Aryl Fluorosulfate Trapped Staudinger Reduction

Article abstract of DOI:10.1021/acs.orglett.7b00406

A chemoselective Staudinger reduction/sulfur(VI) fluoride exchange cascade has been developed to join two chemical segments through an aryl sulfamate ester (RNH-SO₂-OAr) linkage. Aryl fluorosulfate is exploited in this work as the first tetrahe

Full text of DOI:10.1021/acs.orglett.7b00406

Letter
pubs.acs.org/OrgLett
Aryl Fluorosulfate Trapped Staudinger Reduction
†
,∥
,†,‡
,†,§
Gerui Ren, Qinheng Zheng,*
and Hua Wang*
†
‡
§
Department of Chemistry, TSRI Graduate Program, and Department of Chemical Physiology, The Scripps Research Institute, La
Jolla, California 92037, United States
∥
Department of Applied Chemistry, School of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310035,
China
*
S Supporting Information
ABSTRACT: A chemoselective Staudinger reduction/sulfur-
VI) fluoride exchange cascade has been developed to join two
(
chemical segments through an aryl sulfamate ester (RNH−
SO −OAr) linkage. Aryl fluorosulfate is exploited in this work
2
as the first tetrahedral electrophilic trap for the in situ
generated iminophosphorane. Ten examples using azide-
containing compounds are presented.
he Staudinger reaction, a reductive process of an azido
Scheme 1. Design of the Aryl Fluorosulfate Trapped
Staudinger Reduction
1
T
group using a phosphine or a phosphite, has been
recognized as a well-established method to introduce an amine
substituent through the sequence R−X → R−N → R−NH
3
2
(
X = Br, Cl, OTs, etc.). Derived from the original Staudinger
2
3
reduction, Bertozzi and Raines, in parallel, developed the
interrupted variations using intramolecular electrophilic traps.
This advance has so far found several applications in chemical
4
5
biology and materials science. In the current repertoire of the
Staudinger ligation, most methods end up with the formation of
6
a planar, trigonal amide linkage. However, the original concept
of “ligation” stems from the enzymatic process of joining two
nucleic acid segments together via a tetrahedral phosphodiester
bond between the 3′-hydroxyl of one DNA/RNA terminus and
with the assistance of hydrogen bonding (step III). Eventually,
the P−N bond is hydrolyzed to give an aryl sulfamate ester
(step IV), and a connection between the azide moiety and
fluorosulfate moiety is formed. Herein, we report the
development of this novel tetrahedral linkage formation
enabled by a combination of the Staudinger reaction and the
SuFEx chemistry.
7
the 5′-phosphoryl of another. To date, a chemical ligation
process that forges a three-dimensional, sulfur(VI)-based linker
is unknown.
In mimicking the naturally occurring tetrahedral phospho-
diester linkage of DNA/RNA, we sought to utilize the sulfur
atom, a third-row neighbor of the phosphorus atom on the
periodic table, to build a novel class of artificial tetrahedral
linkages. Although the sulfur-containing compounds have long
been used in synthetic chemistry for a variety of trans-
formations, their connective characteristic has been overlooked.
As outlined in Scheme 2, this study began with the synthesis
of 2-(diphenyl)phosphanyl phenyl fluorosulfate (1). Palladium-
(II) acetate catalyzed the carbon−phosphorus coupling
reaction of 2-iodophenol and the diphenylphosphine, giving
9
VI
In 2014, Sharpless reviewed the chemistry of S −F substances
2-(diphenyl)phosphanylphenol (2) in 76% yield. Phenol 2 was
and coined the concept of sulfur(VI) fluoride exchange
then treated with sulfuryl fluoride (SO
N,N-diisopropylethylamine (DIPEA) to provide 2-
diphenylphosphanyl)phenyl fluorosulfate (1) as a white
2 2
F ) in the presence of
8
(
SuFEx). Lying at the heart of SuFEx chemistry is the
(
connective feature of high-valent sulfur. Inspired by Bertozzi’s
work and based on our knowledge of the SuFEx chemistry, we
designed an aryl fluorosulfate trapped Staudinger reduction by
introducing a fluorosulfate group onto a triarylphosphine
crystalline compound in 97% yield. Compound 1 was found
to be stable in air (at least 1 year) and phosphate buffer (at least
10
1
week).
