Stereoselective synthesis of aminoethylamine aspartyl protease transition state isosteres

Article abstract of DOI:10.1016/j.tetlet.2006.07.084

A stereoselective synthesis of aminoethylamine aspartyl protease transition state isosteres 10 and 14 is described. The synthetic approach was designed to allow the introduction of functionality at the central core of the inhibitors, which should enable t

Full text of DOI:10.1016/j.tetlet.2006.07.084

Tetrahedron Letters 47 (2006) 7097–7100
Stereoselective synthesis of aminoethylamine aspartyl
protease transition state isosteres
Alicia Torrado*
Eli Lilly and Co., Lilly, S. A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain
Received 5 April 2006; revised 10 July 2006; accepted 18 July 2006
Available online 10 August 2006
Abstract—A stereoselective synthesis of aminoethylamine aspartyl protease transition state isosteres 10 and 14 is described. The syn-
thetic approach was designed to allow the introduction of functionality at the central core of the inhibitors, which should enable the
identification of small molecule inhibitors of diverse aspartyl protease targets.
Ó 2006 Elsevier Ltd. All rights reserved.
Proteases, which catalyze the hydrolysis of amide bonds
in peptides and proteins, play essential roles in numer-
ous biological processes and are important therapeutic
targets in different diseases including cancer, viral infec-
tions, inflammation and cardiovascular diseases.1 The
aspartyl protease family includes the extremely impor-
tant drug targets, HIV protease2 and b secretase,3 impli-
cated in Alzheimer’s disease. A common strategy in the
design of aspartyl protease inhibitors is the replacement
of the substrate scissile amide bond with a tetrahedral
intermediate isostere, typically a secondary alcohol or
an amine. Three common hydroxyl containing inhibitor
scaffolds include hydroxyethylene, hydroxyethylamine
and statine motifs.4 Amine containing inhibitor scaffolds
such as aminostatine,4 aminoethylamine,5 and amino-
ethylene6 motifs have also been described (Fig. 1).
tors.7,8 Those pharmacophores, which differ from one
another by the stereochemistry (S) and (R) on the
hydroxyl group, engage either one or both of the cata-
lytic aspartates of the enzyme via hydrogen bonds in a
different manner. Due to this difference in the stereo-
chemistry of the secondary alcohol depending on the
isostere, both stereochemistries in the aminoethylamine
motif have been pursued to keep both possibilities for
the hydrogen bond pattern proposed for interaction
with the two active-site aspartyl residues.
The synthesis of the two NH2-isomers in the amino-
ethylamine isostere described herein utilized easily
accessible amino epoxides 1 (Scheme 1),9 and 2 (Scheme
3)10 as the starting materials for the achievement of the
primary amine central core.
The two compounds described in this letter containing
the aminoethylamine motif have been previously
claimed as inhibitors of the beta-secretase enzyme; how-
ever, their published synthesis was not based on a stereo-
selective route and required the separation of each iso-
mer by chiral chromatography at the final step.5 In this
letter, an alternative stereoselective synthesis to the
aminoethylamine motif was investigated due to its pos-
sible use as isostere in other different aspartyl proteases.
Both stereochemistries in the amino group were consid-
ered important based on the published crystal structures
of several hydroxyl-containing aspartyl protease inhibi-
Aziridine 3 was obtained in two steps by the treatment
of (S)-epoxide 1 with NaN3 which afforded the interme-
diate hydroxymethylazide that was closed immediately
to the desired aziridine in the presence of PPh3 with an
inversion of configuration.
For ease of synthesis, the protection of the aziridine with
Boc would be the best choice since removal in the last
step with HCl to form the hydrochloride salt would
facilitate isolation of the product. However, it is well
known that the reactivity of aziridines decreases accord-
ing to the decreased electron-withdrawing ability of the
substituent on the nitrogen atom of aziridine. Based on
this fact, Reider and co-workers11 reported that nosyl-
aziridines are highly reactive electrophiles towards a
variety of nucleophiles and that the resulting primary
Keywords: Aminoethylamine; Aspartyl protease inhibitor; Aziridine.
*
Tel.: +34 91 6633423; fax: +34 91 6233591; e-mail:
torrado_alicia@lilly.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.084

