Convenient preparation of optically active N,N-bis(4-substituted-4- aminobutyl)amines

Article abstract of DOI:10.1016/j.tetasy.2004.12.013

An efficient and convenient method for the synthesis of chiral triamines with two substituents at the α position to the terminal amino group (spermidine analogues) is described. These chiral N,N-bis(4-substituted-4- aminobutyl)amines may have anticancer a

Full text of DOI:10.1016/j.tetasy.2004.12.013

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 739–743
Convenient preparation of optically active
N,N-bis(4-substituted-4-aminobutyl)amines
Kazunori Tsubaki,a,* Tomokazu Kusumoto,a Noriyuki Hayashi,a Daisuke Tanima,a
Kaoru Fujib and Takeo Kawabataa,*
aInstitute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan
bFaculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
Received 7 December 2004; accepted 28 December 2004
Available online 26 January 2005
Abstract—An efficient and convenient method for the synthesis of chiral triamines with two substituents at the a position to the
terminal amino group (spermidine analogues) is described. These chiral N,N-bis(4-substituted-4-aminobutyl)amines may have anti-
cancer activities.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ing of an aziridinium ion with amines.4 However, to the
best of our knowledge, there are no reported methods
for the synthesis of chiral triamines with two alkyl sub-
stituents at the a and a0 positions of a terminal amino
group.5 We report here a convenient and practical meth-
od for the preparation of optically active N,N-bis(4-
substituted-4-aminobutyl)amines 1a–c.
Natural polyamines, for example, spermidine and
spermine which are derived from arginine and methio-
nine through biosynthesis, are important constituents
of cell components. These polyamines play important
roles, such as in cell proliferation, cell differentiation
and stabilization of DNA and RNA.1 Therefore, poly-
amine analogues and their conjugates with other bio-
molecules have been widely investigated as potential
anticancer drugs, gene delivery agents, and so on.2 Sev-
eral efficient methods have been reported for the synthe-
sis of optically active diamines and triamines, based on
the reduction of amide or azide derivatives derived from
amino acids or natural amino products,3 and ring open-
2. Results and discussion
Our concept for the synthesis of optically active 1 was as
follows: (1) both enantiomers could be synthesized, (2) a
variety of substituents could be introduced into the tri-
amine skeleton, and (3) simple handling (UV detection
and low solubility in water). Therefore, we chose benzyl-
oxycarbonyl Z-protected amino acid methyl esters (S)-
2a–c as starting materials. Our synthetic routes for opti-
cally active triamines 1a–c are shown in Scheme 1.
H
H2N
N
NH2
spermidine
Z-protected amino acid methyl esters (S)-2a–c were
treated with 1.6 equiv of DIBAL in toluene at ꢀ78 °C
to give aldehydes 3 in excellent yields. Horner–Wads-
worth–Emmons olefination of aldehydes 3a–c with tri-
ethyl phosphonoacetate proceeded smoothly to afford
4 in good yields. However, some degree of epimerization
took place during two steps, especially in the case of ala-
nine derivative 2a (88% ee). Next, based on a previously
reported method,6,7 the reaction of 4a–c and DIBAL in
the presence of BF3ÆOEt2 in CH2Cl2 provided the
R
R
H
N
H2N
NH2
(S,S)-1a; R = Me
(R,R)-1b; R = i-Pr
(R,R)-1c; R = CH2Ph
*
Corresponding authors. Tel.: +81 774 38 3193; fax: +81 774 38
3197; e-mail: tsubaki@fos.kuicr.kyoto-u.ac.jp
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.12.013

740
K. Tsubaki et al. / Tetrahedron: Asymmetry 16 (2005) 739–743
NHZ
NHZ
CO2Me
NHZ
NHZ
ii
iii
iv
i
H
R
OH
R
R
CO2Et
R
O
(S)-5a (81%) (100:0)b
(S)-5b (93%)a (92:8)b
(S)-5c (75%)a (79:21)b
(S)-3a (97%)
(S)-3b (89%)
(S)-3c (78%)
(S)-2a
(S)-2b
(S)-2c
(S)-4a (100%, 88% ee)
(S)-4b (86%, 98% ee)
(S)-4c (76%. 91% ee)
Ph
R
(S,S)-1a (97%)
(R,R)-1b (87%)
(R,R)-1c (92%)
NHZ
v
vi
R
Br
N
R
ZHN
NHZ
(S)-6a (82%, 89% ee)
(S)-6b (85%)a (90:10)b
(S)-6c (76%)a (80:20)b
(S,S)-7a (74%)
(S,S)-7b (91%)
(S,S)-7c (70%)
a; R = Me, b; R = i-Pr, c; R = CH2Ph
Scheme 1. Reagents and conditions: (i) DIBAL; (ii) triethyl phosphonoacetate; (iii) DIBAL, BF3ÆOEt2; (iv) PPh3, CBr4; (v) benzylamine; (vi)
Pd(OH)2, H2. (a) combined yield, (b) ratio of double/single bonds.
