Journal of Organic Chemistry: 1974

A Brief Synopsis

-Mike DeMartino-Group Meeting: 10-29-2003

Overview

• Some general observations

• The “prime-time-players”…what were theydoing in JOC? (Thanks Dick Vitale, baby!)

• Some selected total syntheses

General Observations fromTitle Perusing

• Heterocyclic chemistry prevalent• Surprisingly little Tin/Palladium chemistry• Lots of Rearrangements:

– Thermal– Photolytic– Acid Catalyzed

• 13C spectroscopy a new thing in organic chemistry?!?• Not many total syntheses, mostly steroids• Sulfur chemistry very prevalent• A lot of degradation chemistry

E.J. Corey (Harvard)-Preparation of an optically active intermediate for the prostaglandins (p. 356)

OO

-A racemic route had previously been developed from (+/–) 1 to (+/–)-11-deoxyprostaglandins

1O

O

1

OH

OH

OLiOH (–)-1-(1naphthyl)ethylamine

3 recrystalizations

OH

OH

O• (–)-1-(1naphthyl)ethylamine

1. Removal of salt

2. 10 N HCl1

-g-Condensation of an allylic Phosphonium Ylide (p. 821)-Generally, allylic phosphorous ylides condense on the a carbon-Many geometric isomers usually obtained

CO2MeH

MePPhPh

•HBr

Hunig's Base

C5H11

Hexanal

O

O

CO2MeMe

C5H11

Generally, E/Z > 190-92 %

9-10%

+

E. J. Corey (p. 256)

Samuel Danishefsky (Univ. of Pitt)-A route to funtionalized heterocycles by homoconjugate addition (p. 1979)

-The use of a highly substituted cyclopropane as an electrophile (generated by reacting the olefin with dimethyl diazomalonate ine the presence of copper bronze)

CO2Me

CO2Me

NH2 NHCO2Me

CO2Me

CO2Me

N

O

O

Hydrazine

MeOH

-Showed in earlier work that mechanism goes through "Spiro-mode"

O

1. 10 % HCl

2.HCl, MeOH

NH CO2Me•HCl

NHH

ODesired pyrrolizidine

NHH

ODesired indolizidine

Samuel Danishefsky (Univ. of Pitt)-Furanoid systems by intramolecular homoconjugate addition (p. 2658)

CO2Me

CO2Me

O

O O NaH

PhH

-O-Alkylation was dominant pathway in all systems they tried in this paper

O

MeO2C

(CO2Me)2

CO2Me

CO2Me

O

O

O

NaH

PhHOR

DMSOO

(CO2Me)2OO

Geometry highly dependent on solvent and therefore solvation of reaction pathway

Gilbert Stork (Columbia)-Regiospecific Aldol condensations of the kinetic lithium enolates of methyl ketones (p. 3459)

-It had previously been difficult to trap the kinetic enolate with alkyl halides-So, used a more reactive electrophile to trap the enolate

O LiO LDA,

THF, –78°Butyraldehyde O OH

65% (90% Kinetic enolate)

O LiO LDA,

THF, –78°Benzaldehyde

Ph

O OH

75-80%

O LiO LDA,

THF, –78°Crotonaldehyde O OH

70%

Barry M. Trost (Wisconson, Madison)-Chemospecificity of allylic alkylations (p. 737)

-Use of cis and trans geranylacetone

-p-allyl complexes are remarkably stable

2Ethylene Gylcol

TsOH, PhH, Reflux

Conditions: PdCl2, NaCl, CuCl, NaOAc in AcOH

OO

PdCl/280%

Barry M. Trost (Wisconson, Madison)Alkylations

NaH

CH3SO2CH2CO2CH31, 2, or 3

H3CO2S CO2CH3 LiI, NaCN, DMF

130°C

H3CO2S

1. HOCH2CH2OH,TsOH, PhH, Reflux

2. Li, C2H5NH2, 0°C

3.H2O, HCl

Barry M. Trost (Wisconson, Madison)-Alkylation of Lactam Derivatives (p. 2475)

N N NO O LiO

MeMeMe

LDA, THF

–78°C

N N NOMe OMeLi

LDA, THF

–78°C

E+ E

OMeE+ E

1

2

-Both of the above examples proceeded with C-alkylation exclusively with alkyl halides, chlorosilanes.-For 1 (Stronger enolate), reaction with methyl vinyl ketone proceeds with 1,2 addition; for 2, (weaker reagent), reaction to MVK proceeded with conjugate additionThis selectivity is due to the less reactive reagent having its charge more delocalized in the transition state. To test this hypothesis, a controll exmeriment:

MVK

22hr,RTN OMe

Me

N OMe

O

Exclusively 1,4 addition, 29%

Barry M. Trost (Wisconson, Madison)-A convienent approach to Methyl 3-oxo-4-pentenoate (p. 2648)

-Not easily synthesized -The two main previous methods either ended with a final step of 7-12% (acid catalyzed elimination), or was based on a retro-Diels-Alder step (great yield, but requires special high-temp pyrolysis apparatus).-Utility seen as an "annelating agent" in the synthesis of terpenes and alkaloids

O

O

PhSHSPh OH

O 1. SOCl2

2.

