The Palladium-Catalyzed Asymmetric Prenylation of Oxindoles and Its Application to the Synthesis of Natural Products

THE PALLADIUM-CATALYZED ASYMMETRIC PRENYLATION OF OXINDOLES AND ITS APPLICATION TO THE SYNTHESIS OF NATURAL PRODUCTS

A DISSERTATION

SUBMITTED TO THE DEPARTMENT OF CHEMISTRY

AND THE COMMITTEE ON GRADUATE STUDIES

OF STANFORD UNIVERSITY

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS

FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

WALTER HIU-WO CHAN

DECEMBER 2016

This work is licensed under a Creative Commons Attribution- Noncommercial 3.0 United States License. http://creativecommons.org/licenses/by-nc/3.0/us/

This dissertation is online at: http://purl.stanford.edu/tr271dd4293

ii I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy.

Barry Trost, Primary Adviser

I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy.

Matthew Kanan

I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy.

Robert Waymouth

Approved for the Stanford University Committee on Graduate Studies. Patricia J. Gumport, Vice Provost for Graduate Education

This signature page was generated electronically upon submission of this dissertation in electronic format. An original signed hard copy of the signature page is on file in University Archives.

iii Abstract

The dimethylallyl or prenyl group is the fundamental structural motif in terpene natural products and is also frequently incorporated into other types of macromolecules and secondary metabolites. Notable among the latter are the prenylated indole alkaloids, which contain a tryptophan residue decorated with one or more isoprene units. The wide-ranging spectrum of promising biological activities exhibited by these alkaloids has stimulated interest in their biosynthesis and chemical synthesis. The selective incorporation of a 3,3-dimethylallyl (“linear” prenyl) or 1,1- dimethylallyl (“reverse” prenyl) at the 3-position of a 3-substituted indole derivative raises the daunting challenge of controlling chemoselectivity, regioselectivity and enantioselectivity in a single process. This work describes our efforts to design a Pd- catalyzed asymmetric prenylation of 3-substituted oxindoles that afforded access to both the linear and reverse-prenylated products. In both caees a quaternary stereocentre was formed that previously was not directly available via a catalytic asymmetric method, and in the case of reverse prenylation, the new C–C bond was formed between this stereocentre and a second quaternary carbon. The Pd-catalyzed allylic alkylation is popularly believed to exhibit a preference for nucleophilic attack at the less substituted carbon to afford the “linear” alkylation products. However, by careful manipulation of the reaction parameters, including the choice of ligand and solvent and the inclusion of halide additives, it was demonstrated that this bias can be reversed to favour nucleophilic attack at the more substituted and electrophilic carbon, thereby affording the “branched” products. Indeed, in our optimized conditions for the regiodivergent asymmetric prenylation of oxindoles, regioselectivities observed under the reverse- prenylation conditions typically exceeded those observed under the linear-prenylation conditions. A variety of 3-substituted and N-protected oxindoles performed well under our optimized reaction conditions. 3-Alkyloxindoles bearing a nearby electron-withdrawing group afforded reverse-prenylated products with good regioselectivity and enantioselectivities as high as 99% ee, and linear-prenyl products were synthesized from the same substrates with moderate regioselectivities and enantioselectivities generally iv exceeding 90% ee. 3-Aryloxindoles afforded reverse-prenylated products with good regioselectivity and enantioselectivities between 80% and 88% ee, and linear- prenylated products with more modest regioselectivities but enantioselectivities ranging from 91% to 99% ee. The alkylation of monoterpene-derived electrophiles using this methodology was also investigated. Enantioenriched 3,3-disubstituted oxindoles bearing a geranyl or neryl group were prepared in good yield, regioselectivity and enantioselectivity from the corresponding geraniol- and nerol-derived electrophiles when ethereal solvents were used. In addition, switching to the use of dichloromethane as a solvent led to a reversal of the regioselectivity in the alkylation of the nerylpalladium species, delivering the linalylated product as a single diastereomer in excellent yield and ee. To the best of our knowledge, this result represents the first known example of vicinal quaternary stereocentres being formed via the Pd-catalyzed asymmetric allylic alkylation. The potential utility of this methodology in natural product synthesis was demonstrated through the efficient total syntheses of ent-flustramides A and B as well as ent-flustramines A and B. By comparing the optical rotation of the natural products to that of the compounds made via asymmetric prenylation, the absolute stereochemistry of the prenylated oxindole products was assigned. This led to the surprising observation that the same enantiomer of ligand produced linear and branched regioisomers of opposite chirality. Efforts were also made toward the total synthesis of meleagrin and its naturally occurring, biologically active derivatives via application of the asymmetric prenylation methodology, and the syntheses of two advanced fragments comprising all the carbon atoms found in the natural product are described.

Contents

1 C3-reverse-prenylated indole derivatives ...... 1 1.1 Introduction ...... 1 1.2 Biologically active C3-reverse-prenylated indole alkaloids ...... 2 1.2.1 The roquefortine/meleagrin family of alkaloids ...... 2 1.2.2 Other fungal alkaloids containing a C3-prenylated tryptophan ...... 3 1.2.3 The flustramine family of alkaloids ...... 4 1.3 Synthesis of C3-reverse-prenylated indole derivatives ...... 5 1.3.1 Synthesis via Claisen rearrangement ...... 7 1.3.2 Synthesis via [2,3]-Wittig rearrangement ...... 11 1.3.3 Synthesis via 2,3-prenyl migration on the indole ...... 13 1.3.4 Synthesis via the use of stoichiometric prenylmetal reagents ...... 14 1.3.5 Synthesis via transition metal catalysis...... 20 1.4 Conclusion ...... 28 1.5 References ...... 29 2 Cross-coupling reactions of substituted allyl donors ...... 36 2.1 Introduction ...... 36 2.2 Cross-coupling of allyltin reagents ...... 37 2.3 Cross-coupling of allylsilane reagents ...... 39 2.4 Cross-coupling of allylcopper reagents ...... 46 2.5 Cross-coupling of allylmagnesium reagents ...... 47 2.6 Cross-coupling of allylboron reagents ...... 48 2.6.1 Arylation ...... 48 2.6.2 Allylation ...... 59 2.6.3 Acylmethylation ...... 69 2.6.4 Acylation ...... 70 2.7 Cross-coupling of allylzinc reagents ...... 71 2.8 Cross-coupling of allylgermanium reagents ...... 73 2.9 Cross-coupling of allylaluminum reagents ...... 73 2.10 Cross-coupling of allylzirconium reagents ...... 74 2.11 Cross-coupling of allylmetals generated via retro-allylation ...... 74 2.12 Cross-coupling via allylic C–H bond activation ...... 80 2.13 Conclusion ...... 81 2.14 References ...... 82 3 Pd-catalyzed asymmetric prenylation of 3-alkyloxindoles ...... 86

3.1 Introduction ...... 86 3.2 Optimization of the asymmetric prenylation of 3-alkyloxindoles by Sushant Malhotra .... 95 3.3 Scope of the asymmetric prenylation of 3-alkyloxindoles ...... 99 3.4 Synthesis of flustramine alkaloids and determination of absolute stereochemistry in the prenylation reaction ...... 103 3.5 Asymmetric geranylation of 3-alkyloxindoles ...... 106 3.6 Experimental ...... 111 3.6.1 General methods ...... 111 3.6.2 Preparation of electrophiles ...... 112 3.6.3 Preparation of oxindole nucleophiles ...... 115 3.6.4 Preparation of prenylated and reverse-prenylated 3-alkyloxindoles ...... 134 3.6.5 Synthesis of (+)-flustramides A and B and (+)-flustramines A and B ...... 164 3.6.6 Optimized procedures for the asymmetric linalylation, geranylation and nerylation of 2- (1-allyl-6-bromo-2-oxoindolin-3-yl)acetonitrile ...... 168 3.6.7 Determination of the relative stereochemistry of 2-(1-allyl-6-bromo-3-(3,7-dimethylocta- 1,6-dien-3-yl)-2-oxoindolin-3-yl)acetonitrile ...... 172 3.7 References ...... 173 4 Pd-catalyzed asymmetric prenylation of 3-aryloxindoles ...... 178 4.1 Introduction ...... 178 4.2 Optimization of the asymmetric prenylation of 3-aryloxindoles ...... 178 4.3 Substrate scope of the reverse and linear prenylation of 3-aryloxindoles ...... 186 4.4 Conclusion ...... 189 4.5 Experimental ...... 190 4.5.1 General methods ...... 190 4.5.2 Prenylation and reverse prenylation of 3-aryloxindoles ...... 191 4.6 References ...... 204 5 Efforts toward the total synthesis of the oxaline/meleagrin alkaloids ...... 206 5.1 Introduction ...... 206 5.2 Retrosynthetic analysis of the meleagrin alkaloids ...... 213 5.3 Synthesis of N-methoxyoxindole substrates for asymmetric prenylation ...... 214 5.4 Installation of the side chain at the 3-position of the oxindole ...... 219 5.5 Asymmetric reverse prenylation of oxindole 5.4.2 ...... 221 5.6 Further manipulation of prenylated nitrile 5.5.1 ...... 224 5.7 Synthesis of the imidazole-containing fragment ...... 225 5.7.1 The formamidation strategy ...... 226 5.7.2 The isocyanoacetate aldol strategy ...... 227 5.7.3 The Heck reaction strategy ...... 228 vii

5.7.4 The Horner-Wadsworth-Emmons olefination strategy ...... 229 5.7.5 Attempts to dehydrate formamide 5.7.17 ...... 230 5.8 Experimental ...... 231 5.8.1 General methods ...... 231 5.9 References ...... 238 Appendix A: Selected Spectra for Chapter 3 ...... 242 Appendix B: Selected Spectra for Chapter 4 ...... 306 Appendix C: Selected Spectra for Chapter 5 ...... 330

viii

List of Schemes Scheme 1.1: Numbering scheme for tryptophan and prenyl group nomenclature ...... 1 Scheme 1.2: Proposed biosynthetic pathway of the roquefortine/meleagrin alkaloids ...... 2 Scheme 1.3: Other reverse-prenylated indole alkaloids derived from fungi ...... 3 Scheme 1.4: Reverse-prenylated flustramine alkaloids and an example of a linear-prenylated flustramine ...... 4 Scheme 1.5: Electrophilic prenylation of indole and tryptamine ...... 5 Scheme 1.6: Claisen rearrangements of 2-(prenylthio)indoles ...... 7 Scheme 1.7: [3,3]-Sigmatropic rearrangement of a sulfur ylide ...... 8 Scheme 1.8: Claisen rearrangement of a 2-(prenyloxy)indole ...... 9 Scheme 1.9: In situ formation and Claisen rearrangement of chiral 2-(prenyloxy)indoles ...... 10 Scheme 1.10: Diastereoselective Claisen rearrangement of 2-(prenyloxy)indoles ...... 11 Scheme 1.11: Indole epoxidation followed by prenyl migration ...... 13 Scheme 1.12: Oxidative cyclization of a tryptamine followed by prenyl migration ...... 14 Scheme 1.13: Conjugate addition of prenylmagnesium bromide to 2-cyanoacrylates ...... 14 Scheme 1.14: Diastereoselective selenenylation-prenylation of a tryptophan ...... 15 Scheme 1.15: Natural products accessed from intermediate 1.3.42 ...... 16 Scheme 1.16: Oxidative cyclization-prenylation of tryptophols ...... 17 Scheme 1.17: Diastereoselective bromination-prenylation of a tryptophan ...... 18 Scheme 1.18: Ir-catalyzed reverse prenylation of 3-substituted indoles ...... 21 Scheme 1.19: Ir-catalyzed exo-selective reverse prenylation of tryptophans ...... 22 Scheme 1.20: Ir-catalyzed diastereodivergent reverse prenylation of tryptophans ...... 23 Scheme 1.21: Ir-catalyzed diastereoselective reverse prenylations using triethylborane ...... 24 Scheme 1.22: Ir-catalyzed reverse prenylation of isatins via transfer hydrogenation ...... 25 Scheme 1.23: Pd-catalyzed regiodivergent prenylation of 3-alkyloxindoles ...... 26 Scheme 1.24: Pd-catalyzed regiodivergent geranylation of 3-alkyloxindoles ...... 27 Scheme 2.1: Cross-coupling of allyl donors ...... 36 Scheme 2.2: Cross-coupling of allyltributyltin with aryl halides ...... 37 Scheme 2.3: Cross-coupling of allylstannanes with allyl electrophiles ...... 37 Scheme 2.4: Branched-selective cross-coupling of allyltrifluorosilanes ...... 39 Scheme 2.5: Mechanism of the cross-coupling of allyltrifluorosilanes ...... 41 Scheme 2.6: Linear-selective cross-coupling of allyltrifluorosilanes ...... 42 Scheme 2.7: Branched-selective cross-coupling of crotylsilanolates ...... 43 Scheme 2.8: Synthesis of a phenol from crotylsilanolate 2.3.9 ...... 44 Scheme 2.9: Improved conditions for the branched-selective cross-coupling of crotylsilanolates ...... 45 Scheme 2.10: Cross-coupling of crotyl and prenyl cyanocuprates ...... 46

Scheme 2.11: Co-catalyzed coupling of allylmagnesium reagents ...... 47 Scheme 2.12: Suzuki coupling of crotylboron reagents...... 48 Scheme 2.13: Arylation of allylboronic acids and a proposed mechanism...... 49 Scheme 2.14: Enantioselective branched-selective arylation of crotyltrifluoroborates ...... 51 Scheme 2.15: Linear-selective arylation of prenylboronates with Pd-NHC complexes ...... 52 Scheme 2.16: Scope of the linear-selective arylation of prenylboronates ...... 54 Scheme 2.17: Ligand-controlled regiodivergent arylation of prenylboronates ...... 55 Scheme 2.18: Ligand control in the regiodivergent arylation of other allylboronates ...... 56 Scheme 2.19: Regioselectivity in the arylation of 1,3-disubstituted allylboronic esters...... 57 Scheme 2.20: Arylation of enantiopure or deuterated 1,3-disubstituted allylboronic esters ...... 58 Scheme 2.21: Ligand regiocontrol in the allylation of monosubstituted allylic carbonates ...... 59 Scheme 2.22: Enantioselective and branched-selective allylation of monosubstituted allylic carbonates ...... 60 Scheme 2.23: Mechanistic studies and proposal for the allylation of monosubstituted allylic carbonates ...... 61 Scheme 2.24: Enantioselective and diastereoselective crotylation of monosubstituted allylic chlorides 63 Scheme 2.25: Branched-selective prenylation of monosubstituted allylic chlorides ...... 64 Scheme 2.26: Further studies in the coupling of substituted allylboronates with allylic chlorides ...... 65 Scheme 2.27: Enantioselective allylation of 1,1-disubstituted allylic electrophiles ...... 66 Scheme 2.28: Regioselective allylation of 1,1,3-trisubstituted allylic acetates ...... 67 Scheme 2.29: Cross-coupling of allylboronic acids with diazoketones ...... 69 Scheme 2.30: Crotylation of benzoyl chlorides ...... 70 Scheme 2.31: Use of a linear-selective allylzinc cross-coupling in the total synthesis of siamenol ...... 71 Scheme 2.32: Linear-selective cross-coupling of allylzinc pivalates ...... 72 Scheme 2.33: Pd-catalyzed cross-coupling of germatrane 2.8.1...... 73 Scheme 2.34: Pd-catalyzed cross-coupling of allylalane 2.10.1 ...... 73 Scheme 2.35: Ni-catalyzed cross-coupling of crotylzirconium reagent 2.9.1 ...... 74 Scheme 2.36: Cross-coupling of an allylpalladium species generated via retro-allylation ...... 74 Scheme 2.37: Regio- and stereoselectivity in the retro-allylative coupling ...... 75 Scheme 2.38: Variation of reaction conditions for the retro-allylative coupling ...... 77 Scheme 2.39: Retro-allylative coupling of substituted allyl precursors ...... 78 Scheme 2.40: Ni- and Pd-catalyzed retro-allylative coupling with allylic carbonates...... 79 Scheme 2.41: Photoredox-mediated cross-coupling of olefins and cyanoarenes ...... 80 Scheme 3.1: Mechanism of palladium-catalyzed allylic alkylation ...... 87 Scheme 3.2: Pd-catalyzed prenylation of carbon nucleophiles ...... 87 Scheme 3.3: Pd-catalyzed prenylation in the synthesis of (±)-trans-chrysanthemic acid ...... 88 Scheme 3.4: Pd-catalyzed geranylation and nerylation ...... 89 x

Scheme 3.5: Internal coordination in nerylpalladium and geranylpalladium complexes ...... 90 Scheme 3.6: Effect of internal olefin on regioselectivity of alkylation ...... 91 Scheme 3.7: Pd-catalyzed prenylation of nitrogen nucleophiles ...... 94 Scheme 3.8: Asymmetric reverse prenylation of 3-alkyloxindoles ...... 99 Scheme 3.9: Asymmetric linear prenylation of 3-alkyloxindoles ...... 102 Scheme 3.10: Catalytic asymmetric synthesis of ent-flustramides and ent-flustramines A and B ...... 104 Scheme 3.11: Geranylated, farnesylated and linalylated indole alkaloids ...... 106 Scheme 3.12: Determination of relative stereochemistry of compound 3.5.2 ...... 108 Scheme 4.1: Substrate scope of the reverse prenylation of 3-aryloxindoles ...... 186 Scheme 4.2: Substrate scope of the linear prenylation of 3-aryloxindoles ...... 188 Scheme 5.1: The oxaline/meleagrin alkaloids ...... 206 Scheme 5.2: First steps in the synthesis of the oxaline core ...... 207 Scheme 5.3: Completion of the synthesis of the oxaline core ...... 208 Scheme 5.4: Asymmetric synthesis of (+)-neoxaline (part 1) ...... 209 Scheme 5.5: Asymmetric synthesis of (+)-neoxaline (part 2) ...... 211 Scheme 5.6: Retrosynthetic analysis of meleagrin ...... 213 Scheme 5.7: Synthesis of 1-methoxyoxindole...... 214 Scheme 5.8: Synthesis of 1-methoxyisatin from 1-methoxyoxindole ...... 216 Scheme 5.9: Unsuccessful syntheses of 1-hydroxyisatin from o-nitrophenylacetic acid ...... 217 Scheme 5.10: Attempted syntheses of 1-methoxyisatin from indoline ...... 218 Scheme 5.11: Preparation of 1-methoxy-3-(cyanomethyl)oxindole ...... 219 Scheme 5.12: Asymmetric prenylation of other N-methoxyoxindoles ...... 223 Scheme 5.13: Hydrolysis of nitrile 5.5.1 to carboxylic acid 5.6.3 ...... 224 Scheme 5.14: Four synthetic approaches to the imidazole-containing fragment...... 225 Scheme 5.15: Synthesis of HWE reagent 5.7.16 and olefination of aldehyde 5.7.6 ...... 229

List of Tables Table 1.1: Phase-transfer-catalyzed [2,3]-Wittig rearrangement ...... 11 Table 1.2: Diastereoselective allylation and reverse prenylation of chiral isatin ketimines ...... 19 Table 1.3: Regioselective 3-tert-prenylation of indole ...... 20 Table 2.1: Regioselectivity in the cross-coupling of allylstannanes with aryl halides ...... 38 Table 2.2: Ligand control in the regioselective cross-coupling of crotyltrifluorosilanes ...... 40 Table 2.3: Effect of crotylsilanolate geometry on regiochemistry of cross-coupling ...... 44 Table 2.4: Regioselectivity in the arylation of crotyltrifluoroborates and a mechanistic proposal ...... 50 Table 2.5: Regioselective allylation of 1,3-disubstituted allylic acetates ...... 67 Table 2.6: Allylation of enantioenriched 1,1,3-trisubstituted allylic acetates ...... 68 Table 3.1: Effect of ligand and nature of nucleophile on the Pd-catalyzed prenylation ...... 92 Table 3.2: Selected optimization studies on the regioselective synthesis of oxindoles 3.2.3 and 3.2.4 ... 96 Table 3.3: Optimization of the reverse prenylation of oxindole 3.3.13 ...... 101 Table 3.4: Alkylation of oxindole 3.2.2 with racemic linalyl carbonate 3.5.1 ...... 107 Table 3.5: Optimization of linalylation, geranylation and nerylation conditions ...... 109 Table 4.1: Ligand screen for the asymmetric reverse prenylation of oxindole 4.2.1 ...... 178 Table 4.2: Influence of solvent and halide on the reverse prenylation of oxindole 4.2.1 ...... 180 Table 4.3: Further optimization of the asymmetric reverse prenylation of oxindole 4.2.1 ...... 182 Table 4.4: Ligand and solvent screen for the asymmetric linear prenylation of oxindole 4.2.1 ...... 183 Table 4.5: Optimization of reaction parameters for the asymmetric linear prenylation of oxindole 4.2.1 ...... 184 Table 5.1: Attempts to oxidize 1-methoxyoxindole to 1-methoxyisatin ...... 215 Table 5.2: Optimization of the asymmetric reverse prenylation of oxindole 5.4.2 ...... 221 Table 5.3: Synthesis of α-bromourocanate derivatives and screening of conditions for the metal- mediated/catalyzed formamidation ...... 226 Table 5.4: Attempted isocyanoacetate aldol condensation ...... 227 Table 5.5: Attempted Heck reactions with 4-haloimidazoles and enamide 5.7.10 ...... 228 Table 5.6: Attempted dehydration of formamide 5.7.17 ...... 230

xii

List of Figures Figure 3.1: Selected examples of flustramine alkaloids ...... 103 Figure 3.2: Rationale for the divergent stereochemistry in the reverse and linear-prenyl products ...... 105 Figure 4.1: Chiral ligands used in Tables 4.1 and 4.4 ...... 179

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To my parents

xiv

1 C3-reverse-prenylated indole derivatives

1.1 Introduction

Scheme 1.1: Numbering scheme for tryptophan and prenyl group nomenclature

Prenylated indole alkaloids comprise an extensive family of secondary metabolites in which a tryptophan residue is decorated with one or more isoprene units. Examples of indoles bearing either a 3,3-dimethylallyl (“linear” prenyl) or a 1,1- dimethylallyl (“reverse” prenyl, “tert-prenyl”, or “isoprenyl”) group on N1, C2, C3, C5 or C7 have been found in natural products, as are indoles substituted with linear prenyl groups at the C4 and C6 positions. Prenylated indole alkaloids have been found in a variety of natural sources, most commonly in Penicillium and Aspergillus fungi, but also in cyanobacteria and bryozoans. The broad spectrum of promising biological activities exhibited by this family of alkaloids has stimulated interest in their biosynthesis and chemical synthesis.1 The selective linear or reverse prenylation of one position of the indole raises issues of chemoselectivity and regioselectivity. The reverse prenylation of C3-substituted indoles poses a particularly interesting challenge in that it entails the formation of a C–C bond between two quaternary centres, one of which is a stereocentre. This review will briefly highlight the range of biologically active natural products containing a C3-reverse- prenylated indole core, and then cover the diversity of methods that have been developed to access these compounds and related structures.

1.2 Biologically active C3-reverse-prenylated indole alkaloids

1.2.1 The roquefortine/meleagrin family of alkaloids

Scheme 1.2: Proposed biosynthetic pathway of the roquefortine/meleagrin alkaloids

A family of C-3 reverse-prenylated indole alkaloids has been isolated from several species of Penicillium fungi, as well as from Aspergillus japonicas in the case of neoxaline (1.2.6).2 all of which ultimately appear to derive from the enzyme-catalyzed reverse prenylation of histidyltryptophanyldiketopiperazine (HTD, 1.2.1) with dimethylallyl pyrophosphate.3,5 A gene cluster that is responsible for the synthesis of roquefortine C, glandicolins and meleagrin in Penicillium chrysogenum has been identified.4 It has been suggested that such nitrogen-rich alkaloids are secreted by the fungi as an extracellular reserve of nitrogen for uptake and metabolism by growing mycelia.5

Due to the widespread use of Penicillium species in commercial fermentation processes and their frequent occurrence in a variety of food products,6 the biological activity of these secondary metabolites has attracted a great deal of attention. The roquefortines and glandicolins have been shown to possess neurotoxic and antibacterial properties.7 Roquefortine C (1.2.2) has been shown to be a potent inhibitor of several human and rat cytochrome P450 enzymes.8 Meleagrin (1.2.4) and its derivatives have displayed antitumor9 and antibacterial10 activity, while oxaline (1.2.5) inhibits cell proliferation and induces cell cycle arrest during the M phase.11

1.2.2 Other fungal alkaloids containing a C3-prenylated tryptophan

Scheme 1.3: Other reverse-prenylated indole alkaloids derived from fungi

Other fungal metabolites that incorporate a C3-prenylated tryptophan also display a diverse range of biological activities. Aszanolenin (1.2.8) and its N-acyl derivatives have been isolated from Aspergillus and Neosartorya strains27 and are substance P inhibitors for the human neurokinin-1 receptor.12 The fructigenines (e.g. 1.2.9) isolated from Penicillium fructigenum and the brevicompanines (1.2.10, 1.2.11) isolated from

Penicillium brevicompactum are plant growth regulators.13,14 Ardeemin (1.2.12) and its derivatives were isolated from Aspergillus fischeri and are very potent multidrug resistance reversal agents, 5-N-acetylardeemin being the most active of them;15 while the related sartoryglabrins (e.g. 1.2.13) isolated from Neosartorya glabra display inhibitory activity toward the breast adenocarcinoma cell line MCF-7.16 Amauromine (1.2.14), isolated from Amauroascus sp. 6237, is a prenylated tryptophan dimer that exhibits strong vasodilation activity.17

1.2.3 The flustramine family of alkaloids

Scheme 1.4: Reverse-prenylated flustramine alkaloids and an example of a linear- prenylated flustramine

The flustramine family comprises over 20 prenylated indole alkaloids isolated from the marine bryozoan Flustra foliacea found in Scandinavian and Canadian waters.18 All of these alkaloids have in common a hexahydropyrrolo[2,3-b]indole nucleus in which a prenyl or reverse-prenyl group is attached at C3. Flustramine A (1.2.15) exhibits muscle relaxant and voltage-gated channel blocking activity.19 Antimicrobial activity has been reported for dihydroflustramine C (1.2.18), flustramine D20 (1.2.19) and flustramine I (1.2.20).18 Linear-prenylated flustramines (e.g. flustramine B, 1.2.16) and their analogues are also known to exhibit biological activity. For instance, debromoflustramine B and its analogues have been evaluated for their

4 butyrylcholinesterase inhibitory activity, (–)-debromoflustramine B being over 7500 times more potent than its (+)-enantiomer.21

1.3 Synthesis of C3-reverse-prenylated indole derivatives

Scheme 1.5: Electrophilic prenylation of indole and tryptamine

Early attempts to prepare C3-reverse-prenylated indole derivatives via electrophilic prenylation highlighted the pitfalls of chemoselectivity and regioselectivity that must be overcome in this transformation. For instance, the Friedel- 22 23 Crafts alkylation of indole or Nb-methoxycarbonyltryptamine (1.3.5) with prenyl bromide (1.3.1) results in formation of mixtures of products arising from linear 5 prenylation at the 3-position possibly followed by a second prenylation elsewhere on the indole, which may occur even when only one equivalent of 1.3.1 is employed. Cu- catalyzed propargylation of indoline with 2-chloro-2-methyl-3-butyne (1.3.8) followed by reduction is a well-established method for the synthesis of N-tert-prenyl indoline derivatives;1c but no reaction occurs when tryptamine 1.3.5 is subjected to the same conditions, while treatment of the sodium salt of 1.3.5 with 1.3.8 in the absence of Cu afforded a mixture of C-propargylated (1.3.9), C-allenylated (1.3.10) and N- propargylated (1.3.11) products.24 While multistep construction of the reverse-prenyl moiety25 or the indoline core26 has occasionally been used as a strategy to access C3-reverse-prenylated indole derivatives, the remainder of this review will focus on methods that install the five- carbon reverse-prenyl unit in a single operation.27 Broadly speaking, such methods can be divided into two categories: methods that install a prenyl group elsewhere on the indole, which then undergoes rearrangement to the 3-tert-prenyl indole (§1.3.1–1.3.3); or a direct intermolecular reaction between an indole derivative and a prenyl species, which may be either nucleophilic (§1.3.4) or electrophilic (§1.3.5) in character. In the last scenario, a transition metal catalyst (Pd, Ru, Ir) is employed to take advantage of the common preference for nucleophiles to attack the more substituted terminus of a π- prenylmetal species, resulting in selective formation of the reverse-prenylated product.

1.3.1 Synthesis via Claisen rearrangement Scheme 1.6: Claisen rearrangements of 2-(prenylthio)indoles

The [3,3]-sigmatropic rearrangement of a 2-(prenylthio)indole was one of the first successful approaches to the selective synthesis of reverse-prenylated indoles. In 7 the first reported total synthesis of amauromine, Takase and coworkers28 treated bis(2- thiomethyl)indole 1.3.12 (Scheme 1.6) with excess prenyl bromide and base to generate a bis-sulfonium species, which underwent the thia-Claisen rearrangement at room temperature over seven days. The two diastereomers 1.3.13 and 1.3.14 were isolated in

15% and 18% yield respectively. Reductive desulfurization of 1.3.14 with TiCl4/LiAlH4 led to formation of amauromine in 15% yield. A similar thia-Claisen rearrangement was exploited by Bhat and Harrison in their synthesis of (–)-dihydroaszonalenin, through which the relative and absolute stereochemistry of naturally occurring aszonalenin was determined.29 Treatment of 2- (methylthio)indole 1.3.15 with prenyl bromide resulted in formation of the desired diastereomer 1.3.16, isolated in 42% yield, as well as the other diastereomer 1.3.17 in 19% yield.

Scheme 1.7: [3,3]-Sigmatropic rearrangement of a sulfur ylide

More recently, Rainier and coworkers investigated the synthesis of 3-allylated indolenines via [3,3]-sigmatropic rearrangement of a sulfur ylide generated using Rh catalysis (Scheme 1.7).30 Modest levels of enantioselectivity were observed in the rearrangement of achiral substrate 1.3.18 in the presence of either Rh2(S-DOSP)4 (1.3.19) or chiral CuI-bisoxazoline catalyst systems. However, highly diastereoselective rearrangements leading to indolenines bearing vicinal quaternary centres were observed with α-substituted thiopyrans such as 1.3.21. Thiopyrans substituted only at the β- or γ- position and lacking an α-substituent were less effective, with diastereoselectivities ranging from 2:1 to 2.3:1. Scheme 1.8: Claisen rearrangement of a 2-(prenyloxy)indole

In 2000, it was found that 3,3-disubstituted oxindoles can be produced by treating 3-methoxycarbonylindole (1.3.22) with N-chlorosuccinimide followed by addition of

9 an allylic alcohol, which gives a 2-(allyloxy)indole that can undergo Claisen rearrangement (Scheme 1.8). Use of prenol (1.3.23) in this protocol led to the formation of 3-tert-prenyloxindole 1.3.24 in 89% yield.31 Oxindoles bearing other types of substituents at the 3-position are also able to undergo this transformation – the rearrangement is not limited to substrates with electron-withdrawing substituents at the 3-position. The diastereoselective installation of a linalyl group has also been achieved via this process.32 This transformation has been used in a short racemic synthesis of debromoflustramine A.33 An asymmetric variant of this methodology using PdII or CuII catalysis leading to chiral 3-allyl and 3-allenyl oxindoles has been developed,34 although the extension to the synthesis of a chiral 3-tert-prenyl oxindole was not reported.

Scheme 1.9: In situ formation and Claisen rearrangement of chiral 2-(prenyloxy)indoles

The Kawasaki group has exploited the use of chiral 2-alkoxyindolines in this type of Claisen rearrangement to achieve enantioselective total syntheses of several flustramine alkaloids,35,37 fructigenine A (1.2.9), and 5-N-acetylardeemin.36 The substrates for the rearrangement (Scheme 1.9) were generated in situ via Horner- Wadsworth-Emmons olefination of a 2-alkoxy-3-indolone (1.3.24, 1.3.25), which underwent olefin isomerization and cleavage of the N-acetyl group under the basic 10 reaction conditions. Upon warming to room temperature, the resulting 2-oxyindole anion rearranged to a 3-tert-prenylated oxindole with excellent chiral transfer. The unneeded n-hexyl side chain was later removed via ozonolysis to the aldehyde followed by methylenation.

Scheme 1.10: Diastereoselective Claisen rearrangement of 2-(prenyloxy)indoles

The use of achiral allylic alcohols in this reaction sequence has enabled the Kawasaki group to prepare flustramines A (1.2.15) and C,37 okaramine M,38 derivatives of 5-N-acetylardeemin,39 a phenserine analogue,40 and oxindoles bearing vicinal quarternary stereocentres41 as racemates. In the last case, moderate to excellent diastereoselectivities were obtained (Scheme 1.10).

1.3.2 Synthesis via [2,3]-Wittig rearrangement

Table 1.1: Phase-transfer-catalyzed [2,3]-Wittig rearrangement

Denmark and Cullen developed a [2,3]-Wittig rearrangement of 3-allyloxy-2- oxindoles that proceeded under phase transfer conditions (Table 1.1).42 The use of tetrabutylammonium bromide as the catalyst in a biphasic mixture of toluene and 5 M KOH resulted in full conversion to the racemic tert-prenyl oxindole 1.3.30 in 30 minutes at 3-5 °C, while the reaction proceeded much more slowly in the absence of catalyst under the same biphasic conditions. The authors proposed two explanations for the rate acceleration by the phase transfer catalyst in this intramolecular reaction. One is that tetraalkylammonium ions coordinate less strongly to the initially formed enolate than metal ions, leading to electronic destabilization of the enolate and thus a higher rate of reaction. The other possibility is that by extracting the enolate away from the interfacial region and into the organic phase, the enolate is no longer solvated by water and is again destabilized, thus favouring the forward reaction. The latter suggestion is supported by the observation that when solid KOH is substituted for the aqueous KOH solution so that the reaction takes place under anhydrous solid-liquid phase transfer conditions, complete rearrangement of 1.3.29 to 1.3.30 still occurs within 30 minutes. A large collection of chiral mono- and bis-alkylated cinchonidine-derived ammonium salts were examined for their ability to effect asymmetric catalysis of this rearrangement. However, the highest enantiomeric excess achieved in such cases was only 48% (entry 4).

1.3.3 Synthesis via 2,3-prenyl migration on the indole Scheme 1.11: Indole epoxidation followed by prenyl migration

As part of their investigation into the biosynthesis of prenylated indole alkaloids, Williams and coworkers treated indole 1.3.31 with Davis oxaziridine 1.3.32 to afford a mixture of four products (Scheme 1.11), including the naturally occurring notoamides C and D.43 While the Williams group initially expected ring-opening of the intermediate epoxide to occur primarily at the 2-position in line with the group’s previous experiences with similar rearrangements,44 the opposite selectivity was observed, presumably owing to participation from the pyranyl oxygen to generate a para-quinone methide-like species. No rationale was provided for the modest diastereoselectivity (~2:1 in favour of the α-isomer) of the reaction, which was mirrored in the conversion of indole 1.3.33 to notoamide J by the same group; the detection of side products was not reported in the latter case.45

Scheme 1.12: Oxidative cyclization of a tryptamine followed by prenyl migration

Another oxidation-triggered migration of a 2-tert-prenyl group to the 3-position of an indole was reported by Lindel and coworkers (Scheme 1.12) in the final step of a racemic synthesis of flustramine C (1.2.17).46 Treatment of deformylflustrabromine

(1.3.34, available in four steps from Nb-methyltryptamine) with N-bromosuccinimide presumably generates brominated indolenine 1.3.35, which undergoes nucleophilic attack followed by 1,5-sigmatropic rearrangement to deliver flustramine C in 90% yield.

The yield for the overall sequence starting from Nb-methyltryptamine was 38%.

1.3.4 Synthesis via the use of stoichiometric prenylmetal reagents Scheme 1.13: Conjugate addition of prenylmagnesium bromide to 2-cyanoacrylates

The first syntheses of tert-prenylated flustramines were achieved by Joseph- Nathan and coworkers (Scheme 1.13),47 who exploited the lack of regioselectivity in

14 the conjugate addition of prenylmagnesium bromide (which exists as an equilibrating mixture of isomers at low temperature48) to prepare both the reverse- and linear- prenylated isomers of these natural products. In a typical example, addition of excess prenylmagnesium bromide to α-cyanoacrylate 1.3.36 followed by spontaneous lactonization afforded a 53:47 mixture of 2-oxofuroindoline regioisomers 1.3.37 and 1.3.38 in a combined 76% yield. The racemic syntheses of dihydroflustramine C (1.2.17) and its regioisomer flustramine E were then accomplished in four further steps from 1.3.37 and 1.3.38 respectively.47c

Scheme 1.14: Diastereoselective selenenylation-prenylation of a tryptophan

The first practical method to access the reverse-prenylated hexahydropyrrolo[2,3- b]indole motif with good control over regioselectivity and stereoselectivity was developed by Danishefsky and coworkers in 1994 (Scheme 1.14).49 Their two-step protocol began with the oxidative cyclization of a tryptophan derivative such as 1.3.39 mediated by N-phenylselenophthalimide, which initially gave a 1:1 mixture of diastereomers but could be equilibrated to a 9:1 mixture in favour of 1.3.40. Subsequent Lewis acid activation generated a benzylic cation which was trapped with prenyl tributyltin (1.3.41) in 60% yield. No products that might have arisen from loss of a proton from the benzylic cation were observed. The strong preference for the 5,5-ring system to adopt a cis configuration results in excellent stereoselectivity in the installation of the prenyl group. This method was used by Danishefsky and coworkers to synthesize amauromine (1.2.14) in five linear steps and 16% overall yield. The synthesis of 5-N-acetylardeemin was accomplished from intermediate 1.3.42 in five further steps and in 11% overall yield from 1.3.39. 15

Scheme 1.15: Natural products accessed from intermediate 1.3.42

Although the use of multiple equivalents of organoselenium and organotin reagents limits the attractiveness of Danishefsky’s method, it has nevertheless been widely applied to the synthesis of reverse-prenylated indole natural products and related structures.50 Matsumara and Kitahara synthesized brevicompanines A and B (1.2.10, 1.2.11) from intermediate 1.3.42.51 Joullié and coworkers reported the first synthesis of roquefortine D (dihydroroquefortine C) from 1.3.42,52 establishing its absolute stereochemistry in the process. The same group also completed the first total synthesis of roquefortine C (1.2.2)53 and its unnatural Z-olefin isomer, isoroquefortine C,54 again via intermediate 1.3.42.

Scheme 1.16: Oxidative cyclization-prenylation of tryptophols

Omura and coworkers applied the selenenylation-prenylation protocol to tryptophol derivative 1.3.43 in a synthesis of the oxaline/meleagrin core (Scheme 1.16).55 Unlike in the case of N-Boc tryptamines, the 1:1 mixture of diastereomers did not equilibrate due to the poorer leaving group ability of oxygen compared to the Boc- protected nitrogen, and the desired less thermodynamically stable isomer 1.3.44 was isolated in 49% yield. An enantioselective approach to the prenylated furoindoline core was later demonstrated by the same group in their asymmetric synthesis of (+)- neoxaline (1.2.6), by which the absolute configuration of the natural product was determined.56 Previous work had shown that Sharpless asymmetric epoxidation followed by ring-opening generates indoline 1.3.47 in good yield and excellent ee.57 17

Protection of the indoline nitrogen as the allyl carbamate and conversion of the 3- hydroxy group to the trichloroacetimidate occurred smoothly, and the resulting compound was treated with prenyl tributyltin and BF3Et2O to afford 3-tert-prenyl furoindoline 1.3.49 in 87% yield and as a single diastereomer.

Scheme 1.17: Diastereoselective bromination-prenylation of a tryptophan

A conceptually related approach to the reverse-prenyl moiety was demonstrated by Qin and coworkers.58 Bromocyclization of tryptophan 1.3.39 with N- bromosuccinimide occurs with very good diastereoselectivity and yield.59 Ionization of bromide 1.3.50 occurs at –78 °C in the presence of two equivalents of silver(I) perchlorate and 1.5 equivalents of caesium carbonate, and the resulting benzylic cation is trapped by prenyl tributyltin in 91% yield. The Qin group used this method to access (−)-ardeemin (1.2.12), (−)-acetylardeemin and (−)-formylardeemin.

Table 1.2: Diastereoselective allylation and reverse prenylation of chiral isatin ketimines

Chen and Xu optimized the diastereoselective Barbier-style allylation of isatin N- tert-butanesulfinyl ketimines (Table 1.2), and found that use of Zn rather than In as the metal (entries 1 and 2),60 protection of N1 with the bulky trityl group (entry 5), and the presence of hexamethylphosphoramide (HMPA) (entries 3–6) was critical to achieving optimal yields and diastereoselectivities. Under such conditions, reverse prenylation occurred with 3,3-dimethylallyl bromide (entry 7) to afford a 3-amino-3-tert- prenyloxindole with very good yield and excellent diastereoselectivity.61

1.3.5 Synthesis via transition metal catalysis Table 1.3: Regioselective 3-tert-prenylation of indole

Since 2005, several methods have appeared for the highly regioselective 3-tert- prenylation of indole with 2-methyl-3-buten-2-ol (1.3.52) using Ru62,63 or Pd64,65 catalysis (Table 1.3). These reactions likely proceed via the intermediacy of a π- prenylmetal complex, which is preferentially attacked by the indole at the more electrophilic internal terminus. The formation of N-prenylation products was not detected in any of these cases.

