A Unified Strategy for the Enantiospecific Total Synthesis of Delavatine A and Formal Synthesis of Incarviatone A

Article abstract of DOI:10.1021/jacs.9b07693

We describe a symmetry-inspired synthetic approach that has enabled a short synthesis of delavatine A and a formal synthesis of incarviatone A, which are two likely biosynthetically related natural products. The indane core of these natural products was constructed through a cascade sequence involving five transformations that occur in a single pot. Leveraging symmetry has allowed us to trace both natural products back to a versatile building block, 3,5-dibromo-2-pyrone, and studies related to site-selective cross-coupling of this polyhalogenated heterocycle are described. In addition, our strategy gave access to a putative biogenetic precursor, from which the syntheses of both natural products were attempted.

Full text of DOI:10.1021/jacs.9b07693

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Article
A Unified Strategy for the Enantiospecific Total Synthesis
of Delavatine A and Formal Synthesis of Incarviatone A
Vignesh Palani, Cedric L. Hugelshofer, and Richmond Sarpong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b07693 • Publication Date (Web): 21 Aug 2019
Downloaded from pubs.acs.org on August 21, 2019
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Page 1 of 14
Journal of the American Chemical Society
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A Unified Strategy for the Enantiospecific Total Synthesis of
Delavatine A and Formal Synthesis of Incarviatone A
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Vignesh Palani, Cedric L. Hugelshofer, and Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, CA 94720 (USA)
Supporting Information Placeholder
ABSTRACT: We describe a symmetry-inspired synthetic approach that has enabled a short synthesis of delavatine A and a formal
synthesis of incarviatone A, which are two likely biosynthetically related natural products. The indane core of these natural products
was constructed through a cascade sequence involving five transformations that occur in a single pot. Leveraging symmetry has
allowed us to trace both natural products back to a versatile building block, 3,5-dibromo-2-pyrone, and studies related to site-selective
cross-coupling of this polyhalogenated heterocycle are described. In addition, our strategy gave access to a putative biogenetic
precursor, from which the syntheses of both natural products were attempted.
INTRODUCTION
The first total synthesis of delavatine A (1) was then
accomplished by Li and co-workers in 2017. While these
13
Secondary metabolites (i.e., natural products) serve as an
important basis for traditional medicines and pharmaceuticals.
Plants of the Incarvillea genus, found in the Himalayas and
1
syntheses each provided access to one of these molecules, we
envisioned, instead, a unified approach to both natural products.
Recently, we disclosed a modular, four-step synthesis of
Southwest China, have long been used in traditional Chinese
1
4
2
,3
delavatine A from 3,5-dibromo-2-pyrone. While our previous
work reported a short synthesis of delavatine A, in this Article,
we describe the evolution of a unified strategy to access both 1
and 3.
herbal medicine. Among the active ingredients responsible
for the biological properties of these herbal remedies are
alkaloids and a variety of natural product “hybrids”. The latter
result from the combination of two or more natural products, or
fragments thereof, to furnish structurally interesting compounds
Scheme 1. Plausible common biosynthetic precursor of
delavatine A and incarviatone A
4
with diverse biological properties. Incarvillea delavayi,
specifically, has been used to treat anemia and dizziness. Two
structurally related natural products, delavatine A (1, Scheme
5
Me
Me
Me
O
H
CHO
1
) and incarviatone A (3) were recently isolated from this
OH
O
A
flowering plant, each displaying distinct bioactivities and also
possessing an unusual molecular scaffold.
N
H
6,7
CHO
O
OH
Delavatine A (1), a structurally unique alkaloid featuring a
cyclopenta[de]isoquinoline skeleton, displays micromolar
antitumor activity against a variety of human cancer cell lines.
B
CHO
6
CHO
CHO
Me
(–)-incarviatone A (3)
On the other hand, incarviatone A (3) possesses a unique
polycyclic skeleton with eight contiguous stereocenters. Initial
Me
delavatine A (1)
Me
2
biosynthetic common
intermediate
bioactivity studies have revealed incarviatone A to be a
8
monoamine oxidase
A
(MAO-A) inhibitor. However,
comprehensive biological studies of 3 were not conducted due
Proposals for the biosynthesis of 1 and 3 have separately
invoked trialdehyde 2 as a common intermediate (Scheme 1).
6
,7
to its poor isolation yield (4.1 mg isolated from 17 kg of dried
7
whole plant). MAO-A antagonists have been implicated in the
Synthetic routes that mimic how natural products are formed in
plants, often starting from simple building blocks and using
highly selective reactions, have long served as a powerful
regulation of cognitive processes such as emotions and certain
9
types of memory, as well as in the prevention of tumor
10
15
proliferation. As such, use of MAO-A inhibitors in the
model for designing bioinspired syntheses. In our case, taking
11
treatment of cancer is currently a hotly pursued research area.
inspiration from the putative biosynthetic link between 1 and 2,
we anticipated that a divergent approach involving synthesis
and a potentially biomimetic modification of 2 could provide
access to both natural products. The success of such a synthetic
route would additionally lend credence to the proposed
biosyntheses. In the past, this mutually beneficial relationship
between biosynthetic hypotheses and organic synthesis has
Synthesis of unique MAO-A inhibitors like 3 could set the stage
for in-depth studies into the connections between MAO-A
inhibition and cancer progression.
The low abundance of incarviatone A (3), together with the
intriguing biological activities of 1 and 3, makes these
compounds attractive targets for total synthesis. A total
1
2
synthesis of 3 was reported by Lei and co-workers in 2015.
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Page 2 of 14
translated into many remarkable total syntheses of natural oxygen or peroxy acids (see Scheme 2b) were explored to
1
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
products in the last several decades.
convert 12 to butenolide 13. Unfortunately, all oxidation
attempts failed, presumably due to the enhanced π-deficiency
of furan 12, now bearing two electron-withdrawing groups.
RESULTS AND DISCUSSION
First generation approach. In determining how to construct
2, we recognized that this trialdehyde features an element of
symmetry (A and B rings, Scheme 1), which we believed could
translate into powerful retrosynthetic disconnections.
Leveraging symmetry (hidden or overt) is a powerful tool for
the identification of simplified precursors, which generally
enhances overall synthetic efficiency. From a retrosynthetic
perspective, we initially envisioned that 2 could be derived from
extended enolate 4, which would undergo 6 electrocyclization
and subsequent reduction of the ester groups in the forward
sense (Scheme 2a). In turn, dienolate 4 could be accessed from
hydroxy butenolide 5 via Wittig olefination and E/Z
isomerization. On the basis of the pseudo-symmetry of 5, we
traced it back to an envisioned diboronic acid (6) and vinyl
triflate 7.
Second generation approach. In light of our inability to
oxidize furan 12 to the corresponding hydroxy butenolide, we
designed an alternative retrosynthesis. Our revised strategy
called for the construction of the indane core of 2 via the
intermediacy of dienolate 14 (cf. 4, Scheme 2a), which in turn
would arise from highly conjugated polyene 15 upon
isomerization. We anticipated that an equilibrium could be
established between polyene 15 and bis-coupled pyrone 16 in
the presence of an alkoxide nucleophile. We anticipated that
this entire transformation (16  14, Scheme 3a) might be
carried out as a one-pot cascade, which would be initiated
through trans-lactonization of bis-coupled pyrone 16 with an
alkoxide.
