Synthesis of functionalized adamantane derivatives: (3 + 1)-scaffolds for applications in medicinal and material chemistry

Article abstract of DOI:10.1055/s-0033-1338470

Due to its rigid cage structure, adamantane has received considerable interest as a scaffold with a defined tetrahedral geometry. In this paper we describe orthogonally functionalized tetrasubstituted adamantane derivatives. These compounds may be conjugated to other functional molecules by standard techniques such as amide formation or click chemistry and are thus useful (3 + 1) scaffolds for medicinal and material chemistry. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338470

1452▌
FEATURE ARTICLE
feature article
Synthesis of Functionalized Adamantane Derivatives: (3 + 1)-Scaffolds for
Applications in Medicinal and Material Chemistry
(3 + 1)-Adamantyl Scaffolds
Carsten Fleck, Elisa Franzmann, Dorith Claes, Aljona Rickert, Wolfgang Maison*
Pharmaceutical and Medicinal Chemistry, University of Hamburg, Bundesstraße 45, 20146 Hamburg, Germany
Fax +49(40)42838-3477; E-mail: maison@chemie.uni-hamburg.de
Received: 16.03.2013; Accepted after revision: 05.04.2013
bromine lowers the reactivity of the system for the next
Abstract: Due to its rigid cage structure, adamantane has received
bromination significantly.18 In consequence each bromine
considerable interest as a scaffold with a defined tetrahedral geom-
derivative 2–5 is easy to prepare selectively by a slightly
modified protocol. However, the conditions required for
etry. In this paper we describe orthogonally functionalized tetrasub-
stituted adamantane derivatives. These compounds may be
conjugated to other functional molecules by standard techniques the synthesis of tribromoadamantane 4 and tetrabromoad-
such as amide formation or click chemistry and are thus useful (3 +
1) scaffolds for medicinal and material chemistry.
amantane 5 are quite harsh.
Key words: adamantane, multivalency, dendrimers, C3 symmetry,
diamandoids
BBr3, Br2
reflux
Br2, reflux
95%
Br
Br
79%
Br
1
3
2
AlCl3, Br2
reflux, 24 h
Fe, Br2
Introduction
reflux, 22 h
64%
80%
Br
AlBr3, Br2
140 °C
Adamantane was first isolated from crude oil in Czecho-
slovakia in 1933.1 It is the lowest diamandoid followed by
diamantane, triamantane etc. and has, like the others,
unique chemical properties.2 The first synthesis of ada-
mantane was achieved by Prelog and Steinwerth in
1941.3,4 Schleyer published in 1957 a practical method to
synthesize adamantane from tetrahydrodicyclopentadi-
ene.5
sealed tube
Br
Br
Br
Br
75%
Br
Br
4
5
Scheme 1 Mono-, di-, tri- and tetrabromoadamantanes 2–5 by selec-
tively bromination of adamantane (1)
A particularly interesting feature of tetrasubstituted ada-
mantanes is the ability to align rigidly four substituents in
a tetrahedral arrangement. The adamantane core may thus
be considered a large replacement for a sp3-carbon.
Due to its rigid cage structure, the adamantyl scaffold is
an interesting tetrahedral building block in many fields,
such as catalysis,6,7 supramolecular chemistry,8–10 materi-
al science,11–14 and medicinal chemistry.15,16 Many bridge-
head-substituted adamantane derivatives have been
described because they are readily accessible by nucleo-
philic substitution or radical reactions.17,18 A number of
mono- and disubstituted derivatives are commercially
available and have been used frequently in medicinal
chemistry as a bulky and lipophilic structural element in
drugs. Tri- and tetrabridgehead functionalized derivatives
are less common, because they are often more difficult to
synthesize. Functionalization of adamantane at the
bridgehead positions requires the activation of a tertiary
C–H bond and does, therefore, often imply drastic reac-
tion conditions.19 This is particularly problematic with
substituted adamantane derivatives, because the reactivity
at each bridgehead position is strongly influenced by the
substituents at the other bridgeheads. A good example is
the bromination of adamantane 1 (Scheme 1),20–22 which
is often the first step in the synthesis of more complex ad-
amantane derivatives. The introduction of each additional
Tetrasubstituted adamantanes of general type 6 are (3 + 1)
scaffolds for applications in medicinal and material chem-
istry. Known examples of these scaffolds include the ami-
no acids 7–9.
Our group started in 2003 with the design of tetrahedral
scaffolds based on the general structure 6 with three func-
tional groups X in a tripodal arrangement and a fourth or-
thogonal functionality Y pointing in opposite direction
(Scheme 2).13,23–25 These scaffolds offer various fields of
applications because threefold rotational symmetry plays
a crucial role in various natural molecular recognition sys-
tems.26–28 Among them are important cell surface recep-
tors,29–33 enzymes,34 siderophores, and natural
adhesives.35,36 For these applications a number of tripodal
scaffolds are known such as 1,3,5-substituted cyclohex-
anes,37 1,3,5-substituted benzenes,38 or cyclopeptides.39
However, these scaffolds lack a fourth position for the
conjugation of effector molecules, which is an essential
component for many fields of application such as surface
functionalization and imaging. Like a central sp3-car-
bon,40 adamantane has three bridgehead positions for con-
jugation of ligands and one additional position for further
SYNTHESIS 2013, 45, 1452–1461
Advanced online publication: 24.04.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338470; Art ID: SS-2013-T0174-FA
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
(3 + 1)-Adamantyl Scaffolds
1453
conjugation (‘3 + 1 system’) of effectors, for example ing,15,41 targeted tumor therapy,44 and material
dyes,41 polymers,42 or other functional molecules.15 We chemistry.42 In this paper we extend this molecular tool-
have described synthetic routes to three adamantyl-based box and describe the synthesis of additional (3 + 1) scaf-
(3 + 1) scaffolds 7,43 8,43 and 923 with orthogonal function- folds with different functionality and spacing.
ality and have reported their application in tumor imag-
Biographical Sketches█
Carsten Fleck studied ly, he moved to the Univer- bohydrate chemistry and the
chemistry at the Justus- sity of Hamburg and joined synthesis of adamantane-
Liebig-University Gießen the research group of Prof. based carbohydrate mimics.
where he obtained his M.Sc. Maison for his Ph.D. stud-
degree in 2010. Subsequent- ies. He is interested in car-
Elisa Franzmann studied degree in 2009. Currently, search interests are focused
chemistry at the Justus- she is a Ph.D. candidate on biomimetic strategies for
Liebig-University Gießen supervised by Professor the functionalization of met-
and obtained her Diploma Wolfgang Maison. Her re- al surfaces.
