Catalytic Enantioselective Pinacol and Meinwald Rearrangements for

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Catalytic Enantioselective Pinacol and Meinwald Rearrangements for the Construction of Quaternary Stereocenters Hua Wu, Qian Wang, and Jieping Zhu* Laboratory of Synthesis and Natural Products, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, BCH5304, CH-1015 Lausanne, Switzerland

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enantioselective allylation has been developed into a powerful synthetic tool for the synthesis of α,α-dialkyl substituted cyclohexanones,6,7 and elegant enantioselective arylation,8,9 alkylation10 as well as Michael addition11,12 have been devised for the synthesis of α-aryl-α-alkyl substituted counterparts. There is also a report on the enantioselective vinylation of cyclopentanones. However, applying the same conditions to cyclohexanone derivatives led to the arylated products with only moderate enantiomeric excess (ee).13 Catalytic enantioselective synthesis of 2-alkynyl-2-arylcyclohexanones and 2,2diarylcyclohexanones 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 new stereocenter, it is important to control the stereochemical outcome in order to exploit fully its synthetic potential.15 However, the priori formation of a carbenium intermediate before the key C−C bond forming process renders the development of the enantioselective version extremely challenging.16 The classic Lewis and Brønsted acid catalysis is inefficient since the association between the intermediate and the catalyst, a prerequisite for the chirality transfer, is difficult to achieve.17 To date, there are only two examples of successful enantioselective pinacol rearrangements. In their seminal work, Antilla and co-workers developed a chiral phosphoric acid (CPA)-catalyzed rearrangement of indolyl diols (Scheme 2a).18 Subsequently, our group reported an enantioselective vinylogous rearrangement of (E)-butene-1,4diols to enantioenriched β,γ-unsaturated ketones (Scheme 2b).19 Both reactions featured 1,2-aryl migration providing enantioenriched linear ketones bearing an α-tertiary stereocenter. On the other hand, Snyder and co-workers reported a CPA-promoted (1.0 equiv) diastereoselective pinacol rearrangement for the synthesis of a complex α-quaternary aldehyde, a key intermediate in their elegant total synthesis of hopeanol.4 The catalytic enantioselective rearrangement of vicinal tertiary diols to ketones bearing an α-quaternary stereocenter has, to the best of our knowledge, not been realized in spite of the significant synthetic importance of the resulting chiral compounds. We report herein the first examples of such enantioselective processes as well as mechanistically related Meinwald rearrangement20 of epoxides for the synthesis of enantioenriched 2-alkynyl-2-arylcyclohexanones 1 and 2,2-diarylcyclohexanones 2 (Scheme 2c). We

ABSTRACT: The development of enantioselective pinacol rearrangement is extremely challenging due to the likelihood involvement of the carbenium intermediate that renders the stereochemical communication between catalyst and substrate difficult to achieve. Herein, we report chiral N-triflyl phosphoramide-catalyzed enantioselective pinacol rearrangement of 1,2-tertiary diols and mechanistically related Meinwald rearrangement of tetrasubstituted epoxides for the synthesis of enantioenriched 2-alkynyl-2-arylcyclohexanones and 2,2-diarylcyclohexanones, respectively. Total synthesis of (+)-mesembrane featuring the catalytic enantioselective pinacol rearrangement as a key strategic step is also documented.

M

any bioactive natural products and pharmaceuticals, such as mesembrane, 1 gracilamine,1 strychnine,2 stephadiamine,3 hopeanol,4 and dihydrobenzofurans (nonsteroidal estrogen receptor β (ERβ) agonist, Scheme 1a),5 contain cyclohexane bearing an all-carbon quaternary stereocenter as a core structure. 2-Aryl-2-alkyl and 2,2-diaryl substituted cyclohexanones are obvious starting materials for the synthesis of these compounds. The Pd-catalyzed Scheme 1. Cyclohexane Bearing an All-Carbon Quaternary Stereocenter: Occurrence and Asymmetric Synthesis

Received: April 28, 2019 Published: July 6, 2019 © XXXX American Chemical Society

