An Organocatalytic Asymmetric Nazarov Cyclization

Basak, A. K.; Shimada, Naoyuki; Bow, William F.; Vicic, David A.; Tius, Marcus A.

doi:10.1021/ja103028r

Cited by 122 publications

(64 citation statements)

References 38 publications

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“…With respect to α-ketoenone 2, tautomerization to either enol isomer is endergonic by at least 0.7 kcal/mol, in agreement with the experimental observation that the enol form is a minor component at equilibrium (2:3 = 85:15). 5 As shown in Figure 1, (E,E)-3 prefers to adopt the s-trans/s-trans conformation, while (Z,E)-3 prefers to adopt the s-trans/s-cis conformation. (Z,E)-3 is thermodynamically more stable than (E,E)-3 by 0.9 kcal/mol, primarily because the intramolecular hydrogen bond between the hydroxyl group and a carbonyl group forms a six-membered ring in (Z,E)-3 but a fivemembered ring in (E,E)-3.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

“…Since TS-5a is higher in energy than TS-5b by 4.5 kcal/mol, the Nazarov reaction from the Z enol does not compete kinetically with the reaction from the E enol, in accord with experimental findings. 5 The energy difference between TS-5a and TS-5b is electronic in origin and can be explained by the theory of torquoselectivity in electrocyclic reactions. 16,17 In the electrocyclic ring-opening reactions of cyclopentenyl cations 17 and retro-Nazarov reactions, 7c,g or in the corresponding ring closures, an electron-donating substituent prefers to be on the outside to minimize the filled−filled orbital interactions between the donor orbital and the σ orbital of the partially broken or formed σ bond.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…This replacement was shown experimentally to only slightly reduce the enantiomeric ratio for the formation of (S,S)-4 from 90.5:9.5 (ΔΔG ‡ = 1.3 kcal/mol) to 86.5:13.5 (ΔΔG ‡ = 1.1 kcal/mol); the sense of asymmetric induction is unaffected. 5 2. Conformations of the Organocatalyst.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Origins of the Stereoselectivity in a Thiourea–Primary Amine-Catalyzed Nazarov Cyclization

et al. 2015

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The origins of stereoselectivity of the Nazarov reactions of α-hydroxydivinylketones catalyzed by a vicinal thiourea-primary amine first reported by Tius have been explored with density functional theory. The electrocyclization transition structures in which the thiourea group of the catalyst donates two hydrogen bonds to the keto carbonyl group of the Nazarov reactant and the primary amine accepts a hydrogen bond from the hydroxyl group of the reactant have been modeled. The enantiomeric Nazarov transition structures, which are conventionally described by the absolute sense of conrotation of the dienone termini ("clockwise" or "counterclockwise") in the literature, are nonplanar and adopt helically chiral conformations. The interactions of these helical electrocyclization transition structures with the chiral catalyst are studied in detail. The organocatalyst is found to employ a combination of hydrogen bonding and steric effects to achieve helical recognition of the Nazarov transition state.

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Section: ■ Results and Discussionmentioning

confidence: 97%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Origins of the Stereoselectivity in a Thiourea–Primary Amine-Catalyzed Nazarov Cyclization

et al. 2015

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“…At best, vicinal quaternary and tertiary stereocenters could be generated. [3] Polarization of the acyclic dienone precursor [4] accelerates the Nazarov cyclization.[5] We have previously disclosed the highly diastereoselective triflimide-catalyzed cyclization that converts dienone 1 into cyclopentenone 2 in 80 % yield [Eq. (1)].…”

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Catalytic Enantioselective Nazarov Cyclization: Construction of Vicinal All‐Carbon‐Atom Quaternary Stereocenters

