Synthesis of adamantane-based trimeric benzoboroxoles

Article abstract of DOI:10.1002/ejoc.201300769

Benzoboroxoles are known to bind 1,2-diol motifs in carbohydrates in an aqueous environment. Their binding properties have been shown to be dependent on additional recognition sites such as peptides and the number of binding epitopes. In this paper we describe the synthesis of trimeric benzoboroxoles based on a rigid adamantyl core structure. The conjugates are assembled using copper-catalyzed click reactions of azide scaffolds with alkynyl-functionalized benzoboroxoles. The design of our trimeric benzoboroxoles followed a biomimetic principle and imitates the trimeric structure of some natural carbohydrate binding proteins (lectins). With an assortment of appropriately functionalized (3 + 1) adamantane scaffolds, trimeric benzoboroxoles have been generated which were combined with additional functional molecules such as dyes and peptides. In summary, we report a highly effective synthetic approach to modular trimeric boronolectines for the assembly of carbohydrate sensors.

Full text of DOI:10.1002/ejoc.201300769

FULL PAPER
DOI: 10.1002/ejoc.201300769
Synthesis of Adamantane-Based Trimeric Benzoboroxoles
Dorith Claes,[a] Malte Holzapfel,[a] Nadine Clausen,[b] and Wolfgang Maison*[a]
Keywords: Medicinal chemistry / Carbohydrate recognition / Click chemistry / Alkynes / Heterocyles / Boron
Benzoboroxoles are known to bind 1,2-diol motifs in carbo-
followed a biomimetic principle and imitates the trimeric
hydrates in an aqueous environment. Their binding proper- structure of some natural carbohydrate binding proteins (lec-
ties have been shown to be dependent on additional recogni-
tion sites such as peptides and the number of binding epi-
topes. In this paper we describe the synthesis of trimeric
benzoboroxoles based on a rigid adamantyl core structure.
The conjugates are assembled using copper-catalyzed click
reactions of azide scaffolds with alkynyl-functionalized
benzoboroxoles. The design of our trimeric benzoboroxoles
tins). With an assortment of appropriately functionalized
(3 + 1) adamantane scaffolds, trimeric benzoboroxoles have
been generated which were combined with additional func-
tional molecules such as dyes and peptides. In summary, we
report a highly effective synthetic approach to modular tri-
meric boronolectines for the assembly of carbohydrate sen-
sors.
Introduction
tances less than 2 nm. It might therefore be possible to
mimic these trimeric binding sites with relatively small mo-
lecules resembling a tripodal carbohydrate recognition mo-
tif.
Carbohydrates are a complex and fascinating class of
biomolecules with various functions in metabolism, as
structural substances and for energy storage.[1] In addition,
carbohydrates play a key role in cell differentiation, cell–cell
and cell–pathogen interactions.[2] In nature, carbohydrates
are recognized by carbohydrate binding proteins, the lec-
tins.[3] Water-soluble lectins (e.g. MBP – Mannose binding
Protein) are used as a first line of defense by the immune
system in recognizing glycotopes on pathogens.[4] Other lec-
tins, such as DC-SIGN, hemagglutinine and CD22 are key
players in viral infections and the immune response.[5] Mim-
icking lectins with small molecules is therefore a highly at-
tractive goal in medicinal chemistry.
Lectins contain one or more carbohydrate recognition
domains (CRDs). As most monomeric carbohydrate–lectin
interactions are of weak affinity and specificity,[6] nature
uses multiple protein–carbohydrate interactions (resulting
in the cluster glycoside effect)[7] to strengthen and specify
the binding process through establishment of multival-
ency.[8] Many multimeric lectins have geometrically defined
multimeric recognition motifs and important derivatives are
trimeric assemblies.[4a,8a] In several pharmaceutically rel-
evant lectins, such as DC-SIGN,[9] the CRDs are assumed
to be assembled closely in a tripodal geometry with dis-
However, achieving carbohydrate binding with small mo-
lecules remains a challenge and only a limited set of struc-
tures has been shown to have useful binding affinities in
water.[10] Boronic acids bind selectively and with reasonable
affinities to different carbohydrates.[11] Particularly, ortho-
donor substituted arylboronic acids (Wulff-type, 1) have
been used as carbohydrate binders because they bind to diol
motifs under aqueous, pH-neutral conditions.[12] Wulff-type
boronic acids with a hydroxymethyl group as donor, so
called “benzoboroxoles” or “benzoxaboroles” (general
structure 2 in Figure 1)[13] have also been studied exten-
sively.[14] They showed reasonable binding affinities and
selectivities for non-reducing sugars in aqueous solution.[15]
Selectivity and affinity of these boronic acids are influenced
by multimerization and additional moieties (e.g. aromatic
rings or peptides) that interact with carbohydrates.[16] These
conjugates have been termed boronolectins and two exam-
ples are depicted in Figure 2.[17] Anslyn reported tripodal
boronic acid 3 containing an aromatic core structure. This
trimer binds to heparin, a useful property for biomedical
applications.[18] Hall reported dimeric benzoboroxole 4
which is able to bind to the TF antigen present on 90% of
human cancer cells.[19] As the same structure lacking the
boronic acids also showed a small but measurable binding
affinity to the TF antigen, it was shown that the boronic
acid moieties influence the binding affinity significantly but
that the overall binding affinity is due to the additional
presence of the peptide.
[a] Department of Chemistry, Pharmaceutical and Medicinal
Chemistry, University of Hamburg,
Bundesstraße 45, 20146 Hamburg, Germany
E-mail: maison@chemie.uni-hamburg.de
Homepage: http://www.chemie.uni-hamburg.de/pha/phachem/
maison/index.html
[b] Institut für Integrative und Experimentelle Genomik,
University of Lübeck
Ratzeburger Allee 160, 23538 Lübeck, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300769.
Herein we describe the synthesis of tripodal boronolec-
tins based on an adamantyl scaffold. The rigid adamantyl
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D. Claes, M. Holzapfel, N. Clausen, W. Maison
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Figure 1. In aqueous solution, boronic acids bind reversibly to diols. Donor-substituted derivatives of arylboronic acids such as the Wulff-
type boronic acids 1 or benzoboroxole 2 combine good chemical stability with a relatively high binding affinity to carbohydrates in
aqueous solution.
8b with one or two carboxylic acids in the side chains,
respectively. Both derivatives were synthesized starting from
cyanoethyl derivatives 5a and 5b (Scheme 1).[24] These start-
ing materials were initially converted into acetamides 6a
and 6b by a Ritter reaction; hydrolysis of the amide and the
cyanide afforded adamantylamino acids 7a and 7b, which
were then protected with Boc2O to give Boc-protected scaf-
folds 8a and 8b.
Figure 2. Selected examples for peptide boronolectins: Anslyn’s
heparin receptor 3 and Hall’s dimeric benzoboroxole 4 which is
able to recognize the TF-antigen.[17,18]
core structure allows the conjugation of three benzoborox-
oles and a reporter moiety such as a fluorescence dye.
Results and Discussion
Synthesis of Adamantyl Scaffolds
Scheme 1. Synthesis of Boc-protected adamantyl scaffolds 8a and
Adamantyl derivatives are versatile tetrahedral (3 + 1)
8b with one and two carboxylic acids for the conjugation of benzo-
scaffolds with a range of applications in Medicinal Chemis-
try,[20] Material Science[21] and Supramolecular Chemis-
try.[22] A number of appropriately functionalized adamantyl
boroxoles.
