Cyclic beta-amino acid derivatives: synthesis via lithium amide promoted tandem asymmetric conjugate addition-cyclisation reactions.
The product distribution upon conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to dimethyl-(E,E)-nona-2,7-dienedioate can be controlled to give either the cyclic 1,2-anti-1,6-anti-beta-amino ester (derived from conjugate addition and intramolecular enolate cyclisation) or the acyclic bis-beta-amino ester derivative (derived from double conjugate addition) in high de. The introduction of a protected nitrogen functionality into the diester skeleton facilitates, after conjugate addition and intramolecular enolate cyclisation, the asymmetric construction of piperidines in high de; variation in the N-protecting group indicates that the highest stereoselectivity is observed with alpha-branched N-substituents. Tandem conjugate addition-aldol reactions can also be achieved stereoselectively, with lithium amide conjugate addition to epsilon- and zeta-oxo-alpha,beta-unsaturated esters giving the corresponding five and six membered cyclic beta-amino esters in high de. N-deprotection by hydrogenolysis of the products arising from these reactions furnishes a range of polyfunctionalised transpentacin and transhexacin derivatives in high de and ee.
Davies
Stephen G
SG
Department of Organic Chemistry, University of Oxford, Chemical Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK. steve.davies@chem.ox.ac.uk
Díez
David
D
Dominguez
Sara H
SH
Garrido
Narciso M
NM
Kruchinin
Dennis
D
Price
Paul D
PD
Smith
Andrew D
AD
D000577:Amides / Q000737:chemistry*; D000598:Amino Acids, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D003500:Cyclization; D008094:Lithium / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009904:Optical Rotation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D013055:Spectrophotometry, Infrared
D000577:Amides; D000598:Amino Acids, Cyclic; D010880:Piperidines; D008094:Lithium