Rapid combinatorial access to macrocyclic ansapeptoids and ansapeptides with natural-product-like core structures

Article abstract of DOI:10.1055/s-2006-950335

14-Membered ansa-cyclopeptide alkaloids are among the most abundant natural macrocycles and thus valuable templates for diversity-oriented synthesis with biological relevance. A rapid synthesis of the core structure is conceivable by a combination of an Ugi four-component reaction with bifunctional building blocks to form the dipeptoid part, followed by a suitable macrocyclization reaction. The latter step is crucial, and an uncommon macroetherification gave the best results. The use of ammonium salts allows direct access to peptides instead of peptoids. Depending on the substitution pattern, some cyclopeptoids show planar chirality despite free rotation of the phenylene group. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950335

PAPER
3997
Rapid Combinatorial Access to Macrocyclic Ansapeptoids and Ansapeptides
with Natural-Product-like Core Structures
a
a
a
b
a
C
M
ombinatorial Access
i
to Ma
c
c
rocyclic
A
n
h
sapeptoids
a
i
nd Ans
e
apeptides l de Greef, Sahan Abeln, Khalid Belkasmi, Alexander Dömling, Romano V. A. Orru,
a,c
Ludger A. Wessjohann*
a
Vrije Universiteit Amsterdam, Department of Organic and Inorganic Chemistry, De Boelelaan 1083, 1081 HV Amsterdam,
The Netherlands
b
c
R & D Biopharmaceuticals (formerly Morphochem AG), Am Klopferspitz 19a, 82152 Martinsried, Germany
Address for correspondence: Leibniz Institute of Plant Biochemistry, Bioorganic Chemistry (NWC), Weinberg 3, 06120 Halle (Saale),
Germany
Fax +49(345)55821309; E-mail: wessjohann@ipb-halle.de
Received 14 October 2005; revised 31 August 2006
ibility.1,7,11 Conformationally defined, proteolytically
Abstract: 14-Membered ansa-cyclopeptide alkaloids are among
the most abundant natural macrocycles and thus valuable templates
for diversity-oriented synthesis with biological relevance. A rapid
stable cyclic peptides of medium ring size consequently
have attracted some attention.2
5–28
This contribution de-
synthesis of the core structure is conceivable by a combination of an scribes a highly efficient, short, and flexible synthetic
Ugi four-component reaction with bifunctional building blocks to route with the potential to generate libraries of natural-
form the dipeptoid part, followed by a suitable macrocyclization re-
product-like cyclic pept(o)ides, which we term ansapep-
action. The latter step is crucial, and an uncommon macroetherifi-
cation gave the best results. The use of ammonium salts allows
direct access to peptides instead of peptoids. Depending on the sub-
29–32
toids.
The basic macrocyclic motif we chose is derived from the
stitution pattern, some cyclopeptoids show planar chirality despite unusual ansa structure of the natural 13-, 14-, or 15-mem-
bered cyclopeptide alkaloids 1 (Scheme 1).1 In these, a
,33
free rotation of the phenylene group.
Key words: alkaloids, cyclopeptides, macrocycles, ansa com- benzene ring is spanned at the 1,3- or, usually, the 1,4-po-
pounds, multicomponent reaction, planar chirality, natural product sition by a peptide-type bridge, which, besides proteino-
analogues
genic amino acids, commonly includes decarboxylated,
D-, b-hydroxy-, and N,N-dialkylated amino acids and is
proteolytically quite stable in blood plasma. A large vari-
The success rate of natural products and products derived ety of cyclopeptide alkaloids 1 are used in folk medicine
therefrom is overproportional in pharmaceutical develop- and were isolated by us and others in small amounts from
1
–7
34–37
ment. Two reasons accepted for this are the evolution- a wide range of (tropical) plants.
Antifungal and anti-
ary advantage of natural products with privileged bacterial activities as well as sedative effects have been at-
structural elements, and the dominance of conserved tributed to some compounds.3
3,38
structural regions (motifs) in the target protein counter-
Several synthetic studies utilizing conventional approach-
1
,8,9
parts.
Furthermore, nature achieves an incredible di-
39–41
es have been published.
nent reactions have been used for the synthesis of some
building blocks.
In a few cases, multicompo-
versity of products derived from very few basic pathway
1
,10
chemistries. However, secondary natural products of-
ten show quite complex structures requiring multistep
syntheses, and rendering backbone variations for lead dis-
covery or quantitative structure–activity studies a lengthy
and costly process. Consequently, only few natural-
product-related libraries have been reported, and even
fewer utilize rapid high-diversity multicomponent
41–47
The efforts have concentrated on the
generation of the central 14-membered macrocyclic ansa
scaffold, which is most critical, since a strained system is
formed. The general approach is to initially synthesize a
suitably functionalized linear (di)peptide chain, and then
close the ring. Thus far, cyclization has been attempted at
40
positions A, B, and D indicated in Scheme 1 in structure
7
,9,11–16
approaches.
48
2
.
Cyclization at positions A and B requires standard
The most relevant structural motifs are amino acid side peptide-bond-formation methods, e.g. the macrolactam-
1
49,50
51
chains, especially in macrocycles. Important recognition ization techniques developed by Pais
and Rapoport,
1
7,18
52,53
or active motifs are often to be found in loops,
and the pioneering work of Joullié and co-workers,
and,
Most cy-
many mimics of constrained peptides and turns have been especially, the excellent work of Schmidt.5
4–56
1
9–24
described,
whereby macrocycles with their structural clization attempts at positions C or D, induced by the in-
semirigidity allow both conformational control and favor- tramolecular formation of an alkyl aryl ether bond were
able entropy reduction, with, at the same time, some flex- not very successful,5
7–59
including unsuccessful biomi-
metic attempts by Lawton’s group.6 However, recently
0,61
Zhu and co-workers described an efficient macrocycliza-
SYNTHESIS 2006, No. 23, pp 3997–4004
x
x.
x
x
.
2
0
0
6
tion procedure based on endocyclic alkyl aryl ether bond
Advanced online publication: 02.11.2006
DOI: 10.1055/s-2006-950335; Art ID: T16505SS
Georg Thieme Verlag Stuttgart · New York
41,46,62
formation by a type-D S Ar reaction.
This approach
N
47,62–65
was expanded to other aryl ether macrocycles.
