Efficient synthesis of 5-amino-6-dialkylamino-4-hydroxypentanamide derivatives for renin inhibitors

Article abstract of DOI:10.3987/COM-11-12224

We report an efficient synthetic method for 5-amino-6-dialkylamino-4- hydroxypentanamide derivatives using Shi Asymmetric Epoxidation and the ring opening of N-(2-nitrobenzenesulfonyl)aziridine with hindered secondary amine as key steps. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-11-12224

HETEROCYCLES, Vol. 83, No. 7, 2011
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HETEROCYCLES, Vol. 83, No. 7, 2011, pp. 1587 - 1602. © The Japan Institute of Heterocyclic Chemistry
Received, 31st March, 2011, Accepted, 10th May, 2011, Published online, 19th May, 2011
DOI: 10.3987/COM-11-12224
EFFICIENT SYNTHESIS OF 5-AMINO-6-DIALKYLAMINO-4-
HYDROXYPENTANAMIDE DERIVATIVES FOR RENIN INHIBITORS
Yuji Nakamura,a,* Yasuyuki Ogawa,a Chie Suzuki,a Teppei Fujimoto,a
Shojiro Miyazaki,a Kazuhiko Tamaki,a Takahide Nishi,a and Hiroshi
Suemuneb
aLead Discovery and Optimization Research Laboratories I, Daiichi Sankyo Co.,
Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. bGraduate School
of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku,
Fukuoka 812-8582, Japan. E-mail: nakamura.yuji.mf@daiichisankyo.co.jp
Abstract – We report an efficient synthetic method for 5-amino-6-dialkylamino-
4-hydroxypentanamide derivatives using Shi Asymmetric Epoxidation and the
ring opening of N-(2-nitrobenzenesulfonyl)aziridine with hindered secondary
amine as key steps.
INTRODUCTION
Renin has an important role in the control of the blood pressure,1 and its inhibitors are expected to not
only treat hypertension, but also prevent disorders in organs such as the heart and kidney.2 Aliskiren (1) is
the first marketed orally active direct renin inhibitor that possesses four chiral carbons in its framework
(Figure 1).3 In 2007, we reported the usefulness of a novel renin inhibitor 2, P1 N-isopropyl motif
analogue of 1.4 2 had a potent renin inhibitory activity close to 1 (in-house data), and this indicates the
possibility of reducing the chemical complexity of 1. To the best of our knowledge, 2 is the first
nanomolar level renin inhibitor which possesses a basic amine group at the P1 position.
A few synthetic routes for the synthesis of 5-amino-6-dialkylamino-4-hydroxypentanamide derivatives
(e.g. 2) have been reported.4,5 However, there seems to be room for improvement because these synthetic
approaches include several moderate-yield steps (30-63%). Thus, it is worth discovering a new efficient
synthetic route to 2 for further structure-activity relationships studies. In this paper, we report the efficient
synthesis of 2, utilizing highly functionalized chiral N-(2-nitrobenzenesulfonyl)aziridine 3 as an
intermediate.

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HETEROCYCLES, Vol. 83, No. 7, 2011
P1
P3
OMe
O
O
O
OMe
H2N
N
H
NH2
OH
P2'
P1'
Aliskiren (1)
P1
N
P3
OMe
O
O
O
OMe
H2N
N
H
NH2
OH
P2'
P1'
2
Figure 1. Structures of Aliskiren and 2
RESULTS AND DISCUSSION
The key features of our strategy are: i) N-C bond formation through direct ring opening of aziridine 3
with secondary amine 4; ii) SN2 substitution of mesylate 5 with the azide group; iii) construction of two
chiral centers by asymmetric epoxidation of (E)-,-unsaturated carboxylic acid 6, followed by
intramolecular lactonization.
Scheme 1. Synthetic strategy for the preparation of 2
Although a number of approaches for the construction of C-2 chiral center of 6 were envisioned (e.g.
Evans asymmetric alkylation), we chose the Ireland-Claisen rearrangement6 of ester 7 with large-scale
synthesis in mind. The preparation of alcohol 8 is described in Scheme 2. The Ireland-Claisen substrate 7
was obtained by acylation of alcohol 9, which was easily prepared from L-(+)-tartaric acid in optically

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1589
pure form.7 Ireland-Claisen rearrangement proceeded under the standard condition. After TMSCl was
added to the enolate formed by 7 and LDA at -78 ℃, the reaction mixture was warmed up to room
temperature to afford (E)-,-unsaturated carboxylic acid 6 (54% yield and 91% ee). The ee value of 6
was enhanced after crystallization with (+)-dehydroabietylamine in n-hexane-CHCl3 (10:1).8 Overall,
enantiomerically pure (S)-6 (99% ee) was obtained in 47% yield from 9 without chromatographic
purification. The first key reaction, asymmetric epoxidation of (E)-,-unsaturated carboxylic acid 6 was
achieved by applying Shi’s method.9 Formation of (3S,4S)-epoxide 10 from 6 followed by one-pot
intramolecular lactonization produced a ratio of 91:9 mixture of alcohol (71% yield) in which the
(5S,1’R)-isomer 8 was predominant as determined by HPLC analysis. In this reaction, a slow addition of
Oxone® and K2CO3 in the aq Na2(EDTA) solution over a period of 6 hours to the reaction mixture of 6
and 1,2:4,5-di-O-isopropylidene--D-erythro-2,3-hexodiulo-2,6-pyranose (11) (1 equiv) was necessary to
complete the reaction. Furthermore, the challenge of reducing the loading amount of 11 was not
successful due to lowering the yield. With the difficulty of isolating a single diastereomer, this mixture
was used for the next step.
Scheme 2. Reagents and conditions: (a) isovaleryl chloride, Et3N, DMAP, CH2Cl2, rt, 95%. (b) (i) LDA,
TMSCl, THF, -78 ℃ to rt (ii) crystallization with (+)-dehydroabietylamine in n-hexane-CHCl3 (10:1),
47%. (c) 11, Oxone®, K2CO3, aq Na2(EDTA), Na2B4O710H2O, dimethoxymethane-MeCN (2:1), 0 ℃,
71%.
Mesylation of 8 with MsCl and Et3N created a diastereomeric mixture of mesylate containing
(5S,1’R)-isomer 5 as a major product (Scheme 3). The second key reaction, SN2 substitution of the
methanesulfonyloxy group with the azide group, was accomplished by treating 5 with sodium azide
(NaN3) in DMPU to obtain (5S,1’S)-azide 12 as a major isomer. Under this conditions, the production of
olefin 13, which was observed when the bromo group was employed instead of the methanesulfonyloxy

