Influence of N-amino protecting group on aldolase-catalyzed aldol additions of dihydroxyacetone phosphate to amino aldehydes

This work examines the influence of N-protecting groups on the conversion and stereoselectivity of dihydroxyacetone phosphate (DHAP) dependent aldolase-catalyzed aldol additions of DHAP to N-protected-3-aminopropanal. Phenylacetyl-(PhAc-), tert-butyloxycarbonyl- (^tBoc-) and fluoren-9-ylmethoxycarbonyl- (Fmoc-)-3-aminopropanal were evaluated as substrates for d-fructose 1,6-bisphosphate aldolase from rabbit muscle (RAMA), and l-rhamnulose-1-phosphate aldolase (RhuA) and l-fuculose-1-phosphate aldolase (FucA), both from Escherichia coli. Using PhAc and ^tBoc ca. 70% conversions to the aldol adduct were achieved, whereas Fmoc gave maximum conversions of ca. 25%. The stereoselectivity of the DHAP-aldolases did not depend on the N-protected-3-aminopropanal derivative. Moreover, inversion of FucA stereoselectivity relative to that obtained with the natural l-lactaldehyde was observed. Both N-PhAc and ^tBoc adduct product derivatives were successfully deprotected by penicillin G acylase (PGA)-catalyzed hydrolysis at pH 7 and by treatment with aqueous TFA (6% v/v), respectively. However, the corresponding cyclic imine sugars could not be isolated, presumable due to the presence of a highly reactive primary amine and a keto group in the molecule, which lead to a number of unexpected reactions.     

Unusual reversal of regioselectivity in antibody-mediated aldol additions with unsymmetrical methyl ketones

A catalytic regio- and enantioselective aldol reaction of various unsymmetrical methyl ketones with para-nitrobenzaldehyde has been developed using aldolase antibodies as the catalysts. It has been found that the sense and level of regioselectivity for the reactions catalysed by antibody 38C2 and 33F12 are highly dependent on the structure of both the donor and the acceptor but in contrast, antibodies 84G3 and 93F3 catalyse the exclusive formation of the linear regioisomer independent of the structure of the reactants examined. The level of enantiocontrol is very high for most reactions. Both linear aldol enantiomers could be accessed through aldol or retro-aldol reactions using the same antibody. Theoretical studies on regioisomeric α- and β-heteroatom substituted enamines derived from unsymmetrical ketones suggest that most of the linear aldol products formed in the presence of antibodies 84G3 and 93F3 must be formed from intermediate enamines which are not the thermodynamically most favourable.     

Stereoselective aldol additions of achiral ethyl ketone-derived trichlorosilyl enolates

Methods for the preparation of geometrically defined enoxy(trichlorosilanes) derived from ethyl ketone enolates have been developed. The addition of enoxy(trichlorosilanes) (trichlorosilyl enolates) to aldehydes proceeds with good yields in the presence of catalytic amounts of chiral phosphoramides. The reaction of Z-trichlorosilyl enolates to aryl aldehydes affords aldol products with good to excellent diastereo- and enantioselectivities. Phosphoramide-catalyzed aldol additions lacked substrate generality providing modest selectivities with unsaturated and aliphatic aldehydes. In all cases, the phosphoramide-catalyzed aldol addition of E-trichlorosilyl enolates to aldehydes provided good yields with moderate to good stereoselectivities.     

Diastereoselective Aldol Reaction with an Acetate Enolate: 2,6-Bis(2-isopropylphenyl)-3,5-dimethylphenol as an Extremely Effective Chiral Auxiliary

A C ₂ -symmetrical phenol was used as a chiral auxiliary in the asymmetric aldol reaction of chiral acetates with various aldehydes [Eq. (a)]. The reaction proceeds readily under mild conditions to provide aldol adducts with high enantioselectivity. LDA=lithium diisopropylamide.     

On the influence of chiral auxiliaries in the stereoselective cross-coupling reactions of titanium enolates and acetals

Titanium enolates from chiral N-propanoyl-1,3-thiazolidine-2-thiones containing bulky substituents at C4 turned out to be excellent platforms to get highly stereocontrolled cross-coupling reactions with acetals. Related oxazolidinethiones also afforded good results, but the corresponding oxazolidinones resulted completely unselective for such reactions, which proves that an exocyclic CS bond is essential to attain a synthetically useful stereocontrol.     

Synthesis of N-substituted 2,4-thiazolidinediones from oxazolidinethiones

A novel reaction has been found between oxazolidinethione and bromoacetyl bromide to afford N-substituted 2,4-thiazolidinediones through an intramolecular nucleophilic substitution reaction. Interestingly a step of elimination was carried out in trisubstituted oxazolidinethiones forming a double bond.     

