Ester analogs

Despite this considerable literature noted above, it was really Bradshaw and coworkers who pioneered the synthesis of macrocyclic ester analogs of crown ethers "... 

The cyclic phosphonate ester analog of the cyclic transition state. Antibodies raised against this phosphonate ester act as enzymes they are catalysts that markedly accelerate the rate of ester hydrolysis. 

The reaction mechanism outlined below for phosphorous acid esters analogously applies for the other two cases. The first step is the addition of the alkyl halide 2 to the phosphite 1 to give a phosphonium salt 3 ... 

Examples of reactions involving replacement and cyclization are the long-known preparation of thiophenes (89) from 1,4-diketones, and the formation of l,2-dithiole-3-thione (90) from the salicylate ester analog (91).120 In the latter instance, oxidative cyclization with formation of an S—S bond has occurred this is a common feature of these reactions, particularly if such a link is needed to complete a five-membered ring. Another example of this aspect is afforded by the reaction of the propane-1,3-dione derivatives (92) which yield 3,5-diaryl-1,2-dithiolylium salts (93) when heated with phosphorus pentasulfide in carbon disulfide, followed by perchloric acid.121... 

Further studies with 60-63 showed that these compounds lacked cell membrane permeability. However, as observed in the previously discussed case of phosphonodiacid derivatives 44-46, the diethyl ester analogs 64-67 possessed... 

This has become something of a standard reaction, since several authors have successfully used different chiral catalysts to effect the conversion in very high chemical and enantiomeric yield. Bergson and Langstrom (41) were the first to show that acrolein and a-isopropylacrolein added to 2-carbomethoxy-l-indanone (A in eq. [6]) in benzene in the presence of the strongly basic tertiary amine (/ )-( + )-2-(hydroxymethyl)quinuclidine to yield optically active ketoesters. Unfortunately, the quinuclidine catalyst was not enantiomerically pure, and neither the chemical nor the optical yields of the aldehydo ester analogous to B (eq. [6]) were reported. 

A sulfenate ester analogous to but with methyl Instead of chlorine Is formed on MCPBA oxidation of the corresponding methallyl thlocarbamate this patent report ( ) does not mention any Intermediates or speculate on the mechanism of the reaction. Formation of the sulfenate ester Is conveniently monitored not only by IR and NMR but also by CI-MS, In the latter case because In contrast to the sulfoxides (7, 9) the sulfenates are sufficiently stable to exhibit a strong molecular Ion (7 ). 

Although other heteroatom and heteroaryl IV-ethylcarbazole oxime ester analogs have previously, the agents of the current invention have unusually high Stepwedge sensitivity. 

Having identified the (+)-stereoisomer as the biologically active isomer, several independent enantioselective syntheses of this stereoisomer were developed. The initial synthesis developed in discovery chemistry employed the diastereoselective aldol condensation pioneered by Braun as the key component. Thus, treatment of aldehyde 13 from the racemic synthesis with the magnesium enolate of (5)-(+)-2-acetoxy-l,l,2-triphenylethanol at -70 °C, afforded 17 in 60% yield as a 97 3 mixture of the / ,5 5,5-diastereomers by HPLC (Scheme 3). Ester exchange employing sodium methoxide provided the methyl ester in quantitative yield. Reaction of this ester with three equivalents of lithio-f-butylacetate at -40 °C afforded the nearly enantiomerically pure r-butyl ester analog of racemic 14 in 75% yield. 

A third route developed by this group started with the commercially available alcohol 32," a compound which has also been the subject of considerable process development due to its use as a common intermediate in the synthesis of several HMGR inhibitors.Conversion of 32 to the 4-halo or 4-nitrobenzenesulfonate 33 followed by displacement with sodium cyanide provided 34 in 90% yield, which is the z-butyl-ester analog of 29. It was noted that this procedure was most scaleable employing the 4-chlorobenzenesulfonate 33a due to the instability of the 4-bromo and 4-nitro-analogs to aqueous hydrolysis. Ra-Ni reduction as before provided the fully elaborated side-chain 35 as the f-butyl ester (Scheme 8). 

The known disuhstituted ketencs include dialkyl-ketcnes, diary lkctcncs. and ihe ester analogs. Rimcthylkelene may be made from u-bromoisobuiy-ryl bromide by reaction with zinc in boiling ether, Diphenylketene may be made similarly, but the usual way lo prepare it is to oxidize benzil hydrazone with yellow mercuric oxide to benzoylphenyldiuzomethnne which, on healing in benzene solution, decomposes inio Ihe ketene. 

Roy, S. D. and E. Manoukian. 1994. Permeability of ketorolac acid and its ester analogs (prodrug) through human cadaver skinl. Pharm. Sci83 1548-1553. 

