The catalytic decarboxylative allylation of enol carbonates: the synthesis of enantioenriched 3-allyl-3'-aryl 2-oxindoles and the core structure of azonazine.

The catalytic asymmetric synthesis of 3-allyl-3'-aryl 2-oxindoles has been shown via the Pd(0)-catalyzed decarboxylative allylation of allylenol carbonates. This methodology provides access to a variety of 2-oxindole substrates (5a-v) with all-carbon quaternary stereocenters (up to 94% ee) at the pseudobenzylic position under additive-free and mild conditions. The synthetic potential of this method was shown by the asymmetric synthesis of the tetracyclic core of the diketopiparazine-based alkaloid azonazine (11).

Sequential Selective C-H and C(sp3 )-+ P Bond Functionalizations: An Entry to Bioactive Arylated Scaffolds.

Organophosphonium salts containing C(sp3 )-+ P bonds are among the most utilized reagents in organic synthesis for constructing C-C double bonds. However, their use as C-selective electrophilic groups is rare. Here, we explore an efficient and general transition-metal-free method for sequential chemo- and regioselective C-H and C(sp3 )-+ P bond functionalizations. In the present study, C-H alkylation resulting in the synthesis of benzhydryl triarylphosphonium salts was achieved by one-pot, four-component cross-coupling reactions of simple and commercially available starting materials. The utility of the resulting phosphonium salt building blocks was demonstrated by the chemoselective post-functionalization of benzylic C(sp3 )-+ PPh3 groups to achieve aminations, thiolations, and arylations. In this way, benzhydrylamines, benzhydrylthioethers, and triarylmethanes, structural motifs that are present in many pharmaceuticals and agrochemicals, are readily accessed. These include the synthesis of two anticancer agents from simple materials in only two to three steps. Additionally, a protocol for late-stage functionalization of bioactive drugs has been developed using benzhydrylphosphonium salts. This new approach should provide novel transformations for application in both academic and pharmaceutical research.

Unsymmetrical 1,1-Bisboryl Species: Valuable Building Blocks in Synthesis.

Unsymmetrical 1,1-bis(boryl)alkanes and alkenes are organo-bismetallic equivalents, which are synthetically important because they allow for sequential selective transformations of C-B bonds. We reviewed the synthesis and chemical reactivity of 1,1-bis(boryl)alkanes and alkenes to provide information for the synthetic community. In the first part of this review, we disclose the synthesis and chemical reactivity of unsymmetrical 1,1-bisborylalkanes. In the second part, we describe the synthesis and chemical reactivity of unsymmetrical 1,1-bis(boryl)alkenes.

Thiourea-Catalyzed Enantioselective Malonate Addition onto 3-Sulfonyl-3'-indolyl-2-oxindoles: Formal Total Syntheses of (-)-Chimonanthine, (-)-Folicanthine, and (+)-Calycanthine.

A general approach to bispyrroloindolines via a key thiourea-catalyzed addition of malonates to 3-sulfonyl-3'-indolyl-2-oxindoles is reported. The enantioselelective process is found to be highly effective (up to 94% ee), where a C-C bond formation leads to the synthesis of a number of 2-oxindoles with an all-carbon quaternary stereocenter.

Cu(ii)-tBu-PHOX catalyzed enantioselective malonate addition onto 3-hydroxy 2-oxindoles: application in the synthesis of dimeric pyrroloindoline alkaloids.

An efficient Cu(ii)-PHOX-catalyzed malonate addition onto 3-hydroxy 3-indolyl-2-oxindoles is envisioned to afford excellent enantioselectivities (up to >99% ee) in high chemical yields. Detailed characterization techniques including X-ray, NMR, CV and EPR experiments suggest that a Cu(ii)-complex is involved as an active species in this process. Applying this strategy, an advanced intermediate of cyclotryptamine alkaloids has been synthesized in few steps for a general approach to bis-cyclotryptamine alkaloids.

An expeditious route to the synthesis of the enantioenriched tetracyclic core of ergot alkaloids via an organocatalytic aldol reaction.

The synthesis of the tetracyclic skeleton of ergot alkaloids has been developed via a key organocatalytic enantioselective aldol reaction using paraformaldehyde as the C1-unit in the presence of thiourea catalyst followed by a key Pd-catalyzed directed coupling accelerated by the DavePhos ligand. Utilizing the aforementioned strategy, we have synthesized a key tetracyclic intermediate in up to 95% ee with high yield.

FeCl3-Catalyzed Allylation Reactions onto 3-Hydroxy-2-oxindoles: Formal Total Syntheses of Bis-cyclotryptamine Alkaloids, (±)-Chimonanthine, and (±)-Folicanthine.

An FeCl3-catalyzed efficient strategy for the allylation reactions of 3-hydroxy-2-oxindoles with allyltrimethylsilane has been developed. The reaction affords a variety of 2-oxindoles having quaternary center at the pseudobenzylic position in an operationally simple and inexpensive procedure. Control experiments using enantioenriched 3-hydroxy-2-oxindole show that the reaction proceeds through in situ generated 2H-indol-2-one (8). The methodology presents an efficient and concise access to the pyrroloindoline alkaloids (±)-deoxyeseroline (1a), (±)-esermethole (1b), (±)-physostigmine (1c), (±)-phenserine (1d), and (±)-physovenine (1e). Eventually, we extrapolated the scope of this methodology to the formal total syntheses of dimeric cyclotyrptamine alkaloids (±)-chimonanthine (3a), (±)-folicanthine (3c), and (±)-calycanthine (4).

Highly chemoselective synthesis of dimeric 2-oxindoles with a C-3/C-5' linkage via Friedel-Crafts alkylations of 2-oxindoles with 3-hydroxy-2-oxindoles.

Simple and convenient Lewis acid-catalyzed Friedel-Crafts alkylations of 2-oxindoles as electron rich aromatics with 3-hydroxy-2-oxindoles as electron deficient partners have been developed. The reaction afforded a variety of dimeric 2-oxindoles with a C-3/C-5' linkage having an all-carbon quaternary center at the pseudobenzylic position in high yields.

Friedel-Crafts alkylations of electron-rich aromatics with 3-hydroxy-2-oxindoles: scope and limitations.

A Lewis acid-catalyzed nucleophilic addition of electron rich aromatics with 3-hydroxy-2-oxindoles 5 was developed. The reaction is believed to proceed through the 2H-indol-2-one ring system 9, which eventually reacts with various electron-rich aromatics to afford a variety of 2-oxindoles with an all-carbon quaternary center at the pseudobenzylic position (4, 8, 13, and 16) in high yields. The methodology provides an expeditious route to the tetracyclic core (3) of diazonamide (1), and azonazine (2) as well as the tricyclic core of asperazine (6a), idiospermuline (6b), and calycosidine (6c) viz. C(3a)-arylpyrroloindolines 7 having an all-carbon quaternary center on further synthetic elaboration.