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1.
Org Lett ; 26(19): 4059-4064, 2024 May 17.
Article in English | MEDLINE | ID: mdl-38709100

ABSTRACT

Herein, we report a nine-step synthesis of belzutifan enabled by a novel Rh-catalyzed asymmetric hydrogenation to install the contiguous fluorinated stereocenters with high enantioselectivity. Moreover, the final ketone reduction in the synthesis proceeds with high diastereoselectivity, leading to the expedient assembly of the stereotriad. In contrast to the original 16-step synthesis, this route avoids a lengthy bromination-oxidation sequence and introduces the sulfone functionality via nucleophilic aromatic substitution, obviating the need for transition metal catalysis.

2.
Org Lett ; 26(4): 804-808, 2024 Feb 02.
Article in English | MEDLINE | ID: mdl-38232150

ABSTRACT

The development of a nucleophilic aromatic substitution (SNAr) reaction for the synthesis of belzutifan and related analogues is disclosed. This classical transformation suffered from reaction stalling, despite prolonged reaction times. Through experimental and mechanistic studies, product inhibition was revealed and rationalized. Herein, we describe our efforts to overcome this synthetic challenge and demonstrate the importance of the judicious choice of the solvent to achieve reactivity.

3.
Angew Chem Int Ed Engl ; 63(13): e202316133, 2024 Mar 22.
Article in English | MEDLINE | ID: mdl-38279624

ABSTRACT

Biocatalytic oxidations are an emerging technology for selective C-H bond activation. While promising for a range of selective oxidations, practical use of enzymes catalyzing aerobic hydroxylation is presently limited by their substrate scope and stability under industrially relevant conditions. Here, we report the engineering and practical application of a non-heme iron and α-ketoglutarate-dependent dioxygenase for the direct stereo- and regio-selective hydroxylation of a non-native fluoroindanone en route to the oncology treatment belzutifan, replacing a five-step chemical synthesis with a direct enantioselective hydroxylation. Mechanistic studies indicated that formation of the desired product was limited by enzyme stability and product overoxidation, with these properties subsequently improved by directed evolution, yielding a biocatalyst capable of >15,000 total turnovers. Highlighting the industrial utility of this biocatalyst, the high-yielding, green, and efficient oxidation was demonstrated at kilogram scale for the synthesis of belzutifan.


Subject(s)
Indenes , Mixed Function Oxygenases , Oxidation-Reduction , Hydroxylation , Biocatalysis
4.
Clin Neurophysiol ; 137: 1-10, 2022 05.
Article in English | MEDLINE | ID: mdl-35231863

ABSTRACT

OBJECTIVE: Brainstem trigeminal-hypoglossal reflexes (THRs), also known as the jaw-tongue reflexes, coordinate the position of the tongue in the mouth in relation to the jaw movement during oromotor behaviors such as mastication, swallowing, vocalization, and breathing. Their use in brainstem surgery however, has never been assessed in spite of its potential benefit possibly due to the lack of a methodology to elicit these reflexes under general anesthesia. METHODS: We proposed a technique to elicit the THRs during total intravenous anesthesia (TIVA) consisting on a V3 infrazygomatic train stimulation paradigm and recording from the Styloglossus (31 patients) and the Genioglossus (21 patients) muscles to elicit long latency responses. RESULTS: The THR was successfully recorded using the V3 stimulation point in 82.1% of patients, of which 96.9% presented a response on the Styloglossus muscle (Jaw-opening reflex) while 0.06% presented a response on the Genioglossus muscle instead (Jaw-closing reflex). CONCLUSIONS: The THRs can be successfully recorded in surgery under general anaesthesia with the predominant reflex seen being the jaw-opening reflex. SIGNIFICANCE: We provide a novel method to elicit the THRs during general anesthesia, which could be of aid in brainstem surgery.


