Biomimetic Synthesis of Lankacidin Antibiotics

Article abstract of DOI:10.1021/jacs.7b08500

We devised short syntheses of lankacidinol and lankacyclinol that feature biomimetic Mannich macrocyclization. The modular construction of the carbon framework of these compounds is amenable to rapid structural diversification for the development of antib

Full text of DOI:10.1021/jacs.7b08500

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Communication
Biomimetic Synthesis of Lankacidin Antibiotics
Kuan Zheng, Defeng Shen, and Ran Hong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08500 • Publication Date (Web): 30 Aug 2017
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Biomimetic Synthesis of Lankacidin Antibiotics
Kuan Zheng1,2, Defeng Shen1,2, and Ran Hong1,*
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1 Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 345 Lingling Road, Shanghai 200032, China;
2 University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China.
Supporting Information Placeholder
target the eubacterial large ribosomal subunit at the peptidyl transꢀ
ABSTRACT: We devised short syntheses of lankacidinol and
lankacyclinol that feature biomimetic Mannich macrocyclizations.
The modular construction of the carbon framework of these comꢀ
pounds is amenable to rapid structural diversification for the deꢀ
velopment of antibiotic and antitumor agents.
ferase center, reigniting their promise for medicinal applications.11
More interestingly, recent studies have revealed that lankacidin
enhances tubulin assembly and displaces taxoids from their bindꢀ
ing site.12
The growing emergence of bacterial resistance, especially for
multidrug resistance phenotypes, has become a major concern to
public health.1 In the past seven decades, the activityꢀguided idenꢀ
tification of antibiotics from microbial sources has disclosed nearꢀ
ly 28,000 compounds, but only less than 1% these compounds
have found direct use as clinical drugs.2 It is no doubt that the
majority of structurally “old” scaffolds remain to be scrutinized.
For those structures with condensed functional groups, the opporꢀ
tunity to reveal novel mechanisms of action is particularly intriꢀ
guing for the development of nextꢀgeneration durable antibiotics
with additional synergistic effect.3 Previously demonstrated as
oral antibiotics for infected livestock, lankacidins (Scheme 1)
have the potential to be part of a new generation of antibiotics to
combat conventional macrolideꢀresistant pathogenic strains.4
However, the labile and densely functionalized moieties within
this family of complex polyketides pose a formidable challenge
for chemical total synthesis and derivatization, thus impeding
further medicinal development for clinical use.
Scheme 1. Lankacidins: structures and biosynthesis. (A) Selected
structures of lankacidins (the carbon numbering is adapted to the biosynꢀ
thesis proposal, see ref 19); other trivial names are shown in parentheses.
(B) Biogenesis proposal. FAD, flavin adenine dinucleotide; PCP, peptidyl
carrier protein.
Lankacidins consist of a class of hybrid polyketideꢀpeptide meꢀ
tabolites that feature a transannulated heptadecane (17ꢀmembered)
framework. The first congener of this category is lankacidin C (1),
which was first described by Gäumann and coworkers in 1960,5
and the stereochemistry was firmly established by Xꢀray analysis
of its hydrazone derivative.6 Lankacidins typically possess dense
functional groups that feature two skipped E,Eꢀdienylic alcohols,
a fully substituted βꢀoxoꢀδꢀlactone and a rare amide residue adjaꢀ
cent to the bridgehead allꢀcarbon quaternary stereocenter (1ꢀ4,
Scheme 1A). The amide side chain is varied by lactoyl or pyruꢀ
voyl groups. Decarboxylated derivatives (losing C1, such as 5)
were also isolated from either Streptomyces rochei or other natuꢀ
ral sources.7 In contrast to a variety of glycosidic macrolides,8 the
biological evaluation of these aglycone compounds revealed
strong antimicrobial activities against Gramꢀpositive pathogens4
