Stereoselective Csp3?Csp2 Cross-Couplings of Chiral Secondary Alkylzinc Reagents with Alkenyl and Aryl Halides

Article abstract of DOI:10.1002/anie.201910397

We report palladium-catalyzed cross-coupling reactions of chiral secondary non-stabilized dialkylzinc reagents, prepared from readily available chiral secondary alkyl iodides, with alkenyl and aryl halides. This method provides α-chiral alkenes and arenes with very high retention of configuration (dr up to 98:2) and satisfactory overall yields (up to 76 % for 3 reaction steps). The configurational stability of these chiral non-stabilized dialkylzinc reagents was determined and exceeded several hours at 25 °C. DFT calculations were performed to rationalize the stereoretention during the catalytic cycle. Furthermore, the cross-coupling reaction was applied in an efficient total synthesis of the sesquiterpenes (S)- and (R)-curcumene with control of the absolute stereochemistry.

Full text of DOI:10.1002/anie.201910397

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Accepted Article
Title: Stereoselective Csp3-Csp2 Cross-Couplings of Chiral Secondary
Alkylzinc Reagents with Alkenyl and Aryl Halides
Authors: Juri Skotnitzki, Alexander Kremsmair, Daniel Keefer, Ye
Gong, Regina de Vivie-Riedle, and Paul Knochel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910397
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10.1002/anie.201910397
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Stereoselective Csp3-Csp2 Cross-Couplings of Chiral Secondary
Alkylzinc Reagents with Alkenyl and Aryl Halides
Juri Skotnitzki‡, Alexander Kremsmair‡, Daniel Keefer, Ye Gong, Regina de Vivie-Riedle and Paul
Knochel*,[a]
Dedicated to Dr. Klaus Römer on the occasion of his 80th birthday
Abstract: We report palladium-catalyzed cross-coupling reactions of
chiral secondary non-stabilized dialkylzinc reagents - prepared from
readily available chiral secondary alkyl iodides - with alkenyl and aryl
halides. This method provided α-chiral alkenes and arenes with very
high retention of configuration (dr up to 98:2) and satisfactory overall
yields (up to 76% for 3 reaction steps). The configurational stability of
these chiral non-stabilized dialkylzinc reagents was determined and
exceeded several hours at 25 °C. DFT-calculations were performed
to rationalize the stereoretention during the catalytic cycle.
Furthermore, the cross-coupling reaction was applied in an efficient
total synthesis of the sesquiterpenes (S)- and (R)-curcumene with
control of the absolute stereochemistry.
increases this configurational stability (several hours at –50 °C in
THF). These chiral alkylcopper organometallics react with
activated alkynes, epoxides, 1-bromoalkynes and allylic halides
with high retention of configuration.[6] Furthermore, these
organocopper reagents were used in the total synthesis of several
pheromones[6a,6c] with high control of all stereocenters.
Transition-metal-catalyzed cross-coupling reactions are widely
used for the construction of complex organic molecules.[1]
Although a range of Csp3-Csp2 coupling reactions have been
developed, only a few are stereoselective.[2] In this context, highly
stereoretentive cross-couplings of enantioenriched α-chiral
alkylzinc reagents are desirable as these reagents are known for
their broad functional group tolerance. However, their preparation
proved to be challenging since oxidative addition of zinc powder
into the carbon-halogen bond proceeds with
a loss of
stereoinformation.[2g]
A
stereoselective palladium-catalyzed
cross-coupling reaction after hydroboration of trisubstituted
alkenes followed by a boron-zinc exchange reaction has been
reported, but proved to be of limited scope.[3] Lately, a
diastereoselective palladium-catalyzed cross-coupling reaction of
cyclic alkylzinc reagents, where the stereoselectivity of the cross-
coupling is thermodynamically controlled has been reported.[4]
This method leads to high selectivities only with cyclic substrates,
which drastically limits the utility of such stereoselective
palladium-catalyzed cross-couplings. So far, the preparation of
non-stabilized optically pure open-chain organometallic reagents
is a challenge for organic synthesis. Recently, we have reported
that chiral secondary alkyllithiums 1 can be readily prepared from
the corresponding optically enriched α-chiral secondary alkyl
iodides 2 via a stereoretentive I/Li-exchange reaction (see
Scheme 1). The configurational stability of these secondary
alkyllithiums is rather moderate (ca. 1 h at –100 °C in a
hexane:ether mixture).[5] However, transmetalation to the
corresponding secondary alkylcopper reagents significantly
Scheme 1. Stereoretentive preparation of secondary alkylzinc reagents 4 and
subsequent palladium-catalyzed cross-coupling reaction with alkenyl or aryl
halides 5.
