Biomimetic Synthesis of (+)-Aspergillin PZ

Article abstract of DOI:10.1002/anie.201809703

The cytochalasans are a large family of polyketide natural products with potent bioactivities. Amongst them, the aspochalasins show particularly intricate and fascinating structures. To gain insight into their structural diversity and innate reactivity, we have developed a rapid synthesis of aspochalasin D, the central member of the family. It proceeded in 13 steps starting from divinyl carbinol and utilized a high pressure Diels–Alder reaction that features high regio- and stereoselectivity. So far, our work has culminated in a biomimetic synthesis of aspergillin PZ, an intricate pentacyclic aspochalasan.

Full text of DOI:10.1002/anie.201809703

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Accepted Article
Title: Biomimetic Synthesis of (+)-Aspergillin PZ
Authors: Julius Reyes, Nils Winter, Lukas Spessert, and Dirk Trauner
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809703
Angew. Chem. 10.1002/ange.201809703
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http://dx.doi.org/10.1002/ange.201809703

10.1002/anie.201809703
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COMMUNICATION
Biomimetic Synthesis of (+)-Aspergillin PZ
Julius R. Reyes,[a,b] Nils Winter,[a] Lukas Spessert,[a] and Dirk Trauner*[a,b]
Dedicated to E.J. Corey on the occasion of his 90th birthday
Abstract: The cytochalasans are a large family of polyketide natural
products with potent bioactivities. Amongst them, the aspochalasins
show particularly intricate and fascinating structures. To gain insight
into their structural diversity and innate reactivity, we have
developed a rapid synthesis of aspochalasin D, the central member
of the family. It proceeded in 13 steps starting from divinyl carbinol
and utilized a high pressure Diels-Alder reaction that features high
regio- and stereoselectivity. So far, our work has culminated in a
biomimetic synthesis of aspergillin PZ, an intricate pentacyclic
aspochalasan.
intricate structures from 10 and 1 or 2 through an oxidative
cascade prompted us to develop a robust, scalable synthesis of
the aspochalasans. This program would also give us an
opportunity to explore the interconnections of the tricyclic
aspochalasins with the pentacyclic ones, in particular with
aspergillin PZ (5).
The cytochalasans comprise an important and ever growing
chapter of natural product chemistry.[1] Since the discovery of
cytochalasins A and B in the 1960s with their eponymous
function (cytos = cell and chalasis = relaxation) targeting the
actin cytoskeleton,[2] the structural diversity of this family has
grown to include members that incorporate a variety of amino
acids, macrocycle sizes and types, and various substitution and
oxygenation patterns. Many members offer an array of
bioactivities that sustain their relevance to both chemists as
synthetic targets and biologists as valuable tools.[3]
Derived from leucine, the antibiotic aspochalasin B (1) and
its co-isolates aspochalasins A, C, and D (2) were elucidated by
Keller-Schierlein and Kupfer in 1979.[4a-b] Notably, they differ
from other members of the cytochalasans by the incorporation of
an extra methyl substituent at C14, resulting in a trisubstituted
(E)-configured double bond (Scheme 1a). Together with the
conformational restriction enforced by the 11-membered ring,
this methyl substitution plays an important role in broadening the
skeletal diversity available to this cytochalasan subclass. For
example, the polycyclic structures of spicochalasin A (4),[4c]
aspergillin PZ (5),[4d] and flavichalasine C (6)[4e] suggest their
origin from 1, 2, and 3, respectively, via the intermediacy of a
carbonium ion at C14. This complexity has recently been further
heightened by the discovery of the heterodimeric, trimeric, and
tetrameric structures of the merocytochalasans (e.g., 7−9).[4f−k]
These compounds were suggested to arise from a combination
of aspochalasin B (1) or D (2) with the pyrogallol epicoccine (10).