desired allylic alcohols 5a–c as well as some over-
reduced saturated alcohols in combined yields of 75–
93%. Since these two products could not be separated
by column chromatography, the mixture was bromi-
nated with CBr4–PPh3 to give the corresponding allyl-
bromides 6a–c, along with the corresponding saturated
bromides, in combined yields of 76–85%. These distur-
bances in chirality and the over-reduction of double
bonds were cleaned up in the subsequent double-allyla-
tion step. Double allylation of benzylamine with 6a–c
furnished the corresponding bis-adducts 7a–c in 70–
91% yields. Under these reaction conditions, only allyl-
bromides reacted smoothly with benzylamine and the
saturated bromides remained. In addition, minor prod-
ucts (R)-6a–c, which arose from epimerization of start-
ing (S)-2 to (S)-4, led to the meso-forms. The ratios of
(R,R):(meso):(S,S) were as follows: for 7a, 0.0:10.5:
89.5, for 7b, 0.6:0.0:99.4, and for 7c, 0.0:7.4:92.6,
respectively. While the meso- and dl-forms were almost
inseparable by column chromatography, meso-7a–c
could be easily removed by trituration with n-hexane/
ether or recrystallization from iso-propyl ether/ethyl
acetate to afford (S,S)-7a–c with >99% de and >99%
ee. Deprotection of the two Z-groups on the terminal
amino groups and one benzyl group on an inner amino
group, as well as reduction of the two double bonds of
(S,S)-7a–c, proceeded under Pd(OH)2/hydrogen balloon
conditions to give the desired 1a–c in excellent yield.
Based on the results of 200 MHz 1H NMR analysis,
the optical purities of 1a–c were 95% ee and above,
since the corresponding diastereomers were not detected
at all.
3. Conclusion
In summary, we have developed a method for the syn-
thesis of chiral triamines with two substituents at the a
position to the terminal amino group. This method is
quite convenient and practical, and is suitable for the
synthesis of chiral triamine derivatives, and might be
useful in the field of biochemistry for the production
of polyamine analogues.