1
7
0
1
2
3
4
5
6
7
8
9
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2
3
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0
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9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Revised retrosynthetic analysis and preliminary
attempts to initiate the cascade sequence.
Scheme 2. Symmetry-inspired first generation approach.
a) latent symmetry inspired retrosynthetic analysis
RO
Me
Me
B(OH)2
O
RO C
O
2
O
CO R
2
Wittig
B(OH)2
6
O
2
+
OTf
E/Z HO
CO R
CO R
2
2
CO R
2
Me
Me
4
5
Me
7
b) forward synthesis progress
Me
EtO C
2
Me
Pd(dppf)Cl2
HBpin,
[Ir(COD)OMe]2
TfO
EtO C
2
8
K CO
2
3
+
THF
THF
B(OH)2
O
O
(92%)
Conditions Results
10
9
TPP, O2 complex
mCPBA complex
CH3CO3H decomp.
Me
Me
EtO C
2
EtO C
2
Me
EtO C
O
2
8, Pd(dppf)Cl2
On the basis of this revised retrosynthetic plan and as the first
step toward preparation of bis-coupled pyrone 16, a Suzuki–
Miyaura borylation of vinyl triflate 8 furnished boronate ester
18 in 96% yield (Scheme 3b). Subsequent Suzuki cross-
K CO
2
3
O
O
O
THF
HO
CO Et
2
CO Et
2
Bpin
(63% over
steps)
2
0
coupling between 3,5-dibromo-2-pyrone (17) and 18 provided
bis-coupled pyrone 19 in 79% yield. With 19 in hand, we were
in a position to experimentally assess methods to initiate the
envisioned cascade sequence (i.e., 16  14, Scheme 3a). Initial
efforts focused on treating 19 with nucleophilic alkoxides under
different conditions. Opening 2-pyrones with an alkoxide in a
2
Me
13
11
Me 12
In preliminary synthetic studies, we encountered difficulties
in accessing the proposed furan diboronic acid 6, which was
only isolated in trace quantities. We therefore instead turned to
a Suzuki coupling between 3-furanylboronic acid (9) and
21
1
8
1,2-fashion, as would be ideal for our synthetic plan, has
known vinyl triflate 8 to furnish mono-coupled furan 10 in
2% yield (Scheme 2b). Using the protocol developed by
precedent in related systems. However, under both thermal and
photolytic conditions, we were unable to isolate any promising
intermediates toward the envisioned cascade product (i.e., 20).
9
19
Hartwig and co-workers, C–H borylation of 10 proceeded
efficiently to furnish boronate ester 11. A second Suzuki
coupling between 11 and vinyl triflate 8 then delivered bis-
coupled furan 12. Several oxidation conditions using singlet
Given the lack of initial success with alkoxide-initiated
openings, we began to investigate other nucleophiles known to
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Journal of the American Chemical Society
react with 2-pyrones.22 Notably, pyrone 19 features
(a) possible reactive sites in bis-coupled pyrone 19
challenges: regioselective ring opening
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
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4
4
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4
4
5
5
5
5
5
5
5
5
5
5
6
electrophilic sites at C2, C4, and C6 (Scheme 4a), and
consequently, three different constitutional isomers can be
expected upon treatment with nucleophiles under varying
reaction conditions. The relative reactivity of each of the
electrophilic sites on 2-pyrones varies significantly depending
Me
4
Me
Me
Me
CO Et
CO Et
CO Et
2
2
2
CO Et
2
O
O
2
O
3
5
2
Nuc
CO2
2
1c
on the nature of substituents. In bis-coupled pyrone 19, which
is substituted with the same electron-withdrawing moieties at
C3 and C5, it was challenging to predict the preferred reactive
site of the nucleophilic attack. Among the three constitutional
isomers, the product resulting from nucleophilic C4-ring
opening (19b) would be the least beneficial for our synthesis,
whereas we believed that accessing either C2-ring opened
product 19a or C6-ring opened product 19c would be
productive for our synthesis.
O1
6
Nuc + Nuc
O
+
4
6
O
Nuc
CO Et
CO Et
CO Et
2
2
2
O
0
1
2
3
4
5
6
7
8
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0
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2
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0
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0
1
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0
1
2
3
4
5
6
7
8
9
0
Me 19
Me 19a
Me 19b
Me 19c
(b) 1,6-ring opening of bis-coupled pyrone 19 with cyclic amine
morpholine
Me
Me
Me
Me
OEt
With these possibilities for nucleophilic opening in mind, bis-
coupled pyrone 19 was treated with a variety of nucleophiles
(see the Supporting Information for all the attempted
CO Et
CO Et
CO Et
2
2
2
O
O
O
O
O
2
3
PT
nucleophiles). Among the nucleophiles that were investigated,
we observed our first successful ring opening upon treating 19
O
6
OH
6
OH
6
O
6
2
4
with cyclic amines. As outlined in Scheme 4b, morpholine
opened 19 in a 1,6-fashion to furnish the decarboxylated
enamine 20, which was isolated in 83% yield as a single
diastereomer. The connectivity in 20 was validated by 2D NMR
analysis, and the reaction was found to work equally well with
other cyclic amines, such as piperidine and pyrrolidine.
Although, cyclic amines proved fruitful in opening 19, we were
unable to avoid the spontaneous decarboxylation event, even by
adding an alkylating agent aimed at intercepting the
intermediate carboxylate.
NH
N
N
N
O
O
O
O
20a
20b
Me
20c
20d
–
CO2
(83%)
Me
CO Et
2
Conditions Results
EtO C
H
N
2
KHMDS decomp.
KH
H
H
decomp.
PhMe
complex
EtO C
2
BF3.OEt2 complex
TBSOTf complex
Scheme 4. Nucleophilic ring opening of bis-coupled pyrone
CO Et
1
9 with cyclic amines.
2
Me
O
Me 21
20
We postulate that morpholine (like the other cyclic amines)
reacts with 19 to give adduct 20a, which opens in a 1,6-fashion
to provide enamine 20b. The latter compound might then
undergo proton transfer to furnish carboxylate ion 20d
presumably via iminium ion 20c. The carboxylate group, now
3
connected to a sp hybridized carbon in 20d, would undergo
rapid decarboxylation to furnish 20. Because the carboxylate
group was essential to access either of the targeted natural
products, this route was ultimately unworkable. However,
cognizant that the lost carboxylate group could be re-installed
at a later stage via a transition metal-catalyzed C–H activation
25
reaction, we continued to explore the benzannulation with
enamine 20. We thus attempted to forge the indane core of 21
through an isomerization/6 electrocyclization/elimination
cascade sequence starting from enamine 20. Mechanistically,
the ring closure can also be considered a 6-endo-trig Michael-
type addition of the generated enolate. Disappointingly, all the
acidic and basic reaction conditions (see Scheme 4b for selected
conditions) that were investigated, returned inseparable product
mixtures or led to nonspecific decomposition of 20.
