Stereoselective synthesis of rac-4′-ethynyl-2′-deoxy- and 4′-ethynyl-2′,3′-dideoxy-2′,3′- didehydronucleoside analogues

Article abstract of DOI:10.1055/s-2007-966009

Synthesis of a racemic 4′-ethynyl-2′-deoxyribose intermediate using stereoselective chelation control is presented. This intermediate is further transformed to 4′-ethynyl-2′-deoxy- and 4′-ethynyl- 2′,3′-dideoxy-2′,3′-didehydronucleoside analogues. Georg T

Full text of DOI:10.1055/s-2007-966009

1
378
PAPER
Stereoselective Synthesis of rac-4¢-Ethynyl-2¢-deoxy- and 4¢-Ethynyl-2¢,3¢-
dideoxy-2¢,3¢-didehydronucleoside Analogues
a
a
a
a
b
c
S
A
tereoselective
S
y
d
nthesis of
4
¢
-
r
E
thynyln
i
ucleos
a
ide
A
nalog
n
ues Maddaford, Philip Wainwright, Rebecca Glen, Ray Fisher, Peter S. Dragovich, Javier Gonzalez,
c
d
d
d
c
Pei-Pei Kung, Donald S. Middleton, David C. Pryde, Peter S. Stephenson, Scott C. Sutton*
a
Peakdale Molecular Ltd., Peakdale Science Park, Sheffield Road, Chapel-en-le-Frith, High Peak, SK23 0PG, UK
Anadys Pharmaceuticals, 3115 Merryfield Row, San Diego, CA 92121, USA
Pfizer Global Research and Development, 10777 Science Centre Drive, San Diego, CA 92121, USA
Pfizer Global Research and Development, Ramsgate Road, Sandwich, CT13 9NJ, UK
Fax +1(858)6788102; E-mail: scott.sutton@pfizer.com
b
c
d
Received 18 October 2006; revised 8 February 2007
O
O
Abstract: Synthesis of a racemic 4¢-ethynyl-2¢-deoxyribose inter-
mediate using stereoselective chelation control is presented. This
intermediate is further transformed to 4¢-ethynyl-2¢-deoxy- and 4¢-
ethynyl-2¢,3¢-dideoxy-2¢,3¢-didehydronucleoside analogues.
H3C
O
H3C
O
NH
O
NH
O
HO
N
HO
N
Key words: HIV, nucleosides, stereoselective synthesis, carbohy-
drates, chelation control
N3
HO
AZT
1
O
NH2
N
H3C
O
F
Highly active antiretroviral therapy (HAART) using two
or more HIV reverse transcriptase inhibitors in combina-
tion with other anti-HIV drugs has dramatically improved
the quality of life and survival of patients infected with
NH
O
HO
N
HO
N
O
O
1
HIV. In the discovery of new HAART agents, viral resis-
HO
tance remains a challenge along with the necessity for im-
proved safety and tolerability. The presence of AZT in
anti-HIV therapy is believed to block or hinder what is
otherwise an easy pathway to resistance (– K65R +/–
2
3
Figure 1 AZT and compounds 1–3
M184V) as observed from clinical findings with and with- yl groups at C-4¢ followed by selective protection of one
2
out inclusion of AZT. However, due to long-term toxicity primary alcohol over the other. This approach is low
3
concerns associated with the use of AZT in HAART, dis- yielding and lengthy. We reasoned that synthesis of 4¢-
covery of a nontoxic nucleoside analogue exhibiting a re- ethynylribose analogues could be simplified by introduc-
sistance profile similar to AZT is desirable. One common tion of the 4¢-group using chelation-controlled addition
structural feature found in recent anti-HIV nucleoside an- onto an acyclic ketone bearing an a-alkoxy protected al-
6
alogues is a 4¢-ethynyl on the ribose moiety (Figure 1). cohol. Ring closure via reduction of the ester to an alde-
The 4’-ethynyl group affords a good combination of po- hyde and cyclization of the tertiary alcohol onto the
tency and low cytotoxicity relative to other structural aldehyde could then provide a suitable furanose for intro-
4
7
changes investigated at the 4¢-position.
For example, compounds 1–3 in Figure 1 all show potent,
duction of the nucleoside base (Scheme 1). Synthesis of
single enantiomer nucleosides, although not demonstrated
here, is feasible when starting with enantiomerically pure
g-keto esters. This paper describes execution of this strat-
egy for synthesis of (±)-1, (±)-2, and (±)-3.
5
j–n
sub-1mM anti-HIV activity and CC >100 mM.
5
0
Existing synthetic methods for introduction of the 4¢-ethy-
nyl group are limited by lack of stereoselectivity, and long
synthetic sequences. The most often used method in-
volves Cannizzaro introduction of geminal hydroxymeth-
5
Synthesis of g-keto ester 8 involved a five-step sequence
depicted in Scheme 2. Alkylation of the lithium enolate of
OPG
O
OMOM
O
OMOM
O
4
O
R MgX
OH
R4
RO
OPG
OH
RO
OPG
R4
MOMO
Scheme 1
SYNTHESIS 2007, No. 9, pp 1378–1384
x
x
.
x
x
.2
0
0
7
Advanced online publication: 05.04.2007
DOI: 10.1055/s-2007-966009; Art ID: M06306SS
Georg Thieme Verlag Stuttgart · New York
©

PAPER
Stereoselective Synthesis of 4¢-Ethynylnucleoside Analogues
1379
O
OH
O
OMOM
O
ii
i
O
O
O
5
6
iii
O
OMOM
OH
O
OMOM
O
iv
O
OTBDMS
O
OTBDMS
8
7
Scheme 2 Reagents and conditions: (i) 1. LDA, THF, –78 °C, 2. acrolein, –78 °C → r.t., 88%; (ii) dimethoxymethane, BF ·OEt , 4 Å pow-
3
2
dered MS, CH Cl , 5–10 °C, 85%; (iii) 1. NMO, OsO , acetone, H O, 2. TBDMSCl, imidazole, CH Cl , 82%; (iv) TPAP, NMO, 4 Å MS,
2
2
4
2
2
2
CH Cl , 92%.
2
2
isopropyl acetate with freshly distilled acrolein resulted in
an 88% crude yield of b-hydroxy ester 5. Protection as the
MOM ether using dimethoxymethane and BF ·OEt was
O
OMOM
TBDMSO
ii
O
i
OR
8
O
OTBDMS
3
2
OH
MOMO
followed by filtration through Celite giving an 85% crude
9
yield of allylic ether 6. Dihydroxylation using catalytic
1
1
0, R = H
OsO , NMO afforded the corresponding diol which was
iii
4
selectively protected at the primary alcohol using
TBDMSCl to afford an 82% yield of 7 as a 3:1 mixture of
diastereomers. Mild oxidation of the secondary alcohol
using TPAP/NMO afforded a 92% yield of keto ester 8 as
a yellow oil.
