Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs

Article abstract of DOI:10.1021/jacs.7b03943

The ability to achieve predictable control over the polarization of strained cycloalkynes can influence their behavior in subsequent reactions, providing opportunities to increase both rate and chemoselectivity. A series of new heterocyclic strained cyclooctynes containing a sulfamate backbone (SNO-OCTs) were prepared under mild conditions by employing ring expansions of silylated methyleneaziridines. SNO-OCT derivative 8 outpaced even a difluorinated cyclooctyne in a 1,3-dipolar cycloaddition with benzylazide. The various orbital interactions of the propargylic and homopropargylic heteroatoms in SNO-OCT were explored both experimentally and computationally. The inclusion of these heteroatoms had a positive impact on stability and reactivity, where electronic effects could be utilized to relieve ring strain. The choice of the heteroatom combinations in various SNO-OCTs significantly affected the alkyne geometries, thus illustrating a new strategy for modulating strain via remote substituents. Additionally, this unique heteroatom activation was capable of accelerating the rate of reaction of SNO-OCT with diazoacetamide over azidoacetamide, opening the possibility of further method development in the context of chemoselective, bioorthogonal labeling.

Full text of DOI:10.1021/jacs.7b03943

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Article
Fine-tuning Strain and Electronic Activation of Strain-promoted 1,3-
Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs
Eileen G. Burke, Brian Gold, Trish T. Hoang, Ronald T Raines, and Jennifer M Schomaker
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 15 May 2017
Downloaded from http://pubs.acs.org on May 15, 2017
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Fine-tuning Strain and Electronic Activation of Strain-promoted 1,3-
Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs
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Eileen G. Burke,1ǂ Brian Gold,1ǂ Trish T. Hoang,2 Ronald T. Raines,1,2 Jennifer M. Schomaker*,1
Department of Chemistry1 and Department of Biochemistry2 University of Wisconsin, Madison, Wisconsin 53706, United
States
Supporting Information Placeholder
chemistry,14 and as synthetic building blocks.15 However, despite
ABSTRACT: The ability to achieve predictable control over the
their successes, key challenges remain in the synthesis, stability,
and chemoselectivity of highly strained cycloalkynes, including
ways to easily increase their water solubility for biological appliꢀ
cations. Herein, we describe the synthesis, reactivity and compuꢀ
tational studies of a set of new strained cycloalkynes and detail
how their unique features offer advantages over traditional cycloꢀ
alkynes.
The typical strategy for increasing the rates of strainꢀpromoted
azide–alkyne cycloaddition (SPAAC) reactions is to augment ring
strain through the inclusion of sp2ꢀhybridized centers (e.g.
DIBO,3b DIBAC,3c BARAC,3d and DIBONE,3f Figure 1B) or
small rings (BCN).3e These modifications have led to improveꢀ
ments in reaction rates that are two orders of magnitude faster
than the corresponding unactivated cyclooctynes. However, inꢀ
creasing the strain also destabilizes the ring, leading to unwanted
reactivity with thiols and incompatibility with certain reaction
conditions that limit potential applications of these cycloalkynes
in biological systems.16
polarization of strained cycloalkynes can influence their behavior
in subsequent reactions, providing opportunities to increase both
rate and chemoselectivity. A series of new heterocyclic strained
cyclooctynes containing a sulfamate backbone (SNOꢀOCT) were
prepared under mild conditions by employing ring expansions of
silylated methyleneaziridines. SNOꢀOCT derivative 8 outpaced
even DIFO in a 1,3ꢀdipolar cycloaddition with benzylazide. The
various orbital interactions of the propargylic and homoproparꢀ
gylic heteroatoms in SNOꢀOCT were explored both experimentalꢀ
ly and computationally. The inclusion of these heteroatoms had a
positive impact on stability and reactivity, where electronic effects
could be utilized to relieve ring strain. The choice of the heteroaꢀ
tom combinations in various SNOꢀOCT significantly affected the
alkyne geometries, thus illustrating a new strategy for modulating
strain via remote substituents. Additionally, this unique heteroaꢀ
tom activation was capable of accelerating the rate of reaction of
SNOꢀOCT with diazoacetamide over azidoacetamide, opening the
possibility of further method development in the context of
chemoselective, bioorthogonal labeling.
