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Totalsynthesisof(‐)‐NakadomarinA

Jakubec,P.;Cockfield,D.M.;Dixon,D.J.

J.Am.Soc.Chem.ASAP.

N

O

N

H

(-)-Nakadomarin A

Outline

o BiologicalacHvity

o Previoussynthesis

o Synthesisfromthepaper

•  Retrosynthesis•  Forwardsynthesis

BiologicalacHvity

N

O

N

H

(-)-Nakadomarin A1

Isolatedin1997fromaseaspongeAmphimedobyKobayashioffthecoastoftheKeramaIslands,Okinawa

onlyknownmemberofthemanzaminefamilytocontainafuranring

Limitedavailabilityfromnature:6mgisolatedfrom1kgofwetsponge

BioacHvityincludesanHcancer,anHfungalandanHbacterial

Kobayashi,J.;Watanabe,D.;Kawasaki,N.;Tsuda,M.J.Org.Chem.1997,62,9236‐9239.

Structure

N

O

N

H

(-)-Nakadomarin A1

Kobayashi,J.;Watanabe,D.;Kawasaki,N.;Tsuda,M.J.Org.Chem.1997,62,9236‐9239.

Structuralfeatures:

• Ringsystem:8/5/5/5//15/6

• 4stereogeniccenters,1quaternary

• Zalkene

PreviousSynthesis

N

O

N

H

(-)-Nakadomarin A1

CompletedSyntheses:(+)‐NakadomarinA:Nagata,NakagawaandNishida,JACS,2003,125,7484YoungandKerr,JACS,2007,129,1465

(‐)‐NakadomarinA:Ono,NakagawaandNishida,ACIE,2004,43,2020

PublishedApproaches:Furstner,JACS,1999,121,11108Magnus,TL,2002,43,947Tius,OL,2003,5,1171Williams,OL,2004,6,4539Funk,OL,2006,8,3833.

Nakagawa’ssynthesis(‐)‐NakadomarinA

Ono,K.;Nakagawa,M.;Nishida,A.Angew.Chem.Int.Ed.2004,43,2020.

ForwardSynthesis:

36longestlinearsteps

2.5mgofthetargetproduct.

Nakagawa’ssynthesis(+)‐NakadomarinA

Forwardsynthesis:37longestlinearsteps

Nagata,T.;Nakawaga,M.;Nishida,A.J.Am.Chem.Soc.2003,125,7484.

Kerr’ssynthesis

(+)‐NakadomarinA

Forwardsynthesis:

29longestlinearsteps

Young,I.S.;Kerr,M.A.J.Am.Soc.Chem.2007,129,1465.

RetrosyntheHcanalysis

Synthesisoffragment7

N

NN

N

SH

NaH, THF

HNO

OTs

N N

NNS

NH

O

N

NN

N

SNa

+THF, reflux, 12 h

96%

9 1011

N N

NNS

N

O

O

O

N N

NNS

N

OO

O

O

Br

NaH, TBAI(cat.)DMSO, 12 h, RT

71%

N N

NNS

N

O

O

O

OO

O

O

m-CPBA, CH2Cl2RT, 14 h

78%

HCl, THFRT, 2 h

98%

121314

N

O

MeOOC

7

Synthesisoffragment7

IntramolecularJulia‐Kocienski

N

O

MeOOC

7

N

O

N

O

MeOOC

N N

NNS

N

OO

O

O

Cs2CO3, DMF, THF, H2O

70 oC, 10 h

56%

LHMDS, THF

MeO OMe

O

-78 oC to 0 oC, 2.5 h

82%

14 15 7

ModifiedJuliaolefinaHon

N

S

S

RO

O

LDA

N

S

S

RO

O

Li

H

O

R'

R

R'

R

R'+

ModifiedJuliaolefinaHon

N

S

S

RO

O

LDA

N

S

S

RO

O

Li

H

O

R'

R

R'

R

R'+

ModifiedJuliaolefinaHon

N

S

S

RO

O

LDA

N

S

S

RO

O

Li

H

O

R'

R

R'

R

R'+

Py,PT,TBTprovidesevenhigherEselecHvitythanBTinintermolecularreacHons.

Julia‐KocienskiolefinaHon

Blakemore,P.R.;Cole,W.J.Kocienski,P.J.Synlef,2008,26.

IntramolecularJulia‐KocienskiolefinaHon

Aissa,C.J.Org.Chem.2006,71,360.

