Highly stereoselective aldol reaction based on titanium enolates from (S)-1-benzyloxy-2-methyl-3-pentanone

Alternative titanium-mediated aldol procedures based on several protected beta-hydroxy ethyl ketones have been surveyed. Eventually, enolization of (S)-1-benzyloxy-2-methyl-3-pentanone (1) with (i-PrO)TiCl3/i-Pr2NEt provided a very reactive enolate that afforded the corresponding 2,4-syn-4,5-syn aldol adducts in high yields and diastereomeric ratios with a broad range of aldehydes.     

Stereoselective aldol condensations via alkenyloxy dialkoxyboranes : mechanistic and stereochemical details

A detailed investigation of the enolization of ketones with ethylenechloroboronate ( ECB ) in the presence of a tertiary amine and the subsequent aldol condensations of these boron enolates was conducted. The enolization with ECB- DPEA system was found to be regioselective except for the case of butanone. The stereochemistry of the enolates derived from ethyl ketones was defined as Z on the basis of ¹H-NMR comparison to the Z enolates obtained by a stereodefined route. A mechanistic model for the enolization is proposed to explain the enolization selectivity. E enolates were found to be more reactive than the Z enolates. The product aldol stereochemistry ( syn ) was correlated to the enolate geometry via a chairlike transition state ( Z enolates ) or via a boatlike transition state ( E enolates ).     

Direct carbon-carbon bond formation via soft enolization: aldol addition of α-halogenated thioesters

α-Halo thioesters undergo soft enolization and syn-selective direct aldol addition to aldehydes in the presence of MgBr(2)·OEt(2) and i-Pr(2)NEt to produce α-halo-β-hydroxy thioesters.     

Boron-mediated aldol reaction of carboxylic esters: complementary anti- and syn-selective asymmetric aldol reactions

The boron-mediated aldol reaction of carboxylic esters is described in detail. Contrary to the general belief that carboxylic esters are inert under the condition of the boron enolate formation, propionate esters are enolized with certain combinations of a boron triflate and an amine. More importantly, the stereochemical course of the aldol reaction can be controlled by the judicious selection of the enolization reagents. Treatment of propionate esters with c-Hex2BOTf and triethylamine produces anti-aldol products, and that with Bu2BOTf and diisopropylethylamine gives syn-aldol products selectively after reaction with aldehydes. Complementary anti- and syn-selective asymmetric aldol reactions with structurally related, readily available chiral norephedrine-derived propionate esters are developed.     

Practical and highly selective oxazolidinethione-based asymmetric acetate aldol reactions with aliphatic aldehydes

[reaction: see text] The utility of a valine-derived oxazolidinethione for auxiliary-based asymmetric acetate aldol reactions is reported. Titanium(IV) chloride, along with (-)-sparteine and N-methylpyrrolidinone, is employed for enolization. Subsequent aldol reaction with aliphatic aldehydes occurs with high diastereoselectivity (from 92:8 to 99:1 dr).     

The vinylogous aldol reaction of unsaturated esters and enolizable aldehydes using the novel Lewis acid aluminum tris(2,6-di-2-naphthylphenoxide)

The synthesis of the novel Lewis acid, aluminum tris(2,6-di-2-naphthylphenoxide) (ATNP), and its use in the vinylogous aldol reaction between methyl crotonate and enolizable aldehydes are described. ATNP is related to Yamamoto's Lewis acid, aluminum tris(2,6-diphenylphenoxide) (ATPH), but the 2-naphthyl groups more effectively block the α-position of aldehydes, enabling the selective enolization of crotonate esters in the presence of enolizable aldehydes. Vinylogous aldol reactions then proceed smoothly and in high yields with a variety of substrates.     

Syn-anti isomerization of aldols by enolization

A variety of aldol adducts are shown to undergo efficient syn-anti isomerization in the presence of imidazole by an enolization mechanism. Isomerizations are high yielding and occur with little or none of the usual byproducts arising from competing elimination or retroaldol reactions. Most substrates reach equilibrium within 0.3-3 days at ambient temperature in chloroform, benzene, or dichloromethane containing 0.3-1 M imidazole. The process is particularly facile for aldols derived from tetrahydro-4H-thiopyran-4-one with rate constants for equilibration varying over ca. 1 order of magnitude for the adducts studied; structurally related aldols derived from cyclohexanone isomerized ca. 3-4 times slower. Isomerization of the acyclic aldol 5-hydroxy-4-methyl-5-phenyl-3-pentanone required heating to 60 degrees C but was achieved with minimal (<5%) retroaldol or elimination. A methoxymethyl ether derivative isomerized 30-40 times slower than the parent aldol. Isomerization of alpha,alpha'-disubstituted aldols and alpha,alpha'-bisaldols indicated low regioselectivity in the enolization. The synthetic utility of the process was demonstrated with the effective preparation of aldol stereoisomers unobtainable by direct methods.     

