(5R,6S)-(R = t-Boc)

[112741-50-1]  · C21H23NO4  · 4-t-Butoxycarbonyl-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazin-2-one  · (MW 353.45) (5S,6R)-(R = t-Boc)

[112741-49-8] (5R,6S)-(R = Cbz)

[105228-46-4]  · C24H21NO4  · 4-Benzyloxycarbonyl-5,6-diphenyl-2,3,5,6-tetrahydro-4H-oxazin-2-one  · (MW 387.46) (5S,6R)-(R = Cbz)


(chiral glycine enolate equivalent useful for the preparation of a-substituted a-amino acids and a,a-disubstituted a-amino acids in high enantiomeric excess2,3)

Alternate Name: t-butyl 6-oxo-2,3-diphenyl-4-morpholinecarboxylate.

Physical Data: R = t-Boc: mp 206 °C. R = Cbz: mp 205 °C.

Solubility: sol THF, CH2Cl2.

Form Supplied in: commercially available as the individual enantiomers or as racemates.

Preparative Method: via a three-step procedure from erythro-2-amino-1,2-diphenylethanol.4

Handling, Storage, and Precautions: no special handling required.

a-Substituted a-Amino Acids.

The N-protected 5,6-diphenyl-2,3,5,6-tetrahydrooxazin-2-ones serve as chiral nucleophilic glycine equivalents by deprotonation at C-3 to give the corresponding enolates.2,3 The enolates are formed using Lithium Hexamethyldisilazide or Sodium Hexamethyldisilazide in THF at low temperature.2 Alkylation is best achieved by addition of the base to a solution of the oxazinone and electrophile in THF-HMPA (10:1) at -78 °C (eq 1)2a or by formation of the sodium enolate in the presence of 15-Crown-5 at -78 °C and subsequent addition of the electrophile (eq 2).3 Alkylation takes place with very high stereoselectivity to afford the C-3 modified oxazinone with the new substituent oriented anti to the C-5 and C-6 phenyl groups.2

The amino acid is released by scission of the benzylic carbon-heteroatom bonds, generally via a reductive process.2-5 Hydrogenolysis and dissolving metal reduction of the Cbz-protected oxazinone gives the amino acid zwitterion directly (eq 3). The t-Boc protected oxazinone undergoes dissolving metal reduction to give the t-Boc amino acid (eq 4). Alternatively, the t-Boc group can be removed from the oxazinone by treatment with Iodotrimethylsilane or Trifluoroacetic Acid and the resulting compound can then be hydrogenated to afford the amino acid zwitterion. Amino acids possessing alkyl, allyl, (ethoxycarbonyl)methyl, hydroxyalkyl, o-aminoalkyl, and methyl-b-D-ribofuranose functionality have been prepared via this enolate chemistry.2,3,6,7

a,a-Disubstituted a-Amino Acids.

The 3-alkyloxazinones also undergo enolization and subsequent alkylation to afford, upon deprotection, a,a-dialkyl a-amino acids.2a,3,8,9a Again, the newly introduced alkyl group is oriented anti to the phenyl groups of the oxazinone. Alkylation by addition of the base to a solution of the oxazinone and electrophile works only with allylic and benzylic halides and can require as much as 2-5 equiv of Potassium Hexamethyldisilazide (eq 5).2a,8 Alternatively, formation of the sodium enolate in the presence of 15-crown-5 followed by addition of the electrophile permits coupling of the enolate even to simple alkyl halides (eq 6).3,9a The disubstituted amino acids are liberated as described above (eq 7).

Boron Enolates.

The oxazinones can be converted to their corresponding boron enolates by treatment with Di-n-butylboryl Trifluoromethanesulfonate and Triethylamine in CH2Cl2.9 The boron enolates react with aldehydes at -78 °C to give b-(hydroxy)alkyl-substituted oxazinones. Condensation of the boron enolate with acetaldehyde followed by recrystallization of the major product and then deprotection affords allothreonine (eqs 8 and 9).9c This approach has been used in the asymmetric synthesis of diaminopimelic acid and derivatives thereof.9a,b

[3 + 2] Dipolar Cycloadditions.

Highly substituted proline derivatives can be prepared by removal of the t-Boc protecting group from the oxazinone followed by condensation of the heterocycle with an aldehyde in the presence of p-Toluenesulfonic Acid in benzene. Under these conditions, Schiff base formation and ylide generation occur. Subsequent [3 + 2] cycloaddition with a dipolarophile affords the bicyclic heterocycle, which is then deprotected to yield the desired proline derivative (eqs 10 and 11).10

Related Reagent.

For the complementary synthesis of a-substituted a-amino acids via a chiral electrophilic glycine equivalent, see 3-Bromo-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.; Im, M.-N. JACS 1991, 113, 9276. (c) Williams, R. M.; Im, M.-N. TL 1988, 29, 6075.
3. Baldwin, J. E.; Lee, V.; Schofield, C. J. SL 1992, 249.
4. (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.
5. For an oxidative deprotection see: Williams, R. M.; Hendrix, J. A. JOC 1990, 55, 3723.
6. Dong, Z. TL 1992, 33, 7725.
7. Dudycz, L. W. Nucleosides Nucleotides 1991, 10, 329.
8. Baldwin, J. E.; Lee, V.; Schofield, C. J. H 1992, 34, 903.
9. (a) Williams, R. M.; Yuan, C. JOC 1992, 57, 6519. (b) Williams, R. M.; Im, M.-N.; Cao, J. JACS 1991, 113, 6976. (c) Reno, D. S.; Lotz, B. T.; Miller, M. J. TL 1990, 31, 827.
10. Williams, R. M.; Zhai, W.; Aldous, D. J.; Aldous, S. C. JOC 1992, 57, 6527.

Peter J. Sinclair

Merck Research Laboratories, Rahway, NJ, USA

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