Asymmetric Sequential Cu-Catalyzed 1,6/1,4-Conjugate Additions of Hard Nucleophiles to Cyclic Dienones: Determination of Absolute Configurations and Origins of Enantioselectivity

Article abstract of DOI:10.1002/chem.201606034

The first stereocontrolled Cu-catalyzed sequential 1,6/1,4-asymmetric conjugate addition (ACA) of C-metalated hard nucleophiles to cyclic dienones is reported. The use of DiPPAM (diphenylphosphinoazomethinylate) followed by a phosphoramidite as the stereo

Full text of DOI:10.1002/chem.201606034

A Journal of
Accepted Article
Title: Asymmetric Sequential Cu-Catalyzed 1,6/1,4 Conjugate
Additions of Hard Nucleophiles to Cyclic Dienones. Determination
of Absolute Configurations and Origins of Enantioselectivity
Authors: Marc Mauduit, Charlie Blons, Marie S T Morin, Thibault E
Schmid, Thomas Vives, Sophie Colombel-Rouen, Olivier
Baslé, Thibault Reynaldo, Cody L Covington, Stephanie
Halbert, Sean N Cuskelly, Paul V Bernhardt, Craig M
Williams, Jeanne Crassous, Prasad L Polavarapu, Christophe
Crévisy, and Hélène Gérard
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To be cited as: Chem. Eur. J. 10.1002/chem.201606034
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10.1002/chem.201606034
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Asymmetric Sequential Cu-Catalyzed 1,6/1,4 Conjugate Additions
of Hard Nucleophiles to Cyclic Dienones. Determination of
Absolute Configurations and Origins of Enantioselectivity
Charlie Blons,[a] Marie S. T. Morin,[a] Thibault E. Schmid,[a] Thomas Vives,[a] Sophie Colombel-
Rouen,[a] Olivier Baslé,[a] Thibault Reynaldo,[b] Cody L. Covington,[c] Stéphanie Halbert,[d] Sean N.
Cuskelly,[e] Paul V. Bernhardt,[e] Craig M. Williams,*[e] Jeanne Crassous,*[b] Prasad L.
Polavarapu,*[c] Christophe Crévisy,*[a] Hélène Gérard*[d] and Marc Mauduit*[a]
Dedication ((optional))
Abstract: The first stereo-controlled Cu-catalyzed sequential
1,6/1,4-asymmetric conjugate addition (ACA) of C-metalated hard
nucleophiles to cyclic dienones is reported. The use of DiPPAM,
followed by a phosphoramidite, as the stereoinducing ligands
facilitated both high ee’s for the 1,6-ACA and high de’s for the 1,4-
ACA reaction components, thus affording enantio-enriched 1,3-
dialkylated moieties. The absolute configurations were determined
using vibrational circular dichroism (VCD) and optical rotatory
dispersion (ORD) spectroscopy, in combination with DFT
calculations and X-Ray analysis. Interestingly, DFT calculations of
the mechanism for the enantioselective 1,6-addition via an
unprecedented Cu-Zn bimetallic catalytic system confirmed this
attribution. Lastly, exploring intramolecular cyclisation avenues on
enantio-enriched 1,3-dialkylated products provided access to the
challenging drimane skeleton.
heightened when the regioselectivity can be directed towards
1,6-adducts, thus opening the opportunity to deploy
a
subsequent 1,4-ACA on the reconjugated 1,6-adduct (Scheme 1,
pathway A/B). Globally, the entire 1,6/1,4-ACA sequential
process delivers enantio-enriched 1,3-dialkylated products in a
straightforward manner circumventing the traditional iterative
1,4/1,4 process (Scheme 1, pathway C/D). However, despite the
tactical advantage such a process could serve in target
orientated synthesis, it has been seldom reported.[2d,2f,3]
Alkyl
O
[Cu]/Alkyl-M
Known
*
R
Y
n
1,4
ee's up to 99%
(C)
(A)
O
n = 0
post-
M = Zn, Al, Mg
functionnalization
R
Y
n
then 1,4
(Iteration)
R = Alkyl or Ar
Alkyl
O
[Cu]/Alkyl-M
Y = Alkyl, Ar, OR, SR, CO2R
n = 1 to 3
Introduction
*
R
Y
n
1,6; 1,8 or 1,10
(D)
then
reconjugation
ee's up to 99%
Copper-catalyzed Asymmetric Conjugate Addition (ACA) to
electron-deficient conjugate polyenes holds great potential for
the installation of otherwise difficult C-C bonds, provided that the
regiochemical outcome of the process is well controlled
(Scheme 1).[1,2] The power of Cu-ACA methodology is further
n = 1
(B)
1,4
Alkyl Alkyl
O
*
*
R
Y
1,6/1,4 sequential ACA adducts
dr's up to 97%
[a]
C. Blons, T. Vives, Drs. M.S.T. Morin, T.E. Schmid, S. Colombel-
Rouen, C. Crévisy, O. Baslé, M. Mauduit
Ecole Nationale Supérieure de Chimie de Rennes, CNRS, UMR
6226, 11 allée de Beaulieu, CS 50837, 35708 Rennes Cedex 7,
France
E-mail: marc.mauduit@ensc-rennes.fr
Drs. T. Reynaldo, J. Crassous
Université de Rennes 1, CNRS, UMR 6226, Campus de Beaulieu,
35042 Rennes Cedex, France.
C.L. Covington, Prof. P.L. Polavarapu
This work
O
O
[Cu]/Alkyl-M
[Cu]/Alkyl-M
reconjugation
Alkyl
*
*
1,6
1,4
[b]
[c]
[d]
R
R
M = Zn
M = Al
Alkyl
R = Me, nBu, (CH2)2OTBDMS, (CH2)2Cl
all-carbon
quarternary
center
Alkyl = Et or Me
Department of Chemistry, Vanderbilt University, Nashville, TN
37235, USA.
Dr. S. Halbert, Prof. H. Gérard
1,6/1,4 sequential ACA process
Sorbonne Universités, UPMC Univ Paris 06, CNRS, Laboratoire de
Chimie Théorique CC 137 - 4, place Jussieu F. 75252 Paris Cedex
05, France.
S.N. Cuskelly, Profs. P.V. Bernhardt, Craig M. Williams
School of Chemistry and Molecular Biosciences, The University of
Queensland, Brisbane, QLD 4072, Australia.
Scheme 1. Copper-catalyzed enantioselective conjugate addition of alkyl-
metal hard nucleophiles to extended electron-deficient alkenes.
[e]
Minnaard, Feringa and co-workers reported in 2010 an efficient
Cu/reversed Josiphos L1 catalytic system for the 1,6-addition of
Supporting information for this article is given via a link at the end of
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MeMgBr to dienic thioesters (Scheme 2-a).[2f] After reconjugation
of the 1,6-adduct, a subsequent 1,4-ACA was performed on
each enantiomer of the Josiphos ligand L2 to give both the syn-
O
O
O
MeMgCl (2 eq.)
