Lactams, resolution

This was transformed into the quaternary d-bromocamphorsulphonate, m.p. 265°, but no resolution has yet been effected. The lactam of 3-carboxyhexahydrocarbazole-1 ll-)3 8 -dipropionic acid (XXIV, with a carboxyl group at C ), CigH jO N, rn.p. 257-8°, has also been prepared. The same authors, with Holmes, have synthesised the lactam of 11-ethylhexahydrocarbazole-l-)3-propionic acid, Ci,H3iON, m.p. 106-8-107-5°, of which (XXrV) is a carboxy-derivative. 

Figure 2.3 An example of a stereospecific biotransformation resolution of bicyclic lactams. A and Ai are an enantiomer pair as are B and Bi.

Figure 6.42 Lipase-catalyzed kinetic resolution of a p-lactam.

You and co-workers have demonstrated a further application of NHCs in the kinetic resolution of formyl p-lactams ( )-265 [103]. Upon treatment with a chiral NHC, the Breslow-type intermediate is formed, followed by ring-opening of the P-lactam moiety, with subsequent trapping of the acylazolium intermediate leading to the enantio-enriched succinimide product 266 and resolved formyl P-lactam (which is reduced to its alcohol 267). The authors note that when R" = H, the products undergo racemisation readily, and this is a possible explanation for the lower levels of enantioselectivity observed in the succinimide products 266 (Scheme 12.60). 

Tryptophan (and also tryptophanol) undergoes a stereoselective cyclocondensation with racemic compound 249, in a very interesting process involving a kinetic resolution with epimerization of the tryptophan stereocenter and simultaneous desymmetrization of the two diastereotopic acetate chains <2005CC1327>, affording the enantiomeri-cally pure lactam 250. A subsequent treatment of the latter compound with trifluoroacetic acid led to the indolo[2,3- ]quinolizidine 251 through an intermediate acyliminium cation (Scheme 50) <20050L2817>. 

The unsaturated amides (RCH=CHCONH2, where R = aryl or heteroaryl) in the presence of sodium acetate and NBS gave 3-bromoazetidin-2-ones 67 in moderate yield, probably by cyclization of 68 <99JCS(P1)2435>. The mesylate 69 cyclized in the presence of base to 70 and, after deprotection, the racemic P-lactam was subjected to lipase-mediated resolution to yield 71 (R = Et, ee 99%) and the amino acid 72 (R = Et, ee 98%) . 

The structural integrity of enzymes in aqueous solution is often compromised by the addition of small quantities of water-miscible organic solvents. However, there are numerous examples, particularly using extremophiles, where enzymes have been successfully employed in organic solvent-aqueous mixtures.A good example is the savinase-catalysed kinetic resolution of an activated racemic lactam precursor to abacavir in 1 1 THF/water (Scheme 1.39). The organic solvent is beneficial as it retards the rate of the unselective background hydrolysis. 

Coates used [Cp2Ti(THF)2] and [(salphen)Al(THF)2] as Lewis acid to convert a variety of epoxides to racemic p-lactones, and substituted aziridines to p-lactams in high yields under mild conditions. PO is selectively converted to p-BL in 95% yield in 4 h at 60°C [117]. However, only racemic p-BL can be obtained from racemic PO. In order to get enantiopure molecules from racemic precursors, the catalytic system has to be stereoselective. This can generally be achieved by the use of a chiral stereo-inducing Lewis acid, which effects a kinetic resolving activation [119, 120]. However, examples of the chiral resolution of PO are rare. 

Fortuitously simultaneous selective reaction and racemisation reactions can be achieved by using two different microorganisms with lactamase and lactam racemase activities respectively, since both have the same pH optimum (pH 8-9). Thus quantitative yields of L-lysine are obtained, rather than the 50% yields usual in resolution processes. In... 

Li and coworkers have previously found that in the presence of an /V-hetero-cyclic carbene catalyst m-4-formyl-(3-lactams underwent the ring expansion reaction to afford succinimide derivatives [242]. More recently, they reported the kinetic resolution version of this transformation attempted with a chiral /V-heterocyclic carbene (Scheme 113), leading to m-4-formyl-(3-lactams with moderate ee of 64% [243]. 

The most representative example of the utility of (3-lactams as acylating agents is the coupling reaction of the (3-lactam 25 Scheme 10, with the sodium salt of vacatin III to give paclitaxel ([69-73] for a recent example involving kinetic resolution of racemic (3-lactams, see [74]), after mild deprotection of the TES group. 

