Highly enantioselective one-pot copper-catalyzed 1,4 addition/ organocatalyzed α-substitution of enals

Article abstract of DOI:10.1002/adsc.201000309

The asymmetric copper-catalyzed addition of dialkylzinc to enals followed by organocatalyzed one-pot aldehyde α-functionalization has been accomplished providing C-C, C-Cl or C-F bond formation. These simple procedures led to the creation of two contiguou

Full text of DOI:10.1002/adsc.201000309

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DOI: 10.1002/adsc.201000309
Highly Enantioselective One-Pot Copper-Catalyzed 1,4 Addition/
Organocatalyzed a-Substitution of Enals
Adrien Quintarda and Alexandre Alexakisa,*
a
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, 1211, Geneva 4, Switzerland
Fax : (+41)-22-379-3215; phone: (+41)-22-379-6522; e-mail: alexandre.alexakis@unige.ch
Received: April 21, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000309.
Abstract: The asymmetric copper-catalyzed addi-
tion of dialkylzinc to enals followed by organocata-
lyzed one-pot aldehyde a-functionalization has
been accomplished providing C C, C Cl or C F
bond formation. These simple procedures led to the
creation of two contiguous stereocenters in excel-
lent enantioselectivities (typical ee=99%). This
methodology has been applied in the synthesis of
(2S,3S) isomer of Valnoctamideꢀ.
agents to a,b-unsaturated aldehydes. This reaction
leads cleanly to the 1,4 adduct under relatively mild
and simple conditions (use of BINAP, at 0 to À208C),
but unfortunately with relatively modest enantioselec-
tivities (around 90:10 er).[6]
Thus, enantioselectivities in the case of two contigu-
ous stereocenters should be improved by combining
the Cu-catalyzed reaction with an enamine step
(Scheme 1). There are several advantages in carrying
À
À
À
Keywords: copper; enals; enantioselectivity; Mi-
chael addition; organocatalysis
Generating high molecular complexity with multiple
stereocenters in a minimum of operations is one of
the great challenges synthetic chemists are facing. The
asymmetric Cu-catalyzed conjugate addition of organ-
ometallic reagents with subsequent electrophilic trap-
ping of the enolate generated in situ, is one of the
methods of choice for such a purpose.[1] Unfortunate-
ly, most of these reactions occur on cyclic systems, are
often limited in terms of electrophiles scope, and
mostly, lead to the formation of only the trans diaste-
reoisomer.[2]
Scheme 1. Proposal for the one-pot copper/enamine reac-
tions.
Recently, enamine catalysis has emerged as a out these two reactions in a one-pot process. First, it
method of choice for the a-functionalization of car- could improve the overall yield, particularly when
bonyl compounds, notably aldehydes, in high enantio- volatile aldehyde intermediates are involved. Further-
selectivity and with a large scope of electrophiles.[3] more, another of the great advantage would be its ap-
Furthermore, this methodology has already shown plication in enantiodivergent synthesis. Indeed, by
widespread applications in cascade reactions due to switching the enantiomers of copper ligand/organoca-
the high compatibility of the reaction system.[4] Thus talyst, each pair of enantiomers and diastereoisomers
combining an enantioselective copper-catalyzed Mi- could be obtained.[4a,7]
chael reaction with an asymmetric enamine organoca-
talytic step would easily lead to highly functionalized of diethylzinc to trans-2-heptenal, catalyzed by copper
enantioenriched compounds.[5]
thiophene carboxylate (CuTC) with (R)-BINAP, was
In a preliminary experiment, the conjugate addition
Recently, our group reported the first enantioselec- followed by trapping with the highly electrophilic
tive copper-catalyzed addition of organometallic re- vinyl sulfone 2 (Scheme 2).[8] Without any amine cata-
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Adv. Synth. Catal. 2010, 352, 1856 – 1860

