Y. Ishihara - 向山 光昭 Baran Lab Group Meeting

Bibliography: An excerpt from Mukaiyama's publication list, published in Heterocycles 2000, 52, 13-66. - Jan 5 1927: Born in Nagano, Japan - 1948: B.Sc., Tokyo Institute of Technology - 1953: Assistant Professor, - 1957: Ph.D., - 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 Prof. Teruaki Mukaiyama - 2002: Move to Kitasato University

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 , 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 non- Japanese nominees and the other from the Japanese nominees.

Publications: Close to 1000 to date. - Science ...1 (Perspective) - Angewandte CIEE ...5 (4 Reviews) Chemistry Letters ...632 - JACS ...22 Bull. Chem. Soc. Jpn ...165 - JOC ...22 - Tetrahedron Lett. ...26 Chemistry Letters, founded - Tetrahedron ...11 in 1972 by Mukaiyama. - Tetrahedron: Asym. ...1 - Minor/inaccessible papers/abstracts <100

1 Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting

Mukaiyama's early years: An organophosphorus chemist Synthesis of phosphoric as an application of oxidation-reduction condensation: O Me Me Me Me

BnOH + R3P + EtO2C-N=N-CO2Et BnO-PR + EtO C-N-NH-CO Et PhNCO + EtNO2 Ph Ph + 3 2 2 N N cat. R3N N N N N H H O O=PR3 + EtO2C-NBn-NH-CO2Et O O J. Am. Chem. Soc. 1960, 82, 5339; O J. Org. Chem. 1962, 27, 3651. ROH + (EtO)2P-OAllyl + EtO2C-N=N-CO2Et RO-P(OEt)2 + EtO2C-NAllyl-NH-CO2Et P(OEt)3

RNCO + P(OEt)3 RNC + O=P(OEt)3 O. Mitsunobu, M. Yamada and T. Mukaiyama, Bull. Chem. Soc. Jpn 1967, 40, 935. Desired product for Mukaiyama OEt EtO OEt O O Ph Six months later... the : P(OEt)3 P P(OEt)3 O O C O Ph Ph R1OH + R P + EtO C-N=N-CO Et + R2CO H ! 3 2 2 2 Ph Ph Ph O. Mitsunobu and M. 1 2 Yamada, Bull. Chem. Ph Ph R O-PR3 + EtO2C-NH-NH-CO2Et + R CO2 Side product: Diphenylketene dimer Soc. Jpn 1967, 40, 2380. O=PR + EtO C-NBn-NH-CO Et + R2CO R1 J. Org. Chem. 1964, 29, 2243. 3 2 2 2 Mitsunobu later expanded the scope of this reaction to include other . Harnessing the ability of phosphorus (III) to reduce...

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 Oxidation-Reduction Condensation: an Extension to the Mitsunobu Reaction (2003) from the same reaction, such that a net loss of water is observed. Essentially, a dehydrating agent, that takes place under neutral conditions. R2CO H Reductant present within Me 1 2 2 1 Ph2POR R CO2R substrate; adamantanols and DMBQ (RCO2)2Hg + R'3P (RCO)2O + Hg + R'3P=O Hg is a good [O] for this reaction! tert-butyl , among other 1 O O R1 = 1º or 2º, 85-96%; 3º, 72-82% 3º R OH, work well; stereospecific inversion for 1º 2 RCO H + Ar Hg + R' P 2 2 3 2 RCO2H + PhCO-CH=CH-COPh + R'3P or 2º; 70-100% inversion for 3º; Me 1 ArOH 1 Ph2POR ArOR mild and neutral reaction, even -H2O 2[H] [O] -H2O 2[H] [O] DMBQ DMBQ works for chloroacetic acid. (RCO) O + Hg + 2 ArH + R' P=O (RCO) O + PhCO-CH CH -COPh + R' P=O 2 3 2 2 2 3 R1 = 1º or 2º, 78-92%; 3º, 62% Chem. Lett. 2003, 32, 300; Bull. J. Org. Chem. 1963, 28, 2024. J. Org. Chem. 1964, 29, 1385. Even 2,6-disubstituted give 70% yield Chem. Soc. Jpn 2003, 76, 1645.

Variations in the type of products made: Esters, , , thioethers, formations: pyrophosphates... also useful in peptide and nucleotide chemistry. R2OH Ph POR1 R2OR1 not formed! Very low yields with DDQ or 2 1 Variations in the type of oxidant used: coupling using DMBQ chloroanil; chiral center at R N Ph PySSPy: Tetrahedron gets inverted; coupling of 3º-3º O Lett. 1970, 22, 1901. 2 ROH are not possible but 2º- 3º 1 R OH 2 1 Precedes Corey- Ph2POR R OR ROH couplings work. O Fluoranil Ph N N S S N Nicolaou macrolac- Chem. Lett. 2003, 32, 984. tonization (JACS 1974). unpublished results

2 Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting

Mukaiyama's Named Reagent: N-Methyl-2-Chloropyridinium Iodide Various hydroxyl activations: OH R3 R3 O 1. Pyridinium salt, Et N 1 2 3 R CO2H R OH 1 2 1 2 3 1 2 + 1 2 1 R CO2R + R R 2. R MgBr R R R R N X base N O R base N O Me I fast Me slow Me 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. X = Cl or Br in original reference: Chem. Lett. 1975, 1045. OH 3 1 R H It turns out that the nature of the alkyl group on , the X group and the R 1. Pyridinium salt, Et3N counterion all affect the yields of the coupling reactions in subtle fashion. • R2 2. R3MgBr, cat. CuI When R1 and R2 are 3º, the yields are dismal with the original Mukaiyama reagent, R1 R2 Chem. Lett. 1978, 785. 1 2 t but using 2-bromo-N-ethylpyridinium tetrafluoroborate with R = R = Bu resulted SPh in a 54% yield (Bull. Chem. Soc. Jpn 1977, 50, 1863). 4 2 4 R Pyridinium salt, Et N R R R1 or R2 can also be SPh, R2 R3 3 generating vinyl sulfides: These findings opened a whole new area of study for -neutral dehydration R1 then LiI 1 3 reactions: The utilization of onium salts of aza-arenes (Review in Angew. Chem. Int. OH R R Chem. Lett. 1978, 413. Ed. 1979, 18, 707-721). 3 Various functional groups generated from ROH + onium salt: Types of onium salts used: R 2 - Inverted ROH (acyclic only) from Cl3CCO2H, followed by saponification, Mukaiyama's Z R N version of a Mitsunobu inversion: Chem. Lett. 1976, 893; + - + - X - RCl from LiCl (acyclic), R3NH Cl or R4N Cl (cyclic): Chem. Lett. 1976, 619; 1977, 383; N N Cl R4 N X - 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, R Y 1 Me R Y 437; FSO3 R = Me or Et; X = F or Cl; R1 = Me, Et or Ph; R2 = H, Me or - RNH2 (acyclic and cyclic) from LiN3 + HMPA, followed by LiAlH4 or H2/Pd reduction: Y = BF4 or FSO3; Z = O or S Ph; R3 = H or Me; R4 = H or Me; Chem. Lett. 1977, 635; - ROPO2OR' (acyclic) from R'OPO2H; exception to the rule - a benzoxazole is used, X = F, Cl or Br; Y = I, BF4 or TsO derivatives formed: 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. O O O O O O S If R has a stereocenter at the carbon bearing the hydroxyl group (i.e. 2º; 3º are R2 not tolerated), it will be inverted, unless R is a sugar, in which anomeric effects R1 N R1 N R1 N R1 SR2 R1 F and neighboring group participation dominate. S R3 Various dehydrations and dethiohydrations: Chem. Lett. Chem. Lett. Chem. Lett. Chem. Lett. Chem. Lett. OH H 1975, 1163. 1976, 711. 1977, 1443. 1976, 711. 1976, 303. 2 - + N N R RNHCS2 Et3NH R-N=C=S Pyr. salt, Et3N R1 Chem. Lett. 1977, 573. Without overlooking the macrolactonization... then H O R1 R2 2 O R1NHC(=S)NHR2 R1-N=C=N-R2 HO OH O HO O OH O Me O Me Chem. Lett. 1976, 1397. Chem. Lett. 1977, 575. Me Me n n O HO HO R1NHC(=S)OMe R-N=C=O OH OH R O O 2 O O Chem. Lett. 1977, 1345. Chem. Lett. 1976, 49: "their R1 Pyr. salt R1 OH 3 RCO-NH2 R C N procedure requires rather ele- Me Me Me Me R3 R unpublished vated Tº; lactonized in better Et3N OH R2 yields than those obtained by J. Am. Chem. Soc. 2003, 125, 5393; RNH-CHO R N C previous methods". Angew. Chem. Int. Ed. 2002, 41, 1787. Chem. Lett. 1977, 179. Chem. Lett. 1977, 697.

3 Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting

Mukaiyama's Claim to Fame: The Mukaiyama A switch to silyl enol : Use of TiCl4 as Lewis acid

O OSiMe3 Lewis acid or OH O OH O O OSiMe3 2 O OH Chem. Lett. 1973,1011; Me3SiCl R CHO + R2 Lewis base J. Am. Chem. Soc. R1 H Y R1 Y R1 Y R1 Me base R1 TiCl R1 R2 1974, 96, 7503. then aq. and/or 4 workup R2 R2 R1 can be H; Reactivity as : RCHO (#78°C) > RCOR' (0°C) >> RCO2R' Y = H, alkyl, Ar, OR, SR Enol silane geometry rarely affects Chem. Lett. 1975, 741; Bull. Chem. Soc. Jpn 1976, 49, 2284. the syn/anti geometry of the product Expanding substrate scope: ...vs. the Evans aldol reaction: OR OSiMe3 OR O O O O O OBBu2 O O OH R3 1 + 5 1 5 R OR R R R Chem. Lett. 1974,15. Y Y 2 R2 TiCl4 R2 Bu BOTf R H 2 O N 2 O N O N R R4 R3 R4 i Pr2NEt then [O] Y 3 Br R Br OH workup OMe 1 O 4 Me Me Me 4 R R OMe R 4 Me Me Me 1 + R R R1 TiCl4 PhMe, Y = alkyl, Ar, OR, SR, Cl, Br but not H "Evans syn aldol" R2 OSiMe 3 R2 OMe O reflux R2 R3 But Evans boron enolate! Rather, Evans = use of chiral oxazolidinone for aldol. Chem. Lett. 1975, 527. ! O OSiMe3 OH O 3 History behind boron-mediated aldols: + R Chem. Lett. 1975, 989; 1976, R1 R2 OR5 R1 OR5 TiCl 2 769. OBR2 Brown et al., JACS 1967, 89, 5708 & 5709; for other 4 R preparations of vinyloxyboranes, see: Hooz et al., R4 R3 R4 MVK + BBu3 n-Pn JACS 1968, 90, 5936; Tufariello et al., JACS 1967, Me 89, 6804; Koster et al., Angew. Chem. 1968, 80, 756. Mechanism of the Mukaiyama aldol reaction:

X3 But no one used boron enolates in aldol reactions! SiMe3 M MX3 X O O O OH O O O X3M X Mukaiyama's fortuitous discovery: 3 1 3 1 3 1 1 R R R R R OH O R H silyl enol R H #Me3SiX aq. workup Bu2B-SBu expected product: Instead: ether R2 R2 R2 Me2CO H2C=C=O h" H2C=C(SBu)2 Me SBu TS for Z-enol silanes: TS for E-enol silanes: Me MX3 MX3 O H O H Bull. Chem. Soc. Jpn 1971, 44, 3215; mechanism corrected in J. Am. 2 2 OH O 2 2 Chem. Soc. 1973, 95, 967 and Bull. Chem. Soc. Jpn 1973, 46, 1807. R H R H R H R H X3M X3M 1 O R1 R1 R3 1 O R1 Bu R H R H 2 2 Me SiO R3 Me SiO R3 R R3 OSiMe R3 OSiMe OBBu2 B 3 3 3 3 Me2CO O O Z-A Z-B anti E-A E-B H C=C=O + Bu B-SBu 2 2 MX3 MX3 O H O H 2 2 OH O 2 2 SBu Me SBu H R H R H R H R Me X3M X3M R1 H O R1 R1 R3 R1 H O R1 The "current" method to generate boron enolates: 3 3 2 3 3 R OSiMe3 R OSiMe3 R Me3SiO R Me3SiO R O OBBu2 2 O OH Z-C Z-D syn E-C E-D Bu2BOTf R CHO Chem. Lett. 1976, The most favorable conformations: A and D. If R2 = large and R3 = small, D is favored; if 1 i 1 1 2 559; 1977, 153. R Me Pr2NEt R R R R2 = small and R3 = large, A is favored. Conclusion: Z/E of the enol silane rarely matters!

4 Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting

Lewis acid-catalyzed Mukaiyama aldol reactions: Titanium tetrachloride reactions (See review in Angew. Chem. Int. Ed. 1977, 16, 817-826): X 3 First catalysis: Trityl salts Characteristics: Strong Lewis acid, strong oxophile and dehydrater; may act as an M SiMe3 electrophile for C!C " bonds. O O O O (Chem. Lett. 1985, 447, Me Si-X 3 1535 and 1871); in situ eg. TiCl + MX + 4 R1 R3 R1 R3 4 Me3Si : SnCl2, Me3SiCl cyclohexanol + benzene cyclohexylbenzene unpublished needs to (Chem. Lett. 1987, 463). (91%) 2 transmetallate 2 R R Typically 1-10 mol%. SEt EtSH, TiCl4 Chiral Lewis acids: The true strength of the Mukaiyama aldol reaction. + Ph OH CH Cl Ph SEt Ph SEt Sn(OTf) , 2 2 2 Chiral diamine, eg. O OSiMe3 Bu Sn(OAc) , OH O O O 2 2 RSH, SR H2O, Bull. Chem. Soc. + chiral diamine 3 TiCl 3 TiCl 3 R 4 R 4 R Jpn 1972, 45, R H SEt R SEt R1 R1 R1 CH2Cl2, !78 °C N Et3N 3723; Chem. Me Me Me Lett. 1973, 479. NHNaph R2 R2 Z enolates work well; E 70-96%; Vinyl chlorides work as well. 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. Aldol-like reactions: OMe TiCl4, OiPr i Enantioselective diol formation: Ti(O Pr)4 Proposed TS for -OBn: + Sn(OTf) , OSiMe3 Ph OMe (80%) Ph O 2 R2 O OSiMe3 Bu Sn(OAc) , OH O 2 2 N R3 Me Ac Me Chem. Lett. 1975, 319. + chiral diamine N Trioxane, R H SEt R SEt Sn TiCl4 CH Cl , !78 °C OTf (Mechanism and stereoselectivity?) 2 2 R1 OBn OBn O Bn Me O 73%, O Chem. Lett. 1974, 381 and 1181. O H O dr 17:3 O Chem. Lett. 1990, 1019; Replacing 72-88%; EtS Bn by TBS results in the syn >96% de, H >95% ee R OSiMe3 i O product (Chem. Lett. 1991, 1901.) O O TiCl4, Ti(O Pr)4 S S OSiMe3 + But the above chiral Lewis acid reagents are stoichio- Ph then HSCH2CH2SH Ph metric! The chiral diamines are "promoters"... Reactions on , -unsaturated ketones work as well. Chem. Simple solution: Replace CH Cl for CH CH CN (Sn-Si exchange is faster; Chem. # $ 2 2 3 2 Lett. 1974, 1223; Bull. Chem. Soc. Jpn 1976, 49, 779. Lett. 1990, 1455), and add the two substrates slowly into the catalyst mix to prevent undesired Me3SiOTf-promoted, racemic aldol formation. Titanium tetrachloride reduced in situ:

Lewis base-catalyzed Mukaiyama aldol reactions: -TiCl4/LiAlH4: ArCl ArH RCH(OMe)2 RCH2OMe Li SiMe Me Me Me 3 Ph Ph OSiMe3 O O O O Ph S S H H 2 OMe LiNR2 Me Me3Si-NR2 1 2 1 2 PhCHO + R R R R MeO MeO OMe OMe Solvent Ph OMe Ph OMe turnover unpublished Me Me Me Me Me Chem. Lett. 1973, 291. -TiCl /Zn: PhCHO PhCH-CHPh PhCH=CHPh LiNPh2 was initially used over LDA, but Li 2-pyrrolidone was optimal; THF did not allow 4 + Chem. Lett. 1973, 1041; turnover but DMF did; a milder version using LiOAc as a base in DMF/H2O systems OH OH precedes TiCl3-based allowed the compatibility of hydroxyl and carboxyl functionalities in the substrate room T°, THF: 98% 1% McMurry coupling (Chem. Lett. 2002, 182 and 858; 2003, 462 and 696). reflux, dioxane: 0% 98% (JACS 1974, 96, 4708).

5 Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting

Miscellaneous reactions Chiral !-hydroxyaldehyde formation: Chem. Lett. 1983, 935; Sugar chemistry: N N anomers are separable and Dean-Stark 1. RMgX RO RO the ! can be converted to the PhCOCHO + NPh H NPh O O N PhH 2. NH4Cl OH N F F " form using BF3; at the time, H H Ph single Ph Ph R this reaction could only be PhHN diastereomer O O Me OTs O O done using anhydrous HF; O OH R H O+ reaction discovered from N NPh CHO 3 Me Me Et3N Me Me analogy of RCO2H to RCOF. Mg O Overall yield: 67-82%; optical purity > 94%. Cram- Ph R chelate TS Chem. Lett. 1978, 1253; 1979, 705. OBn OBn X OH BnO BnO O SnCl , AgClO O Some more Grignard chemistry: 2 4 O DEAD does not give as high yields BnO F + BnO t HO PrMgBr or BuOMgBr (Yoneda et al., JACS 1966, 88, 2328). O 4Å MS OBn BnO BnO Named reaction (??): "Mukaiyama BnO 84% O R OH PipCO-N=N-COPip R H Oxidation"; 2° to ketones BnO dr = 84:16 BnO O (89-96%) OMe BnO work equally well (Bull. Chem. Soc. Pip = N-substituted piperidine Jpn 1977, 50, 2773). BnO OMe Chem. Lett. 1981, 431. Yields and stereoselectivities are typically better than Mixed ether formation from acetals: mixed acetals work best (Chem. Lett. 1975, 305). Cl or Br analogs due to the C-F bond strength at the anomeric position: C#F Cl 552 kJ/mol; C#Cl 397 kJ/mol; C#Br 280 kJ/mol. TiCl + BrMg 4 Protic acid-catalyzed activation: Ph O O (98%) O Ph BnO BnO BnO O cat. HX BnO O Cl + BnO F HO BnO O Some sulfur chemistry: O 5Å MS OBn BnO BnO BnO O BnO Solvent LDA, then BnO O O BnO Ph OMe BnO OMe S NtBu Chem. Lett. 2000, 1250; if DBU is used instead of LDA, 2° amines to imines, (Chem. Lett. 2001, 390) TfOH, Et2O: 98%, !/" = 88:12 Tf2NH, PhCF3: 99%, !/" = 9:91 Cl and N,N-disubstituted hydroxylamines to nitrones HClO4, Et2O: 98%, !/" = 92:8 HSbF6, PhCF3: 100%, !/" =12:88 (ARKIVOC 2001, 10, 58) can be formed. (93%) C4F9SO3H, Et2O: 99%, !/" = 88:12 HB(C6H5)4, PhCF3: 99%, !/" = 7:93 Chem. Lett. 2001, 426; Bull. Chem. Soc. Jpn 2002, 75, 291. Ph S NHtBu O Named reaction (??): "Mukaiyama Chiral "-substituted carboxylic acid formation: NCS or NBS (1.1 eq) Oxidation"; 2° alcohols to ketones O O O R OH R H work equally well. (Chem. Lett. 2001, O Ph R1 O Ph R1 O Ph K2CO3, 4Å MS, CH2Cl2, 846; Tetrahedron 2003, 59, 6739.) 2 TiCl4 R MgBr 0 °C, 30 min (86-100%) R1CHO + Pyr. >75% 2 MeO C CO Me Me Me R Me Me Me 2 2 MeO2C N >76% N N DMAD O >17:3 dr O O Me Me Me Me S + + SMe H3O R1 O Me COPh Me Ph prepared from ephedrine E- O hydrochloride in 3 steps PhOC CO2Me Chem. Lett. 1977, 1165; Bull. Chem. Soc. Jpn 1978, 51, 3368. R2 OH Tet. Lett. 1970, 29, 2565. DMSO: 88% 0% PhH: 27% 70%

6 Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting

Total Synthesis Targets - Application of Synthetic Methodology Integerrimine (Chem. Lett. 1982, 57 and 455): NH2 O O OH O N 1) Me CuLi; CO Me 1) MCPBA (76%) N Me 2 2 Me O 2) CH N (80%) CO2Me 2) LDA; MeCHO O O Me Me O O 2 2 CO2Me N N HS O P O P O Me Me N N Me H H O O O OH H H O H H I N Cl O H 1) (98%) 1) T s O N F (60%) O P O Me O Me Coenzyme A - Coupling with [O]-[H] condensation Me Chem. Lett. 1972, 595. HOCH2CH2TMS OH CO2H 2) LiOH (100%) Me 2) LiOH, H2O2 (71%) Me O O Me Me Me Me Me n Bu Me OH N Me OH Me OH Me OH O Me Me O O dl-Variotin - Ti coupling of acetals Me O Vitamin A - Ti coupling of acetals with silyl enol ethers, and amide CO H 2 CO CH CH TMS via one more with silyl enol ethers formation using Mukaiyama reagent 2 2 2 Chem. Lett. 1975, 1201. Mukaiyama Chem. Lett. 1977, 467; Bull. Chem. condensation Soc. Jpn 1978, 51, 2077. N integerrimine

O O F1! Antigen (Chem. Lett. 2001, 840; Bull. Chem. Soc. Jpn 2003, 76, 1829): O Ph Me N Me OBn BnO A + B + cat. H+ + MS 5Å, then C + NIS O NHMe O Me A N BnO F One-Pot Sequential O Me O(4-Me)Bz Stereoselective N N Glycosylation H H BnO (89%) B HO O Indolmycin - Methyl group introduction via a chiral oxazepine appendage SEt OBn BnO BnO Chem. Lett. 1980, 163. N(4,5-Cl )Phth BnO 2 O O O BnO O O OH BnO BnO O(4-Me)Bz BnO Me Malyngolide - Quaternary C O Cl2Phth-N O O OH OH N stereocenter synthesis via BnO BnO asymmetric !-hydroxyaldehyde NHCbz NHCbz N N N synthesis 3O 3O n CO2H CO2H C9H19 n Ph Chem. Lett. 1980, 1223. C9H19 Reduction of the , removal of the phthaloyl group, acetylation of two N atoms and removal of all protection groups lead to the F1! antigen.

7 Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting

Total Synthesis of Taxol® (Proc. Jpn. Acad. 1997, 73B, 95; Chem. Eur. J. 1999, 5, 121.) BnO O 16. LHMDS, TMSCl Br BnO Me Me OBn 18 AcO O BnO O 17. NBS 21. SmI2 (70%) TBSO Me Me 19 OH O Ph O Me 18. LHMDS, MeI 22. Ac2O (87%) 12 11 10 9 TBSO Me Me CHO Me 7 23. DBU (91%) Me 8 6 19. 1N HCl (83%) Ph N O 13 15 16, 17 20. Swern [O] (95%) O TBSOPMBO Me H Me 3 5 Me 14 1 4 OBn OH 2 PMBO H O Me HO AcO PMBO OBn TESO BzO 20 BnO O OTES Br 60 steps, ~0.02 % overall yield TBSO 25. 0.5 N HCl (97%) Me 26. TPAP-NMO (92%) Me Me OBn BnO Me Me OBn Me tBuLi, CuCN 27. NaOMe (98%, 23:2 dr) MeO Me OTBS Me (Minor enantiomer can be CO Me (92%, 99% brsm) 2 PMBO OBn epimerized) OMe OH O OTBS OPMB Me Me BnO O OH BnO O O OMe Me Me BnO TBSO 28. AlH3 (94%) TBSO 1. Swern [O] (89%) , Sn(OTf) Me Me Me Me 2 29. Me2C(OMe)2 32. H2C=CH(CH2)2Li 2. HC(OMe)3 (93%) OTBS HO MeO Me Me 33. TBAF (96%) CO Me 3. LiAlH (90%) CHO 30. DDQ, H2O (97%) 2 4 31. PDC (90%, 94% 4. Swern [O] (85%) Me H Me H OMe brsm) N PMBO OBn O OBn N , Bu Sn(OAc) Me Me Me 2 2 Me Me BnO O O BnO O O OMe Me Me BnO HO 34. cHxMeSiCl HO Me Me OBn 6. PMB Prot. (95%) Me Me OBn 2 (99%) 36. TPAP-NMO (80%) MeO 7. LiAlH4 (86%) OTBS CO Me OHC Me 35. MeLi (96%) Me 37. PdCl , DMF-H O 2 8. TBSCl (93%) MgBr 2 2 2 Me Me (98%) OMe OH 9. AcOH (87%) PMBO TBSO (77%, 87% brsm, H H 71:16 dr) OH OBn O OBn (68%, 4:1 dr; although the alcohol stereocenter SiMe2cHx is erased after step 31) Me Me Me Me 11. TBSOTf BnO OBn BnO OBn BnO O O HO O O Me Me 12. DIBAL Me Me Me Me 13. Swern [O] (94%) Me O 38. TiCl2, LiAlH4 HO MeO C (43-71%) HO 2 14. MeMgBr (99%) Me Me HOPMBO OTBS 15. Swern [O] (97%) O TBSOPMBO OTBS 39. Na-NH3 Me Me Me H 40. TBAF (100%) H OBn OH Primarily an aldol-based strategy! O OH SiMe2cHx O 8 Y. Ishihara Teruaki Mukaiyama - !"#$% Baran Lab Group Meeting

Formation of the D-Ring Oxetane: End-Game Words of Wisdom... Me [...] The development of novel synthetic methodologies is now an essential part of synthetic organic Me HO O AcO O chemistry. The most fruitful approach to this problem, I believe, is 'to let something come from HO HO O HO HO OTES nothing', i.e. we must discover new possibilities in a field previously neglected, and create innovative Me 41. (Cl3CO)2CO Me concepts in synthetic organic chemistry. It is absolutely essential to carry out one's research on one's Me 42. Ac2O (84%) Me own ideas, unaffected by the current fashion. I have tried to explore new methodologies in this way, Me Me 43. 3N HCl keeping in mind the words 'no imitation' that Professor Toshio Hoshino said to me at the start of my Me 44. TESCl (83%) Me research career. 45. TPAP-NMO An active and original programme is vital to the execution of basic research. Only the research H H (76%) work that has been fostered with one's own hands, thus spreading its roots deep and never being HO O washed away, will survive forever. Fashionable works may soon be forgotten, as quickly as floating HO O weeds. Needless to say, an unpretentious, enduring, and systematic attack on problems is required if O 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 AcO O think that the results of one's chemistry should be published in journals of one's country. [...] Me OTES I have tried to change my topics about every four years. I admit that a deep and thorough study on 46. (Imid)2C=S Me a single topic is very important for a researcher; however, I think it is more significant to change topics 47. P(OEt)3 (53%) Me at various times, especially in the fields of explorationof new methodologies. Perhaps it is related to 48. PCC (78%) t my own nature - I do not like to stick to a particular matter for too long. New ideas come to me, one TESO 51. CuBr, PhCO3 Bu Me after another, and I encourage myself to build new hypotheses and initiate new active research 49. K-Selectride (87%) 52. CuBr (58%) programmes, purposely putting the pressure on myself. 50. TESOTf (98%) H O In the first year, I learn various things about the new problem itself. In the second year, I begin to O 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 O programmes. There may be many things still left undone when I take the move on to the next AcO O AcO O programme, and if any treasures remain they will be left to the hands of many other able chemists. [...] Me OTES Me OTES Me Me (From the review of his life's works in Challenges in Synthetic Chemistry, Clarendon Press, Oxford, 1990, 225 pages.) Me 53. OsO4 (92%, Me TESO 96% brsm) TESO Me Me In basic science it is critical to find the first approach (“seeds-oriented” work), but it is equally Br 54. DBU (42%, important to optimize the approach and to develop new systems (“needs oriented”). In either case, H H O O 81% brsm) O ample time and energy need be invested before a chemist can garner anything useful. Once the AcO fundamental target is reached, however, the whole process appears so easy that anyone else could O 55. Ac2O (91%) O have done it, like the episode of “Columbus! egg”. However, to win through to the result, a researcher O O 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 AcO O someone has already been involved with the topic, dare not to stick to the same topic, but find Me OH something of your own. This is our code, which should never be forgotten. Me 58. TESCl (87%, 92% brsm) 59. Side Chain Acid, [(2-Py)O] CS, Experience and the accumulation of experiences play a very important role in pursuing research 2 work. If a mature hypothesis does not lead you to a satisfactory result, just try once more from the 56. PhLi (94%) Me DMAP (88%, 95% brsm) HO beginning and continue to do the experiments. You will then eventually find an interesting clue, unless 57. HF-py (96%) Me 60. TFA (94%) 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 H O motivating force for associating problems with questions that give you a different idea. Those who HO AcO BzO 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 Ph baccatin III work done (especially at the time of one's youth) will give you love for your work and will furnish you O 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 BzN OH TAXOL!!! an unexpected phenomenon while carrying out experiments. You simply have to be sufficiently aware O 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. PMP Side Chain Acid (From the review of his life's works in Angew. Chem. Int. Ed. 2004, 43, 5590-5614.)

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