Cascade enantioselective synthesis of 3-arylphthalides using chiral auxiliary route

Article abstract of DOI:10.1055/s-2008-1067098

An enantioselective synthesis of 3-arylphthalides was achieved using (S)-1-phenylethylamine as a chiral auxiliary. Reduction of chiral keto amides of 2-aroylbenzoic acids followed by acid-catalyzed lactonization yielded (S)-3-arylphthalides with 75-85% ee.

Full text of DOI:10.1055/s-2008-1067098

1832
SHORT PAPER
Cascade Enantioselective Synthesis of 3-Arylphthalides Using Chiral
Auxiliary Route
Enantioselective
S
n
ynthesis of
3
i
-Arylp
l
hthalide
s
V. Karnik,* Suchitra S. Kamath
Department of Chemistry, University of Mumbai, Vidyanagari, Santacruz (E), Mumbai 400098, India
Fax +91(22)26528547; E-mail: avkarnik@chem.mu.ac.in
Received 16 November 2007; revised 13 March 2008
duction of 2-acylbenzoic acid derivatives, some other use-
Abstract: An enantioselective synthesis of 3-arylphthalides was
achieved using (S)-1-phenylethylamine as a chiral auxiliary. Reduc-
tion of chiral keto amides of 2-aroylbenzoic acids followed by acid-
catalyzed lactonization yielded (S)-3-arylphthalides with 75–85%
ee.
ful methodologies have been reported for the preparation
of chiral 3-substituted phthalides.16,17
A chiral auxiliary approach has been used effectively for
the enantioselective synthesis of g-substituted-g-lactones
by many groups,18,19 including a contribution from our
group.20 The presence of the same basic structural unit in
3-substituted phthalides made us consider the chiral aux-
iliary approach for the synthesis of nonracemic 3-substi-
tuted phthalides. We initially carried out the synthesis of
racemic 3-arylphthalides by reduction of 2-aroylben-
zoates followed by acid-catalyzed lactonization.21 It was
reasoned that the use of a chiral auxiliary in the process
would result in the formation of nonracemic 3-arylphtha-
lides. It was also expected that the forced proximity be-
tween the prochiral centre and the chiral auxiliary would
result in better stereoselectivity than in the previous series
of synthesis of nonracemic g-substituted-g-lactones.
Key words: enantioselective synthesis, (S)-1-phenylethylamine,
chiral auxiliary, reduction, 3-arylphthalides
Chiral 3-substituted phthalide moieties are found in a
large number of natural products and biologically active
compounds, such as 3-n-butylphthalide, (–)-hydrastine,
(–)-narcotine),1 (–)-typhaphthalide,2 vermistatin,3 alcy-
opterosin E,4,5 and cytosporone E.6 Some members of this
group are cytotoxic (vermistatin, alcyopterosin E), anti-
bacterial (cytosporone E), show anticonvulsant,7
antiasthmatic8 and antitumor properties,9 increase the du-
ration of anesthesia,10 and exhibit cerebral anti-ischemic
action (3-n-butylphthalide).11 They also compose part of
the structure of several complex alkaloids (e.g., the con-
vulsant alkaloid bicuculline)12 and serve as intermediates
for their synthesis.
We report here for the first time the formation of nonrace-
mic 3-arylphthalides using chiral auxiliary approach,
without involvement of organometallics or chiral catalyst.
The main strategy adapted by us to prepare nonracemic 3-
arylphthalide was the reduction of chiral amide of 2-aroyl-
benzoic acid followed by acid-catalyzed lactonization,
which involved the use of (S)-1-phenylethylamine as a
chiral auxiliary. The choice of (S)-1-phenylethylamine
was on the basis of its easy accessibility, cost effective-
ness, and wide utility in asymmetric synthesis.22–24 The
synthesis of chiral keto amides of 2-aroylbenzoic acids
and (S)-1-phenylethylamine and their utility in the prepa-
ration of nonracemic 3-arylphthalides are discussed. (S)-
2-Aroyl-N-(a-phenylethyl)benzamides 2a–g were pre-
pared from 2-aroylbenzoic acids 1a–g and (S)-1-phenyl-
ethylamine using DCC as the coupling reagent
(Scheme 1).
