Intermolecular Michael Addition of Substituted Amines to a Sugar-Derived α,β-Unsaturated Ester:  Synthesis of 1-Deoxy-d-gluco- and -l-ido-homonojirimycin, 1-Deoxy-castanospermine and 1-Deoxy-8a-epi-castanospermine

Abstract

The synthesis of polyhydroxylated piperidine alkaloids, namely, 1-deoxy-D-gluco-homonojirimycin 3a, 1-deoxy-L-ido-homonojirimycin 3b, and indolizidine alkaloids 1-deoxy-castanospermine 5a and 1-deoxy-8a-epi-castanospermine 5b, has been achieved. The key step involved is the intermolecular Michael addition of benzylamine to alpha,beta-unsaturated ester 1, derived from D-glucose, which afforded diastereomeric mixture of beta-amino esters 6a and 6b with D-gluco- and L-ido- configuration at C5, respectively. Attempts were made to increase and/or alter the diastereoselectivity at the newly generated stereocenter. The high stereoselectivity, in favor of L-ido-isomer 6b, was achieved under kinetically controlled conditions by using lithium N-benzyl amide as a Michael donor. The beta-amino esters 6a and 6b represent common intermediates to target molecules. Thus, LAH reduction of 6a and 6b, individually, gave beta-amino alcohol 7a and 7b. Sequential hydrogenolysis, selective protection of the amino group, followed by hydrolysis of the 1,2-acetonide functionality, and hydrogenation gave 3a and 3b, respectively. On the other hand, the beta-amino ester 6a was converted to gamma-amino ester 13a by Arndt-Eistert synthesis, which on hydrogenolysis and treatment with sodium acetate gave gamma-lactam 14a. The LAH reduction afforded pyrrolidene. The N-protection-hydrolysis-hydrogenation cascade successfully executed, and 1-deoxy-castanospermine 5a was obtained in good yield. The same sequence of reactions was applied to beta-amino ester 6b, which afforded 1-deoxy-8a-epi-castanospermine 5b.

EMCA and DEEM as Michael Reagents Used in Organic Synthesis

“…Among lately described Michael acceptors [21][22][23] [24] and N-sulfonylimines [25] may be mentioned. As for novel Michael donors [26][27], ascorbic acid [28][29][30], alphasulfinyl vinyllithium [31], lithium N-benzylamide [6], thiocinnamates [32], alphasulfinyl vinylic carboanions [9], [eta] 2 coordinated anisoles [10], N-phenylmaleimide [33], pyridoacridin-4-ones [34] and methyl anthranilates [35] may be given as examples.…”

“…Among methods of heterocyclic compounds synthesis, reactions of 1,4-addition, including Michael reaction, have wide range of usage and large practical significance [1][2][3][4][5][6][7][8][9][10]. EMCA, ethyl ethoxymethylenecyanoacetate, (1), and DEEM, diethyl ethoxymethylenemalonate, (2) (Fig.…”

“…DEEM was used to obtain Rimazolium (3), which is a registered analgesic drug, as well as an analog (4) of Rimazolium, an antagonist of prostaglandines more potent than Phenylbutazone. DEEM was also applied to synthesize compounds with anti-inflammatory (5) or calming and *Address correspondence to this author at the Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Faculty of Pharmacy, Medical University of Lublin, 6 Staszica Str., PL-20081 Lublin, Poland; Tel: +48-81-5324083; Fax: +48-81-5322910: E-mail: agnieszka.kaczor@am.lublin.pl antidepressive (via GABA receptor) activity (6). EMCA was a reagent to produce imidazo[1,2-a]pyrimidines with potential affinity towards opioid and serotonin receptors (7a, 7b) (Fig.…”

Base-Catalyzed Hydroamination of Olefins: An Environmentally Friendly Route to Amines

“…[49] The conjugate addition of benzylamine to an a,bunsaturated ester derived from d-glucose (Scheme 18) affords b-aminoesters (90% yield) with d-gluco and lido configuration at C-5 in a ratio of 30 : 70. [50] A methanol solution of benzylamine was found to react with 1-tert-butyl 4-methyl (2R)-2-isobutyl-3-methylenebutanedioate forming the corresponding Michael adducts (2R,3R)-and (2R,3S)-1-tert-butyl 4-methyl 3-(benzylaminomethyl)-2-isobutylbutanedioate in 70% yield and in a ratio of 10 : 90, respectively (Scheme 18). [51] The conjugate addition of pyrrolidine and piperidine to a-methylene b-lactones forms the corresponding cisand trans-a-(aminomethyl)-b-lactones in good yield (up to 92%) (Scheme 19).…”

Conjugate Addition of Amines to Sugar Derived Olefinic Esters: Synthesis of Glycosylated Amino Esters as Dna Topoisomerase-Ii Inhibitors

“…During the course of this work, [3] a similar study of the conjugate addition of benzylamine to a 3-O-benzylated olefinic ester leading to formation of an azasugar was reported by Patil et al [7] The stereochemistry at C-5 in the major and minor isomers was established as 'S' and 'R', respectively.…”