0-Carbolines 3.4- dihydro-, synthesis

Fig. 5. Synthesis of tetrahydro-zS-carbolines. dihydro-/3-carbolines. and /3-carbolines.

In a recent paper, Schopf and Steuer ° describe the synthesis under physiological conditions of rutaecarpine from 4 5-dihydro-3-carboline perchlorate and a-aminobenzaldehyde. 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

Key intermediate 368 of Swan s ( )-yohimbone (305) synthesis (169) has also been achieved by Kametani et al. (215). Thermolysis of 3,4-dihydro-l-(5-methoxybenzocyclobutanyl)-P-carboline hydrochloride (381) afforded deca-... 

In 1969, Szantay and co-workers published a linear synthesis of (+)-yohimbine and (—)-P-yohimbine (75) in full detail (220). Tetracyclic key intermediate 400, obtained from 3,4-dihydro-p-carboline and a properly substituted a,p-unsatu-rated ketone (173), was treated with a proper phosphonoacetic acid derivative to give unsaturated nitrile 401 or unsaturated ester 402. Catalytic reduction of the latter resulted almost exclusively in 404 with normal stereo arrangement, while reduction of 401 supplied a mixture of normal and epialloindolo[2,3-a] quinolizines 403 and 405, respectively. Dieckmann ring closure of diester 404 gave 18a-methoxycarbonylyohimbone (407) as the thermodynamically favored... 

To synthesize 6-methoxy-3,4-dihydro-beta-carboline (10-meth-oxy-harmalan), add 5-methoxy-tryptamine to acetic anhydride and let stand twelve hours at 10°. Dilute with water, basify and extract with methylene Cl and dry, evaporate in vacuum to get melatonin (I). Reflux (1) in xylene in the presence of P205 to get the title compounds. Other References JMC 7,136(1964) JPS 57,1364 (1968), 59,1446(1970) JACS 70,219(1948) JCS 1602(1921), 1203(1951), 4589,4593(1956) Organic Synthesis 51, 136... 

For the synthesis of the natural blue pigment trichotomine dimethyl ester, L-Trp-OMe was used as a starting material. The first step of this synthesis was conversion into methyl l-methyl-3,4-dihydro-/8-carboline-3-carboxylate with acetyl chloride in TFA (85JOC3322). An improved method starts from the corresponding thioamides via thioiminium salts which cyclize spontaneously in refluxing solvent (82CPB4226). A-Formyl-tryptophan also cyclized readily with no side reactions (68CJC3404). 

A. Synthesis and Reactions of 3,4-Dihydro-P-carboline Reissert Compounds... 

Dodd and co-workers (5) reported the first known synthesis of 11//-indolizino[8,7-h]indoles by the cycloaddition reaction of a nonstabilized ylide 21 and diethylacetylene dicarboxylate (DEAD). The azomethine ylide, formed by the alkylation of the 3,4-dihydro-p-carboline (22) with trimethylsilyl methyl triflate to the triflate salt, followed by in situ desilyation with cesium fluoride, underwent cycloaddition with DEAD at low temperature. The expected major cycloadduct 23 was isolated, along with quantities of a minor product 24, presumed to have been formed by initial reaction of the ylide with 1 equiv of DEAD and the intermediate undergoing reaction with a further equivalent of DEAD before cyclization. Dodd offers no explanation for the unexpected position of the double bond in the newly generated five-membered ring, although it is most likely due to post-reaction isomerization to the thermodynamically more stable p-amino acrylate system (Scheme 3.5). 

Cook s stereospecific synthesis19" of trans-1,3 -disubstituted tetrahydro-/ -carbolines by condensation of iVb-benzyltryptophan methyl ester with aldehydes, coupled with a simple 13C n.m.r. method for differentiating cis- and trans-tetrahydro-/ -carbolines,196 should afford a promising starting point for the synthesis of complex alkaloids. Angenot and his collaborators have also discussed the 13C n.m.r. spectra of a number of / -carboline and 3,4-dihydro-/Tcarboline derivatives.19"... 

An extension of Kametani s earlier synthesis has afforded a neat synthesis of rutaecarpine (24) and hortiacine (10-methoxyrutaecarpine).22" In this modification, the presence of a trifluoromethyl group in (23) (instead of hydrogen, as in Kametani s synthesis) increases the electrophilicity of the protonated form, and also provides a useful leaving group for the final stage of the synthesis a dehydrogenation step is therefore unnecessary (Scheme 3). Rutaecarpine has also been synthesized.226 11-Methoxyrutaecarpine has been simply synthesized by condensation of 7-methoxy- 1-oxo-l,2-dihydro-/ -carboline with methyl anthranilate and phosphorus oxychloride.22c... 

In the synthesis of (+)-dihydrocorynantheol (92) by Kametani et al.,56a the tetracyclic system (93) was constructed by Michael addition of an enamine, derived from the dihydro-/ -carboline (76), to dimethyl 3-methoxyallylidenemalonate, with closure of the lactam ring (Scheme 15). The product (93) was then converted (by unexceptional methods), via the lactam aldehyde (94), into ( )-dihydrocoryn-antheol, the normal stereochemistry in which follows from its mode of formation. 

Langlois and co-workers (82CC1118 85JOC961) succeeded in the total synthesis of vindrosine (46) and vindoline (47) by the imino Diels-Alder cycloaddition using dihydro-)3-carbolines and the diene shown in Scheme 5. 

