Polyenes 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... 

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). 

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]. 

Biomimetic cyclization of polyenes as routes to diterpenoids continues to be explored. The brominative cyclization of geranyl-linalool afforded160 the 3-bromo-manoyl oxide and the boron trifluoride-catalysed cyclization of the diepoxide of p-homogeranylanisole gave 13-methoxy-A-homo-4a-oxopodocarpatrienol.161 Some further synthetic studies of anhydroverticillol have been reported.162... 

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)... 

Electrophilic Addition Reactions. Further work by Johnson on the biomimetic polyene olefin cyclization reactions has shown that asymmetric induction by a chiral centre remote from the initiating cationic centre is possible. This was shown by the preparation of 11 a-methylprogesterone and a stereospecific total synthesis of racemic 11 a-hydroxyprogesterone via this route (Scheme 48). > ... 

Johnson, W. S. Shenvi, A. B. Boots, S. G. An approach to taxodione involving biomimetic polyene cyclization methodology. Tetrahedron 1982, 38, 1397-1404. 

Harring, S. R. Livinghouse, T. Sulfenium ion promoted polyene cyclizations in natural product synthesis. An efficient biomimetic-like synthesis of ( )-nimbidiol. Tetrahedron Lett. 1989, 30, 1499-1502. 

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. 

Epoxides can also serve as effective carbocyclization promotors, either through a polyene cyclization, as in the biomimetic epoxy-olefin cyclization of 100 in the presence of boron trifluoride etherate <99CC325>, or by a Friedel-Crafts approach, as exemplified by the cycli-alkylation of arylalkyl epoxides 102 under the influence of solid acid catalysts <99EJOC837>. 

Regioselective bromination of polyenes.1 The first steps in a biomimetic synthesis of concinndiol (4) from methyl geranylgeranate (2) involve regioselective bromination with 1 followed by cyclization with AgOAc in HOAc to 3 in 20% overall yield. 

Another example is the cyclization of the racemic allylic alcohol 232 at -80°C which furnished the racemic tetracyclic bis-olefin 233 in 70% yield (89, 90). Ozonolysis of 233 gave the bicyclic triketone aldehyde 234 which underwent under acidic conditions a double intramolecular aldol cyclodehydration to produce racemic 16,17-dehydroprogesterone 235. This represents the first synthesis of a steroid via the now so-called "biomimetic" polyene cyclization method. 

In the simulation of enzymes attempts have been made to use steroid matrices and biomimetic reactions of polyene cyclization, comprehensively described in Ref. [10]. 

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. °... 

Johnson et al. have investigated the use of alkynylsilanes as terminators in the synthesis of steroids and triterpenes through biomimetic polyene cyclizations. This strategy was used in the stereospecific synthesis of the tetracyclic ketone (81) using an alkynylsilane as a terminator. Thus, treatment of (80) with trifluoroacetic acid under carefully optimized reaction conditions yielded, after hydrolysis of the ortho ester, the tetracyclic ketone (81 Scheme 39). 

The work of Johnson and his colleagues on biomimetic polyene cyclization has been reviewed. 

Johnson, W.S., Newton, C., and Lindell, S.D., The carboalkoxyallylsilane terminator for biomimetic polyene cyclizations. A route to 21-hydroxyprogesterone types. Tetrahedron Lett.. 27, 6027, 1986. 

Johnson, W.S., Lindell, S.D., and Steele, J., Rate enhancement of biomimetic polyene cyclizations by a cation-stabilizing auxiliary, 7. Am. Chem. Soc., 109, 5852, 1987. 

Allylsilane 31 was employed in fine fashion in the biomimetic polyene cyclization as a key step in a route to the 21-hydroxyprogesterone system80 (equation 75). 

Johnson, W.S. et al. 1977, Asymmetric total synthesis of 1 la-hydroxy progesterone via a biomimetic polyene cyclization , Journal of the American Chemical Society, 99, 8341-3. 

Three major reaction sequences or strategies dominate steroid syntheses (1) Diels-Alder reactions, (2) all kinds of aldol and Michael addition reactions, and (3) biomimetic syntheses corresponding to polyene cyclizations. We shall give a few examples of each of these approaches, starting with the polyene cyclizations (Akhrem and Titov, 1970 Anand et al., 1970 Blickenstaff et al., 1974). 

Polyene cyclization (3, 305-307 4, 531-532 5, 696-697 6, 613-614 7, 389). Johnson et al. have noted that a terminal trimethylsilylacetylenic group influences the structure of the final steroid in biomimetic polyene cyclizations. Thus 1 is cyclized to a D-homosteroid (2) in contrast to the cyclization of 3 to 4. 

Johnson, Corey, and van Tamelen have successfully utilized the biomimetic acid-catalyzed cyclization of polyolehnic substrates for the construction of steroids and some teipenes. Based on the previous work, Ireland and co-workers designed a route to the desired tetracycle 69 utilizing polyene cyclization (Scheme 12), which, although preparatively uncompetitive with the hydrocyanation (Scheme 11), was of some interest. Based on a model study, the symmetric dibromide... 

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