Intramolecular Regioselective Insertion into Unactivated Prochiral Carbon−Hydrogen Bonds with Diazoacetates of Primary Alcohols Catalyzed by Chiral Dirhodium(II) Carboxamidates. Highly Enantioselective Total Synthesis of Natural Lignan Lactones

Abstract

Intramolecular insertion into unactivated prochiral C-H bonds of 3-aryl-1-propyl diazoacetates catalyzed by dirhodium(II) tetrakis[methyl 1-(3-phenyl propanoyl)imidazolidin-2-one-4(R or S)carboxylate], Rh 2 (4R-MPPIM) 4 or Rh 2 (4S-MPPIM) 4 , occurs in 91-96% ee and with virtually complete regiocontrol for the formation of β-benzyl-γ-butyrolactones. This methodology has been applied to the total synthesis of dibenzylbutyrolactone lignans (-)-and (+)-enterolactone, (-)-and (+)hinokinin, and (+)-arctigenin from substituted cinnamic acids in 19-27% overall yields. Aryltetralin lignan (+)-isodeoxypodophyllotoxin was prepared from the reactant 3,4-(methylenedioxy)cinnamic acid in 36% yield overall, and the lactone precursor to (+)-isolauricerisinol was formed in 96.5% ee and 23% yield overall. Applications of the chiral Rh 2 (MPPIM) 4 catalysts to fully aliphatic systems resulting in the formation of β-substituted-γ-butyrolactones with high regiocontrol and with 93-96% ee have demonstrated the generality of this methodology. A model that provides accurate predictions of β-substituted-γ-butyrolactone absolute configurations in these asymmetric metal carbene transformations is described.The synthesis of enantiomerically pure β-substituted γ-butyrolactones of general structure 1 represents a significant challenge for which there have been few solutions. 1,2 These structures are indigenous to a broad spectrum of natural products of which lignan lactones 2 are prominent. 3 Alkylation or carbonyl addition reactions of 1 afford a convenient stereocontrolled entry into virtually all of the structurally diverse class of lignans, 1,3,4 many of which, including (-)-enterolactone (3) and (+)arctigenin (4), have noteworthy biological and medicinal properties. 3,[5][6][7] Numerous strategies have been developed to achieve stereocontrolled syntheses of naturally occurring lig-nans, 1,3,4 including diastereoselective conjugate addition to chiral 2(5H)-furanones and dihydrofurans, 8 select cycloaddition reactions, 9 and the employment of chiral oxazolines. 10 However, diastereoselective alkylation of 9146

Overview of enterolactone biological properties and total synthesis

“…46,50 Changing the catalyst to Rh2(4(S)-MPPIM)4 provided the (S)--butyrolactone enantiomer of 9, with an overall yield of 27% and 91% ee for the total synthesis of (+)-enterolactone, 13. 50,52 Although this method provides moderate yield and good selectivity for enterolactone, it is limited by the difficulty of working with methanesulfonyl azide. Scheme 8.…”

Komplementäre Strategien für die dirigierte C(sp3)‐H‐Funktionalisierung: ein Vergleich von übergangsmetallkatalysierter Aktivierung, Wasserstoffatomtransfer und Carben‐ oder Nitrentransfer

“…Mit Rh 2 -(4S-MPPIM) 4 (491)kann aus dem acyclischen Diazoester 490 das g-Lacton 492 mit hoher Enantioselektivitäte rhalten werden (Schema 95). [194] Doyle zeigte außerdem, dass mit Rh 2 (4S-MCHIM) 4 (494)z wischen zwei prochiralen Alkylgruppen differenziert werden kann. So liefert die Desymmetrisierung des Diazoesters 493 das hoch enantiomerenangereicherte g-Lacton 495.…”

“…[195] Die Anwendung der asymmetrischen C-H-Insertion wird von Doyle in der Synthese des Naturstoffs (+)-Isolauricerisinol (498)d emonstriert (Schema 96). [194] Beim Diazoester 496 erfolgt eine enantioselektive Rhodium(II)-katalysierte intramolekulare C-H-Insertion unter Bildung des g-Lactons 497,w oraus der Naturstoff aufgebaut wird. Taber verwendete außerdem den chiralen Rhodium(II)-Katalysator 500,umdurch C-H-Insertion bei 499 die Bildung des gewünschten Diastereomers 501 für die Synthese von (À)-Astrogorgiadiol (502)zubefçrdern.…”

Dirhodium(II) Carbenes : The Chiral Product Cascade

“…With primary alkyl diazoacetates other than 41, C-H insertion reactions catalysed by Rh 2 (MEPY) 4 proceed with enantioselectivities that are < 70% ee. However, the introduction of 2-oxoimidazolidine catalyst variants 11 has led to enhanced enantioselectivities and excellent regiocontrol (Doyle et al, 1994f, 1995f-h;Müller and Polleux, 1994;Bode et al, 1996). For example, use of Rh 2 (4S-MPPIM) 4 11d provided γ-lactones 44 from diazoacetates 43 derived from primary alcohols equation 11.…”

“…For example, use of Rh 2 (4S-MPPIM) 4 11d provided γ-lactones 44 from diazoacetates 43 derived from primary alcohols equation 11. This methodology provided facile access to a series of naturally occuring lignans, for example (-) enterolactone 45, (+)-arctigenin 46 and (+)-isodeoxypodophyllotoxin 47 (Bode et al, 1996). A = Me, Ph, C 5 H 11 , CH=CH 2 38 24-76% ee 37 …”