The precise biological activity of 3-substituted phthalides
is often crucially dependent on their configuration. Effi-
cient and stereoselective synthetic routes to these products
in enantiomerically pure form are therefore highly desir-
able.
One of the approaches for the preparation of nonracemic
3-substituted phthalides involves enantioselective reduc-
tion of 2-acylbenzoic acids and their derivatives followed
by lactonization. Noyori et al. introduced a BINAP-Ru(II)
catalyzed enantioselective hydrogenation of 2-acylbenzo-
ic esters giving a straightforward entry to optically active
3-substituted phthalides in very high enantioselectivity.13
Brown et al. reported a convenient and general synthesis
of chiral 3-substituted phthalides with equally high enan-
tioselectivity via intramolecular asymmetric reduction of
2-acylbenzoic acids by diisopinocampheylborane and in-
termolecular asymmetric reduction of 2-acylbenzoates
with (–)-B-chlorodiisopinocampheylborane.14 Asymmet-
ric transfer hydrogenation methodology using chiral Ru
complexes has been employed for the preparation of 3-
substituted phthalides.15 In addition to the asymmetric re-
Arriving at this stage, the next step was the enantioselec-
tive synthesis of 3-arylphthalides. This was achieved in a
one-pot reaction by NaBH4 reduction of (S)-2-aroyl-N-(a-
phenylethyl)benzamides 2a–g followed by acid-catalyzed
lactonization (Scheme 2).
Chiral identities of 3-arylphthalides 3a–g were estab-
lished by comparison of their optical rotations with that of
authentic compounds reported in the literature.14,25 The
enantiomeric excesses of (S)-3-arylphthalides 3a–g
(Table 1) were determined by HPLC using a chiral sta-
tionary phase (Chiralcel OD-H, n-hexane–i-PrOH, 98:2).
SYNTHESIS 2008, No. 12, pp 1832–1834
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Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1067098; Art ID: T17607SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Enantioselective Synthesis of 3-Arylphthalides
1833
H
DCC
DMAP, DMAP⋅HCl
CH2Cl2
OH
O
N
H
O
O
O
H
Me
Me
0 °C to r.t.
NH2
+
R1
R3
R1
R3
R2
R2
1a–g
2a–g
Scheme 1 Synthesis of novel chiral keto amides
H
O
O
N
H
O
O
Me
1. NaBH4, MeOH, 0 °C
2. aq HCl (1:1), 0 °C
H
R1
R3
R1
R3
3a–g
R2
R2
2a–g
Scheme 2 Enantioselective synthesis of (S)-3-arylphthalides
(S)-2-Aroyl-N-(a-phenylethyl)benzamides 2a–g, General Proce-
dure
Table 1 Enantioselective Synthesis of (S)-3-Arylphthalides
Entry
Product
3a
R1
R2
H
R3
H
Yield (%) ee (%)
To a stirred solution of 2-aroylbenzoic acid 1a–g (4.9 mmol), (S)-1-
phenylethylamine (0.52 mL, 4.1 mmol), DMAP (0.1 g, 0.83 mmol),
and DMAP·HCl (0.13 g, 0.83 mmol) in anhyd CH2Cl2 (50 mL) at 0
°C was added DCC (0.84 g, 4.1 mmol). The mixture was stirred at
r.t. for 12 h, filtered, and the residue washed with CH2Cl2 (10 mL).
The combined filtrates were washed first with dilute aq HCl (1:1, 20
mL) and then with aq 5% Na2CO3 (20 mL). The organic phase was
dried (Na2SO4) and evaporated. The crude product was crystallized
from CHCl3–PE to give 2a–g as colorless crystals.
1
2
3
4
5
6
7
H
57
58
58
59
57
55
54
75
81
85
85
81
76
78
3b
Me
OMe
Me
Me
Cl
H
H
3c
H
H
3d
Me
H
H
3e
Me
H
(S)-2-Benzoyl-N-(a-phenylethyl)benzamide (2a)
3f
H
Yield: 0.87 g (65%); mp 121–123 °C; [a]D19 –45.8 (c 1.00, MeOH).
