Asymmetric Organocatalytic Synthesis of 4-Aminoisochromanones via a Direct One-Pot Intramolecular Mannich Reaction

Abstract

A highly stereoselective one-pot intramolecular Mannich reaction using 2-oxopropyl-2-formylbenzoates and anilines as substrates, catalyzed by a secondary amine, has been developed. The procedure leads to a new class of 4-aminoisochromanones bearing two adjacent stereocentres in good yields (up to 85%) with excellent cis-stereoselectivities (dr up to 99:1) and ee values of 92–99%.

Key words

organocatalysis - one-pot reaction - asymmetric synthesis - isochromanones - Mannich reaction

The isochroman-1-one framework is a common scaffold of a variety of natural and synthetic compounds showing notable biological activities, such as ochtratoxin A (I),[1] a powerful mycotoxin isolated from Aspergillus ochraceus, the antidiabetic (–)-hydrangenol (II),[2] the aldosterone synthase inhibitor (III),[3] and fusarentin (IV),[4] a natural insecticide (Figure [1]). Due to their interesting chemical and medicinal properties, these compounds have been widely studied in recent years.[5]

Figure 1 Natural 3,4-disubstituted isochromanones with remarkable biological activities

Asymmetric organocatalytic methodologies are becoming an increasingly efficient alternative to the well-established metal-based and enzymatic procedures for the construction of new stereogenic centers.[6] In the vast field of asymmetric synthesis, organocatalytic Mannich reactions have proven to be a powerful and highly selective tool for the synthesis of β-aminocarbonyl compounds under mild conditions.[7] Particularly, after the pioneering work of List in 2000,[8] the direct Mannich reaction between unmodified ketones and in situ generated imines has been widely investigated, because basically this one-pot sequence avoids the time-consuming and costly preparation/purification of the imine intermediate and represents an outstanding resource in total synthesis.[6a] [h] [7b] [c] [9] However, the application of this protocol has been mainly focused on intermolecular approaches and less attention has been given to intramolecular direct Mannich reaction.[7b,9a,b,10]

Mannich-type cyclizations have been involved as key step in numerous total syntheses of complex natural products, but it often required functional group protections as well as the isolation/purification of the intermediates.[11] Nevertheless, in the last decade some examples of organocatalytic intramolecular Mannich and aza-Mannich methodologies have been reported, employing pyrrolidine derivatives,[12] cinchona alkaloids,[13] amino acids,[14] and cyclodextrins as catalysts,[15] as well as under an oxidative coupling.[16]

In 2013, we reported a secondary amine-catalyzed aldol addition reaction for the trans-selective synthesis of 3,4-difunctionalized isochroman-1-one derivatives (Scheme [1]).[17] We envisaged the possibility to employ the 2-oxopropyl-2-formylbenzoate substrates 1 in an intramolecular direct Mannich reaction to achieve a new class of 3-acetyl-4-aminoisochroman-1-ones bearing two contiguous stereogenic centers. This particular 4-aminoisochromanone scaffold has never been achieved nor studied, although related 3,4-diaminoisochromen-1-ones have been synthesized utilizing multicomponent Strecker or Ugi reactions.[18] In view of the previously discussed importance of this particular class of heterocycles, the development of a facile access to a variety of these molecules is of high interest.

Scheme 1 Asymmetric organocatalytic syntheses of 3,4-disubstituted isochromanones

By taking advantage of the well-demonstrated application of pyrrolidine derivatives in organocatalytic asymmetric Mannich reactions, a number of differently substituted prolines were first tested, which can interact with the preformed imine 4 (Scheme [2]). Considering that Mannich and aldol reactions are competing transformations, it was not surprising to isolate the isocumarin 5 as a single product when catalyst C was applied. This outcome could be rationalized by hydrolysis of the imine 4 to form the 2-oxopropyl-2-formylbenzoate 1, which reacts with the catalyst to give 5 or by p-methoxyaniline elimination from 3a. In contrast, no products could be detected when the Jørgensen–Hayashi catalyst E as well as the hydroxyproline D were employed. However, (S)-proline (B) and the tetrazole-substituted catalyst A showed moderate to good reactivity (47% and 70% yield, respectively) accompanied with an excellent stereoselectivity (dr 97:3 and 99% ee in both cases).

Scheme 2 Catalyst screening for the direct intramolecular Mannich reaction

Further optimization involving catalyst A has been carried out by analyzing the effect of both solvents and catalyst loading on the reaction outcome (Table [1]). By changing from the initially used DMSO to DMF, no significant changes in the stereoselectivity were observed (dr 96:4, 99% ee). However, the reaction time was prolonged from 24 to 72 hours (Table [1], entry 2). Subsequently we tested the effects of less polar solvents, but in almost all cases product formation could not be observed (entries 3–7). Further screening of the catalyst loading led to the identification of the best reaction conditions using 20 mol% of A to provide 72% yield, 97:3 dr, and 99% ee (entries 8–10).

Table 1 Optimization of the Reaction Conditions^a

Entry	Solvent	Catalyst A (mol%)	Time (d)	Yield (%)b	drc	ee (%)d
1	DMSO	20	1	70	97:3	99
2	DMF	20	3	70	96:4	99
3	CH2Cl2	20	3	nr	–	–
4	CHCl3	20	3	12	nd	nd
5	MeCN	20	3	22	nd	nd
6	Et2O	20	3	nr	–	–
7	THF	20	3	nr	–	–
8	DMSO	5	1	35	97:3	99
9	DMSO	10	1	50	97:3	99
10	DMSO	30	1	72	97:3	99

^a Unless otherwise stated, the reaction conditions were: 0.2 mmol of 4 and 0.4 mL of solvent (0.5 M); nr = no reaction, nd = not determined.

^b Yield of the isolated product 3a after flash chromatography.

^c Determined via HPLC analysis on a chiral stationary phase.

^d Determined via HPLC analysis on a chiral stationary phase.

