M. E. Rueffer et al. / Tetrahedron: Asymmetry 15(2004) 3297–3300
3299
yielding a heavy white precipitate. The mixture was stir-
red for an additional hour to allow the reaction to reach
O
O
H
OR
i
O
completion and then the Pr2NEtÆHCl filtered and sol-
vent removed in vacuo. Chromatography on basic alu-
mina (hexanes/ether 2:1 then ether) yielded product 5b
Ph
Ph
N
Ph
Ph
N
OtBu
OtBu
1 or 2, 5%
Cs2CO3
CH2Cl2
R
7
1
as a viscous pale yellow oil. H NMR: d 5.3 (s, 2H,
NC(O)CHO), 3.9 (br t, 2H, NCH(cyclohexyl)), 2.9 (br,
2H, NCH(cyclohexyl)), 2.4 (br, 4H, NCHCH2) 1.0–1.9
(m, 44H, cyclohexyl and butyl), 0.9 (t, 6H, CH3). 13C
NMR: d 168.3, 114.6, 76.2, 57.5, 56.3, 53.1, 36.7, 31.1,
30.0, 29.7, 29.1, 26.6, 26.3, 25.9, 25.7, 25.4, 22.9, 14.1
MS: 602 (M+), 376, 251, 181.
Figure 4. Glycine Michael addition.
Table 2. Results of glycine imino ester Michael reactions using CsCO3
as base, 0°C
Catalyst
Ester (R)
Time (h)
% Ee
% Conversion
3.5. Synthesis of tertiary amines 6-dicyclohexyl amine 6b
1
1
2
2
Me
Et
24
24
24
24
6
6
100
100
100
88
Me
Et
11
1
Diamide 5b (2.1g, 3.5mmol) was dissolved in THF.
LAH pellets (1.06g, 27.9mmol) were then stirred in dis-
tilled THF until a slurry formed. The amide solution
was added and the mixture refluxed overnight. After
cooling on ice, the mixture was quenched with a se-
quence determined as xg LAH = xmL H2O = xmL
3M NaOH = 3xmL H2O and stirred until the mixture
became white. This was then filtered through a pad of
Celite. After solvent removal, the oil was chromato-
graphed on basic alumina with a gradient eluent (hexa-
nes–gradient hexanes/ether–ether). Yield: 1.47g (74%).
1H NMR: d 3.6 (br(dd), 2H, NCH2CHO), 2.75 (dd,
2H, NCHHCHO), 2.73 (dd, 2H, NCHHCHO), 2.6 (m,
2H, NCH(cyclohexyl))1.0–1.7 (m, 58H, cyclohexyl and
butyl). 13C NMR: d 111.4, 81.2, 58.2, 49.7, 38.0, 32.6,
31.5, 26.7, 26.6, 26.3, 26.2, 23.1, 14.2 MS: 574 (M+),
195. Anal. (calcd): C, 77.42 (77.29);H, 12.38 (12.27);
N, 4.74 (4.87).
and the mixture was allowed to reflux overnight. Solvent
was removed in vacuo. The remaining dark brown oil
was then attached to a vacuum line and fractionally
distilled. Early cuts (boiling below 120°C) contained
starting materials. Ketal 3 distilled between 120 and
125°C (2Torr) to yield a colorless oil. Yield: 112.64g
1
(70%). H NMR: d 4.7 (s, 2H, C(O)CHO), 4.3 (q, 4H,
OCH2CH3), 1.7 (dd, 4H, OOCCH2), 1.3–1.4 (m, 8H,
CH2CH2CH3), 1.3 (t, 6H, OCH2CH3), 0.9 (t, 6H,
CH2CH2CH3). 13C NMR: d 169.3, 117.0, 76.9, 61.5,
36.7, 25.0, 22.5, 14.5. MS: 331 (M+H+), 274.
