Merging allylic carbon-hydrogen and selective carbon-carbon bond activation

Article abstract of DOI:10.1038/nature12761

Since the nineteenth century, many synthetic organic chemists have focused on developing new strategies to regio-, diastereo-and enantioselectively build carbon-carbon and carbon-heteroatom bonds in a predictable and efficient manner. Ideal syntheses should use the least number of synthetic steps, with few or no functional group transformations and by-products, and maximum atom efficiency. One potentially attractive method for the synthesis of molecular skeletons that are difficult to prepare would be through the selective activation of C-H and C-C bonds, instead of the conventional construction of new C-C bonds. Here we present an approach that exploits the multifold reactivity of easily accessible substrates with a single organometallic species to furnish complex molecular scaffolds through the merging of otherwise difficult transformations: allylic C-H and selective C-C bond activations. The resulting bifunctional nucleophilic species, all of which have an all-carbon quaternary stereogenic centre, can then be selectively derivatized by the addition of two different electrophiles to obtain more complex molecular architecture from these easily available starting materials.

Full text of DOI:10.1038/nature12761

LETTER
doi:10.1038/nature12761
Merging allylic carbon–hydrogen and selective
carbon–carbon bond activation
Ahmad Masarwa1, Dorian Didier1, Tamar Zabrodski1, Marvin Schinkel2, Lutz Ackermann2 & Ilan Marek1
Since the nineteenth century, many synthetic organic chemists have 3. Then selective reactions with two different electrophiles would func-
focused on developing new strategies to regio-, diastereo- and enan-
tioselectively build carbon–carbon and carbon–heteroatom bonds
in a predictable and efficient manner1–3. Ideal syntheses should use
the least number of synthetic steps, with few or no functional group
transformations and by-products, and maximum atom efficiency.
One potentially attractive method for the synthesis of molecular
skeletons that are difficult to prepare would be through the selective
activation of C–H and C–C bonds4–8, instead of the conventional
construction of new C–C bonds. Here we present an approach that
exploits the multifold reactivity of easily accessible substrates9 with
a single organometallic species to furnish complex molecular scaf-
folds through the merging of otherwise difficult transformations:
allylic C–H and selective C–C bond activations10–12. The resulting
bifunctional nucleophilic species, all of which have an all-carbon
quaternary stereogenic centre, can then be selectively derivatized by
the addition of two different electrophiles to obtain more complex
molecular architecture from these easily available starting materials.
The direct transformation of C–H bonds into C–C and C–heteroatom
bonds by means of C–H activation4 has had an enormous impact on
advancing the field of chemical synthesis, because it led to the design of
novel, selective, economic and efficient processes for the utilization of
hydrocarbons5,6. Carbon–carbon bond activation by soluble metal
complexes, an alternativestrategy, is based on either oxidativeaddition
or b-carbon and radical cleavage7. The former approach, requiring the
introduction of pincer-type ligands, has expanded the field by bringing
the metal centre close to the otherwise ‘hidden’ C–C bond through
intramolecular chelation8. However, this system puts some limitations
on synthesis and, except for hydrogenation and the silylation of unac-
tivated C–C bonds7, no other applications were described. The latter
approach relies on strained substrates that do not require such pre-
coordination, but the selectivity of the C–C bond activation remains a
major problem when C–C bonds are differentially substituted9.
Selective C–H bond activation and selective C–C bond activation
are cutting-edge methods that, in combination, may be ideal for acces-
sing complex molecular architectures. Indeed, the ability to design the
preparation of complex molecular skeletons through a succession of
allylic C–H and selective C–C bond activations would pave the way for
new directions in organic synthesis10–12. Unifying these two independ-
ent strategies into a single approach would necessitate perfect control
of both modes of activation. Here we describe the development and
tionalize 3 into the linear adduct 4, which possesses new stereogenic
centres including the original all-carbon quaternary stereocentre (path A;
Fig. 1a). Alternatively, v-ene-cyclopropanes possessing a leaving group 5,
treated under the same conditions, would undergo the allylic C–H
activation followed by a selective C–C fragmentation to lead to non-
conjugated dienes 6 (path B; Fig. 1b).
