Wolfgang Oppolzer (1937 - 1996) Baran Meeting Moritz … · Baran Meeting Moritz Bosse Biskup...

Moritz Bosse BiskupBaran MeetingWolfgang Oppolzer (1937 - 1996)

11 / 8 / 2006

Biography:

1937 born in Vienna, Austria;undergraduate studies at the University of Vienna

1960 - 1964 Ph.D. at the ETH Zürich, CHwith Prof. V. Prelogstructure elucidations of rifamycines

1964 - 1965 PostDoc at Harvard University, USAwith Prof. E.J. Coreyalkylidene transfer from sulfonium ylides

1965 - 1967 PostDoc at the Woodward Res. Inst., CHwith Prof. R.B. Woodwardsynthesis of cephalosporin

1967 - 1974 research chemist at Sandoz Ltd., CHsynthesis of N-heterocycles

1974 - 1996 faculty at the University of Geneva, CHfull professor (1975)

Research Interests:- pericyclic, esp. intramolecular pericyclic reactions - DA-rx, - ene-rx, - 1,3-dipolar-additions, - electrocyclic ringclosures;- chiral auxiliaries

Publications:author / coauthor on over 210 publications ~ 180 original research papers ~ 80 Helvetica Chim. Acta ~ 70 Tetrahedron Letters ~ 15 J. Am. Chem. Soc. - 14 Tetrahedron - 6 Angewandte Chemie


11 / 8 / 2006

Ph.D. - Rifamycin B and derivatives:

In 1959 a complex mixture (containing rifamycins A - F) withantibiotic properties was isolated from A. mediterranei in 1959; rifamycin B is the main active component;

O

NH

OMe

Me

OH

Me

OH

Me

O

CH3

OMe

MeO

Me

OH OH

O

O

OHMe

OO

rifamycin B

NH

O

O O

rifamycin O

NH

O

rifamycin S

O

NH

HO

rifamycin SV

OH

Ox H+

Red

rifamycin S

i. O3

ii. HCO3H

Me

OHHO

HOOC

COOH

COOH

O

OCH3

HO

Me

OH

COOH

COOH

rifamycin SMeI / Ag2O

O

O

OMe

O

NH

O

O

O

OH

O

N

MeO

H+ / MeOH

O

O

OH

O

NH2

OHO

Me

rifamycin SPd / C, H2

tetra-Hydro rif SVOx

tetra-Hydro rif S

rifamycin SPt / C, H2

hexa-Hydro rif SVOx

hexa-Hydro rif S

H

CH H

O

O

OHO

HO

HO

O Me

OH

O

HO

O

Me

OH

O

HO

O Me

O

OH

O

HO

Me

O

OH

Me

HO O

O O

OH

Me Me

CO2HHO2C

O

HO

Me

O O

Me

Me Me

O

OH

HNO3 / H2O

HNO3 /HOAc

C25H42O8 / C24H38O79 : 1

MeO

MeO O

Me

Me

R3

Me

Me

O OMe

R1

R2

MeO

a b c d

R1

R2

R3

MeCOO

Me

OH

Me

MeCOO

OH

HO

Me

MeCOO

Me

HO

MeCOO

degrad.a

1

3

8

1012

15

23

29

2915

1

Me

Me

Me

12

UVNMRMS

acidic extract neutral extract

C37H45NO12

connectivity:

C2-N-C15 !

C12-O-C27/29 ?

MeO-C23/27 ?

X-ray

full connectivityrelative stereoconfig.

syn.

abs. config.


11 / 8 / 2006

2nd Postdoc - Cephalosporin C

J. Am. Chem. Soc. 1966, 88, 852 - 853. / Nobel Lecture 1965

antimicrobial activity

H2N

CO2H

SH

H Me2COHN S

HO2C

t-BuOH, Cl2CO

pyr, CH2Cl2N S

RO2C

O

t-BuO

R = H

R = Me

CH2N2

N

N

CO2Me

CO2Me

BocN S

MeO2C N

COOMe

NH

COOMei. Pb(OAc)4, C6H6

ii. NaOAc, MeOH

BocN S

MeO2C OH

i. MsCl, DIPEADMF

ii. NaN3, H2O

BocN S

MeO2C N3

Al / HgMeOH

BocN S

MeO2C NH2

BocN S

NH

HH

O

Al(Oi-Pr)3, Tol

1 2 3a /3b

456

7 8

HO2CCO2H

OH

OH

i. Cl3CCH2OHp-TsOH, Tol

ii. NaIO4, MeOH

H2OCHO

O O CCl3

9 10

OHC CHO

Na+ CHOH

OCH2CCl3O

O OH

11

!

