Cobalt-Catalyzed Diastereo- and Enantioselective Hydroalkylation of Cyclopropenes with Cobalt Homoenolates

Article abstract of DOI:10.1002/anie.202012122

Catalylic diastereo- and enantioselective hydroalkylation of 3,3-disubstituted cyclopropenes with Co-homoenolate generated in situ from ring-opening of easily accessible cyclopropanols promoted by a chiral phosphine–cobalt complex is presented. Such a process represents the unprecedented and direct introduction of a wide range of functionalized alkyl groups without the need of pre-formation of stoichiometric amounts of organometallic reagents onto the cyclopropane motif, affording multi-substituted cyclopropanes in up to 99 % yield with >95:5 dr and 98:2 er. Functionalization of the products delivered enantioenriched cyclopropanes that are otherwise difficult to access.

Full text of DOI:10.1002/anie.202012122

A Journal of the Gesellschaft Deutscher Chemiker
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International Edition
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Accepted Article
Title: Cobalt-Catalyzed Diastereo- and Enantioselective
Hydroalkylation of Cyclopropenes with Cobalt-Homoenolates
Authors: Wei Huang and Fanke Meng
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012122
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10.1002/anie.202012122
Angewandte Chemie International Edition
COMMUNICATION
Cobalt-Catalyzed Diastereo- and Enantioselective Hydroalkylation
of Cyclopropenes with Cobalt-Homoenolates
Wei Huang,[a] and Fanke Meng*[a]
Dedicated to the 70th anniversary of Shanghai Institute of Organic Chemistry ((optional))
[a]
W. Huang, Prof. Dr. F. Meng
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences
Chinese Academy of Sciences
345 Lingling Road, Shanghai, 200032 (China)
E-mail: mengf@sioc.ac.cn
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Catalylic diastereo- and enantioselective hydroalkylation of
3,3-disubstituted cyclopropenes with Co-homoenolate in situ
generated from ring-opening of easily accessible cyclopropanols
promoted by a chiral phosphine–Co complex is presented. Such a
process represents the unprecedented and direct introduction of a
wide range of functionalized alkyl groups without the need of pre-
formation of stoichiometric amounts of organometallic reagents onto
the cyclopropane motif, affording multi-substituted cyclopropanes in
up to 99% yield with >95:5 dr and 98:2 er. Functionalization of the
products delivered enantioenriched cyclopropanes that are otherwise
difficult to access.
Fe-[17] and Pd-catalyzed carbozincation,[18] hydroalkynylation[19]
and lanthanide-catalyzed hydroamination,[20] hydroalkynylation,[21]
and addition of 2-methyl azaarenes,[22] Co-catalyzed
hydroalkenylation[23] and hydrosilylation,[24] and NHC-catalyzed
hydroacylation[25] have been reported for enantioselective
synthesis of various functionalized cyclopropanes. However, few
protocols have been developed for enantioselective introduction
of diversified alkyl groups to cyclopropenes. Pioneering works by
Marek and co-workers revealed that simple alkyl groups can be
incorporated in high diastereo- and enantioselectivity with
Grignard or organozinc reagents promoted by Cu
complexes.[14b,15b-c] However, only alkyl groups without functional
groups can be introduced. In addition, preparation of sensitive
reagents is necessary and stoichiometric amounts of by-products
are generated.
Enantioenriched functionalized cyclopropanes are important
building blocks that can be transformed to a variety of useful
molecules in organic synthesis, as well as key structures in
biologically active molecules.[1] Therefore, it is of great importance
O
O
to establish
a
versatile approach for diastereo- and
N
H
O
N
H
Et
O
enantioselective preparation of a wide range of functionalized
alkylcyclopropanes in complex molecule synthesis and drug
development (Figure 1).[2] Numerous strategies have been
developed for enantioselective access to cyclopropyl motifs,
including the metal-catalyzed carbene insertion of terminal
alkenes,[3] the Simmons-Smith cyclopropanation of allylic and
homoallylic alcohols,[4] and conjugate addition followed by
cyclization of activated alkenes[5]. Although high selectivity is
achieved through these methods, some limitations are present
(the requirement of an electron-withdrawing group for the carbene
insertion and conjugate addition followed by cyclization and the
presence of a coordinating group for the Simmons-Smith
Tasimelteon
MT1/MT2 agonist
O
HN
CO2H
Me
Me
O
COOH
NH2
N
H
N
O
Belactosin A
Proteasome inhibitor
Integrin inhibitor
Figure 1. Biologically
alkylcyclopropane structures.
