Enantioselective Synthesis of Di- and Tri-Arylated All-Carbon Quaternary Stereocenters via Copper-Catalyzed Allylic Arylations with Organolithium Compounds

Article abstract of DOI:10.1021/acscatal.6b01681

The highly enantioselective copper(I)/N-heterocyclic carbene (NHC) catalyzed synthesis of di- and triarylated all-carbon quaternary stereocenters via asymmetric allylic arylation (AAAr) with aryl organolithium compounds is demonstrated. The use of readily available or easily accessible aryl organolithium reagents in combination with trisubstituted allyl bromides, in the presence of a copper/NHC catalyst, affords important di- and triarylated all-carbon quaternary stereocenters in good yields and enantioselectivities. This method tolerates a wide range of alkyl and substituted aryl groups in the starting allyl bromides, including less common biaryl moieties, which, in combination with diverse organolithium reagents, delivers a broad scope of products in an operationally straightforward and efficient manner.

Full text of DOI:10.1021/acscatal.6b01681

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Letter
Enantioselective Synthesis of Di- And Tri-Arylated All-
Carbon Quaternary Stereocenters via Copper Catalyzed
Allylic Arylations with Organolithium Compounds.
Sureshbabu Guduguntla, Jean-Baptiste Gualtierotti, Shermin S. Goh, and Ben L. Feringa
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01681 • Publication Date (Web): 22 Aug 2016
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ACS Catalysis
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Sureshbabu Guduguntla, Jean-Baptiste Gualtierotti, Shermin S. Goh, and Ben L. Feringa.*
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Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
KEYWORDS: allylic substitution, enantioselective, copper, N-heterocyclic carbene, quaternary stereocenter, triaryl-
methane, organolithium
ABSTRACT: The highly enantioselective copper(I)/N-heterocyclic carbene (NHC) catalyzed synthesis of di- and tri-
arylated all-carbon quaternary stereocenters via asymmetric allylic aryla-
tion (AAAr) with aryl organolithium compounds is demonstrated. The use
of readily available or easily accessible aryl organolithium reagents in com-
bination with trisubstituted allyl bromides, in the presence of a copper
/NHC catalyst, affords important di- and tri-arylated all-carbon quaternary
stereocenters in good yields and enantioselectivities. This method tolerates
a wide range of alkyl and substituted aryl groups in the starting allyl bro-
mides, including less common biaryl moieties, which, in combination with diverse organolithium reagents, delivers a
broad scope of products in an operationally straightforward and efficient manner.
Catalytic methodologies to form congested all-carbon
quaternary stereogenic centers are among the most chal-
lenging transformations in organic synthesis.1 Despite
major progress in recent years,2 new and effective proce-
dures to achieve this transformation are particularly war-
ranted. This holds especially for sterically highly demand-
ing di- and triaryl-substituted quaternary stereocenters,
which are important structural units in bioactive com-
pounds such as haplophytine3a and diazonamide A.3b In
particular, triaryl methane structures4 serve as fluorescent
molecules which have applications in cell imaging,5 selec-
tive sensors for metal ions,6 anticancer agents,7 and potas-
sium ion channel blockers.8 Among the protocols report-
ed recently, asymmetric allylic substitution (AAS) reac-
tions have drawn major attention for the construction of
these quaternary stereocenters due to the versatility and
flexibility of the method.9 Pioneered by Bäckvall and van
Koten in 1995,10 the AAS with organometallic reagents,
catalyzed by copper11 or other transition metals,12 has
proven to be incredibly effective in its capacity to deliver
SN2′-products with tertiary carbon stereocenters in high
yields and enantioselectivities. Via these methods, several
useful synthons can be prepared which have been applied
in the total synthesis of many natural products or biologi-
cally active compounds.13 However, despite the existence
of well-established methods for the construction of ter-
tiary carbon stereocenters, there are remarkably few
methods based on AAS for the construction of all-carbon
quaternary stereocenters. To the best of our knowledge,
only a limited number of reports exist on the use of alkyl
organometallic reagents as nucleophiles in allylic substi-
tution forming quaternary stereocenters; these include
the use of dialkyl zinc,14 boron,15 aluminum16 and Grignard
reagents.17 Furthermore, methods using aryl organometal-
lic reagents to prepare all-carbon quaternary stereocen-
ters are scarce despite the fact that chiral diarylmethanes
are highly relevant for the synthesis of natural products
and pharmaceuticals.3,18 Importantly, Hoveyda and co-
workers succeeded using diaryl zinc19 and aryl aluminum
reagents,20 derived from the corresponding organolithium
reagents, while Hayashi and co-workers21 achieved this
transformation using aryl boronic esters, and Sawamura
and co-workers22 very recently applied azoles as nucleo-
philes (Figure 1a).
