Reaction with 2-Hydroxy, 2- propionate

In the reactions with the propionate derivatives, which provide synthetically useful a-methyl-/3-hydroxy ester derivatives, a combination of Sn(OTf)2, (5)-l-methyl-2-[(A(-l-naphthylamino)methyl]pyrrolidine, and Bu3Sn(OAc)2 gives better results (Eq. 20) [33,35]. The asymmetric aldol reactions proceed with higher enantioselectivity and, in addition, the reactions proceed faster with Bu3Sn(OAc)2 as an additive than with BusSnE A wide variety of aldehydes including aliphatic, aromatic, and a,/3-unsatu-rated aldehydes can be used in this reaction, and the aldol adducts are always obtained in high yields with perfect syn selectivity the enantiomeric excesses of these syn adducts are > 98 %. 

The Reformatsky Reaction consists of the interaction of an ester of an a-halogeno-acid with an aldehyde, a ketone or another ester in the presence of zinc. For example, if a mixture of ethyl bromoacetate and benzaldehyde is heated with zinc, the latter undoubtedly first combines with the ethyl bromoacetate to form a Grignard-like reagent (reaction A), which then adds on to the benzaldehyde Just as a Grignard reagent would do (reaction B). The complex so formed, on acidification gives ethyl p-phenyl-p-hydroxy-propionate (reaction C). Note that reaction A could not satisfactorily be carried out using... 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Carboxylic Acids Obtained by Fermentation of Carbohydrates Lactic (2-hydroxy-propionic) acid obtained by fermentation of glucose and polysaccharides is used by NatureWorks (Cargill/Dow LLC) to prepare polylactide (PLA), a biodegradable or recyclable polymer with a potential production of 140000 t a-1 (Scheme 3.4) [23], This and other potential useful reactions from lactic acid have been reviewed by Datta and Henry [24],... 

Beccalli et al. reported a new synthesis of staurosporinone (293) from 3-cyano-3-(lH-indol-3-yl)-2-oxo propionic acid ethyl ester (1464) (790). The reaction of 1464 with ethyl chlorocarbonate and triethylamine afforded the compound 1465, which, on treatment with dimethylamine, led to the corresponding hydroxy derivative 1466. The triflate 1467 was prepared from 1466 by reaction with trifluoromethanesulfonic anhydride (Tf20) in the presence of ethyldiisopropylamine. The palladium(O)-catalyzed cross-coupling of the triflate 1467 with the 3-(tributylstannyl)indole 1468 afforded the vinylindole 1469 in 89% yield. Deprotection of both nitrogen atoms with sodium ethoxide in ethanol to 1470, followed by photocyclization in the presence of iodine as the oxidizing agent provided the indolocarbazole 1471. Finally, reductive cyclization of 1471 with sodium borohydride-cobaltous chloride led to staurosporinone (293) in 40% yield (790) (Scheme 5.248). 

The reaction of enolates with aldehydes or ketones to produce /3-hydroxy carbonyl derivatives is a very common and a very useful way to make carbon-carbon bonds. A fundamental stereochemical feature of the reaction is diat two new chiral centers are produced from achiral starting materials. Hence syn and anti diastereomers will be produced, each as a pair of enantiomers. This is shown schematically for the reaction of a propionate enolate with isobutyraldehyde. Because they have different energies, the syn and anti diastereomers will be... 

Cobalt tetracarbonyl anion in such hydroxylic solvents as water or methanol also reacts with epoxides at temperatures of 60—100 and at an elevated pressure of carbon monoxide (2000 Ib./in. ) to give esters of j8-hydroxy acids. Thus, ethylene oxide has been found to react with sodium cobalt tetracarbonyl and carbon monoxide in methanol solution at 65 and 2000 Ib./in. to give methyl 3-hydroxy-propionate in a yield of 55% the remainder of the product was acetaldehyde and an involatile oil. It was also shown that this reaction proceeds almost as well at a much lower pressure (three or four atmospheres of carbon monoxide). ... 

In the presence of a trace of an alkaline catalyst, a 3-hydroxy-propionate ester is formed in a good yield as the reaction with tlic primaiy alcohols is very rapid, it is advantageous to run the reaction at a low temperature with excess of alcohol to cut down the polymerization. This is difficult to avsecondary alcohols which, therefore, give rather low yields of hydraerylic estw. 

From aldehydes, we always obtain an fl//>/ffl-hydroxy acid in which the hydroxyl group is linked to the carbon atom which is itself directly linked to carboxyl. Also the resulting hydroxy acid will always contain one more carbon than the aldehyde with which we start. Thus, by starting with any saturated alcohol or acid and obtaining the aldehyde, we may pass to the hydroxy acid next higher in the series. Acetic aldehyde yields a-hydroxy propionic acid. From ketones we also always obtain an alpha- iy 6xoxy acid and likewise increase the number of carbon atoms by one. The a//>/ffl-hydroxy acid obtained, however, will be isomeric with the one obtained from the aldehyde of equal carbon content. This will be seen from the above reactions. 

Methyl ketones are often directly prepared from carboxylic acids by reaction with methyllithium. Other simple alkyl ketones may also be prepared in the same fashion, making this a method that should be considered whenever these substrates are required. An important demonstration of this protocol was reported by Masamune and coworkers in their synthesis of chiral propionate surrogates (Scheme 13). The ethyl and cyclopropyl ketones are important starting materials for macrolide total synthesis and have been prepared on a large scale. The overall yield for the ethyl ketone is 65% using 3.5 equiv. of ethyllithium without protection of the hydroxy group. 

