Synthesis of Galanthamine

The entire process is catalytic the only by-product is water. More than 80% of the process solvent (toluene) can be recovered. The efficiency of amide bond formation is thus hindered by the widespread use of reagents with poor atom economy. The development of reagents with lower mass intensity (MI) factors or catalytic methods such as the exciting application of boric acid or its derivatives to catalyze amide formation in an eco-friendly manner would certainly transform the environmental profile of many processes. 

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Trost, B.M., Tang, W., Toste, ED. (2005) Divergent Enantioselective Synthesis of (—)-Galanthamine and (—)-Morphine. Journal of the American Chemical Society, 127, 14785-14803. 

The asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[h]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. 

We have successfully employed a boric acid-catalyzed strategy in the synthesis of galanthamine (1) [25, 26]. In the total synthesis of 1, a reaction of 26 and 27 was performed to obtain amide 28 in 86% yield, as shown in Scheme 14.6. The advanced intermediate 28 was then converted to the API, 1. 

Scheme 14.6 Eco-friendly amide synthesis synthesis of galanthamine (1) via amide 28.

Scheme 45. Synthesis of ( )-galanthamine (continued next page).

Several other synthetic sequences have been developed that lead to the production of potentially useful intermediates for the total synthesis of galanthamine-type alkaloids. For example, the 4-arylbutyric acid 348 has been converted to the tetrahydrobenzazepine 349 by a modified Curtius reaction followed by cycliza-tion of the intermediate isocyanate with polyphosphoric acid (168). N-Methyla-tion of 349 and photooxidation of the resulting tertiary lactam in the presence of NBS gave 350. 

The structures and the absolute configuration of these alkaloids have been firmly established by chemical and physical methods since that time. The work which has been carried out in this field led to the structural assignment of a new alkaloid, habranthine (155), to the definition of the stereochemistry of chlidanthine (152), and to the synthesis of galanthamine-type derivatives through several approaches. 

With such possibilities for regio-and stereocontrol, Pd-Ag-catalyzed Heck reactions have been and still are widely applied to total synthesis. However, just a few more examples are provided here. Brown et al. described a very convergent enantioselective synthesis of ( )-galanthamine (Scheme 10.35), an Amaryllidaceae... 

Very recently, Node and co-workers improved the efficiency of this particular oxidative phenolic coupling in the context of a synthesis of (+)-galanthamine (51a) [50]. By using a trialkoxyarene as one of the aryl units, they were able to obtain yields of 56b of up to 90 % when the nitrogen was protected with a formyl group and the donor aryl s oxygen atoms were capped by benzyl moieties (Table 11). These authors were even able to isolate an interesting narwedine-type product 57a in low yield. 

A similar kind of strategy, as developed by Kita, has also been successfully applied in a diversity-oriented synthesis of galanthamine-like molecules (Scheme 14) [51]. The... 

Scheme 14. PIFA-mediated, solid-phase synthesis of galanthamine analogue precursors.

A new synthesis of galanthamine has been developed which addresses many of the shortcomings of the previous syntheses. The key step involved in this synthesis is the intramolecular Heck reaction illustrated below <02JA2795>. 

Figure 15.14 Biomimetic solid-phase synthesis of galanthamine-like compounds by Pelish et al. [44].

A number of related couplings have been reported during the synthesis of alkaloids, such as oxocrinine and cryptoplurine [26], the intramolecular coupling of diarylamines to dibenzazepine, and dibenzazocine structures [27], synthesis of galanthamine [28] and phe-nanthropyrrolidines [29], and the intramolecular arylation of enamines [30]. 

Another application of enantioselective allylic substitution is seen in the synthesis of (-)-galanthamine, the parent member of the galanthamine-type Ama-ryllidaceae alkaloids. Displacement of the carbonate group in the racemate with the phenol is accomplished by the Pd catalyst in the presence of the chiral ligand [84]. 

A classical oxidation reaction that involves radicals is the phenolic oxidative coupling, which is introduced in Section 10.5.A.i. In this reaction, electron transfer from a metal salt to a bis(phenol) leads to intramolecular coupling and a quinone product. The early yields were poor. For example, Barton reacted 219 with potassium ferricyanide [K3(Fe(CN)6l and the product was aryl radical 220. This radical reacted with the second phenolic ring in an intramolecular process that gave 221. Loss of a hydrogen led to the quinone narwedine (222) in a synthesis of galanthamine. 53 jjje yield of 222, however, was only 1.4% under optimal... 

Tanimoto H, Kato T, Chida N (2007) Total synthesis of (+)-galanthamine starting from D-glucose. Tetrahedron Lett 48 6267-6270... 

A full account of the asymmetric synthesis of galanthamine from L-tyrosine (c/. Vol. 9, p. 140) is now available. ... 

SCHEME 6 The endgame associated with the first-generation chemoenzymatic synthesis of galanthamine ent-l). 

In contrast to less efficient allylation of alcohols, allylation of phenols proceeds much more smoothly. In the enantioselective synthesis of (—)-galanthamine by Trost, two Pd-catalyzed reactions were utilized. Asymmetric allylation of the bro-movanillin 191 with the cyclic allylic carbonate 192 gave the ether 193 by using ( ] -allyl-PdCl)2 and chiral Trost L-2. Subsequent Heck reaction of 194 afforded 195 in 91 % yield when DPPP was used as a ligand. DPPF and DPPE gave lower yield [74]. 

Taking advantage of the availability of narciclasine (68) from plant extracts, Pettit used the compound as a starting material in an efficient synthesis of pan-cratistatin (77). The same group has also described related approaches for the preparation of a pancratistatin phosphate prodrug (291), as well as for the natural product 7-deoxy-trfl/J5-dihydronarciclasine and related derivatives (292). In another context, an improved protocol for the synthesis of (—)-galanthamine (75), based on the spontaneous resolution of either of the enantiomers of narwedine (83), has been reported (293). 

Guillou et al. [112] used the same type of 6-cxo-cyclization in the total synthesis of ( )-galanthamine, a natural product that we have already come across in the section on 5-eX(9-cyclizations. 

Scheme 12.38 Construction of a quaternary carbon hy the Claisen rearrangement. Scheme 12.39 Total synthesis of galanthamine.

Sigmatropic Rearrangement with Chirality Transfer (1) Synthesis of Galanthamine... 

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