A Biomimetic Approach to C-secolimonoids: Synthesis of CDE Ohchinolide and Nimbolidin Model Compounds

Article abstract of DOI:10.1055/s-2001-16777

A concise and stereoselective synthesis of CDE ohchinolide and nimbolidin model compounds has been accomplished in ten and twelve steps respectively from α-cyclocitral, in 30 percent overall yield. The key step is a biomimetic type of allylic rearrangement induced by thionyl chloride. A potent insect antifeedant activity was found for two of the model compounds synthesised.

Full text of DOI:10.1055/s-2001-16777

LETTER
1399
A Biomimetic Approach to C-secolimonoids: Synthesis of CDE Ohchinolide
and Nimbolidin Model Compounds
A. Fernández Mateos,* E. Martín de la Nava, R. Rubio González
Departamento de Química Orgánica, Facultad de C. Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008-Salamanca,
Spain
Fax +34 923 294574; E-mail: afmateos@gugu.usal.es
Received 27 June 2001
Abstract: A concise and stereoselective synthesis of CDE ohchin-
olide and nimbolidin model compounds has been accomplished in
ten and twelve steps respectively from -cyclocitral, in 30% overall
yield. The key step is a biomimetic type of allylic rearrangement in-
duced by thionyl chloride. A potent insect antifeedant activity was
found for two of the model compounds synthesised.
Key words: stereoselective synthesis, allylic rearrangement,
C-secolimonoids, ohchinolide, nimbolidin
Ohchinolide and nimbolidin1 (Figure 1) are insect anti-
feedants belonging to a large and structurally complex
group of biologically active nortriterpenes named C-sec-
olimonoids. Little attention has been devoted to their bio-
genesis and synthesis,2 although this type of compounds
could be useful in the development of environmentally
safe pest control methods for sustainable agriculture.
Scheme 1
Figure 1
Scheme 2
Proposals have been made regarding the hypothetical bio-
genesis of C-secolimonoids such as ohchinolide, arising
from the hydrolytic cleavage of the 12 -hydroxy-14,15 -
oxide 1, which will be opened to give the 12-aldehyde-
13,14-15 -ol intermediate 2, followed by attack of the hy-
drate aldehyde to the allylic carbon C-15 with inversion
and later oxidation to lactone (Scheme 1).3
However, an easier alternative biosynthesis could be pro-
posed, starting from the 14,15-en-12-oxo intermediate 3,
which after Baeyer-Villiger reaction and allylic rearrange-
ment will give the same type of lactones (Scheme 2).
Scheme 3
This idea inspired our new contribution to the synthesis of
model compounds related to C-secolimonoids, which
promises to be a general and useful procedure.
Here we report a solution to the synthesis of ohchinolide
model compounds, that utilises the electrocyclization
product from the Nazarov reaction 5 as starting material,
and the potential allylic rearrangement of the unsaturated
lactone 6 as the key step (Scheme 4).9
Recently, we published an approach to the synthesis of
CDE C-secolimonoid models starting from -cyclocitral,
using as a key step the Nazarov reaction of -acyl-divi-
nylketone 4 (Scheme 3).4
Synlett 2001, No. 9, 1399–1402 ISSN 0936-5214 © Thieme Stuttgart · New York

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A. F. Mateos et al
LETTER
Scheme 4
Taking advantage of the one-keto group protected as an
enol acetate and the differences between the C-C double
bonds in 5, a catalytic hydrogenation was undertaken to
obtain the keto acetate 7 in a chemo- and stereoselective
manner. The reduction of compound 7 carried out with
NaBH4 gave only the hydroxy acetate 8 in a totally stere-
reoselective way. Further hydrolysis of the acetate afford-
ed the expected hydroxy ketone 9 and the isomeric
hemiketal 10 in equal amounts, as an inseparable mixture.
However, treatment of the mixture with m-chloroperoxy-
benzoic acid gave only one compound, the hydroxy lac-
tone 11, in excellent yield (Scheme 5).10
Figure 2 Formation and X-ray structure of 12.
Scheme 6
Scheme 5 (a) H2 1 atm, Pd/C, AcOEt. (b) NaBH4, MeOH, 0 ºC. (c)
KOH (aq) 5 M, EtOH. (d) m-CPBA, CH2Cl2.
