A shift in retrosynthetic paradigm

Article abstract of DOI:10.1002/chem.200800580

The current state-of-the-art synthesis for the formation of enantiomerically enriched all-carbon quaternary Stereocenters in acyclic system relies on the formation of a single carbon-carbon bond per chemical step by asymmetric catalysis. These extraordina

Full text of DOI:10.1002/chem.200800580

DOI:10.1002/chem.200800580
A Shift in Retrosynthetic Paradigm
Ilan Marek*[a]
Dedicated to Professor Sason Shaik on the occasion of his 60th birthday
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CONCEPTS
cyclic quaternary all-carbon stereocenters include the Heck
reaction, alkylation, arylation, and Michael addition,[1,2]
whereas for the creation of all-carbon quaternary centers in
non-cyclic system (more complicated due to the number of
degrees of freedom associated with these structures), the
most promising results are either the asymmetric allylic al-
kylations,[3] asymmetric conjugate addition,[4] sigmatropic[5]
and Jung epoxide rearrangements,[6] asymmetric alkylation,[7]
and asymmetric nucleophilic allylation[8] (Scheme 1). The
last route to products with quaternary all-carbon stereocen-
ters—nucleophilic allylation of electrophilic species—results
from a combination of a cationic synthon with an ambident
nucleophile provided that the latter is 1) configurationally
stable (no metallotropic equilibrium) and 2) attacked at the
g-carbon atom (Scheme 1).[8]
Abstract: The current state-of-the-art synthesis for the
formation of enantiomerically enriched all-carbon qua-
ternary stereocenters in acyclic system relies on the for-
À
mation of a single carbon carbon bond per chemical
step by asymmetric catalysis. These extraordinary so-
phisticated methods were logically classified among the
most powerful and innovative ones. In this concept arti-
cle, we are proposing a new retrosynthetic paradigm to
solve differently such challenging problems. These new
synthetic pathways lead to the diastereo- and enantio-
À
merically pure formation of three new carbon carbon
bonds in acyclic system, in a one-pot reaction, including
the formation of all-carbon quaternary stereocenters by
using classical reagents and experimental conditions and
from common starting materials.
Keywords: allylation
·
carbometalation
· synthetic
methods · zinc carbenoids
Introduction
Our field of research, synthetic organic chemistry, has now
reached a situation where major changes are needed. We
would like to illustrate this provocative statement by focus-
ing on one of the major achievements of the last few de-
cades, namely asymmetric synthesis. The development of
new and highly enantioselective processes for the creation
Scheme 1. General methods for the creation of all-carbon quaternary ste-
reocenters in acyclic system.
À
À
of carbon carbon or carbon heteroatom bonds was, and
still is, one of the main problems of chemical synthesis. In
contrast to tertiary stereocenters, where a wide variety of
chiral auxiliaries, reagents and catalysts nowadays form the
basis for modern asymmetric synthesis and are a guarantee
for high selectivity, the construction of a quaternary stereo-
center, that is carbon centers with four different non-hydro-
gen substituents, represents the most challenging and dy-
namic area in organic synthesis and still remains the touch-
stone of every enantioselective procedure.[1] The state-of-
the-art would be the asymmetric construction of quaternary
all-carbon stereocenters (all-carbon substituted excluding
therefore tertiary alcohols, ethers, amines, etc.).[2] To under-
stand why this field needs major changes, we should briefly
review the different synthetic approaches for the construc-
tion of quaternary all-carbon stereocenters. The methods
that have been successfully employed for the formation of
These methods are currently the state-of-the-art in our
field (all by asymmetric catalysis). However, one can easily
À
see that only a single carbon carbon bond is formed in the
reaction sequence between two components. Despite this
obvious lack of efficiency, the synthetic challenge imposed
by the inherent difficulties in the creation of all-carbon qua-
ternary centers in acyclic system led logically the synthetic
community to classify them among the most powerful and
innovative ones. This clearly shows that synthetic organic
chemistry reached nowadays an extraordinary levels of
À
sophistication for the creation of one carbon carbon bond
but the development of more efficient synthetic methodolo-
À
gies (i.e., more than one enantioselective carbon carbon
bond created per reaction), is still in its complete infancy.
