2700
F. N. Olsen et al.
Letter
Synlett
As a final test of the robustness of the new Npys-medi-
ated elimination sequence, we explored the possibility of
conducting the activation and elimination steps as a one-
pot operation (Scheme 3). We reacted model substrate Boc-
Ser(OH)-OMe with equimolar amounts of Npys-Cl and tri-
ethylamine at 0 °C, and when full conversion was observed
we added excess DBU to the reaction. In both solvents
(CH2Cl2 and MeCN) tested the formation of dehydroalanine
4 occurred smoothly.
to undergo direct addition to the electrophilic β-carbon of
the Dha or Dhb, although such an ene-type reaction is a
well-known transformation associated with sulfenic ac-
ids.17
In conclusion, we have reported an Npys-activated elim-
ination reaction to construct α,β-dehydroalanine and α,β-
dehydrobutyrine amino acid building blocks. Compared to
alternative methods,18 the conditions are very mild and of-
fer increased possibilities for tuning selectivity. Future work
will focus on the application of this new elimination reac-
tion to selectively introduce α,β-dehydroalanine or α,β-de-
hydrobutyrine functionalities in complex molecules such
natural products or large peptides.
Npys-Cl
(1.2 equiv)
then
DBU
(4 equiv)
OH
O
Et3N (1.2 equiv)
OMe
OMe
BocHN
BocHN
solvent
r.t., 30 min
solvent (50 mM)
0 °C, 1 h
H
O
2
4
solvent
Supporting Information
CH2Cl2: 74%
MeCN: 90%
Supporting information for this article is available online at
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Scheme 3 One-pot Npys activation–elimination of Boc-Ser(OH)-OMe
References and Notes
Based on the stereoselectivity of the threonine elimina-
tion (Z selective) and the significant sensitivity of the reac-
tion to the steric bulk of the base (DIPEA ca. tenfold slower
than triethylamine despite the higher basicity of the for-
mer), we propose that the mechanism of the elimination is
E2-like (Scheme 4). Such a reaction will necessarily involve
a sulfenate (serine and threonine) and a thiosulfenate (cys-
teine) leaving group. Sulfenic acids and their corresponding
sulfenate bases are highly reactive species that will undergo
fast reactions to reach more stable sulfur oxidation states,
with the thiosulfinate dimer being an obvious candidate
(Scheme 4).17 However, despite several attempts we have so
far not been able to conclusively characterize the stable
Npys-derived side products that form during the elimina-
tion of 3 to 4. Notably, the Npys sulfenic acids do not appear
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B
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B
H
O
S
BocHN
R
CO2Me
H
H
E2
N
R
N
+
MeO2C
Boc
O
S
NH
O2N
O2N
sulfenate anion
R = H, Me
(13) (a) For a review, see: Chalker, J. M.; Bernardes, G. J. L.; Lin, Y. A.;
Davis, B. G. Chem. Asian J. 2009, 4, 630. For inspirational exam-
ples, see: (b) Strumeyer, D. H.; White, W. N.; Koshland, D. E.
Proc. Natl. Acad. Sci. U.S.A. 1963, 50, 931. (c) Holmes, T. J.;
Lawton, R. G. J. Am. Chem. Soc. 1977, 99, 1984. (d) Guo, J.; Wang,
J.; Lee, J. S.; Schultz, P. G. Angew. Chem. Int. Ed. 2008, 47, 6399.
(e) You, Y. O.; Levengood, M. R.; Ihnken, L. A. F.; Knowlton, A. K.;
van der Donk, W. A. ACS Chem. Biol. 2009, 4, 379. (f) Chalker, J.
M.; Gunnoo, S. B.; Boututreira, O.; Gerstberger, S. C.; Fernandez-
Gonzalez, M.; Bernardes, G. J. L.; Griffin, L.; Hailu, H.; Schofield,
C. J.; Davis, B. G. Chem. Sci. 2011, 2, 1666.
BocHN
CO2Me
NO2
S
OH
O
S
R
N
S
N
NO2
S
N
2X
O2N
N
O
O2N
thiosulfinate
conjugate-addition product
not observed
Scheme 4 Hypothesized mechanism of the Npys DBU mediated elimi-
nation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2697–2701