Total synthesis of viridiofungins A and B

Article abstract of DOI:10.1021/acs.orglett.1c00971

The total synthesis of viridiofungins A (1) and B (2) via β-lactone 3 in 13 steps is reported. Key steps included an HF-mediated rearrangement of cyclobutene diester 9 to form a bicyclic lactone 6, an olefin cross metathesis between disubstituted alkene 3 and alkene 4 in which isomerization was suppressed, and a novel β-lactone ring opening to form the amide. Deprotection then gave either viridiofungin A (1) or B (2) in high yield.

Full text of DOI:10.1021/acs.orglett.1c00971

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Total Synthesis of Viridiofungins A and B
Liselle Atkin, Angus Robertson, Jonathan M. White, and Mark A. Rizzacasa*
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ABSTRACT: The total synthesis of viridiofungins A (1) and B
(2) via β-lactone 3 in 13 steps is reported. Key steps included an
HF-mediated rearrangement of cyclobutene diester 9 to form a
bicyclic lactone 6, an olefin cross metathesis between disubstituted
alkene 3 and alkene 4 in which isomerization was suppressed, and a
novel β-lactone ring opening to form the amide. Deprotection then
gave either viridiofungin A (1) or B (2) in high yield.
he viridiofungins are a family of alkyl citrate natural
Scheme 1. Retrosynthesis of the Viridiofungins
T
products1 that are nanomolar inhibitors of serine
palmitoyl transferase, the enzyme involved in the first step of
sphingolipid biosynthesis.2 Viridiofungins A (1) and B (2)
(Figure 1) were first isolated3 from the fungus Trichoderma
Figure 1. Viridiofungins A (1) and B (2).
lactone 3 should allow the hindered alkene to participate in the
challenging OCM reaction12 as well as serve as an efficient
means of both protection and subsequent amide formation.
OCM has been utilized in previous approaches to
viridiofungins, but the citrate partners were terminal
alkenes.6,9a β-Lactone 3 could be sourced from orthogonally
protected triester 5 which can be formed by ring opening of
the known lactone 6 utilized in our recent total synthesis of
citrafungin A.10b This approach would not involve any
oxidative transformations but also allow for the synthesis of
the entire family of natural products from a common
intermediate.
viride, and several congeners were later found which differ in
the alkyl chain or lack an α-amino acid moiety.2b,d In addition,
some synthetic analogues with modified amino acid residues
show promise for the treatment of the hepatitis C virus
(HCV).4
The first total synthesis5 of viridiofungin A was reported by
Hatakayama6 (23 step longest linear sequence [LLS]), and this
was followed by two other syntheses by Shibasaki7 (16 step
LLS) and Ghosh8 (16 step LLS). In addition, a number of
routes to various ester derivatives have been described.9 Our
proposed route to the viridiofungins is shown in Scheme 1 and
is based on our recent stereoselective and nonintuitive
approach to alkyl citrate type natural products from cyclo-
butenediesters.10
Received: March 21, 2021
Published: April 22, 2021
As shown in Scheme 1, compounds 1 and 2 could be
accessed by an olefin cross metathesis (OCM)11 between the
common intermediate β-lactone 3 and the known alkene 46
followed by β-lactone ring opening with the appropriate amino
acid. It was envisaged that the minimal steric demand in β-
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© 2021 American Chemical Society
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The synthesis of the bicyclic lactone 6 is summarized in
Scheme 2 and begins with lactone 7, obtained by protection of
Scheme 4. Initial Olefin Cross Metathesis of β-Lactone 3
Scheme 2. Synthesis of Bicyclic Lactone 610b
(S)-(+)-γ-hydroxymethyl-γ-butyrolactone.10a A formal [2 + 2]-
cycloaddition10a,13 between the silylketene acetal derived from
7 and di-t-butylacetylene dicarboxylate (8) gave the cyclo-
butene diester 910b in good yield and high stereoselectivity.
HF•pyridine-induced deprotection, concomitant oxa-Michael
reaction, and intramolecular cyclobutanone ring opening10b,c
gives the bicyclic lactone 6.
Ring opening of the lactone 6 with allyl alcohol followed by
tosylation of the labile alcohol product gave stable tosylate 10
(Scheme 3). Iodine displacement and immediate Zn-mediated
method has been applied to the ring opening of a β-lactone
with a simple amine but, to our knowledge, not with amino
acid esters. When an excess of base was used, we observed low
yields and considerable epimerization of the labile C4
stereocenter. Fortunately, this could be suppressed by the
use of an excess of the amino acid HCl salt to deliver a single
stereoisomer of the amide 16 which was also contaminated
with a similar inseparable amide byproduct.
Scheme 3. Synthesis of Common Intermediate β-Lactone 3
Deprotection of the mixture of 16 and the byproduct with
formic acid and purification by RP-HPLC allowed for the
