Enantioselective Heck‐Matsuda Reactions of Spirocyclopentenyl Hydantoins Directed by Non‐Covalent Interactions: Total Synthesis of the (S, S)‐VPC01091. Issue 16 (9th July 2020)

• Record Type: Journal Article
• Authors: de Oliveira, Valdeir C.; de Oliveira, Juliana M.; Menezes da Silva, Vitor H.; Khan, Ismat U.; Correia, Carlos Roque D.
• Is Part Of: Advanced synthesis & catalysis. Volume 362:Issue 16(2020)
• Page Start: 3395
• Page End: 3406
• Publication Date: 2020-07-09
• Subjects: Heck arylation -- N, N-Ligands -- Enantioselectivity -- VPC01091 -- Multiple sclerosis; Catalysis -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Chemistry -- Periodicals; Chemistry, Technical -- Periodicals; Chemistry -- Periodicals; Catalysis -- Periodicals; Technology, Pharmaceutical -- Periodicals; 547.2
• DOI: 10.1002/adsc.202000443
• Languages: English
• ISSNs: 1615-4150

Abstract

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. Abstract :