Asymmetric michael addition of a recyclable chiral amine: Inversion of stereoselectivity caused by the difference of ethereal solvents

Article abstract of DOI:10.1021/ol8007793

(Chemical Equation Presented) The Michael addition of a chiral amine [(-)-6] to α,β-unsaturated esters (4) was attained and the stereoselectivity was inverted by changing the solvent from diethyl ether to tetrahydrofuran when α,β-unsaturated esters having an aromatic ring at the β-position were employed. In addition, the chiral auxiliary in the Michael adducts (9A) was facilely removed with N-iodosuccinimide to afford β-amino esters (10A) and 2-methoxy-d-bornylaldehyde (11), which can be reclaimed to the chiral amine (6) by reductive amination.

Full text of DOI:10.1021/ol8007793

ORGANIC
LETTERS
2008
Vol. 10, No. 13
2653-2656
Asymmetric Michael Addition of a
Recyclable Chiral Amine: Inversion of
Stereoselectivity Caused by the
Difference of Ethereal Solvents
Manabu Node,* Daisuke Hashimoto, Takahiro Katoh, Shunsuke Ochi,
Minoru Ozeki, Tsunefumi Watanabe, and Tetsuya Kajimoto
Department of Pharmaceutical Manufacturing Chemistry, 21st COE program, Kyoto
Pharmaceutical UniVersity, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
node@mb.kyoto-phu.ac.jp
Received April 5, 2008
ABSTRACT
The Michael addition of a chiral amine [(-)-6] to r,ꢀ-unsaturated esters (4) was attained and the stereoselectivity was inverted by changing
the solvent from diethyl ether to tetrahydrofuran when r,ꢀ-unsaturated esters having an aromatic ring at the ꢀ-position were employed. In
addition, the chiral auxiliary in the Michael adducts (9A) was facilely removed with N-iodosuccinimide to afford ꢀ-amino esters (10A) and
2-methoxy-d-bornylaldehyde (11), which can be reclaimed to the chiral amine (6) by reductive amination.
Asymmetric Michael additions of amines to R,ꢀ-unsaturated
esters are very promising because they afford units of
ꢀ-amino acids that are a part of a number of naturally
occurring bioactive compounds. Many methods of stereo-
selective Michael addition, with amines or amides utilized
as nucleophiles, have been developed up to date in either
catalytic or stoichiometric ways. For example, Davis em-
ployed a chiral phenethyl amide as a nucleophile to attack
R,ꢀ-unsaturated esters to afford derivatives of ꢀ-amino acids,1
while Tomioka achieved the Michael addition of an achiral
silyllithium amide in the presence of a chiral ligand.2 Enders
developed a recyclable N-silylated amide carrying (S)-2-
methoxymethylpyrrolidine as a nucleophile.3
On the other hand, we recently reported the asymmetric
Michael addition of a chiral thiol (1) to R,ꢀ-unsaturated
ketones, which was followed by spontaneous Meerwein-
Pondorf-Varley reduction to afford ꢀ-mercapto alcohols.4,5
The Michael addition of 1 was further applied to R,ꢀ-
(2) (a) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.; Tomioka, K. J. Am.
Chem. Soc. 2003, 125, 2886–2887. (b) Doi, H.; Sakai, T.; Yamada, K.;
Tomioka, K. J. Chem. Soc., Chem. Commun. 2004, 1850–1851. (c) Sakai,
T.; Doi, H.; Kawamoto, Y.; Yamada, K.; Tomioka, K. Tetrahedron Lett.
2004, 45, 9261–9263.
(1) (a) Davis, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1991, 2, 183–
186. (b) Davis, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461–
462. (c) Bunnage, M. E.; Davis, S. G.; Goodwin, C. J. Synlett 1993, 731–
732. (d) Davis, S. G.; Garrido, N. M.; Ichihara, O.; Walters, I. A. S. J. Chem.
Soc., Chem. Commun. 1993, 1153–1155. (e) Davis, S. G.; Ichihara, O.;
Walters, I. A. S. J. Chem. Soc., Perkin Trans. 1 1994, 1141–1147. (f) Davis,
S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1994, 117–118. (g) Davis,
S. G.; Fenwick, D. R. J. Chem. Soc., Chem. Commun. 1995, 1109–1110.
(h) Davis, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1996, 7, 1919–1922.
