Total synthesis of landomycins Q and R and related core structures for exploration of the cytotoxicity and antibacterial properties

Article abstract of DOI:10.1039/d1ra01088c

Herein, we report the total synthesis of landomycins Q and R as well as the aglycone core, namely anhydrolandomycinone and a related core analogue. The synthesis features an acetate-assisted arylation method for construction of the hindered B-ring in the

Full text of DOI:10.1039/d1ra01088c

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Total synthesis of landomycins Q and R and related
core structures for exploration of the cytotoxicity
and antibacterial properties†
Cite this: RSC Adv., 2021, 11, 9426
Yao-Hsuan Lai,‡a Soumik Mondal,‡ab Hsin-Tzu Su,ab Sheng-Cih Huang,ab
Mine-Hsine Wu,c I.-Wen Huang,c Tsai-Ling Yang Lauderdale,c Jen-Shin Song,c
ab
Kak-Shan Shiac and Kwok-Kong Tony Mong
*
Herein, we report the total synthesis of landomycins Q and R as well as the aglycone core, namely
anhydrolandomycinone and a related core analogue. The synthesis features an acetate-assisted arylation
method for construction of the hindered B-ring in the core component and a one-pot aromatization–
deiodination–denbenzylation procedure to streamline the global functional and protecting group
manuipulation. Subsequent cytotoxicity and antibacterial studies revealed that the landomycin R is
a potential antibacterial agent against methicillin-resistant Staphylococcus aureus.
Received 9th February 2021
Accepted 23rd February 2021
DOI: 10.1039/d1ra01088c
rsc.li/rsc-advances
The landomycins (LAs) are a class of angucyclines produced
from Streptomyces species.14 The rst report on LA described the
isolation of LA A to D from S. cyanogenus S136.15 Through the
Introduction
Over the past few decades, the emergence of multidrug-resistant
nosocomial pathogens has become a worldwide issue that is of
concern for scientists and clinical practitioners.1,2 Conse-
quently, new antibiotics and antibacterial strategies are
urgently needed.3,4 However, the development of a new antibi-
otic is a slow process that is associated with a high risk of
failure. Compounds that exhibit antimicrobial capacity in vitro
may be unable to combat the infection in vivo or may be highly
toxic to the host cells.5
Staphylococcus aureus (S. aureus) is a class of Gram-positive
bacteria that is present on the skin and mucous membranes
as a part of normal ora.6 If by chance S. aureus bacteria enter
the bloodstream, they may cause severe infections including
meningitides, endocarditis, and urinary tract infections.7
Staphylococcal infections are common in community and
hospital-acquired settings and treatment of these infections has
been complicated because of the rising incidence of methicillin
resistant S. aureus (MRSA) infections.8 Although vancomycin is the
antibiotic of choice, it may cause nephrotoxicity at high doses.9,10
Therefore, a less or non-toxic antibiotic is desirable.11–13
use of the modern molecular biology techniques, the LA family
has now grown to include more than 100 members.16,17 The
general structure of LA compounds comprises a tetracyclic core,
which is substituted with some hydroxyl groups and a 2-deox-
ysaccharide chain at the C8 position (Fig. 1a).14–17 Based on the
B-ring structure and hydroxyl substitution pattern, four
different core structures have been identied: tetrangulol, 5,6-
anhydrolandomycinone, landomycinone, and 11-deoxy-
landomycinone. The combinations of different core structures
and 2-deoxysaccharide chains provide a rich pool of natural
products for structure and activity relationship studies.
Previous studies of LAs have mainly focused on the anti-
cancer activity, and their potential antibacterial property has
received far less attention.18 Given that the demand for non-
toxic antibiotics is on the rise, we sought to establish a versa-
tile synthetic route to procure the anhydrolandomycinone core
(1), the B-ring unsaturated core analogue (2), the LA Q (3), and
LA R (4) for exploration of the cytotoxic and antibacterial
properties (Fig. 1b).
