Intermolecular Noncovalent Hydroxy-Directed Enantioselective Heck Desymmetrization of Cyclopentenol: Computationally Driven Synthesis of Highly Functionalized cis-4-Arylcyclopentenol Scaffolds

Article abstract of DOI:10.1021/acs.joc.5b02846

New computationally driven protocols for the Heck desymmetrization of 3-cyclopenten-1-ol with aryldiazonium tetrafluoroborates were developed. These new conditions furnished remarkable product selectivity originating from a resident hydroxyl group and the critical choice of the reaction solvent. Mechanistic insights gleaned from theoretical calculations of the putative transition states predicted toluene as an adequate solvent choice to attain high enantioselectivity by strengthening the noncovalent interaction of the substrate hydroxyl group and the chiral cationic palladium catalyst. Laboratory experiments validated the theoretical predictions, and by employing 2% MeOH/toluene as solvent, the Heck-Matsuda reaction provided exclusively the cis-4-arylcyclopentenols 3a-l in good to excellent yields in enantiomeric excesses up to 99%. The performance of the new PyOx ligand (S)-4-tert-butyl-2-(3,5-dichloropyridin-2-yl)-4,5-dihydrooxazole was also successfully evaluated in the Heck-Matsuda desymmetrization of 3-cyclopenten-1-ol. The synthetic potential of these highly functionalized cis-4-arylcyclopentenols is illustrated by a gold-catalyzed synthesis of cyclopenta[b]benzofuran skeletons.

Full text of DOI:10.1021/acs.joc.5b02846

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Article
Intermolecular Non-Covalent Hydroxy-Directed Enantioselective
Heck Desymmetrization of Cyclopentenol: Computationally-driven
Synthesis of Highly Functionalized cis-4-Aryl-Cyclopentenol Scaffolds
Juliana de Oliveira Silva, Ricardo A. Angnes, Vitor H. Menezes da Silva, Bruno M. Servilha,
Muhammad Adeel, Ataualpa A. C. Braga, Aaron Aponick, and Carlos Roque D. Correia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02846 • Publication Date (Web): 02 Feb 2016
Downloaded from http://pubs.acs.org on February 2, 2016
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Intermolecular Non-Covalent Hydroxy-Directed
Enantioselective Heck Desymmetrization of
Cyclopentenol: Computationally-driven
Synthesis of Highly Functionalized cis-4-Aryl-
Cyclopentenol Scaffolds
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Juliana de Oliveira Silva,† Ricardo A. Angnes,† Vitor H. Menezes da Silva, ‡ Bruno M. Servilha,‡
Muhammad Adeel,∥ Ataualpa A. C. Braga,‡ Aaron Aponick§ and Carlos Roque D. Correia*†.
†Departamento de Química Orgânica, Universidade Estadual de Campinas, Cidade Universitária,
Zeferino Vaz, s/n, Campinas, SP, Brazil
‡Departamento de Química Fundamental, Universidade de São Paulo, Avenida Lineu Prestes,
748, Bl. 05 sup. Sl. 0552, Butantã, São Paulo, SP, Brazil.
∥Department of Chemistry, Gomal University, Dera Ismail Khan, 29050, Pakistan.
§Department of Chemistry, Center for Heterocyclic Compounds, University of Florida,
Gainesville, Florida 32611, United States
KEYWORDS: Heck reactions, enantioselective reactions, homogeneous catalysis, DFT studies,
cyclopentene scaffolds.
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Abstract: New computationallyꢀdriven protocols for the Heck desymmetrization of 3ꢀ
cyclopentenꢀ1ꢀol with aryldiazonium tetrafluoroborates were developed. These new conditions
furnished remarkable product selectivity originating from a resident hydroxyl group and the
critical choice of the reaction solvent. Mechanistic insights gleaned from theoretical calculations
of the putative transition states predicted toluene as an adequate solvent choice to attain high
enantioselectivity by strengthening the nonꢀcovalent interaction of the substrate hydroxyl group
and the chiral cationic palladium catalyst. Laboratory experiments validated the theoretical
predictions, and by employing 2% MeOH/toluene as solvent, the HeckꢀMatsuda reaction
provided exclusively the cisꢀ4ꢀarylꢀcyclopentenols 3a-l in good to excellent yields in
enantiomeric excesses up to 99%. The performance of the new PyOx ligand (S)ꢀ4ꢀtertꢀbutylꢀ2ꢀ
(3,5ꢀdichloropyridinꢀ2ꢀyl)ꢀ4,5ꢀdihydrooxazole was also successfully evaluated in the Heckꢀ
Matsuda desymmetrization of 3ꢀcyclopentenꢀ1ꢀol. The synthetic potential of these highly
functionalized cisꢀ4ꢀarylꢀcyclopentenols is illustrated by a goldꢀcatalyzed synthesis of
cyclopenta[b]benzofuran skeletons.
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INTRODUCTION
The Heckꢀreaction is a pivotal method for the formation of carbonꢀcarbon bonds in organic
synthesis.1 An effective and very practical version of this reaction, the soꢀcalled HeckꢀMatsuda2
reaction, relies on arenediazonium salts, mainly the tetrafluoroborates, as arylating reagents
instead of the conventional aryl halides and triflates.2 Arenediazonium salts undergo rapid
oxidative addition towards zerovalent palladium, thus providing a direct access to more reactive
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cationic Heck intermediates. This usually fast, practical and effective arylating method has been
attracting increased interest from the synthetic community in the last few years.3 Furthermore,
the HeckꢀMatsuda reaction has gained increased momentum recently with the discovery of its
enantioselective version.4
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In 2012, Correia and coworkers reported the first examples of the enantioselective Heck–
Matsuda reaction, carrying out the desymmetrization of an unactivated olefin employing chiral
bisoxazoline ligands.4 Shortly thereafter, Sigman and coworkers described the enantioselective
HeckꢀMatsuda arylation of acyclic alkenyl alcohols using the redoxꢀrelay strategy.5 Correia et al.
also reported a similar strategy in 2013 in the enantioselective arylation of cis and transꢀ
butenediols in route to the concise synthesis of γ−arylꢀlactones in good chemical yields and
enantiomeric excesses.6
More recently, we have also demonstrated the synthetic potential of the HeckꢀMatsuda
desymmetrization strategy for the construction of arylated fiveꢀmembered carbocyclic scaffolds
starting from 3ꢀcyclopentenꢀ1ꢀol.7 In spite of its synthetic potential, this particular
desymmetrization method provided two quite distinct products as consequence of the reaction
diastereoselectivity: the more highly functionalized cisꢀ4ꢀarylꢀcyclopentenols 3, as major
products with the enantiomeric excesses (ee’s) ranging from 85% to 99% (Scheme 1), and the
minor 3ꢀarylꢀcyclopentanones 4, in much lower ee’s.
