Catalytic Enantioselective Synthesis of 3-Piperidines from Arylboronic Acids and Pyridine.

Piperidines are frequently found in natural products and are of importance to the pharmaceutical industry. A generally useful asymmetric route to enantiomerically enriched 3-substituted piperidines remains elusive. Here we report a cross-coupling approach to enantioenriched 3-piperidines from pyridine- and sp2-hybridized boronic acids. The key step involves a Rh-catalyzed asymmetric reductive Heck reaction of aryl, heteroaryl, or vinyl boronic acids and phenyl pyridine-1(2H)-carboxylate to provide 3-substituted tetrahydropyridines in high yield and excellent enantioselectivity with a wide functional group tolerance. A three-step process involving i) partial reduction of pyridine, ii) Rh-catalyzed asymmetric carbometalation, and then iii) another reduction provides access to a wide variety of enantioenriched 3-piperidines, including clinically used materials such as Preclamol and Niraparib.

Catalytic asymmetric synthesis of carbocyclic C-nucleosides.

Access to carbocyclic C-nucleosides (CC-Ns) is currently restricted. The few methods available to make CC-Ns suffer from long syntheses and poor modularity, hindering the examination of potentially important chemical space. Here we report an approach to CC-Ns which uses an asymmetric Suzuki-Miyaura type reaction as the key C-C bond forming step. After coupling the densely functionalized racemic bicyclic allyl chloride and heterocyclic boronic acids, the trisubstituted cyclopentenyl core is elaborated to RNA analogues via a hydroborylation-homologation-oxidation sequence. We demonstrate that the approach can be used to produce a variety of enantiomerically enriched CC-Ns, including a carbocyclic derivative of Showdomycin.

A General Catalyst Controlled Route to Prostaglandin F2α.

We report a general, catalyst-controlled route to prostaglandin F2α and its analogues. The approach uses a Rh-catalyzed dynamic kinetic asymmetric Suzuki-Miyaura coupling reaction between a racemic bicyclic allyl chloride and alkenyl boronic esters bearing chiral alcohols to give cyclopentyl intermediates bearing 3 contiguous stereocenters. The route provides advanced intermediates in 99% ee as a single diastereoisomer in all cases examined, with the absolute stereochemistry of the cyclopentane core controlled by the ligand. Intermediates that could be used to produce prostaglandin analogues such as bimatoprost, latanoprost, fluprostenol, and cloprostenol were synthesized. The final two stereocenters were installed via Pd-catalyzed Tsuji-Trost alkylation and iodolactonization. The synthesis of PG F2α was achieved in 19% yield in 16 longest linear steps.

Management of Duodeno-Jejunal Flexure Transection after Blunt Trauma - A Modified Approach.

Background: Small bowel injuries are infrequent after blunt trauma and typically affect fixed segment. Untimely management of such injuries, results in high-output entero-cutaneous fistula which increases morbidity and mortality. Treatment of duodeno-jejunal flexure transection has been traditionally done by pyloric exclusion with gastrojejunostomy, but more recent evidence suggests that end-to-end anastomosis or primary closure may be equally effective in which duodeno-jejunal anastomosis is protected via an external tube duodenostomy. Objective: The objective of the study is to provide a modification to the technique of management of duodeno-jejunal flexure injury, avoiding external tube duodenostomy. Material and Methods: Patients admitted from July 1, 2015 to June 1, 2018 were identified and examined for duodeno-jejunal flexure transection. Non-accidental injury cases were excluded. Results: In the study period, a total of 10 patients were admitted with duodeno-jejunal flexure transection. All cases were admitted 24 hours after the injury and presented with shock. After fluid resuscitation and investigations, they were taken for urgent laparotomy. The whole of duodenum was mobilised, the transected ends were debrided and end-to-end duodenojejunal anastomosis was performed in two-layer fashion. An 18-French Nasojejunal (NJ) tube was placed beyond the anastomosis, and an 18-French nasogastric (NG) tube was placed in the stomach for gastric decompression. A feeding jejunostomy was performed in all cases. Both NG and NJ tubes were removed after bowel movements started and FJ was removed on first follow up. There was no incidence of duodenum related complications, and all were doing well on follow up. Discussion and conclusion: Placing the nasojejunal and nasogastric tube eliminates the need for duodenostomy and gastrostomy, respectively. This method protects the duodeno-jejunal anastomosis and decreases the incidence of duodenum-related complications.