The relative stereochemistry of 11 (and indeed of 8 and 9)
was established by X-ray diffraction analysis of its hy-
drolysis product, the diol acid 12 (Figure 2).5,11
The reaction of 11 with thionyl chloride and pyridine,
which must lead to the unsaturated lactone 6, subject of
the allylic rearrangement that we considered as the corner-
stone of the synthesis, was completely unexpected be-
cause it afforded directly the target CDE ohchinolide
model compound 13 in good yield (72%),12 together with
the unsaturated isomer lactone 14 (10%). The transforma-
tion of 11 by an absolutely stereoselective allylic rear-
rangement to give 13, could be explained by the proximity
of the orbitals through the space of the lactone oxygen and
the carbocation formed after dissociation of the chloro-
sulfite intermediate (Scheme 6).6
Scheme 7 (a) MeONa, MeOH. (b) Ac2O, py, DMAP.
Another less biomimetic way to obtain the ohchinolide
and nimbolidin model compounds was carried out from
the hydroxy lactone 11 through the sequence described in
Scheme 8, which consists of the oxidation of 11 to give
the keto lactone 17, followed by elimination with 1,8-di-
azabicyclo[5.4.0]undec-7-ene and esterification with dia-
zomethane to the keto ester 18. The reduction of 18 with
diborane gave a diastereomeric 3:1 mixture of hydroxy es-
ters 15 and 15a. Acetylation of the major isomer 15 af-
forded the CDE nimbolidin model compound 16.
Hydrolysis of the hydroxy ester 15, followed by the Co-
rey-Nicolau7 lactonization of the hydroxy acid intermedi-
Our next target, the CDE nimbolidin model compound 15,
was obtained from ohchinolide model 13 in two simple
steps: transesterification and acetylation (Scheme 7).
Synlett 2001, No. 9, 1399–1402 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Biomimetic Approach to C-secolimonoids
1401
(5) Crystallographic data (excluding structure factors) for the
structure 12 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC 159677. Copies of the data can be obtained free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK. Fax: 44 1223 336033 or e-mail:
ate, gave the CDE ohchinolide model compound 13.
Following the methods described above, the minor hy-
droxy ester 15a was transformed into the diastereomers of
the CDE nimbolidin and ohchinolide model compounds
13a and 16a. The latter two compounds exhibit very po-
tent insect antifeedant activity against Spodoptera littora-
lis larvae.8
deposit@ccdc.cam.ac.uk.
(6) March, J. Advanced Organic Chemistry, 3rd Ed.; John Wiley
& Sons: New York, 1985.; p. 286.
(7) (a) Corey, E.J.; Nicolaou, K.C. J. Am. Chem. Soc. 1974, 96,
5694. (b) Corey, E.J.; Nicolaou, K.C.; Melvin Jr., L.S. J. Am.
Chem. Soc. 1975, 97, 654.
(8) Assays of insect antifeedant activity of all compounds
described in this work will be published in due course.
(9) All compounds synthesised are racemic although, only one
enantiomer is depicted.
(10) (5aRS,6RS,8RS,8aSR)-6-Hydroxy-5,5,8a-trimethyl-8-
phenyl-octahydro-cyclopenta[b]oxepin-2-one (11). White
solid (CH2Cl2/hexane) mp 148-150 °C. IR (film, ): 3582,
3547, 2955, 1730, 735 cm-1. 1H NMR (CDCl3, : 1.21 (3H, s),
1.30 (3H, s), 1.31 (3H, s), 1.70-1.85 (3H, m), 2.35 (1H, m),
2.50 (1H, m), 2.65 (1H, m), 2.85 (1H, m), 2.97 (1H, t, J = 9.5
Hz), 5.04 (1H, t, J = 7.5 Hz), 7.25-7.50 (5H, m) ppm. 13
C
NMR (CDCl3, : 26.4, 27.4, 31.1, 33.2, 35.1, 36.3, 36.7, 55.8,
60.4, 80.8, 81.1, 127.1, 128.3 (2C), 129.6 (2C), 138.0, 174.2
ppm. MS (EI, m/z): 288 (M+, 15), 173 (100), 117 (100), 91
(20). HRMS (FAB): exp. 289.1771 (M+1, C18H24O3), calc.
289.1804. Anal. Calcd for C18H24O3: C 74.97, H 8.39; Found:
C 75.09, H 8.48.
Scheme 8 (a) PCC, CH2Cl2. (b) i) DBU, toluene, 80 ºC; ii) CH2N2,
diethyl ether. (c) BH3·SMe2, THF, 0 ºC. (d) i) KOH (aq) 5M, EtOH;
ii) HCl (aq) 1M, pH = 5; iii) (pyS)2, PPh3, xilene. (e) Ac2O, py,
DMAP.
(11) (1RS,2SR,3RS,5RS)-4-(2,5-Dihydroxy-2-methyl-3-phenyl-
cyclopentyl)-4-methyl-pentanoic acid (12). Colorless solid
(EtOH) mp 179-182 °C. IR (film, ): 3374, 2971, 1709, 760,
708 cm-1. 1H NMR (CDCl3, : 1.17 (3H, s), 1.19 (3H, s). 1.23
(3H, s), 1.40 (1H, br s), 1.85-2.05 (3H, m), 2.20-240 (2H, m),
2.50 (1H, m), 2.84 (1H, dd, J1 = 8.5, J2 = 11 Hz), 4.40 (1H, m),
7.20-7.35 (5H, m) ppm. 13C NMR (CDCl3, : 25.5, 26.9, 27.5,
29.4, 35.3, 37.1, 40.2, 56.2, 59.9, 74.7, 82.6, 126.8, 128.0
(2C), 129.0 (2C), 139.1, 177.2 ppm. HRMS (FAB): exp.
307.1914 (M+1, C18H26O4), calc. 307.1909.
The relative stereochemistry of compounds 13 and 16 was
established by nOe experiments (Figure 3).
Crystal data: C18H26O4; Mr = 306.39; monoclinic; space
group P21/c; unit cell dimensions a = 10.0017 (5) Å,
b = 10.35.89 (4) Å; c = 16.4097 (9) Å, = 90 º, = 104.824
(5) º, = 90 º; volume 1643.6 (1) Å3; Z = 4, Dx = 1.238 gcm-
3; absorption coefficient 0.694 mm-1; crystal size
Figure 3
0.48 0.24 0.24 mm; range for data collection 4.57 to
65.00 º; limiting indices -11<h<11, 0<k<12, 0<l<18;
R = 0.0350; Rw = 0.0793.
(12) (7RS,8aRS)-5,5,6-Trimethyl-7-phenyl-3,4,5,7,8,8a-hexa-
hydro-cyclopenta[b]oxepin-2-one (13). White solid (t-
BuOMe/hexane) mp 88-90 °C. IR (film, ): 2961, 1732, 764,
702 cm-1. 1H NMR (C6D6, : 0.82 (3H, s), 1.05 (3H, s), 1.20
(1H, m), 1.35 (1H, m), 1.49 (3H, s), 2.01 (1H, d, J = 16 Hz),
2.19 (1H, m), 2.45 (2H, m), 3.22 (1H, d, J = 9.6 Hz), 4.77 (1H,
d, J = 7.3 Hz), 7.10 (1H, m), 7.23 (2H, m), 7.41 (2H, m) ppm.
13C NMR (C6D6, : 14.9, 27.5, 28.8, 31.2, 35.8, 37.5, 37.7,
57.1, 83.6, 126.6, 128.6 (2C), 128.3 (2C), 139.0, 142.0, 143.6,
172.7 ppm. MS (EI, m/z): 270 (M+, 11), 211 (15), 156 (30), 91
(100), 77 (61). HRMS (IE): exp. 270.1631 (M+, C18H22O2),
calc. 270.1620. Anal. Calcd for C18H22O2: C 79.96, H 8.20;
Found: C 79.89, H 8.32.
Acknowledgement
Financial support for this work from the Ministerio de Educación y
Ciencia of Spain PB 98-0251 and the Junta de Castilla y León SA
24/00B is gratefully acknowledged. We also thank the Ministerio de
Educación y Ciencia for the fellowship to E.M.M.N.
References and Notes
(1) (a) Champagne, D.E.; Koul, O.; Isman, M.B.; Scudder,
G.G.E.; Towers, G.H.N. Phytochemistry 1992, 31, 377.
(b) Akhila,A.; Rani, K. Prog. Chem. Org. Nat. Prod. 1999,
78, 48.
(2) Ley, S.V.; Denholm, A.A.; Wood, A. Nat. Prod. Rep. 1993,
109.
(3) Taylor, D.A.H. Prog. Chem. Org. Nat. Prod. 1984, 45, 1.