(3) Enders, D.; Wahl, H.; Bettray, W. Angew. Chem., Int. Ed. 1995, 34,
455–457.
(4) (a) Nishide, K.; Shigeta, Y.; Obata, K.; Node, M. J. Am. Chem. Soc.
1996, 118, 13103–13104. (b) Node, M.; Nishide, K.; Shigeta, Y.; Shiraki,
H.; Obata, K. J. Am. Chem. Soc. 2000, 122, 1927–1936
(5) Nishide, K.; Ozeki, M.; Kunishige, H.; Shigeta, H.; Patra, P. K.;
Hagimoto, Y.; Node, M. Angew. Chem., Int. Ed. 2003, 42, 4515–4517
.
.
10.1021/ol8007793 CCC: $40.75
Published on Web 06/07/2008
2008 American Chemical Society

unsaturated esters to afford ꢀ-sulfinyl esters (2), of which
the reaction was next developed to yield ꢀ-mercapto esters
(3) by taking advantage of the Wagner-Meerwein rear-
rangement (Scheme 1, eq 1).6
solution of tert-butyl cinnamate 4a in an appropriate organic
solvent to the amide prepared (-)-6 (1.5 equiv) and
n-butyllithium (1.5 equiv) and stirring the mixture at -78
°C for 2 h (Table 1). The reaction conducted in a nonpolar
solvent, such as toluene or hexane, did not proceed well in
terms of chemical yield and diastereoselectivity (Table 1,
entries 11 and 12). However, the reactions in diethyl ether
(Table 1, entry 1) and tetrahydrofuran (Table 1, entry 7)
proceeded with satisfactory yields and an excellent contrast
of product ratios, i.e., the diastereoselectivities were com-
pletely inverted by changing the solvent from cyclic to
acyclic ethers (Table 1, entries 1, 4-7, and 10). The reaction
solution of tetrahydrofuran maintained a transparent red color
during the reaction while that of diethyl ether was transparent
yellow.
Scheme 1
.
Strategy for the Asymmetric Michael Addition of
H2S and NH3
Table 1. Effects of Solvents on the Ratios of the Michael
Adducts (9A, 9B)
On the basis of these backgrounds, we embarked on the
development of a novel asymmetric Michael addition to R,ꢀ-
unsaturated esters (4) using a chiral amine with a bi-
cycle[2.2.1] system as a nucleophile, which could be prepared
from commercially available ketopinic acid,7 for establishing
an alternative synthetic pathway for both (R)- and (S)-ꢀ-
amino acids (Scheme 1, eq 2).
Furthermore, increasing the utility of the Michael addition
in terms of atom economy and a method to remove the chiral
auxiliary, norbornane, in recyclable form from the Michael
adducts to afford ꢀ-amino esters 5 were established together.
At the beginning of this study, the chiral amine (-)-6 was
prepared as follows. Ketopinic acid (7) was treated with
benzylamine and p-toluenesulfonyl chloride in the presence
of N-methylimidazole8 to afford amide 8,9,10 the hydroxyl
group of which was methylated by a conventional method
followed by reduction of the amide group with borane to
give (-)-6 (Scheme 2).
entry
solvent
yield (%)a
9A:9Bb
1
2
3
4
5
6
Et2O
74
52
61
45
56
59
15:85
88:12
94:6
15:85
17:83
10:90
Et2O + HMPA (6 equiv)c
Et2O + HMPA (30 equiv)d
i-Pr2O
n-Bu2O
CPME
7
8
9
THF
62
99
63
34
81:19
86:14
91:9
THF + HMPA (6 equiv)c
THF + HMPA (30 equiv)d
oxetane
10
89:11
11
12
toluene
hexane
48
36
52:48
28:72
a Isolated yield. b Ratio determined by 1H NMR.. c -50 °C. d -20 °C.
Scheme 2. Synthesis of Chiral Amino Reagents (6)
On the basis of the difference in the solutions’ colors, the
inversion of the diastereoslectivity could be attributed to the
differences of aggregation forms of the lithium amide in the
solutions, of which forms A and B would be dissociated by
adding tert-butyl cinnamate 4a to construct the transition
states TS-A and TS-B (Figure 1).
