Design and Synthesis of Orthogonally Protected D- and L-β-Hydroxyenduracididines from D-lyxono-1,4-Lactone

Article abstract of DOI:10.1021/acs.orglett.6b02444

A practical synthesis of the orthogonally protected d- and l-β-hydroxyenduracididines (d- and l-βhEnds), the unique, nonproteinogenic α-amino acids found in mannopeptimycin antibiotics, is described. We appropriately applied d-lyxono-1,4-lactone derivativ

Full text of DOI:10.1021/acs.orglett.6b02444

Letter
pubs.acs.org/OrgLett
Design and Synthesis of Orthogonally Protected D- and L‑β-
Hydroxyenduracididines from D-lyxono-1,4-Lactone
Cheng-Kun Lin, Chung-Chien Hou, Yi-Yong Guo, and Wei-Chieh Cheng*
Genomics Research Center, Academia Sinica, 128, Section 2, Academia Road, Taipei 11529, Taiwan
S
* Supporting Information
ABSTRACT: A practical synthesis of the orthogonally protected D-
and L-β-hydroxyenduracididines (D- and L-βhEnds), the unique,
nonproteinogenic α-amino acids found in mannopeptimycin
antibiotics, is described. We appropriately applied D-lyxono-1,4-
lactone derivatives as a starting template and investigated two
transformations: (i) reduction of the lactone in a two-step sequence
and (ii) regioselective ring opening of the benzylidene acetal. By
careful evaluation of reaction conditions, multigram amounts of both
orthogonally protected D- and L-βhEnds were successfully prepared.
acterial infections constitute a grave threat to human
Bhealth, and new molecules, targets, and treatments to
combat multidrug resistant bacteria, such as MRSA (methi-
cillin-resistant Staphylococcus aureus), VRE (vancomycin-
resistant Enterococcus), and MDR-TB (multidrug-resistant
tuberculosis) are urgently sought.1 Instead of developing
molecules that block peptidoglycan-related enzymes’ biological
functions, recent reports show targeting biosubstrates of
peptidoglycan biosynthesis becomes a more attractive and
promising approach to develop new antibiotics.2 For example,
vancomycins have been claimed to target the D-Ala-D-Ala
moiety of Lipid II, which is an essential membrane-anchored
cell-wall precursor, to severely impair peptidoglycan (PGN)
biosynthesis. Unfortunately, overuse of the vancomycins has led
to the emergence of resistant bacterial Enterococci strains since
the mid-1980s.3
Among current naturally occurring glycopeptide antibiotics,4
mannopeptimycins 1 (Figure 1), isolated from a strain of
Streptomyces hygroscopicus, LL-AC98, are a novel class of cyclic
glycopeptide antibiotics with potent activity against clinically
important Gram-positive pathogens, including MRSA and
VRE.5 Although mannopeptimycins have been proposed to
target Lipid II,6 their detailed interactions with Lipid II or
mechanisms of action still are not clear. Such studies would be
invaluable for the development of novel mannopeptimycin
antiobiotics, but progress is hampered by a paucity of scalable
synthetic routes for these complex molecules and their and
building blocks, especially protected D- and L-βhEnds.
Figure 1. Structure of mannopeptimycins 1 and both protected D- and
L-βhEnds.
development of practical methods for their preparation is of
paramount importance.
To date, several methods have been reported by us8 and
others9 for the preparation of βhEnds. The most common
strategy is to use a chiral amino acid or amino acid derivative
such as Garner’s aldehyde or (S)-serinol as the starting
material; build out the carbon backbone by conjugation; and
then install the hydroxyl, amino, and carboxylic acid group
functionality by asymmetric dihydroxylation. Unfortunately,
separation of two enoate intermediates and/or side products
Structurally, the mannopeptimycin core is based on two
unique nonproteinogenic α-amino acids, both the D and
L
forms of βhEnd, which are derived from arginine by post-
translational modification.7 βhEnd contains three contiguous
stereogenic centers at C2, C3, and C4 and a high density of
functional groups including an α-amino acid, hydroxyl group,
and cyclic guanidine moiety. Because of their structurally
unique and interesting but unexplored biological properties, the
Received: August 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02444
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
after the asymmetric dihydroxylation step is very tedious, which
greatly limits this synthetic approach.
