Cp 2 TiCl-catalyzed highly stereoselective intramolecular epoxide allylation using allyl carbonates †

A useful method for the diastereoselective synthesis of vinyl substituted carbo- and heterocycles is described. Highly functionalized structures di ﬃ cult to achieve by other methodologies are obtained in a single step by this procedure.

Epoxides are highly versatile functional groups in organic synthesis owing to the fact that their manipulation yields many attractive final products. Thus, for example, diverse carbon nucleophiles, such as Grignard and organolithium reagents or organocuprates, have been used in ring-opening reactions to install a new C-C bond. 1,2 The intramolecular version of this reaction would allow the preparation of different carbo-and heterocycles with different sizes and functionalities. Nevertheless, the synthesis of suitable polyfunctionalized starting materials is not simple taking into account the chemical incompatibilities between the required reactive partners. In this context, neutral pronucleophiles like olefins or allylsilanes (I, LG = SiR 3 , Scheme 1) are more convenient since they allow better control of the reaction and functional group compatibility. 3 A valuable advantage of the reactions of epoxides with allylsilanes, compared with alkenes, is their ability to stabilize β-carbocations (III, Scheme 1), thereby controlling which carbon of the alkene is the nucleophilic carbon. 4 Moreover the allylsilane can control the direction of the final elimination acting as a good leaving group that stabilizes the generated positive charge (IV, Scheme 1). On the other hand, its main drawback is related to the electrophilic character of the reaction, which implies the use of Lewis acids, such as TiCl 4 , and strict control over the temperature. Another disadvantage of allylsilanes relative to simple alkenes is that extra synthetic steps are necessary because they are generally prepared from oxygenated-allyl groups. Therefore, the direct employment of allylic oxygenated functionalities in epoxide ring-opening reactions retaining the favourable characteristics of allyl silane analogues using very mild reaction conditions would represent an important advance in organic synthesis.
The limitation of this approach is that the corresponding β-carbocations (Scheme 1, III, LG = OCOR) would not be stabilized and the control of the direction of elimination would remain a challenge due to the lack of a carbocation stabilizing group and also a good leaving group. As a result, a cationic pathway can be discarded in this case, and an alternative reaction pathway based on carbon-centered radicals was considered. Cp 2 TiCl 5 -mediated homolytic epoxide opening is a well-known reaction, [6][7][8][9][10][11][12][13][14][15][16][17][18][19] which has allowed many remarkable transformations, including a highly successful bioinspired approach to different natural products. 20 homolytic opening of the epoxide, the β-titanoxy radical generated V would undergo further radical cyclization generating a carbon-centered radical VI. At this point, we expected that an oxygenated function in the β-position would act as a good leaving group, thus directing the final elimination towards IV assisted by Cp 2 TiCl as the Lewis acid. 27,28 In fact, we had previously observed the Cp 2 TiCl-mediated radical fragmentation of β-acetoxy alkyl radicals toward the corresponding alkenes. 21,29 In this alternative radical pathway, Cp 2 TiCl would play a crucial dual role in the intramolecular epoxide allylation with oxygenated-allyl groups: (i) starting the reaction by homolytic opening of the oxirane ring and (ii) controlling the final product obtained by radical fragmentation.
Here we wish to communicate that epoxides can formally be allylated intramolecularly in a highly diastereoselective manner under smooth reaction conditions using easily prepared and handled allylic carbonates as allylation reagents. This approach also allows the preparation of different carboand heterocycles with different functionalities.
Due to the known oxophilic character of Ti(III), our initial studies began testing different allyl pronucleophiles 1a-d and 3, including different oxygenated functional groups such as carbonate, acetate, benzoate, methoxyl or hydroxyl groups. Moreover, an epoxyallylsilane 6 was also tested in order to compare the observed results with oxygenated functions. Remarkably, the new developments in titanocene(III)-regenerating agents now allow the use of substoichiometric amounts of Cp 2 TiCl 2 as a precatalyst. In this context, the combination of 2,4,6-collidine and trimethylsilyl chloride developed in our lab 30 has been extensively used, and it was the choice in this case.
Treatment of compounds 1a-d with Cp 2 TiCl led to the expected cyclic compound 2 with variable yields from 50 to 85% (Scheme 2). It is noteworthy that compound 2 was obtained as a single diastereomer in all cases. NOE-diff. experiments (see the Experimental section) showed a cis relationship between the hydroxyl group at C-3 and the vinyl group at C-5.
When epoxyallylic alcohol 3 was treated with Cp 2 TiCl, cyclic compounds 4 and 5 were isolated in a 2/1 ratio (Scheme 3). In this case, the lack of a better leaving group resulted in a different final process. After homolytic oxirane-opening and subsequent cyclization, Ti(III)-mediated hydrogen abstraction in the radical intermediate yields aldehyde 4 (Scheme 3, process a). 31 Besides, the radical intermediate can abstract a hydrogen-atom from the solvent (THF) leading to reduced product 5 (Scheme 3, process b). 32 Silyl derivative 6 was assayed under the same reaction conditions, leading to a mixture of trimethylsilyl containing compounds 7 and 8 in a 1/0.6 ratio (Scheme 4). 23 These two compounds were obtained by similar hydrogen-atom abstractions mentioned above. Ethyl carbonate derivative 1a (85% yield, Scheme 2) resulted in the best yield and therefore ethyl carbonate was the leaving group of choice for the following reactions.
With the optimized conditions in hand, we explored substrates with different linkers, functionalities and substitution patterns. The results are summarized in Table 1.
The reaction successfully gave different five-and six-membered carbo-and heterocycles with excellent diastereoselectivities in almost all the tested substrates. Titanium-induced cyclization of compound E-1a (Table 1, entry 1) led to compound 2 as Z-1a (Scheme 2), revealing the stereoconvergent nature of the process. Additionally, the reaction proved to be compatible with different functional groups, including esters ( The regiochemistry of the radical epoxide opening mainly depends upon the substitution pattern 33 and controls the size of the obtained final cycle ( Table 1, entries 1 vs. 2 and entries 8 vs. 9). As shown in entry 4, treatment of compound 13 with Cp 2 TiCl led to the formation of a 1/1 mixture of five-and sixmembered rings, as expected from a 1,2-disubstituted oxirane ring. 8,9 However in compound 18 electronic effects control the homolytic epoxide opening, thus only affording the six-membered ring 19. Stereoconvergency was further demonstrated, as diastereomeric mixture 28 (entry 11) gave rise to a single cyclic diastereomer 29. It is also noteworthy that the stereoselectivity  of this cyclization allows the setting up of two stereocenters in six-membered and notably five-membered rings (entries 2 and 9). When the stereocenters are located in 1,3-relative positions a cis stereochemistry between the hydroxyl group at C-3 and the vinyl group at C-5 is observed as in the case of compounds 2, 17 and 23 (entries 1, 5 and 8). On the other hand, compounds presenting contiguous stereocenters showed a trans (entries 2, 7, 9 and 12) or cis relationship (entry 3) between the vinyl and hydroxymethyl groups depending on the substitution pattern of the intermediate radical. Interestingly, in more functionalized substrates even three stereocenters can be allocated stereoselectively (entries 6 and 11). In the case of 1,3-relative positions, cis stereochemistry between the hydroxyl group at C-3 and the vinyl group at C-5 is preserved. The additional stereocenter at C-4 presents a trans stereochemistry with respect to the other two stereocenters. All these stereochemical findings can be rationalized invoking the Beckwith-Houk rules. 34,35 cis Substituted five-membered rings are expected for 5-exo-trig cyclizations (entry 3). Trisubstituted radicals proceed disposing the bulkier substituent (R 2 in Scheme 5a) in a pseudoequatorial position (Scheme 5) thus yielding the observed cyclopentanes 10 and 25 (entries 2 and 9).
Although cyclizations of 6-heptenyl radicals are less studied, a similar reasoning explains the experimental results. In the chair-like transition states all the bulkier substituents (R 1 and R 3 in Scheme 6) are disposed in the equatorial positions. Additional template effects cannot be ruled out in cyclization of compound 28 (entry 11). [20][21][22][23] In the case of entries 4 and 10, the structures of compounds 13 and 26 do not follow these stereochemical trends and mixtures of diastereoisomers are obtained. The intrinsic reactivity of a 1,2-disubstituted epoxide in compound 13 (entry 4) precludes a clear analysis of its stereoselectivity. In compound 26 (entry 10), the transition state may be affected by bulky phenyl sulphonyl groups avoiding a clear chair-like transition state and leading to the formation of both isomers.

