Use of diamines containing the α-phenylethyl group as chiral ligands in the asymmetric hydrosilylation of prochiral ketones

Chiral diamines 1-7 were used in the enantioselective hydrosilylation of prochiral aromatic and aliphatic ketones. Some of these ligands combine chiral backbones and chiral N,N′-α-phenylethyl substituents that give rise to synergistic effects between these two groups and lead to catalysts that exhibit high enantioselectivity.     

Chiral terpene auxiliaries IV: new monoterpene PHOX ligands and their application in the catalytic asymmetric transfer hydrogenation of ketones

New PHOX ligands, derived in three steps from (1R,2S,3R,5R)-3-amino-apopinan-2-ol 1 and (1R,2R,3S,5R)-3-amino-pinan-2-ol 2 were applied as chiral ligands for the formation of ruthenium catalysts. The catalysts were used in asymmetric transfer hydrogenations of prochiral ketones producing the corresponding alcohols in moderate to high yields and enantioselectivity.     

Facile allylboration of ketones with β-benzyloxy-γ,γ-difluoroallylboronate: Preparation of gem-difluorinated homoallylic tert-alcohols

The reaction of β-benzyloxy-γ,γ-difluoroallylboronate, at room temperature and in the absence of catalysts, with a variety of aromatic and aliphatic ketones of varying sterics and electronic requirements furnishes fluorinated homoallylic tert-alcohols in 62-82% yields. Representatives of these alcohols were converted to their corresponding α,α-difluoro-β-hydroxy ketones in 73-85% yields.     

A flexible enantioselective approach to 3,4-dihydroxyprolinol derivatives by SmI2-mediated reductive coupling of chiral nitrone with ketones/aldehydes

A flexible enantioselective approach to polyhydroxylated prolinol derivatives was described, which is based on the samarium diiodide-mediated reductive coupling of the chiral nitrone (3S,4R)-8, derived from d-isoascorbic acid with aldehydes/ketones. Thereby, polyhydroxyprolinol derivatives 9a–e and 9h–j were obtained from aromatic ketones and aliphatic aldehydes in good to excellent yields of 65–91%. These reductive hydroxyalkylations are highly diastereoselective in establishing the C-4 stereogenic center. By this way, the asymmetric syntheses of (?)-8a-epi-swainsonine (4) and (?)-8,8a-di-epi-swainsonine (5) have been achieved.     

An access to α, β-unsaturated ketones via dual cooperative catalysis

A dual cooperative organocatalytic approach for the synthesis of α, β-unsaturated ketones is described. This one pot transformation is realized via a domino Knoevenagel-Michael-retro Michael reaction sequence. Various aliphatic ketones reacted smoothly with aromatic as well as aliphatic aldehydes in presence catalytic amount of Meldrum’s acid and bifunctional amine. The highlights of this protocol are the easy availability of catalysts, high selectivity, and functional group tolerance. The reaction proved to highly E-selective with no side products emanating from self-condensation, unlike the base-mediated reactions.     

Novel cyclic β-aminophosphonate derivatives as efficient organocatalysts for the asymmetric Michael addition reactions of ketones to nitrostyrenes

Three novel catalysts based upon cyclic β-aminophosphonate derivatives 1–3 were designed to catalyze the asymmetric Michael addition reactions of ketones to β-nitrostyrenes. Among the catalysts that have been prepared in this study, cyclic β-aminophosphonic acid monoethylester 3 showed the highest catalytic ability, giving the corresponding Michael adduct in good yields, high enantioselectivities (up to 92% ee), and high diastereoselectivities (syn:anti up to 95:5).     

Asymmetric intramolecular cyclopropanation of diazo compounds with metallosalen complexes as catalyst: structural tuning of salen ligand

Intramolecular cyclopropanation of alkenyl α-diazoacetates and alkenyl diazomethyl ketones was examined by using optically active (ON⁺)Ru(II)(salen) and Co(II)(salen) complexes as catalysts. For the cyclization of 2-alkenyl α-diazoacetates, Co(II)(salen) complexes 9 and 10 were found to be superior catalysts to the corresponding (ON⁺)Ru(II)(salen) complexes 4 and 5. On the other hand, (ON⁺)Ru(II)(salen) complex 2 was found to be the catalyst of choice for the cyclization of 3-alkenyl diazomethyl ketones, and complex 4 was found to be a good catalyst for the cyclization of (E)-4-alkenyl diazomethyl ketones. The present study demonstrates that metallosalen complexes, especially optically active (ON⁺)Ru(II)(salen) and Co(II)(salen) complexes, can serve as efficient catalysts for the cyclization of alkenyl diazocarbonyl compounds, if a suitable salen ligand is used as the chiral auxiliary.     

