Synthesis of the Bioherbicidal Fungus Metabolite Macrocidin A

Article abstract of DOI:10.1021/acs.orglett.6b03240

The second total synthesis of macrocidin A afforded the bioherbicidal fungal metabolite in 16 steps starting from doubly protected l-tyrosine. The 3-octanoyl side chain with the α-methyl group and an ω-bromo epoxide already in place was attached to the te

Full text of DOI:10.1021/acs.orglett.6b03240

Letter
pubs.acs.org/OrgLett
Synthesis of the Bioherbicidal Fungus Metabolite Macrocidin A
Robert G. Haase† and Rainer Schobert*,†
†Organic Chemistry Laboratory, University of Bayreuth, Universitatsstrasse 30, 95440 Bayreuth, Germany
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* Supporting Information
ABSTRACT: The second total synthesis of macrocidin A afforded the bioherbicidal
fungal metabolite in 16 steps starting from doubly protected L-tyrosine. The 3-
octanoyl side chain with the α-methyl group and an ω-bromo epoxide already in
place was attached to the tetramic acid via a Yoshii−Yoda acylation, and the
macrocycle was eventually closed in 55% yield by a Williamson etherification between
the phenolate and the epoxy bromide.
acrocidins A (1) and B (2) are macrocyclic 3-
acyltetramic acids (Figure 1). While the related
biosynthesis. This multimodal effect, which makes resistance
M
development unlikely, combined with its species selectivity and
biodegradability, renders macrocidin A an interesting new crop
protection lead.
The only total synthesis of macrocidin A to date, which also
confirmed its absolute configuration, was published by Pfaltz,
Suzuki, and co-workers in 2009.5 It employed a macro-
lactamization by intramolecular ketene trapping followed by a
Dieckmann cyclization to partition off the pyrrolidine ring.
Syntheses of structurally simplified derivatives of macrocidin A
were reported by Ramana et al.6 and our group.7 Here we
present a conceptually new total synthesis of 1 comprising easy-
to-purify intermediates and lending itself to large-scale
production of 1 or simplified derivatives in the course of lead
optimization studies.
Scheme 1 delineates the retrosynthetic approach. Unlike the
Pfaltz−Suzuki synthesis, ours is based on a late-stage ring-
closing Williamson etherification between the phenolate and
the epoxy bromide of fully functionalized 3-acyltetramic acid 4.
The latter was built up by a Yoshii−Yoda acylation of the
known bisprotected tetramic acid 5,7 derived from protected
tyrosine 6, with carboxylic acid 7. The three stereogenic centers
of 7 were installed by Sharpless epoxidation and Evans
methylation, offering the advantage of easy-to-purify diaster-
eomers after each step. The oct-6-enoic acid backbone of allylic
alcohol precursor 8 was obtained by Negishi coupling between
ω-zincated pentanoyl reagent 9, still attached to the Evans
auxiliary used for introduction of the α-methyl residue, and
vinyl iodide 10.
Figure 1. Structures of macrocidins A (1) and B (2) and ikarugamycin
(3).
polycyclic tetramate macrolactams (PTMs),1 such as ikaruga-
mycin (3),2 are antiprotozoal, antibacterial, or antifungal
metabolites of bacteria featuring annulated carbocyclic ring
systems, the macrocidins are herbicidal metabolites of the
fungus Phoma macrostoma Montagne featuring a para-cyclo-
phane. They were extracted in minute quantities in 2003 by a
Dow AgroSciences group from field isolates of this pathogenic
fungus dwelling on diseased Canada thistles.3 Macrocidin A was
found only lately to induce chlorosis, i.e., bleaching and
withering of susceptible plants, preferentially broadleaf weeds,
by a unique pleiotropic mode of action.4 As a consequence of
its metal chelating propensity, it interferes with vital enzymes
and processes such as electron transfer and the light-harvesting
complex in photosystem II and phytoene synthase and
desaturase, resulting in reduced chlorophyll and carotenoid
The side-chain precursor 8 was prepared starting from 5-
bromovaleric acid (11), which was converted to a mixed
anhydride and attached to the Evans auxiliary (R)-benzyl-2-
oxazolidinone to give imide 12 in 88% yield (Scheme 2). Its
deprotonation with NaHMDS at −78 °C and quenching of the
Received: October 28, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03240
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 1. Retrosynthesis of Macrocidin A
Scheme 2. Synthesis of the Side-Chain Precursor 8
Scheme 3. Sharpless Epoxidation and Completion of the
Side-Chain Precursor 7
resulting enolate with iodomethane gave a separable 10:1
mixture of two product diastereomers. The major isomer 13
was subjected to Finkelstein halogen exchange to afford iodide
14. This was converted in situ to organozinc compound 9
according to a protocol by Huo8 and then treated with vinyl
iodide 10 and PdCl2(dppf) to give the coupling product 17.
