Teruaki Mukaiyama - The Scripps Research Institute
Transcription
Teruaki Mukaiyama - The Scripps Research Institute
Teruaki Mukaiyama - 向山 光昭 Y. Ishihara Prof. Teruaki Mukaiyama Bibliography: - Jan 5 1927: Born in Nagano, Japan - 1948: B.Sc., Tokyo Institute of Technology - 1953: Assistant Professor, Gakushuin University - 1957: Ph.D., University of Tokyo - 1958: Assistant Professor, Tokyo Institute of Technology - 1963: Full Professor, Tokyo Institute of Technology - 1973: Full Professor, University of Tokyo - 1987: Completed his term at the University of Tokyo; move to Tokyo University of Science (formerly Science University of Tokyo) - 1991: President of the Research Institute, Tokyo University of Science - 1992: Distinguished Professor, Tokyo University of Science - 2002: Move to Kitasato University Baran Lab Group Meeting An excerpt from Mukaiyama's publication list, published in Heterocycles 2000, 52, 13-66. Notable chemists originating from the Mukaiyama Group: Isao Kuwajima, formerly at Tokyo Institute of Technology; Eiichi Nakamura, University of Tokyo; Koichi Narasaka, University of Tokyo; Shuu Kobayashi, University of Tokyo; Masahiro Murakami, Kyoto University; Yujiro Hayashi, Tokyo University of Science; Kenso Soai, Tokyo University of Science; the late professor Oyo Mitsunobu, formerly at Aoyama Gakuin University. Mukaiyama Award: - Administered by the Society of Synthetic Organic Chemistry, Japan (SSOCJ). - The award was established in 2005 by SSOCJ to celebrate the 77th birthday of Professor Teruaki Mukaiyama, who received the Order of Culture in 1977 from Japanese government for his outstanding contributions to synthetic organic chemistry and to commemorate his election in 2004 to the National Academy of Science, USA, as a foreign associate. - The award shall be granted to an individual of 45 years old or younger without regard to nationality for their outstanding contributions to synthetic organic chemistry. - Nature: The award consists of $5,000, a medallion, and a certificate. The recipient shall deliver an award lecture at the Seminar on Synthetic Organic Chemistry. - A nomination form can be downloaded from http://wwwsoc.nii.ac.jp/ssocj/ - Selection: The award committee selects two award recipients, one from the nonJapanese nominees and the other from the Japanese nominees. Publications: Close to 1000 to date. - Science ...1 (Perspective) - Angewandte CIEE ...5 (4 Reviews) - JACS ...22 - JOC ...22 - Tetrahedron Lett. ...26 - Tetrahedron ...11 - Tetrahedron: Asym. ...1 - Minor/inaccessible papers/abstracts <100 Chemistry Letters ...632 Bull. Chem. Soc. Jpn ...165 Chemistry Letters, founded in 1972 by Mukaiyama. 1 Teruaki Mukaiyama - !"# $% Y. Ishihara Mukaiyama's early years: An organophosphorus chemist O Ph PhNCO + EtNO2 cat. R3N N H Synthesis of phosphoric esters as an application of oxidation-reduction condensation: Me Me Me Me BnOH + R3P + EtO2C-N=N-CO2Et Ph + N H N O N O N N P(OEt)3 O O Ph RNC + O=P(OEt)3 OEt EtO OEt P O O P(OEt)3 Ph ! Ph P(OEt)3 C O Ph (RCO2)2Hg + R'3P Ph Desired product for Mukaiyama R1OH + R3P + EtO2C-N=N-CO2Et + R2CO2H Side product: Diphenylketene dimer J. Org. Chem. 1964, 29, 2243. [O] 2[H] -H2O (RCO)2O + Hg + 2 ArH + R'3P=O [O] (RCO)2O + PhCO-CH2CH2-COPh + R'3P=O J. Org. Chem. 1963, 