α-isocupreine, an enantiocomplementary catalyst of β-isocupreidine

Article abstract of DOI:10.1002/chem.201302665

Complementary chemistry! α-Isocupreine (α-ICPN) was synthesized for the first time in one step from quinine by treatment with CF ₃SO₃H (see scheme). This compound serves as an enantiocomplementary catalyst to β-isocupreidine (β-ICD)

Full text of DOI:10.1002/chem.201302665

COMMUNICATION
DOI: 10.1002/chem.201302665
a-Isocupreine, an Enantiocomplementary Catalyst of b-Isocupreidine
Yoshito Nakamoto, Fumiya Urabe, Keisuke Takahashi, Jun Ishihara, and
Susumi Hatakeyama*[a]
The Morita–Baylis–Hillman (MBH) reaction including
the aza-version is an atom-economic, efficient carbon–
carbon bond-forming reaction. Due to the utility of highly
functionalized products in synthesis, there has been much in-
terest in the asymmetric version of the MBH reaction.[1] In
1999, we developed a highly enantioselective asymmetric
MBH reaction of aldehydes[2] by use of b-isocupreidine (b-
ICD)[3] as a chiral Lewis base catalyst and 1,1,1,3,3,3-hexa-
fluoroisopropyl acrylate (HFIPA) as an activated alkene
(Scheme 1). In addition, we have demonstrated the synthetic
skeletal rearrangement to give a-isoquinine (a-IQN) (1) in
89% yield. Thereafter, Olah et al. reported that CF3SO3H
also effectively promoted this rearrangement at 508C to
produce 1 in 70% yield.[9] The NOESY spectrum and X-ray
crystallography demonstrated that compound 1 vastly favors
an anti conformation with the 6’-methoxyquinoline moiety
in a horizontal position.[8,9] Given this structural feature, the
demethylated compound 2 is expected to serve as a pseu-
doenantiomer of b-ICD. We report herein the preparation
of a-isocupreine (a-ICPN) (2), a new enantiocomplementa-
ry catalyst of b-ICD, and its catalytic ability.
a-ICPN 2 was first prepared from quinine in 50% yield
by CF3SO3H-promoted rearrangement following Olahꢀs pro-
cedure[9] and demethylation[10] of the rearranged product 1
by using sodium dodecane-1-thiolate at 1308C in DMF
(Scheme 1). During this examination, we found that the first
CF3SO3H treatment directly produced 2 in 19% yield to-
gether with 1 (59%) although the production of 2 had not
been reported in the literature[9] (Table 1, entry 1 and
Scheme 1. b-ICD-HFIPA method.
Table 1. One-step preparation of a-isocupreine from quinine.
utility of this reaction by the syntheses of biologically intri-
guing natural products.[4] This b-ICD-HFIPA method has re-
markable advantages due to the high enantionselectivity,
broad applicability, and availability of both b-ICD and
HFIPA.[2c,5] However, one serious drawback is that this
method cannot be applied to the synthesis of the products
with opposite absolute configuration because the required
enantiomer of b-ICD is not easily available.[6] As one solu-
tion to this problem, we successfully synthesized two effec-
tive enantiocomplementary catalysts of b-ICD from qui-
nine.[7] Nevertheless, since their syntheses required the
lengthy transformations, we still need to develop another
catalyst that is easily available and shows high and opposite
enantioselectivity to that of b-ICD.
Entry
CF3SO3H [equiv]
Conditions
Yield [%][a]
1
2
1[b]
2[c]
3
4
5
275
75
28
28
28
11
508C, 6 h
RT, 24 h
508C, 72 h
508C, 24 h; 808C, 15 h
808C, 24 h
59
64
13
0
0
12
19
0
72
90
65
53
6
508C, 24 h; 808C, 15 h
[a] Isolated yield. [b] Conditions reported by Olah et al. [c] Quinine was
recovered in 30% yield.
Scheme 2). This finding allowed us to investigate the one-
step synthesis of 2 from quinine by using CF3SO3H under
various conditions. Surprisingly, the rearrangement was
found to take place even at room temperature to give 1 in
moderate yield although the reaction did not complete
within 1 day (entry 2). However, when the reaction was con-
ducted at 508C for a longer reaction time, 2 became the
major product (entry 3). Among the conditions examined,
those listed in entry 4 turned out to be optimum for the
preparation of 2. Thus, when quinine was heated in
28 equivalents of CF3SO3H at 508C for 24 h and then at
808C for 15 h, the rearrangement accompanied by demethy-
lation took place cleanly to give 2 in 90% yield. It is impor-
tant to note that under conditions in which quinine was
In 2002, Jacquesy et al. disclosed a novel rearrangement
of quinine in superacid.[8] They found that exposure of qui-
nine hydrochloride to HF-SbF5 at À308C caused a unique
[a] Y. Nakamoto, F. Urabe, Dr. K. Takahashi, Dr. J. Ishihara,
Prof. Dr. S. Hatakeyama
Graduate School of Biomedical Sciences
Nagasaki University
1-14 Bunkyo-machi, Nagasaki 852-8521 (Japan)
E-mail: susumi@nagasaki-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302665.
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12653

