Highly efficient synthesis of medium-sized lactams via intramolecular Staudinger-aza-Wittig reaction of ω-azido pentafluorophenyl ester: Synthesis and biological evaluation of LY411575 analogues

Article abstract of DOI:10.1016/j.tetlet.2004.01.087

A highly efficient method for the synthesis of medium-sized lactams based on intramolecular Staudinger-aza-Wittig reaction of ω-azido pentafluorophenyl ester has been developed. A variety of 7-10 membered lactams were synthesized in excellent yields. Appl

Full text of DOI:10.1016/j.tetlet.2004.01.087

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2323–2326
Highly efficient synthesis of medium-sized lactams via
intramolecular Staudinger–aza-Wittig reaction of x-azido
pentafluorophenyl ester: synthesis and biological evaluation
of LY411575 analogues
Haruhiko Fuwa,* Yumiko Okamura, Yuichi Morohashi, Taisuke Tomita,
Takeshi Iwatsubo, Toshiyuki Kan, Tohru Fukuyama and Hideaki Natsugari*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 25 December 2003; revised 13 January 2004; accepted 21 January 2004
Abstract—A highly efficient method for the synthesis of medium-sized lactams based on intramolecular Staudinger–aza-Wittig
reaction of x-azido pentafluorophenyl ester has been developed. A variety of 7–10 membered lactams were synthesized in excellent
yields. Application of the method to the synthesis of analogues of a potent c-secretase inhibitor LY411575 and their biological
evaluation are also described.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Alzheimerꢀs disease (AD), a major dementing neuro-
degenerative disorder, is currently a serious public
health problem in aging society and over four millions
of victims are annually reported in US alone.1 The exact
pathogenic mechanism of AD is still unveiled, though
many factors have been suggested on the basis of
pathological and pharmacological studies. AD is hall-
marked clinically by progressive cognitive decline and
pathologically by deposition of extracellular proteina-
ceous plaques composed of 40–42amino acid amyloid- b
(Ab) peptides in celebral cortices. Since Ab is produced
from amyloid precursor protein (APP) through proteo-
lytic processing by two types of membrane associated
aspartic proteases termed b- and c-secretase, inhibition
of ꢁamyloidogenicꢀ APP processing by these secretases
are predicted to be intriguing targets toward prevention
and cure of AD.
date (Fig. 1).2 During the course of structure–activity
relationship (SAR) studies on 1, practical synthesis of
medium-sized lactams via lactamization of the corre-
sponding x-amino acids turned out to be rather chal-
lenging than anticipated. An inherent problem
associated with such conventional approach is the dif-
ficulty of handling and purification of x-amino acid, due
primarily to its zwitterionic nature. Very recently, we
found that the 13-membered lactam ring could be con-
structed in an efficient manner based on intramolecular
Staudinger–aza-Wittig reaction3–5 of x-azido pentaflu-
orophenyl (pfp) ester (Scheme 1).6 Thus, treatment of
x-azido pfp ester 2 with phosphine produces imino-
phosphorane 3, which undergoes intramolecular aza-
Wittig reaction to give iminoether 4. Subsequent
hydrolysis affords lactam ring 5. It occurred to us that
this approach might serve as a general strategy for the
construction of synthetically challenging medium-sized
lactam rings. Herein we describe a highly efficient and
The c-secretase inhibitor LY411575 (1, IC50<1 nM in
HEK cells), discovered by researchers at Eli Lilly, is one
of the most potent c-secretase inhibitors reported to
Keywords: Medium-sized lactams; Staudinger reaction; Aza-Wittig
reaction; c-Secretase inhibitor; Structure–activity relationship.
* Corresponding authors. Tel.: +81-3-5841-4775; fax: +81-3-5841-
4775; e-mail addresses: hfuwa@mol.f.u-tokyo.ac.jp; natsu@mol.
f.u-tokyo.ac.jp
Figure 1. Structure of LY411575 (1).
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.087

