The Synthesis of Certain Phomentrioloxin A Analogues and Their Evaluation as Herbicidal Agents

Article abstract of DOI:10.1021/acs.joc.6b02372

A series of 28 analogues of the phytotoxic geranylcyclohexentriol (-)-phomentrioloxin A (1) has been synthesized through cross-couplings of various enantiomerically pure haloconduritols or certain deoxygenated derivatives with either terminal alkynes or borylated alkenes. Some of these analogues display modest herbicidal activities, and physiological profiling studies suggest that analogue 4 inhibits photosystem II in isolated thylakoids in vitro.

Full text of DOI:10.1021/acs.joc.6b02372

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Article
The Synthesis of Certain Phomentrioloxin A
Analogues and Their Evaluation as Herbicidal Agents
Ehab S. Taher, Prue Guest, Amanda Benton, Xinghua Ma, Martin Gerhardt
Banwell, Anthony C. Willis, Tobias Seiser, Trevor W. Newton, and Johannes Hutzler
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02372 • Publication Date (Web): 05 Dec 2016
Downloaded from http://pubs.acs.org on December 9, 2016
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The Synthesis of Certain Phomentrioloxin A Analogues and Their Evaluation as
Herbicidal Agents
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Ehab S. Taher,† Prue Guest,† Amanda Benton,† Xinghua Ma,† Martin G. Banwell,*, †
Anthony C. Willis,† Tobias Seiser,‡ Trevor W. Newton‡ and Johannes Hutzler‡
†Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 2601, Australia
‡BASF SE, CarlꢀBoschstrasse 38, 67056 Luwigshafen, Germany
ABSTRACT: A series of 28 analogues of the phytotoxic geranylcyclohexentriol (–)ꢀphomentrioloxin A (1)
has been synthesised through crossꢀcouplings of various enantiomerically pure haloconduritols or certain
deoxygenated derivatives with either terminal alkynes or borylated alkenes. Some of these analogues
display modest herbicidal activities and physiological profiling studies suggest that analogue 4 inhibits
photosystem II in isolated thylakoids in vitro.
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INTRODUCTION
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Among agricultural pests, weeds have the most significant adverse effects on crop
productivity1 and the absence of good means for controlling them is a primary source of
concern for farmers.2 As a consequence, herbicidal applications outstrip the combined
use of fungicides and insecticides in the USA and probably in many other countries as
well.3 The ongoing development of resistance to current herbicides has prompted an
intense search for new ones with novel modes of action but there has been little recent
success in this regard.4
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Natural products (NPs) have attracted attention as potential sources of new agrochemicals
or at least inspirations for them.5 However, in contrast to the impressive contributions
NPs have made to the development of new therapeutic agents,6 they have not, thus far,
been particularly useful sources of herbicides.4,5 In an effort to redress this situation,
certain studies have focussed on phytotoxic metabolites produced by fungi associated
with economically significant weeds. For example, while seeking new agents to control
the saffron thistle (Carthamus lantus L. ssp. lanatus), a widespread winterꢀgrowing
annual weed of both pastures and crops that has been declared noxious throughout
Australia, Evidente and coꢀworkers7 identified pathogenic strains of Phomopsis sp. and
the teleomorph Diaporthe gulyae associated, respectively, with diseased strains of the
saffron thistle and with the sunflower (Helianthus annuus L.). Three of the various
phytotoxic metabolites produced by these fungi were identified as phomentrioloxins AꢀC
(structures 1ꢀ3, respectively, in Figure 1) that embody a polyoxygenated cyclohexene
“core” and a geranylꢀtype “sideꢀchain”. The illustrated structure of the first of these
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metabolites, viz. compound 1, was confirmed by our synthesis8 of it from a homochiral
cisꢀ1,2ꢀdihydrocatechol of defined absolute stereochemistry that is readily produced
through the wholeꢀcell biotransformation of iodobenzene. A key feature of our synthesis
was the linking of an iodinated monoꢀOꢀmethylated conduritol with the relevant terminal
alkyne using a Sonogashira crossꢀcoupling reaction.
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OMe
OMe
OMe
HO
OH
O
HO
OH
OH
HO
O
OH
2
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Figure 1: The Structures of Phomentrioloxins AꢀC (1ꢀ3, respectively)
Evidente and coꢀworkers carried out a small structureꢀactivity relationship study on
derivatives of phomentrioloxin A. This revealed that various structural modifications of it
led to changes in phytotoxic properties7a,9 and, as a result, it was suggested that such
natural products could form the basis for developing mycoherbicides for the biocontrol of
noxious weeds including saffron thistle. Given the potential flexibility of our synthetic
route to natural product 1 we sought to prepare a collection of otherwise difficultꢀtoꢀ
access analogues and subject these to commerciallyꢀrelevant screening regimes, including
ones that could provide insights into their modes of action. The outcomes of such studies
are reported here.
