Cyclization reactions polyenes

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

Acyl radicals can be generated and they cyclize in the usual manner. A polyene-cyclization reaction generated four rings, initiating the sequence by treatment of a phenylseleno ester with Bu3SnH/AIBN to form the acyl radical, which added to the first alkene unit. The newly formed carbon radical added to the next alkene, and so on. Acyl radicals generated firom Ts(R)NCOSePh derivatives cyclize to form lactams. ... 

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. 

Some excellent examples of cationic polycyclizations, especially in the field of steroid synthesis, were described in Chapter 1. However, these polycyclizations can also be performed using a radical as initiator. Such reactions can be divided into those based on serial 6-mdo-trig cyclizations from polyene acyl precursors [92], radi-... 

Dienes and polyenes can undergo a variety of intermolecular cyclization reactions, the exact nature of which is dependent on the number of double bonds, the relative positions of these bonds with respect to each other, the preferred conformation of the diene or polyene system and the reaction partner. 

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

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. 

A beautiful example of electrocyclic reactions at work is provided by the chemistry of the endiandric acids. This family of natural products, of which endiandric acid D is one of the simplest, is remarkable in being racemic—most chiral natural products are enantiomerically pure (or at least enantiomerically enriched) because they are made by enantiomerically pure enzymes (we discuss all this in Chapter 45). So it seemed that the endiandric acids were formed by non-enzymatic cyclization reactions, and in the early 1980s their Australian discoverer, Black, proposed that their biosynthesis might involve a series of electrocyclic reactions, starting from an acyclic polyene precursor. 

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). 

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. ... 

Over the past twenty years, the intramolecular allylation of aldehydes has been used in the synthesis of natural products containing a-methylene-y-lactones [95-101] (e.g. confertin [99] and cembranolide [100, 101]), polyene-containing macro-lides [102, 103] (e.g. asperdiol [102]) and, more recently, cyclic ether containing natural products (e.g. (-i-Vlaurencin [104] and hemibrevetoxin B [105]). However, the principles that govern the stereoselectivity in these cyclization reactions have only recently been studied in a systematic manner (see below). 

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... 

In a more impressive polyene cyclization, reaction of the optically active allylic alcohol 147 with trifluoroacetic acid and ethylene carbonate followed by workup with K2CO3 in aqueous methanol furnished the optically active product 150. The reaction is initiated by a yyn-selective SN2 reaction with allylic rearrangement (Sn2 ) and proceeds through the carbonate-trapped intermediate 149. Likewise, the reaction of the enantiomer of 147 furnished the enantiomer of 150. The cyclization step was essentially enantiospecific. The process involves total asymmetric synthesis due to a single chiral center in the starting allyl alcohol [24]. 

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. 

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

There are many synthetic examples that use radical cyclization as a key step, and the radical precursor is not limited to iodides or bromides. In Pattenden s synthesis of pentalenene, conjugated selenyl ester 156 was treated with Bu3SnH and AIBN to give a 45% yield of tricyclic ketone 159. Loss of PhSe generated the acyl radical 157, which exists in equilibrium with the ketene radical 156. Radical cyclization via the latter intermediate leads to 159. Cyclization via aryl radicals is also possible. In Schultz s synthesis of hexahydro-phenanthren-2-one derivatives, " aryl bromide 160 was cyclized to 161 in 78% yield under standard conditions. Radical cascade reactions have become quite popular for the synthesis of polycyclic ring systems. In these reaction, polyenes are subjected to radical cyclization, generating tricyclic or even tetracyclic ring systems. 5 Chiral auxiliaries have been used effectively in radical cyclization reactions. ... 

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. ... 

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