This approach would require the use of a single organometallic species
that could mediate a combination of allylic C–H activation, selective
C–C bond activation and selective functionalization with two different
a
Path A
Selective
C–C bond activation
R1
R2
R3
n
1
Allylic C–H bond
activation
[M]
R3
(1) E1–X
(2) E2–X
n
[M]
R1
R2
R3
E2
E1
n
R1
R2
3
4
[M]
Selective
C–C bond activation
R1
R2
R3
n
2
Allylic C–H bond
activation
b
Path B
Elimination
OMe
Selective
C–C fragmentation
(1) [M]
R1
R2
R3
n – 1
(2) H3O+
R3
n
R1 R2
5
6
Allylic C–H bond
activation
Figure 1
|
General approach combining allylic C–H and selective C–C
bond activation towards functionalized adducts. a, On path A, v-ene-
cyclopropanes 1 undergoa metal-mediated allylic C–H activation followed by a
study of reactions in which the challenges of selective C–H bond activa- selective C–C bond activation to lead to bismetalated species 3. Because the
reactivity of an allylmetal species to electrophiles is higher than that of
the alkylmetal species, the first electrophile (E1–X) reacts selectively to
functionalize the c-carbon whereas the second electrophile (E2–X) reacts with
the remaining sp3 organometallic species to give the functionalized acyclic
adduct 4. When alkylidenecyclopropane species 2 are used, the chemistry
proceeds similarly and 4 is formed. b, Alternatively (on path B), when
v-ene-cyclopropane 5 is used, the sequence goes through the combined allylic
C–H activation/selective C–C bond cleavage promoted by an elimination
reaction to give the non-conjugated dienes 6 possessing the all-carbon
quaternary stereocentre. Me, methyl.
tion and selective C–C bond activation are overcome, demonstrating
the efficacy of a synthetic approach that could be converted to the pre-
paration of all-carbon quaternary stereogenic centres in acyclic sys-
tems. We predicted that a direct and expedient approach to such
complex molecular frameworks containing several stereogenic centres
in acyclic systems could result from either v-ene-cyclopropanes 1 or
alkylidenecyclopropanes 2. Ideally, it could proceed through a series of
allylic C–H activations (‘metal-walk’ reactions) followed by a selective
C–C bond activation of the three-membered ring to give intermediate
1The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, Technion-Israel Institute of Technology,
Haifa 32000, Israel. 2Institut Fu¨r Organische und Biomolekulare Chemie, Georg-August-Universita¨t, Go¨ttingen, Tammannstrasse 2, 37077 Go¨ttingen, Germany.
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RESEARCH LETTER
electrophiles. Our solution to this salient problem is based on the Zr-walk of substituents on the cyclopropyl unit furnishes a highly selective C–C
chemistry we developed for the transformation of simple v-unsaturated bond activation21.
fatty alcohols13 and v-non-conjugated enol ether derivatives14 into
Importantly, even if our hypotheses regarding selective bond activa-
tion were correct, the synthetic problem would not yet be fully solved,
allyl- and dienylzirconocene derivatives, respectively15. Recently, a
related enantioselective Heck-type arylation of alkenyl alcohols using
a Pd walk as a redox-relay strategy was reported16,17
because it is necessary to differentiate the reactivity of the two C–metal
bonds in 3a (or 3b) with two different electrophiles. It occurred to us
.
