Polyphenols

Topics Covered In This Meeting:Ellagitannins (hydrolyzable tannins)OligostilbenoidsLignansVarious polyphenolic ethersAnthraquinone natural productsPolyphenolic peptides (Non-RibosomalFlavanoidsLignin Degradation (brief)

OHOH HO OH HO

OHOH

HO

OH

OHcatechol resorcinol pyrogallol phloroglucinol

What is a Polyphenol?Definition #1- Water Soluble (even minimally)- 500-4000 Da- >12 phenolic hydroxy groups- 5-7 aromatic rings/100 Da

-

Hasalm, Nat. Prod. Rep. 1994, 41.

Definition #2- The term “polyphenol” should be used to define compounds exclusively derived from the shikimate/phenylpropanoid and/or the polyketide pathway, featuring more than one phenolic unit and deprived of nitrogen-based functions.

Quideau, "Why bother with polyphenols?", Groupe Polyphenols.

The Basics:- contain multiple phenolic moieties- secondary metabolites of plants, fungi, bacteria, and archea- thought to be ubiquitous in plants - may contain furans, pyrones, biaryls, aryl ethers, pyrans, dioxins, spiro, benzopyrans, O- or C-glycosides -exist as definable monomers and oligomers, as well as heterogeneous oligomers/polymers

Properties:- OXIDATION- OXIDATION- chelate metal ions- precipitate/bind proteins- fluorescent/autofluorescent- facile ionization- generally water soluble

OHO

O P OHO

OH

PEP

OOH

OHO P OH

O

OH

HO

O

O OH

OH

OHO P OH

O

OH

E4Perythrose-4-phosphate

DAHPD-arabino-heptulosonate-

7-phosphate

CO2H

HOOH

OH

shikimate OH

HO2CO

OHO

prephenic acid

Phenylalanine

Gallic acid

TyrosineCO2H

HOOH

OH

4HPP4-hydroxyphenylpyruvic

acid

HOO

OH

OHO

OH

O4-hydroxycinnamic acid

HOO

OH4-hydroxyphenylacetic acid

+

Shikimate Pathway

- Pathway only present in plants, fungi, bacteria, and archaea - produces the major components/ monomers (in blue) of most polyphenols - varous alkylations, oxidations and reductions may take place prior to incorporation

Biological Significance (Plants):- signalling molecules in ripening- allelopathic agents: modulate other plants' growth- phytoalexins: antimicrobial activity (bacterial, fungal, viral, and parasitic)- hardening of non-vegetative tissues- herbivore deterent: taste and astrigent properties- inhibit rot- flame retardant properties- UV protection- variety of pigments- 1-25% of dry plant weight (species depenent)

Biological Significance (Humans):- Antioxidant properties - no FDA recognition (no MOA, no biomarkers, heterogeneity)- possible "anti-nutrients": bind metals and enzymes- Tastes: bitterness/astringency (higher polymer = more astrignet/less bitter)- source of therapeutically effective molecules

Uses:- tanning of leather- dyes for non-synthetic fibers- green chemistry feedstocks- resins, paints, polymers, surfactants, friction linings, wood preservatives, glues (particle board)

Topics Not Covered:- polyphenolic alkaloids- polyphenols with isolated phenolic components- tetracyclines (G.M. - Lin, 2005)

- definitions are likely narrow due to necessity of fields- nitrogen may be incorporated to DAHP in shikimate pathway or prior to transformations "allowed" for cannonical polyphenols

Lignin(non-hydrolyzable tannin)

David Peters Baran Group Meeting5/26/16

(hydrolyzable tannins)- biosynthesized from pentagalloyl glucose, then oxidations and esterifications- tellamigrandins I and II are the most basic members- high concentration in fruits - immunomodulatory: immunosuppresive and tumor necrosis- no therapeutic use to date

- Confirmed the Schmidt-Haslam Hypothesis

R= CO2Bn

Baran Group Meeting5/26/16David Peters Polyphenols

Br

OMeMeO

MeO

ON Cu•pyr

DMF, Δ60%

OMeMeO

MeO

ON N

O

OMe

OMeMeO

(S)

1. TFA, H2O2. Ac2O, Pyr.3. KOt-Bu, H2O

OMeMeO

MeO OMe

OMeMeO

CO2H CO2H

(S)

quant.

