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I am highly honored to be the co-recipient of the Tetrahedron Prize for 2014 with Professor Jiro Tsuji for our work on metal catalyzed allylic alkylation, notably that using palladium. In the context of this award, this report deals only with the evolution of our work. Nevertheless, it is important to note that innumerable groups around the world have and are playing essential roles metal catalyzed allylic alkylations. The reader can find citations to such work in the references to our work that appears in this report. My involvement with this field derived from work in my laboratory dealing with the structure determination and synthesis of the insect juvenile hormone.1 The juvenile hormone is one of three hormones that control the stages of insect development from the pupae to the larvae and finally to the adult. Thus, these hormones, most notably the juvenile hormone that prevented molting was targeted as a potentially more environmentally benign insecticide. The structural relationship of the insect juvenile hormone and methyl farnesoate suggests a possible biosynthetic pathway may be involving the homologation of two of the olefinic methyl groups to ethyl groups. Such an approach, if feasible, would be very attractive, short, and potentially very practical. Unfortunately, such a synthetic protocol did not exist – a fact that intrigued me. While the reactions of the oxygen analog wherein alkylation at the carbon adjacent to the π-unsaturated carbonyl group is one of the most important synthetic reactions, the inability of the all carbon analog to undergo a similar transformation was very attractive.

A tricyclic core containing a 5,7-fused bicyclic unit of rameswaralide was prepared starting from a 1,6-enyne. The synthetic sequence involved (i) ruthenium-catalyzed [5+2]-cycloaddition of 1,6-enyne, (ii) an acyl radical based approach to construct the lactone, and (iii) a regioselective installation of the conjugated double bond by a concomitant sulfenylation–dehydrosulfenylation sequence.

Palladium catalyzed additions of terminal alkynes to alkynoates can lead from preferential to exclusive CC bond formation at the α-carbon and, in the case of ethyl 3-dimethylphenylsilylpropiolate, complete selectivity for α-attack, an unprecedented regioselectivity that requires revision of the earlier assignment of regioselectivity.

Exclusive Z-selectivity in the Ru-catalyzed bromoalkylation of alkynes with vinyl ketones is observed with aryl and other tertiary substituted acetylenic substrates, a feature that has led to an efficient synthesis of a COX-2 inhibitor. © 2000 Elsevier Science Ltd. All rights reserved. In previous papers, we reported the ruthenium-catalyzed haloalkylation of acetylenes could occur with either a cis 1 or trans 2 geometry to form Z-1 or E-1, respectively, as outlined in Scheme 1. 3 The competition of the conversion of 2 to 3 compared to the conversion of 4 to 5 determines the geometric selectivity. Our interest in employing the Z-bromoalkenes (Z-1, XBr) in a cyclopentenone synthesis 4 stimulated the need to enhance the Z-selectivity of the bromoalkylation process. Examination of 3 and 5 suggests that the steric interactions between

[CpRu(CH3CN3)]+PF6− proves to be an effective catalyst for an intermolecular Alder ene type reaction that provides considerable broadening of scope of the process.

The combination of a Pd catalyzed mixed addition of a terminal alkyne with an internal alkyne and radical catalyzed E-Z isomerization provides an atom economical route to Z -enediynes.

The neurochemically active picrotoxane sesquiterpene corianin and several structural analogues have been prepared from inexpensive, commercially available picrotoxin.

Bifurcation of the synthetic pathway affording total syntheses of picrotoxinin, picrotin and corianin from a common synthetic intermediate derived via the palladium catalyzed enyne cycloisomerization leads to the total synthesis of the picrotoxane sesquiterpene methyl picrotoxate.

Asymmetric N-alkylation of α-amino esters in which a new stereogenic center is created at carbon is dictated by the catalyst and not the substrate.

The previous premise that a conjugating electron withdrawing group is required for the title reaction has been challenged and found to be incorrect.

Summary Enantiomerically pure vigabatrin is available in four steps and 59% overall yield from butadiene monoepoxide.

