Allene-based approach to the synthesis of De Novo erythromycinoids

We prepared an advanced synthetic module (bis[allene] macrolactone at center) equipped with two allenes embedded in a macrolactone scaffold. The plan was to effect heterogeneous derivatization of the allenes, in tandem or separately. In addition to diversity, this approach is maximally concise and economic, especially in terms of steps. Moreover, immediate derivatives of the macrocyclic bis[allene] can be taken into further steps, thus providing canonical build-up of erythromycin analogs. To date, our bis[allene] macrolactone has been converted to over 30 novel macrolides. These de novo analogs serve to validate the strategy and lay the ground work for further work. Taken together, the allene-based reactions/transformations employed in this study, such as DMDO oxidation/nucleophile addition, allene osmylation/electrophile addition, bromination, allene oxide rearrangement, spirodiepoxide rearrangement, benzylic migration/elimination, mono- and bis-oxidation of bis[allene], chelation-controlled reduction and oxime formation, demonstrate that 8 of the 11 modifiable carbons in this antibiotic can be modified. It is especially noteworthy that each congener was made in less than three steps from the bis[allene] macrolactone.Ph. D.Includes bibliographical referencesIncludes vitaby Hiyun Ki

Hidden Markov Model Analysis of Multichromophore Photobleaching

The interpretation of single-molecule measurements is greatly complicated by the presence of multiple fluorescent labels. However, many molecular systems of interest consist of multiple interacting components. We investigate this issue using multiply labeled dextran polymers that we intentionally photobleach to the background on a single-molecule basis. Hidden Markov models allow for unsupervised analysis of the data to determine the number of fluorescent subunits involved in the fluorescence intermittency of the 6-carboxytetramethylrhodamine labels by counting the discrete steps in fluorescence intensity. The Bayes information criterion allows us to distinguish between hidden Markov models that differ by the number of states, that is, the number of fluorescent molecules. We determine information-theoretical limits and show via Monte Carlo simulations that the hidden Markov model analysis approaches these theoretical limits. This technique has resolving power of one fluorescing unit up to as many as 30 fluorescent dyes with the appropriate choice of dye and adequate detection capability. We discuss the general utility of this method for determining aggregation-state distributions as could appear in many biologically important systems and its adaptability to general photometric experiments