OOHO

OMeOH

OPh 1. DCC, 4-DMAP

MeOOMe

OMe

CO2H

2. Pd(OH)2, cyclohexene

OHOO

OMeO

HO

O

OMe

OMe

MeO

O

MeO

MeOOMe

DCC, 4-DMAP,1 O-permethyl

tellimagrandin I

1

OOO

OHO

O

O

OH

OH

HO

O

HO

HOOH

O

OHO

HO

HOHO

HOOH

71% (2 steps)

38%

tellimagrandin I

OHHO OBn

CO2Bn

OO OBn

CO2Bn

o-chloranilAr-OH

acid or baseX

OR'R'O OBn

CO2BnO

RO

RO CO2Bn

B(OAc)3

O

O

OBn

OO

R

H

O

O

OBn

OO

R

HOBn

R

OBnR

OHHO OBn

CO2BnO

HO

BnO CO2Bn

OHHO OBn

CO2BnO

BnO OH

CO2Bn

K2CO3, BnBr (R/R' = Bn)

1. NaOAc2. Na2SO4

2:1

+ +

OOO

Ph

OTBSOTBSO

NH

CCl3BnO

BnO

OBn

CO2HO

OBnOBn

HO2C+

R = BnR' = H

CO2HHO

HOOH

HO2C

OHOH

OH OO O

O

OHOH

HOOH

depsidebond

H+

ellagic acidhexahydroxydiphenic acid (HHDP)

galloylgroup

PhH, Δ

BnO

BnO

OBn

CO2RO

OBnOBn

OOO

Ph

TBSOTBSO

O

O

R=

1. Bu4NF2. DCC, DMAP

BnOOBn

OBn

CO2H

BnO

BnO

OBn

CO2RO

OBnOBn

OOO

Ph

GOGO

O

O

R=

1. I2, MeOH2. DCC, DMAP

OTBS

HO2C

G =

OO

PhPh

3.Bu4NF

BnO

BnO

OBn

CO2RO

OBnOBn

OO

O

GOGO O

O

O

HO

OO

PhPh

O

OHO

O

PhPh

R=

1. Pb(OAc)4, pyr.2. H2, Pd/C

OOG'O

OG'

O

O

OHO

HO

HOHO

HOOH

HO

HO

OH

CO2RO

OHOH

O

OG' = 3,4,5-(OH)-C6H2CO

coriariin A

R=

OO

OO

O

OHO

O

PhPh

HO

O

OPhPh O O

OHO

O

PhPh

O

OOH

O

OPh

Ph

Pb(OAc)4, pyr. OO

OOHO

OOPh

Ph

O

O

OO

HO

HO

OO

OO

Ph

Ph

Ph

Ph

OOH

O

O PhPh

29%

UncoupledStarting Material

29%OBn

OBn+

O(2)-O(3) galloyl coupling

0%

Ellagitannins:

BrBrMeO

MeOOMe

OHHO

Ph Ph

BrMeO

MeOOMe

BrMeO

MeOOMe

O

O Ph

PhNaH, THF

t-BuLi;CuCN; O2

-72°C

O

O Ph

PhMeO

MeOMeO

MeO

MeOOMe

1. H2, Pd/C2. KMnO4, cat. Bu4NI, PhH/H2O

1 O-permethyltellimagrandin II

Lipshutz, Tet. Lett. 1994, 5567.

Feldman, Tet. Lett. 1998, 8942.

Feldman, J.O.C. 1996, 6656.Feldman, J.O.C. 2000, 8011.

P-450 oxidation

O OO

OHHO

OHHO

HO O

O

OHHO OH

HO

OHHO

OO

O

HO

OH

OH

OO

O

OH

HO

OH

OHHO

OH

HO

O

O

OO

OH

HO[O], -2H

HO

O

O

OO

OH

OH

OH

HHO

O

OO

OH

O

OOH

H

1,6-addn.+ isomerization

ringcontraction+ enol taut.

O

OO

OH

O

OHO

O HH

OH

OO

OH

O

OHH

OH

OO

OH

O

O

-2Hacutissimin Amongolicain A

- CO2

Quideau, Angew. Chem. Int. Ed. 2013, 11530.

Meyers, J.O.C. 1994, 2577.

HRP, H2O2

2:1 acetone/H2O63% (2:1)

CH2Cl244%

BF3•OEt2 (4 eq.)

t-Bu

OMe

OHHO

OH

H

OHt-Bu

OMe

OH

HO

(±)-gneafricanin F

(±)-gnemonol

- resveratrol isolated from 72 different plant sources accross the world- oxidative dimerization via enzymes- observed as diverse, structurally complex dimers, trimers, dimers of dimers, and oligomers- high concentration in red wines and dark fruits (almost absent in white wine)- extremely diverse biological activities observed- often serve as antifungals for the producer organisms- "French Paradox" - Can diets high in oligosilbenoids counter the effects of a diet high in fat and cholesterol?

