Phase-transfer-catalysed asymmetric synthesis of tetrasubstituted allenes

Article abstract of DOI:10.1038/nchem.1567

Allenes are molecules based on three carbons connected by two cumulated carbon-carbon double bonds. Given their axially chiral nature and unique reactivity, substituted allenes have a variety of applications in organic chemistry as key synthetic intermediates and directly as part of biologically active compounds. Although the demands for these motivated many endeavours to make axially chiral, substituted allenes by exercising asymmetric catalysis, the catalytic asymmetric synthesis of fully substituted ones (tetrasubstituted allenes) remained largely an unsolved issue. The fundamental obstacle to solving this conundrum is the lack of a simple synthetic transformation that provides tetrasubstituted allenes in the action of catalysis. We report herein a strategy to overcome this issue by the use of a phase-transfer-catalysed asymmetric functionalization of 1-alkylallene-1,3-dicarboxylates with N-arylsulfonyl imines and benzylic and allylic bromides.

Full text of DOI:10.1038/nchem.1567

ARTICLES
PUBLISHED ONLINE: 10 FEBRUARY 2013 | DOI: 10.1038/NCHEM.1567
Phase-transfer-catalysed asymmetric synthesis of
tetrasubstituted allenes
Takuya Hashimoto, Kazuki Sakata, Fumiko Tamakuni, Mark J. Dutton and Keiji Maruoka
*
Allenes are molecules based on three carbons connected by two cumulated carbon–carbon double bonds. Given their
axially chiral nature and unique reactivity, substituted allenes have a variety of applications in organic chemistry as key
synthetic intermediates and directly as part of biologically active compounds. Although the demands for these motivated
many endeavours to make axially chiral, substituted allenes by exercising asymmetric catalysis, the catalytic asymmetric
synthesis of fully substituted ones (tetrasubstituted allenes) remained largely an unsolved issue. The fundamental
obstacle to solving this conundrum is the lack of a simple synthetic transformation that provides tetrasubstituted allenes
in the action of catalysis. We report herein a strategy to overcome this issue by the use of a phase-transfer-catalysed
asymmetric functionalization of 1-alkylallene-1,3-dicarboxylates with N-arylsulfonyl imines and benzylic and
allylic bromides.
he creation of enantioenriched materials with the help of that catalytic asymmetric synthesis of a tetrasubstituted carbon
asymmetric catalysis has been one of the most significant chal- centre (Fig. 1a, left, a = b = c = d, a–d = H), which had been
T
lenges in organic chemistry for more than half a century, and considered one of the most challenging issues in the first decade
uncountable efforts have now culminated in many industrial appli- of the twenty-first century, now provides a broad array of solutions
cations of asymmetric catalysis1. Naturally, given its prevalence in for use in constructing chiral tertiary alcohols, tertiary amines and
pharmaceuticals and agrochemicals, the focus of these efforts was all-carbon quaternary centres13–15
.
on the stereoselective construction of central chirality (Fig. 1a,
left) based on one carbon atom.
To open up a novel and robust strategy with which to access tetra-
substituted allenes in a catalytic manner, we report herein the first use
In modern organic chemistry, the demand for enantioenriched of cumulenolate as a prochiral nucleophilic template in concert with a
allenes with axial chirality based on three carbons (Fig. 1a, right) chiral phase-transfer catalyst. Cumulenolate is an anionic nucleophile
is also increasing for synthetic intermediates, molecular materials that can be generated in the presence of a base from the corresponding
and even chiral ligands2–4. Although these strong demands have allenoate, and its reaction with an electrophile results in the formation
motivated much research to make these molecules efficiently, of a functionalized allene (Fig. 1b)16. It is rather surprising that the via-
centre-to-axis chirality transfer from the corresponding enantioen- bility of cumulenolates as a prochiral template in asymmetric syn-
riched propargyl alcohol derivatives is the prevailing method in the thesis had remained completely unexplored, in sharp contrast to the
synthetic community5,6. However, the direct catalytic asymmetric ubiquity of enolates in this regard.