Stereoselective aldol condensations via alkenyloxy dialkoxyboranes: synthetic applications using thioesters

A detailed Investigation of the enolization of phenyl thiopropionate with ethylenechloroboronate (ECB) and diisopropylethylamine (DPEA) and the subsequent aldol condensations of these enolates was conducted. Alkenyloxy dialkoxyboranes derived from thioesters were found to be stereoconvergent: both Z and E enolates give syn aldol condensation products. The thioester additions to chiral aldehydes were studied. Internal selectivity (syn) was usually very high, while the relative stereoselectivity ranged from poor to good, depending on the specific aldehyde used. The aldol products were transformed to known compounds for correlation.     

A kinetically controlled direct aldol addition of α-chloro thioesters via soft enolization

Herein we report that simple α-chloro thioesters undergo soft enolization and direct aldol addition to aldehydes in the presence of MgBr₂·OEt₂ and i-Pr₂NEt. At ?78 °C the reaction proceeds in a kinetically controlled manner giving good diastereoselectivity. Significantly, the transformation is applicable to both enolizable and nonenolizable aldehydes. Moreover, excellent stereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative is used. To our knowledge, this is the first report of a kinetically controlled soft enolization-based aldol addition.     

Chiral ytterbium complex-catalyzed direct asymmetric aldol-Tishchenko reaction: synthesis of anti-1,3-diols

The asymmetric aldol-Tishchenko reaction of aromatic aldehydes with aliphatic and aromatic ketones has been developed as an efficient strategy for the synthesis of anti-1,3-diols in good yield with high diastereocontrol and good levels of enantioselectivity. This domino-type reaction is catalyzed by a chiral ytterbium complex that promotes both the aldol reaction through enolization of the carbonyl compound and the Evans-Tishchenko reduction of the aldol intermediate. The stereochemistry of the resulting diols is also investigated and finally proved by using CD techniques.     

A Designed Amide as an Aldol Donor in the Direct Catalytic Asymmetric Aldol Reaction

The direct catalytic asymmetric aldol reaction offers efficient access to β‐hydroxy carbonyl entities. Described is a robust direct catalytic asymmetric aldol reaction of α‐sulfanyl 7‐azaindolinylamide, thus affording both aromatic and aliphatic β‐hydroxy amides with high ee values. The design of this transformation features a cooperative interplay of a soft and a hard Lewis acid, which together facilitate the challenging chemoselective enolization by a hard Brønsted base.     

Theoretical study of intramolecular aldol condensation of 1, 6-diketones: trimethylsilyl substituent effect

Diastereoselective intramolecular aldol condensations are investigated in an experimental and computational study of 1, 6-diketones. Ab initio results show the importance of the acid medium and disapprove the possibility of a spontaneous cyclization, even for silylated compounds. The combination of both experimental and computational approaches brings valuable information on the mechanism and on the selectivity of the aldol reaction. It is found that the enolization of the diketone is a key step in acid-catalyzed mechanism. The cyclization step bears a very small activation energy. The dehydration of the aldols are discussed.     

Highly diastereofacial anti-aldol reaction: practical synthesis of optically active anti-2-alkyl-3-hydroxycarboxylic acid ester units

A variety of esters derived from commercially available norephedrine were used in diastereoselective anti-aldol reactions. The aldol reaction of designed 2-(N-2-methylbenzyl-N-2,4,6-trimethylbenzyl)amino-1-phenylpropanol esters 4a-d with aldehydes furnished anti-2-alkyl-3-hydroxycarboxylic acid esters in excellent diastereomeric ratios (>98:2) when LDA-Cp2ZrCl2 (0.3 equiv) was used for enolization, followed by transmetalation into the zirconium enolate for aldolization. The novel auxiliary 3 for the anti-aldol reaction does not exhibit the ordinary basicity of tertiary amines; 3 can be extracted from acidic media with organic solvents. Its use is, therefore, very advantageous not only for extraction of the aldol products from the acidic water solutions, but also for recovering the chiral auxiliary 3 after the reductive cleavage. Treatment of aldol or 3-protected aldol products with DIBAL-H or LiAlH4 affords the versatile synthons, 2-alkyl-propane-1,3-diols or those 3-protected diols in >98% ee's together with 3 in nearly quantitative recovery.     

