The breaking beads approach for photocleavage from solid support

Article abstract of DOI:10.1039/d0ob00821d

Photocleavage from polystyrene beads is a pivotal reaction for solid phase synthesis that relies on photolabile linkers. Photocleavage from intact porous polystyrene beads is not optimal because light cannot penetrate into the beads and the surface area exposed to irradiation is limited. Thus, hazardous, technically challenging and expensive setups are used for photocleavage from intact beads. We developed a new concept in which grinding the beads during or prior to irradiation is employed as an essential part of the photocleavage process. By grinding the beads we are exposing more surface area to the light source, hence, photocleavage can be performed even using a simple benchtop LED setup. This approach proved very efficient for photocleavage of various model compounds including fully protected oligosaccharides.

Full text of DOI:10.1039/d0ob00821d

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Bakhatan, I.
Alshanski, D. Grunhaus and M. Hurevich, Org. Biomol. Chem., 2020, DOI: 10.1039/D0OB00821D.
Volume 15
Number 47
21 December 2017
Pages 9945-10124
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
Accepted Manuscripts are published online shortly after acceptance,
rsc.li/obc
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
ISSN 1477-0520
PAPER
I . J. Dmochowski et al.
Oligonucleotide modifi cations enhance probe stability for
shall the Royal Society of Chemistry be held responsible for any errors
single cell transcriptome in vivo analysis (TIVA)
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 6
View Article Online
DOI: 10.1039/D0OB00821D
ARTICLE
The Breaking Beads Approach for Photocleavage from Solid
Support
Yasmeen Bakhatan[a], Israel Alshanski[a], Dana Grunhaus[a] and Mattan Hurevich[a]*
Received 00th January 20xx,
Accepted 00th January 20xx
Photocleavage from polystyrene beads is a pivotal reaction for solid phase synthesis that relies on photolabile linkers.
Photocleavage from intact porous polystyrene beads is not optimal because light cannot penetrate into the beads and the
surface area exposed to irradiation is limited. Thus, hazardous, technically challenging and expensive setups are used for
photocleavage from intact beads. We developed a new concept in which grinding the beads during or prior to irradiation is
employed as an essential part of the photocleavage process. By grinding the beads we are exposing more surface area to
the light source, hence, photocleavage can be performed even using a simple benchtop LED setup. This approach proved
very efficient for photocleavage of various model compounds including fully protected oligosaccharides.
DOI: 10.1039/x0xx00000x
reactors rely on the use of mercury lamps which is hazardous.
Second, light-emitting diode LED in flow reactor is becoming
more common, which is safer, demands the assembly of
Introduction
Photolabile groups provide an additional level of orthogonality
to other common protecting groups.1-3 They are used as handles
to connect solid support to a synthesized molecule in solid
phase synthesis (SPS).4 These linkers are very attractive for SPS
because they are stable to many reaction conditions and can be
liberated under very mild conditions.5-16 Photolabile linkers are
especially valuable for oligosaccharide and glycoconjugate
synthesis because they proved to be orthogonal and stable to
complicated home-made setups or the purchasing of
commercially available and expensive ones. Third, there is
always a risk of insufficient spacing between beads which can
hamper the efficiency of cleavage. Fourth, flow reactors cannot
be paused during irradiation to check for progress.6, 14-16 It is
difficult to reach high cleavage efficiency even in flow probably
because light cannot penetrate the inner part of the beads.24
As a common solid phase practice, the integrity of the beads is
preserved in these photocleavage processes.31 We figured that
since the photocleavage is the last step performed on the solid
support, the integrity of the beads is not important anymore. A
recent report suggested that after stirring polystyrene beads
with a magnetic bar, the ground beads are much smaller than
the original mesh size but are still big enough to be separated
from the cleaved product by simple filtration of the solution.32,
the
multiple
synthetic
manipulations
required.17-23
Photochemical reactions on the solid support are not as
straightforward as in a solution. Polystyrene beads are
insoluble, not transparent and porous. The efficiency of
irradiation depends on the ability of the light not only to cover
the entire surface of the beads but also to penetrate into the
pores that contain the synthesized molecules anchored to
photolabile linkers. Therefore, batch irradiation of solid support
tends to suffer from heterogeneity problems, and
photocleavage is inefficient.24 Irradiation by mercury lamp in
continuous flow reactors provides more efficient photocleavage
because the beads are exposed to the light for a longer time and
from a close distance.25-27 Flow-based irradiation reactor is a
technical improvement that contributed dramatically to
expedite automated synthesis of even extremely large
oligosaccharides and made photolabile linkers the preferred
choice for these transformations.28-30 However, the irradiation
of solid material in flow is still very challenging. First, many
33
We assumed that grinding the beads during the irradiation
will increase the surface area exposed to light and might
improve cleavage efficiency while it will not hamper the simple
filtration separation process. Here, we present a simple
benchtop light-emitting diode (LED) batch system for
photocleavage from the solid support. The system takes
advantage of magnetic stirring to grind the beads during or
before irradiation in to expose more surface area to the light
source. We evaluated the effect of stirring and the size of the
beads on the irradiation efficiency and on the ability to cleave
protected oligosaccharides.
