Enantioselective synthesis lactams

The enantioselective synthesis of the V-benzyl-substituted /3-lactam 274a (NR2 = PhCH2NH), a precursor for carbapenem antibiotics, was described starting from the chiral synthon 5(R)-menthyloxy-2(5//)-furanone 170 (Scheme 71)... 

Zhang YR, He L, Wu X, Shao PL, Ye S (2008) Chiral N-heterocyclic carbene catalyzed Staudinger reaction of ketenes with imines highly enantioselective synthesis of W-Boc P-lactams. Org Lett 10 277-280... 

The chiral reduction of -substituted a,/3-unsaturated lactams with PMHS in the presence of (S)-/ -Tol-BINAP as the chiral ligand with a copper catalyst results in -substituted lactams in excellent yield and with greater than 90% ee.599 This method has been applied in an efficient enantioselective synthesis of the antidepressant (-)-paroxetine (Eq. 356). 

Enantioselective synthesis of analogous p-lactams has been also reported [63]. If the starting imine complex was prepared from the corresponding chiral amine in enantiomerically pure form (Fig. 1), two separable diastereomers were obtained. Using, then, one of the two diastereomers, ck-p-lactams were isolated as single enantiomers. 

The ester enolate-imine condensation, also called Gilman-Speeter reaction, is another well-accepted method for (3-lactam synthesis (Scheme 4) [67-69]. In 1997, Tomioka reported the first example of a direct catalytic enantioselective synthesis of (3-lactam by using this method [70]. The active reagent is a ternary complex (comprising LDA, the ester enolate, and tridentate amino diether), which finally affords the (3-lactam compounds in high yields and good ee values. 

Enantioselective synthesis of /3-lactams from enolate and imine components uses a bifunctional Lewis acid/nucleophile strategy.76 A chiral nucleophile is used to form a zwitterionic enolate, and a metal ion coordinates the imine. The postulated mechanism is supported by kinetic, spectroscopic, and molecular modelling evidence. 

J. Tamariz, Bbbgical Activity of fl-Amino Acids and fl-Lactams in Enantioselective Synthesis of fl-Amino Acids, E. Juaristi, ed., Wiley-VCH, New York, 1997, 45-66. 

The analogous reaction of unsaturated lactones and lactams is strongly accelerated in the presence of alcohols which protonate the copper enolate formed in the conjugate reduction.281 This protocol was used in an enantioselective synthesis of the antidepressant (—)-paroxetine 324. Here, the key step was the conjugate reduction of the lactam 322 by PMHS in the presence of /-amylalcohol and catalytic amounts of CuCl2, ( S)- -tol-BINAP, and sodium /-butoxide, giving the product 323 with 90% yield and 90% ee (Scheme 90).281 The second chirality center was installed by diastereoselective alkylation of 323. 

The enantioselective synthesis of azabicyclic y-lactams starting from 2-azanorbornenones after treatment of a catalytic amount of RuCl2(PCy3)2 (= CHPh) in the presence of ethylene or allyl acetate proceeds also via ring rearrangement—alkene metathesis (ROM-CM-RCM) [41] (Scheme 19). If n = 0 or 3, no RCM occurs and a cyclic dialkenyl compound is formed by cascade ROM-CM reactions. 

Chiral quaternary carbon centers. Meyers et al. have reported an enantioselective synthesis of chiral ot,(t-disubstituted- y-keto acids (6) via the lactam 3 prepared from l-valinol (1) and the y-keto acid 2. Alkylation of 3 with primary alkyl halides gives mainly the endo-isomer (4). /dkylation of 4 also proceeds with endo-selectivity to give 5 with a... 

A method for the enantioselective synthesis of the ftmctionalised carbapenam core 38 from D-serine-derived pyrrolidines has been reported <03JOC187>. Disubstituted pyrrolidines, obtained from the retro Dieckmann reaction of azabicyclo[2.2.1]heptan-2-one-1-carboxylic acid methyl esters, have been used as starting materials to develop concise syntheses of all four stereoisomers of carbapenam-3-carboxylic acid methyl esters <03JOC2889>. The synthesis of 1-methylcarbapenams 39 by intramolecular attack of lactam nitrogen on a 77 -propargylpalladium complex has been reported <03JOC8068>. 

