Total Synthesis of (+)-Cornexistin

Article abstract of DOI:10.1002/ange.202008158

Herein, we describe the first total synthesis of (+)-cornexistin as well as its 8-epi-isomer starting from malic acid. The robust and scalable route features a Nozaki–Hiyama–Kishi reaction, an auxiliary-controlled syn-Evans-aldol reaction, and a highly efficient intramolecular alkylation to form the nine-membered carbocycle. The delicate maleic anhydride moiety of the nonadride skeleton was constructed from a β-keto nitrile. The developed route enabled the synthesis of 165 mg (+)-cornexistin.

Full text of DOI:10.1002/ange.202008158

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Titel: Total Synthesis of (+)-Cornexistin
Autoren: Christian Steinborn, Raphael Wildermuth, David Barber, and
Thomas Magauer
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10.1002/ange.202008158
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Total Synthesis of (+)-Cornexistin
Christian Steinborn†[a], Raphael E. Wildermuth†[b], David M. Barber[c] and Thomas Magauer*[a]
[a]
Christian Steinborn and Prof. Dr. Thomas Magauer
Institute of Organic Chemistry and Center for Molecular Biosciences
Leopold-Franzens-University Innsbruck
Innrain 80–82, 6020 Innsbruck, Austria
E-mail: thomas.magauer@uibk.ac.at
[b]
[c]
Dr. Raphael E. Wildermuth
Research and Early Development, Respiratory & Immunology
AstraZeneca, 431 83 Mölndal, Sweden
Dr. David M. Barber
Research & Development, Weed Control Chemistry, Bayer AG
Crop Science Division
Industriepark Höchst, 65926 Frankfurt am Main, Germany
†
These authors contributed equally
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, we describe the first total synthesis of
(+)-cornexistin as well as its 8-epi-isomer starting from malic acid. The
robust and scalable route features a Nozaki–Hiyama–Kishi reaction,
an auxiliary controlled syn-Evans-aldol reaction and a highly efficient
intramolecular alkylation to form the nine-membered carbocycle. The
delicate maleic anhydride of the nonadride skeleton moiety was
accessible via sequential hydrolysis of a β-keto nitrile. The developed
route enabled the synthesis of 165 mg (+)-cornexistin.
(ozonolysis/ring-expansion retron). The realization of these
strategies required a late stage inversion of the C2 stereocenter
that turned out to be highly problematic.[5]
Due to the rapidly evolving resistance to commercially herbicides,
phytotoxic natural products provide a unique opportunity for the
development of novel herbicides. Cornexistin (1) and
hydroxycornexistin (2) belong to the unique family of nonadride
natural products for which more than 16 members were reported
over the last century.[1] The inherent nine-membered carbocycle
features a delicate maleic anhydride unit and a β-hydroxy ketone
that is linked to a trisubstituted Z-alkene. Both functional groups
were shown to be acid and base labile leading to ring-opening via
hydrolysis of the anhydride or retro-aldol cleavage at C8/C9.[2] In
the course of their studies to elucidate the biosynthesis of 1 and
2, the Cox group determined the absolute stereochemistry by
single crystal X-ray diffraction.[3] While nonadrides show various
biological
antimicrobial, antitumor, antifungal to antibacterial activity,[1d]
and demonstrate outstanding post-emergence herbicidal
activities
ranging
from
cholesterol-lowering,
Scheme 1. A) Previous studies towards the nonadride framework by Taylor and
Clark. B) Retrosynthetic analysis of cornexistin (1) and hydroxycornexistin (2)
based on an intramolecular alkylation strategy. The cyclization precursor 4
arises from a highly convergent three-component coupling strategy.
1
2
activity against monocotyledonous plants that grow in association
with corn.[4] With activity in the range of commercially available
herbicides such as glyphosate or bialaphos, whilst exhibiting low
toxicity to bacteria, fungi and mammalians,[1a-c] 1 and 2 could
represent a unique starting point for the development of novel
broad spectrum herbicides. Cornexistin (1) was reported to inhibit
aspartate amino transferase, however, the exact mode of action
remains unclear.[1d] Several research groups have previously
investigated the total synthesis of cornexistin (1) or
hydroxycornexstin (2), however all efforts to install the correct
substitution pattern failed (Scheme 1A). In seminal work by Clark
and Taylor, 1 and 2 were retrosynthetically dissected at C1–C2
(RCM-retron or NHK-retron) or derived by connecting C2–C7
In the context of our ongoing research program to access xenicin
natural products, we recently identified an intramolecular
alkylation as the key transformation to form a structurally complex
nine-membered carbocycle.[6] For the translation of this strategy
to 1, we first masked the sensitive anhydride unit as the β-keto
nitrile 3 (Scheme 1B). Further disconnection at C5/C6 revealed
the allylic bromide 4. As late-stage stereochemical adjustments
were considered to be of high risk, we decided to introduce the
crucial stereocenters along the northern periphery at an earlier
stage.