et al. 2014

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Abstract:The diastereoselective asymmetric synthesis of vicinal all-carbon-atom quaternary stereocenters is a challenging problem in organic synthesis for which only few solutions have been described. A catalytic asymmetric Nazarov cyclization of fully substituted dienones that provides cyclopentenone derivatives with vicinal quaternary stereocenters in high optical purity and as single diastereoisomers is now reported.The catalytic asymmetric synthesis of vicinal, all-carbonatom quaternary stereocenters presents a difficult challenge for which only a small number of solutions, none of which are completely general, have been described to date.[1] The enantioselective version of the reaction that is shown in Equation (1) would constitute a new solution to this problem. None of the asymmetric Nazarov cyclizations that have been described thus far [2] form vicinal quaternary stereocenters. At best, vicinal quaternary and tertiary stereocenters could be generated. [3] Polarization of the acyclic dienone precursor [4] accelerates the Nazarov cyclization.[5] We have previously disclosed the highly diastereoselective triflimide-catalyzed cyclization that converts dienone 1 into cyclopentenone 2 in 80 % yield [Eq. (1)].[6] The stereochemistry of 2 reveals that a conrotatory process, which is required to conserve orbital symmetry, has occurred. The polarization of "push-pull" dienone 1 and the rapid termination process that is enabled through loss of the 2-(trimethylsilyl)ethoxymethyl (SEM) group contribute to the success of this cyclization, which results in the formation of vicinal all-carbon-atom quaternary stereocenters. Rapid termination is especially important in the case of Nazarov cyclizations that lead to sterically congested products as Wagner-Meerwein rearrangements of the intermediate cyclic cation, which would be driven by relief of steric compression, have to be suppressed.[7] Herein, we report the first catalytic asymmetric Nazarov cyclization of fully substituted dienones for the construction of vicinal all-carbon-atom stereocenters.We had confidence that an asymmetric version of the cyclization that is shown in Equation (1) could be developed through systematic variation of the enol ether and ester groups, which could serve as recognition elements for a catalyst. The process could be optimized through iterative changes in catalyst, solvent, and additive(s). As the enol ether moiety must depart as a stable cation following the cyclization, its choice does not restrict the structural types of cyclopentenones that might be accessed by this reaction.We chose the (R)-BINOL scaffold for our screen of chiral Brønsted acids.[8] The broad utility of this class of compounds for a variety of catalytic asymmetric reactions is related to the ease with which substituents at the C3 and C3' positions can be introduced to quickly assemble a library of catalysts. [9] Catalyst optimization is summarized in Table 1. The phenyl ester group in 3 strongly influenced the enantioselectivity of the reaction. The ethyl ester analo...

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“…An especially effective way to activate the dienone toward cyclization is to incorporate a “push-pull” vinylogous carbonate. [11] Scheme 2 illustrates a synthesis of activated dienones that are ideally suited for the present application. Metalation of 2-(trimethylsilyl)ethoxymethyl (SEM) enol ether 7 according to Knochel’s procedure [12] followed by exposure to ( E )-2-methyl-3-phenylbut-2-enoyl chloride 8 led to dienone 9 in 88% yield from the carboxylic acid as a single ( E,E ) geometrical isomer.…”

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Diastereospecific Nazarov Cyclization of Fully Substituted Dienones: Generation of Vicinal All‐Carbon‐Atom Quaternary Stereocenters

et al. 2013

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The joining of two carbon atoms through a σ bond so as to form vicinal all-carbon atom quaternary centers remains a difficult challenge in organic synthesis. [1] An effective strategy to address the problem is to exploit an orbital symmetry controlled process. [2] We describe herein a diastereospecific Nazarov cyclization [3] that leads to cyclopentenones bearing adjacent all-carbon atom quaternary centers.We are aware of only the three examples of Nazarov cyclizations that lead to two contiguous all-carbon atom quaternary stereocenters during the ring forming step that are shown in Scheme 1. The first two examples in Scheme 1 describe Harding and coworkers' efforts that culminated in the total synthesis of (d,l)-trichodiene. [4] Reaction conditions in both cases were harsh but the yield of cyclic products 2 and 4 that lack sensitive functionality was high. Both reactions were diastereospecific, with the C3a,C3b relative stereochemistry (see compound 2) determined by the conrotation that is required by the selection rule governing the thermal 4π electron process. The third example in Scheme 1 is the oxidative Nazarov cyclization of allenyl ether 5 that was reported by Frontier and coworkers in 2011. [5] The oxyallyl zwitterion that forms spontaneously from the allene oxide following treatment of 5 with dimethyldioxirane (DMDO) underwent stereospecific cyclization to 6 in moderate yield. The zwitterion intermediate is strongly polarized, hence the mild reaction conditions.

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An Organocatalytic Asymmetric Nazarov Cyclization

Cited by 122 publications

References 38 publications

Origins of the Stereoselectivity in a Thiourea–Primary Amine-Catalyzed Nazarov Cyclization

Origins of the Stereoselectivity in a Thiourea–Primary Amine-Catalyzed Nazarov Cyclization

Catalytic Enantioselective Nazarov Cyclization: Construction of Vicinal All‐Carbon‐Atom Quaternary Stereocenters

Diastereospecific Nazarov Cyclization of Fully Substituted Dienones: Generation of Vicinal All‐Carbon‐Atom Quaternary Stereocenters

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