T3P-Promoted, Mild, One-Pot Syntheses of Constrained Polycyclic Lactam Dipeptide Analogues via Stereoselective Pictet-Spengler and Meyers Lactamization Reactions

Article abstract of DOI:10.1021/acs.orglett.5b02145

A new convenient, mild, one-pot procedure is described for the diastereoselective synthesis of constrained 7,5- and 7,6-fused azabicycloalkanes. Using 2-formyl-L-tryptophan and 2-formyl-l-phenylalanine as bielectrophilic building blocks, T3P-mediated Pict

Full text of DOI:10.1021/acs.orglett.5b02145

Letter
pubs.acs.org/OrgLett
T3P-Promoted, Mild, One-Pot Syntheses of Constrained Polycyclic
Lactam Dipeptide Analogues via Stereoselective Pictet−Spengler
and Meyers Lactamization Reactions
,
†
†
†
‡
Mouhamad Jida,* Olivier Van der Poorten, Karel Guillemyn, Zofia Urbanczyk-Lipkowska,
†
,†
́
Dirk Tourwe, and Steven Ballet*
†Research Group of Organic Chemistry, Departments of Chemistry and Bio-Engineering Sciences, Vrije Universiteit Brussel,
Pleinlaan 2, B-1050 Brussels, Belgium
‡
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka Strasse 44/52, 01-224 Warsaw, Poland
*
S Supporting Information
ABSTRACT: A new convenient, mild, one-pot procedure is described for the diastereoselective synthesis of constrained 7,5-
and 7,6-fused azabicycloalkanes. Using 2-formyl-L-tryptophan and 2-formyl-L-phenylalanine as bielectrophilic building blocks,
T3P-mediated Pictet−Spengler and Meyers lactamization reactions were developed to present chiral and polycyclic aminoindolo-
and aminobenzazepinone compounds in excellent yields. The conformationally constrained compounds can serve as templates
for peptidomimetic research or polyheterocyclic privileged scaffolds.
used bicyclic lactam azabicyclo[x.y.z]alkane scaffolds are
found in many natural products and serve as inter-
1
F
mediates in the preparation of molecules possessing interesting
2
biological activities. Additionally, peptide derivatives incorpo-
rating cyclic or bicyclic lactams are widely used for constraining
main chain dihedral angles. These lactams can potentially force
3
a peptide chain to adopt reverse-turn conformations as was
demonstrated for the “bicyclic turned dipeptide” (BTD)
4
azabicyclo[x.y.0]alkane amino acids 1 (Figure 1). These
fused bi- or polycyclic lactams of different ring size (5,4- to
7
,6-fused bicyclic lactams) have been used with success in the
5,6
field of peptide mimicry. Hence, the design and synthesis of
new constrained polycyclic lactams for peptidomimetic
purposes is a topic of considerable interest in medicinal
chemistry. Unfortunately, most of the reported methods for the
synthesis of these privileged templates suffer from poor
diastereoselectivity, which requires chromatographic separation,
and a multistep synthetic strategy.
Figure 1. Azabicyclo[x.y.0]alkane amino acids 1−3.
8
−11
been reported in various medicinal chemistry applications.
Therefore, it was highly desirable to develop short, efficient,
and diastereoselective procedures toward novel 7,5-fused
indolo- and benzazepinone amino acids 2 and 3 (X = S, O).
In addition, mild conditions that could accommodate substrates
Previously, our group reported that tetrahydro-4-amino-
azepinones, derived from amino acids such as phenylalanine
and tryptophan, could also serve as “privileged scaffolds” since
their use resulted in a range of highly potent G protein-coupled
7
receptor ligands. The corresponding 7,5- and 7,6-fused indolo-
Received: July 24, 2015
and benzoazepinones 2 and 3 (Figure 1, X = CH ) have also
2
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02145
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bearing acid- and base-sensitive functional groups are important
(full conversion, 87% isolated yield, > 98% de) in a sealed vial
which was placed in an oil bath (Scheme 1). Only a single
diastereomer was observed, isolated, and characterized as the
isomer having a (S)-configuration of the newly formed
(
Figure 1).
12
13
Pictet−Spengler reactions and Meyers lactamizations are
typical bielectrophile−binucleophile reactions that produce new
stereogenic centers. Recently, we reported several modifications
to common synthetic protocols of the Meyers and Pictet−
Spengler lactamizations for the diastereoselective formation
of 5,5-, 6,5-, and 6,6-fused bicyclic lactams under milder
conditions via solvent- and catalyst-free microwave-assisted
condensation by using enantiopure amino alcohols or amino-
indoles and γ- or δ- keto acids.
