DOMINO REACTIONS IN THE ENANTIOSELECTIVE SYNTHESIS OF BIOACTIVE NATURAL PRODUCTS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 295

OMe

OMe

OMe

OMe

MeO

NH 2

MeO

207
1. AlMe 3 , In(OTf) 3
CH 3 CN, rt, 24 h
2. TfOH, 80°C, 4 h
92%

HN

O AlMe 2

O OEt O

O LA O HN

O

LA

SiMe 2 Ph SiMe 2 Ph SiMe 2 Ph

206 208 209

MeO

MeO MeO

O

O O

steps N

N

N

MeO

MeO MeO

MeO SiMe 2 Ph

SiMe 2 Ph

(+)-Erysotramidine 212

211 (dr = 4:1) 210

SCHEME 9.35 Formal total synthesis of erysotramidine 212 by Tietze and coworkers.

Tietze and coworkers have orchestrated a pathway to ( þ )-erysotramidine ( 212 )
through a three-step domino reaction based on earlier methodology toward the
heterocyclic skeleton of the erythrina and B-homoerythrina alkaloids [76]. These
alkaloids from the Erythrina genus of plant are known for several pharmacological
effects, including sedative, hypotensive, anticonvulsive, and CNS depressing prop-
erties. In the approach to 212 , an initial reaction of trimethylaluminumwith amine 207

forms an aluminium-amide that reacts with enantiopure 206 exclusively at the ester

moiety to give aluminum azaenolate . It followed an intramolecular addition

reaction with the adjacent carbonyl to produce compound

208

(Scheme 9.35).
Elimination of this oxyanion-Lewis acid moiety produces either of two possible
cyclohexane enamines, which upon treatment with trifluoromethanesulfonic acid
forms iminium ion

209

. This species then undergoes a stereoselective electrophilic
aromatic substitution. The main product is the thermodynamically more favored cis -
annulated compound

210

resulting from a re -face attack along with its trans -isomer
(4:1) in an overall yield of 92% yield. Compound

211

is then taken through to the
corresponding tetracyclic alcohol via a Tamao-Fleming oxidation, which is a
precursor to (

211

) [77], constituting a formal total synthesis.
In 1999, Tietze and Zhou applied their recently discovered domino
Knoevenagel/hetero-Diels-Alder reaction to synthesize (

þ )-erysotramidine ( 212

)-hirsutine [78]. This
natural product from the corynanthe subgroup of the indole alkaloids was isolated
from the plant Uncaria rhynchophylla Miq. used for the preparation of the Chinese
folk medicine “Kampo”. ( )-Hirsutine exhibits a pharmacological profile showing a
strong inhibitory effect on the influenza Avirus (subtype H3N2) with an EC 50 value of
0.40-0.57

g/mL, which is about 11-20 times higher than that of the clinically used
ribavirin. Treatment of the three components, enantiopure aldehyde

m

213 (ee 99%),

H