Super Silyl Group Research Articles

Room Temperature Intermolecular Dearomatization of Arenes by an Acyclic Iminosilylene.

A novel nontransient acyclic iminosilylene (1), bearing a bulky super silyl group (-SitBu3) and N-heterocyclic imine ligand with a methylated backbone, was prepared and isolated. The methylated backbone is the feature of 1 that distinguishes it from the previously reported nonisolable iminosilylenes, as it prevents the intramolecular silylene center insertion into an aromatic C-C bond of an aryl substituent. Instead, 1 exhibits an intermolecular Büchner-ring-expansion-type reactivity; the silylene is capable of dearomatization of benzene and its derivatives, giving the corresponding silicon analogs of cycloheptatrienes, i.e. silepins, featuring seven-membered SiC6 rings with nearly planar geometry. The ring expansion reactions of 1 with benzene and 1,4-bis(trifluoromethyl)benzene are reversible. Similar reactions of 1 with N-heteroarenes (pyridine and DMAP) proceed more rapidly and irreversibly forming the corresponding azasilepins, also with nearly planar seven-membered SiNC5 rings. DFT calculations reveal an ambiphilic nature of 1 that allows the intermolecular aromatic C-C bond insertion to occur. Additional computational studies, which elucidate the inherent reactivity of 1, the role of the substituent effect, and reaction mechanisms behind the ring expansion transformations, are presented.

Super silyl-based stable protecting groups for both the C- and N-terminals of peptides: applied as effective hydrophobic tags in liquid-phase peptide synthesis.

Tag-assisted liquid-phase peptide synthesis (LPPS) is one of the important processes in peptide synthesis in pharmaceutical discovery. Simple silyl groups have positive effects when incorporated in the tags due to their hydrophobic properties. Super silyl groups contain several simple silyl groups and play an important role in modern aldol reactions. In view of the unique structural architecture and hydrophobic properties of the super silyl groups, herein, two new types of stable super silyl-based groups (tris(trihexylsilyl)silyl group and propargyl super silyl group) were developed as hydrophobic tags to increase the solubility in organic solvents and the reactivity of peptides during LPPS. The tris(trihexylsilyl)silyl group can be installed at the C-terminal of the peptides in ester form and N-terminal in carbamate form for peptide synthesis and it is compatible with hydrogenation conditions (Cbz chemistry) and Fmoc-deprotection conditions (Fmoc chemistry). The propargyl super silyl group is acid-resistant, which is compatible with Boc chemistry. Both tags are complementary to each other. The preparation of these tags requires less steps than previously reported tags. Nelipepimut-S was synthesized successfully with different strategies using these two types of super silyl tags.

Second Generation of Aldol Reaction.

Since the discovery of the Mukaiyama aldol reaction more than 40 years ago, several landmark publications have inspired researchers in the field. The Mukaiyama AR is one of the most significant named reactions in organic synthesis. In the past few decades, development of the modern AR has been at the forefront in addressing the challenges of regio-, chemo-, diastereo-, and enantioselectivity in organic synthesis. All of these selectivity challenges maybe present in a single pair of reactants, thus controlling the outcome of such a process has great practical value. More than 10 years ago, our group became involved in this iconic carbon-carbon bond-forming process and attempted to very closely investigate all possible features of the AR to solve several issues still encountered by chemists, most notably the selectivity challenges mentioned above. In this context, our group initiated the second generation of the AR based on a Lewis or Brønsted acid-catalyzed process in conjunction with the use of a "super silyl" (tris(trimethylsilyl)silyl) directing group, which has demonstrated unrivalled properties in controlling the outcome of the AR. Using the extraordinary power of the super silyl group, we were able to develop new methods and concepts that broadly impacted the ability to control the selectivity attributes and thus allowed for a highly stereoselective construction of polyketide, halogenated polyketide, polypropionate, and polyol scaffolds through inter- and/or intramolecular aldolization protocols. Our diastereoselective ARs of super silyl enol ethers and aldehydes have shown great efficiency and modularity in producing exclusively and preferentially syn- or anti-adducts, creating up to four new adjacent stereocenters in a one-pot sequential manner and under mild reaction conditions. The super silyl-directed AR does not only provide a solution to stereochemistry control challenges, but also offers an efficient, modular and high yielding technique toward nontrivial construction of complex architectures with unprecedented ease. We believe that the new Lewis- or Brønsted-acid-catalyzed super-silyl-directed AR processes chronicled in our laboratories have come to maturity and now offer a "road map" for strategic stereoselective synthesis of polyketide-like units. Herein we report our recent achievements in the diastereoselective C-C bond formation, through the super-silyl-directed AR, toward the synthesis of complex and sophisticated hydroxy aldehydes. We would like to note that due to the extremely broad range of work reported in this field, only stereoselective AR involving aldehyde-derived super SEEs will be discussed in this Account.

ChemInform Abstract: Enantioselective Formal Syntheses of 11 Nuphar Alkaloids and Discovery of Potent Apoptotic Monomeric Analogues.