2324
H. Fuwa et al. / Tetrahedron Letters 45 (2004) 2323–2326
Table 1. Construction of medium-sized rings via Staudinger–aza-
Wittig strategya
N
PR3
N3
R3P
[Staudinger]
CO2pfp
CO2pfp
Entry
x-Azido pfp ester
Product
Yield
2
5
3
X
X
[aza-Wittig]
Y
Y
N3
NH
N
NH
O
H2O
pfpO2C
O
[hydrolysis]
Opfp
1
11: X ¼ H, Y ¼ H
17: X ¼ H, Y ¼ H
76
81
99
2b
3b
12: X ¼ H, Y ¼ OBn
13: X ¼ OBn, Y ¼ H
18: X ¼ H, Y ¼ OBn
19: X ¼ OBn, Y ¼ H
4
Scheme 1. Reaction pathway of intramolecular Staudinger–aza-Wittig
reaction of x-azido pentafluorophenyl (pfp) ester.
4
93
pfpO2C
N3
N
14
20
H
O
convenient method for the synthesis of medium-sized
lactams via intramolecular Staudinger–aza-Wittig reac-
tion of x-azido pfp ester, and its application to the
generation and biological evaluation of LY411575
analogues.
5
45
82
6c
N3
CO2pfp
HN
15
21
22
O
Synthesis of a representative x-azido pfp ester 11 is
outlined in Scheme 2. The biaryl moiety of 11 was
constructed via borylation–Suzuki–Miyaura coupling
protocol.7;8 Thus, pinacol borylation of 2-bromoaniline
6 followed by in situ Suzuki–Miyaura coupling with aryl
iodide 7 in the presence of Ba(OH)2Æ8H2O afforded
coupling product 88b in quantitative yield. Diazotization
of 8 under standard conditions followed by treatment
with NaN3 gave azide 9. Reduction of the nitrile group
within 9 and NaClO2 oxidation of the derived aldehyde
gave rise to carboxylic acid 10 in 57% yield (three steps).
Coupling of 10 with pentafluorophenol then afforded 11.
In general, x-azido pfp esters are stable enough for
standard aqueous workup, flash chromatography and
storage. Thus, we did not experience any difficulties
upon handling and purification of 11–16 (Table 1).
7d
85
N3
HN
O
CO2pfp
16
a All reactions were performed using n-Bu3P (5 equiv) in toluene
(10 mM) at rt unless otherwise noted.
b THF (10 mM), rt.
c Toluene (10 mM), 100 ꢁC.
d Toluene (3 mM), 100 ꢁC.
on our preliminary investigation, we employed n-Bu3P
(5 equiv) as a reagent and the reactions were carried out
under high-dilution conditions. Cyclization of x-azido
pfp esters (11–14) proceeded smoothly at room tem-
perature to give the corresponding 7- and 8-membered
lactams 17–20 in high yields (entries 1–4). On the other
hand, formation of much challenging larger 9- and
10-membered lactams called for elevated temperature
conditions (toluene, 100 ꢁC) to attain satisfactory yields
(entries 5–7).9
To validate the scope and generality of intramolecular
Staudinger–aza-Wittig reaction of x-azido pfp ester, its
application to a variety of substrates has been per-
formed and the results are summarized in Table 1. Based
With various medium-sized lactams in hand, we next
focused our attention to the synthesis of LY411575
analogues (Scheme 3). N-methylation of lactams (17–20)
were followed by treatment with KHMDS in the pres-
ence of n-BuONO, and subsequent reduction of the
derived oximes with Zn/TFA10 afforded amines 23a–d,
respectively. Condensation of 23a–d with Boc-protected
I
CN
NH2
CN
a
b
+
NH2
Br
6
8
7
L
-alanine (EDC, HOBt), deprotection of the Boc group,
c,d
e
N3
N3
N3
and a second EDC-mediated coupling with 3,5-difluoro-
phenylacetic acid furnished the analogues 24a,2b 24b–d
in good yields. Cleavage of the benzyl ether of 24b,c
under catalytic transfer hydrogenation conditions11
furnished phenolic analogues 25a,b without touching
aryl fluorines. Alkylation of the liberated phenol with
4-(bromomethyl)benzophenone12 or CH3I gave rise to
benzophenone analogues 26a,b or methyl ether ana-
logues 27a,b, respectively.
CN
CO2pfp
CO2H
10
9
11
Scheme 2. Reagents and conditions: (a) 6, pinacolborane, Et3N,
Pd(OAc)2, 2-(dicyclohexylphosphino)biphenyl, dioxane, 80 ꢁC then 7,
Ba(OH)2Æ8H2O, H2O, dioxane, 100 ꢁC, quant; (b) NaNO2, aq. HCl,
THF, 0 ꢁC then NaN3, 0 ꢁC fi rt; (c) DIBALH, CH2Cl2, )78 ꢁC; (d)
NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH/H2O (4:1), 0 ꢁC fi rt,
57% for three steps; (h) Pentafluorophenol, DCC, CH2Cl2, rt, quant.

