Asymmetric synthesis of a potent azepanone-based inhibitor of the cysteine protease cathepsin K

Article abstract of DOI:10.1016/j.tetlet.2005.02.145

In this account we detail the asymmetric synthesis of 1, a potent azepanone-based inhibitor of cathepsin K (K_i = 0.16 nM), which has been shown to inhibit the production of biomarkers of bone resorption in monkeys. The key steps in the synthesi

Full text of DOI:10.1016/j.tetlet.2005.02.145

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2799–2801
Asymmetric synthesis of a potent azepanone-based inhibitor of
the cysteine protease cathepsin K
Robert E. Lee Trout and Robert W. Marquis*
Department of Medicinal Chemistry, Microbial, Musculoskeletal and Proliferative Diseases, GlaxoSmithKline,
Collegeville, PA 19426, USA
Received 3 November 2004; revised 23 February 2005; accepted 24 February 2005
Abstract—In this account we detail the asymmetric synthesis of 1, a potent azepanone-based inhibitor of cathepsin K
(Ki = 0.16 nM), which has been shown to inhibit the production of biomarkers of bone resorption in monkeys. The key steps in
the synthesis sequence were the utility of the Evans aldol reaction coupled with the ring closing olefin metatheses to assemble
the azepanone core contained within 1.
Ó 2005 Elsevier Ltd. All rights reserved.
The papain superfamily of cysteine proteases is a highly
homologous class of enzymes whose members mediate a
diverse array of biological processes in both normal cell
homeostasis and the pathophysiology of disease.1 We
have described recently the design, synthesis, and phar-
macological characterization of 1 (Fig. 1), a potent
azepanone-based inhibitor of the osteoclast-specific cys-
teine protease cathepsin K.2 The racemic synthesis of
this azepanone inhibitor template relied on a final stage
HPLC separation of the C-4 diastereomers to provide
analogs 1 and 2. Azepanone 1, which contains the C4-
S stereochemistry, is a 0.16 nM inhibitor of cathepsin
K while the corresponding C4-R diastereomer 1 was 1/
6000th as potent (Ki,app = 980 nM).
eral asymmetric synthesis routes in which this chiral
center would be controlled throughout were investi-
gated. From a retrosynthesis perspective, it was desir-
able to also control the regiochemistry of the amino
alcohol installation, a feature only partially reduced to
practice in the original synthesis of 1. As shown in
Scheme 1, inhibitor 1 is readily derived from (3R,4S)-
4-amino-1-(pyridine-2-sulfonyl)-azepan-3-ol (3). In race-
mic form we have utilized this intermediate as a linchpin
building block for the synthesis of a variety of cysteine
protease inhibitors, thereby making an asymmetric syn-
thesis of this template all the more desirable. Amino
alcohol 3 was envisioned to derive from the cyclic aldol
adduct 4 via Curtius rearrangement. The acyclic diene 5
would serve as a precursor to formation of the azepine 4
via ring closing olefin metatheses3 and would be assem-
bled via aldol condensation of aldehyde 7 with the chiral
Having established the importance of the C4 stereocen-
ter of azepanone 1 in determining inhibitor potency sev-
O
O
O
O
H
N
H
N
(R)
(S)
N
H
N
H
O
O
O
O
N
S
O
O
N
S
O
O
N
N
2
1
Figure 1. Azepanone-based inhibitors of cathepsin K.
Keywords: Asymmetric synthesis; Aldol; Ring closing olefin metatheses.
*
Corresponding author. Tel.: +1 6109177368; fax: +1 6109176020; e-mail: robert_w_marquis@gsk.com
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.145

