Diastereoselectivity polycyclic systems

The alkylation of cyclopentanoid enolate groups, which are part of polycyclic systems, is a common step in natural product syntheses, particularly in the synthesis of terpenoids and steroids. A high degree of stereoselectivity is usually encountered in such reactions, for example, in the preparation of the bicyclic compounds 17-2054 59. Steric, rather than electronic, control elements determine the diastereoselectivity. 

The development, by Snider, of intramolecular cyclizations of unsaturated p-keio esters with Mn(III) and Cu(II) has been the souree of numerous and speetacular cascades [27]. Intrigued by the potential of this chemistry as a biomimetic approach to polycyclic systems, Zoretic [28] reported the tetracyclization of precursor 46 to provide tetracyclohexyl derivative 47, in which seven asymmetric centers have been established with complete stereocontrol (Scheme 16). This remarkable sequence deserves several comments. The regioselectivity 6-endo-tng) and diastereoselectivity of the initial cyelization is consistent with Snider s seminal studies notably the ester group adopts an axial position to minimize unfavorable dipole/dipole interactions with the ketone. The two subsequent 6-endo-lng cyclizations that can be rationalized by a slower 5-exo mode of cyelization involving a bond formation sandwiched... 

Organo-SOMO catalysis was also applied to polyene cyclization. In 2010, MacMillan reported an enantioselective cyclization reaction of substrates 41 for accessing steroidal and terpenoidal frameworks. They used imidazolidinone 40 instead of catalyst 23, with the aid of copper(ll) triflate as the oxidant. The polyene cyclization took place smoothly, giving polycyclic systems 42 and even more complex compounds 43 or 44 in good yields and with high enantioselectivity and exclusive diastereoselectivity (Scheme 36.12) [18]. 

An electrophilic Pd(ll) source, the dicationic pincer complex Pd(PNP)(BF4)2 (PNP = 2,6-bis(diphenylphosphanylmethyl)pyridine), was exploited in a cascade polycyclization of 1,5- and 1,6-dienes bearing an -OH nucleophile to give polycyclic systems. The diastereoselectivity was consistent with the hypothesis of a cationic intermediate [94], The stability of the metal species intermediate prevented -elimination. Similar result was obtained with a Pt dicationic pincer complex (Scheme 46) [95],... 

A number of reports have appeared on the use of carbonyl-alkene additions to construct oxacyclic ring systems efficiently with high diastereoselectivity. Nakata showed that even the formation of seven-membered cyclic ethers using the transformation can be remarkably efficient and utilised the strategy to form the E ring of the polycyclic ether marine natural product yessotoxin (Scheme 5.34).64... 

Sml2-H20-amine mediated diastereoselective intramolecular couplings were reported for the synthesis of dihydrobenzofuran, and a radical mechanism was proposed to account for this reaction <03OBC2423>. A similar approach for the synthesis of pyridine-fused polycyclic amines was also developed by use of AlBN/BUjSnH as a reducing system <03TL2995>. 

Several detailed investigations of transannular IMDA cycloadditions have appeared in recent years. This transformation promises to become an important synthetic method owing to the potential for the rapid efficient construction of complex polycyclic ring systems. Other potenti strategic benefits include increased reactivity due to diminished entropic requirements (AS ). This is nicely illustrated by the facile cyclization of (101) with a tetrasubstituted dienophile, compared with the unsuccessful IMDA reaction of (102) (Figure 27). Although the cyclization of (101) proceeds with only moderate diastereoselection, many other examples have been reported that exhibit outstanding selectivity, e.g. cyclization of (103). It is conceivable that conformational constraints imposed by the macrocyclic system may lead to improved IMDA stereoselectivity relative to conventional acyclic trienes, but this point has not yet been demonstrated in any published examples. 

Diazafulvene 424 reacts with alkenylcarbenes 425 through a formal [64-3] heterocyclization in a regio- and stereoselective manner to afford dihydroimidazo[l,2- ]pyridines 426. When enyne carbenes are treated with diazafulvene 424, consecutive and diastereoselective [64-2]/cyclopentannulation cyclization reactions take place affording new polycyclic complex systems 429 that can be appropriately demetallated to the corresponding imidazole-based fused systems. Finally, enyne carbenes undergo consecutive [64-2]/[54-l] cyclization reactions with diazafulvene 424 and rt-butyl-NC to yield tetracyclic adducts 432 (Scheme 102) <2006CEJ3201>. 

Timmermans et al. report that diastereoselectivity can be induced in the intramoleuclar meta photocycloaddition of ethenes to the benzene ring as a result of minimisation of steric interactions between substituents on the linking tether of the bichromophore and a methoxy group at the 2-position of the arene unity this type of photoprocess has also been used as a key step in a formal synthesis of crinipellin B (Wender and Dore). New polycyclic cage compounds 43 have been obtained by irradiation of the [3.3,3] (1,3,5) cyclophane 44 (Sakamoto et al.) and Kubo et al. have described the intramolecular [3 + 2] photocycloaddition of bichromophores such as 45 which gives rise to nine- to eleven-membered ring systems 46. 

The intra- and intermolecular arylation/carboalkoxylation of unactivated olefins with indoles and related nucleophiles is also effectively catalyzed by the system PdCl2(CH3CN)2 (5 mol %)/CuCl2 (3 equiv) in methanol under CO (1 atm) at room temperature, to give polycyclic indole derivatives in moderate to excellent yields and with excellent regio- and diastereoselectivity (eq 21).3 ... 

A few additional examples of the use of intramolecular asymmetric HWE reactions to construct fused polycyclic ring systems containing a quaternary carbon have also been reported. The hydrindenone derivative 75 was successfully synthesized from the 1,3-cyclopentadione derivative 74 with high diastereoselectivity (98% de) [45]. The product 75, containing a tetrasubstituted olefinic linkage, was... 

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