Trends in organocatalytic conjugate addition to enones: an efficient approach to optically active alkynyl, alkenyl, and ketone products

Full text of DOI:10.1002/anie.200903790

Communications
DOI: 10.1002/anie.200903790
Organocatalysis
Trends in Organocatalytic Conjugate Addition to Enones: An Efficient
Approach to Optically Active Alkynyl, Alkenyl, and Ketone
Products**
Mꢀrcio Weber Paix¼o, Nicole Holub, Carlos Vila, Martin Nielsen, and Karl Anker Jørgensen*
Asymmetric organocatalysis provides an elegant and easy
procedure to introduce chiral information into a substrate.[1]
Thus, the challenging problem of developing efficient organo-
taining divergent skeletal arrays.[9] Therefore, expanding the
scope of the Michael reaction with respect to the nucleophilic
species would represent an important advance. Herein we
report the first highly enantioselective formal alkynylation,
alkenylation, and homo-ketonylation using the concept of the
conjugate addition of b-keto-heterocyclic sulfones 2 to cyclic
a,b-unsaturated ketones 1, catalyzed by the 9-epi-amino
cinchona alkaloid salt 3. We found that applying b-keto-
sulfone 2 as a reaction partner leads to a privileged addition
intermediate 4,[10] which can be easily transformed into the
corresponding trans-3-alkenyl cyclohexanols 5, b-alkynylke-
tones 6, or the ketone products 7, depending on the applied
reaction conditions (Scheme 1).[11]
À
catalytic methods for C C bond formations has been
attractive to many chemists, and within the past few years
new reaction protocols have been disclosed by numerous
research groups.[1,2]
Within this context, the organocatalytic asymmetric con-
jugate addition of carbon nucleophiles to a,b-unsaturated
carbonyl compounds is a well-documented strategy, which
provides a direct and simple route for the synthesis of
versatile, enantiomerically enriched building blocks.[3] How-
ever, the majority of reports to date are limited to simple
nucleophiles, which lead only to the bond formation between
two sp3-hybridized carbon
atoms.[4] In contrast, asymmet-
ric conjugate addition of sp2-
and sp-hybridized carbon-
based nucleophiles remains a
challenging task.[5,6]
Nowadays, new synthetic
strategies offering high diver-
sity and operational efficiency
are becoming more evident.[7]
In this respect, catalytic
tandem reactions in an iterative
manner are an especially robust
model, which enables the effi-
cient conversion of simple start-
ing materials into a library of
small molecules.[8] The general
concept involves the formation
of a chiral intermediate, which
can be distinctly manipulated,
through different transforma-
tions, to afford products con-
Scheme 1. Organocatalytic asymmetric alkynylation, alkenylation, and homo-ketonylation reactions of
enones.
We began our investigations by examining the ability of
the 9-amino-9-deoxyepiquinine TFA salt (3)[12] to promote
the organocatalytic asymmetric conjugate addition of either
b-keto-1-phenyl-1H-tetrazol-5-yl sulfone (2a) or b-keto-ben-
zothiazol-2-yl sulfone (2b) to cyclohexenone (1a), and some
representative results are presented in Table 1.
To our delight, by performing the reaction in toluene we
were able to isolate the desired Michael adduct 4aa in 80%
yield and 91% ee (Table 1, entry 1). In attempts to improve
the yield and enantioselectivity, we screened several solvents
and different heterocyclic-substituted nucleophiles. Whereas
[*] Dr. M. W. Paix¼o, Dr. N. Holub, C. Vila, M. Nielsen,
Prof. Dr. K. A. Jørgensen
Center for Catalysis Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
Fax: (+45)8619-6199
E-mail: kaj@chem.au.dk
[**] This work was made possible by a grant from The Danish National
Research Foundation, OChemSchool, Carlsberg Foundation, Deut-
sche Forschungsgemeinschaft (N.H.), and a predoctoral grant from
Generalitat Valenciana (C.V.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903790.
