Stereoselective synthesis of 1,3-disubstituted dihydroisoquinolines viaL-phenylalanine-derived dihydroisoquinoline N-oxides

Abstract

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)isoquinolines 12 as single diastereomers.

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Introduction

Tetrahydroisoquinoline (THIQ) systems occur in a wide range of natural products and therapeutic drugs¹ and have been highlighted both as privileged scaffolds² and as useful moieties in fragment-based drug discovery.³ Moreover, there is interest in the use of tetrahydroisoquinolines as ligands in asymmetric catalysis⁴ 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 precursors⁶ 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 1⁸ or imine 2⁵ – with reactivity restricted to additions to electrophiles or nucleophiles respectively (Fig. 1).

Fig. 1 Previous chiral pool-derived THIQ precursors.

We envisaged that nitrone 3 would exhibit much utility in this regard. The core scaffold is readily accessible, in enantioenriched form from L-phenylalanine, and the reactivity of the nitrone group, functionalised via 1,3-dipolar cycloaddition,⁹ nucleophilic addition¹⁰ 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

Scheme 1 Synthetic approaches to 1,3-disubstituted tetrahydroisoquinolines utilising nitrone 3.

Results and discussion

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 2 Synthesis of 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 7–9). 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.

Table 1 Optimization of the addition of organometallic reagents to nitrone 3^a

Entry	RM	Solvent	T (°C)	6a/7a^b	Conv.^c (%)
a Reaction conditions: 3 (0.1 mmol), RM (3 eq.), T, solvent. b Ratio determined by analysis of ^1H-NMR spectra of crude products. Relative stereochemistry determined by 2D-NOESY studies; see ESI for further details. c Determined by ^1H-NMR analysis of crude products.
1	MeMgBr	CH2Cl2	0	4.5/1	>99
2	MeMgBr	PhMe	0	7.1/1	>99
3	MeMgBr	Dioxane	0	3.0/1	>99
4	MeMgBr	^tBuOMe	0	3.5/1	>99
5	MeMgBr	Et2O	0	5.5/1	>99
6	MeMgBr	THF	20	6.0/1	>99
7	MeMgBr	THF	0	7.5/1	>99
8	MeMgBr	THF	−20	7.5/1	>99
9	MeMgBr	THF	−40	7.5/1	>99
10	MeLi	THF	0	3.8/1	>99

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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.

Fig. 2 Selected correlations observed in the 2D-NOESY spectra of tetrahydroisoquinolines 6b and 7b.

Table 2 Addition of organometallic reagents to nitrone 3^a

Entry	RM	Products	6 : 7^a^,^b	Yield^c (%)
a Reaction conditions: 3 (0.3 mmol), RMgBr (3 eq.), THF, 0 °C to r.t. b Ratio determined by analysis of crude ^1H-NMR spectra. Relative stereochemistry determined by 2D-NOESY studies, see Fig. 2 and ESI for further details. c Isolated combined yield after column chromatography.
1	MeMgBr	6a/7a	7.5/1	75
2	EtMgBr	6b/7b	6.5/1	87
3	^iPrMgBr	6c/7c	5.9/1	85
4	AllylMgBr	6d/7d	2.8/1	90
5	PhMgBr	6e/7e	10/1	96

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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 ethyl- and 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).

Table 3 Addition of organometallic reagents to nitrone 8^a

Entry	RM	Product	9/10^b	Yield^c (%)
a Reaction conditions: 8 (0.3 mmol), RMgBr (3 eq.), THF, 0 °C to r.t. b Ratio determined by ^1H-NMR on the reaction crude. Relative stereochemistry determined by 2D-NOESY studies. c Isolated combined yield after column chromatography.
1	EtMgBr	9a/10a	2.5/1	56
2	PhMgBr	9b/10b	3/1	53

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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.

Fig. 3 Proposed mode of addition of Grignard reagents to nitrone 3.

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/CH₂(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 ¹H 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.

Fig. 4 Selected correlations observed in the 2D-NOESY spectrum of 11a.

Table 4 Cycloaddition of nitrone 3 and reduction of cycloadducts 11^a

Entry	R	Product	11 (% yield)	12 (% yield)
a Reaction conditions: (i) CH2=CH2R (5 eq.), toluene, 110 °C; (ii) AcOH, Zn, reflux. b Isolated yield after flash chromatography. Relative stereochemistry determined by 2D-NOESY studies, see Fig. 4 and ESI for further details.
1	Ph	11a/12a	86	33
2	(CH2)3CH3	11b/12b	74	90
3	(CH2)2OBn	11c/12c	61	51
4	(CH2)2SPh	11d/12d	64	47

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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

