Catalytic Enantioselective Pinacol and Meinwald Rearrangementsfor the Construction of Quaternary StereocentersHua Wu, Qian Wang, and Jieping Zhu*

Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale deLausanne, EPFL-SB-ISIC-LSPN, BCH5304, CH-1015 Lausanne, Switzerland

*S Supporting Information

ABSTRACT: The development of enantioselective pina-col rearrangement is extremely challenging due to thelikelihood involvement of the carbenium intermediate thatrenders the stereochemical communication betweencatalyst and substrate difficult to achieve. Herein, wereport chiral N-triflyl phosphoramide-catalyzed enantio-selective pinacol rearrangement of 1,2-tertiary diols andmechanistically related Meinwald rearrangement oftetrasubstituted epoxides for the synthesis of enantioen-riched 2-alkynyl-2-arylcyclohexanones and 2,2-diarylcyclo-hexanones, respectively. Total synthesis of (+)-mesem-brane featuring the catalytic enantioselective pinacolrearrangement as a key strategic step is also documented.

Many bioactive natural products and pharmaceuticals,such as mesembrane,1 gracilamine,1 strychnine,2

stephadiamine,3 hopeanol,4 and dihydrobenzofurans (non-steroidal estrogen receptor β (ERβ) agonist, Scheme 1a),5

contain cyclohexane bearing an all-carbon quaternary stereo-center as a core structure. 2-Aryl-2-alkyl and 2,2-diarylsubstituted cyclohexanones are obvious starting materials forthe synthesis of these compounds. The Pd-catalyzed

enantioselective allylation has been developed into a powerfulsynthetic tool for the synthesis of α,α-dialkyl substitutedcyclohexanones,6,7 and elegant enantioselective arylation,8,9

alkylation10 as well as Michael addition11,12 have been devisedfor the synthesis of α-aryl-α-alkyl substituted counterparts.There is also a report on the enantioselective vinylation ofcyclopentanones. However, applying the same conditions tocyclohexanone derivatives led to the arylated products withonly moderate enantiomeric excess (ee).13 Catalytic enantio-selective synthesis of 2-alkynyl-2-arylcyclohexanones and 2,2-diarylcyclohexanones remains, to the best of our knowledge,unknown (Scheme 1b).Pinacol rearrangement converts 1,2-diols to aldehydes or

ketones under acidic conditions.14 As it generates a newstereocenter, it is important to control the stereochemicaloutcome in order to exploit fully its synthetic potential.15

However, the priori formation of a carbenium intermediatebefore the key C−C bond forming process renders thedevelopment of the enantioselective version extremelychallenging.16 The classic Lewis and Brønsted acid catalysisis inefficient since the association between the intermediateand the catalyst, a prerequisite for the chirality transfer, isdifficult to achieve.17 To date, there are only two examples ofsuccessful enantioselective pinacol rearrangements. In theirseminal work, Antilla and co-workers developed a chiralphosphoric acid (CPA)-catalyzed rearrangement of indolyldiols (Scheme 2a).18 Subsequently, our group reported anenantioselective vinylogous rearrangement of (E)-butene-1,4-diols to enantioenriched β,γ-unsaturated ketones (Scheme2b).19 Both reactions featured 1,2-aryl migration providingenantioenriched linear ketones bearing an α-tertiary stereo-center. On the other hand, Snyder and co-workers reported aCPA-promoted (1.0 equiv) diastereoselective pinacol rear-rangement for the synthesis of a complex α-quaternaryaldehyde, a key intermediate in their elegant total synthesisof hopeanol.4 The catalytic enantioselective rearrangement ofvicinal tertiary diols to ketones bearing an α-quaternarystereocenter has, to the best of our knowledge, not beenrealized in spite of the significant synthetic importance of theresulting chiral compounds. We report herein the firstexamples of such enantioselective processes as well asmechanistically related Meinwald rearrangement20 of epoxidesfor the synthesis of enantioenriched 2-alkynyl-2-arylcyclohex-anones 1 and 2,2-diarylcyclohexanones 2 (Scheme 2c). We

Received: April 28, 2019Published: July 6, 2019

Scheme 1. Cyclohexane Bearing an All-Carbon QuaternaryStereocenter: Occurrence and Asymmetric Synthesis

