Synthesis and Aldol Reactions of Dipropionate Equivalents
2S-4,N-Dim eth yl-N-(2-m eth yl-3-oxopen tan oyl)ben zen e-
su lfon a m id e (5). To a solution of 0.608 g (3.28 mmol) of
N-methyl-p-toluenesulfonamide in 37 mL of CH2Cl2 at -78 °C
was added, dropwise, 1.31 mL (3.28 mmol) of a 2.5 M solution
of n-BuLi in hexanes. After being stirred for 15 min, the
solution was cannulated into a -24 °C solution of 0.333 g (2.98
mmol) of 3 in CH2Cl2 (10 mL). This solution was stirred for
1 h at -24 °C, and then 1 M NaHSO4 (20 mL) was added. The
mixture was warmed to rt, and the aqueous layer was
separated and extracted with CH2Cl2 (2 × 10 mL). The
combined organic layers were dried (Na2SO4) and concentrated
in vacuo, and the residue purified by flash chromatography
to yield 5 (617 mg, 70%). HPLC analysis of the purified product
(Chiralcel OD-H, 0.46 cm × 25 cm, hexane/2-propanol ) 98:2,
flow rate: 0.3 mL/min, λ ) 282 nm) showed a 97:3 mixture of
δ 7.64 (dd, J ) 2.0, 8.4 Hz, 1H), 7.51 (d, J ) 2.0 Hz, 1H), 6.89
(d, J ) 8.4 Hz, 1H), 4.46 (dd, J ) 7.6, 10.9 Hz, 1H), 4.41 (dd,
J ) 5.7, 10.9 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.10-3.05 (m,
1H), 2.61-2.55 (m, 2H), 1.21 (d, J ) 7.0 Hz, 3H), 1.10 (t, J )
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 212.3, 166.0, 153.0,
148.6, 123.5, 122.3, 111.8, 110.2, 65.9, 56.0, 55.9, 45.1, 35.0.
Anal. Calcd for C15H20O5: C, 64.27; H, 7.19. Found: C, 64.52;
H, 7.31.
Gen er a l P r oced u r e for th e a n ti,syn -Ald ol Rea ction . To
a suspension of 0.184 g (0.442 mmol) of anhydrous Sn(OTf)2
in 1.5 mL of CH2Cl2 was added 0.0600 mL (0.430 mmol) of
triethylamine at -24 °C. After 2 min, 0.122 g (0.410 mmol) of
sulfonimide 5 in 1.5 mL of CH2Cl2 was added dropwise, and
the solution was stirred at -24 °C for 1 h. Then reaction
solution was cooled to -78 °C, and 0.440 mmol of the aldehyde
was added dropwise. After 30 min at -78 °C, 1 M NaHSO4
(5 mL) was added, the mixture was warmed to rt and
separated, and the aqueous layer was extracted two times with
CH2Cl2. The combined organic layers were dried over Na2SO4
and concentrated in vacuo. Purification by flash column
chromatography (silica gel, ethyl acetate/hexanes) gave pure
anti,syn-aldol adduct.
Gen er a l P r oced u r e for a n ti,a n ti-Ald ol Rea ction . To a
solution of dicyclohexylboron chloride (0.41 mL, 1.89 mmol)
in Et2O (14 mL) at 0 °C was added Et3N (0.30 mL, 2.16 mmol).
Ketone 8a (380 mg, 1.35 mmol) in Et2O (2 mL) was then added,
and the resulting reaction mixture was stirred for 1 h at 0 °C
before cooling to -78 °C. A solution of the aldehyde (1.62
mmol) in Et2O (2 mL) was then added and stirring continued
for at -78 °C for 3 h before warming to -20 °C for 10 h. The
reaction mixture was then partitioned between Et2O (8 mL)
and pH 7 buffer (8 mL), the aqueous layer was extracted with
Et2O (3 × 15 mL), and the combined organic extracts were
concentrated in vacuo. The resulting oil was partitioned
between MeOH (8 mL) and pH 7 buffer (8 mL) and cooled to
0 °C. H2O2 (4 mL of a 30% aqueous solution) was then added
dropwise. After being stirred at rt for 1 h, the mixture was
diluted with H2O (8 mL) and extracted with CH2Cl2 (3 ×
15 mL). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. Purification by flash column
chromatography (silica gel, ethyl acetate/hexanes) gave pure
anti,anti-aldol adduct.