Our mechanistic rationale was to transform the model v-alkenyl that in 3a (or 3b), the allylzirconocene moiety [C2–Zr] might be signi-
cyclopropane species 1a by means of a zirconocene-mediated migra- ficantly more reactive than the alkylzirconocene moiety [C3–Zr] (ref. 22).
tion of the double bondwith the Negishi reagent18. Indeed, C4H8ZrCp2 Therefore, the addition of the first electrophile should selectively react
would react with the remote double bond of 1a to give the correspond- to give 10 via a SE29reaction, and 10 will then go on to react with a second
ing zirconacyclopropane, 7. Then, through an allylic C–H bond activa- electrophile to form 4 (Fig. 2). On addition of the Negishi reagent to 1a
tion, the g3-allyl intermediate 8 would be generated as a transient (n 5 1) and subsequent hydrolysis, we isolated 4a as the E-isomer in
species and, after hydride insertion, would give rise to the new zirco- excellent yield after hydrolysis (Fig. 2). When D2O was added at the
nacyclopropane, 9, possessing a C–Zr bond in the b-position of the end of the sequence, the bisdeuterated compound 4a(D) was similarly
three-member ring19,20 (Fig. 2). When 9 is formed, an irreversible C–C afforded with an exclusive introduction of deuterium both at the allylic
bond activation proceeding through ring cleavage should take place. If and primary alkyl positions. This tandem allylic C–H activation/selective
the C–C bond activation occurs through the C2–C3 bond, a primary C–C activation was not limited to v-ene-cyclopropanes with a one-carbon
acyclic organometallic species, 3a, could be obtained. Alternatively, tether. Compounds 1b–1d (with respective carbon tethers n 5 2, 3 and
ring opening through the activation of the C1–C2 bond (not shown 6) also underwent this transformation via an initial migration of the
in Fig. 2), would result in an unfavourable trisubstituted organomet- zirconocene through the alkyl chain with formation of 4b–4d in good
allic species. On the assumption that primary organometallic species yields23. This reaction sequence always led to a selective C–C activation
are kinetically and thermodynamically more stable than tertiary of the 1,1-disubstituted v-ene-cyclopropanes 4a–4e (R1, R2 5 alkyl or
organometallic species9, we anticipate an exclusive formation of the aryl) because it led to the preferential formation of a primary alkyl-
constitutional isomer3ain theactivation reaction. Hence, thepresence zirconacyclobutane over a tertiary alkyl-zirconacyclobutane. Because
E1
(1) Cp2ZrC4H8, Et2O
R1
–78 °C to RT, 12 h
CH3
n – 1
E2
(2) E1–X
n
R2
R1
R2
(3) E2–X
1a–1h
4a–4i
E/Z > 99:1
then H3O+
Mechanistic hypothesis for the transformation of 1a (n = 1) into 4
Allylic
C–H bond
activation
Cp2ZrC4H8, Et2O
–78 °C to RT, 12 h
3
R1
R2
R1
R2
R1
R2
R1
R2
[Zr]
1
2
CH3
[Zr]
Et
1a
n = 1
H H
[Zr]
H
9
8
7
[Zr] = Cp2Zr
+
Selective
C2–C3 bond
activation
3
3
[Zr]
[Zr]
R1
R1
E1–X
X[Zr]
E2–X
E1
1
2
E2
E1
1
2
R2
R2
R1 R2
R1
R2
4
3a
3b
10
Representative examples
D
Me
Et
Pr
Hex
D
Me
Ph Ph
4a, 71%
Ph Ph
4b, 58%
Ph Ph
Ph Ph
Ph Ph
4a(D), 71%
n = 1
4c, 61%
n = 3
4d, 55%
n = 6
n = 1
n = 2
E1 = E2 = D
E1 = E2 = H
E1 = E2 = H
E1 = E2 = H
E1 = E2 = H
Me
Hex
Me
Me
Me
Me
HO Me
4i, 55%
Me
Me
I
Me
Bu Bu
HO Me
Ph Ph
Ph Me
Bu Bu
HO Me
Ph Ph
4f, 56%
n = 1
E1 = Me2CO, E2 = H
HO Me
4e, 85%
n = 1
4g, 75%
n = 1
4h, 53%
n = 1
n = 6
E1 = E2 = H
E1 = Me2CO, E2 = H
E1 = Me2CO, E2 = I2
E1 = Me2CO, E2 = H
Figure 2
|
Zirconocene-promoted allylic C–H and C–C bond activation of
allyl-bismetalated organozirconocene derivative 3a, which may be represented
as its s-allylic zirconocene 3b. Because the C2–Zr fragment is more reactive to
electrophiles than is the C3–Zr fragment, the addition of the first electrophile
reacts selectively at room temperature (RT 5 25 uC) with the allylzirconocene
moiety. Also shown are representative examples of the scope of the combined
allylic C–H activation, selective activation and bisfunctionalization of the
resulting organozirconocene species en route to acyclic fragments. Bu, butyl;
v-ene-cyclopropanes. C4H8ZrCp2 reacts with the remote double bond of
1a to give 7 and free butene. Then, through an allylic C–H bond activation,
the g3-allyl intermediate 8 is generated and, after hydride insertion,
zirconacyclopropane 9 is formed. Then an irreversible step occurs
transforming the zirconacyclopropane 9 into allyl-alkyl zirconocene species
3a or 3b. From the two possible C–C bonds that could be activated (C1–C2
versus C2–C3 in 9), only the C2–C3 bond is cleaved, leading to the primary and Et, ethyl; Hex, hexane.