Following a modular design approach of our tripodal
scaffolds such as 8a–d (Scheme 1) are readily available in a boronolectins, we wanted to be able to include additional
few steps from adamantane as a cheap precursor.[23] Scaf- (peptidic) binding motifs next to the benzoboroxoles. Scaf-
folds 8c–d have three carboxylic acid side chains for the folds 8a–d were thus coupled to l-azidohomoalanine 10 to
conjugation of boronic acids (for the assembly of the tripo- give 11a–d (Scheme 2), ideal precursors for the attachment
dal carbohydrate recognition domain) and a fourth position of benzoboroxoles through application of copper-catalyzed
with a primary amine which may be coupled to an ad- cycloaddition of the azide moiety. In addition, the benzyl
ditional functional molecule such as a fluorescent dye. For ester provides an orthogonally protected conjugation site
a systematic study of the binding properties of our trimeric for peptides as an additional element of molecular recogni-
boronolectins, we were also interested in scaffolds 8a and tion. With scaffolds 11a–d in hand, a set of modular com-
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Synthesis of Adamantane-Based Trimeric Benzoboroxoles
Scheme 2. Deprotection of l-azidohomoalanine 9a to the corresponding hydrochloride 10 and the preparation of modular scaffolds 11a–
d. DIEA: N,N-diisopropylethylamine, HATU: O-(7-azabenzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium hexafluorophosphate, HOBt:
hydroxybenzotriazole, EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.
pounds was now available allowing for assembly of boron-
olectins with different numbers and distances of benzo-
boroxoles as carbohydrate recognition motifs.
Assembly of Boronolectins
For the attachment of boronic acids to scaffolds 11a–
d using copper-mediated cycloaddition,[25] suitable alkyne
derivatives are required. We previously reported the synthe-
sis of “clickable” boronic acids and have slightly modified
our protocol as depicted in Scheme 3.[26] The preparation
of alkynyl benzoboroxole 15 starts from commercial alde-
hyde 12 which, after protection and addition of an acet-
ylide, gave pinacol ester 13, following our established proto-
col. To avoid problems with pinacol deprotection and to
simplify the purification of the boronate ester, 13 was then
Scheme 3. Improved synthetic protocol for the synthesis of alk-
converted to 14 with diethanolamine. Boronate 14 can be
easily purified by crystallization.[27] Treatment with HCl ul-
timately afforded target benzoboroxole 15 in a few steps
with good overall yield.
ynylboronic acid 15.
side reaction in previous studies and have therefore used
With scaffolds 11a–d and benzoboroxole 15 in hand we CsF as an additive for our cycloadditions. CsF has been
sought to conjugate them through application of “click reported to suppress deboronation by in situ formation of
chemistry”. Derivatives of arylboronic acids can be prob- boronic acid fluorides.[28] However, with benzoboroxole 15
lematic substrates for CuI-catalyzed cycloadditions due to and scaffolds like 11a–d, this protocol (10 mol-% TBTA,
their propensity for deboronation. We had observed this 10 mol-%, CuBr, CsF, DMF/tBuOH/H2O, 3:1:1, room
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D. Claes, M. Holzapfel, N. Clausen, W. Maison
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temp., 5 h) gave only low yields of the desired cycloaddition
At low temperature and short reaction time (50 °C,
products; deboronation proved to be the major side reac- 2 min, Table 1, Entry 1) incomplete conversions were ob-
tion. In this case, it turned out to be advantageous to run served with a significant quantity of unreacted starting ma-
the reaction without CsF and to limit reaction time. As de- terial left in the crude reaction mixture along with desired
picted in Table 1, several reaction attempts revealed a suit- cycloaddition product 16a. At higher temperature and
able microwave-assisted protocol (Table 1, Entries 6 and 7) slightly longer reaction time (70 °C, 5 min, Table 1, Entry
for conjugation of benzoboroxole 15 to our adamantyl scaf- 2), complete conversion of starting material was achieved
folds.
and desired product 16a was formed along with a minor
Table 1. Microwave-assisted copper catalyzed cycloadditions of azides 9a and 9b with benzoboroxole 15.
Entry
Azide
Conditions[a]
t [min]
T [°C]
ratio 9/16/17[b]
1
2
3
4
5
6
7
9a
9a
9a
9a
9a
9b
9b
CuIISO4/NaAsc
CuIISO4/NaAsc
CuIISO4/NaAsc
CuIISO4/NaAsc/CsF
CuIBr/TBTA
2
5
10
5
5
5
50
70
70
50
70
70
70
40:60:0
0:86:14
0:50:50
2:9:89
0:92:8
0:60:40
0:70:30
CuIISO4/NaAsc
TBTA/CuIBr
5
[a] NaAsc: sodium ascorbate, TBTA: tris(benzyltriazolylmethyl)amine. [b] The ratio of starting material (9), desired cycloaddition product
1
(16) and deboronated cycloaddition product (17) was measured by H NMR analysis of the crude reaction mixture.
Table 2. Copper catalyzed cycloadditions of different adamantane scaffolds 11a–d and alkyne 15.
Azide
Triazole
n
m
R1
R2
Yield [%]
11a
11b
11c
11d
18a
18b
18c
18d
0
0
0
3
2
2
2
0
H
H
X
X
H
X
X
X
72
57
63
75
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Synthesis of Adamantane-Based Trimeric Benzoboroxoles
amount of deboronated byproduct 17a. If the reaction time
was further increased (Table 1, Entry 3), deboronation was
found to become a major side reaction. To our surprise, the
addition of CsF also afforded a large amount of de-
boronated product 17a in this microwave-assisted protocol
(Table 1, Entry 4). The best result for adamantine-based az-
ide 9b was obtained with CuBr combined with the activa-
ting ligand TBTA (Table 1, Entry 7).[29] This protocol was
then used for the assembly of boronolectins 18a–d shown
in Table 2. All cycloaddition products were formed in good
yields after HPLC-purification.
For applications of our boronolectins in binding assays,
it would be advantageous to conjugate marker molecules
such as fluorescence dyes. A representative example is de-
picted in Scheme 4. Starting from adamantylboronic acid
18a, deprotection with TFA gave amine 19. Labeling was
achieved using Promofluor 647, which is commercially
available as the activated NHS ester, to give traceable dye-
conjugate 20.
Scaffolds 11a–d allow the conjugation of functional mo-
lecules using their protected carboxylic acids. This feature
is particularly interesting for the synthesis of boronolectins
bearing additional recognition elements such as peptides
next to the boronic acid moieties. As a representative exam-
ple, azide 11a was deprotected with LiOH to give the corre-
sponding carboxylic acid (Scheme 5). After activation as
the NHS ester, a short model peptide sequence [NH2-G-
R(Pbf)-G-E(tBu)-S(tBu)-rink amide] was conjugated
through amide formation. This pentapeptide is a known
Scheme 4. Synthesis of fluorescent boronic acid 20.
Conclusions
Boronic acids of the benzoboroxole type are known to
RGD-homologue, relevant to cell adhesion processes.[30] Af- bind to carbohydrates in aqueous solution. However, the
ter complete acidic deprotection and HPLC-purification, binding affinities for monomeric carbohydrate–benzo-
adamantyl peptide 21 was obtained in reasonable yield over boroxole interactions are relatively low. Following the tripo-
3 steps. The standard click-protocol was applied to 21 and dal design principle of some lectins as natural (multivalent)
benzoboroxole 15 to afford desired peptide-boronic acid 22 carbohydrate binders, we were able to build up a small col-
in good yield.
lection of lectin mimetics with different numbers and spac-
Scheme 5. Conjugation of a pentapeptide to adamantane scaffold 11a followed by introduction of a boronic acid through the application
of click chemistry. NHS: N-hydroxysuccinimide, EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, TIPS: triisopropylsilane.
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D. Claes, M. Holzapfel, N. Clausen, W. Maison
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cooling bath was removed and the reaction was stirred for 3 d at
room temp. The solvent was removed in vacuo and the residue was
dissolved in EtOAc (10 mL) and 1 m aq. HCl (10 mL). The layers
were separated and the organic phase washed with 1 m aq. HCl
(2ϫ 10 mL) and saturated KHCO3 (3ϫ 10 mL). The organic phase
was dried with anhydrous MgSO4, filtered and concentrated to dry-
ness under reduced pressure. The crude product was purified by
flash chromatography.
ings of benzoboroxole moieties. Key components of these
boronolectins are adamantyl scaffolds 11a–d bearing azide
functionalities and an alkyne functionalized boronic acid
15. Both components were assembled to mono- di- and tri-
valent boronolectins using CuI-catalyzed click chemistry.
The resulting conjugates have been labeled with fluores-
cence dyes and were conjugated to peptides as additional
recognition motifs using an l-azidohomoalanine linker.
