Optimized and Scalable Synthesis of Carba-α-d-Glucosamine

Article abstract of DOI:10.1002/ejoc.202001203

An efficient, high-yielding synthesis of carba-α-d-glucosamine is reported. Key features of this optimized route include an innovative protecting group strategy and an unusual, stereoconvergent Ferrier carbocyclization of a hindered substrate. The sequenc

Full text of DOI:10.1002/ejoc.202001203

Communication
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European Journal of Organic Chemistry
Carbasugars
Optimized and Scalable Synthesis of Carba-α- -Glucosamine
D
Alexander Babczyk,[a][‡] Lukas M. Wingen,[a][‡] and Dirk Menche*[a]
Abstract: An efficient, high-yielding synthesis of carba-α-
D
-
dered substrate. The sequence enables the synthesis of larger
amounts of this structurally novel antibiotic to allow more de-
tailed biological evaluations of its unique mode of action.
glucosamine is reported. Key features of this optimized route
include an innovative protecting group strategy and an
unusual, stereoconvergent Ferrier carbocyclization of a hin-
ribozyme then also catalyzes mRNA self-cleavage,[9,10] which
adds to a unique mode of action. Usually, this mechanism is
necessary for regulation in the process of cell wall biosynthe-
sis.[11] The intracellular concentration of GlcN (α-4), a precursor
of peptidoglycan is regulated by this allosteric inhibition.[12] If
the GlmS riboswitch is activated by CGlcN (3) the cell-wall bio-
synthesis is inhibited because the production of peptidoglycan
is not possible anymore due to a lack of GlcN (α-4). The result
is cell death. Unfortunately, a more detailed analysis of this
unique mode of action as well as further development is se-
verely hampered by supply issues.[9,13,14,15] There are several
synthetic strategies towards carbapyranosides reported in the
literature, using both carbohydrates as starting material[16–20]
and non-carbohydrate approaches.[19,21–25] However, most of
these previous synthetic research does not treat carba analogs
of amino sugars like GlcN (α-4). Consequently, a more efficient
synthetic route to carbasugar 3 is desirable.
Herein, we report the design and implementation of an im-
proved, efficient total synthesis of CGlcN (3), which allows for
reliable and scalable access to this promising antibacterial
agent. Key features of this concise route include a beneficial
uniform protective group strategy and a challenging stereocon-
vergent Ferrier carbocyclization of a hindered epimeric sub-
strate.
Carbapyranosides constitute an important class of natural
products[1] and present key subunits of a variety of elaborated
metabolites.[2] Several of these glycopyranoside analogs dem-
onstrate attractive biological profiles as some enzymes cannot
distinguish these stabilized carbocyclic derivatives from the au-
thentic carbohydrates.[2,3] Prominent examples include cyclo-
phellitol (1, Figure 1) which is a ꢀ-glucosidase inhibitor or the
herbicidal agent carbapyranose MK7067 (2).[2,4,5] Due to higher
stability, carba sugars are often used in drugs to substitute the
more labile glycopyranosides.[6–8]
Figure 1. Structures of cyclophellitol (1), MK7067 (2), α-D-glucosamine (GlcN,
α-4), and its carbocyclic analog carba-α- -glucosamine (CGlcN, 3).
D
Carba-α-
D
-glucosamine (CGlcN, 3) the carbocyclic analog of
α-D
-glucosamine (GlcN, α-4) shows interesting antibiotic activ-
ity against various pathogenic bacteria, including Bacillus sub-
tilis and Staphylococcus aureus.[9] After cellular uptake and C-6
phosphorylation, it effectively activates the glutamine-fructose-
6-phosphate amidotransferase (GlmS) riboswitch in vitro to a
similar extent as the natural substrate α-4. The result is down-
regulation of the GlmS expression.[9] In addition to a mere con-
formational change as observed for other riboswitches, this
As shown in Figure 2, the carbocyclic core 5 of target carba-
sugar 3 was envisioned to arise from a Ferrier rearrangement
of a suitably functionalized pyranoside α/ꢀ-6, in analogy to the
described route.[9,13,15] However, in contrast to this report, a
[a] A. Babczyk, L. M. Wingen, Prof. Dr. D. Menche
Kekulé-Institut für Organische Chemie und Biochemie,
Rheinische Friedrich-Wilhelms-Universität Bonn
Gerhard-Domagk-Str. 1, 53121 Bonn, Germany
E-mail: dirk.menche@uni-bonn.de
https://www.menche.uni-bonn.de/
[‡] Both authors contributed equally to the project
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202001203.
