Cyclization Johnson polyene

A good example of this approach is the Johnson polyene cyclization reaction. The biogenetic 

When this process was extended to tetraene (195), treatment with acid gave the expected tricyclic alcohol (196), but in only 5-10% yield. The remainder of the product mixture was an intractable oil. As the number 

Incorporation of one pre-formed ring into the polyene system to stabilize the conformation. 

This cyclization is a Level 1 intramolecular cyclization as described by Deslongchamps (sec. 10.6.C). In acyclic systems, the conformation required for cyclization may not be the low energy conformation assumed by the polyene. When the polyene is attached to a preformed ring, the conformational stability of that ring will stabilize the entire polyene system, usually in the lowest energy all chair conformation required for efficient cyclization. Cyclopentanoid derivatives were found to be very effective for this purpose. 

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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... 

A reaction called the Johnson polyene cyclization (based on the Stork-Eschenmoser hypothesis) converts triene A into the polycyclic molecule B. When first discovered, an initially formed carbocation at one end of the polyene reacted with a nearby alkene to form a ring containing a new cation. This reacted with another nearby alkene, etc. The reaction was plagued by low yields and formation of polymeric material and decomposition products. This transformation required many years to perfect and two improvements were the use of a cyclopentenol unit on the left to initiate the sequence, which became a cyclopentene unit, and an alkyne unit on the right to end the sequence by generating a methyl ketone. Briefly discuss why these two improvements helped the problems inherent to this reaction. 

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

Johnson in 1993 described an approach to racemic p-amyrin involving application of a biomimctic polyene cyclization.7 In the same year Corey accomplished the enantioseleetive synthesis of compound 4. a key intermediate that opened the way to stereoselective preparation of compounds I, 2. and 3 8 A key step in the synthesis of P-amyrin (1) was the introduction of chiral oxazaboroli-dines for enantioseleetive carbonyl reduction. Ba ed on these methods, generation of an enantiomerically pure epoxide and its stereoselective cationic cyclization led to the pentacyclic system of structure 1 Diastereoselective cyclopropanation and an intramolecular protonation of a carbanion represent other interesting steps in this total synthesis. 

The biomitetic polyene cyclizations pioneered by Johnson have culminated in stabilizing the cation404,405 and extension to the syntheses of pentacyclic triterpenoids in one step from an acyclic precursor )406-409. Johnson summarized his 50 years of research in a review410. 

Steroid Synthesis (Chapter 2).—Notable achievements in the field of total synthesis come again from W. S. Johnson s group. A synthesis of ( )-progester-one featured acetylenic participation in a polyene cyclization. In vitro syntheses... 

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. 

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. 

Johnson el al. have used this asymmetric reduction to effect an asymmetric total synthesis of 11 a-hydroxyprogesterone (6) based on Johnson s method of polyene cyclization (5, 696). The key asymmetric step involved reduction of the ketone 2 to the alcohol 3 with the complex of 1 with lithium aluminum hydride. The yield of 3 was 93% with an enantiomeric ratio of (R) and (S>"of 92 8. The... 

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... 

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. 

In related studies designed to ascertain the elfect of a chiral centre remote from the initiating cationic centre on the stereochemical course of the polyene cyclization, Johnson has made the interesting observation that cyclization of (156), containing a pro-C- chiral centre, leads to only the 1 la-substituted diastereoisomer (157) of the tetracyclic product. Similarly, cyclization of the optically active acetal (158) with SnCU gave the axial and equatorial hydroxy-ethers (159) and (160), respectively, both with ca. 92% enantiomeric purity. ... 

Other reactions described, with varying degrees of success, have been chiral epoxidation, chiral hydrogenation, chiral iodination, and chiral reduction of keto-groups. One of the last reactions is especially interesting in using a chiral phase-transfer catalyst. Finally, Johnson and his co-workers have reported in full the asymmetric induction in their steroid synthesis via polyene cyclization [e.g. (46) (47) with ca. 90 % optical purity]. ... 

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. 

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