Direct Synthesis of N-Protected Serine- and Threonine-Derived Weinreb Amides via Diboronic Acid Anhydride-Catalyzed Dehydrative Amidation: Application to the Concise Synthesis of ­Garner’s Aldehyde

Abstract

An efficient method for the direct synthesis of Weinreb amides derived from serine and threonine derivatives via diboronic acid anhydride-catalyzed hydroxy-directed amidation is described. This is the first successful example of the synthesis of serine- or threonine-derived Weinreb amides using catalytic dehydrative amidations. The methodology could be applied to the concise synthesis of Garner’s aldehyde.

Key words

dehydrative amidation - Weinreb amide - Garner’s aldehyde - organoboron catalysis - diboronic acid anhydride - hydroxy-directed reaction

Publication History

Received: 22 March 2021

Accepted after revision: 10 April 2021

Article published online:
04 May 2021

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• 25 Procedure for the Catalytic Synthesis of Weinreb Amide 4a (Table 1, Entry 8, 1 g Scale) N,O-Dimethylhydroxylamine (3, 25.0 mL, 0.60 M in DCE, 15.0 mmol, 3.0 equiv) was added dropwise over 1 h to a suspension of diboronic acid anhydride 1 (54.0 mg, 0.100 mmol, 2.0 mol%) and Boc-Ser-OH (2a, 1.03 g, 5.00 mmol, 1.0 equiv) in DCE (8.3 mL, total 0.15 M) under reflux (bath temp, 90 °C). After stirring for 24 h under reflux, the reaction mixture was cooled to room temperature. Concentration under reduced pressure furnished the crude product, which was purified by silica gel column chromatography (5% MeOH in CHCl₃) to give tert-butyl (S)-(3-hydroxy-1-[methoxy(methyl)amino]-1-oxopropan-2-yl)carbamate (4a, 1.02 g, 4.08 mmol, 82%). The optical purity of 4a was determined to be >99% ee by chiral HPLC analysis. Analytical Data for Compound 4a R_f = 0.35 (CHCl₃/MeOH = 19:1); [α]_D ²⁵ 14.2 (c 1.0, MeOH); mp 116–117 °C. ¹H NMR (400 MHz, CDCl₃): δ = 5.58 (br s, 1 H), 4.80 (br s, 1 H), 3.83–3.81 (m, 2 H), 3.78 (s, 3 H), 3.23 (s, 3 H), 1.45 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.0, 155.7, 79.8, 63.2, 61.5, 52.4, 32.0, 28.2. IR (KBr): ν = 3473, 3357, 2978, 1060, 1704, 1537, 1363, 1297, 1181, 980, cm^–1. HRMS (ESI): m/z calcd for C₁₀H₂₀N₂NaO₅ [M + Na]⁺: 271.1270; found: 292.1266. HPLC (CHIRALPAK IC^Ⓡ, hexane/i-PrOH = 80:20, 230 nm, flow rate 1.0 mL/min): t _R = 14.4 min (minor), 26.4 min (major).
• 26 In order to compare the catalytic efficiency with 1, we examined the reaction using several organoboron and metal catalysts. As a result, it was shown that 1 exhibits higher catalytic activity compared to previous catalysts under the same conditions. See SI-Table 1 in the Supporting Information for details.
• 27 Procedure for the Synthesis of Garner’s Aldehyde (5, Scheme 4, 1 g Scale) N,O-Dimethylhydroxylamine (3, 25.0 mL, 0.60 M in DCE, 15.0 mmol, 3.0 equiv) was added dropwise over 1 h to a suspension of diboronic acid anhydride 1 (54.0 mg, 0.100 mmol, 2.0 mol%) and Boc-Ser-OH (2a, 1.03 g, 5.00 mmol, 1.0 equiv) in DCE (8.3 mL, total 0.15 M) under reflux (bath temp 90 °C). After stirring for 24 h under reflux (bath temp 90°C), the reaction mixture was cooled to room temperature. Concentration under reduced pressure furnished the crude product, which was subjected to the next step without further purification. BF₃·OEt₂ (125 μL, 1.00 mmol, 0.2 equiv) was added to a solution of the crude mixture and 2,2-dimethoxy propane (3.68 mL, 30.0 mmol 6.0 equiv) in acetone (16.6 mL, 0.3 M). After stirring for 24 h at room temperature, Et₃N (1.0 mL) was added, and the solvent was removed under reduced pressure to give a brown oil, which was dissolved in EtOAc (120 mL). The resulting organic layer was washed with saturated NaHCO₃ aq (30 mL), water (30 mL), and brine (30 mL) successively and dried over Na₂SO₄. Filtration and concentration under reduced pressure furnished the crude product, which was subjected to the next step without further purification. LiAlH₄ (2.50 mL, 1.0 M in THF, 2.50 mmol, 0.50 equiv) was added dropwise to a solution of the crude mixture in THF (50 mL, 0.1 M) at 0 °C. After stirring for 1 h at 0 °C under N₂ atmosphere, saturated KHSO₄ aq (5 mL) was added carefully. The mixture was diluted with Et₂O (120 mL) and washed by water (30 mL) and brine (30 mL) successively and dried over Na₂SO₄. Filtration and concentration under reduced pressure furnished the crude product, which was purified by silica gel column chromatography (20% EtOAc in n-hexane) to give ­Garner’s aldehyde (5, 860 mg, 3.74 mmol, 75% over 3 steps) as a pale yellow oil of rotamer mixture (major/minor = 59:41).²⁸ Analytical Data for Compound 5 Pale yellow oil; R_f = 0.33 (n-hexane/EtOAc = 1:1.5); [α]_D ²⁵ –93.1 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃, rotamer*): δ = 9.61* (br, 0.41 H), 9.55 (br, 0.59 H), 4.34* (br, 0.41 H), 4.20 (br, 0.59 H), 4.12–4.07 (m, 2 H), 1.66–1.44 (m, 15 H). ¹³C NMR (100 MHz, CDCl₃, rotamer*): δ = 199.3, 152.5*, 151.3, 95.0, 94.3*, 81.3*, 81.0, 64.6, 63.8, 63.4*, 28.2, 26.6*, 25.7, 24.6*, 23.7. IR (neat): ν = 2980, 1709, 1367, 1266, 1171, 1095, 1062, cm^–1. HRMS (ESI): m/z calcd for C₁₄H₂₀N₂NaO₅ [M + Na]⁺: 252.1212; found: 252.1210.
• 28 The optical purity of 5 was determined to be >99% ee by chiral HPLC analysis after conversion into the corresponding benzoate (for details see the Supporting Information).