1,
18.4, 25.7, 25.9, 41.1, 65.7, 75.4, 83.4, 91.9, 110.9, 125.7, 128.0,
127.5, 136.8, 140.0, 150.5, 163.9.
MS (CI): m/z (%) = 547 (100) [M+], 548 (40) [M + H+].
Yield: 0.078 g (77%); [a]D22 –6.0 (c 1.02, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-11a.
Anal. Calcd for C28H46O5N2Si2: C, 61.50; H, 8.48; N, 5.12. Found:
C, 61.39; H, 8.63; N, 5.11.
1-{(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimeth-
ylsiloxy)methyl]-5-ethyltetrahydrofuran-2-yl}-5-methylpyrimi-
dine-2,4(1H,3H)-dione [(S,S,S)-11b]
1-{(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldi-
methylsiloxy)methyl]-5-phenyltetrahydrofuran-2-yl}-5-meth-
ylpyrimidine-2,4(1H,3H)-dione [(R,R,R)-11c]
Phenyl sulfide (S,S,R)-10b (0.148 g, 0.31 mmol) was treated with
bis-TMS-thymine according to GP8. After column chromatography
(n-pentane–Et2O, 1:1), product (S,S,S)-11b was obtained as colour-
less crystals.
Phenyl sulfide (R,R,S)-10c (0.241 g, 0.45 mmol) was treated with
bis-TMS-thymine according to GP8. After column chromatography
(n-pentane–Et2O, 1:1), product (R,R,R)-11c was obtained as colour-
less crystals.
Yield: 0.214 g (87%); [a]D23 –37.1 (c 1.05, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-11c.
21
Yield: 0.136 g (88%); mp 137 °C; [a]D +10.4 (c 1.20, CHCl3);
Rf = 0.3 (n-pentane–Et2O, 1:1).
IR (KBr): 2954, 2859, 2362, 1704, 1470, 1417, 1275, 1194, 1086,
1031, 1006, 838, 775, 736 cm–1.
1-{(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimeth-
ylsiloxy)methyl]-5-(4-fluorophenyl)tetrahydrofuran-2-yl}-5-
methylpyrimidine-2,4(1H,3H)-dione [(S,S,S)-11d]
Phenyl sulfide (S,S,R)-10d (0.025 g, 0.05 mmol) was treated with
bis-TMS-thymine according to GP8. After column chromatography
(n-pentane–Et2O, 1:1), product (S,S,S)-11d was obtained as colour-
less crystals.
1H NMR (400 MHz, CDCl3): d = 0.06 (s, 3 H, SiCH3), 0.09 (s, 3 H,
SiCH3), 0.10 (s, 6 H, SiCH3), 0.88 [s, 9 H, C(CH3)3], 0.92 [s, 9 H,
C(CH3)3], 0.93 (m, 3 H, CH3CH2), 1.57 (m, 2 H, CH3CH2), 1.92 (d,
J = 1.1 Hz, 3 H, CH3CCO), 1.96 (ddd, J = 14.6, 3.6, 2.2 Hz, 1 H,
CH2CHOSi), 3.75 (d, J = 10.4 Hz, 1 H, CH2OSi), 3.86 (d, J = 10.4
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 4¢-Quaternary Nucleoside Analogues
1557
21
Yield: 0.015 g (53%); mp 233 °C; [a]D +33.1 (c 0.77, CHCl3);
Rf = 0.3 (n-pentane–Et2O, 1:1).
(EtOAc-MeOH, 20:1), product (R,R,R)-12 was obtained as colour-
less crystals.
IR (KBr): 3415, 2953, 2857, 2361, 2337, 1712, 1664, 1507, 1473,
1271, 1105, 1066, 1003, 935, 838, 778, 665, 551 cm–1.
Yield: 0.095 g (48%); [a]D23 +29.1 (c 1.02, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-12.
