Asymmetric diels-alder and ficini reactions with alkylidene β-ketoesters catalyzed by chiral ruthenium PNNP complexes: Mechanistic insight

Article abstract of DOI:10.1021/ja210372u

Hydride abstraction from the β-position of the enolato ligand of the previously reported complex [Ru(3a-H)(PNNP)]PF₆ (5a; 3a-H is the enolate of 2-tert-butoxycarbonylcyclopentanone) with (Ph₃C)PF ₆ gives the dicationic com

Full text of DOI:10.1021/ja210372u

Article
pubs.acs.org/JACS
Asymmetric Diels−Alder and Ficini Reactions with Alkylidene
β-Ketoesters Catalyzed by Chiral Ruthenium PNNP Complexes:
Mechanistic Insight
Christoph Schotes, Martin Althaus, Raphael Aardoom, and Antonio Mezzetti*
Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093 Zurich, Switzerland
̈
̈
S
* Supporting Information
ABSTRACT: Hydride abstraction from the β-position of the
enolato ligand of the previously reported complex [Ru(3a−
H)(PNNP)]PF6 (5a; 3a−H is the enolate of 2-tert-butoxy-
carbonylcyclopentanone) with (Ph3C)PF6 gives the dicationic
complex [Ru(6a)(PNNP)]2+ (7a) as a single diastereoisomer,
which contains the unsaturated β-ketoester 2-tert-butoxycarbon-
yl-2-cyclopenten-1-one (6a) as a chelating ligand. The methyl
analogue 2-methoxycarbonylcyclopentanone (3b) gives [Ru-
(3b−H)(PNNP)]PF6 as a mixture of noninterconverting
diastereoisomers (ester group of 3b trans to P, 5b; or to N, 5c), which were separated by column chromatography. Hydride
abstraction from 5b (or 5c) yields diastereomerically pure [Ru(6b)(PNNP)]2+ (7b or 7c). Complexes 7b and 7c do not interconvert
at room temperature in CD2Cl2 and form opposite enantiomers of the Diels−Alder adduct upon reaction with Dane’s diene
(1 equiv). X-ray studies of 7a, 5b, and 5c give insight into the origin of enantioselection and the sense of asymmetric induction in the
previously reported asymmetric Diels−Alder and Ficini cycloaddition reactions with 2,3-disubstituted butadienes and ynamides,
respectively. Stoichiometric reactions (substrate coordination, cycloaddition, and product displacement) between [Ru-
(OEt2)2(PNNP)]2+ (2), 6b (or 6a), and Dane’s diene (15, to give estrone derivatives) or N-benzyl-N-(cyclohexylethynyl)-4-
methylbenzenesulfonamide (17, to give cyclobutenamides) suggest that product displacement from the catalyst is turnover limiting.
INTRODUCTION
Chart 1
■
Enantioselective Diels−Alder reactions have witnessed tremen-
dous advances in the last 20 years,1 but the restricted scope of
dienophiles, limited mechanistic understanding, and lack of
reliable stereochemical models with most catalysts are still open
challenges.2 Thus, although the breadth of the substrate scope
in enantioselective Diels−Alder reactions has considerably
increased recently1e driven by Corey’s chiral cationic
oxazaborolidine catalysts,1a,3 acrolein derivatives and unsatu-
rated imides are still the most commonly used dienophiles. In
contrast, poor dienophiles such as α-methylene β-ketoesters
have been rarely studied in asymmetric Diels−Alder reactions,4
probably because the Lewis acidity of most chiral catalysts is
too low for systems whose intrinsic reactivity (that is, for the
uncatalyzed, thermal reaction) is marginal.3
Additionally, bulky unsaturated β-ketoesters, such as the even
less reactive cyclic carboxypentenones, are challenging Diels−
Alder substrates, as they tend to polymerize5 and give keto−enol
tautomerization.6 Therefore, the corresponding tetrahydro-1-
indanones are formed in low yield and under harsh conditions5
unless elaborate protocols are used.7 Overall, alkylidene β-keto-
esters have been rarely used also in other asymmetric catalytic
reactions, and some applications in enantioselective conjugate
addition reactions have appeared only recently.8
highly oxophilic ruthenium/PNNP fragment.9,10 Double chlo-
ride abstraction from the dichloro complex11 [RuCl2(PNNP)]
(1) gives an elusive species that we tentatively formulate as
[Ru(OEt2)2(PNNP)](PF6)2 (2),9 which reacts with saturated β-
ketoesters such as 2-tert-butoxycarbonylcyclopentanone (3a) to
give [Ru(3a)(PNNP)](PF6)2 (4a) (Scheme 1a). The dicationic
β-ketoester adducts of type 4 offer a rare example of the
coordination of a 1,3-dicarbonyl compound in its neutral, non-
enolized form12 and are intermediates in highly enantioselec-
tive C−C and C-heteroatom bond forming reactions of saturated
β-ketoesters, such as Michael addition,12a,b hydroxylation,13 and
fluorination.14
The enhancement of the acidity of the β-ketoester upon
coordination to the dicationic ruthenium PNNP fragment plays
a pivotal role in these reactions, and complexes of type 4 are
Our interest in alkylidene β-ketoesters has developed from
the study of the coordination of their saturated analogues, such
as 2-tert-butoxycarbonylcyclopentanone (3a) (Chart 1), to the
Received: November 4, 2011
Published: December 19, 2011
© 2011 American Chemical Society
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a
Scheme 1. Synthesis of β-Ketoester Complexes
Scheme 3. Asymmetric Ficini Reaction
a
For 11 other examples with different ynamides, see ref 16.
concerning the substrate/catalyst adduct is deemed to be pivotal
to mechanistic understanding, and the key to the broad
applicability of a Diels−Alder catalyst,2 such structurally char-
acterized adducts as 7a are rare. In the specific case of alkylidene
β-ketoesters, the closest analogues are the copper-catalyzed
Michael reactions of alkylidene malonates17 and the iridium-
promoted Nazarov cyclization of divinyl ketones.18,19 We show
herein that the structures of the catalyst adduct 7a with the
unsaturated β-ketoester 6a and some related species give valuable
insight into the mechanistic details of the Diels−Alder and
[2 + 2] cycloaddition reactions.
easily deprotonated to the enolato analogues 5 (Scheme 1b).9,12,14
Recently, we serendipitously discovered that the enolato ligand
(3a−H) in [Ru(3a−H)(PNNP)]PF6 (5a) undergoes β-hydride
abstraction when treated with trityl hexafluorophosphate
(Scheme 1c). The resulting unsaturated β-ketoester 2-tert-
butoxycarbonyl-2-cyclopenten-1-one (6a) remains coordinated
to ruthenium in the well-defined adduct [Ru(6a)(PNNP)]2+
(7a). Alternatively, 7a can be prepared from [Ru(OEt2)2-
(PNNP)](PF6)2 (2) and 6a (Scheme 1d), and analogous com-
plexes are obtained with other 2-alkyloxycarbonyl-2-cyclopenten-
1-ones (Chart 1). We recently described the use of these species
as catalysts for the highly enantioselective cycloaddition reactions
with dienes (Diels−Alder)15 and ynamides (Ficini reaction)16 in
two preliminary reports (see Schemes 2 and 3).
