Speciality Chemicals Magazine MAR / APR 2025 | Page 41

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Bright future of asymmetric transformations

The term ‘ asymmetric synthesis ’ describes reactions that result in chiral compounds where one stereoisomer is preferentially produced . These reactions generally require specialised chiral catalysts that allow highly enantioselective reactions .

Asymmetric transformations ( hydrogenations , hydroformylations , and others ) are key technologies in the fine chemical industries . The molecular structures of pharmaceuticals , agrochemicals and fragrances are becoming increasingly complex and often include chiral centres . Using asymmetric catalysis , chemists can avoid resolution of racemates , which generates unnecessary waste , costs more and is less environmentally friendly .
Chiral catalysts have been demonstrated in the synthesis of several industrially important compounds . BINAP , a chiral bisphosphine ligand , is very effective for asymmetric transition-metal catalysed reactions , and its developer won a Nobel Prize . H8-BINAP , a derivative where the binaphthyl group is partially hydrogenated1 , is increasingly used due to its efficiency and availability . The catalytic complex Ru ( OAc ) ₂ {( S ) -H8-BINAP} has been used to produce ibuprofen ( 97 % ee ) 2 , 3 and ( R ) -citronellol ( 98 % ee ).
Hydroformylation is a well-known process that uses homogeneous catalysts , although the chiral version is a recent development . Chiraphite , a diphosphite ligand , has shown promise in asymmetric hydroformylation . It has been successfully applied in the asymmetric synthesis of
Figure 1 - Asymmetric catalysis in the synthesis of industrially important compounds
( S ) -naproxen4 and was identified as the best ligand to produce (+) -ambruticin5 .
DuPhos and BPE ligands are becoming more popular in asymmetric transformations . These bisphospholane ligands , developed in the early 1990s6 , 7 , provide useful catalysts for enantioselective hydrogenation of C = C and C = N double bonds , including hydroformylation , hydrosilylation8 , and hydroacylation9 .
Chemists at Dow showed that [( S , S ) - Et-DuPhosRh ( COD )] BF₄ catalyses asymmetric hydrogenation to produce crude ( R ) -2-methylsuccinamic acid in 96 % ee . 10 At Chirotech , the R isomer of the same catalyst was used to produce an intermediate for N-Boc D-phenylalanine in 98 % ee at a 150 kg scale . 11
DuPhos and BPE ligands can also be used with base metals . Nickel catalysis with ( S , S ) - or ( R , R ) -Me- DuPhos provides a highly active and enantioselective asymmetric hydrogenation of α , β-unsaturated esters . 12 As part of a cobalt catalytic system , BPE enables asymmetric hydrogenation of α , β-unsaturated carboxylic acids , including acrylic acid derivatives and dehydro-α-
amino acid derivatives , resulting in high ee products such as naproxen and ( S ) -flurbiprofen . 13 BPE ligands have also been used in Ni-catalysed Heck reactions14 and Cu-catalysed enantioselective dearomative alkylation .
However , many promising transformations have not yet been utilised in an industrial setting , possibly due to a lack of qualified suppliers for catalysts and ligands . If availability is a roadblock to more efficient transformations , Sinocompound can help . Our expertise lies in providing catalysts and ligands at various scales , including commercialisation of rare compounds and scale-up to commercial quantities . Whether you need catalysts at a gram scale for validation or larger manufacturing quantities , we can help . ●
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Figure 2 - DuPhos family of ligands & PhBPE
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References : 1 : X . Zhang , K . Mashima , K . Koyano , N . Sayo , H . Kumobayashi , S . Akutagawa & H . Takaya , J . Chem . Soc ., Perkin Trans . 1 , 1994 , 2309 – 2322 . 2 : T . Uemura , X . Zhang , K . Matsumura , N . Sayo , H . Kumobayashi , T . Ohta , K . Nozaki & H . Takaya , J . Org . Chem ., 1996 , 61 , 5510 – 5516 . 3 : K . D . Rainsford , Inflammopharmacology , 2009 , 17 , 275 – 342 .
4 : C . Giordano , M . Villa & S . Panossian , in Chirality in Industry , Eds . A . N . Collins , G . N . Sheldrake & J . Crosby , Wiley , Chichester , 1992 , p . 303 . 5 : P . Liu & E . N . Jacobsen , J . Am . Chem . Soc ., 2001 , 123 , 10772 . 6 : ( a ) M . J . Burk , J . Am . Chem . Soc ., 1991 , 113 , 8518 – 8519 ; ( b ) R . L . Harlow , W . A . Nugent , J . E . Feaster & M . J . Burk , J . Am . Chem . Soc ., 1993 , 115 , 10125 – 10138 ; ( c ) W . A . Nugent , T . V . Rajanbabu & M . J . Burk , Science , 1993 , 259 , 479 – 483 .
7 : M . J . Burk , Acc . Chem . Res ., 2000 , 33 , 363 – 372 . 8 : A . T . Axtell , C . J . Cobley , J . Klosin , G . T . Whiteker , A . Zanotti-Gerosa & K . A . Abboud , Angew . Chem . Int . Ed ., 2005 , 44 , 5834 – 5838 . 9 : W . Zhang & X . Zhang , in Privileged Chiral Ligands and Catalysts , Q . -L . Zhou ( Ed .), Wiley , 2011 . 10 : C . J . Cobley , I . C . Lennon , C . Praquin & A . Zanotti- Gerosa , Org . Process Res . Dev ., 2003 , 7 , 407 – 411 .
11 : M . E . Fox , M . Jackson , G . Meek & M . Willets , Org . Process Res . Dev ., 2011 , 15 , 1163 – 1171 . 12 : M . Shevlin , M . R . Friedfeld , H . Sheng , N . A . Pierson , J . M . Hoyt , L . C . Campeau & P . J . Chirik , J . Am . Chem . Soc ., 2016 , 138 , 3562 – 3569 . 13 : H . Zhong , M . Shevlin & P . J . Chirik , J . Am . Chem . Soc ., 2020 , 142 , 5272 – 5281 . 14 : J . -S . Zhou , X . Huang , S . Teng & Y . -R . Chi , Chem . Commun ., 2021 , 57 , 3933 – 3936 .
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