1, R = Ac
Scheme 3 Reagents and conditions: (i) Ethynylmagnesium bro-
mide, THF–Et O, –78 °C → r.t., 98%; (ii) DIBAL, CH Cl , –78 °C,
1%; (iii) Ac O, DMAP, Et N, CH Cl , 0 °C → r.t., 93%.
2
2
2
8
2
3
2
2
Chelation-controlled addition of ethynylmagnesium bro-
mide to 8 afforded a single diastereomer of tertiary alco-
hol, 9, in 98% yield. The stereochemistry of this product
was predicted from a closely related reaction found in the
Thymidine nucleosides (±)-1 and (±)-2 share a common
route of preparation as depicted in Scheme 4. Silyl Hil-
8
bert–Johnson coupling of silylated thymine with 11 cata-
6
lyzed by TMSOTf proceeded smoothly to afford a 98%
yield of 12 as a 1:1 anomeric mixture. Separation and iso-
lation of the b-anomer at this stage was not straightfor-
ward but protecting group manipulation followed by
anomer separation at intermediate 14 proved successful.
Deprotection of the MOM and silyl ether groups was ac-
complished using anhydrous HCl in MeOH to afford 13 in
literature and suggested by a chelation control model
(
Figure 2). The stereochemical assignment of 9 was estab-
lished only after the desired final nucleoside products had
been synthesized and their stereochemical assignments
confirmed by NOE experiments and comparison to litera-
ture NMR data.
8
5% yield. Silyl protection at the 5¢-OH of 13 gave 14. A
hindered
approach
O
portion of 14 (1:1 mixture of anomers) was purified via
silica gel chromatography to afford pure 14-b in 19%
yield along with a set of fractions containing 14-a/b (9:1
a:b mixture) in 30% yield. Deprotection of 14-b using
O
OTBDS
α-chelate
MOM
9
H
O
O
NH F in MeOH afforded (±)-1 in 33% yield. Another por-
4
Mg
Nu–
Br
tion of 14-b was converted to the secondary mesylate 15-
b under standard conditions. It was discovered that when
1
5-b was treated with TBAF in refluxing THF, simulta-
Figure 2 Chelation control model for the formation of 9
neous elimination of the mesylate and deprotection of the
silyl ether took place to afford (±)-2 in 45% yield.
From 9, ring-closure of the resulting tertiary alcohol was
accomplished via DIBAL reduction of the isopropyl ester
to the corresponding aldehyde followed by spontaneous
The synthesis of (±)-3 begins with silyl Hilbert–Johnson
4
9
coupling of 11 with N -benzoyl-5-fluorocytosine to af-
ford 5-fluorocytidine 16 as a mixture of anomers
7
cyclization. Furanose 10 was isolated in 82% yield fol-
(
Scheme 5). Purification of the mixture was accomplished
lowing silica gel chromatography as a 1:1 mixture of ano-
mers. Final preparation of the ribose coupling partner 11
was accomplished by acetylation of the 1¢-OH group in
via silica gel chromatography to afford 16-b in 31% yield.
Deprotection was conducted as in the thymidine case to
afford (±)-3 in 41% yield. In addition to NOE experiments
performed on the final nucleosides which unambiguously
confirmed the stereochemistry at the anomeric center, the
proton NMRs of racemic nucleosides 1–3 matched the lit-
9
3% yield affording a 1:3 mixture of a:b anomers. The
overall yield of the eight-step procedure to 11 is 42%
Scheme 3).
(
Synthesis 2007, No. 9, 1378–1384 © Thieme Stuttgart · New York

1
380
A. Maddaford et al.
PAPER
Me
Me
1
R O
O
TBDMSO
O
N
O
O
i
ii
N
O
O
11
NH
NH
2
R O
MOMO
13, R = H, R2 = H
1
12
iii
1
4, R1 = TBDMS, R2 = H
iv
O
O
O
Me
Me
Me
NH
O
NH
O
NH
O
1
HO
N
TBDMSO
N
R O
N
O
O
O
vii
vi
MsO
HO
4-β, R1 = TBDMS
±)-1, R1 = H
(
±)-2
1
5-β
1
v
(
Scheme 4 Reagents and conditions: (i) 1. thymine, N,O-bis(trimethylsilyl)acetamide, MeCN, reflux, 1 h, 2. 11, TMSOTf, r.t., 3 h, 98%; (ii)
. AcCl, MeOH, 22 h, 2. NaOMe, MeOH, 85%; (iii) TBDMSCl, pyridine; (iv) anomer separation, 19% pure 14-b; (v) NH F, MeOH, 33%; (vi)
1
4
MsCl, Et N, CH Cl , 5 °C → r.t., 84%; (vii) TBAF, THF, reflux, 2 d, 45%.
3
2
2
NHBz
N
NH2
N
F
F
F
TBDMSO
O
N
N
N
O
NHBz
TBDMSO
HO
O
O
O
i
O
ii
iii
N
11
MOMO
MOMO
HO
16
16-β
(±)-3
Scheme 5 Reagents and conditions: (i) N-benzoyl 5-fluorocytosine, N,O-bis(trimethylsilyl)acetamide, MeCN, reflux, 0.5 h, 2. 11, TMSOTf,
r.t., 2 h, 87%; (ii) separation of anomers, 31% pure 16-b; (iii) 1. AcCl, MeOH, 5 d, 2. NaOMe, MeOH, 41%.
erature NMR data5j–n confirming the stereochemical as- multiplicities are reported, the following abbreviations are used: s
(
(
singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd
doublet of doublets), dt (doublet of triplets). Coupling constants,
signment of 9 and subsequent intermediates.
We have demonstrated an efficient, novel method for the
synthesis of 4¢-ethynyl-substituted nucleoside analogues.
Replacement of ethynylmagnesium bromide with other
Grignard reagents is expected to offer entry into addition-
when given, are reported in Hertz (Hz).
Melting points were obtained on an Electrothermal 9100 melting
point apparatus. Mass spectrometry was carried out on a Waters/
Micromass ZQ2000 instrument. Elemental analyses were obtained
al 4¢-substituted carbohydrates and nucleoside analogues. from Elemental Microanalysis, Okehampton, UK.
