Total synthesis of (±)-dihydroactinidiolide using selenium-stabilized carbenium ion

Article abstract of DOI:10.1016/j.tetlet.2009.07.067

A new, short total synthesis of dihydroactinidiolide 1 is described using selenium carbenium ion-promoted carbon-carbon bond formation as the key step. Our synthetic strategy starts with a lactonization reaction between 1,3,3-trimethylcyclohexene 13 and α-chloro-α-phenylseleno ethyl acetate 14, affording the key intermediate, α-phenylseleno-γ-butyro lactone 15, which reacted via a selenoxide elimination to the target compound 1.

Full text of DOI:10.1016/j.tetlet.2009.07.067

Tetrahedron Letters 50 (2009) 5569–5571
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of ( )-dihydroactinidiolide using selenium-stabilized
carbenium ion
b
c
d
Miguel J. Dabdoub a, , Claudio C. Silveira , Eder J. Lenardão , Palimécio G. Guerrero Jr. ,
*
Luiz H. Viana e, Cristiane Y. Kawasoko e, Adriano C. M. Baroni e,
*
a LASCO, Departamento de Química, FFCLRP, Universidade de São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, SP, Brazil
b Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil
c LASOL, Instituto de Química e Geociências, Universidade Federal de Pelotas, Pelotas, RS, Brazil
d Departamento de Química e Biologia, Universidade Tecnológica Federal do Paraná, UTFPR, Curitiba, PR, Brazil
e Departamentos de Farmácia-Bioquímica e Química, Universidade Federal do Mato Grosso do Sul, Campo Grande, MS, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, short total synthesis of dihydroactinidiolide 1 is described using selenium carbenium ion-pro-
Received 1 June 2009
Revised 10 July 2009
Accepted 14 July 2009
Available online 18 July 2009
moted carbon–carbon bond formation as the key step. Our synthetic strategy starts with a lactonization
reaction between 1,3,3-trimethylcyclohexene 13 and a-chloro-a-phenylseleno ethyl acetate 14, affording
the key intermediate,
the target compound 1.
a
-phenylseleno-
c
-butyro lactone 15, which reacted via a selenoxide elimination to
Ó 2009 Elsevier Ltd. All rights reserved.
This article is dedicated to Professor R. C.
Boscaini (in memoriam) by their valuable
contributions on the organic synthetic
chemistry field
Keywords:
Dihydroactinidiolide
Selenium carbenium ions
Organoselenium compounds
Dihydroactinidiolide 1 was first isolated as felines attractant
from leaves of Actinidia polygama1 and has been identified as a
flavour component in many plants such as tobacco2 and tea.3 The
closely related compounds dihydroactinidiolide 1, tetrahydroactin-
idiolide 2, isodihydroactinidiolide 3, actinidiolide 4, loliolide 5 and
epiloliolide 6 have been studied as germination inhibitors in wheat
grains (Fig. 1).4
Organoselenium compounds have been known for a long time
as versatile reagents in organic chemistry, and in recent years there
has been considerable development of selenium-based methods in
organic synthesis.9 Among the several transformations using orga-
noselenium reagents, the selenium carbenium ion-mediated car-
bon–carbon bond formation has emerged as a useful protocol for
preparation of complex molecules,10–12 as recently demonstrated
in the preparation of naturally occurring heritonin.11a
Dihydroactinidiolide 1 is one of three components of the pher-
omone for queen recognition of the workers of the red imported
fire ant (RIFA), Solenopsis invicta.5 Since its introduction in the early
1930s, RIFA has become a major agricultural and urban pest
throughout the southeastern USA. In addition, fire ants cause both
medical and environmental harm.6
O
O
O
O
O
O
Due to its economic significance, different racemic7 and enan-
tioselective8 syntheses of dihydroactinidiolide 1 have been re-
ported; the most classical one is that described by Mori and
Nakazono.7b
Tetrahydroactinidiolide Isodihydroactinidiolide
Dihydroactinidiolide
1
3
2
HO
O
HO
O
O
O
O
O
epi-Loliolide
6
Actinidiolide
4
Loliolide
5
* Corresponding authors. Tel.: +55 67 33457365 (A.C.M.B.).
