Functional-group-tolerant, nickel-catalyzed cross-coupling reaction for enantioselective construction of tertiary methyl-bearing stereocenters

Article abstract of DOI:10.1021/ja4034999

The first Negishi nickel-catalyzed stereospecific cross-coupling reaction of secondary benzylic esters is reported. A series of traceless directing groups is evaluated for ability to promote cross-coupling with dimethylzinc. Esters with a chelating thioether derived from commercially available 2-(methylthio)acetic acid are most effective. The products are formed in high yield and with excellent stereospecificity. A variety of functional groups are tolerated in the reaction including alkenes, alkynes, esters, amines, imides, and O-, S-, and N-heterocycles. The utility of this transformation is highlighted in the enantioselective synthesis of a retinoic acid receptor agonist and a fatty acid amide hydrolase inhibitor.

Full text of DOI:10.1021/ja4034999

Article
pubs.acs.org/JACS
Functional-Group-Tolerant, Nickel-Catalyzed Cross-Coupling
Reaction for Enantioselective Construction of Tertiary Methyl-
Bearing Stereocenters
Hanna M. Wisniewska,‡ Elizabeth C. Swift,‡ and Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
ABSTRACT: The first Negishi nickel-catalyzed stereospecific
cross-coupling reaction of secondary benzylic esters is reported. A
series of traceless directing groups is evaluated for ability to
promote cross-coupling with dimethylzinc. Esters with a chelating
thioether derived from commercially available 2-(methylthio)-
acetic acid are most effective. The products are formed in high
yield and with excellent stereospecificity. A variety of functional
groups are tolerated in the reaction including alkenes, alkynes,
esters, amines, imides, and O-, S-, and N-heterocycles. The utility
of this transformation is highlighted in the enantioselective synthesis of a retinoic acid receptor agonist and a fatty acid amide
hydrolase inhibitor.
INTRODUCTION
■
In medicinal chemistry, incorporation of a methyl group at a
key position is a common strategy for improving drug potency.1
Inserting a “magic” methyl group can improve efficacy by
multiple mechanisms: increased binding affinity, improved
pharmacokinetics, and greater specificity within a family of
targets. For instance, methyl incorporation can provide
additional surfaces for hydrophobic interactions, resulting in
enhanced binding to the target protein. This effect increases the
potency of the commercial drug Lipitor (Pfizer Inc.), which
features two benzylic methyl groups.2 In addition, replacing a
hydrogen with a methyl group can force a conformational
change and lower the enthalpic cost of binding.3,4 When methyl
placement affords both increased hydrophobic interactions and
a more favorable conformation, the potency has been observed
to increase by 200-fold.4 Additionally, methyl substituents can
prevent formation of toxic byproducts by providing an
alternative soft site for predictable metabolic oxidation.1,5
When oxidation of a benzylic methylene is problematic,
incorporation of a tertiary benzylic site can improve
pharmacokinetics by slowing degradation and drug clearance.1,6
Due to the above reasons, a tertiary benzylic stereocenter
Figure 1. Bioactive small molecules containing a tertiary benzylic
stereocenter.
bearing a methyl group is a common motif in medicinal agents.
For example, the compounds shown in Figure 1 possess
biological activity against a variety of targets, with potential
Previously, we developed a stereospecific nickel-catalyzed
Kumada cross-coupling of benzylic ethers for the formation of
tertiary benzylic stereocenters.9 Unlike enantioselective meth-
ods that employ a chiral catalyst with racemic or achiral starting
applications ranging from treatment of autoimmune disorders
and inflammation to cancer and obesity.7 Stereoselective
methods for the introduction of methyl groups8 are necessary
because stereoisomers typically exhibit different biological
activity. For instance, the enantiomers of MCHR1 antagonist
1 and FAAH inhibitor 3 show at least an order of magnitude
difference in activity (Figure 1).7a,d
Received: April 8, 2013
© XXXX American Chemical Society
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materials, stereospecific methods use an achiral catalyst to
translate the stereochemistry of the starting material to the
product. For example, during the course of our Kumada
coupling, a readily prepared enantioenriched secondary ether10
is transformed to a tertiary benzylic stereocenter with overall
inversion of configuration. While this transformation is highly
stereoselective and has been utilized in synthesis of medicinal
agents with activity against breast cancer and insomnia, the use
of Grignard reagents as the coupling partner precludes
synthesis of highly functionalized compounds such as 2 and 3
without recourse to lengthy protecting group strategies.