RESULTS AND DISCUSSION
■
Hydride Abstraction from Enolato Complex 5a. We
discovered the hydride abstraction reaction in Scheme 1c while
studying the possible involvement of a ruthenium(III) species
in the electrophilic fluorination of 3a with catalyst 2.12c,14,20
Thus, the Ru(II) enolato complex [Ru(3a−H)(PNNP)]PF6
(5a) was treated with a number of one-electron oxidants, in
particular (NH4)2[Ce(NO3)6] (CAN), K2S2O8 (in the presence
of 18-crown-6), AgPF6, and (Ph3C)PF6 in CD2Cl2. Cerium(IV)
ammonium nitrate and potassium persulfate did not react
under these conditions. Instead, AgPF6 gave a mixture of
diamagnetic products whose major component (46%) was the
unsaturated β-ketoester complex 7a, which we were not able to
Scheme 2. Asymmetric Diels−Alder Reaction with
Substituted 2,3-Butadienes
1
identify at this stage. In all experiments, the H and 31P NMR
spectra of the reaction solutions were sharp and furnished no
evidence of paramagnetic species being formed. Eventually, we
discovered that (Ph3C)PF6 (1 equiv) reacts with 5a in CD2Cl2
within seconds, as indicated by a color change from orange to
yellow. The 31P NMR spectrum of the reaction solution
showed quantitative conversion of 5a, and the only observable
product featured an AX pattern at δ 63.2 and δ 50.4 (JP,P′
=
1
29.3 Hz). The H NMR spectrum showed the characteristic
signal for the tertiary C−H hydrogen in Ph3CH (δ 5.59) and a
doublet of doublets at δ 8.38 for the vinylic proton of the
coordinated α-alkylidene β-ketoester, which indicated that a
hydride abstraction at the β-position of the coordinated
deprotonated β-ketoester 3a had occurred (Scheme 1c).
Accordingly, the 13C NMR spectrum of the reaction solution
exhibited signals at δ 131.9 and 188.3 that we assign to the sp2
carbon atoms of the newly formed double bond. The vinylic
proton at δ 8.38 shows correlation cross-peaks to the keto
carbonyl carbon at δ 215.5 and to the ester carbonyl C atom at
δ 165.7 in the long-range 13C,1H-HMQC NMR spectrum
(Chart 2, left). Thus, we formulate the product of the reaction
as the dicationic complex [Ru(6a)(PNNP)]2+, in which the
enolato ligand in complex 5a has been transformed into the
unsaturated β-ketoester 6a. The 13C NMR signal of the olefin
carbon atom is shifted considerably toward higher frequency
compared with a related free enone ester (δ 188.3 vs 171.9,
Chart 2, right). Thus, the coordination to ruthenium enhances
To the best of our knowledge, these are the first enantio-
selective cycloaddition reactions that use cyclic unsaturated β-
ketoesters to give highly enantiomerically enriched molecules.
Such products bear a quaternary all-carbon stereocenter at the
bridgehead position of a bicyclic system and have potential
biological interest.15 Additionally, although structural information
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coordination bond between ruthenium and a neutral oxygen
donor (see below). Nonetheless, we were able to grow crystals
of (rac)-7a.
Chart 2
X-ray Crystal Structure of Complex (rac)-7a. Complex
(rac)-7a was prepared by treating the enolato complex (rac)-5a
(containing the (R,R),(S,S)-PNNP ligand) with (Ph3C)PF6
(1 equiv) in CD2Cl2. Layering the solution directly after the
reaction in an NMR tube with n-hexane gave single crystals of
the centrosymmetric triclinic space group P1, whose asym-
̅
metric unit contains one complex molecule, two [PF6]− anions,
and two CD2Cl2 molecules. Figure 1 shows an ORTEP drawing
the polarization of the CC double bond by withdrawing
electron density from the β-carbon atom of the coordinated
enone 6a.21 The resulting stabilization of the corresponding
LUMO improves the interaction with the HOMO of electron-
rich dienes in Diels−Alder reactions22 and enhances the
reactivity of the CC double bond toward the cycloaddition
reactions discussed below.
1
Both the H and 31P NMR spectrum show that the hydride
abstraction is quantitative and well behaved, as no side-products
(apart from Ph3CH) are detected. The triphenylcarbenium ion
(tritylium cation) reacts with 5a as a hydride abstractor and
hence as a two-electron oxidant to give triphenylmethane23
instead of being reduced by one electron to the trityl radical
and dimerizing to Gomberg’s dimer.24 The hydride-abstracting
properties of tritylium salts have been used in organic reactions,
for instance for the conversion of secondary alcohols to
ketones.25 The trityl cation is known to abstract a hydride from
silyl enol ethers to give the corresponding enones26 and has
been used in transition metal chemistry for hydride abstraction
reactions from alkyl ligands to give carbene complexes,27 but its
reaction with an enolato complex (and β-ketoesters in general)
is, to the best of our knowledge, unprecedented.
Figure 1. ORTEP drawing of (OC-6−42-A-(S,S))-7a (ellipsoids at
30% probability).
The closest literature analogue of enolate oxidation (Scheme 1c)
is the oxidative cleavage of titanium bound enediolates by tri-
phosgene to form cyclopentane-1,2-diones, a reaction whose
mechanism has not been investigated.28 Apart from the general
selenide oxidation−elimination reaction,29 the oxidation of β-
ketoesters to their unsaturated analogues has been achieved
with a combination of Cu(OAc)2 and Pb(OAc)430 or with 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ).31 These methods
make use of highly toxic primary oxidants and often suffer from
moderate yields and narrow substrate scope. Therefore, the
tandem deprotonation/hydride abstraction reaction described
above is an elegant and clean preparation of unsaturated β-
ketoesters on a small scale. We show below that, beyond funda-
mental aspects, this approach is chemically useful for the in situ
preparation of pure catalysts.
of the complex with the (S,S)-PNNP ligand, which is the
enantiomer used in all catalytic reactions discussed below.
The coordination sphere of ruthenium is a distorted octa-
hedron with the absolute configuration OC-6-42-A.32 The
(S,S)-PNNP ligand is arranged in the Λ-cis-β mode and in a
conformation that is very similar to those observed in the
related enolato complex 5a and in the β-keto acid complex
[Ru(3a−tBu)(PNNP)]2+ (8) (3a−tBu is the acid obtained by
12a,33
t
hydrolysis of the BuOC(O) ester group of 3a).
The
unsaturated β-ketoester 6a binds with the keto oxygen O(1)
trans to N(1) and with the ester carbonyl oxygen O(2) trans to
P(2), as in the enolato complex 5a, which suggests that the
hydride abstraction does not cause a major structural rearrange-
ment. The Ru−O(1) distance (trans to N) is significantly shorter
than Ru−O(2) (trans to P) (2.107(2) vs 2.172(2) Å), as
observed in 8,12a and reflects the lower trans influence of the
imino donor as compared to phosphine (Table 1).
