Totalsynthese von Nojirimycin

Abstract

Total Synthesis of Nojirimycin SummmyAddition of the nitrone 3 (from 8 and 9) to furane, followed by oxidation with OsO, and then isopropylidenation gave the fully functionalized glycoside 12 (40% from 8) via tile glycal 10 and the hemiacetal 11. Since the glycoside cleavage of 12. leading to 13 after benzyloxycarbonylation proceeded in a mediocre yield, and since the acetolysis of 12 giving 14 (69%) was not practical, compound 12 was transformed into the hydroxy ester 17 by sequential hydrogenolysis, hydrolysis and benzyloxycarbonylation (69% overall). The hydroxy ester 17 was lactonized to give 18 (87%). Reduction of 18 first with LiBH4 (97%) and then with H,/Pd gave the key compound 20 which was transformed into nojirimycin (1) and into I-deoxy-nojirimycin (2) using prior art. The overall yield of 1 was 19.5%. Einleitung undProblemstellung. -Nojirimycin (1) wurde zuerst als Antibioticum aus Streptomyces-Stammen beschrieben [ 1-31 und spater ebenfalls aus zahlreichen Stammen der Gattung Bacillus [4] sowie unter dem Namen Moranoline aus Blattern des Maulbeerbaumes isoliert [5]. Nojirimycin wurde durch katalytische Hydrierung oder durch Reduktion mit Natriumborhydrid in das I-Desoxynojirimycin (2) ubergefuhrt [ l ] [2], das spater ebenfalls aus Bacillus-und Streptomyces-Stammen isoliert wurde [4] [6]. Nojirimycin und 1 -Desoxy-nojirimycin sind die ersten in der Natur aufgefundenen ctHeterosenn [7] [8] und besonders durch ihre starke Hemmwirkung auf (1-und /i-Glucosidasen bekannt geworden (vgl. [9] und dort zit.Lit.). Nojirimycin und 1 -Desoxy-nojirimycin wurden partialsynthetisch aus Glucose [2] [ 101 und Glucuronolacton [ 1 I] hergestellt; 1-Desoxy-nojirimycin auch aus L-Sorbose [8] [ 121 und durch eine chemisch-mikrobiologische Synthese aus Glucose [ 131. Nachdem sich die Nitrone 3 und 4 bei der asynimetrischen Synthese von Aminosauren bewahrt hatten [14], stellte sich die Frage, wie gut Monosaccharide auf ahnliche Weise totalsynthetisch zuganglich sind, namlich durch Cycloaddition von Monosaccharid-Nitronen an geeignete Olefine. In diesem Zusammenhang hat I )Korrespondenzadresse.

Diastereoselectivity in the Reaction of N‐Glycosyl‐nitrones: 1,3‐Dipolar Cycloaddition and Addition of Phosphite Anion

“…The 'endo'-position of the CH3-C(2) group is expected to cause a large chemical-shift difference for the H2(C3) signals in the 'H-NMR spectrum (cf. [2]). Indeed, 9 b (Ad = 1.38 ppm) and llb (AS = 0.74 ppm) exhibit large differences and 15 (AS = 0.16 ppm), 9 a (Ad = 0.19 ppm), and lla (Ad = 0.29 ppm) small differences.…”

“…of 75% for the addition to a similarly substituted, but conformationally undefined nitrone, both in favour of a (S)-configuration [2]. The corresponding diastereoselectivity for the cycloaddition of methyl acrylate to 7 is 42% and must be compared with the value of 28% (both in favour of a (R)-configuration) for the addition to a conformationally undefined nitrone having a lower degree of substitution (a factor expected to lead to lower diastereoselectivities) [2]. The qualitative and quantitative agreement between the behaviour of 7 and its conformationally undefined analogs is therefore good.…”

“…The diastereoselectivity observed for the induction at C(2) (C(5) of an isoxazolidine) is 81 YO for the cycloaddition of methyl methacrylate to 7 as compared to a d.e. of 75% for the addition to a similarly substituted, but conformationally undefined nitrone, both in favour of a (S)-configuration [2]. The corresponding diastereoselectivity for the cycloaddition of methyl acrylate to 7 is 42% and must be compared with the value of 28% (both in favour of a (R)-configuration) for the addition to a conformationally undefined nitrone having a lower degree of substitution (a factor expected to lead to lower diastereoselectivities) [2].…”

“…The former mode of approach was given preference, since it leads to an antiperiplanar (us. coplanar) arrangement of the developing lone pair at the N-atom and the C(1)-0 bond, and also because the opposite sense of chirality is induced in the cycloaddi-tion to acrylate [l] [2]. It was anticipated that dipolarophiles and nucleophiles should approach such nitrones from the same side.…”

Asymmetric Dearomatization of the Furan Ring Promoted by Conjugate Organolithium Addition to (Menthyloxy)(3‐furyl)carbene Complexes of Chromium

“…[4] Furans have been widely used as dienes [5] and less frequently as dienophiles [6] in [4+2] cycloaddition reactions with alkenes, alkynes, or allenes [5] and with reactive dienes, [6] respectively. These aromatic heterocycles also behave as dienes in [4+3] cycloaddition reactions with in situ generated 2-oxyallyl cations [7] or vinylcarbenoids, [8] as dipolarophiles in [3+2] cycloadditions to nitrones [9] and nitrile oxides, [10] and as olefins in [2+2] photocycloadditions to carbonyl compounds [11] and in rhodium(ii)- [12a] or copper(i)-catalyzed [12b] [2+1] cycloadditions to metal-stabilized a-ketocarbenoids. All these cycloaddition processes lead to different bicyclic or tricyclic skeletons in which the conjugated p system of the furan ring is broken up.…”