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DOI: 10.1055/s-0029-1219436
Synthesis of a Deoxyxylopuromycin Analogue
Publication History
Publication Date:
23 February 2010 (online)
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Abstract
N6-Bis-demethylated deoxyxylopuromycin was synthesized over six steps in 56% overall yield. The key steps are Mitsunobu reaction with DPPA and a Staudinger-Vilarrasa coupling.
Key words
Antibiotic - ribosome - azide - Mitsunobu - Staudinger-Vilarrasa
- Supporting Information for this article is available online:
- Supporting Information
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References and Notes
5′-
O
-(
tert
-Butyldiphenylsilyl)-2′-deoxyadenosine
(6)
TBDPSCl (1.6 g, 5.7 mmol) was added to 5 (1.2 g, 4.8 mmol) in dry pyridine (24
mL), and the solution was stirred for 18 h at r.t. under N2.
H2O (2 mL) was added, stirring was continued for 30 min,
and the volatiles were evaporated. The residue was partitioned (H2O-EtOAc),
and the organic phase was washed with H2O (2 × 50
mL) and brine, then dried (Na2SO4). The volatiles
were evaporated, and the residue was column chromatographed (step
gradient from EtOAc-cyclohexane = 1:1 to 1:0 and
then to EtOAc-MeOH = 95:5) to yield 6 (2.0 g, 88%). R
f
= 0.33 (EtOAc-MeOH = 9:1). ¹H
NMR (300 MHz, CDCl3): δ = 1.06 [s,
9 H, SiC(CH3)3], 2.53 (ddd, 1 H, J = 13.4,
6.2, 4.0 Hz, HA2′), 2.75 (td, 1 H, J = 13.1,
6.4 Hz, HB2′), 3.79-3.98 (m, 2 H, H5′5′′), 4.71-4.75
(m, 1 H, H3′), 5.84 (s, 2 H, NH2), 6.46 (t,
1 H, J = 6.5
Hz, H1′), 7.31-7.45 (m, 6 H, ar), 7.62-7.65
(m, 4 H, ar), 8.02 (s, 1 H, H2), 8.29 (s, 1 H, H8). ¹³C
NMR (70 MHz, CDCl3 + CD3OD): δ = 18.7
(SiC), 26.3 [(CH3)3], 40.6
(C2′), 63.4 (C5′5′′), 70.6 (C3′),
84.0 (C1′), 87.1 (C4′), 118.8 (C5), 127.3 (p-ar), 129.4, 129.4 (o-ar),
132.1, 132.4 (i-ar), 134.9, 135.1 (m-ar), 138.2 (C2), 148.4 (C4), 152.1
(C6), 155.1 (C8). MS (ESI+): m/z = 490.1 [MH]+
6-
N
-[(di-
n
-Butylamino)methylene]-5′-
O
-(
tert
-butyl-diphenylsilyl)-2′-deoxyadenosine
(7)
Compound 6 (600 mg, 1.3 mmol) was dissolved in MeOH
(5 mL). N,N-Di-n-butylformamide dimethylacetal (600
mg, 2.6 mmol) was added, and the solution was stirred for 2 h at
r.t. The volatiles were removed under reduced pressure, and the residue
was purified using silica gel column chromatog-raphy (EtOAc-MeOH = 100:0
to 95:5 step gradient) to yield 7 (750
mg, 98%). R
f
= 0.45 (CH2Cl2-MeOH = 9.5:0.5). ¹H NMR
(300 MHz, CDCl3): δ = 0.82-0.88
(m, 6 H, 2 × NCH2CH2CH2CH3),
0.96 [(s, 9 H, SiC(CH3)3],
1.23-133 (m, 4 H, 2 × NCH2CH2CH2CH3),
1.49-1.62 (m, 4 H, 2 × NCH2CH2CH2CH3),
2.46 (ddd, J = 13.2,
6.0, 3.5 Hz, 1 H, HA2′), 2.57-2.66
