Site-selective incorporation of alpha- and beta-amino acid derivatives : towards new gramicidin S-based bactericides

Site-selective incorporation of alpha- and beta-amino acid derivatives : towards new gramicidin S-based bactericides

Knaap, M. van der

Citation

Knaap, M. van der. (2010, September 8). Site-selective incorporation of alpha- and beta- amino acid derivatives : towards new gramicidin S-based bactericides. Retrieved from https://hdl.handle.net/1887/15935

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Site-Selective Incorporation of α- and β- Amino Acid Derivatives: Towards New

Gramicidin S-Based Bactericides

Proefschrift

ter verkrijging van

de graad van Doctor aan de Universiteit Leiden

op gezag van Rector Magnificus prof. mr. P.F. van der Heijden, volgens besluit van het College voor Promoties

te verdedigen op woensdag 8 september 2010 klokke 15.00 uur

door

Matthijs van der Knaap

Promotores: Prof. dr. H.S. Overkleeft Prof. dr. G.A. van der Marel Copromotor: Dr. ing. M. Overhand

Overige Leden: Prof. dr. A. van Belkum (Erasmus Universiteit) Prof. dr. J. Brouwer

Dr. G.M. Grotenbreg (Singapore National University) Prof. dr. J.C.M. van Hest (Radboud Universiteit) Prof. dr. J. Lugtenburg

This research is supported by the Dutch Technology Foundation STW, which is the applied science division of NWO, and the Technology Programme of the Ministry of Economic Affairs (project number 07109)

Table of Contents

List of Abbreviations………..6

Chapter 1………...………...9 General Introduction

Chapter 2………...31 Synthesis and Biological Evaluation of Asymmetric Gramicidin S Analogues Containing Modified

-Phenylalanine Residues

Chapter 3………...51 Application of the Triazole Moiety in the β-Turn of Gramicidin S to Mimic the Phenyl-Ring

Chapter 4………...65 Synthesis and Evaluation of Smaller Ring Analogues of Peptide Antibiotic Gratisin

Chapter 5………..………..81

New Synthesis of α-Substituted β-Amino Acids

Chapter 6………..…………..93

Mixing α- and β-Amino Acids in the Strand of Gramicidin S Towards a New Class of Cyclic β-Hairpins Chapter 7………..109

Mixing

-α- and β-Amino Acids in the Strand of Gramicidin S Towards a New Class of Cyclic β-Hairpins Chapter 8………..121

Summary and Future Prospects Addendum……….…..131

Samenvatting………...133

List of Publications……….136

Curriculum Vitae………137

Dankwoord………..……138

List of abbreviations

Å Ångstrom aa amino acid

Ac acetyl

All allyl aq aqueous

Ar aryl

At 7-azabenzotriazole AU absorbance units B. cereus Bacillus cereus B. brevis Bacillus brevis B. subtilis Bacillus subtilis

Bn benzyl

Boc tert-butyloxycarbonyl brs broad singlet Bt benzotriazole

Bu butyl

iBu iso-butyl

tBu tert-butyl Bz benzoyl C. antarctica Candida Antarctica

CalB Candida antarctica lipase B CAP cationic amphiphilic peptide Cbz benzyoxycarbonyl CD circular dichroism Cha cyclohexylalanine

CNS coagulase-negative staphylococcus

COSY correlation spectroscopy Cp* pentamethylcyclopentadienyl CROESY correlated rotational nuclear

Overhauser effect spectrosopy d doublet

δ chemical shift Δ dehydro

DBU 1,8-diazabicycloundec-7-ene DCM dichloromethane

dd double doublet ddt double double triplet

DIC N,N’-diisopropylcarbodiimide DiPEA diisopropylethylamine

DMAP N,N-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide

DPPA diphenylphosphoryl azidate dq double quartet

E. coli Escherichia coli E. faecalis Enterococcus faecalis

EC50 median effective concentration ee enantiomeric excess

EPR electron paramagnetic resonance

eq equivalents

er enantiomeric ratio ESI electrospray ionisation Et ethyl

Fmoc 9H-fluorenylmethyloxy- carbonyl

GR gratisin GS gramicidin S h homo

HATU 2-(1H-7-azabenzotriazol-1- yl)--1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium

HCTU 2-(6-chloro-1H-benzotriazole- 1-yl)-1,1,3,3-tetramethyl- aminium hexafluoro- phosphate

HIV human immunodeficiency virus

HMPB 4-(4-hydroxymethyl-3- methoxyphenoxy)butyric acid HPLC high performance liquid

chromatography HRMS high resolution mass

spectrometry IR infrared

J coupling constant

LC/MS liquid chromatography-mass spectroscopy

LDA lithium diisopropyl amide m multiplet/medium M mass

m/z mass/charge ratio MBHA 4-methylbenzhydrylamine

Me methyl

MIC minimal inhibitory concentration

MS molsieves/mass spectrometry MTBE methyl tert-butyl ether

μW microwave NBS N-bromosuccinimide NIS N-iodosuccinimide NMP N-methyl-2-pyrolidone NMR nuclear magnetic resonance NOE nuclear Overhauser effect Nu nucleophile

ORD optical rotatory dispersion Orn ornithine

p para

P. aeruginosa Pseudomonas aeruginosa PE petroleum ether PG protection group

Ph phenyl

pip piperidine ppb parts per billion ppm parts per million

iPr iso-propyl

PyAOP 7-azabenzotriazol-1-yloxy- tris-

(pyrrolidino)phosphonium hexafluorophosphate PyBOP benzotriazol-1-yl-oxy-tris-

pyrrolidinophosphonium hexafluorophosphate q quartet

RNA ribonucleic acid

ROE Rotational nuclear Overhauser effect

RP reversed phase rt room temperature Rt retention time s strong

S. aureus Staphyloccocus aureus S. mitis Streptococcus mitis SAA sugar amino acid sept septet

sext sextet soln solution

SPPS solid-phase peptide synthesis Su succinimidyl

t triplet

TBAI tetrabutylammonium iodide Tfa trifluoroacetate

TFA trifluoroacetic acid THF tetrahydrofuran

TLC thin-layer chromatography TOCSY totally correlated spectroscopy Tol toluene

Tris 2-amino—2-(hydroxymethyl)- 1,3-propanediol

UV ultraviolet v/v volume ratio w weak

Three-letter codes for amino acids are used following the rules as proposed by the IUPAC- IUB Commission on Biochemical

Nomenclature. J. Biol. Chem. 1966, 241, 2491- 2495.