Total synthesis of micrococcin P1 and thiocillin I enabled by Mo(vi) catalyst

Article abstract of DOI:10.1039/C8SC04885A

Thiopeptides are a class of potent antibiotics with promising therapeutic potential. We developed a novel Mo(vi)-oxide/picolinic acid catalyst for the cyclodehydration of cysteine peptides to form thiazoline heterocycles. With this powerful tool in hand,

Full text of DOI:10.1039/C8SC04885A

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Total synthesis of micrococcin P1 and thiocillin I
enabled by Mo(VI) catalyst†
Cite this: DOI: 10.1039/c8sc04885a
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Siddhartha Akasapu,‡ Aaron B. Hinds, ‡ Wyatt C. Powell
*
and Maciej A. Walczak
Thiopeptides are a class of potent antibiotics with promising therapeutic potential. We developed a novel
Mo(VI)-oxide/picolinic acid catalyst for the cyclodehydration of cysteine peptides to form thiazoline
heterocycles. With this powerful tool in hand, we completed the total syntheses of two representative
thiopeptide antibiotics: micrococcin P1 and thiocillin I. These two concise syntheses (15 steps, longest
linear sequence) feature a C–H activation strategy to install the trisubstituted pyridine core and thiazole
groups. The synthetic material displays promising antimicrobial properties measured against a series of
Gram-positive bacteria.
Received 1st November 2018
Accepted 3rd December 2018
DOI: 10.1039/c8sc04885a
rsc.li/chemical-science
The surge in drug-resistant strains of bacteria poses a major
Our retrosynthetic analysis of the synthetic targets led to the
global health threat and the need for expedient discovery of new dissection of the macrocycle into two “top” and “bottom”
therapeutics characterized by novel modes of action represents fragments, which could be united through a peptide coupling
a high priority.1 The thiopeptide family of antibiotics contains and then macrocyclised at the thiazole carboxylic acid adjacent
ꢀ150 members of post-translationally modied peptides of to valine to furnish the nal product(s) (Fig. 1). For construction
ribosomal origin that display antibacterial activities against of the two fragments, we envisioned a convergent approach
drug-resistant pathogens, including methicillin-resistant involving the strategic introduction of selected thiazole rings
Staphylococcus aureus (MRSA).2 All thiopeptide antibiotics through
a catalytic cysteine cyclodehydration. Catalytic
share a common molecular scaffold involving a nitrogen- methods for cysteine cyclodehydrations are scarce despite the
containing heterocyclic core decorated with varying numbers myriad obstacles encountered when employing common stoi-
of thiazol(in)e rings, assembled into macrocycles or acyclic chiometric reagents due to their high Lewis acidity, likely
chains of varying sizes and lengths.2c The macrocycle, whose incompatibility with acid-sensitive groups, possible epimeriza-
size is correlated with molecular targets, is responsible for tion, and generation of undesired by-products.7 We hypothe-
distinct modes of action, allowing thiopeptides to inhibit sized that a MoO2(L)2 complex with the appropriate ligands
bacterial cell growth by means of blocking ribosomal protein might minimize epimerization of the endo- and exocyclic
synthesis.2d Because of their unique biological activities and methylene groups since the cyclization event occurs under
intriguing structure, thiopeptides have received considerable neutral conditions. Furthermore, bidentate ligands may extend
attention from the synthetic community.3 However, the lack of the lifetime of the catalyst and prevent precipitation of hetero-
concise, scalable, and practical syntheses amenable for rapid geneous molybdenum particles.8
molecular modications limits access to these valuable natural
To validate the feasibility of this proposal, we evaluated
products. In this paper, we report a general approach to the a series of Mo(VI) oxide complexes (Table 1). Initially, we studied
synthesis of thiopeptide antibiotics featuring a novel Mo(VI)
oxide catalyst to promote the cyclodehydration of cysteine
residues under mild and neutral conditions and is demon-
strated by the preparation of D series thiopeptides micrococcin
P1 (1)3u,3w,4 and thiocillin I (2),3x,5 This practical and scalable
route is suitable for analogue preparation and site-selective
modications.6
Department of Chemistry, University of Colorado, Boulder, CO 80309, USA. E-mail:
maciej.walczak@colorado.edu
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8sc04885a
‡ These authors contributed equally.
Fig. 1 Selected thiopeptide antibiotics of the D series.
