Asymmetric conjugate addition to α-substituted enones/enolate trapping

Article abstract of DOI:10.1021/ol403104s

An NHC-Cu complex catalyzed the asymmetric conjugate addition (ACA) of various Grignard reagents to nonactivated α-substituted cyclic enones to give 2,3-dialkylated cyclopentanones and cyclohexanones. The Michael addition features the formation of a magnesium enolate intermediate. One-pot diastereoselective trapping of this enolate by alkyl, propargyl, allyl, and benzyl halides led to ketones with contiguous α-quaternary and β-tertiary centers.

Full text of DOI:10.1021/ol403104s

Letter
pubs.acs.org/OrgLett
Asymmetric Conjugate Addition to α‑Substituted Enones/Enolate
Trapping
Nicolas Germain,† Laure Guenee,‡ Marc Mauduit,§ and Alexandre Alexakis*,†
́
́
†Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet, 30, 1211 Geneva 4, Switzerland
‡Laboratory of Crystallography, University of Geneva, Quai Ernest Ansermet, 24, 1211 Geneva 4, Switzerland
§Ecole Mational Super
́ ́
ieure de Chimie de Rennes, UMR 6226, Institut des sciences chimiques de Rennes - Equipe OMC, 11, allee de
Beaulieu, Rennes 7, France
S
* Supporting Information
ABSTRACT: An NHC−Cu complex catalyzed the asym-
metric conjugate addition (ACA) of various Grignard reagents
to nonactivated α-substituted cyclic enones to give 2,3-
dialkylated cyclopentanones and cyclohexanones. The Michael
addition features the formation of a magnesium enolate
intermediate. One-pot diastereoselective trapping of this
enolate by alkyl, propargyl, allyl, and benzyl halides led to
ketones with contiguous α-quaternary and β-tertiary centers.
he copper-catalyzed asymmetric conjugate addition
practice, the sequence still deserves further optimization.
Concerning α-susbtituted enones, the first tests showed that
benzyl bromides were unsuccessfully trapped by aluminum
enolates: the low reactivity toward benzyl iodide can be
circumvented by a stoichiometric addition of methyllithium.4
While racemic conjugate additions/trapping of lithium and
magnesium enolates are largely documented, the one-pot
asymmetric version received by far less attention.5 In our
model, we envisioned that A1,2 strain in the distorted 2-
substituted cyclopentenyl enolate would bring the pseudoaxial
isopropyl unit to shield one face of the enolate for the
diastereoselective formation of ketones bearing two contiguous
tertiary and quaternary centers.6
T
(ACA) is a well-established technology to build
carbon−carbon bonds.1 While manifold methodologies dealing
with the ACA to monosubstituted or β-disubstituted enones are
reported, the particular case of α-substitution remains unex-
plored because of its lack of reactivity. To date, only one
procedure was developed for 2-methylcyclohexenone using
only trimethyl- and triethylaluminum (Scheme 1A).2 However,
Scheme 1. Asymmetric Conjugate Addition to Enones
Due to their prevalence in natural products, developing a
straightforward access to all-carbon quaternary centers is of
great importance.7 The direct construction of ketones with α-
quaternary centers is still a challenge, and except for two
isolated works of Knochel et al. and Trost et al.,8 all of the
methods rely on enolate chemistry.9−12 Nevertheless, only a
few of those aforementioned strategies were applicable to 5-
membered rings.
Herein, we disclose the first ACA of Grignard reagents to 2-
substituted cyclopentenones and cyclohexenones followed by
the trapping of the magnesium enolate by various electrophiles
(Scheme 1B). A double-diastereoselective process in sequential
two-step catalysis and application to the formal synthesis of
natural products are also discussed.
We first examined the reactivity of commercially available 2-
methylcyclopentenone under different reaction conditions.
