A novel and efficient synthesis of chiral C2-symmetric 1,4-diamines

Article abstract of DOI:10.1016/j.tetlet.2008.11.071

A novel and efficient method for synthesis of (R,R)- and (S,S)-C₂-symmetric 1,4-diamines was established. The key steps are a combination of Pinacol Coupling and Corey-Winter olefination.

Full text of DOI:10.1016/j.tetlet.2008.11.071

Tetrahedron Letters 50 (2009) 552–554
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel and efficient synthesis of chiral C2-symmetric 1,4-diamines
*
Lianhong Xu, Manoj C. Desai, Hongtao Liu
Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient method for synthesis of (R,R)- and (S,S)-C2-symmetric 1,4-diamines was established.
The key steps are a combination of Pinacol Coupling and Corey–Winter olefination.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 20 September 2008
Revised 17 November 2008
Accepted 18 November 2008
Available online 24 November 2008
Keywords:
C2-symmetric 1,4-diamines
Corey–Winter olefination
Diastereo- and enantiomerically pure 1,n-diamines (n = 2–5)
are recognized as important structural elements of many biologi-
cally active compounds. In addition, 1,2-diamines are widely used
as chiral auxiliaries and ligands in asymmetric synthesis. There-
fore, it is not surprising that a number of synthetic methods exist
for the diastereo- and enantioselective synthesis of vicinal dia-
mines.1 However, there are limited methods available for synthesis
of other diamines. In one of our medicinal chemistry programs, we
needed to synthesize chiral C2-symmetrical 1,4-diamine 1 (Figure
1). Herein, we report our investigations that led to the sequential
use of Pinacol Coupling and Corey–Winter olefination as methods
of choice for the synthesis of 1,4-diamines.
One direct approach to 1,4-diamine 1 was to utilize the key
intermediate 3 from the published synthesis of lopinavir (2).2 As
shown in Scheme 1, the removal of the hydroxyl group was
achieved through free radical-mediated deoxygenation to provide
diamine 4.3 However, the deoxygenation step required high dilu-
tion and use of tin-containing reagents, and therefore was judged
unsuitable for synthesis on gram-scale which was needed for pre-
paring analogs to establish SARs.
Ph
H2N
Ph
NH2
1
Figure 1.
Ph
O
O
H
N
O
HN
N
N
H
O
OH
Ph
2 lopinavir
Ph
Ph
a, b
PHN
Ph
PHN
Ph
NHP
NHP
OH
3
After we carefully analysed the few methods available for the
diastereoisomeric synthesis of 1,4-diamines in the literature,4 we
decided to use the procedures optimized by Gurjar to generate
the diamine 1 (Scheme 2). Both aldehyde 6b and sulfone 7 were
4
(P is protecting groups)
Scheme 1. Reagents: (a) TCDI; (b) AIBN/Bu3SnH.
prepared from L-phenylalaninol 5. Under Julia olefination condi-
tions, the coupling reaction between aldehyde 6b and sulfone 7
afforded alkene 9. Debenzylation of 9, followed by hydrogenation
and deprotection of the Boc-group, gave diamine 1 from 6b in
33% overall yield. Diamine 1 prepared through this method served
our initial purpose of establishing limited SAR. However, the fact
that the Julia olefination required the use of n-butyllithium at low
temperature (ꢀ78 °C), and a large amount of mercury (for Na/Hg
amalgam) limited its application to large-scale production. In addi-
tion, the necessity of benzyl protection of the amino function of the
aldehyde 6b to facilitate smooth Julia olefination resulted in the use
of sodium/ammonia in the debenzylation step, which presented
further challenges in a multi-gram synthesis for preclinical evalua-
* Corresponding author. Tel.: +1 650 522 5543; fax: +1 650 522 5899.
E-mail address: hliu@gilead.com (H. Liu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.071

