Biology-oriented combined solid-and solution- phase synthesis of a macroline-like compound collection

Article abstract of DOI:10.1002/chem.200901797

Macrolines constitute a class of natural products that has more than 100 members and displays diverse biological activities. These compounds feature a cycloocta[b]indole scaffold that represents an interesting target structure for biology-oriented synthesis (BIOS). We have presented a solid-phase synthesis of isomerically pure cycloocta[b]indoles by employing the Pictet-Spengler reaction and the Dieckmann cyclization as key steps. The scope of this reaction sequence was investigated in more detail by using various additional diversification procedures, such as Pd-catalyzed Sonogashira or Suzuki couplings on a solid phase, thus allowing, for example, the generation of 10-substituted cycloocta-[b]indole derivatives. Finally, solution-phase decoration of the cycloocta[b]indole skeleton by reduction and saponification was evaluated, thereby further extending the scope of the solid-phase synthesis.

Full text of DOI:10.1002/chem.200901797

DOI: 10.1002/chem.200901797
Biology-Oriented Combined Solid- and Solution-Phase Synthesis of a
Macroline-Like Compound Collection
Wolfram Wilk,[a] Andrea Nçren-Mꢀller,[a] Markus Kaiser,[b] and Herbert Waldmann*[a]
Abstract: Macrolines constitute a class
of natural products that has more than
100 members and displays diverse bio-
logical activities. These compounds fea-
ture a cycloocta[b]indole scaffold that
represents an interesting target struc-
ture for biology-oriented synthesis
(BIOS). We have presented a solid-
phase synthesis of isomerically pure cy-
cloocta[b]indoles by employing the
Pictet–Spengler reaction and the Die-
ckmann cyclization as key steps. The
scope of this reaction sequence was in-
vestigated in more detail by using vari-
ous additional diversification proce-
dures, such as Pd-catalyzed Sonoga-
shira or Suzuki couplings on a solid
phase, thus allowing, for example, the
generation of 10-substituted cycloocta-
AHCTUNGTRENNG[UN b]indole derivatives. Finally, solution-
phase decoration of the cycloocta[b]in-
dole skeleton by reduction and saponi-
fication was evaluated, thereby further
extending the scope of the solid-phase
synthesis.
Keywords: biology-oriented
syn-
thesis · natural products · solid-
phase synthesis · synthetic methods
Introduction
classes[4,5] and employed to identify suitable scaffolds for
compound-collection synthesis.[6] Thus, BIOS builds on the
diversity created by nature and aims at local extension in
areas of proven relevance.
Collections of small molecules have proven to be valuable
tools for the study of biological phenomena.[1] In recent
years, various concepts, such as biology-oriented synthesis
(BIOS) or diversity-oriented synthesis (DOS), for the sys-
tematic generation of such compound collections have been
introduced.[2,3]
In the BIOS approach, scaffolds of natural-product classes
that display multiple, biological properties are regarded as
biologically prevalidated starting points for the development
of compound collections. Accordingly, a treelike structural
classification of natural-product (SCONP) frameworks
known to date has been generated, expanded, and comple-
mented to non-natural yet biologically validated compound
The macrolines represent such an interesting natural
product class (Scheme 1). These compounds are character-
ized by a cycloocta[b]indole scaffold and often highly com-
plex structures.[7] Interest in these alkaloids originated from
folk tales that described the medicinal properties of the pro-
ducing plants. To date, more than 100 macroline natural
products have been elucidated. Although the parent epony-
mous compound macroline (1) itself has never been isolated
as a natural product, it has been suggested that macroline
might indeed exist as a natural product that acts as a bio-
mimetic precursor to many alkaloids, such as ajmaline (2) or
macrocarpamine (3).[8] The macrolines feature a wide spec-
trum of biological activities; for example, macrocarpamine
(3) possesses antiamoebic and antiplasmodic properties.[9]
The bisindoles villalstonine (4) and O-acetylmacralstonine
(5a) display antiprotozoal activities, whereas the closely-re-
lated analogue macralstonine (5b) shows antihypertensive
properties.[10] Indeed, several macroline natural products
have shown antiamoebic and antiplasmodial activities.[8,11]
The diverse biological activities of macrolines validates the
cycloocta[b]indole system as a promising scaffold for the
generation of a natural-product-inspired compound collec-
tion.
