Direct Stereoconvergent Allylation of Chiral Alkylcopper Nucleophiles with Racemic Allylic Phosphates

Article abstract of DOI:10.1002/chem.201905361

Copper-catalyzed stereoconvergent allylation of chiral sp³-hybridized carbon nucleophiles with a racemic mixture of acyclic secondary allylic phosphates is reported. In the presence of a copper-catalyst complexed with chiral BenzP* ligand, tandem coupling reaction of vinyl arenes, bis(pinacolato)diboron, and racemic allylic phosphates provided β-chiral alkylboronates possessing (E)-alkenyl moiety through a direct stereoconvergent allylic coupling with concomitant generation of a C(sp³)-stereogenic center. A range of vinyl (hetero)arenes and secondary allylic phosphates bearing 1°, 2°, 3° alkyl and phenyl α-substituents were suitable for the reaction, forming products with high enantioselectivities up to 95 % ee. Density functional theory calculations were conducted in detail to elucidate the origin of the observed regioselectivity of borylcupration and stereoconvergent (E)-olefin formation from racemic allylic phosphates.

Full text of DOI:10.1002/chem.201905361

A Journal of
Accepted Article
Title: Direct Stereoconvergent Allylation of Chiral Alkylcopper
Nucleophiles with Racemic Allylic Phosphates
Authors: Jaesook Yun, Jung Tae Han, Seung-Tae Kim, and Mu-Hyun
Baik
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Direct Stereoconvergent Allylation of Chiral Alkylcopper
Nucleophiles with Racemic Allylic Phosphates
Jung Tae Han, Seoung-Tae Kim, Mu-Hyun Baik,* and Jaesook Yun*
Abstract: Copper-catalyzed stereoconvergent allylation of chiral sp3-
hybridized carbon nucleophiles with a racemic mixture of acyclic
secondary allylic phosphates is reported. In the presence of a copper-
catalyst complexed with chiral BenzP* ligand, tandem coupling
reaction of vinyl arenes, bis(pinacolato)diboron, and racemic allylic
phosphates provided β-chiral alkylboronates possessing (E)-alkenyl
moiety through a direct stereoconvergent allylic coupling with
concomitant generation of a C(sp3)-stereogenic center. A range of
vinyl (hetero)arenes and secondary allylic phosphates bearing
1°,2°,3° alkyl and phenyl α-substituent were suitable for the reaction,
forming product with high enantioselectivities up to 95% ee. Density
functional theory calculations were conducted in detail to elucidate the
origin of the observed regioselectivity of borylcupration and
successfully used in the C–C bond forming reactions with various
electrophiles including carbonyl compounds, imines, and other
reagents.[8,9] Especially, few examples of allylic substitutions of
chiral alkylcopper species were reported with simple allyl
electrophiles in respective reports by other groups[10] and our
group (Scheme 1a).[11] Although these methods were highly
efficient, the reactions accommodated only simple allyl
electrophiles, and the reaction with a racemic secondary allylic
electrophile resulted in a mixture of E/Z stereoisomers.[11a]
Controlling E/Z selectivity in the copper-catalyzed allylic
substitution has been an important issue as it creates an
additional stereocomponent and thus, stereochemically well-
defined prochiral allylic electrophiles or cyclic electrophiles had to
stereoconvergent (E)-olefin formation from racemic allylic phosphates. be used for high stereocontrol.[4b,12] Secondary acyclic allylic
electrophiles were less successful due to their conformatioal
flexibility, often leading to kinetic resolution of electrophiles[12b] or
to production of E/Z mixtures (Scheme 1b).[11a,13] To the best of
The development of synthetic strategies to obtain
stereochemically well-defined, enantioenriched products is an
our knowledge, stereoconvergent coupling between a chiral
ongoing pursuit in organic chemistry. In this regard, transition-
alkylcopper intermediate and a racemic allylic eletrophiles has not
metal catalyzed allylic substitution has been considered as a
been reported. In this article, we report a copper-catalyzed
powerful synthetic tool due to easy incorporation of a versatile allyl
borylative coupling of vinyl arenes and vinyl silanes with racemic
functionality with creation of a stereogenic center from prochiral
allylic phosphates to form β-chiral alkylboronates having well-
allylic electrophiles.[1] While the use of stabilized carbon
controlled, two stereo-components (Scheme 1c).
