Diethylaminosulfur trifluoride-mediated intramolecular cyclization of 2-hydroxycycloalkylureas to fused bicyclic aminooxazoline compounds and evaluation of their biochemical activity against β-secretase-1 (BACE-1)

Article abstract of DOI:10.1016/j.tetlet.2013.07.136

A series of unique bicyclic aminooxazolines were synthesized and found to exhibit micromolar inhibition of β-secretase-1 (BACE-1). The aminooxazolines were procured by an intramolecular diethylaminosulfur trifluoride (DAST)-mediated ring closure of a benz

Full text of DOI:10.1016/j.tetlet.2013.07.136

Tetrahedron Letters 54 (2013) 5802–5807
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diethylaminosulfur trifluoride-mediated intramolecular cyclization
of 2-hydroxycycloalkylureas to fused bicyclic aminooxazoline
compounds and evaluation of their biochemical activity against
b-secretase-1 (BACE-1)
Malcolm P. Huestis a, Wendy Liu a, Matthew Volgraf a, Hans E. Purkey a, Christine Yu b, Weiru Wang b,
Darin Smith c, Guy Vigers c, Darrin Dutcher d, Kevin W. Hunt e, Michael Siu a,
⇑
a Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
b Structural Biology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA
c Structural Biology, Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA
d Enzymology and HTS, Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA
e Medicinal Chemistry, Array BioPharma, 3200 Walnut Street, Boulder, CO 80301, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of unique bicyclic aminooxazolines were synthesized and found to exhibit micromolar inhibition
of b-secretase-1 (BACE-1). The aminooxazolines were procured by an intramolecular diethylaminosulfur
trifluoride (DAST)-mediated ring closure of a benzylic urea onto a secondary alcohol.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 9 July 2013
Revised 19 July 2013
Accepted 25 July 2013
Available online 6 August 2013
Keywords:
Alzheimer’s disease
BACE
Aminooxazolines
b-Secretase
Oxazolines
Alzheimer’s disease is one of the most serious neurodegenera-
tive diseases afflicting modern society.1 The slow transition of pa-
tients from loss of memory to dementia and death not only incurs a
great emotional cost to families, but also carries severe financial
burdens, primarily due to long-term healthcare requirements.2
Decades of research in the pharmaceutical sector has yielded no
disease modifying drugs that halt the progression of the disease,
and so the quest for new protein targets and a deeper biological
understanding of the disease state continues.3
off-target effects with Cathepsin D, promising chemical matter is
currently in human trials.6 Advances in identifying potent amino-
heterocyclic functional groups that interact with the catalytic aspar-
tic acid residues of BACE-1 have allowed for the reduction of tPSA,
MW, and rotatable bonds of inhibitors, resulting in compounds with
good blood–brain barrier penetration (Fig. 1). In addition to the
aspartic acid binding groups, additional potency can be achieved
by aromatic side chains that extend into the P20 and P3 pockets of
the active site.7
Currently, one of the lead protein targets for the treatment of
Alzheimer’s disease is b-secretase-1 (BACE-1).4 Over the last decade,
considerable resources within the drug discovery industry have
been devoted to uncovering small molecule inhibitors of BACE-1.
The initial wave of highly potent peptidomimetic BACE-1 inhibitors
suffered from poor brain penetration and permeability due to high
topological polar surface area (tPSA), molecular weight (MW), and
rotatable bond count.5 Although many recent efforts have still been
confounded by poor blood–brain barrier permeability, as well as
H
O
N
S
H
O
CH3
NH2
N
N
O
NH2
Ar
N
F
F
NH
N
R
F
⇑
Corresponding author. Tel.: +1 650 467 7764.
E-mail address: siu.michael@gene.com (M. Siu).
