7th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-7), http://www.mdpi.net/ecsoc-7, 1-30 November 2003

[D001]

STEREOSELECTIVE CONJUGATE ADDITIONS OF

SELENIUM CONTAINING ENOLATES TO ENONES

M. Tiecco, L. Testaferri, F. Marini, S. Sternativo, C. Santi, L. Bagnoli and A. Temperini

Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica,

Università di Perugia, Italy

Introduction

Organoselenium compounds are commonly employed as useful and powerful reagents in organic synthesis. They allow the chemo, regio and stereoselective introduction of new functional groups into organic substrates to be carried out. Selenium has been successfully introduced into organic substrates either as an electrophile or as a nucleophile. In recent years, several research groups have been involved in the preparation of optically active diselenides which have found extensive application in asymmetric electrophilic addition reactions. Asymmetric inductions from good to excellent have been obtained by us and by other research groups in seleno-alkoxylation,^1a seleno-hydroxylation^1a and selenoazidation² reactions of alkenes as well as in selenium induced cyclofunctionalizations.^1b

On the other hand, asymmetric additions of selenium-containing nucleophiles are still scarcely explored.³ In this field we have successfully investigated the asymmetric aldol condensations between the methyl (R)-camphorselenoacetate and aromatic or aliphatic aldehydes. These reactions proceed with satisfactory to good chemical yields giving mixtures of diastereomeric syn and anti aldols which can be separated by chromatography and obtained as pure enantiomers.⁴

These interesting results prompted us to evaluate the employment of similar nucleophiles for conjugate additions to a,b-unsaturated carbonyl compounds. These reactions have a great synthetic utility, since they generate highly functionalized compounds, but suffer from some complications due to the competing 1,2 additions. Therefore, synthetic and mechanistic studies, particularly in the enantioselective version, are still of large interest.

Results and discussion

Table 1 describes the results of some experiments carried out on chalcone using three different, easily available, selenoacetates: the methyl phenylselenoacetate 1a⁵ and the two novel optically pure selenoacetates 1b,c.

The a-seleno carbonyl compounds 1a-c were treated with 1.1 equiv. of TiCl₄ and 2 equiv. of Et₃N at –78 °C under nitrogen in order to prepare the corresponding titanium enolates. After 1 h, 1.5 equiv. of chalcone, complexed or not with 1.5 equiv. of a Lewis acid, were added and the reaction mixtures were stirred at the same temperature for 3-6 h. The products obtained, the yields and the observed regio (1,4 vs 1,2) and diastereoselectivities (syn:anti) are reported in the Table.

In order to choose the best conditions for a high conversion and a good regio (1,4 vs 1,2 selectivity) and stereocontrol (syn vs anti) and to evaluate the effects of some Lewis acids, preliminary experiments (entry 1-4) were carried out with chalcone and 1a. It is well known, in fact, that Lewis acids can affect the reactivity and the selectivity of Michael-type reactions.⁶ The results obtained indicate that the complexation dramatically influences the stereochemical outcome of these 1,4 additions. By treating chalcone with TiCl_4, it was possible to obtain the 1,4-product 3 having a syn stereochemistry in high yield and with excellent regio and diastereoselectivities. In all the other cases, i.e. without complexation or in the presence of other Lewis acids such as BF₃ or Ti(OiPr)₄, not only greater amounts of 1,2 addition products were formed, but also the anti product 4 was present as the prevalent or even as the single isomer. The explanation for this drastic change in diastereselectivity is not clear at present.

The last three experiments of table 1 refer to the reactions carried out with the selenoacetates 1b-c. The use of titanium enolates generated from these optically pure a-selenoester allowed the syn or the anti adducts to be formed in the enantiomerically pure form.

The results obtained starting from the selenoacetate 1c, both in the presence or in the absence of TiCl₄ (entries 6 and 7), demonstrate that the addition reactions occurred with excellent facial selectivities. In fact, in the former case only the syn product 3c was isolated whereas in the latter case the anti 4c was present, although in poor yield (25%), as the sole reaction product.

The absolute configurations of the benzylic carbon atom of 3c and 4c were determined after removal of the organoselenium moiety by reductive deselenenylation with Ph₃SnH and comparison of the optical rotations of the obtained esters with those already reported in the literature.

Table 1

a) The indicated Lewis acid was used to activate the substrate to the addition.

b) The diastereomeric ratios were determined by ¹H NMR of the crude mixtures. The 3:4 ratios were also confirmed after chromatographic purifications.

c) Yields determined after column chromatography separation.

d) The relative stereochemistries of 3a and 4a were determined by conversion into the corresponding d-lactones after reduction with NaBH₄. The stereochemistry of the other adducts was assigned by comparison of their ¹H NMR spectra with those of 3a and 4a.

The excellent results obtained in terms of yield and selectivity from the TiCl₄-activated reaction between chalcone and 1c, prompted us to carry out similar reactions with other Michael acceptors (Table 2). As already observed in the reaction with chalcone, good or excellent facial selectivities were observed in all cases in favour of the syn isomer 3.

Table 2

An experiment was also carried out with the cyclohex-2-en-1-one. The reaction was very selective and gave rise to the 1,4-addition product 5 as a single isomer (Scheme 1).

Scheme 1

It is interesting to note that, with the exception of chalcone, without the activation of the Lewis acid, the 1,4-additions to enones did not occur and only the 1,2-addition products could be isolated.

The enantiomerically pure a-seleno d-oxoesters 3c-e and 5 can find useful applications as intermediates for further synthetic transformations.

As an example, 3c can be converted into the optically pure trisubstituted tetrahydrofuran 7. As indicated in Scheme 2, the a-seleno d-hydroxyester 6, obtained from 3c by reduction with NaBH₄ in MeOH, cyclizes by intramolecular nucleophilic substitution after activation of the phenylseleno group by conversion into a selenonium ion by treatment with phenylselenenyl triflate.

Scheme 2

Further experiments are in progress in order to find new applications of the enantiomerically pure a-seleno d-oxoesters as chiral building blocks.

Financial support from MIUR, National Project “Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni”, FIRB Project “Progettazione, Preparazione e Valutazione Biologica e Farmacologica di Nuove Molecole Organiche Quali Potenziali Farmaci Innovativi”, Consorzio CINMPIS and University of Perugia, Progetti di Ateneo, is gratefully acknowledged.

References:

[1] a) Tiecco, M. In Topics in Current Chemistry. Organoselenium Chemistry: Modern Developments in Organic Synthesis; Wirth, T., Ed. Springer-Verlag: Heidelberg, 2000, Chapter 2, 7-54. b) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Bagnoli, L.; Santi, C.; Temperini, A. Tetrahedron: Asymmetry.  2001, 12, 3053.

[2] Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini, F.; Bagnoli, L.; Temperini, A. Angew. Chem. Int. Ed. 2003, 42, 3131.

[3] Ponthieux, S.; Paulmier, C In Topics in Current Chemistry. Organoselenium Chemistry: Modern Developments in Organic Synthesis; Wirth, T., Ed. Springer-Verlag: Heidelberg, 2000, Chapter 5, 113-142

[4] Unpublished results from this laboratory.

[5] Lebarillier, L.; Outurquin, F.; Paulmier, C. Tetrahedron 2000, 56, 7483.

[6] Deng, G.; Tian, X.; Qu, Z.; Wang, J. Angew. Chem. Int. Ed. 2002, 41, 2773 and references cited therein.