Highly Enantioselective One-Pot Copper-Catalyzed 1,4 Addition/Organocatalyzed a-Substitution of Enals
(Scheme 3). As expected, excellent enantioselectivi-
ties for the one-pot procedure were obtained in all
cases (99% ee). Small alkyl substituents (R’=Me) as
well as bulky ones (R’=i-Pr) could be used leading to
Scheme 2. Preliminary attempts using vinyl sulfone 2.
lyst, direct quenching of the zinc enolate did not lead
to any diastereocontrol (dr=1/1) with the formation
of numerous side products. However, when commer-
cial (S)-TMS-protected diphenylprolinol catalyst 4a
was used (after quenching of the zinc enolate by addi-
Scheme 3. Scope of the one-pot addition to sulfone 2.
tion of acetic acid), excellent enantioselectivity (99% the same range of yields (57 to 71%) and diastereose-
ee) was obtained for the syn isomer with a good 71% lectivities (dr=75/25 to 85/15). It must be pointed out
isolated yield.[9] Using the (R)-enantiomer 4b, the anti that chloroform had to be added for the second step
adduct was formed predominantly with also an excel- when Me2Zn was used for a better solubilization of
lent 99% ee confirming the reaction potential in enan- the mixture. Furthermore, by choosing the appropri-
tiodivergent synthesis. Using aminal-pyrrolidine cata- ate catalyst/ligand combination, one can synthesize
lysts 4c and 4d, which already gave excellent results either the syn or the anti isomer.
in such additions, also led to the same levels of enan-
To demonstrate the utility of the methodology,
compound 3d was applied to the synthesis of (2S,3S)-
tioselectivity together with slightly higher yield.[10]
Since the two enantiomers of TMS-protected diphe- 2-ethyl-3-methylvaleramide 7 (Scheme 4). This stereo-
nylprolinols 4a and 4b are cheap and commercially isomer of Valnoctamideꢀ (a mild tranquilizer com-
available, this catalyst has been chosen to study the mercialized as a mixture of four stereoisomers) is cur-
scope of the reaction.
rently in preclinical testing and has been prepared by
Structurally different alkyl enals and diethyl- or di- an eight-step synthesis.[11] Oxidation of the aldehyde
methylzinc were then tested in this reaction 3d followed by removal of the sulfone using Mg/
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Scheme 4. Application to the synthesis of (2S,3S) isomer of Valnoctamideꢀ 7.
MeOH led to (2S,3S)-2-ethyl-3-methylvaleric acid 6 Changing from (R)-BINAP to (S)-BINAP for alde-
which can give access in one step to Valnoctamideꢀ as hyde 1a, and using dimethylzinc, induced a total re-
previously reported.[11]
versal from the anti to the syn adduct 8b.
Besides the addition to highly reactive vinyl sulfone
Another interesting reaction is the chlorination of
2, we wondered if this one-pot procedure could be ap- aldehydes which can give access to highly versatile
plied to other electrophiles.
molecules.[14] Preliminary experiments using NCS as
We thus turned out our attention to the organocata- the chlorinating reagent and various commercial orga-
lytic fluorination (Scheme 5). Gratifyingly, the orga- nocatalysts afforded disappointing results (poor con-
nocatalytic trapping was also efficient using NFSI as version, mixture of mono- and di-chlorinated prod-
fluorine source.[12] Excellent enantioselectivities were ucts).[15] Conversely, the direct chlorination of zinc
obtained of the fluorinated adduct 8a using the com- enolates also affords mixture of diastereomers.[2d] For-
mercially available BINAP/4e catalyst combination. tunately, using aminal-pyrrolidine catalyst 4d, a good
This insertion of fluorine is highly interesting due to selectivity for the mono-chlorinated adduct (25/1 to
the importance of fluorine in medicinal chemistry.[13] 99/1) was observed together with good enantioselec-
tivities (ee>98%) using either dimethyl- or diethyl-
zinc reagents (Scheme 6). Furthermore, no other side
products were detected in the crude reaction mixture.
Finally, attempts using other electrophiles as a bro-
mine source, DEAD or PhNO failed. PhNO or
DEAD decomposed in the reaction mixture while
bromination with 4,4-dibromo-2,6-di-tert-butylcyclo-
hexa-2,5-dienone lead to a 1/1 diastereoisomeric ratio.
This is probably due to the racemization of the
carbon stereocenter bearing the bromine atom under
acidic conditions. Finally, nitroolefins did not give any
conversion in the one-pot reaction conditions. It is of
course possible to perform the above reactions in a
two-pot procedure.
In conclusion, we have disclosed here the first one-
pot copper Michael/enamine substitution on enals.
Different dialkylzinc nucleophiles in combination
with various electrophiles could be used leading to
the creation of two stereogenic centers in almost per-
fect enantioselectivities. Furthermore, the reaction
occurs under simple and mild conditions using in
most cases cheap commercially available catalysts
(BINAP and diaryl-prolinol silyl ethers). This repre-
sents the first example of combination of an asymmet-
Scheme 5. One-pot Michael/fluorination sequence.
ric copper-catalyzed step, combined with an enantio-
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Adv. Synth. Catal. 2010, 352, 1856 – 1860

