Ft

HOOC

HOOC

NH2 CHO 40

i-Bu-NC

NH2 CHO 40

NH-i-Bu

NH-i-Bu

Scheme 1.12 U-4CR products of multifunctional educts.

Scheme 1.13 U-4CR products from carbonyl groups containing carboxylic acids.
Scheme 1.14 Six- to eight-membered lactams formed via U-4CR.

Scheme 1.15 Solid-phase synthesis of a polycyclic ring system employing a U-4CR. 1.4 STEREOSELECTIVE U-4CR

After the U-4CR had been introduced, it was soon recognized that this reaction can form diastereomeric products from chiral amine components,61'62 for example, chiral a-ferrocenyl-alkylamines.

As the latter were not easily accessible by chemical synthesis at that time,44 new methods of preparing these ferrocene derivatives were developed and introduced in 1969.63 It was then proved that the U-4CRs of chiral a-ferrocenyl-alkylamines can form diastereomeric a-aminoacid derivatives stereo-selectively, and it was further shown that after the reaction the a-ferrocenyl groups of the products can be replaced by protons, thus resynthesizing the chiral a-ferrocenyl-alkylamines simultaneously.44 Later, the development of this ferrocene chemistry was given up since such syntheses cannot form the products in sufficient quantity and stereoselective purity.64

In 1988 Kunz and Pfrengle65 introduced the preparation of chiral amino acid derivatives by the U-4CR in the presence of 2,3,4,6-tetra-O-pivaloyl-b-d-galacto-pyranosylamine, 57, in the presence of ZnCl2-etherate as catalyst. They obtained excellent stereoselectivity and high yields of their products. One of the disadvantages of such U-4CRs is that only formic acid can be used as the acid component, and the auxiliary group of the products can only be removed by half-concentrated hot methanolic HCl.

A few years later Goebel and Ugi66 formed a-aminoacid derivatives by the U-4CR with tetra-O-alkyl-1-glucopyranosylamines, 58, where any carboxylic acid component can participate. Lehnhoff and Ugi67 used the U-4CR with 1-amino-2-deoxy-2-N-acetylamino-3,4,6-tri-O-acetyl-b-d-glucopyranose, 59, whose large variety of products could be formed stereoselectively in excellent yields. The desired selective cleavage of the auxiliary groups of these products was equally unefficient.

Zychlinski68 prepared 1-amino-5-deoxy-5-acetamido-2,3,4-tri-O-acetyl-b-d-glucopyranose 60 by a synthesis of 11 steps. This amine component undergoes the U-4CRs very well and the products are cleavable by water, but unfortunately they are not very stable.

Ross and Ugi43 prepared 1-amino-5-deoxy-5-thio-2,3,4-tri-O-isobutanoyl-b-d-xylopyranose 61a from xylose via the 5-desoxy-5-thio-d-xylopyranose. The U-4CRs of this amine form a-aminoacid derivatives stereoselectively and in excellent yields. These products have the advantage that their products are stable and their auxiliary group 5-desoxy-5-thio-d-xylopyranose can be cleaved off selectively by mercury(II) acetate and trifluoroacetic acid. The expected steric structure of the corresponding U-4CR product was confirmed by X-ray

measurement. 9

Since Ugi is now an emeritus and he and his co-workers cannot continue their experimental studies, we propose that the analog 1-amino-5-desoxy-5-thio-d-xylopyranose 61b should be prepared and be used as a reagent of U-4CRs. It has a good chance to form stereoselectively high yields of products whose auxiliary group can be selectively removed.

In 1985 Kochetkov et al.70 introduced the preparation of 1-amino-carbo-hydrates from xylose, glucose and 2-acetylamino-glucose just by adding ammonia, and later they improved the preparation of pyranosylamines by using additional ammonium carbonate.71

PivO-RvO\

OPiv

-nh2

OPiv

OR AcHN

Ac0NH2 60

Scheme 1.16 Chiral amino carbohydrates employed in the U-4CR.

Drabik et al.45 prepared these and additional 1-amino-carbohydrates, 62, which were used as the amine components of the U-4CRs. Thus, a-aminoacid derivatives could be prepared stereoselectively in good yields. The stereoselectivity and yields resulted especially well if 0.1 gram equivalent (eq.) ZnCl2-OEt2 or CeCl3-7H2O or ZrCl4 were used as catalysts. Among these, CeCl3-7H2O had a particularly good influence, so that 99% yields and stereoselectivities of 99% d.e. can result.

The auxiliary carbohydrate parts of the products could be removed only moderately. The most efficient cleavages were achieved when the U-4CR products of the amine component 62 were treated with 1 M HCl in methanol at 40°C for 19 h. In that case, yields up to 30% could be achieved; for Y = NH-CO-4-MeOPh in compound 62, the cleavage rate could be increased up to a yield of 46%.

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