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 Approaches to Germanicol and Other Pentacyclic Triterpenes Karavadhi Surendra and E.J. Corey JACS ASAP June 14, 2008

Electrophile-Induced Pyridine Dearomatization Dearomatization by Addition Nuc E Nuc-H + H N N N E E Corey, E.J. and Tian, Y. Org.Lett. 2005 , 7 , 5535-5537 Dearomatization by Spirocyclization Nuc-H Nuc-H E Nuc-H Nuc + H N N N E E O O R O R R N N N N N Tf N OMe Tf OMe OMe

Preliminary Experiments secondary anilide O O NH Tf 2 O N OMe N OMe CH 2 Cl 2 N H Tf -30 to 0 o C 20% tertiary anilide O R O Tf 2 O R N N additive N N OMe Tf CH 2 Cl 2 OMe 0 to 25 o C % yield additive R R= Me, Bn - 47 Me Et 3 N 54 Me DMAP 70 Me 99 pyridine Me 87 2.6 lutidine Bn

Substrate Scope R O Tf 2 O O N R 2,6 lutidine N X N CH 2 Cl 2 ,0-25 o C N X Tf 30 min R R O O R N N O N N X N Tf Tf N OMe + Tf + MeO R R O O N N R % yield regioisomer regioisomer N N 92 Me Tf Tf X 88 Bn PMB 88 X R % yield 77 SO 2 Me % yield R 48 Boc Me Me 43 + 28 F 48 + 11(regioisomer) Me 12 + 17 Bn 50 + 15 PMB 43 + 14 Me 43 + 28

Practical Application towards Spirocyclic Piperidines O O Tf 2 O SO 2 Me O SO 2 Me SO 2 Me 2,6 lutidine N N N N N Tf CH 2 Cl 2 N OMe Tf 0-25 o C OMe OMe NH 2 O SO 2 Me NH O N O N O O N S N Tf Me spirocyclic piperidine core related to biologically active molecules like MK-677 MK-677 MK-677 is growth hormone receptor secretagogue

O SO 2 Me Tf 2 O O O NaH SO 2 Me N N 2,6 lutidine MeSO 2 Cl N OMe N 70% N H CH 2 Cl 2 N OMe Tf 0-25 o C OMe 68% H 2 , Pd/C 1.) BBr 3 , CH 2 Cl 2 SO 2 Me SO 2 Me O O 40 o C EtOH/EtOAc N N 90 bar, 55 o C 2.) Tf 2 O, CH 2 Cl 2 N OMe N OTf Tf Tf 0-25 o C 98% 71% H 2 , Pd/C 1.) LiBHEt 3 , THF, SO 2 Me SO 2 Me O -78 o C EtOH/EtOAc N N 60 bar, 35 o C 2.) Et 3 SiH, CF 3 SO 3 H, N N Tf Tf CH 2 Cl 2 , 25 o C 98% 63% spirocyclic piperidine core

Two Enantioselective Synthetic Approaches to Germanicol OMe OMe OMe TBSO H HO H O O 3 2 4 9 steps H H HO H 1 Germanicol

First Synthetic Approach to Key Intermediate 2 Li 1.) Et 2 O, OMe -78 o C, 1h 1.) MsCl. Et 3 N, THF; O OH TBSO 2.) BaI 2 , THF, -78 o C LiBr, THF TBS 2.) LDA 3.) 3-methoxybenzyl- OMe N bromide, -78 - 0 o C 3 O O TBS 74% O 3.) AcONa-AcOH buffer 88% OMe OMe O 1.) MeAlCl 2 , CH 2 Cl 2 3.) PPA, 23 o C -94 o C, 30 min 30 min 2.) TBSCl, CH 2 Cl 2 H H 33% reflux, 20 h HO TBSO over three steps H 2 H 9 steps

Synthesis of Coupling Precursor towards 4 1.) t-BuLi, OMe OMe 1.) LDA, THF, 0 o C; Et 3 N, THF, OMe THF-Et 2 O, CH 3 I, -60 o C I 2 , 6 o C -105 o C Me Me O 2.) H 2 NNH 2 , EtOH 2.) , -78 o C 80% N N I N(Me) 2 NH 2 reflux 88% 97% OMe OMe n-BuLi, DME, -65 o C, 6 h OMe PPh 3 , imidazole, TMEDA, n-BuLi, I 2 , -78 o C I 2 , benzene I Me 92% 72% N-NH-Trisyl HO I + 7 steps

Second Approach to Key Intermediate 2 OMe OMe 9-BBN, THF, 23 o C, 5 h PdCl 2 (dppf), NaOH, 0 o C I + 78% O 4 O MeAlCl 2 , CH 2 Cl 2 -94 o C, 30 min OMe H H Me H Me HO H 5

Formation of Key Intermediate 2 OMe OMe OMe H H Me Me + H H Me H Me HO HO HO H H H 2 5 6 52% CF 3 SO 2 H, 0 o C, 2 h OMe H H H Me Me HO H

Interesting Results of Coproduct 6 OMe OMe OMe H H H H Me Me Me H H Me Me H Me HO HO HO 5 H H H OMe Me RO Me Me Me Me Me H H Me HO H OMe Me OMe RO Me OMe Me Me Me H H Me HO H Me

Synthesis of Tetracycles OMe OMe 72% HO O H 60% H HO O H OMe OMe 58% H (4:1 pare/ortho) HO O H OMe OMe H 52% HO O H

Synthesis of Pentacycles OMe OMe 55% H HO OMe OMe O H 38% (4:1 para/ortho) H H HO OTBDPS OTBDPS O H 48% H H (9:1 p/o) HO O H