five drugs or clinical candidates derived from natural ... · why pursue total synthesis of natural...

H2N OH OMe

H2NMeMe

•HCl

NMeH HN

Five Drugs or Clinical Candidates Derived From Natural Products!

That Are Produced on Scale by Total Synthesis!

Jeff Garber!MacMillan Group Meeting!

April 27, 2012!

Why Pursue Total Synthesis of Natural Products?

Test New Methodology

Develop New Methodology

Train Organic Chemists

Academic and Pegagogical

Produce Bioactive Molecules

Develop Analogs for Testing

Produce On-Scale for Society

Pragmatic

Why Use Total Synthesis?

Most Economical Only Available Option

Needs to be practical

"taxol problem"

Pragmatic

"taxol problem"

Pragmatic

"taxol problem"

Pragmatic

17%!5%!

S* = NP mimic produced by synthesis!

N = NP as isolated!

ND = NP derivative, semi-synthetic!

S = completely synthetic entity!

Natural products are clearly a useful source of new drugs!

All 1135 new drugs approved from 1981-2010!

Adapted from Newman and Clark, J. Nat. Prod. 2012 311.!

What Makes a Total Synthesis Interesting or Valuable?

Academic Synthesis Commercial Synthesis

Elegant

atom efficiencyconcise route

Creative

Novel Architecture

disconnections methodology

Among many other factors

complex structure first synthesis

Bioactive

produce for testing analog synthesis

Proven Bioactivity

producing for testing or sale

Practicality of Length

Reagent Selection

yield vs. steps reactor time

safety cost

Purification Methods

limit chrom. rextl. improv. ee

availability

Elegant

Creative

Novel Architecture

Bioactive

Proven Bioactivity

Reagent Selection

safety cost

availability

Elegant

Creative

Novel Architecture

Bioactive

Proven Bioactivity

Reagent Selection

safety cost

availability

Recrystallization, Resolution

Improve Activity or Properties

Retain Only Necessary Parts

Shorten Production Route

Production Considerations: Analogues and Natural Products

Target Considerations: Development of Analogues and Derviatives

Utilize Very Robust Chemistry

■ FDA approved in 2001 for treatment of Alzheimer's

■ First studied in USSR in 1950's

■ Used to treat mild to moderate cases

(−)-galanthamine

NMe■ Inhibits acetylcholine esterase

■ USSR used for varous CNS disorders

■ Natural source (daffodils) not considered economical on scale

■ Sanochemia patented (1996) and later improved synthetic route (2008)

(−)-galanthamine: Overview!

(−)-galanthamine

■ Rapid synthesis from readily available materiats

■ Uses spontaneous chiral resolution/crystallization

■ Features oxidative phenolic coupling to form key bonds

(−)-galanthamine

MeONMe

(−)-galanthamine: Retrosynthetic Analysis!

(−)-galanthamine

MeONMe

(−)-galanthamine

MeONMe

2) Br2, AcOH

3) H2SO4

60-65%, three steps

HCOOEt, HCO2H

DMF, reflux

1) MeI, K2CO3 <$10/g NH2

then NaBH4

toluene, reflux

OHCK3[Fe(CN)6]

NOHC OH

Br OMe

−1 e-

NOHC O

Br OMe

racemic

(−)-galanthamine: Dynamic Resolution!

2) Br2, AcOH

3) H2SO4

60-65%, three steps

HCOOEt, HCO2H

DMF, reflux

1) MeI, K2CO3 <$10/g NH2

then NaBH4

toluene, reflux

OHCK3[Fe(CN)6]

NOHC OH

Br OMe

−1 e-

NOHC O

Br OMe

racemic

2) Br2, AcOH

3) H2SO4

60-65%, three steps

HCOOEt, HCO2H

DMF, reflux

1) MeI, K2CO3 <$10/g NH2

then NaBH4

toluene, reflux

OHCK3[Fe(CN)6]

NOHC OH

Br OMe

−1 e-

NOHC O

Br OMe

racemic

2) Br2, AcOH

3) H2SO4

60-65%, three steps

HCOOEt, HCO2H

DMF, reflux

1) MeI, K2CO3 <$10/g NH2

then NaBH4

toluene, reflux

OHCK3[Fe(CN)6]

NOHC OH

Br OMe

−1 e-

NOHC O

Br OMe

racemic

2) Br2, AcOH

3) H2SO4

60-65%, three steps

HCOOEt, HCO2H

DMF, reflux

1) MeI, K2CO3 <$10/g NH2

then NaBH4

toluene, reflux

OHCK3[Fe(CN)6]

