Enantioselective Ene Reaction of Cyclopentadiene and α,β‐Enals Catalyzed by a Diphenylprolinol Silyl Ether

Gotoh, Hiroaki; Masui, Ryouhei; Ogino, Hiroshi; Shoji, Mitsuru; Hayashi, Yujiro

doi:10.1002/anie.200602925

Cited by 123 publications

(45 citation statements)

References 49 publications

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“…A reaction did not occur in the presence of either proline or trifluoromethyl-substituted diarylprolinol 4 (Figure 1), which afforded good results in the Mannich reaction [5] and the aldol reaction [4] of acetaldehyde, respectively. Although diphenylprolinol 2 did not promote the reaction, silyl ether 1, which was developed by our group, [8,10] was effective and provided the Michael product in good yield with excellent enantioselectivity. Notably, the reactivity of diphenylprolinol silyl ether 1 [11] and that of trifluoromethylsubstituted diarylprolinol silyl ether 3, [11] which is an effective organocatalyst in several asymmetric reactions developed by Jørgensen and co-workers, [12] are very different in the present reaction.…”

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Asymmetric Michael Reaction of Acetaldehyde Catalyzed by Diphenylprolinol Silyl Ether

et al. 2008

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Reactions involving organocatalysis have developed rapidly in recent years.[1] Although many kinds of enantioselective reactions of aldehydes involving the enamine-type mechanism [2] have been developed, there has been no report of the successful use of acetaldehyde, despite its usefulness, in catalytic asymmetric reactions.[3] Control of the reactivity of acetaldehyde is difficult because of its high reactivity as both a nucleophile and an electrophile. Moreover, the addition product possesses a reactive a-unsubstituted aldehyde moiety that can potentially react with a nucleophile or an electrophile to give several side products. Recently, however, our group [4] and the group of List [5] independently developed the first enantioselective catalytic reactions of acetaldehyde. We reported a crossed-aldol reaction of acetaldehyde catalyzed by diarylprolinol, and List and co-workers reported the proline-catalyzed Mannich reaction of acetaldehyde.The Michael reaction, a synthetically important carboncarbon bond-forming reaction, is catalyzed enantioselectively by organocatalysts.[6] However, despite the many successful Michael reactions, in which aldehydes act as nucleophiles, [7] we are not aware of any report of a Michael reaction using acetaldehyde. Previously, we developed Michael reactions of aldehydes and nitroalkenes catalyzed by diphenylprolinol silyl ether [8] to afford a-substituted g-nitro aldehydes in nearly optically pure form. The Michael adduct that is generated is synthetically useful; Enders and co-workers developed an elegant domino reaction based on the Michael reaction to generate chiral cyclohexene derivatives with excellent enantioselectivities.[9] In these previous Michael reactions, only asubstituted aldehyde derivatives were synthesized, but it is desirable to prepare chiral a-unsubstituted g-nitro aldehydes with excellent enantioselectivity. Herein, we describe the first example of such a reaction.The Michael reaction of nitrostyrene and acetaldehyde was selected as a model reaction (Table 1). Organocatalysts were examined first and the results are summarized in Table 1. A reaction did not occur in the presence of either proline or trifluoromethyl-substituted diarylprolinol 4 (Figure 1), which afforded good results in the Mannich reaction [5] and the aldol reaction [4] of acetaldehyde, respectively. Although diphenylprolinol 2 did not promote the reaction, silyl ether 1, which was developed by our group, [8,10] was effective and provided the Michael product in good yield with excellent enantioselectivity. Notably, the reactivity of diphenylprolinol silyl ether 1 [11] and that of trifluoromethylsubstituted diarylprolinol silyl ether 3, [11] which is an effective organocatalyst in several asymmetric reactions developed by Jørgensen and co-workers, [12] are very different in the present reaction. After screening solvents, 1,4-dioxane was found to afford the best results.After the reaction conditions were optimized the generality of the reaction was investigated, and the results summarized in Tab...

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Asymmetric Michael Reaction of Acetaldehyde Catalyzed by Diphenylprolinol Silyl Ether

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“…Barbas and co-workers reported that prolinol is an effective organocatalyst in an enantioselective fluoroaldol reaction, in which a similar transition state was proposed. [17] Though the electrophile attacks from the side opposite to the bulky diphenylmethyl moiety in the reaction catalyzed by a diphenylprolinol silyl ether, [11] the aldehyde reacts on the more hindered face of the catalyst in the present case. This is because the aldehyde is activated by coordination to the proton of the hydroxy group through a hydrogen bond.…”

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A Diarylprolinol in an Asymmetric, Catalytic, and Direct Crossed‐Aldol Reaction of Acetaldehyde

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No over‐reacting: A diarylprolinol was found to be an effective organocatalyst of the direct, enantioselective aldol reaction of acetaldehyde, affording β‐hydroxy α‐unsubstituted aldehydes in good yield with excellent enantioselectivity (see scheme). In the proposed transition state the aldehyde reacts on the more hindered face of the intermediate enamine as a consequence of the hydrogen bond between the aldehyde and the OH group of the organocatalyst.