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Scheme 1. Enantioselective Heck arylation of 3ꢀcyclopentenꢀ1ꢀol.
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OH
O
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N2BF4
OH
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+
ref.[7]
+
R
R
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major product
moderate yields
High ee's
minor product
up to 27% yield
Low ee's
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L
Pd
R
OH
Origin of selectivity?
H
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Pd
H
R
HO
The origin of the product selectivity was attributed to a putative stabilizing interaction of the
substrate hydroxyl group with the cationic palladium in an apparent substrateꢀdirectable Heck
arylation. The concept of substrate directable chemical reactions to control regio and
stereoselectivity was elegantly reviewed by Evans, Hoveyda and Fu in 1993.8 Concerning Pdꢀ
catalyzed reactions, Hallberg and coworkers introduced the concept of “chelation control” by
installing an appropriate donor group on the substrate to obtain high regioselectivity in
intermolecular Heck reactions.9 Alper and coworkers also suggested the critical role of a
hydroxyl group in an enantioselective Pdꢀcatalyzed cyclocarbonylation of allylic alcohols
leading to γꢀbutyrolactones.10 More recently, Morken and Blaisdell showed that a hydroxyl
group can also act as a directing group in palladiumꢀcatalyzed crossꢀcoupling reactions (Suzukiꢀ
Miyaura reaction).11 In 2005, Oestreich and coworkers described an intriguing intramolecular
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desymmetrizing Heck reaction of an openꢀchain bisꢀhomoallylic alcohol moiety. According to
the authors, the unprotected hydroxyl group would play a pivotal role in the enantioꢀdetermining
step with the free hydroxyl group acting as a directing group.12 However, in a subsequent paper,
the same authors dismissed the hydroxyl group directing effect during the key migratory
insertion step.13 According to their new conclusions, the mechanism involved a rapid
equilibration of diastereomeric alkeneꢀpalladium (II) complexes prior to the selectivityꢀ
determining event in a typical CurtinꢀHammett scenario (Scheme 2). In the same vein, the
authors emphasized that the stereochemical outcome was controlled by the chiral phosphine
ligand while the hydroxyl group enabled an associative equilibration between intermediates.
Scheme 2. Directing groups in Heck reaction.
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In spite of these scattered examples in the literature, to the best of our knowledge, strong
evidence for an enantioselective heteroatomꢀdirected Heck reaction is still elusive. Therefore,
with the goal of evaluating the actual participation of the hydroxyl group in the Heck
desymmetrization of 3ꢀcyclopentenꢀ1ꢀol, and possibly develop it into a more general synthetic
method, we reinvestigated the arylation process by combining density functional theory (DFT)
studies and laboratory experiments to validate, or not, our previous mechanistic rationale.7
Computational methods have been instrumental in understanding and predicting the mechanism
of many stereoꢀ and enantioselective catalytic systems.14 DFT studies can be regarded as a first
line of investigation to calculate the transition state energy required to form intermediates along
the reaction coordinate under a variety of conditions, such as different solvents. Most ionic Heck
reactions are carried out in polar solvents such as methanol, acetonitrile, dimethyl sulfoxide,
dimethylacetamide, and Nꢀmethylpyrrolidone (NMP).1b Studies have shown that these solvents
stabilize the catalytically active intermediates, thus leading to improved yields and selectivities.
Theoretical calculations for the enantioselective HeckꢀMatsuda reaction were previously
performed by Wang et al. and Wiest et al. using the N,Nꢀligand PyOx.15 However, our studies
using this very same ligand focused on the role of the free hydroxyl group in the reaction’s
stereochemical outcome, and how it could be controlled to provide the desired cisꢀcyclopentenol
Heck adduct 3 as its exclusive product.
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In this report, we disclosed our findings concerning the new optimized conditions for the
HeckꢀMatsuda desymmetrization of 3ꢀcyclopentenꢀ1ꢀol 1 with several aryldiazonium salts to
provide exclusively the desired cisꢀ4ꢀarylꢀcyclopentenol Heck products. These results were
supported by DFT studies based on transition state energy using toluene or MeOH as solvent,
favoring the exclusive formation of Heck product 3 in excellent yields and enantiomeric
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excesses. The hydroxyl group in the substrate plays a crucial role through a nonꢀcovalent
interaction with the cationic palladium in the diastereoꢀ and enantioꢀdetermining step, thus
controlling the product selectivity of the enantioselective HeckꢀMatsuda reaction.
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RESULTS AND DISCUSSION
Computational Studies. One of our first objectives was to look for evidences regarding our
initial hypothesis that a key interaction between the hydroxyl group in the achiral 3ꢀcyclopentenꢀ
1ꢀol and the metal center was indeed providing additional stabilization in the migratory insertion
transition state (TS), thus directing the stereochemical outcome of the HeckꢀMatsuda reaction
(Scheme 1).
Our studies started with a complete search for all eight migratory insertion stereoisomeric
transition states leading to both Heck products. These eight transition structures arise from three
main factors: i) the relative position of the aryl group and olefin in the starting complex, ii) the
endo/exo orientation of the substrate’s hydroxyl group towards the metal center and, iii) the
migratory insertion step in the Re/Si face of the olefin. It was assumed that this last stage refers
to the enantioꢀdetermining step, since the arylꢀpalladium complexes are supposed to be in rapid
equilibrium.15 Consequently, the reaction enantioselectivity should depend solely on the energy
difference between the transition states under typical CurtinꢀHammett conditions.16
Additionally, we performed an investigation on the influence of the solvents (methanol
and toluene) in the stereoselectivity of the reaction. The solvent effects were introduced by the
SMD continuum solvation model.17 Scheme 2 presents the calculated relative free energies for
the transition states of the migratory insertion step in methanol (M) and toluene (T) solutions
(ꢀG‡sol), using 4ꢀchlorophenyl diazonium tetrafluoroborate as a model arylating agent in view of
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its clean Heck reactions in the laboratory, straightforward determination of the product ee’s, and
absolute stereochemistry confirmed by Xꢀray.7
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Scheme 3. Computed energies (in kcal•molꢀ1) for the migratory
βꢀinsertion transition states.