E-mail addresses: migjodab@usp.br (M.J. Dabdoub), adriano@nin.ufms.br (A.C.M.
Baroni).
Figure 1. Dihydroactinidiolide (1) and related compounds.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.067

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M. J. Dabdoub et al. / Tetrahedron Letters 50 (2009) 5569–5571
Versatile reagents to explore the ability of selenium to stabilize
adjacent carbocations are -halo- -phenylseleno esters, first de-
The lactonization reaction between 1,3,3-trimethylcyclohexene
13 and ethyl -chloro- -phenylseleno acetate 14 using SnCl4 as Le-
a
a
a
a
scribed by our group for the preparation of anti-inflammatory aryl
acetic acids via a Friedel–Crafts reaction.11b This useful reagent11c
was used also in the reaction with silyl enol ethers, in the presence
wis acid and CH2Cl2 as solvent at room temperature, afforded the
lactone 15 in 45% yield after 4 h (Scheme 3).23
of ZnBr2 as Lewis acid, giving
yields.11d When terminal and internal alkenes were used as a
nucleophile in the presence of SnCl4, -phenylseleno- ,d-unsatu-
a-phenylseleno-c-keto esters in good
SePh
O
SnCl4 / CH2Cl2
rt, 4h
O
OEt
a
c
+
Cl
45%
rated esters and
a-phenylseleno-c-butyro lactones were synthe-
O
SePh
sized, respectively, in an ‘ene type’ reaction.12
15
14
13
Because of our interest in the synthesis and reactivity of organo-
selenium compounds, we describe here our results on the total
synthesis of dihydroactinidiolide 1 using selenium carbenium
ion-promoted carbon–carbon bond formation as the key step.
Our synthetic strategy is depicted in Scheme 1, and starts with
Scheme 3.
In contrast to what was observed when other internal alkenes
were used,12 the formation of non-cyclized,
-phenylseleno- ,d-
unsaturated esters was not detected in this reaction. Finally, the
reaction between the -phenylseleno- -butyro lactone 15 and
a
c
an ene-reaction between
14 and 1,3,3-trimethylcyclohexene 13, affording the key interme-
diate, -phenylseleno- -butyro lactone 15, which undergoes a sel-
a-chloro-a-phenylseleno ethyl acetate
a
c
30% (v/v) H2O2 gave, via syn-elimination of the selenoxide interme-
a
c
diate,7g,24 the dihydroactinidiolide 1 in 90% yield (Scheme 4).25
enoxide elimination to the target compound 1 (Scheme 1).
O
O
H2O2 / AcOH / THF
0 ºC - rt, 4.5h
O
O
SePh
O
O
90%
+
O
O
OEt
SePh
Cl
1
15
O
SePh
1
14
15
13
Scheme 4.
Scheme 1.
In conclusion, dihydroactinidiolide 1 was prepared directly
from 13 and 14 by a lactonization-selenoxide syn-elimination se-
quence, in an overall yield of 45%. This protocol demonstrated
the applicability of selenium-stabilized carbenium ions in the syn-
thesis of naturally occurring products.
Our initial efforts were made with the aim of preparing the
starting alkene 13. After many unsuccessful attempts using isoph-
orone as the starting material, the alkene 1,3,3-trimethylcyclohex-
ene 13 was prepared from cyclohexanone.13–21
The reaction of cyclohexanone 7 with diethyloxalate in the
presence of sodium ethoxide gave the intermediate 8 in 63% yield
after purification by distillation. Then, the product 8 was immedi-
ately submitted to pyrolysis by treatment with a catalytic mixture
of ground iron and ground glass at 175 °C, giving the carboethoxy
cyclohexanone 9 in 59–62% yield from cyclohexanone.13 Next, the
carboethoxy cyclohexanone 9 was treated with excess of NaH and
MeI, respectively, under reflux for 4 h and then at room tempera-
ture for 36 h, to give 6-carboethoxy-2,2,6-trimethylcyclohexanone
10 in 78% yield.15 Elimination reaction of 10 with p-toluenesulfonic
acid in acetic acid and H2O at rt for 48 h gave 2,2,6-trimethylcyclo-
hexanone 11 in 90% yield.15 The reaction of ketone 11 with p-tol-
uenesulfonylhydrazine gave tosylhydrazone 12 in 70% yield.17,19
The Shapiro reaction between tosylhydrazone 12 and 2 equiv of
BuLi in ether under reflux for 24 h produced the 1,3,3-trimethylcy-
clohexene 13 in 55% yield (Scheme 2).17,19
Acknowledgements
This study was supported by grants from FAPESP, CAPES, FA-
PERGS, FUNDECT-MS and CNPq. Thanks to Dr. Janet W. Reid
(JWR Associates) for assistance in English corrections.
