Study on Pyridine-Boryl Radical-Promoted, Ketyl Radical-Mediated Carbon-Carbon Bond-Forming Reactions.

Ketyl radicals are synthetically versatile reactive species, but their applications have been hampered by harsh generation conditions employing highly reducing metals. Recently, the pyridine-boryl radical received wide attention as a promising organic reductant because of its mildness as well as convenience in handling. While probing the utility of the pyridine-boryl radical, our group observed facile pinacol coupling reactivity that had not been known at that time. This serendipitous finding was successfully rendered into a practical synthesis of tetraaryl-1,2-diols in up to 99% yield within 1 h. Subsequently, upon examinations of various reaction manifolds, a diastereoselective ketyl-olefin cyclization was accomplished to produce cycloalkanols such as trans-2-alkyl-1-indanols. Compared to the previous methods, the stereocontrolling ability was considerably enhanced by taking advantage of the structurally modifiable boryl group that would be present near the bond-forming site. In this full account, our synthetic efforts with the O-boryl ketyl radicals are disclosed in detail, covering the discovery, optimization, scope expansion, and mechanistic analysis, including density functional theory (DFT) calculations.

Stereospecific syn-dihalogenations and regiodivergent syn-interhalogenation of alkenes via vicinal double electrophilic activation strategy.

Whereas the conventional anti-dihalogenation of alkenes is a valuable synthetic tool with highly predictable stereospecificity, the restricted reaction mechanism makes it challenging to alter the diastereochemical course into the complementary syn-dihalogenation process. Only a few notable achievements were made recently by inverting one of the stereocenters after anti-addition using a carefully designed reagent system. Here, we report a conceptually distinctive strategy for the simultaneous double electrophilic activation of the two alkene carbons from the same side. Then, the resulting vicinal leaving groups can be displaced iteratively by nucleophilic halides to complete the syn-dihalogenation. For this purpose, thianthrenium dication is employed, and all possible combinations of chlorine and bromine are added onto internal alkenes successfully, particularly resulting in the syn-dibromination and the regiodivergent syn-bromochlorination.

Relayed Heteroatom Group Transfer: A Structural Reorganization between Bisthioester and Triaminophosphine to α,α-Disulfenylamide.

Simultaneous multiple displacements of organic molecules can lead to a large structural reconstruction with increased complexity that would be difficult to access otherwise. Whereas double displacement such as olefin metathesis is well-established, higher-order versions remain much more challenging, because of their intrinsic thermodynamic disadvantages. Here, we describe a newly discovered relayed heteroatom group transfer process between bisthioesters and triaminophosphines as an unusual example of a formal triple displacement. Through the oxygen/nitrogen exchange between the two simple starting materials, in addition to the 1,2-sulfur migration of a putative carbene intermediate, an organized relocation of the O/S/N groups proceeded to give a variety of α,α-disulfenylamides with excellent efficiency under ambient conditions. The experimental and computational mechanistic studies revealed the sequence of the relayed group shifts via an α,α-disulfenyl phosphonium enolate intermediate as well as the dual role of triaminophosphine as both an oxygen acceptor and a nitrogen donor.

Access to Multifunctionalized Tetrasubstituted Carbon Centers Bearing up to Three Different Heteroatoms via Tandem Geminal Chlorofluorination of 1,2-Dicarbonyl Compounds.

The incorporation of noncarbon heteroatoms into organic molecules typically instills characteristic and often valuable functionalities. The copresence of different heteroatoms can further broaden their utility through the synergistic cooperative effects, which may even lead to the discovery of formerly unavailable properties that are not just a simple accumulation of each function. However, despite increasing interest in the controllable installation of heteroatoms, it has been extremely challenging to construct carbon centers having three different heteroatoms in a synthetically useful manner. In this work, our group's tandem geminal chlorofluorination (Cl, F) strategy was applied to rationally designed heteroatom-bearing 1,2-dicarbonyl substrates, including α-keto thioesters (S), α-keto N-acylindoles (N), and α-keto acylsilane (Si), which resulted in the practical production of doubly or triply heterofunctionalized tetrasubstituted carbon centers with excellent site-selectivity.

Stereochemical modulation of ketyl radical cyclization enabled by pyridine-boryl radicals: catalytic diastereoselective synthesis of trans-2-alkyl-1-indanols.

