6754 J . Org. Chem., Vol. 65, No. 20, 2000
Notes
(m, 7 H), 1.09 (s, 3 H), 1.01 (s, 3 H); 13C NMR (75.5 MHz, CDCl3)
δ 187.06, 171.27, 135.25, 118.28, 90.40, 71.23, 50.19, 49.20, 42.52,
34.64, 31.89, 25.84, 24.14, 21.32, 19.33; [R]25D +12.3° (c 0.2, CH2-
Cl2); high-resolution MS m/e calcd for C15H20NO3SBr 373.0347,
found 373.0353. Anal. Calcd for C15H20NO3SBr: C, 48.25; H,
5.40; N, 3.75. Found: C, 48.10; H, 5.33; N, 3.66.
Exp er im en ta l Section
Gen er a l Meth od s. Diisopropylethylamine and dichlo-
romethane were dried by distillation under N2 from calcium
hydride. TiCl4 (1 M in CH2Cl2) was used as received. All
aldehydes were freshly distilled prior to use. Unless otherwise
noted, all nonaqueous reactions were carried out under a dry
nitrogen atmosphere with oven-dried glassware. Flash chroma-
tography was done on E. Merck silica gel 60 (230-400 mesh).
Melting points (Pyrex capillary) are uncorrected. Concentrations
for rotation data are given as g/100 mL of solvent. Diastereo-
meric excesses (de) were determined by HPLC on a chiralcel OD
column (Daicel Chemical Industries).
Gen er a l P r oced u r e for th e TiCl4-Med ia ted Br om in a -
tion -Ald oliza tion of Th ioim id e 2. Enolization of acetate
thioimide 2 derived from oxazolidinethione 1 with TiCl4 and
diisopropylethylamine and its subsequent reaction with bromine
and aldehydes were performed according to the previously
reported procedure.6 Diastereomer analysis (400 MHz 1H NMR)
of the unpurified mixture revealed the presence of essentially a
single syn bromohydrin aldol. Purification by flash chromatog-
raphy (15% ethyl acetate/hexane, silica gel, 0-5 °C) afforded 3a
(91%), 3b (91%), 3c (94%), 3d (81%), 3e (87%), 3f (90%), and 3g
(84%), 3h (87%).
N-[(2R,3S)-2-Br om o-3-h yd r oxy-4-m et h yl-4-p en t en oyl]-
(1S,5R,7R)-10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo-
[6.2.1.01,5]d eca n e (3e). As described above, 0.24 g (1.0 mmol)
of 2 was converted to its chlorotitanium enolate. Condensation
with 2-methylpropenal (1.4 mmol) provided a crude reaction
mixture. Diastereomer analysis (400 MHz 1H NMR) of the
unpurified mixture revealed the presence of essentially a single
syn bromohydrin aldol. Purification by flash chromatography
(15% ethyl acetate/hexane, silica gel, 0-5 °C) afforded 0.34 g
(87%) of 3e: IR (neat) 3485, 1701 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 6.61 (d, J ) 3.6 Hz, 1 H), 5.20 (bs, 1 H), 5.03 (bs, 1 H),
4.55 (d, J ) 3.6 Hz, 1 H), 4.53 (dd, J ) 8.4, 4.0 Hz, 1 H), 3.19
(bs, 1 H), 2.69-1.81 (m, 5 H), 1.78 (d, J ) 0.4 Hz, 3 H),1.38-
1.21 (m, 2 H), 1.10 (s, 3 H), 1.01 (s, 3 H); 13C NMR (75.5 MHz,
CDCl3) δ 187.16, 171.84, 141.53, 114.27, 90.40, 72.48, 49.22,
48.93, 42.59, 34.68, 31.91, 25.89, 24.16, 21.31, 19.35, 19.23; [R]25
D
+6.4° (c 0.5, CH2Cl2); high-resolution MS m/e calcd for C16H22
-
NO3SBr 387.0504, found 387.0501. Anal. Calcd for C16H22NO3-
SBr: C, 49.48; H, 5.71; N, 3.61. Found: C, 49.53; H, 5.70; N,
3.55.
N -[(2R ,3S )-2-Br om o-3-h yd r oxyh e xa n oyl]-(1S ,5R ,7R )-
10,10-d im e t h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]-
d eca n e (3a ): IR (neat) 3508, 1696 cm-1 1H NMR (400 MHz,
;
N-[(2R,3S)-2-Br om o-3-h ydr oxy-(E)-4-h exen oyl]-(1S,5R,7R)-
CDCl3) δ 6.61 (d, J ) 2.0 Hz, 1 H), 4.54 (dd, J ) 8.0, 4.0 Hz, 1
H), 4.01 (m, 1 H), 2.76-1.20 (m, 12 H), 1.08 (s, 3 H), 0.99 (s, 3
H), 0.90 (m, 3 H); 13C NMR (75.5 MHz, CDCl3) δ 187.52, 172.77,
90.64, 69.52, 51.16, 49.19, 42.52, 36.34, 34.63, 31.53, 25.78, 23.90,
10,10-d im e t h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]-
d eca n e (3f): IR (neat) 3488, 1698 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 6.64 (d, J ) 4.4 Hz, 1 H), 5.87 (dq, J ) 15.6, 6.8 Hz, 1
H), 5.56 (dd, J ) 15.6, 6.8 Hz, 1 H), 4.60 (dd, J ) 6.8, 4.4 Hz, 1
H), 4.54 (dd, J ) 8.0, 4.0 Hz, 1 H), 2.73-1.18 (m, 11 H), 1.07 (s,
3 H), 0.98 (s, 3 H); 13C NMR (75.5 MHz, CDCl3) δ 187.40, 171.77,
130.81, 128.37, 90.43, 71.50, 50.63, 49.14, 42.41, 34.51, 31.43,
21.33, 19.31, 18.56, 18.71, 13.92; [R]25 +48.0° (c 5.1, CH2Cl2);
D
high-resolution MS m/e calcd for C16H24NO3SBr 389.0660, found
389.0661. Anal. Calcd for C16H24NO3SBr: C, 49.22; H, 6.20; N,
3.59. Found: C, 49.31; H, 6.16; N, 3.62.
25.85, 24.17, 21.31, 19.24, 17.87; [R]25 +60.4° (c 4.8, CH2Cl2);
N -[(2R ,3S )-2-Br om o-3-h yd r oxy-4-m e t h ylp e n t a n oyl]-
(1S,5R,7R)-10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo-
[6.2.1.01,5]d eca n e (3b): mp 98-99 °C; IR (KBr) 3636, 1694
D
high-resolution MS m/e calcd for C16H22NO3SBr 387.0503, found
387.0506. Anal. Calcd for C16H22NO3SBr: C, 49.48; H, 5.71; N,
3.61. Found: C, 49.50; H, 5.73; N, 3.56.
cm-1 1H NMR (400 MHz, CDCl3) δ 6.82 (d, J ) 2.0 Hz, 1 H),
;
4.54 (dd, J ) 8.2, 4.0 Hz, 1 H), 3.68 (dd, J ) 8.2, 2.0 Hz, 1 H),
2.68-1.20 (m, 9 H), 1.13 (s, 3 H), 1.09 (d, J ) 6.8 Hz, 3 H), 1.05
(s, 3 H), 0.93 (d, J ) 6.8 Hz, 3 H); 13C NMR (75.5 MHz, CDCl3)
δ 187.51, 173.15, 90.56, 74.85, 49.25, 42.51, 34.59, 31.77, 31.50,
N-[(2R,3S)-2-Br om o-3-h ydr oxy-4-m eth yl-(E)-4-pen ten oyl]-
(1S,5R,7R)-10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo-
[6.2.1.01,5]d eca n e (3g). As described above, 0.24 g (1.0 mmol)
of 2 was converted to its chlorotitanium enolate. Condensation
with cinnamaldehyde (1.4 mmol) provided a crude reaction
mixture.
25.75, 23.83, 21.21, 21.04, 19.28, 18.71, 19.52; [R]25 +46.5° (c
D
2.4, CH2Cl2); high-resolution MS m/e calcd for C16H24NO3SBr
389.0660, found 389.0663. Anal. Calcd for C16H24NO3SBr: C,
49.22; H, 6.20; N, 3.59. Found: C, 49.31; H, 6.16; N, 3.62.
