Bicycles diastereoselective reactions

Hydroxy alkenyl and alkynyl nitriles can be subjected to a one-pot addition-alkylation sequence, leading to polysubstituted products. In the case of open-chain systems, diastereoselectivity from 2.3 1 to 6.6 1 was achieved. Cyclic systems may lead to a highly diastereoselective reaction.234,234a 234c iv-Chloroalkenylmagnesium bromides give bicyclic products (Scheme 77 ) 235>236... 

Silyl allenes such as 48 and enol acetates such as 50 were particularly effective substrates for these reactions. The oxidative cascade reaction of trisubstituted alkene substrate 52 demonstrated a powerful application of ETIC chemistry to form bicycle 53 through consecutive carbon-carbon and carbon-oxygen bond construction. Highly diastereoselective reactions were observed when the nucleophile was... 

Diastereoselective reaction of diimines with sodium in ether leads to the formation of macrocyclic ethers of the type (32 equation 67) and (33 equation 68) in modest yields, However, there are no reports of examples using the templating effect of low-valent transition metals, as used to good effect for intramolecular carbonyl couplings. Electrochemical reduction of imines has been used to produce a variety of bicyclic structures via cyclization-aromatization (equation 69) or transannular cyclization (equation 70). ... 

Martin has made ample use of this strategy for the synthesis of various polyketide natural products. Furan 164, prepared by addition of lithiofuran to a lactaldehyde derivative, gave the bridged ketal 165 upon oxidation and acid catalyzed dehydration <99T3561>. The bicyclic architecture allowed highly diastereoselective reactions which led to 166, a key intermediate for... 

Diels-Alder reactions of 2-pyrones with reactive dienophiles can also be effected without decomposition by use of high pressure (8,254). This version has been used to effect cycloaddition of 3-acyloxy-2-pyrones with vinyl ethers at 25 to give bicyclic adducts in good yield. Use of chiral vinyl ethers can result in diastereoselective reactions. The highest levels of induction are observed with 8-(/3-naphthyl)menthyl vinyl ether and 8-(3,5-dimethylphenyl)menthyl vinyl ether (88 12). 

Chiral, optically pure exo-methylene compounds, as for example dioxolanes and 1,3-oxazolidinones B, have been successfully examined as dienophiles in thermal Diels-Alder reactions with 1,3-butadiene or cyclopentadiene. Similarly highly diastereoselective reactions of dioxinones C with cyclopentadiene in benzene at 80°C have been reported in the literature. Non-catalyzed cycloaddition reactions of Meyers bicyclic lactam with acyclic dienes proceed at moderate temperature (60°C) highly stereoselective furnishing the products in excellent yield. Equally high endolexo selectivities and diastereoselectivities were reported for the reactions that have been carried out at low temperature in the presence of Lewis acids, e.g. ZnCL. ... 

Asymmetric [2 + 2] Photocycloadditions. Intramolecular copper-catalyzed [2 + 2] photocycloaddition is a useful methodology for the preparation of bicyclic cyclobutanes and recent studies deal with its asymmetric version albeit with variable success. Diastereoselective reactions are achieved under the control of stereogenic centers incorporated in the dienic precursors. Both CuOTf and the more stable and easy to handle Cu(OTf)2 are suitable catalysts in this context. In the latter case, it is assumed that the copper(I) species is generated from Cu(OTf)2 under the photochemical conditions. A noteworthy example is the application of the CuOTf-catalyzed [2 + 2] photocycloaddition in the stereoselective total synthesis of the tricyclic sesquiterpene kel-soene (eq 128). ... 

An expedient and stereoselective synthesis of bicyclic ketone 30 exemplifies the utility and elegance of Corey s new catalytic system (see Scheme 8). Reaction of the (R)-tryptophan-derived oxazaboro-lidine 42 (5 mol %), 5-(benzyloxymethyl)-l,3-cyclopentadiene 26, and 2-bromoacrolein (43) at -78 °C in methylene chloride gives, after eight hours, diastereomeric adducts 44 in a yield of 83 % (95 5 exo.endo diastereoselectivity 96 4 enantioselectivity for the exo isomer). After reaction, the /V-tosyltryptophan can be recovered for reuse. The basic premise is that oxazaborolidine 42 induces the Diels-Alder reaction between intermediates 26 and 43 to proceed through a transition state geometry that maximizes attractive donor-acceptor interactions. Coordination of the dienophile at the face of boron that is cis to the 3-indolylmethyl substituent is thus favored.19d f Treatment of the 95 5 mixture of exo/endo diastereo-mers with 5 mol % aqueous AgNC>3 selectively converts the minor, but more reactive, endo aldehyde diastereomer into water-soluble... 

