Total synthesis of lasonolide a university of illinois. Synthesis of zaragozic acid asqualestatin s1 nicolaou. The carbonyl ylide precursor 8 was synthesized starting from di. Squalene synthase catalyzes the first committed step in cholesterol synthesis, mediating the reductive dimerization of farnesyl pyrophosphate item no. The molecular skeleton is formed using the first examples of two critical construction reactions. Carreira zaragozic acid c, evans zaragozic acid c, and nicolaou zaragozic acid a, just two years after the first publications on structure elucidation appeared. Total synthesis of lactacystin and zaragozic acid c using photochemical csp3h functionalization. The core biosynthetic route is via a polyketide synthase pathway from 10 acetates, 4 methyls of methionines, 1 succinate, and 1 benzoic acid. Key steps are an acidmediated acetonide deprotectiondithiane removalketalisation. The target molecules can be natural products, medicinally important active. The zaragozic acids, exemplified by zaragozic acid c 3, are picomolar inhibitors of cholesterol biosynthesis. Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially available precursors. Key steps of this synthesis include an intramolecular oxidative coupling of ketone and malonic ester enolates and an azacope. Total synthesis of zaragozic acid asqualestatin s1 nicolaou.
Sorensen classics in total synthesis targets, strategies, methods this book is a must for every synthetic organic chemist. Total synthesis of zaragozic acid c by an aldolbased. Key steps are an acid mediated acetonide deprotectiondithiane removalketalisation. Stepbystep synthesis recipes with extensive detail are given for more recipes than any other book in existance. A total synthesis of zaragozic acid c by a convergent strategy is described in which the key features include 1 the simultaneous creation of the c4 and c5 quaternary stereogenic centers by a snotf 2promoted aldol coupling reaction between an. Fermentative production, productivity of f10863s and mycological. Holton and his group at florida state university in 1994 was the first total synthesis of taxol generic name. A total synthesis of zaragozic acid c by a convergent strategy is described in which the key features include 1 the simultaneous creation of the c4 and c5 quaternary stereogenic centers by a sn. It usually refers to a process not involving the aid of biological processes, which distinguishes it from semisynthesis.
Zaragozic acid c is an inhibitor of mammalian squalene synthase. Stereoselective total synthesis of zaragozic acid a based. The key transformations include an efficient tandem nallylations n 2. Zaragozic acid c 1 was isolated as a potent squalene synthase inhibitor. Development of synthetic strategies for densely oxygenated natural products. Fragment 5, representing the tricarboxylic acid core portion, is assembled in three key steps. Selfconsistent synthesis of the squalene synthase inhibitor.
Complete schematic view of the 1954 lysergic acid s synthesis performed by robert b. Classics in total synthesis was first in the series by nicolaou, and arguably the best, covering many of the landmark syntheses by big names like corey. Jun 18, 2008 the first total synthesis of actinophyllic acid 1 is reported. Step by step the first total synthesis was approached. Binding modes of zaragozic acid a to human squalene synthase. The holton taxol total synthesis is a good example of a linear synthesis starting from commercially available natural compound patchoulene oxide. The longest linear sequence from an article of commerce consists of thirtyseven steps. An efficient synthetic pathway for the total synthesis of salvianolic acid n has been reported. A short formal total synthesis of zaragozic acid c, this paper is a good reminder of the power of the claisen rearrangement, this time in the ireland modification. A second appearance for zaragozic acid on these webpages the first was by rizzacasa, and a second synthesis by this group the first. Plus, this book represents the first collaboration of the underground. However, there has been lots of work on this natural product family, most of which construct the ketal using the same approach.
A formal total synthesis of zaragozic acid c 1 was achieved by the synthesis of intermediate 2. Zaragozic acid c 1 is characterized by a hydrophilic 2,8dioxabicyclo3. Pmid 15635219 discovery, biosynthesis, and mechanism of action of the zaragozic acids. A step total synthesis of the fungal meroterpenoid berkeleyone a is reported. A total synthesis of zaragozic acid c by a convergent strategy is described in which the key features include 1 the simultaneous creation of the c4 and c5 quaternary stereogenic centers by a snotf2promoted aldol coupling reaction between an. The dissertation committee for maya escobar certifies that. In a follow up experiment,the drug zaragozic acid c was used as an inhibitor for reactioniii. Squalestatin s1 1 also known as zaragozic acid is a picomolar inhibitor of squalene synthase. Herein we describe our firstgeneration approach to the formal synthesis of lasonolide a. The longest linear sequence from our five subtargets is sixteen steps. God is the author of salvation he planned it from the very beginning. Total synthesis of zaragozic acid a squalestatin s1 soham maity.
Total synthesis of zaragozic acid a squalestatin s1. Total synthesis of the squalene synthase inhibitor zaragozic acid c. Strikes ebooks sources, total synthesis, and total. Chemistry that allows selective modification of the carboxylic acid groups of the squalene synthase inhibitor zaragozic acid a 1 was developed and applied to the synthesis of compounds modified. Zaragozic acids also mildly inhibit ras farnesylprotein transferase. Zaragozic acid c is a noncompetitive inhibitor of ggpps in the conditions for reaction iii. The key step involves an irelandclaisen rearrangement of an allylic ester to generate a carboncarbon bond and two asymmetric centers simultaneously. The key reaction steps, the wittig reaction for zstereoselectivity and an intramolecular cyclization for a seven membered ring skeleton, have been optimized to improve the synthetic feasibility and provide the be. Naughty chemists from around the world have contributed their favorite the most comprehensive and detailed book on the underground production of ecstasy and.
