Synthesis, Structural Reassignment, and Antibacterial Evaluation of 2,18-Seco-Lankacidinol B

Article abstract of DOI:10.1002/anie.201808612

Lankacidins are a group of polyketide natural products with activity against several strains of Gram-positive bacteria. We developed a route to stereochemically diverse variants of 2,18-seco-lankacidinol B and found that the stereochemical assignment at C4 requires revision. This has interesting implications for the biosynthesis of natural products of the lankacidin class, all of which possessed uniform stereochemistry prior to this finding. We have evaluated 2,18-seco-lankacidinol B and three stereochemical derivatives against a panel of pathogenic Gram-positive and Gram-negative bacteria.

Full text of DOI:10.1002/anie.201808612

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Accepted Article
Title: Synthesis, Structural Reassignment, and Antibacterial Evaluation
of 2,18-Seco-Lankacidinol B
Authors: Yanmin Yao, Lingchao Cai, and Ian B. Seiple
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Angewandte Chemie International Edition
10.1002/anie.201808612
COMMUNICATION
Synthesis, Structural Reassignment, and Antibacterial Evaluation
of 2,18-Seco-Lankacidinol B
Yanmin Yao, Lingchao Cai, and Ian B. Seiple*
Abstract: Lankacidins are a group of polyketide natural products
with activity against several strains of Gram-positive bacteria. We
developed a route to stereochemically diverse variants of 2,18-seco-
lankacidinol B and found that the stereochemical assignment at C4
requires revision. This has interesting implications for the
biosynthesis of natural products of the lankacidin class, all of which
possessed uniform stereochemistry prior to this finding. We have
including several stereochemical variants. Herein we report the
initial results from those efforts, which have provided material for
microbiological evaluation and have resulted in a structural
reassignment of 2,18-seco-lankacidinol B (4).
O
Me
O
HO
HN
Me
O
A.
B.
HN
O
evaluated 2,18-seco-lankacidinol
B
and three stereochemical
O
HN
Me
O
O
Me
Me
Me
Me
Me
Me
derivatives against a panel of pathogenic Gram-positive and Gram-
negative bacteria.
3
18
Me
4
5
4
5
1
8
15
O
O
O
base -CO2
7
11
13
HO
OH
OH
HO
OH
Me
Me
HN
O
The lankacidin group of natural products was first discovered in
the extracts of Streptomyces rochei over fifty years ago and
contain an unusual 17-membered macrocyclic ring and a highly
Me
lankacidin C (1)
lankacidinol (2)
Me
H
N
O
O
[
1]
18
Me
OH
Me
substituted β-keto-δ-lactone function (Figure 1A). Lankacidin C
1) has inhibitory activity equal to or better than erythromycin
O
OH 18
O
β-keto-δ-lactone core
Me
2
Me
2
Me
Me
Me
(
4
5
4
5
retro-
acid
against many species of Gram-positive bacteria, but is not
susceptible to common forms of erythromycin resistance,
Mannich
O
O
O
O
OH
O
HO
OH
HO
OH
[
2]
making it a promising candidate for further development. In an
effort to improve the therapeutic potential of lankacidins,
McFarland and colleagues at Pfizer pursued structural
modifications by semisynthesis, but their efforts were limited by
the chemical instability of the β-keto-δ-lactone core, which is
Me
Me
O
Me
Me
H
2
,18-seco-lankacidinol A (3)
2,18-seco-lankacidinol B (4)
reported structure)
O
(
Figure 1. A. Selected members of the lankacidin class of natural products,
with structural differences compared to lankacidin C (1) highlighted in blue. B.
Chemical instability of the β-keto-δ-lactone core structure.
[
2b]
required for potent antibiotic activity (Figure 1B).
Fully
synthetic methods to generate lankacidin derivatives could
circumvent many of the limitations of semisynthetic approaches
and enable systematic investigation of structure–activity effects
In the design of our route to lankacidins, we prioritized
convergency and the use of reactions that we anticipated would
have high functional group tolerance so as to streamline the
synthesis of derivatives. Thus, our first efforts were aimed at the
synthesis of two halves of approximately equal complexity, right
half 11 and left halves 17–20 (Scheme 1). The synthesis of right
[
3]
in the class. Three fully synthetic routes to lankacidin natural
[
4]
products have been reported, including an elegant recent
[
4d]
biomimetic approach by Hong and colleagues. To the best of
our knowledge, the effects of modifications of the β-keto-δ-
lactone on antibiotic activity have not yet been systematically
[
5]
investigated.