NOHC OH

Br OMe

−1 e-

NOHC O

Br OMe

racemic

2) Br2, AcOH

3) H2SO4

60-65%, three steps

HCOOEt, HCO2H

DMF, reflux

1) MeI, K2CO3 <$10/g NH2

then NaBH4

toluene, reflux

OHCK3[Fe(CN)6]

NOHC OH

Br OMe

−1 e-

NOHC O

Br OMe

racemic

NMe OH

H2SO4, toluene

9:1 EtOH/Et3N;

reflux

then HCl

NOHC O

Br OMe

NOHC O

Br OMe

LiAlH4, THF, reflux

crystalize and seed

with (−)-narwedine

(±)-narwedine

NMe OH

H2SO4, toluene

9:1 EtOH/Et3N;

reflux

then HCl

NOHC O

Br OMe

NOHC O

Br OMe

LiAlH4, THF, reflux

crystalize and seed

(±)-narwedine

NMe OH

H2SO4, toluene

9:1 EtOH/Et3N;

reflux

then HCl

NOHC O

Br OMe

NOHC O

Br OMe

LiAlH4, THF, reflux

crystalize and seed

(±)-narwedine

H2SO4, toluene

9:1 EtOH/Et3N;

reflux

then HCl

NOHC O

Br OMe

NOHC O

Br OMe

LiAlH4, THF, reflux

crystalize and seed

(±)-narwedine

>99% ee

(−)-narwedine

L-Selektride

(−)-narwedine

(−)-galanthamine•HBr

then HBr, crystallization

•HBr

(−)-galanthamine: Completion of Synthesis!

L-Selektride

(−)-narwedine

•HBr

L-Selektride

(−)-narwedine

•HBr

L-Selektride

(−)-narwedine

•HBr

■ From isovanillin: 16% overall yield, 9 steps (10 including dynamic resolution)

■ From commercial bromide: 27% overall yield, 6 or 7 steps

■ Resolution establishes stereochemistry, no enantioselective reactions

Eribuline: Overview!

H2N OH OMe

highly conserved right hand portion

left half found to be unnecssary

eribuline

halichondrin B

■ Halichondrin B isolated from sponges in 1986

■ Activity further demonstrated by Nat. Cancer Inst.

■ Total synthesis complete by Kishi in 1992

Halichondrin B

H2N OH OMe

eribuline

halichondrin B

Halichondrin B

H2N OH OMe

eribuline

halichondrin B

Halichondrin B

H2N OH OMe

eribuline

halichondrin B

■ Approved to treat metastatic breast cancer in 2010

■ Class has mechanistically unique inhibition pathway

■ Marketed by Eisai with global partnerships

Eribuline

Eribuline: Retrosynthetic Analysis!

H2N OH OMe

OTBSTBSO

TBSO OTBSOMe

TBSO OTBS OMe SO2Ph

■ Highly convergent

■ Late stage coupling

■ Utilizes chiral pool

Bioorg. Med. Chem. 2012 1155

H2N OH OMe

OTBSTBSO

TBSO OTBSOMe

TBSO OTBS OMe SO2Ph

H2N OH OMe

OTBSTBSO

TBSO OTBSOMe

TBSO OTBS OMe SO2Ph

OHOH 1) c-hexanone, pTSA

PhCH3, reflux

2) DIBAL-H, -15 °CPhCH3, THF

OHOH O

ClPh3PCH2OMe

KOtBu, THF

84%, two steps

1) OsO4, NMOacetone, H2O

2) Ac2O, AcOHZnCl2, 40 °C

44%, two steps

AcO OAc

BF3•OEt, MeCN

TMSMeO2C

OAcMeO2C Triton B(OH)

THF, MeOAc

38%, two steps

L-mannonic acid γ-lactone$50/g (Aldrich)

Eribuline: Eastern Fragment!

PhCH3, reflux

OHOH O

ClPh3PCH2OMe

KOtBu, THF

84%, two steps

44%, two steps

AcO OAc

BF3•OEt, MeCN

TMSMeO2C

THF, MeOAc

38%, two steps

PhCH3, reflux

OHOH O

ClPh3PCH2OMe

KOtBu, THF

84%, two steps

44%, two steps

AcO OAc

BF3•OEt, MeCN

TMSMeO2C

THF, MeOAc

38%, two steps

PhCH3, reflux

OHOH O

ClPh3PCH2OMe

KOtBu, THF

84%, two steps

44%, two steps

AcO OAc

BF3•OEt, MeCN

TMSMeO2C

THF, MeOAc

38%, two steps

PhCH3, reflux

OHOH O

ClPh3PCH2OMe

KOtBu, THF

84%, two steps

44%, two steps

AcO OAc

BF3•OEt, MeCN

TMSMeO2C

THF, MeOAc

38%, two steps

Eribuline: Completion of Eastern Fragment!

