Co-reporter:Alexander S. Burns, Alexander J. Wagner, Jennifer L. Fulton, Kyle Young, Armen Zakarian, and Scott. D. Rychnovsky
Organic Letters June 2, 2017 Volume 19(Issue 11) pp:
Publication Date(Web):May 16, 2017
DOI:10.1021/acs.orglett.7b01189
A method for determining the absolute configuration of β-chiral primary alcohols has been developed. Enantioenriched alcohols were acylated in the presence of either enantiomer of the enantioselective acylation catalyst HBTM, and the faster reaction was determined by measuring product conversion using 1H NMR spectroscopic analysis. An empirical mnemonic was developed that correlates the absolute configuration of the alcohol to the faster reacting catalyst. Successful substrates for this method include primary alcohols that bear a “directing group” on the stereogenic center; directing groups include arenes, heteroarenes, enones, and halides.
Co-reporter:Alexander Burtea and Scott D. Rychnovsky
Organic Letters August 18, 2017 Volume 19(Issue 16) pp:
Publication Date(Web):August 1, 2017
DOI:10.1021/acs.orglett.7b01748
The competing enantioselective conversion (CEC) strategy has been extended to cyclic amines. The basis for the CEC approach is the use of two complementary, enantioselective reactions to determine the configuration of the enantiopure substrate. Bode’s chiral acylated hydroxamic acids are very effective enantioselective acylating agents for a variety of amines. Pseudoenantiomers of these acyl-transfer reagents were prepared and demonstrated to react with enantiopure cyclic amines with modest to high selectivity. The products were analyzed by ESI-MS to determine selectivity, and the results were used to assign the configuration of the amine substrate. The method was applicable to a variety of cyclic amines as well as primary amines and acyclic secondary amines. The method is limited to amines that are unhindered enough to react with the reagents, and not all amine substitution patters lead to high selectivity.
Co-reporter:Renzo A. Samame, Christina M. Owens and Scott D. Rychnovsky
Chemical Science 2016 vol. 7(Issue 1) pp:188-190
Publication Date(Web):06 Oct 2015
DOI:10.1039/C5SC03262H
(+)-Fastigiatine was assembled in six steps from (R)-5-methylcyclohex-2-en-1-one. Intermolecular Diels–Alder reaction introduced most of the carbon atoms for the target. The two Boc-protected nitrogen atom building blocks were introduced by a Suzuki coupling and a cuprate addition. A biomimetic transannular Mannich reaction generated the two quaternary centers at a late stage. Each step builds core bonds, and combined with a minimalist protecting group strategy, this approach led to a very concise synthesis.
Co-reporter:Gidget C. Tay, Nicholas Sizemore, and Scott D. Rychnovsky
Organic Letters 2016 Volume 18(Issue 13) pp:3050-3053
Publication Date(Web):June 13, 2016
DOI:10.1021/acs.orglett.6b00881
Progress toward understanding the scope and diastereoselectivity of intramolecular Diels–Alder reactions using 2-cyano-1-azadienes is described herein. The resulting cyanoenamine products are underutilized intermediates in organic synthesis. Assembly of the Diels–Alder precursors was achieved using an improved imine condensation/oxidative cyanation protocol. By this method, several highly substituted indolizidine and quinolizidine architectures were constructed. Quantum mechanical DFT calculations at the B3LYP/6-31+G(d) level of theory were performed for these cyclizations and provide insights into the origins of the observed diastereoselectivities.
Co-reporter:Alexander J. Wagner, Shawn M. Miller, Ryan P. King, and Scott D. Rychnovsky
The Journal of Organic Chemistry 2016 Volume 81(Issue 15) pp:6253-6265
Publication Date(Web):July 14, 2016
DOI:10.1021/acs.joc.6b00816
Two different protocols were developed and optimized to address the need for (1) high sensitivity or (2) convenient utilization in the determination of the absolute configuration of secondary alcohols. The first protocol uses the competing enantioselective conversion (CEC) method to determine configuration on nanomole scale. Reactions were conducted with 145 nmol of the substrate using a 50 μL microsyringe as the reaction vessel, and the absolute configuration was assigned via qualitative determination of the fast reaction by thin-layer chromatography. This protocol resulted in a 50-fold reduction in material required from previous CEC method studies. The approach was evaluated with benzylic and β-aryl systems. The second protocol was optimized to address the needs of practicing medicinal chemists. A one-use CEC kit was developed, where the fast reaction was identified by 1H NMR spectroscopy and thin-layer chromatography. The CEC reaction conditions developed for the microsyringe protocol and the one-use kit both displayed data consistent with pseudo-first-order kinetics in substrate. Therefore, the lower limit of sensitivity for the substrate is limited only by the ability to effectively detect the reaction conversions between alcohol substrate and ester product.
