Diastereodivergent combined carbometalation/zinc homologation/C-C fragmentation reaction as an efficient tool to prepare acyclic allylic quaternary carbon stereocenters

Article abstract of DOI:10.1039/c6sc02191c

A new strategy has been developed to construct enantiomerically enriched acyclic allylic quaternary carbon stereocenters in a single-pot operation through a combined carbometalation/zinc homologation/fragmentation sequence. Proper tuning of the reaction conditions enables the synthesis of the two enantiomers starting from a single enantiomer of the starting material.

Full text of DOI:10.1039/c6sc02191c

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Diastereodivergent Combined Carbometalation − Zinc
Homologation – C-C Fragmentation Reaction as an Efficient Tool
to Prepare Acyclic Allylic Quaternary Carbon Stereocenters
Received 00th January 20xx,
Accepted 00th January 20xx
Sudipta Raha Roy,a Dorian Didier,a Amir Kleinera and Ilan Mareka*
DOI: 10.1039/x0xx00000x
A new strategy has been developed to construct enantiomerically enriched acyclic allylic quaternary carbon stereocenters
in a single-pot operation through a combined carbometalation - zinc homologation – fragmentation sequence. Proper
tuning of the reaction condition enables the synthesis of the two enantiomers starting from a single enantiomer of the
starting material.
www.rsc.org/
stereocenters.15 Herein, we would like to report our efforts to
address this issue by performing a new tandem approach
leading to the formation of two new carbon-carbon bonds in a
Introduction
In the last few decades, numerous approaches to integrate
multiple chemical steps in a single pot operation1 have been
described, offering reliable and powerful strategies for the
synthesis of fine chemicals.2 In this context, construction of
several carbon-carbon (C-C) bonds with simultaneous control
of newly formed asymmetric centers including the formation
of challenging quaternary carbon stereocenters,3 is of
paramount importance for the development of complex
molecular frameworks.4 Particularly interesting would be the
formation of such stereocenters adjacent to allylic motifs4 as
these sub-structures are abundant in biomolecules and
natural products.5 Although several excellent and highly
selective approaches have been reported for the construction
of these acyclic allylic carbon quaternary stereocenters,6-10 it
becomes eventually more intricate when the synthesis has to
be performed in a single pot operation.11 For instance and
although the copper catalysed asymmetric conjugate addition
is probably the most well established transformation (Figure 1,
path A),12 the asymmetric 1,4-addition to an extended
conjugated system is more challenging as the 1,6-addition
product is usually preferred over the 1,4-addition (Figure 1,
path B).13 A more successful alternative approach to reach the
same products is the asymmetric 1,4-addition of vinyl metal
species to Michael acceptors.14 Despite that asymmetric
catalysis coupled with fragmentation of strained building
blocks have been recently reported, none could be used for
the preparation of acyclic allylic carbon quaternary
single-pot operation including the formation of the desired
acyclic allylic quaternary carbon stereocenter (Figure 1, Path C)
from easily accessible starting material.
Figure 1. Approaches to construct allylic quaternary stereocenter
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This combined reaction would consist in the diastereoselective isomer 2asyn can now be prepared as unique diastereoisomer
carbometalation reaction16 of enantiomerically enriched (Table 1, entry 5). The relative configuration of 2asyn has also
substituted cyclopropenyl esters
1
,
followed by
a
been established by comparing the NOE and 13C NMR
homologation reaction17 of the resulting cyclopropyl metal experiments with 2aanti (see Supplementary Information). The
species 2 leading to a cyclopropylmethyl metal 3 that would same trend was also found for the addition of organocopper
subsequently undergo a carbon-carbon bond cleavage18 to species originating from Grignard reagent (prepared by mixing
give the enantiomerically enriched acyclic allylic quaternary MeMgBr and CuI in a 1:1 ratio), although the formation of the
carbon stereocenter
Although this proposed sequence is very appealing, the unique (Table 1, compare entries 1 and 6) but still excellent for the
formation of the linear product directly from , promoted by formation of the syn-diastereoisomer 2asyn (Table 1, entry 8). It
4 as described in Figure 1, path C. anti-addition product 2aanti in THF is less diastereoselective
4
1
a combination of organometallic species in high chemical yield should be noted that such diastereoselective carbometalaton
and with a high enantiomeric ratio, requires a cascade of high- of cyclopropenyl ester such as 1a have already been described
yielding events with a perfect control of all the elementary but it was always achieved through variation of the
steps. It should be noted that enantiomerically enriched organometallic species but never by simple variation of the
starting cyclopropenyl esters
1
are readily accessible through solvent for a given organocopper entities.16
the asymmetric metal-catalyzed decomposition of diazoester
with alkynes,19 the enantiomeric ratio of the acyclic allylic
Table 1: Controlling the diastereoselectivity for the initial carbocupration step
quaternary stereocenter in
4
results from the
CO2Bn
and/or
CO2Bn
CO2Bn
diastereoselectivity of the carbometalation reaction.