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Reported energies are relative to the TS2, which was identified as the lowest energy structure.
b
aCalculated ꢀG‡ values for transition state in methanol solvent (kcal•molꢀ1). Calculated ꢀG‡
values for transition state in toluene solvent (kcal•molꢀ1).
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According to our calculations, the transition state TS2, which has the hydroxyl in an endo
orientation towards palladium, is the lowest energy transition state in both solvents. This result is
in perfect agreement with our previous experimental results using methanol as solvent.7 The next
lowest energy transition state, TS8, also has the hydroxyl group in an endo orientation, but with
the pyridine group of the PyOx ligand in position trans to the aryl moiety. The calculated energy
for TS8 is 1.6 and 1.9 kcal•molꢀ1 higher than the ones obtained for TS2 in methanol and toluene,
respectively. Most probably, such a difference is due to the steric hindrance of the tertꢀbutyl
moiety of PyOx ligand and the arylꢀCl group in TS8 (see Support Information for more details
about the optimized geometry of all transition states). Furthermore, TS2 contains a stabilizing Cꢀ
H π interaction which is absent in TS8.15 Both transition states, TS2 and TS8, are associated
with adduct 3a in methanol and toluene.
Product 4a is expected to arise from a series of synꢀβꢀhydrogen eliminations and synꢀβꢀ
hydrogen reinsertions prior to HꢀPdL diffusion. These iterative relay step reactions were
thoroughly investigated by Wang et al. and Wiest et al. using DFT methods.15 Based on these
studies, it is our reasonable assumption that the relay process is only possible when the hydroxyl
group assumes an exo orientation in the migratory insertion step (see Scheme 1). Thus, the
migratory insertion steps of TS1 and TS7 are the feasible pathways to the formation of 4a. TS1
has energy lower than that for TS7 in both solvents (2.8 and 3.6 kcal•molꢀ1 in methanol and
toluene, respectively). Based on these energy differences, it is reasonable to assume that product
4a originates from TS1. We attributed the higher energy of TS7 compared to TS1 to the steric
hindrance experienced between the tꢀBu group of the ligand and the aryl moiety of the substrate.
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High activation free energies were observed in methanol and toluene to produce adduct 5a (ent-
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4a) by the competitive paths involving TS3 (ꢀG‡sol = 6.0 and 7.5 kcal•molꢀ1) and TS5 (ꢀG‡
=
sol
5.0 and 7.1 kcal•molꢀ1). Adduct 6a (entꢀ3a) can be obtained through TS4 (ꢀG‡ = 3.6 and 4.3
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kcal•molꢀ1) or TS6 (ꢀG‡sol = 2.8 and 3.6 kcal•molꢀ1) in minor amounts (see details in Scheme 3).
Aryl cyclopentenol 6a and the cyclopentenone 5a were indeed minor stereoisomers in our
experiments with methanol. These computational studies nicely support our previously reported
experimental results.7
The influence of the solvent on the selectivity of these reactions was also addressed by
computational studies. As depicted in Scheme 3, the difference between the barriers increased
when methanol was replaced by toluene. It was especially important to understand the solvent
effect on the barrier heights regarding the formation of compounds 3a (TS2) and 4a (TS1). As
mentioned above, the transition state TS1 in methanol is 2.0 kcal•molꢀ1 higher in energy than
TS2. In toluene, this energetic difference increased to 3.3 kcal•molꢀ1, thus suggesting an increase
in the selectivity for the formation of Heck product 3a depending on the solvent.
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Figure 1. Calculated transition states TS1 (exoꢀhydroxyl group) and TS2 (endoꢀhydroxyl group).
Distances for selected bonds are given in angstroms (Å). Mulliken charges, NBO charges (in
parentheses), and APT charges (in square brackets) for the oxygen of hydroxyl group and the
palladium(II) center atom.
Figure 1 shows the optimized geometries with selected bond lengths of TS1 and TS2.
Calculations suggest that an interaction between the hydroxyl group in an endo orientation to the
metal center is the major factor responsible for the stabilization of TS2 in comparison to TS1.
This transition state is characterized by a nonꢀcovalent interaction between the hydroxyl group
and palladium, with O1ꢀPd bond length of 2.974 Å. Mulliken, Natural Bond Orbital (NBO),18
and the Atomic Polar Tensor (APT)19 methods of population analysis were used to estimate the
partial charges on the oxygen of the hydroxyl group and palladium (II). All population analyses
(see Supporting Information) indicate the presence of strong electrostatic interaction between the
negatively polarized hydroxyl group and the cationic palladium center. Similarly, Uyeda and
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Jacobsen reported a detailed computational study on the enantioselectivity of ionꢀcatalyzed
asymmetric Claisen rearrangement where the enantioselectivity relied on attractive electrostatic
interactions to preferentially stabilize a single transition state.20
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The magnitude of this attractive electrostatic interaction should correlate with the
conformational bias of the substrate, and on the reaction medium. In methanol, the cationic
palladium complexes are well solvated due to its polar nature. However, in methanol the
substrate hydroxyl group might also engage in hydrogen bonds with the solvent. Consequently,
this stabilizing electrostatic interaction should be rather weaker in methanol. On the other hand,
in toluene the cationic palladium complexes are less solvated, making the attractive interaction
between the substrate hydroxyl group and palladium center more effective, thus leading to a
more pronounced differentiation between the two transitionꢀstates. As described in the next
section, this energy difference is reflected in a much improved stereo and product selectivity
towards the desired allylic 4ꢀarylcyclopentenol adduct (3).