Table 2. a-Isocupreine-catalyzed reactions of p-nitrobenzaldehyde with
acrylates.
Entry Cat.
Ester Solvent
t [h]
Yield [%],[a] (%ee)[b]
7a
8a
1
2
b-ICD
4
4
4
4
4
4
5
6
DMF
DMF
DMF
THF
2
24
17
60
48
57 (À95)
59 (88)
64 (90)
57 (82)
37 (66)
53 (80)
32 (53)
0
17 (À49)
2
2
2
2
2
2
2
14 (40)
3[c]
4
17 (45)
9 (37)
Scheme 2. Preparation of a-isocupreine.
5
6
7
8
CH2Cl2
0
0
0
0
MeCN/DMF[d] 24
heated at 808C from the beginning, the yield markedly di-
minished due to significant amounts of decomposition
(entry 5). It was also found that the decrease of the amount
of CF3SO3H to 11 equivalents retarded the demethylation of
1 (entry 6). The NOESY spectrum and X-ray crystallogra-
phy[11] of 2 indicate that it also takes an anti conformation in
which the nucleophilic nitrogen atom faces toward the phe-
nolic hydroxy group (Figure 1).
DMF
DMF
24
24
[a] Isolated yield. [b] Determined by HPLC analysis of the corresponding
methyl esters on a chiral stationary phase. [c] 0.2 equiv of 2 was used.
[d] A 1:1 mixture was used because 2 was not completely dissolved in
MeCN.
vent (entries 4, 5, and 6). Regarding an acrylate, HFIPA was
again found to exhibit better results than a-naphtyl acrylate
(5)[12] and methyl acrylate (6) as observed for b-ICD-cata-
lyzed reactions (entries 7 and 8).
We next examined the reactions of various aldehydes with
HFIPA (Table 3). In the case of aromatic aldehydes 3b–e,
Table 3. a-Isocupreine-catalyzed reactions of aldehydes with HFIPA.
Figure 1. ORTEP drawing and significant NOEs (in [D7]DMF) of 2.
Entry
3
2 [equiv]
t [h]
Yield [%],[a] Config. (%ee)[b]
7
8
After having established an effective method for the prep-
aration of 2, we then explored its catalytic ability to pro-
mote the MBH reaction. Initially, we examined the reactions
of p-nitrobenzaldehyde (3a) with three esters 4, 5, and 6
under various conditions (Table 2). As shown in entry 2,
when 3a was reacted with 1.3 equivalents of HFIPA by
using 0.1 equivalents of 2 in DMF at À558C following the
procedure we have established for b-ICD-catalyzed reac-
tions,[5a] ester 7a with a S configuration was obtained in
moderate yield and high enantioselectivity (59%, 88% ee;
ee=enantiomeric excess) together with S-enriched dioxa-
none 8a (14%, 40% ee). As expected, the enantioselectivity
was opposite to that observed for the b-ICD-catalyzed reac-
tion (Table 2, entry 1).[5a] When 0.2 equivalents of 2 were
used, aldehyde 3a was consumed almost completely within
17 h to give 7a with 90% ee in 66% yield. In this case, S-en-
riched 8a was obtained in moderate enantioselectivity
(45% ee) and low yield (17%) (entry 3). THF, CH2Cl2, and
MeCN/DMF turned out to be inferior to DMF as the sol-
1
2
3
4
5
6
7
b
c
d
e
f
0.2
0.2
0.2
0.2
0.1
0.1
0.1
24
48
72
48
15
24
13
91, S (88)
0
0
0
0
73 [84],[c] S (93)
24 [93],[c] S (82)
64 [76],[c] S (88)
45, S (87)
20, R (37)[d]
10, R (46)[e]
17, R (14)[f]
g
h
72, S (83)
59, S (93)
[a] Isolated yield. [b] Determined by HPLC analysis of the corresponding
methyl esters on a chiral stationary phase. [c] The yield in the square
bracket was calculated based on the recovered aldehyde. [d] 67:33 cis/
trans mixture. [e] 75:25 cis/trans mixture. [f] 91:9 cis/trans mixture.
esters 7b–e were obtained with high S selectivity in the
range of 82–93% ee in moderate to good yields although
0.2 equivalents of 2 were required for the reaction to pro-
ceed at a reasonable rate. Interestingly, the corresponding
dioxanones 8b–e were not produced unlike the reaction of
reactive p-nitrobezaldehyde (3a). On the other hand, the re-
