Practical asymmetric synthesis of alpha-branched 2-piperazinylbenzylamines by 1,2-additions of organometallic reagents to N-tert-butanesulfinyl imines.
[reaction: see text] 2-[4-(tert-Butoxycarbonyl)piperazinyl]benzylidene-tert-butanesulfinamides underwent nucleophilic 1,2-addition with different organometallic reagents to give highly diastereomerically enriched adducts. X-ray crystallography of the resulting alpha-branched N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides confirms different mechanisms depending on the organometallic reagent used. Differential deprotection of the N-Boc and the tert-butanesulfinamides was investigated, and the dehydration byproducts have been identified and characterized. To avoid the formation of byproducts in the acidic deprotection step, the N-tert-butanesulfinamide group was converted to the corresponding N-tert-butanesulfonamide (Bus), which allowed for clean orthogonal deprotection. The efficient synthesis and deprotection of the N-Boc-2-piperazinylbenzyl-tert-butanesulfinamides herein described constitutes an attractive method for extensive structure-activity studies in the search for novel ligands of the human melanocortin 4 receptor.
Jiang
Wanlong
W
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., San Diego, California 92130, USA.
Chen
Chen
C
Marinkovic
Dragan
D
Tran
Joe A
JA
Chen
Caroline W
CW
Arellano
L Melissa
LM
White
Nicole S
NS
Tucci
Fabio C
FC
D000447:Aldehydes / Q000737:chemistry; D000478:Alkylation; D001596:Benzylamines / Q000737:chemistry*; D002073:Butanes / Q000737:chemistry*; D002244:Carbon / Q000737:chemistry; D002384:Catalysis; D018360:Crystallography, X-Ray; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry*; D008094:Lithium / Q000737:chemistry; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D013237:Stereoisomerism; D013455:Sulfur / Q000737:chemistry*
D000447:Aldehydes; D001596:Benzylamines; D002073:Butanes; D007097:Imines; C046888:butane; D013455:Sulfur; D002244:Carbon; D008094:Lithium; C030796:benzylamine; D009584:Nitrogen