Solid-phase synthesis of structurally diverse heterocycles by an amide-ketone condensation/N-acyliminium pictet-spengler sequence

Article abstract of DOI:10.1002/chem.201202745

An efficient approach for the solid-phase synthesis of structurally diverse heterocyclic compounds is presented. Under acidic reaction conditions, peptidic levulinamides undergo intramolecular ketone-amide condensation reactions to form cyclic N-acylimini

Full text of DOI:10.1002/chem.201202745

FULL PAPER
DOI: 10.1002/chem.201202745
Solid-Phase Synthesis of Structurally Diverse Heterocycles by an Amide–
Ketone Condensation/N-Acyliminium Pictet–Spengler Sequence
Vitaly V. Komnatnyy,[a] Michael Givskov,[b, c] and Thomas E. Nielsen*[a, c]
Abstract: An efficient approach for the
solid-phase synthesis of structurally di-
verse heterocyclic compounds is pre-
sented. Under acidic reaction condi-
tions, peptidic levulinamides undergo
intramolecular ketone–amide conden-
sation reactions to form cyclic N-acyli-
minium intermediates. In the presence
of a tethered nucleophile, a second cyc-
lization reaction results in the forma-
tion of a fused bicyclic ring system.
The scope of the methodology was
demonstrated by several combinations
of substituted ketones and nucleo-
philes, the latter conveniently originat-
ing from amino acids with functional-
ized side chains, such as tryptophan,
substituted phenylalanines, and cys-
teine. The cyclization sequence pro-
vides diastereomerically pure products
in high yields. In one extension of the
methodology, the resulting relative
stereochemistry of the products enables
the formation of bridged ring systems
by a unique cyclative release mecha-
nism.
Keywords: cyclization
· heterocy-
cles · solid-phase synthesis · tetrahy-
dro-b-carbolines
Introduction
Despite the potential to become a key technology for the
rapid parallel synthesis of small molecules for drug discov-
ery and chemical biology, solid-phase synthesis is most fre-
quently being used to produce polypeptides and other oligo-
meric compounds. With an increasing number of peptide
and peptide mimetic drug candidates in the pipeline, solid-
phase synthesis will likely continue to impact this branch of
pharmaceutical chemistry. However, recent advances in
resin technology and synthetic methodology hold promise
for more substantial impact on small-molecule medicinal
chemistry and chemical biology,[3] entailing, among others,
the development of more quantitative, systematic, and relia-
ble procedures for the synthesis of heterocyclic compounds
on solid supports.[4] Along these lines, we have been particu-
larly interested in the generation of iminium intermediates
for reaction with tethered heteroatom and carbon nucleo-
philes in the synthesis of heterocyclic compounds on solid
supports.[5] With their abundance in biologically active and
pharmacologically important compounds (Figure 1),[6] the
structurally related tetrahydroisoquinoline and tetrahydro-b-
carboline (THBC) ring systems have been synthesized
through a number of variations on the Pictet–Spengler ap-
proach. In the original variant of this classical reaction, aryl-
or heteroarylethylamines condense with aldehydes under
acidic reaction conditions to produce a reactive N-alkylimi-
nium ion, which subsequently cyclizes to form a new hetero-
cycle.
The field of solid-phase organic synthesis has witnessed tre-
mendous development since the pioneering work of Merri-
field.[1] Practically all types of organic reactions, including
oxidative, reductive, carbon–heteroatom, and carbon–
carbon bond forming processes have been transferred to the
solid support, including metal-catalyzed transformations,[2]
powered by the broad availability of new resins with im-
proved capabilities for organic synthesis. The major advan-
tages of supported synthesis are: 1) the isolation of the reac-
tion product (still covalently bound to the support) from re-
agents by simple washing and filtration; 2) the ability to
drive reactions to completion by the use of excessive
amounts of reagents; and 3) the handling of small amounts
of compounds during multistep chemical synthesis. In this
context, it remains essential that transformations on solid
supports proceed quantitatively since any incomplete reac-
tion step along the way leads to a decrease in the purity of
the final product in a cumulative fashion.
[a] V. V. Komnatnyy, Prof. Dr. T. E. Nielsen
Department of Chemistry, Technical University of Denmark
2800 Kgs. Lyngby, (Denmark)
Fax : (+45)45-93-39-68
E-mail: ten@kemi.dtu.dk
[b] Prof. Dr. M. Givskov
Department of International Health, Immunology and Microbiology
Faculty of Health and Medical Sciences
University of Copenhagen, 2200 Copenhagen (Denmark)
Most of the reported solid-supported Pictet–Spengler re-
actions rely on the intermediacy of N-alkyliminium ions,[7]
but since the pioneering work of Wang and Ganesan on the
synthesis of fumitremorgin derivatives,[8] the more activated
N-acyl intermediates have also been frequently utilized.
Using masked aldehyde building blocks, Meldal and co-
workers developed methods for the formation and reaction
[c] Prof. Dr. M. Givskov, Prof. Dr. T. E. Nielsen
Singapore Centre on Environmental Life Sciences Engineering
Nanyang Technological University, Singapore 637551 (Singapore)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202745.
Chem. Eur. J. 2012, 18, 16793 – 16800
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
16793

acid (tryptophan) with a p-nucleophilic side chain (indole)
to the hydroxy-modified PEGA resin. Subsequent Fmoc de-
protection (Fmoc=9-fluorenylmethyloxycarbonyl) and
a
second TBTU-mediated coupling of levulinic acid cleanly
provided substrate 2a for the intramolecular N-acyliminium
Pictet–Spengler type reaction (Scheme 2). Expecting a rela-
tively low reactivity of ketones in the intramolecular con-
densation reaction, we initially screened a range of reaction
conditions (for selected results, see Table 1). The reaction
proceeded slowly when carried out with protic acids, such as
TFA and HCO2H, or Lewis acids, such as BF3·Et2O, in
CH2Cl2 as solvent, at room temperature. However, upon ele-
vating the reaction temperature to 608C in neat formic acid,
the reaction reached full conversion to the desired product
3a within 6 h. Importantly, these conditions neither resulted
in decomposition of the resin nor was any premature de-
tachment of product from the resin observed.
