Asymmetric Synthesis of Both Diastereomers of α,α′-disubstituted Iminodiacetic Acid Derivatives Using Stereoselective Nucleophilic Substitution of α-Bromo Esters

Full text of DOI:10.1002/bkcs.11446

Note
DOI: 10.1002/bkcs.11446
BULLETIN OF THE
E. Youk et al.
KOREAN CHEMICAL SOCIETY
Asymmetric Synthesis of Both Diastereomers of α,α0-disubstituted
Iminodiacetic Acid Derivatives Using Stereoselective Nucleophilic
Substitution of α-Bromo Esters
*
Eunjee Youk, Wongi Park, and Yong Sun Park
Department of Chemistry, Konkuk University, Seoul 05029, South Korea.
*E-mail: parkyong@konkuk.ac.kr
Received January 24, 2018, Accepted March 9, 2018
Keywords: Dynamic kinetic resolution, Nucleophilic substitution, Stereoselectivity, Chiral auxiliary,
Morpholine
α,α0-Disubstituted iminodiacetic acids are structurally inter-
esting and biologically relevant natural products.1 Their
scaffolds also constitute a part of important chiral drugs
such as Enalapril, Enalkiren and Captopril. Furthermore,
their derivatives such as α,α0-disubstituted iminodiethanols
and morpholines have been widely utilized in organic syn-
thesis for their sterically congested and highly functiona-
lized scaffold.2 However, asymmetric synthetic approaches
toward these types of compounds in the conventional litera-
ture are usually limited in scope, as they afford symmetri-
cally disubstituted products and can be used only for the
generation of one diastereomer.3 Herein, we report our
efforts to synthesize both diastereomers of unsymmetrically
disubstituted iminodiacetic acid derivatives by stereoselec-
tive nucleophilic substitution of chiral auxiliary-derived
α-bromo phenylacetates.
two diastereomers of 1 are dynamically resolved under the
reaction conditions. Subsequent reductive removal of the
chiral auxiliary with LiAlH4 at room temperature gave
highly diastereoenriched (S,S)-diol 3 in 58% overall yield
(entry 1). The scope of the two-step (S,S)-diol formation
was investigated using four different L-amino ester nucleo-
philes. The substitutions with L-alanine, L-leucine,
L-valine, and L-phenylglycine methyl esters were examined
as shown in entries 2–5. Treatment of 1 with L-alanine
Table 1. Chiral auxiliary-mediated nucleophilic substitution for
the preparation of iminodiethanols.
Diacetone-D-glucose-mediated nucleophilic substitution
of α-bromo arylacetates with amine nucleophiles has been
developed in our laboratory for stereoselective preparation
of α-amino acid derivatives.4 The chiral information of D-
glucose is transferred via dynamic kinetic resolution in the
substitution at α-bromo carbon center with amine nucleo-
philes. The α-bromo stereogenic center of diacetone-D-glu-
cose-derived α-bromoacetate (1) undergoes rapid
epimerization in the presence of epimerization agents, and
(αR)-1 reacts with an amine nucleophile preferentially to
afford (αS)-substitution product.
Entrya Reactant
R
Overall yield (%)b Dr (αS:αR)c
We first attempted to use this methodology with L-amino
ester nucleophiles for asymmetric syntheses of
α,α0-disubstituted iminodiacetic acid derivatives. As shown
in Table 1, the treatment of two diastereomeric mixture
(1:1) of α-bromo acetate 1 with L-phenylalanine methyl
ester nucleophile (1.2 equiv) in the presence of tetrabutyl
ammonium iodide (TBAI, 1.0 equiv) and diisopropyl ethy-
lamine (DIEA, 1.2 equiv) for 20 h in CH2Cl2 provided the
substitution product in 87% yield with 99:1 diastereomeric
ratio (dr, αS:αR). The observed dr and yield of iminodiace-
tate suggest that the α-bromo stereogenic center is configu-
rationally labile with respect to the rate of substitution and
1
2
3
4
5
6
7
8
1
1
1
1
1
2
2
2
2
PhCH2
Me
isoBu
isoPr
Ph
PhCH2
Me
isoBu
isoPr
58 (3)
62 (4)
40 (5)
33 (6)
51 (7)
62 (3)
66 (4)
70 (5)
61 (6)
99:1
95:5
95:5
94:6
99:1
99:1
98:2
97:3
99:1
9
a
b
c
All substitutions were carried out in CH2Cl2 at rt.
