Total synthesis of sparstolonin B via a palladium-catalyzed aldehyde α-arylation

Article abstract of DOI:10.1016/j.tet.2018.05.012

A concise and convergent total synthesis of sparstolonin B was developed. A palladium-catalyzed aldehyde α-arylation was utilized to construct the carbon skeleton of the natural product. A subsequent simple one-pot procedure effected global deprotection and closure of the final two rings via an unusual autoredox mechanism for the conversion of a bis-hydroquinone intermediate to the natural product. The 6 step synthetic sequence was realized in 18% overall yield.

Full text of DOI:10.1016/j.tet.2018.05.012

Accepted Manuscript
Total synthesis of sparstolonin B via a palladium-catalyzed aldehyde α-arylation
Dalton Kim, Aaron Nash, Jef De Brabander, Jr., Uttam K. Tambar
PII:
S0040-4020(18)30527-1
10.1016/j.tet.2018.05.012
TET 29519
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 April 2018
Accepted Date: 3 May 2018
Please cite this article as: Kim D, Nash A, De Brabander Jr. J, Tambar UK, Total synthesis of
sparstolonin B via a palladium-catalyzed aldehyde α-arylation, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.05.012.
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Total synthesis of sparstolonin B via a
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palladium-catalyzed aldehyde α-arylation
Dalton Kim, Aaron Nash, Jef De Brabander Jr., and Uttam K. Tambar*

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Tetrahedron Letters
journal homepage: www.elsevier.com
Total synthesis of sparstolonin B via a palladium-catalyzed aldehyde α-arylation
Dalton Kima, Aaron Nashb, Jef De Brabander Jr.b, and Uttam K. Tambarb
aDepartment of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, United States
bDepartment of Biochemistry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9038, United States.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A concise and convergent total synthesis of sparstolonin B was developed. A palladium-
catalyzed aldehyde -arylation was utilized to construct the carbon skeleton of the natural
product. A subsequent simple one-pot procedure effected global deprotection and closure of the
final two rings via an unusual autoredox mechanism for the conversion of a bis-hydroquinone
intermediate to the natural product. The 6 step synthetic sequence was realized in 18% overall
yield.
Available online
Keywords:
palladium catalysis
arylation
2009 Elsevier Ltd. All rights reserved
.
total synthesis
autoredox
cross-coupling
1. Introduction
convergent total synthesis of sparstolonin B that would facilitate
the preparation of analogs for medicinal chemistry studies to
optimize the various biological activities of the natural product.
We envisioned the use of a palladium-catalyzed carbon-carbon
bond forming reaction to facilitate the efficient assembly of the
core structure of the natural product.
Transition metal catalysis has fundamentally transformed the
total synthesis of biologically active natural products.1
Palladium-catalyzed cross-coupling chemistry is especially
useful for the formation of carbon-carbon bonds in complex
molecular settings.2 We became interested in the synthesis of the
natural product sparstolonin B because of its unique biological
profile and the potential to assemble its carbon skeleton via
palladium-catalyzed carbon-carbon bond forming chemistry.
Herein, we describe an efficient and convergent total synthesis
of sparstolonin B that features a palladium-catalyzed aldehyde
-
arylation to construct the carbon skeleton of the natural product.
A one-pot procedure was devised to effect global deprotection
and dual cyclization to yield sparstolonin B. Total synthesis of
the natural product was achieved in 18% overall yield in 6 steps
Since the isolation of sparstolonin B in 2011 from the Chinese
herb Sparganium stoloniferum,3 the polyphenolic isocoumarin
has been shown to demonstrate a diverse array of biological
activities.3,4 The natural product’s earliest recognized biological
activity was selective antagonism of toll-like receptors (TLRs) 2
and 4.3 Given the crucial role of TLRs in innate immunity,4a
antagonists of these proteins are attractive candidates for the
treatment of chronic inflammatory diseases,4b as well as severe
sepsis.4c Protective effects of sparstolonin B have already been
demonstrated in septic mice.4d Sparstolonin B has also been
shown to attenuate early liver inflammation in a mouse model of
non-alcoholic steatohepatitis.4e More recently, sparstolonin B was
shown to inhibit HIV-1 transcription by a novel mechanism4f and
induce apoptosis in neuroblastoma cells.4g These diverse and
valuable biological activities have rendered sparstolonin B an
attractive synthetic target.5,6
from
inexpensive
and
commercially available
2,5-
dimethoxybenzoic acid.
2. Results
Our retrosynthetic analysis of sparstolonin B (1) commenced
with a disconnection of the diaryl ether to furnish hydroquinone
2, which could readily be prepared by global demethylation of 3
(Figure 1). We hypothesized that 4-arylisocoumarin 3 could be
derived from the key –arylation of aldehyde 5 with aryl iodide
6. Fragments 5 and 6 could in turn be accessed from
commercially available starting materials.
The first total synthesis of sparstolonin B was reported by
Wang and co-workers in 2015.5 Tang et al. reported an
alternative synthesis in 2017 featuring milder reaction
conditions.6 We were interested in devising a concise and
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
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T
I
er
P
ao
T
2002
Pd(OAc)2 (5 mol%)
Br
O
P(t-Bu)3 (10 mol%)
+
O
Cs2CO3 (1.2 equiv)
Dioxane, 110 ºC
R
R
9
10
Lessi 2011
11
(53%)
Pd2(dba)3 (2.5 mol%)
(t-Bu)3PHBF4 (10 mol%)
+
Br
OMe
13
KHCO3 (2 equiv)
H2O, PTS (15 wt%)
100 ºC
O
O
O
O
12
16
(41%)
O
OMe
OH
OMe
Figure 1. Retrosynthetic analysis of sparstolonin B (1)
O
14
O
15
The synthesis of aldehyde 5 is depicted in Figure 2.
Commercial (2,5-dimethoxy)phenylacetic acid (7) was
quantitatively reduced to aryl alcohol 8 by an excess of lithium
aluminum hydride in THF at 0 °C. Treatment of the resultant
alcohol with Dess-Martin periodinane7 in CH2Cl2 yielded the
desired aldehyde 5 in 83% yield.
Figure 3. Previous protocols for -arylation of aldehydes.
Before attempting the palladium-catalyzed -arylation of
aldehyde 5 with aryl iodide 6, we devised model substrate 2-
halobenzoate 17 to test the viability of the proposed key reaction
(Table 1). We examined a series of reaction conditions, with
various solvents, bases, palladium sources, and ligands. To our
delight, we obtained the desired 4-arylisocoumarin 20 in 65%
yield in the presence of Cs2CO3 as the base, Pd(OAc)2 as the
palladium source, t-Bu3PHBF4 as the ligand precursor, and
dioxane as the reaction medium. This reaction proceeds through
initial formation of
-arylation product 18, followed by
enolization to ester 19 and subsequent cyclization to 4-
arylisocoumarin 20.
Figure 2. Syntheses of aldehyde 5.
The proposed palladium-catalyzed -arylation of aldehyde 5
with aryl iodide 6 is the key transformation in our synthesis of
sparstolonin B, effectively assembling the carbon backbone of
the natural product. Traditionally, the -arylation of aldehydes
has been a challenging transformation due to competing aldol
reactions under basic conditions. An efficient protocol for the
palladium-catalyzed -arylation of aldehydes was reported by
Terao in 2002 (Figure 3).8 Various aldehydes 9 were coupled
with bromobenzene 10 to furnish -arylated aldehydes 11. Soon
thereafter, a similar procedure was developed by Lessi for the
direct synthesis of 4-arylisocoumarins 16 from 2-
arylacetaldehydes such as 12 and methyl 2-halobenzoates such as
13.9 This transformation presumably proceeds through a tandem
-arylation/enol lactonization (12 + 13 -> 14 -> 15 -> 16).
Table 1. Optimization of tandem palladium-catalyzed aldehyde α-
arylation / coumarin formation. PTS = Polyoxyethylene- -
Tocopheryl Sebacate.

