Carbocyclizations diastereoselective

The intramolecular Hiyama reaction is excellently suited for the construction of carbocyclic and heterocyclic ring systems of different size. In most examples, problems of induced diastereoselectivity are involved (Sections 1.3.3.3.9.2.2. and D.2.3.). In the total synthesis of the antitumor germacranolide ( )-costunolide from ( ,.E)-farnesol, the correctly substituted ( , )-cyclodecadiene moiety was constructed by an intramolecular Hiyama reaction22. 

This section describes Michael-analogous processes in which, mostly under electrophilic conditions, ally - or alkynylsilanes undergo addition to enones or dienones (Sakurai reactions). The intramolecular addition of allylsilanes is an extremely useful reaction especially for the construction of carbocyclic ring systems, which occurs in a diastereoselective manner, in many cases with complete asymmetric induction. 

When the cnolate of an enone is brought into reaction with an enone, usually a carbocyclic system is prepared by two consecutive Michael additions (M1MIRC reactions). Due to the lower temperatures employed and the absence of diene polymerization these reactions are useful alternatives for Diels-Alder reactions and proceed in general with high diastereoselectivities. When neither enolate nor enone is cyclic a monocyclic system is formed 338 which can be converted into a bicyclic system when the Michael addition is followed by an aldol reaction339. When, however, the enolate is cyclic a bicyclic or a tricyclic system is formed340 341. 

An interesting strategy for the diastereoselective synthesis of five-membered carbocycles was achieved by the reaction of alkenylcarbene complexes and lithium enolates derived from simple methyl ketones [79]. The use of more or less coordinating solvents (THF or Et20) or the presence of cosolvents such as PMDTA allows the selective synthesis of one or the other diastereoisomer of the final cyclopentene derivative (Scheme 32). 

Similarly a marked increase of regioselectivity has been shown in the catalyzed Diels-Alder reactions of the chiral bicyclic lactame 24 (Scheme 3.9) with a variety of dienes [27] (isoprene, mircene, (E,E)-L4-dimethylbutadiene, 2,3-di-methylbutadiene, 2-siloxybutadiene). The catalyzed reactions were more regio-selective and totally enJo-antz-diastereoselective anti with respect to the bridgehead methyl group). The results of the cycloadditions with isoprene and mircene are reported in Scheme 3.9. The cycloadducts have then been used to provide interesting fused carbocycles [28] with high enantiomeric purity as shown in Scheme 3.10. 

Good yields and high diastereoselectivities were obtained by using zeolites in combination with Lewis-acid catalyst [21]. Table 4.7 illustrates some examples of Diels-Alder reactions of cyclopentadiene, cyclohexadiene and furan with methyl acrylate. Na-Y and Ce-Y zeolites gave excellent results for the cycloadditions of carbocyclic dienes, and combining these zeolites with anhydrous ZnBr2 further enhanced the endo diastereoselectivity of the reaction. An exception is the cycloaddition of furan that occurred considerably faster and with better yield, in comparison with the classic procedure [22], when performed in the presence of sole zeolites. 

Ziegler and Saprong described a stoichiometric cyclization onto an alkyne for the synthesis of the carbocyclic core of entecavir from diacetone glucose. Inverse addition was required to minimize deoxygenation. The highly diastereoselective reaction is tolerant to silylethers [101]. 

A regio- and diastereoselective Pd-catalyzed domino silastannylation/allyl addition of allenes 6/1-236 containing a carbonyl moiety with Bu3Sn-SiMe3 6/1-237 is described by Kang and coworkers [117]. The reaction allows the synthesis of hetero-and carbocyclic compounds with a ring size of five and six. It can be assumed that... 

The reaction of enamines with 2-nitro-2-propen-l-yl pivalate gives 4-nitrocyclohexanones, which is regarded as formal [3 + 3] carbocyclization. The reaction proceeds in high diastereoselectivity (60% to >95% selectivity), see Eq. 4.69 88 If chiral enamines such as that in Eq. 4.68 are employed, the products are obtained with high ee. 

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

With the advent of enantioselective zirconocene-catalyzed alkene carbomagnesiation,27 27a 27c 28 28a chirally modified zirconocenes soon were applied to asymmetric reductive diene carbocyclization.2 a c As demonstrated by the reductive cyclization of 5a,29 highly enantioselective cyclization is enabled through the use Brintzinger s chiral, mszz-zirconocene.30 30a (For the preparation and resolution of chiral tf .szz-zirconocene 6, see Refs 30,30a.) However, moderate diastereoselectivities and yields are generally observed (Scheme 5). 

Hydrosilylation of 1,6-dienes accompanied by cyclization giving a five-membered ring system is emerging as a potential route to the synthesis of functionalized carbocycles.81,81a,81b 82 As its asymmetric version, diallylmalonates 86 were treated with trialkylsilane in the presence of a cationic palladium catalyst 88, which is coordinated with a chiral pyridine-oxazoline ligand. As the cyclization-hydrosilylation products, //ww-disubstituted cyclopentanes 87 were obtained with high diastereoselectivity (>95%), whose enantioselectivity ranged between 87% and 90% (Scheme 25).83 83a... 