4. Experimental section
4.1. Ethyl (2E,4S)-4-{[(benzyloxy)carbonyl]amino}pent-2-
enoate (S)-4a
Triethyl phosphonoacetate (4.41 g, 3.90 mL, 19.6
mmol) was added dropwise to a suspension of sodium
hydride (0.65 g, 16.3 mmol, 60% oil dispersion in
mineral oil) in THF (100 mL) at 0 °C under a nitrogen
atmosphere, and the mixture was stirred for 1 h. (S)-3a
(3.4 g, 16.3 mmol) in THF (60 mL) was added drop-
wise to this suspension at 0 °C and the reaction mix-
ture was stirred for 1 h. The solvent was evaporated
off, and ethyl acetate and water were added to the res-
idue and separated. The organic layer was washed suc-
cessively with water (twice) and brine. After being
dried over sodium sulfate, the solvent was evaporated
in vacuo to give a residue as a pale yellow oil. The res-
idue was purified by column chromatography (SiO2, n-
hexane/ethyl acetate = 4/1–2/1) to give (S)-4a (4.51 g,
20
100% yield). ½aꢁ ¼ ꢀ13:4 (c 0.95, CHCl3, for 88%
D
ee); IR (KBr) 3308, 2979, 1718, 1530 cmꢀ1; H NMR
(200 MHz, CDCl3) d 1.29 (t, J = 7.2 Hz, 3H), 1.30 (d,
J = 7.0 Hz, 3H), 4.19 (q, J = 7.2 Hz, 2H), 4.30–4.60
(m, 1H), 4.70–4.90 (m, 1H, NH), 5.11 (s, 2H) 5.91
(dd, J = 15.6 Hz, J = 1.6 Hz, 1H), 6.88 (dd,
J = 15.6 Hz, J = 4.8 Hz, 1H), 7.20–7.45 (m, 5H);
HRMS Calcd for C15H19NO4: 277.1315. Found:
277.1324; Anal. Calcd for C15H19NO4: C, 64.97; H,
6.91; N, 5.05. Found: C, 64.66; H, 6.87; N, 5.07.
1
DIBAL–BF3ÆOEt2 reduction of 4c in toluene gives al-
most a 1:1 mixture of desired 5c and saturated alcohols.
Our synthetic procedure could be applied to the crude 5c
to obtain enantiomerically pure 7c as follows: starting 4c
(91% ee), 5c (63% combined yield, double bond/single
bond = 48:52), 6c (83% combined yield, 54:46 mixture),
and 7c (49% isolated yield, (R,R):(meso):(S,S) =
0.0:7.4:92.6, after recrystallization >99% de, >99% ee).

K. Tsubaki et al. / Tetrahedron: Asymmetry 16 (2005) 739–743
741
HPLC conditions; CHIRALCEL OD, iso-PrOH/n-hex-
ane = 5/95, 0.5 mL/min, tR 33.9 min (R)-4a, tR 41.1 min
(S)-4a.
1H NMR (200 MHz, CDCl3) d 0.89 (d, J = 7.0 Hz,
3H), 0.91 (d, J = 6.6 Hz, 3H), 1.60–1.90 (m, 2H), 4.00–
4.10 (m, 1H), 4.14 (d, J = 4.6 Hz, 2H), 4.70–4.90 (m,
1H, NH), 5.10 (s, 2H), 5.60 (dd, J = 15.6 Hz,
J = 5.8 Hz, 1H), 5.77 (dt, J = 15.6 Hz, J = 4.6 Hz, 1H),
7.25–7.45 (m, 5H); HRMS Calcd for C15H21NO3:
263.1522. Found: 263.1527; Anal. Calcd for
C15H21NO3Æ0.25H2O: C, 67.27; H, 8.09; N, 5.23. Found:
C, 67.28; H, 8.30; N, 5.31.
20
(S)-4b; colorless oil; ½aꢁ ¼ þ0:5 (c 0.91, CHCl3, for
D
1
98% ee); IR (neat) 3341, 2962, 1714, 1530 cmꢀ1 ; H
NMR (200 MHz, CDCl3) d 0.91 (d, J = 5.6 Hz, 3H),
0.95 (d, J = 5.6 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H), 1.80–
2.00 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 4.10–4.40 (m,
1H), 4.70–4.90 (m, 1H, NH), 5.11 (s, 2H), 5.93 (d,
J = 15.6 Hz, 1H), 6.86 (dd, J = 15.6 Hz, J = 5.6 Hz,
1H), 7.30–7.45 (m, 5H); HRMS Calcd for C17H23NO4:
305.1627. Found: 305.1628; Anal. Calcd for
C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found: C,
66.81; H, 7.60; N, 4.70. HPLC conditions; CHIRAL-
CEL OD, iso-PrOH/n-hexane = 5/95, 0.5 mL/min, tR
23.7 min (R)-4b, tR 25.7 min (S)-4b.
