Total synthesis of (-)-penicimutanin a and related congeners

Article abstract of DOI:10.1039/c9sc05252f

The first total synthesis of penicimutanin A (1) was achieved within 10 steps (LLS). Key innovations in this synthesis consist of (1) a highly efficient electro-oxidative dearomatization; (2) an unprecedented bisoxirane-directed intermolecular aldol reaction from the sterically hindered face of the ketone and (3) the diastereoselective one-step Meerwein-Eschenmoser-Claisen rearrangement enabling the construction of vicinal quaternary stereocenters. Related family members e.g. penicimutanolone (3) and penicimutatin (5) have also been synthesized alongside, elucidating their absolute configurations, hence the absolute configuration of 1.

Full text of DOI:10.1039/c9sc05252f

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Total synthesis of (ꢀ)-penicimutanin a and related
congeners†‡
Cite this: DOI: 10.1039/c9sc05252f
ab
Haiyong Yu,§a Yan Zong§a and Tao Xu
*
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
The first total synthesis of penicimutanin A (1) was achieved within 10 steps (LLS). Key innovations in this
synthesis consist of (1) a highly efficient electro-oxidative dearomatization; (2) an unprecedented
bisoxirane-directed intermolecular aldol reaction from the sterically hindered face of the ketone and (3)
the diastereoselective one-step Meerwein–Eschenmoser–Claisen rearrangement enabling the
construction of vicinal quaternary stereocenters. Related family members e.g. penicimutanolone (3) and
penicimutatin (5) have also been synthesized alongside, elucidating their absolute configurations, hence
the absolute configuration of 1.
Received 17th October 2019
Accepted 13th November 2019
DOI: 10.1039/c9sc05252f
rsc.li/chemical-science
of biological activities from anti-fungal as a histidine kinase
inhibitor to anti-inammatory as well as anti-tumor effects.3–5
Introduction
However, the scarcity of these compounds from natural sources
greatly hampered their further biological proling. What's
more, the absolute conguration of penicimutanin A (1) and
penicimutanolone (3) remained undetermined.
It is clear that to address the aforementioned structural
uncertainty issues, practical and reliable chemical synthesis of
these natural products would be necessary. However, to the best
of our knowledge, total synthesis of penicimutanin A and its
congeners (e.g. 2, 3 and 5) has not been reported.
Fungi have been exploited as rich sources to generate struc-
turally appealing molecules featuring synthetically challenging
motifs and consecutive stereocenters, which oen display
promising bioactivities towards life-threatening diseases.1 In
particular, for deep sea-derived fungal strains, chemical muta-
genesis is commonly used to activate “muted genes” for the
discovery of new natural products.2 Penicimutanin A (1) and B
(2) are two representative secondary metabolites reported by Cui
and coworkers in 2014 (Fig. 1), isolated from a marine-derived
fungal strain identied as Penicillium purpurogenum G59
through chemical mutagenesis.3 An interesting observation is
that, in addition to 1, penicimutanolone (3) and penicimutatin
(5) together with vicinal quaternary center-bearing pyrro-
loindoline-containing4c–g fructigenine A (4)4a,b were also isolated
alongside, indicating their biosynthetic interrelationship. More
importantly, it implied that chemical mutagenesis may have
activated a “linchpin gene” of the marine-derived fungus which
endogenously joined penicimutanolone (3) and fructigenine A
(4) together, in contrast to the terrestrial-derived fungal strain
where only analogues of 3 were isolated.5,6 These secondary
metabolites and their congeners were found to possess a range
The challenge for their synthesis could be three-fold. First,
these natural products are characterized by a fully oxygenated
cyclohexane ring which contains an acid/base-sensitive cis-
aKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and
Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
E-mail: xutao@ouc.edu.cn
bLaboratory for Marine Drugs and Bioproducts, Open Studio for Druggability Research
of Marine Natural Products, Pilot National Laboratory for Marine Science and
Technology, 1 Wenhai Road, Qingdao 266237, China
† This article is dedicated to Professor Zhen Yang on the occasion of his 60th
birthday.
‡ Electronic supplementary information (ESI) available. CCDC 1843076 and
1950968. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c9sc05252f
§ Haiyong and Yan contributed equally to this work.
Fig. 1 Penicimutanin A and the related congeners.
