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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Tetrahedron Lett. Author manuscript; available in PMC 2010 December 1.
Published in final edited form as:
Tetrahedron Lett. 2009 December 1; 50(48): 6621–6623.
doi:  10.1016/j.tetlet.2009.09.055
PMCID: PMC2776744
NIHMSID: NIHMS146071

Asymmetric [4+2] cycloadditions employing 1,3-dienes derived from (R)-4-t-butyldimethyl-silyloxy-2-cyclohexen-1-one

Abstract

1.3-Dienes derived from (R)-4-t-butyldimethylsilyloxy-2-cyclohexen-1-one react with activated dienophiles to form predominately (or sometimes exclusively) syn/endo products. These controlled [4+2] cycloadditions increase the asymmetric complexity from one asymmetric center in the starting material to five asymmetric centers in the products in a single step, and provide a powerful approach for the asymmetric synthesis of compounds containing the bicyclo[2.2.2]octanone carbon skeleton.

(R)-4-t-Butyldimethylsilyloxy-2-cyclohexen-1-one 1 and its (S)-isomer are very useful chiral building blocks and have been widely used in organic synthesis.1 The advantage of using this compound as a starting material is due to its excellent diastereoselectivity in conjugate additions since all stereochemistry is introduced by communication from the stereogenic center at the C-4 position of 1.

Recently, we reported for the first time that the cross-conjugated dienolate 2 derived from 1 can be employed in the double Michael reaction for the asymmetric synthesis of a highly functionalized bicyclo-[2.2.2]octanone 4 (Scheme 1).2 The reaction was exclusively endo selective and occurred at the face anti to the bulky TBSO group to afford only one of the eight possible diastereomers. We have also shown that the combination of the double Michael reaction and an anionic Oxy-cope rearrangement is a powerful approach for the synthesis of the cis-decalin portion of the antitumor natural product superstolide A.2

Scheme 1
Asymmetric double Michael reaction

The successful double Michael reaction prompted investigation of [4+2] cycloadditions. Although the (S)-isomer of 1 was used as a dienophile in Diels-Alder reactions,1q,1s [4+2] cycloadditions using 1,3-dienes derived from 1 or its (S)-isomer have never been reported.

Compound 1 was converted to 1,3-diene 5 in 87% yield (scheme 2). To our surprise, [4+2] cycloaddition between 5 and various α,β-unsaturated compounds proved to be very difficult because 5 was quite unreactive. In addition, 5 was prone to decomposition and aromatization in the presence of a Lewis acid Therefore, the desired [4+2] adducts were never detected. To accelerate the reaction, more reactive dienophiles were needed.

Scheme 2
Failed [4+2] cycloaddition

We were delighted to observe that the [4+2] cycloaddition between 1,3-diene 5 and N-benzyl maleimide 7 gave compounds 8-syn (51%) and 8-anti (43%), which were confirmed by 1D and 2D NMR analysis (Scheme 3). The reaction was exclusively endo selective, but the facial selectivity was poor. Surprisingly, the major product 8-syn was formed when N-benzyl maleimide 7 approached 1,3-diene 5 from the same face of TBSO substituent on the diene plane, which was opposite to what was observed in the double Michael reaction.2

Scheme 3
[4+2] Cycloaddition

The stereochemical outcome of this reaction is similar to various [4+2] cycloadditions involving 1,3-dienes bearing an OR group at the allylic stereogenic center,3 and is proposed to be controlled by the Cieplak effect.4 The preferential syn facial selectivity seen in our system was also observed by others when compound 1 was employed as a dienophile.1q,1s However, the syn vs anti pi-facial selectivity seen during cycloaddition for such systems appears to depend on many factors including the specific diene and the reactivity of the dienophile.5

To improve the facial selectivity the effect of various enol ether substituents was investigated (Scheme 4). It was discovered that the [4+2] cycloaddition between 9 and 7 provided exclusively endo products with the facial selectivity being improved to 4.3:1 (syn:anti), and the combined yield for 10-syn and 10-anti was 95%. To the best of our knowledge, this is the first successful application of a 1,3-diene derived from 1 in a [4+2] cycloaddition.

Scheme 4
A facial and stereoselective [4+2] cycloaddition

Eight different solvents were screened to determine the solvent effect on the facial selectivity of the asymmetric [4+2] cycloaddition between 1,3-diene 9 and N-benzyl maleimide 7. The results are summarized in Table 1. It was found that the facial selectivity (syn:anti) was higher in solvents like benzene, methylene chloride or chloroform. Reactions in polar solvents such as acetone, methanol or acetonitrile gave lower facial selectivity. The preferred choice of solvent is benzene or methylene chloride since chloroform may contain a trace amount of acid that might promote the formation of side products.

