Asymmetric palladium-catalyzed allylic alkylation using dialkylzinc reagents: A remarkable ligand effect

Article abstract of DOI:10.1002/anie.201309074

A serendipitously discovered palladium-catalyzed asymmetric allylic alkylation reaction with diorganozinc reagents, which displays broad functional group compatibility, is reported. This novel transformation hinges on a remarkable ligand effect which overrides the standard "umpolung" reactivity of allyl-palladium intermediates in the presence of dialkylzincs. Owing to its mild conditions, enantioselective allylic alkylations of racemic allylic electrophiles are possible in the presence of sensitive functional groups. Umpole-me-not: A serendipitously discovered palladium-catalyzed asymmetric allylic alkylation reaction with diorganozinc reagents displays broad functional group compatibility. This novel transformation hinges on a remarkable ligand effect which overrides the standard "umpolung" reactivity of allyl-palladium intermediates in the presence of dialkylzinc compounds.

Full text of DOI:10.1002/anie.201309074

Angewandte
Chemie
DOI: 10.1002/anie.201309074
Asymmetric Catalysis
Asymmetric Palladium-Catalyzed Allylic Alkylation Using Dialkylzinc
Reagents: A Remarkable Ligand Effect**
Antonio Misale, Supaporn Niyomchon, Marco Luparia, and Nuno Maulide*
Abstract: A serendipitously discovered palladium-catalyzed
asymmetric allylic alkylation reaction with diorganozinc
reagents, which displays broad functional group compatibility,
is reported. This novel transformation hinges on a remarkable
ligand effect which overrides the standard “umpolung”
reactivity of allyl–palladium intermediates in the presence of
dialkylzincs. Owing to its mild conditions, enantioselective
allylic alkylations of racemic allylic electrophiles are possible
in the presence of sensitive functional groups.
pharmacokinetics by blocking or slowing down typical
oxidative metabolic pathways.[3]
Palladium-catalyzed asymmetric allylic alkylation (AAA)
is a powerful bond-forming synthetic method for the forma-
[4a–c]
À
À
tion of C C and C X bonds,
particularly enabling the
quantitative conversion of chiral racemic substrates into
single enantiomeric products, through deracemization.[4d–h]
The most widely accepted model states that stabilized or
“soft” nucleophiles attack the pivotal allyl–Pd intermediate
through an outer-sphere substitution reaction with inversion
at carbon, thus leading to global retention of configuration.
Conversely, nonstabilized or “hard” nucleophiles generally
afford overall inversion of configuration, as the nucleophile
transmetalates to palladium before reductive elimination to
the final product takes place.[4] Pd-catalyzed AAA reactions
carried out in conjunction with “soft” nucleophiles are well
established in the literature. Unfortunately, most of the work
developed for the latter cannot be easily transposed for
“hard” nucleophiles. Indeed, the use of main-group organo-
metallic reagents such as Grignard reagents and organo-
lithium derivatives is plagued by b-hydride elimination as
a competing mechanistic pathway, leading to reduced prod-
ucts. As a consequence, only few reports describe the use of
“hard” nucleophiles in the context of AAA.[5] In particular,
dialkylzinc reagents are well known to divert the standard
reactivity of Pd–allyl complexes converting them into nucle-
ophilic allyl moieties.[6] This type of “umpolung” chemistry
constitutes a successful class of reactions in its own right
(Scheme 1a), of which the Marshall–Tamaru propargylation
is a prime example that enjoys widespread use in natural
product total synthesis.[7]
T
he stereoselective introduction of isolated, all-alkyl-sub-
stituted stereocenters in cyclic or acyclic frameworks remains
a daunting synthetic challenge.[1] In particular, lone ethyl- and
methyl-bearing tertiary stereocenters are present in many
bioactive substances (Figure 1).[2] Additionally, the methyl or
ethyl substitution of methylene groups can lead to enhanced
Highly enantioselective allylic alkylation reactions
employing organolithium and Grignard reagents as nucleo-
philes can be realized with copper catalysis (Scheme 1b).[8]
However, the high nucleophilicity and basicity of those
reagents is a drawback of these procedures.[9] To the best of
our knowledge, deracemizing allylic alkylation of cyclic,
racemic electrophiles with “hard” nucleophiles (Scheme 1b)
has only been achieved with alkyl lithium or magnesium
derivatives thus far. Herein, we report a Pd-catalyzed
asymmetric allylic alkylation employing dialkylzinc reagents
which relies on a unique ligand effect (Scheme 1c).
