Double Addition of Grignard Reagents to N-Glycosyl Nitrones:  A New Tool for the Construction of Enantiopure Azaheterocycles

Abstract

[Reaction: see text] C-Phenyl-N-erythrosylnitrone 3 behaves as a C1,C1' bis-electrophile, undergoing a double addition of Grignard reagents in a domino fashion to afford acyclic hydroxylamines 4. The reaction proceeds at 0 degrees C with variable degrees of diastereoselectivity, from moderate to good, mainly depending on the organomagnesium reagent used. The usefulness of compounds 4 has been exemplified with the synthesis of pyrroloazepine 12 through a ring closing metathesis key step.

Formal Mixed Double Addition to N-Glycosylnitrones through Addition-Oxidation-Addition to N-Glycosylhydroxylamines

“…In Table 1, the results of nucleophilic additions to 1 (left) and oxidation of the resulting hydroxylamines (right) are reported. The additions were almost completely diastereoselective for formation of (S)-C1¢ diastereoisomers 6a-d, 1,5,6 with the only exception of ethylmagnesium chloride which gave the major hydroxylamine 6c in 60:40 diastereomeric ratio. Oxidation of hydroxylamines 6a-c with MnO 2 gave the desired aldonitrones 7a-c in practically quantitative yields (Table 1).…”

“…1 Their synthetic usefulness is further exemplified by elaboration of enyne 5d to a densely functionalized unsaturated piperidine derivative. Mixed bisadduct 5d was selectively acetylated, then treated with a catalytic amount of 2 nd generation Grubbs' Rucarbene in refluxing CH 2 Cl 2 to give ring-closing enyne metathesis to yield the piperidine diene 8 (Scheme 6).…”

Recent Developments in the Synthesis of Pyrrolidine‐Containing Iminosugars

“…A novel double addition of Grignard reagents to Nglycosyl nitrones has also been used by Goti and coworkers in the synthesis of a biologically active a pyr-roloazepine (Scheme 43). [119] Here, the addition of a threefold excess of allylmagnesium chloride to C-phenyl-Nerythrosylnitrone 236 lead to the formation of the bis-adduct 239, presumably via intermediates 237 and 238. Though four diastereomers were possible, only two were observed with a dr of 4:1 in favour of 239.…”

“…[122] In Hanessian's work, two unnatural polyhydroxylated indolizidines were synthesised via methodology that included the BF 3 ·OEt 2 mediated addition of 2-(trimethylsilyloxy)furan to iminium salts, [118] while Yoda and co-workers used a Grignard addition to a lactam en route to the first total syntheses of the pyrrolizidine tetrols hyacinthacine B 1 (245) and hyacinthacine B 2 (246) (Scheme 44). [119] Here lactam 242 [itself prepared form commercially available (S)-(-)-2-pyrrolidine-5-carboxylic acid] was treated with butenylmagnesium bromide to give a ketone that was diastereoselectively reduced using excess NaBH 4 in the presence of CeCl 3 in dilute EtOH solution (0.005 ) to yield alcohol 243. Mesylation, treatment with tBuOK and in situ cyclisation then gave a separable mixture of diastereoisomers, with the major product being the desired isomer 244.…”

Carbohydrate-auxiliary assisted preparation of enantiopure 1,2-oxazine derivatives and aminopolyols

“…Successful applications of these easily removable auxiliaries in the syntheses of biologically active agents were also reported [26–31]. Apart from the obvious reactivity of N -glycosyl nitrones of type 1 leading to five-membered heterocycles A or to N , N -disubstituted hydroxylamine derivatives B , a twofold nucleophilic addition of an excess of organometallic reagents furnishing compounds of type C (Nu 1 = Nu 2 ) was described and discussed by Goti et al (Scheme 1) [32]. In selected examples, the synthesis of differently substituted products (Nu 1 ≠ Nu 2 ) was possible by consecutive additions of the appropriate Grignard reagents [33].…”