Additions of Carbohydrate-Derived Alkoxyallenes to Imines and Subsequent Reactions to Enantiopure 2,5-Dihydropyrrole Derivatives

Abstract

The additions of six alkoxyallenes bearing carbohydrate-derived chiral auxiliaries to imines were systematically studied. The reactions of three lithiated 1-alkoxypropa-1,2-dienes with an N-tosyl imine revealed that the diacetone fructose-derived auxiliary provided the highest diastereoselectivity of 91:9. The preferred absolute configuration of the newly formed stereogenic center was determined by subsequent ozonolysis of the allene moiety, transesterification and comparison with literature data. The analogous reactions of three axially chiral 3-nonyl-substituted 1-alkoxyallenes with these auxiliaries confirm these results and also prove that the configuration of the generated stereogenic center was only steered by the auxiliaries, whereas the chiral axis has essentially no influence. In general, four diastereomers were obtained in various portions, depending on the ratio of the two precursor allene diastereomers and on the auxiliary employed. The obtained dia­stereomeric allenyl amines were cyclized under different conditions. As expected, under basic conditions, a stereospecific cyclization occurred, whereas under silver nitrate catalysis partial isomerization at the allene stage was observed. Under both conditions the 2,5-cis-disubstituted dihydropyrroles were formed faster than the trans-isomers. Several of the 2-substituted or 2,5-disubstituted dihydropyrrole derivatives could be isolated in diastereomerically pure form and were subsequently converted into the expected pyrrolidin-3-ones by removal of the carbohydrate-derived auxiliary under acidic conditions. The desired products were obtained in good yield and with high enantiopurity. They are suitable starting materials for the synthesis of enantiopure pyrrolidine natural products.

Diastereoselective Synthesis of Axially Chiral Xylose-Derived 1,3-Disubstituted Alkoxyallenes: Scope, Structure, and Mechanism

“… a d.r. was determined by 1 H NMR in CDCl 3 from crude reaction mixtures. b We assumed that the stereochemistry preferentially formed for all the allenes 4b – f was (a S ), taking into account the previous result obtained with 4a and previous studies …”

“…Therefore, there is an increasing need for efficient synthetic methodologies to access axially chiral allenes in an enantio- or diastereoselective manner . Among the recently developed procedures, only very few studies were dedicated to the synthesis of diastereomerically enriched alkoxyallenes, a widely employed class of allenes. , The applied strategy used chiral auxiliaries, however, the scope remained restricted to 1,3-disubstituted allenes bearing alkyl substituents, hence limiting more molecular complexity. For instance, the groups of Tius and Reissig, , respectively, reported the highly diastereoselective synthesis of some 1,3-disubstituted alkoxyallenes using fructose- or camphor-derived chiral auxiliaries in the well-known metal-mediated isomerization , of propargyl ethers (Scheme ).…”

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

“…The last example shown in Scheme 5 demonstrates that allenes with chiral alkoxy substituents are also suitable starting materials in the three-component reaction. We did not study lithiated carbohydrate-derived alkoxyallenes that were good precursors for other applications [38–39], but prepared the allene derived from N-protected alaninol that was converted into β-ketoenamide KE43 in 26% yield [30].…”