Download Stereochemistry: Atropisomers

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Stereochemistry: Atropisomers!
Friday Problem Set!
October 07, 2011!
Kyu Ok Jeon!
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!
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Nomenclature for assigning atropisomers!
counterclockwise : M (minus)
clockwise : P (plus)!
BINOL!
Bringmann, G.; Mortimer, P. A. J.; Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem. Int. Ed. 2005,
44, 5384–5427.!
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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.!
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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.!
Gossypol: biosynthesis!
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hemigossypol!
(S)-gossypol!
(S)-gossypol formation from hemigossypol
yield
crude dirigent protein
boiled crude dirigent protein
Laccase, O2
Laccase, O2
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%ee
56%
0-1%
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.!
Gossypol: chemical synthesis!
Meyers, A. I.; Willemsen. J. J. Tetrahedron 1998, 54,10493–10511.!
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Stobbe condensation!
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Gossypol: chemical synthesis!
TS-I (favored)!
Meyers, A. I.; Willemsen. J. J. Tetrahedron 1998, 54, 10493–10511.!
TS-II (disfavored)!
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Gossypol: chemical synthesis!
Meyers, A. I.; Willemsen. J. J. Tetrahedron 1998, 54, 10493–10511.!
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Knipholone !
Atropoenantioselective
cleavage!
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.!
Intramolecular
biaryl coupling!
Retrosynthetic analysis!
Bringmann, G.; Menche, D. Angew. Chem. Int. Ed. 2001, 40, 1687–1690.!
Synthesis of the anthraquinone building block!
Bringmann, G.; Menche, D. Angew. Chem. Int. Ed. 2001, 40, 1687–1690.!
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Synthesis of the anthraquinone building block!
Bringmann, G.; Menche, D. Angew. Chem. Int. Ed. 2001, 40, 1687–1690.!
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Atropo-enantioselective coupling!
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AlBr3 (5 eq)!
chlorobenzene!
80 ｰC, 2 h, 41%.!
Corey-Bakshi-Shibata (CBS) Reagent!
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.!
Mechanism!
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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.!
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Answer !
Nishii, Y.; Wakasugi, K.; Koga, K.; Tanabe, Y. J. Am. Chem. Soc. 2004, 126, 5358–5359.!
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.!
Ullmann Coupling!
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