O
O
MgBr
CuBr.SMe2
(1 eq.)
O
O
CuBr.SMe2
(5 mol%)
then
crotonization
Me
and
anti-1,3-dimethylated
products;
albeit
in
high
66%
18%
stereoselectivities (up to 92% ee). Interestingly, after conversion
of the thioester group of the syn adduct into an aldehyde and
subsequent olefination, a second 1,6-ACA was attempted, which
afforded (syn, anti) and (syn, syn) 1,3,5-trimethylated products
with moderate and good diastereoselectivities, respectively.
More recently, we reported the stereo-controlled introduction of
two ethyl substituents having a 1,3-relationship, through a
procedure involving a Cu/DiPPAM L3 1,6-ACA of Et2Zn to linear
aryldienones (up to 97% ee) followed by a reconjugation step,
Pseudoguaiane
Scheme 3. Direct access to pseudoguaiane via a sequential 1,6/1,4 conjugate
addition followed by an intramolecular cyclization as reported by Alexakis and
Posner in 1978.
Nevertheless, some efficient catalytic systems were already
described for copper-catalyzed 1,6-ACA of alkyl-metal
nucleophiles to 3-substituted cyclohexenones.[2g,5] The first
example was described by Alexakis and Mauduit in 2008.[2g]
Using a chiral phosphoramidite as the ligand and Et2Zn as the
nucleophile, complete 1,6-regioselectivity and good ee (89%)
were attained. More recently, DiPPAM L3 and a variety of
unsaturated hydroxyalkyl-NHCs, proved quite efficient for the
Cu-catalyzed addition of various dialkylzincs to five- and six-
membered cyclic dienones (ee’s up to 99%).[5b-d] Considering
these pioneering efforts, we envisioned that a sequential 1,6/1,4-
ACA process applied to 3-substituted cyclohexenones, followed
by a subsequent intramolecular cyclisation, could offer direct
synthetic access to natural product scaffolds i.e. the drimane
core A (Fig. 1). This bicyclic skeleton is present in many natural
and
a Cu/Binap L4 catalyzed 1,4-ACA of Et2Zn to the
reconjugated 1,6-adduct (up to > 97% de) (Scheme 2-b).[2d]
a) Feringa and co-workers (2010)
O
Me
O
L1/CuBr·SMe2
MeMgBr
Alkyl
SEt
*
Alkyl
SEt
then DBU
1,6/1,4 (up to 99/1)
78-88% yield, 82-89% ee
PPh2
CuBr.SMe2
Fe
PCy2
MeMgBr
(+)-L2 Josiphos
(-)-L2 Josiphos
L1
(Reversed Josiphos)
Me
Me
O
Me
Me
O
PCy2
occurring
biologically
active
molecules,[6]
such
as
n-Bu
SEt
n-Bu
SEt
*
*
*
*
Fe
PPh2
92% ee
85% ee
stachybotrylactam,[7] sclareolide[8] and coronarine E[9] (Fig. 1),
but constitutes a real synthetic challenge. Besides obtaining
control over the regio- and enantioselectivity of the sequential
conjugate addition (including the formation of all-carbon
quaternary centers),[10] the stereoselective intramolecular
cyclisation via enolate trapping remains highly challenging.
Indeed, although the tandem process consisting of a 1,4-ACA
followed by intermolecular trapping of the enolate is very well
documented,[11] the intramolecular version has been scarcely
reported.[12]
Me
Me
Me
O
O
(-)-L2 (Josiphos)
n-Bu
n-Bu
*
*
SEt
SEt
*
Me
Me
Me
iteration
*
*
*
b) Mauduit and co-workers (2013)
O
L3/Cu(OTf)2
R2Zn
R
O
Alkyl
Ar
*
Alkyl
Ar
then DBU
1,6/1,4 (up to 98/2)
R = Me, Et, n-Bu, i-Pr
40-80% yield, 88-98% ee
L4/CuTC
Et2Zn
LG
O
H
PPh2
PPh2
3
2
1
Ph
P
N
O
intramolecular
cyclization
1,4-ACA 1,6-ACA
Et
Et
O
Ph
R
Me
*
Alkyl
Ar
Na
*
1,4*
O
1,6*
A
(L)-DiPPAM L3
(R)-Binap L4
55-81% yield, 93-97% de
H
H
Scheme 2. First enantioselective sequential 1,6/1,4 Cu-catalyzed conjugate
addition of C-metalated hard nucleophiles to acyclic dienic Michael acceptors
and related iterative processes.
H
OH
Me
Me
O
Me
O
Me
Me
O
While all the examples presented above contain linear dienic
conjugate acceptors, to the best of our knowledge, such a
sequential process starting from 3-substituted cyclic dienones
has only been reported on a single occasion. In 1978 Alexakis
and Posner deployed this strategy during the synthesis of
pseudoguaiane, but in the racemic series (Scheme 3).
OH
(+)-Sclareolide
(isolated from
Salvia sclarea Linn.)
HN
O
O
Antimicrobial and anti-leukemia activity
used also as flavoring agent
Stachybotrylactam
(isolated from
Stachybotrys sp. MF347)
(+)-Coronarine E
(isolated from
Hedychium coronarium)
Antibacterial activity
Anti-inflammatory and
analgesic activity
Figure 1. Top: Envisioned synthetic route to access the bicyclic core of
various biologically active sesquiterpenes (Bottom).
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We report herein the first stereoselective Cu-catalyzed
sequential 1,6/1,4 ACA of carbon-metal nucleophiles to various
3-substituted cyclohexenones leading to enantio-enriched 1,3-
dialkylated moieties. In addition, considering the relative
flexibility of the lateral side chain, we developed a protocol to
determine the absolute stereochemical configuration of the
newly formed stereogenic centers utilising vibrational circular
dichroism (VCD) and optical rotatory dispersion (ORD) analysis
in combination with DFT calculations. Furthermore, a separate
DFT study concerning the mechanism for C-C bond formation
was undertaken to determine the origin of the 1,6-
enantioselectivity. This highly stereoselective catalytic sequential
process, in combination with the subsequent intramolecular
cyclisation, was then applied to the synthesis of the challenging
drimane skeleton.
O
1. L3 (10 mol%)
Cu(OTf)2 (5 mol%)
THF, 0 or 20 °C
16-40 h
O
R
S1-S5
Ph
or
O
+
P
N
O
2. DBU, CH2Cl2, 5 h
ZnEt
*
R
Ph
(3 equiv.)
