A Vinyl Cyclopropane Ring Expansion and Iridium-Catalyzed Hydrogen Borrowing Cascade.

A vinyl cyclopropane rearrangement embedded in an iridium-catalyzed hydrogen borrowing reaction enabled the formation of substituted stereo-defined cyclopentanes from Ph* methyl ketone and cyclopropyl alcohols. Mechanistic studies provide evidence for the ring-expansion reaction being the result of a cascade based on oxidation of the cyclopropyl alcohols, followed by aldol condensation with the pentamethyl phenyl-substituted ketone to form an enone containing the vinyl cyclopropane. Subsequent single electron transfer (SET) to this system initiates a rearrangement, and the catalytic cycle is completed by reduction of the new enone. This process allows for the efficient formation of diversely substituted cyclopentanes as well as the construction of complex bicyclic carbon skeletons containing up to four contiguous stereocentres, all with high diastereoselectivity.

Hydrogen Borrowing Catalysis with Secondary Alcohols: A New Route for the Generation of ß-Branched Carbonyl Compounds.

A hydrogen borrowing reaction employing secondary alcohols and Ph* (Me5C6) ketones to give ß-branched carbonyl products is described (21 examples). This new C-C bond forming process requires low loadings of [Cp*IrCl2]2, relatively low temperatures, and up to 2.0 equiv of the secondary alcohol. Substrate-induced diastereoselectivity was observed, and this represents the first example of a diastereoselective enolate hydrogen borrowing alkylation. By utilizing the Ph* group, the ß-branched products could be straightforwardly cleaved to the corresponding esters or amides using a retro-Friedel-Crafts reaction. Finally, this protocol was applied to the synthesis of fragrance compound (±)-3-methyl-5-phenylpentanol.

Strategic Application and Transformation of ortho-Disubstituted Phenyl and Cyclopropyl Ketones To Expand the Scope of Hydrogen Borrowing Catalysis.

The application of an iridium-catalyzed hydrogen borrowing process to enable the formation of α-branched ketones with higher alcohols is described. In order to facilitate this reaction, ortho-disubstituted phenyl and cyclopropyl ketones were recognized as crucial structural motifs for C-C bond formation. Having optimized the key catalysis step, the ortho-disubstituted phenyl products could be further manipulated by a retro-Friedel-Crafts acylation reaction to produce synthetically useful carboxylic acid derivatives. In contrast, the cyclopropyl ketones underwent homoconjugate addition with several nucleophiles to provide further functionalized branched ketone products.

A chiral pentanidium and pyridinyl-sulphonamide ion pair as an enantioselective organocatalyst for Steglich rearrangement.

Enantioselective ion pair catalysis has gained significant attention due to its ability to exert selectivity control in various reactions. Achiral counterions have been found to play crucial roles in modulating reactivity and selectivity. The modular nature of an ion pair catalyst allows rapid alterations of the achiral counterion to achieve optimal outcomes, without the need to modify the more onerous chiral component. In this study, we report the successful development of a stable chiral pentanidium pyridinyl-sulphonamide ion pair as a nucleophilic organocatalyst for asymmetric Steglich rearrangement. The ion pair catalyst demonstrated excellent performance, leading to enantioenriched products with up to 99% ee through simple alterations of the achiral anions. We conducted extensive ROESY experiments and concluded that the reactivity and enantioselectivity were correlated to the formation of a tight ion pair in solution. Further computational analyses provided greater clarity to the structure of the ion pair catalyst in solution. Our findings reveal the critical roles of NMR experiments and computational analyses in the design and optimisation of ion pair catalysts.

A Spirobicyclo[3.1.0]Terpene from the Investigation of Sesquiterpene Synthases from Lactarius deliciosus.

Milk cap mushrooms in the genus Lactarius are known to produce a wide variety of terpene natural products. However, their repertoire of terpene biosynthetic enzymes has not been fully explored. In this study, several candidate sesquiterpene synthases were identified from the genome of the saffron milk cap mushroom L. deliciosus and expressed in a sesquiterpene-overproducing Escherichia coli strain. In addition to enzymes that produce several known terpenes, we identified an enzyme belonging to a previously unknown clade of sesquiterpene synthases that produces a terpene with a unique spiro-tricyclic scaffold. These findings add to the rich diversity of terpene scaffolds and mushroom terpene synthases and are valuable for biotechnological applications in producing these terpenoids.

Tetramethylphosphinane as a new secondary phosphine synthon.

Secondary phosphines are important building blocks in organic chemistry as their reactive P-H bond enables construction of more elaborate molecules. In particular, they can be used to construct tertiary phosphines that have widespread applications as organocatalysts, and as ligands in metal-complex catalysis. We report here a practical synthesis of the bulky secondary phosphine synthon 2,2,6,6-tetramethylphosphinane (TMPhos). Its nitrogen analogue tetramethylpiperidine, known for over a century, is used as a base in organic chemistry. We obtained TMPhos on a multigram scale from an inexpensive air-stable precursor, ammonium hypophosphite. TMPhos is also a close structural relative of di-tert-butylphosphine, a key component of many important catalysts. Herein we also describe the synthesis of key derivatives of TMPhos, with potential applications ranging from CO2 conversion to cross-coupling and beyond. The availability of a new core phosphine building block opens up a diverse array of opportunities in catalysis.

Dioxaphosphabicyclooctanes: small caged phosphines from tris(hydroxymethyl)phosphine.

Dioxaphosphabicyclo[2.2.2]octanes (L1-L4) have been prepared in a one-pot reaction from tris(hydroxymethyl)phosphine and various α,ß-unsaturated ketones. The non-volatile phosphines oxidise very slowly in air. They possess highly upfield 31P chemical shifts (-59 to -70 ppm), small cone angles (121-140°) and a similar electronic parameter to PPh3. Reaction of L1 with [Rh(acac)(CO)2] gave the complex [Rh(acac)(CO)(L1)] with a ν(CO) of 1981.5 cm-1, whereas reaction L1 with [Rh(CO)2Cl]2 gave [Rh(CO)(L1)2Cl] with a ν(CO) of 1979.9 cm-1, remarkably similar to the CO stretching frequencies reported for analogous PPh3 complexes. The cage phosphines were explored as ligands in rhodium catalysed hydroformylation of 1-octene. All of the ligands gave a linear selectivity to n-nonanal of 68%, regardless of the substituents. However the ligand substituents had a significant effect on the catalyst activity, with increased steric bulk around the coordination environment giving a three-fold increase in aldehyde yield. The phosphines undergo ligand subsitution with [Pd(MeCN)2Cl2] forming square planar trans-[Pd(L)2Cl2] complexes. Subsequent reduction with hydrazine furnishes homoleptic tetravalent [Pd(L1)4] which was applied as a catalyst in Suzuki-Miyaura couplings, furnishing the C-C coupled products in moderate yields.

A new route to bicyclo[1.1.1]pentan-1-amine from 1-azido-3-iodobicyclo[1.1.1]pentane.

From a medicinal chemistry perspective, bicyclo[1.1.1]pentan-1-amine (1) has served as a unique and important moiety. Synthetically, however, this compound has received little attention, and only one scalable route to this amine has been demonstrated. Reduction of an easily available and potentially versatile intermediate, 1-azido-3-iodobicyclo[1.1.1]pentane (2), can offer both a flexible and scalable alternative to this target. Herein, we describe our scrutiny of this reportedly elusive transformation and report our ensuing success with this endeavor.