NaIO4, EtOAc/H2O

84%, two stepsO

NiCl2, CrCl2PhCH3, reflux

65%, two steps

8.3:1 dr

53%, two steps

OTBSOTBS

MeO2CTMS

1) AcOH, H2O90 °C; rextl.

2) TBSOTf, 2,6-lut.MTBE

MeO2CI

NIS, cat. TBSCl

MeCN, PhCH3

DIBALH

-75 °C

2.8%, 15 steps

NaIO4, EtOAc/H2O

84%, two stepsO

65%, two steps

8.3:1 dr

53%, two steps

OTBSOTBS

MeO2CTMS

MeO2CI

NIS, cat. TBSCl

MeCN, PhCH3

DIBALH

-75 °C

2.8%, 15 steps

NaIO4, EtOAc/H2O

84%, two stepsO

65%, two steps

8.3:1 dr

53%, two steps

OTBSOTBS

MeO2CTMS

MeO2CI

NIS, cat. TBSCl

MeCN, PhCH3

DIBALH

-75 °C

2.8%, 15 steps

NaIO4, EtOAc/H2O

84%, two stepsO

65%, two steps

8.3:1 dr

53%, two steps

OTBSOTBS

MeO2CTMS

MeO2CI

NIS, cat. TBSCl

MeCN, PhCH3

DIBALH

-75 °C

2.8%, 15 steps

NaIO4, EtOAc/H2O

84%, two stepsO

65%, two steps

8.3:1 dr

53%, two steps

OTBSOTBS

MeO2CTMS

MeO2CI

NIS, cat. TBSCl

MeCN, PhCH3

DIBALH

-75 °C

2.8%, 15 steps

Eribuline: Northern Fragment Synthesis!

H59%, three steps

1) acetone, H2SO4

2) SO2Cl2, pyr., MeCN

3) H2, Pd/C, THF O

O MeMe

72%, two steps

1) DIBALH, PhCH3, -40 °C

2) TMSCH2MgCl, THF

O MeMe

89%, two steps

1) KHMDS, THF

2) BnBr, KOtBuO

O MeMe

95%, 3:1 dr

tBuOH, H2O

(DHQ)2AQNK2OsO4, K3Fe(CN)6

O MeMeOH

OH56%, >99.5% de

1) BzCl, NMM, DMAP

2) AllylTMS, TiCl3OiPr

recrystalizeO

D-glucorono-6,3 lactone

<$1/g (TCI)

H59%, three steps

1) acetone, H2SO4

3) H2, Pd/C, THF O

O MeMe

72%, two steps

2) TMSCH2MgCl, THF

O MeMe

89%, two steps

1) KHMDS, THF

2) BnBr, KOtBuO

O MeMe

95%, 3:1 dr

tBuOH, H2O

O MeMeOH

OH56%, >99.5% de

1) BzCl, NMM, DMAP

recrystalizeO

<$1/g (TCI)

H59%, three steps

1) acetone, H2SO4

3) H2, Pd/C, THF O

O MeMe

72%, two steps

2) TMSCH2MgCl, THF

O MeMe

89%, two steps

1) KHMDS, THF

2) BnBr, KOtBuO

O MeMe

95%, 3:1 dr

tBuOH, H2O

O MeMeOH

OH56%, >99.5% de

1) BzCl, NMM, DMAP

recrystalizeO

<$1/g (TCI)

H59%, three steps

1) acetone, H2SO4

3) H2, Pd/C, THF O

O MeMe

72%, two steps

2) TMSCH2MgCl, THF

O MeMe

89%, two steps

1) KHMDS, THF

2) BnBr, KOtBuO

O MeMe

95%, 3:1 dr

tBuOH, H2O

O MeMeOH

OH56%, >99.5% de

1) BzCl, NMM, DMAP

recrystalizeO

<$1/g (TCI)

H59%, three steps

1) acetone, H2SO4

3) H2, Pd/C, THF O

O MeMe

72%, two steps

2) TMSCH2MgCl, THF

O MeMe

89%, two steps

1) KHMDS, THF

2) BnBr, KOtBuO

O MeMe

95%, 3:1 dr

tBuOH, H2O

O MeMeOH

OH56%, >99.5% de

1) BzCl, NMM, DMAP

recrystalizeO

<$1/g (TCI)

Eribuline: Northern Fragment Synthesis!1) DMSO, TCAA, Et3N

PhCH3, -10 °C

2) LHMDS, PHSO2Me

H2SO4, acetone

2) NaOtBu, MeI

68%, five steps

O3, heptane;

then LIndlar's, H2

recrystalize

OBzOBz

BnO SO2Ph 1) TMSI, 60 °C

2) Bu4NCl, NaBH(OAc)3

3) K2CO3, MeOH

recrystalize

HO SO2Ph

57%, five steps

MeO SO2Ph

1) 2 M HCl, MeOH

2) TBSCl, imidaz.