©

3
998
M. de Greef et al.
PAPER
D
C
R4
O
O
R4
Ugi-4CR
element I
reduction
to core
O
O
O
N
O
N
NH
NH
A
B
O
R
N
R
NH
R1
R3
R1
R2
R2
Ugi-4CR
R
1
element II
2
general structure
of 14-membered
cyclopeptide alklaoids
A, B, C, D bonds used
for macrocyclization
B: unidirectional
Ugi-macrocyclization
C: Ugi-4CR followed
by macrocyclization
O
R4
O
O
O
R4
R3
CO2
CN
CN
R3
NH
R2
O
synthons required
for B/C approach
O
NH
R2
R1
R1
Scheme 1 Retrosynthesis and synthons/building blocks required for rapid access to the core structure of 14-membered ansa-cyclopept(o)ids
Despite the impressive achievements, these classical cy- 4CR is normally not sensitive to hydroxy groups, we con-
clization approaches are often characterized by low sidered the use of a type-C cyclization with a suitable phe-
yields, or need additional steps such as reduction of an ac- nol(ate) as functionalized building block to be the most
tivator nitro group, or suffer from limited versatility or ap- straightforward strategy. Recently, Zhu followed a classi-
plicability. They are not useful for rapid automated library cal precursor synthesis to use a type-D cyclization for an
construction. Also, the required linear cyclization precur- intramolecular ring closure of an alkyl aryl ether by an
41
sors are often synthesized by lengthy routes resulting in S Ar reaction. However, this approach is target-oriented
N
low overall yields. Finally, in most cases, there is no flex- and not diversity-oriented and requires more complex
ibility in the choice of starting materials and thus in the building blocks, which had to be prepared in seven steps,
substitution pattern of the generated macrocycle.
instead of two to arrive at the basic skeleton. No literature
precedent for type-C macro-etherification is known for
14-membered ansapeptoids.
A closer look at the general structure of cyclopeptides 1
shows that an Ugi four-component reaction (Ugi-4CR)66
could not only be used to prepare the exocyclic peptide Noncommercial phenol isocyanides such as 6 (Scheme 2)
4
2,44
bonds (cf. Ugi-4CR element I in Scheme 1),
but also are crucial to our approach. Isocyanides are most com-
for the more relevant endocyclic a-acylamino amide moi- monly prepared by dehydration of the corresponding N-
ety with different side-chain functionalities in a highly formamide.66 Isocyanide 6 was obtained by N-formyla-
flexible way (Ugi-4CR element II in Scheme 1).
tion of commercially available tyramine. Protection of the
phenol as acetate and subsequent dehydration with phos-
phoryl chloride gave O-acetyl-6. Finally, mild hydrolysis
of the acetate protective group with commercial two mo-
lar ammonia in methanol gave phenol isocyanide 6 in
69% overall yield. A large selection of the other compo-
nents required, aldehydes 3, amines 4, and carboxylic
acids 5 (Scheme 2), are commercially available and af-
fordable. Further acids 5 with an acceptor group in the b-
position can be prepared straightforwardly, e.g. by a
Baylis–Hillman-type reaction. Thus, the full potential of
the original four-component Ugi reaction is maintained,
and the efficient and highly variable synthesis of libraries
of a-acylamino amides 7 is possible (Scheme 2).
Further retrosynthetic analysis shows that the Ugi-4CR
elements, especially element II, can be used not only to
form the a-acylamino amide, but also to simultaneously
macrocyclize the building blocks, to form the desired 14-
7
,11
membered ansa scaffold 2 in a single shot. For the pro-
duction of libraries, this approach is less useful, since the
original four-component reaction is reduced to a three-
component reaction, limiting the flexibility considerably.
The main problems with this setup, however, are (a) the
instability of the required bifunctional precursor with a
carboxylic acid and isocyanide function in the same mol-
69
6
7
ecule, and (b) the increased strain of the Ugi intermedi-
1
1
ates and transition states en route.
It was envisioned that the subsequent strained macrocy-
clization reaction with a phenolate as nucleophile might
be problematic. Initially, a Michael addition on suitably
functionalized a,b-unsaturated linear dipeptides was con-
sidered. Despite the problem that the phenolate has low
nucleophilicity and is a good leaving group for a retro-re-
action, such an approach seemed possible, since it is be-
More efficiently, the 14-membered ansa scaffold 2 can be
prepared in two consecutive steps, combining the diversi-
ty-generating Ugi-4CR with macrocyclization.7,11,25,68
The versatility of the standard Ugi-4CR can be used to
construct a set of linear dipeptoid precursors. The crucial
step will be an efficient macrocyclization. Since the Ugi-
70
Synthesis 2006, No. 23, 3997–4004 © Thieme Stuttgart · New York

PAPER
Combinatorial Access to Macrocyclic Ansapeptoids and Ansapeptides
3999
HO
O
HO
R
O
R4
4
intramolecular ether R4
bond formation
6
CN
O O
N
X
Ugi-4CR
X
O O
N
R2
NH
+
NH
O
R3
yield
Table 1
yield
OH
R3
R3
R1
R1
NH2
R2
R1
Table 1
R2
5
3
2
7
4
intramolecular
Michael addition
3
4
5
7
a,b
CO2H
CHO
NH3
NH2
a
b
c
CO2H
CHO
CHO
O
O
NH2
CO2H
CO2H
N R2
O
R2
O
Cl
NH2 Br
N
OH
N
HO
d
e
R1
N
R1
Br
CO2H
NH2
Scheme 2 Ugi reaction and subsequent macrocyclization to ansapept(o)ides 2. Boxed drawing: The intrinsic chirality of twisted ansa struc-
1
tures (with R = H) results in the formation of enantiomers if the bridge cannot flip. Amide bonds need to be rigid, and behave like endo double
1
bonds (s-trans tautomeric/mesomeric forms shown for clarity). A stereocenter (R ≠ H) allows diastereomers to be formed (for details, see text).
lieved that the natural cyclopeptide alkaloids are formed To avoid b-elimination or a retro-Michael reaction, a
biogenetically by a decarboxylation–Michael addition se- combination of the two unsuccessful reaction types was
3
3
quence. With isocyanide 6 and a,b-unsaturated acids considered as a solution to obtain the 14-membered core
5
a,b, Ugi-4CRs gave a selection of Michael-acceptor compounds. Thus, linear dipeptide 7d was prepared (55%
dipeptoids like 7a,b (Scheme 2, Table 1) and similar yield) as described above, from 2-(bromomethyl)acrylic
Michael-type precursors in good to excellent yields of up acid (5d), isonitrile 6, aldehyde 3a, and amine 4d
to 98%. Cyclization was attempted under various condi- (Scheme 2). Whereas acids 5a–c generally gave the Ugi
tions. Amides 7a and b derived from cinnamic and phe- products 7 in 80–98% yield, somewhat lower yields re-
nylpropargylic acid, respectively, showed no reaction at sulted with acid 5d (often around 50%). This can be attrib-
all in toluene, tetrahydrofuran, or N,N-dimethylacetamide uted to the strong electrophilic nature of the allyl bromide
(
DMA) under neutral or basic conditions (py, t-BuOK, moiety. The intermediate imine formed from the aldehyde
7
0–72
K CO , DMAP, NMM) at various temperatures.
and amine at the beginning of the reaction is in equilibri-
um with its enamine tautomer, depending on the substitu-
tion pattern. Enamines are susceptible to allylation by 5d,
resulting in undesired side products. Thus, in Ugi reac-
tions with acid 5d, either suitably substituted imines or
acidic conditions should be chosen to favor the direct Ugi
reaction over enamine alkylation.
