Enantioselective Heck-Matsuda Reactions of Spirocy... - BV FAPESP
Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Enantioselective Heck-Matsuda Reactions of Spirocyclopentenyl Hydantoins Directed by Non-Covalent Interactions: Total Synthesis of the (S,S)-VPC01091

Full text
Author(s):
de Oliveira, Valdeir C. [1] ; de Oliveira, Juliana M. [1] ; Menezes da Silva, Vitor H. [1] ; Khan, Ismat U. [2] ; Correia, Carlos Roque D. [1]
Total Authors: 5
Affiliation:
[1] Univ Estadual Campinas, Inst Quim, Dept Quim Organ, CP 6154, BR-13083970 Campinas, SP - Brazil
[2] Gomal Univ, Inst Chem Sci ICS, Dera Ismail Khan 29220 - Pakistan
Total Affiliations: 2
Document type: Journal article
Source: ADVANCED SYNTHESIS & CATALYSIS; v. 362, n. 16 JUL 2020.
Web of Science Citations: 0
Abstract

A highly efficient Heck-Matsuda desymmetrization of unsaturated spirohydantoins directed by non-covalent interactions, which allows the construction of two simultaneous stereogenic centers, including a trisubstituted quaternary one, is described. This Heck arylation permitted a novel enantioselective total synthesis of the S1PR1 agonist (also an S1PR3 antagonist) compound VPC01091, a potential drug for the treatment of multiple sclerosis. The broad scope of these enantioselective Heck-Matsuda protocol provided several arylated spiro systems in yields ranging from 76% to 99%, with enantiomeric ratios (er) up to 97:3, and diastereoselectivities (dr) of > 20:1 in all cases studied. The method uses only 2% of Pd(TFA) 2 and 3 mol% of the chiral N,N-ligand Pyrabox in short reaction times of 1-2 h. These enantioselective Heck arylations can also be carried out at the gram scale in high yields with no erosion of their diastereoselectivity or enantioselectivity. The key spiro Heck products (R,R)-21 and (R,R)-27 bearing an aryl iodide moiety or an aryl n-octyl moiety were employed as starting materials for the total enantioselective syntheses of the (S,S)-VPC01091, in overall yields of 20% and 22% respectively after 10 or 9 steps from the starting spirohydantoin, with an er> 95:5. Computational analysis of the enantioselective Heck-Matsuda desymmetrization supports the rationale involving a key non-covalent interaction between the imide carbonyl of the spirohydantoin and the cationic palladium bounded to the chiral N,N-ligand. (AU)

FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
Grantee:Glaucius Oliva
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 14/25770-6 - New frontiers in cross-coupling reactions promoted by palladium: combining enantioselective catalysis, C-H activations, new materials and in flux reactions aiming at high efficiency and sustainability in synthetic processes
Grantee:Carlos Roque Duarte Correia
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 17/18207-1 - Evaluating new palladium chiral catalysts and application in enantioselective Heck-Matsuda reaction development in new olefinic models: computational studies
Grantee:Vitor Hugo Menezes da Silva
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 15/01491-3 - Theoretical study of cross-coupling reactions: homogeneous and heterogeneous catalysis
Grantee:Ataualpa Albert Carmo Braga
Support Opportunities: Regular Research Grants