Polyenes tetracyclization

The achiral triene chain of (a//-rrans-)-3-demethyl-famesic ester as well as its (6-cis-)-isoiner cyclize in the presence of acids to give the decalol derivative with four chirai centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Escherunoser, 1959 W.S. Johnson, 1968, 1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric acid catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such acids activate oxygen functions selectively (K.B. Sharpless, 1970). 

It could be shown that the stereochemical outcome of such radical polycycliza-tions is influenced by the nature of the substituents (H, Me, C02R). For instance, as in the example 3-225, the all-( )-methyl-substituted polyene 3-228 also gave the corresponding all-trans-anti polycycle 3-229 in the presence of Bu3SnH and AIBN. However, the ester-substituted polyene 3-230 led to the cis-anti-cis-anti-cis tetracycle 3-231 under similar reaction conditions (Scheme 3.60). A certain degree of preorganization of the precursor is assumed to be the reason for this result [97]. 

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. 

Polyene cyclization in terpene and steroid synthesis is critically dependent on the terminator in order to generate useful functionalities for further modification of the products. Allyl- and propargylsilanes have proven their value in facilitation of the cyclization and generation of an exocyclic methylene and allene, respectively. Thus, a concise approach to albicanyl acetate [126] and the rapid construction of a tetracyclic precursor of steroids [127] are sufficient to demonstrate the concept. Again, a comparison of the substrates with a silyl group with those having a simple alkyl moiety is very enlightening. 

The tetracyclic natural product 6.38 can be prepared from the linear polyene 6.37 at 100°. This is also believed to be the path followed in its biosynthesis. All the steps are pericyclic. What are they ... 

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. 

The first enantioselective polyene tetracydization starting with a chiral epoxide was reported by Corey et al. in 1997 [8a]. The silylated enol ether 3 (Scheme 1) was converted into the tetracycle 4 by treatment with the Lewis acid MeAlCl2 at -90 °C. The synthetic route is modeled on the biosynthesis of lanosterol from (3S)-squalene 2,3-epoxide and has also been applied to the biomimetic synthesis of tetracyclic polyprenoids from sediment bacteria [8b]. 

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). 

Other, removable cation-stabilizing auxiliaries have been investigated for polyene cyclizations. For example, a silyl-assisted carbocation cyclization has been used in an efficient total synthesis of lanosterol. The key step, treatment of (257) with methyl aluminum chloride in methylene chloride at —78° C, followed by acylation and chromatographic separation, affords (258) in 55% yield (two steps). When this cyclization was attempted on similar compounds that did not contain the C7P-silicon substituent, no tetracyclic products were observed. Steroid (258) is converted to lanosterol (77) in three additional chemical steps (225). 

The cascade is initiated by a conrotatory 8w-electron ring closure of the polyene carboxylic acids 20, 21 to the isomeric cyclo-octatrienes 22 and 23, respectively, which subsequently undergo a disrotatory 6 r-elec-tron cyclization to 24 and 25, respectively. Termination of the cascade by an intramolecular Diels-Alder reaction yields either the tetracyclic endiandric acid 26a, b or the bridged derivative 27. 

A spectacular example of cationic cyclization is the Johnson polyene cyclization, described in Section 10.8.A. Polyenes such as squalene are expected to assume a steroid-like conformation in the lowest energy form (sec. 1.5.E), based on the biogenetic preparation of cholesterol from squalene. In practice, treatment of polyenes with acid led to a very low yield of tri- or tetracyclic products, giving instead significant amounts of polymeric material. Diligent work over many years prevailed, however, and Johnson solved the many problems (as described in sec. 10.8.A) to make this reaction an excellent and efficient synthetic route to di-, tri-, and tetracyclic molecules. One of the later examples of polyene cyclization uses an allyl silane to quench the cyclization process. A Lewis acid was used to initiate the reaction via reaction with the acetal. Treatment of... 

There are many synthetic examples that use radical cyclization as a key step, and the radical precursor is not limited to iodides or bromides. In Pattenden s synthesis of pentalenene, conjugated selenyl ester 156 was treated with Bu3SnH and AIBN to give a 45% yield of tricyclic ketone 159. Loss of PhSe generated the acyl radical 157, which exists in equilibrium with the ketene radical 156. Radical cyclization via the latter intermediate leads to 159. Cyclization via aryl radicals is also possible. In Schultz s synthesis of hexahydro-phenanthren-2-one derivatives, " aryl bromide 160 was cyclized to 161 in 78% yield under standard conditions. Radical cascade reactions have become quite popular for the synthesis of polycyclic ring systems. In these reaction, polyenes are subjected to radical cyclization, generating tricyclic or even tetracyclic ring systems. 5 Chiral auxiliaries have been used effectively in radical cyclization reactions. ... 

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... 

Although the overall yield was modest, an interesting point was elucidated concerning this type of reaction. The polyene 95, although deviating substantially from the pattern of squalene-like disposition of methyl substituents previously studied and in no way simulating a natural intermediate, still cyclizes in significant amounts to a tetracyclic system. 

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