Scalable synthesis of orthogonally protected β-methyllanthionines by indium(III)-mediated ring opening of aziridines

Article abstract of DOI:10.1021/acs.orglett.9b00125

Lantibiotics are a class of peptide antibiotics with activity against most Gram-positive bacteria. Lanthionine (Lan) and β-MeLan are unusual thioether-bridged, non-proteinogenic amino acids, which are characteristic features of lantibiotics. In this paper, we report the facile stereoselective synthesis of β-methyllanthionines with orthogonal protection by nucleophilic ring opening of aziridines. This method leads to an expedient access to β-methyllanthionines and allows production of over 30 g of β-methyllanthionine in a single batch.

Full text of DOI:10.1021/acs.orglett.9b00125

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Scalable Synthesis of Orthogonally Protected β‑Methyllanthionines
by Indium(III)-Mediated Ring Opening of Aziridines
Ziran Li, Zachary Gentry, Brennan Murphy, and Michael S. VanNieuwenhze*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States
S
* Supporting Information
ABSTRACT: Lantibiotics are a class of peptide antibiotics with
activity against most Gram-positive bacteria. Lanthionine (Lan) and
β-MeLan are unusual thioether-bridged, non-proteinogenic amino
acids, which are characteristic features of lantibiotics. In this paper,
we report the facile stereoselective synthesis of β-methyllanthionines
with orthogonal protection by nucleophilic ring opening of
aziridines. This method leads to an expedient access to β-
methyllanthionines and allows production of over 30 g of β-
methyllanthionine in a single batch.
apid outgrowth of multidrug-resistant bacteria poses a
very serious threat to human health. Unfortunately, the
synthesis of mersacidin, large quantities of orthogonally-
protected β-methyllanthionines were required.
R
weapons in our current antibiotic arsenal have become less and
less effective in treating bacterial infections.1 Discovering novel
antibacterial agents, which are active against multiresistant
bacteria, is a significant global health concern. In view of their
unique modes of action,2 lantibiotics such as nisin, mersacidin,
lacticin, and gallidermin are promising candidates for the
development of new antibiotics. Total syntheses of nisin A,
lacticin 3147, and lacticin 481 have been accomplished.3−5
We have initiated a synthetic effort directed at the lantibiotic
mersacidin (Figure 1), which is active against methicillin-
As the characteristic component of lantibiotics, ββ-MeLan
has attracted considerable interest from synthetic chemists. To
date, several syntheses of orthogonally-protected ββ-MeLan
have been reported.7 In summary, synthesis of ββ-MeLan has
been typically achieved through use of one of the following
three approaches (Scheme 1): (i) Lewis acid mediated ring
Scheme 1. Previous Approaches to Orthogonally-Protected
ββ-Methyllanthionine
Figure 1. Structure of ββ-methyllanthionine and mersacidin.
resistant Staphylococcus aureus (MRSA) and vancomycin-
resistant Enterococcus (VRE). Mersacidin is believed to inhibit
the transglycosylation reaction, a key reaction that results in
polymerization of the carbohydrate backbone, during the latter
stages of the peptidoglycan biosynthetic pathway.6
In order to understand the exact mechanism of action and in
order to attempt tuning of biological activity through analog
synthesis, we are currently pursuing the chemical synthesis of
mersacidin. From a structural standpoint, ββ-methyllanthio-
nine is embedded in all four rings of mersacidin. In addition,
the (Z)-aminovinyl sulfide moiety is a derivative of ββ-
methyllanthionine (Figure 1). In order to execute a total
Received: February 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00125
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
opening of N-carbobenzoxyaziridines with cysteine;4,8 (ii) ring
opening of cyclic sulfamidates with cysteine;9 and (iii) SN2
reactions of bromoalanine and β-methylcysteine.10 However,
each of the above methods have their drawbacks, which
present difficulties for their application in a large-scale
synthesis of β-methyllanthionine.