Co-reporter:Richard R. Hill and Scott D. Rychnovsky
The Journal of Organic Chemistry 2016 Volume 81(Issue 22) pp:10707-10714
Publication Date(Web):October 27, 2016
DOI:10.1021/acs.joc.6b01748
Several procedures were evaluated for the preparation of lithium 4,4′-di-tert-butylbiphenylide (LiDBB, Freeman’s reagent) from lithium metal and 4,4′-di-tert-butylbiphenyl (DBB) in THF. Solutions with nominal concentration of 0.4 and 1.0 M were formed. The stability of LiDBB solutions was evaluated over time, and the gradual uptake of lithium metal was observed. At 0 °C the LiDBB solutions were stable for over a week in THF. At 20 °C the LiDBB solution underwent various decomposition pathways, which led to uptake of more lithium metal and the accumulation of side products. These decomposition pathways were studied, and the importance of ethene in the destruction of THF by LiDBB was observed. On a practical note, LiDBB solutions in THF were stable and effective for over a week at 0 °C or for more than 37 weeks when stored under argon at −25 °C. These observations will extend the utility of LiDBB as a reagent in organic synthesis.
Co-reporter:Justin A. Hilf, Michael S. Holzwarth, and Scott D. Rychnovsky
The Journal of Organic Chemistry 2016 Volume 81(Issue 21) pp:10376-10382
Publication Date(Web):August 31, 2016
DOI:10.1021/acs.joc.6b01370
Pyridine rings are common structural motifs found in a number of biologically active compounds, including some top-selling pharmaceuticals. We have developed a new approach to access substituted pyridines. The method aims to provide a reliable synthesis of a diverse range of substituted pyridines through a three-step procedure. Readily available enones are first converted into 1,5-dicarbonyls through a two-step Hosomi–Sakurai allylation/oxidative cleavage sequence, which is followed by subsequent cyclization to the corresponding pyridine using hydroxylamine hydrochloride. A variety of substituted pyridines have been synthesized using this method.
Co-reporter:Matthew A. Perry, Richard R. Hill, Justin J. Leong, and Scott D. Rychnovsky
Organic Letters 2015 Volume 17(Issue 13) pp:3268-3271
Publication Date(Web):June 19, 2015
DOI:10.1021/acs.orglett.5b01422
Reductive lithiation and cyclization of N-Boc α-amino nitriles are often highly stereoselective. The alkyllithium intermediates are formed with varying levels of selectivity, but the alkyllithium geometry does not play a major role in the overall stereoselectivity. The final configuration is determined in the cyclization reaction, where both retention and inversion pathways are observed. Where strong thermodynamic preferences exist in the products, the kinetically controlled alkyllithium cyclization favors the more stable product.
Co-reporter:Anthony M. Burke, Wynne Kandur, Eric J. Novitsky, Robyn M. Kaake, Clinton Yu, Athit Kao, Danielle Vellucci, Lan Huang and Scott D. Rychnovsky
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 17) pp:5030-5037
Publication Date(Web):31 Mar 2015
DOI:10.1039/C5OB00488H
The cross-linking Mass Spectrometry (XL-MS) technique extracts structural information from protein complexes without requiring highly purified samples, crystallinity, or large amounts of material. However, there are challenges to applying the technique to protein complexes in vitro, and those challenges become more daunting with in vivo experiments. Issues include effective detection and identification of cross-linked peptides from complex mixtures. While MS-cleavable cross-linkers facilitate the sequencing and identification of cross-linked peptides, enrichable cross-linkers increase their detectability by allowing their separation from non-cross-linked peptides prior to MS analysis. Although a number of cross-linkers with single functionality have been developed in recent years, an ideal reagent would incorporate both capabilities for XL-MS studies. Therefore, two new cross-linkers have been designed and prepared that incorporate an azide (azide-A-DSBSO) or alkyne (alkyne-A-DSBSO) to enable affinity purification strategies based on click chemistry. The integration of an acid cleavage site next to the enrichment handle allows easy recovery of cross-linked products during affinity purification. In addition, these sulfoxide containing cross-linking reagents possess robust MS-cleavable bonds to facilitate fast and easy identification of cross-linked peptides using MS analysis. Optimized, gram-scale syntheses of these cross-linkers have been developed and the azide-A-DSBSO cross-linker has been evaluated with peptides and proteins to demonstrate its utility in XL-MS analysis.