Pleasingly, the cyclization cascade proceeded in a highly
diastereoselective fashion, providing 3a as a diastereomeri-
cally pure product (>95%) after liberation from the resin
(Scheme 3). As NOE studies could not directly reveal the
identity of 3a, the analogous glycine derivative 3b was syn-
thesized. NOE correlation between the glycine NH-amide
proton and the methyl group at the quaternary center of 3b
indicated the relative stereochemistry shown in Table 1. This
assignment is also supported by the absence of an NOE
signal between said methyl group and the a-proton of the
tryptophan residue. This stereochemical relationship was
Figure 1. A) The Pictet–Spengler reaction for the synthesis of tetrahydro-
b-carbolines. B) Pharmacologically relevant tetrahydro-b-carbolines syn-
thesized by the Pictet–Spengler reaction.
of cyclic N-acyliminium intermediates, which have been ap-
plied to the synthesis of natural-product-like compound col-
lections.[9] However, in analogy with other Mannich-type
processes, the Pictet–Spengler reaction is generally higher
yielding for aldehydes than ketones, although recent prog-
ress has effectively brought ketones within the scope of the
reaction.[10] Herein, we report a new variation of the intra-
molecular N-acyliminium Pictet–Spengler approach, which
relies on efficient ketone–amide condensation for the gener-
ation of sterically congested, yet sufficiently reactive N-acy-
liminium intermediates. The methodology is highly useful
for the stereoselective synthesis of complex and pharmaco-
logically interesting heterocycles in excellent product puri-
ties, notably with ample opportunities for scaffold variation
and substitution, from simple
further confirmed by the synthesis of compound
(Scheme 4).
5
These observations complement previous investigations
on the synthesis of indolizinoindole derivatives via N-acyli-
minium intermediates.[13] Irrespective of whether the reac-
tion mechanism comprises attack of the indole C2 or C3 po-
sition to the presumed N-acyliminium intermediates 2.1a
building blocks.
Results and Discussion
In the present work, readily
available
g-ketocarboxylic
acids were employed as the
carbonyl donor for the amide–
ketone cyclization reaction
(Scheme 1). The base-labile 4-
Scheme 1. Strategy for the solid-phase synthesis of heterocycles by an amide–ketone condensation/N-acylimi-
num Pictet–Spengler sequence.
hydroxymethylbenzoic
acid
(HMBA) linker was coupled to
the resin by activation with O-
(benzotriazol-1-yl)-N,N,N’,N’-
tetramethyluronium tetrafluor-
oborate (TBTU),[11] followed
by MSNT-mediated ester bond
formation[12] (MSNT=1-(mesi-
tylene-2-sulfonyl)-3-nitro-1,2,4-
triazole) to anchor the amino
Scheme 2. Solid-phase synthesis of cyclization precursor 2a.
16794
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Chem. Eur. J. 2012, 18, 16793 – 16800

Solid-Phase Synthesis of Structurally Diverse Heterocycles
FULL PAPER
Table 1. Reaction conditions for intramolecular N-acyliminium Pictet–
Spengler reaction (selected results).
Entry
Acid
Temp.
[8C]
Time
[h]
Conver.
[%][a]
1
2
3
4
5
50% TFA (CH2Cl2)
10% BF3·Et2O (CH2Cl2)
HCOOH
HCOOH
HCOOH
RT
RT
RT
60
2
4
2
2
6
18
15
15
55
100
Scheme 4. Versatile synthetic transformations of a common solid-support-
ed precursor: i) 608C, overnight; ii) 4m HCl (aq), RT, 24 h; iii) NaBH-
AHCTNUGTERN(GNUN OAc)3, heptanal, THF, RT, 12 h; iv) AcCl, Et3N, CH2Cl2, RT, 1 h. The in-
dicated crude purities of products 5–8 were determined by RP-HPLC
60
[a] Conversion of starting material 2a was generally clean according to
RP-HPLC analysis.
(215 nm).
action of furane, thiophene, benzothiophene, and indole
moieties were obtained in excellent yields and purities
(Table 2, entries 1, 6, 9, and 15). Not surprisingly, the Pictet–
Spengler type cyclization was found to depend strongly on
the nucleophilicity of the reactive aromatic side chain. For
example, whereas the benzene moiety of a phenylalanine
residue did not engage in the reaction sequence, the analo-
gous 3,4-dimethoxybenzene derivative reacted smoothly
(Table 2, entry 5) with the intermediate N-acyliminium ion.
In addition to levulinic acid (Table 2, entry 1), several g-
keto carboxylic acid derivatives (Table 2, entries 2–4, 8)
were shown to undergo the analogous cascade reaction se-
quence, generally providing the expected substituted prod-
ucts in excellent purities and yields. Amino acid derivatives
with heteroatomic, nucleophilic moieties in their side chains
were also found to be within the scope of the methodology,
as illustrated by the application of cysteine and homocys-
teine (Table 2, entries 16 and 17) for the formation of [5,5]-
and [5,6]-fused ring systems.
To ultimately fine-tune the biological activity of com-
pounds 3a–s, synthetically tractable handles for appendage
modifications were introduced in a library format. Along
these lines, the synthetically versatile azido-derivative 3e
was smoothly synthesized according to the general proce-
dures outlined above, using azidolevulinic acid[14] as the g-
ketoacid building block. This compound underwent efficient
Cu-catalyzed azide–alkyne cycloaddition reactions using
CuI/sodium ascorbate as the catalytic system.[15] A number
of different alkynes were employed in this transformation,
and, regardless the nature of alkyne, triazole derivatives 4a–
j were formed in excellent yields and purities (Table 3).
Scheme 3. Origin of diastereoselectivity in N-acyliminium Pictet–Spen-
gler-type cyclization reactions.
and 2.1a’, the evolving steric interactions between the car-
bonyl groups translate into the diastereoselectivity noted
above. Although conformation 2.1a’ is associated with more
allylic strain, it is significantly destabilized by the steric re-
pulsion of two carbonyl groups, thus favoring the sterically
less demanding conformation 2.1a, which is believed to ac-
count for the observed diastereoselectivity of the reaction.
