Biorational synthesis of iridomyrmecin diastereomers from catnip oil

Article abstract of DOI:10.1016/j.tetlet.2014.03.030

4S,4aS,7S,7aR; 4R,4aS,7S,7aR; 4S,4aS,7S,7aS, and 4R,4aS,7S,7aS diastereomers of iridomyrmecin have been prepared in 5 steps from 4aS,7S,7aR and 4aS,7S,7aS-nepetalactones, major components of catnip oil. 4S,4aS,7S,7aR and 4R,4aS,7S,7aR-iridomyrmecin have b

Full text of DOI:10.1016/j.tetlet.2014.03.030

Accepted Manuscript
Biorational Synthesis of Iridomyrmecin Diastereomers from Catnip oil
Kamlesh R. Chauhan, Walter Schmidt
PII:
S0040-4039(14)00428-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.03.030
TETL 44352
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 February 2014
5 March 2014
5 March 2014
Please cite this article as: Chauhan, K.R., Schmidt, W., Biorational Synthesis of Iridomyrmecin Diastereomers from
Catnip oil, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.03.030
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Chauhan and Schmidt
Iridomyrmecin
03/13/14
Biorational Synthesis of Iridomyrmecin Diastereomers from Catnip oil
Kamlesh R. Chauhana*and Walter Schmidtb
aUSDA-ARS Invasive Insect Biocontrol and Behavior Laboratory, b Environmental
Quality Laboratory, B-007, BARC-West Beltsville, Maryland, 20705, USA
Key Words: iridomyrmecin, nepetalactone
*Corresponding author: kamal.chauhan@ars.usda.gov ph # 301-504-5166; fax# 301-504-6580
Abstract—4S,4aS,7S,7aR; 4R,4aS,7S,7aR; 4S,4aS,7S,7aS and 4R,4aS,7S,7aS diastereomers of
iridomyrmecin have been prepared in 5 steps from 4aS,7S,7aR and 4aS,7S,7aS-nepetalactones, major
components of catnip oil, major components of catnip oil. 4S,4aS,7S,7aR and 4R,4aS,7S,7aR -
iridomyrmecin have been identified as a defensive compound from Iridomyrmex ants.
Families of cyclopentanoid monoterpenes, also known as iridoids are typical of
the vegetable kingdom, but they are also present as defensive semiochemicals. Because
of their potential application as biopesticides and semiochemicals, iridoids have attracted
attention1. Iridomyrmecin, iridodials, actinidine, and dolichodial as a part of defensive
compounds of Iridomyrmex ants are well documented iridoids2 and led to numerous
synthetic approaches for the synthesis3. In the quest of developing naturally occurring
feeding deterrence against arthropod pest we are evaluating streospecific effects of
known and modified iridoids. Having developed economical separation and isolation of
pure nepetalactone isomers from catnip oil4, we have diverted our attention of exploiting
nepetalactones as chiral synthones5,6. Here we present the gram quantities preparation of
enantiomerically pure iridomyrmecin, isoiridomyrmecin and two trans fused
diastereomers of iridomyrmecin in 5 steps synthesis from nepetalactones without using
chiral auxiliaries or catalysts. This simple approach could specifically be used for the
synthesis of enantiomerically pure dihydronepetalactones and is applicable to chiral
synthesis of numerous cyclopentanoid monoterpene analogues.
1

Chauhan and Schmidt
Iridomyrmecin
03/13/14
1
1
7
7
5
O
2
O
2
7a
4a
7a
4a
6
6
3
3
5
4
4
O
O
R1
R2
R1
R2
1c:
1a:
1b:
R1= H, R2= CH3
R1= H, R2= CH3
R1= CH3, R2= H
1d:R1= CH3, R2= H
O
O
1
1
7
O
7
5
O
7a
4a
2
3
7a
4a
2
6
6
3
5
4
4
2a
2b
Figure 1. Monoterpene-iridomyrmecin: 1a: 4S,4aS,7S,7aR-iridomyrmecin; 1b:
4R,4aS,7S,7aR -isoiridomyrmecin; 1c: 4S,4aS,7S,7aS (trans) iridomyrmecin; 1d:
4R,4aS,7S,7aS- (trans) isoiridomyrmecin; 2a: 4aS,7S,7aR (Z,E)-nepetalactone; 2b:
4aS,7S,7aS (E,Z)-nepetalactone
Initial conversion to iridoid lactones, a surprise revelation from failed oxidation
attempt to form iridodials from iridodiols led us to the development of this synthetic
approach (Figure 2).
Figure 2: PCC oxidation of iridodiols
2