In all the above-mentioned cases, the condensation product 5 has been detected in non-negligible amounts, caused by the previously discussed side reaction. In order to avoid this complication, we subsequently tested unmodified 2-oxopropyl-2-formylbenzoate (1a) and p-anisidine (2a) as substrates under the optimized reaction conditions to perform a one-pot intramolecular Mannich reaction. To our delight, the isochroman-1-one 3a was obtained in better yield (85%) as compared to the former procedure (70% yield), with no loss in either diastereo- or enantioselectivity (dr 98:2, 99% ee) (Scheme [3]).

Scheme 3 Asymmetric organocatalytic synthesis of 3a

Due to the intramolecular character of our transformation and to avoid the possible condensation product under the one-pot condition, it was necessary to push the equilibrium towards the imine formation by using 1.5 equivalents of aniline, as well as a more concentrated solution. Indeed the condensation product 5 could then be detected in only trace amount.

With the optimized reaction conditions in hand, we focused on the general applicability of the developed new protocol by using variously substituted substrates (Table [2]). A broad scope of anilines 2a–f was tested and the corresponding isochromanones 3a–f were obtained in good yields (70–85%) and with very high diatereo- and enantio­selectivities (dr up to 99:1 and 99 ee in almost all cases), irrespective of the steric and electronic nature of the substituents. Similar results have been observed after the introduction of different functional groups on the substrates 1. However, the presence of a bulky substituent R¹ on the 6-position of the aromatic ring led to a decrease of the dia­stereoselectivity to 79:21 (3g). The presence of strongly electron-donating groups on positions 7 and 8 [7,8-(OMe)₂] did not influence the reaction outcome and the corresponding product 3h was obtained with high stereoselectivity (dr 94:6, 98% ee).

Table 2 Investigation of the Substrate Scope^a

3	R1	R2	Time (d)	Yield (%)b	drc	ee (%)d
a	H	4-OMe	1	85	98:2	99
b	H	4-Cl	1.7	70	99:1	99
c	H	4-F	1.7	81	98:2	99
d	H	4-CF3	1.7	81	95:5	99
e	H	4-Me	1.7	72	99:1	99
f	H	4-Br	1.7	84	97:3	92
g	6-Br	4-OMe	1	69	79:21	99
h	7,8-(OMe)2	4-Cl	1	83	94:6	98
i	6-Cl	4-Cl	1	75	98:2	99

^a Unless otherwise stated, the reaction conditions were: 0.2 mmol of 1, 0.3 mmol of 2 (1.5 equiv) in 0.4 mL of solvent (0.5 M), and 0.04 mmol of catalyst A (20 mol%).

^b Yield of the isolated product 3 after flash chromatography.

^c Determined via HPLC analysis on a chiral stationary phase.

^d Determined via HPLC analysis on a chiral stationary phase.

The absolute configuration was unambiguously determined by X-ray crystal structure analysis of compound 3b,[19] and by analogy the configuration of all other products was assigned accordingly (Figure [2]). The cis-configuration of the 3,4-disubstituted δ-lactone ring, different as compared to our previously developed trans-selective 6-enolexo aldolization on the same substrates, is in accordance with literature reports.[9c] Indeed, it has been demonstrated that aldol and Mannich reaction usually show an opposite relative topicity in intermolecular reactions, and this stereochemical outcome may also be reflected in intramolecular reactions.

Figure 2 X-ray crystal structure of compound 3b [19] and proposed transition state for the intramolecular direct one-pot Mannich reaction

The proposed reaction mechanism for the direct one-pot intramolecular Mannich reaction involves the formation of the corresponding imine 4, which is attacked on its Re-face by the Re-face of the E-enamine, formed from the organocatalyst A and the ketone moiety, explaining the observed cis-diastereo- and enantioselectivity.

In summary, we have developed an efficient asymmetric synthesis for the new class of 4-aminoisochromanones via an organocatalytic direct intramolecular Mannich reaction. The one-pot sequence involves an initial imine formation followed by a cis-selective 6-enolexo-exo-trig Mannich reaction catalyzed by a tetrazole analogue of proline to provide the potentially bioactive title heterocycles in good yields (up to 85%) with excellent stereoselectivities (dr up to 99:1, up to 99% ee).

Unless otherwise noted, all commercially available compounds were used without further purification. For preparative column chromatography SIL G-25 UV252 from Macherey-Nagel, particle size 0.040– 0.063 nm (230–240 mesh. flash) was used. Visualization of the developed TLC plates was performed with UV irradiation (254 nm) or by staining with ninhydrin stain (0.5% EtOH solution); P = n-pentane. Optical rotations were measured on a PerkinElmer 241 polarimeter. Mass spectra were recorded on a Finnigan SSQ7000 (EI 70 eV) spectrometer and high-resolution mass spectra on a Thermo Fisher Scientific Orbitrap XL spectrometer. IR spectra were recorded on a PerkinElmer FT-IR Spectrum 100 using ATR-Unit. ¹H and ¹³C spectra were recorded at ambient temperature on Varian Mercury 300, Inova 400, Varian VNMRS-400, or Varian VNMRS-600 spectrometers with TMS as an internal standard. Analytical HPLC was performed on a Hewlett-Packard 1100 Series instrument using chiral stationary phases (Daicel AD, Daicel AS, Daicel IA, Daicel OD, Daicel OJ, Chiralpak IC, or Whelk M columns).

The catalyst A was prepared according to the previously described procedure.[20]

2-Oxopropyl 2-Formylbenzoates 1; General Procedure

Under argon atmosphere, the respective phthalide (7 mmol, 1.0 equiv) was dissolved in CCl₄ (35 mL, 0.2 M). NBS (7.7 mmol, 1.1 equiv) and AIBN (0.7 mmol, 0.1 equiv) were added and the reaction mixture was refluxed for 3 h. After stirring for another 1 h at 0 °C, the mixture was filtered, and the filtrate was concentrated under reduced pressure. H₂O (25 mL) was then added and the suspension was refluxed 2 h. After cooling to r.t., EtOAc was added and the phases were separated. The aqueous phase was extracted with EtOAc (3 × 10 mL), the combined organic phases were dried (anhyd MgSO₄), filtered, and concentrated under reduced pressure to give the crude corresponding 2-formylbenzoic acid. The crude product was dissolved in acetone (14 mL, 0.5 M) and Et₃N (7 mmol, 1.0 equiv), and chloroacetone (7.35 mmol, 1.5 equiv) was added to the suspension. The mixture was refluxed for 2 h, then H₂O was added, the phases were separated, and the aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic phases were dried (anhyd MgSO₄), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the desired 2-oxopropyl 2-formylbenzoate 1.

