Ketones ketophosphonates

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. 

The cyano ketone 89 is converted into the nitrile 90 by heating at 140 C with Pd(Ph3P)4[73,74], The a-ketophosphonate 91 is decarbonylated with PdMe2(PMePh2)2 complex to give the phosphonate 92[75]. 

The term Honwr-Winlsnorth-Emmons reaction refers not only to the illustrated conversion of P-ketophosphonic esters 11 into rx,p ketones 12. but also to the reaction of P-alkoxvcmbonylphosphonic esters 40 to give a.p-unsaturated esters. 

Reduction of activated carbonyl groups of a-keto esters, benzils, cyclohexane-1,2-dione, and o -ketophosphonates by alkylphosphines afforded the corresponding cr-hydroxy esters or ketones in good to excellent yields. A mechanism has been suggested on the basis of deuterium and 180 labelling experiments.380... 

As outlined in Scheme 28, the synthesis of the P-ketophosphonate 131 began with a one-pot anh -aldol/reduction step between ethyl ketone 101 and aldehyde 133, giving the 1,3-syn diol 134 (>30 ldr) [130, 132-136, 145, 146], The diol 134 was then converted into the carboxylic acid 135 in six steps. Completion of the subunit 131 required conversion into the acid chloride and reaction with the lithium anion of methyl-(di-l,l,l-trifluoroethyl)-phosphonate. The C9-C24 aldehyde 132 was prepared in two steps from 136, an intermediate from previous routes [55-58], The Still-Gennari-type coupling of 131 and 132 was readily achieved via treatment with... 

Hydrogenation of olefin 4, followed by 0-desilylation and 0-tosylation next procured tosylate 3, which cyclised readily when exposed to excess potassium hexamethyldisilazide. Elaboration of the ketophosphonate side chain of 20 was accomplished by condensing ester 2 with the lithiated anion of dimethyl methylphosphonate. After concurrent removal of the 1,3-dioxolane acetal and the MOM ether from 20, the resulting secondary alcohol was oxidised with pyridinium chlorochromate (PCC) to produce methyl ketone 1. 

A catalytic route using a manganese (III) complex has been developed for a-hydroxylation of ketones avoiding the use of water or a protic solvent mixtures of a-hydroxyketones and their silyl derivatives were formed in excellent yield. By using a chiral pyrrolidine-based manganese (III) complex as catalyst, asymmetric oxidation was effected, with enantiomeric excess varying from 14 to 62% [30], Another kind of a-functionalized ketones resulted from silyl enol ethers which after the addition of IOB.BF3 were treated with triethyl phosphite a-ketophosphonates were obtained in this way [31] ... 

Pyrimido[5,4-c]-l,2,5-oxadiazinones (417) are suitable starting materials to construct annulated pyrazines. Reaction with carbanions derived from CH-acidic compounds, activated by two different electron-withdrawing functions, proceed in a regioselective manner by initial attack at the N—O bond. Triethyl phosphonoacetate, /f-ketophosphonates, nitro ketones, nitro esters, sulfonylacetates, and JV-acetoacetylglycine have been applied to form 6,7-disubstituted lumazines (418) (Equation (18)) <91H(32)79>. 

Protocol 2 produces the protected fi-formylphosphonate 12 f)-ketophospho-nates may also be synthesized by other methods,23 however, they may not be prepared in unprotected form by the Michaelis-Arbuzov reaction because the Perkow reaction, in which an a-haloaldehyde or ketone and a trialkyl phosphite yield an enol phosphate (e.g. 13, Scheme 5,24 i.e. [P—O] bond formation), competes and frequently dominates (see Section 4). Conversely halocarboxylic acid derivatives (e.g. see Table 7.1, entry 3) and acyl halides (see Protocol 3) react well in the Michaelis-Arbuzov reaction to yield useful functionalized phosphonates. fi-Ketophosphonates are useful reagents for the synthesis of a,fi-unsaturated carbonyl compounds by the Horner-Wadsworth-Emmons reaction,3,4 25 and have other applications.23... 

In the absence of stabilizing forces favoring the enol, the ketone form of enoliz-able a-ketophosphonates prevails. Thus, dimethyl 1-oxopropanephosphonate is in equilibrium with a negligible amount of its enol form in CDC13. 

The vinyl phosphate-P-ketophosphonate rearrangement has also been explored with substituted cyclohexenones. The treatment of enones with LDA under conditions of kinetic control and subsequent reaction with diethyl chlorophosphate gives a single dienyl phosphate. On treatment with an additional equivalent of LDA, a single phosphonate is formed, the regioisomer with a C-P bond at the a -position of the resulting a,P-unsaturated ketone. The respective phosphonates are isolated in an average yield of 70% (Scheme 7.38). ... 

