Hierarchy of management that covers different levels of management
Coumarin ; Synthesis and Medicinal properties
1. Dr. Mohd Kamil Hussain
Asst Professor
Department of Chemistry
COUMARIN: A POTENT SCAFOLDS WITH DIVERSE PHARMACOLOGICAL
PROPERTIES
Heterocyclic Chemistry Lecture-2
Govt Raza PG College Rampur
2. Coumarins are well known naturally occurring 2H-l-benzopyran-2-one derivatives.
Coumarin and their derivatives are important and useful compounds with diverse
pharmacological properties.
The Coumarin nucleus is a fundamental constituent of a number of natural and synthetic
products with different biological activities.
The coumarins have attracted intense interest because of their diverse biological and
pharmacological properties.
Coumarins occur as secondary metabolites in the seeds, roots and leaves of many plant
species, notably in high concentration in the tonka bean and thus the name comes from a
French word, coumarou, for the tonka bean.
Coumarin is also used as a in some dye lasers, and as a sensitizer in older photovoltaic
technologies
O OO O
1
2
3
45
6
7
8
4. CLASSIFICATION OF COUMARINS
COUMARINS
SIMPLE COUMARINS
Eg.coumarin itself and dihydrocoumarin
O O O O
HYDROXY COUMARINS
coumarins have substitutes a hydroxyl group in position 7
O OHO
umbelliferone
O OHO
aesculetine
O OHO
HO
fraxetine
PHUROCOUMARINS
Are formed as a result of furan ring and
coumarin condensation in 6,7 positions or 7,8.
O O
O O
O O
psoralen angelicin
PYRANOCOUMARINS
are result of condensation of coumarin with
2’2’-dimethylpyrane in positions 5,6); 6,7 or 7,8.
O OO
2’2’-dimethylxantyletin
visnadin
BENZOCOUMARINS
benzyl ring condensed with
coumarin in 3,4 positions
O O
3,4-benzocoumarin-
hydroxy-derivative
OH
OH
HO
HO
COUMARINS
CONTAINING
BENZOFURAN
RING
CONDENSED
WITH
COUMARIN IN
3,4 POSITIONS
O O
coumestrole
HO
O
OH
6. Acenocoumarol
anticoagulant that functions as a vitamin K antagonist
Novobiocin
act by an inhibition of the DNA GYRASE enzyme
involved in the cell division in bacteria
Batoprazine
antiaggressive agent, acts as a 5-HT1A and 5-HT1B receptor agonist
O O
OH
Br
Brodifacoum
highly lethal vitamin K antagonist anticoagulant poison. It is
typically used as a rodenticide pesticides
7. Carbocromen is a vasodilator Cloricromen is a platelet aggregation inhibitor
Coumaphos –ectoparasiticide & also used to
control varroa mites in honey bee colonies
Coumatetralyl is an anticoagulant
8. Dicoumarol is an anticoagulant that
functions as a vitamin K antagonist .It is
also used in biochemical experiments as
an inhibitor of reductases
Difenacoum has anticoagulant effects
and is used as a rodenticide
Ensaculin -potential treatment for dementia.
It acts on a number of receptor systems, being
both a weak NMDA antagonist and a 5HT1A
agonist
Ethyl biscoumacetate is a vitamin K
antagonist
9. Hymecromone
(4-methylumbelliferone) is a drug used
in bile therapy. It is used as choleretic
and antispasmodic drugs
Warfarin decrease blood coagulation by
inhibiting vitamin K epoxide reductase .it is an
anticoagulant normally used in the prevention
of thrombosis and thromboembolism.
Tioclomarol is a vitamin K antagonistPhenprocoumon –inhibits vitamin K
epoxide reductase
10. Synthesis of Coumarins
Perkin reaction:
Perkin reaction , involves heating an O-hydroxybenzaldehyde with acetic
anhydride in the presence of sodium acetate at a high temperature to afford a
trans-cinnamic acid, followed by irradiation or treatment with iodine and then
cyclization to afford the . This reaction is also carried out by reacting acetic
anhydride and salicylaldehyde in the presence of trimethylamine as the base
catalyst.
CHO
OH
R
COOH
OH
R
O O
R
Ac2O, AcONa I2
irradiation
1.Ac2O, AcONa 2.H3O+
O O
R
Ac
2 O
Et3 N
O O
R
Org. React., 1942, 1, 210.