2-Oxopropyl 2-Formylbenzoate (1a)

Prepared from commercially available 2-formylbenzoic acid; yield: 1.227 g (85%); yellow oil; R_f = 0.26 (P/Et₂O, 1:1).

IR (ATR): 3450, 2933, 1788, 1725, 1593, 1420, 1367, 1280, 1191, 1128, 1086, 1011, 961, 920, 828, 793, 753, 698, 641 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 10.63 (s, 1 H, CHO), 8.07–8.04 (m, 1 H, CH_ar), 7.98–7.95 (m, 1 H, CH_ar), 7.71–7.65 (m, 2 H, CH_ar), 4.97 (s, 2 H, CH₂), 2.25 (s, 3 H, CH₃).

¹³C NMR (151 MHz, CDCl₃): δ = 200.52, 192.18, 165.67, 137.28, 133.17, 132.93, 131.34, 130.76, 128.62, 69.37, 26.23.

MS (EI⁺, 70 eV): m/z (%) = 206.0 (4, [M]⁺ = [C₁₁H₁₀O₄]⁺), 205.1 (27), 149.1 (97), 133.0 (51), 120.1 (14), 104.1 (100), 93.1 (12), 83.0 (18), 76.1 (98).

MS (CI⁺, methane): m/z (%) = 207 (28, [M + H]⁺ = [C₁₁H₁₁O₄]⁺).

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for [C₁₁H₁₀O₄Na]⁺: 229.0471; found: 229.0471.

2-Oxopropyl 4-Bromo-2-formylbenzoate (1b)

Yield: 280 mg (20%, after 3 reaction steps); pale yellow solid; mp 58–59 °C; R_f = 0.23 (P/Et₂O, 4:6).

IR (ATR): 3436, 3345, 3100, 3036, 2980, 2942, 2851, 1716, 1680, 1580, 1562, 1473, 1426, 1377, 1271, 1179, 1136, 1088, 1010, 957, 878 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 10.60 (s, 1 H, CHO), 8.08 (d, J = 2.0 Hz, 1 H, CH_ar), 7.94 (d, J = 8.3 Hz, 1 H, CH_ar), 7.79 (dd, J = 8.3, 2.1 Hz, 1 H, CH_ar), 4.97 (s, 2 H, CH₂), 2.25 (s, 3 H, CH₃).

¹³C NMR (101 MHz, CDCl₃): δ = 200.10, 190.74, 164.92, 138.66, 136.04, 132.42, 131.61, 129.81, 128.31, 69.44, 26.16.

MS (EI⁺, 70 eV): m/z (%) = 386.1 (6, [M + H]⁺ = [C₁₁H₁₀BrO₄]⁺), 229.1 (19), 227.1 (22), 213.0 (17), 210.9 (11), 184.0 (11), 183.1 (9), 75 (41), 58 (100).

MS (CI⁺, methane): m/z (%) = 315.1 (3, [M + C₂H₅, ⁸¹Br]⁺ = [C₁₃H₁₄BrO₄]⁺), 313.1 (3, [M + C₂H₅, ⁷⁹Br]⁺ = [C₁₃H₁₄BrO₄]⁺), 287.0 (12, [M, ⁸¹Br]⁺ = [C₁₁H₉BrO₄]⁺), 284.9 (13, [M, ⁷⁹Br]⁺ = [C₁₁H₉BrO₄]⁺), 228.9 (18), 226.9 (21), 213.9 (12), 212.9 (95), 211.9 (13), 210.9 (100).

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for [C₁₁H₉BrO₄Na]⁺: 306.9574; found: 306.9576.

2-Oxopropyl 6-Formyl-2,3-dimethoxybenzoate (1c)

Prepared from commercially available 2,3-dimethoxy-6-formylbenzoic acid; yield: 2.369 g (89%); colorless solid; mp 93–95 °C; R_f = 0.5 (P/EtOAc, 4:6).

IR (ATR): 2930, 2853, 1722, 1679, 1572, 1458, 1429, 1372, 1273, 1150, 1049, 962, 908, 828, 791, 743 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 9.90 (s, 1 H, CHO), 7.64 (d, J = 8.5 Hz, 1 H, CH_ar), 7.09 (d, J = 8.5 Hz, 1 H, CH_ar), 4.92 (s, 2 H, CH₂), 3.98 (s, 3 H, OCH₃), 3.92 (s, 3 H, OCH₃), 2.27 (s, 3 H, CH₃).

¹³C NMR (151 MHz, CDCl₃): δ = 202.38, 189.29, 165.91, 157.99, 146.83, 129.50, 128.32, 126.98, 112.81, 69.72, 62.06, 56.39, 26.63.

MS (EI⁺, 70 eV): m/z (%) = 266.3 (1, [M]⁺ = [C₁₃H₁₄O₆]⁺), 209.1 (23), 194.1 (12), 193.1 (100), 165.1 (32), 163.1 (12), 150.1 (12), 149.1 (12), 135.1 (14), 122.1 (23), 121.1 (14), 119.1 (13), 107.2 (27), 106.1 (12), 105.1 (16), 104.1 (16), 79.2 (31), 78.2 (19), 77.2 (36), 76.2 (17), 65.3 (13), 63.3 (18), 58.4 (14), 53.4 (12), 51.3 (35), 50.3 (18).

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for [C₁₃H₁₄O₆Na]⁺: 289.0683; found: 289.0683.

2-Oxopropyl 4-Chloro-2-formylbenzoate (1d)

Prepared from commercially available 4-chloro-2-formylbenzoic acid­; yield: 430 mg (44%); yellow oil; R_f = 0.51 (P/Et₂O, 1:2).

