Catalytic Asymmetric Intramolecular Cyclopropanation Research Articles

Divergent Total Syntheses of (+)‐Vulgarisins A–E

AbstractThe asymmetric total syntheses of (+)‐vulgarisins A–E, which share a rare and highly oxygenated [5‐6‐4‐5] tetracyclic core structure that were isolated fromP. vulgarisLinn., have been described for the first time in a divergent manner. Key transformations include: 1) a catalytic asymmetric intramolecular cyclopropanation to forge the A ring bearing desired stereochemistry at C14; 2) a one‐pot borylation/conjugate addition process for creation of the C1−C11 bond; 3) a Wolff ring contraction to assemble the bicyclo[3.2.0]heptane subunit (CD rings); and 4) a stereocontrolled pinacol cyclization for construction of the central B ring of the natural products.

Divergent Total Syntheses of (+)-Vulgarisins A-E.

The asymmetric total syntheses of (+)-vulgarisins A-E, which share a rare and highly oxygenated [5-6-4-5] tetracyclic core structure that were isolated from P. vulgaris Linn., have been described for the first time in a divergent manner. Key transformations include: 1) a catalytic asymmetric intramolecular cyclopropanation to forge the A ring bearing desired stereochemistry at C14; 2) a one-pot borylation/conjugate addition process for creation of the C1-C11 bond; 3) a Wolff ring contraction to assemble the bicyclo[3.2.0]heptane subunit (CD rings); and 4) a stereocontrolled pinacol cyclization for construction of the central B ring of the natural products.

Enantioselective Total Synthesis of Cotylenin A

A convergent enantioselective total synthesis of cotylenin A is described. The A-ring fragment, prepared via the catalytic asym-metric intramolecular cyclopropanation developed in our laboratory, and the C-ring fragment, prepared from a known chiral compound via a modified acyl radical cyclization, were successfully assembled by the Utimoto coupling reaction. The formidable carbocyclic eight-membered ring of cotylenin A was efficiently constructed by a palladium-mediated cyclization. All the hydroxy groups in the scaffold were stereoselectively introduced and a modified reducing reagent, Me4NBH(O2CiPr)3, has been developed. The sugar moiety fragment was prepared via three consecutive carbon-oxygen bond-forming reactions, and the glycosylation was accomplished using Wan's protocol.

Catalytic Asymmetric Intramolecular Cyclopropanation of α-Diazo-α-Silyl Acetate

The catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of α-diazo-α-silyl acetates to form oxabicyclo[3.2.1]hexane, which proceeds with high yields and enantioselectivities, is described. The maximum enantiomeric excess observed was 96% ee and the absolute configuration of the products was elucidated. The counteranion of the Cu(I) catalyst was found to play a crucial role in determining the yields and enantioselectivities, with highly anionic counteranions improving both yields and enantioselectivities. Our previously reported model explains the enantiofacial selectivity of the reacting alkene.

Enantioselective preparation of C-ring fragment of cotylenin A via catalytic asymmetric intramolecular cyclopropanation of α-diazo β-keto ester

A synthetic pathway to the C-ring fragment of cotylenin A which emerged from our retrosynthetic analysis of cotylenin A is described. The catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of the α-diazo-β-keto ester bearing 2,4,6-trimethylphenyl group as the ester part has been found to afford the crystalline product with high ee, which allowed to establish the approach to the C-ring fragment which required ten-pot operations. The developed approach would be beneficial to a large scale synthesis of the C-ring fragment for the total synthesis of cotylenin A.

Enantioselective approach to polycyclic polyprenylated acylphloroglucinols via catalytic asymmetric intramolecular cyclopropanation.

The formal enantioselective total synthesis of nemorosone, garsubellin A, clusianone, and hyperforin is described. The catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of an α-diazo ketone, a common synthetic intermediate for the above four polycyclic polyprenylated acylphloroglucinols previously reported by us, exhibited low enantioselectivity. However, CAIMCP of the corresponding α-diazo β-keto sulfone afforded the desired product in 79% yield with 84% ee. Investigation of the CAIMCP of the α-diazo β-keto sulfone demonstrated the formation of a rearrangement product in the presence of molecular sieves 4 Å, whereas, in the presence of H2O, the byproduct derived from ring-opening of the desired cyclopropane was observed. X-ray crystallographic analysis suggested that the above two products are derived from the same chiral intermediate. The product derived from ring-opening of the cyclopropane was successfully transformed to the respective synthetic intermediates for the total syntheses of nemorosone, garsubellin A, clusianone, and hyperforin, which had previously been reported by us.