a. Department: The institute of chemistry and The Harvey M. Kreuger Family Center
for Nanoscience and Nanotechnology
Institution: The Hebrew University of Jerusalem.
Results and Discussion
Address: Jerusalem, 91904, Israel.
E-mail: mattan.hurevich@mail.huji.ac.il
Preparation and labelling of photolabile linkers.
Two different photocleavage handles 1 and 2 were prepared in
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
a solution following previously reported procedure.20, 25, 26
A
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 6
ARTICLE
Journal Name
Merrifield resin was treated with 1 under basic conditions to
provide hydroxyl functionalized photolabile linker HP-Linker
(Scheme 1). The HP-Linker was reacted with Fmoc-Cl to provide
FHP-Linker that can be used for loading quantification and
cleavage efficiency evaluation. Similarly, Merrifield resin was
treated with 2 to provide amine functionalized photolabile
linker AP-Linker. The amine of AP-Linker was reacted with
fluorescein to provide the fluorescent photolabile linker FlAP-
Linker for the evaluation of cleavage efficiency by fluorescent
microscopy.
View Article Online
DOI: 10.1039/D0OB00821D
O2N
O2N
O2N
Figure 2. Irradiation without stirring resulted in incomplete cleavage. A) Fluorescent
(left) and regular microscopy images (right) of FlAP-Linker before irradiation. B)
Fluorescent (left) and regular microscopy images (right) of FlAP-Linker after irradiation
for four hours of irradiation without stirring.
c
OH
O
a,b
O
N
6
HO
N
6
HO
N
6
Cbz
FmocO
Cbz
Cbz
1
HP-Linker
FHP-Linker
Cl
O2N
O2N
O2N
The inefficiency of Irradiation of the photolinker without stirring.
O
a,b,d
e
OH
N
H2N
O
Cbz
N
N
BocHN
FlHN
6
FlAP-Linker was irradiated for 2-8 hours in the LED setup
without stirring (Figure 2 and SI). Fluorescent microscopy
images of the beads were taken after each irradiation
experiment and the mean fluorescence intensity was calculated
and compared to the beads before irradiation (SI). The
fluorescence intensity of the beads decreased as a factor of
Cbz
Cbz
AP-Linker
6
6
FlAP-Linker
2
Scheme 1. Synthesis and labelling of amino and hydroxyl photolinkers. Reagents and
conditions: a) DMF/DCM, CsCO3, TBAI, 24 h, 60 °C, 870 mbar. b) CsOAc, DMF, 24 h, 60°C,
870 mbar. c) Fmoc-Cl, piperidine/DCM. d) 10 % TFA/DCM, twice 10 min. e) DMF/DCM,
DIPEA, DIC, HOBt, fluorescein, 24 h.
irradiation
time
showing
that
N-Cbz-N-fluorescein-
Photocleavage setup and cleavage procedure.
