Stereospecific nickel-catalyzed cross-coupling reactions of alkyl grignard reagents and identification of selective anti-breast-cancer agents

Article abstract of DOI:10.1002/anie.201308666

Alkyl Grignard reagents that contain β-hydrogen atoms were used in a stereospecific nickel-catalyzed cross-coupling reaction to form C(sp ³)-C(sp³) bonds. Aryl Grignard reagents were also utilized to synthesize 1,1-diarylalkanes. Sev

Full text of DOI:10.1002/anie.201308666

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Angewandte
Communications
DOI: 10.1002/anie.201308666
Cross-Couplings
Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Alkyl
Grignard Reagents and Identification of Selective Anti-Breast-Cancer
Agents**
Ivelina M. Yonova, A. George Johnson, Charlotte A. Osborne, Curtis E. Moore,
Naomi S. Morrissette, and Elizabeth R. Jarvo*
Abstract: Alkyl Grignard reagents that contain b-hydrogen
We have previously reported the stereospecific nickel-
catalyzed Kumada cross-coupling of methylmagnesium bro-
mide with benzylic ethers (Scheme 1a).[3,4] Furthermore, we
were able to extend the utility of this reaction by employing
atoms were used in a stereospecific nickel-catalyzed cross-
3
3
À
coupling reaction to form C(sp ) C(sp ) bonds. Aryl Grignard
reagents were also utilized to synthesize 1,1-diarylalkanes.
Several compounds synthesized by this method exhibited
selective inhibition of proliferation of MCF-7 breast cancer
cells.
A
lkyl–alkyl cross-coupling reactions have emerged as pow-
erful transformations that provide a new disconnection for the
synthesis of tertiary stereocenters that are difficult to
construct using other methods.[1,2] However, because of the
3
À
inherent reactivity of alkyl metal intermediates, C(sp )
C(sp3) coupling reactions are significantly less common than
2
2
À
their C(sp ) C(sp ) counterparts. In particular, alkyl metal
intermediates are prone to b-hydride elimination, which
results in non-productive pathways. Herein, we report nickel-
catalyzed cross-coupling reactions of alkyl Grignard reagents
that contain b-hydrogen atoms. This method was also utilized
to prepare new compounds that display selective inhibition of
breast cancer cell proliferation.
Scheme 1. Nickel-catalyzed Kumada cross-coupling reactions.
aryl magnesium reagents for the stereospecific synthesis of
triarylmethanes.[5] One class of nucleophiles that remained
elusive comprises long-chain alkyl Grignard reagents
(Scheme 1b). These reagents perform poorly under our
reported cross-coupling reaction conditions, as hydrogenol-
ysis or elimination typically predominate. We hypothesized
that these products result from b-hydride elimination of the
organonickel intermediates, and that we could identify
a system that favors the desired cross-coupling pathway by
fine-tuning of the catalyst.
The bite angle and the steric and electronic environment
of a ligand can have profound effects on the relative rates of
the elementary steps in a catalytic cycle. We evaluated a series
of catalysts (Table 1, entries 1–7) and determined that [Ni-
(acac)2] (acac = acetylacetonate) in the presence of 1,2-
bis(diphenylphosphino)ethane (dppe) afforded 2 as the
major product in good conversion and modest enantiospeci-
ficity (entry 7).[6] To improve the yield of the cross-coupling
reaction, we systematically varied the ligand-to-metal stoi-
chiometry. When the dppe/[Ni(acac)2] ratio was smaller than
2:1, the reaction showed little dependence on the ligand
loading (entries 7 and 8). When more than two equivalents of
dppe were used with respect to [Ni(acac)2], the desired
product was not detected, and 1 was recovered quantitatively
(entry 10). Interestingly, when a 2:1 ratio of dppe/[Ni(acac)2]
was employed, the reaction gave highly variable results
(entry 9); across seven experiments, four provided only
recovered starting material, whereas three provided the
desired product in > 80% yield.[7] We propose that when
[*] I. M. Yonova,[+] A. G. Johnson,[+] C. A. Osborne, Prof. E. R. Jarvo
Department of Chemistry, University of California, Irvine
Irvine, CA 92697 (USA)
E-mail: erjarvo@uci.edu
Homepage: http://chem.ps.uci.edu/~erjarvo
Prof. N. S. Morrissette
Department of Molecular Biology & Biochemistry
University of California
Irvine (USA)
Dr. C. E. Moore
Department of Chemistry and Biochemistry
University of California, San Diego
La Jolla, CA 92093 (USA)
[+] These authors contributed equally to this work.
