Tricyclic intermediate synthesis

A second route to the key tricyclic intermediate A for the synthesis of gibberellic acid was also developed (Ref. 8) ... 

The synthesis of the tricyclic intermediate A was further improved by the development of a short and stereocontrolled synthesis of compound B (Ref. 9) ... 

Cava and Schlessinger have reported the synthesis of 1,2,3-triphenyl-isoindole (65) in 78% yield from 1,3-diphenylisobenzofuran (68) hy reaction with thionylaniline (69) and boron trifluoride. The mechanism proposed for this remarkable transformation involves reaiTangement of the adduct (70) derived from thionylaniline and the isobenzofuran, to the tricyclic intermediate (71). This presumably collapses to the S-sultam (72), which yields the isoindole (65) upon extrusion of sulfur dioxide. Loss of sulfur dioxide, both from S-sultones and unsaturated S-sultams, is well documented. ... 

Other applications of the [6 + 2]- and [6 + 4]-cycloaddition reactions in total synthesis have been reviewed.127 The two representative examples shown in Scheme 38 illustrate their use in the total synthesis of /3-cedrene and the taxane ABC ring system. The total synthesis of /3-cedrene utilized an intramolecular [6 + 2]-reaction128 to set up a tricyclic intermediate and the synthesis of the taxane ABC ring system is accomplished via a [6+ 4]-cycloaddition. 

Pursuing the synthesis of angelmicin B, Mootoo prepared the tricyclic intermediate fragment 93 from D-xylose derivative 90 (Fig. 31).46... 

Iprindol (25) is yet another antidepressant drug that differs structurally from the classical tricyclic antidepressants. Condensation of phenylhydrazine and cyclooctanone by the Rogers-Corson modification of the Fischer indole synthesis affords the tricyclic intermediate, 24. The active hydrogen of 6,7,8,9,10-hexahydro-5H-cyclooct[b]indole (24) is removed by reaction with sodium metal in DMF and the resulting salt condensed with 3-dimethylaminopropyl chloride. There is thus obtained iprindol (25). ... 

In a synthesis of the terpene longifolene, the tricyclic intermediate D was obtained from a bicyclic intermediate by an intermolecular Michael addition. Deduce the possible structure(s) of the bicyclic precursor. 

An alternative synthesis of the tricyclic intermediate (168), together with the elaboration of C-4 with the configuration of both podocarpic and dehydroabietic acids, has been reported. In a stereoselective total synthesis of ( )-callitrisic acid and ( )-podocarpic acid, the C-4 stereochemistry was established by reductive methylation of the enol-ether (169). 

A double alkylation reaction of a tetralone produced the key tricyclic intermediate for the synthesis of (-)-huperzine (Scheme 8E.38). A better enantioselectivity was obtained with the BPPFA-derived ligand 137b, possessing a more extended side arm (n = 3) [183-185]. 

A disappointing feature of Stork s synthesis of the lycorine ring system by intramolecular Diels-Alder reaction of a tricyclic intermediate was that the natural stereoisomer was not the major product of ring-closure (cf. Vol. 10,... 

Meyer and co-workers reported (184) a simple synthesis of a tricyclic intermediate containing the ABE ring system. The sequence for the synthesis of 398 is outlined in Scheme 3. Compound 398 is of interest as an intermediate for synthesis of C20-diterpenoid alkaloids containing a substituent at the C-7 position, e.g., ajaconine, atidine, and spiradine. 

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. 

During the synthesis of alkaloids through berberine and benzo[c]phenanthridine rings, a key tricyclic intermediate may be made by reaction of orc/zo-iodobenzamides with the enolate anion from 2-acetylhomoveratric esters (equation 84)570. Cyclization occurs spontaneously under the reaction conditions. 

Styrene, ethyl acrylate and fumaronitrile have been used to mask (3S)-pentacyclic nitrone 77. After a suitable elaboration of isoxazolidines 78 affording 79, the nitrone moiety was restored by thermally induced cycloreversion (145-180 °C), and the tricyclic intermediate 80 was obtained directly through intramolecular 1,3-DC (31-84% yield). This approach was applied to the synthesis of stereodifferentiated polyhydroxyindolizidines such as 81 <02EJO1941>. 

Three independent syntheses of alkaloids of the celacinnine group have been published. In the synthesis of celacinnine (117) by Wasserman et al. (104), the central reaction used is the transamidation or Zip-reaction (69,105,106). In the first part, the preparation of the nine-membered intermediate 122 was achieved by two different routes. Heating of 4-phenylazeti-dinone (123) with 2-methoxypyrroline (124) led to the bicyclic 4-oxotetra-hydropyrimidine (125). The reaction seems to proceed via the tricyclic intermediate 126 and involves an intramolecular ring opening of a /J-lactam... 

The asymmetric total synthesis of the natural enantiomer (—)-nakadomarin A was completed by Nishida et al. in 2004 (Scheme 8.12) [82]. Diels-Alder reaction between siloxydiene 173 and chiral dienophile 172 (prepared from L-serine in 10 steps [83]) gave the highly functionalized key intermediate hydroisoquinoline 174, which was subjected to Luche reduction, cyclization, and HCl treatment to furnish the tricyclic intermediate 175. Compound 175 was converted to 177 via ozonolysis cleavage of ring B followed by recyclization of the unstable bisaldehyde to a five-membered ring by aldol condensation. The Z-olefin 178 was obtained from Wittig reaction of 177, and was further converted to furan 180 via peroxide 179. The... 

