Synthesis of acremines A, B and F and studies on the bisacremines

Article abstract of DOI:10.3762/bjoc.15.219

The acremines are a family of meroterpenoids isolated from fungi of the genus Acremonium. Here, we present the asymmetric total synthesis of acremine F which hinges on a modestly enantioselective dihydroxylation and a subsequent kinetic resolution via a h

Full text of DOI:10.3762/bjoc.15.219

Synthesis of acremines A, B and F and
studies on the bisacremines
Nils Winter1 and Dirk Trauner*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2271–2276.
1Department of Chemistry, University of Munich, Butenandtstraße
5–13, 81377 Munich, Germany and 2Department of Chemistry, New
York University, 100 Washington Square East, Room 712, New York,
NY 10003, USA
doi:10.3762/bjoc.15.219
Received: 05 March 2019
Accepted: 12 August 2019
Published: 23 September 2019
Email:
Dirk Trauner* - dirktrauner@nyu.edu
Associate Editor: B. Stoltz
* Corresponding author
© 2019 Winter and Trauner; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
meroterpenoid; natural product; selective oxidation; total synthesis
Abstract
The acremines are a family of meroterpenoids isolated from fungi of the genus Acremonium. Here, we present the asymmetric total
synthesis of acremine F which hinges on a modestly enantioselective dihydroxylation and a subsequent kinetic resolution via a
highly selective asymmetric reduction. Chemoselective oxidation of acremine F gave access to acremines A and B. The dimeriza-
tion of acremine F to bisacremine E was investigated but could not be achieved, shedding light on the formation of the acremine
dimers in nature.
Introduction
Endophytic fungi grow in a symbiotic relationship with their In 2015, Wei and co-workers discovered bisacremines E–G, the
plant hosts [1], which is mediated by secondary metabolites [2]. most complex members of the acremine family, from the soil-
In 2005, Torta and co-workers reported the isolation of six derived strain A. persicinum SC0105 [4]. These natural prod-
meroterpenoid natural products, acremines A–F from A20, a ucts are presumed to be derived from two acremine F (5) units
strain of Acreonium byssoides, isolated from grapevine leaves by a formal [4 + 2] cycloaddition followed by condensation and
that were artificially inoculated with Plasmopora viticola oxidation.
(Figure 1) [3]. This class of natural products is characterized by
a highly substituted cyclohexene core, featuring up to three Given the diversity and structural beauty of this class of
stereogenic carbons, which is linked to a prenyl unit. Nature natural products, it is not surprising that the acremine
achieves further diversification by several modes of oxidation family has attracted the attention of the synthetic community
and cyclization. While acremine F (5) exhibited no significant [6-8]. Nevertheless, to the best of our knowledge, no
bioactivity, acremines A–D showed inhibition of P. viticola asymmetric entry to this class of natural products has been de-
sporangia germination.
scribed.
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Beilstein J. Org. Chem. 2019, 15, 2271–2276.
Figure 1: Selected members of the acremine family [3-5].
Our retrosynthetic analysis of 5 is depicted in Scheme 1. The creased the optical purity of 17 to 95% ee. Deprotection of the
prenyl side chain would be introduced by transition metal- diol moiety followed by Stille cross coupling with vinyl stan-
catalyzed cross coupling of vinyl iodide 9. Compound 9 in nane 18 finally gave 5 in excellent yield (Scheme 2).
turn could be traced back to silyl enol ether 10. Ent-10
was first reported by Herzon and co-workers [9] and is derived Since acremine F (5) can be expected to be the biogenetic pre-
from phenol silyl ether 11 via Birch reduction and dihydroxyl- cursor of acremines A (1) and B (2), we wanted to access these
ation.
antifungal derivatives through selective oxidations. Indeed,
treatment of 5 with IBX preferentially oxidized the C1-allylic
alcohol, giving 1 in respectable yield. Prolonged treatment (9 h)
Results and Discussion
Our synthesis started with meta-cresol (12) which was pro- of 5 with a large excess of IBX oxidized both secondary allylic
tected as a TIPS ether and then subjected to Birch reduction alcohols and afforded 2 in good overall yield (Scheme 3).
conditions to afford cyclohexa-1,4-diene 13 [9]. Enantioselec-
tive Sharpless dihydroxylation proceeded in good chemoselec- Bisacremine E (7) was proposed to be formed in nature via
tivity but with modest yield and optical purity (25% ee). Unfor- [4 + 2] cycloaddition involving two acremine F (5) units [4].
tunately, all attempts to improve the enantioselectivity of this Although dimerization of 5 through a Diels–Alder cycloaddi-
reaction failed. We discovered, however, that at a later stage the tion is not electronically favorable, we speculated that this reac-
optical purity could be improved (see below). Diol protection tion might proceed through ionic intermediates (Scheme 4).
gave dioxolane 14, which underwent Saegusa oxidation to
afford enone 15. Subsequent α-iodination gave access to To probe this hypothesis, we tried to generate allylic cation 19
α-iodoenone 16, which could be stereoselectively reduced under by treatment with different acids or under thermal conditions
Corey–Itsuno conditions to yield allylic alcohol 17. The use of a (Table 1). Unfortunately, all conditions led to either decomposi-
chiral oxazaborolidine catalyst led to kinetic resolution and in- tion of the starting material or elimination of the tertiary allylic
Scheme 1: Retrosynthetic analysis of acremine F (5).
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Beilstein J. Org. Chem. 2019, 15, 2271–2276.
Scheme 2: Total synthesis of acremine F (5).
Scheme 3: Synthesis of acremines A and B through selective oxidation of acremine F.
alcohol to the unstable triene 6. As we were able to observe entry 15). Notably, a photoredox catalyst with a lower oxida-
elimination as well as acetate incorporation into the molecule tion potential could not affect any reaction. Next, we tried to en-
the desired cation was clearly formed under a variety of condi- hance the possibility for productive reactivity by tethering two
tions. Nevertheless, none of these could affect the desired cycli- units of 5 and therefore executed the reaction in an intramolecu-
zation. Attempts to enhance the stability of the molecule, and lar way (Scheme 5). Unfortunately, treatment of 23 with various
therefore prevent decomposition, by protection of the non- redox catalysts led either to decomposition or recovery of the
participating alcohols and attempts to generate the allylic cation starting material.
from a cyclic ketal [10-12], aiming for a Gassman-type reac-
tion mechanism, were also unfruitful.
Next, we tried to trigger the cyclization through a [2 + 2] cyclo-
addition followed by vinyl cyclobutane rearrangement [19,20].
While radical cations are known to undergo Diels–Alder reac- We reasoned that the initially formed divinyl cyclobutane [21]
tions with electron-rich dienophiles [13-17], treatment of 5 with should undergo an allylic rearrangement to furnish the decalin
Fukuzumi’s catalyst [18] under illumination with blue light system [22,23]. Condensation should then close the tetrahydro-
only led to decomposition of the starting material (Table 1, furan ring of the natural product. Upon irradiation of 5 using a
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Beilstein J. Org. Chem. 2019, 15, 2271–2276.
Scheme 4: Proposed biomimetic dimerization of 5.
Table 1: Representative screening conditions for the biomimetic cascade.
entry
solvent
additive
temperature
observation
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H2O
H2O
PhMe
oDCB
Et2O
none
none
none
85 °C
100 °C
150 °C
160 °C
rt
45 °C
110 °C
rt
6
decomposition
6
none
decomposition
4 M LiClO4
none
none
12 kbar
AcOH, 12 kbar
CSA
6
6
neat
neat
decomposition
starting material
decomposition
6
decomposition
6 + acetate trapping
6
decomposition
decomposition
starting material
22
MeCN
MeCN
MeCN
neat
MeCN
MeCN
H2O
60 °C
−40 °C to rt
rt
CSA
AcOH
85 °C
90 °C
85 °C
rt
80 °C
rt
HCOOH
H2SO4
Mes-Acr-Ph, lighta
Ni(cod)2, PPh3
DCB, lightb
lightb
DMF
PhMe
MeCN
acetone
rt
22
aBlue LED, bmedium pressure Hg lamp.
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Beilstein J. Org. Chem. 2019, 15, 2271–2276.
Scheme 5: Attempted intramolecular cyclization of 23.
Hg lamp, however, the only productive pathway which could be bisacremine E. Since these extensive studies were unsuccessful
observed was isomerization of the disubstituted double bond and no dimers could be observed under a variety of biomimetic
(Table 1, entries 17 and 18). Again, we attempted to promote conditions, it appears that this transformation requires enzy-
the reaction by tethering two acremine units through a dioxysi- matic catalysis in nature.
lane (Scheme 6) [24-26]. Unfortunately, irradiation of 25 with
and without the presence of different photosensitizers only led
to decomposition.
Supporting Information
Experimental procedures, spectroscopic data and copies of
NMR spectra (PDF) as well as crystallographic data of
compounds 16 and 17. CIF files for 16 (CCDC 1854563)
Conclusion
In conclusion, we report the first asymmetric synthesis of
acremine F (5) relying on the combination of a modestly enan-
tioselective oxidation and a highly enantioselective reduction
with kinetic resolution to access the acremine framework. The
route proved to be scalable and delivered 300 mg of the natural
product. Acremine F could further be converted into acremines
A (1) and B (2) by a selective oxidation providing a versatile
entry into this class of natural products. Furthermore, we inves-
tigated the proposed biomimetic dimerization of 5 to
and 17 (CCDC 1854564) are available free from charge on
https://www.ccdc.cam.ac.uk/structures/).
Supporting Information File 1
Experimental part.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-219-S1.pdf]
Scheme 6: Attempted photochemical cyclization of 25.
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Beilstein J. Org. Chem. 2019, 15, 2271–2276.
24.Fleming, S. A.; Parent, A. A.; Parent, E. E.; Pincock, J. A.; Renault, L.
J. Org. Chem. 2007, 72, 9464–9470. doi:10.1021/jo7014664
25.Ward, S. C.; Fleming, S. A. J. Org. Chem. 1994, 59, 6476–6479.
doi:10.1021/jo00100a063
26.Fleming, S. A.; Ward, S. C. Tetrahedron Lett. 1992, 33, 1013–1016.
doi:10.1016/s0040-4039(00)91847-1
Acknowledgements
The authors thank Dr. Peter Mayer for X-ray structure analysis.
Additionally, we acknowledge the Deutsche Forschungs-
gemeinschaft (SFB 749 and CIPSM) for generous funding. Dr.
Julius R. Reyes is acknowledged for excellent support with the
preparation of this article.
ORCID® iDs
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