From solution-phase studies to solid-phase synthesis: A new indole based scaffold for combinatorial chemistry

Article abstract of DOI:10.2533/000942903777679343

The core structure of a natural product was selected as scaffold for combinatorial library synthesis. The key step for the construction of the 3,9-diazabicyclo[3.3.1]non-6-ene core is a novel Dakin-West/Pictet-Spengler reaction sequence. Route selection for library synthesis was determined by solution-phase experiments. The solid-phase synthesis was developed based on the synthesis worked out in solution. A number of resins and linkers were studied to obtain the best loading and cleavage conditions. Potential target scaffolds using tryptophan, histidine and phenylalanine as building blocks were investigated. These efforts led to the development of a synthesis protocol for a tetracyclic scaffold incorporating tryptophan, useful for the preparation of a combinatorial library.

Full text of DOI:10.2533/000942903777679343

COMBINATORIAL CHEMISTRY
255
CHIMIA 2003, 57, No. 5
Chimia 57 (2003) 255–261
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
From Solution-Phase Studies to Solid-
Phase Synthesis: A New Indole Based
Scaffold for Combinatorial Chemistry
David Orain, Guido Koch* and Rudolf Gigera
Abstract: The core structure of a natural product was selected as scaffold for combinatorial library synthesis.
The key step for the construction of the 3,9-diazabicyclo[3.3.1]non-6-ene core is a novel Dakin-West/Pictet-
Spengler reaction sequence. Route selection for library synthesis was determined by solution-phase exper-
iments. The solid-phase synthesis was developed based on the synthesis worked out in solution. A number
of resins and linkers were studied to obtain the best loading and cleavage conditions. Potential target scaf-
folds using tryptophan, histidine and phenylalanine as building blocks were investigated. These efforts led
to the development of a synthesis protocol for a tetracyclic scaffold incorporating tryptophan, useful for the
preparation of a combinatorial library.
Keywords: Combinatorial chemistry · Dakin-West · Natural products · Pictet-Spengler · Tryptophan
With the emergence of automated solution pounds of these families are characterized enables the introduction of a quaternary
and solid-phase synthesis, combinatorial by a common 3,9-diazabicyclo[3.3.1]non- carbon center with defined stereochemistry.
chemistry has become an essential tool in 6-ene core structural element.
The key step of the synthesis is a novel
the discovery of new therapeutic agents. Recently Myers and Lanman reported sequential Dakin-West/Pictet-Spengler re-
Since the first synthesis of peptide libraries, a very elegant solid-phase synthesis of a action.
a large number of non-peptidic, particularly small series of analogues of (–)-Saframycin
heterocyclic, libraries have been published A [4]. Herein, we would like to report our
[1]. In the process of identifying new scaf- efforts for the solution and solid-phase syn- Solution-phase Synthesis Strategy
folds, a possible approach is to gain inspi- theses of polycyclic compounds bearing a
ration from the pool of diverse natural prod- common 3,9-diazabicyclo[3.3.1]non-6-ene
First, a linear dipeptide was synthesized
ucts [2]. We turned our interest to polycyclic core [5]. Our approach consists of a simple in solution. The first N-α-Boc protected
molecules with defined 3D architecture and linear construction of the molecule prior amino acid required an aromatic side chain
restricted number of rotatable bonds. With to cyclization via an intramolecular Pictet- for the final Pictet-Spengler type cyclization.