© 2020 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH · This is an open access article under the terms of the
Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
Figure 2. Retrosynthetic analysis of CGlcN (3).
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more bulky substrate bearing a benzyl residue at the anomeric could explicitly show, that either anomer reacts with essentially
oxygen was chosen. This would allow for a more convenient identical yield and selectivity, which opens up the valuable op-
and uniform protective group strategy. It was hoped that fully tion of carrying out the sequence with epimeric mixtures, as
benzylated precursor α/ꢀ-6 would be more easily accessible these converge into the desired epimer at a later step of the
from GlcN (α/ꢀ-4) as cheap and readily available starting mate- route (see below).
Gratifyingly, the key Ferrier carbocyclization[13,29,30] of hin-
dered vinyl ether α/ꢀ-6 towards the desired 5-oxo-carbaglucos-
amine 5 could then be implemented. Optimal results were ob-
rial, in contrast to the previous report utilizing a methyl ether
at the anomeric hydroxyl, which had proved to be difficult to
install.[14,26]
As shown in Scheme 1, the implementation of this synthetic tained with mercuric(II) sulfate in a mixture of dioxane and
design was initiated by Cbz-protection of α/ꢀ-4, which effi- 5 m aqueous sulfuric acid (Scheme 3). Again, the influence of
M
ciently proceeded in aqueous solution with benzyl chlorofor- either C-1 configuration was studied, resulting in a similar yield
mate (80 %).[27] Derived α/ꢀ-7 was then elaborated as benzyl- (58 % and 63 %) and selectivity (7:1 and 6:1), confirming that
idene acetal using benzaldehyde and zinc chloride to access α/ the outcome is not affected by the anomeric form of the start-
ꢀ-8,[13] likewise in high yield (93 %). Importantly, both steps ing material. In both cases, desired (S)-isomer 5 was obtained
were readily scalable (25 g), without the need for chromato- as the major product, regardless of whether the α- the ꢀ- or
graphic purification. Both derivatives resided as inseparable, the mixture of α/ꢀ-6 was used.
rapidly equilibrating mixtures of the α- and the ꢀ-anomer, simi-
lar to parent compound α/ꢀ-4.
Scheme 1. Protection of GlcN (α/ꢀ-4).
Scheme 3. Stereoconvergent Ferrier carbocyclization of anomeric vinyl ethers
α- and ꢀ-6 towards 5-oxo-carbaglucosamine 5.
As shown in Scheme 2 the anomeric position of α/ꢀ-8 was
then benzylated using benzyl bromide with NaH in an efficient
and scalable manner (82 %), confirming our synthetic design
and resolving one of the key limitations of the reported
route.[14] Almost identical amounts of the two anomers were
obtained, which can be separated by column chromatography.
After cleavage of the benzylidene acetal of α/ꢀ-9, the resulting
diol α/ꢀ-10 was selectively converted to monoiodide α/ꢀ-11
by an Appel reaction. The primary hydroxyl function of α/ꢀ-10
reacted much faster[28] and using one equivalent of iodine gave
mono iodinated sugar α/ꢀ-11 exclusively. The remaining free
secondary hydroxyl group was then protected with benzyl
bromide under strong basic conditions (NaH), which also led to
the elimination of HI to obtain vinyl ether α/ꢀ-6, in agreement
with an earlier observation for a related substrate.[13] Again, all
four steps proceeded with improved yields.[13] Furthermore, we
The keto function of 5-oxo-carbaglucosamine 5 was then ho-
mologated by an enol ether Wittig reaction towards enol ether
12 (Scheme 4). As shown in Table 1, different reaction condi-
tions were evaluated for optimization of a reported process (en-
try 1),[13] involving solvents DME (entries 2, 3) and THF (entries
4, 5) with or without co-solvent N,N′-dimethylpropyleneurea
(DMPU). Optimal results were obtained in THF and DMPU, re-
sulting in an improved yield (74 %, entry 5 vs. originally re-
ported 60 %, entry 1). The reaction proceeded with high selecti-
Scheme 4. Homologation of 5-oxocarbaglucosamine 5 and subsequent oxy-
mercuration-reduction of the full carbocyclic backbone 12.
