A Mild Multistep Conversion of N-Protected α-Amino Acids into N-Protected β3-Amino Acids Utilizing the Nef Reaction

Brad E. Sleebs; Nghi H. Nguyen; Andrew B. Hughes

doi:10.1055/s-0032-1318344

Synlett, Table of Contents

Synlett 2013; 24(6): 747-751
DOI: 10.1055/s-0032-1318344

letter

A Mild Multistep Conversion of N-Protected α-Amino Acids into N-Protected β³-Amino Acids Utilizing the Nef Reaction

Brad E. Sleebs

^aThe Walter and Eliza Hall Institute of Medical Research, Parkville 3010, Australia

^bDepartment of Medical Biology, The University of Melbourne, Parkville 3010, Australia

,

Nghi H. Nguyen

^cDepartment of Chemistry, La Trobe University, Victoria 3086, Australia Fax: +61(3)94791266 Email: tahughes@optusnet.com.au

,

Andrew B. Hughes*

^cDepartment of Chemistry, La Trobe University, Victoria 3086, Australia Fax: +61(3)94791266 Email: tahughes@optusnet.com.au

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Abstract

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Abstract

Current methods of homologation of α-amino acids to β-amino acids have limitations. To overcome these shortfalls the Nef reaction has been utilized in the multistep synthesis of β³-amino acids from α-amino acids. In this approach, N-protected amino aldehydes, easily accessed from α-amino acids, were transformed into the N-protected γ-amino nitroalkanes. The Nef reaction was then used to smoothly convert the nitroalkanes into the corresponding N-protected β³-amino acids without notable racemization.

Key words

amino acids - amino alcohols - amino aldehydes - nucleophilic addition - enantioselectivity

