Amines total synthesis applications

Hydrido(trialkylsilyl)silyllithiums, preparation, 3, 424 Hydroacylations, olefins, 10, 142 Hydroalkoxylations and etherification, 10, 672 in etherification, 10, 683 Hydroaluminations for C-E bond formation characteristics, 10, 857 chemoselectivity, 10, 859 mechanism, 10, 858 overview, 10, 839-870 stereoselectivity, 10, 861 total synthesis applications, 10, 865 characteristics, 3, 275 process and examples, 9, 268 via Ti(IV) complexes, 4, 658 Hydroaminations actinide-catalyzed, 4, 237 in aminations... 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

The intramolecular insertion reactions of nitrenoids into G-H bonds as described above provide an attractive alternative to conventional methods of amine formation. Both carbamate and sulfamate C-H insertions have been applied successfully to the total syntheses of natural products. - The first application of carbamate G-H insertion was reported by Trost in the total synthesis of methyl-L-callipeltose 118 (Equation (92)).230 Intermolecular G-H insertion of carbamate 117 using 10mol% Rh2(OAc)4, PhI(OAc)4, and DTBMP (2,6-di-/ / -butyl-4-methylpyridine) in dichloromethane (40 °C) furnished methyl-L-callipeltose 118 in 63% yield. In an another independent total synthesis of 118, Panek performed this step in refluxing benzene and improved the yield to 93%.231... 

Christie, B. D. Rapoport, H. Synthesis of optically pure pipecolates from L-asparagine. Application to the total synthesis of (+)-apovinc-amine through amino acid decarbonylation and iminium ion cyclization. J. Org. Chem. 1985, 50, 1239-1246. 

Although electroorganic reactions seem to be useful tools for the transformation of amine derivatives, their application to the total synthesis of natural alkaloids themselves has not always been extensively studied. 

Scheme 2.29 The application of organocatalytic enantioselective a-amination reaction of 3-(4-bromophenyl)-2-methylpropanal 8 for the total synthesis of the optically active cell-adhesion inhibitor BIRT-377 [7b].

Vinyl epoxides can also be used as substrates for formation of optically active allyl amines catalyzed by the same type of chiral palladium complexes as in Eq. (10). By reaction of simple vinyl epoxides with phthalimide as the nitrogen source in the presence of the chiral palladium complexes as the catalyst, very high ee (> 98 %) and regioselectivity (> 97 %) were obtained [26]. A variety of different applications of the use of the palladium-catalyzed approach for the formation of allyl amines and the use of this in total synthesis has been pursued by several research groups, and further details can be obtained in a review by Trost et al. [19d]. 

The same chiral auxiliary has also been used for the stereoselective synthesis of arene-chromium complexes treatment of an aromatic aminal with chromium hexacarbonyl gives the corresponding complex with high diastereomeric excess. This protocol was recently applied in a total synthesis of (—)-lasubine (eq 4). A successful application of 1,2-diaminocyclohexane (as its IR,2R enantiomer) as a chiral auxiliary is illustrated by the di-astereoselective alkylation of the potassium enolate of bis-amide (3) with electrophiles such as benzyl bromide to give bis-alkylated products with excellent diastereoselectivity (eq 5). Lower levels... 

An elegant application of the oxidation of 2-aminofurans has been described by Nicolaou and co-workers (02JA2190, 02JA2202) in model studies directed towards the total synthesis of CP molecules. In this study, the isolable iminobutenolide 80 is formed by cyclisation of the alkoxide 79 (Method B, Section II.B.l.b). Without a stabilising substituent on the ring the equilibrium favours the imine 80 rather than the amine 81 (Scheme 16). However, it is postulated that there is sufficient 2-ami -nofuran in equilibrium for this to be rapidly oxidised to the hydroperoxide 83. At this stage, the final product is determined by the reaction conditions. In strongly acidic conditions, tautomerism to the amine 85 and hydrolysis rationalises the formation of the isolated anhydride 88. Under weakly acidic conditions, formation of... 

