Cyanocycline A and Bioxalomycin 2 Tetrahydroisoquinoline alkaloid - - PowerPoint PPT Presentation

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Cyanocycline A and Bioxalomycin 2 Tetrahydroisoquinoline alkaloid - - PowerPoint PPT Presentation

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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

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SLIDE 1

An Efficient Synthetic Approach to Cyanocycline A and Bioxalomycin β2 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

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SLIDE 2

Cyanocycline A and Bioxalomycin β2

Brugmansia suaveolens

  • Isolated in 1994 from

Steptomyces viridostaticus

  • Isolated in 1970’s from

Streptomyces flavogriseus

  • Tetrahydroisoquinoline alkaloid family
  • Exhibit wide range of biological activity:
  • antitumor, antifungal, antimicrobial
  • Isolated in 1980 from

Actinosynnema pretiosum C-14482

N N O Me MeO O O HO H H Me N H NC H H Cyanocycline A N N O Me MeO O O H H Me N H H H O Bioxalomycin β2 N N O Me MeO O O H H Me N H H H HO HO Naphthyridinomycin N N O H2N O O H H Me N H H H HO R Dnacin A1 R = CN Dnacin B1 R = OH

  • Isolated in 1974 from

Steptomyces lusitanus

Cyanocycline A: J, Antibiot., 1982, 35, 771 Naphthyridinomycin: J, Antibiot., 1975, 28, 497 Bioxalomycin β2: JOC. 1994, 59, 4045 Dnacin A1 and B1: J, Antibiot., 1980 33, 1443 Julia Vargas @ Wipf Group 2 2/17/2008

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SLIDE 3
  • First total synthesis of (+/-) Cyanocycline A: Evans- 1986

Previous Synthesis…

N H OH H O N Me Cbz N CONH2 O N H O N Me N O N Me OMe Me OMe HO MeO2C OMe Me MeO OH N O N Me O Me OMe O HOH2C N O N Me OTBS Me OMe TBSO AcOH2C H OH OH H N O N Me OTBS Me OMe TBSO AcOH2C H OH H N OTBS OH N NMe Me MeO OH OTBS O N O H H H H N NMe Me MeO O OH CN N O H H H H O 1.) H2, Pd/C, CH2O 2.) KOtBu, tBuOH 78% 1.) MsCl, Et3N 2.) PhSeSePh, NaBH4 3.) TFA 4.) t-BuOOH 1.) methyl glyoxalate 2.) SOCl2 3.) SnCl4 46-54% 1.) LiBEt3H 2.) DDQ 91% 1.) Ac2O, DMAP 2.) Zno, TBSCl, DMAP, DIPEA 3.) OsO4, NMO 71% Et4NIO4, TBSO(CH2)2NH2 1.) TFA 2.) LiBEt3H 3.) KN(TMS)2 64% (4 steps) 85% TBSO 1.) Li, NH3; EtOH 2.) NaCN 3.) HF, pyr; Na2CO3, O2 35% 10 steps

31 linear steps

JACS 1986, 108, 2478

  • Chem. Rev. 2002, 102, 1669

Julia Vargas @ Wipf Group 3 2/17/2008

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SLIDE 4

Previous Synthesis…

  • Total synthesis of (+/-) Cyanocycline A: Fukuyama- 1987

JACS 1987, 109, 1587

  • Chem. Rev. 2002, 102, 1669

NHBoc t-BuO2C 1.) NaOEt, EtOH t-BuO O O Me 2.) TsOH, quinoline, -H2O 3.) LiBEt3H N Me t-BuO2C CH2OH Boc 68% LDA, ZnCl2 BnO MeO Me OMe CHO 77% BnO MeO Me MeO t-BuO2C N CH2OH Boc O 1.) TFA 2.) ClCO2(CH2)2CON(Ch)2, DIPEA 3.) TFA 4.) ClCO2Et, Et3N; NH3 (Ch = cyclohexyl) BnO MeO Me MeO t-BuO2C N CO2Me Boc O 1.) H2 (1000psi) Pd/C 2.) H2 (1500psi) Rh/C 3.) BnBr, K2CO3 4.) Jones 5.) MeI, K2CO3 48% 77% BnO MeO Me MeO H2NOC N CO2Me CO2(CH2)2CON(Ch)2 O

