Expedient synthesis of bisabolenol stink bug pheromones via stereodefined cyclohex-2-enones

Article abstract of DOI:10.1016/j.tetlet.2017.04.050

We recently synthesized all stereoisomers of 1,10-bisaboladien-3-ol and 10,11-epoxy-1-bisabolen-3-ol, including three stink bug pheromones, via a rhodium-catalyzed asymmetric addition of trimethylaluminum to diastereomeric mixtures of cyclohex-2-enones. However, yields of trans isomers were low, and scaling reactions using expensive catalysts were cumbersome. Now we describe a new synthesis of bisabolenol stink bug pheromones via (S)- and (R)-4-((R)-6-methylhept-5-en-2-yl)cyclohex-2-enones prepared by enantioselective Michael additions of methyl vinyl ketone to (S)- and (R)-citronellals and lithium hydroxide monohydrate-catalyzed stereoselective cyclizations of intermediate ketoaldehydes. Addition of methyllithium to these enones provided cis- and trans-1,10-bisaboladien-3-ols, which were separated by chromatography on silica and further converted to 10,11-epoxy-1-bisabolen-3-ols. Thus, we developed more convenient syntheses of pheromones of the rice stink bug, the harlequin bug, and brown marmorated stink bug.

Full text of DOI:10.1016/j.tetlet.2017.04.050

Accepted Manuscript
Expedient synthesis of bisabolenol stink bug pheromones via stereodefined cy-
clohex-2-enones
Shyam Shirali, Filadelfo Guzman, Donald C. Weber, Ashot Khrimian
PII:
S0040-4039(17)30488-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.050
TETL 48842
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 March 2017
12 April 2017
14 April 2017
Please cite this article as: Shirali, S., Guzman, F., Weber, D.C., Khrimian, A., Expedient synthesis of bisabolenol
stink bug pheromones via stereodefined cyclohex-2-enones, Tetrahedron Letters (2017), doi: http://dx.doi.org/
10.1016/j.tetlet.2017.04.050
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1
Expedient synthesis of bisabolenol stink bug pheromones
via stereodefined cyclohex-2-enones
Shyam Shirali, Filadelfo Guzman, Donald C. Weber, and Ashot Khrimian*
USDA-ARS, Invasive Insect Biocontrol and Behavior Laboratory, Beltsville Agricultural
Research Center, Bldg. 007, Rm. 301, 10300 Baltimore Avenue, Beltsville, MD 20705 USA.
* To whom correspondence should be addressed, e-mail: ashot.khrimian@ars.usda.gov. Tel:
(301) 504-6138. Fax: (301) 504-5104.

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ABSTRACT
We recently synthesized all stereoisomers of 1,10-bisaboladien-3-ol and 10,11-epoxy-1-
bisabolen-3-ol, including three stink bug pheromones, via a rhodium-catalyzed asymmetric
addition of trimethylaluminum to diastereomeric mixtures of cyclohex-2-enones. However,
yields of trans isomers were low, and scaling reactions using expensive catalysts were
cumbersome. Now we describe a new synthesis of bisabolenol stink bug pheromones via (S)-
and (R)-4-((R)-6-methylhept-5-en-2-yl)cyclohex-2-enones prepared by enantioselective Michael
additions of methyl vinyl ketone to (S)- and (R)-citronellals and lithium hydroxide monohydrate-
catalyzed stereoselective cyclizations of intermediate ketoaldehydes. Addition of methyllithium
to these enones provided cis- and trans-1,10-bisaboladien-3-ols, which were separated by
chromatography on silica and further converted to 10,11-epoxy-1-bisabolen-3-ols. Thus, we
developed more convenient syntheses of pheromones of the rice stink bug, the harlequin bug,
and brown marmorated stink bug.
Keywords: Rice stink bug; Oebalus poecilus; Brown marmorated stink bug; Halyomorpha
halys; Harlequin bug; Murgantia histrionic; Pheromones; Michael addition; Robinson annulation

