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H 3C<br />
H 3CO<br />
Br<br />
726893<br />
NH 2<br />
727083<br />
726842<br />
NH 2<br />
726869<br />
NH 2<br />
NH 2<br />
CH 3<br />
ChiPros Chiral Acids<br />
Enantiopure α- and ß-hydroxy acids and esters are versatile build<strong>in</strong>g<br />
blocks for <strong>the</strong> preparati<strong>on</strong> of a wide range of active pharmaceutical<br />
<strong>in</strong>gredients by <strong>in</strong>corporat<strong>in</strong>g <strong>the</strong>m as esters, amides or e<strong>the</strong>rs, or after<br />
fur<strong>the</strong>r derivatizati<strong>on</strong>, as diols, am<strong>in</strong>o alcohols, thioe<strong>the</strong>rs.<br />
Hydroxy acids are accessible via a range of biotransformati<strong>on</strong>s, am<strong>on</strong>g<br />
<strong>the</strong>m are <strong>the</strong> stereoselective hydrolysis of <strong>the</strong> racemic ester precursor or<br />
reducti<strong>on</strong> of <strong>the</strong> corresp<strong>on</strong>d<strong>in</strong>g keto esters. Hydroxynitrile lyase (HNL)<br />
processes catalyze <strong>the</strong> stereoselective additi<strong>on</strong> of HCN to aldehydes and<br />
ket<strong>on</strong>es yield<strong>in</strong>g s<strong>in</strong>gle-enantiomeric nitriles. 3 Applicati<strong>on</strong> of nitrilases or<br />
a comb<strong>in</strong>ati<strong>on</strong> of nitrile-hydratase plus amidase allows <strong>the</strong> transformati<strong>on</strong><br />
of <strong>the</strong> start<strong>in</strong>g material <strong>in</strong>to <strong>the</strong> desired enantiomer of <strong>the</strong> corresp<strong>on</strong>d<strong>in</strong>g<br />
acid <strong>in</strong> a dynamic k<strong>in</strong>etic resoluti<strong>on</strong> fi nally yield<strong>in</strong>g mandelic<br />
acid derivatives.<br />
BASF developed proprietary processes based <strong>on</strong> dehydrogenases to off er<br />
access to a wide range of α- and ß-hydroxy esters, start<strong>in</strong>g from readily<br />
available keto esters. Due to <strong>the</strong> large range of enzymes available, both<br />
enantiomers can normally be made. Ano<strong>the</strong>r established technology is<br />
enzymatic resoluti<strong>on</strong> us<strong>in</strong>g lipases which <strong>on</strong>ly acylate <strong>on</strong>e enantiomer.<br />
Cl OH<br />
CH 3<br />
O<br />
727067<br />
H 3C<br />
CH3 H3C OH<br />
H 3C<br />
NH2 CH3 726605<br />
726885<br />
NH 2<br />
726923<br />
727342<br />
NH 2<br />
CH 3<br />
CH3 H3C NH2<br />
CH3<br />
OH<br />
726990<br />
O<br />
OH<br />
HN<br />
NH 2<br />
CH 3<br />
726818<br />
NH2 CH3 726613<br />
727180<br />
727032<br />
NH 2<br />
CH 3<br />
NH3 O<br />
H3C OH<br />
727350<br />
Br<br />
CH3<br />
H3CO SO 3<br />
CH 3<br />
ChiPros Chiral Alcohols<br />
Ready to scale up? For competitive quotes <strong>on</strong> larger quantities or custom syn<strong>the</strong>sis, c<strong>on</strong>tact your local <strong>Sigma</strong>-<strong>Aldrich</strong> offi ce, or visit safcglobal.com.<br />
NH 2<br />
726958<br />
NCO<br />
CH 3<br />
726761<br />
726656<br />
CH 3<br />
NH 2<br />
CH 3<br />
Asymmetric Syn<strong>the</strong>sis 5<br />
Chiral alcohols form a versatile class of chiral synth<strong>on</strong>s, s<strong>in</strong>ce <strong>the</strong>y can<br />
be <strong>in</strong>corporated <strong>in</strong>to <strong>the</strong> API structures directly as esters or e<strong>the</strong>rs. They<br />
can be start<strong>in</strong>g materials for <strong>the</strong> formati<strong>on</strong> of am<strong>in</strong>es, amides, thiols,<br />
thioe<strong>the</strong>rs. In additi<strong>on</strong>, after transform<strong>in</strong>g <strong>the</strong> hydroxyl functi<strong>on</strong> <strong>in</strong>to a<br />
leav<strong>in</strong>g group by way of mesylati<strong>on</strong>, tosylati<strong>on</strong> or trifl ati<strong>on</strong>, <strong>the</strong>y can be<br />
used to form new C–C b<strong>on</strong>ds.<br />
Many manufactur<strong>in</strong>g r<str<strong>on</strong>g>out</str<strong>on</strong>g>es make use of asymmetric hydrogenati<strong>on</strong><br />
methods. 4 The two most important biocatalytical processes for <strong>the</strong> formati<strong>on</strong><br />
of chiral alcohols apply lipases and dehydrogenases, respectively. 3<br />
The latter off ers <strong>the</strong> advantage that <strong>on</strong>ly <strong>the</strong> requested enantiomer is<br />
obta<strong>in</strong>ed. Enzyme-catalyzed acylati<strong>on</strong>s us<strong>in</strong>g lipases, however, achieve<br />
<strong>the</strong> resoluti<strong>on</strong> of racemic mixtures of alcohols but with an <strong>in</strong>herent 50<br />
percent maximum yield of <strong>the</strong> total amount of start<strong>in</strong>g material. One<br />
enantiomer of <strong>the</strong> racemic mixture rema<strong>in</strong>s unchanged while <strong>the</strong> antipodal<br />
enantiomer is esterifi ed (Scheme 2).<br />
H 3CO<br />
O<br />
O<br />
CH 3<br />
OH<br />
OH<br />
+ CH3 Lipase<br />
CH3 +<br />
R<br />
Scheme 2: Lipase-catalyzed resoluti<strong>on</strong> of aryl-substituted alcohols.<br />
R<br />
R<br />
O<br />
O<br />
CH 3<br />
OCH 3<br />
Thanks to a variety of commercial and proprietary enzymes at its disposal,<br />
BASF off ers a wide range of aliphatic and cycloaliphatic and aryl-substituted<br />
s<strong>in</strong>gle-enantiomer alcohols under <strong>the</strong> ChiPros brand.<br />
H3C<br />
OH<br />
CH 3<br />
726753 726672<br />
OH<br />
726567<br />
CH 3<br />
H 3C<br />
OH<br />
CH 3<br />
H 3C<br />
OH<br />
727059<br />
CH 3<br />
OH<br />
O<br />
O<br />
727210<br />
CH 3