4,5-methanoprolines

From the seeds of the legume Atelia herbert smithii Pittier (Papilionidae), which seems to repel insect predators, Bell et al. have isolated the new amino acid 2,4-methanoproline (56) (98). This structure has been established by spectroscopic means and confirmed by X-ray diffraction. 

The presence of a pyrrolidine unit in complex systems such as the azabicy-clo[2.1.1]hexane unit of 2,4-methanoproline (56) lends itself to synthesis pertaining to the 1,3-disubstituted cyclobutane part of the molecule. Thus two syntheses of 56 have been published, relying on the [2 + 2] photochemical synthesis of cyclobutanes. A nontrivial problem of the synthesis of these compounds is liberation of the target molecule from its protective groups (Scheme... 

The intramolecular [2 + 2] photocycloaddition of an a-carboxy enamide with an olefin has been elegantly exploited independently by Pirrung and by Clardy and coworkers in the synthesis of the toxic amino acid 2,4-methanoproline via irradiation of 32 (equation 9)15. 

In the amino acid family are a number of interesting cyclopropyl compounds including the bicyclic methanoproline (6), produced by S. zamoyceticus SF-1836 with antibacterial activity against Xanthomonas and B. subtilis strains. The compound is apparently a proline... 

The last step, barium hydroxide-catalyzed hydrolysis of the aminonitrile 2A. followed by sulfuric acid neutralization, gave a racemic mixture of cis- and trans-methanoproline. After removal of barium sulfate and solvent, trituration of the residue with ethanol afforded... 

Further improvements to this route to methanoproline and the syntheses of related amino acids have been reported elsewhere (24.) In this way, chemical manipulation of 3-azabicyclo[3.1.0]hexane has allowed the preparation of multi-kilogram quantities of both cis- and trans-methanoprolines (24). 

In related syntheses of aminocyclopropylcarboxylic acids and acid derivatives, different combinations of protecting groups have been employed and among the compounds made were carnosadine (8), ( + )-2,3-methano-5-oxoproline (9), ( + )-2,3-methanoproline (10), /rani-l-benzoylamino-2-phenylcyclopropane-l-carboxylic acid (11) (and variants with substituted phenyl and thiophene) tra i-l-amino-2-isopropylcyclopropane-l-carboxylic acid (12) and coronamic acid (13). ... 

More recently, 5-hydroxy and 5-fluoro derivatives of the 3,5-methanoproline (26) were analyzed comparatively as N-acetyl methyl esters (Fig. 11.7) by NMR and in the crystalline state for their preferred conformations [90]. In 3,5-methanoproline both pyrrolidine ring puckers are incorporated into the same framework (Fig. 11.7), which allows the dissection of the relative contributions of ring pucker and inductive effects to the conformation of the proline compounds. The hydroxy... 

Fig. 11.7 Structures of N-acetyl-3,5-methanoproline methyl ester (31) and related 4-hydroxy (32) and 4-fluoro (33) derivatives of defined stereochemistry.

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