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group, was not detected.10 Hydrogenation of the diastereomeric mixture of azide in the presence of HCl,
and the subsequent reaction with 2-nitrobenzenesulfonyl chloride (NsCl)11 under the Schotten-Baumann
condition, followed by crystallization gave N-Ns alcohol 14 as a single stereoisomer in 70% yield from
12 (42% yield from 6). The ee value of 14 was determined to be 99% by chiral HPLC analysis. The
structure and absolute configuration of 14 was confirmed by single crystal X-ray analysis as shown in
Figure 2.
Scheme 3. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 ℃, 97%. (b) NaN3, DMPU, 60 ℃, 87%.
(c) (i) cat. Pd-C, H2, HCl, EtOH, rt (ii) NsCl, Et3N, THF-H2O (10:1), rt (iii) crystallization in diisopropyl
ether-AcOEt (10:1), 70% (3 steps from 12).
Figure 2. X-Ray ORTEP of compound 14
The left-hand aziridine 3 was formed by the Mitsunobu reaction of 14 with DEAD and Ph3P in 93% yield
(Scheme 4). On the other hand, the right-hand amine 4 was prepared by reductive amination of known
benzaldehyde 1512 with isopropylamine in 92% yield. Then the final key coupling reaction, the ring

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1591
opening of 3 with secondary amine 4 was attempted. To our delight, the reaction was accomplished by
only heating the solutions of 3 and 4 in toluene to afford the desired coupling product 16 in excellent
yield (98%). Although reductive amination of aldehyde 18 with 4 was planned to obtain 19 as an
alternative method, aldehyde 18 was not obtained by oxidation of alcohol 17. To evaluate the feature of
N-Ns-aziridine intermediate, we performed similar ring opening reactions of aziridine 3 with several
amines (Table 1). Aziridine 3 smoothly reacted with several amines, even less nucleophilic and more
hindered amines such as N-isopropylaniline (24) and 2,2,6,6-tetramethylpiperidine (25) than amine 4, to
produce coupling adducts in good yield. In addition, 3 was relatively stable and no decomposition was
observed after several months of storage in a refrigerator. Meanwhile, we tried for similar reactions in
two other popular N-protected aziridines with amine 4. N-Boc-aziridine gave no desired product, and
N-Cbz-aziridine gave a coupling product in moderate yield (data not shown). With these features,
N-Ns-aziridine 3 was considered to be a useful intermediate for further chemical modifications of 2.
Scheme 4. Reagents and conditions: (a) DEAD, Ph3P, THF, 0 ℃, 93%. (b) 4, toluene, 110 ℃, 98%. (c)
isopropylamine, AcOH, NaBH(OAc)3, CH2Cl2, rt, 92%. (d) (i) cat. Pd-C, H2, HCl, EtOH, rt (ii) Boc2O,
NaHCO3, dioxane-H2O (1:1), rt.

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Table 1. Reaction of aziridine 3 with hindered amines
entry
1
amine
product
yield (%)
76
OMe
O
N
OMe
OMe
OMe
OMe
HN
HN
HN
NHNs
O
OMe
OMe
OMe
O
O
O
O
O
O
20
26
27
28
OMe
O
N
OMe
2
3
72
89
NHNs
O
21
OMe
O
N
OMe
NHNs
O
22
N
4
5
99
95
N
H
NHNs
O
O
23
29
N
N
H
NHNs
O
O
24
30
N
NHNs
6
92
N
H
O
O
25
31
Next, the N-terminal amide bond formation with 16 and 3-amino-2,2-dimethylpropanamide (32)3 was
attempted under neat condition in the presence of 2-hydroxypyridine as a catalyst to afford amide 33 in

