Cyclization tryptamine synthesis

Scheme 13.5 Tryptamine synthesis reported by Beller et al. The HCI generated in this process catalyzes the Fischer indole cyclization, which makes the addition of a Lewis acid such as ZnCl2 unnecessary [13].

The Bischler-Napieralski reaction involves the cyclization of phenethyl amides 1 in the presence of dehydrating agents such as P2O5 or POCI3 to afford 3,4-dihydroisoquinoline products 2. This reaction is one of the most commonly employed and versatile methods for the synthesis of the isoquinoline ring system, which is found in a large number of alkaloid natural products. The Bischler-Napieralski reaction is also frequently used for the conversion of N-acyl tryptamine derivatives 3 into p-carbolines 4 (eq 2). 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

The formation of an iminium ion as 2-530 is also proposed by Heaney and coworkers in the synthesis of a tetrahydro- 3-carboline 2-531 (Scheme 2.120) [282]. Herein, heating a solution of tryptamine (2-526) and the acetal 2-527 in the presence of 10 mol% of Sc(OTf)3 gives in the first step the N, O-acetal 2-528, which then leads to the lactam 2-529 and further to the iminium ion 2-530 by elimination of methanol. The last step is a well-known Pictet-Spengler type cyclization to give the final product 2-531 in 91% yield. 

In the course of our successful synthesis, we identified several limitations of our new method and associated strategy (1) the harsh conditions of the bicyclization reaction do not tolerate base-sensitive functionality such as vinyl halides (2) post-cyclization manipulations such as iododesilylation reactions are complicated by the sensitive/ reactive functionality of the products (a,p-unsaturated aldehyde, indoline, etc.) and (3) the incorporation of the required functionality into the Zincke aldehyde requires the synthesis of a complex tryptamine derivative, resulting in a lengthy, non-convergent route. In order to develop a concise route to strychnine, we would have to address each of these issues, and a straightforward solution to obviate all of these is described below. 

Takano s group reported the first enantioselective total synthesis of (—)-anti-rhine as well (146). Chiral product 235 was prepared via a number of stereoselective reactions. Reductive condensation of 235 with tryptamine, using sodium cyanoborohydride at pH 6, supplied lactam 236, which was reduced by di-isobutylalminum hydride to hemiacetal 237. The latter could be cyclized to (-)-antirhine by simple acid treatment (146). 

Similarly to 8-lactone 260, y-lactone 263, prepared also from ( )-norcamphor (228), proved to be another useful intermediate for the synthesis of all four corynantheidol stereoisomers as well as of the corresponding 18,19-didehydro derivatives. Cleavage of the a-diketone monothioketal moiety in 263 and the formation of amide 265 by its reaction with tryptamine, followed by Bischler-Napieralski cyclization and sodium borohydride reduction, resulted in a mixture... 

The total synthesis of ( )-geissoschizine (30) was reported by Yamada et al. (156) in 1974. The geometrically pure p-nitrophenyl ester 272 was condensed with tryptamine, and then the resulting amide 273 was transformed to lactam aldehyde 274 by hydroxylation with osmium tetroxide, metaperiodate oxidation, and Pictet-Spengler cyclization. 

The first total synthesis of D/E-trans annellated yohimbines, e.g., ( )-yohim-bine (74) and ( )-pseudoyohimbine (88), was published in preliminary form by van Tamelen and co-workers (218) in 1958, while full details (219) appeared only in 1969. Key building block 393, prepared from butadiene and p-quinone, was condensed with tryptamine, yielding unsaturated amide 394, which was subsequently transformed to dialdehyde derivative 396. Cyclization of the latter resulted in pseudoyohimbane 397. Final substitution of ring E was achieved via pyrolysis, oxidation, and esterification steps. As a result of the reaction sequence, ( )-pseudoyohimbine was obtained, from which ( )-yohimbine could be prepared via C-3 epimerization. 

Cascade Addition-Cyclization Reactions Given the importance of cascade reactions in modem chemical synthesis, the MacMillan group has proposed expansion of the realm of iminium catalysis to include the activation of tandem bond-forming processes, with a view toward the rapid constraction of natural products. In this context, the addition-cyclization of tryptamines with a,p-unsaturated aldehydes in the presence of imidazolidinone catalysts 11 or 15 has been accomplished to provide pyrroloindoline adducts in high yields and with excellent enantioselectivities (Scheme 11.3a). This transformation is successful... 

Specific substrates such as diethyl a -acetylglutarate, 2-ethoxycarbonylcyclopentanone and 3-carboxypiperidone are useful for the synthesis of special classes of functionally substituted indoles, as shown in Scheme 10. When cyclization is followed by hydrolytic decarboxylation of the C-2 substituent, these cyclizations provide indoleacetic acids, indolepropionic acids and tryptamines, and 3-(2-aminoethyl)indoles, respectively <72HC(25-1)236). 

One application of lactone 140 as a chiral synthon may be found in the asymmetric synthesis of (+)-12b-epidevinylantirhine (143), a cleaved product of geissoschizol (Scheme 28) [62-63]. Treatment of 140 with tryptamine in hot toluene afforded 142, which cyclized to lactam 142 by mesylation and an Sn2 displacement. Hie Bischler-Napieralski reaction of 142, followed by reduction of the resulting iminium salt with NaBH4, produced stereoselectively, the indolo[2,3-a]quinolizine as a single isomer, which was further reduced with DIBAL to give (+)-12b-epidevinylantirhine (143). 

