An NMR method for assigning relative stereochemistry to beta-hydroxy ketones deriving from aldol reactions of methyl ketones

We describe a simple 1H NMR analysis that permits the stereochemistry of beta-hydroxy ketones to be assigned by visual inspection of the ABX patterns for the alpha-methylene unit of the beta-hydroxy ketone in the 1H NMR spectra. This method has been verified by application to a wide range of beta-hydroxy ketones deriving from aldol reactions of chiral aldehydes with a variety of chiral and achiral methyl ketone enolates (see Tables 1 and 2). The stereochemistry of 54 of these compounds have been assigned by rigorous chemical methods.     

A mild and chemoselective method for the reduction of conjugated isoxazolines to beta-hydroxy ketones

A new procedure for the selective reduction of conjugated Delta(2)-isoxazolines to the corresponding unsaturated beta-hydroxy ketones is described. The use of SmI(2) as the reducing agent and B(OH)(3) to hydrolyze the resulting imine results in a mild, convenient, and chemoselective protocol for this otherwise difficult transformation and complements existing methodology for the preparation of beta-hydroxy ketones via nitrile oxides.     

RuCl3/PPh3: an efficient combination for the preparation of chiral 1,3-anti-diols through catalytic hydrogenation

[reaction: see text] An efficient economical alternative to the commonly used Evans' reagent for the diastereoselective reduction of beta-hydroxy ketones is reported. Thus, ruthenium-mediated hydrogenation of enantioenriched beta-hydroxy ketones using RuCl3 associated to achiral monophosphines allowed the preparation of a series of 1,3-anti-diols in good yields and with a high level of diastereoselectivity. A short screening of ligands pointed out PPh3 as the most effective phosphine, and PCy3 afforded the 1,3-diols with an unexpected moderate syn selectivity.     

Structurally well-defined, recoverable C3-symmetric tris(beta-hydroxy phosphoramide)-catalyzed enantioselective borane reduction of ketones

[reaction: see text] A series of new chiral C(3)-symmetric tris(beta-hydroxy phosphoramide) ligands have been synthesized via the reaction of trisphosphoramide ester and Grignard reagents. The catalytic asymmetric borane reduction of ketones with these new C(3)-symmetric chiral tris(beta-hydroxy phosphoramide)s was investigated. Structurally well-defined, recoverable ligand 1d is an efficient catalyst for the enantioselective borane reduction of both electron-deficient and electron-rich ketones, and high enantioselectivities were achieved (up to 98% ee).     

Ti-catalyzed reformatsky-type coupling between alpha-halo ketones and aldehydes

We describe the first Ti-catalyzed Reformatsky-type coupling between alpha-halo ketones and aldehydes. The reaction affords beta-hydroxy ketones under mild, neutral conditions compatible with ketones and other electrophiles. The catalytic cycle possibly proceeds via bis(cyclopentadienyl)titanium enolates.     

The small peptide-catalyzed direct asymmetric aldol reaction in water

Simple modular di- and tripeptides with a primary amine at the N-terminus catalyze the aqueous asymmetric aldol reaction between unmodified ketones and aldehydes to furnish the corresponding beta-hydroxy ketones with up to 86% ee in water and 99% ee in aqueous media.     

An Efficient Procedure for the Diastereoselective Dehydration of beta-Hydroxy Carbonyl Compounds by CeCl(3).7H(2)O/NaI System

The dehydration of beta-hydroxy ketones and beta-hydroxy esters is a synthetically useful method for the conversion of these compounds to the corresponding alpha,beta-unsaturated derivatives. Cerium(III) chloride heptahydrate in combination with sodium iodide in refluxing acetonitrile acts as an efficient reagent for this conversion. The present procedure, which utilizes cheap and "friendly" reagents, offers the corresponding (E)-enones in good yields as the only isolable products.     

