Enantioselective synthesis of all-carbon quaternary stereogenic centers via copper-catalyzed asymmetric allylic alkylation of (Z)-allyl bromides with organolithium reagents

Article abstract of DOI:10.1002/chem.201406006

A copper/phosphoramidite catalyzed asymmetric allylic alkylation of Z trisubstituted allyl bromides with organolithium reagents is reported. The reaction affords all-carbon quaternary stereogenic centers in high yields and very good regio- and enantiosele

Full text of DOI:10.1002/chem.201406006

DOI: 10.1002/chem.201406006
Communication
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Asymmetric Catalysis |Hot Paper|
Enantioselective Synthesis of All-Carbon Quaternary Stereogenic
Centers via Copper-Catalyzed Asymmetric Allylic Alkylation of
(Z)-Allyl Bromides with Organolithium Reagents
Martꢀn FaÇanꢁs-Mastral,*[a, b] Romina Vitale,[a] Manuel Pꢂrez,[a] and Ben L. Feringa*[a]
Abstract:
A
copper/phosphoramidite
catalyzed
asymmetric allylic alkylation of Z trisubstituted allyl
bromides with organolithium reagents is reported. The
reaction affords all-carbon quaternary stereogenic centers
in high yields and very good regio- and enantioselectivity.
This systematic study illustrates the crucial role of the
olefin geometry of the allyl substrate on the outcome of
the reaction and provides a viable alternative to access
these important structural motifs.
The development of catalytic enantioselective methods for the
construction of all-carbon quaternary stereogenic centers, that
is, carbon atoms bearing four different carbon substituents, is
an important challenge in the field of organic synthesis.[1]
Copper-catalyzed asymmetric allylic alkylation (AAA) with
organometallic reagents[2] of trisubstituted allyl substrates
represents a powerful alternative for the synthesis of these
highly congested structural moieties in acyclic systems. Stereo-
selective procedures using chiral allyl substrates have been de-
veloped.[3] Alternatively, the use of different chiral copper cata-
lysts in combination with organozinc,[4] organoaluminium,[5] or-
ganomagnesium[6] and organoboron[7] reagents has been
shown to be highly effective in the AAA of prochiral trisubsti-
tuted allyl compounds. Recently, we reported, for the first
time, the use of organolithium reagents for the copper-cata-
lyzed allylic alkylation of E trisubstituted allyl bromides.[8,9] By
using a catalyst comprising CuBr·SMe2 and a chiral phosphor-
amidite as ligand, and by selecting a proper combination of
dichloromethane and hexane as solvent and co-solvent, we
could tame the highly reactive alkyllithium reagents and use
them for the regio- and enantioselective synthesis of a range
of all-carbon stereogenic centers, avoiding side reactions such
Scheme 1. Copper-catalyzed AAA of trisubstituted allyl bromides with
organolithium reagents.
as lithium–halogen exchange or homocoupling reactions
(Scheme 1a).
Chiral (Z)-allyl substrates have been commonly used in ste-
reoselective copper-catalyzed AAA reactions in order to obtain
the opposite enantiomer (with similar enantioselectivity) than
the one obtained from the (E)-allyl substrates as a function of
olefin geometry control.[3] However, the use of prochiral Z tri-
substituted allyl substrates in combination with a chiral copper
catalyst has been much less explored and only single examples
have been reported by Hoveyda,[4d,5a] Ohmiya and Sawamura[7d]
and our group.[6b] In these cases the enantioselectivity of the
process is controlled by the chiral catalyst and the product is
obtained either as the antipode of the enantiomer product de-
rived from the E isomer with lower enantioselectivity[4d,5a,7d] or
as the same enantiomer with similar enantioselectivity,[6b] de-
pending on the catalytic system used. As the olefin geometry
of the allyl substrate is an important selectivity parameter, and
lacking comprehensive information on the copper-catalyzed
AAA of Z trisubstituted allyl compounds,[10] we decided to in-
vestigate this reaction using organolithium reagents as part of
our research program based on the development of direct cat-
alytic cross-coupling reactions of these highly reactive com-
pounds.[8,9,11] Herein, we report a catalytic methodology that
allows for the copper-catalyzed AAA of Z trisubstituted allyl
bromides (Scheme 1b). The reaction affords all-carbon
quaternary stereogenic centers in high yields and very good
regio- and enantioselectivity, representing a viable alternative
to the previously reported copper-catalyzed AAA of the E
trisubstituted allyl derivatives.[8]
[a] Dr. M. FaÇanꢀs-Mastral, Dr. R. Vitale, Dr. M. Pꢁrez, Prof. Dr. B. L. Feringa
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
E-mail: b.l.feringa@rug.nl
[b] Dr. M. FaÇanꢀs-Mastral
Present address: Department of Organic Chemistry and
Center for Research in Biological Chemistry and
Molecular Materials (CIQUS), University of Santiago de Compostela
15782 Santiago de Compostela (Spain)
E-mail: martin.fananas@usc.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406006.