[8]
half 11 commences with exposure of oxirane 5 to lithium
Earlier this year, Lu et al. reported the isolation and
structural elucidation of 2,18-seco-lankacidinols A (3) and B (4),
two new members of the lankacidin class that lack the C2-C18
[9]
acetylide (generated from 1-bromopropene and butyllithium)
followed by addition of tert-butyldimethylsilyl chloride to generate
protected diol
7 in 78% yield (Scheme 1A). Oxidative
[
6]
bond that is common to other family members. 2,18-Seco-
lankacidinol B (4) is the first acyclic member of the lankacidin
class to be isolated and likely arises from a modified biosynthetic
deprotection of the PMB group, Mitsunobu displacement of the
resulting primary alcohol with benzo[d]thiazole-2-thiol, and in situ
oxidation of the resulting thioether delivers sulfone 8 in 77%
yield over 2 steps. Julia–Kociensky olefination with commercially
[
7]
pathway. During the course of our efforts to develop a modular
platform for the synthesis of lankacidin antibiotics, we
synthesized acyclic intermediates that closely resembled 4,
available aldehyde 9 provides dienoate 10 in 80% yield as a
[10]
single stereoisomer.
Reduction of the ethyl ester to the
primary alcohol (DIBAL-H) followed by palladium-mediated
[
11]
hydrostannylation delivers right half 11 in 84% yield. The route
to 11 requires 6 steps from 5 and 6, proceeds in 40% overall
yield, and has enabled the production of multi-gram quantities of
this key intermediate.
[*]
Dr. Yanmin Yao, Dr. Lingchao Cai, Prof. Ian. B. Seiple
Department of Pharmaceutical Chemistry and Cardiovascular
Research Institute
University of California, San Francisco
San Francisco, CA 94158, United States
E-mail: ian.seiple@ucsf.edu
We designed our route to the β-keto-δ-lactone functionality to
enable stereochemical control within the ring. By leveraging the
Evans aldol reaction with common intermediate 15 as an
electrophile, it would be possible to generate all four possible
Supporting information for this article is given via a link at the end of
the document.
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Angewandte Chemie International Edition
10.1002/anie.201808612
COMMUNICATION
diastereomeric combinations at C4 and C5 in a predictable
made by comparison to similar intermediates in Hong’s
[
4d]
1
1
fashion. As shown in Scheme 1B, common intermediate 15 is
lankacidin synthesis
and by H– H NOESY NMR analysis of
[
12]
prepared by an aldol reaction between β-iodoacrolein (12) and
acetyl thiazolidinethione 13 (70% yield) followed by silyl
protection of the resulting secondary alcohol and reductive
cleavage of the auxiliary (91%, 2 steps). To access the 4R,5R
and 4S,5S diastereomers, an anti-selective aldol reaction is
required, and our efforts were informed by elegant work by Hong
the final compounds 4 and 23 (see Scheme 2 and supporting
information).
To access the 4R,5S and 4S,5R stereochemical variants,
syn-aldol reactions are required. Under conditions reported by
[
13]
Evans and coworkers,
syn-aldol reaction of β-keto imide 21
[
4d]
with aldehyde 15 followed by lactonization provides 4R,5S left
half 19 in 98% yield over 2 steps. Similarly, aldolization of β-keto
imide 16 followed by lactonization provides 4S,5R left half 20 in
and coworkers in their synthesis of lankacidinol (2).
Thus,
exposure of the boron enolate of β-keto imide 16 to aldehyde
5 in the presence of excess chlorodicyclohexylborane provides
[
13]
1
9
0% yield over 2 steps. Left half 20 was transformed into its
two anti-aldol products, which lactonize upon exposure to
sodium methoxide to provide 4R,5R left half 17 (61% isolated
yield) and 4S,5S left half 18 (21% isolated yield).
Stereochemical assignments of the two diastereomers were
ferrocene carboxylate 22, which readily crystallized from ethyl
ether. X-ray crystallographic analysis confirmed its relative and
absolute stereochemistry.
A. Synthesis of right half 11
1
. DDQ
NaHMDS,
OEt Me
HO
O
OEt
Me
OPMB
2. PPh , DEAD,
3
N
S
O
1. DIBAL-H
2. Pd(OAc)
PCy , HSnBu
3
Me
S
N
O
2
,
HMPA,
OPMB
OTBS
SH
then TBSCl Me
O
9
H
3
O
2
S
5
6
Me
Me
78%
then H O ,
2
Mo
2
O
80%, >20:1 dr
84%, 2 steps
3
Bu Sn
Li
OTBS
(NH
4
)
6
7
24
,
OTBS
OTBS
Me
Me
77%, 2 steps
7
8
10
right half 11
B. Synthesis of 4(R),5(R)-left half (17) and 4(S),5(S)-left half (18) by means of an anti-selective aldol–lactonization cascade.
H
OH
OH
S
TiCl
4
,
1.TBSOTf, 2,6-lut.
