Topic Seminar PPT.pptx

Steph McCabe Research Topic Seminar

30th January 2016

A Second Generation Total Synthesis of (±)-Cycloclavine and Progress Toward an Asymmetric Total Synthesis of (+)-Cycloclavine

1

N H

NH

Steph McCabe @ Wipf Group Page 1 of 25 3/27/2016

2

Overview

PART 1: 1.1 Ergot alkaloids

§  Classification §  Natural sources/ history §  Biological activity and use as pharmaceuticals

1.2 Clavine Alkaloids §  Classification/ examples §  Biosynthesis of clavine alkaloids §  Summary of recent syntheses of clavine alkaloids based on strategic disconnections

•  Clavicipitic acid •  Aurantioclavine •  Rugulovasine A & B •  Cycloclavine

§  Recent syntheses of cycloclavine PART 2:

Experimental Data §  Retrosynthetic analysis §  Second generation total synthesis of cycloclavine §  Efforts toward an asymmetric synthesis of cycloclavine §  Future directions §  Conclusions


3

Classification of Ergot Alkaloids

ERGOT ALKALOIDS

Clavines Lysergic Acid

NHH

NH

8

D

C

BA1

2

HO2CNH

H

NH

8

D

C

BA1

2

H

RR = H or OH

N H

NH

HN H

NH

R

HH

NH

NO

NRR'

H

NH

NOO

NNH

O

N

OR

H OH

R

tetracyclic clavines(ergolines)

tricyclic clavines(secoergolines)

Rearranged clavines Lysergic acid amides ergopeptines

lysergic acid

R = H, CH2OH, CHO

H

NHH

NH

8D

C

BA1

2

Ergoline Core


Ergot Alkaloids Occurrence of Ergot Alkaloids in Nature

§  Ergot alkaloids are produced by the Clavicipitaceae and Trichocomaceae families of filamentous fungi §  These fungi infect cereal grains causing ‘ergot’ §  The fungi have a symbiotic relationship with the plant causing no symptoms of infection

•  Ergot alkaloids produced by the fungi help protect the plant from predation and improve growth, while the fungi gain nutrition and shelter from the plant

4

Nat. Prod. Rep., 2011, 28, 496 Nat. Prod. Rep., 2014, 31, 1328

Ergot on wheat stalks fruiting C. purpurea sclerotia


5

§  Consumption of ergot contaminated grains leads to ergotism (St. Anthony’s fire), a disease common in central Europe in the middle ages

§  Two types of ergotism are recognized: •  ergotismus convulsivus: characterized by hallucinations, convulsions, confusion and irrational behaviour •  ergotismus gangrenous: characterized by gangrene of the feet, legs, hands and arms

History Ergot & Ergotism

§  Ergotism in humans is now rare due to strict guidelines governing the acceptable concentration of ergot bodies in grain, however ergotism still produces serious epidemics in livestock fed contaminated grain.

§  Modern control of ergot is focused on limiting the presence of sclerotia in cereal grains largely through preventative

measures or in particularly bad seasons crops can be saved by separating the ergot kernels from cereal grains based on density or colour


6

Owing to the concurrent development of many of the drugsdiscussed, and the spectrum of activity some pharmaceuticalsdisplay, this review is presented in fungal metabolite classesrather than chronologically or by pharmacology. To providecontext, Fig. 1 displays a timeline of the original discovery of

the pharmaceutical classes. Within each class, the name ofthe fungal metabolite is presented as well as the pharmaceuticalcompanies that supply it and brand names that it is sold under.For those classes that have several members, a time-linedisplaying approval dates is presented for clarity. Table 1

1941 1948 1962 1971 1974 1976 1995

Mycop

heno

lic ac

id

1896 1918 1928 1939

Fingoli

mod

Statins

Echino

cand

ins

Cyclos

porin

Fusidi

c acid

Cepha

lospo

rins

Coumar

ins

Griseo

fulvin

Penici

llins

Ergot

alkalo

ids

Fig. 1. Timeline of the original discovery of the pharmaceutical classes of fungal metabolites.

