Transition metals in organic synthesis, Part 98. 1 Transition metal mediated total synthesis of the potent neuronal cell protecting alkaloid (  )-lavanduquinocin

An efficient total synthesis of (  )-lavanduquinocin, a potent neuronal cell protecting alkaloid from Streptomyces viridochromogenes , is reported. Key-steps are an iron-mediated one-pot construction of the carbazole framework and a nickel-mediated coupling reaction


Introduction
Over the past decades a wide variety of carbazole alkaloids with intriguing structures and useful biological activities has been isolated from diverse natural sources and a range of novel synthetic methodologies to these natural products has been developed. 2In 1983, Furukawa and co-workers reported the isolation of the first carbazole-1,4-quinone alkaloids from terrestrial plants. 35] An example for this class of natural products is lavanduquinocin (1), which was isolated from Streptomyces viridochromogenes 2492-SVS3. 5Lavanduquinocin was shown to protect neuronal hybridoma N18-RE-105 cells from the L-glutamate toxicity with an EC50 value of 15.5 nM.The apoptotic cell death of N18-RE-105 cells, induced by buthionine sulfoximine (BSO) due to depletion of the endogenous reducing agent glutathione, was also suppressed by lavanduquinocin at concentrations higher than 12.5 nM.The toxicity of BSO is considered to involve oxygen-derived free radicals.Thus, the mode of action of lavanduquinocin is dependent on its antioxidative activity. 5It is well known that oxygen-derived free radicals play a pivotal role in the initiation of a variety of diseases, like myocardial and cerebral ischemia, arteriosclerosis, inflammation, rheumatism, senility, autoimmune diseases, and cancer. 6herefore, free radical scavengers are thought to represent potential therapeutic agents for the treatment of these diseases.
The characteristic structural features of lavanduquinocin (1) are an o-benzoquinone moiety, an (R)-2-hydroxypropyl substituent at the 1-position of the carbazole nucleus and a monoterpenoidal β-cyclolavandulyl side chain at C-6.We have developed a highly efficient iron-mediated route for the synthesis of carbazole alkaloids. 7The crucial step of our synthesis is the formation of a C-N bond by an oxidative cyclization of a 5-(2-aminoaryl)-substituted cyclohexadiene-tricarbonyliron complex which can be achieved by oxidation with air in protic medium. 8Extension of this method led to a one-pot construction of the carbazole nucleus by a consecutive C-C and C-N bond formation.The utility of the one-pot procedure for natural product synthesis was demonstrated by the development of elegant routes to carbazoquinocin C (5), 9 carquinostatin A (2), 10,11 lavanduquinocin (1), 12,13 neocarazostatin B, 14 the carbazomycins A and B, 15 and streptoverticillin. 16In the present paper, we describe our synthesis of ()-lavanduquinocin (rac-1) in full detail. 12
The iron complex salt 13 is quantitatively available on large scale by a 1-azabuta-1,3-dienecatalyzed complexation of cyclohexa-1,3-diene (11) with pentacarbonyliron 17 followed by hydride abstraction using triphenylmethyl tetrafluoroborate. 18The second building block for the synthesis of ()-lavanduquinocin (rac-1) is the arylamine 12. Compound 12 was previously used as precursor in our total synthesis of ()-carquinostatin A (rac-2) and was obtained in five steps and 69% overall yield starting from commercial 3-methylveratrole.Reaction of the iron complex salt 13 with two equivalents of the arylamine 12 in acetonitrile at room temperature for seven days in air, followed by demetalation using trimethylamine Noxide 19,20 and aromatization with 10% palladium on activated carbon in boiling o-xylene 21 provided the carbazole 14.Electrophilic bromination of 14 with N-bromosuccinimide (NBS) in tetrachloromethane at reflux afforded regioselectively the 6-bromocarbazole 10 (Scheme 2).
The third component for the synthesis of ()-lavanduquinocin (rac-1) is -cyclolavandulyl bromide (9).3][24] Thus, deprotonation of commercial ethyl senecioate (15) using lithium diisopropylamide (LDA) followed by kinetic quenching with prenyl bromide leads to ethyl lavandulate.Without further characterization this intermediate was subjected to alkaline hydrolysis to give lavandulic acid (16). 22Using optimized reaction conditions, proton-initiated cyclization of 16 afforded crystalline β-cyclolavandulic acid (17) in 78% yield.Reduction of 17 with lithium aluminum hydride provided β-cyclolavandulyl alcohol (18). 23Base-catalyzed allylic bromination of compound 18 with phosphorus tribromide afforded the desired -cyclolavandulyl bromide (9). 24sing this route -cyclolavandulyl bromide ( 9) is available in five steps and 62% overall yield based on ethyl senecioate (15) (Scheme 3).The dinuclear nickel complex 19 was prepared analogously to the known dimeric πprenylnickel bromide complex, 25 which was used by us previously for the total synthesis of carquinostatin A (2) 10,11 and neocarazostatin B. 14 Reaction of -cyclolavandulyl bromide ( 9) with an excess of tetracarbonylnickel in benzene at 60-65 °C afforded after 2.5 h a red-brown solution indicating the formation of the dimeric π-allylnickel bromide complex 19 (Scheme 4).The presumed complex 19 was not isolated and characterized, since this type of dimeric π-allylnickel bromide complexes are known to be very sensitive towards oxidation. 25After evaporation of benzene and unreacted tetracarbonylnickel, the crude complex 19 could be used for the projected cross coupling reaction.Initially, cross coupling of the dimeric π-allylnickel bromide 19 and the 6-bromocarbazole 10 was achieved by reaction of 6-bromocarbazole 10, -cyclolavandulyl bromide (9) and tetracarbonylnickel in a ratio of 1:2:6 (Scheme 5, Table 1).The mixture of -cyclolavandulyl bromide (9) and tetracarbonylnickel was heated at 60-65 °C in benzene for 2.5 h as described above.The crude complex 19 was then treated with 6-bromocarbazole 10 in dry and degassed N,N-dimethylformamide (DMF) at 70 °C under the strict exclusion of oxygen.This procedure provided the desired 6-(β-cyclolavandulyl)carbazole 20 in 50% yield.Moreover, 37% of the starting material 10, the carbazole 14 (formed by hydrodebromination of 10, 8% yield) and the dimer 22 (resulting from homocoupling of β-cyclolavandulyl bromide (9), 34% yield) were isolated.The recovery of large amounts of starting material induced us to perform the coupling reaction using an even larger excess of tetracarbonylnickel (10 equivalents).These conditions afforded in addition to the compounds 20, 10, 14 and 22, the 6-acylcarbazole 21 in 13% yield.Obviously, compound 21 was formed by insertion of carbon monoxide resulting from excess tetracarbonylnickel.The 6-acylcarbazole 21 shows significant activity against Mycobacterium tuberculosis (H37Rv strain) with an MIC value of 4.0 μg mL -1 (8 μM) and is relatively nontoxic for mammalian cells. 26