[**] This work was supported by NIH NIGMS (R01GM100212), the UC
Cancer Research Coordinating Committee, NCI Award P30A062203,
NCI Award F31A177212 (C.A.O.), and the LaVerne Noyes Fellow-
ship (A.G.J.). We thank R. J. Ochoa for advice and assistance with
biochemical assays, Prof. J. A. Prescher, Prof. X. Zi, and C. A. Blair
for helpful discussions, and Prof. M. J. Buchmeier for use of the
fluorimeter. Prof. S. D. Rychnovsky and A. J. Wagner are acknowl-
edged for confirming absolute configurations of enantioenriched
alcohol intermediates by their CEC method. Dr. J. Greaves is
acknowledged for mass spectrometry data. C.E.M. solved the X-ray
structure of (S)-8.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308666.
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Table 1: Optimization of the cross-coupling with the n-pentyl Grignard
reagent.
reagents; the enantiospecificity improved from modest
58% es with nPentMgI to 96% es with nPentMgBr
(entries 12–14). We next examined the impact of catalyst
loading on the enantiospecificity, as in related transforma-
tions, our laboratory had observed an inverse correlation
between catalyst loading and stereochemical fidelity.[10] We
hypothesized that, in analogy to palladium-catalyzed allylic[11]
and benzylic[12] substitution reactions, the key p-benzyl nickel
intermediate could be racemized by nucleophilic attack of
a second nickel species (see below).[13] We were pleased to see
that lower catalyst loadings do provide higher enantiospeci-
ficity; employing only 2 mol% of [Ni(dppe)Cl2] afforded the
desired product in > 99% es without a drop in yield
(entry 16).
We designed a series of chiral benzylic ethers to determine
the scope of the transformation (Table 2). Enantioenriched
ethers can be prepared by several routes. For example,
Corey–Bakshi–Shibata (CBS) reduction[14] of the correspond-
ing ketone or enantioselective alkylation[15] or arylation[16] of
the requisite aldehyde typically provide robust strategies for
their construction.[17]
Entry Ni catalyst
(mol%)
X
Yield 2 ee 2 es 2
[%][a]
Yield 3 Yield 4
[%][b] [%][c] [%][a]
[%][a]
1
2
–
I
I
<5[d]
–
–
–
–
<5[d]
<5[d]
<5[d]
<5[d]
[Ni(acac)2] (10),
no ligand
<5[d]
<5[d]
28
3
[Ni(acac)2] (10),
rac-BINAP (10)
[Ni(acac)2] (10),
DPEphos (10)
[Ni(acac)2] (10),
PPh3 (10)
I
I
I
I
I
I
I
I
I
I
–
86
82
45
66
61
–
91
86
47
<5[d]
27
<5[d]
12
4
5
8
55
14
6
[Ni(acac)2] (10),
dppp (10)
31
12
14
7
[Ni(acac)2] (10),
dppe (10)
69
69 <5
64 <5
87[f] <5
<5
<5
<5
<5[d]
<5[d]
8
[Ni(acac)2] (10),
dppe (15)
95
The reaction of each substrate and Grignard reagent was
first evaluated under our standard reaction conditions
employing 2 mol% of the catalyst. A range of primary alkyl
Grignard reagents afforded the cross-coupled products in
good yields and excellent enantiospecificities (entries 1–4).