1
stereogenic center by 2D H NOESY studies. This result is
14
21
22
consistent with those reported by Amat and Allin for the
stereoselective Meyers lactamization in the case of δ-oxo acids
as bielectrophilic starting material.
15
To explore the substituent scope of this methodology, 4a was
condensed with L-cysteine methyl ester to give 5b in good yield
and high diastereomeric excesses (81% isolated yield, > 98%
de). Furthermore, oxazololactam 5c was prepared as a mixture
of diastereoisomers (34% de) in excellent yield (91%) by
cyclodehydration of a chiral L-serine methyl ester with 4a.
Whereas 5c could not be separated from its epimer 5c′, the
corresponding methylamides 5d and 5d′ were isolated by
column chromatography and used for a NMR study (vide
infra).
Levacher independently developed a one-pot Meyers
lactamization, promoted by pivalic acid under microwave
irradiation (150 °C, 2−10 h), leading to axially chiral 7,5-
fused lactams from biaryl precursors with moderate to good
16
yields and high diastereomeric excesses. Unfortunately, these
acidic conditions are not compatible with acid-labile function-
alities.
As a continuation of our efforts in peptidomimetic design, it
was proposed that the 7,5- and 7,6-fused bicyclic lactam
scaffolds 2 and 3 (X = S, O) could be synthesized via Meyers
For the synthesis of fused oxazolo- and thiazolobenzazepi-
nones 6a−d, the stereoselective Meyers’ cyclocondensation
reaction of N-Phth-2-formyl-L-Phe-OH (4b) with (S)-phenyl-
glycinol, under the optimized conditions, gave access to a
mixture of separable diastereoisomers 6a (72% isolated yield, >
98% de) and 6a′ (21% isolated yield, > 98% de), respectively
(Scheme 2). The relative stereochemistry of the major isomer
17
lactamizations using N-Boc-2-formyl-L-Trp-OH (4a) and N-
18
Phth-2-formyl-L-Phe-OH (4b) as bielectrophiles.
In order to find the best reaction conditions for the synthesis
of fused oxazoloindoloazepinone derivatives 5a−c as a
prototype of the Meyers reaction (Scheme 1), N-Boc-2-
Scheme 2. Synthesis of 7,5-Fused Oxazolo- and
a
Scheme 1. Synthesis of 7,5-Fused Oxazolo- and
Thiazoloindoloazepinones 5a−c
Thiazolobenzazepinones 6a−d
formyl-L-Trp-OH (4a) and (S)-phenylglycinol were chosen as
model substrates. In our initial investigations, classic dehydrat-
ing conditions were applied by conventional heating in toluene
for 24 h, with azeotropic removal of water, and in the presence
or absence of an acid catalyst (AcOH, TFA, PTSA).
Unfortunately, this mainly led to substrate degradation.
Moreover, under mild microwave irradiation no conversion of
the model keto acid 4a in the presence of (S)-phenylglycinol
was observed at 110 °C (5−120 min). In search of milder
lactamization conditions, the reaction was performed with 1−2
a
Overlay of the X-ray structure of 6c (yellow) and the predicted
lowest energy conformer of its N-acetyl N′-methylamide tetrapeptide
model (cyan) is shown.
19
equiv of commercially available propylphosphonic anhydride
T3P, 50 wt % solution in EtOAc) in CH Cl at room
(
2
2
temperature for 18 h. T3P is used as a reactive coupling and
dehydrating reagent, presents low toxicity, low epimerization
tendency, and high functional group compatibility, and its
byproducts are water soluble. Under these conditions, only
weak conversion (ca. 28%) was detected by LC−MS. To our
satisfaction, a full conversion to the desired Meyers’ bicyclic
lactam 5a was obtained by stirring the mixture for 6 h at 50 °C
6a, was determined by NOE studies. Similarly, constrained
dipeptides 6b, 6c, and 6d could be accessed starting from 4b
and the methyl ester of L-Ser, L-Cys, and D-Cys, respectively.