28, 2024. J. Org. Chem. 1964, 29, 1385. Variations in the type of products made: Esters, thioesters, amides, thioethers, pyrophosphates... also useful in peptide and nucleotide chemistry. Ph O unpublished results Oxidation-Reduction Condensation: an Extension to the Mitsunobu Reaction (2003) Reductant present within R2CO2R1 substrate; adamantanols and DMBQ tert-butyl alcohol, among other 1 1 R = 1º or 2º, 85-96%; 3º, 72-82% 3º R OH, work well; stereospecific inversion for 1º or 2º; 70-100% inversion for 3º; ArOH 1 Ph2POR ArOR1 mild and neutral reaction, even DMBQ works for chloroacetic acid. Ph2POR1 N S S N Amide coupling using PySSPy: Tetrahedron Lett. 1970, 22, 1901. Precedes CoreyNicolaou macrolactonization (JACS 1974). Me R2CO2H R1 = 1º or 2º, 78-92%; 3º, 62% Even 2,6-disubstituted phenols give 70% yield O O Me DMBQ Chem. Lett. 2003, 32, 300; Bull. Chem. Soc. Jpn 2003, 76, 1645. Ether formations: Ph2POR1 Variations in the type of oxidant used: N EtO2C-NH-NH-CO2Et + O. Mitsunobu and M. Yamada, Bull. Chem. Soc. Jpn 1967, 40, 2380. Mitsunobu later expanded the scope of this reaction to include other nucleophiles. 2 RCO2H + PhCO-CH=CH-COPh + R'3P 2[H] 3+ R2CO2 O=PR3 + EtO2C-NBn-NH-CO2Et + R2CO2R1 Hg is a good [O] for this reaction! (RCO)2O + Hg + R'3P=O 2 RCO2H + Ar2Hg + R'3P N O. Mitsunobu, M. Yamada and T. Mukaiyama, Bull. Chem. Soc. Jpn 1967, 40, 935. R1O-PR Oxidation-Reduction Condensation (Review in Angew. Chem. Int. Ed. 1976, 15, 94-103): Employs an oxidant that removes 2 H from a reaction, and a reductant that removes 1 O from the same reaction, such that a net loss of water is observed. Essentially, a dehydrating agent, that takes place under neutral conditions. Ph O RO-P(OEt)2 + EtO2C-NAllyl-NH-CO2Et Six months later... the Mitsunobu reaction: Ph Harnessing the ability of phosphorus (III) to reduce... O ROH + (EtO)2P-OAllyl + EtO2C-N=N-CO2Et Ph Ph -H2O BnO-PR3 + EtO2C-N-NH-CO2Et O=PR3 + EtO2C-NBn-NH-CO2Et O J. Am. Chem. Soc. 1960, 82, 5339; J. Org. Chem. 1962, 27, 3651. RNCO + P(OEt)3 Baran Lab Group Meeting Ph2POR1 R2OH R2OR1 not formed! DMBQ R2OH Fluoranil R2OR1 Very low yields with DDQ or chloroanil; chiral center at R1 gets inverted; coupling of 3º-3º ROH are not possible but 2º- 3º ROH couplings work. Chem. Lett. 2003, 32, 984. 2 Teruaki Mukaiyama - !"# $% Y. Ishihara Various hydroxyl activations: Mukaiyama's Named Reagent: N-Methyl-2-Chloropyridinium Iodide R1CO2H N X Me N base fast I OH O R2OH R1 O R1CO2R2 base slow Me + N O N R N Y R4 Cl Me R = Me or Et; X = F or Cl; Y = BF4 or FSO3; Z = O or S R1 FSO3 R1 O N R2 R1 O O R1 N N S R3 Chem. Lett. 1975, 1163. R1 Y O SR2 R1 OH n R3 R2 + R1 R2 Pyridinium salt, Et3N then LiI R3 H • R1 R2 R2 R4 R1 R3 Chem. Lett. 1978, 785. R1 or R2 can also be SPh, generating vinyl sulfides: Chem. Lett. 1978, 413. Various functional groups generated from ROH + onium salt: - Inverted ROH (acyclic only) from Cl3CCO2H, followed by saponification, Mukaiyama's version of a Mitsunobu inversion: Chem. Lett. 1976, 893; - RCl from LiCl (acyclic), R3NH+Cl- or R4N+Cl- (cyclic): Chem. Lett. 1976, 619; 1977, 383; - RBr or RI from LIBr and NaI, respectively (acyclic only): Chem. Lett. 1976, 619; - RSH (acyclic and cyclic) from Me2NC(=S)SNa, followed by LiAlH4: Chem. Lett. 1977, 437; - RNH2 (acyclic