followed by the protection of the amino group with
trifluoroacetic anhydride (TFAA), gave N-TFA protected 8
(79% over two steps). Subsequent conversion of the hydroxyl
group to the azido group at the C4 position with concomitant
inversion of the chirality into the desired 4S configuration was
performed in two steps (80% yield) to give azide 9. Reduction
of azide 9 with tin(II) chloride followed by guanidinylation
with 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea in
the presence of mercury(II) chloride gave guanidine 10 (51%
over two steps).16
As our research interests include the preparation of
glycopeptide antibiotics and bacterial peptidoglycan compo-
nents including Lipid II, as well as the use of these molecules
for biological studies,10 we realized that development of
practical methods for the preparation of both βhEnds is a
prerequisite for the systematic investigation of mannopeptimy-
cin glycopeptide antibiotics.
To date, use of the chiral sugar pool as starting material for
the preparation of the βhEnds has not been extensively
explored.11 D-lyxono-1,4-Lactone 2 is a versatile building block
originally developed by Fleet12 and was considered by us as a
starting material for the asymmetric synthesis of protected D-
and L-βhEnds (Scheme 1). Lactone 2 already possesses intrinsic
As shown in Scheme 3, regioselective reductive ring opening
of benzylidine acetal in 10 was carried out under several typical
Scheme 3. Attempts for Selective Ring Opening or Removal
of Benzylidine of 10
Scheme 1. General Route To Prepare Both D- and L-β-
βhEnds from Azide 3 and 4
conditions such as AlCl3/BH3−NMe3, AlCl3/BH3−THF, or
TMSOTf/BH3−THF. Unfortunately, no desired compound
was observed. Besides, direct removal of benzylidene acetal in
10 under acidic conditions also did not work well. On the basis
of the analysis of mass spectra of crude samples, the unfavorable
δ-lactone or Cbz-deprotected compound was observed.
These disappointing results prompted us to develop a new
synthetic route. After our further evaluation and design, it was
decided to reduce the ester group in azidolactone 3 to form diol
13 (95%)17 followed by selective protection of the primary
alcohol with a bulky TBDPS group to give 14 (Scheme 4).
Expectedly, guanidine 17 was successfully prepared in multi-
gram levels following similar transformations as described in
Scheme 2.
three stereogenic centers, and no extra conjugation with other
backbone fragments would be needed. Also, it can be easily
converted into D-xylono-azide 3 and D-lyxono-azide 4.13
Herein, we report our original design in order to develop a
straightforward and scalable synthetic approach toward the
preparation of orthogonally protected βhEnds 5 and 6, starting
from accessible azidolactones 3 and 4, respectively.
Our synthesis started with the preparation of intermediate 10
(Scheme 2). Enantiopure D-xylono-azide 3, derived from D-
lyxono-1,4-lactone 2, was hydrolyzed14 and methylated15 with
iodomethane under mild conditions to give azido ester 7.
Reduction of the azido group of 7 with tin(II) chloride,
With guanidine 17 in hand, regioselective reductive ring
opening of benzylidine acetal was tested again (Scheme 5). As
shown in Table 1, initial attempts to treat 17 with borane-type
reducing agents in the presence of Lewis acids resulted in either
Scheme 4. Synthesis of Guanidine 17
Scheme 2. Synthesis of Guanidine 10
B
DOI: 10.1021/acs.orglett.6b02444
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Scheme 5. Synthesis of Protected D-βhEnd 5 from
Table 2. Conversion of D-lyxono-Azidolactone 4 to Diol 20
Intermediate 17
entry
conditions
yield (%)
trace
1
2
3
4
NaBH4, MeOH, 0 °C, 2 h
LiBH4, THF, 0 °C, 2 h
L-Selectride, THF, −50 °C, 2 h
(1) DIBAL, DCM, 0 °C, 1 h
(2) NaBH4, MeOH, 0 °C, 1 h
a
64
a
Isolated yield by flash column chromatography.
