Asymmetric synthesis of a highly functionalized bicyclo[3.2.2]nonene derivative

Summary The stereoselective Diels–Alder reaction between an optically active 1,4-dimethylcycloheptadiene and acrolein was effectively promoted by TBSOTf to produce a bicyclo[3.2.2]nonene derivative bearing two quaternary carbons. Seven additional transformations from the obtained bicycle delivered the C 2-symmetric bicyclo[3.3.2]decene derivative, a key intermediate in our synthetic study of ryanodine.


Introduction
Ryanodine (Scheme 1) [1][2][3] is a potent modulator of the intracellular calcium release channels, known as ryanodine receptors [4,5].Its complex architecture, including eight contiguous tetrasubstituted carbons on the pentacyclic ABCDE-ring system, has posed a formidable synthetic challenge.To date, the only total synthesis of a compound in this class of natural products was reported by Deslongchamps, who constructed ryanodol in 1979 [6][7][8][9].Most recently, we reported the synthesis of 9-demethyl-10,15-dideoxyryanodol [10] by taking advantage of the intrinsic C 2 -symmetry of the target molecule.In this synthesis, C 2 -symmetric compounds such as bicyclo [3.3.2]decene 1 were strategically designed, and application of pairwise func-tionalizations of these molecules minimized the total number of steps.
Bicyclo [3.3.2]decene 1 was prepared from C 2 -symmetric bicyclo[2.2.2]octene 2 through a ring-expansion reaction (Scheme 1) [11].We reported the synthetic routes to racemic 2 and enantiomerically pure 2 from 3 and 5, respectively.Specifically, the dearomatizing Diels-Alder reaction between 2,5dimethylbenzene-1,4-diol (3) and maleic anhydride lead to the construction of bicyclo[2.2.2]octene 4, which was then transformed into racemic 2 through electrolysis [11].Alternatively, the Diels-Alder reaction between 3,6-dimethyl-o-quinone Scheme 1: Structure of ryanodine and the Diels-Alder reactions for construction of the potential intermediates of ryanodine.monoacetal 5 and 1,1-diethoxyethylene provided bicyclo[2.2.2]octene 6, which was then converted to enantiopure 2 via an enzymatic kinetic resolution [12].The Diels-Alder reaction was effectively employed in both of these syntheses for construction of the two quaternary carbons at the C1 and C5 positions of ryanodine (highlighted in gray).However, the current route to (+)-2 from racemic 6 generated the unnecessary antipode.Therefore, development of an alternative asymmetric route to 1 was planned to further improve the overall practicality.Here we report an asymmetric Diels-Alder reaction for simultaneous installation of the C1-and C5-stereocenters using the optically active cycloheptadiene derivative 7, and its derivatization into bicyclo[3.3.2]decene 1.
We assumed that the C4-stereocenter of optically active sevenmembered diene 7 would permit the requisite stereoselective Diels-Alder reaction (Scheme 1).Namely, the reaction between 7 and acrolein was expected to stereoselectively introduce the C1, C5 and C12 stereocenters to afford bicyclo[3.2.2]nonene 8.The C11-aldehyde of 8 was then to be utilized as a handle for the ring expansion to access 1.To the best of our knowledge, construction of the two quaternary carbons by the intermolecular Diels-Alder reaction of 1,4-disubstituted cycloheptadiene derivatives has not been reported [13,14].