and cyclic) from LiN3 + HMPA, followed by LiAlH4 or H2/Pd reduction: Chem. Lett. 1977, 635; - ROPO2OR' (acyclic) from R'OPO2H; exception to the rule - a benzoxazole is used, and not an onium salt (the onium is prepared in situ): Chem. Lett. 1978, 349. - RO-(Nucl.Base), i.e. nucleosides, from nucleic acid bases: Chem. Lett. 1978, 605. If R has a stereocenter at the carbon bearing the hydroxyl group (i.e. 2º; 3º are not tolerated), it will be inverted, unless R is a sugar, in which anomeric effects and neighboring group participation dominate. F Various dehydrations and dethiohydrations: Chem. Lett. 1976, 711. Chem. Lett. 1977, 1443. Chem. Lett. 1976, 711. Chem. Lett. 1976, 303. N Without overlooking the macrolactonization... HO 2. R3MgBr, cat. CuI OH X O R1 1. Pyridinium salt, Et3N R4 R3 R2 R1 = Me, Et or Ph; R2 = H, Me or Ph; R3 = H or Me; R4 = H or Me; X = F, Cl or Br; Y = I, BF4 or TsO S 2. R3MgBr SPh R1 Carboxylic acid derivatives formed: O N OH R2 R2 N R2 R1 These findings opened a whole new area of study for redox-neutral dehydration reactions: The utilization of onium salts of aza-arenes (Review in Angew. Chem. Int. Ed. 1979, 18, 707-721). R3 Types of onium salts used: X R1 R3 1. Pyridinium salt, Et3N The course of the reaction (SN2 vs. SN2') depends on the nature of the R groups, and in almost all cases, one isomer predominates. Chem. Lett. 1977, 1257; 1978, 689. Me X = Cl or Br in original reference: Chem. Lett. 1975, 1045. It turns out that the nature of the alkyl group on pyridine, the X group and the counterion all affect the yields of the coupling reactions in subtle fashion. When R1 and R2 are 3º, the yields are dismal with the original Mukaiyama reagent, but using 2-bromo-N-ethylpyridinium tetrafluoroborate with R1 = R2 = tBu resulted in a 54% yield (Bull. Chem. Soc. Jpn 1977, 50, 1863). Z Baran Lab Group Meeting O n O O Chem. Lett. 1976, 49: "their procedure requires rather elevated Tº; lactonized in better yields than those obtained by previous methods". Me HO OH O HO Me O R1 Me J. Am. Chem. Soc. 2003, 125, 5393; Angew. Chem. Int. Ed. 2002, 41, 1787. R2 R1 H N then H2O R2 RNHCS2- Et3NH+ R1NHC(=S)NHR2 O Chem. Lett. 1976, 1397. R2 OH O Me Pyr. salt, Et3N Me HO OH O Me Me O OH R1 Me OH R1NHC(=S)OMe O OH Pyr. salt R3 Et3N R1 R2 Chem. Lett. 1977, 179. R3 RCO-NH2 RNH-CHO R-N=C=S Chem. Lett. 1977, 573. R1-N=C=N-R2 Chem. Lett. 1977, 575. R-N=C=O Chem. Lett. 1977, 1345. R C N unpublished R N C Chem. Lett. 1977, 697. 3 Teruaki Mukaiyama - !"# $% Y. Ishihara Mukaiyama's Claim to Fame: The Mukaiyama Aldol Reaction O R1 OSiMe3 H + R2 OH Lewis acid or Lewis base Y R1 can be H; Y = H, alkyl, Ar, OR, SR A switch to silyl enol ethers: Use of TiCl4 as Lewis acid O R1 then aq. workup OH Y and/or O R1 O Y R2 O N Bu2BOTf O Y N iPr NEt 2 Me Me Me O OBBu2 O R2 H O O then [O] workup R1 R2 "Evans syn aldol" History behind boron-mediated aldols: OBR2 Brown et al., JACS 1967, 89, 5708 & 5709; for other preparations of vinyloxyboranes, see: Hooz et al., MVK + BBu3 n-Pn JACS 1968, 90, 5936; Tufariello et al., JACS 1967, Me 89, 6804; Koster et al., Angew. Chem. 1968, 80, 756. R5 R2 + R3 h" H2C=C=O Instead: expected product: H2C=C(SBu)2 Me Me Bull. Chem. Soc. Jpn 1971, 44, 3215; mechanism corrected in J. Am. Chem. Soc. 1973, 95, 967 and