Asymmetric sulfur ylide reactions with boranes: scope and limitations, mechanism and understanding

The reactions of aryl-stabilized sulfur ylides with organoboranes has been studied under a variety of conditions. At 5 or -78 degrees C, the reaction with Et3B gave a mixture of the first and second homologation products, but at -100 degrees C, only the first homologation product was obtained even with just 1.1 equiv of Et3B. Under these optimized conditions, the chiral sulfur ylides (derived from camphor sulfonic acid) with different aryl groups were reacted with Et3B to give the corresponding alcohols (95-98% yield, 96-98% ee) and amines (74-77% yield, >98% ee). The origin of the high enantioselectivity is discussed. The use of nonsymmetrical 9-BBN derivatives was also explored. It was found that whereas primary alkyl substituents gave mixtures of products derived from competing migration of the boron substituent and the boracycle, all other groups resulted in either exclusive migration of the boron substituent (Ph, hexenyl, i-Pr) or exclusive migration of the boracycle (hexynyl, cyclopropyl). The factors responsible for the outcome of the reactions involving a hindered (i-Pr) and an unhindered (propynyl) substituent were studied by DFT calculations. This revealed that, in the case of an unhindered substituent, the conformation of the ate complex is the dominant factor whereas, in the case of a hindered substituent, the barriers to interconversion between the conformers of the ate complex and subsequent migration control the outcome of the reaction.     

An efficient catalyst- and base-free Suzuki-type coupling reaction

Biaryls were prepared in good yields via a fast and efficient catalyst- and base-free Suzuki-type coupling reaction of sodium tetraphenylborate with iodanes in water at room temperature.     

Amine-directed hydroboration: scope and limitations

Iodine activation induces intramolecular hydroboration of homoallylic and bis-homoallylic amine boranes with good to excellent control of regiochemistry compared to control experiments using excess THF*BH 3. Deuterium labeling and other evidence confirm that the iodine-induced hydroboration reaction of homoallylic amine boranes occurs via an intramolecular mechanism equivalent to the classical 4-center process and without competing retro-hydroboration. Longer carbon chain tethers result in lower regioselectivity, whereas the shorter tether in allylic amines results in a switch to dominant intermolecular hydroboration. Regioselectivity in THF*BH 3 control experiments is higher for the allylic amine boranes compared to the iodine activation experiments, whereas the reverse is true for homoallylic amine borane activation.     

Solid-supported nitroso hetero diels-alder reactions. 2. Arylnitroso dienophiles: scope and limitations

Immobilized arylnitroso dienophiles were prepared and used in hetero Diels-Alder (HDA) reactions with a variety of dienes. Polymer-supported arylnitroso species were prepared on several linkers cleavable by different cleavage reagents and used for (i) optimization of reaction conditions for HDA reactions, (ii) evaluation of the reaction outcome with various dienes, (iii) comparison of relative reactivities of dienes, and (iv) assessment of the stability of HDA adducts toward cleavage conditions typically used in solid-phase preparation (TFA). The outcome of the HDA reactions has been evaluated for a set of 19 dienes, and the relative reactivities of dienes that yielded the expected HDA adducts were compared. Cleaved products were submitted to biological assays, and the results are reported.     

Solid-supported nitroso hetero Diels-Alder reactions. 1. Acylnitroso dienophiles: scope and limitations

Polymer-supported acylnitroso dienophiles were prepared and used in hetero Diels-Alder (HDA) reactions with a variety of dienes. The transient acylnitroso dienophiles were prepared in situ from immobilized hydroxamates, which were attached to solid supports via several linkers each cleavable by different cleavage reagents, and served for the synthesis of both N-unsubstituted and N-derivatized HDA adducts. Model compounds were used to (i) optimize reaction conditions for solid-supported HDA reactions, (ii) evaluate the outcome of the reactions with various dienes, (iii) compare relative reactivities of dienes, and (iv) assess the stability of HDA adducts toward cleavage conditions typically used in solid-phase syntheses. Cleaved products were submitted to biological assays, and the results are reported. The accompanying paper, focused on complementary arylnitroso HDA reactions, includes a comparison of both HDA reactions.     

