9-Silafluorenyl Dichlorides as Chemically Ligating Coupling Agents and Their Application in Peptide Synthesis

Article abstract of DOI:10.1002/anie.201606120

A fundamentally simple, mild, and practical procedure for peptide bond formation is reported that employs a stoichiometric amount of easy-to-access 9-silafluorenyl dichlorides as the coupling agent. Without initial preactivation or elaboration of the carboxylic acid or amine termini of the amino acids, the developed reagent is proposed to act through an unprecedented chemical ligation mechanism, bringing the two coupling partners together before being subsequently eliminated. The desired amides or peptide bonds are thus furnished in good yields and with low to no epimerization.

Full text of DOI:10.1002/anie.201606120

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201606120
German Edition: DOI: 10.1002/ange.201606120
Peptide Synthesis
Hot Paper
9-Silafluorenyl Dichlorides as Chemically Ligating Coupling Agents
and Their Application in Peptide Synthesis
Samuel J. Aspin, Sylvain Taillemaud, Patrick Cyr, and Andrꢀ B. Charette*
Abstract: A fundamentally simple, mild, and practical proce-
dure for peptide bond formation is reported that employs
a stoichiometric amount of easy-to-access 9-silafluorenyl
dichlorides as the coupling agent. Without initial preactivation
or elaboration of the carboxylic acid or amine termini of the
amino acids, the developed reagent is proposed to act through
an unprecedented chemical ligation mechanism, bringing the
two coupling partners together before being subsequently
eliminated. The desired amides or peptide bonds are thus
furnished in good yields and with low to no epimerization.
prior elaboration of one of the coupling partners to generate
a reactive enough species for the formation of the amide
bond. One further and particularly promising method that
avoids the use of superstoichiometric activating agents is the
use of electron-deficient boronic or borinic acids as catalysts
to generate an activated carboxylate. First reported in 1996,[13]
and with many recent improvements,[14] these methods still
generally require the use of a highly functionalized organo-
boron derivative, forcing conditions, and a dilute reaction
medium to achieve good yields.
Herein, we describe an alternative and unprecedented
approach to peptide synthesis,[15] involving the synthesis and
use of a range of previously unreported 9-silafluorenyl
dichlorides as highly effective new coupling reagents.
Unlike with traditional methods, no preactivation of either
amino acid unit is required (Scheme 1a). Instead, we propose
to chemically ligate[16] both amino acid subunits through
T
he boundless abundance of the amide and peptide bond in
pharmaceuticals, biologically active compounds, fine chem-
icals, and polymers clearly exemplifies their formation as one
of the most important reactions in organic chemistry.[1]
However, current methods, although general and high-yield-
ing, have inherent limits, including—but not limited to—
concerns about waste, expense, and the epimerization of
stereocenters. Indeed, to date, most amide and peptide
coupling reactions are still carried out using a stoichiometric
amount of expensive coupling reagents that can also be
potentially hazardous.[2] These methods generally lead to the
formation of a large quantity of byproducts, thus imparting
inverse environmental effects, and these byproducts need to
be separated, sometimes painstakingly, from the final prod-
uct.[3] In light of this, amide bond formation was recently
recognized as a key transformation in which the development
of more efficient processes is required.[4]
In recent years, a number of pioneering new strategies
have been reported for the synthesis of peptide bonds, such as
the catalytic generation of activated carboxylate surrogates
from aldehydes,[5] alcohols,[6] and alkynes,[7] the oxidative
coupling of a-bromo nitroalkanes with amines,[8] the use of
reactive amine surrogates, such as the coupling of isonitriles
with carboxylic acids or thioacids,[9] the coupling of thioacids
with azides,[10] the coupling of isocyanates with carboxylic
acids,[11] and, very recently, the coupling of CDI activated
amino esters with carboxylic acids.[12] However, although
promising and generally efficient, all of these methods still
suffer from the same major limitation: the requirement for
Scheme 1. Traditional and silicon-mediated chemical ligation
approaches. AR=activating reagent, PG=protecting group.
a temporary silicon tether A, which should rearrange upon
heating to produce the desired amide bond by extrusion of an
inert siloxane. The driving force for this transformation
[*] Dr. S. J. Aspin, S. Taillemaud, P. Cyr, Prof. Dr. A. B. Charette
Centre in Green Chemistry and Catalysis
Faculty of Arts and Sciences
À
should be the strength of the newly formed Si O and amide
bonds (Scheme 1b).
