Biomedical Engineering Reference
In-Depth Information
subsequent cleavage from the resin gave the desired polyfunctionalized products
.
Additional reactive sites offered the opportunity for further diversity such as epoxide
ring opening or N-O reductive cleavage. However, thesewere not exploited. This five-
step diversity-generating sequence required tremendous chemical optimization to
ensure that the desired structures were obtained in high yield and high purity,
conditions required while synthesizing thousands of compounds in a single reaction
vessel. It is notable that the final analogues were based on a unique complex molecular
framework and it is questionablewhether the library is structurally diverse or resembles
traditional structurally focused combinatorial libraries. Nevertheless, Tan et al.
demonstrated the biological relevance of the method with the discovery of small
molecules that activate a TGF-
b
-responsive reporter gene in mammalian cells.
14
15.4.3. Stereochemical Considerations
Synthetic processes generating asymmetric centers are appealing to DOS because a
high level of structural complexity and stereochemical diversity can be reached.
Ideally, it is desirable to be able to trigger and control the formation of each possible
stereochemical outcome for a given chemical transformation. This emphasizes the
need to expand not only the repertoire of currently available stereoselective reactions,
but also the invention of novel powerful catalysts to override the selectivity imposed
by the substrate. To fulfill the requirement of DOS, catalysts must promote the
efficient and reliable conversion of a collection of substrates into desired complex
products regardless of the diverse structural nature of the library. Diels-Alder
cycloadditions, potentially generating several stereogenic centers in a single step,
are excellent examples of such complexity-generating processes. These reactions,
controlled by molecular orbitals, typically lead to
endo
-cycloadducts, especially
during intermolecular processes where no structural bias is imposed. Chiral catalysts
have been used to dictate the enantio- and diastereofacial selectivities of the
process [30]. However, the control of regio- and
endo
/
exo
-diastereoselectivities
appears to bemore challenging. The development of a catalyst enabling the controlled
formation of a single
exo
-isomer would be a highly valuable synthetic tool.
Shaw and Mitchell described the linear synthesis of a polycyclic small
molecule-containing library obtained from an asymmetric metal-catalyzed Suga-
Ibata reaction [31,32], followed by a base-catalyzed
C
-alkylation, a Staudinger-
mediated reductive ring closure, and an
N
-alkylation (Scheme 15.4). The synthetic
planning was based on the strategic placement of an azido functionality proximal to a
methyl ester, allowing the selective formation of medium-sized ring-containing
lactams as rigid tricyclic structures
19
-
22
. An aluminum-based chiral catalyst was
employed to promote the condensation of
in excellent
enantiomeric excess with two stereogenic centers at C4 and C5. Both enantiomers of
the catalyst were used, thus providing additional stereochemical diversity. The second
step involved a highly diastereoselective methyl ester
anti
-alkylation, where the
selectivity was directed by the substituent at C5. Products
15
and
16
, giving rise to
17
were then cyclized in the
presence of trimethylphosphine and DBU. A series of electrophiles were finally
reacted with the resulting lactams in the presence of phosphazene base to afford the
final products
19
-
22
. Compounds
18
lacking the azide functionality were converted
18
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