Nevertheless, the configurational stability of these chiral
secondary alkylcopper reagents is restricted to low temperature
reactions. Thus, we envisioned the performance of
a
stereoretentive transmetalation of chiral alkyllithiums of type 1
with an appropriate ether soluble zinc reagent R’ZnX (3), leading
to the mixed dialkylzinc reagents of type 4 (see Scheme 1). These
chiral mixed dialkylzinc reagents may undergo a stereoselective
palladium-catalyzed cross-coupling with alkenyl and aryl halides
of type 5, which would afford α-chiral products of type 6. To
achieve such
a
stereoselective cross-coupling several
requirements should be fulfilled: (1) both the transmetalation step
(conversion of 7 to 8) and the reductive elimination step
(converting 8 to 6) of the catalytic cross-coupling cycle have to be
stereoselective; (2) the secondary dialkylzinc reagent 4 must be
configurationally stable at the cross-coupling temperature and
should contain a group R’, which does not easily participate in the
catalytic cycle. After several preliminary experiments,[7] we chose
Me3SiCH2ZnBr·LiBr (3a) as transmetalating zinc reagent since it
is highly soluble in diethyl ether and readily prepared.[8] To our
delight, these conditions allow for the first time a highly
stereoselective cross-coupling of chiral non-stabilized open-chain
[a]
J. Skotnitzki, A. Kremsmair, Dr. D. Keefer, Y. Gong, Prof. Dr. R. de
Vivie-Riedle, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201910397
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secondary alkylzinc reagents with various alkenyl and aryl halides. to the Pd(I)-dimer catalyst regarding β-hydride elimination and
Hence, we treated the diastereomerically enriched secondary
formation of side products such as dimerization.[7]
t
alkyl iodide syn-2a[5c] with BuLi (2.2 equiv) in a 3:2 mixture of
Table 2. Stability of racemic secondary alkylzinc reagent syn-4a and
subsequent cross-coupling reaction with alkenyl iodide 5a.
pentane:diethyl ether at –100 °C for 10 s leading to an
intermediate alkyllithium species (see Table 1). Addition of
Me3SiCH2ZnBr·LiBr (3a; 0.95 M in diethyl ether, 1.05 equiv) at –
100 °C provided the mixed dialkylzinc species syn-4a. For
performing a subsequent stereoselective palladium-catalyzed
cross-coupling, the choice of the palladium catalyst proved to be
essential.
entry
temperature
time
yield of syn-6a[a]
dr of syn-6a[a]
Table 1: Optimization for palladium-catalyzed cross-coupling reaction of
racemic secondary alkylzinc reagent syn-4a.
1
2
3
4
5
–50 °C
–30 °C
–10 °C
25 °C
10 min
10 min
10 min
60 min
240 min
61%
58%
50%
51%
53%
97:3
97:3
97:3
96:4
89:11
entry
catalyst
yield of syn-6a[a]
dr of syn-6a[a]
89:11
25 °C
1
2
3
4
Pd(PPh3)4
39%
51%
60%
58%
[a] The yield and diastereoselectivity (dr; syn:anti ratio was determined by GC
analysis using dodecane as internal standard.