(m, 1 H, HB2′), 3.28-3.34 (m, 2 H, NCH2CH2CH2CH3),
3.59-3.65 (m, 2 H, NCH2CH2CH2CH3), 3.72-3.85
(m, 2 H, H5′5′′), 4.05-4.09
(m, 1 H, H4′), 4.64-4.68 (m, 1 H, H3′),
6.44 (t, J = 6.6
Hz, 1 H, H1′), 7.25-7.32 (m, 6 H, ar), 7.53-7.58
(m, 4 H, ar), 8.02 (s, 1 H, H2), 8.41 (s, 1 H, H8), 8.91 (s, 1 H,
CH=N). ¹³C NMR (70 MHz, CDCl3): δ = 13.6
(NCH2CH2CH2CH3), 13.8 (NCH2CH2CH2CH3),
19.1 (SiC), 19.6 (NCH2CH2CH2CH3), 20.1
(NCH2CH2CH2CH3), 26.8 [(CH3)3],
29.1 (NCH2CH2CH2CH3),
30.9 (NCH2CH2CH2CH3),
40.6 (C2′), 45.1 (NCH2CH2CH2CH3),
51.7 (NCH2CH2CH2CH3),
64.0 (C5′5′′), 71.7 (C3′), 84.01
(C1′), 87.0 (C4′), 126.1 (C5), 127.7, 129.7, 129.8,
132.7, 132.8, 135.4, 135.4 (Ar), 139.7 (C2), 151.0 (C4), 152.3 (C6),
158.3 (C8), 159.9 (CH=N). HRMS (ESI+): m/z calcd: 629.3635 [MH]+;
found: 629.3636.
9-[3′-Azido-5′-
O
-(
tert
-butyldiphenylsilyl)-2′,3′-dideoxy-β-
d
-xylofuranosyl)-6-
N
-[(di-
n
-butylamino)methylene]-adenine
(8)
To a THF (1.9 mL) solution of 7 (69
mg, 0.11 mmol) and Ph3P (90 mg, 0.33 mmol), a mixture
of DIAD (71 µL, 0.33 mmol) and DPPA (65 µL, 0.33
mmol) in THF (500 µL) was added dropwise at 0 ˚C
under Ar. After 7 h of stirring at r.t., EtOH (1 mL) was added,
and the solution was stirred for 30 min. After evaporation of all
the volatiles, the oily residue was purified by silica gel column
chromatography (EtOAc-cyclohexane = 3:7 to 8:2
step gradient). Ph3PO contained in the chromatographed
product was removed by precipitation from cold Et2O (3
h, 4 ˚C). After the second precipitation the filtrate
was evaporated to yield 8 (61 mg, 85%). R
f
= 0.4 (CH2Cl2-MeOH = 9.5:0.5). ¹H
NMR (300 MHz, CDCl3): δ = 0.94
(2 t, J = 7.3,
7.3 Hz, 6 H, 2 × NCH2CH2CH2CH3), 1.09 [s,
9 H, SiC(CH3)3], 1.21-1.45
(m, 4 H, 2 × NCH2CH2CH2CH3),
1.58-1.71 (m, 4 H, 2 × NCH2CH2CH2CH3),
2.54 (dd, J = 14.8,
0.9 Hz, 1 H, HA2′), 2.83 (ddd, J = 14.0,
7.9, 6.0 Hz, 1 H, HB2′′), 3.38 (t, J = 7.3 Hz,
2 H, NCH2CH2CH2CH3),
3.67-3.75 (m, 2 H, NCH2CH2CH2CH3),
3.96-4.07 (m, 2 H, H5′5′′),
4.19-4.24 (m, 1 H, H4′), 4.41-4.44 (m,
1 H, H3′), 6.41 (dd, J = 7.9,
2.1 Hz, 1 H, H1′), 7.42-7.70 (m, 10 H, ar), 8.19
(s, 1 H, H2), 8.52 (s, 1 H, H8), 9.02 (s, 1 H, CH=N). ¹³C
NMR (70 MHz, CDCl3): δ = 13.6
(NCH2CH2CH2CH3), 13.9 (NCH2CH2CH2CH3),
19.1 (SiC), 19.7 (NCH2CH2CH2CH3), 20.1
(NCH2CH2CH2CH3), 26.8 [(CH3)3],
29.2 (NCH2CH2CH2CH3),
30.9 (NCH2CH2CH2CH3),
39.0 (C2′), 45.1 (NCH2CH2CH2CH3),
51.8 (NCH2CH2CH2CH3),
61.5 (C3′), 61.9 (C5′5′′), 83.1
(C1′), 83.1 (C4′), 125.8 (C5), 125.8, 127.8, 128.3,
131.8, 131.9, 132.0, 135.4 (ar), 139.8 (C2), 151.0 (C4), 156.6 (C6),
157.3 (C8), 158.4 (CH=N). HRMS (ESI+): m/z calcd: 654.3700 [MH]+;
found: 654.3700.