Table 1. Pharmaceuticals currently available in Australia and NewZealand, displaying drug name, structure, pharmaceutical class (underlined),

original fungus (italicised), nature of discovery, and earliest year of approval in Australia[11] and New Zealand[12]

Cephalothin Cephalexin Cephazolin Cefuroxime axetil

1974

CephalosporinsCephalosporium acremonium

Semi-synthetic1989

Cefaclor Cefotaxime Ceftriaxone Ceftazidime

Cefepime Warfarin Cyclosporin Caspofungin

N

S

O OH

HN

O

H

S

N N

S

O

N NNN

N

S

O O

O

HN

O

N O

O

O

NH2

O

H

O

O


Semi-synthetic

N

S

O OH

HN

OS

OO

O

H


Semi-synthetic1988

N

S

O OH

O

HN

O

NH2

H


Semi-synthetic1969

N

S

O OH

O Cl

HN

O

NH2

H2N

H

N

S

O OH

OO

HNN

O

SN

O

O

HN

S

O

H

OHOS

NNH

N

OO

HN

O

SN

NO

N

S

O

H

OO

HN

O

SN

NO

OOH N

O O

OOH NO

HN

NH2

OH

OHN

O

OH

N O

NHOH

O

O

HN

HN

O

OH

NH

NH2

OH

HO

OH

HO

CoumarinsPenicillium sp.

Designed1954

EchinocandinsZalerion arboricola

Semi-synthetic2002

H2N

H2N

!

"


Semi-synthetic1980


Semi-synthetic1981


Semi-synthetic1983


Semi-synthetic1984

N

S

O O

ONO

HNN

O

SN

H


Semi-synthetic1997

!

"

H2N

ON

O

N O

N

O N

ONH

O HN

O

N O

HN

ON

ONNH

OHO

CyclosporinTolypocladium inflatum

Natural1983

(Continued )

828 A. M. Beekman and R. A. Barrow

*

Aus. J. Chem., 2014, 67, 827

Biological Activity of Ergot Alkaloids

Figure 1. Timeline of the initial discovery of pharmaceutical classes of fungal metabolites

§  These classes of fungal metabolites have produced some of the best known/ profitable pharmaceuticals in human medicine

•  Anti-cholesterol statins e.g. rosuvastatin (crestor), atorvastatin (lipitor), antibiotic penicillin and immunosuppressant cyclosporin A

§  Ergot alkaloids possess the widest spectrum of biological activity •  Ranging from anti-migraine to anti-Parkinson agents

HNR

O NO

SH

R1

OHO

HNR

O NO

HS

COOH

O

HO O

HN

iPr

NN O

NHO

N

ON

ON

OiPriBu

N

iBuO

NH

O

N

O

O

iPr

iBu

O

HOO

OH

MeO

O

O

OOMe

MeOCl

O

O OMe

OO O

COOH

O

H

HHO

HHO

O

NHH

NH

R2N

O

NH

N

O

O

NHO H

N

O

N

HO OH

NHO

HNO

OH

OHOH

HOHO

HO

HO O

Bu

6

NH2

OHOH7


Ergoline

serotonin (5-HT) dopamine (DA) epinephrine (adrenalin)

7

Biological Activity of Ergot Alkaloids

norepinephrine (noradrenalin)

§  The broad spectrum of bioactivity exhibited by ergot alkaloids is due to their structural similarity to natural neurotransmitters

§  Ergot alkaloid drugs generally act by mimicking (agonist) or blocking (antagonist) the binding of natural neurotransmitters to their receptors

H

NH

NH

H

HOOH

NH2

HO

NH

NH2

12

3

45

6

78

9 10

1112

13

1415

16

HOOH

NH2HO

HOOH

NHMeHO


8

Ergot Alkaloid Pharmaceuticals

§  The majority of ergot alkaloid pharmaceuticals are semi-synthetically prepared from lysergic acid derivatives

H

NH

NO

NH

OH

H

NH

N

N

O

NH

O

N

H

H

NH

NO

Br

ON

NH

O

N

O

HOH

Ergometrineprevents post partum haemorrhage MOA: a-1A adrenergic agonist

5-HT2 agonist

Cabergoline Parkinson's disease

MOA: D2 agonist

BromocriptineParkinson's disease

Type 2 diabetesMOA: D2 agonist

NHH

NHLysergic acid diethylamide (LSD)

Et2N

O

H

NH

N

ON

HN

O

NO

HHO

Ph

O

Ergotaminemigraine treatment

MOA: 5-HT1B agonist


9

1.2 Clavine Alkaloids

§  Classification/ examples

§  Biosynthesis of clavine alkaloids

§  Summary of recent syntheses of clavine alkaloids based on strategic disconnections