TMSO

O

OMe

OLi SPh

O OTMS

O

OMeO H+

SPhO

OMeO

62-76 %

O

OMe

ONaHPhLi O

OMe

OPhSCH2I

63-80%

1

1Sodium

Metaperiodate SPhO

OMeOO

DO

OMe

O

Summary: 3-step route, 60-76% overall; 5-step route, 60-72% overall

R. F. Heck (Univ. of Delaware :-) )

NH2Br + ++CO

RR'

3N Pd(Br)2(PPh3)2

100°CR

O

NH

Possible Mechanism:

-Palladium caralyzed Amidation of aryl, heterocyclic, and vinylic halides (p. 3327)

R. F. Heck (Univ. of Delaware :-) )-Palladium caralyzed carboalkoxylation of aryl, benzyl, and vinylic halides (p. 3318)

Br + ++COR

R23N Pd(Br)2(PPh3)2

100°C R

O

O R2R1OH

Possible Mechanism:

• The following people did wonderful chemistry in JOC, ‘74,but time constraints cause their omission:– David Evans (UCLA)

• Useful Prostaglandin Intermediate (p. 3176)• Applications of trimethylsilyl cyanide (p. 914)

– Herbert C. Brown• New organoborane structures via alpha-bromination of borapolycyclanes (p. 861)• Synthesis of olefins: alpha-elimination of alpha-chloroboronic esters (p. 2817)• Synthesis of terminal acetylenes via treatment of lithium

ethynyltrialkylborates with Iodine (p. 731)– Herbert House

• Chemistry of Carbanions (p. 3102)• Electron transfer reactions: reduction of enones with Cr(II) compounds

(p. 1173), and of nonconjugated acetylenes (p. 747)– Robert E. Ireland

• Claisen rearrangement of N-Allylketene O,N-Acetals (p. 421)– And of course, many others…

(S)-Carlosic Acid

Blommer and Kappler, p. 113

Temple University

MeO2C

O O

O

t-BuOK

t-BuOHOCO2Me

HOO

OMeO2C

Br2

AcOH

O

HO

OMeO2C

Br

OHOMeMeO

O

O

OO

Et3N (cat), PhH80%

H2, Pd/C

AcOH O

HO

OMeO2C

Cl

O

TiCl4PhNO2

O

HO

OMeO2C

HCl

NaOH

O

HO

OHO2C

(S)-Carlosic Acid

Note: all yields in the synthesis were 70-80%, except the "key step," the cyclization

39%

Cassamedine

Cava and Libsch, p. 577

UPenn

O

O

OMeNH2 O

O

OH

OBr+

Known Compounds

O

O

OMe HN O

Br

O O

PhH, 2hr

76%

O

O

OMe

N

O O

Br

POCl3

CH3CN20 hr, 90%

O

O

OMe

N

O O

Br O

OEtEthylChloroformate

Et3N, 0°C90%

•HCl

O

O

OMe

N

OO

O

OEt

t-BuOKhn, 7hr

PhH, t-BuOH32%

O

O

OMe

N

OO

Me

LiAlH4, AlCl3Et2O, reflux

1.5 hr, 87%

O

O

OMe

N

OO

MeO

OO H

AcOH23%

Cassamedine

-An alkaloid isolated from Cassytha americana

The Sex Pheromone of the Pink Bollworm

Phillip E. Sonnet, p. 3793

U.S. Dept. of Agriculture, Maryland-Isolated from the Pectinophora gossypiella, the pink bollworm moth-Isolated as 1:1 mixture of geometric isomers

Cl OTHPLiH

OTHP

H

1. n-BuLi, THF

2. Cl(CH2)3Br, HEMPA, THF

53%

OTHPCl

84%

PPh3

84%

1. n-BuLi, THF/HMPA

2. Me(CH2)3CHO

OTHPPh3P

•HCl

OTHP

AcCl

AcOH58%

OAc

H2, Pd/BaSO4

Pentane, 84%OAc

NaNO2 (aq)HNO3 (aq)74%

OAc

H2, Pd/BaSO4

Pentane, 80%

OAc

The Sex Pheramone of the Pink Bollworm

The Sex Pheromone of the Pink Bollworm

Phillip E. Sonnet, p. 3793

U.S. Dept. of Agriculture, Maryland-Isolated from the Pectinophora gossypiella, the pink bollworm moth-Isolated as 1:1 mixture of geometric isomers