Conclusions
The spectroscopic data of our synthetic ()-lavanduquinocin (rac-1) are in good agreement with those reported for the natural product (UV, IR, 1 H NMR, 13 C NMR). 5 Thus, the structural assignment of the natural product by Seto et al. has been confirmed by our total synthesis.The present route affords ()-lavanduquinocin (rac-1) in seven steps and 22% overall yield based on the iron complex salt 13 and emphasizes the utility of our iron-mediated carbazole synthesis in paving the way for efficient routes to this class of natural products.

Experimental Section
General.All reactions were carried out using dry solvents under argon atmosphere unless stated otherwise.Flash chromatography: Merck silica gel (0.03-0.06 mm).Melting points: Büchi 535.
UV spectra: Perkin-Elmer Lambda 2 (UV/VIS spectrometer).IR spectra: Bruker IFS 88 (FT-IR).After stirring for 30 min at the same temperature, prenyl bromide (11.9 g, 9.24 mL, 80.0 mmol) was added.The resulting yellow homogeneous reaction mixture was allowed to warm up to room temperature and stirring was continued for 15 h.The mixture was poured into a saturated aqueous solution of ammonium chloride (100 mL) and conc.HCl (9 mL).After separation of the organic layer, the aqueous layer was extracted with diethyl ether (5  25 mL).