Total Synthesis of All (-)-Agelastatin Alkaloids

Mohammad Movassaghi, Dustin S. Siegel and Sunkyu Han

MIT Chemical Science, Advance article

NNH

Br

O

OMe

NHN

OMe

Bioinspired cyclization N

NH

NH

NBr

O

OMe

H

HO

H

H

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

1.4 g batch

Marija Manojlović Wipf group current literature meeting

8-27-2010

Agelastatin alkaloids •  6 Agelastatins A-F isolated so far, differences in substitution pattern

•  Agelastatin A biological activity: –  Singnificant antitumor activity against wide range of tumor cells (in nM range) –  Highly toxic towords anthropods (LC50= 1.7 ppm in brine shrimp assay) –  Insecticidal against beet army worm and corn root worm –  Selectivly inhibits the glycogen synthase kinase-3b, a potential target for the treatment of

Alzheimer’s disease and bipolar disorder.

•  Biosynthetically originate from simpler pyrrole-imidazole alkaloids

NNH

NH

NBr

O

OMe

H

HO

H

H

Agelastatin A

NNH

NH

NBr

O

OMe

H

HO

H

H

Agelastatin B

Br NNH

NH

NBr

O

OMe

OH

HO

H

H

Agelastatin C

NNH

NH

NBr

O

OH

H

HO

H

H

Agelastatin D

NNH

NH

NBr

O

OMe

H

MeO

H

H

Agelastatin E

NNH

NH

NBr

O

OH

H

HO

H

H

Agelastatin F

Br

Pietra et al. J. Chem. Soc., Chem. Commun. 1993, 1305.

Molinski et al. J. Nat. Prod. 1998, 61, 158. Al-Mourabit et al. J. Nat. Prod. 2010, 73, 720.

Movasaghi, Siegel and Han, Chem. Sci. Advance article. Trost and Dong, CEJ 2009, 15, 6910.

N

HN

NH2X = Y = H clathrodinX = H, Y = Br hymenidinX = Y = Br oroidin

NH

O

NHY

X

Previous synthetic work: Agelastatin A - benchmark for showcasing methodology

•  10 total syntheses published prior to the title paper •  First synthesis: Weinreb 1999, first asymmetric synthesis: Feldman 2002.

•  In all previous synthesis cyclopentane ring C is set early and the rest of molecule is elaborated around it

•  Ring C contains 4 stereocenters and this highly substituted cyclopentane was target for showcasing various methodologies.

Weinreb: JOC 1998, 63, 7594 and JACS 1999, 121, 9574. Feldman: JACS 2002, 124, 9060 and JOC 2002, 67, 7096. Hale: OL 2003, 5, 2927 and OL 2004, 6, 2615. Davis: OL 2005, 7, 621 and SC 2009, 39, 1914 (CL in Feb. 2005 by Mike Rishel). Trost: JACS 2006, 128, 6054 and CEJ 2009, 15, 6910. Ichikawa: OL 2007, 9, 2989. Wardrop: OL 2009, 11, 1341. Chida: OL 2009, 11, 2687. Tanaka: OL 2008, 10, 5457 and OL 2009, 11, 3402. Du Bois: ACIE 2009, 48, 3802 (CL in May 2009 by Melissa).

NNH

NH

NBr

O

O

Me

H

HO

H

H

WeinrebFeldmanHaleDavisIchikawaWardropChida

All previous syntheses

Trost

FeldmanTrostWardropTanaka

Du BoisHale

Movassaghi

A B

CD

Weinreb’s synthesis of (±)-Agelastatin A

+ S+

N

O-

CO2Me

PhH, 0 °CN

S

MeO2C

OPhMgBr

THF, -60 °C86% HN

S

MeO2C

OPh

HNMeO2C OSPh

HMPTEtOH, 80 °C

NH

O OH

H

NH

OHH

H

CO2Et

40%+

44%

t-BuOKTHF83%

NBoc

O OH

H

1. SESN=S=NSESPhMe, !

2. NaBH4 NBoc

O OH

HNHSESSharpless-Kresze reaction

HNTMS COCl

DMAP, Et3N, THF, 100%

NBoc

O OH

HNSES

O

NHTMS 1.TBAF, THF, 66%

2. LiOH, THF/H2O NHBoc

OHH

HNH

O

NHTMS

PDC, DMF

61%, 2 stepsNHBoc

O

HNH

O

NHTMS 1. Cs2CO3,

MeOH, 61%

2. NBS, THF, 78%

NNH

Br

O

HH

H

O

NHBoc1. TMSI, CH2Cl2,rt2. MeNCO, NaOH H2O N

NH

NH

NBr

O

OMe

H

HO

H

H

(±)-Agelastatin A

61%

14 steps, 7% overall yield

N-sulfinyl dienophile hetero-DA methodologyAcc. Chem. Res. 1988, 21, 313.