The reaction of diethyl chlorophosphite with ketone enolates has been explored as a direct route to P-ketophosphonates (Scheme 7.41). Instead of attempting isolation of phosphite intermediates, an in situ oxidation of the intermediate products is accomplished by leaving the products open to air. The use of these standard conditions results in the formation of a mixture of C-P and 0-P products. The effect of solvents on the C-P/O-P ratio has been explored, and in many cases the use of Et2O/HMPA improves the ratio. By application of the chlorophosphite/oxidation approach a variety of ketones have been converted into their respective p-ketophophonates in attractive yields. ... 

Other procedures for the synthesis of P-ketophosphonates based on the use of a phosphorus electrophile have been explored. For example, the reaction of dialkyl chlorophosphates with the dilithium derivatives of a-bromo ketones has been described,but the yields of isolated products remain modest. The Lewis acid-catalyzed reaction of oc-hydroxy ketones with dialkyl chlorophosphites constitutes an efficient synthesis of P-ketophosphonates in high yields (92-96%, Scheme 7.42). This reaction is of special value for the preparation of oc-fully substituted P-keto-phosphonates. ... 

A related route to 3-oxoalkylphosphonates involves the conjugate addition of trialkyl phosphites to a,P-unsaturated ketones and hydrolysis of the intermediate oxaphospholenes. The utility of this method is enhanced by the nucleophilic character of the intermediate oxaphosphorane, which facilitates the stereoselective aldol reaction resulting in the formation of p-substituted y-ketophos-phonates. - The pentacovalent oxaphospholene reacts with dialkyl azidocarboxylates to give P-hydrazido-y-ketophosphonates in excellent yields. ... 

The catalytic enantioselective reduction of 1-ketophosphonates has recently been developed. This approach takes advantage of a development in the enantioselective reduction of prochiral ketones to chiral alcohols by means of catalytic amounts of oxazaborolidines with borane as reducing agent. Thus, the enantioselective reduction of 1-ketophosphonates is accomplished by treatment with different boranes, BH. THF (0.9 eq), BII3Me2S (0.66 eq),5 545 qj- catccholborane (1.1 eq)5° 5 6 in different solvent systems in the presence of a catalytic amount of freshly prepared B-n-butyloxazaborolidine, (5) or (R) (Scheme 7.93). The reaction is complete in about 5 h and produces the expected dialkyl 1-hydroxyalkylphosphonates in satisfactory yields (53-98%). 

In contrast to the ready reductive cleavage of a-sulfonyl ketones, reductive dephosphonylation of P-ketophosphonates is surprisingly difficult. All attempts to produce methyl cyclohexyl ketone from di-Zez7-butyl 2-cyclohexyl-2-oxoethylphosphonate by various reducing agents failed... 

Commercially available dimethyl cyclopropylmalonate 30 was converted to mono ester 31 by careful saponification using sodium hydroxide. Coupling with l-amino-2-hexanol afforded the hydroxyamide 32 which was oxidized to ketone 33 under Swern conditions. Condensation to oxazole 34 was effectively achieved by utilizing a two-phase system consisting of dichloromethane and sulfuric acid. Reaction with deprotonated dimethyl methylphosphonate gave the 0-ketophosphonate 35 in an excellent overall yield. 

A versatile method to generate p-ketophosphonates that cannot be generated through the Arbuzov reaction has been developed a-phosphonate enolates of cyclic ketones are obtained through sequential treatment of ketones wiA LDA, diediyl phosphorochloridate and LDA (Scheme Acyclic P-ketophosphonates can also be formed from a-bromo ketones (Scheme 8) and in a similar reaction a-trialkylsilyl enolates can also be obtained (Scheme 9).3 -36 Kuwajima and Takeda employed the reaction of ot-phenylselenylvinyl silyl ethers with lithium and di-methylaminoniq>hthalene (DMAN) to generate ot-silyl enolates (Scheme 10). ... 

A versatile method to generate p-ketophosphonates that cannot be generated through the Arbuzov reaction has been developed a-phosphonate enolates of cyclic ketones are obtained through sequential treatment of ketones with LDA, diethyl phosphorochloridate and LDA (Scheme 7).33-34... 

Acyclic P-ketophosphonates can also be formed from a-bromo ketones (Scheme 8)35 and in a similar reaction a-trialkylsilyl enolates can also be obtained (Scheme 9).35,36... 

In the total synthesis of amphotericin B (170), the Wittig-type reactions were effectively used five times in the construction of the basic skeleton of aglycon 139 (Scheme 21). The HWE reaction of 131 with 132 and the HW reaction of 134 with 135 provided 136, which was converted into ketophosphonate 137 via DCC-DMAP esterification followed by constmction of the polyene part by two consecutive HWE reactions. The final HWE reaction of 137 under K2CO3 and 18-crown-6 or DBU and LiCl conditions efficiently constmcted the 38-membered ring to give ketone 138 in 70% yield, which was converted into aglycon 139. The completion of the total synthesis of amphotericin B (170) by glycosidation is described in Section II.C. 

Cyclopropanation. Sodium enolates of /3-ketophosphonate esters react with ethylene oxide in a sealed tube to form spiroannulated cyclopropyl ketones in moderate yields. Other epoxides give substituted cyclopropane derivatives. 

---