最先端有機元素化学 1: 最新論文からのトピックス

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1 最先端有機元素化学 1: 最新論文からのトピックス A Phosphetane Catalyzes Deoxygenative Condensation of α-keto Esters and Carboxylic Acids via P III /P V O Redox Cycling Zhao, W.; Yan, P. K.; Radosevich, A. T., J. Am. Chem. Soc. 2015, 137, Abstract: A small-ring phosphacycle is found to catalyze deoxygenative condensation of α-keto esters and carboxylic acids. The reaction provides a chemoselective catalytic synsis of α- acyloxy ester products with good functional group compatibility. Based on both stoichiometric and catalytic mechanistic experiments, reaction is proposed to proceed via catalytic P III /P V =O cycling. The importance of ring strain in phosphacyclic catalyst is substantiated by an observed temperature-dependent product selectivity effect. The results point to an inherent distinction in design criteria for organophosphorus-based catalysts operating via P III /P V =O redox cycling as opposed to Lewis base (nucleophilic) catalysis. タイトルとTOCグラフィックから読み取れること ホスフェタン(Pを含んだ四員環) が触媒として作用する 3 価と 5 価オキシドで酸化還元サイクルを形成 α- ケトエステル + カルボン酸の縮合反応 Abstract からさらに読み取れること 生成するのは α- アシロキシエステル 官能基許容性は高い Prof. Radosevich Pennsylvania State University Postdoc w. Dan Nocera@MIT Ph.D. in 2007 w. Dean Toste@UC Berkeley Graduated U. Notre Dame 量論および触媒反応の比較より反応は P III /P V =O サイクルで進行 選択性の温度依存性によりリン含有環の環歪みが重要だと判明 酸化還元サイクルのリン触媒は従来のリン求核触媒と異なる 有機元素化学特論第 7 回