2
3
These rather disappointing results led us to consider an in-
tramolecular nucleophilic substitution reaction to induce
cyclization. First, the chloro-substituted a-acylamino
amide 7c (X = Cl; R = H) was prepared in 96% yield by
an Ugi-4CR from isopropylamine (4b), isobutyraldehyde
3
(
(
3a), 3-chloropropanoic acid (5c), and isocyanide 6
Scheme 2). Subsequently, an S 2-induced cyclization After deprotonation of the phenolic hydroxy function in
N
was attempted with the use of potassium tert-butoxide, al- the linear dipeptoid 7d, intramolecular nucleophilic sub-
kali carbonates, or 4-(N,N-dimethylamino)pyridine as stitution of bromine resulted in the desired 14-membered
bases. Reactions were performed in N,N-dimethylform- ansa-cyclopeptoid 2a. Several attempts have been made to
amide, N,N-dimethylacetamide (DMA), toluene, or ace- optimize the cyclization yield and to counter the moderate
tone at room and reflux temperatures. Unfortunately, no nucleophilic activity of the phenolate anions. Reactions
cyclization products were isolated, and only b-elimination have been attempted with sodium hydride, potassium tert-
of hydrogen chloride to give the corresponding, unreac- butoxide, or potassium carbonate, each in N,N-dimethyl-
tive a,b-unsaturated amides such as 7c¢ could be detected. formamide, acetone, methanol, or tert-butyl alcohol at
Various other cyclization attempts with compounds 7 room temperature. All experiments were carried out with
3
with R = H and X = Cl, Br, OTs, or OH (Williamson and without a catalytic amount of either potassium iodide
ether synthesis or Mitsunobu reaction) also failed. In con- or 18-crown-6. Finally, the use of a vigorously stirred sus-
trast to this, the reaction of 4-bromocrotonic acid (5e) with pension of potassium carbonate and a catalytic amount of
3
a, 4b, and 6 gave a dipeptoid 7k (60% yield), which 18-crown-6 in acetone proved to be the most successful.
could be cyclized to a 15-membered ansa-cyclopeptide in
5% yield and a dimeric 30-membered compound in 50%
yield (c = 1 mM, K CO , cat. KI, acetone).
In this way, the 14-membered ansa-cyclopeptide 2a could
be isolated in 60% yield under dilution conditions (0.6
mM), to avoid dimer formation. To minimize the required
amount of solvent used, the cyclization reaction was also
2
2
3
Synthesis 2006, No. 23, 3997–4004 © Thieme Stuttgart · New York

4
000
M. de Greef et al.
PAPER
Table 1 Linear Ugi Products 7 Obtained from Isonitrile 6 and Subsequent Macrocyclization of 7d–k to 2a
3
4 \b
Starting material
Product
7a
R1
R2
CR CXR
Yield (%)
3a + 4b + 5a + 6
3a + 4b + 5b + 6
3a + 4b + 5c + 6
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Ph
i-Pr
CH=CHPh
C≡CPh
87
98
96
7b
i-Pr
7c
i-Pr
CH CH Cl
2
2
7
c¢
i-Pr
CH=CH2
3
3
3
3
3
3
3
3
7
7
7
7
7
7
7
7
a + 4b + 5d + 6
7d
7e
7f
i-Pr
C(=CH )CH Br
55
2
2
a + 4e + 5d + 6
CH(i-Pr)Me
H
C(=CH )CH Br
55
2
2
b + 4a + 5d + 6
C(=CH )CH Br
12
2
2
b + 4b + 5d + 6
7g
7h
7i
Ph
i-Pr
C(=CH )CH Br
45
2
2
b + 4c + 5d + 6
Ph
Bn
C(=CH )CH Br
36
2
2
b + 4d + 5d + 6
Ph
i-Bu
i-Pr
C(=CH )CH Br
50
2
2
c + 4b + 5d + 6
7j
Bn
i-Pr
i-Pr
i-Pr
Ph
C(=CH )CH Br
14
2
2
a + 4b + 5e + 6
7k
2a
2b
2c
2d
2e
2f
i-Pr
CH=CHCH Br
60
2
d
e
f
i-Pr
C(=CH )CH
60/95c
19
2
2
2
2
2
2
2
2
CH(i-Pr)Me
H
C(=CH )CH
2
C(=CH )CH
87
2
g
h
i
Ph
i-Pr
C(=CH )CH
30
2
Ph
Bn
C(=CH )CH
24
2
Ph
i-Bu
i-Pr
C(=CH )CH
20
2
j
2g
2k
Bn
i-Pr
C(=CH )CH
mixture
25 (+50d)
2
k
i-Pr
CH=CHCH2
a
b
c
d
All new compounds gave the expected spectroscopic data.
Corresponds to –CHR CHXR for products 7 and –CHR CHR – for products 2.
Optimized macrocyclization conditions applied with pseudodilution.
Dimer.
3
4
3
4
11,
performed under pseudo-dilution, by slow addition (2.5 different a-acylamino amides 7d–j in reasonable to good
–
1
mL·min ) of a rather concentrated solution (50 mM) of yields (Scheme 2, Table 1). Crucial for an efficient Ugi-
linear peptoid 7d to a suspension of potassium carbonate 4CR is the initial formation of an imine intermediate.66
and 18-crown-6 in acetone. The carbonate concentration Optimal yields of linear peptoids 7 were obtained with
proved to be critical: too high concentrations of base re- aldehyde–amine combinations resulting in imine interme-
sulted in complicated product mixtures whereas too low diates less prone to tautomerization to the corresponding
concentrations gave, next to the desired ansa-macrocycle enamines.
2
a, unchanged 7d. However, optimization of the potassi-
Subsequently, all seven linear a-acylamino amides 7d–j
were treated with potassium carbonate and 18-crown-6 as
described above to effect cyclization (Scheme 2, Table 1).
Cyclic ansapeptides 2 generally formed smoothly and in
good yields (up to 95%). The low end is occupied by the
cyclic ansapeptoids 2b, 2f, and 2g (Table 1, <20%), ow-
ing to significant dimer formation (2f) and/or a slow con-
um carbonate content (25 mM in acetone) afforded cyclo-
peptide 2a in 95% isolated yield. In this way, solvent
consumption was reduced tenfold, dimer formation was
negligible, and the conversion was almost quantitative
compared to the outcome of the initial cyclization condi-
tions.
