Diastereoselective Ugi Reaction

The diastereoselective Ugi reaction has also been performed by using 2,3,4,6-tetra-O-pivalyl-p-D-galactopyranosyl amine anchored to a solid phase as chiral auxiliary and zinc chloride as Lewis acid affording, after cleavage from the 

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In a similar manner, diastereoselective Ugi reactions have been performed by utilizing immobilized amine 10-35 to give 10-36 (Scheme 10.9) [12]. 

Nenajdenko VG, Reznichenko AL, Balenkova ES (2007) Diastereoselective Ugi reaction without chiral amines the synthesis of chiral pyrroloketopiperazines. Tetrahedron 63 3031-3041... 

Modifications to the Ugi-3CR have been conducted in three main directions (i) changes to the methodology, such as the use of different catalysts, the in situ generation of imines, and the use of convertible isonitriles (ii) development of enantio- and diastereoselective Ugi reactions and (iii) applications of the methodology for the synthesis of new compounds with important biological activity. 

Kunz and co-workers have employed 2,3,4,6-tetra-Q-pivaloyl- 0-D-galactopyranosylamine (21) as a chiral auxiliary in a diastereoselective Ugi reaction for the synthesis of optically... 

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. 

Linderman RJ, Binet S, Petrich SR (1999) Enhanced diastereoselectivity in the asymmetric Ugi reaction using a new convertible isonitrile. J Org Chem 64 336-337... 

The synthesis of chiral pyrroloketopiperazines 174 was achieved via diastereo-selective Ugi reaction, with chiral 2-(2-formyl-l//-pyrrol-l-yl)acetic acids 175 conveniently derived from ot-amino acids [54]. The reaction proceeds with moderate diastereoselectivity trans. cis, up to 4 1) to give the target compounds 174 in good yields (Scheme 30). Noteworthy, the mixture of diastereomeres was separated by column chromatography and could be isolated as single diastereomeres. 

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). 

Linderman and his group applied so-called convertible isonitriles [47] for this type of glycosylamine-based Ugi reaction. The Osilylprotected isonitrile 32 was reacted with tri-O-pivaloylarabinosyl imines or tetra-O-pivaloylgalactosyl imines (Scheme 22). The diastereoselectivity ranked in the same range as that given in Table 4.3. 

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]). 

Aldehydes other than formaldehyde can also be used leading to macrocycles as a mixture of all four possible diastereomers (69b, 71b, Scheme 20). The intrinsic lack of diastereoselectivity of Ugi reaction provided nevertheless an opportunity for chemists to generate libraries of all diastereoisomers by one single operation, a factor that could be exploited in medicinal chemistry. 

The authors mentioned the poor diastereoselectivity observed in the Ugi reaction. Moreover, aHphatic aldehydes gave better results compared to aromatic aldehydes, which has been attributed to the higher reactivity of the corresponding imines. 

A further example for a metal-initiated reaction sequence providing an indole-inspired NP-based complex scaffold was reported by Van der Eycken and coworkers [7]. In this case, a Ugi reaction provided the desired substrate for the sequence of cyclization reactions initiated by the activation of the acetylene with a gold catalyst. The Ugi four-component reaction employed the indole-carboxaldehyde 12, the nitrile 13, amine 14, and carboxyhc acid 15 and led to the formation of the intermediate 16. In the presence of a gold(I) catalyst, instead of the expected indoloazepinone that could be formed via an endo-dig cyclization, a tetracyclic spiroindoline 17 was formed diastereoselectively (Scheme 13.3). 

A highly diastereoselective three-component Ugi reaction was reported, enabling the synthesis of optically pure aminoindoloazepinone derivatives... 

In 2011, Andreana and Santra described an Ugi/Michael/ aza-Michael cascade reaction in aqueous media as strategy for molecular diversity in natural products [71]. Fused aza-spiro tricycles and tetracycles were obtained by nsing microwave irradiation and water as solvent. In this remarkable work, up to four stereogenic centers and six contignons bonds were created with high diastereoselectivity. The reaction started from an Ugi-4CR, which gave the intermediate 85, which underwent a first Michael-type reaction that led intermediate 86. Finally, an additional aza-Michael reaction on 86 yielded the final tricyclic product 87 (Scheme 7.35). 

We found the galactosylamine 24 to be also a very effective template in the Ugi four-component condensation. In a one-pot procedure 24 reacts with an aldehyde, an isocyanide and a carboxylic acid in the presence of zinc chloride to give the corresponding a-amino acid amide derivatives 27 in almost quantitative yield. The diastereoselectivity of the process is even higher than that of the Strecker reaction. At 0 C the (R)-diastereomers 27 are formed preferably in a ratio of about 10-15 1. At -25 to -78 C the diastereoselectivity reaches up to more than 20 1 in favour of the (R)-diastereomer. Equation (12) shows such Ugi reactions of 24 with tert-butyl-isocyanide and formic acid as reactands. 

If one keeps in mind that the Ugi reaction using the carbohydrate templates proceed in a simple one-pot procedure, that a high diastereoselectivity is achieved and pure diastereomers are easily isolated in high yields, that this synthesis does not require the use of organometallic compounds or the exclusion of oxygen, then it is clear that carbohydrates can be very effective tools in challenging chemical stereoselections. 

The use of T1CI4 acting as Lewis acid catalyst in the Ugi reaction between (5)-a-amino acids 20, such as valine, serine, phenylalanine, tryptophan, and even pyroglutamic acid, aromatic aldehydes 9, and a isonitrile 17b (Scheme 11.8), provided mixtmes of products 21 with moderate to good diastereoselectivity [25]. 

The Ugi reactions were carried out using i-butanal as the aldehyde component and N-Boc-glycine and IV-propyl amine or (5)-serine in methanol. The reactions again proceeded with low diastereoselectivity and also a low yield. 

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