IR (ATR): 3851, 3743, 3673, 3451, 3081, 2928, 1727, 1587, 1420, 1371, 1276, 1187, 1105, 899, 844, 774 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 10.59 (s, 1 H, CHO), 8.03 (d, J = 2.1 Hz, 1 H, CH_ar), 7.94 (d, J = 8.3 Hz, 1 H, CH_ar), 7.65 (d, J = 10.4 Hz, 1 H, CH_ar), 4.98 (s, 2 H, CH₂), 2.26 (s, 3 H, CH₃).

¹³C NMR (151 MHz, CDCl₃): δ = 199.97, 190.86, 164.52, 139.81, 135.38, 133.06, 132.82, 130.88, 130.13, 69.55, 26.17.

MS (EI⁺, 70 eV): m/z (%) = 241.0 (3, [M + H]⁺ = [C₁₁H₁₀ClO₄]⁺), 182.9 (53), 166.9 (63), 138.9 (31), 111.0 (24), 75.1 (38), 58.1 (100).

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for [C₁₁H₉ClO₄Na]⁺: 263.0082; found: 263.0082.

Direct Organocatalytic Mannich Reaction; General Procedure

To a solution of the appropriate 2-oxopropyl 2-formylbenzoate 1 (0.2 mmol, 1.0 equiv) in DMSO (0.4 mL, 0.5 M) was added the respective aniline 2 (0.3 mmol, 1.5 equiv) and the mixture was stirred for 2 h. Then the catalyst A was added to the solution (5.6 mg, 0.04 mmol, 20 mol%) and the reaction mixture was stirred at r.t. After completion of the reaction, H₂O (3 mL) was added, and the mixture was extracted with Et₂O (3 × 2 mL). The combined organic phases were dried (anhyd MgSO₄), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography to give the desired cis-(3R,4S)-3-acetyl-4-aminoisochromanone 3a–i.

(3R,4S)-3-Acetyl-4-[(4-methoxyphenyl)amino]isochroman-1-one (3a)

Yield: 53 mg (85%); colorless solid; mp 158–159 °C; R_f = 0.46 (P/Et₂O, 1:2); [α]_D ²⁰ +88.2 (c 1.00, CHCl₃, 99% ee).

HPLC: Whelk M, n-heptane/EtOH (8:2), 0.5 mL/min, λ = 230.4 nm; major diastereomer: t _R = 43.0 min (minor), t _R = 21.4 min (major); minor diastereomer: t _R = 28.2 min (minor), t _R = 24.0 min (major); 98:2 dr, 99% ee.

IR (ATR): 3364, 2956, 2833, 2289, 2185, 2063, 1887, 1717, 1603, 1513, 1457, 1357, 1243, 1113, 1033, 824, 766, 696 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.15 (dd, J = 7.7, 1.1 Hz, 1 H, CH_ar), 7.51 (dtd, J = 30.7, 7.5, 1.2 Hz, 2 H, CH_ar), 7.20 (d, J = 7.5 Hz, 1 H, CH_ar), 6.77 [d, J = 8.9 Hz, 2 H, CH_ar (aniline)], 6.66 [d, J = 8.9 Hz, 2 H, CH_ar (aniline)], 5.00 (d, J = 3.2 Hz, 1 H, CH), 4.97 (dd, J = 10.5, 3.2 Hz, 1 H, NHCH), 3.75 (s, 3 H, OCH₃), 3.56 (d, J = 10.4 Hz, 1 H, NH), 2.42 (s, 3 H, CH₃).

¹³C NMR (151 MHz, CDCl₃): δ = 206.44, 163.77, 154.09, 139.77, 139.54, 134.94, 131.04, 129.43, 126.73, 123.05, 117.61, 115.02, 84.20, 55.77, 55.11, 28.76.

MS (EI⁺, 70 eV): m/z (%) = 312.1 (23, [M + H]⁺ = [C₁₈H₁₈NO₄]⁺), 311.1 ([M]⁺, 100), 239.1 (15), 138.2 (67), 211.1 (40), 210.1 (12), 196.1 (38), 167.1 (19), 147.1 (9), 123.1 (22), 122.1 (40), 118.1 (12), 108.1 (26), 90.2 (12), 89.2 (23), 77.2 (11), 48.5 (61).

MS (CI⁺, methane): m/z (%) = 340.1 (16, [M + C₂H₅]⁺ = [C₂₀H₂₂NO₄]⁺), 313.1 (33), 312.0 (100, [M + H]⁺ = [C₁₈H₁₈NO₄]⁺), 311.0 ([M]⁺, 58.3), 328.0 (9).

HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₁₈H₁₈NO₄]⁺: 312.1230; found: 312.1230.

Anal. Calcd for C₁₈H₁₇NO₄: C, 69.44; H, 5.50; N, 4.50. Found: C, 69.13; H, 5.42; N, 4.42.

(3R,4S)-3-Acetyl-4-[(4-chlorophenyl)amino]isochroman-1-one (3b)

Yield: 44 mg (70%); colorless solid; after measuring the HPLC data, the product was recrystallized from a mixture of PE/Et₂O (1:1); the crystals were filtered and washed with the same solvent mixture; mp 150–151 °C; R_f = 0.46 (P/Et₂O 4:6); [α]_D ²⁰ +162.4 (c 0.50, CHCl₃, 99% ee).

HPLC: Whelk M, n-heptane/i-PrOH (7:3), 0.7 mL/min, λ = 254.4 nm, t _R = 28.7 min (minor), t _R = 11.9 min (major); 99:1 dr, 99% ee.

IR (ATR): 3374, 3057, 2925, 2312m 2089, 1870, 1712, 1596, 1495, 1246, 1093, 765, 692 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.14 (d, J = 7.5 Hz, 1 H, CH_ar), 7.57 (t, J = 7.5 Hz, 1 H, CH_ar), 7.50 (t, J = 7.6 Hz, 1 H, CH_ar), 7.28 (d, J = 7.6 Hz, 1 H, CH_ar), 7.15 [d, J = 8.7 Hz, 2 H, CH_ar (aniline)], 6.67 [d, J = 8.8 Hz, 2 H, CH_ar (aniline)], 5.10 (dd, J = 10.1, 3.0 Hz, 1 H, NHCH), 5.00 (d, J = 3.2 Hz, 1 H, CH), 4.00 (d, J = 10.4 Hz, 1 H, NH), 2.39 (s, 3 H, CH₃).

