Review Specific Bifunctionalization on the Surface of Phosphorus Dendrimers Syntheses and Properties Massimo Petriccone 1,2,3 , Régis Laurent 2,3 , Cédric-Olivier Turrin 2,3,4 , Rosa Maria Sebastián 1 and Anne-Marie Caminade 2,3, * 1 Department of Chemistry, Science Faculty, Universitat Autònoma de Barcelona, Campus de Bellaterra, s/n, 08193 Cerdanyola del Vallès, Barcelona, Spain; massimo.petriccone@uab.cat (M.P.); rosamaria.sebastian@uab.cat (R.M.S.) 2 Laboratoire de Chimie de Coordination du CNRS, 205 Route de Narbonne, CEDEX 4, 31077 Toulouse, France; regis.laurent@lcc-toulouse.fr (R.L.); cedric-olivier.turrin@lcc-toulouse.fr (C.-O.T.) 3 LCC-CNRS, Université de Toulouse, CNRS, 31077 Toulouse, France 4 IMD-Pharma, 205 Route de Narbonne, CEDEX 4, 31077 Toulouse, France * Correspondence: anne-marie.caminade@lcc-toulouse.fr Abstract: Dendrimers are highly branched macromolecules possessing, in most cases, identical terminal functions. However, it is sometimes desirable to have two types of surface functions in order to fulfil specific properties. The stochastic functionalization is frequently used for such purposes, but the presence of an uncontrolled number of each type of terminal function, albeit acceptable for research purposes, has no practical use. Thus, it is highly desirable to find strategies suitable for the precise grafting of two different functional groups on the surface of dendrimers. The easiest way, and the most widely used, consists in using a bifunctional monomer to be grafted to all of the surface functions of the dendrimers. Two other strategies are known but are rarely used: the modification of an existing function, to generate two functions, and the sequential grafting of one function then of Citation: Petriccone, M.; Laurent, R.; Turrin, C.-O.; Sebastián, R.M.; a second function. The three methods are illustrated in this review with polyphosphorhydrazone Caminade, A.-M. Specific (PPH) dendrimers, together with their properties as catalysts, for materials, and as biological tools. Bifunctionalization on the Surface of Phosphorus Dendrimers Syntheses Keywords: dendrimer; phosphorus; bifunctionalization; polyphosphorhydrazone; properties and Properties. Organics 2022, 3, 240–261. https://doi.org/10.3390/ org3030018 1. Introduction Academic Editor: Tomasz K. Olszewski Dendrimers [1] are highly branched three-dimensional macromolecules, which proper- ties are essentially dependent on the type of their terminal functions. Numerous properties Received: 12 May 2022 have been explored already, most of them being related to catalysis, materials, or biol- Accepted: 21 July 2022 ogy/nanomedicine [2]. Dendrimers are synthesized by iterative processes, which afford Published: 3 August 2022 a new generation at the end of each sequence, characterized by a multiplication of the Publisher’s Note: MDPI stays neutral number of terminal functions, most generally by two [3] or three [4], depending on the with regard to jurisdictional claims in branching motives. Such processes generate identical terminal functions on the surface published maps and institutional affil- of the dendrimers, of course depending on the type of dendrimers, and on the synthetic iations. process used. Such terminal functions can be modified uniformly to bring new properties. However, it is desirable in some cases to have two types of terminal functions, each type of functions affording eventually its own properties (for instance, one function for the solubility, the other affording properties for catalysis or biology, or one type of function for Copyright: © 2022 by the authors. the grafting (for instance to materials), with the other functions bringing another property). Licensee MDPI, Basel, Switzerland. In most cases, the presence of two (or even more) functions on the surface of den- This article is an open access article drimers is carried out using a stochastic approach (i.e., an uncontrolled number and location distributed under the terms and conditions of the Creative Commons of each type of functions). However, this approach is contradictory with the aim of having Attribution (CC BY) license (https:// a perfectly controlled and reproducible structure for the dendrimers, contrarily to classi- creativecommons.org/licenses/by/ cal polymers. Even if efforts have been carried out to increase the purity of compounds 4.0/). issued from the stochastic approach [5], batch-to-batch inconsistencies are unavoidable, Organics 2022, 3, 240–261. https://doi.org/10.3390/org3030018 https://www.mdpi.com/journal/organics Organics 2022, 3, FOR PEER REVIEW 2 Organics 2022, 3 having a perfectly controlled and reproducible structure for the dendrimers, contrarily241 to classical polymers. Even if efforts have been carried out to increase the purity of com- pounds issued from the stochastic approach [5], batch-to-batch inconsistencies are una- voidable, and induce and induce in particular in particular undesirableundesirable varying activities varying biological biological[6]. activities To solve[6]. Totype this solve of this type of problem, it is highly desirable to synthesize dendrimers precisely bifunction- problem, it is highly desirable to synthesize dendrimers precisely bifunctionalized on their alized onFigure surface. their surface. Figure 1 displays 1 displaysbetween the difference the difference between both approaches. both approaches. Figure 1. Examples of batches of bifunctionalized bifunctionalized dendrimers. (A) Stochastic functionalization functionalization on the surface of dendrimers. (B) Precise bifunctionalization on the surface of dendrimers. The easiest The easiest way way to to get get dendrimers dendrimers specifically specifically bifunctionalized bifunctionalized on on their their surface surface con- con- sists in grafting on each terminal function a compound bearing sists in grafting on each terminal function a compound bearing already both desired func- already both desired functions tions (Scheme(Scheme 1A). 1A). SuchSuch a method a method has been has been appliedapplied to different to different typestypes of dendrimers of dendrimers and and functions. One can cite for instance as an early example the functions. One can cite for instance as an early example the presence of both a phenyl andpresence of both a phenyl aand a pyrene pyrene on theonsurface the surface of a series of a series of dendrimers of dendrimers built built on anon an arylether arylether scaffold, scaffold, and usedand used for studying charge-transfer processes from the core to the for studying charge-transfer processes from the core to the surface [7]. More recent exam- surface [7]. More recent examples ples concern concern PAMAM PAMAM (polyamidoamine) (polyamidoamine) dendrimers dendrimers functionalized functionalized with different with different ami- aminoacids, to have noacids, to have NH2 groups NH 2 groups together with either OH, SH, or other together with either OH, SH, or other functional groups,functional groups, and and tested for drug delivery [8]. Polyester dendrimers functionalized with both OH and tested for drug delivery [8]. Polyester dendrimers functionalized with both OH and azide, azide, used later on in click chemistry to afford biosensors [9], or functionalized with both used later on in click chemistry to afford biosensors [9], or functionalized with both azide azide and alkyne, as a multipurpose platform, in particular to afford implant adhesives in and alkyne, as a multipurpose platform, in particular to afford implant adhesives in bone bone fracture applications [10] are other more recent examples. Azide alkyne monomeric fracture applications [10] are other more recent examples. Azide alkyne monomeric com- compounds have been used for synthesizing by click chemistry multifunctional nanocarri- pounds have been used for synthesizing by click chemistry multifunctional nanocarriers ers bearing as terminal functions a model drug (R-lipoic acid), a fluorescent dye (BODIPY), bearing as terminal functions a model drug (R-lipoic acid), a fluorescent dye (BODIPY), and a poly(ethylene glycol) (PEG) chain [11]. Other recent examples of grafting directly and a poly(ethylene glycol) (PEG) chain [11]. Other recent examples of grafting directly two functions concern PPI (polypropyleneimine) dendrimers functionalized with both an two functions concern PPI (polypropyleneimine) dendrimers functionalized with both an electroactive carbazole and a mesogenic unit, all dendrimers of this family being liquid electroactive carbazole and a mesogenic unit, all dendrimers of this family being liquid crystalline [12], and also Newkome-type polyamide dendrimers, functionalized with both crystalline one azide and [12], two and also olefinsNewkome-type [13]. A seriespolyamide dendrimers, of bifunctional functionalized dendrimers has beenwith both obtained one fromazide either and two olefins [13]. A series a polyester-polyamide, of bifunctional dendrimers or polyester-lysine, has been obtained or polyamine-lysine from hybrid inter- either a polyester-polyamide, or polyester-lysine, or polyamine-lysine nal structure functionalized on the surface with orthogonally protected aspartic acid [14]. hybrid internal structure The selectivefunctionalized and sequential on the surface withoforthogonally deprotection the amine and protected of the aspartic carboxylicacid [14]. acid ofThe the selective protected aspartic acid was carried out to graft a long PEG (115 units in average), pro- and sequential deprotection of the amine and of the carboxylic acid of the and tected either aaspartic gadoliniumacid complex was carried out or [15,16] to diverse graft a long otherPEG (115 units lanthanide in average), complexes and (Dy, Yb either [17], Eu, aand gadolinium Sm [18]) for complex magnetic [15,16] or diverse resonance other(MRI), imaging lanthanide or two complexes synthetic(Dy, Yb [17], tubulysin Eu, and analogues Sm [18])C26 against forcolon magnetic resonance carcinomas [19]. imaging (MRI), or protected Lysine derivatives two synthetic by two tubulysin different analogues protecting against C26 colon carcinomas [19]. Lysine derivatives protected groups, were grafted on the surface of lysine dendrimers and dendrons. Selective by two differentdeprotec- protect- ing groups, were grafted on the surface of lysine dendrimers tion afforded dendrimers bearing both gadolinium complexes and PEG as MRI contrast and dendrons. Selective deprotection agents [20]. The afforded dendrimers same process bearingtoboth was applied gadolinium a series of dendronscomplexes havingand PEG as MRI a carboxylic acid contrast at the core