Experimental Studies. Our DFT calculations have shown that the hydroxyl group of the
starting cyclopentenol has a strong stabilizing effect when at the endo position with respect to the
cationic palladium, thus supporting our previous hypothesis. Equally important, those
calculations also indicated that this stabilizing effect is even more pronounced in toluene. This
fact suggests that toluene, or other less polar solvents, could provide the desired aryl
cyclopentenol 3 as the exclusive Heck product in high enantioselectivity.
With the computational studies in hand, we evaluated their significance experimentally. The
Heck arylations were then performed in different solvents to probe the reaction selectivity under
these new conditions. Gratifyingly, the tested solvents showed significant effect on the reaction
selectivity. Solvents like 1,4ꢀdioxane, ethyl ether, acetone, dimethyl carbonate, PEGꢀ300 and
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hexane lead to the cisꢀaryl cyclopentenol as the overwhelming major product, albeit in low yields
(14ꢀ31%; see SI for details). THF provided the desired aryl cyclopentenol 3a in excellent yield
and ee, with a good product selectivity of ~9:1 (Table 1, entry 1). In agreement with the
computational studies, the reactions carried out in trifluorotoluene and toluene were much more
selective, affording the aryl cyclopentenol 3a as the exclusive Heck product in high ee’s (Table
1, entry 2 and 3). Toluene gave the highest ee’s (98%) in a good chemical yield of 71%. Given
the high enantioselectivity observed in toluene, we investigated the effect of binary mixtures of
solvents, especially toluene and methanol, as this latter solvent is a common one in most
enantioselective HeckꢀMatsuda reactions. A 1:1 mixture toluene/methanol afforded the allylic
alcohol 3a in an improved yield of 82% along with aryl cyclopentanone 4a (10% yield). By
systematically decreasing the amount of methanol in toluene, we were able to find the optimum
conditions to obtain only cyclopentenol 3a in 88% yield and 99% ee, thus combining high ee’s
and chemical yields (Table 1, entry 6).
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Table 1. Screening of solvents.
Entry
Solvent
THF
Yield 3a (%) ee 3a (%) Yield 4a (%) ee 4a (%)
1
2
88
27
71
95
97
98
11
Traces
ꢀ
0
ꢀ
trifluorotoluene
toluene
3a
ꢀ
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4
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toluene:methanol (50:50)
toluene:methanol (95:5)
toluene:methanol (98:2)
toluene:methanol (99:1)
82
63
88
73
95
99
99
99
10
8
ꢀ
Traces
6a
7a
ꢀ
ꢀ
ꢀ
ꢀ
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aProduct 4a was not observed
.
To expand the synthetic potential of the Heck arylation under the new conditions, its scope was
evaluated with several aryldiazonium salts containing electron donating (EDG) or electron
withdrawing (EWG) groups in different substitution patterns. The design of new N,Nꢀligands for
the Heck reactions or crossꢀcoupling reaction is a subject of great general interest. Small changes
in the electronics of these ligands can have a profound effect on the enantioselectivity,
diastereoselective and chemical yields of the reactions.21 Therefore, the new conditions also
provided us with the opportunity to test the performance of the new PyOx ligand (S)ꢀ4ꢀtertꢀbutylꢀ
2ꢀ(3,5ꢀdichloropyridinꢀ2ꢀyl)ꢀ4,5ꢀdihydrooxazole (L2) in the Heck arylation of cyclopentenol 1,
compared to the commercially available PyOx L1 (Scheme 4).
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Scheme 4. Scope of the new enantioselective Heck desymmetrization of 3ꢀcyclopentenꢀ1ꢀol
using PyOx ligands L1 and L2.
7
8
9
OH
Pd(TFA)2 (2.5 mol%)
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Ligand
(3mol%)
N2BF4
OH
DTBMP
+
2% MeOH/toluene
40 °C, 1-2 h
R
1
2(a-l)
R
3(a-l)
Cl
O
N
O
N
Cl
F3C
Me
Me
Me
Me
N
N
Me
Me
L1
OH
L2
OH
OH
OH
MeO
3b
L1
3c
L1
3d
L1
3a
L1
Cl
OMe
MeO
: 81%; 94% ee
L2: 96%; 96% ee
: 92%; 99% ee
L2: 76%; 96% ee
: 84%; 97% ee
: 90%; 94% ee
L2: 86%; 97% ee
L2: 58%; 80% ee
OH
OH
OH
OH
HO
3e
Cl
3f
3g
L1
3h
L1
O2N
: 86%; 96% ee
Cl
L1a
L2a
: 51%; 86% ee L1
: 61%; 84% ee
: 85%; 97% ee
L2: 76%; 97% ee
: 76%; 97% ee
L2: 78%; 95% ee
L2: 76%; 92% ee
OH
OH
OH
OH
CF3
CF3
O2N
CF3
3i
3j
: 72%; 97% ee L1
: 69%; 97% ee
3k
3l
L1
L1b
L1
: 61%; 99% ee
L2: 76%; 99% ee
: 76%; 98% ee
: 66%; 96% ee
L2c
L2: 86%; 96% ee
L2: 72%; 98% ee
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b
aUsing 10 mol% of Pd(TFA)2 and 11 mol% of the ligand The corresponding ketone 4i was
3
4
5
6
c
obtained in 18% yield in 90% ee. The corresponding ketone 4i was obtained in 23% yield in
88% ee.
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As indicated in Scheme 4, PyOx ligands L1 and L2 showed similar results in the
enantioselective Heck–Matsuda reaction, with ligand L2 performing slightly better for
aryldiazonium salts bearing the electron donating paraꢀmethoxy substituent and the highly
electron withdrawing CF3 substituent. On the other hand, L1 had performed better with orthoꢀ
substituted aryldiazonium salts. Enantiomeric excesses were very high in all instances, except for
3d and 3e using L2, for reasons not yet clear to us since L2 performed well with other ortho
substituted aryldiazonium salts, as exemplified by the Heck products 3i and 3l.
