Ring contraction versus β -elimination in reactions of alkynyl-substituted bicyclic lactol esters with SmI 2 /Pd(0)

Selective addition of alkynyl metal reagents to either carbonyl group of 2-(2-formylethyl)cycloalkanones afforded alkynyl-substituted bicyclic lactols that were further converted into the corresponding acetate or benzoate esters. Reactions of these bicyclic esters with SmI 2 /Pd(PPh 3 ) 4 displayed a divergent behavior which was dependent on the degree of substitution at the alkynyl terminus as well as on the bicycle ring size. Thus, 2-oxabicyclo[4.3.0]nonanes with terminal alkynes gave ring contracted bicyclic alcohols whereas the presence of substituents at the alkynyl terminus or the use of higher bicycloalkane homologues led to enol ethers, as the result of Lewis acid-promoted β-elimination.


Introduction
−2 This reaction is thought to involve the initial formation of an allenylpalladium complex II that is rapidly reduced to an equilibrium mixture of allenic (V) and propargylic (VI) organosamarium intermediates that finally add to the carbonyl group (Scheme 1). 3 Therefore, in this reaction the propargylic acetate acts as a synthetic equivalent of the propargyl anion synthon.−6 We aimed to apply this last reaction to bicyclic substrates 1,2 and 4.These would presumably afford the bicyclic alcohols 3 and 5 (Scheme 2) and this paper reports on the results of that study.

Results and Discussion
Synthesis of starting materials.The representative substrates 1,2 and 4 were prepared using ketoaldehydes 6 as common starting materials (Scheme 3, Table 1).The method initially selected involved in situ protection of the al dehyde carbonyl using tetrakis(diethylamino)titanium according to the procedure developed by Reetz, 8 followed by addition to the ketone to give lactols 7.This procedure worked well for additions to cyclohexanone 6a (Table 1, entries 1−3) but failed when cyclopentanone 6b was used.In this case the starting ketoaldehyde was recovered unchanged.Alternatively, protection of the aldehyde carbonyl of 6b as either a N-(dibenzylaminoalkyl)benzotriazole 9 or N-cyclohexyl imine followed by addition of appropriate alkynyl lithium or magnesium derivatives to the remaining ketone carbonyl afforded moderate yields of lactols 7d,e (Table 1, entries 4,5).Lactols 7 were obtained with moderate to high diastereoselectivity.Acetylation of the lactols using standard conditions afforded in all cases good yields of acetates 1.Alternatively, treatment of lactol 7a with HCl/MeOH led to the corresponding acetal 2 as a single diastereoisomer (Scheme 3).

Scheme 3
For the synthesis of 4, the ketoaldehyde 6b was directly treated with the required alkynyl lithium and the resulting alkoxide intermediate was trapped with benzoyl chloride to afford moderate yields of benzoates 4. Two out of four isomers were observed at most for 1, 2 and 4. The stereochemistry of ring fusion has been determined for both isomers of 1c and the assignments were extended by analogy to 1a, 1b, 1d and 2. Thus, the major isomer of 1c, derived from cyclohexanone 6a, was assigned a cis-ring fusion based on the observed coupling constants (J) for its H-4 proton in the 1 H NMR spectrum (Table 2).These values were intermediate between those expected for axial and equatorial dispositions of that proton.This assignment was confirmed by the temperature dependence shown by the apparent J values of H-4 in that isomer (see Table 2).This indicated a flexible conformation only compatible with a cis ring junction.This analysis did not allow, however, an unambiguous configurational assignment for C-4.On the other hand, H-4 in minor 1c appeared in the 1 H NMR spectrum as doublet of doublets with J = 10.1, 3.1 Hz.This signal remained unchanged over a temperature interval between −30 and 58 o C and this was taken as an indication of a rigid trans ring fusion with an axial disposition for H-4.According to this analysis, the major isomers of cyclopentanone-derived 1d,e would present trans ring junctions as indicated by their H-4 J values (~ 10 and 3 Hz).No stereochemical assignment was made for 4a,b.Reactions with SmI2/Pd(0).The major isomers of lactol esters 1 and 4 were independently treated with 2.2 equivalents of SmI2 and a catalytic amount of Pd(PPh3)4 (5 mol%) at room temperature.The results were drastically dependent on the type of substrate employed and the presence or absence of substituents at the terminal alkynyl position (Scheme 4, Table 3).