•  Clavicipitic acid

•  Aurantioclavine

•  Rugulovasine A & B

•  Cycloclavine

§  Recent syntheses of cycloclavine

Clavine Alkaloids


10

Clavine Alkaloids

NH

OO

HN

rugulovasine A

NH

OO

HN

NOH

NH

H

paspaclavine

NH

HNCOOH

NH

HN

clavicipitic acid aurantioclavine

N H

NHCycloclavinerugulovasine B

NHMeH

NH

OH

H

NHMeH

NH

CHO

H

NHMeH

NH

OH

H

NHMeH

NH

H

OH

NMe2H

NH

H

chanoclavine-Ialdehyde

chanoclavine-I

chanoclavine-II

isochanoclavine-I

6,7-seco-agroclavine

NH

NH

H

epoxyagroclavine

Clavine Alkaloidstricyclic clavines Rearranged clavines

tetracyclic clavines

NH

NH

H

agroclavine

NH

NH

H

elymoclavine

NH

NH

H

festuclavine

NH

NH

setoclavine

NH

NH

penniclavine

N H

NH

H

fumigaclavine B

NH

NH

H

N H

NH

H

fumigaclavine Cfumigaclavine A

OH OHHO

OH

HO AcO AcO

O

67

8


11

Biosynthesis of Clavine Alkaloids

ACIE, 2015, 54, 3004-3007 (aurantioclavine) J. Org. Chem., 1980, 45, 1117 (clavicipitic acid) Nat. Prod. Rep., 2011, 28, 496 Toxins, 2014, 6, 3281 Nat. Prod. Rep., 2014, 31, 1328

CO2H

NH2

NH

DmaWprenyltransferase

CO2H

NH2

NH

EasF N-methyltransferase N

H

CO2H

NH

DMAT N-Me-DMATL-tryptophan

NH

HN

aurantioclavineNH

HNCOOH

clavicipitic acidbenzylic oxidation/aminocyclisation

decarboxylation

OPPSAM

DMAPP

§  The first 5 steps in the biosynthetic pathway are common to all ergot alkaloids and are responsible for the formation of the core ergoline scaffold

•  Most diversification occurs late stage via functionalization of ergoline core however, in some fungi diversification can occur early on via short diverted pathways


12


NH

CO2H

NH

HN H

NH

OH

H

EasE oxidoreductaseEasC catalase

Chanoclavine-IN-Me-DMAT

HN H

NH

O

H

Chanoclavine-Ialdehyde

EasD oxidase

NH

OO

HN

NH

OO

HN

+

??? O

last common precursor

rugulovasine A rugulovasine B


13


lysergic acid subclass

tetracyclicclavine

subclass

H

NH

H

N

agroclavineHN H

NH

O

H

Chanoclavine-Ialdehyde

H

NH

H

N

festuclavine

H

NH

H

N

H

NH

H

N

N H

NH

EasGreductase

EasHdioxygenase

EasA_Af reductase

HN H

NH

O

H spontaneous

cycloclavine

EasGreductase

N H

NH

setoclavine NH

NH

H

elymoclavine

NH

NH

HO2C

lysergic acid

penniclavineEasGreductase

CloAP450

monooxygenasespontaneous/isomerase

OH

OH

N H

NH

OHHO

EasA_NIisomerase


14


H

NH

H

N

festuclavine

NHH

NH

H

fumigaclavine B

NHH

NH

H

fumigaclavine A

NHH

NH

H

fumigaclavine C

HO AcO AcOP450/ FAD

monooxygenase

EasN(FgaAT)

O-acetyltransferase

EasL(FgaPT1)

prenyltransferase


NOH

NH

H

paspaclavine

NHMeH

NH

OH

H

NHMeH

NH

CHO

H

NHMeH

NH

OH

H

NHMeH

NH

H

OH

NMe2H

NH

H

chanoclavine-Ialdehyde

chanoclavine-I

chanoclavine-II

isochanoclavine-I

6,7-seco-agroclavine

NH

NH

H

epoxyagroclavine

Clavine Alkaloidstricyclic clavines Rearranged clavines

tetracyclic clavines

NH

NH

H

agroclavine

NH

NH

H

elymoclavine

NH

NH

H

festuclavine

NH

NH

penniclavine

N H

NH

H

fumigaclavine B

NH

NH

H

N H

NH

H

fumigaclavine Cfumigaclavine A

OHHO

OH

HO AcO AcO

O

67

8

15

Recent Synthetic Approaches to Clavine Alkaloids

NH

NH

setoclavine

OH

NH

HNCOOH

NH

HN

clavicipitic acid aurantioclavine

NH

OO

HN

rugulovasine A

NH

OO

HN N H

NHCycloclavinerugulovasine B


16

Recent Synthetic Approaches to Clavine Alkaloids Clavicipitic Acid

§  Clavicipitic acid is a rearranged clavine alkaloid that was isolated as a mixture of naturally occurring cis and trans diastereomers from Claviceps species of fungi. ( fusiformis and claviceps SD 58)

