Year in Review: JACS 1976Alexandros S. PollatosBaran Group Meeting

10/30/2021

Sir:

January March May July September November

February April June August October December

America turns 200!

Legionnaire’sdisease appears

in Philly

A small computercompany begins in

a CA garage

First space shuttle (Columbia) unveiled

First Ebola pandemic in Sudan

Fidel Castrotakes power in Cuba

Happenings in the Year 1 B.P.B.

First commercialConcorde flights

Had 29 days…

Star Wars filming begins

Federal ElectionCampaign Act signed

JVC releases the‘VHS’ in Japan

Copyright Actof 1976

JACS Stats

Top Publishing Authors:1. George Olah (24)2. L.A. Paquette (14)3. W. J. Hehre (13)4. F. A. Cotton (12)5. H. C. Brown (11)

1,975 Articles (so close)

Most Cited Papers:1. Beta-Scale of Solvent-Hydrogen Bond Acceptor (HBA) BasicitiesKamlet, M. J. et. al., 2, 377. (1,673 citations)2. Structure and Chemistry of Bis(Cyclopentadienyl)-MLN ComplexesLauher, J. W. et. al. 7, 1729. (1,462 citations)3. The alpha-scale of solvent hydrogen-bond donor (HBD) aciditiesTaft, R. W. et. al., 10, 2886. (1,241 citations)4. Carbon-13 nuclear magnetic resonance of polymers spinning at the magic angleSchaefer, J. et. al., 4, 1031. (1,143 citations)5. The Ester Enolate Claisen Rearrangement. Stereochemical Control through Stereoselective Enolate FormationIreland, R. E. et. al., 10, 2868. (1,060 citations)

Science in 1976Nobel Prizes:

Chemistry – William N. Lipscomb ‘for his studies on the structure ofboranes illuminating problems of chemical bonding’

Physics – Richter & Ting ‘for their pioneering work in the discovery of a heavy elementary particle of a new kind’ (J-meson)

Medicine – Blumberg & Gajdusek ‘for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases’

Pop Culture in 1976

‘Rocky’ released ‘staches were in‘Happy Days’ is the most

popular TV show

1

Year in Review: JACS 1976Alexandros S. PollatosBaran Group Meeting

10/30/2021

Metal-Assisted Terpene Synthesis. Myrcene Magnesium Compoundas a New Example of an Enediylmetal System Akutagawa, S. et. al., 23, 7420.

Me

Me Mg, BF3•OEt2

I2/EtBr (act.) Me

Me Mg2+

Me Me

O

then water

Me

Me

MeMe

MeOH

+ isomer+ dialkylated pdt.

Me

Me Me

Mg

89%MgCl2

Me

Me Me

MgCl

ClMg

Me Me

O

Me

Me Me

MeMe

OHHO Me

Me

+

quantitative (1:1)

+

Me

Me

OH2–1) BF3•OEt2

then H2O2, NaOH

hydroboration of starting conjugated dienes

affords glycols

limited scope tested:Me Me

Me

+ analogues

Me

tolerated

terminal substitution& cyclic sytemsnot tolerated

Groovy Organometallics

The Photochemical Induced Cyclization of Allyl Grignard ReagentsCohen, S. et. al., 7, 2013.

MgBr hvether

MgBr

4e–

electrocyclization MgCl

CO2then H2O

OH

O

– phenyl, vinyl, methyl subsituted cyclopropanes studied– electrophile scope not established

Stereoselective One-Pot Dialkylation of gem–Dihalocyclopropanes…Kitatani, K. et. al., 8, 2362.

R1

R2

XXR1

R2

R32CuLi R4X R1

R2

R4R3

Rationale: Bulky cuprate undergoes Cu-X exchange to less hindered halogen, then SN2-type X-alkyl exchangeR1

R2X

X R32CuLi R1

R2CuR3

X R1

R2R3

Cu

O O

ClCl

O O

Mesirenin

(R = OH)&

sesquicarene(R = H)

45-75%

Me Me

Me

MeRR

2

Year in Review: JACS 1976Alexandros S. PollatosBaran Group Meeting

10/30/2021

Allylic Amination of Olefins and Acetylenes by Imido Selenium CompoundsSharpless, K. B. et. al., 1, 269.

SeCl4 2 eq. tBuNH2or TsNH2

Se0TsNClNa

SeNRRN R R

NHR

– same ene + [2,3] shift as Riley Oxidation– broad substrate scope (yields up to 84%)– strict stoichiometric control needed– avoids allylic RAR’s inherent to Riley:

MeSe(NR)2

MeMeSeO2

Physical Organic OdditiesAnionic Rearrangement of 7-Norbornadienol: a 1,3-Sigmatropic ShiftFranzius, B. et. al., 5, 1241.

The Photochemical Synthesis of a Tricyclo[2.2.0.02,5]hexaneAlexander, E. C. et. al., 14, 4324

PhPh

OH

PhPh

O hv

Ph

PhOH

PhOH

Ph

OH

Ph

O

OO

PhO

OCl

pyr.Al-Hg

Ph

O

OOH

Ph

tBuOH, hv

Jones

via*

PhPh

O

HH

γ-abstraction

PhPh

OH

H

*no mech. proposed: my hypothesis

H OH H O

HClCl–

strain release??

Name?2 possibilities:D O D O H O

D

displacement of D to 2-pos’n

orD O

[1,3]

D O D O retention of deuteration pos’n – confirmed

6 π‘allylic-type’

electrocyclicring opening

D OD O

LUMO

inversion required

O D

disrot.or antarafac.with retention

Cyclopropane-Olefin Cross MetathesisGassman, P. G. et. al., 19, 6057 & 6059.

HR

R’+H

R’+ R

WPhCl3AlCl3 or EtAlCl2

– low yields– moderate scope

any synthetic utility?limited ex.

via

HR [W] H

R

[W]O.A.-like[W]

H

R+retro

[2+2]

retrocarbeneinsertion possible,

but unpreced.

N

R

Mo0

quinoneN

R

(Asako) JACS,2018, 15425OH NHR

Ph20%

overall

3

Year in Review: JACS 1976Alexandros S. PollatosBaran Group Meeting

10/30/2021

Stable Cis Dialkyldiazenes (Azoalkanes)…Engel, P. S. et. al., 7, 1971. Total Synthesis of Marasmic Acid

Greenlee, W. J. et. al., 19, 6075.– most cis-azoalkanes rapidly lose nitrogen @ r.t.– cis-diaryldiazenes isomerize to trans, but not back

N N N N

why are these stable compared to, say tBu2N2?adac

norc

vs.

NMe

Me

MeN Me

MeMe

NMe

Me

MeN

MeMe Me

T.S.isom T.S.decomp

norcnort

T.S.isom

T.S.decomp

Key factors for stabilty:– incipient radical (in)stability– bulk of substituents

ΦN2tBu2N2 .46ada2N2 ~.004nor2N2 .0008

Synthetic implications?

NH2

RH2N R’

N

R

N R’

N N

R’

see: (Movassaghi) JACS, 2011, 13002; (Engel) Chem. Rev. 1980, 99

hv

R

R’

R

– N2

RR’ different

products!

MeMe

O

MeMe

OHO

O

OBr

MeMe

CO2H

O

OBr

HMeMe

CO2H

O

O

H

+

Br

1) isobutylene, pTSA2) KOtBu

MeMe

CO2tBu

O

O

H

steps

1) DIBAL-H2) NaBH467% (2 steps)

MeMe

CO2tBu

HO

HO

Selected Total Syntheses

1) phosgene2) DMSO, NEt3

MeMe

CO2tBu

O

OO

O

HO

O

MeMe

TFA

(±)-marasmic acid

via

OR

R

HCl

O

OR

R

HO

OS

Me

Me

OR

RS

H

Me– CO2

Me

(1:1)44% (3 steps)

DMSONEt3

12% (3 steps)

91%

4

Year in Review: JACS 1976Alexandros S. PollatosBaran Group Meeting

10/30/2021

A Total Synthesis of GliotoxinFukuyama, T. et. al., 21, 6723.

O

Ot-Bu

O

NN

S SAr

O

OMe

forms incorrectdiastereomer

Further reading on impactimpact of dipole interactions on Robinson Annulation: (Scanio)JACS 1971, 93, 1539See also:Stratton GM: DiketopiperazinesKnouse GM: Sulfur-containing NPs

OH

R

NN

SS

Ar

O

Me O

NHN

SSAr

O

O

Me

MeHN

OH

O

H2NOH

O

+6 steps

O

ORO

Triton B

approach ofamide nucleophile?

N

NSS Ar

O

O

Me

O

Ot-Bu

O

N OHN

O

OMe

SSAr

‘…a novel solvent-dependent Michael reaction…’

dipole interactionfavored in DCM

epi-pro-gliotoxinformed (3:1), 45%

pro-gliotoxinformed (3:1), 88%

N OHN

O

OHO

Me

SS

in elqm. with oxepin

DMSO

Cl

protections +F.G. interconversion

H1) PhLi, BOMCl2) BCl3

26% (2 steps)(±) gliotoxin

N OH

N

O

OMe

SSAr

R

N OHN

O

OHO

Me

SSAr mCPBA

then HClO4

mechanism?

SSAr

OH

SSAr

OH

hydrolysis

Ar

O + HSS

OH

The Synthesis of ZoanthoxanthinsBraun, M. et. al., 21, 6723.

OO

NH21) Na-Hg

2) then HCl

N NH2NH

N NH2

HO

H+

NNH

N

N

Me

NH2

H2N des-Me-zoanthoxanthin15%

+

HN

N N

N

Me

NH2H2N

pseudozoanthoxanthin A8%

via

NH

NH NH2

N

HN

H2N

Me

N

HN

H2N

Me

NH

HN NH2

[4+6]

then rearom.

[4+6]

then rearom.

later pub. questionsthis proposal… why?(Büchi) JACS, 1978, 4208

30%

65%

5

Year in Review: JACS 1976Alexandros S. PollatosBaran Group Meeting

10/30/2021

Optically Specific Synthesis of Estrone and 19-Norsteroids from 2,6-LutidineDanishefsky, S. et. al., 16, 4975.

NMe

‘tris-annelating agent’

N

O

OMe

O

Me

AA-mediated aldol

1) NaBH42) H2 -Pd/C, NEt33) ketalization

Key Points:– early ex. of successful AA-aldol– careful choice of AA needed in such cases– unusual steroid retron

N

OHMe

OO

Me

O

OMeHN

HO2C RH

N

Me

O

OMeHN

HO2CH

N

Me

after crystalization

1) Li, NH32) NaOH, H2O

3) H+

90% (3 steps)

OHMe

OH

1) Jones ox. (quant.)2) pTSA, AcOH

Me O

H

H

HHO

(+)-estrone

vinylogous aldolization

Me OH

H

H

O

Li, NH3

Me OH

H

H

OH

Which amino acid works best?

Amino acid % ee % yield

L-Phe 86 82

L-Tyr(OMe) 84 82

D-Trp 78 70

L-Ser 35 77

L-Pro 26 67

D-Val 21 72

Possible parallel-displacedπ–π stacking

∆5(10)-19-norsteroid

mechanism?

R

AA-cat. aldol:(Barbas) JACS, 2001, 5620(Lu) Org. Biomol. Chem., 2008, 2047heterocycle-AA π-π-stacking:(Wheeler) JACS, 2019, 11027

see also:

NH

MeR

NMeR

NHMeR

OH

O

then hemiaminalhydrolysis

repeat OMeR

Oaldol

–OH

45%82%

O3) AcBr, Ac2Othen K2CO3, MeOH56% from pyr-ketal

68% frompyr-ketal

steps H

6

Year in Review: JACS 1976Alexandros S. PollatosBaran Group Meeting

10/30/2021

Synthetic Methods for Sesquiterpene α-MethyIene-γ-lactonesSemmelhack, M. F. et. al., 11, 3384.

Pseudoguaianolides – A Popular N.P. Class in ‘76

HO

MeOOMe

HO

MeOOMe

CO2Me

O

CO2Me

BrCO2MeHO

HO+

Zn-Cu

OCO2Me

(Z)-olefin key

ZnBr

O

OMeO

O O

cis-onlypseudoguaianes

guaianes xanthanesrelated cmpds: see Cherny, 2011 GM

= ox.site

or combine bromoaldehyde w Ni:

O

MeO2CNi

Br

BrNi

O

CO2Me

The Total Synthesis of (±)-DamsinKretchmer, K.A. et. al., 11, 3379.

HOO

Me

5 steps

O

Me

MeO2C

Me

OO

1) O3 thenP(OMe)3

Me2) MeI, K2CO3

63% 2:1*

Me

OMe O O

H

(±)-damsin

Me

Me OO

H

The Stereoselective Total Synthesis of Pseudoguaianolides: ConfertinMarshall, J. A. et. al., 14, 4312.

