As the complexity of targeted molecules increases in modern organic synthesis, chemoselectivity is recognized as an important factor in the development of new methodologies. Chemoselective nucleophilic addition to amide carbonyl centers is a challenge because classical methods require harsh reaction conditions to overcome the poor electrophilicity of the amide carbonyl group. We have successfully developed a reductive nucleophilic addition of mild nucleophiles to tertiary amides, secondary amides, and N-methoxyamides that uses the Schwartz reagent [Cp2 ZrHCl]. The reaction took place in a highly chemoselective fashion in the presence of a variety of sensitive functional groups, such as methyl esters, which conventionally require protection prior to nucleophilic addition. The reaction will be applicable to the concise synthesis of complex natural alkaloids from readily available amide groups.
Take the direct path: Sequential nucleophilic addition of N‐methoxyamides using DIBAL and organometallic reagents provided substituted N‐methoxyamines in one pot via five‐membered chelated intermediates (see scheme, DIBAL=diisobutylaluminum hydride). The reaction allows functionalization of acyclic amides and macrolactams without a preactivation step, which is generally required for inert amide carbonyl groups.
A chemoselective approach for the total synthesis of (±)-gephyrotoxin has been developed. The key to success was the utilization of N-methoxyamides, which enabled the direct coupling of the amide with an aldehyde and selective reductive nucleophilic addition to the amide in the presence of a variety of sensitive and electrophilic functional groups, such as a methyl ester. This chemoselective approach minimized the use of protecting-group manipulations and redox reactions, which resulted in the most concise and efficient total synthesis of (±)-gephyrotoxin described to date.
While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long-standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N-alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N-alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N-alkoxy group formed a five-membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL-H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter- and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered α-trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five- and six-membered lactams, and macrolactams.
Auf direktem Weg: Sequenzielle nucleophile Additionen an N‐Methoxyamide durch DIBAL und Organometallreagentien ergeben substituierte N‐Methoxyamine (siehe Schema, DIBAL=Diisobutylaluminiumhydrid). Die über Fünfringchelate verlaufenden Eintopfprozesse eröffnen einen Zugang zu funktionalisierten acyclischen Amiden und Makrolactamen ohne den für reationsträge Amid‐Carbonylgruppen sonst nötigen zusätzlichen Aktivierungsschritt.
The development of a two-step synthesis of multi-substituted N-methoxyamines from N-methoxyamides is reported. Utilization of the N-methoxy group as a reactivity control element was the key to success in this two-step synthesis. The first reaction involves a N-methoxyamide/aldehyde coupling reaction. Whereas ordinary amides cannot condense with aldehydes intermolecularly due to the poor nucleophilicity of the amide nitrogen, the N-methoxy group enhances the nucleophilicity of the nitrogen, enabling the direct coupling reaction. The second reaction in the two-step process was nucleophilic addition to the N-methoxyamides. Incorporation of the N-methoxy group into the amides increased the electrophilicity of the amide carbonyls and promoted the chelation effect. This nucleophilic addition enabled quick diversification of the products derived from the first step. The developed strategy was applicable to a variety of substrates, resulting in the elaboration of multi-substituted piperidines and acyclic amines, as well as a substructure of a complex natural alkaloid.
Three-component allylation and cyanation utilizing a ketone and an N-methoxyamine are reported. The high nucleophilicity of the N-methoxyamine and high electrophilicity of the corresponding iminium ion enable the concise synthesis of α-trisubstituted amines in a single step.
This article describes the full details of our total syntheses of gephyrotoxin and perhydrogephyrotoxin. Our central strategy toward the total synthesis is based on the use of an N-methoxy group as a reactivity control element. The N-methoxyamide group enabled unique transformations, involving i) the direct coupling reaction of the N-methoxyamide with an aldehyde, and ii) the amide-selective reductive allylation. These reactions were never accomplished without the assistance of the N-methoxy group. The amide-selective reductive allylation of the N-methoxyamide was especially practical, and excluded a number of extra steps including protecting group manipulations and redox reactions in the total syntheses.Gephyrotoxin (1) is a constituent isolated from skin extracts of a Colombian tropical poison dart frog, Dendrobates histrionicus in 1977 (Figure 1). 1 The structure of gephyrotoxin (1) was elucidated by spectroscopic approaches, and finally determined by X-ray crystallographic analysis. Gephyrotoxin (1) consists of a tricyclic core and two distinct side chains with five stereogenic carbon centers, three of which are connected to the same nitrogen atom. It possesses an array of neurological activities including mild muscarinic activities. Kishi documented the first total synthesis of («)-gephyrotoxin (1) using a set of stereoselective hydrogenation reactions to establish all five stereocenters in 1980.2a Kishi then achieved the enantioselective total synthesis starting from L-pyroglutamic acid, which resulted in disagreement on the absolute configuration of the natural gephyrotoxin (1).2b The absolute structure of 1 remains inconclusive due to the limited supply of the natural alkaloid. In 1983, Hart reported the total synthesis of («)-gephyrotoxin (1) via cyclization of N-acyliminium ion as a key step.2c,2d Shortly after, Overman disclosed the stereoselective total synthesis of 1, whose key steps were the DielsAlder reaction of the amino diene, and stereoselective reduction using stereoelectronic effects.2e The unique structure of gephyrotoxin (1) has continuously inspired the synthetic community, resulting in a number of formal syntheses based on Kishi's route by a multitude of differing strategies. 24 Very recently, Smith reported the enantioselective total synthesis by use of an elegant cascade strategy. 2f In this full paper, we disclose full details of the development of an efficient strategy for synthesis of 1 using an N-methoxy group as a reactivity control element. 5 In particular, utilization of amide-selective nucleophilic addition enabled the concise and efficient total synthesis of 1.Our research group is engaged in a program devoted to the development of efficient strategies using unique properties of a heteroatomheteroatom bond for assembling complex natural products. Incorporation of a heteroatom to a second heteroatom dramatically changes the original reactivities, and enables new transformations, which are not realized with an isolated heteroatom. As proof of this concept, we took an interes...
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