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Synthesis 2013; 45(12): 1708-1712
DOI: 10.1055/s-0033-1338742
paper
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Organocatalytic Synthesis of trans-3,4-Disubstituted Isochromanones via an Intramolecular Aldol Reaction

Jeanne Fronert
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Fax: +49(241)8092127   Email: enders@rwth-aachen.de
,
Tom Bisschops
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Fax: +49(241)8092127   Email: enders@rwth-aachen.de
,
Elisa Cassens-Sasse
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Fax: +49(241)8092127   Email: enders@rwth-aachen.de
,
Iuliana Atodiresei
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Fax: +49(241)8092127   Email: enders@rwth-aachen.de
,
Dieter Enders*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Fax: +49(241)8092127   Email: enders@rwth-aachen.de
› Author Affiliations
Further Information

Publication History

Received: 16 April 2013

Accepted: 16 April 2013

Publication Date:
08 May 2013 (online)

 
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Abstract

The diastereo- and enantioselective synthesis of 3-acetyl-4-hydroxyisochroman-1-ones via an intramolecular trans-selective aldol reaction employing proline-type organocatalysts is described. Good yields (64–88%) and high stereoselectivities (87 to >95% de, 84–99% ee) are obtained, thus potentially enabling, for example, a new direct entry to carbazolelactone alkaloid natural products.


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Key words

organocatalysis - aldol reaction - asymmetric synthesis - dihydroisocoumarin - enamine activation

The isochroman-1-one heterocyclic unit 1 is a characteristic structural feature in various natural products that show biological activity such as 2–6 illustrated in Figure [1].[1] The carbazolelactone alkaloids 5 and 6 were extracted out of the root bark of Clausena excavata (Rutaceae), which is used in the treatment of snakebites and abdominal pain.[2] However, until now only few asymmetric syntheses of 3,4-disubstituted isochroman-1-ones are known.[3]

Zoom Image
Figure 1 3,4-Disubstituted isochroman-1-one motif 1 and natural products containing the isochromanone unit. Up to now the absolute configurations of 5 and 6 are unknown.

Especially in organocatalysis, the aldolization plays an important role, as it is an elementary reaction offering the possibility to create carbon–carbon bonds with high ste­reoselectivity.[4] Today, the intermolecular aldol reaction between aldehydes and ketones as well as between different aldehydes is well established.[5] However, intramolecular aldol reactions, which can be separated in enolendo and enolexo aldolizations, are less well developed. With their proline-catalyzed 6-enolendo aldolization, Eder, Sauer, and Wiechert as well as Hajos and Parrish described the first organocatalytic asymmetric intramolecular aldol reaction in 1971.[6] Although the organocatalytic 6-enolendo aldol reaction has been applied several times in natural product synthesis,[7] there are only few examples of organocatalytic 6-enolexo aldol reactions. For their synthesis of erythromycin Woodward et al. described a (R)-proline-catalyzed intramolecular aldolization to give both possible diastereomers in good yields and moderate enantioselectivities.[8] List et al. used heptanedial derivatives as well as 7-oxo-octanal in intramolecular aldol reactions to the corresponding cyclohexanes in excellent stereoselectivities and good to excellent yields.[9] Two years later, the organocatalytic asymmetric synthesis of bicyclo[3.n.1]alkanones as another enolexo aldolization was described by the group of Iwabuchi.[10] Compared to 6-enolexo aldolizations, 5-enolexo aldol reactions are known to be less stereoselective.[7] Nevertheless, a highly stereoselective 5-enolexo-exo-trig aldolization was established by our group.[11] We envisaged that this reaction could be extended to the intramolecular aldol reaction of 2-oxopropyl 2-formylbenzoate derivatives 7 to afford the corresponding isochroman-1-ones 8.

We herein present a highly selective synthesis of 3,4-disubstituted isochroman-1-one derivatives 8 via an organocatalytic trans-selective 6-enolexo-exo-trig aldolization (Scheme [1]).