Given our longstanding interest in the chemistry of
pyrogallols and our recent synthesis of epicoccine (10) and its
complex derivatives,[5] the tantalizing prospect of obtaining such
[a]
[b]
Dr. J. R. Reyes, Dr. N. Winter, L. Spessert, Prof. Dr. D. Trauner
Department of Chemistry
Ludwig-Maximilians-Universität München
Butenandtstrasse 5-13, 81377 München (Germany)
Prof. Dr. D. Trauner
Department of Chemistry
New York University
100 Washington Square East, New York, NY 10003 (USA)
E-mail: dirktrauner@nyu.edu
Scheme 1. Selected Aspochalasans and Biosynthetic Relationships.
Supporting information for this article is given via a link at the end of
the document.
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Aspergillin PZ (5) was first isolated in 2002 from
Aspergillus awamori following a screen for antitumor and
antifungal leads, and has since been re-isolated from several
species of Aspergillus as well as from Trichoderma gamsii.[4d-e,6]
Its intricate pentacyclic skeleton features one quaternary carbon
and ten contiguous stereocenters, five of which reside on an
oxabicyclo[3.2.1]octane subunit. To date, the synthetic challenge
posed by this molecule has been answered only once. In
Overman’s landmark synthesis, 5 was obtained in 28 steps from
methyl pyruvate. The evaluation of the synthetic material called
into question the bioactivity of the natural product with respect to
tumor cells.[7] We hypothesized that aspochalasin D (2) is the
likely biogenetic precursor to aspergillin PZ (5) via a “vinylogous
Prins reaction” (Scheme 1b).[8] We reasoned that 5 is formed
from 2 via transannular attack of the nucleophilic trisubstituted
alkene[9] onto an activated enone, followed by interception of the
resultant tertiary carbocation by one of the hydroxy groups.
Herein, we describe a 13-step synthesis of aspergillin PZ
utilizing such a strategy.
was found to work solely on free diol 23 and only in moderate
yields (< 60%).[18,19]
In preparation for the Suzuki-Miyaura cross-coupling to
triene 15, tiglic aldehyde was elaborated to 1,3-dienylboronate
17 as shown in Scheme 2b. Due to volatility and storage
considerations, the lithium acetylide derived from Corey-Fuchs
alkynylation was trapped with TMSCl to provide enyne 16 in
good yield over 2 steps.[20] Following TMS-deprotection, the
crude solution of free enyne was subjected to Cy2BH-
accelerated hydroboration using catecholborane to furnish
catechol ester 17, which was additionally used without
purification.[21] Dienophile precursor 19 was readily prepared
from lactam 18 by C-carbomethoxylation and selenation in
excellent yield.[22] Treatment of selenide 19 with H2O2 then
provided 14, which was used immediately in Diels-Alder studies.
In considering such a solution to the aspochalasans, we
were attracted to the use of 1,3,5-trienes as 4π-components in a
Diels-Alder construction of the isoindolone core, as pioneered by
Stork and used to great effect by Vedejs.[10,11] Following
numerous efforts on a variety of substrates to forge the 11-
membered ring by a ring-closing metathesis at Δ19,20 [12]
we
,
arrived at the strategy shown in Scheme 2a utilizing a Horner-
Wadsworth-Emmons (HWE) macrocyclization (i.e., 13). The
HWE reaction was first explored in cytochalasan synthesis by
Tamm[13] and notably applied in a difficult intramolecular setting
by Myers,[14] albeit with appreciable epimerization of the
stereocenter adjacent to the aldehyde. Oxygenated polyolefin
15 was envisioned to be prepared in a convergent manner by a
Pd-catalyzed cross-coupling of a 1,3-dienylboronate derived
from tiglic aldehyde and a vinyl iodide derived from divinyl
carbinol via Sharpless asymmetric epoxidation and subsequent
kinetic resolution.[15] A selective oxidation of the C18 hydroxyl of
aspochalasin D (2) would then allow access to aspochalasin B
(1) and its relatives.[16]
Our synthesis commenced with the ring-opening of
enantioenriched epoxy alcohol 22 with propargyl magnesium
bromide to provide diol 23 in excellent yield (Scheme 3). Among
the propargyl anions and derivatives of epoxide 22 explored to
establish the 1,2-anti diol of 2, organometallic addition by this
method onto this unprotected epoxy alcohol was the only
reproducible and scalable combination. Diol 23 was then
subjected to a one-pot ozonolysis-reduction sequence and
threefold TBS protection to provide alkyne 24 in excellent yield
over two steps. Formal addition of iodomethane across this
alkyne to yield vinyl iodide 25 was reliably achieved by a two-
step sequence involving silylcupration, alkylative quenching of
the in situ generated vinyl cuprate, and treatment of the resulting
vinyl silane with NIS.[17] Unfortunately, extensive efforts to
achieve this transformation by the method of Negishi
(ZrCp2Cl2/AlMe3) proved to be highly substrate dependent and
Scheme 2. (a) Fragment Assembly and (b) Model [4+2] Cycloaddition.