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... 

The marine metabolite stypoldione (36) has attracted the attention of chemists owing to both its pharmacological properties and its challenging chemical structure. Xing and Demuth have recently reported an elegant synthesis of 36 via the tricyclic intermediate 35 [126,127]. In our laboratory... 

Photochemically induced [2 + 2] cycloaddition is of extraordinary importance in organic synthesis,as this is a method ideally suited for the preparation of sterically congested compounds. The reaction may occur by a concerted mechanism allowed by rules of orbital symmetry, or, more often, via a biradical pathway. For preparative purposes, the most widely exploited is the enone-alkene photochemical [2 + 2] cycloaddition. This reaction proceeds with high regioselectivity, although its stereoselectivity might be low. The first example of the utilization of this reaction for the synthesis of a natural compound, a-cariophyllene 385, was described by Corey (Scheme 2.129). Adduct 386, formed as a mixture of stereoisomers in high yield from simple precursors, was further transformed via the tricyclic intermediate 387 into the... 

Cyclohexadienones formed from phenols have figured as synthetic intermediates in the synthesis of kauranoid diterpenes. The preparation of a similar tricyclic intermediate (140), suitable for conversion into the diterpene alkaloids, has been described. 

A total synthesis of precalciferol (377) has been reported, which involved nucleophilic addition of the lithium salt (374) to the ketone (373), giving the acetylenic tricyclic intermediate (375). Elimination of HOCl from the chloro-hydrin (375) with bis(ethylenediamine)chromium(n) afforded the en-yn-ene (376), which was reduced to precalciferol (377) with Lindlar s catalyst. Thermal isomerization of (377) then afforded vitamin D3 (378). ... 

In Stork s synthesis (148), 5 - methyl - 6 - methoxy - 1 - tetralone (CLXXXIV) was converted into the tricyclic intermediate CLXX XVII in several steps involving condensation with dimethyl carbonate, addition of methyl isopropenylketone, and cyclization to the a, -unsaturated ketone CLXXXVI, followed by catalytic hydrogenation, replacement of the hydroxyl group in the resulting dihydro alcohol by a chlorine atom on treatment with phosphorus oxychloride in pyridine solution, and elimination of hydrogen chloride by methanolic sodium methoxide. 

In the laboratory of V. Singh a novel and efficient stereospecific synthesis of the marine natural product capnellene from p-cresol was developed. After rapidly assembling the desired carbon framework, it was necessary to remove the carbonyl group from the tricyclic intermediate which was accomplished using Barton s deoxygenation procedure. 

The key tricyclic intermediate toward the total synthesis of spinosyn A was assembled by W.R. Roush et al. featuring a one-pot tandem intramolecular Diels-Alder reaction and an intramolecular vinylogous Baylis-Hillman cyclization. The cyclization precursor was prepared via the S-G modified HWE reaction. 

Overman, L. E., Rabinowitz, M. H. Studies toward the total synthesis of (+)-ptilomycalin A. Use of a tethered Biginelli condensation for the preparation of an advanced tricyclic intermediate. J. Org. Chem. 1993, 58, 3235-3237. 

Other applications of the 6-exo Heck cyclization strategy can be found in Ihe synthesis of pentacyclic Strychnos alkaloids by Bosch et al. [98] and tabersonine by Kuehne et al. (99). As illustrated in Scheme 35, 6-exo Heck cyclization of substrate 20S was successful only when Grigg s [100] modified Heck conditions [Pd(OAc), LiCN] were employed to give the tricyclic intermediate 206. Another 6-exo reductive Heck reaction successfully cyclized tetracyclic substrate 207 into pentacyclic tabersonine (208). 

An independent synthesis of the dienes 629 and 630, by Natsume and co-workers (364), constitutes another formal synthesis of these hexacyclic alkaloids. The tricyclic intermediate 631, previously prepared, was converted by a conventional sequence of reactions via the ketoester 632 into the pentacyclic ester 633, which was oxidized to the unsaturated ester 634. Elimination of the C-17 ether substituent then gave 629, and methylation, followed by elimination, gave 630 (Scheme 86). 

Mariano el al. (74) reported in 1984 several approaches to the synthesis of the ring system of cephalotaxine or its derivatives that represented on advanced integration of the experience gained from his earlier model studies (67,68). The tricyclic intermediates 236 and 237 (Scheme 40) and the derivative 204 lacking the complete B-ring (Schemes 35 and 41) were prepared... 

An illustration that demonstrates stereoselectivity as well comes in Ikegama s synthesis of coriolin.12 Allylation of the sodium enolate of cyclopentanone 77 gives one diastereoisomer of the precursor 78 for a Wacker oxidation and cyclisation to give the tricyclic intermediate 79. 

Our synthesis started from hydroxy ketone B (Figure 5.31), which was obtained by asymmetric reduction of prochiral diketone A with fermenting baker s yeast.38 The key step in the present synthesis was the ring formation by intramolecular alkylation of C to give D. To obtain C, the enfifo-hydroxy group of B was first epimerized via retro-aldol/aldol by treatment with p-toluenesulfonic acid in carbon tetrachloride. The tricyclic intermediate D was converted to (+)-pinthunamide (146), mp 187-189°C, [a]D215 = +60 (EtOH), which was identical with the natural product. Its absolute configuration was thus determined as depicted in 146.39... 

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