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1.
Clin Genet ; 104(1): 63-72, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37209000

RESUMO

Cardiomyopathies are diseases of the heart muscle with variable clinical expressivity. Most of forms are inherited as dominant trait, and with incomplete penetrance until adulthood. Severe forms of cardiomyopathies were observed during the antenatal period with a pejorative issue leading to fetal death or medical interruption of pregnancy. Variable phenotypes and genetic heterogeneity make etiologic diagnosis difficult. We report 11 families (16 cases) whose unborn, newborn or infant with early onset cardiomyopathies. Detailed morphological and histological examinations of hearts were implemented, as well as genetic analysis on a cardiac targeted NGS panel. This strategy allowed the identification of the genetic cause of the cardiomyopathy in 8/11 families. Compound heterozygous mutations in dominant adulthood cardiomyopathy genes were found in two, pathogenic variants in co-dominant genes in one, de novo mutations in 5 including a germline mosaicism in one family. Parental testing was systematically performed to detect mutation carriers, and to manage cardiological surveillance and propose a genetic counseling. This study highlights the great diagnostic value of the genetic testing of severe antenatal cardiomyopathy both for genetic counseling and to detect presymptomatic parents at higher risk of developing cardiomyopathy.


Assuntos
Cardiomiopatias , Gravidez , Humanos , Feminino , Cardiomiopatias/diagnóstico , Testes Genéticos , Mutação , Fenótipo , Aconselhamento Genético
2.
Photochem Photobiol Sci ; 21(3): 421-432, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35147919

RESUMO

The characterization of commercially available Corning® Lab Photo Reactor by actinometry at different wavelengths (365, 385, 405 and 475 nm) using azobenzene E ↔ Z photoisomerization is reported. By comparison with photon fluxes determined externally using a radiometer, this method based on NMR spectroscopy is rapid, cheap, robust, reproducible and can applied to UVA-visible range, compared to previously described chemical actinometric protocols. Recalculation of isatin N2-phenylhydrazone isomerization quantum yield at 405 nm gave almost the same value as the literature data ([Formula: see text] = 0.0013) and confirmed the robustness and applicability of this methodology.


Assuntos
Compostos Azo , Fótons , Compostos Azo/química
3.
Org Biomol Chem ; 19(13): 3016-3023, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33885555

RESUMO

Carrying out photoredox direct arylation couplings between aryl halides and aryls in aqueous solutions of surfactants enables unprecedented selectivity with respect to the competing dehalogenation process, thanks to the partition coefficient of the selected sacrificial base. The use of a microfluidic reactor dramatically improves the reaction time, without eroding the yields and selectivity. The design of a metal free sensitizer, which also acts as the surfactant, sizeably improves the overall sustainability of arylation reactions and obviates the need for troublesome purification from traces of metal catalysts. The generality of the method is investigated over a range of halides carrying a selection of electron withdrawing and electron donating substituents.

5.
Clin Genet ; 98(3): 261-273, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32621347

RESUMO

Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a severe congenital visceral myopathy characterized by an abdominal distension due to a large non-obstructed urinary bladder, a microcolon and intestinal hypo- or aperistalsis. Most of the patients described to date carry a sporadic heterozygous variant in ACTG2. More recently, recessive forms have been reported and mutations in MYH11, LMOD1, MYLK and MYL9 have been described at the molecular level. In the present report, we describe five patients carrying a recurrent heterozygous variant in ACTG2. Exome sequencing performed in four families allowed us to identify the genetic cause in three. In two families, we identified variants in MMIHS causal genes, respectively a nonsense homozygous variant in MYH11 and a previously described homozygous deletion in MYL9. Finally, we identified compound heterozygous variants in a novel candidate gene, PDCL3, c.[143_144del];[380G>A], p.[(Tyr48Ter)];[(Cys127Tyr)]. After cDNA analysis, a complete absence of PDLC3 expression was observed in affected individuals, indicating that both mutated transcripts were unstable and prone to mediated mRNA decay. PDCL3 encodes a protein involved in the folding of actin, a key step in thin filament formation. Presumably, loss-of-function of this protein affects the contractility of smooth muscle tissues, making PDCL3 an excellent candidate gene for autosomal recessive forms of MMIHS.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Colo/anormalidades , Predisposição Genética para Doença , Pseudo-Obstrução Intestinal/genética , Proteínas do Tecido Nervoso/genética , Bexiga Urinária/anormalidades , Anormalidades Múltiplas/patologia , Feto Abortado , Actinas/genética , Colo/patologia , Feminino , Homozigoto , Humanos , Recém-Nascido , Pseudo-Obstrução Intestinal/patologia , Masculino , Mutação/genética , Cadeias Pesadas de Miosina/genética , Cadeias Leves de Miosina/genética , Linhagem , Bexiga Urinária/patologia , Sequenciamento do Exoma
6.
Am J Med Genet A ; 176(5): 1091-1098, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29681083

