Metal-Catalyzed RegiodivergentCyclization of γ-Allenols:

Tetrahydrofurans versus Oxepanes

Alcaide*, B., Almendros, P. and Martinez del Campo,T. Angew. Chem. Int. Ed. Early view

Amol Kulkarni @ Wipf Group 1 10/29/2007

β-Lactams: Serine Protease Inhibitiors

N

O2S

CH2R2

COR3

O

R1

R

Human Leucocyte Elastase Inhibitors

N

O2S

CO2t-BuO

X

O R

O

Porcine Pancreatic Elastase Inhibitors

N

O2S

CO2t-BuO

OAc

RHC

Cytotoxic

Veinburg, G. et al., Curr. Med. Chem. 2003, 10, 1741-1751

• Potent inhibitors of serine protease• Poor selectivity • Potent cytotoxicity against HT-1080 and MG-22A cell lines• Monocyclic β latams: Phospholipase A2 inhibition, antifungal activity

Amol Kulkarni @ Wipf Group 2 10/29/2007

Allene Activation Using Transition MetalCatalysis

Bates, R. W. and Satcharoen, V., Chem. Soc. Rev. 2002, 31, 12-21Ma, S., Chem. Rev. 2005, 105, 2829-2871

Commonly employed Metals:Au+1, Au+3, Pd+2, Ag+1, Pt+2

Amol Kulkarni @ Wipf Group 3 10/29/2007

Allenes: Activation With Pd Catalysts

n-C4H9

HO

+ PhIPd(PPh3)4 (5 mol %)

K2CO3, DMF, 55 ˚C, 14 h

Ph

O n-C4H9

+Ph

O

n-C4H9

71 %, (30 : 1)

Pd0 catalysis

Ma, S.; Zhao, S., J. Am. Chem. Soc. 1999, 121, 7943

Pd+2 catalysis

HO

+PdCl2 (5 mol %)

DMA, rt

BrR1

R2 O

R3 R3

R1

R2

(55-86 %)

R1

+PdCl2 (5 mol %)

DMA, rt

BrR2

OH O

R2

R1

(48-78 %)

Ma, S.; Gao, W., J. Org. Chem. 1999, 67, 6104Amol Kulkarni @ Wipf Group 4 10/29/2007

Allenes: Activation with Au Catalysts

OH

Ph

Ph

catalyst (5 mol %)

PhMe, 25 ˚C,

5 min

O

Ph

Ph

+

O CH3

Ph

Ph

catalyst

Au[P(t-Bu)2(o-biphenyl)]Cl + AgOTs

[PtCl(CH2=CH2)]2/P(C6H5CF3)3

1 (%)

96

0

2 (%)

< 1

49

1 2

Widenhofer, R. A. et al., J. Am. Chem. Soc. 2006, 128, 9066

HO

OTBSAuCl3 (10 mol %)

CH2Cl2, rt, 77 %

O

OTBS

(d.r. = 94:6)

Au+1 catalysis

Au+3 catalysis

Hoffmann-Röder, A.; Krause, N., Org. Lett. 2001, 3, 2537Amol Kulkarni @ Wipf Group 5 10/29/2007

OH

Me

BnO

H

C7H15

AgNO3, acetone

rt, 2 h 92 % O

Me

C7H15H H

BnO

Marshall, J. A. et al., J. Org. Chem. 1995, 60, 5550

α-Allenols and Ag+1 Catalysis

NR

HO

O

MeAgNO3 (1 equiv)

THF : H2O (1:1)

reflux, 1 h NR

O

O

R = Me (96 %)R = H (100 %)

Alcaide, B. et al., J. Org. Chem. 2006, 71, 2346

OR'

R

HO

AgNO3, CH3CN

rt, 53 % O R

OR'

Flögel, O., Reißig, H.-U., Eur. J. Org. Chem. 2004, 2797

Amol Kulkarni @ Wipf Group 6 10/29/2007

Synthesis of Allenols

Alcaide, B. et al., Angew. Chem. Int. Ed. Early ViewAmol Kulkarni @ Wipf Group 7 10/29/2007

Hydroalkoxylation: Initial Attempts

NR1

HHHO

OTBS

O

catalyst

NR1O

O OTBS

H H

Catalysts: AgNO3 (54 %), poor diastereoselectivity [PtCl2(CH2=CH2)]2, (12 %), only diastereomer

Alcaide, B. et al., Angew. Chem. Int. Ed. Early View

Synthesis of quaternary center in excellent diastereoselectivity

Amol Kulkarni @ Wipf Group 8 10/29/2007

Hydroalkoxylation: Catalytic Pd+2

Alcaide, B. et al., Angew. Chem. Int. Ed. Early View

Unprecedented Pd+2-catalyzed cyclization of γ-allenols

Amol Kulkarni @ Wipf Group 9 10/29/2007

Hydroalkoxylation: Au+3/ Pd+2 Catalysts

Alcaide, B. et al., Angew. Chem. Int. Ed. Early View

Reversal of the regioselectivity in Au+3-catalyzed reaction

Amol Kulkarni @ Wipf Group 10 10/29/2007

Cyclization of 7: Au+3 Catalysis

Alcaide, B. et al., Angew. Chem. Int. Ed. Early View

Directing effect of the MOM groupSynthesis of fused oxepines using Au+3 catalysis

Amol Kulkarni @ Wipf Group 11 10/29/2007

Proposed Mechanism for Au+3 Catalysis

Alcaide, B. et al., Angew. Chem. Int. Ed. Early View

Amol Kulkarni @ Wipf Group 12 10/29/2007

Proposed Mechanism: Pd+2 Catalysis

Alcaide, B. et al., Angew. Chem. Int. Ed. Early View

Amol Kulkarni @ Wipf Group 13 10/29/2007

Conclusions• Synthesis of fused bicyclic β-lactams bearing a quaternary center was accomplished in good yield and excellent diastereocontrol

• An efficient metal-controlled regiodivergent synthesis of tetrahydrofurans and tetrahydrooxepins has been developed

• The directing effect of the -MOM group afforded reversal of regiochemistry in Au+3-mediated cyclization

• Elucidation of the reaction mechanism and its scope is under investigation

Amol Kulkarni @ Wipf Group 14 10/29/2007

Amol Kulkarni @ Wipf Group 15 10/29/2007