Enantioselective palladium(0)-catalyzed nazarov-type cyclization

Article abstract of DOI:10.1002/anie.201500881

A Pd⁰-catalyzed asymmetric Nazarov-type cyclization is described. The optimized ligand for the reaction incorporates a weakly coordinating pyridine ring into a TADDOL-derived phosphoramidite (TADDOL=α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol). The reaction leads to the formation of cyclopentenones as single diastereoisomers that incorporate two contiguous asymmetric centers, one tertiary and one an all-carbon-atom quaternary stereocenter, in high yield and optical purity. It is noteworthy that the reaction does not require that substrates should be activated by aryl substituents.

Full text of DOI:10.1002/anie.201500881

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201500881
German Edition: DOI: 10.1002/ange.201500881
Asymmetric Synthesis
Enantioselective Palladium(0)-Catalyzed Nazarov-Type Cyclization**
Kei Kitamura, Naoyuki Shimada, Craig Stewart, Abdurrahman C. Atesin, Tꢀlay A. Ates¸in,* and
Marcus A. Tius*
Abstract: A Pd0-catalyzed asymmetric Nazarov-type cycliza-
tion is described. The optimized ligand for the reaction
a catalytic quantity of Pd0.[6] Control experiments had
excluded the possibility that adventitious Brønsted acid or
traces of PdII had led to the reaction.[4g] We recently described
the racemic version of this reaction and one example of the
asymmetric case. In the presence of TADDOL-derived
phosphoramidite ligand 3 (TADDOL = a,a,a,a-tetraaryl-
1,3-dioxolane-4,5-dimethanol), the Pd0-catalyzed cyclization
led to the formation of 2 in 84% yield and 80.5:19.5 e.r.[6] The
absolute stereochemistry of 2 was determined by comparison
with a sample prepared in earlier work and validated by X-ray
crystallographic analysis.[2e]
incorporates
a weakly coordinating pyridine ring into
a TADDOL-derived phosphoramidite (TADDOL = a,a,a,a-
tetraaryl-1,3-dioxolane-4,5-dimethanol). The reaction leads to
the formation of cyclopentenones as single diastereoisomers
that incorporate two contiguous asymmetric centers, one
tertiary and one an all-carbon-atom quaternary stereocenter,
in high yield and optical purity. It is noteworthy that the
reaction does not require that substrates should be activated by
aryl substituents.
Our goals were to first optimize the enantioselectivity of
the reaction and then to define the reaction scope. Since we
lacked a mechanistic hypothesis we initiated our study by
screening chiral diphosphine ligands, using the cyclization of
1 to 2 to evaluate catalysts. The results were disappointing. Of
nearly 25 diphosphines evaluated, often in several different
solvents, none led to the formation of 2 in greater than
23% ee.[7] All reactions were slow at RTwith half-lives of days
or weeks. The first encouraging result was obtained with
monodentate phosphoramidite (MonoPhos) (S)-4, whose use
T
he acid-catalyzed Nazarov cyclization[1] and its asymmetric
version[2] are valuable tools for synthesis.[3] Our interest in the
variants of this reaction[4] led us to design diketoesters typified
by 1 (Scheme 1).[2e] Complementary polarization of the
terminal carbon atoms at the C2 and C6 positions is known
to accelerate the cyclization.[5] It was therefore not surprising
that the enol derivatives of diketoesters related to 1 were
excellent substrates for the Brønsted acid catalyzed Nazarov
cyclization.[2a,e] It was surprising that 1 also underwent
efficient cyclization to form 2 under neutral conditions with
as the ligand led to the formation of 2 in 32% ee.[8]
Significantly, this reaction was complete in less than 24 h
with Pd0 (20 mol%) and a 1:1 P:Pd ratio. In total, nine
commercially available, BINOL-derived MonoPhos[9] ligands
were evaluated (BINOL = 1,1’-bi-2-naphthol), and although
none matched (S)-4 in terms of asymmetric induction, the
reactions were rapid in each case. We therefore focused on
phosphoramidites.
TADDOL-derived phosphoramidites are attractive
because of the ease of their synthesis from inexpensive
tartrate.[10] We assumed that ligand optimization would be
straightforward because the aryl group, amine, and acetal
substituents can be varied independently to provide diverse
ligands. We quickly discovered that changes in two compo-
nents of the ligand, each of which improved performance,
were not additive. Even though TADDOL ligands have been
shown to be exceptionally versatile in catalysis, to date there
is little information available to guide their rational design.[11]
We ascertained that the amine group was the strongest
modulator of asymmetric induction and so we focused
attention on it. Preliminary screening revealed that ligand 5
(Table 1) was effective in transferring asymmetry. We
designed ligand 6 by hypothesizing that limiting the degrees
Scheme 1. Pd0-catalyzed cyclizations. Conditions A: [Pd2(dba)3]
(1 mol%), PPh3 (4 mol%), DMSO (0.2m), 608C, 4.5 h; 91% yield.