Vogel’s Textbook of Practical Organic Chemistry, Wiley, Pearson Education Ltd: UK, 1989
.
11. Kanojia et al. led to the synthesis of 4-methyl-3,7-substituted coumarins as the
key intermediates, via base-catalyzed Perkin condensation reaction in moderate
to good yield.These were furnished by reacting a mixture of 2-
hydroxyacetophenones and 2,4-dimethoxyphenylacetic acid in the presence of
triethylamine in refluxing acetic anhydride.
O
OHO
+
OHO
O
O O OO
O O
O OAcO
AcO OAc
O OAcO
AcO OAcBr
O
O
O
OH
HO
Et3N
Ac2O/refux
1.pyridine, HCl
2.Ac2O/pyridine
NBS/benzoyl peroxide, CCl4
BBr3/DCM
NaOH/H+
2003,WO2003053977, pp.1-306.
Tetrahedron Lett., 2004, 45, 5837.
12. Various coumarins have been prepared via Knoevenagel condensation reaction by
reacting 2-hydroxybenzaldehydes with activated methylene com- pounds in the
presence of an amine (e.g piperidine) .
Knoevenagel condensation reaction
CHO
OH
R
R1
R2
+
O O
R1
R
amine
R1
= CO2H, CO2Et, CONH2, CN
R2
= CO2H, CO2Et,
Org. React., 1967, 15, 204.
Two different mechanisms have been proposed for Knoevenagel reaction
1) formation of an imine or iminium salt, followed by reaction with the enolate of the active
methylene compound, then elimination of the amine and intramolecular ring closure to give the
coumarin
ii) attack by the carbanion formed from the deprotonation of the active methylene compound by the
amine, on the carbonyl group to give the intermediate follow by proton transfer, and ring-closure via
acyl substitution, and finally dehydration to give the coumarin
13. Ionic Liquid as Catalyst and Reaction Medium for Knoevenagel Condensations
The basic ionic liquid 1-butyl-3-methylimidazolium hydroxide, [bmim]OH,
efficiently catalyzes the Knoevenagel condensation of various aliphatic and
aromatic aldehydes and ketones with active methylenes at room
temperature without requirement of any organic solvent
CHO
OH
EWG
CO2Et
0.2 eq. [bmim]OH
r.t, 15-25 min O
EWG
OR R
EWG: COMe, CO2Et
general applicability to a large number of substrates appx.33
mild reaction conditions (room temperature),
clean and fast (7– 40 min) reaction
high isolated yields of products, and
reusability of catalyst and cost-effectiveness
Eur. J. Org. Chem., 2006, 3767-3770
14. The Pechmann condensation is a synthesis of coumarins, starting from a phenol and a
carboxylic acid or ester containing a β-carbonyl group . The condensation is performed
under acidic conditions. The mechanism involves an esterification/transesterification
followed by attack of the activated carbonyl ortho to the oxygen to generate the new ring.
The final step is a dehydration, as seen following an aldol condensation.
With highly activated phenols such as resorcinol, the reaction can be performed under much milder conditions
Tetrahedron Lett., 2001, 42, 9285-9287Heterocyclic Chemistry, 4th edition, Blackwell Science, Oxford, UK, 2000
16. Regioselective one step synthesis of naturally occurring prenyl
coumarin balsamiferone -A cascade Wittig reaction-double Claisen &
Cope rearrangements has been employed .
OO
CHO
Ph3P=C C
O
O
R
+ OO
R
O
Et
O
O O
R
HO
R = Allyl
R = Prenyl (Balsamiferone)
R = Benzyl
PhOPh, reflux, 4 h
O OHO
Balsamiferone
Tetrahedron Lett.: 50; 2009; 6488–6490, ARKIVOC 2011 (ix) 68-76
18. Some recent development in the synthesis of substituted coumarins
The employment of hydrophobic ionic liquids dramatically enhanced the
activity of metal triflates in Friedel-Crafts alkenylations of aromatic
compounds with various alkyl- and aryl-substituted alkynes.