2800
R. E. Lee Trout, R. W. Marquis / Tetrahedron Letters 46 (2005) 2799–2801
OH
O
OH
O
O
H2N
H
N
O
HO
N
H
O
N
O
S
N
O
O
N
S
S
O
N
O
O
N
N
1
3
4
O
O
O
OH
O
O
N
Xc
O
O
+
N
S
N
S
O
N
O
N
5
6
7
Scheme 1. Retrosynthesis of azepanone 1.
crotonate imide 6.4 The high level of stereocontrol
imparted by Evans aldol reaction would be utilized to
install the C4-S stereocenter requisite in 1.
closing olefin metatheses catalyst cleanly effected aze-
pene formation to provide 11 in 75% yield.6 Hydrogena-
tion of 11 under standard conditions (10% Pd–C,
CH3OH, H2) followed by hydrolysis of the chiral auxil-
iary gave azepanol 4. Treatment of 4 with diphenylphos-
The preparation of aldehyde 7 is described in Scheme 2.
Treatment of aminoacetaldehyde dimethyl acetal (8)
with freshly prepared 2-pyridinesulfonyl chloride pro-
vided sulfonamide 9 in 88% yield. Deprotonation of 9
with sodium tert-pentoxide in DMF followed by
quenching this mixture with allyl bromide provided 10
in 51% yield. Removal of the dimethylacetal protecting
group under acidic conditions then provided aldehyde
7 in 51% yield.
phoryl azide effected the Curtius rearrangement,7
a
process known to proceed with retention of configura-
tion,8 to provide the cyclic urethane 12 in 61% yield.9
The 8.55 Hz coupling constant between H3 and H4 in
the 1H NMR of 12 is consistent with the desired cis ring
fusion and suggests that the fidelity of the critical C4 ste-
reocenter was maintained during the Curtius rearrange-
ment. Differential NOE experiments further confirmed
the cis relationship of H3 and H4. Initial attempts to
saponify the cyclic urethane of 12 to produce directly
amino alcohol 3 were low yielding. The vagaries of this
transformation were rectified upon treatment of 12 with
di-tert-butyl dicarbonate to form the intermediate N-
Boc cyclic urethane, which was saponified with cesium
carbonate in methanol and water to give the N-Boc pro-
tected amino alcohol (not shown).10 Removal of the N-
Boc carbamate under acidic conditions provided (3R,
4S)-4-amino-1-(pyridine-2-sulfonyl)-azepan-3-ol (3) as
the hydrochloride salt.
As detailed in Scheme 3 assembly of the azepine ring
system began with the aldol condensation of aldehyde
7 with acrylate 6 utilizing the procedure developed by
Evans and co-workers to provide the diene 5 in 68%
yield.4,5 Based upon the amply precedented nature of
this transformation we have, at this point, assumed that
the product 5 possesses the 3S,4S absolute stereochem-
istry. Treatment of 5 with the Grubbs bis(tricyclohexyl-
phosphine)benzylidineruthenium(IV) dichloride ring
Conversion of amino alcohol 3 to azepanone 1 was
straightforward and is shown in Scheme 4. Acylation
of 3 with N-Boc-leucine in the presence of HOBt and
EDC followed by removal of the N-Boc carbamate pro-
vided the amine hydrochloride 13. Acylation of 13 with
benzofuran-2-carboxylic acid followed by Dess–Martin
periodinane oxidation gave the chiral azepanone 1 in
95% yield.11
O
O
a
b
O
O
O
N
H
S
NH2
O
N
8
9
O
O
In this communication the asymmetric synthesis of the
potent azepanone-based cathepsin K inhibitor 1 has
been detailed. The stereocontrol imparted by the Evans
aldol reaction combined with ring closing olefin metath-
eses for the construction of the 7-membered ring aze-
pane were critical transformations in the synthesis. A
key intermediate of this synthesis sequence is (3R,4S)-
4-amino-1-(pyridine-2-sulfonyl)-azepan-3-ol (3). The
utility of 3 in the asymmetric construction of inhibitors
c
O
O
O
N
N
S
S
O
O
N
N
10
7
Scheme 2. Reagents and conditions: (a) 2-pyridinesulfonyl chloride,
aqueous satd NaHCO3, CH2Cl2, 88%; (b) Na-t-pentoxide, DMF, allyl
bromide, 51%; (c) 3 M HCl/dioxane, THF, 51%.