RESUMO

Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/diagnóstico , Agenesia do Corpo Caloso/genética , Calcinose/diagnóstico , Calcinose/genética , Otopatias/diagnóstico , Otopatias/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Atrofia Muscular/diagnóstico , Atrofia Muscular/genética , Mutação , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Adolescente , Sequência de Aminoácidos , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Masculino , Proteínas do Tecido Nervoso/química , Conformação de Ácido Nucleico , Linhagem , Fenótipo , Conformação Proteica , Reprodutibilidade dos Testes , Análise de Sequência de DNA , Fatores de Transcrição/química
7.
Fetal Pediatr Pathol ; 37(6): 411-417, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30595068

RESUMO

INTRODUCTION: Beckwith-Wiedemann syndrome (BWS) is the most common overgrowth syndrome. Clinical features are highly variable, including occasional posterior fossa malformations but no femoral shortening. CASE REPORT: We report two fetuses with BWS associated with short femurs and corpus callosum hypoplasia. Case 2 was growth restricted. BWS was confirmed by molecular studies showing a loss of methylation at ICR2 at 11p15 chromosomic region in case 1 and a gain of methylation at ICR1 and a loss of methylation at ICR2 locus in case 2. CONCLUSION: Although the phenotype and the genotype of BWS is now well-known, the presence of corpus callosum abnormalities and short femurs expand the phenotypic spectrum of the disorder.


Assuntos
Agenesia do Corpo Caloso/genética , Síndrome de Beckwith-Wiedemann/patologia , Fêmur/anormalidades , Feto , Humanos , Masculino
8.
Prenat Diagn ; 37(11): 1169-1175, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28950416

RESUMO

OBJECTIVES: To analyze the efficiency of prenatal diagnosis of Pierre Robin sequence (PRS) regarding the final specific diagnosis and to determine whether infants have more severe respiratory disorders with than without prenatally suspected PRS. METHODS: Review of the outcome of all prenatal cases of suspected PRS managed in our prenatal diagnosis center during the last 15 years; analysis of the consistency between prenatal and postnatal diagnoses in 2 groups of women with and without a family history of PRS; comparison of the grades of disease severity for infants with and without prenatally suspected PRS. RESULTS: Fifty-nine files were studied. Prenatal and postnatal consistencies of a specific diagnosis of PRS were 100% for women with a family history of PRS and with prenatally suspected nonisolated PRS. It was 78.6% for those with prenatally suspected isolated PRS. We describe 13 terminations of pregnancy. The 41 children living beyond 18 months seem to have more functionally severe phenotypes than the 227 children without prenatally suspected PRS. CONCLUSION: Prenatal diagnosis of isolated PRS is a challenge as other features can be missed. Use of prenatal chromosomal microarray can improve the accuracy of diagnosis. In all cases, adequate neonatal care should be offered.


Assuntos
Síndrome de Pierre Robin/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Gravidez , Ultrassonografia Pré-Natal
9.
Cytogenet Genome Res ; 147(2-3): 103-10, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26735902

RESUMO

Cytogenetic microarray analysis is now the first-tier genetic test used in a postnatal clinical setting to explore genomic imbalances in individuals with developmental disability and/or birth defects. However, in a prenatal setting, this technique is not widely implemented, largely because the clinical impact of some copy number variants (CNVs) remains difficult to assess. This limitation is especially true in France where termination of pregnancy for medical reasons may be performed at any stage of gestation. During a period of 15 months, we investigated 382 fetuses presenting with ultrasound anomalies, using a customized microarray designed to avoid the detection of CNVs raising challenges for genetic counseling. After excluding common aneuploidies, 20/374 (5.3%) fetuses had a pathogenic CNV, among which 12/374 (3.2%) could have been detected by karyotyping, whereas 8/374 (2.1%) were cryptic. Within these 374 cases, 300 were ongoing pregnancies at the time of array comparative genomic hybridization (aCGH) testing. For these pregnancies, we detected 18/300 (6%) pathogenic CNVs, among which 6/300 (2%) were cryptic. Using this approach, only 2/300 (0.6%) of the detected CNVs raised difficulties for genetic counseling. This study confirms the added value of this strategy in a prenatal clinical setting to minimize ethical issues for genetic counseling while enhancing the detection of genomic imbalances.