separation of the two products (Scheme 5). One was identified
Scheme 5. Completion of the Initial Synthesis of 2
elimination10a gave the orthogonally protected triester 5.
Removal of the allyl ester and treatment of the resultant
hydroxyacid with DCC and DMAP afforded β-lactone 11 in
good overall yield. Alkene isomerization was achieved by
treatment with Grubbs II catalyst14 in methanol to give
crystalline 3 (E:Z = 6.7:1), and the structure was confirmed by
a single-crystal X-ray analysis.
After testing a number of catalysts, OCM between alkene 3
and the side chain alkene 4 was best achieved using Grubbs−
Hoveyda catalyst15 (12) to afford the desired labile product
13, but this was contaminated by a very similar inseparable
byproduct which could only be detected by the presence of
some doubled signals in the 13C NMR spectrum along with the
OCM homodimer derived from 4 (Scheme 4). Similar results
were obtained using the dimer9a derived from alkene 4 as the
OCM partner. In any case, we next examined the ring opening
of the lactone with L-phenylalanine t-butyl ester hydrochloride
(15) using sodium 2-ethylhexanoate (14) as base.16 This mild
as viridiofungin B (2), while the other product possessed one
less methylene unit as judged by mass spectrometry and 13C
NMR spectroscopy (one less methylene signal in the 29−30
ppm region). This compound was therefore assigned as the
desmethylene analogue 17. The formation of 17 can be
attributed to production of isomerized alkene side chain 18 in
the OCM reaction probably mediated by traces of a ruthenium
hydride contaminant formed by decomposition of the catalyst
as shown in Scheme 5.17 In this case, the lower reactivity of the
disubstituted alkene in the OCM reaction probably allows for
isomerization to become a significant pathway, and OCM
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between the isomerized alkene 18 and alkene 3 forms the
desmethylene adduct.
Experimental procedures and copies of NMR spectra of
all new compounds (PDF)
While this furnished the target compound viridiofungin B
(2), a more selective route was required. Grubbs and co-
workers have reported that unwanted alkene isomerization of
OCM products by ruthenium hydride contaminants can be
thwarted by the addition of electron-deficient benzoquinones
which neutralize the hydrides without affecting catalyst
reactivity.17 We found that the OCM between the alkene 3
and side chain 4 could be best achieved with catalyst 12 in the
presence of 10 mol % of 2,6-dichlorobenzoquinone without
any formation of the undesired desmethylene compound.
Rapid purification followed by subsequent amide formation
using an excess of either amino acid HCl salt 15 or 19 in the
presence of base 14 gave the amides 16 or 20 as single
stereoisomers. Deprotection of each with formic acid then
afforded viridiofungins A (1) and B (2) in excellent yields
(Scheme 6). The data for the synthetic compounds matched
those reported for the natural products.3
Accession Codes
CCDC 2069178 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Mark A. Rizzacasa − School of Chemistry, The Bio21
Molecular Science and Biotechnology Institute, The University
of Melbourne, Victoria 3010, Australia; orcid.org/0000-
0002-7297-1303; Email: masr@unimelb.edu.au
Authors
Liselle Atkin − School of Chemistry, The Bio21 Molecular
Science and Biotechnology Institute, The University of
Melbourne, Victoria 3010, Australia
Scheme 6. Completion of the Synthesis of 1 and 2
Angus Robertson − School of Chemistry, The Bio21
Molecular Science and Biotechnology Institute, The
University of Melbourne, Victoria 3010, Australia
Jonathan M. White − School of Chemistry, The Bio21
Molecular Science and Biotechnology Institute, The
University of Melbourne, Victoria 3010, Australia;
orcid.org/0000-0002-0707-6257
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00971
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council Discovery Program
(DP200100722) and the University of Melbourne Faculty of
Science Research Grant Support Scheme for funding. We also
thank Dr. Christian Gunawan and Tony Duncan (Circa Pty
Ltd.) for the generous gift of (S)-(+)-γ-hydroxymethyl-γ-
butyrolactone.
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In conclusion, we have developed a highly stereoselective
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tone. Key steps included the stereoselective synthesis of
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mediated rearrangement sequence which allows for simple
orthogonal protection to access triester 5, a challenging olefin
cross metathesis involving the disubstituted alkene 3 without
isomerization and a novel β-lactone ring opening to form the
amide. In addition, no oxidative manipulations were required.
The stable crystalline β-lactone alkene 3 serves as a useful
precursor the viridiofungins as well as analogues for further
evaluation.
■
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