Indeed, a seemingly trivial but rather serious limitation in
practice in our field is set by the mere number of chemical
steps accumulating in linear sequences. This challenging
goal of efficiency (step economy) can be achieved only
through the use of reactions that allow a great increase in
complexity or through operations that incorporate many
steps that collectively achieve the same high complexity in-
crease. Therefore, the invention of new reactions, reaction
sequences, reagents or strategies that allow this complexity
increase in a one-pot reaction are critical to the realization
of step economical syntheses. Surprisingly, multicompo-
[a] Prof. I. Marek
Contribution from the 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 32 000 (Israel)
Fax : (+972)4-829-3709
E-mail: chilanm@tx.technion.ac.il
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I. Marek
nent[9] and domino reactions[10] are well known concepts in
organic synthesis but as soon as the synthetic transformation
is getting more challenging, that is, all-carbon quaternary
stereocenters in non-cyclic system, the more classical way of
Then, aldehyde was added followed by bis(iodomethyl)-
zinc carbenoid 11, independently prepared from 1 equiv of
Et2Zn and 2 equiv of CH2I2.[17] Neither the vinylic organo-
copper 10 nor the zinc carbenoid is reactive enough to add
to aldehydes, however, 10 is readily homologated by a meth-
ylene unit with the zinc carbenoid 11. The in situ reactive
chelated allylzinc species 12 reacts diastereoselectively with
aldehydes, to give after hydrolysis the corresponding adducts
13 in good overall yields and in excellent diastereoselectivi-
ties (Scheme 3).[18]
À
creating carbon carbon bonds in chemistry prevail.
Thus, diastereo- and enantioselective reactions that form
À
multiple carbon carbon bonds in acyclic system, including
the formation of all-carbon quaternary stereocenters and in
a one-pot reaction from easily accessible starting materials
are still extremely challenging and therefore rare despite its
exciting promises.
Asymmetric Nucleophilic Allylation
To illustrate this concept, we initially concentrated our ef-
forts to develop a new route to enantiomerically pure homo-
allylic alcohols 3 in a one-pot reaction possessing this all-
carbon quaternary stereocenters from common starting ma-
terials (alkynes). We reasoned that the most convenient
preparation of in situ allyl metal species 2 would be the ho-
mologation reaction of alkenyl compounds such as 1 with
(iodomethyl)zinc.[11] With respect to all-carbon quaternary
stereocenters as in the final product 3, one has to start with
stereodefined b,b-disubstituted alkenylmetal compounds 1,
which may easily come from a controlled carbometalation
reaction of substituted alkynes 4 (Scheme 2).[12]
Scheme 3. One procedure for the preparation of homoallyl alcohol pos-
sessing all-carbon quaternary stereocenters.
As shown in Table 1, entry 1 versus 2, permutation of the
alkyl groups of the alkyne and the organocopper reagent
allows the independent formation of the two isomers at the
quaternary stereocenter, respectively.[18] Even the methyl-
copper, known to be a sluggish group in carbocupration re-
action,[16a] adds cleanly to alkynyl sulfoxide and gives after
the homologation–allylation reactions, the expected homoal-
lylic alcohol as only one isomer (Table 1, entry 3). Aliphatic
aldehydes were also tested in this reaction but the reaction
was found to be more difficult to control. Although the dia-
stereoselectivity was usually excellent (dr 30:1, Table 1, en-
tries 5 and 6), the reaction is more difficult to control and
yields are lower. The combination of the stereoselective car-
bometalation (introduction of the R1 substituent), the zinc
homologation (introduction of the CH2 unit of the allylzinc
fragment), the intramolecular chelation of the zinc atom by
the sulfoxide (which slow down the metalotropic equilibri-
um), the presence of the p-tolyl group (shields one face)
and the 1,3-allylic strain[19] leads to very high diastereoselec-
tivity when the allylzinc reacts with aldehydes (aryl/alkyl
groups occupies a pseudo-equatorial position) in a Zimmer-
man–Traxler chair like transition state (Scheme 4). Although
this new carbometalation–homologation–allylation one-pot
reaction led, with very high diastereoselectivity, to the corre-
sponding homoallylic alcohols 13, the bis(iodomethyl)zinc
carbenoid 11 had to be prepared independently and further
transferred into the reaction mixture at low temperature.
To improve the reaction sequence, an easier, safer and
even more straightforward procedure was developed. The
first step, namely the regio- and stereospecific carbocupra-
Scheme 2. Requisite for the one-pot formation of homoallylic alcohol de-
rivatives.