Angew. Chem., 2004, 116, 6309-6311
O O
R'
R
O O
R'
R
0.1 eq. Hf(OTf)4
methylcycohexane/[bmin][SBF6}
Synthesis of 4-phenylcoumarins by intramolecular Friedel-Crafts
alkenylations
O O O O
R
R=CH3, Ph
19. Arylpropionic acid methyl esters having a MOM-protected hydroxy group at the
ortho position underwent hydroarylation with various arylboronic acids in MeOH
at ambient temperature in the presence of a catalytic amount of CuOAc, resulting
in the formation of 4-arylcoumarins in high yields after the acidic workup.
Org. Lett., 2008, 10, 5513-5516
Synthesis of 4-Arylcoumarins via Cu-Catalyzed Hydroarylation with
Arylboronic Acids
O O
Ar
R
OMOM
CO2Me
R
Ar B(OH)2
3 eq.
1) 2-10 mol% CuOAc
MeOH, 280C, 6h
2) MeOH / 6 M aq. HCl
(5:4), reflux, 3 h
R= H, OH, OMe
Ar= p-MeC6H4, m-MeC6H4, p-OHCC6H4, m-O2NC6H4
20. A facile, convenient, efficient, and high yielding synthesis of a
combinatorial library of 3-aroylcoumarins has been developed by the
condensation of easily available aroylketene dithioacetals and 2-
hydroxybenzaldehydes in the presence of catalytic amount of piperidine in
THF reflux.
J. Org. Chem., 2006, 71, 8715-8723
Facile Synthesis of a Combinatorial Library of 3-Aroylcoumarins
R CHO
OH
Ar
O
SMeMeS O
O
Ar
O
R0.1eq.
piperidine
THF, 800
C
12-14 h
Fe
O
SMe
SMe Fe
O
O
O
R
R CHO
OH
R CHO
OH
Ar
O
SMeMeS O
O
Ar
R
O
H
SMe
SMe
BH+
O
O
R
SMe
SMe
OH
Ar
O
O
O
R
Ar
+B -B B
-2MeSH
21. Multicomponent synthesis of substituted coumarins
CHO
OH
R2
OR
R1
CO2Me
CO2Me O
R
R1
R2
O
CO2Me
H-NR3
The overall transformation consists of six reactions: Knoevenagel condensation,
transesterification, enamine formation, an inverse electron demand Diels_Alder
(IEDDA) reaction, 1,2-elimination, and transfer hydrogenation.
Org. Lett., 2012, 14 , 310–313
CHO
OH
MeO2C CO2Me
O O
CO2Me
N
O O
CO2Me
22. Expedient Synthesis of Highly Substituted Fused
Heterocoumarins
Org. Lett., 2004, 6 (2), 277–279
N
N O
O
Cl
N
N O O
O
Cl
B(OH)2
TfO
OO
N
N O
O
Cl
CO2Et
i ii
Reagents and conditions: (i) Pd(TPP)4 (5 mol %) in toluene/ethanol/Na2CO3 (2 M in water)
3/1/1, reflux 2 h. (ii) BBr3 (1 M in CH2Cl2; 5 equiv), CH2Cl2, reflux
Y
X O O
R1
R3
R2
R3
n
R1-4: H, OH, NH2
X, Y = C or N
n= 0, 1 or 2
Synthesis involve two major steps: cross coupling and lactonisation.
Efficient access to highly functionalized fused coumarins, coumarino-pyridines,
coumarino-pyrimidines.
23. Synthesis of Coumarins via Palladium-Catalyzed Carbonylative
Annulation of Internal Alkynes by o-Iodophenols
I
OH
R R CO
O
cat. Pd(0)
R
R
O
Mechanism involve the following steps:
(1) reduction of Pd(Ac)2 to the actual Pd(0) catalyst
(2) oxidative insertion of o-iodophenol Pd(0)
(3) insertion of internal alkyne
(4) insertion of CO
(5) attack of phenolic oxygen on the resulting acyl-palladium complex leading to
formation of coumarin and regeneration Pd(0) catalyst.
Org. Lett., 2000, 2 (23), 3643–3646
24. Synthetic Approaches and Biological Activities of
4-Hydroxycoumarin Derivatives
O
OH
O O
OH
O
O
Warfarin
O
OH
O
Coumatetralyl
O
OH
O O
CF3Flucoumafen
S
OH
O O
CF3Difethialone
4-Hydroxycoumarin
Molecules 2009, 14, 4790-4803
25. O
OH
(EtO)2C=O
NaOEt
OH
HO OEt O
OH
O
O
O
OH
O
O
B-
Condensation of ortho-hydroxyacetophenone with ethyl carbonate to give the -
ketoester as the intermediate shown in the enol form. Attack of the phenoxide on
the ester grouping leads to cyclization and formation of the coumarin. Conjugate
addition of the anion from that product to methyl styryl ketone gives the
corresponding Michael adduct.