Department of Chemistry, Universitꢀ de Montreal
P.O. Box 6128, Station Downtown, Montreal, Quꢀbec H3C 3J7
(Canada)
We began our work by examining a simple amidation
reaction between glycine methyl ester hydrochloride salt and
phenylacetic acid to yield amide 1, employing commercially
available dichlorosilanes as coupling agents. To our delight,
E-mail: andre.charette@umontreal.ca
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201606120.
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Table 1: Initial optimization of the reaction conditions.[a]
provide a reagent of similar electronic properties and allow
for more facile approach of both amino acid fragments, giving
rise to higher yields for bulkier coupling partners. Although
not commercially available, this dichlorosilane could be easily
synthesized in one step from 2,2’-dibromobiphenyl and SiCl4
in good yield and purity (Scheme 3).[18]
Entry
Dichlorosilane
NEt3 [equiv]
DMAP [equiv]
Yield[a] [%]
1
2
3
4
5
6
7
8
Me2SiCl2
MePhSiCl2
Ph2SiCl2
Ph2SiCl2
Ph2SiCl2
Ph2SiCl2
Ph2SiCl2
Ph2SiCl2
5.0
5.0
5.0
4.0
6.0
5.0
5.0
5.0
–
–
–
–
trace
26
62
46
54
59
75
56
Scheme 3. Synthesis of 9-silafluorenyl dichloride.
–
0.2
0.5
1.0
Once we had this reagent in hand, it was employed in the
initially optimized amidation reaction between H2N-Gly-
OMe·HCl and phenylacetic acid, giving rise to the desired
amide product in quantitative yield. Having thus identified
a highly efficient silane dichloride coupling partner for the
amidation of simple amines with carboxylic acids, we decided
to explore the generality of this reaction by subjecting a small
range of primary and secondary amines and carboxylic acids
to the developed reaction conditions (Table 2).
[a] Determined by 1H NMR spectroscopy using triphenylmethane as an
internal standard.
after a short optimization (Table 1), we found that the desired
product was formed in up to 75% yield when employing
diphenyldichlorosilane as the limiting reagent, an important
point to note when addressing the problem of waste in
peptide synthesis, along with 5 equivalents of triethylamine
and a catalytic amount of DMAP.[17]
Table 2: Selected amidation reactions.[a]
With our fundamentally simple proof of concept in hand,
we attempted to apply our method directly to the formation
of dipeptides. We first decided to couple Boc-Gly-OH and
H2N-Gly-OMe·HCl and were pleased to find that this
reaction occurred to yield dipeptide 2 in a gratifying 79%
yield. However, when the more sterically challenging cou-
pling of Boc-l-Phe-OH and H2N-l-Phe-OMe·HCl was
attempted, the reaction yield dropped significantly, and 3
was obtained in a moderate 30% yield, although, satisfyingly,
no evidence of epimerization was observed by 1H NMR
spectroscopy (Scheme 2).
[a] Yields of isolated products are given.
In all cases, the desired secondary (1, 5, 6, and 9) and
tertiary amide products (7 and 8) were all furnished in good to
excellent yields. Importantly, supercritical fluid chromatog-
raphy (SFC) traces showed that no epimerization was
observed in the cases where either coupling partner contained
a stereocenter (5 and 6; see the Supporting Information).
Having established that secondary and tertiary amides could
be synthesized in good yields, and with no trace of epimeri-
zation of the stereocenters, we turned our attention to the
more challenging transformation of peptide coupling. Again,
the coupling of Boc-Gly-OH with H2N-Gly-OMe·HCl and
that of Boc-l-Phe-OH with H2N-l-Phe-OMe·HCl were
chosen as model reactions. In both cases, a marked increase
Scheme 2. Initial peptide coupling reactions employing Ph2SiCl2 as the
coupling agent. Boc=tert-butoxycarbonyl, DMAP=4-dimethylamino-
pyridine.
We hypothesized that steric interactions between the
bulky amino acid residues and the dichlorosilane were clearly
hindering the approach of both coupling partners around the
silicon center. We thus looked into modification of the silane
coupling agent, and proposed that the use of conformationally
flat and rigid 9-silafluorenyl dichloride, compound 4a, may
2
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in reaction yield was observed, to 90% for the formation of
the Boc-Gly-Gly-OMe dipeptide (2) and to 67% for Boc-l-
Phe-l-Phe-OMe (3; Table 2). This represents great
improvement on our method, although still not providing
yields high enough to compete with current methods for the
synthesis of these dipeptides.