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73% yield.13 Finally, deprotection of the Ns group of 33 was accomplished with thiophenol and cesium
carbonate in DMF to give P1 N-isopropyl motif analogue 2 in 90% yield (Scheme 5).
In conclusion, we have described an efficient route to renin inhibitor 2 proceeding with high stereocontrol.
With a practical synthetic route to 5-amino-6-dialkylamino-4-hydroxypentanamide derivatives in hand,
further chemical modifications aimed at exploring novel renin inhibitors using this synthetic method are
underway. The results of this work will be published elsewhere.
OMe
N
NHNs
a
b
O
O
O
OMe
16
2
H2N
N
H
OH
33
Scheme 5. Reagents and conditions: (a) 3-amino-2,2-dimethylpropanamide (32), 2-hydroxypyridine,
80 ℃, 73%. (b) PhSH, Cs2CO3, DMF, rt, 90%.
EXPERIMENTAL
General
All chemicals, reagents and solvents were purchased from commercial sources (e.g., Aldrich Chemical
Co., Inc., Tokyo Chemical Industry Co., LTD., KANTO CHEMICAL CO., INC., etc.) where available
1
13
and used without further purification. H NMR and C NMR spectra were obtained on a Varian Unity
400 and 500 MHz spectrometers. Mass spectral data were obtained on a VG Analytical 7070 E/HF mass
spectrometer. Flash column chromatography was performed on silica gel 60 N (spherical, neutral), 40-50
m, purchased from KANTO CHEMICAL CO., INC., or NH silica gel, 100-200 mesh, purchased from
FUJI SILYSIA CHEMICAL LTD.
(1R)-3-Methylbutanoic acid 1-[(benzyloxy)methyl]prop-2-en-1-yl ester (7): A solution of isovaleryl
chloride (19.9 mL, 163 mmol) in CH2Cl2 (20 mL) was added to a solution of 9 (24.3 g, 136 mmol),
triethylamine (28.5 mL, 205 mmol) and 4-dimethylaminopyridine (1.65 g, 13.6 mmol) in CH2Cl2 (250
mL) under ice-cooling over 10 minutes, and the mixture was stirred at rt for 4 h. Water (0.75 mL, 42
mmol) was added to the reaction mixture, and the mixture was further stirred at rt for 15 min. The
reaction mixture was concentrated under reduced pressure and diluted with 150 mL of water, followed by
extraction with AcOEt. Then, the organic layer was washed with 1 N hydrochloric acid, a saturated
sodium bicarbonate aqueous solution and brine, and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated under reduced pressure, and the residue was purified by silica gel column

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1
chromatography (eluent, n-hexane:AcOEt = 9:1) to obtain 7 (35.0 g, 95%) as a yellow liquid. H NMR
(400 MHz, CDCl3):  7.36-7.27 (m, 5H), 5.84 (ddd, J = 17.2, 10.6, 5.9 Hz, 1H), 5.54-5.49 (m, 1H), 5.33
(dt, J = 17.2, 1.2 Hz, 1H), 5.24 (dt, J = 10.6, 1.2 Hz, 1H), 4.58 (d, J = 12.5 Hz, 1H), 4.54 (d, J = 12.5 Hz,
1H), 3.58 (dd, J = 11.0, 5.9 Hz, 1H), 3.56 (dd, J = 11.0, 4.7 Hz, 1H), 2.23 (d, J = 6.6 Hz, 2H), 2.17-2.07
(m, 1H), 0.96 (d, J = 6.6 Hz, 6H). MS (FAB+): 263 (M+H)+.
(2S,4E)-6-(Benzyloxy)-2-isopropylhex-4-enoic acid (6): A solution of n-butyllithium (1.57 M in hexane
solution, 94 mL, 0.15 mol) was added to a solution of diisopropylamine (23 mL, 0.16 mol) in THF (265
mL) under N2 atmosphere and under ice-cooling over 45 min. The mixture was stirred at the same
temperature for 20 min to prepare a solution of lithium diisopropylamide in THF. A solution of 7 (35 g,
0.13 mol) in THF (70 mL) was added to the solution above under cooling in a dry ice-acetone bath over
40 minutes, and the mixture was stirred at the same temperature for 20 min. Then, chlorotrimethylsilane
(39 mL, 0.31 mol) was added to the reaction mixture over 20 min. The mixture was stirred at the same
temperature for 20 min and then further stirred at rt for 3 h. After cooling in an ice bath, MeOH (27 mL,
0.67 mol) was added to the reaction mixture so that the internal temperature did not exceed 20 ℃. The
mixture was further stirred at room temperature for 1 h. The reaction mixture was concentrated under
reduced pressure and diluted with a 1 N sodium hydroxide aqueous solution (270 mL, 270 mmol),
followed by extraction with t-butyl methyl ether. Then, the organic layer was extracted with a 1 N sodium
hydroxide aqueous solution (68 mL, 68 mmol). All aqueous layers were combined and made acidic with
6 N hydrochloric acid (78 mL, 0.47 mol), followed by extraction with AcOEt. Then, the organic layer
was washed with water and brine and dried over anhydrous MgSO4. After filtration, the solvent was
evaporated under reduced pressure to obtain crude 6 (19.0 g, 54%, 91% ee) as a yellow liquid. []D -9.9°
(c 1.07, CHCl3). Optically enriched (S)-6 (13.2 g, 50.3 mmol) was then dissolved in CHCl3 (25 mL) and
treated with a solution of (+)-dehydroabietylamine (20.0 g, 70.1 mmol) in CHCl3 (50 mL). After addition
of n-hexane (750 mL), the salt was allowed to crystallize at rt. The solid material was collected by
filtration, washed with n-hexane, dried, and dissolved in t-butyl methyl ether (80 mL). 1 N Sodium
hydroxide aqueous solution (80 mL, 80 mmol) was added, and the mixture was stirred at rt for 30 min.
After the aqueous layer was separated, organic layer was extracted with 1 N sodium hydroxide aqueous
solution (20 mL, 20 mmol). All aqueous layers were combined and made acidic with 6 N hydrochloric
acid (20 mL), followed by extraction with AcOEt (100 mL). Then, the organic layer was washed with
water and brine and dried over anhydrous MgSO4. After filtration, the solvent was evaporated under
1
reduced pressure to obtain 6 (11 g, 47% from 9, 99% ee) as a colorless liquid. H NMR (400 MHz,
CDCl3):  7.38-7.27 (m, 5H), 5.72-5.62 (m, 2H), 4.47 (s, 2H), 3.99-3.91 (m, 2H), 2.40-2.20 (m, 3H),