active molecules
bearing functionalizaed
Coupling of metal homoenolates represents a direct and
important method to access b-functionalized ketones.[26] Although
significant progress has been made in the formation of
homoenolates from catalytic ring-opening of cyclopropanols
followed by cross-coupling and addition to unsaturated
hydrocarbons,[27] enantioselective transformations remained
scarce.[27e] Yoshikai and co-workers reported an enantioselective
process for addition of the Co homoenolates to oxabicyclic
alkenes in high stereoselectivity albeit with limited scope of the
oxabicyclic alkenes.[27e] We are interested in the development of
a more general and atom-economical solution to incorporation of
Co homoenolates into cyclopropenes, affording enantioenriched
multisubstituted cyclopropanes with functionalized alkyl groups.
The challenges for such a process are the possible low reactivity
cyclopropanation).
A more general approach to prepare
enantioenriched alkylcyclopropanes is catalytic enantioselective
hydroalkylation of cyclopropenes.[6] The advantage is that a broad
range of multisubstituted cyclopropanes can be rapidly accessed
through a single set of transformations without the requisite of pre-
installation of a specific functional group, starting from readily
available materials and catalyst.
In the context of catalytic enantioselective functionalization of
cyclopropenes, Rh-catalyzed hydrostannation,[7] hydroboration,[8]
hydroformylation,[9]
hydroboration,[11]
and
hydronitronylation,[12]
hydroacylation,[10]
Cu-catalyzed
carbocupration,[13]
carbozincation,[14] carbomagnesiation[15] and hydroallylation,[16]
1
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10.1002/anie.202012122
Angewandte Chemie International Edition
COMMUNICATION
and elevated temperature is normally required. It is nontrivial to
control the enantioselectivity. In addition, possible b-H elimination
of the homoenolate might retard the desired pathway. Herein, we
disclosed the first Co-catalyzed atom-economical addition of
homoenolates generated from a wide range of cyclopropanols to
cyclopropenes in high diastereo- and enantioselectivity.
We commenced our studies with the treatment of the 3,3-
disubstituted cyclopropane 1a with cyclopropanol 2a at 70 C in
o
the presence of Co complexes derived from a variety of
phosphine ligands (Table 1, entries 1–9). We found that Co
complex generated from 4h provided the highest efficiency,
diastereo- and enantioselectivity, affording the desired product 3a
in 87% yield and 91:9 er as a single diastereomer. Switching the
solvent from DMSO to MeCN delivered similar yield and
stereoselectivity (entry 10). Lowering the reaction temperature
resulted in an improvement of enantioselectivity without the
diminishment of efficiency (entries 11–12). In contrast to previous
systems,[27c–e] the addition of MeOH and DABCO were
unnecessary for the reaction, whereas the counterion of the Co
salt is crucial for the efficiency and stereoselectivity in the
absence of DABCO (see Supporting Information for more details).
Cobalt halides provided much lower enantioselectivity and
Co(acac)2 promoted the reaction inefficiently. Reduction of the
catalyst loading to 7.5 mol % afforded 3a in 85% yield, >95:5 dr
a) Strategies for enantioselective functionalization of cyclopropenes with C-based nucleophiles
R1
R1
R1
R2
Cu, Pd, Fe
R3M
R3 = alkyl, M = Zn, Mg
R4 = alkenyl, M = Al
R3
R2
R1 R2
Cu
R4M
R4
R2
Rh, Co
R5M
R5 = aryl, alkenyl, M = B(OH)2
R5
b) Enantioselective transformations with Co-homoenolates generated from cyclopropanols
Ph OH
O
O
OH
(R,R)-BDPP
Co(OAc)2
(R,R)-BDPP, CoCl2
Ph
Ph
O
DABCO
MeOH
DABCO
O
and 95:5 er.
A
highly atom-economical, efficient and
c) Co-catalyzed atom-economical enantioselective hydroalkylation with Co-homoenolates (this work)
stereoselective transformation can be achieved through simple
treatment of cyclopropenes and cyclopropanols with a readily
available Co complex without any additive.
O
R1 R2
G
OH
G
chiral Co complex
+
R1 R2
! the first Co-catalyzed enantioselective hydroalkylation of cyclopropenes with Co-homoenolate
! 100% atom economy, high efficiency, diastereo- and enantioselectivity
! broad scope of cyclopropenes and cyclopropanols
O
O
O
O
! high functional-group tolerance and readily available catalyst
Ph
Ph
Ph
Ph
Me
Me
Me
Me
3b
3e
Scheme 1. Catalytic enantioselective transformations of cyclopropenes and
cyclopropanols.
