Total Synthesis of (-)-FD-838 and (-)-Cephalimysin A

Article abstract of DOI:10.1021/acs.orglett.9b02203

We completed a nine-step total synthesis of (-)-FD-838 and (-)-cephalimysin A. Our synthesis features a biogenetically guided assembly of the highly oxidized spirocyclic core by Snider-type tandem epoxidations of the chiral substrate derived from an amino

Full text of DOI:10.1021/acs.orglett.9b02203

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of (−)-FD-838 and (−)-Cephalimysin A
Deokhee Jo† and Sunkyu Han*,†,‡
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
S
* Supporting Information
ABSTRACT: We completed a nine-step total synthesis of (−)-FD-838 and (−)-cephalimysin A. Our synthesis features a
biogenetically guided assembly of the highly oxidized spirocyclic core by Snider-type tandem epoxidations of the chiral substrate
derived from an amino acid derivative. Our synthetic approach provides a general and versatile solution to access spirocyclic
PKS-NRPS-based secondary fungal metabolites.
econdary fungal metabolites with 1-oxa-7-azaspiro[4.4]-
Snon-2-ene-4,6-dione framework constitute a family of
natural products with over 25 members. Since the first
isolation of pseurotin A (1, Figure 1),1 diverse secondary
metabolites with structural variations around the spirocyclic
core have been discovered (Figure 1).2 It is important to note
that potent cytotoxicities have been noticed among this family
of natural products.2 For example, cephalimysin A (6) shows
IC50 values of 15.0 nM and 9.5 nM against murine P388 and
human HL-60 leukemia cell lines, respectively.3 Furthermore,
azaspirene (4) exhibits in vivo antiangiogenic activity by
blocking the vascular endothelial growth factor (VEGF)-
induced phosphorylation of Rik1-associated factor (Raf-1),
rendering it a promising anticancer agent.4
The compelling molecular architecture of this family of
natural products which involves a spirocyclic backbone with
three contiguous stereogenic centers (two of them are
tetrasubstituted carbons), in conjunction with their notable
bioactivities, rendered these fungal metabolites popular targets
for total synthesis.2 The first total synthesis of this type of
natural products was reported by Hayashi and co-workers in
2002.5 The Hayashi team communicated an elegant synthesis
of (−)-azaspirene (4, 15 longest linear steps) via a Lewis acid-
mediated Mukaiyama aldol reaction and a sodium hydride-
promoted intramolecular hydroamidation reaction. In 2014,
the Kuramochi group reported an impressive total synthesis of
( )-berkeleyamide D (3, 7 longest linear steps) via a Darzens
reaction and a late-stage spirocyclization.6 More recently,
̌
Svenda and co-workers published an enantioselective total
synthesis of cephalimysins B (12 longest linear steps) and C
(12 longest linear steps) via a Ni(II)-diamine-catalyzed
conjugate addition of a furanone moiety.7 Besides these
representative examples, Rovis (diastereomers of cephalimysin
A, 12 longest linear steps),8 Tadano ((−)-pseurotin A (1), 37
longest linear steps),9 and Tanabe/Misaki ((−)-azaspirene (4),
29 longest linear steps)10 have also made notable contributions
in this field.
Our group’s interest in biosynthetically inspired synthesis of
complex natural products11−13 have drawn our attention to this
Figure 1. Representative spirocyclic PKS-NRPS-based natural
products and our complexity-driven discoveries with these secondary
fungal metabolites.
Received: June 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02203
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Organic Letters
Letter
a
Scheme 1. Our Retrobiosynthetic and Retrosynthetic Analyses of (−)-FD-838 (5) and (−)-Cephalimysin A (6)
a
ACP = acyl carrier protein, T = thiolation domain.
fascinating type of natural products. Our initial synthetic efforts
were rewarded by the total synthesis of ( )-berkeleyamide D
(3, 10 longest linear steps).14 Keys to this initial report were
the Snider-type tandem epoxidations15 and the biosynthetically
inspired late-stage spirocyclization reaction. We subsequently
planned to apply lessons learned from these synthetic studies
to the total synthesis of structurally more complex azaspirene
(4). Azaspirene (4) contains an additional methyl group at the
“B” peripheral region (Figure 1; see the green moiety of
pseurotin A (1)), and we estimated that the added structural
complexity would result in strategic complications. However,
contrary to this initial assessment, we noticed that the presence
of the methyl group enabled a selective formation of γ-lactam
and prevented the formation of previously observed undesired
seven-membered lactam. This observation led to a more
streamlined total synthesis of ( )-azaspirene (4, 6 longest
linear steps).16 Nonetheless, the total synthesis of enantiomeri-
cally enriched spirocyclic PKS-NRPS (polyketide synthase-
nonribosomal peptide synthetase)-based natural products
using our synthetic strategy has remained elusive so far. In
this report, we describe a nine-step total synthesis of (−)-FD-
838 (5) and (−)-cephalimysin A (6), which was enabled by
our synthetic quest to place the ketone group at the “C”
peripheral region.
