Highly stereoselective 6-endo selenoetherification and selenolactonization. Steric and electronic effects

Michelangelo Gruttadauria,* Carmela Aprile, Serena Riela and Renato Noto
Dipartimento di Chimica Organica "E. Paternò", Viale delle Scienze, Parco d’Orleans II, 90128 Palermo, Italy
Tel ++39 091 596919; Fax ++39 091 596825; E-mail [email protected]

Received: 27 July 2001 / Uploaded 7 August 2001

Abstract: The selective intramolecular cyclization of anti and syn-trans diols 1 and 2 and trans-b-hydroxy acid 3 is discussed in terms of steric and electronic effects. In the 6-endo selenolactonization the unexpected role of the counter ion of the electrophilic PhSe⁺ species on the stereoselectivity is showed.

INTRODUCTION

In recent years we have been involved in studies directed toward stereoselective synthesis of substituted tetrahydrofurans and tetrahydropyrans.^1-5 Our approach is based on intramolecular selenoetherification. Being interested in the 6-endo electrophile-initiated forming reaction, we pursued our researches starting a study on the behaviour of hex-5-en-6-phenyl-2,4-diols in order to get more insight on the steric and electronic effects in the cyclization reaction. Both anti and syn-trans stereoisomers 1 and 2 were considered. In addition, also the trans-b-hydroxy-acid 3 was considered.

In the same period a communication appeared showing unexpected results on 6-endo cyclization of diols with PhSeCl.⁶ In the cyclization of a series of pent-4-en-1,3-diols with phenylselenenyl chloride the reactions gave as major products (diastereoselectivity: 4/1) the tetrahydropyrans in which the oxygen substituent at the 4-position occupies an axial site. This preference was explained by means of stereoelectronic effects. The authors claimed a CO_s*-C=Cp overlap when the C₄ oxygen is equatorially disposed, then exerting a deactivating electron-withdrawing effect. It seemed to us an uncorrected explanation.⁷ Indeed, recently we have pointed out how the Se--O interaction plays a role in the cyclization processes through the intermediate formation of seleniranium ions.^1,3 Moreover, these interaction are well documented.^8-10 In our opinion, the stereoelectronic effect could be related to the Se--O interactions not only in the starting seleniranium ion, but during the course of the cyclization and through the transition state leading to the final tetrahydropyran ring. Axial hydroxy group is closer than equatorial hydroxy group towards the equatorial Se atom and this could be the reason for the observed stereoselectivity.

RESULTS and DISCUSSION

First we considered compound 1. The reaction performed with phenylselenenyl chloride, in the presence of potassium carbonate, from –78 °C to room temperature gave the products 4 and 5 in 82% and 5% yield respectively.

Compound 4 is favoured by steric reasons but, in our opinion, no stabilizing Se--O interaction can takes place. By contrast, compound 5 is disfavoured by steric reasons but, the stabilizing Se--O interaction can takes place. Indeed, this product could come from the crowded transition state 8 that displays the methyl and hydroxy groups in axial position or, more probably, through the twisted transition state 9 that does not have the methyl group in axial position avoiding in such a way the strong 1,3-diaxial repulsion. Both transition states could preserve the Se--O interaction.

The cyclization of compound 2 gave almost exclusively the 2,6-cis tetrahydropyran ring 6 in 93% yield. Less than 1% of compound 7 was detected.

The excellent selectivity could be ascribed to the fact that compound 6 is favoured both by steric¹¹ and electronic reasons (see 10). By converse, compound 7 is disfavoured both by steric and electronic reasons (see 11).