Pd(OAc)2/CPhos
Pd-PEPPSI-iPent
Pd2I2(PtBu3)2
92:8
In a typical procedure, the chiral mixed dialkylzinc reagents (4a-
c) were generated as described above and subsequently warmed
to room temperature over 15 min (see Table 3). The dialkylzinc
reagent was then added dropwise to a stirring solution of 5 mol%
Pd-PEPPSI-iPent and the alkenyl iodide of type 5 (3.0 equiv) in
toluene. After stirring for 1 h at room temperature the
corresponding α-chiral cross-coupling products were isolated in
up to 52% yield and with high retention of configuration (dr up to
98:2). In this way, the stereodefined alkenes syn-6a[13] and anti-
6a were prepared from the corresponding iodides in 43% and
39% yield, respectively (dr = 98:2 and dr = 5:95). Interestingly, the
thermodynamically more stable alkylzinc reagent anti-4a afforded
the corresponding (E)-alkene anti-6a in lower yield and with less
retention of configuration compared to the syn-product. In most
other cases a high retention of configuration (dr >94:6) was
achieved. Thereby, the (E)/(Z)-configuration of the alkenyl iodides
of type 5 turned out to be highly important. All attempts to use (Z)-
alkenyl iodides as cross-coupling partners were unsuccessful
presumably due to steric hindrance in the palladium(II)-
intermediates 7 and 8.[7]
96:4
98:2
[a] The yield and diastereoselectivity (dr; syn:anti ratio was determined by GC
analysis using dodecane as internal standard.
Addition of 5 mol% Pd(PPh3)4 and (E)-1-iodooct-1-ene (5a;
3.0 equiv) as a typical substrate at –50 °C followed by warming to
–25 °C and stirring for 12 h at this temperature provided the
desired cross-coupling product syn-6a with a diastereoselectivity
of syn:anti = 89:11 (entry 1).[9] Using the catalytic system
Pd(OAc)2/CPhos introduced by Buchwald for the coupling of
secondary alkylzinc halides[10] improved the stereoselectivity of
the cross-coupling to syn:anti = 92:8 (entry 2). A further
improvement was observed with the NHC-based catalyst Pd-
PEPPSI-iPent reported by Organ[11], which provided the desired
product syn-6a with a dr = 96:4 (entry 3). Finally, the Pd(I)-catalyst
Pd2I2(PtBu3)2 used by Schoenebeck[12] gave the product syn-6a
with complete retention of configuration (entry 4; dr = 98:2). In
order to obtain a deeper insight into the configurational stability of
these chiral non-stabilized secondary alkylzincs of type 4, we
prepared syn-4a at –100 °C and kept it at various temperatures
(–50 °C to 25 °C) for
a certain time, followed by the
stereoselective cross-coupling with 5a, leading to syn-6a (see
Table 2). We observed high stability of the zinc species syn-4a up
to –10 °C (dr of syn-6a = 97:3). Furthermore, keeping the alkylzinc
reagent syn-4a at 25 °C for 1 h and performing a palladium-
catalyzed cross-coupling provided syn-6a with dr = 96:4. However,
stirring syn-4a at 25 °C for 4 h led to a minimal epimerization (dr
of syn-6a = 89:11). This indicated a high configurational stability
of these chiral secondary mixed dialkylzinc reagents (several
hours at 25 °C). With this result in hand, we slightly modified the
experimental procedure to the effect that the cross-coupling
reaction could be performed at room temperature. Under these
conditions, Pd-PEPPSI-iPent showed superior results compared
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Table 3. Stereoretentive cross-coupling reactions of racemic secondary
alkylzinc reagents 4 with alkenyl iodides 5a-f leading to α-chiral alkenes 6a-h.
withdrawing substituents were used, leading to products 6i-n (38–
59% yield; dr up to 98:2). Thus, the cross-coupling reaction of syn-
4a with bromothiophene derivatives[14] afforded syn-6k-l in 38–
59% yield and with high retention of configuration (dr up to 98:2).