Scheme 1.18: Ir-catalyzed reverse prenylation of 3-substituted indoles

Ruchti and Carreira used [Ir(cod)Cl]2 in conjunction with phosphoramidite ligand 1.3.58 to effect the tandem reverse prenylation-cyclization of 3-substituted indoles bearing a pendant nucleophile (Scheme 1.18).66 Generation of the N-borylated indole using a potassium base and tertiary borane was necessary for prenylation to occur; 7- substituted indoles were not suitable substrates. The use of these reagents in substoichiometric amounts was possible with Nb-tosyl tryptamine substrates such as 1.3.57. Prenylation occurred exclusively at C-3, even in the case of 4-substituted indoles (1.3.60) and selectivity for the reverse-prenyl versus prenyl product exceeded 20:1 in all cases examined. Five- and six-membered ring formation was demonstrated with nitrogen and oxygen nucleophiles and cyclization products were formed as a single diastereomer. For indole substrates not bearing a pendant nucleophile such as 1.3.62, the indolenine product was isolated. Various chiral phosphoramidite ligands were also examined in the reaction but enantiomeric excesses greater than 20% could not be achieved.

Scheme 1.19: Ir-catalyzed exo-selective reverse prenylation of tryptophans

Prenylation-cyclization of tryptophan ester 1.3.64 occurred with 1.3:1 exo:endo selectivity (Scheme 1.19; exo refers to the product where the ester is oriented away from the cup-shaped [3.3.0]-bicycle) when triethylborane was used, but switching to n-hexyl- 22

9-BBN resulted in greater than 20:1 diastereoselectivity in favour of the exo isomer. In contrast, Pd-catalyzed allylation-cyclization of the same substrate gave only the endo isomer.64 An optimized yield of 58% was obtained by using KHMDS rather than KOtBu as the base and conducting the reaction at 0 °C; under these conditions no racemization was detected. The utility of this method was demonstrated in two-step conversions of (+)-1.3.65 and (–)-1.3.65 to (+)-aszonalenin (1.2.8) and (–)-brevicompanine B (1.2.11) respectively.

Scheme 1.20: Ir-catalyzed diastereodivergent reverse prenylation of tryptophans

In 2016, Müller and Stark reported an Ir-catalyzed diastereoselective reverse prenylation of N-borylated tryptophan derivatives (Scheme 1.20) in which either the exo and endo isomer could be selectively produced depending on the choice of borylating 67 agent. Thus, starting from Nb-Boc-L-tryptophan (1.3.66), the use of n-octyl-9-BBN as the borylating reagent afforded a 9:1 mixture of endo:exo products, while switching to triphenylborane resulted in a >20:1 mixture favouring the exo product. The yield in the second case increased from 34% to 83% when one equivalent of phosphoramidite 1.3.67 23 was replaced with carbene precursor 1.3.68, the base was changed from DBU to 1,5,7- triazabicyclo[4.4.0]dec-5-ene (TBD), and the equivalents of the electrophile increased from three to five. Use of the opposite enantiomer of phosphoramidite 1.3.67 results in reversal of the diastereoselectivity, indicating that the stereochemistry of the ligand dictates which prochiral face on the indole undergoes prenylation. Thus all four diastereomers of the pyrroloindoline product can be prepared using the same enantiomer of 1.3.67 by varying the borane and the stereochemistry of the tryptophan substrate. In all cases, exclusive regioselectivity for the reverse-prenylated product was seen with Ir catalysis. However, the use of Pd(PPh3)4 led to exclusive linear product formation in 87% yield, while use of (Cp)Pd(allyl) in conjunction with ligand 1.3.78 led to a 5:2 mixture of branched and linear regioisomers in a combined 32% yield.

Scheme 1.21: Ir-catalyzed diastereoselective reverse prenylations using triethylborane

The use of Et3B in the reverse prenylation-cyclization of tryptophan 1.3.66 occurs in excellent yield (91%) but no diastereoselectivity (1:1 exo:endo). However, in reactions with more elaborate tryptophan derivatives or prenyl electrophiles (Scheme

1.21), good diastereoselectivity was observed with the use of Et3B. Thus the prenylation-cyclization of diketopiperazine 1.3.69 generated pentacycle 1.3.70 in 41% yield and with 20:1 selectivity in favour of the exo isomer. The reaction of 1.3.66 with racemic electrophile 1.3.71 derived from linalool resulted in formation of two stereoisomers (5:1 in favour of the endo isomer; the absolute configuration of the allylic stereocentre was not determined) in 81% yield.

Scheme 1.22: Ir-catalyzed reverse prenylation of isatins via transfer hydrogenation

As part of their investigations into Ir-catalyzed asymmetric C–C bond-forming transfer hydrogenations, the Krische group has developed the use of 1,1-dimethylallene as a reagent for the enantioselective reverse prenylation of aryl, alkyl and α,β- unsaturated aldehydes or the corresponding primary alcohols.68 By extending the scope of this chemistry to isatin substrates (Scheme 1.22), the asymmetric synthesis of 3-tert- prenyl-3-hydroxyoxindoles was also achieved.69 Electron-donating and electron- withdrawing substituents were tolerated at the 5, 6 and 7-positions of the isatin, the corresponding oxindoles being isolated in very good yields and ee. Interestingly, the enantiofacial selectivity of carbonyl addition observed in the prenylation was the opposite to what was observed in the allylation or crotylation of isatins with the same 25 enantiomer of the Ir catalyst. Continuing a trend also observed in the reverse prenylation of aldehydes,68 the prenylation of isatins proceeded at lower temperatures (60 °C) compared to the corresponding allylation or crotylation reactions, which were run at 100 °C for 40 or 72 hours respectively.

Scheme 1.23: Pd-catalyzed regiodivergent prenylation of 3-alkyloxindoles

In 2011, the Trost group reported that the Pd-catalyzed prenylation of 3- alkyloxindoles (Scheme 1.23, 1.3.72, 1.3.75) could be tuned to favour formation of either the linear (1.3.74, 1.3.77) or the branched (1.3.73, 1.3.76) isomer in very good to excellent enantioselectivity.70 Formation of the branched isomer was favoured by the sterically more demanding ligand 1.3.78, such that nucleophilic attack on a π- prenylpalladium complex leads to preferential formation of a species where Pd is bound to the monosubstituted olefin of the branched product, as opposed to one where it is bound to the trisubstituted olefin of the linear product. The choice of solvent also had a 26 critical impact on the regioselectivity; chlorinated solvents such as dichloromethane led to greater selectivity for the branched products, while more nonpolar solvents such as toluene led to greater selectivity for the linear products. The presence of an electron-withdrawing group on the 3-alkyl substituent was necessary for reactivity, but both electron-donating and electron-withdrawing substituents at the 5- or 6-positions on the oxindole were well tolerated. A variety of N- protecting groups could be used in the oxindole, and linear-selective prenylation also worked well for the unprotected N-H oxindole; but the previously optimized conditions for branched product formation led to unusually poor regioselectivity and enantioselectivity when the unprotected oxindole was used as a substrate. The utility of this method was demonstrated in the efficient syntheses of ent- flustramides A and B as well as ent-flustramines A (1.2.15) and B from compounds 1.3.76 and 1.3.77 respectively. This work led to the surprising observation that the same enantiomer of ligand produces linear and branched regioisomers of opposite chirality.

Scheme 1.24: Pd-catalyzed regiodivergent geranylation of 3-alkyloxindoles

The installation of monoterpenoid side chains using this methodology was also investigated by the Trost group (Scheme 1.24), since several examples of natural products containing geranyl-substituted indolines have been recently described.71,18 While the use of geraniol-derived carbonate 1.3.81 led to exclusive formation of the geranyl-substituted oxindole 1.3.83 in good yield and excellent ee, the reaction with nerol-derived carbonate 1.3.82 could once again be tuned to afford either the linalyl (1.3.84) or neryl (1.3.85) isomer with excellent enantioselectivity. The less facile ionization of allylic carbonates in which the olefin is trisubstituted was overcome by increasing the reaction temperature, replacement of Pd2(dba)3CHCl3 with (Cp)Pd(allyl) as the precatalyst, and the use of the more labile 2,2,2-trichoroethyl carbonate in the case of 1.3.82.

1.4 Conclusion The diverse variety of approaches developed for the synthesis of C3-reverse- prenylated indole derivatives is reflective of the widespread interest in the biological activity of these compounds and the need for effective strategies to access them. The first useful methods developed to meet this need were based on the use of a [3,3]- sigmatropic rearrangement, and this remains a reliable and scalable way of preparing these compounds in racemic fashion. However, the construction of enantioenriched C3- reverse-prenylated indoles requires a chiral element to be already present in the substrate – while the Kawasaki group has shown that chiral transfer can take place effectively between starting material and product, a catalytic asymmetric version of this rearrangement is currently unknown. The development of a [2,3]-Wittig rearrangement by the Denmark group is an interesting attempt to overcome this limitation but attempts to conduct this rearrangement asymmetrically have not met with much success so far. Danishefsky’s selenenylation-prenylation protocol was the first reliable method to be developed for the synthesis of enantioenriched C3-reverse-prenylated indoles. It has been used with success by several research groups to access natural products containing this motif and in several cases this has allowed the absolute stereochemistry of those natural products to be determined for the first time. However, the use of multiple equivalents of organoselenium and organotin reagents in this multistep process 28 is undesirable from the standpoint of waste generation and toxicity. The replacement of the organoselenium reagent by NBS developed by the Qin group is a slight improvement in this respect but the general applicability of this revised protocol is unknown. Metal-mediated or catalyzed prenylation of isatins or isatin ketimines is a logical approach to reverse-prenylated 3-amino- or 3-hydroxyoxindoles that has surprisingly not received much attention until quite recently. In particular, the Ir-catalyzed transfer- hydrogenation protocol developed by the Krische group is elegant in its complete atom economy and extremely efficient in terms of asymmetric induction; however, the use of the highly volatile and relatively expensive 1,1-dimethylallene as a starting material does limit the convenience of this method to an extent. The Pd-catalyzed regiodivergent prenylation of 3-alkyloxindoles pioneered by the Trost group was the first catalytic asymmetric approach developed for the synthesis of the 3-reverse-prenylated indoline scaffold. Although the regioselectivity and enantioselectivity of this transformation can be quite sensitive to the specific substitution pattern on the oxindole, it remains a uniquely versatile method for preparing either regioisomer of the prenylated products. The Ir-catalyzed prenylation-cyclization of tryptamines and related compounds is a useful recent extension of this concept, since the cyclized products closely resemble motifs found in several natural products, and the use of Pd in this transformation has been shown to be unsuccessful. The Stark group has obtained excellent diastereoselectivities in the Ir-catalyzed prenylation-cyclization of tryptophan derivatives to afford either the endo or the exo cyclization products. It is striking that catalytic methods not involving transition metals have currently not been successfully developed for the synthesis of C3-prenylated indole derivatives. Given the importance of and sustained interest in this intriguing structural motif, it seems likely this situation will change in the near future.

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25 He, B.; Song, H.; Du, Y.; Qin, Y. J. Org. Chem. 2009, 74, 298–304. 26 Ignatenko, V. A.; Deligonul, N.; Viswanathan, R. Org. Lett. 2010, 12, 3594–3597. 27 Chemoenzymatic reverse prenylation of an indole has been used in a synthesis of aszonalenins: Yin, W.-B.; Cheng, J.; Li, S.-M. Org. Biomol. Chem. 2009, 7, 2202– 2207. 28 Takase, S.; Itoh, Y.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron Letters 1985, 26, 847–850. 29 Bhat, B.; Harrison, D. M. Tetrahedron Letters 1986, 27, 5873–5874. 30 (a) Kennedy, A. R.; Taday, M. H.; Rainier, J. D. Org. Lett. 2001, 3, 2407–2409. (b) Novikov, A. V.; Sabahi, A.; Nyong, A. M.; Rainier, J. D. Tetrahedron: Asymmetry 2003, 14, 911–915. (c) Nyong, A. M.; Rainier, J. D. J. Org. Chem. 2005, 70, 746–748. 31 Booker-Milburn, K. I.; Fedouloff, M.; Paknoham, S. J.; Strachan, J. B.; Melville, J. L.; Voyle, M. Tetrahedron Letters 2000, 41, 4657–4661. 32 Thandavamurthy, K.; Sharma, D.; Porwal, S. K.; Ray, D.; Viswanathan, R. J. Org. Chem. 2014, 79, 10049–10067. 33 Ignatenko, V. A.; Zhang, P.; Viswanathan, R. Tetrahedron Letters 2011, 52, 1269– 1272. 34 (a) Linton, E. C.; Kozlowski, M. C. J. Am. Chem. Soc. 2008, 130, 16162–16163. (b) Cao, T.; Linton, E. C.; Deitch, J.; Berritt, S.; Kozlowski, M. C. J. Org. Chem. 2012, 77, 11034–11055. 35 Kawasaki, T.; Shinada, M.; Ohzono, M.; Ogawa, A.; Terashima, R.; Sakamoto, M. J. Org. Chem. 2008, 73, 5959–5964. 36 Takiguchi, S.; Iizuka, T.; Kumakura, Y.; Murasaki, K.; Ban, N.; Higuchi, K.; Kawasaki, T. J. Org. Chem. 2010, 75, 1126–1131. 37 Kawasaki, T.; Shinada, M.; Kamimura, D.; Ohzono, M.; Ogawa, A. Chemical Communications 2006, 420–422. 38 Iizuka, T.; Takiguchi, S.; Kumakura, Y.; Tsukioka, N.; Higuchi, K.; Kawasaki, T. Tetrahedron Letters 2010, 51, 6003–6005. 39 Hayashi, D.; Tsukioka, N.; Inoue, Y.; Matsubayashi, Y.; Iizuka, T.; Higuchi, K.; Ikegami, Y.; Kawasaki, T. Bioorganic & Medicinal Chemistry 2015, 23, 2010–2023. 32

40 Shinada, M.; Narumi, F.; Osada, Y.; Matsumoto, K.; Yoshida, T.; Higuchi, K.; Kawasaki, T.; Tanaka, H.; Satoh, M. Bioorganic & Medicinal Chemistry 2012, 20, 4901–4914. 41 Matsuta, Y.; Kobari, T.; Kurashima, S.; Kumakura, Y.; Shinada, M.; Higuchi, K.; Kawasaki, T. Tetrahedron Letters 2011, 52, 6199–6202. 42 Denmark, S. E.; Cullen, L. R. J. Org. Chem. 2015, 80, 11818–11848. 43 Grubbs, A. W.; Artman, G. D.; Tsukamoto, S.; Williams, R. M. Angewandte Chemie International Edition 2007, 46, 2257–2261. 44 Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M. J. Am. Chem. Soc. 1996, 118, 557–579. 45 Finefield, J. M.; Williams, R. M. J. Org. Chem. 2010, 75, 2785–2789. 46 Lindel, T.; Bräuchle, L.; Golz, G.; Böhrer, P. Org. Lett. 2007, 9, 283–286. 47 (a) Morales-Ríos, M. S.; Suárez-Castillo, O. R.; Joseph-Nathan, P. J. Org. Chem. 1999, 64, 1086–1087. (b) Morales-Ríos, M. S.; Suárez-Castillo, O. R.; Trujillo- Serrato, J. J.; Joseph-Nathan, P. J. Org. Chem. 2001, 66, 1186–1192. (c) Morales- Rı́os, M. S.; Suárez-Castillo, O. R.; Joseph-Nathan, P. Tetrahedron 2002, 58, 1479– 1484. 48 (a) Whitesides, G. M.; Nordlander, J. E.; Roberts, J. D. Discussions Faraday Soc. 1962, 34, 185−190. (b) Benkeser, R. A. Synthesis 1971, 347−358. 49 (a) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143–11144. (b) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953–11963. 50 For a similar reverse prenylation conducted under basic conditions and in a non- stereoselective context, see: Fuchs, J. R.; Funk, R. L. Org. Lett. 2005, 7, 677–680. 51 Matsumara, K.; Kitahara, T. Heterocycles 2001, 55, 727–733. 52 Chen, W.-C.; Joullié, M. M. Tetrahedron Letters 1998, 39, 8401–8404. 53 Ning, S.; Hehre, W. J.; Ohlinger, W. S.; Beavers, M. P.; Joullié, M. M. J. Am. Chem. Soc. 2008, 130, 6281-6287.

54 (a) Schiavi, B. M.; Richard, D. J.; Joullié, M. M. J. Org. Chem. 2002, 67, 620–624. (b) Richard, D. J.; Schiavi, B.; Joullié, M. M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11971. 55 Sunazuka, T.; Shirahata, T.; Tsuchiya, S.; Hirose, T.; Mori, R.; Harigaya, Y.; Kuwajima, I.; Ōmura, S. Org. Lett. 2005, 7, 941–943. 56 (a) Ideguchi, T.; Yamata, T.; Shirahata, T.; Hirose, T.; Sugawara, A.; Kobayashi, Y.; Ōmura, S.; Sunazuka, T. J. Am. Chem. Soc. 2013, 135, 12568-12571; (b) Yamada, T.; Ideguchi-Matsushita, T.; Hirose, T.; Shirahata, T.; Hokari, R.; Ishiyama, A.; Iwatsuki, M.; Sugawara, A.; Kobayashi, Y.; Otoguro, K.; Ōmura, S.; Sunazuka, T. Chem. Eur. J. 2015, 21, 11855–11864. 57 Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.; Hayashi, M.; Komiyama, K.; Ōmura, S.; Smith, A. B. J. Am. Chem. Soc. 2000, 122, 2122–2123. 58 Wang, Y.; Kong, C.; Du, Y.; Song, H.; Zhang, D.; Qin, Y. Org. Biomol. Chem. 2012, 10, 2793–2797. 59 López, C. S.; Pérez-Balado, C.; Rodríguez-Graña, P.; de Lera, Á. R. Org. Lett. 2008, 10, 77–80. 60 For an example of the In-mediated racemic prenylation of an isatin ketamine, see: Alcaide, B.; Almendros, P.; Aragoncillo, C. Eur. J. Org. Chem. 2010, 2010, 2845– 2848. 61 Chen, D.; Xu, M.-H. Chem. Commun. 2013, 49, 1327–1329. 62 Gruber, S.; Zaitsev, A. B.; Wörle, M.; Pregosin, P. S.; Veiros, L. F. Organometallics 2008, 27, 3796–3805. 63 Sundararaju, B.; Achard, M.; Demerseman, B.; Toupet, L.; Sharma, G. V. M.; Bruneau, C. Angewandte Chemie International Edition 2010, 49, 2782–2785. 64 Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 4592–4593. 65 Usui, I.; Schmidt, S.; Keller, M.; Breit, B. Org. Lett. 2008, 10, 1207–1210. 66 Ruchti, J.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 16756–16759. 67 Müller, J. M.; Stark, C. B. W. Angew. Chem. Int. Ed. 2016, 55, 4798–4802.

68 Han, S. B.; Kim, I. S.; Han, H.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 6916– 6917. 69 Itoh, J.; Han, S. B.; Krische, M. J. Angewandte Chemie International Edition 2009, 48, 6313–6316. 70 Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133, 7328–7331. 71 (a) Okada, M.; Sato, I.; Cho, S. J.; Dubnau, D.; Sakagami, Y. Tetrahedron 2006, 62, 8907. (b) Okada, M.; Yamaguchi, H.; Sato, I.; Tsuji, F.; Dubnau, D.; Sakagami, Y. Biosci., Biotechnol., Biochem. 2008, 72, 914.

2 Cross-coupling reactions of substituted allyl donors

2.1 Introduction

Scheme 2.1: Cross-coupling of allyl donors

Allylation is one of the fundamental transformations in the toolbox of an organic chemist. In a single step, formation of a C–C bond and the introduction of a synthetically versatile olefin moiety is achieved. While the nucleophilic allylation of carbonyl compounds has been extensively documented,1 it is surprising that the use of allylmetals in cross-coupling reactions has not previously been reviewed,2 even though allyl- substituted arenes such as phenylpropenes are a common motif in natural products.3 The present account aims to address this gap in the literature and is organized by allylmetal species (Sn, Si, Cu, Mg, B, Zn, Ge, Zr, Al). Particular emphasis is placed on methods that introduce a substituted allyl group with regiocontrol,4 as both the “branched” and “linear” isomers of the cross-coupled products can be useful compounds. Stereoselective cross-couplings of allyl nucleophiles are also covered comprehensively. In addition, this review also covers methods that do not involve the use of allylmetal reagents but nonetheless introduce an allyl group for cross-coupling with an electrophile. This includes C–C bond fragmentation to generate an allylmetal intermediate as well as allylic C–H bond activation.

2.2 Cross-coupling of allyltin reagents Scheme 2.2: Cross-coupling of allyltributyltin with aryl halides

The first example of an allylmetal species participating as a donor in a Pd- catalyzed cross-coupling reaction with an aryl halide was reported by Migita and coworkers in 1977 (Scheme 2.2).5 They reacted allyltributyltin with aryl bromides in the presence of Pd(PPh3)4 to afford allylated benzenes in good yields. However, coupling with aryl iodides and electron-poor aryl chlorides proceeded less efficiently and electron-neutral aryl chlorides failed to participate in cross-coupling.

Scheme 2.3: Cross-coupling of allylstannanes with allyl electrophiles

Trost6 and Stille7 showed that substituted allylstannanes could be regioselectively coupled with allylic electrophiles to afford the branched products (

Scheme 2.3), but the yields for this process were somewhat modest. Meanwhile, Echavarren and Stille observed that the cross-coupling of allyl- and crotylstannanes with aryl triflates was plagued by several issues including competitive n-butyl transfer, olefin isomerization of the allylated products, and poor regioselectivity in the case of crotylation.8

Table 2.1: Regioselectivity in the cross-coupling of allylstannanes with aryl halides

Tsuji and coworkers found that the choice of ligand had a profound effect on the regioselectivity in the Pd-catalyzed coupling between substituted allylstannane 2.2.6 with iodobenzene (Table 2.1).9 While triphenylarsine and triphenylstibine (entries 1 and 2) strongly favoured formation of the linear product 2.2.7, exclusive selectivity for branched product 2.2.8 was seen when triphenylphosphine or triphenylphosphite was used (entries 5 and 6). When phenyl triflate was used as the coupling partner, good selectivity for the linear product was still observed with triphenylarsine (entry 8), but

38 significant selectivity for the branched product could no longer be obtained (entries 9 and 10).10

2.3 Cross-coupling of allylsilane reagents

Scheme 2.4: Branched-selective cross-coupling of allyltrifluorosilanes

Hiyama and coworkers reported the first branched-selective crotylation and prenylation of aryl halides using trifluorosilanes activated with a fluoride source.11 All reactions were conducted in superheated THF in sealed vials. With Pd(PPh3)4 as the catalyst and tetra-n-butylammonium fluoride (TBAF) as the fluoride source, aryl iodides were selectively coupled over aryl bromides (2.3.2). Aromatic ketones in the

39 substrate did not undergo allylation (2.3.4). Enol triflates were coupled effectively

(2.3.3) using a Pd(OAc)2/dppb catalyst system and tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) as the fluoride source.

Table 2.2: Ligand control in the regioselective cross-coupling of crotyltrifluorosilanes

The choice of ligand in this reaction had a profound influence on the regioselectivity (Table 2.2).12 While the use of dppe and dppp (entries 2 and 3) resulted in selective formation of linear product 2.3.5, with the E isomer generally predominant, the opposite regioselectivity in favour of branched product 2.3.1 was observed with ligands that enforce a larger P-Pd-P bite angle such as dppb, dppent, and PPh3 (entries 4, 5 and 6).

Scheme 2.5: Mechanism of the cross-coupling of allyltrifluorosilanes

To account for these observations, Hiyama and coworkers proposed that allyl 13 transfer from silicon to palladium occurs via an SE’ mechanism (Scheme 2.5). Reductive elimination from the γ-substituted allyl complex A is sterically accelerated by phosphine ligand sets with larger bite angles, leading to branched product formation; while isomerization to the more thermodynamically stable α-substituted allyl complex B can take place with the longer-lived complexes coordinated by less sterically demanding ligands. Reductive elimination from this complex then furnishes the linear products.

Scheme 2.6: Linear-selective cross-coupling of allyltrifluorosilanes

Hiyama and coworkers showed that both aryl bromides and triflates underwent linear-selective crotylation to deliver compound 2.3.6 with good yields and E- stereoselectivity, while the linear-selective prenylation of an aryl triflate to give compound 2.3.7 also occurred with good yield and regioselectivity. However, poor regioselectivity and yield was observed in the prenylation of aryl halides such as 4- iodoacetophenone.

Scheme 2.7: Branched-selective cross-coupling of crotylsilanolates

Denmark and Werner developed fluoride-free conditions for the Pd-catalyzed allylation of aryl halides using bench-stable allylsilanolate salts.14 The use of a π-acidic diene ligand such as norbornadiene (nbd) in conjunction with Pd(dba)2 led to good selectivities for the branched product in the coupling of crotylsilanolate 2.3.9 with a variety of para- and meta-substituted arenes (Scheme 2.7). Benzaldehydes and silylated phenols were among the functionalities tolerated by this protocol. Regioselectivity was relatively poor for certain electron-poor arenes (2.3.13) and arenes posessing large ortho substituents (2.3.15).

Scheme 2.8: Synthesis of a phenol from crotylsilanolate 2.3.9

When a sterically demanding ligand such as 2-(di-tert-butylphosphino)biphenyl was used in the crotylation of 1-bromonaphthalene (2.3.16), 1-naphthol (2.3.17) was surprisingly obtained as the major product, suggesting that a Pd-bound silanolate was formed in the reaction mechanism prior to transmetalation.

Table 2.3: Effect of crotylsilanolate geometry on regiochemistry of cross-coupling

Also noteworthy was the insensitivity of the crotylation reaction to the ratio of E to Z-olefin isomers in the crotylsilanolate (Table 2.3). Consistent yields and excellent regioselectivity for the branched product was observed regardless of the olefin isomer used.

Scheme 2.9: Improved conditions for the branched-selective cross-coupling of crotylsilanolates

Later, Denmark and Werner found that using a trialkylphosphine (introduced as its hydrotetrafluoroborate salt) resulted in a more active catalyst that delivered higher regioselectivities in the branched-selective crotylation of arenes (Scheme 2.9).15 This catalyst system was less sensitive to the electronic and steric nature of the arene substrate. For instance, 2-bromomesitylene was crotylated in 73% yield and with greater than 99:1 selectivity for the branched product 2.3.20.

2.4 Cross-coupling of allylcopper reagents

Scheme 2.10: Cross-coupling of crotyl and prenyl cyanocuprates

The Lipschutz group has studied the reactivity of allylcuprates with 13 electrophiles. While the Gilman reagent (allyl)2CuLi could only be observed by C NMR spectroscopy at –95 °C and decomposed at higher temperatures,16 the higher- order cuprate (allyl)2Cu(CN)Li2 prepared from allyltributylstannane is stable at 0 °C and participates in reactions with epoxides and alkyl halides.17 Interestingly, linear- prenylated products were isolated from the reaction with epoxides while reverse- prenylated products were observed with alkyl halides. A later study of the allylation of enol triflates showed that prenylation of 2.4.5 proceeded with complete selectivity for

46 the linear product 2.4.6, while crotylation of 2.4.7 delivered a mixture of regio- and olefin stereoisomers.18

2.5 Cross-coupling of allylmagnesium reagents

Scheme 2.11: Co-catalyzed coupling of allylmagnesium reagents

Oshima and coworkers developed a Co-catalyzed allylation of primary, secondary and tertiary alkyl halides with Grignard reagents, which likely proceeds via radical intermediates.19 Crotylation of bromide 2.5.1 and iodide 2.5.4 proceeded well and gave predominantly the branched products 2.5.2 and 2.5.5, but prenylation of the same substrates was low-yielding and exhibited poor regioselectivity.

2.6 Cross-coupling of allylboron reagents

2.6.1 Arylation Scheme 2.12: Suzuki coupling of crotylboron reagents

The first examples of the Pd-catalyzed cross-coupling of crotylboron compounds with aryl halides showed that branched product formation was preferred when triphenylphosphine was employed as a ligand (Scheme 1.6). Thus Maeda and Miyaura reacted tricrotylborane (2.6.1) with iodobenzene in the presence of catalytic

Pd(PPh3)4 and aqueous sodium hydroxide in refluxing THF to afford a mixture of crotylbenzenes, the major branched product 2.6.2 being isolated in 74% yield.20 Kalinin and coworkers showed that the allylboronic ester 2.6.4 also preferentially coupled with iodobenzene at the γ-position.21

Scheme 2.13: Arylation of allylboronic acids and a proposed mechanism

Szabó and coworkers reported that the Pd(PPh3)4-catalyzed cross-coupling of γ- substituted allylboronic acids with both electron-rich and electron-poor aryl iodides was completely regioselective for the branched products (Scheme 2.13).22 They noted that a previous study of the cross-coupling of allylsilanes and allylboronates with iodobenzene had observed the formation of mixtures of γ- and β-allylated products as well as coupling products where the silicon or boron group from the substrate was retained, indicating that a mechanism in which carbopalladation was followed by either β- boron/silicon or β-hydrogen elimination might be operative.23 Szabó and coworkers proposed that their reaction might also be proceeding via a similar mechanism. However, the reaction conditions in the earlier report were quite different (heating in a sealed vial at 100 °C for 25 h in acetonitrile, with triethylamine used as the base) from Szabó’s conditions. Furthermore, Szabó and coworkers provided no indication of side product formation (e.g. β-allylated products) in the present reaction that might serve as evidence for the proposed carbopalladation step.

Table 2.4: Regioselectivity in the arylation of crotyltrifluoroborates and a mechanistic proposal

Following the studies of Tsuji in the arylation of allylstannanes9 and Hiyama in the arylation of allylsilanes,12 Miyaura and coworkers examined the effect of ligand in the regioselective coupling of crotyltrifluoroborate salt 2.6.10 with p-bromoanisole using palladium(II) acetate as the precatalyst (Table 2.4).24 While bidentate ligands possessing small bite angles such as dppm and dppe (entries 1 and 2) gave mixtures of regioisomeric products, as did the use of Pd(PPh3)4 (entry 6), ligands with larger bite angles gave exclusively the branched isomer 2.6.11. In the reactions with some of these ligands, low yields were accompanied by formation of anisole, presumably arising from β-hydrogen elimination from the crotylpalladium intermediate followed by reductive 50 elimination. The highest yield (entry 5, 87%) was obtained with 1,1’-bis(di-t- butylphosphino)ferrocene (D-t-BPF) as the ligand.

Scheme 2.14: Enantioselective branched-selective arylation of crotyltrifluoroborates

Enantioselective cross-coupling of potassium crotyltrifluoroborate was accomplished by Miyaura and coworkers using the Josiphos ligand (R,S)-CyPF-t-Bu (Scheme 2.14).25 Enantiomeric excesses ranging from 77% to 90% were observed for a variety of meta- and para-substituted aryl bromides and α-bromoalkenes. Ketones (e.g. 2.3.1) were shown to be tolerated in the reaction. The absolute stereochemistry for two of the crotylated products ((R)-2.6.13, (R)-2.3.10) was assigned by comparison of optical rotation with previous reports of the same enantioenriched compounds in the literature.

Scheme 2.15: Linear-selective arylation of prenylboronates with Pd-NHC complexes

Organ and coworkers reported that the Pd-NHC complex Pd-PEPPSI-IPent catalyzed a highly linear-selective coupling of prenylboronic acid pinacol esters with 26 aryl bromides (Scheme 2.15). Thus while Pd(PPh3)4 favoured the branched product 52

2.6.18 in the coupling between prenylboronic acid pinacol ester (2.6.17) and p- bromoanisole, Pd-PEPPSI-IPent delivered the linear product 2.6.19 with 99:1 regioselectivity. Interestingly, when arylboronate ester 2.6.20 was cross-coupled with prenyl bromide, the use of either Pd(PPh3)4 or Pd-PEPPSI-IPent led to a similar regiochemical outcome, where formation of the linear product 2.6.19 was only slightly preferred. Partial scrambling of olefin geometry in the linear product 2.6.23 was observed in the Pd-PEPPSI-IPent-catalyzed cross-coupling of geranyl boronate (E)-2.6.22, although complete linear selectivity was maintained; while Pd(PPh3)4 again favoured formation of the branched product 2.6.24. More olefin scrambling occurred in the cross- coupling of neryl boronate (Z)-2.6.22, although production of the Z isomer was still modestly favoured (E:Z = 55:45). These results show that while σ-π-σ interconversion between the geranylpalladium and nerylpalladium complexes derived from 2.6.21 and 2.6.24 can take place, reductive elimination occurs rapidly enough to prevent an equilibrium mixture from being formed. Organ and coworkers propose that the preference for linear-selective coupling with the Pd-PEPPSI-IPent catalyst may be a result of a change from an SE’ to an SE mechanism in the transmetalation from boron to palladium. They note that little conversion was seen in the attempted cross-coupling of the reverse-prenyl boronate 2.6.25 with this catalyst, suggesting that the sterically hindered nature of the boronate may have prevented SE transmetalation from taking place.

Scheme 2.16: Scope of the linear-selective arylation of prenylboronates

Aryl bromides and chlorides were good substrates for the linear-selective prenylation (Scheme 2.16), while lower yields were observed with aryl iodides, in which case substantial amounts of homocoupling and iodide reduction products were observed. Coupling yields were generally slightly better for aryl chlorides than bromides, the former being less susceptible to reduction. Electron-poor arenes (2.6.30) or heteranes (2.6.31) tended to couple in lower yields, but the presence of an unprotected ketone was tolerated (2.3.8). Despite the bulkiness of the Pd-PEPPSI-IPent catalyst, ortho-substituted arenes were coupled smoothly (2.6.28).

Scheme 2.17: Ligand-controlled regiodivergent arylation of prenylboronates

Yang and Buchwald investigated the use of biarylphosphine ligands in the cross- coupling of prenylboronic ester 2.6.17 with aryl bromides, chlorides and triflates (Scheme 2.17).27 Excellent selectivities for the branched or linear products were obtained with ligands L1 (tBuXPhos) and L2 respectively. The coupling of heteroaryl substrates typically displayed high selectivity for only one of the regioisomers (e.g. 2.6.35, 2.6.39), although the formation of both the linear-prenylated indole 2.6.33 and reverse-prenylated indole 2.6.37 proceeded efficiently.

Scheme 2.18: Ligand control in the regiodivergent arylation of other allylboronates

Biarylphosphine ligands L4 and L5 successfully catalyzed the highly regioselective linear and branched coupling of other substituted allylboronic esters (Scheme 2.18), such as E- and Z-crotylboronic esters 2.6.40 and 2.6.43 and the cyclic allylboronic ester 2.6.44. The branched-selective coupling of the chiral boronate 2.6.47 afforded compound 2.6.49 with complete diastereoselectivity.

Scheme 2.19: Regioselectivity in the arylation of 1,3-disubstituted allylboronic esters

The use of Ag2O as a base helps promote transmetalation from secondary boronic esters in the Suzuki-Miyaura coupling.28 Crudden and coworkers exploited this in the coupling of 1,3-disubstituted allylboronic esters with aryl iodides.29 With phenyl- substituted boronic esters, good selectivity for the conjugated product (2.6.56, 2.6.61) is observed. With dialkyl-substituted boronic esters, the coupling favoured the γ- arylated product (2.6.53) when the boronic ester was located next to the more sterically

57 demanding substituent (2.6.50), but a 1:1 mixture of α- or γ-arylated isomers (2.6.58 and 2.6.59) was obtained when the boronic ester was located next to the less hindered substituent (2.6.57).

Scheme 2.20: Arylation of enantiopure or deuterated 1,3-disubstituted allylboronic esters

Crudden and Aggarwal investigated the arylation of enantiopure 1,3- disubstituted allylboronic esters.30 The regio- and stereoselectivity of the cross-coupling products of 2.6.63 and 2.6.66 indicate that the major reaction pathway features a syn-

SE’ transmetalation from boron to palladium. Cross-coupling of deuterated boronic ester 2.6.67 (a 90:10 mixture of γ and α D-isomers) resulted in an 85:15 mixture of γ- and α- arylated products, providing further confirmation of the SE’ pathway.

2.6.2 Allylation Scheme 2.21: Ligand regiocontrol in the allylation of monosubstituted allylic carbonates

Morken and coworkers have extensively explored the Pd-catalyzed cross- coupling of allylboronic esters with allyl electrophiles. While the coupling of allylboronic acid pinacol ester with cinnamyl carbonate 2.6.70 proceeded with greater than 20:1 selectivity for the linear product 2.6.72 when triphenylphosphine was used as the ligand (Scheme 2.21, entry 1), excellent regioselectivity for the branched isomer 2.6.71 was observed with bidentate ligands possessing small bite angles (entries 2 to 5).31 Ligands with wider bite angles led to decreased regioselectivity (entries 6 and 7).

Scheme 2.22: Enantioselective and branched-selective allylation of monosubstituted allylic carbonates

Morken and coworkers then explored the potential for asymmetric induction in the Pd-catalyzed allyl-allyl cross-coupling. The biarylbisphosphine (R)-MeO-furyl- BIPHEP effectively catalyzed the asymmetric branched-selective allylation of aryl- and

60 heteroaryl-substituted allylic carbonates (Scheme 2.22). The α- and γ-substituted allylic carbonates 2.6.70 and 2.6.72 behaved almost identically in the reaction with allylboronic acid pinacol ester (72–75% yield, >20:1 regioselectivity, 91% ee), implying that a π-allylpalladium complex may be a common intermediate in both reactions. Lower enantioselectivity was observed in the cross-coupling of electron-poor arenes such as 2.6.73. In cases where the arene substituent was particularly electron-rich, unactivated secondary allylic alcohols such as 2.6.75 were competent electrophiles for the reaction. With alkyl-substituted allylic carbonates, (R,R)-QuinoxP* proved to be the ligand of choice, delivering the coupled products 2.6.78 and 2.6.80 with very good regio- and enantioselectivity.

Scheme 2.23: Mechanistic studies and proposal for the allylation of monosubstituted allylic carbonates

To probe whether allyl transfer was taking place through transmetalation and inner-sphere reductive elimination from palladium or through outer-sphere attack on a π-allylpalladium intermediate, deuterium-labelled boronate 2.6.82 was reacted with cinnamyl carbonate 2.6.70 (Scheme 2.23). The deuterium label was found incorporated into both allyl termini of the product, suggesting that transmetalation from boron to 61 palladium and scrambling of the label via a π-allylpalladium intermediate was likely occurring. Further evidence of an inner-sphere reductive elimination pathway was provided by the allylation of enantioenriched and deuterium-labelled carbonate 2.6.82, which was regio- and stereoselectively converted into 2.6.83. Following anti ionization of the carbonate, π-σ-π equilibration to intermediate B places the deuterium label in the E configuration of the product. Following transmetalation, C–C bond formation must take place via inner-sphere reductive elimination in order to give the stereochemistry observed for 2.6.83. Morken and coworkers proposed that this occurs via 3,3’- elimination from a bis-σ-allylpalladium complex C.32

Scheme 2.24: Enantioselective and diastereoselective crotylation of monosubstituted allylic chlorides

The diastereoselective and enantioselective crotylation of allylic electrophiles was next explored ( Scheme 2.24).33 Yields of coupling product were substantially improved with the use of the more labile allylic chlorides and the addition of CsF to promote transmetalation. Good diastereoselectivity for the anti product (4:1 or better) was observed in all cases. As before, (R)-MeO-furyl-BIPHEP gave the best enantioselectivities in the coupling of aryl-substituted allylic electrophiles, while (R,R)- 63

QuinoxP* performed best with alkyl-substituted electrophiles. Both Z- and E- crotylboronates led to formation of 2.6.85 with identical levels for enantio- and diastereoselectivity, indicating that equilibration of the allylpalladium species was occurring before reductive elimination took place.

Scheme 2.25: Branched-selective prenylation of monosubstituted allylic chlorides

The prenylation of cinnamyl chloride (2.6.84) with prenylboronic acid pinacol ester gave only small amounts of coupling and reduced products (

Scheme 2.25).34 Much better reactivity was observed with the regioisomeric α,α- dimethylallyl boronate, whose couplings in the presence of (R)-MeO-furyl-BIPHEP

64 occurred with good to excellent regioselectivity for the quaternary-carbon-containing products 2.6.92 and 2.6.94, which were also formed with excellent levels of enantioselectivity. However, the quaternary stereocentre-containing product 2.6.95 was formed with only 2:1 diastereoselectivity.