Recently, we have turned our attention to milder coupling
partners in an effort to expand the scope of our reaction.11,12
We chose to focus on organozinc reagents because Negishi
reactions are highly functional group tolerant.13 Stereoselective
sp2−sp3 cross-coupling has been shown for α-chiral organozinc
reagents, which undergo stereospecific Negishi reactions with
aryl and vinyl halides.14 Additionally, the Fu group has
developed enantioselective alkyl−alkyl cross-coupling reactions
using chiral nickel catalysts.15 However, stereospecific sp3−sp3
cross-coupling of alkylzinc reagents with enantioenriched
electrophiles has not yet been reported.
Scheme 1. Traceless Directing Group Strategy for
Promoting Challenging Organometallic Transformations
While Kumada reactions benefit from the high nucleophil-
icity of Grignard reagents, and proceed with simple benzylic
ethers, we postulated that cross-coupling of alcohol derivatives
with the less nucleophilic organozinc reagents would require a
more reactive electrophile. Directing groups have been used in
organic synthesis to promote transformations of otherwise
unreactive substrates.16,17 While incorporation of the directing
group into the body of the substrate is a common strategy, it
can limit the scope of the transformation. A traceless approach
places the directing functionality on the leaving group. Over the
course of the reaction the directing group is cleaved, affording
products that bear no trace of the directing functionality.
Liebeskind demonstrated that traceless directing groups
promote the cross-coupling of thioethers by accelerating the
transmetalation step (Scheme 1a).18 The pendant carboxylic
acid complexes zinc and promotes dissociation of the leaving
group, providing an open coordination site on the nickel center
for transmetalation. Inspired by this work, we designed traceless
directing groups to promote the oxidative addition of sluggish
electrophiles for Kumada couplings (Scheme 1b).9b,19,20
Magnesium coordination to the 2-methoxyethyl ether moiety
is proposed to weaken the benzylic C−O bond, facilitating
oxidative addition. We postulated that a similar strategy could
accelerate cross-coupling reactions with dimethylzinc. A leaving
group bearing a pendant ligand could serve two functions
(Scheme 1c). Coordination to a zinc reagent could activate the
substrate for oxidative addition and facilitate the subsequent
transmetalation step. We anticipated that tuning the properties
of the X and L groups would provide a synergistic enhancement
of reactivity.
pathway. We reasoned that if thioether 5 underwent oxidative
addition, sluggish transmetalation could have resulted in β-
hydride elimination to give alkene 23 as the major product. To
promote transmetalation over β-hydride elimination, we
examined ethers and thioethers bearing a second ligand
(Group 2). While acetal 6 and 2-methoxyethyl ether 8
remained unreactive, hydroxyethyl thioether 7 afforded the
desired cross-coupled product 22 as the major species, albeit
with low enantiospecificity (es).22 To increase the yield and es
of the transformation, we increased the coordinating ability of
the directing group by switching to a pendant pyridyl ligand.
