Biomimetic Organocatalytic C–C-Bond Formations
73
should lead to a decreasing efficiency of the catalyst towards the desired pathway. Afterwards, the developed conditions were evaluated using the α-branched aldehydes 6 as carbonyl components. In spite of
the modest yields (31%–45%), in all cases the expected aldol product
was obtained in very good diastereomeric excess (90%–92% de) with
an increase in the reaction rate when aldehydes bearing a heteroatom
in the β position were used. The given stereochemical assignments are
based on the X-ray crystal structure analysis, which proved an (R)configuration at the newly formed stereogenic centre and is in agreement with the transition state model for the proline-catalyzed aldol reaction. The epimeric aldol products 62 and 64 were easily deprotected
with an acidic ionic-exchange resin (Amberlyst 15) to give the hemiketals 63 and 65 (Scheme 15).
Upon acidic treatment 62 afforded only the pyranose form 63 as
a single anomer, which could be straightforwardly converted into the
4-epi-KDG. In contrast, the aldol 64 provided only the furanose ring
65 in both possible anomeric forms (α:β = 1:1), whose stereogenic centers C(4) and C(5) have the correct configurations as a direct precursor
of 2-keto-3-deoxy-d-glucosonic acid (d-KDG, 58). In conclusion, we
have developed a direct entry to precursors of ulosonic and sialic acids
by means of an organocatalytic approach closely resembling the natural
pathway. Despite the modest yields, the proline catalyzed aldol reaction might easily be scaled up to yield gram amounts of key intermediates for the synthesis of biologically challenging molecules. The high
stereoselectivity of our protocol as well as the broad range of proline
organocatalysis makes it suitable to a wide scope of substrates.
2.3
First Direct Organocatalytic α-Fluorination
of Aldehydes and Ketones
Due to the unique properties of fluorinated compounds there has been
a growing interest in the selective introduction of one or more fluorine atoms into organic molecules (Shimizu and Hiyama 2005; Welch
and Eswarakrishnan 1991; Soloshonok 1999; Chambers 2004). In particular, the resistance to many metabolic transformations, as well as the
increased lipophilicity and stability of fluorine-containing compounds is
of importance to the pharmaceutical and agrochemical industry
73
should lead to a decreasing efficiency of the catalyst towards the desired pathway. Afterwards, the developed conditions were evaluated using the α-branched aldehydes 6 as carbonyl components. In spite of
the modest yields (31%–45%), in all cases the expected aldol product
was obtained in very good diastereomeric excess (90%–92% de) with
an increase in the reaction rate when aldehydes bearing a heteroatom
in the β position were used. The given stereochemical assignments are
based on the X-ray crystal structure analysis, which proved an (R)configuration at the newly formed stereogenic centre and is in agreement with the transition state model for the proline-catalyzed aldol reaction. The epimeric aldol products 62 and 64 were easily deprotected
with an acidic ionic-exchange resin (Amberlyst 15) to give the hemiketals 63 and 65 (Scheme 15).
Upon acidic treatment 62 afforded only the pyranose form 63 as
a single anomer, which could be straightforwardly converted into the
4-epi-KDG. In contrast, the aldol 64 provided only the furanose ring
65 in both possible anomeric forms (α:β = 1:1), whose stereogenic centers C(4) and C(5) have the correct configurations as a direct precursor
of 2-keto-3-deoxy-d-glucosonic acid (d-KDG, 58). In conclusion, we
have developed a direct entry to precursors of ulosonic and sialic acids
by means of an organocatalytic approach closely resembling the natural
pathway. Despite the modest yields, the proline catalyzed aldol reaction might easily be scaled up to yield gram amounts of key intermediates for the synthesis of biologically challenging molecules. The high
stereoselectivity of our protocol as well as the broad range of proline
organocatalysis makes it suitable to a wide scope of substrates.
2.3
First Direct Organocatalytic α-Fluorination
of Aldehydes and Ketones
Due to the unique properties of fluorinated compounds there has been
a growing interest in the selective introduction of one or more fluorine atoms into organic molecules (Shimizu and Hiyama 2005; Welch
and Eswarakrishnan 1991; Soloshonok 1999; Chambers 2004). In particular, the resistance to many metabolic transformations, as well as the
increased lipophilicity and stability of fluorine-containing compounds is
of importance to the pharmaceutical and agrochemical industry