Given our failure to convert enamine 20 to the indane core in
1, we began investigating alternative nucleophiles for opening
bis-coupled pyrone 19 to access a suitable adduct for the
subsequent isomerization/6 electrocyclization/elimination
cascade. Pyrone 19 was subjected to several nucleophiles
sodium azide, hydrides, imides, thiols, enolates, Grignard
reagents, sodium thiocyanate, and sodium cyanide) under a
variety of reaction conditions. To our delight, of these,
2
(
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sequential treatment of 19 with sodium cyanide and methyl
Me
Me
Me
iodide, inspired by the precedent of work conducted by Vogel,26
delivered methyl ester 22 as an inseparable 4.5:1 mixture of
diastereomers (Scheme 5).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CO Et
CO Et
CO Et
2
2
2
O
2
O
O
NaCN
Likely, the cyanide anion undergoes 1,6-addition to provide
O1
6
O
6
CN
O
6
CN
nitrile 22a, which then opens to generate carboxylate ion 22b.
2
The carboxylate group, now appended to a sp hybridized
MeI
97%)
carbon, unlike in intermediate 20d (Scheme 4b), does not suffer
spontaneous decarboxylation and can be trapped with an
alkylating agent to furnish methyl ester 22. Having gained
access to methyl ester 22, we then investigated various
conditions to form the requisite enolate that would induce the
CO2Et
CO2Et
CO2Et
(
Me
Me
22a
Me
22b
19
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Conditions Results
Me
Me
6
 electrocyclization/6-endo-trig Michael-type addition to
KHMDS decomp.
Triton B
complex
decomp.
decomp.
n.r.
CO Et
2
t
CO Et
2
ultimately furnish indane 24. To effect the ring closure in 22,
strong bases (LDA), moderately strong bases (NaHMDS,
LiHMDS, NaH), and soft enolization conditions (TBSOTf,
bis(trimethylsilyl)acetamide) were investigated. Unfortunately,
all our attempts failed to promote the desired ring closure.
KO Bu
Et2AlCl
Et3OPF6
DMSO
97%)
CO Me
2
NC
CO Me
2
(
CN
CO Et
2
During the course of our investigations aimed at converting
methyl ester 22 to indane 24 (see the Supporting Information
for all the attempted reaction conditions), we discovered that
upon heating a solution of 22 in DMSO, the starting material
cleanly converts to a new compound with unchanged mass.
Following careful 2D NMR analysis, the generated product
mixture was established to be the double-bond isomer methyl
ester 23 (6:1 d.r.). We postulate that the isomerization was
promoted by Michael–retro-Michael addition of DMSO to the
CO Et
2
Me
Me
(6:1 d.r.)
23
22
Me
CO Et
2
(4.5:1 d.r.)
CO2Me
KHMDS
CBr4
(47%)
KHMDS
CBr4
(54%)
CO Et
2
Me
Me
24
Me
CO Et
2
CO Et

,-unsaturated methyl ester moiety in 22. Having achieved the
2
desired geometry to effect the ring closure in 23, we were
encouraged to attempt enolization conditions (see Scheme 5 for
selected conditions; see the Supporting Information for all the
attempted reaction conditions) to forge the indane core of 24.
Unfortunately, both basic and acidic reaction conditions
resulted in either nonspecific decomposition or returned
unreacted 23.
Br
DMSO
90%)
CO Me
2
NC
CO2Me
Br
(
Conditions Results
CN
KHMDS decomp.
CO Et
2
KH
Pd]
decomp.
decomp.
CO Et
2
[
Me 25
(9:1 d.r.)
26
(6:1 d.r.)
Me
These unexpected results indicate that deprotonation  to the
nitrile group occurred rather than the desired -deprotonation of
the ,-unsaturated ester moiety, consequently leading to the
unsuccessful ring closure when methyl ester 22 or isomerized
methyl ester 23 was subjected to enolization conditions. With
access to vinyl bromide 25, we also envisioned achieving the
desired ring closure via either 6 electrocyclization, 6-endo-trig
Michael-type addition, or transition-metal catalyzed
intramolecular enolate coupling reaction. Unfortunately, under
all the conditions that were investigated (see Scheme 5 for
selected conditions), we observed nonspecific decomposition of
Interestingly, we observed that treatment of 23 with KHMDS
4
in the presence of CBr gave rise to vinyl bromide 25 in 47%
2
7
yield as a 9:1 mixture of diastereomers. An analogous reaction
was then conducted with methyl ester 22 to give vinyl bromide
2
6 in comparable yield as a 6:1 mixture of diastereomers. In
addition, vinyl bromide 26 converted to the isomerized vinyl
bromide 25 upon heating in DMSO (cf. 22  23), corroborating
their E/Z isomer relationship.
Scheme 5. Nucleophilic ring opening of bis-coupled pyrone
1
9 with sodium cyanide.
2
5.
Concurrently, we recognized that a steric clash between the
highlighted ester groups (see 23, Scheme 6) might distance the
-position of the ,-unsaturated ester moiety from the vinyl
nitrile group. Consequently, this interaction might induce an
undesired, non-productive, pre-organization for the envisioned
ring closure. To counteract this circumstance, we designed a
synthetic sequence where the ester groups would be locked in
position. Toward this end, the carboxylate ion, generated upon
treating bis-coupled pyrone 19 with cyanide ion, was trapped
with HBTU to furnish benzotriazole ester 27. Upon treatment
with trifluoroacetic acid (TFA), 27 was found to isomerize and
could then be amidated with 4-methoxybenzylamine to provide
amide 28 as a single diastereomer in a 50% overall yield
starting from 19. Exposing amide 28 to sodium hydride gave
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Journal of the American Chemical Society
imide 29 as a mixture of E/Z diastereomers (1.25:1 ratio). We
believe the E/Z isomerization at the cyanide-bearing alkene
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
group was either thermodynamically driven or resulted from
deprotonation-protonation of the vinyl hydrogen under the
basic reaction conditions. Having now locked the configuration
and conformation of the triene by installation of the imide, we
investigated the desired ring closure by treating imide 29 under
a variety of enolization conditions. Unfortunately, all the
conditions that were surveyed led to nonspecific decomposition
or returned unreacted 29.
Scheme 6. Imide-lock approach.
