Synthesis and absolute configuration assignment of albucidin: A late-stage reductive deiodination by visible light photocatalysis

Article abstract of DOI:10.1039/c6ob00371k

The synthesis of albucidin and its enantiomer are described. It involves a visible-light photocatalysis deiodination at the late stage. The absolute configuration of natural albucidin is determined as (1R,3S). This work provides a basis for structural mod

Full text of DOI:10.1039/c6ob00371k

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Synthesis and Absolute Configuration Assignment of Albucidin: A
Late-Stage Reductive Deiodination by Visible Light Photocatalysis
Hu Zhang,[a] Peng-Fei Liu,[a] Qiong Chen,[a] Qiong-You Wu,[a] Anne Seville,[b] Yu-Cheng Gu,[b] John
Clough,[b] Shao-Lin Zhou,[a] and Guang-Fu Yang*[a]
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The synthesis of albucidin and its enantiomer are described. It involves a visible-light photocatalysis
deiodination at the late stage. The absolute configuration of natural albucidin is determined as (1R, 3S).
This work provides a basis for structural modification to develop a new type of herbicidal from an old
structure.
www.rsc.org/
In 2009, Hahn and co-workers reported the isolation of a novel
oxetane nucleoside phytotoxin, Albucidin (Fig. 1), from the
fermentation broth of Streptomyces albus subsp. chlorinus
NRRL B-24108.1 The structure of this natural product was only
determined by NMR and MS, and no absolute or relative
stereochemical assignments were made.1 However this
compound has been reported earlier in the literature following
synthetic modification of oxetanocin A in 1991 by Takita.2
Biological testing revealed that this compound showed good
herbicidal activity. Notably, this was the first report of
herbicidal activity for this type of compound compared with its
antiviral activity.3 Therefore, the unique structure and
intriguing herbicidal activity of albucidin aroused our great
interests. At the same time we also desire to investigate its
mode of action and structure-activity relationship. But with
two chiral centers, albucidin is one of 4 possible stereoisomers
and those works are hampered by its unknown stereochemical
configuration assignment. Herein, the total synthesis and
absolute configuration assignment of albucidin are described.
Fig. 1 Structures of albucidin, oxetanocin A and its analogues.
Before the experiment a rational prediction of the possible
configuration and a comprehensive literature search focused
on oxetane nucleoside4 was undertaken. Natural product
oxetanocin A5 which belonging to four-membered nucleoside
family, possesses three chiral centers on the glycosyl moiety
bearing
a
1,3-syn carbon skeleton with definite D-
configuration6 attract our attention. Oxetanocin A and its
synthetic derivatives (Fig. 1), such as β-noroxetanocin,
epinoroxetanocin and azido-oxetane showed impressive anti-
HIV activity,2, 7 whereas, the α-isomers such as α-oxetanocin A
and α-noroxetanocin showed no activity at all, even at
concentrations up to 100 μg/ml.8 In view of the biological
properties, it was hypothesized that albucidin may possess
identical relative stereochemistry with oxetanocin A.
a.Key Laboratory of Pesticide & Chemical Biology, Ministry of Education College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei
430079 (China). E-mail: gfyang@mail.ccnu.edu.cn.
b.Syngenta Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42
6EY, U.K.
At the same time, the 1,3-syn carbon skeleton of albucidin
†
Electronic Supplementary Informaꢀon (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
could also have the L-configuration (Fig. 1) and, indeed, there
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are examples where the L-nucleosides also exhibit excellent method8b and the carboxylate could be synthesized
biological activities.9 Bearing these considerations in mind, conveniently in one step. The unstable chlorooxetanes
was
