Simple, efficient, and modular syntheses of polyene natural products via iterative cross-coupling

Article abstract of DOI:10.1021/ja078129x

This communication describes the discovery of air-stable and highly versatile B-protected haloalkenylboronic acid building blocks for iterative cross-coupling. These reagents enable the total synthesis of polyene natural products with extraordinary levels of simplicity, efficiency, and modularity. Specifically, all-trans-retinal, β-parinaric acid, and one-half of the amphotericin B macrolide skeleton were prepared using only the Suzuki-Miyaura reaction in an iterative manner to bring together collections of simple and readily accessible building blocks. In contrast to their boronic acid counterparts, the intermediate polyenylboronate esters are remarkably stable (to both column purification and storage), which is critical to their successful utilization. Moreover, the reactive boronic acids can be cleanly liberated using very mild aqueous base. These advances have enabled preparation of the longest polyene ever synthesized using the SM reaction. We additionally report, to the best of our knowledge, the first triply metal selective (Zn vs Sn and B) cross-coupling reaction, the first selective cross-coupling with a differentially ligated diboron reagent, and the first cross-couplings between polyenylchlorides and vinylboronic acids. Collectively, these new building blocks and methods can dramatically improve the way polyene natural products and their derivatives are synthesized in the laboratory. Copyright

Full text of DOI:10.1021/ja078129x

Published on Web 12/15/2007
Simple, Efficient, and Modular Syntheses of Polyene Natural Products via
Iterative Cross-Coupling
Suk Joong Lee, Kaitlyn C. Gray, James S. Paek, and Martin D. Burke*
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois at UrbanasChampaign,
Urbana, Illinois 61801
Received October 24, 2007; E-mail: burke@scs.uiuc.edu
Most biologically active small molecules exert their effects via
the perturbation of macromolecular targets.1 There are a few,
however, that operate via higher-order mechanisms that lie outside
this paradigm. The class of “polyene natural products”2 is particu-
larly rich with examples. Perhaps most notable is the antifungal
heptaene macrolide amphotericin B (AmB, 1, Figure 1A), which
self-assembles into a membrane-spanning channel complex with
functional properties reminiscent of protein-based ion channels.3,4
Other polyenes are known to provide structural support for cell
membranes,5 transduce solar energy into mechanical energy,6 serve
as pigments for efficient light harvesting7 and/or species-specific
coloration,8 act as fluorescent probes,9 and/or quench reactive
oxygen species.10 The existence of these natural prototypes suggests
that the potential for small molecules to perform useful functions
in living systems likely extends far beyond that which is currently
utilized. Unfettered synthetic access to these compounds and their
derivatives is paramount for realizing this potential.
boron center.16 Remarkably, this densely functionalized alkene is
stable to silica gel chromatography and storage for at least 1.5 years
on the benchtop under air.
Scheme 1
Moreover, BB1 was found to be a very versatile cross-coupling
partner (Scheme 1). For example, the sp3-hybridized boronate ester
terminus was inert to Buchwald’s anhydrous SM conditions,17 thus
enabling a selective cross-coupling with (E)-styrenylboronic acid
4 to provide dienyl boronate 6 in excellent yield.18,19 A Stille
coupling between BB1 and vinyl stannane 7 was similarly efficient,
yielding butadienyl boronate 8. Moreover, a Heck coupling with
methyl acrylate 9 yielded the unsaturated methyl ester 10 as a single
regio- and stereoisomer.
Figure 1. (A) Channel-forming natural product amphotericin B. (B) Series
of B-protected haloalkenylboronic acid building blocks for polyene synthesis.
The synthesis of polyenes is made challenging by the sensitivity
of conjugated double bond frameworks to light, oxygen, and many
common synthetic reagents, especially protic and Lewis acids.
Controlling stereochemistry during the formation of each double
bond is also a critical issue. Syntheses based on palladium-mediated
cross-coupling are attractive due to the mild, nonacidic, and stereo-
specific nature of these methods.11,12 Among these, the Suzuki-
Miyaura (SM) reaction11d stands out due to its use of nontoxic
boronic acid reagents and well-precedented functional group
compatibility. However, polyenylboronic acids are notoriously
unstable,13 which precludes their general utilization. We recently
developed a simple and flexible strategy for making small molecules
involving the iterative cross-coupling of haloboronic acids protected
as the corresponding pyramidalized N-methyliminodiacetic acid
(MIDA, 2) adducts.14 We herein report a novel collection of
B-protected haloalkenylboronic acid building blocks BB1-BB3
(Figure 1B) that are strikingly stable to purification and storage
and highly selective toward a wide range of cross-coupling reac-
tions. This stability is maintained in the resulting polyenyl MIDA
boronate ester intermediates, thereby enabling the simple, efficient,
and modular construction of a variety of polyene natural products
with higher-order functions.
