An Ir/Zn Dual Catalysis for Enantio- and Diastereodivergent α-Allylation of α-Hydroxyketones

Article abstract of DOI:10.1021/jacs.6b06156

An Ir/Zn dual catalysis has been developed for the enantio- and diastereodivergent α-allylation of unprotected α-hydroxyketones under mild conditions, in the absence of any additional base. The cooperative action of a chiral iridium complex derived from phosphoramidites and a chiral Zn-ProPhenol complex is most likely responsible for its high reactivity, excellent enantioselectivity (up to >99% ee), and good diastereoselectivity (up to >20:1 dr). All four product stereoisomers could be prepared from the same set of starting materials and under identical conditions by simple selection of appropriate catalyst combinations.

Full text of DOI:10.1021/jacs.6b06156

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An Ir/Zn Dual Catalysis for Enantio- and
Diastereodivergent #-Allylation of #-Hydroxyketones
Xiaohong Huo, Rui He, Xiao Zhang, and Wanbin Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b06156 • Publication Date (Web): 22 Aug 2016
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An Ir/Zn Dual Catalysis for Enantioꢀ and Diastereodivergent αꢀ
Allylation of αꢀHydroxyketones
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†,§
‡,§
‡
,†,‡
Xiaohong Huo, Rui He, Xiao Zhang, and Wanbin Zhang*
†
‡
School of Pharmacy and School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan
Road, Shanghai 200240, P. R. China
Supporting Information Placeholder
ABSTRACT: An Ir/Zn dual catalysis has been developed for the
enantioꢀ and diastereodivergent αꢀallylation of unprotected αꢀ
hydroxyketones under mild conditions, in the absence of any adꢀ
ditional base. The cooperative action of a chiral iridium complex
derived from phosphoramidites and a chiral ZnꢀProPhenol comꢀ
plex is most likely responsible for its high reactivity, excellent
enantioselectivity (up to >99% ee), and good diastereoselectivity
Scheme 1. Stereodivergent Synthesis via Bimetallic Catalyꢀ
sis
(up to >20:1 dr). All four product stereoisomers could be prepared
from the same set of starting materials and under identical condiꢀ
tions by simple selection of appropriate catalyst combinations.
Structural motifs containing contiguous stereogenic centers are
found in numerous natural products and important bioactive comꢀ
pounds, and their absolute and relative configurations are often
1
crucial for the expression of their biological activities. The deꢀ
velopment of reliable methodologies that lead to all possible steꢀ
reoisomers of products is a prominent research objective, as well
2
as a significant challenge in asymmetric synthesis. Many classiꢀ
cal strategies have attempted to address this challenge via the use
3
4
of additives, the selection of distinct catalysts, and the use of
5
twoꢀstep sequential reactions with one or two chiral catalysts.
However, few methodologies are able to provide a unified and
predictable route that exerts full control of the absolute and relaꢀ
tive stereochemical configuration of products containing multiple
contiguous stereocenters. Recently, Carreira and colleagues deꢀ
veloped an elegant dual catalyst system for the independent conꢀ
trol of two stereocenters in the αꢀallylation of aldehydes by comꢀ
this area have been achieved recently through elegant contribuꢀ
tions from the groups of Hartwig, Carreira and Stoltz. Howevꢀ
er, the direct use of unprotected αꢀhydroxyketones as nucleophiles
6
,12
in Irꢀcatalyzed allylic substitution remains challenging (Scheme
13ꢀ14
1b).
It is worth noting that αꢀhydroxyketone donors are particꢀ
6ꢀ7
bining iridium and organic catalysis. However, the development
ularly interesting because of the important biological activity of
15ꢀ16
of a cooperative bimetallic catalyst system that utilizes two disꢀ
tinct chiral metal catalysts for the complete stereoisomeric control
of products bearing multiple stereocenters remains underdevelꢀ
the polyoxygenated products.