In addition, 1-bromonaphthalene was used for the cross-coupling
reaction with the dialkylzinc reagents syn-4a and syn-4c leading
to α-chiral naphthalenes syn-6j and syn-6m in good yields (51-
56% yield) and high stereoretention (dr up to 97:3). This cross-
coupling was also extended to optically enriched alkylzinc
reagents leading to the corresponding α-chiral arenes (R)-6o, (S)-
6o and (R)-6p (up to 76% yield, er = 91:9).[15] To demonstrate the
synthetic utility of the method, we performed the natural product
synthesis of the two enantiomers of α-curcumene 10, an aromatic
sesquiterpene.[16] Both enantiomers can be found in nature, e.g.
in essential oils or in the pheromone produced by the red-shoulder
stink bug.[17] Starting from the readily available chiral secondary
alkyl iodide (S)- or (R)-2d,[6a] the corresponding chiral secondary
alkylzinc reagents (S)- or (R)-4d were prepared. Subsequent
palladium-catalyzed cross-coupling reaction with 4-bromotoluene
afforded the natural products (S)-curcumene ((S)-10; 50% yield;
er = 93:7) and (R)-curcumene ((R)-10; 46% yield; er = 7:93).
entry
1
alkylzinc
electrophile
product of type 6[a]
2
3
4
5
6
7
8
9
[a] The diastereoselectivity (dr; syn:anti ratio) was determined by 1H-NMR
spectroscopy and GC analysis.
These conditions were broadly applicable. Hence, we performed
such a cross-coupling reaction with other secondary alkylzinc
reagents 4b-c (see entry 9 and 10). The 1,3-functionalized
secondary alkyl iodide rac-2b was prepared according to
literature procedure, followed by an I/Li-exchange reaction, which
after epimerization (–50 °C, 30 min) led to the chelate-stabilized
lithium species.[5c] Subsequent transmetalation to the
corresponding dialkylzinc reagent syn-4b followed by cross-
coupling with 5a afforded the silyl-protected alkene syn-6g in 43%
yield (dr = 93:7). Furthermore, the 1,4-functionalized dialkylzinc
reagent syn-4c was suitable for cross-coupling reaction leading to
syn-6h in 46% yield and dr = 96:4.
Scheme 2. Cross-coupling reaction of chiral alkylzinc reagents 4 with aryl
bromides
9 leading to α-chiral arenes and heteroarenes (6i-p). [a] The
diastereoselectivity (dr; syn:anti ratio) was determined by 1H-NMR
spectroscopy and GC analysis.
Furthermore, DFT-calculations were performed to gain insight
into the high retention of configuration of secondary alkylzinc
reagents. Therefore, the configurational stability of the chiral
alkylzinc reagents syn-4a and anti-4a was investigated. Solvation
effects were accounted for by the Polarizable Continuum Model
(PCM) as well as by explicit treatment with diethyl ether
molecules.[18] Comparison of the free energies between the two
isomers showed that anti-4a is thermodynamically more stable
than the corresponding alkylzinc reagent syn-4a (∆G = +2.7
kcal/mol). Coordination of one solvent molecule (diethyl ether) to
the zinc site leads to a marginal rise of energy both for syn-4a and
As many pharmaceuticals and natural products contain aromatic
moieties, the preparation of chiral arenes and heteroarenes is of
great interest. Thus, we extended our method to palladium-
catalyzed cross-couplings with aryl bromides of type 9 leading to
the corresponding chiral arenes and heteroarenes (see Scheme
2). Various aryl bromides with electron donating and electron
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anti-4a, which suggests that solvent coordination is not relevant
for the epimerization pathway. This result is in agreement with the
fact that the cross-coupling reaction proceeded also in other
solvents, such as toluene or THF, with high retention of
configuration.[7] We examined two possible pathways, which
could lead to epimerization from syn-4a to anti-4a and vice versa,
namely via a planar transition state ts-4a (see Scheme 3) or by
cleavage of the carbon-zinc bond. Both the transition state energy
of 95.5 kcal/mol and the carbon-zinc bond energy of ca. 35
kcal/mol corroborate the high stability of 4a towards epimerization
at 25 °C. Another important step in this catalytic cross-coupling
cycle, where stereoretention is crucial, is the configurational
stability of the Pd(II)-intermediate 8 (see Scheme 1). We
performed an analogous analysis of potential epimerization
channels on 8 using Pd-PEPPSI. To stay within the computational
feasibility of our quantum chemical method, we simplified the
catalyst by replacing the four experimentally used isopentyl
residues in Pd-PEPPSI-iPent with methyl groups. This allows
slightly more steric flexibility, while the electronic nature around
the Pd(II) and the carbon stereocenter is unaltered. Starting from
a tetrahedral geometry of the four ligands around the Pd(II) center,
the optimization ends in an energetic minimum which exhibits a
nearly planar tetragonal structure.[18] Thus, there are four possible
species for 8, with either the syn- or the anti-isomer in cis (8a) or
trans (8b) position to the alkene (see Scheme 3). A comparison
of configurational stabilities of the four species showed that the
cis-conformer 8a is more stable than the trans-conformer 8b,
which is encouraging since reductive elimination can only occur
from the cis-configuration 8a.
