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Mechanisms of Carbonyl Activation by BINOL N-Triflylphosphoramides

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Mechanisms of Carbonyl Activation by BINOL N-Triflylphosphoramides Mechanisms of Carbonyl Activation by BINOL N-Triflylphosphoramides Enantioselective Nazarov Cyclizations Lovie-toon, Joseph P.; Tram, Camilla Mia; Flynn, Bernard L.; Krenske, Elizabeth H. Published in: ACS Catalysis DOI: 10.1021/acscatal.7b00292 Publication date: 2017 Document version Publisher's PDF, also known as Version of record Citation for published version (APA): Lovie-toon, J. P., Tram, C. M., Flynn, B. L., & Krenske, E. H. (2017). Mechanisms of Carbonyl Activation by BINOL N-Triflylphosphoramides: Enantioselective Nazarov Cyclizations . ACS Catalysis, 7(5), 3466-3476. https://doi.org/10.1021/acscatal.7b00292 Download date: 09. Apr. 2020 This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Research Article pubs.acs.org/acscatalysis Mechanisms of Carbonyl Activation by BINOL N‑Triflylphosphoramides: Enantioselective Nazarov Cyclizations Joseph P. Lovie-Toon,† Camilla Mia Tram,†,‡,∥ Bernard L. Flynn,§ and Elizabeth H. Krenske*,† † School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland 4072, Australia ‡ University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark § Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia *S Supporting Information ABSTRACT: BINOL N-triflylphosphoramides are versatile organocatalysts for reactions of carbonyl compounds. Upon activation by BINOL N-triflylphosphoramides, divinyl ketones undergo rapid and highly enantioselective (torquoselective) Nazarov cyclizations, making BINOL N-triflylphosphoramides one of the most important classes of catalysts for the Nazarov cyclization. However, the activation mechanism and the factors that determine enantioselectivity have not been established until now. Theoretical calculations with ONIOM and M06-2X are reported which examine how BINOL N-triflylphosphoramides activate divinyl ketones and control the torquoselectivity of the cyclization. Unexpectedly, the computations reveal that the traditionally accepted mechanisms for these catalysts (i.e., NH···O C hydrogen bonding or proton transfer) are not the dominant activation mechanisms. Instead, the active catalyst is a less-stable tautomer of the phosphoramide containing a P(NTf)OH group. Proton transfer from the catalyst to the substrate occurs concomitantly with ring closure. The enantioselectivities of Nazarov cyclizations of three different classes of divinyl ketones are shown to depend on a combination of factors, including catalyst distortion, the degree of proton transfer, intramolecular substrate stabilization, and intermolecular noncovalent interactions between the substrate and catalyst in the transition state, all of which relate to how well the cyclizing divinyl ketone fits into the chiral binding pocket of the catalyst. KEYWORDS: BINOL N-triflylphosphoramide, Nazarov cyclization, Brønsted acid, tautomerism, density functional theory, noncovalent interactions ■ INTRODUCTION cyclization. Some of the most efficient asymmetric Nazarov 4 Chiral phosphoric acids derived from the enantiomers of cyclizations reported to date have involved 2 as chiral catalysts. BINOL (1, Figure 1) occupy a prominent role in the field of Scheme 1 shows three examples, which showcase the ability of N-triflylphosphoramides 2 to activate divinyl ketones at low catalyst loadings, leading to rapid and highly enantioselective − cyclizations.5 7 Indeed, the versatility and success of phosphor- amides 2 have significantly boosted the utility of the Nazarov cyclization as a method for the asymmetric synthesis of multistereocenter-containing cyclopentanoids.4 There have been many theoretical studies on BINOL 8,9 Figure 1. BINOL-derived phosphoric acids 1 and N-triflylphosphor- phosphoric acid (1) catalyzed reactions. The stereoselectiv- amides 2. ities of reactions catalyzed by 1 depend on a rather complex combination of covalent and noncovalent interactions which 1 organocatalysis. Their ability to activate basic substrates by occur in the transition state (TS). Noncovalent interactions hydrogen bonding or proton transfer and the ability to tune the ′ that have been found to play a role in BINOL phosphoric acid chiral binding pocket by varying the 3- and 3 -Ar substituents catalyzed reactions include steric crowding, hydrogen bonding, have led to many applications of 1 as chiral catalysts. However, 10 CH−O, π−π,CH−π, cation−π, and electrostatic interactions. certain classes of substrates notably, carbonyl compounds 9 are resistant to activation by 1. For these challenging substrates, While some general predictive rules have emerged, the exact the more acidic BINOL N-triflylphosphoramides 22 have emerged as powerful activating agents.1d,e,3 Received: January 27, 2017 One important application of BINOL N-triflylphosphor- Revised: March 22, 2017 amides 2 to carbonyl activation has been the Nazarov Published: April 17, 2017 © 2017 American Chemical Society 3466 DOI: 10.1021/acscatal.7b00292 ACS Catal. 