MeO SO2Ph

OTBSOTBS

MeO SO2Ph

OTBSOTBS

7.8%, 19 steps

PhCH3, -10 °C

2) LHMDS, PHSO2Me

H2SO4, acetone

2) NaOtBu, MeI

68%, five steps

O3, heptane;

then LIndlar's, H2

recrystalize

OBzOBz

3) K2CO3, MeOH

recrystalize

HO SO2Ph

57%, five steps

MeO SO2Ph

1) 2 M HCl, MeOH

2) TBSCl, imidaz.

MeO SO2Ph

OTBSOTBS

MeO SO2Ph

OTBSOTBS

7.8%, 19 steps

PhCH3, -10 °C

2) LHMDS, PHSO2Me

H2SO4, acetone

2) NaOtBu, MeI

68%, five steps

O3, heptane;

then LIndlar's, H2

recrystalize

OBzOBz

3) K2CO3, MeOH

recrystalize

HO SO2Ph

57%, five steps

MeO SO2Ph

1) 2 M HCl, MeOH

2) TBSCl, imidaz.

MeO SO2Ph

OTBSOTBS

MeO SO2Ph

OTBSOTBS

7.8%, 19 steps

PhCH3, -10 °C

2) LHMDS, PHSO2Me

H2SO4, acetone

2) NaOtBu, MeI

68%, five steps

O3, heptane;

then LIndlar's, H2

recrystalize

OBzOBz

3) K2CO3, MeOH

recrystalize

HO SO2Ph

57%, five steps

MeO SO2Ph

1) 2 M HCl, MeOH

2) TBSCl, imidaz.

MeO SO2Ph

OTBSOTBS

MeO SO2Ph

OTBSOTBS

7.8%, 19 steps

PhCH3, -10 °C

2) LHMDS, PHSO2Me

H2SO4, acetone

2) NaOtBu, MeI

68%, five steps

O3, heptane;

then LIndlar's, H2

recrystalize

OBzOBz

3) K2CO3, MeOH

recrystalize

HO SO2Ph

57%, five steps

MeO SO2Ph

1) 2 M HCl, MeOH

2) TBSCl, imidaz.

MeO SO2Ph

OTBSOTBS

MeO SO2Ph

OTBSOTBS

7.8%, 19 steps

Eribuline: Southern Fragment Synthesis!

1) c-hexanone

H2SO4, 160 °C

2) TMSCl, imidaz.

1) MsCl, Et3N

2) KCN, EtOH/H2O

1) DIBALH, -78 °C

2) AcOH, H2O

3) Et3N, DMAP, Ac2O

recrystalize

65%, three steps

D-quinic acid

73%, two steps

BF3•OEt, MeCN, TCAA

TMSMeO2C

HMeO2C

O1) NaOMe, MeOH

2) LiAlH4, THF OO

$2/g (Aldrich)

1) c-hexanone

H2SO4, 160 °C

2) TMSCl, imidaz.

1) MsCl, Et3N

2) KCN, EtOH/H2O

1) DIBALH, -78 °C

2) AcOH, H2O

3) Et3N, DMAP, Ac2O

recrystalize

65%, three steps

D-quinic acid

73%, two steps

TMSMeO2C

HMeO2C

O1) NaOMe, MeOH

2) LiAlH4, THF OO

$2/g (Aldrich)

1) c-hexanone

H2SO4, 160 °C

2) TMSCl, imidaz.

1) MsCl, Et3N

2) KCN, EtOH/H2O

1) DIBALH, -78 °C

2) AcOH, H2O

3) Et3N, DMAP, Ac2O

recrystalize

65%, three steps

D-quinic acid

73%, two steps

TMSMeO2C

HMeO2C

O1) NaOMe, MeOH

2) LiAlH4, THF OO

$2/g (Aldrich)

1) c-hexanone

H2SO4, 160 °C

2) TMSCl, imidaz.