agents [20]. aThe and both same process gadolinium complexwasand applied to a series galactosyl of dendrons moieties havingasa liver on the surface, car- boxylic targeting acid at the probes imaging core and both [21]. a gadolinium Another complexbearing lysine-dendron and galactosyl a long PEG moieties chainon at the the core (114 units in average) and both a porphyrin analogue and cholic acid, was used for near-infrared fluorescence imaging (NIRFI), magnetic resonance imaging (MRI), positron emission tomography (PET) and dual modal PET-MRI [22]. amines used for opening cyclic carbonates on the surface of polyester dendrimers [23]. The last method concerns the sequential grafting of one function, followed by the grafting of the second one, as illustrated in Scheme 1C. Such a type of reaction is rare, and has been used essentially with dendrimers having dichlorotriazine as terminal functions, reacted in sequential nucleophilic aromatic substitution with two different amines [24]. Organics 2022, 3 MRI (Magnetic Resonance Imaging) contrast agents have been obtained in this way, one 242 amine bearing a ligand suitable for complexing gadolinium, the other an alcohol [25]. Schematization of Scheme 1. Schematization of the the different different methods methods used used for for having having precisely precisely two two types types of of different different functions on the surface of dendrimers. (A)(A) grafting grafting on on each each terminal terminal function function aa compound compound bearing already both desired functions. (B) (B) modifying modifying one one function function already already on the surface, to generate two functions. functions. (C) (C) sequential sequential grafting grafting of of one one function, function, followed followed by by the the grafting grafting of of the second one. the second one. Besides the different Other methods to gettypes twooftypes dendrimers indicated of terminal above, functions another have beentype veryofrarely dendrimerused. is Oneknown for the can cite the versatility possibilityoftoits chemistry, modify namely phosphorus one function already on the dendrimers, surface, to and partic- generate two functions ularly (Scheme 1B). Such(PPH) polyphosphorhydrazone type of reaction haswhich dendrimers, been illustrated with functionalized possess a phosphorus atom at amines each used forpoint branching opening [26].cyclic Theycarbonates on the are generally surface built from of polyester either P(S)Cldendrimers [23]. 3 or hexachlorocy- The last method clotriphosphazene concerns as core the sequential [27]. Their structure isgrafting of one illustrated function, in Figure followed 2 with the first byand the grafting of the second one, as illustrated in Scheme 1C. Such a type second generations. Both generations are displayed as the full chemical structure, but alsoof reaction is rare, and hasa been in linearused form essentially with dendrimers with parentheses after each having layer dichlorotriazine of branching points. as terminal functions, The presence of reacted either in sequential P(S)Cl 2 or aldehyde nucleophilic terminal aromatic functions,substitution depending on withthetwo stepdifferent considered, amines [24]. enables aMRI (Magnetic versatile Resonance reactivity to fulfilImaging) contrast the desired agents have properties. In thisbeen obtained review, we willin this way, one display the amine bearing different methods a ligand used suitable for complexing gadolinium, for the bifunctionalization of phosphorus the other an alcohol dendrimers, [25]. out carried usingBesides themethods the three differentshown types of indendrimers indicated Scheme 1. Besides theabove, another synthesis, type of dendrimer the particular proper- ties of such specifically bifunctionalized dendrimers in different fields such asand is known for the versatility of its chemistry, namely phosphorus dendrimers, partic- catalysis, ularly polyphosphorhydrazone (PPH) materials, and biology will be also emphasized. dendrimers, which possess a phosphorus atom at eachAs branching point [26]. They are generally built from either P(S)Cl for other types of dendrimers, the stochastic grafting of two 3different terminal or hexachlorocy- clotriphosphazene functions was carried as core out in[27]. Their a few structure cases on PPH is dendrimers. illustrated inOne Figure can2citewiththe thestochastic first and second generations. Both generations are displayed as the full grafting of a julolidine fluorophore to mannose-capped dendrimers, able to prevent chemical structure, butacute also in a linear form with parentheses after each layer of branching points. lung inflammation in vivo [28], or of fluorescein isocyanate grafted to a dendrimer bearing The presence of azabisphosphonate terminal functions, able to positively influence the human immunea either P(S)Cl 2 or aldehyde terminal functions, depending on the step considered, enables versatile[29]. system reactivity to fulfil was Such method the desired also usedproperties. In this for grafting review, different we will ratios displaycomplexes of copper the differ- ent methods used for the bifunctionalization of phosphorus dendrimers, [30], gold complexes and polyethylene glycol as terminal functions of PPH dendrimers carried out using the three methods shown in Scheme 1. Besides the synthesis, the particular properties of such specifically bifunctionalized dendrimers in different fields such as catalysis, materials, and biology will be also emphasized. As for other types of dendrimers, the stochastic grafting of two different terminal functions was carried out in a few cases on PPH dendrimers. One can cite the stochas- tic grafting of a julolidine fluorophore to mannose-capped dendrimers, able to prevent acute lung inflammation in vivo [28], or of fluorescein isocyanate grafted to a dendrimer bearing azabisphosphonate terminal functions, able to positively influence the human immune system [29]. Such method was also used for grafting different ratios of copper complexes [30], gold complexes and polyethylene glycol as terminal functions of PPH dendrimers having anti-cancer properties [31], bearing eventually fluorophores inside the structure to decipher the biological mechanism of action [32]. However, the precise number of terminal functions is an important criterium, in particular for biological purposes. Organics 2022, 3, FOR PEER REVIEW 4 having anti-cancer properties [31], bearing eventually fluorophores inside the structure to decipher the biological mechanism of action [32]. However, the precise number of termi- having anti-cancer properties [31], bearing eventually fluorophores inside the structure to Organics 2022, 3 nal functions is an important criterium, in particular for biological purposes. 243 decipher the biological mechanism of action [32]. However, the precise number of termi- nal functions is an important criterium, in particular for biological purposes. Figure 2. Two ways for drawing the 1st and 2nd generations of polyphosphorhydrazone den- drimers: full chemical structure, and linear structure with parenthesis after each layer of branching Figure 2. Two Figure 2. ways for Two ways for drawing drawingthe the1st 1stand and2nd 2ndgenerations generationsofofpolyphosphorhydrazone polyphosphorhydrazone den- dendrimers: points. drimers: full chemical structure, and linear structure with parenthesis after each layer of branching full chemical structure, and linear structure with parenthesis after each layer of branching points. points. 2. Bifunctional Monomers Grafted to the Surface of PPH Dendrimers 2. Bifunctional Monomers Grafted to the Surface of PPH Dendrimers As for the other 2. Bifunctional types of Monomers dendrimers, Grafted the grafting to the Surface of a bifunctional monomer on the of PPH As for the other types of dendrimers, the grafting of aDendrimers bifunctional monomer on the surface of polyphosphorhydrazone dendrimers is easy to carry out (way A in Scheme 1). surface As of forpolyphosphorhydrazone dendrimers the other types of dendrimers, is easyof the grafting toacarry out (waymonomer bifunctional A in Scheme 1). on the The first The first attempts concerned concerned only only fundamental fundamental researches. For instance, the Horner- surface ofattempts polyphosphorhydrazone dendrimers is researches. easy to carryFor out instance, (way A inthe Horner- Scheme 1). Wadsworth-Emmons reaction Wadsworth-Emmons reaction was applied applied to to aldehyde aldehyde terminal terminal functions functions for for the grafting The first attempts concerned was only fundamental researches. For the Horner- instance, the grafting of of diverse diverse amino amino acids, acids, up up to to generation generation 4 4 (Scheme (Scheme 2) 2) [33]. [33]. Wadsworth-Emmons reaction was applied to aldehyde terminal functions for the grafting of diverse amino acids, up to generation 4 (Scheme 2) [33]. Scheme Scheme 2.2. Generation Generation44PPH PPHdendrimer dendrimer functionalized functionalized withwith aminoamino acidacid terminal terminal functions, functions, ob- obtained tained by by Horner-Wadsworth-Emmons Horner-Wadsworth-Emmons reactions reactions on on aldehyde aldehyde terminalterminal groups. groups. Scheme 2. Generation 4 PPH dendrimer functionalized with amino acid terminal functions, ob- tained by Horner-Wadsworth-Emmons reactions on aldehyde terminal groups. However, the use of bifunctional units was essentially applied in the fields of catalysis and biology. In the case of catalysis, many examples of phosphine complexes as terminal functions of dendrimers are known [34]. In a first example of PPH dendrimers, the ter- minal phosphines were used to complex gold, to facilitate imaging of single molecules with high-resolution transmission electron microscopy (HRTEM) [35]. Later on, dendritic complexes were used as catalysts for instance in Stille couplings [36], to dramatically However, the use of bifunctional units was essentially applied in the fields of cataly- sis and biology. In the case of catalysis, many examples of phosphine complexes as termi- nal functions of dendrimers are known [34]. In a first example of PPH dendrimers, the terminal phosphines were used to complex gold, to facilitate imaging of single molecules Organics 2022, 3 244 with high-resolution transmission electron microscopy (HRTEM) [35]. Later on, dendritic complexes were used as catalysts for instance in Stille couplings [36], to dramatically de- crease palladium leaching in Suzuki couplings [37], to increase enantioselectivity in Rho- decrease palladium dium-catalyzed leaching [2+2+2] in