Cyclization strategies to polyenes using Pd(II)-catalyzed couplings of pinacol vinylboronates

Article abstract of DOI:10.1021/ol3020623

As a complement to Pd(0)-catalyzed cyclizations, seven Pd(II)-catalyzed cyclization strategies are reported. α,ω-Diynes are selectively hydroborated to bis(boronate esters), which cyclize under Pd(II)-catalysis producing a diverse array of small, medium,

Full text of DOI:10.1021/ol3020623

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4282–4285
Cyclization Strategies to Polyenes Using
Pd(II)-Catalyzed Couplings of Pinacol
Vinylboronates
Robert G. Iafe, Daniel G. Chan, Jonathan L. Kuo, Byron A. Boon, Darius J. Faizi,
Tomomi Saga, Jonathan W. Turner, and Craig A. Merlic*
Department of Chemistry and Biochemistry, University of California, Los Angeles,
California 90095-1569, United States
merlic@chem.ucla.edu
Received July 25, 2012
ABSTRACT
As a complement to Pd(0)-catalyzed cyclizations, seven Pd(II)-catalyzed cyclization strategies are reported. R,ω-Diynes are selectively hydroborated
to bis(boronate esters), which cyclize under Pd(II)-catalysis producing a diverse array of small, medium, and macrocyclic polyenes with controlled
E,E, Z,Z, or E,Z stereochemistry. Various functional groups are tolerated including aryl bromides, and applications are illustrated.
Palladium-catalyzed cross-coupling reactions are ex-
ceptionally powerful for the construction of a remark-
able diversity of molecules.1 Widely employed for in-
termolecular cross-coupling, this chemistry is extremely
effective for intramolecular cyclizations.2 In particular,
macrocyclizations using Stille and Suzuki protocols are
potent strategies for the synthesis of complex macro-
lides.3 However, a significant strategic disadvantage for
cyclizations is the numerous synthetic steps required to
set up the differentiated end groups with electro- and
nucleophilic components. Several other detrimental
factors associated with these processes are (i) potentially
toxic halogenated substrates, (ii) air-free conditions
required for Pd(0) reactions, and (iii) elevated reaction
temperatures. In addition, some recently developed
methods require expensive specialty phosphine ligands
for the key oxidative addition step.4
(1) For reviews, see: (a) Li, J. J.; Gribble, G. W. Palladium in
Heterocyclic Chemistry; Pergamon: New York, 2006. (b) Tsuji, J. Palla-
dium in Organic Synthesis; Springer: New York, 2010. (c) Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 2004. (d) Inuki, S. Total Synthesis of Bioactive Natural
Products by Palladium-Catalyzed Domino Cyclization of Allenes and
Related Compounds; Springer: New York, 2011. (e) Tsuji, J. Palladium
Reagents and Catalysts: New Perspectives for the 21st Century; Wiley:
Hoboken, NJ, 2004.
(2) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442.
(4) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
6338.
(5) For examples of simple Pd-catalyzed oxidative dimerizations of
boron substrates, rather than cross-couplings, see: (a) Weber, M.; Singh,
(3) For recent examples in complex natural product synthesis, see: (a)
Chen, Q.; Schweitzer, D.; Kane, J.; Davisson, V. J.; Helquist, P. J. Org.
Chem. 2011, 76, 5157. (b) Ghidu, V. P.; Wang, J.; Wu, B.; Liu, Q.;
Jacobs, A.; Marnett, L. J.; Sulikowski, G. A. J. Org. Chem. 2008, 73,
4949. (c) Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Am. Chem. Soc.
2008, 130, 2722. (d) Nicolaou, K. C.; Nold, A. L.; Milburn, R. R.;
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Ed. 2006, 45, 2912. (f) Molander, G. A.; Dehmel, F. J. Am. Chem. Soc.
