“…Indole alkaloids have long held a prominent position in natural product chemistry because of their structural relationship to the essential amino acid tryptophan and the corresponding metabolites of tryptophan, such as the neurotransmitter serotonin. − One group of indole alkaloids studied intensely in recent years has been isolated from Alstonia species. , As shown in Figure , a number of these Alstonia alkaloids are ring-A oxygenated indole bases in the macroline/sarpagine series such as alstophylline ( 1 ), , N b -desmethylalstophylline oxindole ( 2 ), and 11-methoxy- N a -methyldihydropericyclivine (not shown). These bases could presumably be synthesized from 6-methoxy- d -tryptophan via the trans transfer of chirality in the asymmetric Pictet−Spengler reaction. , 1 …”
A concise preparation of optically active L or D-6-methoxytryptophan ethyl ester 21 was developed via the Fischer indole/Scho ¨llkopf protocol from 6-methoxy-3-methylindole 16 (four steps, 58% overall yield). This method was extended to the enantiospecific total synthesis of tryprostatin A (11) via a regiospecific bromination process as a key step. In addition, 6-methoxy-2-bromotryptophan ethyl ester (32), a potential intermediate for indole alkaloid synthesis, was prepared via this strategy.
“…Indole alkaloids have long held a prominent position in natural product chemistry because of their structural relationship to the essential amino acid tryptophan and the corresponding metabolites of tryptophan, such as the neurotransmitter serotonin. − One group of indole alkaloids studied intensely in recent years has been isolated from Alstonia species. , As shown in Figure , a number of these Alstonia alkaloids are ring-A oxygenated indole bases in the macroline/sarpagine series such as alstophylline ( 1 ), , N b -desmethylalstophylline oxindole ( 2 ), and 11-methoxy- N a -methyldihydropericyclivine (not shown). These bases could presumably be synthesized from 6-methoxy- d -tryptophan via the trans transfer of chirality in the asymmetric Pictet−Spengler reaction. , 1 …”
A concise preparation of optically active L or D-6-methoxytryptophan ethyl ester 21 was developed via the Fischer indole/Scho ¨llkopf protocol from 6-methoxy-3-methylindole 16 (four steps, 58% overall yield). This method was extended to the enantiospecific total synthesis of tryprostatin A (11) via a regiospecific bromination process as a key step. In addition, 6-methoxy-2-bromotryptophan ethyl ester (32), a potential intermediate for indole alkaloid synthesis, was prepared via this strategy.
“…[1] Many of approaches to such structures have been investigated, but each method has limitations. Thus, a highly enantioselective procedure to prepare optically active aromatic amines would be valuable, and an enantioselective route to N-aryl allylic amines would be particularly useful because of the dual functionality in these compounds.…”
Aromatic amines with a stereocenter a to the nitrogen atom are important structural motifs in a number of biologically active compounds.[1] Many of approaches to such structures have been investigated, but each method has limitations. Thus, a highly enantioselective procedure to prepare optically active aromatic amines would be valuable, and an enantioselective route to N-aryl allylic amines would be particularly useful because of the dual functionality in these compounds.Allylic substitution catalyzed by transition metals has emerged as a powerful tool for enantioselective formation of CÀC, CÀN, and CÀO bonds. [2][3][4] However, aromatic amines have not been used commonly in allylic amination, [5][6][7] presumably because they are less nucleophilic than the more commonly used benzylamine or stabilized anionic nitrogen nucleophiles. A general and highly enantioselective reaction between an aromatic amine without an activating group on the nitrogen atom and an achiral allylic ester or a racemic branched allylic electrophile has not been reported.Catalysts based on metals other than palladium [8][9][10][11][12][13][14][15][16] and its congeners often form the more hindered, branched product from nucleophilic substitution with unsymmetrical monosubstituted allylic esters. [17][18][19][20] This reactivity complements the regioselectivity of palladium catalysts, which tend to form the linear products. We previously reported asymmetric allylic substitution of achiral allylic carbonates with aliphatic amines and phenoxides to form branched allylic amines and ethers with high regio-and enantioselectivities in the presence of an iridium complex with a phosphoramidite ligand. [21,22] Reactions of aromatic amines did not occur under the conditions developed originally.Our mechanistic studies have shown that the cyclometalated complex 1, generated in situ by treatment of [{Ir(cod)Cl} 2 ] (cod = cycloocta-1,5-diene) and the ligand L 1 with an alkylamine base (Scheme 1), is likely to be the true catalyst in the allylic amination.[23] Reactions conducted with the isolated complex 1 as catalyst occurred faster and with broader scope than those with the combination of [{Ir(cod)Cl} 2 ] and L 1 .We proposed that the initial system failed to catalyze reactions of anilines because aromatic amines are not basic enough to induce cyclometalation, not because aromatic amines are too weakly nucleophilic to react with the iridium allyl intermediate. [23] If so, then the reactions of aniline should occur with a catalyst generated in situ by the action of a separate additive. Herein we report two convenient methods to generate the active catalyst in situ and the use of this catalyst to develop a general reaction of allylic carbonates with aromatic amines.[24] These reactions occur with a broad range of achiral, linear allylic carbonates to give branched chiral allyl aryl amines in excellent yields and with high regioand enantioselectivities (Scheme 2).The cyclometalated complex 1 was generated in pure form by reaction of [{Ir(cod)Cl} 2 ] and...
“…Numerous synthetic approaches to the indoline and indole classes of molecules have been developed over the years because of the prevalence of these structural motifs in natural product chemistry (cf., the indole alkaloids) and indole dyes . Most indoline and indole syntheses have accessed these compounds via conventional organic synthetic routes, , but several groups have recently reported procedures to these molecules using metal-mediated, organometallic protocols for key synthetic steps .…”
The room-temperature reaction of
(PMe3)2Ni(CH2CMe2-o-C6H4)
(3) with 3 equiv of p-tolyl
azide (TolN3) results in evolution of N2 and
clean
formation of the N-p-tolylindoline derivative
TolNCH2CMe2-o-C6H4
(4a), isolated in 82% yield. The reaction
almost certainly proceeds via insertion of an “NTol”
fragment from TolN3 into the Ni−C(aryl) bond to
give
an intermediate azametallacycle
[L
n
Ni(NTol-o-C6H4CMe2CH2)] (5), which then
undergoes C,N-reductive
elimination to afford the indoline 4a.
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