References and notes
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O
O
O
O
O
NaOEt
OEt
O
ground glass /
59-62%
175 ºC
Feº /
diethyloxalate
OEt
O
63%
8
9
7
O
O
TsOH, AcOH, H2O
100 ºC / 48 h
1. NaH / THF rt, 30min
OEt
90%
2. MeI , 36h, 69ºC
78%
11
10
N
NHTs
2 eq. BuLi / ether
34 ºC, 48 h
TsNHNH2 / THF
55ºC, 72 h
55%
70%
13
12
Scheme 2.

M. J. Dabdoub et al. / Tetrahedron Letters 50 (2009) 5569–5571
5571
10. For selenocarbenium ions, see: (a) Silveira, C. C.; Larghi, E. L. J. Braz. Chem. Soc.
1998, 9, 327; (b) Hevesi, L. Phosphorus, Sulfur, Silicon 2001, 171, 57.
11. (a) Silveira, C. C.; Machado, A.; Lenardão, E. J.; Braga, A. L. Tetrahedron Lett.
2004, 45, 4077; (b) Silveira, C. C.; Lenardão, E. J.; Comasseto, J. V.; Dabdoub, M.
J. Tetrahedron Lett. 1991, 32, 5741; (c) Dabdoub, M. J.; Silveira, C. C.; Guerrero, P.
G., Jr. J. Organomet. Chem. 1993, 460, 31; (d) Silveira, C. C.; Braga, A. L.; Machado,
A.; Fiorin, G. L.; Dabdoub, M. J. Tetrahedron Lett. 1996, 37, 9173.
1126, 1019, 992, 957, 857, 825, 736. 1H NMR (80 MHz, d in CCl4): 2.62 (sext.,
J = 6.4 Hz, 1H), 1.40–2.20 (m, 6H), 1.2 (s, 3H), 1.0 (s, 3H), 0.93 (s, 3H); 13C NMR
(20 MHz, d in CCl4): 216.91, 44.79, 41.52, 40.37, 36.46, 25.32, 24.95, 21.26,
14.62.
19. Shapiro, R. H.; Duncan, J. H. Org. Synth. 1971, 51, 66.
20. Spectral data of compound 12: GC–MS m/z 310 (M+2), 309 (M+1), 153, 138,
127, 109 (100%); IR (KBr, cmÀ1): 3387, 3214, 2926, 1597, 1458, 1398, 1340,
1291, 1166, 1093, 1018, 987, 917, 813, 707, 685. 1H NMR (80 MHz, d in CCl4):
7.88 (d, J = 8 Hz, 2H); 7.30 (d, J = 8 Hz, 2H); 2.62–3.06 (m, 4H); 1.23–1.75 (m,
6H); 1.10 (s, 3H); 1.08 (s, 3H), 1.00 (s, 3H). 13C NMR (20 MHz, d in CCl4): 167.69,
143.30, 135.40, 128.92, 127.79, 39.65, 38.07, 31.07, 29.07, 28.56, 28.16, 17.59,
16.53.
12. Silveira, C. C.; Lenardão, E. J.; Araújo, M. A.; Braga, A. L.; Dabdoub, M. J. Synthesis
1995, 1305. and references therein.
