Asymmetric organocatalytic synthesis of trans -3,4-disubstituted isochromanones via an intramolecular aldol reaction

Article abstract of DOI:10.1055/s-0033-1338742

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. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338742

1708▌
PAPER
paper
Asymmetric Organocatalytic Synthesis of trans-3,4-Disubstituted
Isochromanones via an Intramolecular Aldol Reaction
Organocatalytic Synthesis of Isochromanones
Jeanne Fronert, Tom Bisschops, Elisa Cassens-Sasse, Iuliana Atodiresei, Dieter Enders*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received: 16.04.2013; Accepted: 16.04.2013
proline-catalyzed 6-enolendo aldolization, Eder, Sauer,
and Wiechert as well as Hajos and Parrish described the
first organocatalytic asymmetric intramolecular aldol re-
action in 1971.6 Although the organocatalytic 6-enolendo
Abstract: The diastereo- and enantioselective synthesis of 3-ace-
tyl-4-hydroxyisochroman-1-ones via an intramolecular trans-selec-
tive 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 aldol reaction has been applied several times in natural
product synthesis,7 there are only few examples of or-
ganocatalytic 6-enolexo aldol reactions. For their synthe-
example, a new direct entry to carbazolelactone alkaloid natural
products.
Key words: organocatalysis, aldol reaction, asymmetric synthesis,
dihydroisocoumarin, enamine activation
sis of erythromycin Woodward et al. described a (R)-
proline-catalyzed intramolecular aldolization to give both
possible diastereomers in good yields and moderate enan-
tioselectivities.8 List et al. used heptanedial derivatives as
The isochroman-1-one heterocyclic unit 1 is a character- well as 7-oxo-octanal in intramolecular aldol reactions to
istic structural feature in various natural products that the corresponding cyclohexanes in excellent stereoselec-
show biological activity such as 2–6 illustrated in tivities and good to excellent yields.9 Two years later, the
Figure 1.1 The carbazolelactone alkaloids 5 and 6 were organocatalytic asymmetric synthesis of bicyclo[3.n.1]al-
extracted out of the root bark of Clausena excavata (Ru- kanones as another enolexo aldolization was described by
taceae), which is used in the treatment of snakebites and the group of Iwabuchi.10 Compared to 6-enolexo aldoliza-
abdominal pain.2 However, until now only few asymmet- tions, 5-enolexo aldol reactions are known to be less ste-
ric syntheses of 3,4-disubstituted isochroman-1-ones are reoselective.7 Nevertheless, a highly stereoselective 5-
known.3
enolexo-exo-trig aldolization was established by our
group.11 We envisaged that this reaction could be extend-
ed to the intramolecular aldol reaction of 2-oxopropyl 2-
formylbenzoate derivatives 7 to afford the corresponding
isochroman-1-ones 8.
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 ste-
reoselectivity.4 Today, the intermolecular aldol reaction
between aldehydes and ketones as well as between different We herein present a highly selective synthesis of 3,4-di-
aldehydes is well established.5 However, intramolecular substituted isochroman-1-one derivatives 8 via an organo-
aldol reactions, which can be separated in enolendo and catalytic trans-selective 6-enolexo-exo-trig aldolization
enolexo aldolizations, are less well developed. With their (Scheme 1).
R1
*
OH
OH
OH
R2
MeO
*
O
O
OH OH
OH
O
OH
O
OH
O
O
1
2
aigialomycin F (3)
OH
HO
HO
HO
HO
MeO
MeO
HN
HO
HN
HO
O
OH
O
O
OH
O
O
O
4
5
6
Figure 1 3,4-Disubstituted isochroman-1-one motif 1 and natural products containing the isochromanone unit. Up to now the absolute con-
figurations of 5 and 6 are unknown.
