Regioselective domino metathesis of 2-substituted 7-oxanorborn-5-enes

The regiochemistry of the domino metathesis reaction of 2-endo substituted 7-oxanorbornenic allyl amines and allyl ethers have been studied. The results lead to two alternative reaction pathways, starting either by ring-opening metathesis of the endocyclic C=C bond or by carbometallation of the C=C bond of the alkenyl chain.


Introduction
The 7-oxabicyclo[2.2.1]hept-5-ene derivatives (7-oxanorborn-5-enes) are important chiral templates because these compounds show a broad spectra of reactivity, generally in a predictable regio-and stereocontrolled fashion. 1 We have recently been interested in transformations which involve the endocyclic C=C bond, due to the possibility of generating two stereocentres in a single operation using these types of reactions. 2,3,4In these cases, when the starting material is not symmetrically substituted with respect to the C=C moiety, as in the 2-substituted derivatives 1, regiochemical issues arise, which must be understood prior to the development of new synthetic planning starting from these materials (Scheme 1).We have focused our attention on olefin metathesis processes, which have emerged as powerful tools in organic synthesis. 5In particular, ring-closing metathesis (RCM) has been extensively used for the preparation of cyclic compounds from acyclic precursors.In this context, we are particularly interested in the domino metathesis reaction (combination of ring opening -ROM-, cross -CM-and ring closing -RCM-metatheses) 4 as a means of synthesizing bicyclic tetrahydrofuran derivatives from 7-oxanorbornenes in a highly stereoselective fashion (Scheme 2). 6

Scheme 3
In a similar fashion, nucleophilic addition to the C=N linkage of imine 8 occurs with full diastereoselectivity on the exo face of the bicyclic system, giving rise to the endo-amines 9a,b (Scheme 4). 10 Also, the Strecker cyanide addition afforded the α-aminonitrile 9c as a single diastereomer. 11Protection of the amino group of amines 9 with benzyl bromide or di-tert-butyl dicarbonate gave compounds 10.The results of the domino metathesis of compounds 9 and 10 are presented in Table 2.It is worth mentioning that when the endo-7-oxanorborn-5-enylallyl amides 10a-c were treated with 6% [Ru] at 25ºC in the presence of allyl acetate, the reaction was highly regioselective, and compounds 11 were the only isomers that could be detected in the reaction mixture (Scheme 4). 12nder similar reaction conditions (Table 1, entry 1), the allyl ethers 2 afforded a mixture of regioisomers of the cross metathesis and domino metathesis products in low overall yields.Treatment of compound 9a with [Ru] (6% mol) in the presence of allyl acetate led only to the recovery of the starting materials (entry 1).We presumed that this result could stem from deactivation of the catalyst by the NH group. 13On the other hand, protection of the amine as Boc-derivative rendered compounds 10a-c, where the lone pairs on nitrogen are less accessible due to delocalization with the carbamate moiety as well as steric encumbrance.Compound 10a was an active substrate for the metathesis process (entry 2).This result was extended to compounds 10b,c (entries 3-4).It was also noted that the N-benzyl derivative 10d (entry 5) was not an active substrate for the domino metathesis process under these reaction conditions, giving rise to the recovery of the starting material.

Discussion
The domino metathesis reaction of the Boc-protected allyl amines 10a-c took place directly to afford the corresponding oxazabicycles 11 as single regioisomers.On the other hand, under the same reaction conditions, the metathesis of the allyl ethers 2 gave rise to a mixture of products of cross and domino metathesis with low overall yields.An increase in catalyst loading and reaction temperature finally rendered good yields of the domino metathesis products 5 and 6.These were obtained as a mixture of both regioisomers.
On the basis of these observations, the regiochemical outcome of the domino metathesis reactions of 2-substituted 7-oxanorborn-5-enes 2 and 10 could be understood at first by a sequence of ROM-CM-RCM reactions (Scheme 5).Thus, the initial ROM of the endocyclic C=C bond would lead to the formation of two regioisomeric carbenes I-A and I-B.Intermolecular CM with allyl acetate would give rise to the ROM-CM intermediates 3, 4 (X = O) or 12, 13 (X = NBoc).These may be converted to the final products by RCM.

