A novel approach to the synthesis of chiral terminal 1,2-diamines

Full text of DOI:10.1021/jo005677j

J . Org. Chem. 2001, 66, 1919-1923
1919
Sch em e 1. Retr osyn th etic P a th w a y to Key
A Novel Ap p r oa ch To th e Syn th esis of
Ch ir a l Ter m in a l 1,2-Dia m in es
In ter m ed ia te Ald eh yd es 3
Theodoros Markidis and George Kokotos*,†
Laboratory of Organic Chemistry, Department of Chemistry,
University of Athens, Panepistimiopolis,
Athens 15771, Greece
gkokotos@cc.uoa.gr
Received October 11, 2000
In tr od u ction
mendous applications in stereoselective synthesis.12 The
chemistry of vicinal diamines has been recently re-
viewed.13
Compounds incorporating the 1,2-diamine functionality
are of current interest, because they find wide applica-
tions in several fields. Many natural products that exhibit
interesting biological properties, for example, biotin,1
emeriamines,2 and antibacterial peptides,3 contain the
1,2-diamino moiety. In recent years several synthetic
diamines have been employed as medicinal agents,
particularly in chemotherapy. Cisplatin4 and some other
1,2-diaminoplatinum complexes5 are currently used clini-
cally or are at an advanced stage of testing. Alkyl-
substituted amino acid amides and di- and triamines,
including 1,2-diamines, have been reported to be potent
direct non-peptide activators of heterotrimeric G pro-
teins.6 We have recently shown that racemic long-chain
1,2-diamines, such as 1,2-hexadecanediamine, exhibit
interesting antiinflammatory7 and cytotoxic activity.8,9
The importance of 1,2-diamines and of compounds that
are easily prepared from 1,2-diamines, such as 1,2-
bisimines and 1,2-diamides, in organic synthesis is high;
1,2-diamino compounds are valuable synthetic interme-
diates for the preparation of heterocycles10 and for the
construction of nitrogen-containing macrocycles finding
applications in the field of supramolecular and host-
guest chemistry.11 In addition, enantiomerically pure 1,2-
diamines and their derivatives are particularly useful as
chiral auxiliaries or ligands, and they have found tre-
There are several methods for the preparation of 1,2-
diamines that consist of the introduction of a second
amino group into compounds already containing a nitro-
gen functionality. 2-Amino alcohols easily obtained from
natural amino acids14,15 or ephedrine and pseudoephe-
drine have been used as starting materials for the
synthesis of chiral vicinal diamines.16-18 Natural R-amino
acids with one functional group in the side chain may be
modified in several ways, and thus functionalized vicinal
diamines and triamines such as 2,3-diaminopropanol,19,20
4,5-diaminopentanoic acid,21 and 1,2,6-triaminohexane21
have been prepared from serine, glutamic acid, and
lysine, respectively. The biological importance of long-
chain 1,2-diamines and the synthetic importance of 1,2-
diamines bearing a third functional group prompted us
to develop a general method for the synthesis of enan-
tiomerically pure 1,2-diamines starting from natural
R-amino acids (Glu or Asp). The novel method we present
here is based on a Wittig type reaction utilizing chiral
aldehydes already containing two nitrogen atoms.
Resu lts a n d Discu ssion
The retrosynthetic pathway to 1,2-diamines 1 is out-
lined in Scheme 1. Our strategy to synthesize 2-amino-
protected azides 2 was based on the possibility of building
the chain using Wittig type reactions from aldehydes
such as 3, which could be obtained from glutamic or
aspartic acid. These amino acids are inexpensive and
available in both enantiomeric forms. In addition, this
approach permits both convergence in the synthetic
† Fax (301) 7274761. Tel. (301) 7274462.
(1) Marquet, A. Pure Appl. Chem. 1993, 65, 1249-1252.
(2) Shinagawa, S.; Kanamaru, T.; Harada, S.; Asai, M.; Okazaki,
H. J . Med. Chem. 1987, 30, 1458-1463.
(3) (a) Bodanszky, M.; Chatuverdi, N. C.; Scozzie, J . A.; Griffith, R.
K.; Bodanszky, A. Antimicrob. Agents Chemother. 1969, 135-138. (b)
Hausmann, W. K.; Borders, D. B.; Lancaster, J . E. J . Antibiot. Ser. A
1969, 22, 207-210. (c) Uchida, I.; Shigematsu, N.; Ezaki, M.; Hash-
imoto, M. Chem. Pharm. Bull. 1985, 33, 3053-3056. (d) Fujino, M.;
Inoue, M.; Ueyanagi, J .; Miyake, A. Bull. Chem. Soc. J pn. 1965, 38,
515-517. (e) Morimoto, K.; Shimada, N.; Naganawa, H.; Takita, T.;
Umezawa, H. J . Antibiot. 1981, 34, 1615-1618.
(4) Rosenberg, B.; VanCamp, L.; Trosko, J . E.; Mansour, V. H.
Nature 1969, 222, 385-386.
(5) Pasini, A.; Zunino, F. Angew. Chem., Int. Ed. Engl. 1987, 26,
615-624.
(6) Leschke, C.; Storm, R.; Breitweg-Lehmann, E.; Exner, T.; Nu¨rn-
berg, B.; Schunack, W. J . Med. Chem. 1997, 40, 3130-3139.
(7) Kokotos, G.; Constantinou-Kokotou, V.; Noula, C.; Hadjipavlou-
Litina, D. Lipids 1999, 34, 307-311.
(8) Kokotos, G.; Theodorou, V.; Constantinou-Kokotou, V.; Gibbons,
W. A.; Roussakis, C. Bioorg. Med. Chem. Lett. 1998, 8, 1525-1530.
(9) Constantinou-Kokotou, V.; Kokotos, G.; Roussakis, C. Anticancer
Res. 1998, 18, 3439-3442.
(12) Whitesell, J . K. Chem. Rev. 1989, 89, 1581-1590.