Suzuki[38], cycloadditions couplings [37], to increase to be efficiently recycledenantioselectivity using a magnet in in Rhodium-catalyzed [2+2+2] cycloadditions [38], to be efficiently Pd-catalyzed couplings [39], and to switch on and off the catalytic efficiency recycled using a through magnet in a Pd-catalyzed redox controlcouplings [40]. In all[39], and cases of to switch on catalysis, theand off the of efficiency catalytic efficiency different through generations a re- is com- dox paredcontrol using[40]. In all number the same cases of catalysis, of catalyticthesites efficiency of instance (i.e., for different the generations efficiencyisof compared 4 equiv. using of the 1st generation is compared with that of 1 equiv. of the 3rd generation). An of the same number of catalytic sites (i.e., for instance the efficiency of 4 equiv. the 1st example generation is compared with that of 1 equiv. of the 3rd generation). of catalysis with bifunctionalized monomeric phosphines concerned a 3rd generation An example of cataly- den- sis with bifunctionalized monomeric phosphines concerned a 3rd generation dendrimer drimer decorated with chiral iminophosphines derived from (2S)-2-amino-1-(diphe- decorated with chiral iminophosphines derived from (2S)-2-amino-1-(diphenylphosphinyl)- nylphosphinyl)-3-methylbutane, obtained by condensation reactions on the aldehydes 3-methylbutane, obtained by condensation reactions on the aldehydes (Scheme 3). The (Scheme 3). The Pd complex of this dendrimer was used as catalysts in asymmetric allylic Pd complex of this dendrimer was used as catalysts in asymmetric allylic alkylation of alkylation of rac-(E)-diphenyl-2-propenyl acetate or pivalate, using N,O-bis(trimethylsi- rac-(E)-diphenyl-2-propenyl acetate or pivalate, using N,O-bis(trimethylsilyl)acetamide lyl)acetamide (BSA) as base and either LiOAc or KOAc as co-catalyst to produce the nu- (BSA) as base and either LiOAc or KOAc as co-catalyst to produce the nucleophile from cleophile from dimethylmalonate, and to afford 2-(1,3-diphenylallyl)-malonic acid di- dimethylmalonate, and to afford 2-(1,3-diphenylallyl)-malonic acid dimethylester. Conver- methylester. Conversions were almost quantitative in all cases, with isolated yields up to sions were almost quantitative in all cases, with isolated yields up to 97% in the best cases, 97% in the best cases, and ee (enantiomeric excess) up to 94–95%. Contrarily to the mono- and ee (enantiomeric excess) up to 94–95%. Contrarily to the monomeric catalysts, this meric catalysts, this dendritic catalyst could be recovered and reused with the same effi- dendritic catalyst could be recovered and reused with the same efficiency at least 3 times ciency at least 3 times (Figure 3) [41]. (Figure 3) [41]. cs 2022, 3, FOR PEER REVIEW 6 3. Synthesis Scheme 3. Synthesisofofthe the3rd 3rdgeneration generationof of a PPH a PPH dendrimer dendrimer decorated decorated withwith chiral chiral iminophos- iminophosphine phine end end groups. groups. The PdThe Pd complex complex wasasused was used as catalysts catalysts in asymmetric in asymmetric allylic allylic alkylation. alkylation. Figure 3. AllylicFigure alkylation catalyzed 3. Allylic by the alkylation Pd complex catalyzed of the by the G3 dendrimer Pd complex of theshown in Scheme G3 dendrimer 3. in Scheme 3. shown Another example of bifunctional monophosphine concerns a thiazolyldiphe- nylphosphine grafted on the surface of generations 1 and 3 of PPH dendrimers (Scheme 4A). These dendrimers were able to complex palladium, and were used as catalysts in Suzuki couplings (Figure 4A). It was possible to recover and reuse even the first genera- Figure Figure 3. 3. Allylic Allylic alkylation alkylation catalyzed catalyzed by by the the Pd Pd complex complex of of the the G G33 dendrimer dendrimer shown shown in in Scheme Scheme 3. 3. Organics 2022, 3 245 Another example of bifunctional monophosphine concerns a thiazolyldiphe- nylphosphine grafted on the surface of generations 1 and 3 of PPH dendrimers (Scheme 4A). Another example ofwere These dendrimers bifunctional monophosphine able to complex palladium, concerns a thiazolyldiphenylphos- and were used as catalysts in phine grafted Suzuki couplingson the surface (Figure of generations 4A). 1 and It was possible to 3recover of PPHand dendrimers reuse even(Scheme 4A). the first These genera- dendrimers tion at least were able towith four times complex the samepalladium, and contrarily efficiency, were usedtoasacatalysts dendrimer in Suzuki havingcou-tri- plings (Figure 4A).asItterminal phenylphosphine was possible to recover functions. and reusepalladium Interestingly, even the first generation leaching could at least not be four times with the same efficiency, contrarily to a dendrimer having detected with the dendrimer bearing the thiazolyldiphenylphosphines, whereas it was triphenylphosphine as terminal found to befunctions. Interestingly, 173 (±3) ppm with thepalladium dendrimerleaching bearingcould not be detected with[37]. the triphenylphosphine the den- Re- drimer bearing cently, a seriestheof thiazolyldiphenylphosphines, dendrimers (generations 1 and whereas it was found to 2) functionalized be 173 with (±3)ferro- chiral ppm with the dendrimer cenylphosphines wasbearing the triphenylphosphine synthesized (Scheme 4B). These [37]. Recently, were dendrimers a series of dendrimers used as catalysts (generations in 1 and 2) functionalized the ruthenium-catalyzed with chiral redox-switchable ferrocenylphosphines transfer hydrogenation of awas synthesized ketone, yielding (Scheme 4B). These dendrimers were used as catalysts in the ruthenium-catalyzed a slighlty enantioenriched alc ohol (Figure 4B). It has been shown previously that, thanks redox- to the presence of the ferrocene, adding a chemical oxidant or reductant, modifiedohol switchable transfer hydrogenation of a ketone, yielding a slighlty enantioenriched alc the (Figure 4B). catalytic It has activity of been shown previously the complexes, which was that, thanks to reversibly the presence switched of back off, and the ferrocene, on again adding [40]. Theasame chemical oxidant or phenomenon reductant, was observedmodified with thethe catalytic chiral activity of the complexes, ferrocenylphosphines shown in Scheme 4B. The first generation was more active than the second, but practically no was which was reversibly switched off, and back on again [40]. The same phenomenon dif- observed ference in with the was activity chiral ferrocenylphosphines observed depending on the showntypeinofScheme 4B. The substituents onfirst generation the phosphine was more active than the second, but practically no difference in activity was observed [42]. depending on the type of substituents on the phosphine [42]. Scheme Scheme 4. 4. Synthesis Synthesis of of dendrimers dendrimers functionalized functionalized with with thiazolyldiphenylphosphine thiazolyldiphenylphosphine for for which which the the Pd Pd complex was used in Suzuki couplings (A) and chiral ferrocenylphosphines for which the Ru Pd complex complex was was used used in in Suzuki Suzuki couplings couplings (A) (A) and and chiral chiral ferrocenylphosphines ferrocenylphosphines for for which which the the Ru Ru complexes complexes were were used used in in switchable switchable transfer transfer hydrogenations hydrogenations (B). (B). complexes were used in switchable transfer hydrogenations (B). Figure Figure 4. 4. (A) Suzuki coupling (A) Suzuki Suzuki coupling catalyzed coupling catalyzed by catalyzed by Pd by Pd complexes Pd complexes of complexes of the of the dendrimers the dendrimers shown dendrimers shown in shown in Scheme in Scheme4A. Scheme 4A. 4A. (B) Transfer hydrogenation hydrogenation catalyzed catalyzed by by Ru Ru complexes complexes of of the the dendrimers dendrimers shown shown in in Scheme Scheme (B) Transfer hydrogenation catalyzed by Ru complexes of the dendrimers shown in Scheme 4B. 4B. 4B. Besides monophosphines, symmetrical diphosphine derivatives grafted on the surface of phosphorhydrazone dendrimers have been proposed for the complexation of palladium, platinum, rhodium [43], and ruthenium [44]. The Pd complexes were used as catalysts in Stille couplings, whereas the Ru complexes were used as catalysts in Knoevenagel condensations and diastereoselective Michael additions [45]. There is also an example of a diphosphine bearing a chiral substituent based on L-tyrosine methyl ester, as shown in Scheme 5 for the first and third generations of the polyphosphorhydrazone dendrimers. The catalytic properties of this series of dendrimers complexing palladium were compared face of phosphorhydrazone dendrimers have been proposed for the complexation of pal- ladium, platinum, rhodium [43], and ruthenium [44]. The Pd complexes were used as cat- alysts in Stille couplings, whereas the Ru complexes were used as catalysts in Knoevenagel condensations and diastereoselective Michael additions [45]. There is also Organics 2022, 3 an example of a diphosphine bearing a chiral substituent based on L-tyrosine methyl ester, 246 as shown in Scheme 5 for the first and third generations of the polyphosphorhydrazone dendrimers. The catalytic properties of this series of dendrimers complexing palladium were compared with that of the corresponding diphosphine dendritic ligands not bearing with that of the corresponding diphosphine dendritic ligands not bearing the L-tyrosine the L-tyrosine derivative, but derived from tyramine. Both families of dendrimers were derivative, but derived from tyramine. Both families of dendrimers were studied in C-C studied in C-C cross-coupling reactions, namely, Suzuki, Sonogashira, and Heck reac- cross-coupling reactions, namely, Suzuki, Sonogashira, and Heck reactions, all of them tions, all of them being carried out in the presence of water (Figure 5). In all cases, the being carried out in the presence of water (Figure 5). In all cases, the series built from series built from L-tyrosine is less efficient than the series built without it, showing the L-tyrosine is less efficient than the series built without it, showing the negative influence of negative influence of the local hindrance on the catalytic efficiency. However, in all cases, the local hindrance on the catalytic efficiency. However, in all cases, the dendritic catalysts the dendritic catalysts are more efficient than the corresponding monomeric complexes, are more efficient than the corresponding monomeric complexes, of course considering the of course considering the same number of catalytic entities in all experiments. Indeed, the same number of catalytic entities in all