Synthesis from enol phosphates

Hammond, G.B., Calogeropoulou. T., and Wiemer, D.F., The 1,3-migration of phosphorus from oxygen to carbon. A new synthesis of P-ketophosphonates from enol phosphates. Tetrahedron Lett.. 27, 4265, 1986. 

Fig. 4. Ether phospholipid synthesis from dihydroxyacetone-phosphate. (A) Dihydroxyacetone-P acyl transferase (DHAPAT). The first step of ether phospholipid synthesis is catalyzed by peroxisomal DHAPAT. This enzyme is a required component of complex ether lipid biosynthesis and its role cannot be assumed by a cytosolic enzyme that also forms acyldihydroxyacetone-P. (B) Ether bond formation by alkyl-DHAP synthase. The reaction that forms the 0-alkyl bond is catalyzed by alkyl-DHAP synthase and is thought to proceed via a ping-pong mechanism. Upon binding of acyl-DHAP to the enzyme alkyl-DHAP synthase, the pro-f hydrogen at carbon atom 1 is exchanged by enolization of the ketone, followed by release of the acyl moiety to form an activated enzyme-DHAP complex. The carbon atom at the 1-position of DHAP in the enzyme complex is thought to carry a positive charge that may be stabilized by an essential sulfhydryl group of the enzyme thus, the incoming alkox-ide ion reacts with carbon atom 1 to form the ether bond of alkyl-DHAP. It has been proposed that a nucleophilic cofactor at the active site covalently binds the DHAP portion of the substrate.

SCHEME 4.281 Synthesis of protected vinylphosphines from enol phosphates [447]. 

Cymerman-Craig, j., and M. Moyle The synthesis of acetylenes from enol phosphates. Proc. Chem. Soc. (London) 1962, 149. 

The synthesis of the limondd azadiradione, utiiizing a Hg° cyclization-oxidative demercuration sequence with an enol phosphate derived from trans,trans-famesol has been reported. Azadiradione, a te-tracarbocyclic memter of the iimonoid group isoiated from the neem tree, Azadirachta indica, has been converted to other tetracyclic limonoids, and is thus a key intermediate. The sequence is shown in Scheme 33. 

Nigaki alcohol (18) has been identified by spectroscopic and chemical means as a constituent of Picrasma ailanthoides Planchon. Latia luciferin (19) has been synthesized in a stereoselective manner. A key step in this synthesis involves the addition of lithium dimethylcuprate to an enol phosphate derived from a 8-keto-ester to form an a,/3-unsaturated ester. Dehydro-/8-ionilideneacetic acid (20), an important intermediate in the synthesis of abscisic acid, has been prepared, as have the two nor-abscisic acid derivatives (21). The metabolite (22) of abscisic acid has been identified in the seeds of Robinia pseudacacia... 

Highly reactive metallic titanium, prepared from TiCb and potassium, reduces enol phosphates to alkenes, permitting regioselective synthesis of dienes from a,p-unsaturated ketones. ... 

A word about the synthesis of the a-series, a-geraniol (73) and a-nerol (74), is warranted because they are often intermediates in the synthesis of 1-hydroxylated compounds (e.g., some diols described below). Weiler has continued his exploitation of the dianion of methyl acetoacetate to this end. Instead of prenylation (Vol. 4, p. 461, Ref. 73) he carried out a similar series of operations by alkylating the dianion with 4-bromo-2-methyl-l-butene, thus arriving at compounds of the a-series via the keto ester 75, methylating the enol phosphate to 76. He also prepared the double methylene isomer 77 (R = COEt) of geranyl propionate from the intermediate 75. The purpose of synthesizing this propionate was to prepare the pheromone of the San Jose scale, Quadraspidiotus pernicious, which is a mixture of the propionates of 73, 74,... 

The aldol reaction is extensively used in Nature as in the laboratory to make C-C bonds and some aldolases have been used in asymmetric synthesis. One of the most popular has been the fructose-6-phosphate aldolase44 from rabbit muscle, familiarly known as RAMA. The enzymatic reaction combines the enol from dihydroxyacetone phosphate (DHAP) 142 with glyceraldehyde-3-phosphate 143 in a diastereo- and enantioselective aldol reaction. PO in these diagrams means phosphate. 