(4) (a) Fernández Mateos, A.; Martín de la Nava, E.M.; Pascual
Coca, G.; Ramos Silvo, A.I.; Rubio González, R. Synlett 1998,
1372. (b) Fernández Mateos, A.; Martín de la Nava, E.M.;
Rubio González, R. Tetrahedron 2001, 57, 1049.
(7RS,8aSR)-5,5,6-Trimethyl-7-phenyl-3,4,5,7,8,8a-hexa-
hydro-cyclopenta[b]oxepin-2-one (13a). White solid (t-
BuOMe/hexane) mp 74-76 °C. IR (film, ): 2961, 2859, 1728,
762, 706 cm-1. 1H NMR (C6D6, : 0.87 (3H, s), 1.08 (3H, s),
1.20 (1H, m), 1.40 (1H, m), 1.42 (3H, s), 1.70 (1H, m), 2.45
(3H, m), 3.83 (1H, t, J = 7.3 Hz), 4.83 (1H, d, J = 6.4 Hz),
6.94 (2H, m), 7.12 (1H, m), 7.20 (2H, m) ppm. 13C NMR
Synlett 2001, No. 9, 1399–1402 ISSN 0936-5214 © Thieme Stuttgart · New York

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A. F. Mateos et al
LETTER
(C6D6, : 14.7, 27.6, 28.9, 31.2, 36.2, 37.5, 41.5, 55.8, 82.2,
126.5, 127.9 (2C), 128.6 (2C), 140.5, 141.8, 144.2, 172.8
ppm. MS (EI, m/z): 270 (M+, 2), 220 (7), 153 (75), 107 (83),
84 (100), 67 (100). HRMS (IE): 270.1652 (M+, C18H22O2),
calc. 270.1620.
(3RS,5SR)-4-(5-Acetoxy-2-methyl-3-phenyl-cyclopent-1-
enyl)-4-methyl-pentanoic acid methyl ester (16a).
Colorless oil. IR (film, ): 2963, 2874, 1734, 766, 702 cm-1. 1H
NMR (C6D6, : 1.08 (3H, s), 1.15 (3H, s), 1.49 (3H, s), 1.81
(3H, s), 1.90-2.10 (3H, m), 2.25 (1H, m), 2.35 (2H, m), 3.42
(3H, s), 3.75 (1H, t, J = 7.4 Hz), 6.00 (1H, d, J = 6.4 Hz), 6.96
(2H, m), 7.10 (1H, m), 7.18 (2H, m) ppm.13C NMR (C6D6, ):
15.0, 20.6, 27.7, 28.0, 30.2, 35.7, 37.1, 41.2, 50.6, 56.1, 81.5,
126.3, 127.6 (2C), 128.5 (2C), 140.0, 144.1, 144.3, 169.5,
173.4 ppm. MS (EI, m/z): 284 (M+-60, 16), 269 (3), 253 (6),
197 (100), 129 (62), 97 (45), 69 (52), 59 (58).
(3RS,5RS)-4-(5-Acetoxy-2-methyl-3-phenyl-cyclopent-1-
enyl)-4-methyl-pentanoic acid methyl ester (16). White
solid (t-BuOMe/hexane) mp 58-60 °C. IR (film, ): 2961,
2888, 1738, 1728, 764, 702 cm-1. 1H NMR (C6D6, : 1.10
(3H, s), 1.15 (3H, s), 1.54 (3H, s), 1.73 (3H, m), 1.75 (1H, m),
1.85-2.10 (2H, m), 2.35 (2H, m), 2.57 (1H, ddd, J1 = 7.4,
J2 = 9.3, J3 = 14 Hz), 3.24 (1H, d, J = 9.3 Hz), 3.42 (3H, s),
5.90 (1H, d, J = 7.4 Hz), 7.10-7.30 (5H, m) ppm. 13C NMR
(C6D6, : 15.2, 20.7, 27.6, 28.2, 30.2, 35.6, 37.3, 39.1, 50.7,
56.8, 81.1, 126.3, 127.9 (2C), 128.5 (2C), 139.1, 143.4, 144.9,
169.4, 173.5 ppm. MS (EI, m/z): 284 (M+-60, 20), 269 (2), 197
(100), 129 (50), 97 (45), 69 (45). Anal. Calcd for C21H28O4: C
73.23, H 8.19; Found: C 73.33, H 8.23.
Article Identifier:
1437-2096,E;2001,0,09,1399,1402,ftx,en;D10001ST.pdf
Synlett 2001, No. 9, 1399–1402 ISSN 0936-5214 © Thieme Stuttgart · New York