Table 1. Influence of the solvent and DMPU as additive on the yield of vinyl
ether 12.
Entry
Solvent
Cosolvent
Yield
1[13]
2
3
4
5
DME
DME
DME
THF
–
–
60 %
57 %
61 %
54 %
74 %
DMPU (10 equiv)
–
DMPU (10 equiv.)
THF
Scheme 2. Further synthetic elaboration towards vinyl ether α/ꢀ-6.
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vity, giving the (E)-product exclusively. Overall, the procedure 5.3 % overall yield, which compares favorably to a previous
towards 12 was reliable, also on a larger scale, and more than route.[9,13,26] Key features of this improved approach include an
3 g could be readily obtained in the first batch.
Further elaboration of 12 towards protected carbasugar 13
then involved oxymercuration and subsequent reduction of the
innovative protecting group strategy, an unusual Ferrier carbo-
cyclization of a hindered substrate, and optimization of several
previously reported procedures. This new synthetic route
proved to be well-scalable and more than 3 g of the fully func-
tionalized carbocyclic core 12 were obtained in the first batch.
Furthermore, the anomeric influence on the selectivity and
yield of each conversion was studied in detail, demonstrating
that the sequence may be carried out with anomeric mixtures,
as they efficiently converge into the desired epimer in the
course of a beneficial, stereoconvergent Ferrier rearrangement.
This will be important for future scale-up. Following this se-
quence, larger quantities of this novel antibacterial agent may
now be prepared to enable more detailed evaluations of its
unique biological profile and unusual mode of action. Also, the
strategies developed herein may be applicable for the prepara-
tion of designed analogs as well as related carbocycles.
organomercury intermediate,[31] giving
D
-gluco-13g together
-ido configuration 13i (Scheme 4).
The original protocol[13] was again optimized giving the desired
-gluco isomer with improved selectivity (20:1 vs. 7:1). At this
with minor amount of the
L
D
stage, the configurations of 13g and 13i were confirmed by
NOESY-NMR analysis (Figure 3), in combination with key cou-
pling constants. The rather larger values of 5.1 Hz (13g) and
4.6 Hz (13i) for the JH-3, H-4 coupling indicated trans configura-
tions for 13g and 13i. Additionally, the value of 8.1 Hz for the
J
H-4, H-5 coupling constant of 13g confirmed the trans configura-
tion between H-4 and H-5, while no coupling constant could
be determined for the cis coupling of H-4 and H-5 in 13i, due
to unsatisfactory resolution. The transformation of a related
compound of cyclohexanone 5 to the desired D-gluco config-
ured carbon skeleton has also been described in the literature
but with more steps to be carried out.[17] So the method used
here was considered to be more efficient.
Acknowledgments
Financial support was provided by the Deutsche Forschungs-
gemeinschaft (DFG, Project-ID TRR261). We thank Andreas J.
Schneider (University of Bonn) for excellent HPLC support. Open
access funding enabled and organized by Projekt DEAL.
Keywords: Carbasugars · Ferrier carbocyclization · Natural
products · Synthetic methods · Total synthesis
Figure 3. Stererochemical confirmation of
NOESY-correlations.
D-gluco-13g and the L-ido 13i by
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with aqueous NaOH in ethanol to obtain partially deprotected
carbasugar 14 in good yield (79 %, Scheme 5). After initial at-
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Communication
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EurJOC
European Journal of Organic Chemistry
Carbasugars
A scalable route to carba-α- -glucos-
D
amine involves a stereoconvergent
Ferrier rearrangement of hindered
substrates in combination with a uni-
form protective group strategy and
will enable more detailed biological
studies of the unique mode of action
of this potent novel antibiotic.
A. Babczyk, L. M. Wingen,
D. Menche* .......................................... 1–5
Optimized and Scalable Synthesis of
Carba-α--Glucosamine
doi.org/10.1002/ejoc.202001203
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© 2020 The Authors. European Journal of Organic Chemistry
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