The C−C and C−O bond distances in the coordinated
enone ester differ only marginally from average values (Chart 3).34
The conjugation between the C(48)−C(49) double bond and
the carbonyl groups in 7a, whose effect on the 13C NMR
chemical shift of C(48) has been discussed above, does not
significantly affect the C−O distance in the keto group, as
indicated by the comparison with the closest analogue, the
saturated acid complex 8.12a The comparison between 5a and
7a shows the expected differences between an enolato and an
enone ligand, that is, the shortening of the C(48)−C(49) bond
from single to double, the lengthening of the C(45)−C(49)
distance (by 0.08 Å), and the shortening of the carbonyl O(1)−
C(45) bond. The effect is smaller for the O(2)−C(50) bond, as
cis-β-[Ru(6a)(PNNP)]2+ (7a). Complex 7a was independ-
ently prepared by adding 2-tert-butoxycarbonyl-2-cyclopenten-
1-one (6a) to a CD2Cl2 solution of freshly prepared
[Ru(OEt2)2(PNNP)](PF6)2 (2) (Scheme 1d). The reaction
is complete within 15 min, as indicated by a slight color change
of the reaction solution from reddish-brown to orange-red. The
31P NMR spectrum of the reaction solution shows the AX
pattern of 7a as the only identifiable product. However, small
impurities (<2% of total integrated intensity) indicate that this
synthetic pathway is less clean than the hydride abstraction
(Scheme 1a−c). Attempts to prepare 7a by the latter route on a
larger scale (50−100 mg) by precipitation with hexane from the
CD2Cl2 reaction solution led to extensive decomposition. A
similar behavior has been observed for the saturated analogue
4a,12a which is not surprising in view of the labile nature of the
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Table 1. Selected Distances (Å) of 5a, 7a, 5b, and 5c (see also Chart 3)
7a
5a
5b
5c
Ru−P(1)
Ru−P(2)
Ru−N(1)
Ru−N(2)
Ru−O(1)
Ru−(O2)
C(1)···C(49)
C(4)···C(48)
P(1)−Ru−C(49)
C(49)···Ru−P(1)−C(1)
2.2973(8)
2.2692(8)
2.047(3)
2.083(3)
2.107(2)
2.172(2)
3.471(4)
3.760(1)
91.27(5)
−8.3(1)
2.2803(8)
2.2681(8)
2.044(2)
2.097(3)
2.082(2)
2.144(2)
3.554(5)
4.058(5)
92.52(6)
−12.0(1)
2.2820(7)
2.2601(6)
2.050(2)
2.091(2)
2.086(2)
2.128(2)
3.572(4)
4.047(4)
94.85(5)
−11.4(1)
2.280(2)
2.277(2)
2.030(5)
2.072(5)
2.108(4)
2.109(4)
3.47(1)
3.78(1)
92.5(1)
−4.9(3)
Chart 3
the ester moiety is less enolized than the ketone carbonyl12a
and, therefore, gains less double bond character upon hydride
abstraction. The Ru−P and Ru−N distances in 7a and in the
enolato complex 5a are very similar (Table 1). However, the
Ru−O distances are slightly longer in 7a than in 5a, which
reflects the weaker coordination of the neutral unsaturated β-
ketoester in 7a as compared to the anionic enolato ligand in 5a.
Interesting changes on going from the enolato complex 5a to
the enone derivative 7a are the shrinking of the C(1)···C(49)
and C(4)···C(48) nonbonding contacts and of the
C(49)···Ru−P(1)−C(1) torsion angle (Figure 2). Also, the
dihedral angle between the plane defined by C45/C49/C50 of
the β-ketoester and that of the shielding phenyl ring is reduced
from 23.3° to 14.0°.35 These changes indicate enhanced π−π-
interactions between the C(1)−C(6) phenyl ring and the
β-ketoester in 7a as compared to 5a and reflect the higher
π-acidity of the electron-poor enone moiety in comparison to
the enolato ligand. Hence, the two ring systems align and move
closer together in 7a. Interestingly, Corey has proposed that the
π−π-stacking between aromatic groups of the catalyst and
acrolein- or enone-type substrates in the transition state directs
the enantioselectivity of cationic oxazaborolidine catalysts,1a,3
but, to the best of our knowledge, the effect has never been
visualized by X-ray crystallography of a substrate/catalyst adduct.
Catalytic Diels−Alder Reaction. As described in a prelimi-
nary report,15 the dicationic derivative [Ru(OEt2)2(PNNP)]-
(PF6)2 (2) catalyzes the enantioselective Diels−Alder reaction
of the unsaturated β-ketoesters 6 with 2,3-dimethylbutadiene
Figure 2. Partial ORTEP views of 5a and 7a (the PNNP framework is
omitted for clarity, except for the C(1)−C(6) phenyl) (distances in
angstroms). The angles between the C(1)−C(6) phenyl ring and the
C(45)−C(49)−C(50) plane are 23.3(4) and 14.0(4)°, respectively.
(9), 2,3-dimethoxybutadiene (10), and 2,3-(dibenzyloxy)buta-
diene (11) (Scheme 2a). The corresponding alkoxycarbonylte-
trahydro-1-indanones 12−14 are formed at room temperature
overnight with up to 93% ee (Table 2). With Dane’s diene (15),
the estrone derivative (8R,13S,14S)-13-tert-butoxycarbonyl-3-
methoxy-7,8,12,13,15,16-hexahydro-6H-cyclopenta[a]-
phenanthren-17(14H)-one (16a) was quantitatively obtained
with 86% ee or as a single enantiomer after recrystallization
(Scheme 2b). Of the two diastereoisomers (ester-exo and ester-
endo) that are possible with 15, the ester-exo product is favored,
but the diastereomeric ratio strongly depends on the ester
moiety and drops from 27:1 for the tert-butyl ester 6a to 3:1 for
the methyl analogue 6b (before recrystallization).
Under optimized conditions, the reaction with activated
dienes such as 15 gives essentially quantitative yields with a
nearly stoichiometric amount of the reagent, whereas 2,3-
dimethylbutadiene (9) has to be used in excess (10 equiv).
Except for the reaction with 9, a CH2Cl2:Et2O (1:1) solvent
mixture was required to achieve high yields in a reproducible
fashion. Also, high enantioselectivity was only obtained with the
bulky unsaturated β-ketoester 6a (Table 2, entries 4, 5). These
effects are discussed and explained in the context of the
stoichiometric reactions described below.
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tetraaryl-1,3-dioxolane-4,5-dimethanol) and copper bisoxazo-
line complexes.37 Therefore, the ruthenium PNNP catalysts
extend the scope of Diels−Alder reactions in the challenging
task of enantioselective formation of all-carbon quaternary
centers, which is an area of intense research.38 Also, as Corey
has recently reported a procedure to convert the 18-C-methyl
analogue of 16 (that is, with Me instead of CO2R, Scheme 2b)
to estrone methyl ether,39a,b the reaction with Dane’s diene is
potentially useful in the synthesis of enantiomerically pure
estrone derivatives functionalized at the α-carbonyl bridgehead
position. Such biomolecules are interesting in view of their
possible application in the treatment of hormone-dependent
breast cancer as an inhibitor of steroidogenic enzymes39c−e or
as an antimicrotubule agent.39f The possibility to obtain both
ent- and nat-estrone derivatives is appealing, because the two
enantiomeric forms of steroids usually show fundamentally
different behavior.39g
Catalytic Ficini Reaction. In its original version, the Ficini
reaction is the [2 + 2] cycloaddition of an ynamine onto an
enone40 and has been extended to the less reactive ynamides41
only recently. In particular, sulfonyl-substituted ynamides have
been shown to react with cyclohexenone in the presence of a
high loading of a CuCl2/AgSbF6 catalyst, but no diastereose-
lectivity was observed with chiral ynamides.42 Therefore, we
were pleased to discover that [Ru(OEt2)2(PNNP)](PF2)6 (2)
(10 mol %) catalyzes the enantioselective [2 + 2] cycloaddition
between unsaturated β-ketoesters 6a (R1 = tBu) or 6c (R1 = Et)
and N-benzyl-N-(cyclohexylethynyl)-4-methylbenzenesulfon-
amide (17). The corresponding amidocyclobutenes 18 are
formed with moderate to good enantioselectivity as the first
example of an enantioselective Ficini reaction (Scheme 3).
