Asymmetric Electrophilic a-Amidoalkylation 5: Improved Stereoselectivities through New Chiral Auxiliaries

Wanner, Klaus T.; K較tner, Annerose; Wadenstorfer, Elmar

doi:10.3987/com-88-4709

HETEROCYCLES

1988

DOI: 10.3987/com-88-4709

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Asymmetric Electrophilic a-Amidoalkylation 5: Improved Stereoselectivities through New Chiral Auxiliaries

Klaus T. Wanner¹,

Annerose K較tner²,

Elmar Wadenstorfer³

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Cited by 24 publications

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“…For the intramolecular cyclization of 5 to 19 , some acidic conditions were attempted, e.g., BF 3 ·OEt 2 , BF 3 ·2AcOH, and catalytic or stoichiometric amount of TiCl 4 , but these conditions afforded no pentacyclic ring system compounds. Conversely, on exposure to 1.2 equiv of TiCl 4 in the presence of AcOH in CH 2 Cl 2 at room temperature, the intramolecular cyclization of 5 proceeded smoothly through the formation of acyliminium ion 18 to give the pentacyclic system compound 19 as a diastereomer mixture of cis - and trans -fused 7/5 ring system in the ratio of 1:4.3 ( 19a - cis : 19b - trans ) in 18% and 79% isolated yield, respectively. The debenzylation of 19a (enolic form) and 19b (as a 2:1 mixture of two epimers at the 3-position) on 5% Pd−C followed by heating at 100 °C in toluene afforded the target compound 6 , respectively.…”

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A Formal Total Synthesis of (±)-Cephalotaxine Using Sequential N-Acyliminium Ion Reactions

et al. 2002

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[reaction: see text] Novel synthesis of cephalotaxine 1 based on tertiary N-acyliminium ion chemistry starting from alkynylamide 2 was achieved. The key steps include the preparation of pyrroloisoquinoline 4 from alkynylamide 2, the ring expansion of pyrroloisoquinoline 4 to pyrrolobenzazepine 12, and the construction of cyclopentapyrrolobenzazepine ring system 6, all of which are derived from N-acyliminium ion intermediates.

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A Formal Total Synthesis of (±)-Cephalotaxine Using Sequential N-Acyliminium Ion Reactions

et al. 2002

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“…Although trans (12a) and cis (12b) benzoate produced from 6a,b were separated by column chromatography, the existence of rotomers 9) in the 1 H-NMR spectrum made the structural analysis of 12a,b difficult. Hydrogenolysis of 12a,b produced trans (13a) or cis (13b) 4-propyl-3-piperidinyl benzoate, respectively.…”

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Synthesis and Antimalarial Activity of Febrifugine Derivatives.

Takeuchi

Koike

Azuma

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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Febrifugine (1a) is an antimalarial agent which was isolated from Dichroa febrifuga or Hydrangea umbellata with isofebrifugine (1b). 1) Recently Kobayashi et al. corrected the error in the absolute structures of 1a,b, as shown in Fig. 1, by achieving the asymmetric syntheses of all the stereoisomers. 2) We have developed a new synthetic method for 1a,b, 3) and our interest next focused on the structure-activity relationship (SAR) of 1a,b. The difficulty in the purification or antimalarial screening of 1a,b is isomerization 4) between 1a and 1b, which occurs via a reversible Michael reaction. We thought that a derivative in which isomerization did not occur might be a more potent compound. Although much is reported on the SAR of substituents 5) on the 4(3H)-quinazolinone ring, the only known modification of the piperidine ring involves regioisomers of the hydroxy group. 6) In this report, we describe the synthesis and antimalarial activity of derivatives (2a,b) that are regioisomers of the nitrogen atom on the piperidine ring of 1a,b.We prepared 2a,b from 1-benzyl-3-hydroxypyridinium chloride (3) in seven isolated steps by modifying our method for synthesizing 1a,b (Chart 1). The successive O-allylation, reduction, 7) and replacement 8) of the benzyloxycarbonyl (Cbz) group from 3 afforded benzyl 1-(3-allyloxy-1,2,5,6-tetrahydropyridine)carboxylate (4) in 47% yield. The Claisen rearrangement of 4 by heating at 140°C in xylene proceeded smoothly to give benzyl 4-allyl-3-oxo-1-piperidinecarboxylate (5) in 99% yield. Reduction of 5 with sodium borohydride (NaBH 4 ) afforded trans (6a) and cis (6b) benzyl 4-allyl-3-hydroxy-1-piperidinecarboxylate as an inseparable mixture.Purification and structural determination of the inseparable mixture of 6a and 6b were achieved as shown in Chart 2. Although trans (12a) and cis (12b) benzoate produced from 6a,b were separated by column chromatography, the existence of rotomers 9) in the 1 H-NMR spectrum made the structural analysis of 12a,b difficult. Hydrogenolysis of 12a,b produced trans (13a) or cis (13b) 4-propyl-3-piperidinyl benzoate, respectively. In the 1 H-NMR spectrum, the proton at the 3 position on the piperidine ring of 13a was observed at 4.73 ppm with a coupling constant of 4.0 and 9.5 Hz. The proton on 13b, on the other hand, was observed at 5.10 ppm as a single broad peak. Pure 6a and 6b were prepared by hydrolysis of 12a and 12b and led to 7a and 7b, respectively.We previously found that reduction of benzyl 2-allyl-3-oxo-1-piperidinecarboxylate (14) with NaBH 4 at room tem- The regioisomers (2a,b) of the piperidine ring of febrifugine (1a) and isofebrifugine (1b) were synthesized from 4-allyl-3-piperidone (5). Reduction of 5 afforded a mixture of the trans and cis alcohols (6a,b) without diastereoselectivity; this result differentiated it from the reduction of 2-allyl-3-piperidone (14). The antimalarial activity of 2a,b and related compounds was tested.