Due to their modular character, adamantane-based benzo-
boroxoles may be combined with peptide libraries and dyes
or a solid phase making the resulting carbohydrate binders
eligible for binding assays of high throughput.
General Procedure B (peptide coupling with HATU): To a stirred
solution of the appropriate carboxylic acid (1.0 mmol) in abs. DMF
(8 mL), HATU (1.3 equiv./per carboxylic acid) and DIEA
(1.3 equiv./carboxylic acid) were added at 0 °C and the resulting
solution was stirred for 10 min. l-azidohomoalanine 10 (as HCl
salt, 1.3 equiv./carboxylic acid) and DIEA (1.3 equiv./carboxylic
acid) were added. The cooling bath was removed and the reaction
was stirred for 3 d at room temp. The solvent was removed in vacuo
and the residue was dissolved in EtOAc (20 mL) and 0.1 m aq. HCl
(10 mL). The layers were separated and the organic phase washed
with 0.1 m aq. HCl (2ϫ 10 mL) and saturated NaHCO3 (3ϫ
10 mL). The organic phase was dried with anhydrous MgSO4, fil-
tered and concentrated to dryness in vacuo. The crude product was
purified by flash chromatography.
Experimental Section
The following compounds were prepared according to literature
protocols: 5a and 5b,[24] azide 9a,[31] tricarboxylic acid 8c,[23a] tri-
carboxylic acid 8d,[23c] triazide 11c,[20e] pinacol ester 13 and boronic
acid 15.[26]
General Methods: TLC was performed on silica gel aluminum
sheets (Macherey and Nagel). The reagent used for developing
TLC plates was cerium stain (5 g ammonium molybdate, 0.1 g ce-
rium sulfate tetrahydrate, 10 mL sulfuric acid and 90 mL H2O).
Flash column chromatography was performed on silica gel (Mach-
erey and Nagel, 60–200 μm). 1H NMR chemical shifts are refer-
enced to residual non-deuterated solvent (CDCl3, δH = 7.26 ppm.
CD3OD, δH = 3.31; [D6]DMSO, δH = 2.50 ppm). 13C NMR chemi-
General Procedure C (click reaction): To a solution of the appropri-
ate azide (0.1 mmol) in degassed tert-BuOH/H2O/DMF (v/v, 1:1:3),
boronic acid (1.3 equiv./azide moiety), CuBr (0.1 equiv./azide moi-
ety) and TBTA (0.1 equiv./azide moiety) were added. The reaction
vessel was closed and stirred for 5 min in a microwave reactor at
200 W, 70 °C and 7 bar. The solvent was removed in vacuo and the
resulting crude product purified by column chromatography on sil-
ica to give desired boronic acids.
cal shifts are referenced to the solvent signal (CDCl3, δC
=
77.16 ppm. CD3OD, δC = 49.00; [D6]DMSO, δC = 28.06 ppm).
NMR spectra were recorded at 400 (100), or 600 (150) MHz with
Bruker Avance instruments. Not all 13C signals in the isolated
benzoboroxoles were detected due to known carbon–boron cou-
plings and signal broadening.[32] NMR-signals have been assigned
on the basis of 2D NMR (HH-COSY, HMBC and HSQC) experi-
ments. The atom numbers do not refer to IUPAC nomenclature
and are available from the Supporting Information ESI mass spec-
tra were recorded with a TOF Bruker MicroTOF-Q instrument
operating in positive mode. Samples were dissolved in MeCN/H2O
mixtures or pure MeOH and directly injected using a syringe. If
indicated with abs., solvents were dried by distillation from sodium
under a nitrogen atmosphere prior to use. HPLC was performed
with a LaChrom Elite (VWR, pump L-2130) with a UV detector
(L-2400) and collected by a fraction collector (Teledyne ISCO Foxy
R1). Microwave-assisted reactions were performed in a microwave
reactor from CEM. Pentapeptide GRGES was synthesized with
standard Fmoc SPPS (using HOBt, DIEA, NMP) on a peptide
synthesizer CEM Liberty 12 using a Fmoc-Rink-Amid-2CT resin.
As building blocks Fmoc-l-Arg(Pbf)-OH, Fmoc-l-Gly-OH, Fmoc-
l-Ser(tBu)-OH, and Fmoc-l-Glu-(tBu)-OH were used. Cleavage of
the peptide from the resin was achieved with CH2Cl2/TFA (v/v,
99:1) at room temp. for 15 min (four times). The organic phases
were combined, concentrated to dryness and freeze dried with 0.1 m
aq. HCl to give pentapeptide as a colorless solid that was used
without further purification.
1-Amino-3-carboxyethyladamantane 7a: 1-Cyanoethyladamantane
5a (320 mg, 1.70 mmol) was dissolved in Br2 (8 mL), MeCN
(0.89 mL, 17 mmol) and H2O (0.15 mL, 8.5 mmol) and heated to
reflux for 15 h. The reaction mixture was poured on ice and excess
Br2 was reduced with the addition of aqueous Na2SO3 solution
(5 mL). The aqueous solution was extracted three times with
EtOAc (each 20 mL). The combined organic phases were dried
with anhydrous MgSO4, filtered and the solvent was removed in
vacuo to give acetamide 6a (420 mg) as a yellow solid, which was
used in the next step without further purification. Crude acetamide
6a was suspended in H2O (16 mL) and HCl (3.4 mL) and heated
to reflux for 40 h. After cooling to room temp., the solution was
washed with EtOAc three times (each 20 mL) and the solvent was
evaporated in vacuo to give the title compound 7a (hydrochloride
1
salt, 320 mg, 1.23 mmol, 72%). H NMR (400 MHz, D2O, 25 °C):
3
δ = 2.38 [t, J(H,H) = 8.1 Hz, 2 H, 9-H], 2.24–2.22 (m, 2 H, 5-H),
2
2
1.84 (br. d, JH,H = 12.0 Hz, 2 H, 7a-H), 1.78 (br. d, JH,H
=
12.0 Hz, 2 H, 7b-H), 1.62 (br. s, 2 H, 6-H), 1.59 (s, 2 H, 2-H), 1.54–
1.50 (m, 4 H, 4a-H), 1.44 (br. d, 2JH,H = 11.7 Hz, 2 H, 4b-H) ppm.
13C NMR (100 MHz, D2O, 25 °C): δ = 179.5 (C10), 52.8 (C1), 44.1
(C2), 39.4 (C7), 39.2 (C4), 37.1 (C8), 34.1 (C6), 33.8 (C3), 28.8
(C5), 27.8 (C9) ppm. HRMS (ESI): m/z calcd. for C13H21NO2 [M
+ H]+ = 224.1645, found 224.1649.