Figure 1. Literature bicyclic aminoheterocycle BACE-1 inhibitors.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.136

M. P. Huestis et al. / Tetrahedron Letters 54 (2013) 5802–5807
5803
H
which resulted in the synthesis of compounds possessing micro-
molar inhibition of BACE-1. These synthetic efforts are detailed
here and represent a useful extension of the Lellouche–Wipf–Wil-
liams synthesis of oxazolines to fused systems possessing aryl
functionality at the ring junction.9
O
N
O
X
Y
H3C
H3C
To P2'
NH2
NH2
N
F
Given the dihydrothiazine10 and dihydropyrimidinone11 struc-
tural classes of BACE-1 inhibitors in the literature (Fig. 1), we
designed a novel bicyclic aminooxazoline scaffold type (Fig. 2).12
The choice of an aminooxazoline headgroup was based on previ-
ously reported results for tetrahydronaphthalene-based spirocyclic
compounds (Fig. 2) in which this headgroup displayed the best
combination of moderate efflux properties and potency.8 These
bicyclic aminooxazoline targets allow for extension into the P3
pocket (R = Ar), and also provide a vector for aryl or aliphatic
substituents toward P20 (X or Y = N-Ar, N-aliphatic). In order to
maintain reasonable physical properties, we initially aimed to oc-
cupy either P3 or P20, but not both pockets simultaneously. Specif-
N
N
R
In P1
To P3
X = N-Ar Y = CH2 R = H
X = CH2 Y = N-Ar R = H
Y = CH2 R = Ar
X = CH2 Y = CH2 R = Ar
BACE1 IC50 = 4.9 µM
MDR1 BA/AB = 6
X = O
Figure 2. Bicyclic aminooxazoline targets.
While our BACE-1 program has focused primarily on the devel-
opment of compounds possessing spirocyclic headgroups (Fig. 2),8
we briefly investigated the fused heterocyclic headgroup strategy,
H
H
O
O
N
X
Y
OH
X
Y
O
X
Y
O
NH2
DAST
N
H
N
H
NH2
isocyanate
addition
Du Bois
C-H amination
F
F
F
R
R
R
B
A
C
hydroboration-
oxidation
O
Hassner method
I
O
OH
N3
X
Y
X
Y
O
X
Y
epoxide
opening
NH2
H
N
H
NH2
ammonia
F
F
F
R
R
R
X
Y
Ar
D
Figure 3. Retrosynthetic analysis of bicyclic aminooxazolines.
O
NH2
OH
O
O
O
O
I
Br
F
iii)
O
Rh-cat.
ii)
i)
no reaction
Br
F
Br
F
CH3
O
Br
F
+
or degradation
B
O
CH3
CH3
1.5 equiv
H3C
1
(
)-2
(
)-3
75%
23%
35%
(both isomers)
O
O
NH2
F
HN
H
O
O
F
BocN
BocN
F
BocN
F
iv)
H
BocN
ii),iii)
Br
i)
O
CH3
+
B
F
(
)-6
71%
undesired
cyclization mode
CH3
CH3
F
F
F
O
1.5 equiv.
4
78%
(
)-5
H3C
64% over 2 steps
Scheme 1. Reagents and conditions: (i) 5 mol % Pd(dppf)Cl2, 3 equiv K2CO3, 4:1 dioxane/H2O, 80 °C; (ii) (a) 2 equiv BH3.DMS, THF, 0 °C to rt, (b) aq NaOH, H2O2, 0–45 °C; (iii)
(a) 5 equiv Cl3C(CO)NCO, CH2Cl2, (b) 6 equiv K2CO3, MeOH; (iv) 10 mol % Rh2(OAc)4, 1.4 equiv PhI(OAc)2, 2.3 equiv MgO, CH2Cl2, 40 °C.