[a] Dipl.-Chem. W. Wilk, Dr. A. Nçren-Mꢀller, Prof. Dr. H. Waldmann
Department of Chemical Biology
Max Planck Institute of Molecular Physiology
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
and
Technische Universitꢁt Dortmund
Fachbereich Chemie
Otto-Hahn-Strasse 6, 44227 Dortmund (Germany)
Fax : (+49)231-133-2499
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
[b] Dr. M. Kaiser
Chemical Genomics Centre der Max-Planck-Gesellschaft
Otto-Hahn-Strasse 15, 44227 Dortmund (Germany)
To cope with the inherent structural complexity of natural
products such as the macrolines, efficient multistep synthetic
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901797.
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FULL PAPER
ring-closing reaction of a trans-tetrahydrocarboline moiety,
which is derived from a stereoselective Pictet–Spengler reac-
tion. To steer this reaction stereoselectively, a directing
group, usually a benzyl moiety, is introduced at the amino
group of a chiral tryptophan residue, thus resulting in a high
trans stereoselection during the Pictet–Spengler reaction.
We envisioned that a general synthetic entry into the macro-
line structural class on a solid support could be accom-
plished by adapting this methodology. This assumption was
backed by previous reports of diastereoselective Pictet–
Spengler reactions on solid support.[14] In addition, Wang
and Ganesan noted, in accord with the methodology of
Cook and co-workers, that sterically demanding groups at
the amino group of tryptophan increase the stereospecificty
of the Pictet–Spengler reaction to furnish the desired trans
isomer.[15]
Herein, we report fully on the stereoselective solid-phase
synthesis of isomerically pure cycloocta[b]indoles as the nat-
ural-product scaffold of macrolines. We, furthermore, de-
scribe synthetic methods that allow a subsequent derivatiza-
tion of cycloocta[b]indoles in solution, thereby extending
the scope of the presented methodology. For a preliminary
report on our investigation, see reference [12j].
Scheme 1. Examples of macroline natural products: macroline (1), ajma-
line (2), macrocarpamine (3), villalstonine (4), O-acetylmacralstonine
(5a), and macralstonine (5b).
Results and Discussion
In analogy to the reaction sequences developed by Cook
and co-workers, we decided to synthesize the desired macro-
line target stucture 6 from the tetrahydrocarboline moiety 7
by employing an isomerization/cyclization reaction. Com-
pound 7 is derived from a stereoselective Pictet–Spengler
reaction with N-alkylated tryptophan derivatives 8 and
methyl-4,4-dimethoxybutyrate (9) as an aldehyde equiva-
lent. The secondary amines 8 can be obtained from trypto-
phan derivatives 10 by reductive amination (Scheme 2).
Different tryptophan derivatives and the reductive amina-
tion step enable the introduction of diversity during the
solid-phase synthesis. As the chemical properties of the N-
benzylic group are, however, critical for the stereoselection
during the Pictet–Spengler reaction, test reactions with dif-
ferent benzyl groups were first performed in solution
(Scheme 3).
sequences and solid-phase methods that proceed with a high
degree of stereoselectivity are required for successful com-
pound-collection generation. The application of asymmetric
transformations on immobilized substrates is still challeng-
ing as side products cannot be separated during the course
of the synthesis sequence. Therefore, asymmetric transfor-
mations that provide high levels of stereoinduction for solid-
phase organic syntheses have to be developed.[12]
The cycloocta[b]indole scaffold of macrolines features a
cis-configured [3.3.1] bicyclic subsystem, which is angularly
attached to an indole moiety. Clearly, its stereospecific con-
struction is critical for solid-phase approaches to this system
and represents a major obstacle for efficient synthesis. Cook
and co-workers developed an elegant methodology for the
stereospecific generation of this scaffold in solution-phase
chemistry and demonstrated its feasibility in numerous total
syntheses of macroline-based natural products.[7,13] Their ap-
proach is based on selective isomerization and a subsequent
Towards this end, d-tryptophan methyl ester 10 was con-
verted into imine 11 by stirring the corresponding aldehyde
in a suspension of MgSO4 and dichloromethane. Benzylalde-
hyde, 3-methylbenzaldehyde, and 4-fluorobenzaldehyde
Scheme 2. Retrosynthetic approach for the solid-phase synthesis of macroline-like cycloocta[b]indoles.
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H. Waldmann et al.
solid support by employing dif-
ferent benzylic residues on the
tryptophan amino group.
