Ugi reactions stereoselectivity

I.4.4.3.I. Stereoselective Ugi Reactions with Chiral Amines as Auxiliaries... 

Since 1963 stereoselective Ugi reactions have been under investigation. " It has been demonstrated that such asymmetrically induced 4CC proceed only with an appreciable degree of stereoselectivity if a chiral amine component is used whose amino group is directly attached to an asymmetric carbon atom. The chiral a-sulfoxido aldehydes would also be promising asymmetrically inducing chiral templates, but they are not available in enantiomerically pure form. ... 

Under suitable conditions the amine component (43 R = H) for peptide syntheses by a stereoselective Ugi reaction must be a good chiral template, i.e. it must have strong asymmetric inducing power, and it must be endowed with a group that is cleavable from the 4CC product (86) under mild conditions. The search for a suitable chiral amine component (43 R = H) has been the most challenging subproblem in the development of peptide syntheses by stereoselective Ugi reactions. P ... 

In the search for optimum amine components and reaction conditions for the synthesis of peptides by the stereoselective Ugi reaction, model 4CC reactions with TFA as the acid component are very convenient because the products (121) are easy to analyze by F NMR. - ... 

A decisive improvement in the stereoselective performance of the Ugi reaction was achieved by the use of 1-ferrocenylalkylamines, in particular, l-ferrocenyl-2-methylpropylamine. as the inducing chiral auxiliary 18, S7. The iminc formed from the (/ )-enantiomer and isobutyralde-hyde reacts at — 78 °C with tm-butyl isocyanidc and benzoic acid to give the (S )-valine derivative with a diastereoselectivity of about 100 1. 

The Ugi reaction has been successfully applied to the synthesis of oligopeptide derivatives, c.g.. in the construction of a pure tetra-L-valine derivative69. The 2-methylpropanaldimine 2 of (/7)-l-ferroccnyl-2-rnethylpropylarnine with /V-formyl-L-2-amino-3-methylbulanoic acid (3) as the carboxylic acid component and methyl A/-[(.S)-2-isocyano-3-mcthyl-l -nxo-buLyl -L-2-aiuino-3-inethylbutanoate (4) furnishes the diastereomeric valyl-valyl-valyl-valine derivatives in a ratio (S,S[R],S,S)i(S,R[R],S,S) of 91 9. The stereoselectivity of the process can be enhanced to 98.5 1.5 when two equivalents of tetraethylammonium A -formylvalinate are added. 

In conclusion, the use of glycosylamincs as chiral templates in the Ugi reaction provides an efficient and highly stereoselective access to both l- and D-amino acids. 

Of the four components reacting in the Ugi reaction, the isocyanide and the carboxylic acid have only limited influence on the overall stereoselection. For instance, in the synthesis of 13-demethyldysidenin (R)-l and 13-demethylisodysidenin (S)-l from a chiral aldehyde, chiral carboxylic acid, isonitrile and methylamine79. 

A low stereoselection is also reported for an Ugi reaction which is the central step in the total synthesis of the antibiotic ( + )-furanomycin80. The carbohydrate-derived intermediate, formed from the following acetal and (+ )-a-methyIbenzylamine, reacts with benzoic acid and tert-butyl isocyanide to deliver the precursor 2 of the antibiotic and its diastcreomer 3 in equal amounts80. 

Even in Ugi reactions of chiral 4,5-dihydro-3//-pyrrole derivatives with aryloxy substituents vicinal to the cWo-cyclic imino group, a low stereoselectivity was found with either chiral or achiral isocyanides and benzoic acid leading to substituted 2-aminoearbonyl-3-aryl-oxy-1 -benzoylpyrrolid ine derivatives82. 

In contrast to the low stereoselections realized in the above syntheses utilizing imines of various chiral aldehydes79-8 1, an almost complete stereoselectivity is reported for the Ugi reaction of 2,3 4,5-bis-O-isopropylidenearabinose with ammonia, acetic acid and cyclohexyl isocyanide giving the 2-acetamino-2-deoxyglueono amides as the exclusive products84. 

The latter work is a rare example in which a high stereoselectivity was reported for a substrate-controlled Ugi synthesis. In asymmetric Ugi reactions carried out with removable chiral auxiliaries, however, high diastei eoselections were achieved (see Section 1.4.4.3.1.). 

Alternatively, the acidity of the aldehyde-derived CH or CH2 group can be enhanced by converting the isocyanide derived amide into an ester. According to this principle, tandem Ugi-Dieckmann was exploited in the context of carbapenem synthesis, where the first 4-membered ring was built through an intramolecular Ugi reaction of p-amino acid 66. Then, after a three-step manipulation of the carboxylic appendages, a Dieckmann cyclization afforded, stereoselectively, the desired carbapenem skeleton 67 [79]. 

Scheme 16 Two different ways to stereoselectively create 2,5-DKP s via Ugi reaction with two representative 3D conformations of 97 (blue) and 100 (cyan). Yield shown represents yield over ail steps...

The intramolecular Ugi reaction of 6-oxo-4-thiacarboxylic acids 212, benzylamine, and cyclohexyl isonitrile gave hexahydro-l,4-thiazepin-5-ones 213, in some cases with high stereoselectivity (Equation 16) <2003JOC3315>. 

However, they have not yet found many applications in asymmetric Ugi reactions [41-43], and this is probably due to the fact that diastereomeric excesses are often only moderate and strongly influenced by the structure of the side chain of the a-amino acid. A thorough study was carried out by Yamada et al. [42], who observed that the configuration of the newly generated stereocenter of the major diastereoisomer is always opposite to that of the amino ester. Representative examples are shown in Scheme 1.15. Although Yamada often also used chiral protected aminoacids as the carboxylic component, they were proved to have a negligible influence on the stereoselectivity. 

The most selective example is represented by the synthesis of 1,4-benzodiazepin-2,5-diones 37 via Ugi reaction with different a-aminoesters. The use of aromatic aldehyde 35 leads in some cases to very high stereoselectivity in the preparation of intermediate 36, and a single diastereoisomer is isolated after crystallization (Scheme 1.15) [43]. 

To the best of our knowledge only one example of diastereoselective intramolecular Ugi reaction employing a ketoacid is known [80]. The condensation of acid 89 with (S)-l-phenylethylamine proved to be stereoselective, giving a mixture of the four possible diastereoisomers 90 in a 42 42 8 8 ratio, with the trans stereoisomers pre-... 

The Ugi reaction produces a-amino acid amides from four components (isonitrile, carboxylic acid, aldehyde, and amine) in a one-pot reaction. With glycosylamines and ZnCl2 as promoting Lewis acid, a-amino acid amides are obtained [13,45] with excellent stereoselectivity in these reactions. For example, the galactosylamine 2 gave Ugi product 30 with formic acid as carboxylic component and various aldehydes and isonitriles in high yields and a diastereoselectivity of 19 1 in favor of the D-amino acid amides 30 (Scheme 20). 

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]). 

The stereoselectivity of these four-component coupling reactions were remarkable in most cases. Similar Ugi reactions were studied using per-O-pivaloylated L-fucopyranosylamine as... 

The potential advantage of amino acid and peptide syntheses by stereoselective 4CC vs. the traditional methods is not only the smaller number of steps needed, but also the fact that almost any chiral amino acid can be synthesized in both configurations from carbonyl compounds, also as a moiety of a peptide. -Substituted peptide segments with improved solubility are available using the Ugi reaction. These create new possibilities for the synthesis of large peptides. 

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