Polyene Cyclizations and Polycyclic Synthesis

Johnson and his co-workers have developed an efficient chiral approach to the lla-hydroxyprogesterone synthetic precursor (115). ° The chiral centre is introduced by reduction of an a-keto-acetylene with a complex hydride derived from lithium aluminium hydride and Darvon alcohol (116) subsequent elaboration of (115) to the steroidal system established that asymmetric cyclization occurs without any perceptible racemization. 

Kametani, H. Nemoto, H. Ishikawa, K. Shiroyama, H. Matsumoto, and K. Fukumoto, J. Amer. Chem. 

3-Methoxyoestra-l,3,5(10)-triene (122) has been prepared stereospecihcally by a hydroboration-carbonylation procedure. Treatment of the diene (120) with thexylborane resulted in regio- and stereo-selective formation of the carbaborane (121). Carbonylation and oxidation of (121) led to the tricyclic ketone (123) which was readily cyclized by acid catalysis to (122). 

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Polyene cyclizations have been of substantial value in the synthesis of polycyclic natural products of the terpene type. These syntheses resemble the processes by which terpenoid and steroidal compounds are assembled in nature. The most dramatic example of biological synthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, the enzyme presumably functions not only to induce the cationic cyclization but also to bind the substrate in a conformation corresponding to the stereochemistry of the polycyclic product.21... 

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 early Escherunoser-Stork results indicated, that stereoselective cyclizations may be achieved, if monocyclic olefins with 1,5-polyene side chains are used as substrates in acid treatment. This assumption has now been justified by many syntheses of polycyclic systems. A typical example synthesis is given with the last reaction. The cyclization of a trideca-3,7-dien-11-ynyl cyclopentenol leads in 70% yield to a 17-acetyl A-norsteroid with correct stereochemistry at all ring junctions. Ozonolysis of ring A and aldol condensation gave dl-progesterone (M.B. Gravestock, 1978 see p. 279f.). 

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. ... 

Many naturally occurring polyethers such as brevitoxin B (123) have been proposed to biosynthetically derive from the polyepoxidation of polyenes and subsequent cyclization of the resulting polyepoxides (Scheme 3.40) [79, 80]. Such a biomimetic polyene-polyepoxide-polycyclization approach would provide a potentially powerfid and versatile strategy for the synthesis of polyethers, with quick assembly of stereochemically complex molecules from relatively simple achiral polyalkene precursors. The epoxidation with ketone 42 should provide a valuable method to investigate this biosynthetic hypothesis and possible application of the proposed pathway in the synthesis of polyethers. 

Cyclization reactions of (7,77 -enylpalladium complexes are intramolecular insertions of the coordinated double bond into the Pd-C(organic synthesis (intramolecular Heck reactions) and, when polyene substrates are used, sequential insertions in undetected <7,77 -enyls lead to polycyclic compounds in a synthetically very efficient process. Examples of this reaction starting from isolated, well characterized a,if-onyh of palladium are, however, scarce. Equation (62) shows the formation of a tricyclic derivative by cyclization of a a,if-enyl derived from < ti-5-vinyl-2-norbornene promoted by CuCl2. ... 

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