A new synthetic approach to 3-methylene-1-cyclohexanols fused to five-, six-and seven-membered carbocycles through intramolecular cyclization of epoxyallylsilanes

Silylcupration of allene followed by conjugate addition to enones and carbonyl epoxidation provides a simple and high yielding route to epoxyallylsilanes carrying the useful phenyldimethylsilyl group. Lewis acid catalyzed intramolecular cyclization of epoxyallylsilanes is a powerful strategy for carbocyclic annulation of much potential in synthesis. In this article we show A general procedure for the synthesis of 3-methylene-1-cyclohexanols fused to five, six and seven-membered carbocycles by intramolecular cyclization of epoxyallylsilanes, which might be of great interest as an approach to bicyclic systems contained in many naturally occurring products, is described.


Introduction
Organosilicon compounds and in particular allylsilane chemistry have attracted a great deal of attention due to the increasing number of new methodologies that allow useful synthetic transformations. 1 Over the last decade allenes have emerged as one of the best sources for the synthesis of allylsilanes. 2They are readily attacked by silylcuprates giving rise to a great variety of allylsilanes with different substitution patterns. 3The stoichiometry of the silylcuprate (higher or lower order) is responsible for the final regioselectivity of the reaction, leading selectively to allylsilanes when a lower order cyanosilylcuprate (R3SiCuCNLi) is used. 4cheme 1 α,-Unsaturated oxocompounds have been successfully used in this reaction, leading to a wide range of oxo-functionalized allylsilanes, which are valuable intermediates for carbocyclic annulations. 4,5In recent reviews, we have shown a general summary of the advances in allylsilane chemistry and their significance as precursors for the synthesis of three to sevenmembered rings.2b,6 Despite its synthetic potential, the cyclization of epoxyallylsilanes has not been widely explored.Under Lewis acid conditions, nucleophilic substitution usually takes place at the most substituted carbon center of the epoxide 7 unless the presence of electron-withdrawing groups next to the epoxide destabilizes the developing carbocation. 8Contrary to the normal 5-exo 9 or 6endo 10,11 attack, we have recently reported that the acid-catalyzed reaction of epoxyallylsilanes containing the phenyldimethylsilyl 12 or the tert-butyldiphenylsilyl 13,14 group follows an unusual rearrangement-cyclization process which leads to methylenecyclohexanols 12 or to allyl-and vinylsilane-containing cyclohexanols 13 respectively (Scheme 2).

Results and Discussion
Epoxyallylsilanes have been previously prepared by Wittig reaction of an aldehyde with Ph3P=CHCH2SiMe3 followed by epoxidation 15 and by cross metathesis of alkenyl epoxides and allylsilanes. 16We have recently reported 12 a new route for the synthesis of epoxyallylsilanes by silylcupration of allene, followed by capture of the intermediate cuprate with enones and finally sulfur ylide-mediated epoxidation.
In the past years, we have been very actively involved in the study of the silyl-and stannylcupration of allenes and acetylenes and their synthetic applications.2a,17 These reactions take place by syn-addition of copper to one end of the multiple bond and Si or Sn to the other, affording cuprates with structures comparable to 1.The intermediate allylsilane-vinylcuprate 1 can be captured by a great variety of electrophiles giving functionalized allylsilanes.2a For example, the use of α,β-unsaturated oxocompounds leads to oxoallylsilanes of type 2 which have been used as powerful building blocks for cyclopentane annelations.2a,6a,18 Epoxidation of 2 via dimethylsulfonium-ylides gives epoxyallylsilanes 3 in high yield (Scheme 3). 12,13

Scheme 3
In this paper we describe the synthesis and cyclization of epoxyallylsilanes containing five-, six-and seven-membered carbocycles as an efficient route for the construction of bicyclic 3methylene-1-cyclohexanols systems which are present in the skeleton of many terpenoid products.As it is shown, Lewis acid-catalyzed intramolecular cyclization seems to occur with concomitant rearrangement of the epoxy group and trapping of the intermediate aldehyde (Table 2). 19henyldimethylsilylcyanocuprate 20 reacts with allene at -40ºC giving an allylsilanevinylcopper intermediate 1, which was treated with cyclic α,β-unsaturated ketones 4-8 to afford the products of conjugate addition 9-14 in good yield.All the reactions were carried out in the presence of BF3.OEt2 or TMSCl, which considerably increased the yield (Table 1).The cyclic oxoallylsilanes thus obtained were treated with dimethylsulfonium methylide to give in good yield the corresponding epoxides 15-20 (Table 1) apparently as a single diastereomer (single sharp signals in 13 C NMR spectra). 21No attempt was made to assign configurations to the epoxides.

Table 1. Synthesis of oxo-and epoxyallylsilanes.
The stereochemistry of the isolated compound was established by COSY and NOESY spectra, and by examining their 1 H coupling constants.For the entry 5, both diastereomers 13 and 14 could be well separated by LC, and their relative stereochemistry assigned.Both were efficiently epoxidated with retention of their initial configuration.
The most remarkable feature observed in the epoxyallylsilane cyclization is the absence of products resulting from 5-exo or 6-endo cyclization (the normal epoxide cleavage).Instead, we selectively obtained bicyclic 3-methylene-1-cyclohexanols 21-29 derived from an unusual rearrangement-cyclization process (Table 2).The rearrangement of a carbonyl group into an epoxide is known process that is enhanced by the presence of acids. 22However, this is the first time that this sequential tandem reaction is observed in epoxyallylsilanes.The substituents on the silyl group should play an important role because epoxyallylsilanes carrying TMS groups give normal products of 5-exo or 6-endo attack. 11he results collected in Table 2 seems to indicate that in the case of epoxyallylsilanes bearing PhMe2Si groups, rearrangement occurs faster than the nucleophilic substitution on the epoxy group.A two-step mechanism involving rearrangement to intermediate A followed by intramolecular Sakurai-Hosomi cyclization has been proposed (Table 2).The second step (cyclization) must be a fast reaction since aldehyde intermediates of type A never were isolated.To optimize the procedure, several combinations of solvent, temperature, time and Lewis acid were carefully tested.Boron trifluoride etherate in dichloromethane was proven to be the best choice for good yield (table 2).From a synthetic point of view, the reported methodology is highly attractive because it provides an efficient strategy for the construction of bicyclic 3methylene-1-cyclohexanols fused to five-, six-and seven-membered ring systems contained in many natural products.

