Biomedical Engineering Reference
In-Depth Information
TABLE 1.1 The Comparable Effects of Emmacin, the Enantiomers
of Gemmacin, Gemmacin B, Erythromycin, and Oxacillin on Three
Strains of
Staphylococcus aureus
MIC
50
(
g/mL)
MSSA
EMRSA-15
EMRSA-16
Emmacin
2
9
9
(
±
)-Gemmacin B
Not determined
8
8
(
±
)-Gemmacin
2
16
32
Erythromycin
0.5
>
64
>
64
Oxacillin
0.5
>
32
>
32
group [52]. Their synthesis could also be considered to be an example of the
build/couple/pair approach. In what could be identified as the build and couple
stages, they synthesized the four possible diastereomers of
N
-allylpropargylic amino
alcohol
15a-d
in six steps from (
R
)- and (
S
)-phenylalanine using standard methods
[53]. They were then able to transform these compounds into a range of interest-
ing scaffolds, by pairing functional groups using transition metal-catalyzed enyne
cyclizations. When
15a
was used, they saw unusual endoselectivity in an enyne
metathesis cyclization to give seven-membered ring product
16
. Then, protecting the
free hydroxyl group in
15a
as the corresponding acetate
17
gave complete selec-
tivity for the more usual six-membered exoproduct
18
, and also allowed bicyclic
cyclopentenone
19
to be synthesized via a cobalt-catalyzed Pauson-Khand reac-
tion. Treating
15a
with InCl
3
under microwave conditions gave
20
, and treatment
with TBAF resulted in a Smiles rearrangement to give
21
. Interesting bridged bi-
and tricyclic structures
23
and
24
were synthesized by initial S
N
Ar cyclization to
give
22
, followed by subsequent enyne metathesis and Pauson-Khand cyclizations
(Scheme 1.3).
Similar cyclizations were carried out on other isomers of
6
to give a small library
of structurally complex single stereoisomer small molecules. This DOS pathway
provides a useful illustration of the versatility of enyne functionality; this versatility
makes the use of enyne functionality very popular in DOS campaigns [54,55].
1.8.3 Twelve-fold Branching Strategy
The strategies described above are intended to highlight the general themes of pluripo-
tent reactivity and dense functionality commonly utilized in DOS. However, these
concepts are not exhaustive, and there are many examples of DOS campaigns that
resist such generalization, as they do not fall neatly within either category. One
such example is the 12-fold branching strategy reported in 2011 by Robbins et al.
(Scheme 1.4) [56]. In this work, the authors combined two-directional synthesis and
tandem reactions to transform a symmetrical linear ketone
25
into 12 distinct scaf-
folds. Their strategy involved the initial transformation of the central ketone group