JOURNAL OF ORGANIC CHEMISTRY: 1974 A BRIEF SYNOPSIS

Download 13C spectroscopy a new thing in organic chemistry?!? • Not many total syntheses , mostly steroids. • Sulfur chemistry very prevalent. • A lo...

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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 they doing in JOC? (Thanks Dick Vitale, baby!) • Some selected total syntheses

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

LiOH

OH O

(–)-1-(1naphthyl)ethylamine OH

1 OH O

3 recrystalizations

1. Removal of salt • (–)-1-(1naphthyl)ethylamine OH

2. 10 N HCl

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

1

E. J. Corey (p. 256)

O

C5H11 O

H Ph P Ph •HBr

CO2Me Me

Hunig's Base

9-10% +

Hexanal CO2Me Me C5H11 90-92 % Generally, E/Z > 1

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)

O N

CO2Me CO2Me

CO2Me

Hydrazine

CO2Me NH2

MeOH

H CO2Me

N

O

O 1. 10 % HCl 2.HCl, MeOH H H

N

O Desired pyrrolizidine

N

H H

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

NH •HCl

CO2Me

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

CO2Me O

O

CO2Me

NaH

MeO2C

PhH

O

O

(CO2Me)2

CO2Me O

CO2Me O

O

NaH PhH OR DMSO

O O

O

(CO2Me)2 Geometry highly dependent on solvent and therefore solvation of reaction pathway

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

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

LDA,

O

Li

Butyraldehyde

O

OH

THF, –78° 65% (90% Kinetic enolate)

O

LDA,

O

Li

Benzaldehyde

O

OH

THF, –78°

Ph 75-80%

O

LDA,

O

Li

Crotonaldehyde

O

THF, –78° 70%

OH

Barry M. Trost (Wisconson, Madison) -Chemospecificity of allylic alkylations (p. 737) -Use of cis and trans geranylacetone

Conditions: PdCl2, NaCl, CuCl, NaOAc in AcOH

-p-allyl complexes are remarkably stable Ethylene Gylcol 2

TsOH, PhH, Reflux

PdCl/2 80%

O O

Barry M. Trost (Wisconson, Madison) Alkylations NaH 1, 2, or 3

CH3SO2CH2CO2CH3

1. HOCH2CH2OH, TsOH, PhH, Reflux 2. Li, C2H5NH2, 0°C 3.H2O, HCl

H3CO2S

CO2CH3

LiI, NaCN, DMF 130°C

H3CO2S

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

N Me

O

–78°C

N Me

O

OMe

1

Li

N Me

–78°C

N Li

O E

E+

LDA, THF N

E

E+

LDA, THF

2

OMe

N

OMe

-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 addition This selectivity is due to the less reactive reagent having its charge more delocalized in the transition state. To test this hypothesis, a controll exmeriment: O MVK N Me

OMe

22hr, RT

N Me

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

PhSH

1. SOCl2

O Ph

O

S

OH

2.

O Ph

Li O

TMSO

OTMS

S

O

O MeO

62-76 %

O

H+

OMe O Ph

O

PhSCH2I

NaH PhLi

O

O

1

Sodium Metaperiodate

O Ph

S O

D

63-80%

O

O OMe

MeO

1 MeO

O OMe

OMe

S

O

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

O

R. F. Heck (Univ. of Delaware :-) ) -Palladium caralyzed Amidation of aryl, heterocyclic, and vinylic halides (p. 3327) O

NH2 Br R

+

CO

+

+

R'3N

Pd(Br)2(PPh3)2 100°C

Possible Mechanism:

R

N H

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

+

CO

+

R1OH

+

R23N

Pd(Br)2(PPh3)2 100°C

Possible Mechanism:

R

O

R2

• 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 O

O

O O

OH OMe

MeO O

HO

Br O

MeO2C

O

O

MeO2C Et3N (cat), PhH 80%

HO

t-BuOK

O CO2Me

O

t-BuOH 39%

O

O

O

O

HO

HO Cl

AcOH

O

O

TiCl4 PhNO2

MeO2C

MeO2C

HO O

AcOH

MeO2C

O H2, Pd/C

Br2

O

HO2C

(S)-Carlosic Acid Note: all yields in the synthesis were 70-80%, except the "key step," the cyclization

HCl NaOH

Cassamedine Cava and Libsch, p. 577 UPenn -An alkaloid isolated from Cassytha americana OMe