9-[
5
′
-O-
(
tert
-Butyldiphenylsilyl)-3′-[
N
-(9-fluorenyl)-methoxycarbonyl-
O
-methyl-
l
-tyrosyl]amido
-
2′,3′-dideoxy-β-
d
-xylofuranosyl)-6-
N
-[(di-
n
-butylamino)-methylene]adenine
(9)
N-Fmoc-O-Me-l-Tyr (45
mg, 0.11 mmol) and HOBt (18 mg, 0.11 mmol) were co-evaporated with
anhyd THF (3 × 1 mL). The mixture was
dissolved in anhyd THF (1 mL) and cooled down to 0 ˚C
under N2 for 10 min. Diisopropylcarbodiimide (16 µL,
0.10 mmol) was added, and the reaction mixture was stirred at the
same temperature for 15 min and then 10 min at r.t. Me3P
(1 M in THF, 160 µL, 0.16 mmol) was added to 8 (52.6 mg, 0.08 mmol) in THF (1 mL) and
stirred at r.t. for 5 min. The amino acid solution was added to
the iminophosphorane solution and stirred for 4 h at r.t. The reaction
mixture was concentrated under reduced pressure and dissolved in
EtOAc (20 mL) and then washed with sat. aq NaHCO3 solution
(15 mL) and H2O (2 × 20 mL). The
organic layer was dried over Na2SO4, evaporated,
and the residue was purified by silica gel column chromatog-raphy
(CH2Cl2-MeOH = 99.5: 0.5
to 98:2 step gradient) to yield 9 (70 mg, 85%). R
f
= 0.45
(CH2Cl2-MeOH = 9.5:0.5). ¹H
NMR (300 MHz, CDCl3): δ = 0.81-0.91
(m, 6 H, 2 × NCH2CH2CH2CH3),
1.06, 1.07 [2 s, 9 H, SiC(CH3)3],
1.22-1.39 (m, 4 H, 2 × NCH2CH2CH2CH3),
1.52-1.72 (m, 4 H, 2 × NCH2CH2CH2CH3),
1.93 (dd, J = 15.0,
2.9 Hz, 1 H, HA2′), 2.72-2.74 (m, 1
H, HB2′), 1.88 (d, J = 6.1
Hz, 1 H, Hβ), 3.36 (t, J = 7.3
Hz, 2 H, NCH2CH2CH2CH3),
3.56-3.59 (m, 2 H, NCH2CH2CH2CH3),
3.66-3.71 (m, 2 H, H5′′), 3.89 (dd, J = 11.1,
3.9 Hz, 1 H, H5′), 4.01-4.02 (m, 1 H, H4′),
4.11-4.36 (m, 4 H, CH-Fmoc, Hα and CH2-Fmoc),
4.73 (d, J = 7.4 Hz,
1 H, H3′), 5.37 (d, J = 7.3
Hz, 1 H, NH-Fmoc), 5.88 (dd, J = 8.9,
3.5 Hz, 1 H, H1′), 6.49, 6.91 [2 d, J = 8.5 Hz,
4 H, H-o-Ph(OMe)], 7.10-7.80 [m,
18 H, ar (Fmoc and TBDPS)], 8.39 (s, 1 H, H2), 8.94 (s,
1 H, H8), 9.56 (s, 1 H, CH=N).
¹³C
NMR (70 MHz, CDCl3): δ = 13.6
(NCH2CH2CH2CH3), 13.8
