Stereoselective synthesis of 1,3-disubstituted dihydroisoquinolines via L -phenylalanine-derived dihydroisoquinoline N -oxides †

The preparation of chiral pool-derived nitrone 3 and its use in the protecting-group free, stereoselective synthesis of a range of 1,3-disubstituted tetrahydroisoquinolines is described. Grignard reagent additions to nitrone 3 yielded trans -1,3-disubstituted N -hydroxytetrahydroisoquinolines 6 with good levels of selectivity, while 1,3-dipolar cycloadditions to this nitrone provided access to 3-(2-hydroxyalkyl)isoquino-lines 12 as single diastereomers.


Introduction
Tetrahydroisoquinoline (THIQ) systems occur in a wide range of natural products and therapeutic drugs 1 and have been highlighted both as privileged scaffolds 2 and as useful moieties in fragment-based drug discovery. 3 Moreover, there is interest in the use of tetrahydroisoquinolines as ligands in asymmetric catalysis 4 and as chiral bases. 5 The methods for accessing 1,3-disubstituted THIQ's, can be broadly grouped into two strategies, based on either cyclisations of suitably substituted aromatic precursors 6 or functionalisation of isoquinoline-based scaffolds. 7 In an effort to develop a strategy towards enantiodefined tetrahydroisoquinolines, of general use, we became interested in an approach of the latter type utilizing a chiral pool-derived isoquinoline unit with a potentially broad reactivity profile. The only previous approaches with these criteria utilize either 1-lithiated derivative 1 8 or imine 2 5with reactivity restricted to additions to electrophiles or nucleophiles respectively (Fig. 1).
We envisaged that nitrone 3 would exhibit much utility in this regard. The core scaffold is readily accessible, in enantio-enriched form from L-phenylalanine, and the reactivity of the nitrone group, functionalised via 1,3-dipolar cycloaddition, 9 nucleophilic addition 10 and reductive coupling with electrophiles, 11 confers wide scope to this system (Scheme 1). Furthermore, the hydroxymethyl group functions as a readily removable stereocontrol element. 12

Preparation of nitrone 3
Our approach to nitrone 3 centred on the oxidation of the known amine 5 (Scheme 2), accessed by Pictet-Spengler reaction of L-phenylalanine, 13 followed by borane-mediated reduction of the resulting acid. 5 Trialing a range of methods for the direct oxidative conversion of amines to nitrones, revealed that the corresponding isoquinoline N-oxide was a significant byproduct. Best results were achieved using Oxone as oxidant, providing dihydroisoquinoline derived nitrone 3 cleanly, in moderate yield (58%), with no evidence of overoxidation to the corresponding isoquinoline N-oxide. 14 Scheme 1 Synthetic approaches to 1,3-disubstituted tetrahydroisoquinolines utilising nitrone 3.

Addition of organometallic reagents to nitrone 3
With nitrone 3 in hand, the nucleophilic addition of organometallic reagents was initially investigated by screening of a range of solvents and temperatures, using methylmagnesium bromide and methyllithium as test reagents (Table 1). In all cases, full conversion was achieved using 3 equivalents of nucleophile, with the 1,3-trans isomer 6a as the major product. THF provided the best diastereomeric ratios and no advantage was conferred by performing the reaction under cryogenic conditions see (entries [7][8][9]. It is noteworthy that, while the addition of the more reactive methyllithium proceeded with full conversion, stereoselectivity was lower than that obtained with the corresponding Grignard reagent (entry 10 vs. entry 7). Consequently, subsequent studies were performed using Grignard species under the conditions outlined in entry 7.
The addition of different Grignard reagents to nitrone 3 provided, in all cases, the trans-isomer 6 as the major product (Table 2). No discernable trends are evident in Table 2, although the best levels of selectivity were obtained with the larger phenylmagnesium bromide (entry 5). Cis/trans stereochemistry of products 6 and 7 was assigned by 2D NOESY analysis (see Fig. 2 for an example). Strong correlations between the protons of the C1-substituent and H3 were observed in the trans-adduct, while the trans-diaxial correlations between H1 and H3 revealed the cis-diequatorial substitution pattern of the minor adduct, as illustrated on the ethyl-adduct 6b/7b.
The effect of protection of the 3-hydroxymethyl group, in combination with increasing size of the 3-substituent, was investigated by studying the addition of different Grignard reagents to the TBS-protected nitrone 8 (Table 3), prepared by sodium tungstate-catalysed-oxidation of the known TBS-derivative of hydroxymethyl-THIQ 5. 5,15 The addition of both ethyland phenylmagnesium bromide to 8 proceeded in favour of the trans-adducts 9, but with much lower selectivities than those obtained with the unprotected nitrone 3 (compare Table 3, entries 1 and 2 with Table 2, entries 2 and 5, respectively).
These results indicate that, in addition to the metal, (see Table 1, entries 7 and 10, for the addition of MeMgBr and    MeLi, respectively), the nitrone oxygen and the free hydroxyl group play an important role in determining the mode and level of diastereoselectivity in the addition to 3. This hypothesis is supported by the results obtained with imine 2, where the selectivities of the addition of organolithium species are generally lower than those reported in Table 2 for all but the largest nucleophiles. 5 We propose the model depicted in Fig. 3 to account for this selectivity, which involves a cyclic magnesium chelate similar to that hypothesized during additions to N-glycosyl nitrones. 16 In our model, the syn addition is hindered by the pseudo-axial proton at C4.

