A synthesis of 5'-amino-3',5'-dideoxyuridine

Article abstract of DOI:10.1055/s-2000-6346

The synthesis of 3',5'-dideoxy-5'-aminouridine starting from uridine is described.

Full text of DOI:10.1055/s-2000-6346

PAPER
399
A Synthesis of 5’-Amino-3’,5’-dideoxyuridine
David M. Bender, D. David Hennings, Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, USA
Fax +1 (970)4915610; E-mail: rmw@chem.colostate.edu
Received 22 September 1999, revised 26 november 1999
presence of the radical initiator AIBN to give the corre-
sponding 3’-deoxyuridine derivative 5 in 98% yield. Se-
lective deprotection12 of the 5’-O-silyl ether was
accomplished using hydrofluoric acid in acetonitrile to
give the primary alcohol 6 (86%).
Abstract. The synthesis of 3’,5’-dideoxy-5’-aminouridine starting
from uridine is described.
Key words: 3’,5’-dideoxy-5’-aminouridine, mureidomycin, nucleo-
side, deoxygenation, azidation
Several methods for the conversion of the uridine 5’-hy-
droxyl group to the corresponding amine have been re-
ported in the literature. The classical method involves
formation of the mesylate or tosylate derivative followed
by SN2 displacement with azide and subsequent reduction
to produce the corresponding amine.13 More recently,
Yamamoto14 reported the one-pot synthesis of azido de-
rivatives of nucleosides by reaction of the primary alcohol
with a mixture of LiN3/Ph3P/CBr4. When alcohol 6 was
subjected to either of these conditions, only starting mate-
rials were recovered. The Mitsunobu reaction15 is an ef-
fective method for the conversion of alcohols to a variety
of different functional groups and this protocol was ex-
tended to generate the desired 5’-azido intermediate. Al-
cohol 6 was subjected to standard Mitsunobu conditions
(DEAD/Ph3P) in the presence of a freshly prepared tolu-
ene solution of HN3 to give an excellent yield (93%) of
azide 7. Catalytic hydrogenation with 10% Pd/C produced
the 2’-O-TBS-protected amine 8 in 90% yield. This inter-
mediate should be useful as a template for the synthesis of
saturated analogs of Mureidomycin A (1), which could be
obtained via peptide coupling reactions with the free 5’-
amino group. A small amount of 8 was deprotected using
HF to give the title compound 2 in an overall yield of 38%
from uridine.
The synthesis of pyrimidine nucleosides containing a
modified glycosyl moiety has resulted in the generation of
molecules with significant biological activity. Uridine nu-
cleosides which possess a 5’-amino group have been stud-
ied for their antiviral,1 antibacterial2 and antifungal3
properties. Similarly, uridine nucleosides lacking the 3’-
hydroxyl group have been found to exhibit potent
antitumor4 and antiparasitic5 activity. A recently discov-
ered family of antibiotics, the mureidomycins6 (1), the
pacidamycins,7 and the napsamycins8 were all found to
contain an unusual pyrimidine nucleoside having both of
these types of functionality. Ongoing efforts toward the
synthesis of analogs of these natural products required ac-
cess to synthetically useful quantities of suitably protected
derivatives of 5’-amino-3’,5’-dideoxyuridine (2). A search
of the literature did not reveal any previous reports for the
preparation of this compound. Described herein is an effi-
cient procedure to synthesize an O-TBS-(tert-butyldime-
thylsilyl)-protected derivative of 2.
SMe
O
Me
O
OH
H
N
H2N
N
N
H
N
H
CO2H
O
O
5'-Amino-3’,5’-dideoxyuridine (2) was prepared from
uridine in a straightforward and efficient manner. This
procedure also represents a useful application of the Mit-
sunobu reaction as a means to introduce nitrogen func-
tionality in the pentose moiety of nucleosides. This
reaction sequence should be applicable to the synthesis of
similarly functionalized analogs of other pyrimidine as
well as purine nucleosides.
