Cyclization with polyenes

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... 

Regioselective bromination of polyenes.1 The first steps in a biomimetic synthesis of concinndiol (4) from methyl geranylgeranate (2) involve regioselective bromination with 1 followed by cyclization with AgOAc in HOAc to 3 in 20% overall yield. 

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. 

Stereoisomeric alcohols (93) and (94) yielded identical ring-expansion products [e.g. (97)] on formation of carbocations.168 This is evidence of a stepwise reaction in sterol biosynthesis, whereby a tertiary cation [e.g. the model (95)] rearranges to a secondary cation (96)-an anti-Markovnikov rearrangement . The synthetic aspects of biomimetic cyclizations of isoprenoid polyenes were reviewed.169 Included was a detailed discussion of carbenium ion-initiated cyclizations, with a discussion of the different mechanisms that have been proposed. A novel biomimetic carbocation polyene cyclization of a daurichromenic ester was reported an unusual 2 + 2-carbocation cyclization occurred as a side reaction.170... 

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... 

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. 

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 electrocyclization leading to a 1,6-fused cyclohexadiene also takes place with polyenes. A photochemical example from the vitamin A field is exemplified by the conrotatory phot clization of the (7Z)-isomer (IW) of retinal (185) to the bicyclic derivative (187). The photocyclization procedure has also been used in the aromatic series. - Thus the photocyclization-oxidation reaction of l-phenyl-4-(2 -thienyl)-1,3-butadiene (188) gave 4-phenylbenzo[b]thiophene (189). Similarly, the 3 -thienyl analogue (190) afforded 7-phenylbenzo[b]thiophene (191), the reaction exhibiting high selectivity for cyclization to the logically more reactive thiophene nucleus. ... 

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... 

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. 

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. ... 

Neither compound exhibits properties that would suggest aromaticity. The NMR spectra are consistent with polyene structures. Both compounds are thermally unstable and rapidly undergo cyclization back to dihydronaphthalenes ... 

Scheme 12.23 Polyene cyclizations with ortho-substituted BINAP and BIPHEP ligands.

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 " . ... 

The density of the a-polymorph is 1.98 g cm amorphous PVDF has a density of 1.68 g cm . Thus, commercial samples with a density of 1.75-1.78 g cm have 45% crystaUinity. The a-polymorph melts at 170 °C however, the processed polymer, because of its polymorphism, displays no sharp melting point but melts between 150 and 190 °C. The thermal decomposition becomes significant at T > 300°C. Pyrolysis of PVDF yields hydrogen fluoride, the monomer C2H2F2 and C4F3H3 [12]. Up to 600 °C, pyrolysis also yields polyaromatic structures by cyclization of polyenic intermediates formed through HF ehmination [16]. This is a particular advantage over PTFE, which is less likely to yield carbonaceous products. Thus in obscurant applications, PVDF is preferred over PTFE as a fluorine source (see Chapter 11). 

The chiral alkoxytrialkylaluminate, LiBu AlOR [R OH is (—)-A-methyle-phedrin (87)] allows transfer of the Bu" group to carbonyl compounds with moderate (up to 30%) optical induction. (88 L == HMPT) can be used to oxidize trialkyla-lanes. Bu AlH can be used to catalyse the cyclization of polyenes, (89), for example, being obtained from (90) in quite good yield by this method. ... 

The synthesis in Scheme 13.38 combines elements of a biomimetic-type polyene cyclization with a rearrangement similar to that just described in Scheme 13.37. The early stages of the synthesis culminate in the construction of the allylic alcohol in step B. In step C, it is epoxidized using the stereoselective VO(t-BuOOH) method (Section 12.2.1). This epoxidation provides the key intermediate for the polyene cyclization. The mild Lewis acid FeCla is used to promote the cyclization, which terminates in an electrophilic substitution of the methoxyphenyl substituent. Steps E and F convert the methoxyphenyl ring to a diene. This diene undergoes a Diels-Alder reaction in step G. After catalytic reduction of the double bond, the anhydride is subjected to an oxidative bis-decarboxylation (see Section 12.4.2 for discussion of this reaction). The resulting alkene is epoxidized, and the epoxide is reduced. A rearrangement is done at this point. The reaction is similar to that used in Scheme 13.37, except that it involves a saturated, rather than allylic, system. The final steps in the synthesis are those used in Schemes 13.33 and 13.34. 

Yamamoto and Ishihara et al. developed enantioselective polyene cyclization with predictable absolute configurations and excellent enantioselectivities using the chiral LBA (Scheme 10.23) [45]. They further succeeded in produdng new chiral LBA consisting of chiral pyrogallol derivatives and SnCU, which effedively promotes the cyclization of 2-geranylphenol derivatives (Scheme 10.24) [46]. 

The first successful application of RRCM in complex namral product synthesis was reported by Porco et al. in 2005 (Fig. 16) [59]. In the synthesis of oximidine III (51) they successfully cyclized the polyene precursor (52) to access macrolide (53) with a Z-double bond using Hoveyda-Grubbs catalyst... 

The achiral triene chain of (a//-rrans-)-3-demethyl-famesic ester as well as its (6-cis-)-isoiner cyclize in the presence of acids to give the decalol derivative with four chirai centres whose relative configuration is well defined (P.A. Stadler, 1957 A. Escherunoser, 1959 W.S. Johnson, 1968, 1976). A monocyclic diene is formed as an intermediate (G. Stork, 1955). With more complicated 1,5-polyenes, such as squalene, oily mixtures of various cycliz-ation products are obtained. The 18,19-glycol of squalene 2,3-oxide, however, cyclized in modest yield with picric acid catalysis to give a complex tetracyclic natural product with nine chiral centres. Picric acid acts as a protic acid of medium strength whose conjugated base is non-nucleophilic. Such acids activate oxygen functions selectively (K.B. Sharpless, 1970). 

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.). 

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