these considerations in mind, our attention Spengler reaction. In particular this route Four amino acids (3,4-dimethoxy-L-phenyl-
was attracted by the Saframycin, Safracin,
Renieramycin and Ecteinascidin families
(Fig. 1) which show powerful antiprolifer-
ative and antitumor properties making them
very attractive targets [3]. All of the com-
O
O
O
O
O
O
O
O
H
N
H
O
O
N
O
N
N
*Correspondence: Dr. G. Koch
Novartis Pharma AG
Core Technology Area
Combinatorial Chemistry Unit
WSJ-507.7.03
O
O
OH
O
NH
NH
O
O
CH–4002 Basel
Fax: +41 61 324 42 36
E-Mail: guido.koch@pharma.novartis.com
aNovartis Pharma AG
Disease Area Ophthalmology
WKL-127.1.84b
Klybeckstrasse 141
CH–4057 Basel
Saframycin B
Renieramycin E
Fig. 1. Examples of structures from Saframycin and Renieramycin
families: the 3,9-diazabicyclo[3.3.1]non-6-ene core is outlined in red

COMBINATORIAL CHEMISTRY
256
CHIMIA 2003, 57, No. 5
alanine, 3,4,5-trimethoxy-L-phenylalanine,
L-histidine and 5-hydroxy-L-tryptophan)
were chosen for position one. After cou-
pling with the second amino acid methyl
ester, the free carboxylic acid was generated
by hydrolysis. Then, the carboxylic func-
tion was transformed to the corresponding
alkyl ketone under Dakin-West conditions
[6] affording the required ketopeptide prior
to cyclization (Scheme 1). This linear setup
would allow combinatorial synthesis of the
dipeptide unit followed by further diversi-
fication in the Dakin-West step using dif-
ferent anhydrides.
R
R
O
1) Peptide bond with
H2N-CH(R1)-COOMe
O
O
O
H
N
OH
O
N
H
OH
O
N
H
2) Ester hydrolysis
O
R1
R : 3,4-OMe-Ph, 3,4,5-OMe-Ph,
Imidazole, 5-OH-Indole
Dakin-West
R
O
O
O
Pictet-Spengler
R
N
H
H
N
NH
O
N
R2
H
R2
O
R1
R1
The described strategy was applied for
the synthesis of phenylalanine, histidine
and tryptophan derivatives. Initially we
focused on phenylalanine derivatives. The
acyclic precursors 5 and 6 were obtained
in good yields. It is noteworthy that during
the Dakin-West reaction epimerization oc-
curred at the C-α position. An acid-cat-
alyzed Pictet-Spengler type cyclization [7]
was investigated using different condi-
tions: TFA/DCM, HCl/MeOH and p-TsOH.
However, no traces of the expected bicyclic
compound were obtained (Scheme 2).
R2 : alkyl
Scheme 1. General solution-phase route
O
X
O
X
HCl.H2N-Phe-OMe
O
O
O
O
O
N
OH
NHBoc
H
DCC, HOBt, NMM
THF, 16 h, rt
O
NHBoc
3 X = H (77%)
4 X = OMe (65%)
1 X = H
2 X = OMe
1) NaOH 2N/THF
Many examples of Pictet-Spengler
cyclizations between an aldehyde and a
L-DOPAscaffold are known in the literature
but to our knowledge no analogous trans-
formations between a ketone and a free
amino group have been reported. Appar-
ently the methoxyphenyl derivative is not
reactive enough to allow cyclization of the
generated intermediate imine. If compound
6 was treated with p-TsOH in refluxing
toluene, pyrazinone 11 was obtained in
40% isolated yield. The pyrazinone forma-
tion is most likely the result of an oxidation
of the intermediate imine 9. When acety-
lating this intermediate in basic media
N-acetylation of the corresponding enamine
to give 12 was observed. Sodium borohy-
dride reduction resulted in the formation of
reduced compound 10, which was obtained
as a major diastereoisomer (Scheme 3).
Analogous results were observed when
starting from histidine. Under acidic condi-
tions, the acyclic precursor 15 did not form
the bicycle 16. Imine formation was put in
evidence by acetylation of the crude mix-
ture to afford the acylated enamine 17 as
major compound (Scheme 4).