3g
Br
H
H
IR (KBr): 3328, 3066, 3033, 2969, 2929, 2850, 1669, 1626, 1601,
1573, 1495, 1468, 1449 cm–1.
1H NMR (300 MHz, acetone-d6): d = 7.75–7.73 (m, 1 H), 7.57 (d,
J = 7.2 Hz, 1 H), 7.43–7.40 (m, 3 H), 7.35–7.33 (m, 1 H), 7.24–7.16
(m, 6 H), 7.07–7.05 (m, 2 H), 6.33 (s, 1 H), 4.76 (q, J = 7.2 Hz, 1
H), 1.77 (d, J = 7.2 Hz, 3 H).
In summary, the synthesis of novel chiral keto amides of
2-aroylbenzoic acids and the utility of these compounds in
enantioselective synthesis of 3-arylphthalides have been
demonstrated. (S)-3-Arylphthalides were obtained in a
one-pot reaction by NaBH4 reduction of (S)-2-aroyl-N-(a-
phenylethyl)benzamides followed by acid-catalyzed lac-
tonization with 75–85% ee. The chemical yields are rea-
sonable and enantioselectivities observed are satisfactory
MS: m/z = 328.64 [M+].
Anal. Calcd for C22H19NO2: C, 80.24; H, 5.78; N, 4.26. Found: C,
80.32; H, 5.82; N, 4.15.
(S)-2-(4¢-Methylbenzoyl)-N-(a-phenylethyl)benzamide (2b)
to good. The methodology also allows the use of very Yield: 0.94 g (67%); mp 142–143 °C; [a]D19 –45.7 (c 1.00, MeOH).
mild reaction conditions and inexpensive reagents.
IR (KBr): 3324, 3034, 2974, 2935, 1664, 1626, 1601, 1513, 1495,
1469 cm–1.
1H NMR (400 MHz, acetone-d6): d = 7.76–7.75 (m, 1 H), 7.50–7.46
(m, 6 H), 7.25–7.18 (m, 6 H), 6.55 (s, 1 H), 4.76–4.70 (m, 1 H), 2.24
(s, 3 H), 1.77 (d, J = 7.4 Hz, 3 H).
Optical rotations were measured with Jasco DIP-1000 digital pola-
rimeter. Enantiomeric excesses were determined on HPLC Thermo
Finnigan spectra system using Daicel Chiralcel OD column with
UV detector. IR spectra were recorded on Shimadzu FTIR-4200
Anal. Calcd for C23H21NO2: C, 80.47; H, 6.12; N, 4.08. Found: C,
80.56; H, 6.05; N, 4.04.
1
spectrometer. H NMR spectra were scanned in CDCl3 on Bruker
(300 MHz) and Varian Mercury Plus (400 MHz) spectrometers with
TMS as an internal standard. Elemental analyses were carried on
Carlo Enra instrument EA-1108 Elemental analyzer. Mass spectra
were obtained in ESI mode. All melting points are uncorrected.
Boiling point of the petroleum ether (PE) used was in the range of
60–80 °C.
(S)-2-(4¢-Methoxybenzoyl)-N-(a-phenylethyl)benzamide (2c)
Yield: 0.99 g (68%); mp 185–187 °C; [a]D19 –66.4 (c 1.00, MeOH).
IR (KBr): 3325, 3178, 3036, 2928, 2850, 1665, 1626, 1609, 1576,
1512, 1467 cm–1.
Synthesis 2008, No. 12, 1832–1834 © Thieme Stuttgart · New York

1834
A. V. Karnik, S. S. Kamath
SHORT PAPER
1H NMR (400 MHz, acetone-d6): d = 7.78–7.76 (m, 1 H), 7.46–7.44
(m, 2 H), 7.20–7.12 (m, 10 H), 6.73 (s, 1 H), 4.80–4.78 (m, 1 H),
3.77 (s, 3 H), 1.79 (d, J = 7.3 Hz, 3 H).
