Total Synthesis of Disciformycin A and B: Unusually Exigent Targets of Biological Significance

Article abstract of DOI:10.1002/chem.201705550

The first total synthesis of the potent antibiotic disciformycin B (2) is described, which is exceptionally isomerization-prone and transforms into disciformycin A (1) even under notably mild conditions. To outweigh this bias, the approach to 2 hinged on

Full text of DOI:10.1002/chem.201705550

A Journal of
Accepted Article
Title: Total Synthesis of Disciformycin A and B: Unusually Exigent
Targets of Biological Significance
Authors: Alois Fürstner, Yooghoon Kwon, Saskia Schulthoff, Quang
Minh Dao, and Conny Wirtz
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To be cited as: Chem. Eur. J. 10.1002/chem.201705550
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Chemistry - A European Journal
10.1002/chem.201705550
Total Synthesis of Disciformycin A and B: Unusually Exigent Targets of Biological Significance
*
Yonghoon Kwon, Saskia Schulthoff, Quang Minh Dao, Conny Wirtz, and Alois Fürstner
Abstract: The first total synthesis of the potent antibiotic disciformycin B (2) is described, which is
exceptionally isomerization-prone and transforms into disciformycin A (1) even under notably mild
conditions. To outweigh this bias, the approach to 2 hinged on the use of a silyl residue at C4 to lock
the critical double bond in place and hence insure the integrity of the synthetic intermediates en route
to 2. This tactic was instrumental for the preparation of the building blocks and formation of the
macrocyclic ring via ring closing alkyne metathesis (RCAM). To make the end game successful,
however, it proved necessary to cleave the C-silyl protecting group off; it was at this stage that the
exceptional sensitivity of the target became fully apparent.
The ever-faster emergence of resistant pathogenic bacteria renders the vision of a mankind liberated
from the scourge of infectious diseases by effective broad-spectrum antibiotics increasingly
1
obsolete. Therefore the search for new active principles with a different mode of action is highly
2,3
warranted, if not even literally vital on the longer run. It is against this backdrop that the recent
reports on the myxobacterial metabolites of the disciformycin and gulmirecin families must be
4,5,6,7
seen.
These compounds exhibit considerable activity against Gram-positive bacteria, including
several methicillin- or vancomycin-resistant Staphyllococcus aureus strains; most notably, they seem
to address an as yet unknown biological target and hence likely provide new opportunities in the
quest for antibiotics devoid of cross-resistance with approved drugs.
The constitution and stereostructure of these remarkable polyketides were determined by two
independent groups, each of which masterfully complemented the spectroscopic arguments by an
4,5
analysis of the encoding gene cluster. One of these studies suggested that disciformycin B (2)
*
Dr. Y. Kwon, S. Schulthoff, M. Sc. Q. M. Dao, C. Wirtz, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
4
5470 Mülheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
Supporting Information and the ORCHID identification number(s) for the author(s) of this article can be found
under #################
1
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Chemistry - A European Journal
10.1002/chem.201705550
represents the primary product of biosynthesis; interestingly, 2 also proved considerably more active
4
than its sibling 1 in an assay comprising eight different bacterial strains. Yet, preliminary evidence
suggests that 2 is fragile and subject to irreversible double bond migration, which is likely driven by
the higher stability of the trisubstituted enoate in 1 compared to the disubstituted enone motif in the
parent compound 2.
4,5
Intrigued by the biological promise and the synthetic challenge forecasted by these reports, we
embarked into a program aiming at a chemical interrogation of this family of new lead compounds.
Total synthesis is the first step to be taken in order to assess the ingrained metastability of 2 in more
detail and scout possible remedies. At the same time, it is desirable to identify promising sites for
8
late stage modification to be addressed in the next phase of the project. The actual conquest of
disciformycin A and B outlined below meets many of these goals; most notably, it revealed some
remarkable chemical caprices of these targets which will guide our ongoing efforts at establishing a
more scalable route amenable to synthesis-driven mapping of the pharmacophore.