Because the enantiospecific
Pictet–Spengler reaction is per-
formed under strongly acidic
conditions, the base-labile hy-
droxymethylbenzoic
acid
(HMBA) linker was chosen for
attachment of the tryptophan
derivative.[17] The Dieckmann
cyclization is performed under
basic conditions, thus cleavage
from resin and subsequent cyc-
lization to the macroline ring
system were expected to occur
in a convenient one-pot reac-
tion (Scheme 4A).
Scheme 3. Synthesis of cycloocta[b]indoles in solution. a) RCHO, MgSO4, dichloromethane, RT, 3 h;
b) NaBH4, À58C, 6 h (12a: 94%, 12b: 69%, 12c: 78% (over two steps)); c) 10% TFA in CH2Cl2, methyl-4,4-
dimethoxybutanoate (9; 1.1 equiv), RT, 3 days (13a: 86% (13a/14a=25:1), 13b: 83% (13b/14b=20:1), 13c:
To gain further insight into
the stereoselectivity of the
81% (13c/14c=25:1)); d) NaH (3 equiv), MeOH, toluene, reflux, overnight (15a; 78%, 15b; 55%, 15c: Pictet–Spengler reaction on
67%). TFA=trifluoroacetic acid.
solid support, the synthetic pro-
cedure was also repeated with
Fmoc-protected l-tryptophan
were employed as the aldehydes. The crude products were
reduced to secondary amines 12 with NaBH4 at À58C over
6 h. The low-temperature conditions effectively prevented
racemization. Secondary amines 12 were obtained in yields
of 69–94%. With derivatives 12 in hand, the synthetic scope
and suitable reaction conditions of the asymmetric Pictet–
Spengler reaction were tested. Excellent diastereoselectivi-
ties were observed if a reaction time of 3 days at room tem-
perature was employed. These findings are in accordance
with the results of Cook and co-workers who reported an
enantiospecific Pictet–Spengler reaction with 1,3-stereoin-
duction to yield trans-diesters 13 in excellent yields and dia-
stereoselectivities.[13] NMR spectroscopic experiments re-
vealed a diastereoisomeric ratio of 29:1 for 13a/14a. Nota-
bly, the two other benzylic substituents at the amino group
were also tolerated without significant loss of diastereoselec-
tivity. The ring closure of diesters 13 to cylcoocta[b]indoles
15 was achieved by a subsequent Dieckmann cyclization,
which required a prior selective epimerization. After an
acidic workup, b-keto esters 15 were isolated in moderate-
to-good yields of 55–77%. The NMR spectra and optical ro-
tation value of 15a matched the data reported previously
(15a: [a]2D2 =À1778 (c=1 gdLÀ1 in CHCl3); ref. [13b]: [a]2D2 =
À177.48 (c=1 gdLÀ1 in CHCl3)). Further evidence of a cis-
disubstituted b-carboline framework is provided by a down-
field shift of C-1 and C-3 in the 13C NMR spectra, thereby
leading to signals at d=59.0 and 56.0 ppm for C-1 and C-3,
respectively.[16] Thus, the solution-phase synthesis of cyclooc-
ta[b]indoles could be achieved with various substituted ben-
zaldehydes with different electronic properties without de-
composition of the inherently labile N-b-benzyl-moiety.
Based on these successful experiments in solution, we inves-
tigated the adaption of the synthetic methodology onto a
as the starting material, thus resulting in the generation of
the enantiomeric macrolines 24 (Scheme 4B).
The established reaction sequence gave synthetic access
to more than 100 isomerically pure tetracyclic alkaloid ana-
logues with an HPLC purity of more than 90%. The result-
ing b-keto esters 21 or 24 were generally obtained in syn-
thetically very viable yields of 12–62% after six steps and
purification by preparative HPLC, thus indicating a high
overall efficiency of the synthetic sequence (see Table 1 for
representative examples). The established synthetic route is
compatible with a broad range of diversely subsituted alde-
hydes. The highest observed yield of 62% was obtained with
3-bromobenzaldehyde (21a; Table 1, entry 1). An ortho sub-
stitution in the aldehyde was also well tolerated (e.g., 21b
and 24b; Table 1, entries 2 and 18, respectively).
A modification of the synthetic protocol was necessary to
obtain macroline derivatives carrying mono- or bis-hydroxy-
benzyl moieties at the N-b-residue. The addition of DMF to
a final concentration of 10% to the reaction mixture proved
essential, which probably assures full dissolution of the elec-
tron-rich hydroxy-substituted aldehydes during the reaction.