Pyridyl ether 10 was the first of the oxygen series to afford an
appreciable yield of desired product with good es. In contrast,
pyridyl thioether 11 afforded lower yields than 7, with
significant erosion of enantiomeric excess (ee). Carboxylic
acids 12 and 13 afforded the desired product in moderate yield,
but with less than satisfactory es. We reasoned that in order to
achieve higher reactivity and high es we could invert the
RESULTS AND DISCUSSION
■
Identification of Traceless Directing Group for
Negishi Coupling. To test our hypothesis we examined a
range of activating groups to promote the cross-coupling of
benzylic electrophiles with dimethylzinc (Figure 2). As
anticipated, simple benzylic ether 4 was unreactive. Next, we
employed a thioether with the thought that formation of the
zinc−sulfur bond would provide a strong thermodynamic
driving force for the reaction.21 While substrate 5 was more
reactive, elimination to provide styrene 23 was the major
B
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a
Figure 2. Evaluation of leaving groups for cross-coupling with dimethylzinc. Nickel sources used in this reaction included NiCl2·DME, Ni(acac)2,
and Ni(COD)2. Ligands included DPEphos, rac-BINAP, and Xantphos. Solvents included PhMe, THF, and Et2O. Reaction temperatures ranged
between rt and 50 °C. The optimal results for each directing group are shown. For a complete list of reaction conditions for each experiment, please
refer to the SI. Yields were determined either by 1H NMR based on comparison with PhTMS as internal standard or by GC analysis with dodecane
as internal standard. Enantiospecificity (es) = (eeproduct/eesubstrate) × 100%; determined by chiral SFC chromatography. bDPEphos as ligand.
cXantphos as ligand.
carboxylic acid to an isomeric ester. These compounds would
be less likely to undergo radical racemization, which is more
likely for thioethers than ethers, improving the es. In addition,
maintaining the thiol functionality would allow for strong
coordination of zinc to the leaving group. Indeed, a series of
isomeric ester leaving groups provided the desired product in
both synthetically useful yields and high es (Group 3).
Although the ester leaving groups addressed the issue of
chirality transfer, their synthesis necessitated employing
protecting groups to mask the free thiol, which added a step
to the synthetic sequence (see Supporting Information (SI) for
details). Additionally, free thiols are not optimal substrates
because they are susceptible to oxidative decomposition. We
postulated that utilizing 2-(methylthio)ester 18 instead would
simplify substrate synthesis and prevent oxidative decom-
position of the starting material. This directing group is
particularly convenient since (methylthio)acetic acid is
commercially available and can be easily appended onto the
benzylic alcohol through a DCC coupling.23 Functionalized
with the thioether directing group, (R)-18 cross-coupled to
afford (S)-22 in 81% yield and excellent es with overall
inversion of configuration (Figure 2 and Table 1, entry 1).24
Simple esters were also evaluated to determine the
importance of a pendant ligand in these transformations
(Figure 2, Group 4). Both acetyl and pivaloyl esters provided
either high yield or high es, depending on the reaction
conditions (see SI for details). For example, acetate 19 could be
cross-coupled to provide the desired product in 84% yield and
87% es or 45% yield with no loss of chirality. The same trend
was observed for pivaloyl ester 21. While both are viable
alternatives to 18, the presence of the thioether ligand is
necessary for obtaining optimal yields of highly enantioenriched
product.
Scope of Reaction. With the optimal leaving group in
hand, we prepared a range of enantioenriched substrates for
cross-coupling by the general strategies outlined in Scheme 2.
Synthesis of the chiral alcohol intermediates was accomplished
by CBS reduction of the corresponding ketone25 or
C
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Scheme 2. Synthesis of Enantioenriched Benzylic Alcohol
Derivatives for Negishi Cross-Coupling
Table 1. Scope of Cross-Coupling in the Presence of a Range
of Functional Groups
enantioselective arylation of the requisite aldehyde.26,27
Absolute configuration of the intermediate alcohols was
assigned using the accepted models for selectivity for each
reaction.28 The absolute configuration was then confirmed by
the competing enantioselective conversion (CEC) method.29
DCC coupling appended the necessary leaving group with no
loss of ee, providing the starting materials for the trans-
formation.23
A variety of functional groups are well tolerated under our
optimized reaction conditions (Tables 1 and 2). For example,
products containing internal alkenes, 24 and 25, are formed in
high yield and in the case of 25, with high ee (Table 1, entries 2
and 3). Additionally, the increased steric bulk of 24 does not
significantly slow down the reaction. The presence of a TMS-
protected alkyne is also compatible with the reaction conditions
and 26 is formed in 81% yield and 99% es (entry 4). TMS-
alkynes are easily deprotected to the free terminal alkyne, which
provides a convenient functional handle for further elaboration.
