Diastereoselective Acylation Research Articles

Scalable Total Synthesis of Acremolactone B.

Acremolactone B is a pyridine-containing azaphilone-type polyketide. The first total synthesis of this molecule was achieved on a gram scale, based on an aza-6π electrocyclization-aromatization strategy for construction of the tetra-substituted pyridine ring. A bicyclic intermediate was expeditiously prepared by using [2+2] photocycloaddition and chemoselective Baeyer-Villiger oxidation, which was further elaborated to a densely substituted aza-triene. An electrocyclization-aromatization cascade was utilized to forge the tetracyclic core of this natural product, and the side chain was introduced through diastereoselective acylation and reduction.

Scalable Total Synthesis of Acremolactone B

AbstractAcremolactone B is a pyridine‐containing azaphilone‐type polyketide. The first total synthesis of this molecule was achieved on a gram scale, based on an aza‐6π electrocyclization–aromatization strategy for construction of the tetra‐substituted pyridine ring. A bicyclic intermediate was expeditiously prepared by using [2+2] photocycloaddition and chemoselective Baeyer–Villiger oxidation, which was further elaborated to a densely substituted aza‐triene. An electrocyclization–aromatization cascade was utilized to forge the tetracyclic core of this natural product, and the side chain was introduced through diastereoselective acylation and reduction.

Stereoinversion in the diastereoselective acylation of benzoxazine derivatives with 2-aryloxypropionyl chlorides

A comparative study of the kinetic resolution of racemic derivatives of 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine using racemic 2-aryloxypropionyl chlorides was performed. It was found that the acylation of racemic amines with racemic 2-(1-naphthyloxy)propionyl chloride leads to amides enriched with (3R*,2′R*)-diastereomers, while the acylation with 2-phenoxypropionyl chloride gives predominantly (3R*,2′S*)-amides. Quantum chemical modeling of the process of kinetic resolution at the COSMO-CH2Cl2-B3LYP-D3-gCP/def2-TZVP//B3LYP-D3-gCP/def2-SVP level of theory was performed. The computational results are in a good agreement with the experimental data.

Divergent Synthesis of Dihydropyranone Stereoisomers via N‐Heterocyclic Carbene Catalysis

AbstractWe recently developed a novel chiral N‐heterocyclic carbene (NHC) catalyzed dynamic kinetic enantioselective acylation (DKEA) and dynamic kinetic diastereoselective acylation (DKDA) of Achmatowicz rearrangement products to generate useful intermediates for the further synthesis of carbohydrates. In this update, we describe a divergent NHC catalytic strategy for the stereoselective preparation of all four isomers starting from a common racemic precursor. The present report provides easy access to diverse optically pure dihydropyranones.magnified image

Diastereoselective Acylation of Recemic Heterocyclic Amines with N-Phthaloyl- and N-Naphthaloyl-(S)-Amino Aclyl Clorides . Possibility of Parallel Kinetic Resolution

Diastereoselective Acylation of Recemic Heterocyclic Amines with N-Phthaloyl- and N-Naphthaloyl-(S)-Amino Aclyl Clorides . Possibility of Parallel Kinetic Resolution

Diastereoselective Acylation of Racemic Heterocyclic Amines with N-Phthaloyl and N-Naphthaloyl (S)-Amino Acyl Chlorides: Possibility of Parallel Kinetic Resolution

The acylative kinetic resolution of racemic 2-methyl-1,2,3,4-tetrahydroquinoline and 3,4-dihydro-3-methyl-2H-[1,4]benzoxazines with acyl chlorides of N-naphthaloyl-(S)-alanine and N-naphthaloyl-(S)-phenylalanine has been studied. It has been shown that diastereoselective acylation of racemic amines with N-naphthaloyl (S)-amino acyl chlorides results in the predominant formation of (R,S)-amides, whereas acylation of the same amines with N-phthaloyl (S)-amino acyl chlorides proceeds with the opposite diastereoselectivity. The parallel kinetic resolution of racemic 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine using a mixture of acylating agents derived from a single precursor, (S)-phenylalanine, was carried out.

Organocatalyst‐Mediated Dynamic Kinetic Enantioselective Acylation of 2‐Chromanols

AbstractWe recently developed a novel chiral catalyst‐directed dynamic kinetic diastereoselective acylation of hemiacetals for the synthesis of carbohydrates. In this update, we describe a catalytic method for the dynamic kinetic enantioselective acylation of 2‐chromanols using benzotetramisole derived catalysts. High yields and enantiomeric excesses were obtained for a broad range of acylated 2‐chromanols, which are important intermediates for the synthesis of various bioactive pharmaceuticals. We hypothesize that the high stereoselectivity of the reaction originates from a novel cation‐n interaction between the chromanol substrate and the acylated catalyst.magnified image

Chiral Catalyst-Directed Dynamic Kinetic Diastereoselective Acylation of Anomeric Hydroxyl Groups and a Controlled Reduction of the Glycosyl Ester Products.

