Total Synthesis of Chaetoglobin A via Catalytic, Atroposelective Oxidative Phenol Coupling

Article abstract of DOI:10.1021/acs.orglett.8b02183

The first total synthesis of chaetoglobin A (1), which features a chiral axis between two identical highly oxygenated bicyclic cores, was successfully completed in 12 steps from 2,6-dimethoxytoluene. Vanadium-catalyzed oxidative phenol coupling, as a key

Full text of DOI:10.1021/acs.orglett.8b02183

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Chaetoglobin A via Catalytic, Atroposelective
Oxidative Phenol Coupling
Houng Kang,† Carilyn Torruellas,‡ Jinchu Liu,§ and Marisa C. Kozlowski*,†
†Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104,
United States
‡U.S. Army Edgewood Chemical Biological Center, RDCB-DRC-P/Building E3400, Aberdeen Proving Ground, Maryland
21010-5424, United States
§Department of Process Research and Development, Merck Research Laboratories, Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: The first total synthesis of chaetoglobin A (1), which features a chiral axis between two identical highly
oxygenated bicyclic cores, was successfully completed in 12 steps from 2,6-dimethoxytoluene. Vanadium-catalyzed oxidative
phenol coupling, as a key step, enabled generation of the axial chirality.
haetoglobin A is one of the azaphilone dimers that
contains two identical oxygenated bicyclic cores incor-
porating tertiary alcohol stereocenters that are connected
through a chiral axis (Figure 1). It is isolated from the
chemistry has not been delineated. Specifically, it is unclear
whether the stereochemistry of the chiral axis forms first and
directs formation of the tertiary alcohol centers (via 3), if the
tertiary alcohol centers form first and then direct formation of
the chiral axis (via 4), or if these stereoelements are formed
independently.
C
Due to their intriguing structures and biological activities,
numerous attempts to synthesize the azaphilone alkaloids have
been reported since the early 1970s.3 Approaches to
introducing the bicyclic core proceed from either a keto-
formyl precursor or alkynyl-formyl precursor that generate
benzopyrylium salts or pyronoquinones as key intermediates.
Often, acid-catalyzed cycloisomerization, followed by oxida-
tion, was used to construct the 2H-isoquinoline-2,6-dione
backbone. However, no synthetic efforts have been reported
toward azaphilone dimers to date. Recently, we reported an
efficient method to construct a chiral biaryl axis by means of
vanadium-catalyzed enantioselective oxidative phenol cou-
pling.4 The oxidative coupling permits the formation of chiral
axes effectively. Here, we describe the total synthesis of
chaetoglobin A utilizing this stereooselective oxidative phenol
coupling to generate an axial chiral bisphenol dimer 7 as a key
intermediate.
Figure 1. Structure of chaetoglobin A (1) and B (2).
endophytic fungus Chaetomium globosum, which lives in the
stem of Imperata cylindrical. In 2008, Tan et al. reported its
inhibitory ability on the propagation of human breast cancer
and colon cancer cell lines.1 Previous studies on the
biosynthesis of azaphilone alkaloids indicate that its core
backbone is of polyketide origin.2 However, the nature of the
dimerization and generation of attendant axial chiral stereo-
In our retrosynthetic analysis, the final isoquinoline moiety
could be prepared by amination of 5 (Scheme 1). Lewis acid
catalyzed dearomatization followed by oxidation would allow
Received: July 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02183
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
to the need for a more reactive electrophile for Sonogashira
cross-coupling, halogen exchange was undertaken to generate
iodophenol 9 after demethylation. Surprisingly, stepwise
iodination via halogen exchange6 from bromide 13 proved to
be more efficient than direct iodination7 from boronic ester 12.
Following a literature report8 to prepare enantiomerically pure
hydroxyalkyne 17, a nucleophilic ring opening with commer-
cially available propylene oxide 14 and butyne 15 gave internal
alkyne 16. Sequential alkyne isomerization was effected with a
Li/KO-t-Bu in 1,3-diaminopropane. Acetate protection of the
free hydroxyl group provided the desired alkyne 10 in 74%
yield over three steps.