-  The first total synthesis of agelastatin A -  Key steps: hetero DA reaction, Sharpless-Kresze allylic amination (new SES reagent) and internal Michael addition of pyrrole nitrogen -  Why not brominate debromoagelastatin, previously made in Weinreb group?

JOC 1998, 63, 7594. JACS 1999, 121, 9574.

Feldman’s Synthesis of (-)-Agelastatins A and B

-  The first enantioselective total synthesis of (-)-agelastatin A -  Cyclopentane core was synthesized using alkylnyliodonium salt mediated cyclization

JOC 2002, 67, 7096. JACS 2002, 124, 9060.

Cl O 2 stepsO

TMS

1. NaN3, NH4Cl2. n-BuLi, CO2, PMe3

67%

ONH

TMS

O1. NaHMDS, ClC(O)N(CH3)o-NB2. TBAF, AcOH3. LiHMDS, Bu3SnCl

ON

SnBu3

ON

O

o-NBMe

ON

ON

O

o-NBMe

Ts

41%

34%

1. o-NBNH22. DMAP O

N

ON

O

o-NBMe

Ts70%

NOHN

o-NB

1. Cs2CO32. Swern

63%

NN

O

O

HN N

Oo-NB

Me

o-NBH H

hν (350 nm)

NHN

O

H H

NHNHO

H

OMe

1 eq. NBS

MeOH, THF73%

MeOH, THF45%

2.1 eq. NBS

NHN

O

H H

NHNHO

H

OMe

Br NHN

O

H H

NHNHO

H

OMe

Br

Br

(-)-Agelastatin A (-)-Agelastatin B

HNCl

O

NHN

O

H H

NHNHO

H

OMe

Debromoagelastatin Debromoagelastatin

ON

ON

O

o-NBMe

HTs

ON

I

ON

O

o-NBMe

TfO Ph

ON

ON

O

o-NBMe

Ts

PhI(CN)OTf

TolO2SNa

Stang's reagentVilarrasa oxazolidinone

synthesis

Alkylidene carbene chemistry by Feldman:OL 2000, 2, 2603; JOC 2000, 65, 8659;Heterocycles 1999, 51, 1283.

Trost’s Synthesis of (+)- and (-)-Agelastatin A

-  New methodologies such as Pd-catalyzed asymetric allylic alkylation (AAA) using pyrrole as nucleophile and In(OTf)3 catalyzed oxidative aziridine opening using DMSO were developed. -  Both enantiomers of Agelastatin A were synthesized from the same enantiomer of a stereoconducting catalyst.

BocO OBoc

+HNBr

O

OMe [Pd(!-C3H5)Cl]2Cs2CO3, CH2Cl2, rt

NHO

HNO

PPh2 Ph2P

83%, 92% ee

NBr

OMe

O

OBoc

H

1. LiOH THF/H2O, 86%2. (COCl)2, DMF (cat.) NH2OMe, H2O, 85%

NBr

NHOMe

O

OBoc

H

[Pd2(dba)3]·CHCl3(R, R)-LST, Cs2CO3

CH2Cl2, rt(R, R)-LST91% N NBr

O

OMeH H

N Ni-Pr

i-Pr i-Pr

i-Pr

CuCl

PhI=NTs, 4Å MSPhH, 0 °C to rt

52%

N NBr

O

OMeH H

NTs

DMSO, In(OTf)380 °C, 91%

N NBr

O

OMeH H

N

O S+ O-Tol

In(OTf)3

S+Me

Me

N NBr

O

OMeH H

O

NHTs1. Cs2CO3, CH3NCO, CH2Cl2 0 °C to rt, 53%

2. SmI2, THF, 0 °C to rt, 88%

NNH

NH

NBr

O

OMe

H

HO

H

H

(+)-Agelastatin A

BocO OBoc

+HNBr

O

NHOMe

[Pd2(dba)3]·CHCl3(R, R)-LST, AcOH

0 °C to rt82%, 97.5% ee N NMeO

O

BrH H Weinreb's synthesisN

NH

NH

NBr

O

OMe

H

HO

H

H

(-)-Agelastatin A

Pd-catalyzed Asymmetric Allylic Alkylation (AAA)Chem. Rev. 2003, 103, 2921.

JACS 2006, 128, 6054. Chem. Eur. J. 2009, 15, 6910.

Biosynthesys of Oroidin-Based Pyrrole-Imidazole Alkaloids

Ali Al Mourabit and Pierre Potier Eur. J. Org. Chem. 2001, 237.