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RESULTS AND DISCUSSION
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Chemical Synthesis Studies
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The first tranche of phomentrioloxin analogues to be prepared were compounds 4ꢀ14
(Figure 2) wherein variations were made to the nature of the oxygenation pattern in the
cyclohexene core and, in parallel, to the degree of unsaturation in the geranylꢀtype tail
(see structures 10ꢀ14).
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OMe
OH
OMe
OH
OH
OH
MeO
OH
OH
OH
OH
MeO
OH
OH
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OMe
OMe
OMe
OMe
MeO
OH
OH
MeO
OH
OH
HO
OH
OH
MeO
O
O
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10
9
OMe
OMe
OMe
HO
HO
HO
OH
OH
O
O
O
O
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12
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Figure 2: The Phomentrioloxin Analogues 4ꢀ14 Prepared for the Present Study that
Retain the Geranylꢀtype Sideꢀchain
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The second tranche of analogues, namely compounds 15ꢀ22 (Figure 3), also involved
variations in the nature of the oxygenation pattern within the core and, more significantly,
variations to the sideꢀchain. Specifically, the geranylꢀtype tail associated with the natural
product 1 was replaced with a C10ꢀcontaining arylacetylene unit that it was thought would
represent a similarly lipophilic but potentially more stable motif. Several 3,5ꢀdimethoxyꢀ
substituted arylacetylene sideꢀchains were introduced in an effort to explore the impact of
modifications to electron density within this part of the molecular framework.
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OMe
OMe
OMe
OH
HO
OH
OH
MeO
OH
OH
HO
OH
OH
MeO
OH
OH
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OMe
OMe
OMe
OMe
HO
HO
OH
OH
MeO
MeO
OH
O
O
O
O
OH
MeO
OMe
MeO
OMe
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Figure 3: The Phomentrioloxin Analogues 15ꢀ22 Prepared for the Present Study and
Incorporating a Phenylacetyleneꢀtype Sideꢀchain.
The final tranche of analogues, namely compounds 23ꢀ31 (Figure 4), involved, inter alia,
systems incorporating Eꢀ or Zꢀconfigured styrenyl or βꢀarylethylꢀtype sideꢀchains as well
as variations within the core. Throughout the collection of analogues certain acetonideꢀ
containing precursors were also tested as another means of investigating the impact of
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increased lipophilicity of the cyclohexene core on activity. The exhaustively protected
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precursor, 31, to triol 29 was also subject to biological evaluation for the same reasons.
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OMe
OMe
OMe
HO
OH
OH
MeO
OH
OH
HO
OH
OH
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OMe
MeO
OH
OMe
OMe
OH
HO
OH
OH
MeO
OH
OH
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OMe
OMe
OMe
HO
OH
OH
OH
TIPSO
O
O
O
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Figure 4: The Phomentrioloxin Analogues 23ꢀ31 Prepared for the Present Study and
Incorporating a Styrenyl or Phenylethaneꢀtype Sideꢀchain.
The reaction sequence shown in Scheme 1 is indicative of the protocols employed in the
synthesis of the aboveꢀmentioned phomentrioloxin A analogues. It follows that employed
in our synthesis of the “parent” system 1.8 Thus, the cisꢀ1,2ꢀdihydrocatechol 32, which is
readily obtained in enantiomerically pure form through the wholeꢀcell biotransformation
of iodobenzene,10,11 was converted into the corresponding acetonide under previously
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defined conditions and thus affording the known12 and rather unstable compound 33.
Regioꢀ and diastereoꢀselective cisꢀdihydroxylation of the nonꢀhalogenated double bond
within diene 33 proceeded readily under the UpJohn conditions13 to give diol 3412 (62%
from 32) that was subject to twoꢀfold Oꢀmethylation using methyl iodide and thus
providing the bisꢀether 35 in 47% yield. Sonogashira crossꢀcoupling of this last
compound with the known14 and readily accessible terminal alkyne 36 under standard
conditions using cuprous iodide and PdCl2(PPh3)2 in the presence of diethylamine then
gave the targeted phomentrioloxin analogue 9 in 48% yield.
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Scheme 1: Synthetic Sequence Used to Prepare Phomentrioloxin Analogues 8 and 9
OH
OsO4, NMO,
acetone/water
2,2ꢀDMP,
OH
OH
HO
O
O
O
O
pꢀTsOH
18 °C, 1 h
0ꢀ18 °C, 8 h
I
I
I
62% (from 32)
32
34
33
MeI, NaH, 0 °C, 2 h
THF
47%
OMe
MeO
O
O
OMe
OMe
I
MeO
MeO
OH
OH
O
O
CuI,
PdCl2(PPh3)2
35
AcOH/water
+
70 °C, 5 h
81%
Et2NH,
18 °C, 3 h
48%
H
8
9
36
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Hydrolytic cleavage of the acetonide residue within the last compound could be achieved
by heating it in an acetic acid/water mixture at 70 °C for 5 h and thus affording an Oꢀ
methyl ether derivative, 8, of phomentrioloxin in 81% yield. All the spectral data
acquired on compounds 8 and 9 were in complete accord with the assigned structures.
