A divergent approach to the diastereoselective synthesis of several ant-associated Lridoids

Article abstract of DOI:10.1021/ol100077z

(Figure Presented) The ant-associated iridoids nepetalactol, actinidine, dolichodial, isoiridomyrmecin and dihydronepetalactone were prepared from citronellal using a divergent approach. Key features include a three-step synthesis of the individual antipodes of actinidine by a novel tandem cycloaddition/ pyridine formation and a facile diastereoselective synthesis of both enantiomers of dolichodial.

Full text of DOI:10.1021/ol100077z

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1408-1411
A Divergent Approach to the
Diastereoselective Synthesis of Several
Ant-Associated Iridoids
Joel S. Beckett, James D. Beckett, and John E. Hofferberth*
Department of Chemistry, Kenyon College, Gambier, Ohio 43022
hofferberthj@kenyon.edu
Received January 12, 2010
ABSTRACT
The ant-associated iridoids nepetalactol, actinidine, dolichodial, isoiridomyrmecin, and dihydronepetalactone were prepared from citronellal
using a divergent approach. Key features include a three-step synthesis of the individual antipodes of actinidine by a novel tandem cycloaddition/
pyridine formation and a facile diastereoselective synthesis of both enantiomers of dolichodial.
The iridoids have long been recognized as important insect
semiochemicals1 and have recently attracted attention be-
cause of their potential use as control agents for pest species.2
We became interested in the preparation of ant-associated
iridoids because of their putative role as signaling molecules
in unique mutualisms between ants of the genus Iridomyrmex
and certain Australian butterflies.3 In these species-specific
mutualisms, the juvenile stages of the butterfly (egg, pupae,
and larvae) require the constant protection of ant guards for
survival. In return, the butterfly larvae secrete nutritious food
rewards to the ants to recruit and maintain ant guards as they
mature. A female butterfly must lay eggs on appropriate food
plants that are occupied by a specific species of ant-associate
to allow for the survival of her offspring. The discrimination
between ant species by the female butterfly, and thus the
selection of egg-laying site, is thought to be mediated by
semiochemicals produced by the ants, although the nature
of these volatile cues has been previously unexplored.3a
Here we detail the preparation of macroscopic quantities
of several iridoids (1-5, Scheme 1) associated with the
Iridomyrmex4 to allow for comparison with natural ant
extracts and the advance of biological assays. While many
of the target molecules considered here (1-5) have been
prepared by others using varied synthetic strategies,2,5 the
goal of this work was the identification of a divergent
(1) Cavill, C. W. K.; Kubota, T. In Cyclopentanoid Terpene DeriVatiVes,
1st ed.; Taylor, W. I., Ed.; Marcel Dekker, Inc.: New York, 1969; Vol. 2,
pp 203-278.
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Chem. 1996, 4, 351–361. (b) Feaster, J. E.; Scialdone, M. A.; Todd, R. G.;
Gonzalez, Y. I.; Foster, J. P.; Hallahan, D. L. J. Med. Entomol. 2009, 46,
832–840.
(3) (a) Eastwood, R.; Fraser, A. M. Aust. J. Ecol. 1999, 24, 503–537.
(b) Pierce, N. E.; Nash, D. R. In Biology of Australian Butterflies; Kitching,
R. L., Scheermeyer, E., Jones, R. E., Pierce, N. E., Eds.; CSIRO Publishing:
Melbourne, 1999; Vol. 6, pp 279-315. (c) Pierce, N. E.; Braby, M. F.;
Heath, A.; Lohman, D. J.; Mathew, J.; Rand, D. B.; Travassos, M. A. Annu.
ReV. Entomol. 2002, 47, 733–771.
(4) Cavill, G. W. K.; Robertson, P. L.; Brophy, J. J.; Duke, R. K.;
McDonald, J.; Plant, W. D. Insect Biochem. 1984, 14, 505–513.
10.1021/ol100077z  2010 American Chemical Society
Published on Web 03/11/2010

into both stereochemically stable positions (C4a, C7) of the
resulting bicycloadduct (6). Additionally, the dihydropyran
resident in 6 is well suited for chemical differentiation
between the masked aldehyde functionalities. These attributes
coupled with the concise nature of the chemistry leading to
6 motivated us to use it as the key point of divergence in
our synthetic strategy.
Scheme 1. Retrosynthetic Analysis
Preparation of the substrate for enamine/enal cycloaddition
(7) from racemic citronellal was based on literature prece-
dent6,8 with modification (Scheme 2). In our hands, the allylic
Scheme 2. Synthesis of Nepetalactol (1)
chemical synthesis that makes use of a common intermediate
or key synthetic transformation to access all of the targets.
The intramolecular enamine/enal cycloaddition first de-
scribed by Schreiber6 has long been recognized as a valuable
entry into the iridoid carbon skeleton.5v,7 Importantly, the
high diastereoselectivity of this process allows for the parlay
of the single stereocenter in readily available citronellal (8)
oxidation of citronellal with catalytic SeO2 proceeded with
high regioselectivity to produce mixtures rich in the aldol 9.
Direct conversion of citronellal to the desired endial (7) was
not possible even after extended reaction times. Recourse
was made to the oxidation of mixtures of 7 and 9 using
stoichiometric IBX to give the cycloaddition substrate (7).
As reported by Schreiber,6 exposure of 7 to N-methylaniline
for extended reaction times (>10 h) results in a highly
diastereoselective intramolecular cycloaddition. It was clear
(5) (a) Liblikas, I.; Santangelo, E. M.; Sandell, J.; Baeckstrom, P.;
Svensson, M.; Jacobsson, U.; Unelius, C. R. J. Nat. Prod. 2005, 68, 886–
890. (b) Santangelo, E. M.; Liblikas, I.; Mudalige, A.; Tornroos, K. W.;
Norrby, P. O.; Unelius, C. R. Eur. J. Org. Chem. 2008, 5915–5921. (c)
Sakan, T.; Fujino, A.; Murai, F.; Suzui, A.; Butsugan, Y. Bull. Chem. Soc.
Jpn. 1959, 32, 1155. (d) Wuest, J. D.; Madonik, A. M.; Gordon, D. C. J.
Org. Chem. 1977, 42, 2111–2113. (e) Davies, L. B.; Greenberg, S. G.;
Sammes, P. G. J. Chem. Soc., Perkin Trans. 1 1981, 1909–1912. (f) Cossy,
J.; Belotti, D. Tetrahedron Lett. 1988, 29, 6113–6114. (g) Ranarivelo, Y.;
Hotellier, F.; Skaltsounis, A. L.; Tillequin, F. Heterocycles 1990, 31, 1727–
1731. (h) Stepanov, A. V.; Lozanova, A. V.; Veselovsky, V. V. Russ. Chem.
Bull. 1998, 47, 2286–2291. (i) Jones, K.; Escudero-Hernandez, M. L.
Tetrahedron 1998, 54, 2275–2280. (j) Shiao, M. J.; Chia, W. L.; Peng,
C. J.; Shen, C. C. J. Org. Chem. 2002, 58, 3162–3164. (k) Cossy, J.; Belotti,
D.; Leblanc, C. J. Org. Chem. 2002, 58, 2351–2354. (l) Robert, N.; Hoarau,
C.; Marsais, F. Tetrahedron 2007, 63, 3702–3706. (m) Cavill, G. W. K.;
Whitfield, F. B. Proc. Chem. Soc., London 1962, 380–381. (n) Beaupin,
C.; Rossi, J. C.; Vidal, J. P.; Girard, J. P.; Passet, J. Phytochemistry 1980,
19, 1541–1542. (o) Yamane, T.; Takahashi, M.; Ogasawara, K. Synthesis
1995, 444–448. (p) Fleming, I.; Terrett, N. K. J. Chem. Soc., Perkin Trans.
1 1998, 2645–2650. (q) Nagata, H.; Ogasawara, K. Tetrahedron Lett. 1999,
40, 6617–6620. (r) Jahn, U.; Hartmann, P.; Kaasalainen, E. Org. Lett. 2004,
6, 257–260. (s) Zanoni, G.; Agnelli, F.; Meriggi, A.; Vidari, G. Tetrahedron:
Asymmetry 2001, 12, 1779–1784. (t) Chavez, D. E.; Jacobsen, E. N. Org.
Lett. 2003, 5, 2563–2565. (u) Schollhorn, B.; Mulzer, J. Eur. J. Org. Chem.
2006, 901–908. (v) Nangia, A.; Prasuna, G.; Rao, P. B. Tetrahedron 1997,
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2002, 28, 849–864.
1
from H NMR analysis of cycloadduct (6a) that the diaste-
reoselectivity of the reaction was >50:1. Hydrolysis of 6a
with TsOH in wet THF proceeded smoothly to provide
nepetalactol (1, C1 R/ꢀ, 1:10).
The strategy for the conversion of 6a into actinidine (2)
was inspired by reports that 1,5-dialdehydes form pyridines
when reacted with hydroxylamine.9 Treatment of 6a, a
masked 1,5-dialdehyde, with hydroxylamine and TsOH in
THF produced 2 in 69% isolated yield. Motivated by this
transformation, the ability of hydroxylamine to induce both
cycloaddition and pyridine formation was examined (Scheme
3). In the event, 7 is converted directly into actinidine (2) in
Scheme 3. Synthesis of Actinidine (2)
(6) Schreiber, S. L.; Meyers, H. V.; Wiberg, K. B. J. Am. Chem. Soc.
1986, 108, 8274–8277.
(7) (a) Sakurai, K.; Ikeda, K.; Mori, K. Agric. Biol. Chem. 1988, 52,
2369–2371. (b) Dawson, G. W.; Pickett, J. A.; Smiley, D. W. M. Bioorg.
Med. Chem. 1996, 4, 351–361. (c) Santangelo, E. M.; Rotticci, D.; Liblikas,
I.; Norin, T.; Unelius, C. R. J. Org. Chem. 2001, 66, 5384–5387. (d)
Mangion, I. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696–
3697
.
Org. Lett., Vol. 12, No. 7, 2010
1409