We reasoned that the reactivity of our 9-silafluorenyl
dichloride coupling agent could be further tuned through the
addition of electron-withdrawing substituents to the silafluor-
enyl backbone, thus rendering our silane more electrophilic
towards the coupling partners. Silanes 4b to 4 f, bearing
chlorine or fluorine substituents on the backbone of the
silanyl dichloride, were thus synthesized by dilithiation of the
corresponding 2,2’-dibromobiaryls and quenching with SiCl4,
and subsequently tested for their activity as coupling reagents
in our model peptide coupling reactions (Table 3). In
2-position (74%). This result suggests that this configuration
provides the optimal steric and electronic properties to
promote a clean and efficient reaction. Surprisingly, the use
of silafluorenyl dichloride 4d, bearing a more electron-
withdrawing fluoride substituent in the 3-position, resulted
in a diminished yield (75%) compared to its chloride
congener. This could be due to the occurrence of side
reactions, giving rise to a mixture of side products, or perhaps
a
À
due to an increase in Si Cl bond strength, rendering the silane
coupling agent less reactive. Silanes 4e and 4 f, which lack the
rigid fluorenyl backbone, highlight its importance, yielding
the desired dipeptide (3) in just 14% and 26%, respectively.
As silane 4c was previously unreported, an X-ray crystal
structure was sought in order to irrefutably prove its structure
(Figure 1; see the Supporting Information for the X-ray
crystallographic data).
Table 3: Synthesized dichlorosilanes and their activities as peptide
coupling agents.[a]
Figure 1. X-ray crystal structure of silane 4c. Ellipsoids set at 50%
probability.[21]
With the optimal 3,5,5-trichlorosilafluorenyl reagent 4c
and reaction conditions in hand, we next submitted a range of
monoprotected amino acid coupling partners to our devel-
oped method (Table 4). Under the optimized conditions (4c,
NEt3, DMAP), all peptides were obtained in good to excellent
yields. All reactions proceeded cleanly, with only a filtration
and short column chromatography over silica gel being
required for purification. The coupling efficiency seemed,
however, to be somewhat affected by the amino acid a-side
chain. Entries 3 and 4 show a drop in reaction yield from 82%
for the coupling of Boc-l-Phe-OH with H2N-l-Phe-OMe·HCl
to 61% for the coupling of bulkier Boc-l-Val-OH with H2N-
l-Phe-OMe·HCl, and entries 3 and 5 show an improvement to
89% yield when smaller Boc-l-Ala-OH was coupled with
H2N-l-Phe-OMe·HCl, as may be expected. Although not
conclusive, entries 5 and 6 may give some insight into the
order of addition of the coupling partners to the silyl
dichloride reagent. Dipeptide 12, with the bulkier a-side
chain on the N-unprotected amino ester, was obtained in
higher yield (89%) than dipeptide 13 (81%), where the
bulkier a-side chain is present on the free carboxylic acid
amino acid residue. This suggests that the first addition to the
silyl coupling reagent is that of the free amine residue, and the
second, more challenging addition, is that of the free
carboxylic acid residue. Importantly, the method was also
found to be fully compatible with both Boc and Cbz
protecting groups, although with some loss in yield when
[a] Yields of isolated products are given.
addition, silanes 4e and 4 f, lacking either one or both of
the aryl groups from the fluorenyl backbone, were also
synthesized through quenching of their Grignard adducts with
SiCl4 and tested in the peptide coupling. Worth noting is that
several attempted syntheses of silafluorenyl dichlorides 4ga
and 4ha yielded inseparable mixtures of both the desired
product and sila-spiro compounds 4gb and 4hb, and they
were not deemed to be viable coupling reagents owing to their
seemingly difficult synthesis.
Screening of these new halo-substituted 9-silafluorenyl
dichlorides (4b–4d) for the formation of the sterically
challenging Boc-l-Phe-l-Phe-OMe dipeptide (3) revealed
a clear enhancement of reaction yield when compared to
unsubstituted 9-silafluorenyl dichloride (Table 3). Impor-
tantly, silane 4c, bearing a chlorine atom in the 3-position of
the fluorenyl backbone, gave an enhanced yield (82%)
compared to silane 4b, which bears a chlorine in the
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Table 4: Scope of the peptide coupling reaction with dichlorosilane 4c.
residues only. To the best of our knowledge, this is the first
time that such reagents have been applied to these kinds of
transformations through a proposed chemical ligation mech-
anism. The findings of this study provide a strong proof of
concept that 9-silafluorenyl dichlorides can be efficiently used
in peptide coupling with promising results and minimal waste.