Concise, scalable, and enantioselective formal syntheses of eight dimeric and three monomeric nuphar alkaloids were achieved, along with the construction of a stereochemically diverse collection of the first known monomeric analogues having apoptotic activity. The syntheses involved the development of highly enantioselective Bronsted acid catalyzed vinylogous Mukaiyama-Mannich reactions, which feature the unprecedented use of a supersilyl group to control the regio-, enantio- and diastereoselectivity. Biological studies reveal that several of these novel nuphar analogues are even more potent than their dimeric natural product counterparts.

Enantioselective Formal Syntheses of 11 Nuphar Alkaloids and Discovery of Potent Apoptotic Monomeric Analogues

AbstractConcise, scalable, and enantioselective formal syntheses of eight dimeric and three monomeric nuphar alkaloids were achieved, along with the construction of a stereochemically diverse collection of the first known monomeric analogues having apoptotic activity. The syntheses involved the development of highly enantioselective Brønsted acid catalyzed vinylogous Mukaiyama–Mannich reactions, which feature the unprecedented use of a supersilyl group to control the regio‐, enantio‐ and diastereoselectivity. Biological studies reveal that several of these novel nuphar analogues are even more potent than their dimeric natural product counterparts.

Enantioselective Formal Syntheses of 11 Nuphar Alkaloids and Discovery of Potent Apoptotic Monomeric Analogues.

Concise, scalable, and enantioselective formal syntheses of eight dimeric and three monomeric nuphar alkaloids were achieved, along with the construction of a stereochemically diverse collection of the first known monomeric analogues having apoptotic activity. The syntheses involved the development of highly enantioselective Brønsted acid catalyzed vinylogous Mukaiyama-Mannich reactions, which feature the unprecedented use of a supersilyl group to control the regio-, enantio- and diastereoselectivity. Biological studies reveal that several of these novel nuphar analogues are even more potent than their dimeric natural product counterparts.

Silyloxy Amino Alcohol Organocatalyst for Enantioselective 1,3‐Dipolar Cycloaddition of Nitrones to α,β‐Unsaturated Aldehydes

AbstractThe catalytic activity of a simple amino alcohol that contains a bulky super silyl group [i.e., tris(trimethylsilyl)silyl (TTMSS)] bonded to the oxygen atom at the γ‐position along with a primary amine moiety was examined in the enantioselective 1,3‐dipolar cycloaddition of nitrones to α,β‐unsaturated aldehydes. The organocatalyst successfully provided optically active isoxazolidines in good chemical yields (up to 86 %) with excellent diastereoselectivities (endo/exo, up to 96:4) and enantioselectivities (up to 97 % ee). Furthermore, the obtained isoxazolidines were easily converted into γ‐amino diols that contain three contiguous stereogenic centers.

ChemInform Abstract: The Supersilyl Group as a Carboxylic Acid Protecting Group: Application to Highly Stereoselective Aldol and Mannich Reactions.

AbstractThe silyl group ‐Si(SiEt3)3 is used for the first time as stable and effective protecting group in the title reactions.

A Dihydrodisilene Transition Metal Complex from an N-Heterocyclic Carbene-Stabilized Silylene Monohydride

Through the use of an N-heterocyclic carbene (NHC) and the super-silyl group (tBu3Si), the novel silylene hydride 2 could be synthesized and isolated in 41% yield. The reaction of 2 with bis(1,5-cyclooctadiene)nickel(0) afforded complex 3, which represents the first example of a dihydrodisilene transition metal complex. Compounds 2 and 3 were fully characterized, including single-crystal X-ray diffraction analysis. The reaction mechanism for the formation of 3 from 2 was investigated by density functional theory calculations, which showed that migration of the NHC from silicon to nickel takes place in this reaction.

ChemInform Abstract: Generation of Organolithium Compounds Bearing Super Silyl Ester and Their Application of Matteson Rearrangement.

AbstractThe super silyl group Si(SiEt3)3 is found to be an efficient and robust protecting group for carboxylic acids.

Aldol and Mannich Reactions with Supersilyl-Protected Carboxylic Acids

Key words stereoselective aldol reaction - stereoselective Mannich reaction - supersilyl group - lithium

The Supersilyl Group as a Carboxylic Acid Protecting Group: Application to Highly Stereoselective Aldol and Mannich Reactions

Silyl superpowers: The supersilyl group was investigated as a superior carboxylic acid protecting group. Supersilyl esters were also utilized as stable carboxylic acid synthetic equivalents in highly stereoselective aldol and Mannich reactions (see scheme). The value of this method lies in easy photodeprotection and in the rapid synthesis of polyketide subunits.

The Supersilyl Group as a Carboxylic Acid Protecting Group: Application to Highly Stereoselective Aldol and Mannich Reactions

The Supersilyl Group as a Carboxylic Acid Protecting Group: Application to Highly Stereoselective Aldol and Mannich Reactions

β-Siloxy-α-haloketones through highly diastereoselective single and double mukaiyama aldol reactions.

