Modular, catalytic enantioselective construction of quaternary carbon stereocenters by sequential cross-coupling reactions

Article abstract of DOI:10.1021/acs.orglett.6b01580

The catalytic Suzuki-Miyaura cross-coupling with chiral γ,γ-disubstituted allylboronates in the presence of RuPhos ligand occurs with high regioselectivity and enantiospecificity, furnishing nonracemic compounds with quaternary centers. Mechanistic experiments suggest that the reaction occurs by transmetalation with allyl migration, followed by rapid reductive elimination.

Full text of DOI:10.1021/acs.orglett.6b01580

Letter
pubs.acs.org/OrgLett
Modular, Catalytic Enantioselective Construction of Quaternary
Carbon Stereocenters by Sequential Cross-Coupling Reactions
Bowman Potter, Emma K. Edelstein, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: The catalytic Suzuki−Miyaura cross-coupling with
chiral γ,γ-disubstituted allylboronates in the presence of RuPhos
ligand occurs with high regioselectivity and enantiospecificity,
furnishing nonracemic compounds with quaternary centers.
Mechanistic experiments suggest that the reaction occurs by
transmetalation with allyl migration, followed by rapid reductive
elimination.
of these reagents in asymmetric cross-coupling reactions has
he selective and efficient construction of quaternary
Tcarbon stereocenters remains a challenging task for little precedent. Important recent studies in the cross-coupling
of allylboron reagents and C(sp2) electrophiles have shed light
on critical aspects of regioselectivity in C−C bond formation.
Moderate branch-selectivity in cross-coupling of crotyl
boronates and aryl electrophiles was first observed by Kalinin.6
This reaction was developed more broadly by Miyaura, who
found that these reactions could be accomplished enantiose-
lectively with chiral catalysts and that they could exhibit very
high regioselectivity for the γ-coupled products ostensibly by
SE2′ transmetalation followed by rapid reductive elimination.7
Our own group recently disclosed an enantioselective,
intramolecular allyl-aryl cross-coupling to furnish carbocycles
with high levels of selectivity.8 With more hindered γ,γ-
disubstituted reagents, Organ found that Pd-PEPPSI complexes
catalyze linear-selective prenylation of electrophiles,9 while
Buchwald observed that with appropriate choice of phosphine
ligand, either the linear adduct or the branched tert-prenyl
cross-coupling product could be obtained selectively.10 Studies
by Crudden and Aggarwal,11 and more recently by Hall,12
determined that cross-coupling of secondary allylic boronates
could furnish tertiary stereocenters and that such reactions
occur with enantiospecificity. However, to our knowledge the
issue of chirality transfer in the generation of quaternary centers
has yet to be addressed.
With the goal of developing a cross-coupling reaction
sequence that might be accomplished in a single flask process,
our studies commenced by examining the reaction between
nonracemic allylboronate 1 and aromatic electrophiles (Scheme
2). A critical criteria for the eventual development of a tandem
single flask process was to employ the same conditions for the
allyl-aryl cross coupling that were employed for the
enantiotopic-group-selective coupling in Scheme 1 (KOH/
dioxane/H2O). In the final rendition, it was envisaged that one
need not isolate the intermediate allylboronate prior to its
asymmetric catalysis.1 While several advances have been
charted, one method that has not been broadly employed for
this undertaking is the Suzuki−Miyaura cross-coupling
reaction.2 A lack of advances in this area can plausibly be
traced to the expectation that such catalytic reactions would
require the intermediacy of highly hindered tertiary organo-
palladium complexes, and access to these compounds might be
prohibitive. Indeed, aside from asymmetric catalytic allyl−allyl
cross-coupling,3 the combination of an organoboron reagent
and an organic electrophile to furnish a nonracemic quaternary
carbon stereocenter selectively has yet to be accomplished.4 In
this letter, we describe a site-selective cross-coupling of
allylboronates that, when conducted in sequence with
enantiotopic-group-selective cross-coupling, enables a modular
assembly of enantiomerically enriched quaternary carbon
centers from geminal bis(boronates), alkenyl halides, and
C(sp2) electrophiles (Scheme 1).