P1-P4
single regioisomer
O
R
Na
S4
(L)-DiPPAM L3
S1 (R = Me); S2 (R = nBu); S3 & S4 (R = (CH2)2OTBDMS); S5 (R = (CH2)2Cl)
O
O
O
*
*
*
Me
Me
(+)-P1
(-)-P1[c]
68% yield[a], 97:3 e.r.[b]
(-)-P2
50% yield[a], 98:2 e.r.[b]
56% yield[a], 99:1 e.r.[b]
O
O
Results and Discussion
1,6-ACA of diethylzinc to 3-substituted cyclohexenones
catalysed by Cu(OTf)2/(L)-DiPPAM L3
*
*
OTBDMS
(+)-P2[c]
56% yield[a], 97.5:2.5 e.r.[b]
(-)-P3 (from S3)
42% yield[a], 97.5:2.5 e.r.[b]
A set of 3-substituted cyclohexenones S1-S5 was chosen to
investigate the 1,6/1,4-ACA sequential process (Scheme 3).
They differ in nature by the substituent at the delta position, and
the configuration of the delta-gamma double bond. Substrates
S1[2g] and S2[5d] bear an alkyl group, whereas S3-S5 bear a
functional group. The trialkylsilyloxy and the chloro substitutents
were introduced in order to realize intramolecular trapping of the
intermediate enolate formed in the 1,4-ACA, which would lead to
the formation of the bicyclic skeleton (see Figure 1). Finally, the
influence of the E/Z double bond configuration was probed with
substrates S3 and S4. Having the five dienones in hand (see
ESI for details), we studied their behavior in the 1,6-ACA of
diethylzinc catalysed by Cu(OTf)2/(L)-DiPPAM L3. In a slightly
modified procedure,[5c-d] 5 mol% of the copper source and 10
mol% of the ligand, were dissolved in THF before a 1 M solution
of Et2Zn in hexanes was added, followed by a solution of the
dienone in THF. On reaction completion, the mixture was
O
O
*
*
OTBDMS
Cl
(+)-P3 (from S4)
(+)-P4 (from S5)
31% yield[a], 96.5:3.5 e.r.[b]
58% yield[a], 97.5:2.5 e.r.[b]
Scheme 4. Cu/DiPPAM L3 catalyzed 1,6-ACA of diethylzinc to dienones S1-S5.
[a] Isolated yields. [b] Determined by GC or HPLC on chiral columns. [c] (D)-
DiPPAM [(ent)-L3] was used.
Before investigating the subsequent 1,4-ACA on P1-P5 to build
the targeted 1,3-dialkylated moieties, we decided to elucidate the
absolute configuration of the 1,6-stereogenic center and
determine the origin of the enantioselectivity promoted by our
Cu(OTf)2/(L)-DiPPAM L3 catalytic system.
quenched with NH4Cl(s) followed by the addition of
a
dichloromethane solution of DBU to initiate the reconjugation
step. The results are summarized in scheme 4. In all cases, the
desired 1,6-adducts were exclusively formed in moderate to
good yields with excellent enantiomeric ratios ranging from
96.5:3.5 to 99:1. As expected, the involvement of the enantiomer
of DiPPAM L3 for dienone S1-S2 led to the corresponding 1,6-
products (-)-P1 and (+)-P2 having opposite configuration with a
slight alteration of enantioselectivities (respectively 97:3 and
97.5:2.5 e.r.). Fortunately, regardless of the types of functional
groups contained within dienones S3-S5, the catalytic system
remained robust as corresponding 1,6-adducts P3-P4 were
obtained with similarly high enantioselectivities (96.5:3.5 to
97.5:2.5 e.r.); despite a lower isolated yield for P3. Interestingly,
the enantiomeric outcome of the reaction is highly dependent on
the configuration of the gamma-delta double bond, as S3 and S4
afforded opposite enantiomers. Such behaviour, which has
recently been observed by Minnaard and Feringa in the copper
catalysed 1,6-ACA of Grignard reagents to dienic esters,[2a]
shows that isomerization of the double bond during the reaction
does not occur to any significant extent.
Vibrational Circular Dichroism (VCD) and optical rotatory
dispersion (ORD) spectroscopy studies on the P1-adduct:
determination of the absolute configuration
VCD spectroscopy[13-15] is a chiroptical technique operating in the
infrared (IR) domain, which is useful for determining the absolute
configuration (AC) of small molecules when other techniques fail
[e.g. X-ray diffraction, electronic circular dichroism ECD)]. For
example, due to issues with single crystals and the absence of
chromophores, which is the case for most of the molecules
described in this study. Like ECD the absolute configuration
determination using VCD is achievable when the experimental
VCD spectrum is directly compared to that calculated using DFT
methods, provided that Boltzmann averaging is performed over all
the accessible conformations. The experimental IR and VCD
spectra were thus measured for P1, which displayed several
bands in the 1000-1500 cm-1 region (Fig. 2).
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enantiomer spectra with those predicted for
R
absolute
configuration. The calculated spectra were Boltzmann weighted
with Gibbs free energies. The peak similarity ratings obtained
were 0.67 and 0.52 for SimVCD and SimVDF respectively, which
are much larger than those needed for confident
O
assignments.[18,19b,20a] The ORD calculations for the
R
R-(-)-P1
configuration, shown in Fig. 4, match the experimental ORD for (–
)-P1. Therefore, the AC of (–)-P1 can be confirmed as R-(–), and
(+)-P1 as S-(+).
O
Experimental
(b)
(d)
SimVA
50
0
S-(+)-P1
Calculated
1
0,6
SimVCD
SimVDF
0,2
-0,2
-50
0,94
-0,6
0,97
1
1450
1250
1050
cm-1
Wavenumber Scale Factor
400
200
0
Experimental
Calculated
Experimental
Calculated
100
50
0
(a)
(c)
-200
-400
1450
1250
1050
cm-1
cm-1
1450
1250
1050
Figure 2. Experimental IR and VCD spectra of R-(–)- and S-(+)-P1 measured in
CD2Cl2. The VCD has been removed in the region where the solvent strongly
absorbs.
Figure 3. The VA (a), VCD (b), and VDF (c) spectra, with similarity analysis (d),
for R-(–)-P1.