Snyder, Angew. Chem. Int. Ed. 2011, 8629.

Snyder, J. Am. Chem. Soc., 2009, 1753.

Pryce, J.C.S. Chem. Comm. 1977, 208.

Sako, J.O.C. 2004, 2598.Velu, Chem. Eur. J. 2008 11376.

Lin, Chem. Pharm. Bull. 2004, 238.

Li, Synthesis 2010, 3822.Li, Org. Biomol. Chem. 2014, 2273.

OH

HO OH

HOOH

OHOHHO

HO 78

- π-stacked and H-bond stabilized- Head-Tail and Head-Head both available- change in phenolic subst. affects outcome

OH

HO OH

Ag

- Ag-complex sufficiently stable- distorts planarity = no π-stacking

Viniferin-type dimersonlyampelopsin

pallidol, and viniferin-type dimers

Velu, J. Nat. Prod., 2013, 538.

(1:1)

+

AgOAcFeCl3

Baran Group Meeting5/26/16David Peters

OH

OMe

OMe

OMeMeO

OBn

1. DMP2. Me3SI, nBuLi3. Zn2I

OMe

OMe

OMeMeO

OBn

O

NaClO2, NaH2PO4,resorcinol

OMe

OMe

OMeMeO

OBn

OHO

OO

H

HO

OH

HO OHHO

1. BnBr

Li OBn2.

OH

BnO

OBn

BnO OBnBnO

OBn

OH3. BF3•OEt2, Et3SiHO

H

BnO

OBn

BnO OBnBnO

H

OBn

Pd/C, H279%

50% (3 steps)

1. IDSI (2 min.)2. BBr3

36%

hopeahainol D(1.79 kcal mol-1

higher)

heimiol A(bridgehead

epimer)

BCl3, BF3•OEt299% S

Et

Et ICl

I SEt

Et SbCl6

IDSI

79% 85%

OH

OMe

OMe

OMeMeO

OMe

R1 R2

O OR3

O

6 steps p-TsOH;OMe

SH

MeO

OMe

OMe

MeO

OMe

S

OMe

1. mCPBA2. t-BuOH, aq. KOH, CCl4OMe

MeOOMe

OMe

MeOOMe

O-permethylampelopsin D

MeO

MeO

OMe

OMe

MeOOMe

BrBr

Br

BrMeO

MeO

MeOOMe

Br

OMeMeO

H

HO

HO

HOOH

OHHO

HBr

1. (TMS)3SiH, AIBN2. BBr3

ampelopsin F

NBS

Polyphenols

Stilbene

Oligostilbenoids:

Resveratrol

HO

OH

OH

OH HorseraddishPeroxidase (HRP),

H2O2

O

HO

1977

HO OH

OH

OH

OH

HO

AgOAc (1 eq.)97%

≠

OH

O

HO

OH

OH

OH

ε-viniferin

Other oxidants that promote similar transformations of phenolic

stilbenes:FeCl3FeCl3•6H2OCuBr2PbO2VOF3Laccasesoybean peroxidase

FeCl3 or FeCl3•6H2O

OHMeO

OHHO

OHO

HO

HO OMe

OH

OMeOH

HOOH

OHHO

HH

OH

HO OMe

MeO

OHO

HO

HO OMe

OH

OMeOH

OMeO OH

OMeOH

O

OHHO

OH

HO

OMeHO

OMe

HO

HO

OH

O

O OH

HO OMe

H

HO OMe

HO

HOOH

MeO OHHOOH

HO

HO

MeO

MeOOH

HO OMe

HO

O

OH

OMe

OHHO

+ 3 other undisclosed products

isorhapontigenin

HO OH

OHOMet-Bu

FeCl3•6H2O

HO

OH

OH

HOH

H

OH

HOOMe

MeO

t-Bu

t-Bu

OH

OH

OHHO

HO OH

H

OMe

t-But-Bu

MeO

AlCl3, MeNO2PhMe, 50°C

80%

AlCl3, MeNO2PhMe, 50°C

80%

HO

OH

OH

HOH

H

OH

HOOH

HO

OH

OH

OHHO

HO OH

H

OHHO

OH

HOHO OH

OH

OMe

OHt-Bu

t-Bu OH

OMe

BrMeO

MeOOMe

OMeMeO

MeOOMe

N

OCO2Me

Ph

Mg;1,2-dibromoethane;2, THF, Δ

1

2

MeO

MeOOMe

MeO

MeOOMe

N

O

CO2Me

Ph

68% yield, 77% eechiral HPLC purif.

