Iterative Cross-coupling Research Articles

Reactivity of 1,3-enyne MIDA boronates: exploration of novel 1,2-alkyne shift via gem-difluorination.

The discovery of a new class of heteroatom-rich boron-containing molecules (BCMs) and iterative cross-coupling (ICC) partners created a toolbox for future drug developments using organoboron compounds. Herein, we report the potential utility of 1,3-enyne MIDA boronates to access diverse gem-difluoro MIDA boronates via novel 1,2-alkyne shift. This unique reactivity of 1,3-enyne MIDA boronates offers facile access to previously challenging β-difluorinated alkyl borons. Furthermore, we demonstrated the synthesis of various novel furan-based BCMs via 5-endo-dig cyclization and iterative coupling partners via copper-catalyzed hydroboration and platinum-catalyzed diboration reaction.

Unified Total Syntheses of Benzenoid Cephalotane-Type Norditerpenoids: Cephanolides and Ceforalides.

Detailed herein are our synthetic studies toward the preparation of the C18- and C19-benzenoid cephalotane-type norditerpenoids. Guided by chemical network analysis, the core structure of this natural product family was constructed in a concise manner using an iterative cross-coupling, followed by a formal inverse-electron-demand [4 + 2] cycloaddition. Initial efforts to functionalize an alkene group in the [4 + 2] cycloadduct using a Mukaiyama hydration and a subsequent olefination led to the complete C18-carbon framework. While effective, this approach proved lengthy and prompted the development of a direct alkene difunctionalization that relies on borocupration to advance the cycloadduct to the natural products. Late-stage peripheral C-H functionalization facilitated access to all of the known cephanolides in 6-10 steps as well as five recently isolated ceforalides in 8-13 steps.

Convergence of multiple synthetic paradigms in a universally programmable chemical synthesis machine.

Although the automatic synthesis of molecules has been established, each reaction class uses bespoke hardware. This means that the connection of multi-step syntheses in a single machine to run many different protocols and reactions is not possible, as manual intervention is required. Here we show how the Chemputer synthesis robot can be programmed to perform many different reactions, including solid-phase peptide synthesis, iterative cross-coupling and accessing reactive, unstable diazirines in a single, unified system with high yields and purity. Developing universal and modular hardware that can be automated using one software system makes a wide variety of batch chemistry accessible. This is shown by our system, which performed around 8,500 operations while reusing only 22 distinct steps in 10 unique modules, with the code able to access 17 different reactions. We also demonstrate a complex convergent robotic synthesis of a peptide reacted with a diazirine-a process requiring 12 synthetic steps.

A low temperature, vinylboronate ester-mediated, iterative cross-coupling approach to xanthomonadin polyenyl pigment analogues

Approaches to the polyene natural product xanthomonadin, an octaenyl electron-deficient bacterial photoprotective agent, and its debromo analogue, were developed. These involved the iterative cross-coupling of multiple C2-fragments, using a vinylboronate ester as a formal vinyl dianion equivalent. Vinyl iodide starting materials undergo Heck-Mizoroki cross-coupling at ambient temperatures, allowing further iododeboronation to derive the next vinyl iodide. This works in a highly effective manner to access systems of up to pentaene chain length. However, final assembly of polyenylboronates with such polyenyl iodides through their Suzuki-Miyaura cross-coupling was less successful, even at lower temperatures, reflecting the extreme sensitivity of such octaenylxanthomonadin analogues. Despite this, the mild cross-coupling conditions could be effectively applied to the assembly of a range of useful polyenyl building blocks, as well as a truncated pentaenyl-debromoxanthomonadin analogue.

Using Nature's polyenes as templates: studies of synthetic xanthomonadin analogues and realising their potential as antioxidants.

