An Alkyne-Metathesis-Based Approach to the Synthesis of the Anti-Malarial Macrodiolide Samroiyotmycin A

Article abstract of DOI:10.1002/anie.202105732

We report the first total synthesis of samroiyotmycin A (1), a C₂-symmetric 20-membered anti-malarial macrodiolide isolated from Streptomyces sp. The convergent synthetic strategy orchestrates bisalkyne fragment-assembly using an unprecedented Sch?llkopf-type condensation on a substituted β-lactone and an ambitious late-stage one-pot alkyne cross metathesis–ring-closing metathesis (ACM–RCAM) reaction. The demanding alkyne metathesis sequence is achieved using the latest generation of molybdenum alkylidynes endowed with a tripodal silanolate ligand framework. Subsequent conversion to the required E-alkenes uses contemporary hydrometallation chemistry catalysed by tetrameric cluster [{Cp*RuCl}₄].

Full text of DOI:10.1002/anie.202105732

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Accepted Article
Title: An Alkyne Metathesis Based Approach to the Synthesis of the
Anti-malarial Macrodiolide Samroiyotmycin A
Authors: Ektoras Yiannakas, Mark Grimes, James Whitelegge, Alois
Fürstner, and Alison Nicola Hulme
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202105732
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COMMUNICATION
An Alkyne Metathesis Based Approach to the Synthesis of the
Anti-malarial Macrodiolide Samroiyotmycin A
[
a]
[a]
[a]
[b]
Ektoras Yiannakas, Mark I. Grimes, James T. Whitelegge, Alois Fürstner and Alison N.
[
a],
Hulme *
[
a]
E. Yiannakas, M. I. Grimes, J. T. Whitelegge, Prof. A. N. Hulme
School of Chemistry, University of Edinburgh
Joseph Black Building, David Brewster Road
Edinburgh, EH9 3FJ, UK
E-mail: Alison.Hulme@ed.ac.uk
[
b]
Prof. A. Fürstner
Department of Organometallic Chemistry
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr, Germany
Supporting information for this article is given via a link at the end of the document.
Abstract: We report the first total synthesis of samroiyotmycin A (1),
a C -symmetric 20-membered anti-malarial macrodiolide isolated
bonds in general are poorly reactive and ynoates in particular
were beyond reach of the classical catalysts.[24,25] To our
2
from Streptomyces sp. The convergent synthetic strategy
orchestrates bisalkyne fragment-assembly using an unprecedented
Schӧllkopf-type condensation on a substituted β-lactone and an
ambitious late-stage one-pot alkyne cross metathesis – ring-closing
metathesis (ACM-RCAM) reaction. The demanding alkyne
metathesis sequence is achieved using the latest generation of
molybdenum alkylidynes endowed with a tripodal silanolate ligand
framework. Subsequent conversion to the required E-alkenes uses
contemporary hydrometallation chemistry catalysed by tetrameric
4
cluster [{Cp*RuCl} ].
In 2013, Pittayakhajonwut and co-workers reported that the
crude extracts of Streptomyces sp. BCC33756, exhibited potent
activity against a multi-drug resistant (MDR) malarial strain.[1]
A
C
2
-symmetric macrodiolide from this extract, samroiyotmycin A
(
1), was shown to be active against both the MDR malarial strain
-1
P. falciparum K1 (IC50: 3.65 μg mL ) and lung carcinoma cell line
-1 [1]
NCI-H187 (IC50: 24.14 μg mL ). We envisaged rapid access to
this promising scaffold using a one-pot alkyne cross metathesis /
ring closing alkyne metathesis (ACM-RCAM) approach. Our
previous work on the macrodiolide disorazole C
1
,[2] suggested this
would allow rapid construction of the macrodiolide core with
control over both the orientation of subunits and ring size.
A priori, the initial disconnection for this ACM-RCAM
approach can be implemented across either the E-configured
C(5)-C(6)/C(21)-C(22) di-substituted alkenes, or the C(3)-
C(4)/C(19)-C(20) E-enoates (black and grey routes respectively,
Scheme 1 (i)). Comparing end-games: in the former strategy,
conversion of bis(enyne) 2 to the E-configured alkenes in the
absence of protic groups proximal to the acetylene, is likely to be
challenging;[3-5] whilst in the second strategy, conversion of
bis(ynoate) precursor 5 to samroiyotmycin A via ynoate-enyne
isomerisation,[6-13] bisiodination[14] and double Stille/Negishi
coupling,[15,16] has better precedent. Examining the ACM-RCAM
step, although both ACM and RCAM reactions of ynoates have
been explored in isolation previously, the number of successful
examples is small,[17-23] likely because electron-deficient triple
Scheme 1. Convergent one-pot ACM-RCAM approaches to samroiyotmycin A.