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LETTER RESEARCH
the allylic [C2–Zr] bond is more reactive to electrophiles than is the
When ACP 2a is treated with the Negishi reagent, the zirconocene-
primary alkyl-[C3–Zr] bond, the addition of a carbonyl electrophile mediated allylic C–D bond activation releases the initial strain of the
(E1–X 5 MeCOMe) selectively functionalizes the allylmetal fragment, alkylidenecyclopropane system to furnish zirconacyclopropane 9d3. It
whereas the second electrophile (E2–X 5 H3O1, I2) reacts with the then undergoes a cyclopropane C–C bond activation to give zircona-
remaining alkylzirconocene species to give 4f–4i as E-isomers in good cyclobutane 3d3, which is functionalized selectively at the allylic posi-
yields.
This multifold functionalization of a single molecule was also suc-
tion to give 4j in 82% yield by addition of acetaldehyde. In all cases, the
combined allylic C–H bond activation followed by the selective C2–C3
bond activation of alkylidenecyclopropane proceeded smoothly and
only the linear products 4k–4w were formed with no traces of activa-
tion along the C1–C2 bond, even though the activation could have
otherwise occurred at the benzylic position (that is, 4l and 4n).
Because enantiomerically enriched alkylidenecyclopropanes can
cessfully applied to alkylidenecyclopropane derivatives (ACPs) 2 to
furnish linear adducts 4. Alkylidenecyclopropanes are highly reactive
substrates, often giving rise to complex mixtures of products, and
development of mild and selective transformations for this class of
compounds is very useful9,24. In this context, the Zr walk could lead
to particularly interesting transformations of ACPs (Fig. 3). To further easily be prepared25,26, and because the chiral quaternary centre is at no
our mechanistic understanding, we used CD3-labelled ACP 2a as a risk of racemization in the process, the optical purity canbe assumed to
substrate. The migration of a deuterium atom into the vinylic position be identical throughout the rest of the synthesis. Indeed, when enan-
in the product 4j corroborated our hypothesis of allylic C–H activation tiomerically enriched 2b (R1 5 Bu, R2 5 Et, R3 5 H; enantiomeric
(Fig. 3), as follows.
