Co-reporter:Kenzo Yahata, Ning Ye, Kentaro Iso, Yanran Ai, Jihoon Lee, and Yoshito Kishi
The Journal of Organic Chemistry September 1, 2017 Volume 82(Issue 17) pp:8808-8808
Publication Date(Web):July 25, 2017
DOI:10.1021/acs.joc.7b01284
A stereocontrolled synthesis of the left halves of halichondrins was reported. An intramolecular oxy-Michael reaction under basic conditions was used to construct the [6,6]-spiroketal in a stereocontrolled manner. With this approach, the left halves of halichondrins, homohalichondrins, and norhalichondrins were synthesized.
Co-reporter:Kenzo Yahata, Ning Ye, Kentaro Iso, Santhosh Reddy Naini, Shuji Yamashita, Yanran Ai, and Yoshito Kishi
The Journal of Organic Chemistry September 1, 2017 Volume 82(Issue 17) pp:8792-8792
Publication Date(Web):July 25, 2017
DOI:10.1021/acs.joc.7b01283
The right halves of halichondrins A–C were synthesized by coupling the common C20–C37 building block 9 with the C1–C19 building blocks 10a–c, respectively. Catalytic, asymmetric Ni/Cr-mediated coupling was used for three C–C bond formations. For all cases, the stereochemistry was controlled with the Cr catalyst prepared from the chiral sulfonamide identified via the toolbox approach. For (3 + 4)-, (6 + 7)-, and (9 + 10)-couplings, the stereoselectivity of 28:1, >40:1, and ∼20:1 was achieved by the Cr catalysts prepared from (S)-H, (S)-I, and (R)-L, respectively. Unlike the first and second couplings, the third coupling used the structurally complex nucleophile. It was demonstrated that the coupling efficiency was excellent even with the electrophile/nucleophile molar ratio = 1.0/1.1. In addition, the third coupling was achieved with the substrate bearing a free hydroxyl group. The products obtained in the Ni/Cr-mediated couplings were converted to the right halves of halichondrins A–C in excellent overall yields. The right halves of halichondrins A–C (1a–c) were synthesized in 28, 24, and 24 steps from commercial d-galactal in 13.4%, 21.1%, and 16.7% overall yield, respectively.
Co-reporter:Vemula Praveen Kumar, Vaddela Sudheer Babu, Kenzo Yahata, and Yoshito Kishi
Organic Letters May 19, 2017 Volume 19(Issue 10) pp:2766-2766
Publication Date(Web):May 10, 2017
DOI:10.1021/acs.orglett.7b01128
An Fe/Cu-mediated one-pot ketone synthesis was reported. Unlike Ni- and Pd-mediated one-pot ketone syntheses, the reported Fe/Cu-mediated method allowed selective activation and coupling of alkyl iodides over vinyl iodides. The newly developed one-pot ketone synthesis was applied to a synthesis of vinyl iodide/ketone 13, the left half of halichondrin B, as well as vinyl iodide/ketone 8a, the C20–C26 building block of halichondrins.
Co-reporter:Dr. Kenzo Yahata;Dr. Ning Ye;Dr. Yanran Ai;Dr. Kentaro Iso; Dr. Yoshito Kishi
Angewandte Chemie International Edition 2017 Volume 56(Issue 36) pp:10796-10800
Publication Date(Web):2017/08/28
DOI:10.1002/anie.201705523
AbstractUnified, efficient, and scalable syntheses of the halichondrin natural products are reported. A newly developed Zr/Ni-mediated one-pot ketone synthesis was used to couple the two halves of the final product at a late stage in the synthesis. With the use of a slight excess of the left halves, the desired ketones were isolated in yields of 80–90 %. The halichondrins were obtained from these ketones in two steps, namely desilylation and [5,5]-spiroketal formation. The new synthetic route was effective for the total synthesis of all members in the homohalichondrin subgroup. The scalability of this process was demonstrated with halichondrin B; 150 mg of halichondrin B (68 % overall yield) were obtained from 200 mg of the right-half precursor.
Co-reporter:Dr. Yanran Ai;Dr. Ning Ye;Dr. Qiaoyi Wang;Dr. Kenzo Yahata; Dr. Yoshito Kishi
Angewandte Chemie International Edition 2017 Volume 56(Issue 36) pp:10791-10795
Publication Date(Web):2017/08/28
DOI:10.1002/anie.201705520
AbstractA zirconium/nickel-mediated one-pot synthesis of ketones is reported. In the presence of Zn or Mn, Cp2ZrCl2 was found to dramatically accelerate the coupling and suppress side product formation via an ISPy displacement at the same time. Unlike Zn/Pd- and Fe/Cu-mediated one-pot ketone syntheses, the new method is effective for nucleophiles bearing OR or equivalent functional groups at the α-position. A mechanism comprising a nickel catalytic cycle, a zirconium catalytic cycle, and ZrNi transmetalation is proposed, and Cp2ZrCl2 and/or low-valent Zr species are suggested to play crucial dual roles.
Co-reporter:Jung Hwa Lee, Zhanjie Li, Ayumi Osawa, and Yoshito Kishi
Journal of the American Chemical Society 2016 Volume 138(Issue 50) pp:16248-16251
Publication Date(Web):December 8, 2016
DOI:10.1021/jacs.6b11663
Recently reported Pd-mediated one-pot ketone synthesis from an unactivated alkyl bromide and a thioester has been extended to a macrocyclic ketone synthesis. In situ generation of alkylzinc halide via single electron transfer (SET), using NbCpCl4 and CrCl3, was the key for the success of macrocyclization. A new convergent synthesis of eribulin has been achieved, using (1) catalytic asymmetric Ni/Cr-mediated coupling to form the C19–C20 bond, (2) base-induced cyclization to form the methylenetetrahydrofuran ring, and (3) Pd-mediated one-pot ketone synthesis to form the macrocyclic ketone.