In the laboratory of S.F. Martin, a biomimetic approach toward the total synthesis of ( )-strychnine was developed by using tandem vinylogous Mannich addition and HDA reaction to construct the pentacyclic heteroyohimboid core of the natural product.The commercially available 4,9-dihydro-3/-/-P-carboline was first converted to the corresponding A/-acylium ion and then reacted with 1-trimethylsilyloxybutadiene in a vinyiogous Mannich reaction. The resulting cycloaddition precursor readily underwent the expected HDA reaction in 85% yield. 

A new and very neat synthesis of evodiamine and rutaecarpine is described by the authors as a retro mass spectral synthesis , since the original conception was derived from the mode of fragmentation of these alkaloids in the mass spectrometer this involves a familiar retro Diels-Alder fission of ring c. Evodiamine (16a) was thus constructed by a 27r + 47r cycloaddition of 3,4-dihydro-/8-carboline with the keteneimine (17), prepared in situ by elimination of sulphur dioxide from the sulphinamide anhydride (18) (Scheme 7). When the anthranilic acid derivative (19) was used the product was rutaecarpine (20) itself, the initially formed dihydro-... 

Acylation of 3-substituted indoles is more difficult, however 2-acetylation can be effected with the aid of boron trifluoride catalysis." " Indoles, with a carboxyl-containing side-chain acid at C-3, undergo intramolecular acylation forming cyclic 2-acylindoles." Intramolecular Vilsmeier processes, using tryptamine amides, have been used extensively for the synthesis of 3,4-dihydro-p-carbolines, a sub-structure found in many indole alkaloids (P-carboline is the widely used, trivial name for pyrido[3,4-fc]indole). Note that it is the imine, rather than a ketone, that is the final product the cyclic nature of the imine favours its retention rather than hydrolysis to amine plus ketone as in the standard Vilsmeier sequence " this ring closure is analogous to the Bischler-Napieralski synthesis of 3,4-dihydro-isoquinolines (9.15.1.7). 

Although enol ethers have received moderate notice as nucleophiles to quench intramolecular iminium ions, silyl enol ethers have been given scant attention. The first report of a silyl enol ether participating in an intramolecular Mannich reaction is found in Oppolzer and coworkers synthesis of ( )-vincamine (Scheme 14). 2 Dihydro-3-carboline (25) and silyl enol ether (26) were mixed in DMF, then warmed to 70 C for 64 h in the presence of diisopropylethylamine to provide a 1 1 mixture of cis and trans tetracyclic aldehydes (27) in 74% yield. 

As we were not only interested in the development of a racemization method but also wanted to evaluate an asymmetric synthesis articulated around the imine intermediate 7 vide infra), we initially investigated its controlled preparation by oxidation of the unwanted (7 )-TH[3C 4 obtained from the mother liquors. Among the various methods initially tested, good results (approximately 75 to 80% in situ yield of imine 7) were obtained with NaOCl in methanol/THF at 0 to 5°C for 3 h. The major by-product is the overoxidized (3-carboline derivative (5 to 10%), although in some experiments, low levels of the unstable N-chloroamine intermediate were also detected. Later on, approximately 68% in situ yield was obtained with tetra-n-propylammonium perruthenate (0.05 equiv) as catalyst with iV-methylmorpholine oxide (1.5 equiv) as cooxidant in acetonitrile at room temperature. However, in this latter method, up to 16% of totally oxidized (3-carboline was also formed. The imine 7 was then directly reduced with sodium borohydride to produce the racemic material in approximately 50% isolated overall yield. Although the aromatic (3-carboline by-product was easily removed upon salt formation, the above approach suffered from several major drawbacks difficulty to control the overoxidation of the desired dihydro-(3-carboline to the (3-carboline on... 

There are only two reported examples of dihydro-P-carbolines. The first was isoeudistomin U which was initially reported to be a 4-substituted dihydro-a-carboline derivative [95], but whose structure was revised after total synthesis to 3,4-dihydroeudistomin U (165) [114]. Recently, the dihydro—3-carboline (166) was reported from an imdescribed ascidian of the genus Eudistoma [115]. 

The synthesis of rutaecarpine (26) itself from the sulphur analogue (27) of isatoic anhydride and 3,4-dihydro-/3-carboline is reported to proceed in 80% yield " however, the corresponding condensation with isatoic anhydride (25) is unsatisfactory, presumably owing to the instability of 3,4-dihydro-/3-carboline at the high temperature used. This may be circumvented by condensation of (25) with the more stable l-oxo-l,2,3,4-tetrahydro-/S-carboline (28), which affords rutaecarpine directly, a spontaneous dehydrogenation step obviously not being required in this reaction. ... 

Synthesis of left-hand segment began with 7-benzyloxyindole 197. A Vilsmeier-Haack formylation followed by condensation afforded nitroalkene 198. Reduction, acylation with succinic anhydride, and subsequent Bischler-Napieralski cyclization provided dihydro-p-carboline 199. Noyori asymmetric reduction of 199, further treatment with A-iodosuccinimide, followed by activation with silver triflate in the presence of dimethoxy-N,N-diallylaniline furnished the desired coupling product 200. Subsequent saponification and cyclization via a ketene intermediate gave the rearrangement precursor 201. Oxidative skeletal rearrangement initiated by m-CPBA followed by removal of the Fmoc group and conversion of the aniline to the hydrazine furnished Fischer indole precursor 202 (Scheme 35). 

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