Increasing the efficiency of the transannular diels-alder strategy via palladium(II)-catalyzed macrocyclizations

Article abstract of DOI:10.1021/ol303394t

Palladium(II)-catalyzed macrocyclizations of bis(vinylboronate ester) compounds are demonstrated to provide a strategically efficient approach to transannular Diels-Alder reaction substrates. In several systems reported, the macrocycle is preorganized such that cycloaddition at room temperature occurs concomitantly with cyclization. Numerous advantages over palladium(0)-catalyzed cross-coupling approaches are demonstrated.

Full text of DOI:10.1021/ol303394t

ORGANIC
LETTERS
2013
Vol. 15, No. 3
582–585
Increasing the Efficiency of the
Transannular DielsÀAlder Strategy via
Palladium(II)-Catalyzed Macrocyclizations
Robert G. Iafe, Jonathan L. Kuo, Dustin G. Hochstatter, 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 December 12, 2012
ABSTRACT
Palladium(II)-catalyzed macrocyclizations of bis(vinylboronate ester) compounds are demonstrated to provide a strategically efficient approach to
transannular DielsÀAlder reaction substrates. In several systems reported, the macrocycle is preorganized such that cycloaddition at room temperature
occurs concomitantly with cyclization. Numerous advantages over palladium(0)-catalyzed cross-coupling approaches are demonstrated.
Transannular DielsÀAlder (TADA) reactions are a
topologically powerful synthetic strategy for the construc-
tion of polycyclic ring frameworks1 and have been utilized
in the synthesis of complex targets.2 They can exhibit
stereoselectivity not attainable in inter- or intramolecular
DielsÀAlder reactions as elegantly demonstrated by
Roush and co-workers.3 Remarkably, the first character-
ized DielsÀAlderase enzyme catalyzes a TADA reaction.4
The challenge for chemists, though, is synthesis of the
requisite macrocyclic TADA substrate. Macrocyclization
is the crucial issue, and geometric constraints often pre-
clude SN2 type substitutions as the key bond-forming step.
Palladium(0)-catalyzedcross-couplingsare widely usedfor
macrocyclizations and also for formation of strained rings5
and, thus, can be applied toward the synthesis of TADA
substrates. Indeed, Deslongchamps demonstrated the utility
of Stille macrocyclizations as the key synthetic strategy for
the preparation of macrocyclic trienes.6 That approach was
developed to solve the key problem of “The bottleneck of
the TADA strategy resides in the macrocyclization step.”6
Unfortunately, Pd(0)-catalyzed cyclization strategiesare
not without limitations. Vinyl halide intermediates can be
toxic or carcinogenic, Pd(0) reactions require an inert atmo-
sphere, complex ligands can be necessary to promote oxi-
dative addition, and heating is often required which can
preclude isolating strained structures. Most importantly,
macrocyclization substrates must have the end groups
differentiated into electrophilic (i.e., vinyl halide) and nu-
cleophilic (i.e., vinyl metal) components. Inevitably that
requirement translates into lengthy synthetic pathways.
We developed Pd(II)-catalyzed cross-coupling reactions of
vinylboronate esters as a solution to the problems inherent in
Pd(0)-catalyzed cross-couplings.7 Our approach efficiently
prepares cyclic targets in just two steps from R,ω-diynes.
We report herein on the development and application of
Pd(II)-catalyzed macrocyclizations as a strategically efficient
approach to prepare TADA substrates.
(1) Deslongchamps, P. Pure Appl. Chem. 1992, 64, 1831.
(2) For reviews, see: (a) Takao, K.; Munakata, R.; Tadano, K. Chem.
Rev. 2005, 105, 4779. (b) Marsault, E.; Toro, A.; Nowak, P.;
Deslongchamps, P. Tetrahedron 2001, 57, 4243. See also: (a) Li, Y.;
Pattenden, G. Tetrahedron Lett. 2011, 52, 2088. (b) Tortosa, M.;
Yakelis, N. A.; Roush, W. R. J. Am. Chem. Soc. 2008, 130, 2722.
(3) Winbush, S. M.; Mergott, D. J.; Roush, W. R. J. Org. Chem. 2008,
73, 1818.
(4) Kim, H. J.; Ruszczycky, M. W.; Choi, S.-H.; Liu, Y.-N.; Liu, H.-
W. Nature 2011, 473, 109.
(5) (a) Shimamura, H.; Breazzano, S. P.; Garfunkle, J.; Kimball,
F. S.; Trzupek, J. D.; Boger, D. L. J. Am. Chem. Soc. 2010, 132, 7776. (b)
Qian, H.; Yue, W.; Zhen, Y.; Di Motta, S.; Di Donato, E.; Negri, F.; Qu,
J.; Xu, W.; Zhu, D.; Wang, Z. J. Org. Chem. 2009, 74, 6275. (c) Palmer,
W. S.; Woerpel, K. A. Organometallics 1997, 16, 4824.
(6) Marsault, E.; Deslongchamps, P. Org. Lett. 2000, 2, 3317.
(7) Iafe, R. G.; Chan, D. G.; Kuo, J. L.; Boon, B. A.; Faizi, D. J.;
Saga, T.; Turner, J. W.; Merlic, C. A. Org. Lett. 2012, 14, 4282.
r
10.1021/ol303394t
Published on Web 01/23/2013
2013 American Chemical Society

