Constrained bicyclic structures

The discovery of the norcardicins and monobactams demonstrated for the first time that a conformationally constrained bicyclic structure was not necessary for antibacterial activity of (3-lactams [12, 13]. In recent years, various natural and unnatural monocyclic-(3-lactams have been shown to exhibit high biological activity, suggesting that the biological activity of the particular ring is influenced by the type of substitution attached to the azetidin-2-one ring (Fig. 2). 

The structure of 19 was established by X-ray crystallography. It shows a short Fe-C(phenyl) a-bond (2.04 ) when compared to that found in (p5-Cp)Fe(C0)(PPh3>(n -C6H5) (2.14A) (10) and the shortest P-Fe bond observed so far (2.105/1) which may arise from a high Tr-accepting capability and/or a small cone-angle of the constrained bicyclic ligand (11). 

The bicyclic structure (I) (Fig. 7.34) contains one of the side-chain bonds fixed in a ring to prevent rotation round that bond. It was found that this gave a dramatic improvement in activity. The compound was still not active in man, but unlike mirasan, it was active in monkeys. This gave hope that the chemists were on the right track. Further rigidification led to structure II (Fig. 7.34) where two of the side-chain bonds were constrained. This compound showed even more activity in mouse studies and it was decided to concentrate on this compound. 

A different photochemical reaction of 499 leading to bicyclic structure 500 has been observed [72JCS(CC)867]. In contrast, other constrained bicyclic azoxy compounds lacking the cross-ring nitrogen atoms, which are present in 499, do not react in this way. 

Recent patent disclosures reveal efforts to optimize within this template. The amide moiety has been cyclized to give dihydroisoquinolone inhibitors such as 9 and 10 [57]. Using various mono- and bicyclic core structure scaffolds, the amide has also been constrained in isoquinolone,... 

Interestingly, chloropalladation reaction of the more constrained cu-7-methylenebicy-clo[4.1.0]heptane did not afford the expected dis-in kinetic product but rather the rearranged to >/ to rf ) thermodynamic isomer whose structure (as the acac mononuclear complex) was confirmed by X-ray crystallographic analysis (equation 327)394. More recently, 1-aryl-substituted derivatives of this bicyclic methylenecyclopropane (equation... 

The most abundant and widely used monoterpenes, pinenes and their analogues, are often upgraded to more sophisticated structures with a Robinson annelation as the key step. However, as a result of unusual stereochemical constrains imposed by the bicyclic ring, only certain conformational isomers of the pinane skeleton undergo the annelation. Whereas the diketone (41) derived from n. v-inethylnopinone cyclized satisfactorily to the tricyclic ketone under Robinson conditions (Scheme 5.18), the epimeric diketone would not.64... 

Conformational restriction has also been used to determine the bioactive conformation of enzyme-inhibitor systems for which no X-ray crystal structure is available. Thorsett et al. (49) synthesized conformationally restricted bicyclic lactam derivatives of the angiotensin converting enzyme (ACE)inhibitors enalapril (20) and enalaprilat (21) (Fig. 15.9) to characterize torsion angles in the bioactive conformation. Analog (22) was used to constrain the torsion angle psi (T ). Flynn et al. 

Although sertraline appears to differ structurally from the other SSRIs, it is a phenylaminotetralin, in which the diphenylpropylamine nucleus is constrained into a rigid bicyclic ring system (Fig. 21.13). In the early work with the discovery of SSRIs at Pfizer, tametraline was initially synthesized in 1978. Animal studies showed it to be a stimulant and to block NE and DA uptake, a use that Pfizer was not interested in pursuing. Subsequently, one or two chlorine atoms were introduced into tametraline to produce new molecules that were potent inhibitors of 5-HT reuptake in the brain. One of the dichloro compounds was to become known as sertraline. 

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