Glycolate aldol reaction

A new phase-transfer catalyzed asymmetric glycolate aldol reaction was reported that provides diols in low to good yields, high de, and moderate to good ee as illustrated in Scheme 37. The recystalhzation of diol products could enrich the ee to 95%, additionally, the authors used 128 (R = Ph) to synthesize a known (S TJydiol methyl ester to show utility of this new method <05OL3861>. 

SYNTHESIS OF GELDANAMYCIN USING GLYCOLATE ALDOL REACTIONS... 

The f.Z-diene of the seco acid 2 would result from Horner-Emmons and Wittig reactions from aldehyde 3 (Scheme 2). The trimethoxyaniline functionality is carried along as a stable nitrobenzene that would be unmasked at a late stage prior to macrolactam formation. The syn methoxy-hydroxy functionality at C6-7 in 3 is installed using the newly developed glycolate aldol reaction with enal 4 and norephedrine glycolate ester auxiliary 5. This new method is an application of Masamune s recent work with propionate norephedrine aldol reactions.The CIO methyl is installed using the aforementioned hydroboration reaction,... 

Denmark SE, Chung W-J (2008) Lewis base activatimi of lewis acids catalytic enantioselective glycolate aldol reactions. Angew Chem Int Ed 47 1890-1892... 

M.T. Critnrnins, J. She, Enantioselective total synthesis of (+)-gigantecin exploiting the asymmetric glycolate aldol reaction, J. Am. Chem. Soc. 126 (2004) 12790-12791. 

The synthetic utility of this process was enhanced by the development of the glycolate aldol reaction as illustrated in Scheme 7.6. An important feature was that both syn- and anti-1,2-diols could be obtained under identical conditions by appropriately modulating the steric size of the substituents on the silyl ketene acetals [8]. 

N-proteded ester 611 -Schiff bases 367,369 glycolate aldol reaction 164 glycolysis 795... 

Neopentyl glycol (2,2-dimethyl-1-propanol [126-30-7]) another important iadustrial derivative of isobutyraldehyde, is obtained from the aldol reaction product of isobutyraldehyde with formaldehyde followed by hydrogenation. 

It is worth pointing out that the stereochemistry of intermediate 147 at C-9 and C-10 is inconsequential since both positions will eventually bear trigonal carbonyl groups in the final product. The synthetic problem is thus significantly simplified by virtue of the fact that any or all C9-C10 diol stereoisomers could be utilized. A particularly attractive means for the construction of the C9-C10 bond and the requisite C8-C10 functionality in 147 is revealed by the disconnection shown in Scheme 41. It was anticipated that the venerable intermolecular aldol reaction could be relied upon to accomplish the union of aldehyde 150 and methyl glycolate (151) through a bond between carbons 9 and 10. 

Scheme 4 A sequence of RCM-glycol cleavage-transannular aldol reaction in Inoue s total synthesis of merrilactone A (22) [24]...

Conversion of 2 to the highly crystalline oxazolidinone 3 with phosgene has been described by Thornton who has employed this substance as a chiral auxiliary in asymmetric aldol reactions of its N-propionyl derivative. Kelly has also used an oxazoline derived from 3 as a chiral auxiliary in asymmetric alkylation of a glycolate enolate. Oxazolidinone 3 has also been prepared from 2 with diethyl carbonate in the presence of potassium carbonate. The conversion of 2 to the oxazolidinone 3 is accomplished using triphosgene in this procedure because of the high toxicity of phosgene. 

The Evans-Tischenko Reaction generally requires a P-hydroxyketone (developed from an Aldol reaction) to react with an aldehyde. The resulting glycol monoester will be characterized as having high anti-selectivity. 

CO2-PEG system is also effective for the scandium-catalyzed aldol reactions, and poly(ethylene glycol) dimethyl ether (PEG(OMe)2, MW = 500) is more effective than PEG (Scheme 3.12) [57]. Emulsions in C02-PEG(0Me)2 medium are observed when the concentration of the additive is 1 g/L. Not only benzal-dehyde but also substituted aromatics, aliphatic, and a, /]-unsaturated aldehydes react smoothly, and various silicon enolates derived from a ketones, esters, and thioesters also react well to afford the corresponding aldol adducts in high yields. 