Results and discussion
Synthesis of anhydrolandomycinone (1), B-ring unsaturated
core analogue (2), LA Q (3), and LA R (4)
aNational Chiao Tung University, Hsinchu 30010, Taiwan, Republic of China
bNational Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan, Republic of
China. E-mail: tmong@nycu.edu.tw
The total synthesis of LA A and LA D has been reported by Yu
and Yang, but the synthesis of LA Q (3) and LA R (4) with
a different core structure has not yet been realized.19 From
structural perspective, the synthesis of this class of compounds
is non-trivial and yet challenging. Currently available protocols
toward their aglycone core structure and glycone component
cNational Health Research Institutes, Miaoli County 35053, Taiwan, Republic of China
† Electronic supplementary information (ESI) available: Schemes S1 and S2 for
preparation of 19, 20, and 22, Table S1 for comparison of NMR data, raw data
of MTS, and MIC assays, experimental procedures, and NMR spectroscopic data
and spectra were given. See DOI: 10.1039/d1ra01088c
‡ These authors contributed equally.
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Fig.
1 (a) General Structure of LAs. (b) Structures of anhy-
drolandomycinone aglycone core (1), and B-ring unsaturated core
analogue (2), LA R (3) and LA Q (4).
alone are inadequate for procurement of a complete LA scaf-
fold.20,21 Some modications are required for selective removal
of protecting groups and subsequent coupling reactions; but
such modications may not be tolerable to the original proto-
cols. Thereby, we envisaged some synthetic challenges to realize
the structures of our targets. These include: (i) the construction
of a highly hindered B-ring; (ii) stereocontrol of the formation of
the 2-deoxy-b-glycosidic bonds; and (iii) the global deprotection
in conditions tolerated by the rather fragile trideoxy- and
dideoxy-glycosidic bonds (Fig. 1b).22
To tackle these challenges, new synthetic routes were
designed, which was based on the modications of literature
protocols.19–21 To access anhydrolandomycinone core (1) and its
B-ring unsaturated analogue (2), the D-ring and A-ring building
blocks 5 and 6 were prepared from available hydroquinone 7
and dimethylanisole 8, respectively. Based on the building
blocks 5 and 6, the C and B-rings of the core scaffold were
constructed.
Scheme 1 Preparation of (a) D-ring building block 5, (b) A-ring alkyne
building block 6, (c) anhydrolandomycinone (1), and corresponding B-
ring unsaturated core analogue (2).
The preparation of the A-ring building block 6 started with
readily available 3,5-dimethylaniosle 8 (ref. 20b) instead of the
more expensive 3-bromo-5-methylphenol as was the case in our
previous synthesis.20d Thus, bromination of 3,5-dimethylaniosle
8 with Wohl–Ziegler's procedure26 followed by hydroxyl substi-
tution afforded known (3-methoxy-5-methylphenyl)-methanol
11 (Scheme 1b).20b Subsequent directed-ortho lithiation of 11
and regioselective iodination gave (2-iodo-3-methoxy-5-
methylphenyl)methanol 12 as the sole isomer.20b,27 Acetylation
of 12 followed by replacement of the methoxy group with benzyl
ether protection provided 1-(benzyloxy)-3-(bromomethyl)-2-
iodo-5-methylbenzene 13.20d Finally, the substitution of 13
with in situ prepared [3-TMS-prop-2-yn-1-yl] lithium and desi-
lylation completed the preparation of building block 6 in 23%
yield over eight steps.
