Biosynthesis biomimetic cyclization

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 mechanism of these biomimetic cyclizations and that of their enzymatic counterparts is still unknown, but the majority of the evidence favors a synchronous process over a stepwise one. The study of these nonenzymatic simulations of sterol biosynthesis is of fundamental importance because it could clarify and explain processes that could have been operative since the beginning of life forms on Earth. 

The tetracyclic alcohol 179 is produced by the action of boron trifluoride etherate or tin(IV) chloride on the oxirane 178 (equation 85)95. A similar cyclization of the oxirane 180 yields DL-<5-amyrin (181) (equation 86)96. In the SnCLt-catalysed ring-closure of the tetraene 182 to the all-fraws-tetracycle 183 (equation 87) seven asymmetric centres are created, yet only two of sixty-four possible racemates are formed97. It has been proposed that multiple ring-closures of this kind form the basis of the biosynthesis of steroids and tetra-and pentacyclic triterpenoids, the Stork-Eschenmoser hypothesis 98,99. Such biomimetic polyene cyclizations, e.g. the formation of lanosterol from squalene (equation 88), have been reviewed69,70. 

The mechanism of penicillin biosynthesis from the Arnstein tripeptide, 8-(L-a-aminoadipoyl)-L-cysteinyl-D-valine (ACV), has been extensively studied and reviewed by many chemists. Most of the biosynthetic mechanisms have been ascertained by Baldwin and Bradley using an excellent enzymatic technique.55 However, the first step in the biosynthesis of penicillin, conversion of the Arnstein tripeptide to a cis-P-lactam intermediate, is still a fascinating mechanistic problem. Although Baldwin et al. recently proposed a mechanism involving an iron-bound thioaldehyde formation route via a Pummerer-type cyclization, the intermediate for this mechanism has not been identified. The mechanism of selective formation of the cw-P-lactam ring is still also unknown (Fig. 39).56 These types of biomimetic reactions have been chemically studied. An example of an unsuccessful intramolecular Pummerer cyclization of the sulfoxide involving a cysteine moiety under standard Pummerer conditions was reported by Wolfe et al.57 Although Kaneko reported the conversion of the very simple 3-phenylsulfinyl propionamide into a P-lactam with TMSOTf/triethylamine,58 a successful biomimetic synthesis of... 

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. 

Several biomimetic studies involving the nonenzymatic, intramolecular cyclization of synthetic peptides that contain dehydroamino acids and unprotected cysteine residues have been used to investigate the cyclization step of lantibiotic biosynthesis. Short peptides that contain a single Dha or Dhb residue and... 

The same cyclization behavior of the p-polycarbonyl chain—not to fold in the middle, as postulated for the alkaloid biosynthesis (see Scheme 3), but to roll up from an unprotected end—was also observed for the parent compound, the free 3-pentaketone 30, itself, which led in vitro directly to doubly cyclized products like 49 (52). This type of chemical cyclization is sometimes used by nature, as well, and thus could be exploited biomimetically (50,51,53) for a first total synthesis of the aloenin aglycon (52), a natural product from Aloe ar-borescens var. natalensis, in which the carbon chain is similarly folded. The same type of cyclization, using the (3-polycarbonyl chain in its complete, non-decarboxylated form 55, could achieve a still shorter synthesis of 52 (Scheme 9), being even more closely oriented to the biosynthesis (50,51). 

A cascade epoxy alcohol cyclization has been proposed for the biosynthesis of the polycycUc ether natural products [122-124]. In 2003, Holton and coworkers disclosed the first convergent total synthesis of hemibrevetoxin-B (3), in which a biomimetic epoxy alcohol cyclization has been successfully implemented [120]. 

Conventional multistep synthesis of natural products reduces the overall yield of the target molecules. In contrast, biomimetic enantioselective domino reactions, promoted by small-molecule artificial enzymes, are more useful for the practical synthesis of natural products and related compounds. The stereoselective formation of polycyclic isoprenoids by the cyclase-induced cyclization of polypren-oids is one of the most remarkable steps in biosynthesis because this reaction results in the formation of several new quaternary and tertiary stereocenters and new rings in a single step. The use of biomimetic polycyclization with artificial cyclase is the most ideal chemical method for the synthesis of these polycyclic terpenoids. In this chapter, biosynthesis of polycyclic terpenoids, biomimetic stereoselective polyene cyclization induced by artificial cyclases, and total synthesis of bioactive natural products using stereoselective polyene cyclization as a key step will be discussed. 

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