After optimization, the L-tert-leucinol and di-o-tolylmethan-
amine-based Mauduit-type NHC ligand 5 was found to be
the extension to five-membered rings gave low selectivity. From
those limitations, a general approach to face this particularly
challenging Michael addition is needed. Mauduit-type copper-
(I)−N-hetereocyclic carbene (NHC) complexes have shown
potent catalytic activity for the transfer of various organo-
metallic reagents.3 We thus considered using these catalysts to
promote the addition of versatile Grignard reagents to various
α-substituted enones. In addition, the tandem conjugate
addition−enolate trapping is potentially a unique tool for
regio- and diastereoselective α-alkylation of ketones. In
Received: October 29, 2013
© XXXX American Chemical Society
A
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Organic Letters
Letter
optimal for our study using only 0.75 mol % of catalyst
loading.13 The scope of nucleophiles revealed that primary
Grignard reagents were inferior to their branched counterparts
(Table 1, entry 1 vs 2).
Scheme 3. Tandem ACA/Enolate Trapping to α-Substituted
Cyclopentisopropylenones
a,b
Table 1. Scope of Grignard Reagents for the ACA to 2-
Methylcyclopentenone
a
b
c
entry
product
R
yield (%)
dr
er
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
Et
75
88
71
60
85
91
65
90
89
81:19
60:40
91:9
80:20
92:8
i-Pr
3-pentyl
5-heptyl
c-pentyl
c-hexyl
c-heptyl
i-Pr
85.5:14.5
87:13
75:25
52:48
61:39
52:48
60:40
60:40
91.5:8.5
90:10
6g
6b
6b
91.5:8.5
92:8
a
b
er after recrystallization. 7 instead of 4. X-ray crystal structures
d
8
e
(ORTEP) of 16 (thermal ellipsoids shown at 50% probability).
9
i-Pr
93.5:6.5
a
1H NMR spectroscopy showed full conversion for all examples.
dialkylated cyclopentanone. As the X-ray structure of 14
suggests,17 a trans selectivity is observed. Analogously, we
extended our reaction conditions to six-membered rings
(Scheme 4). Diastereoselective formation of cyclohexanones
proceeded with up to 99:1 dr using the same electrophiles as
before.
b
c
d
Trans/cis ratio. Same er value for both diastereomers. Reaction
e
scaled up to 3 mmol. Batch of >3 M of i-PrMgBr.
We then explored the scope of Michael acceptors, and
gratifyingly, 3-isopropyl-2-pentylcyclopentanone could be pre-
pared in 90:10 er (Scheme 2).14 While primary Grignard
Scheme 4. Tandem ACA/Enolate Trapping to α-Substituted
Cyclohexenones
Scheme 2. Application to Other Michael Acceptors
Since trapping of electrophiles led to trans adducts, a second
chiral system is required to invert the selectivity and
independently control the stereochemistry of the α-center.
This sequence formally converts enantiomers to diastereomers,
which are separable isomers. Two-step asymmetric catalysis is
known, but only one displays double-diastereoselective
processes as a second step.18 We thus decided to quench the
magnesium enolate with allyl chloroformate. Racemic ACA
followed by a racemic decarboxylative allylic alkylation gave 2:1
dr (see Scheme 3 and Table 2). This result was rather
surprising since the comparison of eqs 2 and 3 inScheme 2
indicates that a comparable level of diastereoselection can be
reached for β-ethyl and β-isopropyl groups. Once quenched
with HMPA and allyl iodide, magnesium enolate gave 19 in a
perfect 99:1 dr while a 2:1 mixture was obtained with a Pd(η3-
allyl) complex. Considering that allyl vinyl carbonates bearing a
reagents gave lower er for ACA to cyclopentenones, they were
more efficient for the addition to 2-methylcyclohexenone.
Indeed, we validated our concept for the addition of ethyl- and
isopropylmagnesium bromide with, respectively, 90:10 er and
90.5:9.5 er.15 Since the trapping of the magnesium enolate by a
proton gave moderate dr values (Table 1), we envisaged using
other electrophiles (Scheme 3).The reaction of magnesium
enolate with propargyl bromide,16 activated alkyl or allyl
halides, and benzyl bromides yielded synthetically versatile
adducts 12−16 in practical yields and diastereoselectivity up to
99:1 in favor of the trans adduct.
