An Efficient Synthetic Approach to Cyanocycline A and ...ccc.chem.pitt.edu/wipf/Current...

An Efficient SyntheticApproach to Cyanocycline A

and Bioxalomycin β2 via[C+NC+CC] coupling

H. U. Kaniskan and P. GarnerCase 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

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

MeNH

NC

HH

Cyanocycline A

N

N O

Me

MeO

O

O

H

H

MeNH

H H

O

Bioxalomycin !2

N

N O

Me

MeO

O

O

H

H

MeNH

H HHO

HO

Naphthyridinomycin

N

N O

H2N

O

O

H

H

MeNH

H HHO

R

Dnacin A1 R = CNDnacin B1 R = OH

• Isolated in 1974 from Steptomyces lusitanus

Cyanocycline A: J, Antibiot., 1982, 35, 771Naphthyridinomycin: J, Antibiot., 1975, 28, 497

Bioxalomycin β2: JOC. 1994, 59, 4045Dnacin A1 and B1: J, Antibiot., 1980 33, 1443


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

Previous Synthesis…

NH

OH

H

O

N

Me

CbzN

CONH2

O

NH

O

N

Me

NO

N

Me

OMe

Me

OMe

HO

MeO2C

OMe

Me

MeO

OHN

O

N

Me

O

Me

OMe

O

HOH2C

NO

N

Me

OTBS

Me

OMe

TBSO

AcOH2CH

OH

OH

H

NO

N

Me

OTBS

Me

OMe

TBSO

AcOH2CH

OHH

N OTBS

OH

N

NMeMe

MeO

OH

OTBS

O

N

O

H

H HH

N

NMeMe

MeO

O

OH

CN

N

O

H

H HHO

1.) H2, Pd/C, CH2O

2.) KOtBu, tBuOH

78%

1.) MsCl, Et3N

2.) PhSeSePh, NaBH43.) TFA4.) t-BuOOH

1.) methyl glyoxalate

2.) SOCl23.) 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.) LiBEt3H3.) KN(TMS)2

64% (4 steps)

85%

TBSO 1.) Li, NH3; EtOH2.) NaCN

3.) HF, pyr; Na2CO3, O2

35%

10 steps

31 linear stepsJACS 1986, 108, 2478Chem. Rev. 2002, 102, 1669


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

JACS 1987, 109, 1587Chem. Rev. 2002, 102, 1669

NHBoct-BuO2C

1.)

NaOEt, EtOH

t-BuO

O O

Me

2.) TsOH, quinoline, -H2O3.) LiBEt3H

NMe

t-BuO2C

CH2OH

Boc

68%

LDA, ZnCl2

BnO

MeO

Me

OMe

CHO

77%

BnO

MeO

Me

MeOt-BuO2C

NCH2OH

Boc

O

1.) TFA2.) ClCO2(CH2)2CON(Ch)2, DIPEA

3.) TFA4.) ClCO2Et, Et3N; NH3

(Ch = cyclohexyl)

BnO

MeO

Me

MeO

t-BuO2C

NCO2Me

Boc

O

1.) H2 (1000psi) Pd/C2.) H2 (1500psi) Rh/C

3.) BnBr, K2CO34.) Jones5.) MeI, K2CO3

48%77%

BnO

MeO

Me

MeOH2NOC

NCO2Me

CO2(CH2)2CON(Ch)2

O


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

1.) CSA, quinoline

2.) NOCl; NaBH3CN

54%

BnO

MeO

Me

MeO HN

O

NOH

NCO2Me

CO2R

1.) H2 (1500psi), RaNi, Et3N

2.) BnOCH2CHO, AcOH

66%

NH

Me

MeO

OHOBn

HN

H

H HMeO

O

N

H

H

CO2Me

H

CO2R

1.) BnBr, K2CO32.) LiBEt3H, TMEDA

3.) Swern ox.4.) TMSCN, ZnCl25.) BCl3, Ac2O, pyr

37%

N

NMe

MeO

OAc

OAc

CN

HN

H

H HHMeO

CO2R

O

1.) Lawesson's reagent

2.) RaNi3.) ethylene oxide/MeOH

N

NMe

MeO

OAc

OAc

CN

N

O

H

H HHMeO

CO2R1.) NaOH, MeOH2.) KOt-Bu, t-BuOH

3.) MeI, DIPEA4.) Mn(OAc)3, H2SO4

N

NMeMe

MeO

O

OH

CN

N

O

H

H HHO

73% 42%

29 linear steps

JACS 1987, 109, 1587Chem. Rev. 2002, 102, 1669


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

CO2Me

CO2HH

H2N 1.) Boc2O, Et3N

2.) EtSH, DCC, DMAP

CO2Me

COSEtH

BocHN 1.) Et3SiH, Pd/C

2.) CH(OMe)3, CSA

CO2Me

CH(OMe)2H

BocHN

1.) LDA

2.) Ac2O3.) CSA, quinoline

NMe

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, 1669Li, L. Ph.D. Dissertation, Rice University, Houston, TX, 1989


