Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

Abstract

We report here on the use of ethyl nitroacetate as a glycine template to produce α-amino esters. This started with a study of its condensation with various arylacetals to give ethyl 3-aryl-2-nitroacrylates followed by a reduction (NaBH4 and then zinc/HCl) into α-amino esters. The scope of this method was explored as well as an alternative with arylacylals instead. We also focused on various [2 + 3] cycloadditions, one leading to a spiroacetal, which led to the undesired ethyl 5-(benzamidomethyl)isoxazole-3-carboxylate. The addition of ethyl nitroacetate on a 5-methylene-4,5-dihydrooxazole using cerium(IV) ammonium nitrate was also explored and the synthesis of other oxazole-bearing α-amino esters was achieved using gold(I) chemistry.

Bioluminescence Profiling of NanoKAZ/NanoLuc Luciferase Using a Chemical Library of Coelenterazine Analogues

“…With these approaches, out of selected combinations of 12 different nitrostyrenes 13 [15] and two distinct a-amino esters 14 chosen amongst 60 previously reported, [16] we prepared 135 O-acetylated imidazo [1,2-a]pyrazin-3(7H)-ones proluciferins 25, which led, after deprotection,t ot he luciferins 26 listed in Ta bles 1-7. An extensive descriptiono ft he synthesis of these O-acetylated precursors along with ac haracterization of most of the synthetic intermediates is provided in the Supporting Information.M oreover,a sd epicted in Scheme 4, the chemistry used to preparet he methyl-bearing proluciferins 30, 32,a nd 34 leading to the corresponding luciferins 35-37,a lso used the synthetic pathways shown in Scheme2.C ompound 30 was thus obtained in six steps from the b-methyl nitrostyrene 29 and phenylalaninee thyl ester (PheOEt) in 8% overall yield.…”

Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

“…As in our previous report [ 2 ], the goal of this investigation was to reach a very large variety of racemic α-amino esters. In the course of this study, we could point out that, in comparison with ethyl nitroacetate [ 2 ], the use of diethyl malonate ( 4 ) is at least as efficient and far more general, especially for the initial condensation step.…”

“…As in our previous report [ 2 ], the goal of this investigation was to reach a very large variety of racemic α-amino esters. In the course of this study, we could point out that, in comparison with ethyl nitroacetate [ 2 ], the use of diethyl malonate ( 4 ) is at least as efficient and far more general, especially for the initial condensation step. However, as for the reduction of nitroacrylates [ 2 ], the use of borohydrides to reduce some of the resulting alkylidenemalonates 6 turned out to be limiting, even in some cases, tetramethylammonium borohydride instead of sodium borohydride could alleviate this limitation.…”

“…In the course of this study, we could point out that, in comparison with ethyl nitroacetate [ 2 ], the use of diethyl malonate ( 4 ) is at least as efficient and far more general, especially for the initial condensation step. However, as for the reduction of nitroacrylates [ 2 ], the use of borohydrides to reduce some of the resulting alkylidenemalonates 6 turned out to be limiting, even in some cases, tetramethylammonium borohydride instead of sodium borohydride could alleviate this limitation. Besides, out of the many preparations of α-hydroxyimino esters described above, another limitation was encountered when steric hindrance became a previously unreported limiting factor for the oximation of compound 34 , and to a lesser degree compounds 36 or 39 .…”

“…Our current work on the chemistry of imidazo[1,2- a ]pyrazin-3(7 H )-one luciferins [ 1 ] has led us to require a large variety of α-amino esters as starting material. In view of the limitations we encountered in the use of ethyl nitroacetate to reach such variety [ 2 ], we have focused here on diethyl malonate-based methods as an alternative. Indeed, as we reviewed recently [ 3 ], this approach was used for the historic preparation of racemic lysine from diethyl malonate and γ-chlorobutyronitrile [ 4 ] and appears to be of a very large scope.…”