HO
Me
O
HN
O
NH
O
O
H2N
N
O
N
NH
OH
O
1, Mureidomycin A
OH
2
As shown in the Scheme, commercially available uridine
was selectively protected as the 2’,5’-O-TBS derivative 3
following the published procedure.9 The 3’-hydroxyl
group was treated with phenyl chlorothionoformate in the 1H NMR spectra were obtained on a Bruker AC 300 MHz spectro-
meter and chemical shifts were reported in parts per million relative
presence of 4-(dimethylamino)pyridine (DMAP) to give
thiocarbonate 4.10 Using a catalytic amount of DMAP, a
to TMS (0.00), CDCl3 (7.24), DMSO-d6 (2.54), or D2O (4.80). The
numbers in parentheses were specified by Cambridge Isotope Labs,
small quantity of the desired product was isolated after 72
hours. Increasing the amount of DMAP greatly reduced
the reaction time, and when 4 equivalents were used, the
reaction was complete furnishing 4 in good yield (86%)
after only a few hours. Reductive deoxygenation10,11 was
carried out using tributyl or triphenyltin hydride in the
Andover, MA. IR spectra were recorded on a Perkin-Elmer 1600
Series FTIR as KBr pellets or thin films from CH2Cl2 on NaCl
plates. Optical rotations were determined on a Rudolph Research
Autopol III automatic polarimeter at a wavelength of 589 nm (sodi-
um D line) with a 1.0 dm cell and a volume of 1 mL. Specific rota-
tions are reported in degrees per decimeter at 25 °C and
Synthesis 2000, No. 3, 399–402 ISSN 0039-7881 © Thieme Stuttgart · New York

400
D. M. Bender et al.
PAPER
O
O
O
HN
HN
HN
S
O
O
Ph3SnH, AIBN
TBSO
O
HO
N
N
TBSO
HO
TBSCl, pyr.
N
O
Cl
O
O
O
DMAP, MeCN
25°C, 1 h.
toluene, reflux, 24 h.
98%
25°C, 48 h.
70%
O
HO
uridine
OTBS
OH
OTBS
S
86%
PhO
3
4
O
O
O
HN
HN
HN
HN3 (1M in PhMe)
HF/CH3CN
O
O
TBSO
N
O
N3
N
HO
O
N
O
O
O
0-25°C, 1.5h
86%
Ph3P, DEAD, THF
25°C, 24 h
OTBS
OTBS
OTBS
5
6
7
93%
O
HN
HN
H2, 40 psi, 10% Pd/C
O
H2N
HF/CH3CN
N
O
O
H2N
N
O
EtOH, 5h
90%
25°C, 1.5h
90%
OTBS
OH
8
2
Scheme
concentration of grams per 100 mL. Melting points were obtained
using a Mel-Temp apparatus and are uncorrected. Elemental analy-
ses were performed by M-H-W Laboratories in Phoenix, AZ and are
accurate to within ±0.4%. Mass spectra were obtained on a Fisons
VG Autospec at the Chemistry Department at Colorado State Uni-
versity. Column chromatography was performed with Merck silica
gel grade 60, 230-400 mesh, 60 Å. Analytical preparatory TLC was
performed with Merck Kieselgel 60 F254 plates. Reagents and sol-
vents were all commercial grade and used without further purifica-
tion with the exception of THF (distilled over sodium,
benzophenone), CH2Cl2 (distilled over CaH2), Et2O (distilled over
sodium, benzophenone), and DMF and HMPA (dried over 4Å mo-
lecular sieves). All air-sensitive reactions were run under an atmo-
sphere of nitrogen or argon. All glassware was oven or flame-dried
prior to use.
reaction was warmed to 25 ∞C and stirred for 2 h. The layers were
separated and the organic phase was washed with 0.1 M HCl and
H2O, dried (MgSO4) and concentrated to a yellow oil. Kugelrhor
distillation (bp 78-81 ∞C/8 Torr, Lit.16,17 bp 81-83 ∞C/6 Torr) gave
15.6 g (85%) of phenoxythiocarbonyl chloride (phenyl chlorothion-
oformate) as a bright yellow oil.