(Scheme 1). When iminophosporane is formed (steps I and
II), the intramolecular reaction occurs to transfer the imino
Received: February 10, 2017
group from phosphorus(V) to sulfur(VI) as the fluoride leaves
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00406
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of 2-(Diphenylphosphanyl)phenyl
Fluorosulfate (1)
and 3a (Table 1). When we applied a 1:5 (1/3a) molar ratio,
the reaction in the solvent system used for the NMR study only
Table 1. Optimization of the Reaction Conditions
a
b
entry
solvent
time (h)
yield (%)
1
2
3
DMSO/H O (95/5)
3
52
75
2
H O
0.5
0.5
3
2
d
pH 7.4 buffer
100 (95)
95
c
d
4
DMSO/pH 7.4 buffer (5/1)
e
d
With fluorosulfate 1 in hand, we attempted to validate our
proposed Staudinger ligation process. Compound 1 (0.031 M)
was allowed to react with benzyl azide (3a, 0.62 M, 20 equiv) in
DMSO-d with 5% H O (v/v) at 37 °C in an NMR tube
5
DMSO/pH 7.4 buffer (5/1)
3
(92)
a
b
Ratios of volume are stated in the parentheses. Yields were
1
determined by H NMR using methylene bromide as the internal
standard. Isolated yields are stated in the parentheses. 0.15 mmol (1.5
equiv) of 3a and 1.0 mL of mixed solvent were used. Phosphate
buffer, 0.05 M. 1.0 mmol of 1, 1.5 mmol of 3a, and 10 mL of mixed
c
6
2
d
(
Figure 1A). Using triphenylphosphine oxide (δ = 26.4 ppm)
P
e
solvent were used.
gave 52% product after 3 h (entry 1). Surprisingly, when we
performed the reaction neat in a heterogeneous manner with
the starting materials suspended on pure water or aqueous
phosphate buffer, the reaction was somehow facilitated to finish
within 30 min (entries 2 and 3). However, this condition was
found to be inapplicable to a wider range of substrates that are
crystalline at room temperature or 37 °C. Since we observed
that in the heterogeneous conditions 1 was actually dissolved in
3a, it was likely that the “acceleration” was resulted from the
high concentration of the neat reaction (1.6 M versus 0.05 M).
Later, we found that when only 0.5 equiv of excess of 3a in a
homogeneous solution of DMSO and phosphate buffer (pH
7
.4) was used, the product 4a was obtained in 95% isolated
yield in 3 h (entry 4). The same procedure was also effective on
a millimolar scale (entry 5). We then used this homogeneous
condition to study the substrate scope.
The scope of this ligation process is partly revealed in Table
2
. The lack of interference of functional groups is noteworthy.
When the homogeneous condition [i.e., 5/1 (v/v) DMSO/pH
.4 phosphate buffer] was applied, eight new aryl sulfamate
7
esters (4b−i) were obtained in excellent yields (88−96%) with
virtually no side products observed. We found that the ester-
containing molecules 3b and 3c were compatible with this
reaction. The treatment of the compounds 3b and 3c with
fluorosulfate 1 (1.5 equiv) under the homogeneous conditions
described above provided the ligation products 4b and 4c in
9
5% and 91% yield, respectively (entries 2 and 3). Fmoc-
Lys(N )-OH (3d), a building block for solid-phase peptide
3
Figure 1. (A) Reaction of 1 and benzyl azide (3a). (B) Time-course of
the reaction between 1 and 3a monitored by 31P NMR. (C) Plot of ln
synthesis bearing a free carboxylic acid moiety, also reacted with
fluorosulfate 1, yielding the desired aryl sulfamate ester 4d in
[
1] versus time when [3a] is considered constant at 0.62 M. The slope
−
4
−1
8
8% yield (entry 4). Moreover, Leelamine (dehydroabietyl-
suggested a pseudo-first-order rate constant 1.7 × 10 s .