2. DIBAL-H
H
O
O
O
cHex
2 2
BCl, Me EtN,
then NaOMe
Me
Me
Me
4
Me
O
O
I
S
iPr
4
5
iPr
EtN
N
1
2
2
5
+
O
N
O
+
S
O
O
O
7
0%
O
91%, 2 steps
Me Me
Bn
82%, dr 3:1
S
i
Pr
TBSO
I
N
TBSO
I
TBSO
I
HO
I
1
4
15
16
4(R),5(R)-left half (17)
4(S),5(S)-left half (18)
Me
O
1
3
C. Synthesis of 4(R),5(S)-left half (19) and 4(S),5(R)-left half (20) by means of a syn-selective aldol–lactonization cascade.
1.
1
.
O
O
O
O
O
O
O
O
O
OH
N
O
N
O
OH
FeCp
Me
2
Me
Me
O
Me Me
Bn
Me Me
16 Bn
Me
Me
O
Fe
Cl
H
Me
4
5
4
5
2
1
4
5
2
O
TiCl
4
, iPr
EtN
2
O
TiCl EtN
, iPr
4
2
O
pyridine
32%
O
O
2
. NaOMe
TBSO
I
2. NaOMe
TBSO
I
TBSO
I
TBSO
I
9
8%, 2 steps
90%, 2 steps
4
(R),5(S)-left half (19)
15
4(S),5(R)-left half (20)
22
CCDC 1851856
Scheme 1. Synthesis of coupling partners en route to 2,18-seco-lankacidinol B. A. Synthesis of right half 11. B. Synthesis of left halves 17 and 18 by means of an
anti-selective aldol–lactonization cascade. C. Synthesis of left halves 19 and 20 by means of syn-selective aldol followed by lactonization.
a
To complete the synthesis of 2,18-seco-lankacidinols B bearing
all four C4,C5-diastereomeric variations, we attached left half 11
to each right half 17–20 by means of Stille cross coupling
report, see supporting information), and the X-ray
crystallographic data of ferrocene carboxylate 22.
1
13
Much to our surprise, the H- and C-NMR spectra of 4
[
6]
reactions (Scheme 2). The use of
a
tin scavenger
and a highly polar solvent (DMSO) greatly
accelerates the reaction and results in increased isolated yields
(Figure 2, teal traces) did not match the reported spectra of
2,18-seco-lankacidinol B (Figure 2, black traces). Most notably,
the methine proton off of C5 and the C20 methyl protons were
[
14]
(
2 2 4
Ph PO NBu )
[
15]
13
(
see supporting information for optimization details).
These
significantly shifted, as were the C signals corresponding to C3,
convergent coupling reactions proceed efficiently (73–78% yield)
without the need for protection of the free enol ether at C2/C3 or
the primary alcohol at C18. Desilylation of each of the Stille
products with hydrogen fluoride provides 2,18-seco-
lankacidinols B (4, 23–25). Each of the final products 4 and 23–
C5, C6, and C20. Taken together, these discrepancies
suggested to us that the structural differences resided on the β-
keto-δ-lactone ring. We then compared the spectra of remaining
three diastereomers to the reported spectra, we found that the
spectra of the 4R,5S diastereomer 25 (Figure 2, red traces),
which has the opposite C4 stereochemistry as the originally
reported structure, matched very well, necessitating a structural
reassignment of 2,18-seco-lankacidinol B from structure 4 to
structure 25.
2
5 were oils, and we were unable to obtain X-ray-quality crystals
of derivatives thereof. However, the structural assignments are
strongly supported by the Evan’s aldol stereochemical models,
nuclear Overhauser effect data (not included in the isolation
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Angewandte Chemie International Edition
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COMMUNICATION
We measured the inhibitory activity of 4 and 23–25 against a
panel of Gram-positive and Gram-negative bacteria using
levofloxacin as a positive control (Table 1). All four compounds
exhibited no activity up to a concentration of 64 µg/mL against
most strains, although 4, 23, and 25 exhibited weak activity
against H. influenzae ATCC 49247 (32 µg/mL). These data are
consistent with the previously reported weak inhibitory activity of
the biosynthesis. Alternatively, it is possible that epimerization of
the C20 methyl group occurs independent of the biosynthetic
machinery, and may be driven by macrocyclic conformational
stability. The biosynthetic origin of the stereochemical
inconsistencies at C4 remains an interesting unsolved question.
2
,18-seco-lankacidinol B against B. subtilis and S. aureus
[
6]
(
obtained with disk diffusion tests). It is interesting to note that
all four stereochemical derivatives of the β-keto-δ-lactone ring
exhibit poor inhibitory activity, suggesting that the C18
pyruvamide function or the macrocyclic ring (or both) are
required for the antimicrobial properties of the class.