groups. Hence, we envisioned obtaining (−)-FD-838 (5) and
(−)-cephalimysin A (6) by an oxidation of benzylic alcohol
derivative 12. Three contiguous stereogenic centers present in
12 (highlighted in gray) would be established by chiral
information in intermediate 13 via a sequence that involves
tandem epoxidations, spirocyclization, and methoxy substitu-
tion. γ-Lactam 13 would be derived from aldehyde 14 via a
biomimetic intramolecular aldol condensation. Linear pre-
cursor 14 was planned to be accessed from aldehyde 15, β-
ketoester 16, and amine 1720 via aldol and peptide coupling
reactions.
Our synthesis of (−)-FD-838 (5) commenced with an aldol
reaction between commercially available aldehyde 18 and the
dienolate derived from β-ketoester 16 (81% yield, Scheme 2).
a
Scheme 2. Synthesis of 22 and 23
Our synthetic strategy for (−)-FD-838 (5) and (−)-ceph-
alimysin A (6) was inspired by the biosynthetic consideration
of these secondary metabolites (Scheme 1). From a
retrobiosynthetic perspective,17,18 we hypothesized that a
late-stage P450-mediated benzylic oxidation of precursor 7
would yield (−)-FD-838 (5) and (−)-cephalimysin A (6). We
conjectured that oxygenase-based asymmetric epoxidations of
enamide 8, followed by spirocyclization, would produce 7.16
We excogitated that the γ-lactam moiety in 8 would be derived
by an intramolecular condensative cyclization of linear
aldehyde 9. Linear biosynthetic precursor 9 would be derived
from polyketide precursor 10 and phenylalanine derivative 11
by a PKS-NRPS, consistent with studies reported by Tang and
co-workers.19
From a retrosynthetic point of view, we made a strategic
decision to access optically active FD-838 (5) and cepha-
limysin A (6) by a chiral pool synthesis. This call was
predicated on our previous difficulties in accessing optically
active azaspirene (4) from 8-type compounds via asymmetric
epoxidation reactions. Furthermore, our preliminary data
hinted at challenges associated with a late-stage benzylic
oxidation in the presence of other readily oxidizable functional
a
Reagents and conditions: (a) NaH, n-BuLi, THF, −78 °C to 23 °C,
81%; (b) DMP, CH2Cl2, 23 °C, 69%; (c) DMAP, PhCH3, reflux,
50%; (d) EDC·HCl, Cl2CHCO2H, DMSO, PhCH3, 23 °C; (e)
NaOH, EtOAc, H2O, 23 °C; (f) MMPP·6H2O, THF, MeOH, 0 to 23
°C, 26% (3 steps, 22:23 = 1:1).
Subsequent oxidation of the resulting secondary alcohol
yielded tricarbonyl derivative 19 in 69% yield. Treatment of
tert-butyl ester 19 with amino alcohol 17 in the presence of
DMAP provided amide derivative 20 via the acyl ketene
intermediate in 50% yield. Alcohol 20 was then subjected to a
modified Pfitzner−Moffatt oxidation conditions to afford
B
DOI: 10.1021/acs.orglett.9b02203
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Organic Letters
Letter
a
Scheme 3. Proposed Mechanism of a Snider-Type Oxidation and a Subsequent Spirocyclization of Aldehyde 21
a
The formation of only one diastereomer is shown for clarity.
a
aldehyde 21. Base treatment of 21 and the oxidation of the
resulting crude mixture with MMPP (magnesium monoper-
oxyphthalate) provided an inseparable 1:1 mixture of
diastereomers 22 and 23 in a combined yield of 26% over
three steps.
Scheme 4. Total Synthesis of (−)-FD-838 (5)
Detailed reaction mechanism for the transformation of
aldehyde 21 to spirocycle 22 that involves Snider-type tandem
oxidations is presented in Scheme 3.15 Intramolecular aldol
reaction of aldehyde 21 and subsequent β-hydroxy elimination
of the resulting intermediate 24 would yield enone derivative
25. Enone 25 undergoes an immediate tautomerization to
enamide 26. Electrophilic epoxidation of the enamide moiety
in 26 produces epoxide intermediate 27. Intramolecular
epoxide opening by the enol moiety would provide allylic
alcohol intermediate 28. At this stage, MMPP serves as an
oxidant for a diastereoselective hydroxyl directed nucleophilic
epoxidation to provide epoxide intermediate 29. The electron
deficiency of the double bond exerted by two electron-
withdrawing groups, in combination with the directing effect of
the hydroxyl group, might enable this rather challenging
MMPP-mediated nucleophilic epoxidation reaction. The final
step of this cascade reaction is the intramolecular spirocycliza-
tion via the epoxide opening by the enol moiety of 29 to yield
spirocycle 22.
