Polyene cyclization reactions

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. ... 

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]. 

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

Scheme 2.20 Organocatalytic asymmetric radical-mediated polyene cyclization reactions reported by MacMillan.

Five years later, Ley and coworkers [149] reported the total synthesis of tetronasin based on a biosynthetically inspired metal-templated polyene cyclization reaction of open chain precursor 310 (Scheme 1.49). By this transformation, Ley installed simultaneously four new stereocenters and obtained Yoshii s intermediate 312 with complete stereochemical control. 

In 2010, Toste s group reported the first example of a highly enantioselective polyene cyclization reaction in which transition metal-promoted alkyne activation serves as the cyclization initiating event [34], The (MeO-DTBM-BIPHEP)gold(I)-catalyzed reaction offers an efficient method for the stereoselective synthesis of polycyclic compounds... 

Enanlio- and diastereoselective polyene cyclization reactions promoted by small-molecule artificial enzymes have been developed as key steps for the practical synthesis of polycychc terpenoids based on biosynthetic pathways. Several examples as highlighted previously exist in the hterature mimicking the all chair transition state of the nonsterol folding, hi sharp contrast, there have been no successful examples of the polyene cyclization via a chair-boat transition state like sterol folding. In near future, more efficient and more effective catalytic biomimetic polyene cyclization reactions are expected to be developed. 

Chiral pyrogallol (14) derived LBA (15) was developed for enantioselective polyene cyclization reaction as an artificial cyclase by Yamamoto, Ishihara and coworkers in 2004 (Scheme 1.23) [26]. Various tricyclic skeletons have been synthesized with good enantioselectivities (79-85% ee) in the presence of chiral LBA (15). 

Intramolecular condensation reactions to generate six-membered carbocycles are mentioned in section 1.12, the polyene cyclization in section 1.15. 

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. 

As the intermediate formed in a polyene cyclization is a carbocation, the isolated product is often found to be a mixture of closely related compounds resulting from competing modes of reaction. The products result from capture of the carbocation by solvent or other nucleophile or by deprotonation to form an alkene. Polyene cyclizations can be carried out on reactants that have structural features that facilitate transformation of the carbocation to a stable product. Allylic silanes, for example, are stabilized by desilylation.12... 

The incorporation of silyl substituents not only provides for specific reaction products but can also improve the effectiveness of polyene cyclization. For example, although cyclization of 2a gave a mixture containing at least 17 products, the allylic silane 2b gave a 79% yield of a 1 1 mixture of stereoisomers.13 This is presumably due to the enhanced reactivity and selectivity of the allylic silane. 

Polyene cyclizations are of substantial value in the synthesis of polycyclic terpene natural products. These syntheses resemble the processes by which the polycyclic compounds are assembled in nature. The most dramatic example of biosynthesis of a polycyclic skeleton from a polyene intermediate is the conversion of squalene oxide to the steroid lanosterol. In the biological reaction, an enzyme not only to induces the cationic cyclization but also holds the substrate in a conformation corresponding to stereochemistry of the polycyclic product.17 In this case, the cyclization is terminated by a series of rearrangements. 

As with carbocation-initiated polyene cyclizations, radical cyclizations can proceed through several successive steps if the steric and electronic properties of the reactant provide potential reaction sites. Cyclization may be followed by a second intramolecular step or by an intermolecular addition or alkylation. Intermediate radicals can be constructed so that hydrogen atom transfer can occur as part of the overall process. For example, 2-bromohexenes having radical stabilizing substituents at C(6) can undergo cyclization after a hydrogen atom transfer step.348... 

HWE reaction has been used extensively for the synthesis of dienes and polyenes. Examples from recent literature are shown in Table 16 (dienes) and Table 17 (polyenes). HWE reaction also has been used for intramolecular cyclizations leading to polyene macrolides (Table 18). 

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. 

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... 

In the simulation of enzymes attempts have been made to use steroid matrices and biomimetic reactions of polyene cyclization, comprehensively described in Ref. [10]. 

These selection rules can also be obtained from an analysis of polyene cyclizations. If the interaction between the terminal atoms Ca and Cn is bonding (antibonding), it will favor (disfavor) the cyclization. Figure 4.5 shows how the contribution of any given MO changes as a function of the reaction stereochemistry. When p is odd (even) the conrotatory process is disfavored (favored) and the disrotatory process is favored (disfavored). Obviously, the preferred pathway can be deduced by summing the contributions of all of the occupied MOs, up to and including the HOMO ... 

When a cyclic polyene is large enough, it can exist in both cis- and iraws-forms. Our approach to polyene cyclization has tacitly assumed an all cis -n chain in the form of a band or ribbon that would slip smoothly on to the surface of a cylinder of appropriate diameter. Should the orbitals of the two polyenes in (36) have a mismatch in their orbital symmetries, a single twist in the tt band of one of them could remedy this (Fig. 10c). Cycloaddition would now be allowed and the reaction would proceed, provided other factors were favorable. Such cases of Mobius (Zimmerman, 1966), anti (Fukui and Fujimoto, 1966b) or axisymmetric (Lemal and McGregor, 1966), as opposed to Hiickel, syn, or sigma-symmetric ring closure are unknown (or, at least, rare). A Mobius form has, however, been proposed as the key intermediate in the photochemical transformations of benzene (Farenhorst, 1966) in (48) in place of the disrotatory cyclization proposed by van Tamelen (1965). 

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. 

PtCB was shown to catalyze a multistep reaction of an A-methyl indole with pent-3-yn-l-ol in THF effectively, to form a tetrahydrofuran substituted adduct as shown below <07CEJ8285>. Platinum(II) <07JA11880> and gold(I)-catalyzed <07JA3798> polyene cyclizations were known to lead to polycyclic products with a tetrahydrofuran ring embedded. 

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