Aldehydes reaction with//-phosphonates

Phosphonate esters can be deprotonated with sodium hydride or alkoxide anions to give enolate-type anions that react well with aldehydes or ketones to give -alkenes. Alkene-forming reactions with phosphonates are called Horner-Wadsworth-Emmons (or Horner-Emmons, Wadsworth-Emmons, or even Horner-Wittig) reactions. This example is a reaction that was used by some Japanese chemists in the synthesis of polyzonimine, a natural insect repellent produced by millipedes. 

As with all reactions with phosphonates, these conditions are sensitive to the steric environment of the carbonyl and phosphonate. In a reaction directed at intermediates for synthesis of the erythronolides, Paterson and cowoilcers found that the unsubstituted phosphonate (188) added in 82% yield in the presence of molecular sieves (equation 48). When R was methyl the reaction failed with DBU because of competitive elimination of OSiMe2Bu. Model studies with the phosphonate and isopropyl aldehyde were successful, providing the alkene in 78% yield in an ratio of 8 1. The Roush-Masamune... 

Enamide ester, which is a useful synthetic intermediate for a variety of a-amino acids, can be prepared by means of the HWE reaction in the presence of TMG (3) or DBU [20,21]. In the synthesis of teicoplanin aglycon (80) reported by Evans et al. [22], one of the phenylalanine derivatives 79 was synthesized from the aldehyde 75. HWE reaction of aldehyde 75 with phosphonate 76 using TMG (3) in THF gave (Z)-enamide ester 77 in 99% yield. Asymmetric hydrogenation of 77 catalysed by rhodium(I) complex 78 (1 mol%) gave the phenylalanine ester 79 in 96% with 94% ee (Scheme 7.16). 

Since the above methodology provides easy access to a variety of a-amino acid derivatives, many applications for the synthesis of natural products have been reported [23-25]. The HWE reaction of the stericaUy hindered aldehyde 81 with phosphonate 82 using TMG (3) proceeded to give (Z)-enamide 83 in 80% yield from the alcohol (2-step yield) [26]. The resulting enamide 83 was submitted to the asymmetric hydrogenation reaction using Burk s rhodium(l) catalyst [27] to give 84 in 85% yield as the sole product (Scheme 7.17). The a-amino acid ester 84 was successfully converted to neodysiherbaine A (85). 

Davis et al. reported synthetic studies of martefragin A (91) [28]. For the construction of the asymmetric centre next to the oxazole, HWE reaction of the aldehyde and subsequent asymmetric hydrogenation were applied. The HWE reaction of chiral aldehyde 86 with phosphonate 87 in the presence of DBU gave (Z)-enamide ester 88, although epimeriza-tion was observed (75% ee). When the reaction was conducted using TMG (3), epimerization was suppressed (95% ee). Enamide ester was converted to the potential precursor 90 for 91 through the a-amino acid ester 89 via asymmetric hydrogenation (Scheme 7.18). 

Enamide ester synthesis was applied for the synthesis of a complex indole natural product by Okano et al. [29]. (Z)-Enamide ester 94 was obtained by HWE reaction of aldehyde 92 with phosphonate 93 in the presence of TMG (3), in 84% yield. Treatment of the resulting ester with copper iodide (Cul) and CsOAc provided dihydropyrroloindole 95, which was efficiently converted to yatakemycin (96) (Scheme 7.NaN). 

The first total synthesis of archazohd A 111, disclosed by Menche et al. [89], was achieved from the assembly of three main building blocks - ketone 104, aldehyde 105, and alkene 107 (Scheme 6.20). The synthesis was accomplished first by employing a boron-mediated aldol reaction of 105 and 104 followed by a two-step elimination to give iodide 106. Heck reaction of 106 with 107 using dichloropaUadium catalyst and tetra-n-butylammonium chloride (TBACl) additive followed by reaction with phosphonate 108 furnished alkene 109 with E/Z selectivity (6 1). Oxidative removal of the PMB group in 109 and Swern oxidation afforded ketophosphonate 110. 

Reaction of aldehyde 85 with phosphonate 86 should provide enone 87. After proper functionalization of the Cu-Co bridge followed by removal of the isopropylidene blocks (and subsequent reduction), the C18 linear higher-sugar alditols will be available. We did obtain the desired enone 87, however in a moderate yield. Besides the expected product, we isolated also two other compounds that were identified as alcohols 88 and 89 (Figure 10.28). The removal of the benzyl block from either position C7 or C8 occurred under the basic conditions [62] ... 

Details for the synthesis of a resorcylic acid lactone (413) incorporating a trans-enone and an amide in the macrocyclic ring have been desrcibed. The key step of this synthesis included intermolecular olefination reaction of the aldehyde (410) with phosphonate (411) which led to isolation of the ( )-enone (412). The complete removal of MOM and Boc groups from (412) followed by lactamisation gave the desired lactam... 

