Methoxypropene-protected

In 2007, another departure from carbonyl-type activation was marked by Kotke and Schreiner in the organocatalytic tetrahydropyran and 2-methoxypropene protection of alcohols, phenols, and other ROH substrates [118, 145], These derivatives offered a further synthetically useful acid-free contribution to protective group chemistry [146]. The 9-catalyzed tetrahydropyranylation with 3,4-dihydro-2H-pyran (DHP) as reactant and solvent was described to be applicable to a broad spectrum of hydroxy functionalities and furnished the corresponding tetrahydro-pyranyl-substituted ethers, that is, mixed acetals, at mild conditions and with good to excellent yields. Primary and secondary alcohols can be THP-protected to afford 1-8 at room temperature and at loadings ranging from 0.001 to 1.0mol% thiourea... 

Since the introduction of chemically amplified resist systems to DUV technology, the environmental stability and bake latitudes have been the major concern of this type of chemistry. Ketal resist systems have been very robust towards fiiese issues. The methoxypropene protected polyhydroxystyrene resist is our first initial work on ketal system. 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

Oxidative cleavage of the terminal double bond of 49 by ozonolysis to the aldehyde followed by permanganate oxidation to the acid and esterification with diazomethane produced the methyl ester 50. Dieckmann cyclisation of 50, following the procedure developed in Holton s laboratory (LDA, THF, -78 °C, 0.5 h, then HOAc, THF), gave the enol ester 5J in 93% yield (90% conversion). Decarbomethoxylation of 5J. was carried out by temporarily protection of the secondary alcohol (p-TsOH, 2-methoxypropene, 100%), and heating the resulting compound 52 with PhSK in DMF, at 86 °C (3 h) to provide 53a or, after an acidic workup, the hydroxy ketone 53b. 92% yield. 

The authors successfully applied their protocol to the alternative enol ether 2-methoxypropene (MOP) to prepare the MOP ether 1-8 from a subset of the various alcohol substrates as depicted in Scheme 6.21. This high-yielding (92-97%) MOP protection occurred smoothly at room temperature MOP turned out to be so reactive that the uncatalyzed reaction also proceeded albeit at lower rates [118, 145]. 

The second example concerns the study of acetonation of o-mannose (see Scheme 8) and allows a clear distinction between the use of 2,2-dimethoxypropane and 2-methoxy-propene. Thus, whereas D-matmose gives 2,3 5,6-di-0-isopropylidene-D-mannofuranose 5 by reaction of the free sugar with acetone [5,6] as well as with 2,2-dimethoxypropane [96], the major compound (more than 85%) obtained with 2-methoxypropene is 4,6-0-isopropylidene-D-mannopyranose 6 [52]. Once again, a confirmation of the better stability of furanoid acetals in this series is given by the selective hydrolysis of the 2,3 4,6-di-O-isopropylidene-D-mannopyranose 7 (by-product of the preceding reaction or quantitatively obtained by action of 2-methoxypropene on acetal 6), witch gives the furanoid monoacetal 8. Actually, the pyranoid monoacetal 9 can be easily prepared as soon as the anomeric hydroxyl group is protected by acetylation [52]. 

The acetonation under kinetically controlled conditions is also useful for the protection of vicinal rra/u-diols, which are quite reluctant to cyclization into five-membered rings. Although use of 2-methoxypropene has been successful in this objective [61,66], one should recommend the recently discovered uses of reagents that minimized the ring strain by obtaining six-membered rings from vicinal mmr-dials, which are protected (Scheme 10) as 1,4-dioxanes (dispiroacetals, rranr-decalinic system) stabilized by an anomeric effect... 

In order to prevent competing homoallylic asymmetric epoxidation (AE, which, it will be recalled, preferentially delivers the opposite enantiomer to that of the allylic alcohol AE), the primary alcohol in 12 was selectively blocked as a thexyldimethylsilyl ether. Conventional Sharpless AE7 with the oxidant derived from (—)-diethyl tartrate, titanium tetraisopropoxide, and f-butyl hydroperoxide next furnished the anticipated a, [3-epoxy alcohol 13 with excellent stereocontrol (for a more detailed discussion of the Sharpless AE see section 8.4). Selective O-desilylation was then effected with HF-triethylamine complex. The resulting diol was protected as a base-stable O-isopropylidene acetal using 2-methoxypropene and a catalytic quantity of p-toluenesulfonic acid in dimethylformamide (DMF). Note how this blocking protocol was fully compatible with the acid-labile epoxide. 

Compound 1 has also been prepared by the following methods. Addition of ethylmagnesium bromide to the protected cyanohydrin of acetone, followed by hydrolysis and silylation provides 1 1n 40t yield (eq 2).2 Metallation of 1-methoxypropene by butyllithium in pentane gives 1-lithio-l-methoxypropene, which reacts with acetone to give, after hydrolysis and silylation, ketone 1... 

Ciufolini et al. developed carbonyl-ene reactions catalyzed by the 1 1 complex of Yb(fod)3 and acetic acid [19]. 2-Methoxypropene reacted with a variety of aldehydes under the conditions used, providing the protected alcohols in good yields (Eq. 9). Addition of acetic acid was essential —the reaction did not proceed with Yb(fod)3 alone. Addition of silica gel to the reaction mixture was found to enhance the rate of the reaction and to make the reaction clean, although the use of silica gel was not mandatory. Double activation of the aldehydes as a result of coordination to the Yb Lewis acid and hydrogen-bonding with the acidic hydrogen of the acetic acid was proposed for the reaction (Fig. 2). 

The cis- and /ra/i5-l,3,4-oxadiazine-5-carboxylates (311 71%) and (312 57%) are prepared by ring-closure of the erythro- and threo-homers of the diBOC protected hydrazine (310 R = Bu PhjSiO) with 2-methoxypropene <89TL5507>. The more stable /ra i-isomer (312) is also available in 75% yield by base-mediated equilibration of the cw-isomer (311). 

A third member of the family of acid-removable protecting groups is the 2-methoxy-2-methylpropyl functionality. This is introduced by treating the appropriate malate ester with 2-methoxypropene in the presence of a catalytic amount of phosphorus oxychloride [6,20]. The labile ketals 11 are formed in nearly quantitative yield, and are generally used immediately without purification. 

Incorporation of both the hydroxyls of 45a into an acetonide nicely protects both functionalities, and the protection is easily removed under mild acidic conditions. This strategy is accomplished by treating 45a with acetone and PTSA (73% yield) [22], 2,2-dimethoxy-propane and PPTS (93% yield) [55], or 2-methoxypropene and PPTS (70-82% yield) [44] to give the desired acetonide 141. 

But the Merck chemists noticed that amino alcohol itself, certainly once protected, has a remarkable similarity to Evans oxazolidinone auxiliaries anyway, and it turns out that this amino alcohol will function very successfully as a chiral auxiliary, which does not need to be removed, avoiding waste and saving steps The amino alcohol was acylated with the acyl chloride, and the amide was protected as the nitrogen analogue of an acetonide by treating with 2-methoxypropene (the methyl enol ether of acetone) and an acid catalyst. The enolate... 

Both 1,2-diols and 1,3-diols can be protected by treatment with 2-methoxypropene according to the following reaction. 

Monoprotection of Alcohols. 2-Methoxypropene is used as a protective group for aliphatic, " allylic, and propargylic alcohols, masking them as their mixed acetals (eq 1). Deprotection can be accomplished by stirring in MeOH over ion exchange resin, by reaction in methanol with catalytic Acetyf Chloride, by Potassium Carbonate in methanol, or by 20% Acetic Acid. 

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