Dialkylation of cis-2-butene-1,4-diol provided ene-diyne 2,
and hydroboration with pinacolborane catalyzed by
Schwartz’s catalyst using the Srebnik procedure8 gave bis-
(vinylboronate ester) 3 as the macrocyclization substrate
(Scheme 1). A Pd(II)-catalyzed reaction using 10 mol %
palladium(bistriphenylphosphine)dichloride, an aqueous po-
tassium carbonate activator for boron, and chloroacetone as
the reoxidant in methanol solvent at room temperature for
12 h gave tricycle 5 resulting from a tandem cyclization/
TADA sequence as the only observable product in 86%
yield. Cyclization at 60 °C reduced the yield to 42% due to
competing protodeboronation. Thus, reduced temperatures
are preferred and also have strategic advantages (vide infra).
Starting again from cis-2-butenediol, monoalkylation and
Mitsunobu substitution readily provided diyne 6 and hydro-
boration gave substrate 7.13 Pd(II)-catalyzed macrocyclization
under the standard conditions gave a single diastereomer 9
resulting again from a tandem cyclization/TADA sequence
in 72% yield (eq 1). Using a similar synthetic path as that for
3, but starting from trans-2-butene-1,4-diol, substrate 11
was constructed. Cyclization of 11 yielded 13 in 78% yield
(eq 2). In this instance 5 days were required for the reaction
to proceed to completion. Calculations on the TADA
transition state for 12 found the activation energy to be
1.26 kcal/mol lower than that for 4, so the increased reaction
time was due to the palladium-catalyzed step and not the
TADA step.
12-Membered trienes 4, 8, and 12 were not observed during
the reactions likely due to conformational preorganization for
the TADA reaction.14 Notable is that the dienes and dieno-
philes were not activated with electron-donating or -with-
drawing substituents. Such proximity-induced14 reactivity in
TADA reactions was first reported by Deslongchamps.15
Scheme 1. Pd(II)-Catalysis Applied to a TADA Reaction
The stereochemistry of 5 is proposed based on density
functional theory calculations at the B3LYP/6-31G* level9
using the Gaussian 09 package,10 which is known to be
effective for explaining reaction stereoselectivities.11 Calcula-
tions on the endo and exo DielsÀAlder transition state
structures of 4identified two global stationary transition states
(Figure 1). The endo transition state leading to the cis-syn-cis
product is predicted to be 3.54 kcal/mol lower in energy, which
corresponds to a greater than 99.7:0.3 selectivity. Indeed, no
evidence of any other diastereoisomer was detected by TLC or
NMR. The large difference in transition state energies can be
attributed to the preference for a staggered conformation with
respect to forming bonds, or torsional steering.12
(8) Pereira, S.; Srebnik, M. Organometallics 1995, 14, 3127. Some
substrates used a modified protocol: Wang, Y. D.; Kimball, G.;
Prashad, A. S.; Wang, Y. Tetrahedron Lett. 2005, 46, 8777.
(9) B3LYP: (a) Becke, A. D. J. Chem. Phys. 1993, 98, 1372. (b) Lee,
C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. 6-31G*: (a)
Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724. (b)
Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257.
(c) Hariharan, P. C.; Pople, J. A. Theor. Chem. Acta 1973, 28, 213.
(10) Calculations were performed with Gaussian 09 (Frisch, M. J.,
et al.); see Supporting Information for full reference.
(11) (a) Um, J. M.; Houk, K. N.; Phillips, A. J. Org. Lett. 2008, 10,
3769. (b) Iafe, R.; Houk, K. N. Org. Lett. 2006, 8, 3469. (c) Gordillo, R.;
Carter, J.; Houk, K. N. Adv. Synth. Catal. 2004, 346, 1175.
(12) (a) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu,
Y.-D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich,
R. J. Science 1986, 231, 1108. (b) Cheong, P. H.-Y.; Yun, H.;Danishefsky,
S. J.; Houk, K. N. Org. Lett. 2006, 8, 1513. (c) Iafe, R. G.; Houk, K. N.
Org. Lett. 2006, 8, 3469 and references therein.
Figure 1. Calculated endo and exo transition state structures for
TADA reaction of 4 to 5.
Org. Lett., Vol. 15, No. 3, 2013
583