Table 2.
High levels of stereoselectivity were found in the formation and cyclization of epoxyallylsilanes.Except for compound 20, all epoxyallylsilane cyclizations afford selectively cis-fused bicyclic systems.Moreover, formation of 26 and 27 seems to point out that, in some cases, the loss of proton competes favorably with the leaving of silyl group.
The cis stereochemistry of fused rings and the configurations of the phenyl and hydroxyl bearing carbons were assigned by examining their COSY and NOESY spectra.For example, in compound 23 observation of coupling patterns for H(1) δ=4.1 ppm and H(4) δ=3.53 ppm clearly indicates that they are axial (OH/Ph, trans di-equatorial).The former protons also have clear COSY correlations with H(8a) δ=1.86 ppm and H(4a) δ=1.95 ppm respectively.Examination of the NOE correlations between H(4a) and H(8a) shows strong cross-peaks at the coordinates, which support cis-fused stereochemistry.H(4a) also has an intense NOE correlation with H(4) which suggest that both protons are in a syn relationship (Ph/H(4a): anti).Finally, no cross-peaks were found for the correlation H(1)-H(8a), however syn-protons H(1) and Heq(2) δ=2.23 ppm show NOE correlation, thus confirming the anti relationship of H(1) and H(8a).
As it is shown in the example of Scheme 4, addition of cuprate 1 to the enone 6 is followed by stereoselective protonation from the less hindered side of the enolate to give selectively oxoallylsilane 11 (8:1, Table 1).The epoxide 17 undergoes rearrangement, in the presence of boron trifluoride etherate, probably through a cationic intermediary (Scheme 4) to give an intermediate aldehyde A (not isolated).Subsequent cyclization to bicyclic methylenecyclohexanol 23 takes place via a low-energy transition state B (Scheme 4) where the bulky groups attain an equatorial conformation for minimal steric repulsions.The cis-fused ring pattern obtained in most cases might indicate that rearrangement give just the intermediate aldehyde A of cis stereochemistry, however, it is also feasible that the two possible α-epimers of the aldehyde A equilibrate, with the one which can cyclize to give cis-fused products reacting faster and therefore giving rise to the final products.

Scheme 4
In summary, a new route to methylenecyclohexanols fused to five, six and seven-membered carbocyclic rings via epoxyallylsilane cyclization is described.The stereoselectivity of the reaction allows the efficient preparation of 5/6, 6/6 and 7/6 cis-fused bicyclic systems contained in many natural products.An unusual rearrangement-cyclization tandem process has been proposed as a feasible mechanism for the general reaction reported.

Experimental Section
General Procedures.Organometallic reagents were purchased from Aldrich and CuCN from Fluka.The latter was briefly dried in vacuo prior to use.1,2-Propadiene (Allene) was supplied by Air Liquide S. A. in lecture bottles.All reactions were carried out under dry nitrogen.Elemental analyses were performed with a LECO CHNS-932 analyzer sited in the "Parque Científico Tecnológico de la UBU, Pza.Misael Bañuelos s/n, 09001 Burgos Spain".The stereochemistry of compounds has been assigned on the basis of COSY and NOESY experiments. 4 solution of phenyldimethylsilyl-lithium 23 (3 mmol), prepared in THF (3 ml) from phenyldimethylchlorosilane and lithium shots (0 o C to r.t.overnight), was added by syringe to a stirred suspension of copper(I) cyanide (269 mg, 3 mmol) in THF (5 ml) at 0 o C, under argon atmosphere.The resulting black mixture was stirred at this temperature for 30 min, and then used immediately.The solution of the phenyldimethylsilylcyanocuprate 20 (3 mmol) in THF (8 ml) was cooled at -40 o C and a slight excess of allene was added from a balloon.The mixture was stirred for 1 h at this temperature and the reagent 1 is ready to use.The intermediate cuprates resulting from addition to allene are stable enough in solution to be used without special precautions other than dry atmosphere, however long periods of times before using the reagent are not recommended.Reaction of the intermediate cuprate 1 with enones 4-8.Typical procedure 4 BF3.Et2O (0.38 ml, 3 mmol) was added at -78 o C to a stirred solution of the intermediate cuprate 1 (3 mmol) and the mixture stirred for 10 min at this temperature, then 3.5 mmol of the α,unsaturated oxocompound 4-8 in THF (5 ml) were added dropwise at -40 o C and the resulting mixture was kept at this temperature for 1 h.After gentle warming to 0 o C (over 0.5 h) the mixture was quenched with aq sat.NH4Cl solution and extracted with Et2O.The organic phase was dried, evaporated and chromatographed (EtOAc:hexanes) to give the corresponding oxoallylsilanes 9-14 (Table 1).