Kevin H. Sutton

The asymmetric synthesis of β-lactams : Stereocontrolled Asymmetric Tandem Michael Additions and Subsequent Alkylations of E-[(η5-C5H5)Fe(CO)(PPH3)COCH = CHME]. X-ray Crystal Structure of (RS)-E-[(η5-C5H5) Fe (CO) (PPH3) COCH = CHME]

Abstract Michael addition of methyllithium to the E-crotonyl complex (RS)-[η5-C5H5)Fe(CO)-(PPh3)COCHCHMe] followed by trapping of the resultant enolate with methyl iodide gives (RS)-[(η5-C5H5)Fe(CO)(PPh3)COCH(Me)CHMe2] (d.e. > 100:1), also generated by treatment of (RS)-[(η5-C5H5)Fe(CO)(PPh3)COCH2CH(OMe)2] with three equivalents of methyllithium and methyl iodide. Addition of n -butyllithium to the (RS)-E-crotonyl complex followed by protonation with methanol occurs with high diastereoselectivity. Quenching with methyl iodide gives (RS)-[(η5-C5H5)Fe(CO)(PPh3)COCH(Me)CH(Me) n -Bu], also generated by treating either diastereoisomer of [(η5C5H5)Fe(CO)(PPh3)COCH2CH(Me)OMe] with two equivalents of n -butyllithium and methyl iodide. Decomplexatlon gives the known erythro -2,3-dimethyl-heptanoic acid. Similarly, Michael addition of lithium benzylamide and electrophilic quenching with methanol or methyl iodide occurs with high diastereoselectivity and gives upon decomplexation, 4-methyl- and cis -3,4-dimethyl-N-benzyl-β-lactams respectively. The stereochemical results are rationalised by addition occurring to the E-crotonyl complex in the anti (CO to CO) and cisoid conformation and subsequent alkylation of the unhindered face of the E-enolate generated. Confirmation is provided by an X-ray crystal structure analysis of (RS)-E-[(η5-C5H5)Fe(CO)(PPh3)COCHCHMe]. When repeated with the optically pure (S)-E-crotonyl complex, decomplexation gives essentially optically pure (2R) ,(3R)-(-)-N-benzyl-2,3-dimethylheptanamide, (4S)-(-)-4-methyl- and (3R),(4S)-(-)- cis -3,4-dimethyl-N-benzyl-β-lactams.

The asymmetric synthesis of β-lactams. Stereocontrolled asymmetric tandem Michael additions and alkylations of α,β-unsaturated acyl ligands bound to the chiral auxiliary [(η5-C5H5)Fe(CO)(PPh3)]

Michael addition of lithium benzylamide to the enantiomerically pure (S)-E-crotonyl complex of [(η5-C5H5)Fe(CO)(PPh3)] followed by trapping of the resultant enolate with methyl iodide or methanol occurs with high diastereoselectivity and gives after decomplexation the essentially optically pure (3R), (4S)-(−)-3,4-dimethyl- and (4S)-(−)-4-methyl-N-benzyl-β-lactams respectively. Similarly, tandem addition of lithium benzylamide and methylation of the corresponding enantiomerically pure R-(−)-acryloyl complex gave after decomplexation the essentially optically pure (3S)-(−)-3-methyl-N-benzyl-β-lactam.

The stereospecific synthesis of (−)-(8R) and (−)-(8S)-methylcanadine

Abstract Regioselective complexation of the dimethoxy arene ring of canadine to the Cr(CO)2 moiety gives two diastereoisomers which are separated by flash chromatography. Deprotonatlon of either diastereoisomer with n -butyllithium followed by addition of methyl iodide or trimethylsilyl chloride gives C11-methyl- or -trimethylsilylcanadine after decomplexatlon. Each diastereoisomer of the C11-trimethylsilylcanadine complex may be treated with base and methyl iodide to give, after desilylation and decomplexatlon, the enantiomerically pure (-)-(8R) and (-)-(8S) methyl canadines; racemic samples of C8-methylcanadines are prepared via an independent route.

Tricarbonylchromium(0) promoted stereoselective transformations of ephedrine and pseudoephedrine derivatives

Abstract (−)-(1 S ,2 S )-( N ,O-Dimethylephedrine)tricarbonyl chromium(0) (6) and (−)-(1 S ,2 R )-( N ,O-dimethylpseudoephedrine)tricarbonylchiromium(0) ( 22 ) undergo completely stereoselective ortho deprotonation upon treatment with alkyllithium base, followed by addition of an electrophile. In both cases, exclusive removal of the pro -( R )- ortho proton was confirmed by single crystal X-ray structure analyses of the methylated products. Addition of methyllithium onto the ortho -formylated derivative of complex ( 6 ) occurs stereoselectively, the stereochemistry of the major product being confirmed by a single crystal X-ray structure determination. The results presented demonstrate an efficient transfer of chirality from a side chain onto the (arene)tricarbonylchromium(0) complex and back to a different side chain.

Asymmetric synthesis of (R)-(+)-a-methyl-o-methoxybenzyl methyl ether via the stereoselective benzylic elaboration of tricarbonyl (η6-o-methoxybenzyl methyl ether)chromium(0)

Abstract Treatment of tricarbonyl(ν6-o-methoxybenzyl methyl ether)chromium(0) with t-butyllithium followed by an electrophile gives a single diastereoisomer of the corresponding alpha substituted complex. The relative configuration within the product from methylation, tricarbonyl(η6-α-methyl-o-methoxybenzyl methyl ether)chromium(0), has been established via a single crystal X-ray structure analysis and found to be (RS,RS), the stereoselectivity thus arising from a non-chelation controlled mechanism. Repetition of the reaction on homochiral (+)-tricarbonyl(η6-o-methoxybenzyl methyl ether)chromium(0) gives, after decomplexation, homochiral (R)-(+)-α-methyl-o-methoxybenzyl methyl ether.

