Synthesis of 3-alkyl-5-hydroxycyclohex-2-enones via aldolic addition/sulfinate elimination tandem reactions

Article abstract of DOI:10.1016/S0040-4039(03)01085-2

The first synthesis of 3-alkyl-5-hydroxycyclohex-2-enones is reported. An intramolecular cyclization by means of an aldolic addition/sulfinate elimination tandem reactions, performed under mild basic conditions was the key step.

Full text of DOI:10.1016/S0040-4039(03)01085-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4631–4633
Synthesis of 3-alkyl-5-hydroxycyclohex-2-enones via aldolic
addition/sulfinate elimination tandem reactions
Enrique Pandolfi* and Horacio Comas
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad de la Repu´blica, Av. Gral. Flores 2124,
CC 1157 Montevideo, Uruguay
Received 12 April 2003; revised 29 April 2003; accepted 30 April 2003
Abstract—The first synthesis of 3-alkyl-5-hydroxycyclohex-2-enones is reported. An intramolecular cyclization by means of an
aldolic addition/sulfinate elimination tandem reactions, performed under mild basic conditions was the key step. © 2003 Elsevier
Science Ltd. All rights reserved.
As a part of our work on the synthesis and biological
evaluation of Bryophyte constituents,1–3 we devoted
chiefly to the preparation of prelunularin (1) (Fig. 1).
This secondary metabolite isolated from Ricciocarpos
natans,4 showed a novel structural feature consisting of
a 5-hydroxy-3-substituted-cyclohex-2-enone. Recently,
Honda et al.5 established the synthesis of 5-hydroxycy-
clohex-2-enone using an enantioselective deprotonation
of a 1,3-syn-dihydroxy system as the key step, but none
of the reported examples bore an alkyl group at the
3-position. Sato et al.6 previously reported the synthesis
of optically active 5-(tertbutyldimethylsiloxy)cyclohex-
2-enone as well as its 6-substituted derivatives in eight
steps with 17% overall yield.
lithium in anhydrous THF, followed by addition of the
appropriated alkyl halides.8,9 These alkylations pro-
vided the corresponding side chain at the 3-position of
the target molecules. A second alkylation strategy pro-
ceeded in good-to-excellent yields using t-butyllithium
and allyl bromide to obtain 6. Further reductive
ozonolysis of 6 afforded aldehyde 7, which was
unstable under standard acidic conditions required to
perform the ketal deprotection. Using milder conditions
(PPTS/acetone) we recovered only starting material.
Therefore, we resorted to the protection of the carbonyl
group with ethanedithiol in the presence of BF3·Et2O.
Interestingly, formation of the thioacetal proceed simul-
taneously with remotion of the ketal group to afford
ketosulfone 8 according to Scheme 1. Treatment of 8
with HgCl2/CaCO3 in aqueous acetonitrile afforded
ketoaldehydes 9. The overall yield was 15 and 8% for
9a and 9b, respectively.
Being a key intermediate in our synthesis of pre-
lunularin, we embarked upon the synthesis of 3-alkyl-5-
hydroxycyclohex-2-enones which, to the best of our
knowledge, has not been reported in the literature.
At this point we conceived compounds 9 as ‘good
holosynthons’ (holos=global in Greek) according to
Chanon’s definition.10 This concept focuses on a struc-
The synthetic strategy was based on the formation of
the a-sulfonylcarbanion derived from 47 with n-butyl-
Figure 1. Structures of prelunularin 1 and analogs.
Keywords: 3-alkyl-5-hydroxycyclohex-2-enones; tandem reactions; prelunularin analogs.
* Corresponding author. Fax: 598-2-924-1906; e-mail: epandolf@fq.edu.uy
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01085-2