Co-reporter:Wynne V. Kandur, Athit Kao, Danielle Vellucci, Lan Huang and Scott D. Rychnovsky
Organic & Biomolecular Chemistry 2015 vol. 13(Issue 38) pp:9793-9807
Publication Date(Web):13 Aug 2015
DOI:10.1039/C5OB01410G
The cross-linking Mass Spectrometry (XL-MS) technique has enormous potential for studying the interactions between proteins, and it can provide detailed structural information about the interaction interfaces in large protein complexes. Such information has been difficult to obtain by conventional structural methods. One of the primary impediments to the wider use of the XL-MS technique is the extreme challenge in sequencing cross-linked peptides because of their complex fragmentation patterns in MS. A recent innovation is the development of MS-cleavable cross-linkers, which allows direct sequencing of component peptides for facile identification. Sulfoxides are an intriguing class of thermally-cleavable compounds that have been shown to fragment selectively during low-energy collisional induced dissociation (CID) analysis. Current CID-cleavable cross-linkers create fragmentation patterns in MS2 of multiple peaks for each cross-linked peptide. Reducing the complexity of the fragmentation pattern in MS2 facilitates subsequent MS3 sequencing of the cross-linked peptides. The first authentic identical mass linker (IML) has now been designed, prepared, and evaluated. Multistage tandem mass spectrometry (MSn) analysis has demonstrated that the IML cross-linked peptides indeed yield one peak per peptide constituent in MS2 as predicted, thus allowing effective and sensitive MS3 analysis for unambiguous identification. Selective fragmentation for IML cross-linked peptides from the 19S proteasome complex was observed, providing a proof-of-concept demonstration for XL-MS studies on protein complexes.
Co-reporter:Nicholas Sizemore and Scott D. Rychnovsky
Organic Letters 2014 Volume 16(Issue 3) pp:688-691
Publication Date(Web):January 24, 2014
DOI:10.1021/ol4033495
A synthetic route to the isotwistane core of palhinine lycopodium alkaloids is described. A Morita–Baylis–Hillman/intramolecular Diels–Alder (IMDA) strategy sets the vicinal all-carbon quaternary centers present in this family of natural products. The regioselectivity of the IMDA reaction is dictated by the conditions employed for silyl enol ether formation, with one set of conditions providing the core of cardionine and alternate conditions generating the desired isotwistane core of isopalhinine.