2 ORGANIC Introduction: 5価のリンが関係する化学について LETTERS イントロを読む際の注意点 2013!Csp3 Bond Forming Reductive (1) 参考文献は精読しなくても良いので そのabstractと絵だけでも見て流れを掴め Vol. 15, No. 12 (2) まとまった本や総説(review)は何のトピックに関する内容なのかだけわかれば良い nsation of r Keto Esters and Direct Aldol Reaction ble Carbon Pronucleophiles Ref 1は金属含有酵素による酸化反応の総説類 Angewandte Chemie DOI: /anie OXYPHOSPHORANES June Base-Catalyzed Direct Aldolization of a-alkyl-a-hydroxy Trialkyl a M. Fink, Carolyn Labutta, and Alexander T. Radosevich* RefA.2は有機化学における酸化反応をまとめた本 bining with a second molecule of or mono- and polycarbonyl compounds. This opens a convenient route Phosphonoacetates** t o derivatives of 2,2-dihydro-1,3,2-dioxaphosRef 3は各種酸化反応の総説 Chemistry, The Pennsylvania State University, University Park, (Chem. Rev.はちゃんとまとまっている) ring Daisuke system, 11 Uraguchi, and 12. ThisTakashi is, in fact,ooi,* a Michael T.pholane Corbett, and Jeffrey S. Johnson* 6802, United States new approach to creation of carbon-carbon single bonds in polyoxygenated compounds.8 Catalytic direct aldol reactions offer a convenient method for l, 63P pp,m rapid construction of b-hydroxy carbonyl compounds 013 through coupling of carbonyl donors and aldehyde acceptors.[1] The generation of reactive enolate by ABSTRACT a basic or nucleophilic catalyst obviates need to preform an enolate equivalent. Reaction subtypes can be 11, broadly cis R, R 10 12, trans R, R categorized by oxidation state of pronucleophile. W Ketones and aldehydes be used and in direct With somecan a-diketones many aldolization a-keto esters, 2, PIP M. 8 ppm because of ir relatively highcondensation acidity (byisbrønsted base second step of this faster than first 2 : lbase adducts, one; ability in those isolates only catalysis) or ir to cases form one an enamine (by Lewis 11 and 12.direct aldol and Mannich reactions catalysis).[2] Catalytic Pure Appl. Chem. 1964, 9, 337. of trialkyl with are suitably involving donorsthe in reaction carboxylic acid phosphites oxidation state activated monocarbonyl compounds leads directly to [3] Acc. Chem. Res. 1968, 1, 168. f densely functionalized unsymmetrical 1,4-dicarbonyl structural motifs by a phosphorus(iii)-mediated reductive condensaconsiderably more elusive. Mechanistic nuances of se Scheme 1. Base-catalyzed direct-aldolization employing phosphonate 2 : 1 adducts, 1,3,2-dioxaphospholanes.9 This ers and enolizable carbon pronucleophiles is described. The reaction, which is initiated by Kukhtin!Ramirez addition of reactionschem. are happens more diverse and reactions that give products phosphate rearrangement. with 2002, 0- and p-nitr~benzaldehydes,~ phthalrev. 102, 629. lable tris(dimethylamino)phosphine to R-keto ester substrate, proceeds rapidly under mild conditions. d Hfully substituted that are at a carbon atom difficult lotowhich aldehydes18hexafluor~acetone,~ andare fluorenone, Notes 1991 ACIE 2012, 51, Org. Lett. 2013, 15, 3090.achieve. これら3種は典型的な総説の雑誌 We yield reportherein a new base-catalyzed direct 13 and 14, respectively. oxyphosphoranes 3, 63 P ppm Scheme I1 se cases, substituents around glycolate aldoli naddition that relies upon strategic usecarbonyl of tion (2!2!2 ; Scheme 1) through stabilization of group stabilize rearrangement negative charge (Scheme that develops a [1,2] 1). on incipient negative charge. The [1,2] phosphonate phosphate This property of trialkyl phosphites can 2phosphonate phosphate be 1 during formation of 1:rearrangement 2012, 51, tionalized unsymmetrical 1,4-dicarbonyl adapted de- carbon and tobiologically active molecules. This wascarbonyl deployed in development of highly ofacie a-hydroxy phosphonates has been of a small wide variety of strategy five-among synsis c adduct (CH30)3P+OC-HR. In contrast, unsubstie versatile intermediates in organic syn- membered monstrated to 1,4-dicarbonyl compounds, cyclic approaches pentaoxyphosphoranes. Thus, enantioand diastereoselective variants through applicaemployed in formal racemic and enantioselective reductuted aliphatic monoaldehydes yield derivatives of of of trialkyl phosphitesfragments with tion o-quinones 0=6(0R)2 union two C2 carbonyl to chiral forgeiminophosphorane C2!C3 s common target motifs in natural products reaction of catalysts. A consequence of 15, tion of a-keto esters;[7] however, it has seldom been used for 2,2-dihydro-1,4,2-dioxaphospholane ring systems, 3 -~p 1 reaction design is that products containing a leaving group C!C bond construction through umpolung reactivity.