Acyl Pictet-Spengler reaction

The acyl-Pictet-Spengler reaction is also catalyzed by chiral thiourea derivative 6 to provide M-acetyl p-carbolines in high enantioselectivities. Notably, thiourea derivatives can activate not only electronically distinct imine derivatives such as N-alkyl and N-Boc imines but also a weakly Lewis basic N-acyhminium ion with high enantioselectivity using a chiral hydrogen bond donor (Scheme 12.4). 

The Pictet-Spengler reaction is the method of choice for the preparation of tetrahydro-P-carbolines, which represent structural elements of several natural products such as biologically active alkaloids. It proceeds via a condensation of a carbonyl compound with a tryptamine followed by a Friedel-Crafts-type cyclization. In 2004, Jacobsen et al. reported the first catalytic asymmetric variant [25]. This acyl-Pictet-Spengler reaction involves an N-acyliminium ion as intermediate and is promoted by a chiral thiourea (general Brpnsted acid catalysis). 

The phosphoric acid-catalyzed protocols tolerate aromatic and ahphatic aldehydes and thus complement Jacobsen s acyl-Pictet-Spengler reaction which is limited to aliphatic aldehydes. 

Acyl Pictet-Spengler Reactions of Iminium Ions... 

Table 6.25 Thiourea-catalyzed acyl-Pictet-Spengler reactions of imines.

Thiourea-Catalyzed Acyl-Pictet-Spengler Reaction of Imines [13] (p. 223)... 

Tatsui G (1928) Synthesis of carboline derivatives. J Pharm Soc Jpn 48 453 159 Taylor MS, Jacobsen EN (2004) Highly enantioselective catalytic acyl-pictet-spengler reactions. J Am Chem Soc 126 10558-10559 Terada M, Uraguchi D, Sorimachi K, Shimizu H (2005) Process for production of optically active amines by stereoselective nucleophilic addition reaction of imines with C nucleophiles using chiral phosphoric acid derivative. PCT Int Appl WO 2005070875 2005-08-04... 

Taylor, M. S., Jacobsen, E. N. Highly enantioselective catalytic acyl-Pictet-Spengler reactions. J. Am. Chem. Soc. 2004, 126, 10558-10559. Kowalski, P., Mokrosz, J. L. Structure and spectral properties of P-carbolines. Part 9. New arguments against direct rearrangement of the spiroindolenine intermediate into P-carboline system in the Pictet-Spengler cyclization. An MNDO approach. Bull. Soc. Chim. Belg. 1997, 106, 147-149. 

For a thiourea-catalyzed enantioselective acyl-Pictet-Spengler reaction, see Taylor, M.S. and Jacobsen, E.N. (2004) J. Am. Chem. Soc., 126, 10558-10559. 

The acyl-Mannich reaction [34], acyl-Pictet-Spengler reaction [35,36] and cyanosilyla-tion [37] catalysed with bifunctional thiourea catalysts have also been developed by fine tuning of the side chain. 

Amongst the first intramolecular processes developed using thiourea catalysis was that of the acyl-Pictet-Spengler reaction, devised by Jacobsen in 2004 [36,37]. In the initial reaction, thiourea 112 was found to perform well in terms of both yield and enantio-selectivity and a range of substrates were shown to undergo reaction (Table 1.1). 

In 2008, a similar asymmetric Pictet-Spengler reaction was applied to the total synthesis of (+)-yohimbine (209) (11 steps, 14% overall yield), an important member of the monoterpenoid indole alkaloids as shown in Scheme 17.35 [82]. The synthesis involved two key steps, which are the acyl-Pictet-Spengler reaction of tryptamine derivative 199 with aldehyde 203 (97% ee) and a stereoselective intramolecular Diels-Alder reaction of 206 with the simultaneous generation of four new stereogenic centers [83]. 

The same protocol was also applied successfully to the total synthesis of (-i-)-yohimbine (447) (388) (A chiral phosphoric acid-catalyzed approach towards this target was discussed earlier (see Scheme 99)). hi contrast to Hiemstra s approach employing a later stage organocatalytic Pictet-Spengler reaction (385), Jacobsen s synthesis of 447 commenced with the thiourea 473-catalyzed acyl-Pictet-Spengler reaction between tryptamine 468 and the protected hydroxyaldehyde 474. Intermediate 475 was then employed successfully to access (-i-)-yohimbine (447) in a total of 11 steps and in 14% overall yield (Scheme 104) (388). 

The final natural product that will be discussed herein to demonstrate the applicability of asymmetric organocatalysis to assemble the monoterpenoid part of indole alkaloids is (H-)-yohimbine (282) (Scheme 6.46). Yohimbine is a well-known monoterpenoid indole alkaloid that has been isolated from several natural sources and for which the first total synthesis dates back to the 1950s [140]. Two organocatalytic total syntheses of this important natural product have been reported recently by the groups of Jacobsen and Hiemstra [141,142], Jacobsen s synthesis of 282 commenced with the thiourea 170a-catalyzed acyl-Pictet-Spengler reaction between tryptamine 283 and the protected hydroxyaldehyde... 

Since 2004, imines have represented another important class of electrophiles that has been extensively used in aza-F-C alkylation. The first example reported in the literature is illustrated in Scheme 35.9, showing an enantioselective acyl-Pictet-Spengler reaction via condensation of tryptamine with aliphatic aldehydes in the presence of 17 and acetyl chloride to afford substituted tetrahydro- iintermediate imine 52, as N-acyliminium species, is crucial for the reaction outcome no reaction occurs in the absence of AcCl. 

SCHEME 2.76 Chiral thiourea-catalyzed asymmetric acyl-Pictet-Spengler reaction. 

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