Previously available ketyl radical cyclization conditions suffer from low and uncontrollable diastereoselectivity because of the absence of reagent-substrate interactions. In this report, stereochemical modulation was accomplished by taking advantage of the pyridine-boryl radical, which leaves the synthetically modifiable boronate moiety on the carbonyl oxygen near the reacting center during the stereo-determining cyclization step. In consequence, a catalytic diastereoselective synthesis of trans-2-substituted-1-indanols was achieved in the presence of a sterically congested six-membered diboronic ester and an efficient hydrogen atom donor.

Fluorine-Assisted Rearrangement of Geminal Azidofluorides to Imidoyl Fluorides.

Organoazide rearrangement constitutes versatile synthetic strategies but typically requires an extremely strong acid and/or a high reaction temperature. Our group recently discovered the remarkable accelerating effect of the geminal fluorine substituent that enables the facile rearrangement of azides into imidoyl fluorides without the aid of acid under much milder reaction conditions. The role of geminal fluorine was elucidated by both experimental and computational investigations. This new reactivity led to the development of a practical one-step tandem preparative method for potentially useful and bench-stable imidoyl fluorides from a wide range of structurally diverse geminal chlorofluorides. Our additional efforts to expand the reaction scope regarding the migrating group, halogen, and carbonyl function are described, and the synthetic utility of the imidoyl fluoride products was demonstrated in hopes of promoting the use of this under-appreciated functional group in the synthetic organic community.

Synthesis of cis-thiiranes as diastereoselective access to epoxide congeners via 4π-electrocyclization of thiocarbonyl ylides.

Organochalcogen heterocycles are ubiquitously present and widely utilized in various fields. Among them, oxirane has been extensively studied, and all of the stereoisomeric forms are readily available. In contrast, synthetic studies on thiirane were rarely reported, and thus the useful sulfur-congener of oxirane has been difficult to access in a stereodefined form. In this research, a general stereoselective synthesis of cis-thiiranes is accomplished by taking advantage of stereospecific electrocyclization of trans-thiocarbonyl ylides, which are generated in situ from readily available E,E-aldazine N-oxides upon treatment with Lawesson's reagent. This newly developed practical method provides a variety of cis-1,2-diarylthiiranes as essentially single diastereomers in high yields under mild reaction conditions. The intermediacy of trans-thiocarbonyl yilde is confirmed by mechanistic experiments, and the excellent stereocontrol is rationalized by DFT calculation.

α-Fluoroamine synthesis via P(III)-mediated deoxygenative geminal fluorosulfonimidation of 1,2-diketones.

A deoxygenative geminal fluorosulfonimidation of 1,2-diketones was achieved for the synthesis of tetrasubstituted α-fluoroamines under mild conditions. In this study, a transition metal-free formal N-F insertion of N-fluorobenzenesulfonimide was enabled via the Kukhtin-Ramirez reaction employing a dealkylation-resistant P(III) reagent developed in our laboratory. Computational analysis was also performed to obtain a general mechanistic picture, which explained the reactivity and selectivity for this type of reaction.

Synthesis of α-Ketoimidoyl Fluorides via Geminal Fluorine-Promoted Azide Rearrangement.

Despite the promising synthetic potential, the utilization of imidoyl fluorides has been hampered by the lack of broadly applicable preparative methods. Herein, bench-stable α-ketoimidoyl fluorides were synthesized from geminal chlorofluorides through tandem azidation/rearrangement under mild conditions. The efficiency was consistently high, regardless of the steric and electronic environments. The synthetic utility of the α-ketoimidoyl fluoride was also demonstrated. Furthermore, the remarkable accelerating effect of the geminal fluorine substituent was identified and rationalized by density functional theory calculation.

A convenient pinacol coupling of diaryl ketones with B2pin2via pyridine catalysis.

A convenient, pyridine-boryl radical-mediated pinacol coupling of diaryl ketones is developed. In contrast to the conventional pinacol coupling that requires sensitive reducing metal, the current method employs a stable diboron reagent and pyridine Lewis base catalyst for the generation of a ketyl radical. The newly developed process is operationally simple, and the desired diols are produced with excellent efficiency in up to 99% yield within 1 hour. The superior reactivity of diaryl ketone was observed over monoaryl carbonyl compounds and analyzed by DFT calculations, which suggests the necessity of both aromatic rings for the maximum stabilization of the transition states.

Phosphorus(III)-Mediated, Tandem Deoxygenative Geminal Chlorofluorination of 1,2-Diketones.

