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Synlett 2009(9): 1449-1452  
DOI: 10.1055/s-0029-1216743
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Practical Synthesis of Natural Amino Acid Derivatives: Hf(OTf)4-Catalyzed Mannich-Type Reaction of Ketene Silyl Acetals or Enol Silyl Ethers with N,O-Acetals as a Glycine Cation Equivalent

Norio Sakai*, Asuka Sato, Takeo Konakahara
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan
Fax: +81(4)71239890; e-Mail: sakachem@rs.noda.tus.ac.jp;
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Publication History

Received 9 February 2009
Publication Date:
04 May 2009 (online)

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Abstract

The authors demonstrated the Hf(OTf)4-catalyzed Mannich-type reaction of an enol silyl ether and a ketene silyl acetal with an N,O-acetal leading to the preparation of amino acid derivatives. In particular, use of the N,O-acetal having a bis(trimethylsilyl)amino group directly produced N-unprotected aspartic acid derivatives after a standard aqueous workup.

Key words

Mannich-type reaction - N,O-acetal - amino acid - hafnium triflate

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7

When the similar reaction was carried out with only TMSCl (1.2 equiv), the desired Mannich-type reaction did not proceed. In addition, when the reaction was carried out with less than 10 mol% of the hafnium catalyst, e.g., 5 mol%, the product yield of 7 decreased to 80%; TfOH and TMSOTf were ineffective for the present Mannich-type reaction.

8

General Procedure for the Synthesis of N,O -Acetals 2
To a freshly distilled THF solution (100 mL), the corresponding secondary amine (24 mmol), i-Pr2NEt (4.1 mL, 24 mmol), and methyl 2-bromo-2-methoxyacetate (11 mL, 20 mmol) were successively added, and the solution was stirred at r.t. After 2 h, the reaction was quenched by adding a sat. aq soln (2 mL) of NaHCO3. The aqueous layer was extracted with CHCl3, the organic phase was combined, dried over anhyd Na2CO3, filtered, and evaporated under reduced pressure. The crude product was distilled to give the corresponding N,O-acetals 2.
General Procedure for the Hf(OTf) 4 -Catalyzed Mannich-Type Reaction of a Silyl Ether with an N,O -Acetal
An N,O-acetal (0.50 mmol), a silyl ether (0.60 mmol), and Hf(OTf)4 (38.8 mg, 0.0500 mmol) were successively mixed together in CH2Cl2 (2 mL) at r.t. with stirring. The resulting solution was stirred until the reaction reached completion, as shown by TLC (SiO2, hexane-EtOAc = 4:1). The reaction was quenched with a sat. aq soln (2 mL) of NaHCO3. The combined organic layer was dried over Na2CO3 and evaporated under reduced pressure. The crude product was purified by SiO2 column chromatography (hexane and hexane-EtOAc) to afford amino acid derivatives.
Spectral Data for Selected Compounds
2-(1-Piperidinyl)butanedioic Acid 1-Methyl 4-Ethyl Ester (7)
Pale yellow oil. ¹H NMR (500 MHz, CDCl3): δ = 1.24 (t, 3 H, J = 7 Hz), 1.39-1.42 (m, 2 H), 1.52-1.55 (m, 4 H), 2.41 (m, 2 H), 2.58-2.63 (m, 3 H), 2.81-2.86 (m, 1 H), 3.69-3.72 (m, 4 H), 4.13 (q, 2 H, J = 7 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 14.0, 24.2, 26.3, 34.2, 50.8, 51.1, 60.3, 64.1, 171.2, 171.3. MS (EI): m/z (%) = 243 (100) [M+]. HRMS: m/z calcd for C12H21NO4: 243.1471; found: 243.1469. 2-Diallylamino-3,3-Dimethyl-butanedioic Acid 1-Ethyl 4-Methyl Ester (15) Pale yellow oil. ¹H NMR (500 MHz, CDCl3): δ = 1.21 (t, 3 H, J = 7.0 Hz), 1.23 (s, 3 H), 1.26 (s, 3 H), 3.00-3.10 (m, 2 H), 3.30-3.40 (m, 2 H), 3.70 (s, 3 H), 3.83 (s, 1 H), 4.00-4.20 (m, 2 H), 5.10-5.20 (m, 4 H), 5.70-5.80 (m, 2 H). ¹³C NMR (125 MHz, CDCl3): δ = 14.0, 19.9, 25.3, 45.9, 50.9, 56.4, 60.4, 66.8, 117.1, 136.4, 172.3, 177.2. MS-FAB: m/z (%) = 284 (100) [M+ + H]. HRMS-FAB: m/z calcd for C15H25NO4: 284.1857; found: 284.1862.

9

The E/Z ratio of amino acid derivatives 3-5 is nearly in agreement with that of the starting material, enol silyl ether 1.