Organocatalytic enantioselective allylic alkylation of MBH carbonates with β-keto esters

Article abstract of DOI:10.1039/c4ob00682h

The highly stereoselective allylic alkylation of Morita-Baylis-Hillman carbonates with β-ketoesters catalysed by β-ICD is described. The corresponding products containing two adjacent quaternary and tertiary carbon centers were obtained in good yields with high diastereoselectivity (up to 10 : 1 dr) and enantioselectivity (up to 95% ee).

Full text of DOI:10.1039/c4ob00682h

Organic &
Biomolecular Chemistry
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Organocatalytic enantioselective allylic alkylation
of MBH carbonates with β-keto esters†
M. Kamlar,a S. Hybelbauerová,b I. Císařovác and J. Veselý*a
Cite this: Org. Biomol. Chem., 2014,
12, 5071
Received 31st March 2014,
Accepted 22nd May 2014
DOI: 10.1039/c4ob00682h
www.rsc.org/obc
The highly stereoselective allylic alkylation of Morita–Baylis– ped,10,2c but also alternative organocatalytic methods utilizing
Hillman carbonates with β-ketoesters catalysed by β-ICD is Morita–Baylis–Hillman (MBH) adducts in asymmetric allylic
described. The corresponding products containing two adjacent alkylation (AAA) reactions have become popular.11 While the
quaternary and tertiary carbon centers were obtained in good vast majority of literature from the area of Lewis base-catalyzed
yields with high diastereoselectivity (up to 10 : 1 dr) and enantio- AAA methods deals with the preparation of various chiral com-
selectivity (up to 95% ee).
pounds containing nitrogen,12 oxygen,13 other heteroatoms14
or tertiary carbon,15 methods for the preparation of com-
pounds with all-carbon quaternary stereocenters are scarce.16
Readily available β-ketoesters represent a suitable structural
motif, which has been already applied for the construction of
quaternary carbon centers.1a,b,7a,17 With respect to the above
mentioned and our interest in the development of enantio-
selective organocatalytic methods,18 we set out to explore the
application of the MBH adducts as an electrophilic alkylation
partner with β-ketoesters in the AAA reaction. Herein, we wish
to report an enantioselective and regiodivergent allylic alkyl-
ation of α-substituted β-ketoesters with the MBH carbonates
via SN2′–SN2′ pathway using a simple and commercially avail-
able Hatakeyama’s catalyst, β-ICD.19
At the outset of our studies of allylic reactions of MBH
adducts, we consider the use of ethyl 2-oxocyclopentane-1-car-
boxylate (3a) as a prenucleophile together with 2-(methoxycar-
bonyl)-1-phenylallyl tert-butyl carbonate (2a) initiated by
10 mol% of β-ICD as a nucleophilic tertiary amine catalyst.
The reaction performed either in MTBE or in toluene went to
completion in less than 16 h with low regioselectivity (ratio of
γ-/β-adduct 3 : 1) and moderate enantioselectivity (entries
1 and 2, Table 1).
The formation of all-carbon quaternary stereocenters rep-
resents one of the most difficult contemporary challenges in
synthetic organic chemistry. This is particularly difficult due to
synthetic impediment arising from the steric congestion
imposed by the four attached carbons and the limited number
of carbon–carbon bond-forming reactions.1,2 However, the
presence of these motifs is common in natural products and
pharmacologically active substances.3 Several approaches can
be used to form all-carbon quaternary stereocenters including
Diels–Alder reactions and other cycloadditions, carbon-acyla-
tion reactions, Mannich reactions, aldol reactions, conjugate
additions, Robinson annulations, Heck reactions, metal-cata-
lyzed diene, enyne cyclizations, etc.4 Other important modern
strategies suitable for accessing all-carbon quaternary stereo-
centers rely on Pd-catalyzed asymmetric alkylations5 and de-
carboxylative allylic alkylations,6 Cu-catalyzed methods,7 and
Mo-8 and Ir-9,1a,b catalyzed allylic alkylations.
Also, the asymmetric conjugate addition reaction is of
special importance among various synthetic strategies used for
the construction of congested centers. In this area, not only
methods via transition metal catalysis have been develo-
Substitution of the ester moiety at the β-oxoester with the
sterically-demanding tert-butyl group (entry 3, Table 1) gave
the desired product with a similar regioselectivity, but higher
enantioselectivity (82% ee). A further change at the β-oxoester
moiety, specifically the substitution of the cyclopentanone
ring with the more rigid 2,3-dihydro-1-oxo-1H-indene, showed
significant effect on the regioselectivity and diastereoselectivity
of the allylation reaction (entries 5 and 6). On the other hand,
no reaction was observed when the carbonate moiety (OBoc)
was replaced with OAc (entry 7).