Highly Enantioselective One-Pot Copper-Catalyzed 1,4 Addition/Organocatalyzed a-Substitution of Enals
mixture was extracted by three times 10 mL of dichlorome-
thane, the organic layer washed by 5 mL of water, dried
over Na2SO4 and the solvent evaporated to give the crude
product. Purification by flash chromatography using a cyclo-
hexane/ethyl acetate (8/2) mixture afforded the correspond-
ing Michael adduct; yield: 96.0 mg (0.23 mmol, 58%).
1H NMR (400 MHz, CDCl3): d=0.8–0.96 (m, 6H), 1.24–1.42
(m, 2H), 1.81–1.85 (m, 1H), 2.08–2.15 (m, 1H), 2.45–2.56
(m, 1H), 3.01–3.12 (m, 1H), 4.70 (dd, major dia, 1H, J=6.0,
3.2 Hz), 4.75 (m, minor dia, 1H), 7.54–7.96 (m, 10H), 9.53
(s, 1H, minor dia), 9.60 (s, 1H, major dia); 13C NMR
(75 MHz, CDCl3): d=11.9 (CH3), 16.4 (CH3), 22.1 (CH2),
26.5 (CH2), 35.8 (CH), 53.5 (CH), 80.9 (CH), 129.1 (CH),
129.3 (CH), 129.7 (CH), 134.5 (CH), 134.7 (CH), 137.7
(Cquat), 204.1 (CH); MS (ESI): m/z=409.3 [M+H]+; HR-
MS (ESI): m/z=426.1400 [M+NH4]+, calcd. for
C20H28O5S2N: 426.1403.
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Experimental Section
All the relative and absolute configurations were assigned
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General Procedure for the One-Pot Copper Catalysis/
Addition to Sulfone
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enal), and 46.8 mg of (S)-BINAP (11 mol%/enal) in 3.6 mL
of diethyl ether was stirred at room temperature for 20 min
under argon. The solution was then cooled down to 08C
before the dimethylzinc (1.32 mmol, 3.3 equiv. (1,2M in tol-
uene) was added and the solution stirred 15 min at 08C.
Pentenal (0.66 mmol, 1.65 equiv.) in 1 mL of diethyl ether
was then added and the resulting solution stirred at 08C for
14 h. 0.35 mL of acetic acid and 1.5 mL of chloroform were
then added and the mixture warmed up to room tempera-
ture. 20 mol%/sulfone of the TMS-protected diphenyl proli-
nol (26 mg, 0.08 mmol) and then 120.4 mg of the vinyl sul-
fone (0.4 mmol, 1 equiv.) were added. The mixture was
stirred at room temperature for 2 h before the reaction was
quenched by addition of 5 mL of 1M HCl, The reaction
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