Furthermore, the selection of chiral g-keto ester starting
1
0a
10b
Isopropyl 3-Hydroxypent-4-enoate (5)
materials such as (+)-5 and (–)-5 offer entry into ei-
ther enantiomer of 4¢-substituted carbohydrates and nu-
cleoside analogues. When combined with methods to
generate enantiomerically pure g-keto esters, the strategy
To a solution of i-Pr NH (153 mL, 1.09 mol) in THF (750 mL) at
2
–
78 °C was added n-BuLi (680 mL, 1.6 M in hexanes, 1.09 mol)
over 20 min. After stirring for 45 min, isopropyl acetate (115 mL,
.980 mol) was added over 10 min. After stirring a further 45 min,
0
described herein represents a highly versatile approach to a solution of freshly distilled acrolein (65.6 mL, 0.980 mol) in THF
this important class of compounds.
(200 mL) was added over 15 min. The mixture was stirred for 15
min and allowed to self-warm to r.t. and stirred overnight. The mix-
ture was diluted with EtOAc (750 mL) and washed with aq sat.
NMR spectroscopy was performed on a Jeol EXC300 spectrometer,
NH Cl (2 × 100 mL) and brine (2 × 100 mL). The combined organic
4
1
13
operating at 300 MHz ( H NMR) and 75 MHz ( C NMR). NMR
extracts were dried (MgSO ) and concentrated in vacuo to give 5
4
spectra were obtained as CDCl solutions (reported in ppm), using
3
(136 g, 88% crude yield) as a brown oil which was used as such in
the next reaction. An analytical sample was obtained by silica gel
chloroform as the reference standard (7.25 ppm and 77.00 ppm) or
DMSO-d (2.50 ppm and 39.51 ppm) or CD OD (3.4 ppm and 4.8
6
3
column chromatography eluting with 4:1 hexane–EtOAc; R = 0.44
f
ppm, and 49.3 ppm), or internal tetramethylsilane (0.00 ppm) when
appropriate. Other NMR solvents were used as needed. When peak
(4:1 hexane–EtOAc).
Synthesis 2007, No. 9, 1378–1384 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of 4¢-Ethynylnucleoside Analogues
1381
1
H NMR (300 MHz, CDCl ): d = 5.86 (ddd, J = 5.5, 10.4, 17.3 Hz,
Isopropyl 5-{[tert-Butyl(dimethyl)silyl]oxy}-3-(methoxy-
methoxy)-4-oxopentanoate (8)
3
1
H), 5.30 (dt, J = 1.4, 17.3 Hz, 1 H), 5.13 (dt, J = 1.4, 10.4 Hz, 1
H), 5.00–5.08 (m, 1 H), 4.47–4.54 (m, 1 H), 3.06 (d, J = 4.0 Hz, OH,
To a solution of 7 (200 g, 0.570 mmol) in CH Cl (2.0 L) was added
2
2
1
H), 2.56 (dd, J = 4.1, 16.2 Hz, 1 H), 2.48 (dd, J = 8.0, 16.2 Hz, 1
4 Å MS (235 g), N-methylmorpholine N-oxide (73.5 g, 0.630 mol)
and TPAP (4.4 g, 13 mmol). The mixture was maintained at 20–
25 °C with the aid of external ice-water cooling and stirred for 3.5
h. The mixture was filtered through Celite, washed with aq 10%
Na S O (2 × 100 mL) and 1 M aq citric acid (2 × 200 mL). The
H), 1.25 (d, J = 6.3 Hz, 6 H).
1
3
C NMR (75 MHz, CDCl ): d = 171.9, 138.9, 115.4, 69.0, 68.4,
3
4
1.5, 21.9 (2 C).
2
2
3
combined organic extracts were dried (MgSO ), concentrated in
vacuo and the residue purified by flash silica chromatography elut-
ing with 4:1 hexane–EtOAc to give 8 (183 g, 92%) as a yellow oil;
Rf = 0.61 (4:1 hexane–EtOAc).
4
Isopropyl 3-(Methoxymethoxy)pent-4-enoate (6)
To a mixture of 5 (207 g, 1.31 mol), CH Cl (1.75 L),
2
2
dimethoxymethane (1.25 L), and 4 Å powdered MS (410 g) at 5 °C,
was added BF ·OEt (249 mL, 2.0 mol) over 30 min. After 30 min,
3
2
1
the mixture was warmed to 10 °C, stirred for 3 h, then Na CO (250
g) was added over 25 min. After stirring for a further 25 min, the
mixture was filtered through Celite, washed with sat. aq Na CO
H NMR (300 MHz, CDCl ): d = 4.97 (sept, J = 6.3 Hz, 1 H), 4.67
2
3
3
(d, J = 6.9 Hz, 1 H), 4.62 (d, J = 6.9 Hz, 1 H), 4.55 (dd, J = 4.7, 6.9
Hz, 1 H), 4.48 (d, J = 6.9 Hz, 2 H), 2.79 (dd, J = 4.7, 16.2 Hz, 1 H),
2
3
(
(
2 × 300 mL) and dried (MgSO ). Concentration in vacuo gave 6
2.70 (dd, J = 6.9, 16.2 Hz, 1 H), 1.18 (d, J = 6.3 Hz, 6 H), 0.88 (s, 9
H), 0.06 (s, 6 H).
4
223 g, 85%) as a yellow oil which was used directly in the next re-
action. An analytical sample was obtained by silica gel column
13
C NMR (75 MHz, CDCl ): d = 207.9, 169.6, 97.1, 77.0, 68.5, 68.0,
3
chromatography eluting with CH Cl ; R = 0.41 (CH Cl ).
2
2
f
2
2
5
6.1, 37.4, 25.8 (3 C), 21.8 (2 C), 18.4, –5.4 (2 C).
1
H NMR (300 MHz, CDCl ): d = 5.65–5.76 (ddd, J = 7.7, 10.4, 17.9
3
Hz, 1 H), 5.29 (m, 1 H), 5.20 (m, 1 H), 4.96–5.07 (sept, J = 6.3 Hz,
H), 4.67 (d, J = 6.6 Hz, 1 H), 4.54 (d, J = 6.6 Hz, 1 H), 4.42–4.50
m, 1 H), 3.33 (s, 3 H), 2.60 (dd, J = 8.2, 15.0 Hz, 1 H), 2.45 (dd,
J = 5.5, 15.0 Hz, 1 H), 1.20 (d, J = 6.3 Hz, 6 H).