ratio, 98:2) was treated with the Negishi reagent, 4k was obtained with
R3
(1) Cp2ZrC4H8, Et2O
–78 °C to RT, 12 h
R1
R2
E2
E1
(2) E1–X
R3
R1 R2
4j–4w
E/Z > 99:1
(3) E2–X
then H3O+
2a–2j
Mechanistic probe for the transformation of 2a into 4j
Allylic
D
C–H bond
activation
(1) Cp2ZrC4H8, Et2O
–78 °C to RT, 12 h
[Zr]
D
Me
Bu
Me
Bu
Me
Bu
[Zr]
CD
CD2
3
CD2
[Zr] = Cp2Zr
2a
Me
(2) CH3CHO
(3) H3O+
D
D
2
D
D
3
[Zr]
D
1
Bu
9d3
Me
Bu
D
H3C
3
1
2
D
Me Bu
[Zr]
OH
3d3
4j
82%
D
D
Representative examples
D
Me
H3C
Me Bu
(CH2)2Ph H3C
Me Ph
(CH2)2Ph
H3C
Bu Et
H3C
Ph Et
Et
DH2C
Me Et
4o, 90%
CH-CH2Ph
4k, 84%
E1 = E2 = H
ER = 98:2
4m, 92%
4n, 93%
4l, 92%
E1 = E2 = H
E1 = E2 = H
Bn
E1 = E2 = H
E1 = E2 = D
Bn
H3C
Me Et
OH
H3C
Me Et
OH
H3C
OH
I-H2C
OH
Me Ph
Me CH Ph
2
4p, 90%
4q, 90%
4r, 92%
4s, 72%
E1 = CH2O, E2 = H
E1 = CH3CHO, E2 = H
E1 = CH3COCH3, E2 = H
E1 = CH3COCH3, E2 = I2
Me
Me
Me
Me
H3C
OH
H3C
Ph Pr
4u, 62%
OH
I-H2C
Ph Pr
4v, 62%
OH
H3C
OH
Ph Pr
Ph Et
4t, 77%
4w, 68%
DR = 98:2
DR = 98:2
DR = 97:3
DR = 96:4
E1 = CH3COCH3, E2 = H
E1 = CH2O, E2 = H
E1 = CH3COCH3, E2 = I2
E1 = CH3COCH3, E2 = H
R1
R2
[Zr]
R3
Isomerization
A
Figure 3
|
Zirconocene-promoted allylic C–H and C–C bond activation of
carbonyl derivatives as first electrophiles to generate a new stereogenic centre at
a remote position with very high diastereoselectivity before addition of the
alkylidenecyclopropanes. When alkylidenecyclopropane 2a is treated with
C4H8ZrCp2, an allylic C–H activation reaction occurs to give the intermediate second electrophiles. If the reaction is performed without heating before the
9, which undergoes a selective C–C bond activation leading to the intermediate addition of the first electrophile, two diastereomers are obtained in a 3:1 ratio.
3 (Fig. 2). A mechanistic probe and representative examples of substrate scope Therefore, we proposed that the heating allows the isomerization of the
for the reaction of alkylidenecyclopropanes with Cp2ZrC4H8 are shown. We
substitutedallyl fragment into the E-isomer (A). Bn, PhCH2; DR, diastereomeric
note that intermediate 3 reacts, after heating at 60 uC in THF, with various
ratio; ER, enantiomeric ratio.
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OMe
Cp2ZrC4H8, Et2O
–78 °C to RT, 12 h
then AcOH
R1
R2
H
n
R1 R2
n
6a–6g
5a–5g
Mechanistic hypothesis for the transformation of 5a into 6a(D)
Ac
OMe
OMe
OMe
O
[Zr]
D
AcOD
–80 °C
Cp2ZrC4H8, Et2O
–78 °C to RT, 12 h
D
BnO(CH2)2
Me
BnO(CH )
2 2
[Zr]
[Zr] = Cp2Zr
BnO(CH2)2
Fragmentation
BnO(CH2)2
Me
Me
Me
5a
11
12
6a(D)
Allylic
C–H bond activation
Acetolysis
74%
E/Z > 19:1
Representative examples
BnO(CH2)2
Me
Bu Me
Pr Me
Hex Ph
6a, 78%
6b, 63%
6c, 67%
66d, 78%
n = 1
n = 1
n = 1
n = 1
E/Z = 19:1
E/Z > 19:1
E/Z = 19:1
E/Z = 9:1
Pr
Me
Et
PhCH2 Me
Hex Me
6e, 73%
6f, 74%
6g, 62%
n = 1
n = 1
n = 3
E/Z > 19:1
E/Z > 19:1
E/Z = 41:9
Figure 4
|
Merging allylic C–H activation and fragmentation en route to
non-conjugated diene 6 with an excellent E/Z selectivity. After the allylic C–H
activation, the zirconacyclopropane 11 undergoes a fragmentation reaction to
lead to the allylzirconocene species 12. Acetolysis leads to non-conjugated
dienes 6 possessing the all-carbon quaternary stereocentres. Ac, acetyl.
