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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
3
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.
9
Diels-Alder with prochiral diene
10
Synthesis of norzoanthamine
Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science, 2004, 305, 495-499.
11
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.
12
CARBON ELECTROPHILES
WITH CARBON NUCLEOPHILES
13
Carbon nucleophiles and carbon electrophiles
14
Examples of prochiral nucleophiles Examples of prochiral electrophiles
+ others
15
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..
16
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.
17
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.
18
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.
19
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
20
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.
21
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.
23
SN2’ catalyzed by copper : mechanism
Perrone, S. PhD dissertation, 2006. Sofia, A.; Karlström, E.; Bäckvall, J.E. Chem. Eur. J. 2001, 7, 1981-1989.
24
SN2’: synthesis of (-)-sporochnol
Luchaco, C.A.L.; Mizutani, H.; Murphy, K.E.; Hoveyda, A.H. Angew. Chem. Int. Ed. 2001, 40, 1456-1460.
25
OTHER TRANSITION METAL-
CATALYZED REACTIONS
26
Heck reaction
27
Synthesis of furaquinocin E
Trost, B.M.; Thiel, O.R.; Tsui, H-C. J. Am. Chem. Soc. 2003, 125, 13155-13164.
28
Synthesis of spirotryprostatine B
Overman, L.E.; Rosen, M.D. Angew. Chem. Int. Ed. 2000, 39, 4596-4599..
29
Other transition metalcatalyzed reactions
30
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
31
Pauson-Khand reaction : synthesis of magellanine
Ishizaki, M.; Niimi, Y.; Hoshino, O.; Hara, H.; Takahashi, T. Tetrahedron, 2001, 61, 4053-4065.
32
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
33
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.
34
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.
36
SELF-IMMOLATIVE
REACTIONS
37
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
38
Self-immolative reactions
39
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.
40
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.
41
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.
42
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.
43
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 :
45
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
47
Self-immolative reactions
48
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
52
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
53
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.
54
OTHER POSSIBILITIES
55
Not discussed today
56
Conclusion
57
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.
58
Thanks for your attention
59