hexanediamine 4 was cleaved from the solid support. After four
hours of irradiation, there was still a significant fluorescence
signal of the beads (Figure 2B). Full cleavage was not observed
even after eight hours of irradiation. The images also showed
that the integrity of the beads is preserved during irradiation
without stirring. This suggests that either the mixing inefficiency
hampered the exposure of the beads to light or/and that the
ability of UV irradiation to penetrate the beads is limited. To
overcome this potential limitation, we assumed that magnetic
stirring, which increases the mixing efficiency and grinds the
beads, can enhance the exposure to the light source and
improve the photo-cleavage efficiency.33
In our irradiation setup, 25-100 mg of solid support was inserted
into a quartz cuvette with a magnetic bar and 2 ml of
dichloromethane (DCM) were added. This cuvette was placed
on a stirring plate (Figure 1A). A high Power 365 nm LED lamp
was positioned in a 2 cm distance from the cuvette and the
entire setup was covered prior to commencing irradiation
(Figure 1A). After irradiation, the beads were transferred and
collected in a fritted filter Sep-Pak. The cleavage efficiency was
determined either by the Fmoc quantification of the remaining
uncleaved product (FHP-Linker) or by fluorescent microscopy
(FlAP-Linker) (Figure 1). The DCM filtrate from the initial
washing was used to quantify the amount of linker that was
cleaved by irradiation as will be demonstrated later.
The effect of magnetic stirring rate on photocleavage efficiency.
Four irradiation experiments using FHP-Linker were performed
at increasing magnetic stirring rates. Each irradiation was
performed for four hours and after each irradiation experiment,
the cleavage efficiency was determined using a standard Fmoc
quantification analysis (Figure 3).33, 34 This analysis showed that
increasing the stirring rate improves cleavage efficiency. Stirring
at 1060 rpm for four hours provided a cleavage of over 80%. The
integrity of the beads was visualized by microscopy and showed
that increasing the stirring rate enhanced the deformation of
the beads (Figure 3A). It is possible that elevated stirring rates
improve the exposure of the particles to the UV light that leads
to an increase in cleavage efficiency. Another option is that by
increasing the magnetic stirring rate we are applying stronger
compressive forces on the beads which grind them to smaller
particles with larger surface area. Such process will expose
more photolinker to the light which suggests that the
photocleavage efficiency depends on the size of the beads
rather than on the mixing rate itself.
Figure 1. A) LED based photocleavage irradiation setup with stirring. After irradiation,
the product was separated from the solid support by a simple filtration. B) Photo
cleavage of FHP-linker to give NA-linker and N-Cbz-O-Fmoc-hexanolamine, 3. C) Photo
cleavage of FIAP-linker to give NA-linker and N-Cbz-N-fluorescein-hexanediamine 4.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 6
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
cleaved material in the filtrate relies on the use of known
View Article Online
DOI: 10.1039/D0OB00821D
standards and precise analytical protocol. It can be used to
evaluate the efficiency of photocleavage setups or photolabile
linkers. Considering the ongoing debate regarding the accuracy
of Fmoc quantification protocols,35 we feel that our analytical
evaluation of the cleavage is a very good alternative.
To prove the applicability of the method to larger amount of
solid support, we irradiated 100 mg of FHP-Linker for four
hours, evaporated the filtrate solvent and took proton, and
carbon NMR spectra of the cleaved compound 3 without any
purification (SI). The NMR analysis showed a spectrum that
matched to 3 that was synthesized in solution. HRMS and NMR
proved that the new cleavage process can provide clean
products. This also confirms that the process will afford enough
material for biology studies.
Figure 3. Irradiation of FHP-Linker at increasing stirring rate enhanced cleavage
efficiency and the grinding of the solid support beads.
The contribution of grinding the beads prior to photocleavage.
Four to six hours of irradiation is relatively short compared with
common protecting groups removal protocols like
hydrogenolysis using atmospheric hydrogen (8-16 h) but it is still
long compared to standard solid phase cleavage duration like
with TFA (1-4 h) or standard flow photocleavage (1-2 h). This
might limit the number of irradiation experiments that can be
performed in a typical workday. We decided to grind the beads
prior to the irradiation in order to check the influence of beads
size on cleavage efficiency. We stirred FHP-Linker beads for four
hours at 1060 rpm without irradiation. The ground FHP-Linker
beads were then irradiated only for one hour using 1060 rpm
stirring. As a control, we irradiated FHP-Linker beads that were
not pre-grinded under the same conditions. Fmoc
quantification after irradiation of the pre-grinded beads
showed that over 80% of the linker was cleaved off while in the
control experiment only 40% was cleaved (Figure 5).
