Diastereoselective Polyene Cyclizations

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]. 

Enanlio- and diastereoselective polyene cyclization reactions promoted by small-molecule artificial enzymes have been developed as key steps for the practical synthesis of polycychc terpenoids based on biosynthetic pathways. Several examples as highlighted previously exist in the hterature mimicking the all chair transition state of the nonsterol folding, hi sharp contrast, there have been no successful examples of the polyene cyclization via a chair-boat transition state like sterol folding. In near future, more efficient and more effective catalytic biomimetic polyene cyclization reactions are expected to be developed. 

Scheme 1.25 Reagent-controlled diastereoselective polyene cyclization of (S)-19 promoted by (R) or (S)-16.

Scheme 1.26 Diastereoselective polyene cyclization of racemic nerolidol (20) promoted by (/ )-( 6).

Johnson in 1993 described an approach to racemic p-amyrin involving application of a biomimctic polyene cyclization.7 In the same year Corey accomplished the enantioseleetive synthesis of compound 4. a key intermediate that opened the way to stereoselective preparation of compounds I, 2. and 3 8 A key step in the synthesis of P-amyrin (1) was the introduction of chiral oxazaboroli-dines for enantioseleetive carbonyl reduction. Ba ed on these methods, generation of an enantiomerically pure epoxide and its stereoselective cationic cyclization led to the pentacyclic system of structure 1 Diastereoselective cyclopropanation and an intramolecular protonation of a carbanion represent other interesting steps in this total synthesis. 

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). 

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... 

In 2007, Gagne s group succeeded in a regio- and diastereoselective oxidative polycyclization of di- and trienols catalyzed achiral [(dppe)Pt] dications, wherein turnover was achieved by the trityl cation abstracting a hydride from a putative [(dppe)Pt-H] intermediate [32i]. One year later, Gagne s group developed the catalytic enantioselective polyene cyclization induced by [(S)-(xylyl-PHANEPHOS) Pt][(BF )j] catalyst, which was prepared from (S)-(xylyl-PHANEPHOS)PtIj and AgBF in situ (Scheme 9.21) [32j]. This asymmetric catalysis enables the oxidative cascade cyclization of polyalkene substrates [32k] (Scheme 9.15). 

Organo-SOMO catalysis was also applied to polyene cyclization. In 2010, MacMillan reported an enantioselective cyclization reaction of substrates 41 for accessing steroidal and terpenoidal frameworks. They used imidazolidinone 40 instead of catalyst 23, with the aid of copper(ll) triflate as the oxidant. The polyene cyclization took place smoothly, giving polycyclic systems 42 and even more complex compounds 43 or 44 in good yields and with high enantioselectivity and exclusive diastereoselectivity (Scheme 36.12) [18]. 

To obtain high chemical yields and diastereoselectivities, it is necessary to introduce a removable cation-stabilizing group (R = Me2C=CH or F) in the proper position on the polyenic skeleton of 6.75 (Figure 6.64). As usual, the acetal auxiliary is cleaved by oxidation and -elimination ( 1.1.2). These cyclizations are carried out at low temperature (-40 to -90°C), and the Lews acid is either TiCl4/Ti(0/-Pr)4 or SnCl4. 

Selective epoxidation of polyene compound has also achieved with ent 2, the enantiomer of ketone 2. In Morimoto s total synthesis of polyether (+)-aurilol, Shi epoxidation was utilized twice, with ketone 2 and ent-2, respectively." Epoxidation of 79 with ketone 2 gave epoxide 80 with high diastereoselectivity. Epoxide 80 underwent acid catalyzed 5-exo-tet cyclization to produce tetrahydrofuran 81 with the desired stereochemistry. Subsequently, diene 82 was selectively epoxidized with ent-2 only at the trisubstituted olefin to give epoxide 83. Epoxides 80 and 83 played important roles in setting stereocenters in the final product. 

Steroids.—The major work reported in steroid synthesis involves biomimetic cyclizations of polyenes. The diastereoselection that is observed in cyclization of polyenes to give sterols is explained by a transition state in which there is no steric interaction between substituents at C-10 and C-11, in (197). However, it has now been shown that compounds in which no such interactions are possible, but which bear a substituent at C-7, still demonstrate high diastereoselection. Presumably this is due to non-bonded interaction of this substituent inducing diastereoselection in the first-formed C-9-C-10 bond. The formation of (198)... 

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