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Scheme 3. Total Synthesis of (−)-Aspochalasin D and (−)-Aspochalasin B.
Model studies of this [4+2] cycloaddition indicated that the
combination of an ester group at C9 of the dienophile and a
methyl group at C6 was deleterious (Scheme 2b). In stark
contrast to Vedejs’ studies which contain chloroacetyl and
(trimethylsilyl)methyl at these respective positions,[11b,23]
productive cycloaddition could only be achieved under high
pressure conditions.[24] Model triene 20 proved to be moderately
unstable to acid, and pressurizing a solution of 14 and 20 to 9
kbar over 2 hours provided cycloadduct 21 on gram-scale in
52% yield with an isomeric ratio of 6:1. With this result in hand,
we proceeded on toward the aspochalasans. Although the union
of iodide 25 with 17 indeed provided desired triene 15, this
polyene was found to be not only more acid-sensitive, but also
less reactive toward cycloaddition with 14. Simple filtration of the
Suzuki-Miyaura reaction mixture through a short plug of silica
gel, however, was found to suffice, and upon pressurization with
14 to 10 kbar over prolonged exposure (16.5 hours), desired
isoindolone 26 could be obtained in 41% yield with an isomeric
ratio of 13:1. NOESY analyses confirmed that these [4+2]
cycloadditions had indeed taken place with the correct
regioselectivity and in an endo manner with respect to the N-
benzoyl imide.
purification.[25] The structure of 28 was secured by single-crystal
X-ray analysis, showing that the C17 and C18 siloxy groups
adopt
pseudo-equatorial
and
pseudo-axial
positions,
respectively (see Scheme 4).[26]
Having forged the aspochalasan framework, double
desilylation of 28 with excess TBAF completed the total
synthesis of aspochalasin D (2), albeit in moderate yield.
Previously we had established that the bis-TES analog of 28
could be desilylated at 0 °C with near stoichiometric amounts of
TBAF within 10 minutes. In contrast, 28 could not be desilylated
at 0 °C and was slow to react at ambient temperature using a
large excess of TBAF. In congruence with Keller-Schierlein and
Kupfer’s structural studies, treatment of 2 with MnO2 did indeed
provide aspochalasin B, but with accompanying 1,2-diol
cleavage to the corresponding dialdehyde.[4a] We subsequently
discovered that the selective oxidation of the C18 hydroxyl could
be achieved without C-C bond cleavage using DDQ. The
spectral data of aspochalasin D (2) matched closely with that
obtained by Hayakawa,[4b] and the spectral data of aspochalasin
B (1) matched closely with the limited 1H data and incomplete list
of 13C resonances available for aspochalasin B (1) (see
Supporting Information).[4a]
Addition of lithio dimethyl methylphosphonate then effected
N-debenzoylation and concomitant β-keto phosphonate
formation to yield 27. Whereas the use of HF/MeCN effected
rapid threefold TBS deprotection, selective deprotection of the
primary TBS could be achieved using a large excess of
Et3N3HF. Dess-Martin oxidation then provided aldehyde 13
With aspochalasins B and D in hand, we set out to explore
the pentacyclic aspochalasans. Given the sensitivity of the
substrate, we assumed that access to 5 would require a careful
screen of a variety of Lewis acids and Brønsted acids. We
quickly found, however, that deprotection of TBS-silyl ether 28
using HF/MeCN rather than TBAF effected a clean and fast
conversion to aspergillin PZ (5), the spectral data of which were
in excellent agreement with that of natural 5 and Overman’s
synthetic material. This cascade proceeded not only with
exquisite stereoselectivity but also in excellent yield (Scheme 4).
which
was
immediately
used
without
purification.
