Francesc Pérez

(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-aryloxypropanoic acid herbicides and α-chlorocarboxylic acids

Abstract rac -α-Chlorocarboxylic acids, rac - 9a – e , were formally deracemized by reaction of the corresponding acyl chlorides with the chiral auxiliaries ( R )- and ( S )-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, ( R )- and ( S )- 4 , followed by mild alkaline hydrolysis. The highest o.p. (99%) was obtained in the case of ( S )-α-chloropropanoic acid, a known precursor for the synthesis of ( R )-α-aryloxypropanoic acid herbicides such as dichlorprop-P, ( R )- 3a , or mecoprop-P, ( R )- 3b , which, together with their enantiomers, were also obtained in moderate e.e.s by dynamic kinetic resolution from (α RS ,3 S )-4,4-dimethyl-2-oxo-1-phenylpyrrolidin-3-yl α-bromopropanoate, (α RS ,3 S )- 6 , by reaction with the corresponding phenoxide followed by mild acid hydrolysis.

(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in the enantioselective preparation of α-amino acids

Abstract rac-α-Amino acids (rac-1a–d) were formally deracemized by a four-step reaction sequence: (a) protection of the amino function as the phthalimido derivative; (b) acyl chloride formation; (c) diastereoselective reaction with the chiral auxiliaries (R)- or (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone, (R)- or (S)-3; and (d) acid hydrolysis to deprotect both the ester and phthalimido functions. Diastereoselectivities of the intermediate esters 4 were good (82–96% d.e.), except for the case of 4b (41% d.e.), the precursor of valine. The main diastereoisomer of esters 4 was (αR,3S)- or (αS,3R)-, except for 4d: in this case, working at −78°C, the (αR,3R)-diastereoisomer was the main product, which epimerizes easily at the α-position when at room temperature. Acid hydrolysis of esters 4 directly gave the deprotected α-amino acids, with little or no epimerization at the α-position of the α-amino acid and complete recovery of the chiral auxiliary. Only (αR,3R)-4d on acid hydrolysis partially epimerized at the α-position. Moreover, some α-amino acids and their N,N-dibenzyl derivatives were obtained by dynamic kinetic resolution of diastereoisomeric mixtures of α-bromo esters 5 derived from the chiral auxiliaries (R)- or (S)-3 during reaction with dibenzylamine.

(R)- and (S)-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries for the asymmetric synthesis of α-hydroxy acids

Abstract Rac - α -bromo acids, rac-4 , have been converted into ( R )- or ( S )- α -hydroxy acid, (R)- or (S)-9 , by DCC-induced esterification with the chiral auxiliaries (R)- or (S)-1 , followed by reaction with sodium p -methoxyphenoxide in the presence of tetra- n -hexylammonium iodide, conditions of dynamic kinetic resolution, to give quite diastereoselectively the (αR,3S)- or (αS,3R) -α-(p- methoxyphenoxy ) esters, 7 , which were then oxidized with ceric ammonium nitrate and hydrolyzed under controlled acid conditions.

Synthesis, chemical trapping and dimerization of tricyclo[3.3.0.03,7]oct-1(5)-ene, the consummate member of a series of pyramidalized alkenes

The synthesis of tricyclo[3.3.0.03,7]oct-1(5)-ene, 5, the consummate member of a series of pyramidalized alkenes, has been carried out by deiodination of 4 in different ways. Reaction of 4 with sodium in boiling dioxane gave in good yield diene 8, whose formation can be easily explained through the intermediacy of 5 and its cyclobutane dimer 6. Reaction of 4 with t-butyllithium in THF at −78 °C in the presence of 1,3-diphenylisobenzofurane gave 10, a Diels-Alder adduct derived from 5.

Low temperature X-ray diffraction analysis of 4,5,10,11-tetramethyl-heptacyclo[8.2.1.12,5.14,7.18,11.01,8.02,7]hexadecane: DSC, MM2 and 1H NMR study of its [2 + 2]retrocycloaddition to an isomeric diene

Abstract The synthesis of pure 3 has been achieved by deiodination of 1 with NaK alloy at r.t. and by [2+2] photocyclization of diene 4 . X-ray diffraction analysis at −30°C of the thermally unstable 3 shows the cyclobutane ring to be highly rectangular with large central and short lateral bonds. Also, the C4C5 and C10C11 bonds in 3 and diene 4 are very large. A clear neat DSC conversion of 3 to 4 allowed us to obtain the ΔH and the Ea values for this transformation. ΔH is in good agreement with MM2 calculations, while Ea compares well with kinetic measurements in CDCl 3 solution.

