Enol phosphates reduction

Given the large number of tandem cyclization processes that have been explored [63], it is disappointing to note that so few have been promoted electrochemi-cally. There appears to be a significant opportunity for additional exploration. Two tyiws of tandem cathodic cyclizations are discussed below. The first involves generation of a ketyl, and its subsequent cyclization onto a pendant alkene to afford a new radical that closes onto a second alkene [64,65]. The second focuses on chemistry not yet discussed involving the reductive cyclization of enol phosphates of 1,3-dicarbonyl compounds [66]. 

The reductive cyclization of readily available enol phosphates of 1,3-dicarbonyl compounds bearing pendant olefinic units has been explored [66,67]. The chemistry is exceptionally interesting, and provides a unique route to structures possessing a cyclopropyl unit which is suitable for structural elaboration. The reaction occurs in a manner wherein the phosphate-bearing carbon behaves like a carbene that adds to the pendant alkene to form a cyclopropane. While this provides a useful way of viewing the transformation, mechanistic studies indicate that a carbene is not an actual intermediate. Examples are portrayed in Table 11. 

The opportunity for tandem cyclization was explored. Here, the results can be accommodated by postulating the intermediacy of a vinyl radical [66]. For example, the controlled potential reduction of enol phosphate 246 affords 247 as a mixture of stereoisomers, in addition to a 15% yield of the linearly fused tricyclopentanoid 248. Assuming that the initial reduction cleaves the phosphate unit, then there exists the opportunity for the resulting radical 249 to be further reduced to afford a carbanion, or undergo a 5-exo-trig radical cyclization onto the pendant alkene. Given the nature of the products and the fact that they are inconsistent with the expectations of carbanion chemistry, it seems clear that the latter pathway dominates. 

PREPARATION AND REDUCTIVE CLEAVAGE OF ENOL PHOSPHATES 5-METHYLCOPROST-3-ENE... 

The present preparation illustrates a general and convenient method for a two-step deoxygenation of carbonyl compounds to olefins. Related procedures comprise the basic decomposition of p-toluenesulfonylhydrazones, the hydride reduction of enol ethers, enol acetates, enamines, the reduction of enol phosphates (and/or enol phosphorodiamidates) by lithium metal in ethylamine (or liquid ammonia),the reduction of enol phosphates by titanium metal... 

The reductive fission of enol phosphates to form olefins is a... 

Other known methods for preparing O-alkyl enol ethers include, most notably, alcohol elimination from acetals, double bond isomeri2ation in allylic ethers, reduction of alkoxy enol phosphates, and phosphorane-based condensation approaches.5 These methods, however, suffer from poor stereoselectivity, low yields, or lack of generality, if not a combination of these drawbacks. 

Dialkyl alkynes. A recently reported route to these substances involves reductive elimination of enol phosphates of /8-oxo sulfones with sodium amalgam in DMSO-THF at 0°. 

A similar synthesis of alkynes by reductive elimination of enol phosphates of /3-oxosulfones with sodium in liquid ammonia has been reported. ... 

Deoxygenation of phenols. The reduction of enol phosphates to alkenes by titanium metal (8,482) has been extended to reduction of aryl diethyl phosphates to arenes. Yields are in the range 75-95% reduction with lithium in liquid ammonia (1, 248) usually proceeds in low yield. 

Appropriate quenching of a reductively formed lithium enolate with a carboxylic acid anhydride, chloride, methyl chloroformate or diethyl phosphorochloridate yields the corresponding enol esters, enol carbonates or enol phosphates. These derivatives may be transformed into specific alkenes via reductive cleavage of the vinyl oxygen function, as illustrated by the example in Scheme 8. 

This methodology has also been applied to the conversion of alkyl esters into vinyl ethers with high stereoselectivity favoring the (Z)-isomer (Scheme 30). While standard Li/amine reduction conditions were not applicable, the enol phosphates could be reduced using triethylaluminum and tetrakis(tri-phenylphosphine)palladium. 