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Table 1 Invention and optimization of MoO2(L)2-catalyzed cysteine
cyclodehydration
We rationalized the reactivity trend from Table 1 by
a mechanism depicted in Scheme 1A: complex 11 undergoes
a ligand exchange with amide 12, replacing one of the pyridine
coordination sites. Picolinic acid-based ligands that contain
electron-donating groups (e.g., 8d, 9a, 9b) retard the initial
displacement step because the electron-rich heterocycle forms
a tighter complex with the electrophilic Mo(VI), whereas
electron-withdrawing groups at C4 and C6 of the pyridine ring
(e.g., 9c) facilitate the displacement. Once the amide is bound to
Mo (13), a proton transfer occurs from the amide NH to one of
the oxo ligands. This step is likely promoted by a neighbouring
nitrogen atom on the pyridine ring and may proceed intramo-
lecularly. Ring closure from 14 followed by elimination of H2O
and azoline product 16 regenerates catalyst 11. The highest rate
of cyclodehydration of 6 with 8b can be rationalized by its
electron-donating ability combined with steric hindrance of the
methyl group that likely distorts the geometry of the MoO2(L2)
complex, thus accelerating access of the amide substrate. This
mechanistic proposal is consistent with DFT calculations
(Scheme 1B). The most stable conguration of the MoO2(pic)2
complex is the one with pyridine nitrogen atoms in a cis
Entry
L
Time
Yield
Entry
L
Time
Yield
1
2
3
4
5
6
None
8a
8b
8b
8c
16 h
16 h
2.5 h
16 h
16 h
16 h
18%
85%
87%
97%
98%
26%
7
8
9
10
11
12
8e
9a
9b
9c
10
L-Proline
16 h
16 h
16 h
16 h
16 h
16 h
19%
8%
9%
68%
62%
<1%
8d
the cyclodehydration reaction under conditions using only acac conguration (e.g., 11). The Mo–N bond in the unsubstituted
˚
(acetylacetonate) as the ligand (entry 1). We observed that the picolinic acid complex is 2.38 A. This linkage is elongated in
molybdenum complex precipitated from the solution, forming complexes substituted at C4 with an electron-withdrawing group
insoluble particles, resulting in low yields of thiazoline product (9c) and in sterically-congested complexes with the 6-Me group
7. In order to maximize the conversion of 6 into 7, catalyst making the initial ligand exchange more facile. On the contrary,
loadings of MoO2(acac)2 had to be increased up to 60 mol% and attachment of an electron-donating group at the para position
the molybdenum complex had to be added portion-wise over increases the bond strength between Mo and N, demonstrated
a period of 12 h to ensure reproducible yields. We hypothesized by a shortened Mo–N distance in a complex with 9a.
that a bidentate ligand that (a) stabilizes Mo, preventing the
Having established a robust method for the catalytic instal-
formation of heterogeneous particles, and (b) modulates the lation of select thiazole groups, we proceeded towards the
electrophilic character of Mo presented a viable solution to preparation of bottom fragments 25 (Scheme 2). The optimized
these problems. To this end, we investigated a series of ligands
based on the pyridine 2-carboxylate core (entries 2–11). These
additives (20 mol%) were pre-mixed with MoO2(acac)2
(10 mol%) and used directly in the cyclodehydration reactions
with 6. Addition of picolinic acid 8a was sufficient to improve
the yield of 7 to 85% (entry 2) whereas carboxylates with
electron-donating groups such as 8d, 9a, 9b gave 7 in <30%
yield. Although still suboptimal, electron-poor ligands (entries
10 and 11) improved conversion of 6 into 7 with respect to the
original conditions using only the acac ligand. The geometry of
the Mo centre is also important as demonstrated by the reaction
with bis-acid 8e forming a tridentate complex with Mo (entry 7).
We found that a combination of sterics at C6 and a moderate
electron-donating ability of the substituent resulted in excellent
yields of 7 with <1% epimerization (entries 3–5). Although 6-
methyl- and 6-ethylpyridine carboxylates gave comparable
results (entries 2–5), we elected to use 8b as the ligand for
further studies because of the signicant cost difference
between these two reagents. For comparison, a ligand with
a basic sp3 nitrogen completely suppressed the reaction (entry
Scheme
1 (A) Proposed mechanism of Mo-catalysed cyclo-
12). To exclude the possibility that the cyclodehydration reac-
tions are catalyzed by a Brønsted acid, thiol 6 was exposed to
catalytic amounts of pTSA (10 mol%) or 8b (10 mol%) under
otherwise identical conditions from Table 1 and gave 7 in <1%
dehydration (second carboxylate ligand abbreviated for clarity). (B)
Selected geometrical parameters of MoO2(X)2 complexes optimized at
B3LYP/6-31G(d)/LANL2DZ level of theory. The optimized structure of
the thermodynamic complex of MoO2(pic)2, pic ¼ 2-picolinate is
presented in the middle of the catalytic cycle.
ꢁ
aer 16 h at 110 C.