However, these are troublesome
nucleophiles due to their multiple nucleophilic sites and the undeꢀ
fined geometry of the corresponding unstabilized enolate. Herein,
we describe an enantioꢀ and diastereodivergent synthesis for the
αꢀallylation of unprotected αꢀhydroxyketones, a procedure greatly
desired from an atom economy and synthetic efficiency perspecꢀ
8
oped but is highly desired. This desirability resides in: (a) the
abundance of readyꢀmade or commercially available chiral ligꢀ
9
ands and metal catalysts; (b) diverse asymmetric reactions inꢀ
1
0
17
volving metal catalysis; and (c) a large bimetallic catalyst library
created via random combination of two different chiral metal
catalysts for targeted asymmetric metal catalysis (Scheme 1a).
tive.
In continuation of our previous work concerning dual catalysis
for asymmetric allylic substitutions in which transitionꢀmetal
18
Irꢀcatalyzed allylic substitution has become one of the most
powerful methods to construct carbonꢀcarbon and carbonꢀ
heteroatom bonds. A characteristic feature of this process is the
catalysis and enamine catalysis were combined, we envisioned
that a dual catalyst system consisting of a combination of a chiral
16,19
20
zinc complex
and a chiral iridium complex would provide an
1
1
predominant formation of branched products. The introduction
of prochiral nucleophiles to Irꢀcatalyzed allylic substitutions
would provide an effective and reliable method for the synthesis
of the products containing vicinal stereocenters. Indeed, the diaꢀ
stereoꢀ and enantioselective reactions with carbonyl heterocyclic
compounds, aldehydes or βꢀketoesters as nucleophiles in
efficient strategy for the enantioꢀ and diastereodivergent αꢀ
allylations of unprotected αꢀhydroxyketones (Scheme 1b). The
potential advantages of this strategy are as follows: (i) A fiveꢀ
membered ring containing zinc enolate IIꢀ1 will be formed via the
coordination of the zinc atom with the two oxygen atoms of the
carbonyl and the hydroxyl groups. The formation of IIꢀ1 may
improve the nucleophilicity of the carbon atom; (ii) Zinc enolate
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IIꢀ1 has a defined Zꢀconfiguration, which may provide a general
approach to acyclic diastereocontrol; (iii) The cooperative use of a
chiral zinc complex and chiral iridium complex may
reversed via the addition of a Zn catalyst, giving the desired
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product 3a in moderate yields (entries 2−5). After examination of
different ligands (L1−L4), the Trost ligand−ProPhenol (L4) was
shown to give superior results compared to all others tested. The
Zn−ProPhenol complex was therefore chosen as the optimal Zn
a
simultaneously activate the αꢀhydroxyketone and the allyl and
allow for the control of the two stereocenters. This will increase
the possibility of an enantioꢀ and diastereodivergent αꢀallylation
19c
catalyst. Compared to the monoꢀcatalyst consisting of only an Ir
complex, the addition of the Zn catalyst greatly improved the
reactivity and selectivity of the αꢀhydroxyketone. The efficiency
of the Zn−ProPhenol catalyst could be further improved by the
addition of a weak coordinating agent that is able to displace the
7
of αꢀhydroxyketones.
Table 1. Optimization of the αꢀAllylation of αꢀ
a
Hydroxyacetophenone
16b,c,eꢀg,21
product.
Indeed, the addition of a small amount of weak
0
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coordinating agent such as ethylene carbonate, Ph P=O or Ph P=S,
3
3
accelerated the asymmetric transformation under otherwise
identical conditions (entries 6−8). The addition of 4Å MS further
promoted reaction activity, giving 3a in high yields with good
diastereoꢀ and enantioselectivities (entries 9−10). Subsequent
optimization studies showed that the ratio of Et Zn and L4 could
2
be reduced to 1:1.2 to give 3a in 96% yield, 15:1 dr, and >99% ee
(entries 11−13). The unusual Zn/L4 ratio prompted us to
synthesize and apply the ligand L5 to the catalysis. However, this
led to poor catalytic performance (entry 14). Although we are
unable to clarify the underlying reason for the outstanding catalytꢀ
ic performance of the Trost ligand−ProPhenol, the unique geomeꢀ
try of the chiral semiꢀcrown backbone seems to be critically imꢀ
portant for the reactivity and stereocontrol of the catalysis.
