Tricyclic substrate

Lycorine is an alkaloid that has attracted attention from both the synthetic community and pharmacologists. Prior synthetic approaches have included inter-and intramolecular Diels-Alder cycloaddition. Based on a similar retrosynthetic disconnection, Padwa and co-workers (106,109) chose to use a push-pull carbonyl ylide cycloaddition with a disubstituted pyrrolidinone core to generate a tricyclic substrate. The major difference for this synthetic smdy was the availability of a labile proton a to the carbonyl moiety (Scheme 4.53). 

A key step in the recent synthesis of (+)-lauthisan by Cha was the ozonolytic cleavage of the olefinic bond of the tricyclic substrate 127 to afford the cyclic ether 128, Eq. 91 [115]. A series of transformations including an enzymatic desymmetrization completed the total synthesis. 

Although Mucor species produced a large amount of nootkatone (2) from valencene (1), however, only poor yield of similar products as those from valencene (1) was seen in the biotransformation of tricyclic substrate (36). Possible biogenetic pathway of (+) 1(10)-aristolene (36) is shown in Figure 20.20. 

A few decades later, a similar reaction of the tricyclic substrate, N-sulphonyloxy-2,3-norbom-5-enedicarboximide 25 was reported to undergo Lossen rearrangement under basic conditions to yield urea 26. ... 

As for cyclic alcohols, bi- or tricyclic diols of different structures are excellent substrates and furnish excellent results in terms of stereosel tivity [263-267]. Scheme 62 presents a few selected examples of the successful asymmetrization of bi- and tricyclic substrates. 

Another interesting transformation is the intramolecular metathesis reaction of 1,6-enynes. Depending on the substrates and catalytic species, very different products are formed by the intramolecular enyne metathesis reaction of l,6-enynes[41]. The cyclic 1,3-diene 71 is formed from a linear 1,6-enyne. The bridged tricyclic compound 73 with a bridgehead alkene can be prepared by the enyne metathesis of the cyclic enyne 72. The first step of... 

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

The Pschorr reaction also works with substrates containing a bridge other than oxygen. Thus various tricyclic products containing a biaryl subunit are accessible, e.g. carbazoles and fluorenes. 

Mioskowski et al. have demonstrated a route to spirocyclopropanes. As an example, treatment of epoxide 100 with n-BuLi in pentane stereoselectively gave tricyclic alcohol 101, albeit in only 47% yield (Scheme 5.21) [29]. With a related substrate, epoxide 102 stereoselectively gave dicydopropane 103 on treatment with PhLi uniquely, the product was isolable after column chromatography in 74% yield [35]. As was also seen with attempts to perform C-H insertion reactions in a non-transannular sense, one should note that steps were taken to minimize the formation of olefin products, either by the use of a base with low nudeophilicity (LTM P) and/or by slow addition of the base to a dilute solution (10-3 m in the case of 102) of the epoxide. 

Only one procedure has been reported recently within this category. Thus 7-chloro-l-methyl-5-phenyl-2,3-dihydro-lH-benzodiazepin-2-one 4-oxide (437) with dimethyl acetylenedicarboxylate in methylene chloride at 20° C for 3 days gave a separable mixmre of the primary tricyclic adduct, dimethyl lO-chloro-6-oxo-llb-phenyl-5,6,7, 1 lb-tetrahydroisoxazolo[2,3-t/] [ l,4]benzodiazepine-1,2-dicarboxylate (438), and its rearrangement product, 6-chloro-4-(2-methoxalyl-2-methoxycarbonyl-l-phenylvinyl)-l-methyl-3,4-dihydro-2(lT0-quinoxalinone (439) each product afforded 6-chloro-l-methyl-2(l//)-quinoxalinone (440) on refluxing in ethanol (see also Section 1.7.13). However, the final quinoxaline (440) was best obtained in 75% yield) by simply heating the initial substrate (437) and dimethyl... 

Hydantoins have been prepared starting from aminoesters that were first transformed into the corresponding carbanilides (ureas) 144 under standard conditions and then cyclized under microwave irradiation in the presence of Ba(OH)2 in DMF in 2 min and in yields ranging from 91 to 80% (Scheme 51) [91,92], Simple and more complex hi- and tricyclic compounds, such as 145-147, have been prepared with this method that seems versatile and applicable to many substrates. 

It was mentioned above that even alkanes undergo Wagner-Meerwein rearrangements if treated with Lewis acids and a small amount of initiator. An interesting application of this reaction is the conversion of tricyclic molecules to adamantane and its derivatives. It has been found that all tricyclic alkanes containing 10 carbons are converted to adamantane by treatment with a Lewis acid such as AICI3. If the substrate contains more than 10 carbons, alkyl-substituted adamantanes are produced. The lUPAC name for these reactions is Schleyer adamantization. Two examples are... 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

The benzocarbacephems 22 (Fig. 11.12), with (X = Cl or F) or without (X = H) a halogen leaving group, were synthesized by a copper-mediated intramolecular aromatic substitution as the main step.73 74 These tricyclic (3-lactams are also competitive inhibitors of (3-lactamases and not substrates. 

Cyclopentadienylindium(I) has been shown to be effective in the reaction with aldehydes or electron-deficient alkenes to form highly functionalized cyclopentadienes in aqueous media (See Section 8.4.3).101 This reaction with the appropriate substrates can be followed by an intramolecular Diels-Alder reaction in the same pot to provide complex tricyclic structures in a synthetically efficient manner (Scheme 12.4). 

Giros B., Wang Y., Sutter S., McLeskey S., Pfil C., Caron M. Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine... 

A threefold domino RCM was observed by Harrity and coworkers [240] using substrates of type 6/3-39 which, on treatment with the Ru-catalyst 6/3-13, led to the tricyclic compound 6/3-40 in 72% yield. Surprisingly, the diastereomer 6/3-41 gave 6/3-42 in only 38% yield, even using 20 mol% of the catalyst (Scheme 6/3.11). 

Thus, reaction of 6/4-25a gave 6/4-26a as a single product by applying a CO pressure of 50 psi under a nitrogen atmosphere, the isomer 6/4-27 is the main product The procedure can also be used for the synthesis of O- and N-tricyclic lactones as 6/4-26b and 6/4-26c with the epoxides 6/4-25b and 6/4-25c as substrates. 

Nitrooxazoles and 4-nitroisoxazoles 480 are versatile substrates for domino cycloaddition reactions with ethyl vinyl ether 481 to form the tricyclic nitroso acetals 482 and 483 (Equation 129) <1999T13809, 2001T4237>. 

Each of the 3-oxidopyridinium betaine substrates 83, 91, and 98 were extensively investigated for their potential to engage in intramolecular dipolar cycloaddition (Scheme 1.10). Heating a solution of ene-nitrile 83 in variety of solvents failed to effect the desired intramolecular [3+2] dipolar cycloaddition to form the bridged pyrrolidine 100, as tricyclic oxidopyridinium betaine 103 was the only... 

The linkage of uptake to the Na+ gradient may be of physiological significance since transport temporarily ceases at the time of depolarization-induced release of catecholamines. The transport of catecholamines can be inhibited selectively by such drugs as tricyclic antidepressants and cocaine. In addition, a variety of phenylethyl-amines, such as amphetamine, are substrates for carrier thus, they can be concentrated within catecholamine-containing neurons and can compete with the catecholamines for transport. 

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