Journal of the American Chemical Society
Article
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CONCLUSIONS
■
Using an N-oxide/ethylene-glycol-assisted intermolecular P‑K
protocol to enable the use of (E)-alkenes in cyclopentenone
generation, a synergistic bimetallic (Zn/In) Barbier-type
allylation, and N-chloroguanidine-based chlorospirocyclization
to set the two most challenging stereocenters, a robust and
stereocontrolled second-generation route to key spiroaminoke-
tone 9 has been developed (20 and 8 steps, 12 and 4
purifications, <1% overall yield and 13% overall yield,
respectively). In addition to representing a formal synthesis
of palau’amine (8) and massadines,28c the synthesis of
spiroaminoketone 9 presented an opportunity for invention.
The key chlorospirocyclization not only served as an ideal
strategy for clearing the two most challenging stereocenters of
the fully substituted cyclopentyl framework but also provided
the chemical inspiration for CBBG (58). Optimization of these
stable N-chloroguanidines led to the identification of
Palau’chlor (70) as a reactive yet practical chlorinating reagent
for both C−H and N−H chlorinations, ultimately commercial-
ized by Sigma-Aldrich.52 Finally, scalability of common
progenitor 9 to complex members of the PIA family class has
been demonstrated on multigram-scale, routinely providing ∼5
g of 73 from a single batch and final elaboration of the
axinellamines on gram-scale. This enabled a re-investigation of
the biological activity16,17 of 4 and 5, resulting in the surprising
finding that they possess promising activity against a broad
range of bacterial pathogens, suggesting that their scaffold has
the potential for further development.54 This article represents
a case study in which the development of a scalable synthesis to
a complex natural product enabled discoveries in both
chemistry and biology.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, complete data acquisition, and
analytical data for all new compounds, including H and 13C
1
(22) Rodriguez, A. D.; Lear, M. J.; La Clair, J. J. J. Am. Chem. Soc.
2008, 130, 7255.
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78.
NMR spectra. This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Authors
■
(24) Varma, A.; Young, K. D. J. Bacteriol. 2009, 191, 3526.
(25) Stricker, J.; Erickson, H. P. J. Bacteriol. 2003, 185, 4796.
(26) Goehring, N. W.; Beckwith, J. Curr. Biol. 2005, 15, R514.
(27) For a comprehensive list of efforts toward the synthesis of the
complex PIAs (axinellamines, massadines, and palau’amine) prior to
August 2011, see: (a) Seiple, I. B.; Su, S.; Young, I. S.; Nakamura, A.;
Yamaguchi, J.; Jorgensen, L.; Rodriguez, R. A.; O’Malley, D. P.; Gaich,
T.; Kock, M.; Baran, P. S. J. Am. Chem. Soc. 2011, 133, 14710 and
references therein. For studies toward the synthesis of axinellamines
after August 2011, see: (b) Ding, H.; Roberts, A. G.; Harran, P. G.
Angew. Chem., Int. Ed. 2012, 51, 4340. (c) Ding, H.; Roberts, A. G.;
Harran, P. G. Chem. Sci. 2013, 4, 303. (d) Wang, X.; Ma, Z.; Wang, X.;
De, S.; Ma, Y.; Chen, C. Chem. Commun. 2014, 50, 8628 and
references therein.
(28) (a) Yamaguchi, J.; Seiple, I. B.; Young, I. S.; O’Malley, D. P.;
Maue, M.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47, 3578.
(b) O’Malley, D. P.; Yamaguchi, J.; Young, I. S.; Seiple, I. B.; Baran, P.
S. Angew. Chem., Int. Ed. 2008, 47, 3581. (c) Su, S.; Seiple, I. B.;
Young, I. S.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 16490.
(d) Seiple, I. B.; Su, S.; Young, I. S.; Lewis, C. A.; Yamaguchi, J. Angew.
Chem., Int. Ed. 2010, 49, 1095. (e) Su, S.; Rodriguez, R. A.; Baran, P. S.
J. Am. Chem. Soc. 2011, 133, 13922.
Author Contributions
⊥R.A.R. and D.B.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the NIH/
NIGMS (GM-073949) and by NSF (predoctoral fellowship to
R.A.R.). We are grateful to Dr. A. L. Rheingold and Dr. C. E.
Moore for X-ray crystallographic analysis.
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