b
c
d
entry Zn/L
L
additive yield (%)
dr
−
ee (%)
With the feasibility of a chemoꢀ and stereoselective process for
the αꢀallylation of αꢀhydroxyacetophenone established, we then
speculated if the bimetallic catalyst system could furnish product
1
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9
1
1
1
−
−
−
−
−
−
−
nr
−
3
a with full control over the absolute and relative configuration of
1:1
1:1
1:1
2:1
2:1
2:1
2:1
2:1
2:1
1:1
L1
L2
L3
L4
38
48
42
63
71
65
74
94
97
97
1:1
1:1
1:1
3:1
3:1
3:1
3:1
6:1
8:1
79/81
89/89
87/70
93/90
96
its two stereocenters. Under the optimized reaction conditions
(Table 1, entry 12), the reaction of 1a and 2a afforded product
(R,S)−3a in 96% yield, 15:1 dr, and >99% ee when catalyzed with
the (R,R)−L4/(R,R,R)−L6 combination. Significantly, the reaction
allowed for the synthesis of (S,S)−3a in 91% yield, 6:1 dr,
and >99% ee when catalyzed by the (R,R)−L4/(S,S,S)−L6
combination (Scheme 2). The switch in the sense of
diastereoselectivity suggested that the two chiral metal catalysts
were able to almost independently control the configuration of the
two stereocenters. From the same set of starting materials and
under identical reaction conditions, the remaining two
stereoisomers (S,R)−3a and (R,R)−3a were prepared in high yields
and good enantioꢀ and diastereoselectivities (Scheme 2).
e
e
e
f
L4 EC
L4 Ph PO
94
3
L4 Ph PS
94
3
L4 4Å MS
L4 4Å MS
L4 4Å MS
97
g
0
1
2
98
g
Scheme 2. Synthesis of All Four Stereoisomers of 3a
13:1 99
15:1 >99
16:1 >99
g,h
g,i
g
1:1.2 L4 4Å MS
1:1.5 L4 4Å MS
96
96
93
13
1
4
1:1
L5 4Å MS
1:1
87/52
a
Reaction conditions: 1a (0.30 mmol, 1.2 equiv), 2a (0.25 mmol,
.0 equiv), Et Zn (5 or 10 mol %), L1−L5 (5 mol %), [Ir(cod)Cl]
1
2
2
b
(2 mol %), (R,R,R)−L6 (4 mol %), rt, 12 h. Isolated yield. nr = no
c
1
d
reaction. Ratio of dr determined by H NMR integration. Deterꢀ
mined by HPLC analysis using an ODꢀH column. 20 mol % addiꢀ
tives. 50 mg 4Å MS. 100 mg 4Å MS. Et Zn (5 mol %), L4 (6
mol %). Et Zn (5 mol %), L4 (7.5 mol %). EC = ethylene carꢀ
e
f
g
h
2
A number of allylic esters were examined (Table 2). Allylic
esters bearing either electronꢀdonating or electronꢀwithdrawing
groups at the orthoꢀ, metaꢀ, or paraꢀposition of the arene
functionality participated in this reaction to give the desired
products (3b−3n) in high yields and with excellent
stereoselectivities (7:1 to 18:1 dr, 94−>99% ee). Furthermore, the
reactions of naphthylꢀ and heteroarylꢀsubstituted allyl carbonates
were successfully carried out to give their respective products in
good yields and with excellent enantioselectivities (3o−3q).
Commom substituents such as alkyl, styrenyl and ether groups
also gave good results (3r−3u).
i
2
bonate.
