Synthesis Of Tetracyclic Research Articles

Sequential Transformations to Access Polycyclic Chemotypes: Asymmetric Crotylation and Metal Carbenoid Reactions

All in order: Bicyclic and tricyclic chemotypes were accessed through the title transformations. By subsequent pairing of installed functional groups using Heck cyclization or [2+2] photocycloaddition, the synthesis of tetracycles, pentacycles, and condensed polycycles has been achieved with high stereochemical and skeletal variation.

Synthesis of Tetracyclic Indole‐Containing Ring Systems by Intramolecular Cycloadditions of Azomethine Ylides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

OXAZEPINES AND THIAZEPINES 39* SYNTHESIS OF TETRACYCLIC 1,5-BENZOTHIAZEPINES BY THE REACTION OF (Z)-3-ARYLIDENE-1-THIOFLAVANONES WITH 2-AMINOTHIOPHENOL

Article OXAZEPINES AND THIAZEPINES 39* SYNTHESIS OF TETRACYCLIC 1,5-BENZOTHIAZEPINES BY THE REACTION OF (Z)-3-ARYLIDENE-1-THIOFLAVANONES WITH 2-AMINOTHIOPHENOL was published on June 1, 2002 in the journal Heterocyclic Communications (volume 8, issue 3).

Studies on the synthesis of pectenotoxin II: synthesis of a C(11)-C(26) fragment precursor via [3 + 2]-annulation reactions of chiral allylsilanes.

[see reaction]. A synthesis of tetracycle 2 corresponding to the C(11)-C(26) fragment of pectenotoxin II is described. The synthesis features two highly stereoselective [3 + 2]-annulation reactions of chiral allylsilanes, generated via allylboration of aldehydes with the chiral gamma-silylallylborane 4 or the gamma-silylallylboronate 19, for construction of the highly substituted C and E rings.

Stereoselective Synthesis of over Two Million Compounds Having Structural Features Both Reminiscent of Natural Products and Compatible with Miniaturized Cell-Based Assays