3c
3d
70% yield
>95:5 dr, 95:5 er
O
90% yield
>95:5 dr, 95:5 er
O
84% yield
>95:5 dr, 95:5 er
O
66% yield
>95:5 dr, 95:5 er
O
F
NC
Br
F3C
Ph
Ph
Ph
Ph
Me
Me
Me
Me
F3C
Cl
3f
3g
3h
3i
Table 1. Optimization of reaction
93% yield
>95:5 dr, 95:5 er
59% yield
>95:5 dr, 95:5 er
80% yield
>95:5 dr, 95:5 er
85% yield
>95:5 dr, 94:6 er
O
MeO
Ph Me
10 mol % ligand, 10 mol % Co(OAc)2
Ph OH
O
O
O
O
Ph
1.5 equiv DABCO
+
Ph
Ph
Ph
Ph
Me
10 equiv MeOH, solvent (0.067M)
T oC, 12 h
Ph
Me
1a
2a
Me
Me
3a
3j
3l
3m
3k
(1.5 equiv)
86% yield
>95:5 dr, 95:5 er
98% yield
>95:5 dr, 92:8 er
93% yield
>95:5 dr, 92:8 er
90% yield
91:9 dr, 95:5 er
er [c]
na [d]
O
O
O
O
Solvent
T [oC]
Yield [%][a]
dr [b]
Entry
Ligand
Ph
Ph
Ph
Ph
na [d]
92:8
4a
4b
4c
4d
4e
4f
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
70
70
70
70
70
70
70
70
70
70
23
10
10
10
10
<5
47
66
52
87
90
80
87
83
88
91
83
86
86
85
1
2
OMe
OMOM
Ph
Ph
Me
Ph
Et
3q
3o
3p
3n
72.5:27.5
15:85
7:93
87% yield
>95:5 dr, 95.5:4.5 er
71% yield
>95:5 dr, 94:6 er
97% yield
>95:5 dr, 91:9 er
O
55% yield
92:8 dr, 95:5 er
79:21
91:9
3
O
O
O
O
4
Ph
Ph
Ph
Ph
>95:5
93:7
84:16
45.5:54.5
89.5:10.5
91:9
5
O
S
Bn
Me
Me
Me
Me
6
3r
3s
3t
3u
82% yield
>95:5 dr, 95:5 er
98% yield
>95:5 dr, 95:5 er
85% yield
>95:5 dr, 95:5 er
76% yield
86:14 dr, 95:5 er
S
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
4g
4h
4i
7
O
O
8
Ph
Ph
26:74
92:8
9
O
O
4h
4h
4h
4h
4h
4h
Cy
10
11
12
13 [e]
14 [f]
15 [g]
Me
3v
70% yield
92:8 dr, 92:8 er
3w
81% yield
Me Me 88:12 er
95:5
96:4
94:6
Scheme 2. Scope of cyclopropenes.
94:6
95:5
Ph
Me
Ph
Me
Me
With the optimal conditions in hand, we investigated the
substrate scope. As shown in Scheme 2, cyclopropenes bearing
aryl rings substituted with electron-withdrawing (3b–e, 3g–h),
electron-donating (3f), sterically congested groups (3i–k),
heterocycles (3q–t), and halogens (3b–c, 3h) are suitable
substrates. Transformations of cyclopropenes that contain alkyl
groups other than methyl afforded the desired products in 55–
98% yield with greater than 95:5 dr and 91:9–95:5 er (3l–p).
Reaction of the cyclopropene substituted with a benzyl and methyl
PPh2
PPh2
Ph2P
P
Fe
P
PCy2
Ph2P
PPh2
Et
Ph
Ph
4a
Me
4b
4c
4d
i-Pr
Me
P
P
P
Me
i-Pr
i-Pr
Me
Me
Et
Et
P
P
Me
P
P
H
P
P
P
H
Me
t-Bu
t-Bu
i-Pr
Me
Et
4i
4e
4f
4g
4h
[a] Yield of isolated product. [b] Determined by analysis of 1H NMR spectra of
unpurified mixtures. [c] Determined by analysis of HPLC spectra. [d] Not
available. [e] Performed in the absence of MeOH. [f] Performed in the absence
of MeOH and DABCO. [g] The reaction was conducted at a concentration of 0.2
M in the presence of 7.5 mol % Co(OAc)2 and 7.5 mol % 4h without the addition
of MeOH and DABCO.
groups
delivered
lower diastereoselectivity but high
enantioselectivity due to the diminished size difference of the two
alkyl groups (3u), whereas the cyclopropene bearing a cyclohexyl
2
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10.1002/anie.202012122
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COMMUNICATION
and methyl group can be transformed to the desired product in
70% yield with 92:8 dr and 92:8 er.
