Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthdayThe N,O-acetal and N,O-ketal derivatives (oxazolidinones) formed from proline, and aldehydes or ketones are well-known today, and they are detectable in reaction mixtures involving proline catalysis, where they have been considered parasitic dead ends . We disclose results of experiments performed in the early 1970 s, and we describe more recent findings about the isolation, characterization, and reactions of the oxazolidinone derived from proline and cyclohexanone. This oxazolidinone reacts (THF, room temperature) with the electrophiles b-nitrostyrene and chloral (¼ trichloroacetaldehyde), to give the Michael and aldol adduct, respectively, after aqueous workup (Scheme 5). The reactions occur even at À 758 when catalyzed with bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or EtN(i-Pr) 2 (DIPEA) (10%; Table 1). It is shown by NMR (Figs. 1 and 3) and IR analysis (Figs. 2 and 4) that the primarily detectable product (before hydrolysis) of the reaction with the nitro-olefin is again an oxazolidinone. When dissolved in hydroxylic solvents such as MeOH, hexafluoroisopropanol ((CF 3 ) 2 CHOH; HFIP), AcOH, CF 3 COOH, or in LiBr-saturated THF, the ring of the oxazolidinone from cyclohexanone and proline opens up to the corresponding iminium ion (Tables 2 -4), and when treated with strong bases such as DBU (in (D 8 )THF) the enamino-carboxylate derived from proline and cyclohexanone is formed (Scheme 8). Thus, the two hitherto putative participants (iminium ion and enamine) of the catalytic cycle (Scheme 9) have been characterized for the first time. The commonly accepted mechanism of the stereoselective C,C-or C,X-bond-forming step (i.e., A -D) of this cycle is discussed and challenged by thoughts about an alternative model with a pivotal role of oxazolidinones in the regio-and diastereoselective formation of the intermediate enamino acid (by elimination) and in the subsequent reaction with an electrophile (by trans-addition with lactonization; Schemes 11 -14). The stereochemical bias between endo-and exo-space of the bicyclo[3.3.0]octane-type oxazolidinone structure (Figs. 5 and 6) is considered to possibly be decisive for the stereochemical course of events.Helvetica Chimica Acta -Vol. 90 (2007) Finally, the remarkable consistency, with which the diastereotopic Re-face of the double bond of pyrrolidino-enamines (derived from proline) is attacked by electrophiles (Schemes 1 and 15), and the likewise consistent reversal to the Si-face with bulky (Aryl) 2 C-substituents on the pyrrolidine ring (Scheme 16) are discussed by invoking stereoelectronic assistance from the lone pair of pyramidalized enamine N-atoms.1. Introduction. -We would hardly have considered to become engaged in the timely research area of organocatalysis , had not, in the recent literature, the name of one of the present authors (D. S.) been implied in a statement on the mechanism of the stereoselection in proline catalysis (see title) such that this author was incited to ...

A genetic algorithms (GA) based strategy is described for the identification or optimization of active leads. This approach does not require the synthesis and evaluation of huge libraries. Instead it involves iterative generations of smaller sample sets, which are assayed, and the “experimentally” determined biological response is used as an input for GA to rapidly find better leads. The GA described here has been applied to the identification of potent and selective stromelysin substrates from a combinatorial-based population of 206 or 64 000 000 possible hexapeptides. Using GA, we have synthesized less then 300 unique immobilized peptides in a total of five generations to achieve this end. The results show that each successive generation provided better and unique substrates. An additional strategy of utilizing the knowledge gained in each generation in a spin-off SAR activity is described here. Sequences from the first generations were evaluated for stromelysin and collagenase activity to identify stromelysin-selective substrates. GlyProSerThr-TyrThr with Tyr as the P1‘ residue is such an example. A number of peptides replacing Tyr with unusual monomers were synthesized and evaluated as stromelysin substrates. This led to the identification of Ser(OBn) as the best and most selective P1‘ residue for stromelysin.

A series of eight antiviral compounds complexed with human rhinovirus 14 (HRV-14) were previously shown to displace segments of polypeptide chains in the floor of the "canyon" by as much as 0.45 nm in C-alpha positions from the native conformation (J. Badger, I.

We demonstrate the use of a genetic algorithm (GA) search procedure for finding low-energy conformations of small to medium organic molecules (1-12 rotatable bonds). GAS are in a class of biologically motivated optimization methods that evolve a population of individuals where individuals who are more "fit" have a higher probability of surviving into subsequent generations. Here, an individual is a conformation of a given molecule and the fitness is the molecule's conformational energy. In the course of a simulated evolution, the population produces conformations having increasingly lower energy. We test the GA method on a suite of 72 molecules and compare the performance against the CSEARCH algorithm in Sybyl. For molecules with more than eight rotatable bonds, the GA method is more efficient computationally and as the number of rotatable bonds increases the relative efficiency of the GA method grows. The GA method also found energies equal to or lower than the energy of the relaxed crystal structure in the large majority of cases. 0 1993 by John Wiley i 3 Sons, Inc.

Summary.A detailed study of the reaction of catharanthine N-oxide and vindoline has been carried out employing various conditions. Under optimum conditions, which involve low temperatures and trifluoroacetic anhydride as reagent, 3', 4'-dehydrovinblastine (XIII, R = COOCHs), in reasonable yields is essentially the exclusive product. However two additional products, 18'(efii)-3', 4'-dehydrovinblastine (XIV, R = COOCH3) and 1'-hydroxy-3', 4'-dehydrovinblastine (XVI, R = COOCH,) are also often isolated.The reaction, which follows the course of a Polonovski-type fragmentation process, has been extended to the N-oxide derivatives of dihydrocatharanthine and decarbomethoxycatharanthine to provide again a series of bisindole alkaloid derivatives, also vinblastines. A mechanistic rationale is provided to explain the various results obtained. The wealth of structural diversity [3a] and clinical importance [3b] [4] of theCatharanthus alkaloids continues to provide a challenge for devising a general synthetic approach to them. In [a] we provided a detailed discussion of the use of chloroindolenine intermediates for the synthesis of the bisindole alkaloids in the vinblastine (I) series. We now present results relating to a completely different synthetic approach. OH I, R = COOCH3 1) 2)Part VIII, see [Z].For a preliminary report on a portion of this work, see [ I ;