N -[(2R ,3S )-2-Br om o-3-h yd r oxy-3-p h e n ylp r op ion yl]-
(1S,5R,7R)-10,10-d im et h yl-3-t h ioxo-2-a za -4-oxa t r icyclo-
[6.2.1.01,5]d eca n e (3c): mp 113-114 °C; IR (neat) 3524, 1694
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.49-7.24 (m, 5 H), 7.00 (d,
J ) 4.4 Hz, 1 H), 5.28 (d, J ) 4.4 Hz, 1 H), 4.52 (dd, J ) 8.0, 4.0
Hz, 1 H), 2.73-1.20 (m, 8 H), 1.02 (s, 3 H), 0.90 (s, 3 H); 13C
NMR (75.5 MHz, CDCl3) δ 187.19, 171.99, 138.65, 128.30,
126.74, 125.50, 90.40, 72.24, 51.32, 49.08, 42.44, 34.50, 31.53,
1
Diastereomer analysis (400 MHz H NMR) of the unpurified
mixture revealed the presence of essentially a single syn
bromohydrin aldol. Purification by flash chromatography (15%
ethyl acetate/hexane, silica gel, 0-5 °C) afforded 0.38 g (84%)
of 3g: IR (neat) 3480, 1681 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.34-7.15 (m, 5 H), 6.71 (d, J ) 4.8 Hz, 1 H), 6.68 (d, J ) 16.0
Hz, 1 H), 6.20 (dd, J ) 16.0, 3.6 Hz, 1 H), 4.81 (ddd, J ) 4.8, 3.6
1.2 Hz, 1 H), 4.47 (dd, J ) 8.4, 4.0 Hz, 1 H), 3.40 (bs, 1 H), 2.68-
1.15 (m, 7 H), 1.03 (s, 3 H), 0.88 (s, 3 H); 13C NMR (75.5 MHz,
CDCl3) δ 186.66, 170.65, 135.54, 133.03, 127.99, 127.49, 126.19,
126.06, 89.96, 76.95, 71.51, 49.97, 48.82, 42.11, 34.23, 25.48,
25.69, 24.08, 21.03, 18.93; [R]25 +74.5° (c 5.1, CH2Cl2); high-
D
resolution MS m/e calcd for C19H22NO3SBr 423.0503, found
423.0501. Anal. Calcd for C19H22NO3SBr: C, 53.76; H, 5.23; N,
3.30. Found: C, 53.79; H, 5.22; N, 3.36.
23.84, 21.01, 18.80; [R]25 +3.5° (c 0.2, CH2Cl2); high-resolution
D
MS m/e calcd for C21H24NO3SBr 449.0659, found 449.0654. Anal.
Calcd for C21H24NO3SBr: C, 56.12; H, 5.38; N, 3.12. Found: C,
56.03; H, 5.30; N, 3.15.
N-[(2R,3S)-2-Br om o-3-h yd r oxy-4-p en ten oyl]-(1S,5R,7R)-
10,10-d im e t h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]-
d eca n e (3d ). As described above, 0.24 g (1.0 mmol) of 2 was
converted to its chlorotitanium enolate. Condensation with
acrolein (1.4 mmol) provided a crude reaction mixture. Diaster-
N-[(2R,3S)-2,6-Dibr om o-3-h yd r oxyh exa n oyl]-(1S,5R,7R)-
10,10-d im e t h yl-3-t h ioxo-2-a za -4-oxa t r icyclo[6.2.1.01,5]-
d eca n e (3h ). As described above, 0.24 g (1.0 mmol) of 2 was
converted to its chlorotitanium enolate. Condensation with
4-bromobutyraldehyde (1.4 mmol) provided a crude reaction
mixture. Diastereomeric analysis (400 MHz 1H NMR) of the
unpurified mixture revealed the presence of essentially a single
syn bromohydrin aldol. Purification by flash chromatography
(15% ethyl acetate/hexane, silica gel, 0-5 °C) afforded 0.41 g
1
eomeric analysis (400 MHz H NMR) of the unpurified mixture
revealed the presence of essentially a single syn bromohydrin
aldol. Purification by flash chromatography (15% ethyl acetate/
hexane, silica gel, 0-5 °C) afforded 0.31 g (81%) of 3d : IR (neat)
1
3483, 1695 cm-1; H NMR (400 MHz, CDCl3) δ 6.62 (d, J ) 4.4
Hz, 1 H), 5.86 (ddd, J ) 17.2, 10.4, 5.6 Hz, 1 H), 5.42 (dt, J )
17.2, 1.2 Hz, 1 H), 5.28 (dt, J ) 10.4, 1.2 Hz, 1H), 4.67-4.64 (m,
1 H), 4.52 (dd, J ) 8.0, 4.0 Hz, 1 H), 2.98 (bs, 1 H), 2.68-1.18
(87%) of 3h : IR (neat) 3498, 1702 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 6.61 (d, J ) 2.8 Hz, 1 H), 4.56 (dd, J ) 8.0, 4.0 Hz, 1
H), 4.07-4.03 (m, 1 H), 3.65 (bs, 1 H), 3.50-3.40 (m, 2 H), 2.69-
1.22 (m, 11 H), 1.13 (s, 3 H), 1.05 (s, 3 H); 13C NMR (75.5 MHz,
CDCl3) δ 186.67, 171.50, 90.13, 68.78, 50.62, 48.81, 42.12, 34.24,
(10) At present, we know reduction of R,â-epoxy esters under the
same conditions affords only recovered starting materials. A search
for reaction conditions that would effect transformation of epoxy
carboxylates into â-hydroxy carboxylates is currently underway.
33.17, 32.46, 28.39, 28.01, 25.44, 23.57, 20.94, 18.99; [R]25
D
+30.9° (c 3.2, CH2Cl2); high-resolution MS m/e calcd for C16H23
-