A Diosphenol-Based Strategy for the Total Synthesis of - - PowerPoint PPT Presentation

A Diosphenol-Based Strategy for the Total Synthesis of (-)-Terpestacin

Current Literature Presentation Shuli Mao, 06/16/07

Barry M. Trost, Guangbin Dong, Jennifer A. Vance JACS, 2007, 129, 4540-4541.

HO O HO OH (-)-Terpestacin

Shuli Mao @ Wipf Group 1 6/20/2007

Outline

• Isolation and Biological Activities
• Previous Synthesis (3 enantioselective syn)
• Title Paper
• Summary

Shuli Mao @ Wipf Group 2 6/20/2007

Isolation and Biological Activities

Originally isolated from the fungal strain Arthrinium sp. FA 1744 in 1993 Found to inhibit the formation of syncytia (IC50 = 0.46 μg/mL) (giant-multinucleated cells that arise from the expression

• f gp120 on cell surfaces in the course of HIV infection)

Found to inhibit angiogenesis

HO O HO OH (-)-Terpestacin

Oka, M. et al J. Antibiot. 1993, 46, 367. Kwon, H. J. et al J. Antibiot. 2003, 56, 492.

Shuli Mao @ Wipf Group 3 6/20/2007

Previous Synthesis

Total Synthesis:

• 1. Kuniaki Tatsuta: 1998 (1st 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

Shuli Mao @ Wipf Group 4 6/20/2007

Tatsuta Synthesis

O OAc AcO AcO mCPBA BF3

.Et2O

O AcO AcO O H2C=CHMgBr Bu3P, CuI O AcO AcO O 2% HCl/ MeOH O O HO HO O O O Me OBn 1) PPTS, (CH3O)2C(CH3)2; 2) LHMDS, MeI; 3) DIBAL-H; 4) NaH, BnBr, TBAI 1) 80% AcOH(aq) 2) NaIO4 3) LHMDS, AcOMe 4) DMSO, DCC, Py-TFA O MeOOC O Me OBn 1) O3 then PPh3 2) NaOMe/MeOH O MeOOC O Me OBn O O COOMe H H BnO CH3 O O H H BnO CH3 O O 1)H2C=CHMgBr, CuBr-Me2S, TMSCl 2) TBSCl, DIPEA; 3) 9-BBN thenH2O2, NaOH; 4) NaH/THF then AcOH-THF-H2O TBSO CH3 CHO 8 steps Cl CH3 OAc CH3 P(OEt)2 O 1 2 Tri-O-acetyl-D-galactal

Tatsuta, K.; Masuda, N. J. Antibiot. 1998, 51, 602.

Shuli Mao @ Wipf Group 5 6/20/2007

Tatsuta Synthesis (Cont’d)

O O H H BnO CH3 O O 1 Cl CH3 OAc CH3 P(OEt)2 O 2 + O O H H BnO CH3 O O H3C CH3 OAc (EtO)2P H3C O Cs2CO3, CsI 90% O OMOM H BnO H H3C O CH3 H3C COOMe CH3 1) NaBH4/MeOH 2) MOMCl, DIPEA 3) LiOH/MeOH then MeI/HMPA 4) TPAP, NMO 5) DIPEA, LiCl 1) Li-n-BuBH3 2) TBSOTf, 2,6-lut 3) LAH 4) PDC, Zeolite 5) NH2NH2.H2O, NaOH/TEG 6) TBAF 7) MnO2 O OMOM H BnO H H3C CH3 H3C CH3 CH3 O OH H H3C CH3 H3C CH3 CH3 HO BzO OBz 1) 2 M HCl/THF 2) NaBH4/MeOH 3) BzCl, Py, DMAP O H3C CH3 H3C CH3 CH3 HO HO OH 1) Swern 2) 1 M NaOH / MeOH

Shuli Mao @ Wipf Group 6 6/20/2007

Myers Synthesis

Myers, A. G.; Siu, M. J. Am. Chem. Soc. 2002, 124, 4230.