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The syntheses of remaining analogues used in this study are detailed below. In broad
terms, these involved straightforward modifications of the protocols defined above with
the head and tail “sections”/sideꢀchains of these analogues being linked through either
Sonogashira or SuzukiꢀMiyaura crossꢀcoupling protocols. Postꢀcoupling chemical
modifications included acetonide group cleavages, thermally induced Zꢀ to Eꢀolefin
isomerizations, and/or exhaustive catalytic hydrogenations of the olefinic residues within
compounds 23 and 24 (and thus affording, as single diastereoisomers, 25 and 26,
respectively).
The formation of the 7ꢀoxobicyclo[2.2.1]hepteneꢀcontaining analogue 30 from precursor
27 on thermolysis in refluxing chlorobenzene (Scheme 2) clearly involves a
cyclodehydration reaction. Interestingly, under the conditions used there was no
accompanying Zꢀ to Eꢀisomerisation of the styrenyl double bond.
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Scheme 2: Thermally Induced Cyclodehydration of Triol 27 Leading to Compound
30.
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OMe
OMe
O
HO
OH
OH
OH
ClC6H5
reflux
24 h, 25%
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30
Singleꢀcrystal Xꢀray analyses were secured on compounds 15, 23 and 27 as well as
certain precursors to congeners 7, 8, 9 and 17. Details of these are provided in the
Experimental Section and the SI.
The reaction sequence used to prepare compound 4, one of the more active of the
phomentrioloxin analogues, is shown in Scheme 3. Thus, the previously reported epoxide
38,15 which is readily obtained over two steps from diol 34, was subjected to reductive
cleavage with DIBAlꢀH and thus providing the homoallylic alcohol 39 (72%). Oꢀ
Methylation of the last compound under IrvineꢀPurdie conditions then gave ether 40
(47%), the acetonide residue of which was cleaved using acidified AGꢀ50WꢀX8 resin in
THF/methanol to afford cisꢀdiol 41 (88%). Finally, Sonogashira coupling of compound
41 with dienyne 36 under essentially the same conditions as described above for the
conversion 35 + 36 → 9 gave analogue 4 in 64% yield.
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Scheme 3: Reaction Sequence Leading to Phomentrioloxin A Analogue 4
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AcO
Cl
O
OAc
OH
O
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NaOMe
Et2O
Cl
HO
O
O
O
O
O
O
MeCN
0 °C, 1 h
95%
0ꢀ18 °C, 12 h
76%
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I
I
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37
34
DIBAlꢀH
Et2O
–40 °C, 3 h
72%
OMe
OH
OMe
AGꢀ50WꢀX8
acidic resin
OH
OH
O
O
MeI, Ag2O
O
MeOH/THF
20 °C, 24 h
88%
MeCN
82 °C, 16 h
47%
O
I
I
I
39
40
41
compound 36
CuI,
PdCl2(PPh3)2
Et2NH,
20 °C, 20 h
64%
OMe
OH
OH
4
A related sequence of reactions, as shown in Scheme 4, was used to obtain analogue 5.
Thus, compound 3210 was treated with Nꢀbromosuccinimide (NBS) in wet THF and the
resulting bromohydrin 4216 immediately treated with 2,2ꢀdimethoxypropane (2,2ꢀDMP)
and pꢀtoluenesulfonic acid monohydrate (pꢀTsOH•H2O) and sp producing acetonide 43
(71% from 32). Reaction of this last compound with sodium hydroxide in a water/glyme
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mixture then gave epoxide 44 (44%) that was reductively cleaved with DIBAlꢀH and so
producing alcohol 45 (66%) that was Oꢀmethylated under standard conditions and thus
providing ether 46 (71%). An acetonide hydrolysis/Sonogashira coupling sequence then
gave, via intermediate diol 47 (64%) the target analogue 5 in 60% yield over the last step.
