Communication
doi.org/10.1002/ejoc.202001203
EurJOC
European Journal of Organic Chemistry
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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The cyclic carbamate of carbasugar 13g was then saponified
with aqueous NaOH in ethanol to obtain partially deprotected
carbasugar 14 in good yield (79 %, Scheme 5). After initial at-
tempts to effectuate final removal of all benzyl ethers following
a reported procedure (1 atm hydrogen pressure of a solution
of benzylated carbasugar in methanol with 10 % Pd/C as a cata-
lyst) failed in our hands,[9] it was realized that the desired con-
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upon addition of trifluoroacetic acid (10 equiv.) giving target
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Scheme 5. Completion of the total synthesis of CGlcN (3).
In summary, an efficient synthetic route towards carba-α-D-
glucosamine (3) has been reported. The stereoselective se-
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