synthesis of allenes is still in its infancy and only the preparation
As a suitable substrate for this purpose, we opted for the use
of di- and trisubstituted allenes has emerged as an achievable objec- of 1-alkylallene-1,3-dicarboxylate 1 (Fig. 1c) because of its
tive7–10. As for tetrasubstituted allenes (Fig. 1a, right, a = b, c = d, electron-deficient nature, which is necessary for the facile generation
a–d = H), there are no general solutions, but there are a few of cumulenolate under phase-transfer conditions17,18. We found that
limited examples11,12. This situation contrasts sharply with the fact this substrate can be obtained easily in quantity by extending the
a
c
d
1
R1
a
a
CO2R2
a
b
a
b
d
c
d
c
Q*+X–
R3O2C
+
Base
d
d
(chiral quaternary ammonium salt)
b
b
N2
c
c
R3O2C
OR2
O–Q*+
Q*+O–
R3O
CO2R2
R1
Central chirality
Axial chirality
CuI (20 mol%)
CH3CN, r.t.
b
R1
El
Ammonium cumulenolate
Ammonium α-alkynyl enolate
O–
RO
Cumulenolate
R' Electrophile
H
RO2C
R'
Electrophile (= El)
R3O2C
(= El)
CO2R2
R''
El
R3O2C
R''
Chiral tetrasubstituted
allene
1
1
R3O2C
CO2R2
1
R
CO2R2 and/or
R
El
1
R
Figure 1 | Strategy for the catalytic asymmetric synthesis of tetrasubstituted allenes. a, Central chirality (a = b = c = d) and axial chirality (a = b, c = d)
are shown using a mirror plane. b, Use of a cumulenolate as an intermediate can be considered as a direct way to form tetrasubstituted allenes.
c, 1-Alkylallene-1,3-dicarboxylates can be prepared by the copper-catalysed coupling of alkyl propiolates and a-alkyl diazoesters. d, Phase-transfer-catalysed
reaction of 1-alkylallene-1,3-dicarboxylate forms ammonium cumulenolate, which has an ammonium a-alkynyl enolate at the other end of the localized
structure. This poses the issue of regioselectivity in the reaction with an electrophile. The E/Z stereochemistry is drawn arbitrarily. r.t. ¼ room temperature.
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan. e-mail: maruoka@kuchem.kyoto-u.ac.jp
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1567
ARTICLES
a
Table 1 | Optimization of the alleno-Mannich-type reaction.
R4
NHSO2Ar'
SO2Ar'
Me
AgNO3 (1.2 equiv.)
Et3N (3 equiv.)
R4
Ph
NHSO2Ar'
N
H
cat. (2 mol%)
K2CO3 (5 equiv.)
SO2Ar'
tBuO2C
CO2tBu
N
H
CO2tBu
tBuO2C
CO2tBu
tBuO2C
CH3CN
40 °C, 48 h
+
CO2tBu
Solvent
0 °C, 12–68 h
tBuO2C
Ph
Me
Me
Me
1a
91%, 92% e.e.
d.r. = >20/1
6e (92% e.e.)
R4 = 4-PhC6H4
Ar' = 4-MeO C6H4
11
Ar
Ar
Bu
Bu
+
N
+
R4
SO2Ar'
Br–
N
b
c
Bu4NBr (20 mol%)
Cs2CO3 (2 equiv.)
N
6e (92% e.e.)
Br–
Me
tBuO2C
CPME
0 °C, 8 h
Ar
Ar
tBuO2C
3a Ar = 3,4,5-F3C6H2
2 Ar = 3,4,5-F3C6H2
3b Ar = 3,5-(3,4,5-F3C6H2)2C6H3
12
78%, 92% e.e.
d.r. = >20/1
Ar
Ar
OBn
OBn
i. LiOH (5 equiv.)
THF/H2O
40 °C, 12 h
+
N
+
Bn
N
Bn
OBn
OBn
CO2R2
Br–
MeO2C
CO2R2
Br–
ii. AgNO3 (1 equiv.)
iPr2NEt (1 equiv.)
CH3CN
Ar
4a Ar = 3,4,5-F3C6H2
Ar
5 Ar = 3,5-(3,5-(CF3)2C6H3)2C6H3
O
O
Me
13 93%, 95% e.e.