L. Xu et al. / Tetrahedron Letters 50 (2009) 552–554
553
R
BocN
CHO
Ph
Ph
PhSO2
BocHN
H2N
a
(R=H)
6a
6b
OH
Ph
(R=Bn)
NBnBoc
OH
Ph
BocHN
8
5
SO2Ph
Ph
7
Ph
Ph
NH2
c
b
BocHN
Ph
H2N
Ph
NBoc
Bn
9
1
Scheme 2. Reagents and conditions: (a) n-BuLi, THF, ꢀ78 °C; (b) (i) Ac2O, Py, CH2Cl2, rt; (ii) 6%Na–Hg, Na2HPO4, MeOH, rt; (c) (i) Na/liq NH3, THF, ꢀ33 °C; (ii) H2, 10% Pd/C, rt;
(iii) HCl/dioxane.
olefination, such as Julia–Kocienski olefination, was considered
but it only partially removed those limitations discussed above.
We felt that, in order to provide a large quantity of 1,4-diamine 1,
it was necessary to develop a new and efficient synthesis.
A potential route to prepare compound 11, which could be con-
verted to diamine 1 using a similar procedure as in the transforma-
tion of compound 9 to 1, is through metathesis of olefin 10. Olefin
10 was synthesized according to the literature procedure from 6b.5
Unfortunately, no desired olefin 11 was observed after treating ole-
fin 10 with different metathesis conditions6 (Scheme 3).
Ph
Bn
BocN
Bn
BocN
a
6b
X
NBoc
Bn
Ph
Ph
11
10
Scheme 3. Reagents: (a) KHMDS, BrP+Ph3CH3.
Ph
A second method we envisioned, as outlined in Scheme 4, was
one in which diol 13 could be converted into alkene 12 through
Corey–Winter olefination,7 which after hydrogenation should af-
ford desired 1,4-diamine 1. Diol 13 could be easily accessed from
aldehyde 14 through a Pinacol Coupling reaction. Aldehyde 14
would be obtained from commercially available amino alcohol or
amino acid. The combination of Pinacol Coupling and Corey–Win-
ter olefination could provide a new procedure for the synthesis of
chiral C2-symmetrical 1,4-diamines.
CbzHN
NHCbz
1
Ph
12
Ph
OH
Ph
NHCbz
CbzHN
Ph
NHCbz
OHC
OH
13
14
The method is summarized in Scheme 5. Cbz-
L-phenylalaninol
15, prepared easily from
L
-phenylalaninol 58 or obtained from com-
Scheme 4.
mercial sources directly, was oxidized with SO3-pyridine in DMSO
to afford the aldehyde 14. Aldehyde 14 can also be prepared from
tion. The efforts to use aldehyde 6a, where benzyl protection was
absent, for Julia olefination met with failure. Furthermore, prepara-
tion of both aldehyde 6b and sulfone 7 involved many steps. The
synthesis of diamine 1 from commercial phenylalaninol took 12 to-
tal steps, or 9 steps in the longest linear sequence. Modified Julia
either the free acid of or an ester of Cbz-L
-phenylalanine.9 The alde-
hyde 14 was transformed into the diol 13 through an intermolecu-
lar vanadium-assisted Pinacol Coupling reaction according to the
literature procedure.10 As reported in the literature, high diastereo-
meric purity of diol 13 was achieved after recrystallization in tetra-
Ph
O
OH
CbzHN
Ph
CbzHN
Ph
a
c
b
CbzHN
OH
H
NHCbz
OH
Ph
15
14
13
S
Ph
Ph
Ph
e
d
O
CbzHN
Ph
H2N
Ph
CbzHN
Ph
NHCbz
NH2
NHCbz
O
16
12
1
Scheme 5. Reagents and conditions: (a) SO3-pyridine/Et3N/DMSO; (b) VCl3–(THF)3/Zn/THF; (c) TCDI/THF/70 °C; (d) P(OEt)3/160 °C; (e) H2/10%Pd/C/MeOH; over all yield 70–
80% from 13.