OH Ph CH3 N CH3 O CH3 I2, THF, H2O 96% (trans:cis=12:1) O O CH3 I 1) CsO2CCF3, DMF, 90oC then Et2NH, 95% 2) TIPSCl, imid, DMF, 98% O O CH3 TIPSO H3C CH3 OAc O H OH CH3 H3C CH3 Br O H CH3 1) Swern Oxi 2) NaHMDS, Ph3PCH3Br 93% (2 steps) 3) K2CO3, MeOH, 99% 4) MsCl,Et3N then LiBr 1 2 3 4 5 O O H3C CH3 H3C OTIPS O H CH3 H3C CH3 H3C O CH3 CO2CH3 O OTIPS KHMDS, THF, -78oC 86% ( 2 steps) KOH, EtOH; CH2N2; DMP, Py 82% 3 + 5 6 7 O H3C CH3 H3C OTIPS O H CH3 O N O CH3 H3C H3C CH3 H3C OTIPS O H CH3 O NaH, DMF; (CH3)2NCOCl, DMAP, Et3N 81% 8 9 1) DIBAL-H, THF, 85% 2) CH3Li, Et2O, 88% dr= 8.8 :1

Shuli Mao @ Wipf Group 7 6/20/2007

Myers Synthesis (Cont’d)

H3C CH3 H3C OTIPS O H CH3 O 9 H3C CH3 H3C OTIPS O TBSO CH3 I LiI, Sc(OTf)3, THF, 92%; TBSOTf, 2,6-lut, 97% 10 LiN(Si(CH3)2Ph)2, THF 53% (trans: cis = 4.8:1) H3C CH3 CH3 H3C TBSO OTIPS H O 11 H3C CH3 CH3 H3C TBSO OTIPS H OH CO2tBu CH3 CH3CH2CO2tBu LDA 94% 12 1) Red-Al, THF; HOAc 2) Red-Al, toluene 75% H3C CH3 CH3 H3C TBSO O OH HO H3C 13 Martin sulfurane 89% H3C CH3 CH3 H3C TBSO O HO H3C DMDO acetone H3C CH3 CH3 H3C TBSO O HO H3C O 14 15 O H3C CH3 CH3 H3C HO OH H OH H3C CF3COOH, Et2O; Et2NH H3C CH3 CH3 H3C TBSO O HO H3C OH OH 1) K2CO3, MeOH, 73% 2) 1 N HCl, THF, 94% 16

Shuli Mao @ Wipf Group 8 6/20/2007

Jamison Synthesis

O Me + Co(CO)3 Co(CO)3 Me3Si H NMO, DCM 51% O O H H Me SiMe3 1) TIPS I t-BuLi; CuI Me2S, Et2O/THF 2) NaBH4, MeOH 3) TBAF, THF 47% ( 3 steps) O OH H H Me KOt-Bu DMSO 90-95% O OH H H Me TMSCl Et3N 87% O OSiMe3 H H Me Me Me 1 2 3 4 5 6 Me Me HO OH Me OAc 2 7 1) K2CO3, MeOH 2) NaIO4, MeOH/H2O 3) TBSOTf, 2,6-lut 52% (3 steps) O Me OTBS 2 8 H 6 Ni(cod)2 (10 mol%) (R)-9 (10 mol%) Et3B O OSiMe3 H H Me 10 Me OH Me OTBS 2 Fe P Ph Me (R)-9 1) TIPSOTf, 2,6-lut 2) 5% NaOH, MeOH 3) TPAP, NMO 4) 1:1 1N HCl/ THF 5) I2, PPh3, imid 6) LiHMDS, THF 18% (6 steps) O O H H Me Me Me Me OTIPS NaH, MeI H2O toluene 62%, dr > 95:5 O O H H Me Me Me Me OTIPS Me nOe 1) TBAF, THF 2) KHMDS, O2 (1 atm) P(OEt)3 O O HO H Me Me Me Me OH Me K2CO3, MeOH 35% ( 3 steps) O Me Me Me Me OH Me HO HO 11 12 13 70% (dr 3:1, rr 2:1)

Chan, J.; Jamison, T. F. J. Am. Chem. Soc. 2003, 125, 11514.

Shuli Mao @ Wipf Group 9 6/20/2007

Title Paper:Trost Retrosynthesis

Trost, B. M.; Dong, G.; Vance, J. A. J. Am. Chem. Soc. 2007, 129, 4540.

HO O HO OH Pd-AAA & Claisen HO O OH sulfone mediated alkylation RCM PMBO O Br SO2Ph OH + Pd-AAA & Claisen Sakurai OH O

1 13 15 3 7 11 23 1 15 5 6 12 13 11 11 6 1 15 5 1

3-methyl-1,2-cyclopentanedione

Shuli Mao @ Wipf Group 10 6/20/2007

Synthesis of Cyclic 1,2-Diketones

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.