Scheme 2.26: Further studies in the coupling of substituted allylboronates with allylic chlorides

The attempt to form products containing vicinal quaternary carbons such as 2.6.100 led to no reaction. Alkyl-substituted electrophiles such as 2.6.101 also did not undergo prenylation. On the other hand, cyclic boronates coupled with both aryl- and

65 alkyl-substituted electrophiles (2.6.96, 2.6.98) in excellent yield, regioselectivity, diastereoselectivity and enantioselectivity.

Scheme 2.27: Enantioselective allylation of 1,1-disubstituted allylic electrophiles

The allylation of prenyl-like electrophiles proceeded with high levels of enantioselectivity unless the two enantiotopic substituents at the γ-position of the electrophile were not significantly differentiated in size, as was the case with geranyl carbonate 2.6.109 (Scheme 2.27).35 The formation of 1,3-dienes was minimized with the addition of CsF and H2O to the reaction mixture, both of which serve to make the transmetalation process more efficient.

Table 2.5: Regioselective allylation of 1,3-disubstituted allylic acetates

The regioselectivity in the allylation of 1,3-disubstituted allylic acetates with a 1,2-bis(diphenylphosphino)benzene/allylpalladium chloride dimer catalyst system is influenced by both electronic and steric factors (Table 2.5).36 Aryl-substituted electrophiles display a preference to give the conjugated styrenyl product regardless of the original location of the leaving group (compare entries 1 vs. 5), although this regioselectivity is most pronounced with electron-poor arenes (entry 4) and less evident with electron-rich arenes (entry 2). Allylation is also disfavoured next to sterically bulky groups (entries 6 and 7).

Scheme 2.28: Regioselective allylation of 1,1,3-trisubstituted allylic acetates

1,1,3-Trisubstituted allylic acetates were also competent substrates in the allyl- allyl coupling (Scheme 2.28). Both acyclic and cyclic products containing quaternary carbons (2.113, 2.115) were obtained in good yields.

Table 2.6: Allylation of enantioenriched 1,1,3-trisubstituted allylic acetates

The potential for chirality transfer in the cross-coupling of enantioenriched 1,1,3-trisubstituted allylic acetates was examined (Table 2.6). Phenyl- and cyclohexyl- substituted allylic acetates (entries 1 and 4) underwent branched-selective coupling with good levels of chirality transfer, although yields were lower in the latter case. The p- anisyl substrate (entry 2) displayed low levels of regioselectivity in the coupling, while poor chiral transfer was observed with the p-trifluorotolyl substrate (entry 3).

2.6.3 Acylmethylation

Scheme 2.29: Cross-coupling of allylboronic acids with diazoketones

Szabó and coworkers established complementary methods for the regioselective allylation of α-diazocarbonyl compounds using allylboronic acids (Scheme 1.7). Copper(I) thiophenecarboxylate (CuTC) catalyzed the exclusive formation of branched 1,5-enones,37 while palladium(II) catalysis led to formation of the linear regioisomers, with traces of the branched product being detected in certain cases.38 The use of copper(I) iodide in the latter case improved the product yields but had no effect on the regioselectivity and was also not required for reactivity – indeed, the use of CuI in the absence of PdII resulted in no conversion at all. Reactions with trisubstituted boronic acids such as 2.6.122 were lower-yielding but displayed the same regioselectivity patterns, leading to quaternary centre formation when copper catalysis was employed.

2.6.4 Acylation Scheme 2.30: Crotylation of benzoyl chlorides

The use of 1,1’-bis(di-t-butylphosphino)ferrocene (D-t-BPF) was shown to be effective in the Pd-catalyzed cross-coupling of potassium crotyltrifluoroborate with electron-rich benzoyl chlorides (2.6.125), but yields were significantly poorer with substrates that did not contain electron-donating substituents para to the aroyl chloride.39 Only yields of the branched products were reported; no comment was made regarding the formation of decarbonylated products.

2.7 Cross-coupling of allylzinc reagents Scheme 2.31: Use of a linear-selective allylzinc cross-coupling in the total synthesis of siamenol

It is surprising that the use of allylzinc reagents in cross-coupling chemistry has only recently been investigated. Cheong, Buchwald and coworkers reported a highly linear-selective prenylation of aryl bromides40 using prenylzinc bromide–lithium chloride41 in conjunction with a palladacycle precatalyst42 and a biarylphosphine ligand (Scheme 2.31), CPhos being the optimal choice in terms of yield.43 Vinyl triflates, nonaflates and bromides that did not give satisfactory results in the Suzuki coupling previously disclosed by the Buchwald group27 were also smoothly prenylated using this protocol. An efficient synthesis of the prenylated phenol siamenol (2.7.4), which exhibits anti-HIV activity, was carried out using this methodology. A previous synthesis of siamenol had used super-stoichiometric amounts of π-prenylnickel bromide dimer, prepared in situ from the highly toxic tetracarbonylnickel, to install the prenyl group;44 the use of palladium-catalyzed cross-coupling avoids this.

Scheme 2.32: Linear-selective cross-coupling of allylzinc pivalates

Ellwart and Knochel combined allylic chlorides and bromides with zinc dust, lithium chloride and magnesium pivalate in THF.45 Evaporation of solvent afforded solid reagents that can be stored for weeks to years under argon. In the presence of Organ’s Pd-PEPPSI-IPent catalyst (Scheme 2.15), these reagents underwent completely linear-selective coupling with aryl and heteroaryl bromides in good yield (Scheme 2.32) while standard allylzinc halides gave only traces of allylated product. These reagents tolerated the presence of ester or nitrile functionalities, but aldehydes and ketones were preferentially allylated in the presence of aryl bromides.

2.8 Cross-coupling of allylgermanium reagents Scheme 2.33: Pd-catalyzed cross-coupling of germatrane 2.8.1

Faller and Kultyshev investigated the cross-coupling of a variety of pentacoordinated germatranes with aryl iodides.46 Methylcrotylgermatrane 2.8.1 was successfully coupled with 4-iodotoluene in the presence of Pd(dba)2, (2-biphenyl)di- tert-butylphosphine (JohnPhos) and TBAF to give preferentially the linear product 2.8.2, but substantial amounts of homocoupled arene 2.8.3 were also observed.

2.9 Cross-coupling of allylaluminum reagents

Scheme 2.34: Pd-catalyzed cross-coupling of allylalane 2.10.1

A singular example of allylaluminum cross-coupling was demonstrated by Schumann, Schmalz and coworkers. One equivalent of diallylalane dimer 2.9.1, a crystalline solid that is indefinitely stable when stored under nitrogen,47 successfully underwent palladium-catalyzed cross-coupling with 1-naphthalene in 97% yield.48

2.10 Cross-coupling of allylzirconium reagents Scheme 2.35: Ni-catalyzed cross-coupling of crotylzirconium reagent 2.9.1

Oshima and coworkers investigated the allylation and crotylation of aryl halides with organozirconium reagents.49 Some biaryl formation was observed with palladium catalysis, but nickel-catalyzed cross-coupling proceeded smoothly with aryl chlorides, bromides and iodides and afforded predominantly the branched products when crotylzirconium reagent 2.10.1 was used. This reagent was prepared by addition of diisopropyl ketone to a mixture of Cp2ZrCl2 and n-butylmagnesium bromide.

2.11 Cross-coupling of allylmetals generated via retro-allylation Scheme 2.36: Cross-coupling of an allylpalladium species generated via retro-allylation

A conceptually unique strategy to access a σ-allylpalladium intermediate for cross-coupling with aryl halides was developed by Oshima and coworkers. In the proposed mechanism (Scheme 1.11), a Pd0 catalyst undergoes oxidative addition of an 74 aryl halide to form an arylpalladium(II) species. This is then coordinated to a tertiary homoallylic alcohol. Retro-allylation liberates a molecule of ketone while transferring the allyl group to palladium, from which reductive elimination occurs to afford an allylated arene.50

Scheme 2.37: Regio- and stereoselectivity in the retro-allylative coupling

Although the synthesis of the required precursors may be cumbersome, one of the advantages of this retro-allylative coupling is that allyl transfer frequently proceeds with excellent regiospecificity and stereospecificity. For instance, the retro-allylative coupling of γ,γ-disubstituted alcohol 2.11.3 in the presence of 1-bromonaphthalene (2.3.16) was highly selective for the linear product 2.11.4, while the α-substituted alcohol 2.11.6 led to preferential formation of branched product 2.3.11. These results 75 are consistent with the notion that allyl transfer occurs through the α-terminus and that reductive elimination of the allylated arene is fast relative to isomerization of the allylpalladium intermediate. Diastereomerically pure alcohols 2.11.7 and 2.11.8 led to stereospecific formation of (E)- and (Z)-2.3.18 respectively. This stereochemical outcome was rationalized by invoking a chair transition state for the retro-allylation whose conformation is locked by the preference of the t-butyl group to occupy an equatorial position. The high stereospecificity of the transformation provides further evidence that reductive elimination is rapid relative to σ-π isomerization of the allylpalladium intermediate.

Scheme 2.38: Variation of reaction conditions for the retro-allylative coupling

Poor yields were observed with the initially reported reaction conditions in the retro-allylative coupling with aryl chlorides (Scheme 2.38, 6% yield of 2.11.10 from 1- chloronaphthalene) and electron-rich aryl bromides (29% yield of 2.11.11 from 4- bromoanisole). Yields for such substrates were significantly improved by replacing tri(p-tolyl)phosphine with tricyclohexylphosphine as the ligand for the palladium catalyst.51 This modified reaction protocol was extended to the retro-allylative coupling 77 of cyclic homoallylic alcohols such as 2.11.12. Use of microwave heating allowed for a dramatic reduction in reaction time, e.g. from 12 h to 15 min in the synthesis of 2.11.13.52

Scheme 2.39: Retro-allylative coupling of substituted allyl precursors

Oshima and coworkers extended the scope of the retro-allylative coupling to the synthesis of arylated vinyl- and allylsilanes (Scheme 2.39), with good selectivity for the E olefin in the former case and excellent chiral transfer in the latter case.53 While the synthesis of the required silane precursors such as 2.11.16 is typically quite involved, substrate 2.11.14 was available in a one-pot operation by deprotonating allyl(tert-

78 butyl)dimethylsilane with tert-butyllithium/TMEDA at –78 °C, then adding titanium tetraisopropoxide followed by acetone at the same temperature. Trisubstituted olefins such as vinylsilane 2.11.1954 or cinnamonitrile 2.11.22, obtained via cross-coupling of cyanoboration product 2.11.21,55 were also shown to participate successfully in the retro-allylative coupling. While the branched product 2.11.20 was produced as expected in the former case, the linear-arylated product 2.11.23 was the only coupling product observed in the latter case (along with the reduction product 2.11.24), suggesting that equilibration to the more thermodynamically stable linear σ-allylpalladium species took place before the reductive elimination step.

Scheme 2.40: Ni- and Pd-catalyzed retro-allylative coupling with allylic carbonates

The synthesis of 1,5-hexadienes via retro-allylation followed by cross-coupling with a π-allylmetal species was also investigated by Oshima and coworkers (Scheme 2.40).56 Coupling of homoallylic alcohol 2.11.14 with cinnamyl carbonate 2.6.70 delivered the branched product 2.11.26 under palladium catalysis but gave the linear product 2.11.25 when a Ni0/triethylphosphite catalyst system was employed. Fewer side reactions were seen with the nickel catalyst system, which proved to be more generally applicable than the palladium-based system even though the regioselectivity of this process was not always outstanding. For instance, the coupling of alcohol 2.11.27 with crotyl carbonate 2.11.28 resulted in a 37:63 mixture of branched and linear products. 79

2.12 Cross-coupling via allylic C–H bond activation Scheme 2.41: Photoredox-mediated cross-coupling of olefins and cyanoarenes

The direct arylation of an allylic C–H bond is an attractive and underexplored strategy for the construction of allylated arenes.57 In a pioneering example of this approach, Cuthbertson and MacMillan developed a photoredox-mediated coupling of olefins with dicyanobenzenes and cyanopyridines (Scheme 2.41).58 Unsubstituted cyclohexenes participated readily in the transformation, while the coupling of 1,4- dicyanobenzene with substituted cyclohexenes exhibited varying levels of regioselectivity. For instance, while the p-anisyl-substituted cyclohexene product 2.12.4 was formed with greater than 19:1 regioselectivity, the regioselectivity in the phenyl-

80 substituted product 2.12.5 was only 2.1:1. Coupling of acyclic olefins with 1,4- dicyanobenzene resulted in unselective mixtures of regioisomers (2.12.7, 2.12.8).

2.13 Conclusion An impressive range of substituted allyl nucleophiles have been shown to undergo highly regioselective palladium-catalyzed cross-couplings with aryl electrophiles. Branched-selective crotylation of arenes can be achieved effectively using crotylboronates or crotylsilanolates, and Miyaura has shown that an asymmetric crotylation can be achieved using crotyltrifluoroborates in conjunction with a Josiphos ligand. The Buchwald group has developed an efficient method for the reverse prenylation of arenes using prenylboronates. It is perhaps a little surprising that while linear-selective prenylation of arenes has been explored recently by Organ and Buchwald with prenylboronates and by Buchwald and Knochel using prenylzinc reagents, the linear-selective crotylation of arenes has received scant attention after Hiyama’s investigations with allyltrifluorosilanes in the mid-1990s. A variety of more highly substituted allylic boronates have also been coupled successfully with arenes, and good chiral transfer can be achieved with enantioenriched allylboronates in many cases. An impressive series of publications by the Morken group has firmly established the palladium-catalyzed allyl-allyl coupling as an excellent method for the synthesis of a variety of structurally complex 1,5-dienes, in which the regioselectivity, diastereoselectivity, and sometimes even enantioselectivity of the process can be effectively controlled. A noticeable limitation of the methods published thus far is that at least one of the olefins in the product must be monosubstituted. Cross-coupling with other types of electrophiles such as vinyl and alkyl halides is less well established. Also, in general, transformations catalyzed by metals other than palladium have not yet been systematically explored. Most surprisingly, while allylic C–H bond activation has been successfully used as a strategy to introduce carbon and heteroatom nucleophiles, the potential of this strategy has barely begun to be realized in the cross-coupling with electrophilic reagents.

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34 Ardolino, M. J.; Morken, J. P. J. Am. Chem. Soc. 2014, 136, 7092–7100. 35 Zhang, P.; Le, H.; Kyne, R. E.; Morken, J. P. J. Am. Chem. Soc. 2011, 133, 9716– 9719. 36 Le, H.; Batten, A.; Morken, J. P. Org. Lett. 2014, 16, 2096–2099. 37 Das, A.; Wang, D.; Belhomme, M.-C.; Szabó, K. J. Org. Lett. 2015, 17, 4754–4757. 38 Belhomme, M.-C.; Wang, D.; Szabó, K. J. Org. Lett. 2016, 18, 2503–2506. 39 Al-Masum, M.; Liu, K.-Y. Tetrahedron Letters 2011, 52, 5090–5093. 40 Additionally, one example each of prenylation with an aryl chloride, iodide and triflate was given. 41 Ren, H.; Dunet, G.; Mayer, P.; Knochel, P. J. Am. Chem. Soc. 2007, 129, 5376– 5377. 42 Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4, 916–920. 43 Yang, Y.; Mustard, T. J. L.; Cheong, P. H.-Y.; Buchwald, S. L. Angew. Chem. Int. Ed. 2013, 52, 14098–14102. 44 Krahl, M. P.; Jäger, A.; Krause, T.; Knölker, H.-J. Org. Biomol. Chem. 2006, 4, 3215–3219. 45 Ellwart, M.; Knochel, P. Angew. Chem. Int. Ed. 2015, 54, 10662–10665. 46 Faller, J. W.; Kultyshev, R. G. Organometallics 2002, 21, 5911–5918. 47 Schumann, H.; Kaufmann, J.; Dechert, S.; Schmalz, H.-G. Tetrahedron Letters 2002, 43, 3507–3511. 48 Schumann, H.; Kaufmann, J.; Schmalz, H.-G.; Böttcher, A.; Gotov, B. Synlett 2003, 1783–1788. 49 Hirano, K.; Fujita, K.; Yorimitsu, H.; Oshima, K. Synlett 2005, 2005, 1787–1788. 50 Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006, 128, 2210–2211. 51 Iwasaki, M.; Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129, 4463–4469. 52 Iwasaki, M.; Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. Tetrahedron 2007, 63, 5200–5203.

53 Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129, 12650–12651. 54 Wakabayashi, R.; Fujino, D.; Hayashi, S.; Yorimitsu, H.; Oshima, K. J. Org. Chem. 2010, 75, 4337–4343. 55 Ohmura, T.; Awano, T.; Suginome, M.; Yorimitsu, H.; Oshima, K. Synlett 2008, 2008, 423–427. 56 Sumida, Y.; Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 1629–1632. 57 For an example of Fe-catalyzed allylation of aryl Grignard reagents with unactivated olefins, see: Sekine, M.; Ilies, L.; Nakamura, E. Org. Lett. 2013, 15, 714–717. 58 Cuthbertson, J. D.; MacMillan, D. W. C. Nature 2015, 519, 74–77.

3 Pd-catalyzed asymmetric prenylation of 3-alkyloxindoles

3.1 Introduction The dimethylallyl or prenyl group is the fundamental structural motif in terpene natural products and is also frequently incorporated into other types of macromolecules and secondary metabolites.1 Notable among the latter are the prenylated indole alkaloids, which contain a tryptophan residue decorated with one or more isoprene units. The wide-ranging spectrum of promising biological activities exhibited by these alkaloids has stimulated interest in their biosynthesis and chemical synthesis.2 The selective incorporation of a 3,3-dimethylallyl (“linear” prenyl) or 1,1- dimethylallyl (“reverse” prenyl) into one position of the indole raises issues of chemoselectivity and regioselectivity. The prenylation of C3-substituted indole derivatives poses a particular challenge in that it entails the formation of a quaternary stereocentre,3 and in the case of reverse prenylation, one that is vicinal to a second quaternary carbon. Several multi-step protocols have been developed that successfully overcome these challenges (Chapter 1). However, the one-step asymmetric prenylation of a 3-substituted indole derivative using a chiral -prenyl organometallic species had previously not been documented, and although Danishefsky and coworkers had pointed out the possibility of such an approach toward the synthesis of 3-reverse-prenylated indole alkaloids, they were “not optimistic about the prospects for introduction of a 1,1- dimethallyl moiety at the gem-dimethyl carbon in the required series, in serviceable yield, via direct alkylative cyclization.”4

Scheme 3.1: Mechanism of palladium-catalyzed allylic alkylation

Scheme 3.2: Pd-catalyzed prenylation of carbon nucleophiles

While the palladium-catalyzed asymmetric allylic alkylation (Scheme 3.1) has proven to be a most versatile method for the stereoselective construction of C-C bonds,5 previous studies on the behaviour of -prenylpalladium complexes toward nucleophiles had noted that mixtures of regioisomeric products were typically obtained (Scheme 3.2). Trost, Schmuff, and Miller observed that in THF, the sodium salts of dimethyl malonate and methyl 2-(phenylsulfonyl)acetate both exhibited a preference to react with a - prenylpalladium(dppe) complex at the less hindered primary terminus, especially in the case of the latter, bulkier nucleophile.6

On the contrary, Åkermark and coworkers observed that the use of Pd(PPh3)4, which produces a more sterically hindered Pd catalyst than dppe, led to the reverse regioselectivity in the reaction between dimethyl malonate and prenyl acetate, affording a 47:15 mixture of branched and linear products.7 With sterically more hindered ligands, formation of a Pd complex with the monosubstituted olefin of the branched isomer is preferred over the formation of a complex with the trisubstituted olefin of the linear isomer. The differential regioselectivity in favour of the reverse-prenylated product observed with Pd(PPh3)4 was corroborated in a later report by Trost and Merlic, who isolated a 68:32 mixture of branched and linear products in 67% yield when conducting the same reaction in THF.8 Åkermark and coworkers also noted that the more sterically hindered diethyl methylmalonate nevertheless preferred to react at the less hindered position, leading to an 18:23 mixture slightly favouring the linear product. Furthermore, they observed that the reaction of the same nucleophiles with a stoichiometrically generated - prenylpalladium complex led to a similar product distribution, suggesting that both the catalytic and stoichiometric reactions proceeded via the same reactive intermediates.7

Scheme 3.3: Pd-catalyzed prenylation in the synthesis of (±)-trans-chrysanthemic acid

An early application of the regioselective Pd-catalyzed prenylation of stabilized carbon nucleophiles was demonstrated by Gênet and coworkers in their synthesis of (±)- trans-chrysanthemic acid, an important precursor of pyrethroid insecticides.9 Allylic acetate 3.1.1 underwent exclusive alkylation at the tertiary position when treated with the sodium salts of dimethyl malonate or methyl 2-(phenylsulfonyl)acetate in the presence of catalytic Pd(PPh3)4 with yields of 80% and 85% respectively. In both cases, alkylation was accompanied by complete isomerization of the olefin from cis to trans, 88 indicating that π-σ-π equilibration of the prenylpalladium intermediate to its more stable trans configuration occurred before alkylation took place. The complete regioselectivity of the alkylation is likely enforced by the fact that the secondary allylic terminus is adjacent to a tetrasubstituted carbon and is therefore quasi-neopentyl; substitution at this position is therefore strongly disfavoured.

Scheme 3.4: Pd-catalyzed geranylation and nerylation

In a study of more highly substituted prenyl systems, Trost and Verhoeven examined the regioselectivity of nucleophilic attack in Pd-catalyzed alkylations with

89 geranyl and neryl acetate.10 The olefin geometry of either starting material was preserved in the linear product isomer, indicating that π-σ-π interconversion between the nerylpalladium and geranylpalladium complexes did not take place before alkylation. Such an equilibration would proceed via σ-allylpalladium complex 3.1.2, and the placement of Pd on the tertiary carbon destabilizes this intermediate, rendering this process slow relative to nucleophilic attack. In line with previous studies of the prenylation of these two nucleophiles, it was noted that the more sterically encumbered methyl 2-(phenylsulfonyl)acetate exhibited a greater preference for attack at the primary position of the π-prenylpalladium intermediate than dimethyl malonate. More interestingly, the nerylpalladium species was far more susceptible than the geranylpalladium species to nucleophilic attack at the tertiary position. With geranyl acetate, using either nucleophile resulted in predominant formation of the linear product isomer; but with neryl acetate, switching from methyl 2- (phenylsulfonyl)acetate to dimethyl malonate reversed the regioselectivity in favour of the branched product (from 89:11 to 35:65 linear:branched).

Scheme 3.5: Internal coordination in nerylpalladium and geranylpalladium complexes

The greater proclivity of the nerylpalladium complex 3.1.4 to undergo alkylation at the tertiary position has been rationalized by taking into account the possibility of internal coordination by the second olefin of the neryl ligand (Scheme 3.5).11 In geranylpalladium complex 3.1.3, the anti methyl substituent of the allylpalladium

90 species is canted toward the metal, and it and one of the methyl groups on the other olefin must be brought close together if internal coordination is to take place; this steric interaction destabilizes this coordination. However, in nerylpalladium complex 3.1.4, the syn methyl substituent is canted away from the palladium,12 which allows internal coordination of the other alkene to take place without creating destabilizing steric interactions. Nucleophilic attack on this complex at the primary position would lead to Pd-diene complex 3.1.5 while attack at the tertiary position would lead to complex 3.1.6. Complex 3.1.5 is less stable due to both olefins being trisubstituted and the bridge between the olefins being shorter, so formation of this complex is less favorable than formation of complex 3.1.6. Without this possibility of diene chelation, the alkylation of geranyl complex 3.1.3 is sterically driven toward the less hindered primary position, as is typical of less highly substituted allylpalladium complexes.

Scheme 3.6: Effect of internal olefin on regioselectivity of alkylation

Direct evidence that the second olefin plays a significant role in influencing the regioselectivity of the Pd-catalyzed alkylation of monoterpenoid electrophiles was provided by Julia and coworkers (Scheme 3.6).13 When using allylpalladiumchloride dimer as the catalyst, alkylation of linalyl acetate was favoured at the tertiary position over the primary position by a 91:9 ratio. However, when dihydrolinalyl electrophile 3.1.7 was used, alkylation now occurred predominantly at the primary terminus by a 95:5 ratio. These results reinforce the notion that the second olefin does play a key role in stabilizing intermediate 3.1.6 over 3.1.5 and that this plays a critical role in overturning the inherent bias of the geranyl system toward alkylation at the less hindered primary terminus.

Table 3.1: Effect of ligand and nature of nucleophile on the Pd-catalyzed prenylation

Julia and coworkers also studied the effect of ligand on the regioselectivity of the Pd-catalyzed prenylation of stabilized carbon nucleophiles (Table 3.1).13 This study again confirmed that the Pd-dppe catalyst system displays a greater tendency to favour linear products than the more sterically demanding Pd-PPh3 system. The steric demands of the nucleophile also had a significant effect on the regioselectivity. Very good selectivities for the branched products was observed with the least sterically hindered cyano-substituted nucleophiles (entries 4, 5 and 6), while the most sterically demanding nucleophile examined (ethyl 2-(phenylsulfonyl)acetate, entry 7) displayed a marked preference for linear isomer formation. Intermediate levels of regioselectivity were observed with nucleophiles such as malonates and ethyl acetoacetate (entries 1, 2 and 3) which fell between these steric extremes. On the other hand, the regioselectivity of the alkylation was relatively insensitive to the nature of the leaving group on the electrophile – both the tertiary acetate (entry 1) and tertiary p-tolylsulfone (entry 8) gave comparable regioselectivities when the same ligand (dppe or PPh3) was employed for each substrate. The regiochemistry of the electrophile also had little effect on the regioselectivity of the alkylation – similar product ratios were obtained with either dppe or PPh3 as the ligand if the primary acetate 3.1.7 was used in place of the tertiary acetate (entry 9). These observations are consistent with the notion that the regioselectivity of this process is determined by the alkylation step of the catalytic cycle, and not by previous steps such as ionization of the electrophile.

Scheme 3.7: Pd-catalyzed prenylation of nitrogen nucleophiles

The reaction of nitrogen nucleophiles with -prenylpalladium complexes has been extensively investigated by Yudin and coworkers (Scheme 3.7).14 The reaction of aziridine 3.1.8 with prenyl acetate in the presence of catalytic Pd0-BINAP strongly favoured the branched product 3.1.9 over the linear product 3.1.10 when conducted in THF (3.1.9:3.1.10 = 92:8), while lower conversion and a switch in regioselectivity was observed in dichloromethane (3.1.9:3.1.10 = 39:61). Other secondary amines such as piperidine also initially favour branched product formation15 but under the reaction conditions, this product is able to undergo AcOH-catalyzed equilibration to the linear isomer. The less basic aziridine products do not undergo this isomerization, and the isomerization can also be suppressed by the addition of a base such as DBU that does not affect catalyst turnover. In the prenylation of piperidine, use of DBU in conjunction with triethylphosphite as the ligand resulted in an 80% yield of a 99:1 mixture favouring the branched product 3.1.12. It has previously been suggested in the literature that “the poor regioselectivity 94 observed in non-symmetrical allylic substrates has hampered the general use of [the Tsuji-Trost reaction]”16 and this belief has frequently been cited as a motivation for the development of regioselective allylic alkylation methods using other transition metals, including those that install a reverse prenyl group.8,17 Nevertheless, the previous examples demonstrate that the regioselectivity of the Pd-catalyzed prenylation can in fact be controlled by the careful manipulation of the reaction parameters. In particular, the results of the Yudin group with respect to the prenylation of secondary amines and aziridines refute the notion that excellent regioselectivities in favour of reverse- prenylated products cannot be achieved. In investigating the asymmetric prenylation of 3-substituted oxindoles, we sought to show that the lessons learned from these results and our extensive studies of the Pd-catalyzed asymmetric allylic alkylation in general would allow us to design a practical and efficient method to access enantioenriched linear and reverse-prenylated indole derivatives.

3.2 Optimization of the asymmetric prenylation of 3-alkyloxindoles by Sushant Malhotra

Table 3.2: Selected optimization studies on the regioselective synthesis of oxindoles 3.2.3 and 3.2.4

Initial studies on the asymmetric prenylation of oxindole 3.2.2 were carried out by Sushant Malhotra.18 Four commonly used diamine-based ligands developed by the Trost group for the asymmetric allylic alkylation were examined (Table 3.2, entries 1- 19 4) in the reaction of oxindole 3.2.2 with electrophile 3.2.1, and it was found that L2 (entry 1) gave the best combination of regioselectivity (2.0:1) and enantioselectivity

(85%) for the branched product 3.2.3, while L1 (entry 2) was the only one of the four ligands to modestly favour the formation of linear product 3.2.4, although the enantioselectivity was excellent (97%). That the sterically more hindered L2 would preferentially deliver the branched product while the less hindered L1 favours formation of the linear product is a trend that accords with previous studies of the Pd-catalyzed prenylation (§3.1). With bulkier ligands on Pd, formation of a complex with the monosubstituted olefin of the branched product becomes preferred over the formation of a complex with the trisubstituted olefin of the linear product. The choice of solvent and the presence of a halide additive also had a significant impact on the regioselectivity of the prenylation.20 Solvents with relatively higher dielectric constants such as dichloromethane, 1,2-dichloroethane and acetonitrile (entries 5-7) increased the regioselectivity in favour of branched product 3.2.3, while the use of more nonpolar solvents such as benzene, toluene, hexanes and cyclohexane resulted in greater selectivity for the linear isomer (entries 9-13). The regio- and enantioselectivity of the prenylation was slightly enhanced if the reaction was run at room temperature rather than at 60 °C (entry 10 vs. 11). The asymmetric linear prenylation of oxindole 3.2.2 was best achieved in toluene (entry 11), in which case oxindole 3.2.4 was generated in 64% yield and 96% ee. Optimal conditions were found for the asymmetric reverse prenylation of 3.2.2 when 30 mol % of tetrabutylammonium difluorotriphenylsilicate (TBAT) was added to the reaction run in CH2Cl2 (entry 8), which generated compound 3.2.3 in 90% yield and 91% ee. While nucleophilic attack at the less substituted terminus of a π-prenylpalladium complex is kinetically more favourable, attack at the more substituted terminus is thermodynamically favoured due to the greater electropositivity of this carbon and the more stable complex formed between Pd and the monosubstituted olefin of the resulting

97 product. More polar solvents better stabilize the charged intermediates generated during the reaction, disfavouring the kinetically controlled nucleophilic attack leading to the linear product, and resulting in preferential generation of branched isomer 3.2.3. The addition of TBAT provides both a tetrabutylammonium cation and a fluoride anion that may provide further stabilization for the anionic nucleophile and the cationic π- prenylpalladium complex respectively,20,21 leading again to improved regioselectivity for the branched product.

3.3 Scope of the asymmetric prenylation of 3-alkyloxindoles Scheme 3.8: Asymmetric reverse prenylation of 3-alkyloxindoles

Using Malhotra’s optimized conditions, the substrate scope of the asymmetric reverse prenylation was examined (Scheme 3.8). While N-protected oxindoles (allyl, prenyl, PMB, MOM) underwent reverse prenylation with very good regioselectivities (7.7:1 or greater) and enantioselectivies (86 to 90% ee), the unprotected oxindole gave only a 2:1 ratio of 3.3.7 to 3.3.22, and the former in only 32% ee. Substituents of varying steric and electronic properties (Br, OMe, Ph, CO2Me) were well tolerated at the 5- and 6-positions of the oxindole, with the electron-poor 6-carboxymethyloxindole performing especially well in terms of both regioselectivity (15:1) and enantioselectivity (95% ee). This last result indicates that stabilizing the oxindole nucleophile has the effect of slowing down nucleophilic attack, which favours the thermodynamically controlled branched prenylation and also allows more time for π-σ- π equilibration of the prenylpalladium complex leading to a more enantioselective process. The reaction was more sensitive to substitution on the 3-alkyl side chain. While the best enantioselectivity for the reverse prenyl product (>99% ee) was observed in the case of methyl amide 3.3.9, the corresponding methyl ester 3.3.8 was produced in only 77% ee under the same reaction conditions. Replacement of this moiety with others not at the carboxylic acid oxidation level (i.e. dimethyl acetal 3.3.12, primary alcohol 3.3.11, acetate 3.3.10) led to significant decreases in enantioselectivity, regioselectivity, and even reactivity in the last two cases. It appears that a strongly electron-withdrawing group on the alkyl side chain is needed to facilitate enolization of the oxindole substrate. The superior regioselectivity exhibited by cyano-substituted vs. ester-substituted substrates (e.g. 3.3.1 vs. 3.3.8) echoes the observations of Julia and coworkers that the less hindered α-cyanoesters give better regioselectivities than the corresponding malonates in the Pd-catalyzed prenylation (Table 3.1).

100

Table 3.3: Optimization of the reverse prenylation of oxindole 3.3.13

The asymmetric reverse prenylation of oxindole 3.3.13 was re-examined in an attempt to improve the enantioselectivity for product 3.3.8 (Table 3.3). The best enantioselectivity was observed when L1 was used as the ligand (entries 2-5). Screening higher-dielectric solvents as before (entries 6-8) showed that dichloromethane (entry 6) offered the best combination of regioselectivity (2.1:1) and enantioselectivity (91%). While running the reaction under more dilute conditions (entry 9) improved the regioselectivity to 3.2:1, the enantioselectivity decreased to 75% ee. Replacement of TBAT with tetra-n-butylammonium chloride (entry 10) had a similarly deleterious impact on the enantioselectivity (74% ee), perhaps reflecting the weaker coordinating ability of chloride vs. fluoride to palladium.

101

Scheme 3.9: Asymmetric linear prenylation of 3-alkyloxindoles

102

With the conditions previously optimized by Malhotra, the substrate scope of the asymmetric linear prenylation of the same oxindole substrates was examined (Scheme 3.9). While the regioselectivity of the linear prenylation is generally less high than in the reverse prenylation of the same substrates, the enantioselectivity is in many cases superior. N-Substituted oxindoles continued to perform well in the linear prenylation, and unlike what was observed for reverse prenylation, the unprotected oxindole 3.3.22 was delivered with satisfactory regioselectivity (2.9:1 in favour of the linear isomer) and enantioselectivity (86% ee). Substituents at the 5- and 6-positions of the oxindole were again well tolerated. Again the methyl ester 3.3.14 was produced in lower ee than the corresponding nitrile or methyl amide under the same reaction conditions. Substrates with 3-substituents at lower oxidation levels (dimethyl acetal 3.3.26, primary alcohol 3.3.25, acetate 3.3.24) again led to significant decreases in enantioselectivity and reactivity.

3.4 Synthesis of flustramine alkaloids and determination of absolute stereochemistry in the prenylation reaction Figure 3.1: Selected examples of flustramine alkaloids

To demonstrate the utility of the asymmetric prenylation and determine the absolute stereochemistry of the products, we undertook the syntheses of flustramines A (3.4.1) and B (3.4.2). The flustramine family (Figure 3.1) comprises over 20 prenylated indole alkaloids isolated from the marine bryozoan Flustra foliacea found in Scandinavian and Canadian waters.22 All of these alkaloids have in common a brominated hexahydropyrrolo[2,3-b]indole nucleus to which a prenyl or reverse-prenyl group is attached at C3. Smooth and skeletal muscle relaxant abilities have been 103 demonstrated for flustramines A and B. Additionally, flustramine A exhibits voltage- gated channel blocking activity,23 while debromoflustramine B and its analogues have been evaluated for their butyrylcholinesterase inhibitory activity: (–)- debromoflustramine B is over 7500 times more potent than its (+)-enantiomer.24 Antimicrobial activity has been reported for dihydroflustramine C and flustramine D (3.4.4).25 Prior asymmetric syntheses of flustramines A30 and B26,30 as well of several racemic syntheses of flustramine C27 (3.4.3) have been reported.

Scheme 3.10: Catalytic asymmetric synthesis of ent-flustramides and ent-flustramines A and B

Amides 3.3.9 and 3.3.23 were previously reported as intermediates in the total syntheses of flustramides A28 (3.4.5) and B29 (3.4.6) and flustramines A and B.30 Reductive cyclization with alane-dimethylethylamine complex (Scheme 3.10) was carried out on (+)-3.3.9 (prepared using (R,R)-L2) and (+)-3.3.23 (prepared using (S,S)-

L1) to obtain the unnatural (+)-isomers of all four natural products, whose spectral data was in agreement with literature reports.31 Comparison of their optical rotation with the reported values allowed us to assign the absolute stereochemistry for prenylation products 3.3.9 and 3.3.23, and the absolute stereochemistry in the reverse and linear prenylation of other oxindole substrates in this chapter was assigned by analogy with these two compounds. 104

Figure 3.2: Rationale for the divergent stereochemistry in the reverse and linear-prenyl products

To our surprise, the syntheses of ent-flustramide A and B showed that the use of

(R,R)-L1 or L2 in the Pd-catalyzed reaction leads to reverse prenylation taking place on the si face of the oxindole, but linear prenylation on the re face (Figure 3.2). We propose that in both cases, the nucleophile approaches the π-prenylpalladium complex in such a way that charge separation is minimized between the termini of the enolate and the allylic cation. Since the orientation of the prenylpalladium complex is enforced by the chiral ligand, which causes the methyl groups to sit underneath the “flap” in our stereochemical model,20,32 the oxindole must change its face of approach in order to achieve maximum overlap with the π-prenylpalladium complex during the attack at either the primary or tertiary positions.

105

3.5 Asymmetric geranylation of 3-alkyloxindoles Scheme 3.11: Geranylated, farnesylated and linalylated indole alkaloids

During our studies on the asymmetric prenylation of oxindoles, a report33 appeared in the literature describing the discovery of flustramines H, J and P (Scheme 3.11), all of which bear a geranyl side chain in place of the prenyl group more commonly encountered in this family of alkaloids. In the same report, flustramine H was shown to possess broad-spectrum antimicrobial activity. Previously, an unnamed alkaloid bearing a geranyl side chain had also been isolated from the same bryozoan species, Flustra foliacea.25b Geranylated34 and farnesylated35 indoline moieties have been reported in the quorum-sensing peptide pheromones of Bacillus subtilis. While indole alkaloids bearing a linalyl (tert-geranyl) substituent at C3 are unknown, natural products bearing this motif at other positions of the indole are known, e.g. lyngbyatoxin A.36 Prompted by our success in the asymmetric prenylation of oxindoles, we decided to apply our conditions to the asymmetric alkylation with monoterpenoid derivatives, with a view 106 toward synthesizing precursors of these biologically active C3-geranylated molecules. The addition of a substituent on the prenyl electrophile presents an intriguing synthetic challenge by introducing another stereochemical element in the product whose configuration must be controlled.

Table 3.4: Alkylation of oxindole 3.2.2 with racemic linalyl carbonate 3.5.1

Indeed, oxindole 3.2.2 was alkylated by racemic linalyl carbonate 3.5.1 in the presence of (R,R)-L2 to furnish linalyl product 3.5.2 (as a single diastereomer in 90% ee) and geranyl product 3.5.3 in close to a 1:1 ratio along with a small amount of the neryl product 3.5.4 (Table 3.4, entry 1). The geranyl and neryl products were distinguished by the 13C shift of the 3-methyl group, which is more shielded in the 107 geranyl isomer due to steric compression between the cis substituents.10,37 Addition of TBAT (entry 8) resulted in increased formation of the geranyl isomer, likely arising from accelerated π-σ-π isomerization of the nerylpalladium to the more stable geranylpalladium complex occurring before attack of the oxindole nucleophile. The use of other chiral ligands (entries 2-4) or more polar solvents (entries 5-7) failed to significantly bias the product distribution towards the linalyl isomer. All three alkylation products were separable by preparative TLC.

Scheme 3.12: Determination of relative stereochemistry of compound 3.5.2

The relative stereochemistry of the linalyl product 3.5.2 was determined by its conversion to lactone 3.5.6 (Scheme 3.12). NOE correlations on 3.5.6 showed that the aryl and methyl groups lie on opposite faces of the lactone. We hypothesize that the oxindole lactam prefers to occupy an equatorial position on the lactone due to the unfavourable reinforcing dipole-dipole interactions with the lactone that would arise if it occupied the axial position. The absolute stereochemistry of oxindole 3.5.2 was assigned by analogy with prenylation product 3.3.9.

