Enantioselective synthesis of (1S,2S)-1,2-di-tert-butyl and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamines

Article abstract of DOI:10.1016/j.tetlet.2004.08.164

The enantioselective synthesis of sterically congested C ₂-symmetric 1,2-di-tert-butyl and 1,2-di-(1-adamantyl) ethylenediamines was successfully achieved starting from the simple heterocycle, 2-imidazolone. An enantioselective synthesis of ste

Full text of DOI:10.1016/j.tetlet.2004.08.164

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8073–8077
Enantioselective synthesis of (1S,2S)-1,2-di-tert-butyl and
(1R,2R)-1,2-di-(1-adamantyl)ethylenediamines
Alaa A.-M. Abdel-Aziz,a,* Serry A. A. El Bialy,b Fatma E. Godab and Takehisa Kuniedac
aDepartment of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
bDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
cFaculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
Received 12 March 2004; revised 17 August 2004; accepted 27 August 2004
Available online 17 September 2004
Abstract—An enantioselective synthesis of sterically congested 1,2-di-tert-butyl and 1,2-di-(1-adamantyl)ethylenediamines has been
developed. Thus, diastereomerically pure trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 were success-
fully prepared by optical resolution of ( )-trans-4,5-dimethoxy-2-imidazolidinone using apocamphanecarbonyl chloride (MAC-
Cl) followed by stereospecific and stepwise substitution of the dimethoxyl groups using tert-butyl or 1-adamantyl cuprates to pro-
vide (4S,5S)-4,5-di-tert-butyl and (4R,5R)-4,5-di-(1-adamantyl)-2-imidazolidinones 12 and 15, respectively. Furthermore, N-acetyl
4,5-di-tert-butyl and 4,5-di-(1-adamantyl)-2-imidazolidinones 16a,b were enantioselectively deacetylated using a catalytic oxazaboro-
lidine system to provide enantiopure 1-p-tolylsulfonyl-4,5-di-tert-butyl-2-imidazolidinones 12 and 19 and 1-p-tolylsulfonyl-4,5-di-
(1-adamantyl)-2-imidazolidinones 18 and 20, respectively. Finally, N-p-tolylsulfonyl-2-imidazolidinones 12 and 15 were treated with
30equiv of Ba(OH)2Æ8H2O to achieve ring cleavage and to provide (1S,2S)-1,2-di-tert-butylethylenediamine 3 and (1R,2R)-1,2-di-
(1-adamantyl)ethylenediamine 4.
Ó 2004 Elsevier Ltd. All rights reserved.
The vicinal 1,2-diamine functional group represents the
structural unit of a number of bioactive compounds
such as peptide antibiotics, vitamin H, antitumor agents,
and opioid receptor agonists.1 In addition, 1,2-diamines
function as chiral building blocks2 and bidentate lig-
ands3 for transition metals in asymmetric synthesis.
Many reactions have also been described using these
diamines as chiral auxiliaries2 and as aldehyde protect-
ing groups.4 Most of these applications generally use
the 1,2-diphenylethylenediamine 1 or 1,2-diaminocyclo-
hexane 2 frameworks whose preparations have been
fully described (Fig. 1).5 However, in our projects we
were interested in new, congested and benzylic-proton
free chiral 1,2-diamines such as 1,2-di-tert-butyl ethylene-
diamine 3 and 1,2-di-(1-adamantyl)ethylenediamine 4.
There are, however, very few methods available for the
synthesis of vicinal diamines from readily available
starting materials. The addition of Grignard or zinc rea-
gents to the chiral 1,2-bis-imine precursor derived from
glyoxal and (S)- or (R)-methylbenzylamine, followed by
hydrogenolysis to remove the phenylethyl group, has
been shown to be one of two general methods for prep-
aration of these compounds.6 The second method
involves the coupling of nitriles or N-(trimethyl-
silyl)imines promoted by NbCl4(THF).7 These methods
suffer from the lack of stepwise additions and hence,
yield products usually of C2-symmetric 1,2-diamines.
Hence, a versatile route for the chiral synthesis of both
unsymmetric and C2-symmetric 1,2-diamines from
simple, inexpensive starting materials is highly desirable.
Ph
Ph
H2N
NH2
In previous articles8 we reported that (4S,5S)- and
(4R,5R)-1-apocamphanecarbonyl-4,5-dimethoxy-2-imi-
dazolidinones (DMIm)8b 6 and 7 were good candi-
dates for chiral synthons for use in the synthesis of
biologically important 1,2-diamino acids. This strategy
H2N
NH2
H2N
NH2
H2N NH2
1
2
3
4
Figure 1. C2-symmetric vicinal diamines.
