As exemplified by vincristine, paclitaxel, docetaxel, ixabepilone, eribulin, and the antibody–maytansinoid conjugate Kadcyla, anticancer agents based on accustomed articles that adjy microtubule dynamics accept begin ample use in animal medicine.(1) Leiodermatolide, a abyssal macrolide abandoned in 2008 from awkward extracts of a abysmal baptize lithistid blot of the brand Leiodermatium, was articular in affiliation with efforts aimed at the assay of antimitotic agents.(2) Leiodermatolide displays almighty and careful antiproliferative action adjoin a console of animal blight corpuscle curve by advantage of what appears to be a altered apparatus for disruption of tubulin dynamics: while causing aberrant arbor accumulation in two altered blight corpuscle curve at nanomolar concentrations, antiseptic tubulin was artless alike at decidedly college concentrations.(2, 3)
The arresting biological backdrop and absence of leiodermatolide accept motivated efforts adjoin its alertness through de novo actinic synthesis. To date, absolute syntheses of leiodermatolide accept been appear by Fürstner(4) and Paterson.(5) Additionally, several leiodermatolide substructures were able by Maier.(6) Despite this progress, absolute routes to leiodermatolide are on the adjustment of almost 20 accomplish (LLS) or more,(4, 5) warranting added appointment adjoin strategies that adeptness accumulate its amalgam and augment admission to structural analogues.
We accept developed a apartment of reductive C–C band formations advised by basal hydrogen(7a) or hydrogen alteration from alcohols.(7) Appliance of these methods to the amalgam of blazon I polyketides has enabled routes decidedly added abridged than ahead possible.(8) Given the challenges airish by leiodermatolide, a attack adjoin its alertness via hydrogenative coupling was undertaken. Here, we alarm our antecedent admission to the C(1)–C(13) fragment, which exploits a hydrogen-mediated reductive coupling of acetylene to accumulate the C(7)–C(13) fragment and a 2-propanol-mediated reductive coupling of allyl acetate with (E)-2-methylbut-2-enal to assemble the C(1)–C(6) fragment. A stereoselective Sakurai allylation enables abutment of the C(1)–C(6) and C(7)–C(13) fragments.
Retrosynthetically, we envisioned a allied avenue to leiodermatolides A and B from Bits A and B via esterification and (Z)-selective ring-closing metathesis (RCM) (Figure 1).(9) The amalgam of Fragment A, the affair of this report, would be able through Sakurai acknowledgment of allylsilane 6 and α,β-stereogenic chiral aldehyde 12.(10) The requisite allylsilane 6 appeared attainable from allyl booze 2 through anti-Markovnikov Wacker oxidation(11) and copper-catalyzed allylic substitution.(12) The allyl booze 2 could, in turn, be able through 2-propanol-mediated reductive coupling of allyl acetate with tiglic aldehyde 1.(13) The α,β-stereogenic chiral aldehyde 12 is able through hydrogen-mediated reductive coupling of acetylene(14) with “Roche-type” aldehyde 9. On the base of this plan, Fragment A, which incorporates six stereogenic structural features, is attainable in seven accomplish (LLS).
Figure 1. Retrosynthetic assay of leiodermatolides A and B highlighting architecture of the C(1)–C(13) fragment via hydrogenative and transfer-hydrogenative reductive coupling.
The amalgam of allylsilane 6 begins with the 2-propanol-mediated reductive coupling of allyl acetate with tiglic aldehyde 1 (Scheme 1).(13) This acknowledgment was conducted on 40 mmol calibration appliance the iridium agitator adapted by (S)-BINAP at almost 1 mol % loadings. The accessory homoallylic booze 2 was acquired in 78% crop in awful enantiomerically able anatomy (92% ee). The cyclometalated π-allyliridium C,O-benzoate catalyst, which was generated in situ from its components, was recovered from the acknowledgment admixture in 39% yield. Appliance 1 mol % of the recovered catalyst, tiglic aldehyde 1 was adapted to allyl booze 2 on 10 mmol calibration in 73% crop with commensurable levels of enantioselectivity (93% ee). Benzoylation of 2 followed by anti-Markovnikov Wacker blaze of the terminal olefin in the attendance of the allylic benzoate provided the aldehyde 4. Pinnick oxidation(15) delivered carboxylic acerbic 5, which aloft assay with TMS-diazomethane(16) provided the agnate methyl ester. Antecedent attempts to catechumen the allylic benzoate (5-methyl ester) to the allylsilane 6 beneath Fleming’s conditions, which beforehand the cuprate generated from stoichiometric quantities of silyl lithium reagent, cuprous cyanide, and triphenylphosphine,(12a) provided allylsilane 6 in bashful yields and regioselectivities. Fortunately, Oestereich’s accompanying copper-catalyzed allylic barter appliance silylzinc reagents provided above yields and regioselectivities, enabling accumulation of allylsilane 6 in 84% crop as a 14:1 admixture of regioisomers.(12b)
Scheme 1. Enantioselective Amalgam of Allylsilane 6 via 2-Propanol-Mediated Reductive Coupling of Allyl Acetate with Tiglic Aldehyde 1.a
aYields are of actual abandoned by silica gel chromatography. Enantioselectivity was bent by chiral anchored appearance HPLC analysis. See the Supporting Information for added beginning details.
Construction of α,β-stereogenic chiral aldehyde 12 begins with enantioselective benzoylation of diol 7 (Scheme 2).(17) Although the crop in this acknowledgment was modest, awfully low loadings of the calmly able diamine catalyst(18) were adapted (0.5 mol %). Dess–Martin blaze of the constant booze provided the “Roche-type” aldehyde 9.(19) The hydrogen advised reductive coupling of acetylene(14) to aldehyde 9 was absolutely arduous due to aberration at the α-position and the almost alien breadth of the σ-inductive benzoyloxy moiety. Eventually, appliance a cationic rhodium agitator adapted by the Roche ligand,(20) altitude were articular that enabled accumulation of the (Z)-butadienylated adduct 10 in 61% crop as a 5:1 admixture of diastereomers. Protection of the allylic hydroxyl as the TOM ether (iPr3SiOCH2)(21) followed by reductive abatement of the benzoate and Dess–Martin blaze provided the α,β-stereogenic chiral aldehyde 12.
Scheme 2. Enantioselective Amalgam of α,β-Stereogenic Chiral Aldehyde 12 via Hydrogen-Mediated Reductive Coupling of Acetylene with “Roche-Type” Aldehyde 9a
aYields are of actual abandoned by silica gel chromatography. Enantioselectivity was bent by chiral stationary-phase HPLC analysis. See the Supporting Information for added beginning details.
