Sample-path optimization of convex stochastic performance functions

In this paper we propose a method for optimizing convex performance functions in stochastic systems. These functions can include expected performance in static systems and steady-state performance in discrete-event dynamic systems; they may be nonsmooth. The method is closely related to retrospective simulation optimization; it appears to overcome some limitations of stochastic approximation, which is often applied to such problems. We explain the method and give computational results for two classes of problems: tandem production lines with up to 50 machines, and stochastic PERT (Program Evaluation and Review Technique) problems with up to 70 nodes and 110 arcs. Sponsored by the National Science Foundation under grant number CCR-9109345, by the Air Force Systems Command, USAF, under grant numbers F49620-93-1-0068 and F49620-95-1-0222, by the U.S. Army Research Office under grant number DAAL03-92-G-0408, and by the U.S. Army Space and Strategic Defense Command under contract number DASG60-91-C-0144. The U.S. Government has certain rights in this material, and is authorized to reproduce and distribute reprints for Governmental purposes notwithstanding any copyright notation thereon. Sponsored by a Wisconsin/Hilldale Research Award, by the U.S. Army Space and Strategic Defense Command under contract number DASG60-91-C-0144, and the Air Force Systems Command, USAF, under grant number F49620-93-1-0068. Sponsored by the National Science Foundation under grant number DDM-9201813.     

Total synthesis of lucilactaene, a cell cycle inhibitor active in p53-inactive cells

Hetero-bis-metalated 1,3-butadiene is employed in the lynchpin coupling of synthetic fragments of the side chain of the antitumor agent, lucilactaene. Sequential Stille and Suzuki-Miyaura couplings interpolate this unique boron/tin diene into the pentaene chain. The total synthesis of lucilactaene was accomplished efficiently, in just eight linear steps.     

Large-scale synthesis of globotriose derivatives through recombinant E. coli

The carbohydrate chains decorating cell membranes and secreted proteins participate in a range of important biological processes. However, their ultimate significance and possible therapeutic potential have not been fully explored due to the lack of economical methods for their production. This study is an example of the use of a genetically engineered bacterial strain in the preparation of diverse oligosaccharides. Based on an ex vivo biosynthetic pathway, an artificial gene cluster was constructed by linking the genes of five associated enzymes on a plasmid vector. This plasmid was inserted into the E. coli NM522 strain to form globotriose-producing cells ('superbug' pLDR20-CKTUF). The specific strain was conveniently applied to the synthesis of globotriose trisaccharide and its derivatives, as potential neutralizers for Shiga toxin. This work demonstrates a novel and economical method for generating ligand diversity for carbohydrate drug development.     

Microgravimetric study of electrochemically controlled nucleophilic addition of sulfite to polyaniline

The sulfonation of polyaniline (PANI) films by nucleophilic addition of sulfite ion has been controlled through the polymer oxidation state under electrochemical control. The process was monitored by in situ electrochemical quartz crystal microbalance (EQCM), and the polymer oxidation was accomplished by electrode potential steps in sulfite aqueous solutions. The nucleophilic addition of sulfite to PANI only takes place on the oxidized polymer. From the ratio of added mass to the injected charge, the degree of sulfonation has been obtained with a yield as high as 50%. It has been observed that the ion-exchange mechanism during the oxidation-reduction process in the resulting sulfonated polymer is analogous to the polymer produced by electrophilic sulfonation of polyaniline or by copolymerization of aniline with aminosulfonic acids, unlike the ionic exchange observed for unmodified PANI.     

ResonanceRaman spectra of Iron(II) complexes with 4,4′-didodecyloxy-2,2′-bipyridine and 4,4′-dioctadecyloxy-2,2′-bipyridine

The resonanceRaman spectra of Fe(LC ₁₂)₃Cl₂ and Fe(LC ₁₈)₃Cl₂ (whereLC ₁₂ andLC ₁₈ denote 4,4′-didodecyloxy-2,2′-bipyridine and 4,4′-dioctadecyloxy-2,2′-bipyridine, respectively) have been measured along with their excitation profiles. The exciting lines of an Ar⁺ laser have been used. The bands appearing in theRR spectra within 1 200–1 600cm^?1 (expected to arise from thebipy moiety C-N and C-C vibrations) suffer the greatest resonance enhancements. Both depolarization ratios of theRaman bands and excitation profiles reveal the interaction of the resonant electronic states.     