Further examples of cyclobutenamides of type 18, which
belong to a new class of products that feature enantiose-
lective formation of an all-carbon stereocenter at the
bridgehead position of a highly strained unsaturated
[3.2.0] bicycle, have been described in a preliminary report
and their structure and absolute configuration have been
ascertained.16
Table 2. Asymmetric Diels−Alder Reaction of 6a and 6b
a
with Various Dienes
entry dienophile diene product
R1
R2
yield (%) ee (%)
b
c
1
2
3
4
5
6
7
8
9
6a
6a
6a
6a
6a
6b
6b
6b
6b
6b
9
9
12a
12a
13a
14a
16a
12b
12b
13b
14b
16b
tBu
tBu
tBu
tBu
tBu
Me
Me
Me
Me
Me
Me
82
67
86
91
99
88
52
62
90
89
67
67
64
93
86
69
84
66
76
51
c
Me
10
11
15
OMe
OBn
b
c
9
Me
c
9
Me
10
11
15
OMe
OBn
10
a
From ref 15, 2 (10 mol %) as catalyst, room temperature, in CH2Cl2/
b
c
Et2O (1:1) (unless otherwise stated). In pure CH2Cl2. 10 equiv.
As discussed above, the coordination of the alkylidene β-
ketoester 6 to the Ru/PNNP fragment in the adducts of type 7
(Scheme 1d) lowers the energy of the LUMO and activates the
substrate toward cycloaddition of electron-rich dienes. The
stereochemical course of the reaction was determined with the
unsymmetrical diene 15 by reduction of the carbonyl moiety of
its Diels−Alder adduct 16a, esterification with (−)-camphanic
acid chloride, and X-ray structure determination.15a The
absolute configuration of 16a (8R,13S,14S) indicates that the
diene 15 approaches the metal-bound substrate over the less
hindered cyclopentenone ring. In the pericyclic transition state,
the ester residue points away from the forming ring and the
ester-exo product is formed (Figure 3). The approach of the
Unlike the Diels−Alder reactions, which require an excess of
the diene, nearly stoichiometric amounts of the ynamide (1.1
equiv of 17) gave high yields. The reaction tolerates different
substituents on the ynamide, but an electron-donating alkyl
substituent (benzyl or methyl) must be combined with an
electron-withdrawing sulfonyl group (tosyl, mesyl, or 4-
methoxyphenysulfonyl). The resulting balance of electronic
effects had to be optimized to give sufficient reactivity in the
catalytic reaction without promoting the background reaction.
Phenyl, n-hexyl, cyclohexyl, and other groups are tolerated in
the β-position to the nitrogen moiety. At difference with the
Diels−Alder reactions, which are run at room temperature and
mostly in a 1:1 CH2Cl2/Et2O mixture, the optimized
conditions for the Ficini reaction require heating at 55 °C in
a sealed tube over 24 h in pure CH2Cl2.
Figure 3. Sketches of the possible approaches of Dane’s diene (15) to
7a. Part of the methoxybenzene ring of 15 is omitted for clarity.
The enantioselectivity is higher with the tert-butyl derivative
6a than with the smaller 2-ethoxycarbonyl-2-cyclopenten-1-one
(6c) (Scheme 3). This trend has already been observed in the
Diels−Alder reaction, in which the tert-butyl derivative 6a
performs better than the methyl analogue 6b (Table 2, entries
4, 9, and Scheme 2b), and in the previously reported
transformations of the saturated β-ketoesters 3.12a,14 As the
coordination of 6a to the Ru/PNNP fragment gives the adduct
7a as a single diastereoisomer, we speculated that the lower
enantioselectivity observed with the less bulky methyl and ethyl
diene over the ester moiety of 6a, which would result in the
formation of the ester-endo product, is disfavored by the bulky
tert-butyl group. Accordingly, the reaction of 15 with the
methyl ester derivative 6b gives lower endo/exo selectivity.36
Together with Yamauchi’s magnesium Ph-Box system,4
complexes of type 7 are the only highly enantioselective
catalysts for Diels−Alder reactions of alkylidene β-ketoesters,
which give low enantioselectivity with typical two-point binding
catalysts such as titanium(IV) TADDOLato4b (TADDOL is
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To that end, [Ru(OEt2)2(PNNP)]2+ (2) was treated with
2-methoxycarbonylcyclopentanone (3b) (1.1 equiv) in CD2Cl2,
which gave the dicationic complex [Ru(3b)(PNNP)]+ as a
70:30 mixture of diastereoisomers (4b and 4c) (Scheme 4).
Deprotonation with triethylamine (1.2 equiv) yielded the
diastereomeric enolato complexes 5b and 5c in the same
diastereomeric ratio, as indicated by the 31P NMR spectrum
(two AX patterns at δ 50.5/64.3 and δ 49.8/62.5 for 5b and 5c,
respectively). Separation by column chromatography on silica
gave pure 5b and 5c, which show different physical and
chemical properties. The major isomer 5b is a red crystalline
solid and is significantly more soluble in CH2Cl2 and CHCl3
than 5c, which is an orange powder.
Scheme 4. Synthesis of 7b/7c and Stoichiometric
Diels−Alder Reaction with Dane’s Diene
The 13C NMR shifts of the enolized keto and ester moieties
(5b: δ 193.4, 167.5; 5c: δ 191.2, 168.0) are very similar to those
of the tert-butyl ester analogue 5a (δ 192.0, 168.3).12a,b In the
major diastereoisomer 5b, the ester 13C NMR signal at δ 167.5
(but not that of the enolized keto moiety at δ 193.4) shows
coupling to phosphorus (3JP,C =1.5 Hz), which is diagnostic of a
trans arrangement of the ester and phosphine groups. Thus, 5b
has the same structure as the tert-butyl analogue 5a, in which
the ester group of the metal-bound β-ketoester is trans to P(2)
3
t
(as indicated by the JPC of 1.5 Hz to CO2 Bu). In the minor
diastereoisomer 5c, the signal of the ester moiety at δ 168.0
3
shows no P,C-coupling, whereas a JP,C of 1.6 Hz is observed
for the signal of the enolized keto moiety at δ 191.2, which is
thus trans to the phosphine (Scheme 4).
The diastereomeric enolato complexes 5b and 5c have
1
similar H NMR spectra, except for the ester methyl signal,
which is distinctively shifted to lower frequency in the minor
isomer 5c (δ 2.63) as compared to 5b (δ 3.20), probably
because of the ring current of the aromatic framework of the
PNNP ligand (as suggested by the X-ray structure of 5c, see
below). Complexes 5b and 5c can be stored at room temperature
under protective gas atmosphere in the solid state for months
without signs of decomposition or interconversion. Also, no
isomerization is observed in CD2Cl2 solution over 24 h, even in
the presence of diethyl ether as a coordinating cosolvent in 1:1
ratio to CD2Cl2.