After purification, the desired products 6b−d were obtained in
excellent to moderate yields and high diastereoselectivity
(Scheme 2; 31−90% isolated yield, > 98% de). Both reactions
20
B
DOI: 10.1021/acs.orglett.5b02145
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of keto acid 4b with L-Cys methyl ester and D-Cys methyl ester
resulted in the formation of two diastereomers (HPLC dr 80:20
and dr 95:5, respectively). Since bicyclic lactams 6c and 6d
were difficult to separate using silica gel chromatography, they
were purified via diastereoselective precipitation in EtOH. The
stereochemistry at the ring fusion in 6c and 6d was assigned
from the NOESY spectra and that of 6c was confirmed by X-ray
crystallography. In order to study the turn-inducing ability of
the obtained dipeptidic scaffolds 6b−d, similar to previous
studies in our group, the conformational preferences for the
respective N-acetyl N′-methylamide tetrapeptide models were
investigated by molecular modeling (Scheme 2 and the
Supporting Information). Belvisi reported that 7,5-fused
bicyclic lactams of type 1 which lack the aromatic phenyl ring
Scheme 4. Pictet−Spengler Reactions of N-Boc-2-formyl-L-
Trp-OH 4a
23
(
m = 1, n = 3, X = CH , Figure 1) can stabilize (inverse) γ-turn
2
24
conformations in short peptides. In contrast to these results,
the lowest energy conformers of all three N-acetyl-N′-
methylamide tetrapeptide models of dipeptidic bicyclic lactams
6
b−d were not consistent with β- and γ-turn formations. A
NMR study of 5d and 5d′ confirmed the absence of an
intramolecular hydrogen bond (see the Supporting Informa-
tion).
Next, the synthesis of polycyclic lactam 7, which contains a
skeleton that was previously used to prepare dopamine receptor
2
5
ligands, was attempted. The stereocontrolled Pictet−Spengler
reaction, which proceeds via an N-acyliminium ion cyclization,
was carried out by mixing N-Phth-2-formyl-L-Phe-OH (4b) and
tryptamine followed by addition of 1 equiv of T3P and stirring
at room temperature for 6 h in CH Cl to give the desired
In conclusion, a convenient and efficient one-pot synthesis
has been developed for new 7,5- and 7,6-fused bicyclic lactams
via a stereoselective Meyers and Pictet−Spengler lactamization
with propylphosphonic anhydride (T3P) as a neutral catalyst.
This one-pot procedure tolerates acid-sensitive groups such as
the Boc group and offers a simple and very efficient route to a
new class of optically pure aminoindolo- and -benzazepinone
derivatives (i.e., 7,5- and 7,6-fused bicyclic lactams) in high
yields, starting from N-Boc-2-formyl-L-tryptophan (4a) and N-
Phth-2-formyl-L-Phe-OH (4b) as a chiral formylcarboxylic acid.
These azabicyclo[5.3.0]alkane amino acid building blocks of
types 5b, 5c, and 6b−d could serve as constrained dipeptide
scaffolds in diverse bioactive peptide chains. In analogy, the
synthesis of constrained 7,6-fused bicyclic lactams via use of
homoserine and−cysteine amino acids could be envisaged as
well. The structural complexity and the variation in substitution
patterns present in these scaffolds could be suitable for the
preparation of a wide library of compounds, enabling their use
in various biological and medicinal applications.
2
2
product 7 as a single trans diastereomer in good yield and
excellent diastereomeric excess (Scheme 3; 72% isolated yield,
98% de). The relative stereochemistry of product 7 was
determined by X-ray diffraction analysis.
>
Scheme 3. Stereocontrolled Pictet−Spengler Reaction into
Polycyclic Lactam 7
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02145.
Surprisingly, in the case of N-Boc-2-formyl-L-Trp-OH (4a)
and tryptamine, the expected product 8a was not obtained by a
one-pot procedure. Instead, the polycyclic spirolactam 8b was
isolated as a single diastereomer as determined by X-ray
diffraction analysis (Scheme 4). The synthesis of compound 8c
by cyclocondensation reaction of keto acid 4a with L-
tryptophan methyl ester proved to be unsuccessful, leading
mainly to the degradation of starting material 4a. No polycylic
lactam formation was observed either. This problem could
potentially be related to the low solubility of the substrates and
the reaction intermediates. In contrast, under the optimized
Pictet−Spengler conditions, an excellent yield and diaster-
eselectivity (86% isolated yield, >98% de) was obtained for
thiophene derivative 8d, a scaffold related to the reported
Complete experimental procedures, product character-
ization, full spectroscopic data for all new compounds,
and conformational analysis via molecular modeling
(PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*
*
E-mail: mhmd_jida@yahoo.com.
Tel: +32 2 6293292. E-mail: sballet@vub.ac.be.
Notes
26
benzo[a]thieno[3,2-h]quinolizidine.
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b02145
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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