tert-butyl ester was first obtained (8.52 g, 79%) as a pure oil
after flash chromatography eluting with hexane–AcOEt
(60 : 40, v/v) (Found: C, 54.8; H, 7.6; N, 12.7. C15H25N3O5
requires C, 55.0; H, 7.7; N, 12.8%); [α]D ϩ11.4 (c 1 in CHCl3);
δH (500 MHz; CDCl3) 1.45 [9 H, s, C(CH3)3], 1.47 [9 H, s,
C(CH3)3], 1.88 (1 H, m, 3-Ha), 2.20 (1 H, m, 3-Hb), 2.32–2.45
(2 H, overlapping, together 4-H2), 4.17 (1 H, m, 2-H), 5.09 (1 H,
d, J 5.0, NH), 5.20 (1 H, br s, 6-H).
ketone 4a to give, after chromatographic purification (eluting
with AcOEt–MeOH, 90 : 10, v/v), the pyridiniumolate 6a
(1.83 g, 65%) as an oil (Found: C, 66.4; H, 6.8; N, 6.1. C39H49-
N3O9 requires C, 66.6; H, 7.0; N, 6.0%); [α]D ϩ2.3 (c 1, CHCl3);
δH (CDCl3) 1.37 [9 H, s, C(CH3)3], 1.43 [9 H, s, C(CH3)3],
1.89 (1 H, m), 2.02 (1 H, m), 2.71 (2 H, m), 2.96 (1 H, m), 3.31
(1 H, m), 4.20 (1 H, m, NCHCO), 4.27 (1 H, m, NCHCO),
4.56 (2 H, d, J 5.5, NϩCH CH᎐CH ], 4.93–5.10 (4 H, 2 ×
᎐
2
2
OCH Ph), 5.36 (1 H, dd, J 16.9, <1, NϩCH CH᎐CHH), 5.40 (1
᎐
2
2
H, dd, J 10.1, <1, NϩCH CH᎐CHH), 5.62 (2 H, m, 2 × NH),
(ii) Preparation of (S)-6-bromo-2-tert-butoxycarbonylamino-
5-oxohexanoic acid tert-butyl ester 4b. The obtained (S)-2-tert-
butoxycarbonylamino-6-diazo-5-oxohexanoic acid tert-butyl
ester (8.0 g, 24.4 mmol) was treated with a solution of HBr in
AcOH (33%) as described above for the benzyloxycarbonyl ana-
logue and afforded (S)-6-bromo-2-tert-butoxycarbonylamino-
5-oxohexanoic acid tert-butyl ester 4b (6.03 g, 65%) as a pure oil
after flash chromatography eluting with hexane–AcOEt (80 : 20,
v/v) (Found: C, 47.5; H, 7.1; N, 3.7. C15H26BrNO5 requires C,
47.4; H, 6.9; N, 3.7%); TLC (hexane–AcOEt, 50 : 50, v/v; Rf
0.66); [α]D Ϫ1.08 (c 1, CHCl3) (lit.,9 Ϫ0.88); δH (CDCl3) 1.45
[9 H, s, C(CH3)3], 1.47 [9 H, s, C(CH3)3], 1.86 (1 H, m, 3-Ha),
2.19 (1 H, m, 3-Hb), 2.67 (1 H, ddd, J 6.0, 8.5, 18.0, 4-Ha), 2.74
(1 H, ddd, J 7.5, 8.5, 18.0, 4-Hb), 3.89 (2 H, s, 6-H2), 4.19 (1 H,
ddd, J 4.5, 8.0, 8.5, 2-H), 5.06 (1 H, d, J 8.0, NH).
᎐
2
5.91 (1 H, m, NϩCH2CH=), 7.08 (1 H, br s, pyridinium ring
proton), 7.23–7.33 (10 H, Ph), 7.71 (1 H, br s, pyridinium
ring proton).
