Eventually, (R)-sitagliptin was obtained in 90–95% yield and >99% e.e. at 200 g/L
substrate concentration using i-Pr-NH 2 (1M) as amine donor [1931]. Due to its
superior efficiency, the biocatalytic route replaced the Rh[Josiphos]-catalysed
asymmetric enamine hydrogenation process.
An ω-TA was also engineered to adapt it to a process for the synthesis of the
antiarrhythmic agent (all-R)-vernakalant. In this case, enzyme evolution was
directed to provide a transaminase variant with inverted diastereoselectivity with
respect to the chiral center adjacent to the carbonyl moiety. Careful choice of the
reaction conditions allowed the in-situ racemization of the starting ketone, providing a single trans-diastereomer in 81% yield, 99% d.e. and >99% e.e. via dynamic
resolution [1932]. In analogy, dynamic resolution is also feasible for aldehydes
bearing a configurationally unstable center at Cα. This strategy was exploited for
the preparation of the anti-cancer agent (R)-Niraparib, which relies on the
enantioselective amination of a racemic aldehyde precursor as key step. The
δ-amino-ester thus formed undergoes spontaneous ring-closure yielding a lactam,
which efficiently pulls the equilibrium towards product formation [1933].
2.7 Halogenation and Dehalogenation Reactions
Halogen-containing compounds are not only produced by man, but also by Nature
[1934–1936]. A brominated indole derivative – Tyrian purple dye
55 – was isolated
from the mollusc Murex brandaris by the Phoenicians. Since that time, more than
5000 halogenated natural products of various structural types have been isolated
from sources such as bacteria, fungi, algae, higher plants, marine molluscs, insects,
and mammals [1937, 1938]. Whereas fluorinated and iodinated species are rather
rare, chloro and bromo derivatives are found more often. The former are predominantly produced by terrestrial species [1939] and the latter in marine organisms
[1940]. For instance, about 10
7 tons of bromoalkanes such as bromoform and
methylene bromide are released from coastal brown algae Ascophyllum nodosum
into the atmosphere worldwide [1941, 1942]. Although the natural function of
halogenating enzymes is not yet known, they do seem to be involved in the defence
mechanism of their hosts. For instance, some algae produce halometabolites, which
makes them inedible to animals [1943]. In contrast to hydrolytic or redox enzymes,
which have been investigated since about a century, halogen-converting enzymes
are a more recent subject of research after the first halogenase was reported in 1966
[1944–1950].
55 6,6’-Dibromoindigo.
250
2 Biocatalytic Applications
substrate concentration using i-Pr-NH 2 (1M) as amine donor [1931]. Due to its
superior efficiency, the biocatalytic route replaced the Rh[Josiphos]-catalysed
asymmetric enamine hydrogenation process.
An ω-TA was also engineered to adapt it to a process for the synthesis of the
antiarrhythmic agent (all-R)-vernakalant. In this case, enzyme evolution was
directed to provide a transaminase variant with inverted diastereoselectivity with
respect to the chiral center adjacent to the carbonyl moiety. Careful choice of the
reaction conditions allowed the in-situ racemization of the starting ketone, providing a single trans-diastereomer in 81% yield, 99% d.e. and >99% e.e. via dynamic
resolution [1932]. In analogy, dynamic resolution is also feasible for aldehydes
bearing a configurationally unstable center at Cα. This strategy was exploited for
the preparation of the anti-cancer agent (R)-Niraparib, which relies on the
enantioselective amination of a racemic aldehyde precursor as key step. The
δ-amino-ester thus formed undergoes spontaneous ring-closure yielding a lactam,
which efficiently pulls the equilibrium towards product formation [1933].
2.7 Halogenation and Dehalogenation Reactions
Halogen-containing compounds are not only produced by man, but also by Nature
[1934–1936]. A brominated indole derivative – Tyrian purple dye
55 – was isolated
from the mollusc Murex brandaris by the Phoenicians. Since that time, more than
5000 halogenated natural products of various structural types have been isolated
from sources such as bacteria, fungi, algae, higher plants, marine molluscs, insects,
and mammals [1937, 1938]. Whereas fluorinated and iodinated species are rather
rare, chloro and bromo derivatives are found more often. The former are predominantly produced by terrestrial species [1939] and the latter in marine organisms
[1940]. For instance, about 10
7 tons of bromoalkanes such as bromoform and
methylene bromide are released from coastal brown algae Ascophyllum nodosum
into the atmosphere worldwide [1941, 1942]. Although the natural function of
halogenating enzymes is not yet known, they do seem to be involved in the defence
mechanism of their hosts. For instance, some algae produce halometabolites, which
makes them inedible to animals [1943]. In contrast to hydrolytic or redox enzymes,
which have been investigated since about a century, halogen-converting enzymes
are a more recent subject of research after the first halogenase was reported in 1966
[1944–1950].
55 6,6’-Dibromoindigo.
250
2 Biocatalytic Applications