(13) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580-2627.
(14) Kokotos, G. Synthesis 1990, 299-301.
(15) Kokotos, G.; Noula, C. J . Org. Chem. 1996, 61, 6994-6996.
(16) Dieter, K. R.; Deo, N.; Lagu, B.; Dieter, J . J . Org. Chem. 1992,
57, 1663-1671.
(17) Kokotos, G.; Constantinou-Kokotou, V. J . Chem. Res., Synop.
1992, 391; J . Chem. Res., Miniprint 1992, 3117-3132.
(18) Dunn, P. J .; Ha¨ner, R.; Rapoport, H. J . Org. Chem. 1990, 55,
5017-5025.
(19) Demirci, F.; Haines, A. H.; J ia, C.; Wu, D. Synthesis 1996, 189-
191.
(10) Popter, A. E. A. In Comprehensive Heterocyclic Chemistry, Vol.
3; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; p 179.
(11) (a) Yoon, S. S.; Still, W. C. J . Am. Chem. Soc. 1993, 115, 823-
824. (b) Torneiro, M.; Still, W. C. Tetrahedron 1997, 53, 8739-8750.
(20) Pickersgill, I. F.; Rapoport, H. J . Org. Chem. 2000, 65, 4048-
4057.
(21) Kokotos, G.; Markidis, T.; Constantinou-Kokotou, V. Synthesis
1996, 1223-1226.
10.1021/jo005677j CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/31/2001

1920 J . Org. Chem., Vol. 66, No. 5, 2001
Ta ble 1. Wittig Rea ction of Ald eh yd es 9a ,b w ith Va r iou s Ylid es
Notes
reaction conditions
product
R
entry
9
ylide used
solvent
T (°C)
time (h)
10
n
Z:E
yield (%)
1
2
3
4
5
b
b
b
a
Br-Ph3P+(CH2)10CH3, KHMDS
Br-Ph3P+(CH2)14CH3, KHMDS
Br-Ph3P+CH2Ph, KHMDS
Ph3PdCHCOOEt
toluene
toluene
THF
THF
THF
-78 to rt
20
20
6
1
2
a
b
c
d
e
2
2
2
1
2
C10H21
C14H29
Ph
COOEt
COOEt
only Z
only Z
1:3
only E
only E
83
86
63
74
81
-78 to rt
55
50
50
b
Ph3PdCHCOOEt
Sch em e 2. Syn th esis of th e Key In ter m ed ia te
Ald eh yd es 9a ,ba
N-Boc group must be introduced after conversion of the
hydroxy group to the azide group. Reduction of the
methyl ester group of compounds 8a ,b using DIBALH
under controlled conditions produced aldehydes 9a ,b in
excellent isolated yield.
These chiral aldehydes 9a ,b may find wide synthetic
applications as key intermediates. In the present work
we studied the Wittig olefination of 9a ,b using a number
of stabilized and nonstabilized ylides (Table 1). The
generation of the nonstabilized ylides was performed by
treatment of the corresponding triphenylphosphonium
bromides with KHMDS in toluene at 0 °C (entries 1 and
2). The Wittig reaction was carried out at -78 °C and
produced δ,ꢀ-unsaturated azides 10a ,b in high yield. Both
compounds were identified as Z-olefins after 1H NMR
analysis. It is known that the use of KHMDS under such
experimental conditions for the generation of nonstabi-
lized ylides leads to high Z-selectivity.23,24 The ylide
prepared from benzyl-triphenylphosphonium bromide
and KHMDS in THF at room temperature was submitted
to Wittig reaction with aldehyde 9b at 55 °C, affording
compound 10c in 63% yield as a 3:1 E:Z mixture (entry
3). Treatment of aldehydes 9a ,b with ethyl (triph-
enylphosphoranylidene)acetate in THF at 50 °C gave the
E derivatives 10d ,e in high yield (entries 4 and 5).
The Boc protecting groups of 10 can be removed
quantitatively by treatment with HCl in THF. Selective
reduction of the azide group of 10a ,b was carried out by
NaBH4 in the presence of 10% Pd/C. Under these condi-
tions the double bond remained unaffected, while a
partial removal of one Boc group was observed. Thus, free
unsaturated amines 11a ,b can be preferably obtained by
treatment with NaBH4-Pd/C and subsequently HCl/THF
(Scheme 3). Catalytic hydrogenation of compounds 10c,e
in the presence of (Boc)2O led to the saturated protected
1,2-diamines 12a ,b.
a
Reagents and conditions: (a) (i) ClCO2Et, N-methylmorpho-
line, THF, -10 °C, (ii) NaBH4, MeOH, 0 °C to rt; (b) (i) MsCl, Et3N,
CH2Cl2, 0 °C to rt, (ii) NaN3, DMF, 55 °C; (c) (Boc)2O, DMAP,
MeCN, 55 °C; (d) (i) DIBALH, Et2O, -78 °C, (ii) H2O.
procedure and stereoselectivity in the formation of the
double bond.
Methyl esters of N-Boc-protected Glu and Asp (4a ,b)
were converted into alcohols 5a ,b (Scheme 2) by reduc-
tion of their corresponding mixed anhydrides with
NaBH4.14 The hydroxy group of 5a ,b was activated by
conversion to mesylate and replaced by the azido group.
A second Boc group was introduced22 by treatment of 6a ,b
with (Boc)2O in the presence of DMAP. The presence of
the second N-Boc group in compounds 8a ,b minimizes
the nucleophilic power of the nitrogen and is critical,
since reduction of N-monoprotected derivative leads to a
mixture of products. Treatment of amino alcohol 5b with
(Boc)2O in the presence of DMAP produced N,O-di-Boc-
protected amino alcohol 7, indicating that the second
To confirm if any racemization had occurred to the (2S)
chiral center, amino azide 13, obtained from 10b by
treatment with HCl in THF, was converted into the
corresponding MTP amides.25 Coupling of 13 with (S)-
(-) -and (R)-(+)-R-methoxy-R-trifluoromethyl phenylace-
tic acid (MTPA) using 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDC) as a condensing
agent afforded the amides 14a ,b (Scheme 4). The 1H
NMR spectra of the two amides were compared. An
enantiomeric excess > 95% was indicated for 13 by the
(23) Schlosser, M.; Schaub, B.; de Oliveira-Neto, J .; J eganathan, S.
