Zaragozic acid c is an inhibitor of mammalian squalene synthase. Total synthesis of zaragozic acid c home thieme connect. Key steps are an acid mediated acetonide deprotectiondithiane removalketalisation procedure, providing selectively the 2,8dioxabicyclo3. The dissertation committee for maya escobar certifies that. Johnson of the university of north carolina developed j. Synthesis of zaragozic acid asqualestatin s1 nicolaou. While total syntheses have been recorded for zaragozic acid a 3 squalestatin s1 and zaragozic acid c, 4 as well as for zaragozic acid h5, 5 no synthetic studies have been reported to date on zaragozic acid d, which shows the most potent rasfarnesyl protein transferase inhibition in this natural product series. Total synthesis of the squalene synthase inhibitor. Synthesis of zaragozic acid asqualestatin s1 nicolaou 1995. Total synthesis of zaragozic acid a squalestatin s1. The first characterized zaragozic acids, a, b, and c were isolated from an unidentified sterile fungal culture, sporormiella intermedia, and l.
A formal total synthesis of zaragozic acid c 1 was achieved by the synthesis of intermediate 2. Total synthesis of zaragozic acid a squalestatin s1 soham maity. Total synthesis blog organic synthesis of natural products andtaxol. Strikes ebooks sources, total synthesis, and total. The structures of the zaragozic acids and their trimethyl esters were determined by a combination of physical and chemical techniques.
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. Zaragozic acid c 1 was isolated as a potent squalene synthase inhibitor. Journal of the american chemical society, 01 dec 2008, 51. Zaragozic acid c organic synthesis with carbohydrates. Total synthesis of the squalene synthase inhibitor zaragozic acid c. Request permission export citation add to favorites. 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. Chemical studies on the highly potent squalene synthase inhibitor zaragozic acid a 1 have led to the determination of the total absolute stereochemistry of the molecule as shown in figure 3 and. A carbonyl ylide cycloaddition approach to the squalene synthase inhibitors zaragozic acids a and c is described. The zaragozic acids are characterized by a novel 2,8dioxobicyclo3. The preparation of 18 thus constitutes a formal synthesis of zaragozic acid c. Selfconsistent synthesis of the squalene synthase inhibitor zaragozic acid c via controlled oligomerization.
Total syntheses of zaragozic acids a and c by a carbonyl. The family of zaragozic acids has recently regained attention due to further biological activities, e. His recent book titled classics in total synthesis, which he coauthored with erik 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. These targets were isolated in the last decade, and are inhibitors of squalene synthase, and thus have cholesterollowering properties. The first characterized zaragozic acids, a, b, and c were isolated from an. Abstract a novel synthetic approach to the construction of the zaragozic acids, which was used for the asymmetric synthesis of zaragozic acid asqualestatin s1 1. The epub format uses ebook readers, which have several ease of reading. Pmid 15635219 discovery, biosynthesis, and mechanism of action of the zaragozic acids.
Total synthesis and structure elucidation of zaragozic acid d and formal syntheses of zaragozic acids a and c one for all. Total synthesis of zaragozic acid c by an aldolbased. The convergency of this synthesis is demonstrated by the dithiane addition of a variety of c 1 side chains e. Total synthesis of zaragozic acid asqualestatin s1. Four novel zaragozic acids, f10863a, b, c and d, were isolated from a culture broth of the fungus mollisia sp. Here we reported the zaragozic acid a binding mode for the. A retrosynthetic analysis of zaragozic acid c through bond disconnection into its constituent. See all of your criminal friends in print, as this edition has tons of recipes and contributions from. Enantioselective total synthesis of napyradiomycin a1. This family of natural products possesses a unique 4,8dioxabicyclo3.
The aldol approach to zaragozic acid c the main problem in zaragozic acid synthesis. Wo20095979a1 method for obtaining zaragozic acid and. Total synthesis and structure elucidation of zaragozic acid d and formal syntheses of zaragozic acids a and c article mar 2011. A synthesis of a 1,3dithiane corresponding to the c1. Zaragozic acids are a family of natural products produced by fungi. Key steps are an acid mediated acetonide deprotectiondithiane removalketalisation. Squalene synthase catalyzes the first committed step in cholesterol synthesis, mediating the reductive dimerization of farnesyl pyrophosphate item no. Implementation of photochemical c sp3h acylation j. Step by step the first total synthesis was approached. Application of the silylglyoxylate glycolate aldol reaction.
Total synthesis collection 23 anthony crasto molecules. Synthesis of the c1side chain of zaragozic acid d and progress towards a total synthesis. All that total synthesis was minus the crappy stuff plus much, much more tons of new street recipes, theoretical procedures and reinforcement of existing methods. Key steps are an acidmediated acetonide deprotectiondithiane removalketalisation. Sos c 1 building blocks in organic synthesis sos multicomponent reactions. H acylation takahiro kawamata, masanori nagatomo, and masayuki inoue graduate school of pharmaceutical sciences, the university of tokyo, hongo, bunkyoku, tokyo 1033, japan. The carbonyl ylide precursor 8 was synthesized starting from di. Binding modes of zaragozic acid a to human squalene synthase and staphylococcal dehydrosqualene synthase. The zaragozic acids, exemplified by zaragozic acid c 3, are picomolar inhibitors of cholesterol biosynthesis. With the synthesis of the simpler zaragozic acid c sidechain completed. Binding modes of zaragozic acid a to human squalene.
The synthetic material was identical to a sample of natural material. First synthesis of zaragozic acid containing a highly oxygenated bicyclic core. Squalene synthase is the first committed enzyme in sterol synthesis, catalyzing the reductive. Carreira zaragozic acid c, evans zaragozic acid c, and nicolaou zaragozic acid a, just two years after the first publications on structure elucidation appeared. The first total synthesis of zaragozic acid a 50 was successfully finalized from this. F10863 compounds contain a 4,6,7trihydroxy2,8dioxyobicyclo3. A retrosynthetic analysis of zaragozic acid c through bond.
Pdf biological activities of novel zaragozic acids, the. An example of these compounds, zaragozic acid c 1, illustrates the. The nicolaou taxol total synthesis, published by k. Tandem reactions, cascade sequences, and biomimetic strategies in. 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.
This organic synthesis was included in nicolaous book, classics in total synthesis. Binding modes of zaragozic acid a to human squalene synthase. 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. Selfconsistent synthesis of the squalene synthase inhibitor. As illustrated in scheme 2, we applied the carreira protocol to complete the synthesis of zaragozic acid c 1 in four steps from triacetate 18. Synthesis of the c1side chain of zaragozic acid d and. Dissertation or thesis carolina digital repository. Nicolaou and his group in 1994 concerns the total synthesis of taxol. The key step involves an irelandclaisen rearrangement of an allylic ester to generate a carboncarbon bond and two asymmetric centers simultaneously. Installation of the contiguous c4 and c5fully substituted carbons presents a formidable synthetic challenge. Author links open overlay panel alan armstrong a b paul a barsanti a toby j blench a b ron ogilvie c. Complete schematic view of the 1994 zaragozic acid c s synthesis performed by david a. Read synthesis of the c1side chain of zaragozic acid d and progress towards a total synthesis, tetrahedron on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. 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.
381 83 562 577 1417 246 75 1311 81 1363 1328 1072 1036 370 130 519 841 1525 910 1359 318 743 591 1452 1291 888 382 1155 1354 145 1151 373 555 562 534 1391