(i) Ring deconstruction via routes based on C(5)-C(6)/C(21)-C(22) or C(3)-
C(4)/C(19)-C(20) disconnections to key intermediate 6; (ii) Installation of
C(9)/C(10) and C25)/C(26) stereochemistry via cyclocondensation onto α-chiral
aldehyde 9.
1
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COMMUNICATION
knowledge there are no examples of a one-pot ynoate ACM-
RCAM, as required for the assembly of the 20-membered core of
samroiyotmycin A (1). With this in mind, we devised a unified
strategy for construction of the bisalkyne building blocks, which
would allow us to explore both routes. This strategy centered on
desulfonylation of 5-substituted 4-tosyloxazoles
7
and
esterification of the resultant secondary alcohols 6 to give
bisalkyne fragments 4 and 5. Influenced by prior work,[26] we
hypothesised that formation of linchpin fragments 7 (Scheme 1(ii))
could be achieved through a Schӧllkopf-type condensation of 4-
substituted β-lactones 8 with anionic TosMIC.[27-29] If successful,
this ambitious strategy would allow simultaneous installation of
the 1,3-oxazole unit and stereochemistry at C(10). Furthermore,
we envisaged that construction of the diastereomerically pure β-
Scheme 2. Setting C(9) stereochemistry via alkylation of an acylated Evans’
oxazolidinone (i), or Myers’ pseudoephedrine (ii) auxiliary. Reagents and
Conditions: (a) MeI, NaHMDS, THF, − 78 °C, 4.5 h, (11a, 77 %, >20:1 dr; 11b,
9
8%, >20:1 dr); (b) LiOH, H
12b, 94 %ee); (c) CDI, HN(OMe)Me·HCl, CH
3 %ee; 13b, 82% from 11b, 92 %ee); (d) LDA, LiCl, 5-iodo-pent-2-yne or 7-
iodo-hept-2yne, − 78 °C → 0 °C, 2 h, (18a, 79 %, 75:1 dr; 18b, 98 %, 71:1 dr,);
(e) LiAlH , EtOAc, THF/iso-Hexanes (4:3), − 78 °C → 0 °C, 1 h.
2
O
2
, THF/H
2
O (1:1), 0 °C → RT, (12a, 95 %, 93 %ee;
lactones
8 would be possible via an asymmetric ketene
[
30]
2
Cl , 0 °C → RT, 18 h, (13a,
2
cycloaddition to α-methyl aldehydes 9. Our synthetic approach
to exploring these two proposed one-pot ACM-RCAM strategies
is outlined below.
9
4
To explore our novel synthetic approach to setting the C(9)-
C(10) stereochemistry required generation of α-chiral aldehydes
9a/b. Our initial approach focused on the diastereoselective
alkylation of N-acylated oxazolidinones (Scheme 2(i)). Due to
competing elimination reactions observed when alkylating the
propionate derivative, diastereoselective methylation of the
oxazolidinone derivatives 10a/b (see SI for preparation) was the
preferred route. This reaction delivered the N-acyl derivatives
1
1a/b on a multi-gram scale in good to excellent yield (77- 98%)
and with high selectivity (dr >20:1).[31] Hydrolytic cleavage of the
chiral auxiliary in the presence of H gave the corresponding
2
O
2
acids 12a/b in almost quantitative yield (95 %). Conversion to the
configurationally stable Weinreb amides 13a/b was accompanied
by a very slight erosion of enantiomeric purity, as observed by
chiral HPLC. DIBAL-H reduction (Scheme 3(i)) provided the
sensitive α-methyl aldehydes 9a/b, primed for chain elongation by
an acetate aldol equivalent.[32] The asymmetric ketene-aldehyde
cycloaddition catalysed by the Lewis base O-TMS quinine 14 was
chosen for this purpose due to high levels of stereochemical
control exerted by this cinchona alkaloid catalyst in intramolecular
nucleophile-catalyzed aldol lactonisation (NCAL) reactions of α-
or β-substituted aldehyde acids,[33] and in intermolecular NCAL
reactions featuring aldehydes with remote substitution.[34] This
reaction converted crude aldehyde 9a into the thermally unstable
β‐lactone 8a with excellent diastereocontrol over the newly-
formed stereocentre at C(10) (>99:1 dr). To the best of our
knowledge, this is the first example of an intermolecular NCAL
reaction with double diastereodifferentiation, where the catalyst
control dominates over the influence of an α-chiral centre on the
Scheme 3. Introduction of C(10)OH and 4-tosyloxazole functionalities.
