Unsaturated oxazolopiperidone lactams: an unexpected domino-type double conjugate addition – cyclization process

Reactions of 2-acetylindole enolate with unsaturated oxazolopiperidones 3 , 4 and 10 unexpectedly gives pentacyclic dilactams 6 , 7 and 11 , respectively, resulting from a domino-type process involving two successive conjugate additions and a final cyclization.

The kinetic adducts 2a-c (7-H/8a-H trans) resulting from an exo attack were formed as the major products from the activated lactams 1a-c, whereas the alternative endo attack (7-H/8a-H cis) predominantly occurred from the non-activated lactam 1d, leading to the most stable 7-H/8-H trans isomer 2d.The best results in terms of chemical yield were obtained using an excess (5 equiv.) of the nucleophile.
To gain further insight into the factors governing the stereoselectivity of these reactions, in this paper we report similar conjugate addition reactions using the simplest oxazolopiperidone lactams 3 and 4, which lack both the benzyloxycarbonyl and ethyl substituents present in 1 and differ in the configuration of C-8a.
The formation of 6 can be rationalized as outlined in Scheme 3. The lactam enolate i resulting from the initial conjugate addition acts as a nucleophile in a second conjugate addition with another molecule of oxazolopiperidone 3 to give the 3,4-disubstituted 2-piperidone intermediate ii, with a trans-3,4 relative configuration.In fact, there are examples 6 in which the intermediate lactam enolate resulting from the conjugate addition to an unsaturated lactam is trapped in situ by an electrophile to give a trans-3,4-substituted 2-piperidone derivative.The same stereochemistry has been observed in the alkylation of a 4-substituted 2-piperidone enolate. 20A final nucleophilic attack of the new lactam enolate intermediate on the acylindole carbonyl group generates the central six-membered carbocyclic ring leading to 6. Interestingly, both conjugate addition reactions occurred in an exo manner, resulting in a product with a transrelationship between the oxazolidine 2-H and the piperidone 4-H.Scheme 3. Plausible mechanism for the formation of pentacyclic dilactam 6.
The relative configuration of 6 was deduced from the 1 H-and 13 C-NMR data, with the aid of gCOSY, gHSQC (Figure 2) and NOESY experiments (Figure 3).Thus, the coupling constant (J 12 Hz) of the triplet at  2.05 attributable to 13a-H made evident the trans diaxial relationship of this proton with 7a-H and 13b-H.The axial disposition of 7a-H was confirmed from the multiplicity (quartet of triplets) of the signal at  2.20 attributable to this proton, which displays trans diaxial coupling constants (J 12 Hz) with 13a-H and the axial protons of the 7-and 8positions.Finally, the small coupling constant (J 3.6 Hz) between 5a-H and 13b-H revealed a cis 5a-H/13b-H relationship.On the other hand, the positive NOE effects between 13a-H and 8a-H and 14a-H, as well as between the indole 3-proton and 5a-H and 7a-H are in good agreement with the stereochemical assignment depicted for 6.A similar domino-type process, involving two successive exo conjugate additions followed by cyclization, was observed from oxazolopiperidone 4 (3,8a-cis series).The relative stereochemistry of the resulting pentacyclic dilactam 7 was established by NMR on the same grounds as in the above pentacycle 6.

Scheme 4. Conjugate addition of 2-acetylindole enolate to unsaturated lactam 4.
This stereochemical outcome of the above double conjugate additions is in sharp contrast with the endo facial selectivity observed in the conjugate addition of the 2-acetylindole enolate to the analogous ethyl-substituted lactam 1d, 19 thus highlighting the dramatic influence exerted by the C-8 ethyl substituent on the stereoselectivity of the conjugate addition of stabilized anions to oxazolopiperidone lactams.Similar differences in stereoselectivity have been observed when lactams 1d and 3 (or 4) 16 undergo conjugate addition of 2-indoleacetate enolates: whereas the nucleophilic attack takes place on the exo face of 3 or 4, leading to the kinetic products (Scheme 5), the conjugate addition to lactam 1d occurs under thermodynamic control, with endo facial selectivity, to give the more stable trans-4,5-disubstituted 2-piperidone derivative.

Scheme 5. Stereoelectronic control in the conjugate addition.
We then decided to study the conjugate addition to unsaturated lactam 10 (3,8a-trans series), which possesses the same configuration at C-8a as lactam 3 but incorporates a C-8 ethyl substituent.This new lactam was prepared in excellent yield from the known saturated lactam 8, 21 by treatment with KH and methyl benzenesulfinate, followed by heating of the resulting sulfoxides 9 in toluene solution (Scheme 6).Rather surprisingly, in contrast with what was observed from 8-ethyl substituted lactam 1d (3,8a-cis series), the double conjugate addition-cyclization cascade also occurred from lactam 10, leading in excellent overall yield to two pentacyclic dilactams, alcohol 11a (32%) and its dehydration product 11b (48%) (Scheme 7).Scheme 7. Conjugate addition of 2-acetylindole enolate to unsaturated lactam 10.
The results reported herein further illustrate how the outcome of conjugate addition reactions to phenylglycinol-derived unsaturated oxazolopiperidone lactams can be affected by a variety of factors, such as the nature of the nucleophile, the configuration of the stereocenter at the angular position (C-8a), the presence or absence of substituents on the piperidone ring, and the reaction conditions. 1