Total Synthesis of Communesins Jian-Zhou Huang 2012-10-27

Total Synthesis of Communesins

NNH

NN

H

O

O H

NN

NN

H

Cl

Cl

BrN

N

NN

R1H

R2 O

X H

H

H

Jian-Zhou Huang2012-10-27

1, Intrduction2, Model Study

2.1 model study by Stoltz 2.2 model study by Funk

3, Total Synthesis 3.1 Total Synthesis by Yong Qin 3.2 Total Synthesis by Weinreb 3.3 Total Synthesis by Dawei Ma 3.4 Total Synthesis by Funk

4, Conclusion

Contents

1, Intrduction

Ficus microcarpa榕树

NO

NN

H

O

O H

nomofungin

In 2001, Hemscheidt

In 2003, Stoltz and FunkThomas K. Hemscheidt, J. Org. Chem. 2001, 66, 8717

B. M. Stoltz, Tetrahedron Lett. 2003, 44, 1203 R. L. Funk, Org. Lett. 2003, 5, 3169

NNH

NN

H

O

communesin B

O H

Structures of the Communesins

1, Intrduction

NNH

NN

H

O

O H

NN

NN

R1H

R2 O

X H

H

H

communesin A : R1 = Me, R2 = Me, X = O

communesin C : R1 = H, R2 = 2,4-pentadienyl, X = O

communesin D : R1 = CHO, R2 = Me, X = O

communesin E : R1 = H, R2 = Me, X = O

communesin F : R1 = Me, R2 = Me, X = H

communesin G : R1 = Me, R2 = Et, X = O

communesin F : R1 = H, R2 = n-propyl, X = O

communesin B

NN

NN

H

Cl

Cl

Br

perophoramidine

NNH

NN

R1H

R3

R2 O

A BC

DE

FG

communesins

2, Model Study

NH

NH

Boc

TsHN

Cl

CsCO3

CH2Cl2-780C N

N

NHH

TsN

NH

NHH

99 %

Mg, NH4Cl, CH3OH, 80 %

N

Ts

2.1 Biomimetic model study by Stoltz

B. M. Stoltz, Tetrahedron Lett. 2003, 44 , 1203

NH

NH

H

NO

H2N

HN

NH

H

N

H2N

O

+

NNH

HNONHH

NNH

NN

H

O

O H

H

R. L. Funk, Org. Lett. 2003, 5, 3169

2.2, Model study by Funk

NH

N

H

+

O

NH

CO2Et1, i-PrOH, 25OC,12h, 99 %

2, ClCO2Ph,Py, DCM,65 %

NH

N

OCO2Ph

NHCO2Et

NH

N

NCO2Et

160 OC, dichlorobenzene

NN

N

H CO2Et

70 %

KOH,NH2NH2, HOCH2CH2OH

1500CN

NH

N

H

3.1, First Total Synthesis of Communesins F by Yong Qin

Yong Qin , J. Am. Chem. Soc. 2007, 129, 13794-13795

Retrosynthetic analysis

N NH

N N

Ac

N N

N N

R

N N

HN N

R

EtO

N N

HNHN

R

OBocHO

N N

Br

R

O O

N NH

BrO O

N N3

BrO O

N2

3.1 Total Synthesis of Communesins F by Yong Qin

N NH

BrO O

H

H

(g) ClCO2Me, DMAP

CHCl3, rt, 7 h, 93%;

Yong Qin, J. Am. Chem. Soc. 2007, 129, 13794Yong Qin, Org. Lett. 2006, 8, 2187

N N

BrO O

COOMe

N

BrO

O

O

N3

(c)TsNHNH2, TsOH, CHCl3, reflux, 5 h (85%);

(d) DBU,CH2Cl2, 12 h (85%);

Staudinger reaction

N

BrO

N3

O (f) PBu3, aq. THF,0 ¡ãC, 0.5 h (83%)

dr = 1.6 : 1N

BrO

N2

O

N3

(e) CuOTf, CH2Cl2,

rt, 1 h (88%)

N N

BrO O

COOMe

(h) DMAP,CH2Cl2, rt, 6 h,

N N

BrO O

COOMe

(i) NaH, allyl bromide, DMF, 0 - 65 ¡ãC,

4 h (84%)

