Formal synthesis of the bisbenzylisoquinoline alkaloid berbamunine by asymmetric substitution of chiral organolithium compounds

Asymmetric alkylation of enantiomeric tetrahydroisoquinolyl oxazolines was achieved with 96-97% diastereoselectivity. Removal of the oxazoline chiral auxiliary and further transformations provide a straightforward synthesis of the two synthetic intermediates that were previously synthesized by resolution, and which comprise a formal synthesis of berbamunine by Ullman coupling.


Introduction
The bisbenzylisoquinoline alkaloids are a class of compounds having two benzylisoquinoline subunits, which may be similar or dissimilar, joined by one or more ether bridges.One group of structurally identical bisbenzylisoquinolines, of which there are four diastereomers, is shown in Figure 1.Of these, three were first isolated from natural sources: magnoline from the leaves of Magnolia fuscata, 1 berbamunine from Berberis amurensis, 2 and guattegaumerine from Guatteria gaumeri, Since compounds 1 and 2 differ in their absolute configuration, enantiomeric chiral auxiliaries were appended, as illustrated in Scheme 3. Ethoxyoxazolines S-6 and R-6 are readily available from the corresponding oxazolidinone by O-alkylation with triethyloxonium tetrafluoroborate. 7Refluxing the 2-ethoxyoxazolines with tetrahydroisoquinoline 3 in benzene with a catalytic amount of p-TsOH afforded S-7 and R-7 in excellent yield.

Scheme 3. Chiral auxiliary attachment.
Fragment 1 was synthesized in either of two ways, illustrated in Scheme 4, which differ only in the sequence of steps.In the first path, alkylation of S-7 with 4-benzyloxybenzyl chloride gave compound 8 in 83% yield and 96% diastereoselectivity.The stereoisomer ratio was determined by chiral stationary phase chromatography after removal of the oxazoline auxiliary and acylation with 1-naphthoyl chloride, which provides both the enantiomer ratio and the absolute configuration. 8reatment of 8 with acetic formic anhydride removed the auxiliary and formylated the nitrogen in a single step, 9 giving N-formyl tetrahydroisoquinoline 9 in 79% yield.Reduction and bromination then afforded 1 in 60% yield for the two steps.Alternatively, S-7 could be alkylated with 3-bromo-4-benzyloxybenzyl chloride in 75% yield and 96% diastereoselectivity.The oxazoline was removed from 10 by hydrazinolysis and the nitrogen was formylated with acetic formic anhydride to give Nformyltetrahydroisoquinoline 11 in 66% yield for the two steps.After hydrazinolysis, the enantiomer ratio, er, and absolute configuration were determined as above.Reduction then yields 1 in 86% yield.The overall yield via 8 and 9 is 39%, and via 10 and 11 is 43%, while each route requires 4 steps.The identity of this compound was established by comparison of the melting point of the free base and its di-p-tolyltartrate salt, as well as the optical rotations of each, with literature values. 10Scheme 4. Synthesis of fragment 1.
The synthesis of fragment 2 was accomplished as shown in Scheme 5.The R enantiomer of 7 was alkylated with 4-methoxymethoxybenzyl chloride in 84% yield and 97% diastereoselectivity.The stereoisomer ratio and absolute configuration were again established by hydrazinolysis and acylation with 1-naphthoyl chloride, followed by chiral stationary phase HPLC. 8Hydrazinolysis and formylation with acetic formic anhydride gave N-formyl tetrahydroisoquinoline 13 in 77% yield for the two steps.Reduction and deprotection afforded fragment 2 in 60% yield.The preparation of 2 therefore proceeded in 38% overall yield for the 5 steps.

Scheme 5. Synthesis of fragment 2.
In conclusion, the asymmetric synthesis of fragments 1 and 2 constitute a formal synthesis of the bisbenzylisoquinoline alkaloid berbamunine, a route which could also be adapted to the synthesis of its diastereomers.

Experimental Section
General.Tetrahydrofuran and diethyl ether were distilled immediately prior to use from sodium benzophenone ketyl.Tetramethylethylene diamine (TMEDA) was distilled from CaH2 immediately before use.All other solvents used during the synthetic procedures were purified by distillation; other commercial reagents were used as received.All reactions were run under a nitrogen atmosphere.Infrared spectra were obtained as neat films or as a methylene chloride solution.Proton NMR spectra were recorded at either 60 or 400 MHz, and carbon NMR spectra were recorded at 20 MHz; chemical shifts are reported in ppm, relative to TMS.Chiral stationary phase chromatography employed a Bakerbond (R)-DNBPG (covalent) Pirkle column.All melting and boiling points are reported in °C and are uncorrected.Radial chromatography was performed on a Harrison Research Model 7924 Chromatron using silica gel 60 PF254 (E.Merck) containing gypsum.Elemental analyses were performed by Atlantic Microlabs, Norcross, Georgia.
The organic phase was dried (Na2CO3) and concentrated in vacuo.The crude product was then purified by radial chromatography (2% MeOH/CH2Cl2), followed by bulb-to-bulb distillation from calcium hydride.

General procedure B. Metalation and alkylation of tetrahydroisoquinolinyl-oxazolines
The base, t-butyllithium (1.7M solution in pentane, 1.2 equivalents) was added slowly to a 0.2 M solution of the tetrahydroisoquinolinyloxazoline (1 equivalent) in THF at -78 °C.The reaction mixture was stirred at -78 °C for 330 minutes, cooled to -100 °C and quenched with a 0.3 M solution of the electrophile (1.5 equiv) in THF.The reaction temperature was maintained at -100 °C for 30 min and then allowed to warm to room temperature slowly.The mixture was then quenched with brine (10 mL/eq), the organic phase extracted with CHCl3 (10 mL/eq), washed with brine, dried (Na2CO3) and concentrated in vacuo.The crude product was purified via radial chromatography (2% MeOH/CH2Cl2) and/or by kugelrohr distillation from calcium hydride.

General procedure D. Optical purity determination via Pirkle column
A solution of the l-alkyltetrahydroisoquinoline (1 equiv), 1-naphthoyl chloride (1.5 equiv) and triethylamine (3 equiv) in methylene chloride (10 mL/eq) was stirred one-half hour at room temperature.The reaction mixture was diluted with methylene chloride (20 mL/eq), washed with saturated bicarbonate (10 mL/eq) and brine (l0 mL/eq), dried (anhy.K2CO3) and concentrated in vacuo.The crude product was purified by radial chromatography (2% MeOH/CH2C12).The naphthamide derivative was then subjected to HPLC analysis using a R-DNBPG Pirkle column, according to the published procedure. 8General conditions for each run were: solvent, 20 to 25% isopropanol in hexane; flow rate 2.0 mL/min; detection at 240 nm.