Michael additions of phosphonates

The structure of catalyst 428 was proposed as a result of the several experiments shown in Sch. 60 and discussed below [89]. Firstly, it was observed that treatment of ALB catalyst 394 (Sch. 51) with methyllithium produced a solution from which the hexacoordinate aluminum species 434 (M = Li) could be crystallized in 43 % yield. The same compound could also be obtained from solutions prepared from 394 and nBuLi, and the sodium enolate of 425. Solid-state X-ray analysis of this compound revealed that it has the same structiu-e as the species 417 (Sch. 56) isolated by Feringa and coworkers during the preparation of ALB with excess BINOL (Sch. 55) [86]. The tris-BINOL(tris-lithium) alimunum complex 434 is not the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone because the use of this material as catalyst gave the Michael adduct 426 in 28 % yield and 57 % ee which is dramatically lower than obtained by use of catalyst 428 (Sch. 59). In addition, the use of catalyst 434 (M = Li) gave the alkene product 429 in 13 % yield, a product that was not seen with catalyst 428. Additional evidence comes from the reaction between 425 and cyclopentenone with catalyst 434 (M = Li) which gives the adduct 427 in 78 % yield and 12 % ee. 

Table 5) [28], and heteroatom Diels-Alder reactions (Sch. 50) [79,80] but no X-ray structure had ever been reported for it or for the 3,3 -disubstituted derivatives which were first introduced as an asymmetric Claisen catalyst [24-27]. Although compound 435 was found not to induce any reaction between cyclohexenone and phosphonate 425 under the standard conditions for catalyst 428, consistent with the proposed equilibrium of species 394, 431, 432, 433, and 434 is the finding that catalysis of the reactions between cyclohexenone or cyclopentenone and phosphonate 425 with a 2 1 mixture of 434 (M = Li) and 435 gave only the Michael adducts 426 and 427 in 96 % ee and 92 % ee, respectively. Because 394 and 432 are inactive catalysts and 434 results in much lower induction and some 1,2-adduct, it was proposed that the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone was the species 431 resulting from association of ALB catalyst with a metal alkoxide. It was proposed that the stereochemical determining step involved intramolecular transfer of the enolate of 425 to the coordinated cyclohexenone in species 436. 

The application of the Michael addition of phosphonate esters in the synthesis of coronafacic acid was reported by Shibasaki and coworkers and is outlined in Sch. 61 [89]. The Michael adduct ent-427 was prepared in 94 % ee in the same fashion as its enantiomer 427 (Sch. 59) by employing a catalyst prepared from (5)-BINOL. 

The Michael reaction can also be applied to the formation of cyclopropanic systems. Thus, Michael addition of phosphonate carbanions, generated by electrochemical technique or by thal-lium(I) ethoxide in refluxing THF, to a,p-unsaturated nitriles provides a convenient preparation of substituted 2-cyanocyclopropylphosphonates via a tandem Michael addition-cycloalkylation sequence (Scheme 6.25). - - ... 

The conjugate Michael addition of phosphonate-stabilized anions with dimethyl acetylenedicarboxylate has been described. For example, when the sodium salt of dimethyl l-(methoxycarbo-nyljmethylphosphonate is treated with dimethyl acetylenedicarboxylate, an (fij/CZ) mixture of two isomeric P.y-unsaturated phosphonates is isolated in modest yield (37%). ° Addition of enolates derived from diethyl 2-oxocycloalkylphosphonates to dimethyl acetylenedicarboxylate in aprotic conditions results in [n + 2] ring-expanded products in reasonable yields (Scheme 8.50). The reaction proceeds via a tandem Michael-aldol-fragmentation mechanism to give the ring enlarged products. 

Scheme 8.12 Michael addition of phosphonates to unsaturated aldehydes.

The Michael addition of phosphine nucleophiles to nitroalkenes provides novel P-nitro phosphonates, as in Eq. 4.32.38 Yamashita and coworkers have shown that the nucleophilic addition of Ph2POH to chiral nitroalkenes derived from sugars proceeds stereoselectively to the S- -isomer (Eq. 4.32) in high diastereoselectivity (ds 11 1). 