Chimia 1986, 40, 244-245.
(24) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.
(25) Dale, J . A.; Dull, D. L.; Mosher, H. J . Org. Chem. 1969, 34,
2543-2549.
(22) Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed. Engl. 1985,
24, 510-511.

Notes
Sch em e 3. Syn th esis of Ch ir a l 1,2-Dia m in esa
J . Org. Chem., Vol. 66, No. 5, 2001 1921
ethanol stain. THF, toluene, and Et2O were dried by standard
procedures and stored over molecular sieves or Na. N-Methyl-
morpholine was distilled from ninhydrin. All other solvents and
chemicals were of reagent grade and used without further
purification. The phosphonium salts were prepared26 by reflux-
ing PPh3 and the corresponding alkyl halide in MeCN and were
used in the Wittig reactions without purification. EtO2CCHd
P(C6H5)3 was prepared27 by treatment of the corresponding
triphenylphosphonium bromide with NaOH in water at 0 °C for
15 min and was used in the Wittig reactions without purification.
The starting compounds 4a 28 and 4b29 were prepared as
described in the literature.30,31
Gen er a l P r oced u r e for th e P r ep a r a tion of N-P r otected
Am in o Alcoh ols 5a ,b. To a stirred solution of N-protected
amino acid 4a ,b (50.0 mmol) in THF (250 mL) at -10 °C was
added N-methylmorpholine (5.50 mL, 50.0 mmol) followed by
ethyl chloroformate (4.80 mL, 50.0 mmol). After 10 min, NaBH4
(5.67 g, 150 mmol) was added in one portion. MeOH (500 mL)
was then added dropwise to the mixture over a period of 20 min
at 0 °C. The solution was stirred for an additional 20 min and
then neutralized with 1 M KHSO4. The organic solvents were
removed, and the product was extracted with EtOAc (3 × 200
mL). The combined organic phases were washed consecutively
with 1 M KHSO4, H2O, 5% aqueous NaHCO3, and H2O and dried
(Na2SO4), and the solvent was evaporated. The residue was
purified by column chromatography using CHCl3 as eluent.
Meth yl (3S)-3-[(ter t-bu toxyca r bon yl)a m in o]-4-h yd r ox-
a
Reagents and conditions: (a) (i) NaBH4, 10% Pd/C, MeOH,
THF, rt, (ii) 4 N HCl/THF, rt; (b) H2, 10% Pd/C, (Boc)2O, MeOH,
rt.
Sch em e 4. Mosh er Am id es P r ep a r ed for
Deter m in a tion of En a n tiop u r itya
ybu ta n oa te (5a ): yield 76%; colorless oil; [R]23 +6.3 (c 0.5,
D
CHCl3); 1H NMR (200 MHz, CDCl3) δ 1.49 (br s, 9H), 2.62 (d,
2H, J ) 6.3 Hz), 3.65-3.70 (m, 5H), 3.92-4.07 (m, 1H), 5.29 (d,
1H, J ) 7.8 Hz); FAB MS m/z (%) 256 (M+ + Na, 13), 234 (M+
+ 1, 29), 178 (100), 160 (11), 134 (94), 116 (8). Anal. Calcd for
C
10H19NO5 (233.26): C, 51.49; H, 8.21; N, 6.00. Found: C, 51.23;
H, 8.32; N, 5.89.
Meth yl (4S)-4-[(ter t-bu toxyca r bon yl)a m in o]-5-h yd r oxy-
p en ta n oa te (5b): yield 78%; colorless oil; [R]23 -12.8 (c 1,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.49 (br s, 9H), 1.72-1.98
(m, 2H), 2.45 (t, 2H, J ) 7.5 Hz), 3.53-3.76 (m, 6H), 4.80 (d,
1H, J ) 7.8 Hz); FAB MS m/z (%) 270 (M+ + Na, 100), 238 (3),
214 (23), 173 (10), 148 (3). Anal. Calcd for C11H21NO5 (247.29):
C, 53.43; H, 8.56; N, 5.66. Found: C, 53.51; H, 8.63; N, 5.41.
Gen er a l P r oced u r e for th e P r ep a r a tion of Azid es 6a ,b.
To a stirred solution of N-protected amino alcohol 5a ,b (37.0
mmol) in CH2Cl2 (60 mL) were added triethylamine (7.77 mL,
55.5 mmol) and methanesulfonyl chloride (4.44 mL, 55.5 mmol)
portionwise at 0 °C. The mixture was stirred at 0 °C for 30 min
and at room temperature for 30 min. The organic phase was
washed consecutively with brine, 1 M KHSO4, brine, 5% aqueous
NaHCO3, and brine and dried (Na2SO4), and the solvent was
removed.
a
Reagents and conditions: (a) 4 N HCl/THF, rt; (b) (S)-(-)- or
(R)-(+)-MTPA, EDC, Et3N, CH2Cl2, rt.
absence of any diastereomeric proton signal in the
spectrum of each MTP amide, since the NH proton and
the methoxy protons are well resolved. Furthermore, the
19F NMR spectrum of 14b showed only one signal,
indicating that 13 was a single isomer. Thus, the con-
figuration of the (2S) chiral center was not affected
throughout the synthesis.
The mesylate was dissolved in DMF (102 mL). Sodium azide
(7.22 g, 111 mmol) was added, and the mixture was heated at
60 °C for 6 h. The solvent was removed, and the residue was
taken up in EtOAc (3 × 350 mL). The combined organic phases
were washed with brine, dried (Na2SO4), and evaporated. The
residue was purified by column chromatography using a mixture
of EtOAc:petroleum ether 1:1 as eluent.