Cycloaddition reactions of nitrone 3
Next, the preparation of more functionalized, stereodefined 1,3-THIQ systems was investigated via 1,3-dipolar cycloaddition of 3 with a range of alkenes, followed by reduction of the resulting isoxazolidines 11 (Table 4). Styrene and hex-1-ene were chosen as the prototypical model dipolarophiles (entries 1 and 2), alongside functionalized butenes, selected to access products of subsequent synthetic utility (entries 3 and 4). Optimum yields/selectivity were obtained in toluene under reflux conditions. The stereochemistry of the cycloaddition was readily deduced by analysis of 2D-NOESY spectra of cycloadducts 11 (see an example in Fig. 4), which revealed strong correlations between H2/H6 and H10b/CH 2 (OH). In all cases, the exo-1,3-trans-isoxazolidine was exclusively obtained in moderate to good yield and no traces of any other isomers were detected in the 1 H NMR spectra of crude products. The cycloaddition reactions of nitrone 3 with a range of electron deficient systems, including acrylates, were trialed but, unfortunately, failed to provide the corresponding cycloadducts. The subsequent reductive N-O bond cleavage of isoxazolidine 11, with zinc powder in AcOH, proceeded with no stereochemical degradation, 17 providing the corresponding 1,3-THIQ 12a-d in good to moderate yields (Table 2).

Conclusions
In conclusion, we have developed an approach to the synthesis of a range of optically active 1,3-disubstituted tetrahydroisoquinolines from (S)-3-(hydroxymethyl)-3,4-dihydroisoquinoline 2-oxide 3. The addition of Grignard reagents to 3 proceeded with good yields and stereoselectivities, and unprecedented levels of stereoselection were found for the dipolar cycloaddition reaction of alkenes to nitrone 3. This strategy allows the direct assembly of highly functionalized tetrahydroisoquinoline units with up to three stereogenic centres in a simple and effective manner, starting from a readily available chiral substrate.

Experimental
General 1 H NMR and 13 C NMR have been recorded on a JEOL® ECS-400 (400 and 100.6 MHz, respectively) using CDCl 3 as solvent. Chemical shift values are reported in ppm with TMS as internal standard (CDCl 3 : δ 7.26 for 1 H-NMR, δ 77.0 for 13 C-NMR). Data are reported as follows: chemical shifts, multiplicity (s = singlet, quint = quintuplet, m = multiplet), coupling constants (Hz), and integration. IR spectra were recorded on Nicolet® 380 FT/IR -Fourier Transform Infrared Spectrometer. Only the most significant frequencies have been considered during the characterization, and have been reported in cm −1 . High resolution mass spectra were measured on an Agilent Technologies® 6540 Ultra-High-Definition (UHD) Accurate-Mass equipped with a time of flight (Q-TOF) analyzer and the samples were ionized by ESI techniques and introduced through a high pressure liquid chromatography (HPLC) model Agilent Technologies® 1260 Infinity Quaternary LC system. Optical rotations were measured on a Bellingham + Stanley®   Organic & Biomolecular Chemistry Paper ADP 440 + Polarimeter with a 0.5 cm cell (c given in g per 100 mL). All reactions were monitored by thin-layer chromatography using precoated sheets of silica gel 60, 0.25 mm thick (F254 Merck KGaA®). The components were visualized by UV light (254 nm) and phosphomolybdic acid. Flash column chromatography was done using Geduran® Silica gel 60, 40-63 microns RE. The eluent used is mentioned in each particular case. All glassware employed during inert atmosphere experiments was flame-dried under a stream of dry argon. Alkenes reagents were purchased from Sigma-Aldrich or Fisher Scientific and used without further purification. Grignard and organolithium reagents were purchased from Sigma-Aldrich. Anhydrous THF was obtained from a Pure Solv™ Solvent Purification Systems.
(S)-3-(Hydroxymethyl)-3,4-dihydroisoquinoline-2-oxide (3). General procedure for the diastereoselective addition of Grignard reagents A solution of RMgBr (0.9 mmol, 3 eq.) was added to a solution of nitrone 3 (53.1 mg, 0.3 mmol) in THF (1.5 mL). The mixture was stirred at 0°C for 1 h and then warmed to room temperature and quenched with water. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases dried over MgSO 4 , and concentrated under reduced pressure. The crude product, was purified by flash column chromatography eluting with n-hexane/EtOAc (gradient from 10 to 60%) to give the corresponding 1,3-disubstituted tetrahydroisoquinoline-2ol as a yellow oil.