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1.96-1.88 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H). IR (ATR): 1732, 1703, 1454, 1372,
1214, 1165, 1096, 1064, 1027, 970, 736, 697 cm-1. HRMS (ESI+): m/z calcd for C16H22NaO3 [M+Na]+:
285.14666; found [M+Na]+: 285.14618. The ee value of carboxylic acid 6 was determined by chiral
HPLC analysis after conversion to the corresponding methyl ester with (trimethylsilyl)diazomethane and
MeOH (column, CHIRALCEL OD-H (4.6Φ×250 mm); eluent, n-hexane:i-PrOH = 90:10; flow rate, 0.5
mL/min; wave length, 220 nm; tR of (2S)-isomer, 14.7 min; tR of (2R)-isomer, 16.2 min).
(3S,5S)-5-[(1R)-2-(Benzyloxy)-1-hydroxyethyl]-3-isopropyldihydrofuran-2(3H)-one (8): To a 2 L
three-neck round-bottom flask was added the buffer (0.05 M sodium tetraborate decahydrate in 0.4 mM
aq ethylenediaminetetraacetic acid disodium salt, 292 mL), dimethoxymethane (220 mL), acetonitrile
(110 mL), carboxylic acid 6 (10.0 g, 37.9 mmol), tetra-n-butylammonium hydrogen sulfate (576 mg, 1.44
mmol), and ketone 11 (9.80 g, 37.9 mmol). The reaction mixture was cooled with an ice bath. A solution
of Oxone® (32.6 g, 53.0 mmol) in aq ethylenediaminetetraacetic acid disodium salt (0.4 mM, 146 mL)
and a solution of potassium carbonate (30.6 g, 221 mol) in water (146 mL) were added dropwise through
two separate addition funnels over a period of 6 h. At this point, the reaction was quenched by the
addition of AcOEt and water. The mixture was extracted with AcOEt, washed with brine, dried over
anhydrous Na2SO4, and purified by flash chromatography (eluent, n-hexane:AcOEt = 1:1) to afford a 91:9
mixture of alcohol (7.75 g, 71%) in which the (5S,1’R)-isomer 8 was predominant as determined by
HPLC analysis (column, Inertsil ODS-3 (4.6Φ×250 mm); eluent, MeCN: aq 0.1% ammonium acetate =
50:50; flow rate, 1 mL/min; wave length, 220 nm; tR of minor isomer, 11.8 min; tR of major isomer, 12.5
min). Colorless oil. 1H NMR (400 MHz, CDCl3):  major isomer 7.37-7.31 (m, 5H), 4.56 (d, J = 4.7 Hz,
2H), 4.44-4.40 (m, 1H), 3.88-3.83 (m, 1H), 3.63 (dd, J = 9.8, 3.9 Hz, 2H), 3.55 (dd, J = 9.8, 6.3 Hz, 2H),
2.64-2.58 (m, 1H), 2.41 (d, J = 5.0 Hz, 1H), 2.36-2.29 (m, 1H), 2.21-2.04 (m, 2H), 1.02 (d, J = 7.0 Hz,
3H), 0.94 (d, J = 7.0 Hz, 3H). IR (ATR): 1764, 1741, 1453, 1371, 1242, 1173, 1095, 1045, 1010, 969,
948, 912, 736, 698 cm-1. HRMS (ESI+): m/z calcd for C16H22NaO4 [M+Na]+: 301.14158; found [M+Na]+:
301.14152.
(3S,5S)-5-[(1R)-2-(Benzyloxy)-1-methanesulfonyloxyethyl]-3-isopropyldihydrofuran-2(3H)-one (5):
Methanesulfonyl chloride (177 L, 2.29 mmol) was added to a solution of 8 (440 mg, 1.53 mmol) and
triethylamine (464 mg, 4.59 mmol) in CH2Cl2 (15 mL) under ice-cooling, and the mixture was stirred at
the same temperature for 1 h. Water was added to the reaction mixture, followed by extraction with
CH2Cl2. Then, the organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration,
the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column
chromatography (eluent, n-hexane:AcOEt = 3:1) to obtain a diastereomeric mixture of mesylate (528 mg,

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HETEROCYCLES, Vol. 83, No. 7, 2011
1
97%) containing (5S,1’R)-isomer 5 as a major product. Colorless solid. H NMR (400 MHz, CDCl3): 
major isomer 7.39-7.30 (m, 5H), 4.82 (q, J = 5.7 Hz, 1H), 4.64-4.59 (m, 1H), 4.56 (s, 2H), 3.75 (dd, J =
5.7, 1.8 Hz, 2H), 3.04 (s, 3H), 2.65-2.59 (m, 1H), 2.38-2.31 (m, 1H), 2.18-2.09 (m, 2H), 1.02 (d, J = 6.7
Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H). IR (ATR): 1771, 1352, 1172, 1096, 1026, 967, 918, 809, 738, 699, 524
cm-1. HRMS (ESI+): m/z calcd for C17H24NaO6S [M+Na]+: 379.11913; found [M+Na]+: 379.11840.
(3S,5S)-5-[(1S)-1-Azido-2-benzyloxyethyl]-3-isopropyldihydrofuran-2-one (12): Sodium azide (33 mg,
0.50 mmol) was added to a solution of 5 (150 mg, 0.42 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone (DMPU) (3 mL) at rt, and the mixture was stirred at 60 ℃ for 1 d. The reaction
mixture was cooled to rt and poured into ice water, followed by extraction with AcOEt. Then, the organic
layer was washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the solvent
was evaporated under reduce pressure, and the residue was purified by silica gel column chromatography
(eluent, n-hexane:AcOEt = 5:1) to obtain a diastereomeric mixture of azide (111 mg, 87%) containing
(5S,1’S)-isomer 12 as a major product. Colorless liquid. 1H NMR (500 MHz, CDCl3):  major isomer
7.38-7.29 (m, 5H), 4.61-4.53 (m, 3H), 3.79-3.73 (m, 2H), 3.66-3.63 (m, 1H), 2.75-2.70 (m, 1H),
2.20-2.10 (m, 3H), 1.02 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H).
N-{(1S)-2-Hydroxy-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfo-
namide (14): A suspension of 12 (10.1 g, 33.5 mmol), a solution of 4 N hydrochloric acid in dioxane
(16.7 mL, 66.8 mmol) and 10% palladium-carbon (50% wet, 3.57 g) in EtOH (170 mL) was stirred under
H2 atmosphere at rt for 6 h. Hydrogen in the reaction vessel was replaced by N2, and then the reaction
mixture was diluted with EtOH. Palladium-carbon was separated by filtration and washed with EtOH.
The solvent was evaporated from the filtrate under reduced pressure to obtain 8.50 g of crude
aminoalcohol. Triethylamine (10.2 g, 101 mmol) and 2-nitrobenzenesulfonyl chloride (11.1 g, 50.1
mmol) were added to a solution of 8.50 g of crude aminoalcohol in a mixed solvent of THF (170 mL) and
water (17 mL) at rt, and the mixture was stirred at rt for 12 h. The reaction mixture was concentrated
under reduced pressure, followed by extraction with AcOEt. Then, the organic layer was washed with
water, a saturated sodium bicarbonate aqueous solution and brine, and dried over Na2SO4. After filtration,
the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column
chromatography (eluent, AcOEt). Further, diisopropyl ether (110 mL) and AcOEt (10 mL) were added,
and the precipitated solid was collected by filtration to obtain 14 (8.78 g, 70%) as a single stereoisomer.
Colorless solid. 1H NMR (500 MHz, CDCl3):  8.15-8.11 (m, 1H), 7.92-7.88 (m, 1H), 7.77-7.74 (m, 2H),
5.85 (br d, J = 8.3 Hz, 1H), 4.64-4.61 (m, 1H), 3.72-3.62 (m, 3H), 2.69 (ddd, J = 10.3, 6.8, 5.4 Hz, 1H),
2.41 (ddd, J = 13.7, 10.7, 5.4 Hz), 2.20-2.10 (m, 2H), 1.99 (t, J = 5.4 Hz, 1H), 1.00 (d, J = 6.8 Hz, 3H),

