Edge Article
Chemical Science
1–299; (c) O. A. Wong and Y. Shi, Chem. Rev., 2008, 108,
3958–3987.
Conclusions
2 (a) M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Kebeler,
In this study, we have probed the mechanistic basis of a
peptide-based catalyst that is quite effective for the asymmetric
epoxidation of certain types of allylic alcohols. The origin of the
catalyst for these reactions was a combinatorial study that was
minimally biased in terms of the nature of the peptide
sequences that were originally introduced into the library. Of
note, when peptides of shorter sequences were employed,
particular drops in efficiency were observed – suggesting that
essentially every piece of catalyst 6 contributes to its interesting
performance.
On the other hand, examination of other substrates revealed
that the substrate of the screen – farnesol – was not the “best”
substrate for peptide catalyst 6. Some Z-congured allylic alco-
hols provide a higher level of enantioselectivity when subjected
to oxidation with catalyst 6. It seems appropriate to wonder
about the result of performing the entire combinatorial
screening study anew, with Z-allylic alcohols as the test
substrate. Would catalysts like 6 emerge as the best ones? Or
could we design new catalysts for alternative substrates based
on our mechanistic studies?
¨
R. Sturmer and T. Zelinski, Angew. Chem., Int. Ed., 2004, 43,
788–824; (b) N. Xi, L. B. Alemany and M. A. Ciufolini, J. Am.
Chem. Soc., 1998, 120, 80–86; (c) H. K. Chenault, J. Dahmer
and G. M. Whitesides, J. Am. Chem. Soc., 1989, 111, 6354–
6364.
3 (a) W. Zhang and H. Yamamoto, J. Am. Chem. Soc., 2007, 129,
286–287; (b) L. Zhi, Z. Wei and H. Yamamoto, Angew. Chem.,
Int. Ed., 2008, 47, 7520–7522; (c) J. L. Olivares-Romero, L. Zhi
and H. Yamamoto, J. Am. Chem. Soc., 2013, 135, 3411–3413;
(d) Z. Li and H. Yamamoto, J. Am. Chem. Soc., 2010, 132,
7878–7880.
4 (a) Y. Zhu, Q. Wang, R. G. Cornwall and Y. Shi, Chem. Rev.,
2014, DOI: 10.1021/cr500064w; (b) R. L. Davis, J. Still,
T. Naicker, H. Jiang and K. A. Jorgensen, Angew. Chem., Int.
Ed., 2014, 53, DOI: 10.1002/anie.201400241, in press.
5 H. B. Henbest and R. A. L. Wilson, J. Chem. Soc., 1957, 1958–
1965.
6 H. Tian, X. She, L. Shu, Y. Hongwu and Y. Shi, J. Am. Chem.
Rev., 2000, 122, 11551–11552.
7 (a) S. N. Julia, J. Masana and J. C. Vega, Angew. Chem., Int. Ed.,
1980, 19, 929–931; (b) S. Julia, J. Guizer, J. Masana, J. Rocas,
S. Colonna, R. Annuziata and H. Molinan, J. Chem. Soc.,
Perkin Trans. 1, 1982, 1317–1324.
An analysis of the solution structures that may be populated
by peptide 6 offers perspectives that are only partially guiding.
We are able to signicantly limit the eld of possible catalyst
conformations through our studies. Plausible loci of interactions
between catalyst and substrate may be proposed. At the same
time, kinetic experiments show unambiguously that catalyst 6
operates through a mechanism dened by a specic rate accel-
eration relative to that observed with an aliphatic carboxylic acid
catalyst. This observation is consistent with our models and
complementary to a very different sequence that delivers site
selectivity of a different type (7, 6,7-selectivity within farnesol).8e
While a unique transition state model that accounts for observed
selectivity is not derived, features of members of an ensemble of
structures that may contribute to the observed selectivity may be
derived. Taken together, these studies establish further that
combinatorial screens of peptide-based catalysts can oen lead
to catalysts of substantial prowess. The generality of the catalysts
can vary, and their modes of operation can be difficult to
establish denitively. In the end, it may be that these same
challenges persist with catalysts that emanate from studies aptly
termed “rational design.” It remains a theme of some discovery-
based research agendas that “how to do something” can be an
easier question to address than “why does it work?”
8 (a) G. Peris, C. E. Jakobsche and S. J. Miller, J. Am. Chem. Soc.,
2007, 129, 8710–8711; (b) C. E. Jakobsche, G. Peris and
S. J. Miller, Angew. Chem., Int. Ed., 2008, 47, 6707–6711; (c)
D. K. Romney and S. J. Miller, Org. Lett., 2012, 14, 1138–
1141; (d) P. A. Lichtor and S. J. Miller, Nat. Chem., 2012, 4,
990–995; (e) P. A. Lichtor and S. J. Miller, J. Am. Chem. Soc.,
2014, 136, 5301–5308; (f) P. A. Lichtor, The Discovery and
Study of Peptide-Based Catalysts for Selective Epoxidation,
Ph.D. thesis, Yale University, New Haven, CT, 2014.
9 D. Yang, Y.-C. Yip, M.-W. Tang, M.-K. Wong, J.-H. Zheng and
K. K. Cheng, J. Am. Chem. Soc., 1996, 118, 491–492.
10 F. A. Davis, M. E. Havakal and S. B. Awad, J. Am. Chem. Soc.,
1983, 105, 3123–3126.
11 V. K. Aggarwal and M. F. Wang, Chem. Commun., 1996, 191–
192.
12 (a) W. Zhang, J. L. Loebach, S. R. Wilson and E. N. Jacobsen,
J. Am. Chem. Soc., 1990, 112, 2801–2803; (b) Z.-X. Wang,
Y. Tu, M. Frohn, J.-R. Zhang and Y. Shi, J. Am. Chem. Soc.,
1997, 119, 11224–11235.
13 (a) E. R. Jarvo and S. J. Miller, Tetrahedron, 2002, 58, 2481–
2495; (b) S. J. Miller, Acc. Chem. Res., 2004, 37, 601–610; (c)
E. Colby-Davie, S. M. Mennen, Y. Xu and S. J. Miller, Chem.
Rev., 2007, 107, 5759–5812; (d) H. Wennemers, Chem.
Commun., 2011, 47, 12036–12041; (e) For recent examples
see: C. T. Mbofana and S. J. Miller, J. Am. Chem. Soc., 2014,
136, 3285–3292; (f) A. J. Metrano and S. J. Miller, J. Org.
Chem., 2014, 79, 1542–1554.
Acknowledgements
The authors wish to thank Dr. Eric Paulson for discussions about
NMR structure elucidation. This work was supported by National
Institutes of Health (NIH R01-GM096403) to S.J.M. Additionally,
P.A.L. was partially supported by NIH CBI-TB-GM-067543.
14 C. J. Thibodeaux, W.-C. Chang and H.-W. Liu, Chem. Rev.,
2012, 112, 1681–1709.
Notes and references
1 (a) K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2024– 15 F. Kolundzic, M. N. Noshi, M. Tjandra, M. Movassagi and
2032; (b) T. Katsuki and V. S. Martin, Org. React., 1996, 48,
S. J. Miller, J. Am. Chem. Soc., 2011, 133, 9104–9111.
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