Co-reporter:Alexander J. Wagner, Shawn M. Miller, Steven Nguyen, Ga Young Lee, Scott D. Rychnovsky, and Renée D. Link
Journal of Chemical Education 2014 Volume 91(Issue 5) pp:716-721
Publication Date(Web):April 2, 2014
DOI:10.1021/ed4004996
A new undergraduate organic chemistry laboratory experiment has been developed to determine the absolute configuration of enantioenriched secondary alcohols with the competing enantioselective conversion (CEC) method. The CEC method uses both enantiomers of a chiral kinetic resolution reagent in parallel reactions to identify the fast-reacting reagent and thus the configuration of the alcohol. Students working in pairs are given one of three enantioenriched secondary alcohols with an unknown absolute configuration. They assign the molecular structure using the corresponding 1H NMR spectrum and determine the absolute configuration via the CEC method. The parallel reactions are run at room temperature for 1 h using small quantities of solvent, substrate, and catalyst. Students use thin-layer chromatography (TLC) to analyze the parallel reactions and determine the fast reaction qualitatively. The free program ImageJ is used with a picture of the TLC plate to carry out a quantitative analysis of reaction conversion. Data collected in the spring 2013 laboratory course (n = 1036) show that 93.6% of students determined the absolute configuration of their unknown correctly with just a qualitative analysis of the TLC plate. This experiment provides a platform for discussions of stereochemistry, mechanism, kinetics, energy diagrams, and transition states.Keywords: Catalysis; Enantiomers; Hands-On Learning/Manipulatives; Kinetics; Laboratory Instruction; Organic Chemistry; Problem Solving/Decision Making; Second-Year Undergraduate; Stereochemistry; Thin Layer Chromatography;
Co-reporter:Gidget C. Tay, Chloe Y. Huang, and Scott D. Rychnovsky
The Journal of Organic Chemistry 2014 Volume 79(Issue 18) pp:8733-8749
Publication Date(Web):September 9, 2014
DOI:10.1021/jo501580p
A diastereoselective synthesis of cis-2,6-disubstituted tetrahydropyran-4-ones was developed. The key step of this methodology, a silyl enol ether Prins cyclization, was promoted by a condensation reaction between a hydroxy silyl enol ether and an aldehyde to afford substituted tetrahydropyran-4-ones. The cyclization was tolerant of many functional groups, and the modular synthesis of the hydroxy silyl enol ether allowed for the formation of more than 30 new tetrahydropyran-4-ones with up to 97% yield and >95:5 dr. The cyclization step forms new carbon–carbon and carbon–oxygen bonds, as well as a quaternary center with good diastereoselectivity. The method provides a versatile route for the synthesis of substituted tetrahydropyrans.
Co-reporter:Matthew A. Perry, Richard R. Hill, and Scott D. Rychnovsky
Organic Letters 2013 Volume 15(Issue 9) pp:2226-2229
Publication Date(Web):April 17, 2013
DOI:10.1021/ol400788q
A variety of spirocyclic heterocycles have been constructed by a double-alkylation and reductive cyclization approach utilizing α-heteroatom nitriles as trianion synthons. The method provides access to heteroatom-substituted spirocycles in a variety of ring sizes that are found in natural products and are important in pharmaceutical lead development and optimization.
Co-reporter:Matthew A. Perry, Jonathan V. Trinidad, and Scott D. Rychnovsky
Organic Letters 2013 Volume 15(Issue 3) pp:472-475
Publication Date(Web):January 16, 2013
DOI:10.1021/ol303239t
A simple method for determining the absolute configuration of oxazolidinones, lactams, and their derivatives using kinetic resolution catalysts is described. The optically pure substrates were acylated using the (S)-HBTM and the (R)-HBTM catalyst, and the faster reaction was determined. An empirical mnemonic was developed for the assignment of the absolute configuration based on the fast-reacting catalyst.
Co-reporter:Alexander J. Wagner and Scott D. Rychnovsky
Organic Letters 2013 Volume 15(Issue 21) pp:5504-5507
Publication Date(Web):October 15, 2013
DOI:10.1021/ol402643n
A detailed kinetic analysis of the homobenzotetramisole-mediated esterification of the enantiopure secondary alcohol (1R,2S)-2-phenylcyclohexanol is presented. The results of this analysis show that the reaction is first order in the homobenzotetramisole catalyst, first order in (1R,2S)-2-phenylcyclohexanol, and first order in propionic anhydride. Initial rates, the turnover frequency of the catalyst, and “different excess” plots were utilized in this evaluation. Additionally, a “same excess” plot revealed no noticeable catalyst decomposition or product inhibition during the course of the reaction.
Co-reporter:Gidget C. Tay, Michael R. Gesinski, and Scott D. Rychnovsky
Organic Letters 2013 Volume 15(Issue 17) pp:4536-4539
Publication Date(Web):August 20, 2013
DOI:10.1021/ol402095g
A new tetrahydropyranone synthesis has been developed that leads to cis-2,6-disubstituted 3,3-dimethyltetrahydropyran-4-one rings by condensation of an aldehyde and a hydroxy silyl enol ether. The reaction works with a variety of aldehydes to produce the tetrahydropyranone products in moderate to high yields. This new method was applied to the enantioselective synthesis of cyanolide A and its aglycone.