2) Ac2O, AcOH, DMAP
TEA, THF, 45 °C, 16 h
X
X
O
O
O
H+
O
O
NH
N
H
O
NH
O
NHBoc
7 X = H
8 X = OMe
5 X = H (73%)
6 X = OMe (62%)
Scheme 2. L-Phenylalanine derivatives synthesis
O
O
O
O
O
O
N
H
O
O
NHBoc
O
NH
6
HN
NaBH4/MeOH
H+
10
O
O
O
O
H+ = p-TsOH/toluene
O
O
NH
N
N
N
O
O
9
11
Finally, we turned our efforts towards
tryptophan derivatives. Starting from 5-hy-
droxytryptophan dipeptide 19 was obtained
in 63% yield after coupling of 18 and
phenylalanine methylester followed by sub-
sequent ester hydrolysis. Then the car-
boxylic acid function was transformed into
a methyl ketone through a Dakin-West
reaction. Partial racemization at the C-α
stereocenter was observed under the applied
Ac2O/Pyridine
O
O
O
O
NH
N
12
O
Scheme 3. Evidence of the imine formation

COMBINATORIAL CHEMISTRY
257
CHIMIA 2003, 57, No. 5
reaction conditions. The methyl ketone de-
rivative 20 was isolated as a mixture of two
diastereoisomers (57:43) in 77% yield. The
Boc group was cleaved under acidic condi-
tions (20% TFA in DCM), generating a free
amino group, which immediately resulted
in the formation of the cyclic imine with
the methyl ketone followed by an intramol-
ecular Pictet-Spengler reaction. The 3,9-
diazabicyclo[3.3.1]non-6-en-2-one deriva-
tive 21 (100% conversion) was isolated in
62% yield (Scheme 5). The quaternary
stereo center generated during the cycliza-
tion is controlled by the asymmetric center
of L-tryptophan. Target structure 21 was
obtained as a mixture of diastereoisomers
(cis-21/trans-21 57:43) which were sepa-
rated by flash chromatography on silica
gel [8]. The relative configuration between
the methyl and the benzyl group of the
diastereoisomers was determined by mod-
ified 1H-1H ROESY experiments [9] on
a BRUKER DPX 400 MHz. For the cis
diastereoisomer, NOE effects were observed
1) HCl.H2N-Phe-OMe
O
O
DCC, HOBt, NMM
THF, 16 h, rt
H
H
OH
N
N
N
OH
NHBoc
H
O
2) NaOH 2N/THF
N
N
NHBoc
13
14 (72%)
Ac2O, AcOH, DMAP
TEA, THF, 45 °C, 16 h
H
O
N
N
H
N
O
H
TFA/DCM
N
H
O
N
NH
N
NHBoc
15 (25%)
16
1) TFA/DCM
2) Ac2O/Pyridine
3
between (CH216)-NH5 and CH3 -NH5 where
as for the trans diastereoisomer, NOE ef-
fects were observed between (CH11)-NH5
O
3
and CH3 -NH5.
H
N
This solution synthesis has shown that
the planed bicyclic scaffold is accessible
by the application of an intramolecular
Pictet-Spengler strategy. The indole system
was identified to be the preferred target
structure for further investigations on solid-
phase.
NH
N
N
O
17
Scheme 4. Synthesis using histidine as building block
Solid-phase Synthesis Strategy
Solid phase synthesis involves a cy-
clization under acidic conditions and there-
fore required an acid-stable linker. Mohan
and co-workers reported a serine-based
carbamate linker for the attachment of phe-
nolic compounds stable to TFA and organic
bases [10]. The cleavage mechanism is
based on the removal of the TIPS protect-
ing group of a serine side chain by treat-
ment with 1M TBAF in THF. The formed
alkoxy anion attacks intramoleculary the
urethane bond, which results in the release
of the phenolic compound. For this study,
Mohan has used a BocNH-Trp(OH)-OMe
template (Scheme 6).