Due to the difficulties associated with decreasing the acidity
of the vinyl hydrogen, we at this stage decided to proceed with
the alternative approach (b), in which a derivative of 22 bearing
a relatively more electron-withdrawing functional group on the
northern ring needed to be synthesized. As outlined in Scheme
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
Me
CO Et
2
not
proximal
CO Et
2
O
NaCN
HBTU
8
, we sought to prepare aldehyde 31, which features a more
NC
CO Me
O N
2
19
acidic -hydrogen compared to 22, and where deprotonation of
the -hydrogen should be favored over abstraction of the
undesired vinyl hydrogen. In our previously described Suzuki
coupling to synthesize bis-coupled pyrone 19 from 3,5-
dibromo-2-pyrone (17) and boronate ester 18, the order of
reactivity at the 3- or 5-position of 17 was inconsequential since
equivalent coupling partners were introduced. However, by
incorporating different substituents on the cyclopentenyl
moieties in aldehyde 31, the synthesis of 31 now called for a
site-selective cross-coupling of 3,5-dibromo-2-pyrone (17). If
this type of selective coupling could be achieved, aldehyde 31
could be conveniently traced back to 3,5-dibromo-2-pyrone
N
N
DMF
CN
CO Et
CO Et
2
2
Me 23
27
Me
TFA, THF
then PMBNH2
(50% over
2 steps)
Me
Me
Me
O
O
CO Et
2
NC
Me
NC
O
NPMB
O
NPMB
O
NaH
THF
13a
(
17), boronate ester 18, and known stannane aldehyde 32.
E
NH
Site-selective cross-coupling studies. 3,5-dibromo-2-pyrone
PMB
(
17) belongs to a class of -pyrone-derived polyhalogenated
CO Et
CO Et
(72%)
CO2Et
28
2
2
heterocycles that possess two chemically inequivalent C–Br
bonds. In general, retrosynthetic analyses involving site-
29
Me
Me
30
29
28
selective cross-coupling of polyhalogenated heterocycles
(1.25:1)
3
0
enables identification of drastically simplified precursors, and
this has been exploited in both academic and industrial
At this stage, we were confident that the deprotonation of the
vinyl hydrogen rather than the desired -deprotonation of the
3
1
settings.
Scheme 8. Retrosynthetic analysis involving sequential site-
selective cross-coupling of 3,5-dibromo-2-pyrone.

,-unsaturated ester moiety constituted a key problem
(Scheme 7). To circumvent this issue, we envisioned pursuing
two modified approaches: (a) we could either attempt to open
bis-coupled pyrone 19, or substitute the nitrile group in 22 or 23
with a nucleophile that would render the vinyl hydrogen less
acidic; or alternatively (b) we could synthesize a derivative
similar to 22 that contains a more electron-withdrawing
substituent in the northern cyclopentenyl ring which would
enhance the acidity of the -hydrogen. Given our inability to
open bis-coupled pyrone 19 with nucleophiles other than cyclic
amines (Scheme 4b) and cyanide ion (Scheme 5), we instead
chose to attempt a nucleophilic vinylic substitution of the nitrile
group in either 22 or 23. Toward this end, 22 was treated with a
variety of nucleophiles (see Scheme 7 for selected conditions)
to substitute the nitrile group via 1,6- addition–elimination to
generate methyl ester 22-Nuc. To our dismay, all the
nucleophiles that were investigated either returned unreacted
methyl ester 22 or resulted in complex product mixtures. A
similar outcome was encountered when isomerized methyl ester
Cho and co-workers have previously reported site-selective
modifications of 3,5-dibromo-2-pyrone (17) in a variety of
cross-coupling processes leading to formation of
32–34
constitutionally isomeric products.
In addition, the same
group also reported efficient total syntheses of natural products
by employing site-selective cross-coupling of 3,5-dibromo-2-
2
3 was treated with a variety of nucleophiles.
35
pyrone (17). While these studies enabled identification of
Scheme 7. Nucelophilic substitution of nitrile group in
methyl ester 22.
factors important for site-selective cross-coupling with 17, a
comprehensive mechanistic reasoning for the observed
selectivity was not established. While several studies have
sought to predict and rationalize the selectivity in reactions of
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Page 6 of 14
polyhalogenated heterocycles, it has generally remained
strove to gain mechanistic insight into the observed site-
selectivity in 17 by computational methods. A detailed account
2
9,30a
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
challenging.
In some cases, consideration of H NMR
chemical shifts of the C–H bonds in the parent non-halogenated
heterocycles have guided the prediction of site-selective cross-
of this collaborative work and the cumulative mechanistic
insight was described in our initial publication that focused on
3
6
14
couplings in the corresponding polyhalogenated heterocycles.
delavatine A.
However, the predicted outcome by employing this method was
contrary to the observed site-selectivity in 3,5-dibromo-2-
Forward synthesis to access delavatine A (1). With the
conditions for site-selective cross-coupling of 3,5-dibromo-2-
pyrone (17) established, we commenced our forward synthesis
to access aldehyde 31 (Scheme 9). We envisioned selectively
coupling the C5 position in 17 with boronate ester 18, which
following our studies would be achieved by use of both a polar
solvent and addition of CuI. Indeed, the Suzuki coupling
between 17 and 18 in dimethylformamide in the presence of CuI
proved successful and gave mono-coupled pyrone 37 in 75%
yield on multigram scale. Analogously, a site-selective Stille
2
9
pyrone (17). Following this observation, the mechanistic
reasoning for the observed site-selectivity in 17 has remained
largely unexplored.
3
4
Taking inspiration from a report by Cho and co-workers, we
investigated the Suzuki coupling reaction between 3,5-
dibromo-2-pyrone (17) and commercially available
phenylboronic acids (Table 1). We identified that solvent
choice, temperature, and addition of copper(I) iodide (CuI)
appeared to have a marked influence on the observed coupling
selectivity in 17. Our studies, together with the seminal results
obtained by Cho and co-workers, culminated in the conclusion
that in nonpolar solvents such as 1,2-dichloroethane,
tetrahydrofuran, and toluene, C3-coupled product 33 was
primarily formed. In addition, neither the addition of CuI nor
conducting the reaction at elevated temperature influenced the
observed C3-coupling in non-polar solvents. In contrast, when
the reaction was conducted in polar solvents such as dimethyl
sulfoxide, dimethylformamide, and acetone, C5-coupled
product 34 was generally formed as the major product. Notably,
C5-coupled product 34 was observed only in the presence of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
9
coupling between 17 and stannane ester 36 also furnished 37
in 70% yield, when conducted in N-methyl-2-pyrrolidone
(NMP) in the presence of copper(I) thiophene-2-carboxylate
(CuTC). A subsequent Stille coupling between mono-coupled
1
3a
pyrone 37 and stannane aldehyde 32 then delivered bis-
coupled pyrone 38 in 72% yield on multigram scale. A
significant side reaction in this Stille coupling was the
formation of the corresponding homocoupled product of
stannane aldehyde 32. Fortunately, this undesired side reaction
could be eventually suppressed by using 32 as a limiting
reagent. Subjecting mono-coupled pyrone 37 to the previously
established ring-opening conditions with cyanide ion gave rise
to aldehyde 31 in 75% on multigram scale.
1
4
CuI. In other words, conducting the reaction in the absence of
3
7
CuI exclusively generated the C3-coupled product 33. Unlike
the results reported by Cho and co-workers, we did not observe
a switch in C3/C5-selectivity as the temperature was raised
Due to the similarity in reaction conditions of the first
Suzuki/Stille coupling to generate mono-coupled pyrone 37 and
the second Stille coupling to furnish bis-coupled pyrone 38, we
began exploring conditions to accomplish a sequential
Suzuki/Stille–Stille coupling in order to directly access 37 from
3
4
from 23 °C to 50 °C.