Systems have been developed that allow the recycling of catalysts. The first case study involved simple adsorption of proline onto silica gel [6], but the system suffered from a loss in enantioselectivity. More recently, promising results have been obtained with fluorous proline derivatives [64] used for aldol reactions the recycling of fluorous catalysts has been demonstrated using fluorous solid-liquid extraction. Solid phase-supported catalysts through covalent bonds [65] and through noncovalent interactions [66] were also used for aldol reactions. Proline and other catalysts can be recycled when ionic liquids or polyethylene glycol (PEG) were used as reaction solvents [67]. 

Table 6.42 (S)-l-Naphthyl glycolic acid-catalyzed O-nitroso aldol reactions.

T. Nakata et al. developed a simple and efficient synthetic approach to prepare (+)-methyl-7-benzoylpederate, a key intermediate toward the synthesis of mycalamides. The key steps were the Evans asymmetric aldol reaction, stereoselective Claisen condensation and the Takai-Nozaki olefination. The diastereoselective Claisen condensation took place between a 5-lactone and the lithium enolate of a glycolate ester. 

The prototype reaction is the conversion of glyoxal into glycolic acid (equation 2), and here the benzilic acid rearrangement mechanism coincides with that for an intramolecular Cannizzaro reaction. The reaction is observed with other purely aliphatic a-diketones such as f-butyl 2,3-dioxobutyrate and cyclohexane-1,2-dione (equations 3 and 4), but the scope is limited in the aliphatic series by competing (c.g. aldol) reactions. Suitably constructed heterocyclic systems also rearrange, and the conversion of alloxan (3) into alloxanic acid (4) was among the first of the benzilic acid rearrangements to be discovered (equation 5). ... 

Poly(ethylene glycol) grafted on crosslinked polystyrene (PEG-PS) resin has often been used as a polymer support for chiral catalysts of reactions performed in aqueous media. Peptides immobilized to PEG-PS resin have been developed and used as a catalyst for direct asymmetric aldol reactions in aqueous media (Scheme 3.19) [42]. When tripeptide-supported PEG-PS 67 was used as chiral catalyst in the reaction between 70 and acetone, the corresponding aldol product 69 was obtained with 73% ee. Kudo further developed the one-pot sequential reaction of acidic deacetalization and enanhoselective aldol reaction by using an Amberhte and PEG-ST-supported peptide catalyst 67 [43]. The enantioenriched aldol product 72 was obtained in 74% isolated yield from acetal 70 in a one-pot reaction (Scheme 3.20). 

Wennemers found that tripeptide H-Pro-Pro-Asp-NH2 was a highly active and selective catalyst for asymmetric aldol reactions [44]. This peptide was immobihzed to a polymer support and used as a catalyst for the aldol reaction of p-nitrobenzal-dehyde 73 and acetone (Scheme 3.21). By using a TentaGel-supported peptide 73 the aldol adduct 69 was obtained in 89% yield with 75% ee, while a polyethylene glycol-polyacrylamide (PEGA)-supported peptide gave the same adduct in 93% yield and 79% ee [45]. 

Total carbonyl groups in the polymer chain were determined by the method of Imai and Kazusa (22) using 2,4-dinitrophenylhydrazine. The ketone associated with double bonds, -C(0)-(C=C)2-, was measured by UV spectra at Amax — 270 nm with = 2.7 X 103M 1 cm"1 (23). /3-Hydroxyketones, peroxides, and 1,2-glycols and a-hydroxyketones were decomposed respectively with dilute alkali (reverse aldol reaction), potassium iodide in sulfuric acid aqueous solution, and periodic acid in sulfuric acid aqueous solution and then measured by GLC. 

The completion of the total synthesis of FK506 (1) is described in Scheme 34. The coupling of the two segments 222 and 230 was accomplished by phosphine oxide-mediated HW olefination. The addition of 222 to 230 afforded a separable 1 1 mixture, and the less polar diastereomer yielded ( )-olefin 231. After selective removal of the TES group, esterification of 231 with (S)-A-Boc-pipecolic acid (232) under DCC-DMAP conditions followed by dethioacetalization afforded aldehyde 233. The Evans aldol reaction of 233 with 218d installed a glycolate unit, and hydrolysis of the chiral auxiliary followed by TES protection provided 234 ready for macrocyclization. The macrolactamization of 234 was effectively... 

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