This Perspective describes the discovery and development of silyl glyoxylates, a new family of conjunctive reagents for use in multicomponent coupling reactions. The selection of the nucleophilic and electrophilic components determines whether the silyl glyoxylate reagent will function as a synthetic equivalent to the dipolar glycolic acid synthon, the glyoxylate anion synthon, or the α-keto ester homoenolate synthon. The ability to select for any of these reaction modes has translated to excellent structural diversity in the derived three- and four-component coupling adducts. Preliminary findings on the development of catalytic reactions using these reagents are detailed, as are the design and discovery of new reactions directed toward particular functional group arrays embedded within bioactive natural products.

The efficient synthesis of highly substituted cyclopentanols is an important task given the prevalence of this class of compounds in nature. Nitrocyclopentanols are of particular value due to the rich chemistry associated with the nitro group [1] and their potential use as aminocyclopentitol progenitors.[2] Aminocyclopentitols have generated considerable attention because of their significant biological activity and synthetic challenges presented by their often dense functionality and contiguous chiral centers. As such, the development of a flexible synthesis of functionalized nitrocyclopentanols would be a welcome addition to the synthetic toolbox. Herein we report the three-component coupling of silyl glyoxylates, CH 2 = CHMgBr, and nitroalkenes that selectively affords (Z)-silyl enol ether products through a unique vinylogous Michael cascade. The resulting functionality enables the immediate implementation of a second-stage Henry cyclization for the expeditious, diastereoselective synthesis of functionalized nitrocyclopentanols.Silyl glyoxylates are conjunctive reagents for the union of complementary nucleophilic and electrophilic partners linked at a protected glycolic acid junction.[3] The use of these reagents in coupling reactions with alkide and hydride nucleophiles [4] and carbonyl secondary electrophiles has been documented. We endeavoured to expand the utility of silyl glyoxylate chemistry to include Michael acceptors as the secondary electrophile. Nitroalkenes were chosen by virtue of their highly electrophilic character and the synthetic versatility of the nitro functionality. The proposed transformation outlined in Scheme 1 involves the addition of vinyl Grignard to the silyl glyoxylate 1 to reveal, after [1,2]-Brook rearrangement, [5] the (Z)-metallodienolate 2. [4a,c] This intermediate could act as a transient secondary nucleophile capable of engaging the nitroalkene 4 in a vinylogous Michael addition to provide enolsilane 6. As such, the combination of 1 and CH 2 =CHMgBr would function as the synthetic equivalent of the unusual a-keto ester homoenolate synthon, perhaps by way of the C-metalated tautomer 3 of the (Z)-metallodienolate (Scheme 2). [6] An open question at the outset of this inquiry was whether a/g selectivity would exhibit electrophile dependence. Previous silyl glyoxylate-based couplings predominantly provided a-selectivity from metallodienolate intermediates. [4a,c] Moreover, the vinylogous Michael reaction of metallodienolates is infrequently deployed due to an innate kinetic preference for a-addition: evaluation of frontier-orbital densities and HOMO coefficients establish the a-carbon as the more nucleophilic site. [7] While some exceptions exist, [8] successful vinylogous Michael reactions frequently require considerable prefunctionalization to control selectivity and are almost exclusively performed with butenolide derivatives [9] and a,a-dicyanoolefins.[10] A second challenge lies in the management of the relevant rate constants. Stepwise Scheme 1. Divergent silyl glyo...

The three-component coupling of Mg-acetylides, silyl glyoxylates, and nitroalkenes results in a highly diastereoselective Kuwajima-Reich/vinylogous Michael cascade that provides tetrasubstituted silyloxyallene products. The regio- and diastereoselectivity were studied using DFT calculations. These silyloxyallenes were converted to cyclopentenols and cyclopentitols via a unique Lewis-acid assisted Henry cyclization. The alkene functionality present in the cyclopentanol products can be elaborated using diastereoselective ketohydroxylation reactions.

The discovery of the (+)-α-thujone and (-)-β-thujone stereoisomers in the essential oil of sage (Salvia officinalis L.) and dietary supplements is documented for the first time. The detection was accomplished using a chiral resolution protocol of racemic α-/β-thujone on headspace solid-phase microextraction-gas chromatography-mass spectrometry. Because the previously unreported stereoisomers, (+)-α-thujone and (-)-β-thujone, are not commercially available, a three-step synthesis of racemic thujone from commercially available starting materials was developed. Thermolysis studies demonstrated that no racemization at the cyclopropane stereocenters occurs, corroborating that the detection is not an artifact from the hydrodistillation process. The developed chiral resolution of thujone was also used to provide evidence for the absence of the (+)-α-thujone and (-)-β-thujone enantiomers in other common thujone-containing essential oils.

An enantioselective Michael addition of malonates to α,β-unsaturated para-nitrophenyl esters was achieved using the Lewis basic isothiourea HyperBTM, giving excellent levels of product enantioselectivity (up to >99:1 enantiomeric ratio) in good yields and with complete regioselectivity (>20:1 regioselectivity ratio) in the presence of alternative (phenyl ketone and ethyl ester) Michael acceptors. Density functional theory calculations indicate that N-acylation is rate-limiting. This constitutes a rare example of a highly enantioselective addition of simple, readily available malonates to α,β-unsaturated esters.