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Highly efficient and enantioselective syntheses of (2S,3R)-3-alkyl- and alkenylglutamates from Fmoc-protected Garner’s aldehyde

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Abstract

A 6-step enantioselective synthesis of (2S,3R)-3-alkyl/alkenylglutamates, including the biologically significant amino acid, (2S,3R)-3-methylglutamate, protected for Fmoc SPPS, is reported. Overall yields range from 52–65%. Key to the success of these syntheses was the development of a high-yielding 2-step synthesis of Fmoc Garner’s aldehyde followed by a Horner–Wadsworth–Emmons reaction to give the corresponding Fmoc Garner’s enoate in a 94% yield. The diastereoselective 1,4-addition of lithium dialkylcuprates to the Fmoc Garner’s enoate was explored. Significant decomposition occurred when using lithium diethylcuprate and conditions previously reported for the 1,4-addition of lithium dialkylcuprates to Boc or Cbz-protected Garner’s enoate. An optimization study of this reaction resulted in a robust set of conditions that addressed the shortcomings of previously reported conditions. Under these conditions, highly diastereoselective (> 20:1 in most cases) 1,4-addition reactions of lithium dialkyl/dialkenylcuprates to the Fmoc Garner’s enoate were achieved in 76–99% yield. The resulting 1,4-addition products were easily converted into the Fmoc-(2S,3R)-3-alkyl/alkenylglutamates in two steps.

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Fig. 1
Scheme 1.
Scheme 2.
Scheme 3.

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Availability of data and material

NMR spectra for 1, 5, 6, 9–21 and variable temperature 1H NMR experiments for 6, 12–16 are provided in the supplementary information file.

Notes

  1. Cubist Pharmaceuticals Inc. has described in a patent the synthesis of Fmoc-(2S,3R)-3MeGluOallyl in which the key step was the conjugate 1,4-addition of Me2CuLi to the t-butyl ester derivative of oxazolidine 2. Neither the dr of the conjugate addition reaction nor the enantiomeric purity of the Fmoc-3MeGluOallyl was reported.

  2. All the temperatures listed in this paper are internal temperatures that were measured throughout the reaction.

  3. The anti-isomer could not be detected at 60 °C in DMSO-d6.

  4. The reaction was almost quantitative on scales as high as 5 g. On a 10 g scale, the yield dropped to 79% due to the intermediate betaine oiling out which inhibited stirring. In all instances, the reaction proceeds with very high diastereoselectivity and any traces of cis-isomer were easily removed by chromatography.

  5. House and coworkers noted that vinyl cuprates begin to decompose at temperatures > -25 °C (House and Wilkins 1978).

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Funding

This work was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant to S.D.T. (04233–2017). R.M. is grateful to NSERC for a post-graduate scholarship.

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  1. Department of Chemistry, University of Waterloo, 200 University Ave. West, Waterloo, ON, N2L3G1, Canada

    Ryan Moreira & Scott D. Taylor

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  1. Ryan Moreira
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Correspondence to Scott D. Taylor.

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Moreira, R., Taylor, S.D. Highly efficient and enantioselective syntheses of (2S,3R)-3-alkyl- and alkenylglutamates from Fmoc-protected Garner’s aldehyde. Amino Acids 52, 987–998 (2020). https://doi.org/10.1007/s00726-020-02868-7

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