Co-reporter:Jung Hwa Lee
Journal of the American Chemical Society 2016 Volume 138(Issue 22) pp:7178-7186
Publication Date(Web):May 13, 2016
DOI:10.1021/jacs.6b03897
One-pot ketone synthesis has been developed with in situ activation of alkyl halides to alkylzinc halides in the presence of thioesters and Pd-catalyst. The new method provides us with a reliable option for a coupling at a late stage in a convergent synthesis of complex molecules, with use of a near 1:1 molar ratio of coupling partners. First, two facile, orthogonal methods have been developed for preparation of alkylzinc halides: (1) direct insertion of zinc dust to 1°- and 2°-alkyl halides in the presence of LiI in DMI and (2) early transition-metal assisted activation of alkyl halides via a single electron transfer (SET) process. CrCl2 has been found as an unprecedented, inevitable mediator for preparation of alkylzinc halides from alkyl halides, where CrCl2 likely functions to trap R·, generated via a SET process, and transfer it to Zn(II) to form RZnX. In addition to a commonly used CoPc, a new radical initiator NbCpCl4 has been discovered through the study. Second, with use of the two orthogonal methods, three sets of coupling conditions have been developed to complete one-pot ketone synthesis, with Condition A (Pd2dba3, PR3, Zn, LiI, TESCl, DMI), Condition B (A + CrCl2), and Condition C (B + NbCpCl4 or CoPc) being useful for simple linear and α-substituted substrates, simple linear and β-substituted substrates, and complex substrates, respectively. Condition C is applicable to the broadest range of substrates. Overall, one-pot ketone synthesis gives excellent yields, with good functional group tolerance. Controlled formation of alkylzinc halides by a combination of CrCl2 and NbCpCl4 or CoPc is crucial for its application to complex substrates. Interestingly, one-pot ketone synthesis does not suffer from the chemical instability due to the inevitable radical pathway(s), for example a 1,5-H shift. Notably, even with the increase in molecular size, no significant decrease in coupling efficiency has been noticed. To illustrate the synthetic value at a late stage in a complex molecule synthesis, ketone 4sc, containing all the carbons of Eribulin, has been synthesized from 1s and 3c.
Co-reporter:Jingwei Li; Wuming Yan
Journal of the American Chemical Society 2015 Volume 137(Issue 19) pp:6226-6231
Publication Date(Web):April 29, 2015
DOI:10.1021/jacs.5b03499
A unified synthesis of the C1–C19 building blocks 8–10 of halichondrins A–C was developed from the common synthetic intermediates 26a,b. Acetylenic ketones 26a,b were in turn synthesized via selective activation/coupling of polyhalogenated nucleophiles 23a,b with aldehyde 11 in a (Ni)/Cr-mediated coupling reaction. Compared with Ni/Cr-mediated couplings of vinyl iodides and aldehydes, this (Ni)/Cr-mediated coupling exhibited two unique features. First, the coupling was found to proceed with a trace amount or no added Ni-catalyst. Second, TES-Cl, a dissociating agent to regenerate the Cr-catalyst, was found to give a better yield than Zr(Cp)2Cl2. An adjustment of the oxidation state was required to transform acetylenic ketones 26a,b into C1–C19 building blocks 8 and 9 of halichondrins A and B, respectively. In the halichondrin B series, a hydroxyl-directed (Me)4NBH(OAc)3 reduction of E- and Z-β-alkoxy-enones 30 was found cleanly to achieve the required transformation, whereas a DMDO oxidation of E-vinylogous ester 27 allowed to introduce the C13 hydroxyl group with a high stereoselectivity in the halichondrin A series. In the halichondrin C series, Hf(OTf)4 was used to convert the double oxy-Michael product 28 into C1–C19 building block 10.
Co-reporter:Wuming Yan; Zhanjie Li
Journal of the American Chemical Society 2015 Volume 137(Issue 19) pp:6219-6225
Publication Date(Web):April 29, 2015
DOI:10.1021/jacs.5b03498
The C1–C19 building block 46 of halichondrin Bs was synthesized via a selective activation/coupling of β-bromoenone 34 with aldehyde 35 in a Ni/Cr-mediated reaction. The first phase of study was a method development to effect a coupling of a “naked” vinylogous anion with an aldehyde. The study with the coupling of 9 + 10 → 11 revealed: (1) β-bromoenone 9b is a better nucleophile than the corresponding β-iodo- and β-chloroenones 9a,c; (2) (Me)2Phen(OMe)2·NiCl2 13b is a better Ni-catalyst than (Me)2Phen(H)2·NiCl2 13a; and (3) a low Ni-catalyst loading, for example, 0.05–0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for an effective coupling. The second phase of study was a method development to realize a selective activation/coupling of polyhalogenated nucleophiles such as 34. The competition experiment of 10 + 9b over 10 + 31a–c revealed: (1) (Me)2Phen(OMe)2·NiCl2 13b is more effective than (Me)2Phen(H)2·NiCl2 13a for the required selective activation/coupling; (2) a low Ni-catalyst loading, for example, 0.05–0.1 mol % Ni-catalyst against 10 mol % Cr-catalyst, is crucial for discriminating β-bromoenone 9b from the three types of vinyl iodides 31a–c. The third phase of study was an application of the developed method to execute the proposed coupling of 34 + 35 → 36. For this application, a polyether-type Ni-catalyst 37c, readily soluble in the reaction medium, was introduced to achieve the selective activation/coupling with higher efficiency. With use of ion-exchange resin-based device, the coupling product 36 was transformed to the C1–C19 building block 46 of halichondrin Bs without purification/separation of the intermediates.