Scheme 5
The predominant formation of compounds 5 (X = O) starting from the compounds 2 could be accounted for by steric interactions between the endo allyl chain at C-2 of the starting bicycle and the ligands of the metal in the first carbometallation step leading to intermediate I-B and also by steric inhibition of the reactivity of carbene I-B.3c The exclusive formation of compounds 11 (X = NBoc) in the case of amines 10 may be explained in terms of the steric encumbrance of the Boc group, which would render the endo substituent more sterically demanding than in the previous case.This reaction pathway is supported by the isolation of intermediates 3 and 4 (X = O).However, formation of the corresponding regioisomeric intermediates 12 and 13 in the case of amines 10 was not observed.
Therefore, an alternative reaction pathway might be proposed (Scheme 6): initial carbometallation of the C=C bond of the allyl chain in 10 may lead to carbene III, which may be stabilized by chelation with the carbamate moiety.RCM followed by CM with allyl acetate would render exclusively compounds 11.In order to establish the main reaction pathway, we have performed the metathesis reaction starting from propylamine 14 (Scheme 7).The propyl chain in 14 should have the same steric requirements than the allyl chain in 11.Therefore, in the absence of the allyl double bond, the reaction is forced to follow the ROM-CM-RCM pathway.We have observed that the corresponding metathesis products 15 and 16 were obtained in a 60 : 40 ratio.These results parallel those obtained with the allyl ethers 2, and are different from those obtained starting from the allyl amines 10.

Conclusions
The intramolecular domino metathesis reaction of 2-endo substituted 7-oxanorbornenes constitutes a useful process for the assembly of fused tetrahydrofuran rings with defined stereochemistry.This procedure is suitable for the introduction of a quaternary stereogenic center at the bridgehead position C-5 of the resulting new bicyclic analogs.In order to obtain high levels of regioselectivity, the nature of the lateral unsaturated chain is of crucial importance.Thus, regioselectivity is maximal when the domino metathesis reaction is directed first to the double bond of the lateral chain.This may be steered in the presence of groups able to stabilize the intermediate carbene by chelation. 14Instead, the ROM-CM-RCM sequence starting from the C=C endocyclic bond affords the domino metathesis products with diminished regioselectivity.

Experimental Section
General Procedures.Silica gel 60 F 254 was used for TLC, and the spots were detected with UV and vanillin solution.Flash column chromatography was carried out on silica gel 60.IR spectra have been recorded as CHCl 3 solutions. 1H and 13 C NMR spectra were recorded at 200 or 300 MHz and 50.5 or 75.5 MHz.MS was carried out at 70 eV.

General procedure for metathesis of allylic ethers 2a-c
To a solution of 2a-c (0.50 mmol) and allylic acetate (0.50 mmol) in anhydrous CH 2 Cl 2 (13 mL) at rt, was added (Cy 3 P) 2 Cl 2 Ru=CHPh (33 mg, 0.04 mmol) dissolved in CH 2 Cl 2 (2 mL).The reaction mixture was warmed to reflux, for 1-4 h, until the starting material disappeared (TLC monitoring).After conversion was complete, the solvent was removed under reduced pressure.The reaction mixture was filtered through a pad of silica gel, which was washed with a mixture of hexane : ethyl acetate = 3 : 2. After removal of the solvent under reduced pressure, the crude reaction product was dissolved in MeOH (5.5 mL), 10% Pd on charcoal (10%) was added and the mixture was hydrogenated at 50 Psi for 5 h.Fitration of the catalyst and evaporation of the solvent, afforded a brown oil which was purified by chromatography (silica gel, hexane : ethyl acetate = 3 :2 Scheme 1 Scheme 6

Table 1 .
Domino metathesis of allyl ethers 2 a

Table 2 .
Domino metathesis of amines 9 and 10 a (a) All reactions were carried out in CH 2 Cl 2 (0.034 M) with 0.06 mole of [Ru] per mole of 9 or 10.(b) Isolated yields.