1
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Scheme 2. Synthesis of all carbon precursor 17. Reagents and conditions: a) 5, CrCl2, NiCl2, DMF, 0 °C to 23 °C, 58%, d.r. = 1.3:1 at C8; b) TBSOTf, 2,6-lutidine,
CH2Cl2, –78 °C to 23 °C, 94%; c) DIBAL-H, CH2Cl2, –78 °C to –40 °C, 73%; d) DMP, CH2Cl2, 23 °C, 86%; e) 7, Bu2BOTf, NEt3, –78 °C to 23 °C; f) TBSOTf,
2,6-lutidine, CH2Cl2, –78 °C to 23 °C, 72% over two steps; g) EtSH, n-BuLi, THF, 0 °C, 96%; h) MeCN, n-BuLi, THF, –78 °C, 78%; i) HF⋅pyridine, THF/pyridine 2:1,
0 °C, 80%; j) NBS, PPh3, CH2Cl2, –20 °C to –5 °C, 90%; k) DBU, MeCN, 23 °C, 74%; l) Tf2O, NEt3, –78 °C, 85% after three cycles; m) Pd(OAc)2, dppf, CO, DIPEA,
MeOH,
55 °C,
93%.
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene,
DIBAL-H = diisobutylaluminiumhydride,
DIPEA = N,N-diisopropylethylamine,
DMF = N,N-dimethylformamide, DMP = Dess–Martin periodinane, dppf = 1,1'-bis(diphenylphosphino)ferrocene, NBS = N-bromosuccinimide, PMB
methoxybenzyl, PMP = para-methoxyphenyl, TBSOTf = tert-butyldimethylsilyl trifluoromethanesulfonate, THF = tetrahydrofuran.
= para-
synthesis with the mixture of diastereomers. Oxidation of the
primary alcohols 11 utilizing Dess–Martin periodinane gave
aldehyde 12 in 86% yield setting the stage for the following
syn-Evans-aldol reaction. Exposure of 7 to triethylamine in the
presence of dibutylboron trifluoromethanesulfonate generated the
Z-enolate of 7 that underwent a highly-selective syn-aldol reaction
with 12.[13] The aldol product was only contaminated with residues
of 7 (20%) and did not show any detectable amounts of the
undesired anti-product. After silylation of the secondary alcohol
(TBSOTf, 2,6-lutidine), the protected aldol product 13 was
isolated in 72% yield over two steps. Initial attempts to install the
required β-keto nitrile moiety by direct cleavage of the auxiliary
with LiCH2CN (CH3CN, n-BuLi, –78 °C) only resulted in ring-
opening of the 2-oxazolidinone. Therefore, we first treated 13 with
lithium thioethoxide, freshly prepared from n-BuLi and thioethanol,
to effect clean cleavage of the auxiliary to furnish thioester 14 in
almost quantitative yield. Subsequent treatment with LiCH2CN
provided the desired β-keto nitrile moiety in good yield (78%).[14]
Selective deprotection of the primary, allylic TBS-group was
For the introduction of the Z-alkene linked to the allylic alcohol at
C8, we resorted to a Nozaki–Hiyama–Kishi coupling between
vinyl iodide 5 and D-malic acid derived aldehyde 6. Clockwise
functional group manipulations were envisioned to enable
installation of the C2/C3 stereocenters via reliable syn-Evans-
aldol chemistry employing 7.