5804
M. P. Huestis et al. / Tetrahedron Letters 54 (2013) 5802–5807
H
H
F
OH
N3
O
N
O
N
BocN
F
HN
F
BocN
F
BocN
F
BocN
F
O
NH2
NH2
ii)
iii), iv), v)
i)
vi)
F
4
F
F
F
( )-9
56% (3 steps)
( )-8
56%
( )-7
74%
( )-10
78%
O
O
CH3
B
O
H
OH
O
O
CH3
CH3
O
O
O
O
ix), iv), v)
NH2
vii)
viii)
i)
H3C
+
Br
N3
N
I
Br
Br
Br
Br
11
( )-12
( )-13
( )-14
1.5 equiv
BocN
43%
90%
78%
64% (3 steps)
CH3
H3C
H3C
O
B
F
O
F
i)
x)
BocN
vii)
H3C
O
+
BocN
F
BocN
O
OTf
F
F
15
1.1 equiv
16
67%
( )-17
F
50%
73%
ii)
H
H
F
OH
N3
OH
O
N
O
O
NH2
NH2
vi)
v)
BocN
F
iii), iv)
BocN
HN
F
BocN
F
N
N
H
NH2
F
F
F
F
( )-19
84% (2 steps)
( )-21
92%
( )-20
41%
( )-18
23%
Br
Br
OH
N3
i)
xiii)
xi)
xii)
OH
O
+
Br
O
1.55 equiv
Br
Br
Br
22
90%
23
75%
( )-24
90%
( )-25
53%
xiv)
H
OTBS
NH2
OTBS
N3
OH
O
N
O
NH2
iv), xv)
NH2
ix)
v)
N
H
Br
Br
Br
Br
( )-29
80%
( )-28
54% (2 steps)
( )-27
77%
( )-26
83%
Scheme 2. Reagents and conditions: (i) 2 equiv m-CPBA, CH2Cl2; (ii) 10 equiv NaN3, 10 equiv NH4Cl, TFE, 100 °C; (iii) 1 atm H2, 20 mol % PtO2, MeOH; (iv) (a) 40 equiv
TMSNCO, 10–20 mol % H2O, CH2Cl2 or i-PrOH, (b) 5 equiv K2CO3, MeOH; (v) 1.5–5 equiv DAST, CH2Cl2; (vi) 1:1 TFA/CH2Cl2, 0 °C to rt; (vii) 5 mol % Pd(dppf)Cl2, 3 equiv K2CO3,
5:1 dioxane/H2O, 80 °C; (viii) 10 equiv NaN3, 5 equiv NH4Cl, 8:1 MeOH/H2O, 100 °C; (ix) 5 wt equiv Raney Ni, 20 equiv hydrazine hydrate, 20 equiv formic acid, MeOH, 0 °C to
rt; (x) 1.2 equiv LiHMDS, 1.2 equiv PhNTf2, THF, ꢀ78 °C to rt; (xi) 1.5 equiv n-BuLi, THF, ꢀ78 °C; (xii) 10 mol % p-TsOH.H2O, toluene, 110 °C; (xiii) 4 equiv NaN3, 4 equiv NH4Cl,
6:1 TFE/H2O, 80 °C; (xiv) 3 equiv TBSOTf, 5 equiv NEt3, DMF; (xv) 20 equiv HCl in dioxane, 70 °C.

M. P. Huestis et al. / Tetrahedron Letters 54 (2013) 5802–5807
5805
ically, the two isomeric piperidyl aminooxazolines (X = N, Y = CH2
and X = CH2, Y = N) provide alternate vectors toward P20. The 2,4-
difluorophenyl group was chosen to occupy P1 for these targets
without a P3 substituent based on existing literature SAR for this
region. The tetrahydropyranyl aminooxazoline (X = O, Y = CH2)
and cyclohexyl aminooxazoline (X = Y = CH2) targets (without a
practical vector to P20) incorporate a substituent toward P3. These
multiple points of diversity mandated that our synthetic route
enable P20 or P3 diversification at the last step.
Numerous attempts to invoke the Hassner method (Fig. 3A) and
obtain aminooxazolines directly were unsuccessful (not shown).
Iodoisocyanate was recalcitrant to engage either alkene 1 or 4 un-
der a variety of conditions. Furthermore, we were not able to per-
form a direct attack of isocyanate nucleophiles onto in situ
generated iodonium or bromonium ions. Although we hypothe-
sized that there might be a prerequisite for an electron rich alkene,
a variant of 1 possessing 4-methoxyphenyl instead of 3-bromo-4-
fluorophenyl was also unreactive.16
Our retrosynthetic analysis is presented in Figure 3. The most
obvious disconnection (Fig. 3A) was to forge the aminooxazoline
from an aryl alkene D in a single pot by the action of silver(I) cya-
nate and iodine, followed by introduction of ammonia—a method
introduced by Hassner over forty years ago.13 Alternatively
(Fig. 3B), we envisioned the penultimate preparation of a bicyclic
oxazolidinone via Rh-catalyzed C–H functionalization chemistry
developed by Du Bois.14 Finally (Fig. 3C), the target compound class
could potentially arise from the diethylaminosulfur trifluoride
(DAST)-mediated ring closure technique pioneered by Lellouche,
Wipf and Williams.9
In examining the C–H amination route (Fig. 3B), aryl alkene 1
underwent hydroboration–oxidation to provide
a mixture of
regioisomers ( )-2 (Scheme 1, 23% yield). The choice of borane-
dimethylsulfide complex was crucial since neither the tetrahydro-
furan complex, catecholborane, nor 9-borabicyclo[3.3.1]nonane re-