Bu
Me[M] (1.05 eq)
Solvent
Me
Bu
CuI
Bu
Me
1a
1.0 eq
−
45 oC, 30 min
then H3O+
2asyn
2aanti
1.05 eq
Results and discussion
a
We started our research by investigating first the
diastereoselectivity of the carbometalation reaction of
Entry
Me[M]
Solvent
THF
2asyn/2aanti
1
2
3
4
5
6
7
8
MeLi
1:99 (75)
6:94
cyclopropenyl ester 1. In our synthetic plans, the presence of
MeLi
2-MeTHF
Et2O
the ester was not only needed to achieve good
diastereoselectivity for the carbometalation reaction but was
also a key-element for a successful ring-fragmentation of the
newly formed donor-acceptor cyclopropylmethyl metal species
MeLi
89:11
MeLi
Hexane
C6H4Me
THF
97:3
MeLi
99:1 (73)
28:72
MeMgBr
MeMgBr
MeMgBr
3 20
Hence, to address the initial step of this sequence
(transformation of into ), our model substrate
.
Et2O
99:1
C6H4Me
99:1 (72)
1
2
a
1a was consumed completely and the ratio between products 2asyn and 2aanti
was determined by GC-MS of the crude reaction mixture. Numbers in
parentheses represent the isolated yields after purification by column
chromatography.
cyclopropenyl ester (racemic 1a) was treated with various
organocopper species in different solvents as described in
o
Table 1. When 1a was treated at -45 C in THF with 1.05
equivalent of MeCu, easily prepared by mixing MeLi and CuI in
a 1:1 ratio, the carbometalated product 2aanti was rapidly
obtained after hydrolysis (less than 30 minutes) with a very
high anti-diastereoselectivity in good yield (Table 1, entry 1).21
The configuration of 2aanti has been established by NOE
experiments (see Supplementary Information). The
preferential formation of the diastereomer 2aanti can only be
possible when the carbometalation reaction is sterically
driven. The coordinating solvent such as THF makes the
organocopper species less prone to be chelated by the ester
and therefore prefers to react on the re-face of the
cyclopropene derivative 1a. If the assumption that solvent
plays a crucial role in the control of the diastereoselectivity of
the carbometalation step, thus less Lewis basic solvent should
favour the addition on the si-face through coordination of the
organometallic species with the ester. Indeed, when slightly
less coordinating solvent such as 2-methyl THF was used, the
selectivity towards the formation of 2aanti drops slightly (Table
1, entry 2). By further decreasing the Lewis basicity of the
solvent, (Table 1, entries 3 to 5, Et2O, hexane and toluene
respectively), the aptitude of the organometallic species to be
coordinated by the ester group increases and therefore the
Having access to both syn and anti diastereoisomers of the
carbometalated products at will according to the nature of the
solvent, we then moved our attention to the zinc-
homologation reaction of the racemic cyclopropyl copper
species 2Cuanti, first, originating from the carbometalation
reaction of MeCu in THF (from MeLi and CuI as described in
Table 1, entry 1). For this purpose, CH2I2 and Et2Zn, in a 1:1
o
ratio, were added at -45 C to the reaction mixture and upon
warming to -20 oC within 2 hours, the homologated
cyclopropylmethyl zinc derivative22
3 gave 4a as described in
Figure 2. Indeed as cyclopropylcopper 2Cuanti does not react
with CH2I2, the reaction between Et2Zn and CH2I2 occurred first
to lead to the in-situ formation of the zinc carbenoid
ICH2ZnEt.23 Then, 2Cuanti is homologated by the zinc carbenoid
to generate the in-situ reactive cyclopropylmethyl zinc (or
copper) derivative
undergoes
C-C bond fragmentation24. Although the
combined carbometalation zinc homologation
3 (see Figure 1) that instantaneously
a
–
–
fragmentation reactions proceeded smoothly according to our
original plan to give 4a, the conversion of 2Cuanti into 4a was
only moderate (2aanti/4a = 27/73 after hydrolysis).