nucleophiles is prevalent in the Tsuji-Trost-type allylation using
palladium or iridium catalyst,[2] the copper-catalyzed allylic
substitution is distinguished by the use of non-stabilized carbon
nucleophiles. The generation of organocopper nucleophiles from
strongly basic organometallic reagents including Grignard, and
organolithium reagents in earlier research[3] had greatly advanced
to the use of relatively benign organoboron and orgnozirconium
compounds,[4] and further to in-situ generation from alkenes or
alkynes by organocupration.[5]
Chiral alkylmetal species containing
a
sp3-carbon
stereogenic center attached to metal are attractive reagents as
nucleophiles in C‒C bond forming reactions.[6] Despite of their
potential utilities, their synthetic applications were limited by use
of very low temperatures due to intrinsic configurational lability of
the α-metal stereogenic center;[7] recently, chiral secondary
alkylcopper intermediates in-situ generated from alkenes were
[*]
J. T. Han, Prof. Dr. J. Yun
Department of Chemistry, Sungkyunkwan University, Suwon 16149
(Korea)
E-mail: jaesook@skku.edu
S.-T. Kim, Prof. Dr. M.-H. Baik
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST)
Center for Catalytic Hydrocarbon Functionalizations, Institute for
Basic Science (IBS), Daejeon, 34141 (Korea)
E-mail: mbaik2805@kaist.ac.kr
Scheme 1. Allylation of chiral alkylcopper species.
Supporting information for this article is given via a link at the end of
the document.
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From our earlier report on the borylative coupling of vinyl
arenes with primary allylic electrophiles,[11b] we found that the use
of allyl phosphates and N,N-dimethylacetylamide (DMA) solvent
were crucial for good yield of product in the presence of a catalytic
amount of CuCl and a chiral bisphosphine ligand. However,
application of the previous reaction conditions to secondary allylic
phosphate (rac-2a) resulted in moderate yield and
enantioselectivity despite promising E/Z selectivity. Therefore, we
screened
discovered that the short-tethered BenzP* ligand is most effective.
a
series of chiral bisphosphine ligands[14] and
Table 1. Substrate scope of the allylation[a]
[a] E/Z ratios were determined by 1H NMR analysis of the crude reaction mixture; ee values were determined by HPLC analysis.
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The scope of the direct stereoconvergent coupling of
various vinyl arenes (1) with B2pin2 and allylic phosphates (2)
using the catalytic combination of CuCl/ BenzP* was examined
(Table 1). In general, reactions of racemic secondary allylic
phosphates (rac-2a–e) with the R group being a primary or
secondary substituent afforded the desired products (3) after
oxidation with good to excellent E/Z selectivities (88:12 to >99:1)
and good enantiomeric excess (84%‒90%). The E/Z selectivity
increased as the steric bulk of the R group increases from methyl
(2a: 88:12), 1° alkyl (2b: 92:8) to 2°, 3° alkyl, and phenyl (>99:1).
A higher E/Z selectivity (3ia: >99:1) was obtained even with 2a,
when an indole-derived organocopper was used as the
nucleophile. However, an allylic phosphate (2f) with the sterically
demanding tert-butyl group led to product (3af) in decreased
enantioselectivity (66%) despite high E/Z selectivity. While vinyl
arenes (1b‒1e) with an ortho-, electron-donating, or halogen
substituent were suitable substrates for the reaction, vinyl arene
(1f) with a strongly electron-withdrawing CF3 group provided the
desired product in poor yield and ee (40% ee). Vinyl arenes (1g
same ee, revealing that the absolute configurations of the
benzylic carbons of (E)-3aa and (Z)-3aa were the same (Scheme
3a). Reactions of enantiomerically pure starting allylic
phosphates, (R)-2b and (S)-2b yielded the same enantiomeric
product (E)-3ab with similar reactivities and same
enantioselectivity (90% ee for (R)-2b and 90% ee for (S)-2b)
(Scheme 3b and 3c). These results suggest that each of the two
enantiomers of the racemic allylic phosphate is transformed into
the same enantiomeric product at similar reaction rates.
Hammett studies were conducted to investigate the
relationship between electronic variation of the vinyl arene
substrate and enantiomeric ratio of the product (Scheme 4).[15] In
reactions of para-substituted vinyl arenes 1 with allylic phosphate
rac-2d, a linear correlation with negative slope (ρ = −1.64) was
observed between the Hammett substituent constant, σpara and
log(er), demonstrating that electronic variation of the vinyl arene
substrate has a significant impact on the enantioselectivity of the
product. These results indicate that less nucleophilic
benzylcopper species derived from electron-deficient vinyl
arenes such as 1f (–CF3) are not efficient for the allylic
substitution, which can be ascribed to fast racemization[10c,16] of
electron-deficient organocopper intermediates (I) during C‒C
bond formation. In contrast, more nucleophilic benzylcopper
species derived from electron-rich vinyl arenes such 1d and 1h
would react smoothly with the allylic electrophile, preserving
enantiopurity at the benzylic stereocenter, which are in
agreement with our proposed catalytic mechanism.
and 1h) bearing
a naphthyl or piperonyl group were
accommodated under the standard reaction conditions. Vinyl
heterocycles (1i‒1k) including indole, thiophene, and
benzofuran were also suitable for the reaction, affording the
corresponding products in excellent E/Z selectivity and high
enantioselectivity. Furthermore, the reaction of vinyl ferrocene
(1l) and vinyl silane (1m) proceeded smoothly to yield products
in 90% and 84% ee, respectively.
