Synthesis of Methyl l -Kijanosides by Regio- And Stereoselective Ring Opening of 2-Oxazolidinone -Fused Aziridines

Article abstract of DOI:10.1021/acs.orglett.0c00443

Kijanose is one of the most highly functionalized deoxysugars found in nature and a challenging synthetic target. We found that the ring opening of trisubstituted, 2-oxazolidinone-fused aziridines is regio- and stereoselective, and the azide adduct has the same stereochemistry as that of kijanose after converting the azido to a nitro group. Therefore, both α- and β-methyl l-kijanosides were prepared from ethyl l-lactate in 14% total yield.

Full text of DOI:10.1021/acs.orglett.0c00443

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Letter
Synthesis of Methyl L‑Kijanosides by Regio- and Stereoselective Ring
Opening of 2‑Oxazolidinone-Fused Aziridines
Chi-Yun Liu, Venkatachalam Angamuthu, Wei-Chen Chen, and Duen-Ren Hou*
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ABSTRACT: Kijanose is one of the most highly functionalized deoxysugars found in nature and a challenging synthetic target. We
found that the ring opening of trisubstituted, 2-oxazolidinone-fused aziridines is regio- and stereoselective, and the azide adduct has
the same stereochemistry as that of kijanose after converting the azido to a nitro group. Therefore, both α- and β-methyl L-
kijanosides were prepared from ethyl L-lactate in 14% total yield.
riginally isolated from the acidic hydrolysis of an
α-D-kijanoside start from monosaccharides, require more than
10 steps, and often encounter regio- or stereoselectivity issues
(Scheme 1).38−42 On the contrary, the identified gene cluster
for the biosynthesis of kijanimicin suggests that 10 enzymes are
O
antibiotic kijanimicin (2),1−3 D-methyl kijanosides (1)
are one of the most highly functionalized sugars found in
nature (Figure 1).4 Kijanimicin and its related compounds,
Scheme 1. Reported Syntheses of Methyl Kijanosides
Figure 1. Methyl kijanosides and spirotetronate antibiotics.
including tetrocarcins,5−9 arisostatins,10,11 lobophorins,12−18
and microsporanates,19 belong to the family of spirotetronate
antibiotics,20−23 in which kijanose is the common nitrosugar
linked to the polycyclic aglycone (tetronolide). More than 60
spirotetronate antibiotics have been isolated, and most of these
compounds also exhibit antitumor or other biological activities
that have therapeutic potential.24−31 However, the synthesis or
modifications of the spirotetronates rely heavily on enzymatic
synthesis or semisynthesis, as the preparations and linkages of
the aglycone and the deoxysugars remain a challenging
task.32−37 All of the reported chemical syntheses of methyl
Received: February 3, 2020
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© XXXX American Chemical Society
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required for the production of kijanose, starting from glucose-
1-phosphate.4,43,44 A new and convenient synthesis to access
kijanose and its derivatives should be beneficial for further
studies on spirotetronate antibiotics.
Scheme 3. Syntheses of Trisubstituted, 2-Oxazolidinone-
Fused Aziridines
Scheme 4. Syntheses of Optically Active, Trisubstituted
Aziridines Derived from an (E)-Alkene
To simplify the synthesis of kijanose, we felt that the issue of
regioselectivity during the ring opening of aziridines could be
resolved by using trisubstituted, 2-oxazolidinone-fused azir-
́
idines (4, Scheme 2). Joullie’s group has developed a highly
Scheme 2. Regio- and Stereoselective Ring Opening of
Trisubstituted Aziridines
allylic alcohol 10. Protection of the terminal hydroxyl group
and the removal of the TBS group provided chiral, secondary
alcohol 11, which yielded aziridine 13 after treatment with
iodosylbenzene. The stereochemistry of carbamate 12, that is,
(S)-configuration and (E)-olefin, is conserved during the
aziridination step, as shown in the X-ray crystallography of 13
(Figure 2).
stereo- and regioselective ring opening of ethynyl aziridine 3,
in which nucleophiles prefer to attack the more substituted,
propargylic carbon with inversion of configuration.45−47 The
calculation study indicated that the presence of an alkynyl
group stabilizes the transition state and lowers the activation
energy needed for this pathway.48 We speculated that the
beneficial effect of an alkynyl group in aziridine ring opening
could also be implanted by the 2-oxazolidinone-moiety of 4, as
the ring strain is relieved when the ring opening occurs at the
tertiary carbon. Indeed, ring-opening reactions of mono- and
disubstituted, 2-oxazolidinone-fused aziridines have been
studied49,50 and nicely applied.51 The corresponding trisub-
