4- propanedioic

Acetamido-2-(7-chloroindol-3-ylmethyl)propanedioic acid dimethyl ester[6]... 

Also called propanedioic acid or methanedicarboxyhc acid. 

Two closely related methods for the diastereoselective preparation of <5-oxo esters have been developed. The first method uses the chelated lithio enamine 2. These Michael donors are readily available from the tert-butyl ester of L-valine and jS-oxo esters. The Michael addition of this lithio enamine 2 to 2-(arylmethylene)propanedioates, followed by hydrolytic removal of the auxiliary, provides d-oxo esters with contiguous quaternary and tertiary carbon centers with high diastereoselectivity59 60. 

The second method is based on the optically active enamine formed from (S)-prolinol methyl ether and cyclohexanone. This enamine reacts spontaneously with 2-(arylmethylcnc)propane-dioates to give, after hydrolysis, the 2- (.S )-aryl[(,S )-2-oxocyclohexyllmethyl propanedioates 4 in 35-76% yield with d.r. 94 6 > 97 361. 

An efficient synthesis of optically active pentanedioates is possible using ester enolates based on chiral alcohols. This is illustrated by the addition of the lithium (fl-cnolate of (1 R,2S,5R)-5-methyl-2-(1-methyl-l-phenylethyl)cyclohexyl propanedioate to methyl ( )-2-butenoate at — 100 °C which shows simple and induced diastereoselectivity. 

Methyl l-((l/f,25,5/ )-5-Methyl-2-(l-methyl-l-phenyleth l)cyclohexyl Propanedioate (1) Typical Procedure186 ... 

Thus, the lithiated SAMP hydrazones of various methyl ketones on addition to 2-(aryl-methylene)- , 3-propanedionates and propanedinitriles provide, after the removal of the auxiliary, (R)-2-( l-aryl-3-oxobutyl)-1,3-propanedioates and -propanedinitriles with high enantiomeric excess (> 95%) in 50 82% yield (sec Table 6) 195,197. Using similar methods optically active (5-lactones (90% to > 96% ee) are obtained198. 

The Enders method has also been used as a key step in the synthesis of optically active Ar-heterocycles. The use of cyclic 1,3-diketones for the preparation of the SAMP or RAMP lithium azaenolates is shown by the synthesis of substituted 4,6,7,8-tetrahydro-2,5(l//,3//)-quinolinediones 2. Michael addition of 1 with, for example, benzylidene propanedioates followed by removal of the auxiliary and lactamization gives 2 with > 98% ee201. 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

This procedure has been applied as a key step in the synthesis of ( + )-ramulosin. Using dimethyl 1,3-propanedioate or cyanoacetate under basic conditions (20 °C, sodium methoxide) trans-adducts are obtained preferentially (diastereomeric ratios 2.5-l0 1)264. 

A solution of 1.18 g (7 mmol) 4-acetoxy-5,5-dimethyl-2-eyclopcnlonone and 1.13 g (7.1 mmol) of diethyl 1,3-propanedioate in 0.8 mL of ethanol is added to a solution of 40 mg (1.7 mmol) of sodium in 4 mL of ethanol and stirred for 0.5 h at 25 JC. The mixture is acidified with 1 mL of acetic acid and poured into 10 mL of water. The resulting mixture is extracted three times with 10 mL of diethyl ether. The combined ether layers are washed with 10 mL of 5% aq NaHC03,10 mL of brine and dried Over Na,S04. Evaporation of the solvent followed by chromatography (silica gel, henzene/ethyl acetate 30 1) affords the crude product which was recrystallized from hexane yield 478 mg (21 %) mp 65-66°C. 

The stereochemical outcome and the diastereoselectivity of the addition of the anion of diethyl propanedioate to a,/ -unsaturated sulfoxides is dependent on the reaction solvent, the metal counterion and the geometry of the a,/ -unsaturated sulfoxide1 - 3. 

Trifluoro-l-(4-mcthylphcnylsulfinyl)-l-propcne undergoes addition of the sodium salt of diethyl propanedioate in THF in the same stereochemical sense3. 

The Postnitrated Polyurethane Polymer of 3,6-Dinitraza-1,5-Octane Diisocyanate and 2-Methyl-2-Nitro 1,3-Propanedio. n... 

Ethanedioic (oxalic) Propanedioic (malonic) Butanedioic (succinic) Pentanedioic (glutaric) Hexanedioic (adipic) Heptanedioic (pimelic) Octanedioic (suberic) Nonanedioic (azalic) Decanedioic (sebacic) Undecanedioic Dodecanedioic Phthalic Isophthalic Terephthalic 1,4-Naphthalic... 

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