0
Considering the chirality of P1 originates from only one
asymmetric carbon, and due to the fact that the chiral exocyclic
chain is quite flexible, the VCD signals of the (+) and (–)
enantiomers were rather weak. P1 enantiomers display mirror-
-70
23
image specific rotations values ([]D
=
-16.6 and
[]
+17.6 °·cm3·dm−1·g−1 in CH2Cl2, C = 0.016 and 0.019 g/100mL
see ESI for specific rotations at other wavelengths). Nevertheless,
with the aid of a thorough conformational analysis, both VCD
spectra and specific rotation as a function of several wavelengths
could be used to determine the R-(–) and S-(+) absolute
configuration for P1 using theoretical calculations, as described
below. The conformational analysis was performed using the
CONFLEX software package using the MMFF94s force field and a
systematic search.[16] All conformations within 10 kcal/mol were
re-optimized at the B3LYP/6-31G* level. For all conformations
within a reasonable energy threshold, the structures were re-
optimized at the B3LYP/Aug-cc-pVDZ level and VCD and ORD
spectra were calculated at the same level of theory. All quantum
chemical calculations were performed using GAUSSIAN 09.[17] In
addition to VCD analysis, Vibrational Dissymmetry Factor (VDF)
provided an additional level of confidence with the AC
assignment.[18] For quantitative comparison between experiment
and theory, similarity analysis was performed using the ‘sim’
scoring functions,[19a] calculated using the the program
CDSpecTech.[19b] SimVCD and SimVDF ratings can be used to
assign the absolute configurations when used in conjunction with
accurate visual comparison.[20] For R-(–)-P1, 22 unique
conformations were found within 1.6 kcal/mol at the 6-31G* level,
which constitutes ~94% of the Boltzmann weighted average (the
lowest energy conformer is shown in Figure S1 of the ESI).
Gibbs
Electronic
530
Experiment
580
-140
430
480
nm
Figure 4. Comparison of the calculated and experimental ORD values for R-(–)-
P1. The calculated SORs were Boltzmann weighted separately with electronic
and Gibbs free energies.
Theoretical determination of enantioselectivity of 1,6-ACA
catalyzed by Cu/DiPPAM: toward a rationale
Despite the positive experimental results, and the high selectivity
of the Cu/DiPPAM L3 catalyzed 1,6-ACA, little is known about the
mechanistic aspects of this catalytic system.[21] We thus undertook
a computational study (DFT calculations at B3PW91 and double
zeta basis set with polarization, see Computational Details in ESI)
of the pathway for formation of P1 according to a mechanism
proposed by Nakamura et al.,[22] and already successfully
implemented in
a
recent study by our group.[21c] In this
mechanism, the C-C bond formation step takes place in a bi-
metallic species, herein called A1 (Fig. 5 and ESI, Table S1, for
detailed geometrical parameters). In this species, the exocyclic
C=C bond of S1 interacts through a π-bond with the Cu(I) center
while one of the carbonyl lone pair is coordinated to the Zn center,
which thus plays the role of a Lewis acid. In addition to that
proposed by Nakamura, the DiPPAM ligand L3 acts as a bridge
between the two metal centers [Cu(Et) is coordinated to the
The vibrational absorption (VA), VCD, and VDF spectra for (–)-P1
are shown in Figure 3, with similarity analysis comparing the (–)-
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10.1002/chem.201606034
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phosphine part while Zn(Et) interacts with the carboxylate arm of coordinated S1, the S-trans conformation of the C4-C5 bond was
DiPPAM]. Coordination of the cyclic dienone in A1 is well found to be favored by 2.2 kcal mol-1 this preference is not
established with short Cu-C (2.029 Å – 2.172 Å) and Zn-O (2.111 conserved in the adduct A1. The S-cis structures [(e) to (h) in Fig.
Å) bond distances. Significant elongations with respect to the free 6)] are all more stable than their S-trans counterparts. The most
ketone S1 were observed for the C5=C6 (1.405 vs 1.344 Å) and stable arrangement found [structure (g)] is associated with the
C2=O1 (1.257 vs 1.223 Å) bonds, which is in line with significant formation of the S-isomer, in full agreement with the VCD results.
activation of the substrate S1.
It is believed that this conformation is stabilized by a complex
network of CH- interactions. For instance, one interaction is
observed between the t-Bu group and a phenyl group of the
diphenylphosphino moiety. Another interaction involves the CH2 of
the cyclohexenone core and the phenyl group attached to the
imino group.
Ph2P
N
2.18 Å
O
Cu
2.13 Å
O
Et
Zn
Et
6
4
5
S product
R product
O
1.47 Å
17.8
TS1
Et
Zn
O
O
H
O
(a)
0.0
(b)
2.1
N
PPh2
Cu
C
tBu
0.0
A1
(S)
N
PPh2
Ph2P
N
H
(S)
C
Et
O
O
Cu
1.54 Å
Et Cu
O
O
tBu
Zn
Et
Et
6
Zn
O
4
5
Et
O
1.53 Å
Ph2P
Cu
N
O
-36.0
E1
Et
O
Et
Zn
O
Et
Zn
O
6
H
4
5
Ph2P
N
tBu
2
O
3
O
(c)
4.1
(d)
2.3
1
(S)
1.41 Å
Cu
Et
C
Ph2P
N
(S)
C
tBu
O
O
Cu
Et
H
O
Zn
Et
Figure 5. Gibbs free energy profile of the C-C bond formation step relative to the
adduct A1 (Gibbs Free Energy in kcal/mol and distances in Å).
(S)
H
H
N
PPh2
Cu
N
Ph2P
Cu
(e)
-3.1
(f)
-3.3
O
tBu
tBu
C
O
O
Et
Et
O
O
Zn
Zn
O
The 1,6-conjugate addition proceeds through transition state TS1
(Fig. 5 and ESI, Table S1, for detailed geometrical parameters).
The C-C bond is formed on the C=C double bond side on which
the Cu center was coordinated (syn addition). The activation
barrier (in Gibbs Free Energy) is found to be 17.8 kcal.mol-1
whereas the formation of the zinc-enolate complex E1 is
exergonic by 36.0 kcal mol-1. Following the Hammond postulate
for exergonic reactions, the transition state is expected to be an
“early” one and thus reactant-like. The geometrical properties of
TS1 are in agreement with this postulate, as the Cu…Et distance
in TS1 (2.182 Å) is near to the corresponding bond in A1 (1.996
Å). Nevertheless, the forming C-C bond in TS1 remains very long
(2.125 Å), and thus far from the distance obtained in the enolate
product E1 (1.542 Å). It is thus possible to analyze the
enantioselectivity of the reaction by examination of the potential
arrangements of the ketone S1 in the A1 intermediate.[23]
Et
Et
O
Et
H
PPh2
Cu
N
tBu
Zn
(g)
-7.8
(h)
-3.8
(S)
O
Et
tBu
O
Ph2P
Cu
Et
N
O
Zn Et
O
(S)
O
H
Figure 6. Eight possible structures computed for A1 with S-DIPPAM L3 and
cyclic dienone S1 in the S-trans or S-cis conformation at the terminal C=C
double bond. Structures on the left yield the S enantiomer and those on the right
lead to the R. Energies with respect to structure (a) (referred as 0.0) are
provided.
We therefore explored various arrangements with intermediate A1
taking into account i) the two possible conformations of the C4-C5
bond, ii) the two coordination faces of the substrate (pro-R and
pro-S), iii) the two possible geometries of approach from the
DIPPAM plane. This leads to eight possible structures (see Fig.