Me
60 °C, 1 h
10a (95% e.e.)
2 = CHtBu2
4b Ar = 3,5-(3,4,5-F3C6H2)2C6H3
4c Ar = 3,5-(3,5-(CF3)2C6H3)2C6H3
R
Entry Catalyst Ar′
Solvent Yield
(%)*
d.r.†
e.e.
Figure 2 | Derivatizations of the tetrasubstituted allenes. a, Silver-mediated
cyclization of the chiral tetrasubstituted allene proceeds via the axis-to-
centre chirality transfer. b, Intramolecular nucleophilic addition of the
sulfonamide moiety to the electron-deficient central carbon of the allene
gives cis-azetidine. c, Hydrolysis and cyclization of the alkylation product
gives furanone with a tetrasubstituted carbon centre.
(%)‡
1§
2
Bu4NBr 4-tolyl
Toluene
9
56:44 2/2
66:34 59/20
46:54 51/33
84:16 70/51
82:18 86/46
90:10 90/11
80:20 23/29
91:9
86:14 88/26
93:7
92:8
94:6
2
4-tolyl
Toluene 52
Toluene 44
Toluene 93
Toluene 31
Toluene 53
Toluene 30
Toluene 86
Toluene 24
Toluene 85
3
4
5
6
3a
4a
4b
4c
5
4-tolyl
4-tolyl
4-tolyl
4-tolyl
entry 1). The reaction gave the desired tetrasubstituted allene in a
regiospecific manner, albeit in low yield and diastereoselectivity.
The low yield resulted from the slow reaction rate and the partial
overreaction, which produced an azetidine (see Fig. 2b). From this
result, we started to search for a catalyst that simultaneously
controls the diastereo- and enantioselectivity with high productivity.
However, extensive screening of the established chiral catalysts
failed to give any promising selectivities, as exemplified in entries
2 and 3 of Table 1, whereas the reaction yields were improved con-
siderably. Accordingly, we decided to find a new catalyst that fits
into this challenging transformation. This exploration led to the
advent of catalysts 4a–4c, which incorporated (3R,4R)-3,4-bis(ben-
zyloxy)pyrrolidine as a right-hand building block (Table 1, entries
7
4-tolyl
8
9
10
11
12ꢀ
4c
4c
4c
4c
4c
Ph
93/16
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
94/20
94/3
95/ND
CPME
CPME
90
86
Experiments were performed with 1a (0.05 mmol), imine (0.06 mmol), catalyst (0.001 mmol) and
powdered K2CO3 (0.25 mmol) in the solvent (0.5 ml). *Combined yield of the diastereomers
determined by 1H NMR spectroscopy using mesitylene as an internal standard. †Determined by
1H NMR analysis of the crude material. ‡Determined by chiral high-performance liquid
chromatography (HPLC) analysis. §Performed with 20 mol% catalyst. ꢀPerformed at 220 8C.
cat. ¼ catalyst. ND ¼ not determined.
copper-catalysed coupling of alkynes and diazoacetates developed 4–6). Of these catalysts, which bear different aromatic groups at
by Fu and co-workers19 to the combination of alkyl propiolates the 3,3′-positions of the binaphthyl unit, catalyst 4c was especially
and a-alkyl diazoesters (see the Supplementary Information)19–21
.
effective as it gave the tetrasubstituted allene with 90:10 diastereo-
Deprotonation of this substrate at its g-position under phase-trans- meric ratio (d.r.) and 90% enantiomeric excess (e.e.) for the
fer conditions is expected to form the delocalized ammonium major isomer (Table 1, entry 6). The proper setting of the stereocen-
cumulenolate, with the a-alkynyl enolate as the other end of the tres in this catalyst is important because its diastereomer (5) furn-
localized structure (Fig. 1d). Although this delocalization helps to ished the allene with only 23% e.e. (Table 1, entry 7). With this
enhance the acidity of the substrate, it poses the possibility of catalyst set as optimal, we further screened other reaction par-
nucleophilic addition proceeding at the C1-position of 1,3-dicar- ameters to maximize the efficiency of the reaction (Table 1,
boxylate to give an alkyne with a tetrasubstituted carbon centre22–24
.
entries 8–12). This study led to the use of N-4-methoxyphenylsulfo-
nyl imine as the electrophile and cyclopentyl methyl ether (CPME)
as the solvent at 220 8C to give the allene in 86% yield with 94:6 d.r.
