Evans−Tishchenko Coupling of Heteroaryl Aldehydes

Abstract

We thank the EC FP6 (Marie Curie EST Fellowship to PDD; Contract: MEST-CT-2005-020744), The University of Edinburgh and Eli Lilly for funding. Supporting information:Experimental procedures for the synthesis of compounds 3, 4c, 4h-m and 6d-g; spectroscopic data for Evans-Tishchenko minor diastereomers and RAAT products 5e-g. This material is available free of charge via the Internet at http://pubs.acs.org Graphical abstract: AbstractThe low temperature Evans-Tishchenko coupling of a range of functionalised heteroaryl aldehydes with -hydroxy ketones in the presence of a Sm(III) catalyst has been achieved with high yields (90-99%) and good to excellent diastereoselectivity (90:10->95:5 dr). However, at room temperature a retro-aldol aldol-Tishchenko reaction was found to compete with the desired Evans-Tishchenko reaction. Identification of these byproducts has allowed the corresponding aldol-Tishchenko reaction to be optimised for several heteroaryl aldehydes.

Strategy Evolution in the Total Synthesis of (−)‐Leiodermatolide

“…Both the Evans−Tishchenko and Evans−Saksena protocols for 1,3‐anti reduction were ineffective with this substrate. The former yielded the products of a retro‐aldol−aldol−Tishchenko pathway, while the latter conditions led to poor stereocontrol. It was proposed that this was due to the small size of the alkyne substituent, reducing its preference to occupy an equatorial position in the transition state.…”

“…To introduce the remaining C9 stereocentre,t he b-hydroxy ketone 38 was next elaborated into the ynone 39.B oth the EvansÀTishchenko [27] and EvansÀSaksena [38] protocols for 1,3-anti reduction were ineffective with this substrate. Thef ormer yielded the productso far etro-aldolÀaldolÀ Tishchenko pathway, [39] while the latterc onditions led to poor stereocontrol. It was proposed that this was due to the small size of the alkyne substituent, reducing its preference to occupy an equatorial positioni nt he transition state.T he logical way forward was to first effectt he conversion of the alkyne to the larger (Z)-vinyl iodidet oi mprove the stereocontrol in the reduction step.K ishisp rocedure for conjugatea ddition of an iodide nucleophilet o an ynone under acidic conditionsp roved rewarding, preferentially leading to the desired (Z)-vinyl iodide 40.…”

Self‐Assembly of Disorazole C1 through a One‐Pot Alkyne Metathesis Homodimerization Strategy

“…Following on from prior work in our group,21 we planned the formation of bis(alkyne) 3 through the coupling of aldehyde 4 and β‐hydroxy ketone 5 using a heteroaryl Evans–Tishchenko (ET) reaction to set the stereochemistry at C16 (Scheme ) 22. 23 Our initial route to C1–C9 oxazole aldehyde 4 relied upon a lateral lithiation of protected 4‐hydroxymethyl‐2‐methyl‐oxazole 6 24 and coupling to enyne aldehyde 7 25 to generate 8 (Scheme ). Methylation of the resulting free hydroxy group at C6 gave 9 , and deprotection of the hydroxy group at C1, followed by oxidation generated racemic aldehyde (±)‐ 4 (Scheme ).…”

Self‐Assembly of Disorazole C1 through a One‐Pot Alkyne Metathesis Homodimerization Strategy

“…Following on from prior work in our group,[ 21 ] we planned the formation of bis(alkyne) 3 through the coupling of aldehyde 4 and β-hydroxy ketone 5 using a heteroaryl Evans–Tishchenko (ET) reaction to set the stereochemistry at C16 (Scheme 1 ). [ 22 , 23 ] Our initial route to C1–C9 oxazole aldehyde 4 relied upon a lateral lithiation of protected 4-hydroxymethyl-2-methyl-oxazole 6 [ 24 ] and coupling to enyne aldehyde 7 [ 25 ] to generate 8 (Scheme 2 ). Methylation of the resulting free hydroxy group at C6 gave 9 , and deprotection of the hydroxy group at C1, followed by oxidation generated racemic aldehyde (±)- 4 (Scheme 2 ).…”

“…Electron-deficient aldehydes (in particular pyridines and nitrobenzaldehydes) were shown to undergo a Sm III -catalyzed ET reaction, giving 1,3- anti diol monoester products in good to excellent yields (>95:5 d.r.). Unfortunately, indoles, pyrroles, and pyrazoles,[ 23 ] even those containing electron-withdrawing substituents at the heteroatom, gave poor yields or failed to react. Thus, the critical anti stereorelationship at C14–C16 was set using an ET coupling with 3-nitrobenzaldehyde to give 26 (Scheme 5 ); a PMB protecting group was installed, and the hydroxy group at C14 was unmasked through subsequent ester hydrolysis to give 27 .…”