Nucleophilic addition diethyl phosphate

In the initial screening of various Cinchona alkaloids, the addition of diethyl phosphate 41 to IV-Boc imine 40 in toluene revealed the key role of the free hydroxyl group of the catalyst. Replacing the C(9)-OH group with esters or amides only results in poor selectivity. Quinine (Q) was identified as an ideal catalyst. A mechanistic proposal for the role of quinine is presented. Hydrogen-bonding by the free C(9)-hydroxyl group and quinuclidine base activation of the phosphonate into a nucleophilic phosphite species are key to the reactivity of this transformation (Scheme 9). 

A few cases of nucleophilic additions to P-ketophosphonates have been reported. When the a-carbon atom to phosphorus is fully substituted, it appears unlikely that the reaction at phosphorus is competitive with the addition to carbonyl group. Thus, treatment of diethyl 1-fluoro-1-ethoxy-carbonyl-2-ethoxycarbonyl-2-oxoethylphosphonate with Grignard reagents at low temperature in THF gives an ( )/(/) mixture of a-fluoro-a,P-unsaturated diesters in 49-68% yields. The initial step is the nucleophilic attack of Grignard reagent at the carbonyl group, followed by intramolecular elimination of diethyl phosphate (Scheme 7.104). ° ... 

The addition of NEt3 to carboxylic acid 1 generates carboxylate anion which attacked at phosphorus of diethyl cyanophosphonate and subsequently displaces -CN to produce activated carboxylic acid phosphate ester 5. Nucleophilic addition of amine 2 to phosphate ester 5 gives the amide 4 and diethylphosphate.1-3... 

The report on the synthesis of the phosphonate isostere of AZT 5 -phosphate by a BF3-Et20-catalyzed nucleophilic addition of diethyl methanephosphonate to an oxetane prompted us to apply the same reaction conditions to the opening of epoxides. Indeed, when the anion of the same phosphonate was generated with BuLi in THF, followed by the sequential addition of epoxide 10a or 10b and BF3-Et20 at -78°, the corresponding P-hydroxyphosphonates 20 (a and c) were obtained in quantitative yield.26 Extension of this reaction to a phosphorus nucleophile proved to be equally effective. Thus, when diethyl phosphite was condensed with the same epoxides under identical reaction conditions, the corresponding P-hydroxyphosphonates 20 (b and d) were isolated in... 

The inhibition of hLAL by boronic acids and diethyl p-nitrophenyl phosphate (Sando and Rosenbaum, 1985 G. N. Sando and H. L. Brockman, unpublished, cited by Anderson and Sando, 1991) indicates that hLAL is a serine hydrolase. Two lipase/esterase consensus pentapep-tides, G-X-S-X-G, are found, but only one of them appears to be consistent with the packing requirements of the )8-eSer-a nucleophilic motif (see above). Susceptibility of the enzyme to sulfhydryl reagents, and the requirement of thiols for the stability of purified hLAL, prompted Anderson and Sando (1991) to propose that a cysteine residue, or rather a Cys/Ser couple, may be involved in an internal transacylation reaction. It must be pointed out, however, that hLAL has all three cysteines of the gastric enzyme (as well as six additional ones), and so the inhibitory Cys is also there. The same argument proposed herein with respect to hGL, i.e., that a free cysteine is topologically close to the active site, also holds for hLAL. 

When triptolide 1 was reacted with nucleophillic reagents HBr, CH3CH2CH2SH, HOAc, MeOH, ammonium thiocyanide or 4-methoxybenzenesulfonyl chloride, the same C12-C13 epoxide reacted to form compounds 69-73 [70-72], Refluxing 1 for 96 hrs in phosphate buffer solution at pH 4 generated triptriolide 10 in 43% yield [72], In contrast, when 1 was stirred with sodium cyanoborohydride followed by dropwise addition of neat boron trifluoride diethyl etherate at room temperature for 16 hrs, the epoxide ring at C-7-C-8 opened and the compound 74 was obtained. Subsequently, reaction of compound 74 with HC1 at room... 

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