Cascade radical cyclization of polyolefinic vinyl iodides: comparison between 5-exo and 6-endo cyclization of vinyl radicals

We herein describe sequential radical cyclization of acyclic polyenes having a vinyliodide moiety that can act as both of a radical donor and an acceptor during the same reaction. The regioselectivity is extremely dependent on the substrate structure. Tricyclo[8.4.0.0 2,7 ]tetradecene and tricyclo[6.3.0.0 2,6 ]undecane were obtained by cascade radical cyclization from the well-designed substrates, 1-iodo-1,5,9,14-tetraene and 1-iodo-1,5,10-triene, in a single operation.


Introduction
Radical reactions have become valuable tools for the construction of complex molecules and have solved various fundamental problems associated with ionic reactions. 1Out of various types of radical reaction, the cascade (tandem) reaction is one of the most powerful methods to construct a polycyclic ring system in one step from unsaturated acyclic precursors. 2 It is well documented that 5-alkenyl radicals (alkyl radicals) predominantly undergo 5-exo cyclization to give 5-membered products over the 6-endo mode. 3The cascade 5-exo radical cyclization reactions based on the above feature have been developed to synthesize polycyclic 5-membered compounds. 4Although the examples were limited, cascade 6-endo radical cyclizations were investigated and utilized in the syntheses of steroidal skeletons.It was made clear that ketyl radicals are effective for consecutive 6-endo cyclization. 5On the other hand, in 1980s Beckwith and Stork have independently reported that the use of vinyl radicals for a ring closure has shown unique behavior indicating an equilibrium between 5-exo and 6-endo cyclizations. 6,7In this paper The radical reactions were performed by using Bu 3 SnH (TBTH) in the presence of a catalytic amount of AIBN or Et 3 B-O 2 as a radical initiator (Table 1).Under refluxing conditions in benzene at 80 °C, 1 was transformed into the cyclohexene 6a, which was isolated as 6b, after deprotection of the silyl group, as a diastereomeric mixture in the ratio of 1 : 3.5 (entry 1).On the other hand, the treatment of 1 at low temperature (-40 °C), followed by desilylation, provided the cyclopentene 5b as a major product along with 6b (entry 2).The formation of the 6-endo adduct under thermodynamic conditions can be explained as follows based on homoallyl-homoallyl radical rearrangement. 11The radical reaction initially proceeds through 5-exo cyclization in accordance with Baldwin's rule 12 to give the secondary radical species 7.At higher temperature the 5-exo adduct 7 further cyclizes by 3-exo manner to give the unstable intermediate 8.
Cyclopropylcarbinyl radical 8 is rapidly transformed by β-scission into the thermodynamically stable tertiary radical 9, which was consequently transformed into the 6-endo product 6a.Thus, 5-exo or 6-endo adducts could be synthesized from the vinyl radical precursor by changing the reaction temperature.Table 1.Radical cyclization of 1-iodo-1,5-diene 1 a Overall yield in 2 steps.b The ratio was determined by 1 H-NMR.c 6b was obtained as a 3.5:1 diastereomeric mixture.
Next, we planned the sequential radical cyclization of suitably functionalized acyclic substrates to construct polycyclic skeletons.We rationally designed vinyl iodides 10 and 11 as geranylgeranyl and farnesyl motifs, respectively.The terminal unsaturated ester moiety was anticipated to act as a good acceptor to accelerate the radical addition. 131-Iodo-1,5,9,14tetraenoate 10 was prepared from 4 in 8 steps (Scheme 2).Allyl alcohol 12 was prepared by Claisen rearrangement of 4, followed by Barbier reaction with 2-bromopropene.O-Vinylation of 12 provided vinyl ether 13 in 98% yield.Vinyl iodide 14 was prepared by Claisen rearrangement of 13, followed by Wittig olefination and desilylation.14 was obtained as a single isomer having Z configuration with respect to the iodo olefine double bond.Oxidation of hydroxyl group of 14 with Dess-Martin periodinane, 14 followed by HWE reaction, afforded the key substrate 10.
1-Iodo-1,5,10-trienoate 11 was prepared by a short sequence of reactions as shown in Scheme 3. Dimethyl malonate was mono-alkylated with geranyl bromide to afford diene 15 in 71% yield, and further alkylation of 15 with methyl 4-bromocrotonate gave trienoate 16 in 92% yield.The treatment of 16 with a catalytic amount of osmium tetroxide in the presence of Nmethylmorpholine oxide (NMO), followed by oxidative cleavage of the corresponding diol by sodium periodate, provided the desired aldehyde 17 (83% overall yield in two step The radical reaction of tetraene 10 was examined under various conditions; reductive electrolysis, 15 TBTH method, and tris(trimethylsilyl)silane (TTMSH) method (Table 2).The electrolysis, mediated by Ni(cyclam) 2+ of 10 at room temperature, yielded the dodecahydrophenanthrene derivative 18, the cyclopentene derivative 19, and other cyclized products with a 5 : 2 : 3 ratio in low yield (entry 1).The formation of 18 results from the 6-endo, 6-endo, 6-exo cascade cyclization.When the reaction was performed at 100 °C, the ratio of 18 increased considerably but the yield was still low (entry 2).On the other hand, when 10 was exposed to thermal conditions by using TBTH or TTMSH, the desired cascade cyclization proceeded in high yield to give 18 as a major product (entries 3 and 4).Especially, the treatment with TTMSH-AIBN at 80 °C exclusively afforded 18 in 77% yield.The structure of 18 was established by the spectral analysis after conversion of the olefin moiety into the carbonyl function, 16 although the stereochemistry was not determined owing to difficulty of separation of each diastereomer.The free radical reaction at -40 °C using TBTH-Et 3 B in the presence of O 2 gas gave only 19 in very high yield (entry 5).In contrast, the radical reaction of 1-iodo-1,5,10-trienoate 11, which lacks one isoprene unit compared with 10, gives quite different results. 