12
amine), a promising compound for cancer treatment, was also
successfully attached to compound 1 via a sulfur-containing
tetrahedral linkage (entry 5). The ligation process was found to
be effective for the azide-containing monosaccharide, and
nucleotide-derived azides (3f−h) afforded the desired ligation
products in 85−91% yields (entries 6−8). These results
suggested that the hydroxyl group, purine, and the pyrimidine
base were compatible with the ligation reaction, revealing the
possibility of using this new reaction to build up an aryl
sulfamate ester connection between two motifs acting as a
mimic of the phosphodiester linkage. Importantly, we showed
that the intramolecular ligation reaction was highly selective
versus intermolecular reaction (entry 9). Even though a
fluorosulfate group was embedded in the azide substrate, only
as the internal standard, the progress of reaction was monitored
3
1
by P NMR. As the reaction proceeded, the starting material 1
δ = −19.5 ppm, doublet) was consumed, while a new peak in
(
P
the region of phosphorus(V) accumulated (δ = 25.4 ppm)
P
(
Figure 1B). Further analyses of the reaction mixture after 4 h
1
13
using LC−MS, H NMR, and C NMR gave solid evidence for
the formation of the desired “ligation” product 4a. Based on the
3
1
P NMR results, we observed pseudo-first-order kinetics for
the consumption of compound 1. The rate constant (k ) was
obs
−4
−1
11
determined to be 1.7 × 10
s
(Figure 1C).
We then optimized the conditions of the Staudinger
“ligation” between nearly equimolar amounts of compound 1
B
DOI: 10.1021/acs.orglett.7b00406
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Table 2. Aryl Fluorosulfate Trapped Staudinger Reaction
a
b
Method A: as described in Table 1, entry 3. Method B: 1 (0.1 mmol) and azide 3 (0.15 mmol) were dissolved in 1.0 mL of 5/1 (v/v) DMSO/pH
c
7
5
.4 buffer. The mixture was stirred at 37 °C under air atmosphere. Method C: 1 (0.25 mmol) and azide 5 (0.05 mmol) were dissolved in 0.6 mL of
/5/2 (v/v/v) DMSO/DMF/pH 7.4 buffer. The mixture was stirred at under air atmosphere for 1 h. N.D. = not determined.
the substitution of the o-fluorosulfate on the phosphine moiety
was enabled by proximity.
imino group transfer (step III), although very slow, be observed
by LC−MS (∼30% yield after 24 h). For the sulfonyl azide (9)
or oxysulfonyl azide (10), the competing hydrolytic process of
iminophosphorane is predominant.
13
In the recent report on the reengineering of vancomycin,
Sharpless has shown the capability to install an azide handle
onto the complex antibiotic molecule selectively at its “head”
Three other phosphines were examined to study the
electronic effect. It can be concluded from Scheme 3 that,
generally, electron-rich phosphines were oxidized by azides
14
carboxylic acid group. To demonstrate the fidelity of the
present ligating process, we treated the azide derivative of
vancomycin (5) with 5 equiv of compound 1. Within 1 h, the
reaction was complete, and the ligated product 6 was isolated
by preparative HPLC in 94% yield as a white solid (Scheme 3).
Inapplicable examples include 3° alkyl azide, aryl azide,
sulfonyl azide, and oxysulfonyl azide (Figure 2). tert-Butyl azide
11
faster than electron-poor ones. However, although phosphine
11 is oxidized more quickly by the azide (krel,11/1 ∼ 2.5), the
formation of desired 12 was not complete until 2.5 h. The post-
Staudinger processes (steps III and IV) limited the overall
reaction rate, with several intermediates being observed on
LC−-MS (see the Supporting Information for details). When
(
1
7) was untouched under the ligation conditions. Others (8−
0) were, in fact, very reactive regarding the iminophosphorane
an electron-withdrawing group (e.g., −CO H in 13) was
2
formation (steps I and II). Compounds 8, 9, and 10,
respectively, reacted with 1 instantly at autogenous temperature
present on the benzene ring that bears the fluorosulfate group,
the phenoxide departure was preferred over the leaving of a
fluoride anion probably because of its enhanced acidity.
Electron-withdrawing groups on both of the other two benzene
(releasing both heat and gas) to give the corresponding aza-
ylides. However, only in the case of phenyl azide (8) could the
C
DOI: 10.1021/acs.orglett.7b00406
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Scheme 3. Evaluation of Other 2-Phosphanylaryl
Fluorosulfates
ACKNOWLEDGMENTS
■
We thank Professors K. Barry Sharpless and Peng Wu (TSRI)
for support. G.R. thanks Zhejiang Gongshang University for a
visiting investigator fellowship.