Our investigations in this area stem from a serendipitous
observation made during the study of “umpolung”-type
reactions of the cyclobutene substrate rac-1 (Scheme 2).
When this allylic chloride was exposed to catalytic amounts
of [{Pd(allyl)Cl}2], the chiral phosphoramidite L1, and a slight
excess of Et2Zn (2.4 equiv) in the presence of benzaldehyde
derivative 2, the “umpoled” nucleophilic addition product 3
was obtained in good yield.[6] In contrast, when TADDOL-
Figure 1. Natural products bearing lone ethyl or methyl stereocenters.
[*] Dr. M. Luparia
Aptuit (Verona) Srl.
Via Alessandro Fleming 4, 37135 Verona (Italy)
Dr. A. Misale, S. Niyomchon, Prof. Dr. N. Maulide
Faculty of Chemistry, Institute of Organic Chemistry
Wꢀhringer Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
[**] We are grateful to the University of Vienna and the Max-Planck-
Society for support. This work was financed by the DFG (MA 4861/
3-1 and MA4681/3-2) and the ERC (StG FLATOUT to N.M.). We
thank Prof. H. G. Schmalz (University of Cologne) for the generous
donation of chemicals. Some of this research was carried out in the
Max-Planck-Institut fꢁr Kohlenforschung, which we acknowledge
gratefully.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309074.
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Further reaction optimization[11] was carried out employ-
ing L2a, leading to product 6a in high diastereo- and
enantioselectivity. As portrayed in Scheme 4, both primary
and secondary dialkylzinc nucleophiles can be added to the
cyclobutenyl framework with moderate to excellent selectiv-
ities and yields. Although in our previous studies with
cyclobutenyl electrophiles in asymmetric palladium catalysis
we observed a very special influence of the small ring size and
the carboxylic acid moiety,[4i,12] the early success with ester
1 suggested that this alkyl transfer could be a more general
transformation.
We thus directed our attention to cyclohexenyl electro-
philes. In the event, the use of ligand L2b enabled derace-
mizing, asymmetric allylic alkylation with Et2Zn to take place
on chlorocyclohexenes rac-8 with excellent diastereo- and
enantioselectivity. Importantly, the use of cis-8a and trans-8b
led to trans-9a and cis-9b alkylation products, respectively
(Scheme 5). This confirmed that this process takes place with
clean inversion of configuration at the reactive center.
At this juncture, we evaluated the influence of the leaving
group in this alkyl-transfer reaction, and chose 4-phenyl-
cyclohex-1-ene derivatives as substrates (Table 1). Since
a vast majority of the known catalytic asymmetric alkylation
reactions employ allylic halides as electrophiles, we were
enticed by the possibility of using ester leaving groups.[13] Our
results are compiled in Table 1.
Scheme 1. Pd-catalyzed “umpolung” chemistry and state-of-the-art
asymmetric allylic alkylation employing “hard” nucleophiles.
Excellent
diastereocontrol
was
observed, with cis substrates 10a/c–
e converting into the trans epimer of
the product. The temperature values
listed for each substrate represent the
lowest temperature at which reactivity
was observed, and conveys reactivity
differences qualitatively. The acetate
substrate (Table 1, entry 1), along with
the methyl- and phenylcarbonate deriv-
atives (Table 1, entries 3 and 4) dis-
played similar efficiency at À208C,
delivering trans-11a in good to excellent
yield and enantioselectivity. The use of
a more hindered pivaloyl ester (Table 1,
entry 2) led to no reaction observed even
at ambient temperature. The substrate
with a tailor-made (2-methylthio)acetyl
leaving group (Table 1, entry 5), which
was developed in the Ni-catalyzed leav-
Scheme 2. Serendipitous discovery of an unusual ligand effect. TMS=trimethylsilyl.
derived ligand L2a[4i,10] was employed, we were surprised to
observe the ethylated cyclobutene 4 as the only reaction
product (Scheme 2).
ing-group-directed, enantiospecific substitution reported by
Jarvo et al.,[1a] also led to a successful reaction, even at lower
temperature. It is accepted that coordination of the organo-
zinc reagent to the leaving group accelerates oxidative
addition of the substrate to the nickel catalyst. Such an
accelerating effect may also be responsible for the qualita-
tively higher reactivity observed here.