Conditions B: [Pd2(dba)3] (10 mol%), 3 (25 mol%), MeCN (0.06m),
RT, 2.5 h; 84% yield, 80.5:19.5 e.r. DMSO=dimethyl sulfoxide. dba=
dibenzylideneacetone.
[*] Dr. K. Kitamura, Dr. N. Shimada, Dr. C. Stewart, Prof. Dr. M. A. Tius
Chemistry Department, University of Hawaii at Manoa
2545 The Mall, Honolulu, HI 96822 (USA)
E-mail: tius@hawaii.edu
Prof. Dr. M. A. Tius
University of Hawaii Cancer Center
701 Ilalo Street, Honolulu, HI 96813 (USA)
Dr. A. C. Atesin, Prof. T. A. Ates¸in
Chemistry Department, The University of Texas-Pan American
1201 West University Drive, Edinburg, TX 78539-2999 (USA)
[**] K.K. thanks the Yamada Science Foundation for a fellowship. We
thank Prof. A. J. Minnaard for illuminating discussions. T.A.A. and
A.C.A. acknowledge the Texas Advanced Computing Center (TACC)
at The University of Texas at Austin for providing HPC resources
that have contributed to the research results reported within this
paper. URL: http://www.tacc.utexas.edu.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500881.
À
of rotational freedom about the Pd P axis in the mono-
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Table 1: Phosphoramidite ligands for the cyclization of 1 to form 2.[a]
Entry
ligand
R1
R2
e.r. of 2
1
2
3
4
5
6
7
8
9
5
6
7
8
Me
Me
Me
Ph
Me
2-pyridyl
Ph
72:28
88:12
60:40
60:40
97:3
79:21
77:23
73:27[b]
61:39
63:37
Ph
9
Ph
2-pyridyl
2-pyridyl
2-quinolyl
2-pyridyl
3-pyridyl
4-pyridyl
10
11
12
13
14
2-pyridyl
Me
H
Ph
Ph
10
[a] All reactions were performed according to conditions B, Scheme 1.
[b] The ligand was poorly soluble in neat MeCN and was screened in 5:1
MeCN:CH2Cl2.
dentate metal–ligand complex would result in improved
asymmetry transfer. Since strongly coordinating diphosphines
were poorly reactive catalysts, a pyridyl nitrogen atom in
ligand 6 provides a second weak coordination site.[12,13] Ligand
6 led to a large improvement in asymmetric induction, leading
to the formation of 2 in 88:12 e.r., whereas 7 and 8 were not
promising, both leading to the product in 60:40 e.r (Table 1,
entries 2–4). These results suggested that the pyridyl nitrogen
atom rather than the aromatic ring was important. Phosphor-
amidite 9 proved to be even better than 6, leading to 2 in 97:3
e.r., and was chosen for all work. A few of the other ligands
that were screened are shown in Table 1. Ligands 13 and 14 in
which R2 is a 3- or a 4-pyridyl group, respectively, gave results
that were similar to 8 in which R2 is phenyl which, like 13 and
14, does not provide a second coordination site, lending
support to our hypothesis for the role of the pyridine nitrogen
atom.
The reaction solvent exerted a large influence on both the
enantioselectivity as well as the reaction rate.[14] Acetonitrile
was shown to be the best solvent whereas propionitrile was
poor. Modest amounts of water were deleterious to both yield
and enantioselectivity. In the presence of 2 gmmolÀ1 pow-
dered 4 ꢀ molecular sieves (MS) a nearly quantitative yield of
2 was formed with 97:3 e.r. in less than 6 h. In the absence of
the sieves the reaction was complete in 20 h and led to the
formation of 2 in 66% yield with 97:3 e.r. Other dehydrating
agents did not lead to rate acceleration or to improvement of
the yield.[15] The catalyst load was decreased to Pd0 (5 mol%)
and 9 (7.5 mol%), and the scope of the cyclization was
examined (Scheme 2).[16]
Large aliphatic groups at the C2 position were well
tolerated (17–19), although the time to completion increased
with the size of the C2 substituent. A phenyl group at the
C2 position (20) resulted in a long reaction time and 72:28 e.r.
Also, the use of ligand 6 in place of 9 led to the formation of 20
in 90:10 e.r., which suggests an unfavorable competing p-
stacking interaction between one of the phenyl groups of the
ligand with the C2-phenyl substituent. Cyclization was
successful in the case of electron-rich (21–23, 26, 27) as well
Scheme 2. Cyclization products with yields, completion times, and
e.r. values. Unless otherwise noted, reaction conditions were as
described in the Experimental Section. [a] Using ligand 5, 82:18 e.r.
(91%). With ligand 6, 90:10 e.r. (77%). [b] [Pd2(dba)3] (5 mol%) and 9
(15 mol%). [c] [Pd2(dba)3] (15 mol%) and 9 (40 mol%). [d] [Pd2(dba)3]
(20 mol%) and 9 (50 mol%).
as electron-poor (24, 25) aromatic moieties at the C6 position.