Julia Vargas @ Wipf Group 4 2/17/2008

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SLIDE 5

Previous Synthesis…

  • Total synthesis of (+/-) Cyanocycline A: Fukuyama- 1987

1.) CSA, quinoline 2.) NOCl; NaBH3CN 54% BnO MeO Me MeO HN O NOH N CO2Me CO2R 1.) H2 (1500psi), RaNi, Et3N 2.) BnOCH2CHO, AcOH 66% NH Me MeO OH OBn HN H H H MeO O N H H CO2Me H CO2R 1.) BnBr, K2CO3 2.) LiBEt3H, TMEDA 3.) Swern ox. 4.) TMSCN, ZnCl2 5.) BCl3, Ac2O, pyr 37% N N Me MeO OAc OAc CN HN H H H H MeO CO2R O 1.) Lawesson's reagent 2.) RaNi 3.) ethylene oxide/MeOH N N Me MeO OAc OAc CN N O H H H H MeO CO2R 1.) NaOH, MeOH 2.) KOt-Bu, t-BuOH 3.) MeI, DIPEA 4.) Mn(OAc)3, H2SO4 N NMe Me MeO O OH CN N O H H H H O 73% 42%

29 linear steps

JACS 1987, 109, 1587

  • Chem. Rev. 2002, 102, 1669

Julia Vargas @ Wipf Group 5 2/17/2008

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SLIDE 6

Previous Synthesis…

  • Total Synthesis of (+)-Cyanocycline A: Fukuyama- 1987

CO2Me CO2H H H2N 1.) Boc2O, Et3N 2.) EtSH, DCC, DMAP CO2Me COSEt H BocHN 1.) Et3SiH, Pd/C 2.) CH(OMe)3, CSA CO2Me CH(OMe)2 H BocHN 1.) LDA 2.) Ac2O 3.) CSA, quinoline N Me t-BuO2C Boc CH(OMe)2 (+)-Cyanocycline A 93% 95% 77%

  • this enantiospecific synthesis was used

in the determination of the absolute stereochemistry of the natural product 32 linear steps

  • Chem. Rev. 2002, 102, 1669

Li, L. Ph.D. Dissertation, Rice University, Houston, TX, 1989 Julia Vargas @ Wipf Group 6 2/17/2008

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SLIDE 7

Synthetic Strategy…

Brugmansia suaveolens

CHO H2N CHO CHO H2N Ar NH2 I III II +

*

= masked functionality HN H CHO H H2N Ar NH2 H OHC endo-selective [C+NC+CC] N N O Me MeO O O HO H H Me N H NC H H Cyanocycline A N N O Me MeO O O H H Me N H H H O Bioxalomycin β2 + Julia Vargas @ Wipf Group 7 2/17/2008

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SLIDE 8

The [C+NC+CC] Reaction

R' H CHO R H2N C H2 COX* imine formation + R C H N C COX* H H H R' dipole formation O X* C H N C H R C C Z H H Y R' H Ag + 1,3-dipolar cycloaddition H N COX* Z Y R R' H

* * * *

X*= oppolzer's D- or L-camphorsultam

AgI or CuI- catalyzed Asymmetric [C+NC+CC] coupling cascade Highlights:

  • one-pot, molecular cascade

featuring 1,3-dipolar cycloaddition

  • concerted process
  • 2 new C-C bonds
  • up to 4 new chiral centers
  • mild, efficient, selective, high yielding
  • absolute stereocontrol achieved

via chiral, nonracemic substrates

  • r auxiliaries

S N O O Oppolzer's Camphorsultam

  • works well with enolizable and α-chiral aliphatic aldehydes!
  • access to highly functionalized pyrrolidines
  • OL. 2006, 8, 3647
  • Tet. Lett., 2007, 48, 3867

