recent total syntheses published in...

Recent Total Syntheses !Published in Nature!

Eric Newcomb 8/21/2011!

MeMe

MeO

Me

H

Me

N

N

OO

H

H

H

H NH

N

MeH

NH

N

MeCO2Me

NH

N

HCO2Me

NH

N

CO2Me

NH

NO

NH

Me

Me

H

HMe

HNC

MeMe

NH

Me

Me

H

HMe

HNC

MeMeCl

H

Me

NC

MeCl

ClOSO3H

Cl

Cl ClCl

NH

O

NHMeCl

H H

Me

Me

NC

Nature Then and Now!

• In 2010 the acceptance rate was 7.9% (10.287 submitted and 809 accepted)

• In 2010 the impact factor was 36.1

• Much more biologically relevant chemistry is published than synthetic

• Broader interest is a major factor in publication consideration

• Broader interest is determined solely by Nature editors, not referees

• First published Nov. 4th, 1869

• First issue states two objectives:

'The objective which it is proposed to attain by this periodical may be broadly stated as follows. It is intended, First, to place before the general public the grand results of scientific work and scientific discovery; and to urge the claims of science to move to a more general recognition in education and in daily life.'

'Secondly, to aid scientific men themselves, by giving early information of all advances made in any branch of natural knowledge throughout the world, and by affording them an opportunity of discussing the various scientific questions which arise from time to time.'

Collective synthesis of natural products by means of organocascade catalysis!

N

N

OO

H

H

H

H NH

N

MeH

NH

N

MeCO2Me

NH

N

HCO2Me

NH

N

CO2Me

NH

NO

Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Nature 2011, 475, 183.

N

N

HCO2Me

Me

OHPreakuamminicine

NH

N

H MeCHO

N

N

OO

H

H

H

H

NH

CO2Me

N

Et

Norfluorocuraine Didehydrosecodine

Common tetracyclic core

Strychnine

NH

N

MeCO2Me

Vincadifformine

How nature assembles molecules?!


N

N

O

1-Napt-Bu

Me

N

NHBoc

SeMePG

O

N

BocHN

MeSePG

N

NH

O

1-Napt-Bu

Me

NPG

NHBoc

SeMe

NR2

NPG

NHBoc

NR2

NPG

NR2

NR'

NPG

O

NR'

NPG

NHBoc

O

NPG

NHBoc

X

NPG

NBoc X

NPG

NBoc X

N

NH

O

1-Napt-Bu

Me

NPG

NBoc O

common tetracycle

[4+2]

R' = Boc

Path A

X= NR2

Path B

X= OH

Im

1

Im

2

MacMillanʼs bread and butter: iminium catalysis!


N

NHBoc

XPG

Im Im

organocascade catalysis NPG

NBocCHO

common tetracycle

natural products

N

NH

PMBH

CO2MeN

N

PMBH

OH

IOH

(1) (Ph3P)3RhCl tol., PhCN, 120 °C(2) COCl2, Et3N, tol. -45 °C to RT, then MeOH, -30 °C to RT

(3) DIBAL, DCM -78 °C to RT, then TFA 61% yield, over three steps

(1) DBU, K2CO3 DMF, RT

(2) DIBAL, DCM, -78 °C67% yield, over two steps

O

O

IBr

Pd(OAc)2 (25 mol%)Bu4NCl, NaHCO3

EtOAc, RT58% yield

N

N

PMBH

OHO

H

H

PhSH, TFA, 45 °C

66% yield NH

N

H

OHO

H

H

NaOAc, Ac2OAcOH, malonic acid

120 °C69% yield

NAME?

N

N

H

O

H

HO

H(-)-strychnine

Synthesis of (-)-strychnine!


Synthesis of (-)-akuammicine!


N

NH

PMBH

CO2Me

PhSH, TFA, 60 °C

91% yieldNH

NH

HCO2Me

NH

N

HCO2Me

IMe

K2CO3, DMF, RT

76% yield

IMeBr

Pd(OAc)2 (20 mol%)NaHCO3, Bu4NCl

MeCN, 65 °C47% yield N

H

N

CO2MeH Me

(-)-akuammicine

Synthesis of (+)-aspidospermidine & !(+)-vincadifformine!


NH

NBoc

3-steps

61% yieldN

NHBoc

SeMe

ent-Im cat. (20 mol%)

-40 °C to RT, tol83% yield, 97% ee N

O

CHONBoc

Bn Bn

(1) Ph3PCH3I, n-BuLi THF, 0 °C, then AcOH NaCNBH3, 0 °C(2) TFA, DCM, RT

(3) K2CO3, DMF, RT73% yield, over three steps

N

N

Bn

I

IBr

(Ph3P)4Pd, Et3Ntol. 80 °C

65% yield N

N

BnH

Pd(OH)2, H2 (200 psi)MeOH, EtOAc, RT

98% yield

NH

N

MeH

(+)-aspidospermidine

DCM, DMSO(COCl)2

65% yield N

N

Me

n-BuLi, NCCO2MeTHF, -78 °C to RT

57% yield NH

N

MeCO2Me

(+)-vincadifformine

Synthesis of (+)kopsinine & (-)-kopsanone!


