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Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of ( ± )-ezetimibe

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ABSTRACT

An effective synthesis for syn-β-lactams was achieved using a Rh-catalyzed reductive Mannich-type reaction. A rhodium–hydride complex (Rh–H) derived from diethylzinc (Et2Zn) and a Rh catalyst was used for the 1,4-reduction of an α,β-unsaturated ester to give a Reformatsky-type reagent, which in turn, reacted with an imine to give the syn-β-lactam. Additionally, the reaction was applied to the synthesis of (±)-ezetimibe, a potent β-lactamic cholesterol absorption inhibitor.

No MeSH data available.


Plausible mechanism for the Rh-catalyzed reductive Mannich-type reaction.
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Figure 1: Plausible mechanism for the Rh-catalyzed reductive Mannich-type reaction.

Mentions: In some of our previous publications [22–2336], we proposed a reaction mechanism as shown in Fig. 1. In the initial step, the Rh catalyst reacted with Et2Zn to give a rhodium–hydride complex 6 via the elimination of ethylene from the rhodium–ethyl complex 5. The formation of rhodium enolate 7 involved the 1,4-reduction of α,β-unsaturated ester 2 by 6 and the transmetalation with a zinc species to give the Reformatsky-type reagent Int A. This intermediate Int A reacts immediately with the imine to give the corresponding intermediate Int B. Subsequently, intramolecular cyclization of Int B gave the desired β-lactam 3. On the other hand, the possibility of alternative mechanism could not be denied which concerned with the formation of ketene from Int A to give the β-lactam, directly. However, we thought that the reaction proceeded through the above mechanism, because our previous results using similar conditions did not give the corresponding products such as β-propiolactones. It is well known that the substituents on the α- or β-position of α,β-unsaturated carbonyl compounds affect the yields and stereoselectivities [37]. A rhodium–hydride complex derived from [RhCl(cod)]2 seems to be suitable for the reactivity and selectivity in comparison with the corresponding rhodium–hydride complex from RhCl(PPh3)3 which has bulkier ligand.


Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of ( ± )-ezetimibe
Plausible mechanism for the Rh-catalyzed reductive Mannich-type reaction.
© Copyright Policy - Beilstein
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4979637&req=5

Figure 1: Plausible mechanism for the Rh-catalyzed reductive Mannich-type reaction.
Mentions: In some of our previous publications [22–2336], we proposed a reaction mechanism as shown in Fig. 1. In the initial step, the Rh catalyst reacted with Et2Zn to give a rhodium–hydride complex 6 via the elimination of ethylene from the rhodium–ethyl complex 5. The formation of rhodium enolate 7 involved the 1,4-reduction of α,β-unsaturated ester 2 by 6 and the transmetalation with a zinc species to give the Reformatsky-type reagent Int A. This intermediate Int A reacts immediately with the imine to give the corresponding intermediate Int B. Subsequently, intramolecular cyclization of Int B gave the desired β-lactam 3. On the other hand, the possibility of alternative mechanism could not be denied which concerned with the formation of ketene from Int A to give the β-lactam, directly. However, we thought that the reaction proceeded through the above mechanism, because our previous results using similar conditions did not give the corresponding products such as β-propiolactones. It is well known that the substituents on the α- or β-position of α,β-unsaturated carbonyl compounds affect the yields and stereoselectivities [37]. A rhodium–hydride complex derived from [RhCl(cod)]2 seems to be suitable for the reactivity and selectivity in comparison with the corresponding rhodium–hydride complex from RhCl(PPh3)3 which has bulkier ligand.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

An effective synthesis for syn-β-lactams was achieved using a Rh-catalyzed reductive Mannich-type reaction. A rhodium–hydride complex (Rh–H) derived from diethylzinc (Et2Zn) and a Rh catalyst was used for the 1,4-reduction of an α,β-unsaturated ester to give a Reformatsky-type reagent, which in turn, reacted with an imine to give the syn-β-lactam. Additionally, the reaction was applied to the synthesis of (±)-ezetimibe, a potent β-lactamic cholesterol absorption inhibitor.

No MeSH data available.