Co-reporter:Xiaoyong Li, Vaddela Sudheer Babu, Yoshito Kishi
Tetrahedron Letters 2015 Volume 56(Issue 23) pp:3220-3224
Publication Date(Web):3 June 2015
DOI:10.1016/j.tetlet.2014.12.024
With use of the LiTMP-induced Hodgson cyclopropanation of an epoxide-olefin to a bicyclo[3.1.0]hexanol as the key step, a stereoselective total synthesis of photo-mycolactones was achieved. Each of the four diastereomeric epoxide-olefins, selectively prepared from (R)- and (S)-glycidols, yielded the corresponding unique bicyclo[3.1.0]hexanol. Four bicyclo[3.1.0]hexanols 16, dia-16, 19, and dia-19 were converted into four primary alcohols 17, dia-17, 20, and dia-20, the intermediates used in the previous work on photo-mycolactones. This synthesis confirmed the stereochemistry previously proposed for photo-mycolactones.
Co-reporter:Atsushi Ueda ; Akihiko Yamamoto ; Daisuke Kato
Journal of the American Chemical Society 2014 Volume 136(Issue 13) pp:5171-5176
Publication Date(Web):March 7, 2014
DOI:10.1021/ja5013307
A total synthesis of halichondrin A, the phantom member in the halichondrin class of natural products, is reported. The highlights of synthesis include: (1) synthesis of C1–C19 building block 6b via a catalytic asymmetric Cr-mediated coupling of 12 and 13b; (2) synthesis of the right-half of 19 via an asymmetric Ni/Cr-mediated coupling, followed by base-induced furan formation, and Shiina macrolactonization; (3) synthesis of enone 20 via Ni/Cr-mediated coupling of 5 with 19, followed by oxidation; (4) synthesis of halichondrin A from 20, with use of a newly discovered, highly selective TMSOTf-mediated equilibration of C38-epi-halichondrin A to halichondrin A. Two pieces of evidence are presented unambiguously to establish the structure of halichondrin A thus synthesized: one is the synthesis of norhalichondrin A (24) from 19 and 23, and the other is the study of the proton chemical shift difference between synthetic halichondrin A and known members of this class of natural products.
Co-reporter:Xiang Liu ; Xiaoyong Li ; Yu Chen ; Yimin Hu
Journal of the American Chemical Society 2012 Volume 134(Issue 14) pp:6136-6139
Publication Date(Web):March 23, 2012
DOI:10.1021/ja302177z
The importance of the Ni catalyst in achieving catalytic asymmetric Ni/Cr-mediated coupling reactions effectively is demonstrated. Six phenanthroline–NiCl2 complexes 1a–c and 2a–c and five types of alkenyl iodides A–E were chosen for the study, thereby demonstrating that these Ni catalysts display a wide range of overall reactivity profiles in terms of the degree of asymmetric induction, geometrical isomerization, and coupling rate. For three types of alkenyl iodides A–C, a satisfactory Ni catalyst(s) was found within 1a–c and 2a–c. For disubstituted (Z)-alkenyl iodide D, 2c was identified as an acceptable Ni catalyst in terms of the absence of Z → E isomerization and the degree of asymmetric induction but not in terms of the coupling rate. Two phosphine-based Ni catalysts, [(Me)3P]2·NiCl2 and [(cy)3P]2·NiCl2, were found to meet all three criteria for D. The bond-forming reaction at the C16–C17 position of palytoxin was used to demonstrate the usefulness of the Ni catalysts thus identified.
Co-reporter:Yalan Xing ; Sudhir M. Hande
Journal of the American Chemical Society 2012 Volume 134(Issue 46) pp:19234-19239
Publication Date(Web):November 2, 2012
DOI:10.1021/ja309215m
Photochemistry of mycolactone A/B and related unsaturated fatty acid esters is reported. On exposure to visible light, mycolactone A/B gave a mixture of four photomycolactones. Pentaenoates and tetraenoates, representing the unsaturated fatty acid portion of mycolactone A/B, were found to show the reactivity profile parallel with that of mycolactone A/B. The structure of the four photomycolactones was elucidated via (1) structure determination of the four photoproducts in the tetraenoate series; (2) their transformation to the photoproducts in the pentaenoate and then mycolactone series. Triplet quenchers did not affect the photochemical transformation, thereby indicating an event at the singlet state. A concerted, photochemically allowed [4πs + 2πa] cycloaddition was suggested to account for the observed result. This study provided the structurally defined and homogeneous material, which allowed demonstration that photomycolactones exhibit significantly reduced cytotoxicity, compared with mycolactone A/B.
Co-reporter:Jianbiao Peng and Yoshito Kishi
Organic Letters 2012 Volume 14(Issue 1) pp:86-89
Publication Date(Web):December 1, 2011
DOI:10.1021/ol202878v
Two air-stable Ni,Cr-heterobimetallic catalysts have been prepared from ligands 7 and 11, obtained from scyllo-inositol in four and three steps, respectively. Both catalysts smoothly promote Ni/Cr-mediated coupling reactions with a ca. 1:1 molar ratio of coupling partners. The catalyst derived from 11 exhibits a better catalytic profile, thereby allowing Ni/Cr-mediated coupling reactions to be achieved with a wide range of substrates at a low catalyst loading in an operationally simple manner.
Co-reporter:Mingde Shan and Yoshito Kishi
Organic Letters 2012 Volume 14(Issue 2) pp:660-663
Publication Date(Web):January 11, 2012
DOI:10.1021/ol203373d
A concise, stereoselective, and scalable synthesis of the C20–C26 building block of halichondrins and Eribulin is reported. The synthesis relies on three key transformations: regiospecific Ru-catalyzed intramolecular hydrosilylation, highly stereoselective SN2′ substitution, and selective conversion of a C–Si to C–I bond. It is carried out in a 5-pot/4-workup operation without chromatographic purification, except for filtration through a silica-gel plug, to give the C20–C26 building block (dr > 200:1; ee > 99%) in ca. 60% overall yield from epoxide 1.
Co-reporter:Sudhir M. Hande, Yuko Kazumi, W. George Lai, Katrina L. Jackson, Shinji Maeda, and Yoshito Kishi
Organic Letters 2012 Volume 14(Issue 17) pp:4618-4621
Publication Date(Web):August 27, 2012
DOI:10.1021/ol302072b
Two new mycolactones, mycolactones S1 and S2, were isolated from culture agar of Mycobacterium ulcerans subsp. shinshuense. Their structures were established in a three-step procedure: (1) probable structures were speculated from MS analysis; (2) candidates were synthesized; (3) HPLC profiles were established for identification of the natural products. Newly isolated mycolactones correspond to the “oxidized forms” of mycolactone A/B, the causative toxin of Buruli ulcer, isolated from Mycobacterium ulcerans.