O
OH
O
O
O O
O
HO
Acyclic tautomer and cyclic hemiketal tautomer of Warfarin
X-ray crystallographic studies of warfarin show that it exists in tautomeric form, as
the cyclic hemiketal, which is formed from the 4-hydroxycoumadin and the ketone in
the 3-position substituent.
Synthesis of Warfarin
26. Synthesis of flocoumafen
Cl
O
MeO
O
OMe
OMe
OH
EtO2C
O
OMe
OH
OMe
a b
c d e
O O
OH
OH
OMe
f
O O
OH
O
CF3
g
OH
O O
OH
Reagents and conditions: (a) AlCl3, CH2Cl2, –10°C, 16 h; (b) Zinc, I2, BrCH2CO2Et, benzene, reflux, 1 h; (c) (Et)3SiH, TFA,
BF3EtO2, CH2Cl2, reflux, 8 h; KOH/H2O, reflux, 8 h; and then PPA, 80 °C, 1 h; (d) NaBH4, MeOH, rt, 2 h; (e) 4-
hydroxcoumarin, p-TsOH, 80 °C, 3 h; (f) HBr, AcOH, reflux, 6 h; (g) 3-(trifluoromethyl)benzyl bromide, sodium hydride,
THF, 0 °C, 1 h
Molecules 2009, 14, 4790-4803
27. Synthesis of diphenacoum and brodifacoum
CHOR PPh3
+
CH2CO2EtCl-
a
R
EtO2C
R= H, Br
b
R
EtO2C
c
R
O
R
OH
O
OH
O O
OH
O
R
R= H. Diphenacoum
R= Br, brodifecoum
d
e
Reagents and conditions: (a) NaOMe, DMF; (b) BnCu-TMEDA, TMSCl, THF, –78 °C to 30°C; (c) AlCl3, toluene, 90 °C; (d) NaBH4,
EtOH/THF, rt, then PBr3, dichloromethane, 0 °C; (e) HCl(g), 160 °C
Molecules 2009, 14, 4790-4803
28. “Tanshen”, the rhizome of Salvia miltiorrhiza Bunge,has been used in traditional Chinese medicine
(TCM) for the treatment of coronary heart diseases, particularly angina pectoris and myocardial
infarction.
Numerous tanshinones were isolated from S. miltiorrhiza, and diverse medicinal actions were
reported, including antitumor, antioxidant, antimicrobial, antiplatelet aggregation,and antiallergic
activities.
Neo-tanshinlactone with strong and selective anti-breast cancer activity. This compound might be a
useful lead for developing novel and promising anti-breast cancer drug candidates
.
Salvia miltiorrhiza
Neo-tanshinlactone
J. Med. Chem. 2004, 47, 5816-5819
29. O
OMe
a
85%
HO
OMe
R
b
60%
OMe
R
c
95%
OH
R
O
O
OH
O
O
O
e
d
R R
Reagents and conditions: (a) RMgBr, ZnCl2, THF, rt; (b) Pd/C, triglyme, reflux; (c) BBr3,CH2Cl2; (d) malonic
acid,PPA(85% P2O5), 75ºC, 3 h; (e) chloroacetone, HOAc/NH4OAc, toluene/EtOH, reflux, 24 h; (f) NBS, dibenzoyl
peroxide, toluene, reflux; (g) BBr3, CH2Cl2, reflux, 3 h; (h) Ac2O, Et3N, 10 h; (i) 2-chloro-N,N-dimethylethanamine,
K2CO3, acetone, 12 h.
R= Me,Et, iPr, Pr, OMe, OEt,
Synthesis of neo-tanshinlactone and its analogues
30. SP500263 A potent anti-estrogen
Reagents and conditions: (a) POCl3, ZnCl2, 1,2-dichloroethane 70ºC, 4 h; or BF3-OEt2, chlorobenzene, 70ºC, 2 h, 40–60%; (b)
benzoic acid or phenylacetic acid, carbonyl diimidazole, K2CO3, DMAP, DMF, 85ºC, 4 h, 60–70%; (c)) 2-chloroethylpiperidine
hydrochloride, K2CO3, DMF, 5 h, 80ºC, 75%; (f) 30% HBr in acetic acid, 90ºC, 8 h, 60% or ethanethiol, AlBr3, CH2Cl2, room
temperature, 2 h, 75%.