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The intrinsic structural complexity incorporated in the cisꢀarylꢀcyclopentenols 3a-l gives them
a considerable synthetic potential. To demonstrate this point, aryl cyclopentenol 3e was used in
the construction of the more complex chiral scaffold 7e possessing the basic framework of many
important drugs and/or bioactive natural products, such as the thromboxane inhibitor beraprost
and the aplysins.22 The thromboxane inhibitors have attracted intense medical interest in the last
few years and have been the subject of many recent patents.23 Therefore, the phenolic aryl
cyclopentenol 3e was submitted to goldꢀcatalyzed allylic substitution, employing a recently
developed procedure by Aponick et al.24 The goldꢀcatalyzed cyclization afforded the
corresponding fused tricyclic system in good to excellent yield and diastereoselectivity. As
expected, no enantiodepletion was observed in the tricyclic product (see SI, section 5),
demonstrating the synthetic potential of the HeckꢀMatsuda method for the synthesis of complex
chiral scaffolds (Scheme 5).
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Scheme 5. Goldꢀcatalyzed allylic substitution and bioactive compounds bearing the
cyclopenta[b]benzofuran skeleton.
7
8
9
OH
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JohnPhos AuCl
H
H
AgOTf, 4 Å MS
O
DCM, THF
4.5 h, rt.
HO
3e
7e
92%
Examples of molecules containing the cyclopenta[b]benzofuran skeleton
OH
1
2
Thromboxane inhibitors
: R =alkyl R = alkyl (US5496849)
R1
1
: R =
R2 = (CH2)3CO2H
OH
Beraprost
H
H
O
Me
R2
Me
Me
1
2
3
-)-Aplysin
(
: R = R = Me; R = Br
R1
Me
(-)-Debromoaplysin: R1 = R2 = Me; R3 = H
Aplysinol: R1 = CH2OH; R2 = Me; R3 = Br
Isoaplysin: R1 = CH2Br; R2 = Me; R3 = H
O
R3
R2
CONCLUSION
We have demonstrated that computational calculations provided key mechanistic insights
regarding the role of the hydroxyl group in the HeckꢀMatsuda desymmetrization of 3ꢀ
cyclopentenꢀ1ꢀol. DFT calculations strongly agreed with our initial hypothesis of nonꢀcovalent
stabilizing interaction between the substrate hydroxyl group and the cationic metal center. This
critical interaction directs the olefin face undergoing arylation to provide a highly functionalized
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fiveꢀmembered ring product in high yield and enantiomeric excess. New and much improved
reaction conditions were then developed employing a mixture of 2% methanol/ꢀtoluene, which,
with very few exceptions, gave the desired cisꢀ4ꢀarylꢀcyclopentenols 3a-l as the exclusive Heck
products in excellent ee and good to excellent chemical yields. These new chiral scaffolds bear
considerable synthetic potential, which was illustrated by the construct of the more complex
cyclopenta[b]benzofuran skeleton 7a. Overall, the newly developed method brings new insights
about the complexity of the Heck reactions and it demonstrates excellent scope. It is also very
practical, mild providing fast reactions (1ꢀ2 h). Another feature is that it can be carried out under
“openꢀvessel” conditions. Moreover, a new PyOx ligand L2 was introduced with excellent
potential for new enantioselective Heck and palladiumꢀcatalyzed reactions. These results open
new opportunities for enantioselective synthesis of key intermediates based on cyclopentenes
scaffolds. Studies to fully explore those potentials are ongoing and shall be reported in due
course.
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EXPERIMENTAL SECTION
General methods. All the reactions were carried out in a 4 mL or 20 mL vessel under air
atmosphere, unless otherwise stated. Reaction temperatures different from room temperature are
reported as the temperature of the bath surrounding the vessel. All HeckꢀMatsuda reactions
solvents were used without any previous treatment and were obtained from commercial sources.
Hexane and ethyl acetate used for purification/chromatography were of technical grade and
were distilled prior to use.
Commercially available reagents were used as received.
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Analytical thin layer chromatography was performed on TLC Silica gel 60 F245 plates, 0.25
mm thickness. Visualization was accomplished mainly with vanillin (although KMnO4 and
phosphomolybidic acid were also used) as staining solution, followed by heating.
Flash chromatography was performed on silica gel (230ꢀ400 mesh) using standard techniques
and eluted with appropriated ethyl acetate/hexane mixtures.
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NMR analyses were performed on 400 and 500 MHz spectrometers. Spectra were recorded in
CDCl3, or DMSOꢀd6 (depending on the case, see compound description for more details). 1,3ꢀ
Bis(trifluoromethyl)ꢀ5ꢀbromobenzene was used as internal standard for the determination of
1
chemical yields by H NMR (at the methodology optimization stage). Chemical shifts are
reported in ppm, referenced to tetramethylsilane (TMS) or any residual solvent peak. The
1
following residual signals of the deuterated solvents were used as references (CDCl3; H: δ =
1
7.26 ppm, 13C: δ = 77.16 ppm. (CD3)2SO; H: δ = 2.50 ppm, 13C: δ = 39.52 ppm). Data are
reported as follows: chemical shift (δ), multiplicity, coupling constant (J) in Hertz, and
integrated intensity. Abbreviations to denote the multiplicity of a particular signal are s (singlet),
bs (broad singlet), d (doublet), t (triplet), q (quartet), dd (double doublet), dt (double triplet) and
m (multiplet).
HPLC analysis were performed with an UV detector at controlled column temperature with
injection volume of 20 µL using Hexane/2ꢀPropanol as solvent mixture in an isocratic system.
Optical rotations (α) were measured on polarimeter at 20 oC using a quartz glass cell (10 mm
path length).
Infrared (IR) spectra were recorded in an FTIR using attenuated total reflectance (ATR)
technique, with scans between 4000 and 650 cmꢀ1, with 8 cmꢀ1 resolution. The compounds were
analyzed in its pure form, on a germanium sample holder. The maximum absorbing frequencies
are reported in cmꢀ1.
Highꢀresolution MS measurements were obtained with a HDMS. Data was obtained in the V
mode TOF (analizer) and ESI(+) mode (source). The major signals are quoted in m/z.
Melting points were measured in melting apparatus.
