For RAMA the following rules apply to the aldehyde component:
• In general, unhindered aliphatic, α-heterosubstituted, and protected alkoxy aldehydes are accepted as substrates.
• Sterically hindered aliphatic aldehydes such as pivaldehyde do not react with
RAMA, nor do α,β-unsaturated aldehydes or compounds that can readily be
eliminated to form α,β-unsaturated aldehydes.
• Aromatic aldehydes are either poor substrates or are unreactive.
• ω-Hydroxy acceptors that are phosphorylated at the terminal hydroxyl group are
accepted at enhanced rates relative to the nonphosphorylated species.
In contrast to the relaxed specificity for the acceptor, the requirement for DHAP
as the donor is much more stringent. Several isosteric analogs which are more
resistant towards spontaneous hydrolysis have been successfully tested as substitutes for DHAP (Scheme 2.182) [1540], however the reaction rates were reduced by
about one order of magnitude [1541–1544].
Within group-I aldolases, FDP aldolase from rabbit muscle has been extensively
used for the synthesis of biologically active sugar analogs on a preparative scale
(Scheme 2.183). For example, nojirimycin and derivatives thereof, which have
been shown to be potent anti-AIDS agents with no cytotoxicity, have been obtained
by a chemoenzymatic approach using RAMA in the key step. As expected, the
recognition of the α-hydroxy stereocenter in the acceptor aldehyde was low and
gave diastereomers with respect to C 5 [1545, 1546].
O
H
R
OH
OH O
O
R
O
O
HO
R (non-natural substrates)
H, Me, Et, n-Pr, i-Pr, CH=O, CO 2 H, CH 2 F, CH 2 Cl,
CH 2 OCH 2 Ph, (CH 2 ) 2 OH, CH(OCH 3 )CH 2 OH,
(CH 2 ) 2 OMe, CHOHMe, CHOHCH 2 OMe,
CH 2 Ph, COPh, (CH 2 ) 3 CH=O,
CH 2 P(O)(OEt) 2 , 2- and 3-pyridyl,
4-cyclohexenyl, CH 2 O
4
3
R (natural substrates)
D- or L-threose
D- or L-erythrose
L-arabinose, D-ribose,
D-lyxose, D-xylose
FDP aldolase
DHAP
= phosphate
O
P
P
P
,
P
D-glyceraldehyde-3- P
Scheme 2.181 Aldol reactions catalyzed by FDP aldolase from rabbit muscle
PO 3
2O
X
HO
X = O, NH, S, CH 2
Scheme 2.182 Nonnatural DHAP substitutes for fructose-1,6-diphosphate aldolase (RAMA)
2.4 Formation of Carbon–Carbon Bonds
209
• In general, unhindered aliphatic, α-heterosubstituted, and protected alkoxy aldehydes are accepted as substrates.
• Sterically hindered aliphatic aldehydes such as pivaldehyde do not react with
RAMA, nor do α,β-unsaturated aldehydes or compounds that can readily be
eliminated to form α,β-unsaturated aldehydes.
• Aromatic aldehydes are either poor substrates or are unreactive.
• ω-Hydroxy acceptors that are phosphorylated at the terminal hydroxyl group are
accepted at enhanced rates relative to the nonphosphorylated species.
In contrast to the relaxed specificity for the acceptor, the requirement for DHAP
as the donor is much more stringent. Several isosteric analogs which are more
resistant towards spontaneous hydrolysis have been successfully tested as substitutes for DHAP (Scheme 2.182) [1540], however the reaction rates were reduced by
about one order of magnitude [1541–1544].
Within group-I aldolases, FDP aldolase from rabbit muscle has been extensively
used for the synthesis of biologically active sugar analogs on a preparative scale
(Scheme 2.183). For example, nojirimycin and derivatives thereof, which have
been shown to be potent anti-AIDS agents with no cytotoxicity, have been obtained
by a chemoenzymatic approach using RAMA in the key step. As expected, the
recognition of the α-hydroxy stereocenter in the acceptor aldehyde was low and
gave diastereomers with respect to C 5 [1545, 1546].
O
H
R
OH
OH O
O
R
O
O
HO
R (non-natural substrates)
H, Me, Et, n-Pr, i-Pr, CH=O, CO 2 H, CH 2 F, CH 2 Cl,
CH 2 OCH 2 Ph, (CH 2 ) 2 OH, CH(OCH 3 )CH 2 OH,
(CH 2 ) 2 OMe, CHOHMe, CHOHCH 2 OMe,
CH 2 Ph, COPh, (CH 2 ) 3 CH=O,
CH 2 P(O)(OEt) 2 , 2- and 3-pyridyl,
4-cyclohexenyl, CH 2 O
4
3
R (natural substrates)
D- or L-threose
D- or L-erythrose
L-arabinose, D-ribose,
D-lyxose, D-xylose
FDP aldolase
DHAP
= phosphate
O
P
P
P
,
P
D-glyceraldehyde-3- P
Scheme 2.181 Aldol reactions catalyzed by FDP aldolase from rabbit muscle
PO 3
2O
X
HO
X = O, NH, S, CH 2
Scheme 2.182 Nonnatural DHAP substitutes for fructose-1,6-diphosphate aldolase (RAMA)
2.4 Formation of Carbon–Carbon Bonds
209