(S)-5c; (75% combined yield, 59% calculated yield). A
small amount of (S)-5c was subjected to purification
by PTLC to give analytical sample as white powder.
20
Mp = 70.4–71.0 °C; ½aꢁ ¼ þ11:5 (c 0.77, CHCl3,
D
for 91% ee); IR (KBr) 3330, 2942, 1690, 1541 cmꢀ1
;
1H NMR (200 MHz, CDCl3) d 1.51 (br s, 1H, OH),
2.85 (d, J = 6.8 Hz, 2H), 4.05–4.15 (m, 2H), 4.40–4.60
(m, 1H), 4.60–4.90 (m, 1H, NH), 5.06 (s, 2H), 5.60–
5.80 (m, 2H), 7.10–7.40 (m, 10H); HRMS Calcd for
C19H21NO3: 311.1522. Found: 311.1529; Anal. Calcd
for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C,
73.07; H, 7.10; N, 4.48.
20
(S)-4c; pale yellow oil; ½aꢁ ¼ þ2:2 (c 1.12, CHCl3, for
D
1
91% ee); IR (neat) 3325, 2980, 1714, 1531 cmꢀ1 ; H
NMR (200 MHz, CDCl3) d 1.27 (t, J = 7.0 Hz, 3H),
2.80–3.00 (m, 2H), 4.18 (q, J = 7.0 Hz, 2H), 4.50–4.90
(m, 2H), 5.06 (s, 2H), 5.86 (dd, J = 15.6 Hz,
J = 1.4 Hz, 1H), 6.91 (dd, J = 15.6 Hz, J = 5.0 Hz,
1H), 7.15–7.20 (m, 2H), 7.25–7.40 (m, 8H); HRMS
Calcd for C21H23NO4: 353.1627. Found: 353.1626;
Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N,
3.96. Found: C, 71.20; H, 6.62; N, 3.98. HPLC condi-
tions; CHIRALCEL OD, iso-PrOH/n-hexane = 5/95,
0.5 mL/min, tR 48.8 min (R)-4c, tR 68.6 min (S)-4c.
4.3. Benzyl (1S,2E)-4-bromo-1-methylbut-2-enylcarba-
mate (S)-6a
To a stirred solution of (S)-5a (3.10 g, 13.1 mmol) and
carbon tetrabromide (6.5 g, 19.6 mmol) in dichlorome-
thane (130 mL) was added portionwise triphenylphos-
phine (4.1 g, 15.7 mmol) 0 °C under nitrogen
atmosphere. The solution was stirred for 5 h at room
temperature. The reaction mixture was poured into
the mixed solvent of ethyl acetate and water. The
organic layer was separated, washed successively with
water and brine, and evaporated under reduced pres-
sure. Diethyl ether was added to the residue and triphen-
ylphosphineoxide was filtered off. The filtrate was
evaporated under reduced pressure and diethyl ether
was again added to the residue and triphenylphosphine-
oxide was filtered off. The filtrate was evaporated under
reduced pressure and the residue was purified by col-
umn chromatography on silica gel with n-hexane/ethyl
4.2. Benzyl (1S,2E)-4-hydroxy-1-methylbut-2-enylcarba-
mate (S)-5a
To a solution of (S)-4a (4.50 g, 16.2 mmol) in dichlo-
romethane (160 mL), boron trifluoride diethyl etherate
(2.06 mL, 16.2 mmol) was added at ꢀ78 °C under nitro-
gen atmosphere and stirred for 30 min. Diisobutylalumi-
num hydride (0.94 M solution in hexane 69.0 mL,
64.9 mmol) was added dropwise to the solution and stir-
red at ꢀ78 °C for 1.5 h. The reaction mixture was
poured into the mixed solvent of ethyl acetate and 1 N
aqueous hydrochloric acid. The organic layer was sepa-
rated, washed successively with water (twice) and brine.