RO Me

MeO

RO Me

MeHO

RO Me

Me

HO

HOMe

O

ORO O

HMe

Me

O

ORO Me

CO2Me

Me

OH

OHRO Me

Me

O

OHOMe

Me

OO

Me

Jones ox.

1) LAH2) mCPBA

3) MsCl4) Li, NH375% overall

1) CH2I2, Zn-Cu (80%)2) O3, then [O]

1) HClO4

1) LDA, (PhSe)22) H2O23) H2/Pd-C (70% 3 steps)4) KH, MeOCO2Me

1) LAH, KH

1) MnO22) TFA3) NaOH, iPrOH

(±)-confertin

see also: wide range of bioactivity and more recent approaches to synthesisSantana, A. et. al. Eur. J. Org. Chem. 2015, 2093

O

*

1) Ethyl formate, NaH2) NaBH4 then H+

3) TsCl, pyr36% (3 steps)4) pyr (74%)

5 steps23% overall

80% (3 steps)

50-60%

O O

R = tBu

7

MeO2C

Year in Review: JACS 1976Alexandros S. PollatosBaran Group Meeting

10/30/2021

A Novel Molecular Rearrangement of Heteroaromatic N-OxidesAbramovitch, R. A. et. al., 18, 5671.

Wacky Heterocyclic Reactions

NO

Ph

CN+

NH

CN

O

Ph+ N

CNPh

O

A (major) B+

N

CNPh

O

CA:B:C varies withpyridine substiution

Can one pathway explain the products?

NO Ph

CN

NO

PhCN

Ring Contraction of 2-Azidopyridine 1-Oxides and Related CompoundsAbramovitch, R. A. et. al., 6, 1478.

NO

N3 N CN

OH∆

sterically untenable

does not account for all pdts

Proposed Mech.

NO

PhCN

NO

Ph

CNR

RR

R

RR

Hpromotedby base

NCN

Ph

O

N

CNPh

O

B

H

fragmentation

N

CN

OPh

N

CNPh

OC

N

CN

O

Ph taut.

NH

CN

O

Ph

A

N

O

CN

PhH

oddtaut.

∆R

R

Proposed Mech.

NO

NN

N-N2 N

CN

product depends on solvent

benzene

benzene NO

CNH

NOH

CN

nucleophilic solvents

yields and productratios not reported

Possible synthetic utility?

N

R

N3O

inert solv.HN

CN

R

HN

R

O

Nu

nucleophile or solvent

O

RR

NCN

O

RNu–

NOH

Nu R

CNN

Nu R

CN-H2O

hydrolysis

NH

Nu RO +

NH

CN

RNu = MeOH,PhNH2,morpholine

pdt.

8

Year in Review: JACS 1976Alexandros S. PollatosBaran Group Meeting

10/30/2021

Remarkably Stable Organoboranes…Brown, H. C. et. al., 22, 7107.

The Ester Enolate Claisen Rearrangement. Stereochemical Control through Stereoselective Enolate FormationIreland, R. E. et. al., 10, 2868.

Classics and Honorable Mentions

– 9-BBN enters the scene

HB

Me Me

Me

Me Me

Me

OHMe

MeHO BH3 BBN

Conjugate Addition of [BBN] to Methyl Vinyl Ketone. A Convenient Synthesis of γ,δ-Unsaturated KetonesBrown, H. C. et. al., 24, 7832.

BBNR

R1Me

O RR’

Me

OBBN

R

R1

MeOhydrolysis

– analogous cuprate addition would yield polymers– yields mostly 60-80%– rxn does not proceed with other boranes (i.e. Ph2BR)– broad scope BUT:

O

R

RBBN

cisoid relationship

crucial

R

O

R O

RBBN

Not Covered:

PGA2 (Stork)See Classics, vol. 1, Ch. 9

O CO2H

HOMe

H

HR

Me

H

OMe

Me

O

11α-methylprogesterone11α-hydroxyprogesterone(W.S. Johnson)

– Countless organic photochemical and mechanistic studies– Many stable carbocation syntheses (Olah, mostly)– Natural product isolations

+ others

OH

O

O

OH

OH O

OH

OMe

O

MeOH

NH2

carminomycinone(Kende)

O

R1

OR

LDA

LDA/HMPA

O

R1

O

R

TMS

O

R1

OR

TMS

(Z)-enol.

(E)-enol.

CO2H

R

R1

CO2H

R

R1

anti

syn

9