Methyl orthoesters

Exposure of quaternary ammonium salt 163 to NaOMe gives methyl orthoester 37 and ketene acetal 54 as the consequence of a competing Hofmann-type elimination (Equation 33). Elution of 163 as a methanol solution through an anion-exchange resin (Dowex-550-OH, MeOH) leads exclusively to ketene acetal 54 in 89% yield <2004AGE1117>. 

The total synthesis of apoptolidin was accomplished in the laboratory of K.C. Nicolaou. The key C12-C28 vinyl iodide fragment was prepared using the Schwartz hydrozirconation of an internal alkyne followed by trapping of the alkenylzirconium intermediate with iodine (I2). The vinyl iodide was formed as a 6 1 mixture of regioisomers. Under the reaction conditions, the methyl orthoester was converted to the methyl glycoside moiety at C21, which was presumably facilitated by the complexation of Zr with the pyranoside oxygen atom. 

Orthoesters (e.g., methyl orthoacetate) have also been prepared by acid-catalyzed exchange with trimethyl orthoesters, from 16a,17a-dihydroxy-pregnanes with or without a 21-hydroxyl substituent. 

Carboxylic acids can also be protected as orthoesters. Orthoesters derived from simple alcohols are very easily hydrolyzed, and the 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane structure is a more useful orthoester protecting group. These... 

The synthesis93 of N-(2,4-dinitrophenyl)-3-0-(tetra-0-acetyl-/ -D-glu-copyranosyl)-L-threonine methyl ester (131) involved a two-step procedure. First, formation of the intermediate, L-threonine orthoester 130 was achieved by treatment of tetra-O-acetyl-a-D-glucopyranosyl bromide (128) with the methyl ester of N-(2,4-dinitrophenyl)-L-threonine94 (129) under the conditions of the Koenigs-Knorr reaction (see next paragraph), and this was then converted into the L-threonine glycoside 131. 

Unsymmetrical ethers may be produced from the acid-promoted reactions of aldehydes and organosilicon hydrides when alcohols are introduced into the reaction medium (Eq. 173).327,328 An orthoester can be used in place of the alcohol in this transformation.327 335 A cyclic version of this conversion is reported.336 Treatment of a mixture of benzaldehyde and a 10 mol% excess of triethylsilane with methanol and sulfuric, trifluoroacetic, or trichloroacetic acid produces benzyl methyl ether in 85-87% yields.328 Changing the alcohol to ethanol, 1-propanol, 2-propanol, or 1-heptanol gives the corresponding unsymmetrical benzyl alkyl ethers in 45-87% yield with little or no side products.328 A notable exception is the tertiary alcohol 2-methyl-2-propanol, which requires 24 hours.328 1-Heptanal gives an 87% yield of //-lie ply I methyl ether with added methanol and a 49% yield of benzyl n-heptyl ether with added benzyl alcohol under similar conditions.328... 

Pyrrolo[l,2-rf [l,2,4]triazinones 21 were synthesized from methyl ester of /ra j-4-hydroxy-L-proline 72. The synthetic route involved formation of hydrazones followed by cyclisation with orthoesters <1998BMC349>. Similar reactions have been developed with 3-benzylindole-2-carbohydrazides 73 in reaction with triethyl orthoformate, giving the corresponding ring systems indolo[l,2-r][ 1,2,4]triazin-4-oncs 74 <2004JHC7>. 

Carbohydrate orthoesters, first reviewed by Pacsu more than 60 years ago [8], were reported by Fischer et al. [9] as by-products of the Koenigs-Knorr reaction [3] of acetobromo-L-rhamnose (1) with methanol. Orthoacetate 3 was isolated along with the expected a- and P-methyl rhamnosides 2 (Scheme 5.2). However, its true structure was assigned only 10 years later by several research groups [10-12]. 

Addition of alcohols to lactones results in the formation of orthoacid or orthoester derivatives. Thus, reaction of lactone 95a with potassium cyanide in ethanol led to displacement of the tosyl group by cyanide and addition of ethanol to the lactone carbonyl group, to give the orthoacid derivative 95b, which was isolated as its acetate 95c. Mild deacylation of 95c led back to 95b, but under more vigorous reaction conditions the open-chain methyl aldon-ate was obtained (90). 

Wolfbeis investigated the reactions of amines and orthoesters with different CH-acid molecules (81CB3471). When the reactions of aniline, ethyl orthoformate, and dialkyl malonates (2 mol) were carried out at 130-140°C for 4 hr, phenylaminomethylenemalonamates (245) were obtained (81CB3471). Similar reactions with aliphatic amines were unsuccessful. Phenylaminomethylenemalonic acid could not be prepared in the reactions of aniline, methyl orthoformate or orthoacetate, and malonic acid. When these reactions were carried out in 2-propanol, only amidines (246) were obtained. 

In contrast to Mori s synthesis, Pawar and Chattapadhyay used enzymatically controlled enantiomeric separation as the final step [300]. Butanone H was converted into 3-methylpent-l-en-3-ol I. Reaction with trimethyl orthoacetate and subsequent Claisen-orthoester rearrangement yielded ethyl (E)-5-methyl-hept-4-enoate K. Transformation of K into the aldehyde L, followed by reaction with ethylmagnesium bromide furnished racemic ( )-7-methylnon-6-ene-3-ol M. Its enzyme-catalysed enantioselective transesterification using vinylacetate and lipase from Penicillium or Pseudomonas directly afforded 157, while its enantiomer was obtained from the separated alcohol by standard acetylation. 

Ortho esters were reduced to acetals. Refluxing with 0.25mol of lithium aluminum hydride in ether-benzene solution for 4 hours transformed 3-methyl-mercaptopropanoic acid trimethyl orthoester to 3-methylmercaptopropion-aldehyde dimethylacetal in 97% yield [1098]. 

Finally this method opetis the way to the study other orthoesters, substitued by HrouDs different from Tifcthoxyl and methyl, in order to modulate their stability and their reactivity. 

Using the optimized system for the two-component reaction, the same group [89] tested the three-component reaction, starting from an aldehyde, an amine and a phosphite (Scheme 42). An orthoester (trialkyl orthoformate, methyl or ethyl) was added to remove the formed water and to promote the imine formation, which was beneficial for the reaction however, these trials afforded maximally 49% yield due to the low conversions and low selectivities towards the desired aminophosphonates. 

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