A Pd catalyzed desymmetrization of cis-3,6-dibenzoyloxy-2-cyclohexene and a Pd catalyzed cross-coupling constitute key reactions in a synthesis of the non-opioid analgesic (−)-epibatidine.

A 6 step synthesis of the title compound derives from a palladium catalyzed addition of terminal alkynes to acceptor alkynes.

The synthesis and selected transformation of some cyclopentanoid β-ketoxime sulfone derivatives are reported. Utilization of the sulfone group to stabilize adjacent negative charge facilitates smooth alkylation. Subsequent 1,4-elimination of the sulfonyl moiety generates a vinyl nitroso species that is readily intercepted by lithium acetylides.

Summary Asymmetric synthesis of an allylic azide combined with the facility of the [3.3]sigmatropic rearrangement provides a simple strategy for the synthesis of conduramine E.

Oxygen may be introduced to either carbon of 2-allylbutenolides, allowing a simple terminal alkene to be the structural precursor of the hydroxybutenolide tail of acetogenins via ruthenium and osmium catalyzed reactions.

The influence of cyclopropyl substitution on the nature of a palladium complexed trimethylenemethane intermediate was probed.

A concise synthesis of a key A-ring synthon of 1α,25-dihydroxyvitamin D 3 , 1 , has been achieved in 8 steps starting from readily available, inexpensive ethyl-4-chloroacetoacetate. This synthon serves as one of two main coupling partners in our previously developed Pd-catalyzed alkylative enyne cyclization leading toward the total synthesis of 1α,25-dihydroxyvitamin D 3 and potentially useful analogues.

The source of the asymmetric induction using chiral ligands comprising bis(2-diphenylphosphinobenzoyl) derivatives of chiral diamines and diols in palladium(0) catalyzed allylic alkylations is probed.

Using a Ru catalyzed cyclization-addition, a short synthesis of the spiroketal core corresponding to the natural enantiomer of (−)-calyculin A from R-pantolactone emerges.

A series of 1,3-dipolar cycloadditions of munchnones with acetylenic dipolarophiles was studied, wherein factors related to regioselectivity were investigated. The results from munchnones with electronically divergent thioaryl substituents compared with others bearing alkyl substituents suggest that an unsymmetrical transition state structure, rather than FMO perturbation, plays a significant role in regioselection. If eclipsing interactions preclude a highly unsymmetrical transition state however, then minimizing steric interactions becomes important. A pair of complementarily substituted munchnones, differing only in the position of isotopic labels, establishes an inherently symmetrical electronic nature of the mesoionic heterocycle.

Formation of five and six membered rings simultaneously with addition of a functionalized side chain for further elaboration occurred upon exposing a 1:1 mixture of an enyne and a pronucleophile to a palladium catalyst derived from Pd(OAc) 2 and a bidentate ligand.

Asymmetric inductions up to 71% have been observed in a Pd catalyzed version of an intramolecular Alder ene reaction.

A free carboxylic acid substituent facilitates the Pd catalysed cycloisomerization of enynes.

The stereoinduction in formation of γ-hydroxy-α,β-unsaturated enoates using chiral α-sulfinyl esters and chiral aldehydes is a function of the absolute stereochemistry of the sulfoxide, the substituent on the sulfoxide, and the amount of base.

The regioselectivity of nucleophilic attack on unsymmetrical dienyl acetates depends upon the nature of the nucleophile in which the use of the tetrahexylammonium salt decreases the rate of nucleophilic attack. Equilibration of the products does not occur to any significant extent under the conditions reported here.

The previous inability to effect palladium catalyzed cycloadditions of 2-trimethylsilylmethallyl acetate to the carbonyl group of ynones is rectified by the employment of indium acetylacetonoate as a co-catalyst.

In the context of the palladium catalyzed cycloisomerization of enynes, two of the most important tether substituents, the carbonyl group because of its general synthetic versatility and the ketal because of its prospect to induce absolute stereochemistry by employing the ketal from a chiral diol, are probed within the context of a synthesis of chokol C, an antifungal compound produced by Phleum pratense when infected by a pathogenic fungus Epichloe typhina .

