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(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

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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-Doctorate
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