Selective nucleophilic addition reactions of alkyllithium reagents with N-(trimethylsilyl)lactams. Synthesis of cyclic ketimines

Hua, Duy H.; Miao, Shou Wu; Bharathi, S. Narasimha; Katsuhira, Takeshi; Bravo, Ana A.

doi:10.1021/jo00298a062

Cited by 74 publications

(45 citation statements)

References 3 publications

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“…38 We modified Hua’s protocol and developed a single-pot variant involving in situ N -silylation of the hindered α,α-dimethyl δ-lactam 32a followed by addition of an alkyllithium. This procedure directly provided the corresponding cyclic ketimines without the need to isolate the labile N -trimethylsilyl lactam intermediates (Scheme 8b).…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of the Spirocyclic Imine Marine Toxin (−)-Gymnodimine and an Unnatural C4-Epimer

Kong¹,

Moussa²,

Lee³

et al. 2011

J. Am. Chem. Soc.

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The first total synthesis of the marine toxin (−)-gymnodimine (1) has been accomplished in a convergent manner. A highly diastereo- and enantioselective exo-Diels–Alder reaction catalyzed by a bis-oxazoline Cu(II) catalyst enabled rapid assembly of the spirocyclic core of gymnodimine. The preparation of the tetrahydrofuran fragment utilized a chiral auxiliary based anti-aldol reaction. Two major fragments, spirolactam 56 and tetrahydrofuran 55, were then coupled through an efficient Nozaki–Hiyama–Kishi reaction. An unconventional, ambient temperature t-BuLi-initiated intramolecular Barbier reaction of alkyl iodide 64 was employed to form the macrocycle. A late stage vinylogous Mukaiyama aldol addition of a silyloxyfuran to a complex cyclohexanone 83 appended the butenolide and a few additional steps provided (−)-gymnodimine (1). A diastereomer of the natural product was also synthesized, C4-epi-gymnodimine (90), derived from the vinylogous Mukaiyama aldol addition.

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Section: Resultsmentioning

confidence: 99%

Total Synthesis of the Spirocyclic Imine Marine Toxin (−)-Gymnodimine and an Unnatural C4-Epimer

Kong¹,

Moussa²,

Lee³

et al. 2011

J. Am. Chem. Soc.

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“…In addition to these synthetic problems, the biological importance of the spiroimine unit, which contains the F ring (C5 substituent) as the pharmacophore and has been suggested to be responsible for the toxicity and nAChR‐subtype selectivity of cyclic imine toxins, has prompted us to establish an efficient synthetic method for this fragment. To achieve this goal, we selected spirobicyclic lactam 1 (Figure ) as the key intermediate, because lactam 1 was thought to be suitable for modifications at the C28 and C9 positions through metal‐mediated alkylation to give the spiroimine unit . However, an efficient spirobicyclic ring formation that is practically applicable to SPXs has not yet been established; synthetic methods for similar structures with differently sized rings or simpler substitution patterns have previously been reported .…”

Section: Figurementioning

confidence: 99%

Efficient Access to the Functionalized Bicyclic Pharmacophore of Spirolide C by Using a Selective Diels–Alder Reaction

et al. 2017

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Af unctionalized bicyclic lactam that was used as ak ey intermediate in an efficient synthesis of the pharmacophore of potent marine toxin spirolide Cw as synthesized by using ah ighly selective Diels-Alder reaction. To improve the reactivity of this transformation without loss of selectivity, substrates that contained as ilyl ether or silatrane moiety were elaborately designed and converted into the spirobicyclic core structure with stereochemical control over the two asymmetricc enters at the C7 and C29 positions. Moreover, af urther CÀCb ond formation by using aH iyama cross-coupling reaction of the vinyl silatraned erivativef acilitated versatile modification at the C5 position with an aryl or alkenyl substituent.

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“…[187] A concise, two-step procedure for the conversion of lactams into cyclic imines has been disclosed. [188] Silylation of lactams 36 with chlorotrimethylsilane and triethyl-amine in toluene gives excellent yields of the N-silyl lactams 37 (Scheme 18). Nucleophilic addition of an alkyllithium reagent to the carbonyl group then leads, via a Peterson-type alkenation process, to the cyclic ketimines 38 together with trimethylsilanol.…”

Section: Variation 1: By Reductionmentioning

confidence: 99%

“…ø-amino ketones, are obtained. [193] 5-Methyl-3,4-dihydro-2H-pyrrole (38, n = 1; R 2 = Me); Typical Procedure: [188] To a soln of 2-pyrrolidone (36, n = 1; R 1 = H; 17 g, 0.20 mol) and Et 3 N (25 g, 0.25 mol) in toluene (200 mL …”

Section: Variation 1: By Reductionmentioning

confidence: 99%

Product Class 7: Imines

Padwa¹,

Bellus²

2005

Category 4. Compounds With Two Carbon Heteroatom Bonds

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Compounds with the general structure R 1 R 2 C=NR 3 , referred to as imines, were first obtained by Schiff via condensation of ketones and aldehydes with primary amines. Therefore, the condensation products are also called Schiff bases. In addition, the nominations azomethine, ketimine (derived from ketones), aldimine (derived from aldehydes), and anil (derived from anilines) are in use. It is recommended that the terms imine(s), ketimine(s), or aldimine(s) are used, rather than Schiff base(s) or azomethine(s).Since imines have to be considered as analogues of carbonyl compounds, many of the chemical properties are similar to the latter. Imines are used in new C-C bond formations, and reactions with electrophiles (e.g., aldehydes, alkyl halides), and the C=N moiety can undergo nucleophilic reactions. Generally, imines are very useful compounds in organic synthesis, as they are used in several syntheses of aza-heterocyclic compounds. Most imines are stable in an alkaline medium and therefore can be dried over potassium hydroxide. In diluted acid, however, they are easily hydrolyzed. In many cases intermediary imines cannot be isolated because of their lability. The presence of a C=N bond creates the possibility for E/Z isomerism (syn/anti). It has been recognized that such geomet-

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Selective nucleophilic addition reactions of alkyllithium reagents with N-(trimethylsilyl)lactams. Synthesis of cyclic ketimines

Cited by 74 publications

References 3 publications

Total Synthesis of the Spirocyclic Imine Marine Toxin (−)-Gymnodimine and an Unnatural C4-Epimer

Total Synthesis of the Spirocyclic Imine Marine Toxin (−)-Gymnodimine and an Unnatural C4-Epimer

Efficient Access to the Functionalized Bicyclic Pharmacophore of Spirolide C by Using a Selective Diels–Alder Reaction

Product Class 7: Imines

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