2004, 126, 10313. (g) Song, H. Y.; Joo, J. M.; Kang, J. W.; Kim, D. S.;
Jung, C. K.; Kwak, H. S.; Park, J. H.; Lee, E.; Hong, C. Y.; Jeong, S.;
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F. V.; Vieira, A. S.; Stefani, H. A.; Paixao, M. W. Tetrahedron Lett. 2009,
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Synlett 2006, 7, 1027. (c) Oh, C. H.; Reddy, V. R. Tetrahedron Lett. 2004,
45, 5221. (d) Punna, S.; Dıaz, D. D.; Finn, M. G. Synlett 2004, 13, 2351.
(e) Basu, B.; Das, P.; Bhuiyan, M. M. H.; Jha, S. Tetrahedron Lett. 2004,
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Jung, K. W. Tetrahedron Lett. 2002, 43, 7899. (h) Lei, A. W.; Zhang,
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r
10.1021/ol3020623
Published on Web 08/06/2012
2012 American Chemical Society

An approach obviating these problems is oxidative
cross-coupling,5 thus bypassing the high-cost oxidative
addition step typical of Pd(0) coupling. In contrast with
a Pd(0)-catalyzed coupling cycle, a Pd(II)-catalyzed oxida-
tive cross-coupling cycle only requires nucleophilic part-
ners, thus simplifying substrate synthesis. A key cycle
component, although extrinsic to the bond forming steps,
is reoxidation of the Pd(0) complex after reductive elim-
ination. Other key features include elimination of the
problematicaspectsofPd(0) processessuchashalogenated
substrates, air-free conditions, elevated temperatures, and
expensive ligands. These features make a Pd(II)-catalyzed
strategy a process chemistry and green chemistry alterna-
tive to Pd(0) cross-coupling. Recently, oxidative cross-
couplings of alkyl-, alkenyl-, alkynyl-, and aryl-organo-
metallic and even hydrocarbon substrates have been
reported.6 The major challenge is that selective oxidative
alkenylÀalkenyl cross-couplings are not known.5 A solu-
tion to this problem is to tether alkenyl substrates together,
allowing application of this strategy to important classes of
molecules such as polyene macrolides.3,7 We report herein
development of a family ofseven different Pd(II)-catalyzed
protocols for achieving selective E,E, Z,Z, E,Z, and R,R
alkenylÀalkenyl cross-couplings through cyclizations of
vinylboronate substrates. These cyclization strategies offer
significant advantages over traditional Pd(0) methods and
are the beginnings of a series of Pd(II)-catalyzed cycliza-
tions of substrates containing two nucleophilic groups.
While many organometallic reagents could be oxida-
tively coupled in a cyclization,5 we chose vinylboronate
esters8 as they are readily synthesized; are compatible with
a range of functional groups; are stable to air, water
and chromatography; and are not toxic. For example,
bis(vinylboronate ester) 1 was easily prepared9 using
Wang’s10 Zr-catalyzed hydroboration of an R,ω-diyne.
After optimization, we found that Pd(II)-catalyzed macro-
cyclization of 1 to 2 was accomplished utilizing the PdCl2-
(PPh3)2 catalyst, chloroacetone reoxidant, and aqueous
potassium carbonate in methanol (eq 1). Complex phos-
phine ligands are unnecessary as transmetalation is a low
energy process. Tests employing Cu(OAc)2 as the reoxi-
dant led to coupling of vinylboronates with alcohols,11 so
chloroacetone12 was used as the Pd(0) reoxidant. Aqueous
K2CO3 activates boronate esters toward transmetala-
tion.13 Several solvents were screened, and methanol was
found to be optimal; as expected for a macrocyclization,
dilution to 0.002 M was necessary to avoid oligomeriza-
tion. Finally, unlike Pd(0)-catalyzed cross-couplings,
which can require elevated temperatures, these reactions
readily occurredatrt. Using these standardizedconditions,
bisboronate 3 cyclized to macrolide 4 (eq 2). Furthermore,
a diyne containing an internal alkyne provided access to
a macrocyclic diene with a trisubstituted alkene. Synthe-
sis of 5 required more forcing conditions for diyne
hydroboration,9 but Pd(II) cyclization proceeded under
mild conditions providing 6 in good yield and excellent
stereospecificity (eq 3).