Julia Vargas @ Wipf Group 8 2/17/2008

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SLIDE 9

The [C+NC+CC] Reaction

C H2 COXL/D H2N "NC" + R CHO C C H H H EWG "C" "CC" H N COXL EWG R H N COXD EWG R endo-manifold

  • cat. AgI, THF, RT

H N COXL EWG R H N COXD EWG R exo-manifold

  • cat. CuI, ligand,

DMSO, RT

Selectivity in the [3+2] cycloaddition:

S N O O O H N Cu H R EWG H P P Ph2 Ph2 Exo-Si pre-TS ensemble minimized sterics S N O O O H N Ag H R H EWG Endo-Si pre-TS ensemble favorable coordination

Transition State Rational

Highly selective, often exclusively

  • ne stereoisomer.

Julia Vargas @ Wipf Group 9 2/17/2008

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SLIDE 10

Aldehyde Synthesis

BnO MeO Me OMe MgBr + O N Boc N Bn O add 1 to 2, THF, -50 oC (71%) BnO MeO Me OMe O N Boc NOH Bn 1.) Zn, EtOH, aq NH4Cl, 90 oC 2.) CbzCl, NaHCO3 aq-dioxane (80%, two steps) BnO MeO Me OMe O N Boc NBnCbz 1.) ca. TsOH, MeOH, rt 2.) DMP, CH2Cl2, rt (65%, 2 steps) BnO MeO Me OMe O BocHN NBnCbz 1 2

42% overall yield from 2

Julia Vargas @ Wipf Group 10 2/17/2008

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SLIDE 11

Key [C+NC+CC] coupling

S N O O O N H H NHBoc BnCbzN Ar Ag CO2Me Endo-Si

Proposed Pre-TS model:

  • Stereochemical outcome predicted based
  • n previous [3+2] cycloaddition studies
  • Difficulty in confirming relative

configurations by NMR at this stage

  • Later determined by NOE studies of

advanced, rigid intermediate

  • Achieving this intermediate represents

most ambitious application of the asymmetric [C+NC+CC] coupling manifold to date

BnO MeO Me OMe O BocHN NBnCbz BnO MeO Me OMe BocHN NBnCbz HN H CO2Me COXL S N O NH2 O O OMe O + AgOAc (10 mol%), rt, 2h, 74% XL= Oppolzer's camphorsultam (A) (A)

Julia Vargas @ Wipf Group 11 2/17/2008

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SLIDE 12

Brugmansia suaveolens

End Game

(Late stage Fukuyama intermediate)

BnO MeO Me OMe BocHN NBnCbz HN H CO2Me COXL XL= Oppolzer's camphorsultam 1.) H2 atm, Pd/C MeOH, rt 2.) CbzCl, DIEA, THF, 0 oC 3.) TFA, DCM, rt HO MeO Me OMe H2N N H N H COXL Cbz H O (30-36%) BnOCH2CHO, AcOH, 4Å MS, DCM, rt HO MeO Me OMe N H COXL Cbz H H BnO H (75%) BnBr, K2CO3, DMF, 60 oC BnO MeO Me OMe N H N H COXL Cbz H O H BnO H BnO MeO Me OMe N H N H Me H O H BnO H (74%) LiAlH4, THF, 0 oC OH 1.) Swern Oxidation 2.) TMSCN, ZnCl2 (54%) BnO MeO Me OMe N H H H O H BnO H Me N H NC 1.) Lawesson's rgt. C6H6, reflux 2.) Raney-Ni, Acetone, rt BnO MeO Me OMe N H H H BnO H Me N H NC HO MeO Me OMe N H H H HO H Me N H NC O MeOH, 60 oC (sealed tube) (58%) 1.) 2.) BCl3, DCM,

  • 78 oC (52%)

H N N N N O N H O (53%) (63%)

Julia Vargas @ Wipf Group 12 2/17/2008

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SLIDE 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 β2,

thus making this an efficient formal synthesis of it as well. (see: JOC, 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