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Home , Electrophile

Journal of Organic : 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 – Catalyzed • 13C spectroscopy a new thing in ?!? • 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 LiOH OH (–)-1-(1naphthyl)ethylamine O O OH 3 recrystalizations 1

OH O 1. Removal of salt • (–)-1-(1naphthyl)ethylamine 1 2. 10 N HCl OH

-g-Condensation of an allylic Phosphonium Ylide (p. 821) -Generally, allylic phosphorous ylides condense on the a carbon -Many geometric isomers usually obtained E. J. Corey (p. 256)

O C5H11 O 9-10% H CO2Me Ph Hunig's Base P + Ph Me Hexanal •HBr

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)

CO2Me O CO2Me CO2Me H CO2Me N MeOH CO2Me NH2 N O O

1. 10 % HCl

2.HCl, MeOH

H N H NH CO2Me O Desired pyrrolizidine •HCl

H N H O Desired indolizidine -Showed in earlier work that mechanism goes through "Spiro-mode" Samuel Danishefsky (Univ. of Pitt)

-Furanoid systems by intramolecular homoconjugate addition (p. 2658)

CO2Me MeO C CO Me NaH 2 O O 2 PhH (CO2Me)2 O O

CO2Me

CO2Me NaH O O PhH O O (CO2Me)2 OR O O DMSO Geometry highly dependent on solvent and therefore solvation of reaction pathway

-O- was dominant pathway in all systems they tried in this paper Gilbert Stork (Columbia)

-Regiospecific Aldol condensations of the kinetic lithium enolates of methyl (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

LDA, Li O O Butyraldehyde O OH THF, –78°

65% (90% Kinetic enolate)

LDA, Li O O Benzaldehyde O OH THF, –78° Ph 75-80%

LDA, Li O O Crotonaldehyde O OH THF, –78°

70% Barry M. Trost (Wisconson, Madison)

-Chemospecificity of allylic (p. 737) -Use of cis and trans geranylacetone

Conditions: PdCl2, NaCl, CuCl, NaOAc in AcOH

-p-allyl complexes are remarkably stable Gylcol PdCl/2 2 80% TsOH, PhH, Reflux O O Barry M. Trost (Wisconson, Madison)

Alkylations H CO S CO CH H CO S NaH 3 2 2 3 LiI, NaCN, DMF 3 2 1, 2, or 3 CH3SO2CH2CO2CH3 130°C

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

3.H2O, HCl Barry M. Trost (Wisconson, Madison)

-Alkylation of Lactam Derivatives (p. 2475)

E LDA, THF E+ Li 1 N O –78°C N O N O Me Me Me E + LDA, THF E 2 N OMe –78°C N OMe N OMe Li

-Both of the above examples proceeded with C-alkylation exclusively with alkyl halides, chlorosilanes. -For 1 (Stronger enolate), reaction with methyl vinyl 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 Exclusively 1,4 addition, 29% 22hr, N O N OMe RT Me Me 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 1. SOCl2 O OTMS O PhSH Ph Ph S OH 2. Li S O O 62-76 % O O MeO O H+ TMSO OMe

O Ph S

PhSCH I 1 MeO O NaH 2 O O PhLi O O 63-80% OMe OMe

O O O Ph D 1 Metaperiodate S OMe O MeO O

Summary: 3-step route, 60-76% overall; 5-step route, 60-72% overall R. F. Heck (Univ. of Delaware :-) )

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

NH2 O Br ' Pd(Br)2(PPh3)2 + CO + + R 3N N R R H 100°C

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

-Palladium caralyzed carboalkoxylation of aryl, benzyl, and vinylic halides (p. 3318)

O 2 Br 1 2 Pd(Br)2(PPh3)2 R + CO + R OH + R 3N O R R 100°C

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 (p. 731) – Herbert House • Chemistry of (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 O OH HO MeO2C t-BuOK Br2 OMe MeO Et N (cat), PhH 3 O O t-BuOH O AcOH O 80% O CO2Me 39% MeO2C

O HO HO Br HO H2, Pd/C Cl HCl O O O O NaOH O AcOH O TiCl4 MeO2C MeO2C MeO2C PhNO2

HO

O O HO2C (S)-Carlosic Acid

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

Cava and Libsch, p. 577

UPenn -An alkaloid isolated from Cassytha americana

OMe H N O OMe O Br POCl NH O OH PhH, 2hr 3 O 2 O + O 76% CH3CN O O Br 20 hr, 90% O Known Compounds O

