Stereochemistry: Atropisomers - chem.ku.edu · Wolf, C. Dynamic Stereochemistry of Chiral...
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1 Stereochemistry: Atropisomers Friday Problem Set October 07, 2011 Kyu Ok Jeon
Transcript of Stereochemistry: Atropisomers - chem.ku.edu · Wolf, C. Dynamic Stereochemistry of Chiral...
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Stereochemistry: Atropisomers!
Friday Problem Set!
October 07, 2011 !Kyu Ok Jeon!
2 Atropisomers!
Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers (from Greek, a = not and tropos = turn). !
The name was introduced by Kuhn in 1933, but atropisomerism was first detected in 6,6’-dinitro-2,2’-diphenic acid by Cristie in 1922.!
Atropisomers are detectable by NMR if half lives exceed 10-2 sec.!
Atropisomers are isolatable if the half-life is above 1000 sec.!
Wolf, C. Dynamic Stereochemistry of Chiral Compounds:Principles and Applications 2008!
3 Nomenclature for assigning atropisomers!
Bringmann, G.; Mortimer, P. A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384–5427.!
counterclockwise : M (minus)clockwise : P (plus)!
BINOL!
4 Selected examples of naturally occurring axiallyl chiral biaryl compounds!
Bringmann, G.; Mortimer, P. A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005, 44, 5384–5427.!
5 Gossypol!
(S)-gossypol! (R)-gossypol!
In 1886, J. Longmore isolated the main pigment of cotton seeds. (R)-gossypol is more toxic and exhibits significantly greater anticancer activity than the (S)-atropisomer. Most commercial Upland (Gossypium hirsutum) cottonseeds have an (R)- to (S)-gossypol ratio of ~2:3, but some Pima (Gossypium barbadense) seeds have an excess of (R)-gossypol !
Stipanovic, R. D.; Puckhaber, L. S.; Liu, J.; Bell, A. A. J. Agric. Food Chem. 2009, 57, 566–571.!
6 Gossypol: biosynthesis!
hemigossypol!
(S)-gossypol!
Dirigent protein is a protein which dictates the stereochemistry of a compound synthesized by other enzymes.Laccases are copper-containing oxidase enzymes that are found in many plants, fungi, and microorganisms. !
Liu, J. et al. Phytochemistry 2008, 69, 3038–3042. Halls, S. C. et al. Biochemistry 2004, 43, 2587–2595.!
(S)-gossypol formation from hemigossypol yield %ee crude dirigent protein Laccase, O2 22 56% boiled crude dirigent protein Laccase, O2 20 0-1%
7 Gossypol: chemical synthesis!
Meyers, A. I.; Willemsen. J. J. Tetrahedron 1998, 54,10493–10511.!
8 Stobbe condensation!
9 Gossypol: chemical synthesis!
Meyers, A. I.; Willemsen. J. J. Tetrahedron 1998, 54, 10493–10511.!
TS-I (favored)! TS-II (disfavored)!
10 Gossypol: chemical synthesis!
Meyers, A. I.; Willemsen. J. J. Tetrahedron 1998, 54, 10493–10511.!
11 Knipholone !
First isolated in 1984 from African plant species of the genera Bulbine, Bulbinella, and Kniphofia, which are widely used in folk medicine.Antimalarial activity.!Only recently the axial configuration of knipholone has been determined to be M, by quantum chemical CD calculations.!
Retrosynthetic analysis!
Bringmann, G.; Menche, D. Angew. Chem. Int. Ed. 2001, 40, 1687–1690.!
Intramolecular biaryl coupling!
Atropo-enantioselective
cleavage!
12 Synthesis of the anthraquinone building block!
Bringmann, G.; Menche, D. Angew. Chem. Int. Ed. 2001, 40, 1687–1690.!
13 Synthesis of the anthraquinone building block!
Bringmann, G.; Menche, D. Angew. Chem. Int. Ed. 2001, 40, 1687–1690.!
14 Atropo-enantioselective coupling!
AlBr3 (5 eq)!chlorobenzene!80 ｰC, 2 h, 41%.!
15 Corey-Bakshi-Shibata (CBS) Reagent!
Mechanism!
The CBS reagent is a chiral catalyst derived from proline.Also known as Corey’s oxazaborolidine, it is used in enantionselective borane reduction of ketones, asymmetric Diels-Alder reactions and [3+2] cycloadditions.!
16 Chirality exchange from sp3 central chirality to axial chirality !
Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126, 5358–5359.!
17 Answer !
Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126, 5358–5359.!
18 EVL•HMPA!
EVL•HMPA (ethoxyvinyllithium•HMPA complex)!
Shimano, M.; Meyers, A. I. Tetrahedron Lett. 1997, 38, 5415-5418.!
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Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126, 5358–5359.!
20 Ullmann Coupling!