Co-reporter:Alexander J. Wagner and Scott D. Rychnovsky
The Journal of Organic Chemistry 2013 Volume 78(Issue 9) pp:4594-4598
Publication Date(Web):April 17, 2013
DOI:10.1021/jo400432q
A new implementation of the competing enantioselective conversion (CEC) method was developed to qualitatively determine the absolute configuration of enantioenriched secondary alcohols using thin-layer chromatography. The entire process for the method requires approximately 60 min and utilizes micromole quantities of the secondary alcohol being tested. A number of synthetically relevant secondary alcohols are presented. Additionally, 1H NMR spectroscopy was conducted on all samples to provide evidence of reaction conversion that supports the qualitative method presented herein.
Co-reporter:Leah Cleary, Victor W. Mak, Scott D. Rychnovsky, Kenneth J. Shea, and Nicholas Sizemore
The Journal of Organic Chemistry 2013 Volume 78(Issue 8) pp:4090-4098
Publication Date(Web):March 11, 2013
DOI:10.1021/jo4004025
Quantum mechanical calculations have been used to investigate type 2 intramolecular N-acylnitroso Diels–Alder reactions. Experimentally observed regioselectivities and diastereoselectivities of these reactions have been reproduced using B3LYP/6-31+G(d) DFT calculations. The factors that govern selectivity (i.e., tether length, tether substitution and diene substitution) were systematically investigated. Tethers less than 6 carbon atoms lead to 1,3-regioisomers due to conformational restrictions. Substituents on the tether lead to diastereoselective outcomes dictated by transannular interactions in the transition states. The modest diastereoselectivity of diene-substituted substrates is rationalized as arising from reduction of eclipsing interactions in the flattened diene transition states. This method should prove valuable for planning syntheses involving type 2 intramolecular Diels–Alder reactions.
Co-reporter:Shawn M. Miller ; Renzo A. Samame
Journal of the American Chemical Society 2012 Volume 134(Issue 50) pp:20318-20321
Publication Date(Web):December 4, 2012
DOI:10.1021/ja310620c
The absolute configurations of primary amines were assigned using a kinetic resolution strategy with Mioskowski’s enantioselective 1-(R,R) and 2-(S,S) acylating agents. A simple mnemonic was developed to determine the configuration. A pseudoenantiomeric pair of reagents, 1-(R,R) and 2-(S,S)-d3, was prepared and used to assay primary amines on a micromolar scale. The ESI-MS readout of the resulting acetamide products reproduced the selectivity factors from kinetic experiments. The method can be used on mixtures of amines and was validated with amine samples as small as 50 nmol.
Co-reporter:Matthew A. Perry, Matthew D. Morin, Brian W. Slafer, and Scott D. Rychnovsky
The Journal of Organic Chemistry 2012 Volume 77(Issue 7) pp:3390-3400
Publication Date(Web):March 13, 2012
DOI:10.1021/jo300161x
Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent reductive lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski–Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.
Co-reporter:Michael R. Gesinski
Journal of the American Chemical Society 2011 Volume 133(Issue 25) pp:9727-9729
Publication Date(Web):June 3, 2011
DOI:10.1021/ja204228q
The synthesis of the potent molluscicide cyanolide A has been achieved in 10 steps without the use of protecting groups. The synthesis features a key Sakurai macrocyclization/dimerization reaction that simultaneously forms both tetrahydropyran rings and the macrocycle of the natural product.
Co-reporter:Matthew A. Perry ; Matthew D. Morin ; Brian W. Slafer ; Scott A. Wolckenhauer
Journal of the American Chemical Society 2010 Volume 132(Issue 28) pp:9591-9593
Publication Date(Web):June 25, 2010
DOI:10.1021/ja104250b
Reductive lithiation of N-Boc α-amino nitriles generated α-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A1,3-strain effect that biases the conformation of the radical. In cyclohexane rings with α-substituents the net effect is an inversion of configuration on reductive lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with α-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The α-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.
Co-reporter:Maureen K. Reilly and Scott D. Rychnovsky
Organic Letters 2010 Volume 12(Issue 21) pp:4892-4895
Publication Date(Web):October 13, 2010
DOI:10.1021/ol1020515
Alkyl dioxazaborolidines are air-stable and often crystalline organoboranes. A variety of Brønsted acids activate allyl dioxazaborolidines to generate reactive allyl-transfer reagents in situ. These reagents add to aldehydes and ketones to generate the corresponding alcohols in good yields under mild conditions. The E- and Z-crotyl reagents react diastereoselectively with aldehydes and ketones to produce anti and syn adducts, respectively, a result consistent with a cyclic transition state (type I mechanism).