experiments. Indeed, the efficiency of 12 equivalents efficiency of monomericof 12 equivalents catalyst of monomeric is compared with thatcatalyst is compared of 1 equivalent of the with that of 1 equivalent 1st generation dendrimer, of the 1st generation dendrimer, which bears 12 catalytic which bears 12 catalytic entities in a single molecule [46]. entities in a single molecule [46]. Scheme 5. Synthesis Synthesisofofthe the1st 1stgeneration generationofofPPH PPHdendrimer dendrimer bearing diphosphine bearing diphosphine derivatives of L- derivatives of tyrosine methyl ester as terminal functions, and linear representation of the corresponding L-tyrosine methyl ester as terminal functions, and linear representation of the corresponding third third generation. The generation. The palladium complexes were palladium complexes were used used asas catalysts catalysts in in C-C C-C cross-coupling cross-coupling reactions. reactions. Organics 2022, 33, FOR PEER REVIEW Organics 2022, 8 247 Figure 5. Figure Catalytic reactions 5. Catalytic reactions carried carried out out with with Pd Pd complexes complexes of of the the dendrimers dendrimers shown shownin inScheme Scheme5.5. (A) Suzuki coupling; (B) Sonogashira coupling; (C,D) Heck couplings. Even if Even if the theuseuseofofdendrimers dendrimerscan canenable enablea large decrease a large decreaseof metal leaching of metal as indicated leaching as indi- above [37], organocatalysis has been recognized as an interesting alternative cated above [37], organocatalysis has been recognized as an interesting alternative to avoid metals, to including in the field of dendrimeric catalysts [47]. For instance, polyphosphorhydrazone avoid metals, including in the field of dendrimeric catalysts [47]. For instance, polyphos- dendrimers of first- phorhydrazone and fourth-generations dendrimers were decorated with of first- and fourth-generations were(+)-cinchonine decorated withmoieties, (+)-cin- and used as efficient organocatalysts in the α-amination of chonine moieties, and used as efficient organocatalysts in the α-amination several types ofof β-dicarbonyl several types compounds. of β-dicarbonyl It compounds. was possibleIttowas recover andtoreuse possible the and recover dendritic organocatalyst reuse the 10 times dendritic organocat- without alyst loss of 10 times activity without [48]. loss Another of activity example [48]. Another concerned a bifunctional example concerned derivativede- a bifunctional of (+)-cinchonine. In that case, the dendrimer of the first generation had rivative of (+)-cinchonine. In that case, the dendrimer of the first generation had to be to be modified in three steps from the aldehyde terminal functions, to obtain iodine surface modified in three steps from the aldehyde terminal functions, to obtain iodine surface functions. This dendrimer was found suitable for the quaternization of the quinuclidinic N atom of several functions. This dendrimer was found suitable for the quaternization of the quinuclidinic types of (+)-cinchonine (variation of the OR group, see Scheme 6). These compounds N atom of several types of (+)-cinchonine (variation of the OR group, see Scheme 6). These were used as organocatalysts in the asymmetric alkylation of a glycinate Schiff base with compounds were used as organocatalysts in the asymmetric alkylation of a glycinate different types of bromides, in particular benzyl bromide derivatives (Figure 6). The case Schiff base with different types of bromides, in particular benzyl bromide derivatives (Fig- where R is an allyl group was found the most efficient. Recovery and reuse of the catalysts ure 6). The case where R is an allyl group was found the most efficient. Recovery and was carried out five times without a loss of efficiency and with only a minor decrease in reuse of the catalysts was carried out five times without a loss of efficiency and with only enantioselectivity [49]. a minor decrease in enantioselectivity [49]. The grafting of 15-membered tri-olefinic triazamacrocycles on PPH dendrimers was carried out in different ways, one of them consisting in the grafting of a diamine on the P(S)Cl2 terminal functions from generations 1 to 4. This reaction creates a five-membered non-symmetrical heterocycle on each terminal function (Scheme 7), suitable for complex- ing Pt2 (dba)3 . Instead of discrete complexes, platinum nanoparticles were generated in very mild conditions [50], which organized as unprecedented branched supramolecular assemblies of dendrimers and coalesced Pt nanoparticles. Both the size and the degree of branching vary with the generation of the dendrimer, with the G4 dendrimer producing longer networks than smaller dendrimers [51]. These 15-membered macrocycles were also condensed onto the aldehyde terminal functions of dendrimers, followed by reduction of the imine, and affording palladium complexes or palladium nanoparticles, suitable for catalyzing Heck reactions [52]. Analogous compounds bearing long alkyl chains on the aryl groups of the sulfonamides displayed columnar liquid crystal properties [53]. Besides these examples as catalysts, all of the other bifunctional PPH dendrimers synthesized by grafting Figure 6. Asymmetric bifunctional alkylation derivatives of a glycinate werewith Schiff base synthesized for biological different types purposes. of bromides, in par- A series of dendrimers having labile hydrogen atoms (carboxylic acid or ticular benzylbromide derivatives, organocatalyzed with the dendrimer functionalized with (+)-cin-phosphonic acid terminal chonine, as shownfunctions) in Scheme were 6. used for electrostatic interactions with galactosylceramide analogs, potentially suitable against HIV [54]. Within this series, several compounds having a pendant alkyl chain were synthesized, especially in the case of phosphonic acids as terminal groups (Scheme 8). They were synthesized by grafting the bifunctional phenols based on tyramine onto the P(S)Cl2 terminal functions. These compounds alone were Organics 2022, 3, FOR PEER REVIEW 8 Organics 2022, 3 248 found non-toxic, but displayed interesting anti-HIV properties in vitro in the 10−5 –10−6 M range [55]. The galactosyl ceramide analogues were associated with all of these dendrimers in a second step, and were found efficient, but also toxic, inducing a low safety index [56]. Investigations about the stability of the self-associations demonstrated a partial segregation Organics 2022, 3, FOR PEER REVIEWof the different partners, which could explain the cytotoxicity [57]. The use of a fluorescent9 analog of galactosylceramide, having a coumarine derivative in replacement of the alkyl chain, confirmed the ion pair disassembly hypothesis [58]. Figure 5. Catalytic reactions carried out with Pd complexes of the dendrimers shown in Scheme 5. (A) Suzuki coupling; (B) Sonogashira coupling; (C,D) Heck couplings. Even if the use of dendrimers can enable a large decrease of metal leaching as indi- cated above [37], organocatalysis has been recognized as an interesting alternative to avoid metals, including in the field of dendrimeric catalysts [47]. For instance, polyphos- phorhydrazone dendrimers of first- and fourth-generations were decorated with (+)-cin- chonine moieties, and used as efficient organocatalysts in the α-amination of several types of β-dicarbonyl compounds. It was possible to recover and reuse the dendritic organocat- alyst 10 times without loss of activity [48]. Another example concerned a bifunctional de- rivative of (+)-cinchonine. In that case, the dendrimer of the first generation had to be modified in three steps from the aldehyde terminal functions, to obtain iodine surface functions. This dendrimer was found suitable for the quaternization of the quinuclidinic N atom of several types of (+)-cinchonine (variation of the OR group, see Scheme 6). These compounds were used as organocatalysts in the asymmetric alkylation of a glycinate Schiff base with different types of bromides, in particular benzyl bromide derivatives (Fig- ure 6). The case where R is an allyl group was found the most efficient. Recovery and reuse Scheme Scheme of6. 6.the catalysts was Modification Modification ofthe of carried the surfaceout surface ofofa afive times without firstgeneration first generation PPH PPH a dendrimer loss of efficiency dendrimer forfor and thewith enabling enabling the only alkyla- alkylation tion a of minor the quinuclidinic decrease in N atom of several enantioselectivity types [49]. of (+)-cinchonine, used as organocatalysts. of the quinuclidinic N atom of several types of (+)-cinchonine, used as organocatalysts. The grafting of 15-membered tri-olefinic triazamacrocycles on PPH dendrimers was carried out in different ways, one of them consisting in the grafting of a diamine on the P(S)Cl2 terminal functions from generations 1 to 4. This reaction creates a five-membered non-symmetrical heterocycle on each terminal function (Scheme 7), suitable for complex- ing Pt2(dba)3. Instead of discrete complexes, platinum nanoparticles were generated in very mild conditions [50], which organized as unprecedented branched supramolecular assemblies of dendrimers and coalesced Pt nanoparticles. Both the size and the degree of branching vary with the generation of the dendrimer, with the G4 dendrimer producing longer networks than smaller dendrimers [51]. These 15-membered macrocycles were also condensed onto the aldehyde terminal functions of dendrimers, followed by reduction of the imine, and affording palladium complexes or palladium nanoparticles, suitable for catalyzing Heck reactions [52]. Analogous compounds bearing long alkyl chains on the aryl groups of the sulfonamides displayed columnar liquid crystal properties [53]. Asymmetricalkylation Figure 6. Asymmetric alkylationofof a glycinate a glycinate Schiff Schiff base base with with different different types types of bromides, of bromides, in in par- ticular benzylbromide particular benzylbromidederivatives, organocatalyzed derivatives, with the organocatalyzed dendrimer with functionalized the dendrimer with (+)-cin- functionalized with chonine, as shown (+)-cinchonine, in Scheme as shown 6. in Scheme 6. assemblies of dendrimers and coalesced Pt nanoparticles. Both the size and the degree of branching vary with the generation of the dendrimer, with the G4 dendrimer producing longer networks than smaller dendrimers [51]. These 15-membered macrocycles were also condensed onto the aldehyde terminal functions of dendrimers, followed by reduction of Organics 2022, 3, FOR PEER REVIEW 10 the imine, and affording palladium complexes or palladium