3
With the generation of model 4-arylisocoumarin 20 in hand,
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we pursued the synthesis of 2-iodobenzoate 6 for the total
synthesis of sparstolonin B (Figure 4). Commercially available
2,5-dimethoxybenzoic acid (21) was converted to benzamide 22
to facilitate installation of the iodide by directed ortho
metalation.10 Refluxing benzoic acid 21 in thionyl chloride
yielded the corresponding acid chloride, which upon exposure to
diethylamine rendered benzamide 22 in 88% overall yield.
Directed ortho lithiation followed by exposure to 1,2-
diiodoethane yielded iodobenzamide 6 in 70% yield.
Next, we attempted the key palladium-catalyzed aldehyde
-
arylation and subsequent cyclization. Gratifyingly, the coupling
of aldehyde 5 and 2-iodobenzamide 6 yielded an equilibrating
mixture of -arylated aldehyde 23 and enol 24. While these
intermediates did not undergo spontaneous cyclization under the
palladium-catalyzed conditions, treatment with refluxing glacial
acetic acid generated the desired 4-arylisocoumarin 3 in 78%
yield.
We attempted to perform a global removal of the four methyl
protecting groups of tricycle 3 with refluxing HBr and glacial
acetic acid under an atmosphere of oxygen. Surprisingly, these
acidic conditions resulted in the formation of the desired natural
product sparstolonin B (1).
Figure 5. Proposed mechanism for the conversion of tricycle 3 to
sparstolonin B (1).
In conclusion, we have developed a 6 step synthesis of
sparstolonin from commercially available 2,5-
B
dimethoxybenzoic acid (21) in 18% overall yield. Key steps in
our approach include a palladium-catalyzed aldehyde -arylation
to assemble the core structure 3 and an unusual autoredox
mechanism for the conversion of bis-hydroquinone 25 to the
natural product. The application of this flexible synthetic strategy
to the synthesis of unnatural analogs of sparstolonin B and the
exploration of biological activity for these structures are on-going
interests in our group.
Acknowledgments
Financial support was provided by W. W. Caruth, Jr.
Endowed Scholarship, Welch Foundation (I-1748), National
Institutes of Health (R01GM102604), National Science
Foundation (1150875), Sloan Research Fellowship, and UTSW
Quantitative and Physical Sciences Summer Undergraduate
Research Fellowship (QP-SURF).
Figure 4. Completion of total synthesis of sparstolonin B.
References and notes
To account for the conversion of 4-arylisocoumarin 3 to
sparstolonin B (1), we propose the following mechanism (Figure
5). Initial global deprotection of the four methoxy groups results
in the formation of bis-hydroquinone 25. Mono-oxidation in the
presence of oxygen yields the mixed hydroquinone-quinone
intermediate 26. Nucelophilic attack of the hydroquinone to the
electrophilic quinone forms tetracycle 27, and dehydration
furnishes oxocarbenium ion 28. Reduction of intermediate 28
with concomitant oxidation of another equivalent of 25 to 26
generates tetracycle 29 in an autoredox process.11 Subsequent
tautomerization of intermediate 29 leads to the formation of
sparstolonin B (1).
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Highlights
• concise and convergent total synthesis of sparstolonin B
• palladium-catalyzed aldehyde -arylation constructs the carbon skeleton of natural
product
• unusual autoredox mechanism accounts for conversion of a bis-hydroquinone
intermediate to natural product
• 6 step synthetic sequence was realized in 18% overall yield