Results and Discussion
The synthesis of optically active 7 began from crotyl chloride (Scheme 2).The carbon chain extension of crotyl chloride by treatment with acetylacetone and K 2 CO 3 [15], followed by the addition of vinylmagnesium bromide [16], provided 9.The bromoetherification of tertiary alcohol 9 by using NBS led to tetrahydrofuran 10 as a diastereomeric mixture.Next, the baseinduced elimination of HBr converted 10 to diene 11, which underwent the Claisen rearrangement at 170 °C to give rise to heptenone 12 [17][18][19][20][21].The more thermodynamically stable silyl enol ether 13 was regioselectively formed from 12 under Holton's conditions [22], and DDQ-mediated oxidation of 13 resulted in the formation of α,β-unsaturated ketone 14.Asymmetric reduction of ketone 14 was in turn realized by applying a stoichiometric amount of (R)-CBS and BH 3 •SMe 2 to produce 15 (82% ee) [23].The absolute configuration of C4 was determined as S by the modified Mosher method after acylation of Scheme 2: Asymmetric synthesis of 7 and determination of the absolute configuration at C4 of 15 by the modified Mosher method.The numbers are differences in 1 H chemical shifts between 16a and 16b (Δδ = δ16a − δ16b).Scheme 3: Generation of 17 through the 6π-electrocyclic reaction and the Diels-Alder reaction.
We then explored the Diels-Alder reaction between 7 and acrolein to construct the bicyclo[3.2.2]nonene structure (Scheme 3).The Diels-Alder reaction under thermal conditions (100 °C) induced the decomposition of diene 7, and only the starting material was recovered after 10 h (26%).Because of the low reactivity of 7, we applied a Lewis acid to facilitate the reaction.However, the reaction of 7 and acrolein in the presence of BF 3 •OEt 2 (50 mol %) led to formation of the unex-pected bicyclo[2.2.2]octene skeletons 17a and 17b as a 2.9:1 mixture.Under these conditions, BF 3 •OEt 2 -promoted elimination of the allylic siloxy group in 7 generated triene 18, which then isomerized into 19 via a 6π-electrocyclic reaction.Diene 19, which appeared to be more reactive than the original diene 7, then underwent the Diels-Alder reaction to provide 17a and 17b.
Formation of 17a and 17b in Scheme 3 confirmed that selective activation of acrolein in the presence of the Lewis-basic allylic oxygen was a prerequisite to the successful formation  1, entries 4 and 5).Thus, we developed an effective method for synthesis of the requisite stereoisomer 8 by applying a TBSOTf-promoted Diels-Alder reaction [25,26].Most importantly, the C4-stereocenter behaved as the control element to introduce the two quaternary carbons (C1 and 5) and the C12-stereocenter.
The selective formation of 8 out of eight possible isomers is rationalized in Scheme 4. The endo-type transition states would be favored over their exo-type counterparts, and acrolein would approach from the bottom face of 7 to avoid steric interactions with the axially oriented C2-and C4-hydrogen atoms on the top face [27].These considerations eliminate six out of the eight stereoisomeric transition states, and leave only TS-A and TS-B, which in fact correspond to the generated adducts 8 and 20, respectively.TS-A would be preferred over TS-B due to the unfavorable interaction of the two proximal TBS groups in TS-B, allowing formation of 8 as the major compound.afforded 22 as a single stereoisomer, and the obtained 22 was oxidized with DMDO to provide α-hydroxy aldehyde 23 as a diastereomeric mixture (dr = 2.8:1).Compound 23 then reacted with benzyl hydroxylamine to produce oxime 24, LiAlH 4 -treatment of which led to 25.The regioselective ring expansion of seven-membered 25 was induced by treatment with NaNO 2 in acetic acid [28,29], resulting in the formation of eightmembered 27 through the intermediary of 26.Finally, the desilylation of 27 with TBAF and the subsequent oxidation of the resultant hydroxy group delivered the symmetric diketone 1 in optically active form.

Conclusion
In summary, we developed a synthetic route to the optically active seven-membered 7 and established the TBSOTfpromoted stereoselective Diels-Alder reaction between 7 and acrolein to construct highly functionalized bicyclo[3.2.2]nonene 8 bearing two quaternary carbons.Seven additional transformations of 8, including the ring expansion of the seven-membered ring to an eight-membered ring, delivered C 2 -symmetric bicyclo[3.3.2]decene 1, which is the key intermediate in our synthetic studies of ryanodine.