and in vivo antitumor activity against certain cancer cell lines.9 Its
impressive antimicrobial activity guided the launch of lankacidin
A (2) (drug name: Sedecamycin) into the market as an oral veteriꢀ
nary antibiotic (e.g., treatment of swine dysentery).10 Although
the mechanism of action remains unclear, crystallographic analyꢀ
sis revealed that lankacidin C (1) and lankamycin synergistically
Although a certain number of lankacidin derivatives have been
prepared through enzymatic esterification or sophisticated chemiꢀ
cal transformations, these approaches are rather limited, as the
modification of the parent structure was found to be difficult due
to facile cleavage of the C2ꢀC18 bond upon exposure to even mild
acidic or basic conditions.9,10,13 A de novo synthesis arguably
provides far greater opportunities and flexibility for discovering
new bioactive entities.14 Over the past three decades, the fragile
and congested structure has enticed significant interest from sevꢀ
eral groups to forge the C2ꢀC18 bond with elaborate functional
groups at an early stage in their synthetic blueprint.15,16 Only the
Kende group accomplished the landmark synthesis of lankacidin
C (1) with an enormous 34 LLS (longest linear steps) (46 total
steps) from two chiral building blocks.17 Alternatively, a flavinꢀ
dependent amine oxidoreductase (LkcE) was preliminary identiꢀ
fied to biosynthetically participate in the unprecedented intramoꢀ
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Page 2 of 5
lecular Mannichꢀtype cyclization (Scheme 1B).18,19 Kinashi and
Mannich reaction upon exposure to silica gel and mild acidic
conditions (Figure S7).25 Strategically, a stannylated vinylogous
imine precursor 10 was envisioned since chain elongation can be
achieved by Stille coupling.26 Initial forays verifying the R subꢀ
stituent as imine precursors 10a/b resulted in decomposition
without formation of any addition products (Scheme 2A). Altꢀ
hough the Mannich reaction of 10c with lactone 8 resulted in the
requisite adducts, the vulnerability of the sulphonyl group under
Stille coupling conditions hampered further modification. Howevꢀ
er, when the more stable Nꢀacyl N,Oꢀacetal 10d was synthesized,
after an exhaustive evaluation of conventional methods, including
using Brønsted acids and Lewis acids,27 the Mannich reaction
between 8 and 10d remained unfruitful (Scheme 2B). In most
cases, the in situ generated imine was geometrically unstable,
extremely susceptible to tautomerization and possessed only marꢀ
ginal reactivity toward nucleophilic addition. Based on the alcohol
exchange phenomenon reported by BenꢀIshai and coworkers in
the 1960s during the pyrolysis of N,Oꢀacetals,28 we anticipated
that thermal activation of 10d via methanol depletion would preꢀ
sumably release a transient imine under strictly neutral conditions
that may be compatible with our delicate substrates. After a surꢀ
vey of different solvents (Table S2),25 less polar solvents impresꢀ
sively facilitated the conversion of δꢀlactone 8 to the Mannich
adducts in good yields (Scheme 2B). Of particular interest to us is
that N,Oꢀacetal 10d alone was stable in refluxing cyclohexane or
toluene and that a drastic conversion occurred after the addition of
δꢀlactone 8. The optimized conditions were readily applied on a
200ꢀmg scale to generate the requisite Mannich adduct (11) as a
mixture of four stereoisomers in a combined yield of 93%.
1
2
3
4
5
6
7
8
others also uncovered that polyketide synthases from Streptomy-
ces rochei constructed the entire carbon chain first (such as LCꢀ
KA05, 6) and that subsequent oxidation at C18 revealed a reactive
alkenyl Nꢀacyl imine.19ꢀ21 Although the detailed enzymatic underꢀ
pinnings for this extremely rare ringꢀforming reaction remain to
be clarified (such as involving an enolateꢀiminium pair 7), from a
synthetic standpoint, a biomimetic approach would drastically
decrease the number of steps if the proper precursor and reaction
conditions could be defined.