17The radical cyclization reaction of 11 was conducted under similar conditions as above (Table 3).The reaction with TBTH-AIBN under refluxing conditions afforded tricyclo[6.3.0.0 2,6 ]undecanes 20 in 80% yield as a mixture of more than four isomers (entry 1).The cascade reaction proceeded to give a linear-triquinane framework, but unselective formation of several diastereomers was observed.At room temperature the number of stereoisomers was reduced; treatment with TBTH-Et 3 B at room temperature afforded only two isomers, 20a and 20b, in 83% yield with a ratio of 4 : 3 (entry 2).However, when the temperature was further lowered (-40 °C), the yields of mono and doublecyclized products were increased (entry 3).The TTMSH method gave almost similar results to the TBTH method (entries 4 and 5).On the contrary, the cathodic electrolysis, mediated by Ni(cyclam) 2+ , afforded poor production of 20 (entries 6 and 7).After a careful purification by column chromatography on silica gel, only 20a was separated from the mixture of 20a and 20b (from entry 2 in Table 3).The structural assignment of 20a was achieved on the basis of detailed 2D NMR experiments (NOE correlation was shown in Figure 1).Its framework was determined as a cis-syn-cis linear-triquinane and the methoxycarbonyl group at C (7) was located on the convex side of the skeleton.On the contrary, isolation of 20b could not be achieved by any efforts.No epimerization of 20a occurred by treatment with DBU under thermodynamic conditions or by LDA under kinetic conditions.It indicates that the acidic proton at C (7) of 20a stands on the sterically hindered position.When a mixture of 20a and 20b was subjected to kinetic deprotonation conditions (LDA, then aqueous work up), a new epimer was obtained along with 20a and 20b.This suggests that the new epimer is the diastereomer of 20b and, moreover, 20b has a different stereochemistry of a linear-triquinane skeleton from 20a.Based on the mechanistic aspect and Curran's previous results, 17 the framework of 20b might be cis-anti-cis configuration.It is interesting to observe that the radical reactions of acyclic isoprenoid analogs 10 and 11 proceed in different cyclization manners.The reaction of geranylgeranyl analog 10 produces tricyclo[8.4.0.0 2,7 ]tetradecene 18, which is a linear fused six-membered ring carbocycle, through a sequential 6-endo, 6-endo, 6-exo cyclization.Whereas a 5-exo, 5-exo, 5-exo cyclization proceeds in the case of farnesyl analog 11 to give tricylo[6.3.0.0 2,6 ]undacane 20, which is a linear fused five-membered ring carbocycle.The reaction pathways of tetraene 10 and triene 11 can be rationally explained as shown in Scheme 4. In both case, the first radical cyclizations of corresponding 21 and 26 proceed through the kinetically favored 5-exo cyclization to form cyclopentenyl intermediates 22 and 27, respectively.But the cascade sequences may be firmly dependent on the regioselectivity at the second stage of the radical addition.In the former case, 3-exo-trig cyclization undergoes to give intermediate 23 under the thermodynamic conditions, whereas 5-endo-trig cyclization with another olefin moiety can be ruled out by Baldwin's rule.Unstable intermediate 23 is rearranged into thermodynamically stable tertiary alkyl radical 24, which is consistent with the formal 6-endo-trig cyclized intermediate from vinyl radical 21.In the third radical cyclization stage, due to the steric effect, the 6-endo cyclization may be predominant over 5-exo to afford bicyclic radical 25. 18 Finally, the radical reaction completes by the sequential 6-exo-trig cyclization to give the decahydrophenanthrene adduct 18.On the contrary, in the reaction of 11, cyclized radical intermediate 27 will be converted into 28 by means of the 5-exo-trig cyclization.5-Exo cyclization should be much preferred to 3-exo-trig one owing to the stereoelectronic effect. 19Final 5-exo-trig radical cyclization of 28, followed by hydride abstraction, furnishes the linear-triquinane adduct 20.The complementary results of radical reactions of 10 and 11 will be attributed to the characteristic features of radical cascades.In summary, tricyclo[8.4.0.0 2,7 ]tetradecene 18 and tricyclo[6.3.0.0 2,6 ]undecane 20 were obtained by cascade radical cyclization from 1-iodo-1,5,9,14-tetraene 10 and 1-iodo-1,5,10triene 11, respectively, in a single operation.The reactivity and selectivity of the cascade reaction can be controlled by the rational design of the substrate, such as incorporation of an

Experimental Section
General.Procedures.All reactions were carried out under an inert atmosphere.Anhydrous THF, Et 2 O, MeCN, and CH 2 Cl 2 were purchased from the Kanto Chemical Co., Inc.Toluene, DME and benzene were distilled from CaH 2 under atmospheric.Unless otherwise described, the materials were obtained from commercial suppliers and used without further purification.Organic extracts were dried over MgSO 4 , filtered and concentrated under reduced pressure using an evaporator.Unless otherwise described, the 1 H and 13 C NMR spectra were recorded at 300 and 75 MHz, respectively, and were reported in ppm downfield from TMS (δ = 0) for the 1 H NMR and relative to the central CDCl 3 resonance (δ = 77.00)for the 13 C NMR.