Tricyclic methyl ester

The first total synthesis of the Stemona alkaloid (-)-tuberostemonine was accomplished by P. Wipf and co-workers. " The installation of the butyrolactone moiety commenced with the preparation of a Weinreb s amide from a methyl ester. The tricyclic methyl ester substrate was exposed to A/,0-dimethylhydroxylamine hydrochloride and Me2AICI and the tertiary amide was isolated in excellent yield. Next, the bromo ortho ester was treated with LDBB in THF to generate the corresponding primary alkyllithium species, which cleanly and efficiently added to the Weinreb s amide to afford the desired ketone. 

The activated ester alkyne-oxazole 200 underwent facile intramolecular Diels-Alder reaction in refluxing toluene with concomitant loss of acetonitrile to give an 89% yield of the desired tricyclic methyl ester 201. However, 201 could not be converted to the methyl butenolide 202 required to complete the synthesis. 

Thus, the dianion derived from a-amino acid substitutes the /1-chloride to give the ester of 2-(phenylsulfonyl)ethenyl amino acid and subsequent desulfonylation provides N-(benzoyl)vinylalanine methyl ester (62) (equation 61). The conjugate addition of enolates to methyl styryl sulfone (63) and subsequent intramolecular addition to the carbonyl moiety provide a synthetically valuable method for the construction of bicyclic and tricyclic skeletons52. Desulfonylation of the cyclization product 64 with sodium in ethanol-THF gives the diene 65 in good yield (equation 62). 

Reductive decarbonylation and decarboxylation can be carried out by (TMSlsSiH using acyl chlorides, phenylseleno esters, or N-hydroxypyridine-2-thione esters. Examples are shown in Reactions (17)-(19). Hydrolysis of the methyl ester followed by decarbonylation at the C2 position of hexahydropyrro-loindole (+)-17 afforded the desired tricycle (+)-18 in 84% yield and >99% ee. ... 

Conversion of Xa to the Hydrlndan XIII. The ultimate synthetic target of these investigations is a mixture of the tricyclic alcohols XIV (Scheme II). In the Sih synthesis (3) the methyl ester... 

Imine formation via condensation of aminotriazole 260 with l-methyl-4,5-dioxopyrrolidine-3-carboxylic acid methyl ester 259 leads to formation of the linear tricyclic system 261 under base-mediated conditions (Equation 71) <1997PHA276>. 

In the total synthesis of cerorubenic acid-III methyl ester (105), diene 102 was converted to enantiopure tricyclic ketone 103 through an anionic oxy-Cope rearrangement (equation 56)82. Conversion of 102 to 103 afforded the entire ABC substructure of 104 and 105, most notably the double bond occupying a bridgehead site. 

Pentalenolactone E methyl ester (46), an angularly fused sesquiterpene lactone, was first isolated and characterized by Cane and Rossi [38]. One approach to the synthesis of this material is illustrated in Scheme 5. Key to the successful implementation of the plan is the synthesis of butenolide 49, the electrochemi-cally promoted cyclization of 49 to the tricyclic y-lactone 48, ring opening of the latter to convert the linearly fused system to the angularly fused six-membered ring lactone 47, and functional group elaboration leading to the natural product 46 [36,37]. 

Scheme 60). Griesbeck et al. assume that in a non-polar solvent such as benzene the intramolecular electron transfer from the methionic sulfur group is much faster than the abstraction of hydrogen from the hydroxyl group of the unprotected amino acid. C-Hydrogen abstraction leads to 313, whereas previous lactonization of the zwitterionic biradical 311 yields 314. Since the cis-hydroxy acid is not detected it is conceivable that it cyclizes immediately to the lactone 314. Photolysis of the corresponding methyl ester under the same conditions attains improved yields (84% combined) of two diastereomeric tricyclic products in a ratio of 48 52. 

