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Tuesday, June 6, 2023

A Chiral Bifunctional Superbase Catalyst Forges P(V) Stereocenters by Nucleophilic Substitution

Compounds containing a number of phosphorous atoms within the P(V) oxidation state are essential to chemistry, biology and medication (Determine 1).[i] These embrace marketed antiviral medicine resembling resembling Tenofovir alafenamide and Remdesivir, the latter an efficient therapy for Ebola[ii] which has at present additionally been accredited to be used in opposition to SARS-CoV-2.[iii] Different related compounds embrace WHO important medicines listed chemotherapy agent Cyclophosphamide.[iv] Along with being frequent APIs, P(V) containing compounds are additionally extremely related motifs in agrochemistry. A consultant instance is Dow herbicide Zytron.

Determine 1. Consultant bioactive compounds bearing a phosphorous (V) stereocenter.

Artificial approaches to enantiopure P(V) compounds may be subdivided into 5 classes (Determine 2).[v] The primary method is classical decision and/or separation of diastereomers or enantiomers by chromatography (Determine 2, i). A second method revolves round using labile chiral auxiliaries which may be displaced by sequential diastereoselective nucleophilic additions to afford enantioenriched P(V) species (Determine 2, ii). Thirdly, a racemic and electrophilic P(V) compound bearing a single leaving group (and sometimes possessing a chiral sidechain) may be coupled diastereoselectively (and catalytically) to a chiral nucleophile (Determine 2, iii). A subsequent method includes the direct functionalisation of secondary phosphine oxides (SPO) by the use of a steel catalyst bearing chiral ligands to acquire tertiary phosphine oxides. To this point, nonetheless this method has been broadly restricted to the synthesis of all carbon substituted phosphine oxides (Determine 2, iv). The ultimate technique is enantioselective desymmetrisation by which prochiral teams hooked up to a phosphorous centre are differentiated by a chiral catalyst (Determine 2, v). A number of reactions have been developed utilizing this technique, nonetheless, on the inception of this undertaking, none concerned chemistry occurring on the P atom immediately however somewhat generate the P stereocenter not directly (through manipulation of enantiotopic facet chains) inherently limiting their scope.

Determine 2. Classical and up to date approaches to the stereoselective synthesis of enantioenriched, stereogenic at P(V) compounds.

We envisioned a strategically distinct enantioselective desymmetrisation of P(V) species by enantioselective nucleophilic substitution of enantiotopic leaving teams. By even handed selection of leaving group, nucleophile, and catalyst we might receive the specified enantioenriched species in excessive yield and with glorious enantioselectivity (part 1). The desymmetrised substrate would then nonetheless possess one other leaving group, completely poised for a second (doubtlessly enantiospecific) nucleophilic substitution response enabling various downstream derivatisation alternatives (part 2). This two-phase technique would enable for a variety of P(V) compounds to be accessed from a standard intermediate, overcoming one of many primary limitations of present enantioselective desymmetrisation approaches (Determine 3).[vi]

Determine 3. This work: A conceptually totally different technique consisting of two separate phases (1) desymmetrisation and (2) derivatisation. Within the desymmetrisation part a ureidopeptide derived BIMP catalyst can impact an enantioselective nucleophilic discriminating between two similar leaving teams on readily accessible prochiral P(V) compounds. Within the derivatisation part the second leaving group may be changed enantiospecifically by quite a lot of N-, O– and S– based mostly nucleophiles offering entry to a variety of enantioenriched stereogenic at P(V) architectures from a small assortment of enantioenriched intermediates.

When utilizing ortho-substituted phenols as nucleophiles, a ureidopeptide[vii] derived bifunctional iminophosphophorane (BIMP)[viii] catalyst proved uniquely environment friendly at catalysing the enantioselective desymmetrisation. Equally key to the success of the desymmetrisation was the number of the leaving group: too electron poor and the catalyst couldn’t flip over, too electron wealthy and low conversion was noticed. To our delight, ortho-nitrophenols supplied the perfect steadiness of reactivity, enantioselectivity and phenolate basicity which might enable for the BIMP to re-enter the catalytic cycle. From a sensible standpoint, the nitrophenol derived phosphonate esters have been obtained by a one-pot sequence ranging from commercially out there or simply ready alkyl phosphonate esters, phosphonic acids or phosphoryl dichlorides. Moreover, they proved to be exceptionally secure to each air and moisture, might be simply purified by silica gel chromatography and might be saved on the benchtop for months with none precautions.

In a different way substituted ortho-phenols have been discovered to be competent nucleophiles within the desymmetrisation, together with these derived from the pure merchandise thymol and totarol. Equally, we discovered that variations of the R group on phosphorous have been readily accommodated, with (hetero)aryl, alkyl and β-heteroatom substituents resulting in the formation of the corresponding merchandise with excessive yield and enantioselectivity (Determine 4). Importantly, the desymmetrisation step might be carried out on gram scale, offering ample enantioenriched intermediate for the second part of the technique, derivatisation by a subsequent, enantiospecific nucleophilic substitution.

