Synthesis of Cyclopropanes via Hydrogen-Borrowing Catalysis.

Cyclopropanes are highly useful motifs that are often incorporated into drug candidates to improve potency, metabolic stability, or pharmacokinetic properties. An expedient method for the α-cyclopropanation of ketones using hydrogen borrowing (HB) catalysis is described. The transformation occurs via HB alkylation of a hindered ketone with subsequent intramolecular displacement of a pendant leaving group affording the cyclopropanated product. The leaving group can be installed in either the ketone or alcohol component of the HB system, giving access to α-cyclopropyl ketones via two complementary approaches. Conversion to the corresponding carboxylic acids can be achieved in a simple two-step sequence to afford synthetically useful 1,1-substituted spirocyclopropyl acid building blocks.

Redox Reorganization: Aluminium Promoted 1,5-Hydride Shifts Allow the Controlled Synthesis of Multisubstituted Cyclohexenes.

An efficient synthesis of cyclohexenes has been achieved from easily accessible tetrahydropyrans via a tandem 1,5-hydride shift-aldol condensation. We discovered that readily available aluminium reagents, e.g. Al2 O3 or Al(Ot Bu)3 are essential for this process, promoting the 1,5-hydride shift with complete regio- and enantiospecificity (in stark contrast to results obtained under basic conditions). The mild conditions, coupled with multiple methods available to access the tetrahydropyran starting materials makes this a versatile method with exceptional functional group tolerance. A wide range of cyclohexenes (>40 examples) have been prepared, many in enantiopure form, showing our ability to selectively install a substituent at each position around the newly forged cyclohexene ring. Experimental and computational studies revealed that aluminium serves a dual role in facilitating the hydride shift, activating both the alkoxide nucleophile and the electrophilic carbonyl group.

Metal and Activating Group Free C-4 Alkylation of Isoquinolines via a Temporary Dearomatization Strategy.

A simple method for the C-4 alkylation of isoquinolines is described using benzoic acid as a nucleophilic reagent and vinyl ketones as an electrophile. The reaction shows tolerance for substitution at C-3, and C-5-C-8 positions as well as allowing some variation of the vinyl ketone electrophiles. The products contain a carbonyl that can act as a synthetic handle for further manipulations giving esters, amines, or simple alkyl products.

Alcohols as Efficient Intermolecular Initiators for a Highly Stereoselective Polyene Cyclisation Cascade.

The use of benzylic and allylic alcohols in HFIP solvent together with Ti(Oi Pr)4 has been shown to trigger a highly stereoselective polyene cyclisation cascade. Three new carbon-carbon bonds are made during the process and complete stereocontrol of up to five new stereogenic centers is observed. The reaction is efficient, has high functional group tolerance and is atom-economic generating water as a stoichiometric by-product. A new polyene substrate-class is employed, and subsequent mechanistic studies indicate a stereoconvergent mechanism. The products of this reaction can be used to synthesize steroid-analogues in a single step.

Recent advances in the dearomative functionalisation of heteroarenes.

Dearomatisation reactions of (hetero)arenes have been widely employed as efficient methods to obtain highly substituted saturated cyclic compounds for over a century. In recent years, research in this area has shifted towards effecting additional C-C bond formation during the overall dearomative process. Moving away from classical hydrogenation-based strategies a wide range of reagents were found to be capable of initiating dearomatisation through nucleophilic addition (typically a reduction) or photochemically induced radical addition. The dearomatisation process gives rise to reactive intermediates which can be intercepted in an intra- or intermolecular fashion to deliver products with significantly increased molecular complexity when compared to simple dearomatisation. In this Perspective recent examples and strategies for the dearomative functionalisation of heteroaromatic systems will be discussed.

A Vicinal Diol Approach for the Total Synthesis of Molestin E, ent-Sinulacembranolide A and ent-Sinumaximol A.

In this work an approach for the synthesis of furanocembranoid natural products containing the C-7,8-diol moiety is disclosed. This culminated in the first total synthesis of the natural product molestin E, together with ent-sinulacembranolide A and ent-sinumaximol A as well as a thorough exploration of their chemistry. Late-stage ring-closure of the C-7,8-diols to the corresponding epoxides was also demonstrated. Key features of this synthetic strategy include a stereoselective Baylis-Hillman reaction, ring-closing metathesis and Shiina macrolactonisation. Chiral-pool materials were deployed to ensure the desired absolute stereochemistry which was confirmed by late-stage single crystal X-ray diffraction.

Alcohols as Alkylating Agents in the Cation-Induced Formation of Nitrogen Heterocycles.

