Abstract
We describe herein the development of efficient and stereoselective synthetic routes to a series of cis-octalins possessing an all-carbon quaternary center in an angular position.
Polycyclic cis-fused octalin systems bearing angular quaternary carbon centers, of the type 3, can be of considerable value in organic synthesis.1 In principle, this type of functionality could be rapidly reached through Diels-Alder cycloaddition between a substituted butadiene (cf. 1) and a cycloalkene dienophile, conjugated to an exocyclic activating group (E). However, we and others have observed that cyclic dienophiles of the type 22,3 generally exhibit poor reactivity in the Diels-Alder cycloaddition, necessitating exposure to harsh reaction conditions (such as high reaction temperature and prolonged reaction time) or the use of a highly reactive diene. In the course of a program underway in our laboratory, focused on the investigation of new applications of Diels-Alder strategies, we sought to gain ready access to generic octalin motifs of the type 3.
In the light of the difficulties associated with applying the traditional Diels-Alder reaction to the problem at hand, we considered the possibility of adopting the ionic variation en route to 3. Gassman and coworkers were the first to describe the ionic Diels-Alder reaction of α,β-unsaturated ketals, as a useful means by which to prepare cycloadducts under mild reaction conditions.4 More recently, Grieco et. al. developed a modified protocol, which allow α,β-unsaturated ketals to undergo facile ionic Diels-Alder cycloaddition, in the presence of 4.0M LiClO4 in Et2O containing 1.0 mol% camphorsulfonic acid (CSA).5 As described below, we sought to extend the Grieco ionic Diels-Alder protocol to encompass acetal substrates of the type 4.6 The development of this capability could well be a useful method for the preparation of highly substituted, cis-fused octalin systems of the type 3 (Scheme 1).7
Scheme 1.
A proposed route to Cis-fused octalins bearing an angular substituent.
In the event, it was found that, upon exposure to 4.0M LiClO4 in Et2O and 1.0 mol% CSA, diene 5 and dienophile 4 underwent the desired ionic Diels-Alder cyclization to afford a ∼3:1 mixture of the direct acetal cycloadduct and the aldehyde product (9), which presumably arises through hydrolysis of the acetal intermediate. In situ hydrolysis of the acetal was suppressed through the use of freshly distilled dienes in the Diels-Alder step. Subsequent hydrolysis of the acetal cycloadduct delivered the target aldehyde, 9, in 53% yield over two steps (Table 1, entry 1). This protocol was readily extended to a series of acyclic dienes, as shown in Table 1, and moderate overall yields were obtained (41-58% over two steps). When diene 7, possessing a weakly directing group at the 2-position, was investigated, moderate regioselectivity was observed (4:1, para: meta). By contrast, diene 8, possessing substitution at the 1-position, demonstrated very high regioselectivity, and afforded adduct 12 with 10:1 endo selectivity. It is of note that each of the reactions presented in Table 1 were conducted at ambient temperature and pressure. A control experiment, performed in the absence of CSA, resulted only in the recovery of unreacted starting material, confirming the critical role played by Brønsted acid in the reaction sequence. 8
Table 1.
Ionic Diels-Alder reactions and hydrolysis of the resulting acetalsa
Diels-Alder reactions were carried out with 1.00 mmol of 4, 5.00 mmol of diene in 4.0 M LiClO4 (16.0 mmol) in Et2O (4.0 mL), in the presence of 0.5 M CSA in THF (20 μL, 1.0 mol%) at room temperature for 15-17 h.
Isolated yields of the cycloadducts over 2 steps.
p-Directed/m-directed = 4:1.
Endo/exo = 10:1.
In an effort to further explore the utility of this approach to cis-fused octalin motifs, we sought to further functionalize aldehyde adducts 9 and 10. As shown in Scheme 2, the aldehydes were readily converted to the corresponding nitriles (13 and 14, respectively), in a two-step protocol, via the intermediate formation of an aldoxime function.9 In another demonstration of the synthetic versatility of these cycloadducts, aldehydes 9 and 10 were advanced to the octalin esters, 15 and 16, through Pinnick oxidation10 followed by esterification of the resulting carboxylic acids.
Scheme 2.
Derivatization of Angular Aldehydes.
(a) H2NOH·HCl, NaOAc, THF, reflux, 2 h; (b) SOCl2, DMF, 0 to 23 °C, 4 h, 60% over two steps (cis-13), 56% over two steps (cis-14); (c) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH/H2O (4:1, v/v), 23 °C, 2.5 h; (d) TMSCHN2, benzene/CH3OH (3:1, v/v), 0 to 23 °C, 1.5 h, 99% over two steps (cis-15), 88% over two steps (cis-16).
In summary, we have described herein the development of a method which is superior to those currently in use for the preparation of a series of cis-fused octalin derivatives containing an all-carbon quaternary stereocenter at the ring-junction carbon
Supplementary Material
Acknowledgments
This work was supported by the NIH (HL25848 to S.J.D.). We thank Rebecca Wilson for assistance with the preparation of the manuscript and Dr. Peter K. Park (Columbia University) and Dr. Yandong Zhang (Columbia University) for their helpful discussions. We also thank Dr. Yasuhiro Itagaki (Mass Spectral Core Facility, Columbia University) for mass spectral analysis.
Footnotes
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References
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