X-ray Structures of (rac)-5b and (rac)-5c. The enolato
complex (rac)-[Ru(3b−H)(PNNP)]PF6 was prepared from
the racemic (R,R),(S,S)-PNNP ligand as mixture of a major
(5b) and minor (5c) diastereoisomer, which were separated by
column chromatography and crystallized by layering n-pentane
over CH2Cl2 and dilute CHCl3 solutions, respectively. Both
(rac)-5b and (rac)-5c contain a discrete complex cation and the
hexafluorophosphate anion in the asymmetric unit, as well as
disordered solvent molecules. For both diastereoisomers 5b
and 5c, the enantiomer containing the (S,S)-PNNP ligand (as
used in catalysis) is depicted in Figure 4.
In the major diasteroisomer 5b, the coordination sphere of
ruthenium is a distorted octahedron with the OC-6−42-A
absolute configuration32 at ruthenium, and the (S,S)-PNNP
ligand is in the Λ-cis-β configuration as in 7a (Figure 1). As
observed in solution by NMR spectroscopy, the enolato ligand
binds with the keto oxygen O(1) trans to N(1) and with the
ester carbonyl oxygen O(2) trans to P(2), as in the tert-butyl
analogues 5a and 7a. The minor diastereoisomer 5c exhibits the
same cis-β configuration of the (S,S)-PNNP ligand, but the
enolized β-ketoester binds with the ester group trans to N(1)
and exposes the opposite enantioface (re in 5b vs si in 5c).
Thus, the absolute configuration is OC-6-43-A.32 For
convenience, selected interatomic distances of 5b and 5c are
esters may result from imperfect diastereoselectivity of the
binding of the unsaturated β-ketoester to ruthenium. Some
experiments designed to explain these observations are
described below and summarized in Scheme 4.
Stereoselectivity of β-Ketoester Binding. [Ru-
(OEt2)2(PNNP)](PF6)2 (2) was treated with the alkylidene
β-ketoesters 6a−c (1.2 equiv) in CD2Cl2, and the solutions
were analyzed by 31P NMR spectroscopy after a reaction
time of 15 min. A single product (featuring an AX pattern at
δ 63.2/50.4) was observed in case of the bulky ester 6a,
whereas two main species were observed for the analogous
reactions with the methyl ester 6b (δ 64.3/50.5 and δ 62.6/
49.8, 7:1 ratio) and ethyl ester 6c (δ 63.1/49.6 and δ 61.5/
48.6, 5:1 ratio). We assign the two additional signals ob-
served for 6b and 6c to different diastereoisomers of [Ru(6)-
(PNNP)]2+ (7), which was independently proven in the case
of the methyl derivative 6b.
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Figure 5. Space-filling representations (Cerius2) of the X-ray
structures of (OC-6-42-A-(S,S))-5b (major diastereoisomer) and
(OC-6-43-A-(S,S))-5c (minor).
Synthesis of 7b and 7c. The diastereomerically pure
enolato complex 5b (or 5c) reacts instantaneously with
(Ph3C)PF6 (1.05 equiv) in CD2Cl2 to give the substrate/
catalyst adduct 7b (or 7c) (Scheme 4c), as indicated by the
color change of the reaction solution from red-orange to
yellow. When pure major isomer 5b was used, 7b was the only
product, whereas pure 5c formed 7c only. Hence, the reaction
is stereospecific. When the hydride abstraction was performed
with the 70:30 diastereoisomeric mixture of 5b and 5c (that is,
without previous chromatographic separation), 7b and 7c were
formed in the same ratio of the starting materials. In contrast,
the addition of the alkylidene β-ketoester 6b to [Ru-
(OEt2)2(PNNP)]2+ (2) gave 7b/7c with a diastereomeric
ratio of 87:13 (Scheme 5).
Scheme 5. Direct Synthesis of 7b/7c from 2 and 6b
Figure 4. ORTEP drawings of (OC-6-42-A-(S,S))-5b (major
diastereoisomer) and (OC-6-43-A-(S,S))-5c (minor diastereoisomer)
(ellipsoids at 30% probability).
compared with those of the tert-butyl analogue 5a and of the
unsaturated analogue 7a in Table 1 and Chart 3.
Overall, the metrical parameters of 5b and 5c (see
Supporting Information) show that the conformation of the
PNNP ligand are very similar in both diastereoisomers, which
suggests that there is no strong steric preference for the major
diastereoisomer 5b. In contrast, the patterns observed for the
Ru−O distances largely differ in the two diastereoisomers. In
5b, the keto oxygen O(1), which bears the larger negative
partial charge and is trans to nitrogen, features a much shorter
Ru−O bond than the ester carbonyl, which is trans to
phosphorus (2.086(2) vs 2.128(2) Å). Thus, in 5b, the stronger
oxygen donor is trans to the ligand with the lower trans
influence (imine) as compared to phosphine, which is the
electronically favored situation. In the minor isomer 5c,
Ru−O(1) and Ru−O(2) are identical within experimental error,
indicating that the effects of enolization and of trans influence
cancel out. As the stronger donor (the keto group) is trans to
phosphine, this configuration is slightly electronically disfa-
vored. Space-filling models show that the small methyl ester
group can easily be accommodated both in 5b and 5c (Figure 5),
which suggests that the weak diastereoselectivity (70:30)
observed for the methyl ester mainly results from electronic
factors. As these are similar in the methyl derivatives 5b/5c and
in the tert-butyl analogue 5a, the formation of a single
diastereoisomer in the case of the bulky tert-butyl ester complex
5a is mainly dictated by steric factors.
Like 7a,43 the highly reactive and catalytically active
complexes 7b and 7c cannot be isolated and were characterized
1
in solution by H, 31P, and 13C NMR spectroscopy by analogy
to 7a. As in the case of 5c, the minor diastereoisomer of the
alkylidene β-ketoester complex, 7c, exhibits a distinctive low-
frequency shift of the methyl ester signal (7b: δ 3.62, 7c: δ
2.94). The diagnostic coupling (3JP,C) to the trans carbonyl
group (see 5b and 5c above) is not resolved in 7c but is
observed in 7b (3JP,C = 1.5 Hz). After 12 h in CD2Cl2, the pure
diastereoisomers 7b and 7c undergo partial decomposition to
unidentified products, but there is no conversion to the other
diastereoisomer, which confirms that they do not equilibrate
under these conditions (Scheme 4). The complexes are
configurationally stable also in the presence of a coordinating
cosolvent such as diethyl ether (1:1 with CD2Cl2), which fails
to promote ligand exchange.