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(Z)-Allyl bromides 1 required for this study were synthesized
in a straightforward manner according to the synthetic route
depicted in Scheme 2. Reaction of commercially available ethyl
but-2-ynoate with NaI in acetic acid afforded ethyl (Z)-3-iodo-
but-2-enoate with complete Z selectivity.[12] Suzuki coupling,[13]
followed by reduction of the ester moiety and final bromina-
tion of the resulting alcohol gave rise to the desired (Z)-allyl
bromides in good overall yield. The bromination step turned
out to be sensitive to double-bond isomerization and specific
conditions—depending on each substrate—had to be used in
order to minimize this isomerization (see the Supporting
information for further details).
Table 1. Screening of phosphoramidite ligands and reaction conditions.
Entry[a]
1a (Z/E)
L
2a/3a[b]
e.r.[c,d]
1[e]
2
0:100
86:14
86:14
86:14
86:14
86:14
86:14
0:100
96:4
L1
L1
L2
L3
L4
L5
L6
L6
L6
L6
98:2
94:6
n.a.[h]
90:10
95:5
98:2
94:6
90:10
90:10
95:5
92:8 (R)
67:33 (R)
n.a.[h]
73:27 (R)
33:67 (S)
78:22 (R)
9:91 (S)
19:81 (S)
6:94 (S)
5:95 (S)
3[f]
4
5
6[g]
7
8
9
10[e]
96:4
[a] Reactions were performed on a 0.2 mmol scale. nBuLi was diluted
with hexane and added dropwise. Full conversion was reached in all
cases unless otherwise noted. [b] SN2’/SN2 ratio determined by GC and
1H NMR analysis. [c] Determined by chiral HPLC analysis. [d] Absolute
configuration shown in brackets. [e] nBuLi added over 10 h; [f]<10%
conversion; only homocoupling products formed; [g] 85% conversion.
[h] Not applicable.
Scheme 2. Synthesis of (Z)-allyl bromides 1. Conditions: a) NaI (1.6 equiv),
AcOH (6.4 equiv), 1158C, 1.5 h, 92%; b) ArB(OH)2 (1.5 equiv), Pd(OAc)2
(5 mol%), AsPh3 (10 mol%), K3PO4 (3.0 equiv), toluene, 908C, 21 h, 67–88%;
c) DIBAL-H (3.0 equiv), CH2Cl2, À788C, 1 h, 71–97%; d) NBS/PPh3 or PBr3 (see
the Supporting Information).
We started our study on the copper-catalyzed AAA of (Z)-
allyl bromides by performing the reaction between (Z)-1a
(86:14 Z/E mixture) and nBuLi using the conditions previously
reported for the copper-catalyzed AAA of (E)-allyl bromides
(CuBr·SMe2/L1).[8] Interestingly, the use of the (Z)-allyl bromide
gave rise to the same product enantiomer than the one
obtained from the E isomer although with lower enantiomeric
ratio (Table 1, entries 1 and 2).
After screening different phosphoramidite ligands[14]
(entries 2–7), L6 (Figure 1) turned out to be the most effective
for the addition of nBuLi to (Z)-allyl bromide 1a (entry 7). It is
important to note that ligand L6 is more effective for the AAA
of (Z)-1a than for the corresponding E isomer (entries 7 and 8).
These results point at a clear matched/mismatched effect
between the geometry of the olefin and the chiral ligand.
Accordingly, the use of a more Z enriched mixture of 1a
(Z/E=96:4) gave rise to an increase of the enantioselectivity
affording product 2a as the S enantiomer with a very good
6:94 e.r. (entry 9). Finally, a longer addition time of nBuLi led to
a slight enhancement of both the regio- and enantioselectivity,
thus obtaining 2a with an excellent SN2’/SN2 ratio of 95:5 and
5:95 e.r. (entry 10). The fact that the opposite enantiomer of
2a is obtained depending on the absolute configuration of the
binol moiety regardless of the alkene geometry (see for
example, L1 vs. L2) indicates that binol configuration largely
dictates the p-face selectivity and the absolute configuration
of the all-carbon quaternary center.
Figure 1. Chiral phosphoramidite ligands used in this study.
