Asymmetric cyclization biomimetic

Asymmetric cyclization of nerol and famesol.1 A biomimetic cyclization of nerol to limonene can be effected with an aluminum reagent 2 and a chiral leaving group. Thus the neryl ether 3 of R-( + )-2,2 -dihydroxy-1,1 -binaphthyl is cyclized... 

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

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. 

An oxidative cyclization has been exploited as the key step in the elegant asymmetric syntheses of both (+)- and (-)-galanthamine (291) (Scheme 29) (163). This biomimetic synthesis commenced with the secondary amine 311, which was readily prepared by the reductive amination of 3,5-dibenzyloxy-4-... 

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]. 

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. 

The development, by Snider, of intramolecular cyclizations of unsaturated p-keio esters with Mn(III) and Cu(II) has been the souree of numerous and speetacular cascades [27]. Intrigued by the potential of this chemistry as a biomimetic approach to polycyclic systems, Zoretic [28] reported the tetracyclization of precursor 46 to provide tetracyclohexyl derivative 47, in which seven asymmetric centers have been established with complete stereocontrol (Scheme 16). This remarkable sequence deserves several comments. The regioselectivity 6-endo-tng) and diastereoselectivity of the initial cyelization is consistent with Snider s seminal studies notably the ester group adopts an axial position to minimize unfavorable dipole/dipole interactions with the ketone. The two subsequent 6-endo-lng cyclizations that can be rationalized by a slower 5-exo mode of cyelization involving a bond formation sandwiched... 

The isomeric cis-internal olefinic precursor yielded only a cis-decalin derivative, in accordance with the predictions of orbital orientation and overlap. It is important to note that the products of all these biomimetic cyclizations are racemic. However, it is interesting to observe that when an optically active dienic acetal is used, a very high degree of asymmetric induction is realized ... 

Note that seven asymmetric centers are produced in this cyclization with a remarkable stereoselectivity, yielding only two out of 64 possible racemates. This concerted conversion is the closest nonenzymatic approach realized thus far with all-trans configuration. Undoubtedly, the conversion of an open-chain tetraolefinic acetal having no chiral centers into a tetracyclic compound having seven such centers and producing only two out of a possible 64 racemates is a striking tribute to Johnson s method of biomimetic cyclization. 

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. Frei, B. Gopalan, A. S. "Improved Asymmetric Total Synthesis of Corticoids via Biomimetic Polyene Cyclization Methodology" J. Org. Chem. 1981, 46, 1512-1513. Forfurther improvements see Johnson, W. S. Lyle, T. A. Daub, G. W. "Corticoid Synthesis via Vinylic Fluoride Terminated Biomimetic Polyene Cyclizations" J. Org. Chem. 1982, 47, 161-163. 

Mishra, S.J., Upar, K.B., and Bhat, S.V. (2009) Facile asymmetric synthesis of spongianone analogue through biomimetic cyclization. Tetrahedron Lett., 50, 6402-6403. 

---