H N

O

OMe NH2

O

OH

O + O

O

Br

POCl3

Br

PhH, 2hr

O

O

O CH3CN 20 hr, 90%

76% O

Known Compounds

O

OMe

OMe O

O N •HCl

O Br

O

Ethyl Chloroformate

N

O

t-BuOK hn, 7hr

OEt O

Br

PhH, t-BuOH 32%

Et3N, 0°C 90% O

O

O OMe

OMe

OMe

O N

O

OEt O

O O

LiAlH4, AlCl3 Et2O, reflux

O

O

O N

O

1.5 hr, 87%

Me

O

O

AcOH 23%

N

O H O O

O O

Cassamedine

Me

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

H Cl

OTHP

Li 84%

OTHP Cl

OTHP

1. n-BuLi, THF 2. Cl(CH2)3Br, HEMPA, THF 53%

H

OTHP

PPh3 84%

Ph3P •HCl

1. n-BuLi, THF/HMPA

AcCl

2. Me(CH2)3CHO

AcOH 58%

OTHP

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

H2, Pd/BaSO4 OAc

OAc

Pentane, 84%

NaNO2 (aq) HNO3 (aq) 74%

The Sex Pheramone of the Pink Bollworm

H2, Pd/BaSO4 Pentane, 80% OAc

OAc

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-5methoctahydroindolizine, 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

H N

N

C4H9

H C4H9

A

H

N

N

C4H9

H C4H9

C B A Trail Pheromone of the Pink Bollworm

D

1. BuLi 2.

N

N

O

OH

C4H9 1. PhP3•Br2 2. Et3N

H2 PtO2 Na EtOH

H

N H

N H

OH

1. PhP3•Br2 2. Et3N

Br– OH

C4H9

H2 PtO2

1. PhP3•Br2 2. Et3N

A

C+D

A+B

H N C4H9 A

N H C4H9

N

N C4H9

C B A Trail Pheromone of the Pink Bollworm

H N H C4H9 D

OH H3CO

Fagaronine Chloride

OCH3 N

H3CO

Cl– Fagaronine Chloride

Stermitz, p. 3239 Colorado St. Univ., Fort Collins -Extremely active antileukemic alkaloid -Isolated from Faraga zanthoxyloides -Note: synthesis also proved structure

K2CO3 i-PrBr DMF, 92%

OCH3

HNO3:HOAc 1:1

OCH3

HOAc

NO2

NO2

OCH3

H2NNH2, EtOH

Oi-Pr

10% Pd/C 100°C, 99%

NO2

OCH3

hn, 1hr

OCH3

CH3CN:0.8N NaOH 90%

OCH3 OH

H3CO

NH2 OCH3

Br H

H3CO O

Oi-Pr

PhH, 91%

Fagaronine Chloride Stermitz, p. 3239 Colorado St. Univ., Fort Collins -Extremely active antileukemic alkaloid -Isolated from Faraga zanthoxyloides -Note: synthesis also proved structure

Oi-Pr H3CO

Br

OCH3 N

H3CO

1

Oi-Pr 1. Na, NH3(liq)

H3CO

2. 1 3. NH4Cl, 24%

H3CO

OCH3 N

PhNO2/Xylene 180°C

OH OH H3CO H3CO

OCH3 N CH3OSO3–

H3CO 8% NaCl(aq) 88%

H3CO

OCH3 N Cl– Fagaronine Chloride

Dimethyl Sulfate,

(+/–) 11-deoxyprostaglandin E2 Jonh Petterson, John Fried, p. 2506 Syntex, California

I

LiCu

C5H11 O

OMe

1.

C5H11 O

Previous Preocedures

2. Br

C5H11

2. TMSCl, THF O

O CO2Me C5H11

CO2Me

OTMS

Et2O, -78°C

OMe 2

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

O

OH (+/–) 11-deoxyprostaglandin E2

OMe

3-Arylcephalosporins

H N S

O

N

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

H

O

OMe NH

+

Cl

O

Et2O3P

Acetone

O

Reported in 1973 by same the group

N3

S N3CH2COCl Ar CO2CH2C6H4OMe

O2N

N

N O

Et3N

N

CHO

H N

O O2N

H

H

H2

Ar CO2CH2C6H4OMe

Ar CO2CH2C6H4OMe

Glyme

H2N

S

S

NaH

Ar PO3Et3

CO2CH2C6H4OMe

Ar = C6H5 p-C6H4-CO2Me 4-thiazolyl

O

N

S

K2CO3

Ar

N O

Pt

N

H+

S Ar CO2CH2C6H4OMe

H N

O

H2O O2N

S

Ar CO2H 3-Arylcephalosporins O

Firestone, Maciejewicz, Christensen, p. 3384

S

H

S Ar CO2CH2C6H4OMe

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

2,4-DNPH

H2N

H N

O

S

H N

Et3N

Ar CO2CH2C6H4OMe

Anisole

S

O

H N

S

Ar CO2H 3-Arylcephalosporins O

O

N O

Cl

S

H N TFA

S

O

H

S Ar CO2CH2C6H4OMe