Generation of dienone and trienone dianion derivatives : Double deprotonation as a route to lumo-filled π-systems

Conjugated unsaturated carbonyl compounds and their analogues 1 are a^1,3,5...-reagents. An umpolung of this intrinsic reactivity can be achieved by generation of the dianions 2, LUMO filled π-systems, from hydrogenated precursors, see schemes 1 and 2. The preparation of the allylated ketones 3a–d, of the acid derivatives 3e–h, 9, 10, 12 as well as of the dienones 11 is described. Their double deprotonation (→14, 18, 26, 30, 33, 36, and 40) is carried out by sequential treatment with potassium hydride and s-butyllithium/tetramethylethylene diamine (TMEDA) in THF. The decisive role of potassium in the second deprotonation step is demonstrated (Table 1 and eqn (6)). The brightly colored suspensions or solutions of these Li/K-dianions were quenched with the electrophile benzophenone. The products (15, 20, 27, 31, 34, 37, 41) result exclusively from ω-reactivity (d⁵- and d⁷reactivity) of the ambident dianionic nucleophiles (cf formulae 2, n = 2,3).     

Organozinc alkoxide-promoted aldol-Tishchenko reaction of aliphatic aldehydes: an expedient entry to prepare the α-methylene ketones

i-PrOZnEt is an excellent reagent to promote the aldol-Tishchenko reaction of the aliphatic aldehydes tethered with other labile functional groups. The 1,3-diol monoesters 4 were formed as the major products, which could be converted to α-methylene ketones 7 in two steps in good yields.     

Asymmetric oxazaborolidine-catalyzed reduction of prochiral ketones with N-tert-butyl-N-trimethylsilylamine-borane

Employing N-tert-butyl-N-trimethylsilylamine-borane (1) as the borane source and 5-10% (R)-Me-CBS (2), the oxazaborolidine-catalyzed reduction of representative aryl and aliphatic ketones was carried out obtaining the corresponding alcohols (3) in 83-89% isolated yields and 69-98% ee.     

Highly enantioselective cyanosilylation of ketones catalyzed by a bifunctional Ti(IV) complex

A bifunctional catalyst system composed of (S)-prolinamide (2a), titanium(IV) isopropoxide, and phenolic N-oxide (3f) exhibited high catalytic efficiency in the enantioselective cyanosilylation of ketones. In the presence of 2.5 mol % catalyst, a variety of aromatic and aliphatic ketones were converted into the corresponding tertiary cyanohydrin O-TMS ethers in excellent yields (up to 96%) and high enantioselectivities (up to 96% ee). A proposed catalytic cycle was illustrated to explain the origin of the asymmetric induction.     

A divergent method to key unit of tubulysin V through one-pot diastereoselective Mannich process of N,O-acetal with ketone

An efficient diastereoselective approach to access (4R)-hydroxy-(2S)-substituted methyl ketones pyrroles skeleton 4a-s has been developed through Mannich process involving N,O-acetal 6 and ketones and propionaldehyde in excellent yield with high diastereoselectivity (dr up to 99:1). In addition, the utility of this convenient Mannich process is demonstrated by the diastereoselective synthesis of Tuv fragment (2) and its analogue (18) of tubulysin V (1e).     

Samarium diiodide-mediated reductive couplings of chiral nitrones with aldehydes/ketones and acyl chlorides

The SmI₂-mediated and H₂O-promoted reductive cross-coupling reactions of the l-tartaric acid derived nitrone (3S,4S)-8 with aldehydes/ketones, and the l-malic acid derived nitrone (S)-6 with aliphatic acyl chlorides have been investigated, respectively. (2R,3S,4S)-1,3,4-Trihydroxyprolinol derivatives 9a-f were obtained with high C-2/C-3 trans-selectivities, and 72:28-85:15 diastereoselectivities at the carbinol center from aromatic ketones/aldehydes, while low diastereoselectivities for aliphatic aldehydes. Conditions have been established for the syntheses of (2R,3S,4S)-3,4-dihydroxyprolinol derivatives such as 18, by N-O bond cleavage of the corresponding N-hydroxyprolinol derivatives 9b-f, or more conveniently by a one-pot reductive coupling of nitrone 8 and in situ N-O bond cleavage of the resultant coupling product. The 2-acyl-3-benzyloxy-1-hydroxypyrrolidines 10a-f were formed in 48-82% yields, and in 74:26-78:22 diastereoselectivities. It was revealed that the amount of water required for the reaction is substrate-depending.     

Asymmetric indium-mediated Barbier-type allylation reactions with ketones to form homoallylic alcohol products

We report a general method for the enantioselective allylation of both aromatic and aliphatic ketones under indium-mediated Barbier-type conditions. Using 2 equiv of a commercially available amino alcohol, either (1S,2R)-(+)-2-amino-1,2-diphenylethanol ((+)-1) or (1R,2S)-(−)-2-amino-1,2-diphenylethanol ((−)-1) as the chiral auxiliary, good yields and enantioselectivities were achieved. To our knowledge, the enantioselectivities reported herein are the highest obtained for the indium-mediated allylations of ketones, specifically the homoallylic alcohol product obtained from the addition to α,α,α-trifluoroacetophenone provided 80% enantiomeric excess.     

