Weak arene C-h×××o hydrogen bonding in palladium-catalyzed arylation and vinylation of lactones

Article abstract of DOI:10.1002/anie.201300481

Weak force in action: In the title reaction, the palladium catalyst (see figure, left) uses weak CH×××O hydrogen bonding to control the absolute configuration of the new stereocenter. A similar palladium catalyst (right) used conventional NH×××O hydrogen bonding to guide stereoselection. Copyright

Full text of DOI:10.1002/anie.201300481

Angewandte
Chemie
DOI: 10.1002/anie.201300481
Cross-Coupling
ꢀ
Weak Arene C H···O Hydrogen Bonding in Palladium-Catalyzed
Arylation and Vinylation of Lactones**
Zhiyan Huang, Zuliang Chen, Li Hui Lim, Gia Chuong Phan Quang, Hajime Hirao, and
Jianrong (Steve) Zhou*
Metal-catalyzed a-arylation of enolates has become a useful
tool to make biologically and pharmacologically interesting
entities.[1] Several metal catalysts are now available for
asymmetric couplings of enolates of ketones,[2] aldehydes,[3]
and oxindoles,[4] etc. For example, Buchwald et al. reported
asymmetric couplings of a-substituted-g-butyrolactone in the
presence of a strong base (Scheme 1a).[5] Most existing
methods, however, were limited to formation of quaternary
centers. Coupling to form more common tertiary centers
proved to be more difficult, because of fast product race-
mization under basic conditions.
To address this deficiency, the groups of MacMillan and
Gaunt independently reported copper-catalyzed arylation of
silyl ketenimides and enamines formed in situ from aldehydes.
One silyl enolate derived from valerolactone can react with
several diaryliodonium salts to give about 90% ee (Sche-
me 1b).[6] Last year, we disclosed the palladium-catalyzed
asymmetric arylation of acyclic esters (Scheme 1c).[7] When
the a-alkyl chain of acyclic enolates carried an oxygen atom,
poor coupling efficiency and selectivity resulted. Coupling of
the silyl enolate of g-butyrolactone led to less than 20% ee
when Pd/L was used as catalyst.
Enzymatic and chemical resolution of a-aryllactones were
not reported, and resolution of a-arylcarboxylic acids, derived
from the lactones, was also not available.[8] Resolution of a-
arylketones and a-arylsuccinic anhydrides has been reported
to give enantioenriched a-aryllactones, but the ee values were
unsatisfactory.[9] Asymmetric protonation of prochiral eno-
lates such as silyl enolates of ketones was realized recently,
but protonation of a-aryllactones was lacking.[10] In these
approaches, aryl groups must be installed before the absolute
configuration is set.
Herein, we report new chiral phosphines which allow the
a-arylation of lactones to produce tertiary centers in high
stereoselectivity (Scheme 1d). This work describes the first
general method for asymmetric arylation of lactones leading
to the formation of tertiary centers. After lactone opening, the
Scheme 1. Overview of asymmetric couplings of enolates.
HMDS=hexamethyldisilazide, Mes=mesityl, TBS=tert-butyldimethyl-
silyl, Tf=trifluoromethanesulfonyl, TMS=trimethylsily.
[*] Dr. Z. Huang, Dr. Z. Chen, L. H. Lim, G. C. P. Quang,
Prof. Dr. H. Hirao, Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University
a new mode of stereocontrol for metal catalysis was discov-
21 Nanyang Link, Singapore 637371 (Singapore)
E-mail: jrzhou@ntu.edu.sg
resulting hydroxy groups can be transformed to other
ꢀ
functionalities and new C C bonds. More importantly,
ered. Specifically, L1 and L3 can form hydrogen bonds
ꢀ
between the aryl C H bonds of the ligand and the oxygen
[**] We thank the Singapore National Research Foundation (NRF-
atom of palladium enolates.
RF2008-10) and Nanyang Technological University for financial
support, and Johnson-Matthey for a gift of palladium.
Initially, we examined a model coupling between the silyl
enolate of g-butyrolactone with 2-naphthyl triflate
(Scheme 2). We found that L1, bearing an O-2-naphthyl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300481.
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Scheme 2. Catalyst discovery in the model coupling. TBME=tert-
butylmethyl ether.
group, resulted in 84% ee. When the 2-naphthyl group of L1
was replaced by other aromatic rings (phenyl, 1-naphthyl,
m-xylyl, and 2-mesityl), the ee value fell. The use of a cyclo-
hexyl ring also led to moderate ee values.
Later, we used DFT calculations to understand the origin
of the stereoselectivity of L1. To our surprise, both hydrogen
atoms H1 and H8 can form hydrogen bonds with palladium-
bound C-enolates (see below). Based on this new finding, we
designed the ligand L2 having an aromatic NH2 group, which
can form NH···O hydrogen bonds. Indeed, it gave 90% ee in
the coupling reaction (Scheme 2). A similar ligand L3,
bearing an NH(iPr) group, gave 93% ee. L4, having an
NHAc group, gave a lower ee value because of in situ N-
silylation (as detected by ESI). A related ligand L5, having
the NH2 group in the para position, gave only 70% ee. The O-
aryl ligands can be easily made by modification of Buchwaldꢀs
synthesis.[11] The O-aryl groups were introduced from diaryl-
iodonium salts (Scheme 3).