Results and discussion
Diastereo- and enantioselective alleno-Mannich-type reaction. As and 95% e.e. after 30 hours of stirring (Table 1, entry 12).
a primary goal of this study, we set out to investigate the reaction,
With the optimized conditions in hand, we turned our attention to
using imines as the electrophiles, by which tetrasubstituted allenes the investigation of the substrate scope on a 0.1 mmol scale (Table 2).
with an additional vicinal secondary amine stereocentre can be As shown in entries 2–5, aromatic imines that bear methyl or phenyl
generated (Table 1). In consideration of the similarity to groups on the aromatic ring were converted into the desired allenes,
Mannich-type reactions using enolates and imines25, we termed regardless of the position of the substituent. Also, the 2-naphthalde-
the reaction an ‘alleno-Mannich-type’ reaction. In the inaugural hyde-derived imine could be used in the reaction with comparable
experiment, the reaction of di-tert-butyl 1-methylallene-1,3- stereoselectivity (Table 2, entry 6). Electron-poor and electron-rich
dicarboxylate (1a) and benzaldehyde-derived N-tosyl imine was aromatic rings were installed in the resulting allenes with an excellent
implemented in the presence of
a catalytic amount of level of diastereo- and enantioselectivities (Table 2, entries 7, 8, 10
tetrabutylammonium bromide and an excess of K2CO3 (Table 1, and 11). The nitro group was the only inapplicable functionality,
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1567
ARTICLES
Table 2 | Substrate scope of the alleno-Mannich-type reaction.
R4
NHSO2Ar'
H
4c (2 mol% )
K2CO3 (5 equiv.)
SO2Ar'
N
tBuO2C
CO2tBu
tBuO2C
CO2tBu
CPME, –20 °C
22–120 h
R4
Ar' = 4-MeOC6H4
R1
R1
1a R1 = Me, 1b R1 = Et, 1c R1 = Bu,
1d R1 = Bn, 1e R1 = allyl,
1f R1 = prenyl, 1g R1 = propargyl
6
Entry
R1
R4
Yield (%)*
d.r.†
e.e. (%)‡
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Bu
Bn
Ph
2-tolyl
79 (6a)
87 (6b)
80 (6c)
92 (6d)
90 (6e)
84 (6f)
73 (6g)
88 (6h)
ND (6i)
86 (6j)
94:6
97:3
93:7
95:5
91:9
86:14
88:12
89:11
–
94:6
96:4
92:8
76:24
76:24
77:23
72:28
68:32
88:12
94:6
94
92
94
95
92
92
91
2§
3
4
3-tolyl
4-tolyl
4-PhC6H4
2-naphthyl
4-BrC6H4
4-ClC6H4
4-NO2C6H4
3-MeOC6H4
4-MeOC6H4
tBu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5
6ꢀ
7}
8}
9
91
–
10
11
92
96
90
85
86
85
89
91
93 (6k)
73 (6l)
12#
13ꢀ
14**
15**
16**
17**
18**
19††
74 (6m)
92‡‡(6n)
86‡‡(6o)
92‡‡(6p)
98‡‡(6q)
80‡‡(6r)
89 (6a)
H2C¼CHCH2
(CH3)2C¼CHCH2
HC;CCH2
Me
91
96
Experiments were performed with 1 (0.1 mmol) and imine (0.12 mmol), 4c (0.02 mmol) and K2CO3 (0.5 mmol) in the solvent (1 ml). *Isolated yield of the major diastereomer. †Determined by 1H NMR analysis
of the crude material. ‡e.e. of the major diastereomer determined by chiral HPLC analysis. §K2CO3 (0.25 mmol). ꢀ4c (0.04 mmol) and K2CO3 (0.25 mmol). }4c (0.04 mmol) at 230 8C. #4c (0.04 mmol) and
Cs2CO3 (0.5 mmol) at 240 8C. **4c (0.04 mmol). ††Performed on a 1.0 mmol scale. ‡‡Combined yield of two diastereomers.
