Biomimetic polyene cyclizations

Biomimetic-type synthesis may be defined as the design and execution of laboratory reactions based upon established or presumed biochemical transformations. This implies the development of chemical transformations new to the nonbiological area and the elaboration of elegant total synthesis of various natural product precursors. Efforts in this direction have been conducted by two schools one by E. E. van Tamelen (207) and the other by W. S. Johnson (208,209), both at Stanford University. 

Squalene is the precursor of sterols and polycyclic triterpenes. In the 1950s, G. Stork (Columbia University) and A. Eschenmoser (ETH, Zurich) proposed that the biogenetic conversion of squalene to lanosterol involved a synchronous oxidative cyclization pathway. The transformation is acid catalyzed and proceeds through a series of carbonium ions to allow the closure of all four rings. There is now ample evidence that the first step is the selective epoxidation of the -double bond to form 2,3-oxidosqualene (Fig. 5.21). 

The earlier work of van Tamelen showed that squalene can be converted chemically to the 2,3-bromohydrin with hypobromous acid in aqueous glyme (210). In addition, JV-bromosuccinimide (NBS) treatment of squalene in water selectively gives the desired terminal bromohydrin. Treatment with ethanolic base results in the racemic 2,3-oxidosqualene. Using rat liver homogenate under standardized aerobic conditions, racemic 2,3-oxidosqualene finally gives rise to sterol fractions which can be purified by chromatography. 

Furthermore, it was demonstrated that 2,3-oxidosqualene is synthesized directly from squalene in the sterol-forming rat liver system. The former is a precursor of sterols and is far more efficiently incorporated than squalene under anaerobic conditions. Therefore, it seems very likely that the intermediate 2,3-oxidosqualene is cyclized by an enzymatic mechanism that leads to lanosterol, the precursor of cholesterol and other steroid hormones. Of course, in the enzymatic process only one isomer, the 3-S-isomer, of the epoxide is formed. 

Closer examination of the 2,3-oxidosqualene skeleton reveals the presence of three distinct Ti-electron systems designated a, /S, and y-regions (210, 211). 

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

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. 

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. 

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. 

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. 

With this brief overview of the enzymatic conversion of squalene to lanosterol, we can now envisage strategies for the total synthesis of polycyclic natural products in the laboratory. This field of bioorganic chemistry has been called biomimetic polyene cyclizations by Johnson. 

W. S. Johnson (1976), Biomimetic Polyene Cyclizations. Bioorg. Chem. 5, 51-98. 

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. 

Propargyltrimethylsilanes can be readily prepared from halomethyltrimethyl-silane and the 1-yne anion. They have been extensively used in organic synthesis of furanones and allenes, and like silylacetylenes, as terminator groups for biomimetic polyene cyclizations and the generation of steroids. ... 

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. 

This methodology has been applied to a highly stereoselective biomimetic polyene cyclization using chiral tricarbonyl(ii -l-pentadienol)iron complexes to give rise to franj-decaline (Ti -diene)iron complexes. The transformation represents a potential route to bicyclic sesquiterpenes and tricyclic diterpenes (Scheme 4-191). ... 

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