Co-reporter:Lei Liu, James A. Henderson, Akihiko Yamamoto, Paul Brémond, and Yoshito Kishi
Organic Letters 2012 Volume 14(Issue 9) pp:2262-2265
Publication Date(Web):April 24, 2012
DOI:10.1021/ol300672q
The reaction of m-fluorophenylsulfone anions with dialkylboranes, followed by alkaline hydroperoxide oxidation, yields alcohols in high yields. Optimization of the process, scope and limitation, and application to the synthesis of one of the C14–C35 building blocks of E7389, a right half analogue of halichondrin B, are reported.
Co-reporter:Akihiko Yamamoto ; Atsushi Ueda ; Paul Brémond ; Paolo S. Tiseni
Journal of the American Chemical Society 2011 Volume 134(Issue 2) pp:893-896
Publication Date(Web):December 20, 2011
DOI:10.1021/ja2108307
The first total synthesis of halichondrin C has been completed, highlighted by development of the synthetic method to construct the C8–C14 polycycle. Cr-mediated coupling reactions are used seven times to form a new C–C bond. The acid stability of halichondrin C is studied, demonstrating that the macrolactone stabilizes the C8–C14 polycycle, relative to the one present in the C1–C16 model.
Co-reporter:Jianbiao Peng, Xiang Liu, Yoshito Kishi
Tetrahedron Letters 2011 Volume 52(Issue 17) pp:2172-2175
Publication Date(Web):27 April 2011
DOI:10.1016/j.tetlet.2010.11.124
A new catalytic system (cat. (H)2Phen(Me)2·NiCl2 or (MeO)2Dipyr(H)2·NiCl2, cat. Zr(cp)2Cl2, 2 equiv Mn, and 2 equiv LiCl) has been developed to facilitate the homocoupling of a wide range of aryl, alkenyl, and alkynyl halides.
Co-reporter:Yoshito Kishi
PNAS 2011 Volume 108 (Issue 17 ) pp:6703-6708
Publication Date(Web):2011-04-26
DOI:10.1073/pnas.1015252108
Buruli ulcer is a severe and devastating skin disease caused by Mycobacterium ulcerans infection, yet it is one of the most neglected diseases. The causative toxin, referred to as mycolactone A/B, was isolated
and characterized as a polyketide-derived macrolide in 1999. The current status of the mycolactone chemistry is described,
highlighting the stereochemistry assignment of mycolactone A/B; total synthesis; the structure determination of mycolactone
congeners from the human pathogen M. ulcerans, the frog pathogen Mycobacterium liflandii, and the fish pathogen Mycobacterium marinum; the structural diversity in the mycolactone class of natural products; the highly sensitive detection/structure-analysis
of mycolactones; and some biological activity.
Co-reporter:Thomas Spangenberg and Yoshito Kishi
Chemical Communications 2010 vol. 46(Issue 9) pp:1410-1412
Publication Date(Web):01 Feb 2010
DOI:10.1039/B924896J
A boronate-assisted fluorogenic chemosensor in a solid phase is developed, selectively to detect the mycolactones produced by the human pathogen Mycobacterium ulcerans.
Co-reporter:Thomas Spangenberg, Sylvain Aubry, Yoshito Kishi
Tetrahedron Letters 2010 Volume 51(Issue 13) pp:1782-1785
Publication Date(Web):31 March 2010
DOI:10.1016/j.tetlet.2010.01.105
Co-reporter:Katrina L. Jackson, Wenju Li, Chi-Li Chen, Yoshito Kishi
Tetrahedron 2010 66(13) pp: 2263-2272
Publication Date(Web):
DOI:10.1016/j.tet.2010.02.010
Co-reporter:Xiang Liu ; James A. Henderson ; Takeo Sasaki
Journal of the American Chemical Society 2009 Volume 131(Issue 46) pp:16678-16680
Publication Date(Web):October 29, 2009
DOI:10.1021/ja9079308
Two new ligands 1a,b are reported. Upon treatment with 1 equiv of NiCl2·(MeOCH2)2, 1a,b give the corresponding Ni complexes. X-ray analysis of 1a·NiCl2 established that the NiCl2 is selectively coordinated to the phenanthroline nitrogens. Ni/Cr heterobimetallic catalysts 1a,b·CrCl2/NiCl2, prepared from 1a,b·NiCl2, have been shown to behave exceptionally well in catalytic asymmetric Ni/Cr-mediated couplings, with highlights including the following: (1) 1−2 mol % catalyst is sufficient to complete the coupling; (2) only negligible amounts of the dimers, byproducts formed through the alkenyl Ni species, are observed; (3) the coupling goes to completion even with a 1:1 molar ratio of the coupling partners; and (4) the asymmetric induction is practically identical with that obtained from the coupling with the Cr catalysts prepared from (S)-sulfonamides 2a,b. The scope of the new Ni/Cr heterobimetallic catalysts was briefly studied using four additional aldehydes. The applicability of the new catalysts to polyfunctional substrates was demonstrated by two C−C bond formations chosen from the halichondrin/E7389 synthesis as examples.
