Peter A. Jacobi

Toward a General Synthesis of Chlorins

Recently, we described a new synthesis of C,D-ring symmetric chlorins 11, involving 2 + 2 condensation of bis-formyl-dihydrodipyrrins 9 with symmetrically substituted dipyrromethane diacids 10 (Method I). However, while versatile in many aspects, Method I was unsuited to the broader goal of synthesizing fully non-symmetric chlorins of general structure 15, which requires regioselective control over the reacting centers in the A,B- and C,D-ring components. In this paper, we describe four new 2 + 2 strategies that accomplish this differentiation (Methods II-V). Of these, Method V, which combines operational simplicity with moderate to high product yields, proved to be the most effective route, exploiting reactivity differences between the two formyl groups of A,B-rings 9 to impart excellent regioselectivity. Methods II-IV are also useful alternatives to Method V, although in some cases, the appropriately functionalized precursors are less readily available. All four approaches generate single regioisomers of diversely substituted chlorins, and in every case, the 2 + 2 condensation is accomplished in a simple, one-flask procedure without need for additives such as oxidizing agents or metals. Taken together, these methodologies provide expanded access to an array of chlorins for SAR studies that may advance the effectiveness of PDT and other applications.

The binding of analogs of porphyrins and chlorins with elongated side chains to albumin

In previous studies, we demonstrated that elongation of side chains of several sensitizers endowed them with higher affinity for artificial and natural membranes and caused their deeper localization in membranes. In the present study, we employed eight hematoporphyrin and protoporphyrin analogs and four groups containing three chlorin analogs each, all synthesized with variable numbers of methylenes in their alkyl carboxylic chains. We show that these tetrapyrroles’ affinity for bovine serum albumin (BSA) and their localization in the binding site are also modulated by chain lengths. The binding constants of the hematoporphyrins and protoporphyrins to BSA increased as the number of methylenes was increased. The binding of the chlorins depended on the substitution at the meso position opposite to the chains. The quenching of the sensitizers’ florescence by external iodide ions decreased as the side chains became longer, indicating to deeper insertion of the molecules into the BSA binding pocket. To corroborate this conclusion, we studied the efficiency of photodamage caused to tryptophan in BSA upon illumination of the bound sensitizers. The efficiency was found to depend on the side-chain lengths of the photosensitizer. We conclude that the protein site that hosts these sensitizers accommodates different analogs at positions that differ slightly from each other. These differences are manifested in the ease of access of iodide from the external aqueous phase, and in the proximity of the photosensitizers to the tryptophan. In the course of this study, we developed the kinetic equations that have to be employed when the sensitizer itself is being destroyed.

Toward the Synthesis of Cobyric Acid. Enantioselective Syntheses of Completely Differentiated Ring D Synthons

Alkyne acids 11 were prepared in an enantioselective fashion from allylic ester derivatives 18 or 20 by Ireland-Claisen rearrangement, followed by Si-assisted elimination of HBr. The title compounds are attractive ring D synthons for an ongoing synthesis of cobyric acid.

Constructing the Heterocyclic Core of Viridin and Wortmannin

Abstract The furanosteroids are a class of novel fungal metabolites, several of which are potent inhibitors of phosphatidylinositol 3-kinase (PI-3 kinase), an enzyme that plays a key role in the life cycle of cells. The inhibitory activity of these compounds stems from their ability to selectively block certain intracellular signaling pathways, in particular those associated with cell growth and development. As such they hold promise as a new class of therapeutic agents for diseases characterized by rapid cell proliferation, as is the case in cancer. However, the known members of this class are far too toxic and nonselective for development as antitumor agents. Because of this there is intense interest in developing new synthetic pathways to both the naturally occurring compounds, and simpler analogs, in order to better evaluate structure-activity relationships. This chapter outlines a concise synthetic approach to the furanosteroid skeleton that should apply equally well to preparing the biologically important natural products as well as structural analogs.

Synthesis of an Advanced Precursor of Demethoxyviridin

Abstract The synthesis of a potential precursor 3 to demethoxyviridin (1b) is described. The centerpiece of this strategy was the conversion of the previously described dibromoolefin 6 to the masked alkyne β-hydroxyaldehyde 5 in a single step. Further elaboration then produced the alkyne oxazole 4, which on thermolysis, followed by in situ tautomerization and silylation, led directly to 3. Supplementary materials are available for this article. Go to the publishers online edition of Synthetic Communications® for full experimental and spectral details. GRAPHICAL ABSTRACT

An improved synthesis of a ring-C precursor to cobyric acid

Alkyne acid 10 was prepared in enantioselective fashion from allylic ester derivative (R)-18 via an E-selective Ireland-Claisen rearrangement followed by Si-assisted elimination of HBr. The present route offers significant advantages in terms of both scalability and overall yield compared to that previously described. Alkyne acid 10 is an attractive ring-C precursor for an ongoing synthesis of cobyric acid.

On the Methylation of Carboxyl Groups with Methanesulfonyl Chloride in Pyridine

In a recent article Siddiqui et al. described a novel conversion of carboxylic acids to methyl esters, employing the reagent system methanesulfonyl chloride (MsCl) in pyridine at 0 C (Fig. 1). This work caught our attention because of the unusual use of MsCl as an electrophilic methyl group equivalent. As precedent for this transformation the authors cite a article by Nicolaou et al., in which hindered carboxylic acids were treated at 0 C with MsCl/NEt3 followed by diazomethane. [2] However, in the Nicolaou studies methyl esters were formed as byproducts in the synthesis of a-diazoketones from acyl mesylates, by a