108

Table 3.5: Optimization of linalylation, geranylation and nerylation conditions

The regioselectivity and diastereoselectivity in the Pd-catalyzed alkylation and amination37 of geranyl and neryl acetate has previously been shown to correlate with the olefin geometry of the electrophile (Scheme 3.4). Thus we attempted the alkylation of oxindole 3.2.2 with geraniol- and nerol-derived carbonates 3.5.7 and 3.5.8 (Table 3.5). No conversion was observed at room temperature, but at 60 °C moderate

109 conversion was obtained for both electrophiles in ethereal solvents (entries 1 and 3). Alkylation of geranyl carbonate 3.5.7 occurred exclusively at the terminal position without olefin isomerization to furnish geranyl product 3.5.3 as the sole product in 86% ee (entry 1). In contrast, with neryl carbonate 3.5.4 both linear products were formed as well as branched product 3.5.2 as a single diastereomer. Both the conversion and product distribution were affected by the choice of solvent; as in the case with prenyl electrophiles, CH2Cl2 favoured formation of the branched isomer (entry 8) while coordinating solvents favoured the linear isomer (entries 3, 4). However, aromatic solvents only resulted in trace conversion (entries 5, 6). We sought to further improve the enantioselectivity and conversion of the reactions by switching to the more active more reactive palladium precatalyst Pd(Cp)(allyl). Indeed, this allowed us to lower the temperature to 40 °C and generate 3.5.3 from geranyl carbonate 3.5.7 in an optimal 91% ee and 76% yield (entry 2). The same conditions afforded the neryl product 3.5.4 in 94% ee from the neryl carbonate

3.5.8 (entry 7), albeit with modest regioselectivity and yield (41%). In CH2Cl2 (entry 9) the branched product was formed with good regioselectivity (5.1:1 linalyl:neryl with only a trace amount of the geranyl isomer) and excellent enantioselectivity (94%) but conversion remained moderate (32% yield of 3.5.4). By degassing the reaction solvent and switching to the more reactive Troc carbonate 3.5.9 (entry 10), the yield was dramatically improved (92%) and the regioselectivity was increased to 13:1 in favour of 3.5.2 over 3.5.4; in this case the geranyl isomer 3.5.3 could not be detected by 1H NMR of the crude reaction mixture. Our results show that the (η3-geranyl)palladium complex undergoes nucleophilic attack predominantly at the terminal end and does not undergo isomerization to the less thermodynamically stable (η3-neryl)palladium complex. In contrast, nucleophilic attack on a (η3-neryl)palladium complex can be biased towards either the terminal or internal carbons; while its isomerization to the (η3-geranyl)palladium complex is slow but does occur to an extent. Both the contrast in the regioselectivity of nucleophilic attack on these two species (c.f. Scheme 3.5 and explanation thereof) and the ability of the neryl

110 complex to isomerize to the geranyl complex are consistent with the previous observations of the Trost10 and Åkermark37 groups. These results also explain the poor regioselectivity of the initial alkylation with racemic linalyl carbonate 3.5.1 in CH2Cl2. Matched ionization of one enantiomer of carbonate by the chiral Pd-ligand complex gives the (η3-geranyl)palladium complex, while the (η3-neryl)palladium complex is generated from the other enantiomer. With 3 CH2Cl2 as the reaction solvent attack on the internal position of the (η -neryl)palladium complex is favoured, and this leads to formation of one diastereomer of the linalyl product along with a small amount of the neryl product. However, the solvent seems to have no effect on the inherent preference of the (η3-geranyl)palladium complex to react at the terminal end (c.f. Scheme 3.4), so the other diastereomer of 3.5.2 is not produced.

3.6 Experimental

3.6.1 General methods All reagents were obtained commercially unless otherwise noted. Reactions were performed using glassware that was flame-dried under vacuum (~1 Torr). All reactions were performed under an atmosphere of nitrogen. Pd2dba3•CHCl3 was prepared according to a literature procedure.38 Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Organic solutions were concentrated under reduced pressure (~15 Torr) by rotary evaporation. Solvents were purified by passage under 12 psi N2 through activated alumina columns. Chromatography was performed on Silicycle Silia-P Silica Gel (40-63 m). Compounds purified by chromatography were typically applied to the adsorbent bed using the indicated solvent conditions with a minimum amount of added chloroform as needed for solubility. Chiral HPLC analyses were performed on a Thermo Separation Products Spectra Series P-100 or P-200 and UV100 (254 nm or 220 nm) using Chiralcel® columns (OB-H, OC, OD-H, OJ-H), or Chiralpak® column (AD, AS, IA, IB,

IC) eluting with the solvent mixtures indicated. Retention times (Rt) are reported in minutes (min). Thin layer chromatography was performed on EMD Chemicals Silica

Gel 60 F254 plates (250 m). Visualization of the developed chromatogram was

111 accomplished by fluorescence quenching or by staining with p-anisaldehyde or aqueous potassium permanganate.

Nuclear magnetic resonance (NMR) spectra were acquired on either a Varian Inova- 600, a Varian Inova-500, a Varian Mercury-400, or a Gemini-300 operating at 600, 500, 400, or 300 MHz for 1H and 150, 125, 100, or 75 MHz for 13C, respectively, and are referenced internally according to residual solvent signals. Data for 1H NMR are recorded as follows: chemical shift (, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; m, multiplet), integration, coupling constant (Hz). Data for 13C NMR are reported in terms of chemical shift (, ppm). Melting points were obtained on a Thomas-Hoover apparatus in open capillary tubes and are uncorrected. Infrared spectra were recorded on either a Thermo-Nicolet IR100 or a Thermo-Nicolet IR300 spectrometer as thin films using NaCl salt plates or as KBr pellets and are reported in frequency of absorption. Optical rotations were determined using a JASCO DIP-1000 digital polarimeter. The sodium D line (589 nm) and a 50 mm path length were used exclusively, but differences in temperature, solvent, and concentration are indicated. High-resolution mass spectra were obtained from the Vincent Coates Foundation Mass Spectrometry Laboratory at Stanford University (http://mass-spec.stanford.edu) using a Micromass Q-Tof API-US mass spectrometer (Waters Corporation, Milford, MA).

3.6.2 Preparation of electrophiles tert-butyl (2-methylbut-3-en-2-yl) carbonate

Me OH n-BuLi Me OBoc

Me Boc2O Me n-BuLi (17.41 mL of a 2.0 M solution in hexanes) was added to a solution of commercially available undistilled 2-methylbut-3-en-2-ol (3.0 g, 34.8 mmol) in THF (60 mL) at 0 ºC. The mixture was stirred for 15 min at 0 °C before di-tert-butyl dicarbonate (7.6 g, 34.8 mmol) was added. The resulting solution was stirred for 3 h at

112 room temperature and quenched with saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Silica gel chromatography using 10% EtOAc/hexanes afforded 4.0 g (62%) of the desired compound as a colorless oil. The crude oil was purified by vacuum 1 distillation. H NMR (400 MHz, CDCl3): δ 6.11 (dd, J = 17.5, 10.9 Hz, 1H), 5.19 (dd, J = 17.5, 0.6 Hz, 1H), 5.16 (d, J = 11.0 Hz, 1H), 1.53 (s, 6H), 1.46 (s, 9H) matches literature reported values.39

(E)-tert-butyl (3,7-dimethylocta-2,6-dien-1-yl) carbonate

Me Me n-BuLi Me Me

Me OH Boc2O Me OBoc n-BuLi (5.6 mL of a 2.3 M solution in hexanes, 12.96 mmol) was added to a solution of commercially available undistilled geraniol (2.0 g, 12.96 mmol) in THF (50 mL) at 0 ºC. The mixture was stirred for 30 min at 0 °C before di-tert-butyl dicarbonate (2.75 g, 12.96 mmol) was added. The resulting solution was stirred for 3 h at room temperature and quenched with saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted with Et2O (200 mL). The organic layer was concentrated under reduced pressure. Silica gel chromatography using 10% EtOAc/hexanes afforded 2.77 g (84%) of the desired compound as a colorless oil. 40 Spectral data matches previously reported data. Rf = 0.46 (10% EtOAc/hexanes) – 1 KMnO4 stain; H NMR (400 MHz, CDCl3): δ 5.4-5.35 (m, 1H), 5.10-5.05 (m, 1H), 4.58 (d, J = 7.0 Hz, 2H), 2.10-2.0 (m, 4H), 1.69 (s, 3H), 1.67 (s, 3H), 1.58 (s, 3H), 1.47 (s, 9H). tert-butyl (3,7-dimethylocta-1,6-dien-3-yl) carbonate

Me Me OH n-BuLi Me Me OBoc

Me Boc2O Me

113 n-BuLi (5.7 mL of a 2.5 M in hexanes, 14.3 mmol) was added to a solution of (±)- linalool (2.3 mL, 13.0 mmol) in THF (50 mL) at 0 °C. The mixture was stirred at 0 °C for 25 min before di-tert-butyl dicarbonate (2.9 mL, 13.0 mmol) was added. The resulting orange solution was stirred at rt for 3h and quenched with saturated aqueous

NaHCO3. The layers were separated and the aqueous layer was extracted with Et2O (3 x 30 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Silica gel chromatography using 5% EtOAc/hexanes afforded 2.5 g (77%) of the desired compound as a pale yellow oil. TLC

1 Rf = 0.45 (10% EtOAc/hexanes) – KMnO4 stain; H NMR (400 MHz, CDCl3):  6.01 (dd, J = 18.0, 11.0 Hz, 1H), 5.16 (d, J = 18.0 Hz, 1H), 5.13 (d, J = 11.0 Hz, 1H), 5.07 (m, 1H), 1.97 (m, 2H), 1.81 (m, 2H), 1.65 (s, 3H), 1.56 (s, 3H), 1.52 (s, 3H), 1.45 (s,

13 9H); C NMR (100 MHz, CDCl3)  152.1, 141.9, 132.1, 123.9, 113.7, 83.8, 81.6, 39.7,

28.1, 27.6, 25.9, 23.6, 22.6, 17.8; IR (thin film): max 2979, 2932, 1741, 1456, 1413, 1393, 1370, 1300, 1285, 1255, 1155, 993, 924, 861, 794, 720 cm−1; Elemental Analysis: Theoretical C70.83, H10.30 Found C71.02, H10.21.

(Z)-3,7-dimethylocta-2,6-dienyl 2,2,2-trichloroethyl carbonate

To a solution of nerol (0.53 mL, 3.0 mmol) in pyridine (3 mL) was added 2,2,2- trichloroethyl chloroformate (0.44 mL, 3.3 mmol). The mixture was stirred at 25 °C for 24 h, diluted with water (10 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Silica gel chromatography using 5% EtOAc/hexanes afforded 723 mg (73%) of the desired compound as a colorless oil. TLC 1 Rf = 0.59 (10% EtOAc/hexanes); H NMR (400 MHz, CDCl3):  5.42 (m, 1H), 5.09 (m, 1H), 4.75 (s, 2H), 4.71 (d, J = 8 Hz, 2H), 2.17-2.06 (m, 4H), 1.78 (s, 3H), 1.68 (s, 3H),

13 1.60 (s, 3H) ppm; C NMR (125 MHz, CDCl3)  154.2, 144.6, 132.7, 123.6, 118.2,

114

94.7, 77.0, 65.8, 32.5, 26.8, 26.0, 23.8, 17.9 ppm; IR (thin film): max 2965, 2915, 1757, 1445, 1387, 1237, 943, 903, 817, 783, 726 cm−1; HRMS (ES+) calcd for + + C13H19Cl3NaO3 351.0297 found 351.0298 (MNa ).

3.6.3 Preparation of oxindole nucleophiles

2-(1-allyl-6-bromo-2-oxoindolin-3-yl)acetonitrile

To a suspension of NaH (0.144 g of a 60% dispersion in mineral oil, 3.6 mmol) in DMF (20 mL) was added 6-bromoisatin (0.67 g, 3.0 mmol) at 0 °C. The deep purple mixture was stirred 10 min and to it was added allyl bromide (0.43 g, 3.6 mmol, 1.2 equiv). The reaction was stirred at 0 °C for 1h and at rt for 1h during which the purple color dissipated into a deep orange solution. The reaction mixture was quenched with water (100 mL), poured into a separatory funnel, and extracted with ethyl acetate (4 x 25 mL).

The combined organic layers were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was directly taken on to the next step. To a suspension of cyanomethyl triphenylphosphonium chloride (8.10 mg, 24.0 mmol, 1.2 equiv) in benzene (100 mL) was added Hünig’s base (2.97 g, 23.0 mmol) under a steady stream of nitrogen. The reaction mixture was cooled to 0 °C and 1-allyl-6-bromoindoline-2,3-dione (5.32 g, 20.0 mmol) was added portion wise. The reaction mixture was stirred at 25 °C for 12h and quenched with water and extracted into EtOAc (3 x 100 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated. The crude reaction mixture was dissolved in wet methanol (50 mL) and cooled to 0 °C. To the reaction mixture was added solid NaBH4 (0.9 g, 24.0 mmol, 1.2 equiv) in three portions. The reaction mixture was concentrated, diluted with water (50 mL) and ethyl acetate (250 mL). The layers were separated and the aqueous layer 115 was extracted with EtOAc (2 x 20 mL). The combined organic layers were gravity filtered through a bed of NaCl and concentrated under reduced pressure. Silica gel chromatography using a gradient starting from 20% EtOAc/hexanes to 30% EtOAc/hexanes afforded 4.35 g (75% over two steps) of the desired product as a yellow 1 solid. TLC Rf = 0.08 (20% EtOAc/hexanes); m.p. = 79-81 ºC; H NMR (400 MHz,

CDCl3): δ 7.39-7.34 (m, 1H), 7.29-7.20 (m, 1H), 7.30-6.99 (m, 1H), 5.86-5.74 (m,1H), 5.31-5.20 (m, 2H), 4.36-4.27 (m, 2H), 3.66 (dd, J = 9.1, 4.6 Hz, 1H), 3.12 (dd, J = 17.0, 4.6 Hz, 1H), 2.73 (dd, J = 17.0, 9.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) 173.9, 144.8, 130.3, 126.1, 125.7, 124.5, 123.2, 118.5, 116.9, 113.2, 42.8, 41.2, 19.1 ppm; IR

(thin film): νmax 3069, 2924, 2249, 1717, 1606, 1487, 1432, 1371, 1340, 1201, 1112, -1 + + 1061, 926, 807 cm ; HRMS (ES ) calcd for C13H11BrN2NaO 312.9952 found 312.9958 (MNa+).

3.6.3.1 Preparation of 2-(6-bromo-1-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile

6-bromo-1-(3-methylbut-2-enyl)indoline-2,3-dione O

O O NaH Br N O Me Br N H Me Br Me Me

To a suspension of NaH (97 mg of a 60% dispersion in mineral oil, 2.43 mmol) in DMF (10 mL) was added 6-bromoisatin (500 mg, 2.21 mmol) at 0 °C. The deep purple

116 mixture was stirred 10 min and to it was added 1-bromo-3-methylbut-2-ene (307 μL, 2.65 mmol). The reaction was stirred at 0 °C for 1 h and at 25 °C for 1 h during which the purple color dissipated into a bright orange solution. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (20 mL), brine (2 x 30 mL), dried

(Na2SO4), filtered, and concentrated. Silica gel chromatography using 15% EtOAc/hexanes afforded 645 mg (100%) of the title compound as an orange solid. TLC 1 Rf = 0.52 (20% EtOAc/hexanes); m.p. = 75-77 ºC; H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 8.0, 1.6 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 5.19-5.14 (m, 1H), 4.31 (d, J = 6.9 Hz, 2H), 1.84 (d, J <1.0 Hz, 3H), 1.77 (d, J = 1.3 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl3): δ 182.4, 157.5, 151.7, 138.9, 133.4, 126.8, 126.2, 116.3,

114.3, 38.3, 25.7, 18.2 ppm; IR (thin film): νmax 3081, 2966, 2918, 1738, 1605, 1477, -1 + + 1441, 1426, 1369, 1101, 1056, 843 cm ; HRMS (ES ) calcd for C13H12BrNNaO2 315.9949 found 315.9953 (MNa+).

2-(6-bromo-1-(3-methylbut-2-enyl)-2-oxoindolin-3-yl)acetonitrile

To a suspension of cyanomethyl triphenylphosphonium chloride (730 mg, 2.15 mmol) in THF (10 mL) was added solid KOt-Bu (242 mg, 2.15 mmol) under a steady stream of nitrogen. The reaction mixture was cooled to 0 °C and 6-bromo-1-(3-methylbut-2- enyl)indoline-2,3-dione (600 mg, 2.05 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h and quenched with water and extracted into EtOAc (3 x 25 mL).

The organic layers were combined, dried (Na2SO4), filtered, and concentrated. The crude reaction mixture was dissolved in wet methanol (50 mL) and cooled to 0 °C. To the reaction mixture was added solid NaBH4 (160 mg, 4.22 mmol) in two portions. The reaction mixture was concentrated, diluted with water (50 mL) and ethyl acetate (50 117 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x

20 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated. Silica gel chromatography using a gradient starting from 20% EtOAc/hexanes to 40% EtOAc/hexanes afforded 445 mg (67% over two steps) of the title compound as a yellow 1 solid. TLC Rf = 0.14 (20% EtOAc/hexanes); m.p. = 108-109 ºC; H NMR (400 MHz,

CDCl3): δ 7.37 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 8.0, 2.2 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 5.14 (m, 1H, 4.29 (m, 2H), 4.29 (m, 2H), 3.61 (dd, J = 8.0, 3.7 Hz, 1H), 3.10 (dd, J = 18.0, 3.7 Hz, 1H), 2.69 (dd, J = 18.0 8.0 Hz, 1H), 1.83 (s, 3H), 1.74 (s, 3H) ppm; 13 C NMR (100 MHz, CDCl3): δ 173.5, 144.8, 125.7, 125.4, 124.5, 122.9, 117.1, 116.9,

112.8, 41.0, 38.4, 25.6, 18.8, 18.2 ppm; IR (thin film): νmax 2971, 2930, 1718, 1606, -1 + + 1487, 1374 cm ; HRMS (ES ) calcd for C15H15BrN2NaO 341.0265 found 341.0276 (MNa+); Elemental Analysis: Theoretical C56.44, H4.74, N8.78 Found C56.66.23, H5.00, N8.45.

3.6.3.2 Preparation of 2-(6-phenyl-1-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile

6-phenyl-1-(3-methylbut-2-enyl)indoline-2,3-dione

6-Bromo-1-(3-methylbut-2-enyl)indoline-2,3-dione (582 mg, 1.98 mmol) was suspended in a mixture of isopropanol and water (solvents degassed by bubbling through N2). Potassium phenyltrifluoroborate (401 mg, 2.18 mmol) and dichloro[1,1’- bis(diphenylphosphino)ferrocene]-palladium(II) dichloromethane complex (29 mg, 39.6 μmol, 2 mol %) were added, followed by triethylamine (0.83 mL, 5.94 mmol). The orange suspension was heated to reflux (oil bath at 98 °C) for 3 h and ultimately became a brown solution. After cooling to rt, water (10 mL) was added and the mixture was extracted with EtOAc (3x30 mL). The combined organic extracts were washed with 118 brine, dried (Na2SO4) and concentrated in vacuo. Silica gel chromatography using 20% EtOAc/hexanes afforded 135 mg (23%) of the title compound as an orange solid. TLC 1 Rf = 0.23 (20% EtOAc/hexanes); m.p. = 136-138 ºC; H NMR (400 MHz, CDCl3): δ 7.66 (d, J = 8.0 Hz, 1H), 7.60 (m, 2H), 7.54-7.44 (m, 3H), 7.31 (dd, J = 7.6, 1.4 Hz, 1H), 7.03 (d, 1.4 Hz, 1H), 5.23 (m, 1H), 4.39 (d, J = 6.8 Hz, 2H), 1.86 (s, 3H), 1.76 (s, 13 3H) ppm; C NMR (125 MHz, CDCl3): δ 183.4, 158.5, 151.8, 151.7, 139.9, 129.5, 129.4, 127.4, 126.0, 122.7, 117.3, 116.7, 109.6, 38.5, 26.0, 18.6 ppm; IR (thin film):

νmax 3053, 2969, 2927, 1734, 1614, 1427, 1375, 1331, 1162, 1112, 1017, 842, 762, 697 -1 + + + cm ; HRMS (ES ) calcd for C19H18BrNO2 292.1332 found 292.1329 (MH ).

2-(6-phenyl-1-(3-methylbut-2-enyl)-2-oxoindolin-3-yl)acetonitrile

To a suspension of cyanomethyl triphenylphosphonium chloride (127 mg, 0.377 mmol) in benzene (3 mL) was added triethylamine (57 μL, 0.412 mmol) followed by 6-phenyl- 1-(3-methylbut-2-enyl)indoline-2,3-dione (100 mg, 0.343 mmol). The reaction mixture was stirred at 25 °C for 14 h, quenched with water and extracted into EtOAc (3 x 20 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated.

The crude product was dissolved in wet methanol (10 mL) and CH2Cl2 (2 mL) and cooled to 0 °C. To the reaction mixture was added NaBH4 (14.3 mg, 0.377 mmol). After 10 min the reaction mixture was diluted with pH 7 phosphate buffer (5 mL) and extracted with EtOAc (3 x 20 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (10% EtOAc/hexanes) afforded

76 mg (70% over two steps) of the title compound as a yellow solid. TLC Rf = 0.38 1 (40% EtOAc/hexanes); m.p. = 131-132 ºC; H NMR (400 MHz, CDCl3): δ 7.56 (m, 3H), 7.47 (m, 2H), 7.39 (m, 1H), 7.32 (m, 1H), 7.04 (s, 1H), 5.20 (m, 1H), 4.34 (m, 1H), 4.12 (m, 1H), 3.14 (m, 1H), 2.71 (m, 1H), 1.85 (s, 3H), 1.73 (s, 3H) ppm; 13C NMR 119

(125 MHz, CDCl3): δ 174.3, 144.3, 143.1, 141.0, 137.8, 129.2, 128.1, 127.4, 125.0,

124.7, 122.2, 118.0, 117.6, 108.5, 41.6, 38.7, 25.9, 19.4, 18.5 ppm; IR (thin film): νmax 2967, 2929, 2247, 1712, 1619, 1484, 1435, 1378, 1343, 1167, 1122, 760, 698 cm-1; + + + HRMS (ES ) calcd for C21H21N2O 317.1648 found 317.1646 (MH ).

3.6.3.3 Preparation of methyl 3-(cyanomethyl)-1-(3-methylbut-2-enyl)-2-oxoindoline- 6-carboxylate methyl 1-(3-methylbut-2-enyl)-2,3-dioxoindoline-6-carboxylate

A solution of 6-bromo-1-(3-methylbut-2-enyl)indoline-2,3-dione (588 mg, 2.0 mmol), palladium(II) acetate (44.9 mg, 0.20 mmol, 10 mol %), 1,3- bis(diphenylphosphino)propane (82.5 mg, 0.20 mmol) and N,N-diisopropylethylamine (0.35 mL, 2.0 mmol) in dimethylsulfoxide (4.5 mL) and methanol (1.8 mL) was placed under a balloon of CO and stirred at 80 °C for 18 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (3x20 mL). The collected organic layers were washed washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. Silica gel chromatography using 15% EtOAc/hexanes afforded 204 mg (37%) of the title compound as an orange solid. TLC Rf = 0.15 (20% EtOAc/hexanes); m.p. = 120- 1 123 ºC; H NMR (400 MHz, CDCl3): δ 7.79 (dd, J = 7.6, 1.2 Hz, 1H), 7.65 (dd, J = 7.6, 0.6 Hz, 1H), 7.50 (dd, J = 1.2, 0.6 Hz, 1H), 5.19 (m, 1H), 4.37 (d, J = 7.2 Hz, 2H), 3.97 13 (s, 3H), 1.88 (s, 3H), 1.75 (s, 3H) ppm; C NMR (125 MHz, CDCl3): δ 183.9, 165.7, 157.5, 151.0, 139.3, 138.7, 125.32, 125.28, 120.6, 116.6, 111.7, 53.2, 38.6, 26.0, 18.5 -1 ppm; IR (thin film): νmax 2917, 1742, 1726, 1620, 1442, 1281, 1247, 1096, 757 cm ; + + + HRMS (ES ) calcd for C15H16NO4 274.1074 found 374.1072 (MH ).

120 methyl 3-(cyanomethyl)-1-(3-methylbut-2-enyl)-2-oxoindoline-6-carboxylate

To a suspension of cyanomethyl triphenylphosphonium chloride (272 mg, 0.805 mmol) in benzene (5 mL) was added triethylamine (122 μL, 0.878 mmol) followed by methyl 1-(3-methylbut-2-enyl)-2,3-dioxoindoline-6-carboxylate (200 mg, 0.732 mmol). The reaction mixture was stirred at 25 °C for 1.5 h, quenched with water and extracted into EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated. The crude product was dissolved in wet methanol (10 mL) and NaBH4 (27.7 mg, 0.732 mmol) was added. After 5 min the reaction mixture was diluted with pH 7 phosphate buffer (5 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (50% EtOAc/hexanes) afforded 35 mg (16% over two steps) of the title compound as a yellow 1 solid. TLC Rf = 0.25 (40% EtOAc/hexanes); m.p. = 122-125 ºC; H NMR (400 MHz,

CDCl3): δ 7.82 (dd, J = 7.6, 1.5 Hz, 1H), 7.56 (m, 1H), 7.50 (m, 1H), 5.17 (m, 1H, 4.35 (m, 2H), 3.93 (s, 3H), 3.69 (dd, J = 9.2, 4.8 Hz, 1H), 3.13 (dd, J = 16.8, 4.8 Hz, 1H), 2.71 (dd, J = 16.8, 9.2 Hz, 1H), 1.85 (s, 3H), 1.73 (s, 3H) ppm; 13C NMR (125 MHz,

CDCl3): δ 173.7, 166.7, 144.1, 138.4, 131.7, 130.9, 124.9, 124.4, 117.4, 117.1, 110.2,

52.7, 41.7, 38.8, 25.9, 19.1, 18.5 ppm; IR (thin film): νmax 2927, 2249, 1715, 1620, 1452, -1 + + 1283, 1243, 1098, 756 cm ; HRMS (ES ) calcd for C17H19N2O3 299.1390 found 299.1388 (MH+).

121

3.6.3.4 Preparation of 2-(5-methoxy-1-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile

5-methoxy-1-(3-methylbut-2-enyl)indoline-2,3-dione

To a suspension of NaH (124 mg of a 60% dispersion in mineral oil, 2.43 mmol) in DMF (5 mL) was added 5-methoxyisatin (500 mg, 2.82 mmol) at 0 °C. The mixture was stirred for 15 min and to it was added 1-bromo-3-methylbut-2-ene (0.36 mL, 3.10 mmol). The reaction was stirred for 1.5 h while warming to rt, then quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. Silica gel chromatography using 20% EtOAc/hexanes afforded 312 mg (45%) of the title compound as a maroon solid. TLC 1 Rf = 0.13 (20% EtOAc/hexanes); m.p. = 101-103 ºC; H NMR (500 MHz, CDCl3): δ 7.11-7.08 (m, 2H), 6.74 (m, 1H), 5.14 (m, 1H), 4.28 (d, J = 7.0 Hz, 2H), 3.77 (s, 3H), 13 1.80 (s, 3H), 1.72 (d, J = 1.0 Hz, 3H) ppm; C NMR (125 MHz, CDCl3): δ 184.4, 158.1, 156.7, 145.2, 138.4, 124.9, 118.3, 117.4, 112.0, 109.7, 56.2, 38.4, 26.0, 18.5 ppm; IR

(thin film): νmax 2932, 1734, 1622, 1596, 1489, 1437, 1273, 1172, 1145, 1025, 821, 758 -1 + + + cm ; HRMS (ES ) calcd for C14H16NO3 246.1125 found 246.1125 (MH ).

2-(5-methoxy-1-(3-methylbut-2-enyl)-2-oxoindolin-3-yl)acetonitrile

122

To a suspension of cyanomethyl triphenylphosphonium chloride (197 mg, 0.583 mmol) in benzene (5 mL) was added triethylamine (89 μL, 0.636 mmol) followed by 5- methoxy-1-(3-methylbut-2-enyl)indoline-2,3-dione (130 mg, 0.530 mmol). The reaction mixture was stirred at 25 °C for 1.5 h, quenched with water and extracted into EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, and concentrated. The crude product was dissolved in wet methanol (5 mL) and NaBH4 (20.1 mg, 0.530 mmol) was added. After 5 min the reaction mixture was diluted with pH 7 phosphate buffer (5 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. Silica gel chromatography (40% EtOAc/hexanes) afforded 47 mg (33% over two steps) of the title compound as a pale 1 pink solid. TLC Rf = 0.25 (40% EtOAc/hexanes); m.p. = 115-118 ºC; H NMR (500

MHz, CDCl3): δ 7.13 (dd, J = 2.5, 1.0 Hz, 1H), 6.85 (dd, J = 8.5, 2.5 Hz, 1H), 6.75 (d, J = 8.5 Hz, 1H), 5.14 (m, 1H), 4.29 (m, 2H), 4.29 (m, 2H), 3.80 (s, 3H), 3.64 (dd, J = 16.5, 4.4 Hz, 1H), 3.10 (dd, J = 16.5, 3.7 Hz, 1H), 2.68 (dd, J = 16.5, 9.5 Hz, 1H), 1.81 13 (s, 3H), 1.72 (d, J = 1.2 Hz, 3H) ppm; C NMR (125 MHz, CDCl3): δ 173.7, 156.4, 137.5, 137.1, 127.3, 118.2, 117.5, 114.0, 111.7, 110.0, 56.1, 42.0, 38.7, 25.9, 19.4, 18.4 ppm; IR (thin film): νmax 2965, 2930, 2248, 1706, 1600, 1492, 1436, 1296, 1176, 1030, -1 + + + 873, 813 cm ; HRMS (ES ) calcd for C16H19N2O2 271.1441 found 271.1438 (MH ).

3.6.3.5 Preparation of 2-(1-(4-methoxybenzyl)-2-oxoindolin-3-yl)acetonitrile

1-(4-methoxybenzyl)indoline-2,3-dione

O O NaH O O PMBCl N N H PMB 123

To a suspension of NaH (2.99 g of a 60% dispersion in mineral oil, 74.8 mmol) in DMF (200 mL) was added isatin (11.0 g, 74.8 mmol) at 0 °C. The deep purple mixture was stirred 10 min and to it was added freshly prepared p-methoxybenzyl chloride 10.94g, 69.9 mmol). The reaction was stirred at 0 °C for 30 min and warmed to 40 °C for 3 h during which the purple color dissipated into a deep orange solution. The reaction mixture was quenched with water (100 mL), poured into a separatory funnel, and extracted with ethyl acetate (4 x 500 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure.

The crude product was suspended in 4:1 hexanes/Et2O (500 mL) and vacuum filtered to yield the title compound as orange needles (15.94 g, 80%). TLC Rf = 0.14 (20% 1 EtOAc/hexanes); m.p. = 138-140 ºC; H NMR (400 MHz, CDCl3): δ 7.60 (ddd, J = 7.7, 1.3, 0.5 Hz, 1H), 7.48 (ddd, J = 7.7, 7.7, 1.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.26 (s, 2H), 7.08 (ddd, J = 7.7, 7.7, 0.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.80 (ddd, J = 7.7, 1.4, 0.5 Hz, 1H), 4.87 (s, 2H), 3.78 (s, 3H) ppm matches literature reported values;41 IR -1 (thin film): νmax 1739, 1612, 1513, 1469, 1350, 1248 cm .

2-(1-(4-methoxybenzyl)-2-oxoindolin-3-yl)acetonitrile

To a suspension of cyanomethyl triphenylphosphonium chloride (417 mg, 1.24 mmol) in benzene (10 mL) was added triethylamine (136 mg, 1.34 mmol) under a steady stream of nitrogen. To the reaction mixture was added 1-(4-methoxybenzyl)indoline-2,3-dione (268 mg, 1.0 mmol). The reaction was stirred at 25 °C for 2h, diluted with ethyl acetate

(50 mL) and washed with water (20 mL), brine (30 mL), dried (Na2SO4), and concentrated. The crude product (TLC Rf = 0.24 in 20% EtOAc/hexanes) was taken forward without further purification. The crude reaction mixture was dissolved in wet methanol (10 mL) and cooled to 0 °C. To the reaction mixture was added solid NaBH4 124

(76 mg, 2.0 mmol). The reaction mixture was warmed to 0 °C and upon the disappearance of starting material (coincided with the disappearance of the bright orange color) concentrated. The reaction mixture was concentrated to dryness and the resulting solid was dissolved by adding 20 mL EtOAc and 20 mL H2O. The layers were separated and the aqueous layer was extracted with EtOAc (2 x 20 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Silica gel chromatography using a gradient starting from 20% EtOAc/hexanes to 50% EtOAc/hexanes afforded

134 mg (45% over two steps) of the title compound as a yellow solid. TLC Rf = 0.07 1 (20% EtOAc/hexanes); m. p. = 137-139 ºC; H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8.0 Hz, 1H), 7.28-7.21 (m, 3H), 7.09 (dd, J = 7.6 Hz, 1H), 6.86 (d, J = 8.3, 1H), 6.81 (dd, J = 7.0 Hz, 1H), 4.84 (d, J = 15.5, 1H), 4.83 (d, J = 15.5 Hz, 1H), 3.79-3.71 (m, 4H), 3.16 (dd, J = 17.1, 3.8 Hz, 1H), 2.77 (dd, J = 17.1, 9.0 Hz, 1H) ppm; 13C NMR

(100 MHz, CDCl3): δ 74.6, 159.4, 143.5, 129.5, 128.9, 127.4, 125.9, 124.5, 123.4,

117.4, 114.5, 109.9, 55.5, 43.8, 41.7, 19.4 ppm; IR (thin film): νmax 2933, 1713, 1613, -1 + + 1513, 1467, 1364, 1249, 1177, 752 cm ; HRMS (ES ) calcd for C18H16N2NaO2 315.1109 found 315.1105 (MNa+); Elemental Analysis: Theoretical C73.95, H5.52, N9.58 Found C73.72, H5.76, N9.28.

3.6.3.6 Preparation of 2-(2-oxoindolin-3-yl)acetonitrile

(E/Z)-2-(2-oxoindolin-3-ylidene)acetonitrile

O CN

+ - O Ph3P CH2CN Cl O N N H H

To a suspension of cyanomethyl triphenylphosphonium chloride (1.0 g, 2.96 mmol) in THF (10 mL) was added solid KOt-Bu (332 mg, 2.96 mmol) under a steady stream of

125 nitrogen. The reaction mixture was cooled to 0 °C and isatin (431 mg, 2.81 mmol) was added. The reaction mixture was stirred at 25 °C for 30 min and quenched water and extracted into EtOAc (2 x 50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Silica gel chromatography using 38% EtOAc/hexanes afforded 330 mg (69%) of the desired product as an amorphous orange solid. TLC Rf = 0.55 (50% 1 EtOAc/hexanes); m.p. = 164-166 ºC; H NMR (500 MHz, CDCl3): δ 8.07 (d, J = 8.0 Hz, 1H), 7.89 (br s, 1H), 7.40 (dd, J = 7.0, 7.0 Hz, 1H), 7.13 (dd, J = 7.0, 7.0 Hz, 1H),

6.89 (d, J = 7.0 Hz, 1H), 6.31 (s, 1H) ppm; IR (thin film): νmax 3196, 1718, 1614 1464, 778 cm-1. This compound has been previously reported.42

2-(2-oxoindolin-3-yl)acetonitrile CN CN

NaBH4, MeOH O O N N H H

To a solution of (E/Z)-2-(2-oxoindolin-3-ylidene)acetonitrile (50 mg, 0.29 mmol) in wet methanol (4.0 mL) was added solid NaBH4 (11 mg, 0.294 mmol). After 10 minutes when the bright orange color dissipated, the reaction was concentrated, diluted with water (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 5 mL). The organic layers were combined, dried

(Na2SO4), and concentrated under reduced pressure. Silica gel chromatography using a gradient starting from 50% EtOAc/hexanes to 80% EtOAc/hexanes afforded 46 mg (91%) of the desired product compound as a yellow solid. m.p. = 131-132 ºC; 1H NMR

(400 MHz, CDCl3): δ 7.65-7.58 (bs, 1H), 7.50 (d, J = 75 Hz, 1H), 7.33-7.28 (m, 1H), 7.14-7.10 (m, 1H), 6.94 -6.92 (m, 1H), 3.2 (d, J = 4.5 Hz, 1H), 3.70 (d, J = 4.5 Hz, 1H), 3.11 (dd, J = 16.8, 4.7 Hz, 1H), 2.75 (dd, J = 16.8, 9.1 Hz, 1H) ppm matches previously reported data.42

126

2-(1-(methoxymethyl)-2-oxoindolin-3-yl)acetonitrile

To a solution of (E/Z)-2-(2-oxoindolin-3-ylidene)acetonitrile (60 mg, 0.35 mmol) in THF (5 mL) was added NaH (20 mg of a 60% dispersion in mineral oil, 0.49 mmol, 1.4 equiv). The reaction was stirred for 10 minutes at room temperature during which time a deep purple solution developed. To the mixture was added in MOM chloride (40 mg, 0.49 mmol, 1.4 equiv) and the reaction was stirred for 1h during which time the reaction turned light orange. The reaction was quenched with saturated aqueous NaHCO3 (10 mL), extracted into dichloromethane (1 x 20 mL, 1 x 10 mL), and the combined organic layers were concentrated under reduced pressure. The resulting orange solid was suspended in methanol (5 mL) and NaBH4 (24 mg, 0.63 mmol, 1.8 equiv) was added and the reaction was stirred for 30 minutes at room temperature. The reaction was quenched with water (50 mL), poured into a separatory funnel, and extracted into diethyl ether (5 x 30 mL). The organic layers were combined, filtered through solid NaCl, and concentrated under reduced pressure. Silica gel chromatography using a gradient of 20% - 40% EtOAc/hexanes afforded 44 mg (58% over two steps) of the desired product 1 as a light yellow solid. TLC Rf = 0.44 (50% EtOAc/hexanes); m.p. = 97-99 ºC; H NMR

(CDCl3, 400 MHz): δ 7.46 (d, J = 7.5 Hz, 1H), 7.34 (dd, J = 7.8, 7.8 Hz, 1H), 7.14 (dd, J = 7.5, 7.5 Hz, 1H), 7.06 (d, J = 7.8 Hz), 5.13 (d, J = 10.8 Hz, 1H), 5.09 (d, J = 10.8 Hz, 1H), 3.74 (dd, J = 8.2, 4.8 Hz, 1H), 3.31 (s, 1H), 3.08 (dd, J = 16.8, 4.8 Hz, 1H), 13 2.79 (dd, J = 16.9, 8.2 Hz, 1H); C NMR (CDCl3, 400 MHz): δ 174.8, 142.2, 129.3,

124.9, 124.0, 123.4, 116.8, 110.0, 71.3, 56.2, 41.5, 18.9; IR (thin film): νmax 1710, 1614, 1488, 1466, 1356, 1118, 1093, 1070 cm-1; Elemental Analysis: Theoretical C66.05, H5.59, N12.96 Found C66.23, H5.28, N12.67.

127 methyl 2-(6-bromo-1-(3-methylbut-2-enyl)-2-oxoindolin-3-yl)acetate

To a suspension of NaH (60% dispersion in mineral oil, 0.49 g, 12.2 mmol) in THF (3 mL) was added trimethyl phosphonoacetate (1.8 mL, 12.2 mmol) at 0 °C followed by addition of 6-bromo-1-(3-methylbut-2-enyl)indoline-2,3-dione (3.0 g, 10.2 mmol). The reaction mixture was then warmed to rt, stirred for 4 h, quenched with water and extracted with EtOAc (4 x 30 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting yellow solid was dissolved in wet methanol (5 mL) and THF (5 mL) and cooled to 0 °C. To the reaction mixture was added NaBH4 (339 mg, 0.663 mmol). After 5 min the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated. Silica gel chromatography with 40% EtOAc/hexanes afforded 1.29 g (37%) of the desired product as a pale yellow oil that solidified upon standing. TLC Rf = 0.34 (20% 1 EtOAc/hexanes); m.p. = 73-75 ºC; H NMR (400 MHz, CDCl3): δ 7.15 (dd, J = 8.0, 2.0 Hz, 1H), 7.10 (dd, J = 8.0, 1.0 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.15 (m, 1H), 4.30 (m, 2H), 3.70 (m, 1H), 3.68 (s, 3H), 3.07 (dd, J = 17.0, 6.0 Hz, 1H), 2.79 (dd, J = 17.0, 11.0 13 Hz, 1H), 1.83 (s, 3H), 1.74 (s, 3H); C NMR (100 MHz, CDCl3): δ 176.3, 171.6, 145.3, 137.5, 127.3, 125.4, 125.3, 122.0, 117.9, 112.4, 52.3, 41.7, 38.5, 34.8, 25.9, 18.4 ppm; IR (thin film): νmax 2920, 1722, 1606, 1487, 1437, 1373, 1337, 1216, 1167, 1114, 843, -1 813 cm ; Elemental Analysis: Theoretical for C16H18BrNO3: C, 54.56; H, 5.15; N, 3.98. Found: C, 54.78; H, 5.28; N, 3.83.

128

3.6.3.7 Preparation of 2-(6-bromo-1-(3-methylbut-2-en-1-yl)-2-oxoindolin-3-yl)-N- methylacetamide diethyl (2-(methylamino)-2-oxoethyl)phosphonate O O O O MeNH2, MeOH P P EtO OEt EtO NHMe OEt -78 ºC - rt OEt

Methylamine (~4 mL) was condensed into a 100 mL round bottomed flask at -78 ºC. Methanol (8.3 mL) and triethylphosphonoacetate (5.65 g, 25.2 mmol) were sequentially added, an empty balloon was fitted onto the rubber septa and the reaction mixture was gently warmed to room temperature and stirred for 24 h. The reaction mixture was concentrated. Proton NMR indicated a clean and quantitative conversion to the desired product. Proton NMR is in accord with literature reported data.43 1H NMR (400 MHz,

CDCl3) δ 6.80 (brs, 1H), 4.12 (quintet, J = 7.3 Hz, 4H), 2.83 (d, J = 20.4, 2H), 2.82 (d, J = 4.7 Hz, 3H), 1.32 (t, J = 7.3 Hz, 6H).

