New phosphonate-mediated syntheses of cyclopentanoids and prostaglandins

Mikołajczyk, M.; Mikina, Maciej; Żurawiński, Remigiusz

doi:10.1351/pac199971030473

Cited by 29 publications

(15 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…jasmonoids, cyclopentanoid antibiotic, and prostaglandins). The synthesis and functionalization of these scaffolds is not trivial 12. The activities of the enzymes towards these substrates were probed in multi-well format using GC and GC-MS (Fig.…”

mentioning

confidence: 99%

Chemo-enzymatic fluorination of unactivated organic compounds

2008

View full text Add to dashboard Cite

Fluorination has gained an increasingly important role in drug discovery and development. Here we describe a versatile strategy that combines cytochrome P450-catalyzed oxygenation with deoxofluorination to achieve mono-and polyfluorination of non-reactive sites in a variety of organic scaffolds. This procedure was applied for the rapid identification of fluorinated drug derivatives with enhanced membrane permeability.Fluorination has become an increasingly important tool for fine-tuning the pharmacokinetic and pharmacological properties of drugs and lead compounds, leading to a growing number of fluorine-containing pharmaceuticals on the market. 1 Benefits of hydrogen-to-fluorine substitutions arise principally from their effects on membrane permeability, metabolic stability, and/or receptor-binding properties of bioactive molecules. 1-3 In many cases, fluorination of much less active precursors yielded potent drugs, with enhanced bioavailability, reduced toxicity, or improved affinity for the target receptor. 3 A number of methods have been developed for synthesis of fluorinated compounds, 4,5 including asymmetric fluorination strategies 6,7 and chemo-enzymatic approaches 8,9 . Despite this progress, selective incorporation of fluorine at non-activated or weakly-reactive sites of a target scaffold remains difficult and may require several synthetic steps.Here we describe a facile, two-step procedure for the selective fluorination of one or more nonactivated sites in an organic molecule. This approach couples the exceptional ability of cytochrome P450 monooxygenases to selectively insert oxygen into non-reactive C-H bonds with a deoxofluorination (DF) reaction in which the newly generated hydroxyl group is substituted by fluorine by means of a nucleophilic fluorinating reagent (Fig. 1). To test the validity of this approach, we targeted various classes of small molecules, including marketed pharmaceuticals (Supplementary Figure 1 online). For the enzymatic step, we used variants of the bacterial long-chain fatty acid hydroxylase P450 BM3 from Bacillus megaterium. Catalytic self-sufficiency, high monooxygenase activity, and high expression level in E. coli render P450 BM3 an attractive catalyst for in vitro and in vivo applications. 10 For this work, we assembled a panel of 96 P450s derived from a catalytically-promiscuous P450 BM3 variant identified in the early stages of the directed evolution of a proficient alkane monoxygenase. 11 These variants were found to exhibit good activity and various degrees of selectivity on alkanes and non-alkane substrates. 11The first group of test molecules (1, 2 and 3; Fig. 2a,b) contains a cyclopentenone moiety found in several natural products (e.g. jasmonoids, cyclopentanoid antibiotic, and prostaglandins). The synthesis and functionalization of these scaffolds is not trivial. 12 The activities of the enzymes towards these substrates were probed in multi-well format using GC and GC-MS (Fig. 2a). Depending on the substrate, approximately 30 to 50% of the 96 enzyme var...

show abstract

mentioning

confidence: 99%

Chemo-enzymatic fluorination of unactivated organic compounds

2008

View full text Add to dashboard Cite

show abstract

“…Inspired by the trend in pharmaceutical sciences and industry to replace racemic by enantiomeric drugs (so-called “chiral shift”) and as part of our research program on the synthesis and study of the stereostructure–bioactivity relationship in biologically active compounds [18–19], including selected prostanoids [20–22], we decided to synthesize all four rosaprostol stereoisomers 1a–d in enantiomerically pure form (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

A new and expeditious synthesis of all enantiomerically pure stereoisomers of rosaprostol, an antiulcer drug

Perlikowska

Żurawiński

Mikołajczyk

2016

Beilstein J. Org. Chem.

View full text Add to dashboard Cite

SummaryFour enantiomerically pure stereoisomers of rosaprostol (1), an antiulcer drug, were efficiently synthesized from the enantiomers of 2-(dimethoxyphosphoryl)-3-hexylcyclopentanone (3) as chiral substrates. The latter were obtained by resolution of racemic 3 with (+)-(R)-1-(1-naphthyl)ethylamine. The conversion of (+)-3 into rosaprostol stereoisomer (−)-1a was accomplished in four steps in 56% overall yield. According to the same protocol, the second stereoisomer (+)-1c was obtained from (−)-3 in 55% overall yield. A slightly improved procedure of the last two steps of the transformation of (+)-3 into (−)-1a allowed an increase in the overall yield to 64%. The remaining two stereoisomers, (−)-1b and (+)-1d, were obtained from (−)-1a and (+)-1c in 71 and 68% yield, respectively, by a two-reaction sequence, in which a Mitsunobu inversion of configuration at C-5 was the key step.

show abstract

“…The widespread occurrence of cyclopentanoids has led to the development of a variety of approaches for their synthesis [1][2][3][4][5][6]. In the synthesis of natural and unnatural biologically active cyclopentanoids, the preparation of chiral orthogonally functionalized cyclopentane (cyclopentene) block-synthons is important.…”

Section: Introductionmentioning

confidence: 99%