Table 1. Regioselective Reductive Ring Opening of
Benzylidene Acetal 17
Scheme 6. General Transformations To Prepare Protected L-
βhEnd 6 from Diol 20
entry
conditions
yield (%)
trace
1
2
3
4
5
BH3−THF, TMSOTf, DCM, 0 °C
BH3−THF, Cu(OTf)2, DCM, 0 °C
BH3−NMe3, AlCl3, DCM, ether, 0 °C
NaBH3CN, TiCl4, MeCN, 0 °C
a
38
a
b
NaBH3CN, TiCl4 (1M in DCM), MeCN, 0 °C
60 (56)
a
b
Isolated yield by flash column chromatography. Gram-scale
preparation of 18 (5 g).
acetal opening, intramolecular cyclization, and oxidation were
performed to successfully generate the orthogonally protected
L-βhEnd 6 (20% over 11 steps from 20), as was done for D-
βhEnd 5.
the decomposition of starting material or no reaction (Table 1,
entries 1−3).18 In contrast, use of sodium cyanoborohydride in
the presence of titanium(IV) chloride gave the desired alcohol
18 with excellent regioselectivity (entries 4 and 5).19 Use of a
dilute solution of titanium(IV) chloride (1 M in dichloro-
methane) was found to result in a higher yield compared with
neat titanium(IV) chloride (entries 4 vs 5).
Conversion of 18 to 19 was first performed by conversion of
the primary alcohol of 18 to a mesylate group followed by in
situ intramolecular nucleophilic substitution (Scheme 5).
Mitsunobu conditions were impractical as the desired product
was contaminated with DIAD-derived hydrazine and triphe-
nylphosphine, and its purification was found to be laborious.
After removal of the silyl protecting group with TBAF in THF,
the resulting primary alcohol 19 was oxidized under Anelli’s
conditions (Zhao’s modification, NaClO2, NaOCl, TEMPO) to
provide the protected D-βhEnd 5 in 82% yield.20
With a feasible route for the preparation of D-βhEnd 5 in
hand, we attempted a similar approach for the preparation of
the protected L-βhEnd 6, starting from compound 4.
Unexpectedly, the reduction of D-lyxono-azidolactone 4 (4 to
20) was found to behave very differently compared with D-
xylono-azidolactone 3 (3 to 13). As summarized in Table 2, no
desired diol 20 was obtained when sodium borohydride or
lithium borohydride was used (entries 1 and 2). When L-
Selectride was applied, only a trace amount of the product was
observed (entry 3). In the end, a two-step reduction sequence
was successfully developed in which lactone 4 was first reduced
to its corresponding lactol with DIBAL and then reduced to the
diol 20 with sodium borohydride in reasonable yield (64% over
two steps; entry 4).21
In conclusion, a straightforward, practical method for the
preparation of both orthogonally protected D- and L-βhEnd has
been developed. Our method is distinct from those previously
reported because it starts from D-lyxono-lactone derivatives
rather than chiral amino acids and is therefore uniquely
advantageous. First, this starting material has a built-in chirality
(three stereogenic centers), and therefore, no installation of
extra chiral centers is needed. Second, the starting material
already possesses an appropriate length of backbone, so no
carbon−carbon bond-forming steps are required. To reach our
goal, several important transformations, including an amino
group installation, cyclic guanidine formation, reduction of the
lactone in a two-step sequence, and regioselective ring opening
of the benzylidene acetal have been established. Promisingly,
this scalable method to prepare these two unique amino acids
allows for the systematic study of the mannopeptimycin series
of natural products and the development of new antibiotics.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02444.
Experimental procedures and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wcheng@gate.sinica.edu.tw.
Notes
As shown in Scheme 6, several straightforward trans-
formations including O- or N-protection, installation of the
second amino group, guanidinylation, selective benzylidene
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b02444
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ACKNOWLEDGMENTS
■
We thank Academia Sinica and the Ministry of Science and
Technology (MOST) for financial support.
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DOI: 10.1021/acs.orglett.6b02444
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