ASYMMETRIC SYNTHESIS OF

QUATERNARY CARBON CENTERS

Applied to total synthesis

Ioulia Gorokhovik – 02.05.2013

Introduction

• Synthesis of chiral quaternary centers : challenge in synthesis.

When the center is all-carbon, difficulty increased, steric hindrance.

• Many methods could be applied in theory, but in practice only a few are useful. Mostly developed the last 20-30 years

• Presented here :

Synthesis of quaternary centers with 4 non equivalent carbon substituents

general methods, a few examples applied to synthesis

Not presented : enzyme based reactions, use of chiral auxiliaries

2

Outline

1. Asymmetric Diels Alder reactions

2. Combination of carbon nucleophiles with carbon electrophiles

3. Transition metal-catalyzed reactions Heck reaction,

Enyne cyclization,

Pauson-Khand reaction

C-H activation

4. Chirality-transfer reactions Epoxide rearrangements

Cationic cyclizations

Oxy-Cope and Claisen rearrangements

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ASYMMETRIC DIELS-

ALDER REACTIONS

4

Examples of chiral Lewis acids developed

For references see : Corey, E.J.; Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37, 388-401.

5

Diels Alder with prochiral dienophile

6

Synthesis of colombiasin A

Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Angew. Chem. Int. Ed. 2001, 40, 2482-2486.

7

Synthesis of colombiasin A

Nicolaou, K. C.; Vassilikogiannakis, G.; Mägerlein, W.; Kranich, R. Angew. Chem. Int. Ed. 2001, 40, 2482-2486.

Suarez, D.; Sordo, T. L.; Sordo, J. A. J. Org. Chem. 1995, 60, 2848-2852

8

Synthesis of (-)-longithoroneA

Layton, M.E.; Morales, C.A.; Shair, M.D. J. Am. Chem. Soc. 2002, 124, 773-775.

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Diels-Alder with prochiral diene

10

Synthesis of norzoanthamine

Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science, 2004, 305, 495-499.

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Synthesis of mangicol A core

Araki, K.; Saito, K.; Arimoto, H.; Uemura, D. Angew. Chem. Int. Ed. 2004, 43, 81-84.

Exo compounds observed. Endo not

possible because of the ring.

DA outcome depends on stereochemistry of

C3.

Can be explained by energy differences of

the transition states.

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CARBON ELECTROPHILES

WITH CARBON NUCLEOPHILES

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Carbon nucleophiles and carbon electrophiles

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Examples of prochiral nucleophiles Examples of prochiral electrophiles

+ others

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Michael reaction : synthesis of the manzamine family

Jakubec, P.; Hawkins, A.; Felzmann, W.; Dixon, D.J. J. Am. Chem. Soc. 2012, 134, 17482-17485

Jakubec, P.; Cockfield, D.M.; Dixon, D.J. J. Am. Chem. Soc. 2009, 131, 16632-16633..

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Michael reaction : synthesis of (+)-gelsemine,

Fukuyama

Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 4073-4075.

Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42, 36-51.

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Mannich reaction : Studies on gelsemine, Fleming

Clarke, C.; Fleming, I.; Fortunak, J.M.D.; Gallather, P.T.; Honan, M.C.; Mann, A.; Nubling, C.O.; Raithby, P.R.; Wolff, J.J. Tetrahedron, 1988,

44, 3931. Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42, 36-51.

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Robinson annulation for the synthesis of ketones

Aldol reaction forming quaternary centers : very difficult -> solutions needed to favor it

One possibility : enamine catalysis with amino-acids

Hajos, Z.G.; Parrish, D.R. J. Org. Chem. 1974, 39, 1615-1621. Bahmanyar, S.; Houk, K.N. J. Am. Chem. Soc. 2001, 123, 12911-12912.

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MacMillan’s LUMO catalysis

Austin, J. F.; Kim, S.G.; Sinz, C.J.; Xiao, W-J.; MacMillan, D.W.C. Proc. Natl. Acad. Sci. USA, 2004, 101, 5482-5487.

Development of an organocatalyst

that mimics the Lewis acids commonly used

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Syntheses of (-)-flustramine B and diazonamide A

Austin, J. F.; Kim, S.G.; Sinz, C.J.; Xiao, W-J.; MacMillan, D.W.C. Proc. Natl. Acad. Sci. USA, 2004, 101, 5482-5487.

Knowles, R.R. ; Carpenter, J. ; Blakey, S.B. ; Kayano, A.; Mangion, I.K. ; Sinz, C.J.; MacMillan, D.W.C. Chem. Sci. 2011, 2, 308-311.

