A Concise Asymmetric Route to Chiral α-Aminoxy Acids

Abstract

An efficient three-step method has been developed for enantioselective synthesis of chiral α-aminoxy acids from aldehydes. In this method, chiral propargylic alcohols are obtained by asymmetric addition of terminal alkynes to aldehydes. The hydroxyl group then converted to aminoxy group via Mitsunobu reaction and oxidative cleavage of the internal carbon-carbon triple bond produce the carboxylic acid group. This represents a convenient approach to the general asymmetric synthesis of α-aminoxy acids with the advantages of substantial overall yields (37-73%) and high enantioselectivities (81-99% ee).

α-aminoxy acid - asymmetric synthesis - Mitsunobu ­reaction - aldehydes - alkynes

References and Notes

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10

Representative Procedure: Asymmetric Addition of Terminal Alkyne 6 to Aldehyde 1 A flask was charged with Zn(OTf)₂ (1.6 g, 4.4 mmol). Vacuum (<0.5 mbar) was applied, and the flask was heated to 125 ˚C overnight. The flask was cooled to r.t. The vacuum was released and (-)-N-methylephedrine (859 mg, 4.8 mmol) was added. Vacuum (<0.5 mbar) was applied for 0.5 h and then released. To the flask were added toluene (8.0 mL) and Et₃N (485 mg, 4.8 mmol). The resulting mixture was stirred for 2 h at r.t. before propargylic acetate 6 (470 mg, 4.8 mmol) was added in one portion. After stirring for 15 min at r.t., isobutanal (1, 288 mg, 4.0 mmol) was added in one portion. The reaction mixture was stirred at r.t. overnight. The reaction was quenched with sat. NH₄Cl aq solution, followed by extraction with Et₂O. The combined ether extracts were washed with sat. NH₄Cl aq solution and brine, dried over Na₂SO₄, and concentrated. The crude product was purified by flash chromatography to give (S)-4-hydroxy-5-methylhex-2-ynyl acetate [(S)-9]^8d as a colorless oil in 79% yield (539 mg); [α]_D ^²0 -1.1 (c 4.0, CHCl₃). ^¹H NMR (300 MHz, CDCl₃): δ = 4.72 (d, J = 1.7 Hz, 2 H), 4.21 (br s, 1 H), 2.43 (br s, 1 H), 2.10 (s, 3 H), 1.94-1.83 (m, 1 H), 1.01 (d, J = 6.7 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 170.3, 86.6, 79.1, 67.5, 52.3, 34.2, 20.6, 17.9, 17.3.
Mitsunobu Reaction of Propargylic Alcohol: Preparation of ( R )-4-Phthalimidooxy-5-methylhex-2-ynyl Acetate [( R )-16] A solution of compound (S)-9 (85 mg, 0.50 mmol) in THF (3 mL) was dropped to the mixture of N-hydroxyphthalimide (90 mg, 0.55 mmol) and Ph₃P (157 mg, 0.60 mmol) under nitrogen atmosphere. Then, diisopropyl-azodicarboxylate (0.116 mL, 0.55 mmol) was added at 0 ˚C. The mixture was stirred to r.t. over 3 h, at the end of which the solvent was removed. The resulting residue was purified by flash chromatography to afford 97% yield (154 mg) of (R)-16 and 88% ee as determined in HPLC analysis (Chiralcel OD, 6% i-PrOH in hexane, 0.8 mL/min, 254 nm), t _R = 17.0(minor), 20.2 (major). [α]_D ^²0 +76.8 (c 1.0, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.86-7.83 (m, 2 H), 7.78-7.74 (m, 2 H), 4.90 (dt, J = 5.8, 1.7 Hz, 1 H), 4.64 (ABd, J = 15.6, 2.0 Hz, 2 H), 2.30-2.22 (m, 1 H), 2.02 (s, 3 H), 1.17 (d, J = 6.8 Hz, 3 H), 1.13 (d, J = 6.8 Hz, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 169.5, 163.2, 134.2, 128.7, 123.2, 83.3, 82.2, 81.2, 51.6, 31.5, 20.2, 18.2, 17.3. IR (CH₂Cl₂): 2965, 2940, 2875, 1787, 1735 cm^-¹. MS (EI, 20 eV): m/z (%) = 316 (1) [M⁺ + H], 153 (100). HRMS (EI): m/z calcd for C₁₇H₁₈NO₅ [M⁺ + H]: 316.1185; found: 316.1185.
Oxidative Cleavage of Internal Triple Bond: Preparation of ( R )-3-Methyl-2-phthalimidooxy-butyric Acid [( R )-22] To a solution of (R)-16 (58 mg, 0.18 mmol) in MeCN-H₂O (1.25 mL, 3:2) was added NaIO₄ (315 mg, 1.47 mmol). After NaIO₄ was completely dissolved, RuO₂˙H₂O (1 mg) was added. The mixture was stirred vigorously at r.t. Upon confirmation by TLC that most of the starting material converted, Et₂O and H₂O were added to the flask. The aqueous layer was extracted with Et₂O, and the organic layer was washed with H₂O and concentrated. Then CH₂Cl₂ (100 mL) was added to the flask, and the organic layer was washed with H₂O, dried with anhyd Na₂SO₄, and concentrated to give the product (R)-22 as an oil in 93% yield (45 mg); [α]_D ^²7 +69.0 (c 1.0, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 7.88-7.86 (m, 2 H), 7.81-7.79 (m, 2 H), 4.59 (d, J = 5.0 Hz, 1 H), 2.47-2.42 (m, 1 H), 1.24 (d, J = 7.0 Hz, 3 H), 1.18 (d, J = 6.9 Hz, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 172.3, 163.6, 134.8, 128.5, 123.8, 90.4, 30.7, 18.2, 17.5. IR (CH₂Cl₂): 3088, 2966, 2927, 1791, 1735
cm^-¹. MS (EI, 20 eV): m/z (%) = 218 (1) [M⁺ - COOH], 160 (100). HRMS (EI): m/z calcd for C₁₂H₁₂NO₃ [M⁺ - COOH]: 218.0817; found: 218.083.