Understanding the cellular function of a protein usually requires a means to alter the function. This is commonly done by mutating the gene encoding the protein (genetic approach). It can also be done by binding the protein directly with a small molecule ligand (chemical genetic approach). Such ligands, primarily natural products or synthetic variants of them, can either inactivate1 or activate2 protein function. For the chemical genetic approach to have its maximal impact, efficient methods of ligand discovery will be required to provide, in the limit, a small molecule partner for every gene product. Our laboratory has recently described miniaturized cell culture assays for screening large numbers of small molecule ligands, potentially on a genome-wide basis.3 However, despite its success in natural products synthesis, synthetic chemistry has not yet been applied to the synthesis of vast numbers of compounds with structures both reminiscent of natural products and compatible with miniaturized assays. These features of a synthesis will likely be required in order to discover nonnatural compounds having the binding affinities and specificities characteristic of natural products. The synthetic strategy we have undertaken is to develop highly efficient multistep syntheses of natural product-like compounds that include several coupling steps and to use split-pool techniques4 at these steps in order to generate diverse outcomes. This technique requires that one of the coupling substrates be immobilized on a solid support. Our syntheses are further constrained by the water-compatible photolabile supports required when carrying out large numbers (>105) of miniaturized “nanodroplet” cell culture assays aimed at identifying cell permeable ligands.3 This presents a considerable synthetic challenge since the structural elements that provide these properties (e.g., poly(ethylene glycol), nitrobenzyl moieties) are incompatible with numerous reagents used in conventional synthetic chemistry. With these considerations in mind, we first converted shikimic acid, 1, into both enantiomers of epoxycyclohexenol carboxylic acid 2,5 which were then coupled to a photocleavable linker on solid support by standard methods (Figure 1).6 Treatment of the resin-bound epoxycyclohexenol, 3, with various nitrone carboxylic acids,7 7a-f and 9b-d, under esterification conditions yielded tetracyclic compounds 4a-f and 5b-d with complete regioand stereoselectivity, presumably via tandem acylation/1,3-dipolar cycloaddition.8 No intermediate nitrone ester or carboxy isoxazolidine structures were observed. The iodoaryl tetracycles 4b-d and 5b-d were selected for further study since the supportbound aryl iodides could be modified with commercially available reagents, avoiding the need for solution-phase syntheses of numerous nitrone acids. Tetracycles 4b-d and 5b-d are rigid, densely functionalized compounds that can undergo further reactions to introduce a variety of functional groups around the central octahydrobenzisoxazole structure, notably, without the use of protecting groups. The iodoaryl groups can serve as substrates for palladium cross-coupling reactions. The electrophilic lactone and epoxide can react with nucleophiles while simultaneously unmasking alcohols for subsequent reactions. Furthermore, reductive N-O bond cleavage would provide two additional handles for functionalization. We developed several such reactions (Figure 2) with product purity ranging from ∼50 to g98% following photocleavage.9 Since purification is not practical in a large split-pool synthesis, only reactions generating products in g90% purity were acceptable. The most promising reactions were studied in detail to define the scope, limitations, and optimal conditions for each (Figure 3). Iodobenzyl tetracycles 4b-d were selected as scaffolds since (1) See http://www-schreiber.chem.harvard.edu on the Web. (2) Crabtree, G. R.; Schreiber, S. L. Trends in Biochem. Sci. 1996, 21, 418-422. (3) (a) Borchardt, A.; Liberles, S. D.; Biggar, S. R.; Crabtree, G. R.; Schreiber, S. L. Chem. Biol. 1997, 4, 961-968. (b) You, A. J.; Jackman, R. J.; Whitesides, G. M.; Schreiber, S. L. Chem. Biol. 1997, 4, 969-975. (4) (a) Furka, A.; Sebestyen, F.; Asgedom, M.; Dibo, G. Int. J. Pept. Protein Res. 1991, 37, 487-493. (b) Lam, K. S.; Salmon, S. E.; Hersh, E. M.; Hruby, V. J.; Kazmierski, W. M.; Knapp, R. J. Nature 1991, 354, 82-84. (5) (a) Wood, H. B.; Ganem, B. J. Am. Chem. Soc. 1990, 112, 89078909. (b) McGowan, D. A.; Berchtold, G. A. J. Org. Chem. 1981, 46, 23812383. (c) Mitsunobu, O. Synthesis 1981, 1-28. (6) The resin structure shown represents Tentagel S NH2, a poly(ethylene glycol)-polystyrene copolymer, loaded with a photocleavable 3-amino-3-onitrophenylpropionic acid linker. (Brown, B. B.; Wagner, D. S.; Geysen, H. M. Mol. DiV. 1995, 1, 4-12.). (7) Keirs, D.; Overton, K. Heterocycles 1989, 28, 841-848. (8) Tamura, O.; Okabe, T.; Yamaguchi, T.; Gotanda, K.; Noe, K.; Sakamoto, M. Tetrahedron 1995, 51, 107-118. (9) Photocleavage products were analyzed by 1H NMR, FAB-MS, HPLC, and TLC. Figure 1. Synthesis of tetracycles and nitrones. a: X ) H, b: X ) 2-I, c: X ) 3-I, d: X ) 4-I, e: X ) 4-CF3, f: X ) 3,4-(OMe)2.

A Facile Synthesis of Tetracycles of the γ-Lycorane Type

Abstract When an attempted application of the general scheme of alkaloid synthesis, based on the partial hydrogenation of 1 -alkyl-3-acylpyridinium salts and acid-induced cyclization of the resultant 2-piperideines,2 to the construction of an Amaryllidaceae alkaloid system failed in the cyclization step, i.e. the transformation of dihydroisoquinoline 4a (prepared by the treatment of ester 2a 3 with 5-bromo-2 -pentanone ethylene ketal, followed by hydrogenation of the salt over palladium-charcoal) into a tricyclic ketal ester,4 an alternate, route of synthesis still utilizing a previously prepared isoquinoline precursor (3b) was investigated. The initial observation of the easy conversion of 3b into N-methyl (1a) and O-ethyl products (2b) was helpful in this connection.