Work is currently ongoing in our laboratory towards a related
catalytic version of these ligating transformations under
smoother conditions.
Entry
Peptide
Yield[a] [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Boc-Gly-Gly-OMe (2)
99
91
82
61
89
81
77
82
69
86
66
65
81
78
72
85
64
Boc-Gly-l-Phe-OMe (10)
Boc-l-Phe-l-Phe-OMe (3)
Boc-l-Val-l-Phe-OMe (11)
Boc-l-Ala-l-Phe-OMe (12)
Boc-l-Phe-l-Ala-OMe (13)
Boc-l-Met-l-Phe-OMe (14)
Boc-l-Ser(OBn)-l-Ala-OMe (15)
Boc-l-Trp-l-Ala-OMe (16)
Boc-l-Asp(OBn)-Gly-OMe (17)
Boc-l-Pro-Gly-OMe (18)
Boc-l-Pro-l-Ala-OMe (19)
Boc-l-Pro-l-Phe-OMe (20)
Cbz-l-Ala-l-Phe-OMe (21)
Boc-Gly-l-Phe-l-Phe-OMe (22)
Boc-Gly-l-Phe-l-Phe-OMe (22)[b]
Boc-l-Phg-Gly-OMe (23)
Acknowledgements
This work was supported by the Fonds Quꢀbꢀcois de la
Recherche sur la Nature et les Technologies (FQRNT), the
Natural Science and Engineering Research Council of
Canada (NSERC), the Canada Foundation for Innovation,
the Canada Research Chair Program, the FQRNT Centre in
Green Chemistry and Catalysis, and Universitꢀ de Montrꢀal.
S.T. is grateful to the Universitꢀ de Montrꢀal for postgraduate
scholarships. P.C. is grateful to NSERC, FQRNT, Hydro-
Quꢀbec, and the Universitꢀ de Montrꢀal for postgraduate
scholarships.
[a] Yields of isolated products are given. [b] Synthesized using Boc-Gly-l-
Phe-OH and H2N-l-Phe-OMe·HCl under the standard conditions.
Cbz=benzyloxycarbonyl, PG=protecting group.
Keywords: amides · amino acids · peptides · silanes ·
synthetic methods
switching from N-Boc to N-Cbz amino acids (entries 5 and
14). More challenging amino acid residues with longer,
heteroatom-containing side chains were also found to be
well tolerated under our developed conditions, with dipep-
tides 15 to 17 being furnished in good yields. Finally, we
wished to investigate whether our method could be extended
to longer-chain peptide residues. As a proof of concept, Boc-
Gly-l-Phe-l-Phe-OMe (22) was synthesized from H2N-l-
Phe-l-Phe-OMe in 72% yield. The same tripeptide was also
synthesized in 85% yield in an N to C pathway using Boc-
Gly-l-Phe-OH and H2N-l-Phe-OMe·HCl (entry 16). In this
case, the often problematic diketopiperazine side product was
not observed, and the desired tripeptide was delivered in
a higher yield. Finally, Boc-l-Phg-OH was used for the
synthesis of dipeptide 23 (entry 17) to check for a possible
epimerization with such sensitive substrates. Chiral LC
analysis gave an enantiospecificity (es) of 86%.[19] Impor-
tantly, in all cases, the crude mixtures displayed a remarkable
purity according to 1H NMR spectroscopy, the polymeric
siloxane byproduct being removed by simple filtration along
with the ammonium salts.[20]
A series of in situ monitoring experiments were carried
out to identify the putative intermediate A (NMR, MS) but
we have been unable to unambiguously confirm its formation.
However, a series of control experiments support the
proposed mechanism (see the Supporting Information for
details).[20]
In conclusion, a range of new 9-silafluorenyl dichlorides
were synthesized and successfully applied in an unprece-
dented manner in peptide coupling reactions, with good to
excellent yields and limited epimerization on highly sensitive
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Received: June 23, 2016
Revised: August 18, 2016
Published online: && &&, &&&&
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Communications
Peptide Synthesis
S. J. Aspin, S. Taillemaud, P. Cyr,
A. B. Charette*
&&&& — &&&&
9-Silafluorenyl Dichlorides as Chemically
Ligating Coupling Agents and Their
Application in Peptide Synthesis
A chemical ligation mechanism was pro-
posed for amide bond formation with 9-
silafluorenyl dichlorides as new coupling
reagents. This approach enabled the
synthesis of peptides in a simple and
unprecedented manner without preacti-
vation of either the carboxylic acid or
amine termini of the amino acids.
6
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