Chiral dienolates : Stereoselective formation and α-alkylation of the lithium dienolates derived from (RS)-Z-[(n5-C5H5)Fe(CO)(PPh3)COCHCHCH2R] (RMe,Et,n-pr) and (RS)-[(n5-C5H5)Fe(CO)(PPh3)(COCHCMme2)]

Abstract The acyl ligands Z-(COCHCHCH2-R)(RMe,Et, n -Pr) and (COCH-CMe2) bound to the chiral auxiliary [(n5 -C5H5)Fe(CO)(PPh3)] undergo exclusive γ-deprotonation to form the corresponding dienolates which react with electrophiles regio- and stereoselectively at the α-position to give in most cases single diastereoisomers of the corresponding α-substituted-βγ-unsaturated acyl complexes, together with in the former cases complete control over the β,γ-double bond geometry (E).

Tetrahydroisoquinolines. Part 4. Enantioselective conversion of (+)-amphetamine into (+)-(1R,3S,4S)- and (–)-(1S,3S,4R)-1,2,3,4-tetramethyl-1,2,3,4-tetrahydroisoquinoline via tricarbonyl(arene)chromium methodology

Co-ordination of the tricarbonylchromium moiety to the diastereotopic faces of (+)-(3S)-2,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (9) occurs preferentially to the least hindered face. The mixture of tricarbonyl [exo-(3S)-2,3-dimethyl-1,2,3,4-tetrahydroisoquinoline]chromium (11) and tricarbonyl-[endo-(3S)-2,3-dimethyl-1,2,3,4-tetrahydroisoquinoline]chromium (12) thus generated may undergo regio- and stereo-selective exo-1,4-dimethylation by sequential treatment with BuLi–Mel and ButLi–Mel to give (+)-[tricarbonyl-(1R,3S,4R)-1,2,3,4-tetramethyl-1,2,3,4-tetrahydroisoquinoline]chromium (15) and (+)-[tricarbonyl-(1S,3S,4S)-1,2,3,4-tetramethyl-1,2,3,4-tetrahydroisoquinoline]chromium (16). The relative and absolute stereochemistry of (15) is assigned on the basis of differential n.O.e. experiments and confirmed by single crystal X-ray structure determination. Oxidative decomplexation gives (1R,3S,4S)-and (1S,3S,4R)-(–)-1,2,3,4-tetramethyl-1,2,3,4-tetrahydroisoquinolines (17) and (18).

Chiral organometallic NADH mimics: preparation and X-ray crystal structure of racemic (RS)-[Fe(η5-C5H5)(CO)(PPh3)(1-methyl-1,4-dihydronicotinoyl)] and homochiral (R)-(–)-[Fe(η5-C5H5)(CO){PPh2(O-[(–)-menthyl])}(1-methyl-1,4-dihydronicotinoyl)] and asymmetric reduction of ethyl benzoylformate

The racemic complex (RS)-[Fe(η5-C5H5)(CO)(PPh3)(1-methyl-1,4-dihydronicotinoyl)] has been prepared and shown to function as a NADH mimic. An X-ray crystal structure revealed that one face of the 1,4-dihydronicotinoyl moiety is essentially blocked by the triphenylphosphine ligand. The homochiral complex (R)-(–)-[Fe(η5-C5H5)(CO)(PPh2(O-[(–)-menthyl])](1-methyl-1,4-dihydronicotinoyl)] possessing the sterically demanding chiral auxiliary [Fe(η5-C5H5)(CO){PPh2(O)-(–)menthyl)}] at C-3 has also been prepared and shown to reduce ethyl benzoylformate to ethyl mandelate in 52% enantiomeric excess by a combination of steric and chelation control.

Regioselective nucleophilic additions to tricarbonyl(η6-arene)chromium(0) complexes: electronic versus chelation control

Regioselective addition of t-butyl-lithium to tricarbonyl(η6-benzyl alcohol)chromium(0) proceeds to give tricarbonyl(η6-5-methylene-6-exo-t-butylcyclohexa-1,3-diene)chromium(0), which can be isomerised to tricarbonyl(η6-o-t-butyltoluene)chromium(0). Repetition of the reaction on tricarbonyl(η6-1 -phenethanol)chromium(0) gives regio- and stereo-selectively the corresponding 5-ethylidene complex.

Chiral dienolates: formation and stereoselective α-alkylation of the lithium dienolate derived from (Z)-[(η5-C5H5)Fe(CO)(PPh3)COCHCHMe]. X-Ray crystal structure of (RS)-(Z)-[(η5-C5H5)Fe(CO)(PPh3)COCHCHMe]

An X-ray crystal structure analysis of (RS)-(Z)-[(η5-C5H5)Fe(CO)(PPh3)COCHCHMe](2) shows that the crotonoyl group adopts a cisoid conformation in the solid state. In solution it is the cisoid conformation that is deprotonated by butyl-lithium to give the corresponding dienolate (3). Alkylation (Mel, Etl, or PhCH2Br) of the lithium dienolate (3) occurs regiospecifically in the α-position to give stereoselectively the single diastereoisomers (RS,SR)-[(η5-C5H5)Fe(CO)(PPh3)COCHRCHCH2](R = Me, Et, or PhCH2). Protonation of the dienolate (3) gives the β,γ-unsaturated acyl complex [(η5-C5H5)Fe(CO)(PPh3)COCH2CHCH2] exclusively.