HETEROCYCLES, Vol. 83, No. 7, 2011
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0.93 (d, J = 6.8 Hz, 3H). 13C NMR (500 MHz, CDCl3),  178.5, 147.6, 134.3, 133.8, 133.0, 130.6, 125.5,
77.5, 62.4, 58.9, 45.1, 29.1, 26.1, 20.2, 18.3. IR (KBr): 3397, 1749, 1554, 1470, 1380, 1351, 1184, 1063,
1042, 971, 780, 745, 588, 559 cm-1. HRMS (ESI+): m/z calcd for C15H20N2NaO7S [M+Na]+: 395.08889;
found [M+Na]+: 395.08828. The ee value of 14 was determined by HPLC analysis (column,
CHIRALPAK AD-H (4.6Φ×250 mm); eluent, EtOH:n-hexane = 70:30; flow rate, 0.5 mL/min; wave
length, 254 nm; tR of (2’S,4’S,1S)-isomer, 5.6 min; tR of (2’R,4’R,1R)-isomer, 8.8 min). Crystal data:
C15H20N2O7S, orthorhombic, space group P212121, a = 7.33552(18) Å, b = 14.5482(3) Å, c = 16.0057(4)
Å, V = 1708.10(7) Å3, Z = 4, Dc = 1.448 g/cm3, (Cu-K) = 20.639 cm-1. The number of reflections
collected at 123 K was 19554, of which 3120 were independent and used for structure refinement with R1
= 0.0333, wR2 = 0.0811, and Flack parameter = 0.027(18). Full X-ray crystallographic data will be
deposited at the Cambridge Crystallographic Data Centre.
(3S,5S)-3-Isopropyl-5-[(1S)-1-(2-nitrobenzenesulfonyl)aziridine-2-yl]dihydrofuran-2-one (3):
A
solution of diethyl azodicarboxylate in toluene (40%, 1.47 mL, 3.22 mmol) was added to a solution of 14
(1.0 g, 2.7 mmol) and triphenylphosphine (845 mg, 3.22 mmol) in THF (30 mL) under ice-cooling over
10 min, and the mixture was stirred at the same temperature for 10 min. The reaction mixture was
concentrated under reduced pressure, and the residue was purified by silica gel column chromatography
1
(eluent, toluene:acetone = 5:1) to obtain 3 (890 mg, 93%) as a colorless solid. H NMR (400 MHz,
CDCl3):  8.14 (dd, J = 7.4, 1.5 Hz, 1H), 7.83-7.73 (m, 3H), 4.74-4.70 (m, 1H), 3.26-3.23 (m, 1H), 2.83
(d, J = 4.7 Hz, 1H), 2.78 (dt, J = 9.8, 4.7 Hz, 1H), 2.65 (d, J = 4.7 Hz, 1H), 2.41-2.35 (m, 1H), 2.29 (dt, J
= 12.9, 9.4 Hz, 1H), 2.18-2.10 (m, 1H), 1.00 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H). IR (KBr): 1778,
1548, 1369, 1336, 1168, 1114, 974, 933, 782, 770, 602 cm-1. HRMS (ESI+): m/z calcd for
C15H18N2NaO6S [M+Na]+: 377.07833; found [M+Na]+: 377.07748.
Typical Procedure for the Preparation of Amines 4 and 20-22. N-[4-Methoxy-3-(3-methoxy-
propoxy)benzyl]propan-2-amine (4): Sodium triacetoxyborohydride (11.3 g, 53.5 mmol) was added to
a solution of 15 (6.0 g, 27 mmol), isopropylamine (4.7 g, 80 mmol), and acetic acid (4.8 g, 80 mmol) in
CH2Cl2 (135 mL) under ice-cooling, and the mixture was stirred at rt for 16 h. A saturated sodium
bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with CH2Cl2.
Then, the organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the
solvent was evaporated under reduced pressure, and the residue was purified by NH silica gel column
chromatography (eluent, CH2Cl2:MeOH = 10:1) to obtain 4 (6.6 g, 92%) as a colorless oil. 1H NMR (500
MHz, CDCl3):  6.90 (d, J = 2.0 Hz, 1H), 6.85-6.81 (m, 2H), 4.12 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.71 (s,
2H), 3.57 (t, J = 6.1 Hz, 2H), 3.36 (s, 3H), 2.87-2.82 (m, 1H), 2.13-2.08 (m, 2H), 1.09 (d, J = 6.4 Hz, 6H).