Scheme 4. Coupling of g-butyrolactone. The values in parentheses
refer to the ee value obtained with L1. Boc=tert-butoxycarbonyl,
Ts =4-toluenesulfonyl.
Scheme 3. Synthesis of chiral phosphine L3. TEA=triethylamine,
THF=tetrahydrofuran.
oline, indole, and thiophene. Notably, vinyl triflates provided
the products with excellent ee values.
The Pd/L3 catalyst can be applied to the coupling of
various aromatic triflates with g-butyrolactone (Scheme 4).
L3 gave higher ee values than L1 in most cases. Furthermore,
the catalysts tolerated groups such as ester, ketone, and
A single crystal of the p-chlorophenyl product was
obtained and its absolute configuration was determined to
be S, based on X-ray diffraction.[12] The high-resolution
diffraction data was collected at ꢀ1708C using Mo-K
radiation. In this case, chlorine was sufficient to serve as
a heavy atom for assignment of the absolute configuration.[13]
ꢀ
ꢀ
phthalimide, as well as aromatic C F and C Cl bonds. Some
typical heterocycles were also tolerated, and included quin-
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Scheme 7. Coupling of e-caprolactone.
gram-scale synthesis of 2-aryllactones, wherein the palladium
catalyst loading can be as low as 1 mol% (Scheme 8a), and
a simple crystallization can give 96% ee (Scheme 8b).
Scheme 5. Couplings of substituted g-butyrolactones.
Lactone enolates having ring-substituents also coupled to
give the trans-isomers predominantly (Scheme 5). Notably, b-
substituted lactones gave only the trans isomers in greater
than 90% ee, when 3 equivalents of the racemic enolate was
used. If a substituent was present at the g-position, the trans
selectivity fell to 3:1. The diastereomeric pairs can be
separated by silica gel flash chromatography and the major
isomers have the trans configurations, based on X-ray diffrac-
tional analysis.[12]
In couplings of d-valerolactone, L1 proved to be more
selective than L3 (Scheme 6). This selectivity may have
something to do with the conformational difference of the
rings. Heteroaryl and vinyl electrophiles also worked well and
the seven-membered caprolactone reacted smoothly
(Scheme 7). The coupling procedure can be used for the
Scheme 8. Gram-scale coupling.
We have synthesized two drug candidates to demonstrate
the utility of our method. For example, the diastereoselective
arylation of a racemic enolate can give an alcohol in 90% ee
and d.r. value greater than 99:1 (Scheme 9a). After debenzy-
lation and alcohol oxidation, the resulting aldehyde can be
used as a key intermediate in the synthesis of arylkainic acid
analogues reported by Kan and co-workers.[14] The same
aldehyde required a seven-step synthesis as reported by Kan
and co-workers, and featured a rhodium-catalyzed diastereo-
selective carbene insertion. o-Anisylkainic acid is a potent
ligand for ionotropic glutamate receptors, which are involved
in memory and learning processes.[15]
The second example is (ꢀ)-preclamol, a potential drug for
the treatment of neurological disorders such as Parkinsonꢀs
disease, schizophrenia, drug addiction, and depression.[16] The
aryllactone was converted to (ꢀ)-preclamol in four steps
(Scheme 9b). After optimization of the reaction conditions,
each step was high yielding and only one purification was
needed after last step to isolate (ꢀ)-precamol in 94% yield.
This route offers the opportunity to introduce other aryl and
alkyl amine groups for analogue synthesis.
The a-aryl-g-butyrolactone can also undergo lactone
opening in the presence of DIBAL-H, and the product can
be mapped onto a nanomolar CC chemokine receptor
antagonist for potential treatment of arthritis and sclerosis
(Scheme 9c).[17,18] Alternatively, it can be converted into the
Weinreb amide at ꢀ788C (Scheme 9d). At ꢀ108C, Grignard
addition occurred to allow quick access to acyclic a-aryl-
ketones, which were difficult to obtain using other methods
(Scheme 9e).[19]
Scheme 6. Coupling of d-valerolactone.
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Figure 1. Bonding modes between Pd and the lower ring of L1, and
stereoisomers of palladium-bound C- and O-enolate complexes.
ꢀ
We first explored the possibility of direct C C reductive
elimination from the O-enolate complexes.[21] We found that
an abrupt “jumping” of atoms at a certain C-C distance. Also,
isomerization of the O-enolate complexes to more stable
C-enolates had low barriers of about 15 kcalmolꢀ1.
ꢀ
In contrast, direct C C reductive elimination from the
C-enolate complexes proceeded smoothly (Figure 2). The
ꢀ
corresponding barriers for C C bond formation were only 12
and 14 kcalmolꢀ1. In the major-product pathway, the ground
state (Int1a) and transition state (TS1a) were more stable by
4.2 and 2.1 kcalmolꢀ1, respectively, than those in the minor-
product pathway. The origin of stabilization was the double
ꢀ
CH···O hydrogen bond between naphthyl C H bonds and the
palladium-bound C-enolate. In the minor-product pathway,
Scheme 9. Synthetic applications. DIBAL-H=diisobutylaluminum
hydride, Ms=methanesulfonyl.
