Total synthesis of haminol A: An analysis of vinylpyridine metathesis reactivity

Article abstract of DOI:10.1016/j.tetlet.2011.08.153

The total synthesis of haminol A has been completed featuring a masked-alkene metathesis reaction followed by bis-acyloxysulfone elimination to install the 1,3,8-triene subunit. During the course of our synthesis, the metathesis reactivity of 3-vinylpyridine was evaluated and our data suggest the rapid formation of a ruthenium pyridylalkylidene that no longer participates in productive metathesis. A chemotaxis assay using Caenorhabditis elegans demonstrated that haminol A produced an avoidance response from this organism.

Full text of DOI:10.1016/j.tetlet.2011.08.153

Tetrahedron Letters 52 (2011) 5858–5861
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of haminol A: an analysis of vinylpyridine metathesis reactivity
Jennifer M. Storvick a , Evgenia Ankoudinova b, Brianne R. King a, Heather Van Epps b, Gregory W. O’Neil a,
⇑
a Department of Chemistry, Western Washington University, Bellingham, WA 98225-9170, United States
b Department of Biology, Western Washington University, Bellingham, WA 98225-9160, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of haminol A has been completed featuring a masked-alkene metathesis reaction
followed by bis-acyloxysulfone elimination to install the 1,3,8-triene subunit. During the course of our
synthesis, the metathesis reactivity of 3-vinylpyridine was evaluated and our data suggest the rapid
formation of a ruthenium pyridylalkylidene that no longer participates in productive metathesis. A
chemotaxis assay using Caenorhabditis elegans demonstrated that haminol A produced an avoidance
response from this organism.
Received 13 August 2011
Revised 24 August 2011
Accepted 26 August 2011
Available online 2 September 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Olefin metathesis
b-Acyloxysulfones
Pyridine metathesis
Natural products
Alarm pheromones
Olefin metathesis has emerged as an extremely powerful car-
bonAcarbon bond forming reaction used in both organic and
polymersynthesis.1 Ongoingresearchcontinuestoproduceprogres-
sivelyselectiveandrobustcatalystsalongwithnovelapplicationsfor
the preparation of increasingly complex carbon frameworks.2 Re-
cently, our research group has been investigating the use of b-acyl-
oxysulfones as masked alkenes allowing for a metathesis approach
to polyene subunitsdifficult to prepare by standard metathesis tech-
nology.3 We became interested in applying this strategy to the
3-alkylpyridine alkaloid family of natural products that includes
haminols A (1) and B (Fig. 1).4 Originally isolated from the cephalas-
pidean mollusk Haminoea novicula,5 these compounds are also
produced by another species of the Haminoea family, H. orteai.6 This
type of interspecies promiscuity is not uncommon for alarm phero-
mones as evidenced by our own cross-genus behavioral assay,7
although it is often not well understood.8 The receptor and signaling
pathway for haminols A and B responsible for their behavioral activ-
ity are currently not known.
Analogous to our previously described metathesis-based
synthesis of 1,3,8-trienes,9 a synthesis of haminol A was envisaged
to arise by a cross-metathesis/acyloxysulfone reductive-elimina-
tion sequence between 3-vinylpyridine (2) and b-acyloxysulfone
3. Acyloxysulfone 3 was prepared by the addition of the lithium
anion of sulfone 410 to aldehyde 511 followed by in situ acylation
of the resulting alkoxide with benzoic anhydride (Bz2O) giving 3
in 64% yield as a mixture of diastereomers (Scheme 1).
3-Vinylpyridine (2) was prepared from nicotinaldehyde as pre-
viously described,12 that was then to be coupled with 3 by cross-
metathesis (Scheme 2). Compound 2 was deemed less precious
than benzoyloxysulfone 3 and was thus used in excess to statisti-
cally favor the formation of 6.13 Unfortunately, exposure of a
mixture of 2 and 3 to Grubbs’ first- or second-generation catalyst
(7) under a variety of conditions failed to produce any of the de-
sired cross-metathesis product 6, giving mostly unreacted starting
material in all cases.
Our group has successfully employed substrates of type 3 in a
variety of metathesis reactions.9 Initial thoughts, therefore, blamed
the failure of this reaction on the pyridine nitrogen atom as ligating
the ruthenium catalyst and thus altering its metathesis activity.
Pyridine complexes of Grubbs’-type ruthenium catalysts are well
known and have been studied in detail.14 In particular, the so-
called Grubbs’ third-generation catalyst (8) is rapidly formed upon
treatment of catalyst 7 with an excess of pyridine (Scheme 3).15
Importantly, however, complexes of type 8 generally retain
their activity as metathesis catalysts and in some instances display
enhanced metathesis performance compared to 7.16 The ability of
3-vinylpyridine to serve as a nitrogen-bound ligand, therefore,
does not necessarily render compounds of this type incapable of
successful metathesis. Indeed, exposure of 3-vinylpyridine to cata-
lyst 7 in the presence of a large excess of cis-1,4-diacetoxy-2-bu-
tene (9) cleanly gave adduct 10 in 85% yield (Scheme 4).17
To better understand this differential reactivity, the reaction of
3-vinylpyridine (2) with catalyst 7 was monitored by in situ NMR
analysis.18 Addition of a substoichiometric amount of 2 to 7 in C6D6
at room temperature (rt) led to the rapid formation of a new ruthe-
nium alkylidene signal as detected by 1H NMR along with the
⇑
Corresponding author. Tel.: +1 360 650 6283; fax: +1 360 650 2826.
E-mail address: oneil@chem.wwu.edu (G.W. O’Neil).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.153

J. M. Storvick et al. / Tetrahedron Letters 52 (2011) 5858–5861
5859
Figure 1. Masked-alkene metathesis.
Scheme 1. Masked-alkene metathesis triene synthesis.
Scheme 5. Selective ligand substitution by 3-vinylpyridine.
Scheme 2. Attempted 3-vinylpyridine metathesis.
Scheme 6. Metathesis reactivity of complex 12.
Scheme 3. Grubbs’ third-generation catalyst.
Scheme 4. Successful vinyl pyridine metathesis.
liberated styrene (11) (Scheme 5). The 31P NMR spectrum for this
reaction shows a single resonance at 31.0, indicative of tricyclohex-
ylphosphine bound to ruthenium when compared to the signals for
catalyst 7 and free tricyclohexylphosphine.
Figure 2. Vinyl pyridine metathesis reactivity.
an external alkene, as in the case of the reaction with cis-1,4-
diacetoxy-2-butene (Ref. Scheme 4), statistically prevents the
formation of this unproductive intermediate thereby allowing for
cross-metathesis to occur. These results should be considered
when designing a synthesis of vinylpyridine-containing com-
pounds where a cross-metathesis might be attractive.20
For the purposes of our haminol synthesis, using a large excess
of acyloxysulfone 3 for the cross-metathesis with 3-vinylpyridine
was deemed unattractive and an alternative approach was de-
signed. An acyloxysulfone metathesis strategy would be used to
prepare the masked 1,6-diene aldehyde 16. This would then be
coupled with sulfone 1721 in a classical Julia olefination manner
(Fig. 3).22
Taken together, this data is interpreted to indicate preferential
substitution of the styrene ligand and formation of ruthenium pyr-
idylalkylidene 12. Addition of an excess of 2 to the mixture of 7 and
12 obtained generates a new carbene signal in the 1H NMR spec-
trum along with free tricyclohexylphosphine as indicated by 31P
NMR. This data has been tentatively assigned to pyridine complex
13. Importantly, addition of 9 to this same mixture of 7 and 12
failed to produce any of the cross-metathesis product 10 even at
elevated temperatures. Instead the only observable metathesis
products were isomerized bis-acetate 14 and 15 from the parent
catalyst (Scheme 6).
Based on these results, the failure of the cross-metathesis reac-
tion between 2 and 3 (Ref. Scheme 2) can be rationalized as due to
the formation of a ruthenium pyridylalkylidene that no longer par-
ticipates in productive metathesis (Fig. 2).19 The use of an excess of
A synthesis of 16 began with the addition of the lithium anion of
sulfone 4 to nicotinaldehyde (6) followed by in situ acylation with
benzoic anhydride (Bz2O) giving 18 as a separable ꢀ2:1 mixture of