2-(6-bromo-1-(3-methylbut-2-en-1-yl)-2-oxoindolin-3-yl)-N-methylacetamide

O 1. NaH, 2-methyl tetrahydrofuran CONHMe O O O O P Br N EtO NHMe Br N OEt

Me 2. NaBH4, MeOH Me Me Me

To a suspension of NaH (60% dispersion in mineral oil, 0.27 g, 0.68 mmol) in THF (6 mL) was added diethyl (2-(methylamino)-2-oxoethyl)phosphonate (0.17 g, 0.82 mmol) at 0 °C followed by addition of 6-bromo-1-(3-methylbut-2-enyl)indoline-2,3-dione (0.2 g, 0.68 mmol). The reaction mixture was then warmed to rt, stirred for 4 h, quenched with water and extracted with EtOAc (4 x 30 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting yellow solid was dissolved in wet methanol (5 mL) and THF (5 mL) and cooled to 0 °C. To the reaction mixture was added NaBH4 (40 mg, 1.05 mmol). After 5 min the reaction

129 mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered, and concentrated. Silica gel chromatography with 40% EtOAc/hexanes afforded 79 mg

(33%) of the desired product as an amorphous yellow solid. TLC Rf = 0.21 (5% 1 MeOH/CHCl3); H NMR (400 MHz, CDCl3): δ 7.15-7.11 (m, 2H), 6.93-6.87 (m, 1H), 6.49 (bs, 1H), 5.10 (m, 1H), 4.33-4.16 (m, 2H), 3.75 (dd, J = 7.5, 5.7 Hz, 1H), 2.90-2.82 (m, 1H), 2.79 (d, 4.79, 3H), 2.5-2.47 (m, 1H), 1.80 (s, 3H), 1.71 (s, 3H); 13C NMR (500

MHz, CDCl3): δ 177.3, 170.8 144.8, 137.7, 127.7, 125.8, 125.5, 121.9, 117.2, 112.5,

42.3, 38.6, 37.0, 26.7, 25.9, 18.5; IR (thin film): νmax 3326, 3097, 2970, 2931, 1710, 1659, 1605, 1486, 1432, 1374 cm-1; Elemental Analysis: Calc’d for Theoretical C53.08, H4.11, N4.76 Found C53.23, H4.38, N4.70.

3.6.3.8 Preparation of other 3-alkyloxindoles

3-allyl-3-hydroxy-1-(4-methoxybenzyl)indolin-2-one N-(para-methoxybenzyl)isatin (1 g, 3.74 mmol) was dissolved in THF (40 mL) and cooled to -78°. Allylmagnesium bromide (5.2 mL) (5.2 mL, 5.24 mmol) was added and the reaction mixture stirred at -78° for 30 min, then warmed to rt and stirred for 8 h. The reaction was quenched with water (25 mL) and the organic layer washed with water (25 mL) and brine (2 x 25 mL), dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica with 40% EtOAc/hexanes yielded the title compound as a pale 1 yellow solid (854 mg, 74%). TLC Rf = 0.15 (30% EtOAc/hexanes). H NMR (300 MHz,

CDCl3): δ 7.38 (d, J = 8 Hz, 1H), 7.23 (m, 3H), 7.06 (t, J = 8 Hz, 1H), 6.84 (d, J = 8 Hz, 2H), 6.72 (d, J = 8 Hz, 1H), 5.65 (m, 1H), 5.15 (m, 2H), 4.95 (d, J = 15 Hz, 1H), 4.68 (d, J = 15 Hz, 1H), 4.19 (s, 1H), 3.77 (s, 3H), 2.78 (dd, J = 15 Hz, 6 Hz, 1H), 2.66 (dd, J = 15 Hz, 6 Hz, 1H).

130

3-allyl-3-chloro-1-(4-methoxybenzyl)indolin-2-one

Thionyl chloride (1.33 mL, 18.23 mmol) was added to a solution of 3-allyl-3-hydroxy- 1-(4-methoxybenzyl)indolin-2-one (564 mg, 1.82 mmol) in 5 mL dichloromethane and stirred overnight at rt. The mixture was quenched with sat. NaHCO3 (10 mL), diluted with water (10 mL), extracted with EtOAc (3 x 10 mL), dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica with 20% EtOAc/hexanes yielded the title compound as an orange solid (381 mg, 64%). TLC Rf = 0.50 (20% 1 EtOAc/hexanes). H NMR (300 MHz, CDCl3): δ 7.41 (d, J = 8 Hz, 1H), 7.23 (m, 3H), 7.07 (t, J = 8 Hz, 1H), 6.84 (d, J = 8 Hz, 2H), 6.72 (d, J = 8 Hz, 1H), 5.51 (m, 1H), 5.17 (d, J = 15 Hz, 1H), 5.09 (d, J = 6 Hz, 1H), 4.93 (d, J = 15 Hz, 1H), 4.77 (d, J = 15 Hz, 1H), 3.76 (s, 3H), 3.09 (dd, J = 15 Hz, 6 Hz, 1H), 3.01 (dd, J = 15 Hz, 6 Hz, 1H).

N-(para-methoxybenzyl)-3-allyloxindole

Zinc powder (228 mg, 3.49 mmol) was added in one portion to a solution of 3-allyl-3- chloro-1-(4-methoxybenzyl)indolin-2-one (381 mg, 1.16 mmol) in acetic acid (3 mL). The mixture was heated to 70°, stirred for 1 h and vacuum filtered to remove zinc. The acetic acid was removed by azeotroping with heptane (20 mL). The resulting oil was diluted with EtOAc (50 mL) and neutralized with sat. NaHCO3 (5 mL), and the organic layer was washed with water (20 mL) and brine (2 x 20 mL), dried (MgSO4) and concentrated in vacuo. Column chromatography on silica with 25% EtOAc/hexanes yielded the title compound as a colourless oil that solidified on standing at -20 °C (282 131

1 mg, 83%). TLC Rf = 0.35 (20% EtOAc/hexanes). H NMR (300 MHz, CDCl3): δ 7.28 (m, 3H), 7.18 (t, J = 8 Hz, 1H), 7.02 (t, J = 8 Hz, 1H), 6.86 (d, J = 8 Hz, 2H), 6.76 (d, J = 8 Hz, 1H), 5.76 (m, 1H), 5.16 (d, J = 17 Hz, 1H), 5.08 (d, J = 6 Hz, 1H), 4.96 (d, J = 15 Hz, 1H), 4.77 (d, J = 15 Hz, 1H), 3.76 (s, 3H), 3.60 (t, J = 6 Hz, 1H), 2.91 (m, 1H), 2.68 (m, 1H).

3-(2,2-dimethoxyethyl)-1-(4-methoxybenzyl)indolin-2-one

WHC-III-59: N-(para-methoxybenzyl)-3-allyloxindole (300 mg) was dissolved in

CH2Cl2 (20 mL) and cooled to -78 °C. Ozone was bubbled through until the solution began to turn black, at which point it was warmed to room temperature and triphenylphosphine (805 mg) was added. The resulting orange solution was stirred for 5 h and then concentrated in vacuo to give the crude aldehyde which was redissolved in MeOH (5 mL). Trimethyl orthoformate (564 μL) and 10-camphorsulfonic acid (240 mg) were then added and the reaction stirred for 6 h at room temperature. After neutralization with sat. aq. NaHCO3, the aqueous layer was extracted with EtOAc, and the organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo.

This material was then loaded on SiO2 and eluted with 40% EtOAc/hexanes to yield the 1 title compound (210 mg, 60%) as a pale yellow oil. H NMR (300 MHz, CDCl3): δ 7.25 (m, 3H), 7.15 (t, J = 6 Hz, 1H), 6.99 (t, J = 6 Hz, 1H), 6.82 (d, J = 7 Hz, 2H), 6.73 (d, J = 6 Hz, 1H), 4.83 (dd, J = 21, 11 Hz, 2H), 4.71 (t, J = 5 Hz, 1H), 3.74 (s, 3H), 3.59 (t, J = 5 Hz, 1H), 3.34 (s, 3H), 3.27 (s, 3H).

3-(2-hydroxyethyl)-1-(4-methoxybenzyl)indolin-2-one

132

WHC-III-46: NaBH4 (8 mg) was added to a suspension of the crude aldehyde (59 mg) obtained from ozonolysis of N-(para-methoxybenzyl)-3-allyloxindole (see preparation of 3-(2,2-dimethoxyethyl)-1-(4-methoxybenzyl)indolin-2-one) in MeOH. After 10 min the reaction was quenched with water, neutralized with 2 M HCl and extracted with

EtOAc. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was loaded on SiO2 and eluted with 90%

EtOAc/hexanes to yield the title compound (53 mg, 89%) as a colourless oil. TLC Rf = 1 0.47 (90% EtOAc/hexanes). H NMR (300 MHz, CDCl3): δ 7.23 (m, 3H), 7.18 (t, J = 6 Hz, 1H), 7.03 (t, J = 6 Hz, 1H), 6.84 (d, J = 7 Hz, 2H), 6.76 (d, J = 6 Hz, 1H), 4.85 (dd, J = 19, 12 Hz, 2H), 3.94 (br s, 2H), 3.77 (s, 3H), 3.67 (m, 1H), 3.31 (br s, 1H), 2.28 (m, 13 1H), 2.06 (m, 1H). C NMR (CDCl3) 179, 159, 143, 129, 128.3, 128.0, 124, 123, 114, 110, 61, 55, 45, 44, 34. IR (neat, cm−1) 3427, 2933, 1703, 1612, 1513, 1488, 1466, 1357, 1249, 1177, 1034, 751.

2-(1-(4-methoxybenzyl)-2-oxoindolin-3-yl)ethyl acetate

WHC-III-87: To a solution of 3-(2-hydroxyethyl)-1-(4-methoxybenzyl)indolin-2-one

(70 mg, 0.244 mmol) in CH2Cl2 (1 mL) was added (4-dimethylamino)pyridine (2.9 mg, 0.024 mmol), 2,6-lutidine (30 μL, 0.244) and acetyl chloride (21 μL, 0.294 mmol). After stirring over 12 h at RT the reaction was quenched by addition of a few drops of saturated NaHCO3 (aq.), then diluted with H2O, and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), concentrated in vacuo, loaded on SiO2 and eluted with 40% EtOAc/hexanes to yield the title compound as a colourless oil (62 1 mg, 75%). TLC Rf = 0.59 (60% EtOAc/hexanes); H NMR (400 MHz, CDCl3): δ 7.24- 7.30 (m, 3H), 7.21 (m, 1H), 7.05 (m, 1H), 6.87 (m, 2H), 6.79 (d, J = 8.0 Hz, 1H), 4.89 (m, 1H), 4.33 (m, 1H), 4.24 (m, 1H), 3.80 (s, 3H), 2.37 (m, 2H), 1.95 (s, 3H). 13C NMR

(CDCl3) 179, 162, 159, 143, 129, 128.3, 128.0, 124, 123, 114, 110, 61, 55, 51, 45, 44,

133

34. IR (neat, cm−1) 3427, 2933, 1703, 1692, 1612, 1513, 1488, 1466, 1357, 1249, 1177, 1034, 751.

3.6.4 Preparation of prenylated and reverse-prenylated 3-alkyloxindoles

3.6.4.1 Prenylation and reverse prenylation of 2-(1-allyl-6-bromo-2-oxoindolin-3- yl)acetonitrile

2-(1-allyl-6-bromo-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing 2-(1-allyl-6-bromo-2-oxoindolin-3-yl)acetonitrile (9.9 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), (S,S)-L2 (2.0 mg, 2.5 umol, 0.075 equiv), and TBAT (5.5 mg, 0.01 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051

134 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated under reduced pressure. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated under reduced pressure. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 10.7 mg (90% branched product isolated from a 18:1 b:l mixture, 91% ee) of the desired product as a colorless oil. The reaction was repeated on larger scale (2-(1-allyl-6-bromo-2-oxoindolin-3- yl)acetonitrile (99 mg, 0.34 mmol), Pd2dba3•CHCl3 (9 mg, 8.5 umol, 0.025 equiv), (S,S)-

L2 (20 mg, 25 umol, 0.075 equiv), and TBAT (55 mg, 0.1 mmol, 0.3 equiv) in CH2Cl2 (2 mL), tert-butyl (2-methylbut-3-en-2-yl) carbonate (94 mg, 0.51 mmol, 1.5 equiv)) and purified via flash column chromatography (20% EtOAc/hexanes) to afford 105 mg (89% yield of the branched product, 91% ee) of the title compound as a colorless oil. 25 TLC Rf = 0.35 (20% EtOAc/hexanes); [α]D -100.0 (optical rotation run on 92% ee 1 material using (S,S)-L2, c 0.92, CH2Cl2); H NMR (400 MHz, CDCl3): δ 7.23 (d, J = 8.1, 1.8 Hz, 1H), 7.5 (d, J = 8.1 Hz, 1H), 7.1 (d, J = 1.8 Hz, 1H), 5.99 (dd, J = 17.5, 10.8 Hz, 1H), 5.85-5.74 (m, 1H), 5.3- 5.19 (m, 3H), 5.08 (d, J = 17.2 Hz, 1H), 4.44 (ddt, J = 16.5 , 5.2, 2.0 Hz, 1H), 4.25 (ddt, J = 16.5, 5.2, 1.6 Hz, 1H), 3.01 (d, J = 16.9 Hz, 13 1H), 2.84 (d, J = 16.9, 1H), 1.14 (s, 3H), 1.03 (s, 3H) ppm; C NMR (125 MHz, CDCl3): δ 175.8, 144.9, 141.5, 130.3, 126.6, 125.2, 123.0, 118.3, 116.5, 115.6, 112.7, 54.7, 42.6,

41.7, 21.9, 21.9, 21.5 ppm; IR (thin film): νmax 2969, 1714, 1602, 1488, 1436, 1368, -1 ® 1338, 1186, 1115, 1067 cm ; HPLC Rt = 12.32 (major) and 13.52 min (Chiralcel AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 + + + mL/min); HRMS (ES ) calcd for C18H19BrN2NaO 381.0578 found 381.0588 (MNa ).

135

2-(1-allyl-6-bromo-3-(3-methylbut-2-enyl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing 2-(1-allyl-6-bromo-2-oxoindolin-3-yl)acetonitrile (10 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.35 mg, 0.34 umol, 0.01 equiv), and (S,S)-L1 (0.70 mg, 1.0 umol, 0.03 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous PhCH3 (200 μL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2- methylbut-3-en-2-yl) carbonate (9.4 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated in vacuo. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 8.6 mg (71% linear product isolated from a 1:3.2 b:l mixture, 96% ee) of the desired product as a colorless oil. The reaction was repeated on larger scale (2-(1-allyl-6-bromo-2-oxoindolin-3- yl)acetonitrile (99 mg, 0.34 mmol), Pd2dba3•CHCl3 (3.5 mg, 3.4 umol, 0.01 equiv), and

(S,S)-L1 (7.0 mg, 10 umol, 0.03 equiv), toluene (2 mL), tert-butyl (2-methylbut-3-en-2- yl) carbonate (94 mg, 0.51 mmol, 1.5 equiv)) and purified via flash column chromatography (20% EtOAc/hexanes) to afford 86 mg (71% yield of the linear product, 96% ee) of the title compound as a colorless oil. 25 TLC Rf = 0.32 (20% EtOAc/hexanes); [α]D -28.6 (optical rotation run on 96% ee using 1 (S,S)-L1, c 0.67, CH2Cl2); H NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.2Hz, 1H), 7.25 (d, J = 8.2, 1.7 Hz, 1H), 6.98 (d, J = 1.7 Hz, 1H), 5.8-5.7 (m, 1H), 5.28-5.12 (m, 2H), 4.72 (tqq, J = 7.5, 1.3, <1 Hz, 1H), 4.45 (ddt, J = 16.7, 4.8, 1.7 Hz, 1H), 4.17 (ddt, J =

136

16.7, 5.2, 1.5 Hz, 1H), 2.87 (d, J = 16.4 Hz, 1H), 2.65 (d, J = 164, 1H), 2.65 (m, 2H), 13 1.56 (s, 3H), 1.53 (s, 3H) ppm; C NMR (125 MHz, CDCl3): δ 176.6, 144.2, 137.9, 130.5, 128.3, 126.1, 125.0, 123.0, 118.0, 116.6, 116.0, 113.1, 49.3, 42.7, 35.1, 26.1,

25.2, 18.3 ppm; IR (thin film): νmax 2917, 1721, 1605, 1487, 1436, 1374, 1116, 1063 -1 ® cm ; HPLC Rt = 17.28 and 19.39 (major) min (Chiralcel OD chiral column, λ = 254 nm, isocratic elution: 90:10 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES+) + + calcd for C18H19BrN2NaO 381.0578 found 381.0575 (MNa ); Elemental Analysis: Theoretical C53.63, H3.81, N9.62 Found C53.79, H4.03, N9.41.

3.6.4.2 Prenylation and reverse prenylation of 2-(6-bromo-1-(3-methylbut-2-enyl)-2- oxoindolin-3-yl)acetonitrile

2-(6-bromo-1-(3-methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3- yl)acetonitrile

137

A flame-dried vial containing 2-(6-bromo-1-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile (11 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv),

(S,S)-L2 (2.0 mg, 2.5 umol, 0.075 equiv), and TBAT (5.5 mg, 0.01 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 9.2 mg (70 % branched product isolated from a 9.2:1 b:l mixture, 90% ee) of the desired product as a colorless oil, whose spectral 30 25 properties matched literature data. TLC Rf = 0.55 (20% EtOAc/hexanes); [α]D - 1 102.5 (optical rotation run on 93% ee using (S,S)-L2, c 0.94, CH2Cl2); H NMR (500

MHz, CDCl3): δ 7.20 (dd, J = 8.0, 1.5 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 1.5 Hz, 1H), 5.99 (dd, J = 17.4, 10.8 Hz, 1H), 5.19 (d, J = 10.8 Hz, 1H), 5.12-5.05 (m, 2H), 4.43 (dd, J = 15.7, 6.5 Hz, 1H), 4.19 (dd, J = 15.7, 6.6 Hz, 1H), 2.96 (d, J = 16.5 Hz, 1H), 2.82 (d, J = 16.5 Hz, 1H), 1.83 (s, 3H), 1.73 (s, 3H), 1.12 (s, 3H), 1.00 (s, 3H) ppm; 13 C NMR (125 MHz, CDCl3): δ 175.9, 145.3, 141.9, 137.8, 127.0, 126.8, 125.2, 123.2, 117.7, 116.7, 115.7, 112.7, 54.8, 42.0, 38.6, 25.9, 22.1, 22.1, 21.7, 18.5 ppm; IR (thin -1 film): νmax 2970, 1713, 1602, 1486, 1370, 1336 cm ; HPLC Rt = 13.79 and 18.54 (major) min (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i- PrOH, flow rate = 0.8 mL/min).

138

2-(6-bromo-1,3-bis(3-methylbut-2-enyl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing 2-(6-bromo-1-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile (11 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0. 85 umol, 0.025 equiv), and (S,S)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous PhCH3 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 7.3 mg (55 % linear product isolated from a 1:2.6 b:l mixture, >99% ee) of the desired product as a 30 colorless oil, whose spectral properties matched literature data. TLC Rf = 0.41 (20% 25 EtOAc/hexanes); [α]D -21.8 (optical rotation run on 99% ee using (S,S)-L1, c 0.73, 1 CH2Cl2); H NMR (500 MHz, CDCl3): δ 7.35-7.22 (m, 2H), 6.99 (d, J = 1.6 Hz, 1H), 5.09-5.06 (m, 1H), 4.74-4.70 (m, 1H), 4.40 (dd, J = 15.6, 6.5 Hz, 1H), 4.20 (dd, J = 15.5, 6.6 Hz, 1H), 2.88 (d, J = 16.7 Hz, 1H), 2.63 (d, J = 7.6 Hz, 2H), 2.63 (d, J = 16.7 Hz, 1H), 1.84 (s, 3H), 1.76 (s, 3H), 1.59 (s, 3H), 1.55 (s, 3H) ppm; 13C NMR (125 MHz,

CDCl3): δ 176.2, 144.1, 137.6, 137.3, 128.3, 125.5, 124.7, 122.7, 117.5, 116.4, 115.7,

112.6, 48.8, 38.3, 34.9, 25.8, 25.7, 24.7, 18.2, 18.1 ppm; IR (thin film): νmax 2969, 2915, -1 ® 1716, 1604, 1486, 1430, 1375 cm ; HPLC Rt = 10.75 (major) (Chiralcel OJ chiral column, λ = 254 nm, isocratic elution: 90:10 heptane/i-PrOH, flow rate = 0.8 mL/min).

139

3.6.4.3 Prenylation and reverse prenylation of 2-(6-phenyl-1-(3-methylbut-2-enyl)-2- oxoindolin-3-yl)acetonitrile

2-(6-phenyl-1-(3-methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3- yl)acetonitrile

A flame-dried vial containing 2-(6-phenyl-1-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile (10.8 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), (R,R)-L2 (2.0 mg, 2.5 umol, 0.075 equiv), and TBAT (5.5 mg, 0.01 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room 140 temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 8.2 mg (62% branched product isolated from a 11:1 b:l mixture, 89% ee) of the desired product as a colorless oil. TLC Rf = 25 0.32 (20% EtOAc/hexanes); [α]D +46.9 (optical rotation run on 89% ee material using 1 (R,R)-L2, c 0.82, CH2Cl2); H NMR (500 MHz, CDCl3): δ 7.58 (m, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 6.10 (dd, J = 17.5, 11.0 Hz, 1H), 5.21 (dd, J = 11.0, <1 Hz, 1H), 5.18 (m, 1H), 5.11 (dd, J = 17.5, <1 Hz, 1H), 4.51 (dd, J = 15.5, 6.0 Hz, 1H), 4.29 (dd, J = 15.5, 7.0 Hz, 1H), 3.01 (d, J = 16.5 Hz, 1H), 2.88 (d, J = 16.5 Hz, 1H), 1.85 (s, 3H), 1.73 (s, 3H), 13 1.16 (s, 3H), 1.07 (s, 3H) ppm; C NMR (125 MHz, CDCl3): δ 176.3, 144.6, 142.7, 142.4, 141.0,137.3, 129.1, 128.0, 127.4, 127.0, 125.9, 121.3, 118.3, 117.1, 115.4, 108.0,

54.8, 42.2, 38.6, 25.9, 22.3, 22.2, 21.9, 18.5 ppm; IR (thin film): νmax 2968, 2930, 2250, -1 1708, 1617, 1484, 1436, 1376, 1164, 1127, 762, 698 cm ; HPLC Rt = 25.5 (major) and 30.7 min (Chiralcel® OD-H chiral column, λ = 254 nm, isocratic elution: 98:2 heptane/i- + + PrOH, flow rate = 0.8 mL/min); HRMS (ES ) calcd for C26H29N2O 385.2274 found 285.2277 (MH+).

2-(6-phenyl-1,3-bis(3-methylbut-2-enyl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing 2-(6-phenyl-1-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile (11 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), and (R,R)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times

141 with nitrogen. The mixture was dissolved in anhydrous toluene (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 7.6 mg (58% linear product isolated from a 1:2.5 b:l mixture, 90% ee) of the desired product as a 25 colorless oil. TLC Rf = 0.31 (20% EtOAc/hexanes); [α]D +15.1 (optical rotation run 1 on 90% ee material using (R,R)-L1, c 0.57, CH2Cl2); H NMR (500 MHz, CDCl3): δ 7.58 (m, 2H), 7.48 (m, 3H), 7.39 (m, 1H), 7.32 (dd, J = 7.5, 1.6 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 5.12 (m, 1H), 4.79 (m, 1H), 4.45 (dd, J = 15.5, 6.5 Hz, 1H), 4.27 (dd, J = 15.5, 6.5 Hz, 1H), 2.91 (d, J = 16.5 Hz, 1H), 2.66 (m, 2H), 2.66 (d, J = 16.5 Hz, 1H), 13 1.84 (s, 3H), 1.73 (s, 3H), 1.58 (s, 3H), 1.56 (s, 3H) ppm; C NMR (125 MHz, CDCl3): δ 176.8, 143.6, 142.7, 141.1, 137.4, 137.3, 129.2, 128.7, 128.0, 127.4, 124.0, 122.0, 118.3, 117.0, 116.4, 108.2, 49.1, 38.5, 26.1, 25.9, 25.1, 18.5, 18.4 ppm; IR (thin film): -1 νmax 2968, 2915, 2249, 1714, 1618, 1484, 1435, 1378, 762, 698 cm ; HPLC Rt = 35.9, 40.1 (major) min (Chiralcel® AD-H chiral column, λ = 254 nm, isocratic elution: 99:1 + + heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES ) calcd for C26H29N2O 385.2274 found 285.2276 (MH+).

142

3.6.4.4 Prenylation and reverse prenylation of methyl 3-(cyanomethyl)-1-(3- methylbut-2-enyl)-2-oxoindoline-6-carboxylate

methyl 3-(cyanomethyl)-1-(3-methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2- oxoindoline-6-carboxylate

A flame-dried vial containing methyl 3-(cyanomethyl)-1-(3-methylbut-2-enyl)-2- oxoindoline-6-carboxylate (10.1 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol,

0.025 equiv), (R,R)-L2 (2.0 mg, 2.5 umol, 0.075 equiv), and TBAT (5.5 mg, 0.01 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut- 3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room 143 temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 10% EtOAc/hexanes afforded 9.1 mg (68% branched product isolated from a 15:1 b:l mixture, 95% ee) of the desired product as a colorless oil. TLC Rf = 25 0.17 (20% EtOAc/hexanes); [α]D +85.0 (optical rotation run on 95% ee using (R,R)- 1 L2, c 0.91, CH2Cl2); H NMR (500 MHz, CDCl3): δ 7.79 (dd, J = 8.0, 1.5 Hz, 1H), 7.50 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.01 (dd, J = 17.5, 10.5 Hz, 1H), 5.20 (dd, J = 10.5, <1 Hz, 1H), 5.14 (m, 1H), 5.07 (dd, J = 17.5, <1 Hz, 1H), 4.48 (dd, J = 15.5, 6.5 Hz, 1H), 4.28 (dd, J = 15.5, 6.5 Hz, 1H), 3.94 (s, 3H), 3.01 (d, J = 16.0 Hz, 1H), 2.86 (d, J = 16.0 Hz, 1H), 1.87 (s, 3H), 1.73 (s, 3H), 1.14 (s, 3H), 1.02 (s, 3H) ppm; 13C

NMR (125 MHz, CDCl3): δ 175.8, 166.8, 144.4, 141.8, 138.0, 133.2, 131.5, 125.5, 124.0, 117.7, 116.7, 115.8, 109.8, 55.1, 52.7, 42.1, 38.6, 25.9, 22.2, 22.1, 21.6, 18.5 -1 ppm; IR (thin film): νmax 2969, 2250, 1714, 1618, 1453, 1286, 1241, 1099, 762 cm ; ® HPLC Rt = 20.2 (major) and 24.0 min (Chiralcel OD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES+) calcd for + + C22H27N2O3 367.2016 found 367.2015 (MH ). methyl 3-(cyanomethyl)-1,3-bis(3-methylbut-2-enyl)-2-oxoindoline-6-carboxylate

A flame-dried vial containing methyl 3-(cyanomethyl)-1-(3-methylbut-2-enyl)-2- oxoindoline-6-carboxylate (10.1 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0. 85 umol,

0.025 equiv), and (R,R)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous toluene (200 uL),

144 the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 10% EtOAc/hexanes afforded 6.6 mg (50% linear product isolated from a 1:2.4 b:l mixture, 98% ee) of the desired 25 product as a colorless oil. TLC Rf = 0.15 (20% EtOAc/hexanes); [α]D +19.4 (optical 1 rotation run on 98% ee using (R,R)-L1, c 0.66, CH2Cl2); H NMR (500 MHz, CDCl3): δ 7.82 (dd, J = 8.0, 1.6 Hz, 1H), 7.51-7.48 (m, 2H), 5.08 (m, 1H), 4.68 (m, 1H), 4.44 (dd, J = 14.5, 6.5 Hz, 1H), 4.25 (dd, J = 14.5, 6.5 Hz, 1H), 3.94 (s, 1H), 2.90 (d, J = 17.0 Hz, 1H), 2.65 (d, J = 17.0 Hz, 1H), 2.65 (m, 2H), 1.86 (s, 3H), 1.72 (s, 3H), 1.53 13 (s, 3H), 1.51 (s, 3H) ppm; C NMR (125 MHz, CDCl3): δ 176.3, 166.8, 143.4, 138.0, 137.7, 134.7, 131.4, 124.8, 123.6, 117.7, 116.6, 115.9, 110.0, 52.7, 49.4, 38.6, 35.2,

26.05, 25.95, 24.8, 18.5, 18.3 ppm; IR (thin film): νmax 2917, 2250, 1717, 1619, 1452, -1 ® 1284, 1243, 1098, 767 cm ; HPLC Rt = 22.8 (major), 27.6 min (Chiralcel OD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); + + + HRMS (ES ) calcd for C22H27N2O3 367.2016 found 367.2015 (MH ).

145

3.6.4.5 Prenylation and reverse prenylation of 2-(5-methoxy-1-(3-methylbut-2-enyl)- 2-oxoindolin-3-yl)acetonitrile

2-(5-methoxy-1-(3-methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3- yl)acetonitrile

A flame-dried vial containing 2-(5-methoxy-1-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile (9.2 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv),

(R,R)-L2 (2.0 mg, 2.5 umol, 0.075 equiv), and TBAT (5.5 mg, 0.01 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl)

146 carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 10 mg (80% branched product isolated from a 8.3:1 b:l mixture, 84% ee) of the desired product as a colorless oil. TLC Rf = 25 0.20 (20% EtOAc/hexanes); [α]D +74.2 (optical rotation run on 84% ee material using 1 (R,R)-L2, c 1.00, CH2Cl2); H NMR (500 MHz, CDCl3): δ 6.90 (d, J = 2.5 Hz, 1H), 6.83 (d, J = 8.5, 2.5 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 6.07 (dd, J = 17.0, 11.0 Hz, 1H), 5.19 (dd, J = 11.0, 1.1 Hz, 1H), 5.12 (dd, J = 17.0, 1.1 Hz, 1H), 5.08 (m, 2H), 4.43 (dd, J = 16.0, 6.5 Hz, 1H), 4.22 (dd, J = 16.0, 6.5 Hz, 1H), 3.80 (s, 3H), 2.98 (d, J = 16.5 Hz, 1H), 2.81 (d, J = 16.5 Hz, 1H), 1.82 (s, 3H), 1.71 (s, 3H), 1.14 (s, 3H), 1.02 (s, 3H) ppm; 13 C NMR (125 MHz, CDCl3): δ 175.7, 155.6, 142.4, 137.5, 137.0, 129.4, 118.5, 117.0, 115.4, 113.8, 113.0, 109.4, 56.0, 55.2, 42.0, 38.6, 25.9, 22.18, 22.16, 21.9, 18.5 ppm; -1 IR (thin film): νmax 2932, 1734, 1622, 1596, 1489, 1273, 1025, 821, 758 cm ; HPLC Rt = 16.6 (major), 25.0 min (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: + + 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES ) calcd for C22H27N2O3 367.2016 found 367.2017 (MH+).

2-(5-methoxy-1,3-bis(3-methylbut-2-enyl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing 2-(5-methoxy-1-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile (9.2 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), and (R,R)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times

147 with nitrogen. The mixture was dissolved in anhydrous toluene (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 8.0 mg (64% linear product isolated from a 1:2.1 b:l mixture, >99% ee) of the desired product as a 44 25 colorless oil whose spectral data matched literature reports. [α]D +37.4 (optical 1 rotation run on 92% ee material using (R,R)-L1, c 0.80, CH2Cl2); H NMR (500 MHz,

CDCl3): δ 7.04 (d, J = 2.6 Hz, 1H), 6.83 (d, J = 8.5, 2.6 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 5.06 (m, 1H), 4.73 (m, 1H), 4.38 (dd, J = 15.5, 7.0 Hz, 1H), 4.19 (dd, J = 15.5, 7.0 Hz, 1H), 2.86 (d, J = 17.0 Hz, 1H), 2.62 (d, J = 17.0 Hz, 1H), 2.61 (d, J = 8.0 Hz, 2H),

1.81 (s, 3H), 1.71 (s, 3H), 1.56 (s, 3H), 1.54 (s, 3H) ppm; IR (thin film): νmax 2966, -1 2916, 2250, 1708, 1600, 1492, 1436, 1176, 1036, 808 cm ; HPLC Rt = 16.4 (major), 22.2 min (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i- PrOH, flow rate = 0.8 mL/min).

3.6.4.6 Prenylation and reverse prenylation of 2-(1-(4-methoxybenzyl)-2-oxoindolin- 3-yl)acetonitrile

148

2-(6-bromo-1-(4-methoxybenzyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3- yl)acetonitrile

A flame-dried vial containing 2-(1-(4-methoxybenzyl)-2-oxoindolin-3-yl)acetonitrile

(9.9 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), (S,S)-L2 (2.0 mg, 2.5 umol, 0.075 equiv), and TBAT (5.5 mg, 0.01 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 9.2 mg (75% branched product isolated from a 7.7:1 b:l mixture, 88% ee) of the desired product as a colorless oil. TLC Rf = 0.30 (20% 25 EtOAc/hexanes); [α]D -72.9 (optical rotation run on 88% ee material using (S,S)-L2, c 1 0.96, CH2Cl2); H NMR (500 MHz, CDCl3): δ 7.30-7.22 (m, 4H), 7.05 (td, J = 7.6, 1.0 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 7.8 Hz, 1H), 6.06 (dd, J = 17.5, 10.8 Hz, 1H), 5.19 (dd, J = 10.8, 0.9 Hz, 1H), 5.09 (dd, J = 17.5, 0.9 Hz, 1H), 4.95 (d, J = 15.5 Hz, 1H), 4.83 (d, J = 15.5 Hz, 1H), 3.77 (s, 3H), 3.05 (d, J = 16.4 Hz, 1H), 2.89 (d, J = 13 16.4 Hz, 1H), 1.15 (s, 3H), 1.05 (s, 3H) ppm; C NMR (125 MHz, CDCl3): δ 176.3, 159.0, 143.6, 142.0, 129.2, 128.7, 127.7, 127.4, 126.3, 125.4, 122.3, 116.9, 115.2, 114.1,

109.4, 55.2, 54.7, 43.5, 41.9, 29.9, 22.0, 21.7 ppm; IR (thin film): νmax 3403, 2927, 2249, -1 1709, 1610, 1513, 1487, 1466, 1363, 1248, 1177 cm ; HPLC Rt = 23.0 and 35.9 min (major) (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: 90:10 heptane/i- + + PrOH, flow rate = 0.8 mL/min); HRMS (ES ) calcd for C23H25N2O2 361.1911 found 361.1907 (MH+). 149

2-(6-bromo-1-(4-methoxybenzyl)-3-(3-methylbut-2-enyl)-2-oxoindolin-3- yl)acetonitrile

A flame-dried vial containing 2-(1-(4-methoxybenzyl)-2-oxoindolin-3-yl)acetonitrile

(9.9 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0. 85 umol, 0.025 equiv), and (S,S)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen.

The mixture was dissolved in anhydrous PhCH3 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert- butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 6.7 mg (55% linear product isolated from a 1:2.6 b:l mixture, 80% ee) of the desired product as a colorless 25 oil. TLC Rf = 0.24 (20% EtOAc/hexanes); [α]D -30.6 (optical rotation run on 80% ee 1 material using (S,S)-L1, c 1.02, CH2Cl2); H NMR (500 MHz, CDCl3): δ 7.44 (dd, J = 7.8, 0.7 Hz, 1H), 7.22 (ddd, J = 7.8, 7.8, 1.0 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.08 (ddd, J = 7.8, 7.8, 1.0 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 7.8 Hz, 1H), 5.06 (d, J = 15.5 Hz, 1H), 4.75-4.72 (m, 1H), 4.66 (d, J = 15.5 Hz, 1H), 3.77 (s, 3H), 2.92 (d, J = 16.6 Hz, 1H), 2.71-2.69 (m, 2H), 2.68 (d, J = 16.6 Hz, 1H), 1.55 (s, 3H), 1.55 (s, 13 3H) ppm; C NMR (125 MHz, CDCl3): δ 176.9, 159.0, 142.5, 137.1, 129.2, 129.0, 128.4, 127.3, 123.4, 122.9, 116.6, 116.2, 114.1, 109.6, 55.2, 49.0, 43.4, 34.9, 25.8, 25.2, -1 18.1 ppm; IR (thin film): νmax 3416, 2915, 2249, 1713, 1612, 1513, 1466, 1248 cm ; ® HPLC Rt = 20.2 (major) and 22.6 min (Chiralcel OD chiral column, λ = 254 nm, isocratic elution: 90:10 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES+) calcd + + for C23H25N2O2 361.1911 found 361.1907 (MH ).

150

3.6.4.7 Prenylation and reverse prenylation of 2-(1-(methoxymethyl)-2-oxoindolin-3- yl)acetonitrile

2-(1-(methoxymethyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing 2-(1-(methoxymethyl)-2-oxoindolin-3-yl)acetonitrile

(7.4 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), (R,R)-L2 (2.0 mg, 2.5 umol, 0.075 equiv), and TBAT (5.5 mg, 0.010 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 7.0 mg (72% branched product isolated from a 15:1 b:l mixture, 86% ee) of the desired product as a colorless oil. TLC Rf = 0.4 (20% 25 EtOAc/hexanes); [α]D +59.1 (reaction run on 86% ee material using (R,R)-L2, c 0.70,

151

1 CHCl3 using (R,R)-L2); H NMR (400 MHz, CDCl3): δ 7.38-7.33 (m, 1H), 7.32-7.29 (m, 1H), 7.15-7.09 (m, 2H), 6.04 (dd, J = 17.5, 10.8 Hz, 1H), 5.21 (dd, J = 10.8, 0.7 Hz, 1H), 5.17 (d, J = 5.3 Hz, 2H), 5.09 (dd, J = 17.5, 0.7 Hz, 1H), 3.36 (s, 3H), 3.03 (d, J = 16.4 Hz, 1H), 2.87 (d, J = 16.4 Hz, 1H), 1.15 (s, 3H), 1.06 (s, 3H) ppm; 13C NMR (100

MHz, CDCl3): δ 177.0, 142.7, 141.8, 129.4, 127.1, 125.4, 122.9, 116.7, 115.4, 109.9,

71.6, 56.6, 55.5, 41.7, 21.9, 21.8 ppm; IR (thin film): νmax 2930, 1722, 1611, 1367, 1347, -1 ® 1095 cm ; HPLC Rt = 10.9 (major) and 16.1 min (Chiralcel OD chiral column, λ = 254 nm, isocratic elution: 90:10 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES+) + + calcd for C17H20O2N2Na 307.1417 found 307.1408 (MNa ).

2-(1-(methoxymethyl)-3-(3-methylbut-2-en-1-yl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing containing 2-(1-(methoxymethyl)-2-oxoindolin-3- yl)acetonitrile (7.4 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv),

(R,R)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous PhCH3 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 7.1 mg (73% linear product isolated from a 1:2.7 b:l mixture,

95% ee) of the desired product as a colorless oil. TLC Rf = 0.28 (20% EtOAc/hexanes); 25 [α]D +31.9 (optical rotation conducted on 95% ee material using (R,R)-L1, c 0.71, 1 CHCl3); H NMR (400 MHz, CDCl3): δ 7.43 (ddd, J = 7.9, 1.3, 0.6 Hz, 1H), 7.34 (ddd, J = 8.2, 7.9, 1.0 Hz, 1H), 7.15 (ddd, J = 8.2, 7.9, 1.0 Hz, 1H), 7.07 (ddd, J = 7.9, 1.0, 0.6 Hz, 1H), 5.17 (d, J = 11.0 Hz, 1H), 5.09 (d, J = 11.0 Hz, 1H), 4.75 (m, 1H), 3.28 (s,

152

3H), 2.88 (d, J = 16.6 Hz, 1H), 2.68 (d, J = 16.6 Hz, 3H), 1.55-1.54 (m, 6H) ppm; 13C

NMR (125 MHz, CDCl3): δ 177.5, 141.6, 137.3, 129.3, 128.6, 123.5, 123.5, 116.4,

116.1, 110.0, 71.4, 56.0, 49.7, 35.0, 25.9, 25.2, 18.1 ppm; IR (thin film): νmax 2930, -1 1724, 1613, 1487, 1467, 1352, 1095 cm ; HPLC Rt = 24.3 and 25.9 min (major) (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: 98:2 heptane/i-PrOH, flow + + rate = 0.8 mL/min); HRMS (ES ) calcd for C17H20O2N2Na 307.1417 found 307.1409 (MNa+).

