Enantioselective Synthesis of 3,4-Dihydro-1,2-oxazepin-5(2H)-ones and 2,3-Dihydropyridin-4(1H)-ones from β-Substituted β-Hydroxyaminoaldehydes

Abstract

The synthesis of 3,4-dihydro-1,2-oxazepin-5(2H)-ones and 2,3-dihydropyridin-4(1H)-ones from β-substituted β-hydroxyaminoaldehydes is reported. The β-hydroxyaminoaldehydes were prepared by enantioselective organocatalytic 1,4-addition of N-tert-butyl (tert-butyldimethylsilyl)oxycarbamate to α,β-unsaturated aldehydes (MacMillan protocol). Alkyne addition to the aldehydes followed by alcohol oxidation furnished N-Boc O-TBS-protected β-aminoynones. Removal of the TBS protecting group initiated a 7-endo-dig cyclization to yield previously unknown 3,4-dihydro-1,2-oxazepin-5(2H)-ones. Reductive cleavage of the N–O bond of the oxazepinones and Boc-deprotection provided 2-substituted 2,3-dihydropyridin-4(1H)-ones via 6-endo-trig cyclization. 2,3-Dihydropyridin-4(1H)-ones are versatile intermediates that have been used for the synthesis of many alkaloids. The new protocol allows the synthesis of 3-dihydropyridin-4(1H)-ones carrying an array of substituents at C2 that cannot be prepared from commercial β-amino acids or by one-carbon homologation of proteinogenic amino acids. The use of readily available β-hydroxylaminoaldehydes expands the utility of our previously reported method to prepare 2,3-dihydropyridin-4(1H)-ones from β-amino acids as the source of diversity and chirality. A broad substrate scope is possible because β-aminoaldehydes can be prepared from α,β-unsaturated aldehydes by an enantioselective organocatalytic process.

Divergent Total Syntheses of (−)‐Huperzine Q, (+)‐Lycopladine B, (+)‐Lycopladine C, and (−)‐4‐epi‐Lycopladine D

“…Our new synthetic plan began with the preparation of enantiopure enone 9 through a catalytic enantioselective approach (Scheme ). α,β‐Unsaturated aldehyde 23 was prepared in 85 % yield from benzyloxyacetaldehyde 22 through Horner–Wadsworth–Emmons reaction . Subsequent organocatalytic Robinson annulation with tert ‐butyl acetoacetate provided 9 in 70 % yield with 93 % ee .…”

“…a,b-Unsaturated aldehyde 23 was prepared in 85 %y ield from benzyloxyacetaldehyde 22 through Horner-Wadsworth-Emmons reaction. [13] Subsequent organocatalytic Robinsona nnulation [14] with tert-butyla cetoacetate provided 9 in 70 %y ield with 93 % ee. Similar to our previousp rotocol, enone 9 was then treated with allylcuprate, and the resulting enolatew as trapped with aldehyde 25 to afford alcohol 26 in 73 %y ield.…”

Synthesis of Polysubstituted 2,3-Dihydropyridin-4(1H)-one in Water

“…因此, 2,3-二氢-4-吡啶酮的合成受到人们的广泛关注, 已发展了多种合 成方法 [12] . 这些报道的方法主要包括六元氮环化合物 的直接修饰 [13] , 烯胺酮与 α,β-不饱和酰氯的[3＋3]环 合 [14] , 3-苯基环丁酮与腈 [15] 、3-氨基羧酸酯衍生物和乙 酰乙酸酯 [16][17] 、亚胺衍生物和共轭二烯烃 [18][19][20] 的[4＋2] 环合, N-甲酰甲基取代烯酰胺和异腈 [21] 、氨甲酰烯胺酮 和醛 [22][23] 、1,4-二戊烯-3-酮衍生物与胺 [24][25] 的[5＋1]环 合, 以及炔胺酮的分子内环合反应 [26][27][28][29] . 另外, Dong 研 究组利用具有双 Mechael 加成受体结构的 α-烯酰基-α-羰基二硫缩烯酮 [30][31][32][33][34] 与有机胺的[5C＋1N]环合反应, 同 样有效地合成 2,3-二氢-4-吡啶酮 [35] .…”