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IR (ATR): 1512, 1464, 1441, 1423, 1260, 1232, 1160, 1025, 804, 764 cm-1. HRMS (ESI+): m/z calcd for
C15H26NO3 [M+H]+: 268.19127; found [M+H]+: 268.19170.
1
N-[4-Methoxy-3-(3-methoxypropoxy)benzyl]cyclopropanamine (20): colorless oil. H NMR (400
MHz, CDCl3):  6.88 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 8.3, 2.0 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.12 (t,
J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.76 (s, 2H), 3.58 (t, J = 6.4 Hz, 2H), 3.36 (s, 3H), 2.17-2.08 (m, 3H),
0.46-0.36 (m, 4H).
N-[4-Ｍethoxy-3-(3-methoxypropoxy)benzyl]cyclobutanamine (21): colorless oil. 1H NMR (400 MHz,
CDCl3):  6.90 (d, J = 1.6 Hz, 1H), 6.83-6.82 (m, 2H), 4.12 (t, J = 6.6 Hz, 2H), 3.85 (s, 3H), 3.63 (s, 2H),
3.57 (t, J = 6.3 Hz, 2H), 3.35 (s, 3H), 3.32-3.25 (m, 1H), 2.25-2.19 (m, 2H), 2.14-2.07 (m, 2H), 1.73-1.64
(m, 4H).
1
N-[4-Methoxy-3-(3-methoxypropoxy)benzyl]cyclopentanamine (22): colorless oil. H NMR (400
MHz, CDCl3):  6.90-6.81 (m, 3H), 4.12 (t, J = 6.6 Hz, 2H), 3.84 (s, 3H), 3.69 (s, 3H), 3.57 (t, J = 6.1 Hz,
2H), 3.36 (s, 2H), 3.13-3.08 (m, 1H), 2.13-2.08 (m, 2H), 1.88-1.82 (m, 2H), 1.73-1.66 (m, 2H), 1.57-1.33
(m, 5H).
Typical Procedure for the Preparation of Products 16 and 26-31. N-{(1S)-2-{Isopropyl[4-methoxy-
3-(3-methoxypropoxy)benzyl]amino}-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-
nitrobenzenesulfonamide (16): A solution of N-Ns-aziridine 3 (0.19 g, 0.54 mmol) and amine 4 (0.18 g,
0.67mmol) in toluene (7 mL) was stirred at 110 ℃ for 1.5 h. After cooling, the reaction mixture was
concentrated under reduced pressure and the residue was purified by silica gel column chromatography
1
(eluent, n-hexane:EtOAc = 1:1) to obtain compound 16 (299 mg, 98%) as a colorless oil. H NMR (500
MHz, CDCl3):  8.01-7.99 (m, 1H), 7.89-7.87 (m, 1H), 7.77-7.71 (m, 2H), 6.82-6.81 (m, 2H), 6.75 (dd, J
= 7.8, 2.0 Hz, 1H), 5.49-5.40 (br s, 1H), 4.80-4.76 (m, 1H), 4.12-4.09 (m, 2H), 3.87 (s, 3H), 3.60-3.57 (m,
2H), 3.49 (d, J = 13.7 Hz, 1H), 3.35 (s, 3H), 3.24 (d, J = 14.1 Hz, 1H), 2.83-2.77 (m, 1H), 2.71 (dd, J =
13.2, 9.8 Hz, 1H), 2.54-2.50 (m, 1H), 2.20 (dd, J = 13.7, 5.9 Hz, 1H), 2.14-2.01 (m, 5H), 1.96-1.90 (m,
1H), 0.95 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.1 Hz, 6H). IR (ATR): 1768, 1735,
1541, 1511, 1362, 1236, 1163, 1115, 1044, 1025, 953, 852, 781, 741, 730, 655, 585, 557, 521 cm-1.
HRMS (ESI+): m/z calcd for C30H43N3NaO9S [M+Na]+: 644.26258; found [M+Na]+: 644.26177.
N-{(1S)-2-{Cyclopropyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}-1-[(2S,4S)-4-isopropyl-5-
oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide (26): Colorless oil. 1H NMR (400 MHz,

