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 © 2016 by Walter Hiu-Wo Chan. All Rights Reserved. Re-distributed by Stanford University under license with the author. 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. v 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