Synthesis of α-Cyclopropyl-β-homoprolines

Abstract

1-(2-Pyrrolidinyl)cyclopropanecarboxylic acids (alpha-cyclopropyl-beta-homoprolines) were prepared by 1,3-dipolar cycloadditions of cyclic nitrones onto bicyclopropylidene followed by trifluoroacetic acid induced thermal fragmentative rearrangement. With the use of enantiopure pyrroline N-oxides derived from easily available chiral pool molecules, beta-homoprolines were formed with high stereocontrol. The incorporation of one of these new cyclic beta-amino acids into a simple tripeptide was also evaluated. In particular, the sterically hindered nitrogen atom of the highly substituted pyrrolidine 30 was smoothly acylated through the intermediate formation of a mixed anhydride.

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

“…The results shown in Chart 1 [8,9b,11–18] give a clear picture of the feasibility and of the chemical diversity achievable with the process, which was exploited satisfactorily also by other groups than ours [12,15,16] . Monocyclic, as well as bi‐ and tri‐cyclic β‐lactams were produced with similar efficiencies with only two exceptions.…”

“…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] …”

Small Ring Compounds and N‐oxides: Cycloadditions and Related Processes

“…Combined with the in situ nitrone generation, the procedure allowed the synthesis of azetidinones 81 in one step from hydroxylamine salts, aldehydes, and MCPs . For azetidinones with bridge‐head nitrogen, ring opening to homo‐proline derivatives like 104 occurred (Scheme ) ,. Recently, the sequence intramolecular [3+2] nitrile oxide cycloaddition, nucleophilic addition to the C=N bond, and ring contraction was used in the total synthesis of gelsemoxonine (Scheme )…”

Synthesis of a Novel Tetrahydroxylated β-Homoproline

“…3,4 However, among these synthetic peptidomimetics, b-homoproline derivatives have been scarcely investigated, apart from a recent example in which the incorporation of a new cyclic b-amino acid into a simple tripeptide has been evaluated. 5 Moreover, some sulfonamide derivatives of b-homoproline have been recently studied as organocatalysts for Michael and aldol reactions. 6 We present in this Letter a straightforward gram-scale synthesis of a novel b-homoproline 1 that is hydroxylated on the pyrrolidine skeleton as well as on the chain at the a-carbon, by means of a highly selective 1,3-dipolar cycloaddition of L-tartaric acid derived nitrone 2 to g-crotonolactone (3) as the first key step, required for the highly selective installation of three new stereocenters on the target molecule (Scheme 1).…”