A

DOI: 10.1021/jacs.9b04551 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society Scheme 2. Enantioselective Pinacol Rearrangement: Stateof-the-Art

Scheme 3. Scope of the Catalytic Enantioselective Pinacol Rearrangementa

also document the transformation of the hydroxylated aromatic ring, the alkynyl and the carbonyl groups which allowed easy access to a diverse set of synthetic building blocks. A concise total synthesis of (+)-mesembrane is also accomplished featuring the catalytic enantioselective pinacol rearrangement as 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 = 4OH, c 0.05 M) in the presence of a diverse set of CPAs (0.1 equiv, see SI for details) at room temperature for 12 h afforded 1a as an only isolable regioisomer in excellent yield but with only moderate ee. Although the enantioselectivity was moderate, the exclusive formation of 1a was encouraging as it indicated that only one of the two possible carbocations was generated under these mild conditions. The N-triflyl phosphoramide 4a stood out from this initial screening and was chosen for further optimization of the reaction conditions. After systematically varying the solvents, the additives and the temperature, the optimum conditions found consisted of performing the rearrangement of 3a in toluene (c 0.05 M) at −5 °C in the presence of 4a (0.1 equiv) and 3 Å molecular sieves. 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−Schuster rearrangement25,26 was not formed under these conditions. With the optimized conditions in hand, the scope of this catalytic enantioselective pinacol rearrangement was next examined. As shown in Scheme 3, arylalkyne moieties bearing an electron-donating (Me, MeO) and an electron-withdrawing group (F, Cl) at different positions (para, meta and ortho) are compatible with the reaction conditions (adducts 1a−1i). A heterocycle could also be incorporated into the chiral cyclohexanone product (1j). Pleasingly, alkynes with aliphatic substituents such as tBu (1k), nBu (1l) and functionalized alkyls (1n, 1p) were also well tolerated affording the desired products in excellent yields and enantiopurities. The presence of a free phenol group is not an obligation since other electronrich arenes, such as 4-methoxyphenyl (1m), 3,4-dimethoxyphenyl (1n-1q), benzo[d][1,3]dioxole (1r), dihydrobenzofuran (1s), 2-thiophene group (1t) and benzofuran (1u), were compatible with the reaction conditions to give the corresponding rearranged products in high ee values. The

a

Optimum 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. bThe reaction was performed at −10 °C. cThe reaction was performed at −50 °C. dThe reaction was performed at −40 °C. eThe reaction was performed at −30 °C. All the reactions were performed on a 0.1 mmol scale. The ee was determined by supercritical fluid chromatography (SFC) or high performance liquid chromatography (HPLC) analysis on a chiral stationary phase.

enantioselective pinacol rearrangement of indole C-2 substituted diol could not be examined due to its instability. It is worth noting that alkynes containing various types of functional groups such as halide, trimethylsilyl group (TMS) and benzyl ether group (OBn) were compatible with the reaction conditions to afford the functionalized enantioenriched cyclohexanones (1n−1p and 1r). The (S)-absolute configuration of 1a was determined by X-ray crystallographic B

DOI: 10.1021/jacs.9b04551 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society analysis, and the configuration of the other cyclohexanones were assigned by analogy. We next turned our attention to the mechanistically relevant Meinwald rearrangement.20,24,27 Tetrasubstituted epoxides 6 were readily synthesized by a two-step sequence involving McMurry cross-coupling of two different ketones28 followed by epoxidation of the resulting tetrasubstituted alkenes. Gratifyingly, treatment of a toluene solution of 6 in the presence of catalyst 4a and 4 Å molecular sieves (MS) at −78 °C afforded the 2,2-diarylcyclohexanones 2a−2f in excellent yields with high ee values (Scheme 4). Although water was not generated