ChemInform Abstract: Enantioselective Total Syntheses of Cyathane Diterpenoids

AbstractReview: [48 refs.

Enantioselective total syntheses of cyathane diterpenoids.

A Personal Account describing the enantioselective total syntheses of cyathane diterpenoids achieved in the Nakada group. A convergent approach to the cyathane scaffold, the [5-6-7] tricyclic carbon skeleton commonly found in cyathane diterpenoids, has been developed using the catalytic asymmetric intramolecular cyclopropanation (CAIMCP) and baker's yeast reduction. This approach has been successfully applied for the enantioselective total syntheses of (+)-allocyathin B2 , (-)-erinacine B, and (-)-erinacine E. The total synthesis of (-)-erinacine E has been achieved via the acyl group migratory intramolecular aldol reaction, which prevents the retro-aldol reaction and allows the construction of the strained structure. The highly efficient and stereoselective total syntheses of (-)-scabronines G, A, D, and (-)-episcabronine A have been achieved via the oxidative dearomatization/inverse electron demand Diels-Alder reaction cascade. Cascade reactions comprising three and five consecutive reactions were employed for the highly efficient total syntheses of (-)-scabronine A and (-)-episcabronine A, respectively.

Enantioselective Total Synthesis of (+)-Colletoic Acid via Catalytic Asymmetric Intramolecular Cyclopropanation of an α-Diazo-β-keto Diphenylphosphine Oxide

The enantioselective total synthesis of (+)-colletoic acid, a potent naturally occurring 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, is described. This total synthesis features a highly enantioselective catalytic asymmetric intramolecular cyclopropanation of an α-diazo-β-keto diphenylphosphine oxide and five highly stereoselective reactions (cyclopropane opening, Diels-Alder reaction, iodolactonization, alkene formation, and reduction of α,β-unsaturated carboxylic acid).

Preparation of new chiral bisoxazoline ligands for the catalytic asymmetric intramolecular cyclopropanation of α-diazo-β-keto phenyl sulfone to afford a useful bicyclo[3.1.0]hexane derivative

Herein we describe the preparation of novel chiral bisoxazoline ligands with various substituents at the bisoxazoline linkage, for use in the catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of α-diazo-β-keto phenyl-5-hexenyl sulfone to afford a simple, but useful, bicyclo[3.1.0]hexane derivative. The enantioselectivity of the CAIMCP of α-diazo-β-keto phenyl-5-hexenyl sulfone was improved and a product with 84% ee was obtained using 30mol% of the catalyst, which was prepared in situ by CuOTf and the new bisoxazoline ligand with two 3,5-di-tert-butylbenzyl groups at the bisoxazoline linkage. The product was obtained in enantiomerically pure form by a single crystallization, enabling its use as a chiral building block.

Enantioselective divergent approaches to both (−)-platensimycin and (−)-platencin

Enantioselective divergent approaches to (−)-platencin and (−)-platensimycin have been developed. A rationally designed chiral synthetic intermediate, possessing a useful α,β-unsaturated sulfone functionality, which served as a masked ketone as well as a good Michael acceptor, was successfully prepared via the highly enantioselective catalytic asymmetric intramolecular cyclopropanation (CAIMCP) developed in our laboratory.

An enantioselective approach to (−)-platencin via catalytic asymmetric intramolecular cyclopropanation

This Letter describes an enantioselective approach to (−)-platencin. A uniquely functionalized chiral intermediate, which was prepared via the highly enantioselective catalytic asymmetric intramolecular cyclopropanation (CAIMCP) that we have developed, was successfully transformed to Nicolaou’s intermediate in his total synthesis of (−)-platencin.