3.6.4.8 Prenylation and reverse prenylation of 2-(2-oxoindolin-3-yl)acetonitrile

2-(3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing 2-(2-oxoindolin-3-yl)acetonitrile (6.0 mg, 0.034 mmol),

Pd2dba3•CHCl3 (0.9 mg, 0.85 ummol, 0.025 equiv), (S,S)-L2 (2.0 mg, 2.5 umol, 0.075 equiv), and TBAT (5.5 mg, 0.01 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). 153

The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 4.1 mg (50% branched product isolated from a 2:1 b:l mixture, 32% ee) of the desired product as a 45 colorless oil whose spectral properties matched literature data. TLC Rf = 0.67 (50% 25 EtOAc/hexanes); [α]D -48.5 (optical rotation conducted on 32% ee material using 1 (S,S)-L2, c 0.32, EtOH); H NMR (400 MHz, CDCl3): δ 7.98-7.82 (bs, 1H), 7.31-7.27 (m, 2H), 7.07 (dd, J = 7.7, 7.7 Hz, 1H), 6.93 (d, J = 7.7, 1H), 6.09 (dd, J = 17.8, 10.8 Hz, 1H), 5.22 (d, J = 10.8 Hz, 1H), 5.10 (d, J = 17.8 Hz, 1H), 3.0 (d, 1H, J = 16.4 Hz,

1H), 2.85 (d, J = 16.4 Hz, 1H), 1.16 (s, 3H), 1.07 (s, 3H) ppm; IR (thin film): νmax 3286, -1 2916, 1709, 1618, 1469, 1157, 1110 cm ; HPLC Rt = 16.33 (major) and 22.62 min (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: 90:10 heptane/i-PrOH, flow rate = 0.8 mL/min).

2-(3-(3-methylbut-2-enyl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing 2-(2-oxoindolin-3-yl)acetonitrile (6.0 mg, 0.034 mmol),

Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), and (S,S)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous PhCH3 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut- 3-en-2-yl) carbonate (9.4 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 5.1 mg (62% linear product isolated 154 from a 1:2.9 b:l mixture, 86% ee) of the desired product as a colorless oil. TLC Rf = 25 0.07 (20% EtOAc/hexanes); [α]D -53.7 (optical rotation conducted on 82% ee material 1 using (S,S)-L1, c 0.22, EtOH) H NMR (400 MHz, CDCl3): δ 8.16-8.15 (bs, 1H), 7.41 (d, J = 7.6, 0.6 Hz, 1H), 7.29 (ddd, J = 7.8, 7.8, 1.2 Hz, 1H), 7.10 (ddd, J = 7.8, 7.6, 1.0 Hz, 1H), 6.93 (d, J = 7.8, 0.6 Hz, 1H), 4.86-4.82 (m, 1H), 2.87 (d, J = 16.7 Hz, 1H), 2.68 (m, 2H), 2.68 (d, J = 16.7 Hz, 1H), 1.59 (s, 3H), 1.56 (s, 3H) ppm; 13C NMR (125

MHz, CDCl3): δ 178.7, 140.3, 137.2, 129.7, 129.1, 123.8, 123.0, 116.5, 115.9, 110.1, - 49.4, 34.7, 25.9, 24.8, 18.1 ppm; IR (thin film): νmax 3258, 2915, 1716, 1621, 1471 cm 1 ® ; HPLC Rt = 12.0 (major) and 13.33 min (Chiralcel AD chiral column, λ = 254 nm, isocratic elution: 90:10 heptane/i-PrOH, flow rate = 0.8 mL/min). HRMS (ES+) m/z + [MH] calcd for C15H17ON2 241.1335, found 241.1335.

3.6.4.9 Prenylation and reverse prenylation of methyl 2-(6-bromo-1-(3-methylbut-2- enyl)-2-oxoindolin-3-yl)acetate

155 methyl 2-(6-bromo-1-(3-methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3- yl)acetate

A flame-dried vial containing methyl 2-(6-bromo-1-(3-methylbut-2-enyl)-2- oxoindolin-3-yl)acetate (12 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol,

0.025 equiv), (S,S)-L1 (1.8 mg, 2.5 umol, 0.075 equiv) and TBAT (5.5 mg, 0.010 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 8.4 mg (59% branched product isolate from a 2.1:1 b:l, 91% ee) of the desired product 25.3 as a colorless oil. TLC Rf = 0.58 (20% EtOAc/hexanes); [α]D -31.8 (optical rotation 1 run on 88% ee material from (S,S)-L1, c 0.76, EtOH); H NMR (400 MHz, CDCl3): δ 7.09 (dd, J = 7.6, 1.7 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 1.7 Hz, 1H), 5.95 (dd, J = 17.6, 10.8 Hz, 1H), 5.16-5.09 (m, 2H), 5.00 (d, J = 17.6 Hz, 1H), 4.43 (dd, J = 15.6, 6.4 Hz, 1H), 4.20 (dd, J = 15.6, 6.4 Hz, 1H), 3.35 (s, 3H), 3.15 (d, J = 16.0 Hz, 1H), 2.87 (d, J = 16.0 Hz, 1H), 1.83 (d, J = 0.8 Hz, 3H), 1.74 (d, J = 0.8 Hz, 3H), 1.09 13 (s, 3H), 0.95 (s, 3H) ppm; C NMR (125 MHz, CDCl3): δ 178.1, 170.9, 146.1, 142.7, 136.9, 128.9, 126.1, 124.2, 122.0, 118.3, 114.8, 111.8, 54.5, 51.8, 42.0, 38.5, 37.1, 25.9,

22.0, 21.9, 18.5 ppm; IR (thin film): νmax 2966, 2916, 2852, 1736, 1718, 1604, 1487, -1 1435, 1376, 1351, 1201, 1171, 1114, 1062, 878, 840, 809 cm ; HPLC Rt = 8.2 (major) and 22.2 min (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: 97:3

156 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH]+ calcd for

C21H27BrNO3 420.1169, found 420.1165. methyl 2-(6-bromo-1,3-bis(3-methylbut-2-en-1-yl)-2-oxoindolin-3-yl)acetate

A flame-dried vial containing methyl 2-(6-bromo-1-(3-methylbut-2-enyl)-2- oxoindolin-3-yl)acetate (12 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol,

0.025 equiv) and (S,S)-L1 (1.8 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in toluene (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 10.1 mg (71% linear product isolated from a 1:2.9 b:l mixture,

77% ee) of the desired product as a colorless oil. TLC Rf = 0.47 (20% EtOAc/hexanes); 25.4 1 [α]D 0.1 (optical rotation run on 90% ee material from (S,S)-L1, c 0.56, EtOH); H

NMR (400 MHz, CDCl3): δ 7.12 (dd, J = 8.0, 2.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 5.10 (m, 1H), 4.79 (m, 1H), 4.41 (dd, J = 17.6, 6.4 Hz, 1H), 4.21 (dd, J = 17.6, 6.4 Hz, 1H), 3.44 (s, 3H), 3.02 (d, J = 16.4 Hz, 1H), 2.87 (d, J = 16.4 Hz, 1H), 2.40 (m, 2H), 1.83 (d, J = 0.8 Hz, 3H), 1.74 (d, J = 1.0 Hz, 3H), 1.58 (d, J = 13 0.9 Hz, 3H), 1.47 (d, J = 0.9 Hz, 3H) ppm; C NMR (125 MHz, CDCl3): δ 178.8, 170.5, 145.1, 137.0, 136.8, 130.5, 124.9, 124.3, 121.8, 118.4, 116.8, 112.2, 51.9, 49.8, 40.0,

38.4, 36.6, 26.1, 25.9, 18.4, 18.3 ppm; IR (thin film): νmax 3064, 2970, 2930, 1743, 1716,

157

-1 1601, 1487, 1434, 1369, 1336, 1198, 1173, 1119, 1065, 922, 842 cm ; HPLC Rt = 8.9 (major) and 23.6 min (Chiralcel® ODH chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/iPrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH]+ calcd for

C21H27BrNO3 420.1169, found 420.1166.

3.6.4.10 Prenylation and reverse prenylation of 2-(6-bromo-1-(3-methylbut-2-en-1-yl)- 2-oxoindolin-3-yl)-N-methylacetamide

2-(6-bromo-1-(3-methylbut-2-en-1-yl)-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)- N-methylacetamide

A flame-dried vial containing 2-(6-bromo-1-(3-methylbut-2-en-1-yl)-2-oxoindolin-3- yl)-N-methylacetamide (23.6 mg, 0.068 mmol), Pd2dba3•CHCl3 (1.8 mg, 0.85 umol,

0.025 equiv), (R,R)-L2 (4.0 mg, 2.5 umol, 0.075 equiv) and TBAT (11 mg, 0.010 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was 158 dissolved in CH2Cl2 (400 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (18.8 mg, 0.102 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with EtOAc afforded 16.4 mg (58% branched product isolated from a 5.7:1 b:l mixture, >99% ee) of the desired product as a colorless 30 25.4 oil. This compound has been previously reported. TLC Rf = 0.43 (EtOAc); [α]D 1 +26.6 (optical rotation run on 90% ee material using (R,R)-L2, c 0.65, CHCl3); H NMR

(400 MHz, CDCl3): δ 7.11 (dd, J = 8.1, 1.7 Hz, 1H), 7.04 (1H, d, J = 8.1 Hz, 1H), 6.89 (d, J = 1.7 Hz, 1H), 5.96 (dd, J = 17.4, 10.8 Hz, 1H), 5.44 (br d, J = 3.6 Hz, 1H), 5.10 (dd, J = 10.8, 1.1 Hz, 1H), 5.07-5.09 (m, 1H), 4.98 (dd, J = 17.4, 1.1 Hz, 1H), 4.40 (dd, J = 15.8, 6.6 Hz, 1H), 4.21 (dd, J = 15.8, 6.6 Hz, 1H), 3.00 (d, J = 14.0 Hz, 1H), 2.65 (d, J = 14.0 Hz, 1H), 2.50 (d, J = 4.8 Hz, 3H), 1.83 (s, 3H), 1.73 (d, J = 1.2 Hz, 3H),

1.08 (s, 3H), 0.95 (s, 3H) ppm; IR (thin film): νmax 3325, 3084, 2969, 2932, 1710, 1650, -1 1601, 1555, 1487, 1436, 1374, 1335, 1162, 917, 841, 732 cm ; HPLC Rt = 64.4 and 70.2 min (major) (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 98:2 heptane/iPrOH, flow rate = 0.8 mL/min).

2-(6-bromo-1,3-bis(3-methylbut-2-en-1-yl)-2-oxoindolin-3-yl)-N-methylacetamide

A flame-dried vial containing 2-(6-bromo-1-(3-methylbut-2-en-1-yl)-2-oxoindolin-3- yl)-N-methylacetamide (11.8 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol,

0.025 equiv) and (R,R)-L1 (2.0 mg, 2.5 umol, 0.075 equiv) was evacuated and purged

159 three times with nitrogen. The mixture was dissolved in toluene (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 9.5 mg (66% linear product isolated from a 1:2.0 b:l mixture, 94% ee) of the desired product as a colorless oil. This compound has been previously 30 25 reported. TLC Rf = 0.32 (EtOAc); [α]D -1.4 (optical rotation run on 94% ee material 1 using (R,R)-L1, c 1.04, CHCl3); H NMR (400 MHz, CDCl3): δ 7.16 (dd, J = 7.8, 1.7 Hz, 1H), 7.09 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 1.7 Hz, 1H), 5.99 (s, 1H), 5.06 (m, 1H), 4.75 (m, 1H), 4.39 (dd, J = 15.6, 6.6 Hz, 1H), 4.19 (dd, J = 15.6, 6.6 Hz, 1H), 2.80 (d, J = 14.9 Hz, 1H), 2.68 (d, J = 14.2 Hz, 1H), 2.65 (d, J = 4.9 Hz, 3H), 2.48 (d, J = 7.6

Hz, 2H), 1.82 (s, 3H), 1.73 (s, 3H), 1.57 (s, 3H), 1.46 (s, 3H) ppm; IR (thin film): νmax 3320, 2969, 2914, 1715, 1653, 1605, 1557, 1488, 1437, 1378, 1338, 1166, 812 cm-1; ® HPLC Rt = 41.1 and 65.8 min (major) (Chiralcel ODH chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min).

3-(2,2-dimethoxyethyl)-1-(4-methoxybenzyl)-3-(2-methylbut-3-en-2-yl)indolin-2-one

WHC-III-65: A flame-dried vial containing 3-(2,2-dimethoxyethyl)-1-(4- methoxybenzyl)indolin-2-one (11.6 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), (R,R)-L2 (2.0 mg, 1.25 umol, 0.075 equiv) and TBAT (5.5 mg, 0.010 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut- 3-en-2-yl) carbonate (9.5 mg, 0.05 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave 160 the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with EtOAc afforded 4.2 mg (30% branched product isolated from a 1.9:1 b:l mixture, 28% ee) of the desired product as a colorless 1 oil. H NMR (500 MHz, CDCl3): δ 7.32 (m, 2H), 7.14-19 (m, 2H), 6.96 (td, J = 9.5, 1.0 Hz, 1H), 6.84 (m, 1H), 6.75 (d, J = 9.5 Hz, 1H), 6.01 (dd, J = 22, 13 Hz, 1H), 5.07 (dd, J = 13, 1.5 Hz, 1H), 4.99 (dd, J = 22, 1.5 Hz, 1H), 4.94 (d, J = 19 Hz, 1H), 4.68 (d, J = 19 Hz, 1H), 3.84 (dd, J = 11, 4.1 Hz, 1H), 3.76 (s, 3H), 3.10 (s, 3H), 2.77 (s, 3H), 2.54 (dd, J = 18, 11 Hz, 1H), 2.09 (dd, J = 18, 11 Hz, 1H), 1.15 (s, 3H), 0.97 (s, 3H) ppm.

3-(2,2-dimethoxyethyl)-1-(4-methoxybenzyl)-3-(3-methylbut-2-enyl)indolin-2-one

WHC-III-66: A flame-dried vial containing 3-(2,2-dimethoxyethyl)-1-(4- methoxybenzyl)indolin-2-one (11.6 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv) and (S,S)-L1 (1.8 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in toluene (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 5.2 mg (37% linear product isolated from a 1:2.9 b:l 1 mixture, 15% ee) of the desired product as a colorless oil. H NMR (500 MHz, CDCl3): δ 7.32 (m, 2H), 7.14-19 (m, 2H), 6.96 (td, J = 9.5, 1.0 Hz, 1H), 6.84 (m, 1H), 6.75 (d, J = 9.5 Hz, 1H), 6.01 (dd, J = 22, 13 Hz, 1H), 5.04 (d, J = 20 Hz, 1H), 4.80 (m, 1H), 4.63 (d, J = 20 Hz, 1H), 3.84 (dd, J = 11, 4.1 Hz, 1H), 3.77 (s, 3H), 3.12 (s, 3H), 2.95 (s, 3H), 2.54 (dd, J = 18, 11 Hz, 1H), 2.49 (m, 2H), 2.09 (dd, J = 18, 11 Hz, 1H), 1.55 (s, 3H), 1.50 (s, 3H) ppm.

161

3-(2-hydroxyethyl)-1-(4-methoxybenzyl)-3-(2-methylbut-3-en-2-yl)indolin-2-one (2i)

WHC-III-69: A flame-dried vial containing 3-(2-hydroxyethyl)-1-(4- methoxybenzyl)indolin-2-one (10.1 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), (R,R)-L2 (2.0 mg, 2.5 umol, 0.075 equiv) and TBAT (5.5 mg, 0.010 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 7.2 mg (58% branched product isolated from a 1.9:1 b:l mixture, 64% ee) of the desired 1 product as a colorless oil. H NMR (500 MHz, CDCl3): δ 7.27 (m, 2H), 7.20-15 (m, 2H), 6.98 (td, J = 9.5, 1.0 Hz, 1H), 6.83 (m, 1H), 6.75 (d, J = 9.5 Hz, 1H), 6.01 (dd, J = 22, 13 Hz, 1H), 5.06 (dd, J = 13, 1.5 Hz, 1H), 4.98 (dd, J = 22, 1.5 Hz, 1H), 4.87 (d, J = 17 Hz, 1H), 4.77 (d, J = 17 Hz, 1H), 3.84 (dd, J = 11, 4.1 Hz, 1H), 3.77 (s, 3H), 3.19 (m, 2H), 2.45 (m, 1H), 2.16 (m, 1H), 1.15 (s, 3H), 1.01 (s, 3H) ppm.

3-(2-hydroxyethyl)-1-(4-methoxybenzyl)-3-(3-methylbut-2-enyl)indolin-2-one (3i)

WHC-III-70: A flame-dried vial containing 3-(2-hydroxyethyl)-1-(4- methoxybenzyl)indolin-2-one (10.1 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv) and (S,S)-L1 (1.8 mg, 2.5 umol, 0.075 equiv) was evacuated and

162 purged three times with nitrogen. The mixture was dissolved in toluene (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 7.1 mg (57% linear product isolated from a 1:3.1 b:l 1 mixture, 40% ee) of the desired product as a colorless oil. H NMR (500 MHz, CDCl3): δ 7.21 (m, 2H), 7.13-18 (m, 2H), 7.02 (td, J = 9.5, 1.0 Hz, 1H), 6.82 (m, 1H), 6.70 (d, J = 9.5 Hz, 1H), 5.01 (d, J = 16 Hz, 1H), 4.76 (m, 1H), 4.68 (d, J = 16 Hz, 1H), 3.84 (dd, J = 11, 4.1 Hz, 1H), 3.76 (s, 3H), 3.63 (m, 1H), 3.46 (m, 1H), 2.68 (dd, J = 14, 8.0 Hz, 1H), 2.49 (dd, J = 14, 8.0 Hz, 1H), 2.08 (m, 1H), 3.46 (m, 1H), 1.54 (s, 3H), 1.51 (s, 3H) ppm.

2-(1-(4-methoxybenzyl)-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)ethyl acetate (3.x)

WHC-IV-55: A flame-dried vial containing 2-(1-(4-methoxybenzyl)-2-oxoindolin-3- yl)ethyl acetate (11.5 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), (R,R)-L2 (2.0 mg, 2.5 umol, 0.075 equiv) and TBAT (5.5 mg, 0.010 mmol, 0.3 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 3.6 mg (26% branched product isolated from a 2.0:1 b:l mixture, 27% ee) of the desired product as a colorless 163

1 oil. TLC Rf = 0.47 (20% EtOAc/hexanes); H NMR (400 MHz, CDCl3): δ 7.24-7.29 (m, 2H), 7.14-7.20 (m, 2H), 6.98 (m, 1H), 6.84 (m, 2H), 6.74 (d, J = 8.0 Hz, 1H), 6.02 (dd, J = 22, 13 Hz, 1H), 5.07 (dd, J = 13, 1.5 Hz, 1H), 4.95-5.04 (m, 2H), 4.65 (d, J = 16 Hz, 1H), 3.78 (s, 3H), 3.73 (m, 1H), 3.55 (m, 1H), 2.47 (m, 1H), 2.22 (m, 1H), 1.76 (s, 3H), 1.14 (s, 3H), 1.01 (s, 3H) ppm.

2-(1-(4-methoxybenzyl)-3-(3-methylbut-2-enyl)-2-oxoindolin-3-yl)ethyl acetate (3.x)

WHC-IV-56: A flame-dried vial containing 2-(1-(4-methoxybenzyl)-2-oxoindolin-3- yl)ethyl acetate (11.5 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv) and (S,S)-L1 (1.8 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in toluene (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.051 mmol, 1.5 equiv). The reaction was stirred at room temperature for 24 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 4.1 mg (30% linear product isolated from a 1:3.0 b:l mixture,

10% ee) of the desired product as a colorless oil. TLC Rf = 0.27 (20% EtOAc/hexanes); 1 H NMR (400 MHz, CDCl3): δ 7.24-7.10 (m, 3H), 7.01 (m, 1H), 6.82 (m, 1H), 6.67 (d, J = 8.0 Hz, 1H), 5.09 (d, J = 15 Hz, 1H), 4.76 (m, 1H), 4.59 (d, J = 15 Hz, 1H), 3.91 (m, 1H), 3.77 (s, 3H), 3.72 (m, 1H), 2.60 (dd, J = 14, 8.8 Hz, 1H), 2.48 (dd, J = 14, 8.8 Hz, 1H), 2.37 (m, 1H), 2.20 (m, 1H), 1.78 (s, 3H), 1.55 (s, 3H), 1.51 (s, 3H) ppm.

3.6.5 Synthesis of (+)-flustramides A and B and (+)-flustramines A and B

164

(+)-flustramide A

To a solution of (+)-2-[6-bromo-1-(3-methylbut-2-enyl)-3-(2-methylbut-3-en-2-yl)-2- oxoindolin-3-yl]-N-methylacetamide (50 mg, 0.12 mmol) in THF (5 mL) was added

AlH3∙EtNMe2 complex (0.5 M in PhMe, 1.2 mL) dropwise at -15 °C. After 5 min the mixture was treated with THF-water (1:1, 2 mL) and stirred for 30 min while warming to rt. The mixture was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with saturated Na2CO3 (aq.) and brine, dried (Na2SO4) and concentrated in vacuo. Silica gel chromatography with 80% EtOAc/hexanes yielded 24.7 (+)-flustramide A as a yellow oil (43.8 mg, 91%). TLC Rf = 0.64 (EtOAc); [α]D 1 +62.19 (90% ee, c 1.095, EtOH); H NMR (400 MHz, CDCl3): δ 6.92 (d, J = 7.9 Hz, 1H) 6.81 (dd, J = 7.9, 1.7 Hz, 1H), 6.56 (d, J = 1.7 Hz, 1H), 5.77 (dd, J = 17.4, 10.8 Hz, 1H), 5.25 (m, 1H), 5.11 (dd, J = 10.8, 1.1 Hz, 1H), 5.05 (dd, J = 17.4, 1.1 Hz, 1H), 4.82 (s, 1H), 3.92 (d, J = 6.6 Hz, 2H), 2.87-2.81 (m, 2H), 2.54 (d, J = 17.4 Hz, 1H), 1.76 (d,

J = 1.2 Hz, 3H), 1.75 (br s, 3H), 1.02 (s, 3H), 0.93 (s, 3H) ppm; IR (thin film): νmax 2968, 2925, 1695, 1593, 1491, 994 cm-1. Spectral data is in agreement with literature data.30

(+)-flustramine A

165

To a solution of (+)-flustramide A (40 mg, 0.10 mmol) in THF (7 mL) was added

AlH3∙EtNMe2 complex (0.5 M in PhMe, 0.30 mL) dropwise at rt. After 5 min the mixture was treated with THF-water (1:1, 10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated Na2CO3 (aq.) and brine, dried (Na2SO4) and concentrated in vacuo. Silica gel chromatography with 60%

EtOAc/hexanes yielded (+)-flustramine A as a yellow oil (25 mg, 64%). TLC Rf = 0.48 25.2 1 (60% EtOAc/hexanes); [α]D +126.87 (90% ee, c 0.73, EtOH); H NMR (400 MHz,

CDCl3): δ 6.90 (d, J = 7.8 Hz, 1H), 6.68 (dd, J = 7.8,1.5 Hz, 1H), 6.47 (d, J = 1.5 Hz, 1H), 5.94 (dd, J = 17.4, 10.8 Hz, 1H), 5.22 (m, 1H), 5.06 (d, J = 10.8 Hz, 1H), 4.98 (d, J = 17.4 Hz, 1H), 4.34 (s, 1H), 3.90-3.77 (m, 2H), 2.64 (m, 1H), 2.48-2.38 (m, 4H),

2.23 (m, 1H), 1.76-1.69 (m, 7H), 1.00 (s, 3H), 0.94 (s, 3H) ppm; IR (thin film): νmax 2966, 2929, 2792, 1592, 1491, 1373, 1254, 1158, 912 cm-1. Spectral data is in agreement with literature data.30

(+)-flustramide B

To a solution of (+)-2-(6-bromo-1,3-bis(3-methylbut-2-enyl)-2-oxoindolin-3-yl)-N- methylacetamide (31 mg, 0.074 mmol) in THF (3 mL) was added AlH3∙EtNMe2 complex (0.5 M in PhMe, 0.74 mL) dropwise at -15 °C. After 5 min the mixture was treated with THF-water (1:1, 6 mL) and stirred for 15 min while warming to rt. The mixture was extracted with EtOAc (3 x 10 mL) and the combined organic layers were washed with saturated Na2CO3 (aq.) and brine, dried (Na2SO4) and concentrated in vacuo. Silica gel chromatography with 75% EtOAc/hexanes yielded (+)-flustramide A 25.8 as a pink oil (28.4 mg, 95%). TLC Rf = 0.47 (EtOAc); [α]D +73.66 (76% ee, c 1.78, 1 EtOH); H NMR (400 MHz, CDCl3): δ 6.85 (m, 2H), 6.60 (br s, 1H), 5.18 (m, 1H), 166

4.95 (m, 1H), 4.72 (s, 1H), 3.96 (dd, J = 16.0, 6.3 Hz, 1H), 3.88 (dd, J = 15.9, 7.1 Hz, 1H), 2.87 (s, 3H), 2.64 (s, 2H), 2.40-2.27 (m, 2H), 1.75 (d, J = 1.4 Hz, 3H), 1.73 (s, 3H),

1.69 (s, 3H), 1.55 (s, 3H) ppm; IR (thin film): νmax 2966, 2924, 1679, 1601, 1484, 1056 cm-1. Spectral data is in agreement with literature data.30

(+)-flustramine B

To a solution of (+)-flustramide B (25 mg, 0.062 mmol) in THF (5 mL) was added

AlH3∙EtNMe2 complex (0.5 M in PhMe, 0.25 mL) dropwise at rt. After 5 min the mixture was treated with THF-water (1:1, 10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with saturated Na2CO3 (aq.) and brine, dried (Na2SO4) and concentrated in vacuo. Silica gel chromatography with 60%

EtOAc/hexanes yielded (+)-flustramine B as a yellow oil (13.0 mg, 54%). TLC Rf = 24.3 1 0.22 (60% EtOAc/hexanes); [α]D +74.19 (76% ee, c 1.5, EtOH); H NMR (500 MHz,

CDCl3): δ 6.80 (d, J = 7.8 Hz, 1H), 6.73 (dd, J = 7.8, 1.7 Hz, 1H), 6.49 (d, J = 1.7 Hz, 1H), 5.12 (m, 1H), 4.92 (m, 1H), 4.28 (s, 1H), 3.88 (dd, J = 16.1, 5.6 Hz, 1H), 3.79 (dd, J = 16.1, 7.3 Hz, 1H), 2.67 (m, 1H), 2.55 (m, 1H), 2.47 (s, 3H), 2.38 (d, J = 7.6 Hz, 2H), 2.03 (m, 1H), 1.86 (m, 1H), 1.71 (app d, 6H), 1.65 (s, 3H), 1.57 (s, 3H) ppm; IR (thin -1 film): νmax 2961, 2925, 2790, 1599, 1485, 915 cm . Spectral data is in agreement with literature data.30

167

3.6.6 Optimized procedures for the asymmetric linalylation, geranylation and nerylation of 2-(1-allyl-6-bromo-2-oxoindolin-3-yl)acetonitrile

2-(1-allyl-6-bromo-3-(3,7-dimethylocta-1,6-dien-3-yl)-2-oxoindolin-3-yl)acetonitrile

A flame-dried vial containing 2-(1-allyl-6-bromo-2-oxoindolin-3-yl)acetonitrile (10 mg, 0.034 mmol), (Cp)Pd(allyl) (0.4 mg, 1.7 umol, 0.05 equiv), (R,R)-L2 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in degassed (freeze-pump-thaw) anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 10-15 min, and to the resulting orange solution was added (Z)-3,7-dimethylocta-2,6-dienyl 2,2,2-trichloroethyl carbonate (16.8 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at 40 °C for 36 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the linalyl and neryl products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 13.4 mg (92% linalyl product isolated from a 13:1 linalyl:neryl mixture, 91% ee) of the linalyl product as a colorless oil. TLC Rf = 0.47 (20% 25.2 EtOAc/hexanes); [α]D 29.2 (optical rotation run on 75% ee material from (R,R)-L2, 1 c 0.35, EtOH); H NMR (400 MHz, CDCl3): δ 7.22 (dd, J = 8.0, 2.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 5.79 (m, 2H), 5.39 (d, 11 Hz, 1H), 5.22-5.33 (m, 1H), 5.14 (d, J = 18 Hz, 1H), 4.86 (m, 1H), 4.43 (m, 1H), 4.28 (m, 1H), 3.04 (d, J = 16 Hz, 1H), 2.85 (d, J = 16 Hz, 1H), 1.77 (m, 1H), 1.58-1.68 (m, 4H), 1.47 (s, 3H), 13 1.19-1.32 (m, 4H), 1.13 (m, 1H) ppm; C NMR (100 MHz, CDCl3): δ 176.1, 145.2, 140.7, 132.1, 130.5, 126.9, 125.5, 123.9, 123.2, 118.4, 118.2, 116.7, 113.1, 55.4, 45.6,

42.8, 35.3, 25.9, 23.0, 21.9, 17.9, 15.3 ppm; IR (thin film): νmax 3085, 2971, 2919, 2852, -1 2248, 1713, 1599, 1485, 1434, 1364, 1336, 1183, 1116, 1064, 925 cm ; HPLC Rt = 8.9 168

(major) and 23.6 min (Chiralcel® ODH chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH]+ calcd for

C23H28BrN2O 427.1380, found 420.1378.

Key chemical shifts for assignment of branched regioselectivity based on chemical shift and COSY analysis: 1H NMR shows the presence of two terminal olefins with a characteristic splitting pattern, where the linear product would only possess only one such terminal olefin. A single internal double bond proton is observed at 4.8 ppm, whereas the linear isomer would have two such protons. With respect to the chemical shifts of the three methyl groups: two exist at 1.6 and 1.47 ppm (putatively assigned as allylic methyl group) and the other methyl is at 1.2 ppm.

Proton NMR chemical shift for linalylated product. 5.2-5.4 ppm 1.2 ppm H 5.8 ppm Me H H NC Me Me

H 4.8 ppm O N Br H 4.3 & 4.4 ppm H 5.8 ppm H H 5.2-5.4 ppm

(E)-2-(1-allyl-6-bromo-3-(3,7-dimethylocta-2,6-dienyl)-2-oxoindolin-3-yl)acetonitrile

169

A flame-dried vial containing 2-(1-allyl-6-bromo-2-oxoindolin-3-yl)acetonitrile (10 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol, 0.025 equiv), (S,S)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous THF (200 uL), the reaction was stirred at room temperature for 10 min, and to the resulting orange solution was added (E)-tert-butyl (3,7-dimethylocta-2,6-dien-1-yl) carbonate (13.0 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at 60 °C for 48 h and concentrated. NMR analysis of the crude reaction mixture showed exclusive formation of the geranylated product with no linalylated or nerylated byproducts observed. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 11.5 mg (79%, 86% ee) of the desired 24.8 product as a colorless oil. TLC Rf = 0.41 (20% EtOAc/hexanes); [α]D -5.7 (86% ee, 1 c 1.15, EtOH); H NMR (300 MHz, CDCl3): δ 7.29 (d, J = 8 Hz, 1H), 7.25 (dd, J = 8, 2 Hz, 1H), 6.99 (d, J = 2 Hz, 1H), 5.77 (m, 1H), 5.25 (d, J = 8 Hz, 1H), 5.20 (d, J = 13 Hz, 1H), 4.94 (s, 1H), 4.77 (t, J = 8 Hz, 1H), 4.39 (dd, J = 17, 6 Hz, 1H), 4.22 (dd, J = 17, 6 Hz, 1H), 2.88 (d, J = 18 Hz, 1H), 2.65 (m, 3H), 2.00 (s, 3H), 1.89 (m, 4H), 1.68 13 (s, 3H), 1.57 (s, 3H); C NMR (125 MHz, CDCl3): δ 176.7, 144.2, 141.4, 132.0, 130.5, 128.3, 126.0, 125.0, 124.0, 123.0, 118.2, 116.6, 115.9, 113.1, 49.3, 42.7, 40.0, 35.0,

26.6, 25.9, 24.9, 17.9, 16.6 ppm; IR (thin film): νmax 2966, 2919, 2852, 2248, 1721, -1 1604, 1488, 1434, 1372, 1338, 1114, 1064, 928, 809 cm ; HPLC Rt = 24.7 and 27.5 (major) min (Chiralcel® ODH chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH]+ calcd for

C23H28BrN2O 427.1380, found 420.1378.

(Z)-2-(1-allyl-6-bromo-3-(3,7-dimethylocta-2,6-dienyl)-2-oxoindolin-3-yl)acetonitrile

170

A flame-dried vial containing 2-(1-allyl-6-bromo-2-oxoindolin-3-yl)acetonitrile (10 mg, 0.034 mmol), (Cp)Pd(allyl) (0.4 mg, 1.7 umol, 0.05 equiv) and (R,R)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous 1,4-dioxane (200 uL), stirred at room temperature for 10-15 min, and to the resulting orange solution was added (Z)-3,7-dimethylocta- 2,6-dienyl 2,2,2-trichloroethyl carbonate (16.8 mg, 0.51 mmol, 1.5 equiv). The reaction was stirred at 40 °C for 36 h and concentrated. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 3.9 mg (41% neryl product isolated from a 7.6:1:11.3 linalyl:geranyl:neryl mixture, 94% 1 ee) of the desired product as a colorless oil. TLC Rf = 0.38 (20% EtOAc/hexanes); H

NMR (400 MHz, CDCl3): δ 7.30 (d, J = 8.5 Hz, 1H), 7.25 (m, 1H), 6.99 (d, J = 1.6 Hz, 1H), 5.77 (m, 1H), 5.39 (d, 11 Hz, 1H), 5.23 (d, J = 11 Hz, 1H), 5.18 (d, J = 17 Hz, 1H), 5.14 (d, J = 17 Hz, 1H), 5.04 (m, 1H), 4.71 (m, 1H), 4.45 (m, 1H), 4.18 (m, 1H), 2.87 (d, J = 17 Hz, 1H), 2.65 (m, 3H), 1.95 (m, 4H), 1.68 (s, 3H), 1.59 (s, 3H), 1.56 (s, 3H) 13 ppm; C NMR (125 MHz, CDCl3): δ 176.6, 144.2, 141.5, 132.3, 130.5, 128.3, 126.1, 125.0, 124.0, 123.0, 118.0, 116.6, 116.5, 113.2, 49.3, 42.7, 34.8, 32.2, 26.6, 26.0, 25.2,

23.7, 18.0 ppm; IR (thin film): νmax 2921, 2248, 1720, 1604, 1487, 1433, 1373, 1338, -1 24.8 1114, 1063 cm ; [α]D +12.50 (85% ee, c 0.89, EtOH); HPLC Rt = 12.6 and 19.6 (major) min (Chiralcel® ODH chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH]+ calcd for

C23H28BrN2O 427.1380, found 420.1378.

171

3.6.7 Determination of the relative stereochemistry of 2-(1-allyl-6-bromo-3-(3,7- dimethylocta-1,6-dien-3-yl)-2-oxoindolin-3-yl)acetonitrile

6-bromo-1-(2-hydroxyethyl)-5'-(3-hydroxypropyl)-5'-methyl-5',6'- dihydrospiro[indoline-3,4'-pyran]-2,2'(3'H)-dione

Ozone was bubbled through a solution of 2-(1-allyl-6-bromo-3-(3,7-dimethylocta-1,6- dien-3-yl)-2-oxoindolin-3-yl)acetonitrile (115 mg, 0.269 mmol) in CH2Cl2 (10 mL) at -

78 °C until a persistent green color was observed. Upon warming to rt PPh3 (282 mg, 1.076 mmol) was added. After stirring at rt for 12 h the residue was redissolved in methanol (10 mL) and CH2Cl2 (1 mL) and cooled to 0 °C. Sodium borohydride (40.7 mg, 1.076 mmol) was added, and after 30 min the reaction was diluted with water and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, loaded on SiO2 and eluted with 10%

MeOH/CHCl3 to afford the crude triol (TLC Rf = 0.32 (10% MeOH/CHCl3)) as a yellow oil (30 mg, 34%). A sample of this oil (11 mg, 0.027 mmol) was dissolved in 10% HCl (0.1 mL) and stirred at 100 °C for 6 h. The reaction was diluted with water (1 mL) and extracted with EtOAc (3 x 2 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative TLC

(Rf = 0.48 (3% MeOH/EtOAc)) to afford the title compound as a colorless oil (11 mg, 1 quantitative). H NMR (500 MHz, CDCl3): δ 7.23 (dd, J = 8.0, 2.0 Hz, 1H), 7.17 (d, J 172

= 8.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 4.61 (d, J = 12 Hz, 1H), 4.26 (d, J = 12 Hz, 1H), 4.08-4.02 (m, 3H), 3.90 (m, 2H), 3.69-3.61 (m, 2H), 3.52 (m, 1H), 2.95 (d, J = 19 Hz, 1H), 2.68 (d, J = 19 Hz, 1H), 1.52 (m, 2H), 1.40 (m, 2H), 1.03 (s, 3H) ppm. 13C

NMR (125 MHz, CDCl3): δ 178.3, 168.8, 145.2, 131.2, 126.3, 125.9, 123.2, 112.9, 72.9,

62.8, 60.4, 52.5, 43.3, 37.5, 34.5, 29.4, 26.7, 16.5 ppm; IR (thin film): νmax 3390, 2925, 1725, 1601, 1467, 1377, 1286, 1123, 1071 cm-1. HRMS (ES) m/z [MNa]+ calcd for

C18H22BrNO5 434.0579, found 434.0576.

Assignment of relative stereochemistry based on nOe data

3.0% HO 2.1% Me H H O O HO N H H O 1.9% H 0.9%

3.7 References

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177

4 Pd-catalyzed asymmetric prenylation of 3-aryloxindoles

4.1 Introduction Following our success in the asymmetric prenylation of 3-alkyloxindoles, we decided to investigate whether regiocontrol and enantiocontrol could also be achieved with 3-aryloxindoles as nucleophiles. Excellent results with this class of nucleophiles have previously been achieved by our group in the Pd-catalyzed asymmetric alkylation,1 the Mo-catalyzed enantio- and diastereoselective allylation with cinnamyl and related carbonates,2 the Pd-catalyzed enantio- and diastereoselective allylation with benzyloxyallenes,3 the Pd-catalyzed asymmetric benzylation,4 and the Pd-catalyzed asymmetric allylation with allylidene dipivalate.5

4.2 Optimization of the asymmetric prenylation of 3-aryloxindoles Table 4.1: Ligand screen for the asymmetric reverse prenylation of oxindole 4.2.1

178

Figure 4.1: Chiral ligands used in Tables 4.1 and 4.4

Optimization of the reaction conditions to favour the branched product 4.2.2 was conducted on oxindole substrate 4.2.1. A ligand screen (Table 4.1) revealed that L1, L2 and L3 (Figure 4.1, entries 1, 2 and 3) all gave the branched product with about the same enantioselectivity (53-54% ee). Among these, L1 (entry 1) was superior in terms of regioselectivity (3.8:1 4.2.2 : 4.2.3), and thus was selected for further optimization. A

12:1 regioselectivity in favour of the branched product was observed with L4 (entry 4) – the larger bite angle conferred by the anthracene-derived backbone increases the steric 179 demands of the ligand, thus driving the reaction toward formation of a Pd complex with the monosubstituted olefin of the branched product vs. the trisubstituted olefin of the linear product. However, the enantioselectivity of the reaction with L4 was very poor (12% ee). Other ligands examined (entries 5 through 9) gave generally poor enantioselectivities for oxindole 4.2.2. Reactions with ligands where one phosphine was replaced with a σ-donor ligand (entries 6 and 8) gave especially poor regioselectivities – the reduced π-acceptor capability of such ligands has been shown to decrease the electrophilicity of the π-prenylpalladium complex as a whole as well as that of the tertiary carbon in particular, resulting in a greater tendency for nucleophiles to attack at the kinetically favoured primary carbon.6

Table 4.2: Influence of solvent and halide on the reverse prenylation of oxindole 4.2.1

The influence of solvent and additives on the reverse prenylation was next examined (Table 4.2). The addition of 30 mol % tetrabutylammonium difluorotriphenylsilicate (TBAT) (entry 1) improved both the regioselectivity (from 2.8:1 to 3.8:1) and enantioselectivity (from 43% to 54% ee) of the reaction. The

180 presence of TBAT provides a fluoride anion that helps stabilize a σ-prenylpalladium complex,7,8 thus increasing the rate by which it undergoes π-σ-π equilibration to the more stable diastereomer, resulting in increased enantioselectivity of the alkylation. Screening a variety of more polar solvents (entries 3 through 8) generally resulted in further improvement of the regioselectivity in favour of the branched product, but in these solvents the enantioselectivity could not be increased beyond 56% ee. However, it was found that in acetonitrile (entry 6), the branched product 4.2.2 could be delivered with uniquely high enantioselectivity (82% ee) while maintaining very good levels of regioselectivity (4.2.2 : 4.2.3 = 10.2:1). Again, the increased regioselectivity for the branched product in polar solvents is attributed to the better stabilization of the charged intermediates generated during the reaction, which disfavours the kinetically controlled nucleophilic attack at the primary position leading to the linear product.