After dried over sodium sulfate, the solvent was evapo-
rated in vacuo. The residue was purified by column
chromatography (SiO2, n-hexane/ethyl acetate = 1/1) to
acetate = 3/1 as an eluent to afford (S)-6a (3.19 g,
20
D
82%). Mp = 52.8–53.5 °C; ½aꢁ ¼ ꢀ25:0 (c 1.08, CHCl3,
88% ee); IR (KBr) 3309, 1692, 1535, 1453 cmꢀ1
;
1H
NMR (200 MHz, CDCl3) d 1.25 (d, J = 6.8 Hz, 3H),
3.93 (d, J = 6.3 Hz, 2H), 4.20–4.40 (m, 1H), 4.60–4.80
(m, 1H, NH), 5.10 (s, 2H), 5.65–5.90 (m, 2H), 7.30–
7.50 (m, 5H); HRMS Calcd for C13H1681BrNO2:
299.0344. Found: 299.0353; Anal. Calcd for
C13H16BrNO2: C, 52.37; H, 5.41; N, 4.70. Found: C,
52.14; H, 5.47; N, 4.74. HPLC conditions; CHIRAL-
CEL OB-H, iso-PrOH/n-hexane = 5/95, 0.5 mL/min, tR
85.5 min (S)-6a, tR 121.1 min (R)-6a.
give (S)-5a as colorless solid (3.08 g, 81% yield).
21
Mp = 43.1–44.8 °C; ½aꢁ ¼ ꢀ9:4 (c 1.11, CHCl3, 88%
D
1
ee); IR (KBr) 3349, 1710, 1537, 1454 cmꢀ1; H NMR
(200 MHz, CDCl3) d 1.23 (d, J = 6.8 Hz, 3H), 2.00 (br
s, 1H, OH), 4.11 (d, J = 3.5 Hz, 2H), 4.20–4.50 (m,
1H), 4.60–4.90 (m, 1H, NH), 5.09 (s, 2H), 5.60–5.90
(m, 2H), 7.20–7.40 (m, 5H); HRMS Calcd for
C13H17NO3: 235.1208. Found: 235.1212; Anal. Calcd
for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C,
66.06; H, 7.38; N, 5.89.
(S)-6b; (85% combined yield, 77% calculated yield). A
small amount of (S)-5b was subjected to purification
by PTLC to give analytical sample as white powder.
(S)-5b; (93% combined yield, 86% calculated yield). A
small amount of (S)-5b was subjected to purification
by PTLC to give analytical sample as white powder.
20
Mp = 67.8–69.0 °C; ½aꢁ ¼ ꢀ5:8 (c 0.82, CHCl3);
D
IR (KBr) 3297, 2961, 1683, 1547 cmꢀ1
;
1H NMR
20
(200 MHz, CDCl3) d 0.90 (d, J = 6.8 Hz, 3H), 0.92 (d,
J = 6.8 Hz, 3H), 1.60–1.95 (m, 1H), 3.95 (d,
Mp = 55.5–56.1 °C; ½aꢁ ¼ þ7:6 (c 0.76, CHCl3,
D
for 98% ee); IR (KBr) 3308, 2955, 1686, 1543 cmꢀ1
;

742
K. Tsubaki et al. / Tetrahedron: Asymmetry 16 (2005) 739–743
J = 7.2 Hz, 2H), 4.00–4.20 (m, 1H), 4.70–4.85 (m, 1H,
NH), 5.11 (s, 2H), 5.67 (dd, J = 15.0 Hz, J = 5.8 Hz,
1H), 5.75–5.95 (m, 1H), 7.30–7.40 (m, 5H); HRMS
Calcd for C15H2079BrNO2: 325.0677. Found: 325.0672,
Calcd for C15H2081BrNO2: 327.0657. Found: 327.0669;