One of the few examples of a synthetically useful 6-exo-trig cyclization from 3-aza-6-heptenyl radicals is found in the total synthesis of ( )-melinonine-E (159, Scheme 31) by Bonjoch et al. [66]. The cyclization precursor, a,P-unsaturated nitrile 157 was prepared from 1,4-cyclohexanedione monoethylene acetal (156) and tryptamine in 5 steps with 41% overall yield. Initially, when 157 was treated with 1.1 equiv. of n-BujSnH and 0.1 equiv. of AIBN in toluene for 16 h, the expected cyclization to the 2-azabicyclo[3.3.1]nonane ring took place to give 158 only as a minor product, along with its C(14) chloro- and dichloro-substituted derivatives as major products. An additional treatment of the crude mixture with 2.2 equiv. of BujSnH brought about the reduction of the C-Cl bonds to provide nitrile 158 in 38% yield over... 

Pioneering studies on hypervalent iodine-induced reactions toward total syntheses of several natural products had been reported from the 1970s to the early 1980s. That is, Kishi and co-workers accomplished the total synthesis of sporidesmin A (120), which is a toxic metabolite of Pithomyces chartarum, by PIDA-mediated cyclization of tryptamine derivative 121, but, the yield of tricyclic compound 122 was only 30% [85] (Scheme 1). 

Non-tryptamines.—Glycozoline (1) has been very simply synthesized by the thermal cyclization (350 °C) of 4 -methoxy-4-methyldiphenylamine in the presence of iodine.2 Details of the syntheses of girinimbine and mahanimbine have now been published,3 and the method used in the synthesis of the latter has been extended to the synthesis of ( )-isomahanimbine (2) thus, condensation of 2-hydroxy-6-methylcarbazole with citral in pyridine containing a trace of benzoic acid gave... 

Trost s synthesis138 of desethylibogamine (233) illustrates the application of a new approach to alkaloid synthesis, in which the two vital cyclization processes involve catalysis by palladium complexes protection of the nitrogen by formation of an amide, so often necessary in conventional syntheses, is here unnecessary. The first of the cyclization processes, (234)—>(235), results in a very neat formation of the isoquinuclidine ring system via a palladium-catalysed SN2 cyclization of the tryptamine derivative (234) (Scheme 24). 

Takano et al. have reported the first synthesis of ( )-antirhine (71) (Scheme 11),51 in which the problem of generating the desired, less stable (anti) stereochemistry at C-3 and C-15 was overcome by preparing the non-tryptamine fragment (72) from ( )-trinorcamphor (73) via a sequence of stereospecific reactions. Condensation of (72) with tryptamine, followed by cyclization and... 

A different approach was adopted in the synthesis by Justoni and Pessina (111). The Japp-Klingemann reaction of p-benzyloxyphenyl-hydrazine with cyclopentanone carboxylic ester gave the p-benzyloxy-phenylhydrazone of a-ketoadipic acid (XIV) Fischer cyclization of the corresponding dimethyl ester then yielded 5-benzyloxyindole-2-car-boxylic-3-jS-propionic acid (XV). Decarboxylation of XV followed by Curtius degradation and debenzylation eventually afforded 5-hydroxy-tryptamine. 

The structure of harman (II R = H) has been discussed already in connection with that of harmaline. Many additional syntheses of it and of its tetrahydro derivative have been recorded (39-44). Owing to the extremely active 2-position in the indole nucleus, cyclizations which yield quinolines from /3-phenethylamines proceed with greater ease from tryptamines, often yielding the tetrahydro bases under so-called physiological conditions (43, 44). A novel synthesis of harman depends upon... 

Among the wide variety of unsaturated functionalities which participate in the cobalt-mediated [2+2+2] cycloaddition that has proved to be a powerful tool for the assembly of complex polycyclic molecules are a number of aromatic heterocyclic double bonds, such as those in pyrrole and indole <20000L2479, 2001JA9324 and references therein>. Indoles, including those substituted at C-3, can be cyclized, both intra- and intermolecularly, with a wide variety of alkynes to yield functionalized products in moderate to good yields. A stereoselective cobalt-mediated [2+2+2] cycloaddition reaction between the W(pent-2-en-4-ynoyl)indole moiety of tryptamine derivative 1093 (R = (CH2)2NHAc) and acetylene has been employed for the formal total synthesis of strychnine 1097, the most famous Strychnos alkaloid and a commonly used rodenticide and animal stimulant (Scheme 213). 

The oxidative formation of a new pyrrole ring in the indol-3-yl-indoloquinone system afforded a simple synthesis of the Wakayin model compound 1243. Tryptamine 1241 (R= H) was reacted with 2-methoxynaphthoquinone 1242 in refluxing ethanol to afford aminonaphthoquinone derivative 1243 in high yield (68%), but various attempts to oxidatively cyclize compound 1243 (R= H) to compound 1244 failed (Scheme 239) <1998TL7677>. 

The classic chemical synthesis for the preparation of TBC, DBC, and BC is summarized in Fig. 5. Acylation of tryptamines (1) affords indolyl-ethylamides (2), which on Bischler-Napieralski cyclization give DBCs (3)... 

Compound 60 is a mixture of diastereomers, and the structures were proposed on the basis of spectral data and proved to be correct by synthesis from indole-3-acetaldehyde and L-cysteine. It was demonstrated that tryptamine is first converted by MAO to indole-3-acetaldehyde, which spontaneously cyclizes with free L-cysteine present in brain tissues 142). The reaction was strongly inhibited by addition of the MAO inhibitor pargyline, indicating participation of the enzyme in the formation of the aldehyde, but not in the condensation with L-cysteine, which was found to be pH-dependent and probably nonenzymatic 143). It seems possible that compound 60 is identical with material obtained during metabolic degradation of tryptamine in brain tissue 144,145). 

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