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M. Kurosu et al.
PAPER
washed with CH2Cl2 (50, 30, and 20 mL). The combined organic
solvents were dried (Na2SO4), filtered, and concentrated under re-
duced pressure (~10 mmHg). Purification by silica gel chromatog-
raphy (hexanes–CHCl3, 4:1) provided (2,6-dichloro-4-
methoxyphenyl)(2,4-dichlorophenyl)methanone (8.3 g, 85%) as a
white powder.
TLC (hexanes–EtOAc, 5:1) provided a diastereomeric mixture of
the title (2R)-propanoate (34 mg, 92%) as a solid.
IR (film): 1615, 1610 cm–1
1H NMR (400 MHz, CDCl3): d = 7.45 (m, 2 H), 7.36 (m, 2 H), 7.23
(m, 4 H), 7.06 (m, 2 H), 6.81 (m, 2 H), 5.03 (m, 1 H), 4.44 (m, 1 H),
3.73 (s, 3 H), 3.70 (s, 3 H), 1.43 (s, 18 H), 1.37 (d, J = 7.2 Hz, 3 H),
1.15 (d, J = 6.4 Hz, 3 H)
13C NMR (100 MHz, CDCl3): d = 170.9, 159.4, 136.4, 136.2, 135.9,
134.4, 134.1, 134.0, 133.9, 133.6, 130.3, 129.5, 129.4, 126.3, 122.6,
122.5, 121.7, 111.1, 79.9, 69.8, 56.2, 56.1, 49.2, 28.3, 18.9, 18.5
IR (film): 1619, 1584, 1553, 1400, 1309 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.68 (d, J = 8.2 Hz, 1 H), 7.54 (d,
J = 2.1 Hz, 1 H), 7.37 (dd, J = 8.1, 2.1 Hz, 1 H), 6.95 (s, 2 H), 3.87
(s, 3 H).
13C NMR (75 MHz, CDCl3): d = 197.6, 163.8, 142.0, 138.3, 137.7,
136.4, 130.3, 129.9, 127.8, 122.9, 118.4, 117.9, 114.6, 56.1.
HRMS–FAB: m/z [M + Na]+ calcd for C22H23Cl4O5NNa:
544.02280; found: 544.02282
HRMS–FAB: m/z [M + Na]+ calcd for C14H8Cl4O2Na: 370.91761;
found: 370.91765.
Typical Procedure for the Deprotection
The ester of 3d was dissolved in 20% TFA in CH2Cl2 (0.3 M) and
kept for 1 h at r.t. All volatiles were evaporated in vacuo to provide
the carboxylic acid and 5a. The carboxylic acid was separated from
5d by a silica-gel plug (hexanes–EtOAc, 10:1 to CHCl3–MeOH,
5:1) or a back-extraction procedure [solvent system: EtOAc–H2O
(for the extraction of 5d under a basic conditions (NaHCO3),
CHCl3–H2O (for the extraction of the carboxylic acid under an acid-
ic conditions (dil. HCl)].
(2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methanone
(1.0 g, 2.8 mmol) was dissolved in MeOH (15 mL) and cooled to
0 °C. NaBH4 (318 mg, 8.4 mmol) was added to the mixture. The re-
action was quenched with aq NH4Cl (15 mL) and the mixture was
extracted with EtOAc (100, 30, and 20 mL). The combined extracts
were washed with brine (15 mL), dried (Na2SO4), and concentrated
under reduced pressure. Purification by silica gel chromatography
(hexanes–EtOAc, 5:1) provided 3d (980 mg, 97%) as a white pow-
der.
IR (film): 3482, 1438, 1410, 1325 cm–1.
Acknowledgment
1H NMR (300 MHz, CDCl3): d = 7.69 (d, J = 8.4 Hz, 1 H), 7.38 (d,
J = 3.0 Hz, 1 H), 7.31 (dd, J = 8.2, 3.0 Hz, 1 H), 6.91 (s, 2 H), 6.61
(d, J = 2.1 Hz, 1 H), 3.85 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.6, 137.8, 136.3, 133.9, 133.0,
130.5, 129.6, 129.6, 128.0, 126.6, 115.4, 115.4, 70.2, 55.9.
This paper is dedicated to Professor Yoshito Kishi (Harvard Univer-
sity) on the occasion of his 70th birthday. We thank the National In-
stitutes of Health (NIAID grants AI049151, AI018357, and
AI06357) and Colorado State University for generous financial sup-
port.
HRMS–FAB: m/z [M + Na]+ calcd for C14H10Cl4O2Na: 372.93326;
found: 372.93327.