6). In order to properly represent steric and stacking effects, a
dispersion correction was added to the DFT computations
(B3PW91-D3, see Computational Details in ESI). Whereas in non-
Confirmation of the AC by X-ray analysis
When (+)-P3 underwent deprotection to reveal the OH function for
conversion into a leaving group, we observed an undesired, but
ultimately fortuitous intramolecular 1,4-addition of the OH group at
the beta-carbon. This led to the formation of two diastereoisomeric
spiro compounds SPa and SPb which were isolated in moderate
yields (resp. 30% and 33%) after column chromatography
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10.1002/chem.201606034
Chemistry - A European Journal
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(Scheme 5). Fortunately, crystals could be obtained for SPa and experimental conditions close to those already described, or
from X-ray analysis the configuration was determined as 4S, 6R. adapted from the literature,[5b,10k,24] the expected 1,4-adduct P9
Consequently, it was confirmed that (+)-P3 had
R was formed with significant differences in both yield and enantio-
stereochemistry. In the view that (+)-P3 was obtained from a induction. Curiously, although hydroxyalkyl-NHCs L5-L6 usually
Cu/(L)-DiPPAM catalyzed 1,6-ACA involving a (Z)-dienone, this give good results in Cu-ACA, notably in the formation of all-carbon
outcome is in complete agreement with the above VCD/ORD quaternary centers,[10e,k,m] they were found to be quite inefficient
results and theoretical calculations.
toward S6 (i.e. irrespective of the nucleophilic source investigated
noticeable amounts of undesired 1,2-adducts P9b were observed,
see ESI for details). A maximum of 24% yield and 52% ee were
reached with MeMgBr. An improved yield was observed with
O
O
O
AlMe3, but with
a
significantly lower e.r. of 54.5:45.5.
Amberlyst
O
O
(R)
(S)
Phosphoramidite ligands L7-L8 appeared more appropriate in
combination with AlMe3, and in turn surpassed L5-L6 both in
terms of stereoselectivities and yields. The highest result was
gained with L7/(CuOTf)2·C6H6 (83% yield and 98.5:1.5 e.r.).
MeOH, r.t., 7 h
(S)
(S)
(R)
OTBDMS
(+)-P3
SPa, 30%
SPb, 33%
O
O
L5-L9 (4-10 mol%)
Me
Cu source (2.5-4 mol%)
+
Xray structure of SPa
M
*
R
R
method A, B or C
(2 equiv.)
Me
P5-P9
S6 or P1, P2, P4
S6 (R = iPr); P1 (R = *CH(Et)Me); P2 (R = *CH(Et)nBu)
P4 (R = *CH(Et)CH2CH2Cl)
Scheme 5. Synthesis of spiro compounds SPa and SPb; thermal ellipsoid plot
generated with Mercury v3.8 (http://www.ccdc.cam.ac.uk/mercury/) showing the
X-ray crystal structure of SPa with 30% probability ellipsoids.
Method A: Cu(OTf)2 (3 mol%), L5 or L6 (4 mol%), Et2O, 0 °C, 2 h.
Method B: Cu(OTf)2 (4 mol%), L5 (6 mol%), nBuLi (16 mol%), THF, rt, 2.5 h.
Method C: (CuOTf)2.C6H6 (2.5 mol%), L7-L9 (10 mol%), Et2O, -10 °C, 14 h.
Subsequent Cu-catalyzed 1,4-ACA of methyl derived hard
nucleophiles: formation of the all-carbon quaternary centers
Having successfully developed a 1,6-ACA reaction with various
cyclic dienones a search was initiated for a desirable combination
of catalytic system and organometallic nucleophile, which would
provide the optimum 1,4-regio- and enantioselectivity. As depicted
in Figure 7 and scheme 6, two families of chiral ligands were
evaluated (hydroxyalkyl-NHCs L5-L6, and phosphoramidites L7-
L9) along with 2 types of methyl nucleophiles (Grignard reagents
and trialkylaluminums).
O
With L6/MeMgBr (method A): 24% yield[a,b], 76:24 e.r.[c]
L5/AlMe3 (method B): 58% yield[a,d], 54.5:45.5 e.r.[c]
L7/AlMe3 (method C): 83% yield[a], 98.5:1.5 e.r.[c](R)[e]
L8/AlMe3 (method C): 50% yield[a], 97.5:2.5 e.r.[c]
Me
(+)-P9 (from S6)
O
O
With L7/AlMe3
(method C)
:
Me
Me
(R)
(S)
Me
Me
PF6
N
PF6
N
(+)-P5 (from (+)-P1)
(-)-P6 (from (-)-P1)
81% yield[f], 99:1 d.r.[g]
57% yield[f], 99:1 d.r.[g]
N
N
O
O
HO
HO
L5
L6
Cl
(S)
(R)
Me
Me
Ph
N
2-Naph
2-Naph
(-)-P7 (from (-)-P2)
75% yield[f], 98.5:1.5 d.r.[g]
(-)-P8 (from (+)-P4)
56% yield[f], 98.5:1.5 d.r.[g]
O
O
O
O
O
O
P
P
N
P
N
O
Ph
2-Naph
2-Naph
With L9/AlMe3
(method C)
:
(+)-P7 (from (+)-P2)
66% yield[f], 89.5:10.5 d.r.[g]
L9
L7
L8
(S)
Me
Figure 7. Screened Ligands L5-L9 for the 1,4-ACA addition of 3-substituted
cyclohexenones.
Scheme 6. Cu-catalyzed 1,4-ACA of MeMgBr or AlMe3 to 3-substituted
cyclohexenones with ligands L5-L9. [a] NMR yields. [b] 37% of 1,2-adduct P9b
were also formed. [c] The enantiomeric ratio was determined by GC on chiral
columns. [d] 11% of 1,2-adduct P9b were also formed. [e] The absolute
configuration (R) was assigned in accordance with previous results reported by
Alexakis.[12b] [f] Isolated yield. [g] The diastereomeric ratio was determined by GC
on chiral phase columns.