In addition to the indole ring system, various nucleophiles
were considered for this cascade reaction. A number of a-
amino acids with electron-rich aromatic moieties in their
side chains were incorporated between the solid-supported
linker and the levulinic acid residue. Following our opti-
mized procedure, the desired cascade products were ob-
tained as single diastereomers (Table 2). In this way, phar-
macologically interesting heterocycles resulting from the re-
Chem. Eur. J. 2012, 18, 16793 – 16800
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T. E. Nielsen et al.
Table 2. Intramolecular ketone–amide cyclization reactions for the synthesis of het-
erocycles 3a–s.
The azido group may conveniently serve as a
precursor for the amino functionality on solid sup-
port.[15a] Considering the stereochemistry of 3e, we
speculated that if the corresponding amino–methyl
derivative could be formed by reduction of the
azido group and subsequently undergo lactam for-
mation with the ester moiety, it would provide a
strategy for the cyclative release of skeletally com-
plex monoketopiperazine derivatives from the sup-
port.[17] To test this hypothesis, solid-supported 3e
was treated with dithiothreitol (DTT), then 1,8-
Entry
1
R
Nu
Product
Yield [%][a]
82 (95)
methyl
3-indolyl
3a
3c
diazabicycloACHTUNTRGNEUNG[5.4.0]undec-7-ene (DBU), left at 508C
for 12 h, and then removed by filtration. Reward-
ingly, RP-HPLC analysis confirmed the formation
of the cyclative release product, and rapid acidic
work-up (to remove DBU traces) provided 5 in ex-
cellent crude purity (90%).
2
3
cyclopropyl
3-indolyl
3-indolyl
46 (55)
Protonation of the intermediate amino group
should in theory prevent cyclative release. As the
cascade product is attached to the solid support
through an ester bond, it is in fact also possible to
liberate the amino-functionalized compound 6 with
strong acid. It was also possible to protect the
amino group by acylation immediately after reduc-
tion, which opens a route to functionalized com-
pounds, such as 8. The intermediate amine can also
be functionalized by reductive alkylation reactions
immediately after reduction of the azido group,
prior to the cyclative release reactions, which leads
to substituted derivatives 7. Products for all trans-
formations depicted in Scheme 4 were obtained in
high purities (>90%) and yields (>50%).
butyl
3d
3e
n/a (91)
4
azidomethyl
3-indolyl
85 (93)
3,4-dimethoxy-
phenyl
5
6
7
methyl
methyl
3 f
3g
3h
79 (90)
87 (95)
n/a (85)
2-furyl
Conclusion
2-acetophenyl thiomethyl
2-acetophenyl 3-indolyl
In the present work, readily available g-ketoacid
amides of amino acids with nucleophilic side
chains were synthesized on solid support. By treat-
ment with mild acid, a quantitative ketone–amide
condensation occurred to form an N-acyliminium
intermediate, followed by a Pictet–Spengler type
cyclization reaction. In this way, two new rings
were fused with exclusive diastereocontrol of the
stereocenter in the ring junction. Using this meth-
odology, a range of pharmacologically interesting
heterocyclic scaffolds was synthesized in excellent
purities and product yields. The reaction sequence
is broadly useful for the synthesis of structurally di-
verse compounds, as demonstrated by the success-
ful combination of various g-ketoacid amides with
a range of nucleophiles, including electron-rich ar-
omatic and heteroaromatic rings, such as indole,
thiophene, and furan, and heteroatomic residues,
such as thiols. In short, the substrate scope of the
solid-phase intramolecular N-acyliminium Pictet–
Spengler reaction has been extended to ketones.
8
3i
55 (80)
9
methyl
3-thienyl
3j
85 (95)
10
2-acetophenyl 2-furyl
2-acetophenyl 2-thienyl
3k
n/a (91)
11
3l
n/a (91)
16796
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Chem. Eur. J. 2012, 18, 16793 – 16800

Solid-Phase Synthesis of Structurally Diverse Heterocycles
Table 2. (Continued)
FULL PAPER
azido group led to an amine derivative that could
be substituted by various methods, including alky-
lation and acylation, and ultimately applied in a
highly efficient cyclative release from the solid sup-
port. The presented methodology is amenable to
parallel or combinatorial synthesis of novel molec-
ular libraries that are useful for chemical biology
and medicinal chemistry research.
Entry
R
Nu
Product
Yield [%][a]
12
2-acetophenyl 3-thienyl
3m n/a (91)
13
14
methyl
2-thienyl
3n
3o
90 (98)
Experimental Section
General procedures for solid-phase synthesis: Attachment of
the 4-hydroxymethylbenzoic acid (HMBA) linker to the
amino-functionalized PEGA800 (polyethylene glycol dimethyl
acrylamide, 0.4 mmolgÀ1) resin was carried out by activating
4-hydroxymethylbenzoic acid (HMBA, 3.0 equiv) with N-
ethyl morpholine (NEM, 4.0 equiv) and O-(benzotriazol-1-yl)-
2-acetophenyl 3-benzothienyl
n/a (85)
N,N,N’,N’-tetramethyluronium
tetrafluoroborate
(TBTU,
15
16
17
methyl
methyl
methyl
3-benzothienyl
thiol
3p
3r
3s
78 (97)
72 (94)
60 (82)
2.88 equiv) for 5 min in DMF. The resulting solution was
added to the resin and allowed to react for 2 h, and then
washed with DMF (ꢁ6), and CH2Cl2 (ꢁ6). Coupling of the
first amino acid to the HMBA derivatized resin was accom-
plished by treating the freshly lyophilized resin with a mixture
of Fmoc-AA-OH (3.0 equiv), 1-methylimidazole (MeIm,
5.0 equiv), and 1-(mesitylene-2-sulfonyl)-3-nitro-1,2,4-triazole
(MSNT, 3.0 equiv) in CH2Cl2. The MSNT-mediated coupling
was repeated twice. Peptide synthesis and attachment of 4-ke-
toacid building blocks to the amino-functionalized resin were
subsequently accomplished following standard amino acid
coupling procedures (Fmoc-AA-OH, or 4-ketoacid, TBTU,
NEM, DMF), as described above for the attachment of the
HMBA linker to the resin. The usual washing protocol fol-
lowed each coupling and deprotection step. Completion of the
reaction was monitored using the Kaiser test. Fmoc deprotec-
tion was performed with 20% piperidine in DMF for 30 min,
followed by washing with DMF (ꢁ6). For HPLC analysis, ap-
thiomethyl
[a] Yield of isolated product (purity of crude product determined by RP-HPLC is
given in parenthesis).