The investigation began using αꢀhydroxyacetophenone (1a) and
cinnamyl methyl carbonate (2a) as model substrates for the allylic
substitution (Table 1). The asymmetric reaction was first
attempted using a bimetallic catalyst system consisting of a Et Zn
2
complex modified with appropriate amino alcohol ligands
1
9
(
L1−L5)
and an iridium complex derived from
20
phosphoramidites [(R,R,R)−L6]. In the absence of the Zn
catalyst, none of the desired product αꢀhydroxylꢀγ,δꢀunsaturated
ketone (3a) was obtained (entry 1). This situation could be
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The scope of a series of αꢀhydroxyketones was next investigatꢀ
ed (Table 3). αꢀHydroxyacetophenones substituted with Me, OMe,
Br, F, and 3,4ꢀmethylenedioxy groups gave the desired products
the corresponding products in good yields and with excellent enꢀ
antioselectivities, although most of the dr values were slightly
lower than those obtained with the combination of
(R,R)−L4/(R,R,R)−L6.
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(
3v−3z) in high yields and with excellent stereoselectivities (6:1
to 12:1 dr, 90−>99% ee). An αꢀhydroxyketone incorporating a
heteroarene also proved to be a good substrate for this reaction,
affording product 3aa in high yield and excellent
a
Table 4. Representative Examples of Stereodivergence
enantioselectivity.
Additionally,
alkyneꢀsubstituted
hydroxyketone was smoothly used as a nucleophile in this
reaction, providing the desired product 3ab in moderate yield and
high ee.
a
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Table 2. The Substrate Scope of Allylic Carbonates
a
Reaction conditions, please see Table 1, entry 12 with (S,S,S)−L6
instead of (R,R,R)−L6.
To confirm the scalability of the present method, we performed
a gramꢀscale synthesis of (R,S)−3a and (R,S)−3g using the
standard reaction conditions and comparable results were obtained
(Scheme 3). Furthermore, the absolute configuration of (R,S)−3g
was determined by singleꢀcrystal Xꢀray analysis.
Scheme 3. Gramꢀscale Experiments and ORTEP Repreꢀ
sentation of 3g
ꢀ
Scheme 4. Synthetic Transformation of the Allylated αꢀ
Hydroxyketone
a
a
Reaction conditions, please see Table 1, entry 12.
a
Table 3. The Substrate Scope of αꢀHydroxyketones
a
Reaction conditions: (a) allyl iodide, DMF, Cs CO , rt, 6 h. (b)
2
3
Grubbs−Hoveyda catalyst, DCM, 40 °C, 12 h. (c) NaBH , EtOH,
0 C, 2 h. (d) potassium allyltrifluoroborate, CeCl , THF, 50 C, 6
h.
4
o
o
3
Subsequently, synthetic transformations of the product
R,S)−3a were conducted. As shown in Scheme 4, chiral dihydroꢀ
(
a
b
o
Reaction conditions, please see Table 1, entry 12. at 80 C.
pyran 4 could be easily obtained from (R,S)−3a via allylic substiꢀ
tution and ringꢀclosing metathesis using a Grubbs−Hoveyda seꢀ
cond generation catalyst. Reduction of (R,S)−3a with NaBH
furnished compound 5 in 95% yield and 93% ee. The allylation
of (R,S)−3a with potassium allyltrifluoroborate led to the allylated
polyoxygenated product 6 in 93% yield and 96% ee.
In summary, we have developed a new bimetallic catalysis
To evaluate the practicality of the diastereodivergent synthesis,
4
22
we performed the reactions of 1a with different allylic carbonates
using a combination of (R,R)−L4/(S,S,S)−L6 (Table 4). Cinnamyl
carbonates substituted with arenes bearing methyl, halogen, and
other electronꢀwithdrawing substituents reacted smoothly to give
22
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strategy for a oneꢀstep and stereodivergent αꢀallylation of unproꢀ
tected αꢀhydroxyketones by using a chiral iridium complex deꢀ
rived from phosphoramidites and a chiral Zn−ProPhenol complex
in the absence of any additional bases. A range of chiral αꢀ
hydroxylꢀγ,δꢀunsaturated ketones containing vicinal stereocenters
were produced in good yields and with excellent stereoselectiviꢀ
ties. More significantly, the pairwise combination of chiral metal
catalysts allows for complete control over the absolute and relaꢀ
tive configuration of all possible product stereoisomers from the
same set of starting materials under identical reaction conditions.