Anal. Calcd for C15H20BrNO3: C, 55.23; H, 6.18; N,
4.29. Found: C, 54.93; H, 6.29; N, 4.40.
(S,S)-7c; (70% yield). Mp = 83.8–85.1 °C (from iso-pro-
20
pyl ether); ½aꢁ ¼ þ8:8 (c 0.73, CHCl3); IR (KBr) 3325,
D
1
1687, 1525 cmꢀ1; H NMR (200 MHz, CDCl3) d 2.60–
3.00 (m, 8H), 3.35 (s, 2H), 4.35–4.60 (m, 2H), 4.65–
4.85 (m, 2H), 5.06 (s, 4H), 5.40–5.60 (m, 4H), 7.00–
7.40 (m, 25H); HRMS Calcd for C45H47N3O4:
693.3566. Found: 693.3578; Anal. Calcd for
C45H47N3O4Æ0.85H2O: C, 76.21; H, 6.92; N, 5.93.
Found: C, 75.88; H, 6.57; N, 5.93. HPLC conditions;
(S)-6c; (76% combined yield, 61% calculated yield). A
small amount of (S)-5c was subjected to purification
by PTLC to give analytical sample as white powder.
CHIRALCEL
OD,
iso-PrOH/n-hexane = 10/90,
1.0 mL/min, tR 33.2 min (R,R)-7c, tR 49.9 min (meso)-
7c and tR 70.1 min (S,S)-7c.
20
Mp = 70.5–72.0 °C; ½aꢁ ¼ þ2:7 (c 0.73, CHCl3,
D
for 92% ee); IR (KBr) 3317, 3028, 1694, 1504 cmꢀ1
;
1H NMR (200 MHz, CDCl3) d 2.86 (d, J = 6.4 Hz,
2H), 3.95 (d, J = 6.0 Hz, 2H), 4.40–4.60 (m, 1H), 4.65–
4.80 (m, 1H), 5.06 (s, 2H), 5.60–5.80 (m, 2H), 7.00–
7.45 (m, 10H); HRMS Calcd for C19H2079BrNO2:
373.0677. Found: 373.0662, Calcd for C19H2081BrNO2:
375.0657. Found: 375.0658.
4.5. N,N-Bis[(4S)-4-aminopentyl]amine (S,S)-1a
A suspension of (S,S)-7a (100 mg, 0.18 mmol) and palla-
dium hydroxide (10% on carbon 10 mg) in methanol
(2 mL) was stirred for 17 h at room temperature under
hydrogen atmosphere. The reaction mixture was poured
into the mixed solvent of ethyl acetate and water. The
catalyst was filtered off and the filtrate was evaporated
under reduced pressure and the residue was purified by
PTLC with chloroform/methanol/iso-propylamine =
4.4. Dibenzyl {(benzylimino)bis[(2E,4S)pent-2-ene-1,4-
diyl]}biscarbamate (S,S)-7a
10/1/1 as an eluent to afford (S,S)-1a as an oil
21
D
A suspension of (S)-6a (ca. 88% ee, 3.20 g, 10.7 mmol),
benzylamine (584 lL, 5.3 mmol) and potassium carbon-
ate (3.0 g, 21.4 mmol) in DMF (110 mL) was stirred for
13 h at room temperature under nitrogen atmosphere.
The reaction mixture was poured into the mixed solvent
of ethyl acetate and water. The organic layer was sepa-
rated, washed successively with water and brine (three
times). After dried over sodium sulfate, the solvent
was evaporated in vacuo to give the residue as white
(33.6 mg, 97%). ½aꢁ ¼ þ4:0 (c 1.10, MeOH); IR (film)
3341, 2932, 1586, 1470 cmꢀ1
;
1H NMR (200 MHz,
CD3OD) d 1.03 (d, J = 6.4 Hz, 6H), 1.20–1.60 (m,
8H), 2.45–2.65 (m, 4H), 2.70–2.90 (m, 2H); HRMS
Calcd for C10H25N3: 187.2049. Found: 187.2039.