Table 3. Solid-phase Cu-catalyzed azide–alkyne cycloaddition reac-
tions.[16]
proximately 10 mg of resin was swelled in 0.1m NaOH for 2 h, then neu-
tralized with 0.1m HCl (aq) before flushing out the product with a mini-
mum amount of MeCN. For preparative purposes, 200 mg of resin was
swelled in 1 mL of 0.1m NaOH (aq) overnight, then neutralized with an
equimolar amount of 0.1m HCl (aq). The resin was then washed with
MeCN (ꢁ3) and the combined filtrates were concentrated in vacuo to
give the crude reaction product.
General procedure for the synthesis of heterocycles 3a–s by ketone–
amide condensation/N-acyliminium cyclization reactions: The resin bear-
ing the ketone cyclization precursor was treated with neat formic acid at
608C for 6 h, then filtered, washed with water, and swelled in 20% piper-
idine (DMF) for 30 min, followed by the usual work-up procedure.
Entry
R
Product
Purity [%][a,b]
1
2
3
4
5
6
7
8
3,5-difluorophenyl
cyclopropyl
4-phenoxyphenyl
2-thienyl
cyclohexyl
pentyl
cyclopentyl
propyl
2-hydroxypropyl
phenyl
4a
4b
4c
4d
4e
4 f
4g
4h
4i
85
88
85
82
92
88
90
95
92
90
ACHUTNGRENUN(G 5S,11bR)-11b-Methyl-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizinoACHTUNGTRENNUNG[8,7-
b]indole-5-carboxylic acid (3a): Purity: 95%; yield: 82%; 1H NMR
(300 MHz, [D6]DMSO): d=1.60 (s, 3H), 1.85 (dd, J=21.3, 11.6 Hz, 1H),
2.20 (m, 2H), 2.59 (m, 2H), 3.56 (d, J=15.0 Hz, 1H), 4.73 (d, J=7.7 Hz,
1H), 6.96 (m, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.34 (d, J=7.6 Hz, 1H),
11.08 ppm (s, 1H); 13C NMR (75 MHz, [D6]DMSO): d=23.6, 26.1, 31.1,
35.6, 49.9, 51.5, 60.1, 70.4, 104.8, 111.6, 118.6, 118.8, 121.2, 127.3, 136.7,
173.3, 174.6 ppm; RP-HPLC retention time: 5.74 min; HRMS (ESI) m/z
calculated for C16H17N2O3+: 285.12336 [M+H+]; found 285.12341.
9
10
4j
[a] Purity determined by RP-HPLC (215 nm). [b] Yields of isolated com-
pound 4a–j were in the range of 65–80%.
2-((5S,11bR)-11b-Methyl-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino-
AHCTUNGTERG[NNUN 8,7-b]indole-5-carboxamido)acetic acid (3b): Purity: 95%; yield: 87%;
1H NMR (300 MHz, [D6]DMSO): d=1.51 (s, 3H), 2.02 (dd, J=21.3,
11.9 Hz, 1H), 2.34 (td, J=17.1, 9.0 Hz, 2H), 2.72 (m, 2H), 3.24 (d, J=
3.9 Hz, 1H), 3.31 (d, J=4.2 Hz, 1H), 3.46 (m, 2H), 5.07 (d, J=7.8 Hz,
1H), 6.97 (t, J=7.3 Hz, 1H), 7.07 (m, 2H), 7.31 (d, J=8.0 Hz, 1H),
11.20 ppm (s, 1H); 13C NMR (75 MHz, [D6]DMSO): d=20.7, 26.5, 30.6,
34.9, 44.8, 49.9, 59.8, 70.4, 103.5, 111.8, 118.8, 119.1, 121.6, 126.9, 136.7,
When azidomethyl-substituted g-ketoacid amides underwent
this cascade sequence, a convenient azido handle was intro-
duced for appendage substitutions and ligation by CuI-cata-
lyzed azide–alkyne cycloaddition reactions. Reduction of the
Chem. Eur. J. 2012, 18, 16793 – 16800
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16797

T. E. Nielsen et al.
+
138.2, 169.4, 171.6, 174.4 ppm; RP-HPLC retention time: 5.44 min; MS
time: 6.11 min; MS (ESI) m/z calculated for C16H14NO4 284.08: [M+H+
]; found 284.2.
(ESI) m/z calculated for C18H20N3O4+: 342.14 [M+H+]; found 342.3.
A
ACHTUNGTNER(NUNG 5S,11bR)-11b-Methyl-7-oxo-4,5,7,11b-tetrahydrothieno[3’,2’:3,4]pyrido-
G
ACHTUNGTNER[NUNG 2,1-a]isoindole-5-carboxylic acid (3l): Purity: 91%; RP-HPLC retention
time: 6.53 min; MS (ESI) m/z calculated for C16H14NO3S+: 300.06
[M+H+]; found 300.2.
AHCTUNGTERG(NNUN 5S,11bR)-11b-Methyl-7-oxo-4,5,7,11b-tetrahydrothieno[2’,3’:3,4]pyrido-
AHCTUNGERTG[NNUN 2,1-a]isoindole-5-carboxylic acid (3m): Purity: 91%; RP-HPLC reten-
tion time: 6.71 min; MS (ESI) m/z calculated for C16H14NO3S+: 300.06
[M+H+]; found 300.2.