With respect to the development of the sequence
represented in Scheme 1, we recently established an
enantiotopic-group-selective cross coupling to construct
requisite γ,γ′-disubstituted allylboronates.5 However, the utility
Scheme 1. Sequential Cross-Coupling Approach to the
Asymmetric Construction of Quaternary Carbon
Stereocenters
Received: May 31, 2016
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.6b01580
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Organic Letters
Letter
a b
,
Scheme 2. Survey of Substrates for Pd/RuPhos Catalyzed Cross-Coupling of Allylboronates and Electrophiles
a
b
Reactions conducted on 0.1 mmol scale at 60 °C for aryl electrophiles or 50 °C for alkenyl electrophiles. Yield is isolated yield of purified material.
c
Regioisomer ratios were determined by 1H NMR analysis, enantiospecificity determined by chiral SFC analysis. Employed 3.0 equiv of
chloropyridine·HCl and 7.5 equiv of KOH.
engagement in a second cross-coupling. As depicted in Scheme
2, it was found that efficient, site selective, and highly
enantiospecific cross-couplings could be obtained by employing
Pd(OAc)2 in the presence of RuPhos13 ligand. With this
catalyst combination and reaction conditions, efficient reactions
and very high levels of γ:α cross-coupling products were
observed. Moreover, the reaction products were isolated with
>20:1 E/Z olefin stereoisomer ratios and with excellent levels
of enantiospecificity (generally >95% es). As the examples in
Scheme 2 indicate, the reaction appears to be effective with
both electron-rich and electron-poor aryl bromides as the
electrophile. It was also found that aryl chlorides and iodides
participated with similar efficiency: compound 8 could be
accessed from 4-chloroanisole or 4-iodoanisole in 95% yield
and 88% yield, respectively, and in identical selectivity as with
the aryl bromide electrophile. In addition to effective couplings
with aryl electrophiles, heteroaromatic compounds also appear
to participate in the reaction (products 13−17), and products
18−24 demonstrate that alkenyl electrophiles engage in
stereospecific cross-couplings and provide a route to important
1,4 “skipped dienes”14 that bear a quaternary carbon stereo-
center. Also of note, products 26−28 suggest that versatile aryl
chloride, alkene, and silyl ether functional groups can be
accommodated in the allylboronate partner. Lastly, while the
data in Scheme 2 is for reactions conducted on 0.1 mmol scale,
when the synthesis of 9 was conducted on 2 mmol scale, the
reaction proceeded with equal efficiency and selectivity (91%
yield, >95:5 γ:α, 99% es).
The high level of stereospecificity in the Pd/RuPhos
catalyzed allyl-aryl cross-coupling suggests that judicious choice
of substrates can allow the same enantiomer of chiral ligand to
furnish both enantiomers of chiral cross-coupling product. This
feature is demonstrated in Scheme 3, where it is shown that
cross-coupling of boronate 29 with either E or Z-1-bromo-2-
methyl-1-butene15 can furnish diastereomeric cross-coupling
products 30 and 31 in near equal levels of stereoselection.
Subjection of 30 and 31 to catalytic allyl-aryl cross-coupling
furnishes enantiomeric products (R)-32 and (S)-32, both in
high levels of enantiomeric purity. The absolute configuration
of the enantiomers of 32 was established by ozonolysis and
oxidation (Jones reagent) to the derived carboxylic acid
followed by comparison of optical rotation to that for the
known compound.16
With an effective cross-coupling that delivers the γ-coupling
product selectively from γ,γ-disubstituted allylboronates, single-
flask cascade cross-coupling sequences were investigated. First,
to determine whether residual L1·PdCl2 catalyst used for the
cross-coupling of geminal bis(boronates) would undermine the
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Scheme 3. Sequential Cross-Coupling to Furnish
Enantiomeric Products from the Same Enantiomer of
Catalyst
Scheme 5. Catalytic Synthesis of Chiral Hydrocarbon 38
furnished the target hydrocarbon 38 in 72% yield as determined
by 13C NMR versus an internal standard.
