Domino Synthesis of α,β‐Unsaturated γ‐Lactams by Stereoselective Amination of α‐Tertiary Allylic Alcohols

Abstract

Tertiary allylic alcohols equipped with a carboxyl group can be smoothly aminated under ambient conditions by a conceptually new and stereoselective protocol under palladium catalysis. The in situ formed Z‐configured γ‐amino acid cyclizes to afford an α,β‐unsaturated γ‐lactam, releasing water as the only byproduct. This practical catalytic transformation highlights the use of a carboxyl group acting as an activating and stereodirecting functional group to provide a wide series of pharma‐relevant building blocks. Various control reactions support the crucial role of the carboxyl group in the substrate to mediate these transformations.

Pd‐Catalyzed Stereodivergent Allylic Amination of α‐Tertiary Allylic Alcohols towards α,β‐Unsaturated γ‐Amino Acids

“…Althought he selectivity towards the (E)p roduct could not be furtheri mproved, [18] further experiments then focused on achieving ano ptimal yield and stereocontrol towards the (Z)configured product (entries [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Various ligands, including L7 [1,1'-bis(diphenylphosphino)ferrocene, dppf], [12] L13 [1,4-bis(diphenylphosphino)butane, dppb],a nd L15 [1,6-(diphenylphosphino)hexane, dpph] provedt ob ee fficient catalyst systems for the conversion of A,a lthough L12 [1,3-bis(diphenylphosphino)propane, dppp] was outstanding in terms of substrate conversion (quantitative), product yield (94 %), and stereocontrol towards 2a (> 99:1). These conditions differ markedly from those previously found to be optimal for the formation of a,bunsaturated g-lactamsf rom A [L7,P d 2 (dba) 3 ·CHCl 3 (dba = dibenzylideneacetone), CH 3 CN, RT;S cheme 1c].…”

“…Various ligands, including L7 [1,1'-bis(diphenylphosphino)ferrocene, dppf], [12] L13 [1,4-bis(diphenylphosphino)butane, dppb],a nd L15 [1,6-(diphenylphosphino)hexane, dpph] provedt ob ee fficient catalyst systems for the conversion of A,a lthough L12 [1,3-bis(diphenylphosphino)propane, dppp] was outstanding in terms of substrate conversion (quantitative), product yield (94 %), and stereocontrol towards 2a (> 99:1). [12] With these optimized conditions in hand for both the (Z)-(2a)a nd the (E)-stereoisomer (3a), the scope of this stereodi-vergenta llylic amination process was examined, focusing first on the synthesis of the (Z)-stereoisomers by using the conditions reported in entry 15 of Table 2( Scheme2). [12] With these optimized conditions in hand for both the (Z)-(2a)a nd the (E)-stereoisomer (3a), the scope of this stereodi-vergenta llylic amination process was examined, focusing first on the synthesis of the (Z)-stereoisomers by using the conditions reported in entry 15 of Table 2( Scheme2).…”

Domino Synthesis of α,β‐Unsaturated γ‐Lactams by Stereoselective Amination of α‐Tertiary Allylic Alcohols

“…[18] Crystallographic analysis [16] of A (see the Supporting Information) revealed no productive hydrogen bonding to account for intramolecular allylic alcohol activation. Both reactions illustrate that intermolecular COOH···OH hydrogen-bond activation does not play any significant role in the conversion of the allylic substrate.…”

“…Va rious spectroscopic control experiments (see the Supporting Information) were conducted to investigate intramolecular solution-phase hydrogen bonding but no conclusive confirmation of ar equisite HO···HO-C(O) interaction could be established. [16] Hydrogenation of 1a using Pd/C as catalyst gave clean access to 6 (92 %), while the use of ad ifferent reducing medium (NaBH 4 /BiCl 3 )for the more functional 2o provided 7 in 95 % yield. [20] We further explored the synthetic utility of these lactam scaffolds through as eries of site-selective post-modifications (Scheme 3).…”

“…Theu se of other solvents showed, in several cases,s ignificant formation of 1b,w hich is formed after decarboxylation following an aza-Michael addition (see the Supporting Information). Other ligands (L2-L10;entries [11][12][13][14][15][16][17][18][19] were then probed, and the use of L6 (dppf;e ntry 15) showed an encouraging increase in the yield of 1a to 79 %. Theo ptimized reaction conditions for the formation of 1a were achieved by further increasing the amount of L6 to 5mol %and reducing the amount of aniline to 1.1 equivalents (entry 21).…”