ꢀ
We have conducted DFT calculations on the C C
reductive elimination to understand the role of the 2-naphthyl
group in L1 (Scheme 2). The B3LYP functional was used with
Lanl2dz ECP basis set for palladium and 6-31G* basis set for
the other atoms. The solvent effect (tert-butyl methyl ether)
was also taken into account by using IEFPCM method. First,
we examined all possible isomers of the [(L1)Pd(Ar)-
(enolate)] complexes (Figure 1). We found that the PdII
centers preferentially interact with the ipso carbon atom of
the lower ring of L1. The Pd–arene interaction in the
biarylphosphine complexes was previously revealed by
[20]
ˇ
´
Kocovsky, Buchwald, Pregosin, and others. The palladium
complexes having a Pd–O(ether) interaction were 4–6 kcal
molꢀ1 less stable, and structural rearrangement from the latter
to the former was almost barrierless. Thus, we focused on
enolate complexes having Pd–arene interactions in subse-
quent calculations.
ꢀ
Figure 2. Reaction pathway of C C reductive elimination from
C-enolate complexes of L1.
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the carbonyl group pointed away and hydrogen bonds were
lost. Conformational scanning was performed on the complex
lized by a single NH···O(carbonyl) hydrogen bond. In the
minor-product pathway, hydrogen bonds were absent.
N-Methyl-2-pyrrolidone (NMP) can disrupt hydrogen
bonding. Indeed, in the model reaction (Scheme 2), inclusion
of 3 equivalents of NMP led to significant loss of enantiose-
lectivity: 84%!46% ee with L1 and 93%!9% ee with L3.
Notably, the catalytic activity was not affected and product
racemization did not occur. In another experiment, inclusion
of ZnCl2 also led to loss in ee value in the model reaction.
We also conducted calculations on transmetalation and
were surprised to find that transmetaltion did not produce O-
enolates. This data is contrary to common belief. The
abnormality in our reaction may be attributed to coordination
saturation of the palladium center by the lower ring of the
biarylphosphine ligand. When starting from [(L1)Pd(Ar)-
(k2-OAc)] complexes, a relatively high barrier (> 15 kcal
molꢀ1) was found in the acetate-assisted enolate transfer, thus
leading to either O- or C-enolates. If starting from cationic
complexes of [(L1)Pd(Ar)(silyl enolate)], the silyl enolate
was bound to palladium through its b-carbon atom, and acted
like an electron-rich olefin. External attack of the OAc anion
on silicon triggered facile enolate transfer with barriers of less
than 10 kcalmolꢀ1. No O-enolates were produced.
In summary, we disclosed the first general method for
asymmetric arylation of lactones, thus forming tertiary
centers with high ee values. Importantly, we found L1
participates in arene CH···O hydrogen bonding with palla-
dium enolates to control stereochemistry of the new stereo-
centers. L3 was capable of forming NH···O hydrogen bonds.
In our previously reported arylation of acyclic esters (Sche-
me 1c),[7] the ligand L cannot support hydrogen bonding as
determined by our calculations.
ꢀ
Int1a by rotating two C O bonds in the diaryl ether moiety.
The specific conformation which supported the hydrogen
bonding proved to be more stable than other conformers by
a few kcalmolꢀ1 (see the Supporting Information).
Close contact between the CH bonds and oxygen atoms
has been identified in organic crystals and enzymes. They are
accepted as weak hydrogen bonds with a stabilization energy
of 0.5–4 kcalmolꢀ1 and the magnitude of stabilization depend-
ing upon the acidity of the CH bonds and the topology of
donors and acceptors.[22] In our optimized structures of Int1a
(Figure 2), the CH···O hydrogen-bond angles and lengths fell
into the prescribed range. No other chiral metal catalyst was
reported to use the arene CH···O interaction to induce
chirality.[23]
Hydrogen bonding between other types of CH bonds and
oxygen atoms were implicated in asymmetric catalysis, for
example, formyl CH···O hydrogen bonds between aldehydes
and Lewis-acid catalysts derived from B, Ti, and Al. This
proposal of Corey has gained computational support
recently.[24] Later, he proposed a similar role for both vinylic
and methyl CH bonds of ketones.[25] CH bonds that were
acidified by a-substitution have also been seen in a CH···O-
type of interaction in the asymmetric Pauson–Khand reac-
tion[26] and in copper-catalyzed asymmetric allylation of
ketones.[27]
We also examined reductive elimination of C-enolate
complexes supported by L2, which carries an NH2 group
(Figure 3). As expected, in the major-product pathway, both
the ground-state Int2a and transition-state TS2a were stabi-
Received: January 19, 2013
Published online: April 22, 2013
Keywords: cross-coupling · hydrogen bonds · lactones ·
.
palladium
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