We envisage that this bimetallic catalyst strategy will offer new
opportunities for full stereodivergent access to difficult asymmetꢀ
ric transformations.
(7) For perspectives on stereodivergent dual catalysis, see: (a)
Schindler, C. S.; Jacobsen, E. N. Science 2013, 340, 1052. (b) Oliveira, M.
T.; Luparia, M.; Audisio, D.; Maulide, N. Angew. Chem., Int. Ed. 2013,
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6
7
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9
0
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5
6
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8
9
0
1
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3
4
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6
7
8
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all reacꢀ
1
13
(12) (a) Chen, W.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2068.
b) Liu, W.ꢀB.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem.
tions and products, including H and C NMR spectra, HPLC
spectra, crystal data, and crystallographic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
Soc. 2013, 135, 10626. (c) Liu, W.ꢀB.; Reeves, C. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2013, 135, 17298. (d) Chen, W.; Hartwig, J. F. J. Am. Chem.
Soc. 2014, 136, 377. (e) Chen, W.; Chen, M.; Hartwig, J. F. J. Am. Chem.
Soc. 2014, 136, 15825. For the intramolecular reaction, see: (f) Wu, Q.ꢀF.;
He, H.; Liu, W.ꢀB.; You, S.ꢀL. J. Am. Chem. Soc. 2010, 132, 11418.
AUTHOR INFORMATION
Corresponding Author
(13) (a) Evans, P. A.; Lawler, M. J. J. Am. Chem. Soc., 2004, 126, 8642.
wanbin@sjtu.edu.cn.
(b) Jiang, X.; Chen, W.; Hartwig, J. F. Angew. Chem., Int. Ed. 2016, 55,
5819.
(14) For examples of Pdꢀcatalyzed asymmetric allylic alkylation of αꢀ
hydroxyketones, see: (a) Trost, B. M.; Xu, J.; Reichle, M. J. Am. Chem.
Soc. 2007, 129, 282. (b) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem.
Soc. 2008, 130, 11852.
Author Contributions
§
These authors contributed equally.
Notes
The authors declare no competing financial interests.
(15) (a) Davis, F. A.; Chen, B.ꢀC. Chem. Rev. 1992, 92, 919. (b) Tiꢀ
aden, A.; Spirig, T.; Hilbi, H. Trends Microbiol. 2010, 18, 288.
ACKNOWLEDGMENT
(16) The use of hydroxyketones as a donor in asymmetric Aldol and
Mannichꢀtype reactions, see: (a) Yoshikawa, N.; Kumagai, N.; Matsunaga,
S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem. Soc.
2001, 123, 2466. (b) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem. Soc.
2001, 123, 3367. (c) Trost, B. M.; Terrell, L. R. J. Am. Chem. Soc. 2003,
We thank the NSFC (Nos. 21232004 and 21472123) and Science
and Technology Commission of Shanghai Municipality (Nos.
1
4XD1402300 and 15Z111220016) for financial support.
1
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(21) Several bidentate coordinating agents were also explored. For
more details please see the Supporting Information.
(22) The absolute configurations of 5 and 6 were determined by singleꢀ
crystal Xꢀray analysis. For more details please see the Supporting Inforꢀ
mation.
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An Ir/Zn dual catalysis has been developed for the enantioꢀ and diastereodivergent αꢀallylation of unprotected αꢀ
hydroxyketones under mild conditions, in the absence of any additional base. The cooperative action of a chiral iridium
complex derived from phosphoramidites and a chiral ZnꢀProPhenol complex is most likely responsible for its high reactivity,
excellent enantioselectivity (up to >99% ee), and good diastereoselectivity (up to >20:1 dr). All four product stereoisomers
could be prepared from the same set of starting materials and under identical conditions by simple selection of appropriate
catalyst combinations.
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