Figure 1: Formation of all-carbon quaternary stereo-
centers with AAAr
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In recent years our group has reported a number of al-
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
7
L7
96:4
55:45
n.d.
1
2
3
4
5
6
7
8
ternative AAS reactions combining highly reactive alkyl
organolithium reagents as nucleophiles with allyl bro-
mides or allyl ethers as electrophiles in the presence of a
Cu(I)L catalytic system (L = Taniaphos or phospho-
ramidite) to achieve the formation of tertiary carbon ste-
reocenters with excellent regio- and enantioselec-
tivites.13j,23 We extended this protocol, again with alkyl
organolithium reagents, to synthesize quaternary all-
carbon stereocenters with good to high regio- and enanti-
oselectivites.24 Early this year, we reported that the stere-
oselective formation of tertiary stereocenters via AAS
could also be achieved with usually less reactive aryl or-
ganolithium reagents in high regio- and very high enanti-
oselectivities by switching to a Cu(I)-NHC catalytic sys-
tem.18e Aryl lithium reagents have the important ad-
vantage, compared to many other organometallic species,
of being either commercially available or very easy to pre-
pare, even more so than their alkyl counterparts. They
can be readily accessed in various ways such as met-
al−halogen exchange, direct metalation or ortho-
metalation. Due to the advantage of their ready availabil-
ity, these lithium reagents often serve as precursors for
other commonly used organometallic reagents.25
8
L8
44:56
87:13
80:20
44:56
37:63
28:72
10:90
15:85
9
L9
75:25
72:28
55:45
n.d.
10
11
L10
L11
12
13
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17
L12
L13
L14
L15
L16
CuClL16
n.d.
9
n.d.
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n.d.
75:25 (62%)d 97:3
72:28 (61%)d 97:3
aConditions: Allyl bromide (0.2 mmol) in CH2Cl2 (2 mL).
PhLi (0.3 mmol, 1.8 M solution in dibutyl ether diluted with
hexane to a final concentration of 0.3 M) was added over 2 h.
All reactions gave full conversion. b2a/3a ratios and conver-
sions determined by GC–MS and 1H NMR spectroscopy.
cDetermined by chiral HPLC after conversion to the corre-
sponding primary alcohol using a hydroboration–oxidation
procedure (See SI). dIsolated yield of 2a.
We started our investigation of this transformation
with trisubstituted allyl bromide 1a as model electrophile
and commercially available PhLi as nucleophile in the
presence of a catalytic amount of CuBr•SMe2 and chiral
imidazolium salts (Table 1).18e When a solution of PhLi
diluted in n-hexane was added over 2h to an in situ gen-
erated Cu(I)-NHC complex (L1 or L2, 5 mol%) and allyl
bromide in dry CH2Cl2 at –80 °C, we observed the
chemoselective formation of desired SN2′-product 2a as a
roughly equimolar mixture with the corresponding regioi-
someric SN2-product 3a. While imidazolium salts L1 and
L2 had proven to be most suitable in the Cu-AAAr reac-
tion to synthesize tertiary carbon stereocenters with aryl
organolithium reagents,18e these chiral ligands did not
lead to satisfactory results for quaternary centers as both
branched and linear products were observed (entries 1 &
2, Table 1). We therefore pursued our investigation by
screening for a more suitable carbene ligand. Salts L3 and
L4 bearing o-tolyl or o-anisole groups on the two carbene
nitrogens gave high regioselectivity (94:6 & 85:15) but
almost no enantioselectivity (entries 3 & 4). Imidazolium
salts bearing even bulkier substituents such as 2,4,6-
Me3C6H2 (L5) or 2-i-PrC6H4 (L6) led to even higher regi-
oselectivites (98:2 & 87:13), but only slightly better enan-
tioselectivities (up to 67:33 er, entries 5 & 6). Similarly
bulky substituent 2-MeNaphthyl L7 also gave high regio-
and poor enantioselectivity (entry 7). In order to improve
the enantioselectivity we turned our attention to bifunc-
tional ligands such as L8. However this led to a drop in
regioselectivity, which was attributed to the addition of
PhLi to the sulfonate group (entry 8). Moving from satu-
rated imidazolium salts to unsaturated salts such as L9
and L10 led to a significant improvement in enantioselec-
tivity (up to 75:25 er) while retaining good regioselectivity
(up to 87:13, entries 9 & 10). Building on this promising
regio- and enantioselectivity, we continued to screen dif-
Here, we report the first regio- and enantioselective
Cu(I)-catalyzed asymmetric allylic arylation (Cu-AAAr) of
trisubstituted allyl bromides using aryl organolithium
compounds as nucleophiles to yield di- and tri-arylated
quaternary all-carbon stereocenters with high regio- and
very high enantioselectivities (SN2Ꞌ : SN2 up to 92:8, up to
>99:1 er).