However, even by following this new retrosynthetic ap-
proach, the potential metalotropic equilibrium of 3,3-disub-
stituted allylzinc species 2 has to be avoided.[13] Therefore,
we thought to 1) increase the stability of the allylic organo-
metallic species in its a-position by an intramolecular chela-
tion of the zinc atom of 5 by an A–B unit and 2) use this A–
B chelating moiety as a source of chirality and as a regio-
control element for the carbocupration reaction of 7.[14] By
combining all of these parameters, alkynyl sulfoxide 8, easily
available in large quantities by the Andersen synthesis,[15]
were designed as potential starting materials (Scheme 3).
The regio- and stereospecific carbocupration of 8 with
organoACHTREUNGcopper derivatives 9 (obtained from 1 equiv of alkyl-
magnesium halide and 1 equiv of copper salt such as CuBr
or CuI), provides the corresponding metalated b,b-dialkylat-
ed ethylenic sulfoxide 10 in quantitative yields
(Scheme 3).[16]
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Retrosynthetic Paradigm
CONCEPTS
Table 1. Formation of homoallyl alcohols.
Table 2. Improved formation of homoallyl alcohols.
[a]
Entry
R1
R2
RCHOdr
Yield[b]
Entry
R1
R2
R3
dr[a]
Yield[b]
1
2
3
4
5
6
Et
Bu
Et
Bu
Et
Et
Et
PhCHO99:1
PhCHO99:1
PhCHO99:1
PhCHO99:1
BuCHO30:1
BuCHO30:1
78
68
66
68
60
58
1
2
3
4
5
6
7
8
Et
Et
Bu
Ph
Ph
Ph
p-ClC6H4
Ph
p-MeOCOC6H4
p-MeOCOC6H4
p-MeCOC6H4
99:1
99:1
99:1
99:1
98:2
96:4
98:2
96:4
81
82
78
70
80
60
60
60
Bu
Me
Me
Bu
Me
Hex
Hex
Bu
Me
Me
Me
Me
Me
Et
Me
Me
Et
[a] Diastereoisomeric ratio determined on crude 1H NMR spectroscopy.
[b] Isolated yield after purification by column chromatography.
Me
9
Et
Bu
99:1
99:1
83
75
10
Me
Me
11
12
Et
Bu
99:1
97:3
70
60
13CH3
Me
Ph
[a] Diastereoisomeric ratio determined on crude 1H NMR spectroscopy.
[b] Isolated yield after purification by column chromatography.
(Table 2, entries 5, 6, 8, 10) an excellent level of 1,4-stereo-
control is obtained (dr 98:2 to 99:1). Finally, even heteroaro-
matic aldehydes can be used as electrophilic partner in this
reaction (Table 2, entries 9–11).[21] An elegant application of
such method is the diastereoselective preparation of quater-
nary stereocenters with the smallest possible difference be-
tween the two alkyl groups. For this purpose, 13CH3MgI,
easily prepared from iodomethane-13C and Mg0, was trans-
formed into its corresponding organocopper reagent
13CH3Cu and added to propynyl sulfoxide 8. To the vinyl
copper 10 was subsequently added Et2Zn, CH2I2 and benzal-
dehyde to give the corresponding product 13 in 60% yield
and 97:3 diastereomeric excess (Table 2, entry 12).[21]
Scheme 4. Rationalization for the diastereoselectivity.
tion of alkynyl sulfoxide 8 with organocopper derivatives
still provides the corresponding metalated b,b-dialkylated
ethylenic sulfoxide 10 in quantitative yields as originally de-
scribed in Scheme 3, but now aldehydes, Et2Zn and CH2I2
are all added to the reaction mixture at À208C (Scheme 5).
This new approach for the allylation reaction can be ulti-
mately further simplified by a four-component reaction. In
this case, one only needs to prepare an alkylcopper deriva-
tive. Indeed, when alkynyl sulfoxide, benzaldehyde, dialkyl-
zinc and CH2I2 are added simultaneously to the organocop-
per species 9, homoallylic alcohols were obtained in excel-
lent yields and diastereoisomeric ratio as described in
Scheme 6.[21] Each of these reagents reacts specifically in the
appropriate order with its specific “partners”, without any
crossover reactions; the organocopper reagent reacts first
and only with alkynyl sulfoxide, R2Zn and CH2I2 form only
zinc carbenoid, and these two later in situ generated nucleo-
philic species give the allylzinc derivatives that subsequently
allylate the benzaldehyde. In all cases, quaternary and terti-
ary stereocenters were created with excellent diastereoselec-
tivities and in good overall yields (Scheme 6).
