Mixed acetal synthesis

The first total synthesis of the marine dolabellane diterpene (+)-4,5-deoxy-neodolabelline (70) was accomplished by D. R. Williams et al. [58]. The trans-disubstituted dihydropyran moiety in key intermediate 69 was efficiently prepared from mixed acetal 66 by RCM with second-generation catalyst C and subsequent Lewis acid-catalyzed allylation of ethyl glycosides 67 with allylsi-lane 68 (Scheme 12) [59]. 

The conversion of vicinal azido selenides into tetrahydrofiirans by PhSeOTf in MeCN at room temperature is reported <96JOC7085>. 3-Butadienyl tetrahydrofiirans and a-butadienyl y-butyrolactones can be prepared by radical cyclization of P-bromopent-4-en-2-ynyl ethers and mixed acetals <96SL391>. The total synthesis of trilobacin was reported <96JOC7642>. 

Radical cyclization reactions have been extensively applied in synthesis. Among the first systems to be studied were unsaturated mixed acetals of bromoacetaldehyde.323... 

The use of a Lewis acid (e.g., friethylfluoroborate, zinc chloride, stannous chloride, titanium chloride, iron(m)chloride) and other reagents (e.g., iodine, trimethylsilane, trifluoiomethane-sulfonylsilane) have also been recommended. Exhaustive lists of catalysts and conditions can be found in reviews devoted to carbohydrates [5-7], or to general organic chemistry [27,28], However, one can add the new catalyst, which has been introduced for the smooth formation of p-methoxybenzylidene acetals and p-methaxy-phenylmethyl methyl ether [29], namely 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), and has been applied very recently [30] to the synthesis of isopropylidene mixed acetals. 

O. Kjplberg and K. Neumann, Synthesis of acyclic carbohydrate isopropylidene mixed acetals using 2,3-dichioro-5,6-dicyano-p-benzoquinone as a catalyst, Acta Chem. Scand 48 80(1994)... 

A further useful reaction of dialkyl ditinoacetab involves treatmein with bromine in an aprotic solvent, which effects monobromination at C-l. These brominated intennediates react with such nucleophiles as alcohols to form mixed acetal products [24]. This method has proved especially osefid for the synthesis of nucieoside analogues having acyclic sugar chains attached to the heterocycle [25] (Scheme 5). 

The use of the very reactive mixed acetic formic anhydride at room temperature allows the synthesis of chromones unsubstituted at C-2. Especially good yields result when an electron-withdrawing group is present in the acyl moiety of the ketone <78JCR(M)0865>. 

Cellulose esters of the 2-.. 3-. and 4-carbon acids are readily prepared by the cellulose-anhydride reaction the acetate ester and the mixed acetate butyrate and acetate propionate esters arc manufactured and used in large amounts. Esters of higher acids require different synthesis techniques and tend to be prohibitively expensive except as specialty products. Some arc in commercial production, however. Cellulose acclalc phlhalatc, for example, is manufactured for use as an enteric coating on pills. 

An important industrial synthesis of acetic anhydride is via acetic acid and ketone. Mixed acetic anhydrides arc made similarly by passing ketene... 

A highly selective synthesis of homoallylic alcohols has been reported by Tietze et al.,917 who reacted methyl ketones, the chiral norpseudoephedrine derivative 285, and an allylsilane in the presence of a catalytic amount (0.2 mol%) of triflic acid [Eq. (5.340)]. The transformation was interpreted as an SN2 attack of the allylsilane to the protonated mixed acetal 286. The obtained ethers were then cleaved to the final product, homoallylic alcohols. 

In addition to the preparation of a- and /3-hydrastine described above from the betaine (64), another conversion of a tetrahydroberberine into hydrastine has been reported. Acetylophiocarpine, on treatment with ethyl chloroformate, gives the acetoxy-derivative of (88), which can be hydrolysed to the hydroxymethyl compound and then oxidized to the aldehyde by pyridinium perchlorate. Hydrolysis of the acetoxyl group afforded the hemi-acetal (93 R = H), conversion of which into the mixed acetal (93 R = Et) protected the aldehyde system during reduction of N—C02Et to NMe by lithium aluminium hydride. Hydrolysis of the acetal, followed by oxidation, then gave a-hydrastine, and a similar sequence of reactions starting from O-acetyl-13-epi-ophiocarpine afforded / -hydrastine.119 Methods of synthesis of alkaloids of this group have been reviewed.120... 

