Enzymatic cyclization

Recent syntheses of steroids apply efficient strategies in which open-chain or monocyclic educts with appropiate side-chains are stereoselectively cyclized in one step to a tri- or tetracyclic steroid precursor. These procedures mimic the biochemical synthesis scheme where acyclic, achiral squalene is first oxidized to a 2,3-epoxide containing one chiral carbon atom and then enzymatically cyclized to lanostetol with no less than seven asymmetric centres (W.S. Johnson, 1%8, 1976 E.E. van Tamden, 1968). 

Non-enzymatic cyclizations of educts containing chiral centres can lead to products with additional "asymmetric centres. The underlying effect is called "asymmetric induction . Its systematic exploration in steroid syntheses started when G. Saucy discovered in 1971 that a chiral carbon atom in a cyclic educt induces a stereoselective Torgov condensation several carbon atoms away (M. Rosenberger, 1971, 1972). 

A detailed mechanistic study of acid-catalysed monocyclization of 5,6-unsaturated epoxides, such as (66), has now provided compelling evidence for a pathway in which the oxirane C—O cleavage and the C—C bond formation are concerted. These experimental results are now further supported by theoretical evidence for a concerted mechanism of the oxirane cleavage and A-ring formation in epoxysqualene cyclisation, obtained at the RHF/6-31G and B3LYP/6-31 + G levels. The chemical pathway thus parallels the mechanism of the enzymatic cyclization that plays a role in the biosynthesis of isoprenoids. 

D. Garbe, S.A. Sieber, N.G. Bandur, U. Koert, M.A. Marahiel, Enzymatic cyclization of peptidomimetics with incorporated ( )-alkene dipeptide isosteres, ChemBioChem 5 (2004) 1000-1003. 

The synthesis of 273 proceeds through a benzyne intermediate (Scheme 55) <2005TL7443>. An enzymatic cyclization has also been reported (Scheme 56) <1990TL6907>. 

Welle, R. and Grisebach, H., Induction of phytoalexin synthesis in soybean enzymatic cyclization of prenylated pterocarpans to glyceollin isomers. Arch. Biochem. Biophys., 263, 191, 1988. 

Enantioselective (enzymatic) cyclization of 1 could lead to either enantiomer 2 a or 3 a, depending on which face of the internal double bond is attacked at C-6 by the cation derived from the allylic pyrophosphate unit. Re- or Si-face cyclization (see the detailed discussion in Section 4.3.4.1.2.1., p 442 of 1 b would, however, lead to the diastereomers 2b and 3b. respectively. A thorough analysis of the NMR spectrum of the cyclization product of 1 b definitely showed that 2b was formed thus proving the absolute configuration of (-)-fl-irans-berga-motene to be 2a185. 

The epoxy alcohol 47 is a squalene oxide analog that has been used to examine substrate specificity in enzymatic cyclizations by baker s yeast [85], The epoxy alcohol 48 provided an optically active intermediate used in the synthesis of 3,6-epoxyauraptene and marmine [86], and epoxy alcohol 49 served as an intermediate in the synthesis of the antibiotic virantmycin [87], In the synthesis of the three stilbene oxides 50, 51, and 52, the presence of an o-chloro group in the 2-phenyl ring resulted in a lower enantiomeric purity (70% ee) when compared with the analogs without this chlorine substituent [88a]. The very efficient (80% yield, 96% ee) formation of 52a by asymmetric epoxidation of the allylic alcohol precursor offers a synthetic entry to optically active 11 -deoxyanthracyclinones [88b], whereas epoxy alcohol 52b is one of several examples of asymmetric epoxidation used in the synthesis of brevitoxin precursors [88c]. Diastereomeric epoxy alcohols 54 and 55 are obtained in combined 90% yield (>95% ee each) from epoxidation of the racemic alcohol 53 [89], Diastereomeric epoxy alcohols, 57 and 58, also are obtained with high enantiomeric purity in the epoxidation of 56 [44]. The epoxy alcohol obtained from substrate 59 undergoes further intramolecular cyclization with stereospecific formation of the cyclic ether 60 [90]. 