Diethyl 1-Aminoadamantane-3,5-dicarboxylate (7b): 1,3-Dicyanoe-
thyladamantane 5b (0.93 g, 3.80 mmol) was dissolved in Br2
(10 mL), MeCN (2.02 mL, 38.4 mmol) and H2O (0.35 mL,
19.0 mmol) and heated to reflux for 14 h. The reaction mixture was
poured on ice and excess Br2 was reduced with the addition of
aqueous Na2SO3 solution (5 mL). The aqueous solution was ex-
tracted three times with EtOAc (each 20 mL). The combined or-
ganic phases were dried with anhydrous MgSO4, filtered and the
solvent was removed in vacuo to give the acetamide 6b (1.20 g) as
General Procedure A (peptide coupling with EDC/HOBt): To a
stirred solution of the appropriate carboxylic acid (1.0 mmol) in
abs. DMF (8 mL) NEt3 (4.5 equiv./carboxylic acid) was added and
stirred at 0 °C. After 10 min EDC (1.5 equiv./carboxylic acid) was
added and after another 5 min HOBT (1.5 equiv./carboxylic acid)
was added. The solution was stirred for 10 min before azidohomo-
alanine 10 (as HCl salt: 1.5 equiv./carboxylic acid) was added. The
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Synthesis of Adamantane-Based Trimeric Benzoboroxoles
a yellow solid, which was used in the next step without further
purification. Crude acetamide 6b was suspended in H2O (40 mL)
and conc. HCl (8.5 mL) and heated to reflux for 50 h. After cooling
to room temp., the solution was washed with EtOAc three times
(each 50 mL) and the solvent was evaporated in vacuo to give title
compound 7b (hydrochloride salt, 1.21 g, 3.65 mmol, 96%). 1H
417 mg, 1.54 mmol). The crude product was purified by flash
chromatography (PE/EtOAc v/v, 2:1) and title compound 9b ob-
tained as a pale yellow solid (277 mg, 0.699 mmol, 59%). Rf = 0.5
(PE/EtOAc, v/v 2:1, cerium stain). 1H NMR (400 MHz, CDCl3,
3
25 °C): δ = 7.44–7.30 (m, 5 H, Harom), 6.35 (d, JH,H = 7.2 Hz, 1
2
2
H, 6-H), 5.23 (d, JH,H = 12.1 Hz, 1 H, 11a-H), 5.16 (d, JH,H
=
3
NMR (400 MHz, D2O, 25 °C): δ = 2.28 (t, JH,H = 8.1 Hz, 4 H, 9-
12.1 Hz, 1 H, 11b-H), 4.73–4.66 (m, 1 H, 7-H), 3.40–3.24 (m, 2 H,
H), 2.19–2.04 (m, 1 H, 6-H), 1.66 (br. s, 2 H, 7-H), 1.50–1.42 (m, 9-H), 2.22–2.10 (m, 1 H, 8a-H), 2.08–2.02 (m, 3 H, 1-H), 2.02–1.91
2
4
8 H, 2-H, 8-H), 1.32 (br., 4 H, 5-H), 1.18 (d, JH,H = 11.8 Hz, 1
(m, 1 H, 8b-H), 1.86 (br. d, JH,H = 2.5 Hz, 6 H, 2-H), 1.75 (d,
H, 4a-H), 1.10 (d, JH,H = 11.8 Hz, 1 H, 4b-H) ppm. 13C NMR 2JH,H = 12.2 Hz, 3 H, 4a-H), 1.69 (d, JH,H = 12.2 Hz, 3 H,4b-
2
2
(100 MHz, D2O, 25 °C): δ = 179.4 (C10), 53.4 (C1), 43.7 (C4), 43.6
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 178.0 (C5),
171.9 (C10), 135.2 (C12), 128.8 (Carom), 128.7 (Carom), 128.5
(Carom), 67.6 (C11), 50.2 (C7), 47.9 (C9), 39.2 (C2), 36.6 (C4), 31.4
(C8), 28.2 (C1) ppm. HRMS (ESI): m/z calcd. for C22H28N4O3 [M
+ Na]+ = 419.2054, found 419.2047.
(C2), 38.6 (C7), 36.7 (C5), 34.6 (C3), 34.3 (C8), 28.9 (C6), 27.8
(C9) ppm. HRMS (ESI): m/z calcd. for C16H25NO4 [M + H]+
=
296.1856, found 296.1859.
Ethyl
1-(3-tert-Butoxycarbonylamino)adamantane-3-carboxylate
(8a): Amine 7a (1.26 g, 4.85 mmol) was dissolved in H2O/dioxane
(60 mL v/v, 1:1). Boc2O (1.23 g, 5.64 mmol) and Na2CO3 (1.19 g,
11.2 mmol) were added. The pH was adjusted to 10 with 1 m aque-
ous NaOH. The reaction was stirred in an ultrasonic bath for 8 h
and 12 h at room temp. After a reaction time of 3 h, a second
portion of Boc2O (930 mg, 4.26 mmol) was added. The solvent was
evaporated in vacuo and the residue dissolved in EtOAc/H2O
(100 mL v/v, 1:1). The layers were separated and the aqueous phase
washed with EtOAc (2ϫ 50 mL). The pH of the aqueous phase
was adjusted to ≈ 1 with 1 m aq. HCl and extracted with EtOAc
(3ϫ 50 mL). The combined organic phases were dried with anhy-
drous MgSO4, filtered and concentrated to dryness in vacuo to give
L-Azidohomoalanine Benzyl Ester (10): Boc-protected 9a (85 mg,
0.25 mmol) was stirred in CH2Cl2/TFA (v/v, 4:1) at room temp. for
1.5 h. The solvent was removed in vacuo to give the title compound
as a TFA salt. This TFA salt was dissolved in 0.1 m aq. HCl and
MeCN and freeze dried to give title compound 10 as the HCl salt
1
(67 mg, 0.25 mmol, quant.) as a pale yellow oil. 10 as TFA salt H
NMR (400 MHz, CDCl3, 25 °C): δ = 8.58 (br. s, 3 H, 10-H), 7.41–
3
7.28 (m, 5 H, Harom), 5.24 (d, JH,H = 12.0 Hz, 1 H, 3a-H), 5.16
3
3
(d, JH,H = 12.0 Hz, 1 H, 3b-H), 4.20 (t, JH,H = 6.0 Hz, 1 H, 1-
H), 3.59–3.41 (m, 2 H, 9-H), 2.30–2.09 (m, 2 H, 8-H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 169.1 (C2), 162.6 (TFA),
162.2 (TFA), 161.8 (TFA), 161.5 (TFA), 134.1 (C4), 129.2 (Carom),
Boc-protected amine 8a (450 mg, 1.39 mmol, 29%) as a colorless 128.9 (Carom), 128.8 (Carom), 69.0 (C3), 51.2 (C1), 47.1 (C9), 29.3
1
1
solid. H NMR (400 MHz, [D6]DMSO, 25 °C): δ = 11.96 (br. s, 1 (C8) ppm. 10 as HCl salt H NMR (400 MHz, CDCl3, 25 °C): δ =
3
3
H, 11-H), 6.31 (br. s, 1 H, 12-H), 2.12 (t, JH,H = 8.2 Hz, 2 H, 9-
8.86 (br. s, 3 H, 10-H), 7.37–7.27 (m, 5 H, Harom), 5.23 (d, JH,H
12.0 Hz, 1 H, 3a-H), 5.15 (d, JH,H = 12.0 Hz, 1 H, 3b-H), 4.37 (t,
=
3
H), 2.02 (br. s, 2 H, 5-H), 1.75 (br. s, 4 H, 6-H), 1.55 (s, 2 H, 2-H),
1.53–1.47 (m, 2 H, 7-H), 1.34 (s, 9 H, 15-H), 1.34–1.27 (m, 6 H, 4- 3JH,H = 6.0 Hz, 1 H, 1-H), 3.72–3.51 (m, 2 H, 9-H), 2.43–2.22 (m,
H, 8-H) ppm. 13C NMR (100 MHz, [D6]DMSO, 25 °C): δ = 175.0
2 H, 8-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 169.3
(C10), 77.0 (C14), 50.3 (C1), 45.4 (C2), 40.7 (C6), 40.4 (C4), 38.0
(C2), 134.5 (C4), 128.9 (Carom), 128.8 (Carom), 128.6 (Carom), 68.5
(C8), 35.5 (C7), 33.5 (C3), 28.9 (C5), 28.3 (C15), 27.7 (C9) ppm. (C3), 51.2 (C1), 47.0 (C9), 29.6 (C8) ppm. IR (film): ν = 3431,
˜
HRMS (ESI): m/z calcd. for C18H29NO4 [M + Na]+ = 346.1988,
found 346.1989.
2109, 1635 cm–1. HRMS (ESI): m/z calcd. for C11H14N4O2 [M +
H]+ = 235.1190, found 235.1194.
1-(3-tert-Butoxycarbonylamino)-3,5-bis(2-carboxyethyl)adamantane
(8b): Amine 7b (437 mg, 1.48 mmol) was dissolved in saturated aq.