non-conjugated dienes. C4H8ZrCp2 reacts with the remote double bond of
v-ene-cyclopropane methyl ether 5 to induce an allylic C–H activation
followed by a fragmentation of the three-membered ring. The resulting
allylzirconocene, 12, reacts selectively with AcOH to give only the
the same enantiomeric ratio (98:2). Regardless of the E/Z ratio of the reagent, dienes 6a–6g were obtained in good yields and with excellent
starting ACPs, 2, only the E-isomer was formed in the opened adducts E/Z ratios after hydrolysis. Mechanistically, the allylic C–H activation
(E/Z . 98:2). When an excess of D3O1 was added to the ring-opened
leads to zirconacyclopropane 11, which undergoes fragmentation to
product resulting from the treatment of alkylidenecyclopropane 2e
(R1 5 Me, R2 5 Et, R3 5 CH2Ph) with the Negishi reagent, 4o was
isolated in 90% yield with a quantitative incorporation of deuterium
at the allylic and terminal methyl positions. Consistent with our pre-
vious results in which the allylzirconocene [C2–Zr] is more reactive to
electrophiles than is alkylzirconocene [C3–Zr], the addition of a first
electrophile (E1–X 5 HCHO) led to selective functionalization of the
allyl fragment that was then hydrolysed under acidic work-up to give
alcohol 4p in 90% yield (Fig. 3). This selective reactivity of the first
electrophile can be extended to other aldehydes and ketones without
altering the yield of the overall transformation (that is, 4q and 4r,
respectively). The remaining primary organozirconocene species can
then be trapped by a second electrophile (E2X 5 I2) to give the bifunc-
tionalized adduct 4s.
give the allylzirconocene species 12. Owing to the potential steric
interactions between the zirconocene and the quaternary stereocentre,
we proposed that only the isomer 12 would be present, with no evid-
ence for metalotropic equilibrium, under its s-bond form. Hence, 12
reacted with deuterated acetic acid at low temperature, by means of an
SE29 reaction, to give 6a(D) with an excellent positional selectivity.
This sequence was then applied to several other differentially substi-
tuted cyclopropanes, 5a–5f, to give non-conjugated dienes in all cases.
This reaction is not restricted to the one-carbon tether; for example,
6g, which has a three-carbon tether (n 5 3), was also obtained in good
yields. Because enantiomerically enriched cyclopropenyl esters can be
easily prepared27, the formation of non-conjugated dienes possessing
an all-carbon quaternary stereocentre is therefore possible through
this combined sequence of allylic C–H activation-ring fragmentation
(Fig. 4).
We have shown that any cyclopropane species possessing a remote
double bond such as v-ene-cyclopropanes 1 and 5 or alkylidenecyclo-
propanes 2 can be easily transformed into acyclic molecular fragments
possessing two stereogenic centres including the original challenging
all-carbon quaternary stereocentre28–30. This process goes through zir-
conocene-mediated allylic C–H activations followed by highly select-
ive C–C bond activations or fragmentations. Owing to the presence of
the quaternary centre, the resulting bifunctional nucleophilic species
are further derivatized with two different electrophiles to give more
complex molecular architectures arising from simple starting materials.
Overall, this work emphasizes the feasibility of synthetic approaches to
exploit the multifold reactivity of a single substrate to furnish advanced
molecular scaffolds through the combination of transformations that
are otherwise difficult to perform.
