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Synlett 2009(19): 3159-3162  
DOI: 10.1055/s-0029-1218306
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Concise Asymmetric Route to Chiral α-Aminoxy Acids

Xiao-Wei Changa, Dan-Wei Zhang*a, Fei Chenb, Ze-Min Dongb, Dan Yang*a,b
a Department of Chemistry, Fudan University, Shanghai 200433, P. R. of China
b Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax: +86(21)65643575; e-Mail: yangdan@hku.hk;
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Publication History

Received 21 August 2009
Publication Date:
23 October 2009 (online)

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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).

Key words

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

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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.