Table 1. Suzuki couplings with 3,5-dibromo-2-pyrone
3
,5-dibromo-2-pyrone (17) in a single pot. We initially studied
O
O
O
O
the sequential Suzuki–Stille coupling in a single pot. However,
under all the attempted conditions, nonspecific decomposition
of stannane aldehyde 32 was observed and only the mono-
coupled pyrone 37 was isolated. Similar results were observed
when sequential Stille–Stille coupling was carried out using CuI
as the copper source. Attempts to achieve a site-selective C3-
coupling between 17 and 32 prior to the second Stille coupling
was also met with failure. Eventually, we realized that the
addition of CuTC was crucial for enabling the sequential and
one-pot Stille–Stille coupling and bis-coupled pyrone 38 was
obtained in comparable yield. With these established
conditions, pyrone opening with cyanide ion was also attempted
in the same pot to furnish aldehyde 31 directly from 3,5-
dibromo-2-pyrone (17). Excitingly, the one-pot sequential
Stille–Stille–pyrone opening sequence, which generates a
remarkable amount of target-relevant molecular complexity in
a single step, was successful and furnished 31 in 32% overall
yield. A significant amount of bromide 39 was obtained as a by-
product in the sequential Stille–Stille–cyanide opening
sequence, which results from opening of the residual mono-
coupled pyrone 37 (generated in the first Stille coupling).
Fortunately, bromide 39 could be subjected to Stille coupling
with stannane aldehyde 32 to furnish aldehyde 31, thus resulting
in a net 57% combined yield of 31 starting from 3,5-dibromo-
Br
PhB(OH)2
Ph
Br
Ph
O
O
O
O
3
+
+
conditions
5
Br
Br
Ph
Ph
17
33
34
35
b
yield (%) 33:34:35
a
Solvent
With CuI
3 °C
Without CuI
23 °C
2


—c
4
7
DMSO nd:12:nd
DMF
1.01 acetone tr:32:nd
8:13:nd
nr
nr
nr
nr
nr
nr
3
8.25
nd:18:nd 15:37:nd
tr:nd:nd
53:nd:nd
70:nd:nd
47:nd:19
52:nd:nd
2
1
16:29nd
58:tr:11
49:17:nd
56:tr:tr
0.42
.52
DCE
THF
57:13:nd
27:8:nd
55:tr:nd
7
2.38 toluene
aDielectric constant at 20 °C.38 bDetermined by H NMR using
1
c
1,1,2,2-tetrachloroethane as an internal standard. Decomposition
of 17. Conditions: PhB(OH)
2 3 4
(1.2 equiv), Pd(PPh ) (10 mol%),
CuI (1.0 equiv), K CO (2.0 equiv), solvent (0.1 M). nd = not
2
3
detectable, tr = trace, nr = no reaction.
We thus identified the selectivity of cross-coupling with 3,5-
dibromo-2-pyrone (17) to be temperature independent and to
proceed exclusively at C3 in nonpolar solvents both in the
presence and absence of CuI, while coupling is favored at C5 in
polar solvents but only in the presence of CuI. Furthermore, we
2
-pyrone (17).
Scheme 9. Forward synthesis to access aldehyde 31.
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Journal of the American Chemical Society
ratio, where the highlighted hydrogen atoms adopt an anti-
1
2
3
4
5
6
7
8
9
relationship, as determined by analysis of the coupling constant
1
values in the H NMR spectrum. This observation indicates a
4
1
thermally favored disrotatory ring closure of the major E
isomer of silyl enol ether 40.
Scheme 10. Completion of the synthesis of delavatine A (1).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
With aldehyde 31 in hand, we next turned our attention to
investigating if the -deprotonation of the ,-unsaturated ester
moiety could be achieved over deprotonation of the vinyl
hydrogen in 31 (Scheme 10). Toward this end, 31 was treated
under a variety of basic reaction conditions (selected conditions
shown in Scheme 10). We observed rapid decomposition of 31
upon exposure to strong bases such as LDA, LHMDS, or NaH.
In addition, a similarly dissatisfying result was observed when
31 was subjected to the previously established E/Z-
isomerization conditions (cf. 22  23, Scheme 5). Acidic
conditions similarly met with failure. Fortunately, when
aldehyde 31 was subjected to soft enolization conditions
3
(TBSOTf, Et N), silyl enol ether 40 was isolated as a mixture
of diastereomers (12:1) in 93% yield and the vinyl nitrile group
remained untouched. Chromatographic separation of the
product mixture revealed that the major component was the E-
isomer. Our initial investigations with silyl enol ether 40
included attempting several Mukaiyama–Michael-type
reactions to effect the ring closure via the previously proposed
6-endo-trig Michael-type addition pathway. However, all these
conditions did not give rise to any of the desired cyclized
product. Eventually, it was discovered that the ring closure,
proceeding via initial isomerization followed by 6
We then turned toward translating this three step sequence
42
(
31  42) into a one-pot cascade sequence. Our initial studies
aimed at achieving this entire transformation in a single pot
involved sequential addition of reagents. Eventually, we
realized that the equivalents of tert-butyldimethylsilyl
trifluoromethanesulfonate (TBSOTf), triethylamine, and DBU
had a profound impact on the isolated yield of indane aldehyde
4
2 (selected conditions shown in Scheme 10). We observed that
a relatively small excess of TBSOTf and trimethylamine gave a
mixture of both indane aldehyde 42 and benzocoumarin 43,
while the use of a very large excess of DBU exclusively
provided benzocoumarin 43 in poor yield. Following careful
optimization, a 10-fold excess of both DBU and trimethylamine
was determined to be optimal to exclusively obtain indane
aldehyde 42 in 32% yield (12:1 d.r.). It should be noted that
4
0
electrocyclization, simply occurred upon heating 40 in toluene
at elevated temperature. The intermediate cyclized product (41)
was then converted to indane aldehyde 42 (1:0.7 d.r.) upon
treatment with diazabicyclo(5.4.0)undec-7-ene (DBU). The 6
electrocyclization gave rise to two diastereomers in a 2.6:1
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hydrolyzing the intermediate silyl enol ether of this three step
sequence with TBAF furnished 42 with better
diastereoselectivity (12:1 d.r.) compared to when 42 was
obtained from 41 (1:0.7 d.r). The observed diastereoselectivity
could be a result of the “buffered” TBAF conditions in the one-
pot cascade sequence, which we believe could alter the
biomimetic cascade sequence with silyl ether 46, where we
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
believed the corresponding enolate could be generated upon
treatment with a fluoride source that would lead to sequential
desilylation and oxa-Michael addition.