In contrast, the electronic activation of cyclic alkynes4 allows
for increased rates, while effectively decreasing strain in the startꢀ
ing alkyne,4e an approach with the potential to minimize undesired
side reactions (Figure 1C). Previous examples of electronic actiꢀ
vation have capitalized on hyperconjugative π→σ*C–X interacꢀ
tions.4e,17 These orbital interactions are especially important conꢀ
tributors in the transition state (TS); the placement of heteroaꢀ
toms, such as O, N and S, in the propargylic position has been
demonstrated to lower the ꢁE‡ of azide–alkyne cycloaddiꢀ
tions.4e,17 For example, DIFO, an alkyne with two exocyclic proꢀ
pargyl fluorines, shows rate enhancements of ~30ꢀfold in reacꢀ
tions with PhCH2N3, despite the gauche alignment of the particiꢀ
pating orbitals.4a Computational analyses of DIFO analogs carried
out by Gold et al. found that rings containing endocyclic heteroaꢀ
toms, where the participating orbitals display an antiperiplanar
orientation, had a predicted ꢁE‡ that was 1.3 kcal/mol lower in
energy than that of DIFO.4e,17 Mediumꢀsized cycloalkynes with
heteroatoms embedded at the propargylic positions were recently
synthesized by Tomooka and coꢀworkers, and separately by
Yamamoto and coꢀworkers, to target these orbital interactions.
In the case of the Tomooka alkynes, they were found to have cyꢀ
cloaddition rates ~4ꢀfold faster than cyclooctyne.17c However, the
reported synthetic routes were not flexible enough to accommoꢀ
date smaller ring sizes, and the lower strain energies present in the
accessible cycloalkynes prevented reaction rates in the addition to
benzyl azide from surpassing those of DIFO.
Introduction and background.
The development of reactions that display biorthogonal behavꢀ
ior has enabled the study of an array of biomolecules, including
proteins, lipids, and glycans, in living systems.1 Important feaꢀ
tures of biorthogonal reactions include selectivity between endogꢀ
enous functional groups, lack of reactivity towards the native
biological system, fast reaction kinetics and ease of preparaꢀ
tion/incorporation of the chemical reporters into the desired bioꢀ
molecules.1 A handful of reaction classes are wellꢀsuited to fulfill
these requirements, including the Staudinger ligation,2 1,3ꢀdipolar
cycloadditions of azides,3,4 diazo compounds,5 nitrones6 or nitrile
imines,7 oxime or hydrazone formation,8 esterifications,5g,9 teꢀ
trazine ligations10 and others.11
One of the most widely employed reactions in biorthogonal
chemistry is the copperꢀcatalyzed azide–alkyne cycloaddition
(CuAAC); however, the associated toxicity of the metal towards
biological systems has inspired the search for alternative apꢀ
proaches.1,12 The introduction of ring strain into the cycloalkyne
coupling partner was one strategy to meet this need by enabling
rapid 1,3ꢀdipolar cycloadditions with azides in the absence of a
metal catalyst (Figure 1A).3,13 Since this initial report, strained
alkynes have found utility in a range of applications beyond bioꢀ
logical labeling, including the manipulation of proteins,1 materials
Another challenge in the synthesis of new cycloalkynes for
applications in biorthogonal chemistry is identifying ways to
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modulate the polarizability of the alkyne in a manner that enables
While the use of electronic activation in strained alkynes has
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chemocontrol in cycloadditions involving two different 1,3ꢀ
dipoles. Diazo compounds have proven useful in this regard, as
the greater nucleophilic character of this group promotes rapid
reaction rates and chemoselective transformations in the presence
of azides.5 Cycloalkynes that exhibit the ability to further tune for
selective reactivity of a diazo over an azide group are of great
interest for applications in chemical biology to meet the demand
for “orthogonal−bioorthogonal” reactions in bioconjugation and
chemical reporter strategies.1
achieved impressive increases in rate enhancements of 1,3ꢀdipolar
cycloaddition reactions, its full potential will be realized only with
further efforts directed towards balancing stability and reactivity.
We were curious if combining the electronic effects of proparꢀ
gylic and homopropargylic heteroatoms in a strained cyclooctyne
might offer advantages in terms of reactivity, stability and tunabilꢀ
ity compared to similar scaffolds containing only propargyl hetꢀ
eroatoms. In this paper, we describe the successful development
of a strategy for the efficient synthesis of a new class of cycloalꢀ
kynes for chemoselective cycloaddition reactions and report comꢀ
putational studies of important orbital interactions that control the
polarizability, relative reaction rate and reactivity of the alkyne
(Figure 1D).
9
When comparing the strategies of increased strain and electronic
activation to improve the reactivity of a cycloalkyne, it is obvious
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Figure 1. Strain and electronic effects on rate and selectivity of
strainꢀpromoted 1,3ꢀdipolarꢀalkyne cycloadditions.
