Synthesis of analogues of the 2-O-alkyl glycerate part of the moenomycins

doi:10.1016/S0040-4020(01)01167-X

Tetrahedron

Volume 58, Issue 3, 14 January 2002, Pages 545-559

https://doi.org/10.1016/S0040-4020(01)01167-X Get rights and content

Abstract

The title compounds have been prepared by hydroxymethylation of chiral enolates

The title compounds have been prepared by hydroxymethylation of chiral enolates.

Introduction

The moenomycin antibiotics (see, for example, moenomycin A (1),¹ Scheme 1) are the only compounds known with certainty to inhibit the enzyme of the transglycosylation reaction,² one of the last steps in the biosynthesis of peptidoglycan³ (main component of the bacterial cell wall). A mechanism for their mode of action has been proposed.4., 5., 6. It is assumed that they are anchored to the cytoplasmic membrane via the lipid part and bind then highly selectively to the active site of the enzyme via the C–E–F trisaccharide.⁷ Whereas the structural requirements for antibiotic activity in the carbohydrate part have been investigated in great detail,7., 8. little is known how membrane anchoring assists the interaction of the antibiotic with the enzyme. The C₂₅ lipid may be cyclized in its terminal part⁹ as well as saturated without loss of antibiotic activity.¹⁰ However, converting the glyceric acid part into its methyl ester or introducing a single OH group to C-17 or C-18 of the lipid chain abolishes the antibiotic activity completely. Similarly, cleavage of the bond between the glyceric acid unit and the C₂₅ lipid leads to a compound devoid of antibiotic activity.11., 12.

Moenomycin can be degraded very efficiently by ozonolysis into a pentasaccharide derivative in which the chromophore A part is removed and the lipid chain shortened to a glycolaldehyde unit (see formula 2). This aldehyde has been converted into moenomycin analogues with new lipid chains by indium-mediated Barbier reactions with allylic and benzylic halides (2→3)¹³ and by reductive amination reactions (2→4),¹⁴ respectively (see Scheme 1). Most of these compounds were antibiotically inactive. It may be assumed that the polar groups in the lipid chains prevent proper alignment of the antibiotic at the outer face of the membrane.

Membrane anchoring besides assisting recognition of moenomycin by the enzyme is made responsible for the insufficient pharmacokinetics of these antibiotics.¹⁵ Thus, it is important to find access to antibiotically active moenomycin analogues with more appropriate lipid parts. The 2-O-alkylation of suitably 3-O-protected glyceric acid derivatives usually suffers from low yields, probably caused by elimination.¹⁶ Previously, we have developed a synthetic scheme for this class of compounds that commences from d-mannitol and involves (i) protection of the 1-, 3-, 4-, 6-OH groups, (ii) alkylation of the OH-groups at C-2 and C-5, (iii) removal of the protecting groups, (iv) glycol cleavage, and (v) oxidation of the intermediate 2-O-alkylglyceraldehyde.¹⁶ This sequence is lengthy, and it provides, when conducted as described, only one enantiomeric series.¹⁷ It was the purpose of the studies reported below to seek for more convenient routes to structural analogues of the 2-O-alkylglycerate part of the moenomycins.

Section snippets

Synthetic considerations

Our goal was the conversion of compounds of type B (Scheme 2, Y=CH₂ and O, respectively) into the target compounds A by an (overall) enantioselective hydroxymethylation. For compounds B we envisioned the use of simple fatty acids or a synthesis from a nucleophilic synthon of type C and an alkyl halide D. The Evans route¹⁸ seemed well-suited to achieve the desired stereoselective hydroxymethylation. This assumption was reduced to practice (vide infra).

Hydroxymethylation of fatty acids

The Evans oxazolidinone 5 (Scheme 3) was N-acylated with oleic and palmitic acid in the usual way and the acylation products 9A and 9B (Scheme 4) were converted into the boron and the lithium enolates, respectively. The boron enolates were trapped with formaldehyde (freshly prepared solution in CH₂Cl₂) and the lithium enolates with trimethylsilylethoxymethyl chloride (SEM chloride, 7).