NaHCO3/(30 mL v/v, 1:1). Boc2O (420 mg, 1.93 mmol) was added
and the pH adjusted to 10 with 1 m aq. NaOH. The reaction was
stirred at room temp. for 12 h. The solvent was evaporated in vacuo
and the residue solved in EtOAc/H2O (20 mL v/v, 1:1). The layers
were separated and the aqueous phase washed with EtOAc (2ϫ
10 mL). With 1 m aq. HCl the pH of the aqueous phase was ad-
justed to 1 and extracted with EtOAc (3ϫ 20 mL). The combined
organic phases were dried with anhydrous MgSO4, filtered and
concentrated to dryness under reduced pressure to give title com-
pound 8b (212 mg, 0.54 mmol, 36%) as a pale yellow oil. 1H NMR
Azide 11a: This compound was synthesized according to general
procedure B from carboxylic acid 8a (200 mg, 0.618 mmol) with
HATU (306 mg, 0.804 mmol), DIEA (0.28 mL, 1.6 mmol), l-azi-
dohomoalanine 10 (as HCl salt: 231 mg, 0.804 mmol). The crude
product was purified by flash chromatography (PE/EtOAc v/v, 2:1)
and title compound 11a obtained as colorless oil (236 mg,
1
0.437 mmol, 71%). Rf = 0.6 (PE/EtOAc, v/v 1:1, cerium stain). H
NMR (400 MHz, CDCl3, 25 °C): δ = 7.43–7.31 (m, 5 H, Harom),
2
6.16 (d, 3JH,H = 7.5 Hz, 1 H, 11-H), 5.20 (d, JH,H = 12.2 Hz, 1 H,
2
16a-H), 5.17 (d, JH,H = 12.2 Hz, 1 H, 16b-H), 4.76–4.66 (m, 1 H,
12-H), 4.41 (br. s, 1 H, 21-H), 3.40–3.26 (m, 2 H, 14-H), 2.24–2.18
(m, 2 H, 9-H), 2.18–2.14 (m, 1 H, 13a-H), 2.14–2.09 (m, 2 H, 5-
(400 MHz, CD3OD, 25 °C): δ = 2.27 (t, 3JH,H = 8.4 Hz, 4 H, 9-H), H), 2.02–1.92 (m, 1 H, 13b-H), 1.90–1.77 (m, 4 H, 6-H), 1.66 (br.
2
2.14–2.20 (m, 1 H, 6-H), 1.81 (br. s, 2 H, 7-H), 1.63 (d, JH,H
=
s, 2 H, 2-H), 1.64–1.51 (m, 4 H, 4-H), 1.51–1.45 (m, 2 H, 8-H), 1.42
2
12.1 Hz, 2 H, 2a-H), 1.57 (d, JH,H = 12.4 Hz, 2 H, 2b-H), 1.46–
(s, 9 H, 24-H), 1.41–1.35 (m, 2 H, 7-H) ppm. 13C NMR (100 MHz,
1.54 (m, 4 H, 8-H), 1.31–1.46 (m, 13 H, 5-H, 14-H), 1.18 (s, 2 H, CDCl3, 25 °C): δ = 173.7 (C10), 171.8 (C15), 135.1 (C17), 128.82
4-H) ppm. 13C NMR (100 MHz, CD3OD, 25 °C): δ = 178.2 (C10),
79.5 (C13), 52.8 (C1), 46.8 (C4), 46.5 (C2), 41.5 (C7), 41.3 (C5),
39.3 (C8), 35.5 (C3), 31.1 (C6), 29.0 (C9), 28.9 (C14) ppm. HRMS
(Carom), 128.78 (Carom), 128.6 (Carom), 78.8 (C23), 67.7 (C16), 51.3
(C1), 50.3 (C12), 47.9 (C14), 46.1 (C2), 41.6 (C6), 41.1 (C7), 38.8
(C8), 36.0 (C4), 34.3 (C3), 31.6 (C13), 30.4 (C9), 29.6 (C5), 28.6
(ESI): m/z calcd. for C21H33NO6 [M + Na]+ = 418.2200, found (C24) ppm. HRMS (ESI): m/z calcd. for C29H41N5O5 [M + Na]+
418.2210.
= 562.3000, found 562.3008.
Azide 9b: Azide 9b was synthesized according to general procedure
Azide 11b: This compound was synthesized according to general
A from adamantane1-carboxylic acid (214 mg, 1.19 mmol) with procedure B from dicarboxylic acid 8b (0.33 g, 0.94 mmol) with
NEt3 (0.75 mL, 5.3 mmol), EDC (319 mg, 1.66 mmol), HOBT
(254 mg, 1.66 mmol) and azidohomoalanine 10 (as HCl salt:
HATU (0.94 g, 2.5 mmol), DIEA (0.86 mL, 5.0 mmol), l-azido-
homoalanine 10 (as HCl salt: 0.79 g, 2.9 mmol). The crude product
Eur. J. Org. Chem. 2013, 6361–6371
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6367

D. Claes, M. Holzapfel, N. Clausen, W. Maison
FULL PAPER
was purified by flash chromatography (PE/EtOAc v/v, 2:1) and title
(C8), 148.4 (Carom), 135.1 (C19), 131.5 (Carom), 130.7 (C9), 128.81
(Carom), 128.77 (Carom), 128.6 (Carom), 128.0 (Carom), 122.58
(Carom), 122.56 (Carom), 121.9 (Carom), 80.4 (C15), 76.7 (C7), 67.7
compound 11b obtained as a colorless oil (0.27 g, 0.33 mmol,
35%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.40–7.30 (m, 11
3
H, NH, Harom), 6.33 (d, JH,H = 7.3 Hz, 1 H, 11-H), 5.23–5.13 (m, (C18), 51.4 (C12), 46.9 (C10), 33.2 (C11), 28.4 (C16) ppm. HRMS
4 H, 16-H), 4.75–4.67 (m, 2 H, 12-H), 3.40–3.27 (m, 4 H, 14-H),
2.25–2.07 (m, 7 H, 6-H, 9-H, 13a-H), 2.01–1.91 (m, 2 H, 13b-H),
(ESI): m/z calcd. for C25H29BN4O6 [M + Na]+ = 515.2078, found
515.2086. Deboronated triazole 17a: 1H NMR (400 MHz, CDCl3,
1.75 (br. s, 2 H, 7-H), 1.67–1.53 (m, 4 H, 2-H), 1.53–1.47 (m, 4 H, 25 °C): δ = (mixture of diastereomers) = 7.35 (d, 2 H, Harom), 7.29–
8-H), 1.42 (s, 9 H, 24-H), 1.38–1.23 (m, 4 H, 5-H), 1.18–1.06 (m, 7.12 (m, 9 H, Harom), 5.92 (s, 1 H, 5-H), 5.43–5.33 (m, 1 H, 11-H),
2 H, 4-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 173.7 5.00 (s, 2 H, 16-H), 4.33–4.14 (m, 3 H, 8-H, 10-H), 4.14–3.79 (m,
(C10), 171.9 (C15), 135.1 (C17), 128.8 (Carom), 128.7 (Carom), 128.5 1 H, 21-H), 2.41–2.27 (m, 1 H, 9a-H), 2.19–2.05 (m, 1 H, 9b-H),
(Carom), 79.2 (C23), 67.7 (C16), 51.9 (C1), 50.3 (C12), 47.9 (C14), 1.33 (br. s, 9 H, 14-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
45.6 (C2, C4), 41.0 (C7), 40.7 (C5), 38.4 (C8), 34.7 (C3), 31.5 (C13), δ = 171.4 (C15), 155.6 (C12), 142.2 (Carom), 135.0 (Carom), 129.1
30.3 (C9), 29.7 (C6), 28.6 (C24) ppm. HRMS (ESI): m/z calcd. for (Carom), 128.71 (Carom), 128.66 (Carom), 128.56 (Carom), 128.48
C43H57N9O8 [M + Na]+ = 828.4403, found 828.4418.
(Carom), 128.1 (Carom), 127.9 (Carom), 126.5 (Carom), 80.5 (C13), 68.9
(C5), 67.6 (C16), 51.3 (C10), 46.7 (C8), 33.0 (C9), 28.3 (C14) ppm.
HRMS (ESI): m/z calcd. for C25H30N4O5 [M + Na]+ = 498.0863,
found 464.0869.