¹³C NMR (101 MHz, CDCl₃): δ = 206.17, 163.35, 144.30, 139.25, 135.03, 130.92, 129.48, 129.39, 126.41, 124.57, 123.00, 116.07, 83.56, 53.18, 28.53.

MS (EI⁺, 70 eV): m/z (%) = 317.0 (14, [M, ³⁷Cl]⁺ = [C₁₇H₁₄ClNO₃]⁺), 315.0 (44, [M, ³⁵Cl]⁺ = [C₁₇H₁₄ClNO₃]⁺), 244.0 (32), 242.0 (100), 217.0 (20), 216.0 (24), 215.0 (65), 214.0 (49), 147.0 (12), 127.0 (27), 118.0 (12), 111.0 (14), 90.2 (11), 89.1 (16), 77.2 (11), 75.1 (11).

MS (CI⁺, methane): m/z (%) = 344.0 (7, [M + C₂H₅, ³⁵Cl]⁺ = [C₁₉H₁₉ClNO₃]⁺), 317.9 (23, [M + H, ³⁷Cl]⁺ = [C₁₇H₁₅ClNO₃]⁺), 317.0 (13, [M, ³⁷Cl]⁺ = [C₁₇H₁₄ClNO₃]⁺), 316.0 (67), 314.9 (35, [M, ³⁵Cl]⁺ = [C₁₇H₁₄ClNO₃]⁺), 271.9 (12), 258.2 (14), 257.4 (18), 242.0 (24), 216.3 (11), 214.0 (15), 190.1 (11), 188.9 (99), 187.9 (36), 156.0 (17), 149.0 (16), 147.1 (2), 145.4 (13), 130.1 (28), 129.1 (33), 128.0 (100), 127.0 (81), 75.2, (12).

HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₁₇H₁₅ClNO₃]⁺: 316.0735; found: 316.0735.

(3R,4S)-3-Acetyl-4-[(4-fluorophenyl)amino]isochroman-1-one (3c)

Yield: 48 mg (81%); colorless solid; mp 166–167 °C; R_f = 0.66 (P/Et₂O, 4:6); [α]_D ²⁰ +151.3 (c 0.40, CHCl₃, 99% ee).

HPLC: IB, n-heptane/EtOH (9:1), 0.7 mL/min, λ = 230.16 nm; major diastereomer­: t _R = 18.8 min (minor), t _R = 17.1 min (major); minor dia­stereomer: t _R = 22.1 min (minor), t _R = 19.8 min (major); 98:2 dr, 99% ee.

IR (ATR): 3782, 3360, 3047, 2870, 2635, 2454, 2285, 2167, 2050, 1863, 1717, 1603, 1511, 1415, 1362, 1272, 1216, 1109, 811, 696 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.15 (dd, J = 7.8, 1.4 Hz, 1 H, CH_ar), 7.56 (td, J = 7.5, 1.4 Hz, 1 H, CH_ar), 7.49 (td, J = 7.6, 1.2 Hz, 1 H, CH_ar), 7.24–7.21 (m, 1 H, CH_ar), 6.93–6.87 [m, 2 H, CH_ar (aniline)], 6.69–6.63 [m, 2 H, CH_ar (aniline)], 5.02 (dd, J = 10.3, 3.2 Hz, 1 H, NHCH), 5.00 (d, J = 3.3 Hz, 1 H, CH), 3.78 (d, J = 10.3 Hz, 1 H, NH), 2.42 (s, 3 H, CH₃).

¹³C NMR (151 MHz, CDCl₃): δ = 206.28, 163.48, 157.97, 156.39, 141.93, 139.35, 134.93, 130.94, 129.44, 126.48, 122.94, 116.73, 116.68, 116.11, 115.96, 83.83, 54.33, 30.94.

MS (EI⁺, 70 eV): m/z (%) = 300.1 (17), 299.1 (73, [M]⁺ = [C₁₇H₁₄FNO₃]⁺), 227.1 (23), 226.1 (100), 200.1 (9), 199.1 (69), 198.1 (67), 111.1 (12).

MS (CI⁺, methane): m/z (%) = 378.2 (4, [M + C₂H₅]⁺ = [C₂₀H₁₉F₃NO₃]⁺), 350.1 (48), 349.1 (35, [M]⁺ = [C₁₈H₁₄F₃NO₃]⁺), 331.1 (13), 330 (61), 277.1 (23), 276.1 (100), 249.1 (24).

HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₁₈H₁₅F₃NO₃]⁺: 350.0999; found: 350.0999.

(3R,4S)-3-Acetyl-4-{[4-(trifluoromethyl)phenyl]amino}isochroman-1-one (3d)

Yield: 49 mg (81%); colorless solid; mp 168–169 °C; R_f = 0.46 (P/Et₂O 4:6); [α]_D ²⁰ +150.3 (c 0.40, CHCl₃, 99% ee).

HPLC: OD, n-heptane/i-PrOH (9:1), 1.0 mL/min, λ = 254.16 nm; major diastereomer­: t _R = 20.7 min (minor), t _R = 17.4 min (major); minor dia­stereomer: t _R = 10.4 min (minor), t _R = 14.8 min (major); 95:5 dr, 99% ee.

