Synthesis of hydantocidin and C-2-thioxo-hydantocidin

Article abstract of DOI:10.1016/S0008-6215(01)00239-7

Hydantocidin, a naturally occurring strong herbicide, was synthesized in an overall yield of 35.2%, with the accompanying 1′-epi-hydantocidin in overall 9.6% yield from 2,3-O-isopropylidene-D-ribono-1,4-lactone. C-2-thioxo-hydantocidin and its spiro-epimer were also synthesized in an overall yield of 14.4% and 8.5%, respectively.

Full text of DOI:10.1016/S0008-6215(01)00239-7

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Carbohydrate Research 335 (2001) 147–150
Rapid Communication
Synthesis of hydantocidin and C-2-thioxo-hydantocidin
Masao Shiozaki*
Exploratory Chemistry Research Laboratories, Sankyo Co. Ltd., Hiromachi 1-2-58, Shinagawa-ku,
Tokyo 140-8710, Japan
Received 23 July 2001; accepted 23 August 2001
Abstract
Hydantocidin, a naturally occurring strong herbicide, was synthesized in an overall yield of 35.2%, with the
accompanying 1%-epi-hydantocidin in overall 9.6% yield from 2,3-O-isopropylidene-D-ribono-1,4-lactone. C-2-thioxo-
hydantocidin and its spiro-epimer were also synthesized in an overall yield of 14.4% and 8.5%, respectively. © 2001
Elsevier Science Ltd. All rights reserved.
Keywords: Hydantocidin; Herbicide; Synthesis of spiro-hydantoin
thetase inhibitor,2 without showing toxicity to
Together with the explosive increase in the
microorganisms and animals, and without re-
maining for a long period in the soil, may be
used in the near future as a potential herbicide
against glyphosate-resistant weeds. However,
the high cost of hydantocidin production,
whether by fermentation or by total synthe-
sis,3 has made its use as a herbicide impracti-
cable. Therefore, economical production of
hydantocidin is being sought. At this time, the
author has accomplished a fairly good overall
yield for hydantocidin, that is, hydantocidin
(9) was synthesized in overall 35.2% yield,
accompanied by 1%-epi-hydantocidin (9%) in
overall 9.6% yield from 2,3-O-isopropylidene-
world population, deficiency of provisions, en-
vironmental destruction and pollution, and
global warming have become serious prob-
lems. Means for grain production to maintain
this large population have come under in-
creased development. One aspect is the use of
herbicides. Glyphosate has become one of the
most popular herbicides in the world. How-
ever, glyphosate-resistant weeds have been re-
ported recently. In addition, proteins
produced by grain plants recombinated by a
glyphosate-resistant gene are a cause for con-
cern because of the awareness of the existence
of pathogenic proteins.
D
-ribono-1,4-lactone (1). The synthetic route
(Scheme 1) is reported herein.
Hydantocidin produced from Streptomyces
hygroscopicus,1 the first naturally occurring
spiroribofuranose having strong herbicidal ac-
tivity toward annual, biennial and perennial
weeds by action as an adenylosuccinate syn-
The starting material 2,3-O-isopropylidene-
-ribono-1,4-lactone (1), was converted to its
D
5-O-benzyl ether 2 or 5-O-(p-methoxybenzyl)
ether (10) in 95% or 77% yield, respectively,
by treatment with benzyl bromide or p-
methoxybenzyl chloride using NaH as a base.
* Tel.: +81-3-3491-3131; fax: +81-3-5436-8570.
E-mail address: shioza@shina.sankyo.co.jp (M. Shiozaki).
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00239-7

148
M. Shiozaki / Carbohydrate Research 335 (2001) 147–150
Scheme 1. Reagents and conditions: Bn=benzyl; PMB=p-methoxybenzyl; (a) NaH, BnBr or PMB-Cl, DMF, 0 °Cꢀrt, 95% or
77%, respectively; (b) CBrCl3, (Me2N)3P, CH2Cl2, −78ꢀ +24 °C, 16 h, 86% or 95%, respectively. ; (c) m-CPBA, MeOH,
CH2Cl2, 24 °C, 16 h, 4 (54%) and 4% (14%), or 12 (54%) and 12% (13%); (d) KNCS, DMF 80 °C, 16 h, a 4:1 mixture of 5 and 5%
(83%) from 4, a 5:2 mixture of 5 and 5% (72%) from 4%; a 5:1 mixture of 13 and 13% (73%) from 12, and a 3:1 mixture of 13 and
13% (72%) from 12%; (e) NH3, MeOH, rt 2 h, quant; (f) 30% H2O2, NaHCO3, MeCN–H2O, rt, 15 min, quant; (g) H2, Pd/C, EtOAc,
rt, 15 min, quant; (h) CF3COOH–H2O, 0 °C, 30 min, 9 and 9%, quant: CF3COOH–H2O (1:3), −5 °C, 16 h, 16 (61%) and 16%
(16%) from 15, and 16% (94%) from 15%; (i) PhSH, SnCl4, CH2Cl2, −78 °C, 30 min 15 (81%) and recovery of 14 (6%); 15% (76%)
and recovery of 14% (13%).
4:1 diastereomeric mixture by treatment with
m-chloroperoxybenzoic acid according to
Chapleur’s procedure.5 Compound 10 was
also converted to 12 and 12% in 67% yield as a
Treatment of 2 with CCl3Br using (Me2N)3P
(HMPT) as a base gave dichloroolefin 3,4
which was further converted to methyl a-
chlorourosonates 4 and 4% in 68% yield as a