181

Table 4.3: Further optimization of the asymmetric reverse prenylation of oxindole 4.2.1

Finally, the other reaction parameters were also varied to see whether the regio- and enantioselectivity of the transformation could be further improved (Table 4.3). Neither changing the palladium precatalyst to Pd(Cp)(allyl) (entry 2), nor diluting the reaction from 0.17 M to 0.068 M (entry 3), nor lowering the ligand loading from 7.5 mol % to 6 mol % (entry 4) resulted in any significant change to the reaction outcome. Keeping the lower ligand loading while dropping the TBAT loading to 10 mol % and running the reaction at lower temperatures (0–4 °C, entry 5) led to an increase in enantioselectivity; the branched product was formed in 90% yield with 9.0:1 regioselectivity and 87% ee. At lower temperatures the rate of the intermolecular

182 nucleophilic attack is slower relative to intramolecular π-σ-π equilibration, resulting in higher enantioselectivities. Lowering the palladium and ligand loading still further (2 and 2.2 mol % respectively, entry 6) resulted in decreased regioselectivity. Since further dilution of the reaction had been found not to be beneficial (entry 3), increasing the reaction concentration to 0.5 M (entry 7) was attempted, but this resulted in decreased enantioselectivity. Thus the optimized conditions of entry 5 were used in subsequent experiments.

Table 4.4: Ligand and solvent screen for the asymmetric linear prenylation of oxindole 4.2.1

With optimized conditions for the formation of branched product 4.2.2 in hand, efforts turned toward optimization of the reaction conditions to favour linear product 183

4.2.3 (Table 4.4). As in the case of the 3-alkyloxindoles, obtaining good regioselectivity for the linear product proved surprisingly challenging. Of the ligands examined, L1 (Fig. 4, entry 1) gave the best regioselectivity for 4.2.3 (4.2.2 : 4.2.3 = 1:2.7) when the reaction was performed in THF. The enantioselectivity was not as good with this ligand

(82% ee) as it was with L2 (entry 2, 89% ee) or L3 (entry 3, 91% ee) but the regioselectivity was significantly poorer with the latter two ligands. When the reaction was conducted in THF with other ligands (entries 4 and 5) the regioselectivity still favoured the branched product. We elected to move forward with L1 as the ligand that gave the best regioselectivity as well as good enantioselectivity. A variety of ethereal and aromatic solvents were then screened (entries 6–11), since these had been found to be effective at enhancing linear regioselectivity in the prenylation of 3-alkyloxindoles, but in all cases the observed regioselectivities and enantioselectivities were poorer than in THF.

Table 4.5: Optimization of reaction parameters for the asymmetric linear prenylation of oxindole 4.2.1

184

To further improve the regio- and enantioselectivity of the linear prenylation, the other reaction parameters were also varied (Table 4.5). The sensitivity of the Pd- catalyzed allylic alkylation to halide additives was vividly demonstrated by entry 4, in which the addition of 10 mol% TBAT completely reversed the regioselectivity in favour of the branched product. Dilution of the reaction mixture from 0.17 M to 0.0425 M (entry 5) led to a significant drop in enantioselectivity. However, decreasing the palladium loading from 5 to 2 mol % (entry 2) resulted in improved regio- and enantioselectivity, while running the reaction at 0–4 °C also improved the enantioselectivity from 82 to 85% ee. When these two modifications were made simultaneously (entry 6) the linear product 4.2.3 was delivered in 76% yield and a very satisfactory 95% ee, and with 3.1:1 regioselectivity over the branched product 4.2.2. The conditions of entry 6 were therefore adopted for subsequent experiments.

185

4.3 Substrate scope of the reverse and linear prenylation of 3-aryloxindoles Scheme 4.1: Substrate scope of the reverse prenylation of 3-aryloxindoles

With optimized conditions in hand, the scope of the reverse prenylation of 3- aryloxindoles was examined (Scheme 4.1). An unprotected N-H oxindole substrate only afforded oxindole 4.3.1 in 40% ee and 3.2:1 regioselectivity, continuing a pattern of low reactivity, regioselectivity and enantioselectivity also observed with unprotected 3-

186 alkyloxindole substrates. However, N-protected oxindoles 4.2.2, 4.3.4 and 4.3.5 were obtained with regioselectivities better than 9.0:1 and very good enantioselectivity (87 to 88% ee). Aryl groups bearing electron-donating or electron-withdrawing substituents at the meta and para positions were tolerated: the 2-naphthyl oxindole 4.3.3 was produced in 13:1 regioselectivity and 86% ee, and para-methoxyphenyl oxindole 4.3.6 was produced in 5.2:1 regioselectivity and 80% ee, while para-trifluoromethyl oxindole 4.3.7 was produced in 8.7:1 regioselectivity and 80% ee. However, ortho substitution was detrimental to the regioselectivity of the reaction, likely due to the greater steric demands this places on the reaction. Thus even under the conditions optimized for the reverse prenylation, a (2-tolyl)-substituted oxindole was preferentially linear-prenylated in a 1:3.1 ratio of 4.3.8 to 4.3.18. The enantiomers of product 4.3.8 could not be separated by HPLC. 3-Heteroaryloxindole substrates were also examined but gave poor regioselectivities: a 2-(3,5-dimethyl)thiazolyl oxindole gave a 1:1 mixture of branched product 4.3.10 and 4.3.20 under these reaction conditions, although the former was formed in an excellent 93% ee. Likewise, prenylation of the 3-indolyl oxindole also suffers from a lack of regioselectivity for branched product 4.3.9; the enantioselectivity for this product was also relatively low (78% ee). The poor regioselectivity for these substrates may be attributed to the presence of a substituent on the heteroarene at an ortho position relative to the oxindole, which again may have biased the substrate in favour of nucleophilic attack at the less hindered primary position of the prenylpalladium complex.

187

Scheme 4.2: Substrate scope of the linear prenylation of 3-aryloxindoles

As in the case with the reverse prenylation, protection of the oxindole nitrogen is critical for achieving optimal results in the linear prenylation (Scheme 4.2). The linear- prenylated product of the unprotected oxindole (3.7.11) could only be produced in 71% ee, whereas ee’s of 95% or greater were achieved with the protected oxindoles (3.6.3, 3.7.14, 3.7.15). Again both electron-donating and electron-withdrawing groups on the

188 aromatic ring are tolerated (3.7.13, 3.7.16, 3.7.17). However, in contrast with reverse prenylation, ortho substitution on the aromatic ring is tolerated – indeed, its presence improved the regioselectivity for the linear product (e.g. complete regioselectivity in the case of 3.7.18), which was otherwise generally moderate at best. Enantioselectivities for the linear products were generally excellent and superior to those obtained in the reverse prenylation of the same substrates, continuing a reactivity pattern also observed in the prenylation of 3-alkyloxindoles.

4.4 Conclusion A comprehensive examination of all the reaction parameters involved in the Pd- catalyzed prenylation of 3-aryloxindoles has clarified the effects of each parameter on the regiochemical outcome of the reaction. The formation of branched products arising from nucleophilic attack at the more substituted carbon is favoured by the use of sterically demanding ligands, polar solvents, and the presence of halide additives. The formation of linear products arising from nucleophilic attack at the less substituted carbon is favoured by the use of less sterically demanding ligands with poorer π- acceptor ability, less polar solvents, and more sterically demanding nucleophiles. The lessons learned from these optimization studies have been applied to the development of optimized methods for the regioselective, asymmetric reverse and linear prenylation of N-protected 3-aryloxindoles. Very good regioselectivities and enantioselectivities were achieved for the reverse prenylation, while excellent enantioselectivities were obtained from the linear prenylation even though regioselectivities in this case were more modest. It was surprising that N-unprotected 3- aryloxindoles performed poorly in the present transformation, even though they have previously been shown to be superior substrates in other asymmetric alkylation reactions developed by our group.4 However, this behaviour was consistent with the similarly disappointing results observed with N-unprotected 3-alkyloxindoles. Highly hindered oxindole nucleophiles bearing ortho substitution on the 3-aryl or 3-heteroaryl group displayed a strong bias for prenylation at the less hindered carbon, which could only be partially overcome by use of the branched-selective reaction conditions.

189

4.5 Experimental

4.5.1 General methods All reagents were obtained commercially unless otherwise noted. Reactions were performed using glassware that was flame-dried under vacuum (~1 Torr). All reactions were performed under an atmosphere of nitrogen. Pd2dba3•CHCl3 was prepared according to a literature procedure.9 Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Organic solutions were concentrated under reduced pressure (~15 Torr) by rotary evaporation. Solvents were purified by passage under 12 psi N2 through activated alumina columns. Chromatography was performed on Silicycle Silia-P Silica Gel (40-63 m). Compounds purified by chromatography were typically applied to the adsorbent bed using the indicated solvent conditions with a minimum amount of added chloroform as needed for solubility. Chiral HPLC analyses were performed on a Thermo Separation Products Spectra Series P-100 or P-200 and UV100 (254 nm or 220 nm) using Chiralcel® columns (OB-H, OC, OD-H, OJ-H), or Chiralpak® column (AD, AS, IA, IB,

IC) eluting with the solvent mixtures indicated. Retention times (Rt) are reported in minutes (min). Thin layer chromatography was performed on EMD Chemicals Silica

Gel 60 F254 plates (250 m). Visualization of the developed chromatogram was accomplished by fluorescence quenching or by staining with p-anisaldehyde or aqueous potassium permanganate. Nuclear magnetic resonance (NMR) spectra were acquired on either a Varian Inova-600, a Varian Inova-500, a Varian Mercury-400, or a Gemini-300 operating at 600, 500, 400, or 300 MHz for 1H and 150, 125, 100, or 75 MHz for 13C, respectively, and are referenced internally according to residual solvent signals. Data for 1H NMR are recorded as follows: chemical shift (, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; m, multiplet), integration, coupling constant (Hz). Data for 13C NMR are reported in terms of chemical shift (, ppm). Melting points were obtained on a Thomas-Hoover apparatus in open capillary tubes and are uncorrected. Infrared spectra were recorded on either a Thermo-Nicolet IR100 or a Thermo-Nicolet IR300 spectrometer as thin films using NaCl salt plates or as KBr 190 pellets and are reported in frequency of absorption. Optical rotations were determined using a JASCO DIP-1000 digital polarimeter. The sodium D line (589 nm) and a 50 mm path length were used exclusively, but differences in temperature, solvent, and concentration are indicated. High-resolution mass spectra were obtained from the Vincent Coates Foundation Mass Spectrometry Laboratory at Stanford University (http://mass-spec.stanford.edu) using a Micromass Q-Tof API-US mass spectrometer (Waters Corporation, Milford, MA).

4.5.2 Prenylation and reverse prenylation of 3-aryloxindoles All 3-aryloxindole substrates were prepared in accordance with previously published procedures.1,2,4

General procedure A for the asymmetric reverse prenylation of 3-aryloxindoles:

A flame-dried vial containing 3-aryloxindole (0.034 mmol), Pd2dba3•CHCl3 (0.9 mg,

0.85 μmol, 0.025 equiv), (R,R)-L2 (1.8 mg, 2.0 μmol, 0.06 equiv), and TBAT (2.0 mg, 3.4 μmol, 0.1 equiv) was evacuated and purged three times with nitrogen. Anhydrous acetonitrile (200 μL) was added and the reaction was stirred at room temperature for 15 min, then cooled to 0 °C. To the resulting straw-coloured solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (7.6 μL, 0.037 mmol, 1.1 equiv). The reaction was stirred at 4 °C for 16 h and concentrated under reduced pressure. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 10% EtOAc/hexanes afforded the reverse-prenylated product which was distinguishable from the linear regioisomer by its higher Rf.

General procedure B for the asymmetric linear prenylation of 3-aryloxindoles: A flame-dried vial containing 3-aryloxindole (0.034 mmol), Pd2dba3•CHCl3 (0.4 mg, 0.34

μmol, 0.01 equiv) and (R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv) was evacuated and purged three times with nitrogen. Anhydrous tetrahydrofuran (200 μL) was added and the reaction was stirred at room temperature for 15 min, then cooled to 0 °C. To the resulting orange-coloured solution was added tert-butyl (2-methylbut-3-en-2-yl)

191 carbonate (7.6 μL, 0.037 mmol, 1.1 equiv). The reaction was stirred at 4 °C for 16 h and concentrated under reduced pressure. NMR analysis of the crude reaction mixture gave the regioisomeric distribution between the branched and linear products. Preparative thin layer chromatography developing with 10% EtOAc/hexanes afforded the linear-prenylated product which was distinguishable from the branched regioisomer by its lower Rf.

3-(4-fluorophenyl)-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one

WHC-VIII-38: Following general procedure A (using 8.2 mg (0.034 mmol) of 3-(4- fluorophenyl)-1-methylindolin-2-one, Pd2dba3•CHCl3 (0.9 mg, 0.85 μmol, 0.025 equiv), (R,R)-L2 (1.8 mg, 2.0 μmol, 0.06 equiv), and TBAT (2.0 mg, 3.4 μmol, 0.1 equiv)), isolated 9.4 mg (90% yield from a 9.0:1 mixture of branched and linear isomers, 25.4 87% ee) of the title compound as a colourless oil. [α]D 64.87 (87% ee, c 0.94, 1 CH2Cl2); H NMR (500 MHz, CDCl3): 7.89 (m, 2H), 7.72 (d, J = 7.5 Hz, 1H), 7.31 (m, 1H), 7.10 (m, 1H), 6.96 (m, 2H), 6.83 (d, J = 7.5 Hz, 1H), 5.95 (dd, J = 18, 11 Hz, 1H), 5.06 (d, J = 11 Hz, 1H), 4.86 (d, J = 17 Hz, 1H), 3.21 (s, 3H), 1.21 (s, 3H), 0.97 (s, 3H) 13 ppm; C NMR (125 MHz, CDCl3): 176.9, 162.1 (d, J = 245 Hz), 144.0, 131.5, 130.5, 128.3, 127.9, 121.7, 114.4 (d, 20 Hz), 114.0, 108.3, 60.77, 43.99, 26.38, 23.72, 22.59 ppm; IR (thin film): νmax 3083, 2970, 1703, 1610, 1471, 1375, 1351, 1234, 1167, 1088 -1 cm ; HPLC Rt = 5.84 (major) and 7.10 min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z + [MH] calcd for C20H21FNO 310.1629, found 310.1627.

192

3-(4-fluorophenyl)-1-methyl-3-(3-methylbut-2-en-1-yl)indolin-2-one

WHC-VIII-50: Following general procedure B (using 8.2 mg (0.034 mmol) of 3-(4- fluorophenyl)-1-methylindolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol, 0.01 equiv) and (R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 8.0 mg (76% yield from a 1:3.1 mixture of branched and linear isomers, 95% ee) of the title compound as a colourless 25.4 1 oil. [α]D -125.79 (95% ee, c 0.72, CH2Cl2); H NMR (500 MHz, CDCl3): 7.37 (m, 2H), 7.33 (m, 1H), 7.23 (d, J = 7 Hz, 1H), 7.10 (m, 1H), 6.98 (m, 2H), 6.89 (d, J = 7 Hz, 1H), 4.77 (app t, J = 8 Hz, 1H), 3.20 (s, 3H), 2.92 (d, J = 8 Hz, 2H), 1.54 (s, 3H), 1.48 13 (s, 3H) ppm; C NMR (125 MHz, CDCl3): 178.56, 144.03, 135.91, 135.61 (d, J = 3 Hz), 133.86 (d, J = 435 Hz), 129.21, 129.15, 128.49, 125.32, 122.71, 117.95, 115.57,

115.40, 108.47, 56.09, 37.00, 26.64, 26.09, 18.40 ppm; IR (thin film): νmax 3055, 2927, -1 1714, 1612, 1508, 1494, 1470, 1373, 1346, 1232, 1163, 1088 cm ; HPLC Rt = 9.81 (major) and 15.00 min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH]+ calcd for

C20H21FNO 310.1629, found 310.1631.

3-(4-fluorophenyl)-3-(2-methylbut-3-en-2-yl)indolin-2-one

WHC-VIII-66: Following general procedure A (using 7.7 mg (0.034 mmol) of 3-(4- fluorophenyl)indolin-2-one, Pd2dba3•CHCl3 (0.9 mg, 0.85 μmol, 0.025 equiv), (R,R)-L2 (1.8 mg, 2.0 μmol, 0.06 equiv), and TBAT (2.0 mg, 3.4 μmol, 0.1 equiv)), isolated 5.8 mg (48% yield from a 3.2:1 mixture of branched and linear isomers, 40% ee) of the title 23.7 1 compound as a colourless oil. [α]D 26.24 (40% ee, c 0.51, CH2Cl2); H NMR (500

MHz, CDCl3): 7.87 (m, 2H), 7.69 (d, J = 7.5 Hz, 1H), 7.24 (m, 1H), 7.07 (m, 1H), 6.97 193

(m, 1H), 6.87 (d, J = 7.5 Hz, 1H), 5.98 (dd, J = 18, 11 Hz, 1H), 5.08 (d, J = 11 Hz, 1H), 13 4.88 (d, J = 18 Hz, 1H), 1.22 (s, 3H), 1.04 (s, 3H) ppm; C NMR (125 MHz, CDCl3): 179.0, 162.1 (d, J = 245 Hz), 143.8, 141.0, 131.5, 131.4, 131.1, 128.3, 121.7, 114.5 (d,

J = 21 Hz), 114.1, 109.8, 61.17, 43.82, 23.67, 22.63 ppm; IR (thin film): νmax 3207, -1 3084, 2971, 1699, 1619, 1508, 1474, 1413, 1327, 1236, 1167, 834 cm ; HPLC Rt = 13.59 (major) and 28.77 min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH]+ calcd for C19H19FNO 296.1472, found 265.1471.

3-(4-fluorophenyl)-3-(3-methylbut-2-en-1-yl)indolin-2-one

WHC-VIII-67: Following general procedure B (using 7.7 mg (0.034 mmol) of 3-(4- fluorophenyl)indolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol, 0.01 equiv) and (R,R)-

L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 6.6 mg (61% yield from a 1:1.6 mixture 25 of branched and linear isomers, 71% ee) of the title compound as a colourless oil. [α]D 1 -101.64 (71% ee, c 0.59, CH2Cl2); H NMR (500 MHz, CDCl3): 8.40 (s, 1H), 7.36 (m, 2H), 7.25 (m, 1H), 7.18 (d, J = 8 Hz, 1H), 7.06 (m, 1H), 6.99 (m, 2H), 6.94 (d, J = 8 Hz, 1H), 4.83 (m, 1H), 3.00 (dd, J = 15, 8 Hz), 2.91 (dd, J = 15, 8 Hz), 1.54 (s, 3H), 1.51 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): 180.71, 162.17 (d, J = 245 Hz), 140.96, 135.99, 135.42, 132.67, 128.99 (d, J = 8 Hz), 128.33, 125.41, 122.62, 117.64, 115.46 (d, J = 21

Hz), 110.09, 56.49, 36.52, 25.99, 18.27 ppm; IR (thin film): νmax 3245, 2969, 2917, -1 1710, 1619, 1508, 1472, 1233 cm ; HPLC Rt = 9.79 (major) and 14.25 min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 + mL/min); HRMS (ES) m/z [MH] calcd for C19H19FNO 296.1472, found 265.1469.

194

1-allyl-3-(4-fluorophenyl)-3-(2-methylbut-3-en-2-yl)indolin-2-one

WHC-VIII-75: Following general procedure A (using 9.1 mg (0.034 mmol) of 1-allyl-

3-(4-fluorophenyl)indolin-2-one, Pd2dba3•CHCl3 (0.9 mg, 0.85 μmol, 0.025 equiv),

(R,R)-L2 (1.8 mg, 2.0 μmol, 0.06 equiv), and TBAT (2.0 mg, 3.4 μmol, 0.1 equiv)), isolated 8.6 mg (75% yield from a 11:1 mixture of branched and linear isomers, 88% 24.1 1 ee) of the title compound as a colourless oil. [α]D 57.83 (87% ee, c 0.86, CH2Cl2); H NMR (500 MHz, CDCl3): 7.89 (m, 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.27 (m, 1H), 7.08 (m, 1H), 6.97 (m, 1H), 6.82 (d, J = 7.5 Hz, 1H), 5.96 (dd, J = 18, 11 Hz, 1H), 5.79 (m, 1H), 5.17 (m, 1H), 5.15 (d, J = 11 Hz, 1H), 5.07 (d, J = 11 Hz, 1H), 4.87 (d, J = 18 Hz, 1H), 4.45 (dd, J = 17, 2.2 Hz, 1H), 4.25 (dd, J = 17, 2.2 Hz, 1H), 1.22 (s, 3H), 1.01 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): 176.65, 162.07 (d, J = 246 Hz), 143.95, 143.12, 131.59, 131.51, 131.45, 130.50, 128.20, 121.66, 117.72, 114.42 (d, J = 21 Hz), 114.09,

109.19, 60.67, 43.92, 42.47, 23.75, 22.71 ppm; IR (thin film): νmax 3084, 2971, 1702, -1 1609, 1508, 1467, 1358 cm ; HPLC Rt = 8.67 (major) and 10.32 min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 99:1 heptane/i-PrOH, flow rate = 0.8 + mL/min); HRMS (ES) m/z [MH] calcd for C22H23FNO 336.1785, found 336.1780.

1-allyl-3-(4-fluorophenyl)-3-(3-methylbut-2-en-1-yl)indolin-2-one

WHC-VIII-76: Following general procedure B (using 9.1 mg (0.034 mmol) of 1-allyl-

3-(4-fluorophenyl)indolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol, 0.01 equiv) and

(R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 6.1 mg (53% yield from a 1:1.8 195 mixture of branched and linear isomers, 97% ee) of the title compound as a colourless 25.4 1 oil. [α]D -98.79 (97% ee, c 0.61, CH2Cl2); H NMR (500 MHz, CDCl3): 7.37 (m, 2H), 7.29 (m, 1H), 7.23 (d, J = 8 Hz, 1H), 7.09 (m, 1H), 6.99 (m, 2H), 6.86 (d, J = 8 Hz, 1H), 5.78 (m, 1H), 5.20-5.13 (m, 2H), 4.76 (app t, J = 8 Hz, 1H), 4.44 (m, 1H), 4.21 (m, 1H), 3.05 (dd, J = 14, 9 Hz), 2.88 (dd, J = 14, 9 Hz), 1.52 (s, 3H), 1.51 (s, 3H) ppm; 13C

NMR (125 MHz, CDCl3): 178.09, 162.13 (d, J = 245 Hz), 143.10, 135.78 (d, J = 3 Hz), 132.02, 131.41, 128.98, 128.95 (d, J = 8 Hz), 128.23, 125.11, 122.55, 117.88, 117.24, 115.40 (d, J = 21 Hz), 109.29, 56.07, 42.44, 36.92, 25.97, 18.25 ppm; IR (thin film): -1 νmax 2916, 1715, 1611, 1508, 1488, 1466, 1355 cm ; HPLC Rt = 10.13 (major) and 18.92 min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i- + PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH] calcd for C22H23FNO 336.1785, found 336.1785.

3-(4-fluorophenyl)-1-(4-methoxybenzyl)-3-(2-methylbut-3-en-2-yl)indolin-2-one

WHC-VIII-97: Following general procedure A (using 11.8 mg (0.034 mmol) of 3-(4- fluorophenyl)-1-(4-methoxybenzyl)-indolin-2-one, Pd2dba3•CHCl3 (0.9 mg, 0.85 μmol,

0.025 equiv), (R,R)-L2 (1.8 mg, 2.0 μmol, 0.06 equiv), and TBAT (2.0 mg, 3.4 μmol, 0.1 equiv)), isolated 8.9 mg (63% yield from a 16:1 mixture of branched and linear 23.5 isomers, 87% ee) of the title compound as a colourless oil. [α]D 3.73 (87% ee, c 0.84, 1 CH2Cl2); H NMR (500 MHz, CDCl3): 7.91 (m, 2H), 7.72 (d, J = 8 Hz, 1H), 7.21-7.17 (m, 3H), 7.05 (m, 1H), 6.98 (m, 2H), 6.76 (d, J = 8 Hz, 1H), 5.97 (dd, J = 18, 11 Hz), 5.07 (dd, J = 11, 1.0 Hz), 4.94 (d, J = 16 Hz, 1H), 4.88 (dd, J = 18, 1.0 Hz), 4.77 (d, J = 16 Hz, 1H), 3.75 (s, 3H), 1.24 (s, 3H), 1.02 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): 176.90, 161.95 (d, J = 246 Hz), 159.07, 143.88, 143.05, 131.42, 131.36, 130.44, 128.77, 128.08, 127.82, 121.55, 114.31 (d, J = 21 Hz), 114.19, 113.96, 109.20, 60.58, 55.36,

43.85, 43.29, 23.74, 22.63 ppm; IR (thin film): νmax 2933, 1699, 1609, 1511, 1466, 1249

196

-1 cm ; HPLC Rt = 10.53 and 11.84 (major) min (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: 98:2 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z + [MH] calcd for C27H27FNO2 416.5184, found 416.5185.

3-(4-fluorophenyl)-1-(4-methoxybenzyl)-3-(3-methylbut-2-en-1-yl)indolin-2-one

WHC-IX-01: Following general procedure B (using 11.8 mg (0.034 mmol) of 3-(4- fluorophenyl)-1-(4-methoxybenzyl)indolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol,

0.01 equiv) and (R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 9.1 mg (64% yield from a 1:2.3 mixture of branched and linear isomers, 99% ee) of the title compound as 25 1 a colourless oil. [α]D -36.26 (99% ee, c 0.85, CH2Cl2); H NMR 7.38 (m, 2H), 7.24- 7.16 (m, 4H), 7.06 (m, 1H), 7.00 (m, 2H), 6.82 (m, 2H), 6.76(d, J = 8 Hz, 1H), 5.02 (d, J = 16 Hz, 1H), 4.76 (app t, J = 8 Hz, 1H), 4.65 (d, J = 16 Hz, 1H), 3.77 (s, 3H), 3.12 (dd, J = 14, 8 Hz, 1H), 2.90 (dd, J = 14, 8 Hz, 1H), 1.55 (s, 3H), 1.54 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): 178.42, 162.14 (d, J = 245 Hz), 159.06, 143.10, 135.99, 132.06, 128.97, 128.91, 128.66, 128.24, 128.04, 125.04, 122.56, 117.96, 115.41 (d, J = 21 Hz), 114.20, 109.49, 56.04, 55.38, 43.46, 36.86, 26.02, 18.31 ppm; IR (thin film):

νmax 3056, 2915, 2837, 1712, 1611, 1511, 1488, 1466, 1350, 1248, 1178, 1163, 1034, -1 817, 750 cm ; HPLC Rt = 13.38 (major) and 19.66 min (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS + (ES) m/z [MH] calcd for C27H27FNO2 416.5184, found 416.5190.

1-methyl-3-(2-methylbut-3-en-2-yl)-3-phenylindolin-2-one

197

WHC-IX-17: Following general procedure A (using 7.6 mg (0.034 mmol) of 1-methyl-

3-phenylindolin-2-one, Pd2dba3•CHCl3 (0.9 mg, 0.85 μmol, 0.025 equiv), (R,R)-L2 (1.8 mg, 2.0 μmol, 0.06 equiv), and TBAT (2.0 mg, 3.4 μmol, 0.1 equiv)), isolated 8.5 mg (86% yield from a 9.1:1 mixture of branched and linear isomers, 86% ee) of the title 23.9 1 compound as a colourless oil. [α]D 49.77 (86% ee, c 0.78, CH2Cl2); H NMR (400 MHz, CDCl3): 7.91 (m, 2H), 7.75 (d, J = 8 Hz, 1H), 7.32-7.20 (m, 4H), 7.09 (m, 1H), 6.82 (d, J = 8 Hz, 1H), 5.98 (dd, J = 17, 11 Hz, 1H), 5.05 (d, J = 11 Hz, 1H), 4.87 (d, J = 17 Hz, 1H), 3.20 (s, 3H), 1.24 (s, 3H), 0.99 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): 176.88, 144.11, 143.89, 135.73, 130.54, 129.67, 128.03, 127.91, 127.56, 127.07,

121.45, 113.53, 108.03, 61.20, 43.76, 26.22, 23.70, 22.57 ppm; IR (thin film): νmax 3056, -1 2969, 1702, 1609, 1493, 1471, 1375, 1349 cm ; HPLC Rt = 5.84 (major) and 6.76 min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, + flow rate = 0.8 mL/min); HRMS (ES) m/z [MH] calcd for C20H22NO 292.1723, found 292.1715.

1-methyl-3-(3-methylbut-2-en-1-yl)-3-phenylindolin-2-one

WHC-IX-19: Following general procedure B (using 7.6 mg (0.034 mmol) of 1-methyl-

3-phenylindolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol, 0.01 equiv) and (R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 6.9 mg (70% yield from a 1:2.5 mixture of 25 branched and linear isomers, 95% ee) of the title compound as a colourless oil. [α]D - 1 119.48 (95% ee, c 0.62, CH2Cl2); H NMR (500 MHz, CDCl3): 7.40 (m, 1H), 7.35-7.27 (m, 3H), 7.24 (m, 2H), 7.09 (m, 1H), 6.89 (d, J = 8 Hz, 1H), 4.79 (m, 1H), 3.21 (s, 3H), 2.97 (m, 2H), 1.53 (s, 3H), 1.50 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): 178.69, 144.10, 140.00, 135.67, 132.44, 128.73, 128.30, 127.47, 127.42, 125.35, 122.61,

118.19, 108.32, 56.71, 36.70, 26.62, 26.09, 18.41 ppm; IR (thin film): νmax 3056, 2916, -1 1714, 1611, 1493, 1470, 1373, 1345 cm ; HPLC Rt = 11.06 (major) and 13.91 min 198

(Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, + flow rate = 0.8 mL/min); HRMS (ES) m/z [MH] calcd for C20H22NO 292.1723, found 292.1720.

1-methyl-3-(2-methylbut-3-en-2-yl)-3-(naphthalen-2-yl)indolin-2-one

WHC-IX-05: Following general procedure A (using 9.3 mg (0.034 mmol) of 1-methyl-

3-(naphthalen-2-yl)indolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol, 0.01 equiv) and

(R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 10.3 mg (90% yield from a 13:1 mixture of branched and linear isomers, 86% ee) of the title compound as a colourless 23.8 1 oil. [α]D 13.11 (86% ee, c 0.9, CH2Cl2); H NMR (500 MHz, CDCl3): 7.80-7.76 (m, 4H), 7.56 (dd, J = 9, 2 Hz), 7.44 (m, 2H), 7.36 (m, 1H), 7.30 (d, J = 8 Hz, 1H), 7.13 (m, 1H), 6.93 (d, J = 8 Hz, 1H), 6.07 (dd, J = 17, 11 Hz, 1H), 5.08 (d, J = 11 Hz, 1H), 4.90 (d, J = 17 Hz, 1H), 3.22 (s, 3H), 1.29 (s, 3H), 1.06 (s, 3H) ppm; 13C NMR (125 MHz,

CDCl3): 178.52, 144.00, 137.25, 135.63, 133.29, 132.63, 132.38, 128.35, 128.28, 127.55, 126.11, 126.09, 125.46, 125.29, 122.59, 118.04, 108.27, 56.69, 36.40, 26.53,

25.97, 18.33 ppm; IR (thin film): νmax 3056, 2917, 1712, 1610, 1493, 1469, 1372, 1345, -1 1088 cm ; HPLC Rt = 14.65 (major) and 21.36 min (Chiralpak® OJ chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) + m/z [MH] calcd for C24H24NO 341.1780, found 341.1782.

1-methyl-3-(3-methylbut-2-en-1-yl)-3-(naphthalen-2-yl)indolin-2-one

199

WHC-IX-06: Following general procedure B (using 9.3 mg (0.034 mmol) of 1-methyl-

3-(naphthalen-2-yl)indolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol, 0.01 equiv) and

(R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 7.3 mg (62% yield from a 1:3.0 mixture of branched and linear isomers, 99% ee) of the title compound as a colourless 25 1 oil. [α]D -88.52 (99% ee, c 0.73, CH2Cl2); H NMR (500 MHz, CDCl3): 7.80-7.76 (m, 4H), 7.56 (dd, J = 9, 2 Hz), 7.44 (m, 2H), 7.36 (m, 1H), 7.30 (d, J = 8 Hz, 1H), 7.13 (m, 1H), 6.93 (d, J = 8 Hz, 1H), 4.84 (app t, J = 7 Hz), 3.24 (s, 3H), 3.08 (d, 2H), 1.55 (s, 13 3H), 1.53 (s, 3H) ppm; C NMR (125 MHz, CDCl3): 178.52, 144.00, 137.25, 135.63, 133.29, 132.63, 132.38, 128.35, 128.28, 127.55, 126.11, 126.09, 125.46, 125.29,

122.59, 118.04, 108.27, 56.69, 36.40, 26.53, 25.97, 18.33 ppm; IR (thin film): νmax 3056, -1 2917, 1712, 1610, 1493, 1469, 1372, 1345, 1088 cm ; HPLC Rt = 19.23 (major) and 54.31 min (Chiralpak® OJ chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i- + PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH] calcd for C24H24NO 341.1780, found 341.1793.

3-(2,4-dimethylthiazol-5-yl)-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one

WHC-IX-08, WHC-IX-22: Following general procedure A (using 8.8 mg (0.034 mmol) of 1-methyl-3-(2,4-dimethylthiazol-5-yl)indolin-2-one, Pd2dba3•CHCl3 (0.4 mg,

0.34 μmol, 0.01 equiv) and (R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 4.9 mg (43% yield from a 1:1.2 mixture of branched and linear isomers, 78% ee) of the title 25.2 1 compound as a colourless oil. [α]D (78% ee, c 0.52, CH2Cl2); H NMR (400 MHz,

CDCl3): 7.30 (m, 1H), 7.11 (m, 1H), 7.04 (m, 1H), 6.86 (m, 1H), 6.12 (dd, J = 17, 11 Hz, 1H), 5.21 (d, J = 11 Hz, 1H), 5.12 (d, J = 17 Hz, 1H), 3.24 (s, 3H), 2.89 (dd, J = 14, 8 Hz, 1H), 2.60 (s, 3H), 1.81 (s, 3H), 1.27 (s, 3H), 1.19 (s, 3H) ppm; 13C NMR (125

MHz, CDCl3): 176.85, 162.30, 148.13, 143.50, 136.82, 131.70, 130.22, 128.61, 124.20,

200

122.94, 116.62, 108.10, 52.42, 38.40, 26.44, 25.94, 19.11, 18.26, 15.96 ppm; IR (thin -1 film): νmax 2921, 1717, 1610, 1492, 1470, 1372, 1345 cm ; HPLC Rt = 12.82 (major) and 18.17 min (Chiralcel® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); HRMS (ES) m/z [MH]+ calcd for

C19H23N2OS 327.1553, found 327.1559.

3-(2,4-dimethylthiazol-5-yl)-1-methyl-3-(3-methylbut-2-en-1-yl)indolin-2-one

WHC-IX-09: Following general procedure B (using 8.8 mg (0.034 mmol) of 1-methyl-

3-(2,4-dimethylthiazol-5-yl)indolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol, 0.01 equiv) and (R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 9.6 mg (81% yield from a 1:4.7 mixture of branched and linear isomers, >99.5% ee) of the title compound as a 25 1 colourless oil. [α]D (>99.5% ee, c 0.77, CH2Cl2); H NMR (500 MHz, CDCl3): 7.30 (m, 1H), 7.11 (m, 1H), 7.04 (m, 1H), 6.86 (m, 1H), 4.76 (app t, J = 7 Hz, 1H), 3.24 (s, 3H), 2.99 (dd, J = 14, 7 Hz, 1H), 2.89 (dd, J = 14, 8 Hz, 1H), 2.60 (s, 3H), 1.81 (s, 3H), 13 1.53 (s, 3H), 1.47 (s, 3H) ppm; C NMR (125 MHz, CDCl3): 176.85, 162.30, 148.13, 143.50, 136.82, 131.70, 130.22, 128.61, 124.20, 122.94, 116.62, 108.10, 52.42, 38.40,

26.44, 25.94, 19.11, 18.26, 15.96 ppm; IR (thin film): νmax 2921, 1717, 1610, 1492, -1 1470, 1372, 1345 cm ; HPLC Rt = 16.56 (major) and 30.40 min (Chiralcel® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 mL/min); + HRMS (ES) m/z [MH] calcd for C19H23N2OS 327.1553, found 327.1559.

201

1-methyl-3-(3-methylbut-2-en-1-yl)-3-(o-tolyl)indolin-2-one

WHC-IX-20: Following general procedure B (using 8.1 mg (0.034 mmol) of 1-methyl-

3-(o-tolyl)indolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol, 0.01 equiv) and (R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 7.8 mg (75%, 99% ee) of the title compound 25.2 1 as a colourless oil. [α]D 83.06 (99% ee, c 0.74, CH2Cl2); H NMR (500 MHz, CDCl3): 7.68 (d, J = 7 Hz, 1H), 7.30-7.24 (m, 2H), 7.18 (m, 1H), 7.03 (d, J = 7 Hz, 1H), 6.97 (m, 1H), 6.85 (m, 2H), 4.82 (app t, J = 7 Hz, 1H), 3.26 (s, 3H), 3.02 (dd, J = 14, 8 Hz, 1H), 2.95 (dd, J = 14, 8 Hz, 1H), 1.63 (s, 3H), 1.54 (s, 3H), 1.41 (s, 3H) ppm; 13 C NMR (125 MHz, CDCl3): 179.08, 144.14, 138.24, 137.41, 136.07, 133.24, 132.14, 128.06, 127.88, 127.73, 126.20, 123.70, 122.90, 117.22, 107.70, 56.47, 36.90, 26.38,

26.12, 19.72, 18.15 ppm; IR (thin film): νmax 3056, 2966, 2927, 1715, 1611, 1491, 1469, -1 1374, 1344, 1249, 1126, 1087, 752 cm ; HPLC Rt = 22.05 and 26.94 (major) min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, + flow rate = 0.8 mL/min); HRMS (ES) m/z [MH] calcd for C21H24NO 306.1880, found 306.1876.

3-(4-methoxyphenyl)-1-methyl-3-(2-methylbut-3-en-2-yl)indolin-2-one

WHC-IX-52: Following general procedure A (using 8.6 mg (0.034 mmol) of 1-methyl-

3-(4-methoxyphenyl)indolin-2-one, Pd2dba3•CHCl3 (0.9 mg, 0.85 μmol, 0.025 equiv),

(R,R)-L2 (1.8 mg, 2.0 μmol, 0.06 equiv), and TBAT (2.0 mg, 3.4 μmol, 0.1 equiv)), isolated 8.9 mg (81% yield from a 5.2:1 mixture of branched and linear isomers, 80% 25.2 1 ee) of the title compound as a colourless oil. [α]D 41.70 (80% ee, c 0.89, CH2Cl2); H 202

NMR (500 MHz, CDCl3): 7.83 (m, 2H), 7.73 (d, J = 8 Hz, 1H), 7.29 (m, 1H), 7.08 (m, 1H), 6.83-6.80 (m, 3H), 5.97 (dd, J = 18, 11 Hz, 1H), 5.04 (dd, J = 11, 1.0 Hz, 1H), 4.86 (dd, J = 18, 1.0 Hz, 1H), 3.77 (s, 3H), 3.19 (s, 3H), 1.23 (s, 3H), 0.98 (s, 3H) ppm; 13C

NMR (125 MHz, CDCl3): 177.10, 158.50, 144.19, 143.84, 130.85, 130.78, 127.95, 127.77, 127.60, 121.41, 113.44, 112.82, 108.02, 60.56, 55.31, 43.75, 26.18, 23.72,

22.46 ppm; IR (thin film): νmax 3055, 2932, 1701, 1609, 1511, 1494, 1470, 1374, 1350, -1 1252, 1188, 1088, 1033 cm ; HPLC Rt = 7.46 (major) and 11.51 min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, flow rate = 0.8 + mL/min); HRMS (ES) m/z [MH] calcd for C21H24NO2 322.1829, found 322.1836.

