Synthesis of Gentamicin Minor Components: Gentamicin B1 and Gentamicin X2

Article abstract of DOI:10.1021/acs.orglett.0c01107

The clinical aminoglycoside antibiotic gentamicin is a mixture of several difficult-to-separate major and minor components. The relative inaccessibility of the minor components in particular complicates efforts to separate antibacterial activity from nephro- and/or ototoxicity and to clarify the origin of the potentially therapeutically important read-through activity. With a view to facilitating such studies, the synthesis of a fully and selectively protected garamine-based acceptor has been developed from readily available sisomicin. Glycosylation of this acceptor with a 6-azido-6,7-dideoxy-d-glycero-d-glucoheptopyranosyl donor affords gentamicin B1 after deprotection, whereas employment of a 2-azido-2-deoxy-d-glucopyranosyl donor under N,N-dimethylformamide-directed glycosylation conditions affords gentamicin X2 after deprotection.

Full text of DOI:10.1021/acs.orglett.0c01107

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Letter
Synthesis of Gentamicin Minor Components: Gentamicin B1 and
Gentamicin X2
Parasuraman Rajasekaran and David Crich*
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ABSTRACT: The clinical aminoglycoside antibiotic gentamicin is
a mixture of several difficult-to-separate major and minor
components. The relative inaccessibility of the minor components
in particular complicates efforts to separate antibacterial activity
from nephro- and/or ototoxicity and to clarify the origin of the
potentially therapeutically important read-through activity. With a
view to facilitating such studies, the synthesis of a fully and
selectively protected garamine-based acceptor has been developed
from readily available sisomicin. Glycosylation of this acceptor with
a 6-azido-6,7-dideoxy-D-glycero-D-glucoheptopyranosyl donor af-
fords gentamicin B1 after deprotection, whereas employment of a
2-azido-2-deoxy-D-glucopyranosyl donor under N,N-dimethylfor-
mamide-directed glycosylation conditions affords gentamicin X2 after deprotection.
entamicin is a clinically important aminoglycoside
antibiotic used in the treatment of Gram-negative
fibrosis13−15 have resulted in efforts to develop structure−
activity relationships among the various components of
gentamicin and to identify the active principle for use in
read-through therapy. Yet other efforts have focused on
geneticin (G418) as an alternative lead for the development
of compounds with improved read-through activity.16−18
Unfortunately, these efforts are marred by the complexity of
the mixture of gentamicins obtained by fermentation and the
consequent difficulty of isolating pure components. For
example, read-through activity originally assigned to genta-
micin B1 was subsequently found to result from a mislabeled
commercial sample of the closely related regioisomeric
geneticin (G418), with purified gentamicin B1 itself showing
no such activity.19 More recently, gentamicin X2, a further
minor component of gentamicin, was reported to have read-
through activity surpassing that of geneticin.20
In view of the difficulty in obtaining authentic pure
samples of minor gentamicin components, we embarked on
the synthesis of gentamicins B1 and X2 and report here on
the outcome of our studies.
Gentamicin B1 7 has not been synthesized previously.
Gentamicin X2 8 was prepared in 1976 by Mallams and co-
workers in 8 steps and 3.7% overall yield from penta-N-Cbz-
G
bacterial infections that figures on the WHO Essential
Medicines List.1 Produced by fermentation from Micro-
monospora purpurea, gentamicin is supplied as a mixture
comprised mainly of gentamicin C1, gentamicin C1a, and
gentamicin C2 and C2a together with minor amounts of
sisomicin, gentamicins A, B, and B1, 2-deoxystreptamine,
garamine, and garosamine (Figure 1).2−5
The antibacterial activity of aminoglycoside antibiotics
stems from binding of the drugs to the decoding A site on
helix 44 of the small subunit of the bacterial ribosome,
whereas the important side effect of ototoxicity (drug
induced hearing loss) is mainly the result of binding to the
human mitochondrial and, in hypersusceptible patients, to the
human A1555G mutant mitochondrial ribosome.6−8 Amino-
glycoside binding to the decoding A site of the human
cytoplasmic ribosome on the other hand is expected to
convey more systemic toxicity.7 Fortunately, well-mapped
differences in the decoding A sites of bacterial and human
mitochondrial and cytoplasmic ribosomes can be exploited in
the development of novel aminoglycosides with improved
antibacterial activity and reduced toxicity.9−11
Somewhat paradoxically, because aminoglycoside binding
to the human cytoplasmic ribosome results in misreading and
consequently defective protein synthesis, aminoglycosides are
also under intense investigation as potential therapeutics for
genetic diseases arising from the mutation of an amino acid
codon to a premature termination codon (PTC).12 Variable
results presented by gentamicin in clinical trials with patients
suffering from Duchenne muscular dystrophy and cystic
Received: March 26, 2020
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© XXXX American Chemical Society
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Figure 1. Major and minor components of gentamicin, and geneticin (G418).