Scheme 5. Improved one-pot procedure for the formation of homoallyl
alcohols possessing all-carbon quaternary stereocenters.
As discussed previously, neither vinylcopper 10 nor Et2Zn
reacts with aldehydes, and as the transmetalation from vinyl-
copper to vinylzinc is a slow process at À208C, the reaction
between Et2Zn and CH2I2 occurs first to lead to the in situ
formation of the zinc carbenoid 11. This carbenoid readily
homologates the vinylcopper 10 into the allyl species 12,
which reacts diastereoselectively with aldehydes to give the
expected homoallylic alcohols 13 in very high diastereose-
lectivities (Scheme 5). This improved in situ procedure led
to identical diastereoselectivities (Table 2) as compared to
the one previously described (compare entry in Tables 1 and
2) in slightly better yields. Several different alkyl groups
were easily introduced in the carbocupration reaction, which
shows the flexibility of the described method (Table 2).
Functionalized aldehydes can also be used in this allylation
reaction (Table 1, entries 6–8). In these cases, the reaction
proceeds chemoselectively on the aldehyde (no trace of re-
action neither on the ester nor ketone moieties).
Control of the absolute configuration of remote stereo-
centers is also a topic of considerable interest,[20] and when
the quaternary centers possess two identical alkyl groups
Scheme 6. Four-component reaction for the formation of homoallyl alco-
hols possessing all-carbon quaternary stereocenters.
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I. Marek
We initially checked that this four-component reaction
proceeds well with identical alkyl groups such as alkylcop-
per and dialkylzinc (R1 =R3 =Bu) in order to avoid cross-
over experiment. The homoallylic alcohol was isolated in
84% yield and a excellent 94% diastereoisomeric excess for
the remote 1,4-induction (Table 3, entry 1). Evidently, when
reaction can be used for further functionalization; for in-
stance, addition of iodine to give the corresponding vinyl
iodide 15 in 70% yield (Scheme 7).
Table 3. Four-component reaction for the formation of homoallyl alco-
hols.
Entry
R1
R2
R3
dr[a]
Yield[b]
1
2
3
4
5
Bu
Bu
Bu
Et
Bu
Me
Bu
Bu
Me
Bu
Bu
Et
Et
Et
97:3
95:5
98:2
99:1
97:3
84
74
78
80
75
Et
[a] Diastereoisomeric ratio determined on crude 1H NMR spectroscopy.
[b] Isolated yield after purification by column chromatography.
the same reaction was performed on a differently substitut-
ed alkynyl sulfoxide, the reaction proceeded similarly
(Table 3, entry 2). When both alkyl groups of the alkylcop-
per and alkynyl sulfoxide are identical (R1 =R2 =Bu) where-
Scheme 7. Sulfoxide lithium exchange reaction.
as the nature of the alkyl group on the diACHTREaUNG lkylzinc was dif-
ferent (R3 =Et), the corresponding homoallylic alcohol is
also obtained in excellent diastereoisomeric ration and yield
(Table 3, entry 3). In the last two experiments (Table 3, en-
tries 4 and 5), two different alkyl groups for the organocop-
per and the alkynyl sulfoxide were used with Et2Zn as a pre-
cursor for the zinc carbenoid; in both cases, all-carbon qua-
ternary and tertiary centers were created with excellent dia-
stereoselectivities and in good overall yields.
When the same reaction was performed on a non-func-
tionalized alkyne such as 1-hexyne 17, the reaction still pro-
ceeded to give the expected homoallylic alcohol 14 in good
yield but as
a 1:1 mixture of two diastereoisomers
(Scheme 8). In such case, the zinc carbenoid homologation
reaction of vinyl copper leads to the in situ generated allyl-
zinc species 2 that is no more configurationally stable[13] and
therefore the two geometrical isomers resulting from its
metalatropic equilibrium react with the aldehyde.
