The combination of the N-based pincer ligand PyBOX with Pt2+ leads to new catalysts for the enantioselective cycloisomerization of dienyl- and trienyl-ols. The mechanistic combination of electrophilic cyclization followed by rapid protodemetalation is surprising and leads to a powerful construct for developing new reactions

Gagné, Michel R.

Nguyen, Ha

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Enantioselective Cascade Cyclization/Protodemetalation of Polyeneswith N3Pt2+ CatalystsHa Nguyen and Michel R. Gagne*́Department of Chemistry, University of North Carolina at Chapel Hill, CB # 3290, Chapel Hill, North Carolina 27599, United States*S Supporting InformationABSTRACT: The combination of the N-based pincer ligandPyBOX with Pt2+ leads to new catalysts for the enantiose-lective cycloisomerization of dienyl- and trienyl-ols. Themechanistic combination of electrophilic cyclization followedby rapid protodemetalation is surprising and leads to apowerful construct for developing new reactions.KEYWORDS: electrophilic catalysis, cycloisomerization, platinum, protodemetalationThe steroid skeleton is biosynthesized by a fascinatingcationic cascade cyclization of polyenes like squalene orsqualene oxide. The commercial import of bioactive steroids is,however, not matched by synthetic methods for their de novosynthesis. In fact, nearly all steroidal active ingredients areaccessed through semisynthetic means (i.e., derived from thenatural pool). It is, therefore, not surprising that biomimickingstereoselective cascade syntheses of steroid-like compounds isof significant interest.1 The available methods include nonmetalelectrophiles such as Brønsted−Lewis acids,2 haloniums,3organocatalysts,4 and metal electrophiles such as Hg(II),5Pd(II),6 Pt(II),6c,7 Ir(I),8 and Au(I).9 Our group has focused onPt(II)-based catalysts and previously reported that the powerfulelectrophile [(triphos)Pt][BF4]2 can stoichiometrically convertvarious polyenes to form polycyclic Pt-alkyl+ structures withhigh diastereoselectivity.6l,o,pDespite the successful development of catalytic tandemcyclization/β-H elimination,7a,b,h cyclization/fluorination,7f andcyclization/oxygenation7g reactions, the parent cyclization/protonation reaction (a catalytic cycloisomerization) putativelyobtained via protodemetalation of a cyclization-derived Pt-alkylhas not been achieved, because protonolysis of the resultingbulky (triphos)Pt-alkyl+ complexes requires strong acids likeTfOH, which are not compatible with polyene substrates.10This reactivity exemplifies the underlying problem that theproperties of electrophilic alkene activation and protodemeta-lation have opposite ligand preferences, the former favoringelectron-deficient ligands and the latter electron-rich li-gands.11,12 Our own investigations on the (triphos)Pt-R+system have shown that protodemetalation of Pt−C bondswith acids milder than HOTf is feasible when more electron-rich tridentate phosphine ligands are employed; however,electron-rich ligands also decrease the electrophilicity of Pt(II)catalysts and hinder the cascade cyclization portion of thetandem process.7c Herein, we report the development of a newgeneration of chiral platinum catalysts that carry out thecyclization/protodemetalation of polyenes under exceedinglymild conditions.The PyBOX (pyridine-2,6-bisoxazolines) ligands form pincercomplexes with a variety of metals, and they have proven to behighly effective in asymmetric catalysis.13 However, to the bestof our knowledge, there are no reported uses of platinum(II)−PyBOX complexes in catalysis.14 This rarity could be due to thedifficulties in synthesizing such complexes, because “hard”nitrogen ligands tend to be poor ligands for “soft” complexes ofPt(II).15 We report herein that this mismatch has significantcatalytic advantages. Consistent with its poor ligand quality, anespecially labile Pt source, Pt(DMSO)2I2, was required tosuccessfully obtain the cationic (PyBOX)Pt−I+ catalystprecursor; the NNN ligand does not displace the typicalalkene-based precursor.Our studies began with an attempt to synthesize an (NNN)Pt variant of the readily isolable (PPP)Pt−alkyl+ complex-es,6c,7d,e with initial experiments employing the commerciallyavailable isopropyl PyBOX ligand 1a (see Chart 1). (R)-1a waspreactivated by AgBF4 to generate the dication and thenreacted with 2a along with a stoichiometric quantity of Ph2NH.As shown in eq 1, 1H NMR spectroscopy revealed that after 1h, 2a was completely consumed, but the (NNN)Pt-alkyl+complex was not observed; the only observable organic productwas 3a. We presumed that 3a was formed by the rapidprotodemetalation of an unobserved (NNN)Pt-R+ complexwith Ph2NH2+. The lack of 4, a reporter for the build-up of eventrace Brønsted acid,16 indicated that protodemetalation wasReceived: December 14, 2013Revised: January 30, 2014Published: February 3, 2014Research Articlepubs.acs.org/acscatalysis© 2014 American Chemical Society 855 dx.doi.org/10.1021/cs401190c | ACS Catal. 