R. E. Lee Trout, R. W. Marquis / Tetrahedron Letters 46 (2005) 2799–2801
2801
O
OH
O
OH
O
Xc
Xc
a
O
b
O
N
N
Xc
S
S
O
O
N
N
11
6
5
O
OH
O
OH
O
H3
H2N
HCl
e
c-d
HN
H4
f-h
HO
O
O
S
O
O
N
N
N
S
S
O
N
O
N
N
3
12
4
Scheme 3. Reagents and conditions: (a) n-Bu2BOTf, TEA, CH2Cl2, 7, 68%; (b) bis(tricyclohexylphosphine)benzylidineruthenium(IV) dichloride,
CH2Cl2, reflux, 75%; (c) 10% Pd–C, CH3OH, H2, 100%; (d) LiOH, 30% H2O2, THF, H2O, ꢁ10 °C, 89%; (e) (PhO)2P(O)N3, TEA, toluene, reflux,
61%; (f) Boc2O, TEA, DMAP, THF, 92%; (g) Cs2CO3, CH3OH, 66%; (h) 4 N HCl/dioxane, CH3OH, 100%.
3. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
4450; Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem.
Res. 1995, 25, 446–452.
4. Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L.
Tetrahedron Lett. 1986, 27, 4957–4960.
OH
OH
H
N
H2N
a-b
O
H2N
HCl
O
N
N
S
O
S
5. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83–
91.
O
N
O
N
6. Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem.
Soc. 1993, 115, 9856–9857; Nguyen, S. T.; Grubbs, R. H.;
Ziller, J. W. J. Am. Chem. Soc. 1993, 115, 9858–9859.
7. Shiori, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203–6205.
3
13
O
O
H
N
c-d
N
O
8. Campbell, A.; Kenyon, J. J. Chem. Soc. 1946, 25.
23
9. Characterization data for cyclic urethane 12: ½aꢀD ꢁ7.2 (c
H
N
O
O
S
O
N
0.68, CHCl3); IR (CHCl3) 3430, 1770 (s), 1360 (m), 1210
;
(s) cmꢁ1 1H NMR (400 MHz, CDCl3) d 8.70 (d,
J = 4.71 Hz, 1H), 7.97 (m, 1H), 7.92 (dd, J = 7.89,
1.65Hz, 1H), 7.52 (ddd, J = 7.12, 4.90, 1.67 Hz, 1H),
6.08 (s, 1H), 4.99 (ddd, J = 10.6, 8.49, 5.30 Hz, 1H), 4.18
(dd, J = 14.8, 5.11 Hz, 1H), 4.06 (td, J = 9.40, 2.70 Hz,
1H), 3.97 (d, J = 13.6 Hz, 1H), 3.18 (dd, J = 14.8, 10.6 Hz,
1H), 2.97 (t, J = 12.4 Hz, 1H), 1.87 (m, 3H), 1.68 (m, 1H);
13C NMR (125MHz, CDCl 3) d 158.3, 157.2, 150.1, 138.1,
126.8, 122.5, 77.0, 55.7, 52.3, 49.7, 30.4, 26.9; MS (ESI)
m/z 298.0 (M+H)+.
1
Scheme 4. Reagents and conditions: (a) N-Boc-leucine, EDC, HOBt,
TEA, CH2Cl2, 72%; (b) 4 N HCl/dioxane, CH3OH; (c) benzofuran-2-
carboxylic acid, EDC, HOBt, TEA, CH2Cl2 61% for two steps; (d)
Dess–Martin periodinane, CH2Cl2, 95%.
of other cysteine proteases of the papain superfamily
will be detailed in subsequent publications.
10. Ishizuka, T.; Kuieda, T. Tetrahedron Lett. 1987, 28, 4185–
4188.
11. Characterization data for azepanone 1: Mp 179–181 °C
23
(amorphous solid); ½aꢀD +49 (c 1.00, CHCl3); IR (CHCl3)
;
1210 (s) cmꢁ1 1H NMR (400 MHz, CDCl3) d 8.72 (d,
References and notes
3410 (m), 1720 (m), 1660 (s), 1650 (s), 1500 (s), 1340 (s),
1. (a) McKerrow, J. H.; James, M. N. G. Perspect. Drug
Discovery Des. 1996, 6, 1–125; (b) Chapman, H. A.; Riese,
R. J.; Shi, G.-P. Annu. Rev. Physiol. 1997, 59, 63–88.
2. Marquis, R. W.; Ru, Y.; LoCastro, S. M.; Zeng, J.;
Yamashita, D. S.; Oh, H.-J.; Erhard, K. F.; Davis, L. D.;
Tomaszek, T. A.; Tew, D.; Salyers, K.; Proksch, J.; Ward,
K.; Smith, B.; Levy, M.; Cummings, M. D.; Haltiwanger,
R. C.; Trescher, G.; Wang, B.; Hemling, M. E.; Quinn, C.
J.; Cheng, H.-Y.; Lin, F.; Smith, W. W.; Janson, C. A.;
Zhao, B.; McQueney, M. S.; DÕAlessio, K.; Lee, C.-P.;
Marzulli, A.; Dodds, R. A.; Blake, S.; Hwang, S.-M;
James, I. E.; Gress, C. J.; Bradley, B. R.; Lark, M. W.;
Gowen, M.; Veber, D. F. J. Med. Chem. 2001, 44, 1380–
1395.
J = 4.74 Hz, 1H), 8.00 (d, J = 7.81 Hz, 1H), 7.95(td,
J = 7.59, 1.71 Hz, 1H), 7.68 (d, J = 7.25Hz, 1H), 7.54 (m,
2H), 7.49 (d, J = 0.93 Hz, 1H), 7.44 (ddd, J = 8.42, 7.20,
1.23 Hz, 1H), 7.31 (td, J = 7.54, 0.90 Hz, 1H), 7.11 (d,
J = 8.49 Hz, 1H), 6.99 (d, J = 6.67 Hz, 1H), 5.18 (ddd,
J = 11.3, 6.55, 2.84 Hz, 1H), 4.81 (dd, J = 19.1, 1.75Hz,
1H), 4.73 (m, 1H), 4.13 (m, 1H), 3.87 (d, J = 18.9 Hz, 1H),
2.71 (ddd, J = 14.3, 12.1, 2.30 Hz, 1H), 2.26 (m, 1H), 2.16
(m, 1H), 1.85(m, 1H), 1.75(m, 2H), 1.65(br s, 1H), 1.46
(m, 1H), 1.03 (d, J = 1.63 Hz, 3H), 1.01 (d, J = 1.71 Hz,
3H); 13C NMR (125MHz, CDCl 3) d 205.7, 170.6, 158.6,
157.2, 154.8, 150.2, 148.1, 138.2, 127.5, 127.1, 127.0, 123.7,
122.7, 122.5, 111.9, 110.9, 58.7, 57.9, 51.5, 51.4, 41.9, 31.7,
28.3, 24.8, 22.9, 22.1; MS (ESI) m/z 527.4 (M+H)+.