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Scheme 4: Reaction Sequence Leading to Phomentrioloxin A Analogue 5
Br
Br
2,2ꢀDMP
NBS
HO
HO
O
O
OH
OH
OH
OH
pꢀTsOH•H2O
THF/water
20 °C, 18 h
71% (from 32)
20 °C, 18 h
I
I
I
32
43
42
aq. NaOH 20 °C, 48 h
DME 44%
OMe
OH
DIBAlꢀH
Et2O
O
MeI, Ag2O
O
O
O
–40 to 20 °C
20 h, 66%
MeCN
82 °C, 19 h
71%
O
O
O
I
I
I
44
45
46
MeOH/THF
20 °C, 24 h
64%
AGꢀ50WꢀX8
acidic resin
OMe
compound 36
CuI,
PdCl2(PPh3)2
OH
OH
OMe
OH
OH
Et2NH,
20 °C, 21 h
60%
I
47
5
Phomentrioloxin analogue 6 was readily produced from epoxide 38 (Scheme 5) by
reacting this with methanol in the presence of (+)ꢀcamphorsulfonic acid [(+)ꢀCSA]. The
protected conduritol 48 (45%) thus obtained was subjected to acetonide hydrolysis under
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standard conditions and so affording triol 49 (75%). Sonogashira crossꢀcoupling of this
last compound with terminal alkyne 36 then gave compound 6 (40%).
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Scheme 5: Reaction Sequence Leading to Phomentrioloxin A Analogue 6
OH
OH
O
AGꢀ50WꢀX8
acidic resin
MeOH
MeO
MeO
OH
OH
O
O
O
O
(+)ꢀCSA
MeOH/THF
20 °C, 48 h
75%
CHCl3
20 °C, 0.5 h
45%
I
I
I
49
38
48
compound 36
CuI,
PdCl2(PPh3)2
Et2NH,
20 °C, 22 h
40%
OH
MeO
OH
OH
6
The preparation of analogue 7 followed very much the same sort of synthetic pathway
(Scheme 6). Thus, the acetonide unit within the product, 50 (93%), of acidꢀcatalyzed
methanolysis of epoxide 44 was cleaved in the usual way to give triol 51 (36%) that was
itself crossꢀcoupled with alkyne 36 and so affording compound 7 (34%).
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Scheme 6: Reaction Sequence Leading to Phomentrioloxin A Analogue 7
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9
OH
OH
O
AGꢀ50WꢀX8
acidic resin
MeOH
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MeO
MeO
OH
OH
O
O
O
O
(+)ꢀCSA
MeOH/THF
20 °C, 48 h
36%
CHCl3
20 °C, 0.5 h
93%
I
I
I
51
44
50
compound 36
CuI,
PdCl2(PPh3)2
Et2NH,
20 °C, 21 h
34%
OH
MeO
OH
OH
7
The reaction sequence used to prepare the enyne sideꢀchain synthon required for the
preparation of analogues 10ꢀ14 is shown in Scheme 7. This started with the commercially
available and unsaturated ketone 52 that was hydrogenated under conventional conditions
to afforded its saturated counterpart 5317 (81%). This was converted, via a kineticallyꢀ
controlled deprotonation process, into the enol triflate 54 (68%) that was itself subjected
to a Sonogashira crossꢀcoupling reaction with trimethylsilylacetylene and so affording the
silylꢀcapped alkyne 55 (85%). Treatment of this last compound with potassium carbonate
in methanol resulted in removal of the silyl group and the formation of the required
terminal alkyne 56 (73%).
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Scheme 7: Reaction Sequence Leading to the Side-Chain Synthon 56 for the
Preparation of Analogues 10-14
6
7
8
9
(i) iꢀPr2NH
nꢀBuLi
H2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
THF, –78 °C, 1 h
10% Pd on C
OTf
O
O
(ii) PhNTf2, THF
–78 to18 °C, 18 h
68%
MeOH
18 °C, 5 h
81%
54
52
53
TMSCCH
PdCl2(CH3CN)2, CuI
THF, piperidine
18 °C, 1 h
85%
TMS
K2CO3
MeOH
18 °C, 2 h
73%
56
55
The sideꢀchain synthon 56 was first exploited in the synthesis of the phomentrioloxin
analogue 10 by using the reaction sequence shown in Scheme 8. Thus, alcohol 57,8 the
previously reported product of the regioꢀcontrolled Oꢀsilylation of diol 34, was subject to
reaction with methyl iodide in the presence sodium hydride and a chromatographically
separable mixture of the regioꢀisomeric Oꢀmethyl ethers 58 (8%) and 598 (90%) thereby
obtained. Heating a solution of the latter product with wet acetic acid resulted in
hydrolysis of the acetonide group and formation of diol 608 (68%) that was coupled with
compound 56 under the now standard Sonogashira conditions and thus producing
analogue 10 in 80% yield.