To demonstrate the broader synthetic applicability of this version rate.
highly efficient two-step procedure, seven variably func-
It should also be noted that, depending on the bulkiness of
tionalized macrocyclic ansapeptides were prepared manu-
ally and characterized. Thus, five different amines 4a–e
and three different aldehydes 3a–c reacted with 2-(bro-
momethyl)acrylic acid 5d and isocyanide 6 to give seven
the substituents, some cyclization products form as dia-
stereomers, although the molecules contain only one
asymmetric carbon center (see box in Scheme 2).
Synthesis 2006, No. 23, 3997–4004 © Thieme Stuttgart · New York

PAPER
Combinatorial Access to Macrocyclic Ansapeptoids and Ansapeptides
4001
Through cyclization, a chiral plane forms – despite the electron-impact mass spectra were determined at 70 eV on a MAT
9
00 mass spectrometer. LC-MS was carried out on an API-150 ap-
aryl ring being exclusively 1,4-substituted and able to ro-
tate freely (both rims are equivalent in NMR); i.e., com-
pounds 2 deviate from the usual cyclophane-type planar
chirality. Obviously, the tether is twisted by conforma-
tional ring strain, and chirality results in a way similar to
paratus equipped with an Agilent 1100 LC. Separations were car-
ried out by using gradient elution, initiated with MeCN–H O (1:1).
The MeCN concentration was then increased to 90% over 15 min.
Both solvents contained 0.2% AcOH. The negative, as well as the
positive electrospray mass spectra were recorded, using a turbo ion
2
that observed in trans-cyclooctene, but without a double spray source for ionization. HRMS-spectra were measured on a
bond in the ring in this case. The amide bonds, if seen in Finnigan MAT 90 (EI 70eV or CI with isobutene), or on a Bruker
Apex III FT ion cyclotron resonance (ICR) mass spectrometer
tautomeric and mesomeric forms as shown in the repre-
equipped with an Infinity cell, a 7.0 Tesla superconducting magnet,
sentation, may serve as a substitute. Still, the tethers of the
an RF-only hexapole ion guide, and an external ESI source (Agi-
two conformers can flip: the corresponding planar chiral-
lent, off-axis spray). Some products, if prepared and kept as MeOH
ity has not been reported for similar natural products with
soln for ESI reacted by addition to the acrylamide moiety or substi-
2
1
2
R = H or with small R and R . Molecular modeling tution to the allyl bromide moiety. HPLC other than LC-MS was
2
shows that the tether does not flip over if R can not pass done on a Shimadzu apparatus (Alltima C18 5 u, 100 × 2.1 mm).
1
Separations were carried out by using isocratic elution with MeCN–
through between R and the exo-methylene group. As a
H O (55:45; containing 1% HCO H) at a flow rate of 0.2 mL/min.
consequence, the conformers can not interconvert, and di-
astereomerism results, which, e.g., in the case of 2d al-
lows both isomers to be detected by NMR spectroscopy at
low temperatures. This quite unusual behavior will be elu-
cidated in more detail elsewhere.
2
2
Detection was done with a diode array detector. Analytical TLC
was carried out on precoated plates (Merck TLC aluminum sheets,
silica gel 60 F254, Art. No. 5554) and visualized under UV light
(
254 nm), by treating with either aq KMnO , or cerium-molybdato-
4
phosphate reagent followed by heating. Flash chromatography was
performed on silica gel (Merck 60, 230–400 mesh). PE (bp 40–
2
Another special case is 2c (R = H; from 7f in 87% yield),
6
0 °C) was used. Whenever a cyclization was performed under
pseudo-diluted conditions, a syringe pump (SAGE instruments –
41B) was used to maintain constant flow and tin-foil-wrapped sy-
ringes (BD-Plastipack) were equipped with inert peek-tubing
obtained by the direct use of ammonia in the Ugi-4CR,
commonly a difficult problem. Initially, we tried to use 4-
methoxyaniline as a masked ammonia equivalent, but this
3
resulted in complex mixtures (enamine formation). The (0.010 in/0.25 mm) to prevent the reagent from degrading by expo-
direct use of ammonia was more successful in our system, sure to UV light.
although the conditions had to be modified to avoid hemi-
aminal formation, which happens by condensation of an
initially formed benzylidene amine, reaction with the al-
cohol solvent and then with excess benzaldehyde before
Compounds 7 by Ugi-4CR; General Procedure
Freshly distilled amine 4 (2 equiv) and aldehyde 3 (2 equiv) were
added to MeOH (final c = 1 M) and the mixture was stirred for 60
min at r.t. in the presence of a drying agent (Na SO ). Then acid 5
2
4
the Ugi reaction starts. This side reaction can be reduced (1 equiv) was added and stirring continued for another 30 min (or
if an excess of an ammonium salt in a solvent other than shorter for 5d), after which isocyanide 6 (1 equiv) was added. Most-
ly, reactions were completed after 2 h at r.t. (by TLC, EtOAc–
CHCl , 1:1 or EtOAc–PE, 2:1). The mixture was poured into H O
3 2
an alcohol is used. The thus directly accessible ‘normal’
dipeptide bond (R = H) is of great importance for natural
cyclopeptide alkaloids, where N-substitution of the en-
docyclic amide bond is not common and planar chirality
is not described.
2
(50 mL) and extracted with EtOAc (3 × 25 mL). Isolation of the re-
action products was usually by evaporation of excess solvent and
reagents. After flash chromatography, the Ugi products 7 could be
isolated and characterized (see below for selected examples). The
acceptor-substituted allylic bromides are of limited stability, espe-
cially in the presence of nucleophiles such as MeOH (e.g., before
chromatography, on extended storage, or when used in MeOH in
ESI-MS).
In conclusion, we have developed a highly efficient, ex-
tremely short, and flexible two-step route to macrocyclic
ansapeptoids and peptides amenable to automated synthe-
2
sis. Macrocyclic dipeptides (R = H) prepared in this way
are suitable for further synthetic elaboration toward natu- Ugi Product 7a
ral cyclopeptide alkaloids. In addition, the method allows R = 0.50, 0.59 (EtOAc–CHCl , 1:1).
f
3
rapid access to libraries of variably substituted natural-
t = 3.66, 4.44 min (MeCN–1% HCO H in H O, 55:45).
R
2
2
product-like ansa scaffolds with additional functionalities
1
H NMR (400 MHz, CDCl ): d = 0.49 (d, J = 6.8 Hz, 3 H), 0.58 (d,
2
3
(
e.g., R or with other hydroxy isonitrile building blocks),
J = 6.8 Hz, 3 H), 0.74 (d, J = 6.5 Hz, 3 H), 0.77 (d, J = 6.5 Hz, 3 H),
0
or new orientation, or a rare form of planar chirality.