7.06 (s, 1 H), 6.92 (d, J = 7.8 Hz, 1 H), 6.77 (d, J = 7.8 Hz, 1 H),
6.63 (s, 1 H), 2.44 (s, 3 H), 2.31 (s, 3 H).
Anal. Calcd for C16H14O2: C, 80.67; H, 5.88. Found: C, 80.74; H,
5.84.
Anal. Calcd for C23H21NO3: C, 76.88; H, 5.85; N, 3.90. Found: C,
76.76; H, 5.94; N, 3.83.
The analytical data of compounds 3a–g were in accord with the lit-
erature values.26
(S)-2-(3¢,4¢-Dimethylbenzoyl)-N-(a-phenylethyl)benzamide (2d)
Yield: 0.99 g (68%); mp 142–144 °C; [a]D19 –41.8 (c 1.00, MeOH).
IR (KBr): 3323, 2974, 2928, 1673, 1626, 1573, 1494, 1469 cm–1.
References
1H NMR (300 MHz, acetone-d6): d = 7.76–7.74 (m, 1 H), 7.59 (d,
J = 7.3 Hz, 1 H), 7.44–7.41 (m, 2 H), 7.26–7.11 (m, 6 H), 7.00 (d,
J = 7.8 Hz, 2 H), 6.85 (s, 1 H), 4.74 (q, J = 7.3 Hz, 1 H), 2.24 (s, 3
H), 2.03 (s, 3 H), 1.79 (d, J = 7.3 Hz, 3 H).
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31, 1391.
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Phytochemistry 2002, 61, 955.
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Anal. Calcd for C24H23NO2: C, 80.67; H, 6.44; N, 3.92. Found: C,
80.74; H, 6.50; N, 3.85.
(4) Palermo, J. A.; Rodriguez Brasco, M. F.; Spagnuolo, C.;
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(S)-2-(2¢,4¢-Dimethylbenzoyl)-N-(a-phenylethyl)benzamide (2e)
Yield: 0.98 g (68%); mp 141–142 °C; [a]D19 –47.1 (c 1.00, MeOH).
IR (KBr): 3328, 3068, 3027, 2977, 2934, 1674, 1626, 1570, 1494,
1468 cm–1.
1H NMR (400 MHz, acetone-d6): d = 8.13 (d, J = 7.8 Hz, 1 H),
7.77–7.75 (m, 1 H), 7.47–7.42 (m, 2 H), 7.19–7.02 (m, 8 H), 6.59
(s, 1 H), 4.60 (q, J = 7.3 Hz, 1 H), 2.44 (s, 3 H), 2.32 (s, 3 H), 1.85
(d, J = 7.3 Hz, 3 H).
(7) Yu, S.; You, S.; Chen, H. Yaoxue Xuebao 1984, 19, 486;
Chem. Abstr. 1984, 101, 222490c.
(8) Liu, Z.; Song, Y.; Wang, W.; Chen, W.; Wang, X.
Zhongcaoyao 1982, 13, 17; Chem. Abstr. 1982, 97, 174444.
(9) Zheng, G. Q.; Zhang, J.; Kenney, P. M.; Lam, L. K. T. In
Food Phytochemicals for Cancer Prevention I: Fruits and
Vegetables; Huang, M.-T.; Osawa, T.; Ho, C.-T.; Rosen, R.
T., Eds.; ACS Symposium Series 546; American Chemical
Society: Washington DC, 1994, 230.
Anal. Calcd for C24H23NO2: C, 80.67; H, 6.44; N, 3.92. Found: C,
80.62; H, 6.54; N, 3.99.
(S)-2-(4¢-Chlorobenzoyl)-N-(a-phenylethyl)benzamide (2f)
Yield: 0.97 g (66%); mp 164–165 °C; [a]D19 –45.2 (c 1.00, MeOH).
IR (KBr): 3321, 2972, 2932, 2850, 1668, 1626, 1577, 1491, 1469
cm–1.
(10) Sato, H.; Yorozu, H.; Yamaoka, S. Biomed. Res. 1993, 14,
385.
