Total synthesis of 8,9,11,12-tetramethoxy-2-methyl-1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinoline and 8,9,11-trimethoxy-2-methyl-1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinolin-12-ol

We describe here the first total synthesis of two tetrasubstituted 1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinolines (8,9,11,12-tetramethoxy-2-methyl-1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinoline and 8,9,11-trimethoxy-2-methyl-1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinolin-12-ol).


Introduction
The isoquinoline ring system is found in many alkaloids and for this and other reasons the synthesis of isoquinoline derivatives has received considerable attention. 1Nevertheless, naphtho[2,1-f]isoquinolines have received very little chemical attention prior to the recent isolation of two members of the only two natural members of this family -litebamine (9a) 2 and annoretine (9b) 3 Litebamine was the first phenanthrenic alkaloid isolated from Litsea cubeba and its activities as a platelet antiaggregant 4 and as an inhibitor of acetylcholinesterase 5 have been described.Subsequent partial syntheses of litebamine from the aporphine boldine led to the hypothesis of biogenetic degradation of aporphines to 1,2,3,4-tetrahydronaphtho[2,1f]isoquinolines. 5,6Annoretine was isolated from the leaves of Annona montana and it possesses significant cytotoxic activity against different human cell cultures such as KB, P-388, A-549 and HT-29.
We have previously reported some exploratory work on the synthesis of 1,2,3,4tetrahydronaphtho[2,1-f]isoquinolines 7 which was recently applied to the first total synthesis of the disubstituted 1,2,3,4-tetrahydronaphtho[2,1-f]isoquinoline annoretine. 8This exercise allowed us to corroborate the structure proposed for this natural compound and provided a promising strategy for the synthesis of other members of this family of isoquinoline alkaloids.Here we describe the first total synthesis of the tetrasubstituted 1,2,3,4-tetrahydronaphtho[2,1f]isoquinolines O,O-dimethyllitebamine (9c) and O-methyllitebamine 9d, which constitutes a novel contribution to the synthesis of this new family of alkaloids.

Results and Discussion
We first studied the preparation of O,O-dimethyllitebamine (9c), starting from ostyrylphenylethylurethane 3a, which was prepared by Heck 9 coupling of the appropriate halobenzene 1c to styrene 2b.A solution of homoveratrylamine (1a), ethyl chloroformate and Et 3 N was stirred at room temperature for 16 hours to afford the N-ethoxycarbonyl derivative 1b 10 in 93% yield.This compound was subsequently transformed quantitatively into iodobenzene derivative 1c after treatment with IPy 2 BF 4 11 and CF 3 SO 3 H.On the other hand, treatment 12 of 3,4-dimethoxybenzaldehyde (2a) with Ph 3 PCH 3 Br and n-BuLi in THF at room temperature for 4 hours gave the desired styrene 2b 13 in 99% yield.Next, when a deoxygenated solution of 1c, 2b, triethylamine, triphenylphosphine and palladium acetate was heated at 100 °C in a sealed tube for 24 hours, the desired tetrasubstituted o-styrylphenylethylurethane 3a was obtained in 55% yield.The mass spectrum of 3a confirmed the expected molecular weight (m/z = 415) and the E configuration of the stilbene double bond was easily established from its 1 H NMR spectrum, which showed two doublets at 6.84 ppm (1 H, J = 16.0Hz) and 7.25 ppm (1 H, J = 16.0Hz), due to the protons on the double bond.Next, compound 3a was converted into its N-methyl derivative 3b 14 and this was subjected to Bischler-Napieralski cyclization conditions with Tf 2 O 15 .This reaction readily furnished the expected 5-styrylisoquinolinone 4 in 97% yield.We next studied the photochemically induced electrocyclic cyclization 12 of styrylisoquinoline 4. Irradiation of 4 with a 450 W Hanovia medium-pressure lamp equipped with a Pyrex filter gave the expected naphthoisoquinolinone 5, which was identified from its analytical and spectroscopic data.The mass spectrum of this compound confirmed the molecular mass (M + , m/z = 381), two units less than the starting material.In addition, the 1 H NMR spectrum showed signals for a total of four aromatic protons, including a singlet for a proton at 9.27 ppm due to the hydrogen at C (10), which is highly deshielded due to steric interaction with the methoxy substituent at position C (11).On the other hand, transformation of naphthoisoquinolinone 5 into O-methyllitebamine 9d was accomplished in a two-step sequence starting with treatment of 5 with BCl 3 at room temperature during 15 minutes, 16 which led to compound 8 as a result of regiospecific demethylation of the methoxy substituent at C (12).Clear evidence for this process was provided by spectroscopic data, particularly the 1 H NMR spectrum, which showed a highly deshielded singlet for one proton at 12.98 ppm.This signal was assigned to the proton of the hydroxy substituent.The marked downfield chemical shift for this proton, due to its interaction with the carbonyl group, allowed us to establish that demethylation had occurred at the desired position.This conclusion was further supported by HMQC and HMBC experiments, which show a correlation between the OH proton and carbon atoms C(12a) and C( 11), together with a correlation between the methoxy substituent at C (11) and the carbon at C(12a) (Figure 1).These correlations clearly indicate that the hydroxy substituent is located between the carbonyl group and the methoxy substituent.Selective demethylation of the methoxy substituent at C( 12) can be explained as being the result of the initial interaction between naphthoisoquinolinone 5 and BCl 3 , which leads to a coordination complex 6 in which the boron atom is coordinated with oxygen atoms of the carbonyl and methoxy groups.Attack on such a complex by a chloride ion gives a second boron complex 7, hydrolysis of which furnished the resulting phenolic naphthoisoquinoline 8.

Figure 1 .
Figure 1.Important 1 H-13 C coupling observed in the HMQC and HMBC experiments of compound 8.

Finally, reduction of compound 8
with LiAlH 4 provided O-methyllitebamine 9d in 74% yield.Its mass spectrum confirmed the molecular weight expected for the compound (m/z = 353, M + ) and the 1 H NMR spectrum showed at 3.78 ppm a singlet of two protons, corresponding to the methylene arising from reduction of the carbonyl group.Work is now in progress to synthesize litebamine and to prepare a range of non-natural 1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines other than O,O-dimethyllitebamine (9c) and Omethyl-litebamine 9d for chemical and biological studies.