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Allylation reactions

Hong, A.Y.; Stoltz, B.M. Eur. J. Org. Chem. ASAP

22

Pd-catalyzed allylations : synthesis of (+)-allocyathin B2

Trost, B.M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, GM. J. Am. Chem. Soc. 2004, 126, 4480-481. Trost, B.M.; Dong, L.; Schroeder, G.M.

J. Am. Chem. Soc. 2005, 127, 2844-2845. Trost, B.M.; Dong, L.; Schroeder, G.M. J. Am. Chem. Soc. 2005, 127, 10259-10268.

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SN2’ catalyzed by copper : mechanism

Perrone, S. PhD dissertation, 2006. Sofia, A.; Karlström, E.; Bäckvall, J.E. Chem. Eur. J. 2001, 7, 1981-1989.

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SN2’: synthesis of (-)-sporochnol

Luchaco, C.A.L.; Mizutani, H.; Murphy, K.E.; Hoveyda, A.H. Angew. Chem. Int. Ed. 2001, 40, 1456-1460.

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OTHER TRANSITION METAL-

CATALYZED REACTIONS

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Heck reaction

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Synthesis of furaquinocin E

Trost, B.M.; Thiel, O.R.; Tsui, H-C. J. Am. Chem. Soc. 2003, 125, 13155-13164.

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Synthesis of spirotryprostatine B

Overman, L.E.; Rosen, M.D. Angew. Chem. Int. Ed. 2000, 39, 4596-4599..

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Other transition metalcatalyzed reactions

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Pauson-Khand reaction : synthesis of magellanine

Ishizaki, M.; Niimi, Y.; Hoshino, O.; Hara, H.; Takahashi, T. Tetrahedron, 2001, 61, 4053-4065.

Pauson-Khand : sensitive to steric factors in the transition state

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Pauson-Khand reaction : synthesis of magellanine

Ishizaki, M.; Niimi, Y.; Hoshino, O.; Hara, H.; Takahashi, T. Tetrahedron, 2001, 61, 4053-4065.

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C-H insertion with Rh carbenoid species

Advantages :

- Often the conditions are very mild

- Extremely tolerant of functional groups

- Low loadings of catalyst (1 mol%)

Electronic, steric and conformational effects

Direct C-H insertion

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Davies, H.M.L.; Manning, J.R. Nature, 2008, 451, 417-424. Davies, H.M.L.; Dick, A.R. Top. Curr. Chem. 2010, 292, 303-345.

Davies H.M.L. Angew. Chem. Int. Ed. 2006, 45, 6422-6425. Davies H:M:L:, Beckwith, R.E.J. Chem. Rev. 2003, 103, 2861-2903.

Synthesis of (+)-codeine and (+)-morphine

White, J.D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1997, 62, 5250-5251.

White, J.D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64, 7871-7884.

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Enyne cyclization: synthesis of (+)-allocyathin B2

Trost, B.M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, GM. J. Am. Chem. Soc. 2004, 126, 4480-481. Trost, B.M.; Dong, L.; Schroeder, G.M.

J. Am. Chem. Soc. 2005, 127, 2844-2845. Trost, B.M.; Dong, L.; Schroeder, G.M. J. Am. Chem. Soc. 2005, 127, 10259-10268.

35

Enyne cyclization: synthesis of (+)-allocyathin B2

Trost, B.M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, GM. J. Am. Chem. Soc. 2004, 126, 4480-481. Trost, B.M.; Dong, L.; Schroeder, G.M.

J. Am. Chem. Soc. 2005, 127, 2844-2845. Trost, B.M.; Dong, L.; Schroeder, G.M. J. Am. Chem. Soc. 2005, 127, 10259-10268.

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SELF-IMMOLATIVE

REACTIONS

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Self-immolative reactions

A chiral center is sacrified to form another chiral center

First center : created by enantioselective reaction

Second center : created by intramolecular enantiospecific reaction

Often : center bearing heteroatom is sacrificed to form a less readily established

All-carbon quaternary center

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Self-immolative reactions

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Suzuki-Tsuchihashi epoxide rearrangement

Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 5891-5894.

Eom, K.D.; Raman, J.V.; Kim, H.; Cha, J.K J. Am. Chem. Soc. 2003, 125, 5415-5421.

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Synthesis of furaquinocin D

Saito, T.; Suzuki, T.; Morimoto, M.; Akiyama, C.; Ochiai, T.; Takeuchi, K.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1998, 120, 11633-11644.