The “first-generation” approach to disciformycin B (2) as the most potent but also most fragile
member of this series capitalized on the strategic placement of a trimethylsilyl group at C4 (Scheme
9
1
). We conjectured that the enone double bond in a compound of type A, for its trisubstituted
nature and cooperative orbital interactions, should basically lose its migratory aptitude and be
2
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Chemistry - A European Journal
10.1002/chem.201705550
faithfully locked in place. Moreover, traceless cleavage of this chemical “insurance” might be timed
to coincide with global deprotection of the silylated arabinose residue in the projected last step of
the synthesis. While protodesilylation of A (E = Me) paves the way to the parent natural product 2,
the silyl residue also provides a handle for future functionalization of the scaffold at the arguably
critical C4-position.
Scheme 1. Retrosynthetic analysis of disciformycin B (2) based on the use of a C-silyl protecting
group; sketch of the key enabling methodology; DOS = diversity oriented synthesis
The site of closure of the highly decorated and fairly strained 12-membered ring of an intermediate
of type A also deserved careful consideration. Despite much progress in macrolactonization in
10
general, any method involving activated acid derivatives might endanger the integrity of the enone
and/or the chiral center at C2. Alternative methods based on OH activation were not deemed ideal
either, since the C11OH group to be involved in macrolactone formation is allylic to a potentially
isomerization-prone Z-configured double bond. Therefore we opted for macrocyclization at the
trisubstituted C8C9 alkene site: somewhat counterintuitively perhaps, ring closing alkyne
11
metathesis (RCAM) seemed more appropriate than olefin metathesis because the selective
3
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Chemistry - A European Journal
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12
formation of trisubstitued alkenes by RCM is problematic. Even though a cycloalkyne B may look
overly strained at first sight, the enthalpic penalty for bending an acetylene unit away from linearity –
at least to some degree  is modest; it can actually be compensated by reduced transannular strain
13
as a result of the cylindrical shape of this functional group. Moreover, recent work from this
laboratory has shown that propargyl alcohols can be readily elaborated into various trisubstituted
14,15
olefins by way of trans-hydrometalation.
Scheme 2. Preparation of the building blocks: a) PMBOC(=NH)CCl , PPTS (10 mol%), CH Cl , 85%; b)
3
2
2
LiAlH , Et O, 0°C  RT; c) (COCl) , DMSO, iPr NEt, CH Cl , 78°C  RT; d) CBr , Ph P, CH Cl , 75%
4
2
2
2
2
2
4
3
2
2
(
over three steps); e) nBuLi, THF, 78°C, then TMSCl, 78°C  RT, 96% (3.3 g scale); f) (i) Cp Zr(H)Cl,
2
THF; (ii) I , 78°C  RT, 62% (3.3 g scale), 80% (0.6 g scale); g) propyne, 1R,2S-()-N-
2
methylephedrine, Zn(OTf) , iPr NEt, toluene, quant. (dr = 97:3, 3 g scale); h) TBSCl, imidazole, CH Cl ,
2
2
2
2
9
8
8% (11 g scale); i) HS(CH ) SH, BF OEt , CH Cl , 0°C, 83% (9.5 g scale); j) TESCl, imidazole, CH Cl ,
2
3
3
2
2
2
2
2
6% (3.3 g scale); k) (i) (COCl) , DMSO, CH Cl , 78°C  30°C  78°C; (ii) iPr NEt, 78°C  RT; 85%
2
2
2
2
(
4.3 g scale); l) TMSCCCH MgBr, THF, 40°C; m) (S)-1-methyl-3,3-diphenyl-tetrahydropyrrolo-
2
[
1,2c][1,3,2]oxazaborole (6 mol%), catechol-borane, toluene, 78°C  60°C, 61% (over two steps,
2
.5 g scale, ee = 91%); n) K CO , MeOH, 98%; o) TBSCl, imidazole, CH Cl , 92% (2.4 g scale); p) nBuLi,
2
3
2
2
MeI, THF, 78°C  RT, 98% (2.4 g scale); q) TBAF, THF, 88% (1.2 g scale); Cp = cyclopentadienyl; PMB
p-methoxybenzyl; PPTS = pyridinium p-toluenesulfonate; TBAF = tetra-n-butylammonium fluoride;
=
Tf = trifluoromethanesulfonyl; TBS = tert-butyldimethylsilyl; TES = triethylsilyl; TMS = trimethylsilyl
4
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The building block comprising the key alkenylsilane motif was readily obtained from methyl lactate
on multigram scale (Scheme 2). Adaptation of a route previously pursued by our group furnished
16
17
alkyne 7, which underwent regioselective hydrozirconation to give product 8 after quenching with
iodine at low temperature. The required coupling partner 12 was attained by a highly selective
18,19,20
Carreira addition of propyne to commercial isopropylidene glyceraldehyde 9;
standard
21
protecting group management led to the persilylated triol 11, which was subjected to Swern
oxidation to give aldehyde 12 in good yield on a multigram scale. The necessary alcohol segment 16
22
was formed in 91% ee by CBS-reduction of ketone 14, which in turn was readily accessible from
commercial (Z)-2-methylbut-2-enoic acid.