Stoichiometric Diels−Alder Reactions with 7a−c. The
alkylidene β-ketoester complexes 7a−c, formed in situ from the
corresponding saturated β-ketoesters 3a−c as described above,
were used in a series of stoichiometric reactions with Dane’s
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diene (15) to model a single catalytic cycle (Table 3). The
substrate/catalyst adducts 7b and 7c with the methyl ester
Table 3. Diels−Alder Reactions with Dane’s Diene (15) and
a
2 or 7
entry
complex
mol %
added substrate
ee (%)
1
7a
7b
7c
100
100
100
100
100
10
−
−
−
−
90
87
2
b
3
97
c
4
7b/7c (87:13)
56
34
86
85
72
79
51
60
d
5
7b/7c (70:30)
−
6
7a
2
6a
6a
6b
6b
6b
6b
7
10
8
7b
10
e
9
7b
5
c
10
11
7b/7c (87:13)
10
e
7c
5
a
See Supporting Information for details. Absolute configuration of the
b
product is 8R,13S,14S, unless otherwise stated. Absolute configuration
c
is 8S,13R,14R. Prepared from 2 and 6b; see text and Scheme 5.
Figure 6. Partial ORTEP views of 5a and 7a (the PNNP framework is
omitted for clarity, except for the C(1)−C(6) phenyl ring). The angles
between the C(1)−C(6) phenyl ring and the C(45)−C(49)−C(50)
plane are 26.6(2) and 18.0(7)°, respectively.
d
e
Prepared from 2 and 3b (see ref 46). Reaction time was 48 h.
substrate 6b were prepared either as pure diastereoisomers or
as a mixture with predetermined diastereoisomeric ratio. The
diastereomerically pure complex 7a, which contains (S,S)-
PNNP and tert-butoxycarbonyl-2-cyclopenten-1-one (6a),
reacted with 15 (1.1 equiv) to give the Diels−Alder adduct
16a in 87% yield and with 90% ee, as indicated by chiral HPLC
analysis after workup (Table 3, entry 1). The absolute con-
figuration of 16a is 8R,13S,14S, in agreement with an attack
from the upper face of the substrate (Figure 3). Accordingly,
the major diastereoisomer of the methyl ester derivative 7b
forms the same enantiomer of 16b with 87% ee (entry 2),
whereas the minor diastereoisomer 7c reacts with the
opposite sense of induction to give (8S,13R,14R)-16b with
97% ee (entry 3). As discussed for 7a, the preferred approach
of the diene is over the cyclopentenone ring in both cases
(ester-exo, Figure 3). However, the diastereoselectivity drops
from 26:1 for 7a to approximately 5:1 for 7b and 7c with the
same trend observed in catalysis (Scheme 2b).
The fact that the 7c gives enantioselectivity higher than that
of the major diastereoisomer 7b can be explained on the basis
of the X-ray structures of the related enolato complexes 5b and
5c, which can act as models for the substrate adducts 7b and 7c
(Figure 6).44 The C(49)···Ru−P(1)−C(1) torsion angle
(−4.9(3)° vs −11.4(1)°) and the C(1)···C(49) and
C(4)···C(48) separations are much smaller in 5c than in 5b.
Thus, the C(1)−C(6) phenyl ring is closer and better aligned
with the enolato moiety in the minor diasteroisomer 5c, which
enhances the shielding of the re face of the alkylidene
β-ketoester and explains the higher enantioselectivity of the
stoichiometric reaction of Dane’s diene 15 with 7c than with
7b.45
diastereoisomeric mixture of 7b and 7c (Scheme 4)46 gave the
estrone derivative 16b with 34% ee (entry 5). Taking into
account the diastereomeric ratio (70:30) and the inherent
enantioselectivity of the cycloaddition reaction between the
pure diastereoisomers 7b and 7c and 15 as determined from
the above stoichiometric reactions (87% ee for 7b, 97% ee for
7c), we calculate a theoretical value of 36% ee, which is in good
agreement with the experimental value of 34% ee. These results
confirm that the enantioselectivity of the Diels−Alder reaction
is controlled by the diastereoselectivity of the coordination of
the unsaturated β-ketoester to ruthenium.
Effect of Catalyst Stereochemistry. The substrate/
catalyst adduct 7a with tert-butyl ester 6a catalyzes the
Diels−Alder reaction between Danes’s diene (15) with
essentially the same enantioselectivity as the Et2O adduct 2
(both 10 mol %) (86 and 85% ee, Table 3, entries 6, 7). These
values are only slightly lower than in the corresponding
stoichiometric reaction (90% ee, entry 1) and are in agreement
with the observation that the substrate/catalyst adduct 7a is
formed as a single diastereoisomer both by hydride abstraction
from 5a and by reaction of 2 with β-ketoester 6a.
Then, to study the effect of the diastereomeric composition
of the catalyst on the stereochemical course, the Diels−Alder
reaction of 15 was performed with substrate/catalyst adducts of
the methyl derivative 6b with different diastereomeric
compositions (Scheme 6). The pure diastereoisomer 7b as
catalyst gave 16b with an enantioselectivity significantly higher
than that of 2, which reacts with 6b to give a 87:13 dia-
stereoisomeric mixture of 7b and 7c (72 vs 51% ee, Table 3,
entries 8−10). The increase is too large to be caused by the
high enantioselectivity obtained in the first catalytic cycle
(which must be close to 87% ee, as indicated by the stoi-
chiometric reaction, entry 2) and may suggest a memory effect
in which the substitution of the product by the substrate occurs
with retention of configuration at the metal.
To double-check these results, the stoichiometric reactions
with Dane’s diene 15 were run with diastereoisomeric mixtures
of 7b and 7c in different ratios. A 87:13 diastereomeric mix-
ture of 7b and 7c, prepared under the same conditions of cata-
lysis (that is, by addition of 6b (1 equiv) to a solution of 2,
Scheme 5), was treated with Dane’s diene 15. The resulting
Diels−Alder adduct 16b was formed with 56% ee, which is
close to the enantioselectivity of 51% ee observed under catalytic
conditions (Table 3, entries 4 and 10). At difference, a 70:30
However, monitoring the reaction between 6b and 15 with
diastereomerically pure 7b as catalyst (5 mol %) shows that the
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onset of the catalytic reaction, the enantioselectivity was lower
with 7c than with 7b (60 vs 79% ee, Table 3, entries 11 and 9)
but surprisingly higher than with catalyst 2 (51% ee, entry 10).47
Diels−Alder Product Displacement from Catalyst.
After the stoichiometric reaction of the substrate/catalyst
adducts with Dane’s diene (15), the next series of experiments
was designed to study the displacement of the product (16)
from the catalyst by a substrate molecule, which closes the
catalytic cycle. To simulate a single turnover of the catalytic
cycle, diastereomerically pure 7b was treated with diene 15 (1
equiv) in CD2Cl2 in an NMR tube. The 31P NMR spectra of
the reaction solution showed that 7b had reacted quantitatively
within 15 min. Apart from trace impurities, the only signals
observed after this time were an AX pattern that we assign to
[Ru(16b)(PNNP)]2+ on the basis of comparison with an
authentic sample prepared from 2 and isolated 16b (Scheme 8).48
Scheme 6. Catalytic Reactions with Preformed
Substrate/Catalyst Adducts 7b/7c
enantioselectivity gradually drops over 72 h (Table 4). This is
in agreement with the evolution of the catalyst from the initially
Table 4. Enantioselectivity Change during the Reaction of
a
6b with 15 Catalyzed by 7b.
entry
time (h)
ee (%)
Scheme 8. Regeneration of the Substrate/Catalyst Adduct
1
2
3
4
0.5
1
83
80
79
6
b
24
76
a
In a standard catalytic run with 7b (5 mol %), samples (0.1 mL) were
taken with a syringe, filtered through a pad of silica, and analyzed by
b
chiral HPLC. No changes after 72 h.
present diastereomerically pure 7b (which forms 16b with
87% ee) to a mixture of 7b and of the minor diastereoisomer 7c
upon coordination of a new substrate molecule (Scheme 7a,b).