Zoom Image
Scheme 1 Optimization studies of the organocatalytic isochroman-1-one synthesis (Table [1])

Initially, a catalyst screening was carried out for the preparation of 8a with the enantiopure pyrrolidine derivatives 9–12 to find the optimal catalyst (Table [1], entries 1–4). The reactions were conducted at room temperature in DMSO (1.0 M) since DMSO is known as a good solvent for proline derivatives. While catalysts 9 and 10 did not give significant conversions, (S)-proline (11) afforded the desired product 8a within 23 hours in good yield (67%), excellent diastereoselectivity (de >95%) and good enantio­selectivity (ee 84%). By changing the catalyst to the more acidic (R)-5-(pyrrolidin-2-yl)-1H-tetrazole (12),[12] the reaction time could be reduced to only 5 hours with slightly increased yield (71%) and nearly complete diastereo- (de >95%) and enantioselectivity (ee 99%).

To further increase the yield, which is limited due to incipient condensation of the product before full conversion is achieved, several solvents were screened (Table [1], entries 4–9). It turned out that by changing the solvent longer reaction times were needed and yield as well as stereoselectivity decreased.

Table 1 Optimization of the 6-Enolexo-exo-trig Aldolizationa

Entry

Cat.

Solvent

Time (h)

Yield of 8a (%)

de/ee (%)b

1

 9

DMSO

96

–

–

2

10

DMSO

96

–

–

3

11

DMSO

23

67

>95/84

4

12

DMSO

 5

>95/99

5

12

MeCN

72

>95/90

6

12

CHCl3

48

47

>95/78

7

12

DCM

48

63

>95/67

8

12

DMF

24

54

>95/91

9

12

THF

48

68

 68/75

a Reaction conditions: catalyst (30 mol%), solvent (1.0 M), r.t.

b Determined by chiral stationary phase HPLC (Daicel AD).

With the optimum reaction conditions in hand, we conducted aldol reactions with various 2-oxopropyl 2-formylbenzoate derivatives 7 to form the corresponding isochroman-1-ones 8. The reaction proceeded in good yields (64–88%) and with excellent diastereo- (87 to >95% de) and enantioselectivities (84–99% ee) (Scheme [2, ]Table [2]).

Zoom Image
Scheme 2 Substrate scope of the asymmetric aldol reaction (Table [2])

Table 2 Substrate Scope of the Asymmetric Aldol Reactiona

8

R1

R2

Time (h)

Yield (%)

de/ee (%)b

a

H

H

5

71

>95/99

b

7-Br

H

4

71

 87/99

c

6-Cl

H

5

64

 95/84

d

6-Me

H

5

83

 89/96

e

7,8-OMe

H

4

71

>95/93

f

H

Me

4

88

>95/96

a Reaction conditions: Catalyst 12 (30 mol%), DMSO (0.5 M), r.t.

b Determined by chiral stationary phase HPLC.

The reaction is robust and allows a broad range of substituents on the aromatic ring. Independent of the electronic nature of the substituent no significant change in yield and selectivity could be observed. Employing the corresponding acetophenone 7f (R2 = Me) product 8f was generated in good yield (88%) and excellent stereoselectivity (>95% de, 96% ee) forming a tetrasubstituted stereogenic center.

Zoom Image
Figure 2 X-ray crystal structure of 8e

The absolute configuration of the isochromanones was determined by X-ray crystal structure analysis of 8e [13] to be 3R,4R (Figure [2]). The axial orientation of the substituents in 3- and 4-position is consistent with the conformation of the natural product clausevatine F (5). [2]

The relative and absolute configuration can be explained by a Houk–List-type transition state.[14] The Re-face of the enamine attacks the Si-face of the aldehyde furnishing the trans-substituted (3R,4R)-3-acetyl-4-hydroxyisochroman-1-one (Scheme [3]).

Zoom Image
Scheme 3 Postulated transition state for the intramolecular aldol reaction

In conclusion, we have developed a new synthesis of 3,4-difunctionalized isochroman-1-ones via an organocatalytic asymmetric trans-selective 6-enolexo-exo-trig aldol reaction. The application of this reaction in natural product synthesis to the case of clausevatine F is currently in progress in our laboratory.