aDepartment of Organic Chemistry, Faculty of Science, Charles University in Prague,
Hlavova 2030, 128 43 Praha 2, Czech Republic. E-mail: jxvesely@natur.cuni.cz;
Fax: +42-221951226
bDepartment of Teaching and Didactics of Chemistry, Faculty of Science, Charles
University in Prague, Hlavova 2030, 128 43 Praha 2, Czech Republic
cDepartment of Inorganic Chemistry, Faculty of Science, Charles University in
Prague, Hlavova 2030, 128 43 Praha 2, Czech Republic
†Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of 4aa–aj, 5aa–5ad, 6a–c, 7a, chiral HPLC chromatograms of 4aa–aj, 5aa–5ad,
6a–c, 7a, X-ray crystallographic data for 4cd, 6b (CIF) and a spectroscopic study
of absolute configuration 4cd, 5aa. CCDC 953269 and 953270. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/c4ob00682h
In order to verify the appropriateness of the reaction con-
ditions, we subsequently performed screening of other com-
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Table 1 Initial AAA of Morita–Baylis–Hillman esters 2 and β-oxoesters 3a
Entry
X–Y
R1
R2
Solvent
Time (h)
drb
Yield of 4/5 (%)
eec (%)
1
2
3
4
5
6
7
C2H4
C2H4
C2H4
C6H4
C6H4
C6H4
C6H4
Boc
Boc
Boc
Boc
Boc
Boc
Ac
Et
Et
t-Bu
Me
t-Bu
t-Bu
t-Bu
Toluene
MTBE
MTBE
MTBE
Toluene
MTBE
MTBE
16
16
20
16
22
20
120
2 : 1
2 : 1
5 : 2
1 : 1
3 : 1
5 : 1
—
42/15
43/13
47/11
81d
60/10
70
66
58
82
56/64
89
90
—
n.d.
a In a vial 2 (1.1 equiv.), catalyst (0.1 equiv.) and 3 were added in MTBE (1 mL). b Determined by 1H NMR of the crude reaction mixture.
c Determined by chiral HPLC. d Yield of the mixture of diastereomers (3 : 2 ratio).
mercially available tertiary amine catalysts, used in AAA reac- Table 4). In order to study the scope of the AAA reaction,
tions in the prior study16 (Table 2). None of the cinchona alka- various MBH carbonates 5 including changes on the aromatic
loids and C2-symmetric (bis)cinchona alkaloid derivatives ring in the γ-position and the electrodeficient moiety at C-1
tested showed significant effectiveness in the reported allylation were introduced. In almost all cases of substitution of the aro-
reaction. For example, the cinchonidine-catalyzed model reac- matic moiety (R1) with either electron-withdrawing or -donat-
tion afforded the desired product in 20% yield (45% conver- ing groups as well as the change into heteroaryl group, the
sion in 5 days was observed) with moderate diastereoselectivity efficiency and stereocontrol of the AAA reaction were not sig-
(dr 3 : 1) and acceptable enantioselectivity (84% ee, entry 3, nificantly changed and the corresponding products 4ae–ee
Table 2). In connection with the previous study, we focused on were isolated as single diastereomers in good yields with high
the dependence of reaction efficiency on catalyst loading. enantioselectivity (entries 1–5, Table 3). For example, β-ICD in
Interestingly, only slight drops in diastereoselectivity and MTBE catalyzed the AAA reaction between methyl 2-{[(tert-
enantioselectivity were observed when 5 mol% of β-ICD (IV) butoxycarbonyl)oxy](4-methoxyphenyl)methyl}acrylate (2e) and
was used (entry 16). On the other hand, using 2 mol% of the tert-butyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (3e) with
catalyst led to significantly lower conversion of starting good diastereoselectivity (dr 5 : 1) and the α-allylated product
materials into the corresponding allylic product (entry 17). (4ee) was isolated in 85% yield as a single diastereomer with
Next, we screened different solvents and temperature-depen- 91% ee (entry 5). An important drop in stereoselectivity,
dence in order to achieve the corresponding allylic product especially in enantiocontrol of the reaction, was observed in
(4ad) in good yields with high diastereo- and enantio- the presence of strongly electron-withdrawing groups, such as
selectivity. Screening of reaction solvents revealed that the the nitro group (dr 3 : 1, 71% ee, entry 8). Taking into account
model AAA reaction between 2a and 3d catalyzed by β-ICD per- the high reactivity of compound 2h towards conjugate addition
formed well in ether solvents (THF and MTBE), where a signifi- and already reported results of AAA reactions using 2a and
cant drop in formation of β-adduct (Michael adduct) α,α-cyanophenylacetate at lowered temperature (16% ee),16a
compared to toluene commonly used in AAA reactions was our observation with 4he could be satisfying. A significant
observed. The best results with respect to efficiency and stereo- effect on the efficiency, diastereo- and enantioselectivity of the
selectivity of the reaction were obtained in MTBE (entry 6, reaction was also observed when sterically demanding MBH
Table 2). The use of chlorinated solvents, such as DCM, led to carbonate 2i was subjected to the reaction (entry 9). Moreover,
a drop in yield and stereoselectivity of the corresponding the replacement of the aryl moiety with an olefin substituent
product 4ad (entry 7, Table 2).