Furthermore, it was anticipated that the presence of a bulky
(branched) substituent at the beta-position of P1-P4 would make it
more difficult to procure the 1,4-ACA step as compared to those
already described in the literature. Therefore, it was decided to
perform a preliminary study with a simplified substrate S6 bearing
an isobutyl group; a similar feature to P1-P4 (Scheme 5). Under
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10.1002/chem.201606034
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Furthermore, the same level of selectivity was reached when AlEt3 Figure S2 of ESI).
was utilised as the nucleophile (99:1 e.r., see ESI for details). As For the (3R,2'R) diastereomer all conformations within 3.0
the combination of the Cu/phosphoramidite catalytic system with kcal/mol (83 total) were retained at the PM6 level, then 18
trialkylaluminum appeared the most efficient for the 1,4-ACA of conformations were found within 2 kcal/mol at B3LYP/Aug-cc-
sterically congested 3-substituted cyclohexenones, more pVDZ level and were used for VCD and ORD calculations. The
challenging substrates were evaluated (i.e. P1, P2 and P4) experimental VA, VCD, and VDF spectra for both diastereomers
(Scheme 6). When the reaction was carried out with (P5 and P6) and the corresponding calculated spectra for (3R,2'R)
L7/(CuOTf)2·C6H6, the expected products P5, P6, (–)-P7 and P8 and (3R,2'S) diastereomers are shown in Figure 9. Visual
were all isolated in good to high yields (57-81%) and excellent comparison of the calculations reveals that the majority of the
diastereoisomeric ratios (98.5:1.5 to 99:1). However, when VCD features have the same sign, and though there are some
phosphoramidite L9 was deployed in order to obtain (+)-P7, the differences in some band magnitudes, determination of the
1,4-adduct was formed with a lower stereoselectivity (89.5:10.5 relative configuration cannot be made from VCD alone. VDF
e.r.).[24]
comparison seemed to provide more discriminating power for the
1350 cm-1 band, suggesting a correlation between P5 and the
(3R,2'S) diastereomer, with additional support from the positive
band at 1200 cm-1. Though VCD and VDF analysis would suggest
that the (3R,2'S) configuration can be assigned to P5, the
assignment based on only one chiroptical method is not normally
advised,[25] especially when diastereomers exhibit similar spectra.
In the present case, even though the AC at the 2' position may be
fixed from that of the precursor, it is always recommended to
confirm the relative configuration with other methods whenever
possible.
VCD spectroscopy studies on P5, P6 and P7 adducts:
determination of the absolute configuration.
The relative configurations of P5, P6 and P7 were also
investigated by chiroptical spectroscopy. The experimental IR and
VCD of P5 and P6 diastereomers were measured and are
depicted in Figure 8. Although they have a diastereomeric
relationship that encompasses two asymmetric C3 and C2'
carbons, they possess the same IR spectrum and very similar
VCD signals [especially the bisignate peaks around 1300 cm-1 and
1200 cm-1 corresponding to CCH bending modes within the cycle
(see ESI)]. Comparison with theoretical calculations (vide infra)
showed that these two signals arise from the R stereochemistry at
the C3 carbon. In addition, P5 and P6 respectively result from the
asymmetric addition of S-(+) and R-(–)-P1 (i.e. their configuration
at C2' is retained). At this stage it is worth noting that this
stereochemical assignment (i.e. 3R,2'S-(+)-P5, 3R,2'R-(–)-P6) is
in total accord with the result obtained by Alexakis et al.[24a]
2100
(c)
(3R,2'S)
(3R,2'R)
(+)-P5
900
(-)-P6
-300
1600
1400
cm-1 1200
1000
(b)
(3R,2'S)
(3R,2'R)
(+)-P5
500
(-)-P6
-100
1600
O
1400
1200
cm-1
1000
3
2'
400
3R,2'S-(+)-P5
(a)
(3R,2'S)
O
3
2'
(3R,2'R)
(+)-P5
(-)-P6
200
3R,2'R-(-)-P6
0
1600
1400
cm-1 1200
1000
Figure 9. The experimental VA (a), VCD (b), and VDF (c) spectra of P5 and P6
and the corresponding calculated spectra for (3R,2'S) and (3R,2'R)
diastereomers.
Figure 8. Experimental IR and VCD spectra of 3R,2'S-(+)-P5 and 3R,2'R-(–)-P6
measured in CD2Cl2.
The comparison of calculated and experimental optical rotatory
dispersion (ORD) curves provides another means of analysis and
can elevate confidence with the assignment of diastereomers.
ORD curves for P5 and P6 are shown in Figure 10. DFT
calculations predict a change in the sign of the ORD for the
(3R,2'S) configuration from positive at long wavelengths to
negative at shorter wavelengths, and this is seen in the
experimental ORD only for (+)-P5. The (3R,2'R) configuration is
predicted to have negative values of ORD in the 600-400 nm
region with increasing magnitudes at shorter wavelengths, and
Conformational analysis proceeded using the methods outlined
above, except all conformations were optimized at the PM6 level
before proceeding to DFT methods. This additional optimization
was undertaken to reduce the number of conformations. For the
(3R,2'S) diastereomer, all conformations within 3.1 kcal/mol (85
total) were retained at the PM6 level, then 18 conformations were
found within 2 kcal/mol at B3LYP/Aug-cc-pVDZ level and were
used for VCD and ORD calculations (the lowest energy
conformers determined with Gibbs free energies are shown in
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10.1002/chem.201606034
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this is indeed observed experimentally for (-)-P6.
Subsequent intramolecular cyclization : towards the
formation of the drimane skeleton
Having successfully formed the all-carbon quaternary stereogenic
center at the 1,4-position on P1, P2 and P4, the intramolecular
cyclisation leading to the highly desired bicyclic drimane skeleton
was pursued (Scheme 7). Unfortunately, even starting from the
(+)-P4 1,6-adduct bearing the chloro leaving group, failed to
deliver the bicyclic product P10 (Scheme 6, conditions A). On
acidic work up (NH4Cl) the 1,4-adduct (–)-P8 was isolated in 72%
yield. This was not surprising since aluminum enolates are known
to be less reactive.[11c,26] Conversion of the Al enolate into the
corresponding ate-complex with MeLi, and addition of HMPA
(Scheme 6, conditions B), did not improve reactivity unfortunately
(i.e. cyclized product P10 was not detected).[26,27] As the tandem
1,4-ACA/enolate trapping appeared difficult to realize, it was
decided to perform the cyclization starting from isolated P8,
40
0
(3R,2'S)
P5
-40
-80
(3R,2'R)
P6
-120
nm
350
450
550
650
Figure 10. The theoretical and experimental ORD for P5 and P6 and calculated
ORD for (3R,2'S) and (3R,2'R) diasteromers.
