A solid-phase synthetic route to N-acylated α-alkyl-D,L-homoserine lactones

Article abstract of DOI:10.1016/j.tetlet.2020.152328

A synthetic route to N-acylated α-alkyl-D,L-homoserine lactones was established using solid-phase unnatural peptide synthesis (UPS) and combinatorial chemistry. The application of UPS methodology allowed access to racemic N-acylated homoserine lactones (D,L-AHLs) and their α-alkyl structural analogs (α-R¹-D,L-AHLs). The synthesis and characterization of a library of five D,L-AHLs and ten α-R¹-D,L-AHLs prepared from resin-bound amino acids is reported.

Full text of DOI:10.1016/j.tetlet.2020.152328

Tetrahedron Letters 61 (2020) 152328
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A solid-phase synthetic route to N-acylated
lactones
a-alkyl-D,L-homoserine
1
⇑
Ahmed I.M. Ali , Martin J. O’Donnell, William L. Scott, J. Geno Samaritoni
Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic route to N-acylated a-alkyl-D,L-homoserine lactones was established using solid-phase unnat-
Received 3 June 2020
Revised 23 July 2020
Accepted 2 August 2020
Available online 20 August 2020
ural peptide synthesis (UPS) and combinatorial chemistry. The application of UPS methodology allowed
access to racemic N-acylated homoserine lactones ( -AHLs) and their -alkyl structural analogs (
-R1-
-AHLs). The synthesis and characterization of a library of five -AHLs and ten -AHLs prepared
-R1-
from resin-bound amino acids is reported.
D,
L
a
a
D,
L
D
,
L
a
D,L
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Solid-phase
Lactones
Homoserine
Amino acid synthesis
UPS
AHL
Introduction
[9b] resin-bound unnatural amino acids and peptides. In one
example, di-UPS was used to prepare the N-Fmoc- -methyl lac-
a
N-Acylated
L
-homoserine lactones 1 (AHLs, Fig. 1) are known
tone 5 from Wang resin 3 (Scheme 1) [9d]. In the preparation of
4 from 3, the partial conversion of 4 to 5 was observed. Complete
conversion of 4 to 5 was accomplished by subsequent treatment
of the mixture with base.
signaling molecules in the quorum-sensing systems used by
gram-negative bacteria [1]. Once threshold concentrations of AHLs
are reached, a variety of defensive mechanisms, such as the forma-
tion of biofilms, are initiated by bacteria resulting in heightened
virulence. Non-native AHLs with tailored acyl side chains and var-
ied head groups can function as quorum-sensing modulators [2a-
c,3–7]. However, AHLs with modified lactone groups featuring sub-
stitution at the
reported. Thus, the preparation of
investigated, resulting in the generation of
At this initial stage of our investigation into AHLs quaternized at
the alpha position, it was decided to restrict R1 to the homologous
series H, Me, and Bn. Expanding the scope of R1 to include func-
tionalized amino acids could then be pursued in response to
improved quorum-sensing modulation with R1 = methyl and/or
benzyl.
An alternative synthetic approach was designed and is reported
here, wherein lactonization occurs following exposure of a resin-
bound alcohol (THP-protected) to trifluoroacetic acid. This alterna-
tive synthetic approach, represented in Scheme 2, differs from that
reported by Blackwell [2d], Nielssen [3], and Murata [10] in two
respects: a) the sequence provides for the on-resin construction
of a quaternized alpha position affording novel homoserine lac-
tones and b) the alcohol is protected as the THP rather than its tri-
tyl derivative. Advanced intermediate resins 7, in which R1 is
hydrogen (H), Me, or Bn would then be accessible using UPS and
di-UPS methodology [9a,b], starting from commercially available
