C. H. Wang et al. / Tetrahedron Letters 57 (2016) 3046–3049
3047
O
H
H
O
N
N
O
O
H
O
N
N
N
N
H
O
N
H
O
O
N
O
O
Donepezil
(-)Physostigmine
Rivastigmine
R2
(-)Physovenine
R2
R2
N
R2
N
H
N
N
O
O
R
O
R
X
R3
R1
R1
O
R3
H3CO
R4
R4
H3CO
R1
(D)
R1
OH
(B)
(C)
R
(A)
Figure 1. Examples of AChE inhibitors.
and H11 (Fig. 2). Treatment of 8a–c with TBTH and AIBN produced
the desired spirooxindoles (10a, 10j–k), involving the rearrange-
ment of 12 to the more stable radical 13.
O
(1). Diisopropylamine,
O
O
n-BuLi, THF, -10oC
R1
R1
R
O
O
O
O
(2). 2-Bromopropane
THF, -78oC
Hydrolysis of 10a–b with 2 N NaOH in methanol yielded the
corresponding alcohols 14a and 14b, which were then converted
to aldehydes 15a and 15b, respectively using the Dess–Martin oxi-
dation (Scheme 4). Condensation of methyl amine with 15a fol-
lowed by reduction with LiAlH4 afforded 16a. O-demethylation of
16a using BBr3 yielded the phenol 17a. Similarly, 17b was obtained
from 14b. Treatment of the phenols 17a–b with NaH and substi-
tuted isocyanates yielded the desired physostigmine analogs
18a–c.
Treatment of compounds 10a–k and 14a–d with LiAlH4 in THF
under reflux yielded the compounds with physovenine core struc-
tures 19a–j. O-demethylation of compounds 19a–j followed by
reaction with substituted isocyanates furnished the desired physo-
venine analogs 21a–g. The biological activities of the physostigmi-
nes (18a–c) and physovenines (21a–g) analogs are summarized in
Table 1.
NaOMe,
R
MeOH, 0oC
O
2h (25.0%)
O
1a
2a: R=C6H5, R1=H (72.6%)
2b: R=4-Cl-C6H4, R1=H (89.6%)
(1). Diisopropylamine,
n-BuLi, THF, -10oC
O
2c: R=4-CH3-C6H4, R1=H (88.7%)
2d: R=4-CH3O-C6H4, R1=H (40.0%)
2e: R=CH=CHCH3, R1=H (9.4%)
(2). benzyl bromide
THF, -78oC
2i (13.0%)
O
O
R1
NaH
THF
R
O
O
O
P
O
R1
R
O
P(OEt)3
O
O
O
Br
reflux
140oC
1b
1c
2f: R=CH2CH(CH3)2, R1=H (27.0%)
2g: R=R1=CH3 (70.5%)
Scheme 1. Synthesis of substituted c-butyrolactones.
It is evident from the IC50 values reported in Table 1 that in the
physostigmine series the benzyl substituted analogs 18a, 18b, and
18c were inactive against hAChE but active against hBuChE. In the
physovenine series benzyl substituted compounds 21a, 21b, and
21c were selective hBuChE inhibitors with inhibitory potencies in
the submicromolar range. The most active against hBuChE being
21a with an IC50 value of 70 nM and selectivity around 58 folds.
In the alkyl substituted derivatives, 21d, 21e, 21f, and 21g were
slightly selective toward hAChE. Comparing compounds 21f and
spectroscopy established identical molecular compositions of both
the above compounds. NMR spectra of 10h and 10i indicated that
H10 in these compounds appear at d 4.14 and d 4.03 respectively.
The quaternary carbon C9 in 10h appeared at d 54.55, whereas C9
in 10i appeared at d 54.22. Both spiro-oxindoles show identical
correlations in COSY and HMBC. For example in HMBC, C9 shows
correlations with H7, H15, and H11, whereas C1 with H10, H14, and
H17. In addition, 10h showed long range NOE between H7 and
H10, whereas 10i showed the correlations of H7 with both H10
Br R2
Br
H
N
Br
H
N
N
O
R
Br
Cs2CO3
R2X
DMF
2a-2h
O
R
O
R
NH2
Me3Al
acetyl chloride
pyridine, DCM
R1
R1
R1
O
CH3
toluene
O
CH3
O
CH3
O
CH3
O
O
HO
H3C
O
H3C
O
3a: R=C6H5, R1=H (85.7%)
5a: R=C6H5, R1=H, R2=CH3 (97.2%)
4a: R=C6H5, R1=H (84.3%)
3b: R=4-Cl-C6H4, R1=H (88.6%)
3c: R=4-CH3-C6H4, R1=H (97.3%)
3d: R=4-CH3O-C6H4, R1=H (79.8%)
3e: R=CH=CHCH3, R1=H (41.4%)
3f: R=CH2CH(CH3)2, R1=H (57.1%)
3g: R=R1=CH3 (71.2%)
5b: R=4-Cl-C6H4, R1=H, R2=CH3 (97.7%)
5c: R=4-CH3-C6H4, R1=H, R2=CH3 (95.7%)
5d: R=4-CH3O-C6H4, R1=H, R2=CH3 (97.0%)
5e: R=CH=CHCH3, R1=H, R2=CH3 (90.5%)
5f: R=CH2CH(CH3)2, R1=H, R2=CH3 (95.4%)
5g: R=R1=CH3, R2=CH3 (97.4%)
4b: R=4-Cl-C6H4, R1=H (90.8%)
4c: R=4-CH3-C6H4, R1=H (98.7%)
4d: R=4-CH3O-C6H4, R1=H (90.9%)
4e: R=CH=CHCH3, R1=H (85.0%)
4f: R=CH2CH(CH3)2, R1=H (82.5%)
4g: R=R1=CH3 (88.5%)
3h: R, R1= 2-tetrahydrofuran (85.2%)
5h: R, R1= 2-tetrahydrofuran, R2=CH3 (94.2%)
4h: R, R1= 2-tetrahydrofuran (91.4%)
Br R2
Br
H
N
Br
H
N
Br
N
O
R
O
R
O
R
NH2
Cs2CO3
R2X
O
Me3Al
toluene
acetyl chloride
pyridine, DCM
R1
R1
R1
O
R1
O
CH3
O
CH3
O
CH3
O
CH3
DMF
R
O
O
HO
H3C
O
H3C
O
2i: R=C6H5, R1=H
2j: R=R1=H
8a: R=C6H5, R1=H, R2=CH3 (97.6%)
8b: R=R1=H, R2=CH2CH3 (95.5%)
8c: R=R1=H, R2=CH3 (92.5%)
7a: R=C6H5, R1=H (97.5%)
7b: R=R1=H (86.2%)
6a: R=C6H5, R1=H (70.2%)
6b: R=R1=H (75.4%)
Scheme 2. Preparation of radical precursors.