.86 (d, J = 6.6 Hz, 3 H), 0.88 (d, J = 6.6 Hz, 3 H), 0.93 (d, J = 6.6
Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H), 2.65–2.74 (m, 4 H), 2.80–2.87
(
(
m, 2 H), 3.00 (t, J = 11.1 Hz, 2 H), 3.20–3.28 (m, 2 H), 3.51–3.60
m, 2 H), 3.85–3.92 (m, 2 H), 5.12 (s, 1 H), 5.16 (s, 1 H), 5.33 (s, 1
All glassware was flame-dried prior to use. All reagents and sol-
vents were purchased from commercial sources and used as sup-
plied or purified by standard methods. Preparations were carried out
H), 5.41 (s, 1 H), 5.48 (s, 1 H), 5.59 (s, 1 H), 6.76–6.80 (m, 4 H),
7
8
.05–7.08 (m, 4 H), 7.17–7.29 (m, 10 H), 8.27 (t, J = 5.4 Hz, 1 H),
.34 (t, J = 8.4 Hz, 1 H).
under a N atmosphere.
2
1H NMR spectra were recorded in the specified solvents on a Bruker
spectrometer at 200 MHz or at 400 MHz operating at ambient probe
temperature unless stated otherwise. Coupling constants were mea-
1
3
C NMR (100 MHz, CDCl ): d = 20.3, 20.3, 20.6, 20.6, 20.7, 20.8,
3
2
7
0.8, 20.9, 27.3, 27.4, 35.2, 41.3, 41.4, 52.8, 53.2, 68.7, 68.7, 74.7,
7.0, 112.5, 116.0 (2 C), 116.1 (2 C), 116.4, 126.3 (2 C), 126.8 (2
13
sured in Hertz (Hz). C NMR spectra were recorded in the specified
solvents on a Bruker spectrometer at 50 MHz or at 100 MHz oper-
ating at ambient probe temperature unless stated otherwise. NMR
assignments were based on 2D NMR experiments. Low-resolution
C), 128.4 (2 C), 128.7 (2 C), 128.9 (2 C), 129.1 (2 C), 130.1 (2 C),
1
1
30.2 (2 C), 130.6, 140.9, 141.2, 145.7, 147.4, 155.5, 155.6, 173.0,
73.3, 173.4, 173.7.
Synthesis 2006, No. 23, 3997–4004 © Thieme Stuttgart · New York

4
002
M. de Greef et al.
PAPER
ESI-MS: m/z = 439.4 [MH+].
13
C NMR (100 MHz, CDCl ): d = 21.0, 21.5, 33.4, 34.5, 41.3, 51.4,
3
6
2.2, 115.4 (2 C), 117.3, 127.7, 128.0 (2 C), 128.8 (2 C), 129.6 (2
Ugi Product 7d
C), 130.0, 136.1, 140.4, 154.8, 170.0, 170.2.
R = 0.67 (EtOAc–CHCl , 1:1).
f
3
ESI-MS: m/z = 459.4 [M + 1].
1
H NMR (400 MHz, CDCl ): d = 0.84 (d, J = 6.6 Hz, 3 H), 0.92 (d,
3
J = 6.6 Hz, 3 H), 1.16–1.18 (m, 6 H), 2.67–2.75 (m, 2 H), 2.86–2.92
m, 1 H), 3.21 (d, J = 11.1 Hz, 1 H), 3.41–3.54 (m, 2 H), 4.00 (d,
J = 10.3 Hz, 1 H), 4.33–4.42 (m, 2 H), 5.17 (s, 1 H), 5.45 (s, 1 H),
Ugi Product 7h
(
R = 0.32 (EtOAc–CHCl , 1:1).
f
3
t = 6.06 min (MeCN–1% HCO H in H O, 55:45).
R
2
2
6
8
.75 (d, J = 8.4 Hz, 2 H), 7.03 (d, J = 8.4 Hz, 2 H), 7.30 (br s, 1 H),
.45 (t, J = 5.5 Hz, 1 H).
1
H NMR (400 MHz, CDCl , 330 K): d = 2.61–2.65 (m, 2 H), 3.36–
3
3
4
.49 (m, 2 H), 4.10 (d, J = 10.2 Hz, 1 H), 4.39 (d, J = 10.4 Hz, 1 H),
.51 (d, J = 16.5 Hz, 1 H), 4.90 (d, J = 16.5 Hz, 1 H), 5.21 (br s, 1
1
3
C NMR (100 MHz, CDCl ): d = 19.9, 20.3, 20.5, 21.1, 27.0, 33.0,
3
3
1
4.9, 40.7, 52.3, 68.5, 115.4 (2 C), 116.9, 129.6 (2 C), 130.0, 141.1,
55.1, 171.2, 173.5.
H), 5.38 (s, 1 H), 5.46 (s, 1 H), 5.73 (br s, 1 H), 6.69 (d, J = 8.5 Hz,
2
H), 6.87 (d, J = 8.5 Hz, 2 H), 7.15–7.27 (m, 10 H).
ESI-MS: m/z = 425.1 [MH+].
13
C NMR (100 MHz, CDCl , 330 K): d = 33.2, 34.4, 41.2, 51.7,
3
6
1
1
5.9, 115.7 (2 C), 118.7, 119.0, 127.3 (2 C), 128.5 (2 C), 128.7,
28.9 (2 C), 129.5 (2 C), 129.6 (2 C), 130.0, 134.5, 136.8, 139.9,
55.0, 169.1, 170.9.
Ugi Product 7e
R = 0.75 (EtOAc–CHCl , 1:1).
f
3
t = 6.91, 7.32 min (MeCN–1% HCO H in H O, 55:45).