acted with alkene 1, even at elevated temperature. With ( )-2 in
hand, the primary carbamate ( )-3 was secured through one-pot
treatment with trichloroacetyl isocyanate and methanolysis of
the resultant trichloroacetate (35% yield of ( )-3, plus 46% of the
regioisomer).17 In the piperidine series, the hydroboration–oxida-
tion adduct of aryl alkene 4 was transformed directly to the carba-
mate ( )-5 before purification (64% over two steps, plus 13%
regioisomer). For the C–H amination step, tetrahydropyranyl car-
bamate ( )–3 proved completely unreactive under a variety of con-
Scheme 1 depicts our results from the initial approaches A and
B. The aryl alkenes 1 and 4 were easily obtained via Suzuki–Miya-
ura cross-couplings of commercially available starting materials.15
Table 1
BACE-1 SAR exploration for compounds based on tetrahydropyranyl aminooxazoline ( )-14 and cyclohexyl aminooxazoline ( )-29
H
H
O
N
O
N
O
NH2
NH2
R
R
Compd
R
BACE1 IC50
M)
HLM CLhep
(mL/min/kg)
Compd
R
BACE1 IC50
M)
HLM CLhep
(mL/min/kg)
(
l
(l
Cl
30
13.1
11
29
>200
4
Br
F
OCH3
Cl
31
32
37.1
46.4
14
5
39
40
26.6
11.8
—
7
F
CN
Cl
Cl
N
OCH3
CN
33
34
45.8
99.3
6
2
41
42
38
34
18
6
N
N
N
O
35
36
>200
27.3
8
6
43
44
46.7
35.3
11
2
N
F
N
H
N
N
O
O
O
N
N
N
H
N
O
F
N
H
N
H
37
38
3.3
7
6
45
>200
—
N
N
Cl
N
H
O
38.2
CH3

5806
M. P. Huestis et al. / Tetrahedron Letters 54 (2013) 5802–5807
ditions. Interestingly, the piperidine carbamate ( )-5 reacted
smoothly under the original conditions reported by Du Bois to af-
ford oxazolidinone ( )-6 (71% yield), but with no evidence of the
desired benzylic substitution event.18
The synthesis of bicycle ( )-21 began with trifluoromethane-
sulfonation of the enolate derived from N-(tert-butoxycarbonyl)-
piperidone (50% yield of 15, plus 49% regioisomer).23 Subsequent
Suzuki cross-coupling of 15 afforded 16 (67% yield). Epoxidation
(( )-17, 73% yield), azide introduction (( )-18, 23% yield, plus
47% recovered starting material), azide reduction and urea genera-
tion provided compound ( )-19 in 84% yield over two steps. Reac-
tion of ( )-19 with DAST (( )-20, 41% yield) and N-tert-
butoxycarbonyl deprotection afforded 3a-(2,4-difluorophenyl)-
3a,4,5,6,7,7a-hexahydrooxazolo[4,5-c]pyridin-2-amine ( )-21 in
92% yield.24
Finally, cyclohexane-fused aminooxazoline ( )-29 was con-
structed in nine steps from cyclohexanone (Scheme 2). The requi-
site aryl alkene 23 was produced by lithium–halogen exchange of
1,3-dibromobenzene and carbonyl addition onto cyclohexanone
(22, 90% yield) followed by acid-catalyzed dehydration (75% yield).
Thereafter, epoxidation (( )-24, 90% yield), azide introduction (( )-
25, 53% yield), and tert-butyldimethylsilyl protection afforded ( )-
26 (83% yield). Azide reduction (( )-27, 77% yield) was followed by
acidic rupture of the silyl blocking group and urea formation to
afford compound ( )-28 (54% yield over two steps). When com-
pound ( )-28 was submitted to the action of DAST, bicycle ( )-29
was produced in 80% yield.25
The successful preparation of bicyclic aminooxazoline scaffolds
using approach C (Fig. 3) is presented in Scheme 2. Commencing
with aryl alkene 4, epoxidation to ( )-7 proceeded smoothly with
meta-chloroperbenzoic acid (74% yield). Subsequent ring opening
of epoxide ( )-7 with sodium azide provided azidoalcohol ( )-8
(56% yield, plus 11% recovered starting material). In initial studies
on epoxide opening, we obtained mixtures of regioisomers which
were separated and independently characterized spectroscopi-
cally.19 For the major isomer in this case, a 1H–15N HMBC NMR
correlation indicated that the azide was benzylic. Furthermore,
oxidation of ( )-8 to the corresponding ketone, along with the
lack of reactivity of the constitutional tertiary alcohol with
Dess–Martin Periodinane provided additional structural proof.