We commenced our synthesis with the preparation of vinyl
iodide 5, accessible in three steps involving α-iodination (I2,
K2CO3, DMAP) of trans-crotonaldehyde, reduction (BH3⋅Me2S,
NaBH4) to the allylic alcohol and protection (TBSCl, imH).[7]
Aldehyde 6 was available in four steps on large scale (21 g,
d.r. = 1.3:1) starting from D-malic acid (8) (Scheme 2, see
Supporting Information for details).[8] With both building blocks in
hand, we investigated the coupling of the two fragments via
1,2-addition. Common procedures involving halogen-metal
exchange of 5 (t-BuLi, n-BuLi, i-PrMgCl, Et2Zn, [n-Bu2(i-Pr)Mg]Li)
or metal insertion (Mg, Zn, In) were met with failure and only
resulted in decomposition of 5 or the undesired 1,2-addition of the
metal exchange reagent. Eventually, we found that Nozaki–
Hiyama–Kishi conditions (CrCl2, NiCl2) allowed activation of the
vinyl iodide 5 and carbon-carbon bond formation to deliver 9 as a
mixture of two diastereomers at C8 (58%, d.r. = 1.3:1).[9] To
improve the diastereoselectivity, asymmetric versions as reported
by Kishi[10] and Berkessel[11] were also investigated, but did not
lead to product formation. The mixture was not separated, but
directly subjected to TBS-protection and reductive opening of the
para-methoxybenzylidene acetal to reveal a 1:1 mixture of
C8-epimeric primary alcohols 11 in 73% yield.[12] Since the
unnatural C8-epimer of 1 represented a valuable substrate for
structure-activity-relationship studies and separation turned out to
be time-consuming at this stage, we decided to continue the
realized using pyridine hydrofluoride in
a 2:1 mixture of
tetrahydrofuran and pyridine at 0 °C and delivered the free allylic
alcohol in consistent yields of 80%. Subsequent Appel reaction
(NBS, PPh3) completed the synthesis of the highly functionalized
cyclization precursor 4. The robustness of our route allowed for
the preparation of 6.9 g of 4 in a single run. For the key-
intramolecular alkylation, we first screened a range of carbonate
bases in acetonitrile. While lithium carbonate showed no
conversion, sodium carbonate, potassium carbonate and cesium
carbonate all induced the cyclization of 4 to give the nine-
membered carbocycle 3.[15] Within this series, cesium carbonate
showed the highest degree of undesired O-alkylation and
comparable results were obtained for sodium- and potassium
carbonate. The alternative conjugate alkylation was not observed
for
any
of
these
conditions.
The
use
of
2
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10.1002/ange.202008158
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1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) further suppressed further improved to 80%, simultaneously decreasing the amount
O-alkylation and allowed for the preparation of 4.3 g of 3 in 74% of 20 to 4% (entry 4). Performing the reaction in tert-butanol gave
yield. With large quantities of the nine-membered ring in hand, we comparable results, however the reaction required a significantly
next focused on the installation of the last missing carbon bond
and formation of the delicate maleic anhydride motif. We were
pleased to find that treatment of 4 with triflic anhydride and
triethylamine successfully delivered the triflate in 65% yield.
Unreacted starting material 4 (30%) was recycled to increase the
overall yield to 85% after three cycles. Separation of the mixture
of C8-epimers by extensive flash column chromatography was
also performed at this stage to provide 2.1 g of 16. Surprisingly,
the presence of the nitrile was crucial to enable formation of the
triflate. The corresponding keto-ester 27 was resistant to triflation
even after an extensive screen of more than 30 reaction
conditions (see Supporting Information for details).[16] For the
longer reaction time (entry 5). Utilizing the Ghaffar–Parkins
catalyst resulted in clean hydrolysis of 17 to afford 20 as the only
detectable product (entry 6).[17]
To unveil the maleic anhydride moiety, the obtained imidate 19
was further hydrolyzed. Stirring a solution of 19 in a 5:1 mixture
of 0.1 M aqueous hydrochloric acid and tetrahydrofuran resulted
in rapid consumption of the starting material and clean conversion
to 21 in good yields (Scheme 3). For the completion of the
synthesis, selective deprotection and oxidation along the northern
periphery had to be accomplished. To avoid hydrolysis of the
delicate anhydride moiety to the water-soluble diacid, 0.2 M
aqueous hydrochloric acid was used in the work-up procedures
for all anhydride containing intermediates. Cleavage of the para-
methoxybenzyl ether was cleanly achieved upon exposure to
DDQ and delivered alcohol 22 in 88% yield. The subsequent
oxidation also proceeded smoothly, however ketone 23 was
found to be sensitive to silica gel, resulting in a substantial loss of
following carbonylation,
a combination of Pd(OAc)2 and
1,1'-bis(diphenylphosphino)ferrocene (dppf) in methanol was
found to be most effective providing the methyl ester 17 in
excellent yields.