A Ti(Oi-Pr)4 promoted 5- or 6-endo-trig cyclisation to make nitrogen heterocycles is presented. The utilisation of HFIP as a key solvent enables the stereoselective preparation of di- & tri-substituted pyrrolidines and piperidines while forming a new C-C bond at the same time. The process is triggered by a cationic intermediate generated from an allylic or benzylic alcohol and leads to the simultaneous generation of both a C-C and a C-N bond in a single step. Notably, either 2,3-trans- or 2,3-cis-substituted heterocycles can be obtained by using a nucleophilic amine bearing different substituents. Lastly, the stereoselective synthesis of enantiopure products was achieved by using readily available enantiopure acyclic starting materials.

Evolution of the Dearomative Functionalization of Activated Quinolines and Isoquinolines: Expansion of the Electrophile Scope.

Herein we disclose a mild protocol for the reductive functionalisation of quinolinium and isoquinolinium salts. The reaction proceeds under transition-metal-free conditions as well as under rhodium catalysis with very low catalyst loadings (0.01 mol %) and uses inexpensive formic acid as the terminal reductant. A wide range of electrophiles, including enones, imides, unsaturated esters and sulfones, ß-nitro styrenes and aldehydes are intercepted by the in situ formed enamine species forming a large variety of substituted tetrahydro(iso)quinolines. Electrophiles are incorporated at the C-3 and C-4 position for quinolines and isoquinolines respectively, providing access to substitution patterns which are not favoured in electrophilic or nucleophilic aromatic substitution. Finally, this reactivity was exploited to facilitate three types of annulation reactions, giving rise to complex polycyclic products of a formal [3+3] or [4+2] cycloaddition.

Extension of hydrogen borrowing alkylation reactions for the total synthesis of (-)-γ-lycorane.

The total synthesis of (-)-γ-lycorane (10 steps) and synthesis of (±)-γ-lycorane (8 steps) was completed from cyclohexenone. A new two step hydrogen borrowing alkylation of an aziridinyl alcohol, coupled with a Ph* (Me5C6) deprotection/cyclisation procedure was developed for de novo formation of the fused 6,5 heterocyclic ring. This work is one of the first examples of hydrogen borrowing C-C bond formation being used as a key step in a total synthesis project.

Evolution of the Dearomative Functionalization of Activated Quinolines and Isoquinolines: Expansion of the Electrophile Scope.

Herein we disclose a mild protocol for the reductive functionalisation of quinolinium and isoquinolinium salts. The reaction proceeds under transition-metal-free conditions as well as under rhodium catalysis with very low catalyst loadings (0.01 mol %) and uses inexpensive formic acid as the terminal reductant. A wide range of electrophiles, including enones, imides, unsaturated esters and sulfones, ß-nitro styrenes and aldehydes are intercepted by the in situ formed enamine species forming a large variety of substituted tetrahydro(iso)quinolines. Electrophiles are incorporated at the C-3 and C-4 position for quinolines and isoquinolines respectively, providing access to substitution patterns which are not favoured in electrophilic or nucleophilic aromatic substitution. Finally, this reactivity was exploited to facilitate three types of annulation reactions, giving rise to complex polycyclic products of a formal [3+3] or [4+2] cycloaddition.

Development of an enolate alkynylation approach towards the synthesis of the taiwanschirin natural products.

Through the use of model studies, an approach was conceived towards the synthesis of the taiwanschirin family of natural products. These are structurally complex compounds which represent highly challenging and biologically active targets for total synthesis. This work describes a successful synthesis of the complex taiwanschirin fused [8,6,5] core through a novel alkynylation reaction coupled with an intramolecular Heck reaction used to construct the 8-membered ring.

Hydrogen-Borrowing Alkylation of 1,2-Amino Alcohols in the Synthesis of Enantioenriched γ-Aminobutyric Acids.

For the first time we have been able to employ enantiopure 1,2-amino alcohols derived from abundant amino acids in C-C bond-forming hydrogen-borrowing alkylation reactions. These reactions are facilitated by the use of the aryl ketone Ph*COMe. Racemisation of the amine stereocentre during alkylation can be prevented by the use of sub-stoichiometric base and protection of the nitrogen with a sterically hindered triphenylmethane (trityl) or benzyl group. The Ph* and trityl groups are readily cleaved in one pot to give γ-aminobutyric acid (GABA) products as their HCl salts without further purification. Both steps may be performed in sequence without isolation of the hydrogen-borrowing intermediate, removing the need for column chromatography.

Control of Absolute Stereochemistry in Transition-Metal-Catalysed Hydrogen-Borrowing Reactions.