Chauhan and Schmidt
Iridomyrmecin
03/13/14
Availability of 4aS,7S,7aR (Z,E) 2a and 4aS,7S,7aS (E,Z) 2b-nepetalactone
(major components of catnip oil (Nepeta cataria), quantitatively isolated by chemical
separation) 4 was the key to this synthetic approach (Figure 3). Methanolysis of 2a at
room temperature in 5% methanolic NaHCO3 solution (95:5 methanol/water) gave an
isomeric mixture of methyl ester-aldehyde 3, which was quantitatively protected to the
cyclic acetals by azeotropic dehydration with ethane-1,2-diol and then followed by
DIBAL reduction converting ester to hydroxyl moiety to 94% yield over the two steps.
Cyclic acetals 4a and 4b were separated by flash column chromatography7. At this stage,
the absolute configuration at the C-4 asymmetric center of each isomer was established
by NMR spectroscopy (1H, 13C-APT, and COSEY)5 of mono protected aldehyde.
Figure 3: Synthesis of iridomyrmecin 1a/1b; reagents and conditions. (a) NaHCO3 (5%),
MeOH:H2O (95:5), rt; (b) ethane-1,2-diol, toluene, cat. TsOH; (c) DIBAL, toluene, -780C
to 00C; (d) THF:H2O (80:20), 2N HCl, rt (e) PDC, dry DCM, rt.
Deprotection of the cyclic acetal was carried out under mild acidic hydrolysis at room
temperature to quantitative yields of free hydroxyl aldehyde 5, which was oxidized to
conclude the synthesis of iridomyrmecin 1a in 62% and 1b in 58% overall yields8,9.
3

