Cyclopropenes An Accessible Precursor to Enantioenriched Compounds

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

Cyclopropenes: Large Scale Synthesis

1.1.1 From cyclopropanes

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

52g


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


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.


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.


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


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

R1

R3R2

R4

R3R2

R1

R3R2


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.




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


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


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



But only MethylGrignard lead to good enantioselectivities...


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




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.



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.


3.2 Cycloaddition (3+2)



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

3.3 Pauson-Kahn



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


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.


Total Synthesis of (–)-pentalene




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.


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.


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.

Cyclopropenes An Accessible Precursor to Enantioenriched Compounds

Documents

Transcript of Cyclopropenes An Accessible Precursor to Enantioenriched Compounds