Enantioselectivity cyclization, biomimetic

Enantioselective Polyene Cyclization Catalyzed SnCU-BINOL Derivatives. Non-enzymatic enantioselective polyene cyclizations are very attractive alternatives to the multistep synthesis from naturally occurring chiral synthons. The authors have succeeded in the first enantioselective biomimetic cyclization of polyprenoids catalyzed by LBA. (—)-Ambrox is the most important commercial substitute for ambergris, due to its unique olfactory and fixative properties. The successful preparation of (—)-ambrox has been achieved by the enantioselective cyclization of homofamesol promoted by (/ )-BINOL-Me-SnCl4, although the enantioselectivity and diastereoselectivity is moderate (eq 10). 

To demonstrate the effectiveness of the LBA-promoted enantioselective cyclization, we biomimetically synthesized (-)-chromazonarol, a minor constituent of brown Pacific seaweed. The cyclization of 4-benzyloxyphenyl farnesyl ether with (5)-LBA gave the desired tetracyclic compound as the major diastereomer in 44 % ee (Eq. 101). 

Chiral Brpnsted acid (18) has been designed as a new organocatalyst for the biomimetic enantioselective cyclization of 2-geranylphenols (16), which gave rise to the fra 5-fused cyclization products (17) with <98 2 dr and 93% ee ... 

Trost et al. have exploited the Cp2TiCl-promoted 6-exo cyclization of 10 to 13 for the first enantioselective biomimetic total synthesis of the antifungal metabolite (-)-siccanin (15) (Scheme 21) [109]. These authors also observed a minor amount (20%) of by-product 14, presumably derived from the radical intermediate 12 by a process reminiscent of the Sr2 reaction described by Gansauer s group [66]. They took advantage of 14 for the preparation of (-)-5-epz-siccanin (16) (Scheme 21) [109]. 

Optically active aliphatic propargylic alcohols are converted to corticoids (90% ee) via biomimetic polyene cyclization, and to 5-octyl-2(5ii)-furanone. The ee s of propargylic alcohols obtained by this method are comparable with those of the enantioselective reduction of alkynyl ketones with metal hydrides, catalytic enantioselective alkylation of alkynyl aldehydes with dialkyIzincs using a chiral catalyst ((S)-Diphenyl(l-methylpyrrolidin-2-yl)methanol) (DPMPM), and the enantioselective alkynylation of aldehydes with alkynylzinc reagents using A(A-dialkylnorephedrines. °... 

Despite extensive studies on acid-catalyzed diastereoselective polyene-cyclizations, their enantioselective behavior have not yet been reported. The stereochemical implications of polyene-cyclizations can be explained by the Stork-Eschenmoser hypothesis [140], and the most important feature required for an artificial cyclase is asymmetric induction during the initial protonation. Very recently, the author and Yamamoto et al. succeeded in the first enantioselective biomimetic cyclization of polypre-noids catalyzed by LB A [141]. 

Other workers have also used variations of the Kuehne biomimetic approach in the synthesis of ibophyllidine. Das and collaborators (338) prepared the secodine precursor 730 by an obvious modification of the route used in the synthesis of vincadifformine. Acid hydrolysis of 730, followed by quaternization, fragmentation, and cyclization, then gave the ibophyllidine ring system. Use of the racemic aminoacetal (/ 5-731) in the first essential stage in Scheme 109 was reported ultimately to give ibophyllidine (672) and 20-epi-ibophyllidine (673), whereas the simpler aminoacetal 732 gave desethyl-ibophyllidine (674). Subsequent repetition of this synthesis (394), using the chiral 5-aminoacetal (S-731) resulted in an enantioselective synthesis of (-f)-20-epi-ibophyllidine [(-(-)-673]. Similarly, the enantiomeric H-acetal (/ -731) was converted into (-)-20-epi-ibophyllidine [(-)-673]. Contrary to the earlier report, it now appears that no ibophyllidine is produced in these syntheses. 

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. 

The chemical simulation of this biosynthetic process has been developed as an important methodology in organic synthesis. Van Tamelen reported the add-catalyzed cyclization of chiral terminal epoxides of polyprenoids [11]. In contrast, Johnson adopted the acid-catalyzed cyclization of poly-prenic acetals derived from chiral diols [12]. In addition to these pioneering studies, the biomimetic polyene cycliza-tions of polyprenoids, which are induced by a variety of electrophiles such as proton, oxonium ion, halonium ion [13], or metal ion [14], have also been developed. Despite extensive studies on these diastereoselective olefin cyclizations, enantioselective processes using synthetic chiral catalysts had not been developed for a long time. In 1999, Yamamoto s... 

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