294 
claimed that alkaloids were actually demon- 
strated (only, however, on the basis of color 
reactions), but actual isolation of nitrogenous 
compounds has never been successful. The fact 
that the usual testing reagents for alkaloids are 
relatively non-specific was not taken into ac- 
count. Especially ignored was the fact that the 
a-pyrones (which contain no nitrogen) can 
behave similarly to alkaloids in some of these 
tests (Farnsworth et al., 1962). Furthermore, 
F. Fewin, a toxicologist and pharmacologist in 
Berlin, who studied the drug intensively from 
1880 on, was able to demonstrate that the 
anesthetic principle could be extracted from the 
plant with fat solvents, such as petroleum ether. 
Since that time, pharmacognosists and chemists 
have examined almost exclusively the lipid frac- 
tion of the plant. 
MOLECULAR BUILDING BLOCKS OF THE kdWd 
LACTONES (pyrones) : Nine lactones and two 
chalcones (i.e., eleven aromatic compounds) 
have so far been isolated from the plant. None 
of these occur as glycosides. We shall first con- 
sider the lactones, all of whose structures follow 
the pattern shown in Figure 1. The basic skele- 
ton consists of 13 carbon atoms, 6 of them in a 
benzene ring. The benzene ring is linked by a 
2 -carbon bridge to an unsaturated 6-membered 
lactone. At first sight this lactone is reminiscent 
of sorbic acid lactones or of the bufadienolides 
on 
ii 
pi ^C\ 
Vn ----- ' H2 
2/kJUcH=CH-CH 
R HO 0 
och 3 
1 
Fig. 1. Common molecular skeleton of the kawa 
lactones and their hypothetical precursor. 
PACIFIC SCIENCE, Vol. XXII, July 1968 
which are cardiac-active glycosides isolated from 
the plant genus Scilld and from toads. However, 
an important difference should be noted. The 
kdWd lactones contain a methoxyl group as part 
of an enol ether function, which strongly modi- 
fies the behavior of the lactone toward acids 
and alkalies, as compared with the bufadieno- 
lides and other known 5-lactones. In the kdWd 
lactones we are dealing with masked enols of 
p-diketones. The chemical behavior of the kdWd 
lactones is summarized in Figure 2 using kawain 
and dihydrokawain as examples (Borsche et al., 
1914-1933). 
NATURALLY OCCURRING STRUCTURAL VARI- 
ANTS: We have seen that the characteristic 
constituents of kdWd are 5-lactones, which may 
be considered to be a-pyrones bearing a me- 
thoxyl group at carbon 4 and an aromatic styryl 
or phenylethyl moiety at carbon 6. The question 
arises what structural variants of this basic 
skeleton occur in nature. We can distinguish 
two groups of structural variants: (a) variance 
depending on the degree of saturation, and 
(b) variance depending on benzene substitu- 
tion. 
(a) We note that the molecule of the basic 
skeleton, the styryl- a-pyrone, contains three 
non-aromatic double bonds. If one assumes that 
in the biological environment, that is, in the 
plant, each of these three double bonds can be 
saturated independently, eight variants are con- 
ceivable which would differ from one another 
with regard to the degree of saturation. Theo- 
retically, there is no difficulty in synthesizing all 
eight variants. Nature, however, seems to follow 
its own laws in that not all variants which are 
synthetically available in the laboratory occur 
in the plant; a certain limitation or choice 
exists. In our case the following situation ob- 
tains. The kdwd plant lacks all those variants 
which contain the reduced double bond at car- 
bon 3. To put this positively, all naturally occur- 
ring kdwd lactones invariably contain in the 
molecule the enolic double bond. The number 
of structural variants which occur in the plant 
is therefore reduced to 4. Another phenomenon 
is present. The double bond at carbon 7 is 
reduced only when the double bond at carbon 
5 is also in the reduced state. These relationships 
are summarized in Figure 3. 