1) MsCl, Et3N

2) KCN, EtOH/H2O

1) DIBALH, -78 °C

2) AcOH, H2O

3) Et3N, DMAP, Ac2O

recrystalize

65%, three steps

D-quinic acid

73%, two steps

TMSMeO2C

HMeO2C

O1) NaOMe, MeOH

2) LiAlH4, THF OO

$2/g (Aldrich)

1) c-hexanone

H2SO4, 160 °C

2) TMSCl, imidaz.

1) MsCl, Et3N

2) KCN, EtOH/H2O

1) DIBALH, -78 °C

2) AcOH, H2O

3) Et3N, DMAP, Ac2O

recrystalize

65%, three steps

D-quinic acid

73%, two steps

TMSMeO2C

HMeO2C

O1) NaOMe, MeOH

2) LiAlH4, THF OO

$2/g (Aldrich)

KHMDS, MeIPhCH3/THF, -78 °C

recrystalize

LiCl, iPr2NEt

1) 1M HCl, AcOH

62%, three steps

65%, five steps

34:1 dr

NC Me O

DBU, 100 °CO H

1) O3 2) NaBH4

3) K2CO3, H2O

4) NaIO4

(MeO)2PO

75%, four steps

recrystalize

LiCl, iPr2NEt

1) 1M HCl, AcOH

62%, three steps

65%, five steps

34:1 dr

NC Me O

DBU, 100 °CO H

1) O3 2) NaBH4

3) K2CO3, H2O

4) NaIO4

(MeO)2PO

75%, four steps

recrystalize

LiCl, iPr2NEt

1) 1M HCl, AcOH

62%, three steps

65%, five steps

34:1 dr

NC Me O

DBU, 100 °CO H

1) O3 2) NaBH4

3) K2CO3, H2O

4) NaIO4

(MeO)2PO

75%, four steps

recrystalize

LiCl, iPr2NEt

1) 1M HCl, AcOH

62%, three steps

65%, five steps

34:1 dr

NC Me O

DBU, 100 °CO H

1) O3 2) NaBH4

3) K2CO3, H2O

4) NaIO4

(MeO)2PO

75%, four steps

recrystalize

LiCl, iPr2NEt

1) 1M HCl, AcOH

62%, three steps

65%, five steps

34:1 dr

NC Me O

DBU, 100 °CO H

1) O3 2) NaBH4

3) K2CO3, H2O

4) NaIO4

(MeO)2PO

75%, four steps

1) H2, PtO2, MeOH

2) Tf2O, Et3N, -78 °C

3) NaI, DMF I

1) LiBH4, THF, PhCH3

2) Zn, AcOH, MeOH

81%, two steps

CNOH1) HCl, iPrOH

then PhCH3, H2O

2) TBDPSCl, imidaz.O

1) (OMe)NHMe•HCl

AlMe3, DCM

2) TBSCl, imidaz, DMF

99%, four steps

TBSONO

OHOTBDPS

OTBDPS

1) MeMgCl, THF

2) KHMDS, Tf2NPhO

TBSOOTf

OTBDPS

75%, four steps

1) H2, PtO2, MeOH

2) Tf2O, Et3N, -78 °C

3) NaI, DMF I

2) Zn, AcOH, MeOH

81%, two steps

CNOH1) HCl, iPrOH

then PhCH3, H2O

1) (OMe)NHMe•HCl

AlMe3, DCM

99%, four steps

TBSONO

OHOTBDPS

OTBDPS

1) MeMgCl, THF

2) KHMDS, Tf2NPhO

TBSOOTf

OTBDPS

75%, four steps

1) H2, PtO2, MeOH

2) Tf2O, Et3N, -78 °C

3) NaI, DMF I

2) Zn, AcOH, MeOH

81%, two steps

CNOH1) HCl, iPrOH

then PhCH3, H2O

1) (OMe)NHMe•HCl

AlMe3, DCM

99%, four steps

TBSONO

OHOTBDPS

OTBDPS

1) MeMgCl, THF

2) KHMDS, Tf2NPhO

TBSOOTf

OTBDPS

75%, four steps

1) H2, PtO2, MeOH

2) Tf2O, Et3N, -78 °C

3) NaI, DMF I

2) Zn, AcOH, MeOH

81%, two steps

CNOH1) HCl, iPrOH

then PhCH3, H2O

1) (OMe)NHMe•HCl

AlMe3, DCM

99%, four steps

TBSONO

OHOTBDPS

OTBDPS

1) MeMgCl, THF

2) KHMDS, Tf2NPhO

TBSOOTf

OTBDPS

75%, four steps

1) H2, PtO2, MeOH

2) Tf2O, Et3N, -78 °C

3) NaI, DMF I

2) Zn, AcOH, MeOH

81%, two steps

CNOH1) HCl, iPrOH

then PhCH3, H2O

1) (OMe)NHMe•HCl

AlMe3, DCM

99%, four steps

TBSONO

OHOTBDPS

OTBDPS