Reagents and Conditions: (a) DIBAL-H, CH Cl , − 78 °C, 1 h; (b) 14 (10 mol%),
O (1:1 – 2:1), − 78 °C, 18-24 h, > 99:1 dr; (c)
TosMIC, BuLi, THF, - 78 °C to rt, 1 h (7a, 35 %, 96:4 from 11a, or 52%, > 97:3
dr from 18a; 7b 43 %, >20:1 dr from 11b, or 24%, >20:1 dr from 18b); (d) (S)-
2
2
LiClO
4
, AcCl, DIPEA, CH
2
Cl
2
/Et
2
n
(+)-MTPACl, DMAP (10 mol%), TEA, CH
2 2
Cl , rt, 18 h, (15a, 77 %; 15b, 85 %),
(e) (R)-(-)-MTPACl, DMAP (10 mol%), TEA, CH Cl , rt, 18 h (16a, 72%; 16b,
2
2
88 %).
the lithium enolate of 17 using 5-iodopent-2-yne afforded
multigram quantities of amide 18a in very good yield (79 %, 75:1
3
dr). Reductive cleavage of the auxiliary using LiAl(OEt) H
generated in-situ at low temperature gave aldehyde 9a,[
35,36]
which was used directly in the cyclocondensation catalysed by O-
TMS quinine 14 to afford β-lactone 8a (> 99:1 dr). Immediate
condensation of crude 8a with anionic TosMIC provided chiral
alcohol 7a in excellent yield (52 %, over a three-step telescoped
sequence) and with high diastereoselectivity (97:3 dr) on multi-
gram scale. 4-Tosyloxazole 7b was also obtained by adaptation
of this synthetic route; asymmetric alkylation of the acylated
auxiliary with 7-iodohept-2-yne to give 18b, reduction to aldehyde
aldehyde.
condensation of 8a with anionic TosMIC, furnished chiral alcohol
a in excellent overall yield (35% from oxazolidinone 11a,
following five-step telescoped sequence) and with high
Immediate
low-temperature
Schӧllkopf-type
7
a
diastereoselectivity (96:4 dr). When repeated with the longer
chain oxazolidinone 11b, the same five-step sequence yielded
alcohol 7b in 43 % overall yield (> 99:1 dr). In both cases, the
configuration at C(10)OH was confirmed by conversion to Mosher
esters 15 and 16 (see SI for details).
For the total synthesis of samroiyotmycin A, we streamlined
our route by switching to the use of Myers’ acylated
pseudoephedrine auxiliary 17, since the amide formed upon
alkylation can be directly converted to the enantioenriched α-
methyl aldehyde (Scheme 2(ii)). Diastereoselective alkylation of
9
b and elaboration to diastereomerically pure β-lactone 8b.
Careful optimisation of the cycloaddition reaction conditions
showed that use of an equivolume mixture of Et O and CH Cl as
2
2
2
solvent gave the highest conversion and diastereoselectivity for
this substrate. Subsequent condensation of the crude lactone 8b
with TosMIC, delivered fragment 7b in good yield (24 % over a
three-step
telescoped
sequence)
and
similarly high
diastereoselectivity (> 99:1 dr).
2
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COMMUNICATION
A number of methods were initially evaluated for the
Table 1. Optimisation of the one-pot ACM-RCAM of bisalkyne 4.
reductive desulfonylation of advanced intermediates 7a and
[
37-39]
7b.