Isopropyl 5-O-[tert-Butyl(dimethyl)silyl]-2-deoxy-4-ethynyl-3-
O-(methoxymethyl)-erythro-pentanoate (9)
To a solution of 8 (39 g, 0.11 mol) in THF (650 mL) at –78 °C, was
1
(
added 0.5 M ethynylmagnesium bromide in Et O (236 mL, 0.12
2
1
3
mol) over 25 min. The mixture was stirred for 30 min at –78 °C,
then allowed to warm to r.t. over 30 min and stirred for a further pe-
riod of 2 h. The reaction was quenched with 1 M aq citric acid (500
mL) and extracted with EtOAc (2 × 500 mL). The combined organ-
C NMR (75 MHz, CDCl ): d = 170.3, 136.9, 118.1, 94.1, 74.0,
3
6
8.0, 55.6, 41.4, 21.9 (2 C).
Isopropyl 5-O-[tert-Butyl(dimethyl)silyl]-2-deoxy-3-O-(meth-
oxymethyl)pentanoate (7)
To a solution of 6 (409 g, 2.02 mol) in acetone (2.5 L) and H O (500
mL) was added N-methylmorpholine N-oxide (273 g, 2.33 mol) and
OsO (4.0 g, 16 mmol). The mixture was stirred at r.t. for 24 h, di-
luted with brine (750 mL) and aq 1 M Na S O (750 mL), and then
extracted with EtOAc (3 × 2 L). The organics were combined, dried
(
ic extracts were dried (MgSO ) and concentrated in vacuo to give 9
4
(41.1 g, 98%) as a yellow oil which was used directly in the next re-
2
action. An analytical sample was obtained by silica gel column
chromatography eluting with CH Cl ; R = 0.71 (4:1 hexane–
2
2
f
4
EtOAc).
2
2
3
1
H NMR (300 MHz, CDCl ): d = 4.99 (sept, J = 6.3 Hz, 1 H), 4.71
3
MgSO ) and concentrated in vacuo to give the crude diol as a
(d, J = 6.6 Hz, 1 H), 4.68 (d, J = 6.6 Hz, 1 H), 4.11 (dd, J = 3.6, 8.0
Hz, 1 H), 3.82 (d, J = 9.8 Hz, 1 H), 3.71 (d, J = 9.8 Hz, 1 H), 3.33
(s, 3 H), 3.29 (s, 1 H, OH), 2.92 (dd, J = 3.6, 16.2 Hz, 1 H), 2.64 (dd,
J = 8.0, 16.2 Hz, 1 H), 2.41 (s, 1 H), 1.21 (d, J = 6.3 Hz, 6 H), 0.89
4
brown oil. An analytical sample of the intermediate diol was ob-
tained as a mixture of diastereoisomers by silica gel column chro-
matography eluting with EtOAc; R = 0.25 (EtOAc).
f
(
s, 9 H), 0.07 (s, 6 H).
Intermediate Diol
H NMR (300 MHz, DMSO-d ): d = 4.85 (sept, J = 6.3 Hz, 1 H),
13
C NMR (75 MHz, CDCl ): d = 171.6, 97.9, 82.5, 77.9, 72.8, 68.1,
1
3
6
6
6.7, 56.2, 37.5, 25.9 (3 C), 21.9 (2 C), 18.4, –5.36 (2 C).
4
1
2
.70–4.75 (m, 1 H, OH), 4.43–4.60 (m, 2 H and OH), 3.85–3.93 (m,
H), 3.47–3.57 (m, 1 H), 3.24–3.46 (m, 2 H), 3.19 (s, 3 H), 2.47–
.59 (m, 1 H), 2.29–2.41 (m, 1 H), 1.14 (d, J = 6.3 Hz, 6 H).
5
-O-[tert-Butyl(dimethyl)silyl]-2-deoxy-4-ethynyl-3-O-(meth-
oxymethyl)-D-erythro-pentofuranose (10)
1
3
C NMR (75 MHz, DMSO-d ): d = 171.2, 170.8, 97.8, 97.6, 77.9,
To a solution of 9 (41 g, 0.11 mol) in CH Cl (650 mL) at –78 °C,
6
2
2
7
7.3, 73.3, 73.2, 68.4, 63.4, 63.0, 56.1, 37.5, 37.3, 21.9, 21.8.
was added 1.0 M DIBAL (220 mL, 0.22 mol) and the mixture was
stirred for 1.5 h. The reaction was quenched with MeOH (100 mL),
warmed to ~10 °C, and diluted with aq sodium potassium tartrate
The diol was dissolved in CH Cl (2.5 L) and imidazole (138 g, 2.02
mol) was added followed by TBDMSCl (305 g, 2.02 mol) at 0 °C.
The mixture was stirred for 4 h at r.t., washed with aq 1 M citric acid
2
2
(
200 mL). After stirring for 10 min, the mixture was filtered through
Celite and extracted with CH Cl (2 × 1 L). The combined organic
extracts were dried (MgSO ), concentrated in vacuo, and the residue
purified by flash silica gel chromatography eluting with 4:1 to 2:1
hexane–EtOAc to give 10 (28.1 g, 81%) as a colorless oil (1:1 mix-
2
2
(
2 × 500 mL) and dried (MgSO ). After concentration in vacuo, the
4
4
residue was purified by flash chromatography on silica gel eluting
with 4:1 hexane–EtOAc to give 7 (580 g, 82%) as a yellow oil (~3:1
mixture of diastereoisomers); R = 0.21 (CH Cl ).
f
2
2
ture of anomers); R = 0.31 (4:1 hexane–EtOAc).
f
1
Compound 7
H NMR (300 MHz, CDCl ): d = 5.47 and 5.39 (2 ddd, J = 3.6, 3.6,
3
1
H NMR (300 MHz, CDCl ): d = 4.91–5.04 (m, 1 H), 4.61–4.70 (m,
7.1 and 1.6, 4.1, 8.5 Hz, 1 H), 4.61–4.76 (m, 2 H), 4.46 and 4.32 (t
and dd, J = 7.4 and 3.0, 6.3 Hz, 1 H), 3.52–3.75 (m, 3 H), 3.35 and
3.34 (2 s, 3 H), 2.56 and 2.55 (2 s, 1 H), 2.02–2.38 (m, 2 H), 0.87
and 0.83 (2 s, 9 H), 0.07 and 0.06 (2 s, 3 H).
3
2
H), 3.95–4.04 (m, 1 H), 3.59–3.71 (m, 3 H), 3.32 and 3.33 (2 s, 3
H), 2.46–2.79 (m, 2 H and OH), 1.18 (d, J = 6.3, 6 H), 0.86 and 0.85
(
2 s, 6 H).