Isolated yields.
The drs were determined by 1H NMR of the reaction mixture.
Bull. Korean Chem. Soc. 2018
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Wiley Online Library
1

Note
BULLETIN OF THE
ISSN (Print) 0253-2964 | (Online) 1229-5949
KOREAN CHEMICAL SOCIETY
methyl ester, TBAI, and DIEA and following reduction of
the iminodicarboxylic ester with LiAlH4 provided diol 4 in
62% overall yield with 95:5 dr (αS:αR). The same high
selectivities ranging from 99:1 dr to 94:6 dr were observed
with L-leucine, L-valine, and L-phenylglycine-derived
methyl esters in 51–33% overall yields. To improve the
overall yield and dr of diols, we next examined the stereo-
controlling ability of (R)-pantolactone auxiliary under the
same reaction conditions.5 The reactions of (R)-pantolac-
tone-derived α-bromo acetate 2 with L-amino ester nucleo-
philes took place with higher yields, affording diols 3–6 in
70–61% yields. We are pleased to observe higher stereose-
lectivities to produce 3–6 with drs ranging from 99:1 to
97:3 (entries 6–9). In addition, we attempted the reaction of
α-bromo propionate with L-phenylalanine methyl ester
under the same conditions and found that corresponding
diol was afforded in 32% yield with 71:29 dr. The reactions
of α-bromo acetate bearing other aliphatic R substituents
showed much lower selectivities under identical reaction
conditions.
L-phenylalanine methyl ester, TBAI and DIEA at room
temperature, iminodiacetate 16 was produced with a selec-
tivity of 73:27 dr (αS:αR) as shown in Scheme 2. The result
indicates that the L-amino ester nucleophile slightly prefers
(αS)-product in the substitution with α-bromo phenylacetate
and may experience mismatching in the substitution for the
synthesis of (αR)-product.
Three different chiral alcohols known to give (αR)-prod-
uct, such as L-mandelate, L-malate and L-lactate have been
tested for their stereocontrolling ability in dynamic kinetic
resolution of α-bromo esters.7,8 Initial studies were carried
out with methyl L-mandelate. When the diastereomeric
mixture (1:1) of α-bromo ester 13 was treated with TBAI
(1.0 equiv), DIEA (1.2 equiv), and L-phenylalanine methyl
ester (1.2 equiv) in CH2Cl2 at room temperature for 20 h,
the substitution produced (αR)-17 in 51% yield with 89:11
dr. In an effort to improve the stereoselectivity, we exam-
ined substitution reactions of α-bromo acetates 14 and 15
derived from L-malate and L-lactate, respectively. Nucleo-
philic substitutions of 14 and 15 were conducted under the
same reaction conditions as that used for 13. A lower
stereoselectivity was observed in the reaction of 14 with L-
phenylalanine methyl ester to produce 18 in a ratio of
81:19. The reaction of ethyl L-lactate-derived 15 took place
with a higher stereoselectivity, affording 19 with a ratio of
91:9 and 72% yield. In the stereo mismatching reactions of
13–15 with L-amino ester, the stereochemistry of the major
products was dominated by the chiral auxiliary and (αR)-
17–19 were produced with drs ranging from 91:9 to 81:19
as shown in Scheme 2.
The iminodiethanols 3–6 then be transformed to morpho-
lines 8–11 through acid (H2SO4)-catalyzed ether formation
as shown in Scheme 1. The cyclization occurred during
ꢀ
heating to 140 C of diol 3 with concentrated sulfuric acid.
3-Benzyl-5-phenylmorpholine was isolated and treated with
di-tert-butyl dicarbonate to produce stable N-Boc derivative
8 in 27% overall yield. This strategy should provide access
to a broad array of enantiopure trans-3,5-disubstituted mor-
pholines that are difficult to generate using existing meth-
ods.3d-f The same acid-catalyzed cyclization and following
N-Boc protection of diols 4–6 successfully provided highly
diastereoenriched trans-3,5-disubstituted morpholines 9–11
in 31–23% overall yields.6 Our further attempts to improve
the overall yields using Mitsunobu cyclizations with PPh3
and DEAD in THF failed to give a higher yield.