Photochemical cleavage and release of carboxylic acids from alpha-keto amides

In aqueous media, alpha-keto amides LGCH(2)COCON(R)CH(R')CH(3) (1a, R = Et, R' = H; 1b, R = (i)()Pr, R' = Me; 1c, R = Ph, R' = H) with various carboxylate leaving groups (LG) at the C-3 position undergo photocleavage and release of carboxylic acids with formation of diastereomeric 5-hydroxyoxazolidin-4-ones 2a,c in the cases of 1a,c or 5-methyleneoxazolidin-4-ones 3b in the case of 1b. For 1a,b, Phi(photocleavage) = 0.24-0.38, whereas Phi(photocleavage) = ca. 0.05 for 1c. The proposed mechanism involves transfer of hydrogen from an N-alkyl group to the keto oxygen to produce zwitterionic intermediates 4a-c that eliminate carboxylate anions. The resultant imminium ions, H(2)C=C(OH)CON(+)(R)=C(R')CH(3) 5a-c, cyclize intramolecularly to 3b or undergo intermolecular addition of water followed by tautomerization and cyclization to give 2a,c. These inter- or intramolecular trapping reactions of 5 release protons that decrease the pH and cause bleaching of the 620 nm band of the pH indicator, bromocresol green. Determination of the bleaching kinetics by laser flash photolysis methods in the case of 1a gives time constants of 18-137 mus, depending on the leaving group ability of the carboxylate anion, whereas amides 1b show only a small leaving group effect. For 1a, the large leaving group effect is consistent with rate-limiting carboxylate elimination from 4a, whereas the proton release step would be largely rate determining for 1b. Photolyses of 1a (LG = CH(3)CO(2)(-), PhCH(2)CO(2)(-)) in neat CH(3)CN results in carboxylate elimination to form imminium ion 5a, followed by internal return to give aminals.     

Proton affinity of β-oxalylaminoalanine (BOAA): Incorporation of direct entropy correction into the single-reference kinetic method

A new version of the single-reference-extended kinetic method is presented in which direct entropy correction is incorporated. Results of calibration experiments with the monodentate base pyridine and the bidentate base ethylenediamine are presented for which the method provides proton affinities in excellent agreement with published values and reasonable predictions for the protonation entropies. The method is then used to determine the proton affinity and protonation entropy of the non-protein amino acid beta-oxalylaminoalanine (BOAA). The PA of BOAA is found to be 933.1 +/- 7.8 kJ/mol and a prediction for the protonation entropy of -39 J mol(-1) K(-1) is also obtained, indicating a significant degree of intramolecular hydrogen bonding in the protonated form. These results are supported by hybrid density functional theory calculations at the B3LYP/6-311++G**//B3LYP/6-31+G* level. They indicate that the preferred site of protonation is the alpha-nitrogen atom (PA = 935.0 kJ/mol) and that protonated BOAA has a strong hydrogen bond between the hydrogen on the alpha-amino group and one of the carbonyl oxygen atoms on the side chain.     

Total synthesis of erythromycin B

We report the details of the first total synthesis of erythromycin B using two different strategies for the end game. The first of these follows a classical approach in which the desosamine and cladinose residues are sequentially appended to a macrocyclic lactone, which was formed by cyclization of a seco acid derivative, to give a bis-glycosylated macrolide intermediate that is converted into erythromycin B. The second strategy features an abiotic approach in which a seco acid bearing a desosamine residue is cyclized to give a monoglycosylated macrocyclic lactone that is then transformed into erythromycin B via a sequence of steps involving refunctionalizations and a glycosylation to introduce the cladinose moiety. Attempts to prepare a bis-glycosylated seco acid by de novo synthesis were unsuccessful. The syntheses of the key seco acid intermediates feature the oxidative transformation of a furan containing C(3)-C(10) to provide a dioxabicyclo[3.3.1]nonenone that served as a template on which to create the stereocenters at C(6) and C(8). A stereoselective aldol reaction was used to establish the C(11)-C(15) segment, and a stereoselective crotylation was implemented to introduce the propionate subunit comprising C(1)-C(2).