Stereoselective aldol condensation reactions of iron acetyl enolates

By proper choice of counterion, the enolate of η⁵ - CpFe(CO)(PPh₃)COCH₃ will react with aldehydes to form the aldol products with high stereoselectivity.     

Anti-selective aldol reactions with titanium enolates of N-glycolyloxazolidinethiones

[reaction: see text] A highly diastereoselective anti aldol addition utilizing a variety of N-glycolyloxazolidinethiones has been developed. Enolization of an N-glycolyloxazolidinethione with titanium (IV) chloride and (-)-sparteine followed by addition of an aldehyde activated with additional TiCl(4) resulted in highly anti-selective aldol additions, typically with no observable syn isomers. Allyl-protected glycolates demonstrated the highest levels of selection and yields, although O-benzyl and O-methyl glycolyloxazolidinethiones also performed well.     

Chiral enolates for highly stereoselective aldol reactions—Scope and limitations

Enantioselective approaches to the formation of α,β-disubstituted ketones through aldol reactions are compared. A one-pot ACA/aldol domino process is lower yielding than alternative procedures involving enantiomerically pure β-substituted silyl enol ethers. The use of chiral acetals derived from hydrobenzoin provides access to syn and anti diols in moderate to good yields and high diastereoselectivities. A novel synthesis of functionalized β,γ-unsaturated acetals is also described.     

Chiral spiroborate esters catalyzed highly enantioselective direct aldol reaction

Asymmetric catalysis of chiral spiroborate esters with an O₃BN framework toward the direct aldol reaction of acetone and aromatic aldehydes was examined, and a new, efficient chiral catalyst was discovered. In the presence of the novel catalyst, acetone was allowed to react with aromatic aldehydes at 0 °C for 50 h to afford chiral β-hydroxyketone in up to >99% ee and 92% yield. The catalyst, which is readily synthesized, is highly stable to hydrolysis, thermolysis, oxidation, and racemization, can be conveniently recovered.     

PtCl4-catalyzed cyclization of N-acetyl-2-alkynylanilines: A mild and efficient synthesis of N-acetyl-2-substituted indoles

An efficient synthesis of N-acetyl-2-substituted indole derivatives via direct intramolecular hydroamination of N-acetyl-2-alkynylaniline derivatives was developed. The reaction could be applied to a wide range of substrates employing only 1–2?mol% of PtCl₄ as the catalyst to furnish the desired indole products in moderate to excellent yields. The current protocol is efficient, reliable and scalable, and could serve as an important tool for convenient and rapid access to this important class of N-heterocyclic skeleton from readily available substrates.     

Highly diastereoselective aldol additions to five-ring N,O-acetals

Highly diastereoselective aldol additions of pure (2R,4S)-2-tert-butyloxazolidinone-3,4-dicarboxylic acid 3-tert-butyl ester 4-methyl ester 1 are reported. While achiral carbonyl compounds lead to mixtures of diastereomers, the double stereodifferentiation of chiral aldehydes gave a single product isomer. The relative and absolute configurations of the aldol products were assigned by NOESY.     

Development of an N-sulfinyl prolinamide for the asymmetric aldol reaction

A new class of organocatalysts is reported that incorporates an N-sulfinyl amide in place of the carboxylic acid of proline to serve as a hydrogen bond donor, chiral directing group, and solubilizing element. The successful application of this type of catalyst to the asymmetric aldol reaction of acetone and aryl aldehydes, for which proline performs poorly, is also described.     

Generation of rhodium enolates via retro-aldol reaction and its application to regioselective aldol reaction

Retro-aldol reactions of β-hydroxy ketones take place under rhodium catalysis, leading to regioselective formation of the corresponding rhodium enolates. The enolates react with aldehydes in situ to afford the corresponding aldol adducts in high yields.     

Carbohydrates as Chiral Auxiliaries in Stereoselective Synthesis. New Synthetic Methods (90)