7098
A. Torrado / Tetrahedron Letters 47 (2006) 7097–7100
P '
P2
O
HO OH
N
1
H
N
N
H
H
P2'
O
P1
O
Intermediate of peptide hydrolysis
OH R1
OH
OH
O
H
H
H
H
H
N
N
N
N
N
O
R
O
O
R
O
R
Hydroxyethylene
Hydroxyethylamine
Statine
NH2
R
O
NH2 R1
H
NH2
H
H
H
H
N
N
N
N
N
O
O
R
O
O
R
Aminoethylene
Aminoethylamine
Aminostatine
Figure 1. Aspartyl protease inhibitor core motifs.
R
N
H
H
N
O
H
N
H
N
i, ii
iii
iv
OMe
N
Cbz
+
H2N
Cbz
Cbz
4a, R = Ns
4b, R = SES
4c, R = Boc
1
3
5
R
R
NH
NH
H
N
H
v
vi
H
N
N
H2N
+
OMe
Cbz
OMe
N
OH
O
O
6a, R = Ns
6b, R = SES
6c, R = Boc
7a, R = Ns
7b, R = SES
7c, R = Boc
8
2HCl
NH2
R
NH
H
H
vii
H
N
H
N
N
N
N
N
O
OMe
OMe
O
O
O
9a, R = Ns
9b, R = SES
9c, R = Boc
10
Scheme 1. Reagents and conditions: (i) NH4Cl, NaN3, MeOH, 64 °C, 3 h; (ii) PPh3, CH3CN, reflux, 1 h, 66% both steps; (iii) 4-nitrobenzenesulfonyl
chloride, Et3N, CH2Cl2, À20 °C to 10 °C, 30 min, 75% for 4a, b-trimethylsilylethanesulfonyl chloride, Et3N, DMF, 35% for 4b, (Boc)2O, Et3N,
CH2Cl2, rt, overnight, 80% for 4c; (iv) Bu3P, CH3CN, rt, 2 h, 76% yield for 6a, 78% yield for 6b, CH3CN, 85 °C, sealed tube, 20 h, 40% yield for 6c;
(v) H2, Pd/C, EtOH, rt, 3 h, 98 %; (vi) EDCÆHCl, HOBt, DMAP, Et3N, CH2Cl2, rt, 50% yield for 9a, 58% yield for 9b, 60% yield for 9c and (vii) HCl
4.0 M in dioxane, rt, 1 h, 55% after trituration with Et2O for 9c.
nosylamide adducts can be readily cleaved under mild
conditions to provide the primary amines. For this rea-
son, 4-nitrobenzene sulfonyl chloride (nosyl group, Ns),
was the first choice as a protecting group for the aziri-
dine in the proposed synthesis to obtain 4a. Tributyl-
phosphine in acetonitrile was used as an effective
promoting agent for ring-opening of the aziridine to
provide amine 6a in 76% yield.12 Removal of the Cbz
group by hydrogenation followed by an amide
coupling reaction with the isophthalamide carboxylic