Under these modified reaction conditions, hydroxy-substi-
tuted b-keto esters, such as 21c–f or 24d–h (Table 1, en-
tries 3–6 and 20–24, respectively), were accessible from sub-
stituted mono- or bis-hydroxybenzaldehydes and d- or l-
tryptophan in yields of up to 55%. Unfortunately, all at-
tempts to obtain the highly electron-rich tris-hydroxy deriva-
tives, for example, by employing 3,4,5-trihydroxybenzalde-
hyde, failed to deliver the desired products. In addition,
other heteroaromatic aldehydes that carry either a substitut-
ed furan, benzofuran, thiophene, benzothiophene, or pyri-
dine skeleton were subjected to the established synthetic
conditions, thus leading to, for example, N-b-heteroaromat-
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Synthesis and Derivatization of Cycloocta[b]indoles
FULL PAPER
Scheme 4. A) Synthesis of cycloocta[b]indoles 21. a) 2,6-Dichlorobenzoyl chloride (4 equiv), pyridine (3 equiv), Fmoc-d-tryptophan (4 equiv); b) DMF,
RT, 24 h; c) 20% piperidine in DMF, RT, 2ꢃ10 min; d) R1CHO (5 equiv), HC
(OMe)3/CH2Cl2 (1:1), RT, 12 h; e) NaCNBH3 (10 equiv), 20% HOAc in
AHCTUNGTRENNUNG
THF, 08C overnight; f) 15% TFA in CH2Cl2, RT, 2ꢃ5 min; g) methyl-4,4-dimethoxybutanoate (9; 10 equiv), 15% TFA in CH2Cl2, RT, 3 days; h) 15%
Et3N in dichloromethane, RT, 2ꢃ5 min; i) 1m NaOMe in MeOH/1,4-dioxane (1:1), 508C, overnight; j) NaOMe (5 equiv), 10% MeOH in toluene, reflux,
2 days (12–75%). B) The enantiomeric derivatives 24 were synthesized analogously using Fmoc-l-tryptophan as the starting material.
Table 1. Results for the synthesis of representative cycloocta[b]indoles.
Entry
Compound
Structure
Yield [%]
Entry
2
Compound
Structure
Yield [%]
35
1
21a
59
21b
3
5
21c
21e
24
54
4
6
21d
21 f
51
36
7
21g
57
8
21h
50
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H. Waldmann et al.
Table 1. (Continued)
Entry
Compound
Structure
Yield [%]
45
Entry
10
Compound
Structure
Yield [%]
17
9
21i
21j
11
13
21k
54
48
12
14
21l
61
61
21m
21n
15
21o
48
16
21p
51
17
24a
51
18
24b
33
19
21
24c
24e
35
55
20
22
24d
24 f
20
55
23
25
24g
33
32
24
26
24h
45
48
24i
24j
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Synthesis and Derivatization of Cycloocta[b]indoles
FULL PAPER
ic-substituted b-keto esters 21g–p (Table 1, entries 7–16) or
24i,j (Table 1, entries 25 and 26) in high overall yields of
17–61% over six steps and after purification by HPLC.
A modified 4,4-dimethoxybutanoate building block was
synthesized and used in the asymmetric solid-phase Pictet–
Spengler reaction to demonstrate the scope of the reaction
sequence. Following the previously reported protocols
(Scheme 5), nitrobutanoate (26) was obtained in moderate
yields from acrylic ester 25 and nitromethane in the pres-
ence of KOH after a Michael addition.[21] This intermediate
was then converted into 4,4-dimethoxybutanoate (27)
through a Nef reaction in moderate yield.[22] Dimethoxybu-
tanoate (27) was employed in the reaction sequence to
obtain b-keto ester 28 in 44% yield. This approach is re-
markable taking into account the harsh reaction conditions
of the Dieckmann cyclization, which could cause transesteri-
fication of the oxoethyloxoethyl group.
Many naturally occurring macroline-related alkaloids,
such as macralstonine or sarpagine, carry hydroxy or me-
thoxy substitutents at the 10-position of the cycloocta[b]in-
dole scaffold (see compounds 5a,b in Scheme 1).[11a] In prin-
ciple, such modifications could be introduced by properly 5-
functionalized tryptophan derivatives. To explore this possi-
bility, 5-substituted tryptophans were employed in the syn-
thetic sequence. In the first trial, the amino group of com-
mercially available 5-fluoro-, 5-methyl-, or 5-methoxy-substi-
tuted d,l-tryptophan was pro-
tected with the Fmoc urethane
moiety and subjected to the re-
action conditions indicated in
Scheme 6.
