(R = t-Boc) (3S,5S,6R)

[112741-51-2]  · C21H22BrNO4  · 3-Bromo-4-t-butoxycarbonyl-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazin-2-one  · (MW 432.31) (R = t-Boc) (3R,5R,6S)

[127420-01-3] (R = Cbz) (3S,5S,6R)

[111934-06-6]  · C24H20BrNO4  · 4-Benzyloxycarbonyl-3-bromo-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazin-2-one  · (MW 466.33) (R = Cbz) (3R,5R,6S)


(electrophilic glycine equivalent useful for the preparation of a-substituted-a-amino acids in high enantiomeric excess2)

Alternate Name: 3-bromo-5,6-diphenylmorpholin-2-one.

Physical Data: white solid, decomposes upon heating.

Solubility: sol THF, CH2Cl2.

Preparative Methods: N-t-Boc- and N-Cbz-3-bromo-5,6-diphenyl-2,3,5,6-tetrahydrooxazin-2-ones are not commercially available. They are prepared by addition of 1 equiv of N-Bromosuccinimide to a solution of the parent oxazinone (commercially available3 as the individual enantiomers or as racemates) in CCl4 at reflux. Upon cooling of the reaction mixture to 0 °C and filtering off the succinimide, the CCl4 is removed under reduced pressure and the bromooxazinone is obtained in essentially quantitative yield as a white solid and is used without further purification.2

Handling, Storage, and Precautions: generally prepared immediately prior to use. Chromatography on silica gel results in decomposition.

General Reactivity.

The N-protected 3-bromo-5,6-diphenyl-2,3,5,6-tetrahydrooxazin-2-ones serve as chiral electrophilic glycine equivalents. They are prepared as discussed above to yield the anti-diastereomer exclusively (eq 1).2 The bromide is subject to displacement by a variety of reagents under a range of conditions to afford the substituted oxazinone generally with the newly introduced substituent oriented anti to the C(5) and C(6) phenyl groups. Deprotection of the heterocyclic amino acid precursor is accomplished by scission of the benzylic carbon-heteroatom bonds via reductive or oxidative cleavage. The deprotection routes afford the amino acid zwitterion or N-t-Boc amino acid directly but also result in destruction of the chiral auxiliary. Hydrogenolysis of the bromooxazinone with deuterium4c or tritium4a,b using Palladium(II) Chloride as catalyst occurs with net retention of configuration to afford the chiral isotopically labeled glycine (eq 2). Ease of preparation and introduction of the isotope in the final step make this a valuable synthesis of chiral glycines.

Coupling with Allylsilanes.

Allyltrimethylsilanes react with the bromooxazinone in the presence of Zinc Chloride in THF to afford the allylated heterocycles with high selectivity (eq 3).2 The coupling is presumed to take place by an SN1 mechanism in which the Lewis acid promotes expulsion of bromide resulting in iminium ion formation. The heterocyclic iminium ion then undergoes attack by the nucleophile on the least hindered face, giving the anti diastereomer. Hydrogenolysis of the Cbz protected oxazinone (20-50 psi) affords the amino acid zwitterion in good yield and high chemical purity (eq 4).

The amino acids can also be liberated by dissolving metal reduction.2 Treatment of the oxazinone with Lithium or Sodium metal in liquid ammonia at -33 °C effects deprotection (eq 5). Ion exchange chromatography yields the zwitterionic amino acid free of inorganic salts. This procedure has the advantage of permitting the synthesis of amino acids possessing unsaturated side chains. When the dissolving metal reduction is carried out on the t-Boc protected oxazinone, the N-t-Boc amino acid is obtained directly (eq 6).

Coupling with Tin Acetylides.

Trialkyltin acetylides react with the bromooxazinone in the presence of ZnCl2 to furnish the alkyne-substituted heterocycle (eq 7).5 Hydrogenation of the Cbz-protected acetylide adducts yields the aliphatic amino acids in good yield and high enantiomeric excess (eq 8).5b Dissolving metal reduction affords the (E)-vinylglycines, though some racemization is observed. The use of sodium metal in the deprotection results in higher chemical yields (71-80%) and lower enantiomeric excess (56-68%) while the use of lithium metal gives better enantiomeric excess (65-98%) but much lower chemical yields (16-20%) (eq 9).5a

Coupling with Electron-Rich Arenes.