The asymmetric syntheses of the cl sidechains of zaragozic acid a and zaragozic acid c albert j. Key features of the synthesis are the use of a double sharpless asymmetric dihydroxylation reaction of diene 6 to control stereochemistry at four contiguous stereocenters from c3 to c6. Stereoselective total synthesis of zaragozic acid a based on an acetal article in angewandte chemie international edition 3924. Total synthesis of zaragozic acid a squales tatin s1. Formal total synthesis of salvianolic acid n organic. First synthesis of zaragozic acid containing a highly oxygenated bicyclic core. A carbonyl ylide cycloaddition approach to the squalene synthase inhibitors zaragozic acids a and c is described. Little is known of the chemical steps involved in the construction of the 4,8dioxabicyclo3.
N2 the lasonolides are novel polyketides that have displayed remarkable biological activity in vitro against a variety of cancer cell lines. Another feature of this improved synthesis is the construction of the alkyl side chain at c1 by olefin cross. Zaragozic acids production from discomycetes springerlink. Complete schematic view of the 1994 zaragozic acid cs synthesis performed by david a. The family of zaragozic acids has recently regained attention. The key findings from these studies ultimately allowed us to go on and complete a total synthesis of lasonolide a. Total synthesis of gambieric acids chemviews magazine. This article reported an eight steps formal total synthesis of. Zaragozic acids zas belong to a family of fungal metabolites with.
The asymmetric syntheses of the cl sidechains of zaragozic. Each chapter is dedicated to a particular synthesis, explaining the strategy, synthesis, and a discussion of particularly interesting challenges, selectivity, or mechanisms. Wo20095979a1 method for obtaining zaragozic acid and. A retrosynthetic analysis of zaragozic acid c through bond disconnection into its constituent. Oxidative steps during the biosynthesis of squalestatin s1 xmol. A novel synthetic approach to the construction of the zaragozic acids, which was used for the asymmetric synthesis of zaragozic acid asqualestatin s1 1, is described. Sorensen present the most remarkable and ingenious total syntheses from the laboratories of some of the worlds greatest synthetic organic. The asymmetric syntheses of the c1 sidechains of zaragozic. Journal of the american chemical society 2017, 9 5, 18141817. The holton taxol total synthesis, published by robert a.
A retrosynthetic analysis of zaragozic acid c through bond. Installation of the contiguous c4 and c5fully substituted carbons presents a formidable synthetic challenge. Alkene protection against acid using a bromide substituent. In search for new zaragozic acids and their derivatives that are potent inhibitors of squalene synthase, discomycetes of the order leotiales were cultured and their fermentation broth was assayed. Evans tmerck research laboratories, po box 2000, rahway, new jersey 07065 sdepartment of chemistry, harvard university, cambridge, massachusetts 028. Key features of the synthesis are the use of a double sharpless asymmetric dihydroxylation reaction of diene 6 to control stereochemistry at. Recent efficient synthetic routes towards the squalestatins illustrate the mandatory.
Zaragozic acid c organic synthesis with carbohydrates. Key steps are an acid mediated acetonide deprotectiondithiane removalketalisation procedure, providing selectively the 2,8dioxabicyclo3. Mannich rearrangement that assembled the core structure of the natural products unique ring system. Instead, debenzylation and acetylation were achieved under standard conditions to give the triacetate 18, a compound utilized by carreira in the total synthesis of zaragozic acid c. Three strains in 2 unidentified species ofmollisia were found to produce zaragozic acid d3 and three new analogs f10863s. Johnson of the university of north carolina developed j. The first total synthesis of zaragozic acid a 50 was successfully finalized from this product 49 by the requisite deprotection reactions and sidechain. The invention relates to a method for obtaining zaragozic acid and derivatives thereof, to the intermediate compounds of this synthesis and to the use of said intermediate compounds in the preparation of zaragozic acid. Select an approach to total synthesis of the marine ascidian metabolite perophoramidine via a halogenselective tandem heckcarbonylation strategy. Tandem reactions, cascade sequences, and biomimetic strategies in. With the synthesis of the simpler zaragozic acid c sidechain completed, utilization of this approach towards the synthesis of the zaragozic acid a sidechain was examined. The aldol approach to zaragozic acid c the main problem in zaragozic acid synthesis. Structure, properties, spectra, suppliers and links for. Zaragozic acid d and d2 have been isolated from the keratinophilic fungus amauroascus niger.
Excelent east to understand on mdma, and methamphetamine synthesis. Binding modes of zaragozic acid a to human squalene. Key steps are an acidmediated acetonide deprotectiondithiane removalketalisation procedure, providing selectively the 2,8dioxabicyclo3. Squalene synthase is the first committed enzyme in sterol synthesis, catalyzing the reductive condensation of farnesyl pyrophosphate to form squalene. The family of zaragozic acids has recently regained attention due to further biological activities, e. Total syntheses of zaragozic acids a and c by a carbonyl. Waihoensene guided by quaternary center analysis angew.
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