Syntheses and reactions of organozinc compounds bearing
Evans auxiliaries were hitherto unknown, to the best of our
knowledge.
Vinyl iodide 10 was made in 76% yield from 16, a TBS-
protected derivative of propargyl alcohol (15), using Negishi’s
hydrozirconation protocol with DIBAL-H and zirconocene
dichloride.9 Imide 17 was then cleaved to give benzyl ester 18
in 83% yield. Near-quantitative removal of the silyl protecting
group with hydrofluoric acid left allylic alcohol 8, which
underwent diastereoselective Sharpless epoxidation to furnish
epoxy alcohol 19 as a single stereoisomer (Scheme 3).
Alcohol 19 was converted quantitatively to mesylate 20,
which in turn was treated with lithium bromide in acetone to
afford the desired epoxy bromide 21, also in 99% yield.
Hydrogenolytic cleavage of the benzyl ester liberated carboxylic
acid 7 in 89% yield without compromising the epoxide. Overall,
the fully functionalized side-chain precursor 7 was synthesized
in only 10 steps and in 14% yield.
reacting Boc-Tyr(Allyl)-OH (6) with Meldrum’s acid according
to a general protocol by Jouin et al.10 (Scheme 4). Tetramic
acid 5 was then acylated with carboxylic acid 7 employing
Yoda’s modified version11 of the older Yoshii protocol.12 In a
two-step process, compounds 5 and 7 were first reacted with
DMAP and EDC·HCl to give 4-O-acyltetramate 22. Its Fries-
type acyl rearrangement, mediated by NEt3, afforded 3-
acyltetramic acid 23. The addition of CaCl2 was necessary to
Next, N-Boc-(5S)-5-(4-(allyloxy)benzyl)-pyrrolidine-2,4-
dione (5) was prepared in 98% yield as described earlier7 by
B
DOI: 10.1021/acs.orglett.6b03240
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leading to macrocidin A does not require palladium catalysis, as
we had previously assumed7 for the cyclization of structurally
simplified derivatives.
Scheme 4. 3-Acylation and Ring-Closing Etherification
Removal of the tert-butyloxycarbonyl group of 25 with
trifluoroacetic acid eventually gave macrocidin A (1) in
quantitative yield with a specific optical rotation of [α]2D5 +40
(c 0.35, CH3OH). The natural isolate3 was reported to have
[α]2D5 +45 (c 0.35, CH3OH), and the synthetic sample obtained
by Pfaltz, Suzuki, and co-workers5 showed [α]D27 +42 (c 0.18,
CH3OH).
In summary, we developed the second total synthesis of
macrocidin A, which afforded the product in ca. 4% yield over
16 steps. Its chiral intermediates are all easy-to-purify
diastereomers, and it is flexible enough to give access to
analogues with widely varied structures. The Williamson
etherification, which is rarely used as a macrocyclization
method, worked well here, probably because the chelation of
potassium by the added crown ether and the 3-acyltetramic acid
itself enhanced the nucleophilicity of the phenolate and also
oriented the chain ends of the acyclic precursor in a favorable
way. Work is in progress now to identify a simplified herbicidal
lead structure.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03240.