Scheme 5. Stability and Reactivity of Epoxides vs Diols

Scheme 4. Synthesis of 2,2-Diarylcyclohexanones from Tetrasubstituted Epoxidesa

a

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

in this reaction, the presence of MS was important for the reaction outcome and we observed that 4 Å MS was a better additive than the 3 Å counterpart in terms of both the yield and the ee of the rearranged product.29 Since the two aryl substituents in 6 are similar in size, the observed enantioselectivity could be attributed to the stereoelectronic effect. The presence of hydroxyl or methoxy group at the para position in one of the aryl groups fixed effectively, via resonance effect, the geometry of the transient carbenium intermediate leading to the observed enantioselectivity. It is worth noting that epoxide 6g bearing an alkynyl substituent was unstable and was readily hydrolyzed to diol 3q during workup and purification processes, while the cyclobutane derivatives 6h and 6i underwent spontaneous rearrangement during their preparation to afford the corresponding cyclopentanone derivatives 7h and 7i (Scheme 5a). For the sake of comparison, we also prepared a diaryl substituted diol 3v and found that it was more stable than the epoxide counterpart 6e toward the rearrangement. Stable at −78 °C, the diol 3v underwent rearrangement only at −10 °C to 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 place sluggishly to provide 1w in only 7% yield (34% ee). These results are important as it not only clearly illustrated the higher reactivity of the epoxide than diol toward the rearrangement,

but also indicated that the presence of an extra cation stabilizing group (OH, OMe) might not be absolutely needed for the development of enantioselective Meinwald rearrangement (Scheme 5c). Desymmetrizative Meinwald rearrangement was next explored to extend further its application scope (Scheme 6). Epoxidation of alkene 8 with mCPBA afforded the epoxide 9 in 91% yield as a mixture of two diastereomers. Under standard conditions, rearrangement of epoxide 9 furnished 10 in 99% yield with 87% ee. The 3,3-diaryl substituted octahydronaphthalen-2-(1H)-one harboring three stereocenters would not be easily prepared by the known methodologies. Scheme 6. Desymmetrizative Meinwald Rearrangement

a

C

Only the major diastereomer 9 is shown for the sake of clarity. DOI: 10.1021/jacs.9b04551 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society While no detailed mechanistic studies were carried out,30 a plausible reaction pathway for the enantioselective pinacol rearrangement was proposed as illustrated in Scheme 7. The

Scheme 8. Synthetic Transformations of the Rearranged Productsa

Scheme 7. Possible Reaction Pathway of the Pinacol Rearrangement

a Reaction 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%.

N-triflyl phosphoramide 4a would act as a bifunctional catalyst to form a 9-membered ring intermediate A and B with the 1,2diol 3 via hydrogen bonding. The selective dehydration of B delivering the carbocation C would be kinetically and thermodynamically favored. Indeed, the presence of an alkynyl and an electron-rich aryl group would be capable of stabilizing the carbenium intermediate C via the resonance structures C′ and C″. Although ion-pairing itself is nondirectional, its association with the hydrogen bond in C might be able to impose a preorganized three-dimensional structure for the efficient chirality transfer in the subsequent 1,2-alkyl shift process leading to ketone 1. The fact that Meyer−Schuster rearrangement product 5 was not observed under our conditions indicated that the 1,2-alkyl shift was much faster than the intermolecular nucleophilic trapping of the intermediate C″. Although 2- and 4-hydroxybenzyl alcohol derivatives have been used in CPA-catalyzed asymmetric transformations, all the literature precedents involved the in situ generation of neutral quinomethide intermediates. As the 2- and 4-methoxybenzyl alcohols were ineffective substrates in these literature examples, H-bonding rather than ion-pairing was proposed to be responsible for the asymmetric induction.31 It is therefore interesting to note that both pathways are apparently operational in the present pinacol and Meinwald rearrangement reactions.19,32 The presence of a phenol group provided a versatile handle for the functionalization of the rearranged products. As depicted in Scheme 8a, triflation of 1b under standard conditions (Tf2O, Py, CH2Cl2) afforded the triflate 11 in 98% yield. Reduction of 11 under single electron transfer conditions (Pd/C, Mg, MeOH) provided 12 with an unsubstituted phenyl ring.33 Pd-catalyzed Suzuki-Miyaura cross coupling of 11 with phenyl boronic acid provided a