Con clu sion s
In conclusion, we have developed a novel general
method for the synthesis of enantiomerically pure 1,2-
diamines using the aldehydes 9a ,b as key intermediates.
The strengths of the method are in its (1) simplicity and
efficiency, (2) flexibility with respect to the substituent
groups that can be introduced through the olefination
reaction and the chirality of the product, which depends
on the chirality of Glu or Asp, and (3) applicability to
the development of new 1,2-diamines with desired target
structures for biological studies.
Meth yl (3S)-4-a zid o-3-[(ter t-bu toxyca r bon yl)a m in o]bu -
ta n oa te (6a ): yield 70%; colorless oil; [R]23 -19.6 (c 0.5,
D
CHCl3);1H NMR (300 MHz, CDCl3) δ 1.49 (br s, 9H), 2.63 (d,
2H, J ) 6.3 Hz), 3.48 (dd, 1H, J ) 12.4, 9.0 Hz), 3.58 (dd, 1H, J
) 12.4, 5.8 Hz), 3.72 (s, 3H), 4.05-4.20 (m, 1H), 5.12 (br s, 1H);
FAB MS m/z (%) 259 (M+ + 1, 22), 233 (8), 203 (100), 159 (61).
(26) (a) Corey, E. J .; Weinshenker, N. M.; Schaaf, T. K.; Huber, W.
J . Am. Chem. Soc. 1969, 91, 5675-5677. (b) Dawson, M. I.; Vasser,
M. J . Org. Chem. 1977, 42, 2783-2785. (c) Maryanoff, B. E.; Reitz, A.
B.; Duhl-Emswiler, B. A. J . Am. Chem. Soc. 1985, 107, 217-226.
(27) Isler, O.; Gutmann, H.; Montavon, M.; Ru¨egg, R.; Ryser, G.;
Zeller, P. Helv. Chim. Acta 1957, XL, 1242-1249.
Exp er im en ta l Section
Melting points were determined on a melting point apparatus
and are uncorrected. Specific rotations were measured on a
polarimeter using a 10 cm cell. NMR spectra were recorded on
a 200 or a 300 MHz spectrometer. Where applicable, structural
assignments were based on DEPT and COSY experiments.
Analytical TLC plates (silica gel 60 F254) and silica gel 60 (70-
230 or 230-400 mesh) for column chromatography were pur-
chased from Merck. Visualization of spots was effected with UV
light and/or phosphomolybdic acid and/or ninhydrin, both in
(28) Uzar, H. C. Synthesis 1991, 526-528.
(29) Anderson, J . C.; Barton, M. A.; Hardy, P. M.; Kenner, G. W.;
Preston, J .; Sheppard, R. C. J . Chem. Soc. C 1967, 108-113.
(30) Boissonnas, R. A.; Guttmann, St.; J aquenoud, P.-A.; Waller, J .-
P. Helv. Chim. Acta 1955, XXXVIII, 1491-1501.
(31) (a) Moroder, L.; Hallett, A.; Wu¨nsch, E.; Keller, O.; Wersin, G.
Hoppe-Seyler’s Z. Physiol. Chem. 1976, 357, 1651-1653. (b) Pon-
nusamy, E.; Fotadar, U.; Spisni, A.; Fiat, D. Synthesis 1986, 48-49.

1922 J . Org. Chem., Vol. 66, No. 5, 2001
Notes
Anal. Calcd for C10H18N4O4 (258.28): C, 46.50; H, 7.02; N, 21.69.
Found: C, 46.80; H, 7.11; N, 21.75.
Meth yl (4S)-5-a zid o-4-[(ter t-bu toxyca r bon yl)a m in o]p en -
1H), 2.05-2.20 (m, 1H), 2.51-2.60 (m, 2H), 3.38 (dd, 1H, J )
12.4, 5.8 Hz), 3.82 (dd, 1H, J ) 12.4, 9.0 Hz), 4.25-4.37 (m, 1H),
9.80 (s, 1H); FAB MS m/z (%) 365 (M+ + Na, 10), 247 (70), 225
(51). Anal. Calcd for C15H26N4O5 (342.39): C, 52.62; H, 7.65; N,
16.36. Found: C, 52.83; H, 7.68; N, 16.41.
Gen er a l P r oced u r e for th e Wittig Rea ction w ith Non -
sta bilized Ylid es (Com p ou n d s 10a ,b). To a stirred suspension
of the phosphonium salt (3.60 mmol) in dry toluene (20 mL) was
added a 0.5 M solution of KHMDS (6.60 mL, 3.30 mmol) in
toluene dropwise over a period of 5 min at 0 °C under N2. The
bright red solution was stirred for another 15 min and cooled to
-78 °C, and a solution of the aldehyde 9b (1.03 g, 3.00 mmol)
in dry toluene (3 mL) was instantly added. The light yellow
mixture was stirred at room temperature for 20 h. Then, the
ta n oa te (6b): yield 73%; light yellow solid; mp 44-46 °C; [R]23
D
-25.2 (c 1, CHCl3); 1H NMR (200 MHz, CDCl3) δ 1.49 (br s, 9H),
1.73-1.95 (m, 2H), 2.38 (t, 2H, J ) 7.5 Hz), 3.33-3.58 (m, 2H),
3.64-3.85 (m, 4H), 4.66 (d, 1H, J ) 7.8 Hz); FAB MS m/z (%)
295 (M+ + Na, 100), 267 (4), 239 (23), 217 (11), 173 (12). Anal.
Calcd for C11H20N4O4 (272.30): C, 48.52; H, 7.40; N, 20.58.
Found: C, 48.75; H, 7.45; N, 20.75.
