Cyclization of polyene

Cyclization of polyenes by intramolecular rr-attack on an oxirane is an important biochemical reaction (Section 5.05.5.2). 

Polyene Cyclization. Perhaps the most synthetically useful of the carbo-cation alkylation reactions is the cyclization of polyenes having two or more double bonds positioned in such a way that successive bond-forming steps can occur. This process, called polyene cyclization, has proven to be an effective way of making polycyclic compounds containing six-membered and, in some cases, five-membered rings. The reaction proceeds through an electrophilic attack and requires that the double bonds that participate in the cyclization be properly positioned. For example, compound 1 is converted quantitatively to 2 on treatment with formic acid. The reaction is initiated by protonation and ionization of the allylic alcohol and is terminated by nucleophilic capture of the cyclized secondary carbocation. 

The cationic cyclization of polyenes to give multi-ring carbocyclic compounds with many sterically defined centres is one of the more remarkable examples... 

Mercuric ion has been found to be capable of inducing cyclization of polyenes. 

This technique applies to many open-chain compounds, as discussed in later chapters. Pertinent here is the intramolecular cyclization of polyenes (an electrocyclic reaction). 

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. Other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol Besides the aforementioned A-ring aromatic steroids and contraceptive agents, partial synthesis from steroid raw materials has also accounted for the vast majority of industrial-scale steroid synthesis. 

The last plausible pathway is a jt-allylmetal pathway. n-Allylmetal species are well known in organometallic chemistry for alkylations and cyclizations [53]. This pathway is not common for enyne cycloisomerization and most examples available in the literature are associated with the cyclization of polyenes [54, 55]. The... 

Jt-allyl complex can be generated after cyclization, as suggested by Takacs in a Fe(0)-catalyzed cyclization of polyenes. It also can be preformed if an active functional group is present in the allylic position. The palladium-catalyzed intramolecular cycloisomerization reaction of allylic acetates is an efficient method for constructing five- or six-membered rings [56, 57]. An asymmetric approach to this transformation has been studied and so far only poor enantioselectivity has been achieved (0-20% ee) [58]. Very recently, Zhang et al. also reported a Rh-catalyzed cycloisomerization involving a Jt-allylrhodium intermediate formed from an allylic halide [59]. 

Nature often provides excellent suggestions about how to synthesize a compound. After the pathway for the biosynthesis of steroids by cationic cyclization of polyenes was determined, Professor William S. Johnson and coworkers at Stanford University used a very similar reaction to synthesize progesterone. The last part of this synthesis is outlined in the following equations. Alcohol A was prepared in 12 steps with an overall yield of 10%. It was then cyclized to form the steroid ring system. 

The cyclization of polyenes described in previous Reports has been extended to the synthesis of some cembrenols. 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

This review covers the biosynthesis of terrestriai and marine polyethers and discusses their biologic properties and the molecular genetics and enzymology of the proteins responsible for their formation. The biosynthesis of monensin, nanchangmycin, nonactin, and the marine polyether ladders are discussed in detail. Novel enzymes found only in type I polyketide polyether gene clusters that are responsible for the epoxidation and cyclization of polyene biosynthetic intermediates are described. The macrotetrolide biosynthetic gene cluster, which is an ACP-less type II polyketide synthase that functions noniteratively is reviewed. 

SDS micelles were also employed for the light-induced cyclization of polyenes to steroids in low yield. No such reaction was observed in homogeneous organic solutions. Again, it is believed that only one polyene molecule is dissolved within one micelle. On the other hand, trans-cinnsimic acid produced dimeric products after UV irradiation in 1% aqueous CTAB, while no photodimers were formed in homogeneous solutions. ... 

Cyclization of ( )- and (Zy4,8-dimethylnona-3,7-diene-2-one. Acid-catalyzed cyclization of polyenes is now a fairly well-known reaction (3, 305).6 For example cyclization of 6,10-dimethyl-3.5,10-undecatnene-2-one (1) with concentrated sulfuric acid gives ft-ionone (2) in 85% yield.7... 

Biomimetic cyclization of polyenes as routes to diterpenoids continues to be explored. The brominative cyclization of geranyl-linalool afforded160 the 3-bromo-manoyl oxide and the boron trifluoride-catalysed cyclization of the diepoxide of p-homogeranylanisole gave 13-methoxy-A-homo-4a-oxopodocarpatrienol.161 Some further synthetic studies of anhydroverticillol have been reported.162... 

Acidic resins [1, 514, after citation of ref. 17]. The biogenetically patterned cyclization of polyenes by Lewis acid catalysts can also be effected by cation-exchange resins (Amberlite IR-20 and XE-100).17a Thus methyl trans.trans-iarntsate (1) is cyclized by XE-100 in acetic acid to (2), (3), and (4), separable by gas chroma-... 

Cyclization of polyenes. Treatment of fran -geranylgeranic acid chloride (1) with 1 eq. of stannic chloride in methylene chloride at -78° (1.5 hr.) effects cyclization to (2) in 71% yield. The reaction is of interest because it may be representative of the biogenesis of the 14-membered cembrene diterpenes. 

Biomimetiepolyene cyclizations (5, 316). Johnson has reviewed cyclizations of polyenes to polycyclic natural products. 

Cyclization of polyenes. Reaction of nerolidol (1) with this brominating agent (1) in CH2CI2 (20°, 3 hours) yields a- and /J-snyderol, (2) and (3), in low yield. These bromine-containing monocyclic sesquiterpenes have been isolated recently from a marine red algae species. ... 

CycUzations. The biomimctic cyclizations of polyenes have been reviewed by. lohnson (86 references). ... 

Cation-JT interactions are also prominent at the active sites of enzymes involving cationic substrates. Key examples include the blood coagulation serine proteases Factor Xa and thrombin, and a number of enzymes that use S-adenosyhnethionine. a sulfonium ion that serves as nature s ubiquitous methyl transfer agent. A spectacular series of examples is the array of enzymes that catalyze the cationic cyclizations of polyenes in a key step of terpene and steroid biosynthesis. It is now clear that... 

To be of maximum synthetic value, the generation of the cationic site that initiates cyclization must involve mild reaction conditions. Formic acid and stannic chloride have proved to be effective reagents for cyclization of polyunsaturated allylic alcholos. Acetals generate a-alkoxy carbocations in acidic solution and can also be used to initiate the cyclization of polyenes ... 

Polyene cycUzation of epoxy trienylsilanes 114 by use of TiCLj in CH2CI2 containing 2,6-di-tert-butylpyridine at —78°C gives a mixture of 9,10-syw and 9,10-anti bicycles 117 and 118 in comparable amounts (equation 49). The formation of six-membered ring products proceeds through a chair/chair or a chair/boat transition state (i.e. 115 and 116) with similar steric interactions. These results contrast sharply with the consistent bias favoring the chair/chair orientation in the cyclization of polyene epoxides lacking the MesSi substiment " . ... 

Acylation of phenols Cyclization of polyenes Hydrolysis of amides COOH = Terminal thiohydantoin hydrolysis... 

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