Dorith Claes studied chem- of Prof. Maison. She joined are multivalent benzoborox-
istry at the Justus-Liebig- his group for her Ph.D. stud- oles for carbohydrate recog-
University of Gießen and ies and moved from Gießen nition.
obtained her M.Sc. degree to the University of Ham-
in 2010 under the guidance burg. Her research interests
Aljona Rickert studied research project about syn- Prof. Wolfgang Maison and
chemistry at the Justus- thetic multivalent ligands Prof. Holger Zorn. Her re-
Liebig-University
in for cell recognition. Since search focuses on enzymatic
Gießen. She obtained her 2010 she has worked on her allylic oxidations.
M.Sc. degree in 2010 on a Ph.D. under the guidance of
Wolfgang Maison studied Kemp at MIT for a one-year has been a full professor at
chemistry at the University postdoc. From 2001–2006 the University of Hamburg.
of Oldenburg and obtained he was a junior group leader His research interests are
his Ph.D. degree in 2000 un- at the University of Ham- linked to natural product
der the guidance of Prof. burg, before he accepted a syntheses and drug develop-
Jürgen Martens. He joined W2-Professorship at the ment.
the group of Prof. Daniel S. JLU-Giessen. Since 2011 he
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1452–1461

1454
C. Fleck et al.
FEATURE ARTICLE
hydride reduction. The trisamine 14 was conjugated to
2,3-dihydroxybenzaldehyde and 3,4-dihydroxybenzalde-
hyde via imine formation. The resulting triscatecholates
15 and 16 precipitate from ethanol and are analogues of
bacterial siderophores such as enterobactin (Scheme 5).25
NHCbz
DPPA, Et3N,
CH2Cl2, r.t.
then t-BuOH,
CO2H
reflux
NHCbz
HO2C
2
2
58%
BocHN
NHBoc
HO2C
2
Cbz-9
2
2
BocHN
2
11
TFA, CH2Cl2
NHCbz
quant.
H2N
NH2
2
2
H2N
2
12
Scheme 4 Synthesis of tetraamine 12 via Curtius degradation of tri-
carboxylic acid Cbz-9
Scheme 2
NC
CN
2
2
Results and Discussion
NC
2
13
DIBAL-H, THF
Variations at the Ligand-Conjugation Site
83%
O
Scaffolds 7–9 are restricted to the conjugation of ligands
either with a reactive amine functionality via amide for-
mation or with an alcohol moiety via ester formation.
Et3N,
NH2 abs. EtOH,
OH
H2N
R1
R1
OH
quant.
An example is depicted in Scheme 3 with the coupling of
dopamine as a ligand to the scaffold Boc-8. The resulting
triscatecholate 10 is a strong metal binder and may be
used for the functionalization of metal surfaces. To in-
crease the range of suitable ligands to be conjugated, we
aimed for tetraamines like 12 that would be easily ad-
dressed by ligands bearing carboxylic acids or carbonyls.
3
3
3
3
H2N
R1
3
14
3
15
O
Et3N,
abs. EtOH
quant.
R1 =
N
HO
OH
R2 =
N
OH
NHBoc
R2
R2
ClH3N
OH
OH
OH
3
3
HO
R =
R2
OH
3
16
EDC, HOBt,
Et3N, DMF
RHN
NHR
Scheme 5 Synthesis of trisamine 14 and triscatecholates 15 and 16
Boc-8
O
O
50%
O
OH
NHR
10
For many applications of our scaffolds it is interesting to
vary the spacing of the tripodal conjugation site. Starting
from scaffold Cbz-9, we have thus coupled mono Boc-
protected ethylenediamine (Scheme 6). Trifluoroacetic
acid deprotection of the resulting trimeric coupling prod-
uct gave the free trisamine 17. In a similar approach,
tris(cyanoethyl)adamantane 13 was hydrolyzed to the cor-
responding tricarboxylic acid, which was then coupled to
mono-Boc-protected 1,4-diaminobutane using standard
peptide coupling conditions. The resulting product was
OH
Scheme 3 Synthesis of triscatecholate 10 via EDC/HOBt coupling
A Curtis reaction of the known tricarboxylic acid Cbz-942
with diphenylphosphoryl azide (DPPA)45 gave the orthog-
onally protected tetraamine 11. Acidic deprotection gave
the target amine 12 ready for conjugation of ligands
(Scheme 4). A similar trisamine 14 was prepared from
tris(cyanoethyl)adamantane 13,46 via diisobutylaluminum
Synthesis 2013, 45, 1452–1461
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
(3 + 1)-Adamantyl Scaffolds
1455
deprotected with trifluoroacetic acid to give the trisamine because it has three orthogonal functionalities which
18. A similar protocol was used for the synthesis of trisal- might be addressed selectively.
cohol 19, which was obtained by peptide coupling of the
protected amino acid Cbz-9 with ethanolamine.
NHCbz
1. BH3, THF
2. MsCl, Et3N, CH2Cl2
3. NaN3, DMF
N3
N3
NHCbz
Cbz-9
1. HATU, DIPEA,
DMF, Boc-ethylenediamine
2. TFA, CH2Cl2
30%
O
O
20
NH
HN
Cbz-9
95%
H2N
N3
NH2
O
CO2Bn
NH
17
ClH3N
N3
21
NHBoc
H2N
HATU, DIPEA
DMF
O
O
Boc-9
BnO2C
CO2Bn
52%
NH
HN
1. HCl, H2O
2. EDC, HOBt, DMF,
O
O
Boc-1,4-diaminobutane
3. TFA, CH2Cl2
NH
HN
O
N3
N3
13
22
NH
41%
H2N
BnO2C
O
NH2
NH
18
N3
Scheme 7 Synthesis of trisazides 20 and 22
H2N
Variations at the Effector-Conjugation Site
NHCbz
Conjugation of effector molecules like dyes to the steri-
cally hindered bridgehead amines of adamantyl scaffolds
such as 7 or 9 can be problematic if nonactivated or weak-
ly activated carboxylic acids need to be coupled. Spaced
amino groups or alternative functionalities in this position
are therefore attractive. The bromo-substituted tricarbox-
ylic acid 23 is an excellent precursor for the introduction
of a functional group orthogonal to the three carboxylic
acids, because the bridgehead bromine is easily substitut-
ed using radical chemistry (Scheme 8). Treatment of 23
with acrylonitrile gave the cyanoethyl derivative 24,
which was reduced to the spaced amine 27. Alternatively,
bromide 23 was treated with methacrylate to give the
methyl ester 26. Both, the methyl ester 26 and the cyano-
ethyl derivative 24 were also hydrolyzed to tetrakis(car-
boxyethyl)adamantane 25, which is an interesting
tetrahedral building block for the synthesis of dendritic
structures.