OHH3CO
OH
HO
O
OH
O
OHH3CO
HO
O
O OH3CO
HO
O OH3CO
O
N
O OHO
O
N
(a)
(b)
c
(d)
Bioorg. & Med. Chem. Lett. 2004, 14 3407–3410
SP500263 is a potent anti-estrogen,and more effective then Tamoxifen &
Raloxifene
Less toxic then TAM & RAL, Currently under clinical investigation for the
treatment and prevention of Breast Cancer
O OHO
O
N
31. Anti-breast cancer agent SS5020, a novel coumarin antiestrogen
O OH3CO
HOOC
SS5020
SS5020 is novel analogue of SP500263 lacking genotoxic and estrogenic actions, could
be a safer and stronger antiestrogen alternative to TAM and RAL for breast cancer
therapy and prevention.
the results compared with those for TAM, TOR, RAL or SP500263,compounds all being
used clinically or being considered for clinical trials
Int. J. Cancer: 128, 2011,974–982
33. Coumestans
Coumestan is an organic compound that is a derivative of coumarin. Coumestan forms the central core of
a variety of natural compounds known collectively as coumestans. Coumestans, including coumestrol, a
phytoestrogen, are found in a variety of plants. Food sources high in coumestans include split peas, pinto
beans, lima beans, and especially alfalfa and clover sprouts.
Coumestrol.
Wedelolactone
Plicadin
alfalfa
Psoralea plicata
Eclipta alba
34. Combined Directed ortho and Remote Metalation-Suzuki Cross-Coupling Strategies.
Efficient Synthesis of Heteroaryl-Fused Coumarins from Biaryl O-Carbamates
J. Org. Chem. 2009, 74, 4094–4103
35. Efficient Synthesis of Coumarins derivatives via Suzuki Cross-Coupling Strategies
R2
R1 OCONEt2
B(OH)2
Z
I+
R2
R1 OCONEt2
Z
R2
R1 O
Z
O
R1 = H, OMe
R2
= OMe
Z = S, O
Z = O=Coumastans
Z= S = Thiocoumastans
79-93%
Pd(PPh3)4
Toluene/reflux
1.LDA/THF
2.AcOH-reflux
Synthesis of Coumastans and Thiocoumastans:
Suzuki-Miyaura cross-coupling aryl O-carbamoyl ortho-boronic acids with
benzofuran and Benzothiophene iodides
Directed Remote Metalation (DReM) to Heteroaryl-Fused Benzopyranones
from Biaryl O-Carbamates.
J. Org. Chem. 2009, 74, 4094–4103
36. Synthesis of Isocoumastans and Isothiocoumastans Isoazacoumastans
OCONEt2
B(OH)2
Z
+
OCONEt2
O
O
O
Z = S, O, N-Boc
Z = O= Isocoumastane
Z= S = Isithiocoumasten
Z= NBoc =Isoazacoumastans
Pd(PPh3)4
Toluene/reflux
1.LDA/THF
2.AcOH-reflux
BrO O
Z
Z
Suzuki-Miyaura cross-coupling & Directed Remote Metalation
J. Org. Chem. 2009, 74, 4094–4103
O
O
O
O
O
O
O
S
O
O
O
N
Boc
Isocoumastane Isothiocoumastans Isoazacoumastans
37. Synthesis of furo & thieno coumarins
+
Z = S, O,
Z = O= furo[2,3-c] coumarin
Z= S = thieno[2,3-c]coumarin
Pd(PPh3)4
Toluene/reflux
1.LDA/THF
2.AcOH-reflux
OCONEt2
R2
R1 X Z
Y
O
R1
R2
N
O
Et
Et
Z
O Z
O
R2
R1
O
R1
R2
N
O
Et
Et
Z
Z = S
R1
R2
1.LDA/THF/TMSCl
2.AcOH-reflux
O
S
O
TMS R1
R2
O
S
O
TBAF/THF
thieno[3,2-c]coumarin
X/Y = Br,B(OH)2
J. Org. Chem. 2009, 74, 4094–4103
38. Psoralidin
Psoralidin was first isolated from seeds of Psoralea Corylifolia 1948
Psoralea corylifolia (Babchi) is an important plant in the Indian Ayurveda and Tamil Siddha
systems of medicine, and also Chinese medicine.
