I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J ... · 3/5/2010 · I. B. Seiple, S. Su, I. S....

I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J. Yamaguchi, and P. S. Baran, Angew. Chem. Int. Ed. 2009, 49, 1095-1098.

Hong Ren @ The Wulff Group 03-05-10

Synthesized naturally by Stylotella agminata

Cytotoxic and immunosuppressive

In 1993, first isolated by P. J. Scheur and co-workers

In 2007, structure revision proposed by M. Kock

26 Ph. D theses and 31 publications

In 2009, first total synthesis accomplished by P. Baran

Kock, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem. Int. Ed. 2007, 46, 6586-6594.

OHNHN

NH2

ClH2N N

N

O

NNH

NH2

H

H

palau'amine

OHNHHN

NH2

ClH2N N

N

O

HNNH

NH2

H

H

palau'amine


Nine nitrogens

OHNHHN

NH2

ClH2N

N

N

O

HNNH

NH2

H

H

palau'amine


Nine nitrogens

Eight contiguous stereogenic centers

OHNHHN

NH2

ClH2N N

N

O

HNNH

NH2

H

H

palau'amine


Nine nitrogens


Reactive (hemi)aminal moieties

OHNHHN

NH2

ClH2N N

N

O

HNNH

NH2

H

H

palau'amine


Nine nitrogens



Highly polar bis-guanidines

OHNHHN

NH2

ClH2N

N

N

O

HNNH

NH2

H

H

palau'amine


Nine nitrogens




Oxidation-prone pyrroles

OHNHHN

NH2

ClH2N N

N

O

HNNH

NH2

H

H

palau'amine


Nine nitrogens





Strained trans – fused 5,5’- azabicyclic ring

Nine nitrogens





Strained trans – fused 5,5’- azabicyclic ring

Unprecedented hexacyclic core

OHNHHN

NH2

ClH2N

N

N

O

HNNH

NH2

H

H

palau'amine


OHNHHN

NH2

ClH2N N

N

O

HNNH

NH2

H

H

palau'amine


1

2

2’

NH

HN

N

NH2

OH

ClH2N

1

6

14

11

20

17

NH

N

HN

O

NH2

H

10

transannularclosure

NH

HN

N

NH

OH

ClH2N

1

6

14

11

20

17

NH

N

HN

O

NH210

H

amidine tautomer

macro-palau'amine

tautomerization

3 4

amide

formation

NH

HN

N

NH

OH

ClN3

1

6

11

20

17

NH

N

HO

O

NH2

10H

N3

NH

HN

NH

OH

ClN3

6

11

20

17

NH

NNH2

10H

N3

SNAr

Br

N

NH

HN

NH

HN

NO

NH2

H

NH2

OH

ClH2N

HH

1

6

1014

11

20

17

Yamaguchi, J.; Grube, A.; Seiple, I. B.; Young, I. S.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578-3580. Gosselin, P.; Bourdy, C.; Mille, S.; Perrotin, A. J. Org .Chem. 1999, 64, 9557-9565.

Me

Me

OTIPS

CO2MeMeO2C

Me

Me

CO2Me

CO2Me

OTIPS

1. LAH

2. MsCl

3. NaN3

4. TBAF

Me

Me

OH

N3

N3

64%

5 6 7

EtO OEt+ O

BF3•OEt20 °C then RT

OEt OEt

OEt

HCOOH/

HCOONa

H2O, 100 °C

CHO TIPSOTf

NEt3, 0 °C

Yamaguchi, J.; Grube, A.; Seiple, I. B.; Young, I. S.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578-3580.

1. PMBCl

2. O3

85%

O Me

Me

O

PMBO

N3

N3

1. TMSOTf

iPr2NEt

then NBS

2. SiO2

57%

O

Br

HOBr

PMBO

N3

N3

8 9

10 11

1. LiCl

2. TFA

78%

O

Cl

HO Br

HO

N3

N3

1. SO2Cl22,6-lutidine

38-43%

O

ClCl

N3

N3

Br

Me

Me

OH

N3

N3

7

Yamaguchi, J.; Grube, A.; Seiple, I. B.; Young, I. S.; Baran, P. S. Angew. Chem. Int. Ed. 2008, 47, 3578-3580.