Co-reporter:Viengkham Malathong and Scott D. Rychnovsky
Organic Letters 2009 Volume 11(Issue 18) pp:4220-4223
Publication Date(Web):August 19, 2009
DOI:10.1021/ol901623h
Synthesis of ketone aldol products using a non-aldol route was developed. The β-phenylthio alcohols were prepared from optically pure oxiranes. Deprotonation and reductive lithiation generated the key intermediate, a β-oxyanionic alkyllithium reagent. Addition to a Weinreb amide produced the β-hydroxy ketone in >90% yield using only 1.5 equiv of the phenylthio alcohol. Stereoselective reduction of the ketone led to either the syn- or anti-1,3-diol. This simple, convergent sequence was used to prepare aculeatins A, B, and D from a common intermediate.
Co-reporter:Michael R. Gesinski, Kwanruthai Tadpetch and Scott D. Rychnovsky
Organic Letters 2009 Volume 11(Issue 22) pp:5342-5345
Publication Date(Web):October 29, 2009
DOI:10.1021/ol9022062
A tandem dimerization/macrocyclization reaction utilizing the Prins cyclization has been developed. This reaction develops molecular complexity through the formation of highly substituted dimeric tetrahydropyran macrocycles. Mild conditions utilizing rhenium(VII) catalysts were explored for aromatic substrates, while harsher Lewis acidic conditions were used for aliphatic substrates. Both aldehydes and acetals are shown to be viable substrates for this reaction.
Co-reporter:Kevin B. Bahnck and Scott D. Rychnovsky
Chemical Communications 2006 (Issue 22) pp:2388-2390
Publication Date(Web):02 May 2006
DOI:10.1039/B602937J
Prins cyclization using an electron-rich benzaldehyde and a homoallylic alcohol efficiently delivered the fully substituted C-aryl tetrahydropyranoside of kendomycin.
Co-reporter:Javier de Vicente Dr.;John R. Huckins
Angewandte Chemie International Edition 2006 Volume 45(Issue 43) pp:
Publication Date(Web):2 OCT 2006
DOI:10.1002/anie.200602742
A tetrahydropyran intermediate, prepared from (−)-diethyl tartrate, was used to assemble the C31–C67 fragment of amphidinol 3. Both of the tetrahydropyran rings in the natural product were prepared from this intermediate. The polyene segment was assembled with high selectivity.
Co-reporter:Javier de Vicente Dr.;John R. Huckins
Angewandte Chemie 2006 Volume 118(Issue 43) pp:
Publication Date(Web):2 OCT 2006
DOI:10.1002/ange.200602742
Ein Tetrahydropyran-Intermediat, das aus (−)-Diethyltartrat erhalten wurde, war maßgeblich für den Aufbau des C31–C67-Fragments von Amphidinol 3. Beide Tetrahydropyranringe des Naturstoffs gehen auf diese Zwischenstufe zurück. Das Polyensegment wurde mit hoher Selektivität synthetisiert.
Co-reporter:Thomas E. La Cruz and Scott D. Rychnovsky
Chemical Communications 2004 (Issue 2) pp:168-169
Publication Date(Web):04 Dec 2003
DOI:10.1039/B314358A
The preference for syn- or anti-addition of an intramolecular SN2′ cyclization of an alkyllithium species onto a methoxy allyl ether has been proven unequivocally to take place by a syn SN2′ mechanism.
Co-reporter:Garrick K. Packard Dr.;Yueqing Hu Dr.;Andrea Vescovi Dr.
Angewandte Chemie 2004 Volume 116(Issue 21) pp:
Publication Date(Web):12 MAY 2004
DOI:10.1002/ange.200453697
Eine effiziente, konvergente Route mit Cyanhydrinacetonid-Kupplungen vereinfachte die Synthese des Rimocidinolidmethylesters (1), des Aglykons von Rimocidin. Die Cyanhydrinacetonide dienten als β-Hydroxyketon-Syntheseäquivalente beim Aufbau der Polyolkette.