The cross-coupling reactions proceeded with high stereo-
9
[Ni(acac)2] (10),
dppe (20)
0–90[e] 83[f]
10
11
[Ni(acac)2] (10),
dppe (22)
[Ni(cod)2] (10),
dppe (10)
<5[d]
<5[d]
–
–
–
–
<5[d]
<5[d]
chemical fidelity and inversion at the stereogenic center.[18]
trisubstituted olefin was well tolerated in the reaction,
affording product containing convenient synthetic
A
12
13
14
15
16
[Ni(dppe)Cl2] (10)
89
96
95
85
55
51
91
93
58 <5
54
96 <5
98 <5
<5
<5
<5
<5
<5
[Ni(dppe)Cl2] (10) Cl
[Ni(dppe)Cl2] (10) Br
[Ni(dppe)Cl2] (5) Br
[Ni(dppe)Cl2] (2) Br
5
a
a
handle for further functionalization (entry 5). A substituent
at the b-position of the alkyl magnesium reagent resulted in
a low yield of product 11 owing to the formation of large
amounts of elimination byproduct, but the reaction still
proceeded with satisfactory enantiospecificity (entry 7). An
electron-donating methoxy group on the naphthyl ring was
well tolerated and did not result in a loss of stereospecificity
(entries 8 and 9).
For challenging coupling reactions, we could typically
improve enantiospecificity or yield by modifying catalyst
loading and reaction temperature. For example, an electron-
poor fluorinated alkyl magnesium reagent reacted sluggishly;
increasing the catalyst loading to 10 mol% provided the
corresponding product in good yield and high enantiospeci-
ficity (entry 6). A substrate that contains a heterocyclic
moiety also required higher catalyst loading, presumably
because of coordination to and deactivation of the catalyst
(entry 11). For this substrate, addition of [Ni(dppe)Cl2] in two
portions over the course of the reaction permitted the use of
higher catalyst loadings without compromising enantiospeci-
ficity. Diarylmethanol derivatives proved to be a more
challenging class of substrates: reactions with primary alkyl
Grignard reagents resulted in an increased amount of hydro-
genolysis (21%) and low enantiospecificity (77% es).[19] For
diarylmethanol derivatives that are prone to racemization,
lowering the temperature generally increased the enantio-
specificity (entry 12, 91% es).
97[g] 96
>99 <5
[a] Determined by 1H NMR analysis using PhSiMe3 as an internal
standard. [b] Determined by supercritical fluid chromatography (SFC) on
a chiral stationary phase. [c] Enantiospecificity (es)=eeproduct
/
eestarting material ꢀ100%. [d] Recovered and unreacted 1. [e] Reaction was
irreproducible: run 1: <5% yield; run 2: <5% yield; run 3: 90% yield,
85% ee, 89% es; run 4: <5% yield; run 5: <5% yield; run 6: 84% yield,
68% ee, 72% es; run 7: 90% yield, 94% ee, 99% es; [f] Average of runs 3,
6, and 7. [g] Yield of isolated product. BINAP=2,2’-bis(diphenylphos-
phino)-1,1’-binaphthyl, DPEphos=bis[2-(diphenylphosphino)phenyl]-
ether, dppp=l,3-bis(diphenylphosphino)propane.
the ligand loading is ꢀ 2:1, an inactive complex, [Ni(dppe)2],
is formed quantitatively, and the cross-coupling pathway is
shut down. Consistent with this hypothesis, the use of
[Ni(cod)2] (cod = 1,5-cyclooctadiene) in the presence of
dppe provided no product because of the rapid formation of
the [Ni(dppe)2] complex.[8,9] To ensure strict control of the
ligand-to-nickel ratio, we evaluated the complex [Ni-
(dppe)Cl2]. The latter was a competent catalyst for the
reaction affording 2 in good yield, albeit with slightly
diminished enantiospecificity (entry 12). Furthermore, this
nickel(II) salt is commercially available, inexpensive, and air-
and moisture-stable.
To improve the enantiospecificity of the reaction, we
investigated the importance of the identity of the organo-
magnesium reagent. Organomagnesium bromides proved to
be superior to the respective chloride and iodide Grignard
To investigate the generality of this method and evaluate
its applicability to other classes of Grignard reagents, we
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Table 2: Scope of the cross-coupling reaction with alkyl magnesium bromides.
Entry
1
Product
Yield [%][a]
80
S.M. ee [%][b]
Prod. ee [%][b]
es [%]
99
5
92
91
2
3
4
6
7
8
R2 =nPr
93
91
88
97
97
97
97
97
97
>99
>99
>99
R2 =nPent
R2 =(CH2)3Ph
R2 =
5[c]
9
81
97
97
>99
6[d]
7
10
11
R2 =(CH2)3CF3
R2 =iBu
68
40
>99
97
97
90
97
93
8
9
12
13
R2 =nPr
80
88
93
93
92
93
99
>99
R2 =(CH2)3Ph
10[c]
11[e]
12[f]
14
15
16
93
54
67
97
99
97
96
91
>99
97
>99
91
[a] Yield of isolated product after column chromatography on silica gel. [b] Determined by SFC on a chiral stationary phase. [c] [Ni(dppe)Cl2] (5 mol%).