The characteristic features of all these different protocols
for the one-pot preparation of homoallylic alcohols are the
unique combination of 1) stereocontrolled carbometalation
reaction, 2) homologation into allylzinc species without
scrambling the stereochemistry of the double bond, and 3)
diastereoselective allylation reaction of aldehydes controlled
by the stereogenic center of the chiral sulfoxide. The chiral
sulfinyl group plays a multiple role as chelating element to
slow down the metalotropic equilibrium, activator and re-
giocontrol element for the carbometalation reaction of the
alkynyl moiety as well as a chiral auxiliary for the creation
of two new stereogenic centers. However, for further syn-
thetic applications, sulfoxide should only be a chiral synthet-
ic tool and must be disposed of at the end of the se-
quence.[22] Among all the possible methods, the ligand ex-
change reaction of sulfoxides with alkylmetals is one of the
most interesting transformations, since further functionaliza-
tion may increase the complexity of the carbon skele-
ton.[23–25] When the two following homoallylic alcohols
(Scheme 7) were first treated with MeLi and then with
tBuLi in Et2Oat À788C, the corresponding vinyl lithium
species were obtained, by a sulfoxide–lithium exchange re-
action, in excellent yields as determined after acidic hydrol-
ysis (Scheme 7). The enantiomeric ratio (er 96:4) of 14 and
16 were determined by chiral HPLC (chiral column Chiral-
pak AD-H) and was found to be similar to the starting al-
kynyl sulfoxide (ee 92%). Such sulfoxide–lithium exchange
Scheme 8. Non-stereoselective approach to the carbonyl allylation reac-
tions.
To further extend this new approach for the creation of
all-carbon quaternary stereogenic centers, we needed to find
an alternative method to slow down the metalotropic equi-
librium. This approach shouldnꢁt be based anymore on intra-
molecular chelation from the substrate but rather on inter-
molecular chelation through an external ligand. Among all
the possible sources of chiral ligands, we were primarily in-
terested to study the case of enantiopure Ellmanꢁs (R)-N-
tert-butanesulfinimines 18.[27] Beside the fact that sulfini-
mines could be utilized as chiral nitrogen intermediates for
the preparation of a wide range of chiral amines, we were
interested by the potential intermolecular stabilization of
the sulfinimines to the allyzinc species. In our first approach,
disubstituted vinyl iodides 19, easily prepared by carbocup-
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Retrosynthetic Paradigm
CONCEPTS
ration reaction of octyne,[12] were treated with tBuLi in THF
at À788C, followed by addition of one equivalent of CuI to
lead to the corresponding vinylcoppers 20 at À308C. To the
resulting vinylcopper derivatives were consequently added
diethylzinc, methylene iodide and various sulfinimines. The
reaction between diethylzinc and methylene iodide occurs
first to lead to the in situ formation of zinc carbenoid, which
readily homologates the vinyl copper into the allyl species,
as previously described, which reacts diastereoselectively
with (R)-N-tert-butanesulfinimines 18 to give the expected
homoallyl sulfinamines 21 with very high diastereoselectivi-
ties and in good overall yields as described in Scheme 9 and
Table 4.[28]
However, nonbonding interactions contributed by sub-
strate substituents may provide the dominant stereochemical
control element. In many cases, metals have been docu-
mented to pre-associate with polar functional groups in the
vicinity of the reaction center and to influence the stereo-
chemical outcome of the process, providing even an oppo-
site stereochemical outcome.[31] Since the S Obond may op-
À
erate as an acceptor site for Lewis acids,[32] the conformation
of the sulfinimine moiety in the transition state can be influ-
enced by an intramolecular chelation[33] with metallic salts
(Scheme 10).[34] If such a case, the addition of metallic salts
should lead to a chelated intermediate with consequences
that the active and inert volume located on the sulfur atom
are now reversed as compared to the transition state depict-
ed in Scheme 10. The facial selectivity should then be oppo-
site.
Scheme 9. Preparation of homoallylic amine derivatives from vinyl io-
dides.
Scheme 10. Chelated transition state.
Under this assumption, the reaction was performed in the
presence of MgX2. Although MgX2 could be added to the
vinylcopper species 20 the direct carbocupration reaction of
alkyne with RCu, MgBr2 (easily prepared from 1 equiv al-
kylmagnesium halide and 1 equiv CuI)[12] was a more attrac-
tive and efficient route. When the carbocupration was per-
formed in Et2Oat À258C for 4 h, the corresponding vinyl
copper species 20 were formed as described in Scheme 11.
Table 4. Stereocontrol in the allylation reaction from vinyl iodides.