In the preparation of the D-ring building block 5, regio-
selective acetylation of hydroquinone 7 with Zhang's proce-
dure23 followed by sequential benzylation and bromination gave
the known 3-bromo-4-hydroxyphenyl acetate 9.24 Then, 9 was
converted
to
1-(benzyloxy)-2-bromo-4-(methoxy-methoxy)-
benzene 10 through deacetylation and methoxymethyl ether
(MOM) protection (Scheme 1a). Subsequent lithiation of 10 in
couple with Meerwein's salt methylation completed the prepa-
ration of building block 5 in 37% yield over seven steps.25
Because of the poor stability of 5, it was freshly prepared prior to
¨
the Dotz benzannulation shown in Scheme 1c.
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dihydrotetraphene-7,12-diyl-diacetate 16 was procured in
a good 82% yield along with just a trace amount of the deio-
dination product of 15. Removal of the acetyl groups of 16 fol-
lowed by DDQ oxidation and acidic cleavage of the MOM
protecting group gave 5,6-dihydrotetraphene-7,12-dione 17. In
subsequent hydrogenolytic debenzylation, the modied
RANEY®Ni catalyzed hydrogenation conditions were applied;
whereas, the RANEY®Ni catalyst was freshly activated with
NaOH(aq) and triethylamine (Et3N) was added as an acid scav-
enger.30 Under the new conditions, no reduction of the carbonyl
groups at C-ring occurred, while the B-ring was aromatized to
give desired anhydrolandomycinone (1) in a one-pot fashion. In
previous hydrogenation conditions, the carbonyl groups at the
C-ring were also reduced, which had to be recovered by the DDQ
oxidation.19,20d In addition to the synthesis of (1), removal of the
benzyl protecting groups of 17 with BBr3 furnished the B-ring
unsaturated core analogue (2).
For the synthesis of LA Q (3) and R (4), partially protected
anhydrolandomycinone 18 was initially employed as the agly-
cone acceptor, which could be derived from advanced inter-
mediate 16 via four functional- and protecting-group
manipulation steps (Scheme 2a). The 2-deoxytrisaccharide
component of LA Q (3) was assembled from L-rhodinosyl
acetates 19 (ref. 31) and, D-olivosyl acetates 20,19a and 21, while
the 2-deoxy-disaccharide component of LA R (4) was built from
the D-olivosyl acetates 21 and 22 (ref. 19a) (Scheme 2b). L-Rho-
dinosyl acetate 19 was derived from L-rhamnose (Scheme S1†),
and D-olivosyl acetates 20 and 22 were derived from known
glucal 23 according to literature procedures (Scheme S2†).32 6-
Iodo-olivosyl acetate 21 was also prepared from 23 via inter-
mediates 24 and 25 in 20% overall yield (Scheme 2c).
Scheme 2 (a) Preparation of anhydrolandomycinone acceptor 18. (b)
Structures of L-rhodinosyl acetate 19 and olivosyl acetates 20–22. (c)
Preparation of D-olivosyl acetate 21.
With the D- and A-ring building blocks 5 and 6 in hand, we
¨
embarked on the C-ring construction via Dotz benzannulation
(Scheme 1c).28 The annulation was followed by 2,3-dichloro-5,6-
dicyano-benzoquinone (DDQ) oxidation to give the A-ring teth-
ered naphthalene-1,4-dione 14; which through Na2S2O4 reduc-
tion and acetylation was converted to the A-ring tethered
naphthalene-1,4-diacetate 15. Subsequent acetate-assisted
intramolecular directed arylation enabled construction of the
B-ring in a highly congested environment.29 The desired 5,6-
Scheme 3 (a) Preparation of anhydrolandomycinonyl b-olivoside acceptor 27. (b) Preparation of disaccharide imidate donor 29. (c) Total
synthesis of LA Q (3).
