Cyclopropenes

An Accessible Precursor to Enantioenriched Compounds

Lucie ZimmerLiterature Meeting December 1st 2009

Cyclopropenes: Naturally Occuring Products

1-MethylcyclopropeneUsed as synthetic plant growth regulator

O

OH

O

Alutaceonic acid BAntithrombotic

OH

O

Malvalic acidFound in cottonseed oil

Me H

H H

Me

Me

iPrMe

HO

(23R)-23H-isocalysterol

Cyclopropenes: Biologically Active Compounds

Cyclopropenes: Caracteristics

27.5 kcalmol-1 53.7 kcalmol-1

π caracter of the 3-membered ring

Cyclopropenes: Caracteristics

27.5 kcalmol-1 53.7 kcalmol-1

+π caracter of the double bond

=very reactive especially towards πphilic transition metals

π caracter of the 3-membered ring

1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses

2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes

3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn

4. Metathesis

Summary

1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses

2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes

3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn

4. Metathesis

Summary

Cyclopropenes: Large Scale Synthesis

1.1.1 From cyclopropanes

Bolesov’s method revisited by Rubin, M.; Gevorgyan, V. Synthesis 2004, 2004, 796-800.

52g

Cyclopropenes: Large Scale Synthesis

1.1.2 From Alkynes

Rubin, M.; Gevorgyan, V. Synthesis 2004, 2004, 796-800.

•No conversion was observed using 6 and 7 in presence of Rh2(OAc)4

•10 and 12 are obtained in a 10:1 ratio

•12 untouched during the deprotection of 10

Cyclopropenes: Enantioselective Synthesis

1.2.1 Kinetic resolution

Breslow, R.; Douek, M. J. Am. Chem. Soc. 1968, 90, 2698-2699.

HPh

p-MeOPh

COOHH

Ph

p-MeOPh

PhOcinchonine

PhLi

enantioenriched

Liao, L.-a.; Zhang, F.; Dmitrenko, O.; Bach, R. D.; Fox, J. M. J. Am. Chem. Soc. 2004, 126, 4490-4491.

Ph

COOHPh

1) 1- adamantoyl chloride2)

(1.0 equiv) THF, -98°C

(1.0 equiv.)3) TBAF

O

NOLi

O

NOLi

OTBS

Ph

Ph

Ph

PhO

N

O

NO O

OO

HO

91% yielddr >99.5:0.5

87% yielddr >99:1

Cyclopropenes: Enantioselective Synthesis

N

Rh

COOMe

Rh

4

[Rh2(5R-mepy)4]

HN2CHCOOR'

Rh2(5R-MEPY)4

DCM

COOtBuH

H

COOd-MenthylH

H

COOd-MenthylH

H

COOEtH

H

MeO MeO

MeO

69% ee 78% ee

98% de

yield 43%-73%

43% de

MeO

OMe

1.2.2 First enantioselective synthesis

Significance of the diazoSignificance of the polarity of the diazo(e.g. hexyne, dimethylbutyne)

OEt

OEtN2CHCOOMe

OEtEtO

COOMeH

[Rh2(5S-mepy)4]2 mol%

CH2Cl2, rt

85%90% ee

Protopopova, M. N.; Doyle, M. P.; Müller, P.; Ene, D. J. Am. Chem. Soc. 1992, 114, 2755-2757.Imogaï, H.; Bernardinelli, G.; Gränicher, C.; Moran, M.; Rossier, J.-C.; Müller, P. Helv. Chim. Acta 1998, 81, 1754-1764.

Cyclopropenes: Enantioselective Synthesis

RN2CHCOOEt

R

COOEtH

[Rh2(OAc)(dpti)3]0.5 mol%

CH2Cl2, rt

R = Pent, 90%, 95%eeR = tBu, 81%, 92%eeR = CH2OBn, 86%, 92%eeR = CH2Br, 62%, 95%eeR = CH2OCH2CH=CHC6H5, 76%, 95%ee

Lou, Y.; Horikawa, M.; Kloster, R. A.; Hawryluk, N. A.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8916-8918.Lou, Y.; Remarchuk, T. P.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 14223-14230.

Cyclopropenes: Enantioselective Synthesis

Quaternary center formation

Davies, H. M. L.; Lee, G. H. Org. Lett. 2004, 6, 1233-1236.

R

R

COOMePh

[Rh2(S-dosp)4]1 mol%

hexane, rt

R = Ph, 62%, 90%eeR = Bu, 54%, 84%ee

Ph COOMe

N2

N

SO2C6H4R

O

O

Rh

Rh

H

R = C12H25

4

[Rh2(S-dosp)4]

R1

R3R2

R4

R3R2

R1

R3R2

Cyclopropenes: Enantioselective Synthesis

Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46, 7364-7376.

R1

R3R2

R4

R3R2

R1

R3R2

Cyclopropenes: Large Scale Synthesis

6

N O

O Rh

Rh

SO2Ar

Ar = p-tBuCH6H4

N

O

N

O

tBu tBu

1

N Rh

O Rh

COOMe4

2a

NH

COOiBu

Rh

O Rh

5

Cyclopropanation vs Cyclopropenation

Doyle, M. P.; Ene, D. G.; Peterson, C. S.; Lynch, V. Angew. Chem., Int. Ed. 1999, 38, 700-702.

1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses

2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes

3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn

4. Metathesis

Summary

Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117-3179.