compounds containing 1,3-syn carbon skeleton with D and L- obtained by a radical decarboxylative chlorination reaction14. It
4
configuration were selected as the first synthetic targets.
was subsequently subjected to a nucleophilic substitution with
adenine in the presence of 18-crown-6 afforded the single
oxetane nucleoside 58b, 15 which deprotection of the acetal
provided epinoroxetanocin.16 X-ray crystallography confirmed
the structure of epinoroxetanocin (Fig. 2 Compound 10) which
clearly indicated that it was a SN2 displacement during the
transformation of compound
was synthesized by a three-step method similar with Takita.2
Analogously, compound ent- was readily achieved by
4 to 5. Afterwards, compound 7
7
employing L-xylose as the starting material and following the
same synthetic procedure (see ESI). This route provides
concise access to the two enantiomers in enantiomerically
pure from D and L-xylose.
Scheme 1 a) K2CO3/H2O, Br2, 5oC to 0oC, 12 h; b) benzaldehyde,
conc.H2SO4, THF, RT, 12 h, 45% ( two steps); c) CH3SO2Cl,
pyridine, CH2Cl2, 0oC to RT, 18 h, 80%; d) 1N NaOH, methanol,
RT, 15 h, 69%; e) NCS, Pb(OAc)4, CH3COOH:DMF=1:5, N2, 60oC,
30 min, 55%; f) adenine, NaH, 18-crown-6, CH3CN, reflux, 24 h,
39%; g) PTSA, methanol, 60oC, 3 h, 90%; h) benzoyl chloride,
pyridine, 0oC to RT, 30 min, 95%; i) CF3SO2Cl, DMAP, Et3N,
CH2Cl2, N2, 0oC to RT, 15 min; j) NaI, acetone, reflux, 18 h, 76%
( two steps).
Though the D-configuration albucidin has been reported in
the literatures,2, 10 it was synthesized in a tedious route with a
low total yield from D-ribose due to the synthesis of
oxetanocin A (especially the construction of oxetane ring) was
challenging.8a, 10-11 Thus, it is necessary to develop a concise
and unambiguous route to synthesize and confirm the
Scheme 2 a) NaOH, methanol, RT, 1 h, 91% for
1S,3R-albucidin; b) fac-[Ir(mppy)3], p-toluenethiol, DIPEA,
CH3CN, DMF, N2, 1 h, 82% for 1R,3S-albucidin and 87% for
8 and 90% for
9
.
With the critical compound
7 and ent-7 in hand, we then
turned our attention to the construction of 2-deoxy oxetane
nucleoside (Scheme 2). The subsequent radical deiodination
with organotin reagent17 or tin free Barton-McCombie
deoxygenation18 would provide the desired albucidin. But the
organotin reagent is typically toxic and the Barton-McCombie
method is unsuitable for our substrate. Given the recent
progress using visible-light induced deiodination under
relatively mild conditions,19 we sought to apply this protocol
for a late stage deiodination to construct the 2-deoxy oxetane
nucleoside. The major challenge existing within this
transformation is the amino group which will potentially trap
the free radical to cause significant by-product. Gratifyingly,
after screening different reaction conditions,20 we finally found
stereochemistry
of
albucidin
which
would
lay
a basis for following research.
Our synthetic efforts commenced with the construction of
compound and its enantiomer (ent- ) through the known
7
7
intermediate epinoroxetanocin8b but with a modified method
(Scheme 1). Start with cheap and readily available D-xylose,
the lactone
procedure.12 Treatment of
provided the mesylate
1 was synthesized by a two-step one-pot
1
with methanesufonyl chloride
2, followed by ring-contraction
produced the sodium carboxylate 3 13
The employment of
.
mesylate as leaving group was an improvement for literature
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB00371K
that the conditions being developed by Wan and co-workers
are optimal.21 Treatment of 2-deoxy-2-iodo (Compound
8)
with DIPEA and p-toluenethiol in the presence of 1.5 mol% fac-
[Ir(mppy)3] under 1 W blue LED irradiation, the desired
product 1R,3S-albucidin is give excellent yield (82%). Under the
same reaction conditions, compound
87% yield from ent- . Finally, the total synthesis of 1R,3S-
albucidin and 1S,3R-albucidin was accomplished in 12 steps
9 was also obtained in
7
Scheme
3
Proposed mechanism for visible-light induced