An experiment with HMPA, a well-known dissociating
agent for organometals, as an additive supported the hy-
pothesis, i.e., addition of HMPA to the reaction solution of
diethyl ether changed the color from yellow to red and
inverted the diastereoslectivity of the products, similar to the
reaction performed in tetrahydrofuran (Table 1, entries 2 and
3). Addition of HMPA in THF solution gave the same type
of aggregation as in diethyl ether in the presence of HMPA
(Table 1, entries 8 and 9).
Next, the effects of solvents on the Michael addition were
scrutinized by fixing the reaction conditions, i.e., adding a
(6) Nishide, K.; Ohsugi, S.; Shiraki, H.; Tamakita, H.; Node, M. Org.
Lett. 2001, 3, 3121–3124.
(7) Organic Synthsis; Wiley: New York, 1973; Collect. Vol. V, pp
689-691.
(8) Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. AdV. Synth.
Catal. 2003, 345, 1209–1214.
(9) Mino, T.; Hata, S.; Ohtake, K.; Sakamoto, M.; Fujita, T. Tetrahedron
Lett. 2001, 42, 4837–4839
.
Considering the results above, several Michael acceptors
carrying another group instead of the phenyl group were
(10) Li, X.; Lou, R.; Young, C.; Chan, A. S. C.; Wong, W. K.
Tetrahedron: Asymmetry 2000, 11, 2077–2082
.
2654
Org. Lett., Vol. 10, No. 13, 2008

on using tetrahydrofuran as the solvent (Table 2, entries
6-11). Moreover, effects of additives on the reactions of
4a-k in tetrahydrofuran solution were tested (Table 2, see
the values in parenthses). Interestingly, addition of 0.5 equiv
of lithium salts, such as lithium trifluoromethanesulfonate,
generally increased both chemical yield and diastereoselec-
tivity.
The additive exhibited a positive effect in the reaction with
a cinnamate derivative having an electron-withdrawing or
-donating group, especially in the reaction of p-chlorocin-
namate (4b), where the chemical yield was increased from
80% to 91% and the diastereoselectivity was improved from
91:9 to 94:6 by adding lithium triflate (Table 2, entry 2).
Unfortunately, additives such as lithium triflate and trifuo-
roacetate in diethyl ether solution afforded no satisfactory
results.
Figure 1. Assumed transition states of the Michael addition in Et2O
and THF solution.
The newly generated chiral center was first determined to
have an S-configuration by X-ray chrystallography of 9Ad,
which was obtained in the reaction of tert-butyl p-methyl-
cinnamate and (-)-6. The absolute configurations of other
products were speculated on the basis of comparison of
chemical shifts of methoxy and methyl groups of the chiral
subjected to the Michael addition to investigate the influence
of the functional groups on the ꢀ-carbon toward the solvent
effect (Table 2). With the substrates employed in our
11
1
auxiliary in H NMR spectra with those of 9Ad.
Herein, to develop the Michael addition as a general
method to synthesize ꢀ-amino acids or esters, the chiral
auxiliary has to be removed from the Michael adducts.
Although cleavage reactions of the carbon-nitrogen bond
are difficult in general, many methods have been developed.12
Notably, the oxidative dealkylation of secondary amines can
be conducted a little more facilely due to the ease of forming
a Schiff base. In fact, Tomioka reported a practical deben-
zylation of secondary amines by N-chlorosuccin-imide
(NCS), dehydrochlorination, and successive transoximation;13
however, the method did not apply to dealkylation on an
amino group except for debenzylation. Therefore, we tried
to cleave the chiral auxiliary by using N-iodosuccin-imide
(NIS), a softer halonium source than NCS.14 Namely, the
Michael adducts (9A) were treated with 4 equiv of NIS to
afford the ꢀ-amino esters (10A)15 and 2-methoxybornyl
Table 2. Substrate Specificity of the Michael Addition
solvent
THF
Et2O
substrates
yield
(%)b
yield
(%)b 9A:9Bc
entry
4, R
9A:9Bc
1
2
3
4
5
6
7
8
9
a: Ph
b: 4-Cl-Ph
c: 4-MeO-Ph 90 (97)
d: 4-Me-Ph
e: 2-Naph
f: n-Hex
g: c-Hex
h: i-Pr
90 (99)a 93:7 (94:6)d
80 (91)a 91:9 (94:6)d
74a 15:85a
50a 7:93a
65
79
79
29
94:6 (96:4)d
91:9 (94:6)d
92:8 (96:4)d
23:77
22:78
21:79
44:56
83(80)
70 (88)
83a (81)a 95:5a (95:5)d
99 (92)
90 (95)
83 (95)
76 (88)
99 (99)
>99:1 (>99:1)d
>99:1) (93:7)d
91:9 (91:9)d
92:8 (96:4)d
97:3 (97:3)d
(11) The signals assigned for methyl and methoxy groups of 9Ad in
the 1H NMR spectrum were observed at 0.50 and 3.17, respectively, while
those of 9Bd appeared at 0.61 and 3.19.