A benefit of Pd-catalyzed cyclizations is the ability to
prepare strained ring systems.5 In such processes, the pre-
cursor to the strained target is a larger ring palladacycle.
Given the larger ring size and longer PdÀC bonds, typically
12-membered trienes, no macrocyclic dienyne intermedi-
ates were observed.
Products 17, 21, and 25 contain dihydrobenzene rings,
so it might be expected to be subject to aromatization
via hydrogen loss under oxidizing conditions. In prac-
tice, high yields for products were obtained and aro-
matized products were not observed. This is an advan-
tage of being able to perform Pd(II)-catalyzed cycliza-
tions at room temperature in contrast to other types of
cyclizations which typically require heating. In fact,
heating product 17 in air at a mere 60 °C started
aromatization.
2
˚
on the order of 2 A for PdÀC(sp ) bonds, the palladacycle is
not as strained and so is readily formed. Subsequent
reductive elimination forms the desired strained product.
To further increase the ring strain of the intermediate
macrocycle, we explored three 12-membered TADA sub-
strates containing alkyne dienophiles.
Dialkylation of 2-butyne-1,4-diol provided triyne 14 and
hydroboration yielded cyclization substrate 15 (eq 3).13
A
Next we turned to larger ring TADA triene and dienyne
targets. Monoalkylation of cis-2-butene-1,4-diol and DCC
coupling with acid 26 provided diyne 27a which was
hydroborated to yield substrate 28a (Scheme 2).13 Pd(II)-
catalyzed macrocyclization of 28a afforded triene 29a, and
tricycle 30a was not detected. In an attempt to execute the
TADA reaction, 30a was heated at 100 °C for 24 h, but no
TADA product was seen. In contrast with macrocycles 4,
8, and 12thatwere primed for TADAreaction, macrocycle
29a may not readily attain the conformation required
for cycloaddition. Such lack of reactivity has been ob-
served in a TADA system.16 In an exactly analogous series
of transformations,13 2-butyne-1,4-diol was converted
to macrocycle 29b. Even with the more geometrically
constrained alkyne unit in 29b, a TADA reaction was
not observed.
Pd(II)-catalyzed reaction led to tricycle 17 in 84% yield as
the result of a tandem cyclization/TADA process. A similar
sequence starting from 2,5-dimethyl-3-hexyne-2,5-diol pro-
duced tricycle 21 (eq 4). Finally, dialkylation of 1,4-dibromo-
2-butyne with benzylpropargylamine gave triyne 22 that
was carried forward under the standard conditions to
provide tricycle 25 in 71% yield (eq 5). As with all of the
Scheme 2. Macrocyclic Triene 29a and Dienyne 29b
As a direct head-to-head comparison of the efficiency
of our Pd(II)-catalyzed macrocyclization strategy versus
a Pd(0)-catalyzed Stille strategy for TADA substrate
synthesis, we examined a specific target prepared by
Deslongchamps.6 As a component of extensive studies on
TADA reactions, Deslongchamps reported using Stille
(13) See Supporting Information.
(14) Krenske, E. H.; Perry, E. W.; Jerome, S. V.; Maimone, T. J.;
Baran, P. S.; Houk, K. N. Org. Lett. 2012, 14, 3016.
(15) Berube, G.; Deslongchamps, P. Tetrahedron Lett. 1987, 28,
5255.
(16) Jung, M. E.; Zhang, T.-H.; Lui, R. M.; Gutierrez, O.; Houk,
K. N. J. Org. Chem. 2010, 75, 6933. See also: Boeckman, R. K.; Demko,
D. M. J. Org. Chem. 1982, 47, 1792.
(17) An alternate synthesis of 33 via alkylation at 80 °C also yielded
34 instead. Ndibwami, A.; Lamothe, S.; Soucy, P.; Goldstein, S.;
Deslongchamps, P. Can. J. Chem. 1993, 71, 714.
584
Org. Lett., Vol. 15, No. 3, 2013

