Anti-aldol Products Research Articles

Studies towards the Synthesis of (–)-Pulvomycin: Construction of the C12–C40 Segment by a Stereoselective Aldol Reaction

AbstractA convergent strategy was developed for the synthesis of the C12–C40 segment of (–)-pulvomycin. Key step was a diastereoselective aldol reaction between a chiral ethyl ketone representing the C24–C40 fragment and a chiral aldehyde representing the C12–C23 fragment. Both compounds were prepared from enantiomerically pure building blocks in a convergent fashion. The longest linear sequence commenced with a known d-fucose-derived glycosyl donor and entailed a total number of 16 steps. The desired anti-aldol product was obtained in a total yield of 5% over these steps and contains 12 out of 13 stereogenic centers present in the natural product.

Temperature- and Reagent-Controlled Complementary Syn- and Anti-Selective Enolboration-Aldolization of Substituted Phenylacetates.

In contrast to methyl phenylacetates, methyl arylacetates do not provide syn-aldols in the dicyclohexylboron triflate/triethylamine (Chx2BOTf/Et3N)-mediated enolboration-aldolization reaction. However, a combination of a less bulky boron reagent (dibutylboron triflate, n-Bu2BOTf), a bulky amine (i-Pr2NEt), and ambient temperature is required to obtain syn-aldols from methyl arylacetates. The corresponding anti-aldol products have been synthesized by the enolboration-aldolization of methyl arylacetates in the presence of Chx2BOTf/Et3N at a lower temperature. We report the first example of a complementary syn- and anti-selective enolboration-aldolization of arylacetates.

Stereoselective OsO4-mediated dihydroxylation of β-substituted α-trialkylsilyl-β,γ-unsaturated esters

The dihydroxylation of various of α-trialkylsilyl-β,γ-unsaturated esters with OsO4 and NMO has been explored. It has been revealed that these reactions readily allow for a stereoselective dihydroxylation with high levels of dr (>20/1) to afford anti-aldol products with three contiguous stereogenic centers in modest overall yields.

Miniemulsion in biocatalysis, a new approach employing a solid reagent and an easy protocol for product isolation applied to the aldol reaction by Rhizopus niveus lipase

Miniemulsion systems presented a great potential for biocatalytic reactions. However, different limitations jeopardized the applications of this non-conventional medium. In this work, miniemulsion systems (emulsion reactors) were applied for the first time to the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde by Rhizopus niveus lipase allowing a decrease in the catalyst concentration from 20 mg mL−1 to 6 mg mL−1 in comparison with organic solvents. Moreover, the yield increased from ~25% to ~65% for 48 h reactions and the enantiomeric excess increased from ~10% to ~30% for (R,S)-anti-aldol product, showing the potentiality of this non-conventional reaction medium. The advances reported in this work expands the possibilities of the miniemulsion reaction medium to a whole new level, increasing the scope to solid reagents and products, and also different reactions (biocatalytic or not) that requires pH control by buffers with a simple product isolation procedure, enabling future applications of this poorly studied reaction medium.

A Pseudopeptide Polymer Micelle Used for Asymmetric Catalysis of the Aldol Reaction in Water.

Micelles assembled from amphiphilic molecules have proved to be ideal scaffolds to construct artificial catalysts mimicking enzymatic catalytic behavior. In this paper, we describe the synthesis of amphiphilic poly(2-oxazoline) derivatives with l-prolinamide units in the side chain and their application in asymmetric aldol reactions. Upon dissolution in water, the pseudopeptide polymers self-assembled into particles with different sizes, relying on the copolymer composition and distribution of hydrophilic/hydrophobic segments in the polymer chain. A preliminary study has demonstrated that the catalytic activity of these polymeric organocatalysts are strongly dependent on the aggregated architecture. The micelle-type assemblies can act as nanoreactors to efficiently promote the direct aldolisation of cyclohexanone with aromatic aldehydes in aqueous media, affording anti-aldol products in excellent yields (88–99%) and higher stereoselectivities (90/10 dr, 86% ee) compared to their nonmicellar systems under identical conditions.

Access to Anti or Syn 2-Amino-1,3-diol Scaffolds from a Common Decarboxylative Aldol Adduct.

A straightforward synthetic pathway allowing the access to anti or syn 2-amino-1,3-diol scaffolds is presented. The strategy relies on a diastereoselective organocatalyzed decarboxylative aldol reaction of a N-Boc-hemimalonate that is easily formed from commercial N-Boc-diethyl malonate. Although this method has been optimized previously with the N-Bz-hemimalonate analogue, this key step was reinvestigated with the N-Boc derivative to improve the required reaction time, the yield, and the diastereoselectivity. The new conditions enhance this transformation, and quantitative yields and anti/syn ratios up to 96:4 can be obtained. The anti aldol product was easily isolated in pure form and then taken forward as the key precursor in the preparation of both a set of ten N-/O-alkylated anti 2-amino-1,3-diol derivatives and the syn congeners.