Scheme 7. General Stereochemical Course of the Catalytic
Diels−Alder Reaction with 6b and 15
Then, β-ketoester 6b (1 equiv) was added to the above
solution of [Ru(16b)(PNNP)]2+, and the regeneration of the
active species 7b/c was monitored by 31P NMR spectroscopy
(Table 5, entry 1). After 30 min, the product adduct
a
Table 5. Product Displacement by Substrates 6b (or 6a)
substrate
(equiv)
T
regeneration of
b
entry reagent
solvent
CD2Cl2
(°C)
7b+7c (%)
1
2
3
15
15
15
6b (1)
6b (9)
6b (1)
25
25
25
35
40
70
CD2Cl2
CD2Cl2/
c
Et2O
d
4
5
6
15
17
17
6a (1)
6b (1)
6b (1)
CD2Cl2
CD2Cl2
25
25
25
60
5−10
20
CD2Cl2/
c
Et2O
7
17
6b (1)
CD2Cl2
55
100
a
After 30 min of reaction time between the product/catalyst adduct
b
c
and 6a/b. From the total intensity of both diastereoisomers. In a 1:1
ratio. The initial reaction of 15 with 7a took 30 instead of 15 min as
The formation of 7c, which gives the opposite enantiomer of
16b, accounts for the decreasing enantioselectivity. Pure 7c as
catalyst ceteris paribus gave the same sense of induction as that
for 2 and the major diastereoisomer 7b, which rules out a
memory effect. Because of the inverse sense of induction at the
d
with 7b/c.
[Ru(16b)(PNNP)]2+ was still the main species present in
solution (ca. 65%). The formation of the diastereoisomeric
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substrate adducts 7b and 7c was quantitative only after 3 h. The
rate of the product/substrate exchange is unaffected by an excess
of substrate 6b (9 equiv, entry 2) but significantly accelerated in
CD2Cl2/Et2O (1:1) solution (entry 3). The analogous reaction
between 15 and the sterically more demanding tert-butyl β-
ketoester complex 7a is slower than with the methyl analogue
7b, but the dissociation of the corresponding product is faster
(entry 4),49 which possibly explains why 6a and 6b give a similar
reaction profile in the catalytic reaction.
The above results show that (i) the equilibrium between
[Ru(16b)(PNNP)]2+ and [Ru(6b)(PNNP)]2+ lies completely
on the side of substrate coordination, (ii) the product/substrate
exchange is slower than the cycloaddition reaction, and (iii) the
resulting inhibition is operative already at the onset of the
catalytic reaction (when most of the substrate is still present).
We conclude that, in the reaction between 6b and diene 15,
product release from the catalyst is slow as compared to the
cycloaddition reaction, which makes it a prime candidate for the
rate-determining step of the catalytic cycle. This effect is kinetic
in nature, as the substrate/product ratio does not significantly
affect the rate of the exchange reaction.50 Finally, Et2O as
cosolvent accelerates the regeneration of the substrate/catalyst
adduct, possibly because it assists product displacement (Table 5,
entry 3). This explains why a 1:1 mixture of CD2Cl2 and Et2O
(1:1) gives the best results in catalysis with electron-rich, highly
reactive dienes 10, 11, and 15 (Table 2).15,51
Stoichiometric Ficini Reaction. For the sake of com-
parison, 7b was treated with N-benzyl-N-(cyclohexylethynyl)-4-
methylbenzenesulfonamide (17) under the same conditions.
Complex 7b reacted quantitatively within 15 min to give
ruthenium-bound methyl-7-[N-benzyl-4-methylphenylsulfon-
amido]-6-cyclohexyl-2-oxobicyclo[3.2.0]hept-6-ene-1-carboxy-
late (18) (by comparison with an authentic sample). Upon
addition of 6b, the product/substrate exchange gave only about
5−10% of 7b/7c after 30 min (Table 5, entry 5). A CD2Cl2/
Et2O (1:1) solvent mixture accelerates the displacement of the
Ficini product 18 (entry 6), as observed in the Diels−Alder
reaction with 15 (entry 3). However, the effect of Et2O is not
large enough to even reach the rate observed in the Diels−
Alder reaction in pure CD2Cl2 (entry 1).
NMR time scale,52a and the selectivity depends only on the
energy difference between the two diastereoisomeric transition
states.52b Such problems are often intractable, and their
solution must be sought by calculation. A further example is
the highly enantioselective Diels−Alder reaction of 3-
cinnamoyloxazolidin-2-one and cyclopentadiene catalyzed by
[TiCl2(TADDOL)] system,53 whose substrate/catalyst adduct
has been the subject of debate as for its structure,
configuration,54 and even nuclearity.55 Such uncertainties led
Evans to state that “our understanding pertaining to substrate/
catalyst interactions [in Diels−Alder reactions] is still in its
infancy”.56
A commonly used option to model the catalytically active
species with very reactive systems is to use structurally
characterized complexes with strongly coordinating, but
inactive, ancillary ligands as models for the substrate/catalyst
adduct. Examples of this strategy have been reported with many
transition metals such as Cu(II),17 Ni(II),57 Zn(II),58 Rh(III),59
and Fe(II).60 This method, albeit useful, is intrinsically less
reliable than X-ray structure determination of the substrate/
catalyst adducts, as illustrated by Evans’s enantioselective
Michael addition to alkylidene malonates.17b,61
Therefore, a desirable requirement of a Lewis acidic catalyst
is to form adducts with the substrate according to a well-
defined stoichiometry that can be structurally characterized. A
perusal of the literature shows that this dual requirement is met
by a number of ruthenium(II) Diels−Alder catalysts such as
chiral Ru(II) half-sandwich complexes, whose adducts with
methyl vinyl ketone62 and methacrolein63 have been charac-
terized. Together with the already mentioned Ir(III) catalysts
for the Nazarov cyclization,18 these are low-spin d6 octahedral
complexes of 4d and 5d metals with middle- to strong-field
ligands and hence among the most stable64 and inert65
coordination compounds. The low-spin d6 configuration is
the key feature to allow for isolation of reactive intermediate
and reduced rate of exchange in solution, which makes them
amenable to spectroscopic investigation by NMR spectroscopy.
At the same time, the inertness of the complexes is also the
main disadvantage of this approach, as product release from the
catalyst can be a significant issue (see above).
Then, the experiment was repeated in pure CH2Cl2 by
heating at 55 °C in a sealed tube for 30 min. After cooling the
sample to room temperature, the 31P NMR spectrum recorded
immediately thereafter showed quantitative formation of 7b/c
(entry 7). This experiment also shows that the coordination
equilibrium lies completely on the side of [Ru(6b)PNNP]2+, as
in the case of the Diels−Alder reaction. Once again, the
conditions that overcome the kinetic inhibition in the
stoichiometric reaction correspond closely to those of the
optimized catalytic reaction described above.16 In the next
section, we discuss the origin of the slow release of the
cycloaddition product from the catalyst.