This trend in configurational assignments matched that found from
VCD analysis, and therefore the AC and relative configuration of
both diastereomers were confidently assigned. Also this outcome
confirmed the AC at the 3 position to be the R-configuration, and
confirmed that the stereochemistry of the 2' position is retained
from the precursor (+)-P1 and (–)-P1. Finally, the experimental IR
and VCD spectra of (+)- and (–)-P7 were measured and are
depicted in Figure 11. Here again, two asymmetric C3 and C2'
carbons are present. Overall, sample (+)- and (–)-P7 have an
enantiomeric relationship, but they present different enantiomeric
and diastereomeric purities (see Table S2 in ESI). Overall, they
displayed similar IR spectra and mirror-image VCD signals. The
clear bisignate signatures around 1300 cm-1 and 1200 cm-1 that
were also found in P5 and P6, easily enabled assignment of the
3S-(+) and 3R-(-)-P7 absolute configuration by simple
comparison. This result is in total agreement with Alexakis'
results[24a] (vide supra). However, due to the huge number of
conformations accessible to the pendant chain, the VCD
calculations are prohibitive and do not enable absolute
configuration to be assigned clearly at the C2' atom. The absolute
configurations of other ACA products were further assigned by
analogy with the configurations of P1, P5, P6 and P7 determined
by VCD studies (see ESI).
following
a
procedure already described on similar
substrates.[10d,28] In the presence of KH, chloro-ketone P8 was
easily converted into P10, which was isolated in a 93% overall
yield (d.r. 1:1). Hopefully, diastereoisomers 10a and 10b could be
readily separated in 44% and 33% yields, respectively. P10b,
having the trans-fused bicycle (see ESI for details), now sets the
stage for others pursing this class of natural product, where
geminal dimethylation of the carbonyl would play a critical role.[29]
Me2AlO
Cl
O
Cl
O
Cl
Condition[a]
[Cu]/L7
(a)
(S)
(S)
(S)
(R)
(R)
AlMe3
A or B
(-)-P8 only
(+)-P4
Intermediate
enolate
Condition A: 72% yield
B: small amount
O
O
H
KH (2.5 equiv.)
Cl
(b)
(R)
(R)
(R)
THF, rt, 2 h
(S)
Me
Me
(-)-P8 (from (+)-P4)
P10 (93% yield)
50/50 diastereoisomeric mixture
O
H
O
H
H
(R)
(R)
MeMgBr
(S)
(S)
(R)
(R)
(R)
(R)
(R)
Me2TiCl2
SiO2
separation
Me
Me
P10a (44% yield)
(ref. [29])
Me
Drimane skeleton
P10b (33% yield)
O
Scheme 7. Formation of the bicyclic product P10, a direct precursor of the
drimane core: (a) via 1,4-ACA/intramolecular enolate trapping sequence from
(+)-P4 and (b) via intramolecular cyclisation from (-)-P8 adduct. [a] Condition A:
room temperature, 16 h, NH4Cl; Condition B: Concentration; then HMPA, MeLi
(1.4 equiv.), rt, 24 h; then NH4Cl.
*
3S,2'S-(+)- or 3S,2'R-(+)-P7
O
*
3R,2'S-(-)- or 3R,2'R-(-)-P7
*
*: impurity
Conclusions
To conclude, the first stereocontrolled Cu-catalyzed sequential
1,6/1,4-conjugate addition of alkyl-metal nucleophiles to cyclic
dienones has been reported. Various dienones were evaluated
using
a Cu/DiPPAM catalytic system and Et2Zn as the
Figure 11. Experimental IR and VCD spectra of R-(–)- and S-(+)-P7 measured
in CD2Cl2.
nucleophile, which afforded the expected product in high ee’s
(up to 98%) after the reconjugation step. A Cu/phosphoramidite
catalytic system utilising trialkylaluminum reagents proved to be
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10.1002/chem.201606034
Chemistry - A European Journal
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the most efficient combination for the subsequent 1,4-ACA,
which led to the 1,3-dialkylated products, comprising an all-
carbon quaternary center, with excellent de’s (up to 98%). In
addition, despite the relative flexibility of the exocyclic chain, the
absolute stereochemical configuration was established through
vibrational circular dichroism (VCD) and optical rotatory
dispersion (ORD) analysis in combination with DFT calculations.
Furthermore, the mechanism for the 1,6-addition was addressed
through DFT calculations and the proposed catalytic
intermediate determined to be a bimetallic complex, in which Zn
ensures the docking of the carbonyl function and Cu controls the
facial selectivity, and thus the enantioselectivity via a -
interaction. The experimental results were found to be fully
compatible with the theoretically proposed mechanism and have
been confirmed by X-Ray analysis of a functionalized 1,6-ACA
adduct. Lastly, this highly stereoselective catalytic sequential
Acknowledgements
MSTM, SH, HG, CC and MM thank the Agence Nationale de la
Recherche (SCATE project: ANR-12-BS07-0009-01) for
financial support. MM thanks Pr A. Alexakis for generous gift of
phosphoramidite ligands. MM and CC thank J.-P. Guégan for his
contribution to NMR deconvolution studies related to 1,4-ACA
experiments to enone S6 and elucidation of P10
diastereoisomers. CLC and PLP thank the NSF (CHE-0804301)
for financial support. This work was conducted in part using the
resources of the Advanced Computing Center for Research and
Education (ACCRE) at Vanderbilt University, Nashville, TN. J.C.
acknowledges the ANR (10-BLAN-724-1-NCPCHEM). CMW,
PVB and SNC gratefully acknowledge the University of
Queensland for financial support, and the Australian Research
Council (ARC) for a Future Fellowship award (FT110100851) to
CMW
process in combination with
cyclisation was then successfully applied to the enantioselective
synthesis of the challenging drimane core skeleton.
a subsequent intramolecular
Keywords: Asymmetric catalysis • copper • conjugate addition •
VCD/ORD • absolute configuration
Experimental Section
[1]
For general reviews dealing with ACA to extended Michael acceptors,
see: (a) Metal catalyzed Asymmetric nucleophilic addition to electron-
deficient alkenes M. Mauduit O. Baslé, H. Clavier, C. Crévisy, A.
Denicourt-Nowicki, in Comprehensive Organic Synthesis II, Vol. 4
(Eds.: G. A. Molander, P. Knochel), Elsevier, 2014, pp. 189; (b) E. M. P.
Silva, A. M. S. Silva, Synthesis, 2012, 44, 3109; (c) A. G. Csákÿ, G. de
la Herrán, M. C. Murcia, Chem. Soc. Rev. 2010, 39, 4080.
General experimental procedure for Cu(OTf)2/DiPPAM L3 catalyzed
1,6-ACA on dienones S1-S5. A flame dried Schlenk, under an argon
atmosphere, was charged with DiPPAM ligand L3 (21.3 mg, 0.05 mmol,
10 mol%), Cu(OTf)2 (9.0 mg, 0.025 mmol, 5 mol%) and anhydrous THF
(1 mL). The resulting mixture was stirred for 10 min. A 1 M solution of
diethylzinc in hexanes (1.5 mL, 1.5 mmol, 3 equiv.) was added and the
reaction mixture was stirred for 10 min. Finally, a solution of substrate
(0.5 mmol, 1 equiv.) in 0.5 mL of THF was added. The reaction mixture
was stirred for 16-40 h at the required temperature. The reaction was
quenched by the addition of solid NH4Cl (500 mg) and the mixture was
stirred for 1h. Then, anhydrous CH2Cl2 (4 mL) and DBU (100 μL, 0.7
mmol, 1.4 equiv.) were added. The mixture was stirred for 5 h. The
solution was filtered on a small pad of silica, washed with EtOAc, and
concentrated under vacuo. The crude product was purified by flash
chromatography on silica gel (pentane/Et2O 85/15 for P1 and P2,
pentane/Et2O 90/10 to 85/15 for P3, pentane/Et2O 80/20 to 60/40 for P4).
