Ketophosphonate

Reaction ol a haloketones with tnalkylphosphite to give ketophosphonate or vinylphosphate... 

Retrosynthetic cleavage of the A13,14 double bond in 6 significantly simplifies the side-chain appendage attached to C-l2 and affords aldehyde 7 and ketophosphonate 8 as potential precursors. In the synthetic direction, a Homer-Wadsworth-Emmons reaction10 would appear to provide a very simple means of joining intermediates 7 and 8 with concomitant formation of the requisite trans C13-C14 olefin. Retrosynthetic simplification of aldehyde 7 provides intermediate 9, a molecular assembly commonly known as the Corey lactone. 

Scheme 5. Ketophosphonate-aldehyde condensation in the total synthesis of a tylosin system.

With the key building blocks 16-19 secured, attention can now be turned to their coupling and elaboration to the cyclic heptaenone 6 (Scheme 4), from which both amphoteronolide B (2) and amphotericin B (1) could be generated. To this end, the advanced intermediates, hydroxy aldehyde 13 and ketophosphonate carboxylic acid 14 (Scheme 4), were synthesized as outlined below. 

Scheme 13. Retrosynthetic analysis of ketophosphonate carboxylic acid 14.

Scheme 8. Construction of C52-C115 ketophosphonate 30 synthesis of intermediate 28.

Paterson, I. Lyothier, I. (2004) Total Synthesis of (-F)-Discodermolide An Improved Endgame Exploiting a Stih-Gennari-Type Olefination with a C1-C8 3-Ketophosphonate Fragment. Organic Letters, 6, 4933-4936. 

A significant recent report of epoxides in reaction with anionic trivalent phosphorus is of general use for synthetic purposes. Dialkyl phosphite anions react with the less substituted oxirane carbon of arylsulfonyl epoxides to generate in good yield the corresponding 0-ketophosphonates (Equation 3.12).188... 

Of course, the use of tris(trimethylsilyl) phosphite213 214 provides facile access to the free a-hydroxyphosphonic acids. These silyl reagents have been used for the preparation of a wide range of a-substituted phosphonates and -phosphonic acids, starting with ketene,215 a-ketophosphonates,216 ketoesters,217 218 and a,P-unsaturated carbonyl compounds,207/219-221 as well as simple aldehydes and ketones.205 210/219 224 Their use for the preparation of compounds of significant biological interest has been reviewed.125... 

Myers, T.C., Harvey, R.G., and Jensen, E.V., Phosphonic acids. II. Synthesis of y-ketophosphonic acids from methyl ketones via Mannich bases, /. Am. Chem. Soc., 77, 3101, 1955. 

Koh, Y.J. and Oh, D.Y., A new synthesis of (f-ketophosphonates from aryl epoxy sulfones and dialkyl hydrogen phosphite, Tetrahedron Lett., 34, 2147, 1993. 

While technically not "organometallics," enamines are reagents that can provide nucleophilic carbon for new bond formation. Two groups of researchers have reported on the use of such reagents for the formation of new carbon-phosphorus bonds through displacement of chloride from phosphorus.72 73 For example, displacement of bromide from phosphorus tribromide has been used for the introduction of a new thiophosphoryl functionality adjacent to an original carbonyl group (Equation 4.28).72 This approach provides a facile access to (3-ketophosphonates. 

One common approach incorporates an oxazaborolidine-mediated catechol-borane reduction starting from a-ketophosphonates (146).155 The reaction proceeds with good yield and gives excellent ee (up to 99%). 

The asymmetric hydrogenation with BisP RuBr2 may be applied to a wide range of (3-ketoesters, (3-kctoamidcs, and (3-ketophosphonates. Table 9.2 shows typical examples. 

The nucleophilic addition of 1,2-allenic phosphonates with EtOH followed by hydrolysis leads to the formation of /8-ketophosphonates (Scheme 10.75) [83a]. Intramolecular nucleophilic addition of a hydroxyl group with 1,2-allenic phosphonate was also observed to produce 2,3-dihydrofurans [83b]. 

Several addition reactions of mono- and di-enephosphonates have been reported. Diethyl vinylphosphonate reacts at 100 °C with cyclohexanone pyrrolidenamine in a stepwise fashion. Hydrolysis of the initial adduct yields the ketophosphonate (143) but further reaction of the adduct in a Mannich-type process can yield, ultimately, the cyclobutenylphosphonate (144).112 Diethyl butadienephosphonate condenses... 

General.—The relatively unreactive diethyl arylmethylphosphonates have been used quite successfully in alkene synthesis with phase-transfer catalysis.100 In a comparative study it was shown that anions derived from /S-ketophosphonamides (109) have very low reactivity whereas those from 0-ketophosphonates (110) react quite well with aldehydes to give frwjj-alkenes.101 Benzyl dimethyl phosphonoacetate (111) can be used to form alkenes, e.g. (112), from which the benzyl group can be removed by hydrogenolysis without disturbing the C=C bond.102 The carbanions (113) can be... 

Nonhydrolyzable aspartyl adenylate analogues (14—16) (Table 4) have been prepared and tested as inhibitors of E. coli AspRS. Sulfamate (14) is a potent competitive inhibitor (A)= 15 nmol P ), whereas l-aspartol adenylate (15) is a weaker inibitor (A) = 45 pmoll ) with respect to aspartic acid. The corresponding /3-ketophosphonate (16) is also a strong inhibitor (A- = 123 nmol 1 ). Replacing the 5 -oxygen on the ribose with an NH group (compound 17) resulted in an equally potent inhibitor of the S. aureus enzyme (i) = 15 nmol 1 ). ... 

A synthetic approach toward diethylphosphonyl pyrans 64 and 65 was proposed based on the reaction of -ketophosphonates 44 and 45 and UNs (99H(51)1137, 04PS2487). Noteworthy, in the case of the phos-phonate 45 the reaction proceeds regioselectively with formation of 5-ethoxycarbonylpyran 65 only (Scheme 14). 

Numerous structural modifications have been done on these compounds, affording PTPIB inhibitors that are more powerful and more selective toward other phosphatases. Among them, some bis(difluorophosphonates) and bis(difluoro-/l-ketophosphonates) deserve particular attention (Figure 7.10). 

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