Aspidospermidines

Furanones are a class of chiral dienophiles very reactive in thermal cycloadditions. For example, (5R)-5-(/-menthyloxy)-2-(5H)-furanone (28) underwent Diels Alder reaction with cyclopentadiene (21) with complete re-face-selectivity (Equation 2.10), affording a cycloadduct which was used as a key intermediate in the synthesis of dehydro aspidospermidine [27]. 

The field of alkaloid synthesis via tandem cyclizations favors the application of (TMSlsSiH over other radical-based reagents, due to its very low toxicity and high chemoselectivity. For example, cyclization of the iodoarylazide 102, mediated by (TMSlsSiH under standard experimental conditions, produced the N-Si(TMS)3 protected alkaloid 103 that after washing with dilute acid afforded the amine 104 in an overall 83% yield from 102 (Reaction 81). ° The formation of the labile N-Si(TMS)3 bond was thought to arise from the reaction of the product amine 104 with the by-product (TMSlsSil. The skeletons of ( )-horsfiline, ( )-aspidospermidine and (+ )-vindoline have been achieved by this route. - ... 

One of the most readily available easily oxidized sulfides is tetrathiafulva-lene (TTF) and this material readily transfers electrons to good electrophiles such as arene diazonium salts. This reaction has been used to form the tricyclic precursor to the natural product aspidospermidine, stereospe-cifically (Scheme 1.16). Since water is very inert towards attack by free... 

Another domino radical cyclization approach, which allows construction of the B- and E-rings of the alkaloid ( )-aspidospermidine (3-46), has been described by the same group [25]. Transformation of the iodoazide 3-44 into the tetracycle 3-45 was accomplished in 40 % yield by selective attack at the carbon-iodine bond in the... 

Aube took advantage of an intramolecular Schmidt reaction of azide 129 to provide the fused ring heterocyclic lactam 130 as a key step in a total synthesis of (+)-aspidospermidine... 

A new effective metal-ffee radical approach by Murphy et al generates the free radical by treatment with tetrathiafulvalene (TTF).1491 As depicted in scheme 16 the aromatic amine 79 is transformed into the diazonium salt 81 which on treatment with TTF leads to the radical 82. The following stereoselective cyclization gives the hexahydrocarba-zole scaffold 80, a substructure of alkaloids like aspi-dospermidin, strychnin and vinblastin. Also the non-toxic tris(trimethylsilyl)silane was employed for domino reactions, eg. for the preparation of the alkaloid aspidospermidin. 

The versatile cyclohexa-1,4-diene 32a has served as an intermediate for synthesis of (—)-eburnamonine 81 and the Aspidosperma alkaloid (—)-aspidospermidine 84 (Scheme 18).3s Butyrolactone carboxylic acids 78 and 82 were prepared from 32 by modification of the methodology outlined in Scheme 7. The key Pictet-Spengler-type cyclization of 79 under conditions of kinetic control gave an 18 1 mixture of 80 and its C(3) (3-epimer in 93% yield. Subsequent hydroboration... 

The classical Harley-Mason cyclization was utilized en route to (—)-aspidospermidine 84. 9 The synthesis of 84 required 12 steps from the chiral benzamide 12 (X = SiMcs) and was carried out with an overall yield of 19%. 

Aspidospermidine oxime undergoes double skeletal fragmentation to give a tricyclic iminium ion which cyclizes at the a-position of the indole nucleus [94],... 

In a synthesis of aspidospermidine [232] an alkylative rearrangement was employed to gain entry into the pentacyclic skeleton. 

Scheme 16. Application of radical-polar crossover reaction in the total synthesis of ( )-aspidospermidine...

The use of an azide as an efficient radical acceptor with concomitant nitrogen elimination has been applied for the preparation of an intermediate in aspidospermidine synthesis [95CC1409]. Reductive cyclization of 165 at reflux temperature furnished 166, the ABCE tetracyclic portion of aspidospermidine 167, in 95% yield. The cyclization establishes three contiguous chiral centers. 

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