In our experiments, aminomethyl poly-
styrene D-Lanterns from Mimotopes [11]
were used. According to Mohan, we immo-
bilized the BocNH-Trp(OH)-OMe template
on the solid phase. Our synthetic plan re-
quired methyl ester hydrolysis. Under stan-
dard conditions, significant loss of BocNH-
Trp(OH)-OH due to linker cleavage was
observed. No selective hydrolysis reaction
conditions could be found. Therefore, we
HO
HO
1) HCl.H2N-Phe-OMe, DCC,
O
O
HOBt, TEA, THF, 16 h, rt
OH
OH
N
H
2) NaOH 2N, THF, 2 h, rt
NHBoc
N
H
O
N
H
NHBoc
18
19 (63%)
1) AcOH, Ac2O, DMAP,
TEA, THF, 16 h, 45 °C
2) NaOH 2N, THF, 2 h, rt
O
HO
HO
16
NH
HN
3
N
H
H
HO
5
11
O
N
20% TFA/DCM
16 h, rt (62%)
cis-21
O
H
O
N
H
NHBoc
HN
NH
16
20 (77%)
N
H
H
5
3
11
trans-21
Scheme 5. Solution synthesis of 3,9-diazabicyclo[3.3.1]non-6-en-2-one scaffold

COMBINATORIAL CHEMISTRY
258
CHIMIA 2003, 57, No. 5
decided to replace the methyl ester by an
allyl ester function. In this context, we real-
ized a new efficient synthesis of the Mohan
linker by using a preformed protected tem-
plate prepared in solution prior to the an-
chorage on the solid support. Esterification
of amino acid derivative 18 was realized
under conditions reported by Albericio and
co-workers [12] with a mixture of allyl
bromide and diisopropyl ethylamine in ace-
tonitrile. After aqueous work-up and ex-
traction, compound 22 was directly isolated
by precipitation from hexanes in 63% yield.
p-Nitrophenylcarbonate 23 was generated
by treating 22 with p-nitrophenyl chloro-
formate (66% yield after flash chromatog-
raphy). The other part of the linker was
introduced via peptide bond formation with
BocNH-Ser(OTIPS)-OH. After Boc depro-
tection, template 24 was immobilised on
the solid-phase via an urethane bond link-
age (Scheme 7). Cleavage of the immo-
bilised scaffold revealed a loading of around
50% after mass quantification. These low
loading Lanterns were used to check the
feasibility of a solid-phase synthesis.
Solid-phase synthesis of the 3,9-diaza-
bicyclo[3.3.1]non-6-en-2-one scaffold was
initiated by palladium-catalyzed cleavage
[13] of the allyl group from starting
Lanterns 24. Then, phenylalanine allyl ester
was coupled under standard conditions and
the allyl group was subsequently removed
to afford the free carboxylic acid 25. Com-
pletion of the reaction was monitored by
cleavage of cut-off Lantern’s loops with 1M
TBAF/THF and analysis by LC/MS. The
modified Dakin-West reaction required
significantly prolonged reaction time com-
pared to the solution-phase pendant to go
to completion. Cyclization of 26 with 20%
O
O
O
O
O
H
N
O
NHBoc
O
N
H
H
N
HO
+
NHBoc
O
N
H
N
H
O
O
1M TBAF/THF
N
H
O
Si
F-
Scheme 6. Serine-based linker developed by Mohan
18
O
CH3CN/ally bromide
DIPEA, 36 h, rt
N+
O
HO
O
4-NO2PhOCOCl
O
OAll
NHBoc
O
O
TEA, DCM, 5 h, rt
O
N
H
OAll
NHBoc
22 (63%)
N
H
23 (64%)
1) BocNH-Ser(OTIPS)-OH,
HOBt, DIC, NMM,
THF, 50 °C, 24 h
O
NH2
N
H
NH2
2) 20% TFA/DCM,
2 x 90 min
O
Si
37 µmol/Lantern
TEA, DCM,
50 °C, 16 h
Si
O
O
H
N
N
O
O
H
O
OAll
NHBoc
N
H
24
TFA/DCM at RT did not lead to any of the Scheme 7. Template synthesis and loading
expected scaffolds. However, complete
cyclization was observed with 20% TFA in
DCE at 50 °C for 16 h (Scheme 8).