9
To strive to imitate nature’s ingenuity, we envisaged that nonꢀ
productive refunctionalizations (such as redox and protective
manipulation at C3),22 which have plagued all the previous apꢀ
proaches, could be confined to a minimum if all the native oxidaꢀ
tion states are preinstalled within a single linear precursor. Howꢀ
ever, such a fundamentally disparate tactic presents several chalꢀ
lenges. First, the presumptive Nꢀacylꢀ1ꢀazahexatrienes are notoriꢀ
ously unstable to handle, and few protocols for their generation
are available.23 Additionally, βꢀoxoꢀδꢀlactones have been categoꢀ
rized as the least reactive βꢀketoester derivatives for nucleophilic
addition.24 Furthermore, the Mannich adducts are energetically
unfavorable due to their strained structures and would undergo
facile retroꢀMannich reactions under a variety of conditions. A
similar model substrate was declared by Thomas and coworkers to
be “rather unstable, decomposing to give complex mixtures of
products when stored at room temperature”.15f Finally, the essenꢀ
tial macrocyclization with critical stereocontrol remains elusive
due to the insufficient data from conformational studies toward
the synthesis of lankacidins.
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To clarify the stereochemical outcome, the coupling products
were individually subjected to tinꢀiodine exchange.29 The strucꢀ
tures of vinyl iodides 12a and 12b were unambiguously deterꢀ
mined by Xꢀray crystal structure analysis of their corresponding
desilylation derivatives (see SI for details).25 For vinyl iodide 12c,
reduction of the C3ꢀketone delivered diastereomeric alcohols (ds
3:1), from which the major isomer was readily identified as carꢀ
bamate 13c (Scheme 2C). From extensive NMR studies (Figure
S8),25 the newly generated vicinal stereocenters were unambiguꢀ
ously assigned as (2S,18R), which is congruent with those in natuꢀ
ral lankacidins 1ꢀ4 (Scheme 1). With the stereogenic centers in
both components identified (8 and 10d), the preference of the C2ꢀ
Me/C5ꢀH cisꢀadduct will be anticipated through the introduction
of a long C5ꢀtether in the forthcoming intramolecular event. Altꢀ
hough the stereochemical outcome at C18 is difficult to discern,
the Siꢀface addition of the in situ generated imine to yield an Rꢀ
configuration would be a fascinating reward via a biomimetic
macrocyclization.
(A)
Boc
Ph
TBSO
Me
O
HN
Me
O
O
NBoc
Me
Me
O
Me
Bn
Ph
Me HN
*
2
*
Bn
10a (R = OH)
10b (R = SPh)
10c (R = SO2Ph)
cat. PA
(2 mol%)
O
8
(X-ray)
O
O
Bu3Sn
R
9 (isomers)
unstable
(B)
Me
TBSO
HN
TBSO
Me
O
O
O
Me
O
Me
Bn
Me
O
conditions
Me
Me
Bn
+
2
Me HN
*
*
18
O
SnBu3
Bu3Sn
OMe
O
O
8
10d
11a-d (4 isomers)
acid catalyst
thermal conditions
conversion
(8, %)
yield
(11, %)
PPTs, TFA, TsOH,
PAs, HBF4 PPh3, etc.
entry
solvent (reflux, 17h)
•
toluene
tetrahydrofuran
acetonitrile
diisopropyl ether
carbon tetrachloride
n-hexane
44
0
0
30
78
89
93
49
0
1
2
3
4
5
6
7
•
BF3 Et2O, TMSOTf, TiCl4
Ti(iOPr)4, Ti(OEt)4, SnCl4
LiClO4, Mg(ClO4)2, Zn(OTf)2,
Cu(OTf)2, Bi(OTf)3, Sc(OTf)3,
In(OTf)3, La(OTf)3, etc.
7
36
85
97
>98
Given the establishment of Mannich reaction in hand, a strateꢀ
gic disconnection of the requisite long carbon chain was realized
in a polyketide synthase (PKS)ꢀinspired pipeline.14 3ꢀIodoacrolein
(14) was applied to the vinylogous Mukaiyama aldol reaction of a
known silyl enolate 1530 to afford the allylic alcohol in excellent
yield and diastereoselectivity (85% yield, ds 20/1) (Scheme 3).
