Asymmetric [C+NC+CC] Coupling Entry to the Naphthyridinomycin Natural Product Family...

Asymmetric [C+NC+CC] Coupling Entry to the Naphthyridinomycin Natural Product Family:

Formal Total Synthesis of Cyanocycline A and Bioxalomycin β2

Philip Garner, H. Ümit Kaniskan, Charles M. Keyari, and Laksiri Weerasinghe J. Org. Chem. 2011, ASAP

Brandon Parks Wipf Group Current Literature

June 18th, 2011

NN

N

O

O

O

MeO

Me

CN

H

OH

F E D

CB

A

NN

N

O

O

O

MeO

Me

H

F E D

CB

A

O

Brandon Parks @ Wipf Group of 14 6/21/2011

Napthyridinomycin Family

  Belongs to a family of tetrahydroisoquinoline alkaloids

  Isolated primarily from different species of Streptomyces

  Members of family are known “antitumor antibiotics”

  Key Features: –  Hexacyclic core framework –  Quinone functionality –  Piperazine system –  Oxazolidine fragment

Scott, J.D.; Williams, R.M. Chem. Rev. 2002, 102, 1669-1730. Ingh, K.; Sun, S.; Kluepfel, D. Dev. Ind. Microbiol. Ser. 1976, 17, 209-221. Siengalewicz, P.; Rinner, U.; Mulzer, J. Chem. Soc. Rev. 2008, 37, 2676-2690. Wipf, P.; Grace, H.C.; Kim, S.H. Tetrahedron 2006, 62, 10507-10517.

N

N

N

O

O

O

R1

R2 R5

R4

H

OR3

F E D

CB

A


Cyanocycline A and Bioxalomycin β2

  2 prior total syntheses of cyanocycline A have been completed: –  Evans (1985 and 1987) –  Fukuyama (1987 and 1992) –  Wipf (partial – 2006)

Cyanocycline A Bioxalomycin β2

NN

N

O

O

O

MeO

Me

CN

H

OH

F E D

CB

A

NN

N

O

O

O

MeO

Me

H

F E D

CB

A

O


Evans’ Total Synthesis of Cyanocycline A

  31 steps, 1.8% overall   Key Reactions:

–  Pictet Spengler and epoxide opening Evans, D.A.; Biller, S.A. Tet. Lett. 1985, 26, 1907-1910. Evans, D.A.; Illig, C.R.; Saddler, J.C. JACS, 1986, 108, 2478-2479

NH

O

NO

CbzO

NH2

1. H2, Pd/C, CH2O2. KOtBu, tBuOH

(78%)HN

NO

HO

NNAcOH2C

OTBS

TBSO

MeO O

HO

OH

Et4NIO4TBSO(CH2)2NH2

(63%)

NN

N

O

TBSOOH

HOTBSO

MeO

TBSOOAc

1. TFA2. LiBEt3H3. KHMDS

NN

N

O

TBSO

MeO

OHTBSO

OH

1. Li, NH3EtOH

2. NaCN3. HF, py;

Na2CO3, O2(35%)

NN

N

O

O

O

MeO

Me

CN

H

OH

F E D

CB

A


Fukuyama’s Total Synthesis of Cyanocycline A

Fukuyama, T.; Li, L.; Laird, A.A.; Frank, R.K. JACS, 1987, 109, 1587-1589

N

t-BuO2C

Boc

CH2OH

+

OBnMeO

OMeCHO

LDA, ZnCl2(77%) N

tBuO2C

BocOH

HOMeO

MeOOBn

N

H2NOCCO2MeOMeO

MeOOBn

R

R = (CH2)2CON(cHex)2

1. CSA, quinoline2. NOCl, NaBH3CN3. H2 (103 bar), Ra-Ni, Et3N4. BnOCH2CHO, AcOH(36% over 4 steps)

NH

HN

N

OHMeO

MeO

OBn

CO2R

CO2Me

O

1. BnBr, K2CO32. LiBEt3H, TMEDA3. Swern Ox.

NN

HN

OH

CO2R

O

MeO

MeOOBn

OBn


Fukuyama’s Completion of Cyanocycline A

  29 steps, 1.1% overall

  Key Reactions: –  Zinc di-enolate coupling –  Nitrosyl chloride oxidation/oxime formation –  Carbamate protecting group –  Pictet-Spengler

NN

N

CN

CO2RMeO

MeOOAc

OAc

ethylene oxide/MeOH(73%)

NN

N

CN

CO2RMeO

MeOOAc

OAc

O H

1. NaOH, MeOH2. KOtBu, tBuOH

3. MeI, Hünig's Base4. Mn(OAc)3, H2SO4

(42%)

NN

N

O

O

O

MeO

Me

CN

H

OH

F E D

CB

A


Wipf Approach Towards Diazabicyclo[3.2.1]octane Core

NH

CHO

MeO2C

1. Boc2O, DMAP2. NaBH4, MeOH

3. TBSCl, imid., DMAP4. LiOH, MeOH

(37%)N

OTBS

HO2C Boc

OMe

OMe

NH

CO2Et+

1. DEPBT, Et3N2. LHMDS, ClCO2Et

(56%)N

OCO2Et

EtO2CMeO

OMeBocN OTBS

1. TBAF2. BzCl, DMAP

(62%)

NO

CO2EtEtO2CMeO

OMeBocN OBz

20 mol%, Pd2dba3DBU, THF

(94%)

NN Boc

O

EtO2CEtO2C

MeO

OMe

Wipf, P.; Grace, H.C.; Kim, S.H. Tetrahedron 2006, 62, 10507-10517.