7338
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Angew. Chem. Int. Ed. 2009, 48, 7338 –7342

Angewandte
Chemie
Table 1: Initial screening studies: Nucleophilic species and solvents.[a]
sulfones, 2b–i, underwent conjugate addition with consis-
tently high to excellent enantioselectivities, regardless of their
steric or electronic nature (86–98% ee). Both electron-with-
drawing and electron-donating substituents, as well as ortho-,
meta-, and para-substitution patterns were well tolerated,
delivering the desired products with E/Z ratios in the range of
4:1 to 3:1 (Table 2, entries 1–5). The bulky b-keto-sulfone 2h,
derived from 2-naphthylketone, gave the trans-3-alkenyl
cyclohexanol 5ah in
a slightly higher E/Z ratio (5:1)
(Table 2, entry 6), whereupon the employment of the alkyl-
substituted nucleophile 2i resulted in a decrease of yield and
enantioselectivity (Table 2, entry 7).
Entry
Het[b]
Solvent
t [h]
Product
Yield
[%][d]
ee
[%][e]
1
2
3
4
2a
2a
2a
2a
2b
2b
toluene
THF
Et2O
dioxane
dioxane
dioxane
24
48
44
24
24
24
4aa
4aa
4aa
4aa
4ab
ent-4ab
80
67
82
63
96
90
91
94
90
96
94
96
We next evaluated the effect of various enones in the
asymmetric induction (Table 2, entry 8–11). It appears from
these results that the enantioselectivity is very dependent on
the ring size and substitution pattern of the ring. For 1b and
1d, the reaction proceeds well, however, the enantiomeric
excess of the products were 60% and 88% ee, respectively.
Furthermore a 1:1 and 4:1 mixture of E/Z isomers were
obtained (Table 2, entry 8 and 10). Notably, increasing the
ring size to a seven-membered ring led to an improvement in
the enantioselectivity up to 98% ee (Table 2, entry 9). We also
investigated the alkenylation of 1e, wherein the product was
obtained in high enantiomeric excess (94% ee) and a 4:1 E/
Z ratio (Table 2, entry 11).
The absolute configuration of the stereogenic center
formed in the Michael addition step was determined to be S
by chemical comparison to the corresponding ketone of
compound 5cb.[5i] Additionally, in case of all employed six-
membered cyclic enones the products 5 were obtained
exclusively as the anti-configurated diastereoisomer, which
5
6[c]
[a] Reactions conditions: 1 (0.4 mmol), 2 (0.2 mmol), and 3 (20 mol%).
[b] PT=1-phenyl-1H-tetrazol-5-yl; BT=benzothiazol-2-yl. [c] Quasi-en-
antiomer of 3 was used. [d] Yield of the isolated combined diastereo-
mers. [e] Determined by chiral stationary phase HPLC analysis of the
trans-3-alkenyl cyclohexanol 5ab. THF=tetrahydrofuran.
reactions carried out in THF or Et2O were rather slow, we
were pleased to find that reactions performed in dioxane
proceeded with acceptable rates along with high enantiose-
lectivities (Table 1, entries 2 and 3 versus 4). Next, the
nucleophile 2 was modified to observe a possible effect on
the yield and enantioselectivity. Using nucleophile 2b led to
the desired product in higher yield and maintained the
excellent enantioselectivity, 96%
and 94% ee, respectively (Table 1,
Table 2: Organocatalytic alkenylation of a,b-unsaturated ketones 1a-e using b-keto-sulfones 2b-i.[a]
entry 4 versus 5). As expected, the
quasi-enantiomer of the catalyst
furnished the desired product with
virtually the same enantioselectiv-
ity and opposite configuration
(Table 1, entry 6).