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bisoxirane moiety, and is part of a spirocyclic ring skeleton
Our synthesis of deacetyl fructigenine A (40) started with
(Fig. 1). Second, the trans relationship between the C8 hydroxyl selective prenylation of commercially available tryptophan ester 6
group and the bisoxirane represents a unique feature which in 86% yield with isoprenyl bromide 9. The desired prenylation
indicated a non-directed expodiation. Third, controlling the product 10 was condensed with Fmoc-L-tyrosine aer Boc
stereochemistry for forming the labile C2 hemi-aminal ether is removal, affording compound 11 in 76% overall yield. Upon Fmoc
not trivial. On the other hand, the south fragment 40 contains deprotection under standard conditions, the diketopiperazine-
a diketopiperazine fused hexapyrroloindoline, which possessed containing penicimutatin 5 was achieved with 65% yield
a C3 1,1-dimethylpropenyl (reverse prenyl) group generating (Scheme 2A). The intended biomimetic aza-Claisen was proved
a
vicinal all-carbon quaternary stereocenter.7 The highly unviable aer extensive condition screening (see the ESI,‡ for
oxidized hydrophilic core skeletons, together with the lipophilic details). Our rationale is that the intrinsic sp2 hybridized nitrogen
aliphatic side chain of penicimutanin, were postulated to atom of the indole framework inhibited the formation of the chair
account for their observed biological activities.3
transition state TS-5, in which the N-atom was twisted into
In this article, we describe our detailed development of an a transient sp3 hybridized form (TS-5 in Scheme 2A).
efficient and scalable approach for the asymmetric total Given the above results, one-pot diastereoselective
synthesis of penicimutanin A (1), penicimutanolone (3) and Meerwein–Eschenmoser–Claisen (MEC) rearrangement8 was
a
penicimutatin (5).
developed to construct C3 reverse prenylated9 oxindoles from
non-protected C3-ester indole and isoprenyl alcohol through
an AlCl3 catalytic protocol. The L-tryptophan derivative 13 was
subjected to our AlCl3-mediated conditions. To our delight,
the oxindole 16 was achieved in a satisfactory 54% yield with
Results and discussion
Biosynthetically, it was hypothesized that penicimutanin A (1)
could be disconnected into deAc-fructigenine A (40) and pen-
icimutanolone (3) through the hemi-aminal ether formation
(“linchpin” step). The south fragment 40 could be accessed
through a biomimetic aza-Claisen rearrangement followed by
indoline formation from the natural congener 5, which itself
was an N-prenylated diketopiperazine compound and could be
reached from commercially available (S)-tryptophan ester 6. On
the other hand, the northern fragment 3 could be easily
accessed through a side chain attaching aer a diaster-
eoselective aldol reaction from bisoxirane 7, which might be
obtained through an oxidative dearomatization from the
commercially available (S)-Cbz-tyrosine 8. This design features
a biomimetic, convergent strategy, in the hope of obtaining four
natural products from common starting materials (Scheme 1).
Scheme 1 Retro-synthesis.
Scheme 2 Synthesis of fructigenine A (4) and penicimutatin (5).
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Table 1 Selected electrooxidation optimizationa
yield. The known natural product fructigenine 4 (reported3a as
[a]2D0 ꢀ129.3ꢁ (c 0.30, MeOH)) was also successfully obtained
through acylation in 55% yield and spectroscopic data of 4
([a]2D0 ꢀ128.0ꢁ (c 0.35, MeOH)) were in good agreement with
those previously reported (see the ESI‡ for other spectroscopic
data).
Our synthesis of the penicimutanolone (3) started with
oxidative dearomatization of the commercially available (S)-
Cbz-tyrosine (8).10 The recent development and innate sustain-
ability of electrochemistry11 prompted us to develop the electro-
oxidative dearomatization of 8 (Table 1) in a synthetically useful
fashion. The idea is to use an in situ formed milder hypervalent
iodine oxidant ii from PhI (i) (Table 1).12 We rst tried the
electro-oxidation with 1 equivalent of LiClO4 at a constant
electrical current of 2.1 mA in TFE. Gratifyingly, the desired
spirocycle 19 was isolated in 38% yield. We further investigated
the electrical current (entries 2 and 3, Table 1), electrolyte
(entries 2–5) and loading of i (entry 2–5) and concluded that the
reaction can be optimized to 65% isolated yield when using
optimal amounts of the aforementioned factors. Serendipi-
tously, an electrical power cut happened during another trial,
which le the reaction standing still overnight aer only several
hours of electrical oxidation. However the reaction yield was
improved to 82% (entry 6, Table 1). A careful adjustment of
other co-factors and stirring time enabled us to obtain the
oxidative dearomatization reaction in a satisfactory 85% iso-
lated yield.