A. Torrado / Tetrahedron Letters 47 (2006) 7097–7100
7099
acid 8 afforded the desired N-protected compound 9a.
Unfortunately, attempts to remove the nosyl group with
thiophenol in the presence of potassium carbonate in
acetonitrile yielded unreacted starting material as the
only isolated product.
proceed in lower yield than in the previous cases. As
the Boc group is not an electron withdrawing group like
the Ns group, the tributylphosphine did not appear to
assist in the aziridine opening with 3-methoxybenzyl-
amine and starting material was recovered. However,
treatment of the Boc-aziridine with 3-methoxybenzyl-
amine in CH3CN in a sealed tube at 85 °C for 20 h gave
the desired product 6c in 40% yield. The two remaining
steps in the synthetic route (hydrogenation to remove
the Cbz protecting group and the amide coupling step)
proceeded in good yields to give the N-Boc protected
product 9c. This intermediate was readily deprotected
by treatment with 4.0 M HCl in dioxane at room tem-
perature for 1 h to give the corresponding hydrochloride
salt of (S)-aminoethylamine 10.15
The synthesis was then tried with the SES protecting
group (b-trimethylsilylethanesulfonyl). This group was
described as a useful reagent for the protection of
amines as their sulfonamides, which are easily cleaved
by heating with fluoride ion.13 The protection of the azi-
ridine to give 4b and the following ring-opening step to
obtain 6b worked in acceptable yields. Once the ring was
opened, we tried to exchange the protecting group from
SES to Boc to avoid the last heating step. Unexpectedly,
compound 11 was obtained (Scheme 2) which was
formed after deprotection of the SES group and amine
attack to the carbonyl group of the Cbz affording benz-
ylalcohol as a secondary product.14 When the removal
of the SES group was postponed to the last step of the
synthesis, after heating to 110 °C in the presence of fluo-
ride anion, only the decomposition products were
detected.
Available (R)-epoxide 2 served as the starting material
to obtain the (R)-aminoethylamine (Scheme 3).16 The
aziridine was now protected with Cbz in order to distin-
guish between the two amino groups in the molecule.
Following the same synthetic route described above,
the desired product 14 was obtained in an overall yield
of 7% from epoxide 2.15
At this point, the Boc group (tert-butoxy carbonyl) was
chosen to protect aziridine 3 even knowing that the
desired aziridine ring-opening reaction will most likely
In conclusion, a stereoselective route is reported for the
synthesis of the aminoethylenamine-based aspartyl pro-
tease inhibitors 10 and 14 obtained from easily available
tms
O
S O
N
i
OMe
N
N
O
N
OMe
N
N
O
O
6b
11
Scheme 2. Reagents and conditions: (i) TBAF 1.0 M in THF, dioxane, Et3N, (Boc)2O, 110 °C, overnight, 51%.
2HCl
Cbz
N
Cbz
O
H
NH
H
N
H
N
i-iii
iv-v
OMe
H2N
boc
N
H2N
OMe
boc
+
2
12
5
13
2HCl
NH2
H
H
N
vi-viii
N
N
13
+
8
OMe
O
O
14
Scheme 3. Reagents and conditions: (i) NH4Cl, NaN3, MeOH, 64 °C, 3 h; (ii) PPh3, CH3CN, reflux, 3 h, 69% both steps; (iii) 4-benzyl chloroformate,
Et3N, CH2Cl2, rt, 3 h, 75%; (iv) Bu3P, CH3CN, rt, overnight, 35%; (v) 4.0 M HCl in dioxane, rt, 1 h, quantitative; (vi) EDCÆHCl, HOBt, DMAP,
Et3N, CH2Cl2, rt, 71%; (vii) H2, Pd/C, EtOH, rt, 2 h, 72% and (viii) 4.0 M HCl in dioxane, rt, 5 min, 72% after trituration with Et2O.