Macrocyclization under Masamune-Roush conditions (LiCl, i-
Pr2NEt) then provided enone 28 with virtually no epimerization in
46% yield over 3 steps requiring a single chromatographic
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Upon closer consideration of the mechanism of this
transformation, we recognized that a direct vinylogous Prins-
type cyclization of 2 or 28 could not account for 5. Given the
lowest energy conformation of the 11-membered macrocycle,
which was elucidated by NOESY measurements and our X-ray
structure of 28 (Scheme 4, Supporting Information), cyclization
biological activities, in particular with respect to the actin
cytoskeleton.
Acknowledgements
would be expected to yield
a trans-fused tetracyclic or
We thank the Deutsche Forschungsgemeinschaft (SFB 749), the
Alexander von Humboldt Stiftung, and the National Institutes of
Health (1R01GM126228) for financial support of this work.
J.R.R. is grateful to the Alexander von Humboldt Stiftung and
the Carl Friedrich von Siemens Stiftung for a postdoctoral
fellowship. We thank Dr. Peter Mayer (LMU Munich) for X-ray
structure analysis and Martin Maier (NYU) and Dr. Giulio Volpin
(NYU) for computational analysis of aspergillin PZ. Furthermore,
Dr. Antonio Rizzo (Seoul National University), Dr. Felix
Hartrampf (Boston College) and Prof. Dr. Hong-Dong Hao
(Northwest A&F University) are warmly acknowledged for
insightful discussions.
pentacyclic aspochalasan similar to flavichalasine C (6). As such,
the selective formation of aspergillin PZ under acidic conditions
may reflect a Curtin-Hammett scenario. We propose that under
the influence of Brønsted acid an equilibrium is established
between conformers 29 and 30, obtained by bond rotation about
C18-C19. The subsequent ring closure of rotamer 30 is faster
than the cyclization of 29, leading to cis-fused aspergillin PZ (5).
Rotamer 29, by contrast, would afford
a
trans-fused
diastereomer of aspergillin PZ, compound 31. Density functional
theory calculations at the DSD-PBEP86/def2-QZVPP level show
that 5 is more stable than 31 by 35 kJ/mol (see Supporting
Information).
Keywords: Diels-Alder Cycloaddition • High Pressure • Total
Synthesis • Biomimetic Synthesis • Cytochalasans
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Scheme 4. Biomimetic Synthesis of (+)-Aspergillin PZ.
While we were preparing our manuscript for publication
Deng and Tang each reported a biomimetic synthesis of
asperchalasine A (7) and the related heterodimers.[27] Their
elegant work proved the validity of our proposal on the
biomimetic
synthesis
of
the
merocytochalasans
via
isobenzofuran Diels-Alder addition.[28] Their approach also relied
on an efficient total synthesis of 1 and/or 2, which in Deng’s
case is strategically remarkably similar to ours. In our case,
however, the intermolecular Diels-Alder reaction of triene 15
proceeded with a high degree of stereoselectivity and the triene
was not obtained from the chiral pool but via catalytic
asymmetric synthesis. With a robust synthetic entry to the family
at hand, we will further explore the fascinating chemistry of the
aspochalasans and the merocytochalasans and investigate their
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10.1002/anie.201809703
Angewandte Chemie International Edition
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Dr. Julius R. Reyes, Dr. Nils Winter,
Lukas Spessert, Prof. Dr. Dirk Trauner*
Page No. – Page No.
Biomimetic Synthesis of (+)-
Aspergillin PZ.
Delivering under pressure: The cytochalasans are a large family of polyketide
natural products with fascinating structures and potent bioactivities. We have
developed a rapid synthesis of aspochalasin D, the central member of this family. It
proceeds in 13 steps starting from divinyl carbinol and utilized a high pressure
Diels-Alder reaction. So far, our work has culminated in a biomimetic synthesis of
aspergillin PZ, an intricate pentacyclic aspochalasan.
This article is protected by copyright. All rights reserved.