Total synthesis of synechoxanthin through iterative cross-coupling

Article abstract of DOI:10.1002/anie.201102688

The choice is yours: The first total synthesis of the antioxidant carotenoid synechoxanthin was achieved through a novel iterative cross-coupling approach in which the polarity of the bifunctional building blocks is reversed to match the preferred polarity for C-C bond formation (see scheme). The convergent, stereocontrolled, and flexible nature of this synthesis enables systematic studies of the biological activities of this natural product.

Full text of DOI:10.1002/anie.201102688

Communications
DOI: 10.1002/anie.201102688
Natural Product Synthesis
Total Synthesis of Synechoxanthin through Iterative Cross-Coupling**
Seiko Fujii, Stephanie Y. Chang, and Martin D. Burke*
Deficiencies of human proteins that protect cells from lipid
peroxidation have been linked to many prevalent diseases,
including atherosclerosis, neurodegenerative disorders, and
cancer.[1] Remarkably, some species of bacteria have the
ability to thrive in environments of extreme oxidative stress,
which has been attributed to the presence of specialized
carotenoids in their membranes.[2] These natural products
might therefore serve as valuable prototypes for understand-
ing and optimizing the capacity for small molecules to serve as
antilipoperoxidants in human cells. In this vein, a structurally
unique aromatic dicarboxylate carotenoid, synechoxanthin
(1), was isolated in 2008 from the exceptionally reactive
oxygen species (ROS)-resistant cyanobacterium Synechococ-
cus sp. strain PCC 7002.[3] Knocking out 1 through genetic
manipulation of its biosynthetic machinery substantially
diminishes this ROS resistance.[4] With the ultimate goal of
understanding and optimizing the promising antioxidant
activity of this natural product, we herein report its first
total synthesis. This synthesis was achieved using only one
reaction iteratively to assemble three simple and readily
accessible building blocks in a completely stereocontrolled
fashion. This route was enabled by a novel iterative cross-
coupling (ICC) strategy, in which the polarity of the bifunc-
tional building blocks is reversed to match the preferred
polarity for cross-coupling. Moreover, a final one-pot boro-
nate hydrolysis/two-directional double cross-coupling
sequence enabled rapid assembly of the C2-symmetric car-
otenoid core in a highly convergent fashion. The efficient,
completely stereocontrolled, and inherently flexible nature of
this building block-based pathway has opened the door to
systematic studies of the antioxidant functions of 1 and its
derivatives.
when combined with a highly optimized post-olefination
isomerization protocol specifically tailored for each carote-
noid target.[5] However, if the goal is to gain unfettered access
to structural derivatives, then this approach is quite limited.
The use of only stereospecific cross-coupling reactions to
assemble stereochemically defined polyene building blocks
represents an attractive alternative.[6] Ideally, the building
blocks and intermediates in such a pathway would be non-
toxic, stable, and readily accessible. With these goals in mind,
we recently introduced a simple, efficient, and flexible
strategy for small-molecule synthesis that involves the ICC
of haloboronic acids (Figure 1). In our original approach,
Figure 1. A) ICC with haloboronic acids in which the MIDA boronate
serves as a masked boronic acid. B) A novel ICC strategy in which the
polarity of the bifunctional building blocks is reversed and the MIDA
boronate serves as a masked halide.
nucleophilic sp2(B)-hybridized boronic acids are coupled to
the halide termini of bifunctional building blocks having their
boronic acid termini masked as the corresponding sp3(B)-
hybridized N-methyliminodiacetic acid (MIDA) boronates
(Figure 1A).[7,8]
The highly complex nonaene framework found in 1 and
many other C2-symmetric carotenoids represents a substantial
structural and stereochemical challenge. The most commonly
employed strategy to access this motif involves a double
Wittig olefination between a C10-trienedialdehyde and two
C15-polyenylphosphonate salts, which typically leads to mix-
tures of olefin stereoisomers.[5] This approach can be effective
In the process of exploring the application of this strategy
to a synthesis of 1, we recognized an opportunity to achieve
optimal intermediates for cross-coupling by alternatively
starting with an electrophilic organohalide and reversing the
polarity of the bifunctional building blocks employed in the
ICC sequence (Figure 1B).[9] Specifically, 1 contains electron-
withdrawing carboxylic acids at its termini. Electron-deficient
boranes are, in general, poor cross-coupling partners due to
an increased propensity for protodeboronation and homo-
coupling.[10] In contrast, electron-deficient halides tend to be
excellent intermediates, often cross-coupling under milder
conditions and/or in higher yields than their electron-neutral
and -rich counterparts.[11,12] Guided by this logic, we retro-
synthesized 1 into three simple building blocks, 2,[13] 3, and
[*] S. Fujii, S. Y. Chang, Prof. M. D. Burke
Howard Hughes Medical Institute, Department of Chemistry
University of Illinois at Urbana-Champaign
600 S. Mathews Ave, Urbana, IL 61801 (USA)
Fax: (+1)217-244-8024
E-mail: burke@scs.uiuc.edu
Homepage: http://www.scs.illinois.edu/burke
[**] We gratefully acknowledge the NIH (GM090153) for funding.
M.D.B. is an Early Career Scientist of the Howard Hughes Medical
Institute. We also acknowledge Kaitlyn Gray for preliminary studies
of the transformation of MIDA boronates into vinyliodides.
4
[14] using only Suzuki–Miyaura (SM) transforms that involve
activated, electron-deficient halide intermediates (Scheme 1).
This plan required a new type of bifunctional building
block containing a nucleophilic boron terminus and a
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102688.
7862
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Angew. Chem. Int. Ed. 2011, 50, 7862 –7864