Garner’s Retrosynthetic Scheme

Garner, P.; Kaniskan, H. Ü.; Keyari, C.M.; Weerasinghe, L. JOC, 2011, ASAP

NH

HN

OBnMeO

MeO

O

OBn

NN

N

O

O

O

MeO

Me

CN

H

OH

F E D

CB

A

Streckerreaction

NR

CHOPictet-Spengler

reaction

NH2

HN

OHMeO

MeO

O

NR

COX

deprotection andlactamization

OMeMeO

BnON(Bn)Cbz

BocHNHN

CO2Me

OXs

asymmetric[C+NC+CC]

coupling

OMeMeO

BnON(Bn)Cbz

BocHN CHOCO2Me

NSO2

O

NH2

H

+

NO

Boc

OHC

asymmetrichomologation


Key Asymmetric [C+NC+CC] Coupling

R CHO

COXH2N

H

ZY

HR' H+

("C") ("CC")

("NC")

AgI cat.* *

*

HN

R

Y Z

COXR' H

*

imine formation

N COXR

R' H

H HH

dipoleformation

NR

R' H

HX

OAg

H

1,3-dipolarcycloaddition

+H

ZY

H

HNPh(H2C)2 COX

CO2MeMeO2C

BnSLi, BnSHTHF, -20oC

HNPh(H2C)2 COSBn

CO2MeMeO2C

(55%)

Garner, P.; Kaniskan, H.Ü.; Hu, J.; Youngs, W.J.; Panzner, M. Org. Lett. 2006, 8, 3647-3650.

O N

N

R H

HAg S

O2

Endo-Re


Garner’s Total Synthesis of Cyanocycline A

BrBnO

MeO OMe

Mgo, cat. C2H4Br2THF, reflux;1, -50o C

(71%)

ONBoc

N+

Bn

O-+

1BnO

MeO

NOH

ON

OBn

Boc Zn, EtOHsat'd aq. NH4Cl

90o CBnO

MeO

ON

OMe

Boc

NH

Bn

CBzClaq. NaHCO3-dioxane(85% over 2 steps)

BnO

MeO

NBnCbz

ONBoccat. TsOH

MeOH, rt(71%, 80% brsm)

BnO

MeO

NBnCbz

HNBoc

OH

OMe OMe

Dess-MartinperiodinaneCH2Cl2, rt

(85%)

BnO

MeO

NBnCbz

CHOHNBoc

OMe


Garner’s [C+NC+CC] Coupling

OMeMeO

BnON(Bn)Cbz

BocHN CHO CO2Me

NSO2

O

NH2

H

+ 10 mol% AgOAc, rt(73%, dr = 4:1)

OMeMeO

BnON(Bn)Cbz

BocHNHN

CO2Me

OXs

OMeMeO

BnON(Bn)Cbz

BocHNHN

CO2Me

OXs

H+

Sm(OTf)3MeOH, rt

(62%)

OMeMeO

BnON(Bn)Cbz

BocHNHN

CO2Me

CO2Me

OMeMeO

BnON(Bn)Cbz

BocHNHN

CO2Me

CO2Me

H+

OBn

OMeMeO

CbzBnN

NHBocN

H

AgH

O

L

O

OMe

H

NSO

O


Garner’s End Game

OMeMeO

BnON(Bn)Cbz

BocHNHN

CO2Me

COXs

H2 atm, Pd/CMeOH, rt

(57%)

OMeMeO

HONH

HN

O

BocHN

COXs

CbzCl, DIEATHF, 0o C

(85%)

OMeMeO

HONH

N

O

BocHN

COXsCbz

TFACH2Cl2, rt

OMeMeO

HONH

N

O

H2N

COXsCbz

BnOCH2CHOAcOH, 4 Å MS

CH2Cl2, rt(86% over 2 steps)

OMeMeO

HONH

N

O

COXsCbz

HN

OBn

OMeMeO

BnONH

N

O

COXsCbz

HN

OBn

BnBr, K2CO3DMF, 50o C

(81%)

LiAlH4THF, 0o C

(61%)

OMeMeO

BnONH

N

O

HN

OBnOH

1. Swern oxidation2. TMSCN, ZnCl2

(45%)

NN

HNMeO

MeOBnO CN

OBn

O

1. Lawesson's reagentC6H6, reflux

2. Raney-Ni/acetone, rt(63%)

NN

NMeO

MeOBnO CN

OBn


NN

NMeO

MeOBnO CN

OBn

MeOH, 60o C(sealed tube)

(58%)

ON

N

NMeO

MeOBnO CN

OBn

O

BCl3CH2Cl2, -78o C

(52%)

NN

NMeO

MeOOH CN

OH

O

Mn(OAc)3(Fukuyama)

NN

N

O

O

O

MeO

Me

CN

H

OH

F E D

CB

A

Garner’s Formal Completion of Cyanocycline A

  22 steps, 0.3% overall

 Key Reactions: –  Stereoselective Grignard addition –  [C+NC+CC] coupling –  Pictet-Spengler –  Late stage “D” ring closure


Conclusions

  Formal synthesis of bioxalmycin β2 and 3rd completed synthesis (formal) of cyanocycline A

 Currently the shortest synthesis although lower yielding than previous syntheses

  Novel [C+CN+CC] coupling reaction utilized

NN

N

O

O

O

MeO

Me

CN

H

OH

F E D

CB

A

NN

N

O

O

O

MeO

Me

H

F E D

CB

A

O


Asymmetric [C+NC+CC] Coupling Entry to the Naphthyridinomycin Natural Product Family...

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