Having in hand a general and
efficient protocol for the organo-
catalytic conjugate addition, we
turned our attention to the scope
and limitations of the envisaged
transformations. The special value
of the enantiomerically enriched
compounds 5 obtained by the orga-
nocatalytic alkenylation protocol
(Scheme 1, Method A) is partly
because of their importance in the
synthesis of numerous natural
products which are of interest to
the pharmaceutical industry.[13] In
addition, the double-bond unit pro-
vides a convenient handle for sev-
eral structural manipulations.[14] As
shown in Table 2, when the reac-
tion was performed with 1a, a
number of representative b-keto
Entry Enone
Nu (R)
Product Yield [%][b] Product Yield [%][b] E/Z[c] ee [%][d]
1
1a (n=1) 2c (o-Me-C6H4) 4ac
98
90
92
89
90
91
90
96
94
86
93
5ac
5ad
5ae
5af
5ag
5ah
5ai
5bb
5cb
5 db
4eb
64
59
67
57
61
62
48
56
62
63
68
4:1
4:1
3:1
3:1
3:1
5:1
4:1
1:1
5:1
4:1
4:1
98
96
94
93
94
96
86
2
3
4
5
1a (n=1) 2d (o-BrC6H4)
1a (n=1) 2e (m-ClC6H4)
1a (n=1) 2 f (p-MeC6H4)
1a (n=1) 2g (p-FC6H4)
4ad
4ae
4af
4ag
6
1a (n=1) 2h (2-naphthyl) 4ah
7[f]
8[g]
9[g,h]
1a (n=1) 2i [(CH2)2Ph]
1b (n=0) 2b (Ph)
1c (n=2) 2b (Ph)
4ai
4bb
4cb
4db
4eb
60[e]
98[e]
88[e]
94
10[h,i] 1d
2b (Ph)
2b (Ph)
11[h]
1e
[a] Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), and 3 (20 mol%); then NaBH4 (0.6 mmol) in a
toluene/MeOH (4:1) solution. [b] Yield of isolated product. [c] Determined by 1H NMR analysis of the
crude reaction mixture of 5. [d] Determined by chiral stationary phase HPLC analysis of 5. [e] The
ee values were determined by oxidation of the alcohol to the corresponding ketone derivatives. [f] LiBH4
(0.4 mmol) in THF used for the reduction. [g] Observed syn/anti diastereomeric ratio was 1:1.
[h] Reaction was performed at 458C. [i] Observed syn/anti diastereomeric ratio was 1:4.
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was assigned by NOE analysis. Whereas the reduction of 4 db
still resulted in a 1:4 mixture of syn/anti isomer, the selectivity
observed in cases of both 1b and 1c was 1:1.
toward the synthesis of chiral 1,5-dicarbonyl compounds 7
(Scheme 1, Method C)—the homo-ketone addition product
which can be obtained by the same reaction concept. The
reaction is an attractive alternative for the preparation of
these synthetically useful compounds.[16] Consequently, con-
siderable attention has been given to the development of a
new and straightforward catalytic asymmetric method which
can provide this useful synthon. We were pleased to find that
the Michael adducts 4 can be easily converted into the
corresponding enantioenriched 1,5-dicarbonyl compounds 7
by direct addition of solid Na2CO3 in a THF/iPrOH (1:1)
solution. In an effort to realize our goal of generating
synthetically useful products, a wide variety of nucleophiles
and enones were examined and the results are given in
Table 4.
Having been successful in our approach to the develop-
ment of the tandem procedure, we decided to expand this
organocatalytic diversity oriented synthesis to the asymmetric
synthesis of b-alkynylated ketones 6 (Scheme 1, Method B).
We judged this to be critical for our investigation, as the
conjugate addition of alkynyl groups to cyclic a,b-unsaturated
ketones has recently generated tremendous amount of
interest, which originates from their synthetic utility.[15]
To our delight, under weak basic conditions the privileged
intermediate 4 could be transformed into the corresponding
chiral alkyne 6 and it was possible to develop a successful one-
pot procedure for the enantioselective alkynylation of enones.
