New fluorinated unsaturated cyclic a-amino acid esters were obtained by ene reaction of methylenecycloalkanes with electrophilic imines (CF 3 )(MeO 2 C)C=N-PG, followed by rutheniumcatalyzed ring rearrangement involving mixed ROM-RCM metathesis.The ring closing metathesis reaction (RCM) has become an important synthetic tool, due to the development of the well-defined Schrock's molybdenum 1 and Grubbs' ruthenium 2 catalysts, which are able to tolerate most functional groups and are very efficient for the selective synthesis of a variety of carbo-and heterocycles. 3 These compounds were shown to catalyze ring opening metathesis (ROM), 4 which can be combined with cross metathesis. 4-6 To our knowledge, no application of combined ROM-RCM reactions has been described for the preparation of fluorine containing cyclic a-amino acid derivatives, despite the special interest of b-fluorinated a-amino acids, which can function as highly selective and potent inhibitors of pyridoxal phosphate-dependent enzymes. 7,8 The development of straightforward methods for the synthesis of b-fluorinated a-amino acid derivatives thus remains of current interest especially via simple catalytic processes.We now report a novel synthesis of 2-CF 3 -4-alkenyl cyclic amino esters based on two successive reactions: the uncatalyzed ene reaction of methylenecycloalkanes with electrophilic trifluoromethylated imines, followed by ruthenium-catalyzed mixed ROM-RCM reactions leading to ring rearrangement of the resulting cyclopentene or cyclohexene groups, which can potentially be applied to most ene reaction products (Scheme 1). Scheme 1The ene reaction with imines has been performed in the presence of Lewis acid and metal catalysts 9 in order to increase the electrophilicity of the imine carbon atom. The highly electrophilic a-CF 3 -substituted imines of type 1, 10 by contrast, readily react in the absence of catalysts with methylenecyclopentane and methylenecyclohexane to selectively give the ene reaction product, the fluorinated unsaturated a-amino esters 2a-c and 3a-c in 68-98% yields (Scheme 2). The reaction takes place at room temperature for N-protecting groups of the type PG = SO 2 R, whereas the use of the Boc protecting group requires heating at 90-100°C.Scheme 2 PG = SO 2 Me (a); SO 2 Ph (b); Boc (c) In order to perform the alkene metathesis reaction, an allyl group was attached to the nitrogen atom of the amino esters. The N-allylated derivatives 4, 5 were obtained in 49-68% yields on deprotonation of 2, 3 with NaH in DMF and subsequent alkylation with allyl bromide (Scheme 3). 11Scheme 3 4a-c (n = 0); 5a-c (n = 1) Alkene metathesis of the 5-membered ring containing derivatives 4a-c was attempted with 10 mol% of the Grubbs' catalyst Ru=CHPh(Cl) 2 (PCy 3 ) 2 2 in dichloromethane. After 6-8 hours of stirring at room temperature the reaction yielded the ROM-RCM rearranged products, the cyclic n = 0: 2a (98%), 2b (85%), 2c (83%) n = 1: 3a (68%), 3b (79%), 3c (71%) Downloaded by: Collections and Technical Services Department. Copyrighted m...

Novel Synthesis of Cyclic α-Amino Acid Esters via Ene Reaction and Ruthenium-Catalyzed Ring Rearrangement.-Electrophilic imines (I) and methylenecycloalkanes (II) undergo an uncatalyzed ene reaction to yield α-amino esters whose N-allyl derivatives (V) readily undergo ring-openingring-closing metathesis reaction. -(OSIPOV, SERGEY N.; KOBELIKOVA, NATALIA M.; SHCHETNIKOV, GREGORY T.; KOLOMIETS, ALEXEY F.; BRUNEAU, CHRISTIAN; DIXNEUF, PIERRE H.; Synlett (2001) 5, 621-622; Nesmeyanov Inst. Organoelem. Compd., Russ. Acad. Sci., Moscow 117813, Russia; EN)