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An Efficient Synthetic Approach to Cyanocycline A and Bioxalomycin 2 via [C+NC+CC] coupling H. U. Kaniskan and P. Garner Case Western Reserve University , Cleveland, OH J. Am. Chem. Soc. 2007, 129 , 15460-15461 Julia Vargas January 5, 2008

  1. An Efficient Synthetic Approach to Cyanocycline A and Bioxalomycin β 2 via [C+NC+CC] coupling H. U. Kaniskan and P. Garner Case Western Reserve University , Cleveland, OH J. Am. Chem. Soc. 2007, 129 , 15460-15461 Julia Vargas January 5, 2008 Julia Vargas @ Wipf Group 1 2/17/2008

  2. Cyanocycline A and Bioxalomycin β 2 • Tetrahydroisoquinoline alkaloid family • Exhibit wide range of biological activity: - antitumor, antifungal, antimicrobial Me Me N N H H NC O HO N • Isolated in 1994 from N • Isolated in 1970’s from H H H H H H Steptomyces viridostaticus Streptomyces flavogriseus O O N N O O H H MeO O MeO O Me Me Bioxalomycin β 2 Cyanocycline A Me Me N N H H R HO N N HO HO • Isolated in 1974 from • Isolated in 1980 from H H H H H H O Steptomyces lusitanus O Actinosynnema pretiosum C-14482 N N O O H H H 2 N O MeO O Me Dnacin A 1 R = CN Naphthyridinomycin Dnacin B 1 R = OH Bioxalomycin β 2: JOC. 1994 , 59, 4045 Cyanocycline A: J, Antibiot. , 1982 , 35 , 771 Naphthyridinomycin: J, Antibiot. , 1975 , 28 , 497 Dnacin A 1 and B 1 : J, Antibiot. , 1980 33 , 1443 Brugmansia suaveolens Julia Vargas @ Wipf Group 2 2/17/2008

  3. Previous Synthesis… • First total synthesis of (+/-) Cyanocycline A: Evans- 1986 Me Me N 10 steps Cbz N N 1.) H 2 , Pd/C, CH 2 O 1.) MsCl, Et 3 N O O CONH 2 OH O N N 2.) KOtBu, tBuOH 2.) PhSeSePh, NaBH 4 H H H 3.) TFA 78% 4.) t-BuOOH 85% Me Me Me N N N OH 1.) Ac 2 O, DMAP 1.) methyl glyoxalate 1.) LiBEt 3 H H O O O N OH N N 2.) SOCl 2 2.) DDQ 2.) Zn o , TBSCl, OH H OMe 3.) SnCl 4 O OTBS MeO 2 C DMAP, DIPEA AcOH 2 C 91% HOH 2 C MeO 3.) OsO 4 , NMO HO Me O Me TBSO Me 71% Me OMe OMe 46-54% OMe OMe Me O O N OH 1.) Li, NH 3 ; EtOH OH TBSO N O N Et 4 NIO 4 , 1.) TFA H H H H 2.) NaCN H H H O Me Me OTBS N N NMe NMe TBSO(CH 2 ) 2 NH 2 2.) LiBEt 3 H H H 3.) HF, pyr; Na 2 CO 3 , O 2 H N N 3.) KN(TMS) 2 OTBS AcOH 2 C MeO MeO 35% 64% (4 steps) OH O O CN TBSO Me OTBS OH OMe 31 linear steps JACS 1986 , 108, 2478 Chem. Rev. 2002 , 102 , 1669 Julia Vargas @ Wipf Group 3 2/17/2008

  4. Previous Synthesis… • Total synthesis of (+/-) Cyanocycline A: Fukuyama- 1987 O O BnO Boc 1.) t-BuO Me N MeO Me CH 2 OH Boc LDA, ZnCl 2 t-BuO 2 C NHBoc NaOEt, EtOH N Me CH 2 OH 2.) TsOH, quinoline, -H 2 O t-BuO 2 C BnO CHO MeO O 3.) LiBEt 3 H t-BuO 2 C 68% MeO OMe Me 77% BnO BnO 1.) TFA MeO 1.) H 2 (1000psi) Pd/C 2.) ClCO 2 (CH 2 ) 2 CON(Ch) 2 , MeO Boc 2.) H 2 (1500psi) Rh/C CO 2 (CH 2 ) 2 CON(Ch) 2 DIPEA N Me N Me 3.) BnBr, K 2 CO 3 CO 2 Me 3.) TFA CO 2 Me O MeO 4.) Jones O MeO 4.) ClCO 2 Et, Et 3 N; NH 3 t-BuO 2 C 5.) MeI, K 2 CO 3 H 2 NOC 77% 48% (Ch = cyclohexyl) JACS 1987 , 109, 1587 Chem. Rev. 2002 , 102 , 1669 Julia Vargas @ Wipf Group 4 2/17/2008

