792
J. A. Kozlowski et al. / Bioorg. Med. Chem. Lett. 12 (2002) 791–794
generate sodium-4-mercapto acetophenone, which was
coupled in the same pot with 3,4-methylenedioxy-
iodobenzene under Suzuki’s conditions.9 After work up
and chromatography, the ketone was isolated in ꢀ80%
yield. Oxidation of the diphenylsulfide to the sulfone
was accomplished with m-CPBA. Corey’s enantio-
selective reduction gave the chiral (R)-alcohol in >98%
yield and 94% ee.10 Mesylation and displacement with
4-N-Boc-2-(R)-methylpiperazine gave the (S)-benzylic
methyl. Removal of the BOC with acid and reductive
amination N-BOC-4-piperidinone proceeded in good
yield.11 Deprotection of the BOC gave the free piper-
idine, which was converted to amides, sulfonamides,
and ureas with acid chlorides, sulfonyl chlorides, or
isocyanates, respectively.
similar to 1 observed. In looking for alternates to the
Strecker amine moiety, we focused on methyl as a non-
racemizable replacement for the cyano group. Thus,
substituting the cyano of compound 3 with methyl gave
the diastereomeric compounds 6 and 7. A slight pref-
erence for (S)-methyl at the benzylic site was observed,
with 6 was apparent. The importance of the combina-
tion of the benzylic and piperazine methyl together was
Scheme 1. (a) NaH, 0 ꢁC, DMF, add p-fluorobenzaldehyde, warm to
rt, 12 h; (b) 4-cyclohexyl-2-(R)-methylpiperazine, rt, Ti(i-OPr)4,
CH3MgBr or Et2AlCN or NaCNBH3, for R=CH3, CN, H, respec-
tively, flash chromatography; (c) m-CPBA, CH2Cl2, rt.
Compounds with R2 equal to methyl (Table 1) were
prepared from either (R)- or (S)-methyl lactate (Scheme
3). 2-Nitrophenylsulfonyl chloride was treated with
aminoethanol, and the product was acylated with acetic
anhydride in pyridine. This sulfonamide was treated
with the triflate of either (R)- or (S)-methyl lactate, fol-
lowed by reduction of the esters with borane-methyl
sulfide complex. The piperazine was formed from reac-
tion of the diol, activated with triflic anhydride, with the
diphenylsulfonyl-a-methylbenzylamine, prepared as
shown from a-methylbenzylamine. Removal of the sul-
fonamide protecting group, under Fukayama’s condi-
tions,12 gave the free piperazine, which was converted to
9 or 10.
The binding affinities for synthesized compounds
described here were determined using cloned human
muscarinic receptors, as previously described.13 Our
initial objective was to find a compound with affinity
and selectivity comparable to or better than 1, but
without the chiral sulfoxide and a-cyano amine moi-
eties. First we focused on switching the chiral sulfoxide
of 1 to a sulfone, thereby simplifying the synthetic
scheme and avoiding the possibility of metabolic race-
mization of the sulfoxide in vivo. The chirality lost in
changing sulfoxide to sulfone, was introduced again by
addition of a methyl to the piperazine ring (e.g., 3 and 4,
Table 1). A preference for the (R)-configuration for the
R1 methyl was apparent (e.g., 3) with M1/M2 selectivity
Scheme 2. (a) NaHS, DMF, 95 ꢁC, 2 h; (b) 3,4-methylenedioxy-
iodobenzene, CuI, K2CO3, DMF, 100 ꢁC, 6 h; (c) m-CPBA, NaHCO3,
1,2-dichloroethane, rt, 24 h; (d) 0.6 equiv BH3(CH3)2S, THF, rt, 0.2
equiv Corey’s oxoborolidine catalyst; (e) CH3SO2Cl, CH2Cl2, 0 ꢁC,
Et3N; (f) tetramethylpiperidine, 2-(R)-methyl-4-BOC-piperazine,
CH3CN, reflux, 12 h; (g) 6 N HCl, reflux 7 h; (h) NaHB(OAc)3, N-
BOC-4-piperidinone; (i) 6 N HCl, rt 3 h; (j) EtSO2Cl, Et3N, rt.
Table 1.
Compd
R
R1
R2
Ki (nM)
M2
M1/M2
3
4
5
6
7
8
9
10
CN
CN
CH3
(S)-CH3
(R)-CH3
H
(R)-CH3
(R)-CH3
(R)-CH3
(S)-CH3
H
(R)-CH3
(R)-CH3
(R)-CH3
H
H
H
H
H
H
0.16
16
0.6
0.3
0.15
0.3
36
5
Scheme 3. (a) 2-Hydroxyethyl amine, rt, CH2Cl2; (b) acetic anhydride,
pyridine, rt; (c) (R)-CH3CH(OSO2CF3)CO2Et; (d) BH3(CH3)2S, THF;
(e) Tf2O, Collidine, CH2Cl2, 0 ꢁC; (f) 2 equiv Na2CO3, CH3CN, rt
24 h; (g) HSCH2CO2H, LiOH–H2O; (h) Ti(i-OPr)4, cyclohexanone,
NaCNBH3; (i) 1,3-dibromo-5,5-dimethylhydantoin, rt, MeSO3H,
CH2Cl2; (j) n-BuLi, THF, À70 ꢁC, then ArSO2F, warm to rt; (k)
KOH, MeOH, rt.
10
44
30
23
10
10
H
(S)-CH3
(R)-CH3
0.04
0.14
H