Cupric chloride, if present in concentrations above ca. 0.5 M, may cause side reactions to occur in the olefin aiylation reaction similar to those that occur with cupric chloride in the vinyl acetate synthesis mentioned above. The side reaction produces 2-arylethyl chlorides and these products may be made the major ones if cupric chloride is present to the extent of about 2M in 10% aqueous acetic acid solution 29>. The mixed solvent is required to obtain the necessary solubility of the cupric chloride. This is a general reaction useful for producing a variety of 2-arylalkyl halides. For example, 3-phenyl-2-chloropropionaldehyde is obtained in 63% yield by the reaction of phenylpalladium chloride , cupric chloride and acrolein. 

The key intermediate in the total synthesis of furaquinocin was obtained in good yield by a reductive Heck reaction that proceeded with a sterically hindered base pentamethylpiperidine (PMP) <02JA11616>. A new hypothesis for the major skeletal rearrangement (anthraquinone —> xanthone —> coumarin) that occurs in the complex biosynthesis of aflatoxin Bi was proposed. To test this hypothesis, an intermediate 11-hydroxy-O-methylstergmatocystin (HOMST) was synthesized as shown below. The key transformation in this synthesis involved the treatment of an ester-aldehyde with Pr3SiOTf, which smoothly produced a mixed acetal. Direct reduction with DIBAL-H led to the aldehyde. The desired product was eventually obtained via several steps as shown <02JA5294>. 

Various applications of selenium-stabilized carbanions in synthesis have been reported. The mixed acetal 108 derived from benzaldehyde was efficiently metalated by KDA in THF. The a-methoxy-a-methylselanyl benzyl-potassium compound 109 is stable at low temperatures (—78 °C) and reacted with a variety of electrophiles. The reaction products 110, still mixed acetals, are obtained in good yields as shown in Table 3 (Scheme 25).196... 

Later on, Schreiber used consecutively these two reactions in the key step for the synthesis of diterpene (-i-)-epoxydictimene (73), starting from natural (R)-pulegone [116,117]. This approach was built on their preliminary studies on Lewis acid mediated intermolecular Nicholas reactions [118]. They prepared functionalized enyne 70 bearing a mixed acetal. This compound was transformed into its dicobalt-hexacarbonyl complex and, in the presence of a carefully selected Lewis acid, it formed a stabilized carbocation by release of the more accessible ethyl moiety. This cation reacted intramolecularly with the allylsilane giving the central eight membered ring of the natural product... 

An impressive application is the highly stereocontrolled and enandoselective synthesis of (-)-laure-nyne (113 Scheme 54). The key step is the cyclization of the mixed acetal (110) to give the oxocene (112), with the required endocyclic unsaturation at the correct position. The formation of this eight-mem-bered cyclic ether, instead of the corresponding seven-membered ring with an exocyclic double bond, may be rationalized by an intramolecular ene-type reaction of the intermediate oxocarbenium ion (111). 

Cationic cycloadditions. Ionization of p-benzoquinone monoacetals is induced by MejSiOTf in highly polar media (LiClO /EtOAc) and the carbocations are captured in situ by alkenes to give bicyclo[3.2.1]octene derivatives. A synthesis of 2-(l -phenylethoxy)-8-oxabicyclo[3.2.1]oct-6-en-3-one in good enantiomeric purity from furan and a mixed acetal of 2-(triethylsiloxy)acrolein (prepared from pyruvaldehyde dimethylacetal in three steps) is promoted by MejSiOTf. 

Finally, Huang and Panek utilized a Prins-type reaction between a crotylsilane and an aldehyde in their total synthesis of callipeltoside A (28).21 22 In the presence of TfOH, crotylsilane 25 and aldehyde 26 underwent mixed acetal formation and subsequent Prins cyclization to generate dihydropyran 27 in 87% yield as a single diastereomer. This intermediate was carried forward to complete a total synthesis of 28.22... 

Ring-closing metathesis (RCM) has also been employed in the synthesis of substituted furans. Donohoe and co-workers used a ring-closing metathesis strategy to form the furan moiety of (-)-(Z)-deoxypukalide, a compound from the family cembranolides, which have been shown to exhibit neurotoxicity and anti-inflammatory properties. Treatment of a mixed acetal with Grubbs II catalyst, followed by in situ aromatization with PPTS, yielded the disubstituted furan in 85% yield over two steps. Seven additional steps were required to reach of (-)-(Z)-deoxypukalide. 

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