Selectivity in [5+2] Cycloadditions with
Vinylcyclopropane (VCP)
Andrea M. E. Palazzolo
CHEM 535 Seminar
October 20, 2014
University of Illinois at Urbana-Champaign
Seven-Membered Rings In Natural Products
Diels-Alder Analog for Seven-Membered Rings
[4+3]
[4+2]
[4+3] Cycloadditions: Synthesis of Cycloheptenes
[4+3]
Oxygen Substituents needed to stabilize allyl cation
Limited toCycloheptanones
Hill, A.E., Greenwood, G., Hoffmann, H. M. R. J. Am. Chem. Soc. 1973, 95, 1338.
Sasaki, T.; Ishibashi, Y.; Ohno, M. Tetrahedron Lett. 1982,zx 23, 1693.
[4+3]
[4+2]
Diels-Alder Analog for Seven-Membered Rings
[5+2]
Neutral AnalogNo Need for Oxygen
Stabilizing Group
[5+2] Cycloadditions with VCPs
Rhodium Catalyzed [5+2] Cycloaddition with VCP
Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720-4721.
Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A.; Pluess, N. Tetrahedron 1998, 54, 7203-7220.
Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Kadereit, D.; Love, J. A.; Rieck, H.. J. Am. Chem. Soc. 1999, 121, 10042-10043.
Rhodium Catalyzed [5+2] Cycloaddition with VCP
Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720-4721.
Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A.; Pluess, N. Tetrahedron 1998, 54, 7203-7220.
Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Kadereit, D.; Love, J. A.; Rieck, H.. J. Am. Chem. Soc. 1999, 121, 10042-10043.
Rhodium Catalyzed [5+2] Cycloaddition with VCP
Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117, 4720-4721.
Wender, P. A.; Husfeld, C. O.; Langkopf, E.; Love, J. A.; Pluess, N. Tetrahedron 1998, 54, 7203-7220.
Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Kadereit, D.; Love, J. A.; Rieck, H.. J. Am. Chem. Soc. 1999, 121, 10042-10043.
Ruthenium Catalyzed [5+2] Cycloaddition with VCP
Trost, B. M.; Toste, F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122, 2379-2380.
Two Possible Mechanisms
Mechanism depends on:1. Metal (Rh vs Ru)2. Ligand Envionment3. Molecularity
Determining the Selectivity of [5+2] Cycloadditions with VCP
π-Bond Insertion Controls:1. Regioselectivity2. Diastereoselectivity
Regiochemical Outcomes for Intermolecular [5+2] Cycloadditions with VCPs: Two Pathways
Liu, P.; Sirois, L. E.; Cheong, P. H.-Y.; Yu, Z.-X.; Hartung, I. V.; Rieck, H.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 10127-10135.
Xu, X.; Liu, P.; Lesser, A.; Sirois, L. E.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 11012-11025.
Substrate-Substrate Steric Control:
RL Distal
RL Proximal
Favored
Disfavored
*Supported by B3LYP/SDD-6-31G*/CPCM(DCE) Free Energies of Activation
Liu, P.; Sirois, L. E.; Cheong, P. H.-Y.; Yu, Z.-X.; Hartung, I. V.; Rieck, H.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 10127-10135.
Xu, X.; Liu, P.; Lesser, A.; Sirois, L. E.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 11012-11025.
Applies to ALL Ligands; More Prominent in SMALL Ligands
Controlling the Regiochemistry of Intermolecular [5+2] Cycloadditions with VCPs
Ligand-Substrate Steric Control:
Applies to BULKY Ligands Only
Controlling the Regiochemistry of Intermolecular [5+2] Cycloadditions with VCPs
RL Distal
RL Proximal
Disfavored
Favored
*Supported by B3LYP/SDD-6-31G*/CPCM(DCE) Free Energies of Activation
Liu, P.; Sirois, L. E.; Cheong, P. H.-Y.; Yu, Z.-X.; Hartung, I. V.; Rieck, H.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 10127-10135.
Xu, X.; Liu, P.; Lesser, A.; Sirois, L. E.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 11012-11025.
Wender, P. A.; Lesser, A.; Sirois, L. E. Angew. Chem. Int. Ed. 2012, 51, 2736-2740.