O
O
HATU, DIPEA,
DMF, ethanolamine
Cbz-9
NH
HN
49%
HO
OH
O
NH
19
HO
Scheme 6 Preparation of spaced trisamines 17, 18, and trisalcohol
19
For the coupling of densely functionalized and/or polar
ligands47 it is often advantageous to use the Huisgen cy-
cloaddition of alkynes and azides.48,49 Trisazides like 20
and 22 are thus interesting scaffolds for click conjugations
of alkyne functionalized ligands. Trisazide 20 was pre-
pared from the tricarboxylic acid Cbz-9 via borane reduc-
tion, mesylation of the resulting triol, and subsequent
nucleophilic displacement with sodium azide (Scheme 7).
In addition, the amino acid functionalized derivative 22
was prepared from scaffold Boc-9 by peptide coupling
with azidohomoalanine. Trisazide 22 is particularly inter-
esting for the assembly of complex multivalent structures,
Additional (3 + 1) scaffolds were available starting from
amino acid 9 (Scheme 9). Methyl ester 28 was prepared in
80% yield using thionyl chloride in methanol with catalyt-
ic amounts of N,N-dimethylformamide. This triester was
coupled to propiolic acid with N,N′-dicyclohexylcarbodi-
imide to give the alkyne 29 ready for click conjugation of
effector molecules with an azide moiety.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1452–1461

1456
C. Fleck et al.
FEATURE ARTICLE
CN
CO2H
CN
Br
AIBN, Bu3SnH,
toluene, reflux
HCl, H2O
reflux
HO2C
CO2H
HO2C
CO2H
HO2C
CO2H
59%
79%
24
23
25
HO2C
80%
HO2C
HO2C
PtO2, AcOH,
HCl, H2, 30 bar
CO2Me
NaOH,
H2O
88%
63%
AIBN, Bu3SnH,
THF–toluene, reflux
ClH3N
26
CO2Me
HO2C
CO2H
HO2C
CO2H
27
26
HO2C
HO2C
Scheme 8 Bromide 23 as a versatile precursor for the synthesis of (3 + 1) scaffolds 24, 26, and 27 and the tetrahedral scaffold 25 via radical
chemistry
NH2
O
O
SOCl2, MeOH
cat. DMF
NHS
CO2Bn
HN
CO2Bn
CO2H
MeO2C
CO2Me
30
9
64%
Et3N, DMSO
HO2C
9
28
67%
MeO2C
31
HO2C
propiolic acid,
DCC, DMF, r.t.
95%
O
O
O
NHCbz
NHCbz
NHS
HN
2
2
HN
32
Et3N, DMSO
HO2C
CO2H
9
MeO2C
CO2Me
72%
29
33
HO2C
MeO2C
Scheme 10 Elongation of the effector conjugation site via NHS ester
coupling to amino acid 33
Scheme 9 Synthesis of the alkyne-functionalized triester 29
Alternatively, the free amino acid 9 may be directly acyl-
ated with N-hydroxysuccinimide (NHS) benzylglutarate
to give benzyl ester 31 (Scheme 10). A spaced amino
group in 33 was prepared by NHS ester coupling of Cbz-
protected aminohexanoic acid 32.
are (3 + 1) scaffolds with different orthogonal functional-
ities such as alcohols, amines, carboxylic acids, azides, or
alkynes. They may thus easily be conjugated to other
functional molecules by standard coupling techniques
such as amide formation or copper catalyzed click reac-
tions.
Conclusion
The following compounds were prepared according to literature
protocols: 7,43 Boc-8,43 9,23 Boc-9,23 Cbz-9,42 13,46 14,51 21,52 23,23
30,53 and 32.54
We described the synthesis of several new tri- and tetra-
functionalized adamantane derivatives. These compounds
belong to a molecular toolbox for applications in medici-
nal and material chemistry.50 Most derivatives described
TLC was performed on silica gel aluminum sheets. Reagents used
for developing plates were cerium-stain [phosphomolybdic acid
(5.00 g), Ce(SO4)2·4 H2O (2.50 g), H2SO4 (25 mL, and H2O (225
Synthesis 2013, 45, 1452–1461
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
(3 + 1)-Adamantyl Scaffolds
1457
mL)], KMnO4 soln (0.5% KMnO4–1 M aq NaOH), and detection by
UV light was used when applicable. Flash column chromatography
was performed on silica gel (60–200 μm). 1H NMR are referenced
to residual non-deuterated solvent (CDCl3, δH = 7.26; DMSO-d6,
δH = 2.50; CD3OD, δH = 3.31). 13C NMR are referenced to the sol-
vent signal (CDCl3, δC = 77.16; DMSO-d6, δC = 39.52; CD3OD,
δH = 49.0). NMR spectra were recorded on 200 (50), 400 (100), or
600 (150) MHz instruments. ESI MS were recorded on a TOF in-
strument operated in positive or negative mode. Samples were dis-
solved in MeCN–MeOH mixtures and directly injected via syringe.
If indicated with as anhyd solvents, these were dried according to
standard procedures prior to use.55,56
7-(Benzyloxycarbonylamino)adamantane-1,3,5-triethanamine
(12)
A soln of 11 (0.25 g, 0.35 mmol) in CH2Cl2 (40 mL) and TFA (10
mL) was stirred at r.t. for 24 h. The mixture was concentrated in
vacuo and the resulting oil was co-evaporated with CH2Cl2 (3 × 20
mL) to give 12 (0.14 g, 0.34 mmol, 99%) as a colorless oil.
IR (film): 2916, 1689, 1520–1365, 1248–1025, 798–720 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.92–7.70 (m, 6 H), 7.35–7.17
(m, 5 H), 4.92 (s, 2 H), 1.52–1.41 (m, 12 H), 1.21–1.13 (m, 6 H),
1.10–0.94 (m, 6 H).
13C-MR (100 MHz, DMSO-d6): δ 154.1, 137.2, 128.3, 127.7, 64.6,
51.6, 44.7, 44.5, 34.2 34.0, 33.8.
HRMS (ESI): m/z [M + H]+ calcd for C24H39N4O2: 415.3068; found:
415.3060.