The commercially available ester-containing cyclopropanol is a
challenging substrate, as the strong electron-withdrawing ester
group of the resulting Co homoenolate weakened the
coordination of the ketone carbonyl to the Co center, leading to
lower reactivity of the Co homoenolate. As shown in Scheme 4,
further modification of the reaction conditions indicated that the
addition of 20 mol % DABCO and 15 equivalents of MeOH is
necessary to achieve optimal efficiency and enantioselectivity
(see Supporting Information for more details). Increasing the
catalyst loading didn’t provide any improvement, as the catalyst
decomposed faster when the reaction concentration was over
0.05 M. We next explored the scope of the Co homoenolate
derived from cyclopropanol 2b. A variety of cyclopropenes are
suitable substrates (6b–l). The efficiencies are generally lower
than those of reactions with aryl- and alkenyl-substituted
cyclopropanols (36–59% yield) without erosion of the
enantioselectivity (86:14–98:2 er). The resulting enantioenriched
cyclopropane-containing a-ketoesters could be important
precursors for chiral a-hydroxy- and a-aminoesters that are
widely used in the synthesis of biologically active molecules.[29]
Reactions of a wide range of easily accessible cyclopropanols
bearing electron-deficient (5b–f, 5i), electron-rich aryls (5a, 5g,
5j) and heteroaryls (5k–n) proceeded in high efficiency and
stereoselectivity. Transformations of cyclopropanols that contain
sterically demanding aryl groups (5h) and alkyl groups (5o–p)
furnished the desired products with lower enantioselectivity.
Cyclopropanols substituted with alkenyl groups, a class of
substrates that have never been investigated in previous catalytic
enantioselective protocols, reacted in 85–96% with 91:9–94:6 er
as
a
single diastereomer, affording the multisubstituted
cyclopropanes containing a a,b-unsaturated ketone moiety that
can be further functionalized to construct remote stereogenic
centers.[28]
O
O
O
O
Br
OMe
CF3
F
Cl Ph Me
Ph
Ph
Ph
Me
Me
Me
5d
93% yield
5a
97% yield
5b
97% yield
5c
99% yield
>95:5 dr, 94:6 er
>95:5 dr, 90.5:9.5 er
>95:5 dr, 94:6 er
>95:5 dr, 95:5 er
O
Me
O
O
O
Cl
OMe
OH
Ph
O
OH
Ph
10 mol % (R)-CBS
2.0 equiv BH3ꢀꢁꢂꢃ
THF, 23 oC, 12 h
10 mol % (S)-CBS
2.0 equiv BH3ꢀꢁꢂꢃ
THF, 23 oC, 12 h
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
5h
5e
91% yield
5f
5g
95% yield
59% yield
>95:5 dr, 82:18 er
95% yield
>95:5 dr, 93:7 er
>95:5 dr, 93:7 er
>95:5 dr, 95.5:4.5 er
Ph
Ph
Ph
Me
Me
Me
7
3a
95:5 er
8
O
O
O
F
O
98% yield, 4:1 dr, >99:1 er
99% yield, 9:1 dr, >99:1 er
O
OMe
O
O
O
Ph
Ph
Ph
Ph
Me
Me
Me
Me
5.0 equiv m-CPBA, 1.0 equiv TFA
5l[a]
O
5k
89% yield
>95:5 dr, 91.5:8.5 er
5i
79% yield
>95:5 dr, 92.5:7.5 er
5j
CH2Cl2, 22 oC, 60 h
92% yield
>95:5 dr, 95:5 er
91% yield
OMe
Ph
Ph
Me
Me
>95:5 dr, 92:8 er
O
5a
9
O
O
90.5:9.5 er
73% yield, 90.5:9.5 er
S
O
Ph
O
8.0 equiv 1.0 M NaOH (aq)
THF/H2O (1:1), 0 oC, 0.5 h
OMe
NHBoc
4.0 equiv (PhO)2PON3
S
OH
Ph
Ph
O
Ph
Me
Me
Me
then 10 equiv H2O2
22 oC, 6 h
1.0 equiv Et3N, t-BuOH
5m
5n
5o
81% yield
>95:5 dr, 73:27 er
O
81% yield
91% yield
Ph Me
reflux, 24 h
Ph Me
11
Me
Ph
6a
98:2 er
10
99% yield
>95:5 dr,98:2 er
>95:5 dr, 93:7 er
O
>95:5 dr, 92:8 er
89% yield
>95:5 dr, 98:2 er
O
O
Ph
Cy
n-Pr
TMS
O
O
5.0 mol % Cp2TiCl2, 2.5 equiv Zn
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
5.0 equiv Et3N•HCl, CH2Cl2, 22 oC, 6 h
5p[b]
5q
5r
5s
86% yield
>95:5 dr, 91:9 er
94% yield
>95:5 dr, 92:8 er
85% yield
>95:5 dr, 93:7 er
Ph
93% yield
Ph
Me
Me
5o
5p
94:6 er
>95:5 dr, 94:6 er
73% yield
94:6 er
O
O
OMe
Ph
Me
CF3
Ph
Me
5t
96% yield
>95:5 dr, 92:8 er
Scheme 5. Functionalization.
