Regioselective ring openings in the 3,5-dioxa-8-azabicyclo-[5.2.0]nonane ring system

In order to distinguish primary and secondary hydroxyl groups in the presence of a β -lactam moiety benzylidene acetal protection and reductive cleavage were used. When the reductive ring opening was carried out using diisobutylaluminium hydride, the benzylidene acetal group remained intact, while the β -lactam was reduced to the corresponding β -amino alcohol. The acetal cleavage with sodium cyanoborohydride was successful, resulting mainly in a β -lactam compound bearing the benzyloxy group on the secondary carbon atom


Introduction
In the course of our work in the synthesis of 2-iso-oxacephems, we faced the problem of distinguishing between primary and secondary hydroxyl groups with an appropriate protecting group strategy. 1We needed a compound having a protecting group (G), which is stable to acids and mild bases, on the secondary O, but contains a free primary hydroxyl group, which can be mesylated to give 2 (Scheme 1, PMP = p-methoxyphenyl).This compound bears the acetoxy group on the primary carbon atom, presumably due to a transacetylation reaction occurring because of the spatial proximity of the two hydroxyl groups (Scheme 2). 1  After these unsuccessful attempts we tried to use the benzylidene acetal group, which is suitable for protecting diols and is widely used in the carbohydrate chemistry.It is reported that its regioselective reductive cleavage can be accomplished with DIBALH or alane (LAH/AlCl 3 ) to give the free hydroxyl group in the less hindered position and the benzyl ether moiety in the more hindered position (Scheme 3). 2

OH OH
O O OH OBn red.opening

Scheme 3
Although the cleavage with alane cannot be taken into consideration in the presence of the lactam moiety, the usage of DIBALH seemed to be promising due to the fact that we have already used DIBALH in the course of our preliminary work to reduce an ester function without destroying the lactam function. 3As far as we know, the usage of this protecting group strategy is unique among compounds containing a β-lactam function as well.It is also unique in the respect that we investigated these methods in a case of a 1,4-diol.

Results and Discussion
The benzylidene acetal group was built on 1 with benzaldehyde in the presence of a catalytic amount of p-toluenesulfonic acid.Compound 4 was formed in a diastereomerically pure form, the configuration of the new stereocenter was determined by 2D NOESY spectra.The reduction of 4 was carried out according to the common procedure to be found in the literature with DIBALH in CH 2 Cl 2 at 0°C. Surprisingly, the reaction resulted in 6 instead of the expected 5 along with many other minor products.The reaction was carried out also at -78 °C, resulting in the same main compound with a much better yield and fewer minor products.This means that the reactivity of the 7-membered benzylidene acetal moiety in that case is less than that of the βlactam (Scheme 4).As far as we know it is unprecedented to reduce a β-lactam with DIBALH to β-amino alcohol, such reactions can be normally carried out with LAH or diborane.A possible explanation of this observation is the enhanced ring strain in the cis-annelated 4+7 ring system.However, it is reported that p-methoxybenzylidene (PMB) acetals are more sensitive to reductive cleavage, and hence their reactivity might be higher than that of the β-lactam moiety.In this case this protecting group cannot be taken into consideration, because of the sensitivity of the resulting PMB ethers to oxidative circumstances that we must use later in our synthesis to remove the PMP protecting group. 4fter these experiences, we decided to try to open the benzylidene acetal ring using NaCNBH 3 /HCl.It has been reported that with that method a regioselective cleavage also takes place, but resulting mainly in a secondary alcohol. 5Hence we planned the following retrosynthetic pathway (Scheme 5).Contrary to the literature, we found that the main product of the reaction was 5 along with the by-product 9 (Scheme 6).The identification of the two regioisomers was based on 2D HMQC and NOESY spectra.Since the purification of the compounds from inorganic residues proved to be difficult and we also wanted to examine the question of selectivity, we tried to apply further reducing agents, namely NaBH 4 and Na(AcO) 3 BH, but without any reaction taking place.
Compound 5 was mesylated to obtain 10 with methanesulfonyl chloride in the presence of NEt 3 .When 5 contained inorganic impurities (presumably originated from the reagent NaCNBH 3 ) 11 was also formed in high quantity (Scheme 7).The structure of 11 was determined based on its spectra, which were the same as we previously reported. 1Of note is that the NMR sample of 10 in CDCl 3 also transformed completely to 11 after a day of standing.These observations mean that the benzyl ether group in that compound is relatively unstable.Therefore the application of 10 for further synthesis demands increased caution.

Conclusions
In this work we showed the possible utilization of the benzylidene acetal protecting group for distinguishing between primary and secondary hydroxyl groups in the presence of a β-lactam moiety.The 4+7 ring system could be cleaved regioselectively with DIBALH and NaCNBH 3 as well, in the first case the β-lactam ring was opened, in the second case the 1,3-dioxepane ring.
For our purposes the reducing agent NaCNBH 3 proved to be suitable.

Experimental Section
General Procedures.Melting points were determined on a hot stage melting point apparatus and are uncorrected.Optical rotations (c = 1.0 g / 100 cm ) was added to a solution of 4 (0.9 g, 2.6 mmol) in abs.THF (10 mL) in a flame-dried flask under nitrogen atmosphere.Ether saturated with HCl gas was added to the mixture dropwise at 0 °C till no more gas elevation could be observed.After 1 hour of stirring (TLC: CH 2 Cl 2 :EtOAc 10:2, UV + PMA, Rf 4 = 0.6, Rf 5 = 0.45, Rf 7 = 0.3) the insoluble precipitation was dissolved by adding water, the mixture was diluted with EtOAc, the phases were separated and the aqueous phase was extracted 3 times with EtOAc.The combined organic layers were washed with 1N HCl, sat.NaHCO 3 and brine.The solvent was evaporated under reduced pressure, the residue dissolved in EtOAc, and washed with water and brine again.It was dried (MgSO 4 ), the solvent removed, then purified by flash chromatography (CH Scheme 2 Scheme 4 Scheme 5 Scheme 6 Scheme 7