[d] [Ni(dppe)Cl2] (10 mol%). [e] [Ni(dppe)Cl2] was added in two aliquots of 5 mol%, see the Supporting Information for details. [f] 58C, 48 h; 2-
benzylnapthalene formed as a byproduct (15%). Cy=cyclohexyl, Prod.=product, S.M.=starting material.
chose to examine the use of aryl magnesium reagents as
a strategy for the synthesis of chiral 1,1-diarylalkanes, which
are pharmacophores that are found in a range of bioactive
compounds.[20–23] Our laboratory has previously developed the
stereospecific cross-coupling of aryl Grignard reagents with
benzhydryl alcohol derivatives to provide triarylmethanes.[5]
However, this method failed to afford the desired products in
satisfactory yields with simple benzylic alcohol derivatives
such as 1 and was therefore not amenable to the synthesis of
1,1-diarylalkanes. To address this shortcoming, we examined
a variety of substituted aryl Grignard reagents (Table 3).
Under standard reaction conditions, the cross-coupling pro-
ceeded in modest yield with significant formation of the
byproduct from elimination.[24] The efficiency of this process
was improved when the overall reaction concentration was
decreased 2.5 fold, which afforded 17 in 67% yield, along
with the elimination byproduct in only 16% yield (entry 1).
Furthermore, the use of more than two equivalents of
phenylmagnesium bromide was detrimental to the cross-
coupling reaction.[25] The electron-rich aniline- and anisole-
derived organomagnesium reagents afforded the correspond-
ing products in good yields and, in the case of 19, with
excellent stereospecificity (entries 2 and 3). Electron-defi-
cient 4-fluorophenyl- and 2-thienylmagnesium bromides were
also competent coupling partners for this reaction (entries 4
and 5). Electrophiles that contain benzofuran or benzothio-
phene moieties were tolerated in the cross-coupling, affording
24 and 25 in good yields and excellent stereospecificity.
During our initial optimization of the reaction and the
development of the scope, we noted that increased enantio-
specificity could be obtained at lower catalyst loadings (see
above). We hypothesized that the loss of fidelity in the
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Table 3: Scope of the cross-coupling reaction with aryl magnesium bromides.
a mechanism where the formation
of the minor enantiomer is second
order with respect to catalyst con-
centration (Figure 1a).
Having synthesized a variety of
enantioenriched alkanes and diary-
lalkanes, we set out to evaluate
these compounds for their biologi-
cal activity. Compounds that con-
tain the 1,1-diarylalkane scaffold
have demonstrated broad bioactiv-
ity, including against breast
cancer.[21] The cross-coupling prod-
ucts in Tables 2 and 3 were tested
for selective anti-breast-cancer
activity against the MCF-7 breast
cancer cell line relative to the
normal MCF-10A stromal cell line
using a proliferation-based proce-
dure. Selected results of the broad
compound screen are shown in
Figure 2. Several compounds dem-
onstrated selectivity for the inhib-
ition of breast cancer cell prolifer-
ation; results were compared to
those obtained with estrogen recep-
tor antagonist faslodex (ICI
182,780).[28] Thiophene-containing
Entry Product
[Ni(dppe)Cl2] Yield
[mol%]
S.M. ee Prod. ee es
[%][a]
[%][b]
[%][b]
[%]
1
2
3
4
17 R=H
2
5
2
2
67
>99
>99
>99
>99
91
nd[c]
97
92
nd[c]
97
18 R=NMe2
19 R=OMe
20 R=F
80
86[d]
82[d]
87
88
5
6
21
22
10
5
76
80
>99
>99
93
85
94
86
7
23
4
92[d]
96
88
92
8
24
25
10
20
71
76
97
99
95
93
98
94
diarylalkane
(+)-21
inhibited
MCF-7 cell proliferation with an
EC50 value of 5.3 mm (EC50 = half
maximal effective concentration).