Results and Discussion.
Synthesis of strained cycloalkynes. One of the ongoing challengꢀ
es with the use of strained cycloalkynes has been the length and
inflexibility of current syntheses, owing in part to the difficulty of
overcoming entropic disadvantages inherent to forming strained
rings.3 In an alternate approach to these motifs, our route to heterꢀ
ocyclic strained alkynes capitalizes on a unique ring expansion
strategy (Scheme 1).20 Beginning with readily accessible silylated
allenes 1, a regioꢀ, chemoꢀ and stereocontrolled Rhꢀcatalyzed
aziridination forms the key endocyclic methyleneaziridine interꢀ
mediate 2. The silyl group plays a key role in directing the regiꢀ
oselectivity of the aziridination to the distal allene bond, due to
the ability of silicon to engage in hyperconjugative stabilization of
the developing positive charge, as well as by the steric bulk of the
trimethylsilyl (TMS) group.21 In our previous work, we reported
that the remaining alkene of the stable and isolable 2 undergoes
diastereoselective epoxidation, followed by rapid rearrangement
to furnish azetidinꢀ3ꢀones of the general structure 3.22 However, in
the context of this work, it was discovered that treatment of 2 with
tetrabutylammonium fluoride (TBAF) triggered elimination of the
silyl group, followed by ringꢀopening of the aziridine, to yield the
stable strained alkyne 4 (SNOꢀOCT) in 89% yield, with heteroaꢀ
toms incorporated into the ring both at the propargylic and
homopropargylic positions.
Two attractive features of this chemistry are the ability to carry
out the synthesis in a single pot starting from the silylated allene
1, as well as the ease of modifying 1 to readily deliver other useꢀ
ful analogs of 4. These features are particularly useful when inꢀ
Scheme 1. Strained heterocycles from silylated allenes.
that each approach has its own distinct advantages. When strain
alone is utilized, the increasing reaction rate results in a loss of
selectivity. This can be explained via a Hammond–Leffler type
analysis, where increasing strain predistorts the cycloalkyne to not
only resemble the azide cycloaddition TS, but the TS of cycloadꢀ
dition TSs with other dipoles.5e On the other hand, electronic
effects provide for better matching between frontier molecular
orbitals (FMOs), generating more rapid reactivity and higher seꢀ
lectivity.18 This strategy provides advantages not just in terms of
preventing unwanted side reactions, but also allows for the develꢀ
opment of mutually orthogonal chemistries.1,5,19 Advances in our
ability to predictably tune the electronics of the dipolarophile
could enable even better matching between the FMOs of the cyꢀ
cloalkyne and the desired 1,3ꢀdipole.
creased solubility is desired for biological applications, as our
strategy enables the ready introduction of polar functional groups
into the cycloalkyne. Calculations of the log P of known cycloalꢀ
kynes (Figure 1) and our new SNOꢀOCTs (Scheme S1 in the Supꢀ
porting Information) show promise for the ability of our synthetic
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approach to furnish more waterꢀsoluble derivatives. In addition to
sulfonyl functionality into the ring on the reactivity of our new
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the flexibility inherent in the actual synthesis, the sulfamateꢀ
derived cycloalkynes display excellent thermal stability, with the
standard substrate 5 showing no significant decomposition after
heating at 50 °C for 18 h. The alkyne 5 did not decompose upon
exposure to either trifluoroacetic acid (TFA) or aqueous NaOH
for 18 h, stability attributed to lessened strain in the ring due to
the inclusion of heteroatoms in the ring.4e,17 Finally, alkyne 5
remained inert to reaction when stirred in a pH 7 solution of 150
mM reduced glutathione over 24 h, a promising indicator of useꢀ
ful biorthogonality (see Figure S1 in the SI for more details).
cycloalkynes, determining which factors contribute to the obꢀ
served effect is challenging. Computationally, the reactivity of an
octyne derivative containing a homopropargylic sulfonyl group 11
with MeN3 was compared to the same reaction of the parent cyꢀ
clooctyne 9 with MeN3 (Figures 2A–B). It was found that the
Table 1. Comparison of the secondꢀorder rate constants (k2) for
alkyneꢀazide cycloaddition in different solvents.