Hydrogen-borrowing catalysis represents a powerful method for the alkylation of amine or enolate nucleophiles with non-activated alcohols. This approach relies upon a catalyst that can mediate a strategic series of redox events, enabling the formation of C-C and C-N bonds and producing water as the sole by-product. In the majority of cases these reactions have been employed to target achiral or racemic products. In contrast, the focus of this Minireview is upon hydrogen-borrowing-catalysed reactions in which the absolute stereochemical outcome of the process can be controlled. Asymmetric hydrogen-borrowing catalysis is rapidly emerging as a powerful approach for the synthesis of enantioenriched amine and carbonyl containing products and examples involving both C-N and C-C bond formation are presented. A variety of different approaches are discussed including use of chiral auxiliaries, asymmetric catalysis and enantiospecific processes.

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.

A hydrogen borrowing annulation strategy for the stereocontrolled synthesis of saturated aza-heterocycles.

An iridium catalyzed method for the synthesis of saturated aza-heterocycles from amines and diols is reported. A wide range of substituted heterocycles can be obtained using this approach including products bearing substituents at the C2, C3 and C4 positions. Employing water as the solvent, enantiopure diols could undergo annulation with minimal racemization, enabling the synthesis of valuable enantioenriched C3 and C4-substituted saturated aza-heterocycles.

Enantioconvergent alkylation of ketones with racemic secondary alcohols via hydrogen borrowing catalysis.

An enantioconvergent method for the alkylation of o-disubstituted aryl ketones with racemic secondary alcohols is described. This process is mediated by a commercially available iridium catalyst and proceeds via hydrogen borrowing catalysis. The highly enantioenriched ß-substituted ketone products were readily cleaved to a wide range of functional groups via retro-Friedel-Crafts acylation.

Chemo- and Regioselective Synthesis of Acyl-Cyclohexenes by a Tandem Acceptorless Dehydrogenation-[1,5]-Hydride Shift Cascade.

An atom-economical methodology to access substituted acyl-cyclohexenes from pentamethylacetophenone and 1,5-diols is described. This process is catalyzed by an iridium(I) catalyst in conjunction with a bulky electron rich phosphine ligand (CataCXium A) which favors acceptorless dehydrogenation over conjugate reduction to the corresponding cyclohexane. The reaction produces water and hydrogen gas as the sole byproducts and a wide range of functionalized acyl-cyclohexene products can be synthesized using this method in very high yields. A series of control experiments were carried out, which revealed that the process is initiated by acceptorless dehydrogenation of the diol followed by a redox-neutral cascade process, which is independent of the iridium catalyst. Deuterium labeling studies established that the key step of this cascade involves a novel base-mediated [1,5]-hydride shift. The cyclohexenyl ketone products could readily be cleaved under mildly acidic conditions to access a range of valuable substituted cyclohexene derivatives.

Reductive Hydroxymethylation of 4-Heteroarylpyridines.

The activation of pyridinium salts with electron-withdrawing heterocycles enables an iridium-catalyzed reductive hydroxymethylation reaction to proceed smoothly, facilitating the preparation of useful 3D heteroaryl-substituted functionalized piperidines. The methodology is used to prepare 3-hydroxymethylated analogues of pharmaceutical agents. Mechanistically, formaldehyde acts as both a hydride donor and the electrophile, leading to the formation of two new carbon-hydrogen bonds and one new carbon-carbon bond under relatively mild conditions.

Rhodium catalysed C-3/5 methylation of pyridines using temporary dearomatisation.

Pyridines are ubiquitous aromatic rings used in organic chemistry and are crucial elements of the drug discovery process. Herein we describe a new catalytic method that directly introduces a methyl group onto the aromatic ring; this new reaction is related to hydrogen borrowing, and is notable for its use of the feedstock chemicals methanol and formaldehyde as the key reagents. Conceptually, the C-3/5 methylation of pyridines was accomplished by exploiting the interface between aromatic and non-aromatic compounds, and this allows an oscillating reactivity pattern to emerge whereby normally electrophilic aromatic compounds become nucleophilic in the reaction after activation by reduction. Thus, a set of C-4 functionalised pyridines can be mono or doubly methylated at the C-3/5 positions.

Single point activation of pyridines enables reductive hydroxymethylation.

The single point activation of pyridines, using an electron-deficient benzyl group, facilitates the ruthenium-catalysed dearomative functionalisation of a range of electronically diverse pyridine derivatives. This transformation delivers hydroxymethylated piperidines in good yields, allowing rapid access to medicinally relevant small heterocycles. A noteworthy feature of this work is that paraformaldehyde acts as both a hydride donor and an electrophile in the reaction, enabling the use of cheap and readily available feedstock chemicals. Removal of the activating group can be achieved readily, furnishing the free NH compound in only 2 steps. The synthetic utility of the method was illustrated with a synthesis of (±)-Paroxetine.