Entrya Conditions
Time
Yieldb (%)
1
2
3
4
LiClO4 (1 eq.), I ¼ 2.1 mA, PhI (1 eq.)
LiClO4 (10 eq.), I ¼ 6.1 mA, PhI (4 eq.)
LiClO4 (10 eq.), I ¼ 6.1 mA, PhI (4 eq.)
LiClO4 (13 eq.), I ¼ 10 mA, PhI (5 eq.)
8 h
4 h
6 h
6 h
38
64
65
65
65
5
LiClO4 (15.6 eq.), I ¼ 10 mA, PhI (6 eq.) 3 h
6c
7d
LiClO4 (13 eq.), I ¼ 10 mA, PhI (5 eq.)
4 + 6 h 82
LiClO4 (15.6 eq.), I ¼ 10 mA, PhI (6 eq.) 5 + 5 h 85
a
All reactions were run with LiClO4 as the electrolyte, PhI as the additive
and a C(+)/Pt(ꢀ) anode in an undivided cell on a 0.31 mmol scale using
2,2,2-triuoromethylethanol (TFE) as the solvent at a concentration of
0.04 M at ambient temperature for indicated hours with a constant
b
c
electrical current unless otherwise noted. Isolated yields. The
electrical current was stopped aer 4 h but stirring was continued for
d
6 h. The electrical current was stopped aer 5 h but stirring was
continued for 5 h.
synthetically acceptable stereocontrol (d.r.
¼
2.5 : 1).
Compound 16 possessed the key reversely prenylated vicinal
quaternary oxindole motif, which was cyclized through
reductive amination conditions aer Bn-deprotection (66%
yield) and Boc protection (69% yield) to achieve hexahy-
dropyrroloindoline 18 in 46% yield. Compound 18 was
coupled with L-Fmoc-phenylalanine and cyclized upon Fmoc
removal, achieving the deAc-fructigenine 40 in 72% overall
With enough amounts of 19 in hand, we set off to install
the key bisoxirane moiety (Scheme 3). Due to 19's instability,
a selective NaBH4 reduction followed by TES protection were
carried out to release the strain of spirocyclic lactone,
yielding dienone 20 in 45% yield over two steps. A diaster-
eoselective Luche-reduction was performed, providing b-OH
alcohol (d.r. ¼ 3 : 1), which allowed the mCPBA mediated
Scheme 3 Synthesis of penicimutanolone 3.
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Table 2 Selected electrooxidation optimizationa
2). A Lewis acid promoted in situ formation of an electrophilic
oxonium intermediate didn't yield any product either, while
slight decomposition of 26 was observed (entries 2 and 3). It
was hypothesized that the benzyl group of Cbz might block
one side of the oxonium thus inhibiting its reactivity.
Different substrates 27 and 28 were prepared and tested, but
no fruitful results were obtained (entries 3 and 4). To our
delight, 8% of desired 29 could be isolated when TMSCl and
DMAP were used and the efficiency was further improved to
35% (55% brsm) yield when, unexpectedly, acidic conditions
were employed (entry 6). In addition, an X-ray crystallographic
analysis of 28 undisputedly veried all the stereochemistry as
well as absolute congurations corresponding to natural
product 1 (Table 2).