Assuntos
Variações do Número de Cópias de DNA , Feto/metabolismo , Testes Genéticos/métodos , Análise em Microsséries/métodos , Ultrassonografia Pré-Natal/métodos , Aberrações Cromossômicas/embriologia , Hibridização Genômica Comparativa , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/diagnóstico por imagem , Doenças Fetais/genética , França , Aconselhamento Genético , Humanos , Cariotipagem , Gravidez , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
10.
Org Process Res Dev ; 28(8): 3307-3312, 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39171129

RESUMO

A continuous flow approach for the aerobic photo-oxidation of benzylic substrates to ketone and aldehyde products is presented. The resulting process exploits UV-A LEDs (375 nm) in combination with a Corning AFR reactor that ensures effective gas-liquid mixing and leads to short residence times of 1 min. A variety of benzylic substrates are converted to their corresponding carbonyl products, and scalability is demonstrated to produce multigram quantities of products within a few hours. Overall, this continuous flow approach offers several improvements over alternative oxidation methods due to the combined use of air as an oxidant and SAS (sodium anthraquinone-2 sulfonate) as a water-soluble photocatalyst. The use of greener and safer conditions together with process intensification principles renders this flow approach attractive for further industrial applications.

11.
Birth Defects Res ; 113(18): 1324-1332, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34491000

RESUMO

BACKGROUND: Neuronal ceroid lipofuscinoses (NCLs) form a clinically and genetically heterogeneous group of inherited neurodegenerative disorders that share common neuropathological features. Although they are the first cause of neurodegenerative disorders in children, their congenital forms are rarely documented. They are classically due to mutations in the CTSD gene (the CLN10 disease). Affected newborns usually present severe microcephaly, seizures and respiratory failure leading to death within the first postnatal days or weeks. CASES: We report on two siblings, in which exome sequencing identified a novel homozygous CTSD variant. The first sib presented at birth with seizures, rapidly progressive postnatal microcephaly and visual deficiency related to retinal dysfunction. Progressive neurological deterioration leads to death at the age of 24 months. Cathepsin D activity was reduced in the cultured fibroblasts of this patient. The second sib, a fetus of 36 weeks of gestation, was delivered after pregnancy termination for brain abnormalities (in accordance with French Legislation) suggesting a recurrence of the disease. Fetal postmortem examination disclosed neuropathological features consistent with NCL. CONCLUSIONS: Congenital NCL related to CTSD mutations is a neuronal storage disorder that produces in the developing brain diffuse neurodegeneration and white matter atrophy resulting in a progressive and rapidly lethal microcephaly.


Assuntos
Catepsina D , Microcefalia , Lipofuscinoses Ceroides Neuronais , Encéfalo/metabolismo , Catepsina D/genética , Feminino , Humanos , Recém-Nascido , Microcefalia/genética , Mutação/genética , Lipofuscinoses Ceroides Neuronais/genética , Gravidez
12.
Fetal Diagn Ther ; 23(2): 117-20, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18046068

RESUMO

We report a case of abdominal eventration associated with cystic fibrosis, diagnosed by mid-trimester ultrasonography. The defect concerned the abdominal muscles and their aponevrotic sheath, but respected the skin. There was no associated malformation. The outcome was favorable after surgery, and the infant is well at the age of 6 months.


Assuntos
Parede Abdominal/anormalidades , Parede Abdominal/diagnóstico por imagem , Feto/anormalidades , Diagnóstico Pré-Natal/métodos , Adulto , Feminino , Doenças Fetais/diagnóstico , Doenças Fetais/diagnóstico por imagem , Humanos , Recém-Nascido , Gravidez , Ultrassonografia
14.
Birth Defects Res ; 110(6): 538-542, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29316359

RESUMO

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently identified severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay, caused by de novo dominant loss of function mutation in the ASXL3 gene. CASE: We report here the first case of prenatal BRPS in a fetus presenting with arthrogryposis on ultrasound and for pontocerebellar hypoplasia type 1 (PCH1) following neuropathological examination. The diagnosis was done by whole exome sequencing that identified a novel de novo ASXL3 mutation. We review 29 previous published cases. DISCUSSION: The fetopathological examination allowed to extend the phenotype to central nervous system and the genetic study highlights ASXL3 as a dominant gene responsible for PCH1 phenotype. Recognizing heterozygous ASXL3 mutation as a cause of prenatal PCH1 is essential for both large scale molecular analysis in the NGS era and genetic counseling.


