Pictet Thiourea catalyzed

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

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

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. 

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

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]. 

In 2007, the Jacobsen group reported a thiourea-catalyzed Pictet-Spengler reaction in a four-step total synthesis of (+)-harmicine (202), in which the key Pictet-Spengler cyclization of tryptamine derivative indole 199 using thiourea 200 as a catalyst gave the jS-indolyl ethyl hydroxylactams 201 in 97% ee (Scheme 17.34) [81]. The reduction of lactam 201 completed the synthesis of (+)-harmicine (202). 

Scheme 103 Thiourea-catalyzed Pictet-Spengler-typs cyclization in the total synthesis of (-l-)-harmicine (467)...

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

SCHEME 2.77 Chiral thiourea-catalyzed Pictet-Spengler reaction of 3-indolyl hydroxy-lactams. 

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). 

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.

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 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... 

In addition to (V-acyUminium ions, the protioiminium ions (X19) could be activi-ated in a similar anion-binding mechanism (Scheme 2.79). The same group then developed chiral thiourea (289a)-catalyzed two-component Pictet-Spengler reaction of tryptamines 21 and aldehydes under mild conditions. Benzoic acid used as the cocatalyst provided the products desired, with excellent results [110a]. Later, Lee... 

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