It shows inhibitory activities against protein tyrosine phosphatase 1B, which plays a major
role in the negative regulation of insulin signaling
Psoralidin also has great potential as an anticancer agent, showing cytotoxic effects
on gastric (SNU-1 and SNU-16), colon (HT-29), and breast (MCF-7) cancer cell lines
J. Org. Chem. 74, 2009, 2750-2754
39. Total Synthesis of Psoralidin, an Anticancer Natural Product
HO OH OO
BrBr
OO
Cl
O
O O
OEt
O+
O
O O
O O
O
O
O
O
O
HO
OH
Psoralidin
1.Br2, CHCl3 2.K2CO3 ,MeI iPrMgCl/THF Br3. 4. n-BuLi,CO2 5.Oxalyl chlorude
1
2
3, 4
5
6
6.nBuLi,iPrNH2, THF
7.BBr3 DCM, Then reflux
7
J. Org. Chem. 74, 2009, 2750-2754
40. O
OH
Me
H
OHOMe
O
OMe
R OH
OH
Gilvocarcin V, R = vinyl
Gilvocarcin M, R = methyl
O
OHOMe
O
OMe
O
OH
AcO
NMe2
Ravdomycin
O
OHOMe
O
OMe
R
O
OH
HO
Me
Chrysomycin A, R = vinyl
Chrysomycin B, R = methyl
O
OHOMe
O
OMe
R
Defucogilvocarcin V, R = vinyl
Defucogilvocarcin M, R = methyl
O
O
OMe
O
O
OMe
Arnottin I
J. Org. Chem. 2006, 71, 8312-8315
Structures of Gilvocarcins-class of Antibiotics
Isolated from Streptomyces species
It is thought to act as an inhibitor of the catalytic activity of human topoisomerase II.
The metabolite displays potent antibacterial, antifungal, antiviral and antitumor
activity.
42. Anti-HIV-1 Active (+)-Inophyllum B and (+)-Calanolide A
O O
Pr
O
OHMe
Me
(+)-calanolide A (-OH) [(+)]
(+)-calanolide A (a-OH)
Me Me
O O
Ph
O
OHMe
Me
O
MeMe
O
Ph
O
OHMe
Me
O
MeMe
(+)-inophyllum B (+)-inophyllum P
Isolated from Calophyllum lanigerum
Inophyllum B isolated from Calophyllum inophyllum
It is a potent non-nucleoside inhibitor of reverse transcriptase from human
immunodeficiency virus type 1 (HIV-1 RT)
Calanolide A is undergoing phase IB clinical trials
43. Total synthesis of Calanolide
OH
HO OH O
OMe
MeO O
Pr
O
OMe
HO O
Pr
OMe
Me
O
OMe
O
Pr
O
OMe
Me
O
OH
O
Pr
O
OMe
Me
O O
Pr
O
Me
Me
Reagents and conditions: (a)PrCOCl, AlCl3, DCM then quinched by 4N HCl; (65%). (b) Ph3P=CHCO2Et in
PhNEt2, 215°C, 30 min (72%); (c) K2CO3, MeOH; (85%); (d) tigloyl chloride, SnCl4 in CH2Cl2, 78°C,
7 days (72%); (e) (-)-quinine/PhCl, 20 °C, 25 hB[cis-(+)-9 (67%, 98% ee); trans-(-)-9 (21%, 39% ee)]; (f)
MgI2/ K2CO3/PhH, reflux, 15 days (77%); (g) senecioaldehyde, PhB(OH)3, EtCO2H/PhMe, reflux, 1.5 h
[trans-(+)-13 (61%, 91% ee), cis-(+)- 13 (23%, 84% ee)]; (h) LiAlH4/tBuOH/THF, -20 °C, ca. 3 min [(+)-
calanolide A [(+)-1] (88%); (+)-calanolide B (21) (12%)].
