Aza-Prins reaction

Scheme 1). Introduction of a jt bond into the molecular structure of 1 furnishes homoallylic amine 2 and satisfies the structural prerequisite for an aza-Prins transform.4 Thus, disconnection of the bond between C-2 and C-3 affords intermediate 3 as a viable precursor. In the forward sense, a cation ji-type cyclization, or aza-Prins reaction, could achieve the formation of the C2-C3 bond and complete the assembly of the complex pentacyclic skeleton of the target molecule (1). Reduction of the residual n bond in 2, hydro-genolysis of the benzyl ether, and adjustment of the oxidation state at the side-chain terminus would then complete the synthesis of 1. 

An interesting shift from a 1,3-dipolar cycloaddition (see 360) to an intramolecular aza-Prins reaction (361) was achieved by simply changing the reaction conditions. 

Treatment of the same nitrone with TMS-triflate at —40°C afforded a 79% yield of N-hydroxypiperidine 361 in an intramolecular aza-Prins reaction, which is certainly substantially assisted by the TMS group in the aUylic position (see Sakurai reaction) [129]. 

Parchinsky et al. (2011) reported synthesis of symmetrically and unsymmetrically substituted chiral, racemic 1-azaadamantanes via BF3.0Et2-promoted aza-Prins reaction under microwave irradiation. Reaction of ( )-[(4-methylcyclohex-3-en-l-yl) methyljamine with an equimolar amount of an aldehyde in the presence of 1.0 equiv. of Bp3.0Et2 at ISO C for 1 h gives predominantly bicyclic piperidines whereas in presence of excess amount of the aldehydes, symmetrically substituted 1-azaadamantanes are the major products. The yield of the products ranges from 52-83%. 

Diels-Alder reaction to give 226 as an intennediate. When 226 was subjected to healing, an aza-Prins reaction followed by loss of a proton afforded 228 in 77 % overall yield for the entire sequence commencing with diol 224. This late-stage intermediate was readily utilized to complete the total synthesis of the squalene-derived natural product methyl homosecodaphniphyllate (229) [114]. This masterful synthesis qualifies, without doubt, as one of the all-time triumphs in natural products synthesis [116],... 

In furtherance of these smdies, the reaction scope was broadened by employing homopropargylic amines to give the corresponding aza-cycles (Scheme 26) [39, 40]. Hence, the alkyne aza-Prins cyclization between homopropargyl tosyl amines... 

A plausible mechanism for this new alkyne aza-Prins cyclization is outlined in Scheme 27. Thus, reaction of the homopropargyl tosyl amine with an aldehyde promoted by ferric halide generates the W-sulfonyl iminium ion. This intermediate evolves to the corresponding piperidine, via the vinyl carbocation. Ah initio theoretical calculations support the proposed mechanism. 

FeX3 was also found to be an excellent promoter in the classical Prins cycliza-tion (Scheme 10, route H), with the observation of a satisfactory reaction between 3-buten-l-ol and several aldehydes, affording the corresponding c/s-4-halo-2-alkyl tetrahydrop3Tans in good yields [Eq. (1) in Scheme 32] [35], In a similar manner, the methodology can be extended to the piperidine synthesis through an aza-Prins cyclization [Eq. (2), Scheme 32] [41],... 

SL2528>. Aliphatic aldehydes react with the chiral vinylsilane 256 in an InCls-induced aza-silyl-Prins reaction to provide 1,6-trans tetrahydropyridines 257. Hydrogenolysis gave the natural products (-)-solenopsin A (R = -CnH23) and (+)-e/>i-dihydropinidine (R = -Pr), 258 (Scheme 77) <05SL2101>. 

The intramolecular aza-Prins cyclization of 1 to 2 proceeded well, though the desired tetracyclic 2 was only observed when base was included in the reaction medium. In the absence of base, tricyclic alkenes dominated. 

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