Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction

Abstract

SummaryEnantiomerically pure β-aminoalcohols, produced through an organocatalytic Mannich reaction, were subjected to an Ugi multicomponent reaction under classical or Lewis acid-promoted conditions with diastereoselectivities ranging from moderate to good. This approach represents a step-economical path to enantiomerically pure, polyfunctionalized peptidomimetics endowed with three stereogenic centers, allowing the introduction of five diversity inputs.

Diversity‐Oriented Synthesis of Various Enantiopure Heterocycles by Coupling Organocatalysis with Multicomponent Reactions

“…Ugi product Ar [a] dr (S/R) [b] Yield [%] [a] dr (S/R) [ [c] For compounds 5a and 5i, the yields are those already reported in our previous paper (ref. [11] major diastereoisomer had always an (S) configuration (the same trend was reported in our preliminary paper).…”

“…For all Ugi adducts 5, both those described in this paper and those previously reported in our preliminary report, [11] strong analogies in HPLC, TLC, and NMR spectroscopy were found: a) The faster-running isomer in HPLC (reverse-phase) was always the slower-running isomer in TLC (petroleum ether/ EtOAc). This was always the major isomer when the Ugi reaction was carried out in THF with ZnBr 2 as the promoter (method A); b) The 1 H NMR spectrum of the faster-running isomer (HPLC) showed, in all cases, a strong upfield shift for the signals of the isocyanide-derived secondary amide (namely the NH signals, and its neighbors).…”

“…Table summarizes the results of the Ugi reactions leading to the intermediates discussed in this paper. Apart from compounds 5a and 5i , which were already described in our previous paper, these Ugi adducts are all new. Although in most cases the ZnBr 2 ‐catalyzed reaction was found to give higher diastereoselectivity, for some combinations of substrates, method B was found to be superior in terms of yield and/or diastereoselectivity.…”

“…(3 S ,5 S ,6 S ,8a R )‐ and (3 S ,5 S ,6 S ,8a S )‐8a‐(5‐Chlorothiophen‐2‐yl)‐1‐cyclohexyl‐3‐isopropyl‐6‐methyl‐5‐phenyltetrahydro‐1 H ‐imidazo[2,1‐ b ][1,3]oxazin‐2(3 H )‐ones (7a): Compound 5a ‐ S (100 mg, 204 µmol) was dissolved in dry DMF (2 mL), and the solution was cooled to 0 °C. 1,1′‐Sulfonyldiimidazole (SDI; 101 mg, 520 µmol) was added.…”

“…A mixture of Ugi adducts 5j ‐ S and 5j ‐ R was prepared in 51 % overall yield from Boc‐amino alcohol 18 according to method A (see the synthesis of 5b ). The two isomers 5j ‐ S , and 5j ‐ R where separated by chromatography, and identified by 1 H NMR spectroscopy (selected data are reported in the Supporting Information).…”