Oxygenation is also well tolerated under reaction conditions.
Substrates containing a silyl ether or a free alcohol form 27 and
28 in good yield and with high es (entries 5 and 6).
Furthermore, the use of zinc reagents allows for cross-coupling
of substrates containing sensitive functionality such as acetals
(entry 7) as well as electrophilic fragments such as esters (entry
8). We did not observe decomposition of the acetal or addition
to the ester under our reaction conditions. With these
promising results we moved to nitrogenated substrate classes.
N-Heterocycles, amines, and imides are common functional
groups in biologically active molecules (Figure 1, compounds 1
and 3). Since nitrogen-based ligands are often employed in
nickel-catalyzed cross-coupling reactions, we anticipated that
this class of substrates could be problematic. Initially, we
synthesized a morpholine-containing substrate. Morpholine is a
common motif in many pharmaceuticals, including the
antibiotic linezolid, anticancer agent gefitinib, and analgesic
dextromoramide.30 We were pleased to see that the morpholino
ring was well tolerated in our cross-coupling and 31 was formed
in 68% yield (Table 1, entry 9). Imides are also well tolerated in
the reaction; 32 was formed in 84% yield with excellent es
(entry 10). Phthalimides are interesting because they are readily
deprotected to reveal primary amines. Encouraged by these
results, we next designed an indole substrate. This class of
substrates is particularly challenging since the indole moiety
stabilizes carbocation intermediates, which, if formed, would
afford racemic product and increased levels of byproducts
resulting from elimination (Scheme 3a). In prior studies, we
obsereved that cross-coupling of indole substrates under our
original Kumada coupling conditions afforded only racemic
product.31 We found, however, that under our Negishi
conditions, when dimethylzinc is used, 33 couples to form 34
in 91% yield and with excellent es (Scheme 3b).
a
b
Isolated yield after column chromatography. Determined by
c
supercritical fluid chromatography. Enantiospecificity (es) =
(eeproduct/eesubstrate) × 100%. Absolute configuration determined by
comparison of optical rotations with literature values. Please see SI for
details. Approximately 20% styrene byproduct arising from β-hydride
elimination was observed in these reactions. 10−15% styrene
byproduct arising from β-hydride elimination was observed in these
reactions. Less than 10% styrene byproduct arising from β-hydride
elimination was observed in these reactions. Prepared from racemic
d
e
f
g
h
i
substrate. Reaction ran with the following reagents: NiCl2·DME (13
mol %), DPEphos (26 mol %), ZnMe2 (3.8 equiv).
through pathways involving carbocation intermediates. As
predicted, erosion of es was observed at ambient temperatures;
however, upon cooling to 0 °C, excellent transfer of chirality
was observed (Table 2, entry 1). Both electron-poor ((R)-36
and 37) and electron-rich (38 and 40) products were formed in
good yield and es (entries 2, 3, 4, and 6, respectively). To probe
the functional group compatibility of the reaction, we evaluated
a substrate that included an isobutyric acid ester (entry 5).