nanoparticles, suitable for Organics 2022, 3 249 catalyzing Heck reactions [52]. Analogous compounds bearing long alkyl chains on the aryl groups of the sulfonamides displayed columnar liquid crystal properties [53]. Besides these examples as catalysts, all of the other bifunctional PPH dendrimers synthesized by grafting bifunctional derivatives were synthesized for biological purposes. A series of dendrimers having labile hydrogen atoms (carboxylic acid or phosphonic acid terminal functions) were used for electrostatic interactions with galactosylceramide ana- logs, potentially suitable against HIV [54]. Within this series, several compounds having a pendant alkyl chain were synthesized, especially in the case of phosphonic acids as ter- minal groups (Scheme 8). They were synthesized by grafting the bifunctional phenols based on tyramine onto the P(S)Cl2 terminal functions. These compounds alone were found non-toxic, but displayed interesting anti-HIV properties in vitro in the 10−5–10−6 M range [55]. The galactosyl ceramide analogues were associated with all of these den- drimers in a second step, and were found efficient, but also toxic, inducing a low safety index [56]. Investigations about the stability of the self-associations demonstrated a partial segregation of the different partners, which could explain the cytotoxicity [57]. The use of aScheme fluorescent Scheme 7. analog 7. Grafting Grafting ofof of galactosylceramide, 15-membered 15-membered having macrocycles, macrocycles, a coumarine suitable suitable derivative for creating for creating branchedin branched replacement supramolecular supramolecular of the alkyl assemblies chain, of Pt confirmed nanoparticles. assemblies of Pt nanoparticles. the ion pair disassembly hypothesis [58]. Scheme 8. Synthesis of phosphonate dendrimers dendrimers bearing bearing a pendant alkyl chain and a phosphonic acid, and their association with a derivative of galactosylceramide, having anti-HIV anti-HIV properties. properties. Other types Other types ofof phosphonate terminal functions phosphonate terminal functions were were obtained obtained by by synthesizing synthesizing the the appropriate phenol appropriate phenol derivatives. derivatives. (D-L) (D-L) tyrosine tyrosine was was first first reacted reacted with with formaldehyde formaldehyde and and dimethylphosphite, then the carboxylic acid was protected with a dimethylphosphite, then the carboxylic acid was protected with a methyl group, to be methyl group, to be suitable to react with the P(S)Cl surface functions of dendrimers, mostly suitable to react with the P(S)Cl2 surface functions of dendrimers, mostly of first genera- 2 of first genera- tion (Scheme tion (Scheme 9A).9A). These These dendrimers dendrimers bearing bearing azabisphosphonate azabisphosphonate terminal terminal functions functions were were then tested among others to activate human monocytes through then tested among others to activate human monocytes through an anti-inflammatory an anti-inflammatory pathway [29,59], pathway [29,59], but but also also to to multiply multiplynatural naturalkiller killer(NK) (NK)cells, cells,which whichplay playininparticular particulara a key role against cancers [60]. These first properties then led to cure inflammation key role against cancers [60]. These first properties then led to cure inflammation in mice in mice models models of rheumatoid of rheumatoid arthritis arthritis [61], [61], of of multiple multiple sclerosis sclerosis [62], [62], of of Uveitis Uveitis [63],of [63], and and of pso- psoriasis [64]. In view of all of these biological properties, a large study to decipher riasis [64]. In view of all of these biological properties, a large study to decipher the struc- the structure/activity relationship has been carried out [65]. The synthesis of non-symmetrical ture/activity relationship has been carried out [65]. The synthesis of non-symmetrical azabisphosphonate terminal functions was carried out for this purpose. It started from azabisphosphonate terminal functions was carried out for this purpose. It started from 4- 4-hydroxybenzaldehyde, to which diverse primary amines were condensed in the first hydroxybenzaldehyde, to which diverse primary amines were condensed in the first step. step. Addition of dimethylphosphite induced the grafting of one phosphonate. A reaction Addition of dimethylphosphite induced the grafting of one phosphonate. A reaction with with formaldehyde and dimethylphosphite induced the grafting of the second phospho- formaldehyde and dimethylphosphite induced the grafting of the second phosphonate, nate, affording a series of non-symmetric azabisphosphonate monomers (Scheme 9B), also grafted to the 1st generation dendrimer. The primary amines used were, for the first time, Organics 2022, 3, FOR PEER REVIEW 11 Organics 2022, 3, FOR PEER REVIEW 11 Organics 2022, 3 affording a series of non-symmetric azabisphosphonate monomers (Scheme 9B), also 250 affording a series of non-symmetric azabisphosphonate monomers (Scheme grafted to the 1st generation dendrimer. The primary amines used were, for the first time, 9B), also grafted to the and methylamine 1st generation dendrimer. benzylamine Theallyl, [29,60], then primary amines butyl, usedamines and decyl were, for theAll [66]. first time, of these methylamine compounds were and benzylamine [29,60], tested, but they then were allyl, butyl, and decyl amines [66]. All of these methylamine and benzylamine [29,60], thenfound allyl, less butyl,efficient and decylthan the symmetrical amines [66]. All of compounds were tested, azabisphosphonate butforthey functions the were found less activation anti-inflammatory efficient than of the symmetrical monocytes. these compounds were tested, but they were found less efficient than the symmetrical azabisphosphonate functions for the anti-inflammatory activation of monocytes. azabisphosphonate functions for the anti-inflammatory activation of monocytes. Scheme 9. Synthesis of bifunctional phenols from tyrosine (way A) and from 4-hydroxybenzalde- Scheme hyde Scheme 9. Synthesis (way 9. Synthesis ofbifunctional of bifunctional B), and structure phenols of 1st phenols generationfrom from tyrosine oftyrosine PPH (way A) A) dendrimers (way and from modified and from 4-hydroxybenzalde- with them. The anti- 4-hydroxybenzaldehyde hyde (way inflammatory (way B), and structure B), and properties of structure of these 1st generation dendrimers 1st generation of ofwere PPH PPHthen dendrimers modified with them. The tested. modified with them. dendrimers The anti- anti- inflammatory properties of these dendrimers were then tested. inflammatory properties of these dendrimers were then tested. 3. Modification of a Function Already on the Surface of PPH Dendrimers 3. Modification Modification of of aa Function Function Already Already on on the the Surface Surface of of PPH PPH Dendrimers Dendrimers The generation of secondary amines induced by the grafting of functional groups on The generation the surface of secondary of PPH dendrimers amines was induced the only way by the grafting to obtain of functionaldendrimers bifunctionalized groups on the surface surface of of PPH PPH dendrimers dendrimers was was the the only only waywayto to obtain obtain bifunctionalized bifunctionalized by a second modification after a first modification (related to way B of Scheme 1). In a first dendrimers dendrimers by a bysecond a secondmodification modification after a after first a modification first modification (related (related totoway way example, the reaction of Ph2PCH2OH, obtained from the reaction of diphenylphosphineB Bof ofScheme Scheme 1). 1). In In a a first example, the reaction of with paraformaldehyde Ph Ph22PCH22on ofoccurred OH, OH, obtained obtained one among two fromallylamines the reaction of diphenylphosphine diphenylphosphine previously grafted to the with paraformaldehyde paraformaldehyde occurred occurred on on one one among among twotwo allylamines allylamines P(S)Cl2 terminal functions of the dendrimers (Scheme 10). Such specific reaction previously previously grafted graftedwas to tocar- the the P(S)Cl P(S)Cl terminal 2 terminal 2 functions functions of the of the dendrimers dendrimers (Scheme (Scheme 10). Such10). Such specific ried out from generation 1 to generation 7 of the PPH dendrimers built from a trifunctional specific reaction reaction was car- was carried ried out out from generation 1 to generation 7 of the PPH dendrimers built from a core, andfrom from generation generation 1 to 1 generation to generation 7 of4the PPH of the dendrimers PPH dendrimersbuiltbuilt fromfrom a trifunctional the hexa- trifunctional core, and fromcore, and from1generation generation to 1 to 4generation generation of the PPH 4 of the PPH dendrimers dendrimers built from built from the hexa- functional N3P3 core. The phosphines were used for the complexation of either Fe(CO) 4 or the hexafunctional functional N N3P3 core. The P core. The phosphines were used for the complexation 3 3 phosphines were used for the complexation of either Fe(CO)4 or of either W(CO) 5 [67]. Fe(CO) or W(CO)5 [67]. W(CO)45 [67]. Scheme 10. Scheme 10. Grafting of diphenylphosphine as the second functional group to PPH PPH dendrimers. dendrimers. Scheme 10. Grafting of diphenylphosphine as the second functional group to PPH dendrimers. An easy way to get secondary amines as terminal functions functions consists consists in in the the condensa- condensa- Ana easy tion of primarywayamine to get secondary amines on the aldehyde aldehyde as terminal terminal functions functions of consists the in the dendrimers, condensa- dendrimers, followed tion of a primary amine on the aldehyde by the reduction of the imine, to generate terminal generate a secondary functions of secondary amine. It must the dendrimers, be noted followed that this by the reduction of the imine, to generate a secondary reduction occurs only on the imine functions on the surface, and not on amine. It must be the noted that this hydrazone reduction occurs linkages constituting only constitutingthe on the imine theinternal functions internalstructure structureofof on thethe the PPH PPHsurface, and dendrimers. dendrimers. not Such on Such the hydrazone reaction reaction was was car- linkages carried ried constituting outout first first with with the internal structure of the and (S)-(–)-α-methylbenzylamine (S)-(–)-α-methylbenzylamine PPH dendrimers. Such reaction was(both and(R)-(+)-α-methylbenzylamine (R)-(+)-α-methylbenzylamine car- ried out separated first with (S)-(–)-α-methylbenzylamine enantiomers), followed by the reductionand (R)-(+)-α-methylbenzylamine of the imine separated enantiomers), followed by the reduction of the imine bonds with NaBH3CN. bonds with NaBH (both CN. 3 In separated In that that case, case, enantiomers), the the reaction reaction followed by the reduction of diphenylphosphine of diphenylphosphine andand ofparaformaldehyde the imine bonds paraformaldehyde with NaBH occurred occurred 3CN. on on all In allthe of of that the case, NH the groups reaction on the of diphenylphosphine surface of the dendrimerand paraformaldehyde (Scheme 11), occurred contrarily NH groups on the surface of the dendrimer (Scheme 11), contrarily to the example shown to on the all of example the NH groups shown on the surface in Scheme 10. Theofreactions the dendrimer (Schemeout were carried 11),oncontrarily to the generations example 1 to 4, builtshown from a trifunctional core. Study of the chiroptical properties of all of these families of chiral dendrimers allowed to demonstrate for the first time that the value of the molar specific Organics Organics 2022, 2022, 3, 3, FOR FOR PEER PEER REVIEW REVIEW 12 12 Organics 2022, 3, FOR PEER REVIEW 12 in Scheme 10. The reactions were carried out on generations 1 to 4, built from a trifunc- Organics 2022, 3 in Scheme 10. The reactions were carried out on generations 1 to 4, built from a trifunc- 251 tional core. Study of the chiroptical properties of all of these families of chiral dendrimers tional core. Study of the chiroptical properties of all of these families of chiral dendrimers allowed to demonstrate for the first time that the value of the molar specific rotation of allowed to demonstrate for the first time that the value of the molar specific rotation of dendrimers with stereogenic end groups linearly increased with the increase of the num- dendrimers with stereogenic end groups linearly increased with the increase of the num- rotation ber of dendrimers of stereogenic with groups stereogenic end groups linearly increased with the increase of [68]. ber of stereogenic groups [68]. the number of stereogenic groups [68]. Scheme 11. Two-step method for the grafting of two terminal groups from aldehydes. Scheme 11. Scheme 11. Two-step Two-step method method for for the the grafting grafting of of two two terminal terminal groups groups from fromaldehydes. aldehydes. This process was applied for the grafting of a phosphoramidite ligand. In the first This process processwas wasapplied appliedfor thethe for grafting of aofphosphoramidite grafting a phosphoramidite ligand. In the ligand. Infirst the step, first step, butylamine was condensed onto the aldehydes, followed by the reduction of imines butylamine was condensed step, butylamine onto the was condensed ontoaldehydes, followed the aldehydes, by thebyreduction followed of imines the reduction with of imines with NaBH44. The last step was the reaction of the secondary amine with the chlorophos- NaBH 4 . The with NaBH 4. last Thestep last was step the wasreaction of theofsecondary the reaction amine the secondary withwith amine the chlorophosphite the chlorophos- phite derived from (S)-BINOL. The synthesis was carried out on the first, second and third derived phite derived from (S)-BINOL. The synthesis was carried out on the first,second from (S)-BINOL. The synthesis was carried out on the first, secondandand third generations of PPH dendrimers (Scheme 12). Complexation with rhodium provided den- generations of PPH dendrimers (Scheme 12). Complexation Complexation withwith rhodium rhodium provided provided den-den- drimers suitable for catalyzing [2+2+2] cycloaddition reactions (Figure 7). All dendrimers drimers suitable for catalyzing catalyzing [2+2+2] [2+2+2] cycloaddition reactions (Figure 7). All dendrimers afforded afforded the highest yields (up to 99%) and the highest enantioselectivities (up (up to to 98%), afforded thethe highest highest yields yields (up (up to to 99%) 99%) and and the the highest highest enantioselectivities enantioselectivities (up to 98%), 98%), whereas whereas the corresponding monomer afforded poor yields (maximum 49%), with aa very whereas the corresponding monomer afforded poor yields (maximum 49%), with a very the corresponding monomer afforded poor yields (maximum 49%), with very poor enantioselectivity poor enantioselectivity (<5%) [38]. poor enantioselectivity (<5%) (<5%) [38]. [38]. Scheme 12. Grafting Grafting ofofan anaminophosphoramidite aminophosphoramiditeligand ligandonon thethe surface surface of PPH of PPH dendrimers. dendrimers. TheThe Rh Scheme 12. Grafting of an aminophosphoramidite ligand on the surface of PPH dendrimers. The Rh complexes complexes efficiently efficiently catalyzed catalyzed [2+2+2] [2+2+2] cycloadditions. cycloadditions. Rh complexes efficiently catalyzed [2+2+2] cycloadditions. Figure 7. [2+2+2] [2+2+2] cycloaddition cycloaddition reactions reactions catalyzed catalyzed by by the the Rh Rh complex complex of the dendrimers shown in Figure 7. [2+2+2] cycloaddition reactions catalyzed by the Rh complex of the dendrimers shown in Scheme Scheme 12. Scheme 12. 12. Related two-step processes were applied in particular to the 1st generation dendrimers ended with aldehyde groups, to afford phosphonate terminal functions, using different primary amines in the first step. This work is related to the one shown in Scheme 9 concerning the synthesis of dendrimers having anti-inflammatory properties. In the first Organics 2022, 3, FOR PEER REVIEW 13 Related two-step processes were applied in particular to the 1st generation den- Organics 2022, 3 drimers ended with aldehyde groups, to afford phosphonate terminal functions, using 252 different primary amines in the first step. This work is related to the one shown in Scheme 9 concerning the synthesis of dendrimers having anti-inflammatory properties. In the first example, condensation with allylamine was followed by the addition of dime- example, condensation with allylamine was followed by the addition of dimethylphos- thylphosphonate (HP(O)(OMe)2) onto the imine bonds. Such a reaction induced the pres- phonate (HP(O)(OMe)2 ) onto the imine bonds. Such a reaction induced the presence of a ence of a phosphonate and a secondary amine on each terminal function. Attempts to graft phosphonate and a secondary amine on each terminal function. Attempts to graft another another phosphonate on the N-H function failed (Scheme 13), whereas such reaction was phosphonate on the N-H function failed (Scheme 13), whereas such reaction was possible possible on the corresponding monomer (as already shown in Scheme 9) [66]. A similar on the corresponding monomer (as already shown in Scheme 9) [66]. A similar reaction was reaction was carried out with benzylamine. In this case also, it was not possible to react carried out with benzylamine. In this case also, it was not possible to react the secondary the secondary amine, but the phosphonate could be transformed into phosphonic acid amine, but the phosphonate could be transformed into phosphonic acid sodium salt. The sodium same salt. The same bifunctional bifunctional dendrimer dendrimer was also obtainedwas also obtained in another way, byinadding another way, by )add- P(OSiMe 3 3 on ing imine the P(OSiMe 3)3 on the imine (Scheme 13) [60]. However, all of these non-symmetrical com- (Scheme 13) [60]. However, all of these non-symmetrical compounds were found poundsorwere poorly found poorly non-active for the or non-active activation for the activation of monocytes. of monocytes. Scheme 13. Scheme 13. Two-step Two-step processes processes from from aldehydes, aldehydes, affording affording phosphonate phosphonate and and secondary secondary amines amines as as terminal functions of PPH dendrimers. They display poor anti-inflammatory properties. terminal functions of PPH dendrimers. They display poor anti-inflammatory properties. analogousstrategy, An analogous strategy, involving involving the the formation formation of imino-PEG of imino-PEG terminated terminated den- dendrimers, drimers, which which were were subsequently subsequently hydrophosphorylated hydrophosphorylated ledoftoamino-PEG-phosphonate- led to a series a series of amino-PEG- phosphonate-terminated terminated PPH dendrimers PPHfromdendrimers from two G1 to G3 , using G1 to G3, using different waystwo different (Scheme ways 14). Theo- (Scheme retical and14). Theoreticalsize experimental andmeasurements experimental revealed size measurements revealed an efficient surface an efficient capping sur- with PEG face capping chains. with PEG A favorable effectchains. A favorableoneffect of PEG-capping of PEG-capping cytotoxic properties wason cytotoxic properties also evidenced [69]. An wasanalogous work was also evidenced [69].carried out with PPH An analogous workdendrimers was carried grafted to silica out with PPH nanoparticles. dendrimers These graftedmaterials to silica were suitable for nanoparticles. hosting These Ag and materials wereAgsuitable 2 O nanoparticles for hosting (Figure Ag and8).AgThe 2O resulting composites nanoparticles (Figureexhibited antibacterial 8). The resulting activityexhibited composites [70]. antibacterial activity [70]. The addition of dimethylphosphonate (HP(O)(OMe)2 ) was also carried out directly on aldehyde terminal functions, instead of on imines, on generations 2 to 4 of PPH dendrimers. An alcohol and a phosphonate were directly generated, the latter can be converted to a phosphonic acid salt, as shown in Scheme 15. These dendrimers, reacted with titanium tetraisopropoxide, Ti(OiPr)4 , enabled its controlled mineralization. A new family of hi- erarchically porous dendrimer-bridged titanium dioxide materials was obtained in this way [71]. Further studies demonstrated that the dendritic medium provided at low temper- ature, discrete anatase nanocrystals (4.8 to 5.2 nm in size), whereas amorphous titanium dioxide phase is generally obtained in standard conditions. Furthermore, upon thermal treatment, the ring opening Figure 8. Dendrimers linked topolymerization of theAg/Ag SiO2 NPs and hosting cyclophosphazene 2O NPs exhibitingcore prevented, antibacterial up to activity. 