stituted aziridines have been prepared;51−55 however, their
ring-opening reactions and their stereochemistry have not been
studied and utilized.
Starting with geraniol, 2-oxazolidinone-fused, trisubstituted
aziridine 7 was prepared as a single diastereomer after the
formation of carbamate 6 and further oxidation using
iodosylbenzene (Scheme 3).56 This sequence is more concise
with a better yield of 7 than the previously reported
methods.50,55
Figure 2. ORTEP of 13
On the contrary, the Wittig reaction using the nonstabilized
ylide derived from phosphonium salt 14 provided (Z)-majored
alcohol 15 after the treatment of TBAF (Scheme 5).59,60 The
Z-alkene was assigned on the basis of the observed coupling
between the olefinic proton and the allylic methyl group on 1H
NMR. Alcohol 15 was also converted to aziridine 17.
The results for the ring-opening reactions of three
trisubstituted and 2-oxazolidinone-fused aziridines 7, 13, and
17 are summarized in Table 1. N-nucleophiles, such as sodium
azide and anilines, provided the corresponding single products
with yields up to 98% (entries 1, 2, 6−8, 13, and 14). The X-
ray crystallography of 18 is consistent with the expected ring
opening of 7, that is, occurring at the more substituted carbon
with the stereocenter inverted (Figure 3a). C-nucleophiles,
including cyanide and malononitrile, provided the products in
moderate yield (entries 3, 4, 9, 10, and 15). Excellent yields
Optically active aziridines were prepared from ethyl L-lactate,
which was first protected by a tert-butyldimethylsilyl (TBS)
group as compound 8 (Scheme 4).57,58 Reduction and a
Wittig-type reaction with the stabilized ylide gave the (E)-α,β-
unsaturated ester 9, which was reduced by DIBAL-H to form
B
https://dx.doi.org/10.1021/acs.orglett.0c00443
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Scheme 5. Syntheses of Optically Active, Trisubstituted
Aziridines Derived from a (Z)-Alkene
Figure 3. ORTEP of (a) 18 and (b) 29.
were also obtained with thiophenol (entries 5, 11, and 16).
The reaction of 13 and sodium thiocyanate gave the bicyclic
compound 29, which should derive from the addition of the
carbamate group to the initial SCN adduct. The X-ray
crystallography of 29 indicates that the stereochemistry of
the aziridine ring opening of 13 is also in agreement with the
expected pathway (Figure 3b).
Table 1. Nucleophilic Ring Opening of Aziridines
Compound 30 has the required stereochemistry for L-
kijanose. The 2-oxazolidinone was then hydrolyzed and
converted to methyl chloroformate 34 (Scheme 6). Meth-
Scheme 6. Synthesis of Methyl L-Kijanosides
anolysis of the 1,3-dioxolane yielded both α- and β-pyranose
35 (α/β = 5:4). The azido group was reduced, then oxidized to
give the nitro group, and the aimed α- and β-methyl L-
kijanoside, 36a and 36b, were isolated after column
chromatography. Their NMR spectra were consistent with
those of 1a and 1b.2 Thus methyl L-kijanosides were
synthesized for the first time from ethyl L-lactate in 14%
overall yield. Because ethyl D-lactate is also commercially
available, this synthesis could also be applied to prepare natural
D-kijanose.
In summary, we have shown that the ring-opening reactions
of trisubstituted, 2-oxazolidinone-fused aziridines, derived from
both (E)- and (Z)-olefins, are highly regioselective and
stereoselective. This method has been applied to prepare the
deoxysugar kijanose efficiently and circumvent the short-
comings often encountered in the previous syntheses.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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a
b
Isolated yields. 1 mmol scale.
Experimental procedures and spectral data of com-
pounds described herein (PDF)
C
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AUTHOR INFORMATION
Corresponding Author
■
Duen-Ren Hou − Department of Chemistry, National Central
University, Jhong-li 32001, Taiwan; orcid.org/0000-0003-
1072-2915; Email: drhou@ncu.edu.tw
Authors
Chi-Yun Liu − Department of Chemistry, National Central
University, Jhong-li 32001, Taiwan
Venkatachalam Angamuthu − Department of Chemistry,
National Central University, Jhong-li 32001, Taiwan
Wei-Chen Chen − Department of Chemistry, National Central
University, Jhong-li 32001, Taiwan
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101, 4561.
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Ministry of Science and
Technology (MOST 108-2113-M-008-003 and MOST 107-
2113-M-008-014), Taiwan, is gratefully acknowledged. We
thank the Institute of Chemistry, Academia Sinica, and the
Valuable Instrument Center at National Central University for
mass analysis and X-ray crystallography.
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