2’,5’-Bis-O-(tert-butyldimethylsilyl)-3’-O-(phenoxythiocarbon-
yl)uridine (4)
To a stirred solution of 3 (24.84 g, 53.97 mmol) and 4-(dimethyl-
amino)pyridine (24.90 g, 204.0 mmol) in anhyd MeCN (250 mL)
was added dropwise phenyl chlorothionoformate (7.90 mL, 57.10
mmol) under N2 at r.t.. After 1 h, all starting material had been con-
sumed. The solvent was removed under reduced pressure and the
crude solid was dissolved in CH2Cl2 (400 mL) and extracted with
cold 1.0 M HCl (2 × 100 mL), aq sat. NaHCO3 (2 × 100 mL), and
brine (2 × 100 mL). The organic layer was dried (MgSO4) and con-
centrated to give a yellow oil which was purified by silica gel (500
g) column chromatography (4:1 to 1:2 hexanes/EtOAc) to yield
27.00 g (86%) of 4 as a light yellow crystalline solid; mp 54-56 ∞C
(dec.); [a]D +46.2 (c = 1.0, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.12 (12 H, m), 0.91 (18 H, d, J =
9.52 Hz), 3.81 (1 H, 1/2ABq, J = 15.3 Hz), 3.97 (1 H, 1/2 ABq,
J = 12.8 Hz), 4.36 (1 H, m), 4.42 (1 H, t, J = 4.48 Hz), 5.49 (1 H, t,
J = 4.76 Hz), 5.61 (1 H, d, J = 8.1 Hz), 5.92 (1 H, d, J = 3.8 Hz),
6.92-7.39 (5 H, m), 7.88 (1 H, d, J = 8.1 Hz), 8.78 (1 H, s, D2O ex-
changeable).
2’,5’-Bis-O-(tert-butyldimethylsilyl)uridine (3)
Uridine (20.0 g, 81.9 mmol) was dissolved in anhyd pyridine (160
mL) and stirred at r.t. for 10 min. tert-Butyldimethylsilyl chloride
(30.86 g, 204.8 mmol) was added in a single portion and the mixture
was stirred at r.t. for 48 h. The mixture was concentrated under vac-
uum and the resulting crude material was dissolved in CH2Cl2 (500
mL), washed with aq 5% NaHCO3 solution (2 × 100 mL), dried
(MgSO4), and concentrated to a white foam. The product was puri-
fied by silica gel (800 g) column chromatography (Et2O/hexane, 2:1
v/v) to yield 26.3 g (70%) of 3 as a white solid; mp 122 °C (Lit.9 mp
122 °C); [a]D +20.6 (c = 0.5, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.09 (12 H, m), 0.88 (9 H, s), 0.90
(9 H, s), 2.61 (1 H, d, J = 4.8 Hz, D2O exchangeable), 3.79 (1 H, 1/
2Abx, J = 1.1, 11.7 Hz), 3.96 (1 H, 1/2Abx, J = 1.5, 11.7 Hz),
4.05-4.18 (3 H, m), 5.66 (1 H, dd, J = 2.2, 8.1 Hz), 5.94 (1 H, d,
J = 4.1 Hz), 7.96 (1 H, d, J = 8.1 Hz), 9.41 (1 H, s, D2O exchange-
able).
13C NMR (75.48 MHz, CDCl3): d = -5.4, -5.1, -4.8, 18.0, 18.4,
25.6, 25.9, 62.1, 74.2, 77.5, 79.6, 81.9, 89.0, 102.4, 121.6, 126.7,
129.6, 139.6, 150.3, 153.2, 162.5, 189.2.
IR (neat): n = 3413, 1682 cm-1.
HRMS (FAB): m/z calcd for C28H45N2O7SSi2 (MH+): 609.2503.
13C NMR (75 MHz, CDCl3): d = -5.5, -5.4, -5.2, -4.7, 18.0, 18.4,
Found: 609.2487.
25.7, 25.9, 62.5, 70.3, 76.5, 84.7, 88.5, 102.3, 140.0, 150.2, 163.3.