Table3 | Optimization of the alkylation.
H
BnBr
Bn
Ar
Ar
Ar
R3O2C
tBu
tBu
cat. (2 mol%)
CO2R2
R3O2C
CO2R2
CO2R2
+
R3O2C
+
N
+
N
50% KOH(aq.)
solvent, 0 °C
24 h
N
X
N Ph
Me Bn
ii
Me
1a R2 = R3 = tBu
1h R2 = CHtBu2, R3 = tBu
1i R2 = CHtBu2, R3 = Et
1j R2 = CHtBu2, R3 = Me
Me
i
Br–
Br–
Ar
8 X = H, Ar = 3,5-(3,4,5-F3C6H2)2C6H3
9a X = MeO, Ar = 3,5-(3,4,5-F3C6H2)2C6H3
9b X = MeO, Ar = 3,5-(3,5-(CF3)2C6H3)2C6H3
7 Ar = 3,5-(3,4,5-F3C6H2)2C6H3
Entry
Catalyst
R2
R3
Solvent
Yield (%)*
r.r.†
e.e. (%)‡
1§
2
3
4
5
6
7
Bu4NBr
2
3b
2
4c
7
8
8
8
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Et
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
m-xylene
m-xylene
m-xylene
m-xylene
85
48
63
79
65
34
52
56
66
67
76
78
15:85
59:41
27:73
89:11
43:57
62:38
76:24
77:23
74:26
77:23
83:17
86:14
–
33
87
21
CHtBu2
CHtBu2
CHtBu2
CHtBu2
CHtBu2
CHtBu2
CHtBu2
CHtBu2
CHtBu2
46
82
67
79
84
86
94
95
8ꢀ
9ꢀ
10ꢀ
11ꢀ
12}
Et
Et
Et
Me
9a
9b
9b
Experiments performed with 1 (0.05 mmol), benzyl bromide (0.06 mmol), catalyst (0.001 mmol), 50% KOH(aq.) (0.1 ml) in the solvent (0.25 ml). *Combined yield of the regioisomers determined by 1H NMR
using mesitylene as an internal standard. †Determined by 1H NMR of the crude mixture. ‡e.e. of the allene determined by chiral HPLC. §Performed with 20 mol% catalyst. ꢀPerformed with benzyl bromide (0.1
mmol). }Performed with benzyl bromide (0.25 mmol).
with a rapid degradation of the imine (Table 2, entry 9). Use of ali- and butyl groups, were applicable in this reaction (Table 2,
phatic imines was found to be difficult, presumably because of the entries 13 and 14). In addition, benzyl-, allyl-, prenyl- and propar-
competitive isomerization of the imine to the enamide under basic gyl-substituted allene-1,3-dicarboxylates (1d–1g) could be used
conditions. In line with this assumption, we found that a pivalalde- without difficulty (Table 2, entries 15–18). Finally, to demonstrate
hyde-derived aliphatic imine that lacked an a-hydrogen could be uti- scalability, the reaction was performed on a 1.0 mmol scale to give
lized to give the allene with 92:8 d.r. and 90% e.e. (Table 2, entry 12). 6a in 89% yield with 96% e.e. (Table 2, entry 19). The relative and
Then the focus was switched to the 1-alkyl substituent of allene-1,3- absolute configuration of 6e was determined unambiguously by
dicarboxylate. It turned out that the longer alkyl chains, such as ethyl X-ray crystallographic analysis (see the Supplementary Information).
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Table 4 | Substrate scope of the alkylation.