Carbohydrates are inexpensive natural products in which numerous functional groups and stereogenic centers are combined in one molecule. By directed regio-and stereoselective formation of derivatives they can be converted into efficient chiral auxiliaries for controlling asymmetric syntheses. Stereoelectronic effects and pre-orientation of the reactive and shielding groups through formation of complexes can often be used for effective diastereofacial differentiation. In aldol reactions and alkylations on carbohydrate ester enolates intramolecular complexation promotes simultaneous elimination with formation of ketene. The steric, stereoelectronic, and coordinating properties of carbohydrate templates can also be used selectively to attain high levels of asymmetric induction in processes such as Diels–Alder reactions, hetero-Diels–Alder reactions, [2 + 2] cycloadditions, cyclopropanations, and Michael additions. It was possible with bicyclic, strongly stereodifferentiating carbohydrate auxiliaries to achieve a diastereoselective synthesis of carboxylic acid derivatives branched in the β position by a new 1,4-addition of alkylaluminum halides to α,β-unsaturated N-acylurethanes, in which methylaluminum halides and higher alkyl- or arylaluminum compounds behave mechanistically in a strikingly different manners. As complex ligands in chiral reagents and promoters, carbohydrates allow highly stereoselective reductions and aldol reactions that lead, amongst others, to chiral alcohols and β-hydroxy-α-amino acids in excellent enantiomeric excesses. Glycosylamines offer the possibility of versatile stereoselective applications: in the presence of Lewis acids the corresponding aldimines permit high-yielding syntheses of enantiomerically pure α-amino acids by Strecker and Ugi reactions, controlled by steric and stereoelectronic effects and by complex formation. They can be used with equal efficiency for asymmetric syntheses of chiral homoallylamines and for asymmetric Mannich syntheses of β-amino acids and chiral heterocycles, for example alkaloids.     

Lewis acid-catalyzed asymmetric radical additions of trialkylboranes to (1R,2S,5R)-2-(1-methyl-1-phenylethyl)-5-methylcyclohexyl-2H-azirine-3-carboxylate

The asymmetric addition of alkyl radicals to (1R,2S,5R)-2-(1-methyl-1-phenylethyl)-5-methylcyclohexyl-2H-azirine-3-carboxylate (1) yielding the corresponding 2-alkylaziridine-2-carboxylates has been investigated. High diastereoselectivities and good yields were obtained in the addition of primary alkyl radicals to azirine 1, while secondary radicals gave a lower dr. The influence of Lewis acids was also investigated; 10 mol% of CuCl were found to increase the dr.     

Stereoselective titanium-mediated aldol reactions of (S)-2-tert-butyldimethylsilyloxy-3-pentanone

Titanium-mediated aldol reactions based on (S)-2-tert-butyldimethylsilyloxy-3-pentanone, a lactate-derived chiral ketone, provide the corresponding 2,4-syn-4,5-syn adducts in high yields and diastereomeric ratios with a wide array of achiral and chiral aldehydes. Furthermore, spectroscopic studies of intermediates involved in the process have permitted to propose a mechanism that accounts for the experimental results.     

Stereoselective aldol reactions of dihydroxyacetone derivatives catalyzed by chiral Zn2+ complexes

The direct aldol reaction between a protected dihydroxyacetone derivative and 4-nitrobenzaldehyde catalyzed by chiral Zn²⁺ complexes of 1-(n-carboxylalkyl)-7-aminoacyl-1,4,7,10-tetraazacyclododecane is reported. New Zn²⁺ complexes containing l-histidine and carboxylalkyl chains that mimic a class II aldolase, carboxypeptidase A and a serine protease were designed and synthesized. Syn-aldol products were mainly formed by an aldol reaction of acetonide-protected dihydroxyacetone with benzaldehydes and other benzaldehydes in N-methylpyrrolidone (NMP)/alcohol (MeOH, EtOH or 2-PrOH) in good yields with a high degree of diastereo- and enantioselectivity (56%～quant., 57～>99% ee). Mechanistic aspect based on ESI-HRMS, elemental analysis and pH titrations of model ligands is also discussed.     

Photophysical properties and photoreduction of N-acetyl- and N-benzoylphthalimides

The photophysical properties and photoreduction of N-acetylphthalimide (AcP) and N-benzoylphthalimide (BzP), N-3,4,5-trimethoxybenzoylphthalimide (trimethoxyBzP) and N-4-nitrobenzoylphthalimide (nitroBzP) were studied by steady-state and transient techniques. Radicals and their precursor triplet states were detected by flash photolysis. The triplet state properties of AcP and BzP were characterized. In contrast, no triplet absorption was observed with ns-detection for trimethoxyBzP and nitroBzP. Specific products are formed upon electron transfer from triethylamine to the photoexcited acylphthalimides. In addition, H-atom transfer from 2-propanol or other alcohols to the triplet state takes place. The properties of several radical intermediates involved in photoreduction of the acylphthalimides as well as some structure-function relationships are described.     

Direct asymmetric aldol condensation catalyzed by aziridine semicarbazide zinc(II) complexes

Previously obtained semicarbazides derived from N-triphenylmethyl-aziridine-2-carbohydrazide were explored as ligands in Zn(II) catalyzed diastereo- and enantioselective direct aldol reactions. Complexes of aziridine-semicarbazides with Zn(II) were efficient catalysts in reactions of acetone and hydroxyacetone with NO₂-substituted aromatic aldehydes in the presence of water.