Concise total synthesis of AB5046A and AB5046B

Article abstract of DOI:10.1016/j.tetlet.2018.03.038

Two naturally occurring rare 5-oxo β-triketones, AB5046A and AB5046B, were efficiently synthesized in five linear steps with overall yields of 36% and 28%, respectively. The synthetic strategy highlighted the readily preparation of the key intermediate, 3

Full text of DOI:10.1016/j.tetlet.2018.03.038

Accepted Manuscript
Concise total synthesis of AB5046A and AB5046B
Lu-Yao Kong, Qing Cui, Zhong Jin, Xiao-Hua Xu
PII:
S0040-4039(18)30352-6
https://doi.org/10.1016/j.tetlet.2018.03.038
TETL 49807
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
25 January 2018
8 March 2018
15 March 2018
Please cite this article as: Kong, L-Y., Cui, Q., Jin, Z., Xu, X-H., Concise total synthesis of AB5046A and AB5046B,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.038
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Concise total synthesis of AB5046A and AB5046B
a
a
a,
a,b,
Lu-Yao Kong , Qing Cui , Zhong Jin *, Xiao-Hua Xu
*
a
State Key Laboratory of Elemento-Organic Chemistry, Elemento-Organic Chemistry Institute,
College of Chemistry, Nankai University, Tianjin 300071, China
b
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071,
China
Tel.: (+)86-138 2113 7138; Fax.: (+)86-2350 3691
e-mail addresses: zjin@nankai.edu.cn (Z. Jin), xiaohuaxu@nankai.edu.cn (X.-H. Xu).
ABSTRACT
Two naturally occurring rare 5-oxo β-triketones, AB5046A and AB5046B, were efficiently
synthesized in five linear steps with overall yields of 36% and 28%, respectively. The synthetic
strategy
highlighted
the
readily
preparation
of
the
key
intermediate,
3-ethoxy-5-hydroxycyclohex-2-enone, from commercially available phloroglucinol.
Keywords:
-Oxo β-triketone; AB5046A; AB5046B; Herbicidal activity; Synthesis
5
Naturally occurring β-triketones, such as leptospermone 1, isoleptospermone 2, flavesone 3, and
grandiflorone 4, are widely distributed in the plants of Leptospermum, Eucalyptus, and
1
–3
4–6
5,7
Callistemon spp. species (Scheme 1).
Apart from antifungal, antimicrobial,
antiviral,
5
insecticidal and molluscicidal activities, this class of natural triketone derivatives is also known
for their herbicidal properties through the inhibition of p-hydroxyphenylpyruvate dioxygenase
8
–10
(
HPPD), causing bleaching of grass and broadleaf weeds.
To date, several commercial
triketone herbicides, e.g. NTBC 5, sulcotrione 6, and mesotrione 7, have been launched onto the
market following the discovery of the herbicidal properties of leptospermone 1.
Scheme 1. Structures of natural β-triketones and related herbicides.
In 1993, two rare β-triketones, AB5046A 8 and AB5046B 9, were isolated from a fungal
endophyte Nodulisporium sp. (Scheme 2), which was found to induce chlorosis in Japanese
11
barnyard grass. Further evaluation demonstrated that both natural products showed versatile
herbicidal activity against weeds such as Cyperus microiria, Digitaria adscendens, Setaria viridis,
and Panicum Crus-galli, while exhibiting low toxicity towards mammalian animals.
Conventionally, 5-alkyl/aryl substituted β-triketone derivatives can be conveniently prepared
through the intermolecular condensation of chalcones and β-ketoesters or dialkyl malonate, while
for 5-oxo substituted β-triketones no effective methods have been reported. Although recently it
was shown that compound 9 could be produced via the biocatalytic dearomatization of substituted

phloroglucinol by various phloroglucinol reductases (PGRs), low conversions were achieved
1
2
(
PGRcl-his, 8%; PGReu-his, no conversion; PGRde-his, 11%). Therefore, when applying this
class of natural products as lead compounds to investigate their structure-activity relationship, a
synthetically practical method for preparing these derivatives is yet to be developed. In this
communication, we herein report a concise total synthesis of natural AB5046A and AB5046B.
Scheme 2. Structures of AB5046A and AB5046B and their retrosynthetic analysis.
Our retrosynthetic strategy for the synthesis of AB5046A and AB5046B involves the synthesis of
a 5-hydroxy β-diketone from commercially available phloroglucinol 10 and C2-acylation of the
resulting β-diketone (Scheme 2). Initially, we focused on the synthesis of the key intermediate
O-protected 5-hydroxy β-diketone 14 from phloroglucinol 10 (Scheme 3). Reduction of 10 using
o
Raney Ni under a H
2
(5 atm) atmosphere at 125 C gave cis-1,3,5-cyclohexane-triol 11 in 65%
1
3
yield. Subsequently, selective mono-protection of triol 11 with tert-butyldimethylsilyl chloride
(
TBSCl) in the presence of NaH and triethylamine (TEA) successfully afforded the mono
1
4
TBS-ether 12 in 86% yield. To our disappointment, direct oxidation of 12 to O-TBS 5-hydroxy
β-diketone 14 proved unsuccessful under various oxidation conditions, including PCC, IBX,
Dess-Martin periodinane (DMP), and NaOCl/TEMPO. Meanwhile, when using PCC supported by
1
5
silica gel as an oxidant, β-hydroxy ketone 13 was obtained as a main product in 84% yield.
Unfortunately, further oxidation of 13 to the desired β-diketone 14 with a number of oxidants was
unsuccessful and gave an unexpectedly complex mixture.
Scheme 3. Attempted synthesis of O-TBS 5-hydroxy β-diketone 14.
Alternatively, the synthesis of 5-hydroxy β-diketone 15 via partial reduction of phloroglucinol 10
was pursued. It was reported that partial reduction of 10 always formed the corresponding sodium
salt of 5-hydroxy β-diketone 15, which is prone to polymerization during neutralization and is
1
6
therefore difficult to isolate from the reaction mixture. Moreover, 5-hydroxy β-diketone 15
prepared by reduction of phloroglucinol in an alkaline methanolic solution was found to be stable

in its sodium salt form, but dehydrated in a strongly acidic solution to afford resorcinol. As a result,
it was isolated in high yield by passing the reaction mixture through a sulfoacidic cationite resin
1
7
column eluting with methanol. Unexpectedly, the hydrogenation of 10 using Raney Nickel in an
+
alkaline ethanol solution and acidification with H cation exchange resin (D-072), gave the desired
5-hydroxy β-diketone 15 as the major product in 72% yield, along with an unexpected
etherification product 3-ethoxy-5-hydroxycyclohex-2-enone 16 in 10% yield (Scheme 4).
Furthermore, upon increasing the acidification time using an acidic cation exchange resin, enone
16 was isolated in an increased yield. After stirring the reaction solution with an acidic cation
exchange resin for 2 h, the reaction afforded compound 16 as a single product in 83% yield.
Scheme 4. Synthesis of 5-hydroxy β-diketone.
Next, completion of the total synthesis of AB5046A 8 and AB5046B 9 using 16 as a key
intermediate was investigated (Scheme 5). The 5-hydroxy group in 16 was first protected using
chloromethylmethyl ether (MOMCl) in the presence of N-diisopropylethylamine (DIPEA) and
4-dimethylaminopyridine (DMAP), affording enone 17 in 80% yield. Removal of the ethyl group
in ether 17 proceeded with 3M HCl in THF to give β-diketone 18 in 85% yield, which was readily
converted into the C2-acylated triketones 19 and 20 in the presence of dicyclohexlcarbodiimide
1
8
(
DCC) and DMAP at room temperature in 77% and 71% yield, respectively. Finally, treatment
of 5-O-protected triketones 19 and 20 with trimethylsilyl iodine (TMSI) in the presence of 4Å
1
9
o
MS at –30 C provided the target natural products AB5046A 8 and AB5046B 9 in 83% and 70%
yield, respectively. The spectroscopic data of both compounds matches completely those recorded
1
1
for the natural products.
Scheme 5. Synthesis of AB5046A and AB5046B.
In summary, an efficient total synthesis of the naturally occurring β-triketones AB5046A and
AB5046B has been completed using phloroglucinol as a starting material. Both natural products
were concisely synthesized in five linear steps with overall yields of 36% and 28%, respectively.
The present strategy provides an efficient approach to the synthesis of 5-oxo β-triketone
derivatives from inexpensive phloroglucinol. The synthesis of related analogues using the
abovementioned method and evaluation of their herbicidal activity are currently being pursued.

Acknowledgement
This work was supported by Special Fund for Agro-Scientific Research in the Public Interest
(
Grant No. 201403030).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/xxx/xxx
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Graphic abstract
Concise total synthesis of AB5046A and AB5046B
a
a
a,
a,b,
Lu-Yao Kong , Qing Cui , Zhong jin *, Xiao-Hua Xu
*
An efficient total synthesis of naturally occurring 5-oxo β-triketones, AB5046A and AB5046B,
was achieved utilizing the commercial available phloroglucinol as a starting material.

Highlights
Concise total synthesis of AB5046A and AB5046B
a
a
a,
a,b,
Lu-Yao Kong , Qing Cui , Zhong Jin *, Xiao-Hua Xu
*
●
●
●
Total synthesis of two naturally occurring rare 5-oxo β-triketones
Five linear steps with high overall yields for AB5046A and AB5046B
Practical preparation of 3-ethoxy-5-hydroxycyclohex-2-enone from phloroglucinol