2014, 4, 855−859This is an open access article published under an ACS AuthorChoice License, which permitscopying and redistribution of the article or any adaptations for non-commercial purposes.much more rapid than for (PPP)Pt-R+ analogues and thussuggested the feasibility of a general catalytic cyclization/protonation pathway.When this reaction was repeated with 10 mol % (PyBOX)-Pt2+, no desired product was formed after even a prolongedperiod of time. In fact, the only organic product observed inGC was the β-hydride elimination product 5, which was noteven observed under stoichiometric conditions. Intrigued bythis observation, we began a study to test the effect of additiveson the outcome of the reaction, surmising that the principaldifference between stoichiometric and catalytic conditions wasthe presence of excess substrate.In this set of experiments, 1 equiv of 2a was combined with 1equiv of the activated catalyst and 1 equiv of a terminal alkene;the distribution of products was monitored by GC-MS. When 1additional equiv of 2a was added to the mixture, the yield of 3awas drastically reduced, and the major product was 5 (entry 1,Table 1). A significant drop in reaction rate was also noted (12h for 2 equiv of 2a vs 1 h for 1 equiv). Styrene was particularlyadept at shifting the product distribution to 5, though electron-withdrawing groups partially reversed this trend. Notably, in allof these cases, the enantioselectiviy of 3a and 5 were similar,suggesting that both products likely formed from the sameintermediate (the alkyl).The mechanistic source for this additive effect remainsunclear, but this issue can awkwardly be circumvented by thesequential addition of 1 equiv of 2a after the previousequivalent was fully consumed. Better yet is the slow additionof 2a to the catalyst by syringe pump, which enables thesubstrate concentration to be kept suitably low that rapidconsumption occurs and protodemetalation dominates. Thus,adding 10 equiv of 2a over 12 h via syringe pump to theactivated catalyst with 1 equiv of Ph2NH at room temperatureresulted in an excellent isolated yield of 3a, with anenantioselectivity that is only slightly reduced from stoichio-metric conditions (eq 2).Because stoichiometric mixtures of catalyst and 2a effectivelymimicked the efficiency and enantioselectivity of the syringepump addition method, the reaction conditions wereconveniently optimized in this fashion. Controls supportedthe viability of this approach and confirmed that no cyclization/protodemetalation occurred without the platinum complex(entry 2, Table 2).In a previous computational study, bases that hydrogen bondto the protic terminus were found to greatly facilitate thecyclization,17 hence its inclusion (Ph2NH) in the originallytested condition (entry 1, Table 2, 24% ee). Weaker (Ph3N)and stronger (Ph2NMe and PhNH2) bases were alsoexplored,18 but the highest enantioselectivity was achievedwhen no base was employed while still maintaining highconversion to 2a (entry 3). Again, the lack of 4 indicates thatalkyl protonolysis is considerably faster than Brønstedcyclization of 2a.Chart 1. Pre-Catalysts Employed in This StudyTable 1. Effects of Terminal Alkenes on the ReactionOutcomeaGC yield, with hexamethylbenzene as internal standard. beedetermined by chiral GC.ACS Catalysis Research Articledx.doi.org/10.1021/cs401190c | ACS Catal. 2014, 4, 855−859856The reaction outcome depends strongly on the choice ofsolvent, with nonpolar solvents being hampered by poorcatalyst solubility.18 Polar, noncoordinating solvents likenitromethane and nitroethane provided the highest conversionto 3a (entries 3 and 4, Table 2), whereas CH2Cl2 provided onlytraces of 3a (entry 5) due to the formation of inactive(PyBOX)Pt−Cl+ by chloride abstraction from the solvent. Apolar, coordinating solvent such as acetonitrile (entry 6)competitively coordinates to the dicationic platinum catalystand hinders access to the free coordination site on platinum.The identity of the counterion in the silver salt wasunimportant, and lower temperatures did not improve the ee(0 °C, 40% ee).Using the optimum conditions, a series of PyBOX ligandvariants were examined (Chart 1). Across the series stericeffects were found to principally impact catalyst reactivity.Illustrative was 1a and 1f with oxazoline iso-Pr and tert-Bugroups at C2. The former gave high conversion, although thelatter was unreactive even at elevated temperature (entries 3and 8, Table 2). Some sensitivity to the C3-geminal alkyl groupwas also noted for 1a, 1h (R = Me, entry 9), 1i (R = Et, entry10), and 1k (R = Ph, entry 11). As the bulkiness of the C3substituents increased, sharp drops in reactivity were noted,with side products (e.g., 4) forming for the slower reactions.Consistent with unpublished studies showing the necessity of adicationic platinum cyclization initiator, the anionic ligand 1ndid not consume substrate (entry 12). Among all screenedligands, only 1h was comparable to 1a, but the latter’scommercial availability made