Trimethyl phosphonoacetate

Fig. 2.6. Free-energy profile (B3LYP/6-31 + G with ZPE correction) for intermediates and transition structures for Wadsworth-Emmons reactions between the lithium enolate of trimethyl phosphonoacetate anion and formaldehyde in the gas phase and in tetrahydrofuran or ethanol. Adapted from J. Org. Chem., 63, 1280 (1998), by permission of the American Chemical Society.

Epimerizable aldehydes clearly undergo intermolecular Horner-Wadsworth-Emmons olefination with trimethyl phosphonoacetate, by using the weak base, lithium hexaflu-oroisopropoxide [LiOCH(CF3)2], as catalyst.203... 

Z)-OL, -Unsaturated esters,l Wittig-Homer reactions generally show a preference for formation of (E)-alkenes. Thus (E)-a,p-unsaturated esters are obtained preferentially on reaction of aldehydes with trimethyl phosphonoacetate under usual conditions (potassium f-butoxide). Use of a highly dissociated base can favor (Z)-selectivity. The most effective base for this purpose is potassium hexamethyldisilazide, KN[Si(CH3)3]2, in combination with 18-crown-6, although even potassium carbonate with the crown ether is fairly effective. The (Z)-selectivity can be further enhanced by use of 1 as the phos-phonoester. Under these conditions, (Z)-unsaturated esters can be prepared from aliphatic and aromatic aldehydes with Z/E ratios as high as 50 1. The method is also useful for transformation of unsaturated aldehydes to (E,Z)-dienoates and (E,E,Z)-trienoates. 

Olefinations involving phosphonate anions continue to be used and developed. The effect of the cation, temperature and THF or DME as solvent on the stereoselectivity of aliphatic aldehyde olefination with trimethyl phosphonoacetate carbanion has been investigated.71 Low ( /Z) ratios are favoured by potassium cations, low temperature and THF as solvent. The... 

Ando, K. A Mechanistic Study of the Horner-Wadsworth-Emmons Reaction Computational Investigation on the Reaction Pass and the Stereochemistry in the Reaction of Lithium Enolate Derived from Trimethyl Phosphonoacetate with Acetaldehyde. J. Org. Chem. 1999, 64, 6815-6821. 

Synthesis from i-threose Nojirimycin (1) and 1-deoxynojirimycin (2) have been synthesized from 4-6 -( err-butyldimethylsilyl)-2,3-0-isopropylidene-L-threose (118) (Scheme 22) Compound 118 was treated with trimethyl phosphonoacetate to provide the E ester 119, as a single isomer in 95% yield. Reduction of the ester group in 119 followed by Sharpless asymmetric epoxidation of the resulting allylic alcohol afforded the syn-epoxide 120. Treatment of 120 with NaNs and NH4CI in a mixture of 1,2-dimethoxyethane,... 

The preparation of a,j5-unsaturated ester 565 is easily accomplished by treatment of 464 with either trimethyl phosphonoacetate under Homer—Emmons conditions [178] or with the corresponding phosphorane under Wittig conditions [179]. Reduction of the ester to alcohol, conversion to chloride, and displacement with tributyltin lithium gives the allylstannane 566. Reaction of this stannane with aldehydes under Lewis acid catalysis furnishes 2-vinyl-l,3-diol derivatives 567 or 568, the stereochemistry of which depends on the nature of the Lewis acid [179]. The best examples are shown in Scheme 80. 

SCHEME 6. Synthesis of wyerone [19], Reagents (i) n-BuLi, tetrahydrofuran (THF) (ii) 2M H2SO4, Et20 (iii) trimethyl phosphonoacetate, LiOH, THF. 

The trimethyl phosphonoacetate anion reacts with the aldehyde in equilibrium with the otramino alcohol, giving an unsaturated ester. 

In our earlier publication (15) the synthesis of the southern part was described. This is shown in Scheme 2, including some improvements. The diene ester prepared from methacrolein and trimethyl-phosphonoacetate >3 underwent a Diels Alder cyclization with methyl vinyl ketone to give only one regio isomer, which after equilibration with base gave the all trans keto ester 9, in an overall yield of 75%. Linder Wadsworth Emmons conditions, 9 reacted smoothly with the t-butyl dimethylphosphonoacetate 10 to give the a, p unsaturated ester 11. Hydrolysis, followed by acid chloride formation and reduction with n-tributyltin hydride gave the aldehyde 12 the yield over 4 steps was 70%. 

The mechanism of the Horner-Wadsworth-Emmons reaction of the lithium enolate derived from trimethyl phosphonoacetate with acetaldehyde has been investigated by ab initio calculations. Oxaphosphetane formation is rate determining, both in the gas phase and with one ether moleeule solvating. The transition state leading to trans-alkene is more stable than that giving the cis form. 

Ab initio calculations (RHF/6-31 -I- G ) have revealed that the Homer-Wadsworth-Emmons (HWE) reaction of acetaldehyde with the lithium enolate derived from trimethyl phosphonoacetate occurs by a sequence of carbonyl addition, oxaphosphetane formation, pseudorotation, P-C bond cleavage, and then O-C bond cleavage. The transxis alkene ratio (97.5 2.5) is a direct consequence of competitive formation of the corresponding oxaphosphetanes in the rate-determining cyclization step. 

Chiral Horner-Emmons reagents have also been documented. In a study by researchers at Schering directed towards the synthesis of stable prostacyclin analogues, the stereoselective olefmation of ketone 115 was necessary (Equation 14) [70]. Condensation of 115 with the traditional Horner-Wads-worth-Emmons reagent, trimethyl phosphonoacetate, afforded a 1 1 mixture of ester diastereomers. Interestingly, use of the optically active phosphonoacetate 116 furnished 117 selectively (dr=86 14). 

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