NaBH4

CeCl3

OH

ClCl

N3

N3

Br

NH2

BocHN NBoc

DBU

OH

ClCl

N3

N3

N

NHBocBocHN

55%

O

ClCl

N3

N3

Br

11 12 13

IBX

70%, dr = 1.3:1

O

ClCl

N3

N3

BocNN

BocHN

72%

O

N(CHO)2Cl

N3

N3

BocNN

BocHN

NaN(CHO)2

14 15 I

O

O

O OH

IBX


15 16

NH

HN

NH2ClN3

11

20

17

N3

H3N

O

O

N(CHO)2Cl

N3

N3

BocNN

BocHN

50% aq. TFA

then aq 10% TFA

N

OO

Ag

O

N

O

NH

HN

NH2

OH

ClN3

11

20

17

N3

H3N

O

64%

H2NCNbrine

65%

NH

HN

NH2

OH

ClN3

6

11

20

17

NH

NNH2

10H

N3

17 18


18 4

NH

HN

NH2

OH

ClN3

6

11

20

17

NH

NNH2

10H

N3

TFAA/TFA

then Br2

NH

HN

NH2

OH

ClN3

11

20

17

NH

NNH2

10H

N3

Br

54%

OMe

H2N

tBuO2C

OMe

OMe

6

19 20

OMe

HN

tBuO2C

OMe

OMe

NH

HN

NH2

OH

ClN3

11

20

17

NH

NNH2

10H

N3

then TFA

OMe

HN

tBuO2C

OMe

NH

HN

NH2

OH

ClN3

11

20

17

NH

NNH2

10H

N3


20 3 OMe

HN

tBuO2C

OMe

NH

HN

NH2

OH

ClN3

11

20

17

NH

NNH2

10H

N3

NH

HN

N

NH2

OH

ClN3

1

6

11

20

17

NH

N

HO2C

NH210

HN3

H2, Pd(OAc)2

-2MeOH

-

44%

21 2

NH

HN

N

NH2

OH

ClH2N

1

6

11

20

17

NH

N

HO2C

NH210

HH2N

EDC, HOBtNH

HN

N

NH2

OH

ClH2N

1

6

14

11

20

17

NH

N

HN

O

NH210

H

macro-palau'amine


OHNHHN

NH2

ClH2N

N

N

O

HNNH

NH2

H

H

palau'amine

17%

2 2’

1

NH

HN

N

NH2

OH

ClH2N

1

6

14

11

20

17

NH

N

HN

O

NH210

H

macro-palau'amine

then TFA

70 °C

NH

HN

N

NH2

OH

ClH2N

1

6

14

11

20

17

NH

N

HN

O

NH210

macro-palau'amine

25 steps, 0.015% overall yield

Multiple cascade reactions

Minimal use of protection groups: PMBCl

Late-stage, chemoselective, silver-mediated oxidation to the hemiaminal unit

NH

HN

NH2ClN3

11

20

17

N3

H3N

O

then aq 10% TFA

N

OO

Ag

O O

NH

HN

NH2

OH

ClN3

11

20

17

N3

H3N

O

64%

The ambiphilic reactivity of 2-aminoimidazole

Across ring stitching

N N

NH2

N N

NH2

H

E Nuc

NH

HN

NH2

OH

ClN3

6

11

20

17

NH

NNH2

10H

N3

TFAA/TFA

then Br2

NH

HN

NH2

OH

ClN3

11

20

17

NH

NNH2

10H

N3

Br

54%

6

NH

HN

N

NH2

OH

ClH2N

1

6

14

11

20

17

NH

N

HN

O

NH210

macro-palau'amine

9

I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J ... · 3/5/2010 · I. B. Seiple, S. Su, I. S....

Documents

Transcript of I. B. Seiple, S. Su, I. S. Young, C. A. Lewis, J ... · 3/5/2010 · I. B. Seiple, S. Su, I. S....