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homodrimanyl diol was prepared in high yield (>90%) from the
reduction of sclareolide with LiAlH4 in anhydrous THF, corre-
sponding hydroxyl groups were released for further modification or
derivative synthesis. The hydroxyl homodrimanyl acid is readily
available via hydrolysis of (þ)-sclareolide under basic conditions to
free the carboxylic acid for the derivatives.
method is handleable and intuitionistic. The results generated from
this tactic are easy to interpret with significant value. As can be
seen from Fig. 5, all the prepared esters, ethers and amides showed
good activity against R. solani, while only possessed moderate in-
hibition against F. graminearum. Ethers and esters demonstrated
comparable activity against B. cinerea.
As shown in Fig. 4, our bioactivity-guided mixed synthesis is
conceptually and operationally very simple. Versatile homo-
drimanyl derivatives with different substituents at the homocarbon
(C16) were constructed in mixed form intentionally in one pot. The
halogenated hydrocarbons, acids, and amines were selected to
cover a broad range of common functionalities and chemical motifs
and are all available commercially.
The alcohol esters of homodrimanyl diol were prepared with
different organic acids through Steglich reaction (EDCI, DiPEA,
DMAP) in good transformation as detected by HPLC-MASS. Expo-
sure of the diol to halogenated hydrocarbons under basically (NaH
as a base) refluxing tetrahydrofuran (THF) furnished the mixed
products of alcohol ethers. The conversion to acid esters was ach-
ieved by the treatment of homodrimanyl acid salt with halogenated
hydrocarbons. Finally, the acid amides were furnished successfully
from (þ)-sclareolide reacting with the versatile RNH2-DIBALeH
complexes or amidated directly with organic amines as a solvent.
We also tried the conditions of Steglich type reaction for the
transformation of homodrimanyl acid to the corresponding amides,
while the system is disappointing with the revision to (þ)-sclar-
eolide as a major product.
In view of the pivotal effect of the electronegativity and steric
volume of the substituents on the bioactivity of homodrimane
derivatives, and to make the reaction system not so complicated
but comprehensive, the typically pre-selected acids, halogenated
hydrocarbons and amines, with weak/strong electron-
withdrawing/electron-donating groups were placed artificially
(Fig. 4, bottom). The four kinds of derivative mixtures can be ob-
tained in one day by one student, through simple extraction after
quenching the corresponding reactions.
The amide mixture demonstrated more potent bioactivity than
the other three series against all the tested plant pathogens, with
the inhibition of 71.83%, 77.04%, 69.45% and 45.88% at 100 mm g/L
against B. cinerea, R. solani, S. scleotiorum, and F. graminearum,
respectively. The formal oxidation at C16 (mixture C) rather than C17
(mixture A) is likely to be a little beneficial for the improvement of
bioactivity (Fig. 5), as exemplified by the inhibition against R. solani,
S. scleotiorum, and F. graminearum. To some extent, the rigidity of
amides (mixture D) may account for the further enhancement of
activity than acid esters (mixture C).
The initial results from the bioactivity-guided mixed synthesis
protrude the homodrimanyl acid amides (mixture D) for further
optimization (Table 1). With the amide from phenylamine as a
control, similar treatments were applied in the category of different
amines with different core structures (aliphatic, aromatic) and
substituents (electron withdrawing and electron donating groups).
Bioactivity against B. cinerea was selected as the fungicidal indicator
for the screening of higher bioactive mixtures. The biological results
of the sub-mixtures showed the steric effects are much more
obvious than the electronic properties, and the increment of steric
size is detrimental for the bioactivity, since the mixture of amides
from anilines substituted by electron donating groups (CH3, CH3O
at different position) or electron withdrawing groups (momo/
multi-substituted Cl, Br, NO2), only showed weaker bioactivity than
the unsubstituted aniline counterpart.
How to tune the electronic property on the aromatic core
without the increment of steric size? Two approaches were
designed and carried out based on the introduction of fluorine and
replacement of Ph ring by bioisosteric heterocycles. With the
similar atomic size to hydrogen, fluorine also showed many special
or elusive properties including perturbation of physicochemical
and conformational properties, and modulation of lipophilicity etc.
[27,28], it has a remarkable record and will play a continuing role in
medicinal chemistry. Our optimization of the amides with the
mixture of fluorine substituted anilines provided more promising
results. Fine tuning and specific synthesis gave N-(4-fluorophenyl)-
2-((1R, 2R, 4aS, 8aS)-2-hydroxy- 2,5,5, 8a-tetramethyldecahydro-
naphthalen-1-yl)acetamide (D9) as a good fungicidal candidate.
To give support to the conclusions obtained from our intentional
mixture synthesis. Four series of homodrimane derivatives were
3.3. Fungicidal bioactivities and SAR
The antifungal activity of the synthesized four samples,
including alcohol esters (mixture A), alcohol ethers (mixture B),
acid esters (mixture C), and acid amides (mixture D), were
measured against B. cinerea. (Botrytis cinerea), R. solani (Rhizoctonia
solani), S. sclerotiorum (Sclerotinia sclerotiorum) and F. graminearum
(Fusarium graminearum), through the mycelium growth rate
method on potato dextrose agar (PDA). This biologically indicating
Fig. 5. Bioactivities of mixed homodrimanyl derivatives.