From Lys hydrochloride pyrolyzed in vacuo at 600°C for 8-10 min, a tricyclic compound 134 is formed in low yield (80TL2679). Cystine reacts with dopachrome to give an unstable product, but the methyl ester of dopachrome gave a stable pyrrolo[2,3-/i][l,4]benzothiazine 135 (87T5357). 

Thus alkylation and silylation of 231 i could be brought about with methyl iodide and chlorotrimethylsilane in 61 and 66% yield, respectively [108]. In these tricyclic keto esters 231, the carbonyl group at C-6 exerts its usual electron withdrawing effect and thereby increases the kinetic acidity of the adjacent cy-clopropylic proton. Equally important, however, is the effect of the alkoxy group... 

Unlike ynamines, ethyl vinyl ether requires the more electron-deficient 4-nitro-2-phenyl-5-oxazolecarboxylic acid methyl ester 271b for reaction to occur. The initial [4 + 2] cycloadduct 279 undergoes further reaction with ethyl vinyl ether to give the tricyclic oxazoline 280 in 76% yield (Scheme 8.79). 

Another example is compound 214, which imitates the trombin-bound structure of the fibrin peptide A, and is an inhibitor of this protease. The first step of this synthesis, Scheme 63, involves opening of 208 to the seven-membered ring compound 209. Subsequent acylation with 210 to form 211 is followed by an intramolecular oxidative cycloaddition to provide tricyclic lactam 212. Nucleophilic ring opening proceeds readily with glycine methyl ester to afford lactam 213 in 88% yield, which was transformed into 214 using solid-phase protocols [161]. 

The cis bicyclic orthoester 87 can exist in the two different conformations 91 and 92. The conformation 92 corresponds to that of the unreactive tricyclic orthoester 62, i. e. conformer it can therefore be eliminated. Con-former 91 can undergo the cleavage of the axial C —0 bond with stereoelectronic control to produce the lactonium ion 93 which after hydration will give the hemi-orthoester 94. Since the chair inversion in 94 is not favored because the hydroxyalkyl side chain would have to take the axial orientation, it is expected that 94 would give the dihydroxy methyl ester 89 preferentially. 

The indole derivative 1 was heated under reflux in thionyl chloride for 5 hours, then excess of thionyl chloride was removed by distillation and the residue was treated with methanol. This did not, however, give the expected product, viz- the methyl ester of 1 instead, the product (63%) was shown to be the tricyclic compound 2. 

Chloro derivative 291 was obtained from dioxo derivative 70 by treatment of phosphoryl chloride in dimethylformamide at 100°C for 2 hours (80CPB3537). The treatment of chloro derivative 291 with methylhydra-zine in a mixture of ethanol and chloroform under reflux gave 2H-pyrido[ 1,2-a]pyrimidin-2-one 295 and rearranged pyridazino[3,4-6]-quinoxaline 296 in 4.8% and 78% yields, respectively (Scheme 21) (80CPB3537). 3,4-Dihydroquinoxalinone 70 could not be rearranged into pyridazino[3,4-6]quinoxaline 296 by treatment with methylhydrazine. When hydrazine hydrate was employed instead of methylhydrazine, tricyclic ethyl ester 297 (R1 = Et) was obtained. The latter reaction gave methyl ester 297 (R1 = Me) when carried out in a mixture of methanol and chloroform (80CPB3537). 

In all cases but one, irradiation at 313 nm of solutions in acetone produced the same products as obtained from irradiation at 254 nm of solutions in acetonitrile. The exception is the para-cyano compound with n = I. Direct as well as sensitized irradiation produces the cyclooctatriene derivative via the ortho adduct. In acetone, however, the cyclooctatriene undergoes sensitized ring closure to give the angular tricyclic product. Direct irradiation gives the linear compound, as had been reported earlier by Gilbert and co-workers [104], The compound with Z = COOEt and n = 1 was also irradiated, but proved to be unreactive, as had also been found by Gilbert et al. [105] for the methyl ester. The compounds with four-atom tethers (n = 2) react much slower than those with three-atom tethers, but the initial [2 + 2] cycloaddition nevertheless proceeds efficiently. 