Utilizing Different Ligands to Control Regioselectivity
[RhCOD)]+ [Rh(dnCOT)]+Rh(CO)Cl
R = TMS >20:1 (85%) 1:>20 (54%) 1:4 (92%)
Distal Proximal:
R = n-Pr 7.1:1 (76%) 1.1:1 (57%) 5.4:1 (74%)
Metal-Substrate Electronic Control:
Electronic Effect Applies to ALL Ligands
Controlling the Regiochemistry of Intermolecular [5+2] Cycloadditions with VCPs
Disfavored
Favored
Distal
Proximald → π*
*Supported by B3LYP/SDD-6-31G*/CPCM(DCE) Free Energies of Activation
Liu, P.; Sirois, L. E.; Cheong, P. H.-Y.; Yu, Z.-X.; Hartung, I. V.; Rieck, H.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 10127-10135.
Xu, X.; Liu, P.; Lesser, A.; Sirois, L. E.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 11012-11025.
Wender, P. A.; Lesser, A.; Sirois, L. E. Angew. Chem. Int. Ed. 2012, 51, 2736-2740.
Utilizing Different Ligands to Control Regioselectivity
Distal Proximal:
EWG = COMe 1:1.9 (91%) 1:>20 (65%) 1:20 (96%)
EWG = CO2Me 3.0:1 (84%) 1.2:1 (73%) 1.7:1 (95%)
[RhCOD)]+ [Rh(dnCOT)]+Rh(CO)Cl
Liu, P.; Sirois, L. E.; Cheong, P. H.-Y.; Yu, Z.-X.; Hartung, I. V.; Rieck, H.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 10127-10135.
Effect of Competing Steric and Electronic Factors
Steric Controls Predominate over Electronics
6 examples69-90% yield
>20:1
Distal Proximal:
Wender, P. A.; Lesser, A.; Sirois, L. E. Angew. Chem. Int. Ed. 2012, 51, 2736-2740.
Utilizing Different Ligands to Control Regioselectivity
Ar = Ph 7.7:1 (78%) 6.8:1 (68%) >20:1 (95%)
Ar = p-COMe-Ph 11:1 (66%) -- >20:1 (87%)
Ar = p-OMe-Ph 5.9:1 (76%) -- >20:1 (85%)
Distal Proximal:
[RhCOD)]+ [Rh(dnCOT)]+Rh(CO)Cl
Controlling the Regiochemistry of Intermolecular [5+2] Cycloadditions with VCPs
π/π and C-H/πInteractions:
Metal-Substrate Electronic Control:
Ligand-Substrate Steric Control:
Substrate-Substrate Steric Control:
*Supported by B3LYP/SDD-6-31G*/CPCM(DCE) Free Energies of Activation
Liu, P.; Sirois, L. E.; Cheong, P. H.-Y.; Yu, Z.-X.; Hartung, I. V.; Rieck, H.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 10127-10135.
Xu, X.; Liu, P.; Lesser, A.; Sirois, L. E.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 11012-11025.
Controlling the Diasteroselectivity of Intramolecular [5+2] Cycloadditions with VCPs
Trost, B. M.; Shen, H. Schulz, T.; Koradin, C.; Schirok, H. Org. Lett. 2003, 5, 4149-4151.
Trost, B. M.; Nguyen, H. M.; Koradin, C. Tetrahedron Lett. 2010, 51, 6232-6235.
6 examples52-97% yield
Utilizing the Alkoxy Effect to Control Diastereoselectivity
Trost, B. M.; Toste, F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122, 2379-2380
Trost, B. M.; Shen, H. Schulz, T.; Koradin, C.; Schirok, H. Org. Lett. 2003, 5, 4149-4151.
Syn Product
Anti Product
Deactivated
σ* CO orbital overlap with C-C π orbitaldecreases nucleophilicity of alkene
π
σ*
π
σ*
Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007, 129, 11781-11790.
Towards the Synthesis of (±)-Rameswaralide
Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007, 129, 11781-11790.
Towards the Synthesis of (±)-Rameswaralide
Retrosynthetic Analysis of Tricyclic Core[5+2]
Application of [5+2] cycloaddition with VCP
Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007, 129, 11781-11790.
