Synthesis of Amaryllidaceae Alkaloids

The Amaryllidaceae plant family comprises of approximately 75 genera, and so far more than 1100 species have been identified. Members of this highly diverse plant family are endemic in most tropic and temperate areas of the world, and several Amaryllidaceae species have been employed in traditional herbal folk medicine to cure serious health conditions and various diseases [169], 

Amaryllidaceae species have been identified as rich source of structurally intriguing tyrosine-derived secondary metabolites. The great structural diversity of Amaryllidaceae alkaloids is rationalized by the different possibilities to connect the aromatic portions of 4 -0-methylnorbelladine as outlined in the biosynthetic section of this chapter. 

This section is devoted to the discussion of selected syntheses of biologically intriguing Amaryllidaceae constituents—a more comprehensive overview of Amaryllidaceae alkaloids can be obtained from recent review articles [44, 45, 48, 170]. Narciclasine (55) is one of the major secondary metabolites of various Narcissus species. 

Reag its and conditions (a) anodic oxidation, HBF4, MeCN, 0.92-1.00 V, 20 min, 80% (b) NaBH4 (c) CH2I2. Zn/Cu couple (d) Jones oxidation, 42% (e) AC2O, H2SO4,90%. 

SCHEME 12.48 Key steps in Tobinaga s and Evans synthesis of colchicine derivatives. 

---

Martin effected the synthesis of several 3,5-diarylated indoles by a tandem Stille-Suzuki sequence [131]. The latter reaction involves exposure of 3-(3-pyridyl)-5-bromo-l-(4-toluenesulfonyl)indole with arylboronic acids (aryl = 3-thienyl, 2-furyl, phenyl) under typical conditions to give the expected products in 86-98% yield [131], Carrera engaged 6- and 7-bromoindole in Pd-catalyzed couplings with 4-fluoro- and 4-methoxyphenylboronic acids to prepare 6- and 7-(4-fluorophenyl)indole (90% and 74% yield) and 6-(4-methoxyphenyl)indole (73% yield) [29]. Banwell and co-workers employed 7-bromoindole in a Suzuki coupling with 3,4-dioxygenated phenylboronic acids en route to the synthesis of Amaryllidaceae alkaloids [132], Yields of 7-arylated indoles are 93-99%. Moody successfully coupled 4-bromoindole... 

Kita et al. found that phenolic oxidative coupling in case of 272 provides seven-membered N heterocyclic compounds 274 and 275 by bond shift of the initially formed spiro intermediate 273 under suitable conditions. Besides 274 and 275, piperidino-spiroquinone 276 is also formed in this oxidation (Scheme 68). Of particular interest is the recently developed synthesis of amaryllidaceae alkaloids such as (+)-maritidine (Scheme 69) (96JOC5857). 

An impressive enantiopure synthesis of Amaryllidaceae alkaloids has been achieved through the formation of sugar-derived homochiral alkenyl nitrone 265 (Fig. 1.7).[280] While this reagent required lengthy preparation, it underwent an intramolecular dipolar cycloaddition to establish the required stereochemistry of the polycyclic pyrrolidine skeleton of (—)-haemanthidine (266), which was converted to (+)-pretazettine and (+)-tazettine by established procedures (281). 

Recent Advances in the Total Synthesis of Amaryllidaceae Alkaloids... 

---