A further point is that d6 octahedral complexes typically lack
the most conspicuous property of a Lewis acidic catalyst, that is,
the affinity for oxygen-donor ligands. Therefore, special features
must be introduced in these catalysts, such as a high positive
charge (or high formal oxidation state), hard ancillary ligands,
and/or strong π-acceptors.66 Accordingly, ruthenium half-
sandwich Diels−Alder catalysts either contain a strongly π-
accepting bis(perfluorophenyl)diphosphinite ligand62 or bear a
double positive charge,63 whereas Eisenberg’s iridium(III)
complex is dicationic and contains CO as ancillary ligand.18
In the case of [Ru(6a)(PNNP)]2+ (7a), the important features
are the hard nitrogen donors and the dicationic nature of the
complex. As for the latter issue, we have recently reported that
the monocationic adducts [RuCl(OR2)(PNNP)]+ (R = H or
Et) are labile and exist in CD2Cl2 solution in equilibrium with
the five-coordinate complex [RuCl(PNNP)]+.66b Therefore, we
attribute the inert nature of 7a to a combination of several
factors and in particular the chelate effect of the bidentate β-
ketoester, the double positive charge, and the low-spin d6
configuration of these octahedral complexes.67
Chances and Challenges of Low-Spin d6 Lewis Acids.
Lewis acidic catalysts are mostly based on hard, but labile,
Lewis acids, such as early transition metals, lanthanides, Cu(II),
and boron.1b To understand the mechanism of stereoselection
and rationally modify the catalyst, structural information
concerning the substrate/catalyst adduct is required. However,
the characterization of the catalytically active species is not a
trivial task with these systems because of fast exchange
reactions in solution and/or the possibility that many different
complexes coexist in equilibrium. For instance, enal complex-
ation to boron-based Lewis acids is rapidly reversible on the
Finally, the absence of a background reaction with poorly
reactive dienophiles, as observed in the case of the reaction of
alkylidene β-ketoesters with dienes and ynamides, is considered
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(2) Evans, D. A.; Johnson, J. S. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer:
Heidelberg, 1999; Vol. 3, p 1229−1230.
to be an unfavorable basis for highly enantioselective catalytic
Diels−Alder reactions.3 Therefore, we speculate that the
dicationic nature of catalyst 7 and the combination of hard
(N) and soft (P) donors successfully contribute to give a highly
oxophilic, though mild, Lewis acid that is able of activating
alkylidene β-ketoesters without triggering undesired side-
reactions such as polymerization. The above studies show
that the ruthenium PNNP-catalyzed reactions are on a narrow
path between low reactivity of the alkylidene β-ketoester
toward the diene and slow product release, which possibly
provides another explanation why these reactions have
challenged synthetic organic chemists for so long.
(3) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
9992.
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(7) For instance, the reaction of 2-ethoxycarbonyl-2-cyclohexen-1-one
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(9) Mezzetti, A. Dalton Trans. 2010, 7851.
(10) PNNP = (S,S)-N,N′-bis[o-(diphenylphosphino)benzylidene]
cyclohexane-1,2-diamine.
(11) Gao, J. X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15,
1087.
(12) (a) Santoro, F.; Althaus, M.; Bonaccorsi, C.; Gischig, S.;
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Bonaccorsi, C.; Mezzetti, A.; Santoro, F. Organometallics 2006, 25,
3108. (c) Bonaccorsi, C.; Althaus, M.; Becker, C.; Togni, A.; Mezzetti,
A. Pure Appl. Chem. 2006, 78, 391.
(13) Toullec, P. Y.; Bonaccorsi, C.; Mezzetti, A.; Togni, A. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5810.
(14) Althaus, M.; Becker, C.; Togni, A.; Mezzetti, A. Organometallics
2007, 26, 5902.
(15) (a) Schotes, C.; Mezzetti, A. J. Am. Chem. Soc. 2010, 132, 3652.
(b) Schotes, C.; Mezzetti, A. Chimia 2011, 65 (4), 231.
(16) Schotes, C.; Mezzetti, A. Angew. Chem., Int. Ed. 2011, 50, 3072.
(17) (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S.
J. Am. Chem. Soc. 1999, 121, 1994. (b) Evans, D. A.; Rovis, T.;
Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc.
2000, 122, 9134.
(18) (a) Janka, M.; He, W.; Frontier, A. J.; Flaschenriem, C.;
Eisenberg, R. Tetrahedron 2005, 61, 6193. (b) Janka, M.; He, W.;
Haedicke, I. E.; Fronczek, F. R.; Frontier, A. J.; Eisenberg, R. J. Am.
Chem. Soc. 2006, 128, 5312.
CONCLUSION AND OUTLOOK
■
Hydride abstraction from enolato Ru/PNNP complexes gives
well-defined, easily characterized dicationic complexes contain-
ing alkylidine β-ketoesters that are efficient asymmetric catalysts
for Diels−Alder and Ficini reactions with dienes and ynamides,
respectively. The resulting products are highly functionalized
bicyclic molecules containing all-carbon stereocenters. The
ruthenium/PNNP complexes reported herein are noticeable
because they expand the scope of cycloaddition reactions to
unsaturated β-ketoesters, which are rarely used in these
reactions, and are a rare example of fully characterized
substrate/catalyst adducts. The structure and stoichiometric
reactions of such adducts are easily studied and yield valuable
information on the stereochemical course of the reaction and
on the relative rate of the cycloaddition and product release
steps. These insights explain the steric and solvent effects
observed in catalysis. In perspective, the Ru/PNNP catalyst
may allow for a fast screening and optimization of the catalytic
system with different substrates and reagents. This includes the
tuning of the PNNP ligand with electron-withdrawing or
-donating substituents to optimize the Lewis acidity of the
system. In fact, PNNP ligands are easily modified68 and form a
family of ligands that may find broad application in organic
synthesis.
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental protocols, characterization data for new
compounds, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
(19) (a) Structurally characterized TiCl4-adducts with alkylidene β-
ketoesters have been used in Ziegler−Natta catalysis, which does not
involve activation of the CC double bond; see: (b) Kakkonen, H. J.;
Corresponding Author
Mezzetti@inorg.chem.ethz.ch
́
Pursiainen, J.; Pakkanen, T. A.; Ahlgren, M.; Iiskola, E. J. Organomet.
Chem. 1993, 453, 175.
ACKNOWLEDGMENTS
■
(20) The slow oxidation of the Ru(II) catalyst to Ru(III) was considered
as a possible cause of the observed increase of enantioselectivity with time,
which we eventually explained with the accumulation of the fluorinated β-
ketoester during the catalytic reaction.14
We thank Dr. Pietro Butti (ETH Zurich) for the X-ray
structure of 7a.
̈
(21) (a) The shielding constant σ for the chemical shift of non-H nuclei
mainly depends on the paramagnetic term σpara, which is influenced by the
p-electron excitation energy ΔE, and on the expectation value r2p for the
distance of a 2p-electron from the nucleus:21b
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2, followed by deprotonation with triethylamine and hydride
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related to the higher purity of the catalysts obtained with this method
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(Et3O)PF6 is a highly reactive species whose slow degradation upon
storing produces traces of strong acids that may interfere with the
catalytic reaction. A further advantage of hydride abstraction is that the
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