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

Hayashi, Yujiro; Itoh, Takahiko; Aratake, Seiji; Ishikawa, Hayato

doi:10.1002/anie.200704870

Cited by 203 publications

(103 citation statements)

References 54 publications

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“…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.…”

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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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“…"Moreover," Professor List said, "we were also able to develop several applications of our products, some of them of fering shortcuts in the syntheses of newly approved drugs." "Our repor t," said Professor List, "to gether with that of Hayashi and co workers, w ho independentl y de veloped the corresponding cross-aldol reaction, 4 describes the f irst useful applications of acetaldehyde as a nucleophile in or ganic synthesis. We are con vinced of its enor mous potential and are currently investigating several other reactions of acetaldehyde.…”

Section: Proline-catalyzed Mannich Reactions Of Acetaldehydementioning

confidence: 96%

SYNFORM ISSUE 2008/06

Zanda¹

2008

Synthesis

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Yo ur op ini on ab ou t SY NF OR M is we lco me , ple as e co rre sp on d if yo u lik e: ma rk et ing @t hie me -c he mi str y.c omThis document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Dear readers,Organocatalysis continues to represent a major topic and a v ery competitive area of research in the arena of or ganic chemistry. It is therefore not sur prising that three out of the four SYNSTORIES that constitute this new issue of SYNFORM are dedicated to new organocatalytic processes. Professor Kuiling Ding (P. R. of China) shows how to perform an old Baeyer-Villiger reaction in a brand new enantioselective manner using a chiral Brønsted acid as or ganocatalyst. Professor Benjamin List (Ger many) describes how to use a simple yet challenging substrate like acetaldehyde as nucleophile in organocatalytic Mannich reactions. Finally, Dr. Matthew J. Gaunt (UK) reports how phenols can be oxidatively dearomatized in an enantioselective manner by means of organocatalysis. There is little doubt that or ganocatalysis is progressively broadening its scope, although much research remains to be done in order to see more reallife synthetic problems solved by means of this powerful technology. The fourth SYNSTORY covers an extremely exciting piece of bioorganic synthesis reported jointly by Dr. Arata Yajima (Japan) and Professor Yong Qin (P. R. of China) who were able to synthesize and characterize stereochemically a structurally challenging hormone of a funguslike plant pathogen.

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“…[4] In 2008, Hayashi and co-workers reported the first asymmetric aldol reaction of acetaldehyde with good yields and excellent enantioselectivities by using diaryprolinol as the catalyst. [5] Shortly after, the same reaction was tested with a diamine catalyst to afford aldol products with varying yields (34-99 %) and enantioselectivities (69-92 %). [6] Recently, a water compatible diarylprolinol derivative has been reported to promote this reaction in brine, affording aldol products in good yields and ee's.…”

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“…In light of these results, we speculated that application of this concept could provide a convenient solution for the asymmetric cross-aldol reactions of acetaldehyde (Scheme 1). In view of precedents with homogeneous catalysts, [5] we selected and prepared the new PS-diarylprolinols 1 a-b ( Figure 1) to mediate the cross-aldol reaction in combination with the same PS-bound sulfonic acid 2, already used to deoligomerize paraldehyde for Michael additions. [11] For the optimization of reaction conditions, the cascade deoligomerization plus crossaldol reaction between 4-nitrobenzaldehyde and paraldehyde leading after reduction to 4 e was selected ( Table 1).…”

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Highly Enantioselective Cross‐Aldol Reactions of Acetaldehyde Mediated by a Dual Catalytic System Operating under Site Isolation

Fan

Rodríguez‐Escrich

Wang

et al. 2014

Chemistry A European J

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: Polystyrene-supported (PS) diarylprolinol catalysts 1 a (Ar = phenyl) and 1 b (Ar = 3,5-bis(trifluoromethyl)-phenyl) have been developed. Operating under site-isolation conditions, PS-1 a/1 b worked compatibly with PS-bound sulfonic acid catalyst 2 to promote deoligomerization of paraldehyde and subsequent cross-aldol reactions of the resulting acetaldehyde in one pot, affording aldol products in high yields with excellent enantioselectivities. The effect of water on the performance of the catalytic system has been studied and its optimal amount (0.5 equiv) has been determined. The dual catalytic system (1/2) allows repeated recycling and reuse (10 cycles). The potential of this methodology is demonstrated by a two-step synthesis of a phenoperidine analogue (68 % overall yield ; 98 % ee) and by the preparation of highly enantioenriched 1,3-diols 4 and 3-methylamino-1-arylpropanols 5, key intermediates in the synthesis of a variety of druglike structures.The aldol reaction has attracted plenty of interest due to its pivotal role in organic synthesis. [1] Among the various methods available to carry out this reaction enantioselectively, the organocatalytic methods stand out for several reasons: 1) under extremely mild reaction conditions excellent stereocontrol can be achieved in up to two newly formed stereocenters, 2) no prefunctionalization of any of the reactants is required, and 3) the reactions take place in a metal-free environment, which avoids product contamination with toxic metal derivatives. [2] Therefore, important developments have been achieved since the first report on the direct asymmetric intermolecular aldol reaction catalyzed by proline in 2000. [3] The use of acetaldehyde (the simplest enolizable aldehyde), however, has been a great challenge due to its high reactivity and its inherent tendency to oligomerize. [4] In 2008, Hayashi and co-workers reported the first asymmetric aldol reaction of acetaldehyde with good yields and excellent enantioselectivities by using diaryprolinol as the catalyst. [5] Shortly after, the same reaction was tested with a diamine catalyst to afford aldol products with varying yields (34-99 %) and enantioselectivities (69-92 %). [6] Recently, a water compatible diarylprolinol derivative has been reported to promote this reaction in brine, affording aldol products in good yields and ee's. [7] Despite the excellent results in these reports, some problems remain unsolved in this reaction, especially from the practical point of view. For instance, the low boiling point of acetaldehyde (21 O C) seriously hampers its transportation, storage, and handling, therefore increasing cost and energy consumption. From the reaction perspective, the tendency to oligomerization and high reactivity of acetaldehyde is detrimental, since side reactions are common. To overcome these drawbacks, an interesting example was reported recently using vinyl acetate as acetaldehyde precursor in cross-aldol reactions. The recorded enantioselectivities, however, were very low (10-20 %...

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

Cited by 203 publications

References 54 publications

Asymmetric Michael Reaction of Acetaldehyde Catalyzed by Diphenylprolinol Silyl Ether

Asymmetric Michael Reaction of Acetaldehyde Catalyzed by Diphenylprolinol Silyl Ether

SYNFORM ISSUE 2008/06

Highly Enantioselective Cross‐Aldol Reactions of Acetaldehyde Mediated by a Dual Catalytic System Operating under Site Isolation

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