13. Snyder, H. R.; Brocks, L. A.; Shapiro, S. H. Organic Synth. 1943, 2, 531.
14. Spectral data of compound 9: GC–MS m/z 171(M+1), 170, 142, 124, 96, 68
(100%), 55, 41; IR (KBr, cmÀ1): 2963, 2937, 2858, 1743, 1717, 1650, 1617, 1440,
1395, 1373, 1304, 1179, 1081, 1060, 912, 807; 1H NMR (80 MHz, d in CCl4):
12.21 (s, 1H); 4.20 (q, J = 7 Hz, 2H); 3.35 (t, J = 8 Hz, 1H); 2.1–2.55 (m, 4H);
1.55–1.95 (m, 4H), 1.30 (t, J = 8 Hz, 3H). 13C NMR (20 MHz, d in CCl4): 205.82,
172.81, 172.61, 169.99, 97.78, 61.00, 60.13, 57.31, 41.85, 30.10, 29.23, 27.26,
23.43, 22.61, 22.1, 22.16, 14.36, 14.23.
15. Stevens, C. L.; Weinheimer, A. J. J. Am. Chem. Soc. 1958, 80, 4072.
16. Spectral data of compound 10: GC–MS m/z 213(M+1), 212, 184, 167, 139, 115
(100%), 102, 87, 69, 55; IR (KBr, cmÀ1): 3399, 2977, 2935, 1735, 1707, 1462,
1299, 1244, 1207, 1177, 1151, 1120, 1080, 1028, 997, 974, 939, 855, 825, 771,
720, 661. 1H NMR (80 MHz, d in CCl4): 4.15 (q, J = 7 Hz, 2H); 2.60 (s, 1H), 2.44 (s,
1H); 1.45–1.80 (m, 4H); 1.29 (s, 3H); 1.23 (t, 3H), 1.08 (s, 6H). 13C NMR
(20 MHz, d in CCl4): 209.84, 171.82, 60.30, 54.45, 45.34, 39.97, 36.16, 26.22,
24.92, 22.86, 17.95, 13.31.
21. Spectral data of compound 13: 1H NMR (80 MHz, d in CCl4): 5.12 (s, 1H); 1.98–
1.23 (m, 9H); 0.95 (s, 6H)—spectral data in accordance with Ref. 22.
22. Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2007, 129, 8930.
23. Spectral data of compound 15:7g GC–MS m/z 340 (M+2), 339 (M+1), 338, 337
(MÀ1), 336 (MÀ2), 294, 257, 203, 181, 180, 137, 95, 81 (100%), 55; IR (KBr,
cmÀ1): 3473, 2969, 2930, 2860, 2339, 1752, 1577, 1474, 1438, 1379, 1261,
1203, 1163, 1102, 1046, 946, 866, 812, 745, 693. 1H NMR (80 MHz, d in CCl4):
7.55–7.80 (m, 2H), 7.14–7.45 (m, 3H); 3.77 (d, J = 10,1 Hz, 1H); 1.30–2,35 (m,
7H); 1.41 (s, 3H); 1.26 (s, 3H); 0.96 (s, 3H). 13C NMR (20 MHz, d in CCl4):
175.21, 135.48, 129.29, 128.68, 127.62, 84.72, 47.89, 46.53, 43.69, 32.82, 32.02,
30.39, 28.36, 27.03, 21.47.
24. Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120.
25. Spectral data of compound 1 ( )-dihydroactinidiolide:7a GC–MS m/z 181 (M+1),
180, 167, 149, 137, 135, 121, 109, 91, 69, 55 (100%). 1H NMR (80 MHz, d in
CCl4): 5.63 (s, 1H); 1.28–2.70 (m, 6H); 1.51 (s, 3H); 1.15 (s, 3H); 1.0 (s, 3H).
17. Dauben, W. G.; Lorber, M. E.; Vietmeye, N. D.; Shapiro, R. H.; Duncan, J. H.;
Tomer, K. J. Am. Chem. Soc. 1968, 90, 4762.
18. Spectral data of compound 11: GC–MS m/z 141(M+1), 140, 97, 82 (100%), 69,
55; IR (KBr, cmÀ1): 3392, 2967, 2930, 2868, 1706, 1454, 1383, 1315, 1244,