Fmoc-protected glycine, alanine, and phenylalanine on Wang
resins 6.
a
-carbon other than methyl [8], have not been
-alkyl analogs of AHLs 1 was
-R1-
-AHLs 2 (Fig. 1).
a
a
D,L
Unnatural Peptide Synthesis [9] is a solid-phase synthetic strat-
egy to prepare
a-mono (UPS) [9a] and a,a-disubstituted (di-UPS)
Results and discussion
⇑
Corresponding author at: Department of Chemistry and Chemical Biology,
Indiana University Purdue University Indianapolis, 402 N Blackford Street, Indi-
anapolis, IN 46202, United States.
The two routes used to prepare 7 through intermediate resins
10 (R1 = H) and 11 (R1 = Me and Bn) are outlined in Scheme 3.
These routes differ only in the imine group in 10 and 11 used to
E-mail address: jsamarit@iupui.edu (J.G. Samaritoni).
Current address: Texas Tech University, Department of Chemistry and Biochem-
1
activate the
a-carbon toward subsequent alkylation. When
istry, 2500 Broadway, Lubbock, TX 79409, United States.
R1 = H, following Fmoc removal (6 to 9), 9 was converted into its
https://doi.org/10.1016/j.tetlet.2020.152328
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
A.I.M. Ali et al. / Tetrahedron Letters 61 (2020) 152328
(trichlorotriazine-alizarin R) for the detection of free hydroxyl
groups [11] and the result was negative.
Resins 7 were then N-acylated (Scheme 4, step a). Standard cou-
pling conditions with carboxylic acids (hydroxybenzotriazole and
DIC) were suitable for the monoalkylated resins 7 (R1 = H). How-
ever, if R1 = Me or Bn, the quaternary center adjacent to the amino
group can lead to potentially difficult couplings [12]. Therefore, the
acylation of 7 (R1 = Me, Bn) was performed with the more reactive
acid chlorides. Treatment of acylated resins 12 with trifluoroacetic
acid (TFA) over 48 h afforded, through the presumed intermediate
8, the desired racemic lactones 2 in 4–23% overall, purified yield
(63–81% average yield per step) [13].
Fig. 1. General structures of AHLs 1 and a D,L-AHLs 2.
-R1-
benzophenone imine 10 in preparation for monoalkylation. a-Sub-
stituted resins 9 (R1 = Me, Bn) require activation to 11 with 3,4-
dichlorobenzaldehyde, because the introduction of a second alkyl
group at the
a-carbon of benzophenone imine 10 (Scheme 3) is
Alkyl and acyl input variables (R1 and R2CO) were incorporated
in a combinatorial fashion to generate the target compounds
shown in Fig. 2. The synthesis and chemical/biological characteri-
not readily achieved [9b,c,h]. Base-promoted racemic alkylation
of resins 10 and 11 with BTPP and 2-(2-bromoethoxy)tetrahydro-
2H-pyran was followed by hydrolysis of the imine functional
groups to form 7. The hydrolyses of 10 and 11 were performed
(2:1 THF:1N HCl) over 30 min at room temperature. A concern
was whether or not unintended THP removal had occurred during
hydrolysis of the imine resins 10 and 11. A few beads of hydrochlo-
ride resin 7 (R1 = Bn) were subjected to a sensitive color test
zation of 1a-d (L-configuration) were reported by Blackwell in
the investigation of AHLs as modulators of quorum-sensing in
gram-negative bacteria [2e-g]. and were also prepared in this
work. Structures 2a-j represent novel
nized alpha positions prepared as racemates.
a D,L-AHLs with quater-
-R1-
Scheme 1. Lactonization following TFA-promoted release from Wang resin.
Scheme 2. General approach to a D,L-AHLs 2.
-R1-
Scheme 3. Preparation of intermediate resins 7.

A.I.M. Ali et al. / Tetrahedron Letters 61 (2020) 152328
3
Scheme 4. Conversion of THP-protected resins 7 to 2.
Fig. 2. N-Acylated
D,
L-homoserine lactones (% overall purified yield over eight synthetic steps).
Conclusions
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