Microscope analysis after irradiation showed that the pre-
grinded samples contained particles that are much smaller in
comparison with the control. Fluorescence microscopy images
demonstrating bleaching of ground FlAP-Linker beads mesh
after irradiation further demonstrate the difference that results
from the cleavage protocol (SI).
Time-dependent photocleavage efficiency.
We checked what will be the time required to achieve optimal
photocleavage. We irradiated FHP-Linker at 1060 rpm for one
up to six hours (Figure 4). Cleavage efficiency was determined
by Fmoc quantification of the beads after irradiation. The
cleavage after six hours reached over 80%. As an orthogonal
analysis, the amount of cleaved N-Cbz-O-Fmoc-hexanolamine 3
in the filtrate was quantified by UV spectroscopy.
To achieve this, 3 was synthesized in solution and diluted to
provide standard solutions at different concentrations. These
solutions were used to prepare a calibration curve to correlate
between the concentration of 3 and absorbance at 301 nm.
Measuring the UV absorbance of the filtrate solution after
irradiation and fitting it to the calibration curve enabled us to
determine the cleavage efficiency by different methods (Figure
4 and SI). There was a clear correlation between the cleavage
efficiency determined by the amount of 3 in the filtrate to the
one calculated by Fmoc quantification for the beads (Figure 4).
The slightly lower cleavage yields calculated for the filtrate are
probably because we applied only two DCM washes without
shaking and some of the product remains inside the beads. The
accurate quantitative method to evaluate the amount of
Figure 4. Irradiation time effect on cleavage efficiency. The efficiency of cleavage was evaluated by: Left) the quantity of cleaved compound 3 in the filtrate was calculated from
absorbance calibration curve (SI). Right) the amount of linker left on the solid support was determined based on standard Fmoc quantification analysis.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 6
ARTICLE
Journal Name
View Article Online
The rest of the process was performed uDsiOnIg: 1t0y.p10ic3a9/lDa0uOtoB0m0a8t2e1Dd
glycan assembly (AGA) protocols.19 Glycosylations of Fmoc
protected thiomannoside 6 was performed using NIS/TfOH as
activators at low temperature after which Fmoc was removed
and another glycosylation cycle was performed using the exact
conditions as the first one. We intentionally kept the Fmoc on
the disaccharide to enable us to determine the efficiency of
cleavage using spectroscopic analytical methods. After the
second glycosylation, the solid support was removed from the
reaction vessel and the quantity of Fmoc was determined. The
calculated loading after AGA was 0.392 mmol/g because 30 %
of the mass of the beads were attributed to the protected
saccharide. Disaccharide 5 was cleaved off from the same
amount of beads using two irradiation methods. Beads were
irradiated either for one hour without stirring or while stirring
at 1060 rpm after four hours of pre-grinding. After each
cleavage, the amount of Fmoc that remains on the solid support
was determined. The calculated Fmoc loading after irradiation
without stirring was 0.376 mmol/g. This implies that only 6% of
the disaccharide was cleaved. The calculated Fmoc loading
determined following irradiation with stirring after pre-grinding
the beads was 0.09 mmol/g. This shows that using the new
cleavage protocol, 77%. We also calculated the cleavage yield
by measuring the mass of 5 obtained after irradiation of beads
with or without pre-grinding. The yield of photocleavage was
74.3% and 4.2% with and without grinding, respectively, which
is in agreement with the efficiency determined by Fmoc
monitoring. After irradiation of 5 using the breaking beads
protocol, the crude filtrate was collected and analyzed by HPLC,
NMR, and MS showing a purity of over 95%. Disaccharide 5
contains eight aromatic moieties and is a good model for a
typical oligosaccharide synthesized on such linkers.17, 29, 37 The
irradiation studies performed on disaccharide 5 confirms that
the new strategy is applicable for complex compounds and
further highlights the profound advantage of the new cleavage
strategy.