Cleavage experiments with 1M TBAF
in THF solution were very efficient, how-
1) Pd(II)acetate, PPh3, morpholine,
DCM, 2 h, rt
2) p-TsOH.H2N-Phe-OAll, TEA
O
N
O
O
H
DIC, HOBt, THF, 40 °C, 24 h
OH
ever LC/MS analysis of the samples were
sometimes tedious due to the presence of
high concentrations of tetrabutylammonium
salts which saturated the mass detector.
From our initial experiments, we knew that
linker cleavage was observed when inor-
ganic bases were used. Applying similar
conditions, effective cleavage of the final
scaffold was achieved with a cocktail
solution containing 2N NaOH/H2O/THF
(2:8:10) for 2 h at rt. Target compound 4
was recovered in an overall yield of 35%
(after 6 steps, based on 100% loading) with
a purity of 90% after aqueous work-up.
NMR and MS confirmed the structure of 21.
A first outlook of possible diversifi-
cation (acylation and alkylation) on the
N
H
24
O
NHBoc
3) Pd(II)acetate, PPh3, morpholine,
DCM, 2 h, rt
N
H
25
Ac2O, AcOH, DMAP,
TEA, THF, 30 C, 4 d
°
H
1) 20% TFA/DCE,
50 C, 16 h
O
O
HO
°
HN
O
NH
N
H
O
2) 1M TBAF/THF,
2 h, rt or NaOH 2N/
H2O/THF (2:8:10), 2 h, rt
N
H
N
H
O
NHBoc
N
cis/trans-21
H
26
Scheme 8. Solid-phase synthesis of the 3,9-diazabicyclo[3.3.1]non-6-en-2-one scaffold

COMBINATORIAL CHEMISTRY
259
CHIMIA 2003, 57, No. 5
Scheme 9. Functionalization of the immobi-
lized scaffold
O
O
O
NH
HN
N
H
N
H
1) AcCl, Pyridine, DCM, 16 h, rt
2) NaOHaq 2N/H2O/THF (2:8:10),
2 h, rt
1) BnBr, DIPEA, DMF, 50 °C, 24 h
2) NaOHaq 2N/H2O/THF (2:8:10),
2 h, rt
O
O
O
N
NH
HO
NH
N
HO
N
H
N
H
27
28
bridged nitrogen was explored (Scheme 9).
After cleavage, samples were analyzed by
LC/MS which confirmed the mass of the
expected materials with purities around
80% for 27 and 28.
O
OH
O
HO
O
29
O
1) DCC, DCM, 6 h
Due to the low loading, further investi-
gations on the attachment of the template to
the solid-phase were carried out. From our
initial experiments, we knew that the aro-
matic urethane was cleaved under aqueous
basic conditions. These cleavage condi-
tions were compatible with the synthesis
scheme. Therefore we decided to use a link-
er which is cleavable under aqueous basic
conditions. Different spacers for the im-
mobilization were reviewed. A small PEG
chain was immobilised on the solid-phase
by reaction of the anhydride of 29 and
aminomethyl polystyrene D-Lanterns. Then,
the template 22 was loaded to the resin via
ester formation to afford resin 30. A pre-
loaded and direct-loaded [14] γ-aminobu-
tyric linker was also investigated. For the
direct loading pathway, the resin was re-
acted with N-Boc-γ-aminobutyric acid first
and after Boc deprotection the template
was attached by addition of 23 to give the
direct loaded resin 31. In the pre-loading
approach, the linker–template adduct 32
was formed in solution by reaction of 23
with γ-aminobutyric acid before its attach-
ment to the Lantern via peptide bond
formation to afford pre-loaded resin 33
(Scheme 10). The four Lanterns were
subjected to the cleavage conditions
(NaOH/H2O/THF) and the amount of the
released BocNH-Trp(OH)-OH was analyzed
by HPLC. The results are summarized in
Table 1, resin 33 showed a double loading
compared to resins 24, 30 and 31. Mass
quantification after cleavage from 33 gave
a 105% mass recovery of material calcu-
lated from the theoretical 37 µmol/Lantern
loading.