Chiral Calix[4]arenes-Bearing Prolinamide Functionality as Organocatalyst for Asymmetric Direct Aldol Reactions in Water

ABSTRACTThe chiral calix[4]arene derivative (6) bearing an L-prolinamido group has been designed and proved to be a water compatible efficient organocatalysts for a direct enantioselective aldol reaction. Compound 6 catalyzes the aldol reaction of cyclohexanone and a variety of aromatic aldehydes yielding anti-aldol products in high yield with enantioselectivities of up to 93% and diastereoselectivity of up to 95:5.

Direct asymmetric aldol reactions catalysed by trans-4-hydroxy-(S)-prolinamide in solvent-free conditions

Direct asymmetric aldol reactions between 4-nitrobenzaldehyde and cyclohexanone were catalysed by trans-4-hydroxy-(S)-prolinamide (10mol%) in the presence of CH3COOH (10mol%) as the co-catalyst under solvent-free conditions at 15°C. (2S,4R)-4-Hydroxy-N-((S)-1-phenylethyl)pyrrolidine-2-carboxamide 2 efficiently catalysed the asymmetric aldol reaction to afford the product in >99% yield and with 95% ee with an anti/syn ratio of 88:12 after 18h. The additional trans-hydroxyl group on (S)-prolinamide and (S)-1-phenylethylamine both influenced the ee of the predominant anti aldol product. Different benzaldehyde derivatives with cyclohexanone gave the corresponding aldol products in 38–89% yields and with 56–94% ee with anti/syn (100:0–71:29). Catalyst 2 can be used up to 5 continuous cycles for asymmetric aldol reactions between 4-nitrobenzaldehyde and cyclohexanone with overall 91% yield and 86% yield of anti-product with anti/syn (98:2).

Glyoxylic Acid versus Ethyl Glyoxylate for the Aqueous Enantio­selective Synthesis of α-Hydroxy-γ-Keto Acids and Esters by the N-Tosyl-(S a)-binam-l-prolinamide-Organocatalyzed Aldol Reaction

N-Tosyl-(S a)-binam- l -prolinamide is an efficient catalyst for the aqueous aldol reaction between ketones and glyoxylic acid, as the monohydrate or as an aqueous solution, or a 50% toluene solution of ethyl glyoxylate. These reactions led to the formation of chiral α-hydroxy-γ-keto carboxylic acids and esters in high levels of diastereo- and enantioselectivities (up to 97% ee), providing mainly anti aldol products. Only cyclopentanone and cyclohexane-1,4-dione afforded an almost 1:1 mixture of the syn/anti-diastereoisomers; however, the reaction between 4-phenylcyclohexanone and ethyl glyoxylate gave the corresponding syn,syn-product as the major diastereoisomer.

Aqueous organocatalyzed aldol reaction of glyoxylic acid for the enantioselective synthesis of α-hydroxy-γ-keto acids

N-Tosyl-(Sa)-binam-L-prolinamide is an efficient catalyst for the aqueous aldol reaction, between glyoxylic acid, as monohydrate or aqueous solution, and ketones. This reaction led to the formation of chiral α-hydroxy-γ-keto carboxylic acids in high levels of diastereo- and enantioselectivities achieving mainly anti aldol products.

Asymmetric aldol reactions between cyclic ketones and benzaldehyde catalyzed by chiral Zn2+ complexes of aminoacyl 1,4,7,10-tetraazacyclododecane: effects of solvent and additives on the stereoselectivities of the aldol products

The direct aldol reaction between cyclic ketones and 4-nitrobenzaldehyde catalyzed by chiral Zn2+ complexes of aminoacyl 1,4,7,10-tetraazacyclododecane is reported. The anti-aldol products were mainly formed in cyclohexanone/N-methylpyrrolidone(NMP)/MeOH with good diastereo- and enantioselectivity, while syn-aldol adducts were obtained as major products with good enantioselectivity in cyclohexanone/H2O and cyclohexanone/NMP/H2O. The fact that the UV/vis spectra of 2,6-diphenyl-4-(2,4,6-triphenyl-1-pyridinio)phenolate (Reichardt’s dye) were nearly identical in these solvent systems suggests that the switch in the relative configuration of the aldol products is induced by a large excess of H2O rather than the polarity of the solvent system. Furthermore, the addition of a small amount of TFA improved the enantioselectivity of the syn-aldol adducts produced in cyclohexanone/H2O with up to 92% ee (anti/syn ratio=30:70).

Regioselective Carbonylation of trans-Disubstituted Epoxides to β-Lactones: A Viable Entry into syn-Aldol-Type Products

Two new catalysts are reported for the regioselective carbonylation of trans-disubstituted epoxides to cis-β-lactones. The two catalysts display high and opposing selectivities, which generally are difficult to achieve for this class of epoxides. The resulting β-lactones are well-defined precursors for a wide variety of aldol-type compounds. Altogether, carbonylation of disubstituted epoxides is established as a viable and economical entry into syn- and anti-aldol products.

