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

Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of (±)-ezetimibe Motoyuki Isoda1, Kazuyuki Sato1, Yurika Kunugi1, Satsuki Tokonishi1, Atsushi Tarui1, Masaaki Omote*1, Hideki Minami2 and Akira Ando*1 Full Research Paper Address: 1Faculty of Pharmaceutical Sciences, Setsunan University 45-1, Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan and 2Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan Email: Masaaki Omote* - ; Akira Ando* - * Corresponding author Open Access Beilstein J. Org. Chem. 2016, 12, 1608–1615. doi:10.3762/bjoc.12.157 Received: 19 May 2016 Accepted: 06 July 2016 Published: 27 July 2016 Associate Editor: J. P. Wolfe © 2016 Isoda et al.; licensee Beilstein-Institut. License and terms: see end of document. Keywords: β-lactam; ezetimibe; reductive Mannich-type reaction; rhodium–hydride; zinc enolate 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. Introduction The Mannich reaction is an important and classical C–C bondforming reaction between an enolizable carbonyl compound and an imine to give the corresponding β-aminocarbonyl compound. For example, Shibasaki and his colleague reported the asymmetric Mannich reaction using a Lewis acid catalyst [1]. (L)-Proline is known as an excellent promoter for the Mannich reaction [2-6], and besides this, the reaction of the silyl enol ether derivatives with imines was used as an effective method [7-9]. In this situation, a wide variety of Mannich-type reactions have been reported to give β-amino esters and/or β-lactams by using metal enolates [10-17]. In contrast, most of reductive Mannich-type reactions using imines and α,β-unsaturated carbonyl compounds gave β-amino esters, but there are only a few reports for a direct synthesis of β-lactams by reductive Mannich-type reactions [14,18-21]. We recently reported a reductive Mannich-type reaction using a combination of RhCl(PPh 3 ) 3 and Et 2 Zn to give the 1608 Beilstein J. Org. Chem. 2016, 12, 1608–1615. corresponding syn-β-lactams from α,β-unsaturated esters and imines in good to excellent yields together with a small amount of the β-amino esters (Scheme 1) [22,23]. The reaction is very noteworthy because the formation of syn-β-lactams is particularly rare [24-27]. Additionally, various imines can be used for this reaction, and the corresponding β-lactams showed very high syn selectivity. However, some of the reactions using β-substituted α,β-unsaturated esters did not afford the products or gave the products in very low yield (Scheme 2). Herein, we report an expansion for our previous reductive Mannich-type reaction and mechanistic studies for the stereoselectivity of this reaction. Finally the method is applied for the new synthesis of ezetimibe, a potent β-lactamic cholesterol absorption inhibitor. Results and Discussion First of all, we tried to solve the drawbacks of the previously reported method and found that changing the catalyst to [RhCl(cod)]2 greatly improved the reaction. The results from the reaction of the [RhCl(cod)]2 catalyst with various α,β-unsaturated esters are summarized in Table 1. Most of the synthesized β-lactams were obtained with dramatically improved yields, although the β,β-disubstituted α,β-unsaturated ester did not give the product owing to the bulkiness of the β-position (Table 1, entries 1–8). It is interesting that ethyl sorbate (2g) gave the corresponding anti-β-lactam 3Ag in a moderate yield but with an anti-β-lactam stereochemistry indicating that the reaction proceeded via 1,6-reduction, then the resulting nucleophile was trapped by the imine at the α-position (Table 1, entry 9). By using [RhCl(cod)]2, the α,β-unsaturated lactone was also converted to the product with a small improvement in the yield (Table 1, entry 11). Acrylamide 2i also gave the corresponding β-aminoamide 4Ai in a low yield (Table 1, entry 12). In the reaction using α,β-unsaturated lactone 2h, the β-lactam anti-3Ah that has a hydroxy group on the side chain was obtained in a low yield (Table 1, entry 11). This result was of interest because the reaction is applicable to the synthesis of ezetimibe. Ezetimibe is an inhibitor of the cholesterol transporter Niemann–Pick C1 Like 1 Protein (NPC1L1), and is used as a strong cholesterol absorption inhibitor that reduces plasma low-density lipoprotein fraction (LDL-C) [28-30]. Recent studies on the function of NPC1L1 suggest that NPC1L1 may be involved with the internal uptake of the hepatitis C virus (HCV) and absorption of vitamin K [31,32]. Although it has a simple mono β-lactamic structure and appears easy to synthesize, there are relatively few reports for the synthesis of ezetimibe because of its three asymmetric centers [33-35]. First, we examined the reaction conditions using a pilot reaction using imine 1B and 5,6-dihydro-2H-pyran-2-one (2h) (Table 2). Unfortunately, the reaction conditions as above gave a complex mixture that did not contain the desired products as shown in Table 2, entry 1. Heating the reaction mixture at 80 °C Scheme 1: The synthesis of syn-β-lactams using a reductive Mannich-type reaction. Scheme 2: Previous results using β-substituted α,β-unsaturated esters. 1609 Beilstein J. Org. Chem. 2016, 12, 1608–1615. Table 1: Rh-catalyzed Mannich-type reaction using various α,β-unsaturated esters. Entry Substrate 2 1 2 2a 3 4 2b 5 6 2d 7 Rh cat. (mol %) Product RhCl(PPh3)3 (2) 88 [syn/anti = 96:4]b [RhCl(cod)]2 (1) 78 [syn/anti = 88:12]b 3Aa RhCl(PPh3)3 (4) nd [RhCl(cod)]2 (2) 66c 3Ab RhCl(PPh3)3 (2) 34c [RhCl(cod)]2 (2) 77c 3Ad [RhCl(cod)]2 (2) 2e 8 Yield (%)a 98 3Ae [RhCl(cod)]2 (2) nd 2f 3Af 9 59d [E/Z = 93:7]e [RhCl(cod)]2 (2) 2g 3Ag 10 RhCl(PPh3)3 (2) 11d 11 [RhCl(cod)]2 (2) 20d 3Ah 2h 12 27 [syn/anti = 18:82]b [RhCl(cod)]2 (2) 2i 4Ai aIsolated yield. bDiastereomeric ratio [syn/anti] after purification. cThe syn product was obtained as the sole product. dThe anti product was obtained as the sole product. eE/Z ratio by 1H NMR. gave β-aminolactone 4Bh in a very low yield (Table 2, entry 2). When DME and THF were used as the solvents, the desired β-lactam was obtained in low yields (Table 2, entries 3 and 4, respectively). We hypothesized that the low yield was caused by the instability of 2h and the low reactivity of imine 1B under the reaction conditions. Therefore, we added a Lewis acid to assist in the formation of the iminium salt in an effort to improve the reactivity. It was clear that (...truncated)