§  Unusual azepinoindole core bearing two stereocentres presents an interesting synthetic challenge

JOC, 2014, 79, 3255; JOC, 2010, 75, 7626; JOC, 2007, 72, 8115; Eur. J. Org. Chem., 2004, 1244; Chem. Eur. J., 2015, 11340

NH

HNCOOH

(-)-trans clavicipitic acid

NH

HNCOOH

(-)-cis clavicipitic acid

75

3

A B

C

NH

HNCO2HIntramolecular

reductive amination Ir catalyzed

cyclodehydration

SHIBATA (2015)

N-alkylation(±)NH

HNCO2HImine formation

Friedal-CraftsAlkylation

Rh(I)-catalyzed1,2 addition of an

indole-4-pinacolboronic esterto an imine

PIERSANTI (2014)

NH

HNCO2H

Heck/SN2' Aminocyclization

Pd catlyzedIndole formation

JIA (2010)

NH

HNCO2HSN2' Aminocyclization

catalyticenantioselectivephase transfer

alkylation (99% ee)Heck

coupling

PARK (2007)

*

4 steps, 34% overall yield

7 steps, 34% overall yield trans7 steps, 7% overall yield cis

9 steps (to CO2Me)15% overall yield (" ")

11 steps, ~20 % overall yield

5

73

73

73

1

6


17

(-)-Aurantioclavine

§  Same azepinoindole core as Clavicipitic acid

§  Isolated in 1981 from the fungus penicillium aurantiovirens

§  Absolute Stereochemistry was determined to be 7R by Stoltz (based on X-ray analysis of an advanced intermediate)

Recent Synthetic Approaches to Clavine Alkaloids Aurantioclavine

JACS, 2008, 130, 13745; OL, 2014, 16, 996; OL, 2010, 12, 2004; Eur. J. Org. Chem., 2009, 5752 Early racemic synthesis Chem. Pharm. Bull., 1985, 33, 2162; JOC, 1987, 52, 3319

NH

HN7

5

A B

C

NH

HNMitsunobuMitsunobu/

OxidativeKinetic

Resolution Stille

C=O Addition

STOLTZ (2008)

13 steps, <1% overall yield

NH

HN

alkenylationof N-alkylsulfinyl

imine(94% de)

ELLMAN (2005)


formylation/N-alkylsulfinyl

imine formation

SN2

NH

HNPictet-Spengler

ISHIKURA (2009)

3 steps, 26% overall yield(±)

H

DeoxygenationNH

HN

Indole formation

TAKEMOTO (2014)


asymmetric allylic

amination(92% ee)

Suzuki-Miyauracoupling

Suzuki-Miyauracoupling

75

76

1

2

67

6


18

Recent Synthetic Approaches to Clavine Alkaloids Rugulovasine A & B

•  Rugulovasine A and B are modified clavine alkaloids containing a spirolactone moiety

•  They were isolated as a mixture of naturally occurring diastereomers from the fungus penicillium concavo-rugulosum •  Both Rugulovasine A and B were isolated in racemic form and interconverted at room temperature •  Interconversion is proposed to occur via a vinylogous Mannich reaction that proceeds through an achiral 2-alkoxyfuran

intermediate

6

NH

OO

NHMe

NH

OO

NHMe

NH

OMe

NHMeO

rugulovasine A rugulovasine B

A B

CD 5

1011

Stille coupling

Indole Mannich/CN- nucleophilic

addition

MARTIN (2001)

NH

OO

NHMe

intramolecular vinylogousMannich

NH

OO

NHMe

SRN1

intermolecular vinylogousMannich

Indole Mannich/CN- nucleophilic

additionNH

OO

NHMecyclocarbonylation

NHK

JIA (2013)

8 steps 11% overall yield



MARTIN (2001)

1011

5 5

1011

JACS, 2001, 123, 5918; OL, 2013, 15, 3662


19

Ipomea hildebrandtii

Isolation of Ergot Alkaloid Cycloclavine

§  First isolated in 1969 from the seeds of the African morning glory (Ipomea hildebrandtii)

§  Structure elucidation, including relative and absolute stereochemistry (5R,8S, 10S) was determined by X-ray crystallographic analysis of the methobromide salt

•  Optical rotation [α] 20D = + 39 (pyr)

§  Therapeutic potential of cycloclavine remains underexplored (1 patent describes pesticidal properties)

•  “Cycloclavine and derivatives thereof for controlling invertebrate pests” (BASF, 2013)