7-[3-(tert-Butoxycarbonylamino)propyl]-N,N′,N′′-tris[2-(3,4-
dihydroxyphenyl)ethyl]adamantane-1,3,5-tricarboxamide (10)
Compound Boc-8 (0.10 g, 0.24 mmol) was dissolved in DMF (30
mL) and the soln was cooled to 0 °C (ice bath). Et3N (0.39 mL, 2.82
mmol) was added and the soln was stirred for 5 min. EDC·HCl (0.21
g, 1.06 mmol) and HOBt (0.14 g, 1.06 mmol) were added and the
soln was stirred for 5 min. Dopamine hydrochloride (0.20 g, 1.06
mmol) was added and the soln was stirred for 72 h at r.t. The mix-
ture was concentrated and dissolved in a mixture of EtOAc (30 mL)
and 1 M HCl (5 mL); the soln was washed with sat. aq KHSO4 soln
(3 ×). The organic layer was dried (Na2SO4), filtered, and concen-
trated. Evaporation of the solvent gave a colorless solid that was
suspended in Et2O (100 mL) and stirred for 30 min in a water bath
at 30 °C. The resulting slurry was filtered and the procedure was re-
peated (6 ×) to give 10 (99 mg, 0.12 mmol, 50%) as a colorless
sticky solid.
N,N′,N′′-Tris(3,4-dihydroxybenzylidene)adamantane-1,3,5-tri-
propaneamine (15)
Compound 14 (50 mg, 0.16 mmol) was dissolved in anhyd EtOH
(10 mL) and 3,4-dihydroxybenzaldehyde (76 mg, 0.49 mmol) dis-
solved in a small amount of EtOH was added and the soln was
stirred for 24 h under N2 atmosphere. The precipitate was separated
by centrifugation, washed with cold Et2O and a small amount of
EtOH, and dried in vacuo to give 15 (104 mg, 0.16 mmol, 100%) as
a sticky solid.
IR (KBr): 3410, 2901–2842, 1583, 1450, 1383, 1285, 1116, 816
cm–1.
1H NMR (400 MHz, MeOH-d4): δ = 8.05–8.02 (m, 3 H), 7.16–7.14
(m, 3 H), 6.92.6.89 (m, 3 H), 6.72–6.69 (m, 3 H), 3.40–3.10 (br s, 6
H), 1.90 (s, 1 H), 1.50–1.48 (m, 6 H), 1.29–1.27 (m, 6 H), 1.08–1.05
(m, 12 H).
IR (KBr): 3374, 2936, 1633, 1526, 1366, 1285, 1285, 1196–1046
cm–1.
1H NMR (400 MHz, MeOH-d4): δ = 7.74–7.42 (m, 3 H), 6.67–6.65
(m, 3 H), 6.61 (s, 3 H), 6.50–6.48(m, 3 H), 3.31–3.29 (m, 6 H),
3.01–2.98 (m, 2 H), 2.64–2.59 (m, 6 H), 1.76–1.69 (m, 6 H), 1.40–
1.35 (m, 17 H), 1.14–1.12 (m, 2 H).
13C NMR (100 MHz, MeOH-d4): δ = 178.9, 146.2, 144.8, 132.0,
121.2, 117.1, 116.3, 80.0, 43.7, 43.4, 42.3, 40.7, 39.4, 35.8, 35.1,
28.8, 24.2, 12.8.
HRMS (ESI): m/z [M + H]+ calcd for C40H50N3O6: 668.3694; found:
668.3691.
N,N′,N′′-Tris(2,3-dihydroxybenzylidene)adamantane-1,3,5-tri-
propaneamine (16)
Compound 14 (50 mg, 0.16 mmol) was dissolved in anhyd EtOH
(10 mL) and 2,3-dihydroxybenzaldehyde (76 mg, 0.49 mmol) dis-
solved in a small amount of EtOH was added and the soln was
stirred for 24 h under N2 atmosphere. The precipitate was separated
by centrifugation and washed with cold Et2O and a small amount of
EtOH. The solid was dried in vacuo to give 16 (103 mg, 0.16 mmol,
100%) as a sticky solid.
HRMS (ESI): m/z [M + Na]+ calcd for C45H58N4NaO11: 853.3994;
found: 853.3992.
7-(Benzyloxycarbonylamino)-N,N′,N′′-tris(tert-butoxycarbon-
yl)adamantane-1,3,5-triethanamine (11)
Compound Cbz-9 (0.31 g, 0.61 mmol) was dissolved in anhyd
CH2Cl2 (5 mL). DPPA (0.60 mL, 2.38 mmol) and Et3N (0.60 mL,
4.32 mmol) were added and the soln was stirred at r.t. for 8 h. The
mixture was concentrated; the resulting crude product was dis-
solved in t-BuOH (50 mL) and heated under reflux for 24 h (N2 at-
mosphere). The soln was concentrated, the residue was dissolved in
CH2Cl2 (50 mL), and the soln washed with 2 M NaOH (3 × 20 mL).
The organic layer was dried (Na2SO4), filtered, and concentrated.
The resulting crude product was purified by flash chromatography
(silica gel, EtOAc–MeOH, 10:1; Rf = 0.69) to give 11 (0.25 g, 0.35
mmol, 58%) as a yellow oil.
1H NMR (400 MHz, MeOH-d4): δ = 8.47–8.44 (m, 3 H), 6.80–6.75
(m, 6 H), 6.59–6.50 (m, 3 H), 3.53–3.50 (m, 6 H), 1.91 (br s, 1 H),
1.57–1.50 (m, 6 H), 1.31–1.29 (m, 6 H), 1.13–1.10 (m, 12 H).
HRMS (ESI): m/z [M + H]+ calcd for C40H50N3O6: 668.3694; found:
668.3691.
N,N′,N′′-tris(2-Aminoethyl)-7-(benzyloxycarbonylamino)ada-
mantane-1,3,5-tripropanamide (17)
Compound Cbz-9 (0.21 g, 0.41 mmol) and 0.54 g (1.4 mmol)
HATU were dissolved in anhyd DMF (5 mL). DIPEA (0.25 mL,
1.49 mmol) was added and the soln was stirred at 0 °C for 20 min.
Boc-protected ethylenediamine (0.21 mL, 1.33 mmol) was added
and the soln was stirred for 20 h at r.t. The mixture was concentrated
and the residue was dissolved in EtOAc (50 mL). This soln was
washed with sat. aq NaHCO3 (3 ×) and sat. aq KHSO4 (3 ×). The or-
ganic layer was dried (Na2SO4), filtered, and concentrated to give
the Boc-protected trisamine (345 mg, 0.37 mmol, 91%) as a color-
less solid.