ACHTUNGTRENNUNG(5S,11bS)-11b-Butyl-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizinoACHTUNTGREN[NUGN 8,7-
ACHUTNGRENUN(G 5S,9aR)-9a-Methyl-7-oxo-4,5,7,8,9,9a-hexahydrothienoACHTUNGTERN[NUGN 2,3g]indolizine-5-
carboxylic acid (3n): Purity: 98%; yield: 90%; 1H NMR (300 MHz,
[D6]DMSO): d=1.54 (s, 1H), 1.87 (td, J=11.7, 8.8 Hz, 1H), 2.19 (ddd,
J=10.1, 8.4, 4.5 Hz, 2H), 2.58 (ddt, J=11.6, 8.3, 3.6 Hz, 2H), 3.41 (dd,
J=15.8, 1.3 Hz, 1H), 4.64 (dd, J=7.9, 1.22 Hz, 1H), 6.77 (d, J=5.1 Hz,
1H), 7.33 ppm (d, J=5.0 Hz, 1H); 13C NMR (75 MHz, [D6]DMSO): d=
27.1, 28.6, 30.4, 37.1, 50.0, 60.7, 69.7, 122.7, 127.2, 131.9, 141.1, 172.2,
173.1 ppm; RP-HPLC retention time: 5.30 min; HRMS (ESI) m/z calcu-
lated for C12H14NO3S+: 252.06943, [M+H+]; found 252.06882.
b]indole-5-carboxylic acid (3d): Purity: 91%; RP-HPLC retention time:
5.92 min; MS (ESI) m/z calculated for C19H23N2O3+: 327.16 [M+H+];
found 327.3.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1H NMR (300 MHz, [D6]DMSO): d=1.89 (dd, J=23.0, 11.0 Hz, 1H),
2.23 (dd, J=16.5, 10.0 Hz, 1H), 2.68 (m, 2H), 3.51 (d, J=5.4 Hz, 1H),
3.57 (d, J=4.1 Hz, 1H), 4.47 (d, J=11.8 Hz, 1H), 4.83 (d, J=7.7 Hz,
1H), 6.99 (td, J=14.8, 7.1 Hz, 2H), 7.30 (d, J=7.9 Hz, 1H), 7.42–7.34
(m, 1H), 11.11 ppm (s, 1H); 13C NMR (75 MHz, [D6]DMSO): d=23.4,
30.8, 31.1, 51.5, 56.1, 62.4, 69.7, 105.7, 111.1, 118.1, 118.3, 121.0, 126.2,
134.6, 136.1, 173.6, 173.9 ppm; RP-HPLC retention time: 6.06 min; MS
ACHUTNGRENU(NG 7S,13bR)-13b-Methyl-5-oxo-5,7,8,13b-tetrahydrobenzoACHTUGNTREN[NUGN 4’,5’]thieno-
[2’,3’:3,4]pyrido-[2,1-a]isoindole-7-carboxylic acid (3o): Purity: 85%;
RP-HPLC retention time: 7.62 min; MS (ESI) m/z calculated for
C20H16NO3S+: 350.08, [M+H+]; found 350.4.
+
(ESI) m/z calculated for C16H16N5O3 326.12 [M+H+]; found 326.3.
A
ACHTUNGTREN[NUNG 4,5]thieno-
ACHTUNGTRENNUNG(5S,10bR)-8,9-Dimethoxy-10b-methyl-3-oxo-1,2,3,5,6,10b-hexa-
AHCTUNGTRENNUNG
1H NMR (300 MHz, [D6]DMSO): d=1.59 (s, 3H), 2.02 (m, 1H), 2.26 (m,
2H), 2.69 ( m, 2H), 3.58 (d, J=16.1 Hz, 1H), 4.90 (d, J=7.8 Hz, 1H),
7.37 (dtd, J=16.3, 7.2, 1.2 Hz, 2H), 7.69 (dd, J=7.2, 1.2 Hz, 1H),
7.93 ppm (dd, J=7.1, 1.0 Hz, 1H); 13C NMR (75 MHz, [D6]DMSO): d=
25.5, 28.4, 30.8, 37.0, 37.1, 49.6, 61.3, 70.4, 122.2, 123.4, 125.1, 125.1, 126.5,
138.3, 139.1, 142.4, 173.0, 173.5 ppm; RP-HPLC retention time: 6.61 min;
HRMS (ESI) m/z calculated for C16H16NO3S+: 302.08453 [M+H+];
found 302.08461.
hydropyrrolo
[2,1-a]isoquinoline-5-carboxylic acid (3 f): Purity: 90%;
1
yield: 79%; H NMR (300 MHz, [D6]DMSO): d=1.42 (s, 3H), 2.13 (ddd,
J=31.7, 18.5, 9.8 Hz, 2H), 2.42 (m, 1H), 2.64 (m, 1H), 3.02 (d, J=
7.2 Hz, 2H), 3.73 (s, 3H), 3.71 (s, 3H), 4.46 (m, 1H), 6.80 (s, 1H),
6.79 ppm (s, 1H); RP-HPLC retention time: 4.98 min; MS (ESI) m/z cal-
culated for C16H20NO5+: 306.13 [M+H+]; found 306.3.
ACHTUNGTRENNUNG(5S,9aR)-9a-Methyl-7-oxo-4,5,7,8,9,9a-hexahydrofuroACHTUNGTERN[NUGN 2,3g]indolizine-5-
carboxylic acid (3g): Purity: 95%; yield: 87%; 1H NMR (300 MHz,
[D6]DMSO): d=1.40 (s, 3H). 1.73 ppm (dt, J=11.9, 9.3 Hz, 1H), 2.14
(ddd, J=16., 14.25, 8.28 Hz, 2H), 2.58 (m, 2H), 3.39 (d, J=15.75 Hz,
1H), 4.77 (d, J=7.78 Hz, 1H), 6.38 (d, J=1.89 Hz, 1H), 7.46 (d, J=
1.82 Hz, 1H); 13C NMR (75 MHz, [D6]DMSO): d=24.5, 25.8, 30.2, 35.1,
49.4, 59.6, 69.7, 106.9, 123.2, 141.4, 145.9, 172.3,172.6 ppm; RP-HPLC re-
tention time: 5.00 min; MS (ESI) m/z calculated for C12H14NO4+: 235.08
[M+H+]; found 236.2.