*
was based upon a stereodefined introduction of
easily replaceable groups to the 4,5-olefinic moiety of
Corresponding author. Tel.: +20 050 2351626; fax: +20 050
2247496; e-mail: alaa_moenes@yahoo.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.164

8074
A. A.-M. Abdel-Aziz et al. / Tetrahedron Letters 45 (2004) 8073–8077
2-imidazolone 5 in the presence of a chiral auxiliary to
give versatile chiral synthons, followed by stereospecific
and stepwise substitution, to achieve a chiral synthesis
of a wide variety of 1,2-diamino acids after hydrolytic
cleavage of the imidazolidinone ring. Thus, (4S,5S)-1-
apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinone
6 was enantioselectively converted into the diamino ana-
logue 8, the key component of pepstatine, 4-amino-3-
hydroxy-6-methylheptanoic acid. Pepastatine has potent
pepsin inhibition activity.9 Furthermore, (4R,5R)-1-
apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidi-
none 7 was converted into the diamino analogue 9, the
key component of amastatine,10 3-amino-2-hydroxy-5-
methylhexanoic acid. Amastatine is a potent aminopep-
tidase A inhibitor (Scheme 1).
diate, which is generated in situ, might be effectively con-
trolled by the vicinal methoxyl group. The subsequent
N-protection of 10 and 13 with p-tolylsulfonyl chloride,
followed by the removal of the MAC auxiliary with
LiBH4/MeOH yielded N-p-tolylsulfonyl derivatives 11
and 14, respectively. Each product was treated with a
second equivalent of organocuprate, as described above,
to give the sterically congested (4S,5S)-trans-1-p-toly-
lsulfonyl-4,5-di-tert-butyl-2-imidazolidinone 12 and
(4R,5R)-trans-1-p-tolylsulfonyl-4,5-di-(1-adamantyl)-2-
imidazolidinone 15 (Scheme 2).
An alternative route towards the congested trans-
4,5-disubstituted 2-imidazolidinones 12 and 15 was
investigated by the kinetic resolution of the N-acetyl-
derivatives 16a,b in the presence of catalytic amount of
oxazaborolidine.12 The N-acetyl-derivatives 16a,b
smoothly underwent enantioselective deacetylation on
treatment with borane (2equiv) in the presence of
aminoalcohol (+)-17 (0.1equiv). The trans-4,5-di-(1-
adamantyl)-2-imidazolidinone showed promising enan-
tioselective deacetylation with excellent chemical and
optical yields. These results might be explained by the
high steric bulkiness of the adamantyl compared with
the tert-butyl moiety. As is clear from Scheme 3, the
oxazaborolidine system predominantly deacetylated12c
the (4S,5S)-1-acetyl-3-p-tosyl-4,5-di-tert-butyl-2-imida-
zolidinone SS-16a and (4S,5S)-1-acetyl-3-p-tosyl-4,5-
In this letter we describe the synthesis of chiral, sterically
congested vicinal 1,2-diamines using our well defined,
efficient, and stereocontrolled procedures. The diastere-
omeric pure trans-4,5-dimethoxy-1-apocamphanecarbo-
nyl-2-imidazolidinones 6 and 7, which were prepared
from 5,11 were treated with tert-butyl or 1-adamantyl
cuprates (RCu(CN)MgBr/LiCl) in the presence of
BF3ÆOEt2 at ꢀ30°C, to furnish 10 and 13. The forma-
tion of these products can be explained by the regio-
and trans-stereoselective replacement of the methoxyl
group with tert-butyl or 1-adamantyl groups. The
trans-attack of cuprate to the acyliminium ion interme-
CO H
2
MeO
HN
OMe
OH
CO Me
2
N
O
NH
O
TsHN NHBoc
O
6
O
OMe
(MAC)
N
H
8
OH
HN NH
isovalaryl L-valyl L-Valyl NH
O
O
5
pepstatine
MeO
HN
OMe
CO Me
2
-L-Valyl-L-Valyl-L-Aspartic
N
TsHN NHBoc
H N OH
2
O
7
O
OMe
amastatine
9
(MAC)
Scheme 1. The utility of DMIm for the synthesis of pepstatine and amastatine analogues.
t-BuCuCNLi
t-BuCuCNLi
OMe
OMe
LiCl, BF3.OEt2
LiCl, BF3.OEt2
THF, -30 °C, 24 h
(69%)
Ts-Cl, NaH
HN N-MAC
°
TsN NH
TsN NH
THF, rt, 4 h (79%)
THF, -30 C, 24 h
6
(71%)
O
10
O
11
O
12
LiBH4, MeOH
THF, rt, 3 h (quant.)
