Concise and stereoselective synthesis of (±)-Hagen's gland lactone

Abstract

The synthesis of (±)-Hagen's gland lactone 1 has been completed in three steps in 44% from commercially available starting materials. The work is highlighted by a straightforward preparation of butenolide through an epoxide opening using 2-lithiofuran and a concise and stereoselective synthesis of furano-γ-lactone by a novel DBU-promoted sequential isomerization/intramolecular oxa-Michael addition of a hydroxybutenolide.

---

Functionalized bicyclo[3.3.0]furano-γ-lactones constitute key structural features of many structurally and/or biologically interesting natural products such as Hagen's gland lactones,¹ goniofufurone and 7-epigoniofufurone,² crassalactone B and C,³ and cephalosporolides E and F.⁴ Among them, Hagen's gland lactones (1 and 2, Fig. 1) have attracted considerable interest from a number of synthetic groups due to their biological activity and the importance of the construction of bicyclo[3.3.0]furano-γ-lactone.⁵

Fig. 1 Hagen's gland lactones 1 and 2.

Recently, Kim and coworkers reported the highly efficient and stereoselective asymmetric total synthesis of the pyrano-γ-lactone natural product (+)-scanlonenyne by DBU-promoted sequential isomerization/intramolecular oxa-Michael addition as a key step for the synthesis of pyrano-γ-lactone (A → B, Fig. 2).⁶ To apply this methodology to the synthesis of furano-γ-lactones, we set out to synthesize (±)-Hagen's gland lactone (1) from simple building blocks through the epoxide opening reaction by 2-metallofuran and an intramolecular oxa-Michael reaction (C → D).

Fig. 2 DBU-promoted a sequential isomerization/intramolecular oxa-Michael addition.

Our retrosynthetic plan for the stereoselective synthesis of furano-γ-lactone 1 is outlined in Scheme 1. Furano-γ-lactone 1 could be synthesized from hydroxybutenolide 3 by DBU-promoted sequential isomerization/intramolecular oxa-Michael reaction. A substituted furan is more of versatile synthetic intermediate for the construction of γ- or δ-lactone after an appropriate transformation such as silylation/oxidation⁷ or Achmatowicz reaction.⁸ Thus, to find a rapid construction of hydroxybutenolide 3, we decided to use trimethylsilyl (TMS)-furan 4, which could be converted to hydroxybutenolide 3 by oxidation. TMS-furan 4 might be delivered from coupling reaction of epoxide 5 with 2-metallofuran and silylation, which would be a very straightforward method for the synthesis of hydroxybutenolides.⁹

Scheme 1 Retrosynthetic plan.

Our synthesis of (±)-Hagen's gland lactone (1) is outlined in Scheme 2. We focused our efforts on the preparation of hydroxyfuran 6, exploring the epoxide opening reaction by 2-lithiofuran as depicted in our retrosynthetic plan (vide supra). The opening reaction by 2-lithiofuran did not give the desired hydroxyfuran 6 under various reaction conditions. An addition of DMPU did not affect the reaction. However, to our delight, using the corresponding organo-copper reagent of 2-lithiated furan gave rise to the desired product 6 in moderate yield (52% yield). Further optimization efforts revealed that the addition of HMPA to the reaction mixture resulted in superb conversion to the desired adduct (85% yield). Hydroxyfuran 6 was converted into the 2-TMS furan 4 in 85% yield. In addition, the TMS-furan 4 could be obtained from epoxide 5 and furan in an one-pot manner (58% yield) along with hydroxyfuran 6 (11% yield).

Scheme 2 Synthesis of hydroxy TMS-Furan 4.

