Cyclizations cationic polycyclization

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-... 

Inspired by the previous work, the Jacobsen group further developed the enan-tioselective cationic polycyclization. After careful studies on the reaction conditions, the authors selected chiral thiourea catalyst 98 for the asymmetric cyclization of hydroxylactams 99, affording the products 100 in good yields and with excellent enantioselectivity (Scheme 36.26) [32]. 

Closely related to the polyepoxide cascade procedure for the synthesis of polycyclic systems is Corey s biomimetic-type, nonenzymatic, oxirane-initiated (Lewis acid-promoted) cation-olefin polyannulation. By this strategy, compound 96, containing the tetracyclic core of scalarenedial, was constructed by exposure of the acyclic epoxy triene precursor 95 to MeAlCl2-promoted cyclization reaction conditions (Scheme 8.25) [45]. 

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. 

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. 

Removal of the amide function is much easier if the reaction is intramolecular, and —CONEt2 amides (sometimes even —CONPr-i2 amides) may be converted to lactones, lactams and other heterocycles in this way . Addition of an aldehyde or ketone as an electrophile generates a hydroxyl group (in some cases, atroposelectively, as it happens —though this is usually irrelevant to the stereochemistry of the product) which cyclizes to give a lactone via a benzylic cation in acid. This reaction has found wide use in the synthesis of polycyclic aromatics, particularly alkaloids. 

Blechert et al. have proposed a new effective approach to the synthesis of different indole alkaloids using cation domino reactions (95S592, 97AGE1474). The total yield of uleine (7a), produced on the basis of this concept, is 32%, which is quite unique in the synthesis of polycyclic indole alkaloids. Note that this is the total yield, starting from cyclohexenone 46 the yield of the key step of the synthesis - the cyclization of carbazole 47 into 7a is 95% (Scheme 12). 

Upon acylation of some benzyl carbonyl compounds (25, R = H, Me 51, R = OH) dibenzo[a,tropylium salts 65 have been isolated in low yields (5-15 %) along with the major products, 2-benzopyrylium salts. Veratryl acetone 25 (R = Me) as well as homoveratric aldehyde 25 (R = H) (or carboxonium ions 31 which are formed from them) may undergo an oxidative a-cleavage, resulting in the benzyl cation 64. The formation of the same cation from homoveratric acid 51 is the result of decarbonylation of the acylium ion 63. Further interaction of the benzyl cation 64 with the substrate, followed by cyclization and oxidation, results in the polycyclic tropylium salts 65 (82ZOR589). 

As presented in this chapter, olefins can become protonated under acidic conditions, leading to the formation of electrophilic and cationic carbon atoms. Furthermore, because olefins have nucleophilic character, they can add to sites of positive charge. The cascading of this mechanism, illustrated below, generates polycyclic systems through the cation-77 cyclization. 

We will start now to draw squalene in a coiled up way as the next-step is the polycyclization of the epoxide. The basic reaction is best seen first in the flat, though we will draw the stereochemistry immediately. The first alkene cyclizes on to the epoxide and then each remaining alkene cyclizes on to the next to give a stable tertiary cation. 

Interestingly, /3,7-unsaturated a-diazoketones are also sources of cyclo-butanones when they are exposed to protic acid. For example, compound XI furnished XII in high yield upon contact with concentrated sulfuric acid (see Scheme 42.3). In a conceptually analogous reaction, /S.y-unsaturated a-diazoketones proved to be useful in the constmction of cyclopentanones XIV" in a polyolefinic cationic cyclization process reminiscent of the mechanism by which plants in nature build their polycyclic triterpenoid metabolites from squalene, that is, XV - XVI. 

An alkene unit can also be used to generate a cation and cyclize to form a polycyclic aromatic compound. When 229 reacted with acetaldehyde, 230 was produced and this was cyclized by treatment with sulfuric acid to give hydronapthalene (231). This modification does not incorporate the additional ring of the cyclic ketones used in the Bogert-Cook reaction it is sometimes called the Bogert synthesis. 

The biogeneses of cyclic and polycyclic terpenes are usually assumed to involve intermediate carbenium ions, but evidence for this in vivo was given only in some specific cases. In the simple case of monocyclic monoterpenes such as limonene the allylic cation remaining after separation of the pyrophosphate anion cyclizes to a cyclohexyl cation which is deprotonated to (/ )- or (5)-limonene. 

A similar cyclization generates the 14-membered skeleton of cembrane from which other polycyclic diterpenes are derived. 3,7,11,15-Cembratetraene, better known as cembrene A, emerges directly from geranylgeranylpyrophosphate (Fig. 2) involving the 1,14-cyclization of the resulting allylic cation... 

The biogenesis of pimarane, the parent compound of many polycyclic diterpenes, is assumed to arise from Ko-geranylgeranylpyrophosphate After dissociation of the pyrophosphate anion, the remaining acyclic allylic cation undergoes a 1,3-sigmatropic hydrogen shift and thereby cyclizes to a monocyclic carbenium ion which, itself, isomerizes to the ionic precursor of the pimarane skeleton. 

Cyclization reactions of natural rubber and other polymers from conjugated dienes have been known for a long time. The reactions occur in the presence of Lewis and strong protonic acids. They result in loss of elastomeric properties and some unsaturation. Carbon cations form in the intermediate step and subsequent formation of polycyclic structures ... 

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