An important substrate to test the Pd(II)-based mechan-
ism and reaction chemoselectivity is compound 7. Oxida-
tive addition of a Pd(0) species with the aryl bromide
followed by Suzuki cross-coupling with a vinylboronate
unit would lead to oligomeric products. However, an
excellent yield of the desired cyclized product 8 was
obtained using our reaction conditions (eq 4). Thus,
chloroacetone oxidation of the Pd(0) species generated
by reductive elimination of the diene product is consider-
ably faster than aryl bromide oxidative addition.
(6) (a) Shi, W.; Liu, C.; Lei, A. Chem. Soc. Rev. 2011, 40, 2761. (b)
Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (c) Liu,
C.; Jin, L.; Lei, A. Synlett 2010, 2527.
(7) A simple Pd-catalyzed dimerization approach has been reported:
(a) McDermott, T. S.; Mortlock, A. A.; Heathcock, C. H. J. Org. Chem.
1996, 61, 700. (b) Barrett, A. G. M.; Boys, M. L.; Boehm, T. L. J. Chem.
Soc., Chem. Commun. 1994, 1881. (c) Borzilleri, R. M.; Weinreb, S. M.;
Parvez, M. J. Am. Chem. Soc. 1994, 116, 9789.
(8) (a) Vaultier, M.; Alcaraz, G. In Science of Synthesis; Kaufmann,
D., Ed.; Theme Chemistry: Stuttgart, 2004: Vol. 6, p 721. (b) Matteson,
D. S. Stereodirected Synthesis with Organoboranes; Springer: Berlin,
1995. (c) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic
Press: London, 1988.
Switching from E,E to Z,Z macrocyclic dienes, a
modified9 Srebnik14 synthesis of a vinylboronate ester
provided Z,Z-bis(vinylboronate ester) 10 from diyne 9 as
a substrate to cyclize to a Z,Z-diene product (eq 5). The
potentially convenient Miyaura15 protocol fails to provide
Z-vinylboronate esters on complex diyne substrates such
asthis. Substrate10cleanly cyclizedtothe eight-membered
ring product11under the samereaction conditions. Unlike
(9) See Supporting Information
(10) Wang, Y. D.; Kimball, G.; Prashad, A. S.; Wang, Y. Tetrahe-
dron Lett. 2005, 46, 8777.
(11) (a) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am.
Chem. Soc. 2010, 132, 1202. (b) Winternheimer, D. J.; Merlic, C. A. Org.
Lett. 2010, 12, 2508.
(12) Du, X.; Suguro, M.; Hirabayashi, K.; Mori, A.; Nishikata, T.;
Hagiwara, N.; Kawata, K.; Okeda, T.; Wang, H. F.; Fugami, K.;
Kosugi, M. Org. Lett. 2001, 3, 3313.
(13) Satoh, N.; Ishiyama, T.; Miyaura, N.; Suzuki, A. Bull. Chem.
Soc. Jpn. 1987, 60, 3471.
(14) Deloux, L.; Srebnik, M. J. Org. Chem. 1994, 59, 6871.
(15) Ohmura, T.; Yamamoto, Y.; Miyaura, N. J. Am. Chem. Soc.
2000, 122, 4990.
Org. Lett., Vol. 14, No. 16, 2012
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rings containing E,E diene units, rings containing Z,Z
diene units can be as small as five-membered, so a wide
variety of structures can be accessed using this cyclization
strategy.
Scheme 1. Synthesis of Macrocyclic Dienes
The two strategies to E,E and Z,Z cyclic dienes provide
enormous potential for synthetic diversity by introducing
the ring-forming coupling partners late in a synthesis.