The removal of the oxazolidinone group with diisobutylaluminum
hydride and immediate protection of the hydroxyl group with the
tertꢀbutyldiphenylsilyl group provided enal 16 in excellent yield
(93%). After the JuliaꢀKocienski olefination31 with sulfone modꢀ
ule 17, reduction of the corresponding ester delivered advanced
aldehyde 19 in 73% yield over two steps. The final dipropionate
motif was introduced by an Evansꢀaldol reaction of 19 with chiral
βꢀketo imide 20.32 Although the diastereoselectivity (two antiꢀ
isomers, ds 3/1) was moderate, the subsequent KOtBuꢀpromoted
lactonization smoothly removed the chiral auxiliary,
(see Table S1 for details)
cyclohexane
(C)
Me
TBSO
O
Me
O
TBSO
b. NaBH4, MeOH
-78 oC; 73%
syn/anti = 3/1
HN
Me
O
Me
N
O
O
a. I2, THF
Me
Me
Me
Bn
Me
Bn
11c
18
18
-78 oC to rt
91%
2
2
c. (Imd)2CO
LiHMDS, THF
34%
I
I
5
O
O
O
O
12c
13c
Scheme 2. Reaction design. (A) Initial attempts at the Mannich reaction.
(B) Mannich reaction with model substrates. (C) Stereochemical determiꢀ
nation of the adducts (13c as an example, see the Supporting Information
for details). PA = racꢀbinaphtholꢀderived phosphoric acid.
With the above perspectives in mind, an intermolecular model
study was performed using truncated βꢀoxoꢀδꢀlactone 8 as the
principal nucleophile (Scheme 2). The Mannich reaction of 8 with
premade NꢀBoc benzaldimine proceeded smoothly; however, the
corresponding Mannich adduct 9 readily underwent the retroꢀ
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I
OTBDPS
Me
I
20
OTBDPS
e.
a.
15
O
O
I
17
1
2
3
4
5
6
7
c.
13
13
OTBDPS
d.
Me
O
TiCl4, CH2Cl2, -78oC
c-Hex2BCl, EtNMe2
Me
I
Et2O, 0oC then -78oC
2
DIBAL-H
KHMDS, THF
13
83%, ds 20 : 1
5
Me
7
CH2Cl2, -78oC
93% yield
-78oC
78% yield
E/Z 50/1
OTBDPS
b. DIBAL-H, -78oC;
TBDPSCl, imid.
93% yield
then MeOH, tBuOK
THF, rt
Me
O
TBSO
I
15
52% yield
7
TBSO
Me
21
TBSO
O
14
16
18
19
EtO2C
f.
O
10d DMF, rt
57% yield
Pd2(dba)3 (20 mol%)
8
9
Me
Me
HO
Me
Me
24
O
HO
HN
TBSO
TBSO
O
g.
O
O
O
HN
OMe
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
HN
O
h.
O
HN
Me
O
Me
OH
cyclohexane
reflux
18
Me
Me
2
2
Me
2
TASF, H2O
Me
Me
Me
Me
18
18
+
18
O
2
5
Me
Me
DMF, rt
5
32% yield
300-mg scale
O
O
O
OH
HO
HO
OTBDPS
TBSO
TBSO
OTBDPS
Me
Me
Me
Me
22 ( > 5-g made)
2-epi-lankacyclinol (24)
lankacyclinol (5)
23
i.
6% yield
69% yield
HF (40%, aq)
condition i.
CH3CN
Me
38% yield
(88% brsm)
25/3 = 1.5/1
Me
-20oC
HO
OH
O
O
Me
N
EtO2C
TBSO
Me
O
OTBS
Me
Me
NH
O
O
HN
O
O
Me
O
O
Me
Me
2
S
2
S
18
Me
Me
18
O
+
N
O
O
N
O
O
Me Me
O
O
Me
11
7
13
15
(40-g scale)
17
(40-g scale)
The preparations of three modules are provided in the Supporting Materials.