Co-reporter:Isao Kadota;Yueqing Hu;Garrick K. Packard
PNAS 2004 Volume 101 (Issue 33 ) pp:11992-11995
Publication Date(Web):2004-08-17
DOI:10.1073/pnas.0401552101
Polyene macrolide antibiotics are naturally occurring antifungal agents. Members of this class include amphotericin B, which
has been used widely to treat systemic fungal infections. A general synthetic strategy has been devised to prepare polyol
chains associated with the polyene macrolides. Cyanohydrin acetonide alkylations were used to assemble the carbon skeleton,
and a simple modification of the strategy allowed an advanced intermediate to be converted to either the candidin polyol or
the nystatin polyol. The candidin polyol was further elaborated to a protected candidin aglycone. This strategy will be applicable
to other members of the polyene macrolide natural products.
Co-reporter:Garrick K. Packard Dr.;Yueqing Hu Dr.;Andrea Vescovi Dr.
Angewandte Chemie International Edition 2004 Volume 43(Issue 21) pp:
Publication Date(Web):12 MAY 2004
DOI:10.1002/anie.200453697
An efficient, convergent route based on cyanohydrin acetonide couplings was used for the synthesis of the aglycone of rimocidin, rimocidinolide methyl ester (1). Cyanohydrin acetonides were used as β-hydroxyketone synthetic equivalents in the assembly of the polyol chain.
Co-reporter:Angie I. Kim
Angewandte Chemie International Edition 2003 Volume 42(Issue 11) pp:
Publication Date(Web):13 MAR 2003
DOI:10.1002/anie.200390325
A biomimetic [5+2] cyclization of a serrulatane diene (1) forms the basis of a concise synthesis of (−)-elisapterosin B. The diene 1 was prepared in 15 steps by using a Diels–Alder reaction between an oxygenated diene and a quinone, followed by the introduction of the methyl group at C3. The same diene 1 was used to prepare the natural product (−)-colombiasin A by a thermal [4+2] cycloaddition and demethylation.
Co-reporter:Scott D. Rychnovsky;Leo R. Takaoka
Angewandte Chemie International Edition 2003 Volume 42(Issue 7) pp:
Publication Date(Web):17 FEB 2003
DOI:10.1002/anie.200390218
A new ring-forming reaction has been developed in which nitriles act as 1,1-dianion synthons with biselectrophiles. The cyclizations are highly diastereoselective and are capable of forming two adjacent quaternary centers with complete selectivity (see scheme; LiDBB=lithium di-tert-butylbiphenylide).
Co-reporter:Scott D. Rychnovsky;Leo R. Takaoka
Angewandte Chemie 2003 Volume 115(Issue 7) pp:
Publication Date(Web):17 FEB 2003
DOI:10.1002/ange.200390187
Eine neue Ringbildungsreaktion wurde entwickelt; hierbei dienen Nitrile als Synthone für 1,1-Dianionen, die mit Biselektrophilen umgesetzt werden. Die Cyclisierungen verlaufen mit hoher Diastereoselektivität und ermöglichen dabei die selektive Bildung zweier benachbarter Stereozentren (siehe Schema; LiBDD=Lithium(di-tert-butylbiphenylid)).
Co-reporter:Christopher J. Sinz
Angewandte Chemie 2001 Volume 113(Issue 17) pp:
Publication Date(Web):7 SEP 2001
DOI:10.1002/1521-3757(20010903)113:17<3324::AID-ANGE3324>3.0.CO;2-9
Das Antibiotikum Dermostatin A (siehe Bild), ein Oxo-Hexaen-Makrolid, wurde synthetisiert. Schlüsselschritte dabei sind die Cyanhydrinacetonid-Kupplung für die Synthese der Polyolkette und die konvergente Einführung des Polyens durch eine Stille-Kupplung.
Co-reporter:Christopher J. Sinz
Angewandte Chemie International Edition 2001 Volume 40(Issue 17) pp:
Publication Date(Web):7 SEP 2001
DOI:10.1002/1521-3773(20010903)40:17<3224::AID-ANIE3224>3.0.CO;2-D
An oxo-hexaene macrolide antibiotic, dermostatin A (see picture) has been synthesized. Key features of the synthesis include the application of cyanohydrin acetonide couplings for the synthesis of the polyol portion, and the convergent introduction of the polyene segment by means of a Stille coupling.