Ligands used in this study are commercially available, except for L2, which was synthesized
by a modified literature procedure.25
All aryldiazonium tetrafluoroborates (1) were synthesized by a previously reported
procedure.26
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Computational methods. All electronic structure calculations were based on density theory
functional (DFT).27 The transition states were fully optimized in gas phase with local functional
M06ꢀL, suitable for description on thermochemical kinetics and noncovalent interactions of
transition metals, inorganic and organometallic compounds.28 The standard 6ꢀ31G(d) basis set
was adopted for lighter atoms and relativistic pseudopotential method SDD29 for Pd, approaches
are denoted 6ꢀ31G(d), SDD(Pd). This basis set approach was performed for DFT investigation in
other Pd catalyzed CꢀC cross coupling reaction based on PyOx ligand, with a successfully
rationalization on reactivity and enantioselectivity.30 Frequency calculations were carried out in
order to verify that transition states have only one imaginary frequency. Intrinsic Reaction
Coordinate (IRC) method also used to further authentic the transition states.31 Solvent effects for
methanol (M) and toluene (T) were introduced through SMD17 method by singleꢀpoint
calculations in geometries optimized on gas phase at the SMDꢀM06ꢀL/6ꢀ31G(d), SDD(Pd) level
of theory. The transition states are discussed in free energy terms with solvent, thermal, enthalpy
and entropic corrections at 298.15 K and 1 atm, reported in kcal•molꢀ1. All calculations were
performed with Gaussian 09 suite quantum chemical programs.32
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(S)-4-(tert-butyl)-2-(3,5-dichloropyridin-2-yl)-4,5-dihydrooxazole (L2). LꢀtertꢀLeucinol (1.5
equiv, 8.67 mmol, 1.01 g), 3,5ꢀdichloropicolinonitrile (1 equiv, 5.78 mmol, 1.00 g),
Zn(OAc)2.2H2O (2 mol%, 0.12 mmol, 25.3 mg) and 6 mL of hexane were added to a 15 mL
pressure tube containing a stirring bar. The tube was tightly closed and immersed in an oil bath at
110 °C (Careful, pressure is developed), and the resultant mixture was kept stirring overnight at
110 °C in the pressurized tube. The flask was then slowly cooled to room temperature, and
opened carefully (ammonia gas is released). The resulting mixture was concentrated in vacuum
and then purified by column chromatography with hexanes:ethyl acetate as eluent. The product
was obtained in 95% yield as a pale yellow oil (1.49 g, 5.46 mmol). This is a modified literature
procedure.25 [α]20 589(c 0.73, CHCl3) = ꢀ60, 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 2.0 Hz,
1H), 7.84 (d, J = 2.1 Hz, 1H), 4.44 (dd, J = 10.2, 8.6 Hz, 1H), 4.29 (ta, J = 8.4 Hz, 1H), 4.20 (dd,
J = 10.2, 8.3 Hz, 1H), 1.00 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 159.8, 146.5, 143.7, 138.0,
133.5, 132.4, 77.4, 69.2, 34.1, 26.1. HRMS (-ESI) calculated for C12H14Cl2N2O [M+H+]:
273.0556; found 273.0574. IR (neat, cm-1) 2956, 2906, 2871, 1666, 1565, 1442, 1367, 1337,
1266, 1208, 1111, 1041, 961, 912, 830, 661, 577.
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General procedures for the enantioselective Heck-Matsuda arylations. A 4 mL vessel
containing a magnetic stir bar was charged with 2.5 mol% of Pd(TFA)2, 3.0 mol% ligand (L1 or
L2) and a solution of 2% methanol in toluene (1.3 mL) (Note: except for compound 3e, which
demanded 10 mol% of Pd(TFA)2 and 11 mol% of Ligand). The resulting light orange solution
was then stirred for 10 min at 40 oC. At this point it was added 1.1 equiv of DTBMP (2,6ꢀdiꢀtertꢀ
butylꢀ4ꢀmethylpyridine; 0.11 mmol) and 2 equiv of olefin (1; 0.2 mmol), followed by addition of
1 equiv of the appropriate arenediazonium salt (2; 0.1 mmol). The reaction was monitored by
TLC until complete consumption of the diazonium salt (βꢀnapthol test) (2ꢀ6 h).* Next, the crude
reaction mixture was concentrated in vacuum, and the products purified by flash chromatography
using EtOAc/ Hexanes 30% as eluent to afford the Heck products (3a-l and 4i).
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Analytical data for compounds 3a, 3b, 3d, 3e, 3f, 3h, 3i, 3j, 3k and 3l has been previously
reported.7
(1S,4R)-cis-4-(4-chlorophenyl)cyclopent-2-enol (3a). Compound 3a was obtained as a light
brown oil (using procedure A and L1 it was obtained 17.9 mg, 0.092 mmol, 92% yield, >99% ee.
Using procedure A and L2 it was obtained 14.8 mg, 0.076 mmol, 76% yield, 96% ee). ee
o
determined by HPLC analysis (Daicel IC 4.6 mm X 25 cm, column temperature 25 C,
Hexanes/iꢀPrOH 98:2, 1 mL/min, 225 nm, tR = 14.8 min (minor) and tR = 17.6 min (major). The
compound has been fully characterized previously.7
(1S,4R)-cis-4-(4-methoxyphenyl)cyclopent-2-enol (3b). Compound 3b was obtained as a light
brown oil (using procedure A and L1 it was obtained 15.4 mg, 0.081 mmol, 81% yield, 94% ee.
Using procedure A and L2 it was obtained 18.3 mg, 0.096 mmol, 96% yield, 96% ee). ee
determined by HPLC analysis (Kromasil 10 Cellucoat 4.6 mm X 25 cm, column temperature 25
oC, Hexanes/iꢀPrOH 98:2, 1 mL/min, 272 nm, tR = 40.1 min (major) and tR = 43.1 min (minor).
The compound has been fully characterized previously.7
* The test consists of mixing a βꢀnaphthol solution with a small aliquot of the reaction mixture on
a spot test plate (alternatively, a TLC plate can also be employed). Appearance of a deep red
color indicates the presence of aryldiazonium salt.
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(1S,4R)-cis-4-(3-methoxyphenyl)cyclopent-2-enol (3c). Compound 3c was obtained as a light
yellow oil (using procedure A and L1 it was obtained 16.0 mg, 0.084 mmol, 84% yield, 97% ee.