IR (KBr): 3404, 2898–2841, 1644, 1544–1521, 1463, 1359, 1232,
1025, 738 cm–1.
1H NMR (400 MHz, CDCl3, broad signals due to carbamate rota-
tional isomerism): δ = 7.21–7.12 (m, 5 H), 4.90 (s, 2 H), 3.04–2.92
(m, 6 H), 1.57–1.55 (m, 6 H), 1.45 (s, 18 H), 1.35–1.34 (m, 6 H),
1.16–1.14 (m, 6 H).
13C NMR (100 MHz, CDCl3, broad signals due to carbamate rota-
tional isomerism): δ = 155.9, 154.3, 136.5, 129.6, 128.4, 127.9,
78.4, 65.8, 52.3, 45.5, 42.7, 35.6, 35.6, 34.0, 28.4.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.29 (m, 5 H), 5.00 (s, 2 H),
3.33–3.32 (m, 6 H), 3.23 (s, 6 H), 2.11 (t, 3J = 7.5 Hz, 6 H), 1.54–
1.53 (m, 12 H), 1.43 (s, 27 H), 1.11 (d, 2J = 12.2 Hz, 3 H), 1.04 (d,
2J = 12.2 Hz, 3 H).
MS (ESI): m/z [M + Na]+ calcd for C39H62N4NaO8: 737.4460;
found: 737.4463.
13C NMR (100 MHz, CDCl3): δ = 174.4, 157.0, 136.8, 128.7, 128.2,
128.1, 79.7, 66.1, 52.9, 45.3, 45.0, 40.6, 40.6, 38.2, 35.2, 30.3, 28.6.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1452–1461

1458
C. Fleck et al.
FEATURE ARTICLE
HRMS (ESI): m/z [M + H]+ calcd for C48H78N7O11: 928.5754;
found: 928.5759.
MS (ESI): m/z [M + H]+ calcd for C33H50N4O8: 653.3521; found:
653.3520.
A soln of the Boc-protected trisamine (345 mg, 0.37 mmol) in
CH2Cl2 (10 mL) and TFA (2.5 mL) was stirred at 0 °C for 2 h and
allowed to warm to r.t. The mixture was concentrated in vacuo and
the resulting oil was co-evaporated with CH2Cl2 (3 ×) and then with
1 M aq HCl to give 17 (0.25 g, 0.34 mmol, 95%) as the hydrochlo-
ride salt. Trisamine 17 should be used for functionalization without
further purification and is unstable upon storage.
1H NMR (400 MHz, CDCl3): δ = 7.36–7.30 (m, 5 H), 5.01 (s, 2 H),
3.45 (t, 3J = 6.3 Hz, 6 H), 3.08–3.04 (m, 6 H), 2.27–2.23 (m, 6 H),
1.59 (s, 6 H), 1.54–1.50 (m, 6 H), 1.21 (d, 2J = 12.2 Hz, 3 H), 1.12
(d, 2J = 12.2 Hz, 3 H).
3,5,7-Tris(3-azidopropyl)-N-(benzyloxycarbonyl)adamantan-
1-amine (20)
Compound Cbz-9 (0.48 g, 0.96 mmol) was dissolved in anhyd THF
and 1 M BH3 in THF (9.57 mL, 9.57 mmol) was slowly added. The
soln was stirred at r.t. for 24 h. H2O (10 mL) and sat. aq NaHCO3
(10 mL) were added to the mixture. The solvent was removed in
vacuo and the remaining solid was extracted with hot EtOH (3 × 50
mL). The combined extracts were concentrated to give the interme-
diate triol (0.50 g), which was used in the next step without further
purification.
The crude triol was dissolved in anhyd CH2Cl2 (50 mL) and cooled
to 0 °C. Freshly distilled Et3N (0.95 mL, 4.31 mmol) was added and
the soln was stirred at r.t. for 15 min. MsCl (0.33 mL, 4.31 mmol)
was added and the soln was stirred at r.t. for 20 h. MeOH (20 mL)
was added to the mixture and the soln was concentrated. The result-
ing crude product was dissolved in CH2Cl2 (60 mL). The resulting
soln was washed with H2O, sat. aq NaHCO3, and sat. aq NaHSO4,
and dried (Na2SO4). The reaction soln was concentrated to give the
intermediate mesylate, which was again used without further puri-
fication in the next step.
N,N′,N′′-Tris(4-aminobutyl)adamantane-1,3,5-tripropan-
amide (18)
A soln of 13 (7.00 g, 23.7 mmol), concd HCl (40 mL), and H2O (5
mL) was heated to reflux for 20 h. The resulting mixture was poured
into ice-H2O; the product was filtered off, washed with cold H2O
and crystallized (MeCN) to give the tricarboxylic acid (8.00 g, 22.7
mmol, 95%) as a colorless solid.
The tricarboxylic acid (0.30 g, 0.85 mmol) was dissolved in distilled
DMF (60 mL). Et3N (1.52 mL, 11.0 mmol) was added and the soln
was stirred at 0 °C for 5 min. EDC·HCl (63 mg, 2.81 mmol) and
HOBt (0.38 g, 2.81 mmol) were added to the mixture, which was
stirred for 15 min. Mono-Boc-protected 1,4-diaminobutane (0.53 g,
2.81 mmol) was then added and the soln was stirred for 72 h at r.t.
The mixture was concentrated and the residue was dissolved in
EtOAc. This soln was washed with sat. aq NaHCO3 (3 ×) and sat.
aq NaHSO4 (3 ×). The organic layer was dried (Na2SO4), filtered,
and concentrated. The resulting crude product was purified by flash
chromatography (silica gel, 10% MeOH–EtOAc) to give the Boc-
protected trisamine (0.33 g, 0.39 mmol, 46%) as a colorless solid.
The crude mesylate was dissolved in anhyd DMF (40 mL), NaN3
(0.28 g, 4.31 mmol) was added and the soln was stirred at 60 °C for
26 h. The mixture was concentrated, the resulting crude product was
dissolved in EtOAc (30 mL), washed with the same amount of H2O
and sat. aq NaCl soln, dried (Na2SO4), filtered, and concentrated.
The resulting crude product was purified by flash chromatography
(silica gel, CH2Cl2–MeOH, 10:1) to give 20 (0.15 g, 0.27 mmol,
30% over 3 steps) as a yellowish oil.
