Fumiquinazolines, Glyantrypine, and Fiscaline B

Snider et al. has utilized the quinazolinone annelation method (see Sect. 2.2) for the first synthesis of (+)-fumiquinazoline G 23 [248] (the natural product is the (-)-enantiomer; however, a 3 : 2 equilibrium mixture is obtained with base from either fumiquinazoline F or G [89]). (+)-Fumiquinazoline G 23 is the simplest member of a quinazolinone fused to a piperazine-2,5-dione ring. Snider et al. has developed a general procedure for photochemically depro-tectable N-(2-nitrobenzyl)piperazine-2,5-dione 97b, which provides a short and efficient synthesis of fumiqunazoline G (23) (Scheme 22) [241]. Subsequently, more efficient synthesis of (-)-fumiquinazoline F (22) and (-)-glyantrypine (21) has been developed by Avendano, Menendenz, Sollhu-ber et al. (Scheme 22) [252-255]. The regioselective acylation of unprotected 3-arylmethylpiperazine-2,5-diones 97a and 97c (derived from methyl tryptophanate) with TMSCl, Et3N, and 2-azidobenzoylchloride (37) is fol-

ri r2

ri r2

1) TMSCl, EI3N, CH2CI2, 37 (for 97a,c: 54-41%) or 37, NaH, THF, -5-25"C, 2 h (for 97b: 75%)

2) Bu3P, benzene or toluene rt^O'C, 1.5-16 h (78-82%)

3) deprotect if R3 is not H

(34% overall yield from 97a)

(49% overall yield from 97b)

(44% overall yield from 97c)

lowed by the intramolecular Staudinger/aza-Wittig protocol (Scheme 22). The Staudinger/intramolecular aza-Wittig reaction proceeds cleanly affording 21-23 in good yields [252-255]. Fiscalin B [91,92] was synthesized via direct alkylation of N-Boc-3-indolylmethyl bromide of 1-isopropyl-2,4-dihydro-1ff-pyrazino[2,1-fr]quinazoline-3,6-dione by this group [255].

On the other hand, new dehydrative cyclization route of tripeptides based on the Mazurkiewicz protocol [190-192] leading to fumiquinazolines F 22, G 23, and fiscalin B has been developed by Ganesan et al. [191,192]. This Mazurkiewicz-Ganesan cyclization of starting tripeptides has been proven to proceed via the iminooxazine intermediate followed by rearrangements to the pyrazinoquinazolinones by Snider [250] and Hart [256,257], and were used for synthesis of fumiquinazolines (A, B, I [249], or C, E, and H [250]), alantrypinone [256, 257] (see Sect. 3.4.4), and quinazolinobenzodiazepine alkaloids [244-246], etc. Wang, Ganesan, and Sim has applied this method to solid-phase synthesis of fumiquinazolines [258] and related alkalolids [259] (see Sect. 3.4.2).

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