The diastereoselective Sakurai acknowledgment of allylsilane 6 and α,β-stereogenic chiral aldehyde 12 was initially explored beneath altitude appear by Panek (Scheme 3).(10) Standard altitude appliance TiCl4 resulted in decomposition, as did assertive added Lewis acids (e.g., SnCl4, MgBr2·OEt2). Added able after-effects were acquired appliance AlMe2Cl (250 mol %), which led to the accumulation of the silyl-substituted furan 13 as a audible diastereomer as bent by 1H NMR. Although furan 13 could be adapted to Fragment A in 63% crop aloft assay with SnCl4, absolute admission was preferred. It was articular that a added “chloride rich” acknowledgment average adeptness accredit abolishment rather than clearing of the silicon-stabilized cation that forms briefly aloft addition. Indeed, appliance AlEtCl2 (250 mol %), the adapted Sakurai accession artefact Fragment A was acquired in 52% yield. Judicious another of the TOM attention accumulation provided Cram-chelate ascendancy while enabling balmy deprotection in consecutive steps.(21)
Scheme 3. Sakurai Acknowledgment of Allylsilane 6 and Aldehyde 12 To Accumulate Fragment A, Which Incorporates C(1)–C(13) of Leiodermatolides A and Ba
aYields are of actual abandoned by silica gel chromatography. See the Supporting Information for added beginning details.
In summary, we abode the alertness of the C(1)–C(13) fragment of the antimitotic abyssal macrolide leiodermatolide in seven accomplish (LLS) appliance hydrogenative and alteration hydrogenative reductive C–C couplings. Above defining added abridged routes to the leiodermatolides and their structural analogues, the present abstraction has several broader impacts. The alliance of our agee allylation adjustment with Oestereich’s protocol(12b) for regio- and stereospecific accumulation of allylsilanes should augment admission to chiral reagents of this type. Additionally, the generality of the hydrogen-mediated reductive coupling of acetylene with carbonyl compounds to anatomy enantiomerically able (Z)-butadienyl alcohols is demonstrated. Approaching appointment will be adherent to the assay and development of accompanying hydrogen-mediated reductive couplings and their appliance to ambition aggressive synthesis.
J.R. and J.W. contributed equally.
The authors acknowledge no aggressive banking interest.
Acknowledgment is fabricated to the Robert A. Welch Foundation (F-0038), the NIH-NIGMS (RO1-GM069445), and the UT Austin Center for Green Allure and Catalysis for fractional abutment of this research. The Deutsche Forschungsgemeinschaft (J.W.) and the American Blight Society (S.R.) are accustomed postdoctoral acquaintance support. Donggeon Nam is accustomed for able abstruse assistance.
This commodity references 21 added publications.
For called reviews, see:
Jordan, Mary Ann; Wilson, Leslie
Nature Reviews Cancer (2004), 4 (4), 253-265CODEN: NRCAC4; ISSN:1474-175X. (Nature Publishing Group)
A review. Awful activating mitotic-spindle microtubules are amid the best acknowledged targets for anticancer therapy. Microtubule-targeted drugs, including paclitaxel and Vinca alkaloids, were ahead advised to appointment primarily by accretion or abbreviating the cellular microtubule mass. Although these furnishings adeptness accept a role in their chemotherapeutic actions, we now apperceive that at lower concns., microtubule-targeted drugs can abolish microtubule dynamics after alteration microtubule mass; this action leads to mitotic block and apoptosis. In addn. to the accretion arrangement of chem. assorted antimitotic agents, some microtubule-targeted drugs can act as vascular-targeting agents, rapidly depolymg. microtubules of anew formed vasculature to shut bottomward the claret accumulation to tumors.
Dumontet, Charles; Jordan, Mary Ann
Nature Reviews Biologic Discovery (2010), 9 (10), 790-803CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
A review. Microtubules are activating filamentous cytoskeletal proteins composed of tubulin and are an important ameliorative ambition in bump cells. Agents that bind to microtubules accept been allotment of the pharmacopoeia of anticancer analysis for decades and until the appearance of targeted therapy, microtubules were the abandoned another to DNA as a ameliorative ambition in cancer. The screening of a ambit of botanical breed and abyssal bacilli has yielded able new antitubulin agents with atypical properties. In the accepted chase for atypical microtubule-binding agents, added bump specificity, bargain neurotoxicity and aloofness to chemoresistance mechanisms are the three capital objectives.
Rohena, Cristina C.; Mooberry, Susan L.
Natural Artefact Reports (2014), 31 (3), 335-355CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
A review. Covering: backward 2008 to August 2013Nature has yielded abundant classes of chem. audible microtubule stabilizers. Several of these, including paclitaxel (Taxol) and docetaxel (Taxotere), are important drugs acclimated in the assay of cancer. New microtubule stabilizers and atypical formulations of these agents abide to accommodate advances in blight therapy. In this analysis we awning contempo beforehand in the chem. and biol. of these assorted microtubule stabilizers absorption on the avant-garde ambit of bacilli that aftermath these compds., their mechanisms of inhibiting microtubule-dependent processes, mechanisms of biologic resistance, and their interactions with tubulin including their audible bounden sites and modes. A new abeyant role for microtubule stabilizers in neurodegenerative diseases is reviewed.
For abreast and fractional anatomy assurance of leiodermatolides A and B, see:
There is no agnate almanac for this reference.
Paterson, Ian; Dalby, Stephen M.; Roberts, Jill C.; Naylor, Guy J.; Guzman, Esther A.; Isbrucker, Richard; Pitts, Tara P.; Linley, Pat; Divlianska, Daniela; Reed, John K.; Wright, Amy E.
Angewandte Chemie, International Edition (2011), 50 (14), 3219-3223, S3219/1-S3219/71CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Leidermatolide (I) is a structurally altered polyketide-derived macrolide abandoned from deep-water abyssal blot Leiodermatium, whose potentially atypical admission of antimitotic action makes it an agitative new beforehand for anticancer biologic discovery. Its deficient accustomed affluence additionally makes it a prime ambition for acumen a applied synthesis. Advised appear this end, including resoln. of actual configurational issues, will be appear in due course.
Wright, Amy E.; Roberts, Jill C.; Guzman, Esther A.; Pitts, Tara P.; Pomponi, Shirley A.; Reed, John K.
Journal of Accustomed Products (2017), 80 (3), 735-739CODEN: JNPRDF; ISSN:0163-3864. (American Actinic Society-American Society of Pharmacognosy)
Two new analogs of the almighty antitumor compd. leiodermatolide, which we alarm leiodermatolides B (I) and C (II), were abandoned from specimens of a deep-water blot of the brand Leiodermatium calm off Florida. The compds. were antiseptic appliance std. chromatog. methods and the structures authentic through estimation of the HRMS and 1- and 2-dimensional NMR data. I lacks the C-21 hydroxy accumulation begin in leiodermatolide and has according authority as the ancestor compd. accouterment a simpler analog for attainable clin. development. It inhibits the admeasurement of the AsPC-1 animal pancreatic adenocarcinoma corpuscle band with an IC50 of 43 nM. II has a adapted macrolide arena and is >85-fold beneath almighty with an IC50 of 3.7 μM adjoin the aforementioned corpuscle line. These compds. add to the adeptness of the pharmacophore of this chic of almighty antitumor agents.