Selective 1,5-alkylidenecarbene insertion reactions on [3.2.1] oxabicyclic ethers: a new approach toward the AB ring system of ingenol

Two methods to achieve the formal aldol reaction between acetone and two oxabicyclic [3.2.1] ketones are reported. The trimethylsilyl-protected beta-hydroxy ketones are converted by a Wittig reaction into vinyl chlorides as synthetic precursors to alkylidenecarbenes. Selective 1,5 C-H over 1,5 O-Si insertion has been applied to the synthesis of a model for the ABC ring system of ingenol.     

Catalytic asymmetric methallylation of ketones with an (H8-BINOLate)Ti-based catalyst

The first catalytic asymmetric methallylation of ketones is reported. The catalyst, which is generated from titanium tetraisopropoxide, H8-BINOL, 2-propanol, and tetramethallylstannane, reacts with ketones in acetonitrile to afford tertiary homoallylic alcohols in fair to excellent yields (55-99%) and fair to high enantioselectivities (46-90%). Ozonolysis of the resulting products provides access to chiral beta-hydroxy ketones, which are not readily prepared from direct asymmetric aldol reaction of acetone with ketones.     

New mixed phosphonate esters by transesterification of pinacol phosphonates and their use in aldehyde and ketone coupling reactions with nonstabilized phosphonates

Alkylpinacol phosphonates were prepared by rhodium-catalyzed olefin hydrophosphorylation, and attempted alpha-deprotonation of the pinacol derived alkyl phosphonates resulted in ring cleavage. The propensity of the alkylpinacol phosphonates to undergo ring opening was exploited to prepare phosphonic acid monomethyl esters in high yield by transesterification in acidulated methanol. Esterification and alkylation with aldehydes or ketones gave beta-hydroxy mixed phosphonate esters. tert-Butyl and benzylic phosphonate ester protective groups were introduced to improve the efficiency and functional group compatibility of beta-hydroxy phosphonate saponification. The beta-hydroxy phosphonic acid monomethyl esters were dehydrated with diisopropylcarbodiimide, which gave oxaphosphetane intermediates that collapse to an olefin. The overall reaction sequence complements the arsenal of Horner-Wadsworth-Emmons-type coupling reactions.     

Synthesis of tertiary beta-hydroxy amides by enolate additions to acylsilanes

The synthesis of tertiary beta-hydroxy amides from acylsilanes, acetamides, and electrophiles is described. The addition of amide enolates to acylsilanes generates beta-silyloxy homoenolate reactivity by undergoing a 1,2-Brook rearrangement. These unique nucleophiles formed in situ can then undergo smooth addition to alkyl halides, aldehydes, and ketones. Enolates derived from amides are crucial for the success of this process since ketone enolates suffer from internal return of the beta-carbanion onto the carbonyl carbon. The use of optically active amide enolates delivers beta-hydroxy amide products with good levels of diastereoselectivity (>/=10:1).     

Synthesis of beta-hydroxy ketones and vinylsilanes from homopropargylic alcohols by intramolecular hydrosilation

Catalytic intramolecular hydrosilation of nonracemic homopropargylic alcohols affords the corresponding five-membered cyclic siloxanes regiospecifically. Oxidation or alkylmetal addition converts these intermediates into beta-hydroxy ketones or vinylsilanes under mild conditions.     

Reactive barium-promoted Reformatsky-type reaction of alpha-chloroketones with aldehydes

A Reformatsky-type aldol reaction of alpha-chloroketones with aldehydes has been achieved using reactive barium as a low-valent metal in THF; this one-pot process is more effective for obtaining the desired beta-hydroxy ketones in high yields than the stepwise process in which barium enolates are prepared prior to the reaction with aldehydes.     