2) Aminomethyl-
D-Lantern,
DCM, 16 h, rt
CO2All
3) 22, DIC, DMAP, THF
O
48 h, rt
NHBoc
O
O
N
H
O
O
O
N
H
30
31
CO2All
NHBoc
1) Boc-γ-Abu-OH, DIC, HOBt
NMM, THF, 16 h, 45
2) TFA/DCM
O
°
C
H
N
N
H
NH2
3) 23, DMAP, NMM, DCE,
48 h, 50
O
N
H
°C
CO2All
NHBoc
O
H
γ-amino butyric acid, TEA
DMF, 16 h, 50
N
O
22
HO
°C
O
32 (45%)
N
H
aminomethyl-
D-Lantern
HOBt, DIC, NMM
THF, 16 h, 45
°C
CO2All
NHBoc
O
H
N
O
N
H
33
O
N
H
Scheme 10. Linker syntheses
Table 1. HPLC quantification of released compound.
Resin
24
30
31
1.98
33
HPLC Area For
1.56
1.73
4.24
Boc-Trp(OH)-OH (x 106)

COMBINATORIAL CHEMISTRY
260
CHIMIA 2003, 57, No. 5
Attaching a preformed linker–template
adduct resulted in high loaded Lanterns.
These Lanterns were used for the synthesis
as previously described. The cyclization
was realized with 20% TFA in DCE at
50 °C for 16 h. After cleavage, the expected
bicycle was formed, however a more apolar
by-product (27%) was present in the mix-
ture reaction and its structure was eluci-
dated as the pyrazinone derivative 34
(Scheme 11).
To suppress this by-product, many
cyclization cocktails were investigated
(Table 2). The best selectivity was found
with 20% TFA in toluene at 80 °C under
argon but the pyrazinone formation could
not be suppressed completely.
H
O
HO
(64%)
NH
HN
N
H
HN
O
1) 20% TFA/DCE,
16 h, 50
O
O
cis/trans-21
N
H
°C
+
NHBoc
2) NaOH/H2O/THF
O
HN
O
HO
O
N
NH
H
(27%)
N
N
H
34
Scheme 11. Cyclization on full loaded resin
If the methyl ketone was replaced by a
benzyl ketone, less of the pyrazinone by-
product was formed. After cyclization,
alkylation of the nitrogen with benzyl bro-
mide and cleavage, the expected compound
was obtained as the major compound 35
(42%) (non-alkylated material 8%, pyrazi-
none 3%) (Scheme 12).
To avoid pyrazinone formation, we
considered switching from polystyrene
to polyamide backbone solid-support. The
loading of the polyamide Lantern (20 µmole/
Lantern) is lower compared to the poly-
styrene analogue (37 µmole/Lantern). The
preformed linker-template (methyl ketone)
was loaded to the polyamide Lanterns.
After cyclization and cleavage, 21 was the
only compound detectable by HPLC with-
out any trace of pyrazinone by-product
(Scheme 13).
In conclusion, we have realized so-
lution-phase and solid-phase syntheses of
diazabicyclo[3.3.1]nonenone compounds,
where the core structure is an attractive
scaffold for combinatorial synthesis. A first
study showed the feasibility of the syn-
thesis on solid-phase but in low yield. The
linker issue was solved. However, with
higher loading the formation of a pyrazi-
none by-product was observed. The switch
from polystyrene to polyamide support
allowed the elimination of the by-product
formation and the diazabicyclo[3.3.1]
nonenone derivative was obtained in high
purity by solid-phase synthesis. Currently,
outlook of the diversification and possible
modification of the scaffold on solid-phase
are under investigation.