We then further investigated the scope of the reaction.
Results are compiled in Table 2. As depicted in entries 1–5,
racemic acetates and carbonates undergo deracemizing
alkylation by dialkylzinc reagents in good to excellent yields
and very good enantioselectivities. Table 2, entries 6–8 show-
case the excellent functional group tolerance of dialkylzinc
This unusual ligand effect (particularly given the rather
close structural relationship of L1 and L2a) prompted us to
investigate the transformation further in the absence of
electrophiles. An extensive screening of ligands was con-
ducted and selected examples are depicted in Scheme 3.[11] As
shown, chiral phosphoramidites L2/L3, bearing a TADDOL/
TARTROL backbone, are uniquely capable of successfully
promoting the alkyl transfer reaction. With all other ligands,
only the product of halide reduction, cyclobut-2-enoic acid
(7), was observed.
2
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Chemie
nucleophiles, as Weinreb amides,
ketones, and even free aldehydes
(Table 2, entry 7) are tolerated in this
transformation. Allylic piperidine ace-
tates are also suitable electrophiles for
this transformation, which is not lim-
ited to substrates with six-membered
rings (Table 2, entries 9 and 10).
The complementarity of the trans-
formations reported herein relative to
state-of-the-art,
copper-catalyzed
allylic alkylation methodologies is
best expressed by the experiments
depicted in Scheme 6. As shown,
a standard copper-catalyzed asymmet-
ric allylic alkylation[8d] employing
EtMgBr as the nucleophile with the
free ketone 19a leads to extensive 1,2-
addition to the carbonyl group,[11]
generating
a
complex mixture
(Scheme 6a). Additionally, attempted
Cu-catalyzed preparation of a racemic
sample of 22b for the determination of
the enantioselectivity by chromatog-
raphy (HPLC) led to the product
(26a) of reduction of a putative ring-
opened intermediate 25 (Scheme
6b).[8g–i]
Scheme 3. Ligand screening for the ethyl-transfer reaction. e.r. values were determined on the N-
benzylamide derivative of 6a.[11] Yields determined by 1H NMR analysis (internal standard).
Table 1: Leaving-group effect. The d.r. value of product 11a was >95:5 in
all entries (1H NMR analysis of the crude product). Yields refer to
isolated product.[11]
Entry
Leaving group
Substrate
T [8C]
Yield [%]
e.r.
Scheme 4. Catalytic asymmetric alkylation of cyclobutenyl electro-
philes.[11]
1
2
3
4
OAc
OPiv
OCO2Me
OCO2Ph
10a
10b
10c
10d
À20
RT
89
–
76
85
98:2
–
98:2
98:2
À20
À20
5
10e
À40
79
97:3
Interestingly, exposure of linear acetate 27a to similar
reaction conditions cleanly led to the reduced product 28 in
high yield (Scheme 7). A deuterium-labeling experiment
delivered 28d and identified this as the result of “umpo-
lung”-type transmetalation towards a nucleophilic allyl–metal
intermediate, quenching of which likely leads to the observed
product.
The alkylated products obtained offer additional oppor-
tunities for synthetic modification (Scheme 8). Regio- and
stereoselective halohydrin formation affords 29 in 68% yield,
Scheme 5. Inversion of configuration in the catalytic asymmetric
alkylation of cyclohexenyl electrophiles. Yields are for isolated prod-
ucts.[11]
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Table 2: Scope of the deracemizing alkyl-transfer reaction. Reaction
conditions are the same as those in Scheme 5 and yields are for isolated
compounds.
Table 2: (Continued)
Entry Substrate
Product
d.r.
–
Yield e.r.
[%]
Entry Substrate
Product
d.r.
Yield e.r.
[%]
82[c]
90:10
1
99:1 78
94:6
9
81
85:15
88:12
99:1 87
99:1 60
85:15
87:13
2
3
4
10
–
80
[a] d.r. starting material=90:10. [b] Yield of isolated alcohol (DIBALH
reduction). [c] Ratio of 22a to reduced compound 1:1.[11]
99:1 55
84:16
while dihydroxylation leads to highly functionalized cyclo-
hexane 30 in short order.[14] The lone tertiary stereocenter
apparently exerts notable sterecontrol over functionalization
of the neighboring alkene. Furthermore, the cyclobutene
analogue 6a enables a short synthesis of isopilopic acid benzyl
amide 31.[15] Upon ozonolysis and oxidation, the desired
natural product derivative is obtained in 56% yield.
