Tricyclic substances

The tricyclic substance 18A and 18B are both potential synthetic intermediates for synthesis of the biologically active diterpene forskolin. These intermediates can be prepared from the monocyclic precursors shown. Indicate the nature of the reactions involved in these transformations. 

One of the most interesting types of polycyclic carbon compounds prepared in recent years is the group of tricyclic substances known as propellanes. A typical example is tricyclo[3.2.2.0 -5]nonane, which sometimes is called [3.2.2]propellane, 12. The physical properties of several of these are included in Table 12-6. A quick look at formula 12 probably does not suggest any great structural difference from the bicyclic compounds we have discussed previously. However, if one tries to construct a ball-and-stick model of 12, one soon concludes that the propellanes are truly extraordinary substances in that all four carbon bonds at the bridgehead carbons extend, not to the comers of a tetrahedron, or even a distorted tetrahedron as for a cyclopropane ring, but... 

Synthesis of Tricyclic Substances Containing the Bicyclo[3.2.1]octane Carbon Skeleton... 

The cytotoxic sesquiterpenoid (-)-quadrone, isolated from the fungus Aspergillus terreus, possesses the constitution and absolute stereochemistry shown in (218). The tricyclic carbon skeleton of this interesting natural product is the same as that found in compound (198), which, as described above (Scheme 28), is readily prepared by thermolysis of the tricyclic diene (197). Thus, it appeared that the Cope rearrangement of a suitably substituted and functionalized derivative of (197) might serve effectively as a key intermediate in a total synthesis of ( )-quadione (218) that is, successful Cope rearrangement of a substrate, such as (219), would provide, stereoselectively, the tricyclic substance (220). Presumably, the intermediate (220) could then be converted into the keto aldehyde (221), which had already been transformed into ( )-quadrone (218). ... 

Chloroacetaldehyde and 6-amino-8-azapurine, refluxed in sodium acetate solution, gave a tricyclic substance, imidazo[l,2-c][l,2,3]triazolo[4,5-fif]pyrimidine (19). ° ... 

An electrophilic substitution step must be involved in the formation of the tricyclic substance 22 (R = Me) (Eq. 10) the reaction failed when R was ethyl or fert-butyl (21).69... 

Surprisingly, when the acetal is cyclized in the presence of stannic chloride in nitromethane (conditions which had been so successful with the dienic acetal) the reaction takes a completely abnormal course involving rearrangement. The main product is a tricyclic substance. This product could have arrived through a consecutive 1,2-hydride and methyl shifts of a bicyclic cationic intermediate ... 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

The fully unsaturated tricyclic compounds are also used clinically as antidepressants. Carbamazepine (62), for example, is prepared from 10,ll-dihydro-5H-dibenz[b,f]azepine (49) by N-acetylation followed by bromination with W-bromosuccinimide to give 60. Dehydrohalogenation by heating in collidine introduces the double bond. Saponification with potassium hydroxide in ethanol leads to dibenz[b,f]azepine (61), the parent substance for the fully unsaturated analogs. Treatment of the secondary... 

Ciraulo DA, Jaffe JH Tricyclic antidepressants in the treatment of depression associated with alcoholism. Clin Psychopharmacol 1 146—150, 1981 Ciraulo DA, Nace E Benzodiazepine treatment of anxiety or insomnia in substance abuse patients. Am J Addict 9 276—284, 2000 Ciraulo DA, Barnhill JG, Jaffe JH, et al Intravenous pharmacokinetics of 2-hydroxy-imipramine in alcoholics and normal controls. J StudAlcohol 51 366-372, 1990 Ciraulo DA, Knapp CM, LoCastro J, et al A benzodiazepine mood effect scale reliability and validity determined for alcohol-dependent subjects and adults with a parental history of alcoholism. Am J Drug Alcohol Abuse 27 339—347, 2001 Collins MA Tetrahydropapaveroline in Parkinson s disease and alcoholism a look back in honor of Merton Sandler. Neurotoxicology 25 117-120, 2004 COMBINE Study Research Group Testing combined pharmacotherapies and behavioral interventions in alcohol dependence rationale and methods. Alcohol Clin Exp Res 27 1107-1122, 2003a... 

Though these substances are not monocyclic like benzene—and Hiickel s rule should not, strictly, apply to them—the introduction of the transannular bond, that makes them bi- and tricyclic, respectively, seems to cause relatively little perturbation, so far as delocalisation of the n electrons over the cyclic group of ten or fourteen carbon atoms is concerned. 

Rao et al.20 demonstrated a fluorescence polarization immunoassay for evaluating serum concentrations of tricyclic antidepressants (amitriptyline, imipramine, clomipramine, and doxepin) with respect to nonresponse, compliance, therapeutic window, and influences of age, sex, substance abuse, and toxicity. Abbott Laboratories TDx/TDxFLx Toxicology Tricyclic Assay FPIA (fluorescence polarization immunoassay) was used. This assay of 50 /uL samples contained tricyclic antidepressant antibodies raised in rabbits and fluorescein-labeled tricyclic antidepressant as a tracer. The assay was calibrated with imipramine in the range of 75 to 1000 fig/L (268 to 3571 nmol/L). Intra-assay and inter-assay coefficients of variation for internal quality control samples from the manufacturer were 4.2 and 4.7%, respectively. The limits of detection were 72,71,64, and 72 nmol/L for amitriptyline, imipramine, clomipramine, and doxepin, respectively. This high-throughput immunoassay was easy to use although amitriptyline, dosulepine, desipramine, and nortriptyline showed cross-reactivities ranging from 74 to 100%. 

The p-quinonediimines are the parent substances of the indamine dyes and of the tricyclic quinonoid salts of the phenazine, phenthiazine, and phenoxazine groups which are related to them. (Detailed information on this subject is to be found in special works, e.g. of Nietzki-Mayer and of Bucherer.)... 

The side effects of tricyclic antidepressants are largely attributable to the ability of these compounds to bind to and block receptors for endogenous transmitter substances. These effects develop acutely. Antagonism at muscarinic cholinoceptors leads to atropine-like effects such as tachycardia, inhibition of exocrine glands, constipation, impaired micturition, and blurred vision. 

An example of the 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) dehydrogenation is that of converting tricyclic 236a to conjugated substance 236b (87TL4929). 

Tricyclics interact with other drugs and substances at a variety of points during distribution and metabolism. Most interactions occur at the CYP isoenzyme complex in the liver. Other interactions occur at peripheral sites and involve interaction at the noradernergic receptors (a and P). A summary of major TCA drug interactions is given in Table 23.2. 

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