R
2
2
1
Ugi Product 7i
H NMR (400 MHz, CDCl ): d = 0.78–0.94 (m, 24 H), 1.17 (d,
3
R = 0.57 (EtOAc–CHCl , 1:1).
f
3
J = 7.0 Hz, 3 H), 1.20 (d, J = 6.6 Hz, 3 H), 1.89–1.93 (m, 2 H),
2
3
(
(
(
(
1
1
.70–2.75 (m, 4 H), 2.88 (m, 2 H), 3.17 (d, J = 11.1 Hz, 1 H),
.31(d, J = 10.8 Hz, 1 H), 3.42–3.50 (m, 4 H), 3.64 (m, 1 H), 3.86
H NMR (400 MHz, DMSO-d ): d = 0.42 (br s, 3 H), 0.62 (d, J = 6.7
6
Hz, 3 H), 1.03 (br s, 1 H), 2.60 (t, J = 7.1 Hz, 2 H), 3.07 (m, 1 H),
3.29–3.35 (m, 3 H), 4.32 (d, J = 6.9 Hz, 1 H), 4.40 (d, J = 10.2 Hz,
1 H), 5.11 (br s, 1 H), 5.65 (d, J = 15.1 Hz, 2 H), 6.65 (d, J = 8.3 Hz,
2 H), 6.96 (d, J = 8.3 Hz, 2 H), 7.29–7.49 (m, 5 H), 8.12 (br s, 1 H),
9.14 (br s, 1 H).
m, 1 H), 3.97 (d, J = 10.6 Hz, 1 H), 4.03 (d, J = 11.0 Hz, 1 H), 4.22
d, J = 11.0 Hz, 1 H), 4.31 (d, J = 10.6 Hz, 1 H), 5.24 (s, 1 H), 5.34
s, 1 H), 5.51 (s, 1 H), 5.62 (s, 1 H), 6.75 (d, J = 8.2 Hz, 4 H), 7.03
d, J = 8.2 Hz, 4 H), 8.26 (br s, 1 H), 8.72 (br s, 1 H).
3
13
C NMR (100 MHz, CDCl ): d = 17.2, 17.8, 19.4, 19.9, 20.0, 20.35,
C NMR (100 MHz, DMSO-d ): d = 20.0, 20.1, 26.9, 34.0, 34.2,
3
6
2
4
0.43, 20.8, 20.9, 21.8, 27.0, 28.3, 31.2, 31.6, 31.8, 32.9, 34.6, 34.7,
0.6, 40.9, 62.4, 63.1, 69.3, 69.7, 115.4 (4 C), 118.6, 120.2, 129.6
40.4, 51.0, 64.3, 115.0 (2 C), 118.2, 128.2, 128.4 (2 C), 129.2, 129.4
(2 C), 129.5 (2 C), 136.3, 140.1, 155.6, 169.0, 169.4.
ESI-MS: m/z = 473.3 [MH+].
(
4 C), 130.0, 130.1, 141.0, 141.1, 155.0 (2 C), 171.5, 172.3, 172.7,
74.1.
1
ESI-MS: m/z = 453.2 [MH+].
Compounds 2 by Cyclization of 7d–j; General Procedure
+
To a suspension of commercial, dry K
2 3
CO (70 mg, 0.50 mmol) and
ESI-HRMS: m/z [M – Br + OMe + Na] calcd for C H N O Na:
2
3
36
2
4
1
8-crown-6 (20 mg) in dry acetone (20 mL) was added a 50 mM
4
27.25673; found: 427.25675.
soln of 7 in acetone (2.5 mL) over 18 h by a syringe pump. Then
H O (25 mL) was added and the aqueous mixture was extracted
2
Ugi Product 7f
with CHCl (3 × 30 mL). The combined organic layers were washed
3
R = 0.51 (EtOAc–CHCl , 1:1).
f
3
with brine (25 mL) and dried (Na SO ). The solvents were evapo-
2
4
t = 3.38 min (MeCN–1% HCO H in H O, 55:45).
R
2
2
rated at 40 °C under reduced pressure. The crude reaction product
1
was purified by flash chromatography (silica gel, MeOH–CHCl ,
H NMR (400 MHz, CDCl ): d = 2.54–2.65 (m, 4 H), 3.29–3.42 (m,
3
3
7
3
5
:95); this gave pure 2. The less sterically hindered derivatives,
3
4
H), 3.49 (s, 3 H), 3.50–3.55 (m, 1 H), 4.11 (d, J = 10.6 Hz, 1 H),
.17 (d, J = 10.8 Hz, 1 H), 4.20 (d, J = 10.8 Hz, 1 H), 4.67 (d,
e.g. 2c, slowly react with nucleophiles, e.g. MeOH (e.g., when used
in MeOH in ESI-MS).
J = 10.5 Hz, 1 H), 4.82 (s, 1 H), 5.43 (d, J = 6.5 Hz, 1 H), 5.72 (s, 1
H), 5.73 (s, 1 H), 5.77 (s, 1 H), 5.84 (t, J = 5.5 Hz, 1 H), 5.89 (s, 1
H), 6.03 (t, J = 5.8 Hz, 1 H), 6.19 (s, 1 H), 6.65 (dd, J = 2.0, 8.4 Hz,
Ansapeptoid 2a
R = 0.37 (EtOAc–CHCl , 1:1).
4
H), 6.75 (d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2 H), 6.87–7.33
f
3
(
m, 15 H), 7.51 (d, J = 6.5 Hz, 1 H).
1
H NMR (400 MHz, CDCl ): d = 0.87–1.26 (m, 24 H), 2.22–2.29
3
1
3
(m, 1 H), 2.33–2.42 (m, 2 H), 2.50–2.57 (m, 1 H), 2.92–3.01 (m, 2
H), 3.07–3,25 (m, 5 H), 3.27–3.36 (m, 1 H), 4.32–4.51 (m, 4 H),
C NMR (100 MHz, CDCl ): d = 30.0, 33.0, 34.5 (2 C), 41.3, 41.4,
3
5
5.9, 57.5, 63.0, 89.5, 115.4 (2 C), 115.6 (2 C), 120.6, 123.5, 127.2
4
5
6
.67 (d, J = 12.1 Hz, 1 H), 4.82 (d, J = 11.9 Hz, 1 H), 5.20 (s, 1 H),
.21 (s, 1 H), 5.40 (s, 1 H), 5.42 (s, 1 H), 6.73 (d, J = 8.6 Hz, 4 H),
.92 (d, J = 8.6 Hz, 2 H), 6.98 (d, J = 8.4 Hz, 2 H), 8.28 (br s, 2 H).
(
2 C), 127.3 (2 C), 127.6, 128.2 (2 C), 128.5 (2 C), 128.6, 128.9 (2
C), 129.1 (2 C), 129.7 (2 C), 129.7 (2 C), 130.8, 135.2, 135.9, 137.6,
39.9, 140.6, 154.6, 154.8, 165.4, 169.3, 169.6, 170.5.
1
1
3
+
C NMR (100 MHz, CDCl ): d = 20.0 (2 C), 20.3 (2 C), 20.4 (2 C),
ESI-MS: m/z = 417.4 [MH ], 537.6 [M + 1].
3
2
1.27, 21.33, 22.6, 26.8 (2 C), 31.6, 34.1, 34.5, 39.9, 40.2, 52.3 (2
C), 68.6, 68.7, 68.8, 69.1, 114.2, 114.3, 129.4 (2 C), 129.5 (2 C),
31.8, 131.9, 141.8, 141.8, 156.7, 156.8, 171.8, 171.9, 173.2 (2 C).