A series of heterocycle derivatives of 1,1-bis-phosphonate (222), (223), (224) and (225) has been synthesized by Michael addition of 1,1-methylene bis-phosphonate to acceptors such as 5-arylidene rhodamines, 5-benzylidene-2-thiohydantoin, benzylidene or 2(2 -furyliden)-cyanomethyl-l,3-benzothiazoles... 

Unsaturated ter/-butyl esters undergo stereoselective a/iti-Michael addition of a -lithiated phosphonates to give a range of substituted 4-... 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

A number of phosphonate and phosphinate derivatives where the phosphorus atom is directly bonded to non-aromatic cyclic systems have been reported. The synthesis and reactions of a number of compounds with the general structure 103 have been reported. Enantiomerically pure cyclopropanephosphonic acids which are constrained analogues of the GABA antagonist phaclophen, have been prepared by stereocontrolled Michael addition of a-anions derived from chiral chloromethylphosphonamides 104 to a,P-unsaturated esters followed by in situ cyclisation. Other asymmetric syntheses include those of (/ )- and (S)-piper-idin-2-ylphosphonic acid (105) via the addition to trialkyl phosphites to iminium salt equivalents and 4-thiazolidinylphosphonate 106 by catalytic asymmetric hydrophosphonylation of 3-thiazoline. In the latter case both titanium and lanthanoid (which give much better e.e. values) chiral catalysts are used. 

Sawamnra, M., Hamashima, H., and Ito, Y., Rhodium-catalyzed enantioselective Michael addition of (l-cyanoethyl)phosphonate. Synthesis of optically active phosphonic acid derivatives with phosphorussubstituted quaternary asymmetric carbon center, Bull. Chem. Soc. Jpn., 73, 2559, 2000. 

Michael addition has been applied to the formation of cyclopropanic systems. Thus, the addition of phosphonate carbanions generated from tetraethyl dichloromethylenediphosphonate by electrochemical techniques to methyl vinyl ketone provides a preparation of tetraethyl 2-acetylcyclopro-pane-l,l-diphosphonate in good yield (75%)." ... 

The use of diethyl l-(ethoxycarbonyl)vinylphosphonate is based on Michael addition of anionic nucleophiles to the double bond to produce stabilized phosphonate anions capable of undergoing subsequent alkenylation reaction with aldehydes or ketones by a Homer-Wadsworth-Emmons process (Scheme 8.27)." 2 " "... 

Michael addition of metallated camphor derivatives of diethyl aminomethylphosphonate to diethyl vinylphosphonate followed by hydrolysis with 90% aqueous AcOH leads in 73% yield and high diastereoselectivity to tetraethyl A-acetyl 2-amino-l,3-propylenediphosphonate, a phosphonic analogue of glutaric acid (Scheme 8.8V). No racemization occurs under the hydrolysis conditions Similarly, methyl acrylate, after hydrolysis of diastereomerically pure adduct, leads to the phosphonic analogue of pyroglutamic acid further reduced with I.iBlI,/BF. t,() to the phosphoproline diethylester in 61% yield (Scheme 8.87). ... 

Yamaguchi, M., Tsukamoto, Y., Hayashi, A., and Minami, T., A stereoselective Michael addition of a-lithiated phosphonates to a,P-unsaturated esters, Tetrahedron Lett.. 31. 2423. 1990. 

Renewed efforts have been made to sterically control the Michael addition of allylic phosphonate carbanions to cyclic enones. The anions generated by the... 

A further study of additions of nucleophiles to unsaturated phosphonic diesters confirms reaction (23) The asymmetric Michael addition of a ketone to a dialkyl -(alk-l-enyl)phosphonate has been achieved following the deriva-tization of the carbonyl substrate as a chiral hydrazone (Scheme 77) . 

A new synthesis of pentalenic acid (273) with virtually complete stereo- and regio-control uses Michael addition of the carbanion of the allylic phosphonate (272).Phosphonate-based olefination of suitably substituted cinnamaldehydes has been used to prepare a number of (E,E)-l,4-diarylbuta-1,3-dienes (274) with properties suitable for use in liquid crystal display devices. 139 The meso-form (276) of a tetrahydrotetrabenzocyclododecene has been synthesized by bis-alkylation of the bis-ylide (275) (276) isomerizes to the racemic form on heating. 1 11... 

The diastereo- and enantioselective Michael addition of lithiated enantiopure sulfonates (454) bearing an inexpensive chiral sugar auxiliary to activated vinyl phosphonates (455) has produced a variety of functionalized phosphonates (456) in good diastereoselectivities (cfe = 55 73%) (Scheme 114). °... 

