8-Carboline 1-oxide, synthesis

A-Alkylation of amides and amines and dehydrative -alkylation of secondary alcohols and a-alkylation of methyl ketones " have been carried out by an activation of alcohols by aerobic oxidation to aldehydes, with copper(II) acetate as the only catalyst. A relay race process rather than the conventional borrowing hydrogen-type mechanisms has been proposed for the aerobic C-alkylation reactions, based on results of mechanistic studies. A Winterfeldt oxidation of substituted 1,2,3,4-tetrahydro-y-carboline derivatives provides a convenient and efiflcient method for the synthesis of the corresponding dihydropyrrolo[3,2-fc]quinolone derivatives in moderate to excellent yields. The generality and substrate scope of this aerobic oxidation have been explored and a possible reaction mechanism has been proposed. Direct oxidative synthesis of amides from acetylenes and secondary amines by using oxygen as an oxidant has been developed in which l,8-diazabicyclo[5.4.0]undec-7-ene was used as the key additive and copper(I) bromide as the catalyst. It has been postulated that initially formed copper(I) acetylide plays an important role in the oxidative process. Furthermore, it has been postulated that an ct-aminovinylcopper(I) complex, the anti-Markovnikov hydroamination product of copper acetylide, is involved in the reported reaction system. Copper(I) bromide... 

Behforouz s synthesis employed more highly substituted quinoline aldehyde 30, which, when condensed with ester 21, produced /3-carboline 31 without need of a separate oxidation step. Selective hydrolysis of the acetamide group then provided lavendamycin methyl ester in high yield. A few years later, Behforouz and coworkers reported an improved synthesis of 30, thus boosting the overall yield of their lavendamycin synthesis [33]. 

Acetyl-3-methoxycarbonyl-/ -carboline, the alkaloid of Vestia lycioides, has been synthesized by two routes 200,6 the second involves the benzylic oxidation-dehydrogenation of l-ethyl-3-methoxycarbonyl-l,2,3,4-tetrahydro-/ -carboline by means of selenium dioxide in dioxan. A by-product in this oxidation was 1 -acetyl-/ -carboline, which occurs in Ailanthus malabarica. An extension of this reaction led to a simple two-stage synthesis of canthin-6-one (22) from Ab-benzyltryptamine and a-ketoglutaric acid (Scheme 2).206... 

A Mannich-type reaction is used in the PictetSpengler synthesis of tetrahydroisoquinolines 181 (Scheme 108) . Indoles similarly give -carbolines (Section 3.3.1.5.7.4). A variation of the PictetSpengler reaction involves the oxidative cyclization of 182 using ceric ammonium nitrate (CAN) (Scheme 109) <1998JOC860>. 

Hagen TG, Narayanan K, Names J, Cook JM (1989) DDQ oxidations in the indole area. Synthesis of 4-alkoxy-beta-carbolines including the natural products crenatine and l-methoxycanthin-6-one. J Org Chem 54 2170-2178 Hajos ZG, Parrish DR (1974) Asymmetric synthesis of bicyclic intermediates of natural product chemistry. J Org Chem 39 1615-1621... 

Cain, M., Campos, O., Guzman, F., Cook, J. M. Selenium dioxide oxidations in the indole area. Synthesis of p-carboline alkaloids. J. Am. Chem. Soc. 1983, 105, 907-913. 

A new simple oxindole alkaloid, (-)-horsfiline (57) was obtained from Horsfieldia superba (Myristicaceae), in addition to the known alkaloids 6-methoxy-2-methyl-l,2,3,4-tetrahydro-P-carboline (58) and 5-methoxy-A, -dimethyltryptamine [59]. Horsfiline is a simple spiro-pyrrolidinyloxindole, its structure was deduced from spectral data (MS NMR) as well as by partial synthesis from 58 via oxidation with Pb(OAc)4 to the acetoxyindolenine 59, followed by acid catalysed rearrangement (MeOH/AcOH) to ( )-horsfiline (Scheme 2) [59]. 

The racemization of chiral l-substituted-l,2,3,4-tetrahydro-p-carbolines is well known. This reaction is generally performed either under strong acidic (Scheme 6.11, path A) or basic (Scheme 6.11, path B) conditions as well as via oxidation-reduction processes (Scheme 6.11, path C). From a literature review, no optimal method has been developed for a large-scale synthesis. Most methods involve harsh conditions, long reaction times, and expensive reagents, and generally afford poor yields. 

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... 

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). 

At about the same time, Nicolaou and Chen et al. independently reported the synthesis of haplophytine [85]. Retrosynthetically, haplophytine was envisioned by a sequence of Suzuki-Miyaura Coupling, Vilsmeier-Haack reaction, and radical cyclization from indole 205 and vinyl iodide 206. The left-hand domain 205 could arise through the oxidative skeletal rearrangement of enamine 207, which could be obtained from the oxidative coupling of tetrahydro-jS-carboline 208 and diphenol 209 (Scheme 37). 

Structurally, 218 and 219 feature a heptacycUc ring system, containing a twisted 16-membered macrocycle, a hindered quaternary center linking two tryptophan residues and a strained ot-carboline. Recently, Baran and coworkers reported the first synthesis of kapakahines B and F by a diastereoselective, oxidative N-C bond formation and a late-stage shift of structural topology [89]. 

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