A catalytic method is developed for the diastereoselective acylation of the anomeric hydroxyl group in diverse carbohydrates to form either α- or β-anomeric esters. While exclusive formation of the β-isomer was observed in most sugar substrates with one enantiomer of the chiral catalyst, moderate to high α-selectivity was obtained by using the other enantiomer of the chiral catalyst. The resulting α- and β-anomeric esters have very different reactivity toward a reduction reaction.

Enantio- and diastereoselective acylation of prochiral hydroxyl group of pyrimidine acyclonucleosides

The transesterification reaction of series pyrimidine acyclonucleosides was carried out with lipase (EC 3.1.1.3) Amano PS from Burkholderia cepacia (BCL) as biocatalyst. The BCL-mediated acylation of prochiral groups of diols produced the corresponding monoesters in high yield and with enantiomeric/diasteromeric excess from 77 to 99%. The lipase BCL enabled desymmetrization of pro-R hydroxyl groups and gave (2R)-monoesters. Absolute configuration of the products was confirmed by means of ECD spectroscopy supported by theoretical calculations.

Highly diastereoselective acylation of l-menthol by a lipase from Stenotrophomonas maltophilia CGMCC 4254

l-menthol, one of the world’s largest flavor components, is widely utilized in food and cosmetics industries. Disappointingly, menthol which was synthesized by thymol hydrogenation route consisted of diastereomeric menthol mixture, containing several isomers leading to undesirable taste. Therefore, there is a need for efficient and economical way of preparing optically pure l-menthol from diastereomeric mixture. In our work, Stenotrophomonas maltophilia CGMCC 4254 lipase (SML) was chosen as a potential biocatalyst for diastereoselective acylation of l-menthol. Subsequently, different reaction factors were investigated, such as organic solvent, acyl donors, temperature, menthol concentration and molar ratio of donor to l-menthol. SML-catalyzed l-menthol acetylation reaction at 641mM concentration and 35°C resulted in 95.1% conversion (24h) and 93.4% diastereomeric excess (d.e.p), which were much better than commercially available lipases tested. Finally, the acetylation reaction was scaled up to 0.9L, resulting in an average l-menthyl acetate volumetric productivity 1.33g/L/h with 93.4% d.e.p and 95.1% conversion. Therefore, SML is a potentially promising biocatalyst for preparation of optically pure l-menthol from diastereomeric mixture in an industrial scale.

Chiral Catalyst-Directed Dynamic Kinetic Diastereoselective Acylation of Lactols for De Novo Synthesis of Carbohydrate.

The control of the stereochemistry at the anomeric position is still one of the major challenges of synthetic carbohydrate chemistry. We have developed a new strategy consisting of a chiral catalyst-directed acylation followed by a palladium-catalyzed glycosidation to achieve high α- and β-stereoselectivity on the anomeric position. The former process involves a dynamic kinetic diastereoselective acylation of lactols derived from Achmatowicz rearrangement, while the latter is a stereospecific palladium-catalyzed allylic alkylation.

Diastereoselective acylation of 3,4-dihydro-3-methyl-2H-[1,4]benzoxazines with 2-phenoxy carbonyl chlorides

In the search for novel efficient chiral resolving agents, we have studied the diastereoselective acylation of 3,4-dihydro-3-methyl-2H-[1,4]benzoxazine and 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine with acyl chlorides of 2-phenoxy carboxylic acids (2-phenoxypropionic, 2-phenoxyisovaleric, and 2-phenoxy-3-phenylpropionic) in toluene and dichloromethane at different temperatures. HPLC analysis of the acylation products showed the predominant formation of (R∗,S∗)-diastereoisomeric amides in all cases. It was found that acylation with the studied acyl chlorides was highly stereoselective; 2-phenoxyisovaleryl chloride demonstrated the highest stereoselectivity (selectivity factor s up to 499). A model for the diastereoisomeric transition states in the interaction between racemic amine and acyl chloride is proposed.

Diastereoselective Acylation of Racemic Heterocyclic Amines with N-Tosyl-(S)-Prolyl Chloride and its Structural Analogs

A comparative study on the kinetic resolution of racemic amines (2,3-dihydro-4H-1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline derivatives) via diastereoselective acylation with N-tosyl-(S)-prolyl chloride and its structural analogs was performed. The effect of resolving agent structure on the stereoselectivity of heterocyclic amine acylation was examined. The highest stereoselectivity was achieved in the case of acylation with acyl chlorides bearing a conformationally restricted pyrrolidine ring and an aromatic substituent in the protecting group at the nitrogen atom.

