2290
V. W.-F. Tai et al. / Bioorg. Med. Chem. Lett. 24 (2014) 2288–2294
O
O
provide larger quantities of the desired R-isomer 6p required for
HO
HO
a
in vitro and in vivo studies. The availability of chiral amine 19 also
allowed quick access to analogs with different cores. Chiral resolu-
tion of amine 16 was achieved by crystallization of the diastereo-
b
EtO
EtO
6k
8
meric salts30 of amine 16 and (+)-O,O0-di-p-toluoyl-
D-tartaric acid
7
in ethanol (Scheme 3, Method B). The desired R-isomer was ob-
tained as a 2:1 stoichiometry of amine/acid in 26% yield. The abso-
lute stereochemistry of the 3-O-benzoate group was determined
by X-ray crystallography of diastereomeric salt 18 (Fig. 2).23 Wash-
ing with aqueous sodium bicarbonate provided the free base 19 in
88% yield with 97% enantiomeric excess. Using this diastereomeric
crystallization methodology, 10 g of chiral amine 19 was readily
obtained. Similar to Method A, the amine 19 was coupled to acid
3 and the benzoate saponified to give compound 6p in 93% yield
over 2 steps.
A second series of spiro compounds with five-membered oxazo-
lidinone and lactam rings was also identified through focused
screening efforts.31 Amines 21a and 21b were obtained by depro-
tection of commercially available N-Boc derivatives 20a and 20b
respectively. The amines 21a and 21b were coupled to acid 3 under
T3P conditions to give compounds 22a and 22g in 89% and 85%
yield, respectively (Scheme 4). The N-alkyl analogs 22b–22f, 22h
were prepared by simple alkylation of compounds 22a and 22g
with the corresponding halides.
Hydroxyl piperidine analogs 27a–d were prepared as shown in
Scheme 5. Treatment of ketone 14 with potassium cyanide under
basic conditions gave cyanohydrin 23 as a mixture of diastereoiso-
mers in 84% yield. The nitrile group in 23 was reduced under
hydrogen in the presence of platinum oxide and Boc anhydride
to give a mixture of syn- and anti-isomers (rac-24a and rac-24b)
which were easily separated by silica gel chromatography. The rel-
ative stereochemistry of each compound was determined at a later
stage (vide infra). Acid hydrolysis of the Boc group in rac-24a fol-
lowed by oxazolidinone formation with carbonyldiimidazole (CDI)
gave spiro oxazolidinone rac-25a in 77% yield.
Methylation of rac-25a followed by purification using chiral
supercritical fluid chromatography (SFC) gave enantiomers 26a
and 26b each in 25% yield. The absolute stereochemistry of com-
pounds 26a and 26b was determined by vibrational circular
dichroism (VCD) and infrared (IR) analyses (vide supra). Removal
of the protecting groups in 26a and 26b followed by coupling with
core acid 3 gave compounds 27a and 27b, respectively. Similarly,
O
HO
HO
d
c
MeO
MeO
6l
OBn
OBn
O
10
9
Cbz
N
Cbz
N
OH
OH
OH
f
g
e
O
O
O
O
6m
4
+
OH
O
OH OH
11
13
12
Scheme 2. Synthesis of compounds 6k, 6l, 6m. Reagents and conditions: (a) LAH
(4 equiv), Et2O, 0 °C to rt (88%); (b) same steps as in Scheme 1 (66% for 3 steps); (c)
LAH (4 equiv), Et2O, 0–45 °C (47%); (d) same steps as in Scheme 1 (45% for 3 steps);
(e) pentaerythritol (1.5 equiv), pTsOH (0.05 equiv), benzene/DMF (4:6 v/v) heated
to 80 °C for 30 min, 1-Z-piperidone (1 equiv) in benzene/DMF (4:6 v/v) added,
125 °C for 4 days (67%); (f) nBuLi (1.1 equiv), THF, ꢁ25 °C to rt, 30 min; p-TsCl,
ꢁ20 °C to 0 °C for 1.5 h; nBuLi (1.1 equiv) 0 °C to rt, overnight (40% based on 11%
recovery of starting material); (g) last 2 steps as in Scheme 1 (86% for 2 step).
pentaerythritol.27 The diol 12 was converted to mono-tosylate fol-
lowed by treatment with nBuLi in the same pot to give oxetane 13
in 27% yield.28
Hydroxyl piperidine analogs 6n, 6o, 6p and keto analog 6q were
prepared as shown in Scheme 3. Benzoylation of 1-Cbz-4-piperi-
done 4 at the 3-position was carried out using Tomkinson’s proto-
col29 with N-methyl-O-benzoylhydroxylamine hydrochloride in
DMSO to give 14 in 97% yield. Ketalization of ketone 14 with com-
mercially available 1,1-bis(hydroxymethyl)cyclopropane followed
by hydrogenolysis gave racemic amine 16 in 81% yield over 2 steps.
Coupling of core acid 3 with amine 16 gave compound 17 which
was deprotected to give racemic compound 6n. The racemate 6n
was resolved by chiral HPLC to give enantiomers 6o and 6p. Addi-
tionally, the hydroxyl group in racemate 6n was oxidized by DMP
to give ketone 6q. An alternative method was also developed to
Method A
Cbz
N
H
N
CF3
Cbz
N
O
N
N
N
c
b
g
a
d
4
OBzl
OBzl
6q
O
O
O
O
OBzl
Cl
OR
O
O
O
14
17
: R = Bzl
e
f
15
16
6n
: R = H
6o 6p
+
Method B
H
H
H
N
N+
d, e
-
h
i
CO2
O
R
R
6p
16
O
OBzl
OBzl
O
O
O
O
O
-
O
CO2
2
18
19
Scheme 3. Reagents and conditions: Method A: (a) MeHNOC(O)Ph (1 equiv), DMSO, rt (97%); (b) 1,1-bis(hydroxymethyl)cyclopropane (2.5 equiv), pTsOH (0.05 equiv),
toluene, 140 °C, Dean–Stark apparatus (83%) ; (c) H2 (1 atm), 10% Pd/C Degussa type, MeOH (98%); (d) 3 (1 equiv), 16 (1.4 equiv), T3P (1.5 equiv), Hunig’s base (4 equiv), DMF,
0 °C (97%); (e) LiOH.H2O (3 equiv), THF/MeOH/H2O (92%); (f) separation by chiral column, RegisCell™ ODH (25 cm ꢂ 30 mm), 20% IPA in hexanes, 6o (36%), 6p (39%); (g) DMP
(1.2 equiv), DCM, rt (49%). Method B: (h) di-O,O0-di-p-toluoyl-
D-tartaric acid (1 equiv), EtOH, 50 °C to room temperature (26%); (i) aq NaHCO3, EtOAc (23%, 97% ee); (d) 3
(1 equiv), 19 (1.4 equiv), T3P (1.5 equiv), Hunig’s base (4 equiv), DMF (98%); (e) LiOH (3 equiv), THF, MeOH, water (95%).