Asymmetric addition of benzothiazole to N-tert-butanesulfinyl imine for the synthesis of chiral α-branched heteroaryl amines

Zhang, Jinlong; Yang, Yuhong; Mei, Wang; Lin, Li; Wang, Rui

doi:10.1016/j.tetlet.2012.09.131

Cited by 4 publications

(1 citation statement)

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“…The next step, formation of the hindered quaternary, neopentyl stereocenter, required significant process research to identify a safe and scalable alternative to the lithiated ethyl vinyl ether addition/ozonolysis sequence of the discovery synthesis. Strategies involving the addition of nucleophiles such as Me 3 SiCN, lithium trimethylsilylacetylide, and 2-lithiated benzoxazole suffered from problems converting the products to the requisite amino ester. In 1981, Utimoto and co-workers reported the lithiation of dimethoxyacetonitrile and subsequent alkylation with 1-bromooctane .…”

Section: Resultsmentioning

confidence: 99%

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

Tan

et al. 2022

Org. Process Res. Dev.

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The development of large-scale syntheses of two beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors is described. New methodologies were discovered to overcome safety and scalability problems with existing procedures. The sterically hindered quaternary, neopentyl stereocenter was formed in high diastereoselectivity by the addition of a carbamoyl anion to an N-sulfinyl ketimine. An aryl nitrile was installed by a palladium- and cyanide-free electrophilic cyanation affected by transnitrilation of an arylmagnesium derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine side chain was devised based on diethyl malonate and dibenzylamine starting materials. A mild enamine fluorination was developed for the synthesis of a fluoroisobutylamine side chain.

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Section: Resultsmentioning

confidence: 99%

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

Tan

et al. 2022

Org. Process Res. Dev.

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Addition of Non‐Stabilized Carbon‐Based Nucleophilic Reagents to Chiral N ‐Sulfinyl Imines

et al. 2019

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Natural products and pharmaceuticals that contain chiral branched amines are compounds of considerable interest. One strategy for preparing chiral branched amines involves the addition of a nucleophile to an imine bearing a readily cleavable chiral auxiliary. Sulfinamide‐based auxiliaries are well‐suited to this approach because (i) many sulfonamides are commercially available or can be prepared by efficient synthetic methods, (ii) N ‐sulfinyl aldimines and ketimines can be prepared in a straightforward manner, (iii) the chiral amine products are obtained with high diastereomeric ratios across a wide range of carbon‐based nucleophiles, and (iv) the N ‐sulfinyl group is cleaved under mild conditions. This chapter focuses on the addition of non‐stabilized, carbon‐based nucleophiles to N ‐sulfinyl aldimines and ketimines. Specifically, additions of alkyl, alkenyl, aryl, allylic, propargylic, alkynyl, and cyano nucleophiles are presented. Factors that can influence the stereoselectivity of the addition reaction are presented, along with the most prevalent reaction conditions employed for each class of nucleophile. Nucleophilic additions to N ‐sulfinyl aldimines and ketimines are key steps in the syntheses of a number of drug discovery targets and natural products, examples of which are highlighted in this review.

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