Adducts from various quaternary salts have been isolated, in reactions with aldehydes, a-ketoaldehydes, dialkylacylphosphonates and dialkyl-phosphonates, isocyanates, isothiocyanates, and so forth (Scheme 15) (36). The ylid (11) resulting from removal of a Cj proton from 3.4-dimethyl-S-p-hydroxyethylthiazolium iodide by NEtj in DMF gives with phenylisothiocyanate the stable dipolar adduct (12) that has been identified by its NMR spectrum and reactional product, such as acid addition and thiazolidine obtention via NaBH4 reduction (Scheme 16) (35). It must be mentioned that the adduct issued from di-p-tolylcarbodiimide is separated in its halohydrogenated form. An alkaline treatment occasions an easy ring expansion into a 1,4-thiazine derivative (Scheme 17) (35). 

Alkylation of enamines Addition of amines to triple-bond compounds Addition of amines to aldehydes or ketones Reaction between Grignard reagents and formamides Reaction of phosphonates with aldehydes or ketones... 

The final example of a domino process under high pressure, to be discussed in this chapter, is a combination of a Horner-Wittig-Emmons (HWE) reaction with a Michael addition developed by Reiser and coworkers [5]. Hence, reaction of a mixture of an aldehyde such as 10-18, a phosphonate 10-19 and a nucleophile 10-20 in the presence of triethylamine at 8 kbar led to 10-21. By this method, (3-amino esters, 3-thio esters and 3-thio nitriles can be prepared in high yield (Scheme 10.4). Many of these transformations do not occur under standard conditions, thereby underlining the importance of high pressure in organic chemistry. 

An intramolecular cycloaddition also occurred with 3-ylidenepiperazine-2,5-diones such as 124 or 125, obtained by Wittig-Horner-Emmons reaction from phosphonate 121 and aldehydes 122 or 123, respectively. The products of the Diels-Alder reaction are the bridged bicyclo[2.2.2]diazaoctane rings 126 and 127 that have been found in biologically active secondary metabolite such as VM55599 and brevianamide A. The different type of structures employed in this case requires a chemoselective reaction in order to produce the expected products as single diastereoisomers after 20 days (Scheme 18) <2001JOC3984>. 

An interesting approach to carbobicyclic polyhydroxylated compounds was proposed by Jarosz.43 It was based on a Lewis acid transformation of sugar allyltins 82 into dieno-aldehydes 83 with the fi-geometry across the internal double bond exclusively. The Wittig-type reaction of 83 afforded a triene, which underwent cyclization under high pressure, providing derivatives of bicyclo[4.3.0]nonane 84. Alternatively, dienoaldehyde 83 was converted into the phosphonate 85, which afforded the bicyclo[4.4.0]-decene derivatives (86) upon reaction with an aldehyde and simultaneous cyclization of the resulting triene.43 (Fig. 29). 

When methylene bisphosphonate (169) is reacted in a Horner reaction with an aromatic aldehyde, the alkenyl phosphonate 170 is produced (Scheme 5.25). By metalation with LDA in THF, this is converted to the vinyllithium intermediate 171 that, with the ketone 172, affords a Baylis-Hillman reaction-type product, 173 on base treatment, this is converted to the arylallene 174 [67]. 

Method A The phosphonate (25 mmol) and the aldehyde or ketone (35 mmol) are added with stirring at room temperature to TBA-I or TBA-Br (0.27 mmol) in aqueous NaOH (50%, 20 ml) and CH2CI2 (35 ml). On completion of the reaction (the exothermic reaction with the cyano and ethoxy carbonyl compounds is complete after ca. 15 min), the organic... 

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

An important complement to the Wittig reaction is the reaction of phosphonate carbanions with carbonyl compounds.151 The alkylphosphonate esters are made by the reaction of an alkyl halide, preferably primary, with a phosphite ester. Phosphonate carbanions are more nucleophilic than an analogous ylide, and even when R is a carbanion-stabilizing substituent, they react readily with aldehydes and ketones to give alkenes. Phosphonate carbanions are generated by treating alkylphosphonate esters with bases such as sodium hydride, w-butyllithium, or sodium ethoxide. Alumina coated with KF or KOH has also found use as the base.152... 

In related studies, it has been shown that a-fluorobenzylphosphonates ArCHFPO(OEt)2 (38) will undergo Wadsworth-Emmons-type olefination reactions with aldehydes and ketones [57]. 39 was prepared from benzaldehydes and HP(0) (OEt)2, which was fluorinated using diethylaminosulfur tiifluoride for example, diethyl [(3,5-dimethylphenyl)(fluoro)methyl]phosphonate (38) was formed in 91%. An 82% yield of Me 2-[(fluoro)(4-fluorophenyl)methylene]butanoate (1 1 E Z) (40) was obtained from 38 and methyl 2-oxobutanoate (Scheme 13). 

The reaction of 6-methylpyridine-3-carboxylic acid methyl ester with N,0-dimethylhydroxylamine and isopropyl-magnesium chloride in toluene gives the N-methoxyamide derivative (x), which is reduced with diisobutyl aluminium hydride (DIBAL) to afford 6-methylpyridine-3-carbaldehyde (xi). The reaction of the aldehyde (xi) with a phosphite provides the diphenyl phosphonate derivative, which is condensed with 4-(methylsulfonyl)benzaldehyde in the presence of potassium fe/f-butoxide in HF to yield the enimine (xii). Finally, this compound is hydrolyzed with HCI to yield the ketosulfone (ix). 

---