Scheme 61, yielded thiazole 200 as the major product, along with minor amounts of carbinol 201 [152]. On the other hand, treatment of the imine formed from 199 and p-methoxyphenylamine with catalytic tetrabutylammonium cyanide, produced suc-cinimide derivative 202. In both cases, the process is initiated by nucleophilic attack to the carbaldehyde C=0 (or azomethine s C=N) group, which is followed up by an anionic rearrangement. A variation of the above process using as catalysts /V-heterocyclic carbenes (NHC) derived from base treatment of azolium, imidazo-lium, or triazolium salts, has also been developed to access gem-disubstituted succinimides [153, 154]. Unfortunately, an attempt of kinetic resolution of racemic 4-formyl (3-lactams by using chiral NHC resulted in moderate selectivities only [154]. 

An asymmetric synthesis of 3,4,5-trisubstituted-tetrahydro-l-benzazepines has been reported based on a type a ring construction process mediated by triethylaluminium with a chiral amino ester followed by lactam reduction with borane <2006OL2667>. Dynamic thermodynamic resolution in a lithiation-substitution sequence was integral to the preparation of the amino ester. An acid-catalyzed ring construction approach to the asymmetric synthesis of 4,5,6-trisubstituted- and 3,4,5,6-tetrasubstituted azepanes based on chiral acyclic precursors has also been described <2006JA2178>. 

The applications of re-acidic chiral stationary phases include the resolution of a-blockers and /1-blockers, amines, arylacetamine, alkylcarbinols, hydantoins, barbiturates, naphthols, benzodiazapines, carboxylic acids, lactams, lactones, phthaldehydes selenoids, and phosphorus compounds. Hyun et al. [16] achieved a chiral resolution of a homologous series of iV-acyl-x-(l-naphthyl )cthylaminc on AA(3,5-dinitrobenzoyl-(i )-phenylglycine and N-(3,5 - dini tr o ben zoy I)-(,S ) -1 c u c ine CSPs. The authors used hexane-2-propanol (80 20, v/v) as the mobile phase. Similarly, the scope of re-basic CSPs comprises the chiral resolution of / -blockers, amino acids, amines, diamines, amino phosphonates, naphthols, benza-diazapines, carboxylic acids, hydroxy acids, dipeptides, tripeptides, diols,... 

Fermentation methods for synthesis and resolution Reaction with cyclic lactam intermediates Reaction with glycine and aldolase Fractional crystallization... 

A typical chromatogram showing the resolution of various /3-lactam antibiotics from a mixture at pH 3.5 is shown in Fig. 4.5. In terms of the selectivity of the stationary phase, the separation factors a were 1, 2.15 and 1.54 for oxacillin, penicillin G and penicillin V, respectively. 

Holton claimed in a patent application that (3/ ,45)-A-benzoyl-3-0-EE-(3-lactam 11 (5 equiv), obtained through tedious classical optical resolution of racemic t (. -3-hydroxy-4-phenylazetidin-2-one, could be directly coupled with 7-TES-bac-catin III (8) in the presence of 4-dimethylaminopyridine (DMAP) and pyridine and the subsequent deprotection afforded paclitaxel in ca. 82% yield.54 Although this procedure was proved to work by us and by others, the use of a large excess of (3-lactam is obviously inefficient. Moreover, the Holton procedure did not work at all when /V-f-Boc-(3-lactam 12 was used for our attempted syntheses of docetaxel and its 10-acetyl analogue. This is due to the lack of reactivity of the A-r-Boc-(3-lactam 12 toward the C-13 hydroxyl group of a protected baccatin III under the Holton conditions. The lack of reactivity is ascribed to the substantially weaker... 

Gyarmati, Z. Cs. Liljeblad, A. Rintola, M. Bemath, G. Kanerva, T. L. Lipase- catalyzed kinetic resolution of 7-, 8- and 12-membered alicyclic fi-amino esters and N-hydroxymethyl-/ -lactam enantiomers. Tetrahedron Asymmetry 2003, 14, 3805-3814. 

Kaida, Y. and Okamoto, Y. (1992) Optical resolution of P-lactams on 1-phenylethylcarbamates of cellulose and amylose, Chirality 4, 122-124. 

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