Diastereoselectivity, 3 lactams formation

Scheme 12.57 Rationale for enantio- and diastereoselective P-lactam formation...

The mechanism of (3-lactam formation has been investigated extensively. But the rationale for the observed diastereoselectivity in certain cases remains unknown. It has been demonstrated that the stereoselectivity depends on the structure of the imine, acid-chloride, order of addition of the reagents, solvent, temperature, bases, and many other conditions. In many cases, cis (3-lactam was found to be the exclusive or major product when acid chloride (equivalent) was added drop-wise at low-to-room temperature to the solution of imines and a base. However, a trans (3-lactam was the major or exclusive product obtained when a tertiary base was slowly added to the imine and acid chloride (equivalent) solution at high temperature. Georg and Ravikumar established a few rules regarding stereoselectivity in the formation of (3-lactam rings [122]. Computer-assisted calculations were advanced to explain the stereochemical preferences [140-144]. Cossio et al. [140-143] and... 

Molecular mechanics calculations also led to an explanation of the diastereose-lective course of the reaction. Several assemblies of the imino ester, 44, and the zwitterionic enolate were investigated [52]. In accordance with the experimental results it was found that the assembly leading to the cis diastereomer was of lowest energy. Because the lowest-energy trans assembly is several kilocalories higher, or-ganocatalytic / -lactam formation proceeds with an excellent cis diastereoselectivity. 

Chiral crystals formed from chiral molecules can undergo highly diastereoselec-tive photoreactions, while diastereodifferentiation in solution is usually low. Here three types of diastereoselective photoreactions in the crystalline state are presented. Highly diastereoselective Norrish/Yang photocyclization of adamantane [36] and p-lactam formation from oxoamides [37] have been also reported. 

An interesting strategy to the synthesis of thienamycin precursors via aldol addition-hydroxamate approach was developed by Fleming and Kilburn [99]. In this strategy (Scheme 40), the P-silylenolate 249 reacted with the aldehyde 250 to give the aldol product 251 in high diastereoselective fashion. Formation of the hydroxamate 252, followed by cyclization and removal of the benzyloxy group furnished the P-lactam 253. 

A variety of aldehydes including formaldehyde were used to form the imines. /3-Lactam formation was found to be cis-diastereoselective (>98 2 to 88 12, cisdrans ratio) when the chiral oxazolidinone derived acid chloride (6) was used (eq 4). The use of A-[bis(trimethylsilyl)methyl] /3-lactams in synthesis, such as in the preparation of Type-II /3-turn dipeptides have been reported. ... 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

When monothioimide le was irradiated in a benzene solution, [2+2] thietane formation proceeded, producing four p-lactams, syn-2e (A and B) and anti-2e (C and D) (Scheme 4). However, diastereoselectivity in the thietane formation... 

Chiral bicyclic lactams have been successfully utilized by Meyers as chiral dipolarophiles in highly diastereoselective azomethine ylide cycloadditions (73). Treatment of the ylide precursor 218 with the unsaturated, non-racemic dipolar-ophile 219 in the presence of a catalytic amount of TFA led to the formation of tricyclic adducts 220 and 221 in excellent yields (85-100%). The diastereofacial preference for the reaction was dependent on the nature of R with a methyl group... 

In a similar manner to that described for bicyclic lactams (Section 1.1.1.3.3.4.1.5.I.). alkylation reactions of tricyclic lactams, which contain a fused benzene ring adjacent to the carbon undergoing alkylation, have been exploited14. The first alkylation of the benzo-annulated bicyclic lactam 1 gives a mixture of diastereomers, which is then further alkylated. In the second alkylation step, the counterion on the alkoxide, which is formed prior to enolate formation, proved to be crucial for the diastereoselectivity of the subsequent alkylation reaction. The best diastcrcoselectivity was obtained when either dichlorobis(ij5-cyclopentadienyl)zirconium or triisopropoxytitanium chloride was added to the preformed alkoxide, followed by enolization and alkylation. Using this method the second alkylation step gives a satisfactory diastereoselectivity. Hydride reduction of the purified major diastereomer 2, followed by acid treatment of the product, furnishes chiral naphthalenones 414. 