Photoinduced electron transfer promoted cyclization reactions of a-silyl-methyl amines have been described by two groups. The group of Pandey cyclized amines of type 135 obtaining pyrrolidines and piperidines 139 in high yields [148]. The cyclization of the a-silylated amine 140 leads to a 1 1 mixture of the isomers 141 and 142 [149]. The absence of diastereoselectivity in comparison to analogous 3-substituted-5-hexenyl radical carbocyclization stereochemistry [9] supports the notion that a reaction pathway via a free radical is unlikely in this photocyclization. The proposed mechanism involves delocalized a-silylmethyl amine radical cations as reactive intermediates. For stereochemical purposes, Pandey has investigated the cyclization reaction of 143, yielding... 

Evans and co-workers simultaneously developed of the rhodium-catalyzed [4-+2 + 2] car-bocychzation reaction through the identification of a novel mode of reactivity for the five-membered metallacycle intermediate [14, 37]. Evans proposed that 1,3 dienes should be amenable to addition to this intermediate, which would provide a new reaction pathway. The tethered enyne 80 (Scheme 12.9), was expected to afford the metallacycle I, which, upon sequential incorporation of a butadiene and reductive ehmination, would afford the desired 5,8-fused product 81. Additionally it was rationahzed that this transformation should be highly diastereoselective, as outlined in Scheme 12.10. Treatment of the heteroatom-tethered enyne I under standard carbocyclization (Pauson-... 

The addition of zinc enolates to alkenes in the intramolecular version finds several examples in recent literature. Thus, hydrazone 155, subjected to the same treatment reported for 151 (equation 80), undergoes diastereoselective 5-exo-trig (n = 1) or 6-exo-trig (n = 2) carbocyclization to yield -156, which on reaction with the electrophile E+ gives 157 (equation 81)174. 

H. Ito, Y. Motoki, T. Taguchi. and Y. Hanzawa, Zirconium mediated, highly diastereoselective ring contraction of carbohydrate derivatives Synthesis of highly functionalized, enantiomerically pure carbocycles, J. Am. Chem. Soc. 775 8835 (1993). 

Versatile [3 + 2]-cycloaddition pathways to five-membered carbocycles involve the trimethylenemethane (= 2-methylene-propanediyl) synthon (B.M. Trost, 1986). PaIladium(0)-induced 1,3-elimination at suitable reagents generates a reactive n - -methylene-1,3-propa-nediyl complex which reacts highly diastereoselectively with electron-deficient olefins. The resulting methylenecyclopentanes are easily modified, e.g., by ozonolysis, hydroboration etc., and thus a large variety of interesting cyclopentane derivatives is accessible. 

Annulation reactions also proceeded in 72-88% yield with moderate to excellent diastereoselectivity. Even simple l,l,l-trichloro-5-hexenes or 6-heptenes 55 gave chlorinated carbocycles 56 in 54-79% yields [115]. Approximately 10% of products 57 resulting from 6-endo or 7-endo cyclizations were also isolated. 

In the pioneering work by Wilcox and Gaudino, a straightforward route to the carbocyclic analogue of D-fructofuranose, 64, and its 6-phosphate derivative was delineated [14a,b]. As shown in Scheme 9, the first move consisted of Wittig olefination of benzyl-protected arabinose 60 with carboxy-tert-butylmethylene triphenyl phosphorane to deliver unsaturated ester 61, which was then cleverly elaborated into dibromide 62 via a reaction cascade encompassing Swem oxidation of the secondary OH, ester hydrolysis, diastereoselective addition of dibromomethyl lithium, and carboxylic acid methylation. 

A unique member of the seven carbon carbaketose family, namely hept-2-uloseptanosylamine 342, was assembled by Mandal [78,79] during a remarkable total synthesis of chiral carbocyclic nucleosides from D-glucose. Here, a diastereoselective intramolecular nitrone cycloaddition reaction was the decisive move to install the carbaseptanose ring system (Scheme 56). 

Ito, H. et al. Zirconium-Mediated, Highly Diastereoselective Ring Contraction of Carbohydrate Derivatives Synthesis of Highly Functionalized, Enantiomerically Pure Carbocycles. 4.1 1993 [128]... 

The multitude of hetero Diels-Alder reactions found in the literature clearly demonstrates the importance of this transformation. Thus, this type of cycloaddition is today one of the most important methods for the synthesis of heterocycles. Striking features of this method are the tremendous diversity, excellent efficiency especially in those cases where the reactive dienes and dienophiles are formed in situ, and high stereoselectivity in many cases. There is a broad scope and only little limitation. In recent years the use of Lewis acid, the development of diastereoselective and enantioselective reactions as well as the application of high pressure gave an enormous push. In addition, many of the obtained heterocycles can be transformed into acyclic compounds allowing the stereoselective preparation of e.g. amino and hydroxyl functionalized open chain compounds or even carbocycles to be of interest. Also, for the synthesis of natural products, the hetero Diels-Alder reaction is of great value. Since heterocycles,... 

Stereoselective formation of carbocycles has been carried out through [RhCl(cod)]2 (cod = cyclooctadiene) catalyzed reaction of alkenylzirconocene chloride to co-carbonyl carboxymide <07TL6471>. When the camphor sultam auxiliary is incorporated into amide 206, the Rh(I)-catalyzed reaction of alkenylzirconocene chloride 207 forms the cyclization product 211 with high diastereoselectivity. The tt-facial differentiation of the double bond in 206 for the initial attack of vinyl group can be explained by taking into consideration either of the reactive conformers A or B. No matter which reactive conformer is involved, the attack of the vinyl group to the less crowded C p si-face would account for the observed chirality. 

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