Assuntos
Sequenciamento do Exoma , Feto/patologia , Atrofias Olivopontocerebelares/diagnóstico , Atrofias Olivopontocerebelares/genética , Adulto , Diagnóstico Diferencial , Humanos , Fenótipo , Síndrome
15.
Birth Defects Res ; 110(4): 382-389, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29193896

RESUMO

BACKGROUND: OFD1 syndrome is a rare ciliopathy inherited on a dominant X-linked mode, typically lethal in males in the first or second trimester of pregnancy. It is characterized by oral cavity and digital anomalies possibly associated with cerebral and renal signs. Its prevalence is between 1/250,000 and 1/50,000 births. It is due to heterozygous mutations of OFD1 and mutations are often de novo (75%). Familial forms show highly variable phenotypic expression. OFD1 encodes a protein involved in centriole growth, distal appendix formation, and ciliogenesis. CASES: We report the investigation of three female fetuses in which corpus callosum agenesis was detected by ultrasound during the second trimester of pregnancy. In all three fetuses, fetopathological examination allowed the diagnosis of OFD1 syndrome, which was confirmed by molecular analysis. CONCLUSIONS: To our knowledge, these are the first case reports of antenatal diagnosis of OFD1 syndrome in the absence of familial history, revealed following detection of agenesis of the corpus callosum. They highlight the impact of fetal examination following termination of pregnancy for brain malformations. They also highlight the contribution of ciliary genes to corpus callosum development.


Assuntos
Agenesia do Corpo Caloso/diagnóstico por imagem , Feto/diagnóstico por imagem , Síndromes Orofaciodigitais/diagnóstico por imagem , Ultrassonografia Pré-Natal , Feminino , Humanos , Gravidez
16.
Birth Defects Res ; 109(19): 1586-1595, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28758373

RESUMO

BACKGROUND: Fetal cerebral ventricular dilatation (CVD) is a common abnormal prenatal finding that often predicts a poor prognosis. The etiology involves both genetic and nongenetic factors with diverse pathogenic mechanisms. We describe the neuropathological features of CVD in a large cohort of fetuses. The goals are to determine the physiopathological mechanisms and etiologies. METHODS: We retrospectively analyzed a series of 130 fetuses examined at the Necker University Hospital following termination of pregnancy between January 2000 and December 2014. Chiari II and Dandy-Walker malformations were excluded from our study population. Karyotype and/or array comparative genomic hybridization were performed in all cases. Targeted Sanger sequencing or next generation sequencing were carried out in 34 and 5 cases, respectively. RESULTS: We distinguished four groups of pathological entities: (1) midbrain/hindbrain patterning defects (54 cases, 42%), mainly related to aqueduct of Sylvius anomalies (atresia or stenosis); (2) cerebral cytoarchitectonic disorders (16 cases, 12%), essentially resulting from arachnoidal neuroglial ectopia; (3) hemorrhagic and perfusion failure (42 cases, 32%); and (4) nonspecific CVD (18 cases, 14%), without apparent obstruction, cortical malformation, or clastic injury. Although the pathogenic mechanisms of CVD were identified in 86% of cases, the causes, both acquired and genetic, were recognized in 21% of cases only. CONCLUSION: The neuropathological analysis is a powerful tool in the diagnosis of the fetal CVD pathogenic mechanisms and to identify homogeneous groups. The paucity of molecular diagnosis, notably in the major groups of midbrain/hindbrain patterning defects and hemorrhagic and perfusion failure, highlights the needs of future research to improve our current knowledge on CVD causes. Birth Defects Research 109:1586-1595, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Hidrocefalia/diagnóstico , Hidrocefalia/etiologia , Hidrocefalia/patologia , Agenesia do Corpo Caloso/patologia , Malformação de Arnold-Chiari/diagnóstico , Encéfalo/anormalidades , Aqueduto do Mesencéfalo/patologia , Ventrículos Cerebrais/diagnóstico por imagem , Hibridização Genômica Comparativa , Síndrome de Dandy-Walker/diagnóstico , Dilatação , Feminino , Feto/patologia , França , Humanos , Mesencéfalo/patologia , Malformações do Sistema Nervoso/patologia , Gravidez , Cuidado Pré-Natal , Estudos Retrospectivos , Rombencéfalo/patologia , Ultrassonografia Pré-Natal/métodos
17.
Diabetes Care ; 26(11): 2990-3, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14578228