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References

References and Notes

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21 General Procedure B: Preparation of N-Protected β-Hydroxy Nitroalkanes 22–28 Oxalyl chloride (9.56 mmol) was dissolved in CH₂Cl₂ (20 mL), the mixture was cooled to –78 °C, and a solution of dry DMSO (19.1 mmol) in CH₂Cl₂ (5 mL) was added dropwise during 15 min. The N-protected amino alcohol 8–14 (4.78 mmol) in CH₂Cl₂ (15 mL) was added dropwise during 10 min, the resulting solution was stirred for 10 min at –78 °C, and a solution of Et₃N (28.7 mmol) in CH₂Cl₂ (20 mL) was added dropwise during 15 min. After 20 min, H₂O (5.0 mL) was added to the vigorously stirred solution at –78 °C. The resulting slurry was poured in Et₂O (50 mL) and washed with 20% aq KHSO₄ (2 × 30 mL), the layers were separated, and the aqueous layer was back-extracted with Et₂O (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL), dried (MgSO₄), and the solvent was removed under reduced pressure (at <20 °C) to afford the crude aldehyde 15–21, which was immediately used in the next reaction without any further purification. To a solution of crude aldehyde 15–21 and nitromethane (19.1 mmol, 4 equiv) in i-PrOH (30 mL), cooling to 0 °C, was added KF (4.78 mmol, 1 equiv). The reaction mixture was warmed to r.t. and stirred for 8 h, H₂O (50 mL) was added, and the aqueous layer was extracted with Et₂O (3 × 20 mL). The organic layers were washed with H₂O (50 mL), dried (MgSO₄), and concentrated in vacuo. The crude product was subjected to flash column chromatography, eluting with 10–35% EtOAc–hexane to give a diastereomeric mixture of nitro alcohols 22–28. The diastereomeric mixture of β-hydroxy nitroalkanes 22–28 were not characterized and were used directly in the next reaction.
22 General Procedure C: Preparation of N-Protected γ-Amino Nitroalkanes 29–35 To the β-hydroxy nitroalkane 22–28 (1.79 mmol) was added dry Et₂O (20 mL), followed by Ac₂O (3.58 mmol) and DMAP (0.18 mmol). The reaction mixture was stirred at 25 °C for 2 h, and the solvent was evaporated in vacuo. To the resulting crude residue was added 1 N ethanolic NaBH₄ (4 mL) at 0 °C with stirring for 2 h (monitored by TLC). The mixture was acidified with 0.5 N HCl and extracted with Et₂O (3 × 20 mL), and the organic layers were washed with H₂O (1 × 20 mL). The crude was subjected to flash column chromatography, eluting with 10–30% EtOAc–hexane to give the nitroalkanes 29–35. (3S)-N-Benzyloxycarbonyl-3-amino-1-nitrobutane (29) The β-hydroxy nitroalkane 22 (0.48 g, 1.79 mmol) was transformed according to the General Procedure C, which afforded the desired nitro alkane 29 as a clear oil (crystallized on standing; 0.31 g, 70%); mp 45–48 °C; [α]_D ²⁹ +9.2, (c 2.71, MeOH). HRMS (ESI⁺): m/z calcd for C₁₂H₁₆N₂O₄ [M + H]⁺: 253.1183; found: 253.1184. IR (NaCl): ν_max = 3392 (NH), 3349, 3336 (CH), 1680 (CO), 1550 (NO₂), 1242, 1064, 897 cm^–1. ¹H NMR (300 MHz, CDCl₃, 300 K): δ = 7.32 (5 H, s, ArH), 5.06 (2 H, s, ArCH₂O), 4.78 (1 H, d, J = 7.3 Hz, NH), 4.43–4.37 (2 H, m, CH₂NO₂), 3.82 (1 H, br s, NCH), 2.19–2.08 (2 H, m, CH ₂CH₂NO₂), 1.20 (3 H, d, J = 6.6 Hz, CHCH ₃). ¹³C NMR (75 MHz, CDCl₃, 300 K): δ = 155.9 (CO), 136.2, 136.2 (aryl C), 128.6, 128.2, 128.1 (aryl CH), 72.7 (CH₂NO₂) 66.9 (ArCH₂O), 45.1 (NCH), 34.4 (CH₂CH₂NO₂), 21.2 (CHCH₃).
23 General Procedure D – Preparation of the N-Protected β-Amino Acids 36–42 To a solution of nitroalkane 29–35 (0.79 mmol) in DMSO (2 mL) was added NaNO₂ (2.37 mmol) and AcOH (7.9 mmol), and the reaction was heated to 40 °C for 20 h. After cooling to r.t., 1 N HCl was added to the yellow solution, stirring for another 15 min, and the aqueous was extracted with Et₂O (3 × 15 mL). The organic layers were washed with H₂O (2 × 20 mL) and extracted with sat. NaHCO₃ solution (3 × 15 mL). The aqueous layers were acidified to pH 2 with 2 N HCl and then re-extracted with EtOAc (3 × 15 mL). The organic extracts were dried (MgSO₄) and evaporated in vacuo. The residue was subjected to flash column chromatography, gradient eluting with 10–40% EtOAc–hexane to afford the N-protected β-amino acids 36–42. (3S)-N-Benzyloxycarbonyl-3-aminobutanoic Acid 36 Nitroalkane 29 (199 mg, 0.79 mmol) was transformed according to the General Procedure D, and afforded the desired β-amino acid 36 as a white solid (140 mg, 75%); [α]_D ²⁴ –12.5 (c 1.0, CHCl₃); lit. [α]_D ²⁷ –15.7 (c 1.0, CHCl₃).^{17 1}H NMR (300 MHz, CDCl₃, 300 K): δ = 7.33–7.29 (5 H, m, ArH), 5.32 (1 H, NH), 5.08 (2 H, s, ArCH₂O), 4.10 (1 H, HNCH), 2.57 (2 H, s, CH₂), 1.26 (3 H, d, J = 6.7 Hz, CH₃).
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26 Patil BS, Vasanthakumar G.-R, Babu VV. S. Synth. Commun. 2003; 33: 3089

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