Overriding effect of temperature over reagent and substrate size for boron-mediated aldol reaction of methyl phenylacetate

The enolization temperature overrides all other aspects, including the sterics of the alkyl group of the boron reagent and the alkoxy group of the ester during the enolboration–aldolization of phenylacetates. This study has led to the first n-Bu₂BOTf-mediated anti-selective aldol reaction of an ester.     

Synthesis of a new N-acetyl thiazolidinethione reagent and its application to a highly selective asymmetric acetate aldol reaction

[reaction: see text] A new N-acetyl thiazolidinethione reagent, which undergoes highly diastereoselective aldol reactions upon enolization with dichlorophenylborane and (-)-sparteine and subsequent treatment with a variety of aldehydes, is described. This reagent is pseudoenantiomeric to an L-tert-leucine-derived reagent recently described by us and is useful because it avoids the prohibitively costly D-tert-leucine.     

Bifunctional Brønsted Base Catalyzes Direct Asymmetric Aldol Reaction of α‐Keto Amides

The first enantioselective direct cross‐aldol reaction of α‐keto amides with aldehydes, mediated by a bifunctional ureidopeptide‐based Brønsted base catalyst, is described. The appropriate combination of a tertiary amine base and an aminal, and urea hydrogen‐bond donor groups in the catalyst structure promoted the exclusive generation of the α‐keto amide enolate which reacted with either non‐enolizable or enolizable aldehydes to produce highly enantioenriched polyoxygenated aldol adducts without side‐products resulting from dehydration, α‐keto amide self‐condensation, aldehyde enolization, and isotetronic acid formation.     

Artificial aldolases from peptide dendrimer combinatorial libraries

Peptide dendrimers were investigated as synthetic models for aldolase enzymes. Combinatorial libraries were prepared with aldolase active residues such as lysine and proline placed at the dendrimer core or near the surface. On-bead selection for aldolase activity was carried out using the dye-labelled 1,3-diketone 1a, suitable for covalent trapping of enamine-reactive side-chains, and the fluorogenic enolization probe 6. Aldolase dendrimers catalyzed the aldol reaction of acetone, dihydroxyacetone and cyclohexanone with nitrobenzaldehyde. Much like enzymes, the dendrimers exhibited strong aldolase activity in aqueous medium, but were also active in organic solvent. Dendrimer-catalyzed aldol reactions reached complete conversion in 3 h at 25 degrees C with 1 mol% catalyst and gave aldol products with up to 65% ee. A positive dendritic effect in catalysis was observed with both lysine and proline based aldolase dendrimer catalysts.     

Highly stereoselective aldol reactions of titanium enolates from lactate-derived chiral ketones

[reaction: see text] Highly stereoselective titanium-mediated aldol reactions based on lactate-derived ketones are reported. The stereochemical outcome of the process depends on the protecting group (PMB or Bn) and the Lewis acid (i-PrOTiCl(3) or TiCl(4)) used in the enolization step, the corresponding anti-syn or syn-syn aldols being prepared in high yields and with diastereomeric ratios up to 99:1.     

Cycloaldol approach to the isobenzofuran core of eunicellin diterpenes

[reaction: see text] A novel cycloaldol approach to the isobenzofuran core common to many of the eunicellin diterpenes is described. The cycloaldol precursor was prepared by aldol addition of (S)-(+)-carvone and methacrolein followed by etherification to a glycolate ester. Chemoselective enolization of the glycolate ester led to the cycloaldol adduct in high yield and diastereoselectivity. An oxidative rearrangement-allylic diazene rearrangement sequence established the requisite cis ring fusion.     

Acid–Base Pairs in Lewis Acidic Zeolites Promote Direct Aldol Reactions by Soft Enolization

Hf‐, Sn‐, and Zr‐Beta zeolites catalyze the cross‐aldol condensation of aromatic aldehydes with acetone under mild reaction conditions with near quantitative yields. NMR studies with isotopically labeled molecules confirm that acid‐base pairs in the Si‐O‐M framework ensemble promote soft enolization through α‐proton abstraction. The Lewis acidic zeolites maintain activity in the presence of water and, unlike traditional base catalysts, in acidic solutions.