A range of cyclic enones proceeded to react efficiently and
cleanly with a wide variety of nucleophiles as presented in
Table 3.
Table 4: Organocatalytic synthesis of enantioenriched 1,5-dicarbonyl
compounds.[a]
Table 3: Organocatalytic alkynylation of a,b-unsaturated ketones.[a]
Entry Enone
Nu (R)
Product Yield ee
[%][b] [%][c]
1
2
3
4
5
6
7
1a (n=1, R1 =H)
2b (Ph)
7ab
7ac
7ad
7ag
61
57[d]
66
64
51
64
76
94
98
96
97
97
99
94
Entry Enone
Nu (R)
Product Yield ee
1a (n=1, R1 =H)
1a (n=1, R1 =H)
1a (n=1, R1 =H)
1a (n=1, R1 =H)
1c (n=2, R1 =H)
2c (o-MeC6H4)
2d (o-BrC6H4)
2g (p-FC6H4)
2h (2-naphthyl) 7ah
2b (Ph)
[%][b] [%][c]
1
2
3
4
5
6
7
8
1a (n=1, R1 =H)
2b (Ph)
6ab
6ac
6ad
6ag
58
86
59
46
57
40
51
78
95
97
97
95
96
55
99
96
1a (n=1, R1 =H)
1a (n=1, R1 =H)
1a (n=1, R1 =H)
1a (n=1, R1 =H)
1b (n=0, R1 =H)
1c (n=2, R1 =H)
2c (o-MeC6H4)
2d (o-BrC6H4)
2g (p-FC6H4)
2h (2-naphthyl) 6ah
2b (Ph)
2b (Ph)
7eb
7cb
1e (n=1, R1 =Me) 2b (Ph)
[a] Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), and 3 (20 mol%);
then Na2CO3 (0.6 mmol) in a 1:1 mixture of THF/iPrOH. [b] Yield of
isolated product. [c] Determined by chiral stationary phase HPLC
analysis. [d] 20% impurity of byproduct contained.
6bb
6cb
6eb
1e (n=1, R1 =Me) 2b (Ph)
[a] Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), and 3 (20 mol%);
then 2-ethyl-2-methyl-1,3-dioxolane (6.0 mmol), pTSA (0.06 mmol),
toluene; sat. Na2CO3 solution, TBAI (0.24 mmol); 50% aq. TFA.
[b] Yield of isolated product. [c] Determined by chiral stationary phase
HPLC analysis.
To our delight, different arylketo-sulfones 2 could be
employed, generating the desired enantioenriched 1,5-dicar-
bonyl adducts 7 with moderate chemical efficiency and
excellent enantioselectivity (up to 99% ee). The transforma-
tion proved again to be dependent on the steric and electronic
requirements of either the nucleophilic or electrophilic
species. Therefore, an improvement in the yield was observed
when the employed ketone was bearing substituents (Table 4,
entry 7 versus 1) or the nucleophile contained steric bulk,
preferably in the ortho position (Table 4, entry 3 versus 1).
Electron-withdrawing groups were shown to activate the
substrate, furnishing 7ad and 7ag in good yields and in high
enantiomeric excesses (Table 4, entries 3 and 4). This method
was also applicable to enones having other ring sizes. For
example, when 1c was used the chiral 1,5-dicarbonyl com-
pound was obtained in nearly enantiomerically pure form
(Table 4, entry 6).
