Applying Lipase Catalysis to Access the Enantiomers of Dorzolamide Intermediates

Turcu, Mihaela C.; Rantapaju, Maria; Kanerva, Liisa T.

doi:10.1002/ejoc.200900672

Cited by 8 publications

(5 citation statements)

References 20 publications

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“…88 Intermediate 9 would be formed by diastereoselective enzymatic acetylation of the parent alcohol by porcine pancreatic lipase using p-chlorophenylacetate as acylating agent, a biotransformation reaction known from the test set. 89 This parent alcohol would be formed by non-stereoselective reduction of ketone 10 using sodium borohydride. This reduction is predicted with low confidence by TTLAB because this reaction can in fact be performed stereoselectively using LiAlH4.…”

Section: Chemoenzymatic Multistep Retrosynthesis With Ttlabmentioning

confidence: 99%

Chemoenzymatic Multistep Retrosynthesis with Transformer Loops

Kreutter,

Reymond

2024

Preprint

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Integrating enzymatic reactions into computer-aided synthesis planning (CASP) should help devise more selective, economical, and greener synthetic routes. Herein we report the triple-transformer loop algorithm with biocatalysis (TTLAB) as a new CASP tool for chemo-enzymatic multistep retrosynthesis. Single-step retrosyntheses are performed using two triple transformer loops (TTL), one trained with chemical reactions from the US Patent Office (USPTO-TTL), the second one obtained by multitask transfer learning combining the USPTO dataset with preparative biotransformations from the literature (ENZR-TTL). Each TTL performs single-step retrosynthesis independently by tagging potential reactive sites in the product, predicting for each site possible starting materials (T1) and reagents or enzymes (T2), and validating the predictions via a forward transformer (T3). TTLAB combines predictions from both TTLs to explore multistep sequences using a heuristic best-first tree search and propose short routes from commercial building blocks including enantioselective biocatalytic steps. TTLAB can be used to assist chemoenzymatic route design.

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Section: Chemoenzymatic Multistep Retrosynthesis With Ttlabmentioning

confidence: 99%

Chemoenzymatic Multistep Retrosynthesis with Transformer Loops

Kreutter,

Reymond

2024

Preprint

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“…Among the strategies deployed to this end, the bioreduction of the 4-ketosulfone 4 promoted by Neurospora crassa whole cells − or Pichia halophila , (Zeneca) allowed the preparation of trans - 2 with a selectivity of 95% and conversions of 100%. In addition, the kinetic resolution of rac-cis - 3 and rac-trans - 3 by acylation and epimerization were described, in a detailed study, using lipase in organic solvents …”

Section: Introductionmentioning

confidence: 99%

“…In addition, the kinetic resolution of rac-cis-3 and ractrans-3 by acylation and epimerization were described, in a detailed study, using lipase in organic solvents. 24 As a part of our studies aimed to develop a new synthetic approach to 1, we took into consideration the kinetic resolution of diastereoisomeric mixtures of esters 5 or 6 by exploiting Candida antarctica lipase B (CALB) in hydrolytic reactions. However, these attempts were unsuccessful as a parallel, uncatalyzed reaction led to diastereoisomeric mixtures of alcohols 3 largely unbalanced toward the desired transisomer with a cis/trans ratio of up to 7:93.…”

Section: ■ Introductionmentioning

confidence: 99%

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Stereoselective Solvolysis in the Synthesis of Dorzolamide Intermediates

Martinelli

Volpicelli²,

Verzini³

et al. 2023

ACS Omega

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The key intermediate in the synthesis of dorzolamide, (4S,6S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-ol-7,7-dioxide, can be obtained in the diastereoisomerically pure form in two straightforward steps starting from diastereoisomeric mixtures of cis/trans-(6S)- 6-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-yl acetate, regardless of their ratio. The reaction of crucial importance in this scheme is a remarkably stereoselective solvolysis of the acetate ester in an acetone/phosphate buffer mixture as the solvent system. Investigation of this so far unrecognized stereoselective reaction reveals that it proceeds via an S N 1-like pathway as indicated by the correlation of the solvolysis rate constants with the Y OTs values of different solvent mixtures and by trapping of the reaction intermediate with sodium azide. The structure of (4S,6S)-methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-4ol-7,7-dioxide was confirmed by single-crystal X-ray analysis.

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“…In biocatalysis, the advantage of selectivity (both chemo and stereo) is combined with the benefits of a green synthetic strategy. 20 So, our next objective was to resolve the racemic aldol product with commercially available lipase enzymes.…”

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confidence: 99%