Conclusions
A useful method for the diastereoselective synthesis of vinyl substituted carbo-and heterocycles is presented. The protocol is based on the radical opening of an epoxide and subsequent intramolecular addition to an allyl carbonate. Formally, the reaction yields similar products as the allylation of epoxides by the appropriate nucleophile but with several significant advantages. Firstly, the polyfunctionalized substrates required are very easily obtained and handled. Secondly, the cyclization reaction occurs at room temperature and under very smooth conditions highly compatible with diverse functional groups. And lastly, the diastereoselectivity observed is quite remarkable giving rise in most of the cases to a single diastereomer even when three stereogenic centres are generated in the final product. Highly functionalized structures difficult to achieve by other methodologies are obtained in a single step by this procedure. Thus, this method is an interesting tool in the context of organic synthesis.

General remarks
Unless otherwise stated, all reagents and solvents (CH 2 Cl 2 , Et 2 O, MeCN, EtOAc, hexane, DMF, and MeOH) were purchased from commercial sources and used without further purification. Dry THF was freshly distilled over Na/benzophenone. Flash column chromatography was carried out using Silica Gel 60 (230-400 mesh, Scharlab, Spain) as the stationary phase. Analytical TLC was performed on aluminium sheets coated with silica gel with the fluorescent indicator UV 254 (Alugram SIL G/UV 254 , Mackerey-Nagel, Germany) and observed under UV light (254 nm) and/or staining with Ce/Mo reagent or phosphomolybdic acid solution and subsequent heating. All 1 H and 13 C NMR spectra were recorded on Varian 300, 400 or 500 MHz spectrometers at a constant temperature of 298 K. Chemical shifts are reported in ppm and referenced to residual solvent. Coupling constants ( J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: m = multiplet, quint. = quintet, q = quartet, t = triplet, d = doublet, s = singlet, b = broad. Assignment of the 13 C NMR multiplicities was accomplished by DEPT techniques.