Electrophile-Induced Dearomatizing Spirocyclization of N - - PowerPoint PPT Presentation
Electrophile-Induced Dearomatizing Spirocyclization of N -Arylisonicotinamides: A Route to Spirocyclic Piperidines Gareth Arnott, Heloise Brice, Jonathan Clayden, and Emma Blaney Org. Lett. ASAP June 14, 2008 Rapid and Enantioselective Synthetic
N N E
E Nuc-H
N E Nuc
+ H
N
E Nuc-H
N E Nuc
+ H Nuc-H
N
Nuc-H
E
Dearomatization by Addition Dearomatization by Spirocyclization
Corey, E.J. and Tian, Y. Org.Lett. 2005, 7, 5535-5537
N N O R OMe N N O R OMe Tf N Tf N O R OMe
N O N H OMe N O N R OMe
secondary anilide tertiary anilide Tf2O CH2Cl2
Tf2O additive CH2Cl2 0 to 25oC
N NH Tf O OMe N N Tf O OMe
R= Me, Bn R Me Me Me Me Bn additive
DMAP pyridine 2.6 lutidine % yield 47 54 70 99 87 20%
R
N N O R
Tf2O 2,6 lutidine CH2Cl2 ,0-25oC 30 min
N Tf N O R X X N Tf N O R X
+
N Tf N O R X
regioisomer R Me Bn PMB SO2Me Boc % yield 92 88 88 77 48 R Me % yield 43 + 28 12 + 17 X Me F R Me Bn PMB Me % yield 48 + 11(regioisomer) 50 + 15 43 + 14 43 + 28
N Tf N O R
+
N Tf N O R
regioisomer
N Tf N O R OMe MeO
N N O SO2Me OMe
Tf2O 2,6 lutidine CH2Cl2 0-25oC
N N O SO2Me OMe Tf N Tf N O SO2Me OMe O NH N O O NH2 N S Me O O
MK-677
N Tf N SO2Me
spirocyclic piperidine core related to biologically active molecules like MK-677 MK-677 is growth hormone receptor secretagogue
N O N H OMe
NaH MeSO2Cl 70%
N N O SO2Me OMe N Tf N O SO2Me OMe
Tf2O 2,6 lutidine CH2Cl2 0-25oC 68% H2, Pd/C EtOH/EtOAc 90 bar, 55oC 98%
N Tf N O SO2Me OMe
1.) BBr3, CH2Cl2 40oC 2.) Tf2O, CH2Cl2 0-25oC 71%
N Tf N O SO2Me OTf
H2, Pd/C EtOH/EtOAc 60 bar, 35oC 98%
N Tf N O SO2Me
1.) LiBHEt3, THF,
2.) Et3SiH, CF3SO3H, CH2Cl2, 25oC 63% spirocyclic piperidine core
N Tf N SO2Me
O OMe TBSO O OMe OMe HO H H HO H H H
Germanicol 1 2 4 3
9 steps
OH O O TBS O TBSO OMe O OMe O TBSO H H OMe HO H H
1.) MsCl. Et3N, THF; LiBr, THF 2.) LDA 3.) AcONa-AcOH buffer
N TBS OMe
1.) Et2O,
2.) BaI2, THF, -78oC 3.) 3-methoxybenzyl- bromide, -78 - 0oC 1.) MeAlCl2, CH2Cl2
2.) TBSCl, CH2Cl2 reflux, 20 h 3.) PPA, 23oC 30 min 88% 74% 33%
Li
N OMe N(Me)2 N OMe NH2 Me I OMe Me OMe Me HO
1.) LDA, THF, 0oC; CH3I, -60oC 2.) H2NNH2, EtOH reflux Et3N, THF, I2, 6oC 80% 1.) t-BuLi, THF-Et2O,
2.) , -78oC
O OMe I N-NH-Trisyl
+
PPh3, imidazole, I2, benzene 92% n-BuLi, DME, -65oC, 6 h TMEDA, n-BuLi, I2, -78oC 72% 97% 88%
OMe I
O
+
OMe I O OMe
9-BBN, THF, 23oC, 5 h PdCl2(dppf), NaOH, 0oC 78% MeAlCl2, CH2Cl2
OMe HO H Me Me H H H
OMe HO H H OMe HO H Me Me H
+
CF3SO2H, 0oC, 2 h
52% 2 6
OMe HO H Me Me H H
H
5
OMe HO H Me Me H H H
OMe HO H Me Me H OMe HO H Me Me H H H OMe HO H Me Me H H H Me Me RO Me Me H OMe Me OMe HO H Me Me H Me Me RO Me Me H OMe HO H Me Me H Me OMe
O
72% 60% 58% (4:1 pare/ortho) 52%
OMe OMe HO H O HO H O OMe OMe HO H O OMe OMe HO H H H H
O OMe O OMe O OTBDPS OMe H H HO OMe H H HO OTBDPS H H HO H H