2-((3R,7aS)-7a-Methyl-5-oxohexahydropyrrolo
amido)-3-phenylpropanoic acid (3r): Purity: 94%; yield: 72%; 1H NMR
ACHTUNGTNER[NUNG 2,1-b]thiazole-3-carbox-
(300 MHz, [D6]DMSO): d=1.17 (s, 3H), 2.12 (m, 1H), 2.26 (dd, J=10.0,
6.0. Hz, 1H), 1.99 (m, 1H), 2.33 (t, J=4.2 Hz, 1H), 2.40 (m, 1H), 2.69
( m, 1H), 3.09 (ddd, J=31.0, 13.3, 5.2 Hz, 2H), 3.45 (m, 2H), 3.98 (q, J=
5.4 Hz, 1H), 4.54 (dd, J=8.8, 7.4 Hz, 1H), 7.11 (m, 5H), 7.40 ppm (d, J=
5.9 Hz, 1H); 13C NMR (75 MHz, [D6]DMSO) d=29.8, 31.1, 31.2, 35.8,
36.7, 49.2, 55.1, 60.3, 69.7, 78.3, 125.6, 127.6, 129.5, 138.8, 168.1, 172.8,
177.6 ppm; RP-HPLC retention time: 6.21 min; HRMS (ESI) m/z calcu-
lated for C17H21N2O4S+: 349.12164 [M+H+]; found 349.12199.
ACHTUNGTRENNUNG(4S,10bS)-10b-Methyl-6-oxo-3,4,6,10b-tetrahydro-2H-[1,3]thiazinoACHTUNGTRNE[NUGN 2,3-a]-
isoindole-4-carboxylic acid (3h): Purity: 85%; RP-HPLC retention time:
5.81 min; MS (ESI) m/z calculated for C13H14NO3S+: 264.06 [M+H+];
found 264.2.
2-((4S,8aS)-8a-Methyl-6-oxohexahydro-2H-pyrrolo[2,1-b,1,3]thiazine-4-
carboxamido)-3-phenylpropanoic acid (3s): Purity: 82%; yield: 60%.
1H NMR (300 MHz, [D6]DMSO): d=1.01 (s, 3H), 1.83 (dd, J=11.3,
6.0 Hz, 2H), 2.31 (m, 4H), 2.99 (m, 4H), 4.42 (ddd, J=12.1, 8.0, 4.7 Hz,
1H), 4.67 (m, 1H), 7.21 (m, 5H), 7.89 ppm (d, J=7.8 Hz, 1H); 13C NMR
(75 MHz, [D6]DMSO) d=23.1, 24.3, 29.0, 34.6, 37.9, 45.5, 50.9, 56.3, 65.6,
70.4, 126.3, 128.3, 129.9, 140.2, 169.3, 175.4 ppm; RP-HPLC retention
time: 6.31 min; MS (ESI) m/z calculated for C18H22N2O4SNa+: 385.12,
[M+Na+]; found 385.2.
A
ACHTUNGTRENUN[NG 1,2]indol-
ACHTUNGTRENNUNG
1H NMR (300 MHz, [D6]DMSO): d=1.86 (s, 3H), 2.33 (m, 1H), 2.58
(dd, J=15.1, 7.6 Hz, 1H), 3.58 (d, J=14.9 Hz, 2H), 5.12 (d, J=7.4 Hz,
1H), 6.92 (t, J=7.4 Hz, 1H), 7.02 (m, 1H), 7.33 (dd, J=9.9, 3.6 Hz, 2H),
7.46 (t, J=7.4 Hz, 1H), 7.65 (dd, J=15.9, 7.5 Hz, 2H), 8.29 ppm (d, J=
7.6 Hz, 1H); 13C NMR (75 MHz, [D6]DMSO): d=23.4, 27.8, 51.9, 62.5,
69.7, 106.3, 111.0, 118.2, 118.3, 121, 122.5, 122.8, 126.3, 128.1, 130.0, 131.8,
134.4, 136.3, 150.0, 167.9, 172.9 ppm; RP-HPLC retention time: 6.64 min;
HRMS (ESI) m/z calculated for C20H17N2O3+: 333.12390 [M+H+]; found
333.12401.
General procedure for Cu-catalyzed azide–alkyne cycloaddition reac-
tions: CuI (1 equiv) was mixed with sodium ascorbate (1 equiv) and 2,6-
lutidine (2 equiv) in N-methylpyrollidone/water (4:1) for 30 min. The
alkyne (2 equiv) was the added to the resulting solution and the reaction
mixture was added to azido-functionalized resin 2e in a sealed vial. After
10 h, the resin was filtered and washed following the usual procedure.
ACHTUNGTRENNUNG(5S,9aR)-9a-Methyl-7-oxo-4,5,7,8,9,9a-hexahydrothienoACHTUNGTERN[NUGN 3,2 g]indolizine-5-
carboxylic acid (3j): Purity: 95%; yield: 85%; 1H NMR (300 MHz,
[D6]DMSO): d=1.45 (s, 1H), 1.74 (dt, J=12.3, 9.7 Hz, 1H), 2.18 (m,
2H), 2.62 (m, 2H), 3.52 (d, J=15.2 Hz, 1H), 4.71 (d, J=6.9 Hz, 1H),
6.91 (d, J=5.2 Hz, 1H), 7.28 ppm (d, J=5.2 Hz, 1H); 13C NMR
(75 MHz, [D6]DMSO): d=26.0, 26.5, 30.2, 35.4, 49.8, 69.7 123.2, 124.0,
131.2, 140.9, 172.3, 172.6 ppm; RP-HPLC retention time: 5.41 min; MS
(ESI) m/z calculated for C12H14NO3S+: 252.06943 [M+H+]; found
252.06911.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
acid (4a): Purity: 85%; RP-HPLC retention time 7.41 min. MS (ESI)
m/z calculated for C24H20F2N5O3+: 464.15 [M+H+]; found 464.4.
AHCTUNGTRENNUNG
A
acid
A
E
(4b): Purity: 88%; RP-HPLC retention time 6.18 min; MS (ESI)
m/z calculated for C21H22N5O3+: 392.16 [M+H+]; found 392.4.
16798
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16793 – 16800

Solid-Phase Synthesis of Structurally Diverse Heterocycles
FULL PAPER
A
Synthesis of N-alkylated monoketopiperazine derivative 7: Solid-support-
ed 3e (200 mg, loading 0.4 mmolgÀ1) was reduced for 2 h as described
above, then filtered and washed five times with DMF. The resin was
swelled in THF, and heptanal (113 mL, 0.8 mmol) was added. After
5 min, sodium borohydride (30.3 mg, 0.8 mmol) and acetic acid (137 mL,
2.4 mmol) were added to the resin. After 2 h, the resin was filtered and
washed. For the cyclative release, the resin was heated in DMF for 12 h,
and worked up as described above.
