Organic Letters
Letter
be enhanced several-fold yet retain good selectivity by
replacing O−P bond with more stable C−P bond.14 Inspired
by these pioneering studies, we subjected β-methyl dehy-
droamino acid 4c to integrate with the Pro-Leu-His-Ser
sequence to get the phosphono-pentapeptide 5c as a new
phosphatase-stable analogue of PLHSpT.
All the above-used starting dhAAs feature a Z-configuration,
and produced the phosphorylation products with absolute Z-
selectivity. As a comparison, several E-dehydroamino carbox-
ylic alkenes (6a−6d) were also prepared and treated with H-
phosphite 2a under otherwise standard conditions (Scheme
6a). Notably, still only Z-phosphono dhAAs (3c, 3d, 3y, and
driven by the formation of a hydrogen-bond network in a six-
membered ring. The presence of such hydrogen bonds has
been unambiguously confirmed in the X-ray structure of
compound 3a and 3a′.
In conclusion, a stereoselective C(sp2)−H phosphorylation
reaction of trisubstituted dhAAs was realized by means of a
silver-promoted radical relay process. This simple and practical
protocol allows us to obtain the bulky tetrasubstituted
phosphono-dhAAs on a gram scale along with three new
phosphonopeptides. This study not only provides a direct
approach for the introduction of valuable phosphonate group
into amino acid framework, but also offers new precursors for
future asymmetric hydrogenation en route to chiral β-
phosphonoamino acids, the research of which is in progress
in our group.
Scheme 6. Mechanistic Experiments and Proposed
Mechanism
ASSOCIATED CONTENT
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sı
* Supporting Information
The Supporting Information is available free of charge at
Experimental procedures, characterization data, mecha-
nistic studies, DFT calculations, and NMR spectrum
Accession Codes
mentary crystallographic data for this paper. These data can be
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Fa-Guang Zhang − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
and Tianjin Collaborative Innovation Center of Chemical
Science & Engineering, Tianjin University, Tianjin 350072,
P.R. China; Joint School of National University of Singapore
and Tianjin University, International Campus of Tianjin
University, Binhai New City, Fuzhou 350207, P.R. China;
Jun-An Ma − Department of Chemistry, Tianjin Key Laboratory
of Molecular Optoelectronic Sciences, Frontiers Science Center
for Synthetic Biology (Ministry of Education), and Tianjin
Collaborative Innovation Center of Chemical Science &
Engineering, Tianjin University, Tianjin 350072, P.R. China;
Joint School of National University of Singapore and Tianjin
University, International Campus of Tianjin University, Binhai
3z) were formed in similar yields as those observed for Z-
starting materials, suggesting that geometry of the double bond
is not a controlling factor in the C−P bond formation step.
N,N-diprotected substrate 7 completely inhibited the trans-
formation, implying that the N−H group may possess a pivotal
role in triggering the current reaction. Adding a radical
scavenger (TEMPO) to the model reaction system entirely
halted the formation of 3a. Importantly, the alkyl radical-
capture product 8 was obtained in 45% yield, thus strongly
supporting that an uncommon radical-coupling pathway is
presumably operative. Taking these results into consider-
ation,15 a plausible mechanism was proposed as illustrated in
Scheme 6c. First, the N−H bond of trisubstituted dhAAs 1 was
activated through a proton-coupled electron transfer (PCET)
process initiated by Ag2O to give N-centered radical I-1, which
isomerized to a more stable alkyl radical I-2 expeditiously. This
radical species was then arrested by a P-centered radical to
form the imine intermediate I-3. Finally, fully substituted
alkenyl phosphonate 3 was generated with Z-configuration
Authors
Hao-Qiang Cao − Department of Chemistry, Tianjin Key
Laboratory of Molecular Optoelectronic Sciences, Frontiers
Science Center for Synthetic Biology (Ministry of Education),
and Tianjin Collaborative Innovation Center of Chemical
Science & Engineering, Tianjin University, Tianjin 350072,
P.R. China; Joint School of National University of Singapore
D
Org. Lett. XXXX, XXX, XXX−XXX