The solid-phase Nicholas reaction: scope and limitations

Two libraries of alpha-substituted alkynes has been prepared on solid phase using a sequential Sonogashira/Nicholas reaction approach. The scope of nucleophiles in the Nicholas reaction on solid phase has been investigated, including carbon, oxygen, nitrogen, sulfur, fluoride, and hydride nucleophiles. The conditions for the reaction sequence have been optimized in terms of Lewis acid, catalyst for the Sonogashira step, temperature, reaction time, and decomplexation method, enabling the five-step sequence to be performed in 1 day.     

Synthesis of clustered glycoside-antigen conjugates by two one-pot, orthogonal, chemoselective ligation reactions: scope and limitations

Major histocompatibility class II antigens have been bound to clustered glycosides for selective targeting of the dendritic cell mannose receptor. Di-, tetra-, and octavalent glycoside-antigen conjugates have been obtained after two, orthogonal, hydrazone/thioether ligations, performed by using thio derivatives of D-mannose, D-galactose, or D(-)-quinic acid, glyoxylyl (or hydrazino)-N-chloroacetylated lysinyl trees, and N-terminal hydrazino (or glyoxylyl) peptide antigens. Successful one-pot condensations have been developed to account for the nature of the antigens and the valency of the trees.     

The role of achiral pyrazolidinone templates in enantioselective Diels-Alder reactions: scope, limitations, and conformational insights

We have evaluated the role of achiral pyrazolidinone templates in conjunction with chiral Lewis acids in room temperature, enantioselective Diels-Alder cycloadditions. The role of the fluxional N(1) substituent was examined, with the bulky 1-naphthylmethyl group providing enantioselectivities up to 99% ee, while templates with smaller fluxional groups gave lower selectivities. High selectivities were also observed in reactions of 7d with chiral Lewis acids derived from relatively small chiral ligands, suggesting the pyrazolidinone templates are capable of relaying stereochemical information from the ligand to the reaction center. Lewis acids capable of adapting square planar geometries, such as Cu(OTf)2, Cu(ClO4)2, and Pd(ClO4)2, were found to be particularly effective at providing high selectivities. Additionally, substitution at the C-5 position of the pyrazolidinone templates has been shown to be critical for optimal selectivity. Reactions of the optimal pyrazolidinone appended with a number of common dienophiles and various dienes demonstrate the utility of this achiral template. Furthermore, catalytic loadings could be lowered to 2.5 mol % with essentially no loss in selectivity. Pi-Pi interactions were evaluated as a means to explain the unusually high selectivity observed at room temperature. Finally, non-C2-symmetric ligands were employed as a test to determine if chiral relay was operative.     

Novel oxybispyridylboronic acids: synthesis and study of their reactivity in Suzuki-type cross-coupling reactions

This paper sets forth the synthesis of novel oxybispyridylboronic acids, which are prepared from the corresponding halo-oxybispyridines via halogen-metal exchange using n-butyllithium and treatment with triisopropylborate. A range of efficient cross-coupling reactions of these novel boronic acids with selected aryl halides is described. This strategy produces novel pyridylethers of interest in cholinergic medicinal chemistry.     

Titanium mediated alkylidenation of substituted cycloalkenones: scope and limitations

The conversion of the cyclopent-2-enone 5 and cyclohex-2-enones 11a, c-e into corresponding α′-exo-alkylidene compounds using Ti(IV) catalysis, with PPh₃ and an aldehyde, is described.     

Reversible microencapsulation of pybox-Ru chiral catalysts: scope and limitations

Chiral Pybox-Ru catalysts can be microencapsulated into linear polystyrene as a method to recover and recycle the valuable catalyst. These catalysts allow 60-68% yields to be achieved with enantioselectivities in the range 75-85% ee in the benchmark cyclopropanation reaction between styrene and ethyl diazoacetate. The catalyst is soluble in the reaction solvent and is re-encapsulated at the end of the reaction. The great advantage of this methodology is that the chiral ligand does not need to be modified, but the recycling is highly solvent dependent—in contrast with the catalysts immobilized through covalent bonds.     