AHCTUNGTRENNUNG
(4c): Purity: 85%; RP-HPLC retention time: 8.04 min; MS (ESI) m/z
calculated for C30H26N5O4+: 519.19 [M+H+]; found 520.4.
ACHTUNGTRENNUNG
A
acid
(4d): Purity: 82%; RP-HPLC retention time: 6.71 min; MS (ESI) m/z
calculated for C20H20N5O3+: 434.12, [M+H+]; found 434.4.
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
R
acid
+
retention time: 7.61 min; MS (ESI) m/z calculated for C23H30N3O2
380.23 [M+H+]; found 380.4.
:
1
(4e): Purity: 92%; yield: 75%; H NMR (300 MHz, [D6]DMSO) d=1.34
(m, 4H), 1.80 (m, 1H), 1.9 (m, 1H), 2.08 (m, 4H), 2.68 (dd, J=20.0,
8.2 Hz, 2H), 2.94 (dd, J=15.8, 7.5 Hz, 1H), 4.59 (d, J=13.9 Hz, 1H),
5.11 (d, J=13.8 Hz, 1H), 5.29 (d, J=6.6 Hz, 1H), 7.03 (t, J=7.1 Hz, 1H),
7.12 (t, J=7.4 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H),
8.09 ppm (s, 1H); RP-HPLC retention time: 7.01 min; MS (ESI) m/z cal-
Synthesis of acetomidomethyl derivative 8: Solid-supported 3e (200 mg,
loading 0.4 mmolgÀ1) was reduced for 2 h as described above, then fil-
tered and washed with DMF (ꢁ 5), and DCM (ꢁ 5). The resin was swell-
ed in DCM, before triethylamine (7 mL, 0.05 mmol) and acetyl chloride
(4 mL, 0.05 mmol) were added. After 2 h, the resin was washed, and prod-
uct was cleaved from the support and worked up following the usual pro-
cedure.
culated for C24H28N5O3 434.21920 [M+H+]; found 434.21817.
+
ACHTUNGTRENNUNG
E
acid
1
ACHTUNGTNER(NUNG 5S,11bS)-11b-(Acetamidomethyl)-3-oxo-2,3,5,6,11,11b-hexahydro-1H-
(4 f): Purity: 88%; yield: 78%; H NMR (300 MHz, [D6]DMSO) d=0.87
(t, J=5.2 Hz, 3H), 1.29 (m, 4H), 1.56 (m, 2H), 1.81 (m, 2H), 2.61 (m,
4H), 3.54 (m, 1H), 3.66 (d, J=15.0 Hz, 1H), 4.90 (d, J=12.7 Hz, 2H),
5.07 (m, 1H), 6.98 (t, J=7.2 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 7.33 (d, J=
7.9 Hz, 1H), 7.43 ppm (d, J=7.7 Hz, 1H); RP-HPLC retention time:
7.10 min; MS (ESI) m/z calculated for C23H28N5O3+: 422.21 [M+H+];
found 422.2.
indolizinoACTHNUTRGNE[NUG 8,7-b]indole-5-carboxylic acid (8): Purity: 90%; RP-HPLC re-
tention time 5.43 min; MS (ESI) m/z calculated for C18H20N3O4+: 342.14
[M+H+]; found 342.2.
ACHTUNGTRENNUNG
Acknowledgements
N
acid
(4g): Purity: 90%; RP-HPLC retention time: 6.34 min; MS (ESI) m/z
calculated for C23H26N5O3+: 420.20, [M+H+]; found 420.4.
This work was supported by the Center for Antimicrobial Research, the
Danish Council for Strategic Research, and the Technical University of
Denmark. The authors gratefully acknowledge Dr. Sebastian T. Le Que-
ment for stimulating scientific discussions.
ACHTUNGTRENNUNG
G
acid
(4h): Purity: 95%; RP-HPLC retention time: 6.72 min; MS (ESI) m/z
calculated for C21H24N5O3+: 394.18, [M+H+]; found 394.4.
[1] R. Merrifield, J. Am. Chem. Soc. 1963, 85, 2149–2154.
ACHTUNGTRENNUNG
[2] W. M. Bennet, Combinatorial Chemistry:
A Practical Approach
AHCTUNGTRENNUNG
(Methods and Principles in Medicinal Chemistry), Oxford University
Press, New York, 2000.
[3] F. Albericio, The Power of Functional Resins in Organic Synthesis,
Wiley-VCH, Weinheim, 2008.
[4] F. Z. Dçrwald, Organic Synthesis on Solid Phase Supports Linkers
Reactions, Wiley-VCH, Weinheim, 2000.
[5] a) A. Pictet, T. Spengler, Ber. Dtsch. Chem. Ges. 1911, 44, 2030–
2036; b) B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi,
C. A. Maryanoff, Chem. Rev. 2004, 104, 1431–1628.
[6] a) A. Daugan, P. Grondin, C. Ruault, A.-C. Le Monnier de Gouville,
H. Coste, J. Kirilovsky, F. Hyafil, R. Labaudiniꢂre, J. Med. Chem.
2003, 46, 4525–4532; b) E. J. Corey, D. Y. Gin, R. S. Kania, J. Am.
Chem. Soc. 1996, 118, 9202–9203; c) M. Rottmann, C. McNamara,
B. K. S. Yeung, M. C. S. Lee, B. Zou, B. Russell, P. Seitz, D. M.
Plouffe, N. V. Dharia, J. Tan, Science 2010, 329, 1175–1180; d) J. Li,
T. Wang, P. Yu, A. Peterson, R. Weber, D. Soerens, D. Grubisha, D.
Bennett, J. M. Cook, J. Am. Chem. Soc. 1999, 121, 6998–7010.
[7] a) T. E. Nielsen, F. Diness, M. Meldal, Curr. Opin. Drug Discov.