Carrying forward, the amine resulting from azide reduction of
( )-8 was treated with excess trimethylsilylisocyanate20 in the
presence of water to deliver a urea which, when treated with
diethylaminosulfur trifluoride, produced bicyclic aminoxazoline
( )-9 in 56% yield over three steps. Deprotection of ( )-9 was
accomplished with trifluoroacetic acid to produce 7a-(2,4-difluo-
rophenyl)-3a,4,5,6,7,7a-hexahydrooxazolo[5,4-c]pyridin-2-amine
( )-10 (78% yield).21
Tetrahydropyranyl bicyclic aminooxazoline ( )-14 was
obtained in a similar manner from aryl alkene 11 (Scheme 2).
Following epoxidation to ( )-12 (90% yield), ring opening with so-
dium azide was carried out in a mixture of methanol and water to
afford ( )-13 (78% yield, plus 9% of the regioisomer). This solvent
mixture was necessary as trifluoroethanol solvent (used in the
synthesis of compound ( )-8) afforded exclusively the undesired
regioisomer as confirmed by X-ray crystallography of the final
aminooxazoline products. Reduction of azide ( )-13 in this case
was performed with Raney nickel, hydrazine, and formic acid in
methanol. The use of Raney nickel in the absence of hydrazine,
formic acid, or both, resulted in hydrodebromination. The interme-
diate amine was then subjected to urea formation and DAST-med-
iated ring closure to produce bicycle ( )-14 in 64% yield over three
steps.22
The final analogs were synthesized from aminooxazolines ( )-
10, ( )-14, ( )-21, and ( )-29 through Suzuki–Miyaura cross-cou-
plings, Cu-mediated amidations, nucleophilic aromatic substitu-
tions, or alkylations. The piperidyl aminooxazoline analogs based
on compounds ( )-10 and ( )-21 with a variety of P20 substituents
such as carbamates, alkyls, 2-pyridyls, 2-pyrazinyl, and 2-pyrimid-
yls failed to provide IC50 <50 lM (Table S1). Despite poor binding
affinity, X-ray structures in BACE-1 provided some insight into
their binding mode and confirmed that the aminooxazoline func-
tional group could interact with the catalytic aspartic acids in the
active site (Fig. S1).
Accordingly, the bicyclic scaffolds without P20 substituents
were subsequently explored. Extending into the P3 pocket with
the cyclohexyl and tetrahydropyranyl fused ring systems improved
binding affinity for BACE-1 (Table 1). P3 aryl (( )-30 – ( )-32, ( )-
39, ( )–41, ( )–42) and heteroaryl (( )-33, ( )-34, ( )-40, ( )–43,
( )-44) substituents on the tetrahydropyranyl aminooxazoline
Figure 4. X-ray structures of compound ( )-34 (left, 1.38 Å resolution) and compound ( )-40 (right, 1.7 Å resolution) in BACE-1.

M. P. Huestis et al. / Tetrahedron Letters 54 (2013) 5802–5807
5807
G.; Kolmodin, K.; Swahn, B.-M.; von Berg, S.; Bueters, T.; Fälting, J. J. Biol. Chem.
2012, 287, 41245–41257.
and cyclohexyl aminooxazoline scaffolds provided high micromo-
lar activity against BACE-1. The 5-fluoropicolinamido and 5-chlo-
7. Early work in these structural classes: (a) Barrow, J. C.; Stauffer, S. R.; Rittle, K.
E.; Ngo, P. L.; Yang, Z.; Selnick, H. G.; Graham, S. L.; Munshi, S.; McGaughey, G.