REFERENCES
1) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
2) (a) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007. (b) Saxon,
■
(
(
E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000, 2, 2141.
3) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2,
939.
4) For selected reviews, see: (a) van Berkel, S. S.; van Eldijk, M. B.;
van Hest, J. C. M. Angew. Chem., Int. Ed. 2011, 50, 8806. (b) Schilling,
C. I.; Jung, N.; Biskup, M.; Schepers, U.; Brase, S. Chem. Soc. Rev.
hn, M.; Breinbauer, R. Angew. Chem., Int. Ed.
(
1
(
̈
2
2
(
011, 40, 4840. (c) Ko
004, 43, 3106.
̈
5) For selected reports, see: (a) Potzsch, R.; Fleischmann, S.; Tock,
̈
C.; Komber, H.; Voit, B. I. Macromolecules 2011, 44, 3260. (b) Bian, S.;
Schesing, K. B.; Braunschweig, A. B. Chem. Commun. 2012, 48, 4995.
(6) For a review on the group transfer chemistry of iminophosphor-
ane, see: Fresneda, P. M.; Molina, P. Synlett 2004, 1, 1.
(
(
7) Lehnman, I. R. Science 1974, 186, 790.
8) Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2014, 53, 9430.
9) Kapadnis, P. B.; Hall, E.; Ramstedt, M.; Galloway, W. R. J. D.;
Welch, M.; Spring, D. R. Chem. Commun. 2009, 538.
10) The examination of the stability of 1 was enabled by LC−MS. A
.1 mmol portion of 1 was dissolved in 1.0 mL of acetonitrile/pH 7.4
(
(
0
buffer (1/1, v/v). After the mixture was stirred at room temperature
for 1 week, no formation of a new peak on the LC trace was observed.
(11) The reaction is about 10-fold slower than Bertozzi’s methyl
benzoate; see: Lin, F. L.; Hoyt, H. M.; van Halbeek, H.; Bergman, R.
G.; Bertozzi, C. R. J. Am. Chem. Soc. 2005, 127, 2686.
Figure 2. Unsuccessful azide substrates for the new ligation reaction.
(12) (a) Gowda, R.; Madhunapantula, S. V.; Kuzu, O. F.; Sharma, A.;
Robertson, G. P. Mol. Cancer Ther. 2014, 13, 1679. (b) Kuzu, O. F.;
Gowda, R.; Sharma, A.; Robertson, G. P. Mol. Cancer Ther. 2014, 13,
rings (phosphine 15), although also slowing the reaction, did
not change the selectivity in the sulfuryl group transfer event.
In summary, we have developed an aryl fluorosulfate trapped
Staudinger reaction. The concept of Staudinger “ligation” was
extended to the tetrahedral, heteroatom-based electrophile.
This novel method showed great reliability for a variety of
azides in aqueous solution under physiological conditions.
Further study on developing a more effective phosphine
reagent and using this chemistry as a tool for bioconjugation in
a complex system is underway in our laboratory.
1
690.
(13) Aryl fluorosulfate has stringent requirements for its nucleophilic
activation. For an example of proximity-enabled activation in the
protein context, see: Chen, W.; Dong, J.; Plate, L.; Mortenson, D. E.;
Brighty, G. J.; Li, S.; Liu, Y.; Galmozzi, A.; Lee, P. S.; Hulce, J. J.;
Cravatt, B. F.; Saez, E.; Powers, E. T.; Wilson, I. A.; Sharpless, K. B.;
Kelly, J. W. J. Am. Chem. Soc. 2016, 138, 7353.
(14) Silverman, S.; Moses, J. E.; Sharpless, K. B. Chem. - Eur. J. 2017,
2
3, 79.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00406.
Detailed experimental procedures; characterizations of
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*
E-mail: qhzheng@scripps.edu.
E-mail: huawang@scripps.edu.
*
ORCID
Qinheng Zheng: 0000-0002-8440-8673
Hua Wang: 0000-0003-3760-090X
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b00406
Org. Lett. XXXX, XXX, XXX−XXX