Stereospecific cross-coupling of diaryl electrophiles is
challenging because this substrate class is prone to racemization
D
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only a modest yield of the desired ethylated product 41 and
significant amounts of both byproducts 23 and 42 (Table 3,
entry 1). This result is in direct contrast to cross-coupling with
dimethylzinc, where the thiomethyl ether was found to be the
ideal traceless directing group (Figure 2). To suppress these
undesired pathways, we once again turned to tuning the
directing group. During our earlier investigation of leaving
Scheme 3. Cross-Coupling of Indole Electrophiles
Table 3. Cross-Coupling of Diethylzinc
a
Conditions used: NiCl2·DME (10 mol %), DPEphos (20 mol %),
Table 2. Substrate Scope of Diarylethanes
b
ZnEt2 (3.0 equiv), PhMe, rt, 24 h. THF used instead of PhMe.
c
Determined by 1H NMR based on comparison with PhTMS as
internal standard.
groups in reactions with dimethylzinc, we identified thiols 17
and 15 as promising leads (Figure 2). When thiol 17 was
coupled with diethylzinc, the yield of 41 improved and
formation of both 23 and 42 decreased; however, we observed
formation of free alcohol 43 (Table 3, entry 2). We
hypothesized that increased steric bulk at the α-position
would slow addition to the ester; directing group 15 further
improved the yield of desired product to 55% (entry 3).
To determine the stereospecificity of the cross-coupling
reaction with diethylzinc, substrate 44, equipped with the thiol
directing group, was subjected to cross-coupling conditions.
Despite the more challenging nature of this transformation,
product 45 was formed in excellent es (eq 1).
a
b
Isolated yield after column chromatography. Determined by
c
supercritical fluid chromatography. Enantiospecificity (es) =
(eeproduct/eesubstrate) × 100%. Absolute configuration determined by
d
comparison of optical rotations with literature values. Please see SI for
details.
Esters are common masking groups used in prodrugs as they
are readily hydrolyzed in vivo by nonspecific esterases to reveal
the active metabolite bearing a hydroxyl group.32 For example,
the antimuscarinic 1,1-diarylalkane fesoterodine contains an
aryl isobutyric acid ester.33 Our reaction conditions tolerate the
isobutyric acid ester moiety nicely: product 39 was formed
selectively in 76% yield and 99% es, with no competitive cross-
coupling of the aryl ester.
Cross-Coupling with Diethylzinc. The cross-coupling
reaction can be utilized with longer-chain alkylzinc reagents
such as diethylzinc. Reactions employing such reagents are
more complex as additional competitive reaction pathways are
possible: in addition to undesired β-hydride elimination to
afford byproduct 23, hydrogenolysis to provide 42 is also
possible. Indeed, in initial studies 2-(methylthio)ester 18 gave
Synthesis of Biologically Active Arylethanes: Retinoic
Acid Receptor Agonist and Fatty Acid Amide Hydrolase
Inhibitor. The retinoic acid receptors (RARs) are implicated in
several disease states. RARβ is targeted in treatment of certain
cancers;34 modulating RARγ activity could enable treatment of
skin diseases such as psoriasis,35 melanoma,36 and acne.37
Compounds containing the diaryl moiety are isoform selective
ligands for RARβ and γ. 1,1-Diarylethane 2 and BMS 184394,
which is the saponified ester 50, are RARγ agonists.38 RARγ is
known to be sensitive to stereochemistry at the benzylic
position. The (S)-enantiomer of BMS 184394 is 10-fold more
potent than the (R)-enantiomer.7c While racemic 1,1-diaryl-
ethane 2 has activity comparable to that of (S)-BMS 184394,
activities of the two enantiomers of 2 have not been reported.
