Synthesis of α,α-Disubstituted α-Amino Acid Derivatives in Enantiopure Form via Stereoselective Addition of Grignard Reagents to a Chiral Acyclic Nitrone Derived from l-Erythrulose

Abstract

The additions of various Grignard reagents to a chiral nitrone prepared from l-erythrulose take place with variable dia­stereoselectivity. The degree and strength of the facial selectivity can be modified if the reaction is performed in the presence of Lewis acidic additives: zinc bromide enhances attack to the si face whereas diethyl aluminum chloride promotes attack to the re side. The obtained adducts can be then efficiently transformed into protected N-hydroxy α,α-disubstituted α-amino acid derivatives as well as into the corresponding α,α-disubstituted α-amino acids.

Grignard reagents - chiral nitrone - erythrulose - α,α-di­substituted α-aminoacids - N-hydroxy aminoacids

References

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4f Another N-hydroxy compound which displays useful pharmacological properties is the 5-lipoxygenase inhibitor Zileuton: Brooks DW. Bell RL. Carter GW. Dube LM. Rubin PD. Drugs Future  1993,  18:  616 

5a Marco JA. Carda M. Murga J. Rodríguez S. Falomir E. Oliva M. Tetrahedron: Asymmetry  1998,  9:  1679 

5b Carda M. Murga J. Rodríguez S. González F. Castillo E. Marco JA. Tetrahedron: Asymmetry  1998,  9:  1703 

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8b 1,3-Dipolar cycloadditions of this nitrone have also been investigated: Carda M. Portolés R. Murga J. Uriel S. Marco JA. Domingo LR. Zaragozá RJ. Röper H. J. Org. Chem.  2000,  65:  7000 

9 The oximes 1 were obtained as E/Z mixtures, from which only the E isomers showed a good stereoselectivity. Moreover, nitrone 2 was obtained together with a structurally close dioxazine, which was, however, unreactive towards organometallics.

10

A distinct NOE was detected between the N-benzylic hydrogens and the methylene protons of the CH₂OTPS group.

11

We have studied the formation of the nitrone with the aid of quantum-mechanical ab initio methods. The non-isolated E nitrone was found to be more stable than the Z isomer by more than 3 kcal/mol. This indicates that the formation of the Z nitrone is subjected to kinetic control. Preliminary results of studies on possible transition states suggest that that leading to the isolated Z nitrone is lower in energy than the alternative transition state leading to the E isomer (unpublished results with S. Safont).

12

Preparation of Nitrone 3. 1-O-t-butyldiphenylsilyl-3,4-O-isopropylidene-l-erythrulose [6] (19.93 g, 50 mmol) and N-benzyl hydroxylamine (6.16 g, 50 mmol) were dissolved in CH₂Cl₂ (150 mL). Anhyd MgSO₄ (10 g) was added to the mixture and the suspension was stirred under Ar for 48 h at r.t. The reaction mixture was then filtered through Celite, and the Celite pad was subsequently washed twice with CH₂Cl₂ (2 × 30 mL). After complete solvent removal in vacuo, the oily residue was chromatographed on silica gel (hexanes-EtOAc, 7:3). This furnished nitrone 3 as a dense oil (19.65 g, 78%), which could not be induced to crystallize: [α]_D ²⁵ -20.6 (CHCl₃, c 3.7). IR ν_max(film): 3052, 2986, 2934, 2892, 2860, 1577, 1472, 1455, 1428, 1382, 1266, 1212, 1181, 1154, 1112, 1058, 738, 704 cm^-1. HRMS (EI): m/z (rel. int.) = 503.2504 (0.5) [M⁺], 488(10) [M⁺ - Me], 446(16) [M⁺ - t-Bu], 388(45), 341(88), 199(100), 101(96). Calcd for C₃₀H₃₇NO₄Si, M = 503.2492. ¹H NMR (CDCl₃, 500 MHz): δ = 7.80-7.20 (15 H, m), 5.27 (1 H, t, J = 7 Hz), 5.06 (2 H, AB system, J = 11 Hz), 4.53 (1 H, dd, J = 8.5 and 7 Hz), 4.46 (2 H, AB system, J = 12.5 Hz), 3.77 (1 H, dd, J = 8.5 and 7 Hz), 1.35 (3 H, s), 1.29 (3 H, s), 1.10 (9 H, s). ¹³C NMR (CDCl₃, 125 MHz): d = 148.1, 133.2, 132.3, 132.2, 109.7, 19.3 (C), 135.7, 135.6, 135.5, 130.0, 129.1, 128.8, 128.6, 128.5, 128.3, 128.2, 127.8, 127.7, 73.2 (CH), 68.3, 64.5, 56.3 (CH₂), 27.0, 26.0, 24.7 (CH₃).

13

General Reaction Conditions for Grignard Additions to Nitrone 3 with Aqueous Work-up. A solution of 3 (1 mmol) in THF (5 mL) was cooled under Ar to -78 °C and treated with the appropriate Grignard reagent (5 mmol of a commercial solution in THF). After stirring for 5 h at the same temperature, the reaction mixture was quenched with sat. aq NH₄Cl (2 mL); the reaction mixture was stirred for further 5 min, poured into brine and extracted with EtOAc. The organic layers were then dried on anhyd Na₂SO₄ and concentrated in vacuo. Column chromatography of the oily residue on silica gel (hexane-EtOAc mixtures) afforded the corresponding adducts (Table). Additions in the presence of Lewis acid additives were performed in the same way except that the Lewis acid (1 mmol) was added to an ice-cooled solution of 3; the solution was then stirred for 15 min and cooled to -78 °C, prior to addition of the Grignard reagent.
Grignard Additions to Nitrone 3 with acetylating Work-up. For the preparation of amino acid derivatives, the reaction was performed as above except that acetic anhydride (190 µL, 2 mmol) was added dropwise at -78 °C to the reaction mixture. The cooling bath was removed and the mixture was stirred for 30 min at r.t. After quenching with sat. aq NH₄Cl (2 mL), the reaction mixture was stirred for further 15 min, poured into brine and worked up as above.
The configuration of the newly formed stereogenic center was determined by straightforward conversion of adducts 4 into oxazolidinones i (Scheme [5] ) and observation of suitable NOE’s in the latter. Additional support was given by X-ray diffraction analyses of 4 (R = Et), 4 (R = allyl) and 6 (R = Ph). The crystallographic data of these three com-pounds have been deposited at the Cambridge Crystallo-graphic Data Centre (deposition numbers, CCDC-177985 to CCDC-177987).

Scheme 5

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17b

The strong chelating ability of Me₂AlCl is attributed to a bimolecular interchange where the anion (Me₂AlCl₂)^- is formed together with formal transfer of the chelating, highly Lewis acidic species Me₂Al⁺ to the substrate. Obviously, two equivalents of Me₂AlCl are required.