1
3
13
C NMR (75 MHz, CDCl ): d = 171.2, 171.0, 97.5, 97.2, 76.5, 73.1,
C NMR (75 MHz, CDCl ): d = 99.4, 97.6, 96.2, 95.9, 83.7, 83.2,
3
3
7
1
3.0, 67.9, 67.8, 63.7, 63.5, 55.9, 37.33, 37.28, 25.9, 21.9, 21.8,
8.3, –5.4.
81.8, 80.7, 77.4, 76.9, 76.1, 67.1, 67.0, 55.7, 40.9, 40.3, 25.9, 25.8
(3 C), 18.4, 18.3, –5.4, –5.5 (2 C).
Synthesis 2007, No. 9, 1378–1384 © Thieme Stuttgart · New York

1
382
A. Maddaford et al.
PAPER
1
-O-Acetyl-5-O-[tert-butyl(dimethyl)silyl]-2-deoxy-4-ethynyl-3-
(9.1 g, 85%) as a white solid (1:1 mixture of anomers); R = 0.23
f
O-(methoxymethyl)-D-erythro-pentofuranose (11)
(9:1 CH Cl –MeOH).
2
2
To a solution of 10 (28 g, 89 mmol) in CH Cl (400 mL) at 0 °C,
1
2
2
H NMR (300 MHz, DMSO-d ): d = 11.28 (br s, NH), 7.78 and 7.60
6
was added Ac O (8.7 mL, 93 mmol), DMAP (1.1 g, 9.0 mmol) and
2
(
(
2 d, J = 1.4 and 1.4 Hz, 1 H), 6.06 and 6.15 (m, 1 H), 5.60 and 5.47
2 d, J = 4.7 and 5.5 Hz, OH), 5.39 and 5.23 (2 t, J = 6.1 and 6.9 Hz,
Et N (16 mL, 0.12 mol). The mixture was stirred for 30 min, al-
3
lowed to warm to r.t. and washed with 1 M aq citric acid (200 mL).
OH), 4.23–4.36 (m, 1 H), 3.40–3.67 (m, 3 H), 2.55–2.65, 2.16–2.21
and 1.91–1.99 (3 m, 2 H), 1.75 and 1.73 (2 d, J = 1.1 and 1.1 Hz, 3
H).
1
The combined organic extracts was dried (MgSO ) and concentrat-
4
ed in vacuo. The residue was purified by flash chromatography elut-
ing with 4:1 hexane–EtOAc to give 11 (29.6 g, 93%) as a colorless
oil (1:3 mixture of a:b anomers). An analytical sample of each was
obtained by silica gel chromatography eluting with 4:1 hexane–
EtOAc.
3
C NMR (75 MHz, DMSO-d ): d = 164.2, 150.9, 137.2, 136.7,
6
1
7
10.1, 109.5, 86.6, 85.0, 84.4, 82.8, 82.1, 81.7, 80.4, 79.4, 71.0,
0.1, 65.4, 64.4, 39.2, 38.7, 13.1, 12.8.
1
-{5-O-[tert-Butyl(dimethyl)silyl]-2-deoxy-4-ethynyl-erythro-
1
1-b
pentofuranosyl}-5-methylpyrimidine-2,4(1H,3H)-dione (14)
To a solution of 13 (4.40 g, 16.5 mmol) in pyridine (70 mL) was
added TBDMSCl (5.5 g, 36 mmol) and the mixture was stirred for
Rf = 0.51 (4:1 hexane–EtOAc).
1
H NMR (300 MHz, CDCl ): d = 6.27–6.29 (m, 1 H), 4.76 (d,
3
J = 6.9 Hz, 1 H), 4.69 (d, 6.9 Hz, 1 H), 4.54 (dd, J = 6.6, 9.4 Hz, 1
2
0 h. The mixture was concentrated in vacuo, dissolved in CH Cl
2 2
H), 3.77 (s, 2 H), 3.38 (s, 3 H), 2.56 (s, 1 H), 2.29–2.50 (m, 2 H),
2
(100 mL) and washed with aq 1 N HCl (3 × 50 mL). The aqueous
.10 (s, 3 H), 0.89 (s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H).
phase was back extracted with CH Cl (3 × 40 mL) and the organic
extracts were combined, dried (MgSO ) and concentrated in vacuo.
The residue was purified by flash chromatography eluting with 1:1
2
2
1
3
C NMR (75 MHz, CDCl ): d = 169.9, 96.5, 96.3, 83.8, 80.7, 76.2,
5.2, 65.7, 55.7, 38.0, 25.9 (3 C), 21.3, 18.4, –5.26, –5.46.
3
4
7
CH Cl –EtOAc to give 14-b (1.17 g, 19%) as a white solid and 14-
2
2
1
1-a
a/b (1.88 g, 30%, 9:1 a:b mixture of anomers).
Rf = 0.42 (4:1 hexane–EtOAc).
1
14-b
f
H NMR (300 MHz, CDCl ): d = 6.22 (dd, J = 2.5, 5.8 Hz, 1 H),
3
R = 0.45 (19:1 CH Cl –MeOH).
2
2
4
.74 (d, J = 6.9 Hz, 1 H), 4.68 (d, 6.9 Hz, 1 H), 4.37 (dd, J = 4.7, 7.7
1
Hz, 1 H), 3.71 (d, J = 1.4 Hz, 2 H), 3.37 (s, 3 H), 2.50–2.60 (m, 2
H), 2.18 (ddd, J = 2.5, 4.4, 14.0 Hz, 1 H), 0.86 (s, 9 H), 0.04 (s, 3
H), 0.03 (s, 3 H).
H NMR (300 MHz, CDCl ): d = 8.81 (br s, NH), 7.69 (d, J = 1.3
3
Hz, 1 H), 6.23 (dd, J = 4.1, 7.4 Hz, 1H), 4.39–4.45 (m, 1 H), 3.79
(d, 10.7 Hz, 1 H), 3.76 (d, J = 10.7 Hz, 1 H), 2.80–2.89 (m, 2 H),
2.15 (dt, J = 4.1, 14.0 Hz, 2 H), 1.92 (d, J = 1.3 Hz, 3 H), 0.90 (s, 9
H), 0.11 (s, 6 H).
1
3
C NMR (75 MHz, CDCl ): d = 170.5, 97.9, 96.2, 84.6, 80.6, 76.3,
3
6
6.8, 55.7, 38.9, 25.9 (3 C), 21.4, 18.3, –5.2, –5.5.