OH
1
8
OH
1
. right half 11
Pd(PPh , CuTC
Ph PO NBu
OH
Me
2
Me
0Me
2
3
)
4
Me
Me
O
4
5
2
2
4
4
5
75%
O
O
O
2
. HF•Py
85%
HO
OH
TBSO
I
Me
4
(R),5(R)-2,18-seco-lankacidin B (4)
4
(R),5(R)-left half (17)
spectroscopic data does not match reported data
(reported structure–misassigned)
OH
1
8
1
. right half 11
Pd(PPh , CuTC
Ph PO NBu
OH
O
OH
Me
3
)
4
0Me
Me
2
2
Me
Me
O
2
2
4
4
5
4
5
1
13
7
5%
Figure 2. H- and C-NMR spectral comparison of 4 (teal) and 25 (red) to the
O
[6]
O
spectra of the natural product (black). Horizontal axes are expressed in parts
per million (ppm).
2
. HF•Py
85%
HO
OH
TBSO
I
Me
4
(S),5(S)-2,18-seco-lankacidin B (23)
4
(S),5(S)-left half (18)
spectroscopic data does not match reported data
OH
In conclusion, we have developed the first fully synthetic route to
acyclic members of the lankacidin class in a linear sequence of
1
8
OH
O
1
. right half 11
Pd(PPh , CuTC
Ph PO NBu
Me
Me
OH
0Me
3 4
)
2
2
4
5
≤
8 steps from simple precursors (≤10 steps from commercially
Me
Me
O
2
2
4
4
5
7
3%
O
available compounds). This route enabled investigation of
stereochemical variability on the β-keto-δ-lactone core, resulting
in the first chemical synthesis of 2,18-seco-lankacidinol B and
evidence that the original stereochemical assignment of C4
requires revision from R to S. Additionally, we conducted the first
evaluation of stereochemically diverse, acyclic lankacidin
derivatives against a panel of Gram-positive and Gram-negative
bacteria, the results of which suggest that the macrocyclic ring
or the C18 pyruvamide (or both) are required for substantial
antibacterial activity. Efforts to generate cyclic lankacidin
derivatives that grant insight into origin of C4 stereochemical
diversity and have improved chemical stability are underway.
O
2
. HF•Py
81%
HO
OH
TBSO
I
Me
4
(R),5(S)-2,18-seco-lankacidin B (24)
spectroscopic data does not match reported data
4
(R),5(S)-left half (19)
OH
1
8
OH
O
1
. right half 11
OH
Me
Me
Pd(PPh , CuTC
Ph PO NBu
3
)
4
0Me
2
4
5
2
Me
Me
O
2
2
4
4
5
78%
O
O
2
. HF•Py
81%
HO
OH
TBSO
I
Me
4
(S),5(R)-2,18-seco-lankacidin B (25)
spectroscopic data matches reported data
reassigned structure)
4
(S),5(R)-left half (20)
(
Scheme 2. Convergent coupling of right half 11 to left halves 17–20 and
structural reassignment of 2,18-seco-lankacidinol B.
Table 1. Inhibitory activities of 2,18-seco-lankacidinols against selected strains
[
a,b]
of Gram-positive and Gram-negative bacteria.
The reassignment of 4 to 25 makes it stereochemically unique
among reported lankacidin-class natural products, all of which
have been assigned the opposite stereochemistry at C4. This
raises interesting questions about the biosynthesis of 25. The
C20 methyl groups of lankacidin C (1) and lankacidinol (2) are
proposed to be installed by a methyltransferase in the LkcF
module of the lankacidin polyketide synthase, prior to
[
7]
macrocyclization. It is possible that the analogous methyl
transfer in the biosynthesis of 25 proceeds with the opposite
stereochemical preference, or that epimerization occurs during
[
a] Values given in µg/mL, [b] ATCC = American Type Culture Collection.
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Angewandte Chemie International Edition
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COMMUNICATION
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Acknowledgements
This work was supported by the National Center for Advancing
Translational Sciences of the National Institutes of Health
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Entry for the Table of Contents
COMMUNICATION
The first fully synthetic route to 2,18-
seco-lankacidinol B is reported. This
route enabled the synthesis of
stereochemically diverse derivatives,
resulting in the reassignment of the
reported stereochemistry at C4. This
finding has interesting implications for
the biosynthesis and biological activity of
natural products of the lankacidin class.
OH
OH
1
8
18
OH
O
OH
O
Me
Me
Me
Me
Me
Me
Yanmin Yao, Lingchao Cai, Ian B.
Seiple*
4
5
2
4
5
2
O
O
Page No. – Page No.
HO
OH
HO
OH
Synthesis, Structural Reassignment,
and Antibacterial Evaluation of 2,18-
Seco-Lankacidinol B
Me
Me
4
(R),5(R)-2,18-seco-lankacidin B 4(S),5(R)-2,18-seco-lankacidin B
(reported structure–misassigned)
(reassigned structure)
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