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E. Pandolfi, H. Comas / Tetrahedron Letters 44 (2003) 4631–4633
Scheme 1. Preparation of compound 9a and 9b.
tural entity specifically designed to make a major
change of complexity and/or similarity possible in a one
pot reaction.
This synthesis proved to be simple and efficient to
produce the required structures. Currents efforts in our
laboratory are directed to the total synthesis of pre-
lunularin based on this procedure.
The intramolecular cyclization was accomplished as
shown in Scheme 2 by means of an aldolic addition/
sulfinate elimination tandem reactions. The ketoalde-
hyde 9a was dissolved in anhydrous methanol and
treated with K2CO3 (1 equiv.) at room temperature for
5 h† to afford 211 in 30% yield as a racemic mixture. We
also isolated the corresponding 3-pentylphenol (15%)
due to rapid aromatization of 2 under such conditions.
We attempted to replace potassium carbonate by tri-
ethylamine at room temperature or LDA at −78°C in
THF, but no reaction was observed. Using K2CO3, the
ketoaldehyde 9b afforded 312 in 35% yield. In this case,
the corresponding 3-phenetylphenol was not isolated.
Acknowledgements
We would like to thank PEDECIBA (Project URU/97/
016) for financial support, and Horacio Pezaroglo for
running the NMR spectra.
References
1. Gamenara, D.; Pandolfi, E.; Saldan˜a, J.; Dom´ınguez, L.;
Mart´ınez, M.; Seoane, G. Arzneim.-Forsh./Drug. Res.
2001, 51, 506–510.
2. Lo´pez, V.; Pandolfi, E.; Seoane, G. Synthesis 2000, 10,
1403–1408.
In conclusion, we have prepared previously unreported
5-hydroxy-3-substituted-cyclohex-2-enones in six steps.
3. Cullmann, F.; Becker, H.; Pandolfi, E.; Roeckner, E.;
Eicher, T. Phytochemistry 1997, 45, 1235–1247.
4. Kunz, S.; Becker, H. Phytochemistry 1994, 42, 675–677.
5. Honda, T.; Endo, K.; Ono, S. Chem. Pharm. Bull. 2000,
48, 1545.
6. Sato, F.; Hareau, G.; Koiwa, M.; Hikichi, S. J. Am.
Chem. Soc. 1999, 121, 3640–3650.
7. Kondo, K.; Tunemoto, D. Tetrahedron Lett. 1975, 12,
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9. Cooper, G.; Dolby, L. Tetrahedron Lett. 1976, 17, 4675–
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10. Chanon, M.; Barone, R.; Baralotto, C.; Julliard, M.;
Hendrickson, J. Synthesis 1998, 1559–1583.
11. Compound 2: 1H NMR (CDCl3, 400 MHz) l 5.95 (s,
1H), 4.31 (m, 1H), 2.70 (dd, J=16.2 Hz and J=4.1 Hz,
1H), 2.62 (dd, J=17.6 Hz and J=4.4 Hz, 1H), 2.47 (dd,
Scheme 2. Preparation of compound 2 and 3.
† Preparation of 2 (or 3): 9a or 9b (0.23 mmol) was dissolved in 8 mL
of anhydrous methanol and potassium carbonate (0.46 mmol) was
added. The mixture was stirred for 5 h at room temperature and
poured onto 10 mL of water. The aqueous layer was extracted with
ethyl acetate (3×20 mL). The combined extracts were washed with
brine, dried over sodium sulfate and the solvent was removed under
reduced pressure to give a yellow oil. The residue was purified by
flash chromatography (silica gel, hexanes:ethyl acetate 4:6) to give 2
(or 3) as a colorless oil.

E. Pandolfi, H. Comas / Tetrahedron Letters 44 (2003) 4631–4633
4633
12. Compound 3: 1H NMR (CDCl3, 400 MHz) l 5.97 (s,
1H), 4.31 (m, 1H), 2.86 (m, 2H), 2.70 (dd, J=16.3 Hz
and J=3.7 Hz, 1H), 2.60 (m, 3H) 2.45 (m, 2H); 13C
NMR (CDCl3, 100 MHz) l 198.2, 161.9, 140.8, 129.0,
129.6, 126.8, 126.6, 67.1, 46.7, 39.9, 39.0, 33.6.
J=16.2 and J=8.9 Hz, 1H), 2.41 (dd, J=17.6 Hz and
J=7.3 Hz, 1H), 2.26 (t, J=7.5 Hz, 2H), 1.54 (m, 2H),
1.33 (m, 4H), 0.92 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3,
100 MHz) l 198.2, 163.2, 126.2, 67.3, 46.8, 38.9, 38.3,
31.7, 26.9, 22.7, 14.3.