MS (EI): m/z = 344 [M+].
Ugi Product 7g
1
R = 0.38 (EtOAc–CHCl , 1:1).
f
3
1
H NMR (400 MHz, CDCl ): d = 1.07 (d, J = 6.6 Hz, 3 H), 1.39 (d,
3
J = 6.6 Hz, 3 H), 2.63–2.68 (m, 2 H), 3.41–3.48 (m, 2 H), 4.16 (d,
J = 10.2 Hz, 1 H), 4.31 (d, J = 10.2 Hz, 1 H), 4.57 (br s, 1 H), 4.84
Ansapeptide 2c
t = 13.24, 14.23 min (MeCN–1% HCO H in H O, 55:45).
(
br s, 1 H), 5.34 (s, 1 H), 5.50 (s, 1 H), 6.44 (br s, 1 H), 6.66 (d,
R
2
2
J = 8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 7.27–7.32 (m, 5 H).
1
H NMR (400 MHz, DMSO-d ): d = 2.60–2.65 (m, 2 H), 2.72–2.78
6
(
m, 2 H), 3.09–3.49 (m, 4 H), 4.67–4.79 (m, 4 H), 5.48 (d, J = 8.2
Hz, 1 H), 5.52 (d, J = 8.2 Hz, 1 H), 5.77 (s, 1 H), 6.06 (s, 1 H), 6.07
Synthesis 2006, No. 23, 3997–4004 © Thieme Stuttgart · New York

PAPER
Combinatorial Access to Macrocyclic Ansapeptoids and Ansapeptides
4003
(
s, 1 H), 6.78–6.83 (m, 4 H), 7.04–7.07 (m, 4 H), 7.21–7.45 (m, 10
(2) Newman, D. J.; Cragg, G. M.; Snader, K. M. J. Nat. Prod.
2003, 66, 1022.
H), 8.13 (t, J = 5.5 Hz, 1 H), 8.21 (t, J = 5.5 Hz, 1 H), 8.38–8.42 (m,
2
H).
(3) Henkel, T.; Brunne, R. M.; Mueller, H.; Reichel, F. Angew.
Chem. Int. Ed. 1999, 38, 643; Angew. Chem. 1999, 111, 688.
1
3
C NMR (100 MHz, DMSO-d ): d = 33.4 (2 C), 39.4 (2 C), 56.5 (2
6
(4) Lee, M.-L.; Schneider, G. J. Comb. Chem. 2001, 3, 284.
(5) Rouhi, A. M. Chem. Eng. News 2003, 81 (41), 77.
(6) Fehler, M.; Schmidt, J. M. J. Chem. Inf. Comput. Sci. 2003,
C), 67.1 (2 C), 114.5 (4 C), 122.9, 127.0 (4 C), 128.2 (4 C), 129.8
(
4 C), 131.9 (2 C), 137.3 (2 C), 138.6 (2 C), 139.1 (2 C), 156.3 (2
C), 165.1 (2 C), 169.5 (2 C).
MS (EI): m/z = 336 [M+].
4
3, 218.
7) Wessjohann, L. A.; Ruijter, E. Top. Curr. Chem. 2005, 243,
37.
8) Breinbauer, R.; Vetter, I. R.; Waldmann, H. Angew. Chem.
Int. Ed. 2002, 41, 2878; Angew. Chem. 2002, 114, 3002.
(
(
1
Ansapeptoid 2d
Rf = 0.28 (EtOAc–MeOH, 19:1).
1
(9) Breinbauer, R.; Manger, M.; Scheck, M.; Waldmann, H.
Curr. Med. Chem. 2002, 9, 2129.
10) Walsh, C. T. Science 2004, 303, 1805.
11) Wessjohann, L. A.; Ruijter, E. Mol. Diversity 2005, 9, 159.
12) Wessjohann, L. A. Curr. Opin. Chem. Biol. 2000, 4, 303.
13) Ortholand, J. Y.; Ganesan, A. Curr. Opin. Chem. Biol. 2004,
H NMR (400 MHz, CDCl ): d = 1.30 (d, J = 6.0 Hz, 6 H), 2.54 (m,
3
1
4
H), 2.63–2.69 (m, 1 H), 3.30–3.40 (m, 1 H), 3.40–2.59 (m, 1 H),
.44 (d, J = 12.4 Hz, 1 H), 4.56 (br s, 1 H), 4.65 (d, J = 12.1 Hz, 1
(
(
(
(
H), 4.97 (br s, 1 H), 5.28 (s, 1 H), 5.44 (s, 1 H), 6.66 (d, J = 7.6 Hz,
2
H), 6.98 (d, J = 8.3 Hz, 2 H), 7.23–7.33 (m, 5 H), 7.69 (br s, 1 H).
1
3
C NMR (100 MHz, CDCl ): d = 20.6, 21.3, 34.4, 40.5, 51.9, 62.9,
9.0, 114.4 (2 C), 115.0, 126.3, 127.4, 128.4, 128.7, 129.7 (2 C),
31.9, 136.1, 141.3, 156.6, 170.5, 170.8, 171.4.
3
8, 271.
6
1
(
(
14) Nielsen, J. Curr. Opin. Chem. Biol. 2003, 6, 297.
15) Brohm, D.; Metzger, S.; Bhargava, A.; Müller, O.; Lieb, F.;
Waldmann, H. Angew. Chem. Int. Ed. 2002, 41, 307; Angew.
Chem. 2002, 114, 319.
16) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
17) Rose, G. D.; Gierasch, L.; Smith, J. A. Turns in Peptides and
Proteins, In Advances in Protein Chemistry, Vol. 37;
Academic: New York, 1985, 1.
18) Gibson, C.; Sulyok, G.; Schmitt, J. S.; Dechantsreiter, M. A.;
Haubner, R.; Hölzemann, G.; Goodman, S. L.; Kessler, H.
From Proteins to Drugs: The RGD Story, The 8th Akabori
Conference, Japanese–German Symposium on Peptide
Science, Nagoya, Japan, 2000.
(19) Giannis, A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993,
32, 1244; Angew. Chem. 1993, 105, 1303.
(20) Park, C.; Burgess, K. J. Comb. Chem. 2001, 3, 257.
21) McDonald, M.; Aube, J. Curr. Org. Chem. 2001, 5, 417.
22) Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789.
(23) Westermann, B.; Diedrichs, N.; Krelaus, R.; Walter, A.;
Gedrath, I. Tetrahedron Lett. 2004, 45, 5983.
(24) Kruijtzer, J. W. A.; Liskamp, R. M. J. Tetrahedron Lett.
1995, 36, 6969.
MS (EI): m/z = 378.2 [M+].