A series of novel bismetalated lynchpin-type reagents12 were also
created. Specifically, Sonogashira coupling between BB1 and TMS-
acetylene 11 generated hetero-bismetalated enyne 12. Although
Miyaura borylations20 with (E)-1,2-disubstituted vinyl halides are
challenging,20b we found that ligand 5a20c enabled the smooth
conversion of BB1 into the novel bisborylated olefin 14 (an X-ray
structure of 14 is shown in Scheme 2). Like BB1, 14 is a column-
and shelf-stable crystalline solid (stable under air for at least 1.5
years). Finally, Negishi cross-coupling between BB1 and the hetero-
bismetalated vinylzinc reagent 1512d yielded lynchpin 16 in a novel
triply metal selective (Zn vs Sn and B) reaction.
With the goal of developing robust, shelf-stable building blocks
for polyene synthesis, we designed di- and trienyl halides BB2 and
BB3 as the corresponding vinyl chlorides.21 A direct route to the
targeted dienylchloride BB2 was envisioned via a concomitant
metal- and halogen-selective SM cross-coupling between bisbory-
lated olefin 14 and (E)-1-chloro-2-iodoethylene 1722 (Scheme 2).
Due to the absence of a boron p-orbital,14a we hypothesized that
the sp3-hybridized MIDA boronate terminus of 14 would be
unreactive relative to the sp2-hybridized pinacol boronic ester. In
fact, as shown in Scheme 2, single-crystal X-ray diffraction analysis
confirmed the distinct hybridization states of the two boron termini
of 14, and a halogen- and boron-selective cross-coupling with 17
yielded the targeted bifunctional diene BB2 as a column- and shelf-
The first targeted building block containing a single double bond
(BB1) was prepared via complexation of (E)-(2-bromoethenyl)-
dibromoborane 315 with MIDA (Scheme 1). This reaction was
performed on >20 g scale (75 mmol) to yield the desired
bifunctional olefin BB1 as a crystalline, free-flowing solid. X-ray
analysis confirmed unambiguously the pyramidalized nature of the
9
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C O M M U N I C A T I O N S
Scheme 2
Scheme 4
stable crystalline solid. This novel type of selective cross-coupling
with a differentially ligated diboron reagent may prove to be
generally useful.23
The final targeted polyene building block containing three double
bonds (BB3) was prepared via another metal-12i and halogen-
selective cross-coupling between bisfunctionalized reagents 16 and
17 (Scheme 3). Despite containing a potentially sensitive triene
moiety, BB3 is also both column- and shelf-stable.
Another interesting polyene, â-parinaric acid 27, has been used
for more than three decades as a fluorescent probe for membrane
properties.9,28 In addition, related tetraenoic acids demonstrate
remarkable aggregation behaviors,29 including the formation of
antipodal chiral aggregates from a single enantiomer.29b The utility
of 27 and/or its analogues would benefit from more efficient and
modular synthetic access to this class of compounds.30
In this vein, the B-protected chlorodienylboronic acid BB2 was
employed in a modular, three-step synthesis of â-parinaric acid from
readily available starting materials (Scheme 5). Specifically, using
a modification of the newly identified conditions for polyenylchlo-
ride cross-coupling, a selective pairing between the bifunctional
dienylchloride BB2 and (E)-1-butenylboronic acid 2416 yielded the
column-stable all-trans trienyl boronate 25. The B-deprotection of
25 was achieved under mild aqueous basic conditions, and
subsequent cross-coupling with vinyl iodide 2616 yielded â-parinaric
acid as a fluorescent solid.
Although the strength of C-Cl bonds can make the building
blocks that contain them quite stable, it also makes these reagents
relatively unreactive toward cross-coupling.24 Moreover, the struc-
tural and stereochemical labilities of polyene frameworks preclude
the use of forcing conditions. As a result, to the best of our
knowledge, SM cross-coupling between a polyenylchloride and a
vinylboronic acid has never been previously reported.25 To over-
come this challenge, we extensively surveyed a variety of catalysts
with different base and solvent combinations for cross-coupling
between BB3 and model substrate (E)-1-pentenylboronic acid 18.
Ultimately, it was determined that the use of Pd(OAc)2/phosphine
5b17 and Cs2CO3 in THF at 45 °C gave good yields of tetraenyl
MIDA boronate 19 (Scheme 3).18
Scheme 3
Scheme 5
With the three targeted building blocks BB1-BB3 in hand and
their potential for selective cross-couplings verified, we explored
the utility of these new reagents in the context of total syntheses
of polyene natural products that perform higher-order functions.