Olefin synthesis from a,p-unsaturated ketones. Ireland and Pflster1 have extended the procedure of Kenner and Williams (1,248, ref. 2) for deoxygenation of phenols to conversion of a,/3-unsaturated ketones into olefins. For example, the a,)3-unsaturated ketone (1) was reduced by lithium-ammonia to give an enolate anion which reacted with diethyl phosphorochloridate to give the phosphate ester (2) in 56% yield. This ester was reduced in high yield by lithium in a mixture of ethylamine and r-butanol to the olefin (3). It is noteworthy that only one olefin is formed. Actually the conversion of (1) into (3) can be carried out in 50% yield without isolation of the diethyl enol phosphate. 

Fetizon et al.3 used this reaction in a new synthesis of A2-steroids from 3-keto-steroids. For example, dihydrotestosterone acetate (1) is converted in high yield into the 2a-bromoketone (2) with phenyltrimethylammonium perbromide (1, 855). The a-bromoketone is then heated for 3 hours with freshly distilled triethyl phosphite to give the enol phosphate (3). On reduction of (3) with lithium in liquid... 

A series of l-aryl-3,3,3-trifluoro-I-ethanones 77 have been synthesized from the reaction of F02SCF2CC>2Me with p-bromoenol phosphate 76 in the presence of Cul in moderate yields. Enol phosphates are versatile intermediates in organic synthesis.17... 

Corey et al. have used the enol phosphates 80 to synthesize the limonoid intermediate 81 and limonoid 82.45 They have also developed a general preparative scheme via enol phosphates for the synthesis of limonoids, which are biosynthetically derived from triterpenes.45... 

In 2001, Funk reported a synthesis of ( )-FR901483 using an approach very different from those described previously, taking advantage of his amidoacrolein cycloaddition methodology to prepare 1 -alkyl-1 -aminocyclohexane derivatives, starting the synthesis from acyclic compounds. Moreover, Funk neither uses tyrosine derivatives nor needs an inversion at C(9) to install the phosphate unit. In Funk s retro synthetic analysis, shown in Scheme 23, he envisaged that lactam 60 possessed the necessary functionality for the introduction of the C(6) p-methoxy benzyl and C(3) methylamino substituents via enolate alkylation and amination reactions, respectively. 

Alkylation of heterofunctionalities. Etherification of alcohols can be conducted in the absence of solvent using a polyether." The O-alkylation of 1-perfluoro-alkyl-2-fluoroethanols is accompanied by dehydrofluorination thus the products are enol ethers. Selective (9-alkylation of o-aminophenols is observed, and an efficient method for the synthesis of triaryl phosphates from sodium phenolates and... 

In complete contrast to the (l-oxoalkyl)phosphonic acids, for which essentially only one synthesis is available, based on the Michaelis-Arbuzov or Michaelis-Becker reactions, there are several procedures available for the synthesis of those acids with the 0x0 group at C(2) or at a carbon atom site even further from the phosphoryl centre. Historically, esters of (2-oxoalkyl)phosphonic acids were also obtained through application of the Michaelis-Arbuzov and Michaelis-Becker reactions, but it soon became apparent that complications occur, the major one being the concomitant formation, in many instances, of enol phosphates and, in some cases, this reaction became the main one, indeed, sometimes the only one. Several other procedures are now available for the preparation of oxoalkyl acids which place the 0x0 group accurately and with no side reactions of any importance, and these are therefore considered first in the following survey. 

In the total synthesis of ciguatoxins, the enol phosphate 18, derived from the nine-membered laetone 17, was carbonylated smoothly to give the unsaturated ester 19 [11],... 

New strategies for the synthesis of 2-substituted indoles and indolines (101) using acyclic, imide-derived enol phosphates (100), which were readily prepared from o-haloanilides, have been developed based on Suzuki-Miyaura coupling-cyclization sequences by Fuwa and Sasaki (Scheme 22)." ... 

Enol phosphate synthesis from a-halocaiboityls and trialkylphosphites. General scheme ... 

Opening to the -rr-allyl complex 9.214, which was reduced by hydride transfer from formate. Unlike most other nucleophiles (see Schemes 9.32 and 9.34), formate transfers hydrogen with retention, giving the required stereochemistry for the natural product. Completion of the synthesis included a nickel-catalysed Kumada coupling to convert the ketone, via an enol phosphate 9.216, into a methyl group and a McMurry reaction to close the seven-membered ring. 

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