1-adamantylCuCNLi
LiCl, BF3.OEt2
THF, -30 °C, 24 h
(79%)
1-adamantylCuCNLi
LiCl, BF3.OEt2
THF, -30 °C, 24 h
(73%)
OMe
OMe
Ts-Cl, NaH
THF, rt, 4 h (89%)
TsN NH
TsN NH
HN N-MAC
7
LiBH4, MeOH
THF, rt, 3 h (quant.)
O
O
O
13
14
15
Scheme 2. Synthesis of sterically congested 2-imidazolidinones 12 and 15.

A. A.-M. Abdel-Aziz et al. / Tetrahedron Letters 45 (2004) 8073–8077
8075
OH
R
R
NH2
R
R
R
R
(+)-17 (0.1 eq.)
TsN N-Ac
+
TsN N-Ac
TsN NH
O
BH3 .THF (2 equiv.)
THF, 20 °C, 3 h
O
O
12 R= tBu (28%, 76% ee)
R= Bu (71%, 32% ee)
t
19
16a,b
a: R= tBu
18
R= 1-adamantyl (41%, 96% ee)
R= 1-adamantyl (51%, 95% ee)
20
b: R= 1-adamantyl
Scheme 3. Enantioselective deacetylation of ( )-trans-1-acetyl-p-tolylsulfonyl-2-imidazolidinones.
di-(1-adamantyl)-2-imidazolidinone SS-16b (Figs. 2 and
3). The imidazolidinones formed were readily separable
by chromatography on silica gel and were purified by
recrystallization to give enantiomers 12 and 18–20
(Scheme 3). The stereochemistry was determined by
comparison with authentic samples obtained as shown
in Scheme 2.
Our trial to liberate the 1,2-diamine from the unpro-
tected trans-4,5-di-tert-butyl or trans-4,5-di-(1-admant-
yl)-2-imidazolidinones with 30–50equiv of Ba(OH)2Æ
8H2O was unsuccessful. However, treatment of the
N-p-tolylsufonyl-2-imidazolidinones 12 and 15 with
30equiv of Ba(OH)2Æ8H2O in a sealed glass tube at
140°C for 3days afforded N-p-tolylsulfonyl-1,2-diam-
ines 21 and 23, respectively. The C2-symmetric diamines
were obtained either by refluxing 21 or 23 with p-tolyl-
sulfonyl chloride in the presence of NaH and THF as
solvent to give diprotected amines 22 and 2413 or by
removal of the p-tolylsulfonyl groups by titration with
freshly prepared sodium naphthalide solution14 at
ꢀ78°C to give the unprotected diamines 3 and 415
(Scheme 4).
The liberation of the chiral diamines depends on hydro-
lytic ring cleavage of the 2-imidazolidinone using alkali.
In an attempt to gain a better insight on the molecular
structures of the most preferentially deacetylated
enantiomers SS-16a and SS-16b and the difference in
their steric bulkiness, which controls the enantioselective
deacetylation according to Scheme 3, conformational
analysis of these enantiomers was performed by use of
the MM216 force field as implemented in Chem3D.17
The starting atomic coordinates were obtained
from the X-ray data of the structurally related molecule;
( )-1-acetyl-4,5-di-tert-butyl-2-imidazolidinone.8c Full
geometry optimization was carried out with semi-empiri-
cal AM118 as implemented in G98W19 running on a PC.
Calculation of the isopotential molecular surface was
performed with Hyperchem 5.1.20 The most stable
conformers of enantiomers SS-16a and SS-16b resulting
from computational chemistry analysis were superim-
posed in order to reveal the similarities and differences
Figure 2. Superimposition of the lowest energy conformer of com-
pounds SS-16a (yellow) and SS-16b (pink), showing the close match of
the 2-imidazolidinone rings (cyan) and slight differences in the p-
tolylsulfonyl geometry and the significant steric bulkiness of the 1-
adamantyl core.
Figure 3. Electrostatic potential isosurface of the lowest energy conformer of compounds SS-16a (left) and SS-16b (right), negative region colors are
pink and positive region colors are green.

8076
A. A.-M. Abdel-Aziz et al. / Tetrahedron Letters 45 (2004) 8073–8077
+
-
Ba(OH) . 8H O
Na C H
8
2
2
10
TsCl (1.2 eq.)