H. Fuwa et al. / Tetrahedron Letters 45 (2004) 2323–2326
2325
Table 2. Inhibition of Ab40 and Ab42productions by LY411575
X
X
analogues in vitro
Compound
Y
Y
IC50 (nM)
a-c
d-f
Ab40
5.214
7.5
Ab42
n
n
H2N
N
24a
24b
24c
24d
25a
25b
26a
26b
27a
27b
N
H
Me
O
O
50
8
2
17: X = Y = H, n = 0
23a: X = Y = H, n = 0
217
14
2
381
15
0
18: X = H, Y = OBn, n = 0
19: X = OBn, Y = H, n = 0
20: X = Y = H, n = 1
23b: X = H, Y = OBn, n = 0
23c: X = OBn, Y = H, n = 0
23d: X = Y = H, n = 1
37
246
18
2
51
218
20
7
X
13
Y
14
O
H
g
F
N
n
N
H
N
Me
O
Me
O
F
24a: X = Y = H, n = 0
same concentrations. Although incorporation of a bulky
benzophenonemethyl (p-benzoylbenzyl) group at the
C14 position was tolerated as analogue 26a retained
potency, analogue 26b suffered a decrease in its potency
(ca. 47-fold less active for Ab40 inhibition). However,
both methyl ether analogues 27a,b retained potent
activity. Based on these results, it can be concluded that
the incorporation of a substituent at the C14 position is
well tolerated but the modification of the C13 is limited
to a certain extent.
24b: X = H, Y = OBn, n = 0
24c: X = OBn, Y = H, n = 0
24d: X = Y = H, n = 1
X
13
Y
14
O
H
h or i
F
N
N
N
H
Me
O
O
Me
F
25a: X = H, Y = OH
25b: X = OH, Y = H
X
13
As demonstrated in the synthesis of analogues 26–27, it
is worthy to note that diverse alkyl groups could be
selectively attached to the phenol group within ana-
logues 25a,b. Furthermore, in principle, use of CT3I
instead of CH3I in this alkylation process could furnish
potent radioligands (CT3)-27a,b. Thus, although phe-
nolic analogues 25a,b themselves are potent c-secretase
inhibitors, they are also expected to serve as promising
precursors for further elaboration of structural variants
and for the generation of photoaffinity probes16 and
radioligands, useful for biological studies on c-secretase.
Y
14
O
H
F
N
N
N
Me
H
O
O
Me
F
26a: X = H, Y = OCH2C6H4-p-COPh
26b: X = OCH2C6H4-p-COPh, Y = H
27a: X = H, Y = OMe
27b: X = OMe, Y = H
Scheme 3. Reagents and conditions: (a) CH3I, NaH, DMF, 0 ꢁC fi rt;
(b) n-BuONO, KHMDS, THF, 0 ꢁC; (c) Zn, TFA/CH2Cl2 (1:4), rt,
90% (23a), 86% (23b), 88% (23c), 77% (23d) for three steps; (d) Boc-
L
-
In summary, an intramolecular Staudinger–aza-Wittig
reaction of x-azido pfp ester has successfully been
applied to the construction of 7–10 membered lactams,
demonstrating the generality and efficiency of the pres-
ent tactic for the synthesis of medium-sized lactams. Its
application to the synthesis of LY411575 analogues has
also been performed, leading to the generation of new
c-secretase inhibitors. According to the present SAR
studies, efforts toward design and synthesis of photo-
affinity probes based on 1 and their application to bio-
chemical studies on c-secretase are currently underway
in our laboratories and will be reported in due course.
Ala, EDC, HOBt, NMM, THF, 0 ꢁC fi rt; (e) TFA, CH2Cl2, rt; (f) 3,5-
Difluorophenylacetic acid, EDC, HOBt, NMM, THF, 0 ꢁC fi rt, 83%
(24a), 86% (24b), 83% (24c), 80% (24d) for three steps; (g) 20%
Pd(OH)2/C, cyclohexene/EtOH (1:2), reflux, quant (25a), quant (25b);
(h) 4-(Bromomethyl)benzophenone, K2CO3, DMF, 60 ꢁC, 84% (26a),
quant (26b); (i) CH3I, K2CO3, DMF, 60 ꢁC, 73% (27a), 62% (27b).
The ability of analogues 24–27 to inhibit Ab formation
was evaluated by in vitro assay using recombinant C-
terminal fragment of APP as a substrate (Table 2).13;14
Analogues 24a,b showed excellent inhibitory activity for
Ab40 and Ab42productions at low concentrations,
while analogue 24c, in which the benzyloxy group was
attached at the C13 position,15 displayed Ab40 pro-
duction inhibition to a lower extent (ca. 5-fold lower
than that of 24a). Ring-expanded analogue 24d was
found to be approximately 42-fold less active for Ab40
inhibition, suggesting the importance of the ring size of
the dibenzolactam moiety. Phenolic analogues 25a,b
showed potent activity. Interestingly, production of
both Ab40 and Ab42peptides were inhibited at almost
Acknowledgements
This work was financially supported in part by a Grant
for the 21st Century COE Program from Ministry of
Education, Culture, Sports, Science and Technology
(MEXT). Continuous support by Takeda Chemical
Industries, Ltd is gratefully acknowledged.

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H. Fuwa et al. / Tetrahedron Letters 45 (2004) 2323–2326
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