Amino acid based synthesis of chiral long chain diamines and tetramines

Article abstract of DOI:10.3390/71000767

A method for the synthesis of long chain diamines and tetramines starting from natural α-amino acids is reported. Diamines and tetramines were prepared through the Wittig olefination reaction of N-protected amino aldehydes obtained from phenylalanine and lysine. A 1,2,17,18-tetramine was synthesized using (2S)-1-azido-2-[bis(tert-butoxycarbonyl)-amino]-5-oxopentane as key-intermediate compound.

Full text of DOI:10.3390/71000767

Molecules 2002, 7, 767-776
molecules
ISSN 1420-3049
http://www.mdpi.org
Amino Acid Based Synthesis of Chiral Long Chain Diamines
and Tetramines
Vassilios Loukas, Theodoros Markidis and George Kokotos*
Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis,
Athens 15771, Greece. Tel.: (+30) 10 7274496, Fax: (+30) 10 7274761.
*
Author to whom correspondence should be addressed; e-mail: gkokotos@cc.uoa.gr
Abstract: A method for the synthesis of long chain diamines and tetramines starting from
natural α-amino acids is reported. Diamines and tetramines were prepared through the
Wittig olefination reaction of N-protected amino aldehydes obtained from phenylalanine and
lysine.
A
1,2,17,18-tetramine was synthesized using (2S)-1-azido-2-[bis(tert-
butoxycarbonyl)-amino]-5-oxopentane as key-intermediate compound.
Keywords: amino acids, amino aldehydes, diamines, tetramines, Wittig reaction
Introduction
In recent years compounds containing amine functionalities have attracted much attention, because
of their interesting biological properties. The naturally occurring polyamines putrescine, spermidine
and spermine, as well as their synthetic analogues, are involved in various important biological
functions [1]. Compounds incorporating the 1,2-diamine functionality are currently the topic of studies
conducted in several fields, e.g. in chemotherapy and in stereoselective organic synthesis [2].
Natural α-amino acids may be used as starting materials for the synthesis of chiral amines through
modification of the α-carboxy group. For example, enantiopure α-methyl amines have been prepared
from various α-amino acids [3], while 1,2-diamines and triamines have been made from glutamic acid
and lysine respectively [4]. C -Symmetric and pseudo C -symmetric based diols, epoxides and dideoxy
2
2
derivatives of HIV protease inhibitors containing the 1,4-diamine functionality have been synthesized
starting from L-phenylalanine and L-tyrosine [5]. C -Symmetrical chiral 1,4-and 1,5-diamines with
2
stereogenic centers adjacent to the nitrogen atom have been prepared by diastereoselective alkylations

Molecules 2002, 7
768
of bisoxazolidines derived from (R)-phenylglycinol [6]. The total synthesis of N-alkyl and
acylpolyamine derivatives, based on the coupling of N-tritylamino acids with amines and subsequent
reduction, has also been described [7]. We have recently shown that long chain 1,2-diamines exhibit
interesting antiinflammatory [8] and cytotoxic activity [9-11]. Furthermore, we have studied the
interactions of polyamines, lipidic 1,2-diamines and aminoglycosides with nucleic acids [12,13].
Within our research program focused on synthesis and study of polyamines, we present here a
methodology for the synthesis of chiral long chain diamines and tetramines starting from natural α-
amino acids.
Results and Discussion
Our strategy to synthesize chiral long chain diamines and tetramines was based on Wittig
olefination of N-protected α-amino aldehydes with alkylidene triphenylphosphoranes and bis(triphenyl-
phosphoranes). Such aldehydes may be prepared either by reduction of an amino acid carboxy
derivative or by oxidation of 2-amino alcohols [14]. We decided to prepare α-amino aldehydes by
oxidation of 2-amino alcohols, using NaOCl in the presence of a catalytic amount of a TEMPO
derivative, a method which appears superior to the reductive methods in terms of preservation of the
enantiomeric purity [15]. Boc-protected amino alcohols 1a,b, easily prepared from N-tert-
α
ε
butoxycarbonyl-L-phenylalanine and N ,N -di(tert-butoxycarbonyl)-L-lysine by reduction of either
their mixed anhydrides [16] or their acyl fluorides with NaBH [17], were chosen as enantiopure
4
starting materials.
Scheme 1.
Synthesis of diamine 3a
1
. NaOCl, AcNH-TEMPO,
NaBr, NaHCO3
and tetramine
NHBoc
o
3
b
EtOAc, PhCH , H O, -5 C
3
2
R
R
OH
R
+
+
-
-
2
. Br Ph P(CH ) PPh Br ,KHMDS,
3
2 6
o
3
NHBoc
a,b
NHBoc
PhCH , -78 C to rt
3
1
2a,b
4
N HCl/MeOH rt
1
,2
R
a
CH C H
6 5
2
HCl.H N
2
b
(CH ) NHBoc
2 4
NH .HCl
2
3
a
HCl.H N
2
HCl.H N
2
NH .HCl
2
NH .HCl
2
3
b