Chalcones have been proposed (48) as a precursor that is enzymatically cyclized to form flavanone glycosides. The enzyme responsible for this stereospecific ring closure disappears or is inactivated as the fruit matures (5). However, no chalcones have been isolated from citrus. Therefore, if chalcones are a part of the metabolic pathway that leads to the formation of flavanone glycosides they probably exist as short lived, unstable intermediates. It appears unlikely that these compounds play a significant role in mitigating bitterness at their natural levels. 

Abe I, Rohmer M and Prestwich GD (1993) Enzymatic cyclization of squalene and oxidosqualene to sterols and triterpenes. Chem Rev 93, 2189-2206. 

A beautiful example of electrocyclic reactions at work is provided by the chemistry of the endiandric acids. This family of natural products, of which endiandric acid D is one of the simplest, is remarkable in being racemic—most chiral natural products are enantiomerically pure (or at least enantiomerically enriched) because they are made by enantiomerically pure enzymes (we discuss all this in Chapter 45). So it seemed that the endiandric acids were formed by non-enzymatic cyclization reactions, and in the early 1980s their Australian discoverer, Black, proposed that their biosynthesis might involve a series of electrocyclic reactions, starting from an acyclic polyene precursor. 

The epoxy alcohol (47) is a squalene oxide analog which has been used to examine substrate specificity in enzymatic cyclizations by baker s yeast The epoxy alcohol (48) provided an optically active intermediate used in the synthesis of 3,6-epoxyauriq>tene and marmine, and epoxy alcdiol (49) served as an intermediate in the synthesis of the antibiotic virantmycin. In the synthesis of the three stilbene... 

In related work, a series of important studies have been devoted to enzymatic cyclization of unnatural lanosterol precursors. Thus both epoxides (23) and (29), despite being notably different in structure from squalene oxide (32), were transformed enzymatically into the pentanorlanosterol (33a) and dihydrolano-sterol (33b), respectively. These results lend support to the suggestion that the methyl-hydrogen migration sequence rests solidly on physico-chemical... 

With the preceding reviews of the enzymology of monoterpene cyclization and of model studies relevant to the cyclization process, it is possible to formulate a unified stereochemical scheme for the enzymatic cyclization of geranyl pyrophosphate (Figure 4). The proposal which follows is consistent with the implications of parallel advances in related fields, most notably the contributions of Cane (8,16,24,25,52), Arigoni (67) and Coates (68,69) on the stereochemistry of sesquiterpene and diterpene cyclizations, and of Poulter and Rilling (29,70) on the stepwise, ionic mechanism of prenyl transferase, a reaction type of which several monoterpene, sesquiterpene and diterpene cyclizations are, in a sense, the intramolecular equivalents. 

The natural function of the carboxymethylhydantoinase (E. C. 3.5.2.2) is postulated to be the hydrolysis of 5-carboxymethylhydantoin, which is described to be the product of a non-enzymatic cyclization of N-carbamoyl-i-aspartic acid123, 241 and to occur as a side-product in the metabolism of the pyrimidine nucleotide dihydroorotic acid1251. This enzyme often occurs in combination with a ureidosuccinase (E.C. 3.5.1.7)[2S1, which catalyzes the cleavage of the resulting N-carbamoyl aspartic acid to L-aspartic acid (see Fig. 12.4-5). L-5-Carboxymethylhydantoin was first isolated after incubating orotic acid, a six-membered cyclic amide, with crude cell extracts of the anaerobic bacterium Clostridium oroticum125, 261. 

Cyclization Reactions of Oxirans. The search for non-enzymatic cyclizations of squalene oxide and its analogues continues with the report of the direct sterol synthesis of (128) (2%) from (127). Although the yield is low, the procedure involving treatment of (127) in CH2CI2 that contains BF3 -OEt2 and ethene carbonate at 0°C for 20 minutes affords four new rings and seven new asymmetric centres in one laboratory operation. The diepoxide... 

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