Regioselectivity Dieckmann condensation

We begin with the discussion of intramolecular reactions. An example of a regioselec-tive Dieckmann condensation (J.P. Schaefer, 1967) used an educt with two ester groups, of which only one could form an enolate. Regioselectivity was dictated by the structure of the educt. 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

The intramolecular condensation reaction of diesters, the Dieckmann condensation, works best for the formation of 5- to 7-membered rings larger rings are formed with low yields, and the acyloin condensation may then be a faster competitive reaction. With non-symmetric diesters two different products can be formed. The desired product may be obtained regioselectively by a modified procedure using a solid support—e.g with a polystyrene 10 ... 

The anion from (70.5) attacks the nitrile group and a 4-aminopyridine ring is formed in this example, the product is related to the antibacterial agent nalidixic acid. 5-Phenyl esters are useful in regioselectively directing a Dieckmann condensation of the diesters (70.6) to carbacephems. Dieckmann reactions usually requite heating but the enaminic ester (70.7) undergoes cyclization without external heat. 

One of the obstacles to designing the ring closure of the Dieckmann condensation is the regioselective control of the reaction. Although the condensation usually occurs in the direction that forms the most stable enolate, there are at least two possible products competing for formation if the starting diester is unsymmetrical. Naturally, if one of the a-carbons to the... 

Regioselective techniques were developed to direct the cyclization of unsymmetrical esters. An interesting example of this aspect of the Dieckmann condensation is the synthesis of ip-methylcarbapenems by Tanabe and co-workers, ip-methylcarbapenems is a structure that exists in potent and broad antibacterial compounds, such as meropenem and biapenem, which renders it synthetically interesting for the synthesis of some close analogues 30a-d. Thioesters 29 was subjected to cyclization under dehydration type Ti-Dieckmann condensation conditions 3.0 equivalents of the TiCU and 3.3 equivalents of the base BusN were used to give the vinyl... 

The dithiol ester version of the Dieckmann cyclization takes place under milder conditions than the classical reaction, which suggested that the half-thiol diesters should show regioselectivity in their condensation. This has indeed been found to be the case [equation (18)V Regioselectivity of ring closure of certain... 

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