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cyclodehydration conditions were applied to two dipeptides 17 scaffold in 31 was sufficient to stabilize the Mo(VI) catalyst and
followed by oxidation to thiazoles 18 in excellent yields for both prevented decomposition of the Mo complex in the cyclo-
substrates. The remaining portion of the bottom fragment was dehydration reaction thus alleviating the need of further
prepared via a modied Hantzsch method using thioamide 19 stabilization by additional ligands. Next, the Stille coupling with
and bromopyruvate 20 in 94% yield. Coupling of 21 with serine ethyl vinyl ether 33 followed by bromination with NBS afforded
22 followed by a stereoselective (dr > 99 : 1) installation of the bromoketone 34. Inspired by the prior work of Williams,10 we
trisubstituted olen with MsCl and a base (DABCO, Et2NH) converted 34 into thiazole 36 in 86%. Because the exocyclic
resulted in thiazole 24. With this key precursor in hand, the methylene group in the Hantzsch intermediate can undergo
amine and carboxylate groups in 18 and 24 were liberated and epimerization, we optimized the cyclization step by buffering
the subsequent amide couplings resulted in gram-scale the conditions with a bulky base (2,6-lutidine) whereas larger
syntheses of bottom fragments 25 in seven steps for both bases (e.g., 2,6-di-t-butyl-pyridine) were ineffective in promoting
micrococcin P1 and thiocillin I in 47% and 51% overall yield, this transformation. To conrm the optical purity of the newly
respectively.
formed thiazole 36, the carbamate was removed, and the
The synthesis of top fragment 37, common to D series thi- resultant amine was converted into a Mosher amide giving
opeptides, started from a Pd-catalyzed C–H activation of thia- a 95 : 5 dr (determined by 19F NMR). Finally, site-selective
zole 26 (Scheme 3). We found that the yield of this reaction was hydrolysis of the methyl ester in 36 proceeded without
critically dependent on the size of the ester group and the concomitant removal of the i-Pr group to yield top fragment 37
methyl group was incompatible with the cross-coupling condi- in 73%.3l
tions. The reaction of ethyl thiazole ester 26b with Pd(OAc)2
In preparation for the union of the two fragments, the Boc
(5 mol%) and CyJohnPhos (15 mol%) gave, aer conversion protective group was removed from bottom segments 25 to yield
from 28a, methyl ester 28b9 which was then coupled with amine free amines 38 which were then coupled with top unit 37 to
30 following the two-step, selective chlorination of the pyridine afford oligopeptides 39. Next, the i-Pr ester in 39 was removed
core (97%). At this stage, the sulfur protective group was under more forcing conditions (NaOH/H2O), and the resultant
removed, and MoO2(acac)2-catalyzed cyclodehydration and acid was merged with dipeptide 43. The installation of the olen
oxidation afforded 32 in 86% yield. We found that the pyridine was accomplished by elimination of the hydroxyl group in
threonine with MsCl in exclusive Z selectivity. The nal steps of
the synthesis involved global deprotection with HCl to cleave all
alcohol, amine, and carboxylic acid protective groups in one
step, followed by macrocyclization of the resulting amino acid
intermediate with PyAOP furnished micrococcin P1 1 in 22%
yield. The similarity of micrococcin P1 and thiocillin I, which
differ only by a mutation of L-valine into 3-hydroxy-L-valine, led
us to adopt identical conditions for both syntheses, with the
exception of the deprotection for thiocillin I. We found that
acidic conditions alone were insufficient and resulted in only
partial cleavage of the silicon group at the hydroxyvaline posi-
tion (ca. 30%); thus, following the nal macrocyclization, the
resultant precursor was subjected to TBAF to reveal thiocillin I
(2) in 15%. Micrococcin P1 was completed in 14 steps and thi-
ocillin I was completed in 15 steps from known commercial
materials (longest linear sequence).
Having access to two representative members of the thio-
peptide family, we evaluated the in vitro antimicrobial activity
against a panel of recent Gram-positive bacterial strains
(Table 2). Micrococcin P1 and thiocillin I exhibited similar
potencies, showing 2- to 4-fold difference in their minimum
inhibitory concentration (MIC) values in nearly all of the test
bacterial isolates. An exception to this trend was observed for B.
subtilis ATCC 6633, where micrococcin P1 was inactive at 16 mg
mLꢂ1 while thiocillin I displayed activity at concentrations as
Scheme
2 Synthesis of bottom fragments 25. (a) MoO2(acac)2
low as 4 mg mLꢂ1, a result comparable to a previously published
(10 mol%), 8b (20 mol%), PhMe, 110 ꢁC, 2.5 h: 18a – 92%, 18b – 98%; (b)
DBU, CBrCl3, CH2Cl2, 0 ꢁC, 1 h: 18a – 97%, 18b – 91%; (c) 20, NaHCO3, report showing thiocillin I as active at 1.56 mg mLꢂ1 against B.