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Experimentally determined reactivity of SNO-OCTs with benzyl
azide. Noting the improved stability and the previously unreportꢀ
ed substitution pattern of sulfamateꢀderived cycloalkynes, we
were interested in exploring the potential of these molecules for
biological labeling. In addition to stability, useful alkynes for
biorthogonal applications must exhibit fast rates of reaction with
azides at low concentrations that mimic those found in biological
settings.1 In order to assess the reactivity of our new cycloalkynes
(SNOꢀOCT) and enable comparisons with previously reported
alkynes, the second order rate constants (k2) for reaction with
benzyl azide were measured in acetonitrile at ambient temperature
1
using HꢀNMR spectroscopy (Table 1, see the Supporting Inforꢀ
mation for more details). Alkyne 5, bearing an nꢀpentyl side
chain, was chosen as the 'standard' substrate, and its secondꢀorder
rate constant determined to be 0.026 Mꢀ1sꢀ1. To assess the impact
of electronic manipulation on the reaction rate, a series of analogs
were synthesized and their k2 values compared to the k2 value of 5
to give a krel value, as indicated in Table 1.
Modifications to the scaffold of 5 led, in some cases, to draꢀ
matic changes in the observed rates. While NꢀBoc protection of
the propargylic N to furnish 6 resulted in similar reactivity as
compared to 5, substitution of the homopropargylic O of 5 for the
NBoc group of 7 gave a k2 value significantly lower than that of 5.
Increasing the electrophilicity of the exocyclic C–C bond through
addition of an alcohol in 8 tripled the k2 value, giving the fastest
rate of reaction with any of the sulfamateꢀderived cycloalkynes
studied thus far.
inclusion of the sulfonyl moiety relaxes the alkyne bond angles
from 158°/159° in the cyclooctyne 9 (X = Y = CH2) to 161°/161°
in 11 (X = Y = CH2). The fact that increased rates were observed
for 5–8, despite the potential relaxation of the ring strain, suggests
that electronic effects must play a significant role in the increased
reactivity. Comparison with the Tomooka alkynes (Figure 1),
which display similar bond angles of 162°/160°, but k2 values an
order of magnitude slower than 8, suggests that there must be
some other effect operating that goes beyond activation by the
single propargyl heteroatom. Additionally, NBO calculations on
scaffolds based on 11/12 (Figure 2) show a more polar TS in the
cycloaddition reaction due to inductive effects and double hyperꢀ
conjugation through exocyclic C–C propargylic bonds (see the SI
for full details). With these preliminary results in mind, further
computational studies were undertaken to develop an understandꢀ
ing of the role of individual heteroatoms on the reactivity.
Comparison of rates to existing alkynes. As compared to previꢀ
ously reported alkynes, the new SNOꢀOCT cycloalkynes react
with benzyl azide at competitive rates (Table 1A). When comꢀ
pared to OCT (Table 1B), compounds 5, 6 and 8 react substantialꢀ
ly faster, generally by an order of magnitude. Alkynes that rely on
high ring strain to increase reactivity, such as BCN, DIBONE and
DIBAC, have the highest reported rates for cycloalkynes. Howevꢀ
er, testing 8 in CD3OD or 2:1 D2O:CD3CN for direct comparison
with these known alkynes revealed that the rate of reaction with
PhCH2N3 is on the same order of magnitude as BCN, DIBONE
and DIBAC. When compared to electronically activated alkynes,
the sulfamate cycloalkynes 5, 6 and 8 were faster than the exocyꢀ
clic activated MOFO, and 8 was faster than DIFO. Cycloalkyne 8
was also substantially faster than the alkynes bearing two endocyꢀ
clic propargylic heteroatoms reported by Tomooka, despite the
fact that SNOꢀOCT contains only one propargylic heteroatom.
This result was especially intriguing, as the single propargylic
heteroatom in SNOꢀOCT is the nitrogen of the sulfamate, a weak
σꢀacceptor compared to the propargylic oxygen atoms utilized by
Tomooka17c and the exocyclic fluorines in DIFO.4a To better unꢀ
derstand the influence of the propargyl and homopropargyl hetꢀ
eroatoms on the reaction rate, as well as provide insight for the
design of analogs with even greater reactivity, computational
analyses of sulfamateꢀderived cycloalkynes were carried out.
