Stereoselective synthesis of enantiomerically pure D-threo-PDMP; manipulation of a core 2,3-diamino alcohol unit

Article abstract of DOI:10.1016/S0957-4166(00)00319-0

The C(3)-N bond of various non-activated enantiomerically pure aziridine-2-methanols was regioselectively cleaved by nitrogen nucleophiles to provide a variety of β-aminoalanine derivatives in high yields. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00319-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3293–3301
Stereoselective synthesis of enantiomerically pure
D-threo-PDMP; manipulation of a core 2,3-diamino alcohol
unit
Seong-Ho Shin,a Eun Young Han,a Chan Sun Park,a Won Koo Leea,* and Hyun-Joon Hab
aDepartment of Chemistry, Sogang University, Seoul 121-742, South Korea
bDepartment of Chemistry, Hankuk University of Foreign Studies, Yongin 449-791, South Korea
Received 17 May 2000; accepted 8 August 2000
Abstract
The C(3)ꢀN bond of various non-activated enantiomerically pure aziridine-2-methanols was regioselec-
tively cleaved by nitrogen nucleophiles to provide a variety of b-aminoalanine derivatives in high yields.
© 2000 Published by Elsevier Science Ltd.
1. Introduction
Enantiomerically pure and polyfunctionalized small molecules can be used as chiral building
blocks in the asymmetric synthesis of biologically active compounds and the synthesis of these
molecules is an important area in organic chemistry.1 Among such compounds vicinal diamine
and amino alcohol units can be found in a wide range of biologically important molecules.2
Preparations of enantiomerically pure 2,3-amino alcohols and also vicinal diamines from a
variety of sources have been well documented.3 One of the most efficient processes for the
synthesis of enantiomerically pure vicinal diamines is the ring opening of the corresponding
aziridine with nitrogen nucleophiles. Though aziridines are readily accessible synthetic interme-
diates, they have been compared with epoxides due to their low reactivity in ring-opening
reactions with nucleophiles.4 Regioselective ring-openings of activated and non-activated azirid-
ines by azide5 and amine6 nucleophiles have been reported. The ready access to chiral aziridines
and the development of new synthetic transformations have made the aziridine approach more
attractive to synthetic chemists.7 We would like to report the highly regioselective C(3)ꢀN bond
cleavage of non-activated aziridine-2-methanols by azide and amine nucleophiles based on our
previously reported work.8
* Corresponding author. Fax: +82-2-7010967; e-mail: wonkoo@ccs.sogang.ac.kr
0957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00319-0

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2. Results and discussion
Regioselective ring opening reactions of aziridine-2-methanols 1 by the azide TMS–N3 provides
3, through the aziridinium intermediate 2 as the major product (Scheme 1). Sodium azide, NaN3,
was used as a nitrogen source for most of ring-opening reactions of activated aziridines.6 However,
the presence of the a-methylbenzyl substituent on the ring nitrogen requires the activation of the
basic nitrogen prior to the ring opening of 1. Therefore, azido trimethylsilane, TMS–N3, was used
for the activation of the basic ring nitrogen of the N-a-methylbenzyl aziridines and also as the
source of the nitrogen nucleophile to attack the less substituted C(3) position of the aziridines.9
Scheme 1.
The reaction of N-[(S)-a-methylbenzyl]aziridine-2(R)-[1%(R)-alkyl(or aryl)]methanol 1 with two
equivalents of TMS–N3 in CH2Cl2 at room temperature provides the ring-opening products 3a–k
in 80–97% yields after chromatographic purification depending on the substrate (Table 1). The
azido group of 3d was readily reduced by LiAlH4 to provide the corresponding diamino alcohol
4d in 94% yield (Fig. 1).
Table 1
The results of the ring-opening reactions of 1 with TMS–N3
Entry
R
Yield 3 (% isolated)
a
b
c
d
e
f
g
h
i
Methyl
n-Butyl
tert-Butyl
Phenyl
2-Methoxyphenyl
4-Chlorophenyl
1-Hexynyl
4-Fluorophenyl
3-Methylphenyl
2-Thiazolyl
2-Propenyl
85
84
82
88
80
97
91
89
91
88
91
j
k
Glycosylceramide synthase inhibitor PDMP (5,
D
-threo-1-phenyl-2-decanoylamino-3-mor-
pholino-1-propanol) and several 5a-carba-sugar analogues (E and Z isomers) of glycosylceramides,
which have enantiomerically pure 2,3-diamino alcohol units, have been synthesized and extensively
studied.10–15 Recently, modifications of the morpholine13 6 or phenyl17 7 moieties have been carried
out by other groups for the study, evaluation, and also promotion of the activity of these
compounds. However, there have been some limitations in the syntheses reported by other research
16,17
groups
regarding stereochemical control, and the modification of the structure.