  5. Previous Synthesis… • Total synthesis of (+/-) Cyanocycline A: Fukuyama- 1987 O H BnO CO 2 Me HN MeO 1.) H 2 (1500psi), 1.) BnBr, K 2 CO 3 H MeO H Me 1.) CSA, quinoline NOH RaNi, Et 3 N 2.) LiBEt 3 H, TMEDA H CO 2 R N H H N CO 2 R NH Me 2.) BnOCH 2 CHO, AcOH 2.) NOCl; NaBH 3 CN 3.) Swern ox. MeO CO 2 Me 4.) TMSCN, ZnCl 2 MeO HN 54% 66% OH 5.) BCl 3 , Ac 2 O, pyr OBn O 37% O O O HN MeO MeO N O N H H H 1.) NaOH, MeOH H H H H H H Me CO 2 R 1.) Lawesson's reagent Me CO 2 R Me 2.) KOt-Bu, t-BuOH N N NMe H H H N 2.) RaNi N N 3.) MeI, DIPEA MeO MeO MeO 3.) ethylene oxide/MeOH 4.) Mn(OAc) 3 , H 2 SO 4 OAc CN OAc CN O CN 73% 42% OAc OAc OH 29 linear steps JACS 1987 , 109, 1587 Chem. Rev. 2002 , 102 , 1669 Julia Vargas @ Wipf Group 5 2/17/2008

  6. Previous Synthesis… • Total Synthesis of (+)-Cyanocycline A: Fukuyama- 1987 H H H CO 2 H COSEt CH(OMe) 2 H 2 N 1.) Boc 2 O, Et 3 N 1.) Et 3 SiH, Pd/C BocHN BocHN 2.) EtSH, DCC, DMAP 2.) CH(OMe) 3 , CSA CO 2 Me CO 2 Me CO 2 Me 93% 95% Boc 1.) LDA N (+)-Cyanocycline A Me CH(OMe) 2 2.) Ac 2 O 3.) CSA, quinoline t-BuO 2 C 32 linear steps 77% - this enantiospecific synthesis was used in the determination of the absolute stereochemistry of the natural product Chem. Rev. 2002 , 102 , 1669 Li, L. Ph.D. Dissertation, Rice University, Houston, TX, 1989 Julia Vargas @ Wipf Group 6 2/17/2008

  7. Synthetic Strategy… * II CHO H + H 2 N OHC endo-selective HN [C+NC+CC] CHO CHO H 2 N H H 2 N III CHO H NH 2 Ar NH 2 Ar I = masked functionality Me Me N N H H NC O HO N N + H H H H H H O O N N O O H H MeO O MeO O Me Me Bioxalomycin β 2 Cyanocycline A Brugmansia suaveolens Julia Vargas @ Wipf Group 7 2/17/2008

  8. The [C+NC+CC] Reaction Ag I or Cu I - catalyzed Asymmetric [C+NC+CC] coupling cascade H 2 N C COX* Highlights: H H 2 R' - one-pot, molecular cascade CHO + R featuring 1,3-dipolar cycloaddition imine formation - concerted process - 2 new C-C bonds R' H - up to 4 new chiral centers N C COX* R C dipole H - mild, efficient, selective, high yielding H H formation - absolute stereocontrol achieved Ag O H R' via chiral, nonracemic substrates N R C C X* or auxiliaries H H 1,3-dipolar + cycloaddition H H H H Oppolzer's N COX* Camphorsultam R' C C * * Y Z * * R N Z Y S O O X*= oppolzer's D- or L-camphorsultam - works well with enolizable and α -chiral aliphatic aldehydes! OL. 2006 , 8 , 3647 - access to highly functionalized pyrrolidines Tet. Lett ., 2007 , 48 , 3867 Julia Vargas @ Wipf Group 8 2/17/2008