Co-reporter:Dae-Shik Kim ; Cheng-Guo Dong ; Joseph T. Kim ; Haibing Guo ; Jian Huang ; Paolo S. Tiseni
Journal of the American Chemical Society 2009 Volume 131(Issue 43) pp:15636-15641
Publication Date(Web):October 6, 2009
DOI:10.1021/ja9058475
With sequential use of catalytic asymmetric Cr-mediated coupling reactions, E7389 C14−C35 and halichondrin C14−C38 building blocks have been stereoselectively synthesized. The C19−C20 bond is first formed via the catalytic asymmetric Ni/Cr-mediated coupling, i.e., 8 + 9 → 10 (90%; dr = 22:1), in which vinyl iodide 8 is used as the limiting substrate. The C23−C24 bond is then formed via the catalytic asymmetric Co/Cr-mediated coupling, i.e., 13 + 14 → 4 (82%; dr = 22:1), in which the alkyl−iodide bond in 14 is selectively activated over the vinyl−iodide bond. The catalytic asymmetric Ni/Cr-mediated reaction is employed to couple C14−C26 segment 19 with E7389 C27−C35 segment 20 (91%; dr = >55:1). In this synthesis, the C23−O bond is stereoselectively constructed via a double-inversion process, i.e., 21 → 22, to furnish E7389 C14−C35 building block 22 in 84% yield. The same synthetic sequence has been employed to synthesize halichondrin C14−C38 building block 18b, i.e., 16a + 19 → 18b.
Co-reporter:Cheng-Guo Dong ; James A. Henderson ; Yosuke Kaburagi ; Takeo Sasaki ; Dae-Shik Kim ; Joseph T. Kim ; Daisuke Urabe ; Haibing Guo
Journal of the American Chemical Society 2009 Volume 131(Issue 43) pp:15642-15646
Publication Date(Web):October 6, 2009
DOI:10.1021/ja9058487
Cr-mediated coupling reactions are usually achieved with a slight excess of a given nucleophile. To develop a cost-effective use of this process, two different approaches have been studied. The first approach depends on two consecutive catalytic asymmetric Cr-mediated couplings, with use of coupling partners purposely being of unbalanced molecular size and complexity. The second approach rests on the success in identifying the nucleophile, which allows us to achieve the coupling satisfactorily with a 1:1 molar ratio of the coupling partners. The C23−O bond is stereospecifically constructed via reductive cyclization of the oxonium ion, or oxy-Michael cyclization. Both syntheses have a high overall efficiency: E7389 C14−C35 and halichondrin C14−C38 building blocks have been synthesized from the corresponding C27−C35 and C27−C38 aldehydes, respectively, in high overall yields with an excellent stereoselectivity. Because of operational simplicity, the synthesis outlined herein appears to be well suited for scaling.
Co-reporter:Haibing Guo ; Cheng-Guo Dong ; Dae-Shik Kim ; Daisuke Urabe ; Jiashi Wang ; Joseph T. Kim ; Xiang Liu ; Takeo Sasaki
Journal of the American Chemical Society 2009 Volume 131(Issue 42) pp:15387-15393
Publication Date(Web):October 1, 2009
DOI:10.1021/ja905843e
Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides exhibit a broad range of catalyst−substrate matching profiles. A strategy is presented to search for a satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness of this approach, five diverse C−C bond-forming cases have been selected from the halichondrin synthesis. For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)- and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of “≥80% yield with ≥20:1 stereoselectivity in the presence of ≤20 mol % of a Cr catalyst”. For 9 out of the 10 cases studied, a satisfactory catalyst has been found within this pool of sulfonamides. Even for the remaining case, a Cr catalyst inducing stereoselectivity up to 8:1 has been identified.
Co-reporter:Han-Je Kim, Katrina L. Jackson, Yoshito Kishi, Heather R. Williamson, Lydia Mosi and Pamela L. C. Small
Chemical Communications 2009 (Issue 47) pp:7402-7404
Publication Date(Web):26 Oct 2009
DOI:10.1039/B917014F
A novel mycolactone has been identified from Mycobacterium marinum infecting freshwater fish.
Co-reporter:Songbai Liu, Joseph T. Kim, Cheng-Guo Dong and Yoshito Kishi
Organic Letters 2009 Volume 11(Issue 20) pp:4520-4523
Publication Date(Web):September 16, 2009
DOI:10.1021/ol9016595
A catalytic enantioselective propargylation in the presence of 10 mol % of Cr catalyst prepared from Cr(III) bromide and (R)-sulfonamide E furnishes homopropargyl alcohol 8 in 78% yield with 90% ee. Coupled with the workup based on Amano-lipase, this method provides a practical synthesis of optically pure 8 on a multigram scale. With maintenance of its optical purity, 8 has been converted to 1b, the C14−C19 building block of halichondrins and E7389, in two steps.
Co-reporter:Yu-Rong Yang, Dae-Shik Kim and Yoshito Kishi
Organic Letters 2009 Volume 11(Issue 20) pp:4516-4519
Publication Date(Web):September 16, 2009
DOI:10.1021/ol9016589
A practical method is reported to synthesize E7389 C27−C35 building block 13 from 1,2-O-isopropylidene-α-d-5-deoxyglucurono-6,3-lactone (3). This synthesis relies on two key processes: (1) C34/C35-diol is introduced via asymmetric dihydroxylation with dr = 3:1, with the undesired C34-diastereomer effectively removed by crystallization of 11, and (2) the C30 PhSO2CH2 group is introduced stereoselectively (>100:1) via hydrogenation of 12 in the presence of the Crabtree catalyst. The reported synthesis is practically free from chromatographic separation.
Co-reporter:Yonghui Wang Dr.;Hwan-Sung Cheon Dr. Dr.
Chemistry – An Asian Journal 2008 Volume 3( Issue 2) pp:319-326
Publication Date(Web):
DOI:10.1002/asia.200700297
Abstract
Glycosidation of a mannosyl donor in the presence of the Mukaiyama catalyst was found to give exceptionally high α/β selectivity. A systematic study was conducted to reveal that selective β-to-α anomerization accounts for the observed high α/β stereoselectivity. Furthermore, the Mukaiyama catalyst was shown to exhibit an unusual level of substrate and anomer selectivity for the anomerization. On the basis of the combined anomeric and Δ2 effects, a mechanistic rationale was proposed, thereby suggesting the minimum structural moiety essential for the anomerization in question. With this analysis, β-talo-, β-altro-, and β-idopyranosides are predicted to exhibit a reactivity profile similar to β-mannopyranosides, but all other pyranosides should not. This prediction was verified by using β- and α-talopyranosides as an example.
