Palladium-Catalyzed Enantioselective Addition of Two Distinct Nucleophiles across Alkenes Capable of Quinone Methide Formation

Abstract

A sequential intramolecular-intermolecular enantioselective alkene difunctionalization reaction has been developed which is thought to proceed through Pd-catalyzed quinone methide formation. The synthesis of new chiral heterocyclic compounds with adjacent chiral centers is achieved in enantiomeric ratios up to 99:1 and diastereomeric ratios up to 10:1.The formation of two carbon-heteroatom bonds across an alkene is a process which rapidly increases molecular complexity. The osmium-catalyzed Sharpless dihydroxylation 1 is the epitome of enantioselective alkene difunctionalization, though recent research has included other metal catalysts and expanded to the formation of functional groups other than 1,2-diols. 2 Currently, significant focus has been on palladium catalysis, likely due to the efficiency with which palladium activates olefins for nucleophilic attack. 3 However, in order to achieve the second bond construction, β-hydride elimination from a Pd-alkyl intermediate A, which leads to a Wacker-type monofunctionalized alkene product 1 ,4 must be prevented (Scheme 1). The alkene dialkoxylation reaction developed in our laboratory is believed to accomplish this through the formation of a quinone methide intermediate, which allows for attack by a second equivalent of alcohol. 5 Based on this mechanistic proposal, we envisioned an alkene difunctionalization reaction where a sequential intra-intermolecular process would allow for the selective formation of two distinct carbon-heteroatom bonds by employing substrates which contain a nucleophile tethered to the alkene (Scheme 1). We hypothesized initial intramolecular nucleopalladation to form heterocyclic intermediate B. Subsequent formation of a quinone methide intermediate C allows for attack by an exogenous nucleophile to form the product and release Pd 0 , which is reoxidized using molecular oxygen. Herein we report a highly enantioselective addition of two distinct nucleophiles across alkenes capable of quinone methide formation to access oxygen-based heterocycles with contiguous chiral centers.In exploring the possibility of sequential intra-intermolecular alkene functionalization reactions, we examined 2 as a substrate 6 with methanol as the exogenous nucleophile. Under the standard conditions for enantioselective intermolecular alkene dialkoxylation, 5b using (S)-i PrQuinox as the chiral ligand, a low yield of the desired product was observed with promising enantioselectivity, but low diastereoselectivity (Table 1, entry 1). 7 Addition of a catalytic amount of base and removal of molecular sieves led to modest improvements in product yield (entry 2). Reflecting on our intermolecular asymmetric dialkoxylation reaction, where copper improved yield and chemoselectivity but was removed in order to achieve high sigman@chem.utah.edu. Supporting Information Available: Experimental procedures and full spectroscopic data for new compounds are available free of charge via the internet at http://pubs.acs.org. enantioselectivity, we revisited the use of copper...

Oxidative Functionalization of Alkenes

“…An initial mechanistic investigation with the genminally dimethylated substrate 170 led to a product 171 without any detectable enantiomeric excess. This result suggested that the enantioselectivity is generated within the initial alkoxypalladation followed by faster palladium loss from the corresponding quinone methide intermediate than subsequent diastereoselective nucleophilic methoxide addition to the free quinone methide intermediate AM [114]. An extensive mechanistic investigation including kinetic analyses and electronic effects regarding the substrate substitution suggested that the reaction proceeds under nucleopalladation followed by turnover limiting addition of methoxide to the intermediary quinone methide [115].…”

Palladium-catalyzed approach to the synthesis of five-membered O-heterocycles

“…Sigman et al [208,209] developed a highly enantioselective Pdcatalyzed alkene difunctionalization reaction involving the addition of two distinct nucleophiles, a process which allows for the formation of complex chiral molecules from relatively simple starting materials. Under this strategy, Pd-catalyzed alkene difunctionalization can also proceed by intramolecular oxypalladation followed by the addition of nucleophiles such as methanol, n-butanol, benzyl alcohol, trimethylsilylethanol, (−)-myrtenol, azide, and indole to a quinone methide (Scheme 102).…”

Synthese von 1,2,3‐trisubstituierten Indanen durch diastereoselektive Palladium‐katalysierte Oxyarylierung von Indenen mit Arylboronsäuren und Nitroxiden

“…(1)]. [1] Methoden für Dioxygenierungen, [2] Diaminierungen [3] und Oxyaminierungen [4] wurden beschrieben. Im Vergleich zu Difunktionalisierungen, bei denen zwei Heteroatom-Gruppen an das Olefin addiert werden, sind intermolekulare metallvermittelte Carbofunktionalisierungen von Olefinen, auch unter Einbeziehung anderer Metalle als Palladium, selten [Gl.…”

“…Im Vergleich zu Difunktionalisierungen, bei denen zwei Heteroatom-Gruppen an das Olefin addiert werden, sind intermolekulare metallvermittelte Carbofunktionalisierungen von Olefinen, auch unter Einbeziehung anderer Metalle als Palladium, selten [Gl. (2)]. [5][6][7] Wir präsentieren hier unsere Ergebnisse zu hoch stereoselektiven intermolekularen Pd-katalysierten Oxyarylierungen von Indenen mit verschiedenen Arylboronsäuren und dem 2,2,6,6-Tetramethylpiperidin-N-oxyl-Radikal [8] (TEMPO) als Oxidationsmittel und Reagens zur Synthese von 1,2,3-trisubstitutierten Indanen [Gl.…”

“…[12] In Folgestudien zu diesem Thema zeigte sich, dass auch die Inden-Doppelbindung unter oxidativer PdKatalyse mit Arylboronsäuren hoch regio-und stereoselektiv funktionalisiert werden kann. Inden reagierte in Gegenwart von Pd(OAc) 2 [14c] Die Pd-vermittelte Phenylaminoxylierung ergab 3 a mit 65 % ee (siehe die Hintergrundinformationen).…”