Figure 5. Irradiation of FHP-Linker with and without pre-grinding of the beads. This led
to increase in cleavage efficiency. Grinding the beads four hours prior to one hour of
irradiation significantly increased cleavage efficiency compared to the irradiation of
intact beads.
Since irradiation time and stirring rate were identical in both
experiments, it suggested that the increased surface area
contributed to the great cleavage efficiency, and not only the
stirring rate itself. To explore this effect, the active area of the
irradiated particles was calculated based on the diameter
measures in a microscope before and after grinding (SI). Our
calculations show that grinding increases the active area by a
magnitude of 80. This explains the ability to photocleavage
more compound from the pre-grinded particles in 1 h that from
intact beads in 4 h (Fig 3, 100 rpm compared with Fig 5, right).
Achieving over 80% cleavage in only one hour of irradiation
suggests that pre-grinding can be used as a routine to expedite
the process and enable multiple experiments in a typical
workday. To determine whether the mixing rate or the size of
the beads is the crucial factor in photocleavage, irradiation of
complete and ground beads was performed in identical
conditions on a linear shaker at 210 rpm (SI) Unlike magnetic
stirring, shaking does not grind the beads hence the size of the
beads is maintained during the entire cleavage process.33, 36
Although in both cases the mixing rate and time were identical,
irradiation of ground beads in the shaker resulted in 58%
cleavage while only 10.6% of the linker was cleaved off from
intact beads. Since the efficiency in irradiating ground beads
compared to complete ones was still significant, it confirms that
the size of the beads and not the mixing rate is the detrimental
factor in accelerating photocleavage. This suggests that
photocleavage from ground beads instead of from intact ones
might be advantageous also for other irradiation setups.
In all our studies, browning of the resin was observed during
irradiation. Browning of polystyrene beads is
a known
phenomenon that probably results from the formation of
nitrosoaldehyde during photocleavage.38 Such moiety, which
absorbs UV light, might decrease the efficiency of
photocleavage overtime.38
without grinding the beads
OBz
O
FmocO
BnO
BnO
Yield = 6%
OBz
O
FmocO
BnO
hv
6
SEt
BnO
O
OBz
O
AGA x 2
HP-Linker
BnO
BnO
5
O(CH2
)6NHCbz
hv
Fmoc deprotection
Yield = 77%
after grinding the beads
Scheme 2: Synthesis of disaccharide by AGA. The disaccharide was synthesized on HP-
Linker in glyconeer 2.1 from two monomers by performing one cycles of
Synthesis of α-1-6-Mannose disaccharide and its removal from the
support using the breaking beads approach.
glycosylation/deprotection followed by
a second glycosylation. Afterwards, the
saccharide cleaved by UV irradiation with and without grinding the beads prior to
irradiation.
The fully protected α-1-6-dimannose 5 was synthesized on the
FHP-Linker using automated synthesizer glyconeer 2.1 (Scheme
2). HP linker was placed in the glyconeer 2.1 reaction vessel.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 6
Organic & Biomolecular Chemistry
Please do not adjust margins
Journal Name
ARTICLE
However, by grinding the beads prior to irradiation we make
sure that the surface area is large enough to minimize the effect
of browning on photocleavage. The accuracy of our calculated
cleavage efficiency using three orthogonal methods proves that
the browning does not play a crucial role when our method is
used. Although the nature of the Merrifield polystyrene resin
itself might also contribute to this phenomenon, replacing it
with another solid support might hamper its applicability for
peptide and oligosaccharide synthesis. Using smaller beads with
a higher amount of light accessible surface area.
Acknowledgements
View Article Online
The authors thank Prof. Meital Reches fDoOr Im: 1i0c.r1o03s9c/oDp0yOaBn00a8ly2s1iDs
and Prof. Shlomo Yitzchaik for LED irradiation system.
Notes and references
1.
V. San Miguel, C. G. Bochet and A. del Campo, J. Am. Chem. Soc., 2011,
133, 5380-5388.