3.3. Synthesis of diacid chloride 4
Diester 3 (50.0g, 151mmol) was dissolved in methanol
(300mL). LiOHÆH2O (15.88g, 378mmol) was added
and the mixture stirred for 16h. The resulting mixture
was condensed to 75mL, cooled, filtered, and washed
with ether. A small amount was acidified in an ether/
water mixture to obtain spectra in order to establish
purity. The solid was dried in vacuo until needed. A por-
tion of the dicarboxylate (10.0g, 35.0mmol) was taken
into freshly distilled THF. TMS–Cl (13.27mL,
104.9mmol) was added and the mixture stirred for
20min after the solid dissolved. Solvent and excess
TMS–Cl were removed in vacuo. The resulting waxy
solid was stirred with fresh THF and DMF (two drops),
after which oxalyl chloride (9.15mL, 104.9mmol) was
added slowly enough to control the vigorous gas evolu-
tion. The mixture was stirred for 20min after gas evolu-
tion ceased and then solvent and excess oxalyl chloride
removed in vacuo. Vacuum distillation at 140°C (2Torr)
of the dark oil gave acid chloride 4 as a pale yellow oil
(7.35g, 68%). 1H NMR: d 5.1 (s, 2H, ClC(O)CHO)
1.6–1.7 and 1.3–1.4 (m, 12H, CH2CH2CH2CH3), 0.9
(t, 6H, CH3). 13C NMR: d 172.0, 120.9, 83.4, 36.5,
25.9, 22.7, 13.9.
3.6. Synthesis of quaternary ammonium salts 1 and 2-
dicyclohexyl amine 2
Diamine 6b (1.352g, 2.4mmol) was dissolved in CH2Cl2
and methyl triflate (850mg, 5.2mmol) added. The reac-
tion was stirred overnight (though an NMR scale reac-
tion showed the reaction was at least 95% complete
after 2h). The product was chromatographed on basic
alumina with ethyl acetate and then methanol. The
product was eluted in the methanol fractions. A
100mg sample was recrystallized for analysis from
1
CH2Cl2/hexane. Yield: 2.5g (71%). H NMR: d 4.5 (d,
2H, NCH2CHO), 3.9 (dd, 2H, NCHHCHO), 3.7 (d,
2H, NCHHCHO), 3.7 (t, 2H, NCH(cyclohexyl)), 3.5
(t, 2H, NCH(cyclohexyl)), 3.0 (s, 6H, NCH3), 1.1–2.3
(m, 52H, cyclohexyl and butyl), 0.9 (t, 6H, CH3). 13C
NMR: d 116.1, 74.1, 73.8, 62.6, 59.3, 53.5, 43.3, 36.8,
27.8, 27.7, 26.4, 26.3, 26.2, 26.0, 25.9, 25.7, 25.0, 24.9,
25
D
24.8, 22.6, 14.1. Mp 146–148°C. ½a ¼ ꢀ17:0 (c 0.5,
CH2Cl2). Anal. (calcd): C, 54.92 (54.65);H, 8.02
(8.28);N, 3.02 (3.11).
Diisopropyl catalyst 1: 1H NMR: d 4.5 (d, 2H,
NCH2CHO), 4.1 (sept, 2H, NCH(CH3)2), 4.0 (sept,
2H, NCH(CH3)2), 3.9 (dd, 2H, NCHHCHO), 3.7 (d,
2H, NCHHCHO), 3.0 (s, 6H, NCH3), 1.2–1.7 (m,
24H, butyl and NCH(CH3)2), 0.9 (t, 6H, CH3). Mp
155–157°C. [a]D = ꢀ22.9 (c 0.5, CH2Cl2, 25°C). Anal.
(calcd): C, 46.58 (46.88);H, 8.12 (8.14);N, 3.77 (3.77).
3.4. Synthesis of amide 5-dicyclohexylamide 5b
Diacid chloride 4 (10.87g, 35.0mmol) was taken into
freshly distilled THF (50mL) and stirred on ice. Dicy-
clohexylamine (12.65g, 70.0mmol) and diisopropyleth-
ylamine (9.02g, 70mmol) were combined and added,