Thus, a specific target can be accessed from a simple
common precursor or families of isomeric compounds
can be prepared from a common precursor. The cycli-
zation itself is compatible with numerous functional
groups. We illustrated these concepts with a diyne
that was elaborated into three different macrocycles
with high selectivity (Scheme 1). Hydroboration10 of
aminodiyne 12 gave E,E-bis(vinylboronate ester) 13.
Standard Pd(II)-catalyzed cyclization afforded E,E-
macrocyclic diene 14 in a 74% yield. In an alternate
strategy, hydroboration of 12 with modified Srebnik
conditions9,14 gave Z,Z-bis(vinylboronate ester) 15 and
subsequent Pd(II) cyclization afforded Z,Z-macrocyc-
lic diene 16 in a 70% yield. Then taking it to the next
level, we hydroborated 12 using Hoyveda’s16 Ni-cata-
lyzed protocol to access bis(R-vinylboronate ester) 17.
This cleanly produced the internal boronate ester with
exceptional selectivity. Pd(II)-catalyzed cyclization of
17 again using standard reaction conditions afforded
macrocyclic exodiene 18 in a 43% yield. We did not
optimize this yield, but note that cyclization at elevated
temperatures led to increased amounts of substrate
protodeboronation.
Scheme 2. Synthesis of Macrocyclic Dienediesters
Copper-catalyzed hydroboration chemistries developed
by Yun17 and Lipshutz18 provided access to two more
cyclization modalities. R,ω-Diynoate 19 was converted
regio- and stereoselectively to either bis(β-borylenoate)
20 or bis(R-borylenoate) 22 (Scheme 2). Copper chloride
catalyzed hydroboration17 with bis(pinacolato)diboron
provided 20 as a stable, isolable compound that cyclized
under our standard Pd(II) conditions to give 21 in a 76%
yield. In contrast, hydroboration with Stryker’s copper
hydride catalyst18 and pinacol borane provided 22. While
stable to water,18 22 was unstable in the basic methanol of
our Pd-catalyzed cyclization. Thus, a one- pot hydrobora-
tion/cyclization in THF provided product 23. The modest
yield might be attributed to the instability of 22 or the
unoptimized cyclization in a different solvent. These two
examples illustrate regioselective and stereoselective con-
struction of novel densely functionalized tetrasubstituted-
diene macrocyclic targets.
A major question was whether a Pd(II) strategy could
access E,Z-diene products. All bis(vinylboronate ester)
substrates above were prepared in one step via diyne
hydroboration. Alternatively, separate preparation of
vinylboronates followed by connecting them provides an
E,Z-bis(vinylboronate ester) substrate. To examine this
concept, 24 and 25 were linked using Ph2Si(Et2N)Cl19 to
yield substrate 26 (Scheme 3).9 Cyclization of 26 under our
Pd(II) conditions yielded E,Z-macrocycle 27 in good yield.
(16) Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132, 10961.
(17) Lee, J. E.; Kwon, J.; Yun, J. Chem. Commun. 2008, 733.
ꢀ
ꢁ
(18) Lipshutz, B. H.; Boskovic, Z. V.; Aue, D. H. Angew. Chem., Int.
ꢀ
(19) Matsui, R.; Seto, K.; Fujita, K.; Suzuki, T.; Nakazaki, A.;
Kobayashi, S. Angew. Chem., Int. Ed. 2010, 49, 10068.
Ed. 2008, 47, 10183.
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Org. Lett., Vol. 14, No. 16, 2012

This illustrates access to 27 and acyclic E,Z-diene 28
through fluoride-promoted desilylation, presenting a net
selective intermolecular oxidative cross-coupling of vinyl-
boronate esters. While the stepwise assembly here is remi-
niscent of the typical coupling of electro- and nucleophilic
moieties in a Pd(0)-catalyzed process, Pd(II) catalysis
obviates the need for potentially toxic halogenated sub-
strates and air-free conditions.