2 | J. Name., 2012, 00, 1-3
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species (see ligands in Figure 2).25 We were pleased to see that
indeed the addition of TMEDA (L1) or 2-2’-bipyridine (L2) as
ligand improved the conversion of the desired product 4a
Figure 2. Combined carbometalation
reactions on cyclopropenyl ester 1.
− zinc homologation – fragmentation
(
2aanti
/4a = 12/88 and 13/87 respectively after hydrolysis).
The best conversion could be reached when phenanthroline
(
(
L3) was added to 2Cuanti as the ratio became excellent
2aanti 4a = 6/94 after hydrolysis) and the final product 4a
/
could be isolated in 72% yield. This sequence of
carbocupration – zinc homologation and C-C bond cleavage
has been generalized to different functionalized substrates
(see scope in Figure 2) and in all cases, the reactions proceed
smoothly for the one-pot transformation of 1 into 4.
First, both cyclopropenyl esters (–OEt and –OBn respectively)
similarly undergo this combined transformation (compare 4b
to 4c
that the products resulting from the reaction with the benzyl
ester 4b 4d 4g are easier to purify by column
chromatography than the products possessing the ethyl ester
4c 4e 4f) from the remaining carbometalated products after
hydrolysis anti. These combined reactions are not restricted to
, 4d to 4e and 4f to 4g in Figure 2) but it should be noted
(
,
,
)
(
,
,
2
the introduction of a methyl group as various other alkyl
groups could be added in good yields by simply changing the
nature of the starting organocopper reagent (compare 4b to
4d, 4f to 4h and 4g to 4h, Figure 2). The reaction of
cyclopropenyl ester 1d with phenylcopper also proceeds but
we were unable to separate the desired product 4m from the
carbometalated product 2manti after hydrolysis. Similarly,
when we treated vinylcopper derivative (prepared from
ethenylmagnesium bromide and CuI in a 1:1 ratio) as a
representative example of sp2 organometallic species, with
cyclopropenyl ester 1j, the reaction proceeds smoothly but
here again, we were unable to separate the desired product 4n
from the hydrolysed carbometalated product 2nanti. It is
worthwhile mentioning that this sequence of vinyl cupration −
zinc homologation − fragmentation opens new avenues to the
preparation of skipped dienes possessing a quaternary carbon
stereocenter. Notably, the presence of other functional groups
in the starting alkyl chain of the cyclopropenyl esters is well
tolerated (formation of 4j-l, Figure 2). Having established an
easy protocol for the preparation of racemic
simple starting materials, the synthesis of enantiomerically
enriched cyclopropenyl esters 1b (R1 = Ph(CH2)2), (R1
=
4 from these very
1
e
PhCH2) and 1f (R1 = Hex) were easily achieved in good
enantiomeric ratio (1b er 96:4, 1e er 93:7 and 1f er 91:9)
through cyclopropenation of the terminal alkyne with benzyl
diazoacetate
and
Rh2(OAc)(R,R-DPTI)3
(DPTI
=
diphenyltriflylimidazolidinone) as catalyst.26 Interestingly, the
enantiomeric ratios of these cyclopropenyl benzyl esters are
lower than the ones obtained for cyclopropenyl ethyl esters
(ethyl diazoacetate generally leads to enantiomeric ratios in
the range of 97:3) but for the sake of simplicity, we decided to
illustrate our concept with a starting materials that would
require a minimum numbers of chemical steps. When the
sequence of carbocupration – zinc homologation and C-C bond
fragmentation was performed on these enantiomerically
enriched cyclopropenyl esters, enantioenriched acyclic allylic
To improve the conversion, it was then anticipated that
increasing the nucleophilicity of the carbon atom bearing the
organocopper species should increase its reactivity towards
the ambiphilic zinc carbenoid species EtZnCH2I.
To this end, various donor ligands were added to the reaction
mixture to improve the reactivity of the cyclopropyl copper
molecular architectures (4b
,
g
,
h,i) possessing the quaternary
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carbon stereocenter were easily obtained through the creation were prepared in a single-pot operation from cyclopropenyl
of two C-C bonds in a single-pot operation. HPLC analyses (see esters
Supplementary Information) show that the chiral information
1 as illustrated in Figure 4.