SYNTHESIS 2013, 45, 1708–1712
Advanced online publication: 08.05.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338742; Art ID: SS-2013-Z0289-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Organocatalytic Synthesis of Isochromanones
1709
O
OH
O
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).
catalyst 9–12
(30 mol%)
solvent, r.t.
O
O
O
O
O
7a
8a
HO R2
O
O
HO
5
catalyst 12 (30 mol%)
6
7
R2
O
O
DMSO (1.0 M), r.t.
Ph
R1
R1
N
Ph
CO2H
N
CO2H
11
O
N
H
N
N
64–88%
N
H
H
H
8
HN
12
N
OTMS
10
O
7
O
9
8
de 87 to >95%
ee 84 to 99%
Scheme 1 Optimization studies of the organocatalytic isochroman-
1-one synthesis (Table 1)
Scheme 2 Substrate scope of the asymmetric aldol reaction
(Table 2)
Initially, a catalyst screening was carried out for the prep-
aration 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 enantio-
selectivity (ee 84%). By changing the catalyst to the more
acidic (R)-5-(pyrrolidin-2-yl)-1H-tetrazole (12),12 the re-
action time could be reduced to only 5 hours with slightly
increased yield (71%) and nearly complete diastereo- (de
>95%) and enantioselectivity (ee 99%).
Table 2 Substrate Scope of the Asymmetric Aldol Reactiona
8
R1
R2
Time (h) Yield (%) de/ee (%)b
a
b
c
d
e
f
H
H
5
4
5
5
4
4
71
71
64
83
71
88
>95/99
87/99
7-Br
6-Cl
6-Me
7,8-OMe
H
H
H
95/84
H
89/96
H
>95/93
>95/96
Me
a Reaction conditions: Catalyst 12 (30 mol%), DMSO (0.5 M), r.t.
To further increase the yield, which is limited due to in-
cipient condensation of the product before full conversion
is achieved, several solvents were screened (Table 1, en-
tries 4–9). It turned out that by changing the solvent lon-
ger reaction times were needed and yield as well as
stereoselectivity decreased.
b Determined by chiral stationary phase HPLC.
The reaction is robust and allows a broad range of substit-
uents on the aromatic ring. Independent of the electronic
nature of the substituent no significant change in yield and
selectivity could be observed. Employing the correspond-
ing acetophenone 7f (R2 = Me) product 8f was generated
in good yield (88%) and excellent stereoselectivity (>95%
de, 96% ee) forming a tetrasubstituted stereogenic center.
Table 1 Optimization of the 6-Enolexo-exo-trig Aldolizationa
Entry
Cat.
Solvent
Time (h) Yield of de/ee
8a (%) (%)b
The absolute configuration of the isochromanones was
determined by X-ray crystal structure analysis of 8e13 to
be 3R,4R (Figure 2). The axial orientation of the substitu-
1
2
3
4
5
6
7
8
9
9
10
11
12
12
12
12
12
12
DMSO
DMSO
DMSO
DMSO
MeCN
CHCl3
DCM
96
96
23
–
–
–
–
67
5
>95/84
>95/99
>95/90
>95/78
>95/67
>95/91
68/75
72
47
63
54
68
48
48
24
48
DMF
THF
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 con-
ducted aldol reactions with various 2-oxopropyl 2-for-
mylbenzoate derivatives 7 to form the corresponding
Figure 2 X-ray crystal structure of 8e
Synthesis 2013, 45, 1708–1712
© Georg Thieme Verlag Stuttgart · New York

1710
J. Fronert et al.
PAPER
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 aque-
ous phase was extracted with Et2O (3 × 5 mL), the combined Et2O
layers were dried (MgSO4), and the solvent was removed under re-
duced pressure. The crude product was purified by column chroma-
tography to give the desired 2-oxopropyl 2-formylbenzoate 7.
ents in 3- and 4-position is consistent with the conforma-
tion 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-hydroxyisochro-
man-1-one (Scheme 3).
‡
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).