Molecules 2002, 7
769
Oxidation of 1a,b using NaOCl in the presence of a catalytic amount 4-acetamido-2,2,6,6-
tetramethyl-1-piperidinyloxy free radical (AcNH-TEMPO) [18,19] afforded the corresponding N-
protected α-amino aldehydes, which were directly used for the Wittig reaction with
Ph P=CH(CH ) CH=PPh without any additional purification (Scheme 1). The bis(phosphonium) ylide
3
2 4
3
was generated from the corresponding bis(triphenylphosphonium) salt with KHMDS in toluene at 0 °C
and the Wittig reaction was carried out at –78 °C to produce N-protected amines 2a,b. The geometry of
the double bonds was Z (>95%), based on NMR data. It is known that the use of KHMDS for the
generation of non-stabilized ylides under such experimental conditions leads to high Z-selectivity
[
20,21]. Free diamine 3a and tetramine 3b were obtained from 2a,b by treatment with HCl in MeOH.
Wittig reaction of the N-protected α-amino aldehyde derived from lysine with C6 ylide under the
conditions described for the synthesis of 2a,b, produced the Z-unsaturated N,N-diprotected chiral 1,5-
diamine 4 (Scheme 2). Catalytic hydrogenation of 4 resulted to the saturated diamine 5, which was
deprotected by treatment with HCl in MeOH to afford 1,5-diaminododecane (6).
Scheme 2. Synthesis of 1,5-diaminododecane (6)
1
. NaOCl, AcNH-TEMPO,
NaBr, NaHCO3
o
EtOAc, PhCH , H O, -5 C
BocHN
3
2
OH
+
-
2
. CH (CH ) PPh Br , KHMDS,
3 2 5 3
NHBoc
o
PhCH , -78 C to rt
3
1b
H , Pd/C, MeOH
BocHN
BocHN
2
rt
NHBoc
4
4
N HCl/MeOH
rt
NHBoc
5
HCl.H N
2
NH .HCl
2
6
We have recently demonstrated that (2S)-1-azido-2-[bis(tert-butoxycarbonyl)amino]-5-oxopentane
8) is a useful synthon for the preparation of chiral 1,2-diamines [22]. This key-intermediate aldehyde
(

Molecules 2002, 7
770
is prepared from γ-methyl N-tert-butoxycarbonyl-L-glutamate in four steps and 40% overall yield. To
prepare a chiral 1,2,17,18-tetramine, aldehyde 8 was submitted to Wittig olefination with
Ph P=CH(CH ) CH=PPh under the conditions described for the synthesis of 2a,b, to produce chiral
3
2 6
3
diamino diazide 9 (Scheme 3). The geometry of the double bonds was Z, based on NMR data. Free
unsaturated tetramine 10 was obtained after selective reduction of the azide groups of 9 with NaBH in
4
the presence of 10% Pd/C and subsequent treatment with HCl in THF. Under these conditions the
double bonds remained unaffected.
Scheme 3. Synthesis of tetramine 10
O
+
+
O
O
-
-
Br Ph P(CH ) PPh Br ,
KHMDS, PhCH , -78 C to rt
3
2 8
3
ref. 22
o
3
H
N3
N(Boc)2
MeO
OH
NHBoc
7
8
N(Boc)2
N3
1. NaBH , MeOH, Pd/C, THF, rt
4
N3
2
. 4N HCl/THF, rt
N(Boc)2
9
NH .HCl
2
HCl.H N
2
NH .HCl
2
NH .HCl
2
1
0
Conclusions
A route for the synthesis of chiral long chain diamines and tetramines starting from α-amino acids
has been developed. The strengths of the method are in its: (i) simplicity and efficiency, (ii) flexibility
with respect to the chain length, which depends on the chain length of the starting ylides used for the
Wittig olefination reaction, (iii) applicability to the production of both enantiomers depending on the
chirality of the starting α-amino acid.
Acknowledgements
V.L. thanks the Greek Government and the European Commission for a fellowship (E.P.E.A.E.K.).
This work was supported in part by the University of Athens (Special Account for Research Grants).