¹H NMR and ¹³C NMR have been recorded on a JEOL® ECS-400 (400 and 100.6 MHz, respectively) using CDCl₃ as solvent. Chemical shift values are reported in ppm with TMS as internal standard (CDCl₃: δ 7.26 for ¹H-NMR, δ 77.0 for ¹³C-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® 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). NaHCO₃ (6.72 g, 80.0 mmol) was added to a solution of tetrahydroisoquinoline 5 (2.6 g, 16.0 mmol) in THF–CH₃CN 1 : 4 (28 mL) and 0.01 M aqueous EDTA solution (22.4 mL) at 5 °C. Oxone (10.3 g, 16.8 mmol) was then added portionwise over 2 h, and the mixture stirred for 20 min, at 5 °C. Ethyl acetate (80 mL) was added and the aqueous layer further extracted with ethyl acetate (2 × 80 mL). The combined organic extracts were dried over anhydrous MgSO₄ and concentrated under reduced pressure to give nitrone 3 (1.66 g, 59%) as a pale yellow solid; m.p. decomposes T > 145 °C; [α]²⁵_D 174 (c = 3.3, CHCl₃); IR (ATR): ν = 3242, 3054, 2945, 2897 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.80 (s, 1H), 7.35–7.25 (m, 2H), 7.25–7.20 (m, 1H), 7.18–7.14 (m, 1H), 4.51 (br s, 1H), 4.26–4.16 (m, 1H), 4.04 (dd, J = 12.0, 6.9 Hz, 1H), 3.94 (dd, J = 12.0, 3.6 Hz, 1H), 3.22–3.07 (m, 2H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 135.4, 130.0, 129.8, 127.6, 127.5, 127.2, 125.6, 67.2, 62.7, 29.8 ppm; MS (EI, 70 eV): m/z (%) = 177 (M⁺, 8), 130 (100), 115 (34), 103 (22), 77 (26); HRMS (ESI-MeOH): m/z calcd for C₁₀H₁₂NO₂ [M + H]⁺: 178.0863 found 178.0862.

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 MgSO₄, 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-2-ol as a yellow oil.

(1R,3S)-3-(Hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-ol (6a) and (1S,3S)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-ol (7a). Following the general procedure, the reaction of methylmagnesium bromide (3.0 M in Et₂O, 300 μL) with nitrone 3 gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 6a (38 mg, 66% yield) as a yellow oil. [α]²⁵_D −15 (c = 1, CHCl₃); IR (ATR): ν = 3240, 3019, 2973, 2932 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.17–7.10 (m, 2H), 7.10–7.01 (m, 2H), 4.32 (q, J = 7.1, 1H), 3.82 (dd, J = 11.5, 7.6 Hz, 1H), 3.72 (br s, 1H), 3.41–3.34 (m, 1H), 2.93 (dd, J = 16.7, 11.5 Hz, 1H), 2.53 (d, J = 14.8 Hz, 1H), 1.41 (d, J = 7.1 Hz, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 137.6, 132.2, 128.7, 127.3, 126.4, 126.2, 63.2, 62.4, 56.5, 25.8, 21.0 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₁H₁₆NO₂ [M + H]⁺: 194.1176 found 194.1778. 7a (5 mg, 9% yield) as a yellow oil. [α]²⁵_D −27 (c = 1, CHCl₃); IR (ATR): ν = 3257, 2981, 2930, 2880 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.22–7.11 (m, 3H), 7.10–7.04 (m, 1H), 4.06 (q, J = 6.6 Hz, 1H), 3.82–3.78 (m, 2H), 3.16 (brs, 1H), 3.03 (dd, J = 16.2, 12.1 Hz, 1H), 2.65 (d, J = 14.8 Hz, 1H), 1.61 (d, J = 6.6 Hz, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 137.2, 133.0, 128.2, 126.6, 126.4, 126.0, 64.3, 64.0, 62.6, 29.7, 18.4 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₁H₁₆NO₂ [M + H]⁺: 194.1176 found 194.1177.

(1R,3S)-1-Ethyl-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-ol (6b) and (1S,3S)-1-ethyl-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-ol (7b). Following the general procedure, the reaction of ethylmagnesium bromide (3.0 M in Et₂O, 300 μL) with nitrone 3 gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 6b (47 mg, 76% yield) as a yellow oil. [α]²⁵_D +3 (c = 1, CHCl₃); IR (ATR): ν = 3285, 3062, 2931, 2873 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.20–7.12 (m, 2H), 7.10–7.07 (m, 2H), 4.07 (t, J = 7.5 Hz, 1H), 3.84 (dd, J = 10.2, 9.0 Hz, 1H), 3.68 (dd, J = 11.0, 3.5 Hz, 1H), 3.40–3.33 (m, 1H), 2.90 (dd, J = 16.7, 11.7 Hz, 1H), 2.52 (dd, J = 16.7, 5.0 Hz, 1H), 1.76–1.63 (m, 2H), 1.10 (t, J = 7.5 Hz, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 136.7, 132.4, 128.8, 127.8, 126.4, 126.0, 68.9, 63.1, 56.2, 29.4, 24.6, 11.9 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₂H₁₈NO₂ [M + H]⁺: 208.1332 found 208.1334. 7b (7 mg, 11% yield) as a yellow oil. [α]²⁵_D −29 (c = 1, CHCl₃); IR (ATR): ν = 3279, 2961, 2931, 2873 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.22–7.11 (m, 3H), 7.08 (d, J = 7.1 Hz, 1H), 4.00 (t, J = 4.6 Hz, 1H), 3.81 (d, J = 4.9 Hz, 2H), 3.17–3.09 (m, 1H), 2.96 (dd, J = 16.1, 12.0 Hz, 1H), 2.64 (dd, J = 16.1, 4.0 Hz, 1H), 2.29–2.17 (m, 1H), 2.01–1.89 (m, 1H), 0.92 (t, J = 7.3 Hz, 1H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 136.0, 133.9, 128.2, 126.3, 126.3, 125.9, 67.7, 64.9, 63.4, 29.7, 24.1, 9.2 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₂H₁₈NO₂ [M + H]⁺: 208.1332 found 208.1334.