Co-reporter:Yonghui Wang Dr.;Jianguo Ma Dr.;Hwan-Sung Cheon Dr. Dr.
Angewandte Chemie 2007 Volume 119(Issue 8) pp:
Publication Date(Web):9 JAN 2007
DOI:10.1002/ange.200603979
Welche Packung wollen Sie? Charakteristische blauverschobene UV-Absorptionen wurden genutzt, um die Aggregation von C24-Tetraen-Fettsäuren in wässriger Lösung zu verfolgen. Die Aggregation verläuft über drei Zustände (KT1T2; siehe Bild), und es wird vorgeschlagen, dass alle diese Aggregate lokal lamellar sind, sich aber im Packungsmodus des Fettsäure-Rückgrats unterscheiden.
Co-reporter:Nikolaos Papaioannou Dr.;Hwan-Sung Cheon Dr.;Yiqian Lian Dr. Dr.
ChemBioChem 2007 Volume 8(Issue 15) pp:
Publication Date(Web):24 SEP 2007
DOI:10.1002/cbic.200700380
One way or another. New mechanisms are presented to explain the bimodal product distribution in fatty acid biosynthesis catalyzed by Mycobacterium smegmatis FAS I. The predominant formation of palmitic acid and tetracosanoic acid in the presence or absence of the endogenous polysaccharides is due to the removal of the end product by a stoichiometric complex formation with the polysaccharides (indicated in red in the scheme) or by the formation of a stable self aggregate (in blue).
Co-reporter:Hwang-Sung Cheon Dr.;Yonghui Wang Dr.;Jianguo Ma Dr. Dr.
ChemBioChem 2007 Volume 8(Issue 8) pp:
Publication Date(Web):16 MAY 2007
DOI:10.1002/cbic.200790022
Co-reporter:Hwan-Sung Cheon Dr.;Yonghui Wang Dr.;Jianguo Ma Dr. Dr.
ChemBioChem 2007 Volume 8(Issue 3) pp:
Publication Date(Web):11 JAN 2007
DOI:10.1002/cbic.200600499
An experimentally simple, but highly reproducible and reliable method has been developed to follow the complexation event of fatty acid (FA) and FA-CoA with polysaccharides. This method was based on the recent discovery of the unique blue-shifted UV absorption associated with the aggregation of tetraenoic fatty acids (TE-FAs) in aqueous solution. Complexation was monitored by recording the intensity of UV absorption at 250 nm ([free TE-FA]) and 303 nm ([complexed TE-FA]), and the K aggregate of C20t,t,t,t-TE-FA exhibited the ideal property for this purpose. Synthetic 3-O-methyl-D-mannose- and 6-O-methyl-D-glucose-containing lipopolysaccharides were found to exhibit a broad range of the binding affinities with C20t,t,t,t-TE-FAs as well as saturated FAs/FA-CoAs.
Co-reporter:Yonghui Wang Dr.;Jianguo Ma Dr.;Hwan-Sung Cheon Dr. Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 8) pp:
Publication Date(Web):9 JAN 2007
DOI:10.1002/anie.200603979
Why so blue? Unique blue-shifted UV absorptions were used to follow the aggregation of C24 tetraene fatty acids in aqueous solution. Aggregation takes place through three distinct states (i.e. KT1T2; see picture). It is suggested that all of these aggregates are lamellar-type in a local sense but differ in the packing mode of the fatty acid backbone.
Co-reporter:George Topalov Dr. Dr.
Angewandte Chemie International Edition 2001 Volume 40(Issue 20) pp:
Publication Date(Web):10 OCT 2001
DOI:10.1002/1521-3773(20011015)40:20<3892::AID-ANIE3892>3.0.CO;2-H
Remarkable selectivity is exhibited in the photooxidation of 20-methoxychlorin methyl ester (1) to exclusively yield the C1−C20 bond cleaved product 2. This selectivity lends strong support to the hypothesis that a hydroxy or equivalent group at C20 directs the C1−C20 bond cleavage that transforms chlorophylls into krill and dinoflagellate luciferins.
Co-reporter:George Topalov Dr. Dr.
Angewandte Chemie 2001 Volume 113(Issue 20) pp:
Publication Date(Web):10 OCT 2001
DOI:10.1002/1521-3757(20011015)113:20<4010::AID-ANGE4010>3.0.CO;2-0
Eine bemerkenswerte Selektivität beobachtet man bei der Photooxidation von 20-Methoxychlorinmethylester 1, die, unter Spaltung der C1-C20-Bindung, ausschließlich zu 2 führt. Diese Selektivität stützt die Hypothese, dass eine Hydroxygruppe an C20 (oder eine gleichwertige funktionelle Gruppe) die Spaltung der C1-C20-Bindung dirigiert; mit dieser Reaktion werden in Krill und Dinoflagellaten vorkommende Luciferine aus Chlorophyll gebildet.
Co-reporter:Hong-Yu Li Dr.;Yao-Ling Qiu Dr. Dr.
ChemBioChem 2001 Volume 2(Issue 5) pp:
Publication Date(Web):2 MAY 2001
DOI:10.1002/1439-7633(20010504)2:5<371::AID-CBIC371>3.0.CO;2-Y
One conformation preferred: Through circular dichroism and NMR spectroscopic studies, it has been demonstrated that the conformational characteristics of n-type DNA duplexes such as I, II, in which a Watson–Crick base pair model is covalently cross-linked through a CH2 bridge, compare well with those of the native DNA duplex III.
Co-reporter:Choon-Hong Tan Dr.;Yoshihisa Kobayashi Dr. Dr.
Angewandte Chemie 2000 Volume 112(Issue 23) pp:
Publication Date(Web):30 NOV 2000
DOI:10.1002/1521-3757(20001201)112:23<4452::AID-ANGE4452>3.0.CO;2-3
Co-reporter:Yoshihisa Kobayashi Dr.;Choon-Hong Tan Dr. Dr.