Towards the Synthesis of (±)-Rameswaralide
Retrosynthetic Analysis of Tricyclic Core[5+2]
Application of [5+2] cycloaddition with VCP
Alkoxy Effect
Wender, P. A.; Glorius, F.; Husfeld, C. O.; Langkopf, E.; Love, J. A. J. Am. Chem. Soc. 1999, 121, 5348-5349.
Substrate Controlled Diastereoselectivity
Wender, P. A.; Glorius, F.; Husfeld, C. O.; Langkopf, E.; Love, J. A. J. Am. Chem. Soc. 1999, 121, 5348-5349.
Substrate Controlled Diastereoselectivity
Rhodium inserts on opposite face of
bulky t-Bu
Determining the Selectivity of [5+2] Cycloadditions with VCP
π-Bond Insertion Controls:1. Regioselectivity2. Diastereoselectivity
Determining the Selectivity of [5+2] Cycloadditions with VCP
Cyclopropane Cleavage Controls:1. Regioselectivity
Distal
Proximal
Regioselectivity in Cyclopropane Ring Opening
Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Kadereit, D.; Love, J. A.; Rieck, H. J. Am. Chem. Soc 1999, 121, 10042-10043.
Wender, P. A.; Dyckman, A. J. Org. Lett. 1999, 1, 2089-2092.
Regioselectivity in Cyclopropane Ring Opening
Favored with EWG
Favored with Rcis
substituents
Trost, B. M.; Toste, F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122, 2379-2380.
Trost, B. M.; Shen, H. Org. Lett. 2000, 2, 2523-2525.
Distal
Proximal
cis 1,2-disubstituted VCPs
Trost, B. M.; Shen, H. Org. Lett. 2000, 2, 2523-2525.
Wender, P. A.; Dyckman, A. J. Org. Lett. 1999, 1, 2089-2092.
Product RhI catalyst Time YieldRatio
Distal:Proximal
Rcis = CH2OTBS
[Rh(CO) 2Cl]2 1 h 93% 1:0
Rh(PPh3)3Cl/AgOTf 2 h 96% 1:0
Rcis = CH2OTIPS
[CpRu(CH3CN)3]PF6 2 h 85% >20:1
Rcis = CO2Me
[Rh(CO) 2Cl]2 2 h 98% 1.5:1
Rh(PPh3)3Cl/AgOTf 2 h 95% 6.4:1
[CpRu(CH3CN)3]PF6 2 h 90% >20:1
Rcis = COH
[Rh(CO) 2Cl]2 55 °C, 15 h 92% 0:1
[CpRu(CH3CN)3]PF6 0.5 h 83%100%
Epi-Proximal
Distal
Proximal
Aldehyde Isomerization
Trost, B. M.; Toste, F. D.; Shen, H. J. Am. Chem. Soc. 2000, 122, 2379-2380.
Trost, B. M.; Shen, H. Org. Lett. 2000, 2, 2523-2525.
Product RhI catalyst Time YieldRatio
Distal:Proximal
Rtrans = CH2OTBS
[Rh(CO) 2Cl]2 1 h 85% 2.5:1
Rh(PPh3)3Cl/AgOTf 1 h 92% 1:0
Rtrans = CH2OTIPS
[CpRu(CH3CN)3]PF6 2 h 81% 3:1
trans 1,2-disubstituted VCPs
Trost, B. M.; Shen, H. Org. Lett. 2000, 2, 2523-2525.
Wender, P. A.; Dyckman, A. J. Org. Lett. 1999, 1, 2089-2092.
Rtrans = CO2Me
[Rh(CO) 2Cl]2 1 h 93% 1:11
Rh(PPh3)3Cl/AgOTf 1 h 81% 20:1
[CpRu(CH3CN)3]PF6 2 h 90% 1:2
Rtrans = COH
[Rh(CO) 2Cl]2 55 °C, 8 h 98% 0:1
[CpRu(CH3CN)3]PF6 0.5 h 83% 1:12
Distal
Proximal
Ashfeld, B. A.; Martin, S. F. Org Lett. 2005, 7, 4535-4537.
Ashfeld, B. A.; Martin, S. F. Tetrahedron. 2006, 62, 10497-10506.