Communication

pubs.acs.org/JACSCite This: J. Am. Chem. Soc. 2019, 141, 11372−11377

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also document the transformation of the hydroxylated aromaticring, the alkynyl and the carbonyl groups which allowed easyaccess to a diverse set of synthetic building blocks. A concisetotal synthesis of (+)-mesembrane is also accomplishedfeaturing the catalytic enantioselective pinacol rearrangementas a key strategic step.We began our studies using 3a as a test substrate and chiral

phosphoric acids21,22 and N-triflyl phosphoramides (CPA) 423

as catalysts. Stirring a CH2Cl2 solution of 3a (R = Ph, R1 = 4-OH, c 0.05 M) in the presence of a diverse set of CPAs (0.1equiv, see SI for details) at room temperature for 12 h afforded1a as an only isolable regioisomer in excellent yield but withonly moderate ee. Although the enantioselectivity wasmoderate, the exclusive formation of 1a was encouraging asit indicated that only one of the two possible carbocations wasgenerated under these mild conditions. The N-triflylphosphoramide 4a stood out from this initial screening andwas chosen for further optimization of the reaction conditions.After systematically varying the solvents, the additives and thetemperature, the optimum conditions found consisted ofperforming the rearrangement of 3a in toluene (c 0.05 M) at−5 °C in the presence of 4a (0.1 equiv) and 3 Å molecularsieves. Under these conditions, 2-(4-hydroxyphenyl)-2-(phenylethynyl)cyclohexan-1-one (1a) was isolated in 99%yield with 90% ee.24 We noted that α,β-unsaturated ketone 5(Scheme 3) resulting from the competing Meyer−Schusterrearrangement25,26 was not formed under these conditions.With the optimized conditions in hand, the scope of this

catalytic enantioselective pinacol rearrangement was nextexamined. As shown in Scheme 3, arylalkyne moieties bearingan electron-donating (Me, MeO) and an electron-withdrawinggroup (F, Cl) at different positions (para, meta and ortho) arecompatible with the reaction conditions (adducts 1a−1i). Aheterocycle could also be incorporated into the chiralcyclohexanone product (1j). Pleasingly, alkynes with aliphaticsubstituents such as tBu (1k), nBu (1l) and functionalizedalkyls (1n, 1p) were also well tolerated affording the desiredproducts in excellent yields and enantiopurities. The presenceof a free phenol group is not an obligation since other electron-rich arenes, such as 4-methoxyphenyl (1m), 3,4-dimethox-yphenyl (1n-1q), benzo[d][1,3]dioxole (1r), dihydrobenzo-furan (1s), 2-thiophene group (1t) and benzofuran (1u), werecompatible with the reaction conditions to give thecorresponding rearranged products in high ee values. The

enantioselective pinacol rearrangement of indole C-2 sub-stituted diol could not be examined due to its instability. It isworth noting that alkynes containing various types offunctional groups such as halide, trimethylsilyl group (TMS)and benzyl ether group (OBn) were compatible with thereaction conditions to afford the functionalized enantioen-riched cyclohexanones (1n−1p and 1r). The (S)-absoluteconfiguration of 1a was determined by X-ray crystallographic

Scheme 2. Enantioselective Pinacol Rearrangement: State-of-the-Art

Scheme 3. Scope of the Catalytic Enantioselective PinacolRearrangementa

aOptimum conditions: 3 (0.1 mmol), 4a (0.01 mmol, 0.1 equiv),toluene (2.0 mL, c 0.05 M), 3 Å molecular sieves, −5 °C. bThereaction was performed at −10 °C. cThe reaction was performed at−50 °C. dThe reaction was performed at −40 °C. eThe reaction wasperformed at −30 °C. All the reactions were performed on a 0.1mmol scale. The ee was determined by supercritical fluidchromatography (SFC) or high performance liquid chromatography(HPLC) analysis on a chiral stationary phase.

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analysis, and the configuration of the other cyclohexanoneswere assigned by analogy.We next turned our attention to the mechanistically relevant

Meinwald rearrangement.20,24,27 Tetrasubstituted epoxides 6were readily synthesized by a two-step sequence involvingMcMurry cross-coupling of two different ketones28 followed byepoxidation of the resulting tetrasubstituted alkenes. Gratify-ingly, treatment of a toluene solution of 6 in the presence ofcatalyst 4a and 4 Å molecular sieves (MS) at −78 °C affordedthe 2,2-diarylcyclohexanones 2a−2f in excellent yields withhigh ee values (Scheme 4). Although water was not generated

in this reaction, the presence of MS was important for thereaction outcome and we observed that 4 Å MS was a betteradditive than the 3 Å counterpart in terms of both the yieldand the ee of the rearranged product.29 Since the two arylsubstituents in 6 are similar in size, the observedenantioselectivity could be attributed to the stereoelectroniceffect. The presence of hydroxyl or methoxy group at the paraposition in one of the aryl groups fixed effectively, viaresonance effect, the geometry of the transient carbeniumintermediate leading to the observed enantioselectivity.It is worth noting that epoxide 6g bearing an alkynyl

