R

t Hi hli ht f

th

Recent Highlights from the

Danishefsky Laboratory

Danishefsky Laboratory

H

HO

O

O

OH

H

HO

N

O

Me

OMe

O

HO

11-0-Debenzoyltashironin

N

H

NH

11 0 Debenzoyltashironin

NMe

2

Phalarine

Anne-Marie Dechert

N

b

7 2007

November 7, 2007

11-0-Debenzoyltashironin

Background and Structural Features

• Isolated from the pericaps of

Illicium merrillianum

• Shown to induce neurite

outgrowth in fetal rat cortical

g

neurons at low
concentrations

• 7 contiguous stereocenters,

3 all carbon quarternary

OH

H

HO

3 all carbon quarternary
centers

O

HO

OH

O

HO

11-0-Debenzoyltashironin

Synthetic Strategy

Synthetic Strategy

OH

Oxidative

O

OMe

OH

OH

MsO

Oxidative
Dearomatization

O

OMe

O

MsO

OTs

OTs

Transannular

H

HO

Transannular
Diels-Alder

O

MsO

OH

H

HO

OTs

MsO

O

OH

H

HO

O

HO

11-0-Debenzoyltashironin

Danishefsy, et al. J. Am. Chem. Soc. 2006, 128, 16440-16441

Synthetic Strategy

Synthetic Strategy

OH

Oxidative
D

ti

ti

O

OMe

OMe

OH

MsO

Dearomatization

OMe

O

MsO

OTs

OTs

Transannular
Di l

Ald

OH

H

HO

Diels-Alder

O

OTs

MsO

OH

X

OTs

Believed that the cyclization didn’t occur because of the electronic

O

OH

H

HO

and steric constraints that the mesyl enol ether imposed.

O

HO

11-0-Debenzoyltashironin

Danishefsy, et al. J. Am. Chem. Soc. 2006, 128, 16440-16441

Synthetic Strategy

Synthetic Strategy

OH

OMe

OH

OH

Oxidative
Dearomatization

O

OMe

O

Me

H

OTs

OTs

O

OMe

O

Transannular
Diels-Alder

OTs

X

W

i

!

O

HO

OH

H

HO

Wrong epimer!

O

HO

11-0-Debenzoyltashironin

Danishefsy, et al. J. Am. Chem. Soc. 2006, 128, 16440-16441

Synthetic Strategy

Synthetic Strategy

OR

OH

•

O

OR

O

O

OH

H

HO

OTs

HO

OTs

O

HO

OTBS

Br

OBn

OH

OTs

OBn

OH

SnBu

3

Synthesis of the Aryl Bromide

Synthesis of the Aryl Bromide

OH

1. Zn(CN)

2

, HCl (99 %)

2. TsCl (57 %)
3. BnBr, K

2

CO

3

, TBAI (97 %)

1. mCPBA
2. TEA

OH

98 % for 2 steps

OH

OBn

OH

1. NBS (85 %)
2. TBSCl, TEA (87%)

OBn

OTBS

Br

OTs

OTs

Danishefsy, et al. J. Am. Chem. Soc. 2006, 128, 16440-16441

Synthesis of the Aryl Bromide

Synthesis of the Aryl Bromide

OH

1. Zn(CN)

2

, HCl (99 %)

2. TsCl (57 %)
3. BnBr, K

2

CO

3

, TBAI (97 %)

OBn

O

1. mCPBA
2. TEA

OH

OTs

2. TEA

98 % for 2 steps

OH

OTBS

OBn

OH

1. NBS (85 %)
2. TBSCl, TEA (87%)

OBn

OTBS

Br

OTs

OTs

Danishefsy, et al. J. Am. Chem. Soc. 2006, 128, 16440-16441

Synthesis of the Oxidative

Dearomatization Precursor

OBn

OTBS

Br

OH

Pd

2

(dba)

3

, tBu

3

P

OBn

OTBS

OH

1. DMP (98 %)
2. 2-propargyloxyTBS,

Et

2

Zn, Ti(OiPr)

4

(91 %)

OTs

SnBu

3

OBn

OTs

Et

2

Zn, Ti(OiPr)

4

(91 %)

77 %

OBn

OTBS

OH

1. MsCl, TEA

O

OBn

OTs

OTBS

,

2. Me

2

Cu(CN)Li

2

(88 %)

3.Bu

4

NF, AcOH (95 %)

OR

OH

•

HO

OTs

Danishefsy, et al. J. Am. Chem. Soc. 2006, 128, 16440-16441

Oxidative Dearomitization,

Transannular Diels-Alder

OH

O

OBn

•

HO

PIDA

O

OBn

O

•

O

OBn

O

OTs

OTs

OTs

μW

μ

65 %

Danishefsy, et al. J. Am. Chem. Soc. 2006, 128, 16440-16441

End Game

End Game

O

1 mCPBA (71 %)

O

OBn

O

1. NaBH

4

(83 %)

2. TMS-imidazole (99 %)

O

OBn

H

TMSO

1. mCPBA (71 %)
2. Wilkinson's Catalyst,

H

2

(74 %)

OTs

OTs

1 DMP (96 %)

O

OBn

H

TMSO

LiEt

3

BH

O

OBn

H

TMSO

32 %

1. DMP (96 %)
2. HF- pyr, Bu

4

NF (87 %)

3. H

2

, Pd/C (91 %)