Scheme 4
Thus, for cyclopentanone-derived substrates 1d and 4a, with a terminal alkyne, a slow reaction was observed that led to the formation of bicyclic alcohols 3d and 5a, respectively, with good yields and excellent stereoselectivities.However, the reaction took a completely different course when a terminal alkynyl substituent was present in the substrate, as in 1e and 4b.In those cases the only reaction products isolated were the enol ethers 8e and 9b, respectively.Similarly, the reactions of the cyclohexanone-derived 1a-c led predominantly to enol ethers 8a-c, accompanied occasionally by lactols 7, probably the result of hydrolysis of 8 during work-up.The formation of enol ethers 8 does not require the presence of Pd(0) in the medium, as indicated by the result of entry 3 in Table 3.The acetal 2 was inert in the presence of SmI2/Pd(PPh3)4 even under refluxing conditions.The stereochemical assignment of 3d followed from the chemical shift differences found in the carbinolic protons of the diastereomeric mixture of alcohols 3d and 3d' obtained after NaBH4 reduction of the ketone 10 that resulted from the PDC oxidation of 3d (Scheme 5).Thus, H-4 of 3d resonated at δ 4.37 whereas the corresponding proton in 3d', buried in the concave face of the bicyclic structure, was found further upfield at δ 3.8−3.9.The bicycle 5a obtained from 4a was identical in all physical properties to the previously reported material prepared using the route I → VII (Scheme 1).

Results and Discussion
Carbohydrate-derived monocyclic acetals and esters related to 1, 2 and 4 have been employed in ring raction reactions leading to 2-alkynylcyclopentanols, 5,6 a transformation that is readily understood in the mechanistic terms shown in Scheme 1.This reaction is facilitated by Lewis acidic Sm(III) species, inevitably present in the reaction medium, that activate the leaving group (OMe or OCOR) and bring about the initial oxidative addition step that begins the catalytic cycle.Always latent in these reactions is the possibility of β-elimination promoted by the same Lewis acids or even by SmI2. 10 In monocyclic systems with terminal alkynes the oxidative addition is reasonably fast and, as a result, ring opening is favored over β-elimination. 5,6This also seems to be the case with cyclopentanone-derived substrates 1d and 4a.If, on the other hand, the oxidative addition step becomes slower due to the presence of terminal alkynyl substituents, then β-elimination takes over as it is observed in the reactions of 1e and 4b.However, it is also apparent from the strikingly different results observed for 1a and 1d, that the size of the rings containing the bridgehead propargylic position, as well as the axial or equatorial orientation of the leaving group, are also probably important to the outcome of the reaction.Thus, β-elimination from the equatorial leaving group of the conformationally rigid bicycle 1d is expected to be slower than from the much more flexible bicycle 1a where both axial and equatorial orientations of the leaving group are possible at any given time.Additionally, the hybridization change in cyclopentanone-derived 1d in going to an intermediate related to II (Scheme 1) should be more favorable than that taking place in cyclohexanone-derived 1a.Taken together, all these factors give as a result a preferred β-elimination pathway for 1a−c.

Conclusions
The SmI2/Pd(0)-promoted ring contraction of bicyclic lactol esters leads to the expected bicyclic homopropargyl alcohols only when the oxidative addition that initiates the reaction competes efficiently with the alternative Lewis acid-promoted β-elimination.The synthetic potential of the ring contraction process for the preparation of bicyclic systems is significantly restricted by factors that adversely affect oxidative addition, namely (i) the presence of terminal alkynyl substituents and (ii) the development of torsional strain upon ring opening.At the same time, βelimination is facilitated by axial leaving groups with an antiperiplanar β-hydrogen.

Experimental Section
General Procedures.All reactions involving air-and moisture-sensitive materials were performed using standard bench-top techniques. 11Diiodoethane was purified as reported. 12etrahydrofuran (THF) was freshly distilled from sodium/benzophenone and, for reactions with SmI2, it was deoxygenated prior to use.Other solvents were routinely purified using literature procedures. 13Flash column chromatography 14 was performed on silica gel (230−400 mesh).HPLC purifications were carried out with either a LiChrosorb Si60 (7 µm, 25 x 2.5 cm, column 1) or a µ Porasil (10 µm, 19 x 1.5 cm, column 2) column using a refractive index detector.Routine 1 H and 13 C NMR spectra were obtained at 250 MHz and 62.9 MHz, respectively, using CDCl3 as solvent and internal reference (δ 7.26 for 1 H and δ 77.0 for 13 C).IR data include only characteristic absorptions.Mass spectra were obtained at 70 eV.

Table 2 .
Coupling constants J (in Hz) for H-4 in 1 and 2