THF, 0 ꢁC to rt, 16 h then pyridine, TFAA, 0 ꢁC, 20 min, 94%; (d) HCl,
subtilis PCI 219.5 Additionally, micrococcin P1 and thiocillin I
1,4-dioxane, rt, 7 h then 22, HATU, DIPEA, DMF, 0 ꢁC to rt, 1 h, 76%; (e)
were more potent than comparator antibiotics against
vancomycin-resistant E. faecalis.
In summary, we described a general synthetic route toward
thiopeptide antibiotics belonging to the D series. Given the
MsCl, Et3N, CH2Cl2, 0 ꢁC, 1 h then DABCO, Et2NH, 0 ꢁC to rt, CH2Cl2,
16 h, 91%; (f) HCl, 1,4-dioxane, 0 ꢁC to rt, 45 min; (g) Bu2SnO, MeOH,
80 ꢁC, 4 h then LiOH, H2O/THF, 90% (over two steps); (h) HATU,
DIPEA, DMF, 0 ꢁC to rt, 2 h: 25a – 72%, 25b – 78%.
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Scheme 3 Preparation of the top fragment and completion of the syntheses. (a) Pd(OAc)2 (5 mol%), CyJohnPhos (15 mol%), Cs2CO3, DMF,
110 ꢁC, 12 h, 73%; (b) NaOMe, MeOH, ꢂ20 to 0 ꢁC, 99%; (c) i – m-CPBA, CH2Cl2, rt, 2 d; ii – POCl3, DMF, 0 ꢁC, CH2Cl2, 97% (over two steps); (d)
HCl, 1,4-dioxane, rt, 9 h then 30, HATU, DIPEA, DMF, 0 ꢁC to rt, 2 h, 72%; (e) i – TFA, Et3SiH, CH2Cl2, 0 ꢁC, 1 h then MoO2(acac)2 (10 mol%), PhMe,
110 ꢁC, 13 h; (f) MnO2, CH2Cl2, rt, 24 h, 86% (from 31); (g) 33, PdCl2(PPh3)2 (10 mol%), 1,4-dioxane, 90 ꢁC, 18 h, 97%; (h) NBS, THF, pH 7 phosphate
buffer, rt, 1 h, 79%; (i) i – 35, KHCO3, dimethoxyethane, ꢂ40 ꢁC to rt, 24 h then TFAA, 2,6-lutidine, dimethoxyethane, ꢂ20 ꢁC, 20 h, 85%; (j)
Me3SnOH, (CH2Cl)2, 80 ꢁC, 20 h, 73%; (k) HCl, 1,4-dioxane, 0 ꢁC to rt, 30–45 min: 38a – 90%, 38b – 53%; (l) HATU, DIPEA, DMF, 0 ꢁC to rt, 2 h: 39a
– 82%, 39b–53%; (m) NaOH, MeOH, 0 ꢁC to rt, 2 h then 43, HATU, DIPEA, DMF, 0 ꢁC to rt, 2 h; (n) MsCl, Et2NH, CH2Cl2 0 ꢁC to rt, 15 min then
DABCO, Et2NH, CH2Cl2, 0 ꢁC to rt, 2.5 d; (o) HCl, 1,4-dioxane, rt, 16 h then PyAOP, DIPEA, DMF, ꢂ20 ꢁC, 30 min, 22% (for 1 from 39a); (p) TBAF,
THF, 0 ꢁC, 1–2 h, 15% (for 2 from 39b).
Table 2 Minimum inhibitory concentration (MIC) values for micro-
coccin P1 and thiocillin I
for stoichiometric reagents and generates water as the only by-
product. Moreover, the modular approach lends itself into
future SAR studies to attain compounds with desirable prop-
erties for pre-clinical and clinical development.
MIC (mg mLꢂ1
)
Isolate
1
2
Vancomycin Ciprooxacin
S. aureus
ATCC 29213
1974149
1974148
1674621
1674614
4
2
8
1
1
>16
1
2
2
2
1
0.5
1
0.5
Conflicts of interest
0.25
>16
1
>16
0.06
0.25
There are no conicts to declare.
E. faecalis
B. subtilis
0.5 0.5
0.5 >16
4
ATCC 6633
0.25
Acknowledgements
S. pyogenes 1744264
0.5 0.5
This work was supported by the University of Colorado at
Boulder and in part by the NSF (CHE-1753225). Mass spectral
structural commonalities shared by all family members of this analyses were recorded by the University of Colorado Boulder
class, the presented method is easily adaptable to suit the Central Analytical Laboratory Mass Spectrometry Core Facility
preparation of thiopeptides belonging to other series as well as (partially funded by NIH S10 RR026641). Dr Bimala Lama is
derivatives. The novel molybdenum catalyst eliminates the need acknowledged for the assistance with NMR experiments.
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