Two truncated analogues of the polyenyl photoprotective xanthomonadin pigments have been synthesised utilising an iterative Heck-Mizoroki (HM)/iododeboronation cross coupling approach and investigated as models of the natural product photoprotective agents in bacteria. Despite the instability of these types of compounds, both analogues proved to be sufficiently stable to allow isolation, spectroscopic analysis and biological studies of their photoprotective behaviour which showed that despite their shorter polyene chain length, they retained the ability to protect bacteria from photochemical damage; i.e. incorporation of one compound into E. coli provided photoprotective activity against singlet oxygen analogous to the natural photoprotective mechanisms employed by Xanthomonas bacteria, answering key questions about what minimal functionality is required to impart photoprotection, potentially leading to new classes of photoprotective and antioxidants compounds.

Unexpected Alkene Isomerization during Iterative Cross-Coupling To Form Hindered, Electron-Deficient Trienes.

An iterative cross-coupling approach to conjugated trienes was explored as part of a planned stereoselective synthesis of bicyclic terpenes. Using a bifunctional bromoboronate building block, sequential Suzuki coupling reactions were employed to provide a conjugated trienone target containing a tetrasubstituted alkene. During the final cross-coupling step, an unexpected alkene isomerization was observed to give less hindered trans products. Examination of different substrates determined that conjugation to a ketone withdrawing group was responsible for isomerization, rather than steric hindrance of the tetrasubstituted alkene.

Expeditious synthesis of polyacetylenic water hemlock toxins and their effects on the major GABAA receptor isoform.

Classical synthetic approaches to highly unsaturated polyene/yne natural products rely on iterative cross-coupling of linear fragments. Herein, we present an expeditious and unified approach to the unsaturated backbone of polyacetylenes via domino cuprate addition/4π-electrocyclic ring opening of a stereodefined cyclobutene intermediate. This sets the stage for a detailed biological assessment of the role of Virol A and Cicutoxin as inhibitors of GABA induced chloride currents, providing further insight into the interaction of these highly potent toxins towards the GABAA receptor, including the structure-activity relationship of the derivatives.

C–H Activation-Based Transformation of Naphthalenes to 3-Iodo-2-naphthylboronic Acid Derivatives for Use in Iterative Coupling Synthesis of Helical Oligo(naphthalene-2,3-diyl)s

Abstract Oligo(naphthalene-2,3-diyl)s were synthesized by iterative cross-coupling of 1,8-diaminonaphthalene-modified 3-iodo-2-naphthylboronic acids prepared from naphthalenes via Ir-catalyzed C–H borylation, Ru-catalyzed ortho-C–H silylation directed by an anthranilamide-modified boronyl group, and subsequent iododesilylation. The introduction of a chiral diol to the retained terminal boronyl group allowed selective induction of P- or M-helical conformations.

Concise, diastereoconvergent synthesis of endiandric-type tetracycles by iterative cross coupling

Both fused and bridged tetracyclic scaffolds characteristic of endiandric acid-type natural products have been prepared in just seven steps each (longest linear sequence) from Burke's commercial cis-2-bromovinylboronic acid MIDA ester. Three iterative Suzuki–Miyaura couplings using MIDA boronates, including the first such example of a Z–Z coupling, trigger an 8π/6π-electrocyclization cascade. The mixture of endo and exo bicycles thus formed are elaborated into tetracycles via Horner–Wadsworth–Emmons and Diels–Alder reactions. In the process, the endo and exo diastereomers interconvert to ultimately deliver the desired products.

Synthesis of (Z)-1-Thio- and (Z)-2-Thio-1-alkenyl Boronates via Copper-Catalyzed Regiodivergent Hydroboration of Thioacetylenes: An Experimental and Theoretical Study

A Cu-catalyzed divergent hydroboration of thioacetylenes has been achieved, providing (Z)-1-thio- or (Z)-2-thio-1-alkenyl boronates in moderate to high yields with excellent regio- and stereoselectivity, by using pinacolborane or bis(pinacolato)diboron as the hydroborating reagents, respectively. DFT calculations indicate that the sulfur atom plays a key role in determining the regioselectivity through polarizing the C-C triple bonds and participating in the HOMO orbitals. Moreover, the SR group can serve as a good leaving group, resulting in the concise synthesis of six regio- and stereoisomers of trisubstituted alkenes 5 via the iterative cross-coupling of C-B and C-S bonds. Clearly, it will be valuable for assembling stereochemically diverse trisubstituted olefins in organic synthesis.