Having developed a concise and efficient synthetic route to the TMS-furan 4, we turned our attention to intramolecular oxa-Michael reaction of 3 (Scheme 3). To this end, TMS-furan was converted into hydroxybutenolide 3 by the action of m-CPBA in 92% yield.⁷ With hydroxybutenolide 3 in hand, we investigated the intramolecular oxa-Michael reaction. Initially, we were disappointed to find that, upon exposure to DBU (5 eq.)¹⁰ in CH₂Cl₂ (0.01 M), the hydroxybutenolide 3 furnished smoothly the desired furano-γ-lactone 1 with an unsatisfactory diastereoselectivity (1:7 = 3:1, 76% yield).¹¹ However, to our delight, the screening of solvents revealed that THF gave rise to the lactone 1 with high diastereoselectivity and excellent yield (1:7 = 7:1, 96% yield).

Scheme 3 Completion of (±)-Hagen's gland lactone (1).

Our proposed rationale for the observed stereochemical outcome in the oxa-Michael reaction is illustrated in Fig. 3. Initially, we hypothesized that the two products 1 and 7 are equilibrated favoring the thermodynamic product 1. However, our experiments indicated that 1 and 7 do not interconvert under the reaction conditions, which led us to postulate that the diastereoselectivity of the reaction depends on the relative energy levels of transition states E and F. The β,γ-unsaturated butenolide 3 was readily isomerized by DBU to two possible isomeric α,β-unsaturated butenolides 8 and 9.¹² The intramolecular oxa-Michael addition of α,β-unsaturated butenolide 8 via transition state E should proceed faster than that of F because the R group (n-hexyl) in transition state F suffers more steric repulsion with butenolide unit than in E.

Fig. 3 Rationale for observed stereochemical outcome in oxa-Michael reaction.

In conclusion, we have completed the synthesis of (±)-Hagen's gland lactone 1 in three steps in 44% yield, or four steps in 55% yield. Our synthesis is highlighted by the development of a straightforward method for β,γ-unsaturated butenolide synthesis by the coupling reaction of epoxide and 2-lithiofuran and the concise and stereoselective synthesis of furano-γ-lactone by DBU-promoted a novel sequential isomerization/intramolecular oxa-Michael addition of a hydroxybutenolide. Our synthesis constitutes a competitive route compared to the shortest (4-step) sequence ever reported by Fernandes and co-workers.^5k,l Application of this reaction to the stereoselective synthesis of other furano-γ-lactone natural products is underway and will be reported in due course.

Acknowledgements

This work was supported by National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (NRF-2012R1A1A1009271).