1H NMR (300 MHz, CDCl3): d = 0.01 (s, 6 H, SiCH3), 0.16 (s, 3 H,
SiCH3), 0.22 (s, 3 H, SiCH3), 0.77 [s, 9 H, C(CH3)3], 0.94 [s, 9 H,
C(CH3)3], 1.87 (2 m, J = 14.6 Hz, 1 H, CH2CHOSi), 1.96 (d, J = 1.2
Hz, 3 H, CH3CCO), 2.35 (ddd, J = 14.6, 8.2, 4.9 Hz, 1 H,
CH2CHOSi), 3.76 (d, J = 9.9 Hz, 1 H, CH2OSi), 4.17 (d, J = 9.9 Hz,
1 H, CH2OSi), 4.61 (m, 1 H, CHOSi), 6.23 (dd, J = 8.1, 2.5 Hz, 1 H,
CH2CHNCO), 7.05–7.38 (2 m, 4 H, HAr), 7.81 (d, J = 1.2 Hz, 1 H,
NCHCCO), 8.16 (s, 1 H, NH).
N-(9-{(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyl-
dimethylsiloxy)methyl]-5-methyltetrahydrofuran-2-yl}-6-oxo-
6,9-dihydro-1H-purin-2-yl)acetamide [(S,S,S)-13]
Phenyl sulfide (S,S,R)-10a (0.096 g, 0.20 mmol) was treated with
tris-TMS-N-Ac-guanine according to GP8. After column chroma-
tography (EtOAc), product (S,S,S)-13 was obtained as colourless
crystals.
Yield: 0.051 g (46%); mp 162 °C; Rf = 0.6 (EtOAc).
13C NMR (75 MHz, CDCl3): d = –6.0, –5.7, –5.0, –4.9, 12.7, 18.2,
18.4, 25.7, 25.9, 41.1, 65.6, 75.4, 83.4, 91.7, 110.4, 115.2 (d,
JC–F = 21.2 Hz, 2 C, FCCH), 127.7 (d, JC–F = 8.0 Hz, 2 C, FC-
CHCH), 136.0 (d, JC–F = 2.8 Hz, 1 C, FCCHCHC), 136.8, 150.7,
162.4 (d, JC–F = 246.8 Hz, 1 C, FC), 164.1.
IR (KBr): 3167, 2934, 2858, 1697, 1617, 1466, 1373, 1256, 1192,
1098, 840, 779, 641 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.08 (s, 3 H, SiCH3), 0.09 (s, 3 H,
SiCH3), 0.14 (s, 3 H, SiCH3), 0.18 (s, 3 H, SiCH3), 0.86 [s, 9 H,
C(CH3)3], 1.00 [s, 9 H, C(CH3)3], 1.36 (s, 3 H, CCH3), 2.49 (s, 3 H,
CH3CONH), 2.35 (ddd, J = 14.3, 2.2, 2.2 Hz, 1 H, CH2CHOSi),
3.06 (ddd, J = 14.3 Hz, 3J = 6.9, 5.2 Hz, 1 H, CH2CHOSi), 3.88 (d,
J = 10.4 Hz, 1 H, CH2OSi), 4.02 (d, J = 10.4 Hz, 1 H, CH2OSi),
4.25 (dd, J = 5.2, 2.2 Hz, 1 H, CHOSi), 6.65 (dd, J = 6.9, 2.2 Hz, 1
H, CHNCN), 8.28 (s, 1 H, NCHN), 11.74 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = –5.4, –5.3, –4.9, 17.9, 18.4, 22.0,
24.6, 25.6, 26.0, 43.2, 65.2, 75.9, 86.5, 89.6, 110.8, 141.4, 148.2,
153.1, 156.8, 173.6.
MS (CI): m/z (%) = 100 (100), 553 (6) [M + H+].
HRMS: m/z [M – C4H9]+ calcd for C21H36N5O5Si2: 494.226; found:
MS (CI): m/z (%) = 565 (100), 566 (36) [M + H+].
Anal. Calcd for C28H45FO5N2Si2: C, 59.54; H, 8.03; N, 4.96. Found:
C, 59.79; H, 7.96; N, 5.01.
1-{(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldi-
methylsiloxy)methyl]-5-(4-fluorophenyl)tetrahydrofuran-2-
yl}-5-methylpyrimidine-2,4(1H,3H)-dione [(R,R,R)-11d]
Phenyl sulfide (R,R,S)-10d (0.179 g, 0.33 mmol) was treated with
bis-TMS-thymine according to GP8. After column chromatography
(n-pentane–Et2O, 1:1), product (R,R,R)-11d was obtained as colour-
less crystals.
