Synthesis of novel chiral β -amino alcohols and diamino alcohols from products of Ugi 3-component reaction

Novel chiral β -amino alcohols and diamino alcohols, which are useful in catalytic asymmetric syntheses, were prepared from the products of Ugi 3-component reaction.


Introduction
Most catalytic asymmetric syntheses are catalyzed by transition metals in combination with chiral ligands. 1 Among the popular chiral ligands which have been used for this purpose are βamino alcohols. 2In addition, chiral diamino alcohols also have been used as ligands in some catalytic asymmetric syntheses. 3me of the chiral β-amino alcohols are natural products, such as cinchonine, cinchonidine, quinine, quinidine, ephedrine, and norephedrine. 4Most of the chiral β-amino alcohols were prepared from reduction of enantiopure amino acids, 5 Sharpless' aminohydroxylation of olefins, 6 Mannich-type reactions for the direct addition of α-hydroxy ketones to imines, 7 regioselective ring opening of chiral epoxides and aziridines, 8 and nucleophilic addition to α-amino carbonyl compounds and α-hydroxy imines. 9n our previous study, we found that bulky substituents of both aldehydes and α-amino acids make Ugi 3-component reaction (U-3CR) highly stereoselective, and several chiral α,α'iminodiacetic acid analogues were prepared by this method easily with high yield. 10(Scheme 1) By taking advantage of this, we report herein synthesis of novel chiral β-amino alcohols and diamino alcohols from these chiral α,α'-iminodiacetic acid analogues.

Results and Discussion
As shown in Scheme 2, reduction of 1a with LiAlH 4 in anhydrous ether at room temperature for 20 hours generated 2a with selective reduction of an ester group in a good yield.When the reduction ran at room temperature for 2 days, 1a produced 3a with reduction of both ester and amide groups in a good yield.Under this condition, no racemization products could be detected.
On the other hand, when LiAlH 4 reduced 1b at the same condition, only 2b could be generated in a moderate yield and no trace of 3b could be detected.During the reduction, the color changed from yellow to red in 5 minutes, and the reaction was quenched with water.The product 2b was degraded at a longer reaction time before formation of 3b, which has both ester and amide groups reduced.Therefore, a longer reaction time did not result in the production of 3b, but in the reduction of the yield of 2b.
Methylation of 1a and 1b with MeI in acetonitrile in the presence of Na 2 CO 3 generated 4a and 4b, respectively, in good yields.Bulkier alkylating reagents such as benzyl bromide did not react with 1a or 1b under the same condition.It is clear that bulky substituents on 1a and 1b make them less nucleophilic.
When 4a was reduced by LiAlH 4 in anhydrous ether at room temperature for 2 days, 5a and 6a were generated in 39% and 47% yields.In contrast, when LiAlH 4 reduced 4b under the same condition, only 5b could be produced in a moderate yield and no trace of 6b could be detected.During the reduction, the color changed from yellow to red in 5 minutes and then the reaction was quenched with water.The product 5b was degraded at a longer reaction time, and as a result, 6b with reduction of both ester and amide groups could not be obtained at all.