Natural Product

Synthesis

Assignment:
Total Synthesis Of Corylidin

Submitted To:
Dr. Abbas Hassan

Submitted By:

Muhammad Usama Maqsood

Class:

M.Phil Chemistry (Organic) 1st Semester

Corylidin

Hafiz Usama (2019)

Introduction:
While walking the garden of vegetarian or shopping at grocery store looking to spice up the recipe the
one thing that you want in your bucket is parsley.
Parsley is found in central Mediterranean region like Italy, Greece, spain but it now has been
cultivated in the Asia. It is well known for its aroma and taste.
Parsley is a source of flavonoids and antioxidants especially luteolin, apigenin, folic acid, Vitamin K,
Vitamin C and Vitamin A.
Half a tablespoon of dried parsley contains about 6 ug of lycopene and 10.7 ug of Alpha carotene as
well as 82.9 ug of lutein + zeaxanthin and 80.7 ug of beta carotene.
Corylidin is isolated from the parsley plant. It Belongs to the glass off coumestrol. It has antibiotic
properties that inhibits the growth of Pseudomonoas putida, Escherichia coli and Rhizobium meloloti.

Importance:
Corylidin have coumestrol structure.
Coumestrol is a phytoestrogen, mimicking the biological activity of estrogens.
Phytoestrogens are able to pass through cell membranes due to their low molecular weight and stable
structure, and they are able to interact with the enzymes and receptors of cells.
Coumestrol binds to the ERα and ERβ with similar affinity to that of estradiol (94% and 185% of the
relative binding affinity of estradiol at the ERα and ERβ, respectively), although the estrogenic
activity of coumestrol at both receptors is much less than that of estradiol. In any case, coumestrol has
estrogenic activity that is 30 to 100 times greater than that of isoflavones.
Because coumestrol is an estrogen mimic, it is an endocrine disruptor with the potential to affect all
organ systems that are regulated hormonally via estrogens.
Reported Synthesis of Coumesterol:
Coumestans are an important class of naturally occurring tetracyclic
lactones that are characterized by the presence of a fused ring
system comprising coumarin and benzofuran constituent units.
These compounds have been isolated from a variety of plant species
belonging to botanical families such as the Leguminosae, Fabaceae,
and Asteraceae.
They have shown antioxidative, anticarcinogenic, phytoestrogenic,
antibacterial, antifungal, immunomodulatory, neuroprotective, anti-snake-venom, antiosteoporsis, and
antihepatotoxic effects.
Synthesis:
Retrosynthesis and strategy:

FGI

FGI
C-C

C-C

FGI

C-C

Lactamization
Synthesis:

NaH,
130oC, 1h

Coumarin Ring Formation

Pdo

Coupling Via Heck Reaction

H+
-H2O

Formation of Ether Linkage

Pdo

Coupling Via Heck Reaction

2 Mn(OAc)3

Formation of C-C Bond To Form Ring

 i. CH3Li (1 eq.)

ii. CH3TiCl3 (1 eq.)

Di-alkylation of Keto Group

As we don’t know which enantiomer is present in nature, so we have to go through different

routes to identify which enantiomer. So, we use 2 different methods.
In first step, we use OsO4 which produces diol with syn-configuration.

1.

OsO4
+

In second step, we use m-CBPA which produces diol with anti-configuration.

2. m-CPBA

Now, let evaluate the synthesis so that we come up with the best thoughts.
Evaluation:
First of all, we examine how the coumestrol is synthesized.
2-bromo-4-hydroxymandelic acid was successfully obtained through nucleophilic addition of
m-bromophenol to glyoxylic acid in aqueous NaOH. Subsequent reduction of 2-bromo-4-
hydroxymandelic acid in the presence of SnCl2/HCl afforded 2-bromo-4-
hydroxyphenylacetic acid. Perkin condensation between 2-bromo-4-hydroxyphenylacetic
acid and the commercially available o-hydroxybenzaldehydes in the presence of Ac2O/Et3N
smoothly gave acetylated 2′-bromo-3-arylcoumarins. Deacetylation in hot NaOH solution
followed by acidification with diluted HCl afforded 2′-bromo-3-arylcoumarins.
With the 2′-bromo-3-arylcoumarins in hand, all that remained was to facilitate a consecutive
Cu-catalyzed hydroxylation and aerobic oxidative cyclization to assemble the framework of
coumestans.
Although the established protocol that employed Cu(OAc)2/1,10-phen in DMSO/H2O (1:1)
under microwave conditions could facilitate the hydroxylation and aerobic oxidative coupling
processes, the 3-arylcoumarin did not undergo analogous transformation to give coumestrol.
Now we go through our paper synthesis of corylidin.
5-chloro-2-hydroxyacetophenone is obtained through chlorination of 2-
hydroxyacetophenone. Condensation of 5-chloro-2-hydroxyacetophenone with diethyl
carbonate in the presence of excess sodium hydride furnished 6-chloro-4-hydroxy-2H-
chromen-2-one. Coupling of 6-chloro-4-hydroxy-2H-chromen-2-one with 4-bromoresorcinol
in the presence of palladium produces 6-chloro-3-(2,4-dihydroxyphenyl)-4-hydroxy-2H-
chromen-2-one. Protonation further yields 2-chloro-9-hydroxy-6H-benzofuro[3,2-c]chromen-
6-one. Heck reaction affords (Z)-9-hydroxy-2-(3-oxobut-1-en-1-yl)-6H-benzofuro[3,2-
c]chromen-6-one. Coupling in the presence of manganese acetate encloses the ring.
Dialkylation of ketone produces 10-hydroxy-3,3-dimethyl-3,4-dihydro-7H-
benzo[g]benzofuro[3,2-c]chromen-7-one. Oxidation of double bond in the presence of OsO4
produces (1S,2R)-1,2,10-trihydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-7H-
benzo[g]benzofuro[3,2-c]chromen-7-one.
So, here is the comparison.
The reported synthesis of coumsterol is completely different from our synthesis of corylidin
because there is no attempted synthesis of corylidin. Synthesis of coumsterol requires 7 steps
and our synthesis of corylidin also undergoes through 7 steps but our compound is bigger
than that of coumsterol so this means that our synthesis is more efficient and corylidin has
two chiral centers whom configuration is still unknown. Let’s see if someone will attempt its
synthesis in the future.