99:1 78
99:1 85
95:5
84:16
In summary, we have developed the first enantioselective
Pd-catalyzed alkylation employing dialkylzinc reagents as
nucleophiles. This unusual transformation, which thwarts the
standard “umpolung” reactivity of allyl–palladium intermedi-
ates in the presence of diorganozinc reagents, hinges on
a remarkable ligand effect of TADDOL-derived phosphor-
amidites as privileged ligand scaffolds. The broad functional
group tolerance of dialkylzinc reagents renders them poten-
tially complementary alternatives to the commonly employed
alkyl lithium and magnesium analogues. Further studies on
the mechanism and scope of this reaction are in progress.
97:3
97:3
92
72
89:11
90:10
5
99:1 86
99:1 90
93:7
93:7
Received: October 17, 2013
Revised: March 24, 2014
Published online: && &&, &&&&
6
Keywords: alkylation · deracemization · diethylzinc ·
.
enantioselectivity · palladium
7
8
82:18[a] 72[b]
90:10
87:13
[1] For selected methods for the construction of tertiary, benzylic
stereocenters, see: a) H. M. Wisniewska, E. C. Swift, E. R. Jarvo,
J. Am. Chem. Soc. 2013, 135, 9083 – 9090; b) Y. Hatanaka, T.
Hiyama, J. Am. Chem. Soc. 1990, 112, 7793 – 7794; c) J. F.
Paquin, C. Defieber, C. R. J. Stephenson, E. M. Carreira, J. Am.
Chem. Soc. 2005, 127, 10850 – 10851; d) S. Nave, R. P. Sonawane,
T. G. Elford, V. K. Aggarwal, J. Am. Chem. Soc. 2010, 132,
17096 – 17098.
99:1 75
[2] a) H. Fujioka, K. Nakahara, N. Kotoku, Y. Ohba, Y. Nagatomi,
T.-L. Wang, Y. Sawama, K. Murai, K. Hirano, T. Oki, S.
Wakamatsu, Y. Kita, Chem. Eur. J. 2012, 18, 13861 – 13870; b) M.
Amat, M. Pꢀrez, N. Llor, C. Escolano, F. J. Luque, E. Molins, J.
4
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Angewandte
Chemie
Clader, W. J. Greenlee, K. Cox, J. M. Strizki,
B. M. Baroudy, J. Med. Chem. 2002, 45, 3143 –
3160.
[4] a) B. M. Trost, D. L. Van Vranken, Chem. Rev.
1996, 96, 395 – 422; b) B. M. Trost, M. L. Crawley,
Chem. Rev. 2003, 103, 2921 – 2943; c) F. F. Huerta,
A. B. E. Minidis, J. E. Bꢁckvall, Chem. Soc. Rev.
2001, 30, 321 – 331; d) K. Faber, Chem. Eur. J,.
2001, 7, 5004 – 5010; e) J. Steinreiber, K. Faber, H.
Griengl, Chem. Eur. J. 2008, 14, 8060 – 8072; f) H.
Pellissier, Tetrahedron 2011, 67, 3769 – 3802;
g) M. T. Oliveira, D. Audisio, S. Niyomchon, N.
Maulide, ChemCatChem 2013, 5, 1239 – 1247;
h) M. Luparia, M. T. Oliveira, D. Audisio, F.
Frꢀbault, R. Goddard, N. Maulide, Angew. Chem.
2011, 123, 12840 – 12844; Angew. Chem. Int. Ed.
2011, 50, 12631 – 12635.
[5] a) P. Zhang, L. A. Brozek, J. P. Morken, J. Am.
Chem. Soc. 2010, 132, 10686 – 10688; b) L. A.
Brozek, M. J. Ardolino, J. P. Morken, J. Am.
Chem. Soc. 2011, 133, 16778 – 16781; c) M. J.
Ardolino, J. P. Morken, J. Am. Chem. Soc. 2012,
134, 8770 – 8773; d) S. Niyomchon, D. Audisio, M.