Unless otherwise noted, all commercially available compounds were used without further purification. The catalyst 12 was prepared according to the previously described procedure.[12] For preparative column chromatography SIL G-25 UV254 from Macherey-Nagel, particle size 0.040–0.063 mm (230–240 mesh, flash) was used. Visualization of the developed TLC plates was performed with UV irradiation (254 nm). Optical rotations were measured on a Perkin-Elmer 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 Perkin-Elmer FT-IR Spectrum 100 using an ATR-Unit. 1H and 13C NMR 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 IA, Daicel OD, or Chiralpak IC).


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2-Oxopropyl 2-Formylbenzoates 7a–f; General Procedure[1d] [11b]

Under an argon atmosphere the respective phthalide (5.0 mmol, 1.0 equiv) was dissolved in CCl4 (13.5 mL, 0.37 M). NBS (890 mg, 5.0 mmol, 1.0 equiv) and AIBN (41.0 mg, 0.25 mmol, 0.05 equiv) were added and the reaction mixture was refluxed for 2 h. After stirring for another 1 h at 0 °C, the mixture was filtered and the filtrate concentrated under reduced pressure. H2O (10 mL) was added and the suspension was refluxed for 1 h. After cooling to r.t., EtOAc (10 mL) was added and the phases were separated. After extracting the aqueous phase with EtOAc (3 × 10 mL), the combined organic phases were dried (MgSO4), and the solvent was removed under reduced pressure to give the crude corresponding 2-formylbenzoic acid­. The residue was dissolved in DMF (14 mL, 0.36 M) and K2CO3 (1.04 g, 7.5 mmol, 1.5 equiv), KI (83 mg, 0.5 mmol, 0.1 equiv), and a solution of 3-bromo-2-methoxyprop-1-ene in CCl4 (1.37 M, 7.5 mmol, 1.5 equiv) were added. The mixture was stirred at r.t. for 3 h. Sat. aq NH4Cl (15 mL) was added and the aqueous phase was extracted with Et2O (3 × 20 mL). The combined organic phases were washed with 5% aq LiCl (4 × 10 mL), dried (MgSO4), and the solvent was removed under reduced pressure. The residue was dissolved in THF (5 mL), aq 1 M HCl (75 μL, 0.075 mL, 0.015 equiv) was added and the solution was stirred for 1 h. After the addition of 5% aq NaHCO3 (5 mL) and Et2O (5 mL), the aqueous phase was extracted with Et2O (3 × 5 mL), the combined Et2O layers were dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to give the desired 2-oxopropyl 2-formylbenzoate 7.


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2-Oxopropyl 2-Formylbenzoate (7a)

Prepared from commercially available 2-formylbenzoic acid; 670 mg (65%); yellow oil; Rf = 0.15 (n-pentane–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 (300 MHz, CDCl3): δ = 10.65 (s, 1 H, CHO), 8.05–8.11 (m, 1 H, ArH), 7.95–8.01 (m, 1 H, ArH), 7.67–7.73 (m, 2 H, ArH), 4.99 (s, 2 H, CH2), 2.27 (s, 3 H).

13C NMR (75 MHz, CDCl3): δ = 200.0, 192.0, 165.5, 137.0, 133.0, 132.7, 131.2, 130.5, 128.3, 69.2, 25.9.

MS (EI, 70 eV): m/z (%) = 206.1 ([M]+, 4), 205.1 (27), 149.0 (97), 133.0 (51), 120.0 (14), 104.0 (100), 93.0 (12), 83.0 (18), 76.0 (98).

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


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2-Oxopropyl 5-Bromo-2-formylbenzoate (7b)

Yield: 285 mg (20% over 4 steps, starting from 5-bromophthalide); yellow oil; Rf = 0.25 (n-pentane–Et2O, 1:1).

IR (ATR): 3436, 3094, 2939, 2324, 1780, 1717, 1583, 1422, 1372, 1269, 1182, 1131, 1090, 882, 843, 773, 717, 681 cm–1.