OTs

O

OH

HO

H

HO

O

O

HO

OH

H

HO

O

Danishefsy, et al. J. Am. Chem. Soc. 2006, 128, 16440-16441

Phalarine

Phalarine

O

Me

•Isolated from the phalris coerulescens,

h

t i

d i 1999

N

H

N

NH

Me

OMe

characterized in 1999

NH

NMe

2

•Furanobisindole alkaloid

Phalarine

•First synthesis reported by Danishefsky

Synthetic Stratagy

N

Me

OMe

1

1'

2

N

O

Me

N

H

NH

HO

1

2

2'

N

H

N

NH

OMe

Me

2

N

P halarine

NMe

2

O Me

OM

OMe

MeO

N

H

N

CO

2

Me

O H

OMe

N

CO

2

Me

O

The model system gave the opposite of what was desired!

O H

N

H

The model system gave the opposite of what was desired!

Danishefsky, et al. Angew. Chem. Int. Ed. 2007, 46, 1444-1447.

Retrosynthesis

Retrosynthesis

TsHN

N

Me

O

M

O

OMOM

N

H

N

NH

Me

OMe

O Me

NMe

2

Pha larine

N

O

N-Me

O MOM

Li

M O

N

Ts

MeO

O

N

H

N

O Me

Azaspiroindolenine synthesis

Azaspiroindolenine synthesis

OMOM

Li

O

1. LiAlH

4

(99%)

2 NBS H O AcOH (79%)

N

Me

MeO

96 %

N

H

N

OMe

2. NBS, H

2

O, AcOH (79%)

3. LiHMDS, TsCl (89 %)

N

Ts

O

N Me

1. TFA (98 %)

OMe

N

Me

O

OMOM

2. CSA (72 %)

NHTs

N

Ts

O

OMe

OMe

Ts

Danishefsky, S.; et al. Angew. Chem. Int. Ed. 2007, 46, 1444-1447.

Two Mechanistic Possibilities

Two Mechanistic Possibilities

N Me

O

OH

NHTs

-H

2

O

NTs

N Me

HO

Path A

1, 2 Wagner-
Meerwein Shift

N

HO

N

O

M e

Me

OMe

OMe

OMe

OH

OMe

NTs

Path B

N

Ts

NTs

Retro-Mannich

N

HO

Me

O

Me

OMe

OMe

NTs

N Me

Pictet-Spengler

OH

N

Ts

N

NTs

N

HO

OMe

OMe

OM e

N

Ts

N

HO

Me

NTs

N

O

Me

Danishefsky, S.; et al. Angew. Chem. Int. Ed. 2007, 46, 1444-1447.

Attempted Completion

Attempted Completion

O

M

OMe

N

N

Troc

OMe

Troc

N

NTs

N

O

Me

N

Troc

TFA,

95 %

NTs

N

O

Me

N

NHTroc

Zn dust, AcOH

88 %

OMe

NTs

N

O

Me

NH

2

1. NaNO

2

, HCl (aq)

2. KOH (aq),

88 %

O

O

OEt

NTs

88 %

OMe

TsOH

NTs

N

O

Me

NH

CO

2

Et

Danishefsky, S.; et al. Angew. Chem. Int. Ed. 2007, 46, 1448-1450.

< 5% desired product

Attempted Completion

Attempted Completion

OMe

N

Troc

OMe

NTs

N

O

Me

N

N

Troc

TFA,

95 %

NTs

N

O

Me

Troc

N

NHTroc

Zn dust, AcOH

88 %

NTs

OMe

OM

N

O

Me

OMe

NH

2

1. NaNO

2

, HCl (aq)

2. KOH (aq),

O

O

OEt

N

O

Me

OMe

NH

N

CO Et

NTs

88 %

OEt

NTs

CO

2

Et

OMe

TsOH

NT

N

O

Me

NH

CO

2

Et

NTs

< 5% desired product

End Game

End Game

O Me

a Me SCH

2

CO

2

Et SO

2

Cl

2

N

O

Me

O Me

NH

2

a.Me SCH

2

CO

2

Et, SO

2

Cl

2

b. proton sponge
c. Et

3

N, AcOH

66 %

1. BH

3

2. RaNi

(90 % ove r 2 steps)

NTs

Cl

O

OMe

N

Me

Me

AcOH (74 % )

1.

2. Na(Hg), Na

2

HPO

4

(90 %)

,

N

O

O Me

Me

Cl

NTs

N

O

Me

NH

( g),

(

)

N

H

NH

NMe

2

P halarine

Danishefsky, S.; et al. Angew. Chem. Int. Ed. 2007, 46, 1448-1450.

End Game

End Game

N

O

Me

O Me

NH

2

a.Me SCH

2

CO

2

Et, SO

2

Cl

2

b. proton sponge
c. Et

3

N, AcOH

N

O

Me

O Me

NH

66 %

1. BH

3

2. RaNi

(90 % ove r 2 steps)

NTs

N

NTs

N

O

MeS

OMe

N

Me

Me

AcOH (74 % )

1.

,

N

O

O Me

Me

Cl

NT

N

O

Me

NH

2. Na(Hg), Na

2

HPO

4

(90 %)

N

H

NH

NMe

2

NTs

P halarine

Danishefsky, S.; et al. Angew. Chem. Int. Ed. 2007, 46, 1448-1450.