Luparia, N. Maulide, Org. Lett. 2013, 15, 2318 –
2321. For poorly enantioselective Pd-catalyzed
allylic alkylations with organozinc reagents, see:
e) J.-C. Fiaud, L. Aribi-Zouioueche, J. Organomet. Chem. 1985,
295, 383. For a rare non-asymmetric example see: f) I. Stary, P.
Kocovsky, J. Am. Chem. Soc. 1989, 111, 4981 – 4982.
Scheme 6. Complementarity between copper- and palladium-catalyzed alkyl transfer
reactions. DMS=dimethyl sulfide, Ts=tosyl.
[6] For Pd-catalyzed “umpolung” chemistry, see: a) G. P. Howell,
A. J. Minnaard, B. L. Feringa, Org. Biomol. Chem. 2006, 4,
1278 – 1283; b) Y. Tamaru, A. Tanaka, K. Yasui, S. Goto, S.
Tanaka, Angew. Chem. 1995, 107, 862 – 864; Angew. Chem. Int.
Ed. Engl. 1995, 34, 787 – 789; c) S. Zhu, X. Quiao, Y. Zhang, L.
Wang, Q. Zhou, Chem. Sci. 2011, 2, 1135 – 1140; d) M. Kimura,
M. Shimizu, K. Shibata, M. Tazoe, Y. Tamaru, Angew. Chem.
2003, 115, 3514 – 3517; Angew. Chem. Int. Ed. 2003, 42, 3392 –
3395; e) G. Zanoni, S. Gladiali, A. Marchetti, P. Piccinini, I.
Tredici, G. Vidari, Angew. Chem. 2004, 116, 864 – 867; Angew.
Chem. Int. Ed. 2004, 43, 846 – 849.
Scheme 7. Deuterium-labeling experiment on linear substrate 27a.
[7] a) J. A. Marshall, J. Org. Chem. 2007, 72, 8153 – 8166; b) J. A.
Marshall, N. D. Adams, J. Org. Chem. 1999, 64, 5201 – 5204. For
a recent synthetic application, see: c) B. M. Trost, B. M. OꢂBoyle,
D. Hund, J. Am. Chem. Soc. 2009, 131, 15061.
[8] a) M. Pꢀrez, M. FaÇanꢃs-Mastral, P. H. Bos, A. Rudolph, S. R.
Harutyunyan, B. L. Feringa, Nat. Chem. 2011, 3, 377 – 381; b) J.-
B. Langlois, A. Alexakis, Chem. Commun. 2009, 3868 – 3870;
c) D. Grassi, C. Dolka, O. Jackowski, A. Alexakis, Chem. Eur. J.
2013, 19, 1466 – 1475; d) J.-B. Langlois, D. Emery, J. Mareda, A.
Alexakis, Chem. Sci. 2012, 3, 1062 – 1069; e) M. Pꢀrez, M.
FaÇanꢃs-Mastral, V. Hornillos, A. Rudolph, P. H. Bos, S. R.
Harutyunyan, B. L. Feringa, Chem. Eur. J. 2012, 18, 11880 –
11883; f) M. FaÇanꢃs-Mastral, M. Pꢀrez, P. H. Bos, A. Rudolph,
S. R. Harutyunyan, B. L. Feringa, Angew. Chem. 2012, 124,
1958 – 1961; Angew. Chem. Int. Ed. 2012, 51, 1922 – 1925; g) J. F.
Teichert, S. Zhang, A. W. v. Zijl, J. W. Slaa, A. J. Minnaard, B. L.
Feringa, Org. Lett. 2010, 12, 4658 – 4660; h) D. J. Hyett, J. B.
Sweeney, A. Tavassoli, Tetrahedron Lett. 1997, 38, 8283 – 8286.
For authoritative reviews on Cu-catalysis, see: i) A. Alexakis,
J. E. Bꢁckvall, N. Krause, O. Pꢄmies, M. Diꢀguez, Chem. Rev.
2008, 108, 2796 – 2823; j) S. R. Harutyunyan, T. den Hartog, K.
Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008, 108,
2824 – 2852.
Scheme 8. Stereoselective derivatization of alkylation products 14a
and 6a. Bn=benzyl, mCPBA=meta-chloroperbenzoic acid, NBS=N-
bromosuccinimide, NMO=N-methylmorpholine N-oxide, TBABr=
tetrabutylammonium bromide, TEMPO=2,2,6,6-tetramethylpiperidinyl-
oxy.