Chauhan and Schmidt
Iridomyrmecin
03/13/14
Repetition of the foregoing sequence using 4aS,7S,7aS-nepetalactone 2b
proceeded analogously and with comparable yields to give 1c and 1d (Fig. 1). Spectral
data, and physiochemical parameters for 1a and 1b were confirmed10 with authentic
samples of iridomyrmecin and isoiridomyrmecin. Two trans fused iridomyrmecin
diastereomers 1c and 1d synthesized from E,Z-nepetalactone were analyzed and
reported11.
In conclusion, 1R,2S,5R,8R-iridomyrmecin 1a, along with three isomeric
iridomyrmecin, have been conveniently prepared in five steps from readily available
starting materials. Iridomyrmecin enantiomer 1a and 1b are present as defense
compounds in many hemepterea insects and widely used as natural product insecticides.
The availability of iridomyrmecin diastereomers in absolute purity with economically
viable synthesis will facilitate identification of iridoid presence as semiochemicals in
insect and plants. Ease of preparation of racemic iridomyrmecin and isomers will open
exploration of these defensive compounds as biopesticide as well as insect repellents12.
Acknowledgements
We thank Ms. Ute Klingebiel, NMR Facility, USDA-ARS, Beltsville, Maryland, for her
timely help in NMR spectroscopy and stereochemical assignments. We are grateful to
funding provided by Deployed War Fighter Protection Program.
References
1
Bianco, A., "The Chemistry of Iridoids" in "Studies in Natural Products
Chemistry", Atta-ur-Rahman Ed., vo1.7 p.329, Elsevier Science Publishers,
Amsterdam 1990.
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Iridomyrmecin
03/13/14
2
a) Cavill, G. W. K.; Houghton, E.; McDonald, F. J.; Williams, P. J. Insect
Biochem. 1976, 6, 483-490. b) Dewhirst, S. Y.; Birkett, M. A.; Fitzgerald, J. D.;
Stewart-Jones, A.; Wadhams, L. J.; Woodcock, C. M; Hardie, J.; Pickett, J. A. J.
Chem. Ecol. 2008, 34, 1575–1583. c) Choe, D.-H.; Villafuerte, D.B.; Tsutsui,
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a) Cavill, G. W. K.; Hinterberger, H. Aust. J. Chem. 1961, 14, 143–149.
b) Nangia, A.; Prasuna, G.; Bheema Rao, B. Tetrahedron 1997, 53, 14507–14545.
c) Meinwald, J.; Chadha, M. S.; Hurst, J. J.; Eisner, T. Tetrahedron Lett. 1962, 3,
29–33. d) Hooper, A. M.; Donato, B.; Woodcock, C. M.; Park, J. H.; Paul, R. L.;
Boo, K. S.; Hardie, J.; Pickett, J. A. J. Chem. Ecol. 2002, 28, 849-864. e)
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4.
5.
6.
7.
Chauhan, K. R. and Zhang, A. Methods of separating Z,E-nepetalactone and E,Z-
nepetalactone from catnip oil. 2008, U. S. Patent 7,375,239 B2.
Chauhan, K. R.; Zhang, Q.-H.; Aldrich, J. R. Tetrahedron Lett. 2004, 45, 3339-
3340.
Zhang, Q.-H.; Chauhan, K. R.; Erbe, E. F.; Vellore, A. R.; Aldrich, J. R. J. Chem.
Ecol. 2004, 30, 1849-1870.
5% Ethyl acetate in hexane as mobile phase and 230-400-mesh silica gel as
stationary phase.
1
8.
4S,4aS,7S,7aR-iridomyrmecin 1a: H NMR (CDCl3, 300 MHz): δ 4.29 (dd, J =
3.8, 11.5 Hz, 1H,1-Ha), 4.16 (d, J = 11.8 Hz, 1-Hb), 2.74 (q, J = 6.8 Hz, 1H, 7-H),
2.62 (dddq, J = 7.6 Hz, 1H, 4-H), 2.01-1.88 (m, 3H, 6-Ha,7a-H, 5-Ha), 1.82-1.69
(m, 1H, 5-Hb), 1.33-1.35 (m, 1H, 6-Hb), 1.23 (d, J= 7.6 Hz, 3H, 7-CH3), 0.97 (d,
J = 7.3 Hz, 3H, 4-CH3), 0.89-0.90 (m, 1H, 4a-H) ppm; 13C NMR (CDCl3, 75
MHz) δ 175.00, 68.01, 45.53, 43.30, 37.70, 37.21, 34.19, 29.65, 18.29, 12.70
ppm. MS m/z (%): 168 (8) [M]+, 153 (2), 109 (45), 95 (100), 82 (29), 81 (59), 67
(68), 55 (23), 53 (15), 41 (55), 39 (41)
4R,4aS,7S,7aR -isoiridomyrmecin 1b: 1H NMR (CDCl3, 300 MHz): δ 4.38 (dd, J
= 6.1, 11.6 Hz, 1-Ha), 4.01 (dd, J = 11.4, 11.6 Hz, 1-Hb), 2.35-2.38 (m, 1H, 4-H),
2.12 (dq, J = 7.0, 11.2 Hz, 1H, 7-H), 2.05-1.98 (m, 2H, 6-Ha, 5-Ha), 1.90-1.91
(m, 1H, 6Hb), 1.68 (dddd, J = 5.8 Hz, 1H, 7a-H), 1.28-1.32 (m, 2H, 4a-H, 5-Hb),
1.21 (d, J = 7.1 Hz, 3H, 4-CH3), and 1.06 (d, J = 7.1 Hz, 3H, 7-CH3) ppm; 13C
NMR (CDCl3, 75 MHz) δ 175.96, 69.0, 45.22, 43.16, 39.11, 38.25, 35.60, 33.1,
19.12, 13.76 ppm. MS m/z (%): 168 (33) [M]+, 109 (52), 95 (100), 82 (26), 81 (86),
67 (84), 55 (29), 53 (11), 41 (64), 39 (40)
9.
a) Since iridomyrmecin isomers were derived from nepetalactone 2a and 2b, the
absolute configuration remain intact for 1 (7a), 2 (7) and 5 (4a) positions of origin
5