Table 1. Optimization of the Reaction Conditions for
Nucleophilic Ring-Opening of 2a with 1a
a
For example, nucleophilic ring opening of N-carbobenzox-
yaziridines requires a large excess of BF3·OEt2 (4−8 equiv).
Furthermore, these reactions are typically sluggish (3−5 days),
and the yields are frequently poor (e.g., 12%−46%). The cyclic
sulfamidate method gives better yields, but it requires cleavage
of the intermediate sulfamic acid, involving the use of
propanethiol, after the nucleophilic ring-opening reaction.
Additionally, the preparation of the sulfamidate precursors
requires oxidative conditions that are not compatible with allyl
and alloc protecting groups. The bromoalanine route requires
multiple synthetic steps to prepare each of the reaction
partners, and some of these reactions are plagued by low
overall atom efficiencies. As a result, this method is also
unsuitable for large-scale synthesis. To facilitate the total
synthesis of mersacidin, we felt it was necessary to develop a
new method for an efficient and scalable synthesis of
orthogonally-protected ββ-MeLan derivatives.
entry
catalyst
solvent
yield (%)
1
2
3
4
5
6
7
8
DABCO
ZnCl2
Ag(cod)2PF6
LiClO4
BiCl3
In(OTf)3
InBr3
InCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Et2O
0
0
0
0
20
0
36
52
b
9
10
11
InCl3
InCl3
InCl3
46
62
b
Et2O
56
a
b
1a (1 equiv), 2a (1 equiv), catalyst (1 equiv). InCl3 (30 mol %), 16
h
Direct construction of the carbon−sulfur bond in ββ-MeLan
through nucleophilic ring-opening of an orthogonally-pro-
tected N-carbobenzoxyaziridine with an orthogonally pro-
tected cysteine derivative is highly atom economical. More-
over, the preparation of the required cysteine- and aziridine-
derived reaction partners is concise and well-established.11
Various bases, as well as Lewis acids, have been successfully
applied for aziridine ring-opening reactions with carbon,
nitrogen, sulfur, oxygen, and halogen nucleophiles.12,13 To
the best of our knowledge, BF3·OEt2 is the only Lewis acid that
has ever been utilized in the attack of cysteine-derived
nucleophile on aziridine. However, as mentioned above,
since these reactions typically require large excesses of BF3·
OEt2, long reaction times, display intolerance toward acid
labile protecting groups, and proceed in relatively poor yields,
this reaction is unsuitable for large-scale synthesis of β-MeLan
derivatives. These liabilities led us to investigate the develop-
ment of an alternative method to enable an efficient and
scalable synthesis of β-MeLan derivatives via ring opening of
suitable protected aziridines by orthogonally-protected cys-
teine nucleophiles.
The protecting group on the aziridine nitrogen should be
electron-withdrawing in order to activate the aziridine toward
nucleophilic ring-opening. Given this limitation, our efforts
focused on use of the p-nitrobenzyloxycarbonyl (p-NO2-Cbz)
protecting group. Compared to the Cbz protecting group
frequently used in previously reported ββ-MeLan syntheses,
which is difficult to remove by catalytic hydrogenation due to
the presence of the sulfur atom, p-NO2-Cbz can be readily
removed via catalytic hydrogenation or via reductive cleavage
by sodium dithionite.14 Therefore, cysteine derivative 1a and
aziridine derivative 2a were chosen as model substrates for our
initial investigation seeking suitable Lewis acids or bases that
can facilitate the desired ring-opening reaction.
entry 8). When the reaction was performed in Et2O, the yield
improved to 62% (Table 1, entry 10). Based on the reaction
monitoring by TLC, the improved yield was attributed to
suppressed Boc protecting group cleavage when the reaction
was carried out in Et2O relative to DCM. A reduction of the
amount of InCl3 (Table 1, entries 9 and 11) resulted in
increased reaction times and increased product decomposition.