We next focused on the introduction of the methoxy group
at the α-position of the amide nitrogen atom (Scheme 4).
Inseparable diastereomeric mixtures of 22 and 23 were treated
with camphorsulfonic acid in methanol at ambient temperature
with this goal in mind. Interestingly, diastereomers 22 and 23
showed different reactivity under these reaction conditions.
While diastereomer 22 underwent smooth conversion to
methoxy derivative 30 (78% yield with respect to 22),
diastereomer 23 did not convert to the corresponding methoxy
adduct and the majority of the material remained unreacted.
We speculate that the acyl iminium ion formation from
diastereomer 22 is more favorable than from diastereomer 23
and led to the kinetic diastereomer differentiation. Methoxy
derivative 30 was obtained as a single diastereomer with >99%
enantiomeric excess. It is critical to note that the separation of
30 from unreacted 23 was facile by flash column chromatog-
raphy, which rendered our synthetic protocol practical.
Treatment of silyl ether 30 with a mixture of TBAF and
acetic acid provided alcohol 31 in 50% yield. Finally, the
benzylic alcohol moiety in 31 was oxidized to a ketone by
Dess−Martin periodinane to yield (−)-FD-838 (5) in 63%
yield. Spectroscopic data (1H NMR, 13C NMR) of our
a
Reagents and conditions: (a) CSA, MeOH, 23 °C, 39%; (b) TBAF,
AcOH, THF, 23 °C, 50%; (c) DMP, NaHCO3, CH2Cl2, 23 °C, 63%.
synthetic sample of 5 matched those from the isolation
reports21 and previous synthesis.22 Absolute stereochemistry of
our synthetic sample was confirmed by the comparison of
circular dichroism (CD) spectral data of our synthetic sample
and previously reported natural sample. Optical purity of our
synthetic natural product was confirmed by chiral HPLC
analysis enabled by the synthesis of both (+)- and (−)-FD-
838.23
We then applied the synthetic strategy developed for
(−)-FD-838 (5) to the total synthesis of (−)-cephalimysin A
(6), which is the most potent cytotoxic agent (IC50 value of 9.5
nM against human HL-60 leukemia cell line) among the
natural products in this family (Scheme 5). The synthesis
commenced with an aldol reaction between commercially
available (E)-hept-4-enal (32) and β-ketoester 16 (71% yield).
The following steps including oxidation of the secondary
alcohol, peptide coupling, oxidation of the primary alcohol,
intramolecular aldol condensation, Snider-type tandem epox-
idations, spirocyclization, methoxy substitution, and endgame
silyl deprotection/oxidation worked in analogous efficiency to
the synthetic route that led to (−)-FD-838 (5) and afforded
the first synthetic sample of (−)-cephalimysin A (6, [α]D25
−32.6 (c 0.53, EtOH)). The CD spectrum of our synthetic
(−)-cephalimysin A (6) was in complete agreement with that
of the natural sample.23,24
=
C
DOI: 10.1021/acs.orglett.9b02203
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Organic Letters
Letter
a
Scheme 5. Total Synthesis of (−)-Cephalimysin A (6)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sunkyu.han@kaist.ac.kr.
ORCID
Sunkyu Han: 0000-0002-9264-6794
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is dedicated to Professor Younghoon Lee (KAIST)
in memory of his honorable retirement. This work was
supported by the National Research Foundation of Korea
(NRF) grant funded by the Korea government (MSIT)
(2018R1A5A1025208). This work was also supported by the
National Research Foundation of Korea (NRF) grant funded
by the Korea government (MSIT) (2018R1A2B6004479).
a
Reagents and conditions: (a) NaH, n-BuLi, THF, −78 °C to 23 °C,
71%; (b) DMP, CH2Cl2, 23 °C, 82%; (c) 17, DMAP, PhCH3, reflux,
55%; (d) EDC·HCl, Cl2CHCO2H, DMSO, PhCH3, 23 °C; (e)
NaOH, EtOAc, H2O, 23 °C; (f) MMPP·6H2O, THF, MeOH, 0 to 23
°C; (g) CSA, MeOH, 23 °C, 5% (4 steps); (h) TBAF, AcOH, THF,
23 °C, 57%; (i) DMP, NaHCO3, CH2Cl2, 23 °C, 75%.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02203.
Experimental procedures; spectroscopic data; spectro-
1
metric data; copies of H and 13C NMR spectra of all
new compounds; and HPLC traces of synthetic FD-838
(PDF)
D
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