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INTRODUCTION
There are at least four pentatomid stink bug species that use a bisabolenol entity in their
male-secreted pheromone molecules. The rice stalk stink bug, Tibraca limbativentris, sex
pheromone was identified as a mixture of two stereoisomers of zingiberenol, or 1,10-
bisaboladien-3-ol,1 without determining their absolute configuration.2 The sex pheromone of rice
stink bug, Oebalus poecilus, consists of a single isomer of zingiberenol identified as (3R,6R,7S)-
1,10-bisaboladien-3-ol (1).3,4 Interestingly, ginger rhizomes also produce this compound along
with (3S,6R,7S)-1,10-bisaboladien-3-ol (2), as minor components of their sesquiterpene content.5
The aggregation pheromone of the harlequin bug, Murgantia histrionica, was identified as
10,11-epoxy-1-bisabolen-3-ol6,7 and later revealed to be a 1.4:1 mixture of two stereoisomers,
(3S,6S,7R,10S)-10,11-epoxy-1-bisabolen-3-ol (3) and (3S,6S,7R,10R)-10,11-epoxy-1-bisabolen-
3-ol (4)8. Lastly, the brown marmorated stink bug, Halyomorpha halys, has been shown to share
compound 3 as the main component of its aggregation pheromone, along with (3R,6S,7R,10S)-
10,11-epoxy-1-bisabolen-3-ol (5), produced by the male bug in a 3.5:1 ratio.9 The last two stink
bug species are important agricultural pests for which the aggregation pheromones have
successfully been used for detection and monitoring.10,11
For syntheses of abovementioned bisabolenol stink bug pheromones, we earlier explored a
rhodium-catalyzed asymmetric addition of trimethylaluminum to diastereomeric mixtures of
cyclohex-2-enones.9 This conveniently provided two single stereoisomers from one reaction
(Scheme 1) and thus allowed us to build a full library of stereoisomers of bisaboladienols and
epoxybisabolenols.8,9

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Scheme 1. Previous approach (Ref. 9) to bisabolenol stink bug pheromones
However, the use of expensive catalysts and chiral reagents, and more importantly, low
yields of trans isomers, hampered the practical application of this method. To overcome these
shortcomings, we contemplated changing our strategy from the Rh-catalyzed enantioselective
addition to a carbonyl group to introducing chirality in the precursor cyclohexenone molecule
(i.e. ketones 6, and 7), then conducting a non-stereoselective addition of methyllithium and
capitalizing on easy separation of cis- and trans-1,10-bisaboladien-3-ols. Fortuitously, the
stereodefined cyclohex-2-enone 7 has recently been reported in literature,12 thus providing an
assurance for successfully accomplishing the chosen strategy for the synthesis of bisabolenol
stink bug pheromones.
RESULTS AND DISCUSSION
The catalytic enantioselective Michael addition14 of (S)-citronellal to methyl vinyl ketone in
the presence of (R)-diphenylprolinol methyl ether13 provided ketoaldehyde 8 in 65% yield and
95:5 dr (Scheme 2), with the diastereoselectivity in agreement with the originally reported

5
addition of (R)-citronellal to methyl vinyl ketone catalyzed by (S)-diphenylprolinol.12 The latter
reaction in our hands provided ketoaldehyde 9 in 69% yield and 96:4 dr.
Scheme 2. Syntheses of rice stink bug (1), brown marmorated stink bug (3+5), and harlequin bug
(3+4) pheromones through stereoisomeric cyclohexenones 6 and 7
The main challenge in the intramolecular aldol condensation of 8 and 9 to cyclohexenones 6
and 7, respectively, was the requirement to conduct them without significant epimerization at the
stereocenters adjacent to the aldehyde groups. Nicolaou et al. reported a base-catalyzed
cyclization of 9 using KOH/Bu4NOH that provided 7 in 85% yield and 12:1 (92:8) dr. 12
Somewhat reduced diastereoselectivity (83 % de, or 89:11 dr) in the same base-catalyzed