NMRD studies of Gd3+ complexes of DOTPME and DOTPMB indicate q< 1 suggesting that the inner coordination sphere of these complexes is obstructed due to the steric encumbrance of the alkoxy substituents [ 104]. In a multinuclear NMR study of Ln3+ complexes (Ln = La, Gd, Dy, Tm and Yb) with a fluorinated ethyl ester analog of DOTP (F-DOTPME), the 19F NMR spectra reveal up to 16 resonances, which demonstrate that these complexes exist in aqueous solution as a mixture of stereoisomers [105]. [Gd(F-DOTPME)] afforded a water proton relaxivity typical of non-hydrated complexes. 170 NMR of the Dy 1 complex confirmed the lack of a bound water molecule. 

Step 1 Selective cleavage of the -Bu ester (analogous to Boc deprotection). 

Applications with diazo esters that undergo insertion into a C-H bond vicinal to the incipient chiral center demonstrated further advantages of this catalytic methodology for asymmetric synthesis. 2,3,4-Trimethyl-2-pentyl diazoacetate formed lactone 19 exclusively (eq 7) in 60% ee (77% isolated yield) with Rh2(5S-MEPY)4 and Rh2(5/ -MEPY)4 and in 70% ee with the neopentyl ester analog, Rh2(5S-NEPY)4 (82% isolated yield). Cumyl diazoacetate underwent insertion into the normally disfavored 1° C-H bond (eq 8) to yield lactone 20 in 76% ee (30% isolated yield) with... 

The formation of acyl conjugates of vanillamine (capsaicinoids, 20) or vanillic alcohol (capsinoids, 21) with various Cg/Ci3 alkenoic and alkanoic acids is a unique chemical trait of plants from the genus Capsicum. Hot peppers are characterized by the presence of vanillyl conjugates of the amide type, absent or replaced by their nonpungent ester isosters (capsinoids) in bell (sweet) peppers [19]. Indeed, the difference between the sensory properties of capsaicin (la) and its naturally occurring ester analog capsiate (22) is a remarkable example of the biological relevance of isosterism. 

Dirhodium(ll) tetrakis[methyl 2-pyrrolidone-5(R)-oarboxylate], Rh2(5R-MEPV)4, and its enantiomer, Rh2(5S-MEPY)4, which is prepared by the same procedure, are highly enantioselective catalysts for intramolecular cyclopropanation of allylic diazoacetates (65->94% ee) and homoallylic diazoacetates (71-90% ee),7 8 intermolecular carbon-hydrogen insertion reactions of 2-alkoxyethyl diazoacetates (57-91% ee)9 and N-alkyl-N-(tert-butyl)diazoacetamides (58-73% ee),10 Intermolecular cyclopropenation ot alkynes with ethyl diazoacetate (54-69% ee) or menthyl diazoacetates (77-98% diastereomeric excess, de),11 and intermolecular cyclopropanation of alkenes with menthyl diazoacetate (60-91% de for the cis isomer, 47-65% de for the trans isomer).12 Their use in <1.0 mol % in dichloromethane solvent effects complete reaction of the diazo ester and provides the carbenoid product in 43-88% yield. The same general method used for the preparation of Rh2(5R-MEPY)4 was employed for the synthesis of their isopropyl7 and neopentyl9 ester analogs. 

H-nmr spectroscopy readily enables the differentiation of chiral from achiral (meso) diastereoisomers of 3,5- and 2,6-dimethyl-4-phenylpiperidines because in the meso forms the two methyls have identical environments and give rise to the same resonance, while chiral isomers involve an axial-equatorial pair that results in two separate methyl signals (see 39). The configurations of both the chiral 2,6- and 3,5-dimethyl reversed ester analogs of pethidine have been confirmed by X-ray crystallography/27 41)... 

Variants of the ethyl ketone function of methadone, an aspect already broached with mention of dextromoramide, include ester, sulphone, and secondary alcohol functions in addition to (-amides. The ethyl ester analog 14a obtained by treating the acid chloride derived from methadone cyanide with ethanol is markedly inferior in potency to methadone, while the sulfone 14b (obtained by aminoalkylation of benzhydryl ethyl sulfone) is equipotent... 

Tilidine is the minor component of the product of cycloaddition of trans 1-dimethylamino-l,3-butadiene (21a, R = NMe2) to ethyl atropate, a reaction with favored cis stereochemistry. When the butadiene 21a (R = NHC02CH2CC13) was employed, the trans isomer was obtained exclusively and was converted to tilidine in two steps (Zn dust-HAc followed by CH20-NaBH4).(35) Stereochemistry in the series was established by spectroscopic methods, X-ray crystallography, and chemical transformations. t-l-Dimethyl-amino-r-3-propionyloxy-3-phenylcyclohexane, a saturated reversed-ester analog of tilidine, was only feebly active in the MHP test.(62)... 

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