Asymmetric acyl Pictet-Spengler

Table 1.1 Asymmetric Acyl-Pictet-Spengler Thiourea catalyzed reaction...

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

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). 

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 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... 

New modifications of the traditional approach to isoquinoline synthesis via carbocation intermediates continue to be reported. Abnormal products of the Bischler-Napieralski reaction were observed <97JCS(P1)2217>. A stereoselective introduction of a quaternary carbon center in the A-acyliminium cyclization (Scheme 14) of the chiral enamide 46 affords an asymmetric synthesis of tetrahydroisoquinolines <97T2449,3045>. An asymmetric Pictet-Spengler reaction has been developed mediated by the chiral urethane 47 <97T16327>. A Pummerer reaction of A-acyl-A-(aryl)methyl-2-(phenylsulfinyl)ethylamine allows cyclization to the 4-phenylthio-... 

Another important set of bi-component reactions involving C-N and C-C bond formation is based on the Pictet-Spengler reaction, consisting in the cycUzation of electron-rich aromatic moieties onto iminium intermediates. This weU-known sequence constitutes an important domino transformation used for the synthesis of bioactive polyheterocycles. Its organocatalytic asymmetric version was pioneered by Jacobsen and revisited by List, who developed two complementary highly enantioselective accesses to tetrahydro- 3-carbolines from tryptamine-derived imines (Scheme 16.33). Thus, Taylor and Jacobsen [64] reported an enantiomerically pure thiourea-catalyzed cyclization of an acyl iminium intermediate, whereas List and co-workers [65] described the cyclization of an iminium diester intermediate in the presence of a chiral phosphoric acid catalyst. Recently, this methodology has been applied to the synthesis of chiral pyrrolopiperazines [66]. 

Jacobsen has also developed an organocatalysed asymmetric addition of nucleophiles with iV-acyl-iminium ions (Pictet-Spengler) and oxocarbe-nium ions, potentially useful reactions in medicinal chemistry (Scheme 14.97). The mechanism involves the formation of an anionic catalyst-chloride complex which acts as a chiral counter ion directing the approach of nucleophiles to one face of the cationic species. 

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