A Catalytic Asymmetric Ene Reaction for Direct Preparation of α-Hydroxy 1,4-Diketones as Intermediates in Natural Product Synthesis

Abstract

Asymmetric access to α-hydroxy-1,4-diketones has been achieved by direct ene coupling of silyl enol ethers with glyoxal electrophiles, mediated by a chiral N,N′-dioxide–nickel(II) complex catalyst. Successful union of a polyketide silyl enol ether with an α-quaternary glyoxal, generated by dioxirane oxidation of an α-diazo ketone, models a proposed C5–C6 disconnection of the polyketide and spirocyclic imine domains of the marine natural product, portimine.

Synthesis of the C4–C16 Polyketide Fragment of Portimines A and B

“…Purification by chromatography (petroleum ether/EtOAc, 4:1) afforded the title compound 22 (64 g, 16%) as a colorless oil. IR (neat): 2954, 2930, 2857, 1473, 1437, 1378, 1257, 1100, 948, 834 cm −1 (3S,4S)-7-((4-Methoxybenzyl)oxy)-3-methylhept-1-en-4-ol (24). A solution of ligand 21 (6.75 g, 23.2 mmol) and 1,8diazabicycloundec-7-ene (10.4 mL, 69.3 mmol) in DCM (50 mL) was cooled to 0 °C.…”

“…The impressive biological profiles and unique molecular architectures make portimines A and B ( 1 and 2 ) attractive synthetic targets. However, besides the racemic synthesis of the cyclohexene fragment and our previous study toward C5–C6 disconnection of portimine A, no synthetic work related to the portimines has been reported to date. , Given our ongoing interest in spiroimine natural products, − we decided to undertake studies toward the synthesis of portimines A and B ( 1 and 2 ), and the C4–C16 polyketide fragment was chosen as our initial target.…”

“…However, besides the racemic synthesis of the cyclohexene fragment and our previous study toward C5−C6 disconnection of portimine A, no synthetic work related to the portimines has been reported to date. 23,24 Given our ongoing interest in spiroimine natural products, 25−29 undertake studies toward the synthesis of portimines A and B (1 and 2), and the C4−C16 polyketide fragment was chosen as our initial target. One distinctive structural feature of the polyketide domains of portimines A and B (1 and 2) is the densely functionalized syn-α,α′-dihydroxyketone motif, which presents a significant synthetic challenge.…”

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]…”