[6, 8] The linkage2is, 3appealing in its convergency. Syntically, this in reactions with trialkyl phosphites. There is no Ber. Dtsch. Chem. Ges. 1884, 17, (b) Knorr, L. + are directly by development aldolization,ofa circumstance that fully substituted glycolic acid derivatives that would result reason for negative charge on carbond construction is typically achieved viaproduced diverse preges. 1884, 17, subsequent Sustainable Catalysis bonyl carbon; phosphite displacement adds to carbonyl carbon is favorable for nucleophilic reacfrom productive trapping of 2 feature a b-phosphonyloxy functionalized enolonium syntic equivalents, or altere, see: Whittaker, M.; Floyd, C. D.; Brown, P.; 6a: R=Et and gives 1: 1 adduct (CH30)3P+C(O-)HR with tions. of moiety that can serve as an electrophile in secondary transr'a two-electron natively via oxidation a preformed Chem. Rev. 1999, 99, b: R=i-Pr John Wiley & Sons + H I negative charge oxygen. This type of adduct Although analogous to on well-studied isoelectronic [1,2] adds formations,[9] and can be used as intermediates in synive synses of 1,4-dicarbonyl compounds via C1 intermediate enolate.5 New direct for 0 OCH, and mild methods to second carbonyl compound in usual way [4] ents, see: (a) Stetter, H.; Kuhlmann, H. Org. React. Brook rearrangement, sis of biologically active compounds such as tagetitoxin, [1,2] phosphonate phosphate 1,4-dicarbonyls operating under alterna15. We have been able to show, using to yield 4 formation of 5 6 nders, D.; Breuer, K.; Runsink, J.; Teles, J. H. Helv. [10] rearrangement of a-hydroxy phosphonates is comparatively The generation activated aromatic aldehyde pentafluorobenzaldehyde,leustroducsin B, and phoslactomycin A. 9, (c) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. tive conditions might serve as a valuable complement to [5, 6] R m 2 R 3 8 underutilized. and electrophilic trapping of glycolate enolates through Incorporation of an adjacent electron-with2002, 124, (d) Kerr, M. S.; Rovis, T. J. Am. (7) results in formation of oxyphosphoranes 6 that 1,4,2-dioxaphospholane 16 is initial product se traditional approaches.when ~ 1 ' %OH yields and under syntic very mild conditions. 126, (e) Pesch, J.; Harms, K.; Bach, T. Eur. J. in high a base-catalyzed C!O dialkoxyphosphinyl migration was drawing groupof facilitates dialkoxyphosphinyl reactionc!o with trialkyl phosphite.llmigrathis oxy4: 2,3-ANTI We recently reported a phosphorus(iii)-mediated meth- isomerizes slowly to 1,3,2-dioxaphos2025. (f) Mennen, S. M.; Blank, J. T.; Tran-Dub!e, cyclic phosphite esters are employed, spiropentaoxyphosphorane accordingly undertaken. J. E.; Miller, S. J. Chem. Commun. 2005, 195. (g) phosphoranes 3 are obtained. Phosanalogous to of od for synsis R-heterofunctionalized carbonyl pholane exact mechanism of this important Initially, we examined reaction of a-hydroxy phosm. T. Corbett, Prof. Dr.17. J. S. The Johnson haradwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. phonite and phosphinite esters, (R0)2PRand [*] (RO)PRz, ChemSusChem 2013, not known. Moreover, we have no derivatives of R-ketotransformation and6,is1615. ofesters Chemistry h) Ballini, R.; Barboni,J. L.; Org. Bosica, G.; Fiorini, 1991, D. 7b: Chem. R=i-Pr 2, 3 - ~via w reductive condensationdepartment phonate 1 a[11] with an aryl aldehyde in presence of 56, t o give cyclic members of series can be used compelling evidence assuming that all 1,3,25. (i) Custar, D. W.; Le, H.; Morken, J. P. Org. Lett. The University ofon North Carolina at for Chapel Hill X!H pronucleophiles. This method hinges a variety of bases (Table 1). The temperature of reaction (RO)6-,PR,, where n = 1 or 2. The use of tertiary mith, A. B.; Adams, C. M.dehydes Acc. Chem. Res. 2004, which have been obtained from ChemSusChem 2013, 6, is influencing 37, stereoselectivity. Chapel Hill,dioxaphospholanes NC (USA) determined product identity. When reaction was RsP, in but initial were performed neatthis reaction is more limited,, M.; Uria, U.; Vicario, J. L.;Our Reyes, E.;condensation Carrillo, L. reactions J. phosphines, of trialkyl phosphites with activated monoreactions jsj@unc.edu a t room temperature according t o procedure used by cyclic dioxyphosphoranes can be made in this 12, 134, Via C3 homoenolate equivalents: (l) some conducted at room temperature, epoxide 5 was isolated in u.edu L Ref 4a,b Ref 5b-d (5aは取れず) Ref 6a + Ref 6b Ref 7a プロセス化学志向の触媒反応 について書かれた本 Ref 7c GH Ref 7a リン触媒でホスフィンオキシド廃棄を 減らす化学の総説 ヒドロキシ基を活性化して 求核置換する反応(Appel反応)の総説