(1R,3S)-3-(Hydroxymethyl)-1-isopropyl-3,4-dihydroisoquinolin-2(1H)-ol (6c) and (1S,3S)-3-(hydroxymethyl)-1-isopropyl-3,4-dihydroisoquinolin-2(1H)-ol (7c). Following the general procedure, the reaction of isopropylmagnesium bromide (0.75 M in THF, 1.2 mL) with nitrone 3 gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 6c (48 mg, 73% yield) as a yellow oil. [α]²⁵_D +15 (c = 1, CHCl₃); IR (ATR): ν = 3308, 3020, 2956, 2871 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.20–7.12 (m, 2H), 7.12–7.05 (m, 2H), 3.85 (dd, J = 11.3, 8.6 Hz, 1H), 3.79 (d, J = 8.7 Hz, 1H), 3.64 (dd, J = 11.3, 3.6 Hz, 1H), 3.46–3.35 (m, 1H), 2.81 (dd, J = 17.1, 11.3 Hz, 1H), 2.57 (dd, J = 17.1, 6.1 Hz, 1H), 1.85–1.70 (m, 1H), 1.09 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 135.0, 132.8, 129.3, 128.8, 126.5, 125.2, 73.3, 63.2, 56.2, 33.2, 24.5, 21.2, 20.8 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₃H₂₀NO₂ [M + H]⁺: 222.1489 found 222.1483. 7c (8 mg, 12% yield) as a yellow oil. [α]²⁵_D +88 (c = 1, CHCl₃); IR (ATR): ν = 3311, 3020, 2956, 2871 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.22–7.07 (m, 4H), 4.12 (d, J = 3.7 Hz, 1H), 3.93 (dd, J = 11.1, 3.0 Hz, 1H), 3.72 (dd, J = 11.1, 4.5 Hz, 1H), 3.11–3.01 (m, 1H), 2.88 (dd, J = 15.6, 12.4 Hz, 1H), 2.59 (dd, J = 15.6, 3.2 Hz, 1H), 2.29–2.12 (m, 1H), 1.06 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 136.8, 134.9, 127.5, 126.8, 126.1, 126.0, 73.8, 64.9, 63.7, 34.6, 30.9, 20.6, 17.9 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₃H₂₀NO₂ [M + H]⁺: 222.1489 found 222.1482.

(1R,3S)-1-Allyl-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-ol (6d) and (1S,3S)-1-allyl-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-ol (7d). Following the general procedure, the reaction of allylmagnesium bromide (1.0 M in Et₂O, 900 μL) with nitrone 3 gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 6d (44 mg, 67% yield) as a yellow oil. [α]²⁵_D −51 (c = 1, CHCl₃); IR (ATR): ν = 3302, 3076, 3021, 2928, 2044 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.21–7.13 (m, 2H), 7.13–7.04 (m, 2H), 6.01–5.85 (m, 1H), 5.09–5.05 (m, 2H), 4.26 (t, J = 7.4 Hz, 1H), 3.83 (dd, J = 11.2, 8.4 Hz, 1H), 3.68 (dd, J = 11.2, 3.4 Hz, 1H), 3.44–3.35 (m, 1H), 2.92 (dd, J = 16.7, 11.7 Hz, 1H), 2.53 (dd, J = 16.7, 4.7 Hz, 1H), 2.49–2.39 (m, 2H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 135.8, 135.5, 132.5, 128.8, 127.7, 126.6, 126.0, 117.1, 66.8, 63.1, 56.3, 40.6, 24.7 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₃H₁₈NO₂ [M + H]⁺: 220.1332 found 220.1325. 7d (15 mg, 23% yield) as a yellow oil. [α]²⁵_D −41 (c = 1, CHCl₃); IR (ATR): ν = 3280, 3075, 3021, 2927, 2042 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.26–7.14 (m, 3H), 7.14–7.06 (m, 1H), 6.02–5.87 (m, 1H), 5.16 (dd, J = 17.2, 1.6 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 4.15 (t, J = 5.7 Hz, 1H), 3.85–3.74 (m, 2H), 3.21–3.12 (m, 1H), 3.02–2.95 (m, 2H), 2.78–2.69 (m, 1H), 2.63 (dd, J = 16.3, 3.8 Hz, 1H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 136.3, 135.8, 133.8, 128.4, 126.5, 126.4, 126.1, 116.4, 66.1, 64.6, 63.3, 36.8, 28.9 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₃H₁₈NO₂ [M + H]⁺: 220.1332 found 220.1326.