Anal. calcd for C28H44N2O7SSi2: C, 55.23; H, 7.28; N, 4.60. Found:
C, 55.47; H, 7.06; N, 4.57.
IR (neat): n = 3452, 3190, 1683 cm -1
.
2’,5’-Bis-O-(tert-butyldimethylsilyl)-3’-deoxyuridine (5)
Phenyl Chlorothionoformate
Compound 4 (7.51 g, 12.90 mmol) was dissolved in anhyd toluene
(180 mL) and 2,2’-azobis(2-methylpropionitrile) (AIBN, 2.78 g,
16.93 mmol) was added and the solution was degassed with N2 for
Phenol (10.0 g, 106.3 mmol) was dissolved in CHCl3 (64 mL) and
aq 5% NaOH solution (95 mL) and cooled to 0 ∞C in an ice bath.
Thiophosgene (8.1 mL, 106.3 mmol) was added dropwise and the
Synthesis 2000, No. 3, 399–402 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Synthesis of 5’-Amino-3’,5’-dideoxyuridine
401
10 min. Triphenyltin hydride (7.90 g, 22.51 mmol) was added in a
single portion and the solution was heated at reflux temperature for
23 h. The solvent was removed under reduced pressure and the
crude material was purified by silica gel (250 g) column chromatog-
raphy (hexanes to 1:2 hexanes/EtOAc) to give 5.77 g (98%) of 5 as
a white foam; [a]D +9.7 (c = 1.3, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.13 (12 H, m), 0.92 (18 H, m),
1.69-1.76 (1 H, m), 2.01-2.09 (1 H, m), 3.72 (1 H, 1/2 ABq,
J = 12.1 Hz), 4.18 (1 H, 1/2 ABq, J = 12.0 Hz), 4.35 (1 H, d, J = 3.9
Hz), 4.47-4.53 (1 H, m), 5.62 (1 H, d, J = 8.1 Hz), 5.73 (1 H, s),
8.16 (1 H, d, J = 8.1 Hz), 8.50 (1 H, s, D2O exchangeable).
1H NMR (300 MHz, CDCl3): d = 0.08 (3 H, s), 0.12 (3 H, s), 0.88
(9 H, s), 1.69-2.01 (2 H, m), 3.55 (1 H, 1/2ABx, J = 3.9, 13.5 Hz),
3.82 (1 H, 1/2ABx, J = 3.3, 13.5 Hz), 4.39 (1 H, m), 4.55 (1 H, m),
5.70 (1 H, s), 5.74 (1 H, d, J = 8.1 Hz), 7.69 (1 H, d, J = 8.1 Hz),
8.62 (1 H, s, D2O exchangeable).
13C NMR (75 MHz, CDCl3): d = -5.2, -4.8, 14.4, 17.8, 25.6, 35.3,
53.0, 62.1, 78.7, 93.2, 101.7, 139.6, 150.1, 163.6.
IR (neat): n = 3211, 2102, 1713 cm-1.
HRMS (FAB): m/z calcd for C15H26N5O4Si (MH+): 368.1754.
Found: 368.1739.
13C NMR (75 MHz, CDCl3): d = -5.6, -5.5, -5.2, -4.7, 17.8, 18.4,
5'-Amino-2'-O-(tert-butyldimethylsilyl)-3',5’-dideoxyuridine
(8)
23.3, 32.7, 39.3, 62.7, 81.6, 92.3, 100.9, 136.3, 140.3, 150.1, 163.7.
IR (neat): n = 3171, 1682 cm-1.
HRMS (FAB): m/z calcd for C21H41N2O5Si2 (MH+): 457.2554.
The azidouridine 7 (0.30 g, 0.82 mmol) was combined with 10%
Pd/C in absolute EtOH and hydrogenated under 40 psi of H2 for 8
h. The mixture was concentrated to a clear oil under reduced pres-
sure. The product crystallized upon the addition of Et2O to afford
245 mg (88%) of 8; mp 89-91 °C (dec.); [a]D -26.3 (c = 0.3,
CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.08 (3 H, s), 0.12 (3 H, d), 0.89
(9 H, s), 1.65 (2 H, s, D2O exchangeable), 1.80-1.87 (1 H, m),
2.06-2.16 (1 H, m), 3.75 (1 H, d, J = 12.0 Hz), 4.10 (1 H, d, J = 11.7
Hz), 4.48 (2 H, m), 5.63 (1 H, d, J = 0.9 Hz), 5.69 (1 H, d, J = 8.1
Hz), 7.87 (1 H, d, J = 8.1 Hz), 8.62 (1 H, s, D2O exchangeable).