Gen er a l P r oced u r e for th e In tr od u ction of th e Secon d
Boc Gr ou p (Com p ou n d s 7 a n d 8a ,b). To a solution of
compound 5b or 6a ,b (25.0 mmol) in MeCN (42 mL) were added
DMAP (610 mg, 5.00 mmol) and Boc2O (6.00 g, 27.5 mmol), and
the mixture was stirred at room temperature for 3 h. Then,
DMAP (305 mg, 2.50 mmol) and Boc2O (3.01 g, 13.8 mmol) were
added and the mixture was heated at 55 °C for 7 h and stirred
at room temperature overnight. The solvent was removed, and
the residue was purified by column chromatography using a
mixture of EtOAc:petroleum ether 1:4 as eluent.
reaction mixture was quenched with
a saturated aqueous
solution of NH4Cl (26 mL) and extracted with Et2O (3 × 6 mL).
The combined organic phases were washed with brine and dried
(Na2SO4). The solvent was removed, and the residue was purified
by column chromatography using a mixture of EtOAc:petroleum
ether 1:9 as eluent.
Meth yl (4S)-4-[(ter t-bu toxyca r bon yl)a m in o]-5-[(ter t-bu -
toxyca r bon yl)oxy]p en ta n oa te (7): yield 66%; colorless oil;
(2S,5Z)-1-Azid o-2-[bis(ter t-bu toxyca r bon yl)a m in o]h exa -
d ec-5-en e (10a ): yield 83%; colorless oil; [R]23 -2.4 (c 1.2,
D
1
[R]23 -20.9 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.49 [br
CHCl3); H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J ) 6.7 Hz),
D
s, 9H, C(CH3)3], 1.52 [br s, 9H, C(CH3)3], 1.73-1.98 (m, 2H, CH2-
CH), 2.43 (t, 2H, J ) 7.5 Hz, CH2CO), 3.70 (s, 3H, OMe), 3.82-
3.95 (m, 1H, CH), 4.02-4.16 (m, 2H, CH2O), 4.72 (d, 1H, J )
7.8 Hz, NH); 13C NMR (50 MHz, CDCl3) δ 26.8, 27.6, 28.2, 30.5,
49.1, 51.6, 68.3, 79.4, 82.3, 153.3, 155.3, 173.5.
Meth yl (3S)-4-a zid o-3-[bis(ter t-bu toxyca r bon yl)a m in o]-
bu ta n oa te (8a ): yield 75%; light yellow oil; [R]23D -12.4 (c 0.5,
CHCl3); 1H NMR (200 MHz, CDCl3) δ 1.49 [br s, 18H, 2 ×
C(CH3)3], 2.67 (dd, 1H, J ) 16.2, 6.6 Hz, CHHCH), 2.86 (dd,
1H, J ) 16.2, 7.8 Hz, CHHCH), 3.41 (dd, 1H, J ) 12.4, 5.8 Hz,
CHHN3), 3.66 (s, 3H, OMe), 3.74 (dd, 1H, J ) 12.4, 9.0 Hz,
CHHN3), 4.66-4.84 (m, 1H, CH); 13C NMR (50 MHz, CDCl3) δ
27.9 (CH3), 35.6 (CH2), 51.8 (CH3), 52.4 (CH2), 53.1 (CH), 82.9
(C), 152.6 (C), 170.9 (C); FAB MS m/z (%) 381 (M+ + Na, 10),
359 (M+ + 1, 5), 303 (37), 247 (87), 203 (40), 159 (100). Anal.
Calcd for C15H26N4O6 (358.40): C, 50.27; H, 7.31; N, 15.63.
Found: C, 50.43; H, 7.40; N, 15.80.
1.26 (br s, 16H), 1.51 (br s, 18H), 1.52-1.62 (m, 1H), 1.79-1.91
(m, 1H), 1.98-2.15 (m, 4H), 3.29 (dd, 1H, J ) 12.4, 5.8 Hz), 3.75
(dd, 1H, J ) 12.4, 9.0 Hz), 4.28-4.37 (m, 1H), 5.28-5.43 (m,
2H); FAB MS m/z (%) 503 (M+ + Na, 29), 425 (5), 403 (9), 347
(31), 325 (9), 281 (100). Anal. Calcd for C26H48N4O4‚0.5H2O
(489.70): C, 63.77; H, 10.08; N, 11.44. Found: C, 63.61; H, 10.01;
N, 11.44.
(2S,5Z)-1-Azid o-2-[bis(ter t-bu toxyca r bon yl)a m in o]eicos-
5-en e (10b): yield 86%; colorless oil; [R]23 -2.3 (c 1, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J ) 6.7 Hz), 1.26 (br
s, 24H), 1.51 (br s, 18H), 1.52-1.67 (m, 1H), 1.79-1.93 (m, 1H),
1.99-2.12 (m, 4H), 3.29 (dd, 1H, J ) 12.4, 5.8 Hz), 3.75 (dd, 1H,
J ) 12.4, 9.0 Hz), 4.27-4.38 (m, 1H), 5.28-5.45 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 14.1 (CH3), 22.6 (CH2), 23.9 (CH2), 27.2
(CH2), 28.0 (CH3), 29.3 (CH2), 29.5 (CH2), 30.2 (CH2), 31.9 (CH2),
53.5 (CH2), 56.6 (CH), 82.4 (C), 127.9 (CH), 131.1 (CH), 153.1
(C); FAB MS m/z (%) 559 (M+ + Na, 23), 511 (8), 403 (24), 381
(10), 337 (87). Anal. Calcd for C30H56N4O4 (536.80): C, 67.13;
H, 10.51; N, 10.44. Found: C, 67.32; H, 10.60; N, 10.37.
1-{(5S)-6-Azid o-5-[bis(ter t-bu toxyca r bon yl)a m in o]h ex-1-
en yl}ben zen e (10c). The general conditions used to prepare
10a ,b were applied to aldehyde 9b, but the ylide was prepared
at room temperature, the solution of the aldehyde was added at
55 °C, and the Wittig reaction was carried out at 55 °C for 6 h.
