Allylic carbocycles

Substituted TMM complexes also cycloadd to aldehydes in the presence of a tin cocatalyst such as MesSnOAc and MesSnOTs [31]. Reaction of 2-heptenal with methyl precursor (6) gave a mixture of methylenetetrahydrofurans (68) and (69). This regioselectivity is reversed with 10-undecenal and methyl precursor (5), where adduct (70) now predominates over (71). As in the carbocyclic system, the phenylthio group also functions as a regiocontrol element in reaction with cyclohexyl aldehyde. The initially formed adduct (72) eliminates the element of thio-phenol on attempted allyl rearrangement, and the overall process becomes a cycloaddition approach to furans (Scheme 2.21) [20]. 

In a continuation of the theme of simplification of the morphine ring, it was found that one of the carbocyclic rings (that which contained the allyl alcohol in morphine proper) can be dispensed with as well, to give compounds that show the full activity of the natural prototype. These agents, the benzomorphans, are of... 

Trost and co-workers have explored asymmetric transidon metal-catalyzed allylic alkyla-dons. Details on this subject have been well reviewed by Trost and others. With the use of asymmetric palladium-catalyzed desymmetrizadon of meso-2-ene-l,4-diols, cii -l,4-dibenzoy-loxy-2-cyclopentene can be converted to the enandometrically pure cii -4-rfirr-butoxycar-bamoyl-l-methoxycarbonyl-2-cyclopentene. The product is a usefid and general building block for synthesis of carbocyclic analogs of nucleosides as presented in Scheme 5.12. 

The indium-mediated allylation of trifluoroacetaldehyde hydrate (R = H) or trifluoroacetaldehyde ethyl hemiacetal (R = Et) with an allyl bromide in water yielded a-trifluoromethylated alcohols (Eq. 8.56).135 Lanthanide triflate-promoted indium-mediated allylation of aminoaldehyde in aqueous media generated (i-airiinoalcohols stereoselectively.136 Indium-mediated intramolecular carbocyclization in aqueous media generated fused a-methylene-y-butyrolactones (Eq. 8.57).137 Forsythe and co-workers applied the indium-mediated allylation in the synthesis of an advanced intermediate for azaspiracids (Eq. 8.58).138 Other potentially reactive functionalities such as azide, enone, and ketone did not compete with aldehyde for the reaction with the in situ-generated organo-indium intermediate. 

Another domino cuprate 1,4-addition-initiated threefold anionic domino sequence was developed by Chemla and coworkers (Scheme 2.93) [214]. Michael addition of the a, 3-unsaturated ester 2-387 with PhCu(CN)ZnBr was followed by a carbocyclization to give the zinc species 2-388 which can be intercepted by iodine or an allyl bromide affording substituted pyrrolidines 2-389 and 2-390, respectively. 

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... 

Cu-catalyzed domino reactions have been used for the synthesis of carbocycles, as well as for heterocycles such as indoles, benzoxazoles, and quinoxalines. A very useful process is also the combination of the formation of allyl vinyl ethers, followed by a Claisen rearrangement. 

Syntheses of Carbocyclic Compounds (1.V.2.V )-2 (.V )-Amino(4-metho-xyphenyl)methyl]cyclopropan-l-ol 392 (Scheme 1.45) has been prepared by a stepwise procedure involving a 1,3-dipolar nitrile oxide cycloaddition to allyl alcohol followed by a constmction of the cyclopropa d isoxazole system, and reduction of the bicycle (436). 

Michael additions of 7r-allyl species to alkynes were employed for the synthesis of elaborated carbocycles as in the ruthenium-catalyzed cycloisomerization of 1,6-enynes (Equation (188)).1... 

Another approach is based on the palladium-catalyzed intramolecular carbocyclization of the allylic acetate moiety with the alkene moiety (Scheme 96). After the formation of a 7t-allylpalladium complex, with the first double bond the intramolecular carbometallation of the second double bond occurs to form a new C-C bond. The fate of the resulting alkylpalladium complex 393 depends on the possiblity of /3-elimination. If /3-elimination is possible, it generates a metallated hydride and furnishes the cycloadduct 394. This cyclization could be viewed as a pallada-ene reaction, in which palladium replaces the hydrogen atom of the allylic moiety.231... 

A proposed mechanism of the bis(allene) cyclization involves the formation of the allyl(stannyl)palladium species 6, which undergoes carbocyclization to give vinyl(stannyl)palladium intermediate 7 (Scheme 36). Reductive elimination and cr-bond metathesis may lead to the formation of the m-pentane derivative and the bicyclic product, respectively. The cyclization of allenic aldehydes catalyzed by a palladium complex was also reported.163... 

Zr-catalyzed enantio-selective intramolecular diene cyclizations with allylic alcohol and ether substrates afford carbocycles bearing quaternary carbon stereogenic centers the unexpected formation of the aldehyde product 19 is noteworthy. 