Synthetic Strategy…


CHO

H2N

CHOCHO

H2N

Ar

NH2

I

III

II

+

*

= masked functionality

HNH

CHOH

H2N

Ar NH2

HOHC

endo-selective[C+NC+CC]

N

N O

Me

MeO

O

O

HO

H

H

MeNH

NC

HH

Cyanocycline A

N

N O

Me

MeO

O

O

H

H

MeNH

H H

O

Bioxalomycin !2

+


The [C+NC+CC] Reaction

R'H

CHOR

H2NCH2

COX*

imine formation

+

R CH

NC

COX*

HH

HR'

dipole formation

O

X*CH

NCH

R

C C

Z

HH

Y

R' H Ag

+1,3-dipolarcycloaddition

HN COX*

ZY

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 or auxiliaries

SN

O O

Oppolzer's Camphorsultam

- works well with enolizable and α-chiral aliphatic aldehydes!- access to highly functionalized pyrrolidines

OL. 2006, 8, 3647Tet. Lett., 2007, 48, 3867


The [C+NC+CC] Reaction

CH2

COXL/DH2N

"NC"

+

R CHO C C

H

H

H

EWG"C"

"CC"HN

COXL

EWG

R

HN

COXD

EWG

R

endo-manifold

cat. AgI, THF, RT

HN

COXL

EWG

R

HN

COXD

EWG

R

exo-manifold

cat. CuI, ligand,

DMSO, RT

Selectivity in the [3+2] cycloaddition:

S

N

O

O

O

H NCu

H R

EWGH

P

P

Ph2

Ph2

Exo-Si pre-TS ensemble

minimized

sterics

S

N

OO

O

H NAg

H R

HEWG

Endo-Si pre-TS ensemble

favorable coordination

Transition State Rational

Highly selective, often exclusivelyone stereoisomer.


Aldehyde Synthesis

BnO

MeO

Me

OMe

MgBr

+

ONBoc

N

Bn

O

add 1 to 2,

THF, -50 oC

(71%)

BnO

MeO

Me

OMe

O

NBoc

NOH

Bn

1.) Zn, EtOH,

aq NH4Cl, 90 oC

2.) CbzCl, NaHCO3

aq-dioxane

(80%, two steps)

BnO

MeO

Me

OMe

O

NBoc

NBnCbz

1.) ca. TsOH, MeOH, rt

2.) DMP, CH2Cl2, rt (65%, 2 steps)

BnO

MeO

Me

OMe

O

BocHN

NBnCbz

12

42% overall yield from 2


Key [C+NC+CC] coupling

SN

O O

O

NH

HNHBoc

BnCbzN Ar

Ag

CO2Me

Endo-Si

Proposed Pre-TS model:• Stereochemical outcome predicted based on 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

OBocHN

NBnCbz

BnO

MeO

Me

OMe

BocHN

NBnCbz

HN

H CO2Me

COXL

SN

O

NH2

O O

OMe

O

+AgOAc (10 mol%),

rt, 2h, 74%

XL= Oppolzer's camphorsultam (A)

(A)



End Game

(Late stage Fukuyama intermediate)

BnO

MeOMe

OMe

BocHN

NBnCbz

HN

H CO2Me

COXL

XL= Oppolzer's camphorsultam

1.) H2 atm, Pd/C MeOH, rt2.) CbzCl, DIEA, THF, 0 oC

3.) TFA, DCM, rt

HO

MeOMe

OMe

H2N

NH

NH

COXLCbz

H

O

(30-36%)

BnOCH2CHO, AcOH,4Å MS, DCM, rt

HO

MeOMe

OMe

N

H

COXLCbz

H

H

BnO H

(75%)

BnBr, K2CO3,

DMF, 60 oC

BnO

MeOMe

OMe

NH

N

H

COXLCbz

H

OH

BnO H

BnO

MeOMe

OMe

NH

N

H

Me

H

OH

BnO H

(74%)

LiAlH4, THF, 0 oC

OH

1.) Swern Oxidation2.) TMSCN, ZnCl2

(54%)

BnO

MeOMe

OMe

NH

HH

OH

BnO H

MeNH

NC1.) Lawesson's rgt. C6H6, reflux

2.) Raney-Ni, Acetone, rt

BnO

MeOMe

OMe

NH

H

H

BnO H

MeN

HNC

HO

MeOMe

OMe

NH

H

H

HO H

MeN

HNC

O

MeOH, 60 oC(sealed tube) (58%)

1.)

2.) BCl3, DCM, -78 oC (52%)

HN

N N N

O

NH

O

(53%)(63%)


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


An Efficient Synthetic Approach to Cyanocycline A and ...ccc.chem.pitt.edu/wipf/Current...

Documents

Transcript of An Efficient Synthetic Approach to Cyanocycline A and ...ccc.chem.pitt.edu/wipf/Current...