The product was purified by column chromatography using a
mixture of EtOAc:petroleum ether 1:4 as eluent, yielding 10c
(63%) as a colorless oil: 1H NMR (200 MHz, CDCl3) δ 1.49 [br
s, 18H, 2 × C(CH3)3], 1.57-1.81 (m, 1H, CHHCH), 1.91-2.13
(m, 1H, CHHCH), 2.18-2.43 (m, 2H, CH2CHdCH), 3.24-3.39
(m, 1H, CHHN3), 3.70-3.88 (m, 1H, CHHN3), 4.28-4.46 (m, 1H,
CH), 5.64 (dt, 0.25H, J ) 11.6, 7.0 Hz, CH2CHdCH, Z isomer),
6.20 (dt, 0.75H, J ) 15.8, 7.0 Hz, CH2CHdCH, E isomer), 6.36-
6.51 (m, 1H, CHPh), 7.17-7.40 (m, 5H, Ph); 13C NMR (50 MHz,
CDCl3) δ 25.2, 27.8, 27.9, 29.7, 29.8, 30.3, 53.3, 53.5, 56.4, 56.5,
82.5, 82.6, 126.0, 126.6, 127.0, 128.1, 128.4, 128.7, 129.1, 129.7,
130.7, 131.0, 137.5, 153.2; FAB MS m/z (%) 439 (M+ + Na, 28),
417 (M+ + 1, 14), 388 (9), 361 (9), 339 (14), 317 (8), 283 (21),
261 (25), 233 (100), 215 (20). Anal. Calcd for C22H32N4O4
(416.52): C, 63.44; H, 7.74; N, 13.45. Found: C, 63.72; H, 7.79;
N, 13.31.
Meth yl (4S)-5-a zid o-4-[bis(ter t-bu toxyca r bon yl)a m in o]-
p en ta n oa te (8b): yield 79%; light yellow oil; [R]23 -7.1 (c 1.1,
D
CHCl3); 1H NMR (200 MHz, CDCl3) δ 1.49 [br s, 18H, 2 ×
C(CH3)3], 1.78-1.98 (m, 1H, CHHCH), 2.02-2.22 (m, 1H,
CHHCH), 2.38 (t, 2H, J ) 7.5 Hz, CH2CO), 3.33 (dd, 1H, J )
12.4, 5.8 Hz, CHHN3), 3.68 (s, 3H, OMe), 3.79 (dd, 1H, J ) 12.4,
9.0 Hz, CHHN3), 4.24-4.40 (m, 1H, CH); 13C NMR (50 MHz,
CDCl3) δ 25.2 (CH2), 27.9 (CH3), 30.6 (CH2), 51.7 (CH3), 53.3
(CH2), 56.2 (CH), 82.8 (C), 153.0 (C), 173.1 (C); FAB MS m/z (%)
395 (M+ + Na, 22), 373 (M+ + 1, 4), 347 (5), 317 (22), 217 (19),
173 (100). Anal. Calcd for C16H28N4O6 (372.42): C, 51.60; H, 7.58;
N, 15.04. Found: C, 51.41; H, 7.66; N, 15.17.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ald eh yd es
9a ,b. A stirred solution of 8a ,b (18.0 mmol) in dry Et2O (180
mL) was purged with N2 and cooled to -78 °C, and a 1 M
solution of DIBALH (19.8 mL, 19.8 mmol) in hexane was slowly
added. The mixture was stirred at -78 °C for 5 min, and then
the excess of DIBALH was destroyed with H2O (3 mL). The
temperature was raised to room temperature, and the mixture
was stirred for 30 min, dried (Na2SO4), and filtered through
Celite. The solvent was evaporated, and the residue was purified
by column chromatography using a mixture of EtOAc:petroleum
ether 3:7 as eluent.
(2S)-1-Azid o-2-[b is(ter t-b u t oxyca r b on yl)a m in o]-4-oxo-
bu ta n e (9a ): yield 99%; colorless oil; [R]23D +7.6 (c 0.5, CHCl3);
1H NMR (200 MHz, CDCl3) δ 1.49 (br s, 18H), 2.79 (ddd, 1H, J
) 17.8, 6.2, 1.0 Hz), 3.01 (ddd, 1H, J ) 17.8, 7.8, 2.0 Hz), 3.40
(dd, 1H, J ) 12.4, 5.8 Hz), 3.73 (dd, 1H, J ) 12.4, 9.0 Hz), 4.77-
4.92 (m, 1H), 9.72 (s, 1H); 13C NMR (50 MHz, CDCl3) δ 27.9
(CH3), 44.9 (CH2), 51.0 (CH), 52.4 (CH2), 83.1 (C), 152.8 (C), 198.8
(CH); FAB MS m/z (%) 351 (M+ + Na, 51), 329 (M+ + 1, 7), 273
(39), 251 (68), 233 (14), 228 (9), 217 (100), 211 (27), 173 (34).
Anal. Calcd for C14H24N4O5 (328.37): C, 51.21; H, 7.37; N, 17.06.
Found: C, 51.42; H, 7.33; N, 17.39.
Gen er a l P r oced u r e for th e Wittig Rea ction w ith Sta bi-
lized Ylid e (Com p ou n d s 10d ,e). To a solution of aldehyde 9a ,b
(3.00 mmol) in THF (30 mL) was added EtO2CCHdP(C6H5)3
(1.57 g, 4.50 mmol), and the solution was heated at 50 °C for 1
or 2 h. Then, the reaction mixture was quenched with
a
saturated aqueous solution of NH4Cl (26 mL) and extracted with
Et2O (3 × 6 mL). The combined organic phases were washed
with brine and dried (Na2SO4). The solvent was removed, and
the residue was purified by column chromatography using a
mixture of EtOAc:petroleum ether 3:7 as eluent.