(1R,3S)-3-(Hydroxymethyl)-1-phenyl-3,4-dihydroisoquinolin-2(1H)-ol (6e) and (1S,3S)-3-(hydroxymethyl)-1-phenyl-3,4-dihydroisoquinolin-2(1H)-ol (7e). Following the general procedure, reaction of phenylmagnesium bromide (3.0 M in Et₂O, 300 μL) with nitrone 3 gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 6e (67 mg, 87% yield) as a yellow oil. [α]²⁵_D −84 (c = 1, CHCl₃); IR (ATR): ν = 3240, 3061, 3026, 2889 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.29–7.24 (m, 3H), 7.23–7.18 (m, 2H), 7.18–7.12 (m, 1H), 7.12–7.06 (m, 2H), 6.91 (d, J = 7.6 Hz, 1H), 5.33 (s, 1H), 3.77 (dd, J = 11.4, 7.6 Hz, 1H), 3.55 (d, J = 9.2 Hz, 1H), 3.36–3.26 (m, 1H), 2.96 (dd, J = 16.9, 10.1 Hz, 1H), 2.70 (dd, J = 16.9, 5.1 Hz, 1H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 140.6, 134.0, 133.3, 130.2, 129.0, 128.6, 128.2, 127.7, 127.0, 126.2, 70.3, 62.8, 56.7, 26.2 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₆H₁₈NO₂ [M + H]⁺: 256.1332 found 256.1336. 7e (6 mg, 9% yield) as a yellow oil. [α]²⁵_D +4.5 (c = 1, CHCl₃); IR (ATR): ν = 3238, 3061, 3025, 2890 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.35–7.30 (m, 2H), 7.29–7.23 (m, 2H), 7.15–7.08 (m, 2H), 7.03–6.95 (m, 1H), 6.54 (d, J = 7.8 Hz, 1H), 5.35 (br s, 1H), 4.88 (s, 1H), 3.95–3.82 (m, 1H), 3.77 (dd, J = 11.8, 5.3 Hz, 1H), 3.21 (d, J = 11.8 Hz, 1H), 3.14 (dd, J = 27.5, 11.8 Hz, 2H), 2.82 (d, J = 15.6 Hz, 1H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 141.9, 136.6, 133.2, 130.3, 128.3, 128.2, 127.8, 127.7, 126.7, 125.9, 75.1, 64.8, 64.6, 31.6 ppm; HRMS (CI-CH₄): m/z calcd for C₁₆H₁₈NO₂ [M + H]⁺: 256.1332 found 256.1337.

(S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-3,4-dihydroisoquinoline 2-oxide (8). A solution of (S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-3,4-dihydroisoquinoline^5,15 (0.76 g, 2.77 mmol) was added to a solution of sodium tungstate (0.14 g, 0.046 mmol) in methanol (1 mL). A 30% aqueous solution of H₂O₂ (1.0 mL, 8.31 mmol) was added at 0 °C over a period of 30 min and the reaction mixture was warmed to room temperature and stirred overnight. The mixture was concentrated under reduced pressure, diluted with brine and extracted with CH₂Cl₂ (2 × 15 mL). The combined organic layers were dried over anhydrous MgSO₄, and concentrated under reduced pressure. The residue was purified by column chromatography, using CHCl₃–CH₃OH (10 : 1) as eluent, to give nitrone 10 (0.46 g, 57%) as a viscous oil. [α]²⁵_D −36 (c = 1, CHCl₃); IR (ATR): ν = 2952, 2927, 2883, 2855 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.73 (s, 1H), 7.28–7.18 (m, 3H), 7.08 (d, J = 6.9 Hz, 1H), 4.16–4.08 (m, 1H), 3.96 (dd, J = 9.9, 3.8 Hz, 1H), 3.84 (dd, J = 9.9, 7.7 Hz, 1H), 3.42 (dd, J = 16.7, 7.3 Hz, 1H), 3.25 (dd, J = 16.8, 3.2 Hz, 1H), 0.79 (s, 9H), −0.01 (s, 3H), −0.03 (s, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 134.8, 129.6, 129.2, 127.7, 127.6, 127.2, 125.1, 68.8, 61.8, 29.2, 25.5, 18.0, −5.7, −5.78 ppm; HRMS (ESI-MeOH): m/z calcd for C₁₆H₂₆NO₂Si [M + H]⁺: 292.1727 found 292.1734.