1H NMR (400 MHz, CDCl3): δ = 10.46 (s, 1 H, CHO), 7.94 (d, J = 2.0 Hz, 1 H, ArH), 7.84 (d, J = 8.3 Hz, 1 H, ArH), 7.67 (dd, J = 2.2 Hz, 8.3 Hz, 1 H, ArH), 4.89 (s, 2 H, CH2), 2.18 (s, 3 H, CH3).

13C NMR (100 MHz, CDCl3): δ = 200.3, 190.6, 164.7, 138.4, 135.9, 132.2, 131.2, 129.5, 128.0, 69.3, 25.9.

MS (EI, 70 eV): m/z (%) = 285.9 ([M + H]+, 6), 228.9 (19), 226.9 (22), 212.9 (17), 210.9 (11), 183.9 (11), 182.9 (9), 153.9 (5), 155.9 (7), 75.0 (41), 58.0 (100).

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


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2-Oxopropyl 4-Chloro-2-formylbenzoate (7c)

Yield: 241 mg (20% over 4 steps, starting from 4-chlorophthalide); yellow oil; Rf = 0.15 (n-pentane–Et2O, 1:1).

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

1H NMR (400 MHz, CDCl3): δ = 10.60 (s, 1 H, CHO), 8.00 (d, J = 8.4 Hz, 1 H, ArH), 7.90 (s, 1 H, ArH), 7.61 (d, J = 8.4 Hz, 1 H, ArH), 4.95 (s, 2 H, CH2), 2.23 (s, 3 H, CH3).

13C NMR (100 MHz, CDCl3): δ = 200.0, 190.7, 164.6, 139.6, 138.6, 132.8, 132.3, 130.7, 128.4, 69.4, 26.0.

MS (EI, 70 eV): m/z (%) = 241.0 ([M + H]+, 3), 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: 283.0082.


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2-Oxopropyl 2-Formyl-4-methylbenzoate (7d)

Yield: 132 mg (12% over 4 steps, starting from 4-methylphthalide); yellow oil; Rf = 0.21 (n-pentane–Et2O, 1:1).

IR (ATR): 3462, 2928, 1727, 1605, 1421, 1371, 1274, 1180, 1138, 1089, 772 cm–1.

1H NMR (600 MHz, CDCl3): δ = 10.65 (s, 1 H, CHO), 7.94 (d, J = 7.9 Hz, 1 H, ArH), 7.76 (s, 1 H, ArH), 7.46 (d, J = 7.9 Hz, 1 H, ArH), 4.94 (s, 2 H, CH2), 2.46 (s, 3 H, CH3), 2.25 (s, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 200.6, 192.5, 165.5, 143.9, 137.4, 133.6, 130.9, 128.9, 128.7, 69.1, 26.0, 21.5.

MS (EI, 70 eV): m/z (%) = 221.0 ([M + H]+, 3), 162.9 (100), 147.0 (56), 119.0 (23), 91.1 (16), 65.1 (14), 58.1 (11).

HRMS-ESI: m/z [M + Na]+ calcd for C12H12O4Na+: 243.0628; found: 243.0627.


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2-Oxopropyl 6-Formyl-2,3-dimethoxybenzoate (7e)

Yield: 293 mg (22% over 2 steps, starting from commercially available 6-formyl-2,3-dimethoxybenzoic acid); colorless solid; mp 93–95 °C, Rf = 0.2 (n-pentane–Et2O, 1:4).

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 = 9.89 (s, 1 H, CHO), 7.62 (d, J = 8.5 Hz, 1 H, ArH), 7.08 (d, J = 8.5 Hz, 1 H, ArH), 4.90 (s, 2 H, CH2), 3.97 (s, 3 H, OCH3), 3.90 (s, 3 H, OCH3), 2.25 (s, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 202.2, 189.2, 165.8, 157.8, 146.7, 129.3, 128.0, 125.5, 112.8, 69.6, 61.9, 56.2, 26.5.