1
3
C NMR (75 MHz, CDCl ): d = 164.0, 150.4, 136.9, 110.8, 87.0,
3
1
-[5-O-[tert-Butyl(dimethyl)silyl]-2-deoxy-4-ethynyl-3-O-
86.3, 79.4, 79.0, 72.9, 67.5, 40.1, 25.9 (3C), 18.4, 12.8, –5.3, –5.5.
(
methoxymethyl)-erythro-pentofuranosyl]-5-methylpyrimi-
dine-2,4(1H,3H)-dione (12)
14-a
A suspension of thymine (10.5 g, 84.0 mmol) and N,O-bis(trimeth-
ylsilyl)acetamide (41.3 mL, 168 mmol) in MeCN (300 mL) was
heated at reflux for 1 h. The mixture was cooled to r.t. and 11 (15 g,
R = 0.42 (19:1 CH Cl –MeOH).
f
2
2
1
H NMR (300 MHz, CDCl ): d = 8.76 (br s, NH), 7.40 (d, J = 1.1
3
Hz, 1 H), 6.40 (t, J = 6.5 Hz, 1 H), 4.45 (dd, J = 6.0, 11.8 Hz, 1 H),
4
2 mmol) was added followed by TMSOTf (22.7 mL, 125 mmol).
3
2
1
.97 (d, J = 11.0 Hz, 1 H), 3.86 (d, J = 11.0 Hz, 1 H), 2.74 (s, 1 H),
.42–2.51 (m, 1 H), 2.35 (d, J = 6.0 Hz, 1 H), 2.21–2.29 (m, 1 H),
.91 (s, 3 H), 0.93 (s, 9 H), 0.13 (s, 6 H).
The mixture was stirred at r.t. for 3 h, diluted with EtOAc (900 mL)
and washed with sat. aq Na CO (1 L). The aqueous phase was
2
3
back-extracted with EtOAc (700 mL) and the organic layers were
1
3
C NMR (75 MHz, CDCl ): d = 163.6, 150.2, 135.4, 111.3, 84.9,
combined, dried (MgSO ), and concentrated in vacuo. The residue
3
4
8
–
4.0, 78.7, 77.3, 71.6, 66.1, 39.5, 26.0 (3 C), 18.5, 12.6, –5.28,
5.31.
was further purified by flash chromatography eluting with 19:1
CH Cl –MeOH to give 12 (17.4 g, 98%) as a cream-colored foam
2
2
(
1:1 mixture of anomers); R = 0.42 (19:1 CH Cl –MeOH).
f 2 2
1
-(2-Deoxy-4-ethynyl-b-erythro-pentofuranosyl)-5-methylpyri-
1
H NMR (300 MHz, CDCl ): d = 9.40 and 9.33 (2 br s, NH), 7.72
3
midine-2,4(1H,3H)-dione [(±)-1]
and 7.33 (2 s, 1 H), 6.37 and 6.21 (2 dd, J = 5.2, 7.4 and 5.2, 6.6 Hz,
H), 4.61–4.78 (m, 2 H), 4.40–4.48 (m, 1 H), 3.96 and 3.84 (2 d,
J = 11.3 and 11.3 Hz, 1 H), 3.76 (d, J = 1.4 Hz, 1 H), 3.39 and 3.36
2 s, 3 H), 2.49–2.86 (m, 2 H), 2.11–2.28 (m, 1 H), 1.89–1.93 (m, 3
H), 0.92 and 0.88 (2 s, 9 H), 0.07–0.11 (m, 6 H).
Compound 14-b (55 mg, 0.145 mmol) was placed in a conical
1
sealed tube and dissolved in MeOH (1 mL). A 0.5 M solution of
NH F in MeOH (1 mL, 0.5 mmol) was added and the tube was
sealed and heated at 60 °C for 5 h. The solvent was removed and the
residue was purified by preparative HPLC to give (±)-1 (12.4 mg,
33%) as a white solid. The H NMR (DMSO-d ) matched with that
4
(
1
3
1
C NMR (75 MHz, CDCl ): d = 164.2, 163.9, 150.6, 150.4, 136.5,
3
6
5
j
1
7
1
35.3, 111.2, 110.6, 96.5, 96.3, 83.4, 80.2, 79.5, 77.8, 76.9, 76.2,
5.1, 66.8, 65.4, 55.9, 55.8, 39.1, 38.0, 26.0, 25.9 (3 C), 18.5, 18.3,
2.8, 12.7, –5.26, –5.37, –5.49.
reported in the literature.
1-[5-O-[tert-Butyl(dimethyl)silyl]-2-deoxy-4-ethynyl-3-O-
(
methylsulfonyl)-b-erythro-pentofuranosyl]-5-methylpyrimi-
1
-(2-Deoxy-4-ethynyl-erythro-pentofuranosyl)-5-methylpyrimi-
dine-2,4(1H,3H)-dione (15-b)
dine-2,4(1H,3H)-dione (13)
To a solution of 14-b (1.1 g, 3.0 mmol) in CH Cl (100 mL) was
2
2
To a solution of 12 (17 g, 40 mmol) in MeOH (400 mL) was added
AcCl (9.0 mL, 127 mmol) over 3 min. The mixture was stirred at r.t.
for 22 h and NaOMe (8.20 g, 152 mmol) added. After 5 min, the
mixture was concentrated in vacuo and the residue purified by flash
chromatography eluting with 19:1 to 9:1 CH Cl –MeOH to give 13
added Et N (0.50 mL, 3.6 mmol) and MeSO Cl (0.24 mL, 3.1
3
2
mmol) at 5 °C. After 5 min, the mixture was allowed to warm to r.t.
and stirred for 3 h. The mixture was washed with aq 1 N HCl (2 ×
20 mL), dried (MgSO ) and concentrated in vacuo to give 15-b
(1.15 g, 84%) as white foam; R 0.72 (19:1 CH Cl –MeOH).
4
2
2
f
2
2
Synthesis 2007, No. 9, 1378–1384 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of 4¢-Ethynylnucleoside Analogues
1383
1
13
H NMR (300 MHz, CDCl ): d = 8.72 (br s, NH), 7.58 (d, J = 1.4
C NMR (75 MHz, CDCl ): d = 152.9, 152.7, 146.4, 141.5, 138.1,
3
3
Hz, 1 H), 6.27 (dd, J = 4.4, 6.9 Hz, 1 H), 5.29 (dd, J = 4.4, 6.6 Hz,
136.0, 133.1, 130.0, 128.4, 125.1, 96.7, 84.7, 84.2, 79.1, 77.3, 74.2,
1
3
3
H), 3.85 (d, J = 11.2 Hz, 1 H), 3.82 (d, J = 11.2 Hz, 1 H), 2.97–
.16 (m, 4 H), 2.84 (s, 1 H), 2.43 (dt, J = 4.4, 14.6 Hz, 1 H), 1.95 (d,
H, J = 1.4 Hz, 1 H), 0.91 (s, 9 H), 0.11 (s, 6 H).