B.; Holloway, M. K.; Simon, A. J.; Price, E. A.; Sankaranarayanan, S.; Colussi, D.;
Tugusheva, K.; Lai, M.-T.; Espeseth, A. S.; Xu, M.; Huang, Q.; Wolfe, A.; Pietrak,
B.; Zuck, P.; Levorse, D. A.; Hazuda, D.; Vacca, J. P. J. Med. Chem. 2008, 51, 6259–
6262; (b) Zhu, Z.; Sun, Z.-Y.; Ye, Y.; Voigt, J.; Strickland, C.; Smith, E. M.;
Cumming, J.; Wang, L.; Wong, J.; Wang, Y.-S.; Wyss, D. F.; Chen, X.; Kuvelkar, R.;
Kennedy, M. E.; Favreau, L.; Parker, E.; McKittrick, B. A.; Stamford, A.;
Czarniecki, M.; Greenlee, W.; Hunter, J. C. J. Med. Chem. 2010, 53, 951–965;
(c) Malamas, M. S.; Erdei, J.; Gunawan, I.; Turner, J.; Hu, Y.; Wagner, E.; Fan, K.;
Chopra, R.; Olland, A.; Bard, J.; Jacobsen, S.; Magolda, R. L.; Pangalos, M.;
Robichaud, A. J. J. Med. Chem. 2010, 53, 1146–1158.
8. Hunt, K. W.; Cook, A. W.; Watts, R. J.; Clark, C. T.; Vigers, G.; Smith, D.; Metcalf,
A. T.; Gunawardana, I. W.; Burkard, M.; Cox, A. A.; Geck Do, M. K.; Dutcher, D.;
Thomas, A. A.; Rana, S.; Kallan, N. C.; DeLisle, R. K.; Rizzi, J. P.; Regal, K.;
Sammond, D.; Groneberg, R.; Siu, M.; Purkey, H.; Lyssikatos, J. P.; Marlow, A.;
Liu, X.; Tang, T. P. J. Med. Chem. 2013, 56, 3379–3403.
9. (a) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2,
1165–1168; (b) Lafargue, P.; Guenot, P.; Lellouche, J.-P. Heterocycles 1995, 41,
947–958; (c) Burrell, G.; Evans, J. M.; Jones, G. E.; Stemp, G. Tetrahedron Lett.
1990, 31, 3649–3652.
10. (a) Audia, J. E.; Mergott, D. J.; Shi, C. E.; Vaught, G. M.; Watson, B. M.;
Winneroski, Jr., L. L. PCT Int. Appl. (2011), WO 2011005738.; (b) Suzuki, Y.;
Motoki, T.; Kaneko, T.; Takaishi, M.; Ishida, T.; Takeda, K.; Kita, Y.; Yamamoto,
N.; Khan, A.; Dimopoulos, P. PCT Int. Appl. (2009), WO 2009091016.
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Iserloh, U. PCT Int. Appl. (2011), WO 2009131975.
ropicolinamido
aminooxazoline afforded BACE-1 IC50 = 27.3 and 3.3
substituents
on
the
tetrahydropyranyl
M, respec-
l
tively. In the cyclohexyl aminooxazoline scaffold, the 3-chloropyr-
idyl ( )-40, which had an efflux ratio of 2.5 (MDR1-LLC–PK1 @
1 l
M),26 was the most potent analog examined (BACE-1
IC50 = 11.8 lM). The analogs shown in Table 1 generally exhibited
good to moderate human liver microsome stability. The X-ray
structures of inhibitors ( )-34 and ( )-40 show the bicyclic amino-
oxazolines engaging the catalytic aspartic acids while occupying
the P1 and P3 pockets (Fig. 4).27 Interestingly, boat conformations
of the tetrahydropyran- and cyclohexane-based inhibitors ( )-34
and ( )-40 were observed in the X-ray cocrystal structures and
may indicate the ligands adopt a potentially unfavorable confor-
mation to accommodate the flap region over the active site.
In summary, rescaffolding of a spiro-aminooxazoline to a bicyclic
aminooxazoline provided new chemical matter. The synthesis of
these bicyclic aminooxazoline compounds was enabled by the intra-
molecular diethylaminosulfur trifluoride (DAST)-mediated ring clo-
sure of a benzylic urea onto a secondary alcohol. Ultimately, these
bicyclic aminooxazoline analogs did not provide an ideal vector to
access the P20 pocket; however, occupation of the P3 pocket afforded
micromolar biochemical activity against BACE-1.
12. A single example of a related design that features a bicyclic aminothiazoline
has appeared: See Ref. [10b].
13. Hassner, A.; Lorber, M. E.; Heathcock, C. J. Org. Chem. 1967, 32, 540–549.
14. (a) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598–600; (b) Du
Bois, J. Org. Process Res. Dev. 2011, 15, 758–762.