Scheme 1. Key Steps in the Mallams and Paulsen
Syntheses of Gentamicin X2
Scheme 2. Key Elements of the Liu Synthesis of 6′R- and
6′S-Gentamicin X2
Scheme 3. Synthesis of a Garamine-Based Acceptor from
Sisomycin
sisomicin. In the key step, the garamine derivative 14,21
obtained from sisomicin 9, was glycosylated with a per-O-
acetyl-2-deoxy-2-nitroso-α-D-glucopyranosyl chloride 16
under Koenigs−Knorr conditions to obtain the pseudo
disaccharide 18 in 40% yield (Scheme 1).22 A second
synthesis of gentamicin X2 was achieved in 1981 by Paulsen
and co-workers in 4 steps and 3.4% overall yield from a
penta-N-Cbz-gentamicin C complex.23 The core of this
synthesis was glycosylation of garamine derivative 15,
obtained by degradation of gentamicin C complex,24 with
B
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garamine-based acceptor, and that this acceptor would in
turn be readily accessible from sisomicin 9. Thus, by adapting
literature methods, sisomicin 9 was converted to the known
tetraazide 2330 in 54% yield by treatment with triflyl
azide,31,32 and then to the known tertiary carbamate 2433
in 81% yield by standard means. Treatment of 24 with excess
sodium hydride in DMF at 0 °C to effect conversion of the
carbamate to the oxazolidinone was followed by addition of
benzyl bromide and stirring at room temperature to afford
the fully protected sisomicin derivative 25 in 87% yield.
Attempted cleavage of the unsaturated ring from 25 with
Amberlite IR120 H+ resin or with 4 N HCl, according to
literature protocols for related compounds,21,34 was not
effective, but stirring with sulfuric acid in THF at 40 °C
for 48 h21 brought about the desired transformation and
afforded the selectively protected glycosyl acceptor 26 in 85%
yield (Scheme 3).
Scheme 4. Synthesis of 6-Azido-6,7-dideoxy-D-glycero-D-
glucoheptopyranosyl Donor 30
A glycosyl donor suitable for construction of gentamicin B1
was prepared from methyl α-D-glucopyranoside, which was
converted to the known alcohol 2735 in 68% yield by three
straighforward steps as described in the Supporting
Information. Oxidation with the Dess Martin periodinaine36
gave an aldehyde, which on immediate treatment with
methylmagnesium chloride at −78 °C gave the known
heptose derivative 2837 in 56% overall yield (Scheme 4).
Consistent with the literature, 28 was obtained predom-
inantly in the form of the L-glycero-D-gluco-isomer as verified
by conversion to a 4,6-O-benzylidene acetal derivative in
which the newly introduced methyl group occupied the axial
site at C6 (Supporting Information). Triflation of 28
followed by displacement with sodium azide was complicated
by significant elimination, but reaction with diphenylphos-
phoryl azide38 gave the desired D-glycero-D-gluco-configured
azide 29 in 83% yield. Finally, acetolysis of the methyl
glycoside followed by treatment with 4-methylbenzenethiol in
the presence of BF3-etherate afforded the requisite donor 30
in 68% yield.
the 2-azido-2-deoxyglucosyl chloride 17 and mercuric cyanide
as promoter giving pseudo disaccharide 19 in 26% yield
(Scheme 1).