Tetrasubstituted carbon containing two different halogen substituents was constructed in a single-step operation by utilizing the carbene-like reactivity of dioxaphospholene through the tandem reaction of electrophilic and nucleophilic halogenating reagents. It was crucial to devise non-dealkylatable phosphoramidite, which enabled the efficient formation of geminal chlorofluorides from various 1,2-diketones with (PhSO2)2NF and n-Bu4NCl. In addition, selective functionalization of the chlorine substituent was demonstrated, and the absence of halogen scrambling was confirmed.

Peptoid Helix Displaying Flavone and Porphyrin: Synthesis and Intramolecular Energy Transfer.

Natural light-harvesting complexes (LHCs) absorb a broad spectrum of sunlight using a collection of photosynthetic pigments whose spatial arrangement is controlled by a protein matrix and exhibit efficient energy transfer. We constructed a novel light-harvesting protein mimic, which absorbs light in the UV to visible region (280-700 nm) by displaying flavone and porphyrin on a peptoid helix. First, an efficient synthesis of 4'-derivatized 7-methoxyflavone (7-MF, 3 and 4) was developed. The flavone-porphyrin-peptoid conjugate (FPPC) was then prepared via Miyaura borylation on a resin-bound peptoid followed by Suzuki coupling between the peptoid and pigment. Circular dichroism spectroscopy indicated that the FPPC underwent helix-to-loop conversion of the peptoid scaffold upon changing the solvent conditions. A distinct intramolecular energy transfer was observed from 7-MF to porphyrin with greater efficiency in the helix than that in the loop conformation of the peptoid, whereas no clear evidence of energy transfer was obtained for unstructured FPPC. We thus demonstrate the value of the helical peptoid, which provided a controlled orientation for 7-MF and porphyrin and modulated the energy transfer efficiency via conformational switching. Our work provides a way to construct a sophisticated LHC mimic with enhanced coverage of the solar spectrum and controllable energy transfer efficiency.

Ultrafast intramolecular proton transfer reactions and solvation dynamics of DMSO.

Ultrafast intramolecular proton transfers of 1,2-dihydroxyanthraquinone (alizarin-h2) and its deuterated product (alizarin-d2) in dimethyl sulfoxide (DMSO) have been investigated by femtosecond stimulated Raman spectroscopy. The population dynamics in the solute vibrational mode of νC=O and the coherent oscillations observed in all of the skeletal vibrational modes νC=O and νC=C clearly showed the ultrafast excited-state intramolecular proton transfer dynamics of 110 and 170 fs for alizarin-h2 and alizarin-d2, respectively. Interestingly, we have observed that the solvent vibrational modes νS=O and νCSC may also represent ultrafast structural dynamics at the frequencies for its "free" or "aggregated" species. From the kinetic analysis of the νS=O and νCSC modes of DMSO, the ultrafast changes in the solvation or intermolecular interactions between DMSO molecules initiated by the structural changes of solute molecules have been thoroughly investigated. We propose that the solvent vibrational modes νS=O and νCSC of DMSO can be used as a "sensor" for ultrafast chemical reactions accompanying the structural changes and subsequent solute-solvent interactions.

Quantitative imaging of magnetic field distribution using a pyrene-based magnetosensing exciplex fluorophore.

Quantitative imaging of magnetic field distribution was carried out using a pyrene-based magnetosensing exciplex fluorophore, pyrene-(CH2)12-O-(CH2)2-N,N-dimethylaniline (Py-12-O-2-DMA), on a conventional fluorescence microscope with an off-the-shelf LED lamp. No continuous sample supply was required for the process. The solvent system (anisole : DMF, 50 : 50 (v/v)) was carefully selected for monitoring the extent of modulation caused by the external magnetic field. The emission from Py-12-O-2-DMA increased by ca. 1.5 times under an external magnetic field of 50 mT. The pyrene-based reporter was ca. 24.7 times brighter than a previously reported phenanthrene-based complex when excited by using the widely available 355 nm excitation. Moreover, the maximum wavelength up to which Py-12-O-2-DMA could be excited (up to 380 nm) was longer than the wavelength up to which Phen-12-O-2-DMA could be excited. The combined advantages allowed the capture of magnetic field images with a high S/N ratio under milder conditions such as low illumination power, reduced sample concentration, and simpler optical setup. The system was also found to be feasible for 3D magnetic field distribution imaging by two-photon fluorescence microscopy.

Stereoselective Halogenation in Natural Product Synthesis.