Entry
R1
R2
dr[a]
Yield[b]
1
2
3
4
5
6
Et
Me
iPr
Et
Et
Et
Ph
Ph
Ph
>98:2
>98:2
>98:2
>98:2
>98:2
95:5
85
65
87
81
77
75
p-Br-C6H4
p-Ac-C6H4
PhCH=CH
[a] Diastereoisomeric ratio determined on crude 1H NMR spectroscopy.
[b] Isolated yield after purification by column chromatography.
As can be deduced from Table 4, the reaction can be per-
formed by a combination of various sulfinimines and vinyl-
copper derivatives. The alkyl group R1 of the vinyl iodide
can be primary (Table 4, entries 1, 2 and 4–6), as well as sec-
ondary (although in a pseudo axial position in the chair like
transition state, see Table 4, entry 3). The reaction could be
performed in the presence of various aromatic (Table 4, en-
tries 1 to 3), functionalized aromatic (Table 4, entries 4, 5),
and conjugated (Table 4, entry 6) sulfinimines. Only aliphat-
ic sulfinimines lead to poor diastereoisomeric ratio (dr
70:30, not reported in Table 4). Sulfinimine usually prefers
Scheme 11. Preparation of homoallylic amines from alkynes.
Then, Et2Zn, CH2I2 and (R)-N-tert-butanesulfinimines were
all added to the vinyl copper at À308C and after few hours
at the same temperature, the corresponding homoallylic
amines 21 were also obtained as a unique diastereoisomer.
To our delight, the diastereoisomers 8 obtained in the proce-
dure depicted in Scheme 11 are indeed the opposite diaste-
reoisomers that were obtained in Scheme 9 (see Table 5).
This discrepancy can be rationalized by a cyclic transition
state with MgX2 coordinated to the oxygen of the sulfinyl
group and to the zinc atom (as opposite to the antiperipla-
nar situation described in Scheme 9). The high level of pre-
À
to adopt the conformation in which the S Obond and the
lone pair on the nitrogen atom are antiperiplanar, mainly as
*
a result of an important nN PSSÀO negative hyperconjugation
interaction.[29] Such interaction has a high rotational barrier
(41.3 kJmolÀ1) and therefore blocks the conformation of sul-
finimines. The formation of the homoallylic products is ra-
tionalized through a close transition state in which the sub-
stituent of the sulfininimes occupies a pseudo axial position
(see Scheme 9).[30]
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I. Marek
Table 5. Stereocontrol in the allylation reaction from alkynes.
sis, we should first decrease the amount of metallic salts
present in the reaction mixture (to promote a selective che-
lation between the chiral ligand and the intermediate allyl-
zinc species). Consequently, the development of catalytic
carbometalation reaction (first step in our sequence) is abso-
lutely needed (Scheme 13). Only very few approaches are
Entry
R
R1
R2
dr[a]
Yield[b]
1
2
3
4
5
6
Hex
Hex
Hex
Hex
Hex
Bu
Et
Et
Et
iPr
Bu
Hex
p-Br-C6H4
p-Ac-C6H4
Bu
p-Br-C6H4
p-Br-C6H4
p-Br-C6H4
>98:2
>98:2
>98:2
>98:2
97:3
75
67
67
62
70
60
96:4
[a] Diastereoisomeric ratio determined on crude 1H NMR spectroscopy.
[b] Isolated yield after purification by column chromatography.
organization presumably contributes to the very high selec-
tivity for attack opposite to the large tBu group. The scope
of the reaction is broad since functionalized aromatic
(Table 5, entries 1, 2 and 4–6) but also aliphatic sulfinimines
(Table 5, entry 3) leads to excellent diastereoselectivities. As
shown in Table 5 (entry 5 vs 6), permutation of the alkyl
group of the alkyne and the organocopper reagent allows
the independent formation of the two isomers at the quater-
nary carbon center, respectively.
