Rearrangement biomimetic

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

Biosynthesis of the spirobenzylisoquinoline alkaloid ochotensimine (282) via the quinomethide intermediate (Scheme 49) was proposed by Shamma and Jones (7J0). On the basis of this hypothesis, several biomimetic transformations of phenolic protoberberines to spirobenzylisoquinolines have been realized by the base-induced rearrangement via the quinomethide. 

Agelas nakamurai from Japan produced the sesquiterpene sulfone, agelasidine A (353), which possessed antispasmodic activity. The structure was deduced from spectral data [309]. A simple synthesis of agelasidine A (353) utilised a hetero-Claisen rearrangement [310]. A biomimetic synthesis of 353 was also reported [311] and another synthesis of agelasidine A (353) was carried out in three steps from famesol [312]. 

Stereoisomeric alcohols (93) and (94) yielded identical ring-expansion products [e.g. (97)] on formation of carbocations.168 This is evidence of a stepwise reaction in sterol biosynthesis, whereby a tertiary cation [e.g. the model (95)] rearranges to a secondary cation (96)-an anti-Markovnikov rearrangement . The synthetic aspects of biomimetic cyclizations of isoprenoid polyenes were reviewed.169 Included was a detailed discussion of carbenium ion-initiated cyclizations, with a discussion of the different mechanisms that have been proposed. A novel biomimetic carbocation polyene cyclization of a daurichromenic ester was reported an unusual 2 + 2-carbocation cyclization occurred as a side reaction.170... 

The above-described problem demonstrates the first enantioselective synthesis of dysidiolide, a C25 isoprenoid antimitotic agent. The central transformations are the sulfenylation-dehydrosulfenylation sequence to prepare an a,/5-tnone, the biomimetic cationic 1,2-rearrangement to form stereoselectively the bicyclic scaffold, vinyl cuprate displacement of an iodide furnishing the C-l side chain and the photochemical oxidation of furan to generate the j hydroxy-butenolide functionality. 

A biomimetic total synthesis of gambogin and some analogues has been performed, involving two Claisen rearrangements. Both were observed to be accelerated considerably by protic and particularly by aqueous solvents. This has been attributed... 

The formation of the six-membered ether ring via epoxy ester-ortho ester cyclic ether rearrangement supports the hypothesis that epoxy ester-ortho ester cyclic ether rearrangement may be involved in the biosynthesis of ladder-type marine polyether toxins. This reaction represents a biomimetic preparation of medium ring cyclic ethers. 

This rearrangement was studied as a biomimetic version of the NIH shift. Write a mechanism for the reaction. Do you consider it a good model reaction If not, how might it be made better ... 

Traylor (38) has also shown that biomimetic iron N-alkylporphyrins themselves are competent catalysts for epoxidation of alkenes with a rate constant of about 104 M-1 s-1. On the basis of these observations and rearrangement reactions of specific alkenes, Traylor has proposed the reaction sequence outlined in Scheme 3 as representative of the oxidation and N-alkylation reactions of the P-450 model systems. In this scheme, the epoxide and the N-alkylated heme are derived from a common, electron-transfer intermediate (caged ferrylporphyrin-alkene cation radical). Collman and co-workers (28, 29) prefer a concerted mechanism (or a short-lived, acyclic intermediate) for epoxidation and N-alkylation reactions. Both authors note that the reactions catalyzed by cytochrome P-450 (and biomimetic reactions) probably can not be ascribed to any single mechanism. 

Stereospecific 2,3-epoxidation of squalene, followed by a nonconcerted carbocationic cyclization and a series of carbocationic rearrangements, forms lanosterol [79-65-0] (77) in the first steps dedicated solely toward steroid synthesis (109,110). Several biomimetic, cationic cydizations to form steroids or steroidlike nuclei have been observed in the laboratory (111), and the total synthesis of lanosterol has been accomplished by a carbocation—olefin cydization route (112). Through a complex series of enzyme-catalyzed reactions, lanosterol is converted to cholesterol (2). Cholesterol is the principal starting material for steroid hormone biosynthesis in animals. The cholesterol biosynthetic pathway is composed of at least 30 enzymatic reactions. Lanosterol and squalene appear to be normal constituents, in trace amounts, in tissues that are actively synthesizing cholesterol. 

Another area of increasing emphasis is the elucidation of chemical bonding rearrangements either initiated by or accompanying ET for example, coupled proton- (or other ion ) electron transfer cpet) [20, 22] and dissociative ET [80]. Such a focus, of course, lies at the heart of much current research in solar-energy conversion. An especially exciting recent development is the construction of a functioning biomimetic photon-driven proton pump [81]. 

The second reaction involves formation of the cation (the one that is not an intermediate in the first reaction), migration, and elimination. It is difficult at first to see the structure of the resulting cation so we have first drawn it deliberately badly but in the shape of the starting material. These reactions are very biomimetic as almost identical rearrangements occur in the biosynthesis of camphor and its relatives (p. 1440). 

In total syntheses of 3-lactam antibiotics, the formation of 2-azetidinones is crucial. In a biomimetic synthesis, the N—C4 bond is best closed by the open chain hydroxamate (equation 48), because, depending on the different pATa values of the three potentially ionizable positions, only the ring-forming amide is ionized. 3-halohydroxamates are cyclized by base treatment, whereas 3-hydroxyhydroxamates cyclize via the Mitsunobu reaction (diethyl azodicarboxylate, PhsP). More highly substituted precursors yield isomeric 3-lactams after rearrangement. ... 

In K.C. Nicolaou s biomimetic synthesis of 1-O-methylforbesione, the construction of the 4-oxatricyclo[4.3.1.0]decan-2-one framework was achieved by using a double Claisen rearrangement that was followed by an intramolecular Diels-Alder reactionJ This one-pot biomimetic double Claisen rearrangement/intramolecular Diels-Alder reaction cascade afforded the natural product in 63% yield. 

The enantioselective biomimetic total synthesis of the alkaloid (+)-aristotelone was accomplished by C.H. Heathcock and co-workers." The synthetic sequence commenced with a Hg(N03)2-mediated Ritter reaction between (1S)-(-)-P-pinene and 3-indolylacetonitrile. Upon protonation, the pinene underwent a Wagner-Meerwein rearrangement to generate a tertiary carbocation which reacted with the cyano group. The initially formed imine product was reduced to the corresponding amine by sodium borohydride in methanol. 

Nicolaou, K. C., Li, J. "Biomimetic" cascade reactions in organic synthesis construction of 4-oxatricyclo[4.3.1.0]decan-2-one systems and total synthesis of 1-O-methylforbesione via tandem Claisen rearrangement/Diels-Alder reactions. Angew. Chem.. Int. Ed. Engl. 2001,40, 42644268. 

A number of biomimetic syntheses have included Wagner-Meerwein rearrangements. A chemical conversion of humulene (48) to sterpurene (50) involved an interesting series of Wagner-Meerwein rearrangements (see Scheme 19).- - Humulene (48) was converted to the cyclooctenol (51) and thence to the bromide (52) via the protoilludyl cation (49). Treatment of (52) with silver acetate in acetic acid gave racemic sterpurene (50). In contrast the epimeric bromide (53) gave (54). 

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