1) MeMgCl, THF

2) KHMDS, Tf2NPhO

TBSOOTf

OTBDPS

62%, five steps

1) HCl, iPrOH, MeOH

2) PivCl, collidine, DMAP

3) MsCl, Et3N, THFOMe

TBSOOTf

OTBDPS

MsOOTf

3.3% overall

33 steps

O(Cl3CO)2CO

THF97%

2) LiOH, H2O, 60 °C65%, two steps

NHMsMe

MsCl, pyr., DMAPLigand for N-H-K

54% overall

four steps85%

Eribuline: Southern Fragment and Ligand Synthesis!

62%, five steps

1) HCl, iPrOH, MeOH

TBSOOTf

OTBDPS

MsOOTf

3.3% overall

33 steps

O(Cl3CO)2CO

THF97%

NHMsMe

54% overall

four steps85%

62%, five steps

1) HCl, iPrOH, MeOH

TBSOOTf

OTBDPS

MsOOTf

3.3% overall

33 steps

O(Cl3CO)2CO

THF97%

NHMsMe

54% overall

four steps85%

62%, five steps

1) HCl, iPrOH, MeOH

TBSOOTf

OTBDPS

MsOOTf

3.3% overall

33 steps

O(Cl3CO)2CO

THF97%

NHMsMe

54% overall

four steps85%

62%, five steps

1) HCl, iPrOH, MeOH

TBSOOTf

OTBDPS

MsOOTf

3.3% overall

33 steps

O(Cl3CO)2CO

THF97%

NHMsMe

54% overall

four steps85%

MsOOTf

NHMsMe

MeO SO2Ph

3.55 eq CrCl2 and NiCl2,

TBSOTBSO

MeO SO2Ph

TBSOTBSO

1) KHMDS, THF -14 °Cchromatography

2) DIBALH, DCM

68%, three stepsO

MeO SO2PhTBSO

3.55 eq

Et3N, THF1.0 eq

1.1 eq

(20:1 dr before chrom.)

Eribuline: Coupling Western Fragments!

MsOOTf

NHMsMe

MeO SO2Ph

3.55 eq CrCl2 and NiCl2,

TBSOTBSO

MeO SO2Ph

TBSOTBSO

1) KHMDS, THF -14 °Cchromatography

2) DIBALH, DCM

68%, three stepsO

MeO SO2PhTBSO

3.55 eq

Et3N, THF1.0 eq

1.1 eq

(20:1 dr before chrom.)

Eribuline: Coupling Western Fragments!

64%, three steps

MeO SO2PhTBSO

-75 °C then ald.

H HOTBS

nBuLi, THF, 0 °C;

H HOTBS

TBSO TBSO OMe SO2Ph

H HOTBS

1) DMP, DCM

2) SmI2, -78 °C

Eribuline: Completion of Synthesis!

64%, three steps

MeO SO2PhTBSO

-75 °C then ald.

H HOTBS

nBuLi, THF, 0 °C;

H HOTBS

TBSO TBSO OMe SO2Ph

H HOTBS

1) DMP, DCM

2) SmI2, -78 °C

HO OH OMe

H HPPTS, DCM

72%, two steps

1) Ts2O, collidine, pyrid. (cat.)2) NH4OH, iPrOH

3) MeSO3H, NH4OH, H2O

84%, three steps

H2N OH OMe

MeSO3H•

26% for coupling steps

11 final manipulations

HO OH OMe

H HPPTS, DCM

72%, two steps

1) Ts2O, collidine, pyrid. (cat.)2) NH4OH, iPrOH

3) MeSO3H, NH4OH, H2O

84%, three steps

H2N OH OMe

MeSO3H•

26% for coupling steps

11 final manipulations

Arterolane: Complete synthesis!

H2N MeMe

Vennerstrom et al. Nature 2004 900

arterolaneOO

artemesinin

■ First discovered by Chinese army project, Project 523, in 1960's

Artemesinin

■ Use of source plant, Artemsia annua, dates back 2,000 years in China

■ Isolated material approved for worldwide treatment of malaria

■ First synthesized and identified by broad collaboration of chemists in 2001

Arterolane

■ Phase III trials began in India in 2009 by Indian company Ranbaxy

■ Ozonide bridge retains the active radical reactivity found in artemesin, improved PK

