Isocyanides dipeptide

Another kind of combinatorial synthesis can be applied to reactions that assemble the product from several components in a single step, a multicomponent reaction. A particularly interesting four-component reaction is the Ugi reaction, which generates dipeptides from an isocyanide, an aldehyde, an amine, and a carboxylic acid. 

For example, use of 10 different isocyanides and amines, along with 40 different aldehydes and carboxylic acids has the potential to generate 160,000 different dipeptide analogs.65 This system was explored by synthesizing arbitrarily chosen sets of 20 compounds that were synthesized in parallel. The biological assay data from these 20 combinations were then used to select the next 20 combinations for synthesis. The synthesis-assay-selection process was repeated 20 times. At the end of this process the average inhibitory concentration of the set of 20 products had been decreased from 1 mM to less than 11xM. 

Nolte and coworkers reported on the formation of micelles with a helical superstructure from AB amphiphilic diblock copolymers prepared from an amine-end-capped polystyrene that was used as the initiator for the polymerization of various dipeptide-derived isocyanides (Fig. 16). 

Cho et al. describes an alternative synthesis (Scheme 20) of the 2,5 DKP scaffold 92 = 123 via a bifunctional dipeptide 120, an aldehyde 121, and an isocyanide 122 [42]. These commercially available starting materials were added in equimolar amounts to trifluoroethanol at 40°C under nitrogen. The reaction was brought to room temperature and allowed to complete. The standard Ugi workup was used followed by column chromatography. Yields were shown in the range of 21-87%. When this reaction was done in a microwave, time taken for the reaction to complete was decreased significantly and yields increased by a factor of 4. The substitution pattern of this and the previously described (in Scheme 15) are identical however, the reactions use different types of starting materials, for example, dipeptide vs. N- and C-protected amino acids. Thus different stereochemical outcomes can be expected for the two syntheses. 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

A rapid synthesis of cyclodepsipeptides containing sugar moieties was reported by Zhu and coworkers (Scheme 20) [88]. A three-component reaction of a sugar amino acid derivative 20a, an aldehyde b, and a dipeptide isocyanide c, followed by saponification and trifluoroacetic acid-promoted macrocyclization was employed to afford the cyclic amino sugar cyclopeptides d. This approach allows to systematically modify the amino acids and the carbohydrate residue, as well as the size of the macrocycle. Again, the only reagents used to mediate the formation of the... 

More recently, Aitken and coworkers described a short and convergent formal total synthesis of cyclotheonamide C using a process that involves a Passerini reaction, amine deprotection, and an acyl migration (PADAM sequence. Scheme 22) [90]. The key linear pentapeptide 22e is obtained by a Passerini reaction of isocyanide a, Fmoc-amino aldehyde b, and Boc-dipeptide acid e followed by Fmoc removal and consequently 0,N-acyl migration [91]. The macrocyclization was achieved with TBTU and HOBt after Boc and fBu removal in good yield (52%) to furnish intermediate f. 

Chen and co-workers at Procter and Gamble developed a traceless synthesis of 2,5-diketopiperazines [18b] by employing the universal Rink-isocyanide resin. The Ugi-4CR between the resin, aldehydes, amines, and N-Fmoc-protected a-amino acids afforded the resin-bound dipeptide derivatives 131 which were N-deprotected on treatment with piperidine in DMF. Cyclization by heating with 10% AcOH in DCE smoothly provided the desired diketopiperazines 132 in good yields (Scheme 2.47). 

Zhu et al. [103] reported a fadle access to biologically relevant macrocycles bearing an endo diaryl ether bond by means of a tandem Ugi-4CR/SNAr. The reaction between 3-hydroxyphenylacetic [or 3-(3-hydroxyphenyl)propionic] acid, aldehydes, amines, and isocyanide 197 gave the expected dipeptide derivatives 198 as a 1 1 mixture of diastereoisomers. The reaction gave high yields when performed in tri-... 

The synthesis started with an Ugi four-component condensation involving protected glutamic acid 242, aldehyde 243, methylamine and cyclohexenyl isocyanide 244. The resulting dipeptide product 245 was first hydrolyzed to acid 246, which was then coupled with amine 247. Further derivatizations of the resulting tripeptide 248 afforded the desired natural product. 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

Indeed, this MCR worked extremely well by simply stirring the three components in trifluoroethanol (TFE) at room temperature. Interestingly, no high-dilution conditions were required for the above transformation. Authors prepared 12-, 15-and 18-membered macrocycles and even nine-membered medium-sized cycles in excellent yields with diastereoselectivities. Two examples were depicted in Scheme 11. Thus, stirring a TFE solution of aziridine aldehyde 29, dipeptide 30 and ferf-butyl isocyanide at room temperature for 4 h afforded a nine-membered cycle 31 in 83% yield. Similarly, a 18-membered cyclopeptide 33 was obtained in 77% yield by the reaction of 29, pentapeptide 32 and ferf-butyl isocyanide. In both examples, the cyclic compounds 31 and 33 were formed with high diastereoselectivities (dr > 20/1). This is intriguing, as Ugi reaction provided generally low to moderate stereoselection when chiral substrates was used as inputs ([66-72] for enantioselective isocyanide-based MCRs, see [73-80]). 

Peptides. In the presence of an aliphatic isocyanide, amino acids and amines condense to form amides. Yields are increased by addition of ZnCl, CH2CI2 is preferable to alcoholic solvents. Yields of dipeptides range from 25 to 90%. ... 

Isocyanide polymerization has also been used to polymerize peptide-based monomers. Cornelissen et al. [31,32] prepared oligopeptides based on alanine and functionalized the N-terminus with an isocyanide moiety. These monomers were subsequently polymerized using a Ni catalyst into /3-helical poly isocyanopeptides with the dipeptides in the side chain. It was found that these polymers formed rigid rods, which were revealed by AFM to have extremely long persistence lengths. This rigidity was caused by the formation of /5-sheets between the alanines in the side chain. The same group... 

Ecteinascidin 743 is a marine tetrahydroisoquinoUne alkaloid that was isolated from Ecteinascidia turbinata, a mangrove tunicate, and is now approved by the FDA as an orphan dmg under the trade name Yondelis against soft tissue sarcoma and ovarian cancer [27]. Amine 53, isocyanide 54, acetaldehyde 55, and carboxylic acid 56 were heated in MeOH at 70°C to build up the dipeptide 60 in 90% yield (Scheme 6.5). 

Acid-catalyzed iminium ion 57 fonnation is followed by isocyanide 54 addition and capture of the remaining nitrilium ion 58 by the carboxylate of 56 to generate compound 59. A rapid O N acyl transfer takes then place in order to obtain dipeptide 60 as a mixture of epimers at C4. Although the control of the stereochanistry of the newly formed stereocenter still remains a problan of the Ugi reaction, it nicely demonstrates the force of the Ugi MCR, as all of the carbon atoms needed are successively assanbled in a single step [22], Mannich-type 4CR are often used for the synthesis of natural products. One example is the synthesis of the alkaloid ( )-roelactamine 65 (Scheme 6.6). The reaction of piperonal 61 with methylamine, Grignard reagent 62, and acid chloride 63 results in the formation of amide 64, which... 

Type Ib reactions involve the coupling of isocyanides and thioacids under room temperature to generate dipeptide products. Thioacid 398 and isocyanide 399 were... 

SCHEME 7.124 Synthesis of dipeptide 401 using thioacid 398 and isocyanide 399 via a type Ib coupling. 

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