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