65.2, 56.0, 38.6, 26.0, 18.6.
4-Amino-1-(2-deoxy-4-ethynyl-b-erythro-pentofuranosyl)-5-
fluoropyrimidin-2(1H)-one [(±)-3]
1
3
C NMR (75 MHz, CDCl ): d = 160.4, 150.2, 135.5, 111.1, 85.7,
3
To a solution of 16-b (3.0 g, 5.6 mmol) in MeOH (150 mL) was add-
ed AcCl (2.0 mL, 28 mmol) and the mixture was stirred at r.t. for 5
days. NaOMe (1.8 g, 33 mmol) was then added. After 5 min, the
mixture was concentrated in vacuo and the residue purified by pre-
parative HPLC to give (±)-3 (626 mg, 41%) as a white solid; mp
8
–
5.1, 79.1, 78.3, 78.0, 67.0, 39.5, 38.7, 25.9 (3 C), 18.3, 12.8, –5.3,
5.5.
1
-[5-Ethynyl-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]-5-
methylpyrimidine-2,4(1H,3H)-dione [(±)-2]
2
22–223 °C (dec.); R = 0.40 (4:1 CH Cl –MeOH).
f 2 2
To a solution of 15-b (1.05 g, 2.00 mmol) in THF (30 mL) was add-
ed 1.0 M TBAF in THF (6.9 mL, 6.9 mmol) and the mixture was
refluxed for 24 h. A further portion of 1.0 M TBAF in THF (6.9 mL,
1
H NMR (300 MHz, DMSO-d ): d = 8.03 (d, J = 7.4 Hz, 1 H), 7.75
6
(br s, 1 H), 7.51 (br s, 1 H), 5.99–6.07 (m, 1 H), 5.52 (t, J = 5.8 Hz,
6
.9 mmol) was added and refluxed for an additional 28 h. The reac-
1 H), 5.46 (d, J = 5.5 Hz, 1 H), 4.28 (dd, J = 12.7, 7.3 Hz, 1 H),
tion was cooled, concentrated in vacuo and the residue purified by
flash silica chromatography eluting with 7% MeOH–CH Cl to give
3.52–3.69 (m, 2 H), 3.48 (s, 1 H), 2.16–2.28 (m, 1 H), 2.03–2.14 (m,
1 H).
2
2
(
±)-2 (0.26 g, 45%) as a yellow solid; R = 0.57 (7% MeOH–
13
f
C NMR (75 MHz, CDCl ): d = 157.9 (d), 153.7, 138.2, 135.0,
3
CH Cl ).
2
2
1
25.9 (d), 85.1, 84.1, 81.7, 79.4, 69.5, 64.1.
1
H NMR (300 MHz, DMSO-d ): d = 11.33 (br s, NH), 7.55 (d,
6
LRMS (ES+): m/z = 270.12 [M + H].
J = 1.1 Hz, 1 H), 6.85 (t, J = 1.7 Hz, 1 H), 6.32 (dd, J = 1.9, 5.8 Hz,
1
3
H), 6.02 (dd, J = 1.2, 5.8 Hz, 1 H), 5.45 (t, J = 5.8 Hz, OH), 3.53–
.69 (m, 3 H), 1.68 (d, J = 1.1 Hz, 1 H).
References
1
3
C NMR (75 MHz, DMSO-d ): d = 164.4, 151.3, 137.3, 136.0,
6
(
1) (a) Fisch, M. A. AIDS 1999, 13 (Suppl.1), S49. (b)Mitsuya,
H.; Erickson, J. In Textbook of AIDS Medicine; Merigan, T.
C.; Bartlet, J. G.; Bolognesi, D., Eds.; Lippincott Williams &
Wilkins: Baltimore, 1999, 751.
1
27.6, 109.5, 89.4, 87.1, 82.0, 77.9, 66.3, 12.7.
MS: m/z = 249.04 [M + H]+.
4
-(Benzoylamino)-1-[5-O-[tert-butyl(dimethyl)silyl]-2-deoxy-4-
(2) Parikh, U.; Koontz, D.; Sluis-Cremer, N.; Hammond, J.;
th
ethynyl-3-O-(methoxymethyl)-b-erythro-pentofuranosyl]-5-
fluoropyrimidin-2(1H)-one (16-b)
A suspension of N-benzoyl 5-fluorocytosine (13.0 g, 55.8 mmol)
and N,O-bis(trimethylsilyl)acetamide (27.5 mL, 112 mmol) in
MeCN (250 mL) was heated at reflux for 0.5 h. The mixture was
cooled to r.t. and 11 (14.0 g, 39.1 mmol) was added followed by
TMSOTf (14.1 mL, 78.1 mmol). The mixture was stirred at r.t. for
Bacheler, L.; Schinazi, R.; Mellors, J. 11 Annual
Conference on Retroviruses and Opportunistic Infections;
San Francisco, CA, February 8–11, 2004; Paper #54.
(3) Agarwal, R. P. A.; Olivero, O. Mutat. Res. 1997, 390, 223.
(4) (a) Summerer, D.; Marx, A. Bioorg. Med. Chem. Lett. 2005,
15, 869. (b) Dutchman, G. E.; Grill, S. P.; Gullen, E. A.;
Haraguchi, K.; Takeda, S.; Tanaka, H.; Baba, M.; Cheng, Y.-
C. Antimicrob. Agents Chemother. 2004, 48, 1640.
2
h and quenched with sat. aq Na CO (200 mL), and diluted with
2 3
EtOAc (1 L). The EtOAc layer was washed with brine (500 mL),
dried (MgSO ) and concentrated in vacuo. The residue was purified
(c) Kodama, E.-I.; Kohgo, S.; Kitano, K.; Machida, H.;
Gatanaga, H.; Shigeta, S.; Matsuoka, M.; Ohrui, H.;
4
by flash chromatography eluting with 2:1 hexanes–EtOAc to give
Mitsuya, H. Antimicrob. Agents Chemother. 2001, 45, 1539.
(5) (a) Secrist, J. A. III; Winter, W. J. A. Jr. J. Am. Chem. Soc.