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In the construction of LA Q (3), an anhydrolandomycinonyl 19 to give a-rhodinosyl-(1,3)-olivosyl acetate 28 (Scheme 3b). In
b-olivoside acceptor was prepared, which was subsequently the glycosylation, a low À60 ꢀC temperature was applied to
coupled with a non-reducing-end disaccharide donor. In the avoid the cleavage of the fragile 2,3,6-trideoxyglyosidic bond.
preparation of the b-olivoside acceptor, 6-iodo-olivosyl acetate Final replacement of the anomeric acetate group of 28 with N-
21 was converted to an a-olivosyl iodide by treatment with tri- phenyltriuoroacetimidate completed the preparation of
methylsilyl iodide (TMSI) (Scheme 3a).33 Aer formation of the disaccharide imidate donor 29.
iodide intermediate, the DCM and residual TMSI were removed
The availability of donor 29 set the stage for the assembly of
and the crude intermediate was reacted with the phenolate the target (Scheme 3c). Glycosylation of acceptor 27 with donor
nucleophile, which was prepared in situ by deprotonation of 18 29 gave protected LA Q 30 in a high 85% yield with excellent b-
with potassium hexamethyldisilazane (KHMDS). Under the SN2 selectivity. The selectivity of the glycosylation is attributed to the
glycosylation conditions, the desired anhydrolandomycinonyl participatory effect of the 2-iodo substituent group.34 Subse-
b-olivoside 26 was obtained in a satisfactory 68% yield with quent one-pot deiodination and debenzylation of 30 could be
perfect selectivity. Assignment of the conguration of the O-aryl achieved under the same RANEY®Ni hydrogenation conditions
3
2-deoxy-b-glycosidic bond was supported by the JH1-Hax as shown in Scheme 1c. Hydrolysis of the acyl protecting groups
coupling constant of 9.6 Hz. Notably, the above substitution of the deiodinated and debenzylated intermediate concluded
occurred exclusively at C1 position despite the presence of the the synthesis of LA Q (3) in 40% yield over two steps from 30.
iodo substituent at the C6 position. Subsequent removal of the The identity and structure of 3 were conrmed with HRMS and
silyl protecting group afforded the desired b-olivoside acceptor NMR spectroscopy. The proton chemical shis of (3) were in full
27 in 65% yield.
agreement with the data given from an authentic sample (Table
For the preparation of the disaccharide donor, olivosyl S1†).16c
acetate acceptor 20 was coupled with rhodinosyl acetate donor
Scheme 4 (a) Preparation of B-ring unsaturated anhydrolandomycinonyl core acceptor 32. (b) Total synthesis of LA R (4).
Table 1 Inhibitory effects on normal/cancer cell proliferation by anhydrolandomycinone (1), B-ring unsaturated core analogue (2), LA Q (3), and
LA R (4)a
IC50 (mM)
Entry
Compound
NCI-H460
SF-268
Detroit 551
1
2
3
4
Core (1)
B-ring unsaturated core (2)
LA Q (3)
7.00 Æ 0.70
>10.0
>10.0
8.57 Æ 0.34
>10.0
>10.0
9.82 Æ 0.08
>10.0
9.58 Æ 0.66
>10.0
LA R (4)
>10.0
>10.0
a
Values represent the mean Æ SD of three independent experiments.
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Inspired by the one-pot debenzylation and aromatization in R (4), implicating that the anhydrolandomycinone alone is
Scheme 1c, and the one-pot debenzylation and deiodination in more toxic than its glycosylated products.
Scheme 3c, we envisaged a simpler synthetic route for LA R (4),
Aer clarifying the cytotoxicity proles of 1–4, we examined
which would invoke a one-pot three-step, i.e. aromatization– the antibacterial activity with MRSA 4N 216 and 7Y001 (Table
debenzylation–deiodination, procedure. With this aim, 5,6- 2).37,38 Among the compounds examined, only the disaccharide
dihydrotetraphene-7,12-dione 17 in Scheme 1c was coupled substituted LA R (4) exhibited inhibitory activity against MRSA
with 6-iodo olivosyl acetate 21 according to the above SN2-gly- 4N 216 and 7Y001 with the MIC values of 8 and 4 mg mLÀ1
,
coslation procedure to give 5,6-dihydrotetraphene-7,12-dione b- respectively. Although, such a potency is inferior to that offered
olivoside 31 in 68% yield along with ca. 5% of the inseparable by vancomycin (VA), the non-toxic nature of LA R (4) renders it
aromatization product 26 (Scheme 4a). The crude b-olivoside 31 a potential candidate for further optimization.
was subjected to desilylation to give the 5,6-dihydrotetraphene-
7,12-dionyl b-olivoside acceptor 32 along with a small amount
of olivoside 27.
