Co-reporter:Maha L. Shrestha, Wei Qi, and Matthias C. McIntosh
The Journal of Organic Chemistry August 18, 2017 Volume 82(Issue 16) pp:8359-8359
Publication Date(Web):June 22, 2017
DOI:10.1021/acs.joc.7b00428
We report full details of a method for 1,3-reductive transposition of α-alkoxy-α,β-unsaturated hydrazones to provide E-alkenes with high 1,4-stereocontrol between the two respective allylic stereocenters. The process couples a chelation-controlled reduction of the hydrazone with an in situ allylic strain controlled retro-ene reaction of an allyl diazene, i.e., an allylic diazene rearrangement. Such stereotriads are frequently observed motifs in natural products. We observed a fortuitous kinetic preference for the E-hydrazone geometry during the hydrazonation reaction, as only the E-isomers could undergo chelation-controlled reduction.
Co-reporter:Dr. Sefat Alwarsh;Yi Xu; Steven Y. Qian; Matthias C. McIntosh
Angewandte Chemie International Edition 2016 Volume 55( Issue 1) pp:355-358
Publication Date(Web):
DOI:10.1002/anie.201508368
Abstract
Breslow intermediates that bear radical-stabilizing N substituents, such as benzyl, cinnamyl, and diarylmethyl, undergo facile homolytic CN bond scission under mild conditions to give products of formal [1,3] rearrangement rather than benzoin condensation. EPR experiments and computational analysis support a radical-based mechanism. Implications for thiamine-based enzymes are discussed.
Co-reporter:Dr. Sefat Alwarsh;Yi Xu; Steven Y. Qian; Matthias C. McIntosh
Angewandte Chemie 2016 Volume 128( Issue 1) pp:363-366
Publication Date(Web):
DOI:10.1002/ange.201508368
Abstract
Breslow intermediates that bear radical-stabilizing N substituents, such as benzyl, cinnamyl, and diarylmethyl, undergo facile homolytic CN bond scission under mild conditions to give products of formal [1,3] rearrangement rather than benzoin condensation. EPR experiments and computational analysis support a radical-based mechanism. Implications for thiamine-based enzymes are discussed.
Co-reporter:Sefat Alwarsh, Kolawole Ayinuola, Silvana S. Dormi, and Matthias C. McIntosh
Organic Letters 2013 Volume 15(Issue 1) pp:3-5
Publication Date(Web):December 5, 2012
DOI:10.1021/ol303053c
A novel Claisen rearrangement in which the Breslow intermediate is engaged as a hydroxy-substituted N,S-ketene acetal to provide complex 3° alcohols without the use of organometallic reagents is reported. The reaction constitutes an unprecedented reactivity mode for the Breslow intermediate.
Co-reporter:David R. Clay, Matthias C. McIntosh
Tetrahedron Letters 2012 Volume 53(Issue 14) pp:1691-1694
Publication Date(Web):4 April 2012
DOI:10.1016/j.tetlet.2011.12.123
Over the course of developing a multigram scale preparation of epoxy quinol 1 via asymmetric transfer hydrogenation (ATH) using the Noyori Ru(arene)(S,S-TsDPEN) catalysts, we observed several unexpected phenomena, including (i) chemoselective alkene versus ketone reduction of an enedione, (ii) a significant arene ligand effect (p-cymene vs mesitylene) on the reaction pathway, and (iii) solvent-based reversal of the sense of enantioinduction.
Co-reporter:John M. Hutchison, Andrew S. Gibson, David T. Williams, Matthias C. McIntosh
Tetrahedron Letters 2011 Volume 52(Issue 48) pp:6349-6351
Publication Date(Web):30 November 2011
DOI:10.1016/j.tetlet.2011.09.027
The C21–C34 fragment of the potent FKBP12-binding macrolide antascomicin B was prepared using Ireland-Claisen and allylic diazene rearrangements to establish the C26/C27 and the C23 stereocenters, respectively. Directed hydrogenation installed the C29 β-configuration. The fragment possesses 7 of the 11 fixed stereocenters contained in the natural product.
Co-reporter:David R. Clay, Ashley G. Rosenberg, Matthias C. McIntosh
Tetrahedron: Asymmetry 2011 Volume 22(Issue 7) pp:713-716
Publication Date(Web):11 April 2011
DOI:10.1016/j.tetasy.2011.04.022
Epoxy quinol 1a was prepared on a multi-gram scale by Noyori transfer hydrogenative desymmetrization of the readily available meso-epoxy diketone 4. Although the intrinsic enantioselectivity for the desymmetrization was modest (82:18 er at 4% conversion), a highly enantiopure product (99.6:0.4 er) could be obtained in one operation in 44% yield via kinetic resolution of the minor enantiomer with long reaction times (48 h), or in 73% yield by combination with an enzymatic resolution of a 93:7 er mixture.(1S,5R,6S)-5-Hydroxy-7-oxabicyclo[4.1.0]hept-3-en-2-oneC6H6O3Ee > 99%[α]D19=+3.8 (c 1.65, CH2Cl2)Source of chirality: Noyori asymmetric transfer hydrogenationAbsolute configuration: (1S,5R,6S)
Co-reporter:Yonghai Chai, Zonghong Mou, Matthias C. McIntosh
Tetrahedron Letters 2010 Volume 51(Issue 18) pp:2393-2395
Publication Date(Web):5 May 2010
DOI:10.1016/j.tetlet.2010.02.095
The fully substituted hydroisobenzofuran core of the massileunicellins containing eight contiguous stereocenters was prepared in 12 steps from (S)-(+)-carvone. Noteworthy elements of the synthesis include a one-step oxidative rearrangement/epoxidation, a novel stereoselective directed reduction of a keto diol, and a directed hydrogenation of a congested tetrasubstituted alkene.The fully substituted hydroisobenzofuran intermediate for the synthesis of the massileunicellins containing eight contiguous stereocenters was prepared in 12 steps from (S)-(+)-carvone.
Co-reporter:T. David Bateman, Aarti L. Joshi, Kwangyul Moon, Elena N. Galitovskaya, Meenakshi Upreti, Timothy C. Chambers, Matthias C. McIntosh
Bioorganic & Medicinal Chemistry Letters 2009 Volume 19(Issue 24) pp:6898-6901
Publication Date(Web):15 December 2009
DOI:10.1016/j.bmcl.2009.10.079
Three structurally related sets of hydroisobenzofuran analogs of sclerophytin A were prepared in three or four steps from (S)-(+)-carvone via an aldol-cycloaldol sequence. The most potent members of each set of analogs exhibited IC50’s of 1–3 μM in growth inhibitory assays against KB3 cells. The NCI 60-cell line 5-dose assay for analog 6h revealed a GI50 = 0.148 μM and LC50 = 9.36 μM for the RPMI-8226 leukemia cell line, and a GI50 = 0.552 μM and LC50 = 26.8 μM for the HOP-92 non-small cell lung cancer cell line.Seco analogs of sclerophytin A prepared in three or four steps exhibit sub-micromolar growth inhibitory activity against the RPMI-8226 leukemia and HOP-92 non-small cell lung cancer cell lines.
