Pictet diastereoselective

Several factors influence the diastereoselectivity of the Pictet-Spengler condensation to form 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-P-carbolines (39 and 40, respectively). The presence or absence of an alkyl substituent on the nitrogen of tryptophan has a large influence on the relative stereochemistry of the tetrahydro-P-carboline products formed from a condensation reaction with an aldehyde under various reaction conditions. 

Intermediate diketopiperazine derivatives have been employed in the diastereoselective synthesis of benzyltetra-hydroisoquinoline by 1,4-chirality transfer. iV-Cbz-Proline was coupled with 2-(3,4-dimethoxyphenyl)ethylamine and the resulting amide 109, after deprotection, was reacted with phenylpyruvic acid (Cbz = carbobenzyloxy group). Compound 110 underwent acid-catalyzed Pictet-Spengler condensation to yield final tetracyclic... 

An asymmetric carbon-transfer reaction was also performed by using 2-(/>-tolyl)sulfmylmethyltetrahydro-l,3-oxa-zine 143 as the chiral aldehyde equivalent in the Pictet-Spengler ring closure with tryptamine, but only moderate diastereoselectivity ( 40% de) was observed in favor of the (l/ )-tetrahydro-/3-carboline 165, and the enantiopure main product could be isolated only in low yield (Scbeme 26) <2001H(55)1937, 2004T9171>. 

Michael reactions of chiral lithioenamines of p-oxo esters with dimethyl alkylidenemalonates were studied.173-176 Especially the a-alkyl-substituted compounds (161) and (163), derived from L-valine t-butyl ester, afford, after hydrolysis, the adducts (162) and (164), respectively, diastereoselectively and with high ee (Scheme 57).175 In the presence of TMS-C1, even weaker acceptors like acrylates or MVK were shown to react.176 A somewhat related diastereoselective 1,4-addition, followed by a Pictet-Spen-gler-type cyclization, allows the preparation of compound (165 Scheme 58),177 a central intermediate for the synthesis of several alkaloids.177-178... 

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]. 

In a very elegant tandem-type combination of such a modified Pictet-Spengler condensation and an initial Pummerer reaction (e.g. Section 4.2.2.4), the polycyclic framework (75) of the erythrina alkaloid (76 Scheme 37) is formed diastereoselectively, in a single step, from (72) in 72% yield the required acyliminium ion (74) is created by an intramolecular alkylation of the intermediate enamide (73)7 ... 

The factors that control diastereoselection in the construction of 1,3-disubstituted tetrahydro-p-car-bolines are not, as yet, well understood. With many aldehydes a slight preference for forming the trans diastereomer is observed. " This preference is somewhat greater when the indole nitrogen (Na) of the tryptamine is alkylated. Pictet-Spengler cyclizations of Nb-benzyltryptophan methyl ester under Cook s aprotic conditions are reported to provide nearly exclusively the rr 2ni-A b-benzyl-3-methoxycarbonyl-1 -substituted-1,2,3,4-tetrahydro-P-carbolines. ... 

To reach our target molecule, the routes involving the cycUzation step looked particularly attractive. The Bischler-Napieralski or related Friedel-Crafts route offers the potential for an asymmetric synthesis through enantio- or diastereoselective reduction of the imine penultimate intermediate, whereas the Pictet-Spengler approach is the shortest possible pathway. 

Introduction of a 2-prenyl group as an electrophile can also be achieved via Pictet-Spengler condensation of indoles with suitable C5 aldehydes. The cell cycle inhibitor 6-demethoxyfumitremorgin C (47), isolated from Aspergillus fumigatus, can be synthesised by condensation of L-tryptophan methyl ester (42) and prenal (43) as the initial step [68-70]. It is possible to isolate the intermediate imine, which reacts to a mixture of diastereomeric p-carbolines (44) under acidic conditions. A problem is always the low diastereoselectivity of the cyclisation step, as observed for 44 by the Ganesan and Bailey groups in their very similar three-step syntheses of 47 (Scheme 10). 

Previously, Ascic et al. [43] reported the same reaction with the Hoveyda-Grubbs II catalyst and trifluoroacetic acid as a bicatalytic system, but as a racemic version [43]. The intermediate acyliminium ion readily attacks also other tethered nucleophiles, such as trimethoxybenzene, benzothiophene, thiophene, 0,0-dimethyl catechol, and furan, intramolecularly. When tryptophane or the corresponding alanine derivatives are employed, reasonable levels of diastere-oselectivity can be observed for the terminal Pictet-Spengler acyhminium cyclization. Even a tethered alcohol functionahty diastereoselectively traps the chiral acyhminium intermediate, furnishing bicychc OAf-acetals. 

Scheme 5.2. Regio- and diastereoselective Pictet-Spengler cydization of cyclic iminium with (a) indole and (b) dihydroxyphenyl nucleophile.

In 2012, Zhao and coworkers developed an enantioselective strategy for the synthesis of spiroindolenines 94 by a Michael-hemiaminal formation/Pictet-Spengler cascade reaction [54]. The indoles 93 bearing a ketoamido group in 3-position reacted with the enals 16 in the presence of the Jprgensen-Hayashi catalyst (XXIV) to afford the corresponding spiroindolines in excellent yields and enantioselectivities but moderate diastereoselectivities (Scheme 10.33). 

McNulty, J. and Still, I.W.J. (1991) Diastereoselective Pictet-Spengler reactions of L-(boc)prolinal a biomimetic synthesis of eudistomins H and 1, and woodinine. Tetrahedron Lett. 32,4875-4878. 

Cyclization of iminium ions onto arenes were first described by Pictet and Spengler in 1911, with the formation of tetrahydroisoquinoline 152 (Equation 10) [125]. This versatile transformation has been widely used in the diastereoselective synthesis of polycyclic aromatic alkaloids of biological interest, in particular of tetrahydro-/5-carbolines 154 (Equation 11) [126]. A few selected examples that highlight stereoselective Pictet-Spengler reactions are discussed below [9, 103, 127]. 

Diastereoselective Pictet-Spengler reactions of imines prepared from tryptophan esters have been studied in great detail by Cook [9, 128, 129], The resulting trans-substituted tetrahydro-/l-carbolines have formed the cornerstone of numerous total syntheses of alkaloids. As shown in Scheme 11.25, treatment of tryptophan derivative 155 with aldehyde 156 under acidic conditions afforded 157 as a single diastereomer in 95% yield [129]. This functionalized tricyclic structure was subsequently elaborated into (-)-cory-nantheidine (158). 

---