Lewis acid-mediated asymmetric Diels-Alder reactions between 2H-azirines 59, bearing chiral auxiliaries, with enophiles such as 60 afforded mixtures of bicyclic aziridine-2-carboxylates 61 (Scheme 3.20) [68]. 8-Phenylmenthol appeared to be the auxiliary of choice in this reaction in terms of yield and diastereoselectivity. 

High, simple diastereoselection was also observed on the reaction of the anion of racemic (Z)-1-(phenylsulfinyl)-2-butene (2 equiv) with a nonracemic bicyclic chiral enone (1 equiv) giving a 7-1,4-adduct in 82% eeI5b. 

A complete diastereoselective triple Michael addition to form a bicyclic ring structure is also known. In this reaction the new ring is formed by a M1MIRC reaction (see also Sec-... 

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. 

The reaction of the enamines of cyclohexanones with a,ft-unsaluraled sulfones gives mixtures resulting from attack of the enamine at the a- and /(-carbons of the oc,/ -unsaturated sulfone. The ratio of x- and /1-adducts is dependent upon the reaction solvent, the geometry and structure of the sulfone1 4. The diastereoselectivity of these reactions is also poor. The reaction of lithium enolates of cyclic ketones with ( )-[2-(methylsulfonyl)ethenyl]benzene, however, gives bicyclic alcohols, as single diastereomers, that result from initial -attack on the oc,/ -unsaturated sulfone5. 

The 3- and 6-acetoxyvinylcyclohexenes 53 and 54 react with dimethyl-acetylenedicarboxylate to afford bicyclic esters [50]. It is noteworthy that the facial diastereoselectivity depends on the position of the acetoxy group (Scheme 2.21). While the reaction of 53 is completely uwtz-diastereoselect-ive, that of 54 is undiastereoselective, affording a 1 1 mixture of cycloadducts. 

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. 

An enantioselective variant of the diene cydization reaction has been developed by application of chiral zirconocene derivatives, such as Brintzinger s catalyst (12) [10]. Mori and co-workers demonstrated that substituted dial-lylbenzylamine 25 could be cyclized to pyrrolidines 26 and 27 in a 2 1 ratio using chiral complex 12 in up to 79% yield with up to 95% ee (Eq. 4) [ 17,18]. This reaction was similarly applied to 2-substituted 1,6-dienes, which provided the analogous cyclopentane derivatives in up to 99% ee with similar diastereoselectivities [19]. When cyclic, internal olefins were used, spirocyclic compounds were isolated. The enantioselection in these reactions is thought to derive from either the ate or the transmetallation step. The stereoselectivity of this reaction has been extended to the selective reaction of enantiotopic olefin compounds to form bicyclic products such as 28, in 24% yield and 59% ee after deprotection (Eq. 5) [20]. 

Cyclization to six-membered rings (Eq. 15) provided modest diastereoselectivity and required the use of bulkier PhMeSiH2 to prevent olefin hy-drosilylation. Propargyl and homopropargyl amines 94 afforded a variety of heterocycles (Scheme 21), if the catalyst was added slowly over the reaction course to diminish side reactions resulting from metal coordination to the basic amine [56]. The reaction procedure was extended to the diastereoselect-ive bicyclization of dienyne substrate 95, giving 96 as product in a cascade fashion (Eq. 16) [57]. 

A variety of imidazolidinium and pyrrolidinium salts (Fig. 2.38) have been found to catalyze the reaction between nitrones and cyclic a, p-unsaturated aldehydes, affording bicyclic adducts with high diastereoselectivity and enantioselec-tivity (Scheme 2.256) (759). 

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