Using procedure A and L2 it was obtained 16.4 mg, 0.086 mmol, 86% yield, 97% ee). ee
determined by HPLC analysis (Kromasil 10 Cellucoat 4.6 mm X 25 cm, column temperature 25
oC, Hexanes/iꢀPrOH 95:5, 1 mL/min, 270 nm, tR = 17.3 min (major) and tR = 21.9 min (minor),
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1
[α]20 589(c 2.00, CHCl3) = +69 (97% ee sample). H NMR (500 MHz, CDCl3) δ 7.23 (dd, J =
15.8, 8.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.79 – 6.72 (m, 2H), 5.98 (dt, J = 5.6, 2.0 Hz, 1H),
5.95 (dt, J = 5.5, 1.6 Hz, 1H), 4.98 – 4.88 (m, 1H), 3.80 (s, 3H), 3.79 – 3.74 (m, 1H), 2.85 (ddd, J
= 13.7, 8.4, 7.4 Hz, 1H), 1.63 (s, 1H), 1.58 (ddd, J = 13.7, 6.2, 5.1 Hz, 1H). 13C NMR (125
MHz, CDCl3) δ 160.0, 146.9, 137.4, 134.7, 129.7, 119.8, 113.2, 111.8, 77.6, 55.3, 50.0, 44.0.
HRMS (-ESI) calculated for C12H14O2 [M+H+]: 191.1067; found 191.1063. IR (neat, cm-1)
3359, 2938, 2839, 1603, 1586, 1489, 1438, 1267, 1159, 1045, 999, 878, 783, 749, 703.
(1S,4R)-cis-4-(2-methoxyphenyl)cyclopent-2-enol (3d). Compound 3d was obtained as a light
brown oil (using procedure A and L1 it was obtained 17.1 mg, 0.090 mmol, 90% yield, 94% ee.
Using procedure A and L2 it was obtained 11.0 mg, 0.058 mmol, 58% yield, 80% ee). ee
determined by HPLC analysis (Kromasil 10 Cellucoat 4.6 mm X 25 cm, column temperature 25
oC, Hexanes/iꢀPrOH 99:1, 1 mL/min, 272 nm, tR =55.8 min (minor) and tR = 64.6 min (major).
The compound has been fully characterized previously.7
(1’S,4’R)-cis-2-(4’-hydroxycyclopent-2’-enyl)phenol (3e). Compound 3e was obtained as a
light brown oil: (using procedure A and L1 it was obtained 10.0 mg, 0.051 mmol, 51% yield,
86% ee. Using procedure A and L2 it was obtained 10,7 mg, 0.061 mmol, 61% yield, 84% ee.).
o
ee determined by HPLC analysis (Daicel IC 4.6 mm X 25 cm, column temperature 25 C,
Hexanes/iꢀPrOH 95:5, 1 mL/min, 225 nm, tR = 15.5 min (minor) and tR = 18.0 min (major). The
compound has been fully characterized previously.7
(1S,4R)-cis-4-phenylcyclopent-2-enol (3f). Compound 3f was obtained as a light brown oil
(using procedure A and L1 it was obtained 13.6 mg, 0.085 mmol, 85% yield, 97% ee. Using
procedure A and L2 it was obtained 12.2 mg, 0.076 mmol, 76% yield, 97% ee). ee determined
o
by HPLC analysis (Daicel AD 4.6 mm X 25 cm, column temperature 25 C, Hexanes/iꢀPrOH
95:5, 0.8 mL/min, 210 nm, tR = 11.7 min (minor) and tR = 12.7 min (major). The compound has
been fully characterized previously.7
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(1S,4R)-cis-4-(3,4-dichlorophenyl)cyclopent-2-enol (3g). Compound 3g was obtained as light
brown oil (using procedure A and L1 it was obtained 17.4 mg, 0.076 mmol, 76% yield, 97% ee.
Using procedure A and L2, it was obtained 17.9 mg, 0.078 mmol, 78% yield, 95% ee). ee
o
determined by HPLC analysis (Daicel IC 4.6 mm X 25 cm, column temperature 25 C,
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Hexanes/iꢀPrOH 98:2, 1 mL/min, 225 nm, tR = 14.8 min (minor) and tR = 17.6 min (major), [α]20
1
589(c 1.76, CHCl3) = +91 (97% ee sample). H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 8.3 Hz,
1H), 7.25 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.3, 2.1 Hz, 1H), 5.94 (dt, J = 5.6, 2.2 Hz, 1H), 5.82
(dt, J = 5.7, 1.6 Hz, 1H), 4.90 – 4.84 (m, 1H), 3.73 – 3.62 (m, 1H), 2.77 (ddd, J = 13.8, 8.4, 7.4
Hz, 1H), 1.51 (s, 1H), 1.46 (ddd, J = 13.8, 6.0, 4.9 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ
145.5, 136.5, 135.4, 132.6, 130.6, 130.4, 129.5, 127.0, 77.3, 49.2, 43.7. HRMS (-ESI) calculated
for C11H10Cl2O [M+H+]: 229.0181; found 229.0184. IR (neat, cm-1) 3348, 2966, 2932, 1595,
1563, 1469, 1398, 1315, 1134, 1073, 1034, 826.
