Cyclization intramolecular stereochemistry

Wawzonek et al. first investigated the mechanism of the cyclization of A-haloamines and correctly proposed the free radical chain reaction pathway that was substantiated by experimental data. "" Subsequently, Corey and Hertler examined the stereochemistry, hydrogen isotope effect, initiation, catalysis, intermediates, and selectivity of hydrogen transfer. Their results pointed conclusively to a free radical chain mechanism involving intramolecular hydrogen transfer as one of the propagation steps. Accordingly, the... 

The iminium salt 165, derived from acid treatment of 1,4-dihydropyridine 164, on intramolecular cyclization on the indole nucleus gave pentacyclic compound 166 (83T3673). The tmns stereochemistry of H3 and H9 in 166 (biogenetic... 

The smooth intramolecular nucleophilic displacement of biphenyl carboxylic acids leading to benzocoumarins (See Section II.A.) inspired also investigation of the behavior of similar diphenyl ether, diphenyl sulfide and A-methyldiphenyl amine derivatives 458 under similar conditions. However, all these attempts to achieve cyclization to tricyclic compounds 459 were unsuccessful, probably due to the unfavorable stereochemistry for the formation of the required seven-mem-bered transition states and also to the presence of the deactivating bridge groups X (Eq. 42) [68JCS(C)1030]. 

Following Uskokovic s seminal quinine synthesis [40], Jacobsen has very recently reported the first catalytic asymmetric synthesis of quinine and quinidine. The stereospecific construction of the bicyclic framework, introducing the relative and absolute stereochemistry at the Cg- and expositions, was achieved by way of the enantiomerically enriched trans epoxide 87, prepared from olefin 86 by SAD (AD-mix (3) and subsequent one-pot cyclization of the corresponding diol [2b], The key intramolecular SN2 reaction between the Ni- and the Cg-positions was accomplished by removal of the benzyl carbamate with Et2AlCl/thioanisole and subsequent thermal cyclization to give the desired quinudidine skeleton (Scheme 8.22) [41],... 

Finally, in a study of Lewis-acid-catalysed intramolecular attack of acetals on vinylsilanes, to produce allylically unsaturated oxacyclics, it has been found (75) that the alkene stereochemistry can control the mode of cyclization in an exo- or endocyclic sense, as shown here ... 

Studies of the intramolecular cyclization of P-amino acids have included the use of camphor-derived oxazoline A-oxide 66 and a [3+2] cycloaddition reaction as a step in the formation of the amino acid with the required stereochemistry <00OL1053, OOEJOC1595>. A diastereoselective synthesis of a ip-methylcarbapenem intermediate utilises a cyclization of a P-amino acid <99CC2365>. 

Palladium-catalyzed cyclization of alkenes and alkynes were reported by Balme and co-workers.143 144 Intramolecular carbopalladation occurs to give polycyclic compounds. It has been shown that the nucleophile type has a large influence on the cyclization process. Both 5-exo- and 6-endo-cyclization are observed for substrates with nitrile (116 and 118) and ester (120, 122, and 124) substituents, respectively (Scheme 36). When a mixed nucleophile (CN and C02Me) is used, a mixture of 5-exo and 6-endo products is obtained. The chemoselectivity is controlled by the size of the nucleophile used. The stereochemistry of the initial double bond plays an important role on the stereoselectivity of the cyclization. (Z)-olefins (118 and 120) and (/. )-olefins (116 and 124) afford as- (119 and 121) and trans-cyclization products (117 and 123), respectively. 

A Mitsunobu reaction then inverts the C-4 configuration to provide compound 151, and subsequent isomerization provides compound 152, which is ready for Lewis acid-mediated cyclization to construct the eight-membered firing. Using MeiAlOTf as a catalyst, intramolecular cyclization occurs, giving product 153 in which A, B, and C rings have been introduced with the desired stereochemistry (Scheme 7-45). 

Allenylsilanes undergo intramolecular additions to appropriately positioned aldehydes, imines, conjugated esters and alkenes to afford various alkynylcyclopentane and cyclohexane derivatives (Eqs. 9.66-9.70) [66]. The reactions are promoted by SnCl4 or by thermolysis. The stereochemistry of these cyclization reactions is consistent with a concerted sigmatropic process as illustrated in Scheme 9.17. 