The first fragment coupling step (Scheme 3), in contrast, proved challenging since partial E/Z-
isomerization was observed when 8 was subjected to metal/halogen exchange with tBuLi (or nBuLi)
23
even at temperatures as low as 100°C. Gratifyingly, a convenient solution was found by recourse
24
to iPrMgClLiCl as the metalating agent; no scrambling of the olefin geometry was noticed and
product 17 was isolated in 69% yield under conditions that proved practical on scale. The C-silyl
group was vital during the subsequent conversion of 17 into diyne 21 as a first adequate substrate
for macrocyclization. As expected, the enone double bond remained in the proper position during
PMB-ether cleavage and oxidation of the resulting primary alcohol to acid 19, which was best carried
out in two steps. As will become evident below, all compounds studied devoid of this “chemical lock”

are exceptionally isomerization-prone; even contact with ordinary silica gel or neutral Forisil can
entail double bond migration. The successful conversion of 17 to 19 definitely hinges on the
stabilizing function exerted by the alkenylsilane motif.
5
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Scheme 3. Route scouting and dead ends: a) iPrMgClLiCl, THF, 25°C  15°C, then 12, 25°C 
°C, 69% (2.1 g scale); b) DMP, NaHCO , CH Cl , 85% (2.5 g scale); c) DDQ, pH 7 buffer, CH Cl , 0°C 
0
3
2
2
2
2
RT, 91% (2.1 g scale); d) DMP, NaHCO , CH Cl ; e) NaClO , tBuOH, NaH PO , 2-methylbutene, 83% (1.5
3
2
2
2
2
4
g scale), 93% (0.6 g scale); f) 2,4,6-trichlorobenzoyl chloride, Et N, toluene, 0°C  RT, 79% (1.5 g
3
scale); g) 16, EDCI, DMAP (20 mol%), CH Cl , 0°C, 78% (1.1 g scale); h) 30 (40 mol%), CH Cl , toluene,
2
2
2
2
9
0°C, 93% (105 mg scale); i) PTSA, CH Cl , MeOH, 81%; j) [Cp*RuCl] (10 mol%), Bu SnH, CH Cl , 30%
2
2
4
3
2
2
(
+ unidentified by-products); k) PTSA (10 mol%), CH Cl , MeOH, 40°C, 88% (1 g scale); l) isovaleric
2
2
acid anhydride, CeCl (10 mol%), THF, 95% (0.83 g scale); m) 29 (40 mol%), MS 5Å, toluene, reflux,
3
3
8% (27) + 44% (26); n) 30 (35 mol%), CH Cl , toluene, 90°C, 81-90% (510 mg scale); o) PTSA or
2
2
HCOOH or BF OEt , see Text; Cp* = pentamethylcyclopentadienyl; DDQ = dichloro-dicyano-1,4-
3
2
benzoquinone; DMAP = 4-dimethylaminopyridine; DMP = Dess-Martin periodinane; EDCI = 1-ethyl-3-
(
3-dimethylaminopropyl)carbodiimide; MS = molecular sieves; PTSA = p-toluenesulfonic acid
6
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The sensitivity of the material also surfaced in the seemingly trivial esterification of 19 with
homopropargylic alcohol 16 (Scheme 3). Upon formation of the mixed anhydride from 19 and 2,4,6-
25
trichlorobenzoyl chloride, enolization leading to formation of pyrone 20 prevailed. Gratifyingly
though, condensation mediated by EDCI gave diyne 21 in readiness for macrocyclization. Compound
2
5 as an alternative cyclization precursor was derived from 21 by replacing the TES-ether with the
26
signature isovalerate ester, mandating the use of CeCl as catalyst. Although molybdenum
3
alkylidyne silanolate complexes such as 29 as the latest generation of alkyne metathesis catalysts
27
gave the desired product 27, substantial amounts of the acyclic dimer 26 were formed. This
outcome likely reflects severe steric hindrance about the propargylic triple bond which prevents
productive coordination of this site to the rather encumbered catalyst and hence cyclization from
28
29
occurring. In line with previous experience, the catalyst generated in situ from 30/CH Cl proved
2
2
to be sterically somewhat less demanding and therefore allowed product 27 to be formed in 81-90%
yield despite the strain inherent to this compound. As expected, 27 could also be obtained from 21
via 22 by inverting the order of RCAM and isovalerate attachment, again in excellent overall yield.