  9. The [C+NC+CC] Reaction Selectivity in the [3+2] cycloaddition: COX L/D H 2 N C cat. Cu I , ligand, H 2 "NC" cat. Ag I , THF, RT DMSO, RT + H H C C R C HO EWG H "C" H H R "CC" R N N COX L COX L EWG EWG H H R R N N COX D COX D EWG EWG minimized exo-manifold endo-manifold sterics Transition State Rational EWG H favorable H EWG coordination Ph 2 N N O O P N Ag S N Cu S O H Highly selective, often exclusively O H P O O one stereoisomer. Ph 2 H R H R Endo-Si pre-TS ensemble Exo-Si pre-TS ensemble Julia Vargas @ Wipf Group 9 2/17/2008

  10. Aldehyde Synthesis O O N BnO MgBr Boc Boc N add 1 to 2, + BnO NOH MeO OMe THF, -50 o C O N Bn Me (71%) MeO OMe Bn 2 1 Me O O 1.) Zn, EtOH, N BocHN Boc aq NH 4 Cl, 90 o C 1.) ca. TsOH, MeOH, rt BnO BnO NBnCbz NBnCbz 2.) DMP, CH 2 Cl 2 , rt 2.) CbzCl, NaHCO 3 (65%, 2 steps) aq-dioxane MeO OMe MeO OMe (80%, two steps) Me Me 42% overall yield from 2 Julia Vargas @ Wipf Group 10 2/17/2008

  11. Key [C+NC+CC] coupling COX L HN BocHN N NH 2 S O H BocHN CO 2 Me O O BnO BnO O NBnCbz ( A ) AgOAc (10 mol%), + MeO MeO OMe NBnCbz rt, 2h, 74% OMe Me OMe Me O X L = Oppolzer's camphorsultam ( A ) Proposed Pre-TS model: • Stereochemical outcome predicted based on previous [3+2] cycloaddition studies CO 2 Me • Difficulty in confirming relative Endo-Si configurations by NMR at this stage O • Later determined by NOE studies of N Ag S advanced, rigid intermediate N O O H NHBoc H • Achieving this intermediate represents BnCbzN Ar most ambitious application of the asymmetric [C+NC+CC] coupling manifold to date Julia Vargas @ Wipf Group 11 2/17/2008

  12. End Game COX L COX L COX L 1.) H 2 atm, Pd/C Cbz Cbz N HN MeOH, rt N BnO H H H BnOCH 2 CHO, AcOH, H 2 N BocHN 2.) CbzCl, DIEA, N H THF, 0 o C 4Å MS, DCM, rt H H H CO 2 Me HO BnO HO N O NBnCbz N O H H 3.) TFA, DCM, rt H MeO OMe MeO OMe MeO OMe Me Me Me (30-36%) (75%) OH COX L Me Cbz N N BnO BnO H H 1.) Swern Oxidation H H LiAlH 4 , THF, 0 o C BnBr, K 2 CO 3 , H 2.) TMSCN, ZnCl 2 H BnO BnO N N O O H H H DMF, 60 o C H MeO OMe MeO OMe Me Me (54%) (74%) Me Me Me N O N N H H H 1.) NC NC NC MeOH, 60 o C 1.) Lawesson's rgt. BnO HO BnO H H H (sealed tube) (58%) C 6 H 6 , reflux N N N H H H H H H 2.) BCl3, DCM, 2.) Raney-Ni, BnO HO BnO -78 o C (52%) N N N Acetone, rt O O H H H H MeO OMe MeO MeO OMe OMe Me Me Me Brugmansia suaveolens (53%) (Late stage Fukuyama intermediate) (63%) X L = Oppolzer's camphorsultam Julia Vargas @ Wipf Group 12 2/17/2008

  13. In summary… • A formal total synthesis of Cyanocycline A was accomplished in 22 linear steps from commercial material • Cyanocycline A had previously been converted to Bioxalomycin β 2, thus making this an efficient formal synthesis of it as well. (see: J OC , 1994 , 59 , 4045; Adv. Heterocycl. Chem, 1992 , 2 , 189) • The [C+NC+CC] coupling methodology afforded the desired target, reducing the total steps by one-third of that of previous syntheses • The successful application of the [C+NC+CC] coupling technology has now provided access to these complex natural product scaffolds and can provide access to similar members of the Tetrahydroisoquinoline family • The [C+NC+CC] reaction manifold has great potential for introducing structural diversity in natural products and should become a valuable tool in both target and diversity oriented synthesis Julia Vargas @ Wipf Group 13 2/17/2008

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