(1S,4R)-cis-4-(3-nitrophenyl)cyclopent-2-enol (3h). Compound 3h was obtained as light brown
oil (using procedure A and L1 it was obtained 17.6 mg, 0.086 mmol, 86% yield, 96% ee. Using
procedure A and L2, it was obtained 15.6 mg, 0.076 mmol, 76% yield, 92% ee). ee determined
o
by HPLC analysis (Daicel AD 4.6 mm X 25 cm, column temperature 25 C, Hexanes/iꢀPrOH
97:3, 1 mL/min, 210 nm, tR = 41.7 min (minor) and tR = 49.8 min (major). The compound has
been fully characterized previously.7
(1S,4R)-cis-4-(2-nitrophenyl)cyclopent-2-enol (3i). Compound 3i was obtained as light brown
oil (using procedure A and L1 it was obtained 14.8 mg, 0.072 mmol, 72% yield, 97% ee. Using
procedure A and L2, it was obtained 14.2 mg, 0.069 mmol, 69% yield, 97% ee). ee determined
o
by HPLC analysis (Daicel OJꢀH 4.6 mm X 25 cm, column temperature 25 C, Hexanes/iꢀPrOH
96:4, 1 mL/min, 225 nm, tR = 24.9 min (minor) and tR = 27.6 min (major). The compound has
been fully characterized previously.7
(S)-3-(2-nitrophenyl)cyclopentanone (4i). Compound 4i was obtained as light brown oil (using
procedure A and L1, it was obtained 1.7 mg, 0.018 mmol, 18% yield, 90% ee. Using procedure
A and L2 it was obtained 4.7 mg, 0.023 mmol, 23% yield, 88% ee). ee determined by HPLC
o
analysis (Daicel AD 4.6 mm X 25 cm, column temperature 25 C, Hexanes/iꢀPrOH 97:3, 1
mL/min, 225 nm, tR = 21.7 min (major) and tR = 28.3 min (minor). The compound has been fully
characterized previously.7
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(1S,4R)-cis-4-(4-(trifluoromethyl)phenyl)cyclopent-2-enol (3j). Compound 3j was obtained as
light brown oil (using procedure A and L1, it was obtained 13.9 mg, 0.061 mmol, 61% yield,
98% ee. Using procedure A and L2, it was obtained 17.3 mg, 0.076 mmol, 76% yield, 94% ee).
o
ee determined by HPLC analysis (Daicel IBꢀ3 4.6 mm X 25 cm, column temperature 25 C,
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Hexanes/iꢀPrOH 99:1, 1 mL/min, 225 nm, tR = 26.5 min (major) and tR = 28.9 min (minor). The
compound has been fully characterized previously.7
(1S,4R)-cis-4-(3-(trifluoromethyl)phenyl)cyclopent-2-enol (3k). Compound 3k was obtained
as light brown oil (using procedure A and L1 it was obtained 17.3 mg, 0.076 mmol, 76% yield,
98% ee. Using procedure A and L2 it was obtained 19.6 mg, 0.086 mmol, 86% yield, 96% ee).
ee determined by HPLC analysis (Kromasil 10 Cellucoat 4.6 mm X 25 cm, column temperature
o
25 C, Hexanes/iꢀPrOH 99:1, 1 mL/min, 272 nm, tR = 25.0 min (major) and tR = 26.5 min
(minor). The compound has been fully characterized previously.7
(1S,4R)-cis-4-(2-(trifluoromethyl)phenyl)cyclopent-2-enol (3l). Compound 3l was obtained as
light brown oil (using procedure A and L1 it was obtained 15.1 mg, 0.066 mmol, 66% yield,
96% ee. Using procedure A and L2 it was obtained 16.4 mg, 0.072 mmol, 72% yield, 98% ee).
o
ee determined by HPLC analysis (Daicel IB 4.6 mm X 25 cm, column temperature 25 C,
Hexanes/iꢀPrOH 99:1, 1 mL/min, 272 nm, tR = 29.0 min (major) and tR = 30.1 min (minor). The
compound has been fully characterized previously.7
(3aS,8bS)-3a,8b-dihydro-1H-cyclopenta[b]benzofuran (7e). JohnPhosAuCl (3 mol%), AgOTf
(3 mol%) and 30 mg of 4 Å activated molecular sieves where stirred in 0.5 mL of dry CH2Cl2 in
the dark for 10 min. To this mixture, it was added a solution of corresponding phenol in 0.3 mL
of dry CH2Cl2 and 0.5 mL of dry THF. The reaction was left stirring at ambient temperature, in
dark, and monitored by TLC until complete consumption of the phenol. The solvent was then
evaporated and the crude mixture was purified by column chromatography using EtOAc/hexanes
as eluent to afford product 7e as colorless oil (when starting from 38.7 mg or 0.22 mmol of 3e, it
was obtained 32 mg, 0.20 mmol, 92% yield). ee can be determined by HPLC analysis (Daicel
OJꢀH 4.6 mm X 25 cm, column temperature 25 oC, Hexanes/iꢀPrOH 98:2, 1 mL/min, 225 nm, tR
= 8.4 min (major) and tR = 9.2 min (minor). [α]20 589(c 0.67, CHCl3) = ꢀ42 (81 % ee sample). 1H
NMR (500 MHz, CDCl3) δ 7.15 (d, J = 7.3 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 6.85 (t, J = 7.4 Hz,
1H), 6.76 (d, J = 8.1 Hz, 1H), 6.03ꢀ6.00 (m, 1H), 5.87ꢀ5.84 (m, 1H), 5.82 (d, J = 8.1 Hz, 1H),
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4.07 (t, J = 8.1 Hz, 1H), 2.93 (dd, J = 17.0, 8.1 Hz, 1H), 2.58 (d, J = 17 Hz, 1H). C NMR
(125 MHz, CDCl3) δ 158.5, 135.5, 131.6, 129.6, 128.5, 124.9, 120.6, 110.1, 92.6, 43.4, 40.6.
HRMS (+ESI-TOF) calculated for C11H10O [M]: 158.0726; found 158.0720. IR (neat, cm-1)
2928, 1497, 1392, 1224, 968, 756.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, computational methods, characterization
1
13
data and chiral HPLC analyses for compounds 3aꢀl, 4i and 7e, and H and C NMR spectra for
the new compounds L2, 3c, 3g and 7e. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: roque@iqm.unicamp.br.
Author Contributions
The manuscript was written with the contributions of all authors. All authors have given
approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
J. O. S., R. A. A., V. H. M. S., A. A. C. B and C. R. D. C. acknowledge the financial support of
the São Paulo Research Foundation – FAPESP (grants 2013/00544ꢀ0, 2013/25639ꢀ4,
2013/04813ꢀ6, 2015/01491ꢀ3, 2011/23832ꢀ6, and 2013/07600ꢀ3). B. M. S thanks Brazilian
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Ministry for Education – CAPES, for a fellowship. M. A. thanks Third World Academy of
Science ꢀ TWAS and the Brazilian National Research Council – CNPq, for a postꢀdoctoral
fellowship. A.A. thanks the FloridaꢀBrazil Linkage Institute for their support of our programs.
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