i: n-Pr
j: 3-Pen
k: c-Pen
(12) (a) Bhat, R. G.; Ghosh, Y.; Chandrasekaran, S. Tetrahedron Lett.
2004, 45, 7983–7985. (b) Olofson, R. A.; Schnur, R. C.; Bunes, L.; Pepe,
J. P. Tetrahedron Lett. 1977, 1567–1570. (c) Montzka, T. A.; Matiskella,
J. D.; Partyka, R. A. Tetrahedron Lett. 1974, 1325–1327. (d) Acosta, K.;
Cessac, J. W.; Rao, P. N.; Kim, H. K. J. Chem. Soc., Chem. Commun.
1994, 1985–1986. (e) Murahashi, S.-I.; Naota, T.; Miyaguchi, N.; Nakato,
T. Tetrahedron Lett. 1992, 33, 6991–6994. (f) Santamaria, J.; Ouchabane,
R.; Rigaudy, J. Tetrahedron Lett. 1989, 30, 2927–2928. (g) Reich, H. J.;
Cohen, M. L. J. Org. Chem. 1979, 44, 3148–3151.
10
11
a Performed at -78 °C. b Isolated yield. c Ratio was determined by 1H
NMR. d The value in parentheses was the result of the reaction with LiOTf
(0.5 equiv).
(13) (a) Sakai, T.; Doi, H.; Tomioka, K. Tetrahedron 2006, 62, 8351–
8359. (b) Sakai, T.; Yamamoto, Y.; Tomioka, K. J. Org. Chem. 2006, 71,
4706–4709.
experiment (-50 °C), reactions of the R,ꢀ-unsaturated esters
having an aromatic ring at the ꢀ-position 4a-e showed good
contrast depending on the solvents (Table 2, entries 1-5).
Meanwhile, the reaction of 4f having a n-hexyl group
afforded almost no selectivity in diethyl ether (Table 2, entry
6) and those of substrates having another aliphatic group at
the ꢀ-position 4g-k afforded inseparable products composed
of many components with diethyl ether as the solvent.
Interestingly, higher diastereoselectivities were generally
obtained with the substrates 4f-k than the reactions of 4a-e
(14) (a) Katoh, T.; Watanabe, T.; Nishitani, M.; Ozeki, M.; Kajimoto,
T.; Node, M. Tetrahedron Lett. 2008, 49, 598–600. (b) Hanessian, S.; Wong,
D. H.; Therien, H. Synthesis 1981, 394–396.
(15) The absolute configuration of 10Aa was determined by the optical
rotation ([R]21D -24.5) on the basis of values in the literature ([R]D -13.3,
74% ee)16 and the values of ee (>99% ee) were further confirmed by
converting to N-protected derivatives with a Boc group, which were analyzed
by HPLC with a chiral column. In addition, the absolute configuration and
the ee value of the enantiomer of 10Aa (10Ba) derived from 9Ba were
also determined in a similar way ([R]21D +22.8, lit.17 [R]21D +22.4, >96%
ee).
Org. Lett., Vol. 10, No. 13, 2008
2655

aldehyde (11) in good yield (Table 3). It is noteworthy to
emphasize that this is the first reaction where an alkyl group
except methyl and benzyl groups on an amino group was
cleaved efficiently by oxidation with NIS.