With the all carbon precursor 17 in hand, we turned our attention
to the challenging hydrolysis of the nitrile (Table 1). Initial efforts material after purification. We assume that this loss might be a
to directly form the anhydride under acidic conditions either led to result of retro-aldol cleavage or hydrolysis of the sensitive maleic
cleavage of the silyl groups and/or formation of complex product anhydride. Efforts to isolate any byproducts were met with failure.
mixtures. We therefore investigated a stepwise protocol to To avoid purification by column chromatography, the reaction
generate the anhydride. Treatment of 17 in a 5:1 mixture of
tetrahydrofuran and 10% aqueous potassium hydroxide at
mixture was diluted with pentane and the suspension was filtered
over a short plug of Celite. The crude ketone was then directly
elevated temperature led to no conversion and only unreacted exposed to pyridine hydrofluoride in tetrahydrofuran to give
starting material was recovered (Table 1, entry 1). However, (+)-cornexistin in 86% yield over two steps. The obtained
analytical data of synthetic 1 were in full agreement with the data
reported by Nakajima[1b] and Cox.[3b] The C8-epimer 24 of the
natural product and the corresponding imide analogues 25 and
26 were obtained under identical conditions (see Supporting
Information for details). Finally, we also investigated the late-
stage oxidation of 1 to 2. Unfortunately, exposure of 1 to a panel
of oxidation conditions (e.g. SeO2; PIDA, I2, hν or NBS, AIBN) only
led to no reaction or decomposition of 1.
when the hydrolysis was conducted in aqueous methanol, a
mixture of imidate 19 and imide 20 was obtained (entry 2).
Table 1. Hydrolysis of nitrile 17.
entry conditions
result
1
2
3
10% aq. KOH/THF (5:1), 70 °C, 3 h
no conversion
19 (32%), 20 (17%)
10% aq. KOH/MeOH (5:1), 70 °C, 3 h
10% aq. KOH/EtOH (5:1), 70 °C, 3 h
19 (51%), 20 (9%),
18 (33%)
4
5
6
10% aq. KOH/i-PrOH (5:1), 70 °C, 3 h
10% aq. KOH/t-BuOH (5:1), 70 °C, 6 h
19 (80%), 20 (4%)
19 (75%), 20 (4%)
20 (84%)
Ghaffar–Parkins catalyst[a]
,
EtOH/H2O
(4:1), 70 °C, 2 d
[a] Ghaffar–Parkins catalyst = [PtH(PMe2O)2H(PMe2OH)].
Replacement of methanol with ethanol improved the yield of 19 to
51% and reduced the amount of 20 to 9% (entry 3). The
transesterification product 18 (R = Et, 33%) was also isolated and
recycled. Switching the solvent to iso-propanol, the yield was
Scheme 3. n) 0.1 M aqueous HCl/THF 5:1, 23 °C, 90%; o) DDQ, CH2Cl2/H2O
10:1, 0 °C, 88%; p) DMP, CH2Cl2, 23 °C; q) HF⋅pyridine, 0 °C to 23 °C, 86%
over
two
steps.
DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone,
DMP = Dess–Martin periodinane, THF = tetrahydrofuran.
3
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In conclusion, we accomplished the first total synthesis of the
natural herbicide (+)-cornexistin 1. The robust route features a
Nozaki–Hiyama–Kishi reaction and an Evans auxiliary controlled
syn-aldol reaction to rapidly access multigram quantities of the
highly functionalized cyclization precursor 4. Formation of nine-
membered carbocycle was accomplished via a base-mediated
intramolecular alkylation reaction in good yield. The installation of
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(DDQ) and reductive ring-opening. See Supporting
Information for details.
Acknowledgements
This work was supported by Bayer AG. T.M. acknowledges the
support of the Center for Molecular Biosciences (CMBI). We thank
Mario Kendlbacher (University of Innsbruck) for experimental
assistance and MSc Franz-Lucas Haut (University of Innsbruck)
for helpful discussions.
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Keywords: total synthesis • nonadride • herbicidal natural
products • nine-membered carbocycles
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4
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5
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