Synthesis of 3-oxoazacyclohept-4-enes by ring-closing metathesis. Application to the synthesis of an inhibitor of cathepsin K

Article abstract of DOI:10.3987/COM-05-S(T)65

The ring-closing metathesis allows the formation of 3-oxoazacyclohept-4-enes from but-3-enamine. By using this methodology, the synthesis of an inhibitor of cathepsin K was achieved in 10 steps from but-3-enamine.

Full text of DOI:10.3987/COM-05-S(T)65

HETEROCYCLES, Vol. 67, No. 2, 2006
549
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 549 - 554. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd August, 2005, Accepted, 11th October, 2005, Published online, 14th October, 2005. COM-05-S(T)65
SYNTHESIS OF 3-OXOAZACYCLOHEPT-4-ENES BY RING-CLOSING
METATHESIS. APPLICATION TO THE SYNTHESIS OF AN INHIBITOR
OF CATHEPSIN K
Catherine Taillier, Thomas Hameury, Véronique Bellosta,*
and Janine Cossy*
Laboratoire de Chimie Organique, associé au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr; veronique.bellosta@espci.fr
Abstract
–
The ring-closing metathesis allows the formation of
3-oxoazacyclohept-4-enes from but-3-enamine. By using this methodology, the
synthesis of an inhibitor of cathepsin K was achieved in 10 steps from
but-3-enamine.
INTRODUCTION†
Seven-membered ring amino compounds are present in a great variety of natural and non-natural products
which possess interesting biological properties. These molecules have stimulated the development of an
array of methods for their synthesis.1 We were particularly interested in the synthesis of
3-oxoazacyclohept-4-enes, as these compounds can be the precursors of the cyclic skeleton of biologically
active compounds such as stemoamide,2 an insecticide, balanol,3 an inhibitor of protein kinase C (PKC) and,
more particularly, azepanone (I)4 which is an inhibitor of the cysteine protease cathepsin K (Figure 1).
Figure 1. Representative biologically active compounds with an azacycloheptane skeleton.
HO
O
O
O
O
H
HO
O
O
O
H
O
N
N
HO
CO2H
H
O
H
O
4
Me
H
N
O
N
N
H
S
N
OH
O
O
H
N
Stemoamide
Balanol
I
This paper is dedicated to Pr. B. M. Trost on the occasion of his 65th birthday.
†

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HETEROCYCLES, Vol. 67, No. 2, 2006
The aim of this study was to identify a general and convenient strategy for the synthesis of functionalized
3-oxoazacyclohept-4-enes of type (A). The access to compounds of type (A) was envisaged by using a
ring-closing metathesis (RCM) applied to 1-(3’-alkenylamino)but-3-en-2-ones of type (B) which should be
obtained from homoallylamines of type (C) (Scheme 1).
Scheme 1. Retrosynthetic analysis of azepinones of type (A).
O
O
RCM
NHR
N
N
R
R
R'
R'
R'
A
B
C
RESULTS AND DISCUSSION
As the ruthenium catalysts, implied in the metathesis reaction, can be poisoned by the presence of
non-protected amino groups, compounds (3-6), in which the amino group was protected with an
electron-withdrawing group, were prepared (Scheme 2).5 The synthesis of compounds (3-5) (when R' = H
and R = Boc, CBz, 2-PyrSO2-) has been accomplished from but-3-en-1-ol (1). The transformation of
but-3-en-1-ol (1) to the corresponding but-3-enamine (2) was achieved by using a Mitsunobu reaction
involving phthalimide. Treatment of 1 with phthalimide (1.1 equiv.) in the presence of DIAD (1.1 equiv.)
and PPh3 (1.1 equiv.) in THF at 0 °C for 3 h and hydrazinolysis of the resulting phthalimido compound
(H2N-NH2, H2O, EtOH, 80 °C) followed by an acidic work-up led to the chlorohydrate of the
but-3-enamine (2) with an overall yield of 96%.6 In order to obtain the protected homoallylamines (3, 4 and
5), the ammonium salt (2) was treated, under basic conditions, with respectively di-tert-butyl dicarbonate
(Et3N, CH2Cl2, rt; 3 = 66% yield), benzoyl chloride (Na2CO3, CH2Cl2, rt; 4 = 71% yield) and
2-pyridinesulfonyl chloride7 (Et3N, CH2Cl2, rt; 5 = 88% yield). The p-toluenesulfonyl protected
homoallylamine (6) (R' = Ph, R = Ts) was prepared from benzaldehyde in two steps. The first step was the
transformation of benzaldehyde to tosyl imine8 (TsNH2, TsNa, HCO2H, H2O, rt) followed by the addition
of allylmagnesium chloride to the tosyl imine (THF, -15 °C) which led to 6 with an overall yield of 56%.
The transformation of but-3-enamines (3-6) to the desired but-3-enaminoenones (11-14) was achieved in
two steps via the stabilized phosphoranes (7-10). These latter compounds were prepared by alkylation of
the amine with triphenylchloroacetonylphosphorane9 under basic conditions (BuLi, THF, rt) in yields
superior to 55%. The obtained phosphoranes (7-10) were then converted to the α-amino enone (11, 12 and
13) by condensation with acetaldehyde in yields superior to 85%, and to the α-amino enones (14) by
condensation with formaldehyde in 62% yield (Table 1). The use of acetaldehyde instead of formaldehyde