HETEROCYCLES, Vol. 83, No. 7, 2011
1599
CDCl3):  8.09-8.06 (m, 1H), 7.89-7.87 (m, 1H), 7.76-7.70 (m, 2H), 6.78 (d, J = 8.2 Hz, 1H), 6.71 (d, J =
2.0 Hz, 1H), 6.65 (m, 1H), 5.41 (d, J = 8.2 Hz, 1H), 4.69-4.65 (m, 1H), 4.07 (t, J = 6.7 Hz, 2H), 3.86 (s,
3H), 3.70-3.64 (m, 1H), 3.57 (t, J = 6.1 Hz, 2H), 3.51 (d, J = 13.7 Hz, 1H), 3.40 (d, J = 13.7 Hz, 1H),
3.35 (s, 3H), 2.81 (dd, J = 13.1, 8.4 Hz, 1H), 2.63-2.58 (m, 1H), 2.36-2.31 (m, 1H), 2.23-1.96 (m, 5H),
1.65-1.60 (m, 1H), 0.98 (d, J = 6.7 Hz, 3H), 0.92 (d, J = 6.7 Hz, 3H), 0.48-0.36 (m, 2H), 0.28-0.23 (m,
1H), 0.18-0.12 (m, 1H).
N-{(1S)-2-{Cyclobutyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}-1-[(2S,4S)-4-isopropyl-5-
oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide (27): Colorless oil. 1H NMR (500 MHz,
CDCl3):  8.07-8.06 (m, 1H), 7.91-7.89 (m, 1H), 7.77-7.75 (m, 2H), 6.80 (d, J = 7.8 Hz, 1H), 6.75 (d, J =
1.5 Hz, 1H), 6.67 (dd, J = 8.1, 1.7 Hz, 1H), 5.56 (br s, 1H), 4.79-4.76 (m, 1H), 4.11 (t, J = 7.3 Hz, 2H),
3.86 (s, 3H), 3.58 (t, J = 6.4 Hz, 2H), 3.45-3.40 (m, 2H), 3.35 (s, 3H), 3.13 (d, J = 13.7 Hz, 1H),
3.00-2.94 (m, 1H), 2.61-2.51 (m, 2H), 2.17-2.02 (m, 5H), 1.97-1.85 (m, 3H), 1.74-1.67 (m, 1H),
1.61-1.46 (m, 3H), 0.97 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H).
N-{(1S)-2-{Cyclopentyl[4-methoxy-3-(3-methoxypropoxy)benzyl]amino}-1-[(2S,4S)-4-isopropyl-5-
1
oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide (28): Colorless oil. H NMR (400 MHz,
CDCl3):  8.05-8.02 (m, 1H), 7.89-7.87 (m, 1H), 7.76-7.73 (m, 2H), 6.82 (d, J = 2.4 Hz, 1H), 6.80 (s, 1H),
6.74-6.72 (m, 1H), 5.56 (br s, 1H), 4.81-4.77 (m, 1H), 4.13-4.10 (m, 2H), 3.86 (s, 3H), 3.58 (t, J = 6.1 Hz,
2H), 3.54 (d, J = 13.7 Hz, 1H), 3.42-2.39 (m, 1H), 3.35 (s, 3H), 3.27 (d, J = 13.7 Hz, 1H), 3.00-2.92 (m,
1H), 2.73 (dd, J = 13.3, 9.4 Hz, 1H), 2.54-2.49 (m, 1H), 2.26 (dd, J = 13.3, 6.3 Hz, 1H), 2.14-1.89 (m,
5H), 1.63-1.32 (m, 7H), 1.20-1.13 (m, 1H), 0.95 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H).
N-{(1S)-2-(Diisopropylamino)-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitro-
benzenesulfonamide (29): Colorless oil. 1H NMR (400 MHz, CDCl3):  8.16-8.14 (m, 1H), 7.92-7.90 (m,
1H), 7.77-7.75 (m, 2H), 5.54 (br, 1H), 4.90-4.86 (m, 1H), 3.49-3.46 (m, 1H), 2.84-2.78 (m, 2H),
2.72-2.61 (m, 2H), 2.39-2.32 (m, 1H), 2.21-2.10 (m, 3H), 1.01 (d, J = 7.0 Hz, 3H), 0.94 (d, J = 7.0 Hz,
3H), 0.90 (d, J = 6.7 Hz, 6H), 0.77 (d, J = 6.7 Hz, 6H). HRMS (ESI+): m/z calcd for C21H34N3O6S
[M+H]+: 456.2168; found [M+H]+: 456.2164.
N-{(1S)-1-[(2S,4S)-4-Isopropyl-5-oxotetrahydrofuran-2-yl]-2-[isopropyl(phenyl)amino]ethyl}-2-
1
nitrobenzenesulfonamide (30): Colorless oil. H NMR (400 MHz, CDCl3):  7.94 (dd, J = 7.6, 1.8 Hz,
1H), 7.88 (dd, J = 7.6, 1.8 Hz, 1H), 7.75-7.66 (m, 2H), 7.14-7.10 (m, 2H), 6.83-6.79 (m, 1H), 6.59-6.57
(m, 2H), 7.43 (d, J = 7.4 Hz, 1H), 4.78-4.74 (m, 1H), 3.77-3.71 (m, 2H), 3.27 (dd, J = 11.5, 8.2 Hz, 1H),