substituent was unstable and was readily hydrolyzed to diol 3qduring workup and purification processes, while the cyclo-butane derivatives 6h and 6i underwent spontaneousrearrangement during their preparation to afford thecorresponding cyclopentanone derivatives 7h and 7i (Scheme5a). For the sake of comparison, we also prepared a diarylsubstituted diol 3v and found that it was more stable than theepoxide counterpart 6e toward the rearrangement. Stable at−78 °C, the diol 3v underwent rearrangement only at −10 °Cto afford cyclohexanone 2e in excellent yield with 77% ee(Scheme 5b).The phenyl substituted epoxide 6j underwent Meinwald

rearrangement at −90 °C to afford 1w in 76% yield with 65%ee, while the pinacol rearrangement of diol 3w took placesluggishly to provide 1w in only 7% yield (34% ee). Theseresults are important as it not only clearly illustrated the higherreactivity of the epoxide than diol toward the rearrangement,

but also indicated that the presence of an extra cationstabilizing group (OH, OMe) might not be absolutely neededfor the development of enantioselective Meinwald rearrange-ment (Scheme 5c).Desymmetrizative Meinwald rearrangement was next ex-

plored to extend further its application scope (Scheme 6).Epoxidation of alkene 8 with mCPBA afforded the epoxide 9 in91% yield as a mixture of two diastereomers. Under standardconditions, rearrangement of epoxide 9 furnished 10 in 99%yield with 87% ee. The 3,3-diaryl substituted octahydronaph-thalen-2-(1H)-one harboring three stereocenters would not beeasily prepared by the known methodologies.

Scheme 4. Synthesis of 2,2-Diarylcyclohexanones fromTetrasubstituted Epoxidesa

aThe reaction was performed on a 0.1 mmol scale. The ee wasdetermined by SFC or HPLC analysis on a chiral stationary phase.

Scheme 5. Stability and Reactivity of Epoxides vs Diols

Scheme 6. Desymmetrizative Meinwald Rearrangement

aOnly the major diastereomer 9 is shown for the sake of clarity.

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While no detailed mechanistic studies were carried out,30 aplausible reaction pathway for the enantioselective pinacolrearrangement was proposed as illustrated in Scheme 7. The

N-triflyl phosphoramide 4a would act as a bifunctional catalystto form a 9-membered ring intermediate A and B with the 1,2-diol 3 via hydrogen bonding. The selective dehydration of Bdelivering the carbocation C would be kinetically andthermodynamically favored. Indeed, the presence of an alkynyland an electron-rich aryl group would be capable of stabilizingthe carbenium intermediate C via the resonance structures C′and C″. Although ion-pairing itself is nondirectional, itsassociation with the hydrogen bond in C might be able toimpose a preorganized three-dimensional structure for theefficient chirality transfer in the subsequent 1,2-alkyl shiftprocess leading to ketone 1. The fact that Meyer−Schusterrearrangement product 5 was not observed under ourconditions indicated that the 1,2-alkyl shift was much fasterthan the intermolecular nucleophilic trapping of theintermediate C″. Although 2- and 4-hydroxybenzyl alcoholderivatives have been used in CPA-catalyzed asymmetrictransformations, all the literature precedents involved the insitu generation of neutral quinomethide intermediates. As the2- and 4-methoxybenzyl alcohols were ineffective substrates inthese literature examples, H-bonding rather than ion-pairingwas proposed to be responsible for the asymmetricinduction.31 It is therefore interesting to note that bothpathways are apparently operational in the present pinacol andMeinwald rearrangement reactions.19,32

The presence of a phenol group provided a versatile handlefor the functionalization of the rearranged products. Asdepicted in Scheme 8a, triflation of 1b under standardconditions (Tf2O, Py, CH2Cl2) afforded the triflate 11 in98% yield. Reduction of 11 under single electron transferconditions (Pd/C, Mg, MeOH) provided 12 with anunsubstituted phenyl ring.33 Pd-catalyzed Suzuki-Miyauracross coupling of 11 with phenyl boronic acid provided a

biphenyl substituted derivative 13. On the other hand,treatment of 1b with N-bromosuccinimide (NBS) affordedthe dibrominated product 14 that was armed for the furtherfunctionalization.The alkynyl group is also amenable to a diverse set of