N

CHONBoc

BnNBn

N

NBn

N

CO2Me

NBn

N

CO2Me

R

R = SO2Ph

NH

N

CO2Me

NH

N

CO2

H

H

B

NH

HN

OHO

NH

NO

(+)-kopsinine

(-)kopsanone

Et3N, DCM, TMSI0 °C, then

40 °C, then DCMTHF, KOt-Bu, 0 °C

58% yield

PPh3 Br

(1) COCl2, Et3N, tol -45 °C to RT, then MeOH, -30 °C to RT

(2) Pd/C, H2 EtOAc EtOH, 0 °C 69% yield, two steps

PhH, 100 °C86% yield

SO2PhRaney Ni

EtOH, 70 °C

83% yield

1N HCl, 130 °C

200 °C

neat 74% yieldtwo steps

Collective Synthesis Overview!

N

N

H

O

H

HO

H(-)-strychnine

NH

N

CO2MeH Me

(-)-akuammicineNH

N

MeH

(+)-aspidospermidine

NH

N

MeCO2Me

(+)-vincadifformine

NH

N

CO2Me(+)-kopsinine

NH

NO

(-)kopsanone

• 12 steps• 6.4% overall yield

• 10 steps• 10% overall yield




• 11 steps• 8.9% overall yield

Syntheses are short and efficient

"Collective synthesis" concept not new, but likely helps broader interest

Total synthesis of a chlorosupholipid cytotoxin associated with seafood poisoning!

MeCl

ClOSO3H

Cl

Cl ClCl

Nilewski, C.; Geisser, R. W.; Carreira, E. M. Nature 2009, 457, 573.

MeCO2Et

Et4NCl3

DCM, 0 °C, 45 min68% yield

MeCO2Et

Cl

Cl

(1) DIBAL, ethylbenzene 0 °C, 10 min, 72% yield

(2) TBSCl, imid. DCM, 0 °C to RT, 30 min 87% yield

Me

Cl

ClOTBS

(1) OsO4 (5 mol%), NMO acetone/H2O, RT, 19h 68% yield

(2) DABCO, (F3CSO2)2O -78 °C, 10min, then diol, -78 °C to RT, 15h 75% yield (96% BRSM)

Me

Cl

ClOR

O

R = TBSR = H

(1) (COCl)2, DMSO, Et3N DCM, -78 °C to RT, 1.5h

(2)

n-BuLi, THF -78 °C to RT, 30min 62% yield over two steps

Me

Cl

Cl

O

OTBS6

TMSCl, DCM, EtOAc11.5 h

39% yield31% recovered SM4% minor product

Me !

Cl

Cl

OH

OTBS

Cl6

Ph3P OTBSBr6

(+)-CSA (cat)MeOH, RT, 3 h

98% yield4.2:1 Z/E

(1) Et4NCl3, DCM 0 °C, 10 min 51% yield

(2) (+)-CSA, MeOH 12 h, 80% yield

Me !

Cl

Cl

OH

!

Cl

! OHCl

Cl6

Me !

Cl

Cl

OH

!

Cl

!

Cl

Cl6

(1) PhI(OAc)2, TEMPO DCM, RT, 16.5 h

(2) CrCl2, CHCl3 THF, 65 °C 49% over two steps

Cl Me ! !

Cl

Cl

OSO3H

Cl

!

Cl

Cl

Cl

SO3•pyTHF, 30 min

27% yield66% BRSM

Attempted Synthesis!


Name?

Me ! !

Cl

Cl

OSO3H

Cl

!

Cl

Cl

Cl

1H NMR spectral data did not match natural product

2D 1H NMR and 1H-heteronuclear coupling experimentsdetermined relative configuration of product synthesized

Me

Cl

Cl

OSO3H

Cl

Cl

Cl

Cl

Me

Cl

Cl

OSO3H

Cl

Cl

Cl

Cl

Desired Stereochemistry

No match…!

Me ! !

Cl

Cl

OSO3H

Cl

!

Cl

Cl

Cl

1H NMR spectral data did not match natural product

2D 1H NMR and 1H-heteronuclear coupling experimentsdetermined relative configuration of product synthesized

Me

Cl

Cl

OSO3H

Cl

Cl

Cl

Cl


No match…!