2.
3.
P. F. Wang, Asian J. Org. Chem., 2013, 2, 452-464.
M. Samarasimhareddy, I. Alshanski, E. Mervinetsky and M. Hurevich,
Synlett, 2018, 29, 880-884.
As a note, the exact irradiation efficiency might be setup-
dependent. Although there might be variability when the
cleavage will be performed by the similar setup in other labs,
the differences between irradiation of beads with and without
grinding were reproduced multiple times. Furthermore, we
demonstrated that the grinding effect was detrimental for both
stirrer and shaker setups, proving the validity and generality of
the observation. It is logical to think that the presence of UV
active moieties on peptides or saccharides might decrease the
efficiency of irradiation. However, photocleavage of
biopolymers have been demonstrated even with up to
hundreds of UV active moieties.28, 29 The effect of grinding the
beads will not have any negative effect on the efficiency. In
contrast, as demonstrated for disaccharide 5, the enhanced
exposure will make sure that the process still surpasses the
common strategies and might provide an advantage when
many UV absorbing groups are present. Many reports in the
past failed to reach efficient cleavage yields. Most of these
methods rely on very powerful setups sometimes apply filters
or rely on expensive flow systems.6, 14-16, 19, 25 We rely on a LED
lamp with a specific wavelength, do not use any filters and the
setup is as simple as it gets. Still, we managed to get
reproducible and high yield cleavage. Moreover, since we use a
batch reactor, we do not risk any clogging and can also stop for
checking the progress at any time.
4.
5.
H. Venkatesan and M. M. Greenberg, J. Org. Chem., 1996, 61, 525-529.
C. G. Bochet, J. Chem. Soc. Perk. Trans. 1, 2002, DOI: 10.1039/b009522m,
125-142.
R. J. T. Mikkelsen, K. E. Grier, K. T. Mortensen, T. E. Nielsen and K.
Qvortrup, Acs Comb. Sci., 2018, 20, 377-399.
C. M. Acevedo, N. A. Rahman and M. A. Lipton, Abstr. Pap. Am. Chem. S.,
2002, 223, B210-B210.
G. Barany and F. Albericio, J. Am. Chem. Soc., 1985, 107, 4936-4942.
C. DellAquila, J. L. Imbach and B. Rayner, Tetrahedron Lett., 1997, 38,
5289-5292.
L. Y. Qin, A. G. Cole, A. Metzger, L. O'Brien, X. L. Sun, J. Wu, Y. Xu, K. Xu, Y.
Zhang and I. Henderson, Tetrahedron Lett., 2009, 50, 419-422.
K. Qvortrup, V. V. Komnatnyy and T. E. Nielsen, Org. Lett., 2014, 16, 4782-
4785.
S. M. Sternson and S. L. Schreiber, Tetrahedron Lett., 1998, 39, 7451-7454.
P. L. Williams, M. Gairi, F. Albericio and E. Giralt, Tetrahedron, 1991, 47,
9867-9880.
C. P. Holmes, J. Org. Chem., 1997, 62, 2370-2380.
C. P. Holmes and D. G. Jones, J. Org. Chem., 1995, 60, 2318-2319.
R. Minkwitz and M. Meldal, Qsar Comb. Sci., 2005, 24, 343-353.
P. Dallabernardina, F. Schuhmacher, P. H. Seeberger and F. Pfrengle,
Chem. Eur. J., 2017, 23, 3191-3196.
H. S. Hahm, M. Hurevich and P. H. Seeberger, Nat. Commun., 2016, 7.
H. S. Hahm, M. K. Schlegel, M. Hurevich, S. Eller, F. Schuhmacher, J.
Hofmann, K. Pagel and P. H. Seeberger, Proc. Natl. Acad. Sci. U S A, 2017,
114, E3385-E3389.
M. Hurevich and P. H. Seeberger, Chem. Commun., 2014, 50, 1851-1853.
K. C. Nicolaou, N. Watanabe, J. Li, J. Pastor and N. Winssinger, Angew.
Chem. Int. Ed., 1998, 37, 1559-1561.