1978, 100, 2554. (b) Youssefyeh, R. D.; Verheyden, P. H.;
Moffat, J. G. J. Org. Chem. 1979, 44, 1301. (c) Haraguchi,
K.; Tanaka, H.; Miyasaka, T. Tetrahedron Lett. 1990, 31,
227. (d) Haraguchi, K.; Tanaka, H.; Itoh, Y.; Saito, S.;
Miyasaka, T. J. Org. Chem. 1992, 33, 2841. (e) Johnson, C.
R.; Esker, J. L.; Van Zandt, M. C. J. Org. Chem 1994, 59,
9
.66 g (47%) of 16-a as a white solid, 1.95 g (9%) of an anomeric
mixture, and 6.47 g (31%) of 16-b as a white solid.
1
6-a
Mp 145–146 °C; R = 0.60 (2:1 hexanes–EtOAc).
f
1
H NMR (300 MHz, CDCl ): d = 8.11–8.34 (m, 3 H), 7.51–7.59 (m,
3
1
H), 7.41–7.49 (m, 2 H), 6.15–6.21 (m, 1 H), 4.77 (d, J = 6.8 Hz, 1
5854. (f) Haraguchi, K.; Tanaka, H.; Itoh, Y.; Yamaguchi,
H), 4.65 (d, J = 6.8 Hz, 1 H), 4.43 (dd, J = 6.0, 3.3 Hz, 1 H), 3.81
K.; Miyasaka, T. J. Org. Chem. 1996, 61, 851. (g) Marx,
A.; Erdmann, P.; Senn, M.; Korner, S.; Jungo, T.; Petretta,
M.; Imwinkelried, P.; Dussy, A.; Kulicke, K. J.; Macko, L.;
Zehnder, M.; Tiese, B. Helv. Chim. Acta 1996, 79, 1980.
(h) Shuto, S.; Knanzaki, M.; Ichikawa, S.; Matsuda, A. J.
Org. Chem. 1997, 62, 5676. (i) Shuto, S.; Knanzaki, M.;
Ichikawa, S.; Minakawa, N.; Matsuda, A. J. Org. Chem.
(
(
1
d, J = 10.9 Hz, 1 H), 3.76 (d, J = 10.9 Hz, 1 H), 3.37 (s, 3 H), 2.90
dt, J = 14.3, 6.6 Hz, 1 H), 2.18 (s, 1 H), 2.23 (dt, J = 14.3, 3.3 Hz,
H), 0.91 (s, 9 H), 0.09 (s, 6 H).
1
3
C NMR (75 MHz, CDCl ): d = 153.2, 152.9, 146.4, 141.0, 138.0,
3
1
6
36.0, 133.0, 130.0, 128.4, 127.3, 96.0, 87.8, 87.1, 79.4, 78.6, 76.4,
7.4, 55.9, 39.9, 25.9, 18.3.
1
998, 63, 746. Compound 1: (j) Sugimoto, I.; Shuto, S.;
1
6-b
Mori, S.; Shigeta, S.; Matsuda, A. Bioorg. Med. Chem. Lett.
1999, 9, 385. Compound 2: (k) Haraguchi, K.; Takeda, S.;
Tanaka, H.; Nitanda, T.; Baba, M.; Dutschman, G. E.;
Cheng, Y.-C. Bioorg. Med. Chem. Lett. 2003, 13, 3775.
(l) Haraguchi, K.; Takada, S.; Tanaka, H. Org. Lett. 2003, 5,
1399. (m) Haraguchi, K.; Itoh, Y.; Takeda, S.; Honma, Y.;
Tanaka, H.; Nitanda, T.; Baba, M. D.; Dutschman, G. E.;
Cheng, Y.-C. Nucleosides, Nucleotides Nucleic Acids 2004,
Mp 140–141 °C, R = 0.50 (2:1 hexanes–EtOAc).
f
1
H NMR (300 MHz, CDCl ): d = 8.15–8.34 (m, 3 H), 7.50–7.58 (m,
3
1
H), 7.40–7.49 (m, 2 H), 6.22–6.28 (m, 1 H), 4.73 (d, J = 6.9 Hz, 1
H), 4.70 (d, J = 6.9 Hz, 1 H), 4.41 (dd, J = 8.5, 6.9 Hz, 1 H), 4.07
d, J = 11.3 Hz, 1 H), 3.91 (d, J = 11.3 Hz, 1 H), 3.40 (s, 3 H), 2.65–
(
2
0
.78 (m, 1 H), 2.66 (s, 1 H), 2.36 (ddd, J = 13.7, 6.9, 3.3 Hz, 1 H),
.95 (s, 9 H), 0.17 (s, 6 H).
23, 647. Compound 3: (n) Ohrui, H.; Kohgo, S.; Kitano, K.;
Sakata, S.; Kodama, E.; Yoshimura, K.; Matsuoka, M.;
Shigeta, S.; Mitsuya, H. J. Med. Chem. 2000, 43, 4516.
Synthesis 2007, No. 9, 1378–1384 © Thieme Stuttgart · New York

1
384
(
A. Maddaford et al.
PAPER
6) (a) Marco, J. A.; Carda, M.; Gonzalez, F.; Rodriguez, S.;
Zhu, W.; Chong, Y.; Choo, H.; Mathews, J.; Schinazi, R.;
Chu, C. K. J. Med. Chem. 2004, 47, 1631.
Castillo, E.; Murga, J. J. Org. Chem. 1998, 63, 698.
(
b) This reference explains the observed syn addition of
(8) Vorbruggen, H.; Ruh-Pohlenz, C. In Handbook of
Nucleoside Synthesis; Wiley: New York, 2001, 15.
(9) Duschinsky, R.; Gabriel, T.; Hoffer, M.; Berger, J.;
Titsworth, E.; Grunberg, E.; Burchenal, J. H.; Fox, J. J. J.
Med. Chem. 1966, 9, 566.
(10) (a) Tan, C.-H.; Stork, T.; Feeder, N.; Holmes, A. B.
Tetrahedron Lett. 1999, 40, 1397. (b) Song, J.;
ethynylmagnesium bromide by an a-chelate where the
oxygen atom alpha to the ketone forms a 5-ring chelate as
shown in Figure 2. Ether protecting groups other than MOM
are expected to afford good chelation control since the
authors in reference 6 report 91:9 syn-selectivity using
ethynylmagnesium chloride and a ketone substrate having
a-OBn in place of MOM and TBDPS in place of TBDMS.
7) For another nucleoside example of building functionality
into an acyclic intermediate followed by ring-closure, see:
Hollingsworth, R. I. Tetrahedron: Asymmetry 2001, 12, 387.
(
Synthesis 2007, No. 9, 1378–1384 © Thieme Stuttgart · New York