Phosphonate ketals

Examples of nucleophilic attack at the saturated 2-carbon of dihydro-l,4-thiazines, which may be assisted by the neighboring sulfur atom, are shown below. The nucleophiles include water, which was used in the acid-catalyzed hydrolysis of the ketal in 236 (Equation 21) <1982S424>, methanol in the conversion of 214 into a monothioacetal (Equation 22) <1982JHC131>, ethanol and dimethylaniline, which both reacted with 237 (Scheme 29) <1982TL4963>, and triethyl phosphite that was used to convert 238 into the phosphonate 239 required for Wadsworth-Emmons reaction (Equation 23) <2004BML1477>. Compound 240 reacted with both methanol and methanethiol (Equation 24) <1990JME1898>. 

A general methodology for the construction of quaternary carbon atoms at the carbonyl carbon of ketones has been successfully exploited for the facile synthesis of ( )-lycoramine (299) (Scheme 30) (165). Thus, the O-allylated o-vanillin 322 was allowed to react with vinyl magnesium bromide followed by Jones oxidation, and the acid-catalyzed addition of benzyl IV-methylcarbamate to the intermediate a,(3-unsaturated ketone furnished 323. Wadsworth-Emmons olefination of 323 with the anion derived from diethyl[(benzylideneami-no)methyl]phosphonate (BAMP) provided the 2-azadiene 324. The subsequent regioselective addition of n-butyllithium to 324 delivered a metalloenamine that suffered alkylation with 2-(2-bromoethyl)-2-methyl-l,3-dioxolane to give, after acid-catalyzed hydrolysis of the imine and ketal moieties, the 8-keto aldehyde 325. Base-catalyzed cycloaldolization and dehydration of 325 then provided the 4,4-disubstituted cyclohexenone 326. The entire sequence of reactions involved in the conversion of 323 to 326 proceeded in very good overall yield and in one pot. 

Asymmetric synthesis of a chroman. Solladie and Moine have effected an en-antiospecific synthesis of the chroman-2-carboxaldehyde 7, a key intermediate in the synthesis of a-tocopherol, from (R)-( +)-l. The phosphonate 2, derived from 1, undergoes a Wittig-Horner reaction with the dimethyl ketal of pyruvaldehyde to afford the optically active vinyl sulfoxide 3. Condensation of the aldehyde 4 with the lithio derivative of 3 affords, after silyl deprotection, the allylic alcohol 5 as the only diastereoisomer. This... 

In the covalent approach, the print molecules are covalently coupled to polymerisable molecules prior to polymerisation (see Chapter 4). The covalent bonds have to be relatively easy to break to allow cleavage of the print molecules after polymerisation. Print molecules have been coupled to monomers through the formation of boronic, carboxylic and phosphonic ester bonds, amide bonds, imines and ketals. After copolymerisation with a high degree of cross-linker, the print molecules are cleaved from the polymer. A representative example of the covalent approach is shown in Fig. 17.1. 

New mercaptoaryl- and mercaptoheteroaryl-phosphonates (139) have been prepared by or /io-lithiation of the corresponding O, O-diisopropyl S -aryl/hetero-aryl phosphorothioates 138 followed by sulfur to carbon rearrangement. A simple and efficient synthesis of the 2-substituted 3-diethylphosphono 5-methyl-furans 141 from the ketal phosphonate 140 has been reported. Acylation of a-... 

Completion of the monomeric unit was achieved via Swem oxidation and Arbuzov reaction with trimethylphosphite to give the phosphonate 75 in 31% overall yield from the resolved amino alcohol. Dimeric olefination was effected upon deprotonation to yield the macrocycle 76, which could be converted in 81% yield to optically active vermiculine (56) via sequential cleavage of the thioketal and ketal protecting groups. 

Yet another synthesis which employs phosphorus(III)triesters is the reaction which occurs between diethyl trimethylsilyl phosphite and bis(alkylthio)ketals more specifically, such acetals of aromatic aldehydes react in the presence of a Lewis acid (SnCl4 was actually employed) to give diethyl (a-alkylthiobenzyl)phosphonates (reaction 17) ... 

The steroidal a-(isocyanomethyl)phosphonates (130) and (133) have been synthesized by methylation of the carbanions (129) and (132), respectively.66 Compounds (130) and (133) behave as N,P-ketals in that they can be hydrolysed to the corresponding ketones (131) and (134) (Scheme 10). A range of a-substituted a-aminophosphonic acids (136) have been prepared in moderate to excellent yield by the alkylation of the protected a-aminophosphonate (135) with alkyl and aryl halides and Michael acceptors under phase transfer catalysis (Scheme 11).67 The reactions of the lithium carbanion of diethyl prop-2-enyIphosphonate (137) with a,P-unsaturated ketones and esters have been investigated.6S Attack can be at the a- or y-positions in the phosphonate although in all cases Michael addition to the a, p-unsaturated carbonyl is preferred to attack at carbonyl carbon. In some examples simple adducts (138) are formed, but in more complex cases addition is followed by cyclisation to give (139) (Scheme 12). The bisphosphonate (141), which is a potent inhibitor of myo-inositol monophosphatase, has been prepared with the phosphonylation of the carbanion of (140) as a key step.6 9... 

The beauty of our tetracyclic cage target is that the cyclization cascade can be initiated from the front (as we did in Scheme 14) or from the back (Scheme 15). Simply by changing the order of addition in terms of with what the phosphonate is alkylated and then what type of aldehyde with which it reacts, we could easily access substrates that allow a cyclization to proceed from either front or back. In our second attempt, we first alkylated the phosphonate with an allyl bromide (71) containing a vinyl iodide needed for cyclization and then subjected that product (72) to an HWE olefination. Again, we were delighted that this complex acrylic-type acid (74) could be delivered with lead(IV) acetate to form quinone ketal 75. Subsequent heating of this... 

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