Remarkably, monodentate phosphoramidite ligand L6 pro-
motes the formation of the same enantiomer for the addition
of nBuLi to either the Z or E trisubstuted allyl bromide (Table 1,
entries 7–9). This suggests that the alkylcopper/phosphorami-
dite complex recognizes the g center and not the leaving
group of the substrate at the stage of the p-copper(I)/olefin
complex formation.[10] This is in sharp contrast with the results
obtained by the groups of Hoveyda[5a] and Sawamura[7d] in
which they showed that the use of bidentate ligands for the
copper-catalyzed AAA of a Z trisubstituted allyl substrate gave
rise to the opposite enantiomer than the product derived from
the E isomer, most probably arising from a recognition of the
leaving group of the substrate.
Having established the optimized conditions (Table 1,
entry 10), we set out to investigate the scope of the
copper-catalyzed AAA of Z trisubstituted allyl bromides with
organolithium reagents (Table 2).
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Table 2. Copper-catalyzed AAA of (Z)-allyl bromides 1 with organolithium
reagents.
Table 3. Comparison of the copper-catalyzed AAA with organolithium
reagents of (Z)-allyl bromides versus (E)-allyl bromides (results given for
the addition of nHexLi).
Entry
Ar
Z (L6)
E (L1)
2/3
e.r.
2/3
e.r.
1
2
3[a]
4
Ph
95:5
94:6
95:5
94:6
92:8
94:6
94:6
95:5
>99:1
86:14
91:9
88:12
95:5
4-Cl-C6H4
4-Me-C6H4
2-OMe-C6H4
2-Br-C6H4
85:15[b]
96:4
88:12[b]
90:10
Entry[a]
1 (R1)
R2
2/3[b]
Yield [%][c]
e.r.[d] (2)
[c]
[c]
1
2
3
4
5
6
7
8
1a (Ph)
1a (Ph)
1a (Ph)
nBu
Et
95:5
84:16
90:10
94:6
98:2
92:8
94:6
85:15
99:1
90:10
96:4
–
80
42[e]
74
47[f]
46[g]
86
85
78
74
77
80
–
95:5 (2a)
90:10 (2b)
95:5 (2c)
91:9 (2d)
92:8 (2e)
94:6 (2 f)
94:6 (2g)
88:12 (2h)
84:16 (2i)
88:12 (2j)
90:10 (2k)
–
5
–
–
91:9
[a] nBuLi was used. [b] Reaction performed on a 60:40 Z/E mixture. [c] No
conversion.
nHex
nHex
nHex
nBu
nHex
nBu
Et
nBu
nHex
nBu
nBu
nBu
1b (3-Cl-C6H4)
1c (3-F-C6H4)
1d (4-Cl-C6H4)
1d (4-Cl-C6H4)
1e (4-Me-C6H4)
1 f (2-OMe-C6H4)
1 f (2-OMe-C6H4)
1 f (2-OMe-C6H4)
1g (2-Br-C6H4)
1h (2-Me-C6H4)
1i (1-naphthyl)
protons are equivalent in o-methoxy-substituted substrate 1 f
(Figure 2). This diastereotopicity suggests that in substrates
1g–i hindered rotation between the aryl group and the
double bond exists leading to a loss of co-planarity. This might
obstruct the coordination of the alkylcopper complex to these
substrates, thus prohibiting the reaction.
9
10
11
12[h]
13[h]
14[h]
–
–
–
–
–
–
[a] Conditions: see Table 1. Full conversion obtained unless otherwise
noted. [b] SN2’/SN2 ratio determined by GC and 1H NMR analysis. [c] Yield
of isolated product. [d] Determined by chiral HPLC analysis; [e] 60%
conversion; [f] 65% conversion; [g] 64% conversion. [h] No conversion.
This protocol was found to be efficient with organolithium
reagents such as EtLi, nBuLi and nHexLi. All-carbon quaternary
centers 2a–c and 2 f,g were obtained with very good regiose-
lectivity and enantiomeric ratios ranging from 90:10 to 95:5
when the phenyl derivative 1a (entries 1–3) and p-chloro-sub-
stituted substrate 1e (entries 6 and 7) were used. Although
less reactive, m-chloro- and m-fluoro-substituted allyl bromides
1b and 1c (entries 4 and 5) were also effective substrates and
gave rise to the corresponding all-carbon quaternary centers
2d and 2e, respectively, with excellent regio- and enantiose-
lectivity. It is important to note that in these cases, in which
a substrate bearing an aromatic halide (1b–1d) is used, no
traces of side products derived from lithium–halogen ex-
change or nucleophilic aromatic substitution were found,
showing the halide tolerability of this catalytic system. Interest-
ingly, the copper-catalyzed AAA of p-methyl-substituted
substrate 1e, which was obtained as a 60:40 Z/E mixture, still
afforded the corresponding product 2h with a good enantio-
selectivity (entry 8), comparable with the one obtained from
the pure (E)-allyl bromide by our previously reported
procedure (Table 3).