IR (ATR): 3390, 3069, 2925, 2851, 2159, 2077, 2044, 1981, 2894, 1718, 1611, 1535, 1461, 1417, 1323, 1263, 1215, 1157, 1093, 1061, 911, 854, 820, 767, 729, 695 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.13 (dd, J = 7.8, 1.0 Hz, 1 H, CH_ar), 7.60 (td, J = 7.6, 1.3 Hz, 1 H, CH_ar), 7.51 (td, J = 7.7, 1.1 Hz, 1 H, CH_ar), 7.45 [d, J = 8.6 Hz, 2 H, CH_ar (aniline)], 7.34 (d, J = 7.6 Hz, 1 H, CH_ar), 6.79 [d, J = 8.6 Hz, 2 H, CH_ar (aniline)], 5.26 (dd, J = 10.2, 3.3 Hz, 1 H, NHCH), 5.02 (d, J = 3.3 Hz, 1 H, CH), 4.48 (d, J = 10.1 Hz, 1 H, NH), 2.39 (s, 3 H, CH₃).

¹³C NMR (151 MHz, CDCl₃): δ = 206.32, 163.43, 148.53, 139.16, 135.39, 131.11, 129.80, 127.09 (q, J _C,F = 3.7 Hz), 126.57, 123.25, 121.38 (q, J _C,F = 32.8 Hz), 113.65, 83.48, 52.02, 28.71.

MS (EI⁺, 70 eV): m/z (%) = 349.1 (8, [M]⁺ = [C₁₈H₁₄F₃NO₃]⁺), 277.1 (19), 276.1 (100), 250.1 (13), 249.1 (84), 248.1 (85), 208.1 (11), 180.1 (9), 145.0 (25), 118.1 (10), 89.1 (12), 69.2 (11), 48.4 (28).

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for [C₁₇H₁₄FNO₃Na]⁺: 322.0850; found: 322.0846.

(3R,4S)-3-Acetyl-4-(p-tolylamino)isochroman-1-one (3e)

Yield: 43 mg (72%); pale yellow solid; mp 139–140 °C; R_f = 0.51 (P/Et₂O, 4:6); [α]_D ²⁰ +156.6 (c 0.35, CHCl₃, 99% ee).

HPLC: IA, n-heptane/i-PrOH (9:1), 0.7 mL/min, λ = 230.4 nm, t _R = 17.2 min (minor), t _R = 18.7 min (major); 99:1 dr, 99% ee.

IR (ATR): 3352, 2925, 2302, 2084, 1881, 1717, 1614, 1514, 1359, 1260, 1096, 804, 696 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.14 (dd, J = 7.8, 1.3 Hz, 1 H, CH_arom), 7.55 (td, J = 7.5, 1.4 Hz, 1 H, CH_arom), 7.48 (td, J = 7.6, 1.2 Hz, 1 H, CH_arom­), 7.30–7.27 (m, 1 H, CH_arom), 7.01 [d, J = 8.0 Hz, 2 H, CH_arom (aniline)], 6.63 [d, J = 8.4 Hz, 2 H, CH_arom (aniline)], 5.12–5.08 (m, 1 H, CHNH), 5.00 (d, J = 3.3 Hz, 1 H, CH), 3.77 (d, J = 8.0 Hz, 1 H, NH), 2.40 (s, 3 H, CH₃), 2.25 (s, 3 H, ArCH ₃).

¹³C NMR (151 MHz, CDCl₃): δ = 206.36, 163.74, 143.40, 139.86, 135.06, 130.98, 130.16, 129.50, 129.42, 126.65, 123.12, 115.43, 84.02, 53.71, 28.74, 20.61.

MS (EI⁺, 70 eV): m/z (%) = 295.0 (12, [M]⁺ = [C₁₈H₁₇NO₃]⁺), 223.1 (18), 222.1 (93), 196.1 (15), 195.1 (100), 194.1 (69), 118.1 (12), 107.2 (23), 106.1 (20), 91.2 (24), 89.2 (13), 77.2 (12), 65.3 (10).

MS (CI⁺, methane): m/z (%) = 297.2 (8), 296.2 (46, [M + H]⁺ = [C₁₈H₁₈NO₃]⁺), 295.1 (8, [M]⁺ = [C₁₈H₁₇NO₃]⁺), 189.0 (84), 149.1 (22), 108.2 (100), 107.3 (14).

HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₁₈H₁₈NO₃]⁺: 296.1281; found: 296.1279.

(3R,4S)-3-Acetyl-4-[(4-bromophenyl)amino]isochroman-1-one (3f)

Yield: 43 mg (84%); colorless solid; mp 175–176 °C; R_f = 0.66 (P/Et₂O, 4:6); [α]_D ²⁰ +164.1 (c 0.50, CHCl₃, 92% ee).

HPLC: AD, n-heptane/EtOH (7:3), 1.0 mL/min, λ = 230.16 nm; major diastereomer: t _R = 11.7 min (minor), t _R = 9.3 min (major); minor dia­stereomer: t _R = 8.5 min (minor), t _R = 5.1 min (major); 97:3 dr, 92% ee.

IR (ATR): 3379, 3050, 2319, 2083, 1885, 1713, 1592, 1497, 1254, 1081, 778 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.14 (dd, J = 7.8, 1.1 Hz, 1 H, CH_ar), 7.58 (td, J = 7.6, 1.4 Hz, 1 H, CH_ar), 7.50 (td, J = 7.6, 1.1 Hz, 1 H, CH_ar), 7.31–7.26 [m, 3 H, CH_arom and 2 × CH_ar (aniline)], 6.64–6.59 [m, 2 H, CH_ar (aniline)], 5.11 (br s, 1 H, NHCH), 5.00 (d, J = 3.3 Hz, 1 H, CH), 4.01 (br s, 1 H, NH), 2.39 (s, 3 H, CH₃).

¹³C NMR (151 MHz, CDCl₃): δ = 206.36, 163.51, 144.92, 1f39.38, 135.24, 132.47, 131.11, 129.68, 126.59, 123.16, 116.60, 111.84, 83.70, 53.15, 28.73.

MS (EI⁺, 70 eV): m/z (%) = 362.0 (4, [M, ⁸¹Br]⁺ = [C₁₇H₁₄BrNO₃]⁺), 360.8 (4, [M, ⁷⁹Br]⁺ = [C₁₇H₁₄BrNO₃]⁺), 287.9 (29), 185.9 (29), 261 (39), 260.0 (35), 259.0 (42), 258.9 (43), 219.2 (10), 209.2 (23), 207.1 (27), 198.1 (11), 196.1 (12), 193.2 (14), 180.1 (52), 178.1 (27), 173.0 (58), 171.0 (58), 157.1 (31), 155.0 (30), 153.2 (15), 152.0 (30), 151.1 (16), 147.1 (100), 145.0 (30), 118.1 (57), 104.1 (20), 91.2 (32).