3-(4-methoxyphenyl)-1-methyl-3-(3-methylbut-2-en-1-yl)indolin-2-one

WHC-IX-53: Following general procedure B (using 8.6 mg (0.034 mmol) of 1-methyl-

3-(4-methoxyphenyl)indolin-2-one, Pd2dba3•CHCl3 (0.4 mg, 0.34 μmol, 0.01 equiv) and (R,R)-L1 (0.6 mg, 0.75 μmol, 0.022 equiv)), isolated 7.5 mg (69% yield from a 1:3.2 mixture of branched and linear isomers, 91% ee) of the title compound as a 25.2 1 colourless oil. [α]D -103.08 (91% ee, c 0.69, CH2Cl2); H NMR (500 MHz, CDCl3): 7.33-7.29 (m, 3H), 7.24 (d, J = 8 Hz, 1H), 7.08 (m, 1H), 6.88 (d, J = 8 Hz, 1H), 6.83 (m, 2H), 4.78 (m, 1H), 3.77 (s, 3H), 3.19 (s, 3H), 2.95-2.91 (m, 2H), 1.53 (s, 3H), 1.49 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): 178.81, 158.81, 143.95, 135.42, 132.45, 131.87, 128.41, 128.11, 125.17, 122.43, 118.17, 113.93, 108.16, 55.89, 55.38, 36.67,

26.46, 25.95, 18.27 ppm; IR (thin film): νmax 3054, 2930, 1713, 1610, 1511, 1469, 1373, -1 1346, 1251, 1184, 1088, 1035 cm ; HPLC Rt = 17.57 (major) and 27.89 min (Chiralpak® AD chiral column, λ = 254 nm, isocratic elution: 95:5 heptane/i-PrOH, + flow rate = 0.8 mL/min); HRMS (ES) m/z [MH] calcd for C21H24NO2 322.1829, found 322.1828.

203

4.6 References

1 Trost, B. M.; Frederiksen, M. U. Angew. Chem. Int. Ed. 2005, 44, 308–310. 2 (a) Trost, B. M.; Zhang, Y. Chem. Eur. J. 2010, 16, 296. (b) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548–14549. (c) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590–4591. 3 Xu, J. Ph.D. Thesis, Stanford University. 4 Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc. 2010, 132, 15534–15536. 5 Trost, B. M.; Masters, J. T.; Burns, A. C. Angew. Chem. Int. Ed., 2013, 52, 2260. 6 Åkermark, B.; Vitagliano, A. Organometallics 1985, 4, 1275–1283. 7 Burckhardt, U.; Baumann, M.; Togni, A. Tetrahedron: Asymmetry 1997, 8, 155–159. 8 Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545. 9 Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnett, J. J.; Ibers, J. A. J. Organomet. Chem. 1974, 65, 263.

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5 Efforts toward the total synthesis of the oxaline/meleagrin alkaloids

5.1 Introduction

Scheme 5.1: The oxaline/meleagrin alkaloids

The oxaline-meleagrin family of alkaloids (Scheme 5.1) are derived from the roquefortine alkaloids and possess interesting biological properties.1 Meleagrin (5.1.2) and its derivatives such as meleagrin B (5.1.5) have displayed antitumor2 and antibacterial3 activity, while oxaline (5.1.3) inhibits cell proliferation and induces cell cycle arrest during the M phase.4 The intricate polycyclic structure of these alkaloids is

206 also of inherent interest. The triad of adjacent tetrasubstituted carbons at the core of the molecule, two of which are stereocentres and one of which is unusually bonded to three nitrogen atoms, poses a unique synthetic challenge. This, combined with the promising biological activities of these alkaloids, has led to interest in their total synthesis.

Scheme 5.2: First steps in the synthesis of the oxaline core

The Omura group has completed the only published syntheses of any member of these alkaloids thus far. In 2005 they reported a synthesis of the oxaline/meleagrin core lacking the vinylimidazole moiety (Scheme 5.2),5 in which the reverse-prenyl group was installed using Danishefsky’s selenylation-cyclization protocol.6 Regioselective addition of indole to (R)-methyl glycidate (5.1.6) was accomplished in 77% yield using ytterbium(III) triflate as the catalyst. Selective Boc protection of the

207 indole nitrogen delivered prenylation substrate 5.1.8 in 88% yield over three steps from indole 5.1.7. Selenylation-cyclization proceeded with excellent conversion, but a 1:1 mixture of diastereomeric furoindolines was produced which could not be interconverted. Diastereomer 5.1.9 underwent electrophilic prenylation with prenyl tributyltin in the presence of methyl triflate and 2,6-di-t-butylpyridine to afford compound 5.1.11 in 58% yield.

Scheme 5.3: Completion of the synthesis of the oxaline core

The glycineamide side chain of 5.1.12 was installed in 84% yield over five steps, which included several protecting group manipulations (Scheme 5.3). Treatment of this compound with trimethylaluminum resulted in ring-opening of the tetrahydrofuran and recyclization to form the desired six-membered ring of 5.1.13 in 76% yield. Oxidation of the aminal to nitrone 5.1.14 was performed in 46% yield using sodium tungstate and 208 hydrogen peroxide-urea complex, and cyclization of the pendant amide occurred in the presence of silica gel in 63% yield. Finally, methylation of N-hydroxyindoline 5.1.15 proceeded in 29% yield to furnish the tetracyclic core (5.1.16) of the oxaline/meleagrin alkaloids.

Scheme 5.4: Asymmetric synthesis of (+)-neoxaline (part 1)

209

In 2013 an asymmetric synthesis of (+)-neoxaline and the determination of its absolute stereochemistry was reported by the Omura group.7 Sharpless asymmetric epoxidation of tryptophol (5.1.17) delivered furoindoline 5.1.18 in 99% ee and 72% yield (Scheme 5.4).8 Protection of the indoline nitrogen as the allyl carbamate and conversion of the 3-hydroxy group to the trichloroacetimidate occurred in 94% yield.

The resulting compound was treated with prenyl tributyltin and BF3Et2O to afford 3- tert-prenyl furoindoline 5.1.20 in 87% yield and as a single diastereomer, a significant improvement over the same group’s previously described route to the similar tricyclic intermediate 5.1.11. Cleavage of the indole protecting group was followed by reductive opening of the cyclic hemiaminal and indole reprotection. The pendant alcohol thus generated was oxidized quantitatively to the aldehyde using Dess-Martin periodinane. Boric acid-catalyzed addition of methyl isocyanoacetate to aldehyde 5.1.21 generated α-hydroxyamide 5.1.22 as a 2:1 mixture of (9S) and (9R) diastereomers. Oxidation and reduction of the alcohol at this position altered the ratio to 9.5:1 favouring the (9R) diastereomer. Protection of the alcohol was followed by indole deprotection and transamidation.

210

Scheme 5.5: Asymmetric synthesis of (+)-neoxaline (part 2)

The resulting compound 5.1.24 was subjected to sodium tungstate-catalyzed oxidation (Scheme 5.5) to afford a mixture of nitrone 5.1.25 and the desired cyclization product 5.1.26; the former was converted to the latter in the presence of triethylamine,

211 resulting in a 93% overall yield for the oxidation-cyclization sequence. Lead tetraacetate mediated the further oxidation to nitrone 5.1.27, which underwent cyclization of the pendant primary amide in the presence of tetrabutylammonium hydroxide in 93% yield. Meanwhile, the cyclization of (9S)-5.1.27, which had been synthesized from (9S)-5.1.22 using the same reaction sequence as for the other diastereomer, was also attempted under a variety of conditions but could not be accomplished. Since the stereochemistry of the 9-position in the natural product has the S configuration, it was necessary to invert this stereocentre in a synthetic intermediate derived from (9R)-5.1.22. Protection of the hydroxylamine and amide afforded compound 5.1.28, which was subjected to aldol reaction with imidazolecarbaldehyde 5.1.29. While attempts to directly generate the (E)-dehydrohistidine found in the natural product9 in this manner were unsuccessful, dehydration of the intermediate aldol adduct with 1-ethyl-3-(3- dimethylaminopropyl)-carbodiimide (EDC) and CuCl2 resulted in formation of (Z)- dehydrohistidine 5.1.30. After deprotection and methylation of the hydroxylamine, cleavage of the Boc and SEM groups with AlMe3 occurred concurrently with epimerization of the α- siloxyester to deliver compound 5.1.31 with the desired S configuration at the 9- position. The configuration of this stereocentre was confirmed via nOe analysis and reprotection of (9S)-5.1.31 to afford (9S)-5.1.30. Deprotection of the secondary alcohol was accomplished with HF·pyridine in 73% yield. Photoisomerization of olefin 5.1.32 to obtain the naturally occurring (E)-isomer proceeded in 55% yield along with 35% recovered starting material. The optical rotation and CD spectra of 5.1.4 prepared by Omura and coworkers matched that of the naturally occurring (+)-neoxaline, thus confirming its absolute configuration. Omura and coworkers were able to prepare more than 100 mg of the natural product via this approach.

212

5.2 Retrosynthetic analysis of the meleagrin alkaloids Scheme 5.6: Retrosynthetic analysis of meleagrin

Our retrosynthetic analysis of meleagrin (5.1.2, Scheme 5.6) divided the molecule into two fragments: a dehydrohistidine-derived vinyl isocyanide, and a reverse- prenylated N-methoxyoxindole that would be accessed via our newly developed methodology. These two fragments would be united in an intermolecular addition of the isocyanide to a ketene,10 or the oxidative coupling between an isocyanide and an aldehyde.11 Transamidation as demonstrated in Omura’s earlier synthesis of the oxaline core, followed by removal of the imidazole protecting group would complete the synthesis of meleagrin, from which neoxaline and oxaline might also be accessed.

213

5.3 Synthesis of N-methoxyoxindole substrates for asymmetric prenylation Scheme 5.7: Synthesis of 1-methoxyoxindole

Kikugawa and coworkers reported that the cyclization of N-chloroamide 5.3.3 proceeded in 80% yield under their optimized conditions (five equivalents of anhydrous zinc acetate in refluxing nitromethane for 3 min). This cyclization likely proceeds via ionization of the chloride to deliver nitrenium ion 5.3.4, which is trapped by an intramolecular electrophilic aromatic substitution. Unfortunately, Kikugawa’s reported yield could not be reproduced on any scale up to and including that described (90 mmol);12 the best yield obtained in our hands was 56% on 20 mmol scale (Scheme 5.7). Other procedures reported by the Kikugawa group for this cyclization also did not give satisfactory results. Thus the use of silver(I) carbonate in conjunction with

214 trifluoroacetic acid13 gave only ~20% yield of product and was accompanied by significant amounts of decomposition; while N-methoxyamide 5.3.2 failed to cyclize in the presence of (bis(trifluoroacetoxy)iodo)benzene as described in a later report from the Kikugawa group.14

Table 5.1: Attempts to oxidize 1-methoxyoxindole to 1-methoxyisatin

A myriad of attempts to oxidize oxindole 5.3.5 to the corresponding isatin 5.3.6 were largely unsuccessful (Table 5.1). A reported procedure using chromium trioxide 215 in acetic acid at room temperature resulted in a 25% yield,15 while using pyridinium chlorochromate at 70 °C resulted in a similar outcome (27% yield). Other oxidizing conditions (e.g. pyridinium tribromide, iodobenzene diacetate, aerobic conditions) were ineffective, and diazo transfer from p-acetamidobenzenesulfonyl azide also did not proceed. Treatment of the oxindole with nitrous acid afforded oxime 5.3.7 in 58% yield, but attempts to hydrolyze or oxidatively cleave it to the isatin also failed.

Scheme 5.8: Synthesis of 1-methoxyisatin from 1-methoxyoxindole

The synthesis of 1-methoxyisatin via condensation of 1-methoxyoxindole with a suitable reagent to make a 3-alkylideneoxindole, followed by ozonolysis of the olefin, was explored next (Scheme 5.8). Initially a Claisen condensation of 1-methoxyoxindole with ethyl formate in methanolic sodium methoxide was tried. On the most successful attempt the subsequent ozonolysis (which did not require the use of dimethylsulfide to decompose the intermediate ozonide) afforded 1-methoxyisatin in a 48% overall yield from 1-methoxyoxindole, but the yield of the condensation step proved to be extremely

216 capricious. The condensation of 1-methoxyoxindole with acetic anhydride in the presence of Hünig’s base and catalytic DMAP was similarly unreliable, although a yield of 86% for oxindole 5.3.9 was obtained at one point. The ozonolysis of this compound proceeded in 79% yield. Avoiding the use of base proved to be critical in performing this Claisen condensation in a repeatable manner. It was found that 1-methoxyoxindole could be condensed with triethyl orthoformate in the presence of acetic anhydride to afford the ethoxymethylene-substituted oxindole 5.3.10 in 64% yield. Ozonolysis of this product proceeded smoothly to afford N-methoxyisatin (5.3.6) in 88% yield.

Scheme 5.9: Unsuccessful syntheses of 1-hydroxyisatin from o-nitrophenylacetic acid

Other approaches to 1-methoxyisatin were briefly investigated (Scheme 5.9). The synthesis of 1-hydroxyisatin (5.3.13) via thermal decomposition and rearrangement of ortho-nitrophenyldiazoketone 5.3.12 has been reported in the literature, albeit in very low yield.16 The attempt to use rhodium catalysis to effect this transformation led to formation of only trace amounts of the desired isatin.

217

Scheme 5.10: Attempted syntheses of 1-methoxyisatin from indoline

The oxidation of 1-methoxyindole (5.3.15), prepared by one-pot oxidation of indoline with sodium tungstate and methylation (Scheme 5.10),17 to 1-methoxyisatin was also investigated using a recently reported iodine/t-butyl hydroperoxide system.18 Again only trace amounts of the isatin could be isolated after column chromatography. Oxidation to the 3,3-dibromo-2-oxindole (5.3.16) could be achieved in 65% yield17 but the attempt to hydrolyze this oxindole to the isatin, which has been reported for isatins 19 possessing an unsubstituted nitrogen, resulted in no product formation.

218

5.4 Installation of the side chain at the 3-position of the oxindole Scheme 5.11: Preparation of 1-methoxy-3-(cyanomethyl)oxindole

The direct alkylation of an oxindole at the 3-position usually results in formation of bisalkylated products.20 Previously, we had routinely prepared 3-alkyloxindole substrates for the asymmetric prenylation via the Horner-Wadsworth-Emmons olefination of an isatin followed by reduction. However, extensive decomposition of isatin 5.3.6 was seen under the basic conditions required for the HWE reaction, and this was not ameliorated by the use of the less basic Masamune-Roush conditions for the olefination (Scheme 5.11).21 Thus the less basic Wittig phosphorane was prepared, and this reacted with 1-methoxyisatin at room temperature over 10 h to deliver the olefinated product in 86% yield. The attempt to install a pyruvyl side chain using the Wittig phosphorane derived from ethyl bromopyruvate afforded only trace amounts of the olefination product even at 80 °C.

219

Reduction of alkylideneoxindoles with other N-protecting groups was previously accomplished using sodium borohydride. However, in the case of oxindole 5.4.1, extensive decomposition was observed under these conditions and the oxindole 5.4.2 was formed in only 32% yield. Subjecting oxindole 5.4.1 to hydrogenation conditions predominantly led to hydrogenolysis of the N-methoxy group. Suspecting that the oxindole was sensitive to the basic nature of the borohydride reduction, a more neutral reducing agent was sought, and the use of Hantzsch ester and magnesium perchlorate in acetonitrile22 proved to be very effective – complete conversion of the oxindole was observed within minutes and the reduction product was isolated in 83% yield. When the magnesium perchlorate was omitted, the reaction proceeded less rapidly, reaching completion only after one hour, but the desired oxindole 5.4.2 was nevertheless isolated in a satisfactory 87% yield.

220

5.5 Asymmetric reverse prenylation of oxindole 5.4.2 Table 5.2: Optimization of the asymmetric reverse prenylation of oxindole 5.4.2

221

The optimization of the asymmetric prenylation of oxindole 5.4.2 is summarized in Table 5.2. Ratios of branched (5.5.1) vs. linear (5.5.2) products were determined by 1H NMR of the crude reaction mixture and comparison of the integration of the proton bonded to the central carbon of the dimethylallyl fragment. The two products were separable by chromatography. The “naphthyl” ligand L2 gave better regioselectivity for the branched isomer than the parent ligand L1, in accordance with previous results in the asymmetric prenylation of oxindoles. The “anthracenyl” ligand L4 with its larger bite angle displayed excellent regioselectivity for the branched isomer (5.5.1 : 5.5.2 = 16:1). However, both conversion (oxindole 5.5.1 isolated in only 17% yield) and enantioselectivity (14% ee) was poor. This pattern of excellent branched regioselectivity but poor enantioselectivity had previously also been observed in the prenylation of 3- aryloxindoles (Chapter 4). A solvent screen revealed that 1,2-dimethoxyethane (entry 12) afforded the branched isomer in a promising 81% ee, although the regioselectivity favoured the linear isomer slightly (1 : 1.3). Addition of 25 mol % tetrabutylammonium difluorotriphenylsilicate (TBAT; entry 14) reversed the regioselectivity in favour of the branched isomer (2.9 : 1) while maintaining good enantioselectivity (83% ee). Use of other additives such as tetrahexylammonium bromide (entry 13) or t-butanol (entry 15) led to still better regioselectivities, but the enantioselectivity was negatively impacted even when TBAT was added as a co-additive.

222

Scheme 5.12: Asymmetric prenylation of other N-methoxyoxindoles

The ester-substituted oxindoles 5.5.3 and 5.5.5 were also prepared via Wittig olefination of isatin 5.3.6 followed by Hantzsch ester reduction, and reacted under the conditions optimized for oxindole 5.4.2 (Scheme 5.12). However, in both cases the regioselectivity of the prenylation favoured the undesired linear isomer, and the enantioselectivity for the branched products 5.5.4 and 5.5.6 was disappointingly low and did not exceed 80%. It is unclear why the regioselectivity of the reverse-prenylation of N-methoxyoxindole substrates such as 5.4.2, 5.5.3 and 5.5.5 are unusually poor compared to those obtained with substrates bearing other protecting groups on nitrogen (even ones as similar as methyl or methoxymethyl) as described in Chapters 3 and 4.

223

5.6 Further manipulation of prenylated nitrile 5.5.1 Scheme 5.13: Hydrolysis of nitrile 5.5.1 to carboxylic acid 5.6.3

Hydrolysis of nitrile 5.5.1 directly to carboxylic acid 5.6.1 under acidic conditions was unsuccessful (Scheme 5.13). However, the nitrile could be cleanly hydrolyzed to amide 5.6.1 using basic hydroperoxide in DMSO.23 Several methods of varying degrees of mildness for the hydrolysis of primary amides such as 5.6.1 (e.g. refluxing aqueous NaOH or KOH; t-amyl nitrite/acetic acid at 80 °C;24 copper(II) chloride dihydrate/glyoxal25) were evaluated. In all cases, only partial decomposition of the starting material was observed. However, mixing amide 5.6.1 with two equivalents of di-t-butyl dicarbonate in the presence of catalytic DMAP in THF cleanly afforded the bis-BOC-protected amide 5.6.2. This compound underwent hydrolysis smoothly when treated with lithium hydroperoxide to afford the desired carboxylic acid 5.6.3 in 85% overall yield from the nitrile.

224

5.7 Synthesis of the imidazole-containing fragment Scheme 5.14: Four synthetic approaches to the imidazole-containing fragment

Four methods were investigated for the preparation of the formamide-containing imidazole fragment (Scheme 5.14). These were: 1. The Cu- or Pd-mediated formamidation of a vinyl bromide;

2. The aldol condensation of an imidazole-4-carboxaldehyde with methyl isocyanoacetate;

3. The Heck reaction of a 4-haloimidazole with a dehydroalanine derivative;

4. The Horner-Wadsworth-Emmons reaction of amino-substituted phosphonate with imidazole-4-carboxaldehyde derivatives.

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5.7.1 The formamidation strategy Table 5.3: Synthesis of α-bromourocanate derivatives and screening of conditions for the metal-mediated/catalyzed formamidation

Vinyl bromides with the desired E olefin geometry were synthesized from urocanic acid 5.7.1 (Table 5.3).26 Several literature conditions for the Cu-catalyzed, Cu- mediated or Pd-catalyzed27 amidation or formamidation28 of aryl halides were screened for the coupling of these vinyl bromides with formamide, but in all cases only partial or complete decomposition of starting material was observed, and none of the desired coupling product could be isolated.

226

5.7.2 The isocyanoacetate aldol strategy Table 5.4: Attempted isocyanoacetate aldol condensation

The condensation of methyl isocyanoacetate with aryl and aliphatic aldehydes to yield N-formyl dehydroamino acid derivatives is well-precedented in the literature.29,30 The condensation of methyl isocyanoacetate with regioisomerically pure imidazole 5.7.6 (prepared in three steps from imidazole-4-methanol) was examined 29 under a variety of conditions (Table 5.4). The use of strongly basic conditions or ZnCl2 as a Lewis acid31 only resulted in decomposition of the imidazole. A variety of copper 31 32,33 salts (CuCl, CuTC, CuI, Cu2O ) were also investigated as catalysts for this transformation, but the desired product was not observed in any of these cases.

227

5.7.3 The Heck reaction strategy Table 5.5: Attempted Heck reactions with 4-haloimidazoles and enamide 5.7.10

Feringa and coworkers have used a Heck reaction strategy to prepare N-formyl dehydroamino acid derivatives such as 5.7.10 as substrates for asymmetric hydrogenation.30 In that publication, aryl, heteroaryl (furyl) and alkyl bromides and iodides were successfully coupled with enamide 5.7.10 using the ligand-free Jeffery conditions. Unfortunately this coupling reaction could not be extended to N-protected 4-haloimidazoles, which were prepared in isomerically pure fashion according to a literature procedure.34 Under either phosphine-free conditions or in the presence of tri- o-tolylphosphine (Table 5.5) no coupling product was formed, and in the presence of

228

K2CO3 decomposition of the enamide was observed; in all cases the imidazole starting material was recovered.

5.7.4 The Horner-Wadsworth-Emmons olefination strategy Scheme 5.15: Synthesis of HWE reagent 5.7.16 and olefination of aldehyde 5.7.6

Finally, an approach using the Horner-Wadsworth-Emmons olefination was examined (Scheme 5.15). Phosphonate 5.7.14 was prepared from benzyl carbamate in three steps following the procedure of Fukuyama and coworkers.35 The Cbz protecting group was cleaved using transfer hydrogenation conditions, and the resulting unstable amine was immediately treated with an excess of acetic formic anhydride (prepared by mixing acetic anhydride and formic acid) to afford the N-formyl phosphonate 5.7.16 in 60% overall yield. The Horner-Wadsworth-Emmons olefination was examined using a variety of bases and metal additives such as LiHMDS,7 DBU,36 DBU/NaI, DBU/LiCl, NaH/NaI,

229

37 or MgBr2·Et2O/DBU. The most promising conditions involved the use of three equivalents each of the HWE reagent, DBU and NaI in THF, which led to the isolation of a 2.6:1 mixture of inseparable olefin isomers in 56% yield. This mixture of isomers was carried forward in the subsequent dehydration reaction.

5.7.5 Attempts to dehydrate formamide 5.7.17 Table 5.6: Attempted dehydration of formamide 5.7.17

Dehydration of vinyl formamide 5.7.17 to the isocyanide was examined with a 38 variety of basic and neutral conditions reported for this transformation (POCl3, phenyl 39 40 41 dichlorophosphate/Et3N, Tf2O/Hünig’s base, Burgess reagent, 2-chloro-3- 42 ethylbenzoxazolium tetrafluoroborate/Et3N, triphenylphosphonium anhydride bistriflate (Hendrickson’s reagent),43 diphosgene44), but formation of the isocyanide was never observed (Table 5.6).

230

5.8 Experimental

5.8.1 General methods All reagents were obtained commercially unless otherwise noted. Reactions were performed using glassware that was flame-dried under vacuum (~1 Torr). All reactions were performed under an atmosphere of nitrogen. Pd2dba3•CHCl3 was prepared according to a literature procedure.45 Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Organic solutions were concentrated under reduced pressure (~15 Torr) by rotary evaporation. Solvents were purified by passage under 12 psi N2 through activated alumina columns. Chromatography was performed on Silicycle Silia-P Silica Gel (40-63 m). Compounds purified by chromatography were typically applied to the adsorbent bed using the indicated solvent conditions with a minimum amount of added chloroform as needed for solubility. Chiral HPLC analyses were performed on a Thermo Separation Products Spectra Series P-100 or P-200 and UV100 (254 nm or 220 nm) using Chiralcel® columns (OB-H, OC, OD-H, OJ-H), or Chiralpak® column (AD, AS, IA, IB,

IC) eluting with the solvent mixtures indicated. Retention times (Rt) are reported in minutes (min). Thin layer chromatography was performed on EMD Chemicals Silica

Gel 60 F254 plates (250 m). Visualization of the developed chromatogram was accomplished by fluorescence quenching or by staining with p-anisaldehyde or aqueous potassium permanganate.

Nuclear magnetic resonance (NMR) spectra were acquired on either a Varian Inova-600, a Varian Inova-500, a Varian Mercury-400, or a Gemini-300 operating at 600, 500, 400, or 300 MHz for 1H and 150, 125, 100, or 75 MHz for 13C, respectively, and are referenced internally according to residual solvent signals. Data for 1H NMR are recorded as follows: chemical shift (, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; m, multiplet), integration, coupling constant (Hz). Data for 13C NMR are reported in terms of chemical shift (, ppm). Melting points were obtained on a Thomas-Hoover apparatus in open capillary tubes and are uncorrected. Infrared spectra were recorded on either a Thermo-Nicolet IR100 231 or a Thermo-Nicolet IR300 spectrometer as thin films using NaCl salt plates or as KBr pellets and are reported in frequency of absorption. Optical rotations were determined using a JASCO DIP-1000 digital polarimeter. The sodium D line (589 nm) and a 50 mm path length were used exclusively, but differences in temperature, solvent, and concentration are indicated. High-resolution mass spectra were obtained from the Vincent Coates Foundation Mass Spectrometry Laboratory at Stanford University (http://mass-spec.stanford.edu) using a Micromass Q-Tof API-US mass spectrometer (Waters Corporation, Milford, MA).

1-methoxyisatin

WHC-XII-16, WHC-XII-18: To a solution of 1-methoxyoxindole (816 mg, 5 mmol) and 4-(dimethylamino)pyridine (153 mg, 1.25 mmol) in THF (20 mL) was added Hünig’s base (13 mL, 75 mmol) at 0 °C. The reaction was stirred for 5 min and acetic anhydride (5.7 mL, 60 mmol) was added over 1 min. The reaction was maintained at 0 °C for a further 10 min, then warmed to room temperature and stirred for 3.5 h. It was then concentrated in vacuo and taken up in EtOAc. This solution was washed with 1 M

HCl twice, then once with saturated aqueous NaHCO3, and finally once with brine. It was then dried (Na2SO4) and concentrated in vacuo. The residue was loaded on silica and eluted with 25% EtOAc/hexanes to afford 1-(1-methoxy-2-oxoindolin-3- ylidene)ethyl acetate (1.06 g, 86%; Rf = 0.16, 20% EtOAc/hexanes) as a yellow solid.

175 mg (0.71 mmol) of this oxindole was then dissolved in 1:1 MeOH/CH2Cl2 (6 mL) and cooled to -78 °C. Ozone was passed through this solution for 5 min. The resulting yellow solution was purged with N2 and dimethylsulfide (0.16 mL, 2.13 mmol) was added. The solution warmed to room temperature and stirred for 12 h; concentration in vacuo and subsequent silica gel chromatography (25% EtOAc/hexanes) yielded 1- methoxyisatin (99 mg, 79%) as an orange solid. Spectral data agree with literature 15 1 values. H NMR (300 MHz, CDCl3): 7.62 (dd, J = 8, 8 Hz, 1H), 7.56 (d, J = 8 Hz,

232

1H), 7.14 (dd, J = 8, 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 4.07 (s, 3H); mp = 107-109 °C (lit. 110-113 °C).

2-(1-methoxy-2-oxoindolin-3-yl)acetonitrile

WHC-XV-69: To a solution of 1-methoxyisatin (775 mg, 4.37 mmol) in dichloromethane (24 mL) was added 2-(triphenylphosphoranylidene)acetonitrile (1.71 g, 5.68 mmol) (generated from (cyanomethyl)triphenylphosphonium bromide and potassium t-butoxide) in one portion. The mixture was stirred at room temperature for 10 h, then diluted with water. The layers were separated and the aqueous layer extracted with CH2Cl2. The organic layers were combined, dried (MgSO4), and CIV to afford the crude alkylideneoxindole, which was dissolved in acetonitrile (16 mL). To this solution was added diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.11 g, 4.37 mmol). The mixture was stirred for 1 h at room temperature, then concentrated in vacuo and loaded on SiO2. Eluting with 20% EtOAc/hexanes delivered the title compound as a pale orange oil that would solidify when stored at -20 °C (764 mg, 86% over two 1 steps). H NMR (400 MHz, CDCl3): 7.51 (d, 1H, J = 8 Hz), 7.40 (app t, 1H, J = 8 Hz), 7.16 (app td, 1H, J = 8, 1 Hz), 7.04 (d, 2H, J = 8 Hz), 4.04 (s, 3H), 3.68 (dd, 1H, J = 9, 5 Hz), 3.12 (dd, 1H, J = 17, 5 Hz), 2.77 (dd, 1H, J = 17, 9 Hz) ppm; 13C NMR (100 MHz, CDCl3): 169.1, 140.6, 129.9, 124.8, 124.0, 122.2, 117.0, 108.2, 64.0, 40.0, 19.0 -1 ppm. IR (thin film): νmax 2928, 2218, 1697, 1594, 1443, 1309, 932, 742 cm .

2-(1-methoxy-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)acetonitrile

233

WHC-XV-57: A flame-dried vial containing containing 2-(1-methoxy-2- oxoindolin-3-yl)acetonitrile (7.4 mg, 0.034 mmol), Pd2dba3•CHCl3 (0.9 mg, 0.85 umol,

0.025 equiv), (R,R)-L1 (1.76 mg, 2.5 umol, 0.075 equiv) was evacuated and purged three times with nitrogen. The mixture was dissolved in anhydrous CH2Cl2 (200 uL), the reaction was stirred at room temperature for 15 min, and to the resulting orange solution was added tert-butyl (2-methylbut-3-en-2-yl) carbonate (9.4 mg, 0.51 mmol, 1.1 equiv). The reaction was stirred at room temperature for 24 h and concentrated. Crude NMR of the reaction mixture gave the regioisomeric distribution between the branched and linear products. The crude reaction mixture was concentrated. Preparative thin layer chromatography developing with 20% EtOAc/hexanes afforded 7.1 mg (73% linear product isolated from a 2.9:1 b:l mixture, 83% ee) of the title compound as a colorless 25 oil. TLC Rf = 0.28 (20% EtOAc/hexanes); [α]D +31.9 (optical rotation conducted on 1 83% ee material using (S,S)-L1, c 0.71, CHCl3); H NMR (400 MHz, CDCl3): δ 7.39 (app td, J = 8, 1 Hz, 1H), 7.30 (d, J = 8 Hz, 1H), 7.13 (app td, J = 8, 1 Hz, 1H), 7.04 (d, J = 8 Hz, 1H), 6.03 (dd, J = 18, 12 Hz, 1H), 5.22 (d, J = 12 Hz, 1H), 5.10 (d, J = 18 Hz, 1H), 4.01 (s, 3H), 3.02 (d, J = 18 Hz, 1H), 2.85 (d, J = 18 Hz, 1H), 1.17 (s, 3H), 1.08 (s, 13 3H) ppm; C NMR (125 MHz, CDCl3): δ 171.1, 141.7, 140.6, 129.6, 125.7, 124.6, 123.2, 116.5, 115.7, 107.7, 78.4, 63.3, 53.7, 41.8, 22.10, 22.07, 21.7 ppm; IR (thin film): -1 νmax 2899, 1703, 1596, 1445, 1306, 1218, 1069, 741 cm ; HPLC Rt = 24.3 and 25.9 min (major) (Chiralcel® OD chiral column, λ = 254 nm, isocratic elution: 98:2 heptane/i- PrOH, flow rate = 0.8 mL/min).

2-(1-methoxy-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)acetic acid

WHC-XV-94: To a solution of 2-(1-methoxy-3-(2-methylbut-3-en-2-yl)-2- oxoindolin-3-yl)acetonitrile (236 mg, 0.87 mmol) in DMSO (2.4 mL) was added anhydrous potassium carbonate (236 mg) followed by 30% aqueous hydrogen peroxide (0.87 mL) at room temperature. The heterogeneous mixture was stirred for 12 h, diluted 234 with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to provide 2-(1-methoxy-3-(2- methylbut-3-en-2-yl)-2-oxoindolin-3-yl)acetamide (250 mg, 99%) as a white solid. To a solution of this compound (174 mg, 0.6 mmol) and DMAP (7.3 mg, 0.06 mmol) in THF (3 mL) was added di-t-butyl dicarbonate (0.28 mL, 1.21 mmol) at room temperature. The mixture was stirred for 8 h, diluted with water and extracted with

EtOAc. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the doubly Boc-protected amide (270 mg, 92%). To a solution of this amide (208 mg, 0.426 mmol) in THF (3 mL) was added LiOH·H2O (179 mg, 4.26 mmol), 30% aqueous hydrogen peroxide (0.97 mL, 8.52 mmol) and water (1 mL) at room temperature. After stirring for 12 h, saturated aqueous sodium bisulfate was added and the mixture extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The crude product was loaded on SiO2 and eluted with EtOAc/hexanes/acetic acid (80:120:1) to afford the title 1 compound as a yellow oil (115 mg, 93%). H NMR (400 MHz, CDCl3): δ 7.27 (app td, J = 8, 1 Hz, 1H), 7.08 (d, J = 8 Hz, 1H), 6.98 (app t, J = 8 Hz, 1H), 6.90 (d, J = 8 Hz, 1H), 5.93 (dd, J = 18, 11 Hz, 1H), 5.11 (d, J = 11 Hz, 1H), 5.00 (d, J = 18 Hz, 1H), 3.86 (s, 3H), 3.12 (d, J = 18 Hz, 1H), 2.84 (d, J = 18 Hz, 1H), 1.08 (s, 3H), 0.98 (s, 3H) ppm; 13 C NMR (125 MHz, CDCl3): δ 175.5, 173.3, 141.3, 128.6, 126.3, 122.3, 114.8, 107.0,

62.2, 53.3, 41.8, 36.7, 21.95, 21.86 ppm; IR (thin film): νmax 3042, 2931, 2900, 1699, -1 1595, 1444, 1175, 1145, 901 cm .

(E)-Methyl 3-[1-[(2-(trimethylsilyl)ethoxy)methyl]-1H-imidazol-4-yl]acrylate

To a solution of (E)-urocanic acid methyl ester (0.61 g, 4.03 mmol) in dry DMSO (15.0 mL) under argon atmosphere at 0 °C was added dry NaH (powdered 95%, 0.12 g, 4.84 mmol) and the suspension was left at the same temperature for 15 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (0.68 mL, 4.84 mmol) was added in three portions and the reaction mixture was allowed to warm to room temperature for 10 h.

235

The reaction was quenched with 0.5 N NaOH (15 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic phases were washed with twice with brine, dried

(Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (70% EtOAc/hexanes) afforded the title compound as a pale yellow oil. Yield 78%; Rf 1 = 0.35 (80% EtOAc/hexanes); Η ΝΜR (300 MHz, CDCl3): δ 8.58 (s, 1H), 7.52 (d, 1H, J = 16.0 Hz), 7.35 (s, 1H), 6.68 (d, 1H, J = 16.0 Hz), 5.42 (s, 2H), 3.82 (s, 3H), 3.58 (t, 13 2H, J = 8.0 Hz), 0.96 (t, 2H, J = 8.0 Hz), 0.01 (s, 9H); C NMR (125 MHz, CDCl3): δ 166.64, 137.98, 134.48, 130.47, 121.21, 120.59, 50.85, 76.79, 68.14, 51.95, 18.22, 1.44.

IR (thin film): νmax 3055, 2892, 2841, 1671, 1611, 1469, 1408, 1335, 1251, 1077, 845 -1 cm . methyl 2-formamidoacrylate

Prepared via the method of Feringa and coworkers.30 Serine methyl ester hydrochloride (1 g, 6.4 mmol, 1 equiv.), potassium carbonate (3.5 g, 4 equiv.), triethylamine (0.01 mL), and methyl formate (10 mL) were combined and stirred for 40 h at room temperature. The resulting suspension was filtered through a pad of Celite and concentrated in vacuo. The resulting solid was loaded on SiO2 and eluted with 40%- 60% EtOAc/hexanes to afford an 88:12 mixture of trans and cis isomers isolated as a white solid in 89% yield. Rf 0.56 (heptanes-ethyl acetate 1:1). M.p. 51-55 °C (lit. 53-56 °C). 1H NMR (300 MHz, CDCl3) δ 8.56 (d, J = 11.4 Hz, 1H, cis), 8.41 (s, 1H, trans), 7.87 (br, 1H, trans), 7.60 (br, 1H, cis), 6.63 (s, 1H, trans), 5.95 (s, 1H, trans), 5.69 (s, 1H, cis), 5.44 (s, 1H, cis), 3.85 (s, 3H).

236

1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbaldehyde

Sodium hydride (60% dispersion in mineral oil, 440 mg, 11 mmol) was added to a solution of imidazole-4-methanol (981 mg, 10 mmol, 1 equiv.) in DMF (20 mL) and the resulting mixture was stirred for 1 h at room temperature. The resulting yellow mixture was cooled to 0 °C and 2-(trimethylsilyl)ethoxymethyl chloride (1.95 mL, 11 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 18 h, then quenched with pH 7 phosphate buffer and extracted with EtOAc (3x30 mL). The combined organics were washed with saturated aqueous LiCl

(3x25 mL) and brine (25 mL), dried (MgSO4) and concentrated in vacuo to afford a 1:1 mixture of the two N-SEM isomers, 1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazole-4-methanol and 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5- methanol. The crude product was dissolved in 1,4-dioxane (20 mL) and activated MnO2 (Aldrich, 10 g) was added. The resulting suspension was stirred at 80 °C for 2 h, then filtered through a pad of Celite and concentrated in vacuo. The residue was redissolved in MeCN (8 mL) and 2-(trimethylsilyl)ethoxymethyl chloride (0.18 mL, 1 mmol) was added. The resulting solution was heated to 80 °C for 36 h, then concentrated in vacuo, loaded on SiO2 and eluted with 50% EtOAc/hexanes to 100% EtOAc to afford the title compound (1.82 g, 81%) as a yellow oil and single regioisomer by 1H and 13C NMR. 1 H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.71 (s, 1H), 7.68 (s, 1H), 4.60 (s, 2H), 3.56 13 (t, 2H, J = 8.0 Hz), 0.88 (t, 2H, J = 8.0 Hz), -0.04 (s, 9H); C NMR (100 MHz, CDCl3)

δ 186.3, 138.9, 124.6, 94.5, 76.8, 65.2, 18.3, -1.2; IR (thin film): νmax 3055, 2897, 2841, -1 1660, 1509, 1457, 1225, 1126, 1083, 1041, 919, 820 cm .

237 methyl 2-formamido-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4- yl)acrylate

To a solution of methyl 2-(dimethoxyphosphoryl)-2-formamidoacetate (70 mg, 0.3 mmol) and sodium iodide (45 mg, 0.3 mmol) in THF (2 mL) was added DBU (0.045 mL, 0.3 mmol) at 0 °C. After stirring for 2 h at 0 °C, 1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbaldehyde (23 mg, 0.1 mmol) was added and the reaction stirred for 15 h while warming to room temperature. The reaction was quenched with pH 7 phosphate buffer and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was loaded on SiO2 and eluted with 75% EtOAc:hexanes to afford the title compound as a 2.6:1 mixture of olefin isomers (19.1 mg, 56%, pale yellow oil). 1H

NMR (600 MHz, CDCl3) δ 10.86 (br s, 1H, major), 10.20 (br s, 1H, minor), 9.06 (d, 1H, J = 8 Hz, major), 8.38 (d, 1H, J = 8 Hz, minor), 7.79 (s, 1H, minor), 7.67 (s, 1H, major), 7.19 (s, 1H), 5.34 (s, 2H), 3.89 (s, 3H), 3.52 (t, 2H, J = 8 Hz), 0.94 (t, 2H, J = 8 Hz),

0.02 (s, 9H); IR (thin film): νmax 3276, 3011, 2902, 1708, 1689, 1671, 1555, 1457, 1140, -1 944 cm .

5.9 References

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41 Creedon, S. M.; Crowley, H. K.; McCarthy, D. G. J. Chem. Soc., Perkin Trans. 1 1998, 1015–1018. 42 Echigo, Y.; Watanabe, Y.; Mukaiyama, T. Chem. Lett. 1977, 697. 43 McCauley, J. I. Synlett 2012, 23, 2999–3000. 44 Skorna, G.; Ugi, I. Angew. Chem. Int. Ed. Engl. 1977, 16, 259–260. 45 Ukai, T.; Kawazura, H.; Ishii, Y.; Bonnett, J. J.; Ibers, J. A. J. Organomet. Chem. 1974, 65, 263.

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