The corresponding alkylation products 10Aa/10Ba and 10Ab/10Bb were obtained in very satifactory yields (in the

Reaction of geranyl halides with homoenolate equivalents and subsequent hydroxymethylation

Compounds of type B (Scheme 2, Y=CH₂) with an isoprenoid R seemed to be accessible from propionic acid homoenolate equivalents and allyl halides. First the nickelalactone route of Schönecker and Walther was tried.26., 27. In a test reaction under the published conditions (presence of MnI₂) the reaction of 15 (Scheme 6) with ethyl iodide provided the alkylation product in 74% (isolated) yield. However, with geranyl iodide (19a) no C–C bond formation was observed in agreement with a previous

Hydroxymethylation of alkoxy acetates

The sodium alkoxides of geraniol, nerol and of 4-phenylbenzyl alcohol were alkylated with sodium bromoacetate in DMF solution³² and the corresponding alkoxyacetic acids 24A, 24B, and 24C were coupled to the Evans auxiliary 5 (see Scheme 7) in the usual way. The lithium enolates of 25A and 25B were alkylated with the two formaldehyde equivalents 7 and bromomethyl acetate (8b)³³ and that of 25C only with 7. In all experiments the yields were only moderate (around 40%). The acetyl group of the

Merits of the Evans route to 2-substituted 3-hydroxypropionates

The approach described herein makes 2-O-alkylglycerate building blocks for moenomycin analogues easily available in both enantiomeric series. Especially facile is the hydroxymethylation in the fatty acid series (see Scheme 4) and for compound 22d to give compounds of type A (Scheme 2, Y=CH₂). Hydroxymethylation in the alkoxyacetic acid series (see 25 in Scheme 7) which eventually leads to 2-O-alkylglycerates generally proceeds with lower yields (around 40%), probably as a result of a reduced

Synthesis of a new moenomycin analogue

Following an established route methyl (R)-2-hydroxymethylpalmitate (11Ba, see Scheme 4) was converted into a simple moenomycin analogue.³⁵ In these experiments the commercial 2,2,2-trichloroethyl dichlorophosphite³⁶ was converted into the ditriazolide³⁷ which in turn was sequentially treated with 2,3,4,6-tetra-O-acetyl-d-glucose (28) and with 11Ba (Scheme 8). The intermediate phosphite was oxidized with bis(trimethylsilyl)peroxide38., 39. to give the corresponding phosphate 29a. ¹H and ³¹P NMR

General procedures

All O₂- or moisture-sensitive reactions were performed in oven-dried glassware under a positive pressure of argon. Liquids and solutions were transferred by syringe. Small-scale reactions were performed in Wheaton serum bottles sealed with aluminum caps with open top and Teflon-faced septum (Aldrich). Usual work-up means partitioning the reaction mixture between an aqueous phase and the solvent indicated in brackets, drying the combined organic solutions over Na₂SO₄, and removal of solvent by

Acknowledgements

The Leipzig group gratefully acknowledges financial support by the Deutsche Forschungsgemeinschaft, BC Biochemie GmbH (Frankfurt), and the Fonds der Chemischen Industrie.

References (45)

A. Donnerstag et al.
Tetrahedron
(1995)
T.H.D. Bugg
O. Ritzeler et al.
Tetrahedron
(1997)
R. Kosmol et al.
J. Prakt. Chem.
(1997)
M. Kurz et al.
Eur. J. Biochem.
(1998)
S. Vogel et al.
Bioorg. Med. Chem. Lett.
(2000)
S. Vogel et al.
Tetrahedron
(2001)
S. Vogel et al.
Tetrahedron
(2001)
A. Anikin et al.
Angew. Chem.
(1999)
U. Peters et al.
Tetrahedron
(1987)
D.A. Evans et al.
J. Am. Chem. Soc.
(1981)
D.A. EvansD.A. Evans et al.
J. Pure Appl. Chem.
(1981)

R. Fischer et al.

J. Organomet. Chem.

(1992)

P.A. Grieco

J. Am. Chem. Soc.

(1969)

J.H.P. Tyman et al.

J. Chem. Soc., Perkin Trans. 1

(1981)

T. Schubert et al.

Tetrahedron

(1983)

L. Wozniak et al.

Tetrahedron Lett.

(1985)

Y. Hayakawa et al.

Tetrahedron Lett.

(1986)

W.C. Still et al.

J. Org. Chem.

(1978)

D. Kritchevsky et al.

Arch. Biochem. Biophys.

(1952)

van Heijenoort

J. Glycobiol.

(2001)

M. Terrak et al.

Mol. Microbiol.