The enantiomeric excess was determined by GC or HPLC analysis of the
purified compound.
[2]
For selected papers dealing with the regiocontrol of metal-catalyzed
ACA to dienic and polyenic substrates, see: (a) T. den Hartog, Y.
Huang, M. Fañanás-Mastral, A. Mauwese, A. Rudolph, M. Pérez, A. J.
Minnaard, B. L. Feringa, ACS Catal., 2015, 5, 560; (b) J. Lu, J. Ye, and
W.-L. Duan, Chem. Commun., 2014, 50, 698; (c) Z. Ma, F. Xie, H. Yu,
Y. Zhang, X. Wu, W. Zhang, Chem. Commun., 2013, 49, 5292; (d) M.
Magrez-Chiquet, M. S. T. Morin, J. Wencel-Delord, S. Drissi Amraoui, O.
Baslé, A. Alexakis, C. Crévisy, M. Mauduit, Chem. Eur. J., 2013, 19,
13663; (e) M. Tissot, D. Poggiali, H. Hénon, D. Müller, L; Guénée, M.
Mauduit, A. Alexakis, Chem. Eur. J., 2012, 18, 8731; (f) T. den Hartog,
D. J. van Dijken, A. J. Minnaard, B. L. Feringa Tetrahedron: Asymmetry,
2010, 21, 1574; (g) H. Hénon, M. Mauduit, A. Alexakis, Angew. Chem.
Int. Ed., 2008, 47, 9122; (i) T. den Hartog, S. R. Harutyunyan, D. Font,
A. J. Minnaard, B. L. Feringa, Angew. Chem. Int. Ed., 2008, 47, 398.
For an example of Ir/Rh-catalysed sequential 1,6/1,4-ACA, see: T.
Nishimura, Y. Yasuhara, T. Sawano, T. Hayashi, J. Am. Chem. Soc.,
2010, 132, 7872.
General experimental procedure for (CuOTf)2·C6H6/L7 catalyzed 1,4-
ACA on enones (+)-P1, (-)-P1, (+)-P2, (-)-P2, (+)-P4. A flame-dried
Schlenk tube was charged with (CuOTf)2·C6H6 (6.3 mg, 2.5 mol%) and
the chiral phosphoramidite L7 (29.8 mg, 10 mol%). Anhydrous Et2O (1
mL) was added and the mixture was stirred at room temperature for 30
min. Then the Michael acceptor (1.0 equiv., 0.5 mmol) in Et2O (1 mL)
was added dropwise at room temperature and the reaction mixture was
[3]
[4]
[5]
A. Alexakis, M. J. Chapdelaine, G. H. Posner, A. W. Runquist,
Tetrahedron Lett., 1978, 44, 4205.
(a) M. S. T. Morin, T. Vives, O. Baslé, C. Crévisy, V. Ratovelomanana-
Vidal, M. Mauduit, Synthesis, 2015, 47, 2570; (b) C. Jahier-Diallo, M. S.
T. Morin, P. Queval, M. Rouen, I. Artur, P. Querard, L. Toupet, C.
Crévisy, O. Baslé, M. Mauduit, Chem. Eur. J., 2015, 21, 993; (c) M.
Magrez, J. Wencel-Delord, A. Alexakis, C. Crévisy, M. Mauduit, Org.
Lett., 2012, 14, 3576. (d) J. Wencel-Delord, A. Alexakis, C. Crévisy, M.
Mauduit, Org. Lett. 2010, 12, 4335; For an example involving Rh- and
Ir-complexes, see: (e) T. Nishimura, A. Noishiki, T. Hayashi, Chem.
Commun., 2012, 48, 973; (f) T. Hayashi, S. Yamamoto, N. Tokunaga,
Angew. Chem. Int. Ed., 2005, 44, 4224; (g) T. Hayashi, N. Tokunaga, K.
Inoue, Org. Lett. 2004, 6, 305.
stirred for further
5 min before being cooled to -10 ˚C. Then,
trimethylaluminum (0.5 mL of 2 M solution in hexanes, 2.0 equiv.) was
introduced dropwise. Once the addition was complete the reaction
mixture was left at -10 ˚C for 14 h. The reaction was hydrolyzed by the
addition of solid NH4Cl (500 mg) at -10 ˚C, and stirred for 1 h at rt. The
solution was filtered on a pad of silica gel, washed with EtOAc, and
concentrated in vacuo. GC analysis was performed on the crude product
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flash column chromatography to yield the 1,4-adduct (pentane/Et2O 97/3
to 90/10 for P5 and P6, toluene/Et2O, 97/3 for P7 or pentane/Et2O 90/10
to 80/20 for P8). The enantiomeric excess was determined by GC or
HPLC analysis of the purified compound.
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FULL PAPER
C. Blons, M. S. T. Morin, T. E. Schmid,
T. Vives, S. Colombel-Rouen, O. Baslé,
T. Reynaldo, C. L. Covington, S.
Halbert, S. N. Cuskelly, P. V. Bernhardt,
C. M. Williams,* J. Crassous,* P. L.
Polavarapu,* C. Crévisy,* H. Gérard,*
M. Mauduit*
all-carbon
tertiary &
quarternary
centers
1,6/1,4 sequential ACA process
O
O
Determination of absolute configurations
(VCD/ORD)
[Cu]/L*/Et2Zn [Cu]/L**/Me3Al
Elucidation of 1,6-ACA mechanism (DFT)
1,6-ACA
1,4-ACA
*
*
R
Access to the Drimane skeleton
R
up to 98% ee up to 98% de
Me
R = Me, nBu, (CH2)2OTBDMS, (CH2)2Cl L* = DiPPAM; L** = Phosphoramidite
A stereo-controlled Cu-catalyzed sequential 1,6/1,4-ACA of C-metalated hard
nucleophiles to cyclic dienones is reported. High ee’s and de’s were reached, thus
affording enantio-enriched 1,3-dialkylated moieties. The absolute configurations
were determined using VCD and ORD spectroscopy, in combination with DFT
calculations and X-Ray analysis. Interestingly, DFT calculations of the mechanism
for the enantioselective 1,6-addition via an unprecedented Cu-Zn bimetallic
catalytic system confirmed this attribution. This methodology was applied to the
synthesis of drimane skeleton.
Page No. – Page No.
Asymmetric Sequential Cu-Catalyzed
1,6/1,4 Conjugate Additions of Hard
Nucleophiles to Cyclic Dienones.
Determination of Absolute
Configurations and Origins of
Enantioselectivity
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