From D-galactose to enantiopure 3-azabicyclo[3.3.0]octen-7-one derivatives via Pauson–Khand reaction

The 8-substituted-3-azabicyclo[3.3.0]octen-2-one-7-derivatives 18 and 19 have been obtained in enantiomerically pure form from D-galactose in acceptable chemical yield (30%, nine steps) and moderate diastereomeric ratio ( 18:19 = 2.5:1) via intramolecular Pauson–Khand (PK) reaction of the appropriate enyne.


Introduction
The cobalt-mediated carbonylative co-cyclization of an alkene and an alkyne, the Pauson-Khand, (PK), reaction is a flexible method for the synthesis of cyclopentenones. 1 The enantioselective version of this reaction using a chiral inductor covalently bonded to the alkene or the alkyne moiety had led in some cases to useful results. 2 By the use of carbohydrates as sources of chirality, these compounds have been considered as chiral substrates in the intramolecular PK reaction. 3However, the introduction as chiral auxiliaries in these reactions has not been reported previously.Our group has recently reported the first case, 4 using compound 1 derived from D-glucal, obtaining approximately 1:1 mixtures of the diastereomers 2 and 3 (Scheme 1).In order to improve the diastereoselectivity of this reaction we heeded a report by Mulzer et al. 5 who observed that compounds 4 and 5, when treated with dicobalt-octacarbonyl with subsequent thermal decomposition, gave mixtures of diastereomers 6 and 7 in 3:1 and 1:1 ratios, respectively.Thus, the diastereoselectivity of these reactions depends upon the relative stereochemistry of the benzoyl protecting group in 4 and 5 (Scheme 2).With this precedent in mind we speculated that the inversion of the stereochemistry of the stereogenic center at the allylic position of the sugar chain could improve the diastereomeric ratio for the resulting cyclopentenones.We now report our results in this field.

Results and Discussion
The aza-enyne 8 having the D-galacto configuration at the sugar chain was used as starting material (Scheme 3).This compound was obtained from tetra-O-acetyl-D-galactal 11 through a synthetic sequence involving the ring opening to give the aldehyde 13, formation of the propargyl imine 14, reduction, and protection of the resulting amine with tosyl chloride.On the other hand, tetra-O-acetyl-D-galactal 11 was synthesized from D-galactose 9 in two steps without isolation of the intermediate bromide 10. [6][7][8] Scheme 3. Synthesis of aza-enyne 8 from D-galactose.
Having compound 8 in hand, its reaction with Co 2 (CO) 8 during 15 min in CH 2 Cl 2 at RT (18-20 ºC) under CO atmosphere led to complete formation of the complex 16 (Scheme 4, R F 0.39 hexane-ethyl acetate 2:1) which by reaction with N-methylmorpholine N-oxide (NMO) for 1h at RT in CH 2 Cl 2 afforded a mixture of compound 17 (5%) and cyclopentenones 18 and 19 (61% isolated overall yield) in a ratio 18:19 = 2.5:1.From this crude reaction mixture, compound 17 (R F 0.76, hexane-ethyl acetate 1:2) was isolated.On the other hand, fractional crystallization (hexane-ethyl acetate, 1:1) of the mixture 18:19 allowed the isolation of pure 18 [mp 147 ºC, [α] D -123º (c 0.5, CHCl 3 )].The structural determination of compounds 18 and 19 was achieved on the following basis.The X-ray analysis of compound 3 4 shows that, in the solid state, the conformation of this compound is that in which the tosyl group is located under the bicyclic ring (Figure 1).The 1 H-NMR spectrum also indicates that the solution-conformations of 3 and 2 might be similar.Thus, the upfield-shifted peaks for hydrogens H-3a and H-4 show that both protons lie in the shielding region of the aryl group (Figure 1). 9 Under these conditions the signal for hydrogen H-3a is shifted to low-field in the diastereomer having the sugar chain in the α-position compared to the diastereomer with the sugar chain in the β-position.Similarly, the H-4 signal is shifted upfield in the diastereomer with the sugar chain in the α-position.Assuming that the same conformational trend should be expected for compounds 18 and 19 we deduced that the major compound 18 must have an α-sited chain whereas compound 19 must show the opposite configuration.Compound 17 arises from the formal hydrogenolytic cleavage of Pauson-Khand adducts with concomitant double bond migration.This type of products from Pauson-Khand adducts are often obtained and, in some cases, this reaction has been synthetically useful. 10It should be noted that compound 17 was also obtained by reaction of compound 3 with pyridine at 60 ºC (27% isolated yield). 4On this basis we propose the reaction path given in Scheme 5 for the formation of compound 17.Scheme 5. Reaction path for the formation of 17.
In this case, a hydride ion generated from the species HCo(CO) 4 11 abstracts the acidic proton H-3a from the resulting cyclopentanone, yielding the extended enolate ion 20.Protonation (probably by traces of water present in the NMO) affords 21, which can again generate a conjugate carbanion after abstraction of proton H-4.Finally, the protonation during the work-up yields compound 17.
Considering the generally accepted mechanism for the intramolecular PK cycloaddition 12 made explicit for our cases, the observed diastereomeric ratio should depend on the steric demand in the insertion step of the alkene, thereby yielding the corresponding couple of diastereomers (Scheme 6).
Two approaches are possible for the alkene insertion step (Scheme 7) giving the two diastereomeric bicyclopentenones.In the approach (a) there are no important steric interactions between the sugar chain and the cobalt-alkyne complex moiety whereas in (b) the steric interference between the remote Co(CO) 3 moiety and R' appears to be evident.Considering the distance between R' and the Co(CO) 3 group, this steric interaction induces only a relatively small diastereomeric ratio (2.5:1).In the case of the related compounds 2 and 3 derived from Dglucal this interaction occurs between a sterically less demanding acetoxy group an the remote Co(CO) 3 moiety, and no diastereoselectivity was observed at all. 4 In summary, in this report we have shown that the inversion of the configuration at the allylic position of the sugar chain produces a significant change of the stereochemical outcome in the intramolecular PK reaction.

Experimental Section
General Procedures.IPK reactions were carried out under argon atmosphere.Anhydrous CH 2 Cl 2 was distilled from sodium hydride immediately prior to use.Melting points were determined with a capillary apparatus and are uncorrected.Optical rotations were measured at 25 ± 2ºC with a Perkin-Elmer 241 polarimeter.Analytical and preparative TLC were performed on Merck 60 GF 254 silica gel with monitoring by UV light at 254 and 360 nm or by exposure to iodine vapor.Flash chromatography 1 was performed on Merck 60 silica gel (230-400 mesh).Specific rotations [α] D 20 were determined using a Perkin Elmer Polarimeter 141.IR spectra were recorded on a Perkin-Elmer 399 or a Midac FT-IR spectrometer.Solid samples were run as KBr disks and liquids as thin films on NaCl plates.Details are reported as υ max./cm -1 . 1 H-and 13 C-NMR spectra were obtained on a Bruker AM 400 instrument at 400 and 100 MHz, respectively, or on a Bruker AC 200 instrument at 200 and 500 MHz, respectively, in CDCl 3 (Me 4 Si as internal standard) unless otherwise specified.Elemental analyses were carried out using a Leco 932 analyzer at the Universidad de Extremadura.Mass spectra (HRMS/CI + ) were recorded on a VG Autospec spectrometer; only significant fragment ions are reported.