Hans Renata - scripps.edu Renata Royal Chemistry Group Meeting 10/16/2010 ... JCS Perkins 1, 1976,...

Royal ChemistryHans Renata Group Meeting10/16/2010

Scope:- RSC journals (J. Chem. Soc., Chem. Comm. and Perkins Trans. 1 & 2)- Pre-1980 chemistry; non-systematical library reading limited to 1970-1980; online reading limited to 1950-1980- Steroids, morphinans, prostaglandins, tetracyclines, β-lactams antibiotics are (mostly) excluded- 'Land war type' syntheses will be minimized- Well-known and esoteric materials will be covered, the former only in brief

Things you already know (Or you should know)

NMe

O

Tropinone, Robinson, 1917

OHO

Ac

OH

OOHMe AcMe

Usnic acid, Barton, 1956

PhSe O

O

SePh

O

(See tetracycline GM)

CeCl3-NaBH4

Luche, 1978O

MeHO

OO

OAc

aldosterone acetate, Barton, 1960

Also:- Baldwin rules- Barton named reactions (deoxygenation, decarboxylation etc)

Recent Highlights

O

O OHMe

OHAcO

O

MeO2C

OMe

Me

MeO2C

OO

Me

O

HO

azadirachtin, Ley, 2007

O

Me

Me

Me

HO

frondosin, MacMillan, 2010

Natural products isolation

O N NMe

O

Me

Me

Me

H

OHOAcO

O CH2OH

Sn

Sirodesmins, JCS Perkins 1, 1977, 180

O

O

OO

HOMe O

OHO

O

Me

physalin B, JCS (C), 1970, 664

N

OO

OH MeHO

HO

O

AcO

MeOH

leucogenenol (incorrect), JCS (C), 1971, 2599

NN

OMe MeHH

NO2 O

MeMe

OMe

cyclopiamine A, JCS Perkins 1, 1979, 1751

OO

O N

O

O

OMeOMe

O

OAcOAcMe

OR

OR'O

OMe

O O

N

Me

Me

HO

cathedulin E3,JCS Perkins 1, 1976, 2982

Other noteworthy isolation papers:baccatin III, andibenin, andilesin, verticillin,laurenene, phorbol

Me

H


Synthesis of lanosterol

HO

Me

MeMe

MeMe

cholesterolO

Me

MeMe

MeMe

MeMeAcO

Me

MeMe

MeMe

MeMe

AcO

Me

MeMe

MeMe

MeMeBzO

Me

MeMe

MeMe

MeMe

OBzO

Me

MeMe

MeMe

MeMe

Me

Synthesis of the withanolides skeleton

O

R

Me

Me

OAc

O

R

Me

Me

OAc

OR

Me

MeO

R

Me

MeO

O

R

Me

MeO

O

R

Me

MeO

OH

R

Me

MeO

OHO

R=C8H17

Me

MeO

OHO

OMe

Me OH

OH

withaferin A

1. [O]2. KOtBu, MeI

1. LiAlH42. Ac2O, C6H5N

3. NBS, CCl4 then collidine

HCl, CHCl3-40 oC

then NH3, MeOH-60 oC

CO2H

CO3H

thenHCl/EtOH

and benzoylation

1. KOtBu, MeI2. Wollf-Kishner

BzO

Me

Me R

MeMe

Me

HCl

CHCl3

lanostenyl benzoate

JCS, 1957, 1131

1. N2H42. Jones

1. KOH2. POCl3 mCPBA

NaOH1. MsCl2. OsO4

45% 90%2:1 α:β

quant. 85%

JCS Perkins 1,1975, 2295


2 step synthesis of deoxybruceol

Precedence:

HO

O

OH

O O

Me

Me

Me

pyridine

O

MeO

OO

MeMe

JCS, 1960, 3734Model substrate

OH

HO OH

O

Me

Me

Me

pyridineO

O

MeMe

Me

OH

Actual substrate

O

HO OH

O

O

Me

Me

Me

pyridine OO

MeMe

Me

O

O

deoxybruceol

JCS (C), 1971, 788

A model study towards the morellinscf. Nicolaou's synthesis of 1-O-methylforbesione (2001), Theodorakis' synthesis of forbesione anddesoxymorellin (2003)

O

OO

OO

OHMe

MeO

OO

OHMe

Me

O O

decalinreflux

via:

O

OO

OHMe

Me

O O

O

OO

OO

OHMe

Me

MeMe

MeMe Me Me

desoxymorellin

O

HOO

OO

OH MeMe

MeMe Me Me

MeMe

hanburin

JCS Chem Comm, 1971, 966

40%

10%


Oxidative rearrangement of chalcone

Inspiration from biosynthetic pathway

O

OH

enzyme

O

O

Labelling studies: Chem Comm, 1968, 395

O

OMe

OOMe

OTl(OAc)3

MeOHreflux

via:

O

OMe

OMeTl

AcO

OAcJCS (C), 1970, 119JCS (C), 1970, 125

MeO OH MeO

OHMeO

Further applications:

O

O

HO

MeO

OMe

OH

H

H

philenopteran, JCS Perkins 1, 1974, 305

OO

MeMe

Me

OH

OMeheminitidulan, JCS Perkins 1, 1980, 2463

Synthesis of isorotenone from isoflavone

O O

O

OMeMeO

OH

iPr

SOMe

CH2Me

O O

O

OMeMeO

OH

iPrS

MeMe

O

O O

O

OMeMeO

OH

iPrS

MeMe

O

O

O

O

iPr

OH

MeOOMe

O O

O

OMeMeO

O

iPr

pyridine100 oC

O

O

HO

OH

OMeMeO

iPr

In the presence of excess reagent, the following product is observed:


(isolated)

80%


OH

OHO

OOH

HO

OH

OH

HO

OBn

OBn

Me

MeO

COCl

OBn

2. hν

Me

MeOOBn OR

O OH OBn

OBn

1. Me4NOH2. KOH

O

OMe

MeO

OH

BnO OBn

K2Cr2O7

O

OMe

MeO

O

BnO OBn

O

O

OMe

MeO

O

silicagel

O

OBn

OBn O

OMe

MeO

OH

OH

O

OHO

norbikaverin

MnO2


Note: A similar rearrangement also occurred in Pettus' model study towards rubromycin

Synthesis of norbikaverin and bikaverin via quinone rearrangement Synthesis of silybin by oxidative phenol coupling

OH

OMe

OH

O

OO

OOH

HO

OH

OH

OMe

OH

+ regioisomer

JCS Perkins 1, 1980, 775

57%

Note the absence of protecting groups!

Ag2O

18:5 C6H6/Me2CO

1.

14%2 steps

59%

52%

quant.

28%

+

Synthesis of actinioerythrol

X

Me Me

Me Me

X

X=

O

Me Me

MeHO Me

MeMe

O

HO

1. MnO22. NaBH4

astacene actinioerythrol



C-H Activation in Total Synthesis

Total synthesis of ishwaraneTotal synthesis of panamine

O

MeMe

O

MeMe

Me

MeMe

MeMeHO

MeMe

MeMe

Me

MeMe

Me

Me

MeMe

ishwarane


NH

NHN

H

HH

N NHN

H

HH

H H

H

NCS

CH2Cl2

70%

NH

N

N

HH

HO

O

O

CNN

N

H

O

O

N

N

H

O

O

N

N

H

O

O

AcO

Br

N

N

H

O

O

O


Me2CuLi

77%

MeMgI

50% H2SO4

74%2 steps

1. CBr4, MeLi -75 oC

2. warmed to -30 oC, then MeLi

26%

"Three of these steps each results solely in the addition of one carbon atom to the frameworkof the preceding intermediate; only one step involves functional group modification, and pro-tection of sensitive functional groups is not necessary." (Sounds familiar?)

1. hν

OAc

2. PHPB

47%

Na2CO3

76%

NH3

EtOH

65%


RhCl

RhCl

O O

CO CO

RhPPh3

PPh3

O

Cl[RhCl(CO)2]2

40-50 oC

PPh3

Organometallics

C-C Activation

JCS (A), 1968, 845

[RhCl(CO)2]2

RhOCCl O

n

PPh3

RhO OCl PPh3Ph3P


Palladium-catalyzed cyclization

MeMe

Me

Na2PdCl4

MeMe

Me Na2PdCl4

Me

Me

limonenecis-ocimene trans-ocimene

JCS (C), 1970, 2196

Divergent Cyclization of 3,7-Dimethylocta-1,6-diene

Me

Me Me

Me

Me

Me Me

OMe

Me

HOMe

Me

Me

OHMeMe

MeCO2H

MeMe

HCO2H-H2SO4PdCl2

Me2CO(aq)

PdCl2-CuCl2

DMF

Hg(OAc)2

H2O-THF-NaBH4


Metal-catalyzed cyclodimerization

NiPEt3

PEt3

Cl

Me

MeOH

Catalyst is "stable in alcohols or even in air" but "was no longer stable after the reaction anddecomposed to a green solid on exposure to air."

