Review Openingmolecules Up the Toolbox: Synthesis and Mechanisms of Phosphoramidates Emeka J.Review Itumoh 1,2,3, Shailja Data 1,3 and Erin M. Leitao 1,3,* 1 SchoolOpening of Chemical Sciences, up the The Toolbox:University of Auckland, Synthesis 23 Symonds and Street, Mechanisms Auckland 1010, Newof Zealand; Phosphoramidates [email protected] (E.J.I.); [email protected] (S.D.) 2 Department of Industrial Chemistry, Ebonyi State University, Abakaliki 480001, Ebonyi State, Nigeria 3 The MacDiarmidEmeka J. Itumoh Institute1,2,3 for, Shailja Advanced Data 1,3 Materialsand Erin and M. LeitaoNanotechnology,1,3,* Wellington 6140, New Zealand * Correspondence:1 School of Chemicalerin.leitao@ Sciences,auckland.ac.nz; The University Tel.: of Auckland, +64-9923-5567 23 Symonds Street, Auckland 1010, New Zealand; [email protected] (E.J.I.); [email protected] (S.D.) Academic Editor: Frederik Wurm 2 Department of Industrial Chemistry, Ebonyi State University, Abakaliki 480001, Ebonyi State, Nigeria 3 Received: 3 TheJuly MacDiarmid 2020; Accepted: Institute 11 for Augu Advancedst 2020; Materials Published: and Nanotechnology, 12 August 2020 Wellington 6140, New Zealand * Correspondence: [email protected]; Tel.: +64-9923-5567 Abstract:Academic This review Editor: Frederik covers Wurm the main synthetic routes to and the corresponding mechanisms of phosphoramidateReceived: 3 July formation. 2020; Accepted: The 11 August synthetic 2020; Published: routes 13can August be 2020separated into six categories: salt elimination,Abstract: oxidativeThis review cross-coupling, covers the main azide, synthetic reduction, routes to andhydrophosphinylation, the corresponding and phosphoramidate-aldehyde-dienophilemechanisms of phosphoramidate formation. (PAD). The Examples synthetic routesof some can be separatedimportant into compounds six synthesizedcategories: through salt elimination,these routes oxidative are provided. cross-coupling, As azide,an important reduction, class hydrophosphinylation, of organophosphorus and phosphoramidate-aldehyde-dienophile (PAD). Examples of some important compounds compounds,synthesized the applications through these of routesphosphoramid are provided.ate compounds, As an important are classalso ofbriefly organophosphorus introduced. compounds, the applications of phosphoramidate compounds, are also briefly introduced. Keywords: phosphoramidate; synthetic routes; mechanism; applications Keywords: phosphoramidate; synthetic routes; mechanism; applications 1. Introduction1. Introduction to Phosphoramidates to Phosphoramidates and and their their Applications PhosphoramidatesPhosphoramidates (P-N) (P-N) are are a aclass class of organophosphorusorganophosphorus compounds compounds known forknown the presence for the of presence of a singlea single covalent covalent bond between between the tetracoordinatethe tetracoor P(V)dinate atom P(V) and N(III)atom atom. and ThereN(III) are atom. generally There are three types of phosphoroamidates, which are distinguished according to the substitution on the P and generallyN atomsthree (Figuretypes 1of)[ 1phosphoroamidates,]. which are distinguished according to the substitution on the P and N atoms (Figure 1) [1]. O O O P H P R' R' RO N RO N RO P N RO H RO H RO R" I II III R = H, alkyl, aryl R', R" = alkyl, aryl, heteroaryl Figure Figure1. Three 1. Three types types of P-N of P-N based based on on the the substituents directly directly attached attached to the Pto and the N. P and N. Another feature of these organophosphorous compounds, defined as (RO)2P(O)NR’2 (R, R’ = H, Anotheralkyl, aryl, feature heteroaryl), of these is a organophos stable phosphorylphorous bond (Pcompounds,=O). Both P and defined N atoms as are (RO) key2 physiologicalP(O)NR’2 (R, R’ = H, alkyl, aryl,elements heteroaryl), present in is genetic a stable material, phosphoryl energy transfer, bond enzymes, (P=O). Both and other P and biomolecules N atoms and are are key required physiological elementsfor present various lifein processes.genetic material, As such, molecules energy containingtransfer, P-Nenzymes, linkages and are foundother in biomolecules a large array of and are requiredbiologically for various active life natural processes. products As (such,1–7) (Figure molecules2)[ 2,3]. containing For example, P-N Microcin linkages C7 (1 )are (Figure found2) is in a large an antibiotic produced by Escherichia coli [4]. Dinogunellin (2) (Figure2), which is produced in the roe array ofof biologically some fishes, isactive a natural natural toxin [ 5products]. Phosphoarginine (1–7) (Figure and phosphocreatine 2) [2,3]. For (3 example,and 6) (Figure Microcin2) are C7 (1) (Figure important2) is an biologicalantibiotic molecules produced used by as sourcesEscherichia of stored coli