Table 2. Cyclisation solution used and relative amount of the different materials.
Assay
Solution
20% TFA/DCE
[°C] Free amine Bicycle Pyrazinone
T
Atm
air
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
1
2
50 °C
50 °C
50 °C
50 °C
50 °C
80 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
0%
0%
64%
69%
71%
71%
73%
76%
0%
27%
20%
18%
22%
22%
20%
30%
13%
9%
20% TFA/DCE
3
50% TFA/DCE
0%
4
20% TFA/Toluene
50% TFA/Toluene
20% TFA/Toluene
20% TFA/dioxane
20% TFA/MeOH
20% TFA/DMF
20% TFA/CH3CN
20% TFA/Cyclohexane
5% TFA/DCE
0%
5
0%
6
0%
7
60%
70%
72%
0%
8
0%
9
0%
10
11
12
36%
53%
48%
30%
23%
28%
0%
0%
HN
O
H
O
HO
O
O
1) 20% TFA/DCE,
N
H
Acknowledgement
16 h, 50 °
C
N
NH
We thank the Chemistry Council of Novartis
for funding D. Orain, F. Houdière for LC/MS
and CTA associates for their support.
NHBoc
2) BnBr, DIPEA, DMF
16 h, 70 °
3) NaOH/H2O/THF
N
H
O
HN
C
35
O
N
H
Received: March 21, 2003
Scheme 12. Cyclization and alkylation of benzyl ketone derivative

COMBINATORIAL CHEMISTRY
261
CHIMIA 2003, 57, No. 5
HN
O
O
O
1) γ-amino butyric acid, TEA,
N
H
DMF, 16 h, 50 °
C
20
NHBoc
O
HN
2) aminomethyl-Polyamide-D-Lantern
HOBt, DIC, NMM, THF, 16 h, 45 °
C
O
N
H
1) 20% TFA/DCE,
16 h, 50 °
C
2) NaOH/H2O/THF
H
O
HO
HN
NH
N
H
cis/trans-21
Scheme 13. Synthesis on the polyamide Lanterns
3
[1] R.E. Dole, J. Comb. Chem. 2001, 3, 477.
[2] a) D.R. Spring, S. Krishnan, H.E. Black-
well, S.L. Schreiber, J. Am. Chem. Soc.
2002, 124, 1354; b) D.S. Tan, M.A. Foley,
M.D. Shair, S.L. Schreiber, J. Am. Chem.
Soc. 1998, 120, 8568.
[3] I. Manzanares, C. Cuevas, R. Garcia-
Nieto, E. Marco, F. Gago, Curr. Med.
Chem. – Anti-Cancer Agents 2001, 1, 257.
[4] A.G. Myers, B.A. Lanman, J. Am. Chem.
Soc. 2002, 124, 12969.
[5] D. Orain, R. Canova, M. Dattilo, E.
Klöppner, R. Denay, G. Koch, R. Giger,
Synlett 2002, 9, 1443; b) M.T. Todd,
C. Ndubaku, P.A. Bartlett, J. Org. Chem.
2002, 67, 3985; c) P. Yu, T. Wang, F. Yu,
J.M. Cook, Tetrahedron Lett. 1997, 38,
6819; d) N. Saito, S. Harada, M. Yamashita,
T. Saito, K. Yamaguchi, A. Kubo, Tetra-
hedron 1995, 51, 8213; e) F. Hamaguchi,
T. Nagasaka, S. Ohki, Yakugaku Zasshi
1974, 94, 351.
PhH); 7.28 (d, J(H,H) = 6.98 Hz, 2H,
PhH); 7.34 (t, 3J(H,H) = 6.98 Hz, 2H,
PhH); 8.61 (s, 1H, OH), 10.67 (s, 1H,
indole NH). MS (negative electrospray):
m/z (%): 346 (100) [M-H]–.