Bosch, J. Org. Chem. 2004, 69, 8681 – 8693; c) M. M. Cid, E.
Pombo-Villar, Helv. Chim. Acta 1993, 76, 1591 – 1607; d) A.
Endo, M. Kuroda, K. Tanzawa, FEBS Lett. 1976, 72, 323 – 326.
[3] For methyl substitution as a strategy to slow down metabolic
oxidation, see: a) T. G. Burke, Z. Mi, J. Med. Chem. 1993, 36,
2580 – 2582; b) A. Palani, S. Shapiro, H. Josien, T. Bara, J. W.
[9] For Cu-catalyzed procedures employing other nucleophiles, see:
a) R. Shintani, K. Takatsu, M. Takeda, T. Hayashi, Angew.
Chem. 2011, 123, 8815 – 8818; Angew. Chem. Int. Ed. 2011, 50,
8656 – 8659; b) Y. Shido, M. Yoshida, M. Tanabe, H. Ohmiya, M.
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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.
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Communications
Sawamura, J. Am. Chem. Soc. 2012, 134, 18573 – 18576; c) M. A.
Kacprzynski, A. H. Hoveyda, J. Am. Chem. Soc. 2004, 126,
10676 – 10681; d) N. Yoshikai, K. Miura, E. Nakamura, Adv.
Synth. Catal. 2009, 351, 1014 – 1018.
[13] For general analyses of leaving-group effects in Pd catalysis, see:
a) L. A. Evans, N. Fey, J. N. Harvey, D. Hose, G. C. Lloyd-Jones,
P. Murray, A. G. Orpen, R. Osborne, G. J. J. Owen-Smith, M.
Purdie, J. Am. Chem. Soc. 2008, 130, 14471 – 14473; b) C.
Johansson, G. Lloyd-Jones, P. Norrby, Tetrahedron: Asymmetry
2010, 21, 1585 – 1592; c) P. Fristrup, T. Jensen, J. Hoppe, P.
Norrby, Chem. Eur. J. 2006, 12, 5352 – 5360; d) C. Amatore, A.
Jutand, L. Mensah, G. Meyer, J. Fiaud, J. Legros, Eur. J. Org.
Chem. 2006, 1185 – 1192.
[10] a) H. Teller, S. Flꢅgge, R. Goddard, A. Fꢅrstner, Angew. Chem.
2010, 122, 1993 – 1997; Angew. Chem. Int. Ed. 2010, 49, 1949 –
1953; b) H. W. Lam, Synthesis 2011, 2011 – 2043.
[11] See the Supporting Information for further experimental details.
[12] a) D. Audisio, M. Luparia, M. T. Oliveira, D. Klꢅtt, N. Maulide,
Angew. Chem. 2012, 124, 7426 – 7429; Angew. Chem. Int. Ed.
2012, 51, 7314 – 7317; b) D. Audisio, G. Gopakumar, L. Xie, L. G.
Alves, C. Wirtz, A. M. Martins, W. Thiel, C. Farꢆs, N. Maulide,
Angew. Chem. 2013, 125, 6434 – 6438; Angew. Chem. Int. Ed.
2013, 52, 6313 – 6316.
[14] a) G. A. Molander, B. Czakꢇ, D. J. St. Jean, J. Org. Chem. 2006,
71, 1172 – 1180; b) P. Gupta, P. J. Pal, Y. S. Reddy, D. Yashwant,
D. H. Vankar, Eur. J. Org. Chem. 2011, 1166 – 1175.
[15] L. Reichel, G. Schreiber, Pharmazie 1968, 23, 594.
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Asymmetric Catalysis
A. Misale, S. Niyomchon, M. Luparia,
N. Maulide*
&&&& — &&&&
Asymmetric Palladium-Catalyzed Allylic
Alkylation Using Dialkylzinc Reagents: A
Remarkable Ligand Effect
Umpole-me-not: A serendipitously dis-
covered palladium-catalyzed asymmetric
allylic alkylation reaction with diorgano-
zinc reagents displays broad functional
group compatibility. This novel transfor-
mation hinges on a remarkable ligand
effect which overrides the standard
“umpolung” reactivity of allyl–palladium
intermediates in the presence of dialkyl-
zinc compounds.
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