5860
J. M. Storvick et al. / Tetrahedron Letters 52 (2011) 5858–5861
Figure 3. Second-generation haminol synthesis.
Figure 4. The normalized response times of C. elegans to escape the compound-
containing region in the conditions listed. Escape time was measured in seconds
and divided by the mean response time of the corresponding vehicle group. Two
separate t-tests were performed (with a Bonferonni correction for multiple tests):
one tested between the haminol A condition and vehicle (DCM; t = 5.71, p < 0.0001)
and one tested between the copper chloride condition and vehicle (ddH2O; t = 4.65,
p < 0.0001). ⁄⁄⁄p < 0.0001.
elimination. Preliminary behavioral assay data using synthetic
haminol A and C. elegans indicate that the compound does elicit
a response from this organism. Given the large of amount of infor-
mation that is known for C. elegans, it is hoped that this demonstra-
tion may provide entry to unraveling the complexities of alarm
pheromone activity.
Scheme 7. Reagents and conditions: (1) 4, BuLi, Bz2O, 72%; (2) cat. 7, 19, PhMe, 60 °C,
78%; (3) 17, BuLi, Bz2O, 60%; (4) SmI2, DMPU, THF, 98%; (5) TBAF, THF, 52%.
Acknowledgments
Acknowledgment is made to the donors of the American Chem-
ical Society Petroleum Research Fund for support of this research
(49499-UNI). Additional financial support from Western Washing-
ton University, M.J. Murdock Charitable Trust and Research Corpo-
ration departmental development grant, and the Washington
NASA Space Grant Consortium is gratefully acknowledged. The
authors would like to thank the Caenorhabditis Genetics Center
funded by the NIH National Center for Research Resources (NCRR)
for providing the C. elegans strain N2 Bristol used in this work and
Dr. Jacqueline Rose for expert behavioral assay assistance.
diastereomers (Scheme 7). Compound 18 underwent a smooth
cross-metathesis with crotonaldehyde (19) using catalyst 7 to gen-
erate the trans-D6,7 alkene found in the natural product, affording
aldehyde 16 in 78% yield. Chemoselective addition of the lithium
anion of 17 to 16 and acylation gave a complex mixture of stereo-
isomeric benzoyloxysulfones 20 setting the stage for the introduc-
tion of the remaining two olefins by a bis-samarium-mediated
reductive elimination.23 Gratifyingly, treatment of 20 with samar-
ium diiodide in THF/DMPU resulted in clean formation of the all-
trans triene 21 as the major product in excellent yield. Removal
of the silicon protecting group then completed a synthesis of hami-
nol A (1), the natural product obtained in five steps from nicotinal-
dehyde and 17% overall yield.
Supplementary data
Supplementary data associated (complete analytical data and
experimental procedures for compounds 2, 10, 18, 21 and 1 along
with tables comparing NMR data for synthetic 1 versus that for the
natural sample and behavioral assay methods) with this Letter can
be found, in the online version, at doi:10.1016/j.tetlet.2011.08.153.
With our synthetic sample in hand, we set out to examine its
impact, if any, on Caenorhabditis elegans. C. elegans have been used
as a model organism to investigate a variety of biological processes
including chemotaxis.24 A circle avoidance assay25 was performed
using synthetic haminol A with copper chloride, a known deterrent
to C. elegans,24 as a positive control (Fig. 4). In this assay, a small
drop of repellent is delivered to the center of a circular region of
growth media. Single organisms are then placed in close proximity
to the repellent and times recorded for the organism to leave the
circle.7 C. elegans clearly exhibited avoidance behavior when
exposed to haminol A, similar to that reported for the source
organism.6
In conclusion, the total synthesis of haminol A has been com-
pleted further highlighting the utility of b-acyloxysulfones as
masked alkenes, allowing for a metathesis approach to polyene
subunits. The synthesis required a revision of the original strategy
due to the inability to perform a crucial cross-metathesis reaction
involving 3-vinylpyridine. 1H NMR analysis revealed that the fail-
ure of this reaction is due to the rapid formation of a ruthenium
pyridylalkylidene that no longer participates in the productive
metathesis. Efforts are ongoing to better understand the marked
reactivity difference of these complexes relative to the parent cat-
alyst. Our revised synthesis featured a masked olefin metathesis
followed by bis-samarium-mediated acyloxysulfone reductive
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