chemical transformations. Treatment of 1o with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) af-forded silylenol ether 15 in 93% yield. Hydrogenation of 1o(Pd/C, H2, ethyl acetate (EtOAc)) furnished the 2-(2′-trimethylsilylethyl)-2-aryl substituted cyclohexanone 16 in91% yield. Removal of the trimethylsilyl group from 1ofollowed by hydrogenation over Lindlar’s catalyst provided the2-vinyl-2-aryl substituted cyclohexanone 17 in 86% yield overtwo steps. Wittig reaction of the sterically hindered carbonylgroup of 1o occurred smoothly to afford methylenecyclohex-ane 18 in high yield. Finally, removal of TMS group from 1ofollowed by CuI-catalyzed [3+2] cycloaddition of the resultingterminal alkyne with benzyl azide afforded triazole 19 in 99%yield. This last example showcased the advantage of ourmethodology as it is difficultly accessible by other means(Scheme 8b).To illustrate further the synthetic potential of the present

methodology, total synthesis of (+)-mesembrane (20) wasundertaken (Scheme 9). AlCl3-mediated Friedel−Craftsreaction of cyclopentanecarbonyl chloride (21) with 1,2-

Scheme 7. Possible Reaction Pathway of the PinacolRearrangement

Scheme 8. Synthetic Transformations of the RearrangedProductsa

aReaction conditions: (a) Tf2O, pyridine, dichloromethane (DCM), 0°C, 98% yield; (b) Pd/C, Mg, MeOH, rt, 84% yield; (c)Pd(PPh3)2Cl2, PhB(OH)2, Cs2CO3, dioxane/H2O, 120 °C, 3 h,85% yield; (d) NBS, DCM, −40 °C, 81% yield; (e) TBSOTf, Et3N,DCM, rt, 93% yield; (f) Pd/C, H2, EtOAc, rt, 91% yield; (g) K2CO3,MeOH; then Pd on CaCO3, H2, rt, 86%; (h) MePPh3Br, tBuOK,tetrahydrofuran, rt, 88% yield; (i) K2CO3, MeOH; then PhCH2N3,CuI (0.1 equiv), 2,2′-bipyridine (0.1 equiv), DCM, 40 °C, 12 h, 99%.

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dimethoxybenzene (22) followed by bromination of theresulting ketone afforded α-bromoketone 23 in 91% overallyield. Nucleophilic addition of lithium (trimethylsilyl)acetylide (24) to ketone 23 led to an epoxide intermediatewhich was not stable and was hydrolyzed directly to the 1,2-diol 3o. The CPA 4a (5 mol%)-catalyzed enantioselectivepinacol rearrangement of 3o in gram scale (5.0 mmol)afforded, after removal of the TMS group, the enantioenrichedcyclohexanone 25 in 92% yield with 90% ee. A ruthenium-catalyzed anti-Markovnikov hydration of the triple bondfollowing literature procedure34 afforded the aldehyde 2610,12

which, upon intramolecular reductive amination afforded(+)-mesembrane (20).35

In summary, we developed an efficient catalytic enantiose-lective pinacol rearrangement of vicinal tertiary diols andMeinwald rearrangement of tetrasubstituted epoxides. 2-Alkynyl-2-arylcyclohexanones and 2,2-diarylcyclohexanones,inaccessible using the existing synthetic methodologies, wereobtained in excellent yields and enantioselectivities. Theassociation of two noncovalent interactions, i.e., ion-pairingand H-bonding, between the reactive carbenium intermediateand the chiral phosphate might allow the effective chiralitytransfer from catalyst to product.36 The synthetic potential wasillustrated by postfunctionalization of the rearrangementproducts and the development of a concise total synthesis of(+)-mesembrane featuring the catalytic enantioselectivepinacol rearrangement as a strategic transformation.

■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/jacs.9b04551.

Experimental procedures and characterization data,copies of 1H and 13C NMR spectra and SFCchromatograms (PDF)Crystallographic data for 1a (CIF)

■ AUTHOR INFORMATIONCorresponding Author*jieping.zhu@epfl.ch

ORCIDJieping Zhu: 0000-0002-8390-6689NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

We thank financial support from EPFL (Switzerland) and theSwiss National Science Foundation (SNSF 20020-155973).We thank Dr. F.-T. Farzaneh and Dr. Rosario Scopelliti for theX-ray structural analysis of compound 1a.

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Scheme 9. Gram Scale Experiment and Total Synthesis of(+)-Mesembrane

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DOI: 10.1021/jacs.9b04551J. Am. Chem. Soc. 2019, 141, 11372−11377

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