For the cis diastereoisomer 1H NMR (400
MHz, [D6]DMSO, 26°C) δ = 1.44 (s, 3H,
2
CH3); 2.67 (d, J(H,H) = 15.04 Hz, 1H,
IndCHH-); 2.84 (dd, 2J(H,H) = 15.04 Hz,
3J(H,H) = 4.30 Hz, 1H, IndCHH-); 2.95
(dd, 2J(H,H) = 13.97 Hz, 3J(H,H) = 13.97
Hz, 1H, CHHPh); 3.12 (dd, 2J(H,H) =
3
13.97 Hz, J(H,H) = 4.83 Hz, 1H, CHH-
Ph); 3.58 (m, 1H, CCHNHCO); 3.73 (m,
1H, CHNH); 6.97 (m, 1H, NHCO); 6.55
3
4
(dd, J(H,H) = 8.60 Hz, J(H,H) = 2.14
Hz, 1H, ArH); 6.66 (d, 4J(H,H) = 2.14 Hz,
1H, ArH); 7.08 (d, 3J(H,H) = 8.60 Hz, 1H,
ArH); 7.22 (t, 3J(H,H) = 7.52 Hz, 1H,
3
PhH); 7.24 (d, J(H,H) = 7.52 Hz, 2H,
PhH); 7.32 (t, 3J(H,H) = 7.52 Hz, 2H,
PhH); 8.55 (s, 1H, OH), 10.55 (s, 1H,
Indole NH). MS (negative electrospray):
m/z (%): 346 (100) [M-H]–, 460 (25)
[M+CF3COO–], 693 (5) [2M-H]–.
[6] G.L. Buchanan, Chem. Soc. Rev. 1988, 91.
[7] E.D. Cox, J.M. Cook, Chem. Rev. 1995,
95, 1797.
[8] For the trans diastereoisomer 1H NMR
[9] C. Dalvit, G. Bovermann, Magnetic Reso-
nance in Chemistry 1995, 33, 156.
(s, 3H, CH3); 2.07 (dd, J(H,H) = 13.97 [10] Y-L. Chou, M.M. Morrissey, R. Mohan,
(400 MHz, [D6]DMSO, 26 °C) δ = 1.56
2
3
Hz, J(H,H) = 13.98 Hz, 1H, CHHPh);
Tetrahedron Lett. 1998, 39, 757.
2.70 (d, 2J(H,H) = 15.58 Hz, 1H, IndCHH-);
[11] SynphaseTM D-series Lantern from Mimo-
topes, aminomethylated, 36 µmol/Lantern.
2
3
2.88 (dd, J(H,H) = 15.58 Hz, J(H,H) =
6.44 Hz, 1H, IndCHH-); 3.27 (dd, 2J(H,H) [12] J. Alsina, F. Rabanal, C. Chiva, E. Giralt,
= 13.97 Hz, 3J(H,H) = 2.15 Hz, 1H,
CHHPh); 3.72–3.78 (m, 2H, CHNH and [13] General review for the protecting groups
F.Albericio, Tetrahedron 1998, 54, 10125.
CCHNHCO); 5.93 (m, 1H, NHCO); 6.60
strategy on solid-phase: D. Orain, J. Ellard,
M. Bradley, J. Comb. Chem. 2002, 4, 1.
3
4
(dd, J(H,H) = 8.60 Hz, J(H,H) = 2.15
Hz, 1H, ArH); 6.71 (d, 4J(H,H) = 2.15 Hz, [14] For the definition of pre-loading and direct
1H, ArH); 7.16 (d, 3J(H,H) = 8.60 Hz, 1H,
ArH); 7.25 (t, 3J(H,H) = 6.98 Hz, 1H,
loading see: F. Guillier, D. Orain, M.
Bradley, M. Chem. Rev. 2000, 100, 2091.