Remarkably, one-pot addition of methyl iodide to 2-pentyl-
substituted enolate gave 3-isopropyl-2-methyl-2-pentylcyclo-
pentanone 17, the first example of enantioenriched 2,2,3-
B
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Letter
Table 2. Double-Diastereoselective Decarboxylative Allylic
Alkylation
Scheme 5. Application to the Formal Synthesis of Natural
Products
a
b
c
entry
solvent
ligand
conv (%)
dr
er
1
2
3
THF
R
R
S
100
82
90:10
93:7
96:4
97:3
toluene
toluene
100
42:58
99.5:0.5
a
b
c
Conversion measured by 1H NMR spectroscopy. Trans:cis ratio. er
value of the major diastereomer.
stereocenters like 24 have not been explored yet, we decided to
apply the methodology developed by Stoltz et al. In the
constructive case, chiral allyl vinyl carbonate 24 was smoothly
converted to ketone 25 (96:4 er, 90:10 dr) in the presence of
PHOX ligands and tris(dibenzylideneacetone)dipalladium(0)
(Table 2).12,19
The reaction was quantitative in THF using (R)-i-Pr-PHOX.
In toluene, the reaction gave slightly higher enantioselectivity
(97:3) and diastereoselectivity of 93:7 (entry 1 vs 2).20 We
logically tested the other enantiomer (S)-i-Pr-PHOX, and we
were pleased to observe a total conversion and 42:58 dr in favor
of the cis adduct. In this destructive case, the major cis
diastereomer was measured in 99.5:0.5 er.
We eventually turned our attention to the formal synthesis of
natural products. Our sequence offered a concise alternative
route for the preparation (+)-4,5-deoxyneodolabelline or other
neodolabellane skeletons starting from ketone 4.21 Following
the above-mentioned procedure, 2-allyl-3-isopropyl-2-methyl-
cyclopentanone 26 can be synthesized using allyl iodide in 92:8
er and 99:1 dr (Scheme 5A). Another example of allyl halide
has been attempted in the formal synthesis of tetraquinane
diterpenoid crinipellin B.22 Our strategy using the same
conditions as before, with 2-(bromomethyl)-1-butene as
electrophile and stoichiometric addition of methyllithium,
allowed for the preparation of ent-27 in good yield, 92:8 er,
and 99:1 dr (Scheme 5B). Noteworthy, magnesium enolate can
also be activated by methyllithium even if no activation is
essentially required for all the other examples showed in this
communication. We then focused on a key intermediate of the
synthesis of guanacastepene A.23,24 Since the direct trapping
using methyl vinyl ketone (MVK) led to a complex mixture, we
opted for a synthetic equivalent. Addition of trimethylsilyl
iodide to MVK generated (4-iodobutenyloxy)trimethylsilane 28
in situ, which was reacted with the magnesium enolate.25 The
iodine of 28 is then displaced to afford 3-isopropyl-2-methyl-2-
(3-oxobutyl)cyclopentanone ent-29 in 92:8 er and 68:32 dr
after acidic workup (Scheme 5C).
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and complete characterizations
(NMR spectra, GC and HPLC traces of both racemic and
enantioenriched Michael adducts, IR, and HRMS). This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*alexandre.alexakis@unige.ch
Notes
The authors declare no competing financial interest.
In summary, we have developed the first asymmetric
conjugate addition of Grignard reagents to 2-substituted cyclic
enones. The length of the aliphatic side chain and the ring size
had little influence on the outcome of the methodology.
Tandem ACA/enolate trapping was achieved to give
contiguous α-quaternary β-tertiary centers in high er and dr.
We also set up a multistep catalysis in order to produce cis and/
or trans 2,2,3-trisubstituted cyclohexanones in high selectivity.
Studies to extend the scope of this reaction as well as
mechanistic considerations are currently underway in our
laboratory.
ACKNOWLEDGMENTS
■
We thank Professor Clem
Lacour for helpful discussions.
́
ent Mazet and Professor Jer
́
ome
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Letter
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