Figure 4: Combined carbometalation − zinc homologation – fragmentation
reactions for the preparation of the opposite enantiomer
at the carbon atom holding the ester moiety in 1b,c,i was
quantitatively transferred to the final products 4b (er 96:4 ), 4g
and 4h (er 93:7) and 4i (er 91:1), Figure 2. It was therefore
clear that the quaternary stereocenter was at no risk of
epimerization in the whole process and one could prepare the
expected products with the same enantiomeric ratio as in the
starting materials.
In contrast to any typical enantioselective synthesis where the
independent formation of the two enantiomers of a product
can only be achieved by changing the chirality of the ligand (or
substrate)
transformation27, the diastereodivergent carbometalation of
controlled by the nature of the solvent as described in Table 1,
associated
with
the
enantioselective
1,
should therefore lead to the enantiodivergent synthesis of
from the same enantiomerically enriched starting material
(as summarized in Figure 3).
4
1
Figure 3. Diastereodivergent combined carbometalation – zinc homologation –
fragmentation en route to enantioenriched allylic quaternary carbon
stereocenters.
The scope of this new reaction sequence of syn-
diastereoselective carbometalation – zinc homologation and
selective C-C bond cleavage proceeds equally well albeit with
slightly lower yields for the final products 4. To illustrate the
potential of this diastereodivergent approach, both
enantiomers of 4i were prepared from the same cyclopropenyl
ester enantiomer 1f (R1
=
Hex, er 91:9). When the
carbocupration of (S)-1f was performed with MeCu LiI in THF
followed by the subsequent addition of CH2I2, Et2Zn and
phenanthroline ( 3) as ligand, the selective C-C bond cleavage
ꢀ
L
leads to the corresponding allylic (S)-4i with an enantiomeric
ratio of 91:9 in 65 % yield (Figure 5).
Although the best ligand to promote the zinc homologation of
2Cuanti was phenanthroline L3, it was unclear that the same
ligand would be optimal when the first step was performed in
a non-polar solvent. To reach this new goal, one has to
optimise again the reaction sequence for the formation of the
Figure 5: Diastereodivergent strategy for the preparation of enantioenriched
4
desired products
4 from the syn-diastereomer 2Cusyn in the
presence of non-polar solvent (such as toluene, see Table 1,
entries 5 and 8). It was first rapidly found that the zinc
homologation for the transformation of 2Cusyn into 4a was
more efficient when the initial organocopper species was
prepared from an organolithium (R2Cu
instead of an organomagnesium species (R2Cu
ꢀ
LiI, Table 1, entry 5)
MgX2, Table 1,
ꢀ
entry 7). After extensive experiments, we were pleased to see
that the zinc homologation could now be best performed in
the presence of the non-nucleophilic potassium tert-butoxide
ligand (for all other ligands tested, see Supplementary
Information) with addition of THF as co-solvent. It is important
to note that the reaction performed under identical reaction
condition but in the absence of the potassium tert-butoxide
ligand results in very poor conversation, which underline the
effect of this particular ligand on the nucleophilicity of the
metalated carbon center stabilized by the chelating ester.
Once the best experimental conditions were in hands, various
On the other hand, if the same cyclopropenyl ester (S)-1f is
added to the organocopper MeCu LiI in toluene followed by
ꢀ
the subsequent zinc-homologation in the presence of
potassium tert-butoxide as ligand, the selective C-C bond
cleavage provides the allylic (R)-4i in similar yield with almost
the same enantiomeric ratio (er 90:10) in 63% yield (Figure 5).
Conclusions
allylic esters
4 possessing the quaternary carbon stereocenters
4 | J. Name., 2012, 00, 1-3
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A new sequence of diastereoselective carbometalation − zinc-
homologation
– C-C bond cleavage allows the easy
transformation of enantiomerically enriched cyclopropenyl
esters into acyclic allylic moiety bearing the challenging
quaternary carbon stereocenters in a single-pot reaction
through the formation of two new C-C bonds. As the
carbometalation reaction may lead to two different
diastereoisomers according to the nature of the solvent, this
strategy paves the way to the diastereodivergent synthesis of
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Acknowledgements
This research is supported by the European Research Council
under the European Community's Seventh Framework
Program (ERC grant agreement no. 338912) and by the Israel
Science Foundation administrated by the Israel Academy of
Sciences and Humanities (140/12). S.R.R. acknowledges the
Planning and Budgeting Committee (PBC) for the financial
assistance. I.M. is holder of the Sir Michael and Lady Sobell
Academic Chair.
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