1H NMR (400 MHz, acetone-d6): d = 7.73–7.71 (m, 1 H), 7.56–7.50
(m, 2 H), 7.28–7.21 (m, 3 H), 7.20–7.16 (m, 4 H), 7.13–7.07 (m, 3
H), 6.21 (s, 1 H), 4.63 (q, J = 7.3 Hz, 1 H), 1.86 (d, J = 7.3 Hz, 3 H).
(11) Wang, X.-W. Drugs Future 2000, 25, 16.
(12) Hung, T. V.; Mooney, B. A.; Prager, R. H.; Tippett, J. M.
Aust. J. Chem. 1981, 34, 383.
(13) Ohkuma, T.; Kitamura, M.; Noyori, R. Tetrahedron Lett.
Anal. Calcd for C22H18ClNO2: C, 72.63; H, 4.95; Cl, 9.77; N, 3.85.
Found: C, 72.75; H, 4.88; Cl, 9.83; N, 3.80.
1990, 31, 5509.
(14) Ramachandran, P. V.; Chen, G.-M.; Brown, H. C.
Tetrahedron Lett. 1996, 37, 2205.
(15) Everaere, K.; Scheffler, J.-L.; Mortreux, A.; Carpentier, J.-F.
Tetrahedron Lett. 2001, 42, 1899.
(S)-2-(4¢-Bromobenzoyl)-N-(a-phenylethyl)benzamide (2g)
Yield: 1.05 g (63%); mp 146–148 °C; [a]D19 –42.8 (c 1.00, MeOH).
(16) Chang, H.-T.; Jeganmohan, M.; Cheng, C.-H. Chem. Eur. J.
2007, 13, 4356.
IR (KBr): 3321, 3033, 2970, 2851, 1680, 1628, 1602, 1575, 1486,
1469 cm–1.
(17) Matsui, S.; Uejima, A.; Suzuki, Y.; Tanaka, K. J. Chem.
Soc., Perkin Trans. 1 1993, 701.
(18) Nair, V.; Prabhakaran, J. J. Chem. Soc., Perkin Trans. 1
1996, 593.
1H NMR (300 MHz, acetone-d6): d = 7.73–7.72 (m, 1 H), 7.54–7.43
(m, 6 H), 7.32–7.10 (m, 6 H), 6.25 (s, 1 H), 4.72–4.69 (m, 1 H), 1.78
(d, J = 6.0 Hz, 3 H).
Anal. Calcd for C22H18BrNO2: C, 64.71; H, 4.41; Br, 19.61; N, 3.43.
Found: C, 64.74; H, 4.35; Br, 19.71; N, 3.36.
(19) Tamai, Y.; Koike, S.; Ogura, A.; Miyano, S. J. Chem. Soc.,
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(S)-3-(2¢,4¢-Dimethylphenyl)phthalide (3e); Typical Procedure
To a stirred solution of chiral keto amide 2e (714 mg, 2 mmol) in
MeOH (30 mL) at 0 °C was added NaBH4 (76 mg, 2 mmol) in por-
tions and the mixture was stirred for 8 h at the same temperature.
The mixture was then treated with cold aq 1:1 HCl (100 mL) and
stirred for further 12 h at 0 °C. The mixture was extracted with
CHCl3 (3 × 20 mL); the combined CHCl3 extracts were washed with
aq 5% Na2CO3 (20 mL), dried (Na2SO4), and evaporated. The crude
product was crystallized from EtOH to give 3e as white crystals;
yield: 0.27 g (57%); mp 72–73 °C; [a]D19 +26.4 (c 0.5, CHCl3).
IR (KBr): 2957, 2926, 1759, 1612, 1503, 1463 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.95 (d, J = 7.2 Hz, 1 H), 7.65 (t,
J = 7.3 Hz, 1 H), 7.54 (t, J = 7.3 Hz, 1 H), 7.31 (d, J = 7.5 Hz, 1 H),
Synthesis 2008, No. 12, 1832–1834 © Thieme Stuttgart · New York