The Passerini reaction and the Ugi reaction provide a-acyloxyamides and a-acet-amidoamides, respectively. Naturally, these reactions have been applied in the synthesis of peptides and cyclopeptides/cyclodepsipeptides [91]. Recently, the application of these reactions in the synthesis of heterocycles was reported. One of the most notable examples is Fukuyama and co-workers total synthesis of ecteinascidin 743 (Et 743) (148), a complex natural product recently commercialized as an anticancer drug (Scheme 5.46) [92]. Thus, reaction of the amine 149, the amino acid 150, 4-methoxyphenyl isocyanide (151) and acetaldehyde afforded the corresponding Ugi adduct 152 in 90% yield. After a series chemical transformations, 152 was ultimately converted to Et 743. The connection between the structure of Et 743 and the peptidic nature of Ugi adduct is not obvious, but with the deep insight of an experienced synthetic chemist, the non-trivial link can be drawn and be put into practice [93, 94]. 

Apart from the aforementioned results the usefulness of palladium-catalyzed aryl aminations is shown by applications in natural product synthesis. [18] In this regard the total synthesis of the toad poison dehydrobufetenine is... 

Chiral base catalysis is one of the most versatile and broadly applicable types of catalysis. In particular, the potential of tertiary amines to act both as a base and as a nucleophilic catalyst makes chiral tertiary amines like Cinchona alkaloids a privileged catalyst structure in modem synthesis chemistry. In addition, the field of achiral phosphine and carbene catalysis has proven its potential in numerous applications in the past and it is probably only a matter of time until chiral phosphines and carbenes will also be used routinely for other presently demanding natural product total synthesis (Table 7). 

Applications of /3-Tosylethylamine. Borzilleri and Weinreb used TSE amine (3) in an imino-ene cycUzation for the total synthesis of (—)-papuamine. Exposure of the allenylsilane aldehyde 8 to amine 3 in the presence of SnCLj or under thermal conditions generates the corresponding imine, which undergoes stereospecific cyclization to afford the TSE aminoalkyne 9 following workup with TBAF (eq 3). The aminoalkyne 9 was converted to the... 

Despite the powerful potential of the Neber rearrangement, it has been scarcely utilized in the total synthesis of complex natural products. The earliest such application was in Woodward s total synthesis of lysergic acid. Although not utilized in the successful route to this alkaloid, an early approach to the a-aminoketone (24) exploited the Neber rearrangement on compound 22. Preparation of the oxime (23) followed by rearrangement provided the amine hydrochloride 24 in good yield however, this compound was unstable as a free base and could not be processed further en route to lysergic acid. 

The Mitsunobu reaction, discovered by Mitsunobu in the late 1960s, has become one of the most widely used reactions in organic chemistry. The reaction has become the standard method for the inversion of secondary alcohols, the conversion of alcohols into amines and sulfides, and many other applications. New uses for this versatile reaction continue to be developed. The Mitsunobu reaction, due to its mild reaction conditions, has found wide application in total synthesis, and heterocyclic and medicinal chemistry. Since the Mitsunobu reaction has been extensively reviewed during the last thirty years, this chapter will focus primarily on applications of the Mitsunobu reaction during the last fifteen years. This review will cover recent examples for the various uses of the Mitsunobu reaction and introduce several new applications of the reaction. Recently developed phosphine and azadicarboxylate reagents will be covered as well. 

Activated amines such as the ones listed above have been frequently employed in the context of alkaloid total synthesis. The figure below lists a number of key intermediates (133 to 135) prepared via Mitsunobu reaction in the preparation of various alkaloids.Many additional applications of the Mitsunobu reaction in alkaloid synthesis can be found in the slightly older review by Simon, Hosztafi, and Makleit. ... 

In this context, and more recently, an interesting application of this methodology has been described by Faure, Aitken, and coworkers. Thus, they applied PADAM methodology (three-component Passerini reaction-amine deprotection-0,N-acyl migration) as key synthetic step of the linear pentapeptide intermediate in the formal total synthesis of cyclotheonamide C 54, a potent inhibitor of serine protease such as thrombin belonging to a family of cyclic pentapeptides with potential biological activities (Scheme 8.19) [47]. 

The applications of primary and secondary amine-ureas and -thioureas in asymmetric organocatalysis have been reviewed (138 references), as has the use of oxazolidinones as chiral auxiliaries in asymmetric aldols employed in total synthesis (193 references). 

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