Angewandte Chemie 2000 Volume 112(Issue 23) pp:
Publication Date(Web):30 NOV 2000
DOI:10.1002/1521-3757(20001201)112:23<4449::AID-ANGE4449>3.0.CO;2-0
Co-reporter:Thomas G. Minehan
Angewandte Chemie 1999 Volume 111(Issue 7) pp:
Publication Date(Web):26 MAR 1999
DOI:10.1002/(SICI)1521-3757(19990401)111:7<972::AID-ANGE972>3.0.CO;2-X
Aus vier monocyclischen Vorstufen gelang die Totalsynthese der für (+)-Tolyporphin-A-O,O-diacetat vorgeschlagenen Struktur 1-A (X = Ac). Ein Vergleich der spektroskopischen Daten ergab, daß das synthetische Tolyporphin-O,O-diacetat nicht mit dem aus natürlichem (+)-Tolyporphin A (X = H) hergestellten O,O-Diacetat übereinstimmte – eine Korrektur der Struktur dieser Naturstoffklasse war gefordert. Aus einer Reihe von NMR-Experimenten, unter anderem an synthetischen Zwischenprodukten, ließ sich als wahrscheinliche Struktur für den Naturstoff die Struktur 1-B folgern, in der die Konfigurationen der quartären Kohlenstoffzentren C7 und C17 umgekehrt wie ursprünglich angenommen sind.
Co-reporter:Xiaoxin Qiao
Angewandte Chemie International Edition 1999 Volume 38(Issue 7) pp:
Publication Date(Web):26 MAR 1999
DOI:10.1002/(SICI)1521-3773(19990401)38:7<928::AID-ANIE928>3.0.CO;2-O
Structural characteristics of Watson–Crick hydrogen-bonded base pairs are displayed by methylene-bridged base pairs of type A. The shown superposition of the X-ray structure obtained for the base pair A (Rib1=Et; Rib2=Me) over that of a C–G base pair illustrates that A occupies an area similar to that occupied by a traditional Watson–Crick hydrogen-bonded base pair. Temperature-dependent 1H NMR studies indicate that the energy barrier for rotation along its CH2 bridge is about 10 kcal mol−1, and that it exists predominantly in one conformer at −70°C.
Co-reporter:Thomas G. Minehan;Laura Cook-Blumberg;Michèle R. Prinsep;Richard E. Moore
Angewandte Chemie International Edition 1999 Volume 38(Issue 7) pp:
Publication Date(Web):26 MAR 1999
DOI:10.1002/(SICI)1521-3773(19990401)38:7<926::AID-ANIE926>3.0.CO;2-W
Four monocyclic precursors were assembled in the total synthesis of the proposed structure 1-A of (+)-tolyporphin A O,O-diacetate (X=Ac). Comparison of the spectroscopic data demonstrated that synthetic tolyporphin O,O-diacetate did not match the O,O-diacetate prepared from natural (+)-tolyporphin A (X=H), calling for a structural revision of this class of natural products. On the basis of a series of NMR experiments including synthetic intermediates, the structure of tolyporphin A is concluded to be 1-B, in which the configurations of quaternary centers C7 and C17 are opposite to those in the originally proposed structure.
Co-reporter:Thomas G. Minehan
Angewandte Chemie International Edition 1999 Volume 38(Issue 7) pp:
Publication Date(Web):26 MAR 1999
DOI:10.1002/(SICI)1521-3773(19990401)38:7<923::AID-ANIE923>3.0.CO;2-7
Four monocyclic precursors were assembled in the total synthesis of the proposed structure 1-A of (+)-tolyporphin A O,O-diacetate (X=Ac). Comparison of the spectroscopic data demonstrated that synthetic tolyporphin O,O-diacetate did not match the O,O-diacetate prepared from natural (+)-tolyporphin A (X=H), calling for a structural revision of this class of natural products. On the basis of a series of NMR experiments including synthetic intermediates, the structure of tolyporphin A is concluded to be 1-B, in which the configurations of quaternary centers C7 and C17 are opposite to those in the originally proposed structure.
Co-reporter:Thomas G. Minehan;Laura Cook-Blumberg;Michèle R. Prinsep;Richard E. Moore
Angewandte Chemie 1999 Volume 111(Issue 7) pp:
Publication Date(Web):26 MAR 1999
DOI:10.1002/(SICI)1521-3757(19990401)111:7<975::AID-ANGE975>3.0.CO;2-L
Aus vier monocyclischen Vorstufen gelang die Totalsynthese der für (+)-Tolyporphin-A-O,O-diacetat vorgeschlagenen Struktur 1-A (X = Ac). Ein Vergleich der spektroskopischen Daten ergab, daß das synthetische Tolyporphin-O,O-diacetat nicht mit dem aus natürlichem (+)-Tolyporphin A (X = H) hergestellten O,O-Diacetat übereinstimmte – eine Korrektur der Struktur dieser Naturstoffklasse war gefordert. Aus einer Reihe von NMR-Experimenten, unter anderem an synthetischen Zwischenprodukten, ließ sich als wahrscheinliche Struktur für den Naturstoff die Struktur 1-B folgern, in der die Konfigurationen der quartären Kohlenstoffzentren C7 und C17 umgekehrt wie ursprünglich angenommen sind.
Co-reporter:Xiaoxin Qiao
Angewandte Chemie 1999 Volume 111(Issue 7) pp:
Publication Date(Web):26 MAR 1999
DOI:10.1002/(SICI)1521-3757(19990401)111:7<977::AID-ANGE977>3.0.CO;2-D
Ob klassisch H-verbrückt oder kovalent verknüpft: Strukturuntersuchungen an methylenverbrückten Basenpaaren vom Typ A zufolge haben diese mit den H-verbrückten Watson-Crick-Basenpaaren einiges gemeinsam. Die abgebildete Überlagerung der röntgenographisch ermittelten Strukturen des Basenpaars A (Rib1 = Et, Rib2 = Me) und des klassischen C-G-Basenpaars zeigt deren nahezu identische Ausfüllung der Fläche. Temperaturabhängige 1H-NMR-Spektren weisen auf ein bevorzugtes Konformer bei −70°C mit einer Rotationsbarriere entlang der Methylenbrücke von ca. 10 kcal mol−1 hin.
