Iminium cyclization

MgS04, the tetracycles 2-648 were obtained with excellent diastereoselectivity in reasonable yield. The reaction presumably starts with a condensation of the aldehydes 2-645 with the benzyl-protected amine moiety of 2-644 to give an iminium ion which can subsequently cyclize to afford the spirocyclic intermediates 2-646. A [3,3] sigmatropic Cope rearrangement then forms the nine-membered cyclic enamines 2-647 which, after protonation, act as the starting point for another indole iminium cyclization to provide the tetracycles 2-648 via 2-647. 

Enantiomerically pure pipecolic acid (6) is accessible essentially by two well-established synthetic routes (i) cyclization of l- or D-lysine by reaction with disodium nitrosyl-pentacyanoferrate(II) with preservation of configuration at C2 215 216 (ii) ring closure of A ,Ae-bis(A-nitroso-A-tosyl) derivatives of l- or D-lysine, again with retention of chirality at C2. 217 Stereoselective synthesis of pipecolic acid derivatives, substituted in position 4, is achieved using the aza-Diels-Alder reaction of imines with dienes 218-220 or via an ene-iminium cyclization. 221 222 ... 

Peptide aldehydes are fairly reactive and usually exist in solution partially as hydrates Xaa[CH(OH)2] (e.g., 3), which are identified using 13C NMR spectroscopy. 3 3" With amino acids containing nucleophilic side chains, cyclized forms predominate (Scheme 2). Argininal analogues such as Z-Leu-Phe-Arg-H have been shown to exist primarily as the carbinol amine 4 with no spectroscopic evidence for an iminium structure. Lysinal derivatives such as Z-Leu-Phe-Lys-H exist both as a cyclic carbinol amine 5 and as an iminium ion 6 as shown by 3H and 13C NMR spectra. The C-terminal ornithinal analogue Z-Leu-Phe-Orn-H exists primarily as the carbinol amine form 7 and the cyclic iminium form 8 as characterized by the 13C NMR spectra. 3,21 In general, the existence of carbinol and iminium cyclized forms does not preclude the existence of the free or hydrated aldehydes under aqueous conditions. 

In the synthesis of the spermidine alkaloid (+ )-dihydroperiphylline 271), Kibayashi and coworkers [164] employed intramolecular iminium cyclization to achieve the ring closure. As shown in Scheme 91, cleavage of the Boc group of aldehyde 269 resulted in in situ cyclization to the 13-membered ring via iminium formation and subsequent reduction by NaBH4 afforded 270 in 61% yield. 

Overman has shown that camphorsulfonic acid can also be used in nucleophile-promoted alkyne-iminium cyclizations. Alky-lamines can react with formaldehyde and sodium iodide to yield piperidines in good yield. This methodology has been applied in the total synthesis of pumiliotoxin A (eq 4). ... 

General method for nucleophilic displacement (by primary amines) ofjluor-oaromatic substituents to introduce a nudeophile into precursors (at R ) of the acyl iminium cyclization (not applicable in Scheme 19) A 2 m solution of a primary amine in DMSO (5 mb, 66.7 equiv.) was added to the resin bearing the fluoroaromatic substituent (0.5 g, 0.15 mmol, 1 equiv.) and the suspension was shaken (vortexed) at ambient temperature for 16 h. The resin was then filtered off and washed with CH2CI2 (2 x 10 mb) and DMF (3 x 10 mb) to give the desired product. 

In other reactions that proceed via an acyliminium ion, O-vinyl iV,0-acetals rearrange smoothly to /3-(A-acylainino)aldehydes at 0 °C in CH2CI2 in the presence of TMSOTf with moderate to high diastereoselectivities (eq 78). However, TMSOTf failed to promote aprotic alk)fne-iminium cyclizations, which are readily enhanced by TMSCl, TMSBr, or SiCU. On the other hand, TMSOTf assists in the addition of enols to heteroaromatic imines or hydroxyaminal intermediates. ... 

Scheme 2.55 Domino RCM/isomerization/iminium cyclization to give nitrogen heterocycles.

Using a combination of phenyl boronic acid, Pd2(dba)3, tri-ferf-butylphosphine, and potassium fluoride, a tandem Suzuki cross-coupling reaction/isomerization/iminium cyclization sequence was accomplished on A-benzyl-iV-3-bromoprop-2-enyl-1-tryptamine to yield the corresponding l,2,3,4-tetrahydro-/3-carboline in low yield (eq 30). ... 

SCHEME 7.47 Cascade or stepwise reaction of cyclopropanation/ring-opening/iminium cyclization reaction. 

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