On the other hand, no reaction was observed when polar where the desired product was not isolated from (entry 11).
and protic solvents were used (MeCN, MeOH, entries 10 and Next we further examined β-ketoester derivatives (3) under
at γ-position of MBH carbonate led to a complex mixture,
11). It should also be noted that the stereocontrol of the reac- the optimized conditions (Table 4). The alkyl group of the
tion compared to the efficiency is only slightly temperature ester moiety significantly influenced the reaction efficiency
dependent (entries 13 and 14). Moreover, a significant rise of and stereoselectivity of the AAA reaction. In general, sterically
β-selectivity in non-polar solvents at higher reaction tempera- demanding ester moieties, such as tert-butyl and adamant-1-yl,
ture was observed (entry 15 vs. 4).
afforded the corresponding allylated products (4ad–ae) in
After obtaining the optimized conditions, we turned our acceptable yields with good diastereoselectivity (dr 4 : 1–5 : 1)
attention to the scope of the reaction using differently substi- and high enantioselectivity (85–90% ee, entries 4 and 5).
tuted MBH carbonates (2a–l, Table 3) and oxoesters (3a–j, On the other hand, when primary and secondary alkyl esters
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Table 2 Optimization studies focused on solvent, catalyst and temperature influences on AAA of MBH carbonate 2a and β-ketoester 3ea
Entry
Solvent
Catalyst
Temperature (°C)
Time (h)
Conversion (%)
drb
Yield of 4e/5e (%)
eec (%)
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
MTBE
DCM
CHCl3
p-Xylene
MeCN
MeOH
THF
THF
THF
Toluene
MTBE
MTBE
I
II
III
IV
V
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
IV
25
25
25
25
25
25
25
25
25
25
25
25
0
120
120
120
22
120
20
20
20
20
20
120
7
20
60
8
30
70
45
50
45
100
0
100
100
100
100
100
0
100
100
100
100
100
100
3 : 1
2 : 1
3 : 1
3 : 1
—
5 : 1
2 : 1
2 : 1
2 : 1
—
20/—
25/—
20/—
60/10
n.d.
70/—
52/13
25/18
20/17
n.d.
7
59
84
89
—
90
73
65
87
—
9
10
11
12
13
14
15
16
17
—
n.d.
—
3 : 1
5 : 1
5 : 1
3 : 1
4 : 1
4 : 1
56/—
63/—
64/—
50/19
52/—
32/—
87
90
86
88
90d
85e
−20
50
25
25
a In a vial 2 (1.1 equiv.), catalyst (0.1 equiv.) and 3 were added in solvent (1 mL). b Determined by 1H NMR of the crude reaction mixture.
c Determined by chiral HPLC. d 5% mol catalyst loading. e 2% mol catalyst loading.
(3f–h) were employed, diastereo- and enantiocontrol of the ation of 5aa at the alkene moiety was determined based on 1D
reaction dropped down (entries 6–8). Moreover, the isolated NOE NMR experiments (for more details see ESI†).
products 4ag–ah were obtained as a mixture of diastereo-
In order to ascertain the absolute configuration of the allyl-
isomers after column purification. It is noteworthy that a sig- ated β-ketoesters (4), we performed a single X-ray diffraction
nificant influence of ring-expansion in cyclic β-ketoesters (3i,j) analysis of compound 4cd,20 obtained from the reaction of 2c
to diastereoselectivity of the reported AAA reaction was and 3e. As shown in Fig. 1, both stereogenic centers (C2 and
observed (entries 9 and 10). For example, AAA reaction C11) have (R)-absolute configuration. This configuration corre-
between ethyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxy- sponds also to the data obtained from 1D gNOESY NMR experi-
late (3i) and methyl 2-{[(tert-butoxycarbonyl)oxy](4-methoxy- ments (for more information see ESI†).
phenyl)methyl}acrylate (2a) under the optimized conditions
Next, we performed experiments to examine the depen-
afforded the corresponding allylated α-ketoester (4aj) as a dence of enantiocontrol during AAA reaction in connection
single diastereomer in 64% yield with high diastereoselectivity with enantiomeric purity of starting material 2. In the model
(dr 5 : 1) and good enantioselectivity (79% ee, entry 10).