HOCH2CCl3

O

O

H

O

H

12

12

8

80 °C

n-octane

BocN S

N

HH

O

OOCH2CCl3

OH

OTFA

H2O

N

S

H

CHO

OCH2CCl3O

H2N

O

H

13 14

SCl

O

pyr, Tol

N

S

H

CHO

OCH2CCl3O

NH

O

HO

S

15

i. B2H6, THF

ii. Ac2O, pyr

N

S

H

OCH2CCl3O

NH

O

HO

S

OAc

16

N

S

H

ORO

NH

O

HO

S

OAc

R = CH2CCl3R = H

Zn, HOAc

17

18

cephalothin

HOOH

O

O

NH

O

O

i. DCC, THF

N

S

H

CHO

OCH2CCl3O

NH

O

H

ii. Cl3CCH2OHDCC, pyr

O

O

O

TrocHN

CCl319

i. B2H6, THF

ii. Ac2O, pyr

N

S

H

OCH2CCl3O

NH

O

HO

O

O

TrocHN

CCl3

OAc

N

S

H

ORO

NH

O

HO

O

OR

RHN

OAc

CCl3

20

R = CH2CCl3R = H

Zn, HOAc

21

22

cephalosporin c


11 / 8 / 2006

Chemical Reactions

Chemical reactions can be categorized into three classes:

- ionic, e.g. reactions of fragments with paired electrons,

where charges are formed or combined,

- radical, e.g. reactions in which species with unpaired

electrons propagate the reaction,

- pericyclic, e.g. reactions which are characterized by

concerted shifts of electrons in 'cyclic' transition states.

Pericyclic Reactions are characterized by their high

stereoselectivity with regard to products formed.

These high selectivities are rationalized on a MO-level by the

"Conservation of Orbital Symmetry", leading to the highly

ordered TS mentioned.

Major Types of Pericyclic Reactions:

i. electrocyclic reactions are reactions in which a single bond

bond is formed between the termini of a linear system

containing k !-e- and the reversal of these reactions.

ii. cycloadditions & cycloreversions are reactions in which a

contiguous, cyclic moiety is formed from linear precursors or

such a cycle fragments into linear parts.

iii. [i,j]-sigmatropic reactions are reactions in which a "-bond

migrates along flanking systems of #-bonds to the positons [i-

1] and [j-1].

iv. cheletropic reactions are reactions in which two "-bonds terminating at the sam atom are formed or broken.

R

R

R R

R R

R

Ri.

ii.

iii.

iv.

h$

h$

%

O O

D

D

D/H

D/H

H/D

H/D

D/H

D/H

H/D

H/D

H/D D/H

H/D D/H

[1,3][1,5]

O

CO

Angew. Chem. Int. Ed. 1969, 8, 781 - 853.


11 / 8 / 2006

Intramolecular Diels-Alder ReactionsAngew. Chem. Int. Ed. 1977, 16, 10 - 23;ibid. 1984, 23, 876 - 889.

Type I DA Type II DA

CO2Me

130 °C

H

H

CO2Me CO2Me

H

H

CO2Me

130 °C

H.O. House, J. Org. Chem. 1965, 30, 1061.

Pumiliotoxin Cfrom the venom of Dendrobates pumilio and D. auratus

NH

MeH

H H

COOH

H2NH

i. LiAlH4

ii. TsCl / Py HNH

TsO

Ts

KOHMeOH

CH2

NH

Ts

H3C C C CH2 MgBr

HNH

Ts

CHN

HTs

41%32%

Na / NH3

H2NH

H2NH

i.

ii. NaH (2 eq.)DME, -30°Ciii. i-PrCOCl

O

H

NH

O

230 °CN

H

O

MeH

H

NH2 H

MeH

H

i. H2 / Pdii. DIBALiii. HCl

Cl-

(R)-norvaline

COOH

H2NH

(S)-norvalineNH2

MeH

H H

Cl-

Helv. Chim. Acta 1977, 60, 204.

Alternate Routeracemic

OHi. Hg(OAc)2,

ii. !OH

MgBrOO

OH

LiAlH4 / NaOMe

87%

i. base, TBDMSClii. Zn / KCNiii. TBAF75%

OHOH

62%

i. TMSCl, baseii. 245 °Ciii MeOH / KF

51 %

HMe

H OH

i. H2 / Ptii. CrO3

HMe

H O

HMe

H O

2/3

1/3

i. TMSCl, baseii. 245 °Ciii MeOH / KF

O

4/51/5

HMe

H OH

i. H2 / Ptii. CrO3


11 / 8 / 2006

Intramolecular Diels-Alder Reactions

HMe

H R

Pumiliotoxin Ccontinued

R = O

R = NOHH2NOHEtOH

NH

O

MeH

H

p-TsCl, NaOHH2O, dioxane

Me3O+ BF4+

N

MeH

HOMe

n-PrMgBrC6H6, !

N

HMe

H

H2 / Pd

NH

MeH

H

44%exo-product

H

Lysergic Acidracemic synthesis

Helv. Chim. Acta 1977, 60, 48.