Enantioselective synthesis of both enantiomers of 3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone

Abstract The chiral auxiliaries ( R )- and ( S )-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone were obtained in good yield and e.e. by enantioselective reduction of 4,4-dimethyl-1-phenylpyrrolidine-2,3-dione with (−)- and (+)- B -chlorodiisopinocamphenylborane, (−)- and (+)-DIP-Chloride ® , respectively. The ( R )-enantiomer was also obtained by enantioselective hydrogenation of the same precursor using a complex of 1,5-cyclooctadiene Rh(I) and (2 S ,4 S )-1-( tert -butoxycarbonyl)-4-(diphenylphosphino)-2-(diphenylphosphinomethyl)pyrrolidine, ( S,S )-BPPM, as the chiral catalyst.

(R)- and (S)-3-Hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone as chiral auxiliaries in Diels–Alder reactions

Abstract A study of the Diels–Alder reactions of the esters derived from acrylic, methacrylic, trans -crotonic and trans -cinnamic acid and the chiral auxiliaries ( R )- and/or ( S )-3-hydroxy-4,4-dimethyl-1-phenyl-2-pyrrolidinone ( 4 , 17 , 25 and 26 , respectively) with different dienes [cyclopentadiene 5 , isoprene 8 , 11,12-dimethylene-9,10-dihydro-9,10-ethanoanthracene 9 and anthracene 10 ], catalyzed by titanium tetrachloride, is described. Cyclopentadiene gave adducts with esters ( R )- or ( S )- 4 and ( R )- 25 with high endo - and facial -diastereoselectivities. Diene 5 reacted with (±)- 17 without endo -diastereoselectivity and failed to give a cycloadduct with (±)- 26 . Isoprene reacted only with ester ( S )- 4 with high facial -diastereoselectivity. The reaction of 9 with ( R )- 4 failed, because the diene was not stable under the acid reaction conditions. Adducts derived from 10 and esters ( S )- 4 and ( R )- 17 could be obtained with high facial -diastereoselectivity. LiOH-hydrolysis of the adducts derived from esters ( R )- or ( S )- 4 and ( R )- 25 gave the corresponding enantiopure acids, the chiral auxiliaries being completely recovered unchanged. However, hydrolysis of the adduct derived from 10 and ( R )- 17 , required more drastic basic conditions which partially epimerized the chiral auxiliary. X-Ray diffraction analysis of the adducts derived from 10 and esters ( S )- 4 and ( R )- 17 , let us establish their relative configurations and, taking into account the absolute configuration of the starting chiral auxiliary, their absolute configurations.

Inexpensive Synthesis of 3,7-Disubstituted Tricyclo[3.3.0.03,7]octane-1,5-diols

Abstract A synthesis of 3,7-disubstituted tricyclo[3.3.0.03,7]octane-1,5-diols, 2, by intramolecular pinacol reduction of cis-1,5-disubstituted bicyclo[3.3.0]octane-3,7-diones, 1, with low valent titanium species, is described.

Pentacyclo[8.2.1.12,5.14,7.18,11]hexadeca-1,7-diene and its 4,5,10,11-tetramethyl derivative, two highly hyperstable slightly pyramidalized dienes

Abstract Dienes 4a,b and their monohydrogenation products 5a,b have shown to be hyperstable alkenes which could be reduced with diimide or epoxidized with m-chloroperbenzoic acid. Moreover dienes 4a,b show slightly pyramidalized carbon-carbon double bonds which must be responsible for its long-wave lengh UV absorption which allows their photochemical [2 + 2] conversion into cyclobutanes 3a,b in the absence of any photosensitizer and, in the case of 4b, its participation as a dienophile in an inverse-electron demand Diels-Alder reaction with tetrachlorotiophene-S,S-dioxide.