RESUMO

OBJECTIVE: To evaluate perinatal outcome in pregnancies in women with type 1 and type 2 diabetes and the influence of preconception care 10 years after the St. Vincent's declaration. RESEARCH DESIGN AND METHODS: A cross-sectional study was conducted in 12 perinatal centers in France in 2000-2001. The main investigated outcomes were perinatal mortality, major congenital malformations, and preterm delivery. RESULTS: Among 435 single pregnancies, 289 (66.4%) were from women with type 1 and 146 (33.6%) from women with type 2 diabetes. Perinatal mortality rate was 4.4% (0.7% national rate), severe congenital malformations rate was 4.1% (2.2% national rate), and preterm delivery rate was 38.2% (4.7% national rate). Preconception care was provided in 48.5% women with type 1 diabetes and in 24.0% women with type 2 diabetes. Women whose first trimester HbA(1c) was >8% had higher rates of perinatal mortality (9.2 vs. 2.5%; odds ratio 3.9; 95% CI 1.5-9.7; P < 0.005), major congenital malformations (8.3 vs. 2.5%; 3.5; 1.3-8.9; P < 0.01), and preterm delivery (57.6 vs. 24.8%; 1.4; 1.1-1.7; P < 0.005) than those with first trimester HbA(1c) <8%. These results are similar to those reported in France in 1986-1988. CONCLUSIONS: Pregnancies in women with diabetes are still poorly planned and complicated by higher rates of perinatal mortality and major congenital malformations. Despite knowledge of the importance of intensified glycemic control before pregnancy, reaching the St. Vincent's target needs further implementation in France.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Resultado da Gravidez/epidemiologia , Gravidez em Diabéticas/epidemiologia , Estudos Transversais , Feminino , França/epidemiologia , Humanos , Modelos Logísticos , Gravidez , Prevalência
18.
Org Lett ; 17(4): 912-5, 2015 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-25634651

RESUMO

Catalytic asymmetric conjugate addition reactions of alkylzirconium species to acyclic enones are reported. The alkylzirconium nucleophiles are generated in situ by hydrozirconation of alkenes with the Schwartz reagent. The reaction proceeds under mild and convenient conditions. A variety of functionalized nucleophiles can be used, and the method tolerates some variation in enone scope. The method uses a new chiral nonracemic phosphoramidite ligand in a complex with copper triflate.

19.
Nat Protoc ; 9(1): 104-11, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24336474

RESUMO

This protocol describes the catalytic asymmetric formation of all-carbon quaternary centers--a distinctive feature of many natural products and pharmaceuticals--via conjugate addition of alkylzirconium reagents to a tertiary enone. This methodology uses alkenes as starting materials and enables the incorporation of functional groups. The alkylzirconium reagent is generated in situ by mixing the alkene with the Schwartz reagent. The alkylzirconium is added to a solution containing a copper-ligand complex, and then the enone is added to the mixture. The addition of pent-4-en-1-ylbenzene to 3-methyl-2-cyclohexenone is detailed herein as a generic example. This procedure works at room temperature (∼25 °C), and it is scalable to at least 1.5 g. The setup of the reaction takes 3-5 h and the reaction goes to completion within 4-20 h.


Assuntos
Carbono/química , Cicloexanonas/química , Conformação Molecular , Zircônio/química , Alcenos/química , Técnicas de Química Sintética , Compostos Organometálicos/química
20.
Org Lett ; 16(12): 3288-91, 2014 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-24893570

RESUMO

The asymmetric synthesis of ß-substituted lactones by catalytic asymmetric conjugate addition of alkyl groups to α,ß-unsaturated lactones is reported. The method uses alkylzirconium nucleophiles prepared in situ from alkenes and the Schwartz reagent. Enantioselective additions to 6- and 7-membered lactones proceed at rt, tolerate a wide variety of functional groups, and are readily scalable. The method was used in a formal asymmetric synthesis of mitsugashiwalactone.

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