In a recent application, cw-aminoindanol has been employed as a rigid diastereocontrol element in the alkylation of bicyclic lactams and thiolactams of which they are a component. The resulting products form the basis of an enantioselective synthesis of alkaloids. 

A variety of methods are available for the synthesis of heterocyclic carbonyl compounds by radical cyclization. For example, the cyclization of alkoxycarbonyl radicals is particularly useful for the synthesis of five- and six-membered ring lactones [80]. Recent applications of this cyclization method include Zard s photoly-tical transformation of an alkoxycarbonyl dithiocarbonate having a double bond which can serve as a key step in the synthesis of ( )-cinnamolide and RA. Evans s enantioselective synthesis of 4-hydroxy butenolide terminus, which is applicable to the synthesis of mucocin [81J. Amidyl radical cyclizations are frequently utilized for the synthesis of five- and six-membered ring lactams [82]. However, this section only focuses on recent methods for heterocyclic carbonyl compounds by an n-i-1 type strategy based on radical carbonylations. 

Durham TB, MiUer Ml (2003) Enantioselective synthesis of a-amino acids from N-tosyloxy P-lactams derived from P-keto esters. J Org Chem 68 27-34... 

Bonache MA, Gerona-Navarro G, Martfn-Martfnez M, Garcra-Lopez MT, Lopez P, Cativiela C, Gonzilez-Muniz R (2003) Memory of chirality in the enantioselective synthesis of P-lactams derived from amino acids. Influence of the reaction conditions. Synlett 7 1007-1011... 

The only enantioselective synthesis of julandine to date is due to Kibayashi and co-workers (593). Lewis acid-catalyzed condenseition between silyl enol ether 901 and the acyliminium ion formed from the proline-derived lactam 902 was highly diastereoselective (>99% de), giving a 76% yield of the piperidin-2-one 903 (Scheme... 

Derivatives from fi-Lactams Update in Enantioselective Synthesis of p-Amino Acids, 2" edition, E. Juaristi, V. A. Soloshonok, Eds John Wiley Sons, Hohoken, NJ, 2005 Chp. 20, p477. 

The use of chiral sulfoxitnines 1.136 (R = Ph, Tol, Y = ArCH=N) has allowed the enantioselective synthesis of p-aminoesters after cleavage of the S-N bond by CF3COOH [510], Preliminary studies showed that the reaction of C-arenechromium tricarbonyl imines and the lithium enolate of Me2CHCOOEt gave chiral p-lactams after decomplexation with an excellent enantiomeric excess [549, 1291]. 

Development of catalytic approach to the enantioselective synthesis of /3-lactams 01AG(E)4377. 

In 1998, Kawahara and Nagumo reported the first total synthesis of a member of the TAN1251 series [63] and five years later both authors revisited the TAN1251A alkaloid by means of a new enantioselective synthesis (see Section 5.6). The retro synthetic analysis of TAN 1251A is outlined in Scheme 37. The target compound could be obtained by aldol reaction of tricyclic lactam 119, whose disconnection at the amide bond led to the bicyclic amino acid 120, which could be prepared from azaspirocyclic compound 121 by means of alkylation of the secondary amine and Mitsunobu-type chemistry. Azabicycle 121 may be prepared by an intramolecular alkylation of 122, which in turn could be available from allyl derivative 123. The latter can be prepared from carboxylic acid 124 by alkylation and subsequent Curtius rearrangement. 

A recent enantioselective synthesis of homopenicillin took advantage of a new method for the ring expansion of penicillin [79]. Irradiation of the P-ketosulphoxonium ylide 124 resulted in the smooth formation of y-lactam 127. The reaction probably involved the formation of an acylcarbene 125 which undergoes Wolff rearrangement to the ketene intermediate 126. Intramolecular nucleophilic attack formed the new five-membered ring (Scheme 43). Homo-... 

Scheme 15.12 The first enantioselective synthesis of the p-lactam ring with Cinchona alkaloids.

The first highly enantioselective synthesis of the p-lactam ring with Cinchona alkaloids was demonstrated by Lectka and coworkers in 2000. They employed 10 mol% of benzoylquinine (O-Bz-Q) or benzoylquinidine (O-Bz-QD), to condense electron-deficient a-imino esters and ketenes (Scheme 15.12). To ensure in situ ketene formation (in fact a chiral ketene enolate is the reactive species.), proton sponge (PS) was used as a... 

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