OH
OH OH
O
O
OH
HO O
Pr
(a)
(b) (c)
(d) (e) (f)
(g) (h)
cis-(+) : B-Me
trans-(-) : a-Me
on cis-(+)
trans-(+) :a-Me
cis-(+) :b-Me, (+) calanolideD
O
Me Me
O
O O
Pr
O
OHMe
Me
(+)-calanolide A (b-OH) [(+)]
(+)-calanolide B (a-OH)
O
Me Me
44. Total synthesis of Inophyllum
OH
HO OH
O
OMe
HO O
Ph
OMe
Me
O
OMe
O
Ph
O
OMe
Me
O
OMe
O
Ph
O
OMe
Me
O
OMe
MeO O
Ph
(a) (b,c) (d)
trans-(-)cis-(+)
O
OH
O
Ph
O
OMe
Me
cis
O
OH
O
Ph
O
OMe
Me
trans A
O
OMe
O
Ph
O
OMe
Me
trans-(+)
enantiomer
Reagents and conditions: (a) (i) ethyl 3-phenyl-3-oxopropionate/ TfOH, rt, 18 h, (ii) Me2SO4 /K2CO3/
acetone, rt, 16 h (71% in 2 steps); (b) tigloyl chloride/SnCl4/CH2Cl2, 8 °C, 3 days (67%); (c) MgI2 /K2CO3
PhH, reflux, 4 h (84%).(d). (-)-quinine/PhCl, 4 °C, 33 h [cis-(+)-17 (70%, 97% ee), trans-(-)-17;
(e)MgI2/K2CO3/ PhH, reflux, 14 days: [cis-(37%), trans-18 (42%)]; (f)CH2N2 (62%, 96% ee on trans-; 64%,
95% ee on cis).
(e)
(f)
(f)
J. Org. Chem. 2004, 69, 2760-2767
45. O
OH
O
Ph
O
OMe
Me
trans-(-)-A
O O
Ph
O
OMe
Me
O
MeMe
O O
Ph
O
OMe
Me
O
MeMe
trans-(+) cis-(+)
O O
Ph
O
OHMe
Me
O
MeMe
O
Ph
O
OHMe
Me
O
MeMe
(a)
(b)
(+)-inophyllum B (+)-inophyllum P
Reagents and conditions: (a) senecioaldehyde, PhB(OH)3, EtCO2H/PhMe, reflux, 2 h [trans-
(+): 51% (90% ee), cis-(+)- : 23% (84% ee) from trans- (93% ee)]; (b) LiAlH4/t-BuOH/THF,-
20 °C, ca. 3 min [(+)-inophyllum B [(+)]: 91%, (+)-inophyllum P : 9%].
J. Org. Chem. 2004, 69, 2760-2767
Editor's Notes
Vincamine is a peripheral vasodilator that increases blood flow to the brain (sold under the trademark Oxybral SR. it is an indol alkaloid found in the leaves of Vinca minor. Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms. The antihypertensive actions of reserpine are a result of its ability to deplete catecholamines (among other monoamine neurotransmitters) from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral resistance. Reserpine irreversibly blocks the vesicular monoamine transporter (VMAT). This normally transports free norepinephrine, serotonin, and dopamine from the cytoplasm of the presynaptic nerve terminal into storage vesicles for subsequent release into the synaptic cleft ("exocytosis"); unprotected neurotransmitters are metabolized by MAO (as well as by COMT) in the cytoplasm and therefore never reach the synapse.
It could take days to weeks by the body to replenish the depleted VMAT and hence reserpine's effects are long. Pindolol is a nonselective beta blocker with partial beta-adrenergic receptor agonist activity. It possesses ISA (Intrinsic Sympathomimetic Activity
Yohimbine is an alkaloid with stimulant and aphrodisiac effects found naturally in Pausinystalia yohimbe (Yohimbe)Yohimbine has been used as both an over-the-counter dietary supplement in herbal extract form and prescription medicine in pure form for the treatment of sexual dysfunction.
Dolasetron is used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center in the medulla oblongata.
Promanullin is a cyclic nonribosomal peptide. It is an amatoxin, all of which are found in several members of the Amanita genus of mushrooms.Mitragynine itself acts primarily via μ-opioid receptors, although its oxidation product mitragynine-pseudoindoxyl, which is likely to be a major component of kratom that has been aged or stored for extended periods, acts as a fairly selective δ-opioid agonist with little affinity for μ or κ receptorsDelavirdine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) marketed by ViiV Healthcare. It is used as part of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus (HIV) type 1.