Yield: 0.137 g (76%); [a]D21 –33.7 (c 1.11, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-11d.
494.226.
N-(9-{(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyl-
dimethylsiloxy)methyl]-5-methyltetrahydrofuran-2-yl}-6-oxo-
6,9-dihydro-1H-purin-2-yl)acetamide [(R,R,R)-13]
Phenyl sulfide (R,R,S)-10a (0.104 g, 0.22 mmol) was treated with
tris-TMS-N-Ac-guanine according to GP8. After column chroma-
tography (EtOAc), product (R,R,R)-13 was obtained as colourless
crystals; all analytical data correspond with those of (S,S,S)-13.
4-Amino-1-{(2S,4S,5S)-4-(tert-butyldimethylsiloxy)-5-[(tert-bu-
tyldimethylsiloxy)methyl]-5-methyltetrahydrofuran-2-yl}pyri-
midin-2(1H)-one [(S,S,S)-12]
Phenyl sulfide (S,S,R)-10a (0.198 g, 0.42 mmol) was treated with
bis-TMS-cytosine according to GP8. After column chromatography
(EtOAc-MeOH, 20:1), product (S,S,S)-12 was obtained as colour-
less crystals.
Yield: 0.046 g (37%).
26
Yield: 0.099 g (50%); mp >210 °C; [a]D –26.9 (c 1.04, CHCl3);
Rf = 0.3 (EtOAc–MeOH, 20:1).
9-{(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimeth-
ylsiloxy)methyl]-5-methyltetrahydrofuran-2-yl}-1H-purin-
2,6(3H,9H)-dione [(S,S,S)-14]
Phenyl sulfide (S,S,R)-10a (0.064 g, 0.14 mmol) was treated with
tris-TMS-xanthine according to GP8. After column chromatogra-
phy (EtOAc), product (S,S,S)-14 was obtained as colourless crys-
tals.
IR (KBr): 3930, 3894, 3504, 3478, 3371, 2955, 2932, 2890, 2859,
1662, 1626, 1521, 1487, 1410, 1361, 1288, 1256, 1098, 917, 837,
781 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.01 (s, 3 H, SiCH3), 0.07 (s, 3 H,
SiCH3), 0.09 (s, 6 H, SiCH3), 0.85 [s, 9 H, C(CH3)3], 0.92 [s, 9 H,
C(CH3)3], 1.22 (s, 3 H, CH3C), 2.00 (ddd, J = 14.3, 3.1, 3.1 Hz, 1 H,
CH2CHOSi), 2.84 (ddd, J = 14.3, 7.3, 5.3 Hz, 1 H, CH2CHOSi),
3.70 (d, J = 10.3 Hz, 1 H, CH2OSi), 3.87 (d, J = 10.3 Hz, 1 H,
CH2OSi), 4.09 (dd, J = 5.3, 3.1 Hz, 1 H, CHOSi), 5.71 (d, J = 7.4
Hz, 1 H, CHCNH2), 6.15 (dd, J = 7.3, 3.1 Hz, 1 H, CH2CHNCO),
7.90 (d, J = 7.4 Hz, 1 H, CHCHCNH2).
13C NMR (75 MHz, CDCl3): d = –5.4, –5.3, –5.2, –4.7, 18.0, 18.4,
21.7, 25.7, 26.0, 41.9, 65.2, 75.6, 85.2, 88.3, 93.4, 142.1, 155.9,
165.6.
MS (CI): m/z (%) = 227 (100), 471 (25) [M + H+].
HRMS: m/z [M –C4H9]+ calcd for C18H34N3O4Si2: 412.209; found:
22
Yield: 0.054 g (76%); mp 215 °C; [a]D –2.1 (c 1.06, CHCl3);
Rf = 0.7 (EtOAc).