Conclusion
On the other hand, the non-reducing end olivosyl acetate 22
was converted to the trichloroacetimidate donor 33 by standard
In summary, a versatile strategy was established for the total
synthesis of the anhydrolandomycinone core (1), the B-ring
procedures (Scheme 4b). Subsequent glycosylation of b-olivo-
unsaturated anhydrolandomycinone analogue (2), landomycin
side acceptor 32 with donor 33 furnished 8-disaccharidyl-5,6-
Q (3), and landomycin R (4). The strategy employed the acetate-
dihydrotetraphene-7,12-dione 34 in 89% yield, though a tiny
assisted intramolecular arylation for construction of the
hindered B-ring of the anhydrolandomycin core and a one-pot
aromatization, deiodination, and debenzylation procedure
was established to simplify the end-stage functional group
manipulations. In subsequent MTS study, the structure of the B-
ring and the degree of glycosylation of the landomycins appear
amount of glycosylation product arising from contaminant
olivoside 27 was also produced. Without separation, the crude
b-glycoside 34 was subjected to the one-pot aromatization–
debenzylation–deiodination procedure to afford a partially
deprotected LA R intermediate in a satisfactory 55% yield. Final
deprotection of the silyl and acetyl protecting groups concluded
to play a role in the cytotoxicity. Further exploration of the
the total synthesis of LA R (4) in 74% yield over two steps.
antibacterial properties revealed the potential of landomycin R
(4) for inhibition of MRSA 4N 216 and 7Y001.
Exploration of the cytotoxic and antibacterial properties
Having acquired anhydrolandomycinone (1), the B-ring unsat-
Conflicts of interest
urated core analogue (2), LA Q (3) and LA R (4), we evaluated
their cytotoxicity with the [3-(dimethylthiazol-2-yl)-5-(3-carbox-
ymethoxyphenyl)-2-(4-sulfo-phenyl)-2H-tetrazolium] (MTS)
There are no conicts to declare.
assay (Table 1).35,36 Anhydrolandomycinone (1) was found to be
cytotoxic against the cancer cell lines NCI-H460 and SF-268 with
IC50 values at 7.00 Æ 0.70 and 8.57 Æ 0.34 mM, respectively; but
no appreciable cytoxicity was noted for normal cell line Detroit
551 at 10 mM (Entry 1). Intriguingly, such a toxicity pattern was
reversed for the B-ring unsaturated core analogue (2) (Entry 2).
At 10 mM concentration of glycosylated LA Q (3) and R (4), no
appreciable cytotoxic effect was detected for the normal cell line
(Entries 3 and 4). Taken together, the unsaturated B ring and/or
the 2-deoxysaccharide chain appear to play a role in the cyto-
toxicity of the LA compounds.
Acknowledgements
Thanks are given to the Ministry of Science and Technology in
Taiwan (MOST) for nancial support (grant no. MOST 109-2113-
M-009-007).
Notes and references
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To elucidate the extent of the cytotoxicity, we evaluated the
survival rates of Detroit 551 cell line at 10 mM of the compounds,
which were found to be 59.00% Æ 3.26% for the core structure
(1), 104.2% Æ 20.67% for LA Q (3), and 93.56% Æ 10.02% for LA
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MIC (mg mLÀ1) of compound
MRSA strain
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Analogue (2)
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LA R (4)
VA
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General
Strategy
for
Diverse
Syntheses
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