K. C. Nicolaou, N. Winssinger, J. Pastor and F. DeRoose, J. Am. Chem. Soc.,
1997, 119, 449-450.
D. Senf, C. Ruprecht, G. H. M. de Kruijff, S. O. Simonetti, F. Schuhmacher,
P. H. Seeberger and F. Pfrengle, Chem Eur. J., 2017, 23, 3197-3205.
K. L. M. Hoang, A. Pardo-Vargas, Y. T. Zhu, Y. Yu, M. Loria, M. Delbianco
and P. H. Seeberger, J. Am. Chem. Soc., 2019, 141, 9079-9086.
S. Eller, M. Collot, J. Yin, H. S. Hahm and P. H. Seeberger, Angew. Chem. Int.
Ed., 2013, 52, 5858-5861.
M. Hurevich, J. Kandasamy, B. M. Ponnappa, M. Collot, D. Kopetzki, D. T.
McQuade and P. H. Seeberger, Org. Lett., 2014, 16, 1794-1797.
D. Budhadev, K. Saxby, J. Walton, G. Davies, P. C. Tyler, R. Schworer and M.
A. Fascione, Org. Biomol. Chem., 2019, 17, 1817-1821.
O. Calin, S. Eller and P. H. Seeberger, Angew. Chem. Int. Ed., 2013, 52,
5862-5865.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
Conclusions
In summary, a new approach to cleave compounds from
photolabile linkers on solid support was described. A simple
combination of a benchtop LED irradiation and magnetic stirring
provides efficient photocleavage. By using a number of
complementary analytical techniques, we showed that
increasing the surface area of the polystyrene beads by grinding
expedite photocleavage. The strategy was demonstrated for a
fully protected oligosaccharide model, which proves that it is
straightforward, applicable for bio relevant targets, and can be
done in any standard laboratory. This can make the use of
photolabile linkers more accessible to the community. The
method can be very valuable for cleaving complex molecules
from photolabile linkers in high efficiency.
K. Naresh, F. Schumacher, H. S. Hahm and P. H. Seeberger, Chem.
Commun., 2017, 53, 9085-9088.
M. Wilsdorf, D. Schmidt, M. P. Bartetzko, P. Dallabernardina, F.
Schuhmacher, P. H. Seeberger and F. Pfrengle, Chem. Comm., 2016, 52,
10187-10189.
A. Isidro-Llobet, M. N. Kenworthy, S. Mukherjee, M. E. Kojach, K. Wegner,
F. Gallou, A. G. Smith and F. Roschangar, J. Org. Chem., 2019, 84, 4615-
4628.
31.
32.
33.
W. Li, T. Suzuki and H. Minami, Angew. Chem. Int. Ed., 2018, 57, 9936-
9940.
I. Alshanski, M. Bentolila, A. Gitlin-Domagalska, D. Zamir, S. Zorsky, S.
Joubran, M. Hurevich and C. Gilon, Org. Process. Res. Dev., 2018, 22, 1318-
1322.
S. Eissler, M. Kley, D. Bächle, G. Loidl, T. Meier and D. Samson, J. Pept. Sci.,
2017, 23, 757-762.
34.
35.
36.
37.
38.
O. Al Musaimi, A. Basso, B. G. de la Torre and F. Albericio, Acs Comb. Sci.,
2019, 21, 717-721.
J. N. Naoum, I. Alshanski, A. Gitlin-Domagalska, M. Bentolila, C. Gilon and
M. Hurevich, Org. Process. Res. Dev., 2019, 23, 2733-2739.
Y. Yu, S. Gim, D. Kim, Z. A. Arnon, E. Gazit, P. H. Seeberger and M.
Delbianco, J. Am. Chem. Soc., 2019, 141, 4833-4838.
A. Ajayaghosh and V. N. R. Pillai, Tetrahedron, 1988, 44, 6661-6666.
Conflicts of interest
There are no conflicts to declare.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 6
ARTICLE
Journal Name
View Article Online
DOI: 10.1039/D0OB00821D
TOC entry text : Grinding of polystyrene beads accelerates
photocleavage
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins