byu emeritus professors in organic chemistry november · pdf filemechanism 1 2 3 water...

BYU Emeritus Professors in Organic ChemistryNathan Wilde Baran Lab GMNovember 2014

Photo credit: Pastelitodepapa on wikipedia.

Brigham Young University

-Private university owned and run by the Church of Jesus Christ of Latter Day Saints (LDS Church or Mormon Church)-At ~34,000 on-campus students it is the 3rd-largest private university in the US. -BYU started as a small academy in 1865 at Provo, Utah.-The College of Physical and Mathematical Sciences wasn't founded until 1949.

Brigham Young

Some BYU alumni you might know:

NapoleonDynamite

Jeopardy Guy

Twilightauthor

not the president

superbowlchamp

All photos stolen from wikipedia

Edward G. Paul K. LeRoi Nelson Richard T. Hawkins

Angus U. Blackham Morris J. Robins

Emeritus Professors in Organic Chemistry

Jerald S. Bradshaw


Jerald S. BradshawBorn 1933, maybePhD: at UCLA with Donald Cram (the Cram's rule guy)Post-doc: at CalTech with George S. Hammond (the Hammond's postulate guy). Started around 1963.Researcher at Chevron Research Company until about 1966Professor at BYU starting around 1967.

Racemization of carbanions JACS 1963, 85, 1108 (with Cram)

Ph

MeEt H

N NH

Ts

Ph

MeEt

N NH2

Ts

Ph

MeEt H

N NH2

Ph

MeEt

H HEt

Me

Phracemateor or

retention inversion

base

base

[O]

Solvent1,4-dioxanet-BuOHn-BuOH

EtOHMeOH

ethylene glycolDMSOwater

Dielectricconstant (εºC)

2.211182734354980

74% ret.78% ret.68% ret.60% ret.44% ret.37% ret.44% ret.32% inv.

Stericcourse

It doesn't matter if it's oxidation or simply base-catlyzed; all that matters is the solvent and the identity and concetration of the base (alkoxide & hydroxide bases). No base gives 100% racemization.

Substrate

331331

KIO4Br2noneKIO4Br2none

0.300.300.309.709.709.70

32% inv.33% inv.5% inv.12% inv.77% ret.70% ret.

Oxidant [Base] (M)Stericcourse

These are all in water using KOH.

Ph

Me Et

Ph

MeEt

N N HOR

N2

H OR

M+ OH

R

Ph

MeEt

H

retentionmechanism

solvated intimate ion pairPh

Me EtHORROH

symmetrically solvated carbanion

Ph

Me EtN2ROH HOR

asymmetrically solvated carbanion

Ph

MeEt

H

racemizationmechanism

Ph

MeEt

H

inversionmechanism

Ph

MeEt

N N LGH H

Ph

MeEt

N N LGH

Ph

MeEt

NH

N

Ph

MeEt

N N H

This azamine would favor retention because of proximity of the proton.

inversionmechanism

1

2

3Water explanations


O

R1 R2 R4+hν

O

R1

R2

R4

R3

R3

oxetaneR2

R1

OHR1

R2HO

pinacol

R4

R3R2

R1

HO R4

R3R3R4

alcohol hydrocarbon dimer

O

R1 R2

hν O

R1 R2

*

s

intersystemcrossing O

R1 R2

*

t

O

R1 R2

CarbonylCompound

OlefinCompound

% Conv.carbonyl oxetane pinacol

hydrocarbondimer alcohol

benzophenonebenzophenoneacetophenonebenzaldehydebenzaldehyde

acetone

cyclohexene1-hexene

cyclohexenecyclohexene

1-hexenecyclohexene

958590909080

13201538308

47490

1000

>6>10>10>4>4

>26

272817181945

Products (%)

Irradiation of Carbonyl CompoundsJOC 1966, 31, 237w/ Chevron Research Company

12 KOt-Bu

t-BuOH/DMSO140ºC, 8 min

OROR

+

Ar-X % Conv. 1-Ot-Bu 1-OH 2-Ot-Bu 2-OH

1-Br2-Br1-I2-I

1-Cl2-Cl1-F2-F

10010010010086.085.680.372.8

8.58.36.28.85.62.139.6

0

4.86.22.46.06.15.3

58.30

27.827.525.514.49.89.80

48.3

8.510.66.2

18.113.913.4

049.6

Substitutionratio (1/2)

0.370.330.350.360.350.32

only 1only 2

Products (%)

Aryne Chemistry JOC 1971, 36, 314

N

R

Cl

OO

Cl

HOO

OHn

N

R

O

OO

O

On

n R Li Na K Rb Cs Mg Ca Sr Ba Ag

3334518-C-6

HCl

OMeOMeOMe

000000

2.71.63.93.98

11.3

9371

156236

277

311621628

214

1.80

2.64211167

000000

1.070

2.500

26.3

155.89100

316

00

3.313.65.260

312330462770266223

Rate of transport of various metal salts (mol / 24hr x 107) througha membrane containing 10-3 M ligand

Properties of Crown-ether-type macrocycles JACS 1980, 102, 467

X


Angus U. BlackhamBorn: 1926. Died: 2009.PhD: University of Cincinnati with Charles E. FrankProfessor at BYU: about 1960 to about 2000.Had 6 kids. Had 100 posterity when he died.

Spontaneous Ignition of Organic CompoundsIndustrial and Engineering Chemistry 1952, 862.

-2 different mechanisms postulated-metal of container doesn't matter-different additives can drastically change the ignition temp, even at 5 mol%. -example: (t-BuO)2 lowers the ignition temp of dodecane from 232 to 199ºC


Richard T. HawkinsBorn: 1929. Died: 2013.Worked at Phillips Petroleum CompanyDrafted for the Korean War, served as a chemist at Rocky Mountain ArsenalPhD: University of Illinois with H. R. SnyderProfessor at BYU: 1959 to 1995.

Making Stable Boronic and Borinic Acids with SnyderJACS 1960, 82, 3053 and JACS 1960, 82, 3863.

MeMe

MeMgBr

B(OMe)3

then H2OArB(OH)2 + Ar2BOH

– H2O ArBO

BAr

OBAr

O

28 : 1

B OMe Me

3

B OMe

3

Br MeOB

HONBS,

activator KOH

B OOcould never make this

BN

O

RR

B(OH)2

Br

B O

3

Br

H2NH2N

B O

3

NH

H2N– H2O NB

HN

Ortho-Lithiation JOC 1969, 34, 1173

NMe2 n-BuLi B(OMe)3

then H2ONMe2

B(OH)2

Nn-Bu n-BuLi B(OMe)3

then H2O BNn-Bu

OHH messy

SNMe2

n-BuLi benzaldehydeS

NMe2

HO

Ph

Thiophenyl methacrylates On sabbatical at Fabrics and Finishes Department of E. I. duPont de Nemours and Company. Journal of Heterocyclic Chemistry 1974, 11, 291

SRi. n-BuLi

ii. B(OMe)3 SR B(OMe)3-nnn = 3, 2, 1

iii. H2O2, NaOH57-70% one-pot

SR O

SR O

O

Me

methacrolylchloride,pyridine

63-76%

Hydroxy thiophenes and their esters had been pretty rare in the literature.


K. LeRoi NelsonBorn: about 1926. He's still kickin' too.PhD: at Purdue with H. C. BrownProfessor at BYU: 1956 to 1990.

Mononitration of t-butylbenzene with Brown. JACS 1951, 73, 5605R HNO3,

H2SO4

R

NO2

R ortho meta para

Met-Bu

58.4515.8

4.411.5

37.1572.7

But ... how do you get ratios of isomers in 1951? Fractional distillation!

Homomorphs of o-di-t-butylbenzene with Brown. JACS 1953, 75, 24

t-Bu

t-Bu~~

NMe3

t-Bu

NMe3

NMe3

CClMe2

CClMe2

NH2

NH2

MeI NMe2

NMe2

MeI NMe3

NMe2

MeI NMe3

NMe3

NMe3

t-Bu

NMe2

t-Bu

MeI No reaction even after 84 days of refluxing in acetonitrile

CClMe2

CClMe2

Me

OHMe

Me

Me OH

HClO

MeMe

Me Me

No chlorides observed.