Guzman, Esther A.; Xu, Qunli; Pitts, Tara P.; Mitsuhashi, Kaoru Ogawa; Baker, Cheryl; Linley, Patricia A.; Oestreicher, Judy; Tendyke, Karen; Winder, Priscilla L.; Suh, Edward M.; Wright, Amy E.
International Journal of Cancer (2016), 139 (9), 2116-2126CODEN: IJCNAW; ISSN:0020-7136. (John Wiley & Sons, Inc.)
Pancreatic cancer, the fourth arch account of blight afterlife in the United States, has a neg. cast because alteration occurs afore affection manifest. Leiodermatolide, a polyketide macrolide with antimitotic action abandoned from a abysmal baptize blot of the brand Leiodermatium, exhibits almighty and careful cytotoxicity adjoin the pancreatic blight corpuscle curve AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and almighty cytotoxicity adjoin skin, breast and colon blight corpuscle lines. Consecration of apoptosis by leiodermatolide was accepted in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces corpuscle aeon arrest but has no furnishings on in vitro polymn. or depolymn. of tubulin alone, while it enhances polymn. of tubulin contg. microtubule assocd. proteins (MAPs). Observations through confocal microscopy appearance that leiodermatolide, at low concns., causes basal furnishings on polymn. or depolymn. of the microtubule arrangement in interphase cells, but disruption of arbor accumulation in mitotic cells. At college concns., depolymn. of the microtubule arrangement is obsd. Visualization of the growing microtubule in HeLa beef cogent GFP-tagged additional end bounden protein EB-1 showed that leiodermatolide chock-full the polymn. of tubulin. These after-effects beforehand that leiodermatolide may affect tubulin dynamics after anon interacting with tubulin and adumbration at a altered apparatus of action. In a abrasion archetypal of metastatic pancreatic cancer, leiodermatolide apparent cogent bump redn. back compared to gemcitabine and controls. The antitumor activities of leiodermatolide, as able-bodied as the accurate account of antimitotic compds. adjoin cancer, accomplish leiodermatolide an absorbing compd. with abeyant chemotherapeutic furnishings that may arete added research.
Willwacher, Jens; Kausch-Busies, Nina; Fuerstner, Alois
Angewandte Chemie, International Edition (2012), 51 (48), 12041-12046CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
The aboriginal absolute amalgam of the structurally arduous and biol. awful able antimitotic abettor leiodermatolide (I) was able by blame the banned of alkyne metathesis to new frontiers. The called admission is short, efficient, and flexible, and should appropriately authorize for a synthesis-driven mapping of the pharmacophore of this beforehand compd. In chem. terms, this case abstraction corroborates our antecedent cessation that arena closing alkyne metathesis (RCAM) is decidedly adapted for applications to polyunsatd. targets, breadth olefin metathesis generally finds its limits. At the aforementioned time, this analysis shows that absolute amalgam charcoal an basal apparatus for anatomy elucidation, alike in the age of spectroscopy, back ambidextrous with compds. that accommodate spatially absolute stereoclusters.
Mailhol, Damien; Willwacher, Jens; Kausch-Busies, Nina; Rubitski, Elizabeth E.; Sobol, Zhanna; Schuler, Maik; Lam, My-Hanh; Musto, Sylvia; Loganzo, Frank; Maderna, Andreas; Fuerstner, Alois
Journal of the American Actinic Society (2014), 136 (44), 15719-15729CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
It was by way of absolute amalgam that the issues apropos the stereostructure of leiodermatolide (I) accept afresh been solved; with the ambition now actuality actually defined, the mission of amalgam changes as to defended a allusive accumulation of this awfully deficient accustomed artefact acquired from a abyssal sponge. To this end, a scalable avenue of 19 accomplish (longest beeline sequence) has been developed, which appearance a catalytic asym. propargylation of a awful enolizable β-keto-lactone, a arena closing alkyne metathesis and a adapted Stille coupling as the key transformations. Deliberate apostrophe from this able-bodied adapt brought a aboriginal set of analogs into reach, which accustomed the beforehand qualities of I to be assessed. The acquired biodata appearance that I is a almighty cytotoxin in animal bump corpuscle admeasurement assays, acclaimed by GI50 ethics in the ≤3 nM ambit alike for corpuscle curve cogent the Pgp abode transporter. Studies with animal U2OS beef appear that I causes mitotic arrest, micronucleus induction, centrosome accession and tubulin disruption, alike admitting no affirmation for absolute tubulin bounden has been begin in cell-free assays; moreover, the compd. does not assume to act through kinase inhibition. Indirect affirmation credibility at centrosome declustering as a attainable apparatus of action, which provides a potentially advantageous angle in that centrosome declustering agents authority affiance of actuality inherently careful for cancerous over advantageous animal tissue.
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Paterson, Ian; Paquet, Tanya; Dalby, Stephen M.
Organic Letters (2011), 13 (16), 4398-4401CODEN: ORLEF7; ISSN:1523-7052. (American Actinic Society)
The macrocyclic amount I of the abyssal macrolide leiodermatolide was actinic in 19 accomplish through a allied action base boron aldol methodol. to install the requisite stereochem. and a careful Stille coupling acknowledgment for controlled fragment assembly, followed by a Yamaguchi macrolactonization and carbamate accession at the C9-OH.
Paterson, Ian; Ng, Kenneth K.-H.; Williams, Simon; Millican, David C.; Dalby, Stephen M.
Angewandte Chemie, International Edition (2014), 53 (10), 2692-2695CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
Leiodermatolide is an antimitotic macrolide abandoned from the abyssal blot Leiodermatium sp. whose potentially atypical tubulin-targeting apparatus of action makes it an agitative beforehand for anticancer biologic discovery. In following of a acceptable supply, we abode a awful stereocontrolled absolute amalgam (3.2 % yield) based on a allied arrangement of palladium-mediated fragment accumulation and macrolactonization. Boron-mediated aldol reactions were acclimated to configure the three key bits I, II, and III by employing the adapted enantiomer of the lactate-derived ketone (R)- or (S)-PhCO2CH(Me)COEt.
Paterson, Ian; Williams, Simon
Israel Journal of Chemistry (2017), 57 (3-4), 192-201CODEN: ISJCAT; ISSN:0021-2148. (Wiley-VCH Verlag GmbH & Co. KGaA)
This analysis highlights the assorted challenges affected during our contempo complete attack appear (-)-leiodermatolide, a almighty cytotoxic and antimitotic macrolide abandoned from the abyssal blot Leiodermatium sp. This structurally aberrant macrocyclic chemotype represents a able beforehand for anticancer biologic discovery, provided a acceptable accumulation can be able by an able chem. synthesis. Faced with the stereochem. ambiguities arising from our structural appointment work, a adjustable and modular complete action was adopted for the architecture of assorted key fragments, as a commencement to the controlled accumulation of the two diene moieties. Accession of the nine stereocentres was able by the cardinal use of boron-mediated aldol reactions of chiral ketone architecture blocks. Following the basal architecture of the macrocyclic core, we revised our action to avoid some ambiguous steps, enabling a awful allied absolute amalgam of (-)-leiodermatolide.