Chauhan and Schmidt
Iridomyrmecin
03/13/14
(which was established earlier by Dawson et al.). b) Dawson, G.W., Pickett, J.A.,
and Smiley, W.M., Bioorganic & Medicinal Chemistry, 1996, 4, 351-361.
10.
11.
a) Schöllhorn, B. and Mulzer, J. Eur. J. Org. Chem. 2006, 901–908. b) Beckett J.
S., Beckett J. D., and Hofferberth J. E. Org. Lett. 2010, 12 (7), 1408-1411.
1
4S,4aS,7S,7aS (trans) iridomyrmecin 1c: H NMR (CDCl3, 300 MHz): δ 4.47
(dd, J = 4.9, 10.4 Hz, 1H), 4.21 (dd, J = 10.5, 11.8 Hz, 1H,), 3.01 (dq, J = 7.6 Hz,
1H, 4-H), 2.34 (dddq, J = 7.6 Hz, 1H, 7-H), 2.19 (dddd, J = 6.3 Hz, 1H, 4a-H),
2.09-2.14(m, 1H, 6-Ha), 2.02-2.09 (m, 1H, 7a-H), 1.71-1.72 (m, 1H, 5-Ha), 1.41-
1.44 (m, 1H, 5-Hb), 1.31-1.37 (m, 1H, 6-Hb), 1.23 (d, J= 7.6 Hz, 3H, 4-CH3), and
0.87 (d, J = 7.3 Hz, 3H, 7-CH3) ppm; 13C NMR (CDCl3, 75 MHz) δ 175.1, 72.5,
41.0, 38.9, 37.3, 34.1, 31.8, 26.1, 17.1, 13.2 ppm. MS m/z (%): 168 (1) [M]+, 95 (43),
82 (29), 81 (100), 69 (10), 68 (58), 67 (100), 55 (32), 53 (17), 41 (66), 39 (47)
4R,4aS,7S,7aS- (trans) isoiridomyrmecin 1d: 1H NMR (CDCl3, 300 MHz): δ 4.50
(dd, J = 5.6, 10.8 Hz, 1Ha), 4.23 (dd, J = 10.8, 12.2 Hz, 1Hb), 2.37 (dddq, J = 7.6
Hz, 1H, 7-H), 2.25 (dq, J = 7.1, 11.2 Hz, 1H, 4-H), 2.12-2.16 (m, 1H, 6-Ha), 2.01-
2.06 (m, 1H, 5-Hb), 1.91 (br dddd, 1H, 7a-H), 1.79 (br dddd, 1H, 4a-H), 1.35-
1.41 (m, 1H, 6-Hb), 1.31 (d, J = 7.1 Hz, 3H, 4-CH3), 1.18 (d, J = 3.7 Hz,1H, 5-
Ha), and 0.85 (d, J = 7.6 Hz, 3H, 7-CH3) ppm; 13C NMR (CDCl3, 75 MHz) δ
174.0, 72.2, 44.6, 44.5, 44.2, 33.7, 32.6, 30.3, 17.2, 15.7ppm. MS m/z (%):168 (1)
[M]+, 109 (15), 95 (33), 82 (25), 81 (100), 79 (18), 69 (23), 68 (48), 67 (94), 55 (32),
54 (11), 53 (28), 41 (68), 39 (48)
12.
a) 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. b) Chauhan, K. R.; Klun, J.
R.; Debboun, M.; Kramer, M. J. Med. Entomol. 2005, 42, 643-646.
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Chauhan and Schmidt
Iridomyrmecin
03/13/14
Biorational Synthesis of Iridomyrmecin Diastereomers from Catnip oil
Kamlesh R. Chauhana*and Walter Schmidtb
aUSDA-ARS Invasive Insect Biocontrol and Behavior Laboratory, bEnvironmental
Quality Laboratory, B-007, BARC-West, Beltsville, Maryland, 20705, USA
4S,4aS,7S,7aR; 4R,4aS,7S,7aR; 4S,4aS,7S,7aS and 4R,4aS,7S,7aS diastereomers of
iridomyrmecin have been prepared in 5 steps from 4aS,7S,7aR and 4aS,7S,7aS-
nepetalactones, major components of catnip oil.
1
1
7
5
7
5
O
O
2
7a
4a
2
7a
4a
6
6
3
3
4
4
O
O
R1
R2
R1
R2
1c:R1= H, R2= CH3
1d:R1= CH3, R2= H
1a:
1b:
=
=
R1 H, R2 CH3
=
=
H
R1 CH3, R2
7