For example, the carotenoid all-trans-retinal (23) has the ability to
transduce solar energy into mechanical energy and is a critical
functional component of the light-driven proton pump found in
Halobacteria and the photoreception machinery utilized by most
animals.6 Structure/function studies with this natural product have
unique potential to enable the understanding of these phenomena
at the molecular level.6c
The B-protected haloalkenylboronic acid BB1 was utilized in a
highly modular three-step synthesis of retinal from known starting
materials (Scheme 4).26 Specifically, the selective SM coupling be-
tween BB1 and trienylboronic acid 2026d yielded the tetraenyl MIDA
boronate 21. Notably, although the instability of 20 precludes its
isolation in concentrated form,26d tetraenyl MIDA boronate 21 was
isolated via column chromatography as a crystalline solid that can
be stored refrigerated for at least 1 month without decomposition.
A key feature of the MIDA protective group is its capacity for
removal under mild, aqueous basic conditions.14a Given the sensitive
nature of polyenylboronic acids,13 the B-deprotection of intermediate
21 presented a rigorous test for this methodology. In the event,
this deprotection proceeded smoothly, and subsequent SM coupling
of the resulting solution of crude boronic acid with the known
â-bromo enal 2227 succeeded in generating the targeted all-trans-
retinal.
As a final example, the polyene macrolide AmB3 (Figure 1A)
represents a potential prototype for small molecules that replicate
the functions of protein-based ion channels.31 An efficient and
flexible total synthesis of AmB stands to enable the first systematic
dissection of the structure/function relationships that underlie this
small molecule-based ion channel activity.4
In contrast to strategies based on lynchpin-type reagents,12 the
cross-coupling of B-protected haloboronic acids has the theoretical
capacity for limitless iteration.14 Harnessing this potential, the
synthesis of one-half of the AmB macrolide skeleton via recursive
SM coupling, has been achieved (Scheme 6). Specifically, boronic
acid 18 was joined with BB1 to generate dienylboronate 28. A
subsequent series of B-deprotection and coupling of the resulting
dienylboronic acid with trienylchloride BB3 yielded column-stable
pentaenyl MIDA boronate 29. Finally, taking advantage of the
recent discovery in our laboratories that MIDA boronates can be
used directly as surrogates for boronic acids under aqueous SM
conditions,32 a one-pot B-deprotection and cross-coupling with
dienylchloride 3016 yielded one-half of the AmB skeleton 31. To
the best of our knowledge, this is the longest polyene ever
synthesized using the SM reaction. This pathway may ultimately
provide the foundation for an efficient and flexible total synthesis
of this notoriously challenging natural product.33
As demonstrated herein, B-protected haloalkenylboronic acid
building blocks such as BB1-BB3 have potential for broad utility
in the context of total syntheses of polyene natural products. The
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C O M M U N I C A T I O N S
Scheme 6
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(16) See Supporting Information for synthesis and characterization.
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(18) The same yield was observed whether or not this reaction was set up
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iterative cross-coupling approach is particularly well-suited for
making these types of structures due to the ubiquity of Csp2-Csp2
bonds, the mild and stereospecific nature of the coupling methods,
and the exceptional stability of the intermediate polyenyl MIDA
boronate esters. This simple, efficient, and modular strategy stands
to enable the more effective study and widespread utilization of
this class of highly functional small molecules.
(19) Dienyl boronate 6 was stable to storage for at least 2 weeks on the benchtop
under air both as a solid and as a solution in DMSO-d6.
(20) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508-
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(21) Csp2-Cl bonds tend to be much stronger than their Br and I counterparts,
which we expect to impact favorably on the stability of polyenylhalide
building blocks. For example, the bond dissociation energies for Ph-X
) 96, 81, and 65 kcal/mol for X ) Cl, Br, and I, respectively: Grushin,
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(23) Steric-based selective couplings with bispinacolboronic esters are
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Acknowledgment. Dedicated to Prof. P. Beak with deepest
respect and gratitude for his invaluable advocacy and mentorship,
and for partial funding for S.J.L. We also gratefully acknowledge
A.D. Melhado for preliminary studies towards 30, the NIH
(GM080436), the Dreyfus Foundation, and UIUC for funding,
Sigma-Aldrich for a gift of Pd(PPh3)4, Bristol-Myers Squibb and
Xenobe for gifts of AmB, and S. Wilson for X-ray analysis.
(24) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
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also extremely rare. For one example, see: Organ, M. G.; Cooper, J. T.;
Rogers, L. R.; Soleymanzadeh, F.; Paul, T. J. Org. Chem. 2000, 65, 7959-
7970.
Supporting Information Available: Procedures, spectral data, and
spectra for all new compounds. X-ray crystallographic data (cif) for
BB1 and 14. This material is available free of charge via the Internet
at http://pubs.acs.org.
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