Novel Antifungal β‐Amino Acids: Synthesis and Activity Against Candida albicans.

Mittendorf, Joachim; Kunisch, Franz; Matzke, Michael; Militzer, Hans‐Christian; Schmidt, Axel; Schoenfeld, Wolfgang

doi:10.1002/chin.200323187

Cited by 11 publications

(14 citation statements)

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“…was reported by Wu and Hoge [19]. Mittendorf et al synthesized an icofungipen analog (58) in racemic form in seven steps involving reductive amination of keto ester 54 [21] (Scheme 8.13). There have recently been new developments as regards the asymmetric hydrogenation of dehydroamino acids.…”

Section: Syntheses From Cyclic B-keto Estersmentioning

confidence: 99%

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Synthesis of Carbocyclic β‐Amino Acids

Kiss

Forró

Fülöp

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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j367 acids was reviewed by our group in 2001 [1]; the present chapter highlights the chemistry of these compounds published since 2000, with the aim of offering the reader an insight into the most recent developments in this field. Synthesis of Carbocyclic b-Amino AcidsOwing to their significance, a number of methods have been developed for the synthesis of these conformationally restricted molecules in racemic and enantiomerically pure form. The largest groups of carbocyclic b-amino acids and the most intensively investigated are the fiveand six-membered derivatives. One main method of preparation consists of the amidation of 1,2-dicarboxylic anhydrides 4, followed by Hoffmann rearrangement of the resulting amide 5 to amino acid 7. The same starting material, the meso anhydride 4, undergoes partial hydrolysis, followed by the Curtius rearrangement, to give 2-aminocyclohexanecarboxylic acid 7 (Scheme 8.1) ([1] and references cited therein).A widely used method for the synthesis of carbocyclic b-amino acids is the transformation of cycloalkenes via the corresponding bicyclic b-lactams. The 1,2dipolar cycloaddition of chlorosulfonyl isocyanate (CSI) to cycloalkenes 8 led regioselectively to the cycloalkane-fused b-lactams 10, whose acidic hydrolysis resulted in lactam ring opening and formation of the carbocyclic b-amino acid hydrochlorides 11 (Scheme 8.2) ([1] and references cited therein). O O O NH 4 OH COOH CONH 2 1. ROH 2. HO 3. H COOR COOH Curtius degradation COOH NH 2 Hoffmann degradation NaOH, Br 2 1. SOCl 2 2. NaN 3 Dowex 4 5 6 7 Scheme 8.1 Synthesis of carbocyclic b-amino acids by Curtius and Hoffmann rearrangements. CSI NSO 2 Cl O H 2 O NH O HCl, RT COOH NH 2 HCl 8 9 10 11 Scheme 8.2 Synthesis of carbocyclic b-amino acids from b-lactams. 368j 8 Synthesis of Carbocyclic b-Amino Acids 15 16 18 17 16:17:18 = 95.5:1.7:2.8 KOtBu, tBuOH ∆, 3hScheme 8.4 Synthesis of 3-methylcispentacin derivatives by conjugate addition. Synthesis of Carbocyclic b-Amino Acids j369To prepare 3-methyltranspentacin, aminocarboxylate 17 was first obtained in a larger quantity from diastereoisomer 16 by epimerization on treatment with KOtBu in tBuOH; this afforded 17 in quantitative yield and a diastereomeric excess of 99%. N-Deprotection of 17, followed by ester hydrolysis, gave the desired 3-methyltranspentacin in 97% e.e. [9].By using this conjugate addition methodology, Davies et al. also prepared 5-substituted derivatives of cispentacin. The addition of lithium amide (S)-13 to 5-isopropyl-, 5-phenyl-, and 5-tert-butylcyclopentenecarboxylates proceeded with a high degree of selectivity, the major derivatives formed having the amine anti to the 5-alkyl group. N-Deprotection by hydrogenolysis, subsequent acid hydrolysis of the ester, and ion-exchange chromatography furnished 5-substituted cispentacin derivatives in 98% e.e. [10].The asymmetric synthesis of a series of functionalized derivatives was achieved by using amine conjugate addition processes. Four stereoisomers of 2-amino-5carboxymethylcyclopentanecarboxylate were prepared ...

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Section: Syntheses From Cyclic B-keto Estersmentioning

confidence: 99%

“…A series of novel b-amino acids, including cis-2-amino-4-hydroxycyclopentanecarboxylic acid diastereomers, were synthesized and tested for in vitro antifungal activity against Candida albicans by Mittendorf et al [21]. Compounds 164 were prepared as …”

Section: Synthesis Of Functionalized Carbocyclic B-amino Acid Derivatmentioning

confidence: 99%

Synthesis of Carbocyclic β‐Amino Acids

Kiss

Forró

Fülöp

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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“…A compound with a novel mechanism of action, icofungipen is a cyclic ␤-amino acid with anti-Candida activity. 266 The mechanism of action is distinct in that the compound appears to inhibit isoleucyl-transfer RNA synthetase, protein biosynthesis, and fungal cell growth. 267 The spectrum of icofungipen is limited to Candida species and has been effective for treatment of disseminated candidiasis in neutropenic rabbits.…”

Section: Icofungipenmentioning

confidence: 99%

Current Options in Antifungal Pharmacotherapy

et al. 2008

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Infections caused by yeasts and molds continue to be associated with high rates of morbidity and mortality in both immunocompromised and immunocompetent patients. Many antifungal drugs have been developed over the past 15 years to aid in the management of these infections. However, treatment is still not optimal, as the epidemiology of the fungal infections continues to change and the available antifungal agents have varying toxicities and drug-interaction potential. Several investigational antifungal drugs, as well as nonantifungal drugs, show promise for the management of these infections.

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“…Over the last few years, pharmaceutical companies have shown increased interest in the potential biological activity of β‐amino acids and β‐lactams and their utility in synthetic chemistry 1–6. Single‐enantiomer forms of these compounds are potentially useful as chiral synthons in pharmaceutical drug research.…”

Section: Introductionmentioning

confidence: 99%

“…Single‐enantiomer forms of these compounds are potentially useful as chiral synthons in pharmaceutical drug research. In the past, they have been evaluated as antifungal1 and antimalarial agents2 in addition to being utilised in drug candidates targeted at thrombosis3 and cancer treatments 4. More recently, cyclic β‐amino acids have been utilised in matrix metalloproteinase (MMP) inhibitors 5, 6.…”

Section: Introductionmentioning

confidence: 99%

A concise synthesis of single‐enantiomer β‐lactams and β‐amino acids using Rhodococcus globerulus

Lloyd¹,

Lloyd²,

Keene³

et al. 2007

J of Chemical Tech & Biotech

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BACKGROUND: Pharmaceutical companies continue to evaluate β-amino acids and β-lactams in a range of drug candidates. The development of a highly efficient and selective bioresolution of cyclic β-lactam substrates could yield enantiopure lactams and β-amino acids with medicinal potential. The aim of this work was to discover and develop a biocatalyst capable of selectively hydrolysing β-lactam substrates.

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Novel Antifungal β‐Amino Acids: Synthesis and Activity Against Candida albicans.

Cited by 11 publications

References 1 publication

Synthesis of Carbocyclic β‐Amino Acids

Synthesis of Carbocyclic β‐Amino Acids

Current Options in Antifungal Pharmacotherapy

A concise synthesis of single‐enantiomer β‐lactams and β‐amino acids using Rhodococcus globerulus

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