OH
20
(15-g scale)
OH
HO
Me
HO
lankacidinol (3)
neolankacidinol (25)
51% yield
43% yield
Scheme 3. Syntheses of lankacidinol and lankacyclinol. (brsm = based on the recovered starting material)
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and the major congener of δꢀlactone 21 bearing a transꢀ
configuration of C2ꢀMe and C4ꢀMe in the keto form was isolated
in 51% yield. The two transformations were realized in one flask
without any interrupted extraction. With the successful model
study of the Mannich reaction of the N,Oꢀacetal, we were poised
to preinstall a higher oxidation state at C18 through Stille crossꢀ
coupling with the N,Oꢀacetal. Surprisingly, it was found to be
difficult due to the facile displacement of the methoxy group in
the N,Oꢀacetal when phosphine ligands were employed (Table
isolated in 6% yield. The favorable facial selectivity (ds 12/1) in
the protonation reaction may be attributed to the rigid conforꢀ
mation of the polyene macrocyclic ring system and a possible
hydrogen bond of the amide NꢀH group to the C3ꢀenolate.36
The next objective was to identify the optimal reaction condiꢀ
tions to retain the fragile δꢀlactone moiety. Gratifyingly, an aqueꢀ
ous solution of HF (40 wt%) at ꢀ20 °C was found suitable for
global desilylation (Table S4).25 Lankacidinol (3), which is the
most complex congener in this family, was isolated in 51% yield
from 23 as a white powder. The spectroscopic characteristics of
the synthetic sample were identical to the previously reported
data.37 In this reaction mixture, the new congener 25 (coined as
neolankacidinol) of the lankacidins was isolated in 43% yield as a
single diastereomer, and extensive NMR studies revealed a formal
hydroxyl shift occurred along the diene chain in a stereoselective
manner. We assume that this facile rearrangement proceeded
through a cationic intermediate and that the preferred stereochemꢀ
ical outcome was most likely controlled by the rigid conformation
of the macrocyclic ring. Additional experiments established that
neolankacidinol (25) was interconvertable with lankacidinol (3)
under the identical conditions, which can maximize material
throughput to access either target (3 or 25). Although compound
25 has not been previously disclosed, the facile propensity of
hydroxyl relocation indicates a similar process may also occur
under biologically relevant conditions.
S3).26 After examination of
a
plethora of conditions,
tris(dibenzylideneacetone)dipalladium(0) was identified as a suitꢀ
able catalyst to form the critical C15ꢀC16 bond, and the acidꢀ
labile precursor 22 was isolated in 57% yield. The key biomimetic
Mannich reaction was then executed under the optimal conditions
(c = 0.0005 M). After complete consumption of the starting mateꢀ
rial, the major cyclized product 23 was isolated in 32% yield
(48% NMR yield).33 At this juncture, the stereochemistry of 23
was not determined from the severe overlap of the proton signals
in the upfield range. For example, although the cross 2DꢀNOE
correlation of C2ꢀMe/C5ꢀH supported the cis relative configuraꢀ
tion between C2ꢀMe and C4ꢀMe, the chirality at C18 was not
conclusive due to the unclear conformation of the macrocyclic
ring. The fragile nature of the δꢀlactone motif bearing a bridgeꢀ
head quaternary center at C210,19 was thus adopted to furnish
lankacyclinol (5), whose structure was unambiguously confirmed
by the synthetic work of the Williams group (25 LLS, 39 TS).34
After surveying desilylation conditions, a combination of TASF35
and 40 equivalents of water effectively triggered decarboxylation
and desilylation in one pot. Lankacyclinol (5) was isolated in 69%
yield as the major product, and the spectral data were consistent
with those reported in the literature.34 Therefore, the C18 stereoꢀ
chemistry of major isomer 23 was inferred to be the (R)ꢀ
configuration based on the successful elaboration of this material
to the natural product. In addition, the minor C2ꢀepimer 24 was
In summary, we developed short total syntheses of lankacidinol
and lankacyclinol. The salient features of the work include a
modular approach for the rapid installation of all essential stereoꢀ
centers in the linear carbon chain, a unique biomimetic Mannichꢀ
type macrocyclization via thermal activation of an imine, and
judicious desilylation to access the congeners of the lankacidins.
