64
D. Enders, M.R.M. Hüttl, O. Niemeier
tions are replaced by amino groups. They are found as parts of glycoproteins, glycolipids, aminoglycosides, and many biologically active
secondary metabolites containing free, methylated or acetylated amino
groups (Wong CH 2003; Weymouth-Wilson 1997). The substitution of
a hydroxy function by an amino group may alter the properties of the
sugar significantly, for example, its hydrogen bonding properties, solubility, and charge. Consequently, amino sugars play important physiological roles in many glycoconjugates and are of interest for the development of new drugs (Wong 2003).
Initially, the (S)-proline-catalyzed three-component Mannich reaction of 6 with dioxanone (4) and para-anisidine (36), as the amine component, was achieved (Enders et al. 2005b). Thus, in the presence of
30 mol% (S)-proline in DMF at 2°C we obtained the Mannich product
39 in 91% yield and excellent stereoselectivities (>99% de, 98% ee,
see Scheme 11). After recrystallization from heptane/2-propanol (9:1)
39 could be obtained in practically diastereo- and enantiomerically pure
form. Analogous conditions employed for the α-branched aldehydes
also led to very good yields and selectivities. In the case of linear aldehydes such as 41 the results obtained under the above reaction conditions were not as good. Following extensive optimization of the reaction
conditions 41 was obtained in 77% yield and with improved stereoselectivities (88% de, 96% ee) using 38 as a catalyst, acetonitrile as a solvent,
and five equivalents of water. In all cases the syn configuration of the
Mannich products was observed, which was confirmed both by nuclear
Overhauser effect (NOE) measurements and an X-ray crystal structural
analysis. The result is consistent with the transition state proposed by
List et al.
Furthermore, several derivatizations of the Mannich products were
possible, for example, via diastereoselective reduction of the ketone
function or by direct reductive amination, as illustrated for 44 and 45
(Scheme 12) (Enders et al. 2005b, 2006b). Thus, the reduction of 39
with l-selectride proceeded with high stereocontrol to yield the all-synconfigured β-amino alcohol 45, which in its protected form belongs
to the class of the biologically very important 2-amino-2-deoxy sugars (Enders et al. 2005b). Alternatively, the anti-aminoalcohol 44 was
available by Me 4 NHB(OAc) 3 -mediated reduction. The direct reductive
amination was carried out using NaHB(OAc) 3 , BnNH 2 and acetic acid.
D. Enders, M.R.M. Hüttl, O. Niemeier
tions are replaced by amino groups. They are found as parts of glycoproteins, glycolipids, aminoglycosides, and many biologically active
secondary metabolites containing free, methylated or acetylated amino
groups (Wong CH 2003; Weymouth-Wilson 1997). The substitution of
a hydroxy function by an amino group may alter the properties of the
sugar significantly, for example, its hydrogen bonding properties, solubility, and charge. Consequently, amino sugars play important physiological roles in many glycoconjugates and are of interest for the development of new drugs (Wong 2003).
Initially, the (S)-proline-catalyzed three-component Mannich reaction of 6 with dioxanone (4) and para-anisidine (36), as the amine component, was achieved (Enders et al. 2005b). Thus, in the presence of
30 mol% (S)-proline in DMF at 2°C we obtained the Mannich product
39 in 91% yield and excellent stereoselectivities (>99% de, 98% ee,
see Scheme 11). After recrystallization from heptane/2-propanol (9:1)
39 could be obtained in practically diastereo- and enantiomerically pure
form. Analogous conditions employed for the α-branched aldehydes
also led to very good yields and selectivities. In the case of linear aldehydes such as 41 the results obtained under the above reaction conditions were not as good. Following extensive optimization of the reaction
conditions 41 was obtained in 77% yield and with improved stereoselectivities (88% de, 96% ee) using 38 as a catalyst, acetonitrile as a solvent,
and five equivalents of water. In all cases the syn configuration of the
Mannich products was observed, which was confirmed both by nuclear
Overhauser effect (NOE) measurements and an X-ray crystal structural
analysis. The result is consistent with the transition state proposed by
List et al.
Furthermore, several derivatizations of the Mannich products were
possible, for example, via diastereoselective reduction of the ketone
function or by direct reductive amination, as illustrated for 44 and 45
(Scheme 12) (Enders et al. 2005b, 2006b). Thus, the reduction of 39
with l-selectride proceeded with high stereocontrol to yield the all-synconfigured β-amino alcohol 45, which in its protected form belongs
to the class of the biologically very important 2-amino-2-deoxy sugars (Enders et al. 2005b). Alternatively, the anti-aminoalcohol 44 was
available by Me 4 NHB(OAc) 3 -mediated reduction. The direct reductive
amination was carried out using NaHB(OAc) 3 , BnNH 2 and acetic acid.