Suzuki-Tsuchihashi gives compounds that can’t be obtained with aldol reactions

Model studies were made to check the migration

of different substituents.

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Yamamoto epoxide rearrangement

Omodani, T.; Shishido, K. J. Chem. Soc. Chem. Commun. 1994, 2781-2782.

Maruoka, K.; Ooi, T.; Yamamoto, H. J. Am. Chem. Soc. 1989, 111, 6431-6432.

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Fukumoto epoxide rearrangement

Nemoto, H.; Nagamochi, M.; Ishibashi, H.; Fukumoto, K. J. Org. Chem. 1994, 59, 74-79.

Nemoto, H.; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J. Org. Chem. 1992, 57, 1707-1712.

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Jung epoxide rearrangement

Jung, M.E.; D’Amico, D.C. J. Am. Chem. Soc. 1995, 117, 7379-7388. Tonder, J.E.; Tanner, D. Tetrahedron, 2003, 59, 6937-6945.

44

Jung epoxide rearrangement : synthesis of lyngbyatoxine A

Jung, M.E.; D’Amico, D.C. J. Am. Chem. Soc. 1995, 117, 7379-7388. Tonder, J.E.; Tanner, D. Tetrahedron, 2003, 59, 6937-6945.

Solution :

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Self-immolative reactions

46

Cationic cyclization reactions : synthesis of aegiceradienol

Corey, E.J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-8874.

Formation of 3 quaternary carbon centers (and all the other asymmetric centers) in 1 step

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Self-immolative reactions

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Cope and Claisen rearrangements

Transfer of chirality from secondary alcohol to all-carbon quaternary center

Allylic alcohol center easily prepared

49

Oxy-Cope : synthesis of (+)-dihydromayurone

Lee, E.; Shin, I-J.; Kim, T-S. J. Am. Chem. Soc. 1990, 112, 260-264.

Chirality transfer very efficient because alkoxide favored in equatorial position during TS

(better overlapping of orbitals and steric reasons)

50

Ireland-Claisen : synthesis of pinnatoxin

Stivala, C.E.; Zakarian, A. J. Am. Chem. Soc. 2008, 130, 3774-3776..

51

Synthesis of gelsemine, Danishefsky

Ng, F.W.; Lin, H.; Danishefsky, S.J. J. Am. Chem. Soc. 2002, 124, 9812-9824.

Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42, 36-51.

Construction of the first quaternary center : Johnson-Claisen rearrangement

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Ng, F.W.; Lin, H.; Danishefsky, S.J. J. Am. Chem. Soc. 2002, 124, 9812-9824.

Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42, 36-51.

Construction of the second quaternary center : Eschenmoser-Claisen rearrangement

(after many other attempts)

This step : one of the most difficult of the synthesis (6 pages/13)

Synthesis of gelsemine, Danishefsky

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Other rearrangements : synthesis of (+)-gelsemine,

Fukuyama

Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 4073-4075.

Lin, H.; Danishefsky, S.J. Angew. Chem. Int. Ed. 2003, 42, 36-51.

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OTHER POSSIBILITIES

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Not discussed today

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Conclusion

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Good methods were developed – good yields and ees

Problem : find the precursor compatible with the synthesis and the structure of the target

Reviews and books on the topic

• Review : The catalytic enantioselective construction of molecules with quaternary carbon centers

Corey, E.J.; Guzman-Perez, A. Angew. Chem. Int. Ed. 1998, 37, 388-401.

• Review : Asymmetric creation of quaternary carbon centers, Fuji, K. Chem. Rev. 1993, 93, 2037-

2066.

• Review : Enantioselective construction of quaternary centers, Christoffers, J.; Mann, A. Angwe.

Chem. Int. Ed. 2001, 40, 4591-4597.

• Perspective : Catalytic asymmetric synthesis of all-carbon quaternary stereocenters, Douglas, C.J.;

Overman, L.E. Proc. Natl. Acad. Sci. USA 2004, 101, 5363-5367.

• Book : Quaternary stereocenters : challenges and solutions for organic synthesis Edited by

Christoffers, J.; Baro, A. 2005 WILEY-VCH Verlag GmbH&Co. KGaA, Weinheim.

• Review : Enantioselective synthesis of all-carbon quaternary stereogenic centers in acyclic systems

Das, J.P.; Marek, I. Chem. Commun. 2011, 47, 4593-4623.

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Thanks for your attention

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