S.-H. Shin et al. / Tetrahedron: Asymmetry 11 (2000) 3293–3301
3295
Figure 1.
We used various cyclic secondary amines as nucleophiles in the ring opening reactions of 1d
to obtain -threo-PDMP 5 and its analogues by regioselective ring openings of aziridine. Since
D
the aziridine ring is not prone to react with amine nucleophiles, compound 1d was treated with
iodotrimethylsilane (TMS-I) prior to the reaction with cyclic secondary amines. The aziridine
ring readily opens up regioselectively upon treating with iodotrimethylsilane to provide an alkyl
iodide intermediate 8d which then reacts with amine nucleophiles to give alkylation products 9d
in high yields (Scheme 2Table 2).
Scheme 2.
Table 2
The results of ring openings of aziridine-2-methanol 1d by amine nucleophiles
Entry
R1R2NH
Yield 9d (% isolated)
I
II
III
IV
Pyrrolidine
Piperidine
Hexamethyleneimine
Morpholine
95
87
98
99

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S.-H. Shin et al. / Tetrahedron: Asymmetry 11 (2000) 3293–3301
The transformation of 9d-IV into -threo-PDMP 5 was accomplished by catalytic hydrogena-
D
tion in the presence of AcOH to activate the basic nitrogen. After stirring for 4 hours under a
balloon pressure of hydrogen, the palladium catalyst was filtered, the reaction solvent was
concentrated, and then the solvent was changed to THF. Without purification, the residue was
sequentially treated with aqueous sodium hydroxide and decanoyl chloride. We obtained the
1
product 5 as a light brown oil in high yield and H, 13C NMR, specific rotation, and elemental
analysis data of the product agreed with the known data16 (Scheme 3).
Scheme 3. (i) Pd(OH)2, H2, AcOH, MeOH, 40°C; (ii) 10% NaOH, decanoyl chloride
3. Conclusion
According to the above results, the manipulation of a variety of non-activated aziridine-2-
methanols which we had previously reported8 enables us to modify efficiently either the alkyl or
cyclic amine portions. In addition to the readiness of the structural modification, the utilization
of the enantiomer of the aziridine 1 allows control over the stereochemistry and achieves the
synthesis of -threo-PDMP efficiently.
L
4. Experimental
4.1. General method
Flash chromatography was performed on a Tokyo Rikagikai EF-10 with Merck 230–400
mesh silica gel. Melting points were determined on a Thomas–Hoover capillary melting point
1
apparatus and all melting points were not corrected. H NMR spectra were obtained on a
Varian Gemini 200 (200 MHz), Varian Gemini 300 (300 MHz) and Varian Gemini 500 (500
MHz) spectrometer. NMR spectra were recorded in ppm(l) related to tetramethylsilane
(l=0.00) as an internal standard unless stated otherwise and are reported as follows; chemical
shift, multiplicity (br=broad, s=singlet, t=triplet, q=quartet, m=multiplet), coupling con-
stant and integration. Elemental analysis was performed by Carlo Erba EA 1180 elemental
analyzer. Optical rotations were obtained on Rudolph Autopol III digital polarimeter. Data are
reported as follow: [h]2D5(concentration g/100 mL solvent). Solvents and liquid reagents were
transferred using hypodermic syringes. All other reagents and solvents used were grade. All
glassware was dried in an oven at 150°C prior to use. Methylene chloride and triethylamine were

S.-H. Shin et al. / Tetrahedron: Asymmetry 11 (2000) 3293–3301
3297
dried from calcium hydride prior to use. Small and medium scale purifications were performed
by flash chromatography.
4.2. Representative procedure for the ring opening reaction of 1a with azidotrimethylsilane
To a solution of 1a (201 mg, 0.951 mmol) in methylene chloride (CH2Cl2, 3.2 mL) was added
TMS–N3 (0.25 mL, 1.90 mmol). The mixture was stirred for 12 h at room temperature and the
mixture was treated with aqueous 1N HCl solution and then stirred for an additional 1 h. After
the solution was basified with sat. NaHCO3 and the aqueous layer was extracted with CH2Cl2
(1.0 mL×3). The combined organic extracts were dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. Purification by silica gel flash chromatography (EtOAc/hexane 30:70)
gave 154 mg (85%) of 3a as an oil.