Notable aspects of our attempted conditions (selected
conditions shown in Scheme 11) include: (1) using HMDS
derived bases primarily resulted in isolation of delavatine A (1)
due to condensation of trialdehyde 2 with the resulting HMDS;
thermodynamic
distribution
of
the
corresponding
diastereomers. In addition, it was found that benzocoumarin 43
could be converted to indane aldehyde 42 by treatment with
sodium methoxide in methanol. It was later found that in
addition to the TBS silyl enol ether, the corresponding TIPS
silyl enol ether also proved to be a suitable precursor for the
synthesis of 42 via the established cascade sequence. The
indane aldehyde 42 was then reduced with lithium aluminum
hydride to the corresponding triol, which when subjected to
Swern oxidation furnished the proposed biosynthetic common
intermediate, trialdehyde 2. Finally, 2 was treated in situ with
ammonium acetate along with moderate heating to provide
delavatine A (1) in 48% yield over two steps starting from 42.
Delavatine A prepared through the sequence of steps described
(2) other basic conditions either returned unreacted starting
materials or formed complex product mixture; (3) attempts to
generate the enolate derived from silyl ether 46 also led to
unsatisfactory results and either the desilylated quinol was
isolated or nonspecific decomposition was observed. Inspired
by the studies of Lei and co-workers in their synthesis of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12
incarviatone A, we attempted to conduct a phenol aldol
reaction between and magnesium phenolate 47.
2
Unfortunately, this reaction exclusively returned unreacted
trialdehyde 2. At this stage, we hypothesized that our
unsatisfactory results might originate due to the presence of the
highly acidic -hydrogen of the aldehyde group. We reasoned
that the basic reaction conditions might lead to the enolate
derived from trialdehyde 2 thus inhibiting nucleophilic addition
into the aldehyde group.
1
13
here possessed analytical data ( H and C NMR, HRMS, IR,
[
] ) in full agreement with those reported for the naturally
D
5
occurring material. Failing to heat the mixture after addition of
ammonium acetate resulted in formation of an inseparable
mixture of delavatine A along with its isomer featuring a de-
conjugated enal moiety. Following this synthetic sequence,
we were able to access delavatine A (1) in only four steps from
the known compounds 3,5-dibromo-2-pyrone (17), stannane
aldehyde 32, and stannane ester 36 (or in a longest linear
sequence of 10 steps from commercially available (R)-
pulegone).
Scheme 11. Bioinspired attempts to synthesize incarviatone
A (3).
4
3
Forward synthesis to access incarviatone A (3). Our
synthesis of delavatine A (1) was accomplished from its
putative biosynthetic precursor 2, which had not been reported
in any of the previous syntheses of 1 or the structurally related
12,13a
incarviatone A (3).
We believed access to 2 might also
enable a bioinspired synthesis of 3. As outlined in Scheme 11,
biosynthetically, it has been hypothesized that a double aldol
reaction of aldehyde 2 with ent-cleroindicin F (44), a
7
benzofuranone analogue co-isolated with 3, forms structurally
unique hybrid 45. Finally, an intramolecular oxa-Michael
addition of the C15 hydroxy group of 45 into the cyclohexanone
7
moiety would give rise to incarviatone A (3). On the basis of
4
4
this proposal, we planned to use ()-cleroindicin F (rac-44) or
4
5
silyl ether 46 to convert trialdehyde 2 to incarviatone A (3) via
the proposed biosynthetic pathway. To our surprise, trialdehyde
2
was stable to silica and was isolated in 53% yield over two
steps starting from indane aldehyde 42. ()-Cleroindicin F (rac-
4) was accessed from tyrosol in a known three step sequence
4
45
proceeding via 46. Strategically and for practical reasons, we
investigated the double aldol reaction using racemic ()-
cleroindicin F (rac-44), rather than the optically pure analog.
While we believed that under the aldol reaction conditions, rac-
44 would be in equilibrium with its retro-oxa-Michael product
(
(
i.e., the desilylated derivative of 46), the adduct of 2 and 44
45) could also revert to the corresponding starting materials.
Thus, only the final intramolecular oxa-Michael addition should
drive the equilibrium toward the formation of 3, while all
preceding reactions would be highly reversible. Consequently,
we hypothesized that the stereochemistry of the aldol and
Michael addition products could be funneled to provide the
To circumvent the putative equilibration to the undesired
enolate of 2, we decided to conduct the aldol reaction with a
derivative of trisaldehyde 2, where the acidity of the -
hydrogen is tempered. Toward this end, we decided to pursue
12
stereochemical configuration as found in incarviatone A (3).
Following similar reasoning, we also attempted to initiate the
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Journal of the American Chemical Society
further studies with indane aldehyde 42 bearing two ester
groups. Attempts to conduct the aldol reaction between 42 and
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
()-cleroindicin F (rac-44) under a variety of basic conditions
(see Scheme 11 for selected conditions) primarily resulted in
nonspecific decomposition of 42. Similar results were observed
when silyl ether 46 was employed as the substrate. Mild
conditions for the Reformatsky reaction between 42 and several
model activated organozinc reagents were also explored.
Unfortunately, under all these conditions, we mainly isolated
unreacted indane aldehyde 42. To our delight, when 42 and
magnesium phenolate 47 were subjected to phenolate aldol
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
12
conditions (as described by Lei and co-workers) , we
exclusively isolated diol 48 as a single diastereomer in 74%
yield. It should be noted that the stereochemical configuration
at C15, which was assigned by characterizing a later stage
intermediate, is opposite to the one observed in incarviatone A
(
3). However, we chose to continue with this intermediate with
4
6
the aim of inverting the C15-stereochemistry at a later stage.
With diol 48 in hand, we began exploring a variety of options
to temporarily protect the diol moiety in order to effect
conversion of the esters to the corresponding aldehyde groups.
Toward this end, treatment of diol 48 with 2,2-
dimethoxypropane furnished acetonide 49 (Scheme 12). Use of
4
7
48
both a cyclic siloxane or boronic ester as protecting groups
proved ineffective as these groups were susceptible to the
ensuing reducing conditions. DIBAL-H reduction of 49,
49
followed by Ley-Griffith oxidation gave rise to dialdehyde 50
in 73% yield over 2 steps. Selective deprotection of the diol
moiety in the presence of the primary silyl ether group was
exceedingly challenging and nonspecific decomposition of
dialdehyde 50 was observed under a wide variety of conditions.
During the course of our investigations, we observed formation
of hemiacetal 51, when 50 was treated with a stoichiometric
amount of p-toluenesulfonic acid in dichloromethane as the
solvent. Hemiacetal 51 proved to be very stable under both
acidic and basic conditions, and extensive characterization of
this compound enabled us to establish the stereochemical
configuration at C15 in diol 48. Ultimately, treatment of
dialdehyde 50 with catalytic pyridinium p-toluenesulfonate,
afforded a mixture of acetals 52a and 52b. The acetals
generated in situ were then treated with aqueous hydrogen
chloride solution to give the desired globally deprotected C15-
epimerized triol 53. We believe this epimerization occurred as
the diol moiety was deprotected via o-quinone methide
formation.
A selective protection of triol 53 then furnished silyl ether 54.