Molecules 2002, 7
771
Experimental
General
Melting points were determined on a Büchi 530 melting point apparatus and are uncorrected.
Specific rotations were measured at 25 °C on a Perkin Elmer 141 polarimeter using a 10 cm cell. NMR
spectra were recorded on a Varian Mercury (200 MHz) spectrometer. Where applicable, structural
assignments were based on DEPT and COSY experiments. Analytical TLC plates (silica gel 60 F )
2
54
and silica gel 60 (70–230 or 230–400 mesh) for column chromatography were purchased from Merck.
Visualization of spots was effected with UV light and/or staining with phosphomolybdic acid and/or
ninhydrin, both in ethanol. Et O was treated with calcium chloride and stored over Na. Toluene was
2
distilled and stored over Na. All other solvents and chemicals were of reagent grade and used without
further purification. The phosphonium salts were prepared [23] by refluxing PPh and the
3
corresponding alkyl halide in MeCN and were used in the Wittig reactions without purification. The
starting compounds 1a,b were prepared as described in the literature [16,17].
General Procedure for the Preparation of N-Protected Unsaturated Polyamines 2a,b and 4.
To a solution of N-protected 2-amino alcohol 1a,b (5.00 mmol) in a 1:1 mixture of toluene-EtOAc
(
30 mL) were added a solution of NaBr (540 mg, 5.25 mmol) in water (2.5 mL) and AcNH-TEMPO
(11 mg, 0.050 mmol). The resulting biphasic system was cooled at –5 °C and an aqueous solution of
0
.35 M NaOCl (15.7 mL, 5.50 mmol) containing NaHCO (1.26 g, 15 mmol) was added dropwise at
3
-5°C over a period of 1 h under vigorous stirring. After stirring for an additional 15 min at 0 °C, EtOAc
(
30 mL) and water (10 mL) were added. The aqueous layer was separated and washed with EtOAc (10
ml). The combined organic layers were washed consecutively with 1% aqueous citric acid (30 mL)
containing KI (0.18 g), 10% aqueous Na S O (30 mL), and brine and dried (Na SO ). The solvents
2
2
3
2
4
were evaporated under reduced pressure and the obtained crude aldehyde was immediately used for the
Wittig reaction.
-
+
+
-
To a stirred suspension of the phosphonium salt Br Ph P (CH ) P Ph Br (1.54 g, 2.00 mmol) or
3
2 6
3
+
-
CH (CH ) P Ph Br (2.14 g, 5.00 mmol) in dry toluene (27 mL) was added a 0.5 M solution of
3
2 5
3
KHDMS (8.00 mL or 9.10 mL respectively) in toluene dropwise over a period of 5 min at 0 °C under
N . The bright red solution was stirred for another 15 min, cooled to –78 °C and a solution of the
2
aldehyde in dry toluene (5 mL) was then added in one portion. The resulting light yellow mixture was
stirred for 20 h at room temperature, then the reaction mixture was quenched with a saturated aqueous
solution of NH Cl (40 mL), and extracted with Et O (3 × 10 mL). The combined organic layers were
4
2
washed with brine and dried (Na SO ). The solvents were removed and the residue was purified by
2
4
column chromatography using a 3:7 mixture of EtOAc-petroleum ether as eluent.