To our surprise, sonication of fragment 7a in THF/EtOH
Catalyst
Loading
Isolated
yield of 2
(%)
Temp
(°C)
Molarity
(mM)
Time
(h)
Entry
with Na(Hg) amalgam, delivered the fragile chiral alcohol 6a,
which was found to be prone to degradation even on silica.[38]
Gratifyingly, EDC-mediated esterification with acid 19 (see SI for
preparation) furnished the stable bisalkyne 4 and set the stage for
the envisaged one-pot ACM-RCAM reaction. Our synthetic plan
for bisalkyne 5 was to follow this route via tosyl group removal to
give 6b and esterification with 2-butynoic acid 20. Unfortunately,
sonication of both fragment 7b, or its TBS ether 21b, in THF/EtOH
with Na (Hg) amalgam (2.0 - 10.0 equiv., 10 mol% Na) either
failed completely, or led to instantaneous decomposition. Even
(mol %)
a
1
10
60
60
60
60
60
80
50
50
30
30
15
30
2
2
53
55
74
71
71
50
2a
3a
4a
20
20
1
30
1
5a
30
3
the use of SmI
2
with DMPU, reported to be a particularly mild
6b
20
18
alternative,[ only led to the recovery of starting material. This
unforeseen subtlety rendered the ynoate-yne one-pot ACM-
RCAM strategy non-viable and enforced an adjustment to our final
synthetic plan.
39]
[
a] Reaction conditions: catalyst: complex 22a, solvent: toluene, additive: 5 Å
MS. [b] Reaction conditions: catalyst: complex 22b, solvent: toluene, additive: 5
Å MS.
For our one-pot ACM-RCAM investigation, we employed the
two latest generation molybdenum alkylidynes (22a/b) endowed
with the privileged tripodal silanolate ligand framework.[37,38]
Based on prior work from our group, we treated a solution of
bisalkyne 4 in toluene (50 mM) with molybdenum alkylidyne
complex 22a (10 mol%) at ambient temperature, in the presence
of molecular sieves (5 Å) to scavenge the released 2-butyne.[2]
Following the reaction by reverse‐phase LC‐MS (λ=254 nm)
indicated no conversion even after four hours at room
temperature. However, full conversion to cyclobis(enyne) 2 was
attained within two hours, by raising the temperature to 60 °C
(Table 1, entry 5) gave no additional improvements with complex
22b, full-conversion to the desired one-pot ACM-RCAM product 2
was only achieved after overnight heating at 80 °C (Table 1, entry
6) and isolation of the product was hindered by fragmentation of
the catalyst ligand. These results highlight the remarkable
functional group tolerance and robustness of catalyst 22a,[
which activates even the most demanding triple bonds under mild
conditions in the presence of basic heterocycles. We suggest that
the rigidified backbone and greater steric encumbrance of the
coordination sphere of the podand complex 22b, is responsible
for its reduced reactivity, particularly for electron-deficient
substrates such as 1,3-enynes, which are known to be less
reactive.[41]
40]
(
Table 1, entry 1). Routine chromatography gave the cross-dimer
in analytically pure form in 53 % yield. Although no linear dimers,
2
higher-order oligomers, nor the corresponding homo-dimeric
isomer were discernible by LC-MS, we nonetheless suspected
competing concentration-induced polymerisation. This undesired
pathway, which seems to be independent of the initial catalyst
loading (Table 1, entry 2), can be effectively suppressed by
performing the reaction at a higher dilution. Indeed, treatment of
a more dilute solution of monomer 4 (30 mM) with complex 22a
With the desired 20-membered macrocyclic framework in
hand, our two end game steps could be tackled. Inspired by the
recent formal synthesis of the lichen-derived macrolide (+)-
aspicilin,[18] we envisioned that trans-reduction of the newly
formed alkynes to the required E-configured alkenes would be
achieved via
a bis(trans-hydrostannation-protodestannation)
sequence. However, these key steps bore substantial risk, since
electron-rich arenes and 1,3-enynes often act as catalyst poisons
(
20 mol%) gave a significantly improved yield (Table 1, entry 3).
Higher catalyst loading (Table 1, entry 4) and further dilution
Scheme 4. Synthesis of bisalkyne building blocks and bisalkyne cyclic dimers. Reagents and Conditions: (a) TBSOTf, 2,6-lutidine, CH
2
Cl
2
, 0 °C → RT, 18 h, 73 %
(17b); (b) Na/Hg (10 mol % Na), Na
2
HPO
4
, THF/EtOH (1:1), 4 h; (c) EDC·HCl, acid 19, DMAP (10 mol%), CH Cl , 0 °C → RT, 18 h, 70 % over two steps (4); (d)
2 2
see Table 1.