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Scheme 8: Reaction Sequence Leading to Phomentrioloxin A Analogue 10
5
6
7
8
9
OTIPS
MeO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
I
58
(8%)
OH
OH
TIPSOTf
HO
TIPSO
O
O
O
O
2,6ꢀlutidine
MeI, NaH
+
THF
0 °C, 2 h
CH2Cl2
–78 °C to 18 °C, 3 h
84%
I
I
OMe
TIPSO
O
O
34
57
I
59
(90%)
AcOH/water
70 °C, 18 h
68%
OMe
HO
OH
OH
compound 56
OMe
CuI
HO
PdCl2(PPh3)2
OH
OH
Et2NH
18 °C, 3 h
80%
I
60
10
In a slightly different timing of the sideꢀchain installation process, bisꢀether 35 (Scheme
9) was crossꢀcoupled with enyne 56 to give compound 61 (96%) that was itself subject to
acetonide hydrolysis using acetic acid/water. By such means analogue 11 was obtained in
60% yield.
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Scheme 9: Reaction Sequence Leading to Phomentrioloxin A Analogue 11
5
6
7
8
9
OMe
OMe
compound 56
CuI
PdCl2(PPh3)2
OMe
MeO
MeO
O
O
OH
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeO
AcOH/water
O
O
Et2NH
18 °C, 3 h
96%
70 °C, 14 h
60%
I
35
61
11
As was the case with analogue 6, epoxide 38 served as the starting material for the
synthesis of the cyclohexeneꢀcontaining headꢀgroup associated with target compounds 12
and 14 (Scheme 10). In the present case, however, the threeꢀmembered ring within
compound 38 was cleaved with potassium hydroxide and the transꢀdiol 6215 (72%) soꢀ
formed was selectively silylated at the oxygen of the allylic alcohol moiety (rather than
the homoallylic one) using triꢀisoꢀpropylsilyl triflate (TIPSOTf) in the presence of 2,6ꢀ
lutidine and so producing compound 63 (49%). OꢀMethylation of this last compound
proceeded uneventfully and product 64 (65%) was then treated with tetraꢀnꢀ
butylammonium fluoride (TBAF) to give the protected conduritol 65 (90%) that could be
crossꢀcoupled with terminal alkyne 56 to give analogue 14 (68%). Cleavage of the
acetonide residue within this last compound was a straightforward matter and analogue
12 (72%) was thereby obtained.
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Scheme 10: Reaction Sequence Leading to Phomentrioloxin A Analogues 12 and 14
5
6
7
8
9
OH
OH
O
KOH
TIPSOTf
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TIPSO
HO
O
O
O
O
O
O
THF/water
2,6ꢀlutidene
reflux, 48 h
72%
CH2Cl2
–78 to 18 °C, 3 h
49%
I
I
I
63
38
62
MeI, NaH
THF
0 °C, 3 h, 65%
OMe
HO
compound 56
O
O
OMe
OMe
CuI,
TBAF
THF
HO
TIPSO
O
O
O
PdCl2(PPh3)2
Et2NH,
18 °C, 3 h, 68%
18 °C, 2 h
90%
O
I
I
14
65
64
AcOH/water
70 °C, 5 h
72%
OMe
HO
OH
OH
12
The synthesis of analogue 13 is shown in Scheme 11 and exploited an intermediate
associated with the preparation of congener 10 (see Scheme 8). Thus, silyl ether 59 was
treated with TBAF and the resulting alcohol 668 (88%) was then crossꢀcoupled with
enyne 56 in the usual manner and so affording target compound 13 (70%).
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Scheme 11: Reaction Sequence Leading to Phomentrioloxin A Analogue 13
5
6
7
8
9
OMe
OMe
TBAF
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HO
TIPSO
O
O
O
O
18 °C, 2 h
88%
I
I
59
66
compound 56
CuI, PdCl2(PPh3)2
Et2NH,
18 °C, 3 h, 70%
OMe
HO
O
O
13
The aromatic sideꢀchain synthon required for the assembly of the phomentrioloxin
analogues 15ꢀ20 was prepared by the very straightforward reaction sequences shown in
Scheme 12. Thus, the commercially available iodide 67 was crossꢀcoupled with
trimethylsilylacetylene and the product alkyne 68 (68%) treated with potassium carbonate
in methanol and thus delivering the required and previously reported synthon 6918 in 72%
yield. The corresponding dimethoxylated synthon 70 was a commercially available
material.
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Scheme 12: Reaction Sequence Leading to the Side-Chain Synthon 69 for the
Preparation of Analogues 15-20
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
TMS
I
TMSCCH, CuI
K2CO3
PdCl2(PPh3)2
MeOH
Et2NH, 18 °C
18 °C, 1 h
72%
3 h
MeO
OMe
68%
67
70
68
69
Synthon 69 was first exploited in the synthesis of analogues 15 and 19 by crossꢀcoupling
the former compound with the iodinated cyclohexene 66. This process delivered
compound 19 (76%) and the associated acetonide residue was cleaved using aqueous acid
acid and thus affording the triol 15, albeit in just trace amounts.
