Addition of the enolate derived from 2-acetylindole
1a to pyridinium salt 2 followed by in
situ
trapping of the initially formed 1,4-dihydropyridine 3a with
Eschenmoser's salt gives tetracycle
5a. Subsequent elaboration of the exocyclic methylene
and E-ethylidene substituents leads to
N
a-methylervitsine (17a). A similar sequence from the
N
a-protected 2-acetylindole 1c
establishes the
first total synthesis of the 2-acylindole alkaloid ervitsine.
Alternatively, dihydropyridine 3a is
trapped with BrSePh to give the tetracyclic selenide 7a,
which is then converted to N
a-methylervitsine by way of selenoxide 20. The synthesis
of the alkaloids of the ervatamine group
starts with the addition of the enolate derived from
2-acetyl-1-benzylindole (1g) to pyridinium salt
24 and the conversion of the resulting 1,4-dihydropyridine
to 3,5-diacylated dihydropyridine 26g.
Chemoselective reduction of the vinylogous amide moiety of
26g, followed by deprotection of the
indole ring and LiEt3BH reduction leads to diol
37b. On sequential treatment with
Eschenmoser's
salt, methyl iodide, NaCNBH3, and MnO2,
37b is converted to the tetracyclic 2-acylindole
39, from
which the first total synthesis of 19,20-didehydroervatamine and
20-epiervatamine is accomplished
by manipulation of the 1-hydroxyethyl chain. The above syntheses
can be considered as biomimetic,
as cyclization of the key intermediates I and II
mimics the key steps of the biosynthesis of the title
alkaloids.
[structure: see text] A high-yielding totally regioselective intramolecular homolytic acylation of a quinoline ring constitutes the key step in a new synthesis of the pentacyclic indolo[3,2-j]phenanthridine alkaloid calothrixin B.
The dimethyltitanocene methylenation of N-acylamides derived from ortho-vinylanilines, ortho-allylaniline, and ortho-vinylbenzylamine provides the corresponding enamides, which upon exposure to the second generation Grubbs ruthenium catalyst give access to indoles, 1,4-dihydroquinolines, and 1,2-dihydroisoquinolines, respectively. This sequential protocol also allows the synthesis of dihydrobenzoazepines, although the ring-closing metathesis (RCM) step is complicated by the alkene isomerization processes. From certain substrates, the direct annulation is observed in the titanium-mediated step, which is likely to occur through an olefin metathesis-intramolecular olefination sequence.
[reaction: see text] 2-Indolylacyl radicals generated from the corresponding selenoesters under hexabutylditin-hnu conditions undergo regioselective intramolecular reaction with unprotonated pyridines to give polycyclic indolylpyridyl ketones. For substrates bearing a (3-pyridyl)methyl moiety connected to the 3-position of the indole ring, the cyclization provides easy access to ellipticine quinones.
The addition of enolates derived from indole-3-acetic esters
1−3 to pyridinium salts 4,
23, and 24,
followed by acid cyclization of the resulting 1,4-dihydropyridines,
leads to tetrahydro-1,5-methanoazocino[3,4-b]indoles
5−7, 25−27, which have
been subsequently elaborated into 4E-ethylidene(or
4α-ethyl)-hexahydro-1,5-methanoazocino[3,4-b]indoles.
Closure of the six-membered
C ring of akuammiline alkaloids by formation of C-6/C-7 bond from
appropriately
N
(b)
-substituted
derivatives of these tetracyclic ABDE substructures has been
extensively investigated. In the
N-unsubstituted indole series, both cyclization of thionium
ions generated either by Pummerer
reaction from sulfoxide 16 or by DMTSF treatment of
dithioacetal 36 and photocyclization of
chloroacetamide 47 occur upon the indole nitrogen to give
pentacycles 18, 38, and 49,
respectively.
When the indole nitrogen is blocked by a substituent, the thionium
ions derived from sulfoxides 17
and 43 and dithioacetals 37 and 44 do
not cyclize and lead to different products depending on
the
reaction conditions, whereas chloroacetamides 48 and
51 undergo a reductive photodehalogenation.
Attempted radical cyclization of seleno derivatives 53,
55, and 56 under a variety of
conditions
gives the corresponding reduced products. Finally, attempted
photoisomerization of 1-acylindole
62 leads to the
N
(b)
-methyl tetracycle
63.
An indole-templated ring-closing metathesis has been used to create the central nine-membered ring of the cleavamine-type alkaloids. A subsequent intramolecular vinyl halide Heck reaction upon the resulting azacyclononene ring completes the assembly of the strained 1-azabicyclo[6.3.1]dodecane framework of the alkaloids. The usefulness of the approach is illustrated with the synthesis of (±)-cleavamine and (±)-dihydrocleavamine.
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