NaH (2 eq.)
THF, rt, 4 h
°
EtOH, H O
2
THF, -79
30 min.
C
°
140 C, 3 d
TsN NH
TsHN NHTs
TsHN NH
H N NH
2
(73%)
(75%)
(91%)
2
2
O
12
21
22
3
+
-
Ba(OH) . 8H O
Na C H
8
2
2
10
TsCl (1.2 eq.)
NaH (2 eq.)
THF, rt, 4 h
EtOH, H O
2
°
THF, -79
30 min.
(87%)
C
°
140 C, 3 d
TsN NH
H N NH
2
TsHN NH
TsHN NHTs
(68%)
(77%)
2
2
O
15
4
24
23
Scheme 4. Hydrolytic pathway to the vicinal diamines.
Soc. 1992, 114, 7938; (c) Catalytic Asymmetric Synthesis;
Jacobsen, E. J., Ed.; VCH: Ojima, 1993; p 159; (d)
Katsuki, T. J. Mol. Catal. 1996, 113, 87; (e) Mukaiyama,
T. Aldrichim. Acta 1996, 29, 59; (f) Trost, B. M.; Van
Vrancken, D. L. Chem. Rev. 1996, 96, 395.
in structures (Fig. 2). The strategy of overlay fit
was to match two imidazolidinone rings and examine
any spatial differences between the atoms of the tert-
butyl and 1-adamantyl groups. The results showed
that atoms of the tosyl groups occupy slightly different
spatial positions relative to the plane of the 2-imidazo-
lidinones and closely match the tert-butyl and 1-ada-
4. As aldehyde protection see: Alexakis, A.; Mangeney, P. In
Advanced Asymmetric Synthesis; Stephenson, G. R., Ed.;
Chapman & Hall, 1996; p 93.
˚
mantyl groups with RMS values 0.01A (Fig. 2). An
5. For the diamine 1: (a) Pini, D.; Iuliano, A.; Rosini, C.;
Salvadori, P. Synthesis 1990, 1023; (b) Oi, R.; Sharpless,
K. B. Tetrahedron Lett. 1991, 32, 999; (c) Shimizu, M.;
Fujisawa, T. Tetrahedron Lett. 1995, 36, 8607; For the
diamine 2 see: (a) Wieland, A.; Schlichtung, O.; Langs-
dorf, W. V. Z. Phys. Chem. 1926, 161, 74; (b) Swift, G.;
Swern, D. J. Org. Chem. 1967, 32, 511; (c) Whitney, T. A.
J. Org. Chem. 1980, 45, 4214.
6. Addition to imines see: (a) Tom, D. H.; Dietrich, J. Chem.
Ber. 1984, 117, 694; (b) Neumann, W. L.; Rogic, M. M.;
Dunn, T. J. Tetrahedron Lett. 1991, 32, 5865; (c) Alvaro,
J.; Grepioni, F.; Savoia, D. J. Org. Chem. 1997, 62, 4180;
(d) Bambridge, K.; Begley, M. J.; Simpkins, N. S.
Tetrahedron Lett. 1994, 35, 3391.
electrostatic isopotential isosurface was carried out
for the lowest energy conformers of SS-16a and
SS-16b, respectively, to examine the similarity in
electronic and conformational properties. Figure 3
presents the electrostatic potentials (ESP) mapped on
the isosurface of SS-16a and SS-16b, pink colors
indicate negative ESP regions and green colors indicate
positive ESP regions. Comparison of the ESP of SS-16a
with SS-16b shows their electronic similarity and
steric crowding of the aliphatic cage-like core of the
1-adamantyl moiety compared with that of tert-butyl
group.
7. Coupling of nitriles see: Roskamp, E. J.; Pedersen, S. F. J.
Am. Chem. Soc. 1987, 109, 3152.
In conclusion, we have successfully developed an effi-
cient synthesis of 1,2-diamino-1,2-di-tert-butylethane
and of 1,2-diamino-1,2-di-(1-adamantyl)ethane from
trans-4,5-dimethoxy-2-imidazolidinones by optical reso-
lution using apocamphanecarbonyl chloride (MAC-Cl)
or catalytic resolution using an oxazaborolidine. Subse-
quent stereospecific and stepwise substitution of dimeth-
oxyl groups using tert-butyl or 1-adamantyl cuprates
and then ring cleavage using 30equiv of Ba(OH)2Æ8H2O
to provide chiral 1,2-di-tert-butyl and 1,2-di-(1-adamant-
yl)ethylenediamines, which represent potential precur-
sors for biologically active platinum and palladium
complexes.1a
8. (a) Katahira, T.; Ishizuka, T.; Matsunaga, H.; Kunieda, T.