Bull. Chem. Soc. Jpn 1973, 46, 1807. OBBu2 H2C=C=O + Bu2B-SBu Me2CO SBu Me Me The "current" method to generate boron enolates: O OBBu2 O Bu2BOTf R2CHO R1 Me iPr NEt 2 R1 R1 R1 X3M H O R2 Z-A O H R1 Z-C Chem. Lett. 1976, 559; 1977, 153. MX3 X O R1 R2 R3 Chem. Lett. 1975, 527. O Chem. Lett. 1975, 989; 1976, 769. OR5 R2 R3 R4 SiMe3 R3 H R2 H R3 R3 R2 R1 MX3 H Me3SiO OH O X silyl enol ether R1 SBu OR5 TiCl 4 R2 O #Me3SiX TS for Z-enol silanes: SBu Bu2 B O O PhMe, reflux R4 Mechanism of the Mukaiyama aldol reaction: O Me2CO OH O R1 R2 OMe O R4 Mukaiyama's fortuitous discovery: O OH R1 TiCl4 Chem. Lett. 1974,15. R4 OSiMe3 R2 R5 R2 R3 R4 Br OSiMe3 O R1 O R4 + But no one used boron enolates in aldol reactions! OH R1 TiCl4 R3 OMe OMe R1 But Evans ! boron enolate! Rather, Evans = use of chiral oxazolidinone for aldol. Bu2B-SBu R2 OR R4 Br Me Y = alkyl, Ar, OR, SR, Cl, Br but not H OSiMe3 3 + R OR R2 Y Me Me R1 TiCl4 Chem. Lett. 1973,1011; J. Am. Chem. Soc. 1974, 96, 7503. Expanding substrate scope: OH N OH Reactivity as electrophile: RCHO (#78°C) > RCOR' (0°C) >> RCO2R' Chem. Lett. 1975, 741; Bull. Chem. Soc. Jpn 1976, 49, 2284. OR O O R2CHO R1 base Me R2 Enol silane geometry rarely affects the syn/anti geometry of the product O Y OSiMe3 Me3SiCl R1 ...vs. the Evans aldol reaction: O Baran Lab Group Meeting X3M Me3SiO R3 MX3 R2 H H X3M OSiMe3 OH H O O R3 Z-D OSiMe3 OH R3 aq. workup O R1 R3 R2 R2 R3 R1 E-A O R1 H R3 R2 syn O R1 Me3SiO MX3 R2 R1 R3 E-B H X3M H O MX3 R3 E-C X3M OSiMe3 H H R2 H H R3 anti OH O R2 R2 R2 R1 O R1 Z-B H O R1 TS for E-enol silanes: H R1 X3 M H OSiMe3 R2 R1 O R3 Me3SiO E-D The most favorable conformations: A and D. If R2 = large and R3 = small, D is favored; if R2 = small and R3 = large, A is favored. Conclusion: Z/E of the enol silane rarely matters! 4 Teruaki Mukaiyama - !"# $% Y. Ishihara Lewis acid-catalyzed Mukaiyama aldol reactions: X3 M SiMe3 O O O O Me3Si-X R1 R3 R2 needs to transmetallate R1 Titanium tetrachloride reactions (See review in Angew. Chem. Int. Ed. 1977, 16, 817-826): R3 + MX4 R2 First catalysis: Trityl salts (Chem. Lett. 1985, 447, 1535 and 1871); in situ Me3Si+: SnCl2, Me3SiCl (Chem. Lett. 1987, 463). Typically 1-10 mol%. Chiral Lewis acids: The true strength of the Mukaiyama aldol reaction. Sn(OTf)2, Chiral diamine, eg. O OSiMe3 Bu2Sn(OAc)2, OH O chiral diamine + R H SEt R SEt CH2Cl2, !78 °C N Me Me Me NHNaph Z enolates work well; E 70-96%; enolates are mismatched; H 100% de, Chem. Lett. 1989, 297; J. Am. instead of Me works very well. >98% ee Chem. Soc. 1991, 113, 4247. Enantioselective diol formation: O OSiMe3 + R H SEt OBn CH2Cl2, !78 °C Chem. Lett. 1990, 1019; Replacing Bn by TBS results in the syn product (Chem. Lett. 1991, 1901.) Characteristics: Strong Lewis acid, strong oxophile and dehydrater; may act as an electrophile for C!C " bonds. eg. OH O N N R OBn 72-88%; >96% de, >95% ee R1 EtS O O Ph OH O R1 Et3N R2 H OSiMe3 Me OSiMe3 R But the above chiral Lewis acid reagents are stoichiometric! The chiral diamines are "promoters"... Simple solution: Replace CH2Cl2 for CH3CH2CN (Sn-Si exchange is faster; Chem. Lett. 1990, 1455), and add the two substrates slowly into the catalyst mix to prevent undesired Me3SiOTf-promoted, racemic aldol formation. Lewis base-catalyzed Mukaiyama aldol reactions: Li SiMe3 OSiMe3 O O O O LiNR2 Me Si-NR 3 2 Me PhCHO + OMe Solvent Ph OMe Ph OMe turnover Me Me Me Me Me LiNPh2 was initially used over LDA, but Li 2-pyrrolidone was optimal; THF did not allow turnover but DMF did; a milder version using LiOAc as a base in DMF/H2O systems allowed the compatibility of hydroxyl and carboxyl functionalities in the substrate (Chem. Lett. 2002, 182 and 858; 2003, 462 and 696). R2 + Ph OMe Ac 73%, dr 17:3 O + Ph TiCl4, Ti(OiPr)4 OMe Trioxane, TiCl4 O O R3 R1 Vinyl chlorides work as well. OSiMe3 Bull. Chem. Soc. Jpn 1972, 45, 3723; Chem. Lett. 1973, 479. Ph (80%) O Chem. Lett. 1975, 319. O (Mechanism and stereoselectivity?) Chem. Lett. 1974, 381 and 1181. O TiCl4, Ti(OiPr)4 O SEt OiPr Me O Ph O H2O, TiCl4 R3 R1 + SEt SR Aldol-like reactions: Me Ph CH2Cl2 RSH, TiCl4 R3 OTf H unpublished SEt R3 Bn cyclohexylbenzene (91%) EtSH, TiCl4 R2 Sn SEt TiCl4 cyclohexanol + benzene Proposed TS for -OBn: Sn(OTf)2, Bu2Sn(OAc)2, chiral diamine Baran Lab Group Meeting then HSCH2CH2SH S S Ph Reactions on #,$-unsaturated ketones work as well. Chem. Lett. 1974, 1223; Bull. Chem. Soc. Jpn 1976, 49, 779. Titanium tetrachloride reduced in situ: -TiCl4/LiAlH4: S ArCl S R1 R2 ArH H R1 H R2 Chem. Lett. 1973, 291. -TiCl4/Zn: PhCHO RCH(OMe)2 Me Ph OMe 2 MeO RCH2OMe Me Me Ph Ph MeO OMe unpublished PhCH-CHPh + PhCH=CHPh OH OH room T°, THF: 98% 1% reflux, dioxane: 0% 98% Chem. Lett. 1973, 1041; precedes TiCl3-based McMurry coupling (JACS 1974, 96, 4708). 5 Teruaki Mukaiyama - !"# $% Y. Ishihara Miscellaneous reactions Chiral !-hydroxyaldehyde formation: Sugar chemistry: RO RO O O Me OH N F O Me OTs Me Et3N O O Me F O Me OBn BnO Chem. Lett. 1983, 935; anomers are separable and the ! can be converted to the " form using BF3; at the time, this reaction could only be done using anhydrous HF; reaction discovered from analogy of RCO2H to RCOF. F OBn + HO O BnO BnO BnO OMe SnCl2, AgClO4 4Å MS 84% dr = 84:16 N Mg O X O BnO BnO Protic acid-catalyzed activation: O OBn F cat. HX + HO 5Å MS O BnO Solvent BnO BnO OMe TfOH, Et2O: 98%, !/" = 88:12 HClO4, Et2O: 98%, !/" = 92:8 C4F9SO3H, Et2O: 99%, !/" = 88:12 BnO BnO BnO PipCO-N=N-COPip R (89-96%) Pip = N-substituted piperidine O LDA, then Ph O BnO OMe S Tf2NH, PhCF3: 99%, !/" = 9:91 HSbF6, PhCF3: 100%, !/" =12:88 HB(C6H5)4, PhCF3: 99%, !/" = 7:93 O Ph TiCl4 R1CHO + O N Me Pyr. >76% >17:3 dr Me prepared from ephedrine hydrochloride in 3 steps R1 O O N Me E-alkene O Chem. Lett. 2000, 1250; if DBU is used instead of LDA, 2° amines to imines, (Chem. Lett. 2001, 390) and N,N-disubstituted hydroxylamines to nitrones (ARKIVOC 2001, 10, 58) can be formed. NtBu Cl (93%) Ph S NHtBu NCS or NBS (1.1 eq) Chiral "-substituted carboxylic acid formation: O O Ph Me DEAD does not give as high yields (Yoneda et al., JACS 1966, 88, 2328). Named reaction (??): "Mukaiyama Oxidation"; 2° alcohols to ketones work equally well (Bull. Chem. Soc. Jpn 1977, 50, 2773). Some sulfur chemistry: O BnO BnO BnO H R OH Cl O Chem. Lett. 2001, 426; Bull. Chem. Soc. Jpn 2002, 75, 291. O O Ph H3O+ Mixed ether formation from acetals: mixed acetals work best (Chem. Lett. 1975, 305). Cl TiCl4 + BrMg Ph (98%) O O O Ph Chem. Lett. 1981, 431. Yields and stereoselectivities are typically better than Cl or Br analogs due to the C-F bond strength