Molecules 2002, 7
772
(
2S,11S,3Z,9Z)-2,11-Di[(tert-butoxycarbonyl)amino]-1,12-diphenyldodeca-3,9-diene (2a): yield 626
o
25
1
mg (57%); yellow solid; mp 91–93 C; [α] –4.7 (c 0.9, CHCl ); H-NMR (200 MHz, CDCl ) δ
D
3
3
0
.88–1.25 [m, 4H, innermost (CH ) ], 1.44 [br s, 18H, 2 × (CH ) ], 1.68–2.03 (m, 4H, 2 ×
2
2
3 3
CH CH=CH), 2.69 (dd, 2H, J = 10.2, 12.8 Hz, 2 × CHHC H ), 2.93 (dd, 2H, J = 4.4, 12.8 Hz, 2 ×
2
6
5
CHHC H ), 4.34 (br, 2H, 2 × NH), 4.54 (m, 2H, 2 × CHN), 5.19 (dd, 2H, J = 10.0, 10.8 Hz, 2 ×
6
5
CH=CHCH ), 5.36 (dt, 2H, J = 7.7, 10.0 Hz, 2 × CH=CHCH ), 7.12–7.33 (m, 10H, 2 × C H );
2
2
6
5
1
3
C-NMR (50 MHz, CDCl ) δ 27.6, 28.4, 28.8, 42.1, 49.3, 79.2, 126.3, 128.1, 128.9, 129.7, 132.6,
3
1
37.7, 155.0; Anal. Calcd for C H N O (548.77): C, 74.42; H, 8.82; N, 5.10. Found: C, 74.71; H,
3
4
48
2
4
8
.91; N, 4.85.
(
(
[
(
5S,14S,6Z,12Z)-1,5,14,18-Tetra[(tert-butoxycarbonyl)amino]-octadeca-6,12-diene (2b): yield 611 mg
o
25
1
43%); white solid; mp 87–88 C; [α] +0.5 (c 1.0, CHCl ); H-NMR (200 MHz, CDCl ) δ 1.05–1.68
D
3
3
m, 52H, 4 × C(CH ) , innermost (CH ) , 2 × (CH ) CHN], 1.89–2.17 (m, 4H, 2 × CH CH=CH), 3.06
3
3
2 2
2 3
2
dt, 4H, J = 6.4, 6.6 Hz, 2 × CH N), 4.27 (m, 2H, 2 × CHN), 4.52 (br, 2H, 2 × CHNH), 4.67 (br, 2H, 2
2
×
CH NH), 5.13 (dd, 2H, J = 10.2, 10.6 Hz, 2 × CH=CHCH ), 5.40 (dt, 2H, J = 7.4, 10.2 Hz, 2 ×
2
2
1
3
CH=CHCH ); C-NMR (50 MHz, CDCl ) δ 22.8, 27.6, 28.3, 29.0, 29.7, 35.8, 40.3, 47.6, 79.0, 130.4,
2
3
1
32.2, 155.2, 156.0. Anal. Calcd for C H N O (711.00): C, 64.19; H, 9.92; N, 7.88. Found: C, 64.38;
3
8
70
4
8
H, 9.81; N, 7.98.
2
5
(
+
5S,6Z)-1,5-Di[(tert-butoxycarbonyl)amino]-dodec-6-ene (4): yield 1.14 g (57%); yellow oil; [α]
D
1
4.3 (c 1.1, CHCl ); H-NMR (200 MHz, CDCl ) δ 0.87 (t, 3H, J = 6.6 Hz, CH ), 1.18–1.62 [m, 30H,
3
3
3
2
× (CH ) , (CH ) CH , (CH ) CHN], 2.02–2.18 (m, 2H, CH CH=CH), 3.08 (dt, 2H, J = 6.4, 6.6 Hz,
3
3
2 3
3
2 3
2
CH N), 4.22–4.47 (m, 2H, NH, CH), 4.55 (br, 1H, NH), 5.14 (dd, 1H, J = 10.0, 10.8 Hz, CHCH=CH),
2
1
3
5.44 (dt, J = 7.7, 10.0 Hz, CHCH=CH); C-NMR (50 MHz, CDCl ) δ 14.0, 22.3, 22.8, 27.8, 28.3,
3
2
8.4, 29.2, 29.7, 31.1, 35.9, 40.3, 47.6, 79.0, 130.2, 132.6, 155.2, 156.0. Anal. Calcd for C H N O
2
2
42
2
4
(
398.59): C, 66.29; H, 10.62; N, 7.03. Found: C, 66.57; H, 10.73; N, 6.80.
General Procedure for the Preparation of Free Unsaturated Polyamines 3a,b and 6.
A solution of N-protected polyamine (1.00 mmol) in 4 N HCl in MeOH (25 mL) was stirred for 30
min at room temperature. After evaporation, dry Et O was added and the product was filtered and
2
recrystallized from MeOH/Et O.
2
(
2S,11S,3Z,9Z)-1,12-Diphenyl-dodeca-3,9-diene-2,11-diamine dihydrochloride (3a): yield 329 mg
2
5
1
(78%); white solid; [α]
+1.9 (c 0.6, EtOH); H-NMR (200 MHz, CD OD) δ 0.76–1.08 [m, 4H,
D
3
innermost (CH ) ], 1.50–1.92 (m, 4H, 2 × CH CH=CH), 2.76 (dd, 2H, J = 10.2, 12.9 Hz, 2 × CHHPh),
2
2
2
3
.14 (dd, 2H, J = 4.4, 12.9 Hz, 2 × CHHPh), 4.20 (m, 2H, 2 × CHN), 5.32 (dd, 2H, J = 10.0, 10.8 Hz, 2
×
CHCH=CH), 5.56 (dt, 2H, J = 7.7, 10.0 Hz, 2 × CHCH=CH), 7.13–7.47 (m, 10H, 2 × C H );
6
5
1
3
C-NMR (50 MHz, CD OD) δ 28.4, 29.4, 40.8, 51.4, 125.2, 128.4, 130.0, 131.0, 137.1, 138.6; MS
3