MS (CI⁺, methane): m/z (%) = 362.0 (17, [M, ⁸¹Br]⁺ = [C₁₇H₁₄BrNO₃]⁺), 360.0 (18, [M, ⁷⁹Br]⁺ = [C₁₇H₁₄BrNO₃]⁺), 267.1 (9), 207.1 (22), 190.1 (12), 189.0 (100), 174.0 (64), 173.0 (16), 172.0 (64), 171.0 (13), 147.1 (9), 121.1 (16), 93.1 (26), 79.1 (17), 75.2 (44).

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for [C₁₇H₁₄BrNO₃Na]⁺: 382.0049; found: 382.0047.

(3R,4S)-3-Acetyl-6-bromo-4-[(4-methoxyphenyl)amino]isochroman-1-one (3g)

Yield: 54 mg (69%); yellow solid; the two diastereomers were separated by preparative TLC with hexane/i-PrOH (8:2); mp 151–152 °C; R_f = 0.6 (P/Et₂O, 1:2); [α]_D ²⁰ +90.2 (c 0.25, CHCl₃, 99% ee).

HPLC: IC, n-heptane/EtOH (9:1), 1.0 mL/min, λ = 254.4 nm; major dia­stereomer: t _R = 13.0 min (minor) t _R = 11.4 min (major); minor diastereomer: t _R = 24.2 min (minor), t _R = 15.8 min (major); 79:21 dr, 99% ee.

IR (ATR): 3344, 3003, 2932, 2835, 2254, 2068, 1724, 1590, 1509, 1465, 1409, 1360, 1233, 1095, 1035, 907, 826, 782, 727, 690 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.01 (d, J = 8.4 Hz, 0.3 H, CH_ar, minor), 7.99 (d, J = 8.3 Hz, 1 H, CH_ar, major), 7.65 (dd, J = 8.4, 1.9 Hz, 0.4 H, CH_ar, minor), 7.62 (dd, J = 8.4, 1.9 Hz, 1 H, CH_ar, major and 0.22 H, CH_ar, minor), 7.41 (d, J = 1.9 Hz, 1 H, CH_ar, major), 6.87–6.83 (m, 0.6 H, CH_ar, minor), 6.82–6.77 (m, 2 H, CH_ar, major), 6.76–6.72 (m, 1 H, CH_ar, minor), 6.70–6.63 (m, 2 H, CH_ar, major), 5.18 (d, J = 2.7 Hz, 0.5 H, CH, minor), 4.96 (m, 2 H 2 × CH, major and 0.5 H, CH, minor), 3.78 (d, J = 3.5 Hz, 1.5 H, OCH₃, minor), 3.77 (d, J = 3.5 Hz, 3 H, OCH₃, major), 3.70–3.61 (m, 1.4 H, 2 × NH), 2.39 (s, 3 H, CH₃, major), 2.22 (s, 1.3 H, CH₃, minor).

¹³C NMR (151 MHz, CDCl₃): δ = 205.87, 204.27, 162.89, 162.15, 154.09, 141.32, 138.96, 133.19, 132.68, 132.37, 131.81, 131.61, 130.05, 129.47, 121.82, 117.19, 116.39, 116.14, 115.26, 115.03, 114.19, 83.51, 83.29, 65.83, 55.63, 54.40, 53.39, 51.62, 34.11, 28.60.

MS (EI⁺, 70 eV): m/z (%) = 391.0 (15, [M, ⁸¹Br]⁺ = [C₁₈H₁₆BrNO₄]⁺), 389.0 (15, [M, ⁷⁹Br]⁺ = [C₁₈H₁₆BrNO₄]⁺), 335.0 (15), 334.0 (96), 333.0 (20), 332.0 (100), 318 (16), 316 (16), 255.1 (10), 247.0 (11), 246.0 (11), 245.0 (9), 244.0 (10), 210.0 (19), 207.9 (19), 166.0 (10).

MS (CI⁺, methane): m/z (%) = 392.2 (5), 391.3 (5, [M, ⁸¹Br]⁺ = [C₁₈H₁₆BrNO₄]⁺), 390.1 (6), 389.1 (6, [M, ⁷⁹Br]⁺ = [C₁₈H₁₆BrNO₄]⁺), 269.0 (29), 268.1 (13), 267.0 (19), 266.0 (6), 125.2 (7), 124.2 (89), 123.1 (100), 109.2 (10), 108.1 (44), 80.2 (6).

HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₁₈H₁₇BrNO₄]⁺: 390.0341; found: 390.0340.

(3R,4S)-3-Acetyl-4-[(4-chlorophenyl)amino]-7,8-dimethoxyisochroman-1-one (3h)

Yield: 62 mg (83%); pale yellow solid; mp 107–108 °C; R_f = 0.64 (P/EtOAc, 4:6); [α]_D ²⁰ +165.3 (c 0.50, CHCl₃, 98% ee).

HPLC: IC, n-heptane/EtOH (9:1), 1.0 mL/min, λ = 230.4 nm; major dia­stereomer: t _R = 14.8 min (minor) t _R = 15.9 min (major); minor diastereomer: t _R = 37.7 min (minor), t _R = 31.2 min (major); 94:6 dr, 98% ee.