Figure 2. Effect of ortho-substituents on the geometry of the (Z)-allyl
bromides 1.
An interesting feature of the copper-catalyzed AAA of
(Z)-allyl bromides is its complementarity with the AAA of the
corresponding E isomers (Table 3). While the catalytic system
for the (Z)-allyl bromides gives rise to higher enantiomeric
ratios when phenyl and para-substituted substrates are used
(entries 1–3), our previously reported catalytic system for the
copper-catalyzed AAA of (E)-allyl bromides affords excellent
enantioselectivity when ortho-substituted substrates are used,
also in the case of o-bromo-substituted substrates (entries 4
and 5).
In summary, we have developed a catalytic methodology for
the asymmetric allylic alkylation of Z trisubstituted allyl
bromides with organolithium reagents. All-carbon quaternary
stereogenic centers are obtained in high yields with very good
regio- and enantioselectivity. In some cases, the reaction
affords selectivity values higher than the ones obtained
through our previously described asymmetric alkylation of
(E)-allyl bromides. The addition of organolithium reagents to
(Z)-allyl bromides provides a versatile and complementary
method for the synthesis of all-carbon quaternary centers.
An intriguing observation was made when ortho-substituted
(Z)-allyl bromides were used. While the copper-catalyzed AAA
of o-methoxy-substituted substrate 1 f afforded the corre-
sponding products 2i–k with full conversion and good regio-
and enantioselectivity (entries 9–11), the use of other ortho-
substituted (Z)-allyl bromides 1g–i did not result in any
1
conversion. H NMR analysis (see the Supporting Information)
shows that the protons of the CH2Br group of ortho-substitut-
ed (Z)-allyl bromides 1g–i are diastereotopic while these
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Experimental Section
Typical procedure for the copper-catalyzed AAA of Z
trisubstituted allyl bromides with organolithium reagents
A Schlenk tube equipped with septum and stirring bar was
charged with CuBr·SMe2 (5 mol%) and the ligand L6 (5.5 mol%).
Dry CH2Cl2 (1 mL) was added and the solution was stirred under
nitrogen at room temperature for 30 min. Then, allyl bromide
1 (0.2 mmol) was dissolved in dry CH2Cl2 (1 mL) and was added to
the solution which was cooled to À808C. In a separate Schlenk
tube, the organolithium reagent (0.24 mmol) was diluted with n-
hexane (0.8 mL, combined volume of 1 mL) under nitrogen and
added dropwise to the reaction mixture over 5 h using a syringe
pump. Once the addition was complete, the mixture was stirred at
À808C for 10 h. The reaction was quenched with a saturated aque-
ous NH4Cl solution (2 mL) and the mixture was warmed to room
temperature. The aqueous layer was extracted with CH2Cl2 (3ꢄ
5 mL) and the combined organic layers were dried with anhydrous
Na2SO4, filtered, and the solvent was evaporated in vacuo. The
crude reaction mixture was purified by flash chromatography on
silica gel using n-pentane as eluent.
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Acknowledgements
The Netherlands Organization for Scientific Research (NWO-
CW), the National Research School Catalysis (NRSC-C), the Euro-
pean Research Council (ERC advanced grant 227897 to B.L.F.),
the Royal Netherland Academy of Arts and Sciences (KNAW)
and the Ministry of Education Culture and Science (Gravitation
program 024.601035) are acknowledged for financial support.
Keywords: allylic compounds · asymmetric catalysis · copper ·
phosphoramidites · organolithium reagents
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Received: November 7, 2014
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ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
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Asymmetric Catalysis
M. FaÇanꢀs-Mastral,* R. Vitale, M. Pꢁrez,
B. L. Feringa*
&& – &&
Enantioselective Synthesis of All-
Carbon Quaternary Stereogenic
Centers via Copper-Catalyzed
Asymmetric Allylic Alkylation of (Z)-
Allyl Bromides with Organolithium
Reagents
Origin of asymmetry: The copper-
and chiral phosphoramidite ligand L
(see scheme) was found to enable the
formation of all-carbon quaternary
centers in high yields with very good
regio- and enantioselectivity.
catalyzed asymmetric allylic alkylation of
Z trisubstituted allyl bromides with or-
ganolithium reagents was investigated.
A catalytic system comprising CuBr·SMe2
Chem. Eur. J. 2015, 21, 1 – 5
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ꢃ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