Table 1. Screening of Chiral Ligandsa
Entry
Ligand [Cu]
2a:3ab
40:60
60:40
94:6
2a, erc
50:50
50:50
58:42
54:46
62:38
67:33
CuBr•SMe2
1
L1
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
CuBr•SMe2
2
3
4
5
6
L2
L3
L4
L5
L6
85:15
98:2
87:13
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ACS Catalysis
aConditions: Allyl bromide 1 (0.2 mmol) in CH2Cl2 (2 mL).
ferent unsaturated chiral imidazolium salts. Disappoint-
1
2
3
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7
8
PhLi (0.3 mmol, 1.8 M solution in dibutyl ether diluted with
hexane to a final concentration of 0.4 M) was added over 2 h.
All reactions gave full conversion. 2/3 ratios and conversions
ingly, increasing sterics like in bulky ligand precursors L11
and L12 resulted in very poor regio- and enantioselectivi-
ties (entries 11 & 12) while noncyclic carbene precursor L13
or C2-symmetric chiral bisoxazoline L14 led to reversals in
branched to linear selectivity (entries 13 &14). It was de-
cided to switch carbene backbones altogether and test the
activity of triazolium salts. While L15 again did not lead to
satisfying results (entry 15), we were pleased to find that
triazolium salt L16 gave 2a in 62% isolated yield not only
with improved regioselectivity (75:25) but also excellent
enantioselectivity of 97:3 er (entry 16). In order to simplify
the protocol we tested the in principle equivalent pre-
formed copper complex CuClL16 in the reaction which
gave identical results to the in situ formed catalyst (entry
17).
1
determined by GC–MS and H NMR spectroscopy. Er deter-
mined by chiral HPLC after conversion to the corresponding
primary alcohol using a hydroboration–oxidation procedure
(See SI). bIsolated yield of SN2' product. cThe absolute config-
uration of 2a was assigned by comparing the sign of the opti-
cal rotation with the literature value (ref. 21).
