Asymmetric Aldol Reaction of α,α‐Disubstituted Acetaldehydes Catalyzed by Diphenylprolinol Silyl Ether for the Construction of Quaternary Stereogenic Centers

Abstract

The asymmetric cross-aldol reaction of α,α-disubstituted acetaldehydes with commercial ethyl glyoxylate polymer was successfully catalyzed by diphenylprolinol silyl ether 3The aldol reaction is one of the most useful carbon-carbon bond forming reactions in organic chemistry.[1] After the pioneering discovery of the intermolecular proline-mediated aldol reaction of aldehydes and ketones by List, Lerner and Barbas in 2000, there has been great progress in the field of organocatalysed asymmetric aldol chemistry.[2]The cross aldol reaction of two different aldehydes catalyzed by proline was reported by MacMillan in 2002.[3] Although the generated β-hydroxy aldehydes are synthetically useful and versatile chiral building blocks, the reaction is often limited to particular aldehydes. Our group has continuing interest to develop a general organocatalyst for the asymmetric cross-aldol reaction of aldehydes. Through our efforts, we have found trifluoromethyl-substituted diarylprolinol as an effective organocatalyst in the aldol reaction of not only acetaldehyde as the pro-nucleophile, [4] but also ethyl glyoxylate, [5] chloroacetaldehye, [6] trifluoroacetaldehyde ethyl acetal, [7] pyruvaldehyde, [8] succinaldehyde, [9] glyoxal, [10] alkynyl aldehyde, [11] and formaldehyde [12] as the electrophilic aldehyde.An equally continuing challenge for contemporary synthetic organic chemistry is the asymmetric synthesis of allcarbon quaternary stereogenic centers. [13] In this context, there have been only two reports, as far as we are aware, that describe the intermolecular asymmetric aldol reaction to form all-carbon quaternary stereogenic centers. Tanaka [a]

Enamine/Iminium‐based Dual Organocatalytic Systems for Asymmetric Catalysis and Synthesis

“…A diphenylprolinol trimethylsilyl ether ( Cat E‐6) catalysed aldol reaction of ethyl glyoxate 19 with α, α‐disubstituted acetaldehydes 20 was demonstrated by Hayashi et al (Scheme 8). [66] Interestingly, the inclusion of an acid additive to the reaction drastically reduced the reaction time but was also accompanied by a decrease in enantioselectivity. Gratifyingly, the introduction of Schreiner's thiourea catalyst ( Cat 6) drastically reduced the reaction time whilst improving the enantioselectivity.…”

Asymmetric Synthesis of Pantolactone: Recent Advances

“…It was employed by Hayashi et al to catalyze the cross-aldol reaction of α,αdisubstituted acetaldehydes 100 with commercially available ethyl glyoxylate 4 a to construct all-carbon quaternary stereogenic center-bearing aldol adducts 103 in good enantioselectivities but with poor diastereoselectivities (Scheme 30). [93] They found that N,N-bis [3,5-bis(tri-fluoro-methyl)-phenyl]thiourea 102 is an effective additive that not only accelerates the reaction, but also increases the enantioselectivity. Using this process, a class of analogs 104 of L-PL was obtained following reduction with NaBH 4 .…”

Peptide-Catalyzed Highly Asymmetric Cross-Aldol Reaction of Aldehydes to Biomimetically Synthesize 1,4-Dicarbonyls

“…To the best of our knowledge, catalytically asymmetric preparation of these 1,4-dicarbonyls is rarely reported, except for the recently disclosed reaction of ethyl glyoxylate and limited α-branched aldehydes in insufficient enantioselectivity. , Mahrwald and co-worker made a seminal contribution in performing the cross-aldol reaction of ethyl glyoxylate with enolizable aldehydes, achieving good yields and enantioselectivity (85% yield and 79% ee) with 10% l -His as an organocatalyst . Additionally, Hayashi’s group employed diphenylprolinol silyl ether to catalyze the same reaction to construct all-carbon quaternary stereogenic centers in moderate to good enantioselectivity but with poor diastereoselectivity . And notably, the reaction of α-branched aldehydes and α-ketoaldehydes for 1,4-dicarbonyls has not been disclosed to date.…”

“…Then, the reaction was extended to explore the asymmetric α-branched aldehyde with an α-carbon stereocenter to construct 1,4-dicarbonyls bearing an acyclic all-carbon quaternary stereocenter (Scheme ). Highly enantioselective construction of an acyclic all-carbon quaternary stereocenter is a big challenge for the numerous degrees of freedom of the molecule structure. , Under the reconstructed reaction conditions (for data for reoptimization of the reaction conditions, see p S4 in Supporting Information), all reactions proceeded smoothly and uniformly achieved excellent enantioselectivity. The predominant diastereomers are anti, determined by X-ray analysis of the crystal of 6a .…”

“…4 Additionally, Hayashi's group employed diphenylprolinol silyl ether to catalyze the same reaction to construct all-carbon quaternary stereogenic centers in moderate to good enantioselectivity but with poor diastereoselectivity. 5 And notably, the reaction of α-branched aldehydes and αketoaldehydes for 1,4-dicarbonyls has not been disclosed to date. Therefore, it is highly anticipated to develop a new efficient strategy to synthesize highly enantioenriched 1,4dicarbonyls by cross-aldol reaction of α-branched aldehydes with glyoxylates and especially with α-ketoaldehydes.…”