TETRAHEDRON LETTERS Tetrahedron Letters 43 (2002) 3165–3167 Pergamon The versatile conversion of lactams to the -alkylated azacycles via cyclic N,O -acetal TMS ether Young-Ger Suh,* Seok-Ho Kim, Jae-Kyung Jung and Dong-Yun Shin College of Pharmacy, Seoul National University, San 56 -1, Shinlim-Dong, Kwanak -Gu, Seoul 151 -742, South Korea Received 14 February 2002; revised 5 March 2002; accepted 7 March 2002 Abstract—The efficient preparation of the cyclic N,O-acetals from lactams by DIBAL reduction followed by direct trapping of the resulting N,O-hemiacetals using TMSOTf/pyridine system is described. In addition, the facile nucleophilic addition of various carbon nucleophiles at the carbonyl carbons of the lactams through the corresponding N,O-acetals is also reported. © 2002 Published by Elsevier Science Ltd. As a part of our continuing studies directed toward the synthesis of the medium to macrolactam alkaloids, we have been interested in the versatile functionalization of the lactam carbonyl (Fig. 1). 1 Synthetic routes involving cyclic N -acyliminium ions are generally useful strategies that have been applied to a wide variety of synthetic transformations. 2 The use of -alkoxy azacycles as precursors to cyclic N - acyliminium ions has been especially well reviewed. 2 Despite significant progress made in the preparation of these intermediates, most of these methods are limited in that they are only applicable to the five- or six-mem- bered azacycles, and are rarely applicable to the seven- membered azacycle. 3 In fact, unlike the five- and six-membered -alkoxy azacycles, which can be readily prepared by sequential reduction of the corresponding N -acyl lactam or imide and etherification, the synthesis of the medium to large sized -alkoxy azacycle from the corresponding lactam has not been successful due to the considerable difficulty in manipulation of their lac- tam functionality and the instability of the reaction intermediate (e.g. imine or enamine, which were readily hydrolyzed to the corresponding amido aldehyde). In light of the result 4,5 that aluminum alkoxide of hemiac- etal prepared by DIBAL reduction of esters is more stable than the free hemiacetal, we were able to reduce the medium-sized lactam without lactam ring-opening and trap the resulting N,O -hemiacetal. We herein report a novel and versatile method for the preparation of the stable N,O -acetal TMS ether 2 6 as an excellent precursor of cyclic acyliminium ions 3. To the best of our knowledge, such a method in the medium to large-sized lactam systems has not been reported in spite of its significant synthetic utilities. Moreover, the facile nucleophilic additions of various carbon nucleophiles to the resulting N,O -acetal TMS ether in the presence of the Lewis acid are also reported. Our initial studies were carried out by intensive exami- nation of the reaction conditions for the transformation of lactam to N,O -acetal alkyl ether. Surveying a num- ber of trapping reagents commonly used, we have found the TMSOTf/pyridine system 4a,b which only gives satisfactory results as shown in Table 1. Thus, treatment of 1aa with DIBAL (1.2 equiv.) in CH 2 Cl 2 at -78°C followed by sequential addition of pyridine (3 equiv.) and TMSOTf (2.5 equiv.) afforded the N,O -ace- tal 2aa 7 in excellent yield along with a small amount (<5%) of the remaining amido aldehyde 4. 8 The N,O -acetal TMS ethers are quite stable, and can be stored for months at room temperature in 1% Et 3 N/ ether solution. When an MeOTf/pyridine or an Ac 2 O/ Figure 1. * Corresponding author. 0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd. PII:S0040-4039(02)00459-8