Tryptamine derivatives synthesis

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). 

Etryptamine (23) is a tryptamine derivative which has been used as an antidepressant. Its synthesis involves the condensation of indole-3-carboxaldehyde (21) with the active methylene group of 1-nitropropane to form the inner nitronium salt of the substituted nitrovinyl indole (22). This then is readily reduced to etryptamine (23)... 

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. 

The Ir-catalyzed borylation of the indole nucleus is another important development that promises to find widespread use in complex molecule synthesis. Early reports include the functionalization of C(7) and also of C(2), reported by Malezcka and Smith and by Hartwig, respectively [39, 40]. In a report in 2011, Movassaghi, Miller, and coworkers demonstrated the borylation of tryptamine derivative 61 to afford 62 in 70 % yield [41]. This material was subjected to Suzuki-Miyaura cross coupling with 7-bromoindole (63) to set the stage for studying the oxidative rearrangement of 64, which would eventually provide diketopiperazine indole alkaloids such as asperazine (Scheme 11.11). 

The Bischler-Napieralski approach to /J-carboline synthesis is very similar to the Pictet-Spengler one, except that the tryptamine derivative is first... 

General Procedure for the Hydroformylation/Fischer Indole Synthesis. Synthesis of Tryptamine Derivatives in Water. Aminoolefin (1 eq), aromatic hydrazine (1 eq), Rh(acac)(CO)2 (0.3 mol %) and TPPTS (1.5 mol %) are dissolved in H2SO4 (4wt% in H2O, 2.5 wt % olefin), filled in an autoclave and pressurized with lObar H2 and 50 bar CO. After stirring for 3 days at 100 °C ammonia (30 wt% in water) is added and the mixture is extracted with EtOAc. The solvent is evaporated to give the product which purified by column chromatography (silica, CH2C12, PrOH, NEt3) if necessary. 

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). 

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). 

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). 

Palladium acetate was also recently used as catalyst in a multistep stereospecific synthesis of enantiomeric rigid tryptamine derivatives [13]. The chiral auxiliary is Oppolzer s sultam (e.q. (3)). 

Szdntay s later synthesis (343) of 3-oxovincadifformine consisted essentially of an independent synthesis (Scheme 75) of Kuehne s tetracyclic aminoester 562a, which on debenzylation cyclized to 3-oxovincadifformine (97). The double bond was then introduced at the 14,15-position via the thiolactam, in a procedure reminiscent of that adopted by Magnus in his synthesis of 3-oxotabersonine (107). Desulfurization of the intermediate unsaturated thiolactam 586 gave yet another synthesis of tabersonine, whereas oxidative removal of the si r atom gave 3-oxotabersonine (107). Alternatively, condensation of the starting tryptamine derivative 587 with... 

Hydroamination reactions of alkynes provide an alternate route to arylhydrazones that can be utilized in the Fischer indole synthesis. Treatment of arylhydrazine 99 with alkyne 100 in the presence of catalyst system comprised of titanium tetrachloride and /-butylamine afforded arylhydrazone intermediate 101 which underwent a Fischer cyclization to give 1,2,3-trisubstituted indole 102 as a single regioisomer <04TL9541>. A similar titanium-catalyzed hydroamination reaction was utilized to prepare tryptamine derivatives <04TL3123>. 

Tributylprenylstannane can also attack 3-brominated 2-oxindoles, as exploited by Fuchs and Funk in their synthesis of rac-flustramine A (188, Scheme 36) [154]. After preparation of 3-bromoindolin-2-one 186 from the tryptamine derivative 185, prenylstannane 86 acts as a nucleophile introducing the ferf-prenyl group at C3 affording 187. After three more steps, rac-flustramine A (188) was obtained. 

Danishefsky and coworkers utilized a nucleophilic displacement of chloride to synthesize 2,3-disubstituted indoles and, more specifically, to realize the total synthesis of gypsetin (not shown) [34, 35]. Tryptamine derivative 68 is transformed into chloroindolenine 69 by f-butyl hypochlorite. The chloroindolenine 69 undergoes attack at C-2 by various nucleophiles, including indole, to produce, after tautomerization, the 2,3-disubstituted indoles (22-79%). The addition of a Lewis acid, Bp3-OEt2 was found to be necessary for high yields for reagents other than prenyl-9-BBN. 

More recently, Kalaus and Szantay have made use of a similar approach to synthesize a variety of pentacyclic indole alkaloids containing the aspidospermane, ibophyUidine, and iboxyphylline core structures. In one approach, featured in the formal total synthesis of ( )-12-demethoxy-N(l)-acetylcylindrocarine (188) [73], a benzyl-protected tryptamine derivative 183 was treated with an appropriately substituted aldehyde (184) to form the enamine species 185a-b, which then underwent... 

In an alternative approach to the synthesis of similar alkaloids, Kalaus and Szantay chose to construct the D-rings first, before the pivotal Diels-Alder reactions (Scheme 45). Thus, deprotection of the trityl-protected tryptamine derivative... 

The synthesis of several other plant metabolites, such as auxin, indole glucosinolates, anthranilate-derived alkaloids, and tryptamine derivatives, could depend on indole as an intermediate. Indole is also found in the scent of flowers such as lilac and robinia. Therefore, it is possible that the recruitment of an indole-3-glycerol phosphate lyase function from TSA genes might have occurred independently several times during plant evolution. 

A Diels-Alder strategy for the biomimetic total synthesis of ( )-perophoramidine was first described by Prof. Stoltz from Caltech. At nearly the same time, Prof. Funk from the Peimsylvania State University completed the first total synthesis of ( )-perophoramidine using a stepwise formal Diels-Alder reaction of a tryptamine derivative with a bromooxindole. Asymmetric total syntheses of perophoramidine using a biomimetic Diels-Alder strategy should allow determination of the absolute configuration of these alkaloids. 

Another important set of bi-component reactions involving C-N and C-C bond formation is based on the Pictet-Spengler reaction, consisting in the cycUzation of electron-rich aromatic moieties onto iminium intermediates. This weU-known sequence constitutes an important domino transformation used for the synthesis of bioactive polyheterocycles. Its organocatalytic asymmetric version was pioneered by Jacobsen and revisited by List, who developed two complementary highly enantioselective accesses to tetrahydro- 3-carbolines from tryptamine-derived imines (Scheme 16.33). Thus, Taylor and Jacobsen [64] reported an enantiomerically pure thiourea-catalyzed cyclization of an acyl iminium intermediate, whereas List and co-workers [65] described the cyclization of an iminium diester intermediate in the presence of a chiral phosphoric acid catalyst. Recently, this methodology has been applied to the synthesis of chiral pyrrolopiperazines [66]. 

In 2007, the Jacobsen group reported a thiourea-catalyzed Pictet-Spengler reaction in a four-step total synthesis of (+)-harmicine (202), in which the key Pictet-Spengler cyclization of tryptamine derivative indole 199 using thiourea 200 as a catalyst gave the jS-indolyl ethyl hydroxylactams 201 in 97% ee (Scheme 17.34) [81]. The reduction of lactam 201 completed the synthesis of (+)-harmicine (202). 

In 2008, a similar asymmetric Pictet-Spengler reaction was applied to the total synthesis of (+)-yohimbine (209) (11 steps, 14% overall yield), an important member of the monoterpenoid indole alkaloids as shown in Scheme 17.35 [82]. The synthesis involved two key steps, which are the acyl-Pictet-Spengler reaction of tryptamine derivative 199 with aldehyde 203 (97% ee) and a stereoselective intramolecular Diels-Alder reaction of 206 with the simultaneous generation of four new stereogenic centers [83]. 

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