In case of the electron-rich 5-
methoxy-d,l-tryptophan, acetic
acid containing only few drops
of TFA instead of neat TFA
was employed during the
Pictet–Spengler reaction be-
cause Cook and co-workers had
elucidated that these reaction
conditions minimized decompo-
Scheme 5. A) Synthesis of 4,4-dimethoxybutanoate (27). a) MeNO2, KOH, Et2O, RT, overnight (43%); b)
NaOMe, MeOH, RT, 1 h; c) H2SO4, MeOH, À308C (56%, both steps). B) Use of 27 for the synthesis of 28
(44% overall yield).
sition of the 5-methoxytrypto-
phan moiety.[13] The desired 5-
Scheme 6. Synthesis of racemic 10-substituted cycloocta[b]indoles 33. a) 2,6-Dichlorobenzoyl chloride (4 equiv), pyridine (3 equiv), Fmoc-(5-F)-Trp-OH,
Fmoc-(5-Me)-Trp-OH, or Fmoc-(5-MeO)-Trp-OH (4 equiv); b) DMF, RT, 24 h; c) 20% piperidine in DMF, RT, 2ꢃ10 min; d) R1CHO (5 equiv), HC-
ACHTUNGTRENNUNG(OMe)3/CH2Cl2 (1:1), RT, 12 h; e) NaCNBH3 (10 equiv), 20% HOAc in THF, 08C, overnight; f) 5% TFA in CH2Cl2, RT, 2ꢃ5 min; g) methyl-4,4-dime-
thoxybutanoate (9; 10 equiv); h) 1) HOAc in CH2Cl2, RT, 3 days; 2) TFA, 1 h, RT; i) 15% Et3N in CH2Cl2, RT, 2ꢃ5 min; j) 1m NaOMe in MeOH/1,4-di-
oxane (1:1), 508C, overnight; k) NaOMe (5 equiv), 10% MeOH in toluene, reflux, 2 days (33a: 51%, 33b: 42%, 33c: 48%, 33d: 15%). Fmoc=9-fluore-
nylmethoxycarbonyl, Trp=tryphophan.
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H. Waldmann et al.
Scheme 7. Synthesis of racemic 10-phenyl- or 10-phenylethynyl-substituted cycloocta[b]indoles 36. a) Phenylboronic acid (10 equiv), Cs2CO3 (1 equiv),
DME, PdACHTUNGTRENNUNG(OAc)2 (0.5 equiv), PACHTUNREGTGNN(NU o-tolyl)3 (1 equiv), 808C, overnight; b) phenylacetylene (10 equiv), [PdCAHTNUGTREN(NUGN PPh3)4] (1 equiv), 20% DIEA in DMF, CuI
(0.5 equiv), 1008C, overnight; c) 15% TFA in CH2Cl2, RT, 2ꢃ5 min; d) methyl-4,4-dimethoxybutanoate (9; 10 equiv), 15% TFA in CH2Cl2, RT, 3 days;
e) 15% Et3N in CH2Cl2, RT, 2ꢃ5 min; f) 1m NaOMe in MeOH/1,4-dioxane (1:1), 508C, overnight; g) NaOMe (5 equiv), 10% MeOH in toluene, reflux,
2 days (36a: 18%, 36b: 14%). DIEA=diisopropylethylamine, DME=1,2-dimethoxyethane.
substituted d,l-tryptophan derivatives could be successfully
combined with various aldehydes, thereby leading to race-
mic 10-substituted b-keto esters 33a–d in 15–51% yield. Im-
portantly, the electron-rich 10-methoxy-d,l-cycloocta[b]in-
dole derivative 33d was also obtained in 15% overall yield.
After establishing this reaction sequence, we next investi-
gated if a polymer-bound 5-bromo-d,l-tryptophan derivative
could be equipped with additional functional groups by
means of a Pd-mediated coupling reaction before continuing
the reaction sequence with the Pictet–Spengler reaction. To
this end, secondary amine 34a was heated under the condi-
tions for a Suzuki reaction in DME at 808C overnight in the
however, revealed the formation of a dibenzylated side
product of 38 in 9% yield. After piperidine-induced removal
of the Fmoc unit, the resulting amine group was subjected
to reductive amination to yield secondary amine 39. Similar
to previous findings obtained by Cook and co-workers,[13]
the benzylated amine 39 proved to be even more sensitive
to acid-induced decomposition. Consequently, the use of
TFA in the asymmetric Pictet–Spengler reaction led to de-
composition. If, however, acetic acid was used instead of
TFA, the desired carboline 40 was obtained, which was sub-
sequently transformed into cycloocta[b]indole 42 in 8%
yield (Scheme 8), determined after preparative HPLC. This
example is the first for the employment of 5-hydroxytryp-
thophan in this synthetic sequence. 2-Benzyloxy-substituted
cycloocta[b]indoles have not been synthetically accessible so
far.