In contrast to the relative ease with which the highly decorated macrocyclic framework was forged,
the yet missing manipulation of the triple bond proved exceptionally taxing. Although a more
detailed discussion must await a future full paper, the following observations are representative:
14,30
Desilylation of 22 followed by ruthenium catalyzed trans-hydrostannation
of the resulting diol 23
entailed cleavage of the macrocycle via retro-aldol reaction to give product 24. Furthermore, no
conditions were found in which removal of the TBS-ether in 27 did not cause (partial) migration of
the isovalerate ester from C6-OH to the propargylic C7-OH position with formation of the futile
regioisomer 28. Careful analysis of the spectral data suggested that the macrocyclic frame of 27 is
3
indeed fairly rigid; the large J
= 8.9 Hz shows that these protons are held in an antiperiplanar
H6,H7
orientation, which predisposes the C7-OH, once released, for attack onto the adjacent ester and
causes the swift acyl walk.
To avoid this detrimental pathway, we saw us forced to relax the macrocycle by sacrificing the
peripheral C-silyl group that had nicely insured the integrity of the compounds up to this point
31
(
Scheme 4). In fact, protodesilylation of 27 with the aid of AgF worked well, provided the medium
7
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Chemistry - A European Journal
10.1002/chem.201705550
was buffered with HOAc; otherwise positional and/or configurational isomerization was observed.
Likewise, the cleavage of the TBS-ether proceeded under mildly acidic conditions to give the desired
propargyl alcohol 31 without noticeable acyl group migration. Although an analytically pure sample
could be obtained, compound 31 turned out to be exceptionally isomerization-prone; therefore the
crude material was subjected without delay to a hydroxy-directed trans-hydrostannation catalyzed
14,30
by [Cp*RuCl] as previously described by our group.
This transformation is usually distinguished
4
by outstanding levels of selectivity when applied to propargyl alcohols and has already served total
32
33
synthesis well; in the present case, however, a 3:1 (NMR) mixture of regioisomers was formed.
Although the sensitivity of 31 made a detailed investigation impossible, we confidently ascribe this
outcome to the fact that the C7–OH group, which has to guide the incoming catalyst by hydrogen
14
bonding to the [RuCl] subunit, is engaged in competing hydrogen bonding to the neighboring ester
carbonyl group.