(S,S)-1-Benzyl-4-[2-tert-butoxycarbonylamino-2-(tert-butoxy-
carbonyl)ethyl]-5-[3-tert-butoxycarbonylamino-3-(tert-butoxy-
carbonyl)propyl]pyridinium-3-olate 6b
The general procedure was used with benzylamine and bromo
ketone 4b to give, after chromatographic purification (eluting
with CH2Cl2–MeOH, 100 : 5, v/v), the pyridiniumolate 6b
(1.81 g, 66%) as an oil (Found: C, 64.7; H, 8.0; N, 6.3. C37H55-
N3O9 requires C, 64.8; H, 8.1; N, 6.1%); [α]D ϩ4.2 (c 1, CHCl3);
δH (CDCl3) 1.34 [9 H, s, C(CH3)3], 1.37 [9 H, s, C(CH3)3], 1.43
(18 H, s, 2 × C(CH3)3], 1.83 (1 H, m), 1.94 (1 H, m), 2.68 (2 H,
m), 2.89 (1 H, m), 3.30 (1 H, m), 4.13 (2 H, overlapping,
2 × NCHCO), 5.16 (2 H, s, NϩCH2Ph), 5.19 (2 H, m, 2 × NH),
7.20 (1 H, br s, pyridinium ring proton), 7.31–7.39 (5 H, Ph),
7.60 (1 H, br s, pyridinium ring proton).
General procedure for selecting the best conditions for the
preparation of (S,S)-1-benzyl-4-[2-benzyloxycarbonylamino-2-
(tert-butoxycarbonyl)ethyl]-5-[3-benzyloxycarbonylamino-3-
(tert-butoxycarbonyl)propyl]pyridinium-3-olate 6b starting from
benzylamine and bromo ketone 4b (Table 1)
(S,S)-1-Allyl-4-[2-tert-butoxycarbonylamino-2-(tert-butoxy-
carbonyl)ethyl]-5-[3-tert-butoxycarbonylamino-3-(tert-butoxy-
carbonyl)propyl]pyridinium-3-olate 6c
To a solution of benzylamine (5.9 mg, 0.055 mmol) and the
bromo ketone, 4b (50 mg, 0.13 mmol) in CH3CN (2 cm3) was
added anhydrous K2CO3 (27 mg, 0.19 mmol) and the mixture
was stirred under nitrogen for 8 h. At this time the disappear-
ance of the starting bromo ketone was monitored (TLC),
and, in experiments 4 and 5 (Table 1), the mixture was directly
diluted with a new solvent: MeOH (2 cm3, entry 4) or THF (2
cm3, entry 5). In the other cases, the solid K2CO3 was filtered
off, the solvent evaporated off, and the crude residue 5b was
recovered with MeOH (2 cm3, entries 1–3) or THF (2 cm3,
entries 6–8). In all cases naphthalene (11 mg) was added to
the reaction mixture (as internal standard) followed by the
appropriate base: K2CO3 (27 mg, 0.19 mmol, entries 1, 4–6),
TMG (19.6 mg, 0.17 mmol, entries 2 and 8) or DBU (25.8 mg,
0.17 mmol, entries 3 and 7).
The general procedure was used with allylamine and bromo
ketone 4b to give, after chromatographic purification (eluting
with CH2Cl2–MeOH, 100 : 2, v/v), the pyridiniumolate 6c
(1.60 g, 63%) as an oil (Found: C, 62.1; H, 8.4; N, 6.8. C33H53-
N3O9 requires C, 62.3; H, 8.4; N, 6.6%); [α]D ϩ1.8 (c 1, CHCl3);
δH (CDCl3) 1.34 [9 H, s, C(CH3)3], 1.38 [9 H, s, C(CH3)3], 1.43
(18 H, s, 2 × C(CH3)3], 1.84 (1 H, m), 1.94 (1 H, m), 2.70 (2 H,
m), 2.92 (1 H, m), 3.31 (1 H, m), 4.14 (2 H, overlapping,
2 × NCHCO), 4.59 (2 H, d, J 5.6, NϩCH CH᎐CH ), 5.21 (2 H,
᎐
2
2
m, 2 × NH), 5.38 (1 H, dd, J 17.0, <1, NϩCH CH᎐CHH),
᎐
2
5.42 (1 H, dd, J 9.8, <1, NϩCH CH᎐CHH), 5.91 (1 H, m,
᎐
2
NϩCH CH᎐), 7.20 (1 H, br s, pyridinium ring proton), 7.60
᎐
2
(1 H, br s, pyridinium ring proton).