enantiomers (tR(2S) ) 41.7 min, tR(2R) ) 42.9 min): [R]23
)
D
+51.8 (c 0.86, CHCl3); IR(neat film) 2981, 2941, 1719, 1696,
1596, 1457, 1356, 1161, 976; 1H NMR (CDCl3, 400 MHz) δ 7.75
(d, 2H, J ) 8.4 Hz), 7.37 (d 2H, J ) 8.1 Hz), 4.45 (q, 1H, J )
7.1 Hz), 3.15 (s 3H), 2.62-2.49 (m, 2H), 2.46 (s, 3H), 1.35 (d,
3H, J ) 7.1 Hz), 1.07 (t, 3H, J ) 7.2 Hz); 13C NMR (CDCl3,
100 MHz) δ 207.3, 170.9, 145.2, 135.4, 130.1, 127.5, 54.0, 33.6,
33.0, 21.6, 14.2, 7.7. Anal. Calcd for C14H19NO4S: C, 56.55; H,
6.44; N, 4.71; S, 10.78. Found: C, 56.83; H, 6.50; N, 4.44; S,
11.00.
3,4-Dim eth oxyben zoic Acid (2R)-2-Meth yl-3-oxop en tyl
Ester (8a ). To a solution of 1.1822 g of 3 (10.55 mmol) in Et2O
(11 mL) at -78 °C was added 34 mL (34 mmol) of LiAlH4
(1.0 M in Et2O). The resulting solution was stirred for 0.25 h
at -78 °C, and then EtOAc (2 mL) was added, followed by a
solution of 50 mL of a 1 M HCl solution that had been
saturated with NaCl. The mixture was warmed to rt, and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (3 × 50 mL), and the combined organic extracts were
dried over Na2SO4, filtered, and concentrated. Purification by
flash column chromatography gave 7 (861 mg, 70%) as a clear,
colorless oil. The data for this compound matched those
reported previously.5
To a solution of 7 (390 mg, 3.36 mmol) in CH2Cl2 (12 mL)
at 0 °C was added pyridine (0.48 mL, 6.0 mmol) dropwise. 3,4-
Dimethoxybenzoyl chloride (1.01 g, 5.00 mmol) and DMAP (21
mg, 0.17 mmol) were then introduced in one portion. After
being stirred for 10 min, the resulting solution was warmed
to rt and stirred for an additional 30 min. To this solution was
then added NaHCO3 (6 mL of a saturated, aqueous solution).
The layers were separated, the aqueous layer was extracted
with CH2Cl2 (3 × 12 mL), and the combined organic extracts
were dried (Na2SO4) and concentrated in vacuo. Purification
by flash column chromatography gave 8a (829 mg, 88%).
HPLC analysis of the purified product (Chiralcel OD-H,
hexane/2-propanol ) 95:5, flow rate: 0.4 mL/min, λ ) 298 nm)
showed a 99:1 mixture of enantiomers (tR(S) ) 39.5 min,
tR(R) ) 42.7 min): [R]23D -28.0 (c 1.15, CHCl3 ); IR (neat) 2974,
2938, 1715, 1600, 1514, 1463, 1417, 1346, 1274, 1222, 1177,
Ack n ow led gm en t . We thank Dr. Xin Guo for
performing the experiments described in Scheme 9 and
Table 1. We acknowledge the NIH for support of this
work.
Su p p or tin g In for m a tion Ava ila ble: Complete charac-
terization data for compounds 6a -f, 9a , and 10a -d . This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
1134, 1106, 1025, 977, 877 cm-1; H NMR (400 MHz, CDCl3)
J O035668L
J . Org. Chem, Vol. 69, No. 4, 2004 1275