Isao Kuwajima. Supervised Work (Corey) Born Nov BS (Tokyo Institute of Technology) LiCuBu 2 C 7H15 OH

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1 Yuzuru Kanda Baran lab Group eting Biography Supervised Work (Corey) Born ov 11 I BS (Tokyo Institute of Technology) CuBu 2 under T. Mukaiyama C D in chemisty (in the same lab) ex/ 2 = 5.7: Postdoctral (arvard Univ.) under E.J. Corey C 715 > 90% JACS, 1970, esearch Assistant (Tokyo Institute of Technology) Associate Professor (Aoyama Gakuin Univ.) Associate Professor (Tokyo Institute of Technology) Br CuC2C Professor (Tokyo Institute of Technology) C TL, 1972, Professor Emeritus (Tokyo Institute of Technology) C715 TF I C 715 I Kitasato Univ. Kitasato Inst. for fe Science Awards and onors Top Five Most Cited Papers Japan Chemical Society Award, Director of Japn Chemical Society, Carbon-carbon bond-forming reactions of zinc homoenolate of esters. A Chief editor of Bull. Chem. Soc. Jpn., novel three-carbon nucleophile with general synthetic utility, ead of the Society of Synthetic rganic Chemistry Japan Kanto branch, JACS, 1987, 109, (154 citations) Vice-president of the Society of Synthetic rganic Chemistry Japan. Supervised Work (Mukaiyama) g g 2 g 2 1 P g P 3 C Ar C Enantioselective total synthesis of taxol, JACS, 1988, 120, (118 citations) Ar P 3 Enantioselective total synthesis of ( )-taxol, JACS, 2000, 122, (128 citations) 3 P JC, 1963, 917. JC, 1963, JC, 1964, Bull. Chem. Soc. Jpn., 1965, P P Ar = C C C C = nbu BrMg 1 C C Corey lab C CyMgBr Cy Cy P 3 TL, 1969, 23. other supervised works JC,19666, 32. TL, 1966, TL, 1967, Bull. Chem. Soc. Jpn, 1968, 1491 Chlorosilane-accelerated conjugate addition of catalytic and stoichiometric organocopper reagents, Tet, 1989, 45, (104 citations) Key Words organo sulfur, selenium, silicon chemistry, organo copper chemistry,mukaiyama aldol, homoenolate, natural product synthesis, bioactive molecules. 3/MPA-accelerated conjugate addition of catalytic copper reagent. Stereoselective synthesis of enol silyl ethers of aldehydes, TL, 1986, 27, (112 citations)

2 Baran lab Group eting Interest in rgano Sulfur and Dialkylcopper thium Chemistry S S S S S CL, 1972, 291. S Ac S S Cu 2 Synthetic Utility of "F " 6:4 TBAF, MS4A TF S P(Ar) ºC P S TL, 1972, 649. TL, 1972, 737. S =, 0 ºC, 40:33 = nbu, 30 ºC, 62:14 Alkyl-X S S CL, 1974, 625. "naked enolate" JACS, 1975, * TBS group was utilized in synthesis of prostaglandin in 1972 ETSA (1-1.1 eq) TBAF (0.003 eq) no solvent rt ETSA TBAF (cat) TF reflux 98% distilled ETSA TBAF (cat) TF 78 ºC ETSA = JACS, 1976, :8 stereoelectronic control exclusive axial attack (Z) C TBAF (cat) 97% 95% w/ LAD, MPA 52% w/ 3 F (2 eq) 3% w/o ETSA TBAF (cat) C C Mukaiyama-Michael stoichiometric TBAF ETSA TBAF (1 mol%) TBAF (cat) enal TBAF (cat) 0 ºC TMP, acid/base sensitive 91% (E/Z = 14:86) C Zn 2 ETSA, TBAF; C (E) 84% TL, 1978, one pot 52% JACS, 1977, JACS, 1982, JC 1983, 932. rg. Syn., 1983, 61, 122. Zn competitive stereoelectronic/ chelating effects ax/eq = 56:44 TL, 1976, Tet, 1983, 975. ACIE, 1976, 498.

3 Baran lab Group eting eductive lylation ' ' = or a, Bu ' = or a, TF ' ether or benzene β- effect a, Bu a, δ a = C 2 C 2 ' = δ+ ' a TL, 1976, CL, 1976, 993. Bull. Chem. Soc. Jpn., 1978, ' ' CS JACS, 1977, TL, 1979, 4095 TL, 1977, J.C.S. Chem. Comm., 1977, 76. u - MgBr/ enolate BuBr Bu JACS, 1979, Utility of 1,4-dicarbonyl surrogate Bz Bz BF 3 2 Ac Bz omoenolate ( ) (+) ( ) Bz Sn 4 showdomycin (+)-camphenilone racemic K 250 ºC Bz Sn 4 (Z)-lanceol Bz Bz a, VinylMgBr C 2 I 2, 2 Zn 1. C, F - 2. TFA 1. DMP, LA 2. MgI 3. Pb(Ac) 4 Bz JACS, 1977, 961. JC, 1977, CL, 1978, JACS, 1984, rg. Syn., 1987, 65, 17. MDS, ; Bz 1. 3, 2. TFAA C C J. C. S. Chem. Comm., 1980, 251. M M M JACS, 1977, J. C. S. Chem. Comm., 1979, 708. JACS, 1962, M M M

4 Mg homoenolate Mg Mg Cu homoenolate 1,4-addition 1. vinylmgbr C 7 15 a c TBS TBS VinylMgBr TBS Bu (6 mol%) omoenolate vs alkoxide C 7 15 Mg TBS b d = c : d = 60:40 = c : d = 15:80 = C 7 15 c : d = 6:82 2. Bu; Cu S 2 ; ; enone 51% TBAF C C Bu (1.1 eq) Mg C :0 npr TBS * require this specific Cu(I) source * as the key additive 1,2-addition 56% + 11% desired a:b 63:37 Cy 50:50 20 ºC JACS, 1977, J. C. S. Chem. Comm., 1979, 708. "enolate dance" SM 95% Z/E = 98:2 TL, 1980, JACS, 1984, :65 TL, 1984, JACS, 1985, ipr acid chlorides 0:100 0:100 0:100 TL, 1984, JACS, 1985, Ti homoenolate ipr Ti 4 E + Br Ti Ti Scope and limitations X-ray Ti 3 Ti() 4 (0.5 eq) = ipr or ipr Baran lab Group eting Ti ketone ipr ipr ing cleavage regioselectivity 1. Ti 4 2. PC 3. K : 32 : 28(rac) : 11(rac) ipr ipr Ti 3 Ti 3 C C * from homoenolate preparation accelerates the addition to aldehyde Ti JACS, 1983, 652. JACS, 1986, rganometallics, 1993, JACS, 1986, 3745.

5 Ac Zn homoenolate X Zn ipr 2. Ms depresosterol + Zn 2 X = 1. BS I 2. ai Zn, DMA/benzene ing cleavage regioselectivity Zn 2 > 98:1 Ti ipr 1. LDA; C , a 2. Zn 2 Zn 2 Zn Ms CiPr 1. K(aq); (aq) 2. ptsa JACS, 1985, Zn JACS, 1984, > 95% e.e. TL, 1987, Zn 2 2. C JACS, 1987, Utility of Zn homoenolate JACS, 1984, JC, 1985, TL, 1986, 83. JACS, 1987, TL, 1988, CiPr egishi CiPr S 2 with acetal i(cat) S 2 allyl CiPr C C acid chloride CiPr CuBr S 2, MPA or DMF CuBr S 2, or BF 3 2 cortisone Pd or i CuBr S 2,, MPA ex Baran lab Group eting S 2' allyl Zn 2 Pd, C ex C cojugate addition Br 2 2 CuBr S 2,, MPA Br prepared from ZnI 2 (cat) C Bn CiPr CiPr C C carbonylation C *no racemization homo-reformatsky Zn(Ch 2 C 2 CiPr) 2, CuBr S 2 (cat), MPA, BF 3 2 mcpba iprc npr 3 JC, 1986, JACS, 1989, rg. Syn., 1996, 73, 123.

6 Baran lab Group eting Pd homoenolate ArTf, P 3, [Pd(allyl)] 2 0% benzene, 100 ºC CiPr ipr X [PdL n ] + Tf - C 7 15 JACS, 1988, ther successful metals C M = Sn, SnBu 3, Sb, Bi, Te, Ga, g, (E) 57% 25% M Cd, b, In (Z) 59% TL, 1985, tals do not form homoenolate egio/stereo Controlled thiation Ge,, Pb, Al, Zr, Ta, Cr, Mo, W, Ag rganometallics, 1985, 641. Bu El Se Chemistry S Bu; K-a, 1 1 LDBB S Bu Bu d.r. > 95:5 El 2 2 Bull. Chem. Soc. Jpn., 1980, Bu Synlett, 1990,671. Bu Se, S or LDBB; Ti 4 TIPS TIPS TIPS Ac Se 1,3-addition d.r. = 99:1 Bu; Bu; eductive silyl transfer PC, S TIPS TIPS LDBB CL, 1992, Se Se TL, 1980, JACS, 1993, Se (Se) 2, d.r. > 99:1 d.r. > 99:1 TBS Se Se (Se) TBS 2 3 = 83% * TBS 3 = 70% Se = npr 49% d.r. > 99:1 TL, 1979, 419. TL, 1979, *TBP was used syn:anti > 99:1 S e.e > 99% Bull. Chem. Soc. Jpn., 1981, instead of (Se) 2 1,3-addition Se 2 EWG C a Se 2 K S 2 TL 1983, J. C. S. Chem. Comm., 1983, C

7 Baran lab Group eting Utility of reductive silylation s s 1. LDBB s S 2. I 2 s * * * 1. DMD 2. C 2 C; LA Ts, 3 ; a 2 C 3 (aq) 1. DMP 2. BS, ; s s 2 2, a 1. Bu; 2 ; Alkynyl 2. Swern JC, 1998, TL, 2000, ex ex 2 C CSA C PPTS Total Synthesis of Taxusin and its Synthetic Study Ti 4, 3 Sn Sn 4 58% Sn 4 s s 1. DMP 2. BS, ; 2 2, a * * * JC, 1997, C C ex BF 3 2 ex JACS, 1989, Tet, 1992, TBS TBS Ti 4 or a, 3 TBS Ti 4 Ti 4 dead end Tennen Yuki Kagobutsu Toronkai Koen Yoshishu. 1989, 31, 104. Avoiding late stage Birch Piv TIPS X "Cu" Tf dead end Piv Ti 4 TYKTKY, 1994, 36, 266. Piv

8 TES Bn, 3 Bn slow protonation from concave face Bn internal/directed + delivery Bn, 3 TES dead end Bn Bn Total Synthesis of Taxol and its Synthetic Study Sn 4 TIPS inseparable mixture TIPS JACS, 1996, JACS, 1999, Ac Ac taxusin B TIPS Ac Ac 1. Ti 4 2. F/KF 69% Synlett, 1994, 584. TIPS S C A ring TL, 1994, Avoiding C4 ketone TBS Pre-protection of C2 TBS S 1. DIBAL 2. TBSTf 3. 2, hν 4. AIB, Bu 3 Sn 2 1. SmI 2 2. TBAF, BT TBS TBS S Baran lab Group eting, 3 ; S dead end TL, 1999, TBS C 2 I 2, 2 Zn unreactive w/ C1-C2 benzylidene acetal due to C2 chelation to Zn dead end TYKTKY, 1996, 38, 119. JACS, 2000, JACS, 1998, JACS, 2000, Synlett, 2000, a, BT taxol

9 Baran lab Group eting TES TES 2 AlTf TBS DCM, 78 ºC Bn Ti 3 (ipr) 78 to 0 ºC C C C10 α at 78 ºC C10 epimer at 0 ºC 1. CBr 4, P 3 2. DIBAL 3. TBSTf, lutidine TBS Bn 1. TBAF 2. PDC TES TIPS TBS DMI 200ºC Bn Bn C K TES, Im C2 α :β = 1:8 3 ; Bu 3 Sn Bu Bn C TBS C TIPS Bn Bn 1. LA 2. Ac 2 3. PCC K, TIPS PPTS, 3. CuBr S 2, MPA, Ac C Bn 1. K 2 C 3, 2. Swern TBS Bn Br Br TBS 1. TBAF; 2. TBSTf, lutidine 3. LAD, TBSTf TBS Ac Ac Ac F pyridine TBS a CF 3 C 2 * no reaction in TBS taxinine TYKTKY, 1999, 41, 463.

10 Baran lab Group eting Vinyl Sulfide Chemistry M TBS Sulfur directed ene TBS ' S (E) gives better d.r. S chirality transfer 99-80% e.e. TL, 1992, TL, 1994, TES Bu S * LA TBS C Ti 3 (ipr) d.r. >99 TBS S C-C bond cleavage C-C bond formation Bu 1,4-addition Synlett, 1995, 173 TIPS S * TBS TIPS S approach towards anthracyclines JC, 1993, TES S M Ti S ' S S X = : daunomycinone X = : adriamycinone S TIPS C Mannich JC, 1994, 518. TBS TL, 1990, CL, 1992, TBS brassinolide TL, 1993, 477. Bu X eliotridane S JACS, 1993, Sulfur directed [2+3] Bn S SC 5 11 Ac S Ac coriolin TIPS LA Al 2 / Al 3 S Al 2 83% 1:1 TBDPS S Bn Bn 2 Al d.r. = 84:16 SC 5 11 SC 5 11 S C S C S Bn S TBDPS TL, 1993, TIPS SC 5 11 Bn S 24% SC % TL, 1996, TIPS S C S C Synlett, 1996, Al 2 2. TBAF 3. S, Bn S S TL, 1997, 465. JC, 1999, 2648.

11 Baran lab Group eting Total Synthesis of Ingenol and its Synthetic Study Ac Ac S S TIPS Ac Ac Ac Al 2 86% Al 2 Co(C) 3 Co(C) 3 82% 2 Al/ 2 Al Ac S S TIPS 1. Bu; (C 2 )n 2. Ac 2 3. Co 2 (C) 8 S CA Ac S single diastereomer Synlett, 1999, 647. Co(C) 3 acetone, Co(C) % d.r. = 98:1 JACS, 2000, Ac Co(C) 3 Co(C) 3 Co(C) 3 Co(C) 3 S TIPS LA* 77% TIPS Co(C) 3 Co(C) 3 Synthesis of Bioactive Molecules Ar Bn L-proline 1 1. TPAP, M 2. ab 4 C1 α β Br Pd 2 [P(o-tol) 3 ] 2 68% arisugacin B Tet, 2004, Bn Ar Ac Ac kazusamycin A Tet: Asymmetry, 2004, 733. L, 2004, arisugacin A L, 2002, 367. C Ar Al LA* = 2 JC, 1997, JACS, 2003, Chem. ev., 2005, 4661.

12 Baran lab Group eting L, 2005, 841. TBS C C * : madindoline A S: madindoline B L, 2002, 501. Bu neoxaline Ti 4, Zn TF, pyridine 67% physovenol oxaline TL, 2005, TBS Synlett, 2005, JST CEST 1999 research report GKK1032A 2 physovenine C afuredin TL, 2001, L, 2001, C molecules he/his group might be working on I I Borrelidin L, 2004, JC, 2007, herquline A C citreoviral S. Kobayashi ACIE, 2004, pinellic acid TL, 2002, Bioorg. d. Chem. Lett., 2003, 937. herquline B = terpendole A terpendole C JST CEST 1999 research report