13C NMR (75 MHz, CDCl3): d = -5.1, -4.7, 14.4, 17.9, 25.6, 35.7,
62.1, 93.4, 101.5, 140.0, 150.1, 156.7, 163.6.
IR (CH2Cl2): n = 3853, 3744, 3196, 1694 cm-1.
HRMS (FAB): m/z calcd for C15H28N3O4Si (MH+): 342.1849.
Found: 457.2561.
2’-O-(tert-Butyldimethylsilyl)-3’-deoxyuridine (6)
Compound 5 (2.01 g, 4.40 mmol) was dissolved in MeCN (220 mL)
and cooled to 0 ∞C with an ice/water bath. The mixture was treated
with a 5% solution of HF in MeCN (17.0 mL) and stirred at 0 ∞C for
30 min. The mixture was allowed to warm to r.t. and stirred for an-
other hour. The mixture was quenched with solid NaHCO3, filtered,
concentrated under reduced pressure and the residue was chromato-
graphed over silica gel (100 g) (15:1 CH2Cl2/MeOH) to yield 1.30
g (86%) of 6 as a white foam; mp 58-60 ∞C (dec.); [a]D -9.8
(c = 1.0, CH2Cl2).
1H NMR (300 MHz, CDCl3): d = 0.07 (3 H, s), 0.11 (3 H, s), 0.86
(9 H, s), 1.79 (1 H, ddd, J = 2.6, 5.9, 12.8 Hz), 2.02-2.11 (1 H, m),
2.82 (1 H, br s, D2O exchangeable), 3.71 (1 H, 1/2 ABx,
J = 2.6, 12.1 Hz), 4.07 (1 H, 1/2 ABx, J = 1.8, 12.1 Hz), 4.43-4.51
(2 H, m), 5.60 (1 H, d, J = 1.8 Hz), 5.67 (1 H, d, J = 8.1 Hz), 7.82
(1 H, d, J = 8.0 Hz), 9.36 (1 H, br s, D2O exchangeable).
Found: 342.1853.
5'-Amino-3',5’-dideoxyuridine (2)
The aminouridine 8 (8.4 mg, 0.025 mmol) was dissolved in anhyd
MeCN (1.0 mL) and treated with a solution of HF (5%) in MeCN
(1.0 mL). The mixture was stirred at r.t. for 1.5 h at which time the
starting material was consumed (TLC monitoring). The solvent was
removed under reduced pressure giving a white solid which was
triturated with cold EtOH to give 5.0 mg (90%) of 2 as a white solid;
[a]D +7.1 (c = 0.6, 1 N HCl).
13C NMR (75 MHz, CDCl3): d = -5.0, -4.7, 17.9, 25.7, 33.6, 62.6,
76.5, 81.2, 94.0, 101.3, 141.0, 150.1, 163.6.
IR (neat): n = 3399, 1684 cm-1.
HRMS (FAB): m/z calcd for C15H27N2O5Si (MH+):343.1689.
Found 343.1697.
1H NMR (300 MHz, D2O): d = 2.02-2.08 (1 H, m), 2.13-2.21 (1 H,
m), 3.21-3.29 (1 H, dd, J = 9.3, 13.6 Hz), 3.41 (1 H, dd,
J = 2.6, 13.6 Hz), 4.59-4.64 (2 H, m), 5.75 (1 H, d, J = 1.8 Hz),
5.84 (1 H, d, J = 8.1 Hz), 7.62 (1 H, d, J = 8.0 Hz).
13C NMR (75 MHz, D2O): d = 35.5, 42.7, 74.9, 76.7, 94.3, 101.7,
142.2, 151.4, 166.3.