Scheme 13: Reaction Sequence Leading to Phomentrioloxin A Analogues 15 and 19
OMe
OMe
compound 69
CuI,
PdCl2(PPh3)2
OMe
HO
HO
O
O
OH
OH
HO
AcOH/water
O
O
70 °C, 5 h
trace
Et2NH,
18 °C, 3 h, 76%
I
66
19
15
A closely related reaction sequence, as shown in Scheme 14, lead from conduritol 35, via
analogue 20 (72%), to diol 16 although, once again, this last compound was only
obtained in trace amounts.
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Scheme 14: Reaction Sequence Leading to Phomentrioloxin A Analogues 16 and 20
5
6
7
8
9
OMe
OMe
compound 69
CuI,
PdCl2(PPh3)2
OMe
MeO
MeO
O
O
OH
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeO
AcOH/water
O
O
70 °C, 5 h
trace
Et2NH,
18 °C, 3 h, 72%
I
35
20
16
The synthesis of analogue 17 was a little more involved and started (Scheme 15) by
treating silyl ether 58 with TBAF. The acetonide residue associated the product alcohol
71 (80%) was hydrolyzed using aqueous acetic acid and the resulting triol 72 (72%)
crossꢀcoupled with alkyne 69 to give the target compound 17 (73%).
Scheme 15: Reaction Sequence Leading to Phomentrioloxin A Analogue 17
OH
OTIPS
MeO
MeO
O
O
O
TBAF
THF
18 °C, 2 h
80%
O
I
I
71
58
AcOH/water
70 °C, 18 h
72%
OH
MeO
OH
OH
OH
compound 69
CuI,
PdCl2(PPh3)2
MeO
OH
OH
Et2NH,
18 °C, 3 h, 73%
I
72
17
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Closely related reactions sequences were used to prepare analogues 18 (Scheme 16), 21
(Scheme 17) and 22 (Scheme 18).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 16: Reaction Sequence Leading to Phomentrioloxin A Analogue 18
OMe
compound 69
OMe
OMe
HO
OH
OH
CuI,
HO
HO
O
O
OH
OH
PdCl2(PPh3)2
AcOH/water
70 °C, 18 h
78%
Et2NH,
18 °C, 3 h, 70%
I
I
65
73
18
Scheme 17: Reaction Sequence Leading to Phomentrioloxin A Analogue 21
OMe
compound 70
OMe
HO
OH
OH
CuI,
HO
OH
OH
PdCl2(PPh3)2
Et2NH,
18 °C, 3 h, 62%
I
60
MeO
OMe
21
Scheme 18: Reaction Sequence Leading to Phomentrioloxin A Analogue 22
OMe
compound 70
OMe
MeO
OMe
OH
OH
CuI,
MeO
MeO
AcOH/water
OH
OH
PdCl2(PPh3)2
O
O
70 °C, 14 h
70%
Et2NH,
18 °C, 3 h, 62%
I
I
35
74
MeO
OMe
22
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9
The synthesis of the final sideꢀchain synthon required for the present study is shown in
Scheme 19 and simply involved the rhodiumꢀcatalysed and selective addition of pinacol
borane (75) to terminal alkyne 69 and so affording the Zꢀconfigured and βꢀsubstituted
styrene 76 in 52% yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 19: Reaction Sequence Leading to the Side-Chain Synthon 76 for the
Preparation of Analogues 27-31
Sideꢀchain synthon 76 was first exploited in the preparation of the phomentrioloxin
analogues 23, 25 and 27 as shown in Scheme 20. Thus, SuzukiꢀMiyaura crossꢀcoupling
of compound 76 with the conduritol 60 gave analogue 27 (80%) that upon hydrogenation
using 5% rhodium on carbon as catalyst delivered the cyclohexane 25 in 47% yield and
as a single diastereoisomer. The illustrated configuration at the newly created stereogenic
center within compound 25 is assigned on the basis that the hydroxyl groups within
substrate 27 will direct the delivery of hydrogen from the αꢀface and so establishing a βꢀ
oriented sideꢀchain. Extended thermolysis of the Zꢀconfigured alkene 27 in refluxing
chlorobenzene afforded the corresponding Eꢀisomer 23 in 85% yield based on recovered
starting material (brsm).
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Scheme 20: Reaction Sequence Leading to Phomentrioloxin A Analogues 23, 25 and
27
6
7
8
9
OMe
HO
OH
OH
OMe
OMe
compound 76
PdCl2(dppf)•CH2Cl2
HO
OH
OH
H2
HO
OH
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5% Rh on C
Et3N, THF/water
18 °C, 2 h, 80%
MeOH
18 °C, 2 h
47%
I
60
27
25
ClC6H5
reflux, 144 h
85% (brsm)
OMe
HO
OH
OH
23
An analogous series of reactions (Scheme 21) starting with diol 74 led, via Zꢀalkene 28
(78%), to the Eꢀalkene 24 (80% brsm) and to cyclohexane 26 (40%).