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3.05 (dd, J = 14.5, 6.7 Hz, 1H), 2.71-2.65 (m, 1H), 2.35-2.28 (m, 1H), 2.19-2.07 (m, 2H), 1.08 (d, J = 6.7
Hz, 3H), 0.99 (d, J = 3.1 Hz, 3H), 0.97 (d, J = 3.1 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H). HRMS (ESI+): m/z
calcd for C24H32N3O6S [M+H]+: 490.20118; found [M+H]+: 490.20074.
N-[(1S)-1-[(2S,4S)-4-Isopropyl-5-oxotetrahydrofuran-2-yl]-2-(2,2,6,6-tetramethylpiperidin-1-yl)-
ethyl]-2-nitrobenzenesulfonamide (31): Colorless oil. 1H NMR (400 MHz, CDCl3):  8.20-8.17 (m, 1H),
7.91-7.89 (m, 1H), 7.77-7.74 (m, 2H), 6.24 (d, J = 5.5 Hz, 1H), 4.86-4.81 (m, 1H), 3.72-3.65 (m, 1H),
2.74 (dd, J = 15.3, 8.6 Hz, 1H), 2.63-2.57 (m, 1H), 2.41 (dd, J = 15.1, 7.6 Hz, 1H), 2.29-2.21 (m, 3H),
1.60-1.39 (m, 6H), 1.03-0.93 (m, 12H), 0.86 (s, 6H). HRMS (ESI+): m/z calcd for C24H38N3O6S [M+H]+:
496.2488; found [M+H]+: 496.2479.
tert-Butyl {(1S)-2-hydroxy-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamate (17):
Title compound was obtained in the same manner as described for compound 14 except for the use of
di-tert-butyl dicarbonate and sodium bicarbonate in dioxane-water (1:1) at the stage of the reaction with
2-nitrobenzenesulfonyl chloride. Colorless solid. 1H NMR (500 MHz, CDCl3):  4.86 (br, 1H), 4.71-4.67
(m, 1H), 3.83-3.71 (m, 3H), 2.60-2.56 (m, 1H), 2.28-2.22 (m, 1H), 2.19-2.10 (m, 3H), 1.45 (s, 9H), 1.02
(d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H).
(2S,4S,5S)-N-(3-Amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2-isopropyl-6-{isopropyl[4-methoxy-
3-(3-methoxypropoxy)benzyl]amino}-5-{[(2-nitrophenyl)sulfonyl]amino}hexanamide (33): 32 (134
mg, 1.15 mmol) and 2-hydroxypyridine (11 mg, 0.1 mmol) were added to a solution of 16 (0.24 g, 0.38
mmol) in triethylamine (3.8 mL), and the mixture was stirred at 80 ℃ for 2 h. The reaction mixture was
cooled to rt and then concentated under reduced pressure and further stirred at 80 ℃ for 9 h. The
reaction mixture was cooled and then water was added, followed by extraction with CH2Cl2. Then, the
organic layer was dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column chromatography (eluent, CH2Cl2:MeOH
= 20:1) to obain 33 (206 mg, 73%) as a colorless solid. 1H NMR (500 MHz, CDCl3):  8.03-8.01 (m, 1H),
7.82-7.81 (m, 1H), 7.74-7.68 (m, 2H), 6.84-6.78 (m, 3H), 6.38 (t, J = 6.4 Hz, 1H), 6.16 (br s, 1H), 5.87
(br s, 1H), 5.32 (br s, 1H), 5.03 (br s, 1H), 4.16-4.09 (m, 2H), 3.85 (s, 3H), 3.68-3.56 (m, 4H), 3.42-3.38
(m, 2H), 3.36 (s, 3H), 3.23-3.19 (m, 2H), 3.05-2.99 (m, 1H), 2.84 (dd, J = 13.6, 6.8 Hz, 1H), 2.59 (dd, J =
13.6, 3.9 Hz, 1H), 2.14-2.09 (m, 2H), 1.96-1.92 (m, 1H), 1.29-1.23 (m, 2H), 1.19 (s, 6H), 1.08-1.03 (m,
1H), 1.00 (d, J = 4.4 Hz, 3H), 0.99 (d, J = 4.4 Hz, 3H), 0.74 (d, J = 6.4 Hz, 3H), 0.61 (d, J = 6.8 Hz, 3H).
IR (KBr): 1665, 1541, 1513, 1466, 1365, 1261, 1233, 1167, 1124, 586 cm-1. HRMS (ESI+): m/z calcd for
C35H56N5O10S [M+H]+: 738.37479; found [M+H]+: 738.37566.

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1601
(2S,4S,5S)-5-Amino-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxy-2-isopropyl-6-{isopropyl[4-
methoxy-3-(3-methoxypropoxy)benzyl]amino}hexanamide fumalate (2): Cesium carbonate (0.11 g,
0.33 mmol) was added to a solution of 33 (0.21 g, 0.28 mmol) and thiophenol (60 L, 0.56 mmol) in
DMF (2.8 mL) under N2 atmosphere at rt, and the mixture was stirred at the same temperature for 12 h.
Brine was added to the reaction mixture, followed by extraction with CH2Cl2. Then, the organic layer was
dried over anhydrous Na2SO4. After filtration, the solvent was evaporated under reduced pressure, and the
residue was purified by silica gel column chromatography (eluent, CH2Cl2:MeOH:Et3N = 20:1:0 - 10:1:0
- 100:10:1) to afford 2 (132 mg, 90%). Fumaric acid (28 mg, 0.24 mmol) was added to a solution of 2
(128 mg, 0.24 mmol) in MeOH (1 mL), and the mixture was stirred at rt for 5 min. The reaction mixture
was concentrated under reduced pressure, and CH2Cl2 (0.5 mL) was added to the residue. Et2O (5 mL)
1
was further added and the solid was collected by filtration to obtain fumalate as a colorless solid. H
NMR (500 MHz, CD3OD):  7.72 (t, J = 6.1 Hz, 1H), 6.95-6.92 (m, 3H), 6.69 (s, 2H), 4.08 (t, J = 6.4 Hz,
2H), 3.83 (s, 3H), 3.62 (d, J = 3.9 Hz, 2H), 3.59 (t, J = 6.1 Hz, 2H), 3.38-3.29 (m, 6H), 3.07-3.01 (m, 1H),
2.68-2.55 (m, 3H), 2.29-2.24 (m, 1H), 2.06-2.01 (m, 2H), 1.82-1.75 (m, 1H), 1.68-1.63 (m, 1H),
1.50-1.43 (m, 1H), 1.19 (s, 3H), 1.18 (s, 3H), 1.12 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H), 0.94 (d, J
= 2.9 Hz, 3H), 0.93 (d, J = 2.4 Hz, 3H). IR (KBr): 2962, 1663, 1608, 1516, 1470, 1267, 1190, 1166, 1122,
1025, 984, 804, 648 cm-1. MS (FAB+): 553 (M+H)+.
ACKNOWLEDGEMENTS
We are grateful to Dr. Shuichiro Ito and Ms. Tomoko Yoneyama for the X-ray analysis of compound 14.
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