Eth yl (E,5S)-6-a zid o-5-[bis(ter t-bu toxyca r bon yl)a m in o]-
(2S)-1-Azid o-2-[b is(ter t-b u t oxyca r b on yl)a m in o]-5-oxo-
p en ta n e (9b): yield 88%; colorless oil; [R]23D -3.8 (c 1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.49 (br s, 18H), 1.87-1.98 (m,
h ex-2-en oa te (10d ): yield 74%; colorless oil; [R]23D -35.7 (c 2.4,
1
CHCl3); H NMR (200 MHz, CDCl3) δ 1.28 (t, 3H, J ) 7.0 Hz,
CH3), 1.49 [br s, 18H, 2 × C(CH3)3], 2.40-2.55 (m, 1H, CHHCH),

Notes
J . Org. Chem., Vol. 66, No. 5, 2001 1923
2.65-2.83 (m, 1H, CHHCH), 3.36 (dd, 1H, J ) 12.4, 5.8 Hz,
CHHN3), 3.77 (dd, 1H, J ) 12.4, 9.0 Hz, CHHN3), 4.16 (q, 2H,
J ) 7.0 Hz, CH2CH3), 4.36-4.53 (m, 1H, CH), 5.85 (dt, 1H, J )
15.8, 1.0 Hz, CHdCHCO), 6.75-6.92 (m, 1H, CHdCHCO); 13C
NMR (50 MHz, CDCl3) δ 14.2 (CH3), 27.9 (CH3), 33.2 (CH2), 52.8
(CH2), 55.5 (CH), 60.2 (CH2), 82.9 (C), 124.3 (CH), 143.6 (CH),
152.8 (C), 165.9 (C); FAB MS m/z (%) 421 (M+ + Na, 8), 399
(M+ + 1, 91), 299 (7), 281 (5), 255 (5), 243 (64), 197 (20). Anal.
Calcd for C18H30N4O6 (398.46): C, 54.26; H, 7.59; N, 14.06.
Found: C, 54.58; H, 7.65; N, 13.83.
MHz, d6-DMSO) δ 15.1, 23.2, 23.5, 27.8, 29.8, 30.1, 31.1, 32.4,
50.0, 128.8, 132.2; FAB MS m/z (%) 311 (M+ + 1 - 2HCl, 24),
294 (8), 280 (16). Anal. Calcd for C20Cl2H44N2 (383.49): C, 62.64;
H, 11.56; N, 7.30. Found: C, 62.61; H, 11.60; N, 7.18.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e P r otected
Dia m in es 12a ,b. To a solution of 10c,e (1.00 mmol) in MeOH
(10 mL) were added 10% Pd/C (40 mg) and Boc2O (284 mg, 1.30
mmol). The reaction mixture was stirred under H2 for 16 h at
room temperature. After filtration through a pad of Celite, the
solvent was removed and the product was purified by column
chromatography using a mixture of EtOAc:petroleum ether 1:4
as eluent.
Eth yl (E,6S)-7-a zid o-6-[bis(ter t-bu toxyca r bon yl)a m in o]-
h ep t-2-en oa te (10e): yield 81%; colorless oil; [R]23D +21.2 (c 1,
1
CHCl3); H NMR (200 MHz, CDCl3) δ 1.28 (t, 3H, J ) 7.0 Hz,
1-{(5S )-5-[B is (t er t -b u t o x y c a r b o n y l)a m in o ]-6-[(t er t -
bu toxyca r bon yl)a m in o]h exyl}ben zen e (12a ): yield 75%;
CH3), 1.49 [br s, 18H, 2 × C(CH3)3], 1.53-1.73 (m, 1H, CHHCH),
1.88-2.10 (m, 1H, CHHCH), 2.17-2.32 (m, 2H, CH2CHdCH),
3.30 (dd, 1H, J ) 12.4, 5.8 Hz, CHHN3), 3.77 (dd, 1H, J ) 12.4,
9.0 Hz, CHHN3), 4.21 (q, 2H, J ) 7.0 Hz, CH2CH3), 4.23-4.38
(m, 1H, CH), 5.82 (dt, 1H, J ) 15.6, 1.6 Hz, CHdCHCO), 6.92
(dt, 1H, J ) 15.6, 6.8 Hz, CHdCHCO); 13C NMR (50 MHz,
CDCl3) δ 14.2 (CH3), 27.9 (CH3), 28.4 (CH2), 28.9 (CH2), 53.4
(CH2), 56.4 (CH), 60.2 (CH2), 82.8 (C), 122.0 (CH), 147.4 (CH),
153.0 (C), 166.4 (C); FAB MS m/z (%) 435 (M+ + Na, 12), 413
(M+ + 1, 100), 385 (8), 355 (7), 313 (33), 257 (23), 239 (12), 211
(80), 197 (16). Anal. Calcd for C19H32N4O6 (412.48): C, 55.33;
H, 7.82; N, 13.58. Found: C, 55.22; H, 7.86; N, 13.50.
Gen er a l P r oced u r e for th e P r ep a r a tion of th e F r ee
Dia m in es 11a ,b. To a stirred mixture of the azide 10a ,b (2.00
mmol) and 10% Pd/C (80 mg) in THF (10 mL), through which
N2 had been passed for 5 min, were added NaBH4 (227 mg, 6.00
mmol) and MeOH (20 mL) dropwise. After stirring for 20 min,
the catalyst was filtered, the solution was neutralized with 1 M
KHSO4, and the organic solvents were removed. The aqueous
phase was extracted with EtOAc (2 × 30 mL), the combined
organic phases were dried (Na2SO4), and the solvent was
removed.
colorless oil; [R]23 +22.0 (c 0.8, CHCl3); 1H NMR (200 MHz,
D
CDCl3) δ 1.31-1.82 [m, 33H, (CH2)3CH, 3 × C(CH3)3], 2.60 (t,
2H, J ) 7.2 Hz, CH2Ph), 3.25-3.45 (m, 2H, CH2N), 4.17-4.37
(m, 1H, CH), 4.87 (m, 1H, NH), 7.10-7.38 (m, 5H, Ph). Anal.