(1999)

R.C. Goldman et al.

Cur. Med. Chem.

(2000)

N. El-Abadla et al.

Tetrahedron

(1999)

Cited by (11)

Gold-catalysed synthesis of phosphonate-substituted oxetan-3-ones-an easy access to highly strained HWE reagents
2022, Organic Chemistry Frontiers
A convenient approach for the attainment of strained phosphonate-substituted oxetan-3-ones, starting from easy to synthesise alkynyl phosphonates, is presented. With the aid of a pyridine-N-oxide, in a gold-catalysed step an α-oxo carbene species is generated as a key intermediate. After formal OH-insertion, synthetically useful HWE reagents can be attained. The synthetic utility of the obtained building blocks could be demonstrated, which yielded the 2-alkenyl oxetan-3-one scaffold in high yields after the HWE reaction.
Targeting the forgotten transglycosylases
2006, Biochemical Pharmacology
Citation Excerpt :
Welzel et al. have proposed that the different position of the lipid group relative to the second sugar unit in moenomycin A (i.e. 1-lipid, 2-sugar) as compared to the growing peptidoglycan chain (i.e. 1-lipid, 4-sugar), is responsible for the inhibition of the TG enzymes [5]. Structure–activity relationship studies have shown that the minimum requirements for antibacterial activity in vivo are the three rings, C, E and F, which has led to the proposal that these three sugar rings in moenomycin A are involved in binding to the donor-binding site [88] (Fig. 4). In a recent study on S. pneumoniae PBP1b [68], moenomycin prevented binding of lipid II to the PBP, suggesting at least that it can interfere with binding of lipid II to the enzyme.
Forty years ago, moenomycin was reported as a representative of a novel natural product class with strong antibacterial activity against Gram-positive organisms. Moenomycin was developed as an antimicrobial growth promoter in animal feeds. Mechanistically, moenomycin acts via inhibition of the transglycosylation process at the final stage of the peptidoglycan biosynthesis, in particular through binding directly to the transglycosylase enzymes, thereby preventing polymerisation of lipid II into linear peptidoglycan. Despite moenomycin's success, no developments of direct transglycosylase enzyme inhibitors were reported for over 30 years, probably due to the complexities and uncertainties surrounding the transglycosylation process, in particular the number of enzymes involved in the process and their specific roles. The development of better research tools and an improved understanding of the transglycosylation process, together with the increasing threat presented by multidrug-resistant bacteria, have led to a resurfacing of interest in targeting the forgotten transglycosylases. In addition, several new generation glycopeptides in clinical development inhibit the transglycosylation process, adding further value to the approach. In this paper, we summarise some of the developments in the area of transglycosylase inhibitors over the last 10 years.
N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors
2017, Journal of Enzyme Inhibition and Medicinal Chemistry
Greene's Protective Groups in Organic Synthesis: Fifth Edition
2014, Greene's Protective Groups in Organic Synthesis: Fifth Edition
Key chiral auxiliary applications
2014, Key Chiral Auxiliary Applications: Second Edition
Key Chiral Auxiliary Applications: Second Edition
2014, Key Chiral Auxiliary Applications: Second Edition

View all citing articles on Scopus

View full text

Synthesis of analogues of the 2-O-alkyl glycerate part of the moenomycins

Abstract

Introduction

Section snippets

Synthetic considerations

Hydroxymethylation of fatty acids

Reaction of geranyl halides with homoenolate equivalents and subsequent hydroxymethylation

Hydroxymethylation of alkoxy acetates

Merits of the Evans route to 2-substituted 3-hydroxypropionates

Synthesis of a new moenomycin analogue

General procedures

Acknowledgements

Tetrahedron

Tetrahedron

J. Prakt. Chem.

Eur. J. Biochem.

Bioorg. Med. Chem. Lett.

Tetrahedron

Tetrahedron

Angew. Chem.

Tetrahedron

J. Am. Chem. Soc.

J. Pure Appl. Chem.

J. Organomet. Chem.

J. Am. Chem. Soc.

J. Chem. Soc., Perkin Trans. 1

Tetrahedron

Tetrahedron Lett.

Tetrahedron Lett.

J. Org. Chem.

Arch. Biochem. Biophys.

J. Glycobiol.

Mol. Microbiol.

Cur. Med. Chem.

Tetrahedron