4.2.1. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-methylpropanol 3a
1
Rf 0.21 (EtOAc/hexane 20:80). [h]D26=−146.3 (c 2.00, CHCl3). H NMR (200 MHz, CDCl3) l
7.38–7.25 (m, 5H), 3.96 (q, J=6.5 Hz, 1H), 3.64 (m, 2H), 3.35 (dd, J=12.8, 3.0 Hz, 1H), 2.25
(m, 1H), 1.40 (d, J=6.4 Hz, 3H), 1.09 (d, J=6.2 Hz, 3H). 13C NMR (75.4 MHz, CDCl3) l
144.6, 128.8. 127.5, 127.0, 67.0, 59.6, 54.8, 50.1, 25.0, 19.1. Anal. calcd for C12H18N4O: C, 61.52;
H, 7.74; N, 23.91. Found: C, 61.88; H, 7.75; N, 23.71.
4.2.2. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-n-butylpropanol 3b
1
Rf 0.24 (EtOAc/hexane 20:80). [h]D27=−98.6 (c 1.00, CHCl3). H NMR (200 MHz, CDCl3) l
7.33–7.24 (m, 5H), 3.95 (q, J=6.5 Hz, 1H), 3.63 (dd, J=12.6, 4.6 Hz, 1H), 3.39 (m, 2H), 2.33
(m, 2H), 1.38 (d, J=6.5 Hz, 3H), 1.23 (m, 5H), 0.86 (m, 3H). 13C NMR (50.3 MHz, CDCl3) l
144.8, 128.6, 127.3, 126.9, 71.2, 58.1, 55.4, 51.3, 33.5, 27.8, 25.1, 22.7, 13.9. Anal. calcd for
C15H24N4O: C, 65.19; H, 8.75; N, 20.27. Found: C, 65.16; H, 8.97; N, 20.32.
4.2.3. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-tert-butylpropanol 3c
1
Rf 0.46 (EtOAc/hexane 20:80). [h]D26=−99.2 (c 1.00, CHCl3). H NMR (200 MHz, CDCl3) l
7.33–7.24 (m, 5H), 3.97 (q, J=6.6 Hz, 1H), 3.64 (dd, J=12.6, 4.6 Hz, 1H), 3.32 (dd, J=12.6,
4.8 Hz, 1H), 2.98 (d, J=4.9 Hz, 1H), 2.77 (m, 2H), 2.62 (q, J=4.8 Hz, 1H), 1.42 (d, J=6.5 Hz,
3H), 0.70 (s, 9H). 13C NMR (50.3 MHz, CDCl3) l 144.1, 128.7, 127.6, 127.3, 76.4, 55.7, 54.5,
53.2, 34.9, 25.7, 24.2. Anal. calcd for C15H24N4O: C, 65.19; H, 8.75; N, 20.27. Found: C, 65.21;
H, 8.98; N, 20.12.
4.2.4. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-phenylpropanol 3d
Rf 0.24 (EtOAc/hexane 20:80). [h]D28=−134.2 (c 0.50, CHCl3). H NMR (200 MHz, CDCl3) l
1
7.38–7.17 (m, 10H), 4.43 (d, J=8.5 Hz, 1H), 3.52 (dd, J=12.8, 4.0 Hz, 1H), 3.02 (dd, J=12.8,
2.9 Hz, 1H), 2.56 (m, 1H), 1.41 (d, J=6.5 Hz, 3H). 13C NMR (50.3 MHz, CDCl3) l 144.1,
128.7, 127.3, 76.4, 55.7, 54.5, 53.2, 34.9, 25.7, 24.2. Anal. calcd for C17H20N4O: C, 68.90; H, 6.80;
N, 18.90. Found: C, 69.11; H, 6.92; N, 18.61.
4.2.5. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-(2-methoxyphenyl)propanol 3e
Rf 0.12 (EtOAc/hexane 20:80). [h]D26=−141.0 (c 1.00, CHCl3). H NMR (200 MHz, CDCl3) l
1
7.30–7.17 (m, 7H), 6.94–6.78 (m, 2H), 4.83 (d, J=7.4 Hz, 1H), 3.83 (q, J=7.4 Hz, 1H), 3.83

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(q, J=6.4 Hz, 1H), 3.69 (s, 3H), 3.51 (dd, J=12.6, 4.6 Hz, 1H), 3.07 (dd, J=12.8, 3.5 Hz, 1H),
2.72 (m, 1H), 1.37 (d, J=6.6 Hz, 3H). 13C NMR (50.3 MHz, CDCl3) l 128.7, 128.5, 128.0,
127.1, 126.7, 120.9, 110.6, 69.0, 58.9, 55.4, 55.3, 51.1, 24.7. Anal. calcd for C18H22N4O2: C, 66.24;
H, 6.79; N, 17.16. Found: C, 66.38; H, 6.96; N, 17.08.
