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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