Pictet-Spengler-type cyclization

The formation of an iminium ion as 2-530 is also proposed by Heaney and coworkers in the synthesis of a tetrahydro- 3-carboline 2-531 (Scheme 2.120) [282]. Herein, heating a solution of tryptamine (2-526) and the acetal 2-527 in the presence of 10 mol% of Sc(OTf)3 gives in the first step the N, O-acetal 2-528, which then leads to the lactam 2-529 and further to the iminium ion 2-530 by elimination of methanol. The last step is a well-known Pictet-Spengler type cyclization to give the final product 2-531 in 91% yield. 

The versatile cyclohexa-1,4-diene 32a has served as an intermediate for synthesis of (—)-eburnamonine 81 and the Aspidosperma alkaloid (—)-aspidospermidine 84 (Scheme 18).3s Butyrolactone carboxylic acids 78 and 82 were prepared from 32 by modification of the methodology outlined in Scheme 7. The key Pictet-Spengler-type cyclization of 79 under conditions of kinetic control gave an 18 1 mixture of 80 and its C(3) (3-epimer in 93% yield. Subsequent hydroboration... 

Another example of Ugi/Pictet-Spengler two-step procedure was employed by El Kaim et al. to prepare polycyclic 1,4-diketopiperazines 228 [69]. The four-component Ugi reaction of homoveratryl isocyanide 229 and a-ketocarboxylic acids 230 allows the formation of Ugi products, which were treated with trifluor-oactic acid to afford tricychc 2,5-diketopiperazines 228 in a Pictet-Spengler-type cyclization (Scheme 42). 

Heterocycles with a l,2,3,4-tetrahydropyrrolo[l,2-a]pyrazine core are also available through this multicomponent reaction. Compounds with a related structure are of high interest either for synthetic applications or for biological purposes. For the first time we were able to propose a one-pot access to pyrrolopiperazine and azasteroide-type scaffolds, illustrating the potential of this ecocompatible sequence to create molecular complexity and diversity from simple and readily available substrates (Scheme 60) [164]. In this case, the primary amine partner bears a pyrrole nucleophile, which neutralizes the transient iminium intermediate to form a new C-C bond via an intramolecular Pictet-Spengler-type cyclization. 

In 2007, Jacobsen and co-workers reported the enantioselective Pictet-Spengler-type cyclization of P-indolyl ethyl hydroxylactams affording highly enantioenriched indolizidinones and quinolizidinones with fully substituted stereogenic centers [205]. The hydroxylactam substrates prepared either by imide reduction using... 

Scheme 6.52 Products of the asymmetric Pictet-Spengler-type cyclization of p-indolyl ethyl hydroxylactams catalyzed by 53.

Scheme 6.53 Proposed mechanism for the 53-catalyzed asymmetric Pictet-Spengler-type cyclization of P-indolyl ethyl hydroxylactams Hydroxylactam (1) forms chlorolactam (2) followed by chiral N-acyliminium chloride-thiourea complex (3) and the observed product generated by intramolecular cyclization catalysis and enantioinduction result from chloride abstraction and anion binding.

Asymmetric induction in ring closure reactions of central chiral ferrocene derivatives has been reported. Moderate diastereoselectivity was found in the ring closure of the enantiomeric 4-ferrocenyl-2-methyl-2-phenyl-butanoic acids by treatment with trifluoroacetic anhydride (Fig. 4-211) [10]. The diastereoisomeric ketones could be separated by chromatography. A higher induction was observed in an asymmetric Pictet — Spengler type cyclization of a reactive imine formed from enantiomerically pure 2-ferrocenyl-2-propylamine and formaldehyde, as only one isomer of the product was detected (Fig. 4-21 g) [135, 136]. 

