Synthetic approaches to a chiral 4-amino-3-hydroxy piperidine with pharmaceutical relevance

Abstract

Four synthetic strategies were evaluated towards the preparation of (-)-(3R,4R)-1-benzyl-4-(benzylamino)piperidin-3-ol (1), which was constructed with control over the relative and absolute stereochemistry of the 4,3-amino alcohol moiety. The first strategy employed a novel Rh(I) catalyzed asymmetric hydrogenation, while two other strategies exploited the existing stereochemistry in 2-deoxy-D-ribose, and the fourth explored both biocatalytic and classical resolution techniques as a means to impart enantioenrichment to racemic intermediates en route to targeted structure (-)-1.

Regio - and stereoselective synthesis of the iminosugars – 4-substituted 1-benzylpiperidine-3,5-diols

“…There is a general consensus that this outcome of the nucleophilic ring opening is promoted by the bidentate coordination of epoxide 7a organized to produce only 4-substituted regioisomer. [19][20][21][22][23] Such coordination activates the epoxide ring for the nucleophilic attack and shifts the conformational equilibrium (originally in favor the anti-conformer A by ~1.6 kcal/mol 17 ) entirely towards the lithium complex of syn-conformer B, producing only 4-substituted regioisomer upon the epoxide cleavage.…”

Asymmetric Syntheses of (−)-ADMJ and (+)-ADANJ: 2-Deoxy-2-amino Analogues of (−)-1-Deoxymannojirimycin and (+)-1-Deoxyallonojirimycin

“…Thus, the relative configurations within diol 33 and the carbonate precursor 32 were established via chemical correlation. It was anticipated that tetrahydropyridine 34 would be the ideal common precursor for the syntheses of authentic samples of both cis -diol 33 and trans -diol 36 (and the corresponding carbonates cis - 32 and trans - 37 ). The preparation of 34 was achieved via the reduction of N -benzylpyridinium bromide following a literature procedure: treatment of pyridine with BnCl at 140 °C followed by reduction of N -benzylpyridinium bromide with NaBH 4 gave tetrahydropyridine 34 in 81% yield.…”

“…The residue was then partitioned between H 2 O (5 mL) and CHCl 3 / i PrOH (3:1, 5 mL), and the aqueous layer was extracted with CHCl 3 / i PrOH (3:1, 2 × 5 mL). The combined organic extracts were then dried and concentrated in vacuo to give 33 as a yellow oil (60 mg, quant, >99:1 dr); ν max (ATR) 3377 (O–H), 2812, 2926 (C–H); δ H (400 MHz, CD 2 Cl 2 ) 1.63–1.72 (1H, m, C(5) H A ), 1.73–1.78 (1H, m, C(5) H B ), 2.04–2.11 (1H, m, C(6) H A ), 2.26 (1H, app d, J 10.6, C(2) H A ), 2.65–2.72 (1H, m, C(6) H B ), 2.80 (1H, app br s, C(2) H B ), 3.50 (1H, d, J 13.2, NC H A H B Ph), 3.53 (2H, m, NCH A H B Ph, C(4) H ), 3.69–3.71 (1H, m, C(3) H ), 7.23–7.33 (5H, m, Ph ); δ C (100 MHz, CD 2 Cl 2 ) 30.5 ( C (5)), 50.9 ( C (6)), 57.5 ( C (2)), 62.6 (N C H 2 Ph), 69.3 ( C (3)), 69.8 ( C (4)), 127.7 ( p - Ph ), 128.8, 129.5 ( o , m - Ph ), 138.8 ( i - Ph ); m / z (ESI + ) 208 ([M + H] + , 100%); HRMS (ESI + ) C 12 H 18 NO 2 + ([M + H] + ) requires 208.1332; found 208.1331.…”

Asymmetric Hydrogenation of Nonaromatic Cyclic Substrates

“…Good to excellent trans selectivities and enantioselectivities have been obtained (Figure ). A related methodology was applied by Minnaard and Ortiz et al for the synthesis of several drug candidates. , …”