Synthesisoffragment7

IntramolecularJulia‐Kocienski

N

O

N

O

MeOOC

N N

NNS

N

OO

O

O

CsCO3, DMF, THF, H2O

70 oC, 10 h

56%

LHMDS, THF

MeO OMe

O

-78 oC to 0 oC, 2.5 h

82%

14 15 7

N

O

MeOOC

7

FirstexampleofIntramolecularJulia‐Kocienskiincomplexnaturalproductsynthesis

Synthesisoffragment8

O

P

OMe

O

OMe O

OAc

OAc

OHO

OOO

O2N

NaH, BuLi, THF, 0 oC, 1 h

Br

OOAc

OAc

,

THF, RT, 2 h

42%

HCl, EtOH

65 oC, 24 h

69%

(COCl)2

DMSO,

NEt3,

CH2Cl2

- 78 oC to RT

0.5 h

86%

MeNO2, KOH, EtOH

0 oC, 2 h

then MsCl, NEt3- 15 oC to RT 15 min

88%

16 17

18

198

Synthesisoffragment8O

P

OMe

O

OMe O

OAc

OAcNaH, BuLi, THF, 0 oC, 1 h

Br

OOAc

OAc

,

THF, RT, 2 h

42%

16 17

Grieco,P.A.;pogonowski,C.S.J.Am.Chem.Soc.1973,95,3071.

O

P

OMe

O

OMe

NaH, THF

n-BuLi O

P

OMe

O

OMe

Br O

P

OMe

O

OMe

OOAc

OAc

WHE

Synthesisoffragment8

O

P

OMe

O

OMe O

OAc

OAc

OHO

OOO

O2N

NaH, BuLi, THF, 0 oC, 1 h

Br

OOAc

OAc

,

THF, RT, 2 h

42%

HCl, EtOH

65 oC, 24 h

69%

(COCl)2

DMSO,

NEt3,

CH2Cl2

- 78 oC to RT

0.5 h

86%

MeNO2, KOH, EtOH

0 oC, 2 h

then MsCl, NEt3- 15 oC to RT 15 min

88%

16 17

18

198

Synthesisoffragment8

O

OAc

OAc

OHO

HCl, EtOH

65 oC, 24 h

69%17 18

O

OH

acid hydrolysis

HOO

HO

HO

O

HO

H2OH

AcO

H

H

Synthesisoffragment8

O

P

OMe

O

OMe O

OAc

OAc

OHO

OOO

O2N

NaH, BuLi, THF, 0 oC, 1 h

Br

OOAc

OAc

,

THF, RT, 2 h

42%

HCl, EtOH

65 oC, 24 h

69%

(COCl)2

DMSO,

NEt3,

CH2Cl2

- 78 oC to RT

0.5 h

86%

MeNO2, KOH, EtOH

0 oC, 2 h

then MsCl, NEt3- 15 oC to RT 15 min

88%

16 17

18

198

Forwardsynthesis

O

O2N

8

N

O

MeOOC

7

+

NH

HN

HN ON

F3C CF3

20

(15 mol%)

Toluene, 30 oC, 8 days

dr: 91:9

57%

N

MeOOC

O

O2N

O

4

N

O

O

N

O

NO2H2N

H H

O

MeOH, reflux, 3 h

68% 3

Nitro‐Mannich/LactamizaHoncascade

Nitro‐Mannich/LactamizaHoncascade

N

MeOOC

O

O2N

O

4

N

O

O

N

O

NO2H2N

H H

O

MeOH, reflux, 3 h

68% 3

H2N

H H

O

N

+

N

MeOOC

O

NH

O

NO2

nitro-Mannich Lactamization

Forwardsynthesis

N

O

O

N

O

NO2 AIBN, Bu3SnHToluene, reflux, 4 h

3

70%

N

O

O

N

O

21

R NO2

R H

Bu3Sn-H

Bu3Sn-NO2

Forwardsynthesis

N

O

O

N

ON

O

O

N

N

O

N

H

(-)-Nakadomarin A1

21

LiAlH4, toluene, - 20 oC, 1 h

then HCOOH, RT, 14 h

86%22

N

O

N

H

2

DIBAL, toluene, - 20 oC, 1 h

then HCl, 90 oC, 24 h

41%

Grubb's 1st generation catalyst(+)-CSA, CH2Cl2, reflux, 3.5 h62%

62:37 Z/E

SelecHvereducHonoflactam

RCM

Forwardsynthesis

DIBAL, toluene, - 20 oC, 1 h

N

O

O

N

22

N

O

N

H

2

then HCl, 90 oC, 24 h

ReducHon/iminiumionformaHon/diastereoselecHveC‐CbondformingcyalizaHon

N

O

N

HO

N

O

N

H

F-C alkylation like bond formation

Forwardsynthesis

N

O

O

N

ON

O

O

N

N

O

N

H

(-)-Nakadomarin A1

21

LiAlH4, toluene, - 20 oC, 1 h

then HCOOH, RT, 14 h

86%22

N

O

N

H

2

DIBAL, toluene, - 20 oC, 1 h

then HCl, 90 oC, 24 h

41%

Grubb's 1st generation catalyst(+)-CSA, CH2Cl2, reflux, 3.5 h62%

62:37 Z/E

SelecHvereducHonoflactam

RCM

ThefirstexampleofE/ZselecHvitybeingreversedwithandwithoutacid

Thankyou!

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