actions of aliphatic aldehydes 3 f–h yielded S-enriched esters
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a-Isocupreine, an Enantiocomplementary Catalyst of b-Isocupreidine
COMMUNICATION
4 f–h in high enantioselectivity between 82 and 93% ee, al-
though the isolated yields were moderate because of the
production of dioxanones 3 f–h (entries 6–8). In these cases,
the use of 0.1 equivalents of 2 led to the consumption of
most of the aldehydes due to the higher reactivity compared
with aromatic aldehydes.
To further demonstrate the utility of 2 we next examined
aza-MBH reactions of aromatic imines 9 with b-naphthyl
acrylate (10) employing catalyst 11[13] derived from 2 and b-
naphthol under dual catalysis conditions developed by
Masson and Zhu et al.[14] As summarized in Table 4, the re-
elimination of the catalyst[15] takes place to give a (S)-MBH
product or a (R)-aza-MBH product.
In conclusion, we have developed a new cinchona alkaloid
derived catalyst, a-isocupreine (a-ICPN), which is available
in excellent yields in one step from quinine. The present
work demonstrates that a-ICPN can be utilized as an enan-
tiocomplementary catalyst of b-ICD in various b-ICD-cata-
lyzed asymmetric reactions[16] previously established as well
as MBH and aza-MBH reactions.
Experimental Section
a-Isocupreine (2): Quinine (1.02 g, 3.08 mmol) was dissolved in CF3SO3H
(7.7 mL, 86.6 mmol) at 08C and the solution was stirred at room temper-
ature for 10 min. The mixture was heated at 508C for 24 h and then at
808C for 15 h, cooled to room temperature, diluted with ice water
(20 mL) with cooling in an ice bath, and carefully basified by the addition
of Na2CO3 (5.0 g). The mixture was diluted with water, extracted with
CHCl3, washed with brine, dried over K2CO3, and concentrated. Purifica-
tion of the residue with flash column chromatography (SiO2 200 g,
CHCl3/MeOH/Et3N=100:2:1) gave 2 (861 mg, 90%) as a yellow solid,
which upon recrystallization (CHCl3/hexane=7:1), afforded colorless
crystals.
Table 4. aza-MBH reactions of aromatic imines with b-naphthyl acrylate.
Entry
R
t [h]
Yield [%][a]
ee [%][b]
1
2
3
Ph (9a)
48
48
72
72
72
72
93
100
96
51
100
80
83
95
81
96
80
83
p-ClC6H4 (9b)
m-BrC6H4 (9c)
p-(NO2)C6H4 (9d)
b-naphtyl (9e)
p-(MeO)C6H4 (9 f)
4[c]
5
Acknowledgements
6
This work was supported by the Grant-in-Aid for Scientific Research (A)
(22249001) from JSPS and the Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by Organocatal-
ysis” (no. 2304) (24105526) and “Organic Synthesis based on Reaction
Integration” (no. 2105) (24106736) from MEXT.
[a] Isolated yield. [b] Determined by HPLC analysis on a chiral station-
ary phase. [c] The reaction became sluggish due to the poor solubility of
9d in the reaction media.
actions of 9a–f and 10 produced aza-MBH adducts 12a–f
with high R selectivity in the range of 80 to 96% ee, which
is opposite to that observed in the reactions catalyzed by
the corresponding b-ICD-derived catalyst.[14a]
Keywords: asymmetric synthesis
·
cinchona alkaloid
·
·
enantioselectivity
organocatalysts
·
Morita–Baylis–Hillman reaction
The S selectivity of a-ICPN-catalyzed MBH reactions and
the R selectivity of aza-MBH reactions catalyzed by a-
ICPN-derived catalyst 11 can be explained by assuming
zwitter ionic intermediates 13[5b] and 14[14a] stabilized by hy-
drogen bonding, respectively (Figure 2). From these inter-
mediates, a six-membered proton transfer followed by E1cb
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Published online: August 26, 2013
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