15. These aryl alkenes were only stable for a few days, even when stored under
inert atmosphere at 4 °C.
16. Obtained in the dihydropyranyl series through Suzuki–Miyaura coupling under
otherwise identical conditions (46% yield).
Acknowledgment
We thank Ping Wu for purification of BACE-1 protein.
ˇ
´
17. Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521–5524.
Supplementary data
⁄
18. Data for ( )-6: 1H NMR (1.4:1 rotamer ratio, denotes minor rotamer peaks,
500 MHz, CDCl3) d 7.14 (m, 1H), 6.81–6.88 (m, 2H), 5.93 (m, 1H), 5.45 (m, 1H),
5.19⁄ (m, 1H), 4.77 (m, 1H), 4.06⁄ (m, 1H), 3.77 (m, 1H), 3.29 (m, 1H), 3.20 (m,
1H), 1.86–2.00 (m, 2H), 1.49 (br s, 9H).
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2013.07.136.
19. The use of trifluoroethanol (TFE) was crucial in favoring the desired isomer. We
thank Professor Scott E. Denmark for this suggestion.
References and notes
20. Neville, R. G. J. Org. Chem. 1958, 23, 937–938. ⁄
21. Data for ( )-9: 1H NMR (1.4:1 rotamer ratio, denotes minor rotamer peaks,
400 MHz, CDCl3) d 7.77–7.59 (m, 1H), 6.94–6.68 (m, 2H), 4.88–4.77 (m, 1H),
4.77–4.62⁄ (m, 1H), 4.27 (d, J = 14.7 Hz, 1H), 4.10⁄ (d, J = 14.7 Hz, 1H), 3.64–3.39
(m, 3H), 2.44–2.26 (m, 1H), 1.86–1.71 (m, 1H), 1.48 (s, 9H).
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22. Data for ( )-14: 1H NMR (400 MHz, CDCl3) d 7.52 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H),
7.38 (d, J = 7.8 Hz, 1H), 7.29 (dd, J = 7.8, 7.8 Hz, 1H), 4.77 (m, 1H), 4.05 (dd,
J = 13.4, 3.1 Hz, 1H), 3.96–3.83 (m, 3H), 2.34–2.27 (m, 1H), 2.18–2.10 (m, 1H)
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⁄
24. Data for ( )-20: 1H NMR (1.1:1 rotamer ratio, denotes minor rotamer peaks,
400 MHz, DMSO-d6) d 7.71 (q, J = 8.4 Hz, 1H), 7.22 (ddd, J = 11.7, 9.1, 2.6 Hz,
1H), 7.07 (ddd, J = 10.1, 5.6, 1.9 Hz, 1H), 6.15 (s, 2H), 4.69 (m, 1H), 3.59 (d,
J = 13.4 Hz, 1H), 3.48⁄ (d, J = 13.5 Hz, 1H), 3.41–3.31 (m, 2H), 3.26–3.06 (m, 1H),
2.21 (t, J = 8.6 Hz, 1H), 2.04–1.91 (m, 1H), 1.40 (s, 9H), 1.34⁄ (s, 9H).
25. Representative procedure for DAST-mediated cyclization: To an ice-cooled
solution of racemic 1-((1R,2S)-1-(3-bromophenyl)-2-hydroxycyclohexyl)urea
(0.400 g, 1.28 mmol) in dichloromethane (10 mL) under nitrogen was
added diethylaminosulfur trifluoride (0.95 mL, 7.2 mmol). The reaction
mixture was allowed to warm to 24 °C. After 2.5 h, the reaction was
quenched by the addition of saturated aqueous sodium bicarbonate
solution, and the resulting mixture was extracted with dichloromethane. The
collected organics were dried over anhydrous sodium sulfate, filtered, and
concentrated to afford racemic (3aR,7aR)-3a-(3-bromophenyl)-3a,4,5,6,7,7a-
hexahydrobenzo[d]oxazol-2-amine as a yellow solid (370 mg, 80%); 1H NMR
(500 MHz, CD3OD) d 7.62 (s, 1H), 7.38 (m, 2H), 7.24 (m, 1H), 4.58 (m, 1H), 2.00–
1.52 (m, 8H).
26. In vitro MDR1-transfected LLC–PK1 assay run at 1
compound.
27. PDB codes: 4L7G and 4LC7.
lM concentration of test