Notes
Bull. Korean Chem. Soc. 2012, Vol. 33, No. 1 297
Synthesis and Herbicidal Activities of Enantiopure Methiozolins
†,#
Jun Ho Nam, Ki-Hwan Hwang, Suk-Jin Koo, Chong-Hyeak Kim, Chang-Woo Cho, and Young Kwan Ko
‡
‡
§
#
†,*
†
Biomaterials Research Center, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea
*
E-mail: ykko@krict.re.kr
‡
Moghu Reserch Center, Daejeon 305-333, Korea
§
Center for Chemical Analysis, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea
#
Department of Chemistry, Kyungpook National University, Daegu 702-701, Korea
Received October 25, 2011, Accepted November 4, 2011
Key Words : Methiozolin, Absolute configuration determination, Optical isomer, Herbicidal activity, Grass
weeds
It is well known that the worldwide demands for crops and
biomass exceed their supply due to the rapid growth of
world population, limitation of cultivation areas, global
warming, climate change and subsequent lack of water
supply. Herbicides for weeds control have played an
important role in promoting productivity of crops yields and
+59.96 (c = 1.0, CH2Cl2) and that of the second eluted inter-
mediate was −59.95 (c = 1.0, CH2Cl2). Absolute configu-
ration of one enantiopure intermediate with positive specific
optical rotation was determined to be S by single crystal X-
ray diffraction analysis. And the other enantiopure inter-
mediate with negative but the same absolute value of
specific optical rotation could be assigned to have the R
configuration. Enantiopure methiozolins could be synthe-
sized by a coupling reaction of each chiral intermediate (S)-3
or (R)-3 with 2,6-difluorobenzyl chloride under basic
condition as shown in Scheme 1.
1
biomass. Even though a number of herbicides have been
developed for weeds control, more eco-friendly new herbi-
cides having new modes of action are needed because of the
environmental safety issues and occurrence of resistant
2,3
weeds. Recently, a new isoxazoline herbicide methiozolin
possessing thiophene ring for the control of grass weeds in
Specific optical rotation of one enantiopure methiozolin
synthesized from (+)-[5-methyl-3-(3-methylthiophen-2-yl)-
4,5-dihydroisoxazol-5-yl] methanol (S)-3 was +55.0 (c =
1.0, CH2Cl2) and that of the other enantiopure methiozolin
synthesized from (−)-[5-methyl-3-(3-methylthiophen-2-yl)-
4,5-dihydroisoxazol-5-yl]methanol (R)-3 was −54.5 (c = 1.0,
CH2Cl2). Finally, absolute configuration of one enantiopure
methiozolin with positive specific optical rotation was deter-
4,5
turf grass has been commercialized. Methiozolin shows
not only excellent herbicidal efficacy toward several grass
weeds in turf grass but also favorable toxicological and
environmental profiles. Methiozolin has one chiral center in
isoxazoline ring. Up to now, methiozolin has been develop-
ed as a racemate.
However, it was reported that, in many cases, big differ-
ences in biological activities between enantiomers of chiral
6-8
agrochemicals have been observed. In addition, success
stories for the commercialization of chiral agrochemicals
9
10
such as (S)-metolachlor and mefenoxam as a single iso-
mer by Syngenta prompted us to investigate herbicidal
activities of each enantiomer of methiozolin. In our previous
11
paper, the absolute stereochemistry of one enantiopure
intermediate with posititive value of specific optical rotation,
which is the key intermediate for synthesis of optically
active methiozolin, was determined by single crystal X-ray
diffraction analysis after prep- HPLC separation with chiral
stationary phase [(R,R)-WHELK-O1 column] using [5-
methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-
yl]methanol as the racemic mixture. Herein, we want to
describe synthesis of enantiopure methiozolins and compare
herbicidal activities between optical isomers on some grass
weeds under a greenhouse condition.
Key intermediates (S)-3 and (R)-3 for enantiopure meth-
iozolins could be obtained by chiral separation of a racemic
[5-methyl-3-(3-methylthiophen-2-yl)-4,5-dihydroisoxazol-5-
yl]methanol 3 employing chiral prep-HPLC separaton.
Specific optical rotation of the first eluted intermediate was
Scheme 1. Synthesis of enantiopure methiozolins.
Reagents and conditions: (a) H2NOH·HCl, MeOH; (b) NCS,
CH2Cl2, 2-methylpropen-1-ol, NaHCO3. (c) chiral prep-HPLC
separation. (d) 2,6-difluorobenzyl chloride, NaOH, THF