(S)

1. TFA, H2O, Na2SO42. Ac2O, pyr.3. NaOH MeO

MeOOMe

MeO

MeOOMe

OTBSOTBS OH

OH

O 6 steps

MeO

MeOOMe

MeO

MeOOMe

Br

CHO

Me

1. SmI2, HMPAMeO

MeOOMe

MeO

MeOOMe

2. PCC/Al2O3

1:1 (separable)

MeLiMeO

MeOOMe

MeO

MeOOMe

Me

MeOH

MeO

MeOOMe

MeO

MeOOMe

Me

OHMe

(−)-schizandrin (−)-isoschizandrin1:8

+

Meyers, J. Am. Chem. Soc. 1990, 8090.

MeO

MeOOMe

CO2MeCO2H

1. H2, Rh(COD)2BF4, (R,R)-MOD-DIOP

2. NaBH4, CaCl2, KOH, EtOH 0°C MeO

MeO

MeO

O

H

O

LDA,

MeO

MeO

MeO

CHO

MeO

MeO

MeO

O

H

OMeO

MeO OMe

Ru(OCOF3)4, TFA, BF3•OEt2or FeCl3, TFA or Mn(acac)3, TFAor CoF3, TFA or Fe(ClO4)3, TFA

MeO

MeOOMe

O

H

OMeO

MeOOMe

1. DIBAL; Ac2O, pyr.2. Pd(PPh3)Cl2, HCO2NH4; NaOHMeO

MeOOMe

H

MeO

MeOOMe

OHOsO4, pyr;MsCl, pyr;NaH, THF

MeO

MeOOMe

H

MeO

MeOOMe

OMs

O

LiAlH44.3:1

Tanaka, J.O.C. 1995, 4339.Tanaka, Tetrahedron 1995, 11693.

This strategy used to synthesize:(+)-isoschizandrin, (+)-gomisin A, wuweizisu C, gomisin J, gomisin N, and γ-schizandrin

MeO

MeOOMe

MeO

MeOOMe

Me

Me

RuO2•2H2O (or Tl2O3), TFA, TFAA, BF3•OEt2

CH2Cl2, 20°CMeO

MeOOMe

MeO

MeOOMe

Me

Me

Me

Me

OMeOMeMeO

OMe

MeO

MeOMe

Me

MeOMeO

MeO

MeOOMe

OMe

+

1:1(all conditions)

a b

a beupodienonesRobin, Tetrahedron 1994, 1153.

(+)-schizandrin

Polyphenols

Lignans:- not to be confused with Lignin- biosynthesixed by the oxidative dimerzation of cinnamic alcohols- co-nutreints with dietary fiber: high in wheats, rye, flax, strawberries, broccoli- 0.3% wt/wt of flax seed- antioxidants and anti-inflamatory in human health- antibiotics for plant health- often inhibit topoisomerase

OOMe

OSO2Ph1. THF, 2. EtMgBr; 13. Ac2O

(one pot)

MgBr

OMe

OSO2Ph

OMe

OSO2Ph

AcO

AcO

Grubbs-Hoveyda II(5 mol%), ethylene

PhMe, 110°C

OMeOSO2Ph

AcOAcO

OMeOSO2Ph

KOHMeOH/THF

OMeOSO2Ph

HOHO

OMeOSO2Ph

1. CSA2. NaOH

O

HO OMe

HO OMe

O

HO OMe

HO OMe

+

d.r. 1:1

DMF, 50°C

O O

H

H

OH

OH

MeO

OMe

HO OMe

H

OHOMe

O O

H

H

OH

OH

MeO

OMe

HO OMe

H

OHOMe

H

O O

H

HH

OH

OH

MeO

OMeH

HO

MeO

MeOOH

ramonanin Bramonanin C

ramonanin A

- A:B:C 54:9:37 (45%, 24% rsm)- compared separated products with separated crude isolate: showed nat. prod. as racemates- synthesized ramonanin D with cis (2) and trans (3); <1 %

cis substrate

Sherburn, Angew. Chem. Int. Ed. 2015, 1795.

OH

OHOMe

C•

OH

OOMe

•C

HO

OMeO

O

OH

H

HO

OH

OMe

MeO

(−)-pinoresinol

2[O]

enzyme

Snyder, Nature 2011, 461.

Me

O

1

32 2:1

Baran Group Meeting5/26/16David Peters

OMeMeOMeO

OMe

MeO

MeO

OMeMeOMeO

BrH

OMe

R

Br

MeO OMe

1. n-BuLi (2 eq.)2. NBS (1 eq.)

R = BrR = H

2. 5 steps ([O], deprotection/reprotection, homologation. See above)

1.n-BuLi, Ar-CHO

OBnBnOBnO

HH

OBnBnO OBn

O

BnO

BnO

BrMg OBn1.

2. Pd/C, H2; Amberlite

OHHOHO

HH

OHOH

OHO

HO

HO

carasiphenol C

1. Br22. H2, Pd/C3. NBS

Br2

OMeMeOMeO

HH

OMe

Br

Br

MeO OMe

HOHO

HH

OHOH

OHO

HO

HO

OH

OH

OH

ampelopsin H

OHO

HO

HO

Polyphenols

OEt

O

O

OEtO

O

O O O

O O O

O O

OO

O

OO

OH O

O

OH OH O

O

O

KOH, MeOH

39%

(observed)

HO

OH OH

OHO

O

OHMe

pyridine or HCl/AcOH

OH O

OHO

OHHI, AcOH

OH O

HO

OHOH O

HO

OH CrO3, AcOH

emodin antrhone 94%O

70%

emodin 78% (2 steps) Murray, J. Am. Chem. Soc. 1976, 6065.

Li

NEt2

O

R

RO

O

R'OR'Li

R

RO

R'OR'

O

O

R

RO

R'OR'

OMe OMeOMe O

NEt2

O

++

a b

a b

OMe

MeOO

NEt2

sec-BuLi, TMEDA/Et2O;

OMe

OMeMe

O

OMe

MeOO

NEt2

OMe

OMeMe

OH

p-TsOHPhMe, Δ

OMe

OMeMe

O

O

OMe

MeO

63%

1. Pd/C, H2, AcOH2. TFAA, CH2Cl2

MeO

OMe

OMeMe

OMe

O

CrO3

AcOH/H2O

MeO

OMe

OMeMe

OMe

O

O

MeO

OH

OHMe

OH

O

O

BBr3CH2Cl2

-72°C−r.t.

HO

OH

OHMe

OH

O

Ocatenarin

29% overallerythroglaucin

22% overall

Pyr•HCl, 180°C

- route also provided islandicin, digitopurpone, cynodotin, and soranjidiol

Snieckus, J.O.C. 1979, 4802

O

OOMe

OMe

OH

1. Na2S2O4, NaOH; CH2O2. O23. SOCl2

O

OOMe

OMe

OH Cl

EtO

O O1.

2. NaOH3. BCl3

O

OOMe

OH

OH O

1. Na2S2O4; glyoxylic acid, THF Δ2. CH2N2

O

OOMe

OH

OH O

CO2Me

Triton B

O

OOMe

OH

OH

CO2Me

OH

1. AlCl32. Br2, hν3. NaOH

O

OOH

OH

OH

CO2Me

OH

ε-rhodomycinone Krohn, Liebigs Ann. Chem. 1986, 1506.Krohn, Eur. J. Chem. 2002, 1351.

O

OH O SO

O

OH

OH OSO

O

OH

OH O

H

O

R

OH

OH O OH2

RH

H2OOH

OH O

R

O

O OH

R

OH

OH O OH

RH

O

O OH

R

OH

Cold, O2

H3Oheat

O

O OH

Na2S2O4,NaOH;RCHO

THF/H2O

The Marschalk Reaction

OH

O

O

OHOH

CH3

4 stepsO

O

OiPrOiPr

OAc

1. Br2, NaOAc2. KOH3. MnO24. NaClO2, NaOAc, sulfamic acid5. DCC, DMAP,

OMe

MeO OH

O

O

OiPrOiPr

O

Br Br O

MeO

OMe

O

O

OiPrOiPr

Br O

O

Pd(OAc)2, PPh3,NaOPiv

MeO

OMe

O

O

OiPrOiPr

Br O

O

OMe

MeONB

O

H PhPh

Me

BH3, THF

O

O

OiPrOiPr

Br OH

OH

OMe

MeO

81%, 96% ee

PPh3, (CBrCl2)2;Pd/C, H2

O

O

OiPrOiPr

Br OHMe

OMe

MeO

O

O

OHOH

OHMe

OMe

HO

1. TiCl4; TiCl4, Ac2O

2. AlBr3

knipholoneBringmann, Angew. Chem. Int. Ed. 2001, 1687.

cavicularin

Polyphenolic Ethers- generally refers to compounds that contain an Ar-O-Ar linkage, but has also refered to compounds containing aryl ethers not included directly in other polyphenol classes- arise from various biosynthetic pathways and precursors- due to diversity, little coherent biological activity among group- cavicularin represents unique natural product: chirality derived completelty from atropisomerism

I

OH Cu(OAc)2, Et3N4A MS

CH2Cl2, r.t.