6
conversion of 9 to 7 was reported by others.15 Despite our concerted efforts, we were unable to
reproduce the described diastereoselectivity and isolated cyclohexenone 7 in 82:18 dr. We found
that a reflux of the reaction mixture with KOH/Bu4NOH under vigorous stirring for 8 hours as
recommended12 lead to a significant amount of an intermediate compound visible by TLC
(expectedly an aldol product), and the completion of condensation required a prolonged heating
(18-20 h) resulting in 82:18 dr, presumably due to epimerization to (R,R)-diastereomer of 7.16 In
fact, other authors applying the same KOH/Bu4NOH base system for the asymmetric synthesis of
a structurally analogous cryptone also reported a loss of enantiopurity from 92-95% ee (in
starting (S)-2-isopropyl-5-oxohexanal) to 56% ee in final (S)-cryptone.17 Intrigued by a
significant mitigation of the loss of enantiopurity when KOH/Bu4NOH was replaced by LiOH/i-
PrOH (89% ee, or 94.5:5.5 S/R),17 we became interested in using this base system for
cyclizations of ketoaldehydes 8 and 9. Thus, stirring aldehydes 8 and 9 in an 10% isopropanol
solution of lithium hydroxide hydrate at 25 oC for 5 h proceeded without significant
epimerization and provided ketones 6 and 7 in 66% and 67% yields, respectively, and 92:8 dr
(SM=Supplementary Material, p. 6–8). We also found that lithium hydroxide hydrate as a
source of LiOH provided a more reproducible and better stereochemical output than anhydrous
lithium hydroxide, and the cyclization is facilitated by an initial ultrasonication.
A non-stereoselective addition of methyllithium to enone 6 provided (3R,6R,7S)-1,10-
bisaboladien-3-ols (1) in 31% yield and 91:9 dr and (3R,6S,7R)-1,10-bisaboladien-3-ols (2) in
40% yield and 92:8 dr (SM, p. 9–12) easily separated by chromatography on silica. As
mentioned in the Introduction, dienol 1 is a pheromone of the rice stink bug, Oebalus poecilus,3,4
and both dienols 1 and 2 were also found in ginger.5 Analogously to the reaction with 6, a non-
stereoselective addition of methyllithium to enone 7 provided (3S,6S,7R)-1,10-bisaboladien-3-ol

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(10) in 35% yield and (3R,6S,7R)-1,10-bisaboladien-3-ol (11) in 45% yield. Thus, both H. halys
and M. histrionica pheromone precursors were synthesized from one reaction in comparable
yields, whereas the previous synthesis required two Rh-catalyzed reactions (one with (R)-BINAP
and the other one with (S)-BINAP) to make 10 and 11.9 Most importantly, the yield of the
sterically disfavored trans isomer 11 was improved from 5%9 to 45%. Enantioselective
epoxidations of bisaboladienols 10 and 11 were conducted via earlier described asymmetric
dihydroxylations, conversion of intermediate triols to secondary mesylates and further
eliminations to epoxides 3–5.9 The diastereomeric ratios of epoxides 3–5 were about 91:9 (SM,
pp. 13–18), somewhat lower than 95:5 dr reported for these compounds in the previous
communication.9 Hence, there was a need to compare the attractiveness of the newly synthesized
and the original epoxybisabolenol pheromone samples.
A short field trapping experiment with harlequin bugs showed that numbers of both adult and
nymphal bugs attracted to two pheromone treatments, 1.4:1 3/4, of 91:9 and 95:5 dr, were similar
(Table 1).
Table 1. Total numbers of harlequin bugs
attracted to host plants in three-way choice
test, Beltsville, Maryland, 18-24 August
2015.
Lure
treatment
Total adultsa Total nymphsa
1.4:1 3/4,
95:5 dr
120 a
99 a
2 b
37 a
35 a
0 b
1.4:1 3/4,
91:9 dr
Blank

8
a Within the same column, treatments followed by
the same letter do not differ (p<0.05) by exact
binomial test.18
Overall difference among the three treatments is significant by χ² goodness-of-fit test18 (for
adults, χ²=107.6, df=2, p<0.0001; for nymphs, χ²=36.1, df=2, p<0.0001), but these differences
were solely due to differences of both pheromone treatments compared to the blank. Thus,
pheromones produced by the current method can successfully be used for monitoring stink bug
populations.
In conclusion, a new method for the synthesis of bisabolenol stink bug pheromone via
cyclohexenones 6 and 7 was developed providing an easy access to both cis- and trans-1,10-
bisaboladien-3-ols. Because of the availability of both L- and D-prolines, starting compounds to
make (S)- and (R)-diphenylprolinol methyl ether catalysts, the method is expected to be
applicable for syntheses of all stereoisomers of 10,11-epoxy-1-bisabolen-3-ols and 1,10-
bisaboladien-3-ols.
ACKNOWLEDGMENT
Support for this study was from USDA, National Institute of Food and Agriculture, Specialty
Crop Research Initiative grant #2011-51181-30937.
SUPPLEMENTARY MATERIAL

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Supplementary information associated with this article including all experimental procedures and
1H NMR spectra can be found in the online version.
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Accessed 2 March.

Graphical Abstract

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Highlights
• 1,10-Bisaboladien-3-ols were synthesized via stereodefined cyclohex-2-enones
• Lithium hydroxide-catalyzed stereoselective aldol condensations were carried out
• Syntheses of pheromones of three stink bug species were accomplished