IR (KBr): 3231, 2953, 2859, 1702, 1470, 1256, 1190, 1089, 839,
776 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.06 (s, 6 H, SiCH3), 0.12 (s, 3 H,
SiCH3), 0.16 (s, 3 H, SiCH3), 0.84 [s, 9 H, C(CH3)3], 0.98 [s, 9 H,
C(CH3)3], 1.33 (s, 3 H, CH3C), 2.30 (ddd, J = 14.4, 2.5, 2.5 Hz, 1 H,
CH2CHOSi), 3.00 (ddd, J = 14.4, 7.1, 5.2 Hz, 1 H, CH2CHOSi),
3.84 (d, J = 10.2 Hz, 1 H, CH2OSi), 3.97 (d, J = 10.2 Hz, 1 H,
CH2OSi), 4.21 (dd, J = 5.2, 2.5 Hz, 1 H, CHOSi), 6.50 (dd, J = 7.1,
2.5 Hz, 1 H, CH2CHN), 8.14 (s, 1 H, NCHN).
13C NMR (100 MHz, CDCl3): d = –5.4, –5.3, –4.9, 17.9, 18.4, 22.0,
25.6, 26.0, 42.9, 65.1, 75.7, 86.6, 89.8, 105.9, 139.9, 149.5, 151.5,
155.4.
412.209.
4-Amino-1-{(2R,4R,5R)-4-(tert-butyldimethylsiloxy)-5-[(tert-
butyldimethylsiloxy)methyl]-5-methyltetrahydrofuran-2-
yl}pyrimidin-2(1H)-one [(R,R,R)-12]
Phenyl sulfide (R,R,S)-10a (0.199 g, 0.42 mmol) was treated with
bis-TMS-cytosine according to GP8. After column chromatography
MS (CI): m/z (%) = 511 (100) [M + H+].
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York

1558
D. Enders et al.
PAPER
HRMS: m/z [M – C4H9]+ calcd for C19H33N4O5Si2: 453.199; found:
453.199.
References
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methylsiloxy)methyl]-5-methyltetrahydrofuran-2-yl}-1H-
purin-2,6(3H,9H)-dione [(R,R,R)-14]
Phenyl sulfide (R,R,S)-10a (0.101 g, 0.22 mmol) was treated with
tris-TMS-xanthine according to GP8. After column chromatogra-
phy (EtOAc), product (R,R,R)-14 was obtained as colourless crys-
tals.
Yield: 0.047 g (42%); [a]D22 +2.2 (c 0.99, CHCl3); all other analyt-
ical data correspond with those of (S,S,S)-14.
9-{(2S,4S,5S)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldimeth-
ylsiloxy)methyl]-5-methyltetrahydrofuran-2-yl}-6-chloro-9H-
purine [(S,S,S)-15]
Phenyl sulfide (S,S,R)-10a (0.117 g, 0.25 mmol) was treated with
TMS-6-chloropurine according to GP8. After column chromatogra-
phy (n-pentane–Et2O, 1:1), product (S,S,S)-15 (55%) was obtained
as colourless crystals alongside (S,S,R)-15 (0.036 g, 28%).
(S,S,S)-15: Yield: 0.070 g (55%); mp 122 °C; [a]D21 +29.8 (c 0.85,
CHCl3); Rf = 0.04 (n-pentane–Et2O, 1:1).
IR (KBr): 2934, 1559, 1258, 1092, 837, 776 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.02 (s, 3 H, SiCH3), 0.98 (s, 6 H,
SiCH3), 0.12 (s, 3 H, SiCH3), 0.84 [s, 9 H, C(CH3)3], 0.93 [s, 9 H,
C(CH3)3], 1.31 (s, 3 H, CH3C), 2.99 (ddd, J = 14.3, 7.4, 5.2 Hz, 1 H,
CH2CHOSi), 2.44 (ddd, J = 14.3, 2.5, 2.2 Hz, 1 H, CH2CHOSi),
3.80 (d, J = 10.3 Hz, 1 H, CH2OSi), 3.92 (d, J = 10.3 Hz, 1 H,
CH2OSi), 4.25 (dd, J = 5.2, 2.2 Hz, 1 H, CHOSi), 6.53 (dd, J = 7.4,
2.5 Hz, 1 H, CH2CHN), 8.68 (s, 1 H, NCHNCCl), 8.74 (s, 1 H,
NCHNCCCl).