B(OH)2

OTBS I

O

OTBS

1. AD-mix-β t-BuOH/H2O

2. TsCl, Bu2SnO, Et3N; KOtBu, THF I

O

OTBS

O

+

I

O

OTBS

HOI

O

OTBS

HOMe MeLi, CuCN,

BF3•OEt2 Me3Al

B(OH)2

Pd(Ph3)4, CsFO

OTBS

HOMe

E:Z = 6.5:1

B(OH)2

Pd(Ph3)4, CsF(R)-rodgersinol(S)-rodgersinol (E only)

PdCl2(MeCN)2CH2Cl2

Suh, J.O.C. 2007, 666.

Anthraquinone Natural Products- polyketide-derived natural products- not all are deprived of nitrogen (tetracyclines)- often cytotoxic - topoisomerase I and II inihibitors- diversity in oxygenation, O-methylation, gylcosides, and cyclization regiochemsitry

O

O

OH

OHOMe

OH

O

OO

OH

MeH2N

Daunorubicin

85% ee

2Li+

LDA,

Ac

Me

Baran Group Meeting5/26/16

David Peters

PolyphenolsOO

HOOMe

K2CO3, DMF140°C

F

CHOOO

OOMe

OHC1. NaBH42. CBr4, PPh3

O

OOMe

Br H

HO HOO

DCC, DAMP,DMF

MeO CO2H

Br

O HOO

O

Br

OMe

Hermann catalyst,NaOAc

OOMe

PPh3BrO

OH1. PPh3, PhMe, Δ

2. PPTS, neopenyl glycol, PhMe, Δ

DMF, 130°C38%

O

H O

O

MeOYX

X,Y = OX = OH, Y = HDIBAL

K2CO3,18-crown-6,CH2Cl2, Δ

HOO

MeOOH

O

MeO

OOH1. PtO2, H2,

EtOH, Et3N2. NaI, NaOCl, NaOH, aq. MeOH

3. MeI, K2CO34. PPTS, aq. acetone

MeO

O

MeO

1. TiCl4, Mg, THF; arene2. TsNHNH2 NaOAc

I

O

O

MeO

O

MeO

I

1. (TMS)SiH, AIBN, PhMe, Δ2. BBr3cavicularin

(+ proto-deiodination)

OMOM

MOMO

F

S

OMe

OH

MeO1. TsNHNH2, NaHCO32. CsF, CaCO3, DMF, Δ

MeO

OOMe

MOMO

OMOM

OTolp

SpTolO

t-BuLi;

OS

pTol

O:HCMeO

OOMe

MOMO

OMOM

SO SnBr2,

phloroglucinol

MeO

OOMe

MOMO

O

SO CH:

CH:

H4 steps

>95% ee

MeO

OOMe

MOMO

H2N

1. BnNMe3ICl22. NaNO2, AcOH, Na2S2O3,THF, H2O

3. (TMS)SiH, AIBN, NaH2PO4, PhH4. BBr3

OH

HO

HO O

(−)-cavicularin

- antipode of natural product- established abs. configuration

BpinOiPr

OMe

Br

OMeBr

OTBS

Bpin

MeO

MeO

O

OMeO

OOH

PhO2S

MeO

OMe

O

O O

OHPhO2S

MeO

MeO

- OSPhOH- CO2

EtOAc, 4

45°C

MeO

O

OMeMeO

HO

N

HN

N

NH

S

CF3

CF3

MeO

OHHO

H2NO

HN

O

NH

CO2H

HONH2

H2NO

OH

HN

O

NH O

HO

HN

O

CO2H

RP-66453 Biphenomycin A

NHBoc

OHBrBr

O

Br

HNO

O

NHBoc

OBrBr

HO

Br

NHBoc

O

Br

Br

NH2

OHBr Br

NBnO

O

HOO

Br Br

NOH

O

HO

OBr

O

O NOH

OBr Br

NOH

O

HO

OBr

O

O NOH

H2O2, Soy bean peroxidase

aq. buffer pH=5/MeCN (3:1)r.t., 20 min

53%

CrCl2

H2O2, Soy bean peroxidase

aq. buffer pH=4/MeCN (9:1)r.t., 10 min

46%

CAN (2eq.)3 MeCN:1 H2O53%

1. DCC, HOBt, 52. NaHSO3, MeCN/H2O (pH 8)

HO

Br

NHBoc

O

Br

Br

OBr Br

NOH

O

NH

OHBr

NOH

HO2C

1. TFA2. DCC, HOBt (62%

Bastadin 6Shi, J.O.C. 1998, 4269.Kobayashi, Tetrahedron 2005, 7211.