Scheme 1. Retrosynthetic Analysis of Chaetoglobin A (1)
Optimization of Sonogashira coupling between iodide 9 and
alkyne 10 led to the formation of oxidative phenol coupling
precursor 8 in 98% yield (Scheme 3). Using our recently
Scheme 3. Atroposelective Oxidative Phenol Coupling and
Determination of Absolute Axial Stereochemistry
for construction of the corresponding bicyclic core from
formylated dimer 6. We hypothesize that the axial chirality of 6
could direct formation of the tertiary alcohol centers of 5. In
doing so, we could determine the feasibility one of the possible
biosynthetic pathways (i.e., via 3)(Figure 1). Vilsmeier−Haack
formylation could install the necessary formyl groups on
tetraphenol 7. We envisioned the atroposelective oxidative
phenol coupling of 8 would afford pure atropoisomer 7. We
anticipated that the acetoxy stereocenters of 8 would have little
effect on the stereochemical course of the phenol coupling
with the chiral catalyst exerting control. Internal alkynyl
monomer 8 would be prepared from the Sonogashira cross-
coupling of bisphenol 9 and alkyne 10.
Synthetic efforts commenced with preparation of phenol 9
and alkyne 10 as shown in Scheme 2. Iridium-catalyzed
borylation5 of commercially available 11, followed by
halogenation, allowed for the formation of bromide 13. Due
reported atroposelective oxidative coupling of phenols,4
vanadium catalyst 18 was applied to this transformation.
Notably, complete catalyst control over the diastereoselectivity
was observed with the opposite enantiomer of the catalyst
providing the diastereomeric product with comparable dr. The
additives, LiCl and HOAc, which are theorized to activate the
vanadium catalyst result in significant improvements (Table 1).
Treatment of 8 with LiCl as an additive gave high
diastereoselectivity (Table 1, entry 2). Increased catalyst
loading did not show a significant improvement in yield or
selectivity (Table 1, entry 3). Among alternative solvents,
chlorobenzene seemed a promising candidate in terms of
improving yield (Table 1, entry 2 vs 4 and entry 5 vs 6).
Improved yield and comparable selectivity of dimer were
realized with HOAc as the additive and chlorobenzene as
solvent (Table 1, entry 6). Finally, further improved yield and
diastereoselectivity were achieved under more concentrated
reaction conditions (Table 1, entry 7). Use of chiral vanadyl
catalyst 18 under the optimized conditions formed dimer 7 in
67% yield, establishing the axial chiral element with >15:1 dr.
The absolute stereochemistry of product 7 was confirmed by
Scheme 2. Syntheses of Sonogashira Coupling Fragments 9
and 10
B
DOI: 10.1021/acs.orglett.8b02183
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Diastereoselective Oxidative Coupling of 8
Scheme 5. Completion of Synthesis of Chaetoglobin A (1)
c
V-cat 18
(mol %)
yield
(%)
a
b
entry
additive
solvent
dr
d
1
2
3
4
5
6
7
20
20
40
20
20
20
chlorobenzene
toluene
toluene
34 (44)
52 (59)
49 (52)
54 (60)
49 (55)
49 (64)
58 (67)
79:21
92:8
93:7
90:10
87:13
90:10
94:6
LiCl
LiCl
LiCl
HOAc
HOAc
HOAc
chlorobenzene
toluene
chlorobenzene
chlorobenzene
d
20
a
b
c
20 mol %. 0.3 M. Isolated yield based on recovery of substrate in
d
parentheses. 0.5 M.
X-ray crystallographic analysis of the p-bromobenzoyl-sub-
stituted derivative 19.9
With the coupled atropoisomer in hand, our attention
turned to the key oxidative dearomatization reaction,
developed by Porco and co-workers, to generate the bicyclic
core featuring a tertiary alcohol stereocenter.11 Initially, we
tested this transformation using monomeric formylated phenol
20, which was easily prepared from monomer 8 in 85% yield
(Scheme 4). On the basis of the literature, Au(OAc)3 was the
Scheme 4. Oxidative Dearomatization with Monomer 22
that the axial stereochemistry does not create a strong facial
bias. Fortunately, sufficient amounts of each isomer could be
obtained to proceed with the synthesis. The following section
describes the results obtained with the faster eluting symmetric
diastereomer, which could not be definitively assigned as 7S,7’S
or 7R,7’R at this stage.
