126
M. Christmann
strategies. It is no exaggeration to dub catalytic reactions the cornerstones in the design of future sustainable chemical processes. Besides
the field of transition metal-catalyzed processes and enzymatic reactions, organocatalysis has undoubtedly enriched the field of asymmetric
catalysis. The stage is now set to examine its practicability and reliability. In a recent review (de Figueiredo and Christmann 2007), we have
compiled applications of organocatalytic reactions in the synthesis of
drugs and natural products. Here we discuss the role of organocatalysis
in our synthesis (de Figueiredo et al. 2007) of the telomerase inhibitor
UCS1025A from the planning perspective. In addition, applications to
the synthesis of other bioactive molecules are presented.
2
UCS1025A
In a screening program for new fungal metabolites (Nakai et al. 2006),
Yamashita et al. isolated UCS1025A (1) from Acremonium sp. KY4917
(Nakai et al. 2000). The absolute and relative configuration was elucidated by Agatsuma and Kanda using two-dimensional NMR and X-ray
crystallographic analysis (Agatsuma et al. 2002). UCS1025A possesses
a pentacyclic framework with a dense array of eight stereocenters and
an unprecedented furopyrrolizidine (Scheme 1). More interestingly, 1
comprises a new natural product telomerase inhibitor (Shin-ya et al.
2001; Warabi et al. 2003, 2005; Rezler et al. 2005; Doi et al. 2006;
Fürstner et al. 2006) and many groups (Snider and Neubert 2004) have
embarked on its synthesis. In early 2006, Danishefsky (Lambert and
Danishefsky 2006) and Hoye (Hoye and Dvornikovs 2006) succeeded.
Our retrosynthetic analysis disconnects UCS1025A into the tentative
pyrrolizidine-derived enolate 2 and the decalin aldehyde 3 (Scheme 1).
For the synthesis of the pyrrolizidine fragment (2), we identified
maleic anhydride (5, 7 e/kg), aminobutyric acid (6, 120 e/kg) and
trienal 7 as readily available starting materials. In the most ambitious
disconnection, the racemic pyrrolizidine carboxylic acid 4a, could be
assembled, in principle, in a single step from 4-aminobutyric acid (6)
and maleic anhydride (5). A subsequent kinetic resolution via oxaMichael addition would then generate an enantiomerically enriched enolate equivalent, which could in turn add to the aldehyde 3. However,
M. Christmann
strategies. It is no exaggeration to dub catalytic reactions the cornerstones in the design of future sustainable chemical processes. Besides
the field of transition metal-catalyzed processes and enzymatic reactions, organocatalysis has undoubtedly enriched the field of asymmetric
catalysis. The stage is now set to examine its practicability and reliability. In a recent review (de Figueiredo and Christmann 2007), we have
compiled applications of organocatalytic reactions in the synthesis of
drugs and natural products. Here we discuss the role of organocatalysis
in our synthesis (de Figueiredo et al. 2007) of the telomerase inhibitor
UCS1025A from the planning perspective. In addition, applications to
the synthesis of other bioactive molecules are presented.
2
UCS1025A
In a screening program for new fungal metabolites (Nakai et al. 2006),
Yamashita et al. isolated UCS1025A (1) from Acremonium sp. KY4917
(Nakai et al. 2000). The absolute and relative configuration was elucidated by Agatsuma and Kanda using two-dimensional NMR and X-ray
crystallographic analysis (Agatsuma et al. 2002). UCS1025A possesses
a pentacyclic framework with a dense array of eight stereocenters and
an unprecedented furopyrrolizidine (Scheme 1). More interestingly, 1
comprises a new natural product telomerase inhibitor (Shin-ya et al.
2001; Warabi et al. 2003, 2005; Rezler et al. 2005; Doi et al. 2006;
Fürstner et al. 2006) and many groups (Snider and Neubert 2004) have
embarked on its synthesis. In early 2006, Danishefsky (Lambert and
Danishefsky 2006) and Hoye (Hoye and Dvornikovs 2006) succeeded.
Our retrosynthetic analysis disconnects UCS1025A into the tentative
pyrrolizidine-derived enolate 2 and the decalin aldehyde 3 (Scheme 1).
For the synthesis of the pyrrolizidine fragment (2), we identified
maleic anhydride (5, 7 e/kg), aminobutyric acid (6, 120 e/kg) and
trienal 7 as readily available starting materials. In the most ambitious
disconnection, the racemic pyrrolizidine carboxylic acid 4a, could be
assembled, in principle, in a single step from 4-aminobutyric acid (6)
and maleic anhydride (5). A subsequent kinetic resolution via oxaMichael addition would then generate an enantiomerically enriched enolate equivalent, which could in turn add to the aldehyde 3. However,