Thisstrategy holds potentialforinductionof 1,4-diastereoselectivity
in acyclic systems through the transfer of chiral information from
remote positions. To generate such remote diastereoselectivity, alky-
lidenecyclopropane 2i (R1 5 Ph, R2 5 Pr, R3 5 Me) was treated under
the same conditions with the Negishi reagent and the reaction mixture
was heated to 60 uC in tetrahydrofuran (THF) for a few hours before
addition of the first electrophile (Supplementary Information). In this
case, the open adduct 4t was obtained, after hydrolysis, with a diaster-
eomeric ratio of 98:2 in good isolated yield. Interestingly, without
heating the reaction mixture, a modest 3:1 ratio is obtained and may
be attributed to conformational isomers of the substituted allylzirco-
nocene fragment before reaction with the aldehyde; by heating to
60 uC, the most stable thermodynamically E-isomer is quantitatively
formed (A; Fig. 3). This sequence can be extended to other versatile
acyclic adducts while diastereomeric ratios remain excellent (forma-
tion of 4t–4w). Finally, we applied this combined Zr-walk/C–C bond
fragmentation strategy to v-ene-cyclopropanes that possess a stra-
tegically placed leaving group on the cyclopropane ring (Fig. 4).
When cyclopropanes 5a–5g, which are easily prepared by carbometa-
METHODS SUMMARY
To a solution of zirconocene dichloride (496.5 mg, 1.70 mmol) in THF (45 ml) cooled
to 278 uC was added dropwise n-BuLi (1.40 M in hexane, 2.4ml, 3.4 mmol). The
lation reaction of cyclopropenyl esters27, were treated with the Negishi resulting solution was stirred for 1 h at 278 uC. A solution of alkylidenecyclopropane
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LETTER RESEARCH
18. Negishi, E. & Takahashi, T. Organozirconium compounds in organic synthesis.
Synthesis 1–18 (1988).
19. Harada, S., Kiyono, H., Nishio, R., Taguchi, T. & Hanzawa, Y. Complexation of
vinylcyclopropanes with zirconocene21-butene complex:application to the
stereocontrolled synthesis of steroidal side chains. J. Org. Chem. 62, 3994–4001
(1997).
20. Dimmock, P. W. & Whitby, R. J. Zirconium-mediated ring opening of
cyclopropanes. J. Chem. Soc. Chem. Commun. 2323–2324 (1994).
21. Simaan, S., Goldberg, A. F. G., Rosset, S. & Marek, I. Metal-catalyzed ring-opening
of alkylidenecyclopropanes as a new approach to the preparation of
enantiomerically pure all-carbon quaternary stereocenters. Chem. Eur. J. 16,
774–778 (2010).
2 (1.00 mmol) in THF (5 ml) was added, and the reaction mixture was slowly
warmed to 10 uC. After stirring for 13 h, the reaction was heating to 60 uC for
6 h. After cooling the reaction to 10 uC, carbonyl derivative (4 mmol) was added
at 10 uC and the reaction mixture was stirred for 40 min at the same temperature.
Then the second electrophile (5 mmol) was added and the reaction mixture was
stirred for 3 h. An aqueous solution of HCl (1 M) was then added at 0 uC and after
extraction with Et2O, the organic extracts were washed with water, NaHCO3 and
brine, dried (MgSO4), filtered, and concentrated in vacuo to give a crude oil. The
product 4 was obtained pure by silica-gelchromatographyusing gradientmixtures
of ethyl acetate and n-hexane as eluents.
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Received 22 August; accepted 8 October 2013.
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Acknowledgements This research was supported by the Niedersachsen-Technion
Research Cooperation Program, by the Israel Science Foundation administrated by the
Israel Academy of Sciences and Humanities (140/12) and by the European Research
Council under the EuropeanCommunity’sSeventhFrameworkProgramme (ERCgrant
agreement no. 338912). I.M. is holder of the Sir Michael and Lady Sobell Academic
Chair.
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Author Contributions A.M., D.D., T.Z., M.S., L.A. and I.M. planned, conducted and
analysed experiments. I.M. had the idea for and directed the project, and wrote the
manuscript with contributions from A.M. and D.D. All authors contributed to
discussions.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper. Correspondence
and requests for materials should be addressed to I.M. (chilanm@tx.technion.ac.il).
17. Mei, T.-S., Werner, E. W., Burckle, A. J. & Sigman, M. S. Enantioselective redox-relay
oxidative Heck arylations of acyclic alkenyl alcohols using boronic acids. J. Am.
Chem. Soc. 135, 6830–6833 (2013).
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