3 Ref 8. Introduction 2: リンの酸化還元や触媒利用 Ref 9. For stoichiometric deoxygenations by P(III) reagents, see: Rowley, A. G. In Organophosphorus Reagents in Organic Synsis; Cadogan, J. I. G., Ed.; Academic Press: London, 1979; p 295. 三価のリンによる脱酸素化が書かれている書籍 Ref 10,11. a '*. b&p c' = 0 + HSiCl 3 a\\<+!+) HIY13 'a \,I+) (-1 b&p-h OSiCl 3 c' 1 Tetrahedron Lett. 1965, 6, JACS 1969, 91, JACS 2012, 134, Ref 12. Ref 13. Ref 14a. Org. Lett. 2008, 10, Chem. Eur. J. 2013, 19, Ref 14b. ACIE 2009, 48, Wittig 反応の副生成物であるホスフィンオキシドを系内でヒドロシランを用いて還元 J. Org. Chem. 2011, 76, キラルルイス酸触媒による不斉アルドール反応の総説 Acc. Chem. Res. 2000, 33, 432. Chem. Eur. J. 2013, 19, 5854.

4 Introduction 3: リンの酸化還元を伴う触媒反応 Ref 15a. Ref 15c. Ref 17b. Adv. Synth. Catal. 2012, 354, Ref 15b. Eur. J. Org. Chem. 2013, 2013, Ref 15c. 環状リン触媒 Appel 反応まとめ Ref 17a. Pure Appl. Chem. 2013, 85, 817. Ref 17c. ACIE 2012, 124, Chem. Commun. 2014, 50, Chem. Eur. J. 2011, 17, J. Org. Chem. 2010, 75, この論文を読む上での鍵 どうやってリンの酸化還元を使って新しい触媒を構築するのか

5 This Work 1: Catalyst Screening β- ケトエステルとカルボン酸の縮合における触媒探索 脱酸素縮合生成物 単純還元生成物 ( ヒドロシランによる?) Ref 19 既存の 5 員環系触媒 新規 4 員環系触媒 yield a (%) entry R 3 P O solvent T ( C) b 1 PhMe PhMe PhMe b 4 PhMe アミドが良い 5 5 PhMe c 5 PhMe溶媒効果 c 5 1,2-DCE none 1,2-DCE pyrrolidine 1,2-DCE c 10 d 1,2-DCE e a Yields of isolated products. Reactions conducted on 0.56 mmol scale. b Yields based on recovered starting material. c Yield of 9 not determined. d See Scheme 1 for structure. e See ref 25. phosphetaneの配位子応用 Kamer, P. C. J., van Leeuwen, P. W. N. M., Eds. John Wiley & Sons, Ltd.: New York, 2012; pp Ref 20 Phosphetane + PhLiで開環反応が進行する J. Org. Chem. 1967, 32, Ref 21 Phosphetaneの合成と性質に関する総説 Chem. Rev. 2002, 102, 201. グラムスケール合成可能 Phosphetaneの合成論文 Ref 22 J. Org. Chem. 1962, 27, 606. J. Org. Chem. 1962, 27, Scheme 1. Preparation and Stoichiometric Reactivity of Aminophosphetanes a a Reagents and conditions: (a) i. 2,4,4-trimethyl-2-pentene, AlCl 3 ; ii. pyrrolidine, 81% for two steps. (b) PhSiH 3, PhMe, rt, 67%. (c) PhC(O)CO 2 Me (6), p-fc 6 CH 4 CO 2 H(7), PhMe, 50 C, 92%.