Pd(0)-catalyzed macrocyclization of substrate 32, pre-
pared in 12 steps, macrocyclic triene 33 was not observed
and, instead, TADA product 34 was obtained. A potential
reason macrocyclic triene 33 was not seen is that the
reaction was performed at 90 °C.17
Scheme 3. Deslongchamps Transannular DielsÀAlder System6
We applied our Pd(II)-catalyzed macrocyclization strat-
egy to the identical target (Scheme 4). Starting also from
3-methylanisole (31), Birch reduction, selective reductive
ozonolysis, tosylation, alkylation, and hydroboration af-
forded substrate 36 in just five steps. Pd(II)-catalyzed
macrocyclization at rt cleanly yielded triene 33. Triene 33
was sensitive, but unlike Deslongchamps, we were able to
characterize it fully by spectroscopic means. Furthermore,
we were able to observe the TADA reaction in real time
and study the reaction kinetics.18 Heating 33 at 70 °C in
benzene-d6 converted it to TADA product 34 with a half-
life of only 67 min. Thus, it is apparent why Deslong-
champs did not observe the macrocycle from the Pd(0)-
catalyzed reaction at 90 °C.
In conclusion, we demonstrated a rapid and efficient
strategy for the synthesis of transannular DielsÀAlder
cycloaddition macrocycles using Pd(II)-catalyzed cy-
clizations of bis(vinylboronate ester) substrates at rt.
Nine systems were prepared, and a direct comparison
example demonstrated the remarkable efficiency of this
protocol. Six systems reacted by an intriguing tandem
cyclization/TADA sequence due to conformational
preorganization favoring proximity-induced cycload-
dition that is currently under further study. The exam-
ples herein employed E,E-dienes, but E,Z- and Z,
Z-dienes are also accessible,7 making this a powerful
strategy.
Scheme 4. Improved Transannular DielsÀAlder System Using
Pd(II)-Catalysis
Acknowledgment. We thank the ACS Petroleum Re-
search Fund for support of this research. J.L.K. was
supported by the Amgen Scholars and Howard Hughes
Undergraduate Research Fellowship programs.
Supporting Information Available. Experimental pro-
cedures, spectral data for all new compounds, and
calculated geometries and energies. This material is
available free of charge via the Internet at http://
pubs.acs.org.
reactions as an effective entry to macrocyclic trienes,
and one system is shown in Scheme 3. In the pivotal
(18) For computational studies on transition state structures and
energies for TADA reactions of 14-membered trienes, see: (a)
Prathyusha, V.; Ramakrishna, S.; Priyakumar, U. V. J. Org. Chem.
2012, 77, 5371. (b) Wolfe, S.; Buckley, A. V.; Weinberg, N. Can. J. Chem.
2001, 79, 1284.
The authors declare no competing financial interest.
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