Synthesis of Enantiomerically Pure β‐Hydroxy Ketones via β‐Keto Weinreb Amides by a Condensation/Asymmetric‐Hydrogenation/Acylation Sequence

Abstract

An established route to enantiomerically pure β‐hydroxy ketones proceeds through the asymmetric hydrogenation of β‐keto esters, an ester/amide exchange, and the use of the resulting β‐hydroxy amide for the acylation of an organometallic compound. We shortened this route by showing that β‐keto Weinreb amides are hydrogenated with up to 99 % ee in the presence of [Me2NH2]+{[RuCl(S)‐BINAP]2(µ‐Cl)3}– (0.5 mol‐%) at room temp./5 bar. These Weinreb amides were prepared by seemingly obvious yet unprecedented condensations of lithiated N‐methoxy‐N‐methylacetamide with carboxylic chlorides (51–87 % yield). The resulting β‐hydroxy Weinreb amides were used for the acylation of organolithium and Grignard reagents. They thus gave enantiomerically pure β‐hydroxy ketones (28 examples). A selection of these compounds gave anti‐1,3‐diols after another C=O bond hydrogenation, or syn‐1,3‐diols by a Narasaka–Prasad reduction.

Synthesis of acylnaphthylamines and their applications in the formation of benzoquinazolines

“…[29][30][31] On account of that fact, we decided to examine the effectiveness of N-methoxy-N-methylacetamide (AcN(OMe)Me), N-methoxy-N,2,2trimethylpropanamide (PivN(OMe)Me) and N-methoxy-N,2-dimethylpropanamide ( i PrCON(OMe)Me) in the reactions with naphthalene derivatives 1a or 4a. 32 We noticed that bis-lithiated species 1a reacted with AcN(OMe)Me as well as PivN(OMe)Me at ˗20 °C giving corresponding 2a and 2b in merely moderate 30% yield (Table 1, entries 4, 8). Surprisingly, the effectiveness of Weinreb amides (AcN(OMe)Me, i PrCON(OMe)Me) in the acylation of 4a was very low and the desired products 5a,b were formed in trace amounts (Table 1, entries 13,16).…”

“…(29) were prepared by a procedure similar to that in the literature. 26,27,32 General procedure for the preparation of compounds 2,5. Under argon, to a solution of N-Boc-1naphthylamine (1) or N-Boc-1-bromo-2-naphthylamine (4) (2.1 mmol) in dry Et2O (20 mL), at -20 °C, t BuLi solution in pentane or BuLi solution in hexanes (2.2 equiv.)…”

Recent Advances in Methylation: A Guide for Selecting Methylation Reagents

“…This approach has been widely applied in medicinal chemistry since it was introduced in 1981 by Weinreb and Nahm. [202] Another solution is to convertt he carbonyl chloride into the azetidinyl amide 286,anon-planar amide with al arge ring strain. Upon the nucleophilic addition by organometallics, such as organolithium and Grignardr eagents, the amide undergoes acidmediated elimination through the stable tetrahedral intermediate 287 to produce the ketoneproduct 12 (Scheme 28).…”

Synthesis and Stereochemical Assignment of Arenolide

“…Importantly, Lu and Faulkner employed COSY, HMQC, and HMBC to completely assign the 1 H and 13 C NMR spectra and provided the observation that the 13 C resonances for C-19 and C-21 reside at δ 69.1 and 65.5 ppm. By employing a correlation first established by Hoffmann and recently employed by Bruckner, the chemical shifts reported for the C-19 and C-21 13 C resonances are strongly supportive of a 1,3- anti relative configuration (see Supporting Information for details), and thus, compounds 1 and 2 were targeted for synthesis.…”