at the anomeric position: C#F 552 kJ/mol; C#Cl 397 kJ/mol; C#Br 280 kJ/mol. BnO BnO BnO NPh R OH O Overall yield: 67-82%; optical purity > 94%. Chem. Lett. 1978, 1253; 1979, 705. OH BnO OMe Ph CHO Cramchelate TS R O H NPh PrMgBr or tBuOMgBr BnO N 1. RMgX NPh 2. NH Cl 4 PhH single Ph PhHN diastereomer Some more Grignard chemistry: O BnO N H H Ph R N Dean-Stark PhCOCHO + OBn BnO O BnO Baran Lab Group Meeting R2MgBr >75% R1 R2 O H3O+ Chem. Lett. 1977, 1165; Bull. Chem. Soc. Jpn 1978, 51, 3368. R1 R2 O Ph N Me R OH O R K2CO3, 4Å MS, CH2Cl2, 0 °C, 30 min (86-100%) Me Me DMAD H MeO2C Named reaction (??): "Mukaiyama Oxidation"; 2° alcohols to ketones work equally well. (Chem. Lett. 2001, 846; Tetrahedron 2003, 59, 6739.) CO2Me S Me O Me OH MeO2C + COPh Tet. Lett. 1970, 29, 2565. Me DMSO: PhH: O 88% 27% Me SMe Ph PhOC CO2Me 0% 70% 6 Teruaki Mukaiyama - !"# $% Y. Ishihara Total Synthesis Targets - Application of Synthetic Methodology Integerrimine (Chem. Lett. 1982, 57 and 455): NH2 N O HS O Me N H O Me O N H P O O O OH O Me Me 1) Me2CuLi; CO2 1) MCPBA (76%) O O Coenzyme A - Coupling with [O]-[H] condensation Chem. Lett. 1972, 595. N Me H H O H Me P O N 1) TsO O F 1) (60%) Me Me N Me O Me Ph NHMe N O N H N H Me CO2H A B O Me O OH nC H 9 19 OH nC N 9H19 N Ph Malyngolide - Quaternary stereocenter synthesis via asymmetric !-hydroxyaldehyde synthesis Chem. Lett. 1980, 1223. O Me CO2CH2CH2TMS O O via one more Mukaiyama condensation Me O N integerrimine F1! Antigen (Chem. Lett. 2001, 840; Bull. Chem. Soc. Jpn 2003, 76, 1829): BnO Me Indolmycin - Methyl group introduction via a chiral oxazepine appendage Chem. Lett. 1980, 163. OH OH BnO O Me Me Me O 2) LiOH, H2O2 (71%) Me dl-Variotin - Ti coupling of acetals with silyl enol ethers, and amide formation using Mukaiyama reagent Chem. Lett. 1977, 467; Bull. Chem. Soc. Jpn 1978, 51, 2077. O (98%) HOCH2CH2TMS Me O Me Cl Me N OH N O CO2H O OH I Me OH nBu Vitamin A - Ti coupling of acetals with silyl enol ethers Chem. Lett. 1975, 1201. CO2Me Me H Me Me O Me 2) LiOH (100%) Me Me O H Me O CO2Me 2) LDA; MeCHO 2) CH2N2 (80%) O OH O N N P Baran Lab Group Meeting BnO HO BnO BnO C BnO OBn A + B + cat. H+ + MS 5Å, then C + NIS O F O(4-Me)Bz One-Pot Sequential Stereoselective Glycosylation (89%) O SEt N(4,5-Cl2)Phth BnO OH O NHCbz N3 O BnO CO2H OBn BnO O O O BnO BnO O(4-Me)Bz Cl2Phth-N O BnO N3 O O NHCbz CO2H Reduction of the azide, removal of the phthaloyl group, acetylation of two N atoms and removal of all protection groups lead to the F1! antigen. 7 Teruaki Mukaiyama - !"# $% Y. Ishihara Baran Lab Group Meeting Total Synthesis of Taxol® (Proc. Jpn. Acad. 1997, 73B, 95; Chem. Eur. J. 1999, 5, 121.) AcO 18 O Ph Ph N H Me O 12 11 O OH 10 9 O 19 OH Me Me 13 15 14 1 HO 8 16, 17 Me 3 2 BzO 7 O TBSO 6 5 4 H AcO BnO Me 19. 1N HCl (83%) 20. Swern [O] (95%) Me Me PMBO O 20 BnO 16. LHMDS, TMSCl 17. NBS 18. LHMDS, MeI OBn BnO Me Me OBn MeO CO2Me Me HO 1. Swern [O] (89%) 2. HC(OMe)3 (93%) Me OTBS O OMe OH CO2Me 3. LiAlH4 (90%) 4. Swern [O] (85%) Me MeO t BuLi, CuCN (92%, 99% brsm) , Sn(OTf)2 O TBSO OMe Me PMBO N , Bu2Sn(OAc)2 MeO 6. PMB Prot. (95%) 7. LiAlH4 (86%) CO2Me 8. TBSCl (93%) 9. AcOH (87%) OMe OH Me Me OBn BnO Me HO PMBO OMe OHC PMBO TBSO MgBr2 (77%, 87% brsm, 71:16 dr) H OBn HO Me Me BnO 28. AlH3 (94%) 29. Me2C(OMe)2 O TBSO 30. DDQ, H2O (97%) 31. PDC (90%, 94% brsm) Me O Me 32. H2C=CH(CH2)2Li 33. TBAF (96%) Me Me H OBn O Me Me O O Me BnO 34. cHxMeSiCl2 (99%) HO 35. MeLi (96%) Me 36. TPAP-NMO (80%) Me H OH OBn O H OBn 37. PdCl2, DMF-H2O (98%) SiMe2cHx Me Me OBn MeO2C BnO OTBS (68%, 4:1 dr; although the alcohol stereocenter is erased after step 31) OBn Me Me O O Me BnO Me OBn OH Me Me CHO N Me Me 27. NaOMe (98%, 23:2 dr) (Minor enantiomer can be epimerized) Me BnO OMe OTBS OBn 25. 0.5 N HCl (97%) 26. TPAP-NMO (92%) Me Me PMBO Me OTES TBSO OTBS OPMB BnO Me O Me PMBO Me Me OBn Me 21. SmI2 (70%) TBSO 22. Ac2O (87%) CHO Me 23. DBU (91%) O TBSO PMBO BnO Br O Me OBn Me TESO 60 steps, ~0.02 % overall yield Me Br BnO Me 11. TBSOTf 12. DIBAL 13. Swern [O] (94%) 14. MeMgBr (99%) OTBS 15. Swern [O] (97%) BnO Me BnO Me OBn O O Me O TBSO PMBO OTBS Me O Me 38. TiCl2, LiAlH4 (43-71%) Me Me O Primarily an aldol-based strategy! O H OBn Me Me O O Me HO HO HO 39. Na-NH3 Me 40. TBAF (100%) Me Me H OH OH SiMe2cHx 8 Teruaki Mukaiyama - !"# $% Y. Ishihara Formation of the D-Ring Oxetane: End-Game Words of Wisdom... Me Me HO O AcO O HO HO HO HO 41. (Cl3CO)2CO Me 42. Ac2O (84%) Me Me Me 43. 3N HCl Me 44. TESCl (83%) 45. TPAP-NMO H (76%) HO O HO O OTES Me Me Me H O O Me 46. (Imid)2C=S 47. P(OEt)3 (53%) 48. PCC (78%) AcO O OTES Me Me TESO 51. CuBr, PhCO3tBu Me 49. K-Selectride (87%) 50. TESOTf (98%) O H 52. CuBr (58%) O O Me AcO O OTES Me Me 53. OsO4 (92%, 96% brsm) Me TESO Me O H O AcO Br 54. DBU (42%, 81% brsm) 55. Ac2O (91%) AcO O OH Me O O H AcO O 58. TESCl (87%, 92% brsm) 59. Side Chain Acid, [(2-Py)O]2CS, DMAP (88%, 95% brsm) Me HO Me 57. HF-py (96%) HO BzN Me O 56. PhLi (94%) Ph O OTES Me Me TESO O Me BzO 60. TFA (94%) H AcO O baccatin III O OH O PMP Side Chain Acid Baran Lab Group Meeting TAXOL!!! [...] The development of novel synthetic methodologies is now an essential part of synthetic organic chemistry. The most fruitful approach to this problem, I believe, is 'to let something come from nothing', i.e. we must discover new possibilities in a field previously neglected, and create innovative concepts in synthetic organic chemistry. It is absolutely essential to carry out one's research on one's own ideas, unaffected by the current fashion. I have tried to explore new methodologies in this way, keeping in mind the words 'no imitation' that Professor Toshio Hoshino said to me at the start of my research career. An active and original programme is vital to the execution of basic research. Only the research work that has been fostered with one's own hands, thus spreading its roots deep and never being washed away, will survive forever. Fashionable works may soon be forgotten, as quickly as floating weeds. Needless to say, an unpretentious, enduring, and systematic attack on problems is required if you want to obtain fruitful results in basic research. [...] I have submitted all my articles to Chemistry Letters since the first publication in 1972, because I think that the results of one's chemistry should be published in journals of one's country. [...] I have tried to change my topics about every four years. I admit that a deep and thorough study on a single topic is very important for a researcher; however, I think it is more significant to change topics at various times, especially in the fields of explorationof new methodologies. Perhaps it is related to my own nature - I do not like to stick to a particular matter for too long. New ideas come to me, one after another, and I encourage myself to build new hypotheses and initiate new active research programmes, purposely putting the pressure on myself. In the first year, I learn various things about the new problem itself. In the second year, I begin to get some possibilities and then in the third year I have some more results. The fourth year is harvest time, and at the same time I plan what to do next. Thus, I have always pursued new research programmes. There may be many things still left undone when I take the move on to the next programme, and if any treasures remain they will be left to the hands of many other able chemists. [...] (From the review of his life's works in Challenges in Synthetic Chemistry, Clarendon Press, Oxford, 1990, 225 pages.) In basic science it is critical to find the first approach (“seeds-oriented” work), but it is equally important to optimize the approach and to develop new systems (“needs oriented”). In either case, ample time and energy need be invested before a chemist can garner anything useful. Once the fundamental target is reached, however, the whole process appears so easy that anyone else could have done it, like the episode of “Columbus! egg”. However, to win through to the result, a researcher must go through unrewarding months and years of making hypotheses and repeating experiments, and this is exactly what makes a chemist. The most important thing here is “not to imitate others”. If someone has already been involved with the topic, dare not to stick to the same topic, but find something of your own. This is our code, which should never be forgotten. Experience and the accumulation of experiences play a very important role in pursuing research work. If a mature hypothesis does not lead you to a satisfactory result, just try once more from the beginning and continue to do the experiments. You will then eventually find an interesting clue, unless you give up half way. Chemistry is still more or less unpredictable. Wisdom learned not from books or what others said but from one's own experience—which I call “chemical wisdom”—will become a motivating force for associating problems with questions that give you a different idea. Those who have accumulated a lot of such “chemical wisdom” should be able to formulate a seminal hypothesis by the association of small clues. By overcoming difficulties without compromise, hard and steady work done (especially at the time of one's youth) will give you love for your work and will furnish you with “chemical wisdom”, and consequently will lead you to successful later development. The fun of chemistry is in its unexpectedness. There are times when you come to face-to-face with an unexpected phenomenon while carrying out experiments. You simply have to be sufficiently aware and open to accept the seemingly unbelievable. There are still many more valuable ideas remaining to be discovered. The question is how to find them and how to develop them into new possibilities. (From the review of his life's works in Angew. Chem. Int. Ed. 2004, 43, 5590-5614.) 9