synthesis of alelastatins - Chemistry 530 UIC Literature Seminar in Organic Chemistry Movassaghi, M....

UICCHEM 530 Literature Seminar in Organic Chemistry

Movassaghi, M. et al. Chemical Science, 2010, DOI: 10.1039/c0sc00351d

Total Synthesis of all(-)-Agelastatin Alkaloids

Stacy Snyder, Wardrop GroupSeptember 29, 2010

UICUniversity of Illinois at Chicago CHEM 530 Slide

Agelastatin Alkaolids

2

(-)-agelastatin B (-)-agelastatin C

(-)-agelastatin D (-)-agelastatin E (-)-agelastatin F

NBr

NH

O

NN

OMe

HHO

HH H

Br

NBr

NH

O

NN

OMe

HH

H

HO

OH

NBr

NH

O

NN

OH

HH

H

HO

H

NBr

NH

O

NN

OMe

HMeO

HH HN

BrNH

O

NN

OH

HHO

HH H

Br

NBr

NH

O

NN

OMe

HHO

HH H

AB

C

D

12 78

4

(-)-agelastatin A


Biological Properties

3

• Significant anti-tumor activity

• Slows metastasis and cancer cell

proliferation

• Inhibits osteopontin (OPN)

neoplastic transformation

• Selectively inhibits glycogen synthase

kinase-3β, target for Alzheimer’s

disease and bipolar disorder

a. Mason, C. et al., Mol. Cancer Ther., 2008, 7, 548-558. b. Meijer, L. et al., Chem. Biol., 2000, 7, 51-63.

Agelas dendromorphaCoral Sea sponge


Former Synthetic Efforts

4

• 10 different synthesis

• 1999 - Weinrab, 1st total synthesis

• 2002 - Feldman, 1st enantioselective

synthesis of (-)-A and (-)-B

• Wardrop - trichloroacetamide as protecting

group, nucleophile, and urea

• Early C ring introduction, which correspond

to biosynthetic hypothesis


Biosynthetic Hypotheses

5

• Early biosynthesis of C ring followed by B ring

• C ring formed by C8-nucleophile trapping of C4-electrophile

• Stereochemistry attributed to enzyme control

a. Andrade, P. et al. Tet. Lett. 1999, 40, 4775. b. Mourabit, A. & Potier, P. E. J. Org. Chem., 2001, 237.

NH

ONH

N

HN NH2

12

7 48

NBr

NH

O

NN

OMe

HHO

HH H

AB

C

D

1278

4

N

O

NH

NH

N NH

HHH


New Biosynthetic Hypothesis

6

• B ring formed before C ring

• Reverse polarity in C ring formation, C-4 nucleophilic attack on C-8 electrophile

• Substrate directed stereocontrol, enhanced by biosynthetic enzymes

NBr

NH

O

NN

OMe

HHO

HH H

AB

C

D

12 78

4NH

N

NH2

NBrN H

O

H

8

4

Br

H

Cyclooroidin

Poverlin, C. et. al. Org. Let., 2006, 8, 819.


Retrobiosynthetic Analysis

7

pre-agelastatin A

NHN

O

N

Br

NH

O

Me

8OH

NHN

O

N

Br

NH

O

Me

8

4

5NHN

O

NBr N H

O

Me

H HH

H2O 5NH

NO

NBr N H

O

Me

H HH

HO

NH

Br

O NH

NHN

NH2

NH

NHN

NH2

O

NH

Br

12

7

NN

NH2

N

Br

NH

O

Me

NHN

O

N

Br

NH

O

Me

12 7

2

8

2

4

cyclooroidinderivativeoroidin derivative

(-)-Agelastatin A


Retrosynthetic Analysis

8

“pre-agelastatinintermediate”

fromD-aspartic

acid N

Br

NH

O

NHN

O

N

Br

NH

O

Me

8

NHN

O

N

Br

NH

O

Me

8OH

5

OMe

D

OMe

HN

HNMe

O

O5 4

1

1

N

Br

NH

O

8OMe

O

OMe5

NOMeOMe

O

O

NHN

O

NBr N H

O

Me

H HH

HO

O-Me-pre-agelastatin A


Formation of “A” Ring

9

O

OMe

NO

OMe

NBS, DTBMP

THF (92%)

O

OMe

NO

OMeBr

O

OMe

H2NO

OMeO

OMe

OMe DCE, H2O

80 °C, 2 hr(84%)

N

CO

SO2Cl

MeCN, 0 °C

Na(Hg), H2PO4 (82%)