HN

N

NH2

CO2H

histidineHN CO2H

proline

HN

NH2N NH2

HN CO2HBr

NH

HN

NHNH

O

NH

Br

oxidation

N

NNH

NH

O

NH

Br

H+

H

O

NH

Br

NH

NH

NNH

H+

O

N

Br

NH

NH

NHNH

O

N

Br

NH

NH

NNH

hydrationmethylationhydrolysis

NNH

NH

NBr

O

OMe

H

HO

H

H

X = H Agelastatin AX = Br Agelastatin B

Nu: E+

XX X

X X

X

X

48

Title Paper: Biosynthetic Hypothesis and Design Plan for Total Synthesis of Agelastatins

Title Paper: Synthesis of (-)-Agelastatin A

H2N CO2Me

CO2Me

N CO2Me

CO2MeNBS, DTBMP

THF, 92% N CO2Me

CO2MeBr

OMeOOMe

ClCl

H2O, 80 °C, 2 h84% 99% ee

ClSO2NCOMeCN, 0 °C;

Na(Hg), NaH2PO482%

N CO2Me

CO2MeBr

O

H2N

NaBH4, MeOH, 0 °C,TsOH·H2O, rt, 90%

NNH

Br OMe

O

O

O

NNH

Br OMe

O

O

OMe

> 99% ee> 10g scale

> 20g scale

TolSH, AlMe3CH2Cl2, 0 °C, 92%

NNH

Br STol

O

O

OMe

Cy3Sn NH

NH

OMe CuTC, THF

50 °C; HClMeOH, 58%

NNH

Br

O

OMe

NHN

OMe

N NNTol

MeOCy3Sn

CuTC, THF50 °C, 96%> 5g scale

NNH

Br

O

O

OMe

N N

N

MeO

Tol

HCl, MeOH65 °C, 89%

NNH

Br

O

O

OMe

HN

HN Me

O

MeSO3H, H2O, 100 °Cthen MeOH, 71%

NNH

NH

NBr

O

OMe

H

HO

H

H

(-)-Agelastatin A

> 1g scale+NNH

NH

NBr

O

OMe

H

MeO

H

H

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

1 : 2

MeSO3H, H2O, 100 °Cthen MeOH, 66%

The Importance of C13 Bromine Substituent and Imidazolinone

NNH

Br OMe

O

O

O

NNH

Br OMe

O

O

OMe

> 99% ee

N CO2Me

CO2MeBr

O

H2N

NaBH4, MeOH, 0 °C,TsOH·H2O, rt, 90% 77

13 13

No epimerization at C7

CD3OD, 2 hN

NH

Br OMe

O

O

O

713

D

99%racemic

N CO2Me

CO2MeH

O

H2N

NaBH4, MeOH, 0 °C,TsOH·H2O, rt, 90%7

13 NNH

H OMe

O

O

OMe

Significant epimerization at C7

NNH

H

O

OMe

NHN

OMe

MeSO3H, H2O,100 °C, 20 min, 57%

NNH

H

O

NHN

OMe

NNH

Br

O

OMe

NN

NH2H

Dowex, H2O100 °C, 92%

NNH

Br

O

NN

NH2H

Title Paper: Synthesis of (-)-Agelastatins B-F

NNH

NH

NBr

O

OMe

H

HO

H

H

(-)-Agelastatin A

NBS, DTBMPTHF, H2O, 0 °C

84%N

NH

NH

NBr

O

OMe

H

HO

H

H

(-)-Agelastatin B

Br

Amberlyst 15MeOH, 65 °C

96%N

NH

NH

NBr

O

OMe

H

MeO

H

H

(-)-Agelastatin E

NNH

NH

NBr

O

OMe

H

MeO

H

H

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

pyr, 115 °C

99%N

NH

NH

NBr

O

OMe

H

H

DMDO, acetoneH2O, 98%

NNH

NH

NBr

O

OMe

OH

HO

H

H

Amberlyst 15H2O, 100 °C

5 d, 41% NNH

N

NBr

O

OMe

H

HH N

NH

NH

NBr

O

OMe

OH

HO

H

H

(-)-Agelastatin C

NNH

Br STol

O

O

OMeCy3Sn N

HNH2

O1. CuTC, THF, 50 °C;

2. HCl, MeOH62%

NNH

Br

O

OMe

NHHN

O

MeSO3H, H2O100 °C;

HCl, MeOHN

N

Br

O

NHHN

O

H

NNH

NH

NBr

O

OH

H

HO

H

H

(-)-Agelastatin D26%

+ NNH

NH

NBr

O

OH

H

MeO

H

H

9%

NN

Br

O

NHHN

O

H

NHN

HN

HN

O

O

H

HNHN

O

Br

20%

20%

NNH

NH

NBr

O

OH

H

HO

H

H

(-)-Agelastatin D

NNH

NH

NBr

O

OH

H

HO

H

H

(-)-Agelastatin F

Br

NBS, DTBMPTHF, H2O, 0 °C

86%

Conclusions •  All known agelastatin alkaloids were synthesized employing

biosynthetically inspired strategy

•  “Pre-agelastatin” derivatives were obtained in multi-gram quantities

•  C13 bromine substitution was critical for the successful C-ring cyclization

•  Agelastatin A was prepared in 1.4 g batch and bilogical and chemical studies of that compound are ongoing.

•  Authors suggest higher probability for biosynthetic introduction of C13-bromopyrrole and imidazolone substructures prior to C-ring formation and this hypothesis is yet to be experimentally checked.