ClMe

ClOTMS

RH

Cl

ClMe

ClOTMS

H

R

ClMe

Cl

Cl

O

OTBS6

TMSCl

Me

Cl

Cl

O

R

TMS

Cl

Me

Cl

Cl

OH

RCl39%

Me

Cl

Cl

OH

RCl4%

Me

Cl

Cl

OSO3H

Cl

Cl

Cl

Cl

Me

Cl

Cl

OSO3H

Cl

Cl

Cl

Cl

Desired Stereochemistry

Undesired Stereochemistry


Me

Cl

Cl

O TMSCl, DCM, EtOAc, 9 h

43% yield (73% BRSM) Cl

H

OTMSCl

MeR

Me

Cl

ClOTBS

OH

Cl

OTBS6

6

(H5C2)4NCl3, DCM-78 °C, 2 h

93% yield, d.r. = 10:1

Me

Cl

Cl

OH

Cl

ORCl

Cl6 Me

Cl

Cl

OH

Cl

Cl

Cl6 Cl

Me

Cl

Cl

OSO3H

Cl

Cl

Cl

Cl

SO3•pyridine

THF, 20 min99% yield

TEMPO (20 mol%)PhI(OAc)2

DCM, RT, 16.5 h

CrCl2, CHCl3, THF, 65 °C47% yield over two steps

MeCl

HOCl

Cl HR

HCl

H

Cl

Cl

R = TBSR = H

(+)-CSA (cat)MeOH, RT, 3 h

98% yield

7:1 Z/E(Improved from 4.2:1)

(±)-chlorosulpholipid

Revision and success!


Synthesis of a chlorosulpholipid cytotoxin overview!

MeCl

ClOSO3H

Cl

Cl ClCl

• Racemic synthesis• 10 steps• 1.15% yield of desired diastereomer

Short synthesis but racemic

Proposed anchimeric participation of chloridecould prove very important in the synthesis of

other polychlorinated structures

Total synthesis of marine natural products without using protec6ng groups!

NH

Me

Me

H

HMe

HNC

MeMe

NH

Me

Me

H

HMe

HNC

MeMeCl

H

Me

NC

NH

ONHMeCl

H H

Me

Me

NC

Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404.

NH

Me

Me

H

HMe

HNC

MeMe

NH

NC

Me

Me OPP

Me

Me Me

Me

Me

O

NH

Me

Me X

• Function-oriented• PG free• Enzymatic processes

The Phil Baran approach

"Standard" chemistsThe biosynthetic route

• Target-oriented• PG free• No enzymes

N

OH

PG

OPG

NRPG

• Target-oriented• PG needed

Ambiguine H

Approaches to chemical synthesis: selling point!


Total synthesis of (-‐)-‐hapalindole U & (+)-‐ambiguine H!

MeO

NH

R

R = H or Br

LHMDS;Cu(II)-2-ethylhexanoate

THF, -78 °C to RT, 5 min61% yield (R = H)50% yield (R = Br) N

HH

HMe

R

O

NH

Me

Me

H

HMe

O

(5 mol%)

HCOONa, TBABEt3N, DMF, 80 °C, 5 h

65% yield

(1) NH4OAc, NaCNBH3 MeOH/THF, µw (150 °C) 2.5 min; then HCO2H, CDMT

DMAP, NMM, DCM, 2 h, RT(2) COCl2, Et3N, DCM, 0 °C 60% yield over two steps

NH

Me

Me

H

HMe

HNC

(-)-hapalindole U

PPd

PdP

OAc

AcO

ArAr

ArAr

Ar = o-tolyl

NAME?

Four Steps from p-menth-1-en-9-ol

(37% yield)


NH

Me

Me

H

HMe

HNC

t-BuOCl, DCM-78 °C, 12 min;

prenyl-9-BBN-78 °C, 30 min

60% yield

Cl N

Me

Me

H

HMe

H

B

N

ClH

ß-face attackN

Me

Me

H

HMe

H

B

N

ClH

R

R = t-prenyl

hv, Et3N

PhH, 5 h63% BRSM

N

Me

Me

H

HMe

H

B

N

H

R

R = t-prenyl

Cl

N

Me

Me

H

HMe

H

B

NR

R = t-prenyl

H

ClNH

Me

Me

H

HMe

HNC

MeMe

(+)-ambiguine H

Total synthesis of (-‐)-‐hapalindole U & (+)-‐ambiguine H!