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Scheme 21: Reaction Sequence Leading to Phomentrioloxin A Analogues 24, 26 and
28
6
7
8
9
OMe
MeO
OH
OH
OMe
OMe
compound 76
PdCl2(dppf)•CH2Cl2
MeO
OH
OH
H2
MeO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
OH
5 % Rh on C
Et3N, THF/water
18 °C, 2 h, 78%
MeOH
18 °C, 2 h
40%
I
74
28
26
ClC6H5
reflux, 144 h
80% (brsm)
OMe
MeO
OH
OH
24
A more involved reaction sequence was required to secure analogues 29 and 31. Thus, as
shown in Scheme 22, the homochiral cisꢀ1,2ꢀdihydrocatechol 77 was first converted into
the corresponding and wellꢀknown acetonide 78 (85%) under relatively standard
conditions and the latter then subject to a regioꢀ and diastereoꢀselective epoxidation
reaction using mꢀchloroperbenzoic acid (mꢀCPBA). The product oxirane 79 (85%) was
then cleaved using potassium hydroxide in aqueous THF and the resulting transꢀdiol 8019
(70%) selectively monoꢀOꢀsilylated using TIPSOTf in the presence of 2,6ꢀlutidine. The
homoallylic alcohol 81 (51%) soꢀformed was Oꢀmethylated using methyl iodide in the
presence of sodium hydride and the methyl ether 82 (41%) thus obtained engaged in a
SuzukiꢀMiyaura crossꢀcoupling reaction with the borylated alkene 76 to afford analogue
31 (78%). Interestingly, when the last compound was heated in aqueous acetic acid the
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associated acetonide and silyl ether residues were cleaved but the Zꢀconfigured alkene
5
6
moiety remained intact and such that analogue 29 was obtained in 70% yield.
7
8
9
Scheme 22: Reaction Sequence Leading to Phomentrioloxin A Analogues 29 and 31
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
2,2ꢀDMP,
O
O
O
O
OH
OH
mꢀCPBA
pꢀTsOH
CH2Cl2
0ꢀ18 °C, 15 h
85%
CH2Cl2
18 °C, 1 h
85%
Br
79
Br
Br
77
78
KOH
THF/water
ca. 60 °C, 48 h
70%
OMe
OH
OH
TIPSOTf
2,6ꢀlutidene
MeI
NaH
TIPSO
HO
TIPSO
O
O
O
O
THF
0 °C, 3 h
41%
CH2Cl2
–78 to 18 °C, 3 h
51%
O
O
Br
Br
Br
80
81
82
compound 76
PdCl2(dppf)•CH2Cl2
Et3N, THF/water
70 °C, 3 h, 78%
OMe
O
OMe
TIPSO
HO
OH
OH
AcOH/water
O
70 °C, 18 h
70%
31
29
Biological Evaluation Studies
The biological evaluations of compounds 1 and 4ꢀ31 were carried out at BASF’s facilities
at Limburgerhof in Germany. Preliminary evaluations of herbicidal activity were
conducted in a green house. The plant species used for this purpose were Setaria viridis
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(SETVI, green foxtail) and Amaranthus retroflexus (AMARE, pigweed). The outcomes
of conducting such tests are presented in Table 1 and represent the average rating for
each of the two plant species involved. In broad terms, the active compounds caused a
generalised necrosis of the aerial moieties of the plant species against which they were
tested and suggesting they are eliciting their effects via a nonspecific pathway. In
structureꢀactivity terms, variations in the locations, configurations, degrees of Oꢀ
methylation and/or deletions of oxygenꢀcontaining groups could have deleterious impacts
on activity (see Entries 4 and 6) and certainly no obviously beneficial ones (relative to the
parent system 1). Increasing the degree of saturation in the geranylꢀtype sideꢀchain also
had generally negative effects but replacement of such a moiety with an arylacetylene
equivalent led to series of analogues with more pronounced herbicidal effects (see Entries
14, 16, 18 and 20). In contrast, introduction of a styrenyl or βꢀarylethyl sideꢀchain had a
generally negative effect on activity – there were certainly no beneficial ones. A simple
interpretation of these results is that those compounds containing the more stable/durable
arylacetylenic sideꢀchains probably had the longest halfꢀlives under the extended testing
conditions involved and were thus able to exert more sustained herbicidal effects.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
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Table 1: The Evaluation of Phomentrioloxin Derivatives as Nonꢀspecific Herbicides
Against A. retroflexus and S. viridis.