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Rink, Christian; Navickas, Vaidotas; Maier, Martin E.
Organic Letters (2011), 13 (9), 2334-2337CODEN: ORLEF7; ISSN:1523-7052. (American Actinic Society)
The amalgam of the 16-membered amount anatomy of leiodermatolide I has been able in 26 beeline accomplish starting from (R)-Roche ester. The key accomplish in the amalgam of I are a Stille cross-coupling amid two capital bits accepting almost according size. For the trisubstituted C4/C5 bifold band a carbometalation acknowledgment followed by a Suzuki coupling was used. A Yamaguchi macrolactonization furnished the macrolactone of I.
Reiss, Anita; Maier, Martin E.
Organic Letters (2016), 18 (13), 3146-3149CODEN: ORLEF7; ISSN:1523-7052. (American Actinic Society)
The macrocyclic amount I of the abyssal accustomed artefact leiodermatolide (II) was actinic from two key fragments, vinyl iodide III (C1-C11 part) and vinyl stannane IV (C12-C18 part). A Stille coupling led to conjugated Z,Z-diene. The acquired seco acerbic was cyclized appliance a Yamaguchi macrolactonization. Key accomplish in the accumulation of vinyl iodide III were a Paterson aldol reaction, and a Kumada coupling on a triflate deriv. to actualize the C4-C5 trisubstituted bifold bond. The two stereocenters in fragment IV were accustomed by a Marshall-Tamaru reaction. The longest beeline arrangement comprises 20 steps.
For contempo reviews on hydrogenation and alteration hydrogenation for reductive carbonyl addition, see:
Hassan, Abbas; Krische, Michael J.
Organic Action Analysis & Development (2011), 15 (6), 1236-1242CODEN: OPRDFK; ISSN:1083-6160. (American Actinic Society)
A review. Hydrogenation of π-unsatd. reactants in the attendance of carbonyl compds. or imines promotes reductive C-C coupling, accouterment a byproduct-free another to stoichiometric organometallic reagents in an ever-increasing ambit of C=X (X = O, NR) addns. Beneath alteration hydrogenation conditions, hydrogen barter amid alcs. and π-unsatd. reactants triggers address of electrophile-nucleophile pairs, enabling carbonyl addn. anon from the alc. oxidn. level, bypassing detached alc. oxidn. and address of stoichiometric byproducts.
Ketcham, John M.; Shin, Inji; Montgomery, T. Patrick; Krische, Michael J.
Angewandte Chemie, International Edition (2014), 53 (35), 9142-9150CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. The use of alcs. and unsatd. reactants for the redox-triggered address of nucleophile-electrophile pairs represents a broad, new admission to carbonyl addn. chem. Detached redox manipulations that are generally adapted for the address of carbonyl electrophiles and premetalated carbon-centered nucleophiles are appropriately avoided. Based on this concept, a broad, new ancestors of enantioselective C-C coupling reactions that are catalyzed by iridium or ruthenium complexes were developed, which are abbreviated in this Minireview.
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There is no agnate almanac for this reference.
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Kim, Seung Wook; Zhang, Wandi; Krische, Michael J.
Accounts of Actinic Research (2017), 50 (9), 2371-2380CODEN: ACHRE4; ISSN:0001-4842. (American Actinic Society)
A review. Merging the characteristics of alteration hydrogenation and carbonyl addn., we accept developed a new chic of catalytic enantioselective C-C band formations. In these processes, hydrogen alteration amid alcs. and π-unsatd. reactants generates carbonyl-organometal pairs that amalgamate to bear articles of addn. On the base of this mechanistic paradigm, lower alcs. are adapted anon to college alcs. in the absence of premetalated reagents or detached alc.-to-carbonyl redox reactions. In assertive cases, due to a arresting alive alternative for primary vs. accessory alc. dehydrogenation, diols and college polyols are begin to appoint in catalytic stereo- and site-selective C-C band formation-a adequacy that added enhances adeptness by enabling ashen architecture contest after accidental manipulations adherent to the accession and abatement of attention groups. While this Account focuses on redox-neutral couplings of alcs., agnate aldehyde reductive couplings advised by 2-propanol were developed in alongside for best of the catalytic transformations appear herein. Mechanistically, two audible classes of alc. C-H functionalizations accept emerged, which are acclaimed by the admission of pronucleophile activation, specifically, processes wherein alc. oxidn. is counterbalanced by (a) π-bond hydrometalation or (b) C-X band reductive cleavage. Anniversary alleyway offers admission to allylmetal or allenylmetal intermediates and, therefrom, enantiomerically able homoallylic or homopropargylic alc. products, resp. In the broadest terms, carbonyl addn. advised by premetalated reagents has played a axial role in complete org. chem. for able-bodied over a century, but the requisite organometallic reagents affectation issues of safety, crave multistep syntheses, and accomplish stoichiometric quantities of brownish byproducts. The concepts and catalytic processes declared in this Account, conceived and developed wholly aural the author’s lab., arresting a abandonment from the use of stoichiometric organometallic reagents in carbonyl addn. Rather, they reimagine carbonyl addn. as a hydrogen autotransfer action or cross-coupling in which alc. reactants, by advantage of their built-in abbreviation ability, drive the address of brief organometallic nucleophiles and, in accomplishing so, serve dually as carbonyl proelectrophiles. The catalytic allylative and propargylative transformations developed to date affectation capabilities far above their classical counterparts, and their appliance to the absolute amalgam of type-I polyketide accustomed articles accept evoked a step-change in efficiency. Added importantly, the present abstracts beforehand that assorted transformations commonly codicillary on premetalated reagents may now be conducted catalytically after stoichiometric metals. This Account provides the clairvoyant and abeyant practitioner with a archive of enantioselective alc.-mediated carbonyl addns.-a user’s guide, 10-yr retrospective, and foundation for approaching appointment in this arising breadth of catalytic C-C band formation.
For reviews on the appliance of hydrogenative C–C coupling to polyketide construction, see:
Dechert-Schmitt, Anne-Marie R.; Schmitt, Daniel C.; Gao, Xin; Itoh, Takahiko; Krische, Michael J.
Natural Artefact Reports (2014), 31 (4), 504-513CODEN: NPRRDF; ISSN:0265-0568. (Royal Society of Chemistry)
A review. Despite the longstanding accent of polyketide accustomed articles in animal medicine, about all com. polyketide-based drugs are prepd. through fermn. or semi-synthesis. The absence of manufg. routes involving de novo chem. amalgam reflects the disability of accepted methods to concisely abode the prepn. of these circuitous structures. Absolute alc. C-H band functionalization via C-C band basal alteration hydrogenation provides a powerful, new bureau of amalgam blazon I polyketides that bypasses stoichiometric use of chiral auxiliaries, premetallated C-nucleophiles, and detached alc.-to-aldehyde redox reactions. Appliance this appearing technol., absolute syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and academic syntheses of rifamycin S and scytophycin C, were accomplished. These syntheses represent the best abridged routes appear to any affiliate of the resp. accustomed artefact families.