800 ◦ C, the commonly observed anatase-to-rutile phase transformation [72]. Organics 2022, 3, FOR PEER REVIEW 14 Organics 2022, Organics 2022, 33, FOR PEER REVIEW 14 253 Scheme 13. Two-step processes from aldehydes, affording phosphonate and secondary amines as terminal functions of PPH dendrimers. They display poor anti-inflammatory properties. An analogous strategy, involving the formation of imino-PEG terminated den- drimers, which were subsequently hydrophosphorylated led to a series of amino-PEG- phosphonate-terminated PPH dendrimers from G1 to G3, using two different ways (Scheme 14). Theoretical and experimental size measurements revealed an efficient sur- Scheme face capping with 14. PEG Two different chains. routes for effect A favorable the synthesis of a series on of PEG-capping of α-amino-PEG-phosphonate-termi- cytotoxic properties nated PPH dendrimers, having very low cytotoxicity. was also evidenced [69]. An analogous work was carried out with PPH dendrimers grafted to Scheme 14. Two 14. Twodifferent different silica nanoparticles. routes routes These forfor thethe materials synthesis synthesis were of aofseries a series suitable of of α-amino-PEG-phosphonate-termi- forα-amino-PEG-phosphonate-terminated hosting Ag and Ag2O nated The PPH addition of dimethylphosphonate dendrimers, having very low (HP(O)(OMe)2) was also carried out directly cytotoxicity. PPH(Figure nanoparticles dendrimers, having 8). The very low resulting cytotoxicity. composites exhibited antibacterial activity [70]. on aldehyde terminal functions, instead of on imines, on generations 2 to 4 of PPH den- drimers. The An alcohol addition of and a phosphonate were dimethylphosphonate directly generated, (HP(O)(OMe) 2) was alsothecarried latter can be con- out directly verted on aldehyde terminal functions, instead of on imines, on generations 2 to 4 of PPH with to a phosphonic acid salt, as shown in Scheme 15. These dendrimers, reacted den- titanium drimers. tetraisopropoxide, Ti(OiPr)4, enabled An alcohol and a phosphonate wereits controlled directly mineralization. generated, the latterAcan newbefamily con- of hierarchically verted porousacid to a phosphonic dendrimer-bridged salt, as shown intitaniumScheme 15. dioxide Thesematerials dendrimers,wasreacted obtained in with this way tetraisopropoxide, titanium [71]. Further studies demonstrated Ti(OiPr) 4, enabled that the dendritic its controlled medium provided mineralization. at low A new family temperature, of hierarchically discrete porous anatase nanocrystals (4.8 dendrimer-bridged to 5.2 nm titanium in size), dioxide whereas materials amorphous was obtained ti- in tanium dioxide phase is generally obtained in standard conditions. this way [71]. Further studies demonstrated that the dendritic medium provided at low Furthermore, upon thermal treatment, temperature, theanatase discrete ring opening nanocrystalspolymerization (4.8 to 5.2 nmof the cyclophosphazene in size), whereas amorphouscore pre-ti- vented, Figure Figure 8. Dendrimers up tanium8.dioxideto 800°C, linked tophase Dendrimers SiO the 2 NPs commonly is generally linked to SiO and NPs hosting 2 observed obtained and Ag/Ag anatase-to-rutile in hosting 2 O NPs standard Ag/Ag O NPs exhibiting 2 phase conditions. transformation exhibitingFurthermore, antibacterialantibacterial activity. [72]. upon activity. thermal treatment, the ring opening polymerization of the cyclophosphazene core pre- vented, up to 800°C, the commonly observed anatase-to-rutile phase transformation [72]. Scheme Scheme 15.15. Direct Direct addition addition of of H-P(O)(OMe) H-P(O)(OMe)22 onon aldehyde aldehyde terminal terminal functions. functions. These These dendrimers dendrimers efficiently controlled the efficiently controlled the mineralization mineralization of Ti(OiPr)4.. of Ti(OiPr) 4 Scheme 15. Direct addition of H-P(O)(OMe)2 on aldehyde terminal functions. These dendrimers 4. Sequential Sequential Grafting Graftingof ofaaFirst, First,then thenaaSecond Second Function on the Surface of efficiently controlled the mineralization of Ti(OiPr)4. Function on the Surface of PPH Den- PPH Dendrimers drimers As indicated indicated 4. Sequential As in the Grafting in theofintroduction, sequential a Second grafting a First, thensequential introduction, Functionon grafting the ononthe surface the Surface surface of of of dendrimers, PPH Den-as dendrimers, as shown in Scheme 1C, is very rare, and has been carried out only and recently drimersin Scheme 1C, is very rare, and has been carried out only and recently with triazine shown with triazine dendrimers [24,25]. dendrimers [24,25]. On the the contrary, contrary, such aa type type of reaction is carried out since aa long long time time As indicated inOnthe introduction, such sequential of reaction grafting onisthe carried outof surface since dendrimers, as with with polyphosphorhydrazone polyphosphorhydrazone dendrimers, dendrimers, thanks thanks to the to the specific reactivity of the P(S)Cl P(S)Cl22 shown in Scheme 1C, is very rare, and has been carried outspecific only andreactivity recentlyof the triazine with terminal functions. terminal functions. The The possibility possibility of such such sequential sequential reaction reaction was was discovered first first with dendrimers [24,25]. On the contrary,ofsuch a type of reaction is carrieddiscovered out since a long with secondary amines. Indeed, only one Cl of each P(S)Cl2 terminal functions was able to react time secondary amines. with diallylamine Indeed, polyphosphorhydrazone only one Cl dendrimers,of each P(S)Cl terminal thanksHowever, to the specific 2 functions was reactivityCl able ofwas to react the P(S)Cl with (even when used excessively). the remaining able to2 terminal functions. The possibility of such sequential reaction was discovered react with primary amines, such as propargylamine (Scheme 16). This sequential reaction first withis secondary amines. Indeed, only one Cl of each P(S)Cl2 terminal functions was able to react Organics 2022, 3, FOR PEER REVIEW 15 Organics 2022, 3, FOR PEER REVIEW 15 Organics 2022, 3 with diallylamine (even when used excessively). However, the remaining Cl was able254 to with diallylamine (even when used excessively). However, the remaining Cl was able to react with primary amines, such as propargylamine (Scheme 16). This sequential reaction react with primary amines, such as propargylamine (Scheme 16). This sequential reaction is not limited to secondary amines. Indeed, depending on the conditions used (tempera- is not limited to secondary amines. Indeed, depending on the conditions used (tempera- ture and quantity not limited of amine), to secondary it isIndeed, amines. possible to react only depending one on the allylamine conditions on (temperature used each P(S)Cl2 ture and quantity of amine), it is possible to react only one allylamine on each P(S)Cl2 terminal function. and quantity Someitreactions of amine), is possiblewere carried to react out only upallylamine one to the seventh generation on each P(S)Cl2 [73]. terminal terminal function. Some reactions were carried out up to the seventh generation [73]. function. Some reactions were carried out up to the seventh generation [73]. Scheme 16. Sequential addition of two different amines on the surface of PPH dendrimers. Scheme 16. Scheme 16. Sequential addition of Sequential addition of two two different different amines amines on on the the surface surface of of PPH PPH dendrimers. dendrimers. In some cases, the surface functions are P(O)Cl2 instead of P(S)Cl2, but they display surface functions In some cases, the surface functions are are P(O)Cl P(O)Cl22 instead of P(S)Cl P(S)Cl22, but they display the same specific reactivity. In particular, one propargylamine or one allylamine could be the same specific specific reactivity. reactivity.InInparticular, particular,one onepropargylamine propargylamine oror one one allylamine allylamine could could be grafted on each P(O)Cl2 function. As in the previous case, the second reaction can be car- be grafted grafted on on each each P(O)Cl P(O)Cl function. 2 function. 2 As As in in the the previous previous case,case, the the second second reaction reaction can can be be car- ried out with propargylamine when allylamine was already grafted (Scheme 17) [73]. carried ried outout with with propargylamine propargylamine when when allylamine allylamine waswas already already grafted grafted (Scheme (Scheme 17)17) [73]. [73]. Scheme 17. Sequential addition of two different amines on the surface of polyphosphorhydrazone Scheme 17. Sequential addition of two different amines on the surface of polyphosphorhydrazone dendrimers dendrimers having P(O)Cl 2 terminal terminal functions. dendrimers having having P(O)Cl P(O)Cl22 terminal functions. functions. The same type type of of reaction reactionwas wascarried carriedout outmore morerecently recentlytotoobtain obtain compounds compounds bear- bearing The same type of reaction was carried out more recently to obtain compounds bear- ing bothboth a triethoxysilane a triethoxysilane andand a primary a primary amine. amine. Boc-monoprotected Boc-monoprotected ethylene ethylene diamine diamine as as the ing both a triethoxysilane and a primary amine. Boc-monoprotected ethylene diamine as amino the part,part, amino andand3-(triethoxysilyl) 3-(triethoxysilyl) propylamine propylamine as theassilyl part part the silyl werewere chosen. The first chosen. The step first the amino part, and 3-(triethoxysilyl) propylamine as the silyl part were chosen. The first was step the wasgrafting of one the grafting of ofonetheoftwo amines the two (way(way amines a or away b, Scheme or way b, Scheme18), 18), followed followedby the by step was the grafting of one of the two amines (way a or way b, Scheme 18), followed by grafting of the other amine in the second step, affording the same the grafting of the other amine in the second step, affording the same compound in both compound in both cases. the grafting of the other amine in the second step, affording the same compound in both Besides, cases. a largeaexcess Besides, of 1,3-diaminopropane large excess can be used of 1,3-diaminopropane can be asused the second as the amine, secondto directly amine, to cases. Besides, afford a afford a free amine large excess of 1,3-diaminopropane can be used as the second amine, to directly a freeasamine terminal functionfunction as terminal (Scheme 18) [74].18) (Scheme These [74].compounds These compounds were tested were directlyother among afforddendritic a free amine as terminal structures function possessing (Scheme both types 18) [74]. Thesefor of functions compounds thethe were grafting to tested among other dendritic structures possessing both types of functions for grafting tested silica, among followed other dendritic by attempts structures for trapping possessing CO2 ,CO after both types deprotection of functions of the of for the Boc-protected grafting amine, to silica, followed by attempts for trapping 2, after deprotection the Boc-protected to form to silica,a followed byThese attempts for trapping COboth 2, after deprotection