Treatment of amino acid 156, imine and 2-chloro-l-methylpyridinium iodide (Mukaiyama s reagent) in the presence of triethylamine in refluxing dichloro-methane afforded spiro-(3-lactams 157,158. These were obtained as a 1.8 1 mixture of diastereoisomers and separated by column chromatography. The reaction of 159 and imine under the usual experimental conditions resulted in the formation of a single diastereoisomer 160. The absolute (3 S, 4 S, 7 -configuration was assigned on the basis of mechanistic considerations and XH NMR spectra. The presence of the stereocenter affords complete diastereoselectivity (only trans diastereoisomers 157, 158) and enantioselectivity (160). 

The formation of the y-lactams is almost perfectly diastereoselective if cyclic a-amino aldehydes or the aldehyde prepared from valine are used as starting materials. As it is shown in the following scheme, the electroreduction of the obtained optically pure y-lactams followed by the reduction with LAH yields the corresponding optically pure pyrrolizidine and indolizidine skeletons. 

One method for the synthesis of hydroxyalkyl-substituted P-lactams is by the Staudinger reaction, the most frequently used method for the synthesis of P-lactams.86 This method for the preparation of 4-acetoxy- and 4-formyl-substituted P-lactams involves the use of diazoketones prepared from amino acids. These diazoketones are precursors for ketenes, in a diastereoselective, photochemically induced reaction to produce exclusively tram-substituted P-lactams. The use of cinnamaldimines 96, considered as vinylogous benzaldimines, resulted in the formation of styryl-substituted P-lactams. Ozonolysis, followed by reductive workup with dimethyl sulfide, led to the formation of the aldehyde 97, whereas addition of trimethyl orthoformate permitted the production of the dimethyl acetal 98 (Scheme 11.26). 

The chemistry of iron vinylidene complexes is dominated by the electrophilicity of the carbon atom adjacent to the iron organometallic unit. While addition of water leads to an acyl complex (i.e., the reverse of the dehydration shown in equation 10), addition of an alcohol leads to a vinyl ether complex. Similarly, other iron vinyl complexes can be prepared by the addition of thiolate, hydride, or an organocuprate (Scheme 33). " The nucleophilic addition of imines gave enaminoiron intermediates that could be further elaborated into cyclic aminocarbenes. This methodology has been used to provide access to /3-lactams and ultimately penicillin analogs, and good diastereoselectivities were observed (6 1-15 1) (Scheme 34). 04 Iso, vinylidene complexes are intermediates in cyclizations of alkynyl irons with substituted ketenes, acid chlorides, and related electrophiles an example is shown (equation 11). These cyclizations led to the formation of a series of isolable and characterizable cyclic vinyl iron complexes. 

Better inductions by a vicinal amino acid were observed by Ojima and coworkers in the benzylation of chiral /3-lactam ester enolates (255, equation 67) °. Interestingly, the enolate formation occurred at an uncommonly high temperature (0°C) to form the thermodynamic Li-chelated enolate 256, which allowed a stereoselective attack of the electrophile, while the diastereoselectivity with the nonchelated kinetic enolate 259 was significantly lower. Subsequent hydrogenolytic cleavage of lactam 257 delivered S)-a-methylphenylalanine derivative 258 in nearly quantitative yield and high diastereoselectivity. 

Staudinger Reactions. Chiral oxazolidinones have been employed as the chiral control element in the Staudinger reaction as well as the ultimate source of the a-amino group in the formation of p-lactams." Cycloaddition of ketene derived from 4-(S)-phenyloxazolidylacetyl chloride with conjugated imines affords the corresponding p-lactams in 80-90% yields with excellent diastereoselectivity (eq 54). The auxiliary can then be reduced under Birch conditions to reveal the a-amino group. 

Incorporation of substituents in the alkenyl side chain resulted in the formation of the trans-y- and 5-lactams in high conversion and 60% diastereoselectivity (eq 11 and eq 12). In all experiments, the diastereoselectivity was similar to that previously reported by Nagashima et al. using a 2,2 -bipyridine complex. 

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