Conformational restriction cyclization

In most cases, pyrazino[l,2- ]pyrazines have been synthesized as highly saturated derivatives with the aim of preparing conformationally restricted compounds which mimic the secondary structure of reverse-turn regions of peptides and proteins. The saturated pyrazino[l,2- ]pyrazine 241 was synthesized from readily available starting materials, the key steps being the preparation of the keto amide 239 and subsequent tandem cyclizations from [6+0] atom fragments (Scheme 42) <20000L301>. 

Alternatively, if the dehydroamino acid is C-terminal or is central in the peptide chain, then the oxazolone precursor to the dehydropeptide must be in position two in order to apply this methodology (Scheme 7.165). The requisite unsaturated 5(4//)-oxazolone intermediate 518 is obtained from the appropriate precursors following standard cyclization procedures and avoiding experimental conditions that would epimerize the chiral center. This methodology has been applied to access analogues of important peptides including dehydroaspartame, somatostatin, and dermorphin. In these cases, a dehydroamino acid was incorporated into the peptide backbone to study the relationship between conformational restriction and biological properties of the modified peptide. 

A series of conformationally restricted analogues of nicotine and anabasine have been prepared as part of a program studying models of Parkinson s disease and pain (Scheme 8). Transformations of the heterocyclic ketone were key to the program, including cyclization to a third heterocyclic ring <1998BML2173>. 

Moeller has more recently contributed a series of reports describing the further use of this reaction in synthesis. Oxidation of the unsaturated amide 71 in methanolic acetonitrile afforded a substance 72 (equation 37) which could subsequently be converted into conformationally restricted peptide mimics99. Further, anodic oxidation of 73 resulted in intramolecular cyclization to afford 74 (equation 38), which could be converted into bicyclic reverse-turn peptidomimetics100. A similar intramolecular anodic cyclization of 75 into 76 (equation 39) was employed as the key step in total syntheses of the natural products (—)-A58365A and (+)-A58365B101. 

West et al. subsequently studied a number of conformationally restricted carbocy-clic acetals 298a-c with respect to their behavior in copper-catalyzed oxonium ylide cyclization/[ 1,2]-rearrangement reactions. 5-6-Bicyclic acetals 298a underwent the... 

Our studies with cyclic and acyclic diaminoketones provide useful examples of the impact of conformational constraint on inhibitory potency. Tabs. 5.1 and 5.2 show two analogue series that highlight the sometimes dramatic effects that cyclization can have. This modification can have equally dramatic effects on pharmacokinetic properties of the molecules as well. Conformationally restricted analogues have long been a goal of medicinal chemistry efforts such as the one reviewed here. Only recently has sufficient pharmacokinetic data become available to reveal the critical importance of constraint, in the form of reduced rotatable bond count, for improving oral bioavailability [5] as has been seen with compound (Fig. 5.4e) [19]. 

Toniolo C. Conformationally restricted peptides through short-range cyclizations. Int. J. Pept. Protein Res. 1990 35 287-300. 

The work of Veber et al. established that valuable information about the bioactive conformation of a flexible peptide could be obtained by applying the principles of conformational restriction, and several additional examples soon were reported that followed this strategy. Conformationally restricted enkephalin analogs, e.g., 02-13), were formed by cyclizing between positions 2 and 5 of enkephalins (4a-b) (39). Cyclization of a-mela-notropin (14) gave the unusually active analog... 

Transannular cyclization of ketoalkenes was first reported in 1965. Treatment of the conformationally restricted ketone (104) with sodium in moist ether gave the alcohol (105 equation 127). Similarly the ketoalkene (106) transannulated in 73% yield by exposure to sodium in refluxing propanol (equation 128). Conformational restriction is not a prerequisite for transannular reaction thus the caryophyllene (107) undergoes cyclization to the alcohol (108) with lithium in liquid ammonia (equation 129). Transannulation across a nine-membered ring has also been observed upon treatment of ketone (109 equation 130) with samarium diiodide, via cyclization of the ketoalkene (110). Of more practical importance, the electrochemical transannulation of the cyclooct-4-en-l-one gives the bicyclo[3.3.0]octanol (111 equation 131). ... 

The Jacobson-Stockmayer cyclization theory is based on the assumption that all rings are strainless and that the conformational probability of ring closure is given by Eq. 3-2, i.e. conformational restrictions or preferences are absent. This assumption apparently cannot be fulfilled in real systems for small rings (as shown in Sect. 3.2.2). In some systems this leads to a lowering of the concentration of cydics when compared with their equilibrium concentration. This is because the probability of small ring closure is reduced due to the strain caused not only by bond angle deformation but also by bond opposition and transannular interactions. In such a case, as in the discussed earlier l,3-dioxolane-BF3 system, the concentration of small cycles (up to 25-30 bonds) is lower than the calculated one 141... 

G. A. Flynn, E. L. Giroux, and R. C. Dage,/. Am. Chem. Soc., 109, 7914 (1987). An Acyl-Iminium Ion Cyclization Route to a Novel Conformationally Restricted Dipeptide Mimic Applications to Angiotensin-Converting Enzyme Inhibition. 

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