A proposed catalytic cycle for the coupling reaction is
shown in Scheme 2 with the following three steps: (1) Insertion
of a vinyl arene into a chiral ligand-bound copper‒boryl complex
to generate the enantiomerically-enriched β-boryl benzylcopper
species I; (2) direct stereoconvergent C‒C bond formation from
I with the racemic secondary allylic electrophile to yield the
desired coupling product; and (3) regeneration of the L*Cu‒Bpin
species to complete the catalytic cycle.
Scheme 2. Proposed catalytic cycle.
Scheme 3. Experimental studies.
A series of experiments were conducted to obtain
mechanistic insights into the reaction (Scheme 3).
Hydrogenation of a mixture of (E)-3aa and (Z)-3aa obtained from
the reaction afforded a single enantiomeric product 4aa with the
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mechanism and the exact origin of the stereoconvergence in the
tandem coupling process (see Figure S1 in the Supporting
Information for details). Among three plausible reaction
pathways considered for the allylic substitution of the
organocopper intermediate (I), pathway 1 in which oxidative
addition of I toward the allyl phosphate with simultaneous leaving
group displacement (SN2’-oxidative addition) to form a copper(III)
intermediate is favored over oxidative addition of I, ligand
dissociation and reductive elimination (pathway 2) or a stepwise
organocupration followed by β-elimination of a copper complex
(pathway 3) (Figure 1). Interestingly, pathway 3 was often
suggested as a plausible catalytic mechanism of copper-
catalyzed allylic substitution reactions with possible syn or anti-
Cu-LG elimination.[12b,17] Furthermore, calculated reaction
energy profiles with enantiomeric (R)-2d and (S)-2d and
structural examination of possible transition states revealed that
the transition states leading to (E)-intermediate were more facile
than competing (Z)-transition states with less steric hindrance
respectively, which is in good agreement with the experimentally
observed E/Z selectivity. (See Figure S2 in the Supporting
Information for details).
In summary, we have described a copper-catalyzed direct
stereoconvergent coupling of vinyl arenes and racemic acyclic
allylphosphates with a diboron reagent that affords β-chiral
alkylboronates with an (E)-alkenyl moiety. Our catalytic systems
enabled the use of elusive racemic acyclic substrates in a
tandem process that employed chiral organocopper nucleophiles
containing a stereogenic sp3-carbon center in a stereoselective
C–C bond formation. Mechanistic studies and DFT calculations
were conducted to elucidate the reaction mechanism and the
origin of direct stereoconvergence in the tandem coupling
protocol. We anticipate that our strategy will be applicable to
access a variety of chiral molecules.
Scheme 4. Hammett studies.
Experimental Section
Experimental Details. A mixture of CuCl (2.5mg, 0.025 mmol), (R,R)-
BenzP* (7.8 mg, 0.0275 mmol), bis(pinacolato)diboron (190.5 mg, 0.75
mmol) and LiOMe (38.0 mg, 0.75 mmol) in DMA (0.5 mL) were stirred for
15 min in a Schlenk tube under an atmosphere of nitrogen. 1a (0.5 mmol)
dissolved in DMA (0.5mL) and rac-2a (0.75 mmol) were added to the
reaction mixture. The reaction mixture was stirred at 40 °C and monitored
by TLC. Upon completion of the reaction, the reaction mixture was diluted
with diethyl ether (10 mL). The aqueous layer was extracted with diethyl
ether, and the combined organic layers were dried over Na2SO4 and
concentrated in vacuo. To the mixture in THF (2 mL) and water (2 mL)
was added sodium perborate (1.5 mmol). The reaction mixture was
vigorously stirred for 5 h at room temperature. After the reaction was
quenched with water and then, extracted with ethyl acetate. The
combined organic layers were dried over Na2SO4 and concentrated in
vacuo. The product 3aa was purified by silica gel chromatography.
Figure 1. Three possible reaction pathways for allylic substitution of l with
allylic phosphate.
Acknowledgements
Density functional theory (DFT) calculations were carried
out using the (R,R)-BenzP* ligand, styrene, and rac-2d as the
model substrates and provided a reasonable model of the full
This study was supported by National Research Foundation of
Korea (NRF) grants (Nos. 2019R1A2C2005706 and
2019R1A4A2001440), funded by the Korean government
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Keywords: asymmetric allylation • copper • enantioselectivity •
homogeneous catalysis • substitution
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Jung Tae Han, Seoung-Tae Kim, Mu-
Hyun Baik,* Jaesook Yun*
Page No. – Page No.
Direct Stereoconvergent Allylation of
Chiral Alkylcopper Nucleophiles with
Racemic Allylic Phosphates
Direct stereoconvergent coupling of chiral alkylcopper species with racemic allylic
phosphates was developed. Mechanistic studies and DFT calculations explain the
origin of direct stereoconvergence in the tandem coupling process.
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