HETEROCYCLES, Vol. 67, No. 2, 2006
551
led to substituted terminal alkenes which are less inclined to polymerize during their isolation and
purification.
Scheme 2. Synthesis of the homoallylamines (3-6).
i
ii
NH3 Cl
NHR
R = Boc
R = CBz
OH
3
4
5
1
2
R = (2-Pyr)SO2-
NTs
H
O
H
iii
iv
NHTs
Ph
Ph
Ph
6
Conditions and reagents: (i) 1°- Phthalimide, DIAD, PPh3, THF, 0 °C, 2°-
hydrazine, H2O, EtOH, ∆, then 35% aq HCl, rt, 96% (two steps); (ii) Compound (3):
Boc2O, Et3N, CH2Cl2, rt, 66%; compound (4): CbzCl, Na2CO3, CH2Cl2, rt, 71%;
compound (5): (2-Pyr)SO2Cl, Et3N, CH2Cl2, rt, 88%; (iii) TsNH2, TsNa, HCO2H/H2O,
rt, 60%; (iv) AllylMgCl, THF, -15 °C, 94%.
Table 1. Synthesis of the ω-unsaturated α-amino enones (11-14).
Cl
R
R
O
R
Ph3P
R'CHO
R'
N
P
NHP
PPh3
N
P
BuLi, THF, rt
O
O
3-6
7-10
11-14
P = Boc, R = H, R' = Me
7
74%
11
87%
3
P = CBz, R = H, R' = Me
P = (2-Pyr)SO2-, R = H, R' = Me
P = Ts, R = Ph, R' = H
8
9
90%
94%
57%
12
13
14
85%
94%
62%
4
5
10
6
The obtained ω-unsaturated α-amino enones (11-14) were involved in a RCM reaction and the results are
reported in Table 2. All the reactions were carried out with 2.5 to 5 mol% of the second generation Grubbs
catalyst [(4,5-dihydroIMes)(PCy3)Cl2Ru=CHPh]10 at a concentration of 5×10-3 M in refluxing CH2Cl2 for
12 h. The seven-membered azacyclic compounds (15-18) were obtained in yield superior to 90% (Table 2).
As this methodology was efficient in obtaining 3-oxoazacyclohept-4-enes from homoallylic amines, its
application to the synthesis of a potent azepanone-based inhibitor of the osteoclast-specific cysteine
protease cathepsin K, compound (I), was achieved (Scheme 1).

