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Grob Fr agmentations
Dan Tao
Overman Group Meeting
9/24/12
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Electrofugal Fragment
What is a Grob Fragmentation?
• Heterolytic fragmentation is certain combinations of carbon
and hetero atoms which undergo a regulated cleavage into three
fragments.
Unsaturated Fragment
Nucleofugal Fragment
• Heteroatoms seen in the Grob Fragmentation include halogens,
B, O, N, S, and P.
Grob, C. A. Angew. Chem., Int. Ed. 1969, 8, 535.
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Initial Discoveries
Eschenmoser, A.; Frey, A. Helv. Chim. Acta 1952, 35, 1660. Grob,
C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594.
Eschenmoser (1952)
Grob (1955)
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Mechanism and Side Reactions • Grob fragmentations can proceed
in either stepwise or concerted pathways, though the concerted
pathway is typically preferred.
Prantz, K.; Mulzer, J. Chem. Rev. 2010, 110, 3741. Kato, M.;
Tooyama, Y.; Yoshikoshi, A. Bull. Chem. Soc. Jpn. 1991, 64, 50.
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Effects of Nucleophiles/Bases
Prantz, K.; Mulzer, J. Chem. Rev. 2010, 110, 3741.
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Stereoelectronic Requirements
• For concerted Grob fragmentations, the centers must have
anti-periplanar alignment for donation into antibonding
orbitals
Bottini, A. T.; Grob, C. A.; Schumacher, E.; Zergeny, J. Helv.
Chim. Acta 1966, 49, 2516. Wharton, P. S.; Hiegel, G. A. Angew.
Chem. Int. Ed. 1969, 8, 535.
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Application in Synthesis: Ring
Fragmentation
Zurflueh, R.; Wall, E. N.; Siddall, J. B.; Edwards, J. A. J. Am.
Chem. Soc. 1968, 90, 6224. Peng, X.-S.; Wong, H. N. Chem. Asian J.
2006, 12, 111.
• Transformation of 1,3-alkyl substitution into carbonyl and
alkene
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Application in Synthesis: Ring
Expansion
Larionov, O. V.; Corey, E. J. J. Am. Chem. Soc. 2008, 130,
2954.
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Application in Synthesis: Ring
Expansion
Zhang, W.; Dowd, P. Tetrahedron Lett. 1996, 37, 957. Thorton, P.
D.; Burnell, D. J. Org. Lett. 2006, 8, 3195.
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Application in Synthesis: Ring
Expansion
Yoshimitsu, T.; Yanagiya, M.; Nagaoka, H. Tetrahedron Lett.
1999, 40, 5215. Maimone, T. J.; Shi, J.; Ashida, S.; Baran, P. S.
J. Am. Chem. Soc. 2009, 131, 17066.
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Grob-type Fragmentation Variations
• The Eschenmoser–Tanabe Fragmentation (Fragmentation into
alkynes)
Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967,
50, 708. Kamijo, S.; Dudley, G. B. J. Am. Chem. Soc. 2005, 127,
5028.
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Grob-type Fragmentation Variations • Fragmentation into
allenes
Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2010, 49, 8962.
Mori, M.; Kimura, M.; Tanaka, S.; Tamaru, Y. Chem. Commun. 2006,
41, 4303. Kimura, M.; Masahiko, M.; Tamaru, Y. Chem. Commun. 2007,
43, 4504.
• Transition metal-promoted fragmentation
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Enzymatic Catalysis • Oxidosqualene cyclase (OSC) catalyzes Grob
fragmentations of triterpene skeletons
Shibuya, M.; et al. J. Am. Chem. Soc. 2007, 129, 1450. Hoshino,
T.; Sato, T. Chem. Commun. 2002, 291.
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Syn Grob Fragmentations
• Suprisingly, the endo epoxide is favored to undergo Grob
fragmentation over the exo epoxide with anti-alignment
Holton, R. A.; Kennedy, R. M. Tetrahedron Lett. 1984, 25,
4455.
• The authors suggest that “the C1-C2 bond and the C6-O are more
nearly coplanar” in the endo epoxides
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SET-Induced Grob Fragmentations
• Some SET processes are able to undergo fragmentation in both
the syn and anti configurations
Hamura, T.; Suzuki, T.; Matsumoto, T.; Suzuki, K. Angew. Chem.,
Int. Ed. 2006, 45, 6294. Wender, P. A.; Manly, C. J. J. Am. Chem.
Soc. 1990, 112, 8579.
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Other Interesting Examples • Decarboxylative Double
Fragmentation
Sternbach, D.; Jaisli, F.; Bonetti, M.; Eschenmoser, A.;
Shibuya, M. Angew. Chem., Int. Ed. 1979, 18, 634. Kabalka, G. W.;
Li, N. –S. Tejedor, D.; Malladi, R. R.; Trotman, S. J. Org. Chem.
1999, 64, 3157. Yuan, D.-Y.; Tu, Y.-Q.; Fan, C.-A. J. Org. Chem.
2008, 73, 7797.
• Tandem Aldol/Grob Fragmentation
• Tandem Semipinacol Rearrangement/Grob Fragmentation
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Summary
• The Grob fragmentation is a useful reaction in synthesis -in
obtaining functional handles from alkyl 1,3-diol species -in
forming medium to large rings in steriocontrolled fashion •
Variations include use of transition metals, formation of alkynes
or
allenes, and radical-mediated processes
• The Grob fragmentation can be used in tandem with a variety of
other
processes such as the Aldol and Pinnacol reactions