Having successfully developed an asymmetric synthetic
method for the preparation of (S,S)-disubstituted imino dia-
cetic acid derivatives, we next focused our attention on the
preparation of (S,R)-α,α0-disubstituted iminodiacetic acid
derivatives using L-amino ester nucleophiles. In the reac-
tion with L-amino ester nucleophiles, the chiral information
of not only a chiral auxiliary, but also the chiral nucleophile
can be transferred to the new C N bond formation. When
the racemic α-bromo methyl ester 12 was treated with
With the identification of ethyl L-lactate as appropriate
stereocontrolling auxiliary for dynamic kinetic resolution of
α-bromo phenylacetate, we examined the scope of this
methodology with two different L-amino ester nucleophiles
as shown in Scheme 3. Treatment of 15 (50:50 dr) with ala-
nine methyl ester (1.2 equiv), TBAI (1.0 equiv), and DIEA
(1.2 equiv) and following reduction gave 20 in 57% overall
yield with 95:5 dr. This methodology is also practical for
Scheme 2. Nucleophilic substitution of L-phenylalanine with
α-bromo acetates.
Scheme 1. Synthesis of N-Boc-trans-morpholines 8–11.
Bull. Korean Chem. Soc. 2018
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
2

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
at room temperature for 1 h. The reaction was quenched
with saturated NH4Cl solution and the aqueous layer was
extracted with EtOAc. The combined organic extracts were
dried with anhydrous MgSO4, filtered and concentrated
under reduced pressure. Chromatographic separation on sil-
ica gel afforded highly diastereoenriched diols.
(2S)-2-[(2-Hydroxy-(1S)-1-Phenylethyl)Amino]-3-Phenyl
Propanol (3). A pale yellow oil was obtained in 62%
overall yield from 2. 1H NMR (CDCl3, 400 MHz)
7.36–7.10 (m, 10H), 3.90 (dd, J = 8.8, 4.4 Hz, 1H), 3.65
(dd, J = 10.8, 4.4 Hz, 1H), 3.52 (dd, J = 10.4, 8.8 Hz, 1H),
3.41 (dd, J = 10.8, 4.0 Hz, 1H), 3.26 (dd, J = 10.8, 7.2 Hz,
1H), 2.89–2.79 (m, 2H), 2.66–2.62 (dd, J = 12.8, 6.8 Hz,
1H), 2.34 (br, 3H); 13C NMR (CDCl3, 100 MHz) 140.6,
138.6, 129.3, 128.8, 128.5, 127.8, 127.5, 126.4, 67.2, 64.2,
62.1, 57.8, 37.8; HRMS: calcd. For C17H22NO2 [M+ + 1]
272.1651; found 272.1650.
Scheme 3. Synthesis of N-Boc-cis-morpholine.
(2S)-2-[(2-Hydroxy-(1S)-1-Phenylethyl)Amino]Propanol (4).
A pale yellow oil was obtained in 66% overall yield from
2. H NMR (CDCl3, 400 MHz) 7.32–7.25 (m, 5H), 3.95
(dd, J = 9.2, 4.4 Hz, 1H), 3.72 (dd, J = 10.8, 4.4 Hz, 1H),
3.55 (dd, J = 10.8, 9.2 Hz, 1H), 3.50 (dd, J = 10.4, 3.6 Hz,
1H), 3.28 (dd, J = 10.8, 8.4 Hz, 1H), 2.73–2.68 (m, 1H),
2.04 (br, 3H), 1.01 (d, J = 6.4 Hz, 3H); 13C NMR (CDCl3,
100 MHz) 140.9, 128.7, 127.7, 127.5, 66.9, 66.6, 61.2,
51.0, 15.9.
the preparation of iminodiethanol 21 with 94:6 dr in 60%
overall yield from L-leucine methyl ester nucleophile.
Highly diastereoenriched 20 (95:5 dr) was used for the
asymmetric synthesis of cis-3,5-disubstituted morpholine
22 as shown in Scheme 3. Acid-catalyzed dehydrative
cyclization of the diol and N-protection with di-tert-butyl
dicarbonate gave cis-3,5-disubstituted N-Boc morpholine
22 with 99:1 dr in 29% yield over the two steps.6
1
(2S)-2-[(2-Hydroxy-(1S)-1-Phenylethyl)Amino]-4-
MethylPentanol (5). A yellow oil was obtained in 70%
overall yield from 2. 1H NMR (CDCl3, 400 MHz)
7.36–7.27 (m, 5H), 3.91 (dd, J = 9.2, 4.4 Hz, 1H), 3.67 (m,
1H), 3.55 (dd, J = 10.8, 9.2 Hz, 1H), 3.48 (dd, J = 10.8,
3.6 Hz, 1H), 3.22 (dd, J = 10.8, 7.2 Hz, 1H), 2.84 (br, 3H),
2.61–2.55 (m, 1H), 1.54 (m, 1H), 1.40 (m, 1H), 1.22–1.16
(m, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 6.8 Hz,
3H); 13C NMR (CDCl3, 100 MHz) 140.9, 128.7, 127.8,
127.4, 67.2, 64.8, 61.9, 54.5, 41.1, 25.1, 23.5, 22.4.
