A new approach to steroid total synthesis. A nonenzymic biogenetic-like olefinic cyclization involving the stereospecific formation of five asymmetric centers

Johnson, William S.; Semmelhack, M. F.; Sultanbawa, M. Uvais S.; Dolak, Lester A.

doi:10.1021/ja01013a066

Cited by 50 publications

(24 citation statements)

References 4 publications

(6 reference statements)

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“…Stork 2 and Eschenmoser 3 first proposed that polyene cyclizations in nature are electrophilically initiated and proceed through a cationic cascade pathway. Although the Stork-Eschenmoser hypothesis was widely accepted, polyene cyclizations were thought to be limited to the domain of enzymatic transformations until the pioneering works of W. S. Johnson 4 and E. E. van Tamelen, 5 who demonstrated that these reactions still proceed with high diastereoselectivity and synthetically useful yield using solely chemical methods. In the following decades, cationic, anionic, and radical cyclizations of polyenes have been employed as the key step in the laboratory syntheses of hundreds of natural products.…”

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Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes

et al. 2018

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A sulfenium-ion-initiated, catalytic, enantio-selective polyene cyclization is described. Homogeranylar-enes and ortho-geranylphenols undergo polycyclization in good yield, diastereoselectivity, and enantioselectivity. The stereodetermining step is the generation of an enantio-merically enriched thiiranium ion from a terminal alkene and a sulfenylating agent in the presence of a chiral Lewis basic catalyst. The use of hexafluoroisopropyl alcohol as the solvent is crucial to obtain good yields. The thioether moiety resulting from the reaction can be subsequently transformed into diverse oxygen and carbon functionality postcyclization. The utility of this method is demonstrated by the enantioselective syntheses of (+)-ferruginol and (+)-hinokiol.

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confidence: 99%

Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes

et al. 2018

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“…In 1968, Johnson and collaborators achieved the first synthesis of a polyprenoid in a biomimetic fashion (Scheme 1) (Johnson et al, 1968). This achievement stimulated further studies, which have been presented in an excellent review in 2005 (Yoder & Johnston, 2005).…”

Section: Recent Progress In the Biomimetic Synthesis Of Polyprenoidsmentioning

confidence: 99%

Biomimetic Synthesis and Properties of Polyprenoid

Ribeiro¹,

Gotoh²,

Nakatani³

et al. 2011

On Biomimetics

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“…As outlined in Scheme 2-5, dZ-16-dehydroprogesterone (55) has been obtained by the use of the tetraenic alcohol 51 which was, in turn, prepared by multiple routes [39][40][41]. In the initial preparation [39], the cyclopropyl ketone 37 was converted in 88% yield into 38 by condensing with diethyl carbonate (to give a keto ester), alkylating with methylallyl chloride, and then hydrolyzing and decarboxylating by successive treatment with barium hydroxide and hydrochloric acid [42]. This product was readily reduced to the corresponding alcohol which, by a modification of the Julia olefin synthesis [43], was transformed into the dienic bromide 42 (R = CH 2 Br).…”

Section: Total Synthesis From Nonepoxide Precursorsmentioning

confidence: 99%

Biogenetic-like Steroid Synthesis

1974

Organic Chemistry: A Series of Monographs

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The emergence of the correct scheme for the biological conversion of squalene into lanosterol and thence into cholesterol [1][2][3][4] was the starting point for intensive investigations by many workers into the more intimate details of this and similar cyclizations. Particularly intriguing to synthetic chemists was the stereospecificity of this polyolefin cyclization in which a compound (squalene) containing no asymmetric centers was converted into another (lanosterol) possessing seven centers of asymmetry. Theoretically this latter material may exist in 128 different isomeric forms; however, only one is actually produced. A stereoelectronic theory which correctly explained these results was presented independently in 1955 by two groups and has come to be known as the Stork-Eschenmoser hypothesis [5,6]. In its simplest terms the theory predicts that cationic cyclization of trans olefin 1 will lead to the trans fused product 2 via a concerted mechanism involving the entering electrophile Y + and the nucleophile X~. The product obtained should therefore be a result of an antiparallel addition mechanism and should possess substituents X and Y in eis diequatorial relationship. Extension of the olefin chain such that X~ is another ττ-bond will lead to an analogous trans-anti-trans tricycle. Also illustrated in Scheme 2-1 is the related cyclization of a eis olefin 3 to give the eis product 4. Interestingly, when this theory was first tested by Eschenmoser, negative results were 35 2 36 2 Biogeiietiolike Steroid Synthesis Scheme 2-1 obtained [7]. Thus acid-catalyzed cyclization of the methyl ester of irans-demethylfarnesic acid (1, R = C0 2 Me, R' = H) gave the expected trans-decalin derivative; but similar treatment of the eis compound 3 (R = C0 2 Me, R' = H) did not provide the predicted cis-fused decalin. This apparent anomaly was resolved when it was discovered that, under the conditions employed for these cyclizations, the reaction was, in fact, nonconcerted and an intermediate cyclohexane derivative could be isolated (and further converted into the frans-deealin) [6]. Subsequent investigations by numerous workers have solidly established the validity of the Stork-Eschenmoser hypothesis.Although this explanation clarifies much of the biosynthesis of natural terpenoids and sterols, it does not adequately account for the formation of lanosterol (7) from squalene oxide (5). It is at this point that the role of the enzyme is presumed important in biological cyclizations. Thus, the conformation illustrated in 5 (potential B ring in boat form) is suggested to result from the template-like action of the lanosterol cyclase enzyme; a concerted cyclization would then provide an intermediate such as 6 which possesses the stereochemistry necessary to yield 7 upon appropriate methyl-hydrogen shifts. Alternatively, if the enzyme holds the polyolefin in the all-chair conformation, there results various terpenoids of the euphol class. Recent work by van Tamelen has elegantly demonstrated the correctness of these theories [8][9][1...

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A new approach to steroid total synthesis. A nonenzymic biogenetic-like olefinic cyclization involving the stereospecific formation of five asymmetric centers

Cited by 50 publications

References 4 publications

Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes

Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes

Biomimetic Synthesis and Properties of Polyprenoid

Biogenetic-like Steroid Synthesis

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