21
(R,R)-1b; colorless oil; (87%). ½aꢁ ¼ þ17:6 (c 0.44,
D
MeOH); IR (film) 2923, 1560, 1459 cmꢀ1
;
1H NMR
(200 MHz, CD3OD) d 0.85–0.95 (m, 12H), 1.20–1.80
(m, 10H), 2.50–2.75 (m, 6H); HRMS Calcd for
C14H33N3: 243.2675. Found: 243.2687.
powder
((R,R)-7a:(meso)-7a:(S,S)-7a = 0.0:10.5:89.5
determined by HPLC, CHIRALCEL OD, i-PrOH/
n-hexane = 10/90, 1.0 mL/min, k = 254 nm; tR 19.5 min
(R,R)-7a, tR 26.1 min (meso)-7a and tR 30.7 min (S,S)-
7a). The white powder was recrystallized with iso-propyl
ether to afford (S,S)-7a as colorless solid (2.57 g, 74%
20
(R,R)-1c; colorless oil; (92%). ½aꢁ ¼ ꢀ5:4 (c 0.52,
D
MeOH); IR (film) 3350, 3027, 2924, 1454 cmꢀ1
;
1H
NMR (200 MHz, CD3OD) d 1.20–1.70 (m, 8H), 2.50–
2.85 (m, 8H), 2.90–3.05 (m, 2H), 7.15–7.35 (m, 10H);
HRMS Calcd for C22H34N3: 340.2753. Found:
340.2741.
yield, >99% de, >99% ee). Mp = 99.6–100.7 °C (from
20
iso-propyl ether); ½aꢁ ¼ ꢀ23:0 (c 1.02, CHCl3); IR
D
(KBr) 3320, 2797, 1699, 1544 cmꢀ1
;
1H NMR
(200 MHz, CDCl3) d 1.21 (d, J = 6.6 Hz, 6H), 3.02 (d,
J = 4.6 Hz, 4H), 3.51 (s, 2H), 4.15–4.40 (m, 2H), 4.60–
4.80 (m, 2H, NH), 5.09 (s, 4H), 5.45–5.75 (m, 4H),
7.10–7.50 (m, 15H); HRMS Calcd for C33H39N3O4:
541.2941. Found: 541.2943; Anal. Calcd for
C33H39N3O4: C, 73.17; H, 7.26; N, 7.76. Found: C,
72.91; H, 7.25; N, 7.73.
Acknowledgements
This study was partly supported by Grants-in-Aid for
Scientific Research (C), Grants-in Aid for JSPS Fellows,
and the 21st Century COE Program on Kyoto Univer-
sity Alliance for Chemistry from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
(S,S)-7b; (91% yield). Mp = 119.5–120.5 °C (from iso-
20
propyl ether); ½aꢁ ¼ ꢀ3:8 (c 0.74, CHCl3); IR (KBr)
D
3319, 2959, 1687, 1539 cmꢀ1
;
1H NMR (200 MHz,
CDCl3) d 0.87 (d, J = 6.8 Hz, 6H), 0.88 (d, J = 6.8 Hz,
6H), 1.60–1.90 (m, 2H), 3.05 (d, J = 6.0 Hz, 4H), 3.53
(s, 2H), 3.90–4.10 (m, 2H), 4.70–4.90 (m, 2H), 5.09 (s,
4H), 5.40–5.70 (m, 4H), 7.10–7.40 (m, 15H); HRMS
Calcd for C37H47N3O4: 597.3567. Found: 597.3549;
Anal. Calcd for C37H47N3O4Æ0.45H2O: C, 73.35; H,
7.97; N, 6.94. Found: C, 73.18; H, 7.76; N, 6.94. HPLC
conditions; CHIRALCEL OD-H, iso-PrOH/n-hex-
ane = 5/95, 0.5 mL/min, tR 43.6 min (R,R)-7b, tR
55.1 min (meso)-7b and tR 62.3 min (S,S)-7b.
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