(2S)-2-[(2-Hydroxy-(1S)-1-Phenylethyl)Amino]-3-
MethylButanol (6). A yellow oil was obtained in 61%
overall yield from 2. 1H NMR (CDCl3, 400 MHz)
7.36–7.26 (m, 5H), 3.92 (dd, J = 8.8, 4.0 Hz, 1H), 3.68
(dd, J = 10.8, 4.4 Hz, 1H), 3.54 (dd, J = 10.4, 9.2 Hz, 1H),
3.44 (dd, J = 10.8, 4.0 Hz, 1H), 3.30 (dd, J = 10.4, 8.4 Hz,
1H), 2.54 (br, 3H), 2.44–2.40 (m, 1H), 1.95–1.90 (m, 1H),
0.91 (d, J = 6.8 Hz, 6H); 13C NMR (CDCl3, 100 MHz)
140.8, 128.7, 127.8, 127.4, 67.4, 62.3, 61.4, 61.1, 28.3,
19.4, 17.5.
We have developed a convenient synthetic method for
asymmetric syntheses of both diastereomers of unsymmetri-
cally disubstituted iminodiethanols and morpholines
through dynamic kinetic resolution of α-bromo arylacetates.
The highly stereoselective substitutions of (R)-pantolac-
tone-derived α-bromo esters provide iminodiesters with the
“S” stereochemistry predominating at the newly formed
asymmetric center. The “R” stereochemistry can be
obtained utilizing L-ethyl lactate although stereoselectivities
in the substitutions are lowered in comparison to (R)-panto-
lactone-mediated substitutions. This asymmetric synthetic
approach using easily available chiral auxiliaries appears to
offer a substantial advantage over previously reported
methodologies for α,α0-disubstituted iminodiacetic acid
derivatives.
Experimental
General Procedure for the Synthesis of Iminodiethanols
3–7 and 20–21. To a solution of diastereomeric mixture
(1:1) of α-bromo-α-arylacetate (1, 2, 13, 14, and 15) in
CH2Cl2 (0.1 M) at room temperature was added L-amino
ester (1.2 equiv), TBAI (1.0 equiv) and DIEA (3.0 equiv).
The resulting reaction mixture was stirred at room tempera-
ture for 20 h. The solvent in mixture was evaporated and
the crude product was purified by short column chromatog-
raphy on silica gel to give iminodiesters. To a solution of
iminodiester in THF (0.5 M) was added LiAlH4 (1.0 M in
(2S)-2-[(2-Hydroxy-(1S)-1-Phenylethyl)Amino]-2-Phenyl
Ethanol (7). A yellow oil was obtained in 51% overall
1
yield from 1. H NMR (CDCl3, 400 MHz) 7.34–7.20 (m,
10H), 3.64–3.51 (m, 6H), 2.84 (br, 3H); 13C NMR (CDCl3,
100 MHz) 141.1, 128.7, 128.6, 127.5, 127.3, 66.0, 62.0.
(2S)-2-[(2-Hydroxy-(1R)-1-Phenylethyl)Amino]Propanol
(20). A colorless oil was obtained in 57% overall yield
1
from 15. H NMR (CDCl3, 400 MHz) 7.35–7.25 (m, 5H),
3.89 (dd, J = 8.4, 4.0 Hz, 1H), 3.72–3.56 (m, 6H), 3.32
(dd, J = 11.2, 5.2 Hz, 1H), 2.76 (br, 1H), 0.97 (d,
ꢀ
THF, 3 equiv) at 0 C, and the reaction mixture was stirred
Bull. Korean Chem. Soc. 2018
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
3

BULLETIN OF THE
Note
KOREAN CHEMICAL SOCIETY
J = 6.8 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 141.0,
(3S,5S)-N-Boc-trans-3-Isopropyl-5-Phenylmorpholine (11).
