I. Jouanin et al.
13C NMR: 166.7 (d, J = 74.8 Hz, 13CO2Et); 166.3 (d, J = 74.5 Hz,
13C NMR: 193.5 (dd, J = 9.06; 53.3 Hz, 13CHO); 130.7 (d,
13CO2Et); 149.1 (d, J = 71.5 Hz); 148.3 (d, J = 70.7 Hz); 122.1 (d, J = 53.3 Hz, 13CH).
J = 74.5 Hz, 13CH–13CO2Et); 120.4 (d, J = 74.8 Hz, 13CH–13CO2Et);
97.3; 96.1; 75.0 (d, J = 6.29 Hz); 74.4 (d, J = 6.45 Hz); 62.40; 62.39;
Conclusion
60.4; 60.3; 35.2; 33.8; 31.8; 31.7; 30.74; 30.69; 25.6; 25.4; 25.0; 24.4;
22.5; 19.5; 19.4; 14.3; 14.06; 14.05.
In summary, we have designed a synthetic scheme for the
preparation of [1,2-13C2]-4-hydroxy-2(E)-nonenal. Because of its
high reactivity, it has to be produced just before use by acid
deprotection of the stable precursor: [1,2-13C2]-4-[(tetrahydro-
2H-pyran-2-yl)oxy]-2(E)-nonenal.
The path was selected for two requirements: synthesis from a
suitable commercial 13C precursor and location of the stable
isotope at the aldehyde end for the measurement of etheno-
adducts. It is the only possibility so far reported to introduce two
13C at determined positions. The 12C isotope synthesis was
initially developed and the 13C analog was then obtained in
eight steps in the acid labile hydroxy-protected form.
Our synthesis is not short, but the conditions are mild
and neither require hazardous organometallic nor gas reagents.
Yet, although the allylic oxidation was the key step in
the scheme, our linear synthesis suffers from this low yield
step. A convergent approach would avoid this step and improve
the yield in high value 13C product. Improvement
of the synthetic scheme will be developed in future studies.
The scheme opens not only to the synthesis of HNE derivatives
(metabolites, adducts) but also to other alkenals implied in
oxidative stress. We will report later on synthetic improvement
and the development of mass spectrometry analyses with
[1,2-13C2]-4-hydroxy-2(E)-nonenal as internal standard.
[1,2-13C2]-4-[(tetrahydro-2H-pyran-2-yl)oxy-2(E)-nonenol (5b)
Same procedure as for 5a starting from 50 mg (0.175 mmol) of
4b and 350 mL (2 equiv.) of DIBALH.
Yield: 79% (34 mg, 0.139 mmol).
IR (neat): 3467; 3261; 2934; 1441; 1201; 1021; 810.
HRMS: m/z 267.18414 (MNa1 [13C2C12H26O3Na] = 267.18413).
1H NMR: 5.93 (1H, m, CH = 13C); 5.77–5.63 (2H, m, CH = 13C,
=
13CH-13CH2OH); 5.51 (1H, m, = 13CH–13CH2OH); 4.67 (1H, m,
O–CH–O); 4.65 (1H, m, O–CH–O); 4.26 (2H, td, J = 4.46; 8.55 Hz,
CH2–OH); 4.13–4.01 (2H, m, CH2–OH; 2H, m, CH–OTHP); 3.87 (2H,
m, O–CH2); 3.47 (2H, m, O–CH2); 1.82 (2H, m, CH2(THP));
1.74–1.61 (2H, m, CH2(THP)12H, m, CH2-CH-OTHP); 1.45–1.23
(8H, m, (CH2)2THP12H, m, CH2–CH–OTHP); 1.30 (12H, m,
(CH2)3–CH3); 0.87 (6H, t, J = 6.19 Hz, CH3).
13C NMR: 133.4; 132.1 (d, J = 45.9 Hz, =13CH–13CH2OH); 132.1;
129.7 (d, J = 45.9 Hz, =13CH–13CH2OH); 97.6; 94.9; 75.3; 63.2; 63.1
(t, j=45.5 Hz, =13CH–13CH2OH); 63.0; 62.2; 35.8; 34.6; 31.9; 31.8;
30.9; 30.8; 25.6; 25.4; 25.3; 24.9; 22.6; 19.8; 19.5; 14.1; 14.0.
[1,2-13C2]-4-[(tetrahydro-2H-pyran-2-yl)oxy-2(E)-nonenal (6b)
Same procedure as for 6a starting from 31 mg (0.127 mmol) of
5b and 48 mg (1 equiv.) of DMP.
Yield: 62% (19 mg, 0.079 mmol).
IR (neat): 2945; 1653; 1440; 1388; 1342; 1201; 1127; 1077; 1023;
979; 906; 867; 814.
References
HRMS: m/z 265.16862 (MNa1 [13C2C12H24O3Na] = 265.16848).
1H NMR: 9.59 (1H, ddd, J = 5.98; 7.70; 172 Hz, 13CHO); 9.54 (1H,
ddd, J = 5.68; 7.77; 172 Hz, 13CHO); 6.84 (1H, ddd, J = 5.24; 9.19;
14.6 Hz, CH = 13C); 6.68 (1H, ddd, J = 6.09; 9.04; 15.1 Hz, CH = 13C);
6.31 (1H, ddd, J = 7.93; 15.7; 162 Hz, = 13CH–13CHO); 6.21 (1H,
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O–CH–O); 4.56 (1H, t, J = 3.47 Hz, O–CH–O); 4.43 (1H, m,
CH–OTHP); 4.36 (1H, m, CH–OTHP); 3.88 (1H, m, CH2–O); 3.80
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1.30–1.25 (12H, m); 0.87 (6H, m, CH3).
13C NMR: 193.9 (dd, J= 10.5; 53.2 Hz, 13CHO); 193.5 (dd, J= 10.7;
53.0 Hz, 13CHO); 158.5 (d, J= 68.8 Hz, CH = ); 157.4 (d, J=67.7Hz,
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Copyright r 2008 John Wiley & Sons, Ltd.