2
H. Lin et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
OH
O
OH
O
O
MeO
O
HO
O
HO
O
HO
acerogenin B
MeO
acerogenin A
acerogenin C
7
R1
R
N
H
linker-R3
N
R2
MeO
O
RO
O
MeO
O
MeO
36-48
linker: carbamate, urea,
sulfonate, sulfonamide,
ester, and amides
RO
-35
MeO
9
1a R = -CH CH Ph
2
2
2
1
1
b
c
-CH Ph
-CH (CH ) CH
3
2
2 4
macrocycles with
different ring sizes
49-53
Figure 1. Selected examples of bioactive cyclic diarylheptanoids and an overview of library design.
Synthesis of the key macrocycle intermediates 7 and 8 is shown
thylamine gave a pair of diastereomers 25 and 26 (Table 1, entry
17) or 27 and 28 (Table 1, entry 18), respectively.
in Scheme 1. Briefly, 3-(benzyloxy)-4-methoxybenzaldehyde was
first transformed into 2 via a 3-step sequence. This improved pro-
tocol can be easily scaled up in gram scales compared to our pre-
viously reported method.20 Next, in the presence of 10% sodium
hydroxide solution, the aldol condensation of 2 and 3 yielded 4
as a yellow solid in 74% yield. Subsequent hydrogenation of 4 gave
both 5 and 6, which could be easily separated by flash column
chromatography. Under microwave irradiation, final intramolecu-
lar copper-catalyzed Ullmann coupling21 of 5 or 6 afforded the cor-
responding macrocyclic product 7 or 8 in 77% and 80% yields,
respectively.
In addition, 24 with the geranyl amine motif was also synthe-
sized in 79% yield. Ethylamine was used to synthesize 29 (Table 1,
entry 19) to understand the effect of the phenyl group by compar-
ing to 1a. Meanwhile, secondary amines diethylamine, diethanola-
mine, and 1-methylpiperazine were used as substrates to give 30–
32 (Table 1, entries 20–22) in 15–40% yields. Overall, secondary
amines were found to be less reactive in this reductive amination
reaction with generally lower yields presumably due to steric
effects.
The reaction of 4-chloroaniline with 7 proceeded smoothly to
yield the desired product 33 in 57% yield (Table 1, entry 23). How-
ever, the reaction of 7 with bulky amine 1-adamantylamine
(Table 1, entry 24) gave no desired product under the optimized
reaction conditions.
To further evaluate the effect of phenolic hydroxyl groups in
cyclic amine derivatives, two selected amine compounds 1a and
1b were demethylated using boron tribromide to give free phenols
34 and 35 in 74% and 26% yields, respectively (Scheme 2).
In addition to introducing the basic amine moieties on the
macrocyclic ring, a series of macrocyclic derivatives with other
functionalities including ester, amide, urea, carbamate, sulfon-
amide, and sulfonate were also synthesized from 8 or 9 (Table 2).
Briefly, reaction of secondary alcohol 8 with substituted isocyanate
gave the corresponding carbamates 36–38, in which 4-fluo-
rophenyl isocyanate (Table 2, entry 1) gave a higher yield compar-
ing to phenethyl and benzyl isocyanates (Table 2, entries 2 and 3).
Accordingly, macrocyclic urea derivatives 39 and 40 were obtained
by reacting primary amine 9 and phenethyl or 4-fluorophenethyl
isocyanate (Table 2, entries 4 and 5). Furthermore, 8 or 9 reacted
with substituted sulfonyl chloride, carbonyl chloride, or carboxylic
acid led to the formation of corresponding sulfonate 41, sulfon-
amides 42–43, esters 44–46, and amides 47–48 in a range of 26–
99% yields (Table 2, entries 6–13).
Once the key intermediate 7 was in hand, we next expanded the
chemical diversity of macrocyclic amine derivatives by employing
various amine substrates (Table 1). The reduction of in situ formed
imines with NaBH
Specifically, reduction of 7 in concentrated ammonia solution
7 N in methanol) gave primary amine 9 in 50% yield. In the cases
of amine derivatives 12, 15, 19, 22, and 23 (Table 1, entries 4, 7, 11,
4 and 15), low to moderate yields (19–58%) were obtained under
4
gave their corresponding amine products.
(
1
this reaction condition due to the simultaneous formation of the
reduced alcohol by-product 8 from starting material 7. We subse-
quently found that the yield and selectivity of this reductive ami-
nation reaction can be greatly improved by using a milder
reductant NaBH CN, resulting in the desired macrocyclic amine
3
derivatives in good yields with no or only trace amounts of 8 for
most primary amine substrates.
With the optimized conditions, compounds 10 and 11 (Table 1,
entries 2 and 3), with a 3- and 4-carbon linker, respectively, were
designed and synthesized to probe the effect of the spacer length of
the alkyl side chain. Compounds 12–18 (Table 1, entries 4–10)
were synthesized to evaluate different groups and substitution
patterns of the phenyl ring by using substituted phenethyl amines
as the substrates. The amine derivatives 19–21 (Table 1, entries
1
1–13) with different aromatic/heterocyclic ring systems (pyri-
dine, naphthalene, and 1,3-benzodioxole) were also prepared in
moderate to good yields. Compounds 19, 22, and 32 (Table 1,
entries 11, 14, and 22) with two basic nitrogen functionalities on
the side chain of the macrocyclic scaffold were also synthesized.
Accordingly, reaction of 7 with optically pure (R)-(ꢀ)-1,2,3,4-
tetrahydro-1-naphthylamine or (S)-(+)-1,2,3,4-tetrahydro-1-naph-
Finally, based on the promising antibacterial activity of 15
(described below), a focused set of structural analogs 49–53
(Fig. 2) with 12, 14, and 15-membered ring systems as well as dif-
ferent methoxy substitution patterns were next prepared to probe
the SAR. These compounds were synthesized from their corre-
sponding ketone macrocycles and 4-fluorophenethyl amine under
Lin, Hao