Initial, electrochemical reduction of /S-dicarbonyl enol phosphates linked to an ole-finic chain gives cleavage of the phosphate with formation of a vinylic radical [222-224]. Reduction in DMF takes place in the potential range —2.0 to —2.3 V and may lead to bicyclic products as illustrated in Scheme 23. 

Both the enol phosphate method, and the reduction of the keto sulfone to the p-hydroxy sulfone followed by reductive cleavage to produce ( )-alkenes, have been applied to the synthesis of brefeldin A. Gais and cowoikers added the sidfone (462) to the lactone (461), formed the enol phosphate and reduced with sodium and ammonia to the ( )-alkene (463), in a 65% overall yield (equation 107). ... 

Treatment of enolates with (R0)2P(0)C1 also results in 0-trapping to yield the corresponding enol phosphates. Dissolving metal reduction of enol phosphates is a useful procedure for the deoxygenation of ketones with concomitant, regiospecific formation of the alkene. ... 

A connective synthesis of alkynes inspired by the Julia alkenation was developed by Lythgoe and coworkers for the synthesis of la-hydroxy vitamin D3, as shown in Scheme 34. The P-keto sulfone (101) derived by condensation of the the metalated sulfone (99) with the ester (100) was converted to the enol phosphate (102), which on reductive elimination gave the enynene (103). 

The precise conditions for the reductive elimination are important. Use of Na(Hg) in THF-MeOH or THF alone gives messy reactions, owing to substantial cleavage of the P—O bond of the enol phosphate but this can be avoided with Na(Hg) in THF-DMSO. Alternatively, Na in liquid ammonia can be used to effect the reductive elimination but the reaction must be very carefully controlled in order to avoid reduction of the alkyne to a tra/ii-alkene. A deliberate over-reduction of the initial alkyne product to an alkene was used in a synthesis of the intermediate (104) in a synthesis of brefeldin (Scheme 35). ... 

The sequence can also be applied to the enolate anion formed by conjugate addition of organometallic reagents to a,/8-unsaturated ketones. Thus addition of diethyl phosphorochloridate to a mixture of A4-cholestene-3-one (4) and dimethyl-copperlithium gives the diethyl enol phosphate (5) in 55% yield. Reduction of the ester gives the olefin (6) in high yield. 

The method is related to that of Fetizon for preparation of A2-steroids by lithium-ammonia reduction of diethyl enol phosphates generated from 2-bromo-3-ketones (see Triethyl phosphite, this volume). 

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... 

Enol phosphates (332) have also been obtained reductive debromination of the 2a-bromo-3-ketone with triethyl phosphite (Perkow reaction) gave the... 

A related route via enol phosphates provides some rather inaccessible olefins. The 4-methyl-3-ene (333), for example, is obtained by reducing a 4-en-3-one with lithium-ammonia, esterifying the resulting lithium A -enolate (334) with diethyl phosphorochloridate [(EtO)2PCl], and reducing the enol phosphate (335) with lithium. 5/ -Methylation of a 4-en-3-one with lithium dimethylcopper, with in situ conversion of the lithium A -enolate into its phosphate, followed by reduction, similarly afforded the 5 -methyl-3-ene (336). Use of lithium enolates prevents isomerisation of enolate anions, which is likely with other metal salts. ° ... 

The Perkow reaction has been used to generate a wide range of vinyl phosphates. Reaction of trialkyl phosphites with a-halogeno-ketones provide vinyl phosphates.1-5 Alkenes are produced via reduction of the dialkyl enol phosphate using either sodium or lithium in liquid ammonia. 

Enone 69 is converted to the less substituted alkene 71 via the intermediacy of the enol phosphate 70.4 The sequence shown involves reduction with Li/NH3 (liquid) followed by phosphorylation of the resulting lithium enolates with diethyl phosphorochloridate to give 70, which is then treated with Li/EtNIVf-BuOH. Application of such methodology to steroid conversion has been reported by Ireland and Pfister41 and Kanata et al. 2... 

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