H2N MeMe

arterolaneOO

artemesinin

Artemesinin

Arterolane

H2N MeMe

arterolaneOO

artemesinin

Artemesinin

Arterolane

NH2OMe

OMeMeOH, H2O O3, c-hex., DCM, -78 °C

1) NaOH, H2O

2) 1 M HCl, 0 °C

rxtl'd

H2NNH2

rxtl'd, 87%

64% overall

4 steps

Ranbaxy Labs 2011 patent

NH2OMe

1) NaOH, H2O

2) 1 M HCl, 0 °C

rxtl'd

H2NNH2

rxtl'd, 87%

64% overall

4 steps

NH2OMe

1) NaOH, H2O

2) 1 M HCl, 0 °C

rxtl'd

H2NNH2

rxtl'd, 87%

64% overall

4 steps

NH2OMe

1) NaOH, H2O

2) 1 M HCl, 0 °C

rxtl'd

H2NNH2

rxtl'd, 87%

64% overall

4 steps

NH2OMe

1) NaOH, H2O

2) 1 M HCl, 0 °C

rxtl'd

H2NNH2

rxtl'd, 87%

64% overall

4 steps

■ Broad spectrum antiobiotics, though resistance is increasing

■ Produced by Meyers Lab and Tetraphase

■ TP-434 currently in Phase II trials for treatment of resistant infections

TP-434

OHOHOH

OH NMe Me

■ First identified 1945 from soil bacteria

chlorotetracycline

■ Most recent tetracycline derivative (tigecycline) approved in 2005, 1st in 20 years

■ All but those produced by Tetraphase are semi-synthetic variants

TP-434 Synthesis: Overview!

TP-434

OHOHOH

OH NMe Me

chlorotetracycline

TP-434

OHOHOH

OH NMe Me

chlorotetracycline

TP-434

OHOHOH

OH NMe Me

chlorotetracycline

■ Highly convergent, easily modified

■ Multiple generations of dienone synthesis

■ Similar route used to produce mulitple analogs

TP-434

TP-434 Synthesis: Retrosynthetic Analysis!

TP-434

TP-434 Synthesis: C/D Ring Precursor Synthesis!

COOMeH2N

1) BnBr, Cs2CO3

2) NaBH4, MeOH

83%, two steps

1) MsCl, Et3N

2) NHMe2, DMF

98%, two steps

1) n-BuLi, CO2 (g)

2) H2SO4, MeOH

NMeMeN

O63%, two steps

SiMe2PhCl

p-benzoquinone;

then CeCl3, NaBH4

67%72%

SiMe2Ph

PhMe2Si

COOMeH2N

1) BnBr, Cs2CO3

2) NaBH4, MeOH

83%, two steps

1) MsCl, Et3N

2) NHMe2, DMF

98%, two steps

1) n-BuLi, CO2 (g)

2) H2SO4, MeOH

NMeMeN

O63%, two steps

SiMe2PhCl

p-benzoquinone;

then CeCl3, NaBH4

67%72%

SiMe2Ph

PhMe2Si

COOMeH2N

1) BnBr, Cs2CO3

2) NaBH4, MeOH

83%, two steps

1) MsCl, Et3N

2) NHMe2, DMF

98%, two steps

1) n-BuLi, CO2 (g)

2) H2SO4, MeOH

NMeMeN

O63%, two steps

SiMe2PhCl

p-benzoquinone;

then CeCl3, NaBH4

67%72%

SiMe2Ph

PhMe2Si

COOMeH2N

1) BnBr, Cs2CO3

2) NaBH4, MeOH

83%, two steps

1) MsCl, Et3N

2) NHMe2, DMF

98%, two steps

1) n-BuLi, CO2 (g)

2) H2SO4, MeOH

NMeMeN

O63%, two steps

SiMe2PhCl

p-benzoquinone;

then CeCl3, NaBH4

67%72%

SiMe2Ph

PhMe2Si

COOMeH2N

1) BnBr, Cs2CO3

2) NaBH4, MeOH

83%, two steps

1) MsCl, Et3N

2) NHMe2, DMF

98%, two steps

1) n-BuLi, CO2 (g)