(1R,3S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-ethyl-3,4-dihydroisoquinolin-2(1H)-ol (9a) and (1S,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-ethyl-3,4-dihydroisoquinolin-2(1H)-ol (10a). Following the general procedure, the reaction of ethylmagnesium bromide (3.0 M in Et₂O, 300 μL) with nitrone 8 gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 9a (38 mg, 40% yield) as a yellow solid; m.p. 50–51 °C; [α]²⁵_D −12 (c = 1.2, CHCl₃); IR (ATR): ν = 3229, 3063, 2954, 2928, 2856, 1462, 1252, 1100, 834, 774, 748 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.18–7.09 (m, 4H), 6.42 (br s, 1H), 4.05 (dd, J = 8.3, 6.3 Hz, 1H), 3.99 (dd, J = 10.0, 5.6 Hz, 1H), 3.79 (dd, J = 10.0, 6.1 Hz, 1H), 3.31 (td, J = 11.1, 5.6 Hz, 1H), 2.98 (dd, J = 16.7, 11.0 Hz, 1H), 2.66 (dd, J = 16.7, 5.2 Hz, 1H), 1.76–1.67 (m, 2H), 1.09 (t, J = 7.4Hz, 3H), 0.92 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 137.4, 133.3, 128.9, 127.8, 126.3, 126.0, 68.7, 65.5, 56.6, 29.7, 26.1, 25.6, 18.5, 11.9, −5.1, −5.2 ppm; HRMS (ESI-EtOAc): m/z calcd for C₁₈H₃₁NO₂Si [M + H]⁺ 322.2202 found 322.2197. 10a (16 mg, 16% yield) as a yellow oil. [α]²⁵_D −7 (c = 1.5, CHCl₃); IR (ATR): ν = 3263, 3066, 2954, 2928, 2855, 1462, 1252, 1103, 834, 775, 739 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.19–7.11 (m, 4H),5.05 (br s, 1H), 4.03 (dd, J = 10.0, 4.9 Hz, 1H), 3.96 (t, J = 4.6 Hz, 1H), 3.77 (dd, J = 10.0, 6.2 Hz, 1H), 3.09 (m, 1H), 2.93–2.86 (m 1H), 2.79 (dd, J = 16.2, 4.2 Hz, 1H), 2.28–2.17 (m, 1H), 1.98–187 (m, 1H), 0.92 (s, 9H), 0.89 (t, J = 7.2 Hz, 1H), 0.11 (s, 3H), 0.10 (s, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 136.6, 134.6, 128.3, 126.3, 126.2, 126.0, 68.1, 66.1, 63.6, 29.9, 26.1, 24.6, 18.5, 9.2, −5.1, −5.2 ppm; HRMS (ESI-EtOAc): m/z calcd for C₁₈H₃₁NO₂Si [M + H]⁺ 322.2202 found 322.2197.

(1R,3S)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-1-phenyl-3,4-dihydroisoquinolin-2(1H)-ol (9b) and (1S,3S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-phenyl-3,4-dihydroisoquinolin-2(1H)- (10b). Following the general procedure, the reaction of phenylmagnesium bromide (3.0 M in Et₂O, 300 μL) with nitrone 8 gave the 1,3-disubstituted tetrahydroisoquinoline-2-ol 9b (44 mg, 40% yield) as a yellow oil. [α]²⁵_D −4 (c = 1, CHCl₃); IR (ATR): ν = 3213, 3062, 2927, 2855 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.39–7.31 (m, 3H), 7.29–7.28 (m, 2H), 7.25–7.17 (m, 3H), 6.96 (d, J = 7.7 Hz, 1H), 6.92 (s, 1H), 5.28 (s, 1H), 4.06 (dd, J = 10.0, 5.2 Hz, 1H), 3.82 (dd, J = 10.0, 6.7 Hz, 1H), 3.48–3.40 (m, 1H), 3.14 (dd, J = 16.8, 8.3 Hz, 1H), 2.98 (dd, J = 16.8, 5.3 Hz, 1H), 0.92 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 141.8, 134.9, 133.7, 130.0, 128.9, 128.7, 128.1, 127.4, 126.7, 125.9, 70.0, 63.4, 57.5, 27.2, 25.8, 18.2, −5.4, −5.5 ppm; HRMS (ESI-MeOH): m/z calcd for C₂₂H₃₂NO₂Si [M + H]⁺ 370.2197 found 370.2205. 10b (15 mg, 13% yield) as a yellow oil. [α]²⁵_D −55 (c = 1, CHCl₃); IR (ATR): ν = 3306, 3028, 2927, 2854 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.39–7.34 (m, 5H), 7.16–7.11 (m, 2H), 7.04–6.97 (m, 1H), 6.59 (d, J = 7.8 Hz, 1H), 4.89 (s, 2H), 4.16 (dd, J = 9.9, 4.4 Hz, 1H), 3.79 (dd, J = 9.9, 6.9 Hz, 1H), 3.29–3.18 (m, 1H), 3.09 (s, 1H), 3.07 (s, 1H), 0.93 (s, 9H), 0.10 (s, 3H), 0.10 (s, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 142.9, 137.3, 133.5, 129.9, 128.4, 128.1, 127.8, 127.5, 126.5, 125.8, 74.7, 65.3, 64.1, 25.9, 22.7, 18.3, −5.2, −5.3 ppm; HRMS (ESI-MeOH): m/z calcd for C₂₂H₃₂NO₂Si [M + H]⁺ 370.2197 found 370.2203.