Computational analysis of sulfonyl inclusion. While experiꢀ
mental results demonstrate the dramatic effect of introducing the
First, the effect of the propargyl heteroatom was isolated by
replacing the homopropargylic oxygen (Y) with a methylene unit
to furnish 9 and 11 (Figure 2AꢀB). The remaining X atom was
+
varied from CH2 to NH to O to NH2 , both with and without the
endocyclic sulfonyl group. Surprisingly, incorporation of the sulꢀ
fonyl moiety led to deviations in the previously reported trend of
increased reactivity as the acceptor ability of the X atom is inꢀ
creased.4e,17 A hint to the origin of this effect was revealed by
distortion/interaction analysis,23 where large distortion energies
+
were required to reach the TS when X or Y = NH2 , especially for
the sulfonyl containing alkynes 11c and 12c (Figure 2D). Examinꢀ
ing starting geometries reveals substantial relaxation of alkyne
angles and a significantly lengthened S–N bond upon protonation
(Figure 2C). This trend is readily explained by Bent’s rule, where
bond lengths were found to increase with increasing pꢀcharacter.24
+
Calculated S–NH2 bond lengths of 1.88 Å and 1.89 Å are obꢀ
served in 11c and 12c, respectively, versus much shorter S–NH
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Figure 2. Calculated free energies (M06ꢀ2X/6ꢀ311+G(d,p) level of theory with an IEFPCM solvent model for water (radii = UFF))
of activation (kcal/mol) of the lowest energy TSs for cycloaddition of methyl azide with alkynes containing various propargylic and
homopropargylic substituents either without an endocyclic sulfonyl group (A) or containing an endocyclic sulfonyl group (B). (C)
Starting alkyne geometries with selected bond lengths given in Ångstroms and angles in degrees. Hybridizations were obtained
from NBO analyses26 for the sulfur bonding orbitals in S–X and S–Y bonds. Black = carbon; white = hydrogen; blue = nitrogen;
red = oxygen; yellow = sulfur. (D) Distortion/interaction analysis. For a full analysis and further computational details, see Table
a
S6 in the Supporting Information. The syn TS is preferred. Syn refers to the relationship of the azide methyl group relative to the
CꢀX bond.
bond lengths of 1.67 Å and 1.64 Å for compounds 11a and 12a,
respectively. Compared to the S–C length of 1.82 Å for the parent
compound 11 (X = Y = CH2), it is noted that incorporation of
neutral heteroatoms (11/12a and b) decrease the S–X or S–Y
bond length, but protonation leads to an increase. In addition to
hybridization effects, anomeric effects were also found to influꢀ
ence the S–X bond length.25 The endoꢀanomeric effect (nX→σ*S–Y
and nX→σ*S=O) induces double bond character between the S and
X, while the exo anomeric effect (nO→σ*S–X) lengthens the S–X
pate in bondꢀshortening endoꢀanomeric effects. Thus, it is found
that more negative interaction energies provided by increased
acceptor abilities can either be augmented by favorable remote
stereoelectronic effects when X = NH or O or counteracted by
bond lengthening and increased distortion energies when X =
+
NH2 , in accordance with Bent’s rule.
In a second set of computations (Figure 2A–B), the previously
unexplored effects of the homopropargylic Y atom in 10 and 12
was investigated in a similar manner. Because of its remote relaꢀ
tionship to the alkyne, this heteroatom was anticipated to have a
minimal impact on reactivity; however, experimental and compuꢀ
tational findings revealed an unexpected result. Differences in
ꢁG‡ upon Y heteroatom substitution of CH2 with O were found to
be > 2 kcal/mol; in many cases, the contribution of Y to the lowꢀ
ering of the ꢁG‡ neared that of the X heteroatom. This unexpected
+
bond. In the case of X = NH2 , the exo anomeric effect is
strengthened and there is no longer a lone pair to engage in the
endo anomeric effect, as is the case when X = O, leading to an
increased SꢀN bond length. This analysis also explains the shorter
bond length when X = O relative to X = NH, despite an increase
in pꢀcharacter, due to the fact two lone pairs are present to particiꢀ
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increase in reactivity when Y = O or N stems from a decrease in
without the steric bulk and synthetic complexity associated with
the incorporation of fused rings into the strained cycloalkyne.
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distortion energies due to favorable hybridization and anomeric
+
effects, except in the case of Y = NH2 .
Overall, the computationally predicted trend for engaging coopꢀ
erative effects to increase rates in 1,3ꢀdipolar cycloadditions with
MeN3 indicated that X/Y = O/O should be the most reactive cyꢀ
The picture becomes even more complex when both X and Y
heteroatoms are incorporated into the cycloalkyne of 13 (Figure
3), as synergistic effects between the heteroatoms are important to
the relative reactivity of the analogs. Overall, heterocycles of the
form 13 were found to have increased reactivity over the isolated
effects of either X or Y. Because the sulfur must accommodate
electronegative atoms at both positions, the pꢀcharacter utilized by
sulfur in bonding orbitals must be split; the higher pꢀcharacter
observed in S–X and S–Y bonds in compounds 11 and 12 is no
longer possible. This mediates the bond lengthening and subseꢀ
quent release of ring strain observed when X or Y = CH2. Thus,
incorporation of the sulfamate effectively adjusts the strain of the
ring electronically, without the inclusion of sp2 hybridized groups.