Scheme 4. Completion of the total synthesis: a) AgF, HOAc, THF/MeOH/H O (2:2:1); b) HCOOH,
2
THF/H O; c) [Cp*RuCl] (15 mol%), Bu SnH, CH Cl , 50°C; d) CuTC, [Ph PO ][NBu ], MeI, DMSO; 30%
2
4
3
2
2
2
2
4
8
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(+ several unidentified byproducts, see Text); e) [(cod)Pd(Me)Cl], THF, 55°C, 20% (35) + 7% (36) (over
four steps, see Text); f) 37, TMSOTf, CH Cl , 45°C  20°C; g) aq. HF, CH Cl , 27% (+20% recovered
2
2
2
2
substrate, over two steps); h) Et N, CH Cl /MeCN (1:1), quant.; cod = 1,5-cyclooctadiene; CuTC =
3
2
2
copper thiophene-2-carboxylate
Not unexpectedly, 32 was even more fragile than 31 as protodestannation provides yet another easy
destructive outlet. As a consequence, the crude product mixture had to be subjected to C-
methylation as a fourth step to be executed in a row. Unfortunately, this a priori robust
transformation was unsatisfactory under the standard conditions using MeI in combination with
15,34
CuTC/[Ph PO ][Bu N] as promotor;
in addition to the desired product, several new compounds
2
2
4
were formed, of which aldehyde 34 arising from a retro-aldol reaction could be identified; even
milder conditions had to be found to make C-methylation successful. To this end, we contemplated
the use of [(cod)Pd(Cl)Me] as a stoichiometric methyl donor: this complex should engage
alkenylstannane 32 in transmetalation and hence lead to the desired product 35 in a Stille-type
manner. Gratifyingly, this proved to be the case. The resulting product 35, however, is again highly
sensitive and can neither be purified by flash chromatography on ordinary silica gel (double bond
isomerization) nor by reversed-phase HPLC (acyl group migration). A most welcome solution was
found in the use of “acidic silica” previously recommended for the isolation of isomerization-prone
35
compounds. With an average yield of 68% per step (20% overall) for the four consecutive
operations leading from 27 as the last stable bastion to the disciformycin B aglycon 35 the sequence
is certainly not ideal; yet, the outcome must be judged against the exceptional lability of all
compounds passed through, each of which has more than one destructive outlet.
While these lessons will guide future synthetic ventures, the total synthesis could be completed by
36,37
glycosidation of 35 with the arabinose-derived trichloroacetimidate 37
immediately followed by
38
global deprotection of the resulting fragile product with aqueous HF. The spectroscopic data of
4
synthetic disciformycin B (2) are in excellent accord with the literature. In view of the foregoing it is
unsurprising that exposure of 2 to Et N induced quantitative double bond isomerization with
3
formation of disciformycin A (1). Again, the NMR spectra of our samples are in good agreement with
the reported data, except for a characteristic spectral fingerprint, which had not been commented on
9
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Chemistry - A European Journal
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39
by the isolation team even though it had almost certainly been observed: The signals of the geminal
protons H4a/H4b gradually “disappear” when the spectra of 1 are recorded in [D ]-MeOH but do so
4
with different rates. We ascribe this interesting phenomenon to facile enolization of 1 and
+
reprotonation with [D ] from the solvent, which explains the observed topicity.
The total syntheses of the promising antibiotics disciformycin A and B outlined above revealed a
number of intricacies encoded in their molecular structure. The challenges could largely be met by
recourse to a C-silyl substituent serving as an efficient anchor for an unusually isomerization-prone
olefin, a tactic that might well be of interest beyond the current project. Yet, our ability to assess the
conformational space populated by the key macrocyclic intermediates has not gone so far as to
anticipate that this “lock” would engender adverse transannular reactivity and therefore had to be
sacrificed in the final stages of the synthesis. This and other intelligence gathered during our first
generation approach will guide the design of a more productive alternative route; ongoing efforts
will be reported in due course.
Acknowledgement
Generous financial support by the AvH (fellowship to Y. K.) and the MPG is gratefully acknowledged.
We thank Dr. Marc Müller for explorative studies, M. Sc. Felix Anderl for valuable discussions, and
the analytical departments of our Institute for excellent support.
1
0
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For the Table of Contents
Capriccioso: Isomerization of the enone in disciformycin B is unusually facile but goes hand in hand
with substantial loss of bioactivity of this antibiotic. While a strategically placed C-silyl substituent
allowed this chemical unrest to be cushioned until after the macrocycle had been closed, a successful
end-game mandated cleavage of this insurance for the price of handling exceptionally delicate
intermediates.
Keywords: Alkyne metathesis  Antibiotics  Natural Products  Protecting Groups  Total Synthesis
1
1
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2
6
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2
2
Structure 29 is only drawn for clarity; the actual catalyst is partially cross-linked, see: S.
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Chemistry - A European Journal
10.1002/chem.201705550
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33
As expected, attempted addition of Ph SnH under free radical conditions proved incompatible
3
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3
5
1, 1625-1627.
39
1
The 2D spectra (of impure samples) show these signals, while they are missing in the H NMR
spectrum of the purified sample depicted in the Supporting Information of ref. [4].
1
4
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