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

Abstract

β-Turn tetrapeptides were demonstrated to catalyze asymmetric aldol reaction of α-branched aldehydes and α-carbonyl aldehydes, i.e. glyoxylates and α-ketoaldehydes, to biomimetically synthesize acyclic all-carbon quaternary center-bearing 1,4-dicarbonyls in high yield and excellent enantioselectivity under mild conditions. The spatially restricted environment of the tetrapeptide warrants high enantioselectivity and yield with broad substrates. Using this protocol, (R)-pantolactone, the key intermediate of vitamin B5, was readily accessed in a practical, efficient, and environmentally benign process from inexpensive starting materials.

Organocatalyzed Highly Enantioselective Aldol Reaction of Aldehydes for Synthesis of (R)‐Pantolactone

“…Therefore, we successfully developed the second highest enantioselective organocatalyst to the aldol reaction of isobutyraldehyde and ethyl glyoxylate. [19][20][21] Expanding the substrate scope. Under the optimized reaction conditions (Table 1, entry 22), the scope of the substrates was explored (Table 2).…”

“…[20] Lately, our group developed a tetrapeptidecatalyzed protocol and (R)-pantolactone can be achieved in very high yield and enantioselectivity. [21] In spite of this success, peptides are traditionally regarded as very expensive organocatalysts and some inexpensive organocatalysts are strongly desired for cost-effectiveness and practicality. Additionally, types of organocatalysts of high asymmetric induction in this transformation are very scarce and more sorts of organocatalysts are expected.…”

Stereoselective Aldol and Conjugate Addition Reactions Mediated by Proline‐Based Catalysts and Its Analogues: A Concise Review

“…A tetrapeptide with a β‐turn conformation 120 , developed by Da et al ., [77] was used for cross‐aldol reaction of many α‐branched aldehydes with α‐carbonyl aldehydes. The reaction of α‐branched aldehydes 118 with α‐carbonyl aldehydes 119 (glyoxalates or α‐keto aldehydes) furnished the corresponding anti‐ products with good yields (up to 74 %) and excellent enantioselectivities (up to 94 % ee ) (Scheme 20).…”

A Highly EfficientN‐Mesityl Thiazolylidene for the Aliphatic Stetter Reaction: Stereoelectronic Quantification for Comparison of N‐Heterocyclic Carbene Organocatalysts

“…Nevertheless, direct synthesis of aliphatic 1,4‐diketones remains a synthetic challenge, with most current methods limited in scope or efficiency [7–14] . A variety of methods for the synthesis of 1,4‐dicarbonyls containing at least one non‐ketone carbonyl group have been reported, exploiting reactivity differences to achieve chemoselectivity, and in specific substituted systems affording high stereoselectivity [8,15–22] . In contrast to 1,4‐dicarbonyls in general, the synthesis of 1,4‐diketones poses a greater challenge, often requiring use of an excess of one coupling partner and/or significant pre‐functionalisation of substrates to achieve the desired heterocoupling.…”

“…[7][8][9][10][11][12][13][14] A variety of methods for the synthesis of 1,4-dicarbonyls containing at least one nonketone carbonyl group have been reported, exploiting reactivity differences to achieve chemoselectivity, and in specific substituted systems affording high stereoselectivity. [8,[15][16][17][18][19][20][21][22] In contrast to 1,4-dicarbonyls in general, the synthesis of 1,4-diketones poses a greater challenge, often requiring use of an excess of one coupling partner and/or significant pre-functionalisation of substrates to achieve the desired heterocoupling. Reported methods include oxidative homocoupling [23][24][25][26][27] or heterocoupling of ketone enolates, [7,24,[28][29][30][31][32][33][34]35,36] alkylation of enolates, [9,14,[37][38][39][40][41][42] alkylation of acyl anion equivalents [43][44][45][46]…”