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Asymmetric Electrophilic α‐Amidoalkylation, VII¹⁾: Generation, Crystal Structure, and Trapping Reactions of a Chiral 6,7‐Dimethoxy‐1,2,3,4‐tetrahydroisoquinoline Derived N‐Acyliminium Ion

Wanner

Praschak

Nagel

1990

Archiv der Pharmazie

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The camphanic acid amide 4 has efficiently been oxidized with triphenylcarbenium tetratluoroborate (3) to yield the c h i d N-acyliminium ion 1. Trapping reactions of 1 with the silyl nucleophiles 7a-c and 1Oa-f proceeded with stereoselective bond formation, affording the diastereomers (R)-8/(S)-9a-c and (R)-ll/(S)-lta-f, respectively, with diastereoselectivities of up to 93.9/6.1.The amid0 ketones (R)-8/(S)-9a-c were employed in the synthesis of the secondary amines (R)-16a-c, (S)-16a and for the preparation of (-)-homolauda-By X-ray crystallography the conformation of 1 in the crystal lattice was established and the preferred conformation of 1 in solution was elucidated by NOE experiments. Finally, the addition reaction of 7a to the iminium ion 21 derived from menthy1 carbarnate 20 was investigated, which reaction, however, proceeded only with insignificant asymmetric induction. About 50 years ago some patents of the German Tropon-Werke*) directed to the preparation of certain I-arylalkyl substituted tetrahydroisoqui-CH3 nolines, such as, e.g. Ia and Ib, were published. This class of compounds attracted attention mainly since members thereof had been found to be analgetically active.Two decades later a research group at Hoffmann-La Roche, stimulated by that results, developed a series of most interesting synthetic isoquinoline analgetics3). A typical representative is methopholine (10. From animal experiments with methopholine and related compounds it could be concluded that only the respective R-enantiomer is analgetically active. Furthermore, the Swiss group synthesized several analgetics which were far more active than methopholine, for example the aminoalcohols 111 that turned out, however, to be very addictive. It was shown that the analgetic activity strongly depends on the relative configuration of the two chiral centers in I11 (by a factor of 10 or more), although their relative configuration was not determined. Studies concerning the optically active isomers of 111 were not included eithe?), the question as to the stereochemical requirements for the analgetic activity of compounds I11 so remaining unsettled.Therefore, we launched a project which we expected to provide a general access to enantiomerically pure tetrahydroisoquinolines with a chiral center in position 1. In addition to the analgetically active compounds mentioned above some structurally closely related, naturally occuring substances, the phenethylisoquinoline alkaloids4) caused our interest in this project. Recently isolated homola~danosine~)

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Asymmetric Electrophilic a-Amidoalkylation 5: Improved Stereoselectivities through New Chiral Auxiliaries

Cited by 24 publications

References 0 publications

A Formal Total Synthesis of (±)-Cephalotaxine Using Sequential N-Acyliminium Ion Reactions

A Formal Total Synthesis of (±)-Cephalotaxine Using Sequential N-Acyliminium Ion Reactions

Synthesis and Antimalarial Activity of Febrifugine Derivatives.

Asymmetric Electrophilic α‐Amidoalkylation, VII¹⁾: Generation, Crystal Structure, and Trapping Reactions of a Chiral 6,7‐Dimethoxy‐1,2,3,4‐tetrahydroisoquinoline Derived N‐Acyliminium Ion

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Asymmetric Electrophilic a-Amidoalkylation 5: Improved Stereoselectivities through New Chiral Auxiliaries

Cited by 24 publications

References 0 publications

A Formal Total Synthesis of (±)-Cephalotaxine Using Sequential N-Acyliminium Ion Reactions

A Formal Total Synthesis of (±)-Cephalotaxine Using Sequential N-Acyliminium Ion Reactions

Synthesis and Antimalarial Activity of Febrifugine Derivatives.

Asymmetric Electrophilic α‐Amidoalkylation, VII1): Generation, Crystal Structure, and Trapping Reactions of a Chiral 6,7‐Dimethoxy‐1,2,3,4‐tetrahydroisoquinoline Derived N‐Acyliminium Ion

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Asymmetric Electrophilic α‐Amidoalkylation, VII¹⁾: Generation, Crystal Structure, and Trapping Reactions of a Chiral 6,7‐Dimethoxy‐1,2,3,4‐tetrahydroisoquinoline Derived N‐Acyliminium Ion