Chiral N-acyliminium Ions Research Articles

Asymmetric Synthesis of Substituted Piperidine Derivatives Based on the Indirect Cation Pool Method

N-Acyliminium ions having a piperidine skeleton were attractive because the functionalized piperidines frequently show interesting biologically properties. The “indirect cation pool method” 1) is useful to prepare a solution of synthetically valuable N-acyliminium ions having a protecting group that is labile under acidic conditions, because organic cations can be generated and accumulated under neutral conditions. In this presentation we demonstrated utilities of highly enantiomerically enriched chiral N-Acyliminium ions bearing a piperidine skeleton, which are generated by the indirect cation pool method. Almost enantiomerically pure chiral precursor 2 was prepared by using the enantioselective lithiation strategy using chiral diamine 1 (Scheme 1).2) N-Acyliminium ion pool 3 was then irreversibly generated from 2 by the treatment of ArS(ArSSAr)+, which was generated by low temperature electrolysis (Scheme 2). The reaction of 3 with allylstannane gave trans isomer in high diastereomer and enantiomer ratios. In contrast, the coupling between 3 and allylmagnesium bromide afforded cis isomer in high stereoselectivity. As a result, we could selectively synthesized two 1) Suga, S.; Matsumoto, K.; Ueoka, K.; Yoshida, J. J. Am. Chem. Soc. 2006, 128, 7710-7711. Matsumoto, K.; Suga, S.; Yoshida, J. Org. Biomol. Chem. 2011, 9, 2586-2596. 2) Coldham, I.; O’Brien, P.; Patel, J. J.; Raimbault, S.; Sanderson, A. J.; Stead, D.; Whittaker, D. T. E. Tetrahedron: Asymmetry 2007, 18, 2113–2119. Figure 1

Asymmetric Brønsted Acid Catalyzed Nucleophilic Addition to in situ Generated Chiral N-Acyliminium Ions

A new enantioselective Brønsted acid catalyzed nucleophilic substitution of γ-hydroxylactams with indole is presented. The reaction proceeds via an intermediary N-acyliminium ion and provides disubstituted γ-lactams in good yields and with high enantioselectivities.

Reactivity of chiral exocyclic N-acyliminium ions with aromatic derivatives

Chiral N-acyliminium ions obtained from optically active N-[1-(phenylsulfonyl)alkyl]oxazolidin-2-ones at low temperature in the presence of titanium tetrachloride react with electron-rich aromatic compounds to afford the corresponding adducts in good yields and variable diastereoselectivities. Chemoselective cleavage of the oxazolidin-2-one ring with lithium/ammonia affords the corresponding benzylamines in enantioenriched form. The utilization of 4-benzyloxazolidin-2-one as a chiral auxiliary leads to intramolecular cyclization with exclusive formation of one diastereomer. The obtained tricyclic derivatives possess the core structure of some aza analogs of the anticancer drug podophyllotoxin.

Asymmetric Synthesis of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines by Asymmetric Electrophilic α-Amidoalkylation Reactions

An efficient method for the asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines via chiral N-acyliminium ions is presented. The N-acyl-1,2-dihydroisoquinolines (8) and (9) underwent smooth oxidation reactions with Ph 3 C + BF 4 - to give the chiral N-acylisoquinolinium ions (10) and (13), respectively. Stereoselective addition of organomagnesium and organozinc compounds to intermediates (10) and (13) provided the corresponding 1-sub-stituted N-acyl-1,2-dihydroisoquinolines (11/12) and (14/15) in good yields. The diastereoselectivity of these reactions appeared to be dependent on the structure of the N-acyliminium ion intermediates (10) and (13) and on the nature of the trapping reagent with the zinc reagents in general leading to markedly improved stereoselectivities. Pure diastereomers were obtained by preparative HPLC and readily transformed into enantiopure 1-substituted 1,2,3,4-tetrahydroisoquinolines by catalytic hydrogenation and reductive removal of the chiral auxiliary.

Synthesis of Sterically Demanding 3-Silylpyridines and Their Use in Asymmetric Synthesis with Chiral N-Acyliminium Ions

A convenient one-pot procedure for the synthesis of sterically hindered 3-silylpyridines is reported. It is based on 3-lithiopyridine that is generated from commercially available 3-bromopyridine and subsequently trapped with silyl chlorides. 3-Triisopropylsilylpyridine was employed in an asymmetric electrophilic α-amidoalkylation reaction providing a chiral N-acyl-1,2-dihydropyridine in very high regio- and diastereoselectivity. Conjugate reduction of the diene moiety and removal of the chiral auxiliary led to the corresponding 1,2,3,6-tetrahydropyridine in enantiomerically pure form.

Enhanced trans diastereoselection in the allylation of cyclic chiral N-acyliminium ions. Synthesis of hydroxylated indolizidines

A short synthesis of hydroxylated indolizidines is reported. The key steps were the allylation of chiral cyclic N-acyliminium ions derived from malic and tartaric acids, followed by ring-closing metathesis.

Electrogenerated Chiral 4-Methoxy-2-oxazolidinones as Diastereoselective Amidoalkylation Reagents for the Synthesis of β-Amino Alcohol Precursors

A flexible and efficient synthesis of enantiomerically pure 4,5-substituted 2-oxazolidinones − important target molecules as precursors of pharmacologically active 2-oxazolidinones, β-amino alcohols, β-blockers and azasugar derivatives − is described. As starting materials, the enantiopure storage forms of chiral N-acyliminium ions (4RS,5S)-5-chloromethyl-4-methoxy-1,3-oxazolidin-2-one (2) and (4RS,5R)-4-methoxy-5-methyl-1,3-oxazolidin-2-one (3) were used; these are readily available from the chiral pool with the aid of electrochemical transformations. Substitution of the 4-methoxy group in building blocks 2 and 3 with a large variety of organometallic nucleophiles resulted in the trans-diastereoselective formation of enantiopure 4,5-disubstituted 2-oxazolidinones, with a high degree of flexibility in the substituent at the 4-position.

Chiral N-acyliminium ions as new tools in the asymmetric synthesis of CNS-active compounds

Chiral N-acyliminium ions as new tools in the asymmetric synthesis of CNS-active compounds