Co-reporter:Jiasheng Guo;Kevin J. Duffy;Kirk L. Stevens;Peter I. Dalko;Rebecca M. Roth;Matthew M. Hayward
Angewandte Chemie 1998 Volume 110(Issue 1‐2) pp:
Publication Date(Web):12 MAR 1999
DOI:10.1002/(SICI)1521-3757(19980116)110:1/2<198::AID-ANGE198>3.0.CO;2-0
Außerordentlich cytotoxisch sind die aus Meeresschwämmen isolierten Spongipyrane. Sie wirken gegen mehrere menschliche Krebszellinien, wobei das als erste Verbindung dieser Naturstoffklasse isolierte Spongistatin 1 am wirksamsten ist. Die erste Totalsynthese dieses Makrolids wurde nun abgeschlossen. Durch sie wird die von Kitagawa et al. vorgeschlagene relative und absolute Konfiguration bestätigt und nachgewiesen, daß Altohyrtin A und Spongistatin 1 identisch sind.
Co-reporter:Matthew M. Hayward;Rebecca M. Roth;Kevin J. Duffy;Peter I. Dalko;Kirk L. Stevens;Jiasheng Guo
Angewandte Chemie 1998 Volume 110(Issue 1‐2) pp:
Publication Date(Web):12 MAR 1999
DOI:10.1002/(SICI)1521-3757(19980116)110:1/2<202::AID-ANGE202>3.0.CO;2-J
Außerordentlich cytotoxisch sind die aus Meeresschwämmen isolierten Spongipyrane. Sie wirken gegen mehrere menschliche Krebszellinien, wobei das als erste Verbindung dieser Naturstoffklasse isolierte Spongistatin 1 am wirksamsten ist. Die erste Totalsynthese dieses Makrolids wurde nun abgeschlossen. Durch sie wird die von Kitagawa et al. vorgeschlagene relative und absolute Konfiguration bestätigt und nachgewiesen, daß Altohyrtin A und Spongistatin 1 identisch sind.
Co-reporter:Matthew M. Hayward;Rebecca M. Roth;Kevin J. Duffy;Peter I. Dalko;Kirk L. Stevens;Jiasheng Guo
Angewandte Chemie International Edition 1998 Volume 37(Issue 1‐2) pp:
Publication Date(Web):17 DEC 1998
DOI:10.1002/(SICI)1521-3773(19980202)37:1/2<190::AID-ANIE190>3.0.CO;2-0
The most active compound of the extraordinarily cytotoxic spongipyrans, spongistatin 1, isolated from marine sponges, appeared to be identical to altohyrtin A. The total synthesis of this macrolide has now firmly established the relative and absolute stereochemistry proposed by Kitagawa (see picture below), and has also verified that altohyrtin A and spongistatin 1 are identical.
Co-reporter:Jiasheng Guo;Kevin J. Duffy;Kirk L. Stevens;Peter I. Dalko;Rebecca M. Roth;Matthew M. Hayward
Angewandte Chemie International Edition 1998 Volume 37(Issue 1‐2) pp:
Publication Date(Web):17 DEC 1998
DOI:10.1002/(SICI)1521-3773(19980202)37:1/2<187::AID-ANIE187>3.0.CO;2-D
The most active compound of the extraordinarily cytotoxic spongipyrans, spongistatin 1, isolated from marine sponges, appeared to be identical to altohyrtin A. The total synthesis of this macrolide has now firmly established the relative and absolute stereochemistry proposed by Kitagawa (see picture below), and has also verified that altohyrtin A and spongistatin 1 are identical.
Co-reporter:Vaddela Sudheer Babu, Ya Zhou, Yoshito Kishi
Bioorganic & Medicinal Chemistry Letters (1 March 2017) Volume 27(Issue 5) pp:
Publication Date(Web):1 March 2017
DOI:10.1016/j.bmcl.2017.01.036
On exposure to visible light, mycolactone A/B, the causative toxin of Buruli ulcer, rearranges to a mixture of four photo-mycolactones apparently via a rare photochemically-induced [4πs + 2πa] cycloaddition. In order to prevent the rearrangement, two C6′-C7′ dihydromycolactone analogs 6′α-15 and 6′β-15 were designed and synthesized. 6′α-15 and 6′β-15 were shown to be stable under not only photochemical, but also acidic and basic conditions. Cytotoxicity was tested against arbitrarily chosen four cell lines (human Hek-293, human lung carcinoma A-549, human melanoma LOX-IMVI, and mouse L-929), thereby revealing that: (1) both analogs maintain potent cytotoxicity; (2) 6′β-15 exhibits significantly higher potency against human cell lines than 6′α-15; (3) in comparison with parent mycolactone A/B, 6′β-15 exhibits equal potency against human Hek-293, whereas significantly lower potency against human lung carcinoma A-549 and human melanoma LOX-IMVI.
Co-reporter:Han-Je Kim, Katrina L. Jackson, Yoshito Kishi, Heather R. Williamson, Lydia Mosi and Pamela L. C. Small
Chemical Communications 2009(Issue 47) pp:NaN7404-7404
Publication Date(Web):2009/10/26
DOI:10.1039/B917014F
A novel mycolactone has been identified from Mycobacterium marinum infecting freshwater fish.
Co-reporter:Thomas Spangenberg and Yoshito Kishi
Chemical Communications 2010 - vol. 46(Issue 9) pp:NaN1412-1412
Publication Date(Web):2010/02/01
DOI:10.1039/B924896J
A boronate-assisted fluorogenic chemosensor in a solid phase is developed, selectively to detect the mycolactones produced by the human pathogen Mycobacterium ulcerans.