The intramolecular coupling of enolethers with enolethers, styrenes, alkyl-substituted olefins, allylsilanes, and vinylsilanes was systematically studied by Moeller [69]. Many of these coupling reactions turned out to be compatible with the smooth formation of quaternary carbon atoms (Eq. 11) [70], which were formed diastere-oselectively and led to fused bicyclic ring skeletons having a ds-stereochemistry [71]. The cyclization is compatible with acid-sensitive functional groups as the allylic alkoxy group. Moeller has demonstrated in some cases that these reactions can be run without loss of selectivity and yield in a simple beaker with either a carbon rod or reticulated carbon as anode without potential control and a 6-V lantern battery as power supply [71]. 

Intramolecular coupling Some aromatic diketones have been stereoselectively cy-clized under various electrolysis conditions, which, together with the substrate structure, strongly influence the stereochemistry of the formed cyclic diol. Reductive cyclization of 1,8-diaroylnaphthalenes led to trans-diols, 2,2 -diaroylbiphenyls and a, )-diaroylalkanes yielded cis-diols with different stereoselectivities depending on substrate structure and electrolysis conditions (pH, cosolvent) (Fig. 57) [310-312]. 

One of the most synthetically useful anodic C-C bond forming reactions developed to date involves the intramolecular coupling of phenol derivatives with olefins. Yamamura has demonstrated that these reactions tend to lead to three classes of products (Scheme 22) [36]. The type of product generated depended strongly on both the nature and stereochemistry of the functional groups attached to the olefin moiety. For example, consider the two cyclization reactions illustrated in Scheme 23 [37]. In this experiment, the stereochemistry of the initial olefin substrate completely dictated the ring skeleton of the product. 

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. 

The effects of stereochemistry, substitution, and (for 2-phenylimino derivatives) an intramolecular cyclization of the ions [M-H] have been observed in the electron ionization mass spectra of as- and /ra r-fused 4-phenyloctahy-dro-2//-3,l-benzoxazin-2-ones 21 and -2-thiones 22, 2,4-diphenylhexahydro-3,l-benzoxazines 23, and 2-phenyl-imino-4-phenylhexahydro-3,l-benzoxazines 24. The mass spectral behavior was similar for the isomeric compounds, although they could usually be differentiated from each other on the basis of the relative abundances of their characteristic fragment ions <2005ARK(iv)39>. 

Mori has reported the nickel-catalyzed cyclization/hydrosilylation of dienals to form protected alkenylcycloalk-anols." For example, reaction of 4-benzyloxymethyl-5,7-octadienal 48a and triethylsilane catalyzed by a 1 2 mixture of Ni(GOD)2 and PPhs in toluene at room temperature gave the silyloxycyclopentane 49a in 70% yield with exclusive formation of the m,//7 //i -diastereomer (Scheme 14). In a similar manner, the 6,8-nonadienal 48b underwent nickel-catalyzed reaction to form silyloxycyclohexane 49b in 71% yield with exclusive formation of the // /i ,// /i -diastereomer, and the 7,9-decadienal 48c underwent reaction to form silyloxycycloheptane 49c in 66% yield with undetermined stereochemistry (Scheme 14). On the basis of related stoichiometric experiments, Mori proposed a mechanism for the nickel-catalyzed cyclization/hydrosilylation of dienals involving initial insertion of the diene moiety into the Ni-H bond of a silylnickel hydride complex to form the (7r-allyl)nickel silyl complex li (Scheme 15). Intramolecular carbometallation followed by O-Si reductive elimination and H-Si oxidative addition would release the silyloxycycloalkane with regeneration of the active silylnickel hydride catalyst. 

Burke et al. [84] synthetised nagilactone F (55) by a polyenic cyclization initiated with acetal and concluded with vinylsilane, giving an overall yield of 6%. The key steps in this synthesis were the coupling of substrates 166 and 167 with control of the absolute and relative stereochemistry, the cationic biscyclization to form the intermediate tricyclic trans-anti-trans 169 and the formation of the D ring by regio-selective intramolecular remote functionalization. 

T. V. RajanBabu, Stereochemistry of intramolecular free-radical cyclization reactions, Acc. Chem. Res. 24 139 (1991). 

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