it the preferred choice.The optimized condition was subsequently applied to avariety of dienyl and trienyl phenols and alcohols using thesyringe pump method (Table 3). In all cases, the reaction wentto completion with 10 mol % (R)-1a, and the products wereobtained in a highly diastereoselective manner. Electron-withdrawing groups or electron-donating groups on the arylgave products in good yield but lower enantioselectivity than2a. Both 3d and 3e were isolated in low yield due to their highvolatility (entries 4 and 5, 86% and 83% GC yield,respectively). Triene alcohol and triene phenol substratesgave lower isolated yields than did 3a.A proposed catalytic cycle is shown in Scheme 1. It includesthe coordination of the (PyBOX)Pt2+ catalyst to the least-substituted CC bond in the substrate, initiation of theTable 2. Selected Optimization Studiesaentry catalyst solvent base temp yield (%)b ee (%)c1 1a CD3N02 Ph2NH rt >95 242 none CD3NO2 Ph2NH rt 0 N/A3 1a CD3NO2 none rt >95 424 1a EtN02 none rt >95 375 1a CH2CI2 none rt trace N/A6 1a CH3CN none rt 0 N/A7 1a CD3NO2 none 0 °C 95 408 1f CD3NO2 none rt 0 N/A9 1h CD3NO2 none rt >95 4510 1i CD3NO2 none rt 79 4811 1k CD3NO2 none rt 0 N/A12 1n CD3NO2 none rt 0 N/AaAII reactions performed with 1 equiv of [(NNN)Ptl][BF4], activatedwith 1.5 equiv of silver salts (see Supporting Information). bGC yieldwith hexamethylbenzene as internal standard. cee determined by chiralGC.Table 3. Asymmetric Cycloisomerizations Catalyzed by (R)-(i-Pr-PyBOX)Pt2+aaReaction conditions: catalyst (10 mol %), AgBF4 (15 mol %),CD3NO2, rt, substrate added by syringe pump (see SupportingInformation). bThe absolute configuration of 3a was assigned bycomparing to an authentic sample of known configuration preparedfrom the hydrogenation of stereodefined β-hydride eliminatedproducts.7b The remainder were assigned by analogy. cIsolated yield.dee determined by chiral GC. eee determined by chiral supercriticalfluid chromatography. fGC yield. g1 mmol scale.Scheme 1. Proposed Catalytic CycleACS Catalysis Research Articledx.doi.org/10.1021/cs401190c | ACS Catal. 2014, 4, 855−859857cascade to release a proton which rapidly protodemetalates theputative N3Pt-alkyl+ complex A, to generate the polycyclicproduct and turn over the catalytic cycle. Consistent with thisscenario was the cyclization of 2a-d, which generates 3a-d as asingle diastereomer with deuterium residing at the C3 positionof the A ring (sterol numbering) (eq 3). Attempts to isolate thecationic complex A by quenching the reaction with a strongbase such as styrene-bound piperidine, 2,4,6-tert-butylpyridineor proton sponge were not successful.In summary, we have developed a new chiral platinum−PyBOX complex that is capable of the cyclization/protonationof polyenes to polycyclic structures with good yield, highdiastereo-selectivity, and moderate enantioselectivity. Thesestudies also demonstrate that changes in the hard/soft characterof the ligands can significantly increase the tendency for(oxidatively-induced) protodemetalative reactions at a cationicPt(II) center.19 Studies to further understand this observationand to apply this finding to explore other turnover pathways areunderway.■ GENERAL PROCEDURE FOR PT(II)-CATALYZEDCYCLOISOMERIZATION OF POLYENESTo a 3.5 mL vial with a septum cap was added (R)-[(i-Pr-PyBOX)PtI][BF4] (71.0 mg, 0.1 mmol, 0.1 equiv) and AgBF4(29.2 mg, 0.15 mmol, 0.15 equiv) in CD3NO2 (0.5 mL). Theresulting mixture was stirred in the dark for 1 h at roomtemperature. Substrate (1.0 mmol, 1.0 equiv) in CD3NO2 (1.0mL) was loaded into a 1.0 mL Norm-Ject Plastic syringe. Thesyringe was then mounted to a Fisher Scientific Single SyringePump (model no. 14-831-200). The parameters of the syringepump were set as the following: rate of 0.05 mL/h, volume of1.0 mL, and diameter of 5.0 mm. The needle of the syringe waspierced through the septum cap of the vial containing thereaction mixture. The syringe pump was started with the aboveparameters. After the reaction was complete, the product wasisolated from the reaction mixture by preparative thin-layerchromatography.■ ASSOCIATED CONTENT*S Supporting InformationExperimental procedures and characterization data for newcompounds. This material is available free of charge via theInternet at http://pubs.acs.org.■ AUTHOR INFORMATIONCorresponding Author*E-mail: mgagne@unc.edu.NotesThe authors declare no competing financial interest.■ ACKNOWLEDGMENTSWe thank the National Institute of Heath, General Medicine forgenerous support (Grant GM-60578). We also thank Dr. Mee-Kyung Chung for acquiring and analyzing HRMS data. H.N.thanks the Vietnam Education Foundation for funding.■ REFERENCES(1) For reviews, see (a) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu,D. R. Angew. Chem. 2000, 112, 2930−2952;(e) Angew. Chem., Int. 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Enantioselective Cascade Cyclization/Protodemetalation of Polyenes with N 3 Pt 2+ Catalysts

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