554
L. Xu et al. / Tetrahedron Letters 50 (2009) 552–554
References and notes
Ph
H2N
Ph
H2N
1. (a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100,
NH2
NH2
2159. and references cited therein; (b) Lucet, D.; Le Gall, T.; Mioskowski, C.
Angew. Chem., Int. Ed. 1998, 37, 2580–2627. and references cited therein.
2. Kempf, D. J.; Sham, H. L.; Marsh, K. C.; Flentge, C. A.; Betebenner, D.; Green, B.
E.; McDonald, E.; Vasavanonda, S.; Saldivar, A.; Wideburg, N. E.; Kati, W. M.;
Ruiz, L.; Zhao, C.; Fino, L.; Patterson, J.; Molla, A.; Plattner, J. J.; Norbeck, D. W. J.
Med. Chem. 1998, 41, 602.
18
17
Figure 2.
3. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574.
4. (a) Hodgson, D. M.; Humphreys, P. G.; Miles, S. M.; Brieley, C. A.; Ward, J. G. J.
Org. Chem. 2007, 72, 10009; (b) Hodgson, D. M.; Miles, S. M. Angew. Chem., Int.
Ed. 2006, 45, 935; (c) Enders, D.; Meiers, M. Synthesis 2003, 17, 2542; (d)
Yamauchi, T.; Higashiyama, K.; Kubo, H.; Ohmiya, S. Tetrahedron: Asymmetry
2000, 11, 30003; (e) Gurjar, M. K.; Pal, S.; Rao, A. V. R.; Pariza, R. J.; Chorghade,
M. S. Tetrahedron 1997, 53, 4769; (f) Rao, A. V. R.; Gurjar, M. K.; Pal, S.; Pariza, R.
J.; Chroghade, M. S. Tetrahedron Lett. 1995, 36, 2505.
5. Beier, C.; Schaumann, E.; Adiwidjaja, G. Synlett 1998, 41.
6. Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann,
D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58.
7. (a) Alcón, M.; Canas, M.; Poch, M.; Moyano, A.; Pericàs, M. A.; Riera, A.
Tetrahedron Lett. 1994, 35, 1589; (b) Alcón, M.; Poch, M.; Moyano, A.; Pericàs,
M. A. Tetrahedron: Asymmetry 1997, 8, 2967; (c) Robertson, J.; Stafford, P. M.;
Bell, S. J. J. Org. Chem. 2005, 70, 7133.
hydrofuran (THF)/hexanes. Reaction of diol 13 with 1,10-thi-
ocarbonyldiimidazole in refluxed THF yielded cyclic thiocarbonate
16. Treatment of thiocarbonate 16 with triethylphosphite at
160 °C generated alkene 12. We found that the purity of the thiocar-
bonate 16 was very important for a successful elimination. The de-
sired purity of thiocarbonate 16 could be achieved by a quick flash
chromatography or by washing the reaction mixture with dilute
hydrochloric acid. The symmetric alkene 12 was a highly crystalline
compound, and it could be recrystallized easily in ethyl acetate/
hexanes. Finally, hydrogenation of alkene 12 under one atmosphere
of hydrogen catalyzed by 10%Pd/C afforded diamine 1. In this se-
quence, diamine 1 was prepared from diol 13 in excellent yields
(70–80%).11 Using this method, the diamine 1 can be prepared in to-
tal five steps from Cbz-protected phenylalaninol. The reactions
were carried out on hundred-gram scales, and purifications for
the whole sequence were achieved through recrystallizations.
Similarly, the (S,S)-enantiomer 17 (Fig. 2) was synthesized on a
hundred-gram scale following the same sequence starting from
8. Mergmann, M.; Zervas, L. Ber. 1932, 65, 1192.
9. (a) Sergeev, M. E.; Pronin, V. B.; Voyushina, T. L. Synlett 2005, 2802; (b)
Debaene, F.; Silva, J. A. D.; Pianowski, Z.; Durran, F. J.; Winssinger, N.
Tetrahedron 2007, 63, 6577; (c) Nakamura, M.; Miyashita, H.; Yamaguchi, M.;
Shirasaki, Y.; Nakamura, Y.; Inoue, J. Bioorg. Med. Chem. 2003, 11, 5449.
10. Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyermann, C. J.;
Chang, C.; Emmett, G.; Holler, E. R.; Daneker, W. F.; Li, L.; Confalone, P. N.;
McHugh, R. J.; Han, Q.; Li, R.; Markwalder, J. A.; Seitz, S. P.; Sharpe, T. R.;
Bacheler, L. T.; Rayner, M. M.; Klabe, R. M.; Shum, L.; Winslow, D. L.;
Kornhauser, D. M.; Jackson, D. A.; Erickson-Viitanen, S.; Hodge, C. N. J. Med.
Chem. 1996, 39, 3514.
Cbz-D-phenylalaninol. Other alkyl-substituted C2-symmetric 1,4-
11. Typical experimental procedure: Diol 13 (50.0 g, 88 mmol) was dissolved in THF
(1500 ml) with heating, and the solution was cooled to 25 °C. 1,10-
Thiocarbonyldiimidazole (31.3 g, 176 mmol) was added, and the mixture was
refluxed for 60 h. The reaction mixture was cooled to 25 °C and filtered. Then,
the mixture was concentrated to give a brown solid. The solid was dissolved in
ethyl acetate (1000 ml), and the resulted solution was washed with 2.5% HCl
solution (400 ml/200 ml/200 ml), followed by water (200 ml), saturated
sodium bicarbonate solution (200 ml), and brine. The solution was dried over
sodium sulfate and concentrated to give compound 16 as a yellow solid
(56.0 g). To above solid was added triethylphosphite (200 ml), and the mixture
was heated at 165 °C for 24 h. Excess triethylphosphite was removed under
reduced pressure to give compound 12. Recrystallization of the crude material
from ethyl acetate and hexanes gave pure olefin 12 as a white solid (36.5 g) in
77% yield. m/z: 535.1 (M+H)+; 1H NMR (CDCl3) d 7.4–7.0 (20H, m), 5.47 (2H, m),
5.07 (4H, s), 4.62 (2H, m), 4.45 (2H, m), 2.78 (4H, d, J = 6.1 Hz).
diamines, such as diamine 18, were also prepared in a similar man-
ner and in comparable yields when starting from the correspond-
ing amino alcohols or amino acids (Fig. 2).
In conclusion, we have developed a novel and practical method
for diastereoselective synthesis of chiral C2-symmetric 1,4-dia-
mines from easily accessible amino alcohols or amino acids.
Acknowledgment
The authors thank Dr. Randall Halcomb for proof reading the
manuscript and for helpful discussions.