Utilization of Aminophosphonates in the Petasis Boronic Acid Mannich Reaction

Abstract

Aminophosphonates were used as amine components in the Petasis boronic acid Mannich reaction. With the use of α-aminophosphonates, several N-phosphonomethylglycine derivatives were prepared in modest to good yields and high diastereoselectivities. The method affords the possibility of variation for the substituents in the position α to the phosphorus and nitrogen atoms. By using the same methodology, highly functionalized amino acids were prepared starting from (R)-β-amino-α,α-difluoromethylphosphonate.

Key words

boronic acids - aminophosphonates - multicomponent reaction - amino acids - stereoselective synthesis

References and Notes

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• 2a Petasis NA. Akritopoulou I. Tetrahedron Lett.  1993,  34:  583 
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• 6 Petasis NA, and Zavialov IA. inventors; US  6,232,467. 
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10

To a stirred suspension of glyoxylic acid monohydrate (92 mg, 1.00 mmol) in EtOAc (5 mL) tetraethyl pyrrolidine-2,2-diyldiphosphonate (3, 343 mg, 1.00 mmol) was added dropwise, after 5 min 2-thiopheneboronic acid (128 mg, 1.00 mmol) was added in one portion, and the reaction mixture was refluxed over 4 h while monitored by TLC (5% MeOH in CHCl₃). After the completion of the reaction the solvent was evaporated yielding the crude product as yellow oil. Flash chromatography using 5% of MeOH in CH₂Cl₂ afforded 390 mg (80%) of compound 4d as colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 1.05 (t, 3 H, OCH₂CH ₃),1.15 (t, 3 H, OCH₂CH ₃), 1.30 (t, 3 H, OCH₂CH ₃), 1.31 (t, 3 H, OCH₂CH ₃), 1.77-1.84 (m, 2 H, CH₂), 2.19 (m, 2 H, CH₂), 3.01-3.07 (m, 1 H, CH₂), 3.17-3.23 (m, 1 H, CH₂), 3.78-3.88 (m, 1 H, OCH ₂CH₃), 3.90-4.10 (m, 3 H, OCH ₂CH₃), 4.14-4.26 (m, 4 H, OCH ₂CH₃), 5.83 (s, 1 H, CHCOOH), 6.87 (dd, J _HH = 3.7 Hz, J _HH = 5.1 Hz, 1 H, H_thiophene), 7.08 (dd, J _HH = 1.0 Hz, J _HH = 3.7 Hz, 1 H, H_thiophene), 7.20 (dd, J _HH = 1.0 Hz, J _HH = 5.1 Hz, 1 H, H_thiophene). ^¹³C NMR (100 MHz, CDCl₃): δ = 16.2 (d, J _CP = 6.0 Hz, OCH₂ CH₃), 16.5 (d, J _CP = 6.0 Hz, OCH₂ CH₃), 16.5 (d, J _CP = 6.0 Hz, OCH₂ CH₃), 16.6 (d, J _CP = 6.0 Hz, OCH₂ CH₃), 24.0 (t, J _CP = 3.0 Hz, CH₂), 32.3 (t, J _CP = 4.0 Hz, CH₂), 48.1 (d, J _CP = 4.0 Hz, CH₂), 59.8 (s, CHCOOH), 62.3 (d, J _CP = 7.0 Hz, OCH₂CH₃), 63.2 (d, J _CP = 7.0 Hz, OCH₂CH₃), 63.5 (d, J _CP = 7.0 Hz, OCH₂CH₃), 63.5 (dd, J _CP = 150.0 Hz, J _CP = 155.0 Hz, PCP), 64.6 (d, J _CP = 7.0 Hz, OCH₂CH₃), 125.9, 125.9, 128.7, 138.3, 172.5 (s, COOH). ^³¹P NMR (162 MHz, CDCl₃): δ = 20.8 (d, J _PP = 92.3 Hz, 1 P), 23.3 (d, J _PP = 92.3 Hz, 1 P). CI MS (CI, pos.): m/z (%) = 346 (100), 206 (15); MS (CI, neg.): m/z (%) = 482 (100) [M - H]^-, 438 (10), 328 (10), 233 (40), 138 (10), 103 (30), 85 (45). Anal. Calcd for C₁₈H₃₁NO₈P₂S: C, 44.72; H, 6.46, N, 2.90, S, 6.63. Found: C, 44.61; H, 6.41; N, 2.87; S, 6.68.

12

To a stirred solution of pyruvic acid (44 mg, 0.50 mmol) in CH₂Cl₂ (3 mL) aminophosphonate 6 (147 mg, 0.50 mmol) was added dropwise, after 5 min (E)-2-phenylethenyl boronic acid (74 mg, 0.50 mmol) was added in one portion, and the reaction mixture was stirred for 24 h while monitored by TLC (5% MeOH in CHCl₃). The solvent was evaporated, and the residual oil was chromatographed using a gradient of i-PrOH (7 → 13%) in CH₂Cl₂ to yield 75 mg (34%) as a mixture of diastereomers 7b, and 35 mg (15%) as pure major diastereomer. Summary yield 110 mg (49%).
Major diastereomer: ^¹H NMR (400 MHz, CDCl₃): δ = 1.26 (t, 3 H, OCH₂CH ₃),1.33 (t, 3 H, OCH₂CH ₃), 1.50 (s, 3 H, CH ₃), 4.09-4.33 (m, 4 H, OCH ₂CH₃), 4.38 (dd, J _HF = 23.0 Hz, J _HF = 8.0 Hz, 1 H, CF₂CH), 5.94 (d, J _HH = 16.0 Hz, 1 H, PhCH=CH), 6.48 (d, J _HH = 16.0 Hz, 1 H, PhCH=CH), 6.40 (br s, NH), 7.07 (d, J _HH = 7.0 Hz, 2 H, H _Ph), 7.18-7.39 (m, 8 H, H_Ph). ^¹³C NMR (100 MHz, CDCl₃): δ = 16.4 (m, OCH₂CH₃), 22.2 (s, CH₃), 63.5 (s, CHCOOH), 64.7 (d, J _CP = 7.0 Hz, OCH₂CH₃), 65.2 (d, J _CP = 7.0 Hz, OCH₂CH₃), 126.7, 128.07, 128.5, 128.6, 128.6, 129.1, 130.9, 131.5, 136.1. ^¹9F NMR (376 MHz, CDCl₃): δ = -121.6 (ddd, J _FF = 304.0 Hz, J _FP = 108.0 Hz, J _FH = 23.0 Hz, 1 F), -110.6 (ddd, J _FF = 304.0 Hz, J _FP = 104.0 Hz, J _FH = 8.0 Hz, 1 F). ^¹9P NMR (162 MHz, CDCl₃): δ = 6.7 (dd, J _PF = 108.0 Hz, J _PF = 104.0 Hz). Anal. Calcd for C₂₃H₂₈F₂NO₅P: C, 59.10; H, 6.04. Found: C, 59.06; H, 6.14.