Lactone Synthesis by Enantioselective Orthogonal Tandem Catalysis.

In this work, we report enantioselective orthogonal tandem catalysis for the one pot conversion of Meldrum's acid derivatives and alkynes into δ-lactones. This new transformation, which resembles a formal [4+2] cycloaddition with concomitant decarboxylation and loss of acetone, proceeds in high yields and excellent enantioselectivity (up to 99 % ee) over a broad substrate scope. The products are densely functionalized and ripe for further transformations, as demonstrated here by both ring-opening reactions and reduction to saturated lactones. It was discovered that a new and serendipitously formed AgI -Me-StackPhos complex efficiently catalyzes the highly selective 6-endo-dig cyclization, completely reversing the regiochemistry that has been previously reported in related systems. More generally, in this study we identify a pair of compatible catalysts for alkyne difunctionalization that operate concurrently, which enable the alkyne to act as both a nucleophile and an electrophile in sequential one-pot transformations.

Enol Acetates: Versatile Substrates for the Enantioselective Intermolecular Tsuji Allylation.

A highly versatile enantioselective intermolecular Tsuji allylation that generates alpha-quaternary stereocenters is reported. The methodology utilizes a prochiral enol acetate as a substrate, which is the last class of the original Tsuji substrates to be successfully employed in an enantioselective variant of the venerable reaction. This development enables a highly convergent approach that lends itself to rapid diversification and analogue synthesis by facilitating the incorporation of the allyl moiety from an allylic alkoxide, obviating the need for the preparation of allylic enol carbonates. The reaction is operationally simple and employs the readily available PHOX ligand class. More than 30 examples are reported that proceed with enantiomeric excess (ee) values of up to 96% and a scope that tolerates a wide range of functional groups on the allylic component. The enol acetate substrates are readily prepared from both aryl and aliphatic ketones, where the regioselective preparation has long been known utilizing a variety of methods. The power of this methodology lies in its ability to quickly produce a diverse set of single enantiomer products using different allylic alcohols with a common prochiral enol acetate. This is demonstrated here by two rapid formal syntheses of hamigeran B that utilize a common intermediate to intercept both Clive and Stoltz intermediates, and also to prepare novel intermediate analogues.

Enantioselective Alkyne Conjugate Addition Enabled by Readily Tuned Atropisomeric P,N-Ligands.

By the nature of its structure, the 5-membered chiral biaryl heterocyclic scaffold represents a departure from 6-membered P,N-ligands that facilitates tuning and enables ligand evolution to address issues of selectivity and reactivity. In this vein, the Cu-catalyzed enantioselective conjugate alkynylation of Meldrum's acid acceptors is reported using Me-StackPhos. Enabled by this new ligand, the reaction tolerates a wide range of alkynes furnishing the products in high yields and excellent enantioselectivity. The transformation provides access to highly useful chiral ß-alkynyl Meldrum's acid building blocks as demonstrated by an efficient enantioselective synthesis of the preclinical agent OPC 51803.

Expeditious approach to pyrrolophenanthridones, phenanthridines, and benzo[c]phenanthridines via organocatalytic direct biaryl-coupling promoted by potassium tert-butoxide.

A methodology involving a "transition metal-free" intramolecular biaryl-coupling of o-halo-N-arylbenzylamines has been developed in the presence of potassium tert-butoxide and an organic molecule as catalyst. The reaction appears to proceed through KO(t)Bu-promoted intramolecular homolytic aromatic substitution (HAS). Interestingly, this biaryl coupling also works in the presence of potassium tert-butoxide as sole promoter. On extending our approach further, we found that N-acyl 2-bromo-N-arylbenzylamines undergo a one-pot N-deprotection/biaryl coupling followed by oxidation, thus offering an expeditious route to the phenanthridine and benzo[c]phenanthridine skeletons. The strategy has been applied to a concise synthesis of Amaryllidaceae alkaloids viz. oxoassoanine (1b), anhydrolycorinone (1d), 5,6-dihydrobicolorine (2d), trispheridine (2b), and benzo[c]phenanthridines alkaloids dihydronitidine (3b), dihydrochelerythidine (3d), dihydroavicine (3f), nornitidine (3h), and norchelerythrine (3j).