Practical EPC synthesis of 1,2- and 1,3-amino alcohols

Gmeiner, Peter; Kärtner, Annerose; Junge, D.

doi:10.1016/s0040-4039(00)79340-3

Cited by 21 publications

(9 citation statements)

References 8 publications

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“…Related is the conversion of aspartic acid 1p into the N , N -dibenzylamino aldehydes 10r , s . , Compound 21 is also accessible from aspartic acid. , It is a synthetically useful building block because various nucleophiles react at the mesylate function to produce new precursors of hitherto unknown N , N -dibenzylamino aldehydes. For example, a variety of heterocycles such as pyrazole can be introduced (cf 10t ) . Chain extension by the reaction with cuprates or KCN is also possible …”

Section: Nn-dibenzylamino Aldehydesmentioning

confidence: 99%

“…For example, a variety of heterocycles such as pyrazole can be introduced (cf 10t ) . Chain extension by the reaction with cuprates or KCN is also possible …”

Section: Nn-dibenzylamino Aldehydesmentioning

confidence: 99%

“…Although the equilibrium lies completely on the side of the lactol 23 , the compound undergoes diastereoselective Grignard-type reactions . Of course, aldehyde 10u is related to the O-protected forms 10r , s , which were prepared from aspartic acid. −

…”

Section: Nn-dibenzylamino Aldehydesmentioning

confidence: 99%

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Synthesis and Diastereoselective Reactions of N,N-Dibenzylamino Aldehydes and Related Compounds

1999

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Section: Nn-dibenzylamino Aldehydesmentioning

confidence: 99%

“…For example, a variety of heterocycles such as pyrazole can be introduced (cf 10t ) . Chain extension by the reaction with cuprates or KCN is also possible …”

Section: Nn-dibenzylamino Aldehydesmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis and Diastereoselective Reactions of N,N-Dibenzylamino Aldehydes and Related Compounds

1999

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“…The starting dicarbamate ester 5 is prepared within three synthetic steps, starting from ( S )-aspartic acid (1) , by perbenzylation, 2, 8 LiAlH 4 reduction of 2 to form ( S )-2-(dibenzylamino)butane-1,4-diol (3) , 7,9 and bisacylation with 2,2,4,4-tetramethyloxazolidine-3-carbonyl chloride, Cby Cl, (4) 4b (Scheme 3).…”

Section: Results -Selective Substitution Of the 1-h Smentioning

confidence: 99%

Regio- and Stereoselective Lithiation and C-Substitution of (S)-2-(Dibenzylamino)butane-1,4-diol via Dicarbamates

Guarnieri¹,

Sendzik²,

Fröhlich³

et al. 1998

Synthesis

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The 1,4-O , O' -dicarbamate 5 , derived from ( S )-2-(dibenzylamino)butane-1,4-diol, is prepared from L -aspartic acid in three synthetic steps. Deprotonation with sec -butyllithium removes the 1-pro-S proton with essentially complete substratecontrolled diastereoselectivity. The resulting chiral lithium compound 7 is configurationally stable and reacts stereospecifically with retention of the configuration at C-1 with a large number of electrophiles. A good level of enantiofacial selectivity is observed in the addition reaction of 7 with achiral aldehydes. Medium kinetic resolution was observed with racemic 2-alkylcyclohexanones. Quite generally, the reagent 7 achieves the nucleophilic introduction of the (protected) stereohomogeneous 2-amino-1,4-dihydroxybutanide fragment. Decarbamoylation is best achieved by reduction with LiAlH 4 . Deuteration of the 1-pro-S position provides efficient protection against deprotonation in the 1-position owing to a large kinetic H/D-isotope effect. The (-)-sparteinemediated deprotonation therein removes the 4-pro-S -H, which also was achieved for the 1-methylthio-and the 1-phenylthio derivative. The combined strategy makes possible the stereocontrolled chain-elongation of the 2-amino-1,4-dihydroxybutane unit at both termini by C -electrophiles.

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“…Taking advantage of our recently described methodology we were able to functionalize regioselectively the dibenzyl protected aminobutanediol 2a. [17][18][19][20] Thus, activation of 2a by MesCl gave the bis-electrophile 2b which could be transformed into the azido nitrile 3a by subsequent substitution with LiCN and NaN 3 . Due to an activating anchimeric participation of the dibenzylamino group the leaving group in position 1 is exclusively displaced by the nucleophile which is added first.…”

mentioning

confidence: 99%

Homo-Freidinger Lactams: Stereoselective Synthesis of 4-Aminopiperidin-2-one Derivatives from Aspartic Acid

Weber¹,

Gmeiner²

1998

Synlett

Self Cite

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Starting from aspartic acid a stereoselective synthesis of enantiomerically pure 4-aminopiperidin-2-ones which can serve as conformationally restrained ß-amino acid equivalents in peptidomimetics is described. The synthesis is based on the regioselective functionalization of the 1,4-bis-electrophile 2b and a diastereoselective introduction of various side chain equivalents into the lactam α-position of 4b,c.Conformationally locked peptide surrogates have been utilized extensively in the design and development of enzyme inhibitors or neuroreceptor ligands. [1][2][3][4] This strategy afforded valuable information regarding the elucidation of the biologically active conformation of peptides and led to drug candidates with remarkable affinity, selectivity and metabolic stability. 5 Among the numerous developments in this field, incorporating the α-amino carboxamide moiety of a peptide backbone into a Freidinger lactam (I) has proven very successful. 6-10 On the other hand, ß-amino acid derived substructures and the investigation of ß-peptides led to interesting peptidomimetics. 11-13 As far as we know, a combination of these two strategies was not reported yet.As part of our efforts on the synthesis of enantiopure ß-amino acid derivatives, 14,15 here we report the first stereoselective synthesis of 4-aminopiperidin-2-ones as lactam-bridged analogs with a ß-amino carboxamide substructure (Homo-Freidinger lactams, II). Applying this approach, our initial results on lactam-constrained mimetics of the dopamine receptor modulating peptide Pro-Leu-Gly-NH 2 16 are presented.The synthesis of a N-protected 4-aminopiperidine in enantiomerically pure form was planned starting from natural aspartic acid (1). Taking advantage of our recently described methodology we were able to functionalize regioselectively the dibenzyl protected aminobutanediol 2a. [17][18][19][20] Thus, activation of 2a by MesCl gave the bis-electrophile 2b which could be transformed into the azido nitrile 3a by subsequent substitution with LiCN and NaN 3 . Due to an activating anchimeric participation of the dibenzylamino group the leaving group in position 1 is exclusively displaced by the nucleophile which is added first. The formation of regioisomers was not observed. Chemoselective reduction of the azide functionality in the presence of the nitrile group was accomplished under Staudinger conditions 21 giving the amino nitrile 3b in 81 % yield. Alternatively, a more direct preparation of 3b is possible when liquid NH 3 is used as the "second nucleophile" instead of NaN 3 . 22

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Practical EPC synthesis of 1,2- and 1,3-amino alcohols

Cited by 21 publications

References 8 publications

Synthesis and Diastereoselective Reactions of N,N-Dibenzylamino Aldehydes and Related Compounds

Synthesis and Diastereoselective Reactions of N,N-Dibenzylamino Aldehydes and Related Compounds

Regio- and Stereoselective Lithiation and C-Substitution of (S)-2-(Dibenzylamino)butane-1,4-diol via Dicarbamates

Homo-Freidinger Lactams: Stereoselective Synthesis of 4-Aminopiperidin-2-one Derivatives from Aspartic Acid

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