A yellow oil was obtained in 23% overall yield from 6. H
1
128.7, 127.7, 127.3, 66.8, 64.7, 62.7, 52.5, 18.5; HRMS:
calcd. For C11H18NO2 [M+
196.1338.
+
1] 196.1338; found
NMR (CDCl3, 400 MHz) 7.31–7.21 (m, 5H), 4.50 (d,
J = 4.4 Hz, 1H), 4.06 (m, 1H), 3.86–3.75 (m, 3H), 3.44
(m, 1H), 2.42 (m, 1H), 1.07 (s, 9H), 1.04 (d, J = 6.4 Hz,
3H), 0.98 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz) 156.0, 142.0, 128.2, 126.8, 126.4, 79.8, 72.5,
67.5, 57.8, 56.9, 29.0, 27.7, 20.5, 19.0.
(3S,5R)-N-Boc-cis-3-Methyl-5-Phenylmorpholine (22).
A yellow oil was obtained in 29% overall yield from 20.
1H NMR (CDCl3, 400 MHz) 7.59–7.21 (m, 5H), 5.14 (d,
J = 3.6 Hz, 1H), 4.56 (d, J = 12.1 Hz, 1H), 4.14 (m, 1H),
3.77 (dd, J = 12.1, 3.4 Hz, 1H), 3.71 (m, 2H), 1.51 (s, 9H)
(br, 4H), 0.91 (d, J = 7.2 Hz, 3H). The spectral data of 22
were identical to those of the authentic material reported
previously.6
(2S)-2-[(2-Hydroxy-(1R)-1-Phenylethyl)Amino]-4-
MethylPentanol (21). A yellow oil was obtained in 60%
overall yield from 15. 1H NMR (CDCl3, 400 MHz)
7.35–7.26 (m, 5H), 3.90 (dd, J = 8.0, 3.6 Hz, 1H),
3.76–3.57 (m, 3H), 3.31 (dd, J = 11.2, 4.0 Hz, 1H), 3.3
(br, 3H), 2.60 (m, 1H), 1.60–1.57 (m, 1H), 1.28–1.22 (m,
2H), 0.80 (d, J = 6.8 Hz, 3H), 0.68 (d, J = 6.8 Hz, 3H);
13C NMR (CDCl3, 100 MHz), 141.2, 128.6, 127.6, 127.3,
67.1, 63.0, 62.1, 53.9, 42.1, 24.6, 23.0, 22.4.
General Procedure for the Synthesis of N-Boc Morpho-
lines 8, 9, 10, 11 and 22. Diol was stirred in a thick-
walled sealable tube as 1.0 mL of conc. H2SO4 was added
ꢀ
slowly. The tube was sealed and heated at 140 C. After
Acknowledgments. This work was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Edu-
cation (2017R1D1A1B03035502)
7 h, the dark brown mixture was cooled to room tempera-
ture and then poured portion-wise into an ice-cold solution
of KOH. To the solution was added di-tert-butyl dicarbo-
nate (3.0 equiv) and the mixture was stirred at room tem-
perature overnight. The reaction mixture was extracted with
diethyl ether and the combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Chro-
matographic separation on silica gel afforded highly dia-
stereoenriched morpholines.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
References
(3S,5S)-N-Boc-trans-3-Benzyl-5-Phenylmorpholine (8).
A yellow oil was obtained in 27% overall yield from 3. H
1. (a) H. A. Bates, A. Kaushal, P.-N. Deng, D. Sciaky, Biochem-
istry 1984, 23, 3287. (b) R. Nakashima, N. Hayashi,
T. Mizutani, N. Ueda, J. Yamamoto, Y. Kimura, Biosci. Bio-
technol. Biochem. 1993, 57, 1514.
2. (a) R. Dave, N. A. Sasaki, Tetrahedron Asymmetry 2006, 17,
388. (b) H. Li, R. Xu, D. Cole, J. W. Clader, W. J. Greenlee,
A. A. Nomeir, L. Song, L. Zhang, Bioorg. Med. Chem. Lett.
2010, 20, 6606.
3. (a) M. A. Sclaldone, A. I. Myers, Tetrahedron Lett. 1994, 35,
7533. (b) F. Berre’e, A. Debache, Y. Marsac, B. Collet,
P. G. Bleiz, B. Carboni, Tetrahedron 2006, 62, 4027.
(c) C. M. Shafer, T. F. Molinski, J. Org. Chem. 1996, 61,
2044. (d) R. Dave, N. A. Sasaki, Org. Lett. 2004, 6, 15.