NTs

RCO2Et

Me

NO2

4 steps

R = OH

R = BrPPh3, CBr4

DMF, 97%

P(Bu)3, C6H6

80°C, 100%

NTs

PBuBu

Bu

Br -

CO2Me

OHC

NaH, DMSO62 %

NR

CO2Me

R = Ts

R = HNaOH, MeOH95%

i. HCHO, Me2NHHOAc

ii. MeNO2, DMAD

HN

CO2Me

NO2

48%

HN

CO2Me

NO2

NaOMeMeOH

HN

CO2Me

N+ O-

O-

TiCl3 / NH4OAc

MeOH /H2O

H2N-OMe

MeOH / H2O

HN

CO2Me

O

HN

CO2Me

N OMe

HN

CO2Me

N OMe

HN

N OMe

CO2Me

!, dilute

HN

N OMe

CO2Me

64%

67%

H

H MeOSO2FDCM

HN

N+ OMe

CO2Me

H

H

Me

i. Al / HgTHF / H2O

ii. KOHEtOH, H2O

HN

N

CO2Me

HMe

d/l - mixture


11 / 8 / 2006

Intramolecular Ene- & metallo-Ene-ReactionsAngew. Chem. Int. Ed. 1978, 17, 476 - 486;ibid. 1989, 28, 38 - 52.ene-reactions can formally be viewed as a type of sigmatropic rearrangements, where the !-system, that is traversed during the reaction, is not fully connected:

X

R1

R2

R3

X

R1

R2

R3

X

R2/H

R1

R2/H

R3/H

H/R3

X = H --> ene-reactionX = M --> metallo-ene-reaction

intramolecular ene-reactions

Type I Type II

Type III

Z

CR

H

X

Y Z

CX

YH

RZ H

X Y

Z

X Y

H

ZH

XY

Z

XY

Type I Ene-Reaction as the Key Step in the Synthesis of(+/-)-Isocomene

Me

Me

MeH

Me

O

Me

O

O

MeO

i. NaOMe, MeOH

ii. t-BuOK, t-BuOH O

Me

49%

i. t-AmOKC6H6ii. MeI

55%O

H2C

H

Me

Me

280 °C24h17%

"

""

" OMe

Me

H3C

i. H2 / Pd/Cii. t-BuOK / AmONO

iii. NaOCl / NH367%

OMe

Me

H3C

N2h#

MeOH

MeMe

CO2Me

Me

i. LiAlH4

ii. ArSeCN,

PBu3, pyr

71%

80%

MeMe

CH2

MeH Se

O2N

i. NaIO4ii. 80 °C

58%Me

Me

CH2

Me

MeMe

Me

Me

TsOHDCM, 25 °C

75%

(+/-)-isocomene

Helv. Chim. Acta 1979, 62, 1492.


11 / 8 / 2006

Intramolecular Tandem Pd-Ene / Keck-Insertion Reaction

E E EE

OAc

Pd0(dba)2 / PR3

HOAc

E = COOMe

E E

H H

H

H

HPdL2

H H

H

H

E EE

EE

H

H H

H

H

EE

EE

H

Me

EE E

E

OAc

Pd0(dba)2 / PR3

HOAc

3

4

:

HH

HH

PdL2

EE

EE

H

H

H H

H

H

PdL2

EE

EE

H

HH H

H

H

J. Org. Chem. 1991, 56, 6256.

Electrocyclic Ring-Opening of Cyclobutanesortho-Quinodimethanes as Building blocksSynthesis 1978, 793 - 802.

Total Synthesis of (dl)-Chelidonine

O

O

CN

KOH, H2OO

O

CO2H i. Curtius-rearrang.

O

O

NH

ii. BnOH

OBnO

O

O

CHOH2N

OEt

OEt

H2 PtO2, EtOH

i. Hofmanndegrad.

ii. Braundegrad.

H+, Pd/C H2

O

OBr

NaH, DMFNaI77%

O

O

BocN O

O

i. Br2, DCM

ii. t-BuOK, DBUHMPA

30%O

O

NBoc

O

O

!

O

O

BocN

O

O

BocNO

O

O

O

i. B2H6ii. H2O273%

68% 1:1 O

O

BocNO

O

H

H

H

OH

i. LC

ii. CrO3, 0°C

32%

O

O

BocNO

O

H

H

O

i. NaBH4, MeOH

dioxane

ii. H2 / Pd, EtOH

iii. MeI, K2CO3~80% over 3 steps

O

O

NO

O

H

H

Me

OH

J. Am. Chem. Soc. 1971, 93, 3836.


11 / 8 / 2006

Camphor Derivatives a Chiral AuxiliariesTetrahedron 1987, 43, 1969 - 2004.Pure & Appl. Chem. 1990, 62, 1241 - 1250.

e.g. sultams

O

i. sulfonationii. SOCl2iii. NH3

iv. NaOEtv. LiAlH4

S

NH

O O

(+)-camphor

i. NaHii. RCOCl

S

N

O O

R

O

S

N

O O

O

R S

N

O O

OH R LiAlH4 R

OH

OHO3S

i. NaBH4ii. TsCl, pyr O

SO O

i. LDAii H+, H2O OH

SO O

N(i-Pr)2

O

SO O

N(i-Pr)2

RCOCl

O

R

And quite some more applications!

e.g. esters

1,4-addition

DA-rx reductions

Wolfgang Oppolzer (1937 - 1996) Baran Meeting Moritz … · Baran Meeting Moritz Bosse Biskup...

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