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6293
Cl
O
Cl
O
Cl
Cl
HO
Cl
O
O
O
N
N
(a)
O
O
(a)
4
8
Cl
O
Cl
Cl
O
Cl
O
Cl
O
Cl
Cl
Cl
O
(b)
(c)
HO
(b)
(c)
HO
HO
HO
N
O
Cl
+
HO
O
N
O
O
N
N
N
O
O
1
N
O
O
O
3
10
9
5
O
Cl
O
Cl
d)
N
(d)
HO
Br
S
O
O
Cl
N
HO
O
O
Cl
O
11
HO
O
N
N
O
6
N
O
O
12
N
O
Cl
Scheme 2. Armeniaspirole
C
derivatives. Reagents and conditions: (a) MeI
t
HO
(5 equiv), K2CO3 (5 equiv), DMF, 40 °C, 3 h, quant; (b) excess BH3Á BuNH2,THF/
MeCN (9:1), 60 °C, 10 h, 49% of 9 and 13% of 10; (c) Br2 (1.2 equiv), AcOH, RT, 12 h,
68% (d) NaOMe (10 equiv), MeOH, 80 °C, 12 h, 18%.
O
N
7
O
Scheme 1. Armeniaspirol
A derivatives. Reagents and conditions: (a) SO2Cl2
(1.2 equiv), CH2Cl2, rt, 12 h, 72%; (b) isopropyl amine (2 equiv), NEt3 (2 equiv),
CH2Cl2, 50 °C, 12 h, 61%; (c) 2-diethylamino-ethanethiolÁHCl (2 equiv), NaH
(2 equiv), CH2Cl2, 50 °C, 12 h, 65%; (d) pyridin-4-yl-methylamine, (2 equiv), NEt3
(2 equiv), CH2Cl2, 50 °C, 12 h, 73%.
the close biosynthetic relations between Streptopyrrole, the Pyr-
rolomycins and the Armeniaspirols.
Inspired by this biosynthetic pathway, a biomimetic synthesis
to the Armeniaspirole core was envisaged starting from 19
(Scheme 4). The pyrrolo-phenone precursor 19 was readily avail-
able in two steps from N-methyl pyrrole and 2-methoxy-benzoyl
chloride under modified Friedel–Crafts conditions, followed by Le-
wis acid cleavage of the methyl ether.
structure activity relationship and did not show any improved
antibacterial activities except with the incorporation of halogen
into the phenol group.
In first attempts to achieve a spiro-cyclisation intermediate, 19
was subjected to oxidative halogenation conditions with 2 equiv of
bromine in acetic acid at room temperature. However, no cyclisa-
tion was observed. Instead, di-bromination of the pyrrole nucleus
led to a simplified analogue 20 of the pyrrolomycins in 71% yield.
Treatment of 20 with trifluoroacetic acid at room temperature gave
a mixture of products (21 and 22) with a pyrrolobenzoxazin skel-
eton that is found in TAN-876A, a metabolite from Streptomyces
sp. C-70899.12 The reaction 20 with N-bromosuccinimide in acetic
acid at 70 °C finally led to a mixture of mono-, di- and tribrominat-
ed products 23, 24 and 25 with the desired spiro-skeleton, the main
product being the di-bromo derivative.
Reaction of 20 with N-chlorosuccinimide in acetic acid under
optimized conditions gave the trichlorinated spiro-intermediate
27 as a main product in 65% yield (Scheme 5). A dehydrohalogen-
ation with NEt3 in CHCl3 furnished 30, a compound with the cor-
rect racemic Armeniaspirole skeleton, in 92% yield.
Halogenation of the Armeniaspiroles with Br2 or SO2Cl2 fur-
nished selectively the ortho-substituted derivatives (relative to
the phenolic OH function) 4 and 11. The reaction of 1 with the
N-nucleophiles isopropyl amine and pyridine-4-yl-methylamine,
and the S-nucleophile 2-diethylamino–ethanethiol selectively led
to nucleophilic substitution products 5, 7, and 6 at the activated
b-position of the unsaturated lactame. A substitution by O-nucleo-
philes was hardly feasible; the less nucleophilic reagent NaOMe
reacted with 3 under more drastic conditions to give the corre-
sponding methoxy substitution product 12 in low (18%) yield.
Alkylation of the phenol function could be achieved in good to
excellent yields with alkyl bromides or alkyl iodides in dimethyl-
formamide in the presence of K2CO3. The ketone moiety of the fur-
t
an ring could be reduced chemoselectively with excess BH3Á BuNH2
to an 8:2 mixture of the corresponding secondary alcohols 9 and
10.
In order to get access to broader structural variations, a total
synthesis of the Armeniaspiroles was envisaged. In 1999, Raggatt
et al.,10 reported a study on the biosynthesis of streptopyrrole
(XR857) 17, a secondary metabolite isolated from two Streptomyces
sp. with a pyrrolobenzoxazin skeleton (Scheme 3). Isotope labeling
studies established a biosynthetic pathway through a sequence of
oxidation and chlorination steps with a pyrrol-polyketide interme-
diate 13, closely related to the pyrrolomycin-type metabolites from
Streptomyces fumans,11 and a postulated spiro-intermediate 15,
which represents essentially the 1-oxa-6-aza-spiro[4.4]non-8-ene
skeleton of the Armeniaspiroles. Although intermediates 13 and
15 were neither isolated nor characterized, Scheme 3 indicates
A refined approach to Armeniaspiroles bearing the alkyl chain
substitutions is summarized in Scheme 6. We envisioned to con-
struct the highly functionalized tricyclic scaffold starting from
2,6-dimethoxybromobenzene. The alkyl chain was attached
through a Suzuki-Miuyra coupling13 with the corresponding hex-
ylboronic acid that proceeded in 70% yield to afford compound
31. Friedel–Crafts reaction of the latter with pyrrole-2-carbonyl
chloride 32 provided compound 33 in a moderate 60% yield.
The next step of the sequence comprised a selective demethyl-
ation with BBr3 to give compound 34 (82% yield). The later was en-
gaged in the key cyclisation step. After consecutive treatment of 34
with N-chlorosuccinimide in acetic acid and triethylamine, com-