Our results also revealed the possible biogenesis of lankacyclinol
through decarboxylation and stereoselective protonation. An unꢀ
expected stereoselective formal [1,5]ꢀhydroxy shift through the
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(11) M. J. Belousoff, T. Shapira, A. Bashan, E. Zimmerman, H. Rozenꢀ
berg, K. Arakawa, H. Kinashi, A. Yonath, Proc. Natl. Acad. Sci. USA
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Arakawa, Y. Nindita, G. Chan, L. Sun, M. Glover, M. Klobukowski. J.
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Wright, D. T. Hog, K. Yabu, S. R. Allu, T. Fukuzaki, P. N. Carlsen, Y.
Kitamura, X. Zhou, M. L. Condakes, F. T. Szczypiński, W. D. Green, A.
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(15) (a) M. J. Fray, E. J. Thomas, Tetrahedron 1984, 40, 673. (b) M. J.
Fray, E. J. Thomas, D. J. Williams, J. Chem. Soc., Perkin Trans. 1 1985,
2763. (c) E. J. Thomas, A. C. Williams, J. Chem. Soc., Chem. Commun.
1987, 992. (d) J. M. Roe, E. J. Thomas, Synlett 1990, 727. (e) E. J. Thomꢀ
as, A. C. Williams, J. Chem. Soc., Perkin Trans. 1 1995, 351. (f) J. M.
Roe, E. J. Thomas, J. Chem. Soc., Perkin Trans. 1 1995, 359. (g) E. G.
Mata, E. J. Thomas, J. Chem. Soc., Perkin Trans. 1 1995, 785. (h) C. T.
Brain, A. Chen, A. Nelson, N. Tanikkul, E. J. Thomas, Tetrahedron Lett.
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hedron Lett. 2001, 42, 1251. (j) C. T. Brain, A. Chen, A. Nelson, N. Tanꢀ
ikkul, E. J. Thomas, Tetrahedron 2010, 66, 6613.
conjugated system likely resulted from the rigid conformation of
the macrocyclic ring system. Together with the newly synthesized
2ꢀepiꢀlankacyclinol, this study may implicate that more unknown
natural products are yet to be identified, as the optimal conditions
approximated a physiological environment. In comparison to
previous syntheses of lankacidin antibiotics, the current diverted
synthesis was concise and highly efficient (both in 8 LLS, 3.0~4.0%
overall yield) from readily available materials (such as 14 and 15)
and provided a platform for structural modification to previously
inaccessible derivatives. Studies along this line as well as collaboꢀ
rative investigation on biosynthesis are currently underway in this
laboratory and will be reported in due course.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Detailed experimental procedure, and 1H NMR and 13C NMR
spectra, as well as Xꢀray data information (PDF)
Crystallographic data (CIF)
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(b) S. Williams, J. Jin, S. B. J. Kan, M. Li, L. J. Gibson, I. Paterson, An-
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: rhong@sioc.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation
of China (21290184 and 21472223), the Shanghai Science and
Technology Commission (15JC1400400), and the Chinese Acadꢀ
emy of Sciences (XDB20000000, QYZDYꢀSSWSLH026) are
highly appreciated. We also thank Jie Sun and Yanqing Gong
(SIOC) for Xꢀray crystallographic analysis.
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Me
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TBSO
O
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step 1
biomimetic Mannich
macrocyclization
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OMe
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OH
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OH
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step 2
global deprotection
O
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TBSO
OTBDPS
Me
lankacidinol
Me
Me
completed in 8 LLS
(this work)
modular synthesis;
6 steps; gram scale
lankacyclinol
previous [C24-oxo]: 34 LLS, 46 TS previous: 25 LLS, 39 TS
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