6 This Work 2: Substrate Scope Table 2. Examples of Deoxygenative Condensation with Varying Carboxylic Acid Components a Table 3. Examples of Deoxygenative Condensation with Varying α-keto Ester Components a e-rich naphthyl e-deficient* thienyl sulfide thienyl halogen halogen e-deficient e-deficient pyridyl aliphatic o-bromo aliphatic α,β-unsturated free aniline free carbazole thiazolyl intramolecular moderate cyclization = lactone diastereoselectivity a Yields are for isolated products. b Ar = p- t BuC 6 H 4. aldehyde o-acetyl a Yields are for isolated products. benzylic Cl* functional group with * could react with phosphine

7 This Work 3: Temperature-Dependent Selectivity Table 4. Dependence of Product Selectivity on Temperature yield a (%) entry T ( C) a Yields are for isolated products. 低温 = 目的物低収率 単純還元生成物増加 9 は 8 が生成する前の中間体ではない理由 (1) 理由 (2) Figure 2. Correlation between product selectivity and temperature over range 24 C<T < 100 C (see Table 4). Linear fit: ln[(8/9)/t] = 5.26T , R 2 = isokinetic temperature T iso = 48 (8 および 9 の生成速度が同じ温度 ) differential activation parameters ΔΔH = +10.5(9) kcal/mol ΔΔS = 26(6) cal/mol K

8 安息香酸イオンによる求核置換反応 (S N 2) 安息香酸による加プロトン分解 リンの酸化的環化 This Work 4: Proposed Mechanism P=O 部のヒドロシランへの配位 Figure 3. Mechanistic proposal for deoxygenative condensation. 分子内のヒドリド移動は遷移状態がコンパクト = = ヒドリド移動分子内でリンへ : 中間体 39 が生成分子間で 6 へ :9 が生成 ヒドロキシシラン脱離 Ref 27,28 ホスフィンオキシドの還元は分子内ヒドリド移動が律速 JACS 1969, 91, J. Org. Chem. 1974, 39, 265. J. Org. Chem. 2012, 77, Refs 四員環内の典型元素はルイス酸性が高い= Acc. Chem. Res. 1968, 1, 70. Acc. Chem. Res. 1972, 5, 204. JACS 1981, 103, JACS 1992, 114, J. Org. Chem. 1981, 46, Acc. Chem. Res. 2008, 41, JACS 2000, 122, Organometallics 1990, 9, JACS 2004, 126, 14.

9 Or Experiments and Next Approach 他の実験により何かわかるか? 次のアプローチはどうすべきか? そのために何を調べてみる?

10 最後に : レポート課題について s- または p- ブロック元素の化合物の化学に関する 2016 年以降の論文を読み ( 論文はこれらの原子が直接反応や物性に関わるところを観測しているものを選んでください例 : 典型元素の酸化還元 典型元素の関わる光電子物性 典型元素触媒 など ) 以下の点に関して講義資料と同様 A4 用紙数枚程度に WORD ファイルでまとめて PDF とし WORD および PDF の両方を 2017/10/14( 土 ) までに山下へメールで提出 makoto@oec.chembio.nagoya-u.ac.jp 以下の各項目は後ろに行けば行くほど重要です 論文の背景においてどのような研究がなされてきたか?( イントロ参考文献の半分以上はまとめよう ) TOC の絵の貼り付け + 論文内容の一言説明の形でまとめよ 総説等は図不要 入手不可な文献は省略可 この論文において得られた結果は何か? 論文に出てくる結果を全て示せ 直訳ではなく講義プリントのように図を最大限活用して簡潔に説明せよ 得られた結果を説明するための他の実験を提案し それで何がわかるかを理由と共に説明せよ 参考文献があると尚良い 自分ならこの論文をどう改良してさらに次のアプローチを考えるか? その目的およびそれが可能な根拠を明確に示して説明せよ またそのアプローチに対して必要な他の事実を他の論文や SciFinder から探して実現可能性に関して論ぜよ ただし他の人と論文が重なってはダメです 読むべき論文を決定した時点で山下へメールして重複の有無を確認すること メール本文に論文タイトルを書き 該当 PDF を添付してメールを送って下さい 山下の OK が出てからレポート作成を開始してください 早く確認すればするほど論文を読む時間は増えるし 重複の可能性も少ない ラボの同級生 先輩 後輩 教員とのディスカッションを推奨しますが最終的に自分の力で書ききることが最も自分の身になります 成績評価はレポート内容の論理性 妥当性を絶対評価でつけます (= 全員 A も全員 E もありうる ) 採点済の過去レポートを山下研ウェブサイトから見ることができます