A regio- and stereoselective entry to (Z)-β-halo alkenyl sulfides and their applications to access stereodefined trisubstituted alkenes

A mild and efficient preparation of (Z)-β-halo alkenyl sulfides via the K2CO3-promoted hydrothiolation of haloalkynes has been realized, producing (Z)-β-bromo and (Z)-β-chloro vinylic sulfides in high yields with excellent regio- and stereoselectivity. This approach covers a variety of substrates, including both aryl and alkyl haloalkynes. Meaningfully, it allows a facile access to stereodefined (Z)- or (E)-trisubstituted olefins featuring the iterative cross-coupling of carbon-halide and carbon-sulfur bonds of β-halo alkenyl sulfides.

(1-Bromovinyl)-MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis

Iterative cross-coupling represents a potentially general approach for the simple, efficient, and flexible construction of a wide range of functional small molecules. In this context, (1-bromovinyl)-N-methyliminodiacetic acid (MIDA) boronate is a very useful building block for small molecule synthesis. This compound can serve as a starting material for the preparation of a wide range of 1,1-disubstituted olefin-containing MIDA boronates. This compound can also be used for the iterative cross-coupling-based synthesis of various 1,1-disubstituted olefin-containing targets. Collectively, these results contribute to the expanding generality of the MIDA boronate platform.

NickelButadiene Catalytic System for the Cross‐Coupling of Bromoalkanoic Acids with Alkyl Grignard Reagents: A Practical and Versatile Method for Preparing Fatty Acids

Fatty acids are essential to natural life because they act as key components in biological membranes and glycerides, as well as in various biologically active agents, such as prostaglandins and endocannabinoids. For the construction of structurally diverse carbon frameworks of fatty acids, transition-metal-catalyzed cross-coupling reactions appear to be the most straightforward and efficient methods for carbon carbon bond formation and they have been employed in the synthesis of a wide variety of fatty acids with unsaturated bonds. However, these methods are limited to reactions at sp or sp carbon atoms, in which the stereochemistry of the olefinic moieties that are being introduced must be controlled. In contrast to these reactions, cross-coupling reactions between sp-hybridized carbon centers appear to be a useful and, potentially, more-promising tool, because they are applicable to the synthesis of both saturated and unsaturated fatty acids and they are free from the problems associated with double-bond stereochemistry. However, owing to the lower tolerance of the carboxylic group toward organometallic reagents, including transition-metal complexes, protected carboxy groups or their synthetic equivalents are often employed. Herein, we report a convenient and efficient one-pot procedure for the construction of carbon frameworks of fatty acids by using the nickelcatalyzed cross-coupling of alkyl halides that contain a carboxy functionality with Grignard reagents in the presence of 1,3-butadiene as an additive, in combination with an in situ protection procedure. As an example of a synthetic application of this method, the regioisomers of elaidic acid were synthesized through an iterative cross-coupling procedure. In our previous studies, we reported that the Ni-catalyzed cross-coupling reactions of alkyl halides with alkyl Grignard reagents in the presence of butadienes were effective for the construction of hydrocarbon skeletons that contained aprotic polar functionalities, such as ketones, esters, and nitriles. When alkyl halides that contained a carboxylic acid group are subjected to this cross-coupling reaction, without employing tedious protection-deprotection processes, the deprotonation of the carboxylic acid group is unavoidable. Thus, to develop a simple and straightforward route to fatty acids with various carbon chains, we examined the Ni-catalyzed cross-coupling reactions of 6-bromohexanoic acid (1a) with excess amounts of nBuMgCl under various conditions and we found that the expected decanoic acid was obtained in quantitative yield as the sole product, with no evidence of any undesirable side reactions, when the reaction was conducted at 0 8C for 1 h in the presence of 2.4 equivalents of nBuMgCl (Scheme 1). In this reaction, a