5u
95% yield
>95:5 dr, 92:8 er
Scheme 3. Scope of cyclopropanols. [a] The reaction was performed at 25 oC.
[b] The reaction time was 20 h.
The
assortment of enantioenriched
multisubstituted
cyclopropanes can be functionalized in a number of ways to
deliver valuable and otherwise difficult-to-access building blocks
(Scheme 5). Treatment of 3a with (R)-CBS or (S)-CBS in the
presence of 2.0 equivalents of BH3•THF furnished the
diastereomer 7 in 98% yield with 4:1 dr or the other diastereomer
8 in 99% yield with 9:1 dr as a single enantiomer.[30] Baeyer-
Villiger oxidation of 5a selectively cleaved the carbonyl–aryl bond,
O
O
5.0 mol % (S,S)-4h, 5.0 mol % Co(OAc)2
20 mol % DABCO
Ph Me
OH
OMe
MeO
+
O
15 equiv MeOH, MeCN (0.05 M)
40 oC, 12 h
Me
Ph
6a
48% yield
>95:5 dr, 98:2 er
1a
2b
(1.5 equiv)
O
O
O
O
OMe
OMe
OMe
OMe
O
O
O
O
Me
Me
Me
Me
F3
C
affording the ester
9 in 73% yield without erosion of
6c
40% yield
>95:5 dr, 98:2 er
6b
52% yield
>95:5 dr, 94:6 er F3
6d
48% yield
>95:5 dr, 95:5 er
6e
43% yield
>95:5 dr, 95ꢀꢁ:4.5 er
enantioselectivity.[31] The a-ketoester 6a can be decarboxylated
to generate carboxylic acid 10 in 99% yield,[32] which underwent
subsequent Curtius rearrangement to deliver 11 in 89% yield with
98:2 er.[33] The enantioenriched cyclopropane 5p bearing a,b-
unsaturated ketone moiety can be reduced efficiently, addressing
the low enantioselectivity of reactions with alkyl-substituted
cyclopropanols.[34]
C
Br
MeO
O
O
O
O
OMe
OMe
OMe
OMe
Me
O
O
O
O
S
Me
Me
Me
Me
6f
52% yield
>95:5 dr, 95:5 er
6g
59% yield
>95:5 dr, 86:14 er
6h
45% yield
>95:5 dr, 98:2 er
6i
42% yield
>95:5 dr, 95:5 er
S
O
O
O
OMe
OMe
OMe
O
O
O
Me
Et
Ph
6j
36% yield
>95:5 dr, 96:4 er
6k
48% yield
95:5 dr, 91.5:8.5 er
6l
41% yield
>95:5 dr, 93:7 er
O
To gain some preliminary insight into the reaction mechanism,
a series of experiments were performed. Similar with our
hydroalkenylation system, a single diastereomer 3x was obtained
with the deuterium-labeled substrate 1a-D, suggesting that the
addition of the Co homoenolate to the cyclopropane proceeded in
a syn-fashion, and no racemerization of the resulting Co–C bond
Scheme 4. Scope of reactions with the ester-containing cyclopropanol.
3
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10.1002/anie.202012122
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COMMUNICATION
was observed during the protonation process (Scheme 6a).
Treatment of 1a with 1:1 mixture of deuterium-labelled (2c-D) and
non-isotope-labelled (2c) cyclopropanols delivered the addition
products with 22% D incorporation at the cyclopropane ring
(Scheme 6b), indicating that the proton transfer process might be
the rate-determining step (II®III or VII®3a, Scheme 6c).
