Synthesis of 4-hydroxy-β3-homoprolines and their insertion in α/β/α-tripeptides

Abstract

The stereoselective syntheses of 2-cyclopropyl- and (2S)-2-hydroxymethyl-(3R,4S)-4-hydroxy-β(3)-homoproline are described. The reported amino acids were constructed through 1,3-dipolar cycloaddition of strained alkylidenecyclopropanes with enantiopure pyrroline N-oxides derived from malic acid followed by thermal rearrangement of the adducts in the presence of trifluoroacetic acid. The two-step sequence afforded the homoprolines suitably protected to be directly used as building blocks in peptidomimetic synthesis as proved by the synthesis of the two model mixed α/β/α tripeptides Phe-β(3)-HPro-Val.

Progress in the Synthesis and Transformations of Alkylidenecyclopropanes and Alkylidenecyclobutanes

“…For example, adduct 338 (E = CO 2 Me) was synthesized at 60 °C, whereas the corresponding tert -butyl derivative 338 (E = CO 2 t -Bu) underwent TR at 40 °C showing a surprising thermal instability . By choosing an appropriate cycloaddition temperature, the bis-spirocyclopropanated hexahydropyrrolo­[1,2- b ]­isoxazoles 338 , 341 , 343 , 331 , and 345 could be synthesized in good yields starting from BCP and a suitable cyclic nitrone (Scheme ). − …”

“…Analogously, 1,3-DC of the enantiopure pyrroline N -oxide 346 and ethoxycarbonyl-methylenecyclopropane 347 afforded a diastereomeric mixture of 5-spirocyclopropaneisoxazolidines 348 with complete regioselectivity (Scheme ) …”

Synthesis of β‐Lactams and β‐Homoprolines by Fragmentative Rearrangement of 5‐Spirocyclopropaneisoxazolidines Mediated by Acids

“…However, none of the expected carbapenams 11 were isolated, as they spontaneously undergo ring opening and N ‐acylation under the reaction conditions to give the corresponding β‐homoprolines 12 , which incorporated one equivalent of trifluoroacetic acid, in acceptable‐good yields (Scheme 9). [11,20] When a malonyl unit is formed, such as in homoproline 12 d , a decarboxylation occurs to give homoproline 13 . This problem can be avoided by reducing the methoxycarbonyl group to hydroxymethyl at the level of the isoxazolidine, i. e. 10 e (Scheme 9).…”

“…The use of BCP as the dipolarophile with pyrroline N ‐oxides allows, after the acidic fragmentative rearrangement, the formation of interesting cyclopropyl‐substituted β‐homoprolines 20 and the β‐amino acids 21 and 22 in good yield (Scheme 11). [14,17,18,20] …”

“…Homoprolines protected at the nitrogen atom are very convenient building blocks in peptide synthesis, particularly for the synthesis of peptidomimetics. The ability of these β‐amino acids to undergo couplings with proteinogenic α‐amino acids was thoroughly tested [14,20] as shown in Scheme 12 using N ‐acylated homoprolines 12 f and 20 e [20] …”