NH

Br OH O

HO

ON3

+

(a) SOCl2,60 °C,2h;

(b) Et3N, CH2Cl2, 0 °C, 5 h

N N

BrO O

COOMe

(a) OsO4, aq. acetone;

(b) NaIO4, aq. THF95%

(c) NH2OHaHCl, Na2CO3, aq. THF;

(d) H2, Raney-Ni, MeOH, 40 ¡ãC, 3 h

(e) MeONa, MeOH, 70¡ãC, 12 h (98%);

N N

Br

COOMe

HNOHO (f) Dess-Martin reagent, CH2Cl2, rt, 5 min;

(g)NH2OHaHCl, Na2CO3, aq. THF, 10 min;

(h) H2, Raney-Ni, MeOH, 50 ¡ãC,1 h(i) Boc2O, Na2CO3,CH2Cl2 (50% from 17) N N

Br

COOMe

HNOBocHN (j) Pd(OAc)2,P(o-Tol)3,Et3N,

microwave, 2 h (68% 4, 21% of 15 recovered);

N N

COOMe

HNOHN

BocHO

(k) PPTS, CHCl3 rt, 1 h (66% 17, 26% 16)

Yong Qin, J. Am. Chem. Soc. 2007, 129, 13794

N N

COOMe

HNON

Boc

N N

COOMe

HNOHN

Boc

HO

N N

BrO O

COOMe

O

N N

COOMe

NN(n) silica gel, CH2Cl2/MeOH 1:1

50 ¡ãC, 12 h (81% ) (p) NaBH4, AcOH/Ac2O 1:1, 0 ¡ãC, 73%

(o) KOH, MeOH/ H2O 10:1 100 ¡ãC, 24 h

Yong Qin, J. Am. Chem. Soc. 2007, 129, 13794

N NH

NN

O

HH

Communesin F

23 reaction steps3% overall yield

N N

COOMe

NON

HEt

(l) BF4OEt3, iPrNEt2,CH2Cl2 rt, 2 h (95%)

(m) 5% TFA in CH2Cl2, rt, 30 min

N N

COOMe

HNON

Boc

3.2 Total Synthesis by Weinreb

N

OTf

Bn

EtO2C NO2

B(OH)2

+

N

N

O

NO2

COOEt

BOMO

a) [Pd(PPh3)4], DME, H2O

Na2CO380 ¡ãC, 98%;

b) LiOH, H2O, MeOH 50¡ãC, 86 %;

c) SOCl2, reflux then iPr2NEt, CH2Cl2,RT, 12, 87 %;

d) ClCO2Et, CH2Cl2 0¡ãC-RT, 96 %

e) NaH,THF, MeI 0¡ãC-RT, 92 %;

f) Pd(OAc)2, PPh3 DMA, K2CO3

nBu4NBr, 150¡ãC, 90 %.

Steven M. Weinreb, Angew. Chem. Int. Ed. 2010, 49, 2000 –2003

Suzuki-Miyaura reaction

NBn

EtO2C

NO2

NH2

IBOMO

NBn

NO2

NH

OI

OBOM

NCOOEt

NO2

N

OI

OBOM

CH3

H

OBOM =

N

N

O

NO2

COOEt

BOMO

N N

N

COOEt

BOMO

BocH

a) 5% Pt/C, H2 (40 atm) toluene, RT

b) Boc2O, K2CO3,THF H2O, 60¡æ, 87% (2 steps)

c) AlH3¡¤Me2NEt THF, 0¡æ, RT

74%;N

N

O

NHBoc

COOEt

BOMO

h) KOtBu, THF allyl iodide -78¡æ-RT, 87%

d) 1m KOH, EtOH, 94 ¡æ;e) NCN3, MeCN, RT,

93%(2 steps);

i) 1M KOH, EtOH 80¡æ, 94%j) OsO4, NMO THF, H2O then NaIO4, RT

k) NaBH4,EtOH, 0¡æl) MsCl, NEt3 CH2Cl2,0¡æ, 83%

N N

N

H

BOMO

Boc

O

H

OMs


N N

N

H

BOMO

Boc

N

H

CN

H

g) Boc2O, LiHMDS THF, RT, 95%;

f) 1m KOH, EtOH 94¡æ, 60%;