Three new dibromopyrrole alkaloids from the South China Sea sponge Agelas nemoechinata

Three new dibromopyrrole alkaloids, 9-N-methylcylindradine A (1), 1-N-methylugibohlin (2), nemoechine H (3), together with one known dibromopyrrole alkaloid N-methyldibromoisophakellin (4) were isolated from the South China Sea sponge Agelas nemoechinata. Their structures were elucidated by comprehensive spectroscopic methods including HRESIMS and NMR, and the absolute configuration of compound 1 was further confirmed by comparison of optical rotation. Compound 3 exhibited moderate cytotoxic activity against K562 and L-02 with IC₅₀ values of 6.1 μM and 12.3 μM, respectively.     

Aluminum enolates via retroaldol reaction: catalytic tandem aldol-transfer—Tischtschenko reaction of aldehydes with aldol adducts of ketones to ketones

Bidentate aluminum chelates derived from biphenol, binaphthol and catechol were found to be efficient catalysts for aldol-transfer reactions of ketone to ketone aldol adducts with aliphatic or aromatic aldehydes giving rise to the formation of aldol adducts of ketones to the aldehydes. In the presence of an excess of an aliphatic aldehyde, a catalytic tandem aldol-transfer—Tischtschenko reaction is observed. The tandem reaction produces monoesters of 1,3-diols with high anti selectivity and with modest to good chemical yield. 1,2-Unsaturated aldehydes are less reactive in the aldol-transfer reaction and require 2-4 times higher load of the catalyst to be used than aliphatic and aromatic aldehydes. Poor diastereoselectivity was observed in the formation of α-substituted aldols and 2-substituted monoesters of anti-1,3-diols indicating that the aldol-transfer reaction is not diastereoselective with the catalysts studied. The utility of the highly 1,3-anti selective formation of diolmonoesters was found to be limited by acyl migration.     

Enantioselective conjugate addition of ketones to β-nitrostyrenes catalyzed by 1,2-amino alcohol-derived prolinamides

Various l-prolinamides 14, prepared from l-proline and chiral β-amino alcohols, are active bifunctional catalysts for the direct nitro-Michael addition of ketones to β-nitrostyrenes. In particular, catalyst 14e prepared from l-proline and (1S,2R)-cis-1-amino-2-indanol exhibits the highest catalytic performance working in polar aprotic solvents such as NMP. High syn-diastereoselectivities (up to 94% de) and good enantioselectivities (up to 80% ee) were obtained at rt.     

Linear polystyrene anchored l-proline,new recyclable organocatalysts for the aldol reaction in the presence of water

Two l-proline-based linear polystyrene anchored catalysts 1a and 1b have been synthesized efficiently. The catalytic activities and stereoselectivity of these readily tunable and amphiphilic organocatalysts were evaluated in the direct asymmetric aldol reaction of various aromatic aldehydes and ketones. By using 5 mol % of the catalysts, the corresponding products of the aldol reaction were obtained in good yields (up to 94%) and with excellent anti diastereoselectivities (up to 96:4) and enantioselectivities (up to 96% ee) in DMF in the presence of water. The yields of these reactions in a ketone/water mixture were lower than those in wet DMF (up to 76%). However, the stereoselectivity was comparable (up to 93:7 anti/syn ratio and 95% ee, respectively). In addition, catalysts 1a and 1b could be recovered by a simple precipitation and filtration process. They could also be re-used for at least five times without obvious loss of catalytic efficiency.     

Catalytic asymmetric borane reduction of prochiral ketones by the use of diazaborolidine catalysts prepared from chiral β-diamines

The catalytic asymmetric borane reduction of prochiral ketones was examined in the presence of chiral diazaborolidine catalysts prepared in situ from chiral β-diamines and borane. Chiral secondary alcohols were obtained with modest to high enantiomeric excesses (up to 92% ee) using (S)-2-[(4-trifluoromethyl)anilinomethyl]indoline 2f.     

Enantioselective epoxidation of α,β-unsaturated ketones catalyzed by stapled helical l-Leu-based peptides

Stapled helical l-leucine-based heptapeptides were synthesized and used as catalysts for the enantioselective epoxidation of α,β-unsaturated ketones. All N-terminal free stapled peptides were successfully used as chiral catalysts. Among them, the use of H-hS₃,₇hS-10 gave epoxide products with high enantioselectivities of up to 99% ee. Furthermore, the dominant conformations of the N-terminal protected stapled peptides R₃,₇R-10 and hS₃,₇hS-10 were investigated by ¹H NMR, IR, CD spectra, and X-ray crystallographic analysis. The peptide R₃,₇R-10 formed a right-handed (P) α-helix in solution and in the crystalline state, while hS₃,₇hS-10 formed a right-handed (P) 3₁₀-helix in solution.