Staurosporine, synthesis

The cyclized products 393 can be prepared by the intramolecular coupling of diphenyl ether or diphenylamine(333,334]. The reaction has been applied to the synthesis of an alkaloid 394[335]. The intramolecular coupling of benzoyl-A-methylindole affords 5-methyl-5,10-dihydroindenol[l,2-b]indol-10-one (395) in 60% yield in AcOH[336]. Staurosporine aglycone (396) was prepared by the intramolecular coupling of an indole ring[337]. 

The Michael addition of the carbanions derived from esters to nitroalkenes followed by reductive cycLizadon has been used extensively for the preparation of pyrrondin-3-ones fEq 1076 This strategy is used for synthesis of the carbaaole alkaloid staurosporine aglycon CK-352c ... 

The total synthesis of litseaverticillols D, F and G (172 and 173), which are natural products with anti-HIV activity, was achieved recently via a singlet oxygen initiated cascade proposed to be biomimetic (Scheme 64). Finally, allylic alcohols 174a and 174b (Scheme 64) were isolated in a 4/1 ratio via a stereoselective singlet oxygen ene reaction. Stereoisomer 174a is an intermediate in the synthetic route of staurosporine, which is a bioactive alkaloid with hypotensive, antimicrobial and cell cytotoxic properties. 

SCHEME 64. Synthesis of the natural products Utseaverticillols and staurosporine via selective 2 ene reactions... 

Danishefsky and co-workers described a regioselective formation of an oxazo-line 171 from a bis(trichloroacetimidate) 170 in their synthesis of staurosporine. The observed regioselectivity is apparently a result of a vinylogous Schmidt glycosylation (Scheme 8.49). 

On the other hand, hydroquinone (3 pmol/L) prevented the staurosporine-induced apoptosis of HL-60 and the IL-3-dependent murine myeloblastic (32D) cell line it also prevented apoptosis of the 32D cells observed in the absence of IL-3. The myeloperoxidase inhibitor indomethacin opposed the effect of hydroquinone on staurosporine-induced apoptosis of HL-60 cells (Hazel et al., 1995, 1996b). Pretreatment of human leukaemia cells ML-1 with buthionine sulfoximine (100 pmol/L for 24 h), in order to decrease their glutathione content, increased the susceptibility of these cells to hydroquinone-induced inhibition of differentiation caused by phorbol acetate pretreatment with l,2-dithiole-3-thione, which induces reduced glutathione synthesis, prevented the differentiation inhibition of hydroquinone. Treatment of DBA/2 mice with 1,2-dithiole-3-thione, which increased the activity of quinone reductase of bone-marrow stromal cells by 50%, decreased the susceptibility of these cells towards hydroquinone (Trush et al., 1996). 

Oxidative homocoupling of aromatic and heteroaromatic rings proceeds with Pd(OAc)2 in AcOH. Biphenyl (165) is prepared by the oxidative coupling of benzene [104,105], The reaction is accelerated by the addition of perchloric acid. Biphenyl-tetracarboxylic acid (169), used for polyimide synthesis, is produced from dimethyl phthalate (168) commercially [106], Intramolecular coupling of the indole rings 170 is useful for the synthesis of staurosporine aglycone 171 [107]. 

A synthesis of Staurosporine, was facilitated by BOM protection of a phthal-imide and an oxazolidinone [Scheme 8.153].342 Both BOM groups were removed by hydrogenolysis to the corresponding -hydroxymethyl derivatives whereupon treatment with sodium methoxide expelled formaldehyde to release the desired product in 92% overall yield. 

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