HRMS: m/z [M]+ calcd for C H N O : 378.1943; found:
2
3
26
2
3
(
(
3
78.1944.
Ansapeptoid 2e
t = 32.69, 36.17 min (MeCN–1% HCO H in H O, 55:45).
R
2
2
(
1
H NMR (400 MHz, DMSO-d , 330 K): d = 2.44–2.73 (m, 4 H),
6
3
.03–3.57 (m, 4 H), 4.39–4.43 (m, 2 H), 4.55–4.69 (m, 4 H), 4.78–
.83 (m, 2 H), 5.18 (s, 1 H), 5.23 (s, 1 H), 5.38 (s, 1 H), 5.39 (s, 1
4
H), 5.74 (s, 1 H), 5.77 (s, 1 H), 6.65–7.23 (m, 28 H), 7.77 (br s, 2 H).
1
3
C NMR (100 MHz, DMSO-d , 330 K): d = 33.6, 39.7, 63.2, 67.9,
14.6 (2 C), 115.7, 126.7 (4 C), 127.5 (2 C), 127.9, 128.3 (2 C),
29.0, 129.5 (2 C), 131.7, 135.8, 138.4, 141.0, 156.4, 169.0, 170.9.
6
1
1
(
(
MS (EI): m/z = 426 [M+].
+
ESI-HRMS: m/z [M + MeOH + Na] calcd for C H N O Na:
4
2
8
30
2
4
81.2103; found: 481.21085.
Ansapeptoid 2f
Rf = 0.41 (EtOAc–MeOH, 19:1).
1
(25) Hebach, C.; Kazmaier, U. Chem. Commun. 2003, 596.
H NMR (400 MHz, CDCl ): d = 0.79–0.82 (m, 6 H), 1.89 (br s, 1
3
(
26) Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 125.
H), 2.65–2.76 (m, 2 H), 3.22–3.31 (m, 1 H), 3.41–3.52 (m, 3 H),
4
6
(27) Kerr, J. S.; Mousa, S. A.; Slee, A. M. Drug News Perspect.
.51–4.66 (m, 2 H), 5.31 (m, 2 H), 5.53 (s, 1 H), 6.69–6.74 (m, 2 H),
.96–7.00 (m, 2 H), 7.29 (d, J = 9.2 Hz, 5 H).
2
001, 14, 143.
(
28) van Loevezijn, A.; van Maarseveen, J. H.; Stegman, K.;
1
3
C NMR (100 MHz, CDCl ): d = 20.3, 20.5, 27.8, 34.7, 41.0, 59.2,
3
Visser, G. M.; Koomen, G.-J. Tetrahedron Lett. 1998, 39,
6
1
7.2, 69.7, 115.1 (2 C), 117.6, 128.6 (2 C), 128.9 (2 C), 130.2 (2 C),
32.0, 135.6, 135.66, 141.1, 157.3, 170.2, 171.7.
4737.
(
29) Zuckermann, R. N.; Martin, E. J.; Spellmeyer, D. C.;
Stauber, G. B.; Shoemaker, K. R.; Kerr, J. M.; Figliozzi, G.
M.; Goff, D. A.; Siani, M. A.; Simon, R. J.; Banville, S. C.;
Brown, E. G.; Wang, L.; Richter, L. S.; Moos, W. H. J. Med.
Chem. 1994, 37, 2678.
MS (EI): m/z = 392 [M+].
HRMS: m/z [M]+ calcd for C H N O : 392.2100; found:
2
4
28
2
3
3
92.2102.
+
ESI-HRMS: m/z [M + Na] calcd for C H N O Na: 807.4092;
found: 807.4083.
(30) Horwell, D. C. Trends Biotechnol. 1995, 13, 132.
2
48 56
4
6
(
(
(
(
31) Burger, K.; Böttcher, C.; Radics, R.; Henning, L.
Tetrahedron Lett. 2001, 42, 3061.
32) Special issue: Peptide Libraries and Peptide Drugs, Mol.
Diversity 2004, 8, 57–174
33) Gournelis, D. C.; Laskaris, G. G.; Verpoorte, R. Nat. Prod.
Rep. 1997, 14, 75; and ref. 74c.
34) Morel, A. F.; Machado, E. C. S.; Moreira, J. J.; Menezes, A.
S.; Mostardeiro, M. A.; Wessjohann, L. A. Phytochem.
1998, 47, 125.
Acknowledgement
We thank the DFG and NWO for financial support as part of a
CERC3 grant.
References
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(
1) Wessjohann, L. A.; Ruijter, E.; Garcia-Rivera, D.; Brandt,
Phytochem. 1995, 39, 431.
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Synthesis 2006, No. 23, 3997–4004 © Thieme Stuttgart · New York

4
004
M. de Greef et al.
PAPER
(
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2
(
37) Giacomelli, S. R.; Maldaner, G.; Gonzaga, W. A.; Garcia, C.
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4
3
(67) As an example, a derivative with R = Ph and R = H
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stored under an argon atmosphere (see ref. 71). A similar
frame-shifted approach to form the macrocyclic ring via
Ugi-4CR to form moiety I resulted in dimeric structures,
possibly 28-membered rings (see ref. 11).
4
45) Owens, T. D.; Araldi, G.-L.; Nutt, R. F.; Semple, J. E.
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manuscript submitted.
(
48) An unusual C–C-bond-forming aldol macrocyclization was
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(
(
(
(
(
(
(
(
(
49) Frappier, F.; Rocchiccioli, F.; Jarreau, F.-X.; Pais, M.
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(71) Abeln, S. Master Thesis; Vrije Universiteit Amsterdam: The
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(72) Later, the Zhu group in their conventional S Ar approach
N
could prove that the retro-Michael reaction is, indeed,
favored (see ref. 41). In an early work, Schmidt could show
for his related system that sulfide formation occurs by this
approach, but ether formation not (see refs. 58, 59).
1
54) Schmidt, U.; Weinbrenner, S. J. Chem. Soc., Chem.
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1
(73) Broad signals in the H NMR spectrum and the presence of
1
3
additional signals in the C NMR spectrum suggest
coexisting conformers. Spectral data refer to major isomer.
(74) Some recent relevant references (added in proof):
(a) Cristau, P.; Vors, J.-P.; Zhu, J. QSAR & Comb. Sci. 2006,
25, 519. (b) Cristau, P.; Temol-Laib, T.; Bois-Choussy, M.;
Martin, M.-T.; Vors, J.-P.; Zhu, J. Chem. Eur. J. 2005, 11,
2668. (c) Tan, N.-H.; Zhou, J. Chem. Rev. 2006, 106, 840.
(
58) Schmidt, U.; Prantz, E. Angew. Chem., Int. Ed. Engl. 1977,
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