Extending the aforementioned methodology from imidazole to adenine, the Tsuji-Trost reaction between the sodium salt of adenine and allylic acetate 66 gave 67 as a 82 18 mixture of cis trans isomers. Carbocyclic nucleoside 67 was advantageous over normal nucleosides as a drug candidate because it was not susceptible to degradation in vivo by nucleosidases and phosphorylases [52],... 

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

Evans and Kennedy later combined the regioselective rhodium-catalyzed allylic alkylation, using a-substituted malonates, with ring-closing metathesis for the construction of five-, six-, and seven-membered carbocycles (Scheme 10.2) [13]. The combination of these methodologies allowed for the rapid and flexible assembly of carbocycles possessing vicinal ternary-quaternary or quaternary-quaternary stereogenic centers. 

Scheme 10.2 The allylic alkylation/ring-closing metathesis approach to vicinally substituted carbocycles.

Sequential Rhodium(l)-Catalyzed Allylic Substitution/[4-i-2-i-2] Carbocyclization... 

Intermolecular Allylboration. A tandem aza[4+2] cycloaddition/allyl-boration three-component reaction has been designed based on the prece-dented carbocyclic [4- -2] cycloaddition/allylboration and a snbsequent one-pot variant. Thns, the thermal reaction between hydrazonobutadienes 138, A-substitnted maleimides, and aldehydes provides polysnbstituted a-hydroxy-alkylpiperidines 141 via the cyclic allylboronate intermediate 139 and the proposed chairlike transition stmctnre 140 (Eq. 103). Monoactivated dienophiles like acrylates fail to react with heterodienes 138 bnt the scope of aldehydes is very broad both ahphatic and aromatic aldehydes are snitable, inclnding electron-rich ones. An inverse electron-demand variant to access the corresponding dihy-dropyran derivatives via the intermediacy of enantiomerically enriched pyranyl allylic boronate 76 has been snbsequently developed (see Eq. 64). ° ... 

Thermally promoted Claisen rearrangement of simple allyloxypyrimidines is difficult to effect, but is more common with quinazolines where it has been used to prepare allyl derivatives substituted in the carbocyclic ring < 1996HC(55) 1 >. An attempted amino-Claisen rearrangement of a 4-allylaminopyrimidine was unsuccessful <2005AJC368>. 

Intramolecular nitrile oxide cycloadditions were first studied by Garanti and coworkers (24) in 1975, employing 0-allyl derivatives of salicylic aldehyde. The first example of a carbocycle-forming process was reported in 1977 (25). This process (sometimes referred to as INOC) has seen many extensions and applications for the synthesis of natural and unnatural products alike, notably by the groups of Kozikowski, Curran, Fukumoto, and Shishido (see Section 6.4). 

The intramolecular addition of carbon nucleophiles to alkenes has received comparatively little attention relative to heterocyclization reactions. The first examples of Pd-catalyzed oxidative carbocyclization reactions were described by Backvall and coworkers [164-166]. Conjugaled dienes with appended al-lyl silane and stabilized carbanion nucleophiles undergo 1,4-carbochlorination (Eq. 36) and carboacetoxylation (Eq. 37), respectively. The former reaction employs BQ as the stoichiometric oxidant, whereas the latter uses O2. The authors do not describe efforts to use molecular oxygen in the reaction with allyl silanes however, BQ was cited as being imsuccessful in the reaction with stabihzed car-banions. Benzoquinone is known to activate Ti-allyl-Pd intermediates toward nucleophilic attack (see below. Sect. 4.4). In the absence of BQ, -hydride eUm-ination occurs to form diene 43 in competition with attack of acetate on the intermediate jr-allyl-Pd" species to form the 1,4-addition product 44. 

The Tsuji-Trost reaction, more commonly applied to carbocyclic nucleoside synthesis, has been used in the synthesis of famciclovir 21 (Scheme 5) <2000T4589>. Reaction of 2-amino-6-chloropurine with allylic carbonate 22 in the presence of Pd2DBA3 and bis(diphenylphosphino)ethane (DPPE) gave a 1 1 ratio of 23 to 24 after 1 h (DBA = dibenzylideneacetone). However, a ratio of >95 5 in favor of the thermodynamically favored N-9 isomer 23 was subsequently obtained upon further stirring, highlighting the reversibility of the reaction in this specific instance. 

In conjunction with this, Jeong reported the cycloadditions of bis(allyl) and bis(homoallyl) acetals of alkynals leading to bicyclic lactols. Smaltz extended its utility to the synthesis of carbocyclic nucleoside by coupling with nucleophilic substitution of a 7r-allylic palladium complex (Equation (46)). ... 

Intramolecular ionic Diels-Alder reactions were carried out in highly polar media to afford carbocyclic ring systems. The strategy, which obviates the need for high temperatures and pressures, features in situ generation of heteroatom-stabUized allyl cations that undergo subsequent (4 + 2) cycloaddition at ambient temperature. Typically, reactions were complete within 1 hour after addition of substrate. Some cycloadducts were the result of a concerted process, whereas others were formed via a stepwise reaction mechanism (Grieco, 1996). 

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