biphenyl substituted derivative 13. On the other hand, treatment of 1b with N-bromosuccinimide (NBS) afforded the dibrominated product 14 that was armed for the further functionalization. The alkynyl group is also amenable to a diverse set of chemical transformations. Treatment of 1o with tertbutyldimethylsilyl trifluoromethanesulfonate (TBSOTf) afforded 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 in 91% yield. Removal of the trimethylsilyl group from 1o followed by hydrogenation over Lindlar’s catalyst provided the 2-vinyl-2-aryl substituted cyclohexanone 17 in 86% yield over two steps. Wittig reaction of the sterically hindered carbonyl group of 1o occurred smoothly to afford methylenecyclohexane 18 in high yield. Finally, removal of TMS group from 1o followed by CuI-catalyzed [3+2] cycloaddition of the resulting terminal alkyne with benzyl azide afforded triazole 19 in 99% yield. This last example showcased the advantage of our methodology 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) was undertaken (Scheme 9). AlCl3-mediated Friedel−Crafts reaction of cyclopentanecarbonyl chloride (21) with 1,2D

DOI: 10.1021/jacs.9b04551 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society ORCID

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

Jieping Zhu: 0000-0002-8390-6689 Notes

The authors declare no competing financial interest.

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

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(1) Zhong, J. Amaryllidaceae and Sceletium Alkaloids. Nat. Prod. Rep. 2016, 33, 1318. (2) (a) Bonjoch, J.; Solé, D. Synthesis of Strychnine. Chem. Rev. 2000, 100, 3455. (b) Cannon, J. S.; Overman, L. E. Is There No End to the Total Syntheses of Strychnine? Lessons Learned in Strategy and Tactics in Total Synthesis. Angew. Chem., Int. Ed. 2012, 51, 4288. (3) Hartrampf, N.; Winter, N.; Pupo, G.; Stoltz, B. M.; Trauner, D. Total Synthesis of the Norhasubanan Alkaloid Stephadiamine. J. Am. Chem. Soc. 2018, 140, 8675. (4) Total synthesis featuring a diastereoselective pinacol rearrangement as a key step, see: Snyder, S. A.; Thomas, S. B.; Mayer, A. C.; Breazzano, S. P. Total Syntheses of Hopeanol and Hopeahainol A Empowered by a Chiral Brønsted Acid Induced Pinacol Rearrangement. Angew. Chem., Int. Ed. 2012, 51, 4080. (5) Sundén, H.; Ma, J.-N.; Hansen, L. K.; Gustavsson, A.-L.; Burstein, E. S.; Olsson, R. Design of a Highly Selective and Potent Class of Nonplanar Estrogen Receptor β Agonists. ChemMedChem 2013, 8, 1283. (6) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740. (7) Quasdorf, K. W.; Overman, L. E. Catalytic Enantioselective Synthesis of Quaternary Carbon Stereocentres. Nature 2014, 516, 181. (8) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. An Improved Catalyst for the Asymmetric Arylation of Ketone Enolates. J. Am. Chem. Soc. 2002, 124, 1261. (9) Liao, X.; Weng, Z.; Hartwig, J. F. Enantioselective α-Arylation of Ketones with Aryl Triflates Catalyzed by Difluorphos Complexes of Palladium and Nickel. J. Am. Chem. Soc. 2008, 130, 195. (10) Kano, T.; Hayashi, Y.; Maruoka, K. Construction of a Chiral Quaternary Carbon Center by Catalytic Asymmetric Alkylation of 2Arylcyclohexanones under Phase-transfer Conditions. J. Am. Chem. Soc. 2013, 135, 7134. (11) Felker, I.; Pupo, G.; Kraft, P.; List, B. Design and Enantioselective Synthesis of Cashmeran Odorants by Using “Enol Catalysis. Angew. Chem., Int. Ed. 2015, 54, 1960. (12) Yang, X.; Toste, F. D. Asymmetric Addition of α-Branched Cyclic Ketones to Allenamides Catalyzed by a Chiral Phosphoric Acid. Chem. Sci. 2016, 7, 2653. (13) Chieffi, A.; Kamikawa, K.; Åhman, J.; Fox, J. M.; Buchwald, S. L. Catalytic Asymmetric Vinylation of Ketone Enolates. Org. Lett. 2001, 3, 1897. (14) Fittig, R. Ueber inige Derivate des Acetons. Justus Liebigs Ann. Chem. 1860, 114, 54. (15) For a review on semi-pinacol rearrangement, see: Wang, B.; Tu, Y.-Q. Stereoselective Construction of Quaternary Carbon Stereocenters via a Semipinacol Rearrangement Strategy. Acc. Chem. Res. 2011, 44, 1207. (16) (a) Wu, H.; Wang, Q.; Zhu, J. Recent Advances in Catalytic Enantioselective Rearrangement. Eur. J. Org. Chem. 2019, 2019, 1964. (b) Gualandi, A.; Cozzi, P. G. Stereoselective Organocatalytic Alkylations with Carbenium Ions. Synlett 2013, 24, 281.