R5
H
MeO2C
9b (2 mol%)
CO2CHtBu2
MeO2C
CO2CHtBu2
R5Br
CO2CHtBu2
+
+
MeO2C
50% KOH(aq.)
m-xylene, 0 °C
12–36 h
R1 R5
R1
R1
1j R1 = Me, 1k R1 = Et
1l R1 = Bn, 1m R1 = allyl
10
Entry
R1
R5
Yield (%)*
r.r.†
e.e. (%)‡
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Bn
75 (10a)
83 (10b)
72 (10c)
72 (10d)
88 (10e)
82 (10f)§
84 (10g)
85 (10h)
50 (10i)
68 (10j)
89 (10k)
65 (10l)
97 (10m)
86 (10n)
85 (10o)
87 (10p)
86 (10q)
88:12
79:21
82:18
79:21
93:7
88:12
.95:5
83:17
74:26
90:10
71:29
91:9
95
94
95
93
93
95
94
94
91
94
92
96
95
90
94
93
96
4-MeC6H4CH2
3-MeC6H4CH2
3-MeOC6H4CH2
2-CIC6H4CH2
4-BrC6H4CH2
2-BrC6H4CH2
2-NpCH2
H2C¼CHCH2
H2C¼C(CH3)CH2
PhCH¼CHCH2
HC;CCH2
Bn
9
10
11
12
13
14
15
16
17
94:6
Et
Et
Bn
H2C¼CHCH2
HC;CCH2
Bn
87:13
90:10
.95:5
93:7
H2C¼CHCH2
Bn
Experiments performed with 1 (0.1 mmol), alkyl bromide (0.5 mmol), 9b (0.02 mmol) and 50% KOH(aq.) (0.2 ml) in m-xylene (0.5 ml). *Combined yield of the regioisomers. †Determined by 1H NMR of the
crude mixture. ‡e.e. of the allene determined by chiral HPLC. §Isolated yield of the allene.
Regio- and enantioselective alkylation. With the success of the employed did the enantioselectivity of the allene reach a promising
phase-transfer-catalysed alleno-Mannich-type reaction as a means level of 82% e.e., thus compensating for a drop in the regioisomeric
to provide chiral tetrasubstituted allenes with an amino ratio to 62:38 (Table 3, entry 6). We decided to make this the lead
functionality, we decided to move forwards to the use of alkyl catalyst structure and modify the N-aryl group of the piperazine in
halides as electrophiles best suited for phase-transfer catalysis anticipation of improving the regioselectivity. This study led to the
(Table 3)17,18. It became immediately obvious that the alkylation of identification of catalyst 8 with a 3,5-di-tert-butylphenyl group as
1-alkylallene-1,3-dicarboxylates by phase-transfer catalysis raised an N-substituent, with which the regioisomeric ratio could be
the issue of regioselectivity (see Fig. 1d). Namely, the alkylation of improved to 76:24 with some loss of the enantioselectivity (Table 3,
1a with benzyl bromide catalysed by achiral tetrabutylammonium entry 7). In the additional experiments, the replacement of the
bromide gave a mixture of the tetrasubstituted allene i and the tert-butyl ester at C3 of the substrate allene with ethyl ester (1i)
alkyne ii with a central chirality that problematically prefers the and the solvent with m-xylene resulted in a substantial increase in
formation of the alkyne with a 15:85 regioisomeric ratio (r.r.), the enantioselectivity (Table 3, entries 8 and 9). At the last stage of
(Table 3, entry 1). When the chiral quaternary ammonium salt 2 the optimization, the catalyst structure was fine tuned to identify
was used, the regioisomeric ratio could be shifted to the favourable catalyst 9b as optimal (Table 3, entries 10 and 11) and, finally, by
formation of the allene, but the enantioselectivity was use of this catalyst and with methyl ester 1j as substrate, the allene
disappointingly low (Table 3, entry 2). However, use of catalyst 3b could be obtained with 86:14 r.r. and 95% e.e. (Table 3, entry 12).
led to the formation of the allene with a promising 87% e.e., albeit The use of five equivalents of benzyl bromide was required under
a poor 27:73 r.r. (Table 3, entry 3). That the alkyne ii was obtained these optimized conditions because of the competitive degradation
with 91% e.e. in this reaction offers a procedure to form selectively of the substrate under the basic reaction conditions.