Exploring the solid-phase synthesis of 3,4-disubstituted beta-lactams: scope and limitations

This work describes a comprehensive study on the solid-phase synthesis of 3,4-disubstituted beta-lactams. In situ generated ketenes react with immobilized aldimines under mild conditions to generate libraries of beta-lactams in good to very good overall isolated yields. Different commercially available solid supports were studied, with the cost-effective Wang resin proving to be the most effective. The utility of the protocol was also demonstrated by the highly efficient asymmetric versions when homochiral ketenes or homochiral aldimines were used. A practical technique for the preparation of manual solid-phase parallel libraries of biologically interesting beta-lactam compounds, using Mukaiyama's salt as dehydrating agent, is also presented. Reactions were easily monitored by FT-IR and gel-phase 13C NMR using conventional equipment.     

Side-chain migration reactions and ring B aromatization in labdanes: scope and limitations. Synthesis of isofregenedane type tetrahydronaphthalenic diterpenes

The reaction of bicyclic diterpenes with an allylic oxygenated function or an equivalent functionality on ring B in the presence of I₂/benzene afforded a simple and rapid synthesis of tetrahydronaphthalenic diterpenes of the isofregenedane class.     

Sugar-assisted glycopeptide ligation with complex oligosaccharides: scope and limitations

We have previously shown sugar-assisted ligation (SAL) to be a useful method for the convergent construction of glycopeptides. However to date SAL has only been carried out on systems where the thiol auxiliary is attached to a monosaccharide. For SAL to be truly applicable to the construction of fully elaborated glycopeptides and glycoproteins, it must be possible to carry out the reaction when the thiol auxiliary is attached to more elaborate sugars, as these are frequently what are observed in nature. Here we examine the effects of glycosylation at C-3, C-4, and C-6 of the C-2 auxiliary-containing glycan. Model glycopeptides where synthesized chemoenzymatically and reacted with peptide thioesters used in our previous work. These studies reveal that SAL is sensitive to extended glycosylation on the auxiliary-containing sugar. While it is possible to carry out SAL with extended glycosylation at C-4 and C-6, the presence of glycosylation at C-3 prevents the ligation from occurring. Additionally, with glycosylation at C-4 the ligation efficiency is affected by the identity of the N-terminal AA, while the nature of the C-terminal residue of the peptide thioester does not appear to affect ligation efficiency. These studies provide useful guidelines in deciding when it is appropriate to use SAL in the synthesis of complex glycopeptides and glycoproteins and how to choose ligation junctions for optimal yield.     

Metathesis of heteroatom-substituted olefins and alkynes: Current scope and limitations

The use of vinyl- or alkynyl derivatives of the type CC–X or CC–X (where X is an heteroatom) as substrates for metathesis increases further this reaction’s versatility. Selected examples illustrating recent progress in this area of research are presented. Current scope and future potential developments are discussed.     

Rhodium-catalyzed asymmetric cyclodimerization of oxabenzonorbornadienes and azabenzonorbornadienes: scope and limitations

Cationic rhodium(I)-catalyzed cyclodimerization of oxabenzonorbornadienes produced naphtho[1,2-b]furan ring systems in a single step with excellent yields and excellent enantioselectivities. The effect of various Rh(I) catalysts, Ag(I) salts, solvents, and phosphine ligands on the yield and enantioselectivity of the reaction was investigated, and the scope and limitations of this reaction with various oxabicyclic alkenes were studied. Similar results were obtained with the azabenzonorbornadiene analogues, providing the corresponding cyclodimerization products in excellent yields and excellent enantioselectivities.     

Some aspects of the scope and limitations of derivative spectroscopy

Synthesised spectra are used to illustrate discussion of some relationships between recorded absorption profiles and their second and fourth derivative spectra. Limitations arising from the fortuitous overlap of a derivative peak with a neighbouring wing, and the possibilities of resolving spectra into their overlapping bands are also considered. The combined use of second and fourth derivative spectra to ascertain the correct number of bands within an observed profile is described. It is suggested that the practice of computing a least-squares fit of overlapping bands to a spectral profile be changed, because the minimisation achieved often produces a result involving excessive or negative absorbances: the spectral profile should be regarded as a boundary limit and any unaccounted (positive) absorbance then assessed as possible evidence for an additional band. An example is given, concerning the resolution of the spectrum of a thin, single crystal of uranium(IV) oxide at 77 K superimposed on an absorption edge. A comparison of the difference between the observed spectrum and the sum of its resolution into twelve overlapping bands, plus a similar comparison of their fourth derivative spectra, reveals a thirteenth band.