Dromostanolone Propionate, U5P. The semisyn-ihetic androgen dromostanolone propionate. Drolban. lfi-hydroxy-2n -methyl-Sa-androstan-3-onc propionate. 2a-mcthyldihydroteslosterone propionate, is prepared from di-hydrutcstostcronc in a route involving condensation with ethyl formate followed by hydrogenation to give the 2a-methyl derivative and then reaction with propionic anhydride. The compound is supplied in rubber-stoppered vials containing SIX) mg of dromostanolone propionate in 10 mL of sesame oil. with 0.. i% phenol as a preservative. 

The behavior of A -3-ketosteroids on oxidative cleavage - is illustrated by the reaction of testosterone propionate (1). Pettit and Kasturi mixed 9 g. of potassium persulfate and 10 g. of coned, sulfuric acid in a mortar, diluted with 150 ml. of acetic acid, added the mixture to a solution of 9 g. of testosterone propionate in 150 ml. of acetic acid, and let the mixture stand with intermittent shaking at room temperature for 7 days. Workup included saponification and reacidifleation, and the product (2 g.) was characterized as the lactone 3-oxo-17/3-hydroxy-4-oxa-5a-androstane (4). A possible reaction sequence is formulated. 

Table VI summarizes the results of experiments with adipic, sulfosuccinic, sulfopropionic, succinic, glycolic and hydroxy-propionic acids. The results are reported as the sulfite oxidation rate (M/hr) and the degradation rate constant, kd(M ). Analytical accuracy generally allowed determination of kd within -0.1 M l. In experiments with little or no sulfite oxidation, (All, HP3, HP5, HA1, HA3, HA4), there was no measurable degradation of the carboxylic acid. Experiments with 5, 10, and 20 mM adipic acid (A21, A14, A18, A15, A23) showed that the degradation reaction is first order in the carboxylic acid concentration, as expected and modelled by kd-...

As the role of the common precursor 34 is critical, it has been synthesized in large scale by using an Evans syn aldol protocol [39], starting from the commercially available (i )-(-)-methyl 3-hydroxy-2-methyl propionate 1 . This compound was transformed in three steps to aldehyde 32 [40, 41] and used in an Evans aldol reaction with the dibutylboron enolate A. The Weinreb amide formation completed the construction of the common precursor 34 [42] (Scheme 7). From this precursor fragments C1-C8, C9-C14 and C15-C21 were synthesized (Scheme 8). 

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,... 

Scheibler733 has described a laboratory method of preparing acetoacetic ester that is convenient and gives very good yields. In industry it is obtained by use of sodium dust in autoclaves, quantitative yields being claimed734 for this process. Occasionally acetoacetic ester is prepared by condensation of ethyl acetate and used, without isolation, for further reactions, whereby excellent yields of the final products are obtained.735 Ethyl benzoate and acetophenone give dibenzoylmethane in about 70% yield.736 0-Hydroxy-acetophenone, condensed with ethyl propionate and sodium in ether, afford l-(0-hydroxyphenyl)-l,3-pentanedione which is cyclized to 2-ethylchromone in 70-75% yield by hydrochloric and acetic acid.737... 

Polymer bound acrylic ester is reacted in a Baylis-Hillman reaction with aldehydes to form 3-hydroxy-2-methylidenepropionic acids or with aldehydes and sulfonamides in a three-component reaction to form 2-methylidene-3-[(arylsulfonyl)amino]propionic acids. In order to show the possibility of Michael additions, the synthesis of pyrazolones was chosen. The Michael addition was carried out with ethyl acetoacetate and BEMP as base to form the resin bound p-keto ester. This was then transformed into the hydrazone with phenylhydrazine hydrochloride in the presence of TMOF and DIPEA [28]. The polymer bound phenol was readily coupled to a variety of allyl halides by using the Pl- Bu to generate a reactive phenoxide [29]. 

Enantioselective D-A reactions of chiral esters and amides of acrylic acid can be achieved using achiral Lewis acid such as TiCU. After the reaction, enantiomeric pure carboxylic acid can be recovered on hydrolysis. For example, the reaction of acrylic acid with cyclopentadiene using chiral a-hydroxy ethyl propionate 95a as chiral auxiliary in the presence of TiCU gives only one enantiomeric product in large excess (93 %) [82]. The chiral auxiliary 95a reacts with dienophile to produce a chiral ester 95, which participates in the reaction with cyclopentadiene. 

Also obtained by reaction of propionyl chloride (SM) with guaiacol in carbon disulfide in the presence of aluminium chloride for 1 h at 70° (70%) [6671]. SM was formed in situ by action of oxalyl chloride with sodium propionate (method B). Also obtained by oxidation of l-(4-hydroxy-3-methoxyphenyl)-l-propanol (m.p. 69°) [7168],... 

In the absence of a BINOL-Ti(OiPr)4 system, NMI can solely be used as a Lewis acid catalyst to active diethylzinc and de-protonate the alkyne. This was observed in the alkynylation between various aliphatic aldehydes and methyl propionate to yield y-hydroxy-a,/3-hydroxy esters, which could be further functionalized via a base-catalyzed reaction with DMAP and acetic anhydride to give synthetically useful y-hydroxy dienoates (eq 43). ... 

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