Scheme 1. Retrosynthesis of 1 by ICC.
protected electrophilic halide. Mild and general methods for
halide masking are scarce,[7f,15] but it is known that nucleo-
philic vinylboronic acids can be transformed into electrophilic
iodides with retention of stereochemistry.[16] Thus, we pursued
the development of bifunctional building block 3 in which the
MIDA boronate motif serves a new role as a masked
electrophile.
The capacity to carry MIDA boronates through multiple
chemical transformations[7c] enabled facile preparation of 3
(Scheme 2). Specifically, transesterification of 5[7g] afforded
Scheme 3. Synthesis of key intermediate 11 by ICC. dppf = 1,1’-
bis(diphenylphosphino)ferrocene.
electron-deficient aryl iodide 2 with the sp2(B)-hybridized
terminus of bisborylated building block 3[17] afforded 9 in very
good yield as a single stereoisomer. MIDA boronate 9 was
then halodeborylated in a single-pot operation using NaOMe
and I2 to afford 10 in quantitative yield and with complete
retention of stereochemistry. This transformation unmasked a
new electron-deficient halide for a second iteration of SM
coupling. Specifically, activated dienyl iodide 10 was smoothly
coupled with another equivalent of 3 to afford stereochem-
ically pure tetraenyl MIDA boronate 11. Both of the complex
polyenyl MIDA boronates 9 and 11 proved to be stable
crystalline solids that are compatible with standard silica gel
chromatography.
Finally, harnessing the capacity of the versatile MIDA
boronate motif to also represent a masked boronic acid which
can be released and coupled in situ and thereby obviate the
isolation of unstable intermediates,[7d] a highly convergent and
stereospecific assembly of the complete polyene framework
of 1 was achieved (Scheme 4). Specifically, an in situ MIDA
boronate hydrolysis/two-directional double cross-coupling
sequence between two equivalents of 11 and electronically
activated trans-1-iodo-2-bromoethylene 4 yielded synechox-
anthin bismethylester 12 in an overall very efficient one-pot
Scheme 2. Synthesis of bisborylated diene 3.
pinacol ester 6, and trisubstituted olefin 7[7e] underwent
stereoretentive iododestannylation to afford vinyl iodide 8.
Subsequent Stille coupling between 6 and 8 afforded 3 as a
stable, crystalline solid that can be stored for more than six
months without any noticeable decomposition. Distinct
hybridization states (sp2 and sp3) for the two boron atoms in
3 were confirmed unambiguously via single crystal X-ray
analysis (Scheme 2).
With these building blocks in hand, an efficient, polarity-
reversed ICC-based synthesis of key intermediate 11 was
achieved (Scheme 3). Specifically, SM coupling of activated,
Scheme 4. Highly convergent assembly of synechoxanthin (1).
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Communications
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longest polyene prepared to date through SM coupling.
Concomitant hydrolysis of the terminal methyl esters com-
pleted the first total synthesis of 1.
The strategic advances achieved with this pathway have
substantially expanded the power and flexibility of ICC as an
increasingly general platform for small-molecule synthesis.
Moreover, because this building block-based synthesis of 1 is
efficient, convergent, completely stereocontrolled, modular,
and involves stable intermediates, it stands to enable system-
atic dissection of the structure/function relationships that
underlie the very promising activities of this natural antiox-
idant.
Received: April 19, 2011
Published online: June 16, 2011
Keywords: antioxidants · boronates · iterative cross-coupling ·
.
synechoxanthin · total synthesis
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