ARTICLES
NATURE
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Vol 465
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24 June 2010
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α-Halo nitroalkane peptide synthesis
Boc
H
Boc
Ar
H
H
LG
N
N
H
N
N
R
Br
NO2
Ar
C
O
R
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C
=
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O
–
Figure 6
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Enantioselective peptide synthesis. Shown is a carbonyl dianion
synthon approach. Ar, aromatic ring substituent; LG, leaving group; R, alkyl
substituent.
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amide synthesis without epimerization or extensive protection/
deprotection schemes. In addition, the first use of commercially
available bromo nitromethane in stereoselective peptide synthesis
establishes a practical alternative in peptide synthesis to the long-
standing reliance on the carboxylic acid feedstock. This strategic shift
may ultimately enable the efficient fully chemical synthesis of chiral,
non-racemic peptides using a combination of entirely enantioselec-
tive methods and nitroalkane–amine couplings, as demonstrated in
equation (8) (Fig. 5).
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METHODS SUMMARY
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Reactions were carried out in glass vials or round-bottomed flasks. Commercially
available reagents were purchased and used as received unless otherwise noted.
Products were characterized by NMR, infrared spectroscopy (IR), and HRMS.
The enantiomeric excess of chiral, non-racemic aza-Henry adduct 13 was deter-
mined by chiral high-performance liquid chromatography by comparison to an
assay developed using racemic 13. For complete experimental details, including
procedures and full characterization (optical rotation, melting point, IR, 1H and
13C NMR, and HRMS) of all new compounds, see Supplementary Information.
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N bond oxidation: demethylation of N-methyl group in
Full Methods and any associated references are available in the online version of
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Received 22 December 2009; accepted 22 April 2010.
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Supplementary Information is linked to the online version of the paper at
Acknowledgements This work was supported by the Vanderbilt Institute of
Chemical Biology, and in part (catalyst preparation and development) by the NIH
(GM084333 and Chemistry-Biology Interface training grant T32 GM065086 in
support of D.M.M.).
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alcohols and amines with liberation of H2. Science 317, 790 792 (2007).
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by the extrusion of dihydrogen. J. Am. Chem. Soc. 130, 17672 17673 (2008).
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hydrochloride salts. J. Am. Chem. Soc. 128, 13064 13065 (2006).
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Author Contributions The reaction was conceptualized and reduced to practice by
B.S. and J.N.J. Experiments were performed by B.S. (mechanism and scope) and
D.M.M. (scope). The manuscript was prepared by J.N.J. with input from all
coauthors.
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Author Information Reprints and permissions information is available at
Readers are welcome to comment on the online version of this article at
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17. Chan, W. K., Ho, C. M., Wong, M. K. & Che, C. M. Oxidative amide synthesis and
N-terminal alpha-amino group ligation of peptides in aqueous medium. J. Am.
Chem. Soc. 128, 14796–14797 (2006).
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