+
+
cloalkyne, followed by X/Y = NH2 /O and X/Y = O/NH2 . Experꢀ
+
imental attempts at mimicking X/Y = NH2 /O via synthesis of an
N–Boc analog 6 (see Table 1) gave a slightly slower rate than
X/Y = NH/O in 5. The failure of Boc incorporation to provide
increased reactivity may stem from steric interactions of the Boc
group with the neighboring sulfonyl group, thus counteracting the
increased acceptor abilities (see the Supporting Information for
further details). While the chemistry described in Scheme 1 canꢀ
not be employed to afford O in the X position, alternative apꢀ
proaches towards the syntheses of these substrates are currently
underway and will be reported in due course.
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This is reflected in the ꢁE‡
values, which are smaller than
distortion
those of compounds 11 and 12, while the ꢁE‡
values are
Table 2. Energies and free energies of activation (kcal/mol) of
the lowest energy TSs for each cycloadditions of Nꢀmethyl
diazoꢀ (14) and azidoacetamide (15) reacting with alkynes conꢀ
taining various propargylic and homopropargylic substituents.
Geometries optimized at the M06ꢀ2X/6ꢀ311+G(d,p) level of
theory with an IEFPCM solvent model for water (radii = UFF).
Bold indicates compounds that were tested experimentally.
aIndicates the synꢀTS is favored. Syn refers to the relationship
of the R group relative to the C–X bond.
interaction
14
15
X
Y
ꢁE‡
15.4
13.5
11.3
11.8
13.8
12.8
ꢁG‡
26.9
25.8
21.3
23.2
25.0
24.7
ꢁE‡
15.3
13.5
11.6
12.5
14.1
13.0
ꢁG‡
27.2
25.6
24.1
24.0
26.6
25.6
CH2
NH
O
NH2
CH2
CH2
CH2
NH
CH2
CH2
CH2
CH2
NH
O
NH2
NH
O
11
11a
11b
11c
12a
12b
12c
13a
+
14.2a 26.5a 13.7a 25.5a
+
+
+
+
Figure 3. (A) Free energies of activation (kcal/mol) of the
lowest energy TSs for cycloadditions of methyl azide with
alkynes containing various propargylic and homopropargylic
substituents. Geometries were optimized at the M06ꢀ2X/6ꢀ
311+G(d,p) level of theory with an IEFPCM solvent model for
water (radii = UFF). Inset: ꢁꢁG‡ relative to X = Y = CH2 and
distortion/interaction analysis. For a full analysis and further
details, see Tables S6 in the Supporting Information. (B) Startꢀ
ing alkyne geometries with selected bond lengths given in
Ångstroms and angles in degrees. Hybridizations were obꢀ
tained from NBO analysis and are given for sulfur bonding
orbitals in S–Y bonds. Black = carbon; white = hydrogen;
blue = nitrogen; red = oxygen; yellow = sulfur.
12.3
10.7
11.3
10.1
8.4
7.9
10.6
8.6
24.4
21.9
23.2
21.8
20.2
19.9
22.5
20.4
21.1
23.1
12.5
11.5
12.0
10.8
9.4
9.3
11.3
9.6
25.3
23.8
24.8
23.5
21.9
21.8
23.9
23.4
23.8
24.1
13b NH
NH
O
O
NH2
NH
O
13c
13d
13e
13f
13g
13h
13i
O
NH2
+
NH2+ NH
NH2+
O
NH2
O
NH2
8.9
10.1
10.3
10.6
13j NBoc
Reaction of alkynes with azides and diazo compounds. More
polar transition states were predicted for the reaction of azides
with sulfamateꢀbased cycloalkynes by NBO analysis.26 The inꢀ
creased polarity of 1,3ꢀcycloadditions employing diazo groups has
been utilized to achieve chemoselective reaction in the presence
of competing azide 1,3ꢀdipoles; this tunable selectivity is especialꢀ
ly apparent in polar aqueous media.5,27 To determine whether our
cycloalkynes exhibit similar behavior, reactions of 11, 12, and 13
with azidoacetamide 15 and the more polarized diazoacetamide
fairly similar. Remote hybridization effects have previously been
utilized to increase strain in fused ring systems; this finding proꢀ
vides a new strategy of modulating strain based on the electronic
character of remote heteroatoms. Thus, such an approach provides
the distinct advantage of enabling the fineꢀtuning of ring strain
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14 were compared both computationally and experimentally (Taꢀ
ble 2 and Figure 4).