The preparation of a- and b-naphthyl derivatives 28 and 29,
respectively, indicates that steric bulk at C6 is well tolerated.
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Replacing the methyl group in 2 at the C5 position by an ethyl
group (giving 30) resulted in small decreases in optical purity
and yield and an increase in the time to completion. Place-
ment of a phenyl group at the C5 position led to a further
decrease of the optical purity of product 31. An ethoxy
substituent at C5 led to nearly racemic product 32 whereas no
cyclization was detected when a fluorine substituent was
placed at the C5 position (33). Aryl substitution at C6 is not
necessary to activate the cyclization, as cyclopentenones
34–40 demonstrate. The times to completion are, however,
much longer for the all-aliphatic products, necessitating
a heavier catalyst load (34–35 and 38–40).
Based on our preliminary results from ongoing mecha-
nistic studies using DFT calculations,[17,18] we propose the
following mechanistic pathway: a) coordination of Pd to the
alkene group of the substrate[19] followed by enol tautome-
rization of the diketoester; b) concerted proton transfer from
the enol to the carbonyl with the formation of a Pd–p-allyl
complex and intramolecular nucleophilic attack to form the
The solvation-corrected energy of the transition state
leading to the major enantiomer was calculated to be
3.2 kcalmolÀ1 lower than that leading to the formation of
the minor enantiomer. Further mechanistic studies will be
reported in a separate manuscript.
We have described a catalytic asymmetric Nazarov-type
cyclization that takes place under neutral conditions. The
products are formed in 44–99% yield with up to 98:2 e.r.
Yields and optical purities are generally high. Two contiguous
asymmetric centers, one tertiary and one an all-carbon-atom
quaternary stereocenter, are formed. All products were
isolated as single diastereoisomers. Activation of the sub-
strate through aryl substitution at the C6 position is not
required but is beneficial to the rate of the reaction. We
expect that the reaction described herein will be part of
a larger family of metal-mediated Nazarov-type cyclizations.
For example, when [Ni(cod)2] (cod = 1,5-cyclooctadiene) was
used in place of [Pd2(dba)3] in the reaction described in the
Experimental Section, racemic 2 was formed as a single
diastereoisomer.
À
C C bond (Scheme 3). The stereochemistry determining step
Experimental Section
A mixture of [Pd2(dba)3] (6 mg, 6 mmol, 2.5 mol%), phosphoramidite
9 (12 mg, 18 mmol, 7.5 mol%), and activated 4 ꢀ MS (480 mg,
2 gmmolÀ1) in MeCN (5 mL) was stirred for 10 min at RT under
argon. To this mixture was added a solution of diketoester 1 (69 mg,
0.24 mmol) in MeCN (1 mL). After stirring for 6 h at RT, the mixture
was filtered through celite and the volatiles were removed under
vacuum. The product was purified by silica-gel column chromatog-
raphy (hexane:EtOAc = 85:15) to produce 2 (68 mg, 98%, 97:3 e.r.)
as a colorless oil.[2e]
Scheme 3. Proposed mechanism.
is the one in which the initial coordination of Pd takes place to
one of the two enantiofaces of the alkene. The P atom and the
pyridyl N atom of the ligand occupy the remaining two
coordination sites on the Pd center.
The points of closest contact between catalyst and bound
substrate are between the pyridyl group of the ligand and the
C6 Ph and the C5 Me groups, and also between one Ph group
of the TADDOL ligand and the C2 Me group (Figure 1).[18]
Keywords: asymmetric synthesis · cyclization ·
enantioselectivity · palladium · TADDOLs
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Figure 1. The key steric interactions between the TADDOL
phosphoramidite ligand, the metal, and the substrate.
The latter point of contact is essential for controlling the
stereochemical outcome as one Ph group of the ligand gets in
the way of the Me group at the C2 position during the
cyclization leading to formation of the minor enantiomeric
product. To the best of our understanding, chirality transfer
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C2 position and one of the Ph groups on the ligand.
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Received: January 29, 2015
Revised: March 6, 2015
Published online: && &&, &&&&
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Communications
Asymmetric Synthesis
K. Kitamura, N. Shimada, C. Stewart,
A. C. Atesin, T. A. Ates¸in,*
M. A. Tius*
&&&& — &&&&
Enantioselective Palladium(0)-Catalyzed
Nazarov-Type Cyclization
Stereoselective cycles: A Nazarov-type
Pd0-catalyzed asymmetric cyclization is
reported. The reaction forms cyclopent-
enones as single diastereoisomers that
incorporate two contiguous asymmetric
centers in high yield and optical purity.
The optimized ligand L incorporates
a weakly coordinating pyridine ring into
a TADDOL-derived phosphoramidite.
dba=dibenzylideneacetone. MS=
molecular sieves.
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