70% isolated yield under these reaction conditions. Using
this tandem cycloaddition/pyridine formation, actinidine (2)
was prepared in three synthetic operations from citroneallal
in 28% overall yield. This methodology was applied to
prepare the individual antipodes of actinidine from enantio-
merically enriched citronellal without event.
of adopting an antiperiplanar orientation relative to the
bromine. Exposure of 10a to t-BuOK at 50 °C in THF over
4 h results in the formation of a single elimination product
with the desired exo-oriented double bond. While scrutiny
1
of the crude product mixture by H NMR revealed the
exclusive formation of the expected intermediate, this
intermediate proved to be unstable to silica gel chromatog-
raphy. The addition of an acidic step (1 N HCl) in the workup
resulted in complete hydrolysis of the masked aldehydes and
gave rise to a single diastereomer of dolichodial (3) in 87%
yield. The relative stereochemistry of 3 was established
(1S,2R,3S, racemic) by NOESY correlations and comparison
to published spectra.11
Attention was next turned to the preparation of dolichodial
(3, Scheme 4). Exposure of 6a to NBS in the presence of
Scheme 4. Synthesis of Dolichodial (3)
In contrast to 10a, exposure of 10b to t-BuOK in THF
results in rapid elimination (<5 min) even at ambient
temperature. Vicinal protons on both the pendant methyl
group and C4a are capable of adopting an antiperiplanar
orientation relative to the bromine. As anticipated, 1H NMR
analysis of the reaction mixture revealed the presence of two
distinct elimination products. After acidic workup, two pairs
of diagnostic aldehyde signals, putatively corresponding to
3 and the undesired endocyclic elimination product 11, were
1
evident in the H NMR spectrum (C6D6 δ 9.01 (d, J ) 1.8
Hz, 1H), 9.12 (s, 0.4H), 9.25 (d, J ) 2.3 Hz, 0.4H), 9.66 (s,
1H)). However, purification of the crude mixture by silica
gel chromatography provided only 3 in modest yield (14%).
In order to indirectly establish the presence of 11, the reaction
was repeated and the crude reaction mixture was reduced
with NaBH4 prior to purification to give a mixture of 12a
and 12b in a 1:4 ratio. The dominance of 12b in the product
mixture is consistent with the preferred deprotonation oc-
curring at C4a resulting in formation of the endocyclic double
bond.
Notably, the elimination of 10a and 10b resulted in the
preparation of a single diastereomer of 3 without epimer-
ization at C2 to form anisomorphal. In sum, dolichodial (3)
was prepared in five synthetic operations from citronellal in
13% overall yield. This synthesis was repeated using
enantiomerically enriched citronellal to prepare both antipo-
des of 3 without event. To the best of our knowledge, this is
the first reported synthesis of the “unnatural” enantiomer
(1S,2R,3S) of dolichodial (3).
The preparation of two biologically important diastereo-
mers of dihydronepetalactone, 4a and 4b, exploits the
differing steric environment of the two faces of the enol
resident in 6a and 14 (Scheme 5).5w,12 Catalytic hydrogena-
tion (Pd/C) of 6a occurs exclusively from the concaVe face
to provide pyran 13 (C1 R/ꢀ, 1:10) after hydrolysis of the
aniline residue. Steric shielding of the conVex face of the
molecule by the C1 aniline residue appears to exert a strong
influence on the approach of the catalyst. Oxidation of 13
with Fetizon’s Reagent proceeded smoothly to yield dihy-
methanol resulted in the regioselecive and stereospecific
formation of the bromo acetals 10a and 10b. The product
ratio (10a/10b, 3:4) is consistent with electrophilic attack
occurring more readily from the concave face of the bicyclic
starting material (6a). This facial selectivity can be rational-
ized by considering the steric impact of the aniline residue
on the convex side of 6a. It proved important to slowly add
a solution of the electrophile (NBS, 1.1 equiv) to the cold
reaction mixture (0 °C) to avoid the addition of bromine to
the aromatic ring of the aniline residue. Even when great
care is exercised, a small proportion of the corresponding
dibromide (<10%) is evident in the H NMR spectrum of
the purified products.
Bimolecular elimination of 10a and 10b is governed by
well-established stereoelectronic principles.10 In the case of
10a, only the protons on the vicinal methyl group are capable
1
(8) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526–
5528.
(11) Wang, B.; Dossey, A. T.; Walse, S. S.; Edison, A. S.; Merz, K. M.,
Jr. J. Nat. Prod. 2009, 72, 709–713.
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1975, 40, 2987–2990. (b) Fu, X.; Cook, J. M. J. Org. Chem. 1993, 58,
661–672.
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Wolinsky, J.; Dickerson, D.; Slabaugh, M.; Nelson, D. Tetrahedron Lett.
1965, 4097–4102. (b) Kigawa, M.; Tanaka, M.; Katsuhara, T.; Sugama,
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Org. Lett., Vol. 12, No. 7, 2010