ChemInform Abstract: Synthesis of N‐Cbz‐Substituted β3‐Amino Ketones Utilizing 4‐Substituted 1,3‐Oxazinan‐6‐ones.

AbstractThe approach to the synthetically important chiral β‐amino ketones involves diastereoselective acylation of 1,3‐oxazinan‐6‐ones followed by acidic decarboxylation.

Investigation on the chemoenzymatic synthesis of threo- and erythro-β-hydroxy-l-glutamic acid derivatives

► Transformation of a malonic semialdehyde derivative in β-hydroxy glutamate precursors by aldolase. ► Separation of the two epimers by lipase PS. ► Assignment of configurations by Kazslauskas’ model and H-2 and H-3 chemical shifts. ► Possibility of transforming the products into β-hydroxy glutamic acid derivatives. A derivative of the malonic semialdehyde was transformed by means of a bioconversion catalyzed by the enzyme l -threonine aldolase from E. coli into a 6:4 epimeric mixture of two precursors of β-hydroxy glutamic acid. The enzyme was selective for the formation of the ( S )-configuration at C-2, whereas the configuration at C-3 was not controlled. The two epimers were separated exploiting a diastereoselective acylation in organic solvent catalyzed by lipase PS. The relative and absolute configurations of the products were preliminarily assigned on the base of the model proposed by Kazslauskas for the stereopreference of lipase PS and by comparison of the chemical shifts of the H-2 and H-3 protons of the two homologues. The possibility of transforming the obtained products into β-hydroxy glutamic acid derivatives by conventional chemical reactions was demonstrated.

ChemInform Abstract: Syntheses of Methylenolactocin (VIIa) and Nephrosterinic Acid (VIIb) via Diastereoselective Acylation and Chemoselective Reduction—Lactonization.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Syntheses of methylenolactocin and nephrosterinic acid via diastereoselective acylation and chemoselective reduction–lactonization

The syntheses of methylenolactocin, nephrosterinic acid and their derivatives can be achieved by using the efficient diastereoselective acylation of dimethyl itaconate–anthracene adduct followed by tandem chemoselective reduction–lactonization.

Determination of the absolute stereochemistry and asymmetric total synthesis of madindolines A and B: a practical improvement to a second-generation approach from the first-generation

In this report, we describe an efficient, highly convergent, stereocontrolled first total synthesis and a second-generation synthesis of madindolines A 1 and B 2 , potent selective inhibitors of interleukin 6. The key steps include (1) asymmetric oxidative ring-closure reaction of tryptophol 3 to construct a chiral 3a-hydroxyfuroindoline 4 using the modified Sharpless asymmetric epoxidation condition, (2) highly diastereoselective acylation to build up the quaternary carbon center, and (3) intramolecular acylation of ester 32 with allylsilanes to produce the full substituted cyclopentenedione units. Our first synthetic route defines for the first time both their relative and absolute configurations. Moreover, a more efficient second-generation synthesis was designed, which is suitable for gram-scale preparation of these compounds.

The biocatalyzed stereoselective preparation of polycyclic cyanohydrins

The enzyme-mediated preparation of enantiomerically or diastereomerically enriched polycyclic cyanohydrins has been investigated. Oxynitrilase-catalyzed cyanurations gave excellent results with the bicyclic aldehydes tested. On the other hand, enantio- or diastereoselective acylation, catalyzed by lipase PS or subtilisin, proved to be a more versatile methodology, giving good results even with sterically hindered polycyclic cyanohydrins. Specifically, the steroidal cyanohydrin derivative 4b was isolated with a 89% de.

Enantioselective total synthesis of (+)-dibromophakellstatin.

The first enantioselective total synthesis of (+)-phakellstatin and (+)-dibromophakellstatin was achieved. Key steps in the synthesis were a desymmetrization of the diketopiperazine (S,S)-cyclo (Pro, Pro) via a diastereoselective acylation, an intramolecular Mitsunobu reaction to introduce the C6 aminal, and a tandem Hofmann rearrangement/cyclization to simultaneously introduce the C10 quaternary aminal center and deliver the cyclic urea. The synthesis also demonstrates the unusual stability of pyrrolo aminals. Importantly, this strategy has the potential for producing phakellstatin derivatives, derived from (R,R)-cyclo (Pro, Pro), necessary for biological studies. A similar annulation protocol is also expected to be applicable to the synthesis of palau'amine.