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not report the absolute configuration of the more active
stereoisomer.7d Since our cross-coupling proceeds with net
inversion, the configuration of the product can be readily
assigned when the configuration of the enantioenriched alcohol
is known.29,41 We began our synthesis with addition of aryl
lithiate 54 to 1-Boc-piperidine-4-carboxaldehyde to afford
racemic 56, followed by oxidation to ketone 55 (Scheme
5).42 Subsequent CBS reduction afforded the requisite
Scheme 4. Enantioselective Synthesis of Retinoic Acid
Receptor Ligand 2
a
a
Scheme 5. Synthesis of FAAH Inhibitor 3
a
(a) Mg, THF, rt, 2 h; (b) B(OMe)3, Et2O, 0 °C, 1 h, 94%; (c) 1 M
HCl; (d) i) Et2Zn (6.0 equiv), PhMe, 65 °C, 24 h, ii) 48, 49 (0.10
equiv), PhMe, 0 °C, 24 h; (e) 51, DCC, DMAP, CH2Cl2, rt, 12 h,
90%; (f) NiCl2·DME (10 mol %), Xantphos (20 mol %), ZnMe2 (3.0
equiv), PhMe, 0 °C, 24 h; (g) 1 N NaOH, THF:MeOH (1:1), 60 °C,
2 h, 92%.
We envisioned using our cross-coupling strategy as a key step in
the synthesis of enantioenriched acid 2. We began our synthesis
with bromide 46, which was converted to boronic acid 47 from
the corresponding Grignard reagent by quenching with
trimethoxyborane followed by hydrolysis (Scheme 4).39
Enantioselective arylation of aldehyde 48 according to the
Bolm strategy furnished the desired enantioenriched alcohol
(R)-50 in 94% yield and 94% ee.27b The traceless directing
group was then installed by DCC coupling23 and the substrate
was subjected to standard cross-coupling conditions. Diaryl-
ethane 53 was obtained in 92% yield with excellent transfer of
stereochemical information (97% es). We confirmed that the
cross-coupling reaction proceeded with inversion at the
benzylic center by preparation of a crystalline derivative that
was subjected to X-ray crystallographic analysis (see SI for
details).40 Saponification with 1 N NaOH provided the desired
retinoic acid receptor ligand (S)-2 in high yield.7c
We next applied our methodology to the synthesis of fatty
acid amide hydrolase (FAAH) inhibitor 3. FAAH is a
membrane-bound serine hydrolase, which has recently gained
interest for pain treatment as an alternative target to
cannabinoid receptor 1 (CB1). Inactivation of FAAH produces
analgesic and anti-inflammatory effects in rodents without the
weight gain that commonly accompanies CB1 agonists.7d The
first reported synthesis of 3 featured a sodium borohydride
reduction followed by chiral chromatography to separate the
enantiomers. While the authors demonstrated that the two
enantiomers exhibited a 20-fold difference in activity, they did
a
54 (1.0 equiv), THF, −78 °C to rt, 1 h, 75%; (b) MnO2 (20 equiv),
CH2Cl2, rt, 9 h, 72%; (c) (S)-Me-CBS (10 mol %), H3B·SMe2 (2.0
equiv), THF, 0 °C, 16 h, 99%, 67% ee, recrystallized to 95% ee; (d)
51, DCC, DMAP, CH2Cl2, rt, 12 h, 83%; (e) NiCl2·DME (10 mol %),
DPEphos (20 mol %), ZnMe2 (3.0 equiv), PhMe, rt, 24 h; (f) Br2,
THF, 0 °C, 6 h, 24%; (e) NiCl2·DME (10 mol %), DPEphos (20 mol
%), ZnMe2 (3.0 equiv), PhMe, rt, 24 h, 75%; (g) TFA, CH2Cl2, rt, 30
min; (h) 61, CH2Cl2, rt, 20 h 68% over 2 steps.
enantioenriched alcohol intermediate in 93% ee.25b,c We
assigned the absolute configuration of alcohol 56 as R on the
basis of the accepted model for selectivity in CBS reductions,28a
which was then confirmed by the CEC method.29 The directing
group was installed by a DCC coupling without loss of ee.23
Cross-coupling of 57 under our optimized reaction conditions
afforded the methyl-bearing benzylic stereocenter in 87% yield
with 99% es.