4.2.6. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-(4-chlorophenyl)propanol 3f
Rf 0.26 (EtOAc/hexane 20:80). [h]D26=−114.6 (c 1.00, CHCl3). H NMR (200 MHz, CDCl3) l
1
7.38–7.11 (m, 9H), 4.42 (d, J=8.3 Hz, 1H), 3.92 (q, J=6.5 Hz, 1H), 3.57 (dd, J=12.9, 4.1 Hz,
1H), 3.04 (dd, J=12.8, 2.8 Hz, 1H), 1.42 (d, J=6.5 Hz, 3H). 13C NMR (50.3 MHz, CDCl3) l
144.1, 139.7, 133.7, 128.8, 128.6, 128.3, 127.5, 126.8, 73.0, 60.3, 55.2, 49.9, 25.0. Anal. calcd for
C17H19ClN4O: C, 61.72; H, 5.79; N, 16.94. Found: C, 62.00; H, 5.87; N, 16.66.
4.2.7. (R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-(1-hexynyl)propanol 3g
Rf 0.28 (EtOAc/hexane 20:80). [h]D26=−88.0 (c 1.00, CHCl3). H NMR (200 MHz, CDCl3) l
1
7.35–7.23 (m, 5H), 4.22 (m, 1H), 3.96 (q, J=6.4 Hz, 1H), 3.65 (dd, J=12.6, 4.4 Hz, 1H), 3.52
(dd, J=12.5, 3.5 Hz, 1H), 2.60 (m, 1H), 2.18 (m, 2H), 1.39 (m, 7H), 0.88 (t, J=7.0 Hz, 3H). 13C
NMR (75.4 MHz, CDCl3) l 144.6, 128.7, 127.3, 87.3, 78.3, 63.0, 59.2, 55.3, 50.8, 30.6, 24.8,
22.0, 18.4, 13.5. Anal. calcd for C17H24N4O: C, 67.97; H, 8.05; N, 18.65. Found: C, 68.11; H,
7.87; N, 18.69.
4.2.8. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-(4-fluorophenyl)propanol 3h
1
Rf 0.22 (EtOAc/hexane 20:80). [h]D28=−136.0 (c 0.50, CHCl3). H NMR (200 MHz, CDCl3) l
7.38–6.92 (m, 9H), 4.42 (d, J=8.4 Hz, 1H), 3.93 (q, J=6.3 Hz, 1H), 3.57 (dd, J=13.0, 3.8 Hz,
1H), 3.01 (dd, J=12.8, 2.4 Hz, 1H), 2.48 (m, 1H), 1.42 (d, J=6.2 Hz, 3H). 13C NMR (50.3
MHz, CDCl3) l 128.7, 128.5, 127.5, 126.8, 116.9, 115.5, 115.1, 73.1, 60.4, 55.2, 49.9, 25.1. Anal.
calcd for C17H19FN4O: C, 64.95; H, 6.09; N, 17.82. Found: C, 65.07; H, 5.76; N, 17.65.
4.2.9. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-(3-methylphenyl)propanol 3i
1
Rf 0.29 (EtOAc/hexane 20:80). [h]D27=−128.0 (c 1.00, CHCl3). H NMR (200 MHz, CDCl3) l
7.37–6.99 (m, 9H), 4.40 (d, J=8.4 Hz, 1H), 3.91 (q, J=6.5 Hz, 1H), 3.54 (dd, J=12.8, 4.0 Hz,
1H), 3.03 (dd, J=12.8, 2.7 Hz, 1H), 2.54 (m, 1H), 2.28 (s, 3H), 1.40 (d, J=6.5 Hz, 3H). 13C
NMR (75.4 MHz, CDCl3) l 144.5, 141.2, 138.3, 128.9, 128.5, 127.7, 127.5, 127.0, 124.3, 73.6,
60.1, 55.0, 49.7, 24.9, 21.2. Anal. calcd for C18H22N4O: C, 69.65; H, 7.14; N, 18.05. Found: C,
69.96; H, 7.15; N, 17.75.