Devel. 2003, 6, 801–814; b) T. Le Quement, R. Petersen, M. Meldal,
T. E. Nielsen, Biopolymers 2010, 94, 242–256.
(4i): Purity: 92%; RP-HPLC retention time: 5.62 min; MS (ESI) m/z cal-
culated for C21H24N5O4+: 409.18 [M+H+]; found 410.4.
ACHTUNGTRENNUNG
A
acid
(4j): Purity: 90%; RP-HPLC retention time: 6.90 min; MS (ESI) m/z
calculated for C24H22N5O3+: 428.16, [M+H+]; found 428.2.
Synthesis of monoketopiperazine derivative 5: Solid-supported 3e
(200 mg, loading 0.4 mmolgÀ1) was swelled in 0.1m dithiothreitol (DMF,
4 mL) and then DBU (12 mL, 0.8 mmol) was added. The resin was heated
to 608C overnight, then filtered and washed repeatedly with acetonitrile.
The combined filtrates were concentrated in vacuo, and the residue was
purified by preparative RP-HPLC.
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
(300 MHz, [D6]DMSO): d=2.38 (m, 4H), 2.71–2.53 (m, 1H), 2.98 (m,
2H), 3.35 (m, 1H), 3.68 (d, J=12.0 Hz, 1H), 4.57 (d, J=4.6 Hz, 1H),
7.00 (t, J=7.4 Hz, 1H), 7.10 (dt, J=8.2, 1.39 Hz, 1H), 7.35 (d, J=8.1 Hz,
1H), 7.41 (d, J=7.8 Hz, 1H), 7.78 (d, J=3.9 Hz, 1H), 11.23 ppm (s, 1H);
RP-HPLC retention time: 4.88 min; HRMS (ESI) m/z calculated for
C16H16N3O2+:, 282.12369 [M+H+]; found 282.12396.
[8] H. Wang, A. Ganesan, Org. Lett. 1999, 1, 1647–1649.
[9] a) T. E. Nielsen, S. Le Quement, M. Meldal, Org. Lett. 2005, 7,
3601–3604; b) S. T. Le Quement, T. E. Nielsen, M. Meldal, J. Comb.
Chem. 2007, 9, 1060–1072.
Synthesis of aminomethyl derivative 6: Solid-supported 3e (200 mg, load-
ing 0.4 mmolgÀ1) was reduced with dithiothreitol for 2 h according to the
procedure above, then washed according to the usual procedure and
lyophilized. The resin was swelled in 4m HCl (aq) for 24 h, and the prod-
uct was worked up by filtration. The combined filtrates were concentrat-
ed in vacuo to give the crude product.
[10] a) M. J. Van den Eynden, K. Kunchithapatham, J. P. Stambuli, J.
Org. Chem. 2010, 75, 8542–8549; b) Y. Lee, B. Min, Y. Park, J. Lee,
S. Lee, Tetrahedron 1999, 55, 2–7; c) A. Zawadzka, A. Leniewski,
J. K. Maurin, K. Wojtasiewicz, Z. Czarnocki, Org. Lett. 2001, 3, 997–
999; d) I. T. Raheem, P. S. Thiara, E. N. Jacobsen, Org. Lett. 2008,
10, 1577–1580; e) F. R. Bou-Hamdan, J. L. Leighton, Angew. Chem.
2009, 121, 2439–2442; f) C. Holloway, M. E. Muratore, R. L. Storer,
D. J. Dixon, Org. Lett. 2010, 12, 4720–4723; g) M. E. Muratore,
ACHTUNGTRENNUNG((5S,11bS)-5-Carboxy-3-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizinoACHTUNTGREN[NUGN 8,7-
b]indol-11b-yl)methanaminium (6): Purity 90%; RP-HPLC retention
+
time 5.62 min; MS (ESI) m/z calculated for C16H20N3O2 356.15 [M+H+
]; found 356.2.
Chem. Eur. J. 2012, 18, 16793 – 16800
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16799

T. E. Nielsen et al.
C. A. Holloway, A. W. Pilling, R. I. Storer, G. Trevitt, D. J. Dixon, J.
Am. Chem. Soc. 2009, 131, 10796–10797; h) M. E. Muratore, L. Shi,
A. W. Pilling, R. I. Storer, D. J. Dixon, Chem. Commun. 2012, 48,
6351–6353; i) R. Tsuji, M. Nakagawa, A. Nishida, Tetrahedron:
Asymmetry 2003, 14, 177–180; j) H. Waldmann, G. Schmidt, H.
Henke, M. Burkard, Angew. Chem. 1995, 107, 2608–2610; Angew.
Chem. Int. Ed. Engl. 1995, 34, 2402–2403; k) T. Yang, L. Campbell,
D. J. Dixon, J. Am. Chem. Soc. 2007, 129, 12070–12071.
1981, 46, 164–168; c) G. Casnati, A. Dossena, A. Pochini, Tetrahe-
dron Lett. 1972, 13, 5277–5280.
[14] R. Vallinayagam, H. Bertschy, Y. Berger, V. Wenger, R. Neier, Syn-
thesis 2007, 2007, 3731–3735.
[15] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708–2711; Angew. Chem. Int. Ed. 2002,
41, 2596–2599; b) C. W. Tornøe, C. Christensen, M. Meldal, J. Org.
Chem. 2002, 67, 3057–3064.
[11] R. Knorr, A. Trzeciak, W. Bannwarth, D. Gillessen, Tetrahedron
Lett. 1989, 30, 1927–1930.
[12] B. Blankemeyer-Menge, M. Nimtz, R. Frank, Tetrahedron Lett.
1990, 31, 1701–1704.
[16] A. E. Cohrt, J. F. Jensen, T. E. Nielsen, Org. Lett. 2010, 12, 5414.
[17] A. Ganesan in Linker Strategies in Solid-Phase Organic Synthesis
(Ed.: P. Scott), Wiley, New York, 2009, pp. 135–151.
[13] a) T. E. Nielsen, M. Meldal, J. Org. Chem. 2004, 69, 3765–3773;
b) F. Ungemach, M. DiPierro, R. Weber, J. Cook, J. Org. Chem.
Received: July 31, 2012
Published online: November 6, 2012
16800
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 16793 – 16800