JCS Chem Comm, 1970, 131050% (distillation)

80 psi CO,Ph3P,

Pd(acac)2

EtOH

OEt

O

71.5%JCS Chem Comm, 1971, 1067

Me2CO


Organometallics

Synthesis of lactones via iron carbonyl complexes

Me

Me

O hν,Fe(CO)5

Me

Me

O

Fe(CO)3O

CAN

EtOH-H2O

OMe

Me O

O samecondition

OO

O O

samecondition

OO

not observed


Extension to lactam synthesis

Me

Me

O

Fe(CO)3O

ZnCl2,PhCH2NH2

Me

Me

N

Fe(CO)3O

CH2Ph

CANN

O

MeMe

Ph

N

Me

Me

O

Ph

Other substrates led exclusively to β-lactams


Synthesis of casbene- putative biogenetic precursor of tigliane and ingenane terpenoids

O

MeO2CMe

Me

Br

MeMe

Me

Me

Me

Br

MeMe

Me

Me

MeJCS Perkins 1, 1980, 1711

Palladation and platination

Ph

NOH

Me

MePh

N

Me

NaOAc,Na2PdCl4

HO

2


NNO

Me Na2PdCl4 NMe

Pd

PdCl

NO

Cl

2

JCS Dalton, 1980, 2282

Me

Me Me Me Me

N2

Side note:CuI, THF

0 oC

Ni(CO)4

10%

75%

34%

56%

38%

65-70%

79%

O


Heterocyclic Chemistry

Nitrenes in heterocyclic chemistry

ClNO2

Cl

FeC2O4

NN

Cl

Cl

Cl

Cl

N

NCl

ClCl

Cl

230-250 oC

HN

NO2

PhCl N

N

Ph

ClFeC2O4

270-290 oC

JCS (C), 1968, 119

Using ferrous oxalate

Using triethyl phosphite

NO2

R P(OEt)3

reflux NH

R

36-83% yield

+ 2 (EtO)3PO

Also applicable to the preparation of

NN Ar

NN

NAr

JCS, 1965, 4831

Extension of this methodology to other heterocycles

NMe Cl

PhO2N

NH

N

Cl

Me

JCS (C), 1968, 1006

O

N

O2N O

O

OPh

N O

NO

OPh

JCS (C), 1969, 385

O2NO

OMe

ON

OO

OMe

JCS (C), 1974, 861S

NO2X N

H

S X

JCS (C), 1970, 2437

Ph

O

H

R OH

O RPhca. 20%

OH

H

R OH

Ph

ORHO

JCS Perkins 1, 1979, 1703Applicable to the synthesis of substituted N-alkyl pyrroles as well

hν

via

A photochemical synthesis of furans

+

P(OEt)3

reflux

P(OEt)3

reflux

P(OEt)3

reflux

P(OEt)3

reflux50-85% yield

45%

17%

57%


Heterocyclic ChemistryPyridynes and quinolynes

N

NNN

H2N

Pb(OAc)4

N

PhPh

Ph

Ph

N

NNN

H2NPb(OAc)4

N

PhPh

Ph

Ph

63%

70%

Note: 2,3-pyridyne and 2,3-quinolyne gave poor yields

CH2Cl2

CH2Cl2

JCS (C), 1969, 1758

Quinolone synthesis

NHMe

PhSCH2CH2CO2EttBuOCl

then NaOMe NMe

OX X


Indole synthesis

NH2

MeOH

R

Br

KNH2

NH3 NH

MeO

RR

NH


Modification:

NH2

R2 OH

R1

Br

R1NR'

R2R'NH2

MeOHheat

17-82%


An interesting reaction of nitroarenes with Grignard reagents

X

Y

NO2X

Y

NO

OMgR

R HX

Y

NOR


PhPh

O

Ph Ph

PhPh

O

Ph Ph

2 RMgX

R = nBu or Ph(CH2)2

BF3

Me


Biosynthesis of quinine from loganin - A labelling study

O

HO Me

OGlu

MeO2C

H

HNH

NH

O

MeO2C

OGlu

H

H

N

NH

HO

MeO

Barton's proposal for the biosynthesis of acutumine


O OMe

OMeO OMe

NMe

O OMe

OMeO OMe

NMeO

O

OMeO OMe

NMe

O

HO2C OMeOH

OMeO OMe

NMe

OH

O

MeO

OMeO OMe

NMe

OH

O

MeO

OMeO OMe

NMe

OH

O

MeO

HCl

acutumineJCS (C), 1968, 929

Also, see Wipf's discussion on this pathway:Org Biomol Chem, 2007, 5, 58

Organoborane chemistryAnnelation via hydroboration-carbonylation

Alkaloid Biosynthesis

RBH2RB

H

H 1. 70 atm CO2. H2O2, NaOAc

H

H O

60% isolated

Product scope

O O O OH HH H

H H H H67% 40% 66% 62%


Reaction of cyclic organoboranes with MVK

1. BH3, THF, 0 oC2. MVK iPrOH/THF reflux

3. alkaline H2O2 HO Me

O

85%, prep GLC yield


Formation of brominated boracyclanes and their reaction

B

HBr2

B

H

Br

alkalineH2O2

H

OH 60%


**

*

Hans Renata - scripps.edu Renata Royal Chemistry Group Meeting 10/16/2010 ... JCS Perkins 1, 1976,...

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