MS (EI, 70 eV): m/z (%) = 266.3 ([M]+, 1), 209.2 (100), 193.2 (49), 179.2 (5), 165.2 (10), 150.2 (7), 135.2 (6), 122.2 (11), 107.2 (9), 77.2 (12), 51.0 (17).

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


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2-Oxopropyl 2-Acetylbenzoate (7f)

Yield: 958 mg (87% over 2 steps, starting from commercially available 2-acetylbenzoic acid); orange oil; Rf = 0.4 (n-pentane–Et2O, 1:4).

IR (ATR): 3449, 3069, 3003, 2921, 2851, 1726, 1575, 1421, 1362, 1280, 1183, 1135, 1110, 1067, 963, 764, 709, 595 cm–1.

1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 6.3 Hz, 1 H, ArH), 7.58 (dd, J = 6.3, 7.4 Hz, 2 H, ArH), 7.45 (d, J = 7.4 Hz, 1 H, ArH), 4.88 (s, 2 H, CH2), 2.56 (s, 3 H, CH3), 2.33 (s, 3 H, CH3).

13C NMR (75 MHz, CDCl3): δ = 202.8, 201.1, 166.3, 142.7, 132.5, 130.3, 130.0, 128.1, 126.7, 69.1, 29.9, 26.1.

MS (EI, 70 eV): m/z (%) = 221.2 ([M]+, 1), 205.1 (9), 190.0 (9), 147.0 (100), 104.9 (15), 76.0 (22), 57.0 (32).

HRMS-ESI: m/z [M + Na]+ calcd for C12H12O4Na+: 243.0628; found: 243.0627.


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Intramolecular trans-Selective Aldol Reaction; (3R,4R)-3-Acetyl-4-hydroxyisochroman-1-ones 8a–f; General Procedure

The respective 2-oxopropyl 2-formylbenzoate 7 (0.3 mmol, 1.0 equiv) and (R)-5-(pyrrolidin-2-yl)-1H-tetrazole (12; 0.09 mmol, 13 mg, 0.3 equiv) were dissolved in DMSO (0.6 mL, 0.5 M) and stirred at r.t. (for reaction times, see Table [2]). Column chromatography of the crude solution afforded the desired 3-acetyl-4-hydroxyisochroman-1-one 8.


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(3R,4R)-3-Acetyl-4-hydroxyisochroman-1-one (8a)

Yield: 73 mg (71%); colorless solid; mp 130–132 °C; de >95%; ee 99% [determined by chiral stationary phase HPLC (Daicel AD)]; Rf  = 0.25 (n-pentane–Et2O, 1:4); [α]D 20 –18.7 (c 1.00, CHCl3).

IR (ATR): 3341, 1722, 1695, 1599, 1461, 1413, 1373, 1293, 1237, 1108, 1058, 1025, 997, 961, 889, 848, 780, 755, 724, 695 cm–1.

1H NMR (600 MHz, CD3OD): δ = 8.04 (d, J = 7.6 Hz, 1 H, ArH), 7.67 (t, J = 7.6 Hz, 1 H, ArH), 7.50–7.54 (m, 2 H, ArH), 5.35 (d, J = 3.2 Hz, 1 H, CH), 5.14 (d, J = 3.2 Hz, 1 H, CH), 2.20 (s, 3 H, CH3).

13C NMR (151 MHz, CD3OD): δ = 202.4, 164.0, 138.1, 134.2, 129.3, 129.2, 128.2, 124.1, 87.0, 64.2, 25.4.

MS (EI, 70 eV): m/z (%) = 206.1 ([M]+, 2), 188.0 (55), 163.0 (12), 146.0 (60), 135.0 (35), 117.0 (11), 105.0 (19), 77.0 (24).

HRMS-ESI: m/z [M + H]+ calcd for C11H11O4 +: 207.0652; found: 207.0649.


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(3R,4R)-3-Acetyl-7-bromo-4-hydroxyisochroman-1-one (8b)

Yield: 61 mg (71%); yellowish solid; mp 138–141 °C; de 87%; ee 99% [determined by chiral stationary phase HPLC (Daicel IA)]; Rf  = 0.25 (n-pentane–Et2O, 1:4); [α]D 20 +51.0 (c 1.00, CHCl3).

