Hydroxy protection esters

Developed as a carboxyl protective group for peptide synthesis because of its stability to hydrogenolysis and acidic conditions, the acetol (hydroxy acetone) ester is prepared by DCC coupling (68-92% yield) of the acid with acetol. It is cleaved with TBAF in THF. ... 

Allyl carbonate esters are also useful hydroxy-protecting groups and are introduced using allyl chloroformate. A number of Pd-based catalysts for allylic deprotection have been developed.209 They are based on a catalytic cycle in which Pd° reacts by oxidative addition and activates the allylic bond to nucleophilic substitution. Various nucleophiles are effective, including dimedone,210 pentane-2,4-dione,211 and amines.212... 

In a synthetic application of this double inversion sequence, tris(benzyloxy)bromo boronic ester 6 obtained in the ribose sequence (Section 1.1.2.1.3.2.) is converted to the 4-methoxyphenyl-methoxy derivative 7 in the usual way. 2,3-Dichloro-5,6-dicyano-l,4-benzoquinone cleaves the protecting group to furnish the a-hydroxy boronic ester 8. Conversion of the a-hydroxy boronic ester 8 to the methanesulfonate 9 followed by displacement of the sulfonate by phenylmethoxide yields a-benzyloxy boronic ester 10, which is a diastereomer of one of the ribose intermediates37. 

From the beginning of the 1960s, the progress in depsipeptide chemistry was connected with the utilization and further development of the mixed anhydride approach for the initial formation of the ester link between a suitably N-protected amino acid and the hydroxy acid ester. The reagent predominantly applied for the construction of the depsipeptide unit was benzenesulfonyl chloride in pyridine. This reagent, introduced by Shemyakin and co-workers in depsipeptide chemistry, was shown to be an efficient reagent for the formation of the ester bond between a protected amino acid and the hydroxy add component (Scheme 4).[21 22 ... 

Scheme 4 General Route to Protected O-Aminoacyl Hydroxy Acid Esters by the Benzenesulfonyl Chloride Method...

Kleinman and co-workers 20 synthesized a lactone precursor to the (2/ ,46, 56 )- -hydroxy-ethylene dipeptide stereoselectively in four steps using the lithium salt of ethyl propiolate as a homoenolate equivalent. As summarized in Scheme 11, addition of ethyl lithiopropiolate to a protected a-amino aldehyde affords hydroxy acetylenic esters as a mixture of dia-stereomers. Reduction of the acetylene group and subsequent lactonization gives a readily separable (4S)-lactone-enriched mixture. Direct alkylation with alkyl halide and lithium hexamethyldisilanazide yields the tram-lactone as the major stereoisomer. 

Carreira and co-workers have also extended the scope of aldehydes that may be utilized in catalytic addition reactions to include stannylpropenal 108 as a substrate (Table 8B2.12, Entry 7). The adduct produced from the aldol addition of 105 is isolated with 92% ee and serves as a useful building block, as it is amenable for further synthetic elaboration (Scheme 8B2.9). Thus, vinylstannane 109 is a substrate for Stille cross-coupling reactions to give a diverse family of protected acetoacetate adducts 110. Following deprotection of the masked keto ester, the corresponding hydroxy keto ester 111 may be converted to either the syn or anti skipped polyols 112 or 113. A recent total synthesis of macrolactin A by Carreira and co-workers utilizes aldol... 

The classical method for tert-butyl esterification involves nnineral add catalyzed addition of the amino acid to isobutene. Both, N-protected, e.g. Z-Xaa-OH, and unprotected amino acids form tert-butyl esters with isobutene in the presence of catalytic amounts of sulfuric acid or TosOH. " Another efficient method is the transesterification of an acetic acid tert-bvXy ester catalyzed by perchloric acid. " Amide tert-butylation was recognized as a side reaction in the presence of perchloric acid, but could be completely suppressed by using sulfuric acid. Both methods, acid-catalyzed addition to isobutene and the transesterification of acetic add terf-butyl esters, result in simultaneous terf-butyl-ation of hydroxy and sulfanyl groups. A synthetic route to Z-Thr-OtBu, Z-Ser-OtBu, and Z-Hyp-OtBu without conconnitant O-alkylation involves the hydroxy protection by the acetoacetyl group, which is readily cleaved by treatment with 2 equivalents of hydrazine in EtOH for 30 minutes. ... 

The Sharpless regioreversed asymmetric aminohydroxylation protocol was used as a key step in the total synthesis of ustiloxin D by M.M. Joullie and co-workers.The ( )-ethyl cinnamate derivative was subjected to in situ generated sodium salt of the N-Cbz chloroamine in the presence of catalytic amounts of the anthraquinone-based chiral ligand to afford the desired A/-Cbz protected (2S,3R)-(3-hydroxy amino ester in good yield and with good diastereoselectivity. 

The synthesis of this valuable optically active P-ketophosphonate has been improved by using the protected hydroxy half-ester as substrate."" " Thus, it has been found that low-temperature treatment of the protected 1-adamantanamine salt of chiral monomethyl ester in THF with dimethyl... 

Seebach completed the first synthesis of optically active 9 as depicted in Scheme 4.2. ° Protected alcohol 10, available from an optically active p-hydroxy butyric ester, was alkylated with 2-lithio-1,3-dithiane. Deprotonation of this material followed by formylation with DMF then afforded 11. Chain extension to the unsaturated ester was accomplished via a Wittig condensation and deprotection to produce the monomeric unit 12 in 57% overall yield from 10. Double lactonization under Mitsunobu conditions (DEAD-PhjP) afforded a 60%... 

Ketoatnides, ketonitriles and keto esters may all be reacted selectively at the ketone function (equations 14 16). In fact, esterification was found to be the best of several hydroxy-protecting methods for the transformation shown in Scheme 6. ... 

For many further syntheses, it is necessary to block the hydroxy functions of tartaric acid. This can be done by acid-catalyzed formation of cyclic acetals or ketals (1,3-dioxolanes) with carbonyl compounds, e.g., 43. Acetone, acetophenone, benzaldehyde, pivalaldchydc, and other simple carbonyls have been used for this purpose28 31,42-43. The protected esters of tartaric acid, used as starting materials for many purposes (Sections 2.3.2. and 2.5.3.), can be prepared in a one-pot procedure. 

Meanwhile, the Ireland-Claisen rearrangement of protected a-hydroxy aUylic esters found various applications in natural product syntheses, what clearly underlines the potential of this synthetic protocol. Several examples are described by Kallmerten et al. For example, rearrangement of (Z)-configured ester 35 gave rise to the required anti rearrangement product 36, which was converted in five steps into the dilactone 37, a precursor of the antifungal metabolite avenaciolide (Scheme 5.2.11) [23]. 

To overcome these problems some safety-catch hnkers were developed by the groups of, for example, Merrifield [111], Cowell and Jones [112] as well as Main [110]. All studied o-hydroxy-phenyl esters because of their moderate stabihty concerning reactions with nucleophiles in their protected form and because of their low stabihty towards nucleophiles in the unprotected form (phenol-derivatives). These researches confirm former results describing on the one hand low reactivity concerning sterically hindered ester hnkers and on the other hand high reactivity for arylesters bearing an 0-hydroxy-substituent that supports nucleophilic cleavage via anchimeric as-... 

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