Feng, Jiajie; Kasun, Zachary A.; Krische, Michael J.
Journal of the American Actinic Society (2016), 138 (17), 5467-5478CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
A review. The development and appliance of stereoselective and site-selective catalytic methods that anon catechumen lower alcs. to college alcs. are described. These processes absorb the characteristics of alteration hydrogenation and carbonyl addn., base alcs. and π-unsatd. reactants as redox pairs, which aloft hydrogen alteration accomplish brief carbonyl-organometal pairs en avenue to articles of C-C coupling. Unlike classical carbonyl addns., stoichiometric organometallic reagents and detached alc.-to-carbonyl redox reactions are not required. Addnl., due to a alive alternative for primary alc. dehydrogenation, the site-selective modification of glycols and college polyols is possible, streamlining or eliminating use of attention groups. The absolute syntheses of several iconic blazon I polyketide accustomed articles were undertaken appliance these methods. In anniversary case, the ambition compds. were prepd. in decidedly beneath accomplish than ahead achieved.
For called reviews on (Z)-selective alkene metathesis, see:
Herbert, Myles B.; Grubbs, Robert H.
Angewandte Chemie, International Edition (2015), 54 (17), 5018-5024CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Olefin cantankerous metathesis is a decidedly able transformation that has been exploited abundantly for the accumulation of circuitous products. Until recently, however, amalgam Z-olefins appliance this methodol. was not possible. With the assay and development of three families of ruthenium-based Z-selective catalysts, the accumulation of Z-olefins appliance metathesis is now not abandoned attainable but acceptable added accustomed in the literature. In particular, ruthenium complexes contg. cyclometalated NHC architectures developed in our accumulation accept been apparent to activate assorted cantankerous metathesis reactions with aerial action and, in best cases, abreast absolute selectivity for the Z-isomer. The types of cantankerous metathesis reactions advised appropriately far are presented actuality and explored in depth.
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Jain, Nareshkumar F.; Takenaka, Norito; Panek, James S.
Journal of the American Actinic Society (1996), 118 (49), 12475-12476CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
The faculty and akin of 1,2-asym. consecration accept been evaluated in the Lewis acid-promoted addn. of (R)- and (S)-MeCH:CRCH(SiMe2Ph)CH2CO2Me (R = H, Me, Et) with (S)-R1OCH2CHMeCHO (R1 = CH2Ph, SiPh2CMe3). These aldehydes are commissioned at the β-position with benzyloxy to reinforce chelation and tert-butyldiphenylsilyloxy to anticipate chelation with TiCl4, a bidentate Lewis acid. To det. the aftereffect of addnl. stereogenic centers on the stereochem. beforehand of these reactions, bifold stereodifferentiating crotylation reactions were performed on silyl-protected aldehydes address up to bristles adjoining stereocenters. Those expts. provided a abutting affinity to band architecture and synthons encountered in the amalgam of polypropionates. The attributes of the Lewis acerbic and the chirality of the silane reagent were begin to comedy a cardinal role in the faculty (syn or anti band construction) and akin of carbonyl diastereoface selectivity.
Panek, James S.; Liu, Ping
Journal of the American Actinic Society (2000), 122 (45), 11090-11097CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
A awful allied asym. amalgam of the actin-depolymg. abettor (-)-mycalolide A was able through the accumulation and abutment of the C1-C19 trisoxazole fragment I (R = Br; R1 = CH((S)-OMe)CH((R)-Me)CO(E)-CH=CHCH2CH((S)-OSiPh2Bu-t)CH2CO2H) and the C20-C35 aliph. fragment II, resp. The C1-C19 trisoxazole fragment I was complete via a Kishi-Nozaki coupling amid the C1-C6 subunit III and the C7-C19 subunit I (R = OSiPh2Bu-t; R1 = CH((S)-OMe)CH((R)-Me)CHO) which in about-face was acquired from a awful stereoselective crotylation acknowledgment of (3S,4E)-Me 3-(dimethylphenylsilyl)-4-hexenoic acerbic with trisoxazole aldehyde I (R = OSiPh2Bu-t; R1 = CHO) . The amalgam of II was able appliance chiral silane-based band architecture methodol. for the accession of the stereochem. relationships. Abutment of the avant-garde C1-C19 average I and II through a Schlosser-Wittig protocol, macrocyclization appliance Yamaguchi conditions, and consecutive anatomic accumulation adjustments completed the absolute amalgam of (-)-mycalolide A. The amalgam accepted the about and abs. stereochem. of (-)-mycalolide A, and illustrated the appliance of chiral silane-based C-C band architecture methodol. to the asym. amalgam of circuitous mols.
Wickens, Zachary K.; Skakuj, Kacper; Morandi, Bill; Grubbs, Robert H.
Journal of the American Actinic Society (2014), 136 (3), 890-893CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
The aldehyde-selective oxidn. of alkenes address assorted oxygen groups in the allylic and homoallylic position was able with a nitrite-modified Wacker oxidn. Readily attainable oxygenated alkenes were breakable in up to 88% aldehyde crop and as aerial as 97% aldehyde selectivity. The aldehyde-selective oxidn. enabled the rapid, enantioselective amalgam of an important biologic agent, atomoxetine. Finally, the admission of adjacent anatomic groups on this anti-Markovnikov acknowledgment was explored, accouterment important basal mechanistic insight.
Fleming, Ian; Higgins, Dick; Lawrence, Nicholas J.; Thomas, Andrew P.
Journal of the Actinic Society, Perkin Transactions 1: Organic and Bio-Organic Allure (1972-1999) (1992), (24), 3331-49CODEN: JCPRB4; ISSN:0300-922X.
Primary and accessory allylic acetates and benzoates acknowledge with the dimethyl(phenyl)silylcuprate reagent to accord allylsilanes, provided that the THF in which the cuprate is prepd. is dild. with ether afore addn. of the allylic ester. The acknowledgment is analytic regioselective in some cases: (i) back the allylic arrangement is more-substituted at one end than the other, e.g., as in the acknowledgment of Me2C:CHCH2OC(O)Ph → Me2C:CHCH2SiMe2Ph; (ii) back the steric hinderance at one end is neopentyl-like, as in the reactions I (R = Me, Ph, CHMe2, n = 1, 2) → II; and (iii) back the disubstituted bifold band has the Z configuration, as in the reactions Z-PhCH:CHCHMeOAc → PhCH(SiMe2Ph)CH:CHMe or, better, because the silyl accumulation is acceptable absorbed to the less-sterically hindered end of the allylic system. The regioselectivity is bigger if a Ph carbamate is acclimated in abode of the ester, and a three-step agreement accumulating the alloyed cuprate on the abrogation accumulation is used, or, best of all, because the silyl accumulation is afresh acceptable absorbed to the less-sterically hindered end of the allylic system. This arrangement works able-bodied to move the silyl accumulation assimilate the added commissioned end of an allyl system, but abandoned back the move is from a accessory allylic carbamate to a tertiary allylsilane. Allyl(trimethyl)silanes can be fabricated appliance alkyl- or arylcuprates on trimethylsilyl-contg. allylic esters and carbamates. The acknowledgment of the silylcuprate with allylic esters and the three-step arrangement with the allylic carbamates are stereochem. complementary, the above actuality stereospecifically anti and the closing stereospecifically syn. Homochiral allylsilanes can be fabricated by these methods with aerial levels of stereospecificity.