Entrya Substrate Conditions
Yieldb (%)
Although the coupling efficiency is still low, we nevertheless
tried it on the real substrates of penicimutanolone 3 and deAc-
fructigenine 40. As shown in eqn (1), natural product pen-
icimutanin A (1) was successfully achieved under modied
conditions in 26% (77% brsm) yield demonstrating our
biomimetic hypothesis. The spectroscopic data of synthetic
C40,C60-(R,R)-penicimutanin A ([a]2D5 ꢀ91.1ꢁ (c 0.25, MeOH))
1
2
3
4
5
6
7c
26
26
26
27
28
26
26
THF, rt, 4 h
0
0
0
0
0
8
TMSI, 0 ꢁC, TEA, 40 DCM
TMSCl, KBr, 0 ꢁC, TEA, 40 DCM
TMSBr, 0 ꢁC, TEA, 40 DCM
TMSBr, 0 ꢁC, TEA, 40 DCM
TMSCl, NaI, ꢀ20 ꢁC, DMAP, 40 DCM
PTSA, MS, 40 MeCN/AcOH ¼ 10/1
35 (55)
a
All reactions were run with 1 equivalent of a Lewis acid and 2
correspond to the natural sample of penicimutanin
A
equivalents of a base on a 0.1 mmol scale with DCM (1 mL) at 0 ꢁC
and stirring overnight unless otherwise noted. Isolated yields. ([a]2D5 ꢀ99.7ꢁ (c 0.5, MeOH)) very well thus conrming its
b
c
˚
PTSA was used in 1 equivalent and 4 A MS was added, MeCN/AcOH
absolute conguration (see Table S1 in the ESI‡ for a full
¼ 10/1 mixture (1 mL) was used instead of DCM, and the reaction was
comparison of NMR data).
stirred at 60 ꢁC for 72 hours.
epoxidation to proceed smoothly affording 22 as a single
diastereoisomer in 51% overall yield. The key reaction
precursor 23 was obtained in 80% yield upon DMP oxidation.
Crystallographic analysis showed unambiguous structural
evidence of compound 23.13
(1)
It was hypothesized that introduction of an acetonyl group at
the C8 position could be delivered from the more sterically
hindered b-face of 23, thus affording the desired stereoisomer
by utilizing the bisoxirane moiety as a directing group (Scheme
3). With this assumption, the proposed bisoxirane-directed 1,2-
Conclusion
addition was attempted by in situ generation of the oxophilic
cerium-enolate instead of its traditional lithium counterpart.
Gratifyingly, the transformation was realized in a 72% yield,
In summary, we have completed the rst total synthesis and
determined the absolute congurations of penicimutanin A (1)
and its related congeners penicimutanolone (3), fructigenine A (4)
with a resultant diastereoselective (d.r. ¼ 10 : 1) formation of
the desired a-OH isomer 24. The efficacy of this challenging
and penicimutatin (5) in a highly convergent and biomimetic
diastereoselective 1,2-addition step was attributed to a better
fashion from the commercially available (S)-tryptophan and (S)-
chelation effect of the cerium-enolate as well as its reduced
tyrosine derivatives for the rst time. The highly concise total
basicity. With the core skeleton in hand, side chain 25 (see the
synthesis of 3 (10 step LLS) was enabled by an improved and
ESI‡ for preparation and characterization of 25) was coupled
highly efficient electro-oxidative dearomatization as well as an
with compound 24 over a three-step sequence, affording pen-
unprecedented diastereoselective 1,2-addition directed by the
bioxirane moiety. A modied one-pot diastereoselective MEC
rearrangement was developed to reach fructigenine A (4) in only 6
steps. Further investigation of this methodology in natural
icimutanolone 3 in an overall 47% yield. The spectroscopic data
of synthetic C40,C60-(R,R)-penicimutanolone ([a]2D5 ꢀ1.0ꢁ (c 0.88,
MeOH)) correspond to penicimutanolone (3) ([a]2D5 ꢀ3.5ꢁ (c 1.0,
MeOH)) very well thus conrming the absolute conguration of
product synthesis and biological proling of penicimutans is
C40 and C60 of the natural product.
currently on-going in our group.
At this point, the linchpin14 step conditions were investi-
gated. Different substrates and conditions were screened
Conflicts of interest
(Table 2). Simply mixing the desilylation fragment 26 and
south fragment 40 didn't provide the product 29 (entry 1, Table
There are no conicts to declare.
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Acknowledgements
We thank “1000 Talents Plan for Young Professionals” and OUC
for a start-up fund. The project was partially funded by the NSFC
(No. U1706213, U1606403 and 81973232, 81991522), National
Science and Technology Major Project of China (No.
2018ZX09735-004) and SOA (MBRCU201802). T. X. is a Taishan
Youth Scholar (tsqn20161012). Qingdao government is
acknowledged for a grant of “Leading Innovative Scholars”
Program. We thank professor Guangbin Dong of UChicago for
helpful discussion and proofreading the manuscript. We thank
Mr Jian-Yu Zhang of OUC for help with X-ray crystallography.
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13 CCDC 1843076 (23) and 1950968 (29) contain the ESI‡
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