The Mallams synthesis was prescient in that it employed
DMF as solvent resulting in the selective formation of the
axial glycoside,25−27 but it required several steps for the
selective acetylation of tris-N-(Cbz)-garamine to obtain
acceptor 14, and reduction of the oxime 16 subsequent to
glycosylation. The Paulsen synthesis relied on regioselctive
glycosylation of the gaaramine diol 15, but consequently only
gave a moderate yield of 26%, and employed mercuric
cyanide as promoter. More recently, Liu and co-workers
prepared 6′R- and 6′S-monodeuterio gentamicin X2 (Scheme
2)28 by an initial glycosylation of the deoxystreptamine
derivative 20, itself obtained by enzymatic desymmetrization
of 2-deoxystreptamine according to Wong,29 with thioglyco-
side 21. This step was followed, after deacetylation, by a
second regioselective glycosylation with the garosamine
donor 22 that was prepared by degradation of gentamicin
and subsequent derivatization.
Coupling of acceptor 26 with donor 30 was accomplished
with N-iodosuccinimide and silver triflate in dichloromethane
We envisaged that both gentamicins B1 and X2 would be
readily prepared from a common pseudo disaccharyl
Scheme 5. Synthesis of Gentamicin B1 and Gentamicin X2
C
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at −30 °C in the presence of 4 Å molecular sieves. This
reaction afforded the desired glycoside 31 in 76% yield as the
pure α-anomer, with the high selectivity seemingly a function
of the extra substitution at the 6-position of the donor
(Scheme 5). Coupling of acceptor 26 with p-tolyl 2-azido-
3,4,6-tri-O-benzyl-2-deoxy-α,β-D-thiogluopyranoside 32, pre-
pared according to the literature method,39 under the same
conditions gave the glycoside 33 in 62% yield as a 3:1 α,β-
mixture, but activation with NIS and TMS triflate in
dichloromethane in the presence of DMF25−27,40 afforded
the pure α-anomer of 33 in 51% yield together with 13% of
the recovered glycosyl acceptor 23 (Scheme 5). Deprotection
of both 31 and 33 was accomplished by hydrogenolysis over
palladium hydroxide on charcoal followed by heating to 60
°C with aqueous barium hydroxide, with final purification by
filtration on Sephadex C25 and lyophilization from aqueous
acetic acid. In this manner gentamicin B1 7 and gentamicin
X2 8 were obtained in 56% and 61% yield from 31 and 33,
respectively, in the form of their peracetate salts (Scheme 5).
Overall the synthesis of gentamicin B1 was accomplished
from sisomicin 9 in 6 steps and 13.8% yield. The synthesis of
gentamicin X2 was achieved from sisomicin 9 in 6 steps and
10.1% yield, which compares favorably with the precedent
(Schemes 1 and 2). The straightforward syntheses of the
common acceptor 26 and of the two donors 30 and 32,
together with the relatively high yields and excellent
selectivities of the coupling reactions, suggest that these
syntheses are potentially scalable should the need for larger
quantities of material arise. We anticipate that other minor
components of gentamicin should be similarly readily
available by glycosylation of 23 should the need arise.
ACKNOWLEDGMENTS
■
We thank the NIH (AI123352) for support of this work and
̈
Professor Erik C. Bottger, University of Zurich, Institute of
Medical Microbiology, for stimulating discussion.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01107.
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T.; Chow, C. S.; Polikanov, Y. S.; Schacht, J.; Vasella, A.; Bottger, E.
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Complete experimental and characterization details and
copies of 1H and 13C NMR spectra of all new
compounds (PDF)
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Osinnii, I.; Gysin, M.; Haldimann, K.; Fang, Q.-J.; Shcherbakov, D.;
AUTHOR INFORMATION
Corresponding Author
■
̈
Hobbie, S. N.; Sha, S.-H.; Schacht, J.; Vasella, A.; Bottger, E. C.;
David Crich − Department of Pharmaceutical and Biomedical
Sciences, Complex Carbohydrate Research Center, and
Department of Chemistry, University of Georgia, Athens,
Georgia 30602, United States; orcid.org/0000-0003-2400-
0083; Email: david.crich@uga.edu
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susceptibility to the aminoacyltranserferase (3)-IV resistance
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Complete contact information is available at:
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Notes
The authors declare the following competing financial
interest(s): D.C. is a cofounder of and an equity holder in
Juvabis AG, a biotech company developing novel amino-
glycoside antibiotics.
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