How do you tell when your methyl iodide is consumed in 1953? Have you ever heard of the ebullioscopic technique?

They made a standard curve of % MeI in MeOH vs. refluxing temperature. Used that to decide how far the reaction had proceeded.


Edward G. PaulBorn: 1931. Died: 2014.PhD: at University of Utah with W. J. HortonProfessor at BYU: 1965 to 1996

Studies Towards Isopimpinellin JOC 1959, 24, 2000OMe

OMe

OMe

MeOOMe

OH

OMe

MeO

OCl

1. HCl, ZnCl2, NCCH2Cl

2. HBr, AcOHPh N

MeH

O, POCl3

1. NaOAc2. LAH3. H2, Raney Ni

4.

OMe

OMe

MeO O

H

O

1. AlCl32.

NC OHO

OMe

OMe

O OO

HO2C

NaHSO3,pyridine

OMe

OMe

O OO all the oxidantsOMe

OMe

O OO

isopimpinellin


Morris J. RobinsBorn: maybe 1939.PhD: Arizona State University with Roland RobinsProfessor at University of Alberta in Edmonton: 1969 to 1986Professor at BYU: 1987 to 2009Has a 3.9/5.0 rating on ratemyprofessors.com.

First Synthesis of Dideoxy nucleosides at ASU. JACS 1964, 86, 3585

N

N N

N

NH2

O

HOTs

HHHH

TrO2'-deoxy-adenosine

1. TrCl2. TsCl

1. AcOH2. EtSH, NaOEt3. "sponge Ni"

N

N N

N

NH2

O

HH

HHHH

HO

Fusion of purines and sugars, NMR analysis JACS 1965, 87, 4934

N

N N

N

NHAc

O

HOAc

HHHH

AcO AcOH

N

N NH

N

NHAc

O

HOAc

HHHH

AcOOAc

O

HOAc

HHH

AcO

N

NN

N

Cl

Cl

H

2,6-dichloropurine, chloroacetic acid,

neat

α-anomer

37.5% NH3

H2, Pd/C

α-fused purines

Biological activity, Cladribine J. Med. Chem 1972, 15, 735

N

N N

N

NH2

O

HOH

HHHH

HOR

α or β

R anomer E. coli S. faeciumLeukemia

L-12102-Cl-adenine2-Cl-adenosineClClOMeOMeSMeSMeNHNH2NH2

αβαβαβββ

2050

100020

1000100010001000

40>1000

10030

40030

100010001000800

10001000

305

1000.07100

8100100100100

LC50 (µM)

The Cl, β compound is now called Cladribine and is used to treat hairy cell leukemia and multiple sclerosis. It was first designed by Dennis Carson here at TSRI and Robins was the first to synthesize it.

Dichloro purine nucleosides w/o fusion Can. J. Chem. 1981, 59, 2601

N

N N

N

O

sugar

HOadenosine

1. mCPBA2. enzymatic deamination

1. Ac2O2. POCl3 N

N N

N

sugar(Ac's)

Cl

Cl61% fromadenosine

N

N N

N

sugar

NH2

Me2N

1. NH32. NMe2

guanosine

1. Ac2O2. POCl3

N

N N

N

sugar(Ac's)

Cl

H2N

~1:1 anomeric ratio


Non-aqueous diazotization Can. J. Chem. 1981, 59, 2608

N

N N

N

sugar(Ac3)

R

H2N

N

N N

N

sugar(Ac3)

R

Cl

N

N N

N

sugar(Ac3)

R

Br

N

N N

N

sugar(Ac3)

R

F

N

N N

N

sugar(Ac3)

NH2

F

t-BuONOHF•pyr

NH3

t-BuONOHF•pyr

t-BuONOSbBr3

t-BuONOSbCl3

CH2Br2

DCE

R = NH2, Cl, F

Deoxygenations to make DNA from RNA JACS 1981, 103, 932 Full paper: JACS 1983, 105, 4059

baseO

OHOH

HHHH

HO baseO

OHO

HHHH

O

i-Pr2SiO

i-Pr2Si PhOS

Cl

baseO

HOH

HHHH

HO

2. HSnBu3 AIBN3. TBAF

1.

overall yields:adenosine: 78%uridine: 68%Buzzwords of yesteryear: "smooth and efficient" ...