Calcd for C27H44N2O6 (492.65): C, 65.83; H, 9.00; N, 5.69.
Found: C, 65.75; H, 9.06; N, 5.61.
E t h yl (6S)-6-[b is(ter t-b u t oxyca r b on yl)a m in o]-7-[(ter t-
bu toxyca r bon yl)a m in o]h ep ta n oa te (12b): yield 78%; color-
less oil; [R]23 +37.6 (c 0.5, CHCl3); 1H NMR (200 MHz, CDCl3)
D
δ 1.28 (t, 3H, J ) 7.0 Hz, CH3), 1.31-1.82 [m, 33H, (CH2)3CH,
3 × C(CH3)3], 2.27 (t, 2H, J ) 7.5 Hz, CH2CO), 3.28-3.46 (m,
2H, CH2N), 4.14 (q, 2H, J ) 7.0 Hz, CH2CH3), 4.17-4.31 (m,
1H, CH), 4.87 (m, 1H, NH); 13C NMR (50 MHz, CDCl3) δ 14.2
(CH3), 24.7 (CH2), 25.8 (CH2), 27.9 (CH3), 28.3 (CH3), 29.7 (CH2),
34.2 (CH2), 43.3 (CH2), 56.9 (CH), 60.2 (CH2), 82.3 (C), 153.4
(C), 155.7 (C), 173.5 (C). Anal. Calcd for C24H44N2O8 (488.62):
C, 59.00; H, 9.08; N, 5.73. Found: C, 58.79; H, 9.15; N, 5.65.
Gen er a l P r oced u r e for th e P r ep a r a tion of Mosh er
Am id es of Am in o Azid e 13 (Com p ou n d s 14a ,b). To a stirred
solution of amino azide 13 (93 mg, 0.25 mmol) in CH2Cl2 (2.5
mL) were added Et3N (0.042 mL, 0.30 mmol), (R)-(+)- or (S)-(-
)-R-methoxy-R-(trifluoromethyl)phenylacetic acid (70 mg, 0.30
mmol), and EDC (58 mg, 0.30 mmol) at 0 °C. The reaction
mixture was stirred at 0 °C for 30 min and at room temperature
overnight. After removal of the solvent and column chromatog-
raphy using a mixture of EtOAc:petroleum ether 1:9 as eluent,
the product isolated (yield 85% for 14a , 88% for 14b) was used
for NMR analysis.
The tert-butoxycarbonyl group was removed by treatment with
4 N HCl in THF (24.0 mL) for 30 min at room temperature. After
evaporation, Et2O was added and the product was filtered and
recrystallized from MeOH/Et2O.
(2S,5Z)-Hexa d ec-5-en e-1,2-d ia m in e
d ih yd r och lor id e
(11a): yield 77%; light yellow solid; [R]23D -13.1 (c 0.4, MeOH);1H
NMR (200 MHz, CD3OD) δ 0.86 (t, 3H, J ) 6.7 Hz), 1.24 (br s,
16H), 1.59-1.72 (m, 2H), 1.96-2.20 (m, 4H), 2.98-3.15 (m, 2H),
3.32-3.45 (m, 1H), 5.22-5.45 (m, 2H); FAB MS m/z (%) 255 (M+
+ 1 - 2HCl, 100), 238 (31), 224 (30). Anal. Calcd for C16Cl2H36N2‚
H2O (345.39): C, 55.64; H, 11.09; N, 8.11. Found: C, 55.88; H,
11.07; N, 8.23.
Ch a r a cter istic NMR Ch em ica l Sh ifts (in p p m ). (2S,5Z)-
1-Azidoeicos-5-en -2-am in e (S)-Mosh er am ide (14a): 1H NMR
(300 MHz, CDCl3) δ 3.48 (q, 3H, J ) 1.5 Hz), 5.24-5.47 (m, 2H),
6.80 (d, 1H, J ) 8.4 Hz).
(2S,5Z)-1-Azid oeicos-5-en -2-a m in e (R)-Mosh er a m id e
(14b): 1H NMR (300 MHz, CDCl3) δ 3.44 (q, 3H, J ) 1.5 Hz),
5.30-5.52 (m, 2H), 6.89 (d, 1H, J ) 8.4 Hz); 19F NMR (188 MHz,
CDCl3, reference with external TFA) δ 8.94 (s).
(2S,5Z)-Eicos-5-en e-1,2-d ia m in e d ih yd r och lor id e (11b):
yield 79%; light yellow solid; [R]23D -12.0 (c 0.5, MeOH); 1H NMR
(300 MHz, d6-DMSO) δ 0.86 (t, 3H, J ) 6.7 Hz, CH3), 1.24 [br s,
24H, (CH2)12], 1.59-1.72 (m, 2H, CH2CH), 1.96-2.20 (m, 4H,
CH2CHdCHCH2), 3.07 (br s, 2H, CH2N), 5.28-5.46 (m, 2H, CHd
CH), 8.46 (br s, 6H, 2 × NH3);1H NMR (200 MHz, d6-DMSO,
irradiation at 2.06 ppm) δ 0.86 (t, 3H, J ) 6.7 Hz, CH3), 1.24
[br s, 24H, (CH2)12], 1.60-1.69 (m, 2H, CH2CH), 3.08 (d, 2H, J
) 6.0 Hz, CH2N), 3.38-3.44 (m, 1H, CH), 5.32 (d, 1H, J ) 10.6
Hz, CHdCH), 5.41 (d, 1H, J ) 10.6 Hz, CHdCH); 13C NMR (50
Ack n ow led gm en t. This work was partially sup-
ported by the Greek Secretariat for Research and
Technology (PENED 99 Ε∆ 173).
J O005677J