Unfortunately the AAA reaction performed with less steri- the allylated product (4ad) and the MBH carbonate (2a) at
cally demanding oxoesters containing cyclopentanone different conversions (Fig. 1, ESI†). Moreover, we accomplished
reaction of 2a with 3d, we measured the enantiomeric purity of
a
moiety (3a–c) afforded a significant amount of β-adduct an AAA reaction of enantiomerically enriched 2a (77% ee) with
(11–40% yield, entries 1–3). For example, treatment of 2a with 4ad (for more details see ESI†). All the collected data clearly
3a furnished, in addition to 4aa (45% yield, 58% ee), by- indicate very slight changes (1–2%) in enantioselectivity (90%
product 5aa in 13% yield as a racemic mixture. E-Configur- ee) of the final product 4ad and significant kinetic resolution
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Table 3 Substrate scope of AAA screened on the reaction of β-oxoester
3e with various MBH carbonates 2a
Entry R1
R2
Time (h) drb
Yield (%) eec (%)
1
2
3
4
5
6
7
8
Ph
OMe 20
OMe 19
OMe 20
OMe 14
OMe 18
OMe 16
OMe 19
OMe 17
5 : 1 70
90
88
93
78
91
88
83
71
p-ClPh
p-BrPh
o-BrPh
p-MeOPh
p-MePh
1-Thienyl
p-NO2Ph
1-Naphthyl OMe 20
Ph
E-Styryl
4 : 1 60
4 : 1 60
3 : 1 21
4 : 1 82
4 : 1 50
5 : 1 70
3 : 1 70
10 : 1 42
2 : 1 26 (46)d
Fig. 1 View on one of the two symmetrically independent molecules of
4cd with the atom numbering scheme. The displacement ellipsoids are
drawn at the 50% probability level.
9
10
11
95
Me
10
91 (95)e
—
OMe 16
—
n.d. f
12
120
—
n.d.
—
a In a vial 2 (1.1 equiv.), β-ICD (0.1 equiv.) and 3 were added in MTBE
(1 mL). b Determined by 1H NMR of the crude reaction mixture.
c Determined by chiral HPLC. d Yield of the mixture of diastereomers
(3 : 2 ratio). e ee of the minor diastereomer from the isolated mixture of
diastereomers (ratio 3 : 2). f Unidentified mixture of products.
Table 4 Substrate screening of AAA using differently substituted oxo-
esters 3a
Scheme 1 Reduction of compound 4 to alcohol 7a and lactones 6a–c.
Time
(h)
Yield of ee
The versatility of the reaction has been demonstrated by the
conversion of 4ac, 4ad and 4aj into appropriate lactones 6 and
conversion of 4ad into alcohol 7a (Scheme 1). A simple
reduction of 4 by NaBH4 in MeOH was accompanied by self-
lactonization affording the corresponding lactones 6a–c as
single diastereomers. The absolute configuration (S-C2, S-C3,
R-C4, S-C5) of lactone 6b was determined using X-ray diffrac-
tion analysis (Fig. 2).21
Entry
R
X–Y
n
drb
4/5 (%) (%)c
1
2
3
4
5
6
7
8
9
10
Et
C2H4 CH2
C2H4 CH2
C2H4 CH2
C6H4 CH2
16
13
20
20
13
15
12
16
2 : 1 45/13
3 : 1 36/40
58
77
82
i-Pr
t-Bu
t-Bu
5 : 2 47/11
5 : 1 70
4 : 1 50
2 : 1 40
1 : 1 61d
1 : 1 81e
10 : 1 40
5 : 1 64
90
85
69
1-Adamantyl C6H4 CH2
i-Pr
Et
Me
t-Bu
Et
C6H4 CH2
C6H4 CH2
C6H4 CH2
65/71
56/64
84
C6H4 C2H4 50
C6H4 C2H4 14
79
a In a vial 2 (1.1 equiv.), β-ICD (0.1 equiv.) and 3 were added in MTBE
(1 mL). b Determined by 1H NMR of the crude reaction mixture.
c Determined by chiral HPLC. d Yield of the mixture of diastereomers
(ratio 3 : 1). e Yield of the mixture of diastereomers (3 : 2 ratio).
Conclusions
To summarize, we have developed a regioselective organocata-
lytic allylic alkylation of β-ketoesters using MBH carbonates.
The reaction catalyzed byβ-ICD affords the corresponding pro-
ducts containing vicinal tertiary and quaternary carbon
of the MBH carbonate 2a. Our observations are in full agree- centers in good yield with high diastereo- and enantio-
ment with already reported data15i and the generally accepted selectivity. Next, the allylated products can be further con-
mechanism pathway as well.
verted into valuable pyranose derivatives via reduction/
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