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Organic Letters
Letter
tambromycin (1), which was isolated in 48% yield after
purification using reversed phase C18 flash chromatography. A
comparison of the spectral properties of synthetic material to
the published spectra of natural isolates was initially hampered
by an observed pH dependence in the organization and shift of
the resonances. In both reported spectra of isolated, natural
tambromycin a strong formic acid peak is present.4,5 We
postulated that the observed incongruity between our initial
spectra and the published work resulted from a difference in
protonation state. Indeed, upon the addition of a small amount
of formic acid, the collected NMR spectra shifted to tightly
align with that of the natural material (see Supporting
Information for a tabulated comparison of chemical shifts).
Analysis of the synthetic material by high resolution tandem
mass spectrometry, infrared spectroscopy, and optical rotation
further supported the identity of the sample, thereby
establishing the completion of the total synthesis. Overall,
tambromycin (1) was accessed in 13 steps (longest linear
sequence) from 4-methyoxy indole (12) with a combined yield
of 1.3%.
In conclusion, a concise total synthesis of the unusual
tetrapeptide natural product, tambromycin (1), has been
achieved. The route features a scalable, completely regiose-
lective iridium-catalyzed C−H borylation allowing straightfor-
ward installation of the indole C6 chlorine substituent, as well
as a diastereoselective amination to efficiently produce the
novel amino acid, tambroline (11). Access to synthetic
tambromycin (1) will facilitate future exploration of its
biological activity and mechanism of action and enable
investigations into structure−activity relationships among the
related family of peptide natural products.
edges the National Science Foundation for the award of a
Graduate Research Fellowship.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00700.
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S
Full experimental details and characterization data
(NMR, MS, IR and optical rotation) for all new
compounds (PDF)
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AUTHOR INFORMATION
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Corresponding Author
ORCID
Richard B. Silverman: 0000-0001-9034-1084
Neil L. Kelleher: 0000-0002-8815-3372
Regan J. Thomson: 0000-0001-5546-4038
Author Contributions
⊥G.P.M. and J.C.R. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The research was supported by the National Institutes of
Health under Award Numbers AT009143 (to N.L.K. and
R.J.T.) and D012016 (Integrated Molecular Structure Educa-
tion and Research Center at Northwestern University), as well
as the NIH supported Chemistry of Life Processes Training
Grant T32-GM105538 (to G.P.M.). J.C.R. gratefully acknowl-
D
DOI: 10.1021/acs.orglett.8b00700
Org. Lett. XXXX, XXX, XXX−XXX