(2) Marx, A.; Summerer, D. Synlett 2004, 217.
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(4) For an overview, see: (a) Perspectives in Nucleoside and
Nucleic Acid Chemistry; Kisakürek, M. V.; Rosemeyer, H.,
Eds.; VHCA: Zürich, 2000. For a review on aza
nucleosides, see: (b) Yokoyama, M.; Momotake, A.
Synthesis 1999, 1541. For a review on thio nucleosides, see:
(c) Yokoyama, M. Synthesis 2000, 1637. (d) Alho, M. A.
M.; Errea, M. I.; Sguerra, V. L.; D’Accorso, N. B.; Talarico,
L. B.; Garcia, C. C.; Damonte, E. B. J. Heterocycl. Chem.
2005, 42, 979.
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Ed. 2001, 40, 3012; Angew. Chem. 2001, 113, 3101.
(7) For a review on C-nucleosides, see: Wu, Q.; Simons, C.
Synthesis 2004, 1533.
13C NMR (100 MHz, CDCl3): d = –5.4, –5.3, –5.2, –4.9, 18.0, 18.4,
22.0, 25.6, 26.0, 41.7, 65.3, 75.7, 83.5, 89.4, 131.7, 144.3, 150.5,
150.8, 151.5.
(8) Hess, M. T.; Schwitter, U.; Petretta, M.; Giese, B.; Naegli,
H. Biochemistry 1997, 36, 2332.
(9) Enders, D.; Hieronymi, A.; Ridder, A. Synlett 2005, 2391.
(10) For a review, see: Enders, D.; Voith, M.; Lenzen, A. Angew.
Chem. Int. Ed. 2005, 44, 1304.
MS (CI): m/z (%) = 227 (100), 514 (27) [M + H+].
Anal. Calcd for C23H41ClN4O3Si2: C, 53.83; H, 8.05; N, 10.92.
Found: C, 53.73; H, 8.03; N, 10.82.
(11) For reviews, see: (a) Job, A.; Janeck, C. F.; Bettray, W.;
Peters, R.; Enders, D. Tetrahedron 2002, 58, 2253. On
hydrazone cleavage, see: (b) Enders, D.; Wortmann, L.;
Peters, R. Acc. Chem. Res. 2000, 33, 157.
9-{(2R,4R,5R)-4-(tert-Butyldimethylsiloxy)-5-[(tert-butyldi-
methylsiloxy)methyl]-5-methyltetrahydrofuran-2-yl}-6-chloro-
9H-purine [(R,R,R)-15]
Phenyl sulfide (R,R,S)-10a (0.131 g, 0.28 mmol) was treated with
TMS-6-chloropurine according to GP8. After column chromatogra-
phy (n-pentane–Et2O, 1:1), product (R,R,R)-15 (42%) was obtained
as colourless crystals alongside (R,R,S)-15 (0.050 g, 35%).
(12) CCDC 617802 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.
(13) Imamoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita, T.;
Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904.
(14) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
(R,R,R)-15: Yield: 0.060 g (42%); [a]D21 –31.3 (c 0.69, CHCl3); all
other analytical data correspond with those of (S,S,S)-15.
(15) (a) Sugimura, H.; Osumi, K.; Yamazaki, T.; Yamaya, T.
Tetrahedron Lett. 1991, 32, 1813. (b) Sujino, K.; Sugimura,
H. Synlett 1992, 553. (c) Nicolaou, K. C.; Seitz, S. P.;
Papahatjis, D. P. J. Am. Chem. Soc. 1983, 105, 2430.
(16) Enders, D.; Breuer, I.; Drosdow, E. Synthesis 2005, 3239.
Acknowledgment
We thank Dr. Jan Runsink for NOE investigations. This work was
supported by the Deutsche Forschungsgemeinschaft (Sonderfor-
schungsbereich 380) and the Fonds der Chemischen Industrie. We
thank the companies Bayer AG, BASF AG, Wacker Chemie, and
Degussa AG for the donation of chemicals.
Synthesis 2008, No. 10, 1545–1558 © Thieme Stuttgart · New York