IR (ATR): 3358, 2940, 2844, 2325, 2099, 1925, 1726, 1582, 1489, 1417, 1363, 1269, 1198, 1133, 1051, 956, 901, 821, 736, 675 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.13 (dd, J = 12.3, 8.2 Hz, 2 H, CH_ar), 7.07 (dd, J = 16.0, 8.6 Hz, 2 H, CH_ar), 6.98 (d, J = 8.4 Hz, 1 H, CH_ar), 6.67 (dd, J = 13.4, 8.8 Hz, 2 H, CH_ar), 6.60 (d, J = 8.7 Hz, 1 H, CH_ar), 5.05 (d, J = 2.06 Hz, 0.21 H, NHCH, minor), 5.01–4.96 (m, 1 H, NHCH, major), 4.88–4.85 (m, 1.13 H, CH, major and minor), 4.14 (d, J = 9.5 Hz, 1.25 H, NH, major and minor), 3.96 (d, J = 4.8 Hz, 3.82 H, OCH₃, major and minor), 3.89 (s, 0,67 H, OCH₃, minor), 3.86 (s, 3 H, OCH₃, major), 2.36 (s, 3 H, CH₃, major), 2.19 (s, 0.72 H, CH₃, minor).

¹³C NMR (151 MHz, CDCl₃): δ = 206.80, 205.38, 160.25, 159.80, 154.22, 151.79, 144.63, 132.00, 129.68, 129.47, 129.22, 124.33, 124.08, 121.88, 118.01, 117.94, 117.35, 116.34, 116.07, 115.00, 83.27, 82.97, 61.76, 61.72, 56.35, 56.32, 53.50, 51.37, 28.76, 27.21.

MS (EI⁺, 70 eV): m/z (%) = 377.5 (16, [M, ³⁷Cl]⁺ = [C₁₉H₁₈ClNO₅]⁺), 376.5 (25), 375.5 (35, [M, ³⁵Cl]⁺ = [C₁₉H₁₈ClNO₅]⁺), 320.5 (29), 319.5 (15), 318.5 (100), 304.5 (25), 303.5 (14), 302.5 (71), 258.4 (12), 207.5 (33), 192.4 (10), 150.7 (12), 149.3 (13), 127.3 (13), 111.2 (17).

MS (CI⁺, methane): m/z (%) = 404.5 (11, [M + C₂H₅, ³⁵Cl]⁺ = [C₂₁H₂₃ClNO₅]⁺), 378.5 (36, [M + H, ³⁷Cl]⁺ = [C₁₉H₁₉ClNO₅]⁺), 377.5 (26, [M, ³⁷Cl]⁺ = [C₁₉H₁₈ClNO₅]⁺), 376.5 (100, [M + H, ³⁵Cl]⁺ = [C₁₉H₁₉ClNO₅]⁺), 375.5 (24, [M, ³⁵Cl]⁺ = [C₁₉H₁₈ClNO₅]⁺), 304.4 (15), 302.4 (47).

HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₁₉H₁₉ClNO₅]⁺: 376.0946; found: 376.0954.

(3R,4S)-3-Acetyl-6-chloro-4-[(4-chlorophenyl)amino]isochroman-1-one (3i)

Yield: 53 mg (75%); colorless solid; mp 168–169 °C; R_f = 0.6 (P/Et₂O, 4:6); [α]_D ²⁰ +160.4 (c 0.50, CHCl₃, 99% ee).

HPLC: IA, n-heptane/EtOH (7:3), 0.7 mL/min, λ = 254.4 nm, t _R = 19.8 min (minor), t _R = 13.4 min (major); 98:2 dr, 99% ee.

IR (ATR): 3366, 3080, 2962, 2852, 2261, 2086, 1993, 1887, 1729, 1597, 1488, 1414, 1362, 1241, 1188, 1087, 1013, 970, 823, 782, 728, 682 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.11 (d, J = 2.1 Hz, 1 H, CH_ar), 7.53 (dd, J = 8.2, 2.2 Hz, 1 H, CH_ar), 7.24 (d, J = 8.2 Hz, 1 H, CH_ar), 7.18–7.14 [m, 2 H, CH_ar (aniline)], 6.68–6.64 [m, 2 H, CH_ar (aniline)], 5.08 (s, 1 H, NHCH), 4.98 (d, J = 3.3 Hz, 1 H, CH), 3.96 (s, 1 H, NH), 2.39 (s, 3 H, CH₃).

¹³C NMR (151 MHz, CDCl₃): δ = 205.89, 162.38, 144.17, 137.72, 135.87, 135.26, 130.87, 129.66, 128.09, 125.09, 124.64, 116.34, 83.61, 52.92, 28.72.

MS (EI⁺, 70 eV): m/z (%) = 354.1 (1, [M, 2 × ³⁷Cl]⁺ = [C₁₇H₁₃Cl₂NO₃]⁺), 353.1 (7) 352.1 (9, [M, ³⁷Cl and ³⁵Cl]⁺ = [C₁₇H₁₃Cl₂NO₃]⁺), 351.0 (38), 350.1 (15, [M, 2 × ³⁵Cl]⁺ = [C₁₇H₁₃Cl₂NO₃]⁺), 349.0 (57), 294.0 (15), 292.0 (24), 280.0 (11), 279.0 (11), 278.0 (62), 277.0 (18), 275.9 (100), 51.0 (27), 250.0 (22), 249.0 (42), 248.0 (28), 181.0 (10), 127.0 (19), 111.0 (11).

MS (CI⁺, methane): m/z (%) = 354.1 (2, [M, 2 × ³⁷Cl]⁺ = [C₁₇H₁₃Cl₂NO₃]⁺), 353.1 (3), 352.0 (15, [M, ³⁷Cl and ³⁵Cl]⁺ = [C₁₇H₁₃Cl₂NO₃]⁺), 351.1 (6), 350.0 (23, [M, 2 × ³⁵Cl]⁺ = [C₁₇H₁₃Cl₂NO₃]⁺), 241.0 (16), 225.0 (35), 224.0 (17), 223.0 (100), 222.0 (13), 168.9 (19), 166.9 (57), 130.0 (14), 129.0 (14), 128.0 (46), 127.0 (40), 85.0 (35), 83.0 (53).

HRMS (ESI⁺): m/z [M + Na]⁺ calcd for [C₁₇H₁₃Cl₂NO₃Na]⁺: 372.0165; found: 372.0164.

No conflict of interest has been declared by the author(s).

Acknowledgment

Support from the European Research Council (ERC Advanced Grant 320493 ‘DOMINOCAT’) is gratefully acknowledged.

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