Finally, the sulfinyl group is readily cleaved under mild
acidic conditions to provide the free amine derivatives in
quantitative yields with an all-carbon quaternary stereogenic
center in acyclic system (see Scheme 12).[28]
Scheme 13. Copper-catalyzed carbozincation of alkynyl sulfones.
known for such transformations[12] and we concentrated our
initial efforts towards the copper-catalyzed carbozincation of
alkynyl sulfones, which are known to give two geometrical
isomers by carbocupration reactions.[35] We were pleased to
observe that alkynyl sulfones (as alkynyl sulfoximines and
sulfoxides) also react cleanly with a copper-catalyzed addi-
tion of alkylzinc derivatives to lead to a single regio- and
stereoisomer in good isolated yields as described in
Scheme 13 and Table 6. Primary-, secondary-, functionalized
Clearly, such new strategies are really powerful for the ef-
À
ficient assembly of three new carbon carbon bonds, two
Table 6. Copper-catalyzed carbozincation reaction.
new stereogenic centers including the extremely challenging
all-carbon quaternary one, in a one-pot reaction from com-
mercially available alkyne. Nonetheless, one can easily see
that such methodologies still requires the need of a full
equivalent of chiral auxiliaries attached either on the nucle-
ophile (Schemes 3–6) or on the electrophile (Schemes 9–11).
Although these auxiliaries can be easily removed (Scheme 7
and 12), the next challenging issue, far beyond the current
state-of-the-art would combines the diastereo- and enantio-
Entry
RZnX
E-X
E
Yield[a]
1
2
3
4
5
6
Bu2Zn
HCl
HCl
HCl
HCl
I2
H
H
H
H
70
72
92
55
65
60
Et2Zn
iPrZnBr[b]
MeOCO
Et2Zn
Et2Zn
(CH2)3Zn[c]
I
allyBr
allyl
[a] Yields determined after purification by chromatography on silica gel.
[b] Generated from the corresponding Grignard reagent and ZnBr2.
[c] Prepared from the corresponding alkyl iodide and zinc dust.
À
selective creation of several carbon carbon bonds with a
catalytic amount of chiral ligand in a one-pot reaction from
alkynes. However, the beauty of this reaction generates also
its own limitation: as magnesium, lithium, zinc and copper
salts are coexisting in the reaction mixture, they may also
strongly interfere for a specific chelation of any chiral li-
gands with a given organometallic species. Therefore, to
have a better chance to succeed towards asymmetric cataly-
derivatives react regio- and stereoselectively with alkynyl
sulfones.[36] The addition is syn and the resulting sp2 organo-
metallic derivatives can easily react with classical electro-
philes. Now, the only organometallic species in the reaction
mixture is the dialkylzinc species catalyzed by 5 mol% of
copper salt. This new catalytic
carbozincation reaction opens
new horizons for the catalytic
À
assembly of three new carbon
carbon bonds by the method
previously described with the
creation of the expected all-
carbon quaternary stereocen-
ters.
Conclusion
The current state-of-the-art for
the formation of enantiomeri-
Scheme 12. Cleavage of the sulfinyl group into free homoallylic amines possessing enantiomerically pure qua-
ternary stereogenic centers.
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Chem. Eur. J. 2008, 14, 7460 – 7468

Retrosynthetic Paradigm
CONCEPTS
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cally pure all-carbon quaternary stereocenters in acyclic
À
system relies on the formation of a single carbon carbon
bond per chemical step by asymmetric catalysis. These ex-
traordinary sophisticated methods were logically classified
among the most powerful and innovative ones. In this con-
cept article, we describe an alternative method that would
[9] D. J. Ramꢂn, M. Yus, Angew. Chem. 2005, 117, 1628; Angew. Chem.
Int. Ed. 2005, 44, 1602.
À
now rely on the efficient creation of three new carbon
carbon bonds in a one-pot reaction from common and even
commercially available starting material through the combi-
nation of a 1) regio- and stereoselective carbometalation re-
action, 2) in situ homologation of the resulting organocop-
per with a zinc carbenoid, 3) intra- or intermolecular chela-
tion of the zinc moiety, and 4) diastereoselective allylation
reaction. The key features in all these reactions are the high
degree of stereocontrol, the level of predictability, and the
ease of execution. We believe that such efficient methodolo-
gies should find a wide range of applications in synthesis
and we are currently extending this concept to asymmetric
alkylation reactions. The next challenging step would be to
combine this described concept with asymmetric catalysis
and efforts towards this goal are currently ongoing in our re-
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Acknowledgements
The author thanks the Israel Science Foundation administrated by the
Israel Academy of Sciences and Humanities (grant No 459/04), the
German-Israeli Foundation for Scientific Research and Development
(GIF Research Grant No. I-871-62.5/2005), the United States–Israel Bi-
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Published online: June 18, 2008
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