Abstract I N X X = N-PG or O PG Cu(OTf)2(5 mol%) rac-Binap (6 mol%) RMgX, THF, 0°C X = N-PG PG= -Boc, 4a -Cbz, 4b R N Rh(I) salt phosphine ligand R-B(OH)2 X PG R NH PGHN 5 6 N O PG PG= -Boc, 1a -Cbz, 1b Cu(II)/Ligand "R-M" M = MgI, RZn, R2Al R N OH PG 2 Cu(II)/Ligand "R-M" M = MgCl up to >98/<2 regioisomeric ratio R N PG HO 3 up to 93/7 regioisomeric ratio X B2pin2 Ni(cod)25 mol% ligand 7.5 mol% K3PO4 toluene, MeOH rt XH Bpin XH OH XH R OH NaBO3 X=NTs RCHO 7, X= O, 8, X= NTs 9 10 11 12 one-pot Abstract
The development of stereoselective reactions that permit the selective generation of different products from the same precursor simply by varying the reaction conditions or the catalysts are at the center of academic and synthetic interest. We have focused our attention on [2.2.2]-acylnitroso bicyclic systems N-Boc 1a or N-Cbz 1b protected, in a copper-catalyzed alkylative ring-opening reactions with organometallic reagents to give new substituted cyclohexenyl hydroxamic acids of type 2 and 3 with a definite stereo- and regioselectivity. A remarkable effect of the halogen of the Grignard reagent was observed [Chapter 1].1
We also examined the regio- and stereoselective ring opening of hetero Diels-Alder cycloadducts of type 4 with different nucleophiles, and trans-1,2-disubstituted cyclopentenes of type 5 were obtained.2 Moreover, we obtained trans-1,4-disubstituted monoprotected hydrazine cyclopentenes of type 6 by means of a novel one-pot rearrangement allylic alkylation with Grignard reagents using copper as the metal catalyst [Chapter 2].2
Scheme 1 Metal-catalyzed ring-opening reactions of acylnitroso cycloadducts 1a,b and 4a,b
The ring opening of aziridines with carbon or boron nucleophiles represents a useful entry into substituted amines. An unprecedent mild nickel-catalyzed ring opening of vinyl epoxides
7 and aziridines 8 with bis(pinacolato)diboron 9 was achieved to afford new functionalized allylic
boron derivatives 10.3
Abstract II N Ph PG R3Al CH2Cl2, 0°C Ph R NHPG PG = -Ts, 14a -Cbz, 14b PG = -Ts, 13a -Cbz, 13b N O CH3 COOH 16 (85%) Ac2O, r.t Cu(OTf)2 N 15 isoquinuclidines and azasugar derivatives
These compounds (10) can be easily oxidized to synthetically useful bis-allylic 1,4-aminoalcohols
12. Alternatively, allylic boronates can be trapped in a one-pot procedure with aldehydes to give
alicyclic bis-homoallylic 1,3-aminoalcohols, 1,3-diols and 1,3-diamines (type 11) containing three contiguous stereocenters with a high stereoselectivity [Chapter 3].
The regioselective ring-opening of N-protected 2-phenylaziridines of type 13 was accomplished by the addition of organoalanes in dichloromethane. With this simple method it is possible to introduce alkyl, alkenyl and alkynyl substituents at the benzylic position of the phenylaziridine to give the corresponding β-phenyl-β-substituted amines 14, as useful precursors for intramolecular hydroaminations, in high yields [Chapter 4].4
Scheme 3 Regioselective ring-opening of 13a,b with organoaluminum reagents
The direct addition of unmodified carboxylic acid anhydrides to the pyridine nucleus has very little precedents and the yields were very low. We have developed a novel copper-catalyzed Perkin acyl-Mannich reaction of pyridine and acetic anhydride for the synthesis of N-acetyl-1,2-dihydropyridine acetic acid 16 as the main product.
Scheme 4 Copper-catalyzed Perkin acyl-Mannich reaction
The 1,2-dihydropyridine 16 is a valuable building block for the synthesis of very interesting systems such as isoquinuclidines and azasugar derivatives [Chapter 5].
1 Crotti, S.; Bertolini, F.; Di Bussolo, V.; Pineschi, M; Org. Lett. 2010, 12, 1828-1830 2
(a) Crotti, S.; Bertolini, F.; Macchia, F.; Pineschi, M.; Chem. Comm. 2008, 3127-3129. (b) Crotti, S.; Bertolini, F.; Macchia, F.; Pineschi, M.; Adv. Synth. Catal. 2009, 351, 869-873
3 Crotti, S.; Bertolini, F.; Macchia, F.; Pineschi, M. Org. Lett. 2009, 11, 3762-3765