N
N
N
OH
O
N
H
N
IR (ATR): 3450, 2933, 1788, 1725, 1593, 1420, 1367, 1280, 1191,
1128, 1086, 1011, 961, 920, 828, 793, 753, 698, 641 cm–1.
O
(R)
(R)
O
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).
O
O
13C NMR (75 MHz, CDCl3): δ = 200.0, 192.0, 165.5, 137.0, 133.0,
O
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).
Scheme 3 Postulated transition state for the intramolecular aldol re-
action
HRMS-ESI: m/z [M + Na]+ calcd for C11H10O4Na+: 229.0471;
found: 229.0471.
In conclusion, we have developed a new synthesis of 3,4-
difunctionalized isochroman-1-ones via an organocatalyt-
ic asymmetric trans-selective 6-enolexo-exo-trig aldol re-
action. The application of this reaction in natural product
synthesis to the case of clausevatine F is currently in prog-
ress in our laboratory.
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.
Unless otherwise noted, all commercially available compounds
were used without further purification. The catalyst 12 was pre-
pared according to the previously described procedure.12 For pre-
parative 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 per-
formed with UV irradiation (254 nm). Optical rotations were mea-
sured 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
1
Spectrum 100 using an ATR-Unit. H and 13C NMR spectra were
2-Oxopropyl 4-Chloro-2-formylbenzoate (7c)
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).
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.
2-Oxopropyl 2-Formylbenzoates 7a–f; General Procedure1d,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 stir-
ring 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 re-
duced 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
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.
Synthesis 2013, 45, 1708–1712
© Georg Thieme Verlag Stuttgart · New York

PAPER
Organocatalytic Synthesis of Isochromanones
1711
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).
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:
13C NMR (151 MHz, CDCl3): δ = 200.6, 192.5, 165.5, 143.9, 137.4,
207.0649.
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;
(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]D20 +51.0 (c 1.00, CHCl3).
found: 243.0627.
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).
2-Oxopropyl 6-Formyl-2,3-dimethoxybenzoate (7e)
Yield: 293 mg (22% over 2 steps, starting from commercially avail-
able 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.
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).
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,
HRMS-ESI: m/z [M + Na]+ calcd for C11H9BrO4Na+: 306.9576;
129.3, 128.0, 125.5, 112.8, 69.6, 61.9, 56.2, 26.5.
found: 306.9581.
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).
(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]D20 +29.2 (c 1.00, CHCl3).
HRMS-ESI: m/z [M + Na]+ calcd for C13H14O6Na+: 289.0683;
found: 289.0683.
IR (ATR): 3333, 2928, 1701, 1593, 1375, 1279, 1236, 1189, 1084,
958, 894, 846, 783, 735, 691 cm–1.
1H NMR (600 MHz, acetone-d6): 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).
2-Oxopropyl 2-Acetylbenzoate (7f)
Yield: 958 mg (87% over 2 steps, starting from commercially avail-
able 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.
13C NMR (151 MHz, acetone-d6): δ = 201.9, 161.7, 140.5, 139.3,
131.1, 129.6, 127.8, 123.5, 86.5, 63.9, 26.0.
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).
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).
+
13C NMR (75 MHz, CDCl3): δ = 202.8, 201.1, 166.3, 142.7, 132.5,
HRMS-ESI: m/z [M + H]+ calcd for C11H10ClO4 : 241.0262; found:
130.3, 130.0, 128.1, 126.7, 69.1, 29.9, 26.1.
241.0264.
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.
(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]D20 +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-d6): 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).
Intramolecular trans-Selective Aldol Reaction; (3R,4R)-3-Ace-
tyl-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.
13C NMR (151 MHz, acetone-d6): 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).
(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]D20 –18.7 (c 1.00, CHCl3).
+
HRMS-ESI: m/z [M + H]+ calcd for C12H13O4 : 221.0808; found:
IR (ATR): 3341, 1722, 1695, 1599, 1461, 1413, 1373, 1293, 1237,
1108, 1058, 1025, 997, 961, 889, 848, 780, 755, 724, 695 cm–1.