A protocol whereby addition of alkynylalanes to alkylidenemalonates is followed by palladium catalyzed allylation permits vicinal β-alkynylation α-allylation in a single operation

Pd catalyzed reactions of vinyl epoxides and triphenylsilanol provide regioselective introduction of an oxygen nucleophile to create a 2-en-1,4-diol either as a monosilyl ether or a free diol.

Whereas 1,6-enynes possessing disubstituted acetylenes cyclize under Pd catalysis via a 5-exo-trig mode, such cyclizations of 1,6-enynes possessing a t

A general strategy for the synthesis of lactaranes, marasmanes, sterpuranes as well as isolactaranes which share a common structural motif begins to emerge based upon a tandem Pd catalyzed cycloisomerization - thermal cycloaddition sequence.

Replacing allylic alkylations involving allylic halides, carboxylates, etc. by the simple addition of pronucleophiles to dienes enhances efficiency of use of raw materials and reduces generation of stoichiometric by-products.

With proper choice of Pd(O) catalyst, especially by employment of a novel bidentate phosphite ligand, and substitution pattern of substrate, eight and nine membered carbocyclic ring formation dominates the normally much more favorable six and seven membered ring formation.

Evidence is presented to support the interpretation that the intramolecular enyne metathesis catalyzed by a novel palladacyclopentadiene catalyst leads to fused bicycles via two possible isomeric cyclobutene intermediates which are related by H shift.

Either E,E-3,9-dimethylundecadien-1,11-diol or its E,Z-isomer is selectively available via Pd catalyzed allylic alkylation as a function of alkylating agent and catalyst - an observation that establishes that reactions of vinyl epoxides and their related vinyl carbonates do not proceed through a common intermediate.

An enantiocontrolled synthesis of (+)-phyllanthocin from methyl R-3-hydroxyisobutyrate and the acrylic ester of D-pantolactone is accomplished in 20 steps in 5% overall yield.

The mechanism of the unusual cyclopropanation of norbornenes via oxatrimethylenemethane palladium complexes is probed by regiochemical labels to establish the symmetry of the reactive intermediate.

The reaction of vinyl epoxides with isocyanates proceeded with overall retention of configuration.

Isopropylmagnesium bromide in the presence of bis-(triphenylphosphino)- nickel(II) chloride reduces vinyl sulfides stereospecifically to the corresponding olefins without overreduction - a process which serves as a key step in the synthesis of the sex pheromone of the Douglas fir tussock moth.

The source of a rate retardation of the trimethylsilyl substituent in an alkylation reaction is probed.

The cycloaddition of 2-trimethylsilylmethylallyl acetate to aldehydes is co-catalyzed by a Pd(o) complex and a trialkyltin acetate.

Two syntheses of verrucarinic acid highlighting an oxidative cleavage of hydroxysulfides and use of mandelate esters for chromatographic resolution are reported.

Allyl acetates smoothly eliminate the elements of acetic acid in the presence of O,N-bis (trimethylsilyl) acetamide and molybdenum hexacarbonyl; a simple sequence permits elaboration of saturated aldehydes into α,β,γ,δ-dienoateswhich resulted in a four step synthesis of trichonine.

Protonic acid promoted ring-opening of epoxides by dimethyl sulphoxide at room temperature followed by treatment with diisopropylethylamine at −78°, affords α-ketols in modest to good yields.

Hydrogen peroxide in the presence of (NH4)6Mo7O24 · 4H2O and potassium carbonate is a chemoselective method to oxidize secondary alcohols to ketones and to oxidize aldehydes to acids, the latter also accelerated by cerium chloride.

Asymmetric epoxidation of tiglyl alcohol combined with Pd(0) catalyzed conversion to the vicinal diol with retention of configuration provides an efficient asymmetric synthesis of a key intermediate to (+)-citreoviral and related compounds.

Unsymmetrical allyl-allyl couplings occur between allylstannanes and allyl acetates catalyzed by palladium(O) and a novel direct coupling of an allyl acetate in the presence of a distannane and a palladium(O) catalyst is also possible.