cell division is not artificiall mdu ce welynloidj muliple chro ens Wc and the required dose is

borderline toxic. mosume groups. Typical ciomalth. In praclically every becn used to induice the
increased , sometimes by up lo 150 % alkaloid-containing plant where colchicine has os). Typical
cffects are larger fnowers, pollen gra a polyploidy, the alkaloid content has becn remarkedly .

Pharmacology

he history of colchicum indicates highly speeific folkloric use, uppression of gout. At a dose of i mg
every 2 hr for 8 hr, and a maintcnanco bse of 500 ug twice a day, colchicine is still regarded as the
mosi s the mosi c catnient. In 1889. it was reported that colchicinc had the ability to arre melaphasc.
Unil the 1930s and 1940s this startling obscrvation pi ile interest. But at that time two patential arcas
for the useo are explored, Onc was the possibility of using colchicinc as an a ent, and the second was
cvaluation of the genctic effects produc ants Although colchicine effectively regressed umors in dogs
and mi c, W

COLCHICUM

Colchicum is another of the ancient drugs of mankind. and the poisonous rature of the autmn crocus
wus probably known to the Greek physician Dioscurides. The name of the genus is laken from the
ancieat kingdom of Ceichis. where the drug was used in poisonous potions. Some of the other
hamus ander which the drug is known include hermodactyl. ephemcron, and surujan In Aribic
writings of the sixth and seventhı centurics the drug is rec ommendcd fer usc in the truit ment of
gout, Ibnt the small differenee between the therapcutic and toxic doses reduced its use in classical
and meuieval times Colchicum corm is derived from the plant Colchieum auumnule L. (Lil- iaccac)
native lo many parts of Europe, and commercial supplies come from P'olind. Czechoslavakia,
Yugoslavia, and llolland. Colchicine content is i the ringe n.25-0.6 % . The ripe seeds are an
alternative source of colchicine . where the conten ! rnay bc as high as 1.2 % . As well as 19 species
ol Colchicum, colchicine-lype alkaloids are also present in at least 10 other genera of the Liliaceae,
including Aulroeynbn, Gloriase, ind Merendera sp

CHEMISTRY

Colehicinc (796). beeause of the amidc functionality, is ncutral, and darkens on exposure to light. It
forms yellow crystals containing CHCl or C,H uf crystallization, and from water it gives a trihydrate.
The solubility charac- teristics of colchicine nre most unusual; it is soluble in water, alcohol, and
chloroform, but only slightly soluble in petroleum cther In the 1940s therc wns intense intercst in the
chemistry of the B and C rings of coichicine, particularly aller Dewar suggested that colchicinc con-
Gined a tropolone ring. Much of the chemistry of the tropolone system was studicd with colchicine.
Some of the early reviews of colchicine give the dethils of the carly chemical work andi only some of
tiransformutions will be

liscussed here. Dilute acid on colchicine (796) alfords the deme olchiceine 797; which can be
methylated to a mixiure of colchicinn sacolchicine 798 Treatment of colchiccinc with alkalinc
hydrogen peroxidc and reatment with phosphorus pentaxide, and then osmium tetroxide, 1o eive
wo substituted phcnanthrencs, 800 and 801. The structures of these wore onlirmed by synthesis oid
derivalive 799, which conld be further degraded by

and 798 for colchicine and it was not until an X-ray analysis w n 1952 that 796 was found to be
correct. Tliese data could not however distinguish between the structures colchicine has been the
roducts of UV irradiation. There arc three phutoisomers ol c which are known as n-. B. and y-
lumicolchicines, and v h Some of the most intensely studied chemistry of i(7). phutoisomers of
colehicine (796), oisomers of colchicine (796). have the structures 402, 803, and 804. A lcast two of
these may occur naturally. is s result of the cxposure of 796 to sunlight. These rearrange lie fist
cxamples of photochemical clectrocyclic reactions, n i substantial interest in the photochemistry of
troponoids ctions, and stimulated

2.sintesis

Synthesis bodwad c are at leasi six syntheses of colchicine (796) or close rela sone are of commercial
significance. That the groups obe s schonmoser, Van Tamelen, and Scotu have been involved in ths
imes indicates the i Ther sf colchicine at various L iportance and synthetic chak

leng: presented by this molecule. Clearly thesc syntheses caunot be pre- wsd in detail here. Van
Tamelen's and Eschemonoscr's syntheses each harve 805 or a close relative as an carly intermediatc,
and 806 as a late inter- mediate, but quite different routes have been used to introduce the tro-
gclone ring. The further clahortion of 806 to colchicine (796) involves mcthylaion, bromination with
N-bromosuccinimide. and d isplacement of

coLCuicINE the bromine with ammonia. The product was then and acctylated to give colchicine
(796). A new cfficient approach to a key intermediale in tho Anodie oxidation The additional carbon
of 807 gave lhc sprodienone N08 in 80 % yield . of the topolonc ring was introduced by a Simnions-
Simith reac by oxidation of the alcohol to afford 809. Treatment of thied acctic anhydride-sulfuric
aciel at room lempcrature then aforded amiloisocalchic.nc ( HW ) in 90 % yield ( Schc me 103 )
chicinc has been reported by T'ohinaga and co-workers slom compound with esicel-

is luc to Woodward and heme 104 The most clshoralc synthesis of colchicinc (796) is duc to
Woodwitre co-workers and at this time represented significant new chemistty isothiazole serics.
Some of the key intermediates are shown in Seheme 8.35.3 Biosynthesis siructure of colchicine (796)
has stimulated an exicnsive on of is biosynthesis by several groups. The principal invest group has
been that of Batersby, who has summarized the work in th novel struciure of colchieine (790) has
stinulated an extensive ta orf s area

101 Intermiedistes in the Wounlward synihesis of Ring A and carbons 5, 6. and 7 of colchicine are
derived from phenyl- alanine. The incorporation of (3. "C- and [ring.Cjtyrosines was specific nt C-12
and C-9 respectively, and the nitrogen of 796 was found to be derived froni the amino acid nitrogen
of lyrosine. However lyrosines wcre not specifically incorpurated, indicating that carbons
biosynthesis. and that the tropolone ring system lormed by expansion of the aromatic ring with the
benzylic carhon atom

ie key progressive steps in deternining the biosynthcsis of colchicine 96) were the isolation of
androcymbine (792) from Androcymbiun melcu oides, and the demonstration that il was well and
specifically incorporatcd lo 796. But whal of the dcrivation of this compound? Autumnaline (811)
incd from a Colehicu sp. and labeled specifically at C.9, was next dilicd and found to be an ellicient
precursor, thercby establishing the sequenec atitumnaline (811). O-mcthylandrocymbine (790), and
linally col evaluated chicine (796). Var also evalua substilution of colchicine. The steps belwce evd
but were poorly incorporated, suggesting that the particular tupaltern of autumnalinc (8I1) wiis
correct for the true precursor iously substituted phenethylisoquinoline precursors werc ted l study.
Variously substituted cinnamic acids were cvaluated s, bul excepl for cinnamic acid, none were
effective precursors te sugested that reduction of the double bond takes place oxylation of the
aromatic ring Present indications are that the own in Scheme 105 is probably correct to the point of
O-methylan c (790). Beyond this compound no intermediates are known, and phenylalanine (1) and
autumnaline (81) as precursors, and it has been anism for ring expansion to the tropolone is
conjecturc.