This trend was further exacerbated when catalytic amounts of
InCl3 were employed. Further experimentation revealed that 1
molar equiv of InCl3 in Et2O at room temperature provided
the optimal conditions for the desired aziridine ring-opening
reaction.
With the optimal conditions identified in our model reaction
system, the substrate scope was subsequently investigated. As
shown in Scheme 2, a variety of cysteine derivatives performed
well in the InCl3-mediated aziridine ring-opening reactions to
provide ββ-MeLan derivatives (e.g., 3a−c,e,f) in good yields.
To our delight, the reaction also worked well when the C-
terminal cysteine carboxyl group was not protected; 3g and 3h
were obtained in yield of 88% and 50%, respectively. These
products can be directly utilized for further peptide assembly
or for direct preparation of unusual S-[(Z)-2-aminovinyl]-
(3S)-3-methyl-D-cysteine (AviMeCys)an important unit of
several lantibiotics (including mersacidin) with highly potent
biological activitiesvia diphenylphosphoryl azide (DPPA)-
mediated decarboxylation15 or Ni-promoted decarbonylation
of amino acid thioesters.16 In general, our data appear to
support the notion that better yields are obtained in reactions
that do not utilize reaction partners with acid-labile protecting
groups (e.g., Boc, tert-butyl).
After the exploration of the substrate scope, we tested our
optimized substrates and reaction conditions for a large-scale
synthesis of ββ-MeLan (Scheme 3). To our delight, the yields
remained consistent with those observed in our model systems
when the reactions were carried out on a small scale. For
example, reactions 1 and 2 (Scheme 3) proceeded smoothly to
deliver over 30g of ββ-MeLan 3g and 3b in yields of 86% and
62%, respectively.
As noted in Table 1, ZnCl2, Ag(cod)2PF6, LiClO4, In(OTf)3,
and DABCO failed to afford the desired product 3a (Table 1,
entries 1−4 and 6). BiCl3 and InBr3 gave 3a in yields of 20%
and 36%, respectively (Table 1, entries 5 and 7). When the
mixture of 1a and 2a was treated with InCl3 in DCM at room
temperature, product 3a was obtained in 52% yield (Table 1,
B
DOI: 10.1021/acs.orglett.9b00125
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
amino acid through activation with diphenylphosphoryl azide
afforded the orthogonally protected A-ring of mersacidin in
25% yield over the two-step sequence.
Scheme 2. Substrate Scope of the InCl3-Mediated Ring-
Opening Reaction of Cysteines and Aziridines
a
In summary, we have developed a rapid and efficient
synthesis of orthogonally-protected ββ-methyllanthionines via
indium(III)-mediated nucleophilic ring opening of aziridines
under mild conditions. The reaction conditions tolerated
various protecting groups schemes, and large quantities of ββ-
methyllanthionines can be produced in a single batch. The
development of this efficient method to quickly access ββ-
methyllanthionines, in quantity, will substantially assist efforts
directed at the total synthesis of mersacidin and other
lantibiotics. Our own efforts in this area will be reported in
due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00125.
Experimental procedures, spectroscopic data of the
1
obtained compounds and copies of H and 13C NMR
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mvannieu@indiana.edu.
ORCID
a
All reactions were carried out with 1 (2.5 mmol), 2 (2.5 mmol), and
InCl3 (1.0 equiv) in Et2O (25 mL) at 25 °C.
Brennan Murphy: 0000-0002-7765-7612
Michael S. VanNieuwenhze: 0000-0001-6093-5949
Scheme 3. Thirty-Gram Scale Synthesis of ββ-MeLan and
Synthesis of the A Ring of Mersacidin
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Indiana University and the National Institutes of
Health (GM 111537) for financial support.
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■
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DOI: 10.1021/acs.orglett.9b00125
Org. Lett. XXXX, XXX, XXX−XXX