GENERAL SYNTHESIS

of alkaloids
The first steps in an alkaloid pathway are the most crucial, acting as the gateway to a new chemical space.
They are important metabolically, as they direct flux away from primary and into specialised metabolism. They
are significant chemically and enzymatically as they involve the formation of a new molecular structure. They
also play a foundational role in the evolution of the pathways.

There are four steps that are typically present in the first steps of complex alkaloid biosynthesis: (i)
accumulation of an amine precursor, (ii) accumulation of an aldehyde precursor, (iii) formation of an iminium
cation and (iv) a Mannich-like reaction (Scheme 1). This final step is often considered the “scaffold-forming”,
signature, or first-committed step into a pathway.

of
Biosynthesis Alkaloids

÷
Terpenoid Indole Alkaloids '
Other alkaloids:
Betalains

Benzylisoquinoline Alkaloids

Tropane Alakaloids Purine Alkaloids

Terpenoid Indole Alkaloid
Catharanthus roseus produces a wide range of terpenoid indole alkaloids (TIA). Many of them, such as vinblastine and vincristine, have significant
bioactivity. They are valuable chemotherapy drugs used in combination with other drugs to treat lymphoma and leukemia. The TIA biosynthetic
pathway has been investigated for many years, for scientific interest and for their potential in manufacturing applications, to fulfill the market
demand.
The medicinal plant Catharanthus roseus (L.) G. Don is of enormous pharmaceutical interest because it contains about 130 terpenoid indole
alkaloids (TIAs), some of which exhibit strong pharmacological activities. Jamalicine is an antihypertensive alkaloid. Vinblastine and vincristine, which
are bisindole alkaloids derived from coupling vindoline and catharanthine, were the first natural drugs used in cancer therapy and are still among the
most valuable agents used in the treatment of cancer, to date. All TIAs in C. roseus are derived from the central precursor strictosidine, which is a
fusion product of the shikimate pathway–derived tryptamine moiety and the plastidic nonmevalonate pathway–derived secologanin moiety. The
anticancer agents vinblastine and vincristine are produced exclusively by C. Roseus. More importantly, the TIA biosynthetic pathway is under strict
developmental and environmental control.
The biosynthetic pathway of C. roseus TIA has been investigated for many years, but the whole process is not completely understood. Overall,
three stages could be recognized in the biosynthesis of bisindole alkaloids:
(1) Formation of tryptamine and secologanin: Tryptamine is biosynthesized from the shikimate pathway and secologanin from the terpenoidalkaloids;
(2) Formation of monomeric alkaloids: Tryptamine and secologanin are combined to form strictosidine, which is further converted to monomeric
alkaloids like vindoline and catharanthine;
(3) Formation of bisindole alkaloids: Vinblastine and vincristine synthesize from the coupling of catharanthine and vindoline.

Figure 01. Biosynthesis of Catharanthus TIAs. Solid arrows indicate confirmed enzymatic conversions, whereas, the broken arrows
indicate unknown enzymatic conversions.
Abbreviations - G10H: geraniol 10-hydroxylase; TDC: Tryptophan decarboxylase; STR: strictosidine synthase; SGD: Strictosidine β-D-
glucosidase; T16H: 16-hydroxylase; OMT: O-methyltransferase; NMT: N-methyltransferase; D4H: Desacetoxyvindoline 4-hydroxylase;
DAT: Deacetylvindoline-4-O-acetyltransferase; AVLBS: Anhydrovinblastine synthase
Benzylisoquinoline Alkaloids
Benzylisoquinoline alkaloids, such as the analgesic compounds morphine and codeine, and the antibacterial
agents berberine, palmatine, and magnoflorine, are synthesized from tyrosine in the Papaveraceae,
Berberidaceae, Ranunculaceae, Magnoliaceae, and many other plant families. It is difficult to produce alkaloids
on a large scale under the strict control of secondary metabolism in plants, and they are too complex for
cost-effective chemical synthesis. The benzylisoquinoline alkaloid is made from tyrosine, which is converted
to (S)-reticuline via a multi-step enzymatic process. (S)-reticuline is then converted into berberine, coptisine,
palmatine, columbamine, and magnoflorine, among other proberberines
Tropane Alakaloids

Alkaloids possess quite complex structures, and the study of biosynthesis of these alkaloids has a long history. It is generally
thought that the tropane moiety arises from complex enzymatic processes involving phytochemical precursors. Incorporation of
radioactive labeled precursors has eased monitoring pathway on which the tropane derivatives are formed. Recent studies
making use of labeled ornithine (7), N-methylornithine (8), and 1,4-butanediamine (9) prepared biosynthetically, have firmly
established these precursors and representative examples of complex tropane alkaloids found in Solanaceae plant. After the
establishment of the origins of these precursors, attention has been directed mainly toward those alkaloids which, in addition
to the tropane residue, contain a 9- or 10-carbon atom unit such as 3α-senecioyloxy-6β-tropane. These units exist in many
variant forms, but certain recurrent features led to the belief that many variants have a common phytochemical precursors, for
instance, L-ornithine (7) is believed to be converted to diamine (9) by specific enzyme such as hyoscyamine-6β-hydroxylase
(H6H) and the former (9) is considered the precursor in biosynthesis of the bicyclic [3.2.1] skeleton of tropane alkaloids.