Pr

HOMgCl

Et2O, rt

HO

Pr

67%

H. G. Richey, Jr., R. M. Bension, J. Org. Chem. 1980, 45, 5036.Nakamura, M.; Isobe, H.; Nakamura, E. Chem. Rev. 2003, 103, 1295-1326.Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2002, 124, 11566-11567.Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125, 7198-7199.Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2004, 126, 3688-3689.

• hydrostannylation• silastannylation• stannastanylation• hydroboration• carbocupration• hydrogenation...

Cyclopropenes: Carbometallation

Diastereo- and Enantioselective:

Key metalsRhPd

Cyclopropenes: Carbometallation

Liao, L.-a.; Fox, J. M. J. Am. Chem. Soc. 2002, 124, 14322-14323.

Cyclopropenes: Enantioselective Synthesis

Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, 5600-5601.

Cyclopropenes: Enantioselective Synthesis

Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, 5600-5601.

MeMgCl sparged with air can be replaced by MeOH (1 équiv.)

Good yields

Excellent ees

1,2- and 1,2,3-trisubstitued cyclopropanes

Cyclopropenes: Enantioselective Synthesis

Liu, X.; Fox, J. M. J. Am. Chem. Soc. 2006, 128, 5600-5601.

But only MethylGrignard lead to good enantioselectivities...

Cyclopropenes: Carbometallation

Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 5382-5383.

Cyclopropenes: Carbometallation

Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 5382-5383.

Cyclopropenes: Enantio- Synthesis of Cyclopropanes

Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, 13804-13809.

Entry R1 R2 R3 Yield dr (2:3)

1 Ph Me H 87 11:1

2 p-Cl-C6H4 Me H 71* 8:1

3 p-F-C6H4 Me H 91* 12:1

4 Ph CH2OMOM H 72 10:1

5 Ph CH2OAc H 75* 7:1

6 Ph COOMe H 90 1:1

7 COOMe Me H 64 24:1

8 CMe2OBn Me H 91 2 only

9 Ph Me Me 80* 7:1

R3

R2R1 Rh(CO)2acac

dppf (P*:Rh = 2:1)

H2/CO 1:1, 150 psi60 °C, PhMe

R2R1

R2R1

CHO CHO

R3R3

21 3

Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, 13804-13809.

Cyclopropenes: Enantio- Synthesis of Cyclopropanes

Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, 13804-13809.

Cyclopropenes: Enantio- Synthesis of Cyclopropanes

Sherrill, W. M.; Rubin, M. J. Am. Chem. Soc. 2008, 130, 13804-13809.

Cyclopropenes: Enantio- Synthesis of Cyclopropanes

1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses

2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes

3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn

4. Metathesis

Summary

3.1 Diels-Alder

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Cortistatin A

Magnus, P.; Littich, R. Org. Lett. 2009, 11, 3938-3941.

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Endo kinetic preference seems to be eroded by the extremely exothermic relief

of the cyclopropenyl ring strain in the transition state

of the Diels Alder.

LaRochelle, R. W.; Trost, B. M.; Krepski, L. J. Org. Chem. 1971, 36, 1126–1136.Al Dulayymi, A. R.; Al Dulayymi, J. R.; Baird, M. S. Tetrahedron, 2000, 56, 1115–1125.Van Royen, L. A.; Mijngheer, R.; De Clercq, P. J. Tetrahedron 1985, 41, 4667–4680.

Magnus, P.; Littich, R. Org. Lett. 2009, 11, 3938-3941.

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Magnus, P.; Littich, R. Org. Lett. 2009, 11, 3938-3941.

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

3.2 Cycloaddition (3+2)

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

DeAngelis, A.; Taylor, M. T.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 1101-1105.

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

DeAngelis, A.; Taylor, M. T.; Fox, J. M. J. Am. Chem. Soc. 2009, 131, 1101-1105.

3.3 Pauson-Kahn

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Pallerla, M. K.; Fox, J. M. Org. Lett. 2005, 7, 3593-3595.

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Pallerla, M. K.; Fox, J. M. Org. Lett. 2005, 7, 3593-3595.

Pallerla, M. K.; Yap, G. P. A.; Fox, J. M. J. Org. Chem. 2008, 73, 6137-6141.

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Total Synthesis of (–)-pentalene

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

Cyclopropenes: Enantio-Synthesis of Cyclic Compounds

1. Syntheses of cyclopropenes 1.1 “Racemic” syntheses 1.2 “Enantioselective” syntheses

2. Carbometallation 2.1 From enantioenriched cyclopropenes 2.2 From racemic cyclopropenes

3. Cycloadditions 3.1 Diels-Alder 3.2 (3+2) 3.3 Pauson-Kahn

4. Metathesis

Summary

Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds

Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2007, 129, 3824-3825.

Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877-6882.

Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds

Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds

Van Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 6877-6882.

Hoveyda, A. H.; Lombardi, P. J.; O'Brien, R. V.; Zhugralin, A. R. J. Am. Chem. Soc. 2009, 131, 8378-8379.

Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds

Hoveyda, A. H.; Lombardi, P. J.; O'Brien, R. V.; Zhugralin, A. R. J. Am. Chem. Soc. 2009, 131, 8378-8379.

Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds

Cyclopropenes: Enantio- Synthesis of Aliphatic Compounds

Conclusion

Pro-chiral and enantioenrichied cyclopropenes are easily accessible.

Cyclopropenes are pretty stable reactive intermediates.

They react by their intracyclic double bond.

They can be used for the formation of cyclopropanes, engaged in various cycloaddition reactions as well as ring opening strategies.

Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117-3179.

methylene and alhylidene derivatives

Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117-3179.Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem., Int. Ed. 2007, 46, 7364-7376.