4.2.10. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-(2-thiazolyl)propanol 3j
1
Mp 68–70°C, Rf 0.27 (EtOAc/hexane 30:70). [h]2D6=−81.2 (c 0.50, CHCl3). H NMR (200
MHz, CDCl3) l 7.68 (d, J=3.3 Hz, 1H), 7.32–7.16 (m, 6H), 4.79 (d, J=6.4 Hz, 1H), 3.83 (q,
J=6.6 Hz, 1H), 3.68 (dd, J=12.6, 4.7 Hz, 1H), 3.59 (dd, J=12.6, 4.3 Hz, 1H), 2.85 (m, 1H),
1.38 (d, J=6.5 Hz, 3H). 13C NMR (50.3 MHz, CDCl3) l 172.9, 144.2, 142.4, 128.7, 127.4, 126.7,
119.2, 71.1, 59.2, 55.6, 50.9, 24.6. Anal. calcd for C14H17N5OS: C, 55.43; H, 5.65; N, 23.08; S,
10.57. Found: C, 55.53; H, 5.87; N, 22.90; S, 10.26.
4.2.11. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-azido-1(R)-(2-propenyl)propanol 3k
Rf 0.38 (EtOAc/hexane 30:70). [h]D26=−158.2 (c 1.00, CHCl3). H NMR (200 MHz, CDCl3) l
1
7.38–7.25 (m, 5H), 4.96 (d, J=13.9 Hz, 2H), 3.92 (m, 2H), 3.60 (dd, J=12.5, 4.5 Hz, 1H), 3.30

S.-H. Shin et al. / Tetrahedron: Asymmetry 11 (2000) 3293–3301
3299
(dd, J=12.5, 3.2 Hz, 1H), 1.45 (s, 3H), 1.40 (d, J=6.5 Hz, 3H). 13C NMR (75.4 MHz, CDCl3)
l 144.6, 144.5, 128.8, 127.5, 126.9, 114.5, 75.0, 55.4, 54.9, 50.2, 24.7, 16.7. Anal. calcd for
C14H20N4O: C, 64.59; H, 7.74; N, 21.52. Found: C, 64.68; H, 7.76; N, 21.30.
4.3. Representative procedure for the ring opening reactions of 1d by amine nucleophiles
To a solution of the substrate 1d (60 mg, 0.237 mmol) in 0.79 mL of acetonitrile (CH3CN)
was added sodium iodide (107 mg, 0.711 mmol) and trimethylsilyl chloride (90 mL, 0.711 mmol)
at room temperature. After the solution was stirred for 1 h 50 min, pyrrolidine was added to the
mixture. The solution was heated to the boiling point of the solvent for 2 h. The dark brown
reaction mixture was quenched with aqueous 1.2N hydrochloric acid solution and then was
treated with sat. NaHCO3. The organic layer was separated and the aqueous layer was extracted
with methylene chloride (10 mL×3). The combined organic extracts were washed with 20 mL of
brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel
flash chromatography (MeOH/EtOAc 30:70) gave 73 mg (95%) of 9a as brown oil.
4.3.1. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-pyrrolidino-1(R)-phenylpropanol 9d-I
Rf 0.26 (MeOH/EtOAc 30:70). [h]D26=−19.4 (c 1.00, CHCl3). H NMR (500 MHz, CDCl3) l
1
7.10–7.36 (m, 10H), 4.80 (d, J=3.9 Hz, 1H), 3.76–3.80 (q, 1H), 2.87 (m, 1H), 2.61–2.72 (m, 6H),
1.79–1.81 (m, 4H), 1.24–1.25 (d, J=6.35 Hz, 3H). 13C NMR (125 MHz, CDCl3) l 145.4, 142.1,
127.9, 126.9, 128.8, 126.5, 76.0, 56.7, 55.2, 55.1, 24.5, 23.5. Anal. calcd for C21H28N2O: C, 77.74;
H, 8.70; N, 8.63. Found: C, 77.70; H, 8.93; N, 8.67.