Subsequent elaboration of key intermediate 58 to FAAH
inhibitor 3 was accomplished in four steps. To introduce the
requisite methyl substituent on the benzothiophene ring, we
chose to employ a second cross-coupling reaction. Bromination
at the 3-position of the benzothiophene provided 59,43 which
was then subjected to cross-coupling conditions. A Suzuki
cross-coupling with methylboronic acid required elevated
temperatures and did not proceed to conversion, resulting in
F
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(3) (a) Zimmerman, J.; Buchdunger, E.; Mett, H.; Meyer, T.; Lydon,
N. B.; Traxler, P. Bioorg. Med. Chem. Lett. 1996, 6, 1221.
(b) Zimmerman, J.; Furet, P.; Buchdunger, E. ACS Symp. Ser. 2001,
796, 245.
(4) Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J.
Med. Chem. 2012, 55, 4489.
an inseparable mixture of desired product, starting material, and
several byproducts. In contrast, Negishi cross-coupling
provided 60 in 75% at ambient temperature. Subsequent
deprotection and treatment with pyridine-3-isocyanate (61)
provided the FAAH inhibitor 3.44 Since the absolute
configuration of 56 was readily assigned as R, our synthesis
afforded enantioenriched (S)-3. In the event that both
enantiomers were required for testing, synthesis of (R)-3 via
(S)-56 could be achieved using the other enantiomer of the
CBS catalyst. Therefore, our stereospecific Negishi cross-
coupling methodology can be used to construct both
enantiomers of the product for biological testing.
(5) For examples of methyl substitution to improve metabolic
stability of heterocycles, see: (a) Obach, R. S.; Kalgutkar, A. S.; Ryder,
T. F.; Walker, G. S. Chem. Res. Toxicol. 2008, 21, 1890. (b) Talley, J. J.;
Bertenshaw, S. R.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Kellogg,
M. S.; Koboldt, C. M.; Yuan, J.; Zhang, Y. Y.; Seibert, K. J. Med. Chem.
2000, 43, 1661. (c) Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto,
M. J.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.;
Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J. Med. Chem.
2000, 43, 775.
(6) For an example of methyl substitution at the benzylic position as
part of a strategy to slow down metabolic oxidation, see: Palani, A.;
Shapiro, S.; Josien, H.; Bara, T.; Clader, J. W.; Greenlee, W. J.; Cox, K.;
Strizki, J. M.; Baroudy, B. M. J. Med. Chem. 2002, 45, 3143.
(7) (a) Mihalic, J. T.; Chen, X.; Fan, P.; Chen, X.; Fu, Y.; Liang, L.;
Reed, M.; Tang, L.; Chen, J.-L.; Jaen, J.; Li, L.; Dai, K. Bioorg. Med.
Chem. Lett. 2011, 21, 7001. (b) Pereira, A. R.; Strangman, W. K.;
Marion, F.; Feldberg, L.; Roll, D.; Mallon, R.; Hollander, I.; Andersen,
R. J. J. Med. Chem. 2010, 53, 8523. (c) Yu, K.-L.; Spinazze, P.;
Ostrowski, J.; Currier, S. J.; Pack, E. J.; Hammer, L.; Roalsvig, T.;
Honeyman, J. A.; Tortolani, D. R.; Raczek, P. R.; Mansuri, M. M.;
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Ahn, K.; Kesten, S.; Lazerwith, S. E.; Song, Y.; Morris, M.; Fay, L.;
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2009, 19, 2865.
CONCLUSIONS
■
In summary, we have developed a stereospecific nickel-
catalyzed Negishi-type alkyl−alkyl cross-coupling for the
introduction of benzylic methyl substitutents found in bio-
logically active small molecules. Reactions proceed with high
levels of chirality transfer. The mild reaction conditions are
compatible with a variety of functional groups including
alkenes, protected alkynes, acetals, and esters. Heterocycles,
amines and imides are also well tolerated in these reactions.