N N

N

Boc

BOMO

Boc

O

H

H

N N

N

Boc

BOMO

Boc

O

H

N N

N

H

Boc

O

H

N3

O

N N

N

H

BOMO

Boc

O

H

OMs

N N

Boc

HN

H

O

OHN

Boc

N N

Boc

HN

H

OH

OHN

Boc

N N

Boc

HN

H

ON

Boc

N N

Boc

N

H

ON

Boc

N

N N

N

Boc

N N

N

H

O

Boc

O

H

OMs

N N

N

H

O

Boc

O

H

N3

c) NaN3, DMF, 90¡æ, 61%;

d) Me2CO, 10% NaOH/H2O

60¡æ, 93%;

e) Boc2O, LiHMDS THF, RT, 81%;

f) PMe3, THF,H2O 70¡æ, 88%.

g) MeLi, THF, -78¡æ, 73%;

h) PPTS, CHCl3 RT, 62%; i) Me3OBF4, iPr2NEt

CH2Cl2, RT, 86%

j) 5% TFA, CH2Cl2 RT, 88%;


a), Pd(OH)2, H2 THF, RT

b) DMP, CH2Cl2,RT, 75% (2 steps)

Pearlman¡s̄ catalyst

cross-aldol reaction

N

N N

NH

Ac

l) 40% TFA in CH2Cl2 RT, 66% (2 steps).

k) NaBH4,Ac2O, HOAc

N

N N

N

Boc


30 reaction steps

Dawei Ma, J. Am. Chem. Soc. 2010, 132, 13226–13228

3.3 Total Synthesis by Dawei Ma

N NH

NN

O

HH

Communesin F

N N

HN O

OH

HO

BocN N

BrN O

Boc

PhTBSO

N O2N

BrN O

PhTBSO

N

N

Ph

OTBS

O

NO2

Br

NH

N

Ph

OTBS

O

NO2

Br

Oxidative coupling


NH

Br OH

(d) LiHMDS, THF, -78 ¡ãC then I2, -78 ¡ãC to rt;

N

Br

O2N

N O

PhTBSO

(e) Fe,NH4Cl, tBuOH, H2O,reflux

(f) KOtBu, MeI, THF, 0 ¡ãC.


(a) IBX, DMSO;

(b) NaBH(OAc)3;

H2NPh

OTBSNH

Br HN

Ph

OTBS

(c) BOPCl, Et3N CH2Cl2,0 ¡ãC to rt;

O

HONO2

NH

BrN

O

NO2Ph

TBSO

N

BrN O

PhTBSO

NH

N

BrN O

PhTBSO

NH

+

50 % 16 %

3.3 Total Synthesis by Dawei Ma

N

BrN O

PhTBSO

NH

N

Br

HN O

N

Boc

OH

(a) KHMDS (Boc)2O THF, 0 ¡ãC

(b) KOtBu, ether, rt;

(c) TBAF, THF

(d) LiOH¡¤H2O DMSO, 100 ¡ãC;

(e) HCl, THF 60 ¡ãC;

(f) NaIO4,K2OSO4(H2O)2, NMO, THF, H2O;

(g) NaBH4, MeOH;

(i) MsCl, Et3N

CH2Cl2, 0 ¡ãC

N

N O

N

Boc

OMs(j) NaN3,nBu4NBr

DMF, 90 ¡ãC;

N

N O

N

Boc

N3


N

Br

HN O

N

Boc

N

HN O

N

Boc

OH

HO

N

BrN O

PhTBSO

N

Boc

N

BrN O

PhHO

N

Boc

(h) Pd(OAc)2,P(o-Tol)3, PMP nBu4NBr,microwave 3:2 2-methyl-3-buten-2-ol/DMF

HO

I

(k) P(nBu)3, 80 ¡ãC;

toluene

N

N O

N

Boc

N3

N

N N

N

Boc

(l) NaBH4, HOAc,

Ac2O;

N NH

NN

O

HH

Communesin F


Angew. Chem. Int. Ed. 2011, 50, 12008 –12011Communesins A and B :