Schmidtmann, Eric S.; Oestreich, Martin
Chemical Communications (Cambridge, United Kingdom) (2006), (34), 3643-3645CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
Isotopic desymmetrization, as able-bodied as (stereo)chem. correlation, has aflame cogent aspects of the σ-π-σ apparatus of Cu-catalyzed allylic barter reactions: an enantiospecific and regioselective admission to α-chiral silanes is presented.
For called examples of enantioselective alcohol-mediated carbonyl allylation catalyzed by iridium, see:
Kim, In Su; Ngai, Ming-Yu; Krische, Michael J.
Journal of the American Actinic Society (2008), 130 (20), 6340-6341CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
Protocols for awful enantioselective carbonyl allylation from the alc. or aldehyde oxidn. akin are declared based aloft alteration hydrogenative C-C coupling. Acknowledgment of allyl acetate to benzylic alcs. RCH2OH (R = Ph, 4-O2NC6H4, 4-MeOC6H4, 1-methyl-2-indolyl, etc.) in the attendance of an iridium agitator acquired from [IrCl(cod)]2 and (R)-BINAP delivers articles of C-allylation (R)-RCH(OH)CH2CH:CH2. Employing isopropanol as terminal reductant, acknowledgment of allyl acetate to aryl aldehydes RCHO in the attendance of an iridium agitator acquired from [IrCl(cod)]2 and (-)-TMBTP delivers identical articles of C-allylation. In all cases examd., barring levels of enantioselectivity are obsd. Thus, enantioselective carbonyl allylation is able from the alc. or aldehyde oxidn. akin in the absence of any preformed allylmetal reagents. These studies ascertain a abandonment from preformed organometallic reagents in carbonyl addns. that transcend the boundaries of oxidn. level.
Kim, In Su; Ngai, Ming-Yu; Krische, Michael J.
Journal of the American Actinic Society (2008), 130 (44), 14891-14899CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
Under the altitude of alteration hydrogenation employing an iridium agitator generated in situ from [Ir(cod)Cl]2, chiral phosphine ligand (R)-BINAP or (R)-Cl,MeO-BIPHEP, and m-nitrobenzoic acid, allyl acetate couples to allylic, aliph., or benzylic alcs. to accouter articles of carbonyl allylation with aberrant levels of asym. induction. The actual aforementioned set of optically able carbonyl allylation articles are attainable from enals , aliph. aldehydes , and aryl aldehydes, appliance iridium catalysts ligated by (-)-TMBTP or (R)-Cl,MeO-BIPHEP beneath identical conditions, but employing isopropanol as a hydrogen donor. A catalytically alive cyclometallated circuitous V, which arises aloft ortho-C-H admittance of iridium assimilate m-nitrobenzoic acid, was characterized by single-crystal x-ray diffraction. The after-effects of isotopic labeling are constant with action of sym. iridium π-allyl intermediates or accelerated interconversion of σ-allyl haptomers through the bureau of a sym. π-allyl. Competition expts. authenticate accelerated and capricious hydrogenation-dehydrogenation of the carbonyl accomplice in beforehand of C-C coupling. However, the coupling products, which are homoallylic alcs., acquaintance actual little abrasion of optical abstention by way of redox equilibration beneath the coupling conditions, although isopropanol, a accessory alc., may serve as terminal reductant. A believable catalytic apparatus accounting for these observations is proposed, forth with a stereochem. archetypal that accounts for the obsd. faculty of abs. stereoinduction. This agreement for asym. carbonyl allylation transcends the barriers imposed by oxidn. akin and the use of preformed allyl metal reagents.
Schmitt, Daniel C.; Dechert-Schmitt, Anne-Marie R.; Krische, Michael J.
Organic Letters (2012), 14 (24), 6302-6305CODEN: ORLEF7; ISSN:1523-7052. (American Actinic Society)
The cyclometalated π-allyliridium 3,4-dinitro-C,O-benzoate circuitous adapted by (R)- or (S)-Cl,MeO-BIPHEP promotes the alteration hydrogenative coupling of allyl acetate to β-stereogenic alcs. with acceptable to accomplished levels of catalyst-directed diastereoselectivity to accouter homoallylic alcs. Alien cyberbanking furnishings of the C,O-benzoate of the agitator comedy a crit. role in suppressing epimerization of the brief α-stereogenic aldehyde.
Dechert-Schmitt, Anne-Marie R.; Schmitt, Daniel C.; Krische, Michael J.
Angewandte Chemie, International Edition (2013), 52 (11), 3195-3198CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
A site-selective redox allylation of 1,3-glycols with allyl acetate through iridium-catalyzed advantage dehydrogenation of primary alc. is described. This adjustment accustomed chemo- and stereoselective carbinol CH-allylation in the absence of attention groups, chiral auxiliaries, premetalated reagents, and detached alc.-to-aldehyde redox manipulations.
Shin, Inji; Wang, Gang; Krische, Michael J.
Chemistry – A European Journal (2014), 20 (41), 13382-13389CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
The iridium-catalyzed, attention group-free amalgam of 4-hydroxy-2,6-cis- I [R = Me, Bu-t, Ph] and II or trans-pyrans III and IV through alternating nucleophilic and electrophilic allylations of chiral 1,3-diols occurs with complete levels of catalyst-directed diastereoselectivity in the absence of attention groups, premetallated reagents, or detached alc.-to-aldehyde redox reactions.
Kong, Jong Rock; Krische, Michael J.
Journal of the American Actinic Society (2006), 128 (50), 16040-16041CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
Exposure of aldehydes or α-ketoesters to according vols. of acetylene and hydrogen gas at ambient temp. and burden in the attendance of cationic rhodium catalysts provides articles of carbonyl Z-butadienylation, which appear via multicomponent coupling of four mols.: two mols. of acetylene, a mol. of abreast dicarbonyl compd., and a mol. of basal hydrogen. The aggregate abstracts beforehand a catalytic apparatus involving carbonyl admittance into a cationic rhodacyclopentadiene average acquired via oxidative dimerization of acetylene. Hydrogenolytic break of the constant oxarhodacycloheptadiene via academic σ-bond metathesis provides the artefact of carbonyl addn. and cationic rhodium(I) to abutting the catalytic cycle. Studies involving the hydrogenation of 1,6-diyne 14a (I) in the attendance of α-ketoester 6a (II) approve the proposed catalytic mechanism. These multicomponent couplings represent the aboriginal use of acetylene gas, a basal chem. feedstock, in metal-catalyzed reductive C-C band formation.
Skucas, Eduardas; Kong, Jong Rock; Krische, Michael J.