Experimental details of chemical syntheses, character-
izations, and NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: Rainer.Schobert@uni-bayreuth.de. Fax: +49 (0)921
552671. Phone: +49 (0)921 552679.
ORCID
Rainer Schobert: 0000-0002-8413-4342
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
prevent racemization of the α-stereogenic center in the acyl
residue, possibly by chelate complex formation. Compound 23
was deallylated in methanol with Pd(PPh3)4 as a catalyst and in
the presence of potassium carbonate to give phenol 4.13 This
was submitted to a ring-closing Williamson etherification. Since
this reaction does not normally proceed well for the alkylation
of phenols with alkyl bromides, we had to apply special
conditions. Phenol 4 was dissolved in DMF and heated for 24 h
together with an excess of potassium carbonate, 0.5 equiv of
crown ether 18-c-6, and trace amounts of tetrabutylammonium
iodide (TBAI) to afford a 55% yield of the N-Boc protected
macrocidin A 25. We assume that cyclization takes place only
when a relatively nucleophilic phenolate anion can attack a
nearby iodide, generated in situ by TBAI. The crown ether
would sequester part of the potassium, keeping the phenolate
anion “naked”, and the rest of the potassium should be chelated
by the exocyclic and amide oxygens of the 3-acyltetramic acid
with the usual Z configuration,14,15 thus forcing the side chain
to point toward the phenolate as shown in structure 24. It is
also worth noting that the ring-closing etherification step
We are indebted to our past Ph.D. and graduate students Dr.
Ellen Wiedemann, Dr. Bertram Barnickel (AZ Electronic
Materials, Merck Group, Germany), Benjamin Christen, and
Dr. Anders Kroscky (Dr. Knoell Consult GmbH, Mannheim,
Germany) for exploring alternative synthetic routes to
macrocidin A.
REFERENCES
■
(1) Cao, S.; Blodgett, J. A. V.; Clardy, J. Org. Lett. 2010, 12, 4652−
4654.
(2) Jomon, K.; Kuroda, Y.; Ajisaka, M.; Sakai, H. J. Antibiot. 1972, 25,
271−280.
(3) Graupner, P. R.; Carr, A.; Clancy, E.; Gilbert, J.; Bailey, K. L.;
Derby, J. A.; Gerwick, B. C. J. Nat. Prod. 2003, 66, 1558−1561.
(4) Hubbard, M.; Taylor, W. G.; Bailey, K. L.; Hynes, R. K. Environ.
Exp. Bot. 2016, 132, 80−91.
(5) Yoshinari, T.; Ohmori, K.; Schrems, M. G.; Pfaltz, A.; Suzuki, K.
Angew. Chem., Int. Ed. 2010, 49, 881−885.
(6) Ramana, C. V.; Mondal, M. A.; Puranik, V. G.; Gurjar, M. K.
Tetrahedron Lett. 2006, 47, 4061−4064.
C
DOI: 10.1021/acs.orglett.6b03240
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) Barnickel, B.; Schobert, R. J. Org. Chem. 2010, 75, 6716−6719.
(8) Huo, S. Org. Lett. 2003, 5, 423−425.
(9) Huang, Z.; Negishi, E. Org. Lett. 2006, 8, 3675−3678.
(10) (a) Jouin, P.; Castro, B.; Nisato, D. J. Chem. Soc., Perkin Trans. 1
1987, 1, 1177−1182. (b) Hosseini, M.; Kringelum, H.; Murray, A.;
Tønder, J. E. Org. Lett. 2006, 8, 2103−2106.
(11) Sengoku, T.; Nagae, Y.; Ujihara, Y.; Takahashi, M.; Yoda, H. J.
Org. Chem. 2012, 77, 4391−4401.
(12) Hori, K.; Arai, M.; Nomura, K.; Yoshii, E. Chem. Pharm. Bull.
1987, 35, 4368−4371.
(13) Vutukuri, D. R.; Bharathi, P.; Yu, Z.; Rajasekaran, K.; Tran, M.;
Thayumanavan, S. J. Org. Chem. 2003, 68, 1146−1149.
(14) Biersack, B.; Diestel, R.; Jagusch, C.; Sasse, F.; Schobert, R. J.
Inorg. Biochem. 2009, 103, 72−76.
(15) Zaghouani, M.; Nay, B. Nat. Prod. Rep. 2016, 33, 540−548.
D
DOI: 10.1021/acs.orglett.6b03240
Org. Lett. XXXX, XXX, XXX−XXX