Suzuki, Angew. Chem. Int. Ed. 2013, 10472

Harrowven, Angew. Chem. Int. Ed. 2005, 3899.

Beaudry, Angew. Chem. Int. Ed. 2014, 10500.

O

OOMOM

Cl

3 steps

(+)-cavicularin

Br

OBn

O

OMe

ONH

PO

OMeOMe

Cbz

tetramethyl-guanidine, THF

OMe

ONH

PO

OMeOMe

NH

Cbz

OHN

Boc

1. 1,3-propanediol, H2SO42. n-BuLi; B(OiPr)3; H2SO4

tetramethyl-guanidineTHF/H2O

Br

OBn

CbzHN CO2Me

(HO)2B

OBn

O

1. Pd(OAc)2, P(o-tolyl)3, K2CO3, PhMe2. LiOH, dioxane

BnO OBn

O

HO2C NHCbz

BnO OBn

HO2C NHCbz CO2MeHNO

BocHN

1. (S,S)-Et-DuPHOS-Rh H2 (80 bar), THF

2. ClCOOiBu, NMM pentafluorophenol

BnO OBn

NHCbz CO2MeHNO

NHBocHNCbz

O

C6F5O

1. HCl, dioxane; Et3N, THF (0.06 M) 76%2. TMSOTf, TFA, thioanisole

desoxy-Biphenomycin A

(biphenomycin A also prepared)

Schmidt, Synthesis 1992, 1025.Kreuger, Org. Process Res. Dev. 2011, 1348. CbzHN

Polyphenolic Peptides:- not included are non-interacting phenols- gernally isolated from fungi or bacteria- Non-ribosomally derived polypeptides- show a broad range of activities; antibacterial, antifungal, anti-parasitic, cytotoxic- built of tyrosine and modified aromatic amino acids - generally modified (halogenation/ P450 [O]) after NRPS module

HN

MeON

OH

MeO

HN CO2Me

HO

HNN

HArylomycin A

5

4

MeO

MeO

Baran Group Meeting5/26/16David Peters

O

O

MeON

O OH

Me

Polyphenols

F

F F

BnO

OBn

F

OBn

OBnTBSO

O

1. n-BuLi, 6; epoxide, BF3•OEt22. MEMCl, DIPEA, n-Bu4NI3. TBAF

HOOMEM

OBnOBn

BnO

F

OBn

DMF, 0°C

KHO

OMEM

OBn

OBn

OBn

BnO

1. TsOH•H2O phloroglucinol2. H2, Pd(OH)2/C THF/MeOH/H2O

(−)-epicatechin

OH

OBnOBn

4 steps

BnOH, NaH, NMP

Suzuki, Chem. Lett. 2006, 1006.Suzuki, Chem. Comm. 2012, 8425.

O

OBn

OBn

OBn

OBn

BnO

OAc

O

OBn

OBn

OBn

OBn

BnODDQ; AcOH

CH2Cl2

BF3•OEt2Nucleophile

O

OH

OBn

OBn

OBn

BnO

Nu

Suitable Nucleophiles: > 80% in most cases

OTBS

OiPr

OTBS

Ph

SnPh3

HN

MeO2CMe2SiN3 PhSH

OMe

MeO OMe

β-selective, except with permethoxy-phloroglucinol(α-selective)

BnO O

BnO

HAr

HR

α

β pseudo-chair T.S.

pseudo-boat T.S.

O

OAc

OBn

OBn

OBn

BnO

OAc

H

BF3•OEt27

complex mixture(oligomers/polymers)

BF3•OEt27 (1.2 eq)NBS O

OAc

OBn

OBn

OBn

BnO

OAc

BrO

OAc

OBn

OBn

OBn

BnOBr

O

OBn

OBn

OBn

OBn

BnO

70-90%> 84 d.r.

1. BF3•OEt2O

OAcOBn

OBn

OBn

BnO

SPh2. NIS, 7 O

OAc

OBn

OBn

OBn

BnOBr

O

OAc

OBn

OBn

OBn

BnO

O

OAc

OBn

OBn

OBn

BnO

procyanidin

- (Catechin)24 synthesized throuh itterative coupling MW = 17336 Da- Br- and Bn- removed sequentially due to HBr decomp.Suzuki, PNAS 2004, 12002.

Suzuki, Angew. Chem. Int. Ed. 2011, 4862.