Subject(s)
Reflex , Tongue , Anesthesia, General , Brain Stem , Electromyography , Humans , Jaw/physiology , Reflex/physiology , Tongue/physiology
5.
Nat Chem ; 10(9): 968-973, 2018 09.
Article in English | MEDLINE | ID: mdl-30061616

ABSTRACT

Molecular recognition plays a key role in enzyme-substrate specificity, the regulation of genes, and the treatment of diseases. Inspired by the power of molecular recognition in enzymatic processes, we sought to exploit its use in organic synthesis. Here we demonstrate how a synthetic rhodium-based catalyst can selectively bind a dehydroamino acid residue to initiate a sequential and stereoselective synthesis of cyclic peptides. Our combined experimental and theoretical study reveals the underpinnings of a cascade reduction that occurs with high stereocontrol and in one direction around a macrocyclic ring. As the catalyst can dissociate from the peptide, the C to N directionality of the hydrogenation reactions is controlled by catalyst-substrate recognition rather than a processive mechanism in which the catalyst remains bound to the macrocycle. This mechanistic insight provides a foundation for the use of cascade hydrogenations.


Subject(s)
Peptides, Cyclic/chemistry , Catalysis , Coordination Complexes/chemistry , Hydrogenation , Molecular Conformation , Peptides, Cyclic/chemical synthesis , Rhodium/chemistry , Stereoisomerism
6.
J Am Chem Soc ; 139(31): 10777-10783, 2017 08 09.
Article in English | MEDLINE | ID: mdl-28715208

ABSTRACT

A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki-Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of a Pd(OAc)2/RuPhos catalytic system. Both the enol tosylation and Suzuki-Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either the E- or Z-olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki-Miyaura coupling. However, under the optimized cross-coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species.


Subject(s)
Alkenes/chemistry , Carbon/chemistry , Stereoisomerism , Palladium/chemistry
7.
Org Lett ; 19(1): 114-117, 2017 01 06.
Article in English | MEDLINE | ID: mdl-27973857

ABSTRACT

Dehydrophenylalanine is used as a traceless turn-inducer in the total synthesis of dichotomin E. Macrocyclization of the monomer is achieved in high yields and selectivity over cyclodimerization under conditions 100 times more concentrated than previously achieved. The enamide facilitates ring closing, and Rh-catalyzed hydrogenation of the unsaturated cyclic peptide results in selective formation of the natural product or its epimer, depending on our choice of phosphine ligand. NMR analysis and molecular modeling revealed that the linear peptide adopts a left-handed α-turn that preorganizes the N- and C-termini toward macrocyclization.

8.
J Am Chem Soc ; 136(26): 9471-6, 2014 Jul 02.
Article in English | MEDLINE | ID: mdl-24937681

ABSTRACT

Under Rh(I) catalysis, α-ketoamides undergo intermolecular hydroacylation with aliphatic aldehydes. A newly designed Josiphos ligand enables access to α-acyloxyamides with high atom-economy and enantioselectivity. On the basis of mechanistic and kinetic studies, we propose a pathway in which rhodium plays a dual role in activating the aldehyde for cross-coupling. A stereochemical model is provided to rationalize the sense of enantioinduction observed.


Subject(s)
Aldehydes/chemistry , Amides/chemistry , Rhodium/chemistry , Catalysis , Chemistry Techniques, Synthetic , Isotope Labeling , Ketones/chemistry , Models, Chemical , Molecular Structure , Stereoisomerism
9.
Chemistry ; 20(17): 5013-8, 2014 Apr 22.
Article in English | MEDLINE | ID: mdl-24623522

ABSTRACT

We demonstrate copper(II)-catalyzed acylation and tosylation of monosaccharides. Various carbohydrate derivatives, including glucopyranosides and ribofuranosides, are obtained in high yields and regioselectivities. Using this versatile strategy, the site of acylation can be switched by choice of ligand. Preliminary mechanistic studies support nucleophilic addition of a copper-sugar complex to the acyl chloride to be turnover limiting.


Subject(s)
Carbohydrates/chemical synthesis , Copper/chemistry , Monosaccharides/chemistry , Acylation , Carbohydrates/chemistry , Catalysis , Monosaccharides/chemical synthesis , Stereoisomerism
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