ChemInform Abstract: Non‐Racemizing Synthesis and Stereoselective Reduction of Chiral α‐Amino Ketones.

Abstract

291ChemInform Abstract The first systematic study is given of the non-racemizing synthesis of the chiral α-amino ketones (IV) from the α-amino acids (I) and the non-chelation controlled reduction of (IV) to the amino alcohols (V). For the ketones (IV) e.e. values in the range of 98.5-100% are found.

Synthesis and Diastereoselective Reactions of N,N-Dibenzylamino Aldehydes and Related Compounds

“…Because the latter are not as general as one would like, nonchelation controlled hydride reduction of ketones 11 constitutes an important complementary strategy. 3,133,134 Moreover, ketones 11 can be transformed in other ways as well, reduction in the final step then being an option.…”

“…32,66 In most cases it is more elegant to prepare the ketones directly from activated amino acid derivatives which in turn are accessible from the N,Ndibenzylamino acids 172. 22,133,134 Accordingly, the latter are first prepared by tribenzylation of amino acids 1 with BnBr/K 2 CO 3 in water followed by the addition of KOH, 1,4-dioxane and methanol to the reaction mixture containing the intermediate esters 14. A reflux period of 6-28 h is then necessary for ester hydrolysis, depending upon the particular substrate.…”

“…137 The acids 172 are then converted into Weinreb-type amides 173. 22,134 This has been carried out for 173a, b, d, and e in yields of 53-72%. The formation of amide 173b was optimized (92% yield) by choosing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide as the activator in the presence of Hu ¨nigs base in DMF instead of the usual DCC/Et 3 N. 138 The amides were then reacted with Grignard or organolithium reagents at -30 to -40 °C.…”

“…The formation of amide 173b was optimized (92% yield) by choosing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide as the activator in the presence of Hu ¨nigs base in DMF instead of the usual DCC/Et 3 N. 138 The amides were then reacted with Grignard or organolithium reagents at -30 to -40 °C. 22,134,138 Under these conditions, there is no erosion of configurational integrity of the ketones (at -10 to 0 °C, 5-10% racemization may occur). 22,134 Some of the compounds were also prepared by application of the Gilman-Jorgenson ketone synthesis (11b, v, w) 22,134,139,140 or the Mukaiyama one-pot ketone preparation based on the use of anhydrides 174 ( 11a, b, c, k, l, x).…”

“…22,134,138 Under these conditions, there is no erosion of configurational integrity of the ketones (at -10 to 0 °C, 5-10% racemization may occur). 22,134 Some of the compounds were also prepared by application of the Gilman-Jorgenson ketone synthesis (11b, v, w) 22,134,139,140 or the Mukaiyama one-pot ketone preparation based on the use of anhydrides 174 ( 11a, b, c, k, l, x). 22,134,139 Although no attempts were made to treat the benzylesters 14 themselves with simple alkyllithium or Grignard reagents, several cases are known in which functionalized organolithium reagents do in fact undergo smooth acylation with formation of the desired ketones without displaying undesired double addition, e.g., 175, 141 176a, 142 176b, 142,143 145 and 179.…”