Antirhines

This suite of BVMOs is available via whole-cell expression systems and represents a complementary platform of biocatalysts for diverse applications in chiral synthesis. Representatives of this collection were utilized in the enantiodivergent synthesis of the indole alkaloids alloyohimbane and antirhine from a fused bicyclic precursor (Scheme 9.19) [151]. 

B. CORYNANTHE ALKALOIDS 1. Antirhine and Antirhine jVb-Metho Salts... 

Antirhine (11) was isolated first from Antirhea putaminosa (F. Muell.) Bail, in 1967 (79). Final determination of the stereostructure of antirhine, including conformational analysis, has been reported by Bisset and Phillipson (20). They established that the thermodynamically more stable conformer possesses a cis-quinolizidine ring junction as shown in formula 11 however, some of the conformer with a trans junction (11") is also present. 

Antirhine methobromide (12) has been isolated from Strychnos camptoneura Gilg and Busse (20) however, it is not certain that this is the naturally occurring form of the alkaloid. In view of H-NMR evidence, a orientation was suggested for the Ab-methyl group of 12. 

The other antirhine iVb-metho salt, namely, antirhine Ab-(3-methochloride (13) has been isolated from Amsonia elliptica Roem. and Schult. (27). Demethylation... 

Several total syntheses of antirhine (11) and 18,19-dihydroantirhine (14) have been developed during the last decade. Wenkert et al. (136) employed a facile route to ( )-18,19-dihydroantirhine, using lactone 196 as a key building block. Base-catalyzed condensation of methyl 4-methylnicotinate (193) with methyl oxalate, followed by hydrolysis, oxidative decarboxylation with alkaline hydrogen peroxide, and final esterification, resulted in methyl 4-(methoxycar-bonylmethyl)nicotinate (194). Condensation of 194 with acetaldehyde and subsequent reduction afforded nicotinic ester derivative 195, which was reduced with lithium aluminum hydride, and the diol product obtained was oxidized with manganese dioxide to yield the desired lactone 196. Alkylation of 196 with tryptophyl bromide (197) resulted in a pyridinium salt whose catalytic reduction... 

The first synthesis of ( )-antirhine (11) has been published by Takano and co-... 

Takano s group reported the first enantioselective total synthesis of (—)-anti-rhine as well (146). Chiral product 235 was prepared via a number of stereoselective reactions. Reductive condensation of 235 with tryptamine, using sodium cyanoborohydride at pH 6, supplied lactam 236, which was reduced by di-isobutylalminum hydride to hemiacetal 237. The latter could be cyclized to (-)-antirhine by simple acid treatment (146). 

After completing the enantioselective total synthesis of (+)-18,19-dihydro-antirhine [(+)-14](i40), Kametani et al. reported (394) the synthesis of (—)-antirhine [(-)-ll] by using (3S)-[3-hydroxy-( )-prop-l-enyl]cyclopentanone as a chiral synthon. 

An application of the ynamine cycloaddition is found in a synthesis of dihydro-antirhine [167]. The transition state with matching polarized addends is adopted. The cycloadduct becomes fragmentable upon hydrolysis. 

Pictet-Spengler isoquinoline synthesis. The final steps in a synthesis of (—)-antirhine (2), a Corynanthe-type indole alkaloid, involved partial reduction of the lactam 1 to a hemiamina), which cyclizes to 2 in the presence of dilute HC1,2... 

The leaves of Nauclea latifolia contain naufoline, angustine, cadambine, 3a-dihydrocadambine, and a new alkaloid, naulafine, which has been formulated,57 on spectroscopic evidence, as (81). Another new alkaloid is strychno-rubigine (10-methoxyisositsirikine), which occurs in the root bark of Strychnos rubiginosa DC.58 Antirhine and pleiocarpamine have been found in the leaves and stem bark of Alstonia odontophora Boiteau [A. roeperi van Heurck et Mull.-Arg.],59 and pleiocarpamine, pleiocarpamine N-oxide, geissoschizine,... 

A retrosynthetic synthesis of (—)antirhine (Fig. 11) was performed through the monoacetate (1) and lactone (2) which was condensed with tryptamine. Product 3 was then finally converted, through a number of intermediates, to the tetracyclic (—)-antirhine, resulting in a remarkable overall yield of 13% (starting from the monoacetate 1), together with the 3-epimer (+)-antirhine at a yield of 6%. This strategy allowed the chemo-enzymatic synthesis of both (—) - and (+)-antirhines [82]. 

Fig. 11 Complete synthesis of the major alkaloid (—)-antirhine known from the plant Antirhea putaminosa (except for formation of 1, all other reaction steps were not enzyme-catalysed)...

Takano et al. have reported the first synthesis of ( )-antirhine (71) (Scheme 11),51 in which the problem of generating the desired, less stable (anti) stereochemistry at C-3 and C-15 was overcome by preparing the non-tryptamine fragment (72) from ( )-trinorcamphor (73) via a sequence of stereospecific reactions. Condensation of (72) with tryptamine, followed by cyclization and... 

The bisindole alkaloids alstomacrophylline 108 and alstomacroline 109 have been isolated from the root bark of Alstonia macrophylla along with the monomeric indole alkaloid 20- f-antirhine <1997P757>. A dimeric indole alkaloid, schischkiniin 110, was isolated from the seeds of Centaurea schischkinii <2005T9001>. 

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