221.0805.
(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]D20 –178.0 (c 1.00, CHCl3).
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.
IR (ATR): 3494, 2941, 1728, 1582, 1486, 1453, 1414, 1269, 1225,
1127, 1073, 1027, 971, 845, 691 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1708–1712

1712
J. Fronert et al.
PAPER
(4) (a) Berkessel, A. Asymmetric Organocatalysis: From
1H NMR (600 MHz, acetone-d6): 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-d6): 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.
Biomimetic Concepts to Applications in Asymmetric
Synthesis; Wiley-VCH: Weinheim, 2005. (b) Dalko, P. I.;
Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138; Angew.
Chem. 2004, 116, 5248. (c) Seayad, J.; List, B. Org. Biomol.
Chem. 2005, 3, 719. (d) Mahrwald, R. Chem. Rev. 1999, 99,
1095. (e) Mahrwald, R. Modern Aldol Reactions; Wiley-
VCH, 2004. (f) Palomo, C.; Oiarbide, M.; Garcia, J. M.
Chem. Soc. Rev. 2004, 33, 65.
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.
(5) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600.
(6) (a) Hajos, Z. G.; Parrish, D. R. German Patent DE 2102623,
1971. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974,
39, 1615. (c) Eder, U.; Sauer, G. R.; Wiechert, R. German
Patent DE 2014757, 1971. (d) Eder, U.; Sauer, G.; Wiechert,
R. Angew. Chem., Int. Ed. Engl. 1971, 10, 496; Angew.
Chem. 1971, 83, 492.
(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]D20 +158.0 (c 1.00, CHCl3).
IR (ATR): 3453, 2923, 2857, 2424, 2295, 1731, 1453, 1387, 1232,
1029, 874, 702 cm–1.
(7) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem.
Rev. 2007, 107, 5471.
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.
(8) Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan, K.;
Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne, L. J.;
Card, P. J.; Chen, C. H.; Chênevert, R. B.; Fliri, A.; Frobel,
K.; Gais, H.-J.; Garratt, D. G.; Hayakawa, K.; Heggie, W.;
Hesson, D. P.; Hoppe, D.; Hoppe, I.; Hyatt, J. A.; Ikeda, D.;
Jacobi, P. A.; Kim, K. S.; Kobuke, Y.; Kojima, K.;
Krowicki, K.; Lee, V. J.; Leutert, T.; Malchenko, S.;
Martens, J.; Matthews, R. S.; Ong, B. S.; Press, J. B.; Rajan
Babu, T. V.; Rousseau, G.; Sauter, H. M.; Suzuki, M.;
Tatsuta, K.; Tolbert, L. M.; Truesdale, E. A.; Uchida, I.;
Ueda, Y.; Uyehara, T.; Vasella, A. T.; Vladuchick, W. C.;
Wade, P. A.; Williams, R. M.; Wong, H. N.-C. J. Am. Chem.
Soc. 1981, 103, 3210.
Acknowledgment
(9) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem.
Int. Ed. 2003, 42, 2785; Angew. Chem. 2003, 115, 2891.
(10) Itagaki, N.; Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org.
Lett. 2005, 7, 4185.
(11) (a) Enders, D.; Niemeier, O.; Straver, L. Synlett 2006, 3399.
(b) Enders, D.; Fronert, J.; Bisschops, T.; Boeck, F. Beilstein
J. Org. Chem. 2012, 8, 1112.
(12) (a) Franckevičius, V.; Knudsen, K. R.; Ladlow, M.;
Longbottom, D. A.; Ley, S. V. Synlett 2006, 889.
(b) Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry
2004, 15, 1831.
(13) CCDC 933118 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif or by writing to the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk.
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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Synthesis 2013, 45, 1708–1712
© Georg Thieme Verlag Stuttgart · New York