with 2.6% and 1.7% overall yield. At the same time we deiodination of compound
8.
obtained the crystal structures of these two compounds and as
data indicated that the retention time of the 1R,3S-albucidin
matched the natural albucidin which was quite different from
that of 1S,3R-albucidin (see ESI). Herbicidal activity (Table 1)
assay for post- and pre-emergence also showed that 1R,3S-
albucidin and natural albucidin had a similar spectrum and
levels of herbicidal activity and, in addition, the symptoms
were the same, namely bleaching and stunting of the plants;
however 1S,3R-albucidin did not show weed control potential.
Therefore, based on the above results, we confirmed that the
absolute configuration of natural albucidin was assigned as
(1R,3S).
expected they contain a 1,3-syn carbon skeleton (Fig. 2).
Compound 10
1R,3S-albucidin
1S,3R-albucidin
Fig. 2 Single crystal structures of representative compounds.
21
Based on the previous literature19,
,
a
proposed
is
Table 1 Comparison of herbicidal activity in soil-based test
mechanism of Ir-catalyzed deiodination of compound
8
depicted in Scheme 3. Upon irradiation by visible light, the
ground state [Ir(mppy)3] is excited to the excited state
post
pre
Compound
rate[a]
(ppm)
[
*
Ir(mppy)3], through oxidative quenching,
donates an electron to the carbon-iodide bond in compound
and is then reduced to the ground state by iPr2NEt. The
generated carbon radical intermediate undergoes hydrogen
atom abstraction from p-toluenethiol to give the reduced
product D-albucidin. Subsequently the radical intermediate
[*Ir(mppy)3]
8
Natural albucidin
1R,3S-albucidin
1S,3R-albucidin
1000
1000
1000
70 70 60 60 50 60 60 80
60 40 70 70 80 80 70 90
Ⅰ
0
0
0
30
0
0
0
0
Ⅱ
[a] Rate is in grams per hectare (g/ha).
captures a hydrogen atom from intermediate
the p-toluenethiol and the Intermediate
Ⅲ
Ⅳ
regenerated
could be
In conclusion, the total synthesis of albucidin and its
enantiomer have been accomplished in 12 steps in ~2.6% and
1.7% overall yield, respectively. The enantiomer is reported
for the first time by us. It involves a visible-light photocatalysis
deiodination as the key step at the late stage and to the best
of our knowledge, it is the first time applying visible-light
induced deiodination in natural products total synthesis. The
absolute configuration of natural albucidin was assigned as
(1R,3S). The determination of the absolute configuration of
albucidin not only provide a basis for further research into its
mode of action, but also offer a foundation for structural
decomposed easily. So the p-toluenethiol may act as a
hydrogen-atom shuttle or hydrogen donor and could improve
the reaction efficiency.
With 1R,3S- and 1S,3R-albucidin in hand, we were able to
compare their NMR spectrum, chiral HPLC data and herbicidal
activity with natural albucidin. The analytical data, including
1
the H and 13CNMR and HRMS of 1R,3S- and 1S,3R-albucidin,
were identical with natural albucidin (see ESI). But chiral HPLC

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modification to develop a new type of herbicidal from an old
structure. The synthesis of analogues of albucidin is current
ongoing in our group, and will be reported in due course.
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We thank Syngenta for their kind help in screening the
compounds for biological activity and providing the analytic
data of natural albucidin. We are grateful to the financial
support for this work from the NSFC (No. 21332004).
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The total synthesis and absolute configuration assignment of
albucidin might pave the way for synthetic and medicinal
chemists to further research on this type of bioactive
molecules.
Hu Zhang, Peng-Fei Liu, Qiong Chen, Qiong-You Wu, Anne
Seville, Yu-Cheng Gu, John Clough, Shao-Lin Zhou and
Guang-Fu Yang*
Page No. – Page No.
Synthesis and Absolute Configuration Assignment
of Albucidin: A Late-Stage Reductive Deiodination
by Visible Light Photocatalysis