Bridgehead lactams

Using intramolecular Diels-Alder reactions, Lease and Shea130 have prepared a series of bridgehead olefins, which at the same time are bridgehead lactams with the nitrogen atom at the other bridgehead (30). In these, the C=C double bond and the amide bond are subject to the same kind of distortion. The distortions decrease in the series 30a-30c. 

The goal of generating a plot of distortion energy versus geometric distortion parameters for amides based upon experimental and/or high-level calculational data (e.g. Figure 1) has yet to be achieved. X-ray structures for bridgehead lactams 17-24 [13,40,48-50] and for some distorted acyclic amides [41] have been published. While there are numerous published X-ray structures for beta-lactams, 1,3-diadamantyl derivative 25 [51] is the only such alpha-lactam. 

Thanks to quinicine 3 and cinchonicine 4 Pasteur achieved the first separation of racemic tartaric acid. This resolution is considered a milestone in organic chemistry. Conversely, the transformation of quinotoxine 3 into quinine in three steps is part of the (formal) Rabe-Kindler/Woodward-Doering synthesis of quinine as has recently been reaffirmed by R.M. Williams and his group (cf. Section 11.5.3). Meroquinene ester 7 is a 3,4-disubstituted piperidine formed from quininone 5 (cinchoninone) and base in the presence of 302. In this reaction, an activated bridgehead lactam is a key intermediate that is opened by KOBu1. Three stereocenters are lost and only two stereocenters survive in the course of this transformation (Scheme 12.3) [4]. 

A series of bridgehead lactam bicydics has been prepared from rubanone. The sensitive parent lactam has also been generated. 

Ethyl chloroformate/triethylamine Expansion of N,N-heterocycles via bridgehead lactams Elimination of N-methylene bridges... 

The intramolecular Schmidt reaction has provided a solution to the problem of bridgehead lactam synthesis. The bridged lactams incorporate a twisted amide unable to achieve standard planar geometry and can undergo rapid hydrolysis. Reaction of ketoazide with HBF4 in ether results in a mixture of two latams from which the desired quinoclidone 92 is isolated in 38% yield after recrystalization. ... 

A novel method for the expansion of N,N-heterocycles through bridgehead lactams has been reported . The rearrangement of cyclopropyliniines to pyrrolines opens new routes to alkaloids with 3-arylpyrrolidine units such as the tobacco alkaloid myosmine Variations in temp., solvent, or pH are sufficient to alter the ring system of amaryllidaceae alkaloids so that skeletal interconversions can be achieved under mild conditions... 

Similarly a marked increase of regioselectivity has been shown in the catalyzed Diels-Alder reactions of the chiral bicyclic lactame 24 (Scheme 3.9) with a variety of dienes [27] (isoprene, mircene, (E,E)-L4-dimethylbutadiene, 2,3-di-methylbutadiene, 2-siloxybutadiene). The catalyzed reactions were more regio-selective and totally enJo-antz-diastereoselective anti with respect to the bridgehead methyl group). The results of the cycloadditions with isoprene and mircene are reported in Scheme 3.9. The cycloadducts have then been used to provide interesting fused carbocycles [28] with high enantiomeric purity as shown in Scheme 3.10. 

Lactam sulfonium salts bearing a dihydrothiopyran skeleton with a sulfonio bridgehead have been synthesized. Tricyclic benzothiazinium salts 87 were prepared by [4+2+]-polar cycloaddition of a thionium intermediate 99, generated from the corresponding a-chloro sulfide 98, in the presence of silver perchlorate in moderate to good yields (see Equation (28) and Table 17) <1997J(P1)309>. Cycloaddition with isoprene 41b gave adducts 87b and 87c as a... 

The asymmetric synthesis of (+)-Codeine 432 devised by White and colleagues included a Beckmann rearrangement to introduce the nitrogen atom in the carbocyclic structure (equation 182). Even though two isomeric lactams 430 and 431 were obtained as a result of the rearrangement, the preferential migration of the bridgehead carbon atom produced 430 as the predominant isomer. The synthesis of the non-natural enantiomer of Codeine was completed after oxidation, olefin formation and reduction. 

The bicyclic peptides that have been synthesized with at least one lactam ring correspond to the structures shown in Scheme 22, and examples of such syntheses of homodetic or mixed homodetic/heterodetic structures are listed in Table 12. For bicyclic or polycyclic cystine peptides see Sections 6.1 and 6.2. In the ring structures of types I-III both rings derive from side-chain-to-side-chain cyclizations. In the structures of types IV-VI an cofunctionalized amino acid is employed as bridgehead. This can be linked directly to three... 

Tricyclic P-lactams not having a bridgehead nitrogen atom have been obtained by intramolecular Friedel-Crafls reactions <99T5567> and from the intramolecular Diels-Alder reactions of 1,3-dienes generated from a mesylate 79 <99TL1015>. Other tricyclic P-lactams e.g., 80 have been obtained by intramolecular nitrone-alkene cycloaddition <99TL5391>. 

The presence of the double bond, which differentiates penems from penams, allows enamine resonance which renders the bridgehead nitrogen atom less basic and weakens the C(7)-N(4) bond, and hence facilitates /3-lactam hydrolysis. As a consequence, they are more labile than the penams, and such instability issues narrow the range of chemical reactivity of the penem skeleton. 

The strain at the carbon of the carbonyl group in fused bicyclic /3-lactams having a bridgehead nitrogen atom and different sizes of the fused ring can be seen from the effect on the 13C chemical shift of that atom (Table 2) <2004EJ04840>. 

The /3-lactam 84 with a bridgehead nitrogen atom is isomerized in the presence of base to its stereoisomer 85 and to a rearranged tricyclic /3-lactam 86 without a bridgehead atom in 34% and 61% yield, respectively (Equation 8). A mechanism for the process is proposed <2004EJO4397>. 

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