Benzylic alcohols are activated for cross-coupling using a
traceless directing group that is easily installed by DCC
coupling with commercially available (methylthio)acetic acid.
Using this methodology, we report enantioselective synthesis of
two bioactive molecules. This strategy enables biological testing
of such compounds in their enantioenriched form, allowing for
a more complete evaluation of their activity.
(8) For methods to construct methyl-bearing tertiary benzylic
stereocenters, see: (a) Hatanaka, Y.; Hiyama, T. J. Am. Chem. Soc.
1990, 112, 7793. (b) Imao, D.; Glasspoole, B. W.; Laberge, V. S.;
Crudden, C. M. J. Am. Chem. Soc. 2009, 131, 5024. (c) Paquin, J.-F.;
Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 10850. (d) Nave, S.; Sonawane, R. P.; Elford, T. G.;
Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 17096. (e) Podhajsky, S.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
4435. (f) Pam
́
ies, O.; Andersson, P. G.; Dieg
́
uez, M. Chem.Eur. J.
AUTHOR INFORMATION
Corresponding Author
erjarvo@uci.edu
2010, 16, 14232. (g) Wang, X.; Guram, A.; Caille, S.; Hu, J.; Preston, J.
P.; Ronk, M.; Walker, S. Org. Lett. 2011, 13, 1881. (h) Mazuela, J.;
Norrby, P.-O.; Andersson, P. G.; Pam
■
́ ́
ies, O.; Dieguez, M. J. Am. Chem.
Soc. 2011, 133, 13634.
Author Contributions
(9) (a) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J. Am.
Chem. Soc. 2011, 133, 389. (b) Greene, M. A.; Yonova, I. M.; Williams,
F. J.; Jarvo, E. R. Org. Lett. 2012, 14, 4293.
‡H.M.W. and E.C.S. contributed equally.
Notes
(10) For representative strategies, see: (a) Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1990; Vols. 1−3. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J.
Am. Chem. Soc. 1987, 109, 5551. (c) Kitamura, M.; Suga, S.; Kawai, K.;
Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071. (d) Kitamura, M.;
Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.; Akutagawa, S.;
Ohta, T.; Takaya, H.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 629.
(e) Fu, G. C. Acc. Chem. Res. 2000, 33, 412. (f) Copeland, G. T.;
Miller, S. J. J. Am. Chem. Soc. 2001, 123, 6496. (g) Ferreira, E. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725. (h) Jensen, D. R.;
Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475.
(i) Zhang, F.-Y.; Yip, C.-W.; Cao, R.; Chan, A. S. C. Tetrahedron:
Asymmetry 1997, 8, 585.
(11) Stereospecific Suzuki cross-coupling to form triarylmethanes:
Harris, M. R.; Hanna, L. E.; Greene, M. A.; Moore, C. E.; Jarvo, E. R. J.
Am. Chem. Soc. 2013, 135, 3303.
(12) For a closely related transformation, see: Zhou, Q.; Srinivas, H.
D.; Dasgupta, S.; Watson, M. P. J. Am. Chem. Soc. 2013, 135, 3307.
(13) (a) Knochel, P.; Leuser, H.; Gong, L.-Z.; Perrone, S.; Kneisel, F.
F. Polyfunctional Zinc Organometallics for Organic Synthesis. In
Handbook of Functionalized Organometallics: Applications in Synthesis;
Knochel, P., Ed.; Wiley: Weinheim, 2005; p 251. (b) Phapale, V. B.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH NIGMS (R01GM100212)
and the University of California Cancer Research Coordinating
Committee. Prof. Scott D. Rychnovsky and Alexander J.
Wagner are acknowledged for confirming absolute config-
uration of enantioenriched alcohol intermediates by their CEC
method (see SI for details). Justin A. Hilf is acknowledged for
synthesis of two racemic substrates (Table 1, entry 9 and
Scheme 3B). Dr. John Greaves is acknowledged for mass
spectrometry data.
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