We observed that (À)-21 (EC50 =
6.5 mm) and the racemic mixture
(EC50 = 7.3 mm) were both nearly as
efficacious as the (+) enantiomer.
Interestingly, the structurally anal-
ogous diarylalkane 25 exhibited
a similar level of inhibition. Control
experiments confirmed that thio-
9[e]
[a] Yield of isolated product after column chromatography on silica gel. [b] Determined by SFC on
a chiral stationary phase. [c] Enantiomers could not be separated by SFC on a chiral stationary phase.
[d] Calculated yield; see the Supporting Information for details. [e] [Ni(dppe)Cl2] was added in two
aliquots of 10 mol%, see the Supporting Information for details. nd=not determined, Prod.=product,
S.M.=starting material.
transfer of stereochemical information resulted from racemi-
zation of the enantioenriched p-benzyl nickel intermediate
(S)-27 by reaction with a low-valent nickel species (Fig-
ure 1a). This mechanism contrasts alternatives where stereo-
chemical information is eroded during a competitive radical
oxidative addition reaction or homolysis of the carbon–nickel
bond in 27.[13,26] Consistent with our hypothesis, experiments
performed in the presence of one equivalent of TEMPO
afforded neither improvement nor erosion of the enantiospe-
cificity of the reaction. We sought to obtain experimental
evidence to further support or refute the bimolecular
racemization mechanism. Based on our mechanistic hypoth-
esis, the formation of the major and minor enantiomers
should be first and second order with respect to catalyst
concentration, respectively. Derivation of rate laws indicates
that if that is the case, the ratio of the two enantiomers would
be directly proportional to 1/[catalyst].[27] Indeed, a plot of
[(S)-17]/[(R)-17] versus 1/[Ni(dppe)Cl2] yielded a good fit for
a linear equation (Figure 1b). The data are consistent with
phene (28) and benzothiophene (29) did not inhibit cell
growth. Furthermore, whereas replacing the thiophene
moiety with different aryl groups, such as phenyl (17), para-
methoxy (19), or para-fluoro (20) substituents, resulted in
similar selective inhibition of cancer cell proliferation, com-
pounds containing hydrocarbon chains (9 and 7) were much
less potent. These results provide new lead compounds with
selective inhibition of breast cancer cell growth.
In conclusion, we have developed a stereospecific nickel-
catalyzed Kumada cross-coupling that tolerates Grignard
reagents with extended alkyl chains. This catalytic system is
also amenable to reactions of aryl and heteroaryl magnesium
reagents for the synthesis of 1,1-diarylalkanes. Reactions
typically proceeded with higher enantiospecificity at lower
catalyst loadings, and mechanistic experiments are consistent
with racemization of the p-benzyl nickel intermediate.
Biological testing of compounds that were synthesized using
this method identified several promising lead compounds that
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Keywords: alkyl Grignard reagents · breast cancer ·
.
enantiospecificity · Kumada coupling · nickel
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Figure 1. Nickel-catalyzed racemization of the p-benzyl nickel inter-
mediate.
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Figure 2. Anti-breast-cancer activity of selected compounds at a con-
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and a normal breast cell line (MCF-10A). Cell proliferation is repre-
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exhibit selective inhibition of breast cancer cell proliferation
in the low micromolar range.
Received: October 5, 2013
Revised: November 20, 2013
Published online: January 29, 2014
[17] The competing enantiomer conversion method can be used to
assign the absolute configuration of secondary alcohols; see:
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A. J. Wagner, S. D. Rychnovsky, J. Org. Chem. 2013, 78, 4594 –
4598.
[18] See the Supporting Information for details.
[19] At room temperature, 16 was obtained in 71% yield and 77% ee,
and 2-benzylnaphthalene was formed in 21% yield.
[23] For representative alternative strategies for the enantioselective
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[24] 17 was formed in 54% yield, 92% ee, and 95% es, along with the
elimination byproduct in 34% yield.
[25] When PhMgBr (4 equiv) was used, 17 was obtained in 19%
yield, with 37% unreacted starting material and 34% elimina-
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À
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[27] For full details of the derivation, see the Supporting Information.
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