Molecules 2002, 7
773
+
(
FAB) m/z (%): 349 (M +1, 100), 332 (28), 240 (12). Anal. Calcd for C Cl H N (421.46): C, 68.40;
2
4
2
34
2
H, 8.13; N, 6.65. Found: C, 68.19; H, 8.25; N, 6.43.
(
(
(
5S,14S,6Z,12Z)-Οctadeca-6,12-diene-1,5,14,18-tetramine tetrahydrochloride (3b): yield 374 mg
2
5
1
82%); white solid; [α] +2.4 (c 2.5, EtOH); H-NMR (200 MHz, CD OD) δ 1.47 [br, 8H, innermost
D
3
CH ) , 2 × CH CH CHN], 1.55–1.97 (m, 8H, 2 × CH CHN, 2 × CH CH N), 2.19 (br, 4Η, 2 ×
2
2
2
2
2
2
2
CH CH=CH), 2.94 (t, 4H, J = 7.2 Hz, 2 × CH N), 4.10 (br, 2H, 2 × CHN), 5.35 (dd, 2H, J = 10.2, 10.6
2
2
1
3
Hz, 2 × CHCH=CH), 5.82 (dt, 2H, J = 7.4, 10.2 Hz, 2 × CHCH=CH); C-NMR (50 MHz, CD OD) δ
2.4, 27.0, 27.6, 29.0, 32.9, 39.3, 53.7, 124.9, 137.5; MS (FAB) m/z (%): 311 (M +1, 100), 277 (18).
3
+
2
Anal. Calcd for C Cl H N .H O (474.39): C, 45.57; H, 9.35; N, 11.81. Found: C, 45.31; H, 9.54; N,
1
8
4
42
4
2
1
1.70.
2
5
(
-
(
5R)-Dodecane-1,5-diamine dihydrochloride (6) [24]: yield 183 mg (67%); pale yellow solid; [α]
D
1
1.3 (c 0.8, EtOH); H-NMR (200 MHz, CD OD) δ 0.90 (t, 3H, J = 6.4 Hz, CH ), 1.19–1.82 [m, 18H,
CH ) , (CH ) CH], 2.96 (t, 2H, J = 7.6 Hz, CH N), 3.18 (m, 1H, CH); C-NMR (50 MHz, CD OD) δ
3
3
1
3
2
6
2 3
2
3
1
4.4, 23.2, 23.7, 26.1, 28.3, 30.2, 30.5, 32.9, 33.2, 33.6, 40.4, 52.9. Anal. Calcd for C Cl H N
1
2
2
30
2
(
273.29): C, 52.74; H, 11.07; N; 10.25. Found: C, 52.51; H, 11.33; N, 10.09.
(5R)-1,5-Di[(tert-butoxycarbonyl)amino]-dodecane (5)
To a solution of 4 (399 mg, 1.00 mmol) in MeOH (10 mL) was added 10% Pd/C (40 mg). The
reaction mixture was stirred under H for 18 h at room temperature. After filtration through a pad of
2
®
Celite , the solvent was evaporated under reduced pressure. Yield 365 mg (91%); white solid; mp 63–
4 C, [α] –2.3 (c 1.0, CHCl ); H-NMR (200 MHz, CDCl ) δ 0.85 (t, 3H, J = 6.4 Hz, CH ), 1.15–
.62 [m, 18H, 2 × (CH ) ], 3.08 (dt, 2H, J = 6.4, 6.6 Hz, CH N), 3.37–3.61 (m, 1H, CH NH), 4.28 (d,
H, J = 9.2 Hz, CHNH), 4.64 (br, 1H, CH); C-NMR (50 MHz, CDCl ) δ 14.0, 22.6, 23.0, 25.8, 28.3,
o
25
1
6
1
1
2
D
3
3
3
3
3
2
2
1
3
3
8.4, 29.2, 29.5, 29.7, 31.7, 35.2, 35.6, 40.3, 50.3, 78.8, 155.8, 156.0; Anal. Calcd for C H N O
2
2
44
2
4
(
400.60): C, 65.96; H, 11.07; N; 6.99. Found: C, 65.89; H, 11.01; N, 7.03.
(2S,17S,5Z,13Z))-1,18-Diazido-2,17-di[bis(tert-butoxycarbonyl)amino]-octadeca-5,13-diene (9)
-
+
+
-
To a stirred suspension of phosphonium salt Br Ph P (CH ) PPh Br (4.00 mmol, 3.19 g) in dry
3
2 8
3
toluene (54 mL) was added a 0.5 M solution of KHMDS (16.0 mL) in toluene dropwise over a period
of 5 min at 0 °C under N . The bright red solution was stirred for another 15 min and cooled to –78 °C,
2
and a solution of the aldehyde 8 (8.00 mmol, 2.76 g) in dry toluene (8 mL) was instantly added. The
light yellow mixture was stirred at room temperature for 20 h. Then, the reaction mixture was
quenched with a saturated aqueous solution of NH Cl (70 mL) and extracted with Et O (3 × 16 mL).
4
2
The combined organic phases were washed with brine and dried (Na SO ). The solvent was removed,
2
4
and the residue was purified by column chromatography using a 1:9 mixture of EtOAc-petroleum ether
as eluent. Yield 1.31 g (43%); colorless oil; [α]25 = –3.5 (c 1.2, CHCl ); H-NMR (200 MHz, CDCl )
1
D
3
3