+

O

OMe

NO

OMeBr

ONH2

+


Mechanism

10

NBr R N

Br R

EASOCN

SO2Cl

H

NSO2Cl

O

NBr R

H

NSO2Cl

O

NBr R

H

NSO2Cl

O

NBr R

N

OH

SO2Cl

NBr R

O

HN S

O

O

Cl SET

Na / Hg NBr R

O

N S

O

O

Cl

NaH

-NaO2SCl

NBr R

O

NH

SET

Na / Hg NBr R

O

NH

H+

NBr R

O

NH2


Formation of B Ring

11

O

OMe

NO

OMe

Br

ONH2

MeOHN

Br

NH

O

OOMe

O

NaBH4, MeOH;

TsOH, H2O (90%, 99% ee)

N

Br

NH

O

OMeOMe

O

NBr H

H

OMe

OMeO

NBr

H

OMe

OMeO

H

8

7


O-Me-Pre-Agelastatin A

12

HSC6H4-p-Me, AlMe3,

CH2Cl2, 0 °C (92%)

N

Br

NH

O

OMeS

O

+N N

N

Me

C6H4-p-Me

OHx3Sn

CuTC

THF, 50 °C(96%)

N

Br

NH

O

OMe

ON N

N

Me

C6H4-p-Me

O

N

Br

NH

O

OMeOMe

O

HCl (0.5 N),

MeOH, 65 °C(89%)

N

Br

NH

O

OMe

O HN

HN

MeO

15

N

Br

NH

O

OMe

NN

OMe

H

(+)-O-Me-pre-agelastatin A


Completion of (-)-Agelastatin A

13

(-)-Agelastatin A(49%, 99%ee)

NBr

NH

O

NN

OMe

HMeO

HH HN

BrNH

O

NN

OMe

HHO

HH H

(-)-O-Me-di-epi-agelastatin A(22%)

+

2 : 1

MeSO3H, H2O, 100 °C,

66%

5-exo-trig

N

Br

NH

O

OMe

NN

OMe

H MeSO3H,

H2O, 100 °C N

Br

NH

O

NN

OMe

HH MeOH

7


Total Synthesis of (-)-Agelastatin A

14

• 8 steps

• 22% overall yield

• 20g scale

• Obtain 1.4g batch of (-)-Agelastatin A


(-)-Agelastatin B

15

NBr

NH

O

NN

OMe

H

HO

HH H

(-)-agelestatin A

NBS, DTBMP

THF : H2O, 0° C(84%)

NBr

NH

O

NN

OMe

H

HO

HH H

(-)-agelestatin B

Br


(-)-Agelastatin C

16

Amberlyst 15

H2O, 100 °C, 5 d N

BrNH

O

NN

OMe

HH

H (41%) NBr

NH

O

NN

OMe

HH

H

HO

OH

(-)-agelastatin C

NBr

NH

O

NN

OMe

H

MeO

HH H

pyr, 115 °C

(99%)N

BrNH

O

NN

OMe

HH H

DMDO,

acetone, H2O(98%) N

BrNH

O

NN

OMe

HH

H

HO

OH

(-)-O-Me-di-epi-agelastatin A


(-)-Agelastatin D

17

N

Br

NH

O

OMe

S

O

+

Hx3Sn

HN

O

HN

H

CuTC, THF, 50 °C

HCl, MeOH(62%)

N

Br

NH

O

OMe

NN

OH

H 1. MeSO3H, H2O, 100° C;

2. HCl, MeOH

NBr

NH

O

NN

OH

HH

H

HO

H

(-)-agelastatin D26%

+N

BrNH

O

NN

OH

HH

H

MeO

H

9%

N NH

O

Br

20%

+

N NH

O

20%

HN

HN

H

HO

+


(-)-Agelastatin E & F

18

NBr

NH

O

NN

OMe

HHO

HH H

(-)-agelastatin A

Amberlyst 15

MeOH, 65 °C2 h

(96%)N

BrNH

O

NN

OMe

HMeO

HH H

(-)-agelastatin E

NBr

NH

O

NN

OH

HHO

HH H

(-)-agelastatin D

NBS, DTBMP

THF, H2O, 0 °C(86%) N

BrNH

O

NN

OH

HHO

HH H

Br

(-)-agelastatin F


Conclusion

19

• Total synthesis of (-)-agelastatins A - F based on new biosynthetic hypothesis

• First total synthesis of (-)-C, D, E, and F

• Shortest synthesis of (-)- A to date

• Developed a new imidazolone annulation strategy

• Results support the late stage 5-exo-trig C-ring formation

UICUniversity of Illinois at Chicago CHEM 530 Slide 20

Thank you foryour attention!

synthesis of alelastatins - Chemistry 530 UIC Literature Seminar in Organic Chemistry Movassaghi, M....

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