reactions that employ two or more different 1,3ꢀdipoles with two
1
2
3
4
5
6
7
8
or more different cycloalkynes to afford mutually orthogonal
reactivity.1,5,19 Such strategies offer the ability to label various
components of complex processes either sequentially19a,b,fꢀh or
simultaneously.19cꢀe,i While the majority of efforts in this area
have utilized the small size of the azide or other dipoles to afford
selectivity over the sterically bulky, yet highly reactive tetrazine
moiety,19cꢀg,j few reports of utilizing electronic differences in diꢀ
poles5 and dipolarophiles4g have been disclosed. Previous reports
have shown complete selectivity of diazoacetamides over the
analogous azides, however, these systems suffer from either relaꢀ
tively slow reaction kinetics5a or unstable reacting partners,5c,f
shortcomings that our new cycloalkyne scaffolds can be employed
to overcome with further optimizations.
Computationally, the difference in ꢁG‡ for the two transition
states in the reaction of various analogs of 11, 12, and 13 with
both 14 and 15 were explored (Table 2). When looking at the
isolated effects of the X atom (Y = CH2, 11a–c), minimal differꢀ
+
ences were seen for X = NH (11a). When X = NH2 (11c), howꢀ
ever, a larger gap was observed, due to the increased nucleophilicꢀ
ity of the diazoacetamide 14 compared to that of the azidoacetamꢀ
ide 15. For both 14 and 15, a similar decrease in total distortion
energies to reach their respective TSs for the reaction with 11c is
observed relative to the reactions with the parent 11 (X = Y =
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CH2; ꢁꢁE‡ = 1.1 kcal/mol and 0.7 kcal/mol, respectively. See
dist.
the Supporting Information for additional details). The alkyne
distortion energy increases in both cases, due to geometric conꢀ
siderations that were previously discussed, while both dipole disꢀ
tortions decrease as a result of closer energy FMOs provided by
the LUMOꢀlowering effects of the electronegative propargylic
heteroatom. The factor responsible for this differentiation in reacꢀ
tivity also results from FMO considerations, due to the higher
energy HOMO of the diazoacetamide 14 relative to the azido
analogue 15.5e This decreased FMO gap results in a much larger
Experimentally, chemoselectivity was investigated by comparꢀ
ing the rates of reaction of various cycloalkynes with both A and
D, which correspond to the Nꢀbenzyl acetamide analogues of 14
and 15 (Figure 4). For previous strainꢀactivated alkyne cycloaddiꢀ
tions, reported rate differences are minimal, with the best selectivꢀ
ity ~2:1. Gratifyingly, SNOꢀOCT derivatives 5 and 6 displayed
much larger rate differences in the competing 1,3ꢀdipolar cyꢀ
cloadditions with A and D to yield 16a-b and 17a-b, respectively.
When X = NBoc, this rate difference for the production of 17c-d
vs. 16c-d is 3.3:1, but when X = NH, the rate difference between
the production of 17a-b vs. 16a-b increases to an excellent selecꢀ
tivity of 11:1. As mentioned previously, the Boc group can inꢀ
crease the acceptor properties of the C–N bond, but is not a good
mimic of the NH2+ moiety, due to its bulky nature. Efforts to afꢀ
ford both faster reaction kinetics with azides and higher selectivity
between both diazo compounds and other reagents utilized in
chemical biology are currently underway.
interaction energy for the reaction of 14 with 11c (ꢁꢁE‡ = –
int.
13.8 kcal/mol) compared to both the reaction of 15 with 11c
(ꢁꢁE‡int. = –10.3 kcal/mol) and the reactions of 14 and 15 with the
parent compound 11 (X = Y = CH2; ꢁꢁE‡int. = –11.3 kcal/mol and
ꢁꢁE‡int. = –8.2 kcal/mol, respectively).
Isolating the effects of the Y heteroatoms provides interesting
results. For Y = O (12b), the diazoacetamide reaction is favored,
but interestingly, when Y = NH2+ (11c), this trend is reversed and
the azide is expected to be favored by a similarly large margin
(ꢁꢁG‡ = 1.1 kcal/mol). These results suggest the exciting possiꢀ
bility that alkyne reactivity could be electronically tuned to favor
different 1,3ꢀdipoles.