Co-reporter:Renzo A. Samame, Christina M. Owens and Scott D. Rychnovsky
Chemical Science (2010-Present) 2016 - vol. 7(Issue 1) pp:NaN190-190
Publication Date(Web):2015/10/06
DOI:10.1039/C5SC03262H
(+)-Fastigiatine was assembled in six steps from (R)-5-methylcyclohex-2-en-1-one. Intermolecular Diels–Alder reaction introduced most of the carbon atoms for the target. The two Boc-protected nitrogen atom building blocks were introduced by a Suzuki coupling and a cuprate addition. A biomimetic transannular Mannich reaction generated the two quaternary centers at a late stage. Each step builds core bonds, and combined with a minimalist protecting group strategy, this approach led to a very concise synthesis.
Co-reporter:Anthony M. Burke, Wynne Kandur, Eric J. Novitsky, Robyn M. Kaake, Clinton Yu, Athit Kao, Danielle Vellucci, Lan Huang and Scott D. Rychnovsky
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 17) pp:NaN5037-5037
Publication Date(Web):2015/03/31
DOI:10.1039/C5OB00488H
The cross-linking Mass Spectrometry (XL-MS) technique extracts structural information from protein complexes without requiring highly purified samples, crystallinity, or large amounts of material. However, there are challenges to applying the technique to protein complexes in vitro, and those challenges become more daunting with in vivo experiments. Issues include effective detection and identification of cross-linked peptides from complex mixtures. While MS-cleavable cross-linkers facilitate the sequencing and identification of cross-linked peptides, enrichable cross-linkers increase their detectability by allowing their separation from non-cross-linked peptides prior to MS analysis. Although a number of cross-linkers with single functionality have been developed in recent years, an ideal reagent would incorporate both capabilities for XL-MS studies. Therefore, two new cross-linkers have been designed and prepared that incorporate an azide (azide-A-DSBSO) or alkyne (alkyne-A-DSBSO) to enable affinity purification strategies based on click chemistry. The integration of an acid cleavage site next to the enrichment handle allows easy recovery of cross-linked products during affinity purification. In addition, these sulfoxide containing cross-linking reagents possess robust MS-cleavable bonds to facilitate fast and easy identification of cross-linked peptides using MS analysis. Optimized, gram-scale syntheses of these cross-linkers have been developed and the azide-A-DSBSO cross-linker has been evaluated with peptides and proteins to demonstrate its utility in XL-MS analysis.
Co-reporter:Wynne V. Kandur, Athit Kao, Danielle Vellucci, Lan Huang and Scott D. Rychnovsky
Organic & Biomolecular Chemistry 2015 - vol. 13(Issue 38) pp:NaN9807-9807
Publication Date(Web):2015/08/13
DOI:10.1039/C5OB01410G
The cross-linking Mass Spectrometry (XL-MS) technique has enormous potential for studying the interactions between proteins, and it can provide detailed structural information about the interaction interfaces in large protein complexes. Such information has been difficult to obtain by conventional structural methods. One of the primary impediments to the wider use of the XL-MS technique is the extreme challenge in sequencing cross-linked peptides because of their complex fragmentation patterns in MS. A recent innovation is the development of MS-cleavable cross-linkers, which allows direct sequencing of component peptides for facile identification. Sulfoxides are an intriguing class of thermally-cleavable compounds that have been shown to fragment selectively during low-energy collisional induced dissociation (CID) analysis. Current CID-cleavable cross-linkers create fragmentation patterns in MS2 of multiple peaks for each cross-linked peptide. Reducing the complexity of the fragmentation pattern in MS2 facilitates subsequent MS3 sequencing of the cross-linked peptides. The first authentic identical mass linker (IML) has now been designed, prepared, and evaluated. Multistage tandem mass spectrometry (MSn) analysis has demonstrated that the IML cross-linked peptides indeed yield one peak per peptide constituent in MS2 as predicted, thus allowing effective and sensitive MS3 analysis for unambiguous identification. Selective fragmentation for IML cross-linked peptides from the 19S proteasome complex was observed, providing a proof-of-concept demonstration for XL-MS studies on protein complexes.
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