Determine 4. Choose scope for the desymmetrisation stage: ranging from air and moisture secure nitrophenol derived phosphonate esters (obtained by a one-pot synthesis from quite a lot of commercially out there or readily ready P(V) precursors) a spread of enantioenriched P(V) merchandise bearing (hetero)aryl and alkyl substituents have been synthesized, enabled by BIMP catalysis. The merchandise nonetheless possess a nitrophenol leaving group, poised for a second enantiospecific nucleophilic substitution.

Critically, the second nitrophenol leaving group might be simply displaced by a variety of biologically related main and secondary alcohol-based nucleophiles resembling these derived from DNA and RNA nucleosides, additionally enabling the synthesis of an analogue of the antiviral drug sofosbuvir.[ix] Thiols and amines is also used to displace the remaining nitrophenol enantiospecifically. In a associated transformation, a substrate bearing a benzylic alcohol might be employed to impact the displacement intramolecularly offering entry to an enantioenriched P(V) compound bearing the cycloSal prodrug motif.[x]

Determine 5. Choose scope for the derivatization stage: from a single enantioenriched intermediate, various excessive worth P(V) compound may be obtained with excessive enantiospecificity. Alternatively, nucleophilic displacement can happen intramolecularly affording compounds bearing the medicinally related cycloSal prodrug motif.

To achieve perception into the origin of enantioselectivity for the desymmetrisation step, DFT research have been carried out, led by Dr. Ken Yamazaki of Okayama College. The computational research revealed that addition of the phenol nucleophile to the P(V) electrophile is the rate- and enantio-determining step of the response with the formation of the pentacoordinate intermediate and elimination of the nitrophenol being energetically downhill. An in depth evaluation of the non-covalent interactions between the catalyst and substrate within the transition state resulting in the most important enantiomer revealed the important thing function of the ureidopeptide H-bond donor in interacting with the nitro group on one of many leaving teams by a further H-bond interplay which was absent in all different (much less enantioselective) BIMP catalysts assessed which possessed extra typical urea and thiourea derived scaffolds.

Determine 6. Computational research revealed a believable response pathway and elucidated the important thing non-bonding interactions between the ureidopeptide derived BIMP catalyst and the mannequin substrate accountable for the excessive ranges of enantioselectivity noticed within the desymmetrisation by nucleophilic substitution.

Now possessing an arsenal of ureidopeptide BIMP catalysts at our disposal and guided by in depth computational research we view this work as an open door to extra basic, environment friendly, and modular protocols for the synthesis of those precious P(V) containing moieties. Efforts to render the enantioselective desymmetrisation amenable to a wider vary of nucleophiles while producing much more versatile enantioenriched intermediates are nicely underway in our laboratories, we shall be delighted to share our thrilling findings within the coming months.


[i] Rodriguez, J. B. & Gallo-Rodriguez, C. The Position of the Phosphorus Atom in Drug Design. ChemMedChem 14, 190 –216 (2018).

[ii] Warren, T. Ok. et al. Therapeutic efficacy of the small molecule GS-5734 in opposition to Ebola virus in rhesus monkeys. Nature 531, 381–385 (2016).

[iii] Wang, Y. et al. Remdesivir in adults with extreme COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 395, 1569–1578 (2020).

[iv] OMS. World well being group mannequin checklist of important medicines. Ment. Holist. Heal. Some Int. Perspect. 119–134 (2019).

[v] Lemouzy, S., Giordano, L., Hérault, D. & Buono, G. Introducing Chirality at Phosphorus Atoms: An Replace on the Current Artificial Methods for the Preparation of Optically Pure P-Stereogenic Molecules. European J. Org. Chem. 2020, 3351–3366 (2020).

[vi] Following the disclosure of this work as a preprint (Formica, M. et. al. Catalytic Enantioselective Nucleophilic Desymmetrisation of Phosphonate Esters. ChemRxiv, 2022 doi: 10.26434/chemrxiv-2021-5714s-v2), and whereas this manuscript was below revision a sublime and complementary catalytic enantioselective nucleophilic desymmetrisation of phosphoryl dichlorides was disclosed by the Jacobsen group using anion binding catalysis: Forbes, Ok. C., Jacobsen, E. N. Enantioselective hydrogen-bond-donor catalysis to entry various stereogenic-at-P(V) compounds. Science, 376, 1230 (2022).

[vii] Diosdado, S. et al. Catalytic Enantioselective Synthesis of Tertiary Thiols From 5 H -Thiazol-4-ones and Nitroolefins: Bifunctional Ureidopeptide-Primarily based Brønsted Base Catalysis. Angew. Chemie Int. Ed. 52, 11846–11851 (2013).

[viii] Formica, M., Rozsar, D., Su, G., Farley, A. J. M. & Dixon, D. J. Bifunctional Iminophosphorane Superbase Catalysis: Functions in Natural Synthesis. Acc. Chem. Res. 53, 2235–2247 (2020).

[ix] Simmons, B., Liu, Z., Klapars, A., Bellomo, A. & Silverman, S. M. Mechanism-Primarily based Resolution to the ProTide Synthesis Drawback: Selective Entry to Sofosbuvir, Acelarin, and INX-08189. Org. Lett. 19, 2218–2221 (2017).

[x] Meier, C. cycloSal phosphates as chemical trojan horses for intracellular nucleotide and glycosylmonophosphate supply – Chemistry meets biology. Eur. J. Org. Chem. 1081–1102 (2006).

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