Scheme 5
.
Synthesis of Dihydronepetalactones 4a and 4b
Scheme 6. Synthesis of Isoiridomyrmecin (5)
dronepetalactone 4a. As has been observed by others,5w,12b
nepetalactol (1), with its anomeric hydroxyl group oriented
on the conVex face of the molecule, is also capable of
directing the reducing agent to the concaVe face and produces
13 under catalytic hydrogenation conditions (Pd/C).
Nepetalactone (14) was prepared from 6a using the
synthesis described by Schreiber (6a f 1 f 14).6 In contrast
to 6a and 1, hydrogenation (Pd/C) of 14 provided dihy-
dronepetelactone 4b as the major diastereomer (90%
de).5w,12a This result is consistent with the primary steric
influence on the approach of the catalyst to 14 being the
fused cyclopentane ring although stereocontrol is not com-
plete in this instance. In sum, two biologically significant
dihydronepetalactones, 4a and 4b, were prepared in six
synthetic steps from citronellal with an overall yield of 25%
and 20%, respectively.
Access to isoiridomyrmecin (5) required chemical dif-
ferentiation of the masked aldehydes resident in 6a (Scheme
6). As in the preparation of 4a, catalytic hydrogenation of
6a established the C4 stereocenter found in 5. Treatment of
the resulting aminal with BF3·OEt2 and 1,2-ethanedithiol
converted the remaining masked aldehyde to the correspond-
ing dithiolane, and the liberated primary alcohol was
protected as a benzyl ether (15). In a one-pot procedure,
the dithiolane was removed by treatment with CAN,13 and
the free aldehyde was reduced with NaBH4 to preserve the
stereochemistry at the C7a position. Subsequent acetylation
of the newly formed primary alcohol gave the orthogonally
protected diol 16. Reductive removal of the benzyl protecting
group followed by oxidation of the resulting primary alcohol
using the conditions developed by Sharpless14 yielded the
carboxylic acid 17. Transesterification of 17 with catalytic
TsOH in ethanol provided isoiridomyrmecin (5) in quantita-
tive yield.
In conclusion, we have prepared five ant-associated
iridoids by a divergent approach using the readily available
starting material citronellal and common reagents. Biological
examination of the iridoids prepared in this program is
ongoing. Additionally, we are exploring the tandem cycload-
dition/pyridine formation methodology, developed during our
preparation of actinidine (2), for its potential in preparing
other molecules containing the cyclopenta[C]pyridine sub-
structure.
Acknowledgment. We gratefully acknowledge Kenyon
College and the NSF (RUI-0511119) for financial support.
The mass spectrometry analyses were performed at the Mass
Spectrometry Facility of the University of Akron, which
acknowledges financial support from NSF for the acquisition
of the instruments (DMR-0821313).
Supporting Information Available: Experimental pro-
cedures, characterization data, and NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
OL100077Z
(13) Ho, T.-L.; Ho, H. C.; Wong, C. M. J. Chem. Soc., Chem. Commun.
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