IR (ATR): 3343, 3083, 2920, 2481, 1706, 1589, 1379, 1244, 1115, 1062, 883, 843, 776, 689 cm–1.

1H NMR (600 MHz, CD3OD): δ = 7.93 (d, J = 8.1 Hz, 1 H, ArH), 7.72 (s, 1 H, ArH), 7.70 (d, J = 8.1 Hz, 1 H, ArH), 5.32 (d, J = 3.6 Hz, 1 H, CH), 5.12 (d, J = 3.6 Hz, 1 H, CH), 2.23 (s, 3 H, CH3).

13C NMR (151 MHz, CD3OD): δ = 202.1, 163.2, 140.3, 132.5, 130.9, 130.5, 128.6, 123.1, 86.7, 63.7, 25.4.

MS (EI, 70 eV): m/z (%) = 285.1 ([M]+, 13), 240.9 (83), 224.0 (45), 212.9 (100), 197.9 (26), 182.9 (30), 154.9 (34).

HRMS-ESI: m/z [M + Na]+ calcd for C11H9BrO4Na+: 306.9576; found: 306.9581.


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(3R,4R)-3-Acetyl-6-chloro-4-hydroxyisochroman-1-one (8c)

Yield: 46 mg (64%); colorless solid; mp 165–167 °C; de 95%; ee 84% [determined by chiral stationary phase HPLC (Chiralpak IC)]; Rf = 0.2 (n-pentane–Et2O, 1:4); [α]D 20 +29.2 (c 1.00, CHCl3).

IR (ATR): 3333, 2928, 1701, 1593, 1375, 1279, 1236, 1189, 1084, 958, 894, 846, 783, 735, 691 cm–1.

1H NMR (600 MHz, acetone-d 6): δ = 8.01 (d, J = 8.2 Hz, 1 H, ArH), 7.57–7.59 (m, 2 H, ArH), 5.41 (d, J = 3.4 Hz, 1 H, CH), 5.29 (d, J = 3.4 Hz, 1 H, CH), 2.27 (s, 3 H, CH3).

13C NMR (151 MHz, acetone-d 6): δ = 201.9, 161.7, 140.5, 139.3, 131.1, 129.6, 127.8, 123.5, 86.5, 63.9, 26.0.

MS (EI, 70 eV): m/z (%) = 240.1 ([M]+, 4), 222.1 (8), 197.0 (52), 181.0 (17), 169.0 (100), 152.0 (15), 139.0 (38), 123.0 (15), 111.0 (23), 77.2 (42), 51.2 (27).

HRMS-ESI: m/z [M + H]+ calcd for C11H10ClO4 +: 241.0262; found: 241.0264.


#

(3R,4R)-3-Acetyl-4-hydroxy-6-methylisochroman-1-one (8d)

Yield: 55 mg (83%); colorless solid; mp 134–136 °C; de 89%; ee 96% [determined by chiral stationary phase HPLC (Chiralpak IC)]; Rf = 0.18 (n-pentane–Et2O, 1:4); [α]D 20 +43.2 (c 1.00, CHCl3).

IR (ATR): 3343, 2927, 1696, 1610, 1447, 1375, 1290, 1240, 1179, 1066, 1000, 902, 956, 841, 792, 740, 698 cm–1.

1H NMR (600 MHz, acetone-d 6): δ = 7.88 (d, J = 7.9 Hz, 1 H, ArH), 7.35 (d, J = 7.9 Hz, 1 H, ArH), 7.34 (s, 1 H, ArH), 5.32 (d, J = 3.2 Hz, 1 H, CH), 5.19 (d, J = 3.2 Hz, 1 H, CH), 2.41 (s, 3 H, CH3), 2.23 (s, 3 H, CH3).

13C NMR (151 MHz, acetone-d 6): δ = 202.4, 162.5, 144.8, 130.1, 129.3, 129.3, 128.2, 122.1, 86.8, 64.4, 26.0, 20.2.

