3124
M. A. Ashwell et al. /Bioorg. Med. Chem. Lett. 11 (2001) 3123–3127
t
Scheme 1. (a) BuPh2SiCl, imidazole, CH2Cl2, 82%; (b) Pd/C, cyclo-
hexene, EtOH, 94%; (c) R-(+)-glycidol, PPh3, DEAD, THF, 56%;
t
(d) BuPh2SiCl, imidazole, CH2Cl2, 98%; (e) MCPBA, CHCl3, 85%;
(f) Raney Ni, H2, THF, 73%; (g) mesyl chloride, THF, iPr2NEt, 66%;
(h) Boc2O, CH2Cl2, 96%; (i) NaOH, MeOH, 79%; (j) R-(+)-glycidol,
DEAD, PPh3, 70%.
Scheme 2. (a) b-Ethoxyacryl chloride, Et3N, benzene, 99%; (b) HCl,
78%; (c) Raney Ni, H2 iPrOH, THF, 47%; (d) 48% HBr, heat, 80%;
(e) acetone, water, K2CO3, PhCH2Br, 27%; (f) K2CO3, 2-butanone,
(2S)-(+)-glycidyl-3-nitrobenzenesulfonate, 82 and 32% for 13 to 14;
(g) NaNO2, H2O, HCl (concd); (h) NaOH, 3-hydroxypyridine, 22%
steps g and h; (i) K2CO3, acetone, (2S)-(+)-glycidyl-3-nitrobenzene-
sulfonate, 28%; (j) Raney Ni, ethanol; (k) phosgene, CH2Cl2, 51% for
steps j and k.
with the commercially available (2S)-(+)-glycidyl-3-
nitrobenzenesulfonate.
In the case of epoxide 17, an alternate synthesis to that
previously disclosed11 was developed starting from
trisubstituted phenol 15. Here the alkylation with (2S)-
(+)-glycidyl-3-nitrobenzenesulfonate was performed
prior to the reduction of nitroaniline 16 and ring closure
with phosgene yielding 17 (Scheme 2).
Alternatively, when phenethylamines were the target ago-
nists epoxides such as 20 were constructed or purchased
[(R)-(+)-3-chlorostyrene oxide for the preparation of
37a]. An alternative strategy required chiral amino
alcohol 23, and this was prepared as shown in Scheme 3.
The preparation of the scaffold piperidine 27 is shown
in Scheme 4. Selective protection of the primary amine
of 24 as the BOC amide was followed by reductive
amination with 4-benzylpiperidinone to yield 26.
Removal of the benzyl protecting group gave the sec-
ondary amine 27.
Scheme 3. (a) PhCH2Br, NaOMe, MeOH, 80%; (b) Br2, CHCl3, 87%;
(c) NaBH4, ethanol, THF, 96%; (d) K2CO3, 2-butanone, 74%; (e)
MeSO2Cl, pyridine, CH2Cl2, 47%; (f) CuBr2, CHCl3, 57%; (g) (R)-2-
methyl-CBS-oxazaborolidine, BH3, THF, 61%; (h) NaN3, DMSO;
(i) H2, Pd/C, MeOH, 71% for steps h and i.
Reaction of 27 with isocyanates or with triphosgene
followed by an amine provided ureas 28 depending on
reagent availability. Following purification and removal
of the BOC group with formic acid the formate salt 28
was used directly or treated with NaOH to liberate the
free base.
eration of the aldehyde 38 and subsequent reductive
amination provided phenethylamines such as 37c.12
Ureas 35 proved more difficult to prepare. The instabil-
ity of the intermediate nitro aldehyde, generated by
oxidation of 30, could be avoided if the Dess–Martin
oxidation was followed immediately by protection as the
dimethyl acetal to give 31 as shown in Scheme 5. Reduc-
tion of the nitro group of 31 provided aniline 32. Ureas
35 were obtained from 32 as described for 27 above.
The in vitro data for a selection of simple alkyl ureas
based on the 4-aminopiperidine scaffold is presented in
Table 1. In general molecules of this type (29a–f) have
comparable human b3-AR agonism relative to the stan-
dard isoproterenol, considerably weaker b2-AR agon-
ism and some selectivity over b1-AR agonism. The
greatest receptor subtype selectivity is found when the
alkyl group is an extended straight chain (cf. 29a and
29b). Importantly the potency of b1-AR agonism
appears to fall offas the chain length increases.
Intermediate ureas 28 were reacted directly with epox-
ides in the presence of a hindered organic base, thus
providing access to either aryloxypropanolamines or
phenethylamines as shown in Scheme 6. This reaction
was not regiospecific and access to the starting epoxides
was not always feasible. An alternative approach is
illustrated in the preparation of 37c. Here, in situ gen-
An extensive selection of aryloxypropanolamines was
prepared holding the alkyl urea portion of 29a constant.
The importance of the 4-hydroxy group of 29a was
demonstrated by its removal to give 29g which is an