Azide 11d: This compound was synthesized according to general
procedure A from tricarboxylic acid 8c (87 mg, 0.20 mmol) with
NEt3 (0.36 mL, 2.7 mmol), EDC (173 mg, 0.90 mmol), HOBT
(138 mg, 0.90 mmol), and l-azidohomoalanine 10 (as HCl salt:
212 mg, 0.90 mmol). The crude product was purified by flash
chromatography (PE/EtOAc v/v, 1:3) and title compound 11d ob-
tained as a colorless oil (28 mg, 26 μmol, 13%). Rf = 0.5 (PE/
EtOAc, v/v 1:2, cerium stain). 1H NMR (400 MHz, CDCl3, 25 °C):
Benzoboroxole 16b: This compound was synthesized according to
general procedure C from azide 9b (76 mg, 0.19 mmol) and boronic
acid 15 (33 mg, 0.19 mmol), CuBr (2.8 mg, 20 μmol) and TBTA
(10 mg, 19 μmol). After a reaction time of 5 min a second amount
of boronic acid 15 was added (10 mg, 19 μmol). Title compound
16b (59 mg, 0.11 mmol, 56%) was isolated after purification by
HPLC (Nucleodur RP18, 10ϫ250 mm ID, 5 μm particle, 70%
MeOH in H2O with 0.1% HCO2H, 203 nm, tR = 27.8) as a color-
less solid. As a side product, deboronated triazole 17b was isolated
as a colorless solid (14 mg, 26 μmol, 26%, tR = 15.6). Boronic acid
16b: 1H NMR (400 MHz, CDCl3, 25 °C): δ = (mixture of dia-
stereomers) = 7.80–7.72 (m, 1 H, 16-H), 7.48–7.26 (m, 9 H, Harom),
6.53–6.46 (m, 1 H, 6-H), 6.38 (s, 1 H, 18-H), 5.13–5.01 (m, 2 H,
11-H), 4.70–4.57 (m, 1 H, 7-H), 4.34–4.23 (m, 2 H, 9-H), 2.52–2.38
(m, 1 H, 8a-H), 2.33–2.20 (m, 1 H, 8b-H), 2.00 (br. s, 3 H, 1-H),
1.82 (br. s, 6 H, 2-H), 1.60–1.57 (m, 6 H, 4-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 178.8 (C5), 171.34 (C10), 171.28 (C10),
155.12 (C17), 155.08 (C17), 148.7 (C19), 135.0 (C12), 131.4 (Carom),
130.7 (C16), 128.79 (Carom), 128.78 (Carom), 128.6 (Carom), 128.5
(Carom), 128.0 (Carom), 122.5 (Carom), 121.9 (Carom), 76.11 (C18),
76.09 (C18), 67.9 (C11), 67.8 (C11), 50.02 (C7), 50.01 (C7), 46.9
(C9), 40.9 (C3), 39.1 (C2), 36.5 (C4), 32.84 (C8), 32.78 (C8), 28.1
(C1) ppm. HRMS (ESI): m/z calcd. for C31H35BN4O5 [M + Na]+
3
δ = 7.48–7.29 (m, 15 H, Harom), 6.43 (d, JH,H = 7.1 Hz, 3 H, 13-
H), 5.21 (d, 2JH,H = 12.1 Hz, 3 H, 18a-H), 5.15 (d, 2JH,H = 12.1 Hz,
3 H, 18b-H), 4.75–4.65 (m, 3 H, 14-H), 4.53 (br. s, 1 H, 8-H), 3.32
3
(t, JH,H = 6.6 Hz, 6 H, 16-H), 3.15–2.99 (m, 2 H, 7-H), 2.19–2.09
(m, 3 H, 15a-H), 2.02–1.89 (m, 9 H, 4-H, 15b-H), 1.54 (s, 6 H, 2-
H), 1.51–1.36 (m, 11 H, 6-H, 11-H), 1.26–1.18 (m, 2 H, 5-H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 175.7 (C12), 171.5 (C17),
155.1 (C9), 135.1 (C19), 128.81 (Carom), 128.77 (Carom), 128.59
(Carom), 79.3 (C10), 67.7 (C18), 50.5 (C14), 47.9 (C16), 42.6 (C2),
42.4 (C7), 40.1 (C5), 39.4 (C4), 34.2 (C1), 31.3 (C15), 28.5 (C11),
23.5 (C6) ppm. HRMS (ESI): m/z calcd. for C54H67N13O11 [M +
H]+ = 1074.5156, found 1074.5171.
Boronic Acid 15: Boronate 13 (0.50 g, 1.9 mmol) was dissolved in
Et2O (8 mL) and diethanolamine (0.19 mL, 1.9 mmol) was added.
A colorless solid precipitated and was collected by filtration to give
intermediate 14. Boronate 14: 1H NMR (400 MHz, CD3OD,
25 °C): δ = 7.45–7.37 (m, 1 H, Harom), 7.26–7.09 (m, 3 H, Harom),
4
1
6.34 (d, JH,H = 1.5 Hz, 1 H, 7-H), 3.77 (s, 4 H, 10-H), 3.03 (s, 4
= 577.2598, found 577.2610. Deboronated Triazole 17b: H NMR
H, 11-H), 2.75 (br. s, 1 H, 9-H) ppm. Boronate 14 was dissolved in
0.1 m aq. HCl (5 mL) and EtOAc (5 mL) and stirred at room temp.
for 12 h. The layers were separated and the aqueous phase was
washed with EtOAc (3ϫ 5 mL). The organic layers were combined,
dried with Na2SO4, filtered and the solvent was removed under
reduced pressure. The crude product was purified by flash
chromatography (PE/EtOAc v/v, 2:1) to give title compound 15 as
a pale yellow solid (150 g, 0.93 mmol, 49%). The analytical data
was identical with the literature data.[26]
(400 MHz, CDCl3, 25 °C): δ = (mixture of diastereomers) = 7.47–
3
7.42 (m, 2 H, Harom), 7.38–7.27 (m, 9 H, Harom), 6.37 (d, JH,H
=
7.6 Hz, 1 H, 6-H), 6.02–5.98 (m, 1 H, 18-H), 5.10–5.06 (m, 2 H,
11-H), 4.66–4.59 (m, 1 H, 7-H), 4.29 (t, 3JH,H = 7.0 Hz, 2 H, 9-H),
2.54–2.43 (m, 1 H, 8a-H), 2.35–2.24 (m, 1 H, 8b-H), 2.05–2.00 (m,
4
3 H, 1-H), 1.84–1.80 (br. s, 6 H, 2-H), 1.74 (d, JH,H = 12.4 Hz,
4
3 H, 4a-H), 1.68 (d, JH,H = 12.4 Hz, 3 H, 4b-H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 178.4 (C5), 171. 4 (C10), 151.3
(Carom), 141.9 (Carom), 135.0 (Carom), 128.8 (Carom), 128.7 (Carom),
128.6 (Carom), 128.16 (Carom), 128.15 (Carom), 126.6 (Carom), 126.5
(Carom), 69.4 (C18), 67.8 (C11), 49.9 (C7), 46.9 (C9), 40.9 (C3), 39.2
(C2), 36.5 (C4), 32.9 (C8), 28.2 (C1) ppm. HRMS (ESI): m/z calcd.
for C31H36N4O4 [M + Na]+ = 551.2629, found 551.2642.