dimethoxybenzene (22) followed by bromination of the resulting ketone afforded α-bromoketone 23 in 91% overall yield. Nucleophilic addition of lithium (trimethylsilyl) acetylide (24) to ketone 23 led to an epoxide intermediate which was not stable and was hydrolyzed directly to the 1,2diol 3o. The CPA 4a (5 mol%)-catalyzed enantioselective pinacol rearrangement of 3o in gram scale (5.0 mmol) afforded, after removal of the TMS group, the enantioenriched cyclohexanone 25 in 92% yield with 90% ee. A rutheniumcatalyzed anti-Markovnikov hydration of the triple bond following literature procedure34 afforded the aldehyde 2610,12 which, upon intramolecular reductive amination afforded (+)-mesembrane (20).35 In summary, we developed an efficient catalytic enantioselective pinacol rearrangement of vicinal tertiary diols and Meinwald rearrangement of tetrasubstituted epoxides. 2Alkynyl-2-arylcyclohexanones and 2,2-diarylcyclohexanones, inaccessible using the existing synthetic methodologies, were obtained in excellent yields and enantioselectivities. The association of two noncovalent interactions, i.e., ion-pairing and H-bonding, between the reactive carbenium intermediate and the chiral phosphate might allow the effective chirality transfer from catalyst to product.36 The synthetic potential was illustrated by postfunctionalization of the rearrangement products and the development of a concise total synthesis of (+)-mesembrane featuring the catalytic enantioselective pinacol rearrangement as a strategic transformation.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b04551. Experimental procedures and characterization data, copies of 1 H and 13 C NMR spectra and SFC chromatograms (PDF) Crystallographic data for 1a (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*jieping.zhu@epfl.ch

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DOI: 10.1021/jacs.9b04551 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Communication

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M. N.; Rodriguez, J. B. Mechanistic Insights into a Chiral Phosphoric Acid-Catalyzed Asymmetric Pinacol Rearrangement. J. Org. Chem. 2018, 83, 14683. (b) For the enantioselective Povarov reaction, see: Calleja, J.; González-Pérez, A. B.; De Lera, A. R.; Á lvarez, R.; Fañanás, F. J.; Rodríguez, F. Enantioselective Synthesis of Hexahydrofuro[3,2c] quinolines through a Multicatalytic and Multicomponent Process. A New “aromatic sandwich” Model for BINOL-Phosphoric Acid Catalyzed Reactions. Chem. Sci. 2014, 5, 996. (31) For a selected example of catalytic enantioselective transformations involving neutral orthoquino methide intermediates, see: (a) Wilcke, D.; Herdtweck, E.; Bach, T. Enantioselective Brønsted Acid Catalysis in the Friedel−Crafts Reaction of Indoles with Secondary ortho-Hydroxybenzylic Alcohols. Synlett 2011, 2011, 1235. (b) El-Sepelgy, O.; Haseloff, S.; Alamsetti, S. K.; Schneider, C. Brønsted Acid Catalyzed, Conjugate Addition of β-Dicarbonyls to In Situ Generated ortho-Quinone Methides-Enantioselective Synthesis of 4-Aryl-4H-Chromenes. Angew. Chem., Int. Ed. 2014, 53, 7923. (c) Hsiao, C.-C.; Liao, H.-H.; Rueping, M. Enantio- and Diastereoselective Acess to Distant Stereocenters Embedded within Tetrahydroxanthenes: Utilizing ortho-Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalysis. Angew. Chem., Int. Ed. 2014, 53, 13258. (d) Wang, Z.; Ai, F.; Wang, Z.; Zhao, W.; Zhu, G.; Lin, Z.; Sun, J. Organocatalytic Asymmetric Synthesis of 1,1Diarylethanes by Transfer Hydrogenation. J. Am. Chem. Soc. 2015, 137, 383. (e) Hsiao, C.-C.; Raja, S.; Liao, H.-H.; Atodiresei, I.; Rueping, M. Ortho-Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalyzed Cycloadditions with Unactivated Alkenes by Exclusive Activation of the Electrophile. Angew. Chem., Int. Ed. 2015, 54, 5762. (f) Zhao, W.; Wang, Z.; Chu, B.; Sun, J. Enantioselective Formation of All-carbon Quaternary Stereocenters from Indoles and Tertiary Alcohols Bearing a Directing Group. Angew. Chem., Int. Ed. 2015, 54, 1910. (g) Zhao, J.-J.; Sun, S.-B.; He, S.-H.; Wu, Q.; Shi, F. Catalytic Asymmetric Inverse-Electron-Demand Oxa-Diels−Alder Reaction of In Situ Generated ortho-Quinone Methides with 3-Methyl-2-Vinylindoles. Angew. Chem., Int. Ed. 2015, 54, 5460. (h) Li, S.; Zhang, J.-W.; Li, X.-L.; Cheng, D.-J.; Tan, B. Phosphoric Acid-Catalyzed Asymmetric Synthesis of SPINOL Derivatives. J. Am. Chem. Soc. 2016, 138, 16561. (i) Xie, Y.; List, B. Catalytic Asymmetric Intramolecular [4 + 2] Cycloaddition of In Situ Generated ortho-Quinone Methides. Angew. Chem., Int. Ed. 2017, 56, 4936. (j) Lin, J.-S.; Li, T.-T.; Liu, J.-R.; Jiao, G.-Y.; Gu, Q.-S.; Cheng, J.-T.; Guo, Y.-L.; Hong, X.; Liu, X.-Y. Cu/Chiral Phosphoric AcidCatalyzed Asymmetric Three-Component Radical-Initiated 1,2Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc. 2019, 141, 1074. (32) Qian, D.; Wu, L.; Lin, Z.; Sun, J. Organocatalytic Synthesis of Chiral Tetrasubstituted Allenes From Racemic Propargylic Alcohols. Nat. Commun. 2017, 8, 567. (33) Mori, A.; Mizusaki, T.; Ikawa, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Mechanistic Study of a Pd/C-catalyzed Reduction of Aryl Sulfonates Using the Mg-MeOH-NH4OAc System. Chem. - Eur. J. 2007, 13, 1432. (34) Li, L.; Zeng, M.; Herzon, S. B. Broad-spectrum Catalysts for the Ambient Temperature anti-Markovnikov Hydration of Alkynes. Angew. Chem., Int. Ed. 2014, 53, 7892. (35) (a) Verma, P.; Chandra, A.; Pandey, G. Diversity-oriented Approach toward the Syntheses of Amaryllidaceae Alkaloids via a Common Chiral Synthon. J. Org. Chem. 2018, 83, 9968. (b) Bao, X.; Wang, Q.; Zhu, J. Palladium-Catalyzed Enantioselective Desymmetrizing Aza-Wacker Reaction: Development and Application to the Total Synthesis of (−)-Mesembrane and (+)-Crinane. Angew. Chem., Int. Ed. 2018, 57, 1995 and references cited therein. . (36) For an alternative activation mode of carbenium, see: Tsuji, N.; Kennemur, J. L.; Buyck, T.; Lee, S.; Prévost, S.; Kaib, P. S. J.; Bykov, D.; Farès, C.; List, B. Activation of Olefins via Asymmetric Brønsted Acid Catalysis. Science 2018, 359, 1501.

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DOI: 10.1021/jacs.9b04551 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX