Shuli Mao @ Wipf Group 1 6/20/2007 A Diosphenol-Based Strategy for the Total Synthesis of (-)-Terpestacin Barry M. Trost, Guangbin Dong, Jennifer A. Vance JACS, 2007, 129, 4540-4541. O HO HO OH (-)-Terpestacin Current Literature Presentation Shuli Mao, 06/16/07
Shuli Mao @ Wipf Group 2 6/20/2007 Outline • Isolation and Biological Activities • Previous Synthesis (3 enantioselective syn) • Title Paper • Summary
Shuli Mao @ Wipf Group 3 6/20/2007 Isolation and Biological Activities O HO HO OH (-)-Terpestacin � Originally isolated from the fungal strain Arthrinium sp. FA 1744 in 1993 � Found to inhibit the formation of syncytia (IC 50 = 0.46 μ g/mL) (giant-multinucleated cells that arise from the expression of gp120 on cell surfaces in the course of HIV infection) � Found to inhibit angiogenesis Oka, M. et al J. Antibiot. 1993 , 46 , 367. Kwon, H. J. et al J. Antibiot. 2003 , 56 , 492.
Shuli Mao @ Wipf Group 4 6/20/2007 Previous Synthesis � Total Synthesis: 1. Kuniaki Tatsuta: 1998 (1 st racemic and enatioselective) 2. Andrew Myers: 2002 (enatioselective) 3. Timothy Jamison: 2003 (enatioselective) � Partial or Core Synthesis: 1. Kei Takeda & Eiichi Yoshii: 1995 2. Denis Heissler: 1999 3. Marcus Tius: 2005
Tatsuta Synthesis Shuli Mao @ Wipf Group 5 6/20/2007 AcO AcO AcO O AcO O O H 2 C=CHMgBr mCPBA AcO AcO O O HO 2% HCl/ MeOH O . Et 2 O Bu 3 P, CuI BF 3 HO OAc O Tri- O -acetyl-D-galactal 1) PPTS, (CH 3 O) 2 C(CH 3 ) 2 ; 1) 80% AcOH(aq) O 2) LHMDS, MeI; Me 1) O 3 then PPh 3 2) NaIO 4 O MeOOC O 3) DIBAL-H; Me 2) NaOMe/MeOH 3) LHMDS, AcOMe OBn 4) NaH, BnBr, TBAI O O 4) DMSO, DCC, Py-TFA OBn 1)H 2 C=CHMgBr, O O O H CuBr-Me 2 S, TMSCl H O Me COOMe 2) TBSCl, DIPEA; O O MeOOC O O 3) 9-BBN thenH 2 O 2 , NaOH; OBn BnO BnO 4) NaH/THF then AcOH-THF-H 2 O H H CH 3 CH 3 1 CH 3 CH 3 CH 3 8 steps TBSO CHO Cl P(OEt) 2 OAc O 2 Tatsuta, K.; Masuda, N. J. Antibiot. 1998 , 51 , 602.
Shuli Mao @ Wipf Group 6 6/20/2007 Tatsuta Synthesis (Cont’d) H 3 C O O H O O CH 3 CH 3 Cs 2 CO 3 , H O O CsI + O Cl P(OEt) 2 O BnO CH 3 90% H BnO OAc O 2 H O CH 3 1 (EtO) 2 P CH 3 OAc H 3 C 1) Li -n -BuBH 3 H 3 C 2) TBSOTf, 2,6-lut 1) NaBH 4 /MeOH H 3 C OMOM 3) LAH 2) MOMCl, DIPEA OMOM H CH 3 4) PDC, Zeolite 3) LiOH/MeOH H CH 3 COOMe O 5) NH 2 NH 2 .H 2 O, then MeI/HMPA CH 3 O NaOH/TEG 4) TPAP, NMO BnO H BnO 6) TBAF 5) DIPEA, LiCl H CH 3 7) MnO 2 CH 3 H 3 C O H 3 C O H 3 C H 3 C OH O CH 3 1) 2 M HCl/THF CH 3 1) Swern HO CH 3 HO 2) NaBH 4 /MeOH 2) 1 M NaOH CH 3 3) BzCl, Py, DMAP / MeOH BzO HO H CH 3 CH 3 H 3 C OBz H 3 C OH
Myers Synthesis Shuli Mao @ Wipf Group 7 6/20/2007 O O CH 3 CH 3 O CH 3 1) CsO 2 CCF 3 , DMF, I 2 , THF, H 2 O 90 o C then Et 2 NH, 95% Ph CH 3 O O N 96% OH CH 3 2) TIPSCl, imid, DMF, 98% ( trans : cis =12:1) TIPSO I 3 2 1 OH O O H H 1) Swern Oxi CH 3 CH 3 2) NaHMDS, Ph 3 PCH 3 Br 93% (2 steps) H 3 C OAc H 3 C Br 3) K 2 CO 3 , MeOH, 99% 4) MsCl,Et 3 N then LiBr CH 3 CH 3 5 4 O O H O CH 3 CH 3 KHMDS, KOH, EtOH; OTIPS OTIPS THF, -78 o C CH 2 N 2 ; DMP, Py H 3 C 3 + 5 H 3 C O CO 2 CH 3 82% 86% ( 2 steps) H 3 C H 3 C dr= 8.8 :1 O CH 3 CH 3 6 7 H 3 C O N H CH 3 O NaH, DMF; H O CH 3 (CH 3 ) 2 NCOCl, O CH 3 O 1) DIBAL-H, THF, 85% DMAP, Et 3 N H 3 C H 3 C 2) CH 3 Li, Et 2 O, 88% OTIPS 81% OTIPS H 3 C H 3 C O CH 3 CH 3 9 8 Myers, A. G.; Siu, M. J. Am. Chem. Soc. 2002 , 124 , 4230.
Myers Synthesis (Cont’d) Shuli Mao @ Wipf Group 8 6/20/2007 I O H TBSO CH 3 O LiI, Sc(OTf) 3 , THF, 92%; CH 3 O LiN(Si(CH 3 ) 2 Ph) 2 , THF H 3 C TBSOTf, 2,6-lut, 97% OTIPS H 3 C H 3 C OTIPS 53% ( trans: cis = 4.8:1) H 3 C CH 3 9 CH 3 10 CH 3 TBSO CH 3 TBSO CH 3 H O H OH 1) Red-Al, THF; HOAc CH 3 CH 2 CO 2 t Bu CO 2 t Bu H 3 C 2) Red-Al, toluene LDA H 3 C OTIPS OTIPS 94% 75% H 3 C H 3 C 11 CH 3 CH 3 12 CH 3 CH 3 TBSO CH 3 TBSO TBSO H 3 C H 3 C H 3 C HO DMDO HO Martin HO acetone sulfurane H 3 C H 3 C O H 3 C O O 89% OH H 3 C H 3 C O H 3 C CH 3 13 CH 3 15 14 CH 3 CH 3 CH 3 HO TBSO H 3 C OH H 3 C CF 3 COOH, 1) K 2 CO 3 , MeOH, 73% H HO Et 2 O; Et 2 NH 2) 1 N HCl, THF, 94% H 3 C H 3 C O OH OH H 3 C H 3 C O OH CH 3 CH 3 16
Jamison Synthesis Shuli Mao @ Wipf Group 9 6/20/2007 O OH H 1) TIPS H Me 3 Si O NMO, DCM O Co(CO) 3 t -BuLi; CuI I O + SiMe 3 Me 2 S, Et 2 O/THF Co(CO) 3 51% H 2) NaBH 4 , MeOH H H Me Me Me 3) TBAF, THF 1 2 3 4 47% ( 3 steps) OH OSiMe 3 H H TMSCl O O KO t- Bu DMSO P Et 3 N Me Ph Fe 90-95% 87% H H Me Me Me Me 6 5 ( R )- 9 6 1) K 2 CO 3 , MeOH OH O Ni(cod) 2 (10 mol%) 2) NaIO 4 , MeOH/H 2 O Me OAc OTBS H ( R )- 9 (10 mol%) 3) TBSOTf, 2,6-lut HO 2 2 Et 3 B Me Me Me 52% (3 steps) 8 70% (dr 3:1, rr 2:1) 7 1) TIPSOTf, 2,6-lut Me OSiMe 3 H 2) 5% NaOH, MeOH O O NaH, MeI 3) TPAP, NMO H Me H 2 O 4) 1:1 1N HCl/ THF OH O OTBS toluene H 5) I 2 , PPh 3 , imid Me 62%, dr > 95:5 H 6) LiHMDS, THF 2 Me Me Me Me OTIPS 18% (6 steps) 10 11 nOe Me Me Me 1) TBAF, THF O O Me O Me Me 2) KHMDS, H HO Me Me K 2 CO 3 , Me O 2 (1 atm) HO O O MeOH P(OEt) 3 H H 35% HO ( 3 steps) Me Me Me OTIPS Me OH Me Me OH 13 12 Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2003 , 125 , 11514.
Shuli Mao @ Wipf Group 10 6/20/2007 Title Paper:Trost Retrosynthesis sulfone mediated alkylation 5 6 O O 7 3 1 Pd-AAA & Claisen 1 HO HO 15 15 13 13 11 RCM 11 23 HO OH 12 OH O Pd-AAA & Claisen O 1 PMBO OH Br 15 5 Sakurai 1 + 3-methyl-1,2-cyclopentanedione 6 11 SO 2 Ph OH Trost, B. M.; Dong, G.; Vance, J. A. J. Am. Chem. Soc. 2007 , 129 , 4540.
Synthesis of Cyclic 1,2-Diketones Shuli Mao @ Wipf Group 11 6/20/2007 O O H 2 SeO 3 or SeO 2 O dioxane, H 2 O 1) ~17% O O O 2 CuBr 2 DMSO Br O CHCl 3 / EtOAc KI, Na 2 CO 3 2) 90% 65% O O O O O Zn-TMSCl O O 15% H 2 SO 4 Py-CrO 3 3) DCM OH O O 73% 75% 92% O OCH 3 OCH 3 O HO H H 3 CO SO 2 Ph O SO 2 Ph Et 2 AlCl 4) Li 76% H C 8 H 17 C 8 H 17 5) O I 2 /Cu(OAc) 2 /AcOH/H 2 O O reflux, 24h, 40% HO H H 1) Hach, et. al , Org. Syn. 1963 , 229. 2) Macomber, et. al , J. Org. Chem. 1975 , 40 , 1990. 3) Vankar, et. al , Tetrahedron Lett. 1987 , 28 , 551. (4) Trost, et. al . J. Am. Chem. Soc. 1987 , 109 , 4124. (5) Horiuchi, et. al . Synthesis 1989 , 10 , 785.
Shuli Mao @ Wipf Group 12 6/20/2007 Title Paper: Diosphenol-Based Strategy Strategy 1: Pd-AAA & Claisen rearrangement OH O R 5 O R 4 O OH O R 1 * * R R 3 R 2 R 1 R 2 * R 4 R 5 R R R 3 R 4 ' R 3 ' OH R 5 ' R 4 ' R 5 ' R 1 ' O * R 2 ' * O R 1 * R 1 ' R 2 ' R R 3 ' O R 2 * R 4 R 5 R 1 * R R 3 R 2 * R 4 R 5 R 3 Strategy 2: Michael addition O OH O O R 1 R R 1 R R 2
Title Paper:Trost Synthesis Shuli Mao @ Wipf Group 13 6/20/2007 isoprene monoepoxide, . CHCl 3 (1 mol%), Pd 2 dba 3 O O O Pd(OAc) 2 ( R , R )-L (2.6 mol%), microwave, OH O Cs 2 CO 3 Bu 4 NCl (50 mol%), DCM; HO CHCl 3 OTIPS then TIPSOTf, 2,6-lut 78% (2 steps) OTIPS E/Z = 4:1 3 2 1 95%, 88-96% ee 1) MgBr 2 .Et 2 O, O O allyltrimethylsilane 86%, dr= 5.7:1 O O PMBO O 2) PMBCl, Cs 2 CO 3 , Br NH HN cat. Bu 4 NI, DMF, 79% OTIPS PPh 2 Ph 2 P 4 3) TBAF, THF, 86% 5 4) CBr 4 , PPh 3 , 88% ( R , R )-L 1) Ti(O i Pr) 4 , TBHP, L-DET, DCM, -20 o C, 80%, 98% ee HO SO 2 Ph SO 2 Ph 2) Py, I 2 , PPh 3 ; H 2 O, 74% OH 7 6 Grubbs 2nd Gen cat O O (10 mol%), benzene, 1) LHMDS (2 eq), 5 3 RT, c = 0.001 M THF/HMPA , 74-85% 1 PMBO 8 PMBO 2) Pd(OAc) 2 (20mol%), DPPP 35-44% E isomer 15 (25mol%), NaBH 4 , DMSO, 77% 13 8 9 12 OH OH
Title Paper:Trost Synthesis (Cont’d) Shuli Mao @ Wipf Group 14 6/20/2007 O O 1) microwave, DME; 1) MgBr 2 .Et 2 O, DMS, 93% 2) PMBCl, Cs 2 CO 3 , PMBO O . CHCl 3 (2.5 mol%), 2) 10 , Pd 2 dba 3 cat. Bu 4 NI, DMF; 3) Ac 2 O, Py. ( S , S )-L (7.5 mol%), DCM, RT, 89%, dr>15:1 69% (3 steps) 9 OH OH OBoc 11 10 O O K 2 OsO 2 (OH) 4 (1 mol%), 1) NaIO 4 (DHQ) 2 PHAL (5 mol%), PMBO 2) NaBH 4 PMBO K 3 Fe(CN) 6 , k 2 CO 3 , t BuOH/H 2 O (1:1), 0 o C HO 78% ( 2 steps) HO 65% (~80% brsm) OAc OAc 13 12 O O 1) LiOH, 89% PMBO HO 2) MgBr 2 .Et 2 O, DMS, DCM, 74% HO OAc HO OH 14
Shuli Mao @ Wipf Group 15 6/20/2007 Summary Steps Yields Key Transformations 38 0.45% alkylation & HWE Tatsuta (from tri- O -acetyl-D-galactal) 20 5.4% alkylation Myers (from $ ( R,R )-pseudoephedrine propionamide) Jamison 20 0.06% alkylation & reductive coupling (from $ β -methallyl alcohol) between aldehyde and alkyne 19 0.2% sulfone mediated alkylation, Trost (from $ 3-methyl-1,2- RCM, Pd-AAA & Claisen cyclopentanedione)
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