Tetrahedron, 1969, 25, 5879 PCT Int. Appl. WO2014096238 A1, 2013

N H

NH(+)-Cycloclavine

58

10


20

Recent Synthetic Approaches to Clavine Alkaloids Cycloclavine

N H

NH(+)-Cycloclavine

58

10

DE

A B

C

N-alkylation/intramolecular aldol

NH

N

Cyclopropanation

7 steps, 1% overall yieldfrom Uhle's ketone derivative

Fragmentation/1,3-dipolar cycloaddition

NH

N

Cyclopropanation

EDA additionRadical cyclization NH

N

Cyclopropanation

Aza-Cope Mannich

NH

N

1,2 C=O Addition/ IMDAF

intramolecular methylene-cp DA

N-alkylation

14 steps, 1.2% overall yield

8 steps, 7% overall yield (formal synth.)14 steps, <1 % overall yield (total synth.)

12 steps (formal synthesis)6% overall yield

SZANTAY (2008) WIPF (2011)

CAO (2014) BREWER (2014)

Tetrahedron, 2008, 64, 2924; Tetradhedron Lett,, 2014, 56, 197; JOC, 2014, 79, 122; JACS, 2011, 133, 7704


Szántay's Approach (2008)

21

Tetrahedron, 2008, 64, 2924

N-alkylation/intramolecular aldol

NH

N

Cyclopropanation

Szantay (2008)

NH

OBr

NH

O

OEt

THF, 48%LHMDS, THF-70 °C, 50%

1.

2.NH

N

HO

O

EtO

NH

NMe

NH

NCH2N2, Pd(OAc)2

CH2Cl232% (BRSM)

HN

OOH

steps

4 steps, 14%

4-bromo Uhle's ketone


Brewer’s Approach (2014)

22

Tetradhedron Lett,, 2014, 56, 197

Fragmentation/1,3-dipolar cycloaddition

NH

N

Cyclopropanation

EDA addition

Brewer

NH

N

NPiv

OTBSOH

N2

EtO2C

SnCl4

CH2Cl2, 0 °C,10 min, 80 %

NPiv

O

CO2Et

HN

OOTMS

PhMe0 °C-120 °C

65%NH

NEtO2C

Szantay'sintermediate

NPiv

OTBSOH

N

EtO2C

N

SnCl4

NPiv

O

N

EtO2C

N

TBS

NPiv

CO2Et

N

DBU/ H2OPiv deprotection


Cao’s Approach (2014)

23

JOC, 2014, 79, 122

Radical cyclization NH

N

Cyclopropanation

Cao

Aza-Cope Mannich

NTs

BrO OH

NHTs

FeCl3, CH2Cl2, reflux, 0.2 h, 83% NTs

Br

N TsHO

NTs

N Ts•O

Br

H

NTs

N TsO

H

Br

NH

NMe

H

NTs

NTsH

NTs

NTs

H

PhSn-Bu3SnH, AIBN,

benzene, reflux, 91%

Br

Szantay's intermediate

cycloclavine

isomerizationdeprotectionmethylation

1) NaBH42) PhSSPh PBu3

NTs

Br


Wipf’s Approach (2011)

24

Dr Filip Petronijevic JACS, 2011, 133, 7704

NH

N

Addition/ IMDAF

intramolecular methylene-cp DA

N-alkylation

Wipf

NO

H

NO

CO2CH3H

HN

O1. µW, PhCF3, 195 °C, 1 h 52% (72% brsm)

2. TBAF, THF, rt, 85 %

OH

1. MsCl, Et3N, CH2Cl2, 0 °C, 1 2.

NaH, DMF, rt, 12 h67% (2 steps)

3. NaHMDS, THF, -78 °Cthen TBSCl

1. MeOC(O)Cl, 70 °C3 h, 71%

2. LDA, THF, -78 °C, 1 hthen TMSCl (1.3 equiv)

then Pd(OAc)2 (1.3 equiv)CH3CN, 12 h, rt 67%

TBSO N

(±)-cycloclavine

O NBoc LAH, THF

66 °C, 30 min,quant

NCO2CH3

H

HN

SnBu31.

n-BuLi, THF, -78 °C, 51%

2. 180 °C, PhCF3, µW, 30 min 44% (56% brsm)

OH


25

Acknowledgements

•  Prof. Peter Wipf •  Group Members Past and Present •  Mass Spec, NMR, X ray facilities •  Mary E. Warga Predoctoral Fellowship •  Arts & Sciences Fellowship


Documents

Topic Seminar PPT.pptx