of the Boc-protected amine, to carbamate. form a carbamate. compounds having These compounds having types both of types functions on the surface of functions on thewere sur- amine, not the to mostform a carbamate. efficient. Indeed, These compounds dendrons possessinghavinga bothtriethoxysilyl single types of functionsgroup on the core at the sur- face were not the most efficient. Indeed, dendrons possessing a single triethoxysilyl group face and were not the most efficient. Indeed, dendrons possessing a single triethoxysilyl group at theseveral core and primary severalamines primary on amines the surface were on the found surface to be were moretoefficient found be more[75].efficient [75]. at theBesides core and theseveral primary grafting of two amines on the amines, it issurface were found also possible to beboth to graft moreanefficient amine [75]. and a phenol. Such type of reaction was carried out up to now only on P(O)Cl2 terminal functions. After the grafting of either allyl amine or propargylamine, the second step was the grafting of 4-hydroxybenzaldehyde, in basic conditions. The aldehydes were then used for the condensation with hydrazine in large excess, or for Wittig reactions with the ylide Ph3 P=CH-C≡N (Scheme 19) [73]. Hydroxybenzaldehyde could react also when bulky diallylamine was grafted in the first step [76]. Organics 2022, Organics 2022, 33, FOR PEER REVIEW 16 255 Scheme 18. Other examples of sequential addition of two different amines on PPH dendrimers, to be grafted to silica, and used for trapping CO2. Besides the grafting of two amines, it is also possible to graft both an amine and a phenol. Such type of reaction was carried out up to now only on P(O)Cl2 terminal func- tions. After the grafting of either allyl amine or propargylamine, the second step was the grafting of 4-hydroxybenzaldehyde, in basic conditions. The aldehydes were then used for the condensation with hydrazine in large excess, or for Wittig reactions with the ylide Ph 3P=CH-C≡N Scheme Scheme 18. Other(Scheme 18. Other examples19) examples of [73]. Hydroxybenzaldehyde ofsequential sequential additionofoftwo addition could twodifferent different react amines amines also onon PPH PPH when bulkytodi- dendrimers, dendrimers, to be be grafted allylamine to silica, was and graftedused in for the trapping first step grafted to silica, and used for trapping CO2 . CO 2. [76]. Besides the grafting of two amines, it is also possible to graft both an amine and a phenol. Such type of reaction was carried out up to now only on P(O)Cl2 terminal func- tions. After the grafting of either allyl amine or propargylamine, the second step was the grafting of 4-hydroxybenzaldehyde, in basic conditions. The aldehydes were then used for the condensation with hydrazine in large excess, or for Wittig reactions with the ylide Ph3P=CH-C≡N (Scheme 19) [73]. Hydroxybenzaldehyde could react also when bulky di- allylamine was grafted in the first step [76]. Scheme 19. Sequential Sequentialaddition additionofof anan amine andand amine of 4-hydroxybenzaldehyde on the of 4-hydroxybenzaldehyde on surface of PPH the surface of dendrimers. PPH dendrimers. The presence of the aldehydes as shown in Scheme 19 enabled the continuation of the synthesis of dendrimers having pendant internal functions inside the structure. These pendant groups were either an allylamine, or 1-aminomethylpyrene, or 1-pyrenebutanoic hydrazide. The aldehydes were reacted with H2 NNMeP(S)Cl2 , as in the classical synthesis of PPH dendrimers (Scheme 20) [77]. Scheme 19. Sequential addition of an amine and of 4-hydroxybenzaldehyde on the surface of PPH dendrimers. The presence of the aldehydes as shown in Scheme 19 enabled the continuation of The presence the synthesis of the aldehydes of dendrimers as shown having pendant in Scheme internal 19 enabled functions the structure. inside the continuation of These the synthesis pendant of dendrimers groups having were either an pendant allylamine, orinternal functions insideor 1-aminomethylpyrene, the structure. These 1-pyrenebutanoic pendant groups hydrazide. were either The aldehydes an allylamine, were orH1-aminomethylpyrene, reacted with 2NNMeP(S)Cl2, as in the orclassical 1-pyrenebutanoic synthesis Organics 2022, 3 hydrazide. The aldehydes were reacted with H NNMeP(S)Cl , as in the classical 256 synthesis of PPH dendrimers (Scheme 20) [77]. 2 2 of PPH dendrimers (Scheme 20) [77]. Scheme 20. Amino derivatives of allyl or pyrene as pendant functions inside polyphosphorhydra- 20. 20.AminoAmino zone dendrimers. Scheme derivatives of allyl orof derivatives pyrene allylas or pendant functions pyrene inside polyphosphorhydra- as pendant functions inside zone dendrimers. polyphosphorhydrazone dendrimers. Besides the sequential use of two amines, or of an amine and a phenol shown in the Besides previous the sequential Schemes, use ofuse the sequential twoofamines, or of an two phenols was amine and a phenol also attempted shown on the in the surface of previous Schemes, the the sequential sequential use use ofof two two phenols phenols was was also also attempted polyphosphorhydrazone dendrimers. The reaction is less clean than with amines, as it of attempted onon the the surface surface is of polyphosphorhydrazone polyphosphorhydrazone difficult to avoid a small percentagedendrimers. dendrimers. The Thethan (less reaction reaction 5%) of is less is either less clean clean thanthan withwith amines, amines, homodisubstitution, oras itas unre-is it is difficult difficult acted P(S)Cl to avoid to avoid 2. Theagrafting a small small of apercentage percentage phenol(less (less than than derivative 5%) 5%) of of of either either ethacrynic homodisubstitution, homodisubstitution, acid, followed by the or or graft- unre- unreacted acted ing P(S)Cl of P(S)Cl either . The2 .grafting The grafting of a phenol of a phenol 24-hydroxybenzaldehyde derivative orderivative the phenol ofof of azabisphosphonate ethacrynic ethacrynic the acid, followed acid, followed by the by thecarried were graft- grafting ing of of eithereither 4-hydroxybenzaldehyde 4-hydroxybenzaldehyde or the or the phenol phenol of the of the azabisphosphonate azabisphosphonate out (Scheme 21). Ethacrynic acid grafted on the entire surface of phosphorhydrazone den- were were carried carried drimers out out (Schemewas(Scheme 21). shown 21). Ethacrynic Ethacrynic acidanti-proliferative acidstrong to display grafted grafted on theon the entire entire surface surface of phosphorhydrazone of phosphorhydrazone activities against both liquidden-and dendrimers drimers was was [78]. shown shown to display to display strong strong anti-proliferative anti-proliferative activities activities against against bothboth liquidliquid and solid tumors However, these unsymmetrical compounds were not tested [79]. and solidsolid tumors tumors [78].[78]. However, However, thesethese unsymmetrical unsymmetrical compounds compounds werewere not tested not tested [79].[79]. Scheme 21. Scheme 21. Grafting Grafting of of aa phenol phenol derivative derivative of of ethacrynic ethacrynic acid acid and and other other phenols phenols on on the the surface surface of of Scheme PPH PPH 21. Grafting dendrimers dendrimers of aanticancer having having phenol derivative anticancer of ethacrynic acid and other phenols on the surface of properties. properties. PPH dendrimers having anticancer properties. 5. Conclusions The specific bifunctionalization on the surface of dendrimers is still an ongoing chal- lenge. Among the three different ways that have been already proposed, the easiest and most widely used with all types of dendrimers is the grafting of a monomer possessing already both desired functions. The other two methods (i.e., the modification of a first function by a second one, and the sequential grafting of the first and then the second func- Organics 2022, 3 257 tion) have been rarely used on dendrimers in general, but relatively more frequently with polyphosphorhydrazone dendrimers than with other types of dendrimers. For example, the condensation of primary amines with the aldehyde terminal functions affords imines, which can be either reduced, for further reactivity on the NH, or directly reacted with com- pounds such as phosphonates or P(OSiMe3 )3 . The sequential grafting of two functions on P(X)Cl2 (X = S, O) terminal functions was carried out essentially with two different amines, but also in some cases with an amine and a phenol, or with two different phenols. Besides the pioneering works with polyphosphorhydrazone dendrimers which were carried out for purely fundamental researches, the presence of two different functions was also used for catalysis, for materials, and for biological purposes. Despite being challenging, the specific presence of two functions on the surface of dendrimers offers new opportunities for the future, in particular for increasing the solubility in specific media such as water and for dendrimers having catalytic or biological properties. In this regard, efforts should be engaged to develop efficient new strategies leading to sophisticated and highly controlled multifunctional dendrimeric architectures. Author Contributions: Conceptualization, A.-M.C.; writing—original draft preparation, A.-M.C.; writing—review and editing, M.P., R.L., C.-O.T., R.M.S. and A.-M.C.; visualization, A.-M.C.; su- pervision, R.L., R.M.S. and A.-M.C.; project administration, R.M.S. and A.-M.C.; funding acquisi- tion, R.M.S., C.-O.T. and A.-M.C. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860322 for the ITN-EJD “Coordi- nation Chemistry Inspires Molecular Catalysis” (CCIMC). Data Availability Statement: Not applicable. Acknowledgments: Thanks are due to the CNRS (Centre National de la Recherche Scientifique, France), to the ANR (Agence Nationale de la Recherche, France), to Ministerio de Ciencia, Innovación y Universidades (PID2019-106171RB-I00) and Generalitat de Catalunya (2017 SGR00465 project) for financial support. Conflicts of Interest: Cédric-Olivier Turrin is co-founder and CEO of IMD-Pharma. Anne-Marie Caminade is a shareholder of IMD-Pharma. References 1. Tomalia, D.A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin, S.; Roeck, J.; Ryder, J.; Smith, P. A New Class of Polymers– Starburst-Dendritic Macromolecules. Polym. J. 1985, 17, 117–132. [CrossRef] 2. Caminade, A.M.; Turrin, C.O.; Laurent, R.; Ouali, A.; Delavaux-Nicot, B. Dendrimers: Towards Catalytic, Material and Biomedical Uses; John Wiley & Sons Ltd.: Chichester, UK, 2011; p. 538. [CrossRef] 3. Newkome, G.R.; Shreiner, C.D. 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