Finally, the decoration of the cycloocta[b]indole skeleton
in solution was investigated and could be achieved through
reduction of the b-keto group. To this end, b-keto esters 21
were treated with five equivalents of NaBH4 at 08C for 8 h,
thus leading to, for example, the corresponding b-hydroxy
esters 43a,b after acidic workup in moderate-to-good yields
(Scheme 9).[24] A small number of b-keto esters were further
converted into the corresponding acids by stirring overnight
in 15% TFA in an acetonitrile/H2O mixture. Direct reverse-
phase HPLC purification without previous workup led to
the b-keto acids 44 in 75–81% yield (Scheme 9). These b-
keto esters 44 were stable at room temperature but did not
tolerate higher temperatures due to decarboxylation.[13]
In conclusion, we have developed an efficient solid-phase
synthesis to both enantiomeric series of the cycloocta[b]in-
dole framework, thus yielding access to this important alka-
loid class in high yield with a short synthesis time. The N-b-
position of this structural framework can be further
presence of Cs2CO3, Pd
ACHUTGTNERN(NGU OAc)2 (50 mol%), and PACHTUNTGERN(NUGN o-tolyl)3
(1 equiv) as the catalytic system (Scheme 7).[23]
After the subsequent Pictet–Spengler reaction and Die-
ckmann cyclization, the desired 10-biphenyl-substitued cy-
cloocta[b]indole 36a was isolated in 18% overall yield
(Scheme 7). Additionally, a Sonagashira coupling with 34b
and phenylacetylene in DMF/DIEA and [PdACTHUNRTGNEUNG(PPh3)4]/CuI as
the catalytic system led to a 2-phenylethynyl-substituted cy-
cloocta[b]indole 36b in 14% yield (Scheme 7). These exam-
ples are the first of 10-phenyl- or 10-ethynyl-substituted cy-
cloocta[b]indoles and represent, to the best of our knowl-
edge, the first examples of Pd-mediated couplings on the 5-
bromo-d,l-tryptophan skeleton on a solid phase.
Alternatively, we envisioned integration of l-hydroxytryp-
tophan into the synthetic route. The hydroxy group at the 5-
position should represent a point for further diversification,
for example, by alkylation. Toward this end, Fmoc-l-5-hy-
droxytryphophan was loaded on the HMBA resin and sub-
jected to benzylation with 2,5-difluorobenzylbromide in
DMF/KI with Cs2CO3 as a base at 808C overnight. Two
equivalents of 2,5-difluorobenzylbromide were sufficient to
completely benzylate the 5-hydroxy group. LCMS analysis,
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Synthesis and Derivatization of Cycloocta[b]indoles
FULL PAPER
Scheme 8. Synthesis of 2-benzyloxy-substituted cycloocta[b]indole 42. a) 2,6-Dichlorobenzoyl chloride (4 equiv), pyridine (3 equiv), Fmoc-(l)-(5-OH)-
Trp-OH (4 equiv); b) DMF, 2,5-difluorobenzyl bromide (2 equiv), Cs2CO3 (5 equiv), KI (1 equiv), 808C, overnight; c) 20% piperidine in DMF, RT, 2ꢃ
10 min; d) R1CHO (5 equiv), HC
ACTHNURTGNEUNG(OMe)3/CH2Cl2 (1:1), RT, 12 h; e) NaCNBH3 (10 equiv), 10% HOAc in THF, 08C, overnight; f) 5% TFA in CH2Cl2,
RT, 2ꢃ5 min; g) methyl-4,4-dimethoxybutanoate (9; 10 equiv), 15% HOAc in CH2Cl2, RT, 3 days; h) 15% Et3N in CH2Cl2, RT, 2ꢃ5 min; i) 1m NaOMe
in MeOH/1,4-dioxane (1:1), 508C, overnight; j) NaOMe (5 equiv), 10% MeOH in toluene, reflux, 2 days (42: 8%).
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Acknowledgements
This research was supported by the Fonds der Chemischen Industrie.
Chem. Eur. J. 2009, 15, 11976 – 11984
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: June 30, 2009
Published online: September 25, 2009
11984
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