Tetrahedron Lett. 2001, 42, 6319; (b) Seo, R.; Ishizuka, T.;
Abdel-Aziz, A. A.-M.; Kunieda, T. Tetrahedron Lett.
2001, 42, 6353; (c) Abdel-Aziz, A. A.-M.; Matsunaga, H.;
Kunieda, T. Tetrahedron Lett. 2001, 42, 6565, and
references cited therein.
9. Umezawa, H.; Aoyagi, T.; Morishima, H.; Matsuzaki, M.;
Hamada, M.; Takeuchi, T. J. Antibiot. 1970, 23, 259.
10. Aoyagi, T.; Tobe, H.; Kojima, F.; Hamada, M.; Takeuchi,
T.; Umezawa, H. J. Antibiot. 1978, 31, 636.
11. Wang, P. C. Heterocycles 1985, 23, 3041.
12. (a) Ishizuka, T.; Kimura, K.; Ishibuchi, S.; Kunieda, T.
Chem. Pharm. Bull. 1990, 38, 1717; (b) Ishizuka, T.;
Kimura, K.; Ishibuchi, S.; Kunieda, T. Chem. Lett. 1992,
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Ishizuka, T.; Matsunaga, H.; Kunieda, T. Tetrahedron
Lett. 2000, 41, 8533, and references cited therein.
References and notes
13. Compound (S,S)-22: (75%), mp 193–194°C (hexane/CH2-
24
1. (a) Lueet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem.,
Int. Ed. 1998, 37, 2580; (b) Imagawa, K.; Hata, E.;
Yamada, T.; Mukaiyama, T. Chem. Lett. 1996, 291; (c)
Bruncko, M.; Khuong, T.-A. V.; Sharpless, K. B. Angew.
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2. For a review, see: Bennani, Y. L.; Hanessian, S. Chem.
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3. As bidentate ligand see: (a) Tomioka, K. Synthesis 1990,
541; (b) Corey, E. J.; Sarshar, S.; Bordner, J. J. Am. Chem.
Cl2); ½aꢁD ꢀ40.7 (c 1.00, CH2Cl2); 1H NMR(CDCl
,
3
500MHz): d 7.72–7.70 (d, 4H, J = 8.5Hz), 7.29–7.27 (d,
4H, J = 8.5Hz), 4.46–4.44 (d, 2H, J = 7.9Hz, NH
exchangeable with D2O), 3.63–3.61 (d, 2H, J = 7.9Hz),
2.43 (s, 6H), 0.85 (s, 18H); Anal. C24H36N2O4S2: calcd
CHN: 59.97, 7.55, 5.83, found CHN: 60.00, 7.58, 5.86.
Compound (R,R)-24: (77%), mp 210–211°C (hexane/CH2-
28
Cl2); ½aꢁD ꢀ9.5 (c 1.00, CH2Cl2); 1H NMR(CDCl
,
3
500MHz): d 7.77–7.76 (d, 4H, J = 8.6Hz), 7.23–7.22 (d,

A. A.-M. Abdel-Aziz et al. / Tetrahedron Letters 45 (2004) 8073–8077
8077
4H, J = 8.6Hz), 4.89–4.87 (d, 2H, J = 7.9Hz, NH
exchangeable with D2O), 3.68–3.66 (d, 2H, J = 7.9Hz),
2.44 (s, 6H), 2.00 (s, 4H), 1.95–1.44 (m, 26H). Anal.
C36H48N2O4S2: calcd CHN: 67.89, 7.60, 4.40, found
CHN: 67.50, 7.78, 4.28.
19. Gaussian 98, Revision A.7, Frisch, M. J.; Trucks, G. W.;
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26
15. Compound (S,S)-3: yellow oil (91%); ½aꢁD +3.9 (c 1.50,
CH2Cl2);21 1H NMR(CDCl 3, 500MHz): d 3.21 (s, 4H),
2.70 (s, 2H), 0.90 (s, 18H). Compound (R,R)-4: colorless
29
1
oil (87%); ½aꢁ ꢀ19.6 (c 1.00, CH2Cl2); H NMR(CDCl 3,
500MHz): d D2.91 (s, 4H), 2.60 (s, 2H), 1.97 (s, 4H), 1.66–
1.37 (m, 26H).
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