In spite of the absence of a substituent at C₁ (C=O instead of C-CH₃), high stereoselectivity was observed in the cyclization of compound 3. As a first approach, compound 3 was allowed to react with PhSeCl (1 eq.) and potassium carbonate (3 eq.) at –78 °C to give compounds 14 and 15 (table, entry 1) through transition states 12 and 13. We were disappointed to find poor results. Indeed no selectivity was found, however, increasing the amount of PhSeCl we were delighted to find interesting results. The diastereoselectivity (determined by ¹H-NMR) increased when we used higher amount of PhSeCl (table, entries 2,3). Moreover, using PhSeCl (2 eq.) and TBACl (1 eq.) we found the same diastereoselectivity obtained using only PhSeCl (3 eq.) (table, entry 4). Finally, increase in stereoselectivity was observed when the cyclization reaction was performed with PhSeBr (2 eq.) instead of PhSeCl. Compounds 14 and 15 were obtained in 93:7 ratio with excellent yield (94%).

The d-lactones were isolated by crystallization. When the reaction mixture was purified by chromatography we got a mixture of d-lactones 14 and 15 and g-lactone 16. Then the mixture of d-lactones 14 and 15 was stirred in dichloromethane with silica gel and then eluted giving a quantitative yield (98%) of 4,5-trans-g-lactone 16 with excellent diasteromeric ratio (>95:5).

The acid conditions realized with silica gel caused the protonation of d-lactones and the intramolecular Se attack at C₆ to give ring opening. The intermediate seleniranium ions 17 and 18 then cyclized to give the thermodynamic g-lactone with excellent stereoselectivity. Semiempirical calculations (PM3) showed 16 more stable than 14 of ca. 3 kcal/mol.

The cyclization realized under kinetic conditions afforded exclusively the d-lactones because the phenyl group can support the partial positive charge at C₆ allowing the rupture of C₆-Se bond, whereas the allylic OH group disfavour the attack at C₅.¹

CONCLUSION

In conclusion the most important factors in the intramolecular selenoetherification are the steric interactions in the transition states leading to the cyclized products; however, Se--O interactions, though less important, still play a role. On the other hand, electronic effects as well as the X^- ion seem to be very important in the cyclization leading to the d-lactone. At the best of our knowledge the effect of the concentration and the nature of X^- ions on the stereoselectivity of cyclizations with PhSeX is showed for the first time. Our results represent a simple and efficient way for the stereoselective synthesis of aryl substituted d-lactones and benzyl substituted g-lactones. A detailed study is under progress for the stereoselective synthesis of d-lactones and complete results will be presented in the due course.

ACKNOWLEDGMENTS

Financial support from the University of Palermo (funds for selected research topics) and Italian MURST within the National Research Project "Non-aromatic heterocycles in stereocontrolled processes" is gratefully acknowledged.

REFERENCES and NOTES

1. Gruttadauria, M.; Aprile, C.; D’Anna, F.; Lo Meo, P.; Riela, S.; Noto, R. Tetrahedron, 2001, 57, 0000.
2. Gruttadauria, M.; Lo Meo, P.; Noto, R. Tetrahedron, 2001, 57, 1819.
3. Gruttadauria, M.; Aprile, C.; Riela, S.; Noto, R. Tetrahedron Lett., 2001, 42, 2213.
4. Gruttadauria, M.; Lo Meo, P.; Noto, R. Tetrahedron, 1999, 55, 14097.
5. Gruttadauria, M.; Lo Meo, P.; Noto, R. Tetrahedron, 1999, 55, 4769.
6. Hart, D. J.; Patterson, S.; Zakarian, A. Heterocycles, 2000, 52, 1025.
7. In our opinion the CO_s*-C=Cp overlap should take place when the C₄ oxygen is axially disposed.
8. Spichty, M.; Fragale, G.; Wirth, T. J. Am. Chem. Soc., 2000, 122, 10914.
9. Wang, X.; Houk, K. N.; Spichty, M.; Wirth, T. J. Am. Chem. Soc., 1999, 121, 8567.
10. Wirth, T. Tetrahedron, 1999, 55, 1.
11. Axial C₄ hydroxy group is less bulky than groups at C₂ or C₆.