Double-action haloketones: A super silyl group enabled the first highly diastereoselective Mukaiyama aldol reactions of α-chloro- and α-fluoroketones with a wide range of aldehydes, providing anti-β-siloxy-α-haloketones. This process is compatible with one-pot double-aldol methodology and allows for rapid access to new halogen-modified polyketide fragments bearing up to four contiguous stereocenters.

Effect of the “Supersilyl” Group on the Reactivities of Allylsilanes and Silyl Enol Ethers

Kinetics of the reactions of allylsilanes (1) and silyl enol ethers (2) with benzhydrylium ions (3) were studied by UV-vis spectroscopy in dichloromethane at 20 °C. The less than three times higher reaction rates of the tris(trimethylsilyl)silyl compounds in comparison to the corresponding trimethylsilyl compounds indicate that the previously reported strong electron-donating effect of the supersilyl group operates only in the α-position and not in the β-position.

A Comparative Study of (tBu3Si)SiX2SiX2(SitBu3) (X = Cl, Br, I) Including the Result of the X-Ray Structure Analysis of (tBu3Si)SiI2SiI2(SitBu3)

AbstractThe tetraiodotetrasilane (tBu 3 Si)SiI 2 SiI 2 (SitBu 3 ) can be prepared from precursor (tBu 3 Si)SiH 2 SiH 2 (SitBu 3 ). When (tBu 3 Si)SiH 2 SiH 2 (SitBu 3 ) was treated with an excess of iodine at 120 °C, (tBu 3 Si)SiI 2 SiI 2 (SitBu 3 ) was formed. X-ray quality crystals of (tBu 3 Si)SiI 2 SiI 2 (SitBu 3 ) were grown from benzene at ambient temperature. The tetraiodotetrasilane (tBu 3 Si)SiI 2 SiI 2 (SitBu 3 ) crystallizes in the monoclinic space group C2/c, a = 10.0110(10) A, b = 13.9130(10) A, c = 25.422(2) A, β = 99.072(4)°, V = 3496.6(5) A 3 , Z = 4, d calcd = 1.829 g cm 3 ; R 1 = 0.0844, wR 2 = 0.1854 for 3,017 reflections with I > 2σ(I). X-ray-crystallographic data show that the bromo and iodo derivatives (tBu 3 Si)SiX 2 SiX 2 (SitBu 3 ) (X = Br, I) are isomorphous. The solid-state structure of (tBu 3 Si)SiI 2 SiI 2 (SitBu 3 ) as well as those of (tBu 3 Si)SiX 2 SiX 2 (SitBu 3 ) (X = Cl, Br) reveals a staggered conformation which adopts a trans-orientation of the supersilyl substituent. Unequal dihedral angles as found in (tBu 3 Si)SiX 2 SiX 2 (SitBu 3 ) (X = Cl, Br, I) indicate that these compounds are sterically overcrowded.Graphical AbstractIn the solid-state (tBu 3 Si)SiI 2 SiI 2 (SitBu 3 ) features a staggered conformation which adopts a trans-orientation of the supersilyl group. However the solid-state structure of (tBu 3 Si)SiI 2 SiI 2 (SitBu 3 ) reveals unequal dihedral angles.[IMAGE]

ChemInform Abstract: The Super Silyl Group in Diastereoselective Aldol and Cascade Reactions

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Super Silyl Group for a Sequential Diastereoselective Aldol—Polyhalomethyllithium Addition Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Super Silyl Group for a Sequential Diastereoselective Aldol−Polyhalomethyllithium Addition Reaction

The super silyl group governs high diastereoselectivity and yields for a sequential aldol-polyhalomethyllithium addition reaction. This unique silyl group is necessary to obtain the diastereoselectivities associated with this sequential reaction, capable of generating two new stereocenters. Alpha-polyhalomethylcarbinols are generated with the simple and inexpensive dihalomethanes and trihalomethanes.

The unique reactivity of "super silyl" in organic synthesis: A theoretical study

We recently developed a new use of the super silyl group in organic reactions, and showed that it has unique reactivity. One of the reactions using this reagent is diastereoselective Mukaiyama aldehyde cross-aldol reaction catalyzed by a highly active Bronsted acid. This reaction produced syn-1,3-diol derivatives with high yield and high stereoselectivity. Certain features and outcomes of the reaction were not clear, so we decided to investigate the reaction mechanism through a theoretical study. In this paper, structures of super silyl species were observed as the subject of study. First 1 and 2 were investigated so that the effect of a TMS group adjacent to a silicenium ion could be determined. Interestingly, it was found that the TMS group stabilized the silicenium ion. It is presumed that the stability of the tris(trimethylsilyl) silicenium ion (TTMSS+) is related to the unique reactivity of super silyl group in theses reactions. We also investigated equivalent structures of silyl enol ethers (SEE) and found an unusual structure of 5. This structure is a result of unusual interactions between the silyl portion and enol ether (EE) portion; 1) C=C and Si-Si bonds, 2) lone pair of oxygen and Si-Si bond.