A Trail Pheromone of the Pharaoh Ant

Sonnet, Oliver, p. 2663

U.S. Dept. of Agriculture, Maryland-Isolated from the Monomorium pharaonis, the Pharaoh Ant-It was known that the pheromone had the general structure of 3-butyl-5-methoctahydroindolizine, but absolute stereochemistry of active pheromone was not elucidated-Synthesized all four stereoisomers because they were interested in the pheromone's utility as a pest control agent

N

C4H9

N

C4H9

N

C4H9

N

C4H9

H

H

H

H

A B C DA Trail Pheromone of the Pink Bollworm

N

C4H9

N

C4H9

N

C4H9

N

C4H9

H

H

H

H

N

1. BuLi

2.

C4H9

ON

OH

H2PtO2

NH OH

NaEtOH

NH OH

H

1. PhP3•Br22. Et3N

NBr–

C4H9

A B C D

1. PhP3•Br22. Et3N

1. PhP3•Br22. Et3N

A + B C + D A

H2PtO2

A Trail Pheromone of the Pink Bollworm

N

OH

OCH3H3CO

H3COCl–

Fagaronine Chloride

OCH3

OCH3

OCH3

Oi-Pr

NO2

Fagaronine Chloride

Stermitz, p. 3239

Colorado St. Univ., Fort Collins

NH2OCH3

Oi-Pr

NO2OCH3

OCH3

HNO3:HOAc1:1

HOAc

hn, 1hr

CH3CN:0.8N NaOH90%

NO2OCH3

OH

K2CO3i-PrBr

DMF, 92%

H2NNH2,EtOH

10% Pd/C100°C, 99%

BrH3CO

H3CO

PhH, 91%O

H

-Extremely active antileukemic alkaloid-Isolated from Faraga zanthoxyloides-Note: synthesis also proved structure

NBrH3CO

H3CO

Oi-Pr

OCH3

N

Oi-Pr

OCH3H3CO

H3CO1

1. Na, NH3(liq)

2. 13. NH4Cl, 24%

Dimethyl Sulfate,

PhNO2/Xylene180°C

N

OH

OCH3H3CO

H3CO

CH3OSO3–

8% NaCl(aq)

88%N

OH

OCH3H3CO

H3COCl–

Fagaronine Chloride

Fagaronine Chloride

Stermitz, p. 3239

Colorado St. Univ., Fort Collins

-Extremely active antileukemic alkaloid-Isolated from Faraga zanthoxyloides-Note: synthesis also proved structure

(+/–) 11-deoxyprostaglandin E2

Jonh Petterson, John Fried, p. 2506

Syntex, California

I C5H11

PreviousPreocedures

O OMe

C5H11

O OMe

LiCu

2

O1.

Et2O, -78°C

2. TMSCl, THF C5H11

O OMe

OTMS

1. Li, NH3(liq)Ferric Nitrate (trace)

Br CO2Me2.C5H11

OH

CO2MeO

(+/–) 11-deoxyprostaglandin E2

N

S

ArCO2H

O

HN H

OS

3-Arylcephalosporins

3-Arylcephalosporins

Firestone, Maciejewicz, Christensen, p. 3384

Merck Sharp and Dohme Research, New Jersey

S

H NH

Et2O3PO

O

OMe

+

Reported in 1973 by same the group

Cl Ar

O

K2CO3

Acetone N

S Ar

O

CO2CH2C6H4OMe

NaH

GlymePO3Et3

N

S

ArCO2CH2C6H4OMe

N3CH2COCl

Et3NN

S

ArCO2CH2C6H4OMe

O

N3H

H2

PtN

S

ArCO2CH2C6H4OMe

O

H2N H

N

S

ArCO2CH2C6H4OMe

O

N HO2N CHO

O2N

H+

H2ON

S

ArCO2CH2C6H4OMe

O

N H

O2N

Ar = C6H5 p-C6H4-CO2Me 4-thiazolyl

-Semisynthetic B-Lactam Antibiotics-High potency, acid stable, high degree of tolerance by man-Many modifications prior to this work

2,4-DNPHN

S

ArCO2CH2C6H4OMe

O

H2N HEt3N

S Cl

O N

S

ArCO2CH2C6H4OMe

O

HN H

OS

TFA

Anisole N

S

ArCO2H

O

HN H

OS

3-Arylcephalosporins

3-Arylcephalosporins

Firestone, Maciejewicz, Christensen, p. 3384

Merck Sharp and Dohme Research, New Jersey-Semisynthetic B-Lactam Antibiotics-High potency, acid stable, high degree of tolerance by man-Many modifications prior to this work