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“…In particular, the trialkylsilyl-protected diarylprolinols (4-6) pioneered by Hayashi and coworkers and Jørgensen and co-workers provided the product in excellent chemical yield and with high enantioselectivity. [6] With respect to our hypothesis concerning the pK a window accessible for catalysis with these catalysts, the analogous phenylthioester of 1 a was unreactive, whereas the trifluoroethyl thioester was reactive.…”

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“…[3,6] As illustrated in Scheme 2, we screened a number of these organocatalysts together with benzoic acid co-catalyst, for catalysis of the Michael addition of thioester 1 a to cinnamaldehyde 2 a. A number of the pyrrolidine-based catalysts were effective.…”

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Towards Organocatalytic Polyketide Synthases with Diverse Electrophile Scope: Trifluoroethyl Thioesters as Nucleophiles in Organocatalytic Michael Reactions and Beyond

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Catalytic asymmetric synthesis based on simple ester nucleophiles remains an unmet challenge in organic synthesis. The difficulty with this class of potential nucleophiles lies in the relatively inert nature of the proton at the a-position of a simple carboxylic ester; the pK a value is approximately 19.[1]Direct asymmetric transition-metal-based approaches [2] are well developed for carbonyl compounds bearing activating electron-withdrawing groups at the a-position, and organocatalytic approaches [3] allow for effective nucleophile generation from simple ketones and aldehydes (via in situ enamine formation). In contrast, effective ester-based approaches are rare. Nature, however, has developed a diverse and elegant solution to this problem in its use of acyl-CoA thioesters and diverse families of polyketide synthase enzymes, which catalyze the reactions of a variety of thioesters like acetylCoA, propionyl-CoA, malonyl-CoA, and others en route to the synthesis of medicinally important polyketides and metabolically important fatty acids.[4] This fact has not escaped the attention of organic chemists, and recently the groups of Shair, Cozzi, Wennemers, and Ricci have reported catalytic enantioselective reactions based on either metal catalysis or organocatalysis.[5] Significantly, each of these reports utilizes malonic acid half thioesters as enolate precursors, and the decarboxylation of the malonic acid half thioester is used to drive enolate formation. We sought a more atom economical approach that would not require decarboxylation as a driving force for enolization, and would thus not be constrained by the requirement of an activating carboxylate group at the a-position of the thioester.Herein we detail the first enantioselective thioester addition reactions of simple trifluoroethyl thioesters. We not only demonstrate the enantioselective organocatalytic Michael reactions involving a,b-unsaturated aldehydes, but also the versatility of the trifluoroethyl thioester system in nitroolefin-based Michael, aldol, and amination reactions. We believe that trifluoroethyl thioesters will prove to be important nucleophiles in a wide range of both organocatalytic and metal-based direct catalytic asymmetric reactions.As noted above, the use of esters in direct catalytic asymmetric synthesis is challenging since the proton at the aposition, which must be removed to generate the nucleophilic enolate, has a relatively high pK a value. We desired an approach that would not be limited by malonic acid half thioester decarboxylation for enolate generation (Scheme 1).Rather, we sought to activate a-proton removal by electronic tuning at the thioester such that a wide variety of carboxylic ester derivatives might serve as nucleophiles. Indeed, Natures access and use of thioester enolates is neither limited to the use of malonic acid half thioesters nor their decarboxylative generation of an active enolate. [4] Direct organocatalytic methods based on amine catalysis have a functional pK a barrier for nucleophile activation that lies ...

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Enantioselective Ene Reaction of Cyclopentadiene and α,β‐Enals Catalyzed by a Diphenylprolinol Silyl Ether

Abstract: The opposite result: A diphenylprolinol silyl ether promotes an intermolecular enantioselective ene reaction of α,β‐enals with cyclopentadiene. This is the first example of cyclopentadiene acting as the ene component, and not the diene, with α,β‐enals.

Cited by 123 publications

References 49 publications

Asymmetric Michael Reaction of Acetaldehyde Catalyzed by Diphenylprolinol Silyl Ether

Asymmetric Michael Reaction of Acetaldehyde Catalyzed by Diphenylprolinol Silyl Ether

A Diarylprolinol in an Asymmetric, Catalytic, and Direct Crossed‐Aldol Reaction of Acetaldehyde

Towards Organocatalytic Polyketide Synthases with Diverse Electrophile Scope: Trifluoroethyl Thioesters as Nucleophiles in Organocatalytic Michael Reactions and Beyond

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