2) H2SO4, MeOH

NMeMeN

O63%, two steps

SiMe2PhCl

p-benzoquinone;

then CeCl3, NaBH4

67%72%

SiMe2Ph

PhMe2Si

Amano lipase-PSNEt3, 23 °C

4 mol % Pd(dppf)Cl2

HCO2NH4, DMF

NaHMDS, THF, -50 °C

62%, one step

PhMe2Si

O MeMe

PhMe2Si

KHMDS, -10 °C120 °C

PhCH3, 10 h

4 mol % Pd(dppf)Cl2

HCO2NH4, DMF

62%, one step

PhMe2Si

O MeMe

PhMe2Si

KHMDS, -10 °C120 °C

PhCH3, 10 h

4 mol % Pd(dppf)Cl2

HCO2NH4, DMF

62%, one step

PhMe2Si

O MeMe

PhMe2Si

KHMDS, -10 °C120 °C

PhCH3, 10 h

4 mol % Pd(dppf)Cl2

HCO2NH4, DMF

62%, one step

PhMe2Si

O MeMe

PhMe2Si

KHMDS, -10 °C120 °C

PhCH3, 10 h

4 mol % Pd(dppf)Cl2

HCO2NH4, DMF

62%, one step

PhMe2Si

O MeMe

PhMe2Si

KHMDS, -10 °C120 °C

PhCH3, 10 h

20 mol% LiOtBu-45 to -20 °C

equil. ratio

DCM, 0 °C

64%, three steps

NO NO2 H

NMe Me

12.8:1

4 M NaH2PO4

THF, MeOH60 °C

TBSOTf, 2,6-lutid.HN

OBnOTBS

■ From Michael-Claisen: 5 steps, 35 %, no chromatographic purificiation

■ Overall: 13% yield from alkyne, 14 steps including all starting materials

TP-434 Synthesis: A/B Ring Precursor Synthesis!

equil. ratio

DCM, 0 °C

64%, three steps

NO NO2 H

NMe Me

12.8:1

4 M NaH2PO4

THF, MeOH60 °C

OBnOTBS

equil. ratio

DCM, 0 °C

64%, three steps

NO NO2 H

NMe Me

12.8:1

4 M NaH2PO4

THF, MeOH60 °C

OBnOTBS

equil. ratio

DCM, 0 °C

64%, three steps

NO NO2 H

NMe Me

12.8:1

4 M NaH2PO4

THF, MeOH60 °C

OBnOTBS

1) sBuLi, TMEDA;

2) (COCl)2; then PhOH

OMeCO2H

OMeCOOPh

OBocCOOPh

Methen MeI

52%, two steps

2) Boc2O, DMAP

1) BBr3, DMF

94%, two steps

LDA, TMEDA, THF 2) H2, Pd/C

41%, 2 steps

1) aq. HF

1) HNO3, H2SO4

2) H2, Pd/C

OBnOTBS

OBocCOOPh

OBnOTBS

82%, 2 steps

2) pyrrolidine

11 additional steps

25 total steps

<1.6% overall

1 dose ≈ 1.4 g alkyne

TP-434 Synthesis: Cyclization and Final Steps!

41%, 2 steps

1) aq. HF

1) HNO3, H2SO4

2) H2, Pd/C

OBnOTBS

OBocCOOPh

OBnOTBS

82%, 2 steps

2) pyrrolidine

11 additional steps

25 total steps

<1.6% overall

41%, 2 steps

1) aq. HF

1) HNO3, H2SO4

2) H2, Pd/C

OBnOTBS

OBocCOOPh

OBnOTBS

82%, 2 steps

2) pyrrolidine

11 additional steps

25 total steps

<1.6% overall

41%, 2 steps

1) aq. HF

1) HNO3, H2SO4

2) H2, Pd/C

OBnOTBS

OBocCOOPh

OBnOTBS

82%, 2 steps

2) pyrrolidine

11 additional steps

25 total steps

<1.6% overall

41%, 2 steps

1) aq. HF

1) HNO3, H2SO4

2) H2, Pd/C

OBnOTBS

OBocCOOPh

OBnOTBS

82%, 2 steps

2) pyrrolidine

11 additional steps

25 total steps

<1.6% overall

•HCl

CO2HOH

fingolimod

myriocin

■ From thermophilic fungii species

■ Isolated in 1994, studied for bioactivity

■ Approved in 2010 for treatment of MS

■ Immunosuppressant agent

■ Developped by Novartis

Structure distilled to necessary parts

■ Inhibits sphingosine phosphate receptor

Reduced toxicity, improved PK profile

Persp. Med. Chem. 2007, 11.

■ Limits lymphocyte release into blood

Fingolimod: Introduction!

•HCl

CO2HOH

fingolimod

myriocin

•HCl

CO2HOH

fingolimod

myriocin

AlCl3, DCM Na(0), EtOH

C8H17 C8H17

CO2EtEtO2CO

CO2EtC8H17

2) LiAlH4, THF

1) Et3SiH, TiCl4, DCMOH

6 M HCl, EtOH

•HCl

70%, two steps

38% overall yield

5 steps

Fingolimod: Complete synthesis!

five drugs or clinical candidates derived from natural ... · why pursue total synthesis of natural...

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