energies[4]. Dinogunellin in invertebrates (2) and (Figure vertebrates, 2), which is producedrespectively in the roe [6 ].of Phosphoramidonsome fishes, is (a4) natura (Figurel2 ),toxin derived [5]. from PhosphoarginineStreptomyces tanashiensis and phosphocreatine, inhibits (3 and 6) the(Figure thermolysin 2) are enzyme, important which isbiological a key factor molecules in the development used ofas varioussources diseases of stored [7,8]. Lastly, energies in invertebratesphosmidosine and vertebrates, and agrocin 84 (respectively5 and 7) (Figure 2[6].) are Phosphoramidon nucleotide antibiotics isolated(4) (Figure from Streptomyces2), derived from Streptomyces tanashiensis, inhibits the thermolysin enzyme, which is a key factor in the development Molecules 2020, 25, 3684; doi:10.3390/molecules25163684 www.mdpi.com/journal/molecules of various diseases [7,8]. Lastly, phosmidosine and agrocin 84 (5 and 7) (Figure 2) are nucleotide antibiotics isolated from Streptomyces durhameusis and Agrobacterium radiobacter and are used to control gray mold disease and crown gall disease in plants, respectively [9,10]. Molecules 2020, 25, x; doi: FOR PEER REVIEW www.mdpi.com/journal/molecules Molecules 2020, 25, 3684 2 of 37 durhameusis and Agrobacterium radiobacter and are used to control gray mold disease and crown gall diseaseMolecules in 2020 plants,, 25, x FOR respectively PEER REVIEW [9,10 ]. 2 of 37 Figure 2. Phosphoramidate motifs in natural products: Microcin C7 (1), Dinogunellin (R = residue Figure 2. Phosphoramidate motifs in natural products: Microcin C7 (1), Dinogunellin (R = residue of of fatty acid) (2), Phosphoarginine (3), Phosphoramidon (4), Phosmidosine (5), Phosphocreatine (6), fatty acid) (2), Phosphoarginine (3), Phosphoramidon (4), Phosmidosine (5), Phosphocreatine (6), Agrocin 84 (7). Agrocin 84 (7). Due to the inherent physiochemical properties of the phosphorus atom including its polarizability, Due to the inherent physiochemical properties of the phosphorus atom including its multivalency, varying oxidation states, and low coordination number, a diverse range of compounds polarizability, multivalency, varying oxidation states, and low coordination number, a diverse range containing the P-N motifs have been synthesized [11]. These P-Ns are widely used in medicine for the of compounds containing the P-N motifs have been synthesized [11]. These P-Ns are widely used in control and treatment of various diseases, in agriculture as pesticides for crop protection, in industry as medicine for the control and treatment of various diseases, in agriculture as pesticides for crop novelprotection, fire-retardant in industry compounds as novel to fire-retardant delay the flammability compounds of to polymeric delay the compounds, flammability and of in polymeric the fields ofcompounds, analytical and and coordination in the fields chemistry. of analytical Therefore, and coordination synthetic P-N chemistry. compounds Therefore, are not only synthetic researched P-N outcompounds of academic are interest, not only but researched they also have out commercialof academic applications. interest, but Uses they for also P-Ns have can becommercial separated intoapplications. 5 main classes: Uses for agriculture, P-Ns can industry,be separated analytical into 5 chemistry,main classes: synthetic agriculture, chemistry, industry, and analytical medicinal chemistrychemistry, (Figure synthetic3)[12 chemistry,–18]. and medicinal chemistry (Figure 3) [12–18]. Molecules 2020, 25, x FOR PEER REVIEW 3 of 37 Molecules 2020, 25, 3684 3 of 37 Molecules 2020, 25, x FOR PEER REVIEW 3 of 37 FigureFigureFigure 3.3. 3. ApplicationsApplications Applications of ofof phosphoramidates. phosphoramidates. 1.1. Phosphoramidates in Agriculture 1.1.1.1. Phosphoramidat Phosphoramidates esin in Agriculture Agriculture This class of organophosphates (with common names such as cruformate, fenamiphos, ThisThis class class of oforganophosphates organophosphates (with (with commoncommon names suchsuch asas cruformate,cruformate, fenamiphos, fenamiphos, and and andfosthietan)fosthietan) fosthietan) has has been has been beenwidely widely widely used used in used in pest pest in management management pest management forfor crop for protectionprotection crop protection (Figure (Figure 3) 3) (Figure [19–21]. [19–21].3 )[P-Ns P-Ns19 –for21 for ]. P-Nspestpest control for control pest affect control affect the the a nervousff ectnervous the sy nervous systemstem of of system pests/insects pests/insects of pests by/insects inhibiting by inhibitingacetylcholinesteraseacetylcholinesterase acetylcholinesterase (AChE), (AChE), a a (AChE),majormajor neurotransmitter aneurotransmitter major neurotransmitter [22–25]. [22–25]. In [In22 addition, –addition,25].