Concerning the application of the 1H NMR ABX analysis for assignment of stereochemistry to aldols deriving from aldehydes lacking beta-branches

[reactions: see text] Attempts to apply the 1H NMR ABX method for assignment of stereochemistry of beta-hydroxy ketones to aldols 4-10 deriving from alpha-methyl aldehydes lacking beta-branches reveals that the presence of a beta-branch in the aldehyde reaction partner is necessary so that the average chemical environment of Ha and Hb is different for the Felkin and anti-Felkin aldols (see conformational pairs A/B and C/D, respectively). When the chiral alpha-methyl aldehyde lacks a beta-branch, as in the case of the aldehyde precursors to 4-10, the conformational energies of E and F (for the Felkin beta-hydroxy ketone derivatives), and conformers G and H for the anti-Felkin aldols, are too close in energy (within each pair), such that the average chemical and magnetic environments of Ha and Hb in the two diastereomers cannot be easily distinguished. This analysis provides a rational basis for application of the 1H NMR ABX pattern analysis to other beta-hydroxy ketone derivatives.     

Catalytic hydrogenation of alpha,beta-epoxy ketones to form beta-hydroxy ketones mediated by an NADH coenzyme model

[reaction: see text] The hydrogenation of alpha,beta-epoxy ketones can be mediated by a catalytic amount of BNAH or BNA(+)Br(-) to form corresponding beta-hydroxy ketones in high yield. Na2S2O4 is used as the reducing agent to convert BNA(+)Br(-) to BNAH. A radical mechanism has been proposed to understand many observations of this catalytic reaction.     

Asymmetric Mukaiyama aldol reaction of nonactivated ketones catalyzed by allo-threonine-derived oxazaborolidinone

Asymmetric Mukaiyama aldol reaction of nonactivated ketones is realized for the first time by using an oxazaborolidinone catalyst derived from O-benzoyl-N-tosyl-allo-threonine. By employing a dimethylsilyl ketene S,O-acetal as a nucleophile, a variety of acetophenone derivatives afford the corresponding tertiary beta-hydroxy carbonyl compounds with high enantioselectivity up to 98% ee.     

Catalytic, asymmetric transannular aldolizations: total synthesis of (+)-hirsutene

We report an asymmetric, catalytic transannular aldolization that provides polycyclic products useful for natural product synthesis. We found that a proline-derivative catalyzes the transannular aldol reaction of 1,4-cyclooctanediones to the corresponding cyclic beta-hydroxy ketones in good yields and with high enantioselectivities. The utility of our reaction has been demonstrated in a total synthesis of (+)-hirustene.     

Exclusive alpha-coupling in the aldol reaction of unsaturated trimethylsilyl esters: an efficient and practical direct synthesis of unsaturated beta-hydroxy acids

The lithium enolates of trimethylsilyl but-3-enoate and 3-methylbut-3-enoate reacted with aldehydes and saturated or aromatic ketones at -70 degrees C to give exclusively the alpha-condensation products in excellent yields. The unsaturated beta-hydroxy acids thus obtained were directly identified, and the usual conversion into their methyl esters with diazomethane was not necessary. Unsaturated ketones underwent Michael reaction through alpha-addition leading to the unsaturated 5-oxo acids.     

2-Deoxy-2-iodo-beta-glucopyranosyl fluorides: mild and highly stereoselective glycosyl donors for the synthesis of 2-deoxy-beta-glycosides from beta-hydroxy ketones

2-Deoxy-2-iodo-beta-glucopyranosyl fluoride 14 is a highly stereoselective glucopyranosyl donor that may be activated under mild conditions. Application of this new glycosyl donor to the glycosidation reactions of a variety of acceptors including beta-hydroxy ketones affords beta-glycosides with high efficiency and stereoselectivity. [reaction--see text]     

Enantioselective C-C bond synthesis catalysed by enzymes

The enantioselective synthesis of C-C bonds is often the pivotal step of a synthesis. Nature has made a variety of versatile enzymes available that catalyse this type of reaction very selectively under mild conditions. Cyanohydrins, acyloins (alpha-hydroxy ketones), alpha-hydroxy acids and aldols (beta-hydroxy ketones) are very efficiently synthesised enantioselectively with the aid of C-C bond forming enzymes, which we discuss in this tutorial review. In the case of the alpha-hydroxy acids the applications of nitrilases in a synthetic dkr even allows a disconnection that has no enantioselective chemical equivalent.