It has been reported <1998CC2315> that a similar [2+2] intramolecular cyclization of (2-cyclohex-l-enyl-2-methyl-propionyl)phenyl-thiocarbamic acid O-methyl ester leads to the formation of tricyclic thietane in 85% yield (Table 2). 

In the course of their synthesis of colchicine [102], Banwell and coworkers found that the tricyclic intermediate 74, Fig. (15), aromatized in the presence of //-toluenesulfonic acid to give the colchinol analogue 75 [103]. The methyl ester 76 and the previously described methyl ether 72 obtained from 75 were found to be potent inhibitors of tubulin polymerization. 

Burgess et al. (128) reported the catalyst screening of a 96-member array of catalytic systems L20 on a C-H insertion reaction of substrate 9.77 (Fig. 9.32), a transformation usually catalyzed by rhodium (138) or copper salts (139) in the presence of chiral ligands (140). The stereochemical outcome was measured on the diastereomeric couple 9.79-9.80, obtained following uncatalyzed oxidation of 9.78 (Fig. 9.32), to simplify the determination of the chiral products while evaluating the stereoselectivity of the tricycle formation. The stereoselectivity of the C-H insertion was not significantly influenced by the presence of the (L)-methyl ester (128). 

The structures of the vast majority of PD-5 inhibitor compounds aimed at erectile dysfunction consist of modified purines. The structure of the recently approved drug for this indication tadalafll (113) differs markedly from the prototypes. Tryptophan methyl ester (108) provides the starting material for large scale enantioselective synthesis. Condensation of that compound with piperonal (109) in the presence of acid leads to formation of the tricyclic intermediate (110). This transform involves initial addition of the amine to the aldehyde. The carhocation from the newly formed carhinolamine then attacks the indole 2-position to form the the fused piperidine. The stereochemistry of the new chiral center is guided by that from the tryptophan carhon across the ring. The secondary amine is next acylated with chloroacetyl chloride in the presence of triethylamine to afford 111. Reaction of this intermediate with methylamine goes on to form the desired product in a single step. This reaction can he rationalized... 

In the laboratory of K. Fukumoto, the stereoselective total synthesis of (+)-A -capnellene was carried out using an intramolecular Diels-Alder reaction to obtain a tricyclic 5-5-6 system. Since the target molecule was a triquinane, the six-membered ring had to be converted to a five-membered one, a transformation achieved by a Wolff rearrangement. The required a-diazo ketone was prepared via a deformylative diazo transfer reaction and was photolyzed in methanol. The ring-contracted methyl ester was isolated as a 3 1 mixture of separable isomers favoring the a-isomer. 

The conversion of the tricyclic keto-ester (112) via the bromohydrin (113) into methyl 7,16-dioxo-17-norkauran-19-oate (114) constitutes a formal total synthesis of gibberellin Aj2. 

Ring opening of tricycle 17 with sodium methoxide afforded the methyl ester 19 in quantitative yield. The use of these tricyclic intermediates allows preparation of a variety of esters simply by varying the alcohol employed (17). 

Acids 23 and 24 were carried on, via the tricycles 25 and 26, to the methyl esters 27 and 28 respectively. The yield of ester 28 was low since it was prepared from impure acid 24. 

Chemistry of the Tricyclic Diterpenoids.—The addition of chlorosulphonyl isocyanate to the methyl esters of levopimaric and neoabietic acids with the formation of C-12 carboxyamides has been described.63 The well documented aromatic substitution reactions of dehydroabietic acid continue to be examined,64 together... 

As described in Section 4.1. (Scheme 29), in the frequently reviewed synthesis of N-acetyl ( )-clavicipitic acid methyl ester (167) by Hegedus [80, 81], intramolecular aminopalladation of 164 was accomplished by a Pd(n)-catalyzed process lo give the tricyclic azepinoindole 16S. 

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