Ester-enolate-imine approach

A stochiometric approach was applied by Van Koten and co-workers [29], who used chiral carbosilane dendrimers as soluble supports in the in situ ester enolate-imine condensation in the synthesis of /Mactams (e.g. 19, Scheme 20). The formation of the /Mactam products proceeded with high trans selectivity, and with the same level of stereoinduction as was earlier established in reactions without the dendritic supports, (i.e. the use of the enantiopure dendritic support did not affect the enantioselectivity of the C-C bond formation). After the reaction, the dendrimer species could be separated from the product by precipitation or GPC techniques and reused again. 

This method can be effectively applied to the preparation of /S-lactam compounds. The ester enolate-imine condensation approach to j8-lactam formation has been developed over the past decade. Thienamycin and related carbapenems have been the focus of particular attention because of their structural uniqueness and potent antibacterial activity. 

Among the most suitable methods for the synthesis of appropriately substituted monocyclic P-lactams [16], the chlorosulphonylisocyanate-alkene approach, the acid chloride-imine method, the ester enolate-imine condensation and the hydroxamate approach have received considerable attention in P-lactam synthesis. 

Therefore, in principal, condensation of a primary amine with an enantiomerically pure ketone should allow asymmetric synthesis of a-substituted primary amines. This approach has been applied to the synthesis of a-amino acids, for example, using the imine prepared from a-amino esters and (l.S, 2,S ,5,S )-2-hydroxy-3-pinanone, via an amino-substituted ester enolate anion with some success39 40. Application of this approach to simple primary amines has seldom been reported. 

An enolate-imine coupling reaction has been used to give the side chain in 59% yield in the key step (272). In this approach the imine 7.4.13 was coupled with the enol 7.4.14 in the presence of MgBr2 to give the adduct 7.4.15 this compound was converted to side chain methyl ester in three steps. 

In one approach, an imine moiety was generated in situ by reaction of a methoxy carbamate with lithium diisopropylamide. This imine was then condensed with an ester enolate to give the amino-ester, protected as a carbamate. Reaction of 4,70 with lithium diisopropylamide gave imine 4.71, for example. Subsequent reaction with... 

Our approach was based on the ring opening of fluoroalkyl p-lactams. These p-lactams can be obtained either through a [2+2] ketene-imine cycloaddition with a fluoroacetaldimine, or by the cyclocondensation of an alkoxy or silyloxy ester enolate on this same fluoroacetaldimine. The preparation of fluoroalkyl P-lactams 16 (Rf = CF3, CFjH and CF2CI) and the preparation of homochiral P-lactams and isoserines 14 and 15, have been have investigated with success by these two approaches. 

The scope was then extrapolated to the two-step three-component aza-Baylis-Hillman setup to obtain (3-amino-a-methylene structures. A two-step approach was chosen to avoid the competition between the aldehyde and the imine for the reaction with the enolate, that would lead to mixtures of Baylis-Hillman and aza-Baylis-Hillman adducts, that is (3-hydroxy and (3-amino esters [87]. 

Other pitxlnig approaches have involved the use of oximes, imines, and enol esters, although these types of eom-pounds have not been used clinically. A number of agents contain imine and oxime linkage.s. sueh as many of the third-generation cephalo.sporins (e.g cefotaxime, cefiizoxime), but these are not prodnigs. 

Asymmetric alkylation of imines has been employed most frequently for the construction of chiral amino moieties involved in the syntheses of nitrogen heterocycles and amino acids [17]. This approach is also useful for fluorinated amino acid synthesis as shown in Scheme 9.7. Mannich reaction of enolate with imino ester 23 in the presence of L-proline gives a-amino esters 24 and 25 enantio-and diastereoselectively [18]. 

Stevens and co-workers have also attempted to develop a fundamentally different approach to the tricyclic amino ketone 463 which is used in the Fischer cyclization approach to the Aspidosperma skeleton (240). Condensation of the aldehyde-ester 553 with protected keto amine 554 gave an imine (555) which, upon heating with ammonium chloride at 160°, afforded the 2-pyrroline ester 556 in 70% yield. Treatment with dry hydrochloric acid gas in ether was followed by acid hydrolysis of the ketal, and base-catalyzed cyclization produced a mixture of two enol ethers (557 and 558) the latter predominating. The major isomer was reduced with lithium aluminum hydride and the hydroxy enol ether dehydrated in hot... 

---