Interestingly, the energy barrier is significantly lower for ts-8a and
ts-8b than it is for ts-4a, which suggests that a potential loss of
stereoinformation occurs more likely at the Pd(II)-intermediate 8.
Nevertheless, we presume that the minimal epimerization of the
secondary alkylzinc reagents may be due to polymolecular
exchange reactions between these zinc reagents, which may
involve the salts LiBr and LiI.
In summary, we have shown that chiral non-stabilized dialkylzinc
reagents can be prepared via an I/Li-exchange reaction and
subsequent transmetalation with Me3SiCH2ZnBr·LiBr (3a) with
high retention of the configuration. These chiral dialkylzincs are
configurationally stable at room temperature for at least four hours
and undergo Csp3-Csp2 cross-coupling reactions with various
alkenyl and aryl halides, leading to α-chiral alkenes and arenes
with high stereoretention. DFT-calculations were performed to
explain the high stability of the chiral dialkylzincs and the retention
of configuration during the catalytic cycle. Additionally, this
method was used for the preparation of (S)- and (R)-α-curcumene
10 in good enantioselectivity. Further mechanistic studies and
applications are currently under investigation in our laboratories.
Experimental Section
See Supporting Information.
Author Contributions
‡J. Skotnitzki and A. Kremsmair contributed equally.
Acknowledgements
We thank the SFB749 for financial support. We also thank
Albemarle for the generous gift of chemicals. J. S. thanks the
FCI-foundation for a fellowship.
Keywords: cross-coupling • lithium • palladium • zinc • natural
products
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reagent anti-4a to syn-4a and Pd(II)-intermediates of type 8. Molecular
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4a and syn-4a. Bottom: Stabilities of syn- and anti-8a and 8b.
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ts-8b (39.7 kcal/mol; anti-8b to syn-8b) and carbon-palladium
bonding energies of syn-8a (47.7 kcal/mol), anti-8a (47.2
kcal/mol), syn-8b (41.6 kcal/mol), and anti-8b (40.1 kcal/mol)
corroborate the experimentally found retention of configuration.
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suitable for cross-coupling reaction. For a detailed screening table, see
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[15] The enantiomeric ratio was determined by chiral GC-analysis or chiral
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COMMUNICATION
Juri Skotnitzki, Alexander Kremsmair,
Daniel Keefer, Ye Gong, Regina de
Vivie-Riedle and Paul Knochel *
Page No. – Page No.
Stereoselective Csp3-Csp2 Cross-
Couplings of Chiral Secondary
Alkylzinc Reagents with Alkenyl and
Aryl Halides
Chiral couplings made easy: Chiral secondary alkylzinc reagents underwent
stereoselective palladium-catalyzed cross-coupling reactions with alkenyl and aryl
halides. These chiral mixed dialkylzincs are configurationally stable at room
temperature for several hours. DFT-calculations were performed to rationalize the
overall retention in the catalytic cycle. This method was applied in the total synthesis
of the sesquiterpenes (S)- and (R)-curcumene.
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