Biomedical Engineering Reference
In-Depth Information
with modest diastereoselectivity. The crude cycloadducts were isolated in about
90% purity.
Based on this methodology, a small prototype library of nine compounds was
synthesized with overall yields ranging from 12 to 37%. Diastereoselectivities ranged
from 1 : 1 to 5 : 1 as a result of endo/exo cycloaddition modes, as shown in Table 5.1.
Since a large variety of aldehydes and a more limited selection of enol ethers are
available commercially, this one-pot three-component domino sequence should be
amendable to the synthesis of more extensive and quite diverse libraries.
The Aube group made use of a Diels-Alder-acylation sequence to assemble an
N
-
alkyloctahydroisoquinlin-1-one-8-carboxamide library (Scheme 5.2) [8]. Although
the mechanistic pathway for this domino sequence is still undefined, it is believed to
involve either the Diels-Alder reaction followed by an intramolecular acylation, or
the reverse sequence (i.e., acylation, then cycloaddition). The optimal cycloaddition
conditions for the aminoethyl-tethered butadienes
5
and maleic anhydride involved
microwave irradiation at 165
◦
C in 1,2-dichloroethane. All isoquinolinone-carboxylic
acids
7
were obtained as single stereoisomers in good yields (68 to 80%). Six struc-
turally diverse heterocyclic building blocks were further elaborated in a parallel
format to generate a 72-membered compound library through conversion to amides
8
(Scheme 5.2 and Table 5.2).
The Aube group also reported an elegant Diels-Alder-Schmidt domino reaction
approach to the tricyclic core ring systems of various
Stemona
alkaloids (Scheme 5.3)
[9]. This synthetic strategy not only provided the four contiguous stereocenters of the
Stemona
core but also proved to be sufficiently efficient for total synthesis applications
[10]. Several of these library members have recently been shown to have potent
binding efficiencies to numerous GPCR receptors (i.e., sigma 1/2, adrenergic alpha
1/2) [11].
The treatment of azidoethyl-tethered butadienes
9
with cyclohexenenones (or
cyclopentenones) in the presence of stoichiometric BF
3
.
OEt
2
exclusively provided
the endo-cycloadduct ring-expanded lactam products
11
. It was also found that SnCl
4
could promote this reaction sequence to afford high to exclusive ratios of endo iso-
mers. In many instances, the cycloadducts
10
were not isolated, as these intermediates
underwent a subsequent intramolecular Schmidt reaction under Diels-Alder reaction
conditions. Based on this methodology, a series of six-tricyclic templates were pre-
pared in sufficient quantities to allow for further diversifications (Scheme 5.4).
The carbonyl group containing intermediates
11
were converted further to either
phenylamines or 4-phenylpiperazine derivatives via imine formation with TiCl
4
/
Ti(O
i
-Pr)
4
followed by reduction with NaBH
3
CN (Scheme 5.4). In most cases, these
aminations were unselective and gave inseparable mixtures of diastereomers, with
the exception of phenylamine
12
. The configuration in this series of analogs was
firmly established by the x-ray structure analysis of a dichlorobenzamide deriva-
tive. The diastereomerically pure
-phenylamines
12
were converted to
a set of structurally diverse tertiary amines
16
by a second reductive amination
(Scheme 5.5).
A stereochemically diverse collection of carbamates
13
was readily assembled
from the corresponding alcohols derived from the pivotal ketone intermediates
11
- and