General procedure for the cycloaddition reactions of nitrone 3

A solution of nitrone 3 (0.1 g, 0.56 mmol) in dry toluene (5 mL) was heated to 80 °C. A solution of the corresponding alkene (5 eq.) in dry toluene (5 mL) was added dropwise and the reaction was heated at 110 °C overnight. Removal of the solvent under reduced pressure yielded the crude product as a dark brown oil. Purification by flash chromatography eluting with EtOAc/cyclohexane (1 : 1) gave the corresponding products 11.

((2R,5S,10bR)-2-Phenyl-1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinolin-5-yl)methanol (11a). Following the general procedure, reaction of styrene (2.8 mmol, 322 μL) with nitrone 3 gave the cycloadduct 11a (26 mg, 86% yield) as a yellow oil; [α]²⁵_D −29 (c = 3.6, CHCl₃); IR (ATR): ν = 3372, 3027, 2937, 2886, 1733, 1241, 1047, 927, 794, 699 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.46–7.43 (m, 2H), 7.42–7.37 (m, 2H), 7.36–7.31 (m, 1H), 7.21–7.14 (m, 3H), 7.09–7.07 (m, 1H), 5.44 (dd, J = 9.5, 4.5 Hz, 1H), 4.88 (dd, J = 10.3, 8.2 Hz, 1H), 3.94–3.93 (m, 2H), 3.35–3.30 (m, 1H), 2.97 (dd, J = 16.4, 11.5 Hz, 1H), 2.82–2.72 (m, 2H), 2.68–2.62 (m, 1H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 141.1, 134.7, 132.2, 128.6, 128.2, 128.0, 127.0, 126.9, 126.4, 79.1, 66.2, 64.1, 56.9, 45.5, 31.5 ppm; HRMS (ESI-EtOAc): m/z calcd for C₁₈H₁₉NO₂ [M + H]⁺: 282.1494 found 282.1489.

((2S,5S,10bR)-2-Butyl-1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinolin-5-yl)methanol (11b). Following the general procedure reaction of 1-hexene (2.8 mmol, 350 μL) with nitrone 3 gave the cycloadduct 11b (17 mg, 74% yield) as a yellow oil; [α]²⁵_D −6 (c = 1, CHCl₃); IR (ATR): ν = 3405, 2953, 2858, 1454, 1050, 944, 748, 713 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.20–7.14 (m, 2H), 7.10–7.09 (m, 2H), 4.60 (t, J = 9.2, 1H), 4.41 (dq, J = 12.6, 6.1 Hz, 1H), 3.86–3.85 (m, 2H), 3.29 (br s, 1H), 3.20–3.14 (m, 1H), 2.85 (dd, J = 16.3, 11.6 Hz, 1H), 2.70 (dd, J = 16.4, 3.6 Hz, 1H), 2.40–2.31 (m, 2H), 1.72–1.66 (m, 1H), 1.64 (m, 1H), 1.44–1.30 (m, 4H), 0.92 (t, J = 6.9 Hz, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 135.3, 132.2, 128.3, 127.1, 126.8, 126.4, 77.6, 66.7, 63.9, 56.5, 42.4, 35.0, 31.6, 28.2, 22.8, 14.1 ppm; HRMS (ESI-EtOAc): m/z calcd for C₁₆H₂₃NO₂ [M + H]⁺: 262.1807 found 262.1802.