In terms of reaction mechanism, one of two reasons could
account for the γ-selectivity in the RuPhos/Pd catalyzed allyl-
aryl cross-coupling reaction. In line with studies by Buchwald10
on the construction of quaternary carbons by Pd-catalyzed
coupling of allylboronates and related studies by Aggarwal and
Cruuden,11b it could be that stereospecific SE2′ transmetalation
is followed by rapid reductive elimination; alternatively, the
transmetalation (either SE2′ or SE2) generates a π-allyl complex
that favors reductive elimination at the more substituted
carbon. To probe these possibilities, substituted secondary
allylboronate 39 was subjected to Pd/RuPhos catalyzed cross-
coupling and found to react with >98% γ-selectivity to give 40
(eq 4, Scheme 6); in contrast, when regioisomeric tertiary
subsequent enantiospecific allyl-aryl cross-coupling reaction, we
probed whether L1·PdCl2 would effect cross-coupling of
bromobenzene and in situ generated allylboronate. As depicted
in eq 1 (Scheme 4), heating with PhBr at the end of a cross-
Scheme 4. Single-Flask Sequential Cross-Couplings
Scheme 6. Mechanistic Experiments and the Origin of
Regioselectivity
coupling between geminal bis(boronate) 29 and alkenyl
bromide 33 resulted in low conversion of allylboronate 34
thus L1·PdCl2 appears to be ineffective at allyl-aryl cross-
coupling. To probe the capacity for a single-flask cascade
sequence, 29 and 33 were then subjected to cross-coupling with
L1·PdCl2 with KOH in dioxane/water, then 4-chloroanisole
was added followed by Pd(OAc)2 and RuPhos. Upon heating
to 60 °C for an additional 14 h, coupling product 8 was isolated
in 64% yield and 93:7 er (eq 2). A similar single-flask reaction
sequence furnished 22 with comparable yield and selectivity.
We considered that an intriguing example of the utility of the
cascade cross-coupling sequence to deliver quaternary com-
pounds might lie in the construction of nonracemic 38
(Scheme 5), the simplest all-carbon quaternary-center-contain-
ing compound.17 This compound has recently been addressed
by Aggarwal18 and Cramer19 through approaches employing
asymmetric homologation and selective cleavage of enantio-
topic C−C bonds, respectively. As depicted in Scheme 5, 38
was readily prepared in a three-step sequence involving
asymmetric cross-coupling of bis(boronate) 35 with alkenyl
halide 36, to give 37. Subsequent stereospecific cross-coupling
of 37 with vinyl bromide followed catalytic hydrogenation
allylboronate 41 was subjected to the reaction conditions,
regioisomer 42 was produced in excellent selectivity (eq 5).
This pair of observations effectively rules out the possibility for
π-allyl isomerization of (allyl)palladium intermediates. Collec-
tively, the site-selectivity of the reaction, the configuration of
the product alkene, and the correlation between allylboronate
configuration and product configuration is most in line with an
inner-sphere syn-SE2′ transmetalation that operates by structure
A below (eq 6, Scheme 6).
C
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Organic Letters
Letter
J.-H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L. Angew.
Chem. 2012, 124, 543.
(14) Jie, M.; Pasha, M. K.; Syed-Rahmatullah, M. S. K. Nat. Prod. Rep.
In summary, we have reported a stereospecific cross-coupling
reaction that applies to highly substituted allylboronates and
furnishes quaternary stereocenters with outstanding stereo-
selection. Along with enantiotopic-group-selective cross-cou-
pling, the allyl-aryl cross-coupling can be run as a part of a two
step sequence to create useful chiral hydrocarbons directly from
simple precursors.
1997, 14, 163.
(15) Lim, S.; Wipf, P. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068.
(16) Ruano, J. L. G.; Martin-Castro, A. M.; Tato, F.; Torrente, E.;
Poveda, A. M. Chem. - Eur. J. 2010, 16, 6317.
(17) (a) Hoeve, W. T.; Wynberg, H. J. Org. Chem. 1980, 45, 2754.
(b) Fujita, T.; Obata, K.; Kuwahara, S.; Miura, N.; Nakahashi, A.;
Monde, K.; Decatur, J.; Harada, N. Tetrahedron Lett. 2007, 48, 4219.
(c) Fujita, T.; Obata, K.; Kuwahara, S.; Nakahashi, A.; Monde, K.;
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(d) Simaan, S.; Goldberg, A. F. G.; Rosset, S.; Marek, I. Chem. -
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01580.
(18) Pulis, A. P.; Blair, D. J.; Torres, E.; Aggarwal, V. K. J. Am. Chem.
Soc. 2013, 135, 16054.
(19) Seiser, T.; Cramer, N. J. Am. Chem. Soc. 2010, 132, 5340.
Procedures, characterization, and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: morken@bc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The NIH (GM-64451) is acknowledged for financial support;
B.P. is grateful for a LaMattina graduate fellowship.
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