Subsequent dearomatization of 54 afforded dienone 55b as an
inseparable mixture of C15 diastereomers in 33% yield, along
with the undesired C19-epimer (55a) in 27% yield. Lei and co-
workers have previously reported the conversion of dienone
5
5b to incarviatone A (3) using tetrabutylammonium fluoride
1
(TBAF). The H NMR of dienone 55b was in full agreement
1
2
with the previously reported data. Our access to 55b thus
constitutes a formal synthesis of 3 that occurs in 10-steps from
known 3,5-dibromo-2-pyrone (17) [or in the longest linear
sequence of 16 steps from commercially available (R)-
pulegone].
CONCLUSION
In summary, in this Article, we have detailed various
synthetic studies toward the divergent syntheses of delavatine
A (1) and incarviatone A (3). Our initial efforts focused on
assembling the indane core that is shared by these natural
products from both symmetric bis-coupled furan 12 and bis-
coupled pyrone 19. In order to circumvent a problematic
deprotonation of a highly acidic α-vinyl hydrogen in methyl
Scheme 12. Completion of the formal synthesis of
incarviatone A (3).
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esters 22 and 23, the cyclopentenyl rings were differentiated by
replacing one of the ester groups with an aldehyde substituent.
This modification was critical to achieving the synthesis of
delavatine A (1) and incarviatone A (3). Key features of our
synthetic route include, (a) sequential Stille–Stille coupling
followed by ring opening with cyanide ion occurring in a single
pot; (b) a cascade sequence involving five transformations (silyl
enol ether formation, E/Z isomerization, 6π electrocyclization,
desilylation, and aromatization) occurring in a single pot; and
Shen, Y. H.; Lin, S.; Tang, J.; Tian, J. M.; Liu, X. H.; Zhang,
1
2
3
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9
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W.-D. Two new alkaloids from Incarvillea mairei var.
grandiflora. Helv. Chim. Acta. 2009, 92, 165. (e) Fu, J. J.; Jin,
H. Z.; Shen, Y. H.; Zhang, W.-D.; Xu, W. Z.; Zeng, Q.; Yan,
S. K. Two novel monoterpene alkaloid dimers from Incarvillea
arguta. Helv. Chim. Acta. 2007, 90, 2151.
(3) (a) Nakamura, M.; Chi, Y. M.; Yan, W. M.; Nakasugi, Y.;
Yoshizawa, T.; Irino, N.; Hashimoto, F.; Kinjo, J.; Nohara, T.;
Sakurada, S. Strong Antinociceptive Effect of Incarvillateine,
a Novel Monoterpene Alkaloid from Incarvillea sinensis. J.
Nat. Prod. 1999, 62, 1293. (b) Nakamura, M.; Kido, K.; Kinjo,
J.; Nohara, T. Antinociceptive substances from Incarvillea
delavayi. Phytochemistry, 2000, 53, 253. (c) Nakamura, M.;
Kido, K.; Kinjo, J.; Nohara, T. Two Novel Actinidine-Type
Monoterpene Alkaloids from Incarvillea delavayi. Chem.
Pharm. Bull. 2000, 48, 1826. (d) Nakamura, M.; Chi, Y. M.;
Yan, W. M.; Yonezawa, A.; Nakasugi, Y.; Yoshizawa, T.;
Hashimoto, F.; Kinjo, J.; Nohara, T.; Sakurada, S. Structure-
(c) the first reported access to the putative biogenetic precursor
(2). While all our efforts to convert the biosynthetic common
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intermediate to incarviatone A (3) were unsuccessful, we
achieved a formal synthesis of 3 from an alternative common
intermediate, thus developing a divergent synthetic route to
access 1 and 3. Overall, our studies culminated in the
development of a symmetry-inspired, concise and modular
approach to 1 and 3, which has set the stage for the synthesis of
a library of structurally related analogues to unravel the
biological properties of these natural products.
Antinociceptive Activity Studies of Incarvillateine,
Monoterpene Alkaloid from Incarvillea sinensis. Planta Med.
001, 67, 114.
a
2
(
4) (a) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Natural product
hybrids as new leads for drug discovery. Angew. Chem. Int. Ed.
ASSOCIATED CONTENT
Supporting Information
2
003, 42, 3996. (b) Chen, C.; Li, X.; Neumann, C. S.; Lo, M.
M.-C.; Schreiber, S. L. Convergent diversity-oriented synthesis
of small-molecule hybrids. Angew. Chem. Int. Ed. 2005, 44,
The Supporting Information is available free of charge on the ACS
Publications website at DOI:
2
249.
(5) Editorial Committee. Chinese Herb; Shanghai Science and
Technology Publisher: Shanghai, 1999, 21, 6435.
6) Zhang, Z.; Yang, F.; Fu, J.-J.; Shen, Y.-H.; He, W.; Zhang, W.-
Experimental details and spectroscopic data (PDF)
(
D. Delavatine A, structurally unusual
a
AUTHOR INFORMATION
Corresponding Author
cyclopenta[de]isoquinoline alkaloid from Incarvillea delavayi.
RSC Adv. 2016, 6, 65885.
(7) Shen, Y.-H.; Ding, Y.; Lu, T.; Li, X.-C.; Tian, J.-M.; Li, H.-L.;
Shan, L.; Ferreira, D.; Khan, I. A.; Zhang, W.-D. incarviatone
A, a structurally unique natural product hybrid with a new
carbon skeleton from Incarvillea delavayi, and its absolute
configuration via calculated electronic circular dichroic
spectra. RSC Adv. 2012, 2, 4175.
8) Carradori, S.; Petzer, J. P. Novel monoamine oxidase
inhibitors : a patent review (2012 – 2014). Expert Opin. Ther.
Patents 2015, 25, 91.
*
rsarpong@berkeley.edu
ORCID
Richmond Sarpong: 0000-0002-0028-6323
(
Notes
The authors declare no competing financial interest.
(
9) (a) Hare, M. L. C. Tyramine oxidase: A new enzyme system in
liver. J. Biochem. 1928, 22, 968. (b) Blaschko, H.; Richter, D.;
Schlossmann, H. The inactivation of adrenaline. J. Physiol.
ACKNOWLEDGMENT
V.P. acknowledges TRDRP for a predoctoral fellowship. C.L.H. is
grateful for a postdoctoral scholarship from the Swiss National
Science Foundation. Financial support for this research was
provided to R.S. by the National Science Foundation (NSF CHE-
1856228). We appreciate and are grateful for the insightful
discussions with Prof. C.-G. Cho (Hanyang University, Korea)
regarding mechanistic studies of the site-selective cross-coupling
chemistry. We thank Dr. Hasan Celik for assistance with NMR
experiments.
1
937, 90, 1. (c) Zeller, E. A. Üeber den enzymatischen Abbau
von Histamin und Diaminen. Helv. Chem. Acta 1938, 21, 880.