Molecules 2002, 7
774
δ 1.28 [br s, 8H, (CH ) ], 1.43–1.65 [m, 38H, 4 × C(CH ) , 2 × CHHCHN], 1.74–1.90 (m, 2H, 2 ×
2
4
3 3
CHHCHN), 1.91–2.13 (m, 8H, 2 × CH CH=CHCH ), 3.29 (dd, 2H, J = 12.2, 5.6 Hz, 2 × CHHN ),
2
2
3
3
.76 (dd, 2H, J = 12.2, 9.4, 2 × CHHN ), 4.35 (m, 2H, 2 × CHN), 5.23–5.46 (m, 4H, 2 × CH=CH);
3
1
3
C-NMR (50 MHz, CDCl ) δ 24.0, 27.2, 28.0, 29.3, 29.7, 30.2, 53.6, 56.6, 82.5, 128.0, 131.1, 153.2;
3
+
MS (FAB) m/z (%): 785 (M +Na, 100), 736 (8). Anal. Calcd for C H N O (762.99): C, 59.82; H,
3
8
66
8
8
8
.72; N; 14.69. Found: C, 59.56; H, 8.99; N, 14.63.
(2S,17S,5Z,13Z)-Octadeca-5,13-diene-1,2,17,18-tetramine tetrahydrochloride (10)
To a stirred mixture of the diazide 9 (1.53 g, 2.00 mmol) and 10% Pd/C (100 mg) in THF (15 mL),
through which N had been passed for 5 min, were added NaBH (454 mg, 12.00 mmol) and MeOH
2
4
(
1
40 mL) dropwise. After stirring for 20 min, the catalyst was filtered, the solution was neutralized with
M KHSO and the organic solvents were removed. The aqueous phase was extracted with EtOAc (2
4
×
30 mL), the combined organic phases were dried (Na SO ) and the solvent was removed. The tert-
2
4
butoxycarbonyl group was removed by treatment with 4 N HCl in THF (30 mL) for 30 min at room
temperature. After evaporation, Et O was added and the product was filtered, and recrystallized from
2
1
MeOH-Et O. Yield 612 mg (67%); yellow solid; H-NMR (200 MHz, CDCl ) δ 1.24 [br s, 8H,
2
3
innermost (CH ) ], 1.58–1.71 (m, 4H, 2 × CH CHCH N), 1.89–2.19 (m, 8H, 2 × CH CH=CHCH ),
2
4
2
2
2
2
3
.00–3.17 (m, 4H, 2 × CH N), 3.30–3.56 (m, 2H, 2 × CHN), 5.21–5.45 (m, 4H, 2 × CH=CH); MS
2
+
(FAB) m/z (%): 311 (Μ +1 – 4HCl, 100). Anal. Calcd for C Cl H N ·H O (474.39): C, 45.57; H,
1
8
4
42
4
2
9
.35; N; 11.81. Found: C, 45.35; H, 9.49; N, 11.69.
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