(e) M. D’hoogh, T. Vanlangendonck, K. W. To¨rnroos, N. De
Kimpe, J. Org. Chem. 2006, 71, 4678. (f ) M. L. Leathen,
B. R. Rosen, J. P. Wolfe, J. Org. Chem. 2009, 74, 5107.
4. H. J. Kim, Y. Kim, E. T. Choi, M. H. Lee, E. S. No,
Y. S. Park, Tetrahedron 2006, 62, 6303.
5. R. N. Ben, T. Durst, J. Org. Chem. 1999, 64, 7700.
6. In references 4 and 5, it was established that (αS)-products were
provided in the substitution of both 1 and 2 with various amine
nucleophiles. We confirmed the relative configuration of mor-
pholine 22 by comparing the NMR spectra with those of previ-
ously reported F. Segat-Dioury, O. Lingibe, B. Graffe, M.-
C. Sacquet, G. Lhommet, Tetrahedron 2000, 56, 233.
1
NMR (CDCl3, 400 MHz) 7.33–7.22 (m, 10H), 4.57 (dd,
J = 10.0, 4.4 Hz, 1H), 4.15 (d, J = 11.6 Hz, 1H), 3.92 (dd,
J = 12.0, 4.4 Hz, 1H), 3.76 (d, J = 12.0 Hz, 1H), 3.57 (d,
J = 11.6 Hz, 1H), 3.39 (m, 1H), 3.17 (m, 1H), 2.88 (dd,
J = 12.8, 2.8 Hz, 1H), 1.18 (s, 9H); 13C NMR (CDCl3,
100 MHz) 156.3, 141.9, 138.6, 129.7, 128.6, 128.3, 126.9,
126.5, 126.1, 80.4, 73.1, 66.6, 56.1, 55.0, 35.9, 27.4;
HRMS: calcd. For C22H28NO3 [M+ + 1] 354.2069; found
354.2067.
(3S,5S)-N-Boc-trans-3-Methyl-5-Phenylmorpholine (9).
1
A yellow oil was obtained in 31% overall yield from 4. H
NMR (CDCl3, 400 MHz) 7.32–7.21 (m, 5H), 4.51 (dd,
J = 9.6, 4.8 Hz, 1H), 4.17 (m, 1H), 3.87–3.74 (m, 3H),
3.37 (dd, J = 12.0, 10.0 Hz, 1H), 1.33 (d, J = 6.4 Hz, 1H),
1.13 (s, 9H); 13C NMR (CDCl3, 100 MHz) 156.4, 142.0,
128.3, 126.8, 126.2, 80.1, 72.8, 71.3, 55.6, 48.6,
27.9, 16.2.
(3S,5S)-N-Boc-trans-3-Isobutyl-5-Phenylmorpholine (10).
1
A yellow oil was obtained in 25% overall yield from 5. H
NMR (CDCl3, 400 MHz) 7.32–7.20 (m, 5H), 4.49 (dd,
J = 10.0, 4.4 Hz, 1H), 4.04 (d, J = 10.4 Hz, 1H), 3.93 (d,
J = 11.6 Hz, 1H), 3.85 (dd, J = 12.0, 4.4 Hz, 1H), 3.74 (m,
1H), 3.38 (m, 1H), 2.00 (m, 1H), 1.64–1.61 (m, 2H), 1.16
(s, 9H), 0.97 (d, J = 6.4 Hz, 6H); 13C NMR (CDCl3,
100 MHz) 156.1, 141.9, 128.3, 126.8, 126.1, 80.0, 72.8,
67.8, 55.9, 51.3, 38.6, 27.9, 25.1, 23.9, 21.5.
7. (a) J. Baek, J. I. Jang, Y. S. Park, Bull. Korean Chem. Soc.
2011, 32, 4067. (b) Y. Kim, K. J. Park, Y. S. Choi, M. Lee,
Y. S. Park, Bull. Korean Chem. Soc. 2013, 34, 2531.
8. Y. M. Lee, K. H. Kang, H.-M. Min, H. J. Lim, E.-H. Park,
Y. S. Park, Arkivoc 2010, ii, 1.
Bull. Korean Chem. Soc. 2018
© 2018 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
4