The Evans Aldol–Prins cyclization: a general and stereoselective method for the synthesis of 2,3,4,5,6-pentasubstituted tetrahydropyrans

Abstract

A general and stereoselective method to synthesize 2,3,4,5,6-pentasubstituted tetrahydropyrans in three steps starting from three different aldehydes is described. Key substrates β,γ-unsaturated N-acyloxazolidin-2-ones were subjected to an "Evans Aldol-Prins" protocol to generate five σ-bonds and five stereocenters in only a one-pot process with yields up to 60% and excellent stereoselectivities.

Stereoselective Synthesis of Highly Substituted Tetrahydropyrans through an Evans Aldol–Prins Strategy

“…These by-products could be punctually detected during the synthesis of the bicycles 5. 6a and 6c were described in our previous publication, 30 and 6b, 6x and 6y were never isolated. 0.32 mmol, 0.7 equiv) and the mixture was heated at 60 ºC for 8 h. After that, it was allowed to warm to rt and Ba(OH)2•8H2O (432 mg, 1.37 mmol, 3 equiv) was added.…”

“…Molecules index which correlates the numeration of the molecules discussed herein with those exposed in our previous report; 30 copies of 1 H and 13 C NMR spectra for new products and 2D NMR spectra for representative products.…”

“…Except products 5c-Ac, 5l, 5r, 5u, 5ag, 5ah and 5ai the rest of bicycles 5 were described in our previous publication (see Supporting Information for the correlation of the molecules numbering between both publications). 30 14.2 (q, C4' or C4''), 18.6 (t, C1'''), 20.91 (q, NCH2CH2OCOCH3), 22.6 (t, C3' or C3''), 22.6 (t, C2' or C2''), 27.6 (t, C2' or C2''), 32.1 (t, C1''), 34.0 (t, C1'), 41. Synthesis of the 2-oxonia-Cope rearranged isomers 6.…”

“…[27][28][29] This absence of a general method encouraged us to propose a strategy based in the combination of the well-known Evans aldol addition, as a powerful tool to construct the necessary homoallylic alcohol, and the Prins cyclization to yield the target highly substituted THPs (Scheme 1). 30 Thus, this Evans aldol-Prins (EAP) protocol suggests that a 2,3,4,5,6-pentasubstituted THP 1 could be accessed via the Prins cyclization of an aldehyde R 3 CHO and the syn-aldol 2. 31 ,-Unsaturated alcohols 2 bear a N-acyl oxazolidin-2-one moiety at  position.…”

“…Acids 4a-c are commercially available and they were used as received without further purification. Acids 4d-f were described in our previous publication,30 and they were stable for at least 12 months stored under Ar at -18 ºC.General procedure for the synthesis of the N-acyl oxazolidin-2-ones 3. All the subsequent operations were carried out under an Ar atmosphere.…”