Journal of the American Actinic Society (2007), 129 (23), 7242-7243CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
The aboriginal awful enantioselective catalytic vinylation of aldimines to accouter allylic amines is reported. Acknowledgment of arom. and aliph. N-arylsulfonyl aldimines to according vols. of acetylene and hydrogen gas at 45 °C and ambient burden in the attendance of chirally adapted cationic rhodium catalysts provides the (Z)-dienyl allylic amines, e.g., I, in awful optically able anatomy (93-98% ee) and as audible geometrical isomers (>95:5, Z/E). The coupling articles appear via multicomponent coupling of four mols.: two mols. of acetylene, a mol. of aldimine, and basal hydrogen. Unlike added imine addns. involving nonstabilized carbanions, the present agreement circumvents use of preformed organometallic reagents.
Han, Soo Bong; Kong, Jong Rock; Krische, Michael J.
Organic Letters (2008), 10 (18), 4133-4135CODEN: ORLEF7; ISSN:1523-7060. (American Actinic Society)
Hydrogenative coupling of acetylene to α-chiral aldehydes appliance enantiomeric rhodium catalysts ligated by (S)-MeO-BIPHEP and (R)-MeO-BIPHEP delivers the diastereomeric articles of carbonyl-(Z)-butadienylation with acceptable to accomplished levels of agitator directed diastereofacial selectivity. Diastereomeric L-glyceraldehyde acetonide adducts were adapted to the four isomeric enoates, e.g. I, apery a academic amalgam of all eight L-hexoses.
Williams, Vanessa M.; Kong, Jong Rock; Ko, Byoung Joon; Mantri, Yogita; Brodbelt, Jennifer S.; Baik, Mu-Hyun; Krische, Michael J.
Journal of the American Actinic Society (2009), 131 (44), 16054-16062CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
The catalytic apparatus of the hydrogen-mediated coupling of acetylene to carbonyl compds. and imines has been examd. appliance three techniques: (a) ESI-MS and ESI-CAD-MS analyses, (b) computational modeling, and (c) expts. wherein accepted acknowledging intermediates are absent to alternating acknowledgment products. ESI-MS anal. of acknowledgment mixts. from the hydrogen-mediated reductive coupling of acetylene to α-ketoesters or N-benzenesulfonyl aldimines approve a catalytic apparatus involving C=X (X = O, NSO2Ph) admittance into a cationic rhodacyclopentadiene acquired by way of acetylene oxidative dimerization with consecutive Bronsted acerbic cocatalyzed hydrogenolysis of the constant oxa- or azarhodacycloheptadiene. Hydrogenation of 1,6-diynes in the attendance of α-ketoesters provides akin coupling products. ESI accumulation spectrometric anal. afresh corroborates a catalytic apparatus involving carbonyl admittance into a cationic rhodacyclopentadiene. For all ESI-MS expts., the structural assignments of ions are accurate by multistage collisional activated dissocn. (CAD) analyses. Added abutment for the proposed catalytic apparatus derives from expts. aimed at the interception of accepted acknowledging intermediates and their aberration to alternating acknowledgment products. For example, rhodium-catalyzed coupling of acetylene to an aldehyde in the absence of hydrogen or Bronsted acerbic cocatalyst provides the agnate (Z)-butadienyl ketone, which arises from β-hydride abolishment of the proposed oxarhodacycloheptadiene intermediate, as corroborated by isotopic labeling. Addnl., the accepted rhodacyclopentadiene average acquired from the oxidative coupling of acetylene is absent to the artefact of reductive [2 2 2] cycloaddn. back N-p-toluenesulfonyl-dehydroalanine Et ester is acclimated as the coupling partner. The apparatus of this transformation additionally is corroborated by isotopic labeling. Computer archetypal studies based on d. anatomic access (DFT) abutment the proposed apparatus and analyze Bronsted acerbic cocatalyst assisted hydrogenolysis to be the best difficult step. The aggregate studies accommodate new acumen into the acuteness of cationic rhodacyclopentadienes, which should facilitate the architecture of accompanying rhodium-catalyzed C-C couplings.
Del Valle, David J.; Krische, Michael J.
Journal of the American Actinic Society (2013), 135 (30), 10986-10989CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
The triene-contg. C17-benzene ansamycins trienomycins A and F were prepd. in 16 accomplish (longest beeline sequence, LLS) and 28 absolute steps. The C11-C13 stereotriad was generated via enantioselective Ru-catalyzed alc. CH syn crotylation followed by chelation-controlled carbonyl dienylation. Enantioselective Rh-catalyzed acetylene-aldehyde reductive coupling advised by aerial H2 was acclimated to anatomy a diene that ultimately was subjected to diene-diene arena closing metathesis to anatomy the macrocycle. The present admission is 14 accomplish beneath (LLS) than the above-mentioned syntheses of trienomycins A and F, and 8 accomplish beneath than any above-mentioned amalgam of a triene-contg. C17-benzene ansamycin.
Bal, Balkrishna S.; Childers, Wayne E., Jr.; Pinnick, Harold W.
Tetrahedron (1981), 37 (11), 2091-6CODEN: TETRAB; ISSN:0040-4020.
Three methods for the oxidn. of α,β-unsatd. aldehydes to the agnate acids were studied. These were MnO2 oxidn. of the cyanohydrin deriv., assay with Caro’s acid, and acknowledgment with NaClO2. The aftermost was the best method, giving authentic acerbic in aerial yield. E.g., propenal I (R = H) with NaClO2 (Me3COH, MeCH:CMe2, aq. NaH2PO4, allowance temp., overnight) gave 90% I (R = OH).
Lei, Xiaoguang; Porco, John A., Jr.
Journal of the American Actinic Society (2006), 128 (46), 14790-14791CODEN: JACSAT; ISSN:0002-7863. (American Actinic Society)
The enantioselective absolute amalgam of the diazobenzofluorene antibacterial (-)-kinamycin C (I) is reported. The admission involves tartrate-mediated, asym. nucleophilic epoxidn. of a functionalized quinone monoketal to assemble the awful commissioned D-ring.
Seyferth, Dietmar; Dow, Alan W.; Menzel, Horst; Flood, Thomas C.
Journal of the American Actinic Society (1968), 90 (4), 1080-2CODEN: JACSAT; ISSN:0002-7863.
Me3SiCHN2 (I) was prepd. by alleviative Me3SiCH2Cl with NH3 to accord Me3SiCH2NH2 which back advised with urea and HCl gave Me3SiCH2NHCONH2 (II). II was again advised with HNO2 to accord Me3SiCH2N(NO)CONH2 which was afflicted with 20% KOH to accord I and hexamethyldisiloxane. The ir and N.M.R. spectra of I were discussed. I back advised with AcOH gave Me3SiCH2OAc and equimolar amts. of Me3SiOAc and MeOAc. I in Decalin underwent 1,3-dipolar addn. to acrylonitrile to accord a white solid with a conjugated 2-pyrazoline structure. I back added to a C6H6 abeyance of CuCl at allowance temp. gave cis- (II), and trans-1,2-bis(trimethylsilyl)ethylene (III). The CuCl-catalyzed I decompn. in C6H6 in attendance of balance cyclohexene gave anti-7-(trimethylsilyl)norcarane as a above artefact and 7-(trimethylsilyl)norcarane isomer; II and III as accessory products. The CuCl-catalyzed decompn. of I in the attendance of balance cis-4-methyl-2-pentene gave, in addn. to II and III, the 2 isomers of 1-methyl-2-isopropyl-3-(trimethylsilyl)cyclopropane.
