Design and synthesis of propellane derivatives and oxa-bowls via ring-rearrangement metathesis as a key step

Summary Various intricate propellane derivatives and oxa-bowls have been synthesized via a ring-rearrangement metathesis (RRM) as a key step starting from readily accessible starting materials such as p-benzoquinone, 1,4-naphthoquinone and 1,4-anthraquinone.


Introduction
The synthesis of complex target structures requires bonddisconnection analysis of the target molecule, eventually to arrive at simple starting materials by working in an opposite direction to a chemical synthesis.The 'retrosynthetic analysis' was first introduced by E. J. Corey and defined as "it is a problem solving technique for transforming the structure of a synthetic target molecule to a sequence of progressively simpler structures along a pathway which ultimately leads to a simple or commercially available starting materials for a chemical synthesis" [1] .Generally, this type of retrosynthetic analysis has been used to design [2][3][4][5][6] the target molecule.However, a "transformation-based" retrosynthetic approach is rarely used.In the transformation-based strategy the target and precursor compounds are related by a rearrangement as the key transformation.The advantages of the rearrangement-based strategy are: the target molecule can be assembled from less obvious and more accessible precursors.Several C-C bonds are formed in a simple manner by taking advantage of the key rearrangement and the overall synthetic economy of the process can be enhanced.One can design unprecedented synthetic routes to complex targets [7] through the rearrangement-based approach.In this regard, the ring-rearrangement metathesis (RRM) [8][9][10][11][12] is useful and moreover, the stereochemical information can be transferred from the starting material to the final product during the RRM.In continuation of our interest to design novel molecules via metathesis [13][14][15][16][17][18][19][20] we conceived a new and simple route to propellane derivatives and oxa-bowls [21][22][23][24][25][26].This strategy starts from simple starting materials and involves a Diels-Alder (DA) reaction [27,28] and RRM as the key steps.

Strategy
The retrosynthetic strategy to diverse propellane derivatives and oxa-bowls is shown in Figure 1.Oxa-bowl 1 can be synthesized from the tetracyclic compound 2 using RRM, which could be obtained from the known DA adduct 3 by O-allylation.On the other hand, the propellane derivative 7 may be synthesized from the tetraallyl compound 6 by a RRM sequence.Further, the tetraallyl compound 6 can be assembled from the C-allyl derivative 4 via reduction followed by O-allylation.The C-allyl derivative 4 may be obtained from the known DA adduct 3 by a C-allylation sequence which in turn could be prepared by the DA reaction of the corresponding 1,4-quinones (p-benzoquinone, 1,4-naphthoquinone or 1,4-anthraquinone) with a freshly cracked cyclopentadiene.To realize the synthetic strategy (Figure 1) to various propellane derivatives [29][30][31] and oxa-bowls, we commenced with the preparation of a known DA adduct 3a [32].Subsequent ally-lation of 3a with allyl bromide in the presence of NaH delivered the aromatized compound 2a in 42% yield.Then, the tricyclic compound 2a was subjected to RRM with Grubbs 1 st generation (G-I) catalyst in the presence of ethylene to furnish the tetracyclic compound 1a in 75% yield (Scheme 1).The structures of compounds 2a and 1a have been confirmed on the basis of 1 H, 13 C NMR and DEPT-135 spectral data and further supported by HRMS data.
To expand the strategy, another DA adduct 3b was prepared from the commercially available 1,4-naphthoquinone and freshly cracked cyclopentadiene by following the literature procedure [33].Allylation of adduct 3b under similar reaction conditions as described above gave O-allylated compound 2b and C-allylated compound 4a in 70% and 28% yields, respectively.Then, treatment of the O-allyl compound 2b with G-I catalyst in the presence of ethylene at room temperature (rt) produced the RRM product, a pentacyclic oxa-bowl 1b in 90% yield.When the C-allyl compound 4a was treated with G-II catalyst in CH 2 Cl 2 at rt or in refluxing toluene, the propellane derivative 5a was obtained in 69% yield (Scheme 2).The structures of the new compounds 2b, 4a, 1b and 5a have been established on the basis of 1 H and 13 C NMR spectral data and further supported by HRMS data.
Next, another DA adduct 3c was prepared from readily available starting materials.In this regard, 1,4-anthraquinone was prepared from quinizarin (1,4-dihydroxyanthraquinone) by using the literature procedure [34] and the known DA adduct 3c was obtained by a cycloaddition reaction [35] of 1,4anthraquinone and cyclopentadiene.
Again, allylation of the DA adduct 3c with allyl bromide in the presence of NaH afforded the O-allylated compound 2c in 41% and the C-allylated compound 4b in 7% yield.Compound 2c was further subjected to RRM with G-I catalyst in the presence of ethylene to deliver the hexacyclic oxa-bowl 1c in quantitative yield (Scheme 3).
Having the C-allylated DA adducts 4a,b in hand, compound 4a was reduced with diisobutylaluminium hydride (DIBAL-H) at Scheme 2: Synthesis of RRM products 1b and 5a starting from DA adduct 3b.Scheme 3: Synthesis of the hexacyclic compound 1c using RRM.
−74 °C to furnish diol 8a in 81% yield along with a minor amount of compound 9 (8%).The formation of compound 9 may be explained on the basis of a retro-DA reaction [36] followed by reduction and elimination.In the same way, reduction of C-allyl compound 4b under similar reaction conditions gave diol 8b in 88% yield.
In the next step, diols 8a,b were O-allylated with allyl bromide in the presence of NaH to furnish the desired RRM precursors 6a,b in 67% and 79% yields respectively (Scheme 4).
Finally, the tetraallyl derivatives 6a,b were subjected to RRM with G-I catalyst in the presence of ethylene at rt to produce the corresponding propellane/oxa-bowl hybrids 7a,b in 71% and 97% yields, respectively.The new compounds 2c, 4b, 1c, 8a,b, 9, 6a,b and 7a,b have been fully characterized by using spectroscopic techniques ( 1 H, 13 C NMR and DEPT-135) and HRMS data.

Conclusion
We have successfully synthesized diverse heterocycles 1a-c in a simple manner starting from the known DA adducts 3a-c, including the propellane/oxa-bowl hybrids 7a,b and propellane derivative 5a.Interestingly, the structurally complex propellane/ oxa-bowl hybrids 7a,b were obtained through a four step synthetic sequence starting from simple DA adducts 3b,c, which are otherwise difficult to synthesize following conventional retrosynthetic routes.This methodology can easily be extended