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We examined the substituent effect of the group R on
the γ- position of the allyl bromide 1 using p-MeC6H4Li as
a nucleophile on four different substrates (Table 3). Sub-
strates 1i and1j bearing methyl and ethyl substituents at
the γ-position led to the desired products 2i and 2j (Table
3) with almost similar results in terms of regio- and enan-
tioselectivity to model substrate 1a. Substrate 1k bearing a
more sterically demanding i-propyl substituent at the γ-
position gave the product 2k with similar regioselectivity
to 2i and 2j but with moderate enantioselectivity (68:32
er). Having a phenyl substituent at the γ-position of the
substrate (1l) allowed us to synthesize a rare chiral triaryl
methane product 2l with three different aromatic groups
and a synthetically flexible vinyl group in 34% isolated
yield with good enantioselectivity (Table 3). Chiral all-
carbon quaternary triarylmethane moieties are highly
valuable but as far as we know very few methods exist for
their synthesis.4
Having optimized conditions in hand we investigated
the substrate scope of the reaction of allyl bromides 1 with
PhLi using chiral N-heterocyclic carbene complex Cu-
ClL16 as catalyst. First the substitution at the aryl R1 posi-
tion was varied while maintaining the alkyl R2 moiety as a
methyl substituent in combination with PhLi as a nucleo-
phile (Table 2). Substrates 1b, 1c and 1d, bearing a bro-
mide at the ortho, meta or para positions of the aromatic
ring, respectively, gave the desired products 2b, 2c and 2d
(Table 2) with excellent enantioselectivites (97:3 to >99:1
er) and, with a few exceptions, moderate to good regiose-
lectivities (70:30 to 92:8). The catalytic conversion also
displayed high chemoselectivity, with no competing side
reactions such as substitution or lithium halogen ex-
change observed. Notably, exceptionally high regio- and
enantioselectivity was obtained when using ortho-bromo
substituted 1b (99.5:0.5 er); this may be due to further
halogen bonding interaction with the catalyst. In con-
trast, substrate 1e bearing an o-methoxy substituent led
to product 2e with high enantioselectivity but with de-
creased regioselectivity. Substrates having either a p-
methyl substituent (1f) or an extended conjugated system
(1g) also gave the corresponding products 2f and 2g with
good regio- and high enantioselectivity. Moving from
cinnamyl type substrates to non cinnamyl allyl bromide
1h led to 2h (Table 2) with good regio- but moderate en-
antioselectivity.
Table 3. Effect of γ-Substituenta,b
aConditions: Allyl bromide (0.2 mmol) in CH2Cl2 (2 mL). p-
MeC6H4Li (0.4 mmol) was diluted with hexane to a final con-
centration of 0.4 M and was added over 2 h. 2a/3a ratios and
1
conversions determined by GC–MS and H NMR spectrosco-
Table 2. Substrate Scopea,b
py. Er determined by chiral HPLC after conversion to the
corresponding primary alcohol using
a hydroboration–
b
oxidation procedure (See SI). Isolated yield of SN2' product.
c10 mol % of CuClL16 was used.
Finally, we studied the scope of the reaction in terms of
the aryl lithium partner under our standard conditions.
These were readily prepared by adapting previously re-
ported procedures18e and were tested on substrate 1b (Ta-
ble 4). Fully deuterated PhLi gave the desired product 2m
with high regio- (93:7) and excellent enantioselectivity
(>99:1 er). Adding diverse alkyl substituents at the para
position of the aryl lithium did not affect the outcome of
the reaction and gave products 2n and 2o with very high
regio- and enantioselectivities. Electron rich p-methoxy
substituted aryl lithium gave product 2p without any de-
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Table 4. Scope of Aryl lithium Compoundsa,b
1
2
3
4
5
6
7
8
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aConditions: Allyl bromide (0.2 mmol) in CH2Cl2 (2 mL).
Ar′Li (0.4 mmol) was diluted with hexane to a final concen-
tration of 0.4 M and was added over 2 h. All reactions gave
full conversion. 2/3 ratios and conversions determined by
1
GC–MS and H NMR spectroscopy. Er determined by chiral
HPLC after conversion to the corresponding primary alcohol
b
using a hydroboration–oxidation procedure (See SI). Isolat-
c
ed yield of SN2' product. 10 mol % of CuClL16 was used and
p-OMeC6H4Li was diluted in toluene.
In summary, a highly enantioselective synthesis of qua-
ternary all- carbon stereocenters via Cu-catalyzed direct
allylic arylation using organolithium compounds is re-
ported. A Cu(I)-NHC catalytic system proved to be essen-
tial for this transformation and allowed the preparation of
a wide range of di- and tri-arylated vinyl methane com-
pounds with good to excellent enantioselectivites. This
transformation is also highly atom economical as LiBr is
the only stoichiometric waste during this transformation.
* E-mail: b.l.feringa@rug.nl
The authors declare no competing financial interests.
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Supporting Information. Experimental details and spectra
are provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
The Netherlands Organization for Scientific Research (NWO-
CW), the Royal Netherland Academy of Arts and Sciences
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tion (SNSF), and A*STAR are acknowledged for financial sup-
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