Development of Catalytic Asymmetric Intramolecular Cyclopropanation of α-Diazo-β-Keto Sulfones and Applications to Natural Product Synthesis

The catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of α-diazo-β-keto sulfones developed in our laboratory and applications to the total synthesis of natural products are described. CAIMCP features (a) a wide applicability, not only to the preparation of bicyclo[n.1.0]alkanes and tricyclo[4.n.0.0]alkenes, but also to the enantioselective total synthesis of natural products, (b) the formation of highly crystalline products, which facilitate the production of enantiomerically pure synthetic intermediates, and (c) the generation of products with a variety of functionalities, such as cyclopropane, ketone, and sulfone, beneficial to the total synthesis of natural products.

Synthetic studies on (−)-scabronine A

This Letter describes synthetic studies on (−)-scabronine A utilizing a new chiral building block successfully prepared via the catalytic asymmetric intramolecular cyclopropanation (IMCP) of an α-diazo-β-keto sulfone. The crucial transformations in this study are the coupling reaction of two fragments between the positions adjacent to a quaternary carbon center, the intramolecular aldol reaction, the C14 hydroxyl-directed hydrogenation, and the ring-expansion reaction to furnish the 5-6-7 tricyclic cyathane skeleton.

Catalytic Asymmetric Intramolecular Cyclopropanation of 2‐Diazo‐3‐oxo‐6‐heptenoic Acid Esters.

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, please click on HTML or PDF.

Highly enantioselective preparation of tricyclo[4.4.0.0 5,7]decene derivatives via catalytic asymmetric intramolecular cyclopropanation reactions of α-diazo-β-keto esters

The enantioselective preparation of the tricyclo[4.4.0.0 5,7]dec-2-ene derivatives via the catalytic asymmetric intramolecular cyclopropanation (CAIMCP) reactions of α-diazo-β-keto esters with excellent ee (95–98% ee) is described. The chiral building blocks reported herein would be versatile intermediates for enantioselective natural products synthesis.

Studies on the Structure—Enantioselectivity Relationships in the Catalytic Asymmetric Intramolecular Cyclopropanation Reaction of α‐Diazo‐β‐keto Sulfones Possessing a Methyl‐Substituted Phenyl Group.

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, please click on HTML or PDF.

Catalytic Asymmetric Intramolecular Cyclopropanation of 2-Diazo-3-oxo-6-heptenoic Acid Esters

This manuscript describes studies on the catalytic asymmetric intramolecular cyclopropanation (IMCP) of 2-diazo-3-oxo-6-heptenoic acid esters. The enantioselectivity depends on the bulkiness of the ester moiety, and the 2,6-di-tert-butyl-4-methylphenyl ester of 2-diazo-3-oxo-6-heptenoic acid provided the product with 78% ee, suggesting that the catalytic asymmetric IMCP of α-diazo-β-keto esters could be a key reaction for the enantioselective syn­thesis of natural products as well as artificial molecules.

Enantioselective total synthesis of (+)-digitoxigenin

An enantioselective total synthesis of (+)-digitoxigenin is described. This total synthesis is accomplished in a convergent manner using two chiral fragments prepared via the catalytic asymmetric intramolecular cyclopropanation and baker’s yeast mediated reduction developed by us, respectively. This convergent synthesis would be useful for preparing some new derivatives of digitoxigenin for SAR studies and could be applied for the total synthesis of other cardenolides left unprepared.

Studies on the structure–enantioselectivity relationships in the catalytic asymmetric intramolecular cyclopropanation reaction of α-diazo-β-keto sulfones possessing a methyl-substituted phenyl group

This manuscript describes studies on structure–enantioselectivity relationships in the catalytic asymmetric intramolecular cyclopropanation (IMCP) reaction of α-diazo-β-keto sulfones possessing a methyl-substituted phenyl group. Enantioselectivity of the IMCP reaction of the α-diazo-β-keto sulfones was varied by the position of a methyl group on the phenyl group in the substrate, and the 2,3-dimethylphenyl sulfone 11h provided the product 12h in 95% yield with 93% ee. This yield is superior to that of the substrate with a mesityl sulfone 11b, and the product 12h is useful because alkylation of its cyclopropane-opened β-keto sulfone derivative 15h provides the C-alkylated product as a major product.