Each resulting mixture was stirred at 25 ЊC under a oxygen
atmosphere for the appropriate time (Table 1), with monitoring
of the formation of title compound 6b by HPLC.
(S,S)-1-Benzyl-4-[2-benzyloxycarbonylamino-2-(tert-butoxy-
carbonyl)ethyl]-5-[3-benzyloxycarbonylamino-3-(tert-butoxy-
carbonyl)propyl]pyridinium-3-olate 6d
Application of the general procedure selected for the preparation
of 1,4,5-trisubstituted pyridinium-3-olate nucleus (6a–d)
The general procedure was used with benzylamine and bromo
ketone 4a to give, after chromatographic purification (eluting
with AcOEt–MeOH, 100 : 15, v/v), the pyridiniumolate 6d
(1.96 g, 65%) as an oil (Found: C, 68.6; H, 6.7; N, 5.5.
C43H51N3O9 requires C, 68.5; H, 6.8; N, 5.6%); [α]D ϩ4.1 (c 1 in
CHCl3); δH (CDCl3) 1.34 [9 H, s, C(CH3)3], 1.42 [9 H, s,
C(CH3)3], 1.85 (1 H, m), 1.98 (1 H, m), 2.67 (2 H, m), 2.91 (1
H, m), 3.31 (1 H, m), 4.19 (2 H, overlapping, 2 × NCHCO),
4.90–5.09 (6 H, 2 × OCH2Ph and NϩCH2Ph), 5.57 (2 H,
m, 2 × NH), 7.07 (1 H, br s, pyridinium ring proton), 7.22–7.36
(15 H, Ph), 7.56 (1 H, br s, pyridinium ring proton).
To a solution containing benzylamine or allylamine (4 mmol)
and the appropriate bromo ketone 4a or 4b (8.8 mmol)
in CH3CN (80 cm3) was added anhydrous K2CO3 (1.85 g,
13.2 mmol) and the mixture was stirred under nitrogen for
8 h. At this time the disappearance of the starting bromo
ketone was monitored (TLC), the solid K2CO3 was filtered off
on a pad of Celite, and the solvent was evaporated off under
reduced pressure. The residue (5a–d) was then dissolved in
MeOH (80 cm3) and TMG (1.5 cm3, 12 mmol) was added
to the mixture, which was vigorously stirred at 25 ЊC under an
oxygen atmosphere for 6 h. At this time, the solvent was
removed under reduced pressure and the residue was purified
by rapid chromatography.
(S,S)-4-[2-Benzyloxycarbonylamino-2-(tert-butoxycarbonyl)-
ethyl]-5-[3-benzyloxycarbonylamino-3-(tert-butoxycarbonyl)-
propyl]-3-hydroxypyridine 7a
(i) Using Pd0 chemistry. To a solution of 1-allyl-4,5-
disubstituted pyridinium-3-olate derivative 6a (1.41 g, 2 mmol)
and 2-mercaptobenzoic acid (1.54 g, 10 mmol) in CH2Cl2
(150 cm3), was added tetrakis(triphenylphosphine)palladium(0)
(121 mg, 0.1 mmol). The resulting orange solution was stirred
(S,S)-1-Allyl-4-[2-benzyloxycarbonylamino-2-(tert-butoxy-
carbonyl)ethyl]-5-[3-benzyloxycarbonylamino-3-(tert-butoxy-
carbonyl)propyl]pyridinium-3-olate 6a
The general procedure was used with allylamine and bromo
J. Chem. Soc., Perkin Trans. 1, 2001, 2404–2408
2407