Anal. Calcd for C15H26N2O5Si: C, 52.61; H, 7.65; N, 8.18. Found:
C, 52.73; H, 7.70, N; 8.23.
Preparation of Hydrazoic Acid Solution
A slurry of NaN3 (5.0 g, 0.08 mmol) in H2O (5 mL) was covered
with anhyd toluene (50 mL) and cooled to 0 °C while stirring under
N2. Conc. H2SO4 (2.2 mL, 0.04 mmol) was added dropwise over 10
min. Upon completion of the addition, the flask was placed in a
-78 °C bath and the toluene was decanted off and dried (MgSO4).
A small aliquot of the toluene solution was diluted with H2O and ti-
trated with aq 1 M NaOH solution using phenolphthalein indicator.
Typical concentrations of HN3 ranged from 0.6 to 1.5 M. These so-
lutions were generally used immediately, but could be stored at 0 °C
for several days if necessary.
HRMS (FAB): m/z calcd for C9H14N3O4 (MH+): 228.0984. Found:
228.0991.
Acknowledgement
This work was supported by the National Science Foundation and
the National Institutes of Health. Mass spectra were obtained on in-
struments supported by the National Institutes of Health Shared In-
strumentation Grant GM49631.
5’-Azido-2’-O-(tert-butyldimethylsilyl)-3',5’-dideoxyuridine
(7)18
2’-O-(tert-butyldimethylsilyl)-3’-deoxyuridine (6; 500 mg, 1.46
mmol) was dissolved in freshly distilled THF (10 mL) and stirred at
r.t. under Ar. Ph3P (422 mg, 1.61 mmol) was added followed by
HN3 (1.52 mL of a 1.06 M solution in toluene, 1.61 mmol) and
DEAD (254 mL, 1.61 mmol). The mixture was stirred at r.t. under
argon for 24 h. The solvent was removed and the residue was chro-
matographed over silica gel (20:1 CH2Cl2/MeOH) to yield 498 mg
(93%) of 7 as a colorless oil; [a]D -38.6 (c = 0.3, CH2Cl2).
References
(1) (a) Lin, T.-S.; Neenan, J.P.; Cheng, Y.-C.; Prusoff, W.H. J.
Med. Chem. 1975, 19, 495.
(b) Lin, T.-S.; Chai, C.; Prusoff, W.H. J. Med. Chem. 1976,
19, 915.
(c) Schinazi, R.F.; Chen, M.S.; Prusoff, W.H. J. Med. Chem.
1979, 22, 1273.
Synthesis 2000, No. 3, 399–402 ISSN 0039-7881 © Thieme Stuttgart · New York

402
D. M. Bender et al.
PAPER
(2) Paul, P.; Lutz, T.M.; Osborn, C.; Kyosseva, S.; Elbein, A.D.;
Towbin, H.; Radominska, A.; Drake, R.R. J. Biol. Chem.
1993, 268, 12933.
(3) Ohrui, H.; Kuzuhara, H.; Emoto, S. Tetrahedron Lett. 1971,
45, 4267.
J.Antibiot. 1989, 42, 512.
(c) Fernandes, P.B.; Swanson, R.N. Hardy, D.J.; Hanson,
C.W.; Coen, L.; Rasmussen, R.R.; Chen, R.H., J.Antibiot.
1989, 42, 521.
(8) Chaterjee, S.; Nadkarni, S.R.; Vijayakumar, E.K.S.; Patel,
M.V.; Ganguli, B.N.; Fehlhaber, H.-W.; Vertesy, L.,
J.Antibiot. 1994, 47, 595.
(4) (a) Webb, T.R.; Mitsuya, H.; Broder, S.J. J. Med. Chem. 1988,
31, 1475.
(b) Lin, T.-S.; Yang, J.-H.; Liu, M.-C.; Shen, Z.-Y.; Cheng,
Y.-C.; Prusoff, W.H.; Birnbaum, G.I.; Giziewicz, J.;
Ghazzouli, I.; Brankovan, V.; Feng, J.-S.; Hsiung, G.-D. J.