(NCH2CH2CH2CH3), 19.1
(SiC), 19.7 (NCH2CH2CH2CH3),
20.1 (NCH2CH2CH2CH3),
23.4, 26.7 [(CH3)3], 29.2
(NCH2CH2CH2CH3), 30.9 (NCH2CH2CH2CH3),
38.1 (C2′), 38.7 (Cβ), 45.2 (NCH2CH2CH2CH3),
47.1 (CH-Fmoc), 48.8 (C3′), 51.8 (NCH2CH2CH2CH3),
57.1 (C5′5′′), 62.6 (OCH2 Fmoc),
66.8 (Cα), 82.7 (C4′), 84.5 (C1′), 113.6 [o-Ph(OMe)], 119.8, 125.0, 127.4,
127.5, 127.6, 128.3, 128.5, 130.2, 131.7, 131.8, 131.9, 131.9, 132.1,
133.1, 135.4, 135.5, 135.5, 141.2, 141.5, 143.7, 143.8 (Ar), 149.4
(C4), 151.8 (C2), 157.2 (C6), 157.2 (C=O), 158.3 (C8),
169.97 (CH=N). HRMS (ESI+): m/z calcd: 1049.5085 [M + Na]+;
found: 1049.5084.
9-(3′-
O
-Methyl-
l
-tyrosyl)amido-2′,3′-dideoxy-β-
d
-xylofuranosyl)adenine
(4)
Compound 9 (65 mg, 0.08
mmol) was dissolved in 33% MeNH2-EtOH
(8 mL), and the mixture was stirred overnight at r.t. in a closed
vessel. The solution was concentrated under reduced pressure, and
the residue was dissolved in MeOH (2 mL) and then NH4F
(16 mg, 0.43 mmol) was added. The reaction mixture was warmed to
50-55 ˚C for 4 h. The volatiles were
evaporated, and the residue was washed with EtOAc (3×)
and then purified by a preparative thin-layer column chromatography
using i-PrOH-NH3-H2O (8:0.5:0.5)
as the eluent to obtain 4 (24 mg, 90%). ¹H
NMR (300 MHz, CD3OD): δ = 1.95-2.01
(m, 1 H, HA2′), 2.67-2.77 (m, 2 H,
HB2′, Hβ), 3.44 (t, J = 7.2
Hz, 1 H, Hα), 3.49 (s, 3 H, OMe), 3.61-3.65 (m,
2 H, H5′5′′), 3.99 (dd, J = 9.7, 5.4
Hz, 1 H, H4′), 4.55-4.59 (m, 1 H, H3′),
6.03 (dd, J = 8.4, 5.1
Hz, 1 H, H1′), 6.58 [d, J = 8.6
Hz, 2 H, o-Ph(OMe)], 6.98 [d, J = 8.6 Hz,
2 H, m-Ph(OMe)], 8.05 (s, 1
H, H2), 8.11 (s, 1 H, H8). ¹³C NMR
(125 MHz, CD3OD): δ = 39.4
(C2′), 39.9 (Cβ), 50.8 (C3′), 55.6 (OMe),
57.1 (Cα), 61.8 (C5′5′′), 83.3
(C4′), 86.0 (C1′), 115.1 [2 × C-o-Ph(OMe)], 122.4 (C5), 127.9 [C-p-Ph(OMe)], 131.7 [2 × C-m-Ph(OMe)], 142.6 (C2), 148.9
(C4), 153.5 (C8), 157.7 (C6), 160.5 [C-i-Ph(OMe)],
169.9 (C=O). HRMS (ESI+): m/z calcd: 428.2046 [MH]+;
found: 428.2047.