Compounda
Compounda
Entry
Averaged
Resultb
+
Entry
Averaged
Resultb
++
1 c
4 c
5 c
6 c
7 c
8
18
19
20
21
22
23
24
25 d
26 d
27
28
29 d
30
31
–
1
2
16
17
18
19
20
21
22
23
24
25
26
27
28
29
+
+
0
+
++
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
4
5
+
0
++
0
6
7
+
0
0
9
8
0
10
11 c
12
13
14
15
16
17
9
+
0
+
10
11
12
13
14
15
+
+
0
0
+
+
++
+
+
+
–
–
b
c
aCompounds applied at 2 kg a.i./ha unless otherwise specified; Qualitative result over the two plant species used;
Compounds 1, 4, 5, 6, 7 and 11 were applied at 1 kg a.i./ha; d Compounds 25, 26 and 29 were applied at 1.145, 1. 333
and 1.625 kg a.i./ha, respectively. Evaluation was carried out using a scale from 0–100. 100 means complete
destruction of at least the aerial moieties, and 0 means no damage, or normal course of growth.) 0–25: 0 (no or very
low activity); >25–50: + (moderate activity); >50–75: ++ (good activity); >75: +++ (very good activity).
Physiological profiling (PP) protocols were used for the purposes of trying to draw
conclusions regarding the mode of action of the phomentrioloxin analogues as herbicides
as well as for ranking their selectivities and potencies. PP20 involves an array of
physiological and bioassays that allow for differentiation between the distinct responses
of different structures (whole plant, tissue, meristem cells, organelles), developmental
stages (seed germination, vegetative growth), types of metabolism (phototrophic,
heterotrophic) and physiological processes. The assays are designed to be sensitive, allow
facilitated uptake and translocation of the applied compounds and include all potential
herbicidal target sites. The bioassays included those involving heterotrophic cleaver
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(Galium mollugo) and photoautotrophic green alga (Scenedesmus obliquus) cell
suspensions, isolated white mustard (Sinapis alba) shoots and germinating cress
(Lepidum sativum) seeds. The physiological assays included studies of the Hill reaction
of isolated wheat thylakoids, respiration measurements in cleaver cell suspensions, the
formation of reactive oxygen species, chlorophyll fluorescence and ATP measurements
in Lemna plants, carbon dioxide assimilation measurements in cleaver (Galium aparine)
plants and toluidine blue staining of cress hypocotyls for detecting any inhibition of very
longꢀchain fatty acid (VLCFA) biosynthesis.
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In broad terms, phomentrioloxin A (1) as well as analogues 9 and 20 generated
weak/inconclusive PPs. Analogues 5, 6, 7 and 11 had minor effects on the growth of
heterotrophic Galium suspension cells, unicellular algae and Lemna plants indicating
uptake limitations or rapid metabolic detoxification. In addition, analogue 7 caused
moderate inhibition of cress germination in a lightꢀdependant manner. The most
consistent effect among these compounds was a moderate inhibition of carbon dioxide
assimilation indicating a notꢀfurtherꢀcharacterised inhibitory effect on photosynthesis.
Analogues 15, 16, 19 and 22 caused moderate inhibition of cell division in heterotrophic
suspension cells together with intensified green leaf pigmentation in Lemna plants. The
origins of these effects remain unknown. The PP of compound 4 differed somewhat from
the others as this analogue caused moderate inhibition of the Hill reaction and must thus
be having an effect on photosynthetic electronꢀflow. In addition, lightꢀdependant
inhibition of cress germination was observed. Inhibition of the Hill reaction is a typical
finding for photosystem II (PS II) inhibitors. However, such inhibitors are also usually
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strong inhibitors of algae and Lemna growth, a feature not observed for analogue 4. This
might indicate that the compound is able to inhibit PSII in isolated thylakoids in vitro but
is rapidly detoxified in a cellular environment.
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CONCLUSIONS
The present study serves to highlight the utility of our previously reported8 synthesis of
phomentrioloxin A in generating a diverse range of analogues. However, the biological
evaluation of these analogues has revealed that, as a class and despite some earlier
indications to the contrary,7a,9 the phomentrioloxins are unlikely to be useful leads for the
development of new herbicidal agents.
EXPERIMENTAL SECTION
General Protocols.
Unless otherwise specified, proton (1H) and carbon (13C) NMR spectra were recorded at
room temperature in baseꢀfiltered CDCl3 on a spectrometer operating at 400 MHz for
proton and 100 MHz for carbon nuclei. The signal due to residual CHCl3 appearing at δH
7.26 and the central resonance of the CDCl3 “triplet” appearing at δC 77.0 were used to
1
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1
reference H and C NMR spectra, respectively. H NMR data are recorded as follows:
chemical shift (δ) [multiplicity, coupling constant(s) J (Hz), relative integral] where
multiplicity is defined as: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet or
combinations of the above. Infrared spectra (νmax) were recorded on a FTIR
Spectrometer. Samples were analyzed as thin films on KBr plates. Lowꢀresolution ESI
mass spectra were recorded on a singleꢀquadrupole liquid chromatographꢀmass
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