IR (film): 3339, 2908–2844, 2096, 1725, 1507, 1453, 1351–1150,
1118, 1025, 737 cm–1.
IR (KBr): 3425, 2918–2849, 2416, 1687, 1536, 1450, 1391–1381,
1271–1109 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.05–6.94 (m, 3 H), 5.27–5.19 (m,
3 H), 3.31–3.30 (m, 6 H), 3.20–2.17 (m, 6 H), 2.23–2.06 (m, 7 H),
1.64–1.52 (m, 12 H), 1.52–1.40 (m, 33 H), 1.40–1.30 (m, 6 H),
1.21–1.03 (m, 6 H).
1H NMR (400 MHz, CDCl3): δ = 7.30–7.21 (m, 5 H), 4.97 (s, 2 H),
4.62 (s, 1 H), 3.16 (t, 3J = 8.6 Hz, 6 H), 1.51–1.45 (m, 12 H, 5–H),
1.12–0.95 (m, 12 H).
13C NMR (100 MHz, CDCl3): δ = 158.5, 136.4, 128.3, 127.9, 65.9,
52.6, 51.9, 45.5, 45.2, 39.8, 34.9, 22.3.
HRMS (ESI): m/z [M + Na]+ calcd for C27H38N10NaO: 557.3071;
found: 557.3067.
13C NMR (100 MHz, CDCl3): δ = 174.5, 156.6, 79.3, 46.6, 41.5,
40.5, 39.8, 39.5, 33.7, 30.6, 29.4, 28.2, 27.8, 27.1.
HRMS (ESI): m/z [M + Na]+ calcd for C46H82N6NaO3: 885.6035;
found: 885.6045.
N,N′,N′′-Tris[(S)-3-azido-1-(benzyloxycarbonyl)propyl]-7-ben-
zyloxycarbonylaminoadamantane-1,3,5-tripropanamide (22)
Boc-9 (90 mg, 0.19 mmol), HATU (469 mg, 1.20 mmol), and
DIPEA (0.22 mL, 1.20 mmol) were dissolved in anhyd DMF
(8 mL) at 0 °C. After 10 min azidoamine 21 (333 mg, 1.20 mmol)
and DIPEA (0.22 mL, 1.20 mmol) in anhyd DMF (5 mL) were add-
ed. The reaction was warmed to r.t. and stirred for 69 h. The solvent
was evaporated in vacuo and the crude product dissolved in EtOAc
(20 mL). The organic layer was washed with 1 M aq HCl (3 ×
10 mL) and sat. NaHCO3 (3 × 10 mL). The organic layer was sepa-
rated, dried (MgSO4), and filtered, and the solvent was evaporated.
The crude product was purified by column chromatography (silica
gel, PE–EtOAc, 1:2; Rf = 0.4) to give 22 (110 mg, 0.10 mmol, 52%)
as a colorless oil.
A soln of the Boc-protected trisamine (0.16 g, 0.19 mmol) in
CH2Cl2 (40 mL) and TFA (15 mL) was stirred at r.t. for 24 h. The
mixture was concentrated in vacuo and the resulting oil was co-
evaporated with CH2Cl2 (3 ×) to give 18 (0.10 g, 0.18 mmol, 94%)
as a colorless oil. Trisamine 18 should be used for functionalization
without further purification and is unstable upon storage.
MS (ESI): m/z [M + H]+ calcd for C31H58N6O3: 563.4643; found:
563.4641.
7-(Benzyloxycarbonylamino)-N,N′,N′′-tris(2-hydroxyethyl)ad-
amantane-1,3,5-tripropanamide (19)
1H NMR (400 MHz, CD3OD): δ = 7.27–7.42 (m, 15 H), 5.18 (d,
2J = 12.3 Hz, 3 H), 5.13 (d, 2J = 12.3 Hz, 3 H), 4.54 (d, 3J = 5.1 Hz,
1.5 H), 4.52 (d, 3J = 5.1 Hz, 1.5 H), 3.32–3.45 (m, 6 H), 2.15–2.30
(m, 6 H), 2.02–2.15 (m, 3 H), 1.85–1.97 (m, 3 H), 1.53 (s, 6 H),
1.44–1.51 (m, 6 H), 1.42 (s, 9 H), 1.13 (d, 2J = 12.1 Hz, 3 H), 1.04
(d, 2J = 12.1 Hz, 3 H).
13C NMR (100 MHz, CD3OD): δ = 177.0, 172.9, 137.1, 129.6,
129.4, 129.3, 79.3, 68.1, 53.4, 51.5, 49.0, 46.4, 46.0, 39.8, 36.1,
31.6, 30.1, 28.9.
Compound Cbz-9 (0.10 g, 0.19 mmol) and HATU (0.274 g, 0.72
mmol) were dissolved in anhyd DMF (5 mL). DIPEA (0.1 mL, 0.6
mmol) was added and the soln was stirred at 0 °C for 20 min. Etha-
nolamine (0.045 mL, 0.72 mmol) was added and the soln was
stirred for 20 h at r.t. The mixture was concentrated and the residue
was dissolved in H2O. This soln was washed with CH2Cl2 (3 ×) and
concentrated to give 19 (0.063 g, 0.10 mmol, 49%) as a colorless
solid.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.23 (m, 5 H), 4.96 (s, 2 H),
3.56 (t, 3J = 5.3 Hz, 6 H), 3.30–3.24 (m, 6 H), 2.12 (m, 6 H), 1.48–
1.39 (m, 12 H), 1.06–0.96 (m, 6 H).
HRMS (ESI): m/z [M + Na]+ calcd for C57H73N13NaO11: 1138.5445;
found: 1138.5445.
Synthesis 2013, 45, 1452–1461
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
(3 + 1)-Adamantyl Scaffolds
1459
7-(2-Cyanoethyl)adamantane-1,3,5-tripropanoic Acid (24)
A soln of bromide 23 (0.315 g, 0.73 mmol), acrylonitrile (0.14 mL,
2.12 mmol), Bu3SnH (0.38 mL, 1.44 mmol), and AIBN (0.012 g,
0.07 mmol) in THF–toluene (1:1, 20 mL) was heated to reflux for 6
h. The resulting mixture was poured into 2 M NaOH (50 mL) and
EtOAc (50 mL). The phases were separated and the aqueous phase
was washed with EtOAc (2 ×). The aqueous phase was acidified
with 4 M HCl and extracted with EtOAc (3 × 50 mL). The combined
organic phases were dried (Na2SO4), filtered, and concentrated to
give 24 (0.262 g, 0.65 mmol, 79%) as a yellowish solid; mp 216 °C.