3
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COMMUNICATION
in the trans-hydrostannation reaction.[42] This stems from the
ability of these substrates to bind to the [Cp*Ru] fragment through
4
6
kinetically stable η or η complexation, halting further trans-
hydrometallation of the alkyne triple bond (A and B, Scheme 4
(
i)).[43] Furthermore, neighbouring group coordination often
facilitates both the productive binding of the [Cp*Ru] and the
selective proximal delivery of SnBu to the triple bond (C and D,
3
Scheme 4(ii)).[43] In the absence of directing groups, we
anticipated that a double hydrostannation reaction would lead to
a statistical mixture of proximal and distal stannylated products (E,
F and G, Scheme 4(iii)). All of which derive from a double trans-
hydrometallation process and can effectively deliver the
desired E-configured alkenes upon protodestannation. In practice,
hydrostannation of bis(enyne) 2 with the aid of tetrameric
ruthenium
catalyst 23 proceeded
smoothly
at
ambient
temperature to deliver an ill-defined mixture of stannylated
products, which was not separable by flash chromatography on
silica or reverse‐phase HPLC. Therefore, the overall trans-
selectivity of the double hydrostannation reaction was only
determined after protodestannation had taken place.
Despite the ease of forging and subsequent elaboration of
the macrocyclic core, protodestannation of the alkenylstannanes
was particularly taxing. Treatment of the mixture of stannanes
with TFA, silica, TBAF or even in situ generated HF, in both
coordinating and non-coordinating media led either to no
conversion or to decomposition. Confronted by this impasse, we
resorted in a different approach. Given that most synthetic
methodologies available for the downstream functionalisation of
alkenylstannanes rely on the reversible transmetalation of tin to
copper in polar solvents, we considered protodestannation via the
formation of an organocopper species in the presence of a tin
scavenger and an exogeneous proton source. After extensive
experimentation we found that employing a mixture of DMF-
MeOH (10:1) in the presence of copper(I) salt 24 at ambient
temperature led to successful protodestannation (Scheme 4(iv)),
furnishing the desired (5E,21E) isomer (1) as the major
stereoisomer (crude HPLC ratio 78:22, (1):E/Z isomers). To our
satisfaction, the analytical and spectroscopic data of the synthetic
sample of 1, matched those of the natural product.
Scheme 5. Trans-hydrometallation and end game steps: (i) Unproductive 1,3-
enyne hydrometallation; (ii) Protic group assisted trans-hydrostannation; (iii)
Expected products from the double trans-hydrostannation of bis(enyne) 2 (iv)
In summary, we have completed the first total synthesis of
the anti-malarial macrodiolide samroiyotmycin A (1) (9 steps
longest linear sequence, with an overall yield of 6 %). This
convergent and scalable route, showcases an initial asymmetric
alkylation of commercial 17, followed by a three-step telescoped
sequence to set the C(10)OH stereochemistry and install the 1,3-
oxazole unit, utilising an unprecedented Schӧllkopf-type
condensation on enantioenriched beta-lactones. Forging the rigid
macrocyclic core was achieved by an efficient one-pot ACM-
RCAM reaction using the latest generation of alkyne metathesis
Reagents and Conditions: (a) tetrameric complex 23 (10 mol%), Bu
3
SnH,
CH Cl , RT, 0.5 h; (b) 24, DMF/MeOH (10:1), rt, 2 h, 30 % over two steps after
2
2
preparative HPLC.
Acknowledgements
We thank the EPSRC (studentship to E.Y.; 1940702), the
Leverhulme Trust (scholarship to E.Y.; SAS-2019-012) and the
AG Leventis Foundation (scholarship to E.Y.). for financial
support. We thank Ms Sandra Kestermann, Mrs Heike Hinrichs,
Ms Sophia Begoihn and Mrs Conny Wirtz from the analytical
departments at MPI for the technical support.
2
catalysts. While the final elaboration to the desired C -symmetric
macrodiolide was possible via a delicate trans-hydrostannation-
protodestannation sequence. These results demonstrate that,
when combined with contemporary hydrometallation chemistry,
the one-pot ACM-RCAM can be a powerful manifold for the
assembly of complex molecular architectures. We anticipate that
this synthetic route will provide a solid base for future exploration
of other members of this family, and the design of analogues with
improved application profiles.
Keywords: alkynes • hydrostannation • metathesis • natural
products • total synthesis
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Forging of the 20-membered macrocylic core of samroiyotmycin A can be readily achieved by combining a Mo-catalysed one-pot
alkyne cross-metathesis ring-closing metathesis of bisalkyne building blocks and Ru-catalysed hydrometallation chemistry. These
key transformations have enabled the first total synthesis of this antimalarial C -symmetric macrodiolide.
2
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