19 reaction steps6 % overall yield


Raymond L. Funk, J. Am. Chem. Soc. 2012, 134, 16941−16943

N NH

NN

O

HH

Communesin FN N

H

COOMeH2N

OH

H

NH

N

Br COOMeHN

H

Boc

Ts

N

BrN3 NH

OH

NH

N

OH

N3

H

Br

NH

N3Br

NH

O

Br

N

O

3.4 Total Synthesis by Funk

NH

N3

Br

NH

O

Br

+

N

BrN3 NH

OH

0.8equivAg2CO3CH3CN

rt, 16h70 %

ab, TsCl,NaH O¡ãC, 0.5h

c, MeOH,rt 16h, 61%

d, Me3OBF4, CsCO3 DCM, rt, 24h,70%e, PtO2, H2, Boc2O EtOAc, rt, 16h

f, Mg, MeOH rt, 18h,70%

i, TBSOTf,DCM lutidine, rt, 3h KF, MeOH,rt, 1h

j, AlMe3, DCM, 87% 0¡ãC 1h

k, KHMDS, THF -78¡æ, 0.5h

ICH2CN, THF-78¡æ, 0.5


N NH

N

H

O

H

N NH

N

H

O

CN

NH

N

Br COOMeN3

H

HS OO

N N

Br

CH3

COOMeHN

H

Boc

HH

g, Pd(OAC)2,K2CO3, H2O, DMF, 90¡ãC, 93%

h,Hg(OTf)3, DCM rt, 20h, 86%

N NH

COOMeN

H

HN N

H

COOMeHN

H

H

Boc Boc

3.4 Total Synthesis by Funk

HO

m, NH3, NH4Cl MeOH, rt, 1h

NaBH3CN, 72h

N NH

N

H

O OH

n, Ag2O,Et3N DMAP,DCM rt, 0.5h 51%

N NH

NN

O

HH

Communesin F


l, LiAlH4, THF 60¡æ, 1.5h

N NH

N

H

O

CN

15 reaction steps6.7% overall yield

N NH

N

H

HN

N

BrO

N3

O

2007, Yong Qin

NH

N3Br

N

O

2012, Funk

NBn

NO2

N

OI

OBOM

2010, Weinreb

N

Br

O2N

N O

PhTBSO

2010, Dawei Ma

4, Conclusion

NNH

NN

R1H

R3

R2 O

A BC

DE

FG

communesins

Thank You!

Oxidative Coupling

HC CO2R +LiN THF

-78¡æLiC CO2R

CuBr2C CO2RRO2C

C CO2R

Cu(I)

Lindert, A. J. Am. Chem. Soc.1971, 93, 4605-4606

Phil S. Baran, J. Am. Chem. Soc. 2004, 126, 7450-7451

O

H

NH

+LHMDS(3 eq)

copper(¢ò)2-ethylhexanoateO

H

N+

4 eq

O

H

N+

NH

OH H

NH

NCSH H

(+)-hapalindole

M. E. Hermes ,J. Am. Chem. Soc., 1964, 86 , 4506

N N

N

COOEt

BOMO

BocH

N

N

NCN

N N

N

H

Boc

N NN

H

NC

N N

N

H

Boc

N

N2

H

NC

N N

N

H

BOMO

Boc

N

H

CN

Hf) 1m KOH, EtOH 94¡æ, 60%;

g) Boc2O, LiHMDS THF, RT, 95%;

N N

N

H

BOMO

Boc

O

H

H

d) 1m KOH, EtOH, 94 ¡æ;e) NCN3, MeCN, RT,

93%(2 steps);

OBOM OBOM

N N

N

Boc

BOMO

Boc

O

H

H

N2

Staudinger reaction

N N NR'

N N NR' N N

R'

N PR3

R3P

N N

N

R'

- N2R NPR3

H2O

R NH2

+

PR3O

R3PMechanism

The Staudinger reaction or Staudinger reduction is a chemical reaction in which the combination of an azide with a phosphine or phosphiteproduces an iminophosphorane intermediate Combined with the hydrolysis of the aza-ylide to produce a phosphine oxide and an amine, this reaction is a mild method of reducing an azide to an amine. Triphenylphosphine is commonly used as the reducing agent, yielding triphenylphosphine oxide as the side product in addition to the amine

Documents

Total Synthesis of Communesins Jian-Zhou Huang 2012-10-27