There is no agnate almanac for this reference.
Calter, Michael; Hollis, T. Keith; Overman, Larry E.; Ziller, Joseph; Zipp, G. Greg
Journal of Organic Chemistry (1997), 62 (5), 1449-1456CODEN: JOCEAH; ISSN:0022-3263. (American Actinic Society)
Pd(II) complexes contg. chiral diamine ligands were advised as asym. catalysts for the barter of allylic imidates to allyl amides. The best catalysts were cations acquired by dechlorination of dichloro[(S)-2-(isoindolinylmethyl)-N-methylpyrrolidine]palladium(II) with argent salts in CH2Cl2. Agitator I was advised thoroughly and apparent by 1H NMR and x-ray anal. to be a C1 sym. dimer. Accompanying catalysts accepting assorted counterions and anionic ligands were additionally prepd. and advised as asym. catalysts for the barter of allylic N-(4-trifluorophenyl)benzimidate II to allylic benzamide III. Barter of II in CH2Cl2 (48 h at 40°) in the attendance of 5 mol % of I afforded (-)-III in 69% crop and 55% ee. Enantioselection was added to 60% back an isomerically authentic sample of I was employed. Chem. alternation of III with (R)-norvaline accustomed that (-)-III has the R abs. configuration. A cyclization-induced barter apparatus requires that in the above alleyway the imidate nitrogen attacks the re face of the olefin with Pd accommodating to the si face. These studies aggregate the aboriginal abode of asym. catalysis of the barter of allylic imidates to allylic amides. However, cogent hurdles abide to be affected afore the enantioselective barter of allylic imidates becomes a applied avenue to enantioenriched nitrogen compds.
For a accompanying oxidation, see:
Sheddan, Neil A.; Arion, Vladimir B.; Mulzer, Johann
Tetrahedron Letters (2006), 47 (37), 6689-6693CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
The aftereffect of allylic (C15) and homoallylic (C11) substituents on cantankerous metathesis reactions with Corey lactone derivs. was described. This action has led to the acknowledged syntheses of PGF2α and PGJ2.
Schmid, Rudolf; Cereghetti, Marco; Heiser, Bernd; Schoenholzer, Peter; Hansen, Hans Juergen
Helvetica Chimica Acta (1988), 71 (4), 897-929CODEN: HCACAV; ISSN:0018-019X.
The axially dissym. diphosphines (-)-(R)- and ( )-(S)-(6,6′-dimethylbiphenyl-2,2′-diyl)bis(diphenylphosphine) [(-)-(R)-I and ( )-(S)-I, BIPHEMP] were prepd. from (R)- and (S)-6,6′-dimethylbiphenyl-2,2′-diamine, resp., via Sandmeyer reaction, lithiation, and phosphinylation. Racemic 4,4′-dimethyl- and 4,4′-bis(dimethylamino)-substituted analogs (II) and the 6,6′-bridged analog 1,11-bis(diphenylphosphino)-5,7-dihydrodibenz[c,e]oxepin (III) were prepd. and bound into optically authentic (R)- and (S)-enantiomers via complexation with di-μ-chlorobis[(R)-2-[1-dimethylamino)ethyl]phenyl-C,N]dipalladium(II) (IV). The mol. structures of the diphosphines (S)-I and (R)-III and of two acquired cationic Rh(I) complexes, [Rh((S)-I)(nbd)]BF4 and [Rh((R)-III)(nbd)]BF4 (nbd = 8,9,10-trinorborna-2,5-diene) were detd. by x-ray analyses. Abs. configurations were accustomed for ( )-(S)-I by x-ray analyses of both the chargeless diphosphine and of the acquired Rh(I) complex, and for (-)-(R)-III by x-ray anal. of the acquired Rh(I) complex. Configurational assignments for the commissioned BIPHEMP analogs II were able by bureau of 1H NMR comparisons of the Pd(II) complexes acquired from the diphosphines and IV and by bureau of CD comparisons. The BIPHEMP ligand I and analogs II and III are the aboriginal examples of optically alive bis(triarylphosphines) contg. an axially dissym. biphenyl moiety. All these new diphosphines accepted to be accomplished asymmetry-inducing ligands in Rh(I)-catalyzed isomerizations of N,N-diethylnerylamine affording citronellal enamine of 98-99% ee.
Schmid, Rudolf; Foricher, Joseph; Cereghetti, Marco; Schoenholzer, Peter
Helvetica Chimica Acta (1991), 74 (2), 370-89CODEN: HCACAV; ISSN:0018-019X.
The new axially dissym. diphosphines (R)- and (S)-(6,6′-dimethoxybiphenyl-2,2′-diyl)bis(diphenylphosphine) [(R)- and (S)-I] and their analogs accept been actinic in enantiomerically authentic anatomy by a complete arrangement which employs, as key steps, an ortho-lithiation/iodination acknowledgment and a consecutive Ullmann acknowledgment of the constant iodides. The Ullmann acknowledgment constitutes a new and able avenue to 2,2′-bis(phosphinoyl)-substituted biphenyl systems. Abs. configurations were accustomed for (R)-I by x-ray anal. of the acquired Pd complex. I accepted to be as able as the ahead declared diphosphine (6,6′-dimethylbiphenyl-2,2′-diyl)bis(diphenylphosphine) in enantioselective isomerizations and hydrogenations.
Pitsch, Stefan; Weiss, Patrick A.; Jenny, Luzi; Stutz, Alfred; Wu, Xiaolin
Helvetica Chimica Acta (2001), 84 (12), 3773-3795CODEN: HCACAV; ISSN:0018-019X. (Verlag Helvetica Chimica Acta)
A adjustment for the accession of the 2′-O-[(triisopropylsilyl)oxy]methyl (=tom) accumulation into N-acetylated, 5′-O-dimethoxytritylated ribonucleosides is presented. The agnate 2′-O-tom-protected phosphoramidite architecture blocks were acquired in authentic anatomy and were auspiciously alive for the accepted amalgam of oligoribonucleotides on DNA synthesizers. Beneath DNA coupling altitude (2.5 min coupling time for a 1.5-μmol amalgam scale) and with 5-(benzylthio)-1H-tetrazole (BTT) as activator. 2′-O-tom-protected phosphoramidites apparent av. coupling yields >99.4%. The aggregate of N-acetyl and 2′-O-tom attention groups accustomed a reliable and complete two-step deprotection, aboriginal with MeNH2 in EtOH/H2O and again with Bu4NF in THF, after accessory abolition of the artefact RNA sequences.
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