Med. Chem. 1991, 34, 693.
(9) Ogilvie, K.K.; Beaucage, S.L.; Schifman, A.L.; Theriault,
N.Y.; Sadana, K.L. Can. J. Chem. 1978, 56, 2768.
(10) (a) Robins, M.J.; Wilson, J.S. J. Am. Chem. Soc. 1981, 103,
932.
(5) (a) Moorman, A.R.; LaFon, S.W.; Nelson, D.J.; Carter, H.H.
Biochem. Pharmacol. 1991, 42, 207.
(b) Robins, M.J.; Wilson, J.S.; Hansske, F. J. Am. Chem. Soc.
1983, 105, 4059.
(b) Nakajima-Shimada, J.; Hirota, Y.; Aoki, T. Antimicrob.
Agents Chemother. 1996, 40, 2455.
(11) Barton, D.H.R.; McCombie, S.W. J. Chem. Soc., Perkin Trans
1 1975, 1574.
(c) el Kouni, M.H.; Naguib, F.N.M.; Panzica, R.P.; Otter,
B.A.; Chu, S.-H.; Gosselin, G.; Chu, C.K.; Schinazi, R.F.;
Shealy, Y.F.; Goudgaon, N.; Ozerov, A.A.; Ueda, T.; Iltzch,
M.H. Biochem. Pharmacol. 1996, 51, 1687.
(6) (a) Inukai, M.; Isono, F.; Takahashi, S.; Enokita, R.; Sakaida,
Y.; Haneishi, T. J. Antibiot. 1989, 42, 662.
(12) Nelson, T.D.; Crouch, R.D. Synthesis 1996, 1031.
(13) (a) Horwitz, J.P.; Tomson, A.J.; Urbanski, J.A.; Chua, J. J.
Org. Chem. 1962, 27, 3045.
(b) Skaric, V.; Katalenic, D.; Skaric, D.; Salaj, I. J. Chem.
Soc., Perkin Trans 1 1982, 2091.
(14) Yamamoto, I.; Sekine, M.; Hata, T. J. Chem. Soc., Perkin
Trans. 1 1980, 306.
(b) Isono, F.; Inukai, M.; Takahashi, S.; Haneishi, T. J.
Antibiot. 1989, 42, 667.
(15) Mitsunobu, O. Synthesis 1981, 1.
(c) Isono, F.; Katayama, T.; Inukai, M.; Haneishi, T. J.
Antibiot. 1989, 42, 674.
(16) Miyazaki, M.; Nakanishi, K. Jap. Patent 1322 (1957); Chem.
Abstr. 1958, 52, 4684.
(d) Sakaida, Y.; Takahashi, S.; Kinoshita, T.; Nakamura, T.;
Inukai, M., J.Antibiot. 1993, 46, 1203.
(e) Isono, F.; Inukai, M. Antimicrob. Agents. Chemother.
1991, 35, 234.
(f) Inukai, M.; Isono, F.; Takatsuki, A. Antimicrob. Agents
Chemother. 1993, 37, 980.
(17) Available from Aldrich Chemical.
(18) Due to potential safety considerations of handling the azide,
smaller scale reactions were conducted from this point
forward. Although no safety problems were encountered with
this substrate, conservative reaction scales seemed the most
prudent approach.
(g) Brandish, P.E.; Burnham, M.K.; Lonsdale, J.T.; Southgate,
R.; Inukai, M.; Bugg, T.D.H. J. Biol. Chem. 1996, 271, 7609.
(7) (a) Karwowski, J.P.; Jackson, M.; Theriault, R.J.; Chen, R.H.;
Barlow, G.J.; Maus, M.L., J.Antibiot. 1989, 42, 506.
(b) Chen, R.H.; Buko, A.M.; Whittern, D.N.; McAlpine, J.B.,
Article Identifier:
1437-210X,E;2000,0,03,0399,0402,ftx,en;M02799SS.pdf
Synthesis 2000, No. 3, 399–402 ISSN 0039-7881 © Thieme Stuttgart · New York