Sonogashira reactions of iodouracilTet. Lett. 1981, 22, 42. Tet. Lett. 1988, 29, 2855. J. Med. Chem 2005, 48, 4690.

HN

N

O

Osugar(PGs)

I2,CAN HN

N

O

Osugar(PGs)

Ialkyne,

CuI,Pd(PPh3)2Cl2

Et3NHN

N

O

Osugar(PGs)

R

HN

NOsugar(PGs)

R1R

R1 = O, NH2

These types of compounds have shown inhibitory effects against varicella-zoster virus (except omit the sugar).

Selective reduction of C-3' sugar ketone JOC 1990, 55, 410base

O

OTBSOH

HHHH

TBSO

adenosine

baseO

OTBS

HHH

TBSO

O

Dess-Martin

baseO

OTBS

HHH

TBSO

H

OHNaBH4

baseO

OTBS

HHH

HO

O

TFA

NaBD4

baseO

OTBS

HHH

HO

D

OHMechanism-based inhibition of ribonucleotide reductaseJACS 1999, 121, 1425 and references therein.

baseO

FOH

FHH

PPO baseO

HH

PPO

HO F

O

O F

H

Mec

hani

sm o

f ge

mcit

abin

eM

echa

nism

of r

ibon

ucle

otid

e re

duct

ases

Robins made the 2'-Cl and 2'-OTs that helped everyone figure out what the mechanism is.


AO

OAcOAc

HHHH

Fluorine! JOC 1993, 58, 3800. JACS 1996, 118, 2519

RSA

O

OAcOAc

HHHH

RSFEt2NSF3

(DAST),SbCl3

U(Bz)O

OO

HHHH

(2-pyr)O2S

(EtO)2OP

Me Me

UO

OO

HHHH

(2-pyr)O2S

(EtO)2OP

Me Me

F1. KH, selectfluor2. NH3, MeOH

AO

OHOH

HHHH

F

Biochem. 1994, 33, 3758This was used to study some biology.

Amine activated as a triazole leaving groupJACS 1994, 116, 9331. Full paper: JACS 1995, 117, 5951

N

N N

N

NH2

sugar

N NMe2N NMe2

TMSCl

N

N N

N

N

sugar

46%

NN

N

N N

N

R

sugar

nucleophile

R = OMe, SMe, NMe2

This works for all kinds of purinyl-type amines.Suzuki does all of the leaving groups Org. Lett. 2004, 6, 3421. Org. Lett. 2005, 7, 1149.

N

N N

N

R

sugar(PGs)

N

N N

N

Ar

sugar(PGs)

ArB(OH)2,Ni or Pd,

base R = imidazol-1-yl, 1,2,4-triazol-4-yl, F, S(alkyl), SO2(alkyl)Ar = anything you want

The 7/9-regioselectivity problem with purinesJOC 1996, 61, 9207. JOC 2006, 71, 7773

HN

N N

N

O

HN

N NH

N

O

AcHN OAcO

OAcOAc

HHHH

AcO

1. OTMSMe

TMSN

2. TMSOTf,AcHN

sugar(Ac's)

9

7

7:9 = ~15:1

N

N NH

N

O

AcHN

NPh2

O

same as aboveN

N N

N

O

AcHN

NPh2

O

sugar(Ac's)

only the 9-isomer was observed!

N

N NH

N

NH2 O Cl

(p-tol)CO2

(p-tol)CO2

NaH, MeCN, then

N

N N

N

NH2

sugar(Ac's)

7:9 = ~3:1

N

N NH

N

NO Cl

(p-tol)CO2

(p-tol)CO2

NaH, MeCN, then

N

N N

N

N

sugar(Ac's)

N-9 only!Single anomer!

NPh

Ph

NPh

Ph

Cl Cl~100%

NH3,MeOH

N

N N

N

NH2

sugarCl

a more efficient way to make cladribine

~50% yields

byu emeritus professors in organic chemistry november · pdf filemechanism 1 2 3 water...

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