References

1. (a) K. L. Hagen, Proc. Hawaii. Entomol. Soc., 1953, 15, 115; (b) G. R. Buckingham, Ann. Entomol. Soc. Am., 1968, 61, 233; (c) H. J. Williams, M. Wong, R. A. Wharton and S. B. J. Vinson, J. Chem. Ecol., 1988, 14, 1727.
2. (a) X. P. Fang, J. E. Anderson, C. J. Chang, P. E. Fanwick and J. L. J. McLaughlin, J. Chem. Soc., Perkin Trans. 1, 1990, 1655; (b) X. F. Fang, J. E. Anderson, C. J. Chang, P. E. Fanwik and J. L. J. McLaughlin, J. Nat. Prod., 1991, 54, 1034.
3. P. Tuchinda, B. Munyoo, M. Pohmakotr, P. Thinapong, S. Sophasan, T. Santisuk and V. Reutrakul, J. Nat. Prod., 2006, 69, 1728.
4. (a) M. J. Ackland, J. R. Hanson, P. B. Hitchcock and A. H. Ratcliffe, J. Chem. Soc., Perkin Trans. 1, 1985, 843; (b) V. Rukachaisirikul, S. Pramjit, C. Pakawatchai, M. Isaka and S. Supothina, J. Nat. Prod., 2004, 67, 1953; (c) J. L. Oller-Lopez, M. Iranzo, S. Mormeneo, E. Oliver, J. M. Cuerva and J. E. Oltra, Org. Biomol. Chem., 2005, 3, 1172.
5. (a) G. C. Paddon-Jones, C. J. Moore, D. J. Brecknell, W. A. König and W. Kitching, Tetrahedron Lett., 1997, 38, 3479; (b) H. B. Mereyala and R. R. Gadikota, Chem. Lett., 1999, 273; (c) H. B. Mereyala and R. R. Gadikota, Tetrahedron: Asymmetry, 2000, 11, 743; (d) H. B. Mereyala, R. R. Gadikota, K. S. Sunder and S. Shailaja, Tetrahedron, 2000, 56, 3021; (e) G. C. Paddon-Jones, C. S. P. McErlean, P. Hayes, C. J. Moore, W. A. König and W. Kitching, J. Org. Chem., 2001, 66, 7487; (f) D. Agrawal, V. Sriramurthy and V. K. Yadav, Tetrahedron Lett., 2006, 47, 7615; (g) G. Banda and I. E. Chakravarthy, Tetrahedron: Asymmetry, 2006, 17, 1684; (h) E. Paz-Morales, R. Melendres and F. Sartillo-Piscil, Carbohydr. Res., 2009, 344, 1123; (i) P. Kapitán and T. Gracza, ARKIVOC, 2008, viii, 8; (j) S. J. Gharpure, L. N. Nanda and M. K. Shukla, Eur. J. Org. Chem., 2011, 6632; (k) R. A. Fernandes and P. Kattanguru, J. Org. Chem., 2012, 77, 9357; (l) D. A. Chaudhari, P. Kattanguru and R. A. Fernandes, Tetrahedron: Asymmetry, 2014, 25, 1022; (m) A. M. Lone, B. A. Bhat, W. A. Shah and G. Mehta, Tetrahedron Lett., 2014, 55, 3610.
6. H. Lee, K. W. Kim, J. Park, H. Kim, S. Kim, D. Kim, X. Hu, W. Yang and J. Hong, Angew. Chem., Int. Ed., 2008, 47, 4200.
7. (a) I. Kuwajima and H. Urabe, Tetrahedron Lett., 1981, 22, 5191; (b) H. K. Lee and H. N. C. Wong, Chem. Commun., 2002, 2114 . For a review on oxidation of furan, see: ; (c) P. Merino, T. Tejero, J. I. Delso and R. Matute, Curr. Org. Chem., 2007, 11, 1076.
8. (a) O. Achmatowicz Jr, P. Bukowski, B. Szechner, Z. Zwierzchowska and A. Zamojski, Tetrahedron, 1971, 27, 1973; (b) J. M. Harris and A. Padwa, J. Org. Chem., 2003, 68, 4371; (c) C. A. Leverett, M. P. Cassidy and A. Padwa, J. Org. Chem., 2006, 71, 8591; (d) M. A. Ciufolini, C. Y. W. Hermann, Q. Dong, T. Shimizu, S. Swaminathan and N. Xi, Synlett, 1998, 105; (e) M. A. Ciufolini and C. Y. Wood, Tetrahedron Lett., 1986, 27, 5085.
9. (a) R. E. Ireland, T. K. Highsmith, L. D. Gegnas and J. L. Glesson, J. Org. Chem., 1992, 57, 5071; (b) D. M. Hodgson, M. J. Fleming and S. J. Stanway, J. Org. Chem., 2007, 72, 4763; (c) For a review on chemistry of furan, see: K.-S. Yeung, Top. Heterocycl. Chem., 2012, 29, 47.
10. An addition of catalytic amount (50 mol%) of DBU did not affect the selectivity, however the yield is slightly decreased probably due to the prolonged reaction time.
11. The diastereoselectivity is determined by ¹H NMR, see ESI.†.
12. We could isolate an inseparable 2.5 : 1 (or 1 : 2.5) mixture of butenolides 8 and 9 by quenching the reaction with aq. HCl and re-subjected them into the same reaction condition to afford roughly same result (1 : 7 = 6 : 1). The relative stereochemistries of α,β-unsaturated butenolides 8 and 9 were not determined.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures including spectroscopic and analytical data for (±)-1, 3, 4, 6, 7 along with copies of ¹H and ¹³C NMR spectra. See DOI: 10.1039/c4ra11763h

---