4.3.2. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-piperidino-1(R)-phenylpropanol 9d-II
Rf 0.21 (MeOH/EtOAc 10:90). [h]D26=−35.5 (c 1.00, CHCl3). H NMR (200 MHz, CDCl3) l
1
7.14–7.33 (m, 10H), 4.74–1.80 (d, J=4.0 Hz, 1H), 3.71–3.81 (q, 1H), 2.92–3.00 (m, 1H),
2.39–2.47 (m, 1H), 1.44–1.80 (m, 6H), 1.21–1.24 (d, J=6.6 Hz). 13C NMR (125 MHz, CDCl3)
l 145.60, 142.24, 128.33, 127.82, 126.83, 126.80, 126.52, 126.49, 76.05, 59.76, 55.39, 55.36, 55.06,
26.08, 24.46, 24.08. Anal. calcd for C22H30N2O: C, 78.06; H, 8.93; N, 8.28. Found: C, 78.23; H,
8.93; N, 8.21.
4.3.3. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-hexamethyleneimino-1(R)-phenylpropanol 9d-III
1
Rf 0.67 (MeOH/EtOAc 10:90). [h]D26=−33.7 (c 1.00, CHCl3). H NMR (200 MHz, CDCl3) l
7.17–7.33 (m, 10H), 4.70 (d, 1H), 2.83–3.00 (m, 1H), 2.55–2.83 (m, 7H), 1.55–1.94 (b, 8H),
1.21–1.24 (d, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) l 145.62, 142.47, 128.27, 127.74,
126.74, 126.48, 76.39, 75.74, 59.58, 56.84, 56.15, 56.37, 28.07, 26.61, 24.42. Anal. calcd for
C23H32N2O: C, 78.37; H, 9.15; N, 7.95. Found: C, 78.320; H, 9.397; N, 7.946.
4.3.4. 2(R)-N-[(S)-h-Methylbenzyl]amino-3-morpholino-1(R)-phenylpropanol 9d-IV
Rf 0.33 (EtOAc). [h]2D6=−32.2 (c 1.00, CHCl3). H NMR (300 MHz, CDCl3) l 7.08–7.33 (m,
1
10H), 4.66 (d, J=4.1 Hz, 1H), 3.68–3.73 (m, 5H), 2.40–2.59 (m, 6H), 1.20 (d, J=6.9 Hz, 3H).
13C NMR (75 MHz, CDCl3) l 145.09, 142.17, 128.24, 127.84, 126.75, 126.31, 126.71, 75.22,
66.76, 59.76, 55.93, 54.24, 24.26. Anal. calcd for C21H28N2O2: C, 74.08; H, 8.29; N, 8.23. Found:
C, 74.257; H, 8.239; N, 7.917.

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4.4. Preparation of PDMP 5 ( -threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol)
D
To a solution of 9d-IV (230 mg, 0.676 mmol) in methanol (3.4 mL) were added acetic acid (77
mL, 1.35 mmol), and Pd(OH)2 (25 wt%, 69 mg). The mixture was stirred under a balloon
pressure of hydrogen for 4 hours at 40°C. The catalyst was filtered and the reaction solvent was
removed under reduced pressure and the residue was dissolved in 3.0 mL of tetrahydrofuran.
The solution was treated with 10% aqueous NaOH (0.8 mL, 1.8 mmol) and was sequentially
treated with decanoyl chloride (0.13 mL, 0.607 mmol). Upon completion of reaction, as judged
by TLC, the mixture was treated with water. The organic layer was separated, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. Purification by silica gel flash column
chromatography (EtOAc only) gave 212 mg (two step yield: 81%) of the product as a light
16
1
brown oil. Rf 0.40 (EtOAc). [h]2D5=+8.02 (c 0.30, CHCl3, Lit.
[h]2D5=+8.05) H NMR (500
MHz, CDCl3) l 7.31 (m, 5H), 5.84 (d, J=6.83 HZ, 1H), 4.96 (d, J=3.90 Hz, 1H), 4.28 (m, 1H),
3.72 (t, J=4.88, 4.39 Hz, 4H), 2.47–2.62 (m, 6H), 2.10 (t, J=7.32, 7.81 Hz, 2H), 1.50 (m, 2H),
1.23–1.31 (m, 12H), 0.88 (t, J=6.83 Hz, 3H). 13C NMR (125 MHz, CDCl3) l 173.6, 140.9,
128.2, 127.5, 125.9, 75.1, 66.8, 59.6, 54.2, 51.1, 36.6, 31.7, 29.3, 29.2, 29.1, 29.0, 25.5, 22.5, 14.0.
Anal. calcd for C23H38N2O3: C, 70.73; H, 9.81; N, 7.17. Found: C, 70.69; H, 9.81; N, 7.20.
Acknowledgements
Financial Support from the KOSEF (1999-1-123-001-5 and 97-0501-02-01-3) is gratefully
acknowledged.
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