alkynes with a quaternary carbon centre. These two experiments
With the optimized reaction conditions in hand, the substrate
clearly indicated the possibility of controlling not only the scope was examined on a 0.1 mmol scale. As shown in Table 4,
enantioselectivity, but also the regioselectivity by elaborating a benzylic bromides that bear a variety of functionalities at an
catalyst. However, before we pursued this solution, we decided to arbitrary position could be used to give the corresponding tetra-
examine a substrate-controlled strategy as a facile way to bias the substituted allenes in good yields with high enantioselectivities
regioselectivity of the alkylation, assuming that replacement of one that ranged from 93% to 95% (Table 4, entries 1–8). There was
tert-butyl ester at C1 of the substrate allene with a bulkier ester an apparent tendency for the regioselectivity to be improved
would prevent alkylation from occurring at its a-position. As substantially when a sterically encumbered benzylic bromide, such
anticipated, the reaction of di-(tert-butyl)methyl ester 1h using as 2-chlorobenzyl bromide, was utilized (Table 4, entries 5 and 7).
catalyst 2 provided the allene with an improved regioselectivity of In addition to benzylic bromides, allylic bromides (such as allyl
89:11 r.r., albeit with low enantioselectivity (Table 3, entry 4). bromide, methallyl bromide and cinnamyl bromide) were utilized
Encouraged by this result, next we screened extensively a variety of (Table 4, entries 9–11). Use of propargyl bromide resulted in a
catalysts using substrate 1h to find a highly enantioselective process. higher regioselectivity compared to the selectivity using allyl
However, it was difficult to identify a catalyst that both attained a bromide (Table 4, entry 12). Finally, the alkylation was conducted
satisfactory enantioselectivity and retained the regioselectivity. with other 1-alkylallene-1,3-dicarboxylates (1k–1m) to give the corres-
For example, the use of catalyst 4c, which was optimal in the ponding tetrasubstituted allenes regioselectively in good yields and
above-described alleno-Mannich-type reaction, was completely enantioselectivities (Table 4, entries 13–17). The absolute configur-
inefficient as it resulted in 43:57 r.r. and 46% e.e. (Table 3, entry 5). ation of 10f was determined unambiguously by X-ray crystallographic
Only when catalyst 7, which contained N-phenylpiperazine, was analysis after the derivatization (see the Supplementary Information).
4
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1567
ARTICLES
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stituted allenes, we implemented the endo-cyclization of the amino
functionality to give the densely functionalized dihydropyrrole 11
via an axis-to-centre chirality transfer (Fig. 2a)26,27. This cyclization
was facilitated in a stereospecific manner by the use of silver nitrate
as the catalyst, which transferred the chirality of the allene in the ter-
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Conclusion
Whereas a vast majority of chiral compounds are now within the
reach of synthetic chemists by exercising asymmetric catalysis,
chiral tetrasubstituted allenes have remained an elusive objective
in this regard. To conquer this frontier, we introduced the
concept of asymmetric functionalization of cumulenolates under
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either diastereoselectivity or regioselectivity, respectively. By elabor-
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well-established enolate chemistry, it is envisaged that a variety
of catalysts and electrophiles could be used in combination with
cumulenolates to give chiral allenes.
formation of C–C bonds by addition to imines and hydrazones: a ten-year
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´
´
´
26. Alvarez-Corral, M., Mun˜oz-Dorado, M. & Rodrıguez-Garcıa, I. Silver-mediated
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Received 22 October 2012; accepted 3 January 2013;
published online 10 February 2013
Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and Technology, Japan. K.S. and M.J.D.
thank the Japan Society for Promotion of Science and the Great Britain Sasakawa
Foundation, respectively, for fellowships, respectively.
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Author contributions
T.H. conceived the study and wrote the manuscript. K.S. principally performed the
experiments. F.T. and M.J.D. performed experiments on alkylation. K.M. organized the
research. All authors contributed to designing the experiments, analysing data and editing
the manuscript.
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Additional information
Supplementary information and chemical compound information are available in
the online version of the paper. Reprints and permission information is available online at
http://www.nature.com/reprints. Correspondence and requests for materials should be
addressed to K.M.
9. Boutier, A., Kammerer-Pentier, C., Krause, N., Prestat, G. & Poli, G.
Pd-catalyzed asymmetric synthesis of N-allenyl amides and their Au-catalyzed
Competing financial interests
The authors declare no competing financial interests.
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