テレビ帯における周波数共用技術の進展

(R,R)-Dimethyl tartrate acetonide 7 in THF/HMPA undergoes deprotonation with LDA and reaction at −78 °C during 12–72 h with a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated tartrates 17, 24, 33a–f, 38a,b, 41 of R,R-configuration, i.e., a stereoretentive process (13–78% yields). Separable trans-dialkylated tartrates 34a–f can be co-produced in small amounts (9–14%) under these conditions, and likely arise from the achiral dienolate 36 of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ketones 21 and 26 and then Bamford–Stevens-derived diazoesters 23 and 27, respectively. Only triethylsilyl-protected diazoester 27 proved viable to deliver a diazoketone 28. The latter underwent stereoselective carbonyl ylide formation–cycloaddition with methyl glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct 29, to give the 3,4,5-tricarboxylate-2,8-dioxabicyclo[3.2.1]octane core 31 of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates 33a,d,f, and 38a on reaction with NaOMe in MeOH at reflux favour (≈75:25) the cis-diester epimers epi-33a,d,f and epi-38a (54–67% isolated yields), possessing the R,S-configuration found in several monoalkylated tartaric acid motif-containing natural products

Total synthesis of (–)-6,7-dideoxysqualestatin H5 by carbonyl ylide cycloaddition and cross–electrophile coupling

The work presented in this thesis focuses on the total synthesis of (–)-6,7- Dideoxysqualestatin H5. Particular emphasis was the development of a cross– coupling strategy for direct delivery of the side chain towards the end of the synthesis. Various methods investigated to perform the key Csp3–Csp2 coupling initially led to the Fu variant of the Negishi coupling at elevated temperatures and subsequent cross– electrophile coupling at rt. Key features of the asymmetric synthesis of (–)-6,7- dideoxysqualestatin H5, include: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a β-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalysed cyclic carbonyl ylide formation-cycloaddition by cogeneration of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalysed Csp3–Csp2 cross–electrophile coupling between tricarboxylate core and unsaturated side-chain to complete the natural product. Following completion of the natural product, further work was carried out on the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyls. The scope and limitations of reacting unsaturated tosylhydrazones with O3 followed by Et3N for the generation of 1,4- and 1,5-diazocarbonyl systems were explored. Tosylhydrazones, from tosylhydrazide condensation with readily available δ- and ε- unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-ε-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Tosylhydrazones from cyclic enones also allowed access to 1,4- and 1,5-diazocarbonyl systems using the ozonolysis–Et3N strategy.</p

Total synthesis of (â)-6,7-dideoxysqualestatin H5 by carbonyl ylide cycloaddition and crossâelectrophile coupling

The work presented in this thesis focuses on the total synthesis of (â)-6,7- Dideoxysqualestatin H5. Particular emphasis was the development of a crossâ coupling strategy for direct delivery of the side chain towards the end of the synthesis. Various methods investigated to perform the key Csp3âCsp2 coupling initially led to the Fu variant of the Negishi coupling at elevated temperatures and subsequent crossâ electrophile coupling at rt. Key features of the asymmetric synthesis of (â)-6,7- dideoxysqualestatin H5, include: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a β-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalysed cyclic carbonyl ylide formation-cycloaddition by cogeneration of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalysed Csp3âCsp2 crossâelectrophile coupling between tricarboxylate core and unsaturated side-chain to complete the natural product. Following completion of the natural product, further work was carried out on the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyls. The scope and limitations of reacting unsaturated tosylhydrazones with O3 followed by Et3N for the generation of 1,4- and 1,5-diazocarbonyl systems were explored. Tosylhydrazones, from tosylhydrazide condensation with readily available δ- and ε- unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-ε-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Tosylhydrazones from cyclic enones also allowed access to 1,4- and 1,5-diazocarbonyl systems using the ozonolysisâEt3N strategy.</p

Alkene Ozonolysis in the Presence of Diazo Functionality: Accessing an Intermediate for Squalestatin Synthesis

Studies on both the propensity for intramolecular cycloaddition between diazo and alkene functionality, and the tolerance of α-substituted α-diazoesters towards ozone in the presence of an alkene, led to chemoselective alkene ozonolysis of an ε-unsaturated-α-diazoester to give a key racemic diazoketone for the synthesis of 6,7-dideoxysqualestatin H5.</jats:p

Alkene ozonolysis in the presence of diazo functionality: accessing an intermediate for squalestatin synthesis

Studies on both the propensity for intramolecular cycloaddition between diazo and alkene functionality, and the tolerance of α-substituted α-diazoesters towards ozone in the presence of an alkene, led to chemoselective alkene ozonolysis of an ε-unsaturated-α-diazoester to give a key racemic diazoketone for the synthesis of 6,7-dideoxysqualestatin H5

On the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyl compounds

The scope and limitations are described of reacting unsaturated tosylhydrazones with O3 followed by Et3N for the generation of 1,4- and 1,5-diazocarbonyl systems. Tosylhydrazones, from tosylhydrazide condensation with readily available δ- and ε-unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-ε-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Using the ozonolysis–Et3N strategy, tosylhydrazones from cyclic enones give 2,5- and 2,6-diazoketones with aldehyde or ester functionality at the 1-position; the α-diazoaldehydes prefer the s-trans conformation, with a rotation barrier of 74 kJ mol−1 at 25 °C determined by NMR. This one-pot ozonolysis/Bamford–Stevens chemistry demonstrates both the tolerance of tosylhydrazones to ozone, and the subsequently added amine playing a dual role to directly transform the intermediate tosylhydrazone ozonides into products containing reactive diazo and ketone functionalities; such adducts are of particular value as precursors to cyclic carbonyl ylides for 1,3-dipolar cycloadditions

Synthesis of (−)-6,7-Dideoxysqualestatin H5 by Carbonyl Ylide Cycloaddition–Rearrangement and Cross-electrophile Coupling

An asymmetric synthesis of (−)-6,7-dideoxysqualestatin H5 is reported. Key features of the synthesis include the following: (1) highly diastereoselective <i>n</i>-alkylation of a tartrate acetonide enolate and subsequent oxidation–hydrolysis to provide an asymmetric entry to a β-hydroxy-α-ketoester motif; (2) facilitation of Rh­(II)-catalyzed cyclic carbonyl ylide formation–cycloaddition by co-generation of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalyzed Csp³–Csp² cross-electrophile coupling between tricarboxylate core and unsaturated side chain to complete the natural product