One-Pot C–N/C–C Cross-Coupling of Methyliminodiacetic Acid Boronyl Arenes Enabled by Protective Enolization

Iterative cross-coupling is a highly efficient and versatile strategy for modular construction in organic synthesis, though this has historically been demonstrated solely in the context of C-C bond formation. A C-N cross-coupling of haloarene methyliminodiacetic acid (MIDA) boronates with a wide range of aromatic and aliphatic amines is reported. Successful cross-coupling of aliphatic amines was realized only through protective enolization of the MIDA group. This reaction paradigm was subsequently utilized to achieve a one-pot C-N/C-C cross-coupling sequence.

β-Oligofurans

An iterative cross-coupling strategy has led to the first synthesis of the β-oligofuran family. Every member of the series of dibrominated analogues has been accessed from the bifuran to the octafuran, along with representative diiodides, non-halogenated congeners and cyclic analogues. Solution phase spectra indicate rapid conformational interchange at ambient temperature. Whereas DFT calculations reveal the existence of several similar energy conformations, molecular structures from single crystal X-ray analyses exhibit common conformational motifs throughout the oligomeric series.

Synthesis of Synechoxanthin

Synechoxanthin was isolated in 2008 from the cyanobacterium Synechococcus sp. strain PCC 7002. It is being studied for its ­exceptionally strong antioxidant properties. The total synthesis is achieved here using an iterative cross-coupling approach for a rapid and stereocontrolled assembly of the polyene chain.

Pinene-Derived Iminodiacetic Acid (PIDA): A Powerful Ligand for Stereoselective Synthesis and Iterative Cross-Coupling of C(sp3) Boronate Building Blocks

Efficient access to chiral C(sp3) boronates in stereochemically pure form is critical for realizing the substantial potential of such building blocks in complex-molecule synthesis. We herein report that a pinene-derived iminodiacetic acid (PIDA) ligand enables the highly diastereoselective synthesis of a wide range of oxiranyl C(sp3) boronates from the corresponding olefins. These oxiranyl PIDA boronates, in turn, can be readily transformed into unprecedented stable α-boryl aldehydes via a novel 1,2-migration of the boronate group that proceeds with complete maintenance of stereochemical purity. B-Protected haloboronic acids containing dual sp3-hybridized C centers are readily accessible via this platform, and the herein demonstrated capacity for stereocontrolled iterative C(sp3) cross-coupling with this novel type of bifunctional reagent to access a medicinally important chiral small-molecule target in highly enantioenriched form represents a substantial advance for the building-block-based approach to synthesis.

Cover Picture: Total Synthesis of Synechoxanthin through Iterative Cross-Coupling (Angew. Chem. Int. Ed. 34/2011)

Cover Picture: Total Synthesis of Synechoxanthin through Iterative Cross-Coupling (Angew. Chem. Int. Ed. 34/2011)

Total Synthesis of Synechoxanthin through Iterative Cross‐Coupling

Total Synthesis of Synechoxanthin through Iterative Cross‐Coupling

( Z)-(2-Bromovinyl)-MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis

Iterative cross-coupling represents a potentially general approach for the simple, efficient, and flexible construction of a wide range of functional small molecules. In this context, ( Z)-(2-bromovinyl)- N-methyliminodiacetic acid (MIDA) boronate is a very useful building block for small molecule synthesis. This compound can serve as a starting material for the preparation of a wide range of cis-alkene-containing MIDA boronates. This compound can also be used for the iterative cross-coupling-based synthesis of various cis-olefin-containing targets. Collectively, these results contribute to the expanding generality of the MIDA boronate platform.