Letter Cite This: Org. Lett. 2017, 19, 6686−6687
pubs.acs.org/OrgLett
Highly Diastereoselective Cationic Cyclization Reactions Convert a Common Monocyclic Enone to Bicyclic Precursors for the Synthesis of Retigeranic Acids A and B Simon Breitler,†,‡ Yixin Han,‡ and E. J. Corey* Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States S Supporting Information *
ABSTRACT: A novel method is demonstrated for the diastereoselective conversion of a monocyclic enone to a pair of bicyclic intermediates which enable the stereocontrolled enantioselective syntheses of retigeranic acids A and B.
R
and isopropyl groups are cis (9). The process is noteworthy mechanistically and because of its simplicity and because it enables an enantioselective synthesis of retigeranic acid B.3 The chiral monocyclic α,β-enone 4 was treated with tertbutyldimethylsilyl triflate (TBSOTf) and triethylamine in CH2Cl2 at −78 °C, and the solution was gradually warmed to 0 °C to produce the dienone TBS enol ether 6 as shown in Scheme 2. Exposure of 6 to 0.2 equiv of trimethylsilyl triflate in
etigeranic acids A (1) and B (2) co-occur in substantial amounts (0.5−3% by weight) in the Himalayan lichens Lobaria retigera and Lobaria subretigera which grow at high altitudes (up to 13500 feet) (Figure 1).1,2 These structurally
Scheme 2. Diastereoselective Cyclization of 4 to 9 via 6, 7, and 8
Figure 1. Retigeranic acids A and B.
unique sesterterpenes result from a remarkably intricate and powerful biosynthetic construction, which is far beyond synthetic emulation. The pioneering study of Shibata led to the determination of retigeranic acid as 1 using X-ray crystallography. That structure was confirmed by the total chemical synthesis of (±)-1 which also revealed the presence of an isomeric substance in the original isolates, the structure of which was later determined to be 2 by X-ray crystallography.4,5 We recently described a method for the enantioselective desymmetrization of dienone 3 to α,β-enone 4, which can be converted to the chiral bicyclic enone 5 in one step (Scheme 1).6,7 Since racemic 5 had been converted to (±)-retigeranic acid A,3 the synthesis of 5 in chiral form provides a route to the chiral natural product 1. In this paper, we report an interesting transformation of 4 to the diastereomer of 5 in which methyl
CH2Cl2 at 0 °C to ambient temperature until 6 was fully converted (by TLC analysis) gave, after isolation, a mixture of the trans-fused bicyclic products 7 and 8 (ratio 2.2:1 by 1H NMR analysis). Both 7 and 8 underwent isomerization to the same desired bicyclic enone 9 using a catalytic amount of triflic acid in CH2Cl2 at 23 °C (62% overall yield from 4). Starting with 4 of 85% ee (92.5/7.5 er), we obtained 9 of 85% ee which was free of the diastereomeric bicyclic enone 5. The diastereomers 5 and 9 were converted with triflic acid in methylene chloride at reflux to an equilibrium mixture of 9 and 5 in a ratio of 65:35.
Scheme 1. Enantioselective Synthesis of 5, a Key Intermediate for the Synthesis of Retigeranic Acid A
Received: November 1, 2017 Published: December 1, 2017 © 2017 American Chemical Society
6686
DOI: 10.1021/acs.orglett.7b03412 Org. Lett. 2017, 19, 6686−6687
Organic Letters
■
The synthesis of either bicyclic enone 5 or 9 from the common precursor 4 is both noteworthy and provocative from a mechanistic perspective. We suggest that the results are understandable in terms of the differing reactivities of the monocyclic cationic species which initiate cation−olefin cyclization and divergent reaction pathways as shown in Scheme 3.
Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Simon Breitler: 0000-0003-1895-2176 Yixin Han: 0000-0002-4941-092X Present Address
Scheme 3. Pathways for Formation of Either 5 or 9 by Cationic Cyclization Processes Originating from 4
†
(S.B.) F. Hoffmann-La Roche Ltd., pRED − Therapeutic Modalities, preclinical CMC, 4070 Basel, Switzerland. Author Contributions ‡
S.B. and Y.H. contributed equally.
Notes
The authors declare no competing financial interest.
■ ■
ACKNOWLEDGMENTS We are grateful to Pfizer, Inc. for a research grant and the Swiss National Science Foundation for a Fellowship to S.B.
The transformation of the monocyclic enone 4 to the bicyclic enone 5 probably occurs as a consequence of direct fivemembered ring closure by way of the highly reactive complex 10 to produce the cis-fused cation 11. Two suprafacial hydrogen shifts then convert 11 to 5. The formation of 9 by protonation of the silyl dienol ether 6 is most readily explained as proceeding via the silyloxy-carbocation 12 by cyclization to form the trans-fused decalin cation 13, which by ring contraction would afford the carbocation 14. Suprafacial hydrogen 1,2-shifts from 14 would then lead to the bicyclic enone 9. The fundamental reason for the dramatically different modes of cyclization of the activated intermediates 10 and 12 is consequential to the much higher electron deficiency and reactivity of 10 as compared to 12. That difference in turn traces back to the electronic differences of the substituents on the cationic oxygen of 10 and 12. The vacant orbital of aluminum raises the energy of cation 10, whereas the hyperconjugative electron donating effect of Me2-t-BuSi stabilizes cation 12. We surmise that the approach described herein can be applied to the synthesis of other fused ring systems to provide diastereocontrol of the product.
■
REFERENCES
(1) (a) Rao, P. S.; Sarma, K. G.; Seshardri, T. R. Curr. Sci. 1965, 34, 9. (b) Rao, P. S.; Sarma, K. G.; Seshardri, T. R. Curr. Sci. 1966, 35, 147. (2) (a) Kaneda, M.; Takahashi, R.; Iitaka, Y.; Shibata, S. Tetrahedron Lett. 1972, 13, 4609−4611. (b) Sugawara, H.; Kasuya, A.; Iitaka, Y.; Shibata, S. Chem. Pharm. Bull. 1991, 39, 3051−3054. (3) Corey, E. J.; Desai, M. C.; Engler, T. A. J. Am. Chem. Soc. 1985, 107, 4339−4341. (4) Because of its intriguing structure, retigeranic acid (1) has been a synthetic target of several research groups. For subsequent successful syntheses, see: (a) Wright, J.; Drtina, G. J.; Roberts, R. A.; Paquette, L. P. A. J. Am. Chem. Soc. 1988, 110, 5806−5817. (b) Wender, P. A.; Singh, S. K. Tetrahedron Lett. 1990, 31, 2517−2520. (c) Hudlicky, T.; Fleming, A.; Radesca, L. J. Am. Chem. Soc. 1989, 111, 6691−6707. (5) For a review on retigeranic acid, see: Adams, D. R.; Hudlicky, T. In Total Synthesis of Natural Products; Li, J. J., Corey, E. J., Eds.; Springer-Verlag: 2012; pp 235−258. (6) Han, Y.; Breitler, S.; Zheng, S.-L.; Corey, E. J. Org. Lett. 2016, 18, 6172−6175. (7) Snider, B. B.; Rodini, D. J.; van Straten, J. J. Am. Chem. Soc. 1980, 102, 5872−5880.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03412. Experimental procedures and characterization data for all reactions and products, including 1H NMR and 13C NMR spectra as well as NOE studies (PDF) 6687
DOI: 10.1021/acs.orglett.7b03412 Org. Lett. 2017, 19, 6686−6687