Electron-rich aromatics such as trimethoxybenzene, furan, and 2-methylfuran also couple the bromooxazinone in the presence of ZnCl2 to afford the 3-aryloxazinones stereoselectively (eq 10).2a,6 This process introduces a third benzylic carbon-heteroatom bond into the molecule and thereby precludes the reductive deprotections described. An alternative oxidative deprotection was developed.6 Removal of the t-Boc protecting group followed by acid catalyzed opening of the heterocycle and subsequent oxidative cleavage with Sodium Periodate affords the arylglycines in moderate yield (eq 11).

Coupling with Silyl Enol Ethers and Silyl Ketene Acetals.

Silyl enol ethers can couple to the bromooxazinone to give both the syn and anti diastereomers.2,7 The reaction can proceed via the SN1 mechanism discussed above or by a Lewis acid assisted SN2 displacement of the bromide. The reaction conditions can be manipulated to favor the SN1 (stronger Lewis acids, more polar solvents) or SN2 path (weaker Lewis acids, less polar solvents) (eqs 12 and 13).2a

Coupling with Organozincs and Organocuprates.

Alkylzinc chlorides and alkyl- and arylcuprates couple with the bromooxazinones with a high degree of diastereoselection but in lower yields.2,6 Reduction of the bromide to the parent oxazinone is a significant side reaction and is attributed to the reaction taking place via an electron-transfer, radical-radical coupling.2a Substituted phenyl and naphthyl glycines have been prepared by coupling of the bromide with the corresponding organocuprate and employing the oxidative deprotection described above (eqs 14 and 15).6

1-Aminocyclopropane-1-carboxylic Acids.

These amino acids are prepared by a multistep procedure involving treatment of the bromooxazinone with Trimethyl Phosphite to give the corresponding phosphonate at the 3-position. Ylide formation and condensation with an aldehyde produces the a,b-dehydrooxazinone adduct possessing the (E) configuration (eq 16). Cyclopropanation with either Diazomethane or Dimethylsulfoxonium Methylide occurs with little diastereoselectivity. In contrast, cyclopropanation with (diethylamino)phenylsulfoxonium methylide is highly selective (eq 17).8 Unexpectedly, delivery of the methylene occurs on the face of the heterocycle syn to the phenyl rings. The reason for this selectivity has not yet been determined. Deprotection with Li0/NH3 yields the N-t-Boc-1-aminocyclopropane-1-carboxylic acids (eq 18).

The a,b-dehydrooxazinone adducts can also undergo 1,3-dipolar cycloadditions as demonstrated in the synthesis of S-(-)-cucurbitine (eqs 19 and 20).9

For the complementary synthesis of a-substituted-a-amino acids via a chiral glycine enolate equivalent see 4-t-Butoxycarbonyl-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazin-2-one.

1. (a) Williams, R. M. Aldrichim. Acta 1992, 25, 11. (b) Williams, R. M. Synthesis of Optically Active a-Amino Acids; Pergamon: Oxford, 1989.
2. (a) Williams, R. M.; Sinclair, P. J.; Zhai, D.; Chen, D. JACS 1988, 110, 1547. (b) Sinclair, P. J.; Zhai, D.; Reibenspies, J.; Williams, R. M. JACS 1986, 108, 1103.
3. Listed in the Aldrich Catalog as t-butyl 6-oxo-2,3-diphenyl-4-morpholinecarboxylate and benzyl 6-oxo-2,3-diphenyl-4-morpholinecarboxylate.
4. (a) Ramer, S. E.; Cheng, H.; Vederas, J. C. PAC 1989, 61, 489. (b) Ramer, S. E.; Cheng, H.; Palcic, M. M.; Vederas, J. C. JACS 1988, 110, 8526. (c) Williams, R. M.; Zhai, D.; Sinclair, P. J. JOC 1986, 51, 5021.
5. (a) Williams, R. M.; Zhai, W. T 1988, 44, 5425. (b) Zhai, D.; Zhai, W.; Williams, R. M. JACS 1988, 110, 2501.
6. (a) Williams, R. M.; Hendrix, J. A. CRV 1992, 92, 889. (b) Williams, R. M.; Hendrix, J. A. JOC 1990, 55, 3723.
7. Williams, R. M.; Sinclair, P. J.; Zhai, W. JACS 1988, 110, 482.
8. Williams, R. M.; Fegley, G. J. JACS 1991, 113, 8796.
9. Williams, R. M.; Fegley, G. J. TL 1992, 33, 6755.

Peter J. Sinclair

Merck Research Laboratories, Rahway, NJ, USA

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