At last count, nearly 5000 halogenated natural products have been discovered. In approximately half of these compounds, the carbon atom to which the halogen is bound is sp(3) -hybridized; therefore, there are an enormous number of natural products for which stereocontrolled halogenation must be a critical component of any synthesis strategy. In this Review, we critically discuss the methods and strategies used for stereoselective introduction of halogen atoms in the context of natural product synthesis. Using the successes of the past, we also attempt to identify gaps in our synthesis technology that would aid the synthesis of halogenated natural products, as well as existing methods that have not yet seen application in complex molecule synthesis. The chemistry described herein demonstrates yet again how natural products continue to provide the inspiration for critical advances in chemical synthesis.

General approach to the synthesis of the chlorosulfolipids danicalipin A, mytilipin A, and malhamensilipin A in enantioenriched form.

A second-generation synthesis of three structurally related chlorosulfolipids has been developed. Key advances include highly stereocontrolled additions to α,ß-dichloroaldehydes, kinetic resolutions of complex chlorinated vinyl epoxide intermediates, and Z-selective alkene cross metatheses of cis-vinyl epoxides. This strategy facilitated the synthesis of enantioenriched danicalipin A, mytilipin A, and malhamensilipin A in nine, eight, and 11 steps, respectively.

Approaches to the chemical synthesis of the chlorosulfolipids.

Since the initial discovery of the chlorosulfolipids in 1969, the chemical synthesis community largely ignored these compounds for nearly four decades, perhaps because they contain a high density of chlorine atoms, which suggested that these molecules and any projected synthetic intermediates might be unstable. Beginning in 2008, a sudden flurry of synthesis activity by several research groups, including our own, appeared in the literature. In this Account, we highlight our work from the last several years on the chemical synthesis of the chlorosulfolipids. Our work in this area began with attempts to stereoselectively generate the abundant dichloroalcohol functional group arrangements in these natural targets. In these early studies, we learned that many polychlorinated intermediates were far more stable than anticipated. We also developed a method for the diastereoselective dichlorination of allylic alcohol derivatives that permitted access to the syn,syn-dichloroalcohol stereotriad found in several chlorosulfolipids. Concurrently, we investigated an approach to mytilipin A that included multiple intermediates bearing aldehydes with ß-leaving groups, but this route proved intractable. However, we leveraged what we had learned from this approach into our first success in this area: we synthesized danicalipin A via a route that introduced all of the polar functional groups using alkene oxidation reactions. By adapting this relatively general strategy, we completed an enantioselective synthesis of malhamensilipin A. This body of work also resulted in the full stereochemical elucidation of danicalipin A and the structural revision of malhamensilipin A. Finally, with the advent of Z-selective alkene cross metathesis, we developed a second-generation synthesis that featured this strategy in place of a poorly performing Wittig olefination that plagued our first approach. In addition to this new convergent step, we developed a reliable protocol for diastereoselective addition to highly sensitive α,ß-dichloroaldehydes and a method for kinetic resolution of complex vinyl epoxides. Altogether, these advances led to a synthesis of enantioenriched mytilipin A in only eight steps. In the context of this work, we discovered a number of highly stereoselective reactions that might offer new, broadly applicable lessons in acyclic stereocontrol. Moreover, this research testifies to the stability of polychlorinated molecules and should inspire confidence in the use of aliphatic chlorides in other applications, including in discovery chemistry.

A synthesis of the chlorosulfolipid mytilipin A via a longest linear sequence of seven steps.

Magnificent seven: The chlorosulfolipid mytilipin A was synthesized in racemic form in seven steps and in enantioenriched form in eight steps. Key transformations include a highly diastereoselective bromoallylation of a sensitive α,ß-dichloroaldehyde, a kinetic resolution of a vinyl epoxide, a convergent and highly Z-selective alkene cross-metathesis, and a chemoselective and diastereoselective dichlorination of a complex diene.

Lewis base activation of Lewis acids: catalytic, enantioselective addition of glycolate-derived silyl ketene acetals to aldehydes.

A catalytic system involving silicon tetrachloride and a chiral, Lewis basic bisphosphoramide catalyst is effective for the addition of glycolate-derived silyl ketene acetals to aldehydes. It was found that the sense of diastereoselectivity could be modulated by changing the size of the substituents on the silyl ketene acetals. In general, the trimethylsilyl ketene acetals derived from methyl glycolates with a large protecting group on the alpha-oxygen provide enantiomerically enriched alpha,beta-dihydroxy esters with high syn-diastereoselectivity, whereas the tert-butyldimethylsilyl ketene acetals derived from bulky esters of alpha-methoxyacetic acid provide enantiomerically enriched alpha,beta-dihydroxy esters with high anti-diastereoselecitvity.