7100
A. Torrado / Tetrahedron Letters 47 (2006) 7097–7100
10. For the preparation of the N-Boc (R,S) amino epoxide see:
(a) Reetz, M. T.; Binder, J. Tetrahedron Lett. 1989, 30,
5425–5428; (b) Nq, J. S.; Przybyla, C. A.; Liu, C.; Yen, C.;
Muellner, F. W.; Weyker, C. L. Tetrahedron 1995, 51,
6397–6410; (c) Beaulieu, P. L.; Wernic, D. J. J. Org. Chem.
1996, 61, 3635–3645; (d) Luly, J. A.; Dellaria, J. F.;
Plattner, J. J.; Soderquist, J. L.; Yi, N. J. Org. Chem. 1987,
52, 1487–1492; (e) Sham, H. L.; Betebenner, D. A.; Zhao,
C.; Wideburg, N. E.; Saldivar, A.; Kempf, D. J.; Plattner,
J. J.; Norbeck, D. W. J. Chem. Soc., Chem. Comm. 1993,
13, 1052–1053; (f) Suzuki, T.; Honda, Y.; Izawa, K.
Tetrahedron Lett. 2005, 46, 5811–5814.
starting materials in acceptable yields. Those cores
should provide a new approach to aspartic protease
inhibitors incorporating a number of functional different
groups.
Acknowledgements
´
The author wants to thank Rosario Gonzalez and James
R. McCarthy, for critical reading of this manuscript.
11. Maligres, P. E.; See, M. M.; Askin, D.; Reider, P. J.
Tetrahedron Lett. 1997, 38, 5253–5256.
References and notes
12. Hou, X.-L.; Fan, R.-H.; Dai, L.-X. J. Org. Chem. 2002,
67, 5295–5300.
13. Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron
Lett. 1986, 27, 2099–2102.
1. Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359–
1472.
2. Thompson, L. A.; Tebben, A. J. Annu. Rep. Med. Chem.
2001, 36, 247–256.
3. (a) Beher, D.; Graham, S. L. Exp. Opin. Invest. Drugs
2005, 14, 1385–1409; (b) Thompson, L. A.; Bronson, J. J.;
Zusi, F. C. Curr. Pharm. Des. 2005, 11, 3383–3404; (c)
Wolfe, M. S. J. Med. Chem. 2001, 44, 2039–2060.
4. (a) Bursavich, M. G.; Rich, D. H. J. Med. Chem. 2002, 45,
541–558; (b) Cooper, J. B. Curr. Drug Targets 2002, 3,
155–173; (c) Leung, D.; Abbenante, G.; Fairlie, D. P. J.
Med. Chem. 2000, 43, 305–341.
5. (a) Uchikawa, O.; Aso, K.; Koike, T.; Tarui, N.; Hirai, K.
WO 2004/014843, 2004; (b) Hom, R.; Tucker, J.; John, V.;
Shah, N. WO 2005/095326, 2005.
6. Yang, W.; Lu, W.; Lu, Y.; Zhong, M.; Sun, J.; Thomas, A.
E.; Wilkinson, J. M.; Fucini, R. V.; Lam, M.; Randal, M.;
Shi, X.-P.; Jacobs, J. W.; McDowell, R. S.; Gordon, E.
M.; Ballinger, M. D. J. Med. Chem. 2006, 49, 839–842.
7. Hong, L.; Koelsch, G.; Lin, X.; Wu, S.; Terzyan, S.;
Ghosh, A. K.; Zhang, X. C.; Tang, J. Science 2000, 290,
150–153.
14. Spectral data of by-product 11: MS for C19H23N3O2: 326
(M++H); 1H NMR (CDCl3, 300 MHz) d: 7.4–7.2 (6H, m),
6.9–6.7 (3H, m), 4.52 (2H, s), 4.47 (1H, br s); 3.79 (3H, s),
3.75–3.65 (1H, m), 3.37 (1H, dd, J = 11.7, 2.8 Hz), 3.3–3.2
(1H, m), 3.1–3.0 (2H, m), 2.90 (1H, dd, J = 13.3, 5.6 Hz),
2.69 (1H, dd, J = 13.3, 9.1 Hz).
15. Spectral data of final compounds 10 and 14: Compound
10, MS for C32H42N4O3: 531 (M++H); 1H NMR
(CD3OD, 300 MHz) d: 7.9–7.5 (4H, m); 7.4–7.1 (8H, m),
7.01 (1H, d, J = 8.5 Hz); 4.8–4.6 (1H, m), 4.30 (2H, s),
4.10 (3H, s), 4.1–4.0 (1H, m), 3.9–3.7 (1H, m), 3.4–3.2 (4H,
m), 3.1–2.9 (4H, m), 1.7–1.5 (2H, m), 1.4–1.3 (2H, m), 1.02
(3H, t, J = 6.7 Hz), 0.70 (3H, t, J = 6.7 Hz). Compound
14, MS for C32H42N4O3: 531 (M++H); 1H NMR
(CD3OD, 300 MHz) d: 7.9–7.5 (4H, m); 7.4–7.1 (8H, m),
7.01 (1H, d, J = 8.5 Hz); 4.8–4.7 (1H, m), 4.36 (2H, s),
4.1–3.9 (1H, m), 3.84 (3H, s), 3.8–3.7 (1H, m), 3.6–3.4 (4H,
m), 3.2–3.0 (4H, m), 1.8–1.6 (2H, m), 1.6–1.4 (2H, m), 1.02
(3H, t, J = 6.7 Hz), 0.70 (3H, t, J = 6.7 Hz).
16. Both protecting groups (Cbz and Boc) at the epoxide
could be used to obtain both final compounds ((S)-
aminoethylamine 10 and (R)-aminoethylamine 14) starting
from the appropriate configuration at the epoxide ((S) or
(R)) following Schemes 1 and 3. For instance, the N-Boc
(S,S) amino epoxide is now commercially available and
the synthesis of 10 can be done following the same
synthetic route as described for 14 (Scheme 3).
8. Patel, S.; Vuillard, L.; Cleasby, A.; Murray, C. W.; Yon, J.
J. Mol. Biol. 2004, 343, 407–416.
9. For the preparation of the N-Cbz (S,S) amino epoxide see:
(a) Albeck, A.; Persky, R. Tetrahedron 1994, 50, 6333–
´
6346; (b) Catasu´s, M.; Moyano, A.; Pericas, M.; Riera, A.
Tetrahedron Lett. 1999, 40, 9309–9312; (c) Honda, Y.;
Katayama, S.; Kojima, M.; Suzuki, T.; Kishibata, N.;
Izawa, K. Org. Biomol. Chem. 2004, 2, 2061–2070.