Butyrolactams formation

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. 

The first-generation synthesis of levetiracetam (3), as shown in Scheme 14.9 [29], starts with benzoyl protection and oxidation of (S)-aminobutanol (32), which gives rise to the corresponding N-benzoyl protected (S)-aminobutyric acid (33). After N-benzoyl amidation and deprotection, (S)-aminobutyramide (34) is obtained. Chemoselective butyrolactam ring formation using the intermediate 34 and 4-chlorobutyryl chloride finally affords levetiracetam (3). 

In combination with the incremental advances concerning reaction conditions in recent years, especially for low-pressure carbonylations, there is a trend toward increasing use of this chemistry to synthesize advanced building blocks. In this respect carboxylation of alkenes with an appropriate alcohol or amine function leads to the formation of lactones or lactams. Thus, cobalt, rhodium, or palladium chloride/copper chloride catalysts convert allyl and homoallyl alcohols or amines to the corresponding butyrolactones or butyrolactams, respectively [15]. 

The amides used were either reagent or spectrograde chemicals. Reagent grade urea was recrystallized and solutions were made just prior to use to reduce cyanate formation. Substituted ureas were either recrystallized or distilled. Butyrolactam and caprolactam were respectively distilled and recrystallized. All compounds were checked to assure their dryness. Water for use in solution preparation was deionized prior to distillation from a glass still. The solutions used for a typical experiment were a series of four to six equal volume dilutions wherein weight was recorded in addition to volume so that molalities could be calculated. Dilution studies were made in duplicate or triplicate except for the substituted ureas for which twenty to thirty runs were made. The measured heats, q, ranged from 3 jucal s" to 2.0x 10 jucal s" and each determination required about 3 ml of sample. The reproducibility of the measured heats was +20% at 3 cal s S +10% at 10 jucal s" 2% at 50 /ical s and 1% above 50 jucal s . ... 

Murai and Chatani extend the method from aromatic imines to , -unsaturated imines in 2002. Very interestingly, no formation of the anticipated cyclopen-tadienones was detected, yet, y-unsaturated y-butyrolactams were formed (Table 15.6) [11]. 

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