M. Shiozaki / Carbohydrate Research 335 (2001) 147–150
149
4:1 diastereomeric mixture via compound 11
by the same procedure. Treatment of 4% at
80 °C for 1 h in DMF gave a 3:1 mixture of 4
and 4%. Therefore, compound 4 is more ther-
modynamically stable than 4%. Thus, at high
temperature, compound 4% gradually changed
to 4 until equilibration was reached (Scheme
1).
soluble urea 18, hydantoin 20, and cyclic car-
bonate 22, respectively (Table 1). Deprotec-
tion of the benzyl ether of 7 and 7% by means
of hydrogenolysis using Pd/C as a catalyst
quantitatively gave 8 and 8%, respectively. Fi-
nally, the O-isopropylidene protecting groups
of 8 and 8% were quantitatively cleaved by
treatment with 3:1 CF3COOH–H2O at 0 °C
for 30 min according to a previously reported
procedure3f to give 9 and 9% (1%-epi-hydanto-
cidin having still strong herbicidal activity ac-
cording to Ref. 8), respectively. Thus,
hydantocidin (9) was synthesized in overall
35.2% yield accompanying 1%-epi-hydantocidin
(9%) in overall 9.6% yield from 2,3-O-isopropyl-
After separation of 4 and 4% or 12 and 12%
chromatographically, treatment of 4 with
potassium thiocyanate at 80 °C for 16 h in
DMF gave a 4:1 inseparable mixture of 5 and
5% in 83% yield. The same treatment of com-
pounds 4%, 12, and 12% gave a 5:2 inseparable
mixture of 5 and 5% in 72% yield from 4%, a 5:1
inseparable mixture of 13 and 13% in 73% yield
from 12, and a 3:1 inseparable mixture of 13
and 13% in 72% yield from 12%, respectively.
Treatment of the 4:1 mixture of 5 and 5%
with NH3 in MeOH afforded a 4:1 mixture of
spiro-thiohydantoins 6 and 6% in quantitative
yield according to the ratio of the starting 5
and 5%. The same procedure for both com-
pounds 13 and 13% gave spiro compounds 14
and 14%, respectively, in quantitative yield.
After chromatographic separation of 6 and
6%, treatment of each compound with 30%
H2O2 and NaHCO3 in 3:2 MeCN–H2O
yielded 7 and 7%, respectively, in quantitative
yield.6 This procedure was also applicable for
the oxidation of thiourea 17, thiohydantoin 19
and cyclic thiocarbamate 217 to give a water
idene- -ribono-1,4-lactone (1).
D
On the other hand, treatment of solutions
of 14 and 14% in CH2Cl2 with PhSH and SnCl4,
at −78 °C under nitrogen gave 15 and 15% in
81% and 76% yields, respectively, along with
the recovery of 14 (6%) and 14% (13%).9 Fi-
nally, the protecting O-isopropylidene group
of 15 was cleaved by treatment with 3:1
CF3COOH–H2O at 0 °C for 30 min according
to a previously reported procedure3f to give a
mixture of 16 (61%) and 16% (16%). However,
the same treatment of 15% gave 16% in 94%
yield. It is reported that both compound 16
and 16% are comparable with hydantocidin 9 in
herbicidal activity toward many different
types of weeds.7 As a result, C-2-thioxo-hy-
dantocidin (16) and its spiro epimer 16% were
synthesized in overall yields of 14.4% and
8.5%, respectively.
Table 1
Thus, hydantocidin (9), 1%-epi-hydantocidin
(9%), C-2-thioxo-hydantocidin (16), and 1%-epi-
C-2-thioxo-hydantocidin (16%) were synthe-
Oxidation of thiourea (17), thiohydantoin (19), and cyclic
thiocarbamate (21) with 30% H2O2 in 3:2 1 M aq NaHCO3 at
24 °C
sized
from
D
-ribono-1,4-lactone
via
corresponding isothiocyanates 5, 5%, 13, and
13%†.
Acknowledgements
Entry Substrate
Time (min)
Product Yield (%)
I thank Dr. Shigeru Mio for helpful advice
and discussions.
1
2
3
17
19
21
4 a
30
20
18
20
22
57
100
96
a Prolonged reaction time causes production of the mor-
pholine N-oxide of 18.
1
† All new compounds were characterized by IR, H NMR,
MS and elemental analysis.

150
M. Shiozaki / Carbohydrate Research 335 (2001) 147–150
Taylor, H.; Watkin, D. J.; Winchester, B. G.; Fleet, G. W.
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