As outlined in entries 1–5 of Table 3, both electron-rich
and electron-poor aromatic nucleophiles 2 reacted success-
fully with cyclohexenone as the electrophile, providing the
products 6 with excellent enantiomeric excesses and good
yields. Interestingly, an electron-donating group attached at
the ortho position was found to be beneficial to both the yield
and selectivity (Table 3, entry 2, 86% yield and 97% ee). The
efficiencies of the transformation vary significantly, probably
as a result of the differing steric and electronic properties of
the various intermediates. Thus, the alkynylation reaction 1e
gave a higher yield compared to the unsubstituted ketone
derivative 1a (Table 3, entry 8 versus entry 1). Furthermore,
the transformation again proved to be dependent on the ring
size of the enone used, as organocatalytic alkynylation of 1c
furnished the product in higher enantiomeric purity than that
of 1b (Table 3, entry 7 versus 6).
In conclusion, we have demonstrated that by application
of an organocatalytic tandem strategy, a library of small
important optically active organic molecules can rapidly and
efficiently be achieved starting from a common set of starting
As a result of our success on the alkenyl- and alkynylation
reactions with enones 1, our attention was then directed
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Organocatalytic addition of b-keto heterocyclic sulfones to cyclic a,b-
unsaturated ketones: Avial equipped with a magnetic stirring bar was
charged with the nucleophile 2 (0.2 mmol, 1 equiv), the catalyst 3
(0.04 mmol, 0.2 equiv), and dioxane (2 mL). After addition of the
ketone 1 (0.4 mmol, 2 equiv) the reaction mixture was stirred for 24 h.
The volatiles were then removed under vacuum and the residue was
purified by flash chromatography.
Alkenylation: A vial equipped with a magnetic stirring bar was
charged with the addition product 4 (0.2 mmol, 1 equiv) and toluene
(2 mL). After cooling the reaction mixture to À308C, NaBH4
(0.6 mmol, 3 equiv) was added, and then MeOH was introduced
(0.25 mL). The reaction temperature was maintained at this temper-
ature and stirred for 3–12 h: The reaction mixture was then quenched
by the addition of a sat. NH4Cl solution, and then extracted with
EtOAc. The collected organic solution was then dried over MgSO4,
concentrated in vacuum, and the resulting residue was purified by
flash chromatography methods.
Alkynylation: A vial equipped with a magnetic stirring bar was
charged with the addition product 4 (0.2 mmol, 1 equiv), 2-ethyl-2-
methyl-1,3-dioxolane (6 mmol, 30 equiv), toluene (0.5 mL), and p-
toluenesulfonic acid (0.06 mmol, 0.3 equiv). The reaction mixture was
stirred for 12 h before it was washed sequentially with a sat. NaHCO3
and sat. Na2CO3 solution. Without drying, the volatiles were removed
under vacuum, the crude product was redissolved in toluene (2 mL),
and then a sat. Na2CO3 solution (2 mL) and Bu4NI (0.24 mmol,
1.2 equiv) were added. The reaction mixture was stirred at 458C for
48 h and then the phases were separated. The organic phase was
washed with water, dried over MgSO4, and evaporated. The obtained
crude product mixture was filtered through a plug of silica gel before
it was dissolved in toluene (2 mL). Then a 50% aqueous solution of
TFA (2 mL) was added to the reaction mixture. After stirring for 1 h,
the reaction mixture was quenched by the addition of a sat. NaHCO3
solution and then extracted with EtOAc. The collected organic
solution was dried over MgSO4, evaporated and the obtained
alkynylated products 6 were pure as determined by NMR analysis.
1,5-Dicarbonyl compounds: A vial equipped with a magnetic
stirring bar was charged with the addition product 4 (0.2 mmol,
1 equiv), THF (1 mL), iPrOH (1 mL), and Na2CO3 (0.6 mmol,
3 equiv). The reaction mixture was stirred at 458C for 96 h . The
reaction mixture was then partitioned between EtOAc and water and
the aqueous layer was additionally extracted with EtOAc. The
collected organic solution was dried over MgSO4, evaporated, and the
resulting residue was purified by flash chromatography.
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Received: July 10, 2009
Published online: September 8, 2009
Keywords: alkenes · alkynes · dicarbonyl groups · enones ·
.
organocatalysis
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