Table 1
Solvent effect on the facial selectivity (10-syn:10-anti)

Seven reactive dienophiles were chosen to study the scope and limitation of this asymmetric [4+2] cycloaddition, and the results are summarized in Table 2. All reactions provided exclusive endo products with the facial selectivity favoring the syn product, and the yields for the syn/endo products were very good. The reaction between 9 and 15 had to be carried out in the presence of 0.1 eq. of 2,6-lutidine (entry 3, Table 2), otherwise traces of maleic acid promoted formation of the aromatized side product, phenyl acetate. The yields for 16-syn and 16-anti were not isolated yields. This was because both products contain the anhydride moiety, which decomposed on silica gel during flash column chromatography, resulting in lower yields. Since the reaction was very clean, and only these two products were detected in its unpurified 1H NMR spectrum, and therefore spectral integration of the respective products was used to reflect the real ratio of 16-syn and 16-anti.

Table 2
Asymmetric [4+2] cycloadditions between 1,3-diene 9 and various reactive dienophiles

Compound 17 was a much more reactive dienophile, and the reaction was complete in 15 minutes at -20 °C to afford exclusively 18-syn with nearly quantitative yield (entry 4, Table 2). On the other hand, no desired [4+2] cycloaddition product was isolated after 9 and the relatively less reactive 196 were heated in a sealed tube at 120 °C (entry 5, Table 2). The reaction between 9 and 20 was carried out at 60 °C in a sealed tube whereas the reaction between 9 and 22 had to be heated to 100 °C in a sealed tube. These experiments have shown that various active dienophiles are suitable substrates for this asymmetric [4+2] cycloaddition.

We then turned our attention to the scope of chiral 1,3-dienes. Four chiral 1,3-dienes 24,7 26,8 289 and 3010 were prepared from compound 1 and investigated in the asymmetric [4+2] cycloaddition with N-benzyl maleimide 7 (Table 3).

Table 3
Asymmetric [4+2] cycloadditions between N-benzyl maleimide 7 and various 1,3-dienes derived from compound 1

Entry 1 indicates that an iodo group at the 3 position of the 1,3-diene had no effect on the facial selectivity (entry 1, Table 3). However, introducing a methyl group at either the 1 or 4 position of the 1,3-diene slightly improved the facial selectivity, and the yields of the major syn adducts were also improved to over 80% (entries 2 and 3, Table 3). These results were consistent with the reaction between 1,3-diene 30 and 7 (entry 4, Table 3). The [4+2] adduct 31-syn was isolated in 87%, and the anti product was not detected. It should be noted that among four newly created stereogenic centers in 31-syn two of them are bridgehead quaternary carbons, which are difficult to construct.

In summary, a facial- and stereoselective [4+2] cycloaddition employing 1,3-dienes derived from (R)-4-t-butyldimethyl-silyloxy-2-cyclohexen-1-one 1 has been developed. We have demonstrated for the first time that these 1,3-dienes can react with activated dienophiles to form predominately (or sometimes exclusively) syn/endo products. These highly controlled [4+2] cycloadditions can increase the asymmetric complexity from one asymmetric center in the starting material to five asymmetric centers in the products in a single step, and provide a powerful approach for the asymmetric synthesis of compounds containing the bicyclo[2.2.2]octanone carbon skeleton. Application of this new method to total synthesis of natural products is underway, and will be reported in due course.

Acknowledgments

This work was financially supported by a Grant (1R01CA109208-01A2) from the National Institutes Health. We thank Dr. Ying Kang and Mr. Changgang Lou for the preparation of compounds 28 and 24.

References

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7. Synthesis of compound 24: Compound 1 reacted with I2 in the presence of pyridine to provide (R)-4-(t-butyldimethylsilyloxy)-2-iodo-2-cyclohexen-1-one in 63% yield, which was transformed to 24 in 71% yield via the same procedure used in the preparation of 9.
8. Synthesis of compound 26: Compound 1 reacted with LDA followed by the addition of MeI to give (4R)-4-(t-butyldimethylsilyloxy)-6-methyl-2-cyclohexen-1-one in 66% yield, which was transformed to 26 in 92% yield via the same procedure used in the preparation of 9.
9. Synthesis of compound 28: Conjugate addition of lithium cyano methyl cuprate to compound 1 in the presence of TMSCl provided silyl enol ether that underwent Saegusa oxidation to give (4R)-3-methyl-4-(t-butyldimethylsilyloxy)-2-cyclohexen-1-one in 68% yield, which was transformed to 28 in 84% yield via the same procedure used in the preparation of 9.
10. Synthesis of compound 30: Conjugate addition of lithium cyano n-butyl cuprate to compound 1 in the presence of TMSCl provided silyl enol ether that underwent Saegusa oxidation to give (4R)-3-n-butyl-4-(t-butyldimethyl-silyloxy)-2-cyclohexen-1-one in 70% yield. Treatment with LDA followed by the addition of MeI afforded (4R)-3-n-butyl-4-(t-butyldimethylsilyloxy)-6-methyl-2-cyclohexen-1-one in 82% yield, which was transformed to 30 in 70% yield via the same procedure used in the preparation of 9.