11. The reduction of 11 without purification and then
protection of the resulting primary alcohol with tert-
butyldimethylsilyl chloride completed the synthesis of the
vinyl stannyl fragment 12 in 78% yield in three steps. (Z)-
Vinyl bromide 16 was synthesized by the stereoselective
Wittig reaction as the key step. Thus, aldehyde 13, which
was prepared by the monoprotection of ethylene glycol as
the tert-butyldiphenylsilyl ether followed by the Swern
oxidation,12 was reacted with the Wittig reagent, triphenyl-
carbethoxybromomethylenephosphorane 14,13 to provide 15.
The ratio of Z to E was 10:1 based on an NMR analysis.
After removal of the TBDPS group by treatment with TBAF,
the Z and E stereoisomers were separated by column
chromatography on silica gel to give pure (Z)-vinyl bromide
16 in 87% yield in two steps. The Pd(0)-catalyzed Stille
coupling between the stannane 12 and bromide 16 fortunately
proceeded in the presence of 5 mol % tetrakis(triphenylphos-
phine)palladium(0) and 2 equiv of lithium chloride in
dimethyl formamide at 85 °C to produce 17 in 72% yield
with retention of their stereochemistry (Scheme 3). The
achieve the efficient oxidation of the dihydropyridine to the
corresponding pyridine, we planned to prepare the trimethyl-
silylimine derivative 19 by utilizing the Peterson reaction
between 18 and lithium bis(trimethylsilyl)amide.15 The
treatment of the (E)-carbonyltrienal 18 with excess lithium
bis(trimethylsilyl)amide in THF at room temperature cleanly
produced the corresponding N-trimethylsilyl-1,2-dihydro-
pyridine derivative within 5 min via the Peterson reaction
followed by the smooth aza-6π-electrocyclization of the
resulting intermediary azatriene 19. The reaction mixture of
the unstable 1,2-dihydropyridine derivative was then continu-
ously treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) as an oxidant16 to successfully yield the desired
pyridine derivative 20 in one pot. The reaction of the crude
20 with lithiun aluminum hydride gave 21 in 77% total yield
from 18.17 No Michael adducts of LiN(TMS)2 to the
3-carbonyltrienal system or other byproducts were detected
in the reaction mixtures. This efficient one-pot procedure of
the Peterson reaction, aza-6π-electrocyclization and oxida-
tion, provides a new entry for the synthesis of the substituted
pyridine derivative. Finally, the synthesis of the bis-aldehyde
4, mp 91 °C, was successfully realized from 21 by the
deprotection of the TBDMS group followed by oxidation
with manganese dioxide. The spectral characteristics (1H and
13C NMR) of the thus-synthesized bis-aldehyde 4 were in
good agreement with those reported by Nakanishi and co-
workers.18
Scheme 3
In conclusion, we achieved the formal synthesis of the
ocular age pigment A2-E by focusing on the efficient one-
pot synthesis of the pyridine derivative by utilizing the
Peterson reaction of (E)-3-carbonyl-2,4,6-trienal with lithium
bis(trimethylsilyl)amide, the facile aza-6π-electrocyclization
of the corresponding 1-azatriene derivative, and oxidation.
The sequence of the reactions is compatible with Nakanishi’s
hypothetical metabolic pathway of A2-E. A new stereo-
selective synthesis of (E)-3-carbonyl-2,4,6-trienal compounds
by the Pd(0)-catalyzed cross-coupling between vinylstannane
and vinyl bromide was also established.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research 09480145 from the Ministry
of Education, Science and Culture of Japan.
OL991320U
oxidation of 17 with manganese dioxide nicely provided 18
in 85% yield.14 Thus, the new stereoselective synthesis of
3-alkoxycarbonyl-2E,4E,6E-trienal was achieved. This method
is believed to be more general and practical for the synthesis
of (E)-3-alkoxycarbonyl-conjugated aldehydes. The next step
is the key to the synthesis of Nakanishi’s intermediate 4. To
(15) (a) Hart, D. J.; Kanai, K.; Thomas, D. G.; Yang, T.-K. J. Org. Chem.