Enantioselective Total Synthesis of Tremulenediol A and Tremulenolide A
Ashfeld, B. A.; Martin, S. F. Org Lett. 2005, 7, 4535-4537.
Ashfeld, B. A.; Martin, S. F. Tetrahedron. 2006, 62, 10497-10506.
Enantioselective Total Synthesis of Tremulenediol A and Tremulenolide A
Application of [5+2] cycloaddition with VCP
[5+2]
Retrosynthetic Analysis
Proximal
Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007, 129, 11781-11790.
Towards the Synthesis of (+)-Frondosin A
Towards the Synthesis of (+)-Frondosin A
Application of [5+2] cycloaddition with VCP
[5+2]
Retrosynthetic Analysis
Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007, 129, 11781-11790.
Distal
Determining the Selectivity of [5+2] Cycloadditions with VCP
Cyclopropane Cleavage Controls:1. Regioselectivity
Determining the Selectivity of [5+2] Cycloadditions with VCP
Reductive Elimination Controls:1. Periselectivity
Expanding the Scope of Cycloadditions with VCPs
Expanding the Scope of Cycloadditions with VCPs
Expanding the Scope of Cycloadditions with VCPs
Selection Between [(5+2)+1] and [5+2]
Wender, P. A.; Gamber, G. G; Hubbard. R. D.; Zhang, L. J. Am. Chem. Soc. 2002, 124, 2876-2877.
[(5+2)+1]
[5+2]
Rh Catalyzed [(5+2)+1] Cycloadditonswith VCPs
Wender, P. A.; Gamber, G. G; Hubbard. R. D.; Zhang, L. J. Am. Chem. Soc. 2002, 124, 2876-2877.
Wegner, H. A.; de Meijere, A.; Wender, P. A. J. Am. Chem. Soc. 2005, 127, 6530-6531.
[(5+2)+1] Products
48%
8%
0.0
Free Energy (kcal/mol)
ΔG‡ = 29.3
ΔG‡ = 20.0
ΔG‡ = 14.5
Developing π-Rh coordination facilitates reductive elimination
Selectively Achieving [(5+2)+1] Cycloadditions: Insight into Alkenes
*B3LYP/SDD-6-31G*/LANL2DZ+ECP computational analysis
Adapted from: Yu, Z.-X.; Cheong, P. H.-Y.; Liu, P.; Legault, C. Y.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 2378-2379.
Ethylene
AcetyleneAllene
Preferential [(5+2)+1] Cycloadditions with Alkenes
Wang, Y.; Wang, J.; Su, J.; Hang, F.; Jiao, L.; Liang, Y.; Yang, D.; Zhang, S.; Wender, P. A.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 10060-10061.
sp3-sp3 RE
sp2-sp3 RE
[(5+2)+1]
[5+2]
More Favorable Reductive Elimination for [(5+2)+1]
Jiao, L.; Yuan, C. Yu, Z.-X. J. Am. Chem. Soc. 2008, 130, 4421-4430.
Total Synthesis of (±)-hirsutene and (±)-1-desoxyhypnophilin
Jiao, L.; Yuan, C. Yu, Z.-X. J. Am. Chem. Soc. 2008, 130, 4421-4430.
Total Synthesis of (±)-hirsutene and (±)-1-desoxyhypnophilin
Application of [5+2] cycloaddition with VCP
Retrosynthetic Analysis
[(5+2)+1]
Fan, X.; Zhuo, L.-G.; Tu. Y. Q. Yu, Z.-X.; Tetrahedron. 2009, 65, 4709-4713.
Divergent Total Synthesis using [(5+2)+1] Cycloadditions
[(5+2)+1]
Wender, P. A.; Bi, F. C.; Brondey, M. A.; Gosselin, F. Org Lett. 2001, 3, 2105-2108.
Total Synthesis of Cyanthane Core
[5+2]
[5+2] Cycloadditions with VCPs
Future Directions: Towards a Homologous Diels-Alder
• Delve deeper into the mechanism of [5+2] cycloadditions• To distinguish between metallacyclopentene
and metallacyclohexene pathway• To understand the role of metal, ligands, and
molecularity
• Expand the scope of the reaction to include:• Hetero-π components• Epoxides and Aziridines
Acknowledgments
Prof. Denmark
CHEM 535
Prof. Burke
The Burke Group