Asymmetric Synthesis of Chiral 1,3‐Diaminopropanols: Bisoxazolidine‐Catalyzed CC Bond Formation with α‐Keto Amides

Abstract

The ever-increasing demand for enantiopure drugs and agrochemicals, and the use of chiral building blocks in polymers, liquid crystals, and other materials has generated a strong stimulus for the development of asymmetric methods that utilize previously unexplored starting materials to generate efficient access to new and emerging target compounds.[1] New drug candidates that bear a chiral 1,3-diaminopropanol moiety or a corresponding oxazolidinone derivative have recently been introduced for the treatment of tuberculosis, Alzheimers disease, and nosocomial infections caused by bacteria that are resistant to common antibiotics. [2] The formation of these challenging structures relies on multistep syntheses from chiral epoxy alcohols or esters and typically involves laborious protection/deprotection protocols. We envisioned that the enantioselective synthesis of Nsubstituted 1,3-diaminopropanols could be accomplished in three steps by nitroaldol reaction of a-keto amides, which are unexplored starting materials in asymmetric catalysis, and subsequent reduction of the nitro and amide groups (Scheme 1). The first catalytic asymmetric nitroaldol reaction was developed in 1992 by Shibasaki and coworkers, who used a BINOL-derived rare-earth-metal complex.[3] This reaction has since received considerable attention and its value for the synthesis of important chiral building blocks and complex target compounds has been demonstrated by many research groups.[4] Relatively few examples of asymmetric nitroaldol reactions with ketones [5] are known compared to the wealth of reactions with aldehydes. The use of a-keto amides has not been reported to date, in fact, catalytic asymmetric intermolecular C À C bond formations with a-keto amides have so far been elusive. [6] We expected that careful reduction of the nitro group in a-hydroxy b-nitro propanamides would avoid problems with the facile retro-aldol reaction [7] and thus lead to a practical route to a series of chiral 1,3-diaminopropanols. [8] In recent years, chiral 1,3-oxazolidines have found increasing use as ligands and auxiliaries in asymmetric synthesis, which may be attributed to the intriguing ring topology and the possibility of modular synthesis from amino alcohols.[9] We have previously introduced bisoxazolidine L1 and showed several applications of this C 2 -symmetric N,Odiketal in asymmetric catalysis (Scheme 2).[10] Despite the ease of preparation of L1, which can be obtained in a single step from inexpensive cis-1-amino-2-indanol and 1,2-cyclohexanedione, the synthesis of other diketone-derived bisoxazolidines is not straightforward and requires careful selection of starting materials and reaction conditions.[11] Accordingly, we chose to prepare a series of new ligands L2-L7 derived from (1R,2S)-aminoindanol analogues and several diketones to vary the rigidity of the N,O-diketal backbone and to explore the catalytic performance of fluxional bisoxazolidines in the nitroaldol reaction with keto amides.The synthesis of L2 started with the bromination of 1,2-...

Identification, Synthesis, and Biological Evaluation of the Major Human Metabolite of NLRP3 Inflammasome Inhibitor MCC950

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Synthesis of 1-indanones with a broad range of biological activity

“…Wolf and Xu have synthesized 7-methyl substituted 1-indanone 241 utilizing 1,3-pentadiene ( 238 ) and 2-cyclopentenone ( 239 ) as starting compounds [ 96 ]. 7-Methyl substituted 1-indanone 241 has been obtained in the Diels–Alder reaction between 1,3-pentadiene ( 238 ) and 2-cyclopentenone ( 239 ) followed by the oxidative aromatization with Pd/C ( Scheme 67 ).…”

The Aldol Reaction of α‐Ketoamide with α,β‐Unsaturated Ketone in KOH Aqueous Medium

“…To the best of our knowledge, there are only few reports of nucleophilic addition to the keto group of acyclic‐keto amides to synthesize acyclic disubstituted α‐hydroxy amides. In 2011, Xu and Wolf reported a Henry reaction of various α‐ketoamides with nitromethane by copper‐catalyzed to prepare 2‐hydroxy‐3‐nitro‐propanamides with high yields (Scheme 1c) [7] . In 2021, Kohari and co‐workers developed an organocatalyzed aldol reaction of α‐ketoamides with acetone in the presence of a tripeptide catalyst to yield 2‐hydroxy‐propanamides up to 99 % yield (Scheme 1d) [8] .…”