OMe OMe O O Ethyl N OEt t-BuOK N O h , 7hr O Chloroformate n •HCl Br Br O PhH, t-BuOH Et3N, 0°C 32% 90%

O O O O OMe OMe OMe O O O LiAlH , AlCl O N 4 3 O Me N OEt Et2O, reflux N O O O Me O H O 1.5 hr, 87% AcOH 23% O O O O O O Cassamedine 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 Li 1. n-BuLi, THF OTHP OTHP Cl 84% 2. Cl(CH ) Br, H 2 3 HEMPA, THF 53%

OTHP OTHP PPh3 Cl Ph3P 84% •HCl

1. n-BuLi, THF/HMPA AcCl AcOH 2. Me(CH2)3CHO 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

H , Pd/BaSO 2 4 OAc Pentane, 84% OAc

NaNO2 (aq) HNO The Sex Pheramone of the 3 (aq) Pink Bollworm 74%

H2, Pd/BaSO4 OAc

Pentane, 80% 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-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

H H N N N N H H

C4H9 C4H9 C4H9 C4H9 A B C D A Trail Pheromone of the Pink Bollworm 1. BuLi N N 2. O OH

C4H9

1. PhP3•Br2 H2 2. Et3N PtO2 Na EtOH

H N N N – H H Br OH OH C4H9

H2 1. PhP •Br PtO 3 2 1. PhP3•Br2 2 2. Et N 3 2. Et3N

A + B C + D A

H H N N N N H H

C4H9 C4H9 C4H9 C4H9 A B C D A Trail Pheromone of the Pink Bollworm OH

H3CO Fagaronine Chloride OCH3 N H3CO Cl– Stermitz, p. 3239 Fagaronine Chloride

Colorado St. Univ., Fort Collins

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

HNO :HOAc NO2 NO OCH3 3 2 1:1 OCH hn, 1hr 3 OCH3 CH CN:0.8N NaOH OCH3 HOAc 3 OCH3 90% OH

H3CO Br NO2 H NNH , NH K2CO3 2 2 2 OCH EtOH H i-PrBr 3 OCH3 H3CO DMF, 92% 10% Pd/C O Oi-Pr 100°C, 99% 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 Oi-Pr

1. Na, NH3(liq) H3CO Br OCH H3CO Dimethyl Sulfate, 3 OCH3 N 2. 1 N PhNO2/Xylene H3CO 3. NH4Cl, 24% H3CO 1 180°C

OH OH H3CO OCH3 H3CO 8% NaCl(aq) OCH3 N H3CO N 88% – H3CO Cl – Fagaronine Chloride CH3OSO3 (+/–) 11-deoxyprostaglandin E2

Jonh Petterson, John Fried, p. 2506

Syntex, California

LiCu C5H11 1. O OTMS I C5H11 Et O, -78°C O OMe Previous O OMe 2 Preocedures C H 2. TMSCl, THF 5 11 2 O OMe

O 1. Li, NH3(liq) Ferric Nitrate (trace) CO2Me C5H11 2. Br CO2Me OH (+/–) 11-deoxyprostaglandin E2 H H 3-Arylcephalosporins N S

S O N O Ar Firestone, Maciejewicz, Christensen, p. 3384 CO2H 3-Arylcephalosporins 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

OMe O S S K2CO3 Ar NaH H NH Ar + Cl N PO Et Acetone 3 3 Glyme O O Et2O3P CO2CH2C6H4OMe O Ar = C6H5 Reported in 1973 by p-C6H4-CO2Me same the group 4-thiazolyl

H N H H2N S S 3 S H2 N3CH2COCl N N N Ar Ar Pt O Ar Et N O 3 CO CH C H OMe CO2CH2C6H4OMe CO2CH2C6H4OMe 2 2 6 4

H N H N S + S O2N CHO H N N Ar Ar O H2O O CO CH C H OMe CO2CH2C6H4OMe O2N 2 2 6 4 O2N 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

H H H H2N S Et N N S 2,4-DNPH 3 N S O N Ar O O O Ar CO CH C H OMe 2 2 6 4 S Cl CO2CH2C6H4OMe

H H N S TFA S O N Anisole O Ar CO2H 3-Arylcephalosporins