References
(1) Dini, C. Curr. Top. Med. Chem. 2005, 5, 1221.
(2) (a) Kurosu, M.; Narayanasamy, P.; Crick, D. C.
Heterocycles 2007, 72, 339. (b) Kurosu, M.; Mahapatra, S.;
Narayanasamy, P.; Crick, D. C. Tetrahedron Lett. 2007, 48,
799. (c) Kurosu, M.; Biswas, K.; Crick, D. C. Org. Lett.
2007, 9, 1141. (d) Kurosu, M.; Crick, D. C. Tetrahedron
Lett. 2006, 47, 5325.
(3) (a) Handbook of Reagents for Organic Synthesis: Activating
Agents and Protecting Groups; Pearson, A. J.; Roush, W. R.,
Eds.; Wiley: New York, 1999. (b) Greene, T. W.; Wuts, P.
G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley & Sons: New York, 1999.
(4) The nucleophilicity of diphenylmethanol may be increased
due to: 1) introduction of the methoxy group at the 4-posi-
tion, and 2) stereoelectronic effects of the chloro substituents
on the aromatic rings.
(5) 50% regeneration of 3d was observed with 1 N aq NaOH at
50 °C for one hour.
(2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methyl
Nonanoate; Typical Procedure for the Esterification of 3d
To a stirred soln of alcohol 3d (148 mg, 0.42 mmol) in CH2Cl2 (3.0
mL) was added n-nonanoic acid (84 mg, 0.53 mmol), DIC (98 mL,
0.60 mmol), and DMAP (146 mg, 1.2 mmol). After 3 h at r.t., the
reaction was quenched with 0.5 N HCl (3 mL) and the mixture was
extracted with EtOAc (30 mL). The combined extracts were washed
with aq NaHCO3 (15 mL) and brine (15 mL), dried (Na2SO4), and
concentrated under reduced pressure. Purification by silica gel chro-
matography (hexanes–EtOAc, 20:1 to 10:1) provided the title
nonanoate (194 mg, 0.39 mmol, 94%) as an oil.
IR (film): 1615, 1428, 1315 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.49 (s, 1 H), 7.36 (m, 2 H), 7.21
(m, 1 H), 7.06 (d, J = 1.8 Hz, 1 H), 6.80 (d, J = 2.1 Hz, 1 H), 3.72
(s, 3 H), 2.42 (t, J = 1.8 Hz, 2 H), 1.28 (m, 12 H), 0.89 (t, J = 6.7 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 172.3, 159.4, 136.2, 135.6, 134.6,
134.0, 133.5, 130.1, 129.4, 126.2, 122.5, 122.3, 111.1, 68.5, 56.2,
34.1, 31.7, 29.2, 29.1, 29.0, 24.8, 22.6, 14.1.
(6) No deuterium exchange at the a-position of the esters upon
quenching with CD3OD and aldol reactions with
benzaldehyde were observed.
HRMS–FAB: m/z [M + Na]+ calcd for C23H26Cl4O3Na: 513.05338;
found: 513.05340.
(7) The –CO–O– linkage and the ether methine proton showed
a deviation of 20.2° out of a preferential common plane.
(8) We have synthesized a variety of esters with N-protected
D- or L-amino acids. Significant separation of signals for a
diastereomeric mixture of esters at the a-position of the
carbonyl group is observed in the 1H NMR spectra; however,
so far no separation of the diastereomers of 4d has been
observed on TLC. These characteristics may be applied to
the determination of the stereochemistry of unknown
a-chiral carboxylic acids by using optically pure 3d. The
synthesis of (+)-3d and (–)-3d will be reported elsewhere.
(2,6-Dichloro-4-methoxyphenyl)(2,4-dichlorophenyl)methyl
(2R)-2-(tert-Butoxycarbonylamino)propanoate
To a stirred soln of alcohol 3d (25 mg, 0.071 mmol) in CH2Cl2 (1.0
mL) was added Boc–D-Ala–OH (20 mg, 0.11 mmol), DIC (26 mL,
0.17 mmol), and DMAP (27 mg, 0.22 mmol). After 3 h at r.t., the
reaction was quenched with 0.5 N HCl (1 mL) and the mixture was
extracted with EtOAc (15 mL). The combined extracts were washed
with aq NaHCO3 (10 mL) and brine (10 mL), dried (Na2SO4), and
concentrated under reduced pressure. Purification by preparative
Synthesis 2007, No. 16, 2513–2516 © Thieme Stuttgart · New York