((2R,5S,10bR)-2-(2-(Benzyloxy)ethyl)-1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinolin-5-yl)methanol (11c). Following the general procedure, reaction of 4-benzyloxybut-1-ene¹⁸ (2.8 mmol, 454 mg) with nitrone 3 gave the cycloadduct 11c (42 mg, 61% yield) as a yellow oil. [α]²⁵_D −1.21 (c = 9.9, CHCl₃); IR (ATR): ν = 3421, 3027, 2916, 2882, 1454, 1361, 1096, 910, 733, 697 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.38–7.27 (m, 5H), 7.21–7.15 (m, 2H), 7.12–7.07 (m, 2H), 4.64–4.55 (m, 2H), 4.52 (s, 2H), 3.86 (d, 4.2 Hz, 2H), 3.65–3.60 (m, 2H), 3.24 (br s, 1H), 3.17 (ddd, J = 11.7, 7.9, 4.0 Hz, 1H), 2.88 (dd, J = 16.3, 11.6 Hz, 1H), 2.72 (dd, J = 16.4, 3.6 Hz, 1H), 2.48–2.36 (m, 2H), 2.05–1.92 (m, 2H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 138.1, 135.0, 132.1, 128.3, 128.1, 127.6, 127.5, 126.9, 126.7, 126.2, 77.2, 74.8, 73.1, 66.9, 66.1, 63.6, 56.5, 42.2, 35.2, 31.4 ppm; HRMS (ESI-EtOAc): m/z calcd for C₂₁H₂₅NO₃ [M + H]⁺: 340.1913 found 340.1907.

((2R,5S,10bR)-2-(2-(Phenylthio)ethyl)-1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinolin-5-yl)methanol (11d). Following the general procedure, reaction of but-3-en-1-yl(phenyl)sulfane¹⁹ (2.8 mmol, 459 mg) with nitrone 3 gave the cycloadduct 11d (50 mg, 64% yield) as a yellow oil. [α]²⁵_D −91 (c = 1, CHCl₃); IR (ATR): ν = 3408, 3058, 2930, 2884, 1582, 1438, 1051, 1024, 944, 736, 690 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.37–7.35 (m, 2H), 7.32–7.28 (m, 2H), 7.21–7.06 (m, 5H), 4.63–4.54 (m, 2H), 3.86 (s, 2H), 3.19–3.07 (m, 3H), 2.99 (ddd, J = 13.1, 8.3, 7.2 Hz, 1H), 2.88 (dd, J = 16.2, 11.6 Hz, 1H), 2.72 (dd, J = 16.4, 3.6 Hz, 1H), 2.45–2.30 (m, 2H), 2.08–1.91 (m, 2H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 135.8, 134.8, 132.1, 129.2, 128.9, 128.1, 126.9, 126.8, 126.3, 126.1, 75.7, 66.1, 63.7, 56.7, 42.1, 34.7, 31.4, 29.9 ppm; HRMS (ESI-EtOAc): m/z calcd for C₂₀H₂₃NO₂S [M + H]⁺: 342.1528 found 342.1522.

General procedure for the reduction of cycloadducts 11¹⁶

Zinc dust (5.0 eq.) was added to a solution of cycloadduct 11 (1 eq.) in 50% acetic acid : water at room temperature. The mixture was stirred under reflux for 3 h. After cooling, the mixture was neutralized with saturated aqueous NaHCO₃ and the aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic phases were dried over MgSO₄, concentrated under reduced and the residue purified by column chromatography.

(R)-2-((1R,3S)-3-(Hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-1-phenylethanol (12a). Following the general procedure, reduction of cycloadduct 11a (50 mg, 0.18 mmol) gave 1,3-disubstituted THIQ 12a (17 mg, 33% yield) as a yellow oil. [α]²⁵_D −0.42 (c = 2.4, CHCl₃); IR (ATR): ν = 3300, 3060, 3024, 2918, 1655, 1450, 1057, 1028, 743, 700 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.45 (d, J = 7.4 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H), 7.27–7.23 (m, 1H), 7.12–7.03 (m, 3H), 6.82–6.80 (m, 1H), 5.09 (t, J = 4.3 Hz, 1H), 4.4 (br s, 2H), 4.17 (dd, J = 11.2, 2.2 Hz, 1H), 3.76 (dd, J = 11.1, 3.8 Hz, 1H), 3.59 (dd, J = 11.2, 6.3 Hz, 1H), 3.30–3.24 (m, 1H), 2.69 (dd, J = 16.5, 4.2 Hz, 1H), 2.56 (dd, J = 16.4, 10.7 Hz, 1H), 2.44 (ddd, J = 14.8, 11.4, 3.6 Hz, 1H), 1.98 (ddd, J = 14.7, 5.2, 2.8 Hz, 1H), ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 144.7, 138.0, 134.0, 129.4, 128.2, 126.7, 126.2, 125.9, 125.4, 72.3, 65.1, 51.5, 48.6, 41.8, 30.4 ppm; HRMS (ESI-EtOAc): m/z calcd for C₁₈H₂₁NO₂ [M + H]⁺: 284.1651 found 284.1645.