7-(3-Aminopropyl)adamantane-1,3,5-tripropanoic Acid Hy-
drochloride (27)
A soln of nitrile 24 (0.10 mg, 0.25 mmol) and PtO2 (0.011 mg, 0.05
mmol) in glacial AcOH–concd HCl (1:1, 14 mL) was hydrogenated
(30 bar H2) for 6 d. The resulting mixture was filtered through celite
and the solvent was evaporated in vacuo to give 27 (99 mg, 0.22
mmol, 80%) as a colorless oil.
1H NMR (400 MHz, DMSO-d6): δ = 2.87 (s, 2 H), 1.87 (s, 2 H), 1.71
(br s, 8 H), 1.59–1.54 (m, 6 H), 1.35 (s, 12 H).
13C NMR (100 MHz, DMSO-d6): δ = 175.2, 68.3, 45.5, 45.1, 37.9,
37.4, 33.7, 33.5, 28.0, 20.7.
HRMS (ESI): m/z [M + H]+ calcd for C22H36NO6: 410.2537; found:
410.2545.
IR (KBr): 2923, 2261, 1707, 1453, 1411, 1315, 1224, 1153 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 2.42 (t, 3J = 7.9 Hz, 2 H), 2.14
(t, 3J = 7.9 Hz, 6 H), 1.42 (t, 3J = 7.7 Hz, 2 H), 1.35 (t, 3J = 8.1 Hz,
6 H), 1.01 (d, 2J = 9.5 Hz, 12 H).
13C NMR (100 MHz, DMSO-d6): δ = 175.2, 121.7, 44.9, 44.5, 38.0,
37.8, 33.8, 33.5, 27.8, 10.4.
HRMS (ESI): m/z [M + H]+ calcd for C22H30NO6: 405.2151; found:
405.2168.
Trimethyl 7-Aminoadamantane-1,3,5-tripropanoate (28)
Compound 9 (0.75 g, 1.85 mmol) was dissolved in anhyd MeOH
(75 mL) and cooled to 0 °C. SOCl2 (1.3 mL, 11.1 mmol) was added
slowly. Additionally anhyd DMF (5 drops) was added to the mix-
ture. The mixture was stirred for 24 h at r.t. After concentration in
vacuo the residue was dissolved in aq NaHCO3 and extracted with
EtOAc (3 × 50 mL). The combined organics were dried (Na2SO4),
filtered, and concentrated to give 28 (0.48 g, 1.17 mmol, 64%) as a
colorless solid.
1H NMR (400 MHz, CDCl3): δ = 3.63 (s, 9 H), 2.22 (t, 3J = 8.0 Hz,
6 H), 1.50 (t, 3J = 8.0 Hz, 6 H), 1.19 (s, 6 H), 1.04 (d, 2J = 12.0 Hz,
3 H), 1.01 (d, 2J = 12.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.6, 51.7, 49.6, 49.1, 45.1,
37.5, 35.3, 28.2.
Adamantane-1,3,5,7-tetrapropanoic Acid (25)
Method A: A soln of 24 (0.073 g, 0.18 mmol), concd HCl (0.5 mL),
and H2O (0.1 mL) was heated to reflux for 48 h. The solvent was
evaporated to yield 25 (0.045 g, 0.11 mmol, 59%) as a colorless sol-
id.
Method B: A soln of bromide 23 (0.10 g, 0.23 mmol), methyl acry-
late (0.06 mL, 0.68 mmol), Bu3SnH (0.130 mL, 0.49 mmol), and
AIBN (0.004 g, 0.02 mmol) in THF–toluene (1:1, 20 mL) was heat-
ed under reflux for 6 h. The resulting mixture was poured into aq
10% NaOH (50 mL) and EtOAc (50 mL). The phases were separat-
ed and the organic phase was extracted with 10% aq NaOH (2 ×).
The aqueous phase was acidified with HCl and extracted with EtO-
Ac (3 × 50 mL). The combined organic phases were dried (Na2SO4),
filtered, and concentrated to give 25 (0.068 g, 0.16 mmol, 63%) as
a yellowish solid; mp 229 °C.
MS (ESI): m/z [M + H]+ calcd for C22H36NO6: 410.2537; found:
410.2538.
Trimethyl 7-(Propynoylamino)adamantane-1,3,5-tripropano-
ate (29)
Compound 28 (0.69 g, 1.58 mmol) and propiolic acid were dis-
solved in anhyd CH2Cl2 and cooled to 0 °C. After 5 min, DCC (0.42
g, 2.03 mmol) was added and the soln was stirred at r.t. for 24 h. The
formed dicyclohexylurea was filtered off and the filtrate was con-
centrated. The resulting crude product was purified by flash chro-
matography (silica gel) to give 29 (0.63 g, 1.50 mmol, 95%) as a
yellow oil.
IR (KBr): 2896, 2843, 1691, 1406, 1310, 1209, 1149 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.05 (s, 4 H), 2.14 (t, 3J = 7.8
Hz, 8 H), 1.35 (t, 3J = 7.6 Hz, 8 H), 0.99 (s, 12 H).
13C NMR (100 MHz, DMSO-d6): δ = 175.1, 45.0, 37.8, 33.4, 27.8.
HRMS (ESI): m/z [M + Na]+ calcd for C22H32NNaO8: 447.1989;
IR (film): 3259, 2919–2851, 2104, 1732, 1651, 1535, 1453–1437,
1353–1199, 1087–1018 cm–1.
found: 447.1988.
1H NMR (400 MHz, CDCl3): δ = 5.96 (s, 1 H), 3.58 (s, 9 H), 2.69
(s, 1 H), 2.18 (t, 3J = 8.2 Hz, 6 H), 1.56 (s, 6 H), 1.46 (t, 3J = 8.2 Hz,
6 H), 1.08 (d, 2J = 12.0 Hz, 3 H), 0.98 (d, 2J = 12.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.3, 151.1, 78.1, 71.7, 54.9,
51.6, 44.8, 44.3, 37.3, 34.8, 27.9.
HRMS (ESI): m/z [M + Na]+ calcd for C25H35NNaO7: 484.2306;
found: 484.2308.