Potential synthetic applications are significant, and
many reported Pd(0)-catalyzed macrocyclizations might
have employed these strategies.3 One application is pre-
paration of substrates for transannular DielsÀAlder
(TADA) reactions22 which are immensely powerful for
the synthesis of complex natural products.3c,23,24 Indeed,
Pd(II) cyclization of E,E-bis(vinylboronate ester) 32, pre-
pared by Wang hydroboration10 of an enediyne,9 at rt led to
34 in 72% yield as the sole product (eq 7). No intermediate
macrocycle 33 was observed during the reaction. We will
report details on this and other TADA applications of our
Pd(II) cyclization strategy in a subsequent paper.
Scheme 3. Synthesis of Cyclic and Acyclic Dienes
A powerful reaction of Pd(II) intermediates is insertion
of moieties such as CO, alkynes, alkenes, dienes, and
allenes.20 As long as the rate of insertion is faster than
the second intramolecular transmetalation step, a variety
of new Pd(II)-catalyzed cyclization strategies become
available. To illustrate this concept, we opted for an
intramolecular alkyne insertion. Thus, substrate 29 was
prepared using the modified Srebnik conditions and cy-
clized to yield 82% of bipyranylidene Z,Z,Z-triene 31 as a
single isomer (eq 6). The internal alkene Z stereochemistry
was assumed based upon well-established precedents for
cis insertions via intermediate 30.20 This system demon-
strates yet another Pd(II) cyclization strategy starting from
a simple diyne.21
In conclusion, we demonstrated seven new efficient
Pd(II) cyclization strategies for cyclic polyene synthesis.
The cyclizations occurred at rt, were not air sensitive, and
avoided potentially genotoxic vinyl halide substrates. R,ω-
Diynes were rapidly converted stereospecifically and regio-
selectively to cyclic E,E- or Z,Z- or exodimethylene dienes.
A Pd(II) catalytic cycle was supported by compatibility with
an aryl bromide. A bis(ynoate) led to either R,R- or β,β-
linked cyclic dienediesters. Access to acyclic or macrocyclic
E,Z-dienes was demonstrated, and adding alkyne insertion
into the catalytic cycle led to a strategy for a cyclic Z,Z,Z-
triene. Finally, rapid synthesis of a TADA substrate was
demonstrated. These Pd(II) cyclization strategies should
find wide application for synthesis of cyclic molecules.
(20) Negishi, E., de Meijere, A. Handbook of Organopalladium
Chemistry for Organic Synthesis; Wiley: New York, 2002.
(21) Larock reported a related process for simple symmetric inter-
molecular diarylation of alkynes. See: Zhou, C.; Larock, R. C. J. Org.
Chem. 2006, 71, 3184.
Acknowledgment. This work was supported by the
Research Corporation and the ACS Petroleum Research
Fund. J.L.K. acknowledges support from Amgen Scholars
and Howard Hughes Undergraduate Research programs.
ꢁ
(22) For reviews on TADA reactions, see: (a) Marsault, E.; Toro, A.;
Nowak, P.; Deslongchamps, P. Tetrahedron 2001, 57, 4243. (b)
Deslongchamps, P. Pure Appl. Chem. 1992, 64, 1831.
(23) For examples, see: (a) Anzo, T.; Suzuki, A.; Sawamura, K.;
Motozaki, T.; Hatta, M.; Takao, K.; Tadano, K. Tetrahedron Lett.
2007, 48, 8442. (b) Mergott, D. J.; Frank, S. A.; Roush, W. R. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 11955. (c) Vanderwal, C. D.; Vosberg,
D. A.; Weiler, S.; Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393. (d)
Evans, D. A.; Starr, J. T. Angew. Chem., Int. Ed. 2002, 41, 1787.
(24) For application of Pd(0) cyclizations to TADA substrates, see:
Marsault, E.; Deslongchamps, P. Org. Lett. 2000, 2, 3317.
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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