NH

Me

Me

H

HMe

HNC

t-BuOCl, DCM-78 °C, 12 min;

prenyl-9-BBN-78 °C, 30 min

60% yield

Cl N

Me

Me

H

HMe

H

B

N

ClH

ß-face attackN

Me

Me

H

HMe

H

B

N

ClH

R

R = t-prenyl

O

MeH

MeCl

HNH

LHMDS;Cu(II)-2-ethylhexanoate

THF, -78 °C to RT, 20 min62% yield

NH

HO

Me

MeCl

H H

(1) Montmorillonite K-10 µw (120 °C), 6 min 57% yield BRSM

(2) NH4OAc, NaCNBH3 3 A MS, MeOH/THF )), 18 h, 42% yield

NH

H

MeCl

H H

Me

MeH2N

NH

H

MeCl

H H

Me

MeNC

HCO2H, CDMTDMAP, NMM

DCM, RT, 30 min;

Et3N, COCl2DCM, 0 °C, 10 min

98% yield

NMeCl

H H

Me

MeNC

H

DDQ, H2O

THF, 0 °C, 30 min92 % yield

taut.

NHMeCl

H H

Me

Me

NC

XeF2, H2OMeCN, RT, 5 min

44% yield NMeCl

H H

Me

Me

NC

FXeF

H

F

OH2

NMeCl

H H

Me

Me

NC

H

F OH

NMeCl

H H

Me

Me

NC

H

OH

MeMeCl

H

Me

NC

NH

O

(+)-welwitindolinone A

(-)-fischerindole I

Total synthesis of (-‐)-‐fischerindole I & (+)-‐welwi6ndolinone A!


PG-‐free total synthesis overview!


NH

Me

Me

H

HMe

HNC

(-)-hapalindole U

NH

Me

Me

H

HMe

HNC

MeMe

(+)-ambiguine H

MeMeCl

H

Me

NC

NH

O

(+)-welwitindolinone A

NHMeCl

H H

Me

Me

NC

(-)-fischerindole I

• 7 steps• 2.14% yield BRSM



• 8 steps• 7.61% yield

Very efficient in terms of step count

PG-free (broader interest?)

Creative approach to this family

The total synthesis of (-‐)-‐cyanthiwigin F by means of double cataly6c enan6oselec6ve alkyla6on!

MeMe

MeO

Me

H

Me

Enquist, J. A.; Stoltz, B. M. Nature 2008, 453, 1228.

(-)-cyanthiwigin F: Retrosynthesis!


MeMe

MeO

Me

H

Me

Pd-cuprateenol triflate coupling

MeO

Me

H

Me

O radical-inducedcyclization

MeO

Me

Me

O single potRCM/cross-metathesis

O

Negishi-coupling

O

O O

O

O

O

O

O

double catalyticenantioselective

alkylation

(-)-cyanthiwigin F: Synthesis!


OO

O

O

(1) Allyl alcohol NaH, PhMe reflux NAME RXN?

(2) K2CO3, MeI acetone, reflux 51% yield

O

O

O

O

O

O1:1 mixture of

racemic:meso diastereomers

N

O

Ph2P

t-BuPd(dmdba)2

Et2O, RT78% yield

O

O

O

O(R,R)

99% eed.r. = 4.4:1

meso

OO

O

O

(1) Allyl alcohol NaH, PhMe reflux NAME RXN?

(2) K2CO3, MeI acetone, reflux 51% yield

O

O

O

O

O

O1:1 mixture of

racemic:meso diastereomers

N

O

Ph2P

t-BuPd(dmdba)2

Et2O, RT78% yield

O

O

O

O(R,R)

99% eed.r. = 4.4:1

Claisen-Dieckmann

meso

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

O

(R,R)

meso-(R,S)

(S,S)

(S)

(R)

(R,R)

(S,R)

(R,S)

(S,S)

(R)

(S)

(R,R)

meso-(R,S)

(S,S)

81% yield

18% yield

<1% yield

(-)-cyanthiwigin F!


O

O

KHMDSPhN(Tf)2

THF, -78 °C73% yield

OTf

O

Zn, TMSCl1,2-dibromoethane

THF, 65 °Cthen Ph(PPh3)4

78% yield

O

(10 mol%)

PhH, 60 °C;NaBO3, THF/H2O

51% yield

O

OH

t-BuSHAIBN

PhH, 80 °C57% yield

O

O

H

O

H

O

H

H

(1) KHMDS PhN(Tf)2 THF, -78 °C 60% yield

(2) i-PrMgCl CuCN, THF; Pd(dppf)Cl2 63% yield

1.8 : 1

I

N N

MeMeCl2Ru

Oi-Pr

B OO

(-)-cyanthiwigin F: Synthesis!


(-)-cyanthiwigin F: Overview!


O

H

(-)-cyanthiwigin F

• 9 steps• 2% yield• 99% ee

Efficient in terms of step count

PG-free synthesis

Double catalytic enantioselective alkylationsets quaternary centers early

Five points on publishing syntheses in Nature!

1. Broader intrests matter

2. Step count is king

3. Yield does not matter

4. Biological relevance can help

5. Even with 1-4, one still needs novelty

recent total syntheses published in...

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