Elsevier

Tetrahedron: Asymmetry

Volume 28, Issue 12, 15 December 2017, Pages 1756-1764
Tetrahedron: Asymmetry

Asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680

https://doi.org/10.1016/j.tetasy.2017.09.022Get rights and content

Abstract

The asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 are reported. Conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to the requisite (E)-α,β-unsaturated ester followed by in situ enolate oxidation with (−)-(camphorsulfonyl)oxaziridne (CSO) gave the corresponding anti-α-hydroxy-β-amino esters. Sequential Swern oxidation followed by diastereoselective reduction gave the corresponding syn-α-hydroxy-β-amino esters. Subsequent N-debenzylation (i.e., hydrogenolysis for microginin 612, and NaBrO3-mediated oxidative N-debenzylation for microginins 646 and 680) followed by acid catalysed ester hydrolysis gave the corresponding syn-α-hydroxy-β-amino acids, the N-terminal components of microginins 612, 646 and 680, in good yield. An analogous strategy for elaboration of the enantiopure anti-α-hydroxy-β-amino esters facilitated the asymmetric synthesis of the corresponding C(2)-epimeric α-hydroxy-β-amino acids.

Graphical abstract

The asymmetric syntheses of the N-terminal syn-α-hydroxy-β-amino acid components of microginins 612, 646 and 680, and the corresponding C(2)-epimeric anti-α-hydroxy-β-amino acids, are reported using diastereoselective aminohydroxylation of the requisite (E)-α,β-unsaturated esters as the key step.

  1. Download : Download high-res image (87KB)
  2. Download : Download full-size image

Introduction

The microginins are a sub-class of linear peptides that have been isolated from a genus of cyanobacteria known as Microcystis.1 Microginins typically contain between four to six amino acids (e.g., microginin 478 12 and microginin 299-C 23) and are characterised by a functionalised β-amino acid at the N-terminus as well as the presence of tyrosine residues. Microginin FR1 3 (often simply called “microginin”) was the first in this class to be isolated from the blue-green alga Microcystis aeruginosa.4 In 2016, three new microginins, viz. microginin 612 4, microginin 646 5 and microginin 680 6, were isolated from Microcystis aeruginosa UTEX LB2386.5 Microginin 612 4 contains a rare amino acid residue, 3-amino-2-hydroxyoctanoic acid (ahoa)6 and microginin 646 5 and microginin 680 6 are the first chlorinated examples of the ahoa fragment in a natural product (Fig. 1).

We have previously synthesised both diastereoisomers of 3-amino-2-hydroxydecanoic acid (ahda), 13 and 15, as part of the structural elucidation of microginin FR1 3, and concluded the unknown N-terminal amino acid component of microginin FR1 3 was (2S,3R)-syn-ahda 15 by spectroscopic comparison.7 Diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide (R)-8 to α,β-unsaturated ester 7 followed by in situ enolate oxidation with (+)-CSO 9 gave the corresponding anti-α-hydroxy-β-amino ester 10 in 63% yield and >99:1 dr. Catalytic hydrogenolysis of 10 gave amine 11, and subsequent acid-mediated ester hydrolysis gave (2R,3R)-3-amino-2-hydroxydecanoic acid 13 in 59% yield (from 10). The corresponding C(2)-epimer 15 was accessed via cyclisation of the corresponding benzamide 12 under Mitsunobu conditions to give oxazoline 14 and global hydrolysis of 14 with 6.0 M HCl furnished (2S,3R)-3-amino-2-hydroxydecanoic acid 15 in 64% yield (from 12). Accordingly, it was anticipated that the asymmetric syntheses of syn-α-hydroxy-β-amino acids, the N-terminal components of microginin 612 4, microginin 646 5 and microginin 680 6, and the corresponding C(2)-epimers 1921 could be achieved via diastereoselective aminohydroxylation of the requisite α,β-unsaturated ester as the key step (Scheme 1).

Section snippets

Results and discussion

The requisite α,β-unsaturated esters 23, 25 and 29 were prepared from the corresponding aldehydes via olefination methodology. Hexanal 22 and 6-chlorohexanal (which was prepared from 6-chlorohexan-ol 24 by treatment with IBX) were treated with ylid 30 to give the corresponding α,β-unsaturated esters 23 and 25, respectively in 98:2 dr [(E):(Z)] in each case. Purification via flash column chromatography afforded 23 and 25 in 87 and 83% isolated yield, respectively, and >99:1 dr [(E):(Z)] in each

Conclusion

In conclusion, the asymmetric syntheses of the N-terminal α-hydroxy-β-amino acid components of microginins 612, 646 and 680 were achieved via diastereoselective aminohydroxylation of the requisite (E)-α,β-unsaturated ester followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position via sequential Swern oxidation/diastereoselective reduction to give the corresponding syn-α-hydroxy-β-amino esters as the key steps. Suitable N-debenzylation (either catalytic

General experimental

All reactions involving organometallic or other moisture-sensitive reagents were carried out under a nitrogen atmosphere using standard vacuum line techniques and glassware that was flame dried and cooled under nitrogen before use. Solvents were dried according to the procedure outlined by Grubbs and co-workers.17 BuLi was purchased as a solution in hexanes and titrated against diphenylacetic acid before use. All other reagents were used as supplied without prior purification. Organic layers

References (18)

  • K. Ishida et al.

    Tetrahedron

    (2000)
  • K. Ishida et al.

    Tetrahedron

    (1998)
  • T. Okino et al.

    Tetrahedron Lett.

    (1993)
  • W.K. Strangman et al.

    Tetrahedron Lett.

    (2016)
  • G. Aghapour et al.

    Synth. Commun.

    (2008)
  • S.G. Davies et al.

    Tetrahedron: Asymmetry

    (2005)
    S.G. Davies et al.

    Tetrahedron: Asymmetry

    (2012)
  • S.G. Davies et al.

    J. Org. Chem.

    (2013)
    S.G. Davies et al.

    Tetrahedron

    (2013)
    M. Brambilla et al.

    Tetrahedron

    (2014)
    S.G. Archer et al.

    Tetrahedron Lett.

    (2016)
    M. Buchman et al.

    J. Org. Chem.

    (2016)
  • S.G. Davies et al.

    Tetrahedron: Asymmetry

    (2012)
    S. Kawata et al.

    J. Am. Chem. Soc.

    (1997)
  • S.G. Davies et al.

    Org. Lett.

    (2015)
There are more references available in the full text version of this article.

Cited by (0)

View full text