7-[2-(Methoxycarbonyl)ethyl]adamantane-1,3,5-tripropanoic
Acid (26)
A soln of bromide 23 (0.10 g, 0.23 mmol), methyl acrylate (0.06
mL, 0.68 mmol), Bu3SnH (0.130 mL, 0.49 mmol), and AIBN
(0.004 g, 0.02 mmol) in THF–toluene (1:1, 20 mL) was heated un-
der reflux for 6 h. The resulting mixture was poured into sat. aq
NaHCO3 (50 mL) and EtOAc ((50 mL). The phases were separated
and the aqueous phase was washed with EtOAc (2 × 50 mL). The
aqueous phase was acidified with HCl and extracted with EtOAc (3
× 10 mL). The combined organic phases were dried (Na2SO4), fil-
tered, and concentrated to give 26 (0.099 g, 0.22 mmol, 88%) as a
yellowish solid; mp 150 °C.
7-{(3-(Benzyloxycarbonyl)propanoyl]amino}adamantane-
1,3,5-tripropanoic Acid (31)
Compound 9 (0.314 g, 0.78 mmol) was dissolved in anhyd DMSO
(5 mL). Et3N (0.225 mL, 1.6 mmol) and 30 (0.29 g, 0.95 mmol)
were added. The mixture was stirred for 72 h at r.t. The solvent was
removed in vacuo and the residue was dissolved in sat. aq NaHCO3
(20 mL) The soln was washed with EtOAc (2 × 20 mL), acidified
with HCl, and extracted with EtOAc (3 × 20 mL). The combined or-
ganic layers were dried (Na2SO4), filtered, and concentrated to give
31 (0.29 g, 0.50 mmol, 67%) as a yellowish solid.
IR (KBr): 2962, 2846, 1709, 1453, 1261, 1058 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 11.99 (s, 3 H), 3.57 (s, 3 H),
2.24 (t, 3J = 8.0 Hz, 2 H), 2.14 (t, 3J = 7.7 Hz, 6 H), 1.37–1.33 (m,
6 H), 0.99 (s, 12 H), 0.87 (t, 3J = 7.3 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 175.2, 174.0, 51.3, 48.5, 45.0,
44.7, 37.8, 35.4, 33.5, 32.8, 27.8.
1H NMR (400 MHz, CD3OD): δ = 7.40–7.32 (m, 5 H), 5.12 (s, 2 H),
2.62 (t, 3J = 6.5 Hz, 2 H), 2.44 (t, 3J = 6.6 Hz, 2 H), 2.25 (t, 3J = 8.0
Hz, 6 H), 1.58 (s, 6 H), 1.52–1.48 (m, 6 H), 1.15 (d, 2J = 12.1 Hz, 3
H), 1.09 (d, 2J = 12.1 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C23H34NNaO8: 461.2151;
found: 461.2153.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1452–1461

1460
C. Fleck et al.
FEATURE ARTICLE
13C NMR (100 MHz, CD3OD): δ = 178.2, 174.2, 173.5, 137.6,
129.6, 129.2, 129.1, 67.4, 54.8, 46.2, 45.5, 39.0, 35.8 32.2 30.6,
29.1.
HRMS (ESI): m/z [M + H]+ calcd for C30H40NO9: 558.2698; found:
558.2689.
(13) Li, Q.; Rukavishnikov, A. V.; Petukhov, P. A.; Zaikova, T.
O.; Jin, C.; Keana, J. F. W. J. Org. Chem. 2003, 68, 4862.
(14) Willey, T. M.; Fabbri, J. D.; Lee, J. R. I.; Schreiner, P. R.;
Fokin, A. A.; Tkachenko, B. A.; Fokina, N. A.; Dahl, J. E.
P.; Carlson, R. M. K.; Vance, A. L.; Yang, W. L.;
Terminello, L. J.; van Buuren, T.; Melosh, N. A. J. Am.
Chem. Soc. 2008, 130, 10536.
(15) Misra, P.; Humblet, V.; Pannier, N.; Maison, W.; Frangioni,
J. V. J. Nucl. Med. 2007, 48, 1379.
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Khim. Zh. 1988, 54, 437.
7-{(6-(Benzyloxycarbonylamino)hexanoyl]amino}adamantane-
1,3,5-tripropanoic Acid (33)
Compound 9 (1.26 g, 3.12 mmol) was dissolved in DMSO (20 mL).
Et3N (1.70 mL, 12.5 mmol) and 32 (1.70 g, 4.68 mmol) were added.
The mixture was stirred for 12 h at r.t. and concentrated. The residue
was dissolved in EtOAc (20 mL) and washed with sat. aq KHSO4.
The organic layer was concentrated and the residue dissolved in 1
M NaOH (20 mL). After washing with EtOAc, the alkaline soln was
acidified with HCl and extracted with EtOAc (3 × 50 mL). The
combined extracts were dried (Na2SO4) and filtered and the solvent
was removed in vacuo to give 33 (1.37 g, 2.22 mmol, 72%) as a yel-
lowish solid.
1H NMR (400 MHz, CD3OD): δ = 7.34–7.29 (m, 5 H), 5.06 (s, 2 H),
3.11 (t, 3J = 7.0 Hz, 2 H), 2.27 (m, 6 H), 2.10 (t, 3J = 7.5 Hz, 2 H),
2
1.66–1.45 (m, 16 H), 1.38–1.28 (m, 2 H), 1.17 (d, J = 12.2 Hz, 3
H), 1.11 (d, 2J = 12.2 Hz, 3 H).
(23) Maison, W.; Frangioni, J. V.; Pannier, N. Org. Lett. 2004, 6,
4567.
(24) Lamanna, G.; Russier, J.; Menard-Moyon, C.; Bianco, A.
Chem. Commun. 2011, 47, 8955.
13C NMR (100 MHz, CD3OD): δ = 178.1, 175.6, 129.5, 128.9,
128.7, 67.3, 54.8, 46.3, 45.6, 41.6, 39.0, 37.8, 35.9, 30.6, 29.0, 27.3,
26.7, 26.3.
(25) Oganesyan, A.; Cruz, I. A.; Amador, R. B.; Sorto, N. A.;
Lozano, J.; Godinez, C. E.; Anguiano, J.; Pace, H.; Sabih,
G.; Gutierrez, C. G. Org. Lett. 2007, 9, 4967.
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4834; Angew. Chem. Int. Ed. 2006, 45, 4718.
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1998, 110, 2908; Angew. Chem. Int. Ed. 1998, 37, 2755.
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487.
HRMS (ESI): m/z [M + H]+ calcd for C33H47N2O9: 615.3276; found:
615.3273.
Acknowledgment
We gratefully acknowledge support from the Deutsche Forschungs-
gemeinschaft.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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