2017, 7, 3466−3476 ACS Catalysis Research Article − Scheme 1. Enantioselective Nazarov Cyclizations Catalyzed by BINOL N-Triflylphosphoramides 25 7 combination of interactions that controls the selectivity in any during the conrotatory 4π electrocyclic ring closure for 6 but given example can only be understood through TS modeling. anticlockwise for 3 (see red arrows in Scheme 1). Asymmetric organocatalysis involving BINOL phosphora- Third, we examine the Nazarov cyclization of 8 (reaction C). mides 2 has recently begun to attract the attention of This reaction was developed by Tius as part of an elegant theoretical chemists. Goodman and Grayson11 studied strategy for the construction of vicinal all-carbon quaternary 7 phosphoramide-catalyzed asymmetric propargylations of alde- stereocenters. Cyclization of 8, catalyzed by 2d, gave after loss hydes by allenyl boronates. They modeled the TS as a of the stable diphenylmethyl cation the sterically congested hydrogen-bonded complex containing an NH···O hydrogen cyclopentenone (S,S)-9 in an enantiomeric ratio (er) of 98:2 bond between the catalyst and one of the boronate oxygens. (clockwise conrotation). Catalyst 2e, containing Ph groups t The differing levels of stereoselectivity provided by N- instead of BuC6H4 groups, gave lower selectivity. fl Little is known about the factors that determine the direction tri ylphosphoramide versus phosphoric acid catalysts in the fl propargylation reactions were explained by analyzing how the of conrotatory ring closure in N-tri ylphosphoramide-catalyzed Nazarov cyclizations.14 A recent paper by Tu and co-workers CF3 group altered the shape of the binding pocket. Houk and Rueping12 examined N-triflylphosphoramide-catalyzed cyclo- reported computations on a phosphoramide-catalyzed Nazarov additions of hydrazones and alkenes. They used theoretical cyclization/semipinacol rearrangement cascade which led to spiro[4.4]nonane derivatives.15 On the basis of density calculations to explore the catalyst−substrate binding modes functional theory (DFT) calculations with B3LYP, the authors and to determine whether catalysis involved hydrogen bonding suggested that steric clashing between the substrate and the from the acidic NH group to the substrate or proton transfer. catalyst controlled the stereoselectivity in that case. Equally In this paper we use theoretical calculations to investigate fl importantly, the exact mechanism of activation of divinyl how N-tri ylphosphoramides 2 activate divinyl ketones and ketones by N-triflylphosphoramides 2 is unknown. Different control enantioselectivity, in three distinct Nazarov cyclizations ··· fi authors have depicted these reactions as involving either NH (Scheme 1). The rst of our three case studies focuses on the OC hydrogen bonding or the transfer of a proton from 2 to cyclization of dihydropyranyl vinyl ketone 3 (reaction A). This the carbonyl group to form a chiral contact ion pair (Scheme 1, reaction was reported by Rueping in his original publication, 1d,e,3−7 5,13 lower right). Here, we use density functional theory which introduced 1 and 2 as Nazarov cyclization catalysts. calculations to address this question and to explain the Both 1 and 2 catalyzed the cyclization of 3, giving mixtures of enantioselectivities of the three reactions depicted in Scheme cis- and trans-cyclopentenones 4 and 5. The electrocyclization 1. Unexpectedly, the calculations reveal that catalysts 2 do not installs the chiral center at C4, favoring C4-S. Enolization of the use either of the traditionally drawn activation modes (Scheme product then gives a mixture of C5 epimers (4 and 5). 1). Instead, the active catalyst is a less-stable tautomer of 2 Phosphoramides 2 gave superior enantioselectivities in containing a P(NTf)OH group. This discovery has comparison to 1, with enantiomeric excesses (ees) as high as significant implications for the understanding and development 95%. of BINOL N-triflylphosphoramide-catalyzed reactions. Our second case study focuses on the Nazarov cyclization of divinyl ketone 6 (reaction B). This reaction was employed by ■ THEORETICAL CALCULATIONS Flynn et al. in a concise formal synthesis of the anticancer Density functional theory calculations were performed with 6 natural product (+)-roseophilin. Nazarov cyclization of 6, Gaussian 09.16 To explore the mechanism of divinyl ketone catalyzed by 2b or 2c, followed by hydrolytic trapping of the activation by
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