Benzoboroxole 16a: This compound was synthesized according to
general procedure C from azide 9a (57 mg, 0.17 mmol) and boronic
acid 15 (35 mg, 0.22 mmol), CuBr (2.4 mg, 17 μmol) and TBTA
(9.0 mg, 17 μmol). Title compound 16a (77 mg, 0.16 mmol, 92%)
was isolated after purification by HPLC (Nucleodur RP18,
Benzoboroxole 18a: This compound was synthesized according to
10ϫ250 mm ID, 5 μm particle, 65% MeOH in H2O with 0.1% general procedure C from azide 11a (50 mg, 0.093 mmol) and bo-
HCO2H, 230 nm, tR = 13.8 min) as a colorless solid. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = (mixture of diastereomers) = 7.76
(d, 3JH,H = 7.1 Hz, 1 H, 9-H), 7.50–7.42 (m, 2 H, Harom), 7.41–7.27
(m, 7 H, Harom), 6.41 (s, 1 H, 7-H), 5.51–5.29 (m, 1 H, 13-H), 5.11–
ronic acid 15 (20 mg, 0.13 mmol), CuBr (1.3 mg, 0.093 mmol) and
TBTA (5.0 mg, 0.093 mmol). Title compound 18a (47 mg,
0.064 mmol, 72%) was isolated after purification by HPLC (Nucle-
odur RP18, 10ϫ250 mm ID, 5 μm particle, 75% MeOH in H2O
5.05 (m, 2 H, 18-H), 4.44–4.22 (m, 3 H, 10-H, 12-H), 2.52–2.34 (m, with 0.1% HCO2H, 5 mL/min, 210 nm, tR = 23.4 min) as a color-
1 H, 11a-H), 2.29–2.12 (m, 1 H, 11b-H), 1.41 (s, 9 H, 16-H) ppm. less solid. 1H NMR (400 MHz, CDCl3, 25 °C): δ = (mixture of
13C NMR (100 MHz, CDCl3): δ = 171.4 (C17), 155.12 (C8), 155.08 diastereomers) = 7.78 (d, 3JH,H = 7.0 Hz, 1 H, 15-H), 7.48–7.27 (m,
6368
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Eur. J. Org. Chem. 2013, 6361–6371

Synthesis of Adamantane-Based Trimeric Benzoboroxoles
9 H, Harom), 6.53 (br., 1 H, 11-H), 6.36 (s, 1 H, 17-H), 5.08 (d, acid 15 (16.4 mg, 104 μmol), CuBr (1.1 mg, 7.8 μmol) and TBTA
4JH,H = 3.4 Hz, 2 H, 25-H), 4.74–4.60 (m, 1 H, 12-H), 4.40–4.22
(4.1 mg, 7.8 μmol). Title compound 18d (30 mg, 8.9 μmol, 75%)
(m, 2 H, 14-H), 2.55–2.36 (m, 1 H, 13a-H), 2.36–2.22 (m, 1 H, 13b-
was isolated after purification by HPLC (Nucleodur RP18,
H), 2.22–2.11 (m, 2 H, 9-H), 2.08 (br. s, 2 H, 5-H), 1.93–1.70 (m, 10ϫ250 mm ID, 5 μm particle, 80% MeOH in H2O with 0.1%
4 H, 6-H), 1.68–1.46 (m, 4 H, 2-H, 7-H), 1.43 (s, 9 H, 33-H), 1.41–
HCO2H, 5 mL/min, 220 nm, tR = 22.7 min.) as a colorless solid.
1.22 (m, 6 H, 4-H, 8-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): 1H NMR (400 MHz, CD3OD, 25 °C): δ = (mixture of dia-
3
δ = 174.4 (C10), 171.2 (C24), 155.1 (C16), 148.6 (Carom), 135.0
stereomers) = 7.75–7.71 (m, 3 H, Harom), 7.66 (d, JH,H = 7.0 Hz,
(Carom), 131.5 (Carom), 130.8 (C15), 128.82 (Carom), 128.78 (Carom), 3 H, 17-H), 7.65–7.24 (m, 24 H, Harom), 6.31 (s, 3 H, 19-H), 5.10–
128.6 (Carom), 128.5 (Carom), 128.04 (Carom), 128.00 (Carom), 122.54 5.05 (m, 6 H, 27-H), 4.48–4.33 (m, 9 H, 14-H, 16-H), 3.00 (t, 3JH,H
(Carom), 122.46 (Carom), 122.0 (Carom), 79.1 (C32), 76.11 (C17),
76.06 (C17), 67.79 (C25), 67.75 (C25), 51.3 (C1), 50.3 (C12), 47.2 H, 15b-H), 1.84 (s, 6 H, 4-H), 1.53–1.44 (m, 6 H, 2-H), 1.44–1.39
(C14), 47.1 (C14), 45.9 (C2), 41.5 (C6), 41.1 (C4), 38.8 (C8), 35.9
(m, 11 H, 6-H, 11-H), 1.21–1.13 (m, 2 H, 5-H) ppm. 13C NMR
= 6.8 Hz, 2 H, 7-H), 2.59–2.46 (m, 3 H, 15a-H), 2.40–2.26 (m, 3
(C7), 34.2 (C3), 32.7 (C13), 32.6 (13), 30.2 (C9), 29.6 (C5), 28.6 (100 MHz, CD3OD, 25 °C): δ = 179.1 (C12), 172.4 (C26), 149.4
(C33) ppm. HRMS (ESI): m/z calcd. for C38H48BN5O [M + Na]+
= 720.3546, found 720.3550.
(Carom), 137.0 (Carom), 132.2 (Carom), 131.4 (C17), 129.6 (Carom),
129.43 (Carom), 129.36 (Carom), 128.9 (Carom), 123.4 (Carom), 80.0
(C10), 76.9 (C19), 68.2 (C27), 51.5 (C14), 48.1 (C16), 43.7 (C3),
43.1 (C2), 42.0 (C7), 41.4 (C5), 40.3 (C4), 32.0 (C15), 28.8
(C11) ppm. HRMS (ESI): m/z calcd. for C81H88N13B3O17 [M +
Na]+ = 1570.6626, found 1570.6647.
Benzoboroxole 18b: This compound was synthesized according to
general procedure C from azide 11b (76 mg, 0.092 mmol) and bo-
ronic acid 15 (39 mg, 0.24 mmol), CuBr (2.6 mg, 0.0184 mmol) and
TBTA (9.8 mg, 0.018 mmol). Title compound 18b (60 mg,
0.053 mmol, 57%) was isolated after purification by HPLC (Nucle-
odur RP18, 10ϫ250 mm ID, 5 μm particle, 80% MeOH in H2O
with 0.1% HCO2H, 230 nm, tR = 17.7 min.) as a colorless solid.
1H NMR (400 MHz, CD3OD, 25 °C): δ = (mixture of dia-
1-(L-triazolbenzoboroxole-homoalanin-Bn)-carboxyethylada-
mantane 19: The Boc-protected amine 18a (9.0 mg, 13 μmol) was
stirred in CH2Cl2/TFA (v/v, 4:1) at room temp. for 1.5 h. The sol-
vent was removed in vacuo, the residue dissolved in 0.1 m aq. HCl
and MeCN and freeze dried to give the free amine 19 (8.2 mg,
13 μmol, quant.) as a colorless solid. This amine was used without
4
3
stereomers) = 7.74 (d, JH,H = 3.8 Hz, 2 H, Harom), 7.69 (d, JH,H
= 7.2 Hz, 2 H, Harom), 7.48–7.41 (m, 2 H, Harom), 7.39–7.28 (m, 14
H, Harom), 6.34 (s, 2 H, 23-H), 5.09 (s, 4 H, 16-H), 4.44 (t, 3JH,H
=
any further purification in the next step. 1H NMR (400 MHz,
7.0 Hz, 4 H, 14-H), 4.41–4.36 (m, 2 H, 12-H), 2.53–2.41 (m, 2 H,
13a-H), 2.32–2.21 (m, 2 H, 13b-H), 2.21–2.14 (m, 4 H, 9-H), 2.14–
2.09 (m, 1 H, 6-H), 1.77 (s, 2 H, 7-H), 1.62–1.52 (m, 4 H, 2-H),
1.48–1.33 (m, 15 H, 5b-H, 8-H, 33-H), 1.33–1.26 (m, 2 H, 5b-H),
1.05–1.17 (m, 2 H, 4-H) ppm. 13C NMR (100 MHz, CD3OD,
25 °C): δ = 177.1 (C10), 172.4 (C15), 156.4 (Carom)149.3 (Carom),
137.0 (Carom), 132.3 (Carom), 131.4 (Carom), 129.6 (Carom), 129.44
(Carom), 129.36 (Carom), 129.0 (Carom), 124.2 (Carom), 123.4 (Carom),
79.3 (C32), 76.9 (C23), 68.2 (C16), 52.8 (C1), 51.4 (C12), 48.2
(C14), 46.9 (C4), 46.4 (C2), 41.6 (C7), 41.4 (C5), 40.0 (C8), 35.7
(C3), 32.5 (C13), 31.1 (C6), 30.8 (C9), 28.9 (C33) ppm. HRMS
(ESI): m/z calcd. for C61H71B2N9O12 [M + H]+ = 1144.5487, found
1144.5491.