O H2SeO3 or SeO2 dioxane, H2O O O 1) O 2 CuBr2 CHCl3/ EtOAc O Br DMSO KI, Na2CO3 90% 65% O O 2) O O O 3) Zn-TMSCl DCM O O OH Py-CrO3 O O O 15% H2SO4 O O 92% 75% 73% 4) O Li SO2Ph H3CO HO OCH3 SO2Ph OCH3 O H H 76% C8H17 H O C8H17 H HO O I2/Cu(OAc)2/AcOH/H2O reflux, 24h, 40% 5) ~17% Et2AlCl

Shuli Mao @ Wipf Group 11 6/20/2007

Title Paper: Diosphenol-Based Strategy

OH O R O O R

*

R5 R4 R3 R1 R2

*

O OH R

*

R1 R2 R3 R4 R5

*

O O R

*

R1 R2 R3 R4 R5

*

R5' R4' R3' R2' R1'

*

O OH R

*

R1 R2 R3 R4 R5

*

R5' R4' R3' R1' R2'

Strategy 1: Pd-AAA & Claisen rearrangement Strategy 2: Michael addition

O O R1 R O OH R1 R R2

Shuli Mao @ Wipf Group 12 6/20/2007

Title Paper:Trost Synthesis

OH O isoprene monoepoxide, Pd2dba3

.CHCl3 (1 mol%),

(R, R)-L (2.6 mol%), Bu4NCl (50 mol%), DCM; O O OTIPS then TIPSOTf, 2,6-lut 95%, 88-96% ee HO OTIPS O microwave, CHCl3 O OTIPS O Pd(OAc)2 Cs2CO3 78% (2 steps) E/Z= 4:1 1) MgBr2.Et2O, allyltrimethylsilane 86%, dr= 5.7:1 2) PMBCl, Cs2CO3,

• cat. Bu4NI, DMF, 79%

3) TBAF, THF, 86% 4) CBr4, PPh3, 88% HO SO2Ph 1) Ti(OiPr)4, TBHP, L-DET, DCM, -20oC, 80%, 98% ee 2) Py, I2, PPh3; H2O, 74% SO2Ph OH 1) LHMDS (2 eq), THF/HMPA , 74-85% 2) Pd(OAc)2(20mol%), DPPP (25mol%), NaBH4, DMSO, 77% PMBO O OH PMBO O Br 1 2 3 4 5 5 6 7 8 PMBO O OH Grubbs 2nd Gen cat (10 mol%), benzene, RT, c = 0.001 M 35-44% E isomer 9 NH HN O O PPh2Ph2P

(R, R)-L

1 15 3 8 12 13

Shuli Mao @ Wipf Group 13 6/20/2007

Title Paper:Trost Synthesis (Cont’d)

O O OH PMBO O OAc PMBO O OAc HO HO PMBO O HO OAc HO O HO OH 1) MgBr2.Et2O, DMS, 93% 2)10, Pd2dba3

.CHCl3 (2.5 mol%),

(S, S)-L (7.5 mol%), DCM, RT, 89%, dr>15:1 1) microwave, DME; 2) PMBCl, Cs2CO3,

• cat. Bu4NI, DMF;

3) Ac2O, Py. 69% (3 steps) K2OsO2(OH)4 (1 mol%), (DHQ)2PHAL (5 mol%), K3Fe(CN)6, k2CO3, tBuOH/H2O (1:1), 0oC 65% (~80% brsm) 1) NaIO4 2) NaBH4 78% ( 2 steps) 1) LiOH, 89% 2) MgBr2.Et2O, DMS, DCM, 74% 11 12 13 14 PMBO O OH 9 OBoc 10

Shuli Mao @ Wipf Group 14 6/20/2007

Summary

Tatsuta 38 0.45% alkylation & HWE (from tri-O-acetyl-D-galactal) Myers 20 5.4% alkylation (from $ (R,R)-pseudoephedrine propionamide) Jamison 20 0.06% alkylation & reductive coupling (from $ β-methallyl alcohol) between aldehyde and alkyne Trost 19 0.2% sulfone mediated alkylation, (from $ 3-methyl-1,2- RCM, Pd-AAA & Claisen cyclopentanedione) Steps Yields Key Transformations

Shuli Mao @ Wipf Group 15 6/20/2007