Starting from L-tryptophan, immobilized on hydroxyethyl polystyrene through its carboxylic group, the intermediate a,[3-unsaturated imine (554) was formed by reaction with 3-methylcrotonaldehyde in pure trimethyl orthoformate (TMOF). The imine was then allowed to react with Fmoc chloride in the presence of pyridine to afford the required tetrahydro-[3-carboline (555) through an N-acylimin-ium ion mediated Pictet-Spengler-type cyclization. Further manipulation of the Pictet-Spengler product afforded the desired demethoxy-FTC as the minor cis isomer, along with its C-3 trans epimer (556) (diastereoisomeric ratio 1 3) (Scheme 115). 

Recently, Jacobsen and co-workers reported conceptually novel counteranion catalysis employing the thiourea 17 (Figure 10.16) [64]. Thiourea 17 catalyzed the Pictet-Spengler-type cyclization of hydroxylactams and the corresponding cycliza-tion products were obtained with excellent enantioselectivities (Equation 10.32). The authors proposed the cationic intermediate 18, in which the thiourea coordinates to the chloride anion. 

The Pictet-Spengler type cyclization has been carried out with 85, which on treatment with benzaldehyde or 3,4-dimethoxybenzaldehyde and PPA in acetic acid gave 86 [R1 = Ph, 3,4-(OMe)2C6H3 R2 = R3 = R4 = H R6 = R6 = OMe] in good yields. However, the reaction did not proceed with aliphatic aldehydes. An alternative reaction of 85 with... 

Raheem, I.T., Thiara, P.S., Peterson, E.A. and Jacobsen, E.N. (2007) Enantioselective Pictet-Spengler-type cyclizations of hydroxy lactams H-bond donor catalysis by anion binding. Journal of the American Chemical Society, 129, 13404-13405. 

Mimosine (34) and mimosinamine (35) readily undergo Pictet-Spengler-type cyclizations to yield pyrido[l,2-a]pyrazines (36) and (37) respectively. ... 

Although the Skraup/Doebner-von Miller reaction represents one of the most common reaction for the synthesis of quinoline core for more than a century, its mechanism is still dedebated. To date, both of the two more popular mechanistic explanations are involving fragmentation-recombination pathways. In the first one, initially the amine reacts with the aldehyde or ketone under acidic conditions to form an imine. Dimerization and Pictet-Spengler type cyclization forms a diazetine core. Protonation and subsequent cyclization-ring cleavage reaction assembles the isoquinoline nucleus. 

Scheme 1.28 Pictet-Spengler-type cyclization of a hydroxylactam in the synthesis of (+)-harmicine...

Scheme 1.29 Potential mechanism of the Pictet-Spengler-type cyclization of hydroxylactams...

However, the final Pictet-Spengler intramolecular cychzation required the further optimization because there are two modes of nucleophilic attack by indole or DOPA moiety. When indoles underwent Pictet-Spengler-type cyclization with cyclic A-acyliminium moieties that were generated in situ from masked aldehyde and amide nitrogen under acidic conditions, two modes of nucleophilic attack became possible—at carbon positions C2 and C3 in indole (Scheme 5.2a). C2 attack can afford the formation of a 3,9-diazabicyclo... 

Intramolecular nitro-Michael cyclization to 29 is completed in THF at room temperature with 2 mol of cesium fluoride and myristyltrimethylammonium bromide as promoters. Prevailing trans,trans-isomet 29 is separated by crystallization and the nitro derivative reduced to amine 30 in 98 % yield. Treatment with MeONa in MeOH afforded lactame 31, which is reduced by LiAUTi to known pyrrolidine derivative 2. Direct conversion of 2 to P-lycorane by Pictet-Spengler type cyclization using paraformaldehyde and mineral acid failed. Synthesis was accomplished in high yield by a detour, methoxycarbonylation to 32, cyclization to 33 and final LiAllTj-reduction of six-membered lactame to ( )- lycorane TM 9.5. 

Scheme 26.14 Enantioselective Pictet-Spengler-type cyclization.

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