It has been found that oxidation of tropane ring can be achieved by molecular oxygen in the presence of ferrous ions. Also, it
has been found that these keto forms of tropane can be catalyzed by an enzyme called reductase [12]. For instance, the
biosynthesis pathway to tropane alkaloids, tropinone (10), is reduced by reductase to tropine (2).
Purine Alkaloids

In a narrow sense, purine alkaloid biosynthesis means caffeine formation from xanthosine. Less than four enzymes are
involved in the reactions. Typically, the most abundant purine alkaloid is caffeine. Other purine alkaloids found in some plant
species are intermediates in pathways associated with the biosynthesis and catabolism of caffeine.
The xanthine skeleton of purine alkaloids is derived from purinenucleotides which are converted intoxanthosine, the first
committedintermediate in the caffeine biosyn-thetic pathway. Xanthosine is syn-thesized from at least four different
sources of purine nucleotides: (i) denovo purine synthesis, (ii) the S-adenosyl-L-methionine (SAM) cycle,(iii) the adenylate
pool, and (iv) theguanylate pool (Figure 2). The available evidence indicates the most important routes are the production
of xanthosine from xanthosine 5′-monophosphate derived from denovo purine nucleotide biosynthesis, and from adenosine
released from S-Purine alkaloids, such as caffeine(1,3,7-trimethylxanthine) and theo-bromine (3,7-dimethylxanthine), are
significant dietary components occurring in coffee, tea and chocolate, as well as a variety of carbonated soft drinks,
including CocaCola and Red Bull. Caffeine was discovered in tea (Camellia sinensis) and coffee (Coffea arabica) in the
1820s. Compared with other alkaloids,such as nicotine, morphine andstrychnine, purine alkaloids are dis-tributed widely in
the PlantKingdom1. The presence of caffeine,albeit in relatively low amounts inmost instances, has been reported inabout
100 species in 13 orders of plants, mainly Dicotyledoneae. Caffeine is found in high concentrations (2.8% of the dry
weight) inyoung leaves of first-flush shoots oftea. The beans of most cultivars ofArabica coffee (Coffea arabica) con-tain
approximately 1% caffeine,whereas Robusta coffee (Coffeacanephora) contains approximately2%. The main purine alkaloid
in cacao (Theobroma cacao), from where cocoa is derived, istheobromine with seeds containing adenosyl-L-homocysteine
via the SAM cycle3. Feeding studies with 14C- or 15N-labelled precursors andthe tissue segments from variousorgans of
tea, coffee and cacao plantshave shown that the major route to theobromine and caffeine biosynthesis is xanthosine →7-
methylxantho-sine→7-methylxanthine→theobromine→caffeine.
Other alkaloids: Betalains

Betalains are synthesized from Tyrosine. Tyrosine is hydrolyzed to form L-DOPA. L-DOPA will be converted to Betalamic
acid which is the backbone of all Betalain compounds via DOPA-4,5- dioxygenase. Alternatively, L-DOPA is also oxidized
to cyclo-DOPA. Cyclo-DOPA and Betalamic acid condenses and form Betanidin. Betanidin is glucosylated to form Betanin
which is a simple Betacyanin (a betalain pigment). This synthesis usually occurs in the cytoplasm and endoplasmic
reticulum.
References :
Jianhua Z., Mingxuan W., Wei W.,  and Rongmin Y. Biosynthesis and Regulation of Terpenoid Indole
Alkaloids in Catharanthus roseus. Pharmacogn Rev. 2015 Jan-Jun; 9(17): 24–28. doi:
10.4103/0973-7847.156323PMCID: PMC4441158. PMID: 26009689
Alsamarrai, A. (2018, July 8). Synthesis of Tropane Derivatives. IntechOpen. Reviewed: December 7th, 2018
Published: November 8th, 2019. DOI: 10.5772/intechopen.83382. Retrieved from https://
www.intechopen.com/chapters/68581

Ashihara, Hiroshi & Yokota, Takao & Crozier, Alan. (2013). Biosynthesis and Catabolism of Purine Alkaloids.
Advances in Botanical Research. 68. 111-138. 10.1016/B978-0-12-408061-4.00004-3.

Crozier, Alan & Ashihara, Hiroshi. (2006). The cup that cheers. Caffeine biosynthesis: Biochemistry and
molecular biology. Biochemist. 2006. 23-26. 10.1042/BIO02805023.

"La Vie en Rose”’: Biosynthesis, Sources, and Applications of Betalain Pigments. (2018). Betalain
Biosynthesis, 3–6. https://www.cell.com/molecular-plant/pdf/S1674-2052(17)30307-6.pdf