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HETEROCYCLES, Vol. 67, No. 2, 2006
Table 2. Synthesis of azepinones (15-18).
R
(4,5-dihydroIMes)(PCy3)Cl2Ru=CHPh
O
R'
(2.5-5 mol%)
N
P
O
N
P
CH2Cl2, ∆, 12 h
c = 5 x 10-3 M
R
11-14
15-18
11
P = Boc, R = H, R' = Me
P = Cbz, R = H, R' = Me
15
90%
12
13
16
17
97%
96%
P = (2-Pyr)SO2-, R = H, R' = Me
P = Ts, R = Ph, R' = H
14
18
99%
Two syntheses of I have been disclosed, one non-stereocontrolled synthesis4 leading to I as a mixture of the
two epimers at C-4 which were separated by HPLC and one enantioselective synthesis. 11 The shortest
synthesis was the non-stereocontrolled synthesis which was achieved in 12 steps from allylamine.4 To
perform the enantiomerically enriched synthesis,11 an Evans aldol reaction was used as the key-step and 15
steps were necessary to complete the synthesis from aminoacetaldehyde dimethyl acetal. By using our
methodology, the synthesis of compound (I) as a mixture of the two C-4 epimers was realized in 10 steps
from homoallylamine chlorohydrate. In order to introduce the peptido side-chain, the synthesis of
compound (I) was planed from the α-amino ketone (20) which should be obtained from the previously
synthesized 3-oxoazacyclohept-4-en-one (17) (Scheme 3).
Scheme 3. Retrosynthetic analysis of cathepsin inhibitor (I).
O
O
Cl
H3N
I
N
N
SO2-(2-Pyr)
SO2-(2-Pyr)
20
17
Compound (17) was transformed to the azido compound (19) in two steps. The first step was the formation
of the α-bromoazepanone (18) via the 1,4-addition of an “hydride” generated by the addition of DIBALH
(4 equiv.) in the presence of a cyanocuprate [CuCN (2 equiv.), BuLi (2 equiv.), THF, -50 °C, 2 h] and
activation of the resulting intermediate enolate with MeLi (1 equiv.), in the presence of HMPA (3 equiv.),
(-50 °C, 30 min) to form a more reactive aluminate enolate which can react with bromine (10 equiv., -50 °C
to -20 °C, 1 h) to furnish the α-bromo ketone (18).12,13 Without purification, α-bromo ketone (18) was

HETEROCYCLES, Vol. 67, No. 2, 2006
553
converted to the α-azido ketone (19) in 45% overall yield (from 17) by treatment with NaN3 (NaN3, DMF,
rt). After hydrogenation of 19 in acidic conditions (H2, 10% Pd/C, MeOH/HCl), the resulting chlorohydrate
(20) was condensed with the N-Boc-L-leucine14 (EDCI, HOBT, Et3N, CH2Cl2, rt) to furnish the desired keto
amide (21) in a 51% overall yield (from 19). After cleavage of the N-Boc group (4M HCl in dioxane,
MeOH) and condensation with benzofuran-2-carboxylic acid in the presence of EDCI and HOBt,
compound (I)15 and its epimer (I') were isolated in 52% overall yield ( Scheme 4).
Scheme 4. Synthesis of I.
O
O
Br
Al
O
i
ii
N
N
SO2-(2-Pyr)
SO2-(2-Pyr)
SO2-(2-Pyr)
O
N
SO2-(2-Pyr)
17
18
iii
O
O
O
H
Cl
N
H3N
N3
iv
BocHN
v
O
N
N
N
SO2-(2-Pyr)
SO2-(2-Pyr)
20
21
19
vi, vii
O
O
O
O
H
H
N
N
H
N
N
O
O
H
O
+
O
O
N
N
S
S
O
O
I
I'
N
N
Conditions and reagents: (i) 1°- DIBALH (4 equiv.), CuCN (2 equiv.), BuLi (2 equiv.), THF - 50 °C, 2 h, then 2°-
HMPA (3 equiv.), MeLi (1 equiv.), -50 °C, 30 min; (ii) Br2 (10 equiv.), -50°C to -20 °C, 1 h; (iii) NaN3, DMF (45% from
17); (iv) H2, 10% Pd/C, MeOH/HCl; (v) N-Boc-L-Leucine, EDCI, HOBt, Et3N, CH2Cl2, rt, 51% (two steps); (vi) 4M HCl
in dioxane, MeOH, rt, 2.5 h; (vii) benzofuran-2-carboxylic acid, EDCI, HOBt, Et3N, CH2Cl2, rt, 52% (two steps).
CONCLUSION
By applying a RCM to ω-unsaturated α-amino enones, 3-oxo azacyclohept-4-enes were obtained in good
yields. Furthermore, by using this methodology, we were able to shorten the synthesis of compound (I), an
inhibitor of cathepsin K.

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ACKNOWLEDGEMENTS
One of us (C. T.) thanks the MRES for a grant.
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