Construction of azaspirocyclic skeletons mediated by the carbonyl of Weinreb amide: formal total synthesis of (±)-cephalotaxine

Facile stevens rearrangement of the Weinreb amide and the subsequent key steps mediated by the carbonyl of Weinreb amide led to the construction of azaspirocyclic skeletons of some typical alkaloids....

The Application of 1,2-Oxazinanes as Chiral Cyclic Weinreb Amide-type Auxiliaries Leading to a Three Component One-Pot Reaction

1,2-Oxazines were synthesised via a copper-catalysed aerobic acyl nitroso Diels-Alder reaction from 1,4-disubstituted 1,3-dienes and N-Boc-hydroxylamine. From this, 1,2-oxazinanes were received in a novel follow-up reaction path. The stability of several 1,2-oxazines and 1,2-oxazinanes towards organometallic compounds was tested to rate their operability as cyclic chiral Weinreb amide auxiliaries. 3,6-Di-tert-butyl-1,2-oxazinane gave the best results and was introduced as chiral Weinreb amide-type auxiliary to yield chiral α-substituted ketones in a diastereomeric ratio of up to 98:2. The removal of the auxiliary can be performed with BuLi to form unsymmetrical α-chiral ketones. Thereafter, the chiral auxiliary can be re-isolated and purified by sublimation in vacuum.

Antipsychotic drug Cariprazine synthesis: An improved and commercially viable synthetic approach

: The novel synthetic route to an antipsychotic drug Cariprazine was developed and demonstrated on a commercial scale. The synthesis of Cariprazine is achieved from N-(4-oxocyclohexyl) acetamide by using various reactions such as Wittig-Horner reaction, reduction of alkene, hydrolysis of ester, deacylation, amidation, reduction of weinreb amide to yield the corresponding aldehyde, and finally reductive amination of aldehyde in presence of the corresponding amine to form Cariprazine. In this article, we report a novel intermediate 2-[trans-4-(3,3-Dimethylureido)cyclohexyl]-N-methoxy-N-methylacetamide by avoiding potentially genotoxic substances/intermediates, tedious, drastic reaction conditions.

Efficient synthesis of α,β-dichlorinated ketone from α,β-dichlorinated Weinreb amide through simple work-up procedure

An efficient synthesis of α,β-dichlorinated ketones from α,β-dichlorinated Weinreb amides is described. Quenching with nonaqueous HCl avoided side reactions associated with the typical a work-up procedure. The amide accepted various...

Palladium Catalyzed Stereoselective Arylation of Biocatalytically Derived Cyclic 1,3-Dienes: Chirality Transfer via a Heck-Type Mechanism

Microbial arene oxidation of benzoic acid with Ralstonia eutropha B9 provides a chiral highly functionalized cyclohexadiene, suitable for further structural diversification. Subjecting this scaffold to a palladium-catalyzed Heck reaction effects a regioselective and stereoselective arylation of the cyclohexadiene ring. The arylation proceeds with a highly selective 1,3-chirality transfer of stereogenic information installed in the microbial arene oxidation. Quantum chemical calculations have provided insight<br>into the mechanism of the palladium catalyzed arylation. The high selectivity can be explained both by a kinetic preference for the observed arylation position and, interestingly, by reversible carbopalladation in competing positions. Functional groups that were well tolerated on the diene substrate included a range of esters, amides and a Weinreb amide, affording a total of 23 different products<br>in good yields. These products, which can be considered as latent enolic nucleophiles, also possess a unique three dimensional structure which can be utilized in further stereoselective transformations. This was demonstrated by subjecting one of the products, which contained a protected aldehyde, to a tandem deprotection – cyclization sequence. The reaction proceeded with complete stereoselectivity<br>and afforded a tricyclic ketone product possessing four stereogenic centers. This demonstrates the capability of the method to introduce stereochemical complexity from a planar molecule such as benzoic acid in just a few steps.<br>

Palladium Catalyzed Stereoselective Arylation of Biocatalytically Derived Cyclic 1,3-Dienes: Chirality Transfer via a Heck-Type Mechanism

Microbial arene oxidation of benzoic acid with Ralstonia eutropha B9 provides a chiral highly functionalized cyclohexadiene, suitable for further structural diversification. Subjecting this scaffold to a palladium-catalyzed Heck reaction effects a regioselective and stereoselective arylation of the cyclohexadiene ring. The arylation proceeds with a highly selective 1,3-chirality transfer of stereogenic information installed in the microbial arene oxidation. Quantum chemical calculations have provided insight<br>into the mechanism of the palladium catalyzed arylation. The high selectivity can be explained both by a kinetic preference for the observed arylation position and, interestingly, by reversible carbopalladation in competing positions. Functional groups that were well tolerated on the diene substrate included a range of esters, amides and a Weinreb amide, affording a total of 23 different products<br>in good yields. These products, which can be considered as latent enolic nucleophiles, also possess a unique three dimensional structure which can be utilized in further stereoselective transformations. This was demonstrated by subjecting one of the products, which contained a protected aldehyde, to a tandem deprotection – cyclization sequence. The reaction proceeded with complete stereoselectivity<br>and afforded a tricyclic ketone product possessing four stereogenic centers. This demonstrates the capability of the method to introduce stereochemical complexity from a planar molecule such as benzoic acid in just a few steps.<br>

Recent Developments in Weinreb Synthesis and Their Applications

N-methoxy-N-methyl amides or Weinreb amides are worthy embranchment of amide group and their rich functional groups in organic synthesis become a strong else unfeasible conversion. Weinreb amides are produced as an intermediate product of the reaction of carboxylic acids, acid chloride or esters with organometallic reagents, which was first uncovered in 1981. The direct conversion of carboxylic acids or acid chlorides or esters to ketones or aldehydes using organometallic reagents do not lead in high yields, because the intermediate ketones are still highly reactive toward the organometallic reagent. However, after derivatization to the corresponding Weinreb Amide, reaction with organometallics does give the desired ketones, as the initial adduct is stabilized and doesn't undergo further reactions. A nucleophilic addition to the Weinreb amides results in a unique and stable five-membered cyclic tetrahedral intermediate which protects the over-addition, leading to a selective conversion.