Asymmetric Synthesis of the C1-C6 Portion of the Psymberin Using an Evans Chiral Auxiliary.

The C1-C6 region of the potent cytotoxic agent psymberin has been synthesized. The key transformations of the synthesis are an auxiliary-controlled addition of a Sn(II)-glycolate enolate to an aldehyde to yield the anti aldol product and transforming the primary alcohol into a terminal olefin utilizing organoselenium chemistry.

Syn-Selective Kobayashi Aldol Reaction Using Acetals

The Kobayashi aldol reaction has been used to construct anti-aldol products by remote stereoinduction. Since the product of the Kobayashi aldol reaction has a typical polyketide structure, this reaction has been applied to the total synthesis of natural products. By varying this reaction, it was found that the reaction with acetals in the presence of Lewis acid proceeded to give syn adducts in high stereoselectivity. This is the first example of the stereoselective reaction of the chiral dienol ether and acetals.

Asymmetric direct aldol reactions catalyzed by chiral amine macrocycle–metal(ii) complexes under solvent-free conditions

Solvent-free asymmetric aldol reactions between cyclohexanone and 4-nitrobenzaldehyde using chiral amine macrocycle–metal(II) complexes as catalysts in a ball mill afforded the anti-aldol product as the major isomer with up to 93% ee.

Syn-Selective Kobayashi Aldol Reaction Using the E,E-Vinylketene Silyl N,O-Acetal

The Kobayashi aldol reaction is one of the most powerful methods to synthesize the polyketide skeleton and has been applied to the total synthesis of natural products. This methodology has been used to construct anti-aldol products, and only a few precedents on the syn-selective Kobayashi aldol reaction are known. A syn-selective Kobayashi aldol reaction by using the E,E-vinylketene silyl N,O-acetal and an excess amount of Lewis acid is presented.

A new chiral primary–tertiary diamine-Brønsted acid salt organocatalyst for the highly enantioselective direct anti-aldol and syn-Mannich reactions

A new primary–tertiary diamine catalyst is easily prepared in a few steps from inexpensive, commercially available, enantiopure materials. This organocatalyst can be effective catalyzed the direct asymmetric aldol and Mannich reactions. The anti-aldol products can be obtained with up to a 99:1 anti/syn ratio and >98 % ee, while the syn-Mannich products could be obtained with up to a 99:1 syn/anti ratio and >99 % ee. Catalyst 1c can be used efficiently on a large scale with the enantioselectivities of the anti-aldol and syn-Mannich reactions being maintained at the same level, which offers a great possibility for application in industry.

Anti-Selective Direct Catalytic Asymmetric Aldol Reaction of Thiolactams

An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Brønsted base cooperative catalyst comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.

Syn-Selective Vinylogous Kobayashi Aldol Reaction

The Kobayashi aldol reaction has become a prominent transformation in polyketide syntheses. This methodology takes advantage of the directing effects of the Evans auxiliary and allows the stereoselective incorporation of a four carbon segment with two additional methyl branches establishing an anti-relationship between the two newly formed chiral centers. So far this transformation was restricted to anti-aldol products. We present here a modified protocol that provides the corresponding aldol product with high syn-selectivity.

Origins of reversing diastereoselectivity of α,β-dichloro-γ-butenolides and γ-butyrolactams in direct vinylogous aldol addition: a computational study

Oxygenated five-membered ring compounds are more widespread in nature than the corresponding aza-analogues due to their more interesting biological activity. In our earlier studies, we have reported a simple methodology to synthesize novel synthons like 5-(1′-hydroxy)-γ-butenolide and 5-(1′-hydroxy)-γ-butyrolactam through the direct vinylogous aldol addition reaction. The observed diastereoselectivities for γ-butyrolactones and γ-butyrolactams were not understood in that report. We have reported herein a detailed computational study to understand the observed diastereoselectivity of α,β-dichloro-γ-butenolides and α,β-dichloro-γ-butyrolactams. The transition state calculations performed with B3LYP/cc-pVDZ level of theory to examine the diastereoselectivity of α,β-dichloro-γ-butenolides and α,β-dichloro-γ-butyrolactams have been found to be in good agreement with the observed experimental results. The origin of selectivity is examined by an activation strain model and molecular electrostatic potential (MESP) surfaces. The distortion energies calculated using the activation strain model revealed the origin of diastereoselectivities for butenolides and butyrolactams. The reversal in stereochemical outcome of α,β-dichloro-γ-butenolides and α,β-dichloro-γ-butyrolactams is due to the presence of a large substituent at the nitrogen center of the γ-butyrolactams. We have further revealed the enhanced diastereoselectivity of these butenolides while reacting with the aromatic aldehydes bearing ortho substituents. The generated molecular electrostatic potential (MESP) surfaces have shown an additional Vmin of value = −115.0 kcal mol−1 responsible for enhanced diastereoselectivity with ortho-substituted benzaldehydes as compared to unsubstituted benzaldehyde. The difference in transition state distortion energies of syn and anti aldol products are found to correlate with their corresponding differences in activation energies.