Scheme 4.50 The 84e-catalyzed enantioselective Michael addition of P-ketoesters to vinyl bis-phosphonates.

Various carbocyclic structures were accessed via a highly regio- and enantioselective aminocatalytic Michael addition of cyclic enals to vinyl phosphonates followed by a one-pot intramolecular HWE reaction. ... 

Using a similar strategy, Hayashi described synthesis of dipeptidyl peptidase IV inhibitor ABT-421. The key reaction was Michael addition of acetaldehyde to a nitroalkene, followed by another Michael addition to unsaturated phosphonate and then HWE annulation. Lu and coworkers applied a different approach to the same molecule. They used ot,p-unsaturated aldehyde and a premade nitrophosphonate. ... 

The Yamamoto group developed tethered bis(8-quinolinolato)-Al complex 26-catalysed asymmetric Mukaiyama-Michael additions of silyl enol ethers to ot,p-unsaturated acyl phosphonates (Scheme 19.30). A range of tetra-substituted trimethylsilyl enol ethers reacted well and formed the adducts with all-carbon quaternary stereocentres in 80-99% enantiomeric excess. 

Scheme 19.30 A mmetric Mukaiyama-Michael additions of silyl enol ethers to a,p-unsaturated atyl phosphonate catalysed by bis(8-quinolinolato)-Al complex.

Prior to the work on prostaglandins, Hayashi and coworkers found a new route to effectively produce the dipeptidyl peptidase IV-selective inhibitor ABT-341 (Scheme 14.6) [14]. The strategy also comprised a Michael addition and HWE reaction, but these were in this case used to generate disubstituted cyclohexene carboxylates instead. After a diphenylprolinol silyl ether (10 mol%)-promoted asymmetric Michael addition of acetaldehyde (2.0 equiv) to nitroalkene 38 (97% ee) in 1,4-dioxane in 5 h, another Michael addition was initiated by addition of vinyl phosphonate 40 (1.2 equiv) under basic conditions (CS2CO3, 2.0 equiv) at 0 °C in dichloromethane. The subsequent intramolecular HWE reaction in ethanol at room temperature afforded the cyclohexene in 15 min., which was isomerized in situ by the addition of DiPEA (10 equiv) to yield trans-43. 

Phosphorus-based synthons for acetoacetic ester and acetylacetone derivatives are described the phosphonate (78) has been used in the preparation of the /S-ketoester (79), a key intermediate in a synthesis of the fungal sex hormone, trisporic acid B methyl ester (80). Michael addition of an a-methylene ketone to 2,2-diethoxyvinylidenetriphenylphosphorane followed by loss of ethanol gives a valuable reagent (81) for the preparation of 1,3-dioxopent-4-enes by Wittig reaction with aldehydes the intermediate enol ethers (82) can be isolated if desired. 

Friedel-Craft Alkylation Conjugated Additions. In the last decade, several methodologies have been developed to enantios-electively alkylate the Al-methylindole via a conjugated addition. One of them uses an a./S-unsaturated acylphosphonate as electrophile and a scandium(III) PyBox as chiral catalyst. After the Michael addition, the phosphonate moiety is directly converted into an ester by adding the corresponding alcohol in the presence of DBU. The desired product is isolated in 88% yield and 98% ee (eq... 

The highly electrophilic cationic bis(8-quinolinolato)aluminum complex 407 enabled Yamamoto and coworkers to perform Mukaiyama-Michael additions of silyl enol ethers to crotonylphosphonates 406. The procedure was not only applicable to enol silanes derived from aryl methyl and alkyl methyl ketones (a-unsubstituted silicon enolates) but also to several cycfic a-disubstituted silyl enol ethers, as illustrated for the derivatives of a-methyl tetralone and indanone 405 in Scheme 5.105. Despite the steric demand of that substitution pattern, the reaction occurred in relatively high chemical yield with varying diastereoselectivity and excellent enantiomeric excess of the major diastereomer. The phosphonate residue was replaced in the course of the workup procedure to give the methyl esters 408. The protocol was extended inter alia to the silyl enol ether of 2,6,6-tetramethylcyclohexanone. The relative and absolute configuration of the products 408 was not elucidated [200]. 

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