(S)-1-((1R,3S)-3-(Hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)hexan-2-ol (12b). Following the general procedure, reduction of cycloadduct 11b (17 mg, 0.07 mmol) gave 1,3-disubstituted THIQ 12b (16 mg, 90% yield) as a yellow oil. [α]²⁵_D−0.21 (c = 4.7, CHCl₃); IR (ATR): ν = 3310, 3062, 2926, 2857, 1452, 1123, 1035, 743 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.14–7.01 (m, 4H), 4.43 (dd, J = 10.8, 2.4 Hz, 1H), 3.82 (br s, 3H), 3.70 (dd, J = 11.1, 3.7 Hz, 1H), 3.54 (dd, J = 11.0, 7.3 Hz, 1H), 3.26–3.20 (m, 1H), 2.73 (dd, J = 16.4, 4.1 Hz, 1H), 2.56 (dd, J = 16.4, 10.2 Hz, 1H), 2.10 (ddd, J = 14.2, 11.3, 3.0 Hz, 1H), 1.73–1.61 (m, 2H), 1.56–1.1.25 (m, 6H), 0.91 (t, J = 6.9 Hz, 3H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 138.3, 133.8, 129.4, 126.3, 126.2, 126.0, 69.4, 64.8, 51.3, 48.9, 40.3, 36.8, 30.5, 28.3, 22.8, 14.1 ppm; HRMS (ESI-EtOAc): m/z calcd for C₁₆H₂₅NO₂ [M + H]⁺: 264.1964 found 264.1958.

(R)-4-(Benzyloxy)-1-((1R,3S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)butan-2-ol (12c). Following the general procedure, reduction of cycloadduct 11c (27 mg, 0.08 mmol) gave 1,3-disubstituted THIQ 12c (14 mg, 51% yield) as a yellow oil. [α]²⁵_D −0.31 (c = 3.2, CHCl₃); IR (ATR): ν = 3298, 3061, 3028, 2916, 2857, 1452, 1362, 1090, 1027, 740, 697 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.28–7.18 (m, 5H), 7.06–6.89 (m, 4H), 4.43 (s, 2H), 4.36 (dd, J = 10.9, 2.5 Hz, 1H), 4.01–3.92 (m, 4H), 3.64 (dd, J = 11.2, 3.8 Hz, 1H), 3.53 (t, J = 6.1 Hz, 2H), 3.45 (dd, J = 11.1, 7.4 Hz, 1H), 3.20–3.14 (m, 1H), 2.64 (dd, J = 16.5, 4.3 Hz, 1H), 2.49 (dd, J = 16.5, 10.4 Hz, 1H), 2.02–1.95 (m, 1H), 1.88–1.81 (m, 1H), 1.78–1.64 (m, 2H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 138.4, 138.2, 133.7, 129.5, 128.5, 127.9, 127.8, 126.6, 126.5, 126.2, 73.4, 68.5, 67.8, 64.9, 51.4, 49.1, 41.1, 36.8, 30.6 ppm; HRMS (ESI-EtOAc): m/z calcd for C₂₁H₂₇NO₃ [M + H]⁺: 342.2069 found 342.2064.

(R)-1-((1R,3S)-3-(Hydroxymethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-4-(phenylthio)butan-2-ol (12d). Following the general procedure, reduction of cycloadduct 11d (47 mg, 0.13 mmol) gave 1,3-disubstituted THIQ 12d (22 mg, 47% yield) as a white solid; m.p. 60–62 °C; [α]²⁵_D −6 (c = 2, CHCl₃); IR (ATR): ν = 3369, 3070, 2919, 1581, 1479, 1437, 1090, 1027, 735, 689 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ_H = 7.25 (d, J = 7.4 Hz, 2H), 7.18 (t, J = 7.6 Hz, 2H), 7.09–7.02 (m, 31H), 7.00–6.97 (m, 1H), 6.92–6.90 (m, 1H), 4.31 (dd, J = 10.8, 2.6 Hz, 1H), 3.94–3.88 (m, 1H), 3.71 (br s, 3H), 3.61 (dd, J = 11.1, 3.8 Hz, 1H), 3.44 (dd, J = 11.1, 7.2 Hz, 1H), 3.16–3.03 (m, 2H), 2.95–2.88 (m, 1H), 2.64 (dd, J = 16.5, 4.3 Hz, 1H), 2.46 (d, J = 16.4, 101 Hz, 1H), 2.02 (ddd, J = 14.2, 11.2, 3.1), 1.96–1.87 (m, 1H), 1.75–1.67 (m, 1H), 1.62 (ddd, J = 14.7, 6.6, 3.1 Hz, 1H) ppm; ¹³C NMR (101 MHz, CDCl₃): δ_C = 128.3, 136.6, 133.9, 129.7, 129.0, 128.9, 126.5, 126.4, 126.2, 125.9, 68.6, 65.1, 51.6, 49.0, 40.4, 36.5, 30.7, 30.3 ppm; HRMS (ESI-EtOAc): m/z calcd for C₂₀H₂₅NO₂S [M + H]⁺: 344.1684 found 344.1679.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

J. F.-F. thanks the University of Alicante for a placement studentship. M. W. thanks the Erasmus+programme for funding her internship. B. M. thanks the European Commission for a Marie Curie Career Integration Grant, the EPSRC for a First Grant and the RS for a travel grant.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8ob02007h

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