MS (EI, 70 eV): m/z (%) = 220.1 ([M]+, 2), 202.1 (6), 187.1 (7), 175.1 (56), 149.1 (100), 119.1 (34), 91.1 (45), 77.2 (20), 65.2 (20), 51.1 (16).

HRMS-ESI: m/z [M + H]+ calcd for C12H13O4 +: 221.0808; found: 221.0805.


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(3R,4R)-3-Acetyl-4-hydroxy-7,8-dimethoxyisochroman-1-one (8e)

Yield: 57 mg (71%); colorless solid; mp 137–139 °C; de >95%; ee 93% [determined by chiral stationary phase HPLC (Daicel AD)]; Rf  = 0.09 (Et2O); [α]D 20 –178.0 (c 1.00, CHCl3).

IR (ATR): 3494, 2941, 1728, 1582, 1486, 1453, 1414, 1269, 1225, 1127, 1073, 1027, 971, 845, 691 cm–1.

1H NMR (600 MHz, acetone-d 6): δ = 7.29 (d, J = 8.3 Hz, 1 H, ArH), 7.21 (d, J = 8.3 Hz, 1 H, ArH), 5.24 (d, J = 3.1 Hz, 1 H, CH), 5.17 (d, J = 3.1 Hz, 1 H, CH), 3.88 (s, 3 H, OCH3), 3.85 (s, 3H, OCH3), 2.17 (s, 3 H, CH3).

13C NMR (151 MHz, acetone-d 6): δ = 202.3, 159.2, 154.5, 150.4, 131.1, 123.2, 118.8, 117.1, 86.5, 65.1, 60.4, 55.6, 25.9.

MS (EI, 70 eV): m/z (%) = 266.1 ([M]+, 43), 248.0 (83), 221.2 (30), 205.1 (59), 193.1 (100), 177.1 (75), 149.1 (48).

Anal. Calcd for C13H14O6: C, 58.64; H, 5.30. Found: C, 58.90; C, 5.69.


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(3R,4R)-3-Acetyl-4-hydroxy-4-methylisochroman-1-one (8f)

Yield: 58 mg (88%); colorless oil; de >95%; ee 96% [determined by chiral stationary phase HPLC (Daicel OD)]; Rf = 0.4 (n-pentane–Et2O, 1:4); [α]D 20 +158.0 (c 1.00, CHCl3).

IR (ATR): 3453, 2923, 2857, 2424, 2295, 1731, 1453, 1387, 1232, 1029, 874, 702 cm–1.

1H NMR (600 MHz, CD3OD): δ = 7.98–7.99 (m, 1 H, ArH), 7.69–7.74 (m, 2 H, ArH), 7.50–7.47 (m, 1 H, ArH), 5.11 (s, 1 H, CH), 2.38 (s, 3 H, CH3), 1.43 (s, 3 H, CH3).

13C NMR (151 MHz, CD3OD): δ = 203.4, 163.8, 147.0, 134.6, 129.2, 128.1, 123.4, 122.2, 86.2, 69.0, 28.3, 23.0.

MS (EI, 70 eV): m/z (%) = 221.2 ([M]+, 2), 205.1 (3), 177.1 (2), 163.1 (13), 147.1 (100), 131.0 (32), 105.0 (33), 91.1 (13), 77.1 (22), 51.0 (15).

HRMS-ESI: m/z [M + Na]+ calcd for C12H12O4Na+: 243.0628; found: 243.0627.


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Acknowledgment

This work was supported by the Deutsche Forschungsgemeinschaft (DFG priority programme organocatalysis). We thank BASF SE and the former Degussa AG for the donation of chemicals.



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Figure 1 3,4-Disubstituted isochroman-1-one motif 1 and natural products containing the isochromanone unit. Up to now the absolute configurations of 5 and 6 are unknown.
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Scheme 1 Optimization studies of the organocatalytic isochroman-1-one synthesis (Table [1])
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Scheme 2 Substrate scope of the asymmetric aldol reaction (Table [2])
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Figure 2 X-ray crystal structure of 8e
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Scheme 3 Postulated transition state for the intramolecular aldol reaction