An Improved Industrial Synthesis of Florfenicol plus an Enantioselective Total Synthesis of Thiamphenicol and Florfenicol

Wu, Guanhui; Schumacher, Doris P.; Tormos, Wanda; Clark, Jon E.; Murphy, Bruce L.

doi:10.1021/jo961479+

Cited by 43 publications

(17 citation statements)

References 14 publications

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“…In the literature, several approaches for the synthesis of florfenicol have been reported . But none of the reported procedures could be adopted as such because our requirement was for the [ S ‐methyl‐ 14 C]‐florfenicol.…”

Section: Resultsmentioning

confidence: 99%

A novel no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐¹⁴C]‐florfenicol

Srinivas

Prabhakar

Unny

et al. 2013

Labelled Comp Radiopharmac

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In this paper is reported a novel reaction scheme for the no-carrier-added submicromolar scale radiosynthesis of [S-methyl-(14)C]-florfenicol that has been newly designed, developed and employed by us successfully. The [(14)C]-product was obtained in an overall radiochemical yield of 30% based on [(14)C]-methyl iodide taken for the reaction with a radiochemical purity of more than 96%. The specific activity of the product was ~50 mCi (1.85 GBq)/mmol. Chlorosulfonation of compound I was followed by sodium salt formation in situ and it was succeeded by the introduction of [(14)C]-methyl group by coupling with [(14)C]-CH3 I. Subsequently, the oxazolidin-2-one protecting group was opened up by a reaction with sulfuric acid in dioxane and later, the amino group was dichloroacetylated with methyl-2,2-dichloroacetate in triethylamine to obtain [S-methyl-(14)C]-florfenicol.

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Section: Resultsmentioning

confidence: 99%

A novel no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐¹⁴C]‐florfenicol

Srinivas

Prabhakar

Unny

et al. 2013

Labelled Comp Radiopharmac

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“…Unfortunately, although methods were explored to recycle the L-isomer, difficulties were encountered, which highlighted the poor efficiency of this approach. An alternative asymmetric synthesis method that has been described involves the reaction of the substituted aldehyde via an aldol condensation with malonic acid (Scheme (6)) [54]. Dehydration and decarboxylation gave the trans cinnamic acid derivative, which after conversion to the acid chloride, was reduced to the transallylic alcohol.…”

Section: Chemical Approaches To 2-amino-13-diolsmentioning

confidence: 99%

α, α -Dihydroxy Ketones and 2-Amino-1,3-diols: Synthetic and Process Strategies Using Biocatalysts

Hailes¹,

Dalby²,

Lye³

et al. 2010

COC

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There is increasing interest in the use of biocatalysts in synthetic applications due to their ability to achieve highly stereoselective and atom efficient conversions. Recent developments in molecular biology techniques and synthetic biology have also enhanced potential applications using non-natural substrates. Here we review strategies to , '-dihydroxy ketones and 2-amino-1,3-diols via the use of transketolase, a carbon-carbon bond forming biocatalyst, and the enzyme transaminase which converts aldehydes and ketones to amines. Using an integrated strategy we have investigated new chemistries and assays, identified novel biocatalysts and used directed evolution strategies, together with miniaturization studies and modelling to achieve rapid and predictive process scale-up.The use of biocatalysts for the synthesis of biologically active compounds is of increasing interest to the chemical, pharmaceutical and biotechnology sectors in the search for sustainable, cost effective, synthetic strategies. In addition, developments in molecular biology tools and protein and pathway engineering, leading to improved biocatalyst substrate tolerance, specific activities and processing properties are resulting in extensive possibilities for the use of enzymes in synthesis. Current interest in synthetic biology approaches and also cascade reactions, with applications in biofuel synthesis as well as routes to pharmaceuticals, will result in exciting developments and opportunities using biocatalysts in the next decade. At UCL, a multidisciplinary approach has been established in the Departments of Chemistry, Biochemical Engineering and Structural and Molecular Biology (BiCE programme) focusing initially on biocatalytic approaches to , '-dihydroxy ketones and 2-amino-1,3-diols [1]. This has led to the development of new biocatalysts and chemistries and new miniaturization tools for rapid and predictable process scale-up. This review will focus on the use of two enzymes, transketolase (TK) (EC 2.2.1.1) and transaminase (TAm) for the synthesis of the important structural motifs , '-dihydroxy ketones and 2-amino-1,3-diols and biocatalyst scale-up tools.

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“…The application of directed evolution has also produced novel TK mutants capable of processing alternative aldehyde substrates (variation of R group) and thus into equivalent chiral aminodiols via the two sequential biotransformations. Such aminodiol functionality is present in many natural and synthetic biologically active molecules including antibiotics [27], alkaloids [28] and amino sugars [29]. However, the biocatalytic synthesis of non-natural sugars and aminodiols using TK and TAm is kinetically slower than for the naturally catalysed reactions, and so the scale-up to industrial synthesis is partly hampered by the gradual loss of TK activity during the prolonged reaction times required.…”

Section: Introductionmentioning

confidence: 99%

Structural stability of an enzyme biocatalyst

Dalby

Aucamp

George

et al. 2007

Biochemical Society Transactions

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TK (transketolase) undergoes inactivation during biocatalytic processes due to oxidation, substrate and product inhibition, reactivity of aldehyde substrates, irreversible inactivation at low pH, and dissociation of cofactors. However, the contribution of protein denaturation to each of these mechanisms is not fully understood. The urea-induced reversible denaturations of the apo- and holo-enzyme forms of the homodimeric Escherichia coli TK have been characterized, along with the reconstitution of holo-TK from the apoenzyme and cofactors. An unusual cofactor-bound yet inactive intermediate occurs on both the reconstitution and holo-TK denaturation pathways. The denaturation pathways of the holo- and apoenzymes converge at a second intermediate consisting of a partially denatured apo-homodimer. Preliminary investigation of the denaturation under oxidizing conditions reveals further complexity in the mechanisms of enzyme deactivation that occur under biocatalytic conditions.

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An Improved Industrial Synthesis of Florfenicol plus an Enantioselective Total Synthesis of Thiamphenicol and Florfenicol

Cited by 43 publications

References 14 publications

A novel no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐¹⁴C]‐florfenicol

A novel no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐¹⁴C]‐florfenicol

α, α -Dihydroxy Ketones and 2-Amino-1,3-diols: Synthetic and Process Strategies Using Biocatalysts

Structural stability of an enzyme biocatalyst

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An Improved Industrial Synthesis of Florfenicol plus an Enantioselective Total Synthesis of Thiamphenicol and Florfenicol

Cited by 43 publications

References 14 publications

A novel no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐14C]‐florfenicol

A novel no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐14C]‐florfenicol

&#945;, &#945; -Dihydroxy Ketones and 2-Amino-1,3-diols: Synthetic and Process Strategies Using Biocatalysts

Structural stability of an enzyme biocatalyst

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A novel no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐¹⁴C]‐florfenicol

A novel no‐carrier‐added submicromolar scale radiosynthesis of [S‐methyl‐¹⁴C]‐florfenicol

α, α -Dihydroxy Ketones and 2-Amino-1,3-diols: Synthetic and Process Strategies Using Biocatalysts