3
CD3OD, 25 °C): δ = (mixture of diastereomers) = 7.72 (d, JH,H
=
=
4
7.3 Hz, 1 H, 15-H), 7.53–7.21 (m, 9 H, Harom), 6.41 (d, JH,H
5.2 Hz, 1 H, 17-H), 5.11 (s, 2 H, 25-H), 4.58–4.50 (m, 2 H, 14-H),
4.42–4.33 (m, 1 H, 12-H), 2.58–2.46 (m, 1 H, 13a-H), 2.36–2.28
(m, 1 H, 13b-H), 2.28–2.19 (m, 4 H, 5-H, 9-H), 1.88–1.76 (m, 4 H,
4-H), 1.70–1.64 (m, 2 H, 7-H), 1.62–1.57 (m, 2 H, 2-H), 1.57–1.44
(m, 6 H, 6-H, 8-H) ppm. 13C NMR (100 MHz, CD3OD, 25 °C): δ
= 176.2 (C10), 171.6 (C24), 155.2 (Carom), 148.7 (Carom), 137.1
(Carom), 132.4 (Carom), 131.5 (C15), 129.6 (Carom), 129.4 (Carom),
129.3 (Carom), 129.2 (Carom), 125.2 (Carom), 123.5 (Carom), 76.2
(C17), 68.2 (C25), 53.6 (C1), 51.3 (C12), 51.1 (C12), 50.0 (C2), 48.6
(C14), 41.1 (C7), 41.0 (C4), 39.6 (C8), 39.5 (C8), 35.8 (C3), 35.52
(C6), 35.50 (C6), 32.2 (C13), 30.60 (C5), 30.58 (C5), 30.46 (C9),
30.44 (C9) ppm. HRMS (ESI): m/z calcd. for C33H40BN5O5 [M +
H]+ = 598.3201, found 598.3207.
Benzoboroxole 18c: This compound was synthesized according to
general procedure C from azide 11c (56 mg, 48 μmol) with boronic
acid 15 (31 mg, 0.20 mmol), CuBr (2.2 mg, 15 μmol) and TBTA
(8.0 mg, 15 μmol). Title compound 18c (50 mg, 31 μmol, 63%) was
isolated after purification by HPLC (Nucleodur RP18,
10ϫ250 mm ID, 5 μm particle, 80% MeOH in H2O with 0.1%
HCO2H, 5 mL/min, 210 m, tR = 22.9 min.) as a colorless solid. 1H
NMR (400 MHz, CD3OD, 25 °C): δ = (mixture of diastereomers)
Fluorescent benzoboroxole 20: Amine 19 (3.8 mg, 5.0 μmol) was
stirred in abs. DMF and NEt3 (15 μL, 0.11 mmol) was added. The
reaction solution was cooled to 0 °C and Promofluor 647 (100 μL,
c = 0.013 m, 1.31 μmol) was added dropwise. The reaction was
stirred for 4 h and a second amount of Promofluor 647 (100 μL, c
= 0.013 m, 1.31 μmol) was added at 0 °C. The reaction was stirred
for 12 h and the solvent evaporated in vacuo. The crude product
was purified by HPLC (Nucleodur RP8, 10ϫ250 mm ID, 5 μm
particle, 50% MeCN in H2O with 0.1% HCO2H, 3 mL/min,
250 nm, Ex = 657 nm, Em = 672 nm, tR = 9.0 min) and product
20 (0.442 mg, 0.362 μmol, 14%) isolated as a blue solid. HRMS
4
3
= 7.74 (d, JH,H = 2.4 Hz, 3 H, Harom), 7.69 (d, JH,H = 7.4 Hz, 3
H, Harom), 7.48–7.25 (m, 24 H, Harom), 6.34 (s, 3 H, 14-H), 5.08 (s,
6 H, 22-H), 4.43 (t, 3JH,H = 6.9 Hz, 6 H, 11-H), 4.41–4.35 (m, 3 H,
9-H), 2.53–2.40 (m, 3 H, 10a-H), 2.32–2.21 (m, 3 H, 10b-H), 2.21–
3
2.14 (m, 6 H, 6-H), 1.52 (s, 6 H, 2-H), 1.45 (t, JH,H = 7.7 Hz, 6
2
H, 5-H), 1.40 (s, 9 H, 30-H), 1.11 (d, JH,H = 12.0 Hz, 3 H, 4a-H),
(ESI): m/z calcd. for C65H75BN7O12S2 [M – H]2– = 609.7465,
–
2
1.02 (d, JH,H = 12.0 Hz, 3 H, 4b-H) ppm. 13C NMR (100 MHz,
found 609.7481.
CD3OD, 25 °C): δ = 176.7 (C7), 171. 5 (C21), 155.5 (Carom), 149.5
(Carom), 136.9 (Carom), 132.1 (Carom), 131.3 (Carom), 129.4 (Carom),
128.9 (Carom), 123.9 (Carom), 123.1 (Carom), 122.6 (Carom), 79.2
(C29), 76.7 (C14), 68.0 (C22), 53.9 (C1), 51.2 (C9), 47.8 (C11), 46.4
(C4), 45.9 (C2), 39.6 (C5), 35.7 (C3), 32.2 (C10), 30.7 (C6), 28.8
(C30) ppm. HRMS (ESI): m/z calcd. for C84H94 B3N13O17 [M +
H]+ = 1590.7243, found 1590.7280.
Azide 21: Bn-protected carboxylic acid 11a (75 mg, 0.14 mmol) and
LiOH (12 mg, 0.50 mmol) were dissolved in THF/H2O (20 mL v/v,
1:1) and stirred at room temp. for 2 h. The solvent was evaporated
and the residue dissolved in Et2O/H2O (20 mL, v/v 1:1). The layers
were separated and the organic phase was washed with 1 m aq.
HCl (2ϫ 10 mL). The aqueous phase was extracted with Et2O (3ϫ
10 mL) and the organic layers combined, dried with anhydrous
MgSO4, filtered and concentrated to dryness in vacuo. The re-
Benzoboroxole 18d: This compound was synthesized according to
general procedure C from azide 11d (28 mg, 26 μmol) with boronic
Eur. J. Org. Chem. 2013, 6361–6371
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6369

D. Claes, M. Holzapfel, N. Clausen, W. Maison
FULL PAPER
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sulting carboxylic acid, EDC (37 mg, 0.23 mmol) and NHS (22 mg,
0.19 mmol) were dissolved in abs. DMF (5 mL) and stirred under
N2 for 16 h. The solvent was evaporated under reduced pressure
and the residue dissolved in EtOAc/H2O (20 mL v/v, 1:1). The or-
ganic layer was washed with H2O (2ϫ 10 mL) and the aqueous
layer extracted with EtOAc (3ϫ 10 mL). The organic layers were
combined, dried with anhydrous MgSO4, filtered and concentrated
to dryness in vacuo. The resulting NHS-ester was used without
further purification. H2N-G-R(Pbf)-G-E(tBu)-S(tBu)-rink amide
(126 mg, 0.108 mmol) was dissolved in abs. DMF (5 mL) and the
pH adjusted to 8 with NEt3. The reaction solution was stirred for
15 min at 0 °C and the NHS-ester (47 mg, 0.086 mmol) was added.
The reaction was stirred at room temp. for 24 h. The solvent was
evaporated under reduced pressure and the crude product dissolved
in 4.4 mL TFA, 0.1 mL TIPS, 0.25 mL H2O and 36 mg phenol.
The reaction was stirred for 48 h at room temp. and the solvent
removed under reduced pressure. The crude product was purified
by HPLC (Nucleodur RP8, 2% MeCN in H2O with 0.1% HCO2H
than 2%Ǟ80% in 20 min MeCN in H2O with 0.1% HCO2H,
5 mL/min, 210 nm, tR = 13.2 min). Title compound 21 (13 mg,
16 μmol, 18%) was obtained as a colorless solid. HRMS (ESI): m/z
calcd. for C35H58N14O10 [M + 2H]2+ = 418.2308, found 418.2316.
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Published Online: August 15, 2013
Eur. J. Org. Chem. 2013, 6361–6371
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6371