were employed as the Michael acceptor. The addition of
lithium triflate to the reaction by using tert-butyl cinnamate
and its derivatives as the substrate increased the chemical
yield and enhanced the stereoselectivity. Moreover, the chiral
auxiliary in (-)-6 was facilely cleaved with 4 equiv of NIS
to afford ꢀ-amino esters 10A and 2-methoxy-d-bornylalde-
hyde (11), which was reclaimable to (-)-6 by reductive
amination with benzylamine. Our method seems to be
practical because of high chemical and optical yields,18 and
no observation of a decrease in optical purity during the
removal of the chiral auxiliary from Michael adducts to
afford ꢀ-amino esters.2 An application to the synthesis of
(+)-negamycin will appear in a future publication.19
Table 3. Complete Deprotection of the Michael Adducts with
NIS (4 equiv)
Acknowledgment. This research was financially supported
in part by the Frontier Research Program of the Ministry of
Education, Culture, Sports and Technology, Japan.
yield
entry
substrate
R
10A
11
1
2
3
4
5
6
9Aa
9Ac
9Ad
9Af
9Ag
9Ah
Ph
76
84
80
69
89
68
93
99
97
76
93
88
Supporting Information Available: Experimental details
and spectroscopic data of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
4-MeO-Ph
4-Me-Ph
n-Hexa
c-Hex
OL8007793
i-Pra
(18) n-Butyllithium (2.77 M solution in n-hexane, 107 µL, 0.295 mmol)
was added to a solution of (1S,2R)-(-)-2-methoxybornyl-10-benzylamine
[(-)-6] (80.7 mg, 0.295 mmol) in tetrahydrofuran (2 mL) at -50 °C and
the mixture was stirred for 30 min. Then, a solution of (E)-tert-butyl
3-phenyl-2-propenoate (4a) (40.2 mg, 0.197 mmol) in tetrahydrofuran (1
mL) was added to the reaction mixture, which was stirred for another 1 h.
The reaction was quenched by adding a saturated aqueous solution of sodium
bicarbonate and the mixture was extracted with diethy ether. The organic
layer was washed with a saturated aqueous solution of sodium chloride,
dried over sodium sulfate, and evaporated. The residue was purified by
silica gel column chromatography (n-hexane:ethyl acetate ) 10:1) to afford
a mixture of tert-butyl (S)-(-)-3-phenyl-3-[(1S,2R)-2-methoxybornyl-10-
benzylamino]propanoate [(-)-9Aa] (79.1 mg, 85%) and 9Ba (5.9 mg, 5.4%)
as colorless needles. N-Iodosuccinimide (NIS: 119.4 mg, 0.53 mmol) was
added to a solution of 9Aa (63.4 mg, 0.133 mmol) in dichloromethane (1.5
mL) at room temperature and the mixture was stirred for 1 h. The reaction
was quenched by adding a saturated aqueous solution of sodium bicarbonate
and the mixture was extracted with chloroform. The organic layer was
successively washed with a saturated aqueous solution of sodium chloride
and sodium thiosulfate, dried over potassium carbonate, and evaporated.
The residue was purified by silica gel column chromatography (n-hexane:
ethyl acetate ) 15:1 to 5:1, and then chloroform:methanol ) 30:1) to afford
10Aa (22.3 mg, 76%) and 11 (22.4 mg, 93%).
a It is noteworthy to emphasize that adding 4 equiv of NIS at once into
the reaction mixture reduced the chemical yield; therefore, 2 equiv of NIS
was added twice at an interval of 1 h.
Another advantage of the protocol is that the 2-methoxy-
d-bornylaldehyde (11) can be reformed to the chiral amine
(-)-6 in 85% yield by reductive amination with benzylamine
in the presence of sodium borohydride.
In conclusion, we succeeded in establishing a novel
stereoselective Michael addition to tert-butyl esters of R,ꢀ-
unsaturated acids by using the chiral amine (-)-6 as a
nucleophile. The diastereoselectivity was dramatically in-
verted by changing the solvent from diethyl ether to
tetrahydrofuran when aromatic substrates, such as cinnamate,
(16) Matsuyama, H.; Itoh, N.; Yoshida, M.; Kamigata, N.; Sasaki, S.;
Iyoda, M. Chem. Lett. 1997, 37, 5–376.
(19) Hayashi, Y.; Regnier, T.; Nishiguchi, S.; Sydnes, M. O.; Hashimoto,
D.; Hasegawa, J.; Katoh, T.; Kajimoto, T.; Shiozuka, M.; Matsuda, R.; Node,
M.; Kiso, Y. J. Chem. Soc., Chem. Commun. 2008, 237, 9–2381.
(17) Ukaji, Y.; Takenaka, S.; Horita, Y.; Inomata, K. Chem. Lett. 2001,
254–255.
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