Bioconjugation of SNO-OCT with RNase 1. To assess the utility
of SNOꢀOCTs in a biological context, the maleimideꢀlinked comꢀ
pound 19 was synthesized from 18 (Scheme 2). The primary alcoꢀ
hol of 18 was protected with a TBS silyl ether, as the presence of
a free alcohol triggered an N- to Oꢀacyl shift after amine functionꢀ
alization; the resulting ester linkage was problematic for bioconꢀ
jugation studies. Formation of the amide linkage proceeded
smoothly to afford 19. To ensure that the amide linkage did not
However, when the combined effects of both the X and Y atoms
are analyzed, the switch in chemoselectivity is absent. Instead, all
of the heteroatom combinations favor reaction with the diazoꢀ
acetamide 14. The situation where X = NH and Y = O 13b gives a
+
ꢁꢁG‡ = 1.9 kcal/mol, while changing to X = NH2 13h gives an
even larger preference for reaction with 14 over 15 (ꢁꢁG‡ = 3.0
Scheme 2. Synthesis of 19.
significantly affect the rate of 1,3ꢀdipolar cycloaddition, kinetic
studies of the reaction of 19 with benzyl azide were carried out in
CD3CN, giving a rate of 0.026 Mꢀ1sꢀ1 (see the Supplementary Inꢀ
formation for details). The decrease in rate compared to 8 is exꢀ
pected, due to the inclusion of the bulky TBS group, but compares
well to the rate seen with our parent SNOꢀOCT 5.
Figure 4. Chemoselectivity in the reaction of strained cycloalꢀ
kynes with two different 1,3ꢀdipoles.
To highlight the utility of SNOꢀOCT 19 in a biological context,
we sought to carry out the 1,3ꢀdipolar cycloaddition on a SNOꢀ
OCT–protein conjugate. As a model protein, we chose human
ribonuclease 1 (RNase 1). Replacement of Pro 19 with Cys proꢀ
vides a variant, P19C RNase 1,28 that allows for facile conjugation
to 19, providing the SNOꢀOCT–RNase 1 conjugate via the wellꢀ
established thiol–maleimide conjugation strategy (Figure 5). The
kcal/mol). In the case of 13h, the more nucleophilic diazoacetamꢀ
ide 14 benefits from the favorable FMO arguments discussed
above, without the counterꢀproductive bondꢀlengthening and reꢀ
laxation of strain that is seen in compound 11c. This prediction
points to the intriguing possibility of developing bioorthogonal
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SNOꢀOCT–RNase 1 conjugate was then reacted with 5 equiv of
azideꢀPEG3ꢀbiotin for 2 h at ambient temperature to yield the
1
biotin–RNase 1 conjugate, as confirmed by mass spectrometry
(experimental details and mass spec data are contained in the
Supporting Information).
ASSOCIATED CONTENT
Supporting Information
2
3
4
Experimental procedures and spectral data for all new comꢀ
pounds, as well as computational methods and details are supplied
in the Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
5
6
7
8
9
AUTHOR INFORMATION
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Corresponding Author
schomakerj@chem.wisc.edu
Author Contributions
ǂEGB and BG contributed equally to this manuscript.
ACKNOWLEDGMENT
JMS thanks the NIH R01 GM111412 and RTR thanks the NIH
R01 GM044783 for funding. BG thanks the Arnold and Mabel
Beckman Foundation for support as a Postdoctoral Fellow. The
NMR facilities at UWꢀMadison are funded by NSF (CHEꢀ
9208463, CHEꢀ9629688) and NIH (RR08389ꢀ01). The National
Magnetic Resonance Facility at UWꢀMadison is supported by
NIH (P41GM103399, S10RR08438, S10RR029220) and NSF
(BIRꢀ0214394). Computational resources were supported in part
by Grant No. CHEꢀ0840494 (NSF). The authors thank Dr.
Charles Fry of the University of WisconsinꢀMadison for assisꢀ
tance with NMR kinetic studies and Matthew R. Aronoff of the
University of Wisconsin for synthesis of the azidoacetamide.
REFERENCES
Figure 5. Conjugation of maleimide–SNOꢀOCT to P19C
RNase 1, followed by the 1,3ꢀdipolar cycloaddition of azideꢀ
PEG3ꢀbiotin.
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A mild and efficient synthetic strategy for the preparation of
new strained cycloalkynes has been reported. Transition metalꢀ
catalyzed aziridination and subsequent ring expansion of a silyl
allene precursor delivers the cycloalkyne product, while allowing
facile derivatization to modulate the stability, reactivity and/or
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