(10) For selected literature precedence on role of MAO-A in cancer
progression, see: (a) Liu, F.; Hu, L.; Ma, Y.; Huang, B.; Xiu,
Z.; Zhang, P.; Keyuan, Z.; Tang, X. Increased expression of
monoamine oxidase A is associated with epithelial to
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non-small cell lung cancer. Oncol Lett. 2018, 15, 3245. (b) Wu,
J. B.; Shao, C.; Li, X.; Li, Q.; Hu, P.; Shi, C.; Li, Y.; Chen, Y.-
T.; Yin, F.; Liao, C.-P.; Stiles, B. L.; Zhau, H. E.; Shih, J. C.;
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891. (c) Biswas, P.; Dhabal, S.; Das, P.; Das, P.; Swaroop, S.;
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Role of monoamine oxidase a (MAO-A) in cancer progression
and metastasis. Cancer Cell Microenviron. 2018, 5, 1623.
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oxidase A in advanced prostate cancer. J. Cancer Res. Clin.
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4
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pyrone, see the following: Lee, J.-H.; Park, J.-S.; Cho, C.-G.
Regioselective Synthesis of 3-Alkynyl-5-bromo-2-pyrones via
Pd-Catalyzed Couplings on 3,5-Dibromo-2-pyrone. Org. Lett.
Me
Me
Me
2
002, 4, 1171.
(33) For site-selective Stille coupling of 3,5-dibromo-2-pyrone see,
Kim, W.-S.; Kim, H.-J.; Cho, C.-G. Regioselectivity in the
Stille Coupling Reactions of 3,5-Dibromo-2-pyrone. J. Am.
Chem. Soc. 2003, 125, 14288.
34) For site-selective Suzuki coupling of 3,5-dibromo-2-pyrone
see, Ryu, K.-M.; Gupta, A. K.; Han, J. W.; Oh, C. H.; Cho, C.-
G. Regiocontrolled Suzuki-Miyaura Couplings of 3,5-
Dibromo-2-pyrone. Synlett 2004, 12, 2197.
35) For selected total syntheses employing site-selective cross-
coupling of 3,5-dibromo-2-pyrone, see the following: (a) Shin,
H.-S.; Jung, Y.-G.; Cho, H.-K.; Park, Y.-G.; Cho, C.-G. Total
synthesis of ()-lycorine from the endo-cycloadduct of 3,5-
dibromo-2-pyrone and (E)--borylstyrene. Org. Lett. 2014, 16,
CHO
1) LiAlH4
THF
N
N
2
CO Me
+
2) (COCl)2
(
DMSO, Et N
3
CO2Et
CH Cl
CHO
CHO
2
2
then NH4OAc
3 °C
Me
Me
delavatine A (1)
Me
2
42
(i)
(
(44) (a) Carreño, M. C.; Gonzálex-López, M.; Urbano, A. Oxidative
de-aromatization of para-alkyl phenols into para-
peroxyquinols and para-quinols mediated by oxone as a source
of singlet oxygen. Angew. Chem. Int. Ed. 2006, 45, 2737. (b)
Barradas, S.; Carreño, M. C.; Gonzálex-López, M.; Latorre, A.;
Urbano, A. Direct stereocontrolled synthesis of
polyoxygenated hydrobenzofurans and hydrobenzopyrans
from p-peroxy quinols. Org. Lett. 2007, 9, 5019.
(45) Zhao, K.; Cheng, G.-J.; Yang, H.; Shang, H.; Zhang, X.; Wu,
Y.-D.; Tang, Y. Total synthesis of incarvilleatone and
incarviditone: Insight into their biosynthetic pathways and
structure determination. Org. Lett. 2012, 14, 4878.
5
718. (b) Cho, H.-K.; Lim, H.-Y.; Cho, C.-G. (E)--
Borylstyrene in the Diels–Alder reaction with 3,5-dibromo-2-
pyrone for the synthesis of ()-1-epi-pancratistan and ()-
pancratistan. Org. Lett. 2013, 15, 5806. (c) Jung, Y.-G.; Kang,
H.-U.; Cho, H.-K.; Cho, C.-G. -Silyl styrene as a dienophile
in the cycloaddition with 3,5-dibromo-2-pyrone for the total
synthesis of ()-pancratistatin. Org. Lett. 2011, 13, 5890. (d)
Tam, N. T.; Jung, E.-J.; Cho, C.-G. Intramolecular imino
Diels–Alder approach to the synthesis of the aspidosperma
alkaloid from 3,5-dibromo-2-pyrone. Org. Lett. 2010, 12,
2012. (e) Tam, N. T.; Cho, C.-G. Total synthesis of ()-crinine
via the regioselective Stille coupling and Diels–Alder reaction
of 3,5-dibromo-2-pyrone. Org. Lett. 2008, 10, 601. (f) Chung,
S.-I.; Seo, J.; Cho, C.-G. Tandem Diels–Alder cycloadditions
of 2-pyrone-5-acrylates for the efficient synthesis of novel
tetracyclolactones. J. Org. Chem. 2006, 71, 6701.
(
46) In Lei’s synthesis of incarviatone A (Ref. 12), several strategies
were discussed to invert the C15-stereochemical configuration.
(47) For selected examples that use dichlorodiisopropylsilane as
protecting groups for diols, see, (a) Gazaille, J. A.; Abramite,
J. A.; Sammakia, T. Toward the synthesis of (+)-peloruside A
via an intramolecular vinylogous aldol reaction. Org. Lett.
2
012, 14, 178. (b) Chando, K. M.; Bailey, P. A.; Abramite, J.
A.; Sammakia, T. Regioselective ring opening of di-
isopropylsilylenes derived from 1,3-diols with alkyl lithium
reagents. Org. Lett. 2015, 17, 5196. (c) Hugelshofer, C. L.;
Magauer, T. A divergent approach to the marine diterpenoids
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(+)-dictyoxetane and (+)-dolabellane V. Chem. Eur. J. 2016,
1
2
3
4
5
6
7
8
9
22, 15125. (d) Panek, J. S.; Jain, N. F. Total synthesis of
rutamycin B and oligomycin C. J. Org. Chem. 2001, 66, 2747.
48) Shimada, N.; Urata, S.; Fukuhara, K.; Tsuneda, T.; Makino, K.
(
2
,6-Bis(trifluoromethyl)phenylboronic esters as protective
groups for diols: A protection/deprotection protocol for use
under mild conditions. Org. Lett. 2018, 20, 6064.
(49) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
Preparation and use of tetra-n-butylammonium per-ruthenate
(TBAP reagent) and tetra-n-propylammonium per-ruthenate
(TPAP reagent) as new catalytic oxidants for alcohols. J.
Chem. Soc., Chem. Commun. 1987, 1625. (b) Ley, S. V.;
Norman, J.; Griffith, W. P.; Marsden, S. P.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
–
Tetrapropylammonium perruthenate, Pr
catalytic oxidant for organic synthesis. Synthesis 1994, 1994,
39.
4 4
N RuO , TPAP: A
6
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table of Contents Graphic
symmetry inspired unified strategy
Me
Me
O
H
A
OH
O
Br
3
O
O
A
N
3
3
H
O
OH
5
5
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Br
B
B
CHO
CHO
incarviatone A
Me
Me
delavatine A
1
4
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