Unexpectedly, we found that 10% deuterium was also
incorporated at ketone a-position. Control experiments revealed
that the addition product 5a cannot undergo enolization followed
by protonation to introduce deuterium, whereas enolization of the
Co homoenolate intermediate IV might occur under the reaction
conditions. Based on all the observations, the proposed catalytic
cycle is shown in Scheme 6c. The acetate that coordinated at Co
center underwent intramolecular deprotonation followed by b-C–
C bond cleavage to generate the Co homoenolate IV, which
added to the cyclopropene and protonated with HOAc to furnish
3a and regenerated the catalyst I.
Acknowledgements ((optional))
This work was financially supported by Strategic Priority
Research Program of the Chinese Academy of Sciences (Grant
No. XDB20000000), National Natural Science Foundation of
China (Grant No. 21702222, 21821002), Shanghai Rising-Star
Program (Grant No. 19QA1411000) and the Science and
Technology Commission of Shanghai Municipality (Grant No.
17JC1401200).
Keywords: cobalt • cyclopropanes • enantioselective catalysis•
hydroalkylation • small ring
[1]
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Angew. Chem. Int. Ed. 2014, 53, 5504–5523; Angew. Chem. 2014, 126,
5608–5628; b) D. T.-K. Chen, R. H. Pouwer, J.-A. Richard, Chem. Soc.
Rev. 2012, 41, 4631–4632; c) P. Tang, Y. Qin, Synthesis 2012, 44,
2969–2984; d) L. A. Wessjohann, W. Brandt, T. Thiemann, Chem. Rev.
2003, 103, 1625–1648.
O
7.5 mol % Co(OAc)2
7.5 mol % 4h
D D
(a)
Ph Me
H
Ph OH
Ph
+
MeCN (0.2 M), 10 oC, 12 h
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D
D
Ph
Me
1a-D
2a
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(1.5 equiv)
88% yield
>95:5 dr, 95:5 er
O
(b)
MeO
MeO
22% D
D/H
OH
OD
7.5 mol % Co(OAc)2
7.5 mol % 4h
2c
(0.5 equiv)
2c-D
(0.5 equiv)
H/D
OMe
Ph
Me
MeCN (0.2 M), 23 oC, 40 min
10% D
Ph Me
5a
30% conv., 28% yield
1a
O
O
7.5 mol % Co(OAc)2, 7.5 mol % 4h
MeCN (0.2 M), 23 oC, 12 h
20 mol % CD3CO2D, 2.5 equiv 2c-D
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OMe
Ph
Me
OMe
Ph
MeO
Me
5a
5a
>95% recovery, <5% D incorporation
O
5.0 mol % Co(OAc)2, 5.0 mol % 4h
OD
8% D
H/D
MeCN (0.3 M), 23 oC, 12 h
H/D
MeO
44% D
2c-D
12
11% yield
(c)
Proposed Catalytic Cycle
3a
P
P
Co
HOAc
[3]
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IV
Scheme 6. Preliminary mechanistic studies.
In conclusion, we have developed the first example of a Co-
catalyzed diastereo- and enantioselective hydroalkylation of
cyclopropenes via Co homoenolate intermediates generated from
ring-opening of a wide range of easily accessible cyclopropanols.
A high diversity of enantioenriched cyclopropanes can be
prepared through this highly efficient, stereoselective, and atom-
economical approach, promoted by an earth-abundant metal salt
and a commercially available chiral ligand. Further mechanistic
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studies
and
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hydrofunctionalization
of
cyclopropenes are underway.
4
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5
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Entry for the Table of Contents
Insert graphic for Table of Contents here. ((Please ensure your graphic is in one of following formats))
O
O
Ph
7.5 mol % Co(OAc)2
7.5 mol % (R,R)-Et-DUPHOS
R2 R1
OMe
OMe
Ph
Ph
Me
Me
Ph
MeCN, 10 oC, 12 h
O
O
R1 = aryl, alkyl
R2 = alkyl
G
OH
TMS
O
G = aryl, alkenyl, alkyl, ester
Ph
Me
Me
commercially available
or easily accessible
57 examples
up to 99% yield, >95:5 dr, 98:2 er
A new approach for highly atom-economical, efficient, diastereo- and enantioselective hydroalkylation of cyclopropenes promoted by
an easily accessible Co complex was developed. This protocol represents the first example of introduction of a wide range of Co
homoenolates generated from ring-opening of cyclopropanols to the cyclopropanes.
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