1983, 48, 289. (b) Cainelli, G.; Giacomini, D.; Panunzio, M.; Martelli, G.;
Spunta, G. Tetrahedron Lett. 1987, 28, 5369. (c) Uyehara, T.; Suzuki, I.;
Yamamoto, Y. Tetrahedron Lett. 1990, 31, 3753.
(16) (a) Omote, Y.; Komatsu, T.; Kobayashi, R.; Sugiyama, N. Tetra-
hedron Lett. 1972, 93. (b) Dommisse, R.; Desseyn, H. O.; Alderweireldt,
F. C. Spectrochim. Acta 1973, 29, 107.
(17) Data for 21: IR (neat, cm-1) 3385, 3218, 2955, 2930, 2895, 2857,
1
(11) Oddon, G.; Uguen, D. Tetrahedron Lett. 1998, 39, 1153.
(12) Tidwell, T. T. Synthesis 1990, 857.
(13) (a) Denney, D. B.; Ross, S. T. J. Org. Chem. 1962, 27, 998. (b)
Speziale, A. J.; Ratts, K. W. J. Org. Chem. 1963, 28, 465.
1603, 1472, 1254, 1111, 1078, 839, 777; H NMR (400 MHz, CDCl3) δ
0.08 (s, 6H), 0.92 (s, 9H), 1.97 (s, 3H), 4.15 (brs, 2H), 4.68 (s, 2H), 6.56
(brd, 1H, J ) 1.2 Hz), 7.04 (brd, 1H, J ) 3.7 Hz), 7.17 (s, 1H), 8.46 (d,
1H, J ) 5.1 Hz); 13C NMR (100 MHz, CDCl3) δ -5.33, 15.25, 18.42,
25.93, 63.46, 68.09, 118.36, 121.34, 122.56, 142.45, 148.95, 150.10, 157.14;
EI HRMS m/e calcd for C16H27NO2Si (M+) 293.1811, found 293.1804.
(18) Data for 4: mp 91 °C; IR (KBr disk, cm-1) 2361, 1709, 1684, 1372,
1150, 831; 1H NMR (400 MHz, CDCl3) δ 2.29 (s, 3H), 7.35 (s, 1H), 7.69
(d, 1H, J ) 4.9 Hz), 7.90 (s, 1H), 9.01 (d, 1H, J ) 4.9 Hz), 9.69 (s, 1H),
10.14 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 11.11, 121.71, 123.88, 142.02,
142.74, 145.66, 151.33, 156.11, 190.95, 195.41; EI HRMS m/e calcd for
C10H9NO2 (M+) 175.0633, found 175.0624.
(14) Data for 18: IR (neat, cm-1) 1726, 1672, 1248, 841; 1H NMR (400
MHz, CDCl3) δ 0.09 (s, 6H), 0.93 (s, 9H), 1.36 (t, 3H, J ) 7.1 Hz), 1.79
(s, 3H), 4.14 (s, 2H), 4.32 (q, 2H, J ) 7.1 Hz), 6.32 (d, 1H, J ) 11.2 Hz),
6.52 (d, 1H, J ) 7.3 Hz), 6.83 (d, 1H, J ) 15.4 Hz), 7.09 (dd, 1H, J )
15.1, 11.2 Hz), 10.11 (d, 1H, J ) 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ
-5.40, 14.11, 14.45, 18.40, 25.89, 61.87, 67.40, 121.34, 122.73, 130.02,
137.88, 145.75, 146.50, 166.57, 191.29; EI HRMS m/e calcd for C18H30O4-
Si (M+) 338.1913, found 338.1912.
Org. Lett., Vol. 2, No. 3, 2000
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