Asymmetric Synthesis by the Intramolecular Haloetherification Reaction of Ene Acetal: Discrimination of Prochiral Dienes in Cyclohexane Systems

Abstract

Asymmetric synthesis based on the desymmetrization of symmetric compounds is one of the most powerful ways to get optically pure compounds, especially for the substrates having prochiral carbon atom(s), and many methodologies by chemical reactions, for examples refs. 1-4, [1][2][3][4] and enzymatic ones, for examples refs. 5-9, 5-9) have already been developed. Recently, we have developed a new asymmetric synthesis of 1,4-and 1,5-diols from the ene aldehydes involving the intramolecular haloetherification reaction of their C 2 -symmetric acetals as a key step (Eq. 1). 10,11) (1)We then planned to extend this methodology to the symmetric compounds with two prochiral olefins. If the reaction can successfully discriminate the diastereotopic groups and their faces, it will be quite useful for constructing optically active compounds because it can produce chiral non-racemic compounds bearing multichiral centers and the remaining olefin can be used for further transformations (Eq. 2). (For examples of discrimination of prochiral two olefinic groups by halocyclization using chiral auxiliary, see refs 12-18.) [12][13][14][15][16][17][18] (2)Based on this idea, we studied the intramolecular haloetherification reaction of cyclohexa-1,4-dienes 1 having the C 2 -symmetric acetal on the side chain and found that the reaction discriminated the two prochiral olefins in a highly diastereoselective manner to give 2 as the major product (Chart 1).19) The alkoxy group of the mixed acetals was then converted to an alkyl group. The obtained alkylated compounds 3 were subjected to several transformation reactions forming optically active cyclohexane derivatives with multichiral centers. We now present the full details of our study. Results and DiscussionThe optically active monosubstituted cyclohexadiene acetals (1a, b) were synthesized as follows (Chart 2). The cyclohexadiene acetals (4, 5) were prepared from benzoic acid according to a literature procedure. 20) Their transacetalization with (ϩ)-hydrobenzoin 21) gave 1a and 1b in good yields. The disubstituted cyclohexadiene acetals (1c, d) were synthesized from compound 6, which was obtained by reductive alkylation 22) of methyl benzoate followed by reduction with DIBAL-H (Chart 3). Protection of the hydroxy group of 6 by the tert-butyldiphenylsilyl (TBDPS) group and selective deprotection of the resulting disilyl ether afforded 7 in good yield. The Swern oxidation 23) of 7 followed by acetalization with (ϩ)-hydrobenzoin produced the optically active 3,3-disubstituted cyclohexadiene acetal silyl ether 1c. The desilyla- A novel asymmetric synthesis of the cyclohexane derivative functionalized by some substituents has been developed from the diene acetals (1), prepared from the corresponding diene aldehyde and (؉)-hydrobenzoin. The treatment of 1 with NBS in the presence of MeOCH 2 CH 2 OH predominantly afforded 2 in a stereoselective manner. Subsequent alkylation of the methoxyethoxy group produced the optically active cyclohexene compounds (3) in good yields. The stereoselective ch...

Reaction of Acetals with Various Carbon Nucleophiles under Non‐Acidic Conditions: CC Bond Formation via a Pyridinium‐Type Salt

“…[3] We have previously reported the reaction of methoxyethoxy acetals with Grignard reagents, and a substitution reaction occurred by chelation of the magnesium ion with the methoxyethoxy group. [4] a,b-Unsaturated acetals could react with Grignard reagents alone or in the presence of a Lewis acid. [5] Organocuprates activated by BF 3 ·Et 2 O could also react with acetals [6] via oxonium ion intermediates.…”

“…On the other hand, the use of organometallic reagents as nucleophiles is not very common. Some acetals, such as a,b-unsaturated acetals, can react with these reagents to give substituted products [2][3][4][5] or the Lewis-acid-activated organocuprates can react with the acetals. [6] Therefore, nucleophiles for CÀC bond formations are rather limited.…”

Diastereoselective Desymmetrization of Symmetric Dienes and its Synthetic Application

“…This reaction stereoselectively proceeded via the chiral bicyclic cationic intermediates, and the subsequent nucleophilic addition of an alcohol to the oxonium ion intermediate afforded 59, which have two newly formed chiral centers on the prochiral atom and the acetal center of the starting materials 58. The chiral auxiliary unit derived from the C 2 -symmetric diol could be removed by various procedures, i.e., Birch reduction, hydrogenolysis, and fragmentation promoted by CAN [38,39] We then studied the intramolecular bromoetherification reaction of the substituted cyclohexadiene having the C 2 -symmetric acetal 60 and found that the reaction successfully discriminated the two prochiral olefins in a stereoselective manner to provide 61 in 63% yield [40,41] (Scheme 22). This reaction was useful for constructing complex molecules because it could produce optically active cyclohexane derivatives bearing multiple chiral centers and the remaining olefin, which promised further transformations.…”

“…The sterically hindered acetal moiety derived from the C 2 -symmetric acetal could fix the cyclohexene ring conformation promising high regio-and stereoselective transformations. For example, the dihydroxylation of 62 with OsO 4 stereoselectively proceeded from the less hindered face to give the corresponding diol 63 in 85% yield as a single product [41] (Scheme 23). Enantioselective reactions with chiral catalysts are well-known as more powerful methods than diastereoselective approaches with chiral auxiliaries for asymmetric synthesis.…”

Development of Highly Stereoselective Reactions Using Lone Pairs of Oxygen Atoms

“…2), [19][20][21][22][23][24][25][26][27][28][29] 2) ベックマン開裂反応の v-ニトリルオキソニウ ムイ オン中 間体への 種々の 炭素求 核種導入 反応 （Eq. 3), [30][31][32][33][34] 3) ジアセタートから酸素の孤立電子 対の押し出しにより容易に生成するジカチオン等価 体を利用する不斉合成反応（Eq.…”