Suzuki, Tet. Lett. 2002, 7753.Ohmori, The Chemical Record 2011, 252.

OH

HO OMe

OBr

DIPEA, CH2Cl2

OH

HO OMe

O1. MeOCHCl2, TiCl42. NaBH3CN, HCl THF, pH<4

OH

HO OMe

OMe

N I

(3 eq.)

OH

HO OMe

O

NMe2H

46%30% (41% rsm) 95%

8

8

PhMe, Δ

- Mallotojaponin C and 14 analogs prepared this way- >60% yield in all coupling reactions- all analogs tested against P. falciparum, T. brucei, and T. brucei farnesyl transferase

OH

HO OMe

O

OHHO

O

MeOMe

mallotojaponin B

Cariou and Dubois, Org. Lett. 2016, 708.

NH

CO2Me

OH

OCbz

1. NBS2. MeI, K2CO33. CF3CO3H4. HCl5. LiOH, THF/H2O

NH

CO2H

OMe

CbzOH

Br

EDCI, HOAtNH

CO2Me

FNO2

O

NHCbz

OMeOHBr

NH CO2Me

O

NHCbz

OMeOBr

K2CO3

DMSO, r.t.58%

NH

CO2Me

OMe

CbzOTBS

Br

P(o-tolyl)3, Pd2(dba)3,1M Na2CO3,PhMe/MeOH

85°C

NH

OMe

BocB(OH)2

OMOM

OMe OMe OTBS

CO2MeHNHNBoc Cbz

OMOM

OMe OMeOTBS

NH

MeO2CHN CO2H

Boc

ONH2

OMe OMeOTBS

CO2MeH2NNHO Boc

HNHO2C

1

2

Substrate

Substrate

EDCI/HOAt

EDCI/HOAt

HATU

HATU

DEPBT

DEPBT

PyBOP

PyBOP

DPPA

DPPA

FDPP

FDPP

1

1

26

26

29

29

0

0

-

-

0

0

64

64

2

2

53

53

30

30

14

14

19

19

-

-

18

18

cyclictriepetide

(see table)

% yield of various coupling approaches

Boger, Tet. Lett. 2002, 407.Boger, Tet. Lett. 2003, 4019.

Zhu, Angew. Chem. Int. Ed. 2003, 4238.

- total synthesis completed by Zhu, et al. in 2003. - performed Suzuki coupling last (40% yield)- produces thermally more stable S atropisomer; confirmed natural is R.

Flavanoids:

OHO

OHOH

OH

OH

Catechin

-- biosynthezised from cinnamic acid and 3 malonyl additions- almost all -OH patterns/cis and trans observed naturally- Flavanols: 3-OH- Flavonols: ketone at C4- present in tea, wine, fruits, cocoa (8x more in apple than wine per serving)- no supported beneficial health effects - Lawsuits and FDA cautionary warnings due to false claims

Toward RP-66453

For strategies in the synthesis of Vancomycin see Classics in Total Synthesis II.

Recently In Polyphenol Synthesis

O

OBn

OBn

OBn

OBn

BnO

6

7

I

NO2

Baran Group Meeting5/26/16David Peters

34

Lignin Degradation- 170 billion metric tons of lignocellulose in commercial stream per year (20 to 40% is lignin)- Can make up to 25% of dry plant mass- very little use for it - currently only 5% used (low-value materials)- high yielding, selective, low cost degredation process would be very attractive- has possibility of providing "renewable" chemical feedstocks- Challenges: relatively unreactive moities, enormous chemical diversity for a substance with one name

Polyphenols Baran Group Meeting5/26/16David Peters Baran Group Meeting

5/26/16

Survey of Top Procedures to Date

Method Reagents Temperature (°C)

Pressure(MPa)

MainProducts Yield (%)

Acid formic acid 10 wt%EtOH 81 wt% 380 25

methoxyphenolscatecholsphenols

2.91.52.0

Base 2 wt% NaOH 350 25syringol

hydroxy acetophenoneguiacol

4.11.61.1

Metal Cat. Pt/C (4 wt%), formic acid (16 wt%),

EtOH (80 wt%)350 - 4-propylguiacol

4-methylguiacol7.85.0

Ionic Liquid 9Mn(NO3)2

100 8.4 2,6-methoxyl-1,4-benzoquinone 11.5

SupercriticalFluid water 300 25

catecholsphenolcresols

287.512

N

N

Me

CF3SO3

9

Ji, J. Appl. Chem. 2014, 1.

Zhang, Chem. Rev. 2015, 11559.

R

R

O

O