At this juncture, selective acylation of the tertiary alcohol
centers was needed, which could be achieved either by
deacylation of the secondary alcohols followed by selective
acylation of the tertiary alcohols or by global acetylation
followed by selection deacylation of the less hindered
secondary alcohols. The former possibility takes advantage of
the greater reactivity of the alcohols adjacent to the ketone.13
Upon removal of the acetyl groups from 5, the resultant
product was found to be prone to decomposition. As such, the
latter alternative became a focus. Acetylation of 5 afforded
product 23 in 22% over three steps from 6, which represent six
sets of chemical transformations due to the dimeric nature of
the material (Scheme 4). Unexpectedly, selective deprotection
of the secondary acetoxy group in the presence of the sterically
congested tertiary acetoxy group was challenging. Attempted
hydrolysis of 23 with acidic or basic conditions led
decomposition that was faster than deprotection. We explored
a wide range of hydrolysis conditions,14 including enzymatic
methods,15 and finally established that 10 equiv of Ti(O-i-Pr)4
in CH2Cl2 at elevated temperature afforded free hydroxylated
24 in 52% yield (Scheme 4). Exposure of oxygenated bicycle
24 to excess NH4OAc furnished synthetic chaetoglobin A (1)
in nearly quantitative yield.
optimal Lewis acid for this transformation. These conditions
efficiently provided the desired oxygenated core 21 upon IBX
oxidation as assessed by the yield monomer 22 after
acetylation (72% yield over three steps).
With dimer 7, several methods to formylate adjacent to the
alkyne chain were surveyed.10 Ultimately, the Vilsmeier−
Haack formylation with preformed (chloromethylene)-
dimethyliminium chloride at −35 °C provided bisformylated
product 6 in 86% yield (Scheme 5) without acyl deprotection,
which occurred in many of the other conditions screened due
to acid byproducts formed during generation of the active
acylating species.
With dimer 6, however, Au(OAc)3-catalyzed dearomatiza-
tion did not generate desired product 5 but caused
decomposition. After screening several Lewis acids, we found
that AgOTf12 gave a similar result in the model system from
Scheme 4 (63% overall yield from 20). To our delight,
cycloisomerization of 6 performed similarly with AgOTf, and
subsequent oxidation with a hypervalent iodine reagent, IBX,
allowed access to bicyclic dimer 5 (Scheme 5). We had
theorized that the chiral axis would influence the stereo-
chemistry during formation of this tertiary alcohol center with
the bulk of the 2H-isoquinoline-2,6-dione backbone blocking
one stereoface. However, the reaction gave a 1:1:1 mixture of
the three possible isomers (7S,7’S; 7S,7’R; 7R,7’R), indicating
The spectroscopic data from synthetic 1 were in accord with
those reported in the literature for chaetoglobin A.1 In
particular, the 13C NMR gave 17 differentiable carbons
supporting the symmetric structure. The chemical shifts of
those signals closely matched those from the natural product,
securing evidence that the correct diastereomeric relationship
between the tertiary alcohols and the stereoaxis had been
generated. Importantly, circular dichroism data obtained from
the synthetic material proved identical to that from the natural
C
DOI: 10.1021/acs.orglett.8b02183
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
product (Figure 2), which indicates that both the same
absolute and relative stereochemistries are established.
research. Partial instrumentation support was provided by the
NIH and NSF (1S10RR023444, 1S10RR022442, CHE
0840438, CHE-0848460, 1S10OD011980). Drs. Rakesh
Kohli and Charles W. Ross III (UPenn) are acknowledged
for obtaining HRMS data. We thank Prof. Virgil Percec and
Benjamin Partridge (UPenn) for assistance with CD measure-
ments. We are grateful to Dr. Patrick Carroll for assistance with
crystallographic structures.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02183.
Experimental procedures, compound characterization,
crystallographic data, NMR spectra (PDF)
Accession Codes
CCDC 1822188−1822189 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: marisa@sas.upenn.edu.
ORCID
Carilyn Torruellas: 0000-0001-5575-0894
Marisa C. Kozlowski: 0000-0002-4225-7125
Notes
́
477. (l) Boulange, A.; Peixoto, P. A.; Franck, X. Diastereoselective
IBX Oxidative Dearomatization of Phenols by Remote Induction:
Towards the Epicocconone Core Framework. Chem. - Eur. J. 2011,
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Genet, C.; O’Brien, P.; Porco, J. A. Synthesis of the Azaphilones
(+)-Sclerotiorin and (+)-8-O-Methylsclerotiorinamine Utilizing
(+)-Sparteine Surrogates in Copper-Mediated Oxidative Dearomati-
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the NIH (GM-112684) and the NSF
(CHE1464778, CHE1764298) for financial support of this
■
D
DOI: 10.1021/acs.orglett.8b02183
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DOI: 10.1021/acs.orglett.8b02183
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