Total Synthesis of Pericoannosin A

Article abstract of DOI:10.1021/acs.orglett.8b01768

The first total synthesis of pericoannosin A (1) containing 15 steps in the longest linear sequence with an overall yield of 5.5% is reported. The hybrid peptide-polyketide was isolated from the endophytic fungus Periconia sp. F-31 and bears a unique tric

Full text of DOI:10.1021/acs.orglett.8b01768

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Pericoannosin A
Daniel Lu
̈
cke,*,† Yannick Linne,† Katharina Hempel,† and Markus Kalesse*,†,‡
†
̈
Institute for Organic Chemistry and Centre of Biomolecular Drug Research (BMWZ), Leibniz Universitat Hannover,
Schneiderberg 1B, D-30167 Hannover, Germany
‡Helmholtz Centre for Infection Research (HZI), Inhoffenstrasse 7, D-38124 Braunschweig, Germany
S
* Supporting Information
ABSTRACT: The first total synthesis of pericoannosin A (1)
containing 15 steps in the longest linear sequence with an overall
yield of 5.5% is reported. The hybrid peptide−polyketide was
isolated from the endophytic fungus Periconia sp. F-31 and bears a
unique tricyclic core structure. The key steps are a glycolate aldol
reaction and a Diels−Alder reaction utilizing an Evans auxiliary for
controlling the stereochemistry. Furthermore, a late-stage equili-
bration was employed.
uring the last ten years, the endophytic fungus Periconia
sp. F-31, isolated from the medicinal plant Annona
Scheme 1. Retrosynthetic Analysis
D
muricata, turned out to be a rich source of natural products
showing a variety of structural motives as well as different
biological properties, such as anticancer and anti-inflammatory
activities.1 In 2015 and 2016, Dai and co-workers reported the
isolation of two diastereomeric natural products named
pericoannosin A (1)2 and pericoannosin B (2)3 (Figure 1),
Figure 1. Structures of pericoannosin A (1) and B (2).
exhibiting a hexahydro-1H-isochromen-5-isobutylpyrrolidin-2-
one skeleton that has not been found in any other natural
product so far. In addition to its interesting structural motif,
pericoannosin A (1) shows a moderate anti-HIV activity (IC50
= 69.9 μM)2 and is being screened for its applications in
pharmaceutical research.4
In light of our ongoing work with hybrid peptide−polyketide
natural products,5 we focused our efforts on the total synthesis
of pericoannosin A (1) aiming for the first synthetic approach
toward its unique tricyclic core structure. In our retrosynthetic
analysis (Scheme 1), we envisioned lactol formation via
nucleophilic attack of an alcohol to a ketone as one of the last
steps of our synthesis. Based on the assumption of the natural
product as the thermodynamically most stable diastereomer,
we expected the stereogenic centers at C2 and C3 to either
adopt the desired configuration during cyclization or be easily
equilibrated afterward. The required precursor, β-keto amide 3,
should be obtained from an aldol reaction of aldehyde 4 and
Teoc-lactam 5. While the lactam can be derived from Boc-L-
Received: June 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01768
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
leucine (6),6 a sequence composed of a Diels−Alder reaction7
and subsequent homologation starting from dienophile 7 was
planned for the synthesis of aldehyde 4. Dienophile 7 itself can
be traced back to commercially available tiglic aldehyde (8)
with an olefination and a glycolate aldol reaction8 in mind as
the key transformations.
Scheme 3. Synthesis of Teoc Lactam 5
The first step of our synthesis was a glycolate aldol reaction
of tiglic aldehyde (8) and PMB-oxazolidinone 9.9 Subse-
quently, a three-step sequence consisting of TBS protection,
PMB deprotection, and reductive removal of the Evans
auxiliary led to diol 11, which was cleaved using silica gel-
supported sodium periodate.10 The obtained aldehyde was
submitted to a Horner−Wadsworth−Emmons (HWE) olefi-
nation with phosphonate 1211 utilizing Masamune−Roush
conditions12 yielding dienophile 7 in a good overall yield of
84%. The following Diels−Alder reaction of dienophile 7 and
isoprene (13) gave the desired product 14 in the expected dia-
and regioselectivity.7 To our regret, Diels−Alder product 14
was obtained in an inseparable mixture with the 1,4-adduct 15
arising from the addition of an ethyl moiety.7b Fortunately, this
impurity could be removed over the course of the following
four-step homologation process consisting of reductive
removal of the Evans auxiliary, an Appel reaction,13 SN2
displacement with potassium cyanide, and DIBAL reduction to
give aldehyde 4 in a good overall yield of 60% (Scheme 2).
Our initial plan was to use Boc-lactam 166 for the ensuing aldol
reaction, but we experienced the acid-mediated elimination of
the C11 TBS-ether. Thus, a protecting group switch to the 2-
(trimethylsilyl)ethyl (Teoc) carbamate 5 was performed
(Scheme 3).
Obtained Teoc-lactam 5 and aldehyde 4 were subjected to
an aldol reaction leading to the desired aldol product 17 in a
mixture of four diastereomers. With the entire carbon skeleton
in place, the last transformation before removal of the
protecting groups was oxidation of the newly formed alcohol
at C3. Though no full conversion could be achieved, 2-
iodoxybenzoic acid (IBX) gave the best results in comparison
to other screened conditions (Dess−Martin, Ley−Griffith,
Swern). Nevertheless, most of the starting material could be
recovered. With β-keto amide 3 in hand, global deprotection
inducing the cyclization remained as the last challenge. During
our attempts to address this problem, it turned out that the
TBS ether could only be cleaved by using hydrogen fluoride,
whereas Teoc deprotection worked only using TBAF.
Therefore, we had to perform a stepwise deprotection
approach starting with removal of the TBS group. The use
of triethylamine trihydrofluoride cleaved the TBS ether and
induced the cyclization yielding lactol 18 in a 2:1 mixture of
two diastereomers. This mixture was treated with an excess of
TBAF cleaving the Teoc carbamate and equilibrating both
diastereomers to a single compound, pericoannosin A (1,
Scheme 4).
Scheme 2. Synthesis of Aldehyde 4
In summary, we accomplished the first total synthesis of
pericoannosin A (1) in the longest linear sequence of 15 steps
with an overall yield of 5.5% starting from commercially
Scheme 4. Endgame of the Synthesis
B
DOI: 10.1021/acs.orglett.8b01768
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(7) (a) Evans, D. A.; Chapman, K. T.; Hung, D. T.; Kawaguchi, A.
T. Angew. Chem., Int. Ed. Engl. 1987, 26, 1184−1185. (b) Evans, D.
A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238−
1256.
(8) (a) Evans, D. A.; Bender, S. L. Tetrahedron Lett. 1986, 27, 799−
802. (b) Jones, T. K.; Mills, S. G.; Reamer, R. A.; Askin, D.; Desmond,
R.; Volante, R. P.; Shinkai, I. J. Am. Chem. Soc. 1989, 111, 1157−
1159.
available tiglic aldehyde (8). The key steps of our synthesis
were a stereoselective glycolate aldol reaction and a stereo-
selective Diels−Alder reaction. Furthermore, it is worth noting
that our expectation of the natural product as the
thermodynamically most stable compound could be proven
by late-stage equilibration.
ASSOCIATED CONTENT
* Supporting Information
(9) Sokolsky, A.; Wang, X.; Smith, A. B., III Tetrahedron Lett. 2015,
■
S
56, 3160−3164.
(10) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622−
2624.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01768.
(11) Aldrich, L. N.; Berry, C. B.; Bates, B. S.; Konkol, L. C.; So, M.;
Lindsley, C. W. Eur. J. Org. Chem. 2013, 2013, 4215−4218.
(12) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183−2186.
Experimental